HIGH-YIELD NOTES OF PATHOLOGY 2010 EXAM 1 CELL

1. Adaptations

(when applied to individual cells, the following conditions are theoretically reversible)

A. hyperplasia benign

= increase in the number of essentially normal cells growth-factor driven proliferation prostatic hyperplasia (BPH) is due to an increase in the number of glandular epithelial cells and stromal cells (decreased apoptosis) enlarged lymph nodes due follicular hyperplasia (increased numbers of B lymphocytes in increased numbers of germinal centers) endometrial hyperplasia due to estrogen effect (may be a cause of post-menopausal uterine bleeding) Leydig cell hyperplasia with aging (due to decreased testosterone production with positive feed back stimulation) wart of the skin (verruca vulgaris) is an example of viral-induced hyperplasia (ie increased numbers of epidermal keratinocytes) hyperplasia of the parathyroid glands may be primary or secondary (chronic renal failure is usually the cause of the latter) congenital adrenal hyperplasia (CAH) due to enzyme deficiency that decreases cortisol and increases ACTH lactotroph hyperplasia in anterior pituitary during pregnancy note that gravid uterus has both hypertrophy and hyperplasia = increase in the size of individual cells ("trophy" refers to organs and individual cells) increased production of proteins enlarged cardiac muscle due to eccentric and concentric hypertrophy (may result from hypertension; increases ventricular wall thickness) cardiac hypertrophy is associated with the re-expression of the ANF (atrial natriuretic factor) gene in the myocardial cells of the ventricle enlarged skeletal muscle with exercise or anabolic steroid use enlarged smooth muscle of gastric pylorus due to congenital pyloric stenosis note that in mitotically capable tissue cellular hypertrophy and tissue hyperplasia frequently coexist phenobarb increases size of hepatocyte (hypertrophy) by increasing amount of smooth endoplasmic reticulum (SER) due to P-450 induction = decrease in the size of cells; results from decreased protein synthesis and increased protein degradation this term is applied to an organ rather than to cells, it refers to the decreased size of the organ (eg brain atrophy is due to loss of neurons) in practice this may represent either a reversible (eg. muscle) or irreversible (eg. brain) finding atrophy of skeletal muscle; histology shows small, angular or pointed muscle fibers causes of skeletal muscle atrophy include denervation atrophy, Duchenne's muscular dystrophy, immobilization testicular atrophy can be seen in undescended (cryptorchid) testicle, as an aging change, or prolonged exogenous anabolic steroid use decreased blood flow (ischemia) can cause atrophy, an example is Goldblatt kidney, which is a small kidney resulting from renal artery stenosis
when

B. hypertrophy

C. atrophy

D. metaplasia

= replacement of one normal cell type by another type (often due to chronic irritation) reprogramming of stem cells squamous metaplasia of cervix (at transformation zone) or bronchial epithelium (bronchial columnar epithelium to squamous epithelium) gastric or intestinal metaplasia of lower esophagus (Barrett's esophagus) due to gastric-esophageal reflux disease (GERD) (squamous to columnar) intestinal metaplasia of the stomach (seen in atrophic gastritis) myeloid metaplasia (spleen is most common site) due to fibrosis of marrow (myelofibrosis) osseous metaplasia seen in myositis ossificans (bone forms in muscle after trauma with hemorrhage)

E. aplasia

= failure of cell production (an example is aplastic anemia, which is due to failure of multipotential stem

cells)
F. hypoplasia

= reduction in the size due to a decreased number of cells gonads (hypogonadism) in Turner syndrome (XO) or Klinefelter syndrome (XXY) or confusing terms refers to disorganized and abnormal growth (atypia); example is dysplasia of uterine cervix due to infection with HPV dystrophy refers to defective nutrition or degenerative disorder (such as muscular dystrophy) desmoplasia refers to fibrous tissue formation in stroma of tumor (example is breast cancer forming scirrhous carcinoma) neoplasia refers to uncontrolled clonal proliferation of cells
dysplasia

G. related

2. Cell

Injury (reversible and irreversible)

1. common

A. general

mediators of cell injury include: oxygen delivery by the blood (hypoxia) decreases oxidative phosphorylation (aerobic respiration) in mitochondrial which decreases ATP production hypoxia can result from decreased blood supply (ischemia) or decreased oxygen capacity of the blood (anemia, CO poisoning) note: decreased pO2 in arterial blood is called hypoxemia b) chemicals many different possibilities here cyanide causes cellular injury by directly inhibiting mitochondrial enzymes, such as cytochrome oxidase (aka cytochrome a + a3) mercuric chloride causes cellular injury by binding to the sulfhydryl groups of proteins of cellular membranes cells that concentrate mercury, such as the cells of the GI tract and the kidney, are most likely to be damaged c) free radicals have a single unpaired electron in outer orbit and are highly reactive with proteins, lipids, and carbohydrates examples: superoxide, hydroxyl free radicals, carbon tetrachloride free radical (formed in liver by cytochrome P-450 in the SER) examples of free radical damage: ischemia with reperfusion injury, carbon tetrachloride injury, radiation, neutrophil killing substances that protect from oxygen free radical damage include: catalase (which is present in peroxisomes (microbodies), which contain amino oxidates, hydroxyacid oxidase, and catalse; peroxisomes are abnormal in Zellwegers syndrome, which is a congenital disorder characterized by severe damage and liver failure) (catalase converts H2O2 to O2 and water); glutathione peroxidase (converts either hydroxyl radicals or H2O2 to water), and superoxide dismutase (converts superoxide to hydrogen peroxide); Tylenol inhibits glutathione peroxidase. examples of anti-oxidants: vitamin E and sulfhydryl containing compounds (such as cysteine, methionine, and glutathione) d) loss of calcium homeostasis (increased calcium in cytoplasm will activate many enzymes) activates mitochondrial permeability transition, phospholipases, proteases, endonucleases, and ATPases 2. damage to cell membranes plays a central role and 4 subcellular systems are particularly vulnerable: aerobic respiration in mitochondria, plasma membrane, protein synthesis, and genetic apparatus B. reversible cell injury decreased ATP production (especially with hypoxia or ischemia) decreases the plasma membrane sodiumpotassium pump decreased functioning of ATP-dependent membrane Na-K membrane pump increases sodium inside cell (decreased efflux) and increases potassium outside cell (decreased influx) change in electrolytes causes isosmotic gain of water (hydropic change) which causes swelling of cell (cloudy) and cellular organelles decreased energy production by mitochondria increases glycolysis, lactic acid, and decreases pH which causes chromatin clumping and may activate lysosomal enzymes
a) decreased

dissociate from rough endoplasmic reticulum (RER), which decreases protein production by cell change (appearance of lipid vacuoles in the cytoplasm) may occur in tissue dependent on fat metabolism (especially the heart and liver) C. irreversible cell injury 1. by definition leads to cell death 2. two consistent markers of profound disturbances in membrane function and inability to reverse mitochondrial dysfunction dense bodies (calcifications) are formed in mitochondria (eg. flocculent densities in heart early after MI) cytochrome c is released from mitochondria and induces apoptosis (see section on apoptosis) 3. cell death causes release of cellular or lysosomal enzymes (eg. inc serum troponin, SGOT, LDH, and CPK after MI) 4. nuclear degeneration can be seen microscopically as: pyknosis (small round, dark nucleus) karyolysis (nucleus disappears) karyorrhexis (fragmented nucleus) 5. cells not irreversibly injured may die with reperfusion due to production of oxygen free radicals (induces autocatalytic damage) morphologic example is contraction bands after MI with reperfusion
fatty 3. Necrosis

ribosomes

accidental cell death when a cell cannot compensate for an injury and loses its integrity

A. characteristics

many cells or clusters of cells; with necrosis the cells swell random degradation of DNA (smear of DNA; no ladder); nucleus: pyknosis, karyorrhexis, and karyolysis necrosis is usually due to hypoxia or toxins (see irreversible injury section in notes) inflammation present (due to ruptured cell membrane) morphologic characteristics depend on whether protein denaturation (coagulation) or digestion (liquefaction) predominates with coagulative necrosis the cells lose their nuclei, but the cell outlines remain; in contrast, with liquefactive necrosis nothing remains B. examples coagulative necrosis: usually due to tissue ischemia (infarction) such as in heart (MI), liver, kidneys, (not ischemia in brain!); caused by low pH liquefactive necrosis: usually due to bacterial infection a strong neutrophil response releases lots of enzymes that digest the dead cells (i.e. pus); also brain infarction (seen when lots of lysosomal enzymes are present, such as PMNs) fat necrosis may be enzymatic (acute or chronic pancreatitis, where lipases digest fats) or traumatic (involving the breast) caseous necrosis (amorphic debris in center of necrosis has a "cheesy" gross appearance) = tuberculosis gummatous necrosis (late stage of syphilis) fibrinoid necrosis: usually seen with autoimmune disease (type III hypersensitivity); mx: inflammation and hyaline material around blood v's gangrene (due to ischemia to extremities) = dry (mainly coagulative necrosis) or wet (mainly liquefactive necrosis due to bacterial infection); mx of gangrene: marked acute and chronic inflammation with extensive necrosis and ulceration of the skin
4. Apoptosis

involves

("apoptosis" means "a falling away") cell suicide

A. characteristics apoptosis single

as originally defined as a purely morphologic process cells (not large groups of cells); no inflammatory response (cell membrane does not rupture and there is no release of macromolecules) apoptotic cells shrink with increased eosinophilia of cytoplasm; forms apoptotic bodies, which may be engulfed by macrophages apoptotic bodies have intact membranes but with phosphatidyl serine on outside (normally located on inner membrane)

is an active process (fairly fast; minutes): activation of endonucleases (cleaves at nucleosomes) causes peripheral condensation of chromatin (most characteristic feature) and DNA "ladder" (multiples of DNA base pair fragments; seen with agarose gel electropheresis) apoptosis requires energy! Cells with mitochondrial dysfunction will be unable to make ATP and undergo apoptosis. If a cell is injured, it is a race to apoptosis before the cell runs out of energy; otherwise, necrosis takes place. B. mechanisms: two basic phases 1. initiation phase, during which caspases are activated; two distinct pathways: a) extrinsic (receptor mediated) pathway: mediated by cell surface death receptors, members of the tumor necrosis factor receptor (TNF) family; contain a cytoplasmic death domain (DD) (1) type 1 TNF receptor (TNFR1) has death domain (DD); binds to TNF; may stimulate or inhibit apoptosis stimulates apoptosis: TNFR1-TNF complexes activates TRADD (TNF-receptor-adaptor protein with a death domain), which activates FADD, which activates caspase 8 inhibits apoptosis: sometimes TNFR1 binding to TRADD binds to adapter proteins such as NFKB/IK transcriptional regulatory system; IK is degraded by proteasome while NF-KB enters nucleus and causes increased gene expression (increased survival) spinal muscle atrophy results from mutations of NAIP (neuronal apoptosis inhibitory protein) (2) Fas (CD95) receptor Fas ligand (FasL) is produced by immune cells and stimulates apoptosis by binding to Fas (CD95) to activate FADD (Fas-associated death domain), which activates caspase 8 cytotoxic T lymphocytes stimulate apoptosis by expressing FasL or secreting substances like perforin, a transmembrane pore-forming molecule that promotes entry of granzyme B, which cleaves proteins and activates cellular caspases. b) intrinsic (or mitochondrial) pathway: does not involve death receptors; results from increased permeability of mitochondria (1) bcl-2 (location is outer mitochondrial membrane, endoplasmic reticulum, and nuclear envelope) antiapoptotic cytochrome c is released from mitochondria (via bax channels, which are up regulated by p53) cytochrome c binds to and activates Apaf-1 (apoptosis activating factor), which then stimulates caspase cascade (via caspase 9) bcl-2 inhibits apoptosis by blocking bax channel and by binding to Apaf-1 and sequestering it 2. execution phase: final phase during which cell death occurs a) activation of caspases ("c" refers to a cysteine protease; "aspase" refers to cleavage after aspartic acid residues) initiator caspases: caspase-8 (death receptor pathway) and caspase-9 (mitochondrial pathway) executioner caspases: caspase-3 and caspase-6 caspases make cuts of selected proteins in nuclei (lamin, Dnase inibitor, DNA repair enzymes) or cytoplasm (cytoskeleton, ROCK) C. physiologic 1. think physiologic apoptosis with any process where tissue shrinks in size "programmed cell death" during embryogenesis (removal of "webs" between fingers and toes, elimination of 50% of neurons in CNS) involution of the thymus with aging hormone-induced involution: endometrium during menses, lactating breast after weaning, ovarian follicles, prostate after castration death of proliferating B cells in germinal centers (bcl-2 is not activated); eaten by macrophages (forming tingible-body macrophages) neutrophils in circulation undergo apoptosis after a few days D. pathologic viral hepatitis (Councilman bodies are apoptotic bodies) cytotoxic CD8 T cell destruction of viral-infected hepatocytes (this is a type IV hypersensitivity reaction) reduced apoptosis by activation of bcl-2 in nodular non-Hodgkin's lymphoma due to t(14;18) translocation (bcl-2 is on chromosome 18) drug-induced toxic epidermal necrosis (TEN) is related to presence of Fas on keratinocytes (treat with immunoglobulin to block Fas from FasL)

apoptosis

 graft-versus-host axotomy 5. Autophagy

induced cell death of keratinocytes in the epidermis induced neuronal death in CNS neurons (need growth factor from target to survive normally)

and heterophagy A. general lysosomes have an acidic pH and degrade macromolecules from intracellular organelles (autophagy) or extracellular products (heterophagy) primary lysosomes are cytoplasmic vacuoles that contain numerous acid hydrolases (such as acid maltase) produced by the golgi proteins or enzymes containing mannose-6-phosphate are most likely to be incorporated into lysosomes primary lysosomes combine with vacuoles to form secondary lysosome (multivesicular body, or phagolysosome) if the material is not digestible (such as lipofuscin or hemosiderin, but not glycolipids), the end result may produce residual bodies proteasomes primarily degrade endogenous proteins; ubiquitin is a "protein-tag" that marks proteins to be destroyed within proteasomes note: insulin can oppose ubiquitin-proteosome degradation of plasma proteins B. autophagy = degradation of intracellular organelles autophagic vacuoles (autosomes) combine with primary lysosomes (late endosomes) to form autophagolysosomes degradation by lysosomal enzymes forms residual body, which is excreted by exocytosis or transformed into lipofuscin (polymerized lipids resulting from [usually] a free radical insult) C. heterophagy = degradation of extracellular material phagocytosis (endocytosis) is ingestion of extracellular material clathrin-coated endocytic vesicles contain extracellular material (phagocytic vacuoles or phagosomes) phagosomes combine with primary lysosomes (late endosomes) to form phagolysosomes (secondary lysosomes, aka multivesicular bodies) degradation by lysosomal enzymes forms residual body, which is excreted by exocytosis or transformed into lipofuscin if the extracellular material is a ligand coupled to a receptor, then the clathrin-coated endocytic vesicle is called a compartment of uncoupling of receptor and ligand (aka CURL), and the receptors are then recycled to the plasma membrane change A. general 1. note fatty change of heart may be secondary to diphtheria, which is caused by Corynebacterium diphtheriae (the D in DPT) diphtheria exotoxin (not endotoxin) blocks protein synthesis by irreversible inactivation of elongation factor 2 (EF-2) signs = pseudomembrane formation of larynx and fatty change of heart (alternating layers of normal and fatty change produces "tiger stripes"), which leads to heart failure 2. differential of clear spaces in cytoplasm of cells as seen with microscopy: glycogen (special stain is PAS positive material that is diastase sensitive) water (hydropic change, no special stain for water) lipid (special stain is oil red O) B. triglycerides 1. an example of intracellular triglyceride accumulation is fatty change in liver (steatosis); mechanisms include increased free fatty acid delivery to liver (usually secondary to increased lipolysis) seen with starvation, diabetes mellitus, corticosteroid use, and alcohol increased formation of triglyceride is seen with alcohol use (note: alcohol also causes NADH > NAD, increased fatty acid synthesis, and decreased fatty acid oxidation); hypoxia also inhibits fatty acid oxidation. decreased formation of apoprotein (with decreases lipoprotein VLDL) is seen with carbon tetrachloride (uncommon now), protein malnutrition (kwashiorkor), and orotic acid carbon tetrachloride is metabolized to toxic free radical (trichloromethyl) that damages RER and decreases production of apoprotein and VLDL

6. Fatty

C. cholesterol foamy

(histological slit like clear spaces with pointed ends are cholesterol clefts) macrophages: may form xanthomas in tendons or soft tissue, xanthelasma around eyelids (micro: lipidladen histiocytes in dermis), or cholesterolosis in gall bladder foam cells in atherosclerosis (originate from monocytes [macrophage] or smooth muscle cells)

7. Hyaline

change is not a specific substance, but rather a morphologic characteristic described microscopically as having a red "ground glass appearance" 1. note: routine stain is H&E (hematoxylin and eosin) stain hematoxylin is a basic dye (dark blue color) that has a positive charge and binds to negative charges like nucleic acids (DNA, RNA) eosin is a acid dye (pink/red color) that has a negative charge and binds to positive charges like proteins B. Mallory bodies (alcoholic hyaline) are aggregates of prekeratin intermediate filaments within hepatocytes (have a "ropey" red histologic appearance) C. viral inclusions (usually intranuclear; with eosinophilic intranuclear inclusions think nucleoli or viral inclusions); examples: herpes: multinucleated giant cells, intranuclear eosinophilic inclusions (Cowdry bodies), "ground-glass" nuclei cytomegalovirus (CMV): giant cells with intranuclear or intracytoplasmic inclusions adenovirus (causes infection in lungs): "smudge" cells (nuclei appear smudged) D. protein accumulations: Russel bodies (immunoglobulin from plasma cells) can be intracellular (if multiple called a Mott cell or grape cell or morula cell) or extracellular Dutcher bodies are intranuclear immunoglobulin aggregates (may be seen in plasma cells from individuals with Waldenstrom's macroglobulinemia) hyaline protein in renal tubular epithelial cells note examples of abnormal protein folding disorders: some types of alpha-1 antitrypsin mutation (which cant be excreted from hepatocytes and accumulates in liver), decreased G6PD (glucose-6-phosphate), and prion disorders
A. hyaline

8. Intracellular A. iron:

accumulations seen as yellow-brown hemosiderin granules differential of brown (or yellow-brown) granules in hepatocytes includes hemosiderin, bile, and lipofuscin Prussian blue is a special stain for hemosiderin, which is composed primarily of aggregates of ferritin (not free iron) causes of excess iron include hemosiderosis (eg excess iron from transfusions) or familial hemochromatosis (excess iron absorption from gut) or things such as bruising (release of large amounts of iron into the tissue/blood). B. bile: in hepatocytes, bile canaliculi (may form bile plugs), or bile ducts; with jaundice bilirubin accumulates and may cause icterus (yellow eyes) C. copper: Wilsons disease (decreased copper excretion from hepatocytes) D. carbon: in lung causes anthracosis or coal worker's pneumoconioses, the severe form is called black lung disease (mx shows dark black pigment) E. melanin: seen in melanocytes, melanophages (macrophages that have eaten melanin), nevus cells, or melanoma cells F. lipofuscin (indicates previous oxidative stress) undegradable polymerized lipids histologically seen as fine, granular, golden-brown intracytoplasmic pigment lipofuscin is a "wear and tear" pigment composed of lipids and phospholipids from lipid peroxidation by free radicals of subcellular membranes lipofuscin does not stain with Prussian blue stain, trichrome stain, oil red O stain, or PAS stain (seen best with electron microscopy) lipofuscin deposition is seen with aging, cachexia, severe malnutrition (see autophagy); in the heart it may produce brown atrophy

9. Calcification A. dystrophic 1. normal

calcification serum calcium levels

2. abnormal

(dystrophic) tissue abnormal nidus for apatite deposition atherosclerosis b) damaged heart valves (calcified bicuspid AV, which produces aortic stenosis) c) CNS lesions (tumors with dystrophic calcification may be seen with X-ray) tumor of cortex in adult = oligodendroglioma hypothalamus tumor = craniopharyngioma periventricular calcification in kids: CMV or toxoplasmosis (the latter from infected cat feces and tends to have diffuse cerebral calcifications) d) tumors with formation of psammoma bodies (small laminated calcification due to single cell necrosis; think papillary or whorling tumors) thyroid = papillary carcinoma ovary = papillary tumors (especially papillary serous cystadenocarcinoma) meningioma or mesothelioma e) pancreatitis pancreas releases lipases which generate free fatty acids and carboxyl groups; the carboxyl groups mop up free calcium, forming plaques. This is known as fat necrosis.
a) severe

B. metastatic

calcification tissue (due to precipitation of supersaturated solution of calcium phosphate) 2. increased serum calcium levels (hypercalcemia) 3. causes of hypercalcemia: think "chimps" (all are associated with dec PTH except for hyperparathyroidism) good to know this list cancer = paraneoplastic syndromes (such as secretion of parathyroid hormone-related peptide, PTHrP) or ATLL (adult T cell leukemia/lymphoma) hyperparathyroidism (primary): excess production of parathyroid hormone iatrogenic (drugs) or immobilization (bone is reabsorbed) multiple myeloma (calcium is released from bone by IL-6, which stimulates osteoclasts) primary hypercalcemia = inc vitamin D or inc milk consumption (milk-alkali syndrome) sarcoidosis (and other granulomatous diseases) because the epithelioid cells of granulomas may secrete vitamin D
1. normal

10. Cellular

aging shortening = incomplete replication of chromosome ends (telomeres) associated with decreased telomerase (increased telomerase in cancers) B. Werner's syndrome caused by a defective DNA helicase characterized by premature aging: early cataracts, increased atherosclerosis and cancer first causes symptoms during late teens; typically first identified when an adolescent fails to have a normal growth spurt C. progeria an inheritable syndrome of unknown etiology characterized by premature aging: baldness, stiffness of joints, cardiovascular problems, wrinkled-skin, and dwarfism symptoms begin around the age of 6-12 months of age (in the first 10 years of life)
A. telomere

INFLAMMATION
11. Cardinal

signs of inflammation rubor (redness): mainly due to prostaglandins and nitric oxide (but also histamine and bradykinin) causing vasodilation of arterioles calor (heat): mainly due to prostaglandins and nitric oxide causing vasodilation of arterioles (initially due mainly to nitric oxide) tumor (swelling): due to increased vascular permeability of venules by histamine (initial swelling), bradykinin, C3a, C5a, leukotrienes C4,D4,E4 dolor (pain): mainly due to bradykinin (prostaglandin E2 sensitizes nerve endings to the effects of bradykinin) sometimes a 5th sign is added: functio laeso (loss of function), which is due to swelling and pain

12. Steps

of inflammation transient (very transient) vasoconstriction is due to neural stimulation B. vasodilation vasodilation occurs mainly in arterioles (mainly caused by prostaglandins and nitric oxide, but also by histamine and bradykinin) vasodilation causes increased blood flow which produces symptoms of red color (rubor) and hot (calor) C. increased vascular permeability occurs mainly in venules, caused by histamine (initial swelling), bradykinin, complement components C3a and C5a, and leukotrienes C4,D4,E4 increased vascular permeability causes inflammatory edema (exudate) and produces sign of tumor (swelling) exudates have large numbers of cells, debris, and protein, all of which produces an inc specific gravity of the fluid (greater than 1.020) transudates have low protein content (mainly albumin), little or no cellular material, and low specific gravity. Mechanisms of increased vascular permeability: gaps due to endothelial contraction caused by histamine and leukotrienes acting on venules; short lived leukocyte-dependent injury leukocytes acting on venules and pulmonary capillaries; long lived new blood vessel formation persists until intercellular junctions are formed direct injury fast, perhaps long lived increased transcytosis caused by VEGF acting on venules D. neutrophils events in blood vessels 1. margination (pavementing): leukocytes move from central axial (laminar) position peripherally due to sluggish flow (stasis) and increased blood viscosity) 2. adhesion (binding to endothelial cells due to adhesion molecules) a) receptors (1) selectins (a lectin is a protein that binds a carbohydrate) selectins include E-selectin (aka ELAM-1), P-selectin (aka CD62), and L-selectin (aka LAM-1) selectins have an extracellular domain related to sugar-binding lectins E-selectin is a lectin that binds sialyl Lewis-X antigen on neutrophils (i.e. addressin) P-selectin: normally stored in Weibel-Palade bodies of endothelial cells; with inflammation it is redistributed to the cell surface (motivated by histamine and thrombin) (2) integrins are composed of an alpha and beta chain, eg. beta 2 integrins = CD18 plus one of the following: CD11a to form LFA-1 (leukocyte function antigen-1) CD11b to form complement receptor 3 (CR3), which is also called Mac-1 CD11c to form CR4 (aka gp150,95) (3) immunoglobulin family: includes ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) b) initial phase is called rolling and is due to weak binding of selectins on endothelial cells to sialyl Lewis-X antigen on neutrophils (i.e addressin) c) later phase is tight binding and is due to integrins on neutrophils binding to ICAM-1 on endothelial cells (binding of a chemokine to a chemokine receptor on the neutrophil causes the integrin to switch from a low-affinity state to a high-affinity state) E. diapedesis = transmigration of leukocytes from blood vessels into tissue F. chemotaxis = movement of cells toward a certain site or source due to chemotactic factors such as C5a, leukotriene B4, arachidonic acid metabolites, and IL-8 chemotactic factors bind to Gq receptors on neutrophils to activate phospholipase C and increase cytoplasmic IP 3 and calcium
A. vasoconstriction:

13. Leukocyte

activation and killing (heterophagy)

A. activation 1. results:

production of arachidonic acid metabolites, degranulation, oxidative burst, secretion of cytokines, modulation of adhesion molecules 2. leukocyte cell surface receptors (also see section on cell surface receptors) a) Toll-like receptors: innate immunity to bacterial lipopolysaccharide and other substances b) seven-transmembrane G-protein coupled receptors: recognize short peptides containing N-formylmethionyl residues and other substances

for cytokines: example is receptor for gamma-interferon, which is produced by natural killer cells for opsonins: opsonins increase phagocytosis of bacteria by phagocytic cells (such as neutrophils) IgG (a type of immunoglobulin) binds to bacteria then Fc portion of IgG binds to Fc receptor (such as on neutrophils) C3 binds to certain complement receptors (CR1 binds C3b; 2,3, and 4 bind iC3b) macrophage cell surface receptor C1q binds microbes opsonized with plasma MBL (mannose-binding lectin) B. recognition and attachment mannose receptor: a macrophage lectin that binds terminal mannose or fructose residues of glycoproteins and glycolipids macrophage scavenger receptor: bind modified LDL particles and a variety of microbes C. phagocytosis 1. phagosome (the engulfed particle) + a primary lysosome forms a phagolysosome (note that acid enzymes are in lysosomes) 2. in phagolysosome is "respiratory burst" a) O2 is converted to O2 (superoxide) by the action of NADPH oxidase b) O2 is then converted to H2O2 (hydrogen peroxide) by spontaneous dismutation or by superoxide dismutase c) H2O2 is further converted to free radicals or acids: Fenton reaction: with Fe+++ to form OH (hydroxyl free radical) with myeloperoxidase (neutrophil azurophilic granules) and Cl- to form hypochlorous acid (which can form the green color of pus) d) NO (from Arginine by NO-synthase), reacts with superoxide to generate peroxynitrite. e) note: breakdown of hydrogen peroxide is via catalase or glutathione oxidase catalase is an enzyme (in peroxisomes) that converts hydrogen peroxide to H2O + O2 (note: staph aureus contains catalase) glutathione peroxidase (which can be found as a branch point off of the hexose monophosphate shunt) in cytoplasm also converts hydrogen peroxide to H2O f) cells in a hypoxic environment will be unable to produce reactive oxygen species and unable to kill pathogens via the respiratory burst (this underlies most gangrene situations) 3. non-oxygen products in neutrophil lysosomes include hydrolases, lysozyme, and defensins 4. extracellular release of material from neutrophils (lysosomal enzymes, oxygen-derived metabolites, and arachidonic acid metabolites)
d) receptors 14. Disorders A. LAD

c) receptors

of inflammation (leukocyte adhesion deficiency) type I is due to decreased beta2 integrins (ie., decreased CD18) severe recurrent bacterial infections (increased neutrophils in blood but no neutrophils in tissue at the site of infection) decreased wound healing (also causes delayed separation of umbilical cord) B. Chediak-Higashi syndrome: inheritance is autosomal recessive (AR) abnormal fusion of phagosome and primary lysosome due to abnormal microtubules (lysosomal trafficking gene mutation) giant lysosomes in leukocytes and abnormal formation of melanin in melanocytes, which causes albinism recurrent infections with pyogenic bacteria; most develop "accelerated phase": an aggressive lymphoproliferative disease results in pancytopenia and death C. Chronic Granulomatous Disease (CGD): inheritance is most often x-linked recessive (XR) defective NADPH oxidase (enzyme on membrane of lysosomes that converts O2 to superoxide and stimulates oxygen burst) recurrent infections with catalase positive organisms (Staph aureus) abnormal nitroblue tetrazolium dye test (normal is production of purple color, abnormal result is no color production) cascade

15. Complement A. general: the

complement cascade is a cascade of serum proteins, the purpose of which is analogous to the military (ie break things and kill people)

 terminology: B. pathways 1. classic

"a" is the little piece (usually floats away as a mediator); "b" is the big piece (acts as a "handle")

pathway pathway a) initiation needs preformed C3b along with factors B and D normally low levels of C3 in the blood are converted into C3a and C3b by a slow process called "C3 tick-over" some C3b may combine with factor B to form C3bB, which subsequently reacts with factor D and properdin some C3b may instead attach to factor H, which causes C3b to be inactivated by being converted to iC3b by factor I attachment to factor H is increased by sialic acid, which is more abundant in certain organisms, such as streptococcus pneumonia, H. influenza, and N. meningitidis organism with sialic acid can inhibit the alternate complement system and instead will need to be killed via the classic complement pathway 3. lectin pathway mediated by mannan-binding lectin (aka mannan-binding protein, MBP), which is made in the liver MBP is homologous to C1q of classic complement pathway (this pathway bypasses C1q activation step) initiation: MBP binds to mannose-containing carbohydrates on bacteria and viruses C. activation 1. classic pathway is activated by immune complexes especially IgM, IgG (involves C1, C2, C4, and C3; therefore with activation all are decreased) 2. alternate pathway (bypasses C1, C2, and C4 and begins at C3; therefore only C3 is decreased) is activated by: aggregated IgA (disorders associated with IgA include dermatitis herpetiformis, Henoch-Schonlein purpura, and Berger's disease) LPS (lipopolysaccharide)/endotoxin (which causes septic shock) and cobra venom C3 nephritic factor, which is seen in type II membranoproliferative glomerulonephritis (MPGN), aka dense deposit disease D. products (basic function of complement is direct cell lysis, attract leukocytes to sites of inflammation, and activate leukocytes) C3b and C4b are an important opsonins C5a causes chemotaxis and leukocyte activation C3a, C4a, C5a are anaphylatoxins (they increase vascular permeability and cause vasodilation by inc histamine release from mast cells) C5-9 forms the membrane attack complex (puts pores into cells) E. deficiencies deficiency of early complement components (C2 or C4) causes SLE-like syndrome (due to dec removal of circulating immune complexes) deficiency of C3 causes recurrent pyogenic bacterial infections deficiency of C6, C7, and C8 causes recurrent infections with Neisseria species (cell lysis with MAC is important normal defense against Neisseria) deficiency of decay accelerating factor (DAF), which normally inhibits complement activation by accelerating the decay of C3 convertase, causes paroxysmal nocturnal hemoglobinuria (complement mediated lysis causes pancytopenia) deficiency of C1 esterase inhibitor, which normally breaks down C1s and inhibits XIIa and the conversion of HMWK to bradykinin, causes hereditary angioedema (recurrent facial swelling, especially around lips, due to excess C2 kinin and bradykinin, the latter substance increases vascular permeability, dilates blood vessels, contracts smooth muscle, and causes pain)
2. alternate 16. Arachidonic

acid metabolism (phospholipase A2, which is inhibited by corticosteroids, converts phospholipids in cell membrane to arachidonic acid) A. lipoxygenase 5-lipoxygenase forms leukotrienes, which generally cause vasoconstriction, bronchoconstriction, and increased vascular permeability 12-lipoxygenase (in platelets) forms lipoxins from lipoxin A4 (LXA4) and lipoxin B4 (LXB4) made by neutrophils

inhibit neutrophil chemotaxis and adhesion to endothelium leukotrienes include HETE and LTB4 slow-reacting substance of anaphylaxis = LTC4, D4, and E4 (cause vasoconstriction and bronchoconstriction) aspirin-induced asthma results from relative excess bronchoconstriction of leukotrienes C4, D4, E4 (rx with antileukotrienes) leukotrienes are degraded by aryl sulfatase from eosinophils leukotrienes from fish oil (linoleic acid) may modify inflammation because they are less potent than those derived from arachidonic acid B. cyclooxygenase (COX): involved in the formation of prostaglandins 1. prostaglandin I2 (prostacyclin) is produced by endothelial cells causes vasodilation and inhibits platelet aggregation binds to Gs to stimulate adenyl cyclase and increase cAMP 2. thromboxane A2 is produced by platelets (which are thrombocytes) causes vasoconstriction and stimulates platelet aggregation binds to Gq to stimulate PLC to increase IP3 and subsequently increase cytoplasmic calcium 3. prostaglandin E2 fever production (PGE2 is produced in the anterior hypothalamus by the action of IL-1 from macrophages) PGE2 keeps the ductus arteriosus open (used in patient with transposition of great arteries, TOGA) osteoid osteoma is a bone tumor that causes pain at night in young adult males due to production of PG E2 4. prostaglandin F2 (causes uterine contraction, dysmenorrhea, and bronchoconstriction) excess uterine contraction due to PG F2 may cause dysmenorrhea (treat with indomethacin) 5. drugs that inhibit cyclooxygenase: a) note: cyclooxygenase 1 (COX1) is present in the stomach; cyclooxygenase 2 (COX2) is present at sites of inflammation COX-1 is constitutively expressed; COX-2 is inducible b) drugs that inhibit both COX1 and COX2 aspirin (used to treat fever, dysmenorrhea, osteoid osteoma, prevent MI, the latter by decreasing thromboxane) indomethacin (used to close a patent ductus arteriosus) c) drugs that selectively inhibit COX2: celecoxib (Celebrex) and rofecoxib (Vioxx)
chemotactic 17. Chemical A. terms

lipoxins

mediators of inflammation

the effect of a substance is on the cell that secreted the substance paracrine: the effect of a substance is on neighboring cells to the cell that secreted the substance endocrine: the effect of a substance that travels via the blood is on cells located at some distance from the cell that secreted the substance (hormones are the prime example of endocrine effect) B. histamine and serotonin 1. histamine (found in mast cells, basophils, platelets) release is stimulated by temperature, IgE antibodies, anaphylatoxins, IL-1, and IL-8 actions (via H1 receptors) include dilation of arterioles (constrict large arteries), increased vascular permeability (initial swelling), redistribution of P-selectin 2. serotonin (5-hydroxytryptamine or 5-HT); breakdown product is 5-HIAA (5-hydroxy indole acetic acid) found in platelets and enterochromaffin cells and has actions that are similar to histamine; it stimulates smooth muscle cells a carcinoid tumor is a type of tumor that can secrete large amounts of serotonin C. cytokines 1. interleukins (think "Hot T-bone stEAk": IL-1 for fever (hot), IL-2 for T cells, IL-3 for bone marrow, IL-4 for IgE production, and IL-5 for IgA production) a) IL-1 (interleukin-1) (tumor necrosis factor [TNF] has similar actions) source is macrophages, antigen-presenting cells, and other somatic cells stimulates acute phase reactions (fever due to PGE2 produced in ant hypothal, peripheral leukocytosis [with increased bands], decreased appetites) increase acute phase proteins (C-reactive protein, alpha-1 antitrypsin, haptoglobin, alpha2 macroglobulin)

autocrine:

protein (CRP) is made in the liver and can be used to differentiate bacterial infection (elevated CRP) from viral infection (decreased CRP) stimulates endothelial cells (increased leukocyte adherence, increased procoagulation) and fibroblasts (increased proliferation and synthesis) other effects include decreased appetite and altered sleep patterns b) IL-2 is produced by T-helper cells and stimulates CD-8 lymphocytes and NK cells and inc IL-2 receptors of T-helper cells (autocrine effect) c) IL-3 is multi-CSF and stimulates pluripotential stem cells in the bone marrow d) IL-4 is produced by TH2 cells and stimulates TH2, inhibits TH1, and stimulates class switching to IgE e) IL-5 is produced by TH2 cells and stimulates eosinophils (increase their number and function) and secretion of IgA f) IL-6 is produced by TH2 cells and macrophages and stimulates the production of acute phase proteins g) IL-8 is produced by macrophages and is a major chemoattractant for neutrophils, T cells, and basophils h) IL-12 is produce by B cells and macrophages and stimulates TH1 and inhibits TH2; IL-12 induces NK cells to secrete IFN-, which stimulates macrophages 2. interferons (IFNs) type I (antiviral) IFNs are produced by most cells and include alpha-IFN, beta-IFN, and omega-IFN type II (immune) is gamma-IFN (source is CD8 cells, TH1 cells, and NK cells) D. chemokines 1. chemokines are activators and chemoattractants for leukocytes 2. bind to G-protein linked surface receptors (CXCR or CCR) which are serpentine receptors having 7 transmembrane loops 3. subfamilies (based on position of conserved cystine residues) C-X-C are the alpha chemokines which are produced by activated macrophages and endothelial cells to act on neutrophils (eg., IL-8) C-C are the beta chemokines which are produced by T cells and attract monocytes, eosinophils, basophils, lymphocytes (not PMN's) C are the gamma chemokines which lack two (1st and 3rd) conserved cysteines and are relatively specific for lymphocytes 4. some of the receptors for chemokines are coreceptors for entry of HIV into cells (possible therapeutic modality) E. nitric oxide (NO) source includes endothelial cells (endothelial-derived relaxing factor), macrophages, brain NO is synthesized from L-arginine by the enzyme nitric oxide synthase (NOS) types of NOS: eNOS (endothelial), nNOS (neuronal), iNOS (inducible) a calmodulin-mediated influx of calcium can greatly increase the synthesis of endothelial cell nitric oxide NO relaxes vascular smooth muscle (vasodilation) through Gt second messenger (stimulates guanyl cyclase causes increased cGMP) also decreased platelet aggregation and adhesion (markedly excess nitric oxide can produce shock) note: NO2 (sic) is used by some body-builders to supposedly increase muscle strength and stamina; NO2 contains arginine, not NO F. kinins the kinin system generates vasoactive peptides from kininogens through the action of specific proteases called kallikreins factor XIIa (from Hageman factor, coagulation factor XII, contacting collagen or basement membranes) converts prekallikrein to kallikrein kallikrein converts HMWK (high molecular weight kininogen) to bradykinin (kallikrein also converts plasminogen to plasmin) bradykinin increases vascular permeability, dilates blood vessels, contracts smooth muscle, and causes pain (dolor)
18. Outcomes/morphologic A. outcomes

C-reactive

patterns/systemic effects of inflammation of acute inflammation complete resolution healing by connective tissue replacement (fibrosis) progression to chronic inflammation B. morphologic patterns

inflammation = fluid without fibrin or fibrinogen; may be seen in skin blisters or effusions (eg pericardial or pleural effusions) fibrinous inflammation (contains fibrin) is seen in fibrinous ("bread and butter") pericarditis (clinical sign is pericardial friction rub) suppurative (purulent, eg "pus" with lots of neutrophils) inflammation can be caused by pyogenic ("pus"forming) bacteria note that in contrast to "pyogenic", "pyrogenic" means fever producing catarrhal inflammation (phlegmonous or coryza) is excessive mucous secretions (runny nose) abscess = collection of neutrophils with necrotic cellular debris (results from liquefactive necrosis) pseudomembranous colitis: Clostridium difficile infection (mx: mushroom-shaped inflammatory debris on surface of yellow colonic mucosa) ulcer = a local defect that results from the sloughing of necrotic inflammatory tissue from the surface of an organ (eg. peptic ulcer disease); ulcers involve the entire epithelium in contrast to erosions which dont (eg gastric erosions) C. systemic effects of inflammation fever (secondary to increased PGE2 in the anterior hypothalamus), leukocytosis (increased numbers of leukocytes), and acute phase reactions acute phase reactions include decreased appetite, increased degradation of proteins, and the synthesis of acute phase proteins by the liver acute phase proteins include C-reactive protein, alpha-1-antitrypsin, alpha-2 macroglobulin, amyloid, complement, and coagulation proteins Bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute phase proteins. The APPs inclue C-reactive protein and mannose binding lectin, both of which activate the complement system. increased erythrocyte sedimentation rate (ESR): nonspecific lab test that measures the rate that red cells settle to the bottom of a tube of blood factors that decrease the normal repulsion between red cells (eg fibrinogen and gamma globulins) will increase the ESR
19. Inflammatory A. acute

serous

cells inflammation (fast response to injury providing leukocytes and plasma proteins to injured areas) 1. neutrophils ("polys" or PMN's) normally have 3-5 lobes, while more than 5 lobes = hypersegmented (think megaloblastic anemia) are first cells to arrive at sites of inflammation (therefore neutrophils are acute inflammatory cells); grossly these sites may appear white primary (azurophilic) granules (myeloperoxidase, lysozyme, defensins) and secondary (specific) granules (lysozyme, alk phosph, NADPH oxidase) reaction to bacterial infections is typically neutrophils (increased numbers in the peripheral blood called neutrophilia) band is the precursor cell (increased bands in blood, called "left-shift", is seen with acute inflammation and bacterial infections) B. chronic inflammation (inflammation of "prolonged" duration) 1. lymphocytes normally is a small cell with a round to oval nucleus with little to no cytoplasm types of lymphocytes include B cells (which form plasma cells), T cells, and NK cells (large granular lymphocytes) plasma cells have a "clock-face" chromatin, a perinuclear hof (Golgi), and abundant RER (to produce immunoglobulin) reaction to viral infections is typically lymphocytic (lymphocytosis in peripheral blood) 2. monocytes normally have kidney-bean shaped nucleus with "ropey" chromatin and cytoplasmic vacuoles monocytes in tissue are called macrophages or histiocytes (activated macrophages with abundant cytoplasm are called epithelioid cells) part of the reticuloendothelial system (RES) which includes Kupffer cells of the liver, alveolar macrophages of the lung (which may form "heart failure cells"), microglial cells of the central nervous system, osteoclasts of the bone, and Langerhans cells of the skin 3. eosinophils normally are bilobed and have abundant eosinophilic cytoplasmic granules (dark center with EM)

with allergies, asthma, and parasitic infections; may form Charcot-Leyden crystals in sputum of pts with asthma granules contain major basic protein (MBP; causes tissue damage), arylsulfatase, histaminase (neutralizes histamine) MBP is a highly cationic protein that is toxic to parasites and can cause the lysis of mammalian epithelial cells they do not contain alkaline phosphatase (which is found in neutrophils) or muramidase (which is found in monocytes) 4. basophils/mast cells bind to IgE (have receptors for Fc portion of IgE) and release basophilic granules (histamine, heparin, leukotrienes, PAF) 5. Neutrophils can be abundant (e.g., osteomyelitis the infection isnt necessarily hiding, its just that it takes the immune system to deal with an infection in the bone)
20. Granulomas A. definition:

increased

granulomas are aggregates of activated macrophages (epithelioid cells), which are derived from monocytes in blood lymphocytes and giant cells may also be present in a ring surrounding the epithelioid cells epithelioid cells have abundant cytoplasm (because they secrete lots of products) and may fuse together to form multinucleated giant cells giant cells may contain star-shaped inclusions called asteroid bodies (a nonspecific finding, but think noncaseating granulomas and sarcoid) with time granulomas may become fibrotic, hyalinize, or calcify (can see with X-ray) B. caseating granulomas (gross: "cheesy" appearance) are seen with mycobacterial infections: think tuberculosis (acid fast bacilli [AFB] = mycobacteria) may also see Langhans giant cells (which has horseshoe-shaped arrangement of nuclei) C. non-caseating granulomas 1. parasites and fungal infections (rare bacterial diseases include leprosy, syphilis, and cat-scratch disease) 2. foreign-body reaction (suture is a common type of foreign material; suture is polarizable) 3. Some autoimmune conditions (e.g., Crohns Disease) 4. sarcoidosis young African-American females (unknown etiology; cultures will be negative) hypercalcemia (epithelioid cells convert vitamin D to its active form) enlarged hilar lymph nodes ("potato nodes") due to non-caseating granulomas lung disease is restrictive disease (interstitial fibrosis) increased serum ACE levels (angiotensin converting enzyme), which is normally produced by endothelial cells in lung non-caseating granulomas may have Schaumann bodies and asteroid bodies REPAIR
21. Cell

cycle/growth factors A. cell cycle 1. normal cycle: G1 (presynthetic); S (DNA synthesis); G2 (premitotic); M (mitosis) 2. types of cells: a) stem cells unique cells capable of asymmetric replication (self-renewal); located in special sites called niches embryonic stem cells: pluripotential, capable of forming all the tissues of the body adult stem cells: usually only able to differentiate into a particular tissue hepatic stem cells: located in the canals of Hering of the liver; give rise to precursor cells called oval cells; in addition, hepatocytes can replicate and bone marrow stem cells can regenerate hepatocytes (so, 3 methods of regeneration for the liver) satellite cells: located in the basal lamina of myotubules; can differentiate into myocytes after injury limbus cells: located in the canals of Schlemm are stem cells for the cornea hair follicle bulge contains epidermal stem cells other sites for stem cells are the base of the crypts of the colon and the dentate gyrus of the hippocampus b) labile cells are continuously dividing cells (eg. epithelial cells); labile cells are most sensitive to radiation

(quiescent cells) are not dividing (G0) but can divide if necessary (cells of liver, kidneys, mesenchymal cells, endothelial cells) d) permanent (nondividing) cells (eg. neurons, myocardial cells); however, neural stem cells have been found in the brain. B. growth factors 1. epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha) binds to c-erb B1 receptor, which has tyrosine kinase activity is mitogenic for epithelial cells and fibroblasts 2. hepatocyte growth factor (HGF) (aka "scatter factor") mitogenic for most epithelial cells (including liver, lung, breast, and skin) receptor for HGF is product of c-MET 3. vascular endothelial growth factor (VEGF): plays a key role in promoting angiogenesis by stimulating endothelial cell migration, endothelial cell proliferation, and increasing vascular permeability 4. platelet derived growth factor (PDGF) is found in platelets (alpha granules), endothelial cells, smooth muscle stimulates migration and proliferation of fibroblasts, smooth muscle cells, and monocytes 5. fibroblast growth factors (FGF) (basic FGF is secreted from activated macrophages, acidic FGF is found in neural tissue) functions include angiogenesis, wound repair, development, and hematopoiesis 6. transforming growth factor-beta (TGF-beta) can be either a growth stimulator or growth inhibitor depending on its concentration growth inhibitor for most epithelial cell types and leukocytes stimulates proliferation of fibroblasts and smooth muscle cells; potent fibrogenic agent; strong antiinflammatory promotes collagen formation by inhibiting macrophage production of collagenases (steroids, also) 7. transforming growth factor-alpha (TGF-alpha) normally a growth stimulator speeds things up stimulates replication of hepatocytes and certain epithelial cells 8. cytokines (see cytokine section)
22. Cell

c) stable

A. cell

receptors/signal transduction surface receptors 1. note: lipophilic substances (eg steroid hormones) dont bind to surface receptors, but pass through membrane to bind to intracellular receptors 2. receptors with intrinsic kinase (usually tyrosine kinase) activity many of this type are growth factor (EGF, FGF, PDGF, TGF-, HGF, VEGF, insulin) receptors and many are composed of dimers binding of 2 receptors (dimerization) causes autophosphorylation (one receptor subunit phosphorylates the other in the dimer) 3. receptors without intrinsic catalytic activity are usually receptors for cytokines 4. G-protein receptors a) general G-proteins may be monomeric (example is product of c-ras) or trimeric, the latter receptor contains seven transmembrane loops all G proteins are inactive when bound to GDP, active when bound to GTP, and have intrinsic GTPase activity when active (therefore they can inactivate themselves) b) Gs binding to receptor stimulates adenyl cyclase, which converts ATP to cAMP (which usually activates protein kinases) phosphodiesterase converts cAMP to 5'AMP (this enzyme is inhibited by methyl xanthines such as caffeine and theophylline) cholera toxin inhibits breakdown of active Gs-GTP to inactive Gs-ADP ("on switch" on) c) Gi binding to receptor inhibits adenyl cyclase, which causes decreased cAMP pertussis toxin inhibits formation of active Gi-GTP ("off switch" off) d) Gq binding to receptor stimulates phospholipase C which converts PIP2 to IP3 and DAG IP3 increases intracytoplasmic calcium by releasing it from ER and mitochondria

stimulates protein kinase C and lipase (to form arachidonic acid) include leukocyte chemotaxis and activation, platelet activation, and some growth factors e) Gt (aka transducin) (1) binding to receptor stimulates guanylate cyclase, which converts GTP to cGMP (2) example: rhodopsin is found in rods of retina and is responsible for night vision (3) previously included nitric oxide (not nitrous oxide, which is laughing gas) is secreted from endothelial cells and causes vasodilation by relaxing smooth muscle of blood vessels (note that Viagra inhibits phosphodiesterase type 5 and prolongs effects of cGMP) ANF (atrial natriuretic factor) increases sodium excretion, decreases blood volume, and inhibits aldosterone secretion f) G12/13: new; role may include cell growth and differentiation, ionic homeostasis, and signal integration 5. Toll-like receptors (TLRs) essential role in response to bacterial lipopolysaccharide (LPS), bacterial proteoglycans, and unmethylated CpG nucleotides mediate the innate immune response to PAMPs (pathogen-associated molecular pattern) examples of PAMPs: bacterial lipopolysaccharide (endotoxin), lipoteichoic acid, and peptidoglycan TLRs, in conjunction with CD14, bind to LPS and activate leukocytes to produce cytokines and reactive oxygen intermediates (ROIs) B. signal transduction 1. mitogen-activated protein kinase (MAP kinase) important pathway of signaling by growth factors (note dimerization and autophosphorylation of tyrosine residues) one pathway is binding of bridging protein complex (GRB2 and SOS) to inactive ras-GDP (note that ras is a monomeric G protein) activated ras binds to raf, which binds and phosphorylates MEK (a MAP kinase), and eventually ERK translocates to the nucleus and phosphorylates transcription factors such as c-jun and c-fos 2. PI-3-kinase (a minority of growth factors use this pathway) 3. inositol-lipid (IP3): this pathway seen with Gq receptors (see above) 4. cyclic adenosine monophosphate (cAMP): this pathway seen with Gs and Gi receptors (see above) 5. JAK/STAT (signal transducer and activator of transcription) signaling system: this pathway seen with some receptors that lack intrinsic tyrosine kinase activity (e.g. receptors for cytokines)
examples 23. Extracellular

DAG

matrix A. fibrous structural proteins include collagens and elastins 1. collagen (is red in routine H&E stains; stains blue with trichrome stain): has high content of glycine and hydroxyproline a) types (1) interstitial (fibrillar) collagens are the most abundant type I is found in skin, bone, tendons, and mature scars type II is found in cartilage type III is found in embryonic tissue, blood vessels, pliable organs, and is the first type deposited in wounds (2) nonfibrillar (amorphous) collagens type IV is found in basement membranes (antibodies to type IV collagen are found in Goodpasture disease) type V is found in connective tissue and blood vessels type VI is found in connective tissue b) biosynthesis (secreted by fibroblasts) within nucleus: transcription of DNA with post-transcriptional modification within RER & Golgi: translation forms pro-alpha chains with hydroxylation (needs vitamin C) and glycosylation to from triple helix within extracellular space: remove propeptides from procollagen to form collagen; cross-linking (needs lysyl oxidase and copper) to form fibrils 2. elastin

ability of tissue to stretch and recoil; lots of elastin are present in blood vessels (especially the aorta), uterus, skin, and ligaments has high content of glycine (like collagen) but has little hydroxyproline and no hydroxylysine elastin core is surrounded by fibrillin (which serves as a scaffolding) B. cell adhesive molecules (CAM); homotypic = interaction between same cell; heterotypic = interaction between different cell types 1. fibronectin (secreted by fibroblasts, monocytes, endothelial cells): large glycoprotein consisting of two chains held together by disulfide bond links extracellular matrix component and macromolecules to integrins chemotactic for fibroblasts and endothelial cells; promotes angiogenesis 2. laminin: cross-shaped structure found within basement membrane laminin binds cells to matrix components (collagen type IV and heparan sulfate) 3. cadherin dependent on calcium to function ("calcium-dependent adherence protein") connect plasma membranes on adjacent cells to form zonula adherens and desmosomes 4. immunoglobulin superfamily 5. integrins and selectins C. proteoglycans and hyaluronan 1. proteoglycans are glycoproteins that contain a core protein linked to carbohydrates (which is the main composition of proteoglycans) the carbohydrate portion of the proteoglycan is called a mucopolysaccharide (aka glycosaminoglycan, aka GAG) examples of mucopolysaccharides (GAGs) include hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, and keratin sulfate proteoglycans regulate extracellular matrix structure and permeability; modulate cell growth and differentiation 2. hyaluronan: binds large amounts of water and provides resilience and lubrication to connective tissue, especially cartilage of joints. HA is not linked to a protein backbone; only the sulfates are.
24. Repair/wound

provides

healing

A. angiogenesis

from either endothelial precursor cells (EPCs) or pre-existing vessels (sprouting) proteolytic degradation of BM (via matrix metalloproteinases), migration and proliferation of endothelial cells, maturation most important factor is VEGF (vascular endothelial growth factor): stimulates endothelial cell migration and proliferation other factors promoting angiogenesis include basic FGF, vascular EGF, and fibronectin B. scar formation inflammation, proliferation, and then maturation 1. tissue remodeling: degradation of collagen and ECM proteins by matrix metalloproteinases (MMPs), which are not serine proteinases interstitial collagenases (MMP-1,2, and 3) cleave fibrillar collagen types I, II, and III gelatinases (MMP-2 and 9) degrade amorphous collagen and fibronectin stomelyisns (MMP-3, 10, and 11) act on a variety of ECM components 2. scars are composed of collagen (type III deposited first, then type I in mature scars), which stains blue with trichrome stain last step for wound strength: structural modifications of collagen fibers (cross-linking, increased fiber size) occur after collagen synthesis 3. primary union = healing by first intention (eg. a surgical or sharp incision) sequence: blood clot in the wound, neutrophils influx into the wound, granulation tissue peaks. 75% to 80% tensile strength attained 4. secondary union = larger defect that heals with granulation tissue formation and scar contraction (i.e. a foot ulcer on a diabetic) 5. granulation tissue = proliferating endothelial cells and fibroblasts C. complications
steps:

angiogenesis

1. pyogenic

granuloma = excessive granulation tissue (with inflammatory cells) producing small mass (note the misnomer here) 2. keloid excess proliferation of collagen in scars forms large, irregular, raised lesions microscopically keloids have broad dense bands of collagen in dermis common location is ear lobes (secondary to ear piercing); keloids are more common in African-Americans 3. fibromatosis (fibrosis is due to collagen deposits; fibrosis never completely goes away) formation of desmoids palmar fibromatosis = Duptuyren's contracture (inability to extend fourth and fifth fingers) penile fibromatosis (curved penis) = Peyronie's disease abdominal fibromatosis in woman with previous C-section = desmoid unilateral fibrosis of sternocleidomastoid muscle = congenital torticollis nodular (pseudosarcomatous) fasciitis: a reactive fibroproliferative lesion; forms palpable nodules in the extremities 4. contractures: extensive scars overlying joints that limit their movement; can cause permanent flexure FLUIDS AND HEMODYNAMICS
25. Edema

(exudates and transudates) triple response of Sir Thomas Lewis to a scratch (for historical note) dull red line is produced by transient vasoconstriction of arterioles (due to effects of nerves or chemicals) red halo (flare) is produced by vasodilation of precapillary arterioles (hyperemia) swelling (wheal) is produced by increased endothelial permeability causing edema B. exudates (inflammatory edema) due to inflammation (inflammatory edema) with increased blood vessel permeability (of post-capillary venules) composition of an exudate = increased protein, increased cells, and specific gravity > 1.020 C. transudates (non-inflammatory edema) 1. composition of a transudate = no increased protein nor cells, and specific gravity < 1.012 2. due to abnormality of Starling forces, which refers to the equation: fluid movement = k[(Pc - Pi) - (Oc - Oi)], where k is a constant, Pc is capillary hydrostatic pressure, Pi is interstitial hydrostatic pressure, Oc is capillary osmotic pressure, and Oi is interstitial oncotic pressure a) increased hydrostatic (venous) pressure (classic example is congestive heart failure) b) decreased oncotic pressure, which is due to dec serum albumin (hypoalbuminemia); albumin is the most abundant protein in blood liver disease causes decreased production of albumin (nephrotic syndrome) renal disease (nephrotic syndrome) causes increased excretion of albumin c) lymphatic obstruction is due to tumors, surgery, or microfilaria Wuchereria bancrofti and Brugia malayi, which are transmitted by mosquitos, cause massive edema of legs or groin (elephantiasis) an example is a pleural effusion with lymph fluid (lots of fat causing a turbid supernate) is lymphatic obstruction by tumor 3. note: kidney may retain sodium and water (retention of sodium may be due to decreased intravascular volume causing increased aldosterone) edema in body cavities: hydrothroax, hydroperitoneum, hydropericardium anasarca is extreme generalized edema involving the extracellular space in subcutaneous tissue, visceral organs, and body cavities ascites is clinically apparent accumulation of fluid in the peitoneal cavity; may be due to cirrhosis pitting edema: typically in dependent areas; how much is present is proportional to severity of edema
A. note

26. Hyperemia

A. hyperemia

(congestion), hemorrhage, and hemostasis (excess amount of blood within an organ) 1. active hyperemia (red color) results from increased arterial supply (seen with blushing, exercise, inflammation) 2. passive hyperemia (blue-red color), also called congestion, results from impaired venous blood flow: classic example is congestive heart failure (CHF) CHF may produce pulmonary hemorrhage (erythrocytes in alveoli), which can lead to hemoptysis (coughing up blood)

produces heart failure cells (hemosiderin-laden macrophages) in alveoli (macrophages phagocytize the intra-alveolar erythrocytes) CHF also produces nutmeg liver (due to central passive congestion, which is congestion in acinar zone 3 of liver) CHF can also produce pleural effusions (transudates) with clear yellow fluid and no cells (except for some mesothelial cells) B. hemorrhage petechiae are minute hemorrhages (< 2 mm); usually due to abnormality involving either platelets (thrombocytopenia) or blood vessels purpura ("purple spots") are hemorrhages that are 2 mm to 1 cm in size ecchymoses ("bruises") are large hemorrhages (> 1 cm) (in tissues may be called hematomas); usually due to trauma bleeding into body cavities: hemothorax, hemopericardium, hemoperitoneum (i.e. ascites), hemarthrosis (joints) C. hemostasis (clotting to control bleeding) first is transient arteriolar vasoconstriction (due to neurogenic mechanisms or local factors such as endothelin) then primary plug (primary hemostasis, due to platelets), then secondary plug (secondary hemostasis, due to coagulation cascade) note: hemostasis (clotting to control bleeding) is not the same thing as homeostasis
27. Endothelial

CHF

cells

A. pro-coagulation stimulates

effects extrinsic coagulation cascade by producing tissue factor (thromboplastin) major activator of the extrinsic clotting cascade stimulates platelets by producing vWF (von Willebrand factor) and PAF (platelet activating factor) inhibits fibrinolysis by producing t-PA (plasminogen activator) inhibitor B. anti-coagulation effects inhibits coagulation cascade by producing heparin-like molecules (which stimulate anti-thrombin III), protein C and S (inactivate Va and VIIIa), and thrombomodulin (modulates function of thrombin to instead activate protein C) inhibits platelets by producing prostacyclin (PGI2) and nitric oxide stimulates fibrinolysis by producing tissue-type plasminogen activators (t-PA)
28. Platelets A. platelet

steps of hemostasis 1. platelet adhesion (platelets adhere to exposed subendothelial collagen) GpIb on platelets binds to vWF (von Willebrand factor) which binds to subendothelial collagen decreased vWF is von Willebrand disease; decreased GpIb causes Bernard-Soulier syndrome 2. platelet activation involves 2 second messenger systems a) binding of GpIb to vWF bound to collagen stimulates PLA2 which forms thromboxane from arachidonic acid (inhibited by aspirin) b) binding to Gq (by ADP, thromboxane, thrombin) stimulates PLC to eventually form IP3 and DAG DAG stimulates phosphokinase C to cause release of alpha granules (fibrinogen, PDGF) and dense bodies (ADP and more) IP3 increases cytoplasmic calcium which causes movement and change of shape of platelets (which leads to platelet aggregation) 3. platelet aggregation forms the primary plug (primary hemostasis) platelet-to-platelet binding via fibrinogen binding to GpIIb/IIIa receptors (decreased GpIIb/IIIa seen with Glanzmanns thrombasthenia) platelet aggregation can be measured with a densitometer: as platelets aggregate, less light is scattered and the curve decreases a normal aggregation response of platelets to a potent platelet aggregating substance (like collagen) is a curve is that is split into 2 phases phase I is due to platelet aggregation in response to the substance that was added (like collagen) phase II results from platelets releasing substances (such as stored in dense bodies) that cause additional platelet aggregation

 platelet

aggregation is inhibited by aspirin and increased cAMP in platelets (which results from prostacyclin binding to Gs receptor) absence of phase II can result from absent platelet granules and decreased formation of these substances, such as by aspirin
29. Coagulation 1. the

cascade (secondary hemostasis)

A. pathways

division into two pathways is mainly an artifact of in vitro testing; the two pathways are highly interconnected 2. intrinsic pathway (now called contact activation pathway): measured by PTT (partial thromboplastin time) and includes (in order) factors XII, XI, and IX conversion of XII to XIIa is stimulated by exposure to a negatively charged surface (collagen, basement membrane, and endotoxin), this is the contact phase the primary complex on collagen is HMWK, prekallikrein and XII (Hageman factor) activation of XII is not required for hemostasis; patients with a deficiency of XII, prekallikrein, or HMWK do not bleed patients with XI deficiency have a mild bleeding disorder, possibly because thrombin feedback activation of XI is important XIIa in conjunction with HMWK activates XI (to XIa) XIa activates IX to IXa IXa in complex with VIIIa forms the intrinsic X-ase complex 3. extrinsic pathway (now called tissue factor pathway): primary pathway for the initiation of blood coagulation; main role is to generate a "thrombin burst" includes factor VII (conversation of VII to VIIa is stimulated by tissue factor) tissue factor (aka coagulation factor III) is a non-enzymatic lipoprotein expressed on cells such as fibroblasts and macrophages tissue factor bound to VIIa activates factor X; tissue factor bound to VIIa activates IX measured by PT (prothrombin time) 4. common pathway: measured by PTT and PT and includes factors X, V, prothrombin (II), and fibrinogen a) activation of factor X by dual pathways: either intrinsic path or extrinsic pathway extrinsic X-ase complex (calcium, VII, TF, and X) activates both X and IX intrinsic X-ase (tenase) complex (calcium, VIIIa, IX, and X) on the surface of platelets activates X factor V is released from platelet alpha granules during platelet activation b) formation of thrombin (II) from prothrombin (1) formation is stimulated by prothrombinase complex: Xa, V, calcium, PF3 (2) thrombin functions can be either pro-coagulation or anti-coagulation: thrombin activates its receptor through a proteolytic cleavage pro-coagulation functions include stimulating platelet aggregation and formation of fibrin activation of V, VIII, XI (perhaps why a XI deficiency can cause bleeding), XIII (to cross-link fibrin) anti-coagulation (when modulated by thrombomodulin) functions include activation of protein C note that thrombin can correct PTT in factor X deficiency, but won't correct abnormal PTT in fibrinogen deficiency c) formation of fibrin from fibrinogen (note that fibrin + primary plug forms the secondary plug) thrombin cleaves fibrinopeptides A and B from the N-terminal ends of the A-alpha and B-beta chains fibrin polymers are cross-linked by XIIIa (tertiary hemostasis; factor XIII is aka fibrin stabalizing factor) B. vitamin K-dependent factors (vit K is cofactor for the conversion of glutamic acid residues to gammacarboxyglutamic acid residues) 1. coagulation factors II, VII, IX, and X (also protein C and protein S) 2. Warfarin (Coumadin or dicumarol) inhibits vitamin K factors and prolongs PT and PTT; but use PT (PT/INR) as screening test for therapy add heparin (stimulates ATIII) initially with Coumadin therapy because the initial decrease in protein C and S will increase risk of clots C. general lab findings normal PTT with normal PT = normal finding (in a patient with bleeding problems, think thrombocytopenia, mild vWD deficiency, platelet dysfunction, and vascular disorders)

 abnormal normal

(prolonged) PTT with normal PT(INR) = abnormal intrinsic pathway (think factor VIII or vWD first) PTT with abnormal (prolonged) PT = abnormal extrinsic pathway (think factor VII) abnormal (prolonged) PTT with abnormal (prolonged) PT = abnormal common pathway (eg factor V)
30. Clearing

clots protease inhibitors 1. antithrombin III inactivates IXa, Xa, XIa,, XIIa,and thrombin heparin stimulates ATIII, which prolongs PTT, but with therapy look out for heparin-induce thrombocytopenia (paradoxically increased risk for thrombosis) note heparin is an anticoagulant proteoglycan in mast cells, but heparan is a proteoglycan found in the extracellular matrix 2. proteins C and S inactivate Va and VIIIa (deficiency associated with recurrent thromboemboli and recurrent spontaneous abortions) 3. C1 esterase inhibitor inhibits XIIa, XIa, and kallikrein (deficiency is seen in hereditary angioedema) 4. Tissue factor pathway inhibitor (TFPI) inactivates Xa and TF-VIIa B. fibrinolytic system: involves plasmin (which is formed from plasminogen) plasmin splits fibrin into fibrins split products (FSP) (aka fibrin degradation products, FDP), one of which is dimmer of the D region (D-dimer), and degrades fibrinogen, VIII, and V FSP are characteristically increased in DIC (disseminated intravascular coagulation); also increased with pulmonary embolus activators of plasminogen to plasmin (PA = plasminogen activators) include tissue type plasminogen activator (tPA), u-PA (urokinase), and streptokinase; keep in mind that there are also plasminogen activator inhibitors (PAIs) to balance out the plasminogen activators streptokinase can be used early to treat MI by lysis the clot (thrombus) that is occluding the coronary artery inhibitors of plasminogen include PA inhibitor produced by endothelial cells
A. plasma

31. Thrombosis A. a

thrombus is an intravascular blood clot; an extravascular blood clot is a hematoma B. risk factors for formation of thrombi = Virchow's triad: 1. endothelial damage (the dominant influence) normal endothelium is constitutively suppressing coagulation 2. abnormal blood flow such as stasis (major factor for venous thrombisis) and turbulence 3. hypercoagulable states a) primary (familial) deficiency of antithrombin III, protein C, or protein S (all associated with recurrent thromboemboli and spontaneous abortions) mutant coag factor V (Leiden mutation), which is very common and causes resistance of factor V to degradation by protein C elevated levels of prothrombin (due to mutation in prothrombin gene) or homocysteine (mutation in methyltetrahydrofolate gene) b) secondary (acquired) (1) associated with immobilization (bed rest, coach class syndrome), trauma/burns, pregnancy, cancer, smoking, birth control pills (estrogen is a procoagulant [promotes fibrinogen] necessary to prevent excess bleeding during childbirth) (2) heparin: heparin-induced thrombocytopenia (HIT) syndrome due to formation of anti-platelet antibodies; about 1% of patients will get thrombosis (HITT) related to use of unfractionabted heparin; instead us low-molecular weight heparins do NOT give platelets to pts with HITT (3) lupus anticoagulant lupus anticoagulant is an autoantibody against cardiolipin (anionic phospholipid similar to platelet factor 4 on platelets) these antibodies bind to the surface of platelets and make them "sticky" now is called antiphospholipid syndrome because the term "lupus anticoagulant" is a misnomer (it is not an anticoagulant, most patients with the antibody do not have lupus, and most patients with lupus dont have this antibody) characterized by recurrent venous or arterial thrombi, repeated miscarriages, cardiac valvular vegetations, thrombocytopenia

C. types

of thrombi thrombi head of thrombus has platelets and fibrin while tail of thrombus (downstream) has lines of Zahn (alternating layers of cells and platelets) are attached to blood vessel wall and may become organized (recanalization to restore blood flow) 2. postmortem thrombi no attachment to blood vessel wall currant jelly (many RBC's) and chicken fat (plasma without RBC's) appearance D. locations of thrombi 1. arterial thrombi common locations include heart (mural thrombi after MI's and rheumatic heart disease) and aorta (atherosclerosis and aneurysms) thrombosis of GI mesentery causes sudden intense abdominal pain that is worse than MI, but out of proportion to clinical findings (note that free air under diaphragm with x-ray = perforation)) 2. venous thrombosis (phlebothrombosis or thrombophlebitis) most venous thrombi occur in legs (superficial or deep veins) thrombosed external hemorrhoid (usually resolves spontaneously) may cause recurrent bright-red blood per rectum and painful swollen lump in anorectal region phlegmasia alba dolens is postpartum thrombosis of iliofemoral vein by gravid uterus (causes swelling of entire leg, painful white leg)
1. premortem 32. Emboli A. thrombotic 1. venous

emboli

site of origin is deep leg veins which embolize to lungs (pulmonary emboli) and cause chest pain, tachypnea, and dyspnea a saddle embolus is a large embolus that obstructs the bifurcation of the pulmonary arteries and causes sudden death larger PEs close to the pleura may cause inflammation that results in pleuritic chest pain (pain on inspiration) lung and liver are somewhat resistant to ischemic necrosis due to their dual blood supplies (e.g. pulmonary and bronchial arteries) 2. arterial (systemic) may originate in heart (mural thrombi after MI) or aorta, but are common in the legs and in the brain associated with atherosclerosis (cholesterol clefts are present microscopically) peripheral arterial embolism produces pain, pallor, paralysis, paresthesias, pulselessness (5 P's) and gangrene 3. paradoxical emboli are from systemic veins to systemic arteries (therefore need communication between veins and arteries, such as ASD) B. non-thrombotic emboli 1. fat emboli (stain for fat is oil red O or sudan black) secondary to major trauma (fracture of long bones) or liposuction fat embolism syndrome: pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia symptoms typically begin 1-3 days after injury: tachypnea, dyspnea, and tachycardia can be fatal because free fatty acids can damage endothelial cells and surfactant (ARDS) and also obstructs CNS blood flow 2. air emboli more than 100cc of low solubility gas in the bloodstream (C02 is a high solubility gas, so isnt a problem) obstetric complication (ruptured uterine veins) or complication of head and neck surgery acute disease is "the bends" (seen with divers surfacing too quickly), while chronic disease is called Caissons disease most common cause of pulmonary barotrauma is breath-holding during an ascent from a scuba dive; this can rupture air spaces by the expanding gas in the lungs and form air emboli 3. amniotic fluid emboli may result from complication of childbirth and cause disseminated intravascular coagulation (DIC has increased fibrin degradation products D dimers) microscopic reveals fetal squamous epithelial cells in the blood vessels in lung of the mom

common

to amniotic fluid retention in which squamous epithelial cells are present within the alveoli of the lungs of the fetus 4. bone marrow emboli are usually an incidental finding due to CPR that fractures ribs
33. Infarcts

compare

and shock

A. infarcts

= ischemic coagulative necrosis (except liquefactive necrosis in brain) infarcts pale or anemic infarcts result from arterial occlusion in solid organs (heart, spleen, and kidneys; chronic infarct in kidney seen as a depressed area) 3. red infarcts: may result from occlusion of veins or arteries classic example of hemorrhagic infarcts that result from venous occlusion are torsion of ovaries or testes (surgical emergency) hemorrhagic infarcts that result from arterial occlusion occur in loose tissue, congested tissue, or tissue with double circulation (dual circulation = liver and lungs; collateral circulation = small intestines and brain) note: in general thrombotic strokes in the CNS are white infarcts while emboli strokes are red (hemorrhagic) bilateral hemorrhagic infarction of adrenals is Waterhouse-Frederickson syndrome (due to N. meningitidis infection) B. shock 1. etiology (multiple types of shock) acute medical condition associated with a fall in blood pressure a) cardiogenic shock = decreased cardiac function due to MI, arrhythmia, tamponade, aortic stenosis (clinical: distended neck veins) b) hypovolemic shock = decreased blood volume due to hemorrhage, adrenal insufficiency, fluid loss (vomiting and diarrhea) c) septic shock = pooling of blood in peripheral vessels due to gram-negative bacterial endotoxins LPS binds to CD14 on monocytes and then to Toll-like receptor protein 4 (TLR-4) release of tumor necrosis factor, interleukin-1, and interleukin-6 systemic vasodilation, reduced myocardial contractility, endothelial injury and activation, DIC d) anaphylactic shock = pooling of blood in peripheral vessels due to vasoactive substances (IgE-mediated) (1) anaphylactoid reaction similar to anaphylactic shock, but not due to IgE e) neurogenic shock spinal cord injury or anesthetic accident causes loss of vascular tone and consequent pooling of blood 2. stages compensated stage = early hypotension; corrected by reflex tachycardia and peripheral vasoconstriction (cold, clammy, pale extremities) decompensated stage = decreased blood pressure, decreased renal output (oliguria), metabolic acidosis irreversible stage leads to coma and death 3. organ morphology heart may have hypercontraction bands of myocytes (irreversibly injured myocardial cells that are reperfused) lung may have hyaline membranes lining alveoli (ARDS or shock lung) kidney may develop acute tubular necrosis, while adrenal may have depletion of lipid in cortical cells ("stress response") 4. treatment dobutamine is a beta-1 agonist used to increase cardiac output by increasing contractility dopamine at low doses keeps the kidneys perfused norepinephrine is used for its alpha-1 agonist effects; it increases peripheral resistance to maintain perfusion to vital organs
2. white

1. infarcts

NEOPLASIA
34. Terminology

(benign): to name a neoplasm usually add "oma" to the end of the term describing the cell of origin of the

tumor A. epithelial origin 1. glands = adenoma

adenoma of thyroid or tubular adenoma of colon of breast, which is composed of stroma and ducts pleomorphic adenoma of the salivary glands, which is composed of more than one neoplastic cell type (ie, ducts in a myxoid stroma) cystadenomas (which may contain serous fluid or mucin) are typically found in the ovary 2. columnar epithelial cells may contain or secrete mucin (stains for mucin = mucicarmine and PAS) B. mesenchymal (non-epithelial) origin smooth muscle (mx: long cells with spindle-shaped nuclei) = leiomyoma (found in uterus and wall of stomach); MC benign tumor in women skeletal muscle = rhabdomyoma (mx: cross-striations, "spider cells", "strap cells" or "tadpole cells"); muscle stains red with trichrome fibroblasts (secrete collagen) = fibroma (special stain is trichrome) fat cells = lipoma (which has a fibrous capsule; if has lots blood vessels = angiolipoma) blood vessels = hemangioma (rbc's in lumen); angioma is a generic term referring to a tumor of vessels, either hemangioma or lymphangioma lymphatics = lymphangioma (lined by endothelial cells; no rbc's in lumen); a benign lymphangioma found in the neck is called a cystic hygroma C. other (confusing terms and more) polyp = "bump" (example is an adenomatous polyp of the colon); a pedunculated polyp has a stalk; a sessile polyp (flat) has no stalk villous (or papilloma) = papillary (finger-like) structures (example is a villous polyp of the colon or papilloma of larynx) teratoma (elements from all three germ cell lines: endoderm, ectoderm, and mesoderm) = benign teratoma (in ovary are usually cystic, called dermoid cyst) desmoid = abdominal fibromatosis in woman with previous C-section (mx shows spindle-shaped cells within dense collagenous tissue) melanocytes = nevus (actually composed of nevus cells, which are melanocytes which didnt quite complete their migration to the epidermis) mesothelial cells = benign mesothelioma (example is benign mesothelioma of lung) plasma cells = plasmacytoma (location outside marrow is upper respiratory tract; some patients may eventually develop multiple myeloma) hamartoma = right place, wrong structure (example is hamartoma of lung, which is composed of mature hyaline cartilage) choristoma = wrong place, right structure; ectopic rest (eg ectopic gastric epithelium in Meckel's diverticulum of distal ileum) chordoma = benign tumor originating from embryonic remnants of the primitive notochord
fibroadenoma 35. Terminology A. epithelial

follicular

(malignant) origin (malignancy = carcinoma) squamous epithelium = squamous cell carcinoma (keratin production and intercellular bridges; EM shows tonofilaments and desmosomes) glands (with lumens) = adenocarcinoma (mx: disorganized infiltrating glands in "back-to-back" arrangement) (stain with mucicarmine or PAS) transitional epithelium: urinary bladder or renal pelvis B. mesenchymal origin (malignancy = sarcoma) smooth muscle = leiomyosarcoma (count number of mitoses to differentiate benign and malignant smooth muscle neoplasms) skeletal muscle = rhabdomyosarcoma (contains desmin or actin); one type, found in the vagina of young females, is a sarcoma botryoides fibroblasts = fibrosarcoma (mx see "herringbone" pattern) fat cells = liposarcoma (contains lipoblasts, which have multiple cytoplasmic lipid vacuoles that indent the nucleus) blood vessels = hemangiosarcoma (note that the correct term is not hemangiocarcinoma) lymphatics = lymphangiosarcoma (note that the correct term is not lymphangiocarcinoma) nerves: neuroma or neurofibroma C. other (confusing terms and more)

= malignant teratoma (immature or neural elements) from a totipotent stem cell; the more differentiate the teratoma is, the more benign it becomes melanocytes = malignant melanoma plasma cells = multiple myeloma (mx shows greater than 20% plasma cells in bone marrow) lymphocytes = lymphoma (Hodgkins lymphoma or non-Hodgkins lymphoma) leukocytes = acute or chronic leukemia (acute leukemia contains blasts, which are immature cells having immature chromatin and nucleoli) acute promyelocytic leukemia: promyelocytes have lots of cytoplasmic granules that if released with therapy can cause DIC mesothelial cells = malignant mesothelioma (the development of mesotheliomas is associated with exposure to asbestos) clear cell carcinomas: kidney (renal cortex) and vagina signet cell carcinoma: stomach and ovaries note: most tumors in kids are "blastomas", eg retinoblastoma, neuroblastoma, nephroblastoma, hepatoblastoma, etc
teratoma 36. Benign

versus malignant neoplasms

A. general

are usually monoclonal proliferations, while polyclonal proliferations are usually reactive processes can be demonstrated in women heterozygous for polymorphic X-linked markers (eg glucose-6phosphate dehydrogenase) random X chromosome inactivation implies polyclonality, while non-random X chromosome inactivation implies monoclonality in normal tissue (polyclonal) the X chromosome is randomly inactivated, but in neoplasms (monoclonal) it is non-randomly inactivated can examine immunoglobulin heavy chain genes to assess clonality of B lymphocytes; TCR-alpha gene for clonality of T lymphocytes note for calico cat: the genes controlling coat color are on the X chromosome; the X inactivation is relatively large for coat color; different colors (polyclonal) can be seen grossly B. benign tumors histology reveals uniform appearance (no pleomorphism) and well-differentiated (they closely resemble the cell of origin) slow growth (mitoses are scant); are well circumscribed (well demarcated) and may have fibrous capsule do not invade tissue, blood vessels, or lymphatics; remain localized (don't metastasize), C. malignant tumors 1. rapid growth that is not uniform and not differentiated (pleomorphic histology, which, at extreme = anaplasia, which is very bad) rapid growth is associated with the presence of mitoses and nucleoli (both can be seen in reactive processes, such as granulation tissue) cancers have atypical mitoses such as tripolar, tetrapolar, and pentapolar mitoses (normal mitosis is bipolar) needs new blood vessels (angiogenesis); angiogenic factors include vascular endothelial growth factor and basic fibroblast growth factor 2. dysplasia ("disordered growth") abnormal cell growth that is theoretically reversible and commonly preneoplastic (premalignant) sequence: normal; metaplasia or hyperplasia; dysplasia (intraepithelial); carcinoma in-situ (CIS; no invasion); invasive malignancy; mets mild dysplasia then moderate dysplasia then severe dysplasia (distinguish by location of mitoses and degree of atypia) mitoses: mild dysplasia has mitoses in lower third of epithelium; moderate dysplasia in middle third; severe dysplasia in upper third dysplasia of cervix is due to HPV (human papillomavirus) infection and is called cervical intraepithelial neoplasia (CIN) full-thickness involvement of epithelium without maturation or invasion is called carcinoma in-situ (not reversible like dysplasia) 3. locally invasive; irregular, infiltrative "crab-like" growth with no capsule (cancer means "crab-like") benign tumors tend to grow as cohesive masses with well-defined borders
monoclonality

neoplasms

include adhesion to and invasion through basement membrane, passage through extracellular matrix, and invasion into blood vessels matrix metalloproteinases (eg type IV collagenase) degrade the basement membrane and extracellular matrix and allow tumor invasion perineural invasion seen with adenoid cystic carcinoma of parotid and cancer of prostate or pancreas 4. capable of metastasis a) gross of organ with multiple masses usually indicates metastases (single mass is usually primary) b) spread is via blood vessels (hematologic spread) or lymph vessel (lymphatic spread) or seeding of body cavities and surfaces c) hematologic spread is more characteristic of sarcomas, while lymphatic spread is more characteristic of carcinomas (much overlap) d) lymphatic spread subcapsular sinus may be first site of microscopic implantation in a lymph node sentinel node: the first node in a regional area that receives lymph flow from a primary tumor e) pattern of lymph node involvement follows natural routes of lymphatic drainage; examples: breast cancers: usually start in upper outer quadrant; metastasize to axillary lymph nodes (not the internal mammary arteries) enlarged cervical lymph nodes, sentinel nodes, may be the initial presentation of an abdominal malignancy cancers of the external male genitalia first metastasize to regional inguinal lymph nodes testicular cancers metastasize to periaortic lymph nodes (not inguinal lymph nodes) f) induration of the rectal pouch may be due to "seeding" from an ovarian tumor g) All tumors (except basal cell carcinoma and gliomas) will metastasize
37. Epidemiology A. incidence

steps

= number of new cases per year; prevalence = number of cases in population at a given time (ignoring skin and CIS; skin cancer is the MC cancer) male = prostate > lung (most common cause of death) > colon female = breast > lung (most common cause of death) > colon most common cancer in kids is leukemia (most common cause of death in kids is automobiles) stomach cancer rate is decreasing; lung cancer rate is increasing B. geography Central Africa has high incidence of liver cancer (secondary to hepatitis B infection and aflatoxin, which is secreted by aspergillus flavus) India and China has high incidence of nasopharyngeal carcinoma (secondary to EBV) China also has high incidence of hydatidiform mole (a gestational abnormality) Japan has gastric cancer (due to smoked foods) and ATLL (secondary to HTLV-1) C. predisposition 1. hereditary (examples) autosomal dominant inherited cancer syndromes: childhood retinoblastoma (RB gene), familial polyposis coli (APC gene), Li-Fraumeni syndrome (p53 gene), multiple endocrine neoplasias (MEN1 and RET genes), hereditary nonpolyposis colon cancer (MSH2, LMH1, and MSH6 genes), nevoid basal cell carcinoma syndrome (PATCH gene) defective DNA repair syndromes (see below): usually autosomal recessive, except for hereditary nonpolyposis colon cancer familial cancers (multiple genes): breast cancer, ovarian cancer, pancreatic cancer 2. non-hereditary (examples) actinic keratosis: squamous cell carcinoma of the skin pernicious anemia (chronic atrophic gastritis): gastric adenocarcinoma H. pylori infection: gastric adenocarcinoma of the intestinal type chronic gastric reflux (Barrett's esophagus): adenocarcinoma of esophagus ulcerative colitis: adenocarcinoma of the colon cirrhosis: hepatocellular carcinoma (hepatoma)
2. rates 38. Control

1. incidence

of cell cycle

A. substances 1. cyclins

are produced at varying amounts during cell cycle (ie, they cycle) are unstable and degraded through the ubiquitin-proteasome pathway examples of cyclins: a G1 cyclin is cyclin D; S-phase cyclins include cyclins E and A; a mitotic cyclin is cyclin B cyclin D (bcl-1) is located on chromosome 11 and inc expression in mantle cell lymphoma due to t(11;14) during G1 cyclin D binds to and activates CDK4 forming a cyclin D-CDK4 complex, which has critical role controlling RB gene 2. cyclin-dependent kinases (CDKs) constitutively expressed but inactive (activated by cyclins and phosphorylation) examples of CDKs: a G1 CDK is CDK4; an S-phase CDK is CDK2; an M-phase CDK is CDK1 CDK4 froms a complex with cyclin D (as above) (remember aid: D is the 4th letter in the alphabet) CDK2 forms a complex with cyclin E in lage G1; forms a complex with cyclin A at the S phase CDK1 forms a complex with cyclin B, which acts on the G2/M transition 3. inhibitors of CDKs (CDKI's): a) Cip/Kip family broad inhibitors, such as p21 (production is increased by p53), p27 (responds to TGF-beta), p57 b) INK4/ARF family p16INK4a binds to cyclin D-CDK4 and inhibits the ability of cyclin D-CDK4 complex to phosphorylate RB p14ARF increases p53 levels by inhibiting MDM2 activity B. checkpoints 1. G1/S transition (DNA damage checkpoint): a) Rb protein (pRb) (1) unphosphorylated pRb is active and binds to E2f (cell cycle stops between G1 and S) (2) phosphorylated pRb (pRb-P) is inactive phosphorylated by cyclins, such as cyclinD/CDK4, CDK6 and cyclinE/CDK2 (active when phosphorylated) pRb-P releases E2F, which then binds to E2F site and activates S phase genes (and cell cycle continues) pRb-P is converted back to pRb during the M phase b) p53 (1) normally p53 protein level is low; increased by DNA damage through an ATM-dependent pathway ATM (ataxia-telangiectasia mutated) senses double stranded DNA breaks (2) three major functions: growth arrest, DNA repair, apoptosis (3) stops cell-cycle by increased production of p21, which inhibits Cdk2, or GADD45, which inhibits Cdc2 (4) induces apoptosis (a) if DNA damage is corrected then increased mdm2 (murine double minute 2) mdm2 is the major regulator of p53; it destroys p53 via ubiquitin/proteasome-dependent degradation (no apoptosis) amplification of the human homolog of mdm2 has been found in some human tumors (b) if DNA damage is not corrected then increased bax (inhibits bcl-2) and IGF-BP3 (which blocks IGF) (5) p53 can also activate mir-34, a micro RNA that inhibits translation of both growth-promoting genes and anti-apoptosis genes (6) radiotherapy is better if p53 activity is maintained (and p53 not mutated) (7) familial (germline) mutations of p53 seen in Li-Fraumeni syndrome c) CDK inhibitors of the Cip/Kip (p21, p27) and INK4/ARK (p16INK4a, p14ARK) families are tumor suppressors that oppose cycling 2. between S and G2 = cyclinA/CDK2, CDK1 3. G2/M transition (mitosis entry checkpoint)= cyclinB/CDK1 (phosphorylated product is active) cyclin B is synthesized as cell moves into G2 cyclin B binds to constitutive CDK1 (aka cdc2) forming cyclin B/CDK1 complex, which is activated by phosphorylation and enables the cell to enter M
they

cyclins

 after C. other

4. anaphase

mitotic division, cyclin B is degraded by the ubiquitin-proteasome pathway (in the proteasome) (spindle assembly checkpoint): Mad2/Bub1 inhibits APC

notes

increased

cell proliferation by increased cyclins (such as increased cyclin D), increased CDKs, or decreased inhibitors (eg., p16) most malignancies have mutations involving either p16, cyclin D, CDK4 or Rb
39. Oncogenes A. general

activating mutations are dominant (only need activation of one gene to get an effect)

are genes that are associated with neoplasia p-onc = proto-oncogenes, which are genes coding for normal growth and differentiation c-onc = cellular (cancer) oncogene v-onc = same genes within viruses (certain types of retroviruses) 2. mechanisms changing normal p-onc to abnormal c-onc include retroviruses and chromosomal abnormalities B. expression 1. growth factors: c-sis codes for beta chain of platelet derived growth factor; overexpressed with astrocytomas and osteogenic sarcomas hst-1 and int-2 code for fibroblast growth factors; overexpressed in some GI and breast cancers 2. growth factor receptors c-erb B1 and c-erb B2 (c-neu) code for epidermal growth factor receptor; overexpressed with breast CA and lung squamous cell CA c-fms codes for receptor for colony stimulating factor, CSF; point mutation associated with leukemia RET codes for receptor for glial cell line-derived neurotrophic factor; point mutations associated with MEN types 2A and 2B KIT codes for stem cell (steel) factor receptor; point mutations associated with stromal tumors of the GI tract 3. abnormal membrane protein kinase: c-abl codes for membrane non-receptor associated tyrosine kinase; translocation associated with chronic myelocytic leukemia (CML) causes constitutive expression of the tyrosine-kinase; inhibited by Gleevec 4. GTP-binding proteins (c-ras) c-ras codes for RAS protein, which excites MAP kinase pathway by recruiting cytosolic raf-1 RAS protein is anchored to cell membrane by farnesyl moiety (inhibited by farnesyl transferase) like all G proteins, RAS protein is inactive when bound to GDP, active when bound to GTP, and has intrinsic GTPase activity when active the function of RAS protein-GTP is greatly enhanced by binding to GAP (GTPase activating protein) binding to GAP also increases RAS protein-GTP inactivating itself; this is inhibited by point mutations in cras mutations of ras gene are the single most common oncogene abnormality carcinomas have mutations of KRAS; bladder tumors have HRAS mutations; hematopoietic tumors have NRAS mutations neurofibromin is a type of GAP found in neural tissue that binds to p21; abnormal neurofibromin is seen with neurofibromatosis I 5. nuclear transcription factors c-myc: translocated in Burkitt's lymphoma N-myc: amplified in neuroblastoma L-myc: amplified in small cell carcinoma of the lung
40. Anti-oncogenes A. general

1. oncogenes

recessive (need inactivation of both genes)

are tumor suppressor genes that normally regulate signal transduction or nuclear transcription of anti-oncogenes may result in the formation of tumors (possibly multiple) B. Rb (chromosome 13q) is associated with the development of retinoblastoma and osteogenic sarcoma 1. tumors result from deletion of 13q (loss of retinoblastoma anti-oncogene which normally stops cell cycle between G1 and S phases) note: SV40 and HPV E7 protein bind to pRb and stop it from binding to E2F (functionally inactive) 2. two hit hypothesis of Knudsen
deletions

anti-oncogenes

hit is first deletion (either inherited in germ line cells in the familial form, or sporadic somatic mutation in the sporadic form) one hit (heterozygosity) does not affect cell behavior; need two hits for tumor development second hit is second deletion (somatic mutation in both familial and sporadic cases); results in loss of heterozygosity (LOH) sporadic form associated with single (unilateral) tumors; familial form associated with multiple (and bilateral) tumors 3. retinoblastoma produces leukocoria (white pupil) in child because the mass inhibits normal red reflex (mx see a "small blue cell" tumor) C. p53 (chromosome 17q); see cell cycle checkpoints normally regulates damaged DNA by stopping cell cycle during G1 ("molecular policeman") by increased production of p21 or GADD45 associated with many tumors and also the Li-Fraumeni syndrome (familial inheritance of multiple tumors at young age) D. APC/beta-catenin pathway: APC and beta-catenin are components of the WNT signaling pathway; normally beta-catenin is down-regulated by APC and levels are low stimulation by WNT molecules or mutations of APC are associated with increased intracellular beta-catenin levels in the nucleus beta-catenin forms a complex with TCF and increases transcription of c-MYC, cyclin D1 and other genes dysregulation of APC/beta-catenin seen with colon cancer (familial adenomatous polyposis) and liver cancers postulated sequence for development of colon cancer: normal epithelium; hyperproliferative epithelium (due to mutation of APC); early adenoma (due to loss of DNA methylation); intermediate adenoma (due to mutation of ras); late adenoma (due to loss of DCC); carcinoma (due to loss of p53) E. INK4a/ARF locus: familial melanoma, pancreatic adenocarcinoma, and esophageal squamous cell carcinoma F. TGF-beta pathway: colon cancers, gastric cancers, pancreatic cancers G. BRCA-1 and BRCA-2: involved with transcriptional regulation and DNA repair; mutation associated with breast cancer and ovarian cancer H. NF-1 (chromosome 17): neurofibromatosis type 1 (abnormal neurofibromin, a type of GAP in neural tissue) I. NF-2 (chromosome 22); product is merlin (which has homology with RBC protein 4.1); neurofibromatosis type 2 (bilateral acoustic neuromas) J. VHL: renal cell carcinoma (von Hippel-Lindau disease) K. PTEN: endometrial cancers and glioblastomas; normally PTEN blocks cell cycle by increasing p27; Cowden syndrome L. WT-1 (chromosome 11p) : deletion of WT-1 tumor suppressor gene is associated with Wilms' tumor and aniridia (no iris) M. cadherins: germ line mutations of the E-cadherin gene can predispose to familial gastrc carcinoma N. Patched (PTCH): mutations seen with Gorlin (nevoid basal cell carcinoma) syndrome; normally functions as a receptor for Hedgehog proteins
41. DNA

first

repair defects and hereditary syndromes repair defect 1. hereditary nonpolyposis cancer (HNPCC) syndrome autosomal dominant abnormal DNA mismatch repair genes; microsatellite instability is a hallmark of defective mismatch repair microsatellites are tandem repeats of one to six nucleotides scattered throughout the genome germline mutations in MSH2, MLH1, PMS, and PMS2 genes associated with familial cancers of the colon (cecum and proximal colon) B. nucleotide excision repair defect 1. xeroderma pigmentosa decreased endonuclease causing defect in repairing pyrimidine (thymidine) dimers caused by UV light individuals develop multiple skin cancers in sun exposed skin C. homologous recombination defects HR is the only way to repair large defects in DNA uses intact DNA as a copy to repair the damaged copy 1. ataxia telangiectasia
A. mismatch

in ATM gene; individuals are sensitive to x-rays (increased risk lymphoid malignancies and leukemia) Purkinje cell loss; immunodeficiency recurrent infections (due to decreased IgA levels), oculocutaneous telangiectasia, cerebellar ataxia; and hypogonadism think if child presents with recurrent sinopulmonary infections + unsteadiness walking 2. Fanconis anemia increased sensitivity to DNA cross-linking agents (increased risk of leukemia) hypoplastic thumbs and radii other signs: anemia (pancytopenia) with mental retardation, small eyes, small genitalia, and renal abnormalities 3. Blooms syndrome severe immunodeficiency, growth retardation, and increased sensitivity to radiation (increased risk of many different types of cancers) short stature, "parrot"-beak nose, and facial ("butterfly") rash cell cultures reveals quadriradial configurations and increased sister chromatid exchange defect involving BLM helicase, which normally participates in DNA repair by homologous recombination
42. Chromosomal A. point

mutations

changes mutations c-ras normally codes for monomeric G-protein p21 and point mutations are associated with adenocarcinomas ret is associated with multiple endocrine neoplasia types II, III B. translocations t(9;22): c-abl on chromosome 9 associated with CML t(8;14): c-myc on chromosome 8 associated with Burkitt's lymphoma t(14;18): bcl-2 on chromosome 18 (activation inhibits apoptosis) associated with nodular (follicular) nonHodgkins lymphoma t(11;14): bcl-1 (cyclin D1) on chromosome 11; associated with mantle cell lymphoma t(11;22): EWS gene on chromosome 22; associated with Ewing sarcoma of bone C. gene amplifications 1. N-myc forms homogenous staining regions (HSR) and double minutes (small, chromosome-like structures) associated with neuroblastoma, an adrenal medullary tumor of children (think the "N" in N-myc standing for neuroblastoma) the amount of amplification of N-myc is proportional to the prognosis 2. c-neu or c-erb B2: breast, ovarian, and gastric cancer D. epigenetic changes tumor suppressor genes may be silenced by hypermethylation of promoter sequences without a change in DNA base sequence

43. Chemicals A. initiators 1. general

produce irreversible changes in cells, such as mutations (they affect DNA), but alone are not sufficient to induce tumors need appropriate dose for initiator to have effect, but small doses can accumulate with time may be direct acting, or may need to be activated (eg, by microsomal cytochrome P-450-dependent monooxidase in SER of hepatocytes) 2. examples alkylating agents (anti-cancer drugs) aromatic hydrocarbons include tobacco smoke (many tumors), benzene (leukemias), vinyl chloride (angiosarcomas of the liver) aromatic amines, such as beta-naphthylamine (associated with cancer of the urinary bladder) azo dyes (associated with tumors of the liver) aflatoxin is produced by moldy peanuts with Aspergillus flavus (associated with hepatoma) asbestos (associated with mesotheliomas and lung tumors) arsenic (?in drinking water) (associated with skin, bladder, and lung cancer; ??kidney/liver)

initiators

increase growth rates, have a threshold level, effect is reversible (with time), cant cause tumors alone, and must come after initiation examples include saccharin (bladder cancer in rats) and hormones (estrogen and DES [diethylstilbestrol], which has estrogenic properties) any prolonged abnormal proliferation of cells is associated with an increased risk of malignancy C. potential carcinogens are screened by the Ames test which detects mutagenic effects on bacteria cultures
B. promoters: 44. Radiation UV

and viruses

A. radiation

radiation (UVB) produces pyrimidine (thymine) dimers in DNA (normally these are fixed by nucleotide excision repair pathway) UVB has shorter wavelength (more energy/photon); UVC is filtered by ozone ionizing radiation (x-rays and gamma rays) cause breaks in nucleic acids radon is associated with lung cancer in non-smokers (check basements for radon) hierarchy of susceptibility: leukemia > thyroid > breast, lung, salivary gland > skin, bone, GI tract B. viruses 1. DNA viruses a) HPV (different subtypes): histologically see koilocytosis (shrunken, shriveled nuclei surrounded by clear space) cervical neoplasia (types 16 and 18) condyloma (types 6 and 11) verruca vulgaris penile carcinoma (seen particularly in homosexual males) and anal carcinoma juvenile laryngeal papillomatosis b) EBV African Burkitt's lymphoma (small noncleaved non-Hodgkin's lymphoma) carcinoma of the nasopharynx (normal epithelial cells in pharynx have EBV receptors, which is CD21) B cell immunoblastic lymphoma (especially those that develop with immunosuppression after tissue transplantation) c) hepatitis B and hepatitis C are associated with liver cancer (hepatocellular carcinoma) d) HHV 8 (Kaposi sarcoma-associated herpesvirus) is associated with Kaposi's sarcoma 2. RNA viruses: retroviruses RNA-viruses that have unique features such as reverse transcriptase and long terminal repeats, which activate adjacent genes) acute transforming viruses carry their own oncogene (v-onc) through a process called transduction slow transforming viruses need to find a p-onc to activate (through a process called insertional mutagenesis) other retroviruses carry unique genes (Tax and Rex) such as HTLV-1; Tax gene upregulates interleukin-2 production HTLV-1 is associated with adult T cell leukemia/lymphoma (malignancy of CD4 T lymphocytes endemic in Southern Japan and Caribbean characterized by skin rash, hypercalcemia, and multilobated [cloverleaf] lymphocytes)
45. Host

defenses antigens products of mutated oncogenes and tumor suppressor genes (eg RAS, p53, and BCR-ABL proteins) products of other mutated genes abnormally expressed cellular proteins (tyrosinase and MART in melanomas; cancer-testis antigens MAGE and BAGE) oncofetal antigens: CEA (carcinoembryonic antigen) and AFP (alpha-fetoprotein) altered cell-surface glycolipids and glycoproteins (eg CA-125 and CA-19-9) cell-type specific differentiation antigens: example is lymphomas and CD markers B. antitumor effector mechanisms: cytotoxic T lymphocytes, natural killer cells, macrophages, antibodies C. mechanisms of escape from surveillance antigen-negative variants, decreased expression of MHC molecules, immunosuppression, antigen masking, apoptosis of cytotoxic T cells
A. tumor

46. Paraneoplastic

syndromes (syndromes that are not due to mass effect of tumor or metastases; may result from ectopic production of hormones, etc) A. skin: acanthosis nigricans (pigmented axilla) may be associated with visceral malignancies; also associated with obesity and insulin resistance B. endocrine Cushing's syndrome (increased cortisol or increased ACTH) is associated with lung cancer (small cell carcinoma) carcinoid syndrome (inc serotonin stimulates smooth muscle causing facial flushing, wheezing, and diarrhea) is associated with carcinoid tumor of the SI SIADH (syndrome of inappropriate ADH secretion) (also ANP) is associated with lung cancer and intracranial neoplasms hypercalcemia (increased PTH-related peptide) is associated with lung cancer or multiple myeloma hypoglycemia (secretion of insulin-like substances) is associated with liver cancer and tumors of the mesothelium (mesotheliomas) polycythemia (erythropoietin) is associated with kidney tumors, liver tumors, and cerebellar vascular tumors (cerebellar hemangioblastoma) C. neurologic: myasthenia gravis is associated with thymoma, bronchogenic cancer produces muscle weakness D. bone and joints: hypertrophic osteoarthropathy (clubbing of fingers) may be associated with lung cancer or lung disease in general characterized by proliferation of skin and osseus tissue at distal parts of the extremities; caused by elevated PGE2; more common with adenocarcinoma of the lung, as opposed to small cell carcinoma of the lung; periostosis of long bones, synovial effusions of large joints E. coagulation endocardial valvular vegetations (called marantic endocarditis, from marasmus which means starvation, or nonbacterial thrombotic endocarditis) can be seen in patients with end-stage disseminated cancer (carcinomatosis) migratory thrombophlebitis (venous thrombosis - Trousseau's syndrome): carcinoma of the pancreas (usually adenocarcinoma of head of pancreas), bronchogenic carcinoma DIC: adenocarcinomas and acute promyelocytic leukemia (M3-AML) versus stage (grade is histology; stage is clinical) degrees of differentiation = GRADE of tumor (also related to number of mitoses); the grade correlates well with prognosis well-differentiated (good prognosis) moderately-differentiated (intermediate prognosis) poorly-differentiated (bad prognosis); anaplasia is very bad; undifferentiated (primitive) cells are also high grade B. clinical extent or spread of malignancy = STAGE of tumor more prognostic value than grade (usually): low number (stage I) is good prognosis, while high number (stage IV with mets) is bad prognosis TNM staging: T=tumor size; N=lymph node status (# of lymph node mets); M=# of non-lymph node metastases AJC (American Joint Committee) system: stages 0 to IV
A. variable

47. Grade

48. Clinical/laboratory

diagnosis (including tumor markers) A. cytology: PAP smear, FNA (fine needle aspiration) B. immunocytochemistry/tumor markers 1. beta-hCG (human chorionic gonadotropin) gestational trophoblastic disease (eg. choriocarcinoma, hydatidiform mole) certain germ cell tumors of the ovaries and testes: dysgerminomas and seminoma (10% of cases) 2. AFP (alpha-fetoprotein): liver cancer and germ cell tumors (eg. yolk sac tumors, embryonal carcinoma, NOT seminoma) 3. PSA (prostate specific antigen): adenocarcinoma of prostate and some cases of BPH (benign prostatic hyperplasia) 4. PAP (prostatic acid phosphatase): adenocarcinomas of prostate that extend beyond the prostate capsule (stage C or D) 5. CEA (carcinoembryonic antigen); don't confuse with CAE, chloroacetate esterase, a histochemical stain used to differentiate acute leukemias adenocarcinomas of colon, pancreas, stomach, lung, and breast (nonspecific marker) used to monitor recurrence for colon adenocarcinoma

ovarian cancer melanoma, neural tumors, and astrocytomas 8. HMB-45: malignant melanoma 9. intermediate filaments keratin: all epithelial cells (carcinomas) vimentin: mesenchymal cells (sarcomas) desmin: muscle cells (uterine leiomyomas, rhabdomyomas) neurofilament: neurons and neural crest derivatives (pheochromocytomas, neuroblastomas) glial fibrillary acidic protein (GFAP): glial cells (astrocytomas, ependymomas) C. EM (electron microscopy): may be useful in diagnosis of poorly-differentiated malignancies membrane-bound dense core neurosecretory bodies are found in many "neuroendocrine" tumors such as neuroblastoma, carcinoid, and small cell carcinoma of the lung; contain synaptophysin and chromogranin A desmosomes and tonofilaments are characteristically seen in squamous cell carcinomas microvilli of adenocarcinomas are characteristically short, blunted, and have a terminal web microvilli of lymphoid tumors lack a terminal web D. other: benign pituitary adenomas may impinge on optic chiasm and produce loss of vision in both temporal fields of vision (tunnel vision)
7. S-100:

6. CA-125:

BLOOD VESSELS
49. Review/congenital A. arteries types

abnormalities

of arteries include large elastic (aorta and branches), medium muscular, and small arteries or arterioles (<2mm) composition includes tunica intima, internal elastic lamina, tunica media, external elastic lamina, tunica adventitia (contains vasa vasora) arterioles regulate blood pressure (they are the princpal resistance to blood flow) B. capillaries types of capillaries include continuous, fenestrated (eg glomeruli), and discontinuous (sinusoids of liver, spleen, and bone marrow) composition includes endothelial cells, basement membrane (type IV collagen), and pericytes functions include: respond to inflammatory mediators, convert angiotensin I into angiotensin II, breakdown lipoproteins, release prostacyclin C. veins thin wall (because of lower pressure), no internal elastic lamina, may have valves post-capillary venules in lymph nodes may have high (cuboidal) endothelial cells (HEV) HEV have CD34 on their surface that reacts to L-selectin on certain types of lymphocytes (reason certain lymphocytes home to lymph nodes) veins regulate distribution of blood volume (increased permeability of veins with inflammation) portal veins connect capillaries to capillaries (eg portal vein to liver, portal vein supplying anterior pituitary) D. lymphatics: thin wall, lined by endothelial cells, has valves, no red cells in lumen E. cells 1. endothelial cells (ECs) immunohistologic stains that identify ECs include CD31 (PECAM-1), CD34, and vWF (von Willebrand factor) contain Weibel-Palade bodies (which contain vWF) 2. vascular smooth muscle cells (SMCs) responsible for vasoconstriction and dilation in response to various stimuli vascular injury stimulates SMC growth; formation of neointima (intimal thickening) by SMCs in response to injury F. AV fistulas (can be either congenital or acquired): sx is pulsatile mass (pressing may cause bradycardia and an increase in diastolic blood pressure) causes of acquired AV fistulas include penetrating injuries, Pagets disease of bone, rupture of an aneurysm, and arterial graft penetrating injuries are the most common cause (and the most commonly associated penetrating injury is from a knife)

50. Atherosclerosis

(general) = generic term for thickening and hardening of the arteries 1. types include arteriolosclerosis, Monckeberg's medial calcific sclerosis, and atherosclerosis (which has atheromas) 2. Monckeberg's arteriosclerosis patients older than 50 medial calcific sclerosis (pipestem appearance grossly); no decrease in lumen (therefore no clinical symptoms) no inflammation and no involvement of intima or adventitia B. atherosclerosis is a disease of elastic arteries and large or medium-sized muscular arteries C. locations for atherosclerosis: abdominal aorta > coronary artery > popliteal artery > carotid artery D. sequence of events (American Heart Association types): 1. type I (initial) lesion: isolated macrophage foam cells 2. type II (fatty streak) lesion: mainly intracellular lipid accumulation fatty streaks are the earliest lesion of atherosclerosis 3. type II (intermediate) lesion: type II lesion with small extracellular lipid deposits 4. type IV (atheroma) lesion: type II lesion with core of extracellular lipid 5. type V (fibroatheroma) lesion: simple plaques are composed of fibrous cap, cellular zone (smooth muscle cells, macrophages) and central core (necrotic cells, cholesterol clefts, foam cells) 6. type VI (complicated) lesion: complicated plaques have calcification, fissures, ulceration, hemorrhage (cause thrombosis and arterial emboli) E. clinical signs of atherosclerosis include angina, claudication (muscle pain), cold-numb extremities, decreased peripheral pulses and arterial bruits
A. arteriosclerosis

51. Risk

factors for atherosclerosis risk factors: 1. potentially controllable a) hypertension (diastolic elevation), which damages endothelial cells b) smoking (damages endothelial cells, decreases HDL, increases fibrinogen and PA inhibitor) c) DM (increased TG and VLDL, increased vWF and thromboxane, decreased HDL, prostacyclin, plasminogen activator, nitric oxide) d) hyperlipidemia (the most important factor for individuals younger than 45): increased cholesterol, LDL (bad) cholesterol, triglyceride are bad; increased HDL (good cholesterol) decreases risk 2. nonmodifable: increasing age, male gender, family history, genetic abnormalities B. minor risk factors include 1. lack of exercise, obesity, birth control pills 2. estrogen increases TG, increases HDL, decreases LDL (increased HDL:LDL, which is good) increased liver synthesis of II, VII, IX, X, decreased ATIII, which increases risk of thrombosis post-menopausal rx with estrogen/progesterone: increased MI first year (due to increased risk thrombosis), decreased MI afterwards (due to increased HDL:LDL ratio) 3. increased homocystine = homocystinuria (??etiology may be antibody to chlamydia pneumoniae) may result from enzyme deficiency: decreased cystathionine synthetase increases methionine and decreases cystathionine; decreased methyl tetrahydrofolate reductase or methyl transferase decreases methionine and increases cystathionine note that increased homocysteine may result from high protein diets with decreased pyridoxine (vit B6), vit B12, and folate homocysteine binds to LDL through disulfide bonds causing LDL to aggregate and precipitate in vessels causing atherosclerosis signs include atherosclerosis, subluxed lens (ddx is Marfan syndrome), osteoporosis, thrombosis, mental retardation 4. lipoprotein (a) lipoprotein(a) is an altered form of LDL that contains the apoprotein B100 linked to apoprotein(a)
A. major

has structural homology to plasminogen; the similar areas are called kringles (because they look similar to a type of Danish pastry) Lp(a) competes with plasminogen in clots, this competition decreases the ability of plasminogen to form plasmin and clear clots increased blood levels of lipoprotein(a) are related to increased risk of coronary and cerebral vascular disease 5. CRP (C-reactive protein): increased CRP levels are associated with increased risk for stroke or myocardial infarction 6. Type-A personality
52. Pathogenesis

lipoprotein(a)

of atherosclerosis (response to injury hypothesis) damage secondary to increased lipids (hyperlipidemia or diabetes), increased blood pressure, or smoking results in increased vascular permeability and increased adhesion of leukocytes (monocytes) B. influx of monocytes: monocytes adhere to damaged endothelial surface and enter intima where they transform into macrophages and accumulate lipid (oxidized LDL or oxidized VLDL, which can be produced by free radicals) through the scavenger pathway to form foam cells vitamin E, an anti-oxidant, may become incorporated into lipoproteins and prevent the oxidation of unsaturated free fatty acids C. smooth muscle proliferation smooth muscle cells accumulate lipid to form foam cells and excrete extracellular matrix material (collagen and proteoglycans) increased growth promoters for smooth muscle cells, such as platelet derived growth factors (PDGF) and basic fibroblast growth factor (BFGF) decreased growth inhibitors for smooth muscle cells, such as beta-TGF (transforming growth factor) from macrophages and endothelial cells, and heparin-like molecules from endothelial cells and smooth muscle cells Intimal thickening neointima by SMCs in response to injury (can be observed as part of normal aging)
A. endothelial

53. Hypertensive

vascular disease

A. definitions

(HBP) is blood pressure greater than 140/90mmHg as taken on three separate occasions hypertension is hypertension with blood pressure less than 210/120mmHg; first treatment is lifestyle modifications hypertensive urgency is blood pressure greater than 210/120mmHg without symptoms hypertensive emergency is blood pressure greater than 210/120mmHg with symptoms or end-organ damage B. causes most cases (more than 90%) are idiopathic, multifactorial, or essential (primary) hypertension causes of secondary HBP ("CHAPS") = Cushing syndrome, hyperaldosteroneism, aortic coarctation, pheochromocytoma, renal artery stenosis Cushing syndrome is associated with steroid-mediated retention of sodium in the kidneys (renin and angiotensin are not involved) in younger men, MC cause of secondary hypertension is excessive alcohol intake in younger women, MC cause of secondary hypertension is taking birth control pills (second is renal artery stenosis) the MC cause of death in individuals with untreated hypertension is coronary artery disease C. regulation of normal blood pressure 1. blood pressure is proportional to cardiac output and peripheral vascular resistance 2. role of kidneys: renin (from the JGA) converts angiotensinogen to angiotensin I decreased GFR increases sodium reabsorption by proximal tubules natriuretic peptides inhibit sodium reabsorption in distal tubules (increase sodium excretion and diuresis) D. involvement of small muscular arteries = arteriolosclerosis 1. hyaline arteriolosclerosis = hyaline change due to blood proteins in intima benign hypertension (benign nephrosclerosis) also seen with diabetes mellitus (effects both afferent and efferent arterioles in kidneys)
non-urgent

hypertension

2. hyperplastic also

arteriolosclerosis = proliferation of cells within intima and media called onion-skinning see fibrinoid change + acute necrosis of vessel (necrotizing arteriolitis) severe (malignant) hypertension (malignant nephrosclerosis): diastolic > 140; may get eye changes, bleeding, etc (loaclized abnormal dilations of a blood vessel or the heart)

54. Aneurysms true

A. definitions/terms

aneurysm: bounded by arterial wall components (ie wall is intact); false aneurysm: breach in the wall with formation of hematoma mycotic aneurysm: weakening of wall results from infection of a major artery saccular aneurysms: spherical in shape; fusiform aneurysms: elongated B. atherosclerotic aneurysms location is most often the abdominal aorta (eg AAA) between renal arteries and bifurcation of the aorta clinically felt as pulsatile mass (but may rupture and cause sudden, severe abdominal pain and hypotension in male older than 55) may form thrombi and lead to arterial emboli; may obstruct a vessel or adjacent structure C. luetic aneurysms due to tertiary syphilis (treponema infection) secondary to obliterative endarteritis (endarteritis obliterans); mx see plasma cells around small blood vessels, such as vasa vasorum of aorta aneurysm is located in the ascending (thoracic) aorta and may produce aortic regurgitation, rupture, or occlude the coronary ostia "tree-bark" appearance of aorta grossly D. dissecting aneurysms due to cystic medial necrosis of aorta (loss of elastic tissue in media) associated with hypertension (seen in older males) and Marfan syndrome (due to defect in fibrillin gene) transverse tear in intima (ascending aorta) causes dissection of blood into media produces acute tearing chest pain (may radiate to back) and hypotension "double-barrel" aorta seen with x-ray main cause of death is rupture into body cavity (pericardial, pleural, peritoneal) E. berry aneurysms location is usually bifurcation of arteries in circle of Willis (most common location is bifurcation of anterior communicating artery) rupture will cause subarachnoid hemorrhage berry aneurysms are associated with polycystic renal disease F. microaneurysms: seen in cerebral vessels (due to hypertension) or retinal vessels (due to diabetes)
55. Vasculitis A. giant

(large and medium vessels) cell arteritis affects branches of carotid artery such as temporal artery (temporal arteritis) and ophthalmic artery (can lead to blindness) unilateral headaches, jaw claudication, and impaired vision (usually in elderly females) increased ESR (erythrocyte sedimentation rate), but this is a non-specific finding half of patients have systemic involvement with syndrome of polymyalgia rheumatica (malaise and muscle aches) microscopic of temporal artery biopsy reveals granulomatous inflammation with giant cells or breaks in internal elastic lamina 1/3rd are unremarkable and may have to treat based only on clinical suspicion treat with steroids to prevent blindness B. Takayasus arteritis younger females (Asians) thrombosis (acute obstruction) and fibrosis (thickening) of aortic arch (stenosis) = aortic arch syndrome pulseless disease because decreased pulse and BP in upper extremity (check blood pressure in both arms in young Asian woman) increased ESR and ocular problems C. macroscopic polyarteritis nodosa (PAN)

disease, but spares small vessels of lungs and kidneys (may have renal disease from involvement of renal arteries) macroPAN is not associated with glomerulonephritis or leukocytoclastic vasculitis variable signs including hypertension, arthralgia, myalgia, and sudden abdominal pain (due to mesenteric thrombosis) 1/3rd have hepatitis B antigen in serum (positive HBsAg, negative p-ANCA) fibrinoid necrosis of medium sized vessels, not smaller than arteries (not venules) good response to immunosuppression with steroids and Cytoxan D. Kawasakis syndrome (mucocutaneous lymph node syndrome; think "kids, koronary, konjunctiva, kawasaki") infants and young kids (especially in Japan) oral erythema (muco) + skin rash (cutaneous) + lymph adenitis (and fever) inflammatory coronary artery aneurysms (may cause MI or rupture); leading cause of acquired heart disease in kids in North America and Japan usually spontaneously resolves; IV gamma globulin with aspirin may decrease the incidence of coronary artery involvement
56. Vasculitis

multisystem

(small vessels) polyarteritis nodosa microscopic PAN is better called microscopic polyangiitis because affects vessels smaller than arteries (like venules) signs include flu-like syndrome with hematuria (glomerulonephritis) and hemoptysis (involvement of pulmonary capillaries) often ANCA positive (about 1/2 with p-ANCA; 1/2 with cANCA), but no deposits in glomerulus (pauci-immune glomerulonephritis) p-ANCA is an anti-myeloperoxidase antibody (p-ANCA = perinuclear staining pattern of ANCA) hypersensitivity angiitis: fragmented neutrophils around small blood vessels = leukocytoclastic vasculitis B. other causes of small vessel arteritis with leukocytoclastic vasculitis: 1. Henoch-Schonlein purpura (negative ANCA) hemorrhagic urticaria (palpable purpura) in children after upper respiratory infections IgA immune deposits in small vessels (alternate complement path) IgA deposits in mesangium produces nephritic syndrome (focal segmental glomerulonephritis) 2. Wegeners granulomatosis focal necrotizing vasculitis and acute necrotizing granulomas of upper and lower respiratory tract transbronchial biopsies reveal large, serpiginous necrosis with peripheral, palisading macrophages involvement of kidneys may produce RPGN (rapidly progressive glomerulonephritis) type III positive ANCA (if kidney involved), mainly c-ANCA (anti-proteinase 3) (c-ANCA = cytoplasmic staining pattern of ANCA) because the incidence of microPAN is greater than Wegeners, most cANCA positive pts may have microPAN rather than Wegener's signs include perforation of nasal septum, chronic sinusitis, hemoptysis, hematuria treatment is with cyclophosphamide, corticosteroids, and/or methotrexate 3. Churg-Strauss (allergic vasculitis) necrotizing vasculitis with granulomas of respiratory tract; associated with bronchial asthma associated with IgE immune deposits and peripheral eosinophilia; almost 1/3rd to 1/2 positive for ANCA (usually pANCA)
A. microscopic

57. Other

inflammatory vascular disorders A. Buerger's disease smokers disease (treatment is to quit smoking) thromboangiitis obliterans: segmental thrombosing vasculitis of small peripheral arteries and veins; mx shows thrombosis with microabscesses; x-ray shows corkscrew appearance of muscular artery branches causes intermittent claudication (instep claudication of foot), severe pain, and may produce gangrene in fingers and toes positive Allen's test = pallor of hand after temporarily occluding radial artery during exercise B. infections associated with blood vessels

1. fungal

infections include Mucor and Aspergillus (inhalation of airborne spores with blood-borne spread to brain causing cerebral infarct) 2. Rickettsia (vector-borne obligate intracellular bacteria that infect endothelial and vascular smooth muscle cells causing vasculitis) a) typus group (no eschar) (1) epidemic typhus is caused by Rickettsia prowazekii (spread by body lice) fever, headache, maculopapular rash on trunk and extremities (centrifugal rash spares face, palms, soles) positive Weil-Felix reaction to OX-19 strains of proteus vulgaris (2) murine typhus is caused by Rickettsia typhi (spread by rat flea) b) spotted fevers: eg. Rocky Mountain Spotted Fever (more also in Great Smoky Mountains) caused by Rickettsia rickettsii (spread by wood tick Dermacentor) headache, fever, and centripetal rash that begins peripherally and spreads centrally (involves entire body including palms and soles) note: if transmitted by tick, rash probably begins peripherally; if transmitted by flea, rash probably begins centrally positive Hess capillary test, positive proteus OX19 and OX2 Weil-Felix reaction c) other scrub typhus is caused by Rickettsia tsutsugamushi (spread by chigger bite) Q fever is caused by Coxiella burnetii Ehrlichiosis is caused by Ehrlichia sennetsu (spread by tick bite): fever and lymph adenitis but no eschar or rash
58. Miscellaneous A. Raynauds

vascular disorders phenomenon 1. primary = Raynauds disease (think "disease has no disease") vasospasm of arteries of digits in younger females precipitating events include cold or emotional upset painful ischemia that leads to characteristic color change: white (blanching); blue (cyanosis); red 2. secondary = Raynauds syndrome, which is due to arterial narrowing that is secondary to another disease initially consider sending blood to the lab looking for antinuclear antibodies to rule out an autoimmune disease B. veins 1. varicose veins legs: secondary to increased pressure (causes include prolonged standing, pregnancy, obesity, thrombophlebitis) increased portal pressure causes esophageal varices and hemorrhoids at anal-rectal junction 2. thrombophlebitis (phlebitis refers to inflammation of veins) migratory thrombophlebitis = Trousseaus sign (associated with visceral malignancies, especially carcinoma of the pancreas) phlegmasia alba dolens = painful white leg seen in later months of pregnancy due to deep leg vein thrombophlebitis 3. superior vena cava syndrome: secondary to obstruction by malignancies clinical = dilation of veins of upper thorax and neck; edema and plethora (redness) of face, neck, and upper thorax C. lymphatics 1. lymphangitis may be due to bacterial spread through lymphatics (most common are group A beta-hemolytic streptococci) 2. lymphedema can result from obstruction to lymphatic drainage primary: congenital defect, familial Milroy disease, or lymphedema praecox secondary: obstruction secondary to many causes (tumor, filariasis, surgery) D. pathology of vascular interventions balloon angioplasty and endovascular stents vascular replacement

59. Tumors

A. benign

tumors of vessels (contain blood) capillary or cavernous juvenile (strawberry) hemangiomas: found in young children; leave alone, most regress in couple of years (but be careful around the eyes) 2. lymphangioma (contain lymph) capillary or cavernous, the latter is aka cystic hygroma and is found in the neck of kids or individuals with Turner syndrome ("web neck") 3. glomus tumor is a very painful lesion under fingernail (mx shows vascular spaces lined by nests of uniform cells) 4. vascular ectasias nevus flammeus (birthmark) shows dilated vessels in dermis spider angiomas show dilated subcutaneous arterioles around a central arterial that blanches with pressure (associated with increased estrogen, such as pregnancy and cirrhosis) 5. hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): developmental malformations of dilated capilaries and veins on skin and mucus membranes 6. bacillary angiomatosis is seen in immune deficiencies (such as AIDS) infection with gram-negative bacilli of Bartonella genus (B. henselae causes cat-scratch, B. quintana caused trench fever in WWII) microscopy shows capillary proliferation with numerous stromal neutrophils, nuclear dust, and granular material (containing bacteria) B. malignant tumors of blood vessels 1. Kaposi's sarcoma: all forms are associated with HHV-8 (which produces homologs to IL-6, IL-8, bcl-2, and cyclin D) a) clinical groups: classic type (develop on the lower legs of older patients, relatively indolent) African-type transplant-associated type AIDS associated type (widespread lesions, especially skin and viscera that are very malignant) b) microscopic reveals spindle stromal cells, slit-like spaces, and extravasation of erythrocytes 2. hemangioendothelioma wide spectrum of vascular neoplasms intermediate in prognosis between benign hemangiomas and malignant angiosarcomas example is the epithelioid hemangioendothelioma 3. angiosarcomas mx: vascular spaces lined by highly atypical endothelial cells (but breast angiosarcomas have a deceptively benign histiologic appearance) endothelial cell marker is CD31 liver angiosarcomas are related to arsenic, Thorotrast (previously used as contrast material for X-ray), and polyvinyl chloride (used in plastics)
1. hemangiomas

1
HIGH-YIELD NOTES OF PATHOLOGY 2010 EXAM 2 HEART
60. Normal A. myocardium

myocytes striated muscle cells (fibers); blunt-end, branched, 1-2 central nuclei, and intercalated discs (not triads at junction of A band and I band); rather, dyads at the Z-lines 2. sarcoplasmic reticulum: the major storage site for calcium storage in a non-contracting myocyte 3. myofibrils are composed of sarcomeres (from Z line to Z line), which are the basic contractile unit A (anisotropic) band is the area where myosin is located (contains myosin and actin); constant width I (isotropic) band is area where myosin isnt (contains only actin); variable width H band (contains myosin only) M line is the center of the H band Z line is the location of T tubules note with contraction: no change in A band; decrease in sarcomere length, I band, H band 4. myofilaments actin (thin filaments): double helix of two chains (G-actin monomers); associated with tropomyosin and troponin myosin (thick filaments): contain rod-like portion and globular head, which is site of ATPase activity 5. tropomyosin 6. troponin: troponin T binds to tropomyosin; troponin I binds to actin (inhibits interaction of myosin and actin); troponin C is binding site for calcium 7. hormones = ANF (atrial natriuretic factor) secreted in response to volume expansion (effect is via Gt increasing cGMP) inhibits sodium reabsorption in distal tubules of kidneys: causes increased sodium excretion in urine (ie natriuresis) antagonizes effect of renin-angiotensin-aldosterone system (inhibits renin and aldosterone) and inhibits secretion of ADH 8. conduction system: SA node is pacemaker; location is junction of right atrial appendage and superior vena cava B. blood supply left anterior descending (LAD) supplies the anterior 2/3rd of septum, anterior LV, apex of heart right coronary artery (RCA) supplies RV and posterior 1/3rd of septum (if right dominant) circumflex artery supplies lateral LV and posterior LV posterior descending (PD) supplies the posterior 1/3rd septum, posterior and inferior LV right dominant (most cases) = PD originates from RCA; left dominant = PD originates from LCA (circumflex) C. valves D. aging: many changes, including increased epicardial fat decreased size of LV cavity calcification of mitral annulus and aortic valve fewer myocytes, increased collagenized connective tissue
61. Heart

1. cardiac

A. causes

failure and pathophysiology of congestive heart failure (CHF) 1. systolic dysfunction = decreased pumping a) high output failure = diseases with increased cardiac output (eg anemia, hyperthyroidism, and beriberi, which is due to decreased thiamine) b) low output failure = diseases that decreased cardiac output (eg aortic stenosis, hypertension) c) causes of systolic dysfunction include

2
volume (increased preload) due to mitral or aortic regurgitation, anemia (due to decreased viscosity of blood), hyperthyroidism (increased cardiac output to meet the bodys increased metabolic demand), beriberi excess pressure (increased afterload) due to hypertension (systemic or pulmonary), aortic stenosis, cor pulmonale decreased contractility due to myocardial infarction, ischemic heart disease, drugs (alcohol), infections, toxins, decreased myocardial cell contractile function d) heart compensates to increase cardiac output and stroke volume by: Frank-Starling mechanism: increased preload (left ventricular end diastolic volume) neuro-hormonal: increased contractility (NE stimulating beta-1 receptors) (positive ionotropic agents) hypertrophy: more actin, myosin, sarcomeres, mitochondria increased ventricular compliance (increased volume); note compliance is the inverse of elasticity 2. diastolic dysfunction = decreased filling (causes include mitral stenosis, amyloidosis, pericardial disease, myocardial fibrosis) these things make the heart stiff (decreased compliance); also left ventricular hypertrophy makes the chamber size smaller (is often caused by systolic dysfunction) and less compliant 3. Usually, you can treat systolic function by compromising diastolic function (and vice versa) ex. giving a diuretic to someone with CHF decrease filling (=diastolic dysfunction) to increase pumping (=systolic fnct) B. cardiac hypertrophy 1. general pathologic hypertrophy is associated with abnormal () gene expression and increased risk for heart failure mx: increased cytoplasm and nucleus ("box-car" nucleus DNA replication in the absence of cell division) 2. concentric hypertrophy response to pressure overload (increased afterload), such as hypertension (most common), AS, weight lifting; sarcomeres proliferate in parallel; contributes to diastolic dysfunction that leads to systolic dysfnct increased ventricular wall thickness causes the wall to be stiffer (decreased compliance); no change in size of ventricular cavity (no dilation) ventricular cavity size should decrease 3. eccentric hypertrophy response to volume overload (increased preload), such as AR, MR, long-distance running; sarcomeres proliferate in series no increase in ventricle thickness, but there is an increase in size of ventricular cavity (dilation) and the wall is less stiff C. results of congestive heart failure: the failing heart decreases cardiac output (forward failure) with backing-up of blood (backward failure) 1. right-sided CHF a) acute right CHF can increase jugular venous pressure and possibly cause sudden death b) chronic right CHF causes systemic congestion classic signs = jugular venous distention (JVD), hepatomegaly, splenomegaly, and generalized edema (anasarca) (eg ascites and pedal edema) liver shows nutmeg appearance due to central passive congestion 2. left-sided CHF a) acute failure causes hypoxia due to pulmonary edema and pulmonary hemorrhage (may produce hemoptysis) syncope, hypotension, shock, sudden death b) chronic failure most often caused by ischemic heart disease, valvular disease (aortic stenosis), or hypertension lung symptoms = DOE (dyspnea on exertion), orthopnea (shortness of breath when supine), and PND (paroxysmal nocturnal dyspnea) mx of lungs can show pulmonary edema (transudate), pulmonary hemorrhage (can cause hemoptysis), and heart failure cells may produce right ventricular failure (most common cause of right CHF is left CHF) decreased renal blood flow causes renal failure (prerenal azotemia) and increased renin (edema) D. Forward heart failure poor organ perfusion left sided (kidneys, brain) E. clinical 1. physical diagnosis: look for enlarged liver/spleen, pitting edema of legs, breathing problems, medical history
excess

3
2. clinical

tests:

examine walls, ejection fraction (normal is 50-60%; bad is < 40%) (B-type natriuretic protein): ventricles release BNP to increase Na loss and decrease blood volume; fairly specific for ventricular dilation 3. older therapy: digoxin: increased contractility but increased apoptosis 4. newer therapy: decrease load on the heart with ACE inhibitors and beta-blockers (contraindicated for those with compromised systolic function), also give diuretics
BNP 62. Acyanotic

echocardiogram:

(left-to-right shunts) overload increases blood flow through lungs and increases pulmonary pressure (pulmonary hypertension) eventually will cause RV hypertrophy and reverse blood flow (right to left) = late cyanosis (tardive) called Eisenmenger's syndrome clubbing and polycythemia ("blue kids") B. atrial septal defects (ASD) are the most common congenital heart disease presenting in adults blood flow: left atrium thru ASD to right atrium to right ventricle to lungs to left atrium increased blood flow (volume overload) to RA produces RV dilation and eccentric hypertrophy in adults produces palpitations, exertion dyspnea, systolic flow murmur, widely split fixed S2, right axis deviation (acyanosis) most common type is ostium secundum: located in the middle portion of the septum at the level of the fossa ovalis (foramen ovale) ostium secundum ASD + mitral stenosis together is called Lutembacher syndrome sinous venous defect is located high in the atrial septum near the superior vena cava ostium primum type is located low in the atrial septum persistent AV canal combines atrial and ventricular septal defects C. ventricular septal defects (VSD) are the most common congenital cardiac anomaly membranous defects are large; muscular defects are small (called Roger's disease) and usually close as heart enlarges blood flow: left ventricle thru VSD to right ventricle to lungs to left atrium to left ventricle increase blood flow (volume overload) produces LV dilation and hypertrophy and RV dilatation and hypertrophy sx include dyspnea, poor growth (no cyanosis), and pansystolic murmur over left lower sternal border with biventricular hypertrophy; earlier development of pulmonary hypertension than with an ASD D. patent ductus arteriosus (PDA) refers to communication between aorta and pulmonary artery distal to left subclavian artery produces a continuous "machinery type" heart murmur keep open (in patient with transposition of great arteries) with PGE2 but close with indomethacin (inhibits PGE2), give aspirin or other NSAIDs, give PGE1 (prostadil; inhibits PGE2) increased blood flow to lungs causes RV hypertrophy (due to pressure overload) and LV dilation and hypertrophy (due to volume overload) associated with maternal rubella during pregnancy, Downs syndrome, post-birth hypoxia (premature babies) E. atrioventricular septal defect (AVSD) partial AVSD: primum ASD and a cleft anterior mitral leaflet, causing mitral insufficiency complete AVSD (seen with Down syndrome): large combined AV septal defect and large common AV valve
A. volume

63. Cyanotic/obstructive A. right-to-left 1. tetralogy

shunts: early cyanosis ("blue babies") of Fallot (TOF): most common cause of congenital cyanotic heart disease; fainting episodes, convulsions, other neurologic findings a) due to anterosuperior displacement of infundibular septum b) child will squat to relieve cyanosis (tet spell; triggered by things that decrease systemic resistance or by inspiration), because increased peripheral resistance decreases right-to-left shunt. Increased preload on the right or decreased preload on the left will exacerbate the problem c) pathologic findings obstruction to RV outflow (pulmonary stenosis)

4
septal defect (over-riding) aorta (over the VSD) right ventricular hypertrophy (causes "boot-shaped" heart on x-ray) concentric hypertrophy d) compare to tricuspid atresia (which results from unequal division of AV canal; with enlarged MV) associated with hypoplasia of the right ventricle, ASD and VSD (which maintains circulation) 2. transposition of the great vessels (TOGA) due to failure of the truncoconal septum to spiral during development (associated with diabetic mothers) RV outflow (anterior) is aorta while LV outflow (posterior) is pulmonary artery (pulmonary trunk) incompatible with life unless shunt is present (ASD or PDA) presents with cyanosis (most common cause of cyanosis in neonate; blue newborn) x-ray: normal heart size with narrow mediastinum ("egg on a string" appearance) therapy with PGE keeps ductus open until surgery B. both left-to-right shunt and right-to-left shunt = persistent truncus results from failure of spiral septum to develop and separate truncus arteriosus into aorta and pulmonary artery result is single vessel for aorta and pulmonary artery; therefore blood mixes and is both left-to-right shunt and right-to-left shunt C. obstruction 1. coarctation of the aorta (more common in males) a) preductal type = infantile form coarctation proximal to patent ductus arteriosus (in close to heart) more severe symptoms; associated with Turner syndrome b) postductal = adult form (1) coarctation distal to closed ductus arteriosus (ligamentum arteriosum) (2) discrepancy between blood pressure of upper and lower extremities proximal to coarctation is increased BP, which causes headaches and dizziness distal to coarctation is dec BP, which causes weak pulses (check femoral pulses on physical exam) (parvis & tardis pulse in the lower extremities = small and late pulse) (3) increased collateral circulation in internal mammary (internal thoracic) arteries (causes rib notching, seen with x-ray)
dextroposition 64. Ischemic ventricular

heart disease (IHD)

A. general

angina, MI, chronic IHD, heart failure, and sudden cardiac death coronary syndrome = acute MI (transmural or non-transmural), unstable angina, and sudden cardiac death B. epidemiology 1. prevention a) eating fish: omega 3 fatty acids (decrease LDL, slight increase in HDL) best is salmon: wild (Alaska, North Atlantic); note: farm-raised ("Atlantic salmon") has increased PCB's and decreased omega 3's also good: sardines/herring b) increase HDL (hard to do): some alcohol, aerobice exercise, niacin C. pathogenesis decreased coronary perfusion relative to myocardial demand most often due to atherosclerosis; inflammation plays an important role in all stages of atherosclerosis abrupt changes in atherosclerotic plaque (ulceration) followed by thrombosis risk factors for plaque ulceration: thin fibrous cap, lots of lipid, lots of inflammation D. chronic IHD E. sudden cardiac death: most often due to a lethal arrhythmia about 20% of the time acute coronary syndrome presents as sudden death.
acute 65. Angina

categories:

A. stable

= chest pain that is not worse with deep breath (typical) most common clinical form of angina (most often secondary to ischemia produced by atherosclerosis of coronary arteries)

5
pain occurs with exercise, stress, excitement (in contrast to MI, pain with stable angina goes away with rest, usually less than 10 minutes) no infarction or serum enzyme changes nonspecific EKG changes = ST segment depression (subendothelium of LV) and T wave inversions pain relieved by rest (decreased oxygen demand) and nitroglycerin (increased perfusion by nitric oxide induced vasodilation) other therapy includes beta-blockers (propranolol) and calcium-channel blockers (verapamil) B. Prinzmetal angina atypical angina because pain occurs at rest (due to coronary vasospasm, which may be precipitated by alpha agonists) younger patients than stable angina; incidence in males and females is the same EKG changes = ST segment elevation (transmural ischemia) pain usually occurs between midnight and 8 am pain relieved by nitroglycerin (increase perfusion) and calcium channel blockers (these work best) avoid beta blockers because they may cause unopposed alpha stimulation which can cause vasospasm C. unstable (crescendo) angina worsening pain = increased frequency of pain (less effort or at rest) or increased duration of pain due to formation of overlying non-occlusive thrombus, and indicates an MI is near (MI results from thrombus that completely occludes lumen) mx shows severe coronary artery atherosclerosis with fissures and hemorrhage treat with same drugs as for stable angina and hospitalize
66. Pathogenesis/types/sites A. types 1. subendocardial seen retrosternal

of MI (myocardial infarction)

infarcts (inner 1/3rd of myocardium) in elderly (associated with generalized hypotension); affect more than 1 vessel; may be patchy don't get Q waves (non-Q wave infarction) don't get ST segment elevation (non-ST elevation MI, aka "NSTEMI") (aka white clot) 2. transmural (full thickness) infarcts common type (result from obstruction to blood flow in a single coronary artery; proximal LAD most often) Q waves in certain leads; before Q waves get ST segment elevation (due to transmural ischemia) aka "STEMI" (aka a red clot) B. pathogenesis obstruction to coronary blood flow due to thrombosis of atherosclerotic coronary artery (rare cause is cocaineinduced vasospasm) most common site of obstruction is proximal 2 cm of the left anterior descending artery obstruction produces coagulative necrosis; irreversibly injured cells can see flocculent densities, which are calcifications in mitochondria reperfusion in irreversibly injured cell can produce contraction bands (may be seen with streptokinase therapy) "ischemic preconditioning": a brief ischemic interval (5 min) protects the heart from subsequent severe ischemia (and decrease size of infarcts) "stunning": loss of function after brief periods of ischemia (due to reversible free radical damage to SR, which alters calcium transport) C. sites usually in the epicardial, major arteries: left anterior descending (LAD) has 50% of MIs right coronary artery (RCA) has 30% of MIs circumflex artery has 20% of MIs
67. Healing

A. gross

changes of MI changes 0-12 hours = none 12-24 hours = dark mottling 1-3 days = yellow-tan infarct center 4-7 days = hyperemic (red) border

6
days = red-purple border 2 weeks = gray-white scar B. light changes 0-12 hours = usually none (?wavy fibers), but may see contraction bands due to reperfusion of irreversibly injured cells 12-24 hours = coagulative necrosis 1-3 days = coagulative necrosis + neutrophils 4-7 days = coagulative necrosis + neutrophils + macrophages (during this period is time for cardiac rupture; maximally soft) 7-14 days = coagulative necrosis + neutrophils + macrophages + granulation tissue > 2 weeks = fibrosis (scar), which will not go away C. EM changes 0-1/2 hour = reversible changes (eg mitochondrial swelling) 1-12 hours = irreversible changes (eg flocculent densities in mitochondria)
> 68. Clinical 7-14

features of MI A. diagnosis 1. symptoms include sudden, crushing, substernal pain +/- radiation to jaw or left arm with nausea, vomiting, and sweating (adrenergic signs) atypical presentation (without pain) may be seen in women, elderly, diabetic patients 2. EKG changes (gold standard for first 6 hours) ST elevation due to transmural ischemia (may return to normal) inverted T waves (persist) followed by abnormal Q waves due to transmural infarction (persist) 3. serum enzymes first 8 hours use troponin (troponin-I levels begin to increase 4-6 hours after the onset of chest pain, reach maximal serum concentration in about 12-24 hours, and remain elevated for about 4 to 8 days) first 24 hours can use CPK (MB fraction will exceed 5%): levels begin to rise at 4-8 hours, peaks at 12-24 hours, and returns to normal in 3-4 days next (peak at day 2) is AST (SGOT), but is not specific last (days 2 to 7) use LDH (flipped LDH = LDH1 > LDH2), which peaks at day 4 4. new cardiac markers (using monoclonal antibodies): a) myoglobin: a small monomer with a rapid rise and fall in serum (narrow window) that may be used to test the effect of "clot-busting" drugs b) CK-MB mass assay CK-MB leaks into lymphatics, not capillaries, therefore not detectable for first 4 hours by 8 hours nearly 100% sensitive; peaks 12-24 hours; baseline in 3-4 days specific (some in skeletal muscle, important in marathon runners); need to relate to total CK c) cardiac troponin T and cardiac troponin I (cardiac troponin is different from skeletal muscle troponin) two phases of increase after MI: first phase is rapid (due to release of small cytoplasmic pool), second is more prolonged (due to release of troponin associated with myofilaments) leaks into lymphatics (detected by 4 hours); remains elevated for 4 to 8 days; sensitivity almost 100% at 8 hours; but unstable angina may increase troponin levels troponins are very good at detecting serious later event (MI, sudden death) d) bottom line: no ideal marker; sensitivity is bad during the first 4 hours; sensitivity is better from 4 to 8 hours; then very good; specificity issues vary CK-MB and troponins have similar timelines, but troponins are predictors of adverse outcomes and remain elevated longer (replace LDH for late diagnosis) role of myoglobin is controversial; but rapid serial detection may be beneficial B. therapy streptokinase can be used early to dissolve thrombus (streptokinase stimulates formation of plasmin, which breaks down fibrin)

7
artery bypass with saphenous vein or internal mammary artery (grafts can last for 10 years) three vessel disease, diffuse disease, or left main coronary artery disease angioplasty (balloon dilation), but half will re-stenose in one year small daily dose of aspirin will decrease incidence of recurrence (inhibition of cyclooxygenase will increase prostacyclin to thromboxane ratio by decreased production of thromboxane by platelets) Diet saturated fats increase both HDL and LDL; unsaturated fats lower both HDL and LDL; monounsaturated fats (olive oil) are the best for you, trans-saturated fats are the worst (lower HDL and increase LDL) Dont smoke, exercise, stay on top of your health! Glucose control: impaired fasting glucose is above 100, above 125 is diabetes; diabetes is perhaps more of a risk factor for heart disease than hyperlipidemia!
coronary 69. Complications

of MI (90%) are the most common cause of sudden cardiac death within 1 hour after an MI B. LV failure and pulmonary edema (60%) C. cardiogenic shock (high risk of mortality) D. infarction (can be new infarction or extension of previous infarction) E. pericarditis can occur 1-3 weeks after MI (called Dresslers syndrome, which is an autoimmune disorder; sx = fever, pericarditis, increased ESR) acute pericarditis produces pericardial chest pain (worse with inspiration, better by sitting up), friction rub, EKG changes, and pulsus paradoxus F. mural thrombosis (due to stasis) may give rise to systemic emboli (if embolus to brain may produce neurologic symptoms (embolic stroke) after MI) G. ventricular aneurysm (most likely will lead to chronic CHF) H. rupture on days 3-7 (when the infarcted myocardium is maximally soft) rupture of free wall produces hemopericardium (acute cardiac tamponade) rupture of septum produces left-to-right shunt and heart failure rupture of papillary muscle produces new onset of mitral regurgitation or new murmur
A. arrhythmias

70. Hypertensive

heart disease A. systemic hypertensive heart disease clinical history of increased blood pressure (hypertension) and no other cardiac disease to explain LV hypertrophy (such as AS) effects left side of heart (LV hypertrophy causes left axis deviation on EKG) increased risk of arrhythmias and sudden death B. pulmonary hypertensive heart disease 1. affects right side of heart (heart disease is called cor pulmonale, and can result from several different lung disorders) right ventricular hypertrophy causes right axis deviation on EKG acute cor pulmonale (due to massive pulmonary embolus) causes right ventricular dilatation (and tricuspid regurgitation) without hypertrophy 2. secondary to diseases affecting lung parenchyma (COPD and interstitial fibrosis) pulmonary vessels (pulmonary emboli and pulmonary vascular sclerosis) chest wall movement (kyphoscoliosis, marked obesity, and neurologic diseases) valve (note: right side is rare but may be due to carcinoid syndrome of certain drugs [?fen-phen]) (aortic stenosis) result of congenital bicuspid aortic valve, degenerative calcific AS (dystrophic calcification), and rheumatic heart disease; however, unlike rheumatic fever, commissural fusion is not normally seen. stenosis causes pressure overload (increased afterload) then concentric hypertrophy (increased contractility), decreased compliance, and LV failure (develop a diastolic dysfunction, followed by pulmonary congestion and then followed by right heart failure) patients develop angina (secondary to increased oxygen demand by hypertrophied muscle and decreased blood supply through coronary arteries) and syncope (decreased systemic circulation or due to arrhythmias)

71. Aortic

A. AS

8
midsystolic ejection murmur with paradoxically split S2 (split during expiration, not inspiration, due to delay in left-sided blood ejection = A2 delay) SAD = syncope, angina, dyspnea; once angina develops, one-year survival is only 50% B. AR (aortic regurgitation) result of congenital abnormality, Marfans syndrome, inflammation, aneurysms (syphilis = treponema pallidum), trauma volume overload (due to regurgitation) causes increased LVEDV then eccentric hypertrophy (increased contractility), increased compliance and afterload patients develop hyperdynamic (bounding) pulse (water-hammer pulse) with head bob due to wide aortic pulse pressure high-pitched decrescendo ("blowing") diastolic murmur at left sternal border
72. Mitral crescendo-decrescendo

valve (mitral stenosis) result of congenital abnormality or rheumatic heart disease (most common); rare cause is mitral annular calcification small left ventricle due to decreased LV filling and decreased LVEDV (no LV hypertrophy), hypertrophic and dilated left atrium (LA) dilated LA causes dysphagia by pressing on esophagus and hoarseness by pressing on recurrent laryngeal nerve), hypertrophic right ventricle prone to develop arrhythmias (palpitations) and thrombi of left atrium (may emboli to brain and produce neurologic findings) venous congestion and hemorrhage of lungs produces dyspnea, fatigue, and hemoptysis rumbling late diastolic murmur with opening snap (early diastolic opening snap is characteristic of MS) B. MR (mitral regurgitation) result of rheumatic heart disease or myxomatous degeneration (causing prolapse); anything that dilates the annulus regurgitation causes dilation and hypertrophy of left ventricle and left atrium increased LA pressure with time (chronic disease) can cause pulmonary fibrosis, pulmonary arterial hypertension, and RV hypertrophy (not dilation) thrombi may form in left atrium (may emboli to brain and cause neurologic signs) high-pitched "blowing" holosystolic murmur C. MV prolapse due to myxomatous degeneration of MV (usually posterior leaflet due to long chordae tenineae) which billow into left atrium during systole microscopically can see myxomatous degeneration of the outer zona fibrosa with thickening of the inner zona spongiosa common disorder seen in 10% of population, often young females (also associated with Marfans syndrome) causes systolic murmur with mid-systolic click
A. MS

73. Vegetative

Endocarditis A. Rheumatic Heart Disease small, warty vegetations (1-2 mm) along the lines of closure of the valve leaflets B. Infective Endocarditis large, irregular masses on the valve cusps that can extend onto the chordae C. NBTE small, bland vegetations (1-5 mm), usually attached at the line of closure D. Libman-Sacks endocarditis has small to medium sized vegetations (1-4 mm) on either or both sides of the valve leaflets in patients with SLE or anti-phospholipid syndrome heart disease

74. Rheumatic A. general

acute

rheumatic fever is seen in children (age 5-15) 1-4 weeks after group A beta-hemolytic strep (pyogenes) infection of pharynx (not skin) upper respiratory infection; 3% with strep infection get RHD features of group A strep = catalase negative, M protein confers virulence, sensitive to bacitracin, produce streptolysin S and O (test is ASO)

9
disorder due to anti-streptococcal antibodies that cross-react with the heart (not direct effect of bacteria in heart) molecular mimicry; the antibodies are directed against collagen epitopes B. diagnosis: Jones criteria (need 2 major or 1 major + 2 minor) 1. major criteria joints = polyarthritis (inflammation of joints) pancarditis (see below) nodules = subcutaneous rheumatic nodules (mx shows pallisading histiocytes around areas of necrosis) erythema = skin lesions (erythema nodosum or erythema marginatum, which is a macular skin rash, often in a "bathing suit" distribution) Sydenham's chorea (involvement of basal ganglia); not related to Huntington's chorea 2. minor criteria fever arthralgia (pain in joints) prolonged PR interval previous history of rheumatic fever increased acute phase reactants (ESR and C-reactive protein) C. pancarditis (seen with acute rheumatic fever) 1. endocarditis (valvulitis) = friable vegetations on valves (MC is mv) along the lines of closure; can produce murmurs 2. myocarditis = microscopic appearance reveals Aschoff body, which is composed of fibrinoid necrosis without bacteria Anitschkow cells (modified monocytes [possibly myocytes] that look like caterpillar cells) and Aschoff giant cells (Anitschkow cells will fuse to form Aschoff bodies) 3. fibrinous pericarditis (bread and butter pericarditis) D. chronic changes endocarditis heals by fibrosis fibrosis of endocardium of left atrium is called MacCallums patch fibrosis causes stenosis of valves (fish mouth or button-hole); incidence of valve involvement is MV > AV >> TV
75. Infective autoimmune

(bacterial) endocarditis infection form large friable vegetations on cardiac valves (MV is most commonly affected) B. mx of vegetations shows inflammatory cells, fibrin (red color), and bacteria (dark blue/purple color) C. acute = rapid onset (< 6 weeks) of highly virulent organisms (Staph aureus) in previously normal valves (onset of new murmur) D. subacute (SBE) = insidious onset (> 6 weeks) of organisms of low virulence (alpha-strep viridans) in abnormal valves in patient with bacteremia (dental procedures) (therefore need prophylaxis) E. IV drug abusers have right-sided disease (TV) with Staph aureus and unusual organisms (Candida species, etc) F. anemia, fever, and positive blood cultures (may need multiple cultures) G. may embolize and form Roth spots in retina (round white spots of coagulated fibrin that are surrounded by hemorrhage) splinter hemorrhages in nails systemic infarcts, such as CNS, myocardial, and splenic infarcts (the latter causing LUQ abdominal pain) H. may form immune complexes that can cause glomerulonephritis and vasculitis Oslers nodes (tender red nodules in fingers and toes) Janeway lesions (red nontender papules in palms and soles)
A. bacterial

76. Other

A. nonbacterial

endocardial disorders thrombotic endocarditis (NBTE) associated with hypercoagulable states marantic endocarditis have vegetations that are sterile (nonbacterial) associated with wasting (cachexia), such as advanced cancer small vegetations (fibrin precipitates on valve leaflets) that are single to few and are located along the line of closure

10
embolize and cause systemic infarctions endocarditis sterile, medium-sized vegetations found on both sides of valves in patients with SLE associated with anti-phospholipid syndrome, ie presence of lupus anticoagulant (anti-cardiolipin autoAb), makes platelets sticky and increase thrombosis C. carcinoid heart disease 1. pearly white endocardial plaques plaques are formed secondary to vasoactive amines and peptides (eg serotonin) secreted by a carcinoid tumor found only on right side of heart (serotonin and bradykinin are inactivated by monoamine oxidase [MAO] in endothelium of lung) MAO-A degrades norepinephrine (NE) and serotonin (MAO-inhibitors are anti-depressants that increase NE and serotonin); MAO-B degrades dopamine plaques are composed of smooth muscle cells and collagen fibers in an acid mucopolysaccharide matrix similar lesions seen with fen-phen (a diet suppressant), Redux (a diet suppressant) and methysergide or ergotamine therapy for migraine headaches Redux (dexfenfluramine) increases satiety and increases serotonin fen-phen is the combination of fenfluramine and phentermine (which is not phentolamine); phentermine increases norepinephrine and decreases appetite both Redux and fen-phen are associated with pulmonary hypertension and valvular heart disease 2. carcinoid heart disease is associated with primary carcinoid tumor of small intestine that secrete vasoactive amines (serotonin or bradykinin) heart disease occurs with liver mets or large primary tumor (serotonin and bradykinin are inactivated by liver; breakdown product 5-HIAA in urine) signs and symptoms are secondary to vasoactive substances (especially serotonin) classic sx = episodic skin flushing (facial), cramps, diarrhea, and asthma-like bronchoconstriction (expiratory wheezing)
B. Libman-Sachs 77. Cardiomyopathies can

(heart diseases that result from a primary abnormality in the myocardium) A. dilated (congestive) cardiomyopathy 1. most common type of cardiomyopathy 2. may be primary (idiopathic) or secondary to: alcohol (most common) or anthracyclines (chemotherapy), such as doxorubicin (Adriamycin) adriamycin is used in chemotherapy and causes lipid peroxidation of myofiber membranes (see clear spaces in myocytes with EM) beriberi (due to deficiency of vitamin B1, thiamine) cobalt (used as a foam stabilizer in beer, but not this country) cocaine (other signs of cocaine use include euphoria, anxiety, psychosis, angina pectoris or MI in young person due to coronary vasospasm) Coxsackie virus (note that viral myocarditis is associated with numerous lymphocytes in the myocardium) hemochromatosis (increased iron deposition in pt with "bronze diabetes"); most common COD in hemochromatosis is CHF pregnancy (occurs in third trimester or post partum; 50% of individuals have full recovery) 3. four chamber dilation with hypertrophy flabby, globular balloon-shaped heart hypocontracting (increased LV end-diastolic volume and pressure) leads to congestive heart failure mx: non-specific; may have interstitial fibrosis 4. note: arrhythmogenic RV cardiomyopathy (dysplasia) markedly thin RV with extensive fatty infiltration and interstitial fibrosis caused by defective cell adhesion proteins in the desmosomes can cause syncope or sudden cardiac death related disorder: Naxos syndrome: abnormal gene coding for plakoglobin (gamma-catenin); also has hyperkeratosis of plantar palmar skin

11
B. hypertrophic 1. mutation

cardiomyopathy in cardiac beta-myosin heavy chain gene (familial cases have AD inheritance) 2. asymmetric septal hypertrophy (ASH) causes hypercontractility and (looks like concentric hypertrophy): obstruction of ventricular outflow at the level of (or just below) the aortic valve IHSS (idiopathic hypertrophic subaortic stenosis) and asymmetric septal hypertrophy (ASH) small ventricular cavity with impaired diastolic filling (banana shaped-cavity) anterior movement of mitral valve during systole (SAM of MV) is characteristic histology reveals myocyte hypertrophy and disarray in septum with fibrosis are prone to arrhythmias (due to abnormal muscle organization and decreased coronary artery perfusion) 3. signs and symptoms syncope on exertion or sudden death in young athletes (such as high school basketball) double-peaked pulse and double apical impulse EKG with left axis deviation and big Q waves in inferior and lateral leads ejection murmur made worse with exercise, inspiration, and Valsalva maneuver (compare with aortic stenosis where the murmur gets better with inspiration) better with squatting (compresses veins of legs and incerases blood return to right side of heart) or lying down (also increases blood return to heart) 4. treatment decrease contractility with beta-adrenergic blockers or calcium channel blockers can use antiarrhythmic drugs; can do surgery to reduce the size of the ventricular septum do NOT use glycosides such as digitalis (increased contractility) or diuretics (decreased intravascular volume) C. restrictive/obliterative cardiomyopathy: causes include sarcoidosis, amyloidosis (amyloid is Congo red positive material), storage disorders (Pompe's is type II glycogen storage disease) endocardial fibroelastosis ("cream cheese" gross appearance): most common in first 2 years of life; if diffuse can lead to cardiac decompensation and death; abnormality of the endocardium leading to abnormal elastic and muscle fibers; may be associated with mumps endomyocardial fibrosis (Loeffler's syndrome is associated with eosinophilia in adults; African-type is associated with too much serotonin from green bananas); also cerium from cassava; the abnormal myocardium is susceptible to mural thrombi
78. Pericardium A. pericarditis viral

(produces "friction rub" clinically; classic EKG finding is low-voltage, diffuse ST-segment elevation) infections (coxsackie B, echo, HIV) are the most common cause of acute pericarditis fibrinous (bread and butter) pericarditis is associated with MI (pt presents with friction rub, chest pain, and fever) serous pericarditis (few inflammatory cells) are due to immunologic reaction or virus (Coxsackievirus) suppurative pericarditis (mx shows neutrophils) is due to bacteria, fungi, parasites hemorrhagic pericarditis is due to malignancy or tuberculosis (which also can cause caseous pericarditis) constrictive pericarditis causes decreases diastolic filling and decreases heart sounds B. pericardial effusions 1. sudden filling (such as ruptured LV) produces cardiac tamponade, the signs of which include: a) Beck's triad = soft heart sounds, increased jugular venous pressure, decreased BP b) pulsus paradoxus (greater than normal 10 mm drop in BP with inspiration) normally inspiration decreases intrathoracic pressure which increases return to right-side heart (due to dilation of vessels going to RV) and decreases return to left side (due to pooling of blood in lungs) which will decrease BP (due to Frank-Starling effect) with cardiac tamponade the RV bulges into LV and decreases blood return to LV even more than normal which decreases BP even more pulsus paradoxus is seen with cardiac tamponade, pulmonary disease, and superior vena cava syndrome 2. serous effusions are due CHF (most common) (develops slowly and is usually asymptomatic) or hypoproteinemia

12
3. serosanguineous

effusions are usually due to trauma (tumor or TB), while hemopericardium is due to trauma or ventricular rupture

79. Other

heart disorders A. myocarditis (inflammation of the myocardium that is associated with nonischemic myocyte necrosis) 1. bacterial causes include diphtheria (exotoxin blocks EF-2 and causes fatty heart) and Borrelia burgdorferi (which causes Lyme disease); might ultimately cause an autoimmune reaction similar to rheumatic fever 2. viral causes are the most common form of myocarditis commonly due to Coxsackie B virus (positive-sense RNA virus of the Picornavirus family) microscopically seen infiltrate of lymphocytes (which are cytotoxic T lymphocytes) 3. protozoan causes include Trypanosoma cruzi (Chaga's disease in South America) and Toxoplasmosis (think AIDS) mx of Chagas in heart: myocardial fibers have small cystic structures filled with multiple small, dot-like structures C's with Chaga's: cruzi, cone-nose bug, chaga's disease, cardiac failure, C-shaped organisms B. metabolic disorders 1. thyroid disease: thyroid hormones increase cardiac contractility and increase protein synthesis in the heart (which leads to cardiac hypertrophy) hypothyroidism decreases cardiac output (by decreasing both stroke volume and heart rate) and increases peripheral resistance hyperthyroidism causes increased cardiac output and decreased peripheral resistance (which results in warm sensitivity) 2. thiamin deficiency (wet beriberi): decreased peripheral resistance and increased cardiac output (which results in high output cardiac failure) 3. carnitine deficiency: carnitine is produced in the liver and is used to transport medium and long chain FA into mitochondria for energy production C. tumors 1. metastases are most common (especially from breast and lung, possibly by direct extension) 2. primary tumors a) myxoma are the most common primary tumor of the heart in adults "ball and valve" tumor of left atrium (most common site): can obstruct blood (and cause sudden death) flow or embolize sx include intermittent syncope and murmur (or even death) when pt lies on left side; murmur is variable with position microscopy reveals stellate cells in a loose myxoid (mucin-like material) background 10% of patients have familial cardiac myxoma (Carney) syndrome with skin pigmentation and endocrine overactivity; due to abnormal PRKAR1 gene, which codes for regulatory subunit of cAMP-dependent protein kinase A b) rhabdomyomas the most common primary tumor of the heart in kids associated with tuberous sclerosis, which has clinical triad of angiofibromas, seizures and mental retardation D. cardiac transplantation: complications 1. allograft rejection scheduled endomyocardial biopsy is the only reliable means of diagnosing acute cardiac rejection mx: interstitial lymphocytic inflammation 2. graft arteriopathy late, progressive, diffuse stenosing intimal proliferation of the coronary arteries may lead to a silent MI (since the heart is denervated and the patient doesnt feel the ischemic pain)

LUNG
80. Normal A. conducting

airways

13
contains cartilage, smooth muscle, ciliated epithelial cells, pseudostratified epithelium, mucus (goblet) cells, K cells (neuroendocrine cells) a) cilia cilia contain longitudinal microtubules (axoneme) and have nine doublet microtubules uniformly spaced around two central microtubules dynein arms extend unidirectionally from each of the doublet microtubules radial spokes extend from each of the outer doublets toward the central area nexin is an elastic protein that connects adjacent doublet microtubules 2. terminal bronchiole: has ciliated simple columnar epithelium, smooth muscle, Clara cells lacks cartilage, mucous cells, and pseudostratified epithelium goblet cells become Clara cells, which secrete mucus and GAGs and metabolize toxins via cytochrome P450 in SER B. acinus (note: lobule = 3-5 terminal bronchioles and their acini 1. respiratory bronchiole (same as terminal bronchiole but are interrupted by alveoli); alveolar duct; alveolar sac (atrium); alveolus note: respiratory bronchiole is the last division of the pulmonary airway system to contain (at least some) cilia 2. alveolus type I pneumocytes: flat, line majority of surface, more vulnerable to injury type II pneumocytes: cuboidal, have surface microvilli and lamellar bodies (contain surfactant) make surfactant, which keeps lungs from collapsing with expiration), and proliferate to repair damage (type II pneumocyte hyperplasia) macrophages: originate from monocytes and can form heart-failure cells 3. interstitium: contains capillaries, lymphatics, and interstitial cells
81. Congenital 1. bronchus:

anomalies and atelectasis anomalies pulmonary hypoplasia: most often secondary to space-occupying lesions in the uterus, oligohydramnios, impaired fetal respiratory movements congenital pulmonary airway malformation (CPAM): a hamartomatous lesion of the lung pulmonary sequestration: discrete mass of lung tissue without any normal connection to the airway system B. atelectasis = lung collapse; grossly may resemble liver (note: atelectasis is an important cause of post-op fever; can rule out PE with lack of calf tenderness) 1. resorption (absorptive or obstructive) obstruction is due to mucus, tumors, or foreign bodies (eg. inhaled peanut in child) mediastinum shifts toward atelectatic lung 2. compression congestive heart failure (increased pleural fluid causes increased pressure) mediastinum shifts away from atelectatic lung 3. contraction: secondary to fibrosis (not reversible like the other two are)
A. congenital

82. Acute

lung injury edema 1. general fluid in lung decreases lung compliance microscopic reveals pale pink fluid within alveoli if pulmonary hemorrhage also see heart failure cells (hemosiderin-laden macrophages) chest x-rays reveals peribronchial fluid (cuffing) and fluid in interlobular septa (Kerley B lines) 2. types cardiogenic (hemodynamic) pulmonary edema (transudate): due to abnormalities of Starling forces (especially increased hydrostatic force with CHF) noncardiogenic (many causes) pulmonary edema (exudate) is due to microvascular injury or alveolar injury B. hyaline membranes in lungs
A. pulmonary

14
(acute respiratory distress syndrome) of adult respiratory distress syndrome are many and include sepsis, infections (viral), aspiration, trauma, fat emboli, drugs, shock, burns causes sudden onset of respiratory problems (severe hypoxemia that does not improve with 100% oxygen because of shunting) clinical: dyspnea, tachypnea, hypoxemia/cyanosis; chest x-ray reveals white out lung neutrophil products cause injury to type I pneumocytes and endothelial cells, which increases capillary permeability and leads to pulmonary edema pathology is called DAD (diffuse alveolar damage) histology reveals hyaline membranes (edema + fibrin + dead cells) lining the alveoli and hyperplasia of type II pneumocyte phases: edema; exudate (hyaline membranes); interstitial inflammation; resolve or organize (interstitial fibrosis) 2. HMD (hyaline membrane disease or respiratory distress syndrome of the newborn) seen in premature infants (most common cause of death in premature infants) immature lungs have decreased surfactant (dipalmitoyl phosphatidylcholine) production (made by type II pneumocytes after 35 weeks gestation) atelectasis causes hypoxemia and CO2 retention (acidosis), which causes pulmonary vasoconstriction and endothelial and epithelial cell damage increased lecithin causes L/S (lecithin-sphingomyelin) ratio of >2 = fetal maturity grossly the lungs are collapsed (atelectasis), stiff, and look like liver microscopic is identical to ARDS (hyaline membranes) associated with C-sections and diabetes mellitus in mom (mom's increased glucose increases fetal insulin secretion which inhibits the effects of steroids, including lung maturation and formation of surfactant) treatment for mom give corticosteroids before birth treatment for infant give artificial surfactant after birth; also mechanical ventilation with CPAP (continuous positive airway pressure) important note: oxygen therapy may cause retrolental fibroplasia (ROP) in the eyes and bronchopulmonary dysplasia C. acute interstitial pneumonia (AIP): clinically similar to ARDS but of unknown etiology (idiopathic ARDS)
causes 83. Diffuse 1. ARDS

pulmonary disease (general) (airway): obstruction increases resistance to airflow 1. classify COPD (chronic obstructive pulmonary disease) by location of obstruction: acinus = emphysema (decreased elastic recoil) bronchiole = bronchiolitis bronchus = asthma (but changes are reversible), bronchiectasis (dilated bronchi due to repeated infections), chronic bronchitisanything that narrows the airway 2. pulmonary function tests decreased expiratory flow rates with decreased maximal midexpiratory flow; decreased FEV1 normal to increased TLC (total lung capacity) and RV (residual volumne), due to air trapping; decreased FVC (forced vital capacity) FEV1/FVC <= 75% = obstruction B. restrictive 1. disorders of chest wall (scoliosis, polio, myasthenia gravis) or interstitium of lung (infiltrative) eg, interstitial fibrosis, pneumonia, edema, ARDS, sarcoidosis 2. pulmonary function tests a) decreased RV, TLC, and VC b) normal to increased expiratory flow rates c) FEV1/FVC > 75% = no obstruction FVC and FEV1 > 80% = within normal limits FVC and FEV1 <= 80% = restrictive lung disease
A. obstructive

84. Emphysema

15
A. general

enlargement of airspaces (hyperinflation) due to destruction of walls (without fibrosis) is imbalance between proteases (elastase) and anti-protease (alpha1antitrypsin) decreased elastic recoil and increased lung compliance causes expiratory collapse of airways, which leads to obstruction (breathe through pursed lips = pink puffers = increased pressure keeps the airways from collapsing) irreversible obstruction causes decreased flow (FEV1/FVC < 75%), decreased FVC, increased volume (increased TLC, FRC, RV) increased A-a gradient due to V/Q mismatch by destroying the alveolar septum, you are reducing the number of capillaries = dead space (V/Q = infinity) B. centriacinar (centrilobular) destruction of proximal acinus due primarily to cigarette smoking (caused by things that were inhaled); effects apical portion of lung most; big holes that are not evenly distributed damage is irreversible (damage is not repaired if individual quits smoking) C. panacinar (panlobular) destruction of entire acinus (not entire lobe) is due to decreased alpha1antitrypsin (A1AT is inactivated by cig smoke) normal allele is PiMM and the bad allele is PiZZ (think "PAN PiZZa") effects lower lobes of lung most; smaller, more evenly distributed holes also associated with liver disease (cirrhosis) due to the accumulation of alpha1antitrypsin in hepatocytes D. other 1. compensatory (hyperinflation): response to loss of lung substance elsewhere (eg, post-surgery) 2. obstructive overinflation air is trapped within lung, such as by a tumor or foreign object tension pneumothorax: causes acute, severe one-side chest pain and trouble breathing; hyper-resonant lung percussion with decreased breath sounds; x-ray shows trachea shifted away from affected lung; rx with insertion of chest tube 3. bullous (paraseptal or subpleural) can cause spontaneous pneumothorax in young adult who will present with sudden pleuritic chest pain and SOB (decreased breath sounds with lungs that are hyper-resonant to percussion and decreased tactile fremitus) 4. interstitial emphysema: air in connective tissue of lungs, mediastinum, or subcutaneous tissue E. Treatment: oxygen is the only thing shown to increase survival
cause 85. Chronic

abnormal

bronchitis A. general persistent cough with sputum production for more than 3 months in 2 consecutive years (usually due to smoking) microscopic may show copious mucus plugging of airways with hyperplasia of mucus glands/goblet cells increased Reid index = increased thickness of gland layer/thickness of bronchial wall (should be 0.4) B. compare chronic bronchitis to emphysema (both usually due to smoking, therefore may be much overlap and combination of both) 1. chronic bronchitis ("blue bloaters") dyspnea mild (late) productive cough with copious sputum production; infections common (associated with fever) giving 100% O2 to severe chronic bronchitis can take away ventilatory drive decreased PaO2 (hypoxemia) produces hypoxia and cyanosis (appears "blue" clinically); shunting of blood cyanosis causes increased hematocrit and increased pulmonary artery pressure; cor pulmonale common (large heart due to RV hypertrophy) cor pulmonale can lead to RV failure and systemic edema (bloaters) 2. emphysema dyspnea severe (early) not associated with cough or infections

16
no

cyanosis (appears "pink" clinically when compared to chronic bronchitis); no cyanosis = normal hematocrit and no cor pulmonale (small heart) "pink puffers" = patients with barrel-chest (increased a-p diameter of chest); lean forward and breath through pursed-lips
86. Asthma A. immunologic 1. most

(extrinsic) asthma common form, which is atopic (allergic = may present with hay fever, asthma, eczema) 2. familial form associated with more severe symptoms that begin in childhood and disappear with age 3. type I hypersensitivity reaction = macrophages stimulate T helper (TH2) lymphocytes (imbalance between type 2 helper T cells and type 1 helper T cells), which then stimulate B lymphocytes (via IL-4, 5, and 6) to form plasma cells that secrete IgE eosinophils (peripheral eosinophilia) via IL-5 and mast cells via IL-3 mast cells secrete cytokines that increase other leukocytes, such as neutrophils and monocytes, this being the late-phase reaction mast cell products include histamine, leukotrienes, prostaglandins, and bradykinin 4. chemical mediators of bronchoconstriction include leukotrienes C4, D4, E4, histamine, and prostaglandin D2 5. may be related to polymorphism of ADAM-33 gene, which is expressed by lung fibroblasts and bronchial smooth muscle cells B. non-immunologic (intrinsic) asthma 1. due to neurologic abnormality caused by non-reaginic (viruses), drugs (aspirin), and other (stress, exercise, cold) (but is still considered to be a type I hypersensitivity reaction) aspirin-induce asthma is seen in adults with triad of nasal polyps, rhinitis, and bronchoconstriction aspirin-induce asthma is due to excess leukotriene production due to imbalance between leukotriene production and inhibition of prostacyclins 2. neural imbalance affects ASM (airway smooth muscle) cell excess parasympathetic (cholinergic) stimulation of M3 and alpha1 receptors result in bronchoconstriction C. symptoms are due to bronchial hyperresponsiveness that causes reversible bronchoconstriction and secretion reversible obstruction causes decreased flow (FEV1/FVC < 75%), decreased FVC, increased volume (increased TLC, FRC, RV) wheezing (expiratory), cough (secondary to mucus production and vagal stimulation), dyspnea, hypoxia, tachypnea (increased respiratory rate) note that hypercapnia (increased PaCO2) and respiratory acidosis are bad signs (pt tires from work of breathing, breaths slowly and retains CO2) D. microscopic acute (seen in sputum) include Curschmanns spirals (mucus plugs) and Charcot-Leyden crystals (needle-like crystals from eosinophil membranes) chronic histologic changes include smooth muscle hypertrophy and hyperplasia
87. Bronchiectasis A. general

dilated bronchi and bronchioles to obstruction and repeated infections: scarring results in dilated, thick-walled bronchioles B. etiology 1. primary ciliary dyskinesia a) Kartagener's syndrome (immotile cilia syndrome) is due to decreased ATPase-containing dynein arms classic triad = sinusitis, situs inversus (cardiac apical impulse in right 6 intercostal space), and bronchiectasis also produces sterility and chronic nonproductive cough 2. cystic fibrosis due to repeated infections (especially pseudomonas) 3. allergic bronchopulmonary aspergillosis (ABPA): important complication of asthma and cystic fibrosis C. clinical: severe, persistent cough; foul-smelling, sometimes bloody sputum; dyspnea and orthopnea
due 88. Fibrosing

premanent

pulmonary diseases tend to be chronic

17
A. idiopathic caused

pulmonary fibrosis (IPF); interstitial fibrosis by repeated cycles of acute lung injury (alveolitis) by unidentified agent repeated alveolar injury (many causes) leads to injury to type I pneumocytes, hyperplasia of type II pneumocytes wound healing produces exuberant fibroblastic proliferation; results in characteristic "fibroblastic foci" process is variable over space (some normal areas; some abnormal) and time (early fibrous foci and dense scars) usual mx: is UIP (usual interstitial pneumonitis histological pattern, but can be seen with other disorders) end-stage grossly is "honeycomb" lung with lots of large cysts mostly lower lung zones clinical: does not respond to steroids (poor prognosis), dyspnea on exertion, dry cough, endothelin receptor agonists seem to help improve the clinical course Pirfenidone in phase 3 triales for IPF inhibits all of the usual growth factors B. nonspecific interstitial pneumonia (NSIP) diffuse interstitial lung disease; unknown etiology (much better prognosis than UIP; most don't progress to honeycomb lung) whereas IPF is caused by repeated injury, NSIP is thought to be due to a single, acute injury to the alveoli (monophasic) will all be either early fibrosus or all dense scars not both no characteristic mx features present; variable over space but not variable over time (in contrast to UIP) generally don't find early damage (fibroblastic foci) at time of diagnosis produces dyspnea, dry cough; has the potential to progress to IPF C. cryptogenic organizing pneumonia (COP) aka bronchiolitis obliterans-organizing pneumonia (BOOP) a common response to infectious or inflammatory injury; is essentially a late-phase pneumonia where the original pneumonia didnt have a real specific cause microscopy reveals polypoid plugs of loose fibrous tissue filling bronchioles (bronchiolitis obliterans) and alveoli (organizing pneumonia) looks like small islands of fibrous tissue in the alveolar space
89. Pneumoconioses

(pulmonary dust diseases) = non-neoplastic lung reaction to environmental dusts (Note that Caplans syndrome is a pneumoconiosis plus rheumatoid nodules in the lungs) A. carbon anthracosis (black pigment in macrophages, little cellular reaction, no fibrosis) is seen in city dwellers (pollution) and cigarette smokers coal workers pneumoconiosis (coal dust contains carbon and silica): pts may have cough with blackened sputum; coal dust is weakly fibrogenic simple CWP (coal workers pneumoconioses) have small lesions (< 2 mm) called coal macules or coal nodules if < 2 cm, found around the bronchioles; are generally asymptomatic or have very few symptoms complicated CWP have large lesions (> 2 cm) and is also called progressive massive fibrosis (PMF) start to have significant symptoms with a significantly worsened prognosis PMF can complicate any pneumoconiosis; but more common with CWP and silica B. silica the most prevalent chronic occupational disease in the world (also seen in sandblasters (inhalation of sand) and mine workers) birefringent particles are ingested by macrophages which then release fibrotic factors (fibrosis) and die (fibrosis without inflammation) profoundly fibrogenic early lesions are small fibrotic nodules, while late lesions have concentric fibrotic layers with "eggshell" calcification leads to end stage lung disease acellular fibrosis of the upper zone of the lung think silicosis; interstitial fibrosis of the lower lobes think asbestosis increased risk of developing tuberculosis (with an increased risk for cancer); silica particles interfere with macrophage ability to deal with mycobateria C. asbestos straight, stiff asbestos (amphibole fibers containing silicate) are eaten by macrophages which then release factors causing fibrosis (pulmonary interstitial fibrosis) and localized fibrous pleural plaques (asbestos can also form serpentine fibers [curly], but these are not as likely to cause asbestosis as amphibole fibers are) asbestos bodies are dumbbell-shaped particles covered with iron (ferruginous bodies), they stain with Prussian blue

18
in ship builders (eg shipyard workers) and plumbers (long latency period) ivory-white pleural plaques, mesotheliomas, and cancers cancer associations include bronchogenic (synergistic effect with smoking), laryngeal, and possibly stomach and colon cancer note that Caplan syndrome = rheumatoid nodule (mx shows central necrosis surrounded by palisading histiocytes) + coal, silica, or asbestos D. beryllium seen in certain industry and aerospace workers chronic reactions are cell-mediated immunity (type IV hypersensitivity reaction) that produce non-caseating granulomas E. talc seen in IV drug abusers (used to "cut" drugs) polarizable foreign material (around blood vessels) that can produce foreign body-type granulomas
cause 90. Granulomatous A. sarcoid young seen

diseases

black females with hypercalcemia and enlarged hilar lymph nodes ("potato nodes" with chest x-ray) reveals non-caseating granulomas with epithelioid cells (negative cultures); may try to biopsy conjunctiva inclusion in giant cells: asteroid bodies (stellate products of lipoprotein metabolism) and Schaumann bodies (concentric laminated, calcified bodies) abnormal immunity: cutaneous anergy, decreased cell-mediated immunity, decreased CD4 cells in the peripheral blood, increased CD8 cells in the peripheral blood (since CD4s accumulate in the lungs) lung disease is restrictive disease (interstitial fibrosis) Kveim skin test is not used any more (inject material from individual with sarcoid into another and look for noncaseating granuloma formation) blood angiotensin converting enzyme levels may be elevated B. hypersensitivity pneumonitis immunologic mediated interstitial damage (need to dx early and remove causative agent to prevent progression to fibrotic lung disease) mx: interstitial pneumonitis with chronic inflammation and possible fibrosis Farmer's lung (sudden development of malaise along with dyspnea, fever, and cough ) is caused by thermophilic actinomycetes that grow on hay byssinosis is associated with cotton, linen, or hemp; bagassosis is associated with sugar cane bird-breeder's lung (a type of restrictive lung disease) caused by bird droppings or feathers Humidifier/AC lung thermophilic bacteria
microscopy 91. Other

pulmonary disorders eosinophilia 1. sx include cough, fever, weight loss and peripheral eosinophilia 2. categories acute eosinophilic pneumonia with respiratory failure (px: prompt response to corticosteroids) simple pulmonary eosinophilia (Loffler syndrome) tropical eosinophilia: caused by infection with microfilariae secondary eosinophilia: parasites, fungi, bacteria, allergies, etc idiopathic chronic eosinophilic pneumonia B. smoking-related interstitial diseases 1. DIP (desquamative interstitial pneumonitis) mx intra-alveolar sheets of macrophages with dusty brown pigment (smokers' macrophages) associated with smoking; good response to steroid therapy and smoking cessation (no fibrosis) 2. respiratory bronchiolitis-associated interstitial lung disease common histologic lesion (smokers' macrophages) found in cigarette smokers C. PAP (pulmonary alveolar proteinosis) 1. general
A. pulmonary

19
signs include cough with production of gelatinous chunks (may be associated with exposure to silica dust) accumulation of surfactant microscopic shows dense, granular, PAS-positive (carbohydrate-containing) material in alveoli 2. types acquired PAP (most common type): caused by anti-GM-CSF antibody; GM-CSF normally stimulates alveolar macrophages to degrade surfactant congenital PAP: mutations in different genes: surfactant protein B (SP-B), GM-CSF, and GM receptor beta chain secondary PAP D. aspiration may aspirate food or mineral oil (lipid pneumonia); sx is cough without fever more often causes abnormality on right side, ie right lower lobe (because right bronchus is more vertical than left) E. drugs: examples of effects include bronchospasm (aspirin), hypersensitivity reaction (methotrexate), and fibrosis (bleomycin or amiodarone) F. sleep apnea syndrome: typically obese adult male with loud snoring, unrestful sleep, headaches upon awakening, excessive daytime sleepiness rx with continuous positive airway pressure compare to narcolepsy: sudden transition from consciousness into REM sleep
92. Pulmonary clinical

emboli and hypertension emboli (PE) possible scenario: post-surgical patient in bed develops sudden shortness of breath (confirm diagnosis with V/Q scan or increased fibrin split products) usually thromboemboli: source is usually thrombi (clots) from deep leg veins (DVT); abnormal Doppler study of the veins of the lower extremity risk factors include smoking, prolonged bed rest, decreased protein C, pregnancy (and many more) other types include air emboli, amniotic emboli, fat emboli, and bone marrow emboli gross appearance: wedge-shaped red infarct; mx: hemorrhagic infarction (because of dual blood supply; pulmonary artery and bronchial artery) most are thromboemboli are small and due no harm, but large emboli can produce acute cor pulmonale or sudden death (due to saddle embolus) may see electromechanical dissociation on EKG; PE can cause hypoxemia (which is decreased PaO2) due to increased dead air space rx initially with IV heparin to prevent further clots and emboli; then switch to oral warfarin B. pulmonary hypertension 1. general mx see pulmonary vascular sclerosis, but pathognomonic are plexiform lesions (intraluminal angiomatous tufts or webs) produces right ventricular hypertrophy (cor pulmonale) with right axis deviation on EKG 2. primary pulmonary hypertension is usually seen in young females (age 20-40) who present shortness of breath and chest pain caused by mutations in the bone morphogenetic protein receptor 2 (BMPR2) signaling pathway normally in vascular smooth muscle BMPR2 signaling inhibits proliferation and promotes apoptosis 3. secondary pulmonary hypertension is associated with hypoxic lung diseases (hypoxia stimulates vasoconstriction in the lung, but in other parts of the body, hypoxia causes vasodilation) heart disease that cause pulmonary hypertension, including MV disease, left ventricular failure, and congenital left to right shunts may also be secondary to diet pills (Redux, fen-phen) or recurrent thromboemboli (weird cause is drinking Jamaican bush tea) 4. Idiopathic dyspnea, syncope; once you develop symptoms, the prognosis is fairly poor
A. pulmonary

20
93. Hemorrhagic

syndromes syndrome antibodies vrs the noncollagenous portion (alpha-3 chain) of type IV collagen of basement membrane of lungs and kidneys (linear deposits of IgG) males age 20-40 with pulmonary hemorrhage (hemoptysis) and renal involvement (hematuria from RPGN) treat with plasma exchange B. idiopathic pulmonary hemosiderosis is found in kids and is similar to Goodpastures (but no male predominance, no renal changes, no Ab's) C. hemorrhagic syndromes with angiitis include Wegener's granulomatosis and Churg-Strauss syndrome 1. Wegeners granulomatosis focal necrotizing vasculitis and acute necrotizing granulomas of upper and lower respiratory tract transbronchial biopsies reveal large, serpiginous necrosis with peripheral, palisading macrophages positive ANCA (if kidney involved), mainly c-ANCA (anti-proteinase 3) (c-ANCA = cytoplasmic staining pattern of ANCA) signs include perforation of nasal septum, chronic sinusitis, hemoptysis, hematuria 2. Churg-Strauss (allergic vasculitis) necrotizing vasculitis with granulomas of respiratory tract and asthma associated with IgE and peripheral eosinophilia
A. Goodpasture

94. Pulmonary A. general

infections mechanisms to avoid infections: mucus and cilia (note that influenza virus secretes neuraminidase which destroys mucus) alveolar macrophages, T cells, and lymphoid aggregates (mucosa associated lymphoid tissue = MALT) because lung originates from endoderm IgA in secretions B. bacterial pneumonia 1. clinical signs = acute onset of fever, chills, malaise (feeling sick), peripheral leukocytosis, cough with sputum production rusty sputum think strep pneumonia (a good sputum specimen has many PMNs and few epithelial cells) mucoid or "currant jelly" sputum think Klebsiella pneumoniae pleuritic pain and pleural friction rub = fibrinosuppurative pleuritis 2. selected bacteria a) Strep pneumoniae (pneumococcus) is the most common cause a gram-positive lancet-shaped diplococcus; often stains poorly and may appear gram-negative polysaccharide capsule; many capsular serotypes, therefore vaccinate with many different capsular carbohydrates bile soluble, susceptible to Optochin, and shows a Quellung reaction (capsular swelling) high rate of oropharyngeal colonization: 40% of kids less than 5 years old (this rate decreases with age) not always in pathogenic mode; switches into invasive pathogenic mode with change in gene expression increasing incidence of penicillin resistance tendency to cause lobar pneumonia b) Haemophilus influenza very small coccobacillary gram-negative bacteria; very hard to detect in sputum gram stain because of size pneumonia is milder and more insidious; vaccine given to kids to prevent meningitis defenses: pili (stick to respiratory epithelium); secretes protein factor (inhibits cilia) and protease (that degrades IgA) may cause epiglottitis c) Moraxella catarrhalis: second most common bacterial cause of acute exacerbation of COPD (also elderly) gram-negative coccobacillus d) Staphylococcus aureus (gram-positive coccus that typically is seen forming grape-like clusters) frequently seen following viral infections (i.e. is opportunistic) typically causes bronchopneumonia, causes abscess formation; increasing resistance to antibiotics; methicillin resistance is very common (MRSA)

21
pneumoniae rod (most common gram-negative bacillus causing pneumonia); sputum may be gelatinous due to capsular polysaccharide seen in diabetics or alcoholics; abrupt and prostrating onset; frequently lobar pneumonia; lower survival f) Pseudomonas aeruginosa nosocomial pneumonia (also "hot tub folliculitis"); infection in neutropenic patients and cystic fibrosis children greenish color sputum; tendency to invade blood vessels g) Legionella pneumonia is due to Legionella pneumophila water-borne: associated with water reservoirs, cooling units (air conditioners), humidifiers (even sprinklers in grocery stores) infects freshwater amoeba and human macrophages; transmission is via inhalation produces high fever, nonproductive cough, pleuritic chest pain (flu-like syndrome) extrapulmonary sx: diarrhea, abdominal pain, azotemia, hematuria culture takes awhile; rapid test is DFA (direct fluorescent antibody); since we aren't colonized by this organism, even saliva is OK for test histology shows bronchopneumonia with mononuclear infiltrate (macrophages) surrounding necrotic tissue gram stain shows no organisms, but rods are seen with silver stains treatment is with erythromycin h) pneumonic plague is due to yersinia pestis (organism has "safety-pin appearance and is spread by the rat flea) i) Bacillus anthracis (a large spore-forming gram-positive rod; square-ended "box car" morphology; cultures have "medusa head" appearance) (1) associated with sheep farmer, veterinarian, wool worker; used as a weapon of biological terrorism (2) three distinct forms of anthrax depending on how it enters the body (a) cutaneous anthrax starts with a small bump; within a few days, forms painless, open sore with a tell-tale black center of dead tissue (malignant pustule) this form of anthrax is highly treatable; but about 20% of untreated victims die (b) inhalation anthrax initially like the common cold, but it can rapidly progress to severe pneumonia with difficulty breathing and shock fatal if not treated; must start treatment in the incubation period (1-6 days) before sx, mortality can decrease to 1%; not contagious (c) gastrointestinal anthrax begins with loss of appetite, nausea, vomiting, and fever; progresses to vomiting of blood and severe diarrhea fatal in 25% to 60% of cases but is extremely rare in humans; almost unknown in the U.S 3. morphology a) bronchopneumonia patchy inflammation involving one or more lobes (usually inferior lobes) = lobular pneumonia suppurative exudate filling bronchi, bronchioles and spilling over into adjacent alveoli patients are infants, aged, or individuals with chronic debilitating diseases b) lobar pneumonia (spread is through pores of Kohn, which connect alveolus to alveolus); involvement of entire lobe by virulent organism (1) four classic stages of lobar pneumonia congestion = edema, bacteria, few cells red hepatization = many cells (red cells and PMNs) and fibrin gray hepatization = dying cells and increased fibrin resolution = gone (not the same as organization, which is bad) C. interstitial pneumonia (aka primary atypical pneumonia) 1. general produces headache, malaise, dry hacking nonproductive cough ("walking pneumonia")
gram-negative e) Klebsiella

22
patchy inflammation (lymphocytes) of interstitium (walls of alveoli) in one or more lobes (this being the reason it's called "atypical") 2. causes include viruses, Chlamydia psittaci, C. pneumoniae, and Mycoplasma pneumoniae; viral causes include CMV (large cells with intranuclear inclusions), measles (measles pneumonia), influenza A & B, adenovirus a) influenza virus envelope contains viral hemagglutinin and neuraminidase, which determine the viral subtype antigenic drift produces epidemics; antigenic shifts produces pandemics (three in this century: 1918, 1957 and 1968) variation through antigen shifts and drifts makes vaccine difficult sx: fever (often higher in children), cough, sore throat, runny or stuffy nose, headache, muscle aches, often extreme fatigue most people recover completely within 1-2 weeks, but frequently creates conditions for secondary bacterial pneumonia H5N1 associated with high levels of cytokines ("cytokine storm"; knocking out NF-KB will help reduce the cytokine storm -> makes virus more lethal [any immune response is better than no immune response]), lung tropism (viral pneumonia), rapid replication, and multi-organ failure b) mycoplasma pneumoniae has no cell wall, like chlamydia; therefore penicillin, etc don't work (rx with erythromycin); culture takes weeks is associated with IgM anti-I cold agglutinins c) respiratory syncytial virus (RSV) most common cause of fatal acute respiratory infection in infants and young; ubiquitous; everyone infected by 4 years of age reinfection can occur; winter epidemics; doesn't culture well; diagnose with direct fluorescent antibody test; treat with nebulized ribavirin RSV is a common cause of wheezing in children under the age of 2 mx: intracytoplasmic pink inclusions and cell that grow together (in a syncytium) d) hantavirus hantavirus pulmonary syndrome (HPS) is a potentially fatal infectious respiratory disease endemic to North and South America; first recognized in 1993 in New Mexico transmitted by infected rodents through urine, droppings, or saliva sx: mild fever for 3-5 days (then precipitous decline in health), thrombocytopenia, atypical lymphocytes, myocardial depression mx: looks like pulmonary edema, not ARDS rx: supportive treatment only the pulmonary edema isnt really damaging, so if you can keep the person alive on a heart-lung machine until the pulmonary edema clears, the patient will be fine D. SARS (severe acute respiratory syndrome) respiratory illness with onset after 2/1/2003; etiology is a coronavirus (SARS-CoV) areas of transmission: mainland China, Taiwan, Hong Kong, Singapore, Toronto; probably came from bats lab: peripheral lymphopenia sx: cough, SOB, fever, x-ray evidence of pneumonia; non-respiratory sx include headaches, diarrhea, nausea and vomiting mx of lungs: hyaline membranes, interstitial mononuclear inflammation, desquamation of pneumocytes into alveoli rx: protease inhibitors, steroids not effective, ribavirin not effective, hyperimmune serum might work E. lung abscess fever and prominent cough with production of copious amounts of foul smelling purulent sputum changes in patient position causes paroxysms of coughing; x-ray reveals air-fluid level note that aspiration more often on right side (posterior basal lobe) common pathogen is staph aureus
95. Systemic diffuse

mycoses (fungi) capsulatum is a dimorphic fungus that causes a flu-like syndrome

A. histoplasmosis Histoplasma

23
find yeast within the cytoplasm of macrophages (intracellular) by inhalation of soil contaminated with bird (starlings, chickens) or bat droppings in Ohio and Mississippi valleys sx: similar to TB, usually self-limited and asymptomatic but can be chronic and progressive B. blastomycosis Blastomyces dermatiditis is a dimorphic fungus that causes disease in Ohio and Mississippi Valleys dimorphic = hyphal (elongated fungal form) in soil (inhale spore); in body becomes yeast (seen in tissue) microscopically shows a characteristic broad-based budding yeast; also double-contour (bulls-eye) appearance sx: non-specific flu-like symptoms (hacking cough, chest pain, fever, chills; may be asymptomatic) C. coccidiomycosis inhalation of arthrospores of dimorphic fungus Coccidioides immitis causes fever, cough, pleuritic chest pain microscopically see large spherules filled with many small endospores classic location is Southwest United States (San Joaquin Valley fever) hyphal forms in cultures very contagious D. Pneumocystis pneumonia is due to Pneumocystis (jirovecii) carinii (a fungus that behaves like a protozoa) seen in immunosuppressed individuals (AIDS): may be presenting sign microscopically see foamy material in alveoli silver stains show organisms that have cup shapes or central dots treat with TMP-SMX (trimethoprim/sulfamethoxazole [bactrim]), pentamidine, folic acid inhibitors E. candidiasis due to Candida albicans = budding yeast with non-branching pseudohyphae (germ tube formation in culture at 37 degrees C) and blastocysts pseudohyphae are tandem arrays of elongated yeast forms without hyphae clinically see white plaques (thrush) in immunocompromised individuals (neonates, diabetics, steroid use, AIDS) also causes endocarditis in IV drug abusers and vaginitis after antibiotic use F. aspergillosis caused by Aspergillus species (inhaled) which have thin septate hyphae with acute-angle branching (not dimorphic) fruiting bodies (when exposed to air can form fungus ball (aspergilloma) in lung cavity) G. Paracoccidioides aka South American blastomycosis "mariner's wheel" histologic appearance H. Cryptococcosis Cryptococcus neoformans (encapsulated yeast (not dimorphic) that has mucicarmine-positive capsule) also causes CNS infection in immunosuppressed patients (use India ink stain of CSF to cause negative staining of capsule) I. mucormycosis nasal infection (blood-tinged nasal discharge) in diabetic patients broad, non-septate hyphae with right angle branching ("bread mold fungi" = Mucor, Rhizopus, Absidia, Cunninghamella) J. sporotrichosis (sporothrix schenckii) dimorphic fungus seen in rose-growers (thorns); mx shows cigar-shaped yeast surrounded by eosinophilic material
acquired 96. Mycobacteria A. TB 1. first histologically

exposure (spread by inhalation) is called primary pulmonary TB granulomas = epithelioid cells (activated macrophages) plus central caseous necrosis and Langhans giant cells granulomas = delayed type hypersensitivity reaction (a type IV hypersensitivity reaction) most common site is a subpleural lesion near the fissure between the upper and lower lobes (areas with greatest air flow)
caseating

24
complex = parenchymal subpleural lesion (interlobar fissure between upper and lower lobes) plus enlarged hilar lymph nodes risk factors include immunosuppression, low socioeconomic status, long-term care, Native American heritage (not exposure to asbestos) virulence is secondary to components of TB cell wall (eg cord factor and sulfatides) 2. re-exposure or further disease a) secondary pulmonary TB is typically at apex of lungs (areas of high PAO2 due to V/Q mismatch) normal: ventilation (V) at base > apex; perfusion (Q) at base > apex; V/Q ratio at apex > base b) progressive diseases: cavitary fibrocaseous TB (usually found in the apex) erosion into blood vessels causes miliary TB (multiple small white lesions in lungs and other organs) involvement of spine is Potts disease, while involvement of cervical lymph nodes is scrofula 3. signs and symptoms = fever, weight loss, night sweats, cough, hemoptysis 4. diagnosis a) culture may take weeks to grow; use special stains to identify they have a high lipid content and abundant mycolic acid in their cell wall they stain with carbolfuscin and are acid fast bacilli (their waxy coat causes them to retain red dye when treated with acid) b) TB skin test (Mantoux test) intradermal injection of PPD (purified protein derivative) a positive reaction is >0.5 cm induration at 48 hours (a type IV hypersensitivity reaction) false positive reaction after BCG (Bacille Calmette-Guerin), which is an attenuated M. bovis strain used outside the United States as prophylaxis (then cant use PPD for diagnosis) 5. treatment = first line of drugs include isoniazid, rifampin, ethambutol, pyrazinamide B. MOTT 1. MOTT = mycobacteria other than tuberculosis (atypical mycobacteria) 2. M. avium-intracellulare (MAI) infection is seen in patients with AIDS (many organisms are present microscopically, but no granuloma are formed) 3. M. marinum disease is associated with swimming pools and aquariums (organism inhabits water and marine organisms) 4. M. leprae causes leprosy (Hansens disease); organisms cannot be cultured (except in armadillo) a) tuberculoid leprosy flat, erythematous plaques with positive lepromin test (cell-mediated immunity intact) non-caseating granulomas with rare bacilli b) lepromatous leprosy (anergic) extensive macules, papules, nodules (on face = lion face) palpable enlarged nerves (acid fast bacilli in nerves); destruction of nerves causes peripheral neuropathy negative lepromin test (find many CD8+ suppressor cells = cell-mediated immunity suppressed) no granulomas but macrophages with lots of bacilli = foam cells or leprae cells
97. Lung Ghon

neoplasms A. general bronchogenic carcinomas arise from bronchi and are the leading cause of cancer death clinical presentation = cough, hemoptysis, "coin" lesion on chest x-ray tumors at apex (Pancoast tumors) may invade C8-T1,2 (causing pain in ulnar portion of arm) or invade cervical sympathetic plexus and cause Horner syndrome = ptosis (lid drop), miosis (pupil constriction), anhidrosis (no sweating) hoarseness may be due to recurrent laryngeal nerve involvement other paraneoplastic syndromes include SIADH (inc ADH causing dec sodium), Cushing's syndrome (due to inc ACTH), hypercalcemia (inc PTrP) B. squamous cell carcinoma microscopic reveals keratin pearl formation, intracytoplasmic keratin production, and intercellular bridges (EM finds desmosomes)

25
centrally and is linked to smoking; preceded for years by squamous metaplasia then dysplasia then carcinoma-in-situ highest frequency of p53 mutations of all histologic types of lung cancer C. adenocarcinoma microscopically see glandular formation (probably most common histologic type now of lung cancer) found peripherally (association with fibrosis is sometimes called scar carcinoma) K-RAS mutations are seen primarily in adenocarcinoma D. bronchioloalveolar carcinoma (BAC) found peripherally, multiple lesions with pneumonia-like spread through pores of Kohn (may look like pneumonia on x-ray) mx: well-differentiated, mucus-secreting, columnar epithelial cells that infiltrate along the alveolar walls not related to smoking; well-differentiated tumor (good prognosis) E. small cell carcinoma aka oat cell carcinoma; mx: scant amounts of cytoplasm, nuclei are small, round, and rarely have nucleoli neuroendocrine tumor (membrane-bound dense core neurosecretory granules by EM) found at hilum (centrally) and is linked to smoking may have ectopic hormone production (paraneoplastic syndromes) clinically aggressive with early metastases, therefore therapy is not surgery but is chemotherapy F. large cell carcinoma non-small cell carcinoma with no cellular differentiation = undifferentiated large cell carcinoma G. neuroendocrine tumors 1. carcinoid neuroendocrine tumor that arises for Kulchitsky cells (membrane-bound dense core neurosecretory granules by EM) may produce the carcinoid syndrome due to serotonin production = wheezing, cutaneous flushing, recurrent diarrhea not related to smoking; may behave in benign or malignant fashion mx: individual tumor cells are quite regular with uniform nuclei; the aggressive form has necrosis and atypical mitoses typical carcinoids: no p53 mutations or BCL2/BAX imbalance; these are seen in atypical carcinoids
98. Other found

tumors

A. hamartoma:

benign neoplasm composed of cartilage arranged in a haphazard fashion; usually an incidental finding myofibroblastic tumor C. mediastinum 1. anterior mediastinum (think "T'") a) thymus (1) hypoplasia = DiGeorges syndrome (2) hyperplasia is defined histologically by the presence of reactive follicles (B cell proliferation); associated with myasthenia gravis (3) malignant lymphomas of the thymus include non-Hodgkins T cell lymphoblastic lymphoma and Hodgkins disease (nodular sclerosis type) (4) leukemia (acute lymphoblastic leukemia of T cell type) (5) thymomas: originate from epithelial cells of thymus may be benign or malignant; malignant signs include infiltration and capsular invasion plus pleural implants or distant metastasis histology shows epithelial neoplasms with varying numbers of nonneoplastic T lymphocytes paraneoplastic syndromes include myasthenia gravis, pure red cell aplasia (low hematocrit in newborn), and aplastic anemia b) thyroid and parathyroid lesions (ectopic) c) germ cell tumors include seminoma and teratoma 2. middle mediastinum = pericardial and bronchogenic cysts 3. posterior mediastinum = neurogenic tumors including schwannomas, neurofibromas, and ganglioneuromas
B. inflammatory

26
99. Pleura A. pleural

effusions (fluid in the pleural cavity) = non-inflammatory edema (inflammatory cells not present) a) clinical definition needs 2 of the following 3: ratio of pleural fluid protein to serum protein less than 0.5 ratio of pleural fluid LDH to serum LDH less than 0.6 pleural fluid LDH less than 2/3rds the upper limit of normal serum LDH b) causes abnormalities of Starling forces causes hydrothorax (usually due to CHF) and chylothorax (tumor obstructing lymphatics causes milky fluid) hemothorax is due to trauma or ruptured aortic aneurysm 2. exudates = inflammatory edema (due to increased vascular permeability); empyema refers to "pus" (inflammatory exudate) in the pleural cavity causes include neoplasms, infections (bacteria may cause empyema; see suppurative infection in the adjacent lung), PE, connective tissue disease B. pleural tumors 1. solitary (localized) fibrous tumor benign tumor (pleural fibroma or pleural plaque); not related to asbestos exposure tumor cells are CD34 positive and keratin negative 2. malignant mesothelioma related to asbestos exposure (mx may see ferruginous bodies) mx: two types of cells: epithelium-like lining cells and mesenchymal stromal cells electron microscopy reveals long microvilli with abundant tonofilaments staining patterns: perinuclear keratin staining; positive for acid mucopolysaccharide (inhibited by hyaluronidase); positive for calretinin negative for CD34, CEA and Leu-M1
1. transudates

KIDNEY
100. Normal A. anatomy

has renal corpuscles and the convoluted tubules (both proximal convoluted tubules and distal convoluted tubules) renal corpuscles have the glomerulus and Bowmans capsule medulla has about 15 renal pyramids containing the loops of Henle and the collecting tubules renal papilla: at the tip (apex) of each pyramid; collecting tubules empty into the minor calyces via the duct of Bellini medullary pyramids are separated by the renal columns, while bundles of straight tubules within the cortex are called medullary rays nephron: glomerulus + proximal tubule + loop of Henle + distal tubule + collecting tubule B. blood vessels blood flow: renal artery; interlobar artery; arcuate artery (travels parallel to the kidney surface at the corticalmedullary junction); interlobular artery; afferent glomerular arteriole; efferent glomerular arteriole; then either peritubular capillary network or vasa recta; then arcuate vein medulla does not have its own arterial blood supply; depends on blood from efferent arterioles C. glomeruli 1. glomerulus has endothelial cells, basement membrane, visceral epithelial cells (podocytes), mesangial cells (mesenchymal origin, phagocytic, can secrete matrix, collagen, and biologically active mediators) 2. mesangium of the glomerulus is located between the glomerular capillaries 3. filtration barrier (from blood vessels to urine space) a) sequence: fenestrations (no diaphragm) of endothelial cells; subendothelial space; basement membrane; subepithelial space; filtration slits (with diaphragms) between pedicles (feet) of podocytes b) composition of basement membrane lamina rara externa: contains heparan sulfate, which is an anion that stops negatively charged molecules

cortex

27
lamina lamina D. tubules urine

densa: contains type IV collagen rara interna: contains heparan sulfate

flow: proximal convoluted tubule (PCT); descending limb of loop of Henle; thin limb of loop of Henle; ascending thick limb (TAL) of loop of Henle; distal convoluted tubule (DCT); collecting ducts (CD); duct of Bellini; minor calyx; major calyx; pelvis; ureter proximal tubular epithelial cells have abundant, long microvilli (brush border) and numerous mitochondria (more vulnerable to ischemic injury than the distal tubular cells) macula densa cells are specialized distal tubular epithelial cells located at the juxtaglomerular apparatus (JGA) juxtaglomerular cells are modified smooth muscle cells of the afferent arteriole at the JGA that make renin connecting tubules and collecting tubules have two types of specialized epithelial cells, namely principal cells (remove sodium and secrete potassium) and the intercalated cells (remove potassium and secrete hydrogen ions) E. interstitium peritubular interstitial cells produce both prostaglandins and erythropoietin
101. Renal

failure (progressive daily increase in serum creatinine is diagnostic for acute renal failure) 1. prerenal causes include hypovolemia (hemorrhage, hypotension, shock, congestive heart failure) and arterial occlusion (thromboembolism) decreasing GFR leads to oliguria, inc resorption of sodium and water, and very concentrated urine ratio of BUN:creatinine is increased (20:1) urine is maximally concentrated (up to 1500 mosm/L) and the urinary sediment has scant findings 2. renal a) causes include: acute tubular necrosis (ATN) is the most common cause of acute renal failure vascular diseases, glomerular diseases, acute interstitial nephritis (with hemoptysis think Wegener's or Goodpasture's) b) ration BUN:creatinine is more toward normal (10:1 to 15:1) c) urinary sediment may provide clues to cause: tubular epithelial cells and WBCs = ATN and acute interstitial nephritis RBCs and RBC casts = vasculitis and proliferative GN eosinophils suggest allergic nephritis or atheroembolic disease 3. postrenal: due to obstruction (eg stones or BPH in males); may produce hydronephrosis B. chronic azotemia which refers to inc BUN and creatinine (azotemia + constellation of clinical findings = uremia) normochromic normocytic anemia due to dec production of EPO renal osteodystrophy due to dec activation of vitamin D (which also dec calcium) hyperkalemia (which can cause cardiac arrhythmias) due to dec excretion of potassium metabolic acidosis due to dec excretion of acid (hydrogen ions) inc retention of sodium and water causes inc IV volume (inc blood pressure) inc phosphate (may cause metastatic calcification and subsequent hypocalcemia) urine may have waxy casts in the urine sediment
A. acute

102. Congenital/dysplasia/cysts A. renal

agenesis normal aminotic fluid metabolism: secreted by fetus in urine, swallowed by fetus, absorbed by intestines, then back to kidney bilateral renal agenesis (failure of metanephric diverticulum (uteric bud) to develop) produces Potter syndrome (sequence) sx of Potter's include oligohydramnios and characteristic facial features (wide-set eyes, low-set floppy ears, and a broad-flat (parrot-beak) nose) unilateral renal agenesis is associated with a single umbilical artery, rather than the normal two umbilical arteries

28
B. cystic

renal dysplasia: flank mass in children; gross shows "bunch of grapes"; mx shows primitive collecting ducts and islands of mesenchyme (cartilage) C. polycystic renal disease 1. adult type autosomal dominant disorder due to mutation in PKD1 gene (most cases) on chromosome 16 which produces protein called polycystin 1 some cases due to mutation in PKD2 gene, the product of which is polycystin-2 (may ve a calciumpermeable cation channel) bilateral (always), enlarged kidneys due to multiple large cysts (external surface shows multiple cysts) mx shows functioning nephrons between cysts, which arise from tubules patients present with pain, hematuria, hypertension, and progressive renal failure (uremia) 15% associated with polycystic liver disease and berry aneurysms (circle of Willis) 2. infantile type autosomal recessive disorder characterized by bilateral enlarged kidneys with smooth surface and radiallyoriented cysts may be related to PKHD1 gene, which codes for fibrocystin mx shows dilation of all collecting tubules associated with congenital hepatic fibrosis 3. medullary sponge kidney benign (nonfamilial) disorder characterized by multiple cystic dilations of the collecting ducts in the medulla patients may develop hematuria, UTI, and recurrent renal stones 4. nephronophthisis-medullary cystic disease complex cortical tubulointerstitial damage causes renal insufficiency tubular atrophy may produce ADH resistant polyuria with sodium wasting several gene defects identified, including NPH1 (product is nephrocystin), NPH2, NPH3, MCKD1, MCKD2
103. Glomerular A. terms: focal

terms/mechanisms/deposits

= involvement of only some glomeruli diffuse = all glomeruli are involved segmental = only parts of the glomerulus are involved global = entire glomerulus is involved B. mechanisms 1. antibody-mediated injury a) in-situ immune complex formation (1) intrinsic glomerular antigens (linear IF staining) anti-GBM disease Heymann's nephritis,which is a type of GN produced in rats by injecting them with preparations of proximal tubular brush border (2) antigens deposited within the glomerulus (granular IF): drugs or DNA b) deposited as circulating antibody-antigen (immune) complexes (granular IF) (1) subepithelial (between the basement membrane and epithelial cells) diffuse proliferative glomerulonephritis (DPGN) (post-streptococcal): IgG/C3 granular deposits that are large and irregular ("humps") membranous glomerulopathy (MGN): IgG/C3 granular deposits that are small and uniform deposits ("string of popcorn") (2) basement membrane (intramembranous) membranoproliferative glomerulonephritis (MPGN), type II: C3/+or- IgG with dense deposits (dense deposit disease) (3) subendothelial (between the basement membrane and the endothelial cells) membranoproliferative glomerulonephritis, type I: IgG, IgM granular deposits with C3 +/- C1q/C4 SLE: lots of substances ("full house" pattern), but "wire loop" lesions are somewhat characteristic (4) mesangial

29
segmental glomerulonephritis (FSGN) = Berger's disease (IgA nephropathy); IgA/C3 deposits ("holly leaf" appearance) Henoch-Schonlein purpura: IgA deposits; also "holly leaf" pattern 2. cell-mediated injury
104. Glomerular focal

clinical syndromes syndrome hematuria (red blood cells and red blood cell casts in urine) is the main feature hypertension and edema due to retention of salt and water oliguria and variable proteinuria (<3.5g/day) B. nephrotic syndrome marked proteinuria (>3.5g/24 hours) is the main feature dec serum protein due to dec albumin (hypoalbuminemia) produces edema (retain sodium and water) hyperlipidemia due to inc liver synthesis of cholesterol (compensatory mechanism to maintain oncotic pressure by increased apoprotein synthesis hyperlipidemia results in oval fat bodies, fatty casts, and Maltese crosses in urine
A. nephritic

105. DPGN

(diffuse proliferative glomerulonephritis): most commonly due to acute post-streptococcal glomerulonephritis reveals proliferation of endothelial cells, mesangial cells, and neutrophils immunofluorescence reveals granular IgG and C3 EM reveals subepithelial humps ("lumpy-bumpy"); note: MGN also subepithelial deposits that are smaller and uniform 1-3 weeks after streptococcal infection = group A beta hemolytic (strep pyogenes) of pharynx or skin; clinically see inc serum ASO (anti-streptolysin O antibodies, cultures negative, and low serum complement nephritic syndrome with hematuria (RBC casts), mild periorbital edema, inc blood pressure prognosis = children recover, but adults may worsen
microscopic

106. RPGN

(rapidly progressive glomerulonephritis)

A. general

reveals crescents in glomeruli = crescentic glomerulonephritis are composed of epithelial cells (visceral and parietal), inflammatory cells, and fibrin secondary to very bad damage to basement membrane (ruptures) and lots of material leak through B. type I 1. linear immunofluorescence produce linear deposits of IgG and C3 (type II hypersensitivity reaction) 2. most cases are Goodpastures disease (anti-glomerular basement membrane against the noncollagenous portion of type IV collagen) males age 20-40 pulmonary hemorrhage produces hemoptysis and renal involvement produces hematuria chronic hemorrhage leads to anemia treatment is plasmapheresis or plasma exchange to remove autoantibodies from serum C. type II immune complexes (granular staining IF = type III hypersensitivity reaction) idiopathic or primary glomerular disease such as MPGN (II>I) and DPGN systemic diseases (such as post-infection, SLE, Henoch-Schonlein purpura) D. type III pauci-immune (very little deposits) Wegeners granulomatosis involving lungs and kidneys can be c-ANCA positive (cytoplasmic anti-neutrophil cytoplasm antibody; anti-proteinase 3) microscopic polyarteritis: frequently p-ANCA (perinuclear anti-neutrophil cytoplasmic antibody) idiopathic crescentic GN: have mostly p-ANCA
crescents 107. MGN immune

histology

(membranous glomerulopathy) complex (III) mediated (which has a granular immunofluorescence pattern and damage via C5b-9, no inflammation)

30
histology electron

reveals thickened basement membrane but no increase in number of cells microscopy reveals subepithelial deposits (between epithelial cells and the basement membrane) immunofluorescence reveals granular IgG and C3, but are quite uniform and may simulate linear pattern (string of "popcorn") stages: I = subepithelial deposits (basement membrane OK); II = basement membrane forms spikes (use silver stains to see basement membrane well); III = basement membrane forms "spikes and domes" most cases are idiopathic, but may be secondary to cancer, SLE, infections (hepatitis B), drugs (gold and penicillamine) produces nephrotic syndrome (second most common cause of nephrotic syndrome in adult) and nonselective proteinuria
108. MCD

(minimal change disease) lipoid nephrosis because lipid in tubules, fat bodies in urine dec basement membrane polyanions (heparan sulfate) causes selective proteinuria (loss of albumin > globulins) single band (albumin) in urine protein electropheresis light microscopy reveals normal glomeruli electron microscopy shows "fusion" and flattening of foot processes of podocytes no deposits (no immunoglobulin or complement) seen in children (most common cause of nephrotic syndrome in children) a mutation in the nephrin gene (NPHS1) causes a hereditary form of congenital nephrotic syndrome (Finnish type) with minimal change glomerular morphology prognosis is good, treat with steroids (no tendency to develop chronic renal failure)
called

109. FSGS

(focal segmental glomerulosclerosis) (not all = focal) glomeruli are affected (only parts not entire glomerulus affected = segmental) may misdiagnose as MCD (because see "foot fusion" with EM), but steroids are of no benefit immunofluorescence reveals granular IgM and C3 urine protein electropheresis reveals multiple bands (non-selective proteinuria) cause is idiopathic or secondary (i.e. heroin or AIDS; more severe disease in HIV patients) mutations in NPHS2 gene, which encodes for podocin, have been associated with autosomal recessive forms of FSGS a severe form: collapsing variant of FSGS; one form is associated with HIV infection (podocytes infected with HIV) nephrotic (nonselective) +/- hematuria
some

110. MPGN

(membranoproliferative glomerulonephritis) A. histology thick basement membrane = "membrano" while inc mesangial cells = "proliferative" "split" basement membrane: "tram-track" appearance, which is due to mesangial cell processes entering BM B. type I MPGN children and young adults (nephrotic/nephritic); may be associated with hepatitis C infection subendothelial deposits of IgG, IgM, C3 + C1q/C4 C. type II MPGN = dense deposit disease ribbon-like deposits in lamina densa of basement membrane deposits of C3 and properdin due to activation of alternate complement pathway by C3 nephritic factor (an IgG autoantibody that binds alternate pathway C3 convertase, therefore dec serum C3 with normal C1 and C4) (focal segmental glomerulonephritis) A. glomerular necrosis (instead of the sclerosis seen in FSGS) B. Bergers disease = IgA nephropathy (inc serum polymeric IgA) recurrent hematuria (most common cause of nephritic syndrome worldwide) clinical associations include respiratory infection (usual), celiac disease (gluten-sensitive) and dermatitis herpetiformis inc mesangial cells and mesangial ("holly leaf" or "tree in winter" pattern) deposits of IgA, C3, and properdin (alternate complement pathway activation)

111. FSGN

31
C. Henoch-Schonlein purpura

purpura of lower extremities (hemorrhagic urticaria of the extensor surfaces) in children with arthritis and colicky abdominal pain mesangial IgA and C3

112. Other

glomerular disorders nephritis (hereditary syndromes of isolated hematuria) 1. Alport syndrome = hereditary nephritis (seen in Mormon's); most cases are x-linked dominant inheritance recurrent hematuria, progressive nerve deafness (high frequencies), cataracts, dislocated lens due to lack of globular domain of type IV collagen mx: thinning, splitting, and fragmentation of basement membrane; foam cells in glomeruli and tubules 2. thin basement membrane disease (MC cause of benign familial hematuria): diffuse thinning of GBM; no eye or ear abnormalities; excellent prognosis B. chronic glomerulonephritis: end-stage glomerular disease of various types of glomerulonephritis C. SLE: WHO (World Health Organization) classification = 5 classes (all the result of the deposition of DNA-antiDNA immune complexes) class I = no changes class II = mesangial GN class III = focal proliferative GN class IV = diffuse proliferative GN (the most common class): deposits are mainly in a subendothelial location (produce a characteristic "wire loop" appearance due to thickening of the capillary wall) class V = diffuse membranous GN; deposits are in a subepithelial location D. diabetes mellitus; most common cause of nephrotic syndrome nodular glomerulosclerosis = Kimmelstiel-Wilson disease (differentiate form amyloid because amyloid is Congo red positive) glycogen nephrosis = Armanni-Ebstein lesion capsular drops are round eosinophilic masses attached to capsule of Bowman's space also see hyaline arteriosclerosis of afferent and efferent arterioles; inc thickness of basement membranes
A. Hereditary

113. Tubules/interstitium A. general

results of tubular disease (urine having a static specific gravity of about 1.010) metabolic acidosis, normal anion gap (due to the renal loss of bicarbonate) nocturia (urination at night) polyuria (increased urine production) B. acute tubular necrosis (ATN) 1. ischemic ATN (most common cause of ATN) focal regions of tubular necrosis with intervening unaffected areas rupture of basement membrane (tubulorrhexis) 2. nephrotoxic ATN necrosis most prominent in proximal tubule; basement membranes of tubules are not involved may be caused by heavy metals (mercury, lead), ethylene glycol (antifreeze; see calcium oxalate crystals and hydropic or vacuolar degeneration of proximal convoluted tubules; rx with IV ethanol), and drugs uric acid (birefringent, needle-like crystals) may be seen in patients treated for leukemias and lymphomas aminoglycosides (see myeloid bodies, whorled lipid inclusions) 3. clinical phases = initial prodromal phase (36 hours), oliguric phase (10 days), diuretic phase (hypokalemia is a problem), recovery phase (third week) C. acute pyelonephritis infection of kidney with gram-negative bacteria (usually E. coli) gross reveals multiple white spots on surface of kidney (usually the upper and lower poles called "polar abscesses") histology reveals neutrophils in renal tubules and interstitium acute onset of high fever, chills, flank pain (this differentiates pyelonephritis from acute cystitis) urine reveals mild proteinuria, neutrophils (pyuria), bacteria, and white cell casts (latter is pathognomonic)
isosthenuria

32
factors include renal calculi, diabetes mellitus (glycosuria), urinary obstruction, vesicoureteral reflux, catheterization, and short urethra in females D. chronic pyelonephritis ascending infection secondary to chronic obstruction or chronic vesicoureteral reflux (causing chronic, recurrent infections) gross is similar to chronic GN, but chronic pyelonephritis has asymmetrical changes and larger cortical scars mx: chronic inflammation of the interstitium with sclerotic glomeruli and "thyroidization" of the tubules (dilated tubules filled with colloid casts) signs and symptoms include hypertension, chronic renal failure, pyuria and bacteriuria E. chronic analgesic nephritis associated with phenacetin use, especially with combinations of analgesics such as aspirin + phenacetin (because aspirin inhibits formation of prostaglandins that cause vasodilation) mx shows characteristic combination of minimal change disease and acute tubular necrosis F. allergic interstitial nephritis: drug-induced (ampicillin or NSAID's) mx shows interstitial mononuclear inflammation with eosinophils sx include fever, eosinophilia, skin rash, renal changes
114. Renal predisposing

vascular disorders (note: chronic ischemic glomerular injury, such as with nephrosclerosis, is characterized by thickening and wrinkling of the glomerular capillaries) A. benign nephrosclerosis associated with benign hypertension (diastolic < 130mmHg) and diabetes mellitus finely granular surface of kidney grossly smaller vessels have hyaline arteriolosclerosis and fibroelastic hyperplasia note that hormones that can inc blood pressure include glucocorticoids, thyroid hormones, epinephrine, growth hormone, aldosterone B. malignant nephrosclerosis associated with malignant hypertension (diastolic > 130mmHg) sx: severe headache, flame-shaped retinal hemorrhages with AV-nicking, papilledema "flea-bitten" surface (multiple red petechiae) of kidney vessels with fibrinoid necrosis and hyperplastic arteriolitis ("onion-skinning") markedly increased serum renin levels (which will cause further vasoconstriction) C. renal artery stenosis (RAS) 1. causes: atherosclerosis is most common (seen in older men) fibromuscular hyperplasia is seen in younger women (angiography shows "string of beads" sign) RAS is a cause of secondary hypertension (think "CHAPS" = Cushing's, hyperaldosteronism, aortic coarctation, pheochromocytoma, RAS) 2. if unilateral = Goldblatt kidney stenotic kidney is small due to ischemia (atrophy) stenosis protects kidney from effects of inc blood pressure (i.e. hyaline arteriolosclerosis) nonstenotic kidney is normal size, but with changes of inc blood pressure 3. clinical a) results: classic dyad of sx are sudden hypertension with low potassium (and not taking diuretics) dec blood flow causes hyperplasia of juxtaglomerular apparatus and inc renin secretion inc renin secretion causes inc aldosterone effect = hypertension with hypernatremia and hypokalemic alkalosis may hear audible renal artery bruit positive captopril test (administration of captopril results in increased plasma renin activity) b) treatment treat with angioplasty and stenting; maybe ACE inhibitors (captopril) for unilateral disease but ACE inhibitors may cause acute renal failure with bilateral disease by preferential vasodilation of the efferent arteriole D. thrombotic microangiopathies 1. general

33
IV thrombi (fibrin microthrombi in glomeruli) leads to renal failure hemolytic anemia (see schistocytes in peripheral blood) thrombocytopenia (platelets are used up) leads to bleeding (vomiting blood and hematuria) 2. causes hemolytic-uremic syndrome (HUS): classic in children (after eating meat with verocytotoxin-producing E. coli); adult form in post-partum females atheroembolic renal disease sickle cell nephropathy
microangiopathic 115. Gross multiple

renal findings A. scars depressed cortical scars overlying necrotic renal papillae = analgesic nephropathy and diabetes mellitus (broad) U-shaped cortical scars= chronic pyelonephritis (reflux causes scars involving poles only, while obstruction produces scars all over the kidney) (wedge-shaped) V-shaped cortical scars = renal infarct (due to arterial emboli from arterial atherosclerosis) B. surface fine granular surface = benign nephrosclerosis (hyaline appearance to walls of arterioles) multiple red spots due to petechial hemorrhages ("flea bitten") = malignant nephrosclerosis ("onion-skinning" of arterioles) multiple white spots = acute pyelonephritis C. other 1. papillary necrosis associated with diabetes mellitus, sickle cell anemia, phenacetin use IVP shows "ring sign" = radiolucent sloughed papilla surrounded by radiodense contrast material in calyx 2. diffuse cortical necrosis may be due to OB complication, DIC, or arterial emboli calculi (stones)

116. Renal

A. general

affects 5 to 10% of Americans during their lifetime; males more than females; third decade; may run in families causes: make too much of a precipitant; make too little of an inhibitor (such as GAG's, citrate, which chelates things like calcium, and nephrocalcin), certain conditions (eg, low pH promotes precipitation of some stuff); malformations; infections may produce severe colicky flank pain (costovertebral tenderness where pt can't find comfortable position) and hematuria (no rebound tenderness) complications include obstruction, hydronephrosis and pyelonephritis B. calcium most common type of renal stone (but they are usually are not pure and have mixed composition) radiopaque stones composed of calcium oxalate (most common type), calcium phosphate, or both 55%: pts have hypercalciuria without hypercalcemia; may be due to increased absorption of calcium by intestines, decreased renal tubular reabsorption of calcium, or idiopathic fasting hypercalciuria with normal PTH function 20%: pts have increased uric acid secretion; calcium oxalate nucleates on uric acid crystals in collecting ducts 5%: pts have hyperoxaluria, hereditary or acquired, the latter due to intestinal over absorption; sometimes in vegetarians (spinach has lots of oxalate) 5%: pts have both hypercalcemia and hypercalciuria; 10%: miscellaneous and unknown causes C. magnesium ammonium phosphate triple stones or struvite (staghorn) stones (these are nidus for UTI's); radiopaque associated with alkaline urine due to infection with urea-splitting (urease-positive) organisms (proteus) or staphylococcus; urease hydrolyzes urea to produce carbonate and ammonia (increases pH) D. uric acid: radiolucent stones (in plain films; can still see with CT scan) secondary to hyperuricemia, such as associated with gout or inc cell turnover (patients treated for leukemia or lymphoma) they have low urine pH so normal amounts of uric acid in urine will precipitate out

nephrolithiasis:

34
E. sodium F. cystine

biurate stones have a "thorn-apple" appearance stones hexagonal crystals in urine; stones are radiolucent (in plain films; can still see with CT scan) rare, but can be seen in children with hereditary defect in renal transport of amino acids, such as cystinuria (cystine tends to be less soluble than other amino acids) = abnormal renal tubular reabsorption of dibasic amino acids (inc urine cysteine, ornithine, arginine, lysine)

117. Renal

tumors cell carcinoma 1. classic triad of signs = hematuria, flank pain, and palpable abdominal mass (cigarette smoking is the biggest risk factor) 2. associated paraneoplastic syndromes (polycythemia due to paraneoplastic secretion of EPO) 3. found in renal parenchyma, usually cortex (transitional cell carcinomas are found in the hilum); often grossly yellow due to lipid in tumor cells 4. histologic types a) clear cell (nonpapillary) carcinoma (the most common type) uniform cells with clear cytoplasm (positive for glycogen and lipid) may be sporadic, familial, or associated with VHL disease (von Hippel-Lindau disease) associated with deletion on chromosome 3 involving the VHL gene, which codes for a protein that is part of a ubiquitin ligase complex involved in targeting other proteins for degradation b) papillary carcinoma associated with mutated MET gene (a protooncogene that is the tyrosine kinase receptor for hepatocyte growth factor; not with 3p deletion c) chromophobe renal carcinoma B. Wilms tumor (nephroblastoma) clinical scenario = children with abdominal mass (normal VMA levels) due to deletion of WT-1 (deletion involving chromosome 11) histology reveals undifferentiated mesenchymal cells and immature tubules and immature glomeruli (abortive glomeruli) seen with WAGR syndrome (Wilms tumor, aniridia, genital anomalies, and mental retardation) which may be due to mutation of PAX 2 also may be associated with hemihypertrophy of the body C. other tumor of kidney pelvis = transitional cell carcinoma xanthogranulomatous pyelonephritis = large yellow nodule containing foamy macrophages and inflammatory cells associated with Proteus infection angiomyolipoma = tumor composed of blood vessels ("angio"), muscle ("myo"), and fat ("lipo"); may be associated with tuberous sclerosis
A. renal

HIGH-YIELD NOTES OF PATHOLOGY 2010 EXAM 3 HEAD AND NECK

117. Teeth A. caries

(tooth decay): minerals of tooth dissolved by acid metabolic end products of bacteria B. gingivitis dental plaque: complex mass of microorganisms from the normal oral flora, proteins from saliva, and desquamated epithelial cells calculus: mineralized bacterial plaque C. peridontitis: inflammatory process affecting suporting structures of teeth (periodontal ligaments, alveolar bone, cementum)
118. Inflammatory/reactive A. fibrous

lesions of the oral cavity proliferative lesions 1. irritation fibroma located on the buccal mucosa along the bite line or at the gingivodental margin mx: nodular mass of fibrous tissue covered by squamous mucosa (fibroepithelial polyp); few inflammatory cells present 2. pyogenic granuloma: mx shows proliferating fibroblasts, small blood vessels, and inflammatory cells (not granuloma) pregnancy tumor 3. peripheral ossifying fibroma: duller, less red than pyogenic granuloma; mx shows new bone formation 4. peripheral giant cell granuloma (giant cell epulis) an epulis is a localized reactive inflammatory lesion of the oral cavity that presents as a mass mx: multinucleate, foreign-body type giant cells within a fibroangiomatous stroma 5. gingival hyperplasia may result from certain drug use (Dilantin) B. aphthous ulcer (canker sore) very common and very painful; white punched out lesion with erythematous border may be seen in Behcet syndrome with genital ulcers, conjunctival ulcers, and neurologic symptoms C. glossitis beefy-red appearance of tongue due to atrophy of papillae and thinning of mucosa associated with nutritional deficiencies (eg vitamin B12, riboflavin, niacin, pyridoxine) Plummer-Vinson syndrome: iron-deficiency anemia, glossitis, esophageal dysphagia of the oral cavity simplex virus (HSV) type 1 (labialis); clinical shows clear vesicles on a red base causes "fever blisters or "cold sores (HSV will lie dormant in trigeminal ganglia) mx (Tzank smear) shows ground glass nuclei, intranuclear eosinophilic inclusions (Cowdry A inclusions), and multinucleated giant cells note: aphthous ulcers ("canker sores") are not caused by infection but appear during febrile illnesses or stress B. candida (moniliasis) pseudomembranous form is called thrush (white patches = leukoplakia) microscopically see budding yeast, hyphae, and pseudohyphae can be scraped off to reveal an erythematous inflammatory base C. phycomycosis is Mucor (bread mold) infection (in nasal cavity think diabetics (ketoacidosis) or immunosuppressed individuals)
A. herpes

119. Infections

120. Oral

mainfestations of systemic disease leukoplakia white confluent patches of fluffy ("hairy") hyperkeratotic thickenings; these cant be scraped off as with thrush due to mixed infection with HIV and EBV in patients with AIDS; occurs on side of tongue (rather than middle) histology shows marked hyperkeratosis, parakeratosis, and acanthosis (epithelial hyperplasia) with "balloon cells" in the upper spinous layer B. scarlet fever is due to strains of group A beta-hemolytic strep (streptococcus pyogenes) that produce an erythrogenic (rash) toxin child with sore throat, extensive erythematous (morbilliform) rash (with desquamation), and increased ASO
A. hairy

tongue (fiery red) due to prominent papillae or strawberry tongue (white coated) due to hyperemic papillae C. rubella (German measles) = 3-day fever, coryza, skin rash (began on face, spread to trunk), lymphadenopathy (female with immune complex polyarthritis) D. measles (rubeola, a paramyxovirus) high fever, cough, coryza, conjunctivitis (3 c's); blue spots on buccal membrane (Koplik spots); red rash begins on face and moves to trunk and palms microscopy reveals Warthin-Finkeldey giant cells (with numerous nuclei) complications include SSPE (subacute sclerosing panencephalitis) and giant cell pneumonia E. infectous mononucleosis F. diphtheria is caused by Corynebacterium diphtheriae (the D in DPT) 1. diphtheria exotoxin (not endotoxin) blocks protein synthesis by irreversible inactivation of elongation factor 2 (EF-2) 2. pseudomembrane formation of larynx 3. fatty change of heart (tiger stripes) leads to heart failure 4. Schick test = inject diphtheria toxin intradermally positive skin reaction (edema and necrosis) means susceptible to diphtheria negative skin reaction means immune to diphtheria
121. Tumors/precancerous A. leukoplakia a

raspberry

lesions of the oral cavity

clinical term for any white lesion; until proven otherwise via histologic examination, all leukoplakia must be considered precancerous microscopically may see increased thickness of epithelium or increased keratin note that erythroplakia is red lesion that consists of atypical epithelial cells and has increased risk of malignancy B. malignant tumors 1. lip, tongue, oral cavity: the most common histologic type in these areas is squamous cell carcinoma a) multiple risk factors including tobacco use, alcohol, HPV (esp type 16) b) pathogenesis is a multistep process loss of heterozygosity (LOH) and hypermethylation at 9p21 inactivates p16: associated with change from normal to hyperplasia LOH at 17p with mutation of p53: associated with dysplasia common late event: amplification and overexpression of cyclin D1 at 11q13 C. cysts of the oral cavity 1. follicular cysts develop from epithelium of tooth follicle (if tooth unerupted it's called a dentigerous cyst) 2. odontogenic keratocyst is found at root of tooth keratinized squamous epithelium (wavy epithelial surface) if multiple may be associated with basal cell carcinoma of skin important because of risk of recurrence and aggressive behavior 3. periapical (radicular) cysts (most common cyst of oral cavity) are characterized by chronic inflammation of tooth apex 4. palatine cyst results from abnormal development of pharyngeal pouch II (palatine tonsil develops from pharyngeal pouch II) D. odontogenic tumors 1. ameloblastoma is a locally aggressive tumor (typical location is in mandible, while a similar tumor of the sella turcica is a craniopharyngioma) gross shows multiple cysts that are filled with a thick, "motor-oil"-like fluid mx shows nests of tumor cells that are dark and crowded at periphery with loose tissue in center (similar to stellate reticulum of a developing tooth) 2. odontoma: most common odontogenic tumor; has extensive deposits of enamel and dentin; probably hamartomas, cured by local excision
122. Nose/nasopharynx A. inflammations 1. rhinitis a) infections

(inflammation of the nose) (acute) rhinitis:

with the common cold (coryza) which is produced by viral infections (adenoviruses, echoviruses, and rhinoviruses) increased mucus secretions result in catarrhal inflammation b) allergic rhinitis (hay fever): a type I hypersensitivity reaction (atopy) with numerous eosinophils, plasma cells and lymphocytes c) nasal polyps: microscopically see eosinophils and plasma cells d) chronic rhinitis rhinoscleroma: eastern Europe and Central America; due to klebsiella rhinoscleromatis; forms nodular masses with ulceration; mx shows numerous foamy macrophages filled with bacteria (Mikulicz cells) rhinosporidiosis: South India and Sri Lanka; caused by rhinosporidium seeberi; mx shows large spherules filled with endospores rupture of the nasal septum can result from chronic nose 'picking' and chronic cocaine sniffing (mx shows foreign body-type granulomas) rhinophyma: complication of severe acne rosacea; enlargement of the nose ('W.C. Fields nose') due to hyperplasia of the sebaceous glands 2. sinusitis 3. pharyngitis/tonsillitis a) herpangina are vesicular lesions (pharynx) due to coxsackievirus A b) whooping cough (whoops = paroxysms of multiple expiratory coughs followed by inspiratory whistle) due to Bordetella pertussis (the T in DPT, which contains killed bacteria); grows on Bordet-Gengou medium Bordetella pertussis toxin ADP ribosylates Gi and increased cAMP levels associated with peripheral lymphocytosis (instead of the normal neutrophilia with bacterial infections) c) actinomyces (israelii and bovis) gram-positive filamentous bacilli (not acid fast, in contrast to nocardia which is partially acid fast) normal inhabitant in anaerobic areas such as tonsillar crypts cervicofacial actinomycosis = multiple abscesses with draining sinuses ("lumpy jaw); may have yellow flakes grossly B. necrotizing lesions invasive fungal infections (mucormycosis) Wegener granulomatosis lymphoma (so-called lethal midline granuloma or polymorphic reticulosis) C. tumors 1. nasopharyngeal angiofibroma is seen in adolescent males; recurrent serious epistaxis; may produce marked bleeding during surgery 2. sinonasal papillomas: most are exophytic (finger-like projections with fibrovascular core) septal papilloma (most common) inverted papilloma (most important biologically): benign but locally aggressive cylindrical papilloma 3. isolated plasmacytoma 4. olfactory neuroblastoma (esthesioneuroblastoma) a small, round, blue cell tumor of the nose (EM shows membrane-bound dense core neurosecretory granules) positive for NSE (neuron-specific enolase), S-100 protein, and chromogranin 5. nasopharyngeal carcinoma associated with EBV; is common in Africa (kids) and China (adults) histologic patterns: keratinizing or non-keratinizing squamous cell carcinoma; undifferentiated carcinoma
123. Larynx A. inflammation 1. croup

seen

(a group of conditions involving inflammation of the upper airway that leads to a characteristic barking cough when a child is crying) affects kids from 3 months to 5 years; MC pathogen is parainfluenza type 1; lateral neck film may show subglottic narrowing ("steeple sign") 2. acute epiglottitis (caused by hemophilus influenza or viruses)

acute high fever, dysphagia, drooling, muffled voice ("sniffing dog" position = sitting with neck hyperextended and chin protruding) lateral x-ray shows swollen epiglottis obliterating the vallecula (classic "thumbprint sign") do not examine pt's throat unless anesthesiologist is present (this may precipitate laryngospasm and airway obstruction) B. reactive nodules singer's nodule (due to excessive use of voice): bilateral lesions polyps: unilateral lesions C. laryngeal carcinoma: the most common histologic type is squamous cell carcinoma most are found in the glottis (glottic carcinomas), which includes the true vocal cords and the anterior commissure the glottis has minimal lymphatics (therefore glottic carcinomas may be cured with radiation or surgery) supraglottic carcinomas are above the glottis (eg the arytenoids, epiglottis, aryepiglottic fold, false vocal cords, mucosa of ventricle) subglottis includes the area below the vocal cord to the level of the first tracheal cartilage transglottic carcinomas are advanced glottic or supraglottic carcinomas that have crossed the ventricle D. papillomas: multiple squamous cell (juvenile) papillomas are seen in children and are due to HPV types 6 and 11
124. Ears A. inflammation 1. otitis

sx:

externa

of the external auditory canal; due to viruses, bacteria, or fungi sx: ear pain (worse when pinna is moved) 2. chondrodermatitis nodularis helicus a painful nodule in helix of males secondary to trauma (microscopy shows ulceration and chronic inflammation of underlying cartilage) 3. otitis media (acute infection of middle ear) sx: earache (not worse when pinna is moves), fever, and tense, red tympanic membrane that bulges outward chronic otitis media may cause ingrowth of keratinizing squamous epithelium that forms a cholesteatoma (keratin-filled cyst) 4. acute labyrinthitis is due to virus (most common) or bacteria that produces sudden, unilateral hearing loss +/acute vertigo B. otosclerosis familial bilateral hearing loss that produces progressive deafness microscopic reveals new spongy bone formation around stapes and oval window C. Meniere's disease middle age males (more than females) due to imbalance between endolymph secretion and endolymph absorption increased endolymph pressure in cochlear duct causes hydropic dilation of endolymph system symptoms include fluctuating hearing loss, episodic vertigo (+/- nausea and vomiting), and tinnitus D. autoimmune inner ear disease (probable cause of Rush Limbaugh's deafness); clinically similar to Meniere's disease (mx shows lymphocytes) sx: unexplained progressive hearing loss (sensorineural), tinnitus, feelings of rapid movement in the ear rx: steroids, cochlear implant E. benign paroxysmal positional vertigo (BPPV) transient (less than 1 minute), episodic, sudden severe attack of vertigo and nystagmus when head is tilted certain way (classically while turning in bed) a common form of peripheral (end-organ) vertigo that results from a dislodged otolith causing disturbances in the semicircular canals note: peripheral causes of vertigo produce horizontal nystagmus; vertical nystagmus indicates a central lesion F. tumors 1. external ear has typical skin cancers (basal cell carcinoma and squamous cell carcinoma) 2. middle ear has glomus jugulare tumor involves adventitia of internal jugular vein and base of skull a paraganglioma (chemodectoma) similar to carotid body tumor (composed lobules of cells (zellballen) in highly vascularized stroma; bleeds easily)

infection

125. Neck A. cysts

of neck (differentiate by location) (lymphoepithelial) cyst is located in the lateral neck (doesn't move with swallowing); derived from remnants of the pharyngeal apparatus thyroglossal duct cyst is a cyst in midline of anterior neck (moves superiorly when patient swallows) B. carotid body tumor a paraganglioma (chemodectoma) located at the bifurcation of the common carotid artery histologic appearance does not reliably predict its clinical course
branchial 126. Salivary

glands dry mouth (major feature of the autoimmune disorder Sjogren syndrome) B. inflammation (sialadenitis) may be secondary to duct calculi (sialolithiasis), infections, or Sjogren syndrome elevated serum amylase associated with meningoencephalitis is most likely secondary to acute viral parotiditis a mucocele is a cyst filled with mucin found on the lip that results from a ruptured minor salivary duct (mx shows cyst filled with mucous material) usually a result of trauma a ranula is a mucocele that arises when the duct of the sublingual gland has been damaged C. benign neoplasms 1. pleomorphic adenoma (mixed tumor) is the most common type of salivary gland tumor usual location is superficial lobe of parotids (surgery tries to spare cranial nerve VII) dont shell out with surgery because if incomplete removal it will recur tumor is composed of a mixture of epithelial structures and mesenchyme-like stroma (mucoid, myxoid, or chondroid-like) if becomes malignant it's called a carcinoma ex pleomorphic adenoma 2. Warthins tumor (aka adenolymphoma or papillary cystadenoma lymphomatosum) may be multicentric and bilateral; prediliction for tail of parotid gland mx shows cystic, cleft-like spaces with numerous lymphocytes in the walls the epithelium forms papillary folds composed of a double layer of oncocytic cells (pink cytoplasm due to many mitochondria) D. malignant neoplasms 1. mucoepidermoid carcinoma is composed of squamous epithelial cells (# proportional to malignancy) and mucus-secreting cells (positive mucicarmine) 2. adenoid cystic carcinoma (cylindroma) grow along nerves (facial); incomplete removal with surgery so they recur late and lead to death microscopic finding is a cribriform pattern ("Swiss cheese) 3. acinic cell carcinoma is slow growing ( microscopy reveals glands with vacuolated epithelial cells) resembles normal serous acinar cells; like Warthin tumors, these can be bilateral
A. xerostomia:

127. Eyes

(Robbin's Chapter 29) is forward displacement of the eye; can result from increased orbital contents

A. orbit 1. proptosis 2. inflammation

sinus infection may spread to the orbit (eg Mucormycosis in diabetic patient) orbital inflammation (orbital inflammatory pseudotumor): mx: chronic inflammation with variable degrees of fibrosis 3. neoplasms: most commonly are vascular in origin (capillary hemangioma in kids) B. eyelids glands of eyelids: sebaceous (holocrine) glands of tarsus = Meibomian (main) glands; of lashes = Zeis glands; apocrine (have apical "snouts") near lid margin = glands of Moll chalazion is foreign body granulomas around sebaceous glands due to rupture of sebaceous glands (if recurrent must r/o sebaceous carcinoma) sty (hordeolum) is inflammation of the eyelids basal cell carcinoma is the most common malignancy of the eyelid; prediliction for the lower eyelid and medial canthus
idiopathic

uncontrolled

are yellow plaques around the eyelids that are most often found in females (mx reveals lipid-filled macrophages in the dermis) C. conjunctiva 1. acute bacterial conjunctivitis causes "red eye" (newborn infection (ophthalmia neonatorum) due to N. gonorrhea) 2. viral conjunctivitis is due to adenovirus (a non-enveloped icosahedral DNA virus with spikes extending from each vertex of the capsid) 3. chlamydial infections inclusion conjunctivitis ("swimming pool conjunctivitis) trachoma is the most common cause of blindness in underdeveloped countries (pannus formation is due to epithelial hyperplasia) 4. solar degenerations (histology reveals degenerated collagen) = pinguecula (not over cornea) or pterygium (clear mass over cornea) 5. neoplasms: squamous cell carcinoma and conjunctival melanoma D. sclera: may appera blue when thin (due to Tyndall effect), eg osteogenesis imperfecta E. cornea (inflammation of the cornea is called interstitial keratitis); abnormalities of the cornea will produce cloudy corneas layers of cornea = epithelium (nonkeratinizing stratified squamous), Bowman's membrane (condensed stroma, not true basement membrane), stroma, Descemet's membrane (true basement membrane, ie PAS positive), and the endothelium herpes infections clinically reveal branching (tree-like) fissures in cornea arcus senilis is aging accumulation of lipid at periphery of cornea Kayser-Fleischer ring (copper color) is copper accumulation in cornea in an individual with Wilsons disease band keratopathy (BK): calcific BK due to calcium deposited in Bowman's layer; actinic BK due to solar elastosis keratoconus: cornea has a conical shape; due to thinning of cornea with breaks in Bowman's layer Fuch's endothelial dystrophy: due to a loss of endothelial cells; causes stromal edema and bullous keratopathy; mx: may see abnormal basement membrane material (guttata) F. anterior segment 1. aqueous circulation: produced by ciliary processes of ciliary body, then into posterior chamber, then through pupil into anterior chamber, then absorbed peripherally at angle, which contains trabecular meshwork and canal of Schlemm 2. lens aging disorders include cataracts and presbyopia (decreased accommodation with increasing age; lose near vision; cant' see well in dark first) dislocated (ectopic) lens is seen with Marfan syndrome and homocystinuria never has been a primary cancer reported of the lens (may be due to fact that lens has no blood supply) 3. glaucoma (may see "halos" around lights) secondary to increased intraocular pressure, which may cause degeneration of optic disk and optic nerve can be either open angle glaucoma (most common) or closed angle glaucoma (obstruction to aqueous flow, usually at angle between iris and cornea) acute angle closure may cause sudden eye pain and loss of vision when leaving dark room (or with mydriatics) 4. inflammation anterior synechiae: adhesions between the iris and the trabecular meshwork of the cornea posterior synechiae: adhesions between the iris and the anteior surface of the lens G. uvea 1. uvea is composed of choroid (pigmented layer, choriocapillary layer, Bruch's membrane), ciliary body (ciliary processes make aqueous fluid), and iris 2. inflammation of iris = iritis associated with inflammatory bowel disease granulomatous inflammation is due to sarcoid or sympathetic ophthalmia (injury of one eye results in inflammation of both eyes) child or adult with chorioretinitis is usually due to CMV or toxoplasmosis (in kids think TORCH (toxoplasma, other, rubella, CMV, herpes simplex) for encephalitis, ocular defects, and cardiac abnormalities)

xanthelasma

3. neoplasms

common intraocular malignancy of adults is metastasis to the uveas (usually the choroid) common primary intraocular malignancy of adults is uveal melanoma H. retina and vitreous 1. anatomy/histology layers of retina retinal pigment epithelium (RPE), photoreceptor layer (rods and cones), external limiting membrane, outer nuclear layer (of rods and cones), outer plexiform layer, inner nuclear layer (horizontal cells, bipolar cells, amacrine cells, Muller cells), inner plexiform layer, ganglion cell layer, optic nerve fiber layer, inner limiting membrane 2. hypertension causes arteriolar narrowing, flame-shaped hemorrhages, macular star, cotton-wool spots 3. macula a) age-related macular degeneration (ARMD) ARMD is most common cause of blindness with age atrophic (dry) ARMD: diffuse or discrete deposits in Bruch's membrane (drusen) and geographic atrophy of RPE exudative (wet) ARMD: hallmark is choroidal neovascular membranes b) cherry red macula seen with Neiman-Pick, Tay-Sachs, and Sandhoff's diseases (see genetics) 4. retinitis pigmentosa is due to loss of cones and rods (begins at periphery) and causes night blindness and loss of peripheral vision 5. ROP (retinitis of prematurity): premature infants receiving high-dose oxygen; forms fibrovascular mass behind lens (called retrolental fibroplasia) 6. retinoblastoma clinically the mass causes a white pupil (leucoria) in child microscopy reveals rosettes (Flexner-Wintersteiner and Homer-Wright) sporadic form is unilateral and has unifocal tumors familial (bilateral) form causes multiple tumors and early age (also develop osteogenic sarcoma) due to loss of 2 retinoblastoma genes (the produce of which normally stops the cell cycle between G1 and S) I. optic nerve 1. anterior ischemic optic neuropathy (AION): due to spectrum of injuries to optic nerve ranging from ischemia to infarction 2. papilledema: edema of the head of the optic nerve J. end-stage eye (phthisis bulbi): features include ciliochoroidal effusion, cyclitic membrane, chronic retinal detachment, optive nerve atrophy, ossesous metaplasia
most

most

GI
128. Esophagus A. normal;

4 general layers of GI tract consists of epithelium, lamina propria, muscularis mucosa submucosa has submucosal plexus (Meissner's plexus = enteric (intrinsic) nervous) muscularis externa consists of inner circular (decreases lumen diameter), myenteric plexus (Auerbach), and outer longitudinal (shortens GI segment) serosa (adventitia) has connective tissue and mesothelial cells (thoracic portion of esophagus does not have serosa) B. terms dysphagia: difficult swallowing (not pain with swallowing) heartburn: retrosternal burning pain after meals (caused by reflux) hematemesis: vomiting blood, either bright red (fresh) or dark brown "coffee grounds" (stomach, with time) retching ("dry heaves": vomiting against closer LES (fails to relax) melena: dark tarry stools C. congenital 1. TEF (tracheoesophageal fistula) most common type has blind upper pouch with distal portion connecting to trachea (type C) may produce polyhydramnios in utero signs include "spitting up milk" and gastric air bubble with x-ray VATER syndrome = vertebral defects, anal atresia, tracheoesophageal fistula, renal dysplasia 2. webs, rings, stenosis
mucosa

are mucosal folds located in the upper esophagus above the aortic arch rings are mucosal rings located at the squamocolumnar junction below the aortic arch Plummer-Vinson syndrome = dysphagia (webs in upper esophagus), atrophic glossitis, and anemia (signs include koilonychia = spoon nails) D. motor dysfunction 1. esophageal motility patterns normal is increased resting pressure in UES and LES, coordinated relaxation with swallowing with a propulsive peristaltic wave progressive systemic sclerosis (scleroderma) has normal peristalsis in upper esophagus, absent peristalsis in lower, low resting pressure in LES skeletal muscle disorders have absent peristalsis in pharynx and upper esophagus (where striated muscle is found) achalasia has absent peristalsis in lower esophagus, increased resting pressure of LES, absent LES relaxation 2. achalasia no relaxation of LES (increased resting LES pressure) due to decreased ganglion cells in myenteric plexus (Auerbach's plexus) results in progressive dysphagia (the hallmark symptom) dilated and tortuous esophagus with distal stenosis (x-ray reveals "bird beak" or "rat's tail" narrowing in distal esophagus) esophageal carcinoma (squamous cell) in about 5% cause is unknown in most cases, but in South America may be due to Chagas disease, which is caused by Trypanosoma cruzi Trypanosoma cruzi (transmitted by reduviid bug) cause bipalpebral swelling, ipsilateral retroauricular and cervical lymph nodes (Romana sign), dilated cardiomyopathy, megaesophagus 3. hiatal hernia burning retrosternal pain (heartburn) that is worse when lying rolling type (10%) (paraesophageal) = reflux rare, but may be strangulated sliding type (90%) = reflux more common (but still reflux is present in only about 10% of patients with hiatal hernia) 4. diverticula Zenker's diverticula are false diverticula formed by herniation of the mucosa at the junction of the pharynx and esophagus traction diverticula are true diverticula (composed of all layers) located in the mid-portion of the esophagus due to external scarring epiphrenic diverticula are located immediately above the LES (epigastric) 5. lacerations a) Mallory-Weis tears: tears at the gastroesophageal junction; result from retching/vomiting (seen in alcoholics and pregnant females) b) Boerhaave syndrome post-emetic rupture (perforation) of esophageal wall with retching (vomiting against closed LES); alcoholic, pregnant, or bulimic pts develops severe retrosternal pain after vigorous vomiting (mediastinal emphysema) E. varices found primarily in patients with cirrhosis (usually alcoholics) because increased portal pressure causes portocaval shunting (portal vein to left gastric vein to esophageal varices to azygous vein to inferior vena cava) upper GI shows "string of beads" defect in esophagus microscopically see dilated veins in submucosa risk of hemorrhage, which can cause hematemesis, melena (black, tarry stools), and risk of exsanguination (bleeding to death) F. esophagitis 1. reflux esophagitis (GERD = gastro-esophageal reflux disease) due to delayed gastric emptying, increased acidity, decreased LES tone gross reveals red mucosa with superficial erosions microscopic reveals hyperplasia of basal cells with elongation of lamina propria papillae and intraepithelial neutrophils and eosinophils
Schatzki

webs

retrosternal pain ("heartburn), especially when lying (pain relieved by antacids) LES pressure (from increased dietary protein and antacids) may decrease symptoms; decreased LES (from alpha-adrenergic antagonists, beta-adrenergic agonists, anticholinergics, increased dietary fats, alcohol, caffeine, smoking, prostaglandin E2) may increasesymptoms 2. Barretts esophagus a) complication of chronic reflux esophagitis b) columnar epithelium in distal esophagus (metaplasia) c) gross reveals velvety red (normal = pink-tan) d) histologic patterns columnar epithelial cells = mucous cells that have neutral (gastric) mucin (PAS positive), but not near EGJ intestinal metaplasia = mucous cells and goblet cells which have acid mucin (PAS positive and alcian blue, pH 2.5 positive) e) important is increased risk adenocarcinoma in individual with Barrett's 3. infections candida produces white plaques grossly (smears reveal yeast forms and pseudohyphae) herpes esophagitis microscopically shows intranuclear eosinophilic inclusions and multinucleated giant cells with ground-glass nuclei G. tumors benign tumors: leiomyomas (characteristic smooth concave defect with sharp borders), fibromas, and lipomas malignant tumors are usually squamous cell carcinomas (adenocarcinomas are found in lower esophagus associated with Barret's) predisposing factors for esophageal squamous cell carcinoma includes alcoholism, tobacco smoking, tobacco chewing, and achalasia
causes increased 129. Stomach A. normal

cardia (next to EG junction), fundus (superior dome-shaped part), body (majority of middle), antrum (distal one-third), pylorus (most distal) cells: parietal (oxyntic) cells (secrete hydrochloric acid and are found in fundus and body), chief cells (secrete pepsinogen (which when converted to pepsin autocatalyzes itself) and are found in fundus and body), mucus secreting cells, endocrine cells B. congenital 1. diaphragmatic hernia abdominal contents into thorax (abnormal location of bowel gas with x-ray) physical exam reveals thorax with absent breath sounds, but positive peristaltic bowel sounds due to failure of pleuroperitoneal canal (foramen of Bochdalek) to close produces respiratory distress in newborn (cause of death is pulmonary hypoplasia) 2. pyloric stenosis projectile non-bilious vomiting and palpable "olive" midepigastric mass in newborn during 2nd or 3rd week of life due to hypertrophy of smooth muscle barium swallow may show "string sign" or "beak sign" lab: hypokalemia, hypochloremia, and metabolic alkalosis treatment is surgery (cut the hypertrophied stenotic band) 3. gastric heterotopia (normal tissue is misplaced) locations include mid-esophagus and small intestines; may cause unexplained peptic ulcer in small intestines in adult C. gastritis 1. acute gastritis a) causes of acute erosive (hemorrhagic) gastritis include (1) drugs, such as alcohol and NSAIDs (2) ischemia, shock, and stress associated with severe burns = Curlings ulcers (think "burns = hot = curling iron") associated with intracranial lesions = Cushings ulcers (high risk of hemorrhage) b) mucosal erosions are not full mucosal thickness and can be found in any part of stomach

regions:

are not associated with H. pylori gastritis a) Type A (A for autoimmune gastritis) (1) autoantibodies to parietal cells (not associated with H. pylori) is called pernicious anemia decreased intrinsic factor causes decreased vitamin B12 (megaloblastic anemia) decreased acid (achlorhydria/hypochlorhydria), therefore no peptic ulcers atrophic gastritis means decreased numbers of parietal cells (2) increased serum gastrin (causes increased risk gastric carcinoma) (3) location is body and fundus (inflammation with lymphocytes and plasma cells + atrophy = chronic atrophic gastritis); also see intestinal metaplasia b) Type B (B for bug gastritis) (1) Helicobacter pylori gastritis (no autoantibodies present and gastrin is low to normal) stain for organisms is Steiners silver stain or Giemsa stain (see small curved rods) organisms are urease positive, which can be used as diagnostic test (the urease breath test) expression of bacterial toxins, such as cytotoxin association gene A (CagA) and vacuolating cytotoxin gene A (VacA) (2) location is antrum (inflammation with lymphocytes, plasma cells, +/- neutrophils (active inflammation) = active chronic gastritis) (3) associated with peptic ulcers, such as chronic duodenal ulcer (100%) and chronic gastric ulcer (75%) (4) more frequently associated with cancer, including gastric lymphomas (MALTomas), which may regress with antibiotic therapy for H. pylori (5) therapy for Helicobacter: triple therapy = metronidazole, bismuth salicylate, and either amoxicillin or tetracycline double therapy = omeprazole and clarithromycin 3. special forms of gastritis eosinophilic gastritis: idiopathic condition that has prominent eosinophilic infiltrate of all layers of the stomach allergic gastroenteropathy: disorder of kids producing diarrhea, vomiting, growth failure: mx: infiltrate of eosinophils lymphocytic gastritis: associated with celiac disease granulomatous gastritis: associated with Crohn disease, sarcoidosis, infection, systemic vasculitis graft-versus-host disease: seen after bone marrow transplantation reactive gastropathy: mx: foveolar hyperplasia, loss of mucin, mucosal edema, dilated capillaries (no neutrophils) D. peptic ulcers (peptic means acid) 1. gross benign ulcers (most common location is proximal duodenum) are round, punched-out with smooth base and rugae that radiate outward from ulcer base; active granulation tissue at base of ulcer in contrast, ulcers that result from malignancies have raised irregular margins 2. clinical/therapy upper GI bleeding (proximal to ligament of Trietz) produces melena (dark, tarry stools); most common cause is duodenal ulcers in contrast, lower GI bleeding (distal to ligament of Trietz) produces hematochezia (which can also result from brisk bleeding regardless of site) decreased acid with cimetidine (H2 receptor antagonist), omeprazole (proton pump inhibitor) frequent small meals (no cigarettes, coffee, alcohol), antibiotics (for H. pylori) or surgery (vagotomy or antrectomy) note factors that increased hydrochloric acid secretion by gastric parietal cells include acetylcholine stimulation of M1 receptors; histamine stimulation of H2 receptors; gastrin, increased intracellular calcium ion levels; increased intracellular cAMP levels (not prostaglandins) 3. gastric ulcers pain greater (think G for gastric and greater) with meals H. pylori in 2/3rds (also due to NSAIDs) associated with decreased mucosal protection against gastric acid secretion may develop into or from a malignancy (in contrast to duodenal ulcers) with perforation see free air under the diaphragm on abdominal x-ray
2. chronic

c) erosions

ulcers decreases (think D for duodenum and decreases) with meals almost always associated with H. pylori increased gastric acid or decreased mucosal protection to acid no increased risk of malignancy anterior duodenal ulcers cause perforation (rebound tenderness and abdominal rigidity due to peritonitis; xray shows pneumoperitoneum) posterior duodenal ulcers can erode into gastroduodenal artery and cause hemorrhage E. miscellaneous conditions 1. gastric dilation 2. indigestible material phytobezoars are derived from plant material (fibers, leaves, roots, etc) trichobezoar is a "hair ball" formed from ingested hair (young anxious females) and decaying food surrounded by mucoid coat 3. hypertrophic gastropathy (not gastritis) a) Menetrier's disease = marked hyperplasia of the surface mucous cells with atrophy of the glands gastric secretions contain excess mucus and decreased hydrochloric acid (due to glandular atrophy) excess protein loss may cause protein-losing gastroenteropathy with hypoalbuminemia and peripheral edema b) hypertrophic-hypersecretory gastropathy: associated with hyperplasia of parietal and chief cells c) gastric gland hyperplasia secondary to excess gastrin (Zollinger-Ellison syndrome) 4. gastric varices F. tumors 1. benign tumors: polyps most are non-neoplastic (hyperplastic); mx: hyperplastic foveolar epithelium with inflammation adenoma: contains dysplastic epithelium (therefore, has malignant potential) inflammatory fibroid polyp (eosinophilic granuloma): mx shows inflamed vascularized fibromuscular tissue with eosinophilic infiltrate 2. gastric cancer (histologically most are adenocarcinomas) a) high incidence in Japan, China, Iceland (decreasing in USA) b) predisposing factors include dietary nitrites, smoked/salted foods, chronic atrophic gastritis, polyps (hyperplastic and adenomas), H. pylori c) intestinal type is associated with previous intestinal metaplasia (but incidence has been decreasing) gross shows irregular ulcer with raised, irregular margin (note that size does not tell benign from malignant ulcer) d) diffuse type (signet ring carcinoma = separate infiltrating cells with intracellular mucin) gross shows thick "leather-bottle" wall (called linitis plastica ) spread to ovaries is called a Krukenberg tumor, while spread up thoracic duct to left supraclavicular lymph node is called Virchow's node e) classification in-situ carcinoma = confined within basement membrane of glands intramucosal = through basement membrane into lamina propria (not beyond muscularis mucosa) early = confined to mucosa and submucosa (regardless of lymph node status) advanced (late) = beyond submucosa 3. gastric lymphoma stomach is most common site of origin for extranodal lymphoma; type is B-cell mucosa-assocaited lymphoid tissue lymphoma 4. GIST (gastrointestinal stromal tumors) 70% occur in the stomach; most of these behave in a benign fashion 30% occur in the small intestines; most of these behave in a malignant fashion GIST have abnormalities of KIT gene (CD117); therapy with Glivec (formerly known as STI571); also used to treat CML c-KIT is the receptor for stem cell factor mx: spindle cell tumors that stain positively with CD117; negatively with desmin and S-100
pain

4. duodenal

 spindle

cell tumors that are negative for CD117 and positive for desmin are leiomyomas; likely to be found in the wall of stomach (tell benign from malignant tumors by number of mitoses and presence of atypia)

130. Small

and large intestines A. normal 1. vasculature celiac supplies the stomach, duodenum, liver and pancreas superior mesenteric supplies rest of small intestines (jejunum and ileum), ascending colon, transverse colon inferior mesenteric supplies distal colon to rectum 2. small intestinal mucosa a) villi: finger-like projections covered by epithelial lining cells b) Brunner glands: abundant submucosal mucus glands in the duodenum c) epithelial cells columnar absorptive cells: dense array of microvilli on their luminal surface (brush border) and underlying microfilaments (terminal web) goblet cells: mucin-secreting cells endocrine cells stem cells Paneth cells: have bright eosinophilic granules containing antimicrobial proteins (such as defensins) 3. colonic mucosa function: reabsorb water and electrolytes is flat (lacks villi) 4. neuromuscular function intrinsic (myenteric): Meissner plexus (at base of submucosa) and Auerback plexus (between inner circular and outer longitudinal muscle layers) extrinsic (autonomic innervated) B. congenital 1. abdominal wall omphalocele (abdominal muscle fails to form) has herniation of abdominal contents into ventral membranous sac gastroschisis (portion of abdominal wall does not form) has extrusion of intestines; no peritoneal covering; separate from umbilicus 2. duodenal atresia newborn with persistent bilious vomiting after feeding; failure to pass meconium; polyhydramnios during pregnancy "double bubble" on x-ray (air in stomach and proximal duodenum) 3. imperforate anus due to failure of perforation of membrane separating endodermal hindgut and ectodermal anal dimple clinical: no stool passage; associated with fistulas to urinary bladder and vagina 4. choanal atresia neonate with cyanosis that is increasewith feeding, but decreased with crying (catheter can't pass through nose) choana normally allows communication between nasal fossa and nasopharynx 5. Meckels (true) diverticulum a) the most common congenital anomaly of the GI tract (due to persistence of omphalomesenteric (vitelline) duct) b) "2"'s: 2% of population <2 feet from ileocecal valve 2 inches long presents within first 2 years of life (possible painless bright red blood per rectum or obstruction due to intussusception) 2 types of epithelium (heterotopic tissue = choristoma), ie. gastric (bleeding and iron deficiency anemia) and pancreatic 6. Hirschsprungs disease (congenital megacolon)

parasympathetic ganglion cells (no myenteric or submucosal plexi) due to failure of neural crest cell migration mx shows hypertrophy of nerve fibers without ganglion cells (definitive diagnosis requires biopsy) no peristalsis (spastic obstruction with proximal dilation); aganglionosis starts at anorectal junction and extends proximally infant or neonate with chronic constipation, abdominal distention, or failure to pass stool or meconium; rectal exam reveals empty contracted rectum therapy is surgery (resect aganglionic section) C. entercolitis 1. diarrhea and dysentery (low-volume, painful, bloody diarrhea) classification includes secretory, osmotic (due to magnesium or lactase deficiency), or infections dumping syndrome may occur after gastric resection due to too rapid gastric emptying (increased volume of food delivered to duodenum causes a marked fluid shift into small intestines causing hypovolemia and release of vasoactive substances causing sweating, tachycardia, and flushing followed by too rapid carbohydrate absorption causes too much insulin release and hypoglycemia) 2. viral gastroenteritis gastroenteritis ("stomach flu); summer outbreaks think enterovirus; winter outbreaks think rotavirus rotavirus is an important global cause of infant gastroenteritis (major cause of acute diarrhea in US during winter), can be severe (dehydration) parvovirus (Norwalk agent) is a major cause of diarrhea in older children and adults, often mild disease 3. bacterial entercolitis a) Shigella colitis (bacillary dysentery) produces high fever and severe diarrhea (10-40stools/day) with blood and mucus (Shigella toxin activates adenylate cyclase) b) typhoid fever is due to Salmonella typhi organism invades small intestinal mucosa, invades macrophages, and travels to regional nodes, after 1-3 week incubation the organism travels via the bloodstream back into intestinal lumen and back to intestinal lymph nodes (Peyers patches in ileum) to cause longitudinal mucosal ulcers symptoms include bradycardia, fever ("stepladder" pattern), headache, muscle ache, erythematous macules on trunk (rose spots), and positive Widal test 5% become carriers due to infection of gall bladder of kidneys (ie., "typhoid Mary) c) Campylobacter C. jejuni: most common cause of community-acquired inflammatory enteritis C. fetus: opportunistic pathogen (newborns, or individuals with weakened immunity) d) Vibrio cholera (actively motile "darting" gram negative bacillus) do not invade epithelium, but exotoxin causes adenosine diphosphate ribosylation of Gs which increasescAMP ("on switch permanently on) increased intestinal secretion of fluid and electrolytes; secretory diarrhea ("rice-water" stools due to flecks of mucus) e) Clostridium difficile pseudomembranous enterocolitis (gross reveals yellow plaques in colon) secondary to antibiotics (clindamycin, ampicillin, tetracycline) exotoxin is cytotoxic to mucosal epithelial cells and causes voluminous green diarrhea (watery diarrhea with pus and mucus) microscopic reveals mushroom-shaped (suppurative) inflammatory exudates overlying mucosal erosions treatment is stopping causative antibiotic and starting vancomycin or metronidazole f) yersinia enterocolitica and pseudotuberculosis produce fever, diarrhea, enlarged mesenteric lymph nodes, and right lower quadrant abdominal pain (mimics appendicitis) g) enterotoxigenic E. coli (ETEC) produces cholera-like toxin that causes watery diarrhea (no invasion by E. coli) causes travelers diarrhea and diarrhea epidemics in neonatal units h) enterohemorrhagic E. coli (EHEC) secretes Shiga-like toxin and produces hemorrhagic colitis (associated with HUS) i) staph food poisoning enterotoxin-producing staph aureus cause nausea, vomiting, diarrhea and abdominal cramps; sx occur within hours is self-limited disorder (no risk death)

no

4. parasitic

enterocolitis
massive

a) nematodes

lumbricoides (roundworm) infection may cause intestinal obstruction infection in lungs causes cough and wheezing (Loefflers syndrome) (2) strongyloides stercoralis (threadworm) causes bloody diarrhea (in lungs = larval migrans) (3) hookworm (necator species; ancyclostoma species)may cause iron deficiency anemia due to chronic GI blood loss stool may show characteristic non-bile-stained (clear), segmented eggs with a clear space separating the shell from the developing larva inside treat with mebendazole and iron therapy (for the anemia) (4) enterobius vermicularis (pinworm ) causes anal pruritus in kids (identify with anal "Scotch-tape test) stool may show ovoid thin-walled eggs that are flattened on one side and contain developing larva (5) trichuris trichiura (whipworm): heavy infection causes bloody diarrhea and rectal prolapse b) cestodes taenia solium (larval migrans = cysticercosis which may form multiple cysts in brain) and saginata diphyllobothrium latum (fish tapeworm) may cause decreased vitamin B12 (megaloblastic anemia) c) protozoa (1) amebiasis is due to Entamoeba histolytica ingestion of cysts (feces contaminated food or water) with release of trophozoites ameba lack mitochondria (Krebs cycle) and are obligate fermenters of glucose to ethanol (metronidazole inhibits ferredoxin-dependent pyruvate oxidoreductase) grossly see "flask-shaped ulcers in colon, microscopically organisms may contain phagocytosed erythrocytes sx: lower abdominal pain, cramps, colitis, tenesmus, flatulence, bloody diarrhea may spread to liver and form amebic abscess (2) giardiasis is due to Giardia lamblia ingest cysts, binucleate pear-shaped flagellated trophozoites in duodenum organisms attach to surface of epithelial cells (most common histology is atrophy of villi) causes cramping abdominal pain, diarrhea, and steatorrhea (foul-smelling frothy feces) treat with metronidazole (3) cryptosporidium very small (2-4 microns) organisms that are acid-fast (acid-fast oocysts in stool = cryptosporidia) disease in immunosuppressed individuals (AIDS) produces profuse, non-bloody watery diarrhea outbreaks in Wisconsin in rainy years are due to water run-off from dairy farms D. miscellaneous disorders 1. necrotizing enterocolitis (NEC) an acute, necrotizing inflammation of the small and large intestines with transmural necrosis most common acquired GI emergency of neonates pathognomic finding on plain films is pneumatosis intestinalis (gas in the bowel wall) 2. collagenous colitis has increased subepithelial collagen layer in colon (patients may develop chronic watery diarrhea) 3. lymphocytic colitis has chronic watery diarrhea with a prominent intraepithelial lymphocytic infiltrate 4. neutropenic colitis (typhlitis): life-threatening acute inflammatory destruction of cecal mucosa in neutropenic individuals 5. solitary rectal ulcer syndrome cause is motor dysfunction of the anorectal musculature characteristic triad: rectal bleeding, mucus discharge from the anus, superficial ulceration of the anterior rectal wall E. malabsorption 1. general most common sx is chronic diarrhea; hallmark is steatorrhea (foul-smelling, greasy stool positive for fecal fat) decreased fat-soluble vitamins (ADEK) and decreased iron and folate (causes a macrocytic-hypochromic anemia)

(1) ascaris

 causes 2. sprue

include inadequate gastric mixing, decreased bile acids, decreased intestinal transit time, abnormal intestinal mucosa, altered intestinal flora sprue = celiac disease or gluten-induced enteropathy (seen in individuals of northern European

a) nontropical

descent) autoimmune intolerance to gliadin, which is the water-insoluble wheat protein gluten of wheat, oats, barley, and rye antigliadin, anti-endomesial, or anti-tissue transglutaminase antibodies small intestine biopsy reveals villous atrophy (blunted, spade-like villi) with hyperplastic crypts treatment is to remove gluten from diet (histology reverts to normal) associated with dermatitis herpetiformis b) tropical sprue is an acquired disorder due to chronic bacterial infection (therefore treatment is with broadspectrum antibiotics) geographic sites include Caribbean (but not Jamaica), Far East, India histology is the same as nontropical sprue, that is, villous atrophy (not hyperplasia) 3. Whipples disease multisystem disease, but mainly small intestine signs include diarrhea (steatorrhea with increased fecal fat), weight loss, polyarthritis (extra-intestinal involvement) lamina propria of small intestines filled with foamy macrophages with PAS-positive cytoplasm (with rodshaped bacteria) due to Tropheryma whippelii (a gram positive actinomycete) treatment is with antibiotics (tetracycline) 4. lactase (a disaccharidase) deficiency produces milk intolerance and symptoms of bloating, cramping, diarrhea after consuming dairy products 5. abetalipoproteinemia genetic defect in the synthesis of apolipoprotein B; therefore no chylomicrons, VLDL, or LDL in the blood mucosal absorptive cells have lipid inclusions (the villous structure and architecture are normal) acanthocytes (red blood cells with irregular spicules) in peripheral smear symptoms improve by restricting dietary fats to mainly medium-chain fatty acids F. inflammatory bowel disease (IBD) 1. Crohns disease most often involve small intestines (regional enteritis), but can involve any area of intestines (rectum often spared) involvement (or surgery) of ileum may produce malabsorption and B12 deficiency); may present with abdominal mass in right iliac fossa patients present with pain, diarrhea, weight loss, malabsorption (remitting and relapsing course) involvement is segmental (sharp demarcation between diseased and uninvolved segments) and produces "skip areas" longitudinal serpiginous ulcers produce "cobblestone gross appearance transmural involvement produces fissures, fistulas, and obstruction fibrosis produces "lead pipe or "garden hose appearance with "creeping fat around outside of gut intestinal obstruction or "string sign with x-ray (short segment of colon with narrow lumen) microscopic reveals transmural inflammation with non-caseating granulomas (25-75%) extra-intestinal manifestations include migratory arthritis, uveitis, and erythema nodosum prognosis is characterized by multiple remission/relapses (increased risk of cancer, but not as great as with ulcerative colitis) 2. ulcerative colitis begins on left side colon (rectum involved in all cases), extends proximally without skip lesions (diffuse) and does not involve small intestines may be "patchy" (varies in intensity) patients present with bloody mucus diarrhea, lower abdominal pain, cramps superficial mucosal involvement (not transmural) produces numerous superficial ulcerations with pseudopolyps (inflammatory polyps) microscopic shows crypt abscesses with crypt distortion (no involvement of the wall and no wall thickening) development of dysplasia is important prognostic indicator

manifestations include arthritis, uveitis, pyoderma gangrenosum, and sclerosing pericholangitis (causes obstructive jaundice) complications include increased risk adenocarcinoma (10%) (which is preceded by epithelial dysplasia), severe bleeding, and toxic megacolon G. vascular abnormalities 1. ischemic bowel disease a) transmural infarction is more common in small intestines, which do not have collaterals of colon (dual blood supply) most cases are due to thrombosis or embolism of superior mesenteric artery sx: acute abdomen with abdominal pain, nausea, vomiting 2. angiodysplasia is dilated tortuous vessels (vascular ectasia) of right colon in elderly (produces lower GI bleeding) 3. hemorrhoids are dilations of anal and perianal venous plexi external hemorrhoids = inferior hemorrhoidal plexus, internal hemorrhoids = superior hemorrhoidal plexus thrombosis of external hemorrhoid can produce acute constant anal pain that is worse with defecation with a tense purple mass in anal verge H. diverticulosis 1. diverticula are outpouchings of mucosa true diverticula involve all layers of intestine (Meckels) false diverticula dont include muscle (most are acquired and outpouch through weak point in wall, typically where vessels enter) 2. colon diverticulosis are found in older patients (secondary to decreased dietary fiber, which causes increased intraluminal pressure) most common location is sigmoid colon (left side) chronic bleeding (blood loss) causes heme-positive stools and iron deficiency anemia most common cause of acute lower GI bleed in individual over 40; see gross blood per rectum inflammation of diverticula = diverticulitis (signs include left-sided abdominal pain, fever and leukocytosis = "left-sided appendicitis) I. intestinal obstruction 1. incarcerated hernia indirect inguinal hernias involve the internal inguinal ring; direct inguinal hernia involve the posterior wall of the inguinal canal indirect inguinal hernias are more common and result from persistence of the processus vaginalis femoral hernia: bulge below the inguinal ligament medial to the femoral artery (inguinal hernias present above the inguinal ligament) 2. adhesions that develop after surgery 3. intussusception = "telescoping" of one portion of the intestines into another MC cause of bowel obstruction in first two years of life infant presents with acute onset of abdominal pain with mucus and bloody diarrhea (currant jelly); "sausageshaped" abdominal mass may be reduced with diagnostic barium enema; air contrast enema is diagnostic and often curative 4. volvulus = "twisting" of the intestines (may occur in sigmoid colon of elderly due to redundant mesentery) signs include acute abdominal pain, inability to pass flatus, markedly distended abdomen (neurophilic leukocytosis) bloody colonic discharge with shedding of dark colonic mucosa is due to colonic necrosis sigmoid volvulus is a common cause of large bowel obstruction; may see "bird beak" sign with barium study treat with sigmoidoscopic decompression 5. meconium ileus (ileal obstruction by thick meconium) is seen in newborns with cystic fibrosis J. tumors of the small intestines 1. benign most common benign tumors include adenomas, mesenchymal tumors (leiomyomas), and lipomas most adenomas occur in the region of the ampulla of Vater sx: occult blood loss; mx: similar to adenomas of the colon 2. malignant most malignant tumors are adenocarcinoma and occur in the duodenum involvement of the ampulla of Vater may cause early obstructive jaundice

extra-intestinal

risk factor is chronic inflammation associated with Crohn's disease polyps 1. non-neoplastic a) hyperplastic polyps are very common (aging change) but no increased risk of cancer grossly look like "dewdrops (<5mm), while microscopy reveals increased cytoplasmic mucin and serrated ("saw tooth) appearance b) hamartomatous polyps (1) juvenile (retention) typically found in rectum of children or young adults (may have self-amputation of polyp) cystically dilated glands, stroma with marked inflammation (no adenomatous change or increased risk of cancer) juvenile polyposis syndrome (AD inheritance): juvenile retention polyps of colon; slight increased risk of colon cancer (2) Peutz-Jeghers syndrome hamartomas of small intestine (most common site is the jejunum) slight increased risk of colon cancer also see pigmented macules of the buccal mucosa and circumoral skin (3) Cowden syndrome intestinal hamartomatous polyps (no malignant potential), facial trichilemmomas, acral keratoses, oral papillomas increased risk of thyroid and breast cancers germ line mutation of the PTEN gene on chromosome 10 (4) Cronkite-Canada syndrome: GI hamartomatous polyps and ectodermal abnormalities (nail atrophy, skin pigmentation, alopecia) c) inflammatory polyps are pseudopolyps (seen in inflammatory bowel disease) 2. neoplastic a) adenomatous change = stratified epithelial cells with hyperchromatic nuclei and decreased mucin b) size correlates with malignant potential (villous polyps are usually the largest and are most associated with malignancy) c) may cause hemoccult-positive stool (chronic blood loss may cause iron-deficiency anemia) d) types of adenomatous polyps: tubular adenomas: the smallest adenomatous polyps; have the least malignant risk; mx shows dysplastic epithelium forming tubules and glandular structures mixed tubulovillous (villoglandular) villous polyps (papillary structures) (the largest adenomatous polyps and have the most malignant risk) 3. syndromes a) familial (adenomatous) polyposis coli syndrome (FAP) (AD inheritance) deletion of APC gene (adenomatous polyposis coli) on chromosome 5 adenomatous polyps appear in colon at 10-20 years of age risk of cancer is 100% (therefore rx is total colectomy) b) Gardner syndrome (AD inheritance) adenomatous polyps in colon and small intestine (increased risk periampullary carcinoma) risk of cancer is 100% extra-intestinal manifestations include jaw osteomas, epidermal cysts of skin c) Turcot syndrome adenomatous polyps of colon risk of cancer is 100% associated with CNS neoplasms, such as glioblastoma multiforme d) hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (aka Lynch syndrome) increased risk of colorectal cancer and extraintestinal cancer (particularly the endometrium) mutations in DNA repair genes leads to microsatellite instability L. colon cancer 1. molecular pathology: the pathogenesis of colon cancer is a multistep process involving many oncogenes and anti-oncogenes a) APC (adenomatous polyposis coli) gene is a tumor-suppressor gene that functions as a "gatekeeper" gene
K. colon

major

binds to and forms complex with beta-catenin and E-cadherin beta-catenin is not in complex it can act as an oncogene by binding to T cell factor-lymphoid enhancer factor (Tcf-Lef) proteins genes activated by beta-catenin:Tcf complex stimulate proliferation and inhibit apoptosis mutations of APC cause decreased binding to beta-catenin and are found in FAP and Gardner syndrome b) human mismatch repair genes (hMSH1, hMSH2) function for genetic "proofreading" during DNA replication (called "caretaker" genes) inherited mutations seen in hereditary nonpolyposis colon carcinoma (HNPCC) c) methylation abnormalities involve K-ras, DCC (deleted in colon cancer), and p53 2. predisposing factors dietary risk factors include increased dietary carbohydrates and fat and decreased dietary fiber inflammatory bowel disease (especially ulcerative colitis) adenomatous polyps, which have epithelial dysplasia (and are found in multiple polyposis syndromes) 3. anatomic locations left-sided colon ("napkin ring or "apple core) lesions are associated with rectal bleeding and intestinal obstruction right-sided colon (polypoid mass) lesions are associated with occult blood (hemoccult positive) and iron deficiency anemia 4. histology reveals adenocarcinoma 5. clinical a) lab bleeding will cause positive stool for occult blood and decreased serum hemoglobin positive CEA, especially with mets (used clinically to watch for recurrence) b) stage (Astler-Coller modification of Dukes classification) A = mucosa (or submucosa, this being arbitrary) B1 = into muscularis propria; B2 = through muscularis propria C1 = into muscularis propria with lymph node metastasis; C2 = through muscularis propria with lymph node metastasis D = distant spread M. carcinoid tumor 1. originate from neuroendocrine cells (argentaffin cells, APUD cells, Kulchitsky cells) 2. sites (cancer risk is parentheses): appendix (1%) > ileum (60%) > rectum (15%) 3. gross reveals yellow-tan, firm tumor (multiple in small intestines) 4. microscopy highly vascular with uniform nests of cells (vascular invasion does not imply malignancy, can only tell malignancy by metastatic spread) cells stain positive with silver stains (argentaffin and argyrophil), NSE (neuron-specific enolase) stain, and chromogranin EM reveals membrane-bound dense-core neurosecretory granules 5. carcinoid syndrome may produce carcinoid syndrome due to production of serotonin (5hydroxytryptamine; 5HT), which stimulates smooth muscle need metastasis to liver or a very large primary tumor to develop carcinoid syndrome abdominal cramps and diarrhea due to contraction of GI smooth muscle asthmatic (expiratory) wheezing due to bronchospasm episodic cutaneous flushing due to skin vasodilation caused by histamine serotonin inactivated to 5HIAA (5-hydroxyindole acetic acid) in liver and lungs by monoamine oxidase in endothelial cells (increased urine 5-HIAA) carcinoid heart disease = fibrosis and stenosis of right-side valves (TV and PV) produces pearly white endocardial plaques treat with octreotide N. GI lymphomas 1. MALT lymphoma MALTomas arise from B cells of mucosa-associated lymphoid tissue (MALT); common site is stomach remain localized in GI tract and can be treated with surgical resection
when

normally

may reveal small lymphocytes with irregular nuclei invading epithelial glands (lymphoepithelial lesions) 2. Mediterranean lymphoma a B-cell lymphoma of small intestines that arises from chronic mucosal plasmacytosis (immunoproliferative small intestinal disease) 3. intestinal T-cell lymphoma: usually associated with long-standing malabsorption, eg sprue-associated lymphoma O. appendix 1. appendicitis secondary to obstruction of lumen (fecalith) gross reveals congestion with purulent exudate on surface, while microscopic reveals neutrophils within wall produces abdominal pain (right lower quadrant at McBurneys point, which is 2/3rds the distance from the umbilicus to the anterior iliac spine) may see Sentinel loop on X-ray (distended bowel suggestive of localized ileus secondary to inflamed abdominal viscera, such as appendicitis, pancreatitis, cholecystitis) 2. tumors: carcinoid tumor, mucocele, mucinous cystadenoma P. peritoneum 1. inflammation (peritonitis) sterile peritonitis: mild leakage of bile or pancreatic enzymes rupture of the biliary system acute hemorrhagic pancreatitis surgical procedures 2. infection (bacterial peritonitis): due to secondary extension of bacteria through wall of hollow viscus 3. sclerosing retroperitonitis (Ormond disease) 4. tumors primary: mesotheliomas (very rare) desmoplastic small round cell tumor: t(11;22) produces a EWS-WT1 fusion gene LIVER
131. Normal A. microarchitecture

histology

= hepatic lobule (hexagonal) = central vein (terminal hepatic venule) periphery = portal triad (bile duct, hepatic artery, portal vein) note: bile flows from bile canaliculi to bile ductules (cannals of Hering) to bile ducts 2. functional = hepatic acinus zone 1 = highest concentration of oxygen and substances in blood; gluconeogenesis, oxidative energy metabolism, urea synthesis zone 2 = in between zone 1 and zone 3 zone 3 = glycolysis, lipogenesis, highest concentration of liver metabolites, farthest from oxygenated blood supply B. cells 1. endothelial cells (line sinusoids) 2. Kupffer cells (within sinusoids): are phagocytic (marcrophage) cells; have receptors for carbohydrates, Fc portion of immunoglobulin, C3 of complement 3. Ito (perisinusoidal stellate) cells: found in subendothelial space of Disse (between hepatocytes and endothelial cells); store vitamin A; synthesize collagen in cirrhosis 4. hepatocytes hepatocytes immediately abutting the portal tract are called the limiting plate SER (smooth endoplasmic reticulum): conjugate bilirubin, detoxify drugs, synthesize cholesterol RER (rough endoplasmic reticulum): synthesize protein (albumin, coagulation factors, enzymes)
center 132. Patterns

1. classic

A. degeneration

of hepatic injury and intracellular accumulation ballooning degeneration: swollen hepatocytes with irregularly clumjped cytoplasmic organelles and large clear spaces

degeneration: retained biliary material produces a diffuse foamy (lacy) appearance to hepatocytes (seen with cholestatic liver injury) steatosis: accumulation of triglyceride fat droplets in hepatocytes B. necrosis and apoptosis 1. focal necrosis randomly occurring necrosis of single cells or small clusters of cells acidophilic (Councilman) bodies are due to apoptosis (eg cytotoxic CD8 T cells destroy viral-infected hepatocytes) causes include viral, toxic, bacteria 2. zonal necrosis (zonal = identical changes in all liver lobules) a) centrizonal (centrilobular) = acinar zone 3 (1) viruses, carbon tetrachloride, chloroform, anoxia (ischemia from heart failure or shock) (2) drugs metabolized to toxins in zone 1 can cause necrosis downstream in zone 3; an example is acetaminophen (Tylenol): normal (non-toxic) amounts of acetaminophen are converted to nontoxic metabolites excess acetaminophen is hydroxylated by P450 to hepatotoxin (N-acetyl-benzyoquioneimine) that is detoxified by glutathione excess acetaminophen depletes glutathione stores; then toxic compound will kill hepatocytes in acinar zone 3 treatment with N-acetylcysteine may increaseglutathione stores b) midzonal = yellow fever (uncommon), which is an RNA type B togavirus spread by Aedes mosquito mite c) peripheral (periportal = around portal tracts) necrosis is associated with phosphorous poisoning and pregnancy 3. submassive/massive a) submassive necrosis liver cell necrosis crosses lobular boundaries "bridging necrosis = necrosis from portal areas to central veins b) if severe = massive necrosis (1) soft, yellow, flabby, decreased size, winkled capsule (acute yellow atrophy) (2) causes include hepatitis viruses (usually B or C) drugs and chemicals, such as halothane, acetaminophen, INH, and methyldopa chemicals, such as Amanita phalloides mushrooms (rapid toxicity = amanita muscaria; delayed toxicity = amanita phalloides), chlorinated hydrocarbon insecticides, chloroform, carbon tetrachloride C. inflammation D. regeneration E. fibrosis: generally irreversible hepatic damage; may eventually produce cirrhosis
133. Laboratory A. enzymes 1. transaminases aspartate

feathery

evaluation of liver disease

(aminotransferases); need cofactor vitamin B6 (pyridoxine) aminotransferase (AST, SGOT) is mitochondrial enzyme found in many different cells in the body AST transfers the amino group of aspartic acid to alpha-ketoglutaric acid to form oxaloacetic acid and glutamic acid alanine aminotransferase (ALT, SGPT) is non-mitochondria and is found mainly in the liver; it forms pyruvate if ALT increase > AST increase think liver cell necrosis due to viral hepatitis if AST increase > ALT increase think alcoholic hepatitis (think "toAST"), this is possibly because alcohol is a mitochondrial toxin (releasing the mitochondrial AST) or because alcoholics have a dietary deficiency of pyridoxine, which is involved in the rate limiting step in ALT synthesis 2. alkaline phosphatase slight increase = liver parenchymal disease marked increase = extrahepatic obstruction (think bile ducts and biliary tract) 3. gamma-glutamyl transpeptidase (GGT) microsomal enzyme that regulates the transport of amino acids across cell membranes

 causes B. test

4. glucuronosyltransferase

of increase are similar to alk phosph + alcohol (which induces microsomal enzymes) (UGT) conjugates bilirubin

categories

1. hepatocyte

integrity: cytosolic hepatocellular enzymes (AST, ALT, LDH) 2. biliary excretory function substances normally excreted in bile: serum bilirubin, urine bilirubin, serum bile acids plasma membrane enzymes: alkaline phosphatase, GGT, serum 5'-nucleotidase 3. hepatocyte function proteins secreted into the blood: serum albumin (decreased with severe liver disease), prothrombin time hepatocyte metabolism: serum ammonia, aminopyrine breath test, galactose elimination
134. Liver

failure

A. metabolic

abnormalities predisposes to peripheral edema increased blood ammonia (may be due to increased gut bacterial deamination of amino acids or decreased ammonia conversion to urea in liver) decreased hormone metabolism (decreased clearance by liver or decreased production of binding proteins by liver) leads to increased estrogen (produces spider angiomas; gynecomastia in males), aldosterone, ADH B. clinical abnormalities fector hepaticus is pungent odor ("musty" or "sweet and sour" odor) in the breath due to formation of volatile sulfur-containing mercaptans in gut spider angioma (has central pulsating dilated arteriole), gynecomastia, jaundice, bleeding, ascites (possible complication is spontaneous bacterial peritonitis, which can lead to sepsis; dx by finding more than 500 PMN's/microliter in the ascites fluid), edema (due to decreased albumin) prolonged prothrombin time (PT), not corrected by vitamin K, correlates with severity of disease hepatic encephalopathy includes cerebral dysfunction (delirium, convulsions, coma) and asterixis (liver flap); often precipitated by protein, GI bled, or infection; rx to lower ammonia levels special type: hepatorenal syndrome = worsening renal failure (azotemia = increased BUN) with oliguria (no pathologic changes in kidney, renal disease is reversible)
hypoalbuminemia: 135. Cirrhosis/portal A. cirrhosis 1. pathology

hypertension

liver cell necrosis with regenerative (hyperplasia) nodules; disruption of the architecture of the entire liver (focal scarring is not cirrhosis) fibrosis involving both the central veins and the portal triads obstructs sinusoidal blood flow (causing portal hypertension) bridging fibrosis is from one triad to another triad interstitial collagens (types I and III) deposited in lobules by perisinusoidal stellate cells (Ito cells), which normally (quiescent) store vitamin A 2. classifications (don't use because does NOT correlate with etiology): micronodular (<3cm) in general is due to chronic insult (alcohol, Laennecs cirrhosis) macronodular (>3cm) in general is due to acute insult (post-infectious or drug-induced) 3. clinical features cirrhosis can lead to portal hypertension (and esophageal varices with a risk of severe bleeding) and liver failure all causes of cirrhosis have increased risk of hepatocellular carcinoma B. portal hypertension 1. cause: most often due to cirrhosis 2. clinical consequences a) ascites: excess fluid in the peritoneal cavity b) porto-systemic venous shunts at rectum produces hemorrhoids (superior, middle and inferior rectal veins) at EGJ produces esophageal varices (left gastric-azygous) around umbilicus produces "caput medusae (paraumbilical-inferior gastric) c) splenomegaly

diffuse

d) hepatic 136. Jaundice

encephalopathy results as portal vein blood bypasses liver

and cholestasis (jaundice = increased bilirubin; unconjugated (indirect) BR is fat soluble; conjugated (direct) BR is water soluble (urine may be dark)) A. bilirubin and bile formation bilirubin is the end product of heme degradation heme oxygenase oxidizes heme to biliverdin, which is reduced to bilirubin by bilverdin reductase bilirubin is bound to serum albumin and taken up by hepatocytes by carrier-mediated uptake at the sinusoidal membrane in hepatocytes bilirubin is conjugated with glucuronic acid by the enzyme UGT then excreted as bilirubin glucuronides into bile bilirubin glucuronides are deconjugated by bacterial beta-glucuronidases and degraded to colorless urobilinogens, which are excreted in the feces B. results of jaundice icterus = yellow skin and sclera (differential diagnosis is increased carotene, which doesn't change color of sclera) also develop pruritus (secondary to increased bile acids) and skin xanthomas (due to abnormal cholesterol metabolism) kernicterus = neonatal increased free unconjugated bilirubin crosses blood-brain barrier and deposits in lipid-rich basal ganglia (grossly yellow-brown) also develop increased alkaline phosphatase and decreased fat soluble vitamins (ADEK) mx shows cholestasis, bile duct proliferation, bile plugs (in cannaliculi) and bile lakes (think extrahepatic biliary obstruction) C. increased hemolysis (causes excess bilirubin production, too much for liver to handle) hemolytic anemias or ineffective erythropoiesis (pernicious anemia or thalassemia) lab findings: decreased hemoglobin, increased indirect bilirubin, normal serum direct bilirubin, and increased urine urobilinogen (normal serum alkaline phosphatase; normal serum AST) D. hepatocellular abnormalities 1. decreased uptake of bilirubin by hepatocytes may be due to drugs 2. decreased conjugation (to form bilirubin-glucuronide) causes an increased unconjugated bilirubin a) physiologic jaundice of newborn increased bilirubin (indirect) on day 2-4 is mainly due to decreased levels of UGT (bilirubin-UDPglucuronyl transferase) note: physiologic jaundice develops 24-48 hours after birth; jaundice present at birth and in the first day of life is pathologic (occurred in utero) kernicterus (unconjugated bilirubin deposition in brain (lipid rich basal ganglia) if bilirubin > 20mg% ; causes mental retardation) treatment (if needed) is expose skin to light (440-470nm), which activates oxygen and converts bilirubin to photobilirubin which is excreted in urine (hydrophilic and less bound to albumin) b) Crigler-Najjar syndromes type I (no UGT) is fatal during the neonatal period (bile is colorless) type II (decreased UGT) produces a mild disease and may treat with phenobarb (induces enzymes in SER causing hyperplasia of SER) c) Gilberts syndrome (mildly decreased UGT) is usually asymptomatic (7% population), but may develop mild symptoms (of jaundice) with stress or fasting d) breast milk jaundice elevated indirect bilirubin in breastfed newborn developing between days 4-7 of life; persists longer than physiologic jaundice (upto 6 weeks) may be due to hormones in breast milk that inhibits UGT compare to breastfeeding jaundice, which occurs before first 4-7 days of life; due to insufficient breast milk (decreased plasma volume) 3. lab findings hepatocellular injury: normal serum Hgb; increased serum indirect BR; increased serum direct BR; increased serum alkaline phosphatase; increased serum AST; increased urinary urobilinogen E. impaired transport (causes increased conjugated (direct) bilirubin) 1. Dubin-Johnson syndrome is due to defective excretion of bilirubin glucuronide and other organic anions from hepatocytes

of the canalicular protein, the multidrug resistance protein 2 (MRP2) cytoplasmic globules in hepatocytes and black liver grossly (not associated with liver failure) urine ratio of coproporphyrin I to coproporphyrin III of 5:1 2. Rotor syndrome is similar to Dubin-Johnson syndrome but not black grossly; and liver histology is normal F. obstruction 1. intrahepatic obstruction causes cholestasis, bile plugs and bile duct proliferation; extrahepatic obstruction is more likely to produce bile lakes (this distinction is important for surgery, especially in neonates) 2. extrahepatic obstruction is due to gallstones or cancer Courvoisiers law = obstructive jaundice with dilated (palpable) gallbladder = cancer (adenocarcinoma) of head of pancreas obstructive jaundice without palpable gallbladder = gallstones (chronic cholecystitis) 3. findings include increased direct bilirubin, increased alkaline phosphatase, pale stools, increased urine bilirubin (dark urine), decreased urine urobilinogen G. cholestasis 1. general signs include jaundice, pruritus, dark urine, light stools, and increased serum alkaline phosphatase characteristic lab finding is elevated serum alkaline phosphatase mx: accumulation of bile pigment in hepatocytes, feathery degeneration 2. familial intrahepatic cholestasis benign recurrent intrahepatic cholestasis (BRIC): recurrent episodes of cholestasis without progression to chronic liver disease progressive intrahepatic cholestasis 1 (PFIC-1), progressive intrahepatic cholestasis 2 (PFIC-2), and progressive intrahepatic cholestasis 3 (PFIC-3)
pigmented 137. Viral

absence

hepatitis (other viral causes include EBV (most common of these other because of IM), yellow fever (midzonal necrosis), CMV, herpes, which produces Cowdry A bodies in nuclei) A. hepatitis A virus RNA picornavirus; naked icosahedral nucleocapsid and single-stranded RNA; non-envelop virus, as usual for oral viruses (resistant to low pH of stomach) fecal-oral transmission (enteral) = "infectious hepatitis associated with eating contaminated seafood and children in day care (not seasonal) short incubation period (3 weeks) with mild acute illness (very rarely death), but causes more severe illness in adults anti-hepatitis A IgG is not good for diagnosis; instead best test to detect active hepatitis A is IgM HAV antibody (it's also the first antibody) immunity is with IgG anti-HAV NOT associated with carrier state, chronic hepatitis, or increased risk of malignancy hep A vaccine: in US use for community outbreaks, people at high risk (travelers to endemic areas, homosexual males, IV drug abusers, or pt with chronic liver disease), or communities with high rates (eg Alaska natives) B. hepatitis B virus DNA hepadnavirus (double-stranded) that contains a DNA-dependent DNA polymerase (similar to RNAdependent DNA polymerase of reverse transcriptase of HIV); therefore treatment with 3TC or adenovir transmission is parenteral = "serum hepatitis; most common mode of transmission is sexual contact infective particle is the intact HBV particle (Dane particle, 42nm), while spheres and filaments (22nm) are noninfective incubation period is about 3 months (6 weeks - 6 months) during acute disease about 10% of individuals develop serum sickness-like syndrome (eg macroscopic PAN, with fibrinoid necrosis of blood vessels) first antibody produced is anti-HBc (window period is after decreased HBs antigen and before increased antiHBs antibody: - HBsAg; - HBeAg; - anti-HBs; + anti-HBc) no formation of anti-HBs antibodies leads to persistence of HBsAg = carrier state no formation of anti-HBeAg leads to persistence of HBeAg = infectivity and active disease therefore, if persistence of HBeAg with HBsAg = symptomatic carrier (chronic active hepatitis), which has increased risk of developing liver cancer: hepatitis profile shows + HBsAg; + HBeAg; - anti-HBs; + anti-HBc aymptomatic carrier has HBsAg and anti-HBc but lacks HbeAg and anti-HBs antibodies

profile for previous immunization with hepatitis B surface antigen shows - HBsAg; - HBeAg; + antiHBs; - anti-HBc C. hepatitis C virus RNA flavivirus, single-stranded (previously called nonAnonB hepatitis); unstable, multiple genotypes and subtypes parenteral transmission, especially post-transfusion (through blood only; transmission through needle stick is much less likely than with hep B) incubation is about 3 to 20 weeks acute illness is mild or asymptomatic; factors making it worse include alcohol use, age > 40, HIV infection elevated levels of anti-HCV IgG do not confer immunity; even with chronic infection will make anti-HCV antibodies characteristic changes are episodic elevations of serum transaminases and fatty change of liver (steatosis) chronic "smoldering" infection: undulating levels of virus in blood (if only screen blood for elevated ALT levels, then will miss some cases) >50% progress to chronic state (increased risk of developing chronic hepatitis and subsequent cancer) portal inflammation with destruction of limiting plate = piecemeal necrosis (chronic active hepatitis) D. hepatitis D virus Delta agent = defective RNA virus that needs HBV (HBsAg) transmission is parenteral (blood transfusions and IV drugs) clinical disease due to acute coinfection with HBV or superinfection of HDV on chronic HBV carriers (the latter has a increased risk of chronic hepatitis and cirrhosis); to prevent hep D, prevent hep B, but some places (southeast Asia) with lots of hep B have very little hep D E. hepatitis E virus single-stranded RNA calicivirus; enteric (resembles HAV); not a problem in the US; infection in underdeveloped countries (China) <1% acute mortality (except 10% mortality if patient is pregnant), worse prognosis with increasing age; no carrier state, no chronic disease outbreaks due to fecal-contaminated water; minimal person-to-person transmission (compare to hep A) F. other hepatitis viruses hepatitis F virus: no F agent has yet been identified hepatitis G virus: inappropariately named as it replicates in mononuclear cells, is not hepatotopic, and does not elevate serum aminotransferases
138. Acute

hepatitis

and chronic viral hepatitis syndromes A. acute viral hepatitis 1. microscopic: may show liver cell drop-out (single cell necrosis) and apoptosis (apoptotic Councilman bodies), but apoptotic cells are cleared rapidly and may not see as many as were there; ballooning degeneration (swelling), and focal inflammation 2. clinical stages: patients present with fever/malaise, jaundice, clay-colored stools, and dark urine a) preicteric (prodrome) GI symptoms include anorexia, nausea and vomiting, and altered olfaction and taste (loss of taste for coffee and cigarettes, think HBV) extrahepatic signs include malaise, fatigue, mild fever, photophobia, myalgia, urticaria, arthralgia and arthritis b) icteric increased direct bilirubin causes jaundice, while disrupted bile flow can cause light stools and dark urine coagulation abnormalities can cause ecchymoses (prolonged PT is and important prognostic lab test) c) convalescence and recovery: oral-fecal spread (HAV and HEV) don't have chronic infections; blood spread (HBV, HCV, and HDV) do have chronic disease (chronic hepatitis) B. chronic viral hepatitis 1. chronic hepatitis symptomatic (fatigue, malaise, fever) with elevated serum transaminases microscopy reveals portal triaditis with destruction of limiting plate (piecemeal necrosis) ground glass cytoplasm = hepatitis B (due to HBsAg in cytoplasm; HBcAg is in nucleus); fatty change = hepatitis C in time chronic hepatitis leads to fibrosis

severity of chronic hepatitis is assessed on biopsy by grading the degree of inflammation and staging the extent of fibrosis 2. complications of chronic hepatitis may develop cirrhosis (basement membrane material is laid down under sinusoidal endothelial cells; decreasing the fenestrations and making these capillaries more like regular capillaries elsewhere; then materials can't get thru as normally they can) increased risk of hepatocellular carcinoma 3. differential diagnosis includes autoimmune chronic active hepatitis type 1 = females with anti-smooth muscle and anti-nuclear antibodies ("lupoid hepatitis"), but negative for viral markers (bad prognosis) type 2 = kids (Mediterranean ancestry) with anti-liver-kidney-muscle (anti-LKM) antibody C. fulminant hepatitis
139. Liver

the

infections causes include Staph aureus (with toxic shock syndrome), Salmonella typhi (typhoid syndrome), gut flora (ascending cholangitis) B. parasites 1. amebiasis is due to Entamoeba histolytica cause "flask-shaped ulcers in colon and may spread to liver and form amebic abscess (filled with "achovy paste" material) signs of liver abscess include RUQ abdominal pain, fever, weight loss, and hepatomegaly treat symptomatic amebiasis with metronidazole (Flagyl) 2. Schistosoma (mansoni and japonicum) infectious schistosome larvae from freshwater snails penetrate human skin and eventually migrate to portal veins marked portal fibrosis (with granulomas) may produce gross appearance similar to stem of a clay pipe ("pipestem" fibrosis) 3. Echinococcus granulosa causes hydatid cyst (risk of anaphylaxis if ruptured) ingestion of tapeworm eggs in dog feces (definitive host is dog, therefore is also associated with sheep and sheepherders) eggs hatch in duodenum and invade to liver, lungs, bones mx reveals cyst with thick, acellular, laminated eosinophilic wall; fluid within the cyst contains numerous small larval capsules with scoleces ("brood capsules") 4. Clonorchis sinensis (Chinese liver fluke) infects bile ducts and also has increased risk of bile duct carcinoma
A. bacteria:

140. Drugs A. classification

(dose related) response: acetaminophen and high dose IV tetracycline (idiosyncratic) response may produce massive necrosis (INH, halothane, methylDOPA) or cholestasis B. results fatty change may be due to salicylates, high dose IV tetracycline, ethanol centrilobular necrosis may be due to carbon tetracholide or acetaminophen veno-occlusive disease may be due to alkaloids (bush tea) peliosis hepatis may be due to anabolic steroids and birth control pills hepatocellular carcinoma may be due to vinyl chloride, thorotrast, and aflatoxin angiosarcoma may be due to vinyl chloride, thorotrast, and arsenic
unpredicatable 141. Steatosis A. types 1. macrovesicular 2. microvesicular

predictable

= accumulation of neutral lipid (triglyceride) in hepatocytes

= single large vacuole, peripheral nucleus; alcohol is the most common cause = many small vacuoles, central nucleus, due to Reye's syndrome and some drugs a) Reyes syndrome seen in children who present with vomiting 3-5 days after a viral infection (especially VZV and influenza B) ?relationship to salicylates (don't give baby aspirin to child with cold)

mitochondria (large budding and branching), microvesicular steatosis, hypoglycemia, cerebral edema, and coma b) acute fatty liver of pregnancy (seen during third trimester) and tetracycline toxicity B. mechanisms increased free fatty acid delivery to liver (starvation, corticosteroids, diabetes mellitus, alcohol, surgery for marked obesity) decreased formation of apoprotein (carbon tetrachloride and protein malnutrition, called kwashiorkor) other effects of alcohol: increased lipid synthesis and decreased lipid oxidation in liver, and decreased export of VLDL from liver C. alcoholic liver disease 1. alcoholic steatosis (reversible) NADH >> NAD; causes decreased beta-oxidation of fatty acids, decreased gluconeogenesis, and increased triglyceride synthesis 2. alcoholic hepatitis (reversible) may occur after binge drinking mx: Mallory bodies (prekeratin intermediate filaments) and fibrosis around central vein called perivenular fibrosis or central hyaline sclerosis 3. alcoholic cirrhosis (but < 15% of alcoholics develop cirrhosis) mx shows fibrosis with regenerating hepatocellular nodules D. nonalcoholic fatty liver disease (NAFLD): a type of chronic hepatitis characterized by liver damage similar to alcohol-induced liver damage risk factors: diabetes mellitus, obesity, hyperlipidemia, rapid weight loss, malnutrition (kwashiorkor), and bypass surgery sx: usually asymptomatic, but can develop fatigue, malaise, right upper quadrant abdominal discomfort, and hepatomegaly lab: elevated liver enzymes, increased serum cholesterol, triglyceride, and glucose ultrasonography: diffuse increased density that is similar in appearance to cirrhosis liver biopsy is the best diagnostic test for confirming the diagnosis; mx: macrovesicular steatosis nonalcoholic steatohepatitis (NASH): a subtype of NAFLD having steatosis, inflammation, and hepatocyte ballooning and necrosis
142. Metabolic

abnormal

liver disease

A. hemochromatosis

hemochromatosis is due to chronic severe anemia (thalassemia and sideroblastic anemia) with multiple blood transfusions note: increased iron in Kupffer cells and not hepatocytes is called hemosiderosis primary hemochromatosis is AR disorder where the basic defect is increased iron absorption from small intestines hemochromatosis gene (HFE) encodes an HLA class I-like molecule that regulates intestinal absorption of dietary iron the critical site for HFE expression is the basolateral surface of the small intestinal crypt epithelial cell where it complexes with the transferrin receptor "bronze diabetes = triad of micronodular cirrhosis, diabetes mellitus, and skin pigmentation lab: increased serum iron with increased ferritin, increased % saturation of TIBC, and increased bone marrow iron increased iron in hepatocytes and Kupffer cells (Prussian blue stain) produces cirrhosis (increased incidence of hepatocellular carcinoma) increased iron in islets of pancreas causes decreased insulin (secondary diabetes mellitus) iron in heart causes dilated cardiomyopathy and congestive heart failure (the most common cause of death in hemochromatosis) skin pigmentation is due to increased MSH activity due to increased POMC (proopiomelanocortin ) due to decreased cortisol from adrenal cortex treat with repeated phlebotomy or deferoxamine (but need to screen family members of probands for hemochromatosis) B. Wilsons disease decreased ceruloplasmin due to failure of copper to be excreted from liver as ceruloplasmin

secondary

to abnormal copper transporting ATPase; gene is called ATP7B copper in liver, brain, cornea, urine (but serum copper levels are variable); stain for copper is rhodamine stain hepatolenticular degeneration of basal ganglia, especially putamen (extrapyramidal dysfunction causes choreiform movements) eyes have Kayser-Fleischer rings (green color) due to copper deposited in Descemets membrane at the sclerocorneal junction dementia, liver failure, and increased risk of hepatocellular carcinoma treat with penicillamine and dietary copper restriction (shellfish, liver, legumes) C. decreased alpha 1 antitrypsin due to defective folding of the protein microscopically see red cytoplasmic aggregates (PAS positive diastase resistant) of alpha1antitrypsin in hepatocytes lung disease is panacinar (panlobular) emphysema 2% PiZZ allele has biggest risk for hepatocellular carcinoma
increased 143. Intrahepatic

due

bile duct disease (sx: jaundice, pruritus, dark urine, light stools, and increased serum alkaline phosphatase; end stage is green (bile stained) liver) A. secondary biliary cirrhosis (usually extrahepatic obstruction): most common cause in adults is extrahepatic cholelithiasis followed by malignancies B. primary biliary cirrhosis (PBC) autoimmune disorder found primarily in middle aged females antimitochondrial antibodies, such as antibodies against the E2 subunit of the pyruvate dehydrogenase complex bile ducts have granulomas with lymphocytic infiltrate (florid duct lesion) increased triglyceride and cholesterol cause xanthomas and increased risk of atherosclerosis malabsorption of fat (steatorrhea), vitamin D and calcium (osteomalacia and osteoporosis), vitamin K (easy bruising), vitamin A (night blindness), and vitamin E (dermatitis) C. primary sclerosing cholangitis (PSC) a disorder primarily of males < 40 years of age periductal fibrosis ("onion-skinning) around bile ducts in portal triad (characteristic "beading" of bile ducts with x-ray) associated with chronic ulcerative colitis (70%) and positive p-ANCA signs include jaundice, pruritus, dark urine, light stools, and increased serum alkaline phosphatase; increased risk of cholangiocarcinoma D. anomalies of biliary tree Von Myenburg complexes: small clusters of dilated bile ducts (bile duct microhamartomas) in fibrous stroma near portal triad; no clinical significance polycystic liver disease: associated with adult (AD inheritance) polycystic kidney disease congenital hepatic fibrosis: associated with child (AR inheritance) polycystic kidney disease Caroli disease: segmental dilation of the larger ducts of the intrahepatic biliary tree Alagille syndrome: liver is almost normal but the portal tract bile ducts are absent; caused by mutations in Jagged1 gene, which is a ligand for the Notch transmembrane receptors disorders (presinusoidal) due to portal vein thrombosis or splenomegaly infarcts due to portal vein thrombosis are rare because of liver's dual blood supply (portal vein and hepatic artery) in neonates, extrahepatic obstruction of the portal vein (Banti syndrome) results from umbilical vein sepsis due to umbilical catherization infarct of Zahn is not a true infarct, but is obstruction of intrahepatic branches of portal vein (mx see sinusoidal dilation and congestion) B. intrahepatic (sinusoidal) most commonly due to cirrhosis (which is the most common cause of portal hypertension) peliosis hepatis is focal dilated sinuses and irregular cystic spaces filled with blood that can result from anabolic steroid use or Bartonella henselae infection (bacillary angiomatosis) in AIDS patient C. posthepatic (postsinusoidal) can be due to:
A. prehepatic

144. Circulatory

1. RV

failure: causes central passive congestion (acinar zone 3); seen grossly as nutmeg liver syndrome (thrombosis of hepatic vein) acute onset of RUQ abdominal pain, hepatomegaly, ascites, and hematemesis associated with P. vera, pregnancy, PNH, and hepatocellular carcinoma 3. hepatic veno-occlusive disease (sinusoidal dilation syndrome) due to obliteration of hepatic vein radicles, central vein (often seen after bone marrow transplants) sx are tender hepatomegaly, ascites, weight gain, and jaundice
2. Budd-Chiari 145. Pregnancy/transplants A. hepatic

disease associated with pregnancy 1. preeclampsia and eclampsia preecclampsia = maternal hypertension, proteinuria, peripheral edema, coagulation abnormalities ecclampsia = preeclampsia plus hyperreflexia and convulsions HELLP = hemolysis, elevated liver enzymes and low platelets 2. acute fatty liver of pregnancy: dx depends on biopsy showing characteristic microvesicular fatty change; primary treatment for AFLP is termination of the pregnancy 3. intrahepatic cholestasis of pregnancy: sx include onset of pruritus in third trimester with dark urine, light stools, and jaundice B. hepatic complications of organ or bone marro transplantation 1. drug toxicity ("liver toxicity") after bone marrow transplantation sx: weight gain, tender hepatomegaly, edema, ascites, hyperbilirubinemia mx: centrolobular necrosis with inflammation; ends in veno-occlusive disease (sinusoidal obstruction syndrome) 2. GVH (graft-versus-host) disease (seen after bone marrow transplanatation) and liver (allograft) rejection (seen after liver transplant) 3. nonimmunologic damage to liver allografts
146. Liver

tumors A. nodular hyperplasias 1. focal nodular hyperplasia characteristic gross finding is tumor with central stellate scar mx shows hepatic nodules surrounded by fibrous bands having numerous proliferating bile ducts associated with birth control pills (?), but not associated with development of carcinoma 2. nodular regnerative hyperplasia entire liver has many nodules (no fibrosis); seen with renal and bone marrow transplants; causes portal hypertension mx: nodules composed of plump hepatocytes; layer of atrophic cells at the rim of each nodule B. benign neoplasms 1. hemangioma (cavernous) is the most common benign tumor of liver (usually incidental finding, but may cause bleeding) mx shows multiple small endothelial-lined spaces filled with blood 2. adenomas include liver cell adenoma (associated with anabolic steroids and oral contraceptives; not premalignant) and bile duct adenoma mx of liver cell adenoma shows cords of unremarkable hepatocytes with no lobular architecture formation C. malignant 1. hepatoblastoma most commonly found in young children (MC primary malignancy of the liver in kids) frequent activation of the Wnt/beta-catenin signaling pathway by stabilizing mutations of beta-catenin 2 microscopic variants: epithelial type and mixed epithelial/mesenchymal type 2. angiosarcoma is a malignancy of blood vessels (associated with vinyl chloride, Thorotrast, arsenic) 3. hepatocellular carcinoma is the most common primary malignant tumor of liver in adult associations include hepatitis B and C, aflatoxin (from aspergillus flavus causing moldy grains and nuts), and any cause of cirrhosis increased AFP (alpha fetoprotein), which is also increased with yolk-sac tumors and fetal neural tube defects microscopically see cords (trabeculae) of malignant hepatocytes (which may have bile in cytoplasm, best characteristic)

 fibrolamellar

4. cholangiocarcinoma

variant = found in females, no increased AFP, grossly encapsulated, better prognosis (malignancy of bile ducts) is associated with Thorotrast, liver fluke (Clonorchis sinensis),

and PSC
147. Gallbladder:

normal and congenital abnormalities lacks a muscularis mucosae and submucosa ducts of Luschka: remnants of embryonic bile ducts located in the wall of the gallbladder next to the liver Rokitansky-Aschoff sinuses: small outpouchings of the mucosa that penetrate into the muscle wall phyrgian cap: refers to a folded expanded fundus (Phyrgia was an ancient country in Asia Minor; Smurfs wore phyrgian caps)
gallbladder

148. Gallstones A. general

stones are asymptomatic but symptoms include RUQ pain after eating fatty meal and abdominal pain radiating to right scapula non-palpable gallbladder in patient with obstructive jaundice = impacted gallstones gallstone ileus: abdominal x-ray reveals free airy in biliary system and dilated small bowel with round filling defect medical treatment with chenodiol (chenodeoxycholic acid) decreases chol and increases bile acids (complications include diarrhea and increased LDL) B. cholesterol stones 1. clinical most common type in west and high incidence in Native Americans increased cholesterol associated with hyperlipidemias, obesity, increased calories in diet, clofibrate therapy, increased HMG-CoA reductase increased cholesterol may produce cholesterolosis, which refers to finding cholesterol-laden macrophages in gallbladder mucosa Fs = fat, fertile, female, forties and fifties (flatulence?) 2. gross shows multiple, round, yellow stones (radiolucent) 3. pathogenesis (steps) involves: need supersaturation to make any type of crystal (eg, increased cholesterol secretion and decreased bile acid secretion) decreased 7 alpha hydroxylase decreases bile salts and increases cholesterol); rate limiting step in the synthesis of bile acids (7-alpha-hydroxylase acts on cholesterol to form cholate) defective vesicle formation (forms large multilamellar vesicles) crystal nucleation forms nidus; formation of biliary sludge; and accretion (process by which small things become big) C. bilirubin stones 1. clinical associations include east locations (Asians), chronic hemolytic anemias (sickle cell anemia and thalassemia), infections (Clonorchis sinensis), and ileal disease (clue is gallstones in nulliparous or child) 2. gross shows pigment stones, which are black or brown, molded stones (radiopaque) 3. pathogenesis black stones results when increased bilirubin combines with calcium brown stones result when vesicles and micelles acted upon by bacteria with release of free bile acids, free fatty acids, unconjugated bilirubin, which combine with calcium and mucin to form brown stones
149. Inflammation

most

of the gallbladder (cholecystitis) A. acute cholecystitis signs include acute colicky RUQ pain, fever, leukocytosis; Murphy's sign is palpation of RUQ causes sharp pain and cessation of inspiration cause is obstruction of cystic duct by stone with secondary superinfection (EEEK! bugs: E. coli, Enterobacter cloacae, Enterococcus, Klebsiella species) microscopically see acute inflammation (neutrophils) treatment is surgery; complication is subdiaphragmatic abscess (sx: spiking fever, RUQ abdominal pain, complex fluid collection under diaphragm) B. chronic cholecystitis

 signs

include recurrent biliary pain (colic) that lasts only a few hours (no fever or leukocytosis) with cholelithiasis microscopically see thickened wall with chronic inflammation and Rokitansky-Aschoff sinuses treatment is either medical or surgical
associated 150. Extrahepatic A. disorders

bile ducts and tumors of the extrahepatic bile ducts 1. choledocholithiasis and ascending cholangitis choledocholithiasis = stones in the biliary tree; may be a cause of acute bile duct obstruction, resulting in jaundice, pain, and sepsis cholangitis = bacterial infection of the bile ducts, usually precipitated by gallstone blocking common bile duct Charcot triad = jaundice, fever, and RUQ abdominal pain; for Reynold's pentad add altered mental status and hypotension ascending cholangitis = infection of the intrahepatic biliary radicles 2. biliary atresia extrahepatic biliary atresia is the most common cause of neonatal cholestasis 2 types:fetal form (associated with other abnormalities) and perinatal form (normally developed biliary tree is destroyed after birth) sx: obstructive jaundice (dark urine, clay-colored stools) with direct hyperbilirubinemia 3. choledochal cysts: congenital dilations of the common bile duct (in adults associated with Caroli disease) B. tumors carcinoma of the gallbladder: adenocarcinoma carcinoma of the extrahepatic bile ducts

PANCREAS
151. Normal A. embryology: 1. ducts:

note dorsal primordium and ventral primordium

B. histology/anatomy

main = Wirsung (into ampulla of Vater into duodenum); accessory = Santorini (pancreas divisium is when this is main duct, 5% of people) 2. parenchyma a) exocrine: acinus ("bunch of grapes") and ductal cells ductal columnar epithelial cells secrete aqueous component of pancreatic juice (lots bicarbonate) acinar cells secrete enzyme component of pancreatic juice (lots of enzymes, such as amylase) b) endocrine: islets of Langerhans (1) main B cells: 66% of cells; secrete insulin; located in central part of islet (blood flow is here first); EM shows dark center, light periphery A cells: 15% of cells; secrete glucagon; located in periphery of islet; EM shows dark center, gray periphery D cells: 5% of cells; secrete somatostatin; located throughout islet; EM shows gray throughout F cells: <5% of cells; secrete pancreatic polypeptide; located throughout islet (also in exocrine pancreas); EM shows dark dot (2) minor: Di (secrete VIP); G cells (secrete gastrin)
152. Congenital A. congenital

anomalies associated with germ line homozygous mutations in the IPF1 gene pancreas divisum: accessory duct is major excretory duct annular pancreas is caused by cleavage of the ventral pancreatic bud and rotation of the two portions in opposite directions around the duodenum; may cause narrowing or obstruction of the duodenum ectopic pancreas: abnormal locations (heterotopia) include stomach, duodenum, Meckel diverticula, and ileum B. cystic fibrosis (see chapter 10) 1. genetics autosomal recessive disorder (most common lethal genetic disorder affecting white population, 1/2000)
agenesis:

base deletion causes defective chloride channel (decreased glycosylated chloride channel) exocrine function a) CFTR gene (CF transmembrane conductance regulator) on chromosome 7 which normally is cAMPregulated chloride channel may be volume-absorbing (airways and intestines), salt-absorbing (sweat ducts) or volume-secretory (pancreas) in the lungs chloride ions normally flow into the lumen of the airways; sodium ions and water flow out in the skin chloride ions and sodium ions normally flow out of the lumen of the sweat ducts b) result of abnormal chloride channel: decreased water in secretions; thick mucus secretions (increased viscosity = mucoviscidosis) with cystic fibrosis in the lungs there is decreased chloride ions into the lumen with increased sodium ions and water out of the lumen with cystic fibrosis in the skin there is decreased chloride and sodium ions out of the lumen of the sweat ducts increased salt (NaCl) in sweat is the diagnostic test ("child tastes salty") 3. pancreas plugged dilated ducts with chronic inflammation, atrophy of acini, and fibrosis = cystic fibrosis decreased lipase causes malabsorption and steatorrhea (deficiencies of fat-soluble vitamins ADEK) 4. lungs plugged bronchi leads to atelectasis and bronchiectasis recurrent infections, especially staphylococcus aureus and pseudomonas species 5. other findings GI findings include neonatal intestinal obstruction (meconium ileus) can present in infancy as failure to thrive bile duct obstruction produces jaundice obstruction of vas deferens and seminal vesicles causes sterility in males
2. abnormal 153. Acute

hemorrhagic pancreatitis A. etiology 2 most common are alcohol ingestion (most common, usually follows episode of heavy drinking) and gallstones in bile duct rarer causes include hypercalcemia (which stimulates the activation of trypsinogen in the pancreatic duct), hyperlipidemia, trauma (children) hereditary pancreatitis is caused by germ line mutations in the cationic trypsinogen gene (PRSS1); recurrent pancreatitis usually beginning in childhood inherited homozygous inactivating mutations in the SPINK1 gene (serine protease inhibitor, Kazal type 1) can lead to pancreatitis B. pathology is due to release of pancreatic enzymes 1. lipase local effect is enzymatic fat necrosis general effects is systemic fat necrosis (also interferes with surfactant and can cause ARDS) pancreatic ascites = "chicken broth" fat globules in peritoneal fluid due to lipase 2. trypsin (and chymotrypsin) activate many things including elastase, which produces vascular injury (hemorrhage and shock) Hageman factor, which can lead to DIC 3. amylase release has no clinical effects (but increase is used for diagnosis) C. clinical = medical emergency epigastric pain (severe and constant) that radiation to back fever, nausea and vomiting, and obstructive jaundice discoloration of flank (Turners sign) and umbilicus (Cullens sign) = extensive disease hypocalcemia is a poor prognostic sign (signs are perioral numbness and painful leg cramps) pseudocyst (seen clinically as epigastric mass) is a possible outcome (due to obstruction of (epiploic) foramen of Winslow) lab tests for diagnosis include increased amylase and lipase pancreatitis

154. Chronic

A. etiology rarer

includes alcohol (most common) and gallstones in biliary tract causes include cystic fibrosis (kids), recurrent acute pancreatitis, pancreas divisum B. pathology ducts have areas of obstruction (due to fibrosis and stones) that causes dilatation acini are atrophic with chronic inflammation and fibrosis of interstitium C. clinical results 1. severe pain that is constant or intermittent 2. signs of maldigestion: decreased lipase causes steatorrhea (bulky, light-colored stools) and diarrhea decreased calcium (secondary to decreased vitamin D) and decreased vitamin B12 (secondary to decreased releasing of R-binding proteins) malabsorption of fat-soluble vitamins (ADEK) 3. diabetes mellitus (loss of insulin-producing beta cells) 4. obstructive jaundice 5. complication: pancreatic pseudocyst (called "pseudo" because there is no true epithelial lining): nonmotile fluidfilled mass next to pancreas; may compress the common bile duct and produce abdominal pain, N/V, jaundice
155. Exocrine A. cysts:

cysts and tumors congenital cysts and pseudocysts B. cystic neoplasms serous tumors (microcystic adenomas or serous cystadenomas) are benign; lined by glycogen-rich cells mucinous tumors may be benign (mucinous cystadenomas) or malignant (mucinous cystadenocarcinomas) intraductal papillary mucinous neoplasms (IPMNs): lack dense "ovarian"-type storma of mucinous cystic neoplasms solid-cystic (papillary-cystic) tumor is seen in women younger than 35 and is usually cured by resection C. common malignancy = adenocarcinoma most common location is head of pancreas (which produces biliary obstruction) Courvoisiers law = obstructive jaundice with dilated (palpable) gallbladder = cancer of head of pancreas pain is usually the first symptom; pancreatic carcinoma is the only cancer that has increased incidence in diabetics migratory thrombophlebitis associated with pancreatic cancer = Trousseau's sign more than 90% are associated with mutations of K-RAS tumors (see chapter 24) = islet cell adenomas (mx shows proliferation of uniform small cells forming nests and trabeculae) A. A cell = glucagonomas most are malignant mild diabetes (no ketosis) as glucagon stimulates liver glucose production leads to increased glucose (polyuria and polydipsia) skin rash (necrolytic migratory erythema) secondary to decreased amino acid because excessive glucagon stimulates liver uptake venous thrombi B. B cell = insulinomas 1. most common type of pancreatic islet cell adenoma 2. most are benign (only 10% are malignant) 3. Whipples triad signs and symptoms of hypoglycemia = dizziness, confusion, increased sweating (not ketosis) symptoms relieved by glucose glucose < 40mg/dl 4. clinically measure C peptide increased C peptide = insulinoma or medications that stimulate endogenous insulin production decreased C peptide = insulin antibodies or surreptitious injection of insulin (excess self-medication or Munchausen syndrome) C. G cells = gastrinoma most are malignant and may be associated with MEN (multiple endocrine neoplasia) type I

156. Endocrine

the Zollinger-Ellison syndrome = increased acid production by stomach causes recurrent peptic ulcers (duodenum and jejunum) triad = increased acid, peptic ulcers of duodenum and jejunum, islet cell tumor (also increased thickness of gastric mucosa) D. D cells = somatostatin 1. 80% malignant 2. classic triad: diabetes mellitus (not ketosis-prone) due to inhibition of glucagon and insulin by somatostatin cholelithiasis due to inhibition of CCK by somatostatin steatorrhea due to inhibition of CCK and H+ by somatostatin E. VIPomas = Vermer-Morrison syndrome is WDHA = watery diarrhea, hypokalemia, and achlorhydria

causes

PITUITARY
157. Normal A. embryology

pituitary: outpouching of roof of mouth (Rathke's pouch), ectoderm that forms the roof of the stomodeum posterior pituitary: from floor of third ventricle (diencephalon) B. anatomy 1. hypothalamus: anterior and inferior to thalamus; extends from chiasm to mammillary bodies a) main central control area of visceral system; with pituitary, forms the link between neural and endocrine systems b) mnemonic: HEAL (Homeostasis, Endocrine, Autonomic, Limbic) c) three divisions: periventricular circadian rhythms (suprachiasmatic nucleus), ADH secretion (supraoptic and paraventricular nuclei), pituitary releasing factors (arcuate nucleus) lesions produce DI or SIADH, sexual precocity, hyper or hypo pituitary syndromes d) medial thermoregulation, sleep induction, satiety lesions of medial hypothalamus produce insomnia, hyperphagia lesions of anterior medial produce hyperthermia; posterior-medial usually produce poikilothermia e) lateral cortical arousal, appetite lesions produce hypersomnia, aphagia, adipsia 2. pituitary a) resides in pituitary fossa (sella turcica) which is formed within the sphenoid bone; the pituitary is well protected by the bony sella. Lateral to the pituitary are the cavernous sinuses; inferior is the sphenoid sinus, superior is the hypothalamus, including the optic chiasm b) anterior pituitary (adenohypophysis) (1) pars distalis (pars glandularis): largest portion; contains all hormone-producing cells (2) pars intermedia (intermediate lobe) lies between pars distalis and pars nervosa; poorly developed in humans (vestigial) may contain colloid-containing cysts (Rathke's cysts) (3) pars tuberalis: surrounds the cranial part of the infundibulum; origin of craniopharyngiomas (4) median eminence c) posterior pituitary (neurohypophysis) infundibulum (continuous with hypothalamus) and pituitary stalk (infundibular stalk) pars nervosa (posterior lobe): stores vasopressin and oxytocin C. histology of pituitary 1. posterior lobe unmyelinated nerves (axons from hypothalamus) specialized glial cells (modified astrocytes) called pituicytes neurosecretory granules form Herring bodies; contain hormones 2. anterior lobe: 3 types of glandular cells can be distinguished by H&E according to their cytoplasmic staining a) chromophobes: cytoplasm clear; histology not specific and represent many different cell types b) acidophils (stain orange or red with acid dyes): sommatomammotrophs (the majority of mammotrophs and somatotrophs are found laterally while the majority of corticotrophs are found medially) somatotrophs: GH (growth hormone); most numerous cell type; located in lateral wings lactotrophs (mammotrophs): prolactin c) basophils (stain blue with basic dyes) are thyrotrophs: TSH; gonadotrophs: FSH/LH, and corticotrophs, containing ACTH corticotrophs contain POMC (proopiomelanocortin); precursor molecule of ACTH (and more) inhibited by glucocorticoids, corticotrophs then form "Crooke's hyaline"
158. Adenomas A. General 1. As

anterior

and hyperpituitarism

in all endocrine gland pathology, pituitary pathology manifests as hyperfunction, mass effect, and/or hypofunction

is usually due to functioning pituitary adenoma, (normal anterior pituitary has small acini or lobules and 3 cell types intermixed; adenomatous pituitary = loss of lobularity and 1 cell type) 3. mass effect may occur when an adenoma becomes a macroadenoma (> 1 cm) impingement on blood vessels, meninges, or periosteum causes headache compression of central inferior portion of optic chiasm causes bitemporal hemianopsia (peripheral (temporal) visual fields = "tunnel vision") very large tumors can compress third ventricle and cause hydrocephalus or invade cavernous sinus and cause CN palsy (3, 4, 6 or 1st division of V) 4. may secrete hormones (signs and symptoms depend upon which hormone is secreted) 5. may treat with transsphenoidal surgical resection 6. pituitary apoplexy: neurosurgical emergency due to spontaneous infarction/hemorrhage with blood reaching the subarachnoid space causing increased intracranial pressure and headaches; if the infarction/hemorrhage occurs or reaches inside the cavernous sinus, CN palsy B. prolactin (PRL) secreting tumor, or prolactinoma 1. most common type of pituitary tumor 2. signs and symptoms (females typically present with microadenomas (<1cm); males present with macroadenomas) females present with galactorrhea and amenorrhea (and decreased LH and decreased estradiol) hypogonadism in females (amenorrhea and infertility) and males (impotence and decreased libido) 3. treat with dopamine agonist (such as bromocriptine) which directly inhibits prolactin secretion; note that PRL is the only pituitary hormone under net negative control (ie, release of the pituitary from the control of hypothalamus causes increase in PRL secretion) 4. therefore, hyperprolactinemia can occur in conditions other than functional tumor such as the use of dopamine antagonist drugs (methyldopa and reserpine) and mass effect, inflammation or trauma on the stalk (stalk effect), destruction of the hypothalamus by any etiology, etc. C. somatotropic (GH) adenomas 1. typically macroadenomas 2. secrete growth hormone (2nd most common hormone secreted by functioning tumors), which also stimulates hepatic secretion of IGF-1; can treat with somatostatin 3. associated with missense mutation involving GNAS1 (the mutant form called gsp) which decrease the GTPase activity of the alpha subunit of Gs 4. symptoms depend upon age of patient: a) children = gigantism (excess bone growth at epiphyses) b) adults = acromegaly generalized bone enlargement such as hands (spade-like), jaw, skull (increased hat size), but no increased height (epiphyses already closed) increased size of cartilage (enlarged nose and ears) and increased size of soft tissue (coarse facial features) can confirm by fasting plasma GH levels or failure to suppress GH production in response to oral load of glucose secondary diabetes mellitus (growth hormone is insulin antagonist) high incidence of carpal tunnel syndrome (sx = intermittent numbness and tingling in the fingers) D. corticotroph (ACTH) tumors 1. typically microadenomas 2. increased ACTH secretion causes increased cortisol secretion. Prolonged increased circulating cortisol due to any reason produces the clinical state known as Cushings syndrome; when Cushings syndrome is due to a pituitary adenoma, the situation is known as Cushings disease. 3. note that high dose dexamethasone suppresses pituitary release of ACTH impaired glucose tolerance produces diabetes mellitus central obesity, moon facies, weakness, hirsutism, hypertension, glucose intolerance, osteoporosis, neuropsych abnormalities, striae, etc. (see adrenal) Crookes hyaline (composed of keratin intermediate filaments) appears in (nontumorous) basophil cells of the adenohypophysis in patients with hypercortisolism due to any cause 4. increased skin pigmentation due to increased melanin stimulating hormone or melanogenic effects of high ACTH (via POMC)

2. hyperpituitarism

syndrome = (historical entity and term; adrenalectomy no longer done under these circumstances) explosive growth of a corticotroph adenoma after removal of adrenal glands for treatment of Cushing's syndrome; also see skin pigmentation E. other adenomas gonadotroph (LH, FSH-producing) adenomas: macroadenomas, usually behave or silent (null cell) adenomas; associated with (paradoxical) secondary gonadal hypofunction thyrotroph (TSH-producing) adenomas (~1% of pit tumors), rare cause of hyperthyroidism non-functioning adenomas: most are silent tumors of gonadotrophic lineage; using the most sensitive methods available, true hormone negative tumors are unusual contrary to what the old literature states F. pituitary carcinoma quite rare (<1% pit tumors) requires the demonstration of distant metastases (ie, microscopic appearance not sufficient to make dx)
159. Hypopituitarism A. Acute

5. Nelson's

(occurs when ~75% of anterior pituitary is lost) (rare event) 1. Sheehans syndrome = post-partum pituitary necrosis (term now extended to non-obstetric population; DIC, trauma, thrombosis, etc) sudden infarction of anterior lobe because it's supplied by portal network (portal vessels are low pressure) physiological hyperplasia of pituitary during pregnancy with increased interstitial pressure in fixed space of sella spares posterior pituitary because it has separate arterial blood supply (high pressure) first sign is decreased or complete failure of lactation, then next sign is secondary (persistent) amenorrhea due to decreased gonadotropins B. chronic 1. clinical presentation depends upon age of patient a) children have decreased growth hormone causing dwarfism GH-deficient dwarfs (decreased GH and IGF-1) respond to exogenous GH Laron type dwarfs (increased GH and decreased IGF-1) lack hepatic GH receptors pygmies (normal levels GH and decreased IGF-1) have a post GH receptor defect b) adults have effects of decreased gonadotropins (decreased FSH/LH) causing hypogonadism 2. causes: a) nonsecretory (chromophobe) pituitary adenoma: space-occupying lesions cause pressure atrophy of normal pit (gonadotropins lost first, cause hypogonadism); pituitary apoplexy (hemorrhage or infarction of a pituitary adenoma with production of sx of meningeal irritation, decreasing LOC cranial nerve palsies) b) pituitary surgery or radiation c) Rathke cleft cyst: lined by ciliated cuboidal epithelium with occasional goblet cells d) empty sella syndrome (uncommon) primary cause is abnormal diaphragma sella (herniation of arachnoid through defect with pulsatile CSF from 3rd ventricle above) secondary cause is infarction or necrosis of a pituitary adenoma that causes loss of everything in the sella e) hypothalamic suprasellar tumors; hypothalamic causes tend to produce DI whereas intrasellar processes do not. f) Rare genetic causes g) any of a number of base of brain inflammatory disorders, e.g., sarcoid, TB meningitis, idiopathic inflammatory states pituitary syndromes (diabetes insipidus) 1. causes: any destructive inflammatory, or neoplastic process at base of brain (sarcoid, vasculitis); trauma; hereditary; drug-induced decreased ADH (antidiuretic hormone) = central DI (may also be caused by lithium or demeclocycline) lack of renal response = nephrogenic DI drugs, such as lithium which blocks renal receptors (lithium therefore can be used to treat SIADH, signs and symptoms: polyuria and polydipsia (excess thirst) inability to concentrate urine with fluid restriction; hyper-osmotic volume contraction

160. Posterior A. DI

is dilute urine (specific gravity < 1.006) with serum osmolality > 290 mOsm/L and increased serum sodium (hypernatremia) note: all serum electrolyte values are elevated because of water loss 2. differential diagnosis primary polydipsia (but this is associated with hyponatremia) diabetes mellitus (but this has increased glucose in urine) 3. treatment is adequate fluid intake and: central DI = intranasal desmopressin, an ADH analog that is also used to treat nocturnal enuresis nephrogenic DI = hydrochlorothiazide, indomethacin, or amiloride (ADH will have no effect) B. Syndrome of Inappropriate Antidiuresis (SIAD) 1. Usually due to excess antidiuretic hormone (ADH) (also known as arginine vasopressin or AVP) secretion that is unrelated to plasma osmolarity hence the syndrome has historically been referred to as syndrome of inappropriate ADH (SIADH) in most patients with this syndrome ADH is secreted regardless of serum osmolality (classic SIADH) ADH levels may be suppressed but (only) at a serum sodium level lower than normal (reset osmostat). Levels of ADH are too high at normal serum sodium levels. Some (rare) patients have mutations in the vasopressin receptor that are activating. These patients have the syndrome despite undetectable serum levels of ADH 2. excessive resorption of water causes increased extracellular fluid volume (hypoosmotic volume expansion) decreased serum osmolality (serum osmolality = 2Na+ + glu/18 + BUN/2.8); compare to water deprivation with increased serum osmolality inability to secrete a dilute urine (urine osmolarity > serum osmolarity) oliguria; water retention causes all serum electrolyte levels to be decreased hyponatremia causes weakness, lethargy, confusion, convulsions, coma too rapid correction of hyponatremia can produce central pontine myelinolysis 3. causes include paraneoplastic secretion of ADH, especially small cell carcinoma of the lung, but many other tumors can secrete ADH CNS diseases (huge list including infections, hemorrhages and masses) and pulmonary disease (various infections) drugs, a long list such as vincristine, SSRIs and chlorpropamide
161. Hypothalamic A. Gliomas,

hallmark

suprasellar tumors especially pilocytic astrocytoma and less commonly fibrillary astroyctoma B. Craniopharyngiomas a tumor of childhood (peak in teens) and early adulthood possibly derived from vestigial remnants of Rathkes pouch similar to ameloblastoma of jaw (histology recapitulates the developing enamel organ of the tooth) multiloculated cysts filled with brown oily fluid ("motor oil"), cholesterol crystals, and calcifications (practically diagnostic radiographically) mx see palisading columnar epithelial cells at the margin of groups of tumor cells similar to pituitary tumors it can compress optic chiasm and cause bitemporal hemianopsia ("tunnel vision")biologically benign but difficult to completely remove due to its location C. germinoma (a hypothalamic tumor that presents with diabetes insipidus is nearly always germinoma) biologically and histologically the same as seminoma D. tumor-like lesions of the hypophysis 1. cyst 2. inflammatory disorders sarcoid infections lymphocytic hypophysitis granulomatous hypophysitis

NEUROPATHOLOGY
162. Normal

cells

A. neurons

1. classification

unipolar: sensory neurons; dorsal root and CN sensory ganglia; mesencephalic nucleus of CN V CN I, VIII, and retina multipolar: most neurons in the CNS 2. cell body (perikaryon) the neuron is a highly polarized cell all the usual subcellular organelles Nissl substance: highly developed and layered rough ER is the subcellular correlate of Nissl substance filamentous structures: microtubules; microfilaments; neurofilaments microtubules are randomly oriented 3. dendrites: multiply branching with decreasing caliber of branches. May contain all cellular organelles, although few are present at narrowest point of dendritic arbor. Signals conducted toward cell body. 4. axons: usually a single process with uniform caliber originating from cell body (via axon hillock which lacks Nissl substance) contains vesicles, neurotubules, mitochondria, neurofilaments (lacks rough endoplasmic reticulum, which forms Nissl substance) all microtubules are oriented the same way, with polymerization occurring towards the axon terminal B. glial cells 1. astrocytes largest glial cells; contain glial fibrillary acidic protein (GFAP), an intermediate filament fibrous astrocytes are in white matter; protoplasmic astrocytes are in gray matter astrocytic foot processes surround all capillaries and underlie pial membrane 2. oligodendroglia: produce myelin of CNS (function is homologous to peripheral Schwann cells); damage to these cells can produce demyelination unlike Schwann cell, oligodendrocyte can myelinate multiple nodes of multiple axons unlike Schwann cell, oligodendrocytes lack a basal lamina 3. ependymal cells contain cilia, which are anchored by blepharoplasts (basal bodies); also have microvilli line brain ventricles and central canal of spinal cord choroid plexus epithelium is specialized epithelium that produces CSF derived from ependyma 4. microglia: bone marrow (monocyte) derived, not a true glial (neuroectoderm-derived) cell Resident histiocytes of brain; mobile cell with mobile processes Complex physiological properties currently under active investigation: antigen presentation, innate immunity, cytokine and chemokine production Properties of the perivascular microglia different than those of the intraparenchymal region C. cell reactions to injury 1. neurons acute neuronal injury forms the red neuron (morphology of irreversible injury, a form of coagulative necrosis), also known as eosinophilic neuronal necrosis = bright eosinophilia of the cytoplasm, loss of Nissl PLUS shrinkage and hyperchromatism of the nucleus with loss of nucleolus. Can be seen beginning about 12 hours after insult. Final common pathway of many neuronal insults, but usually ascribed to hypoxia or ischemia subacute and chronic neuronal injury ("degeneration"): cell loss with reactive gliosis; may be apoptotic, may be trans-synaptic when a majority of afferent input is lost to a group of neurons chromatolysis (axon reaction) is characterized by margination of Nissl substance; swelling of cytoplasm and displacement of nucleus to periphery enlargement of nucleolus; this is the classical response of neurons to axotomy, especially those whose axons originate in the CNS and project to the periphery (best example anterior horn cells) neuronal inclusions: aging (lipofuscin), herpes (Cowdry body), rabies (Negri body), CMV, many other inclusions associated with neurodegenerations although neurogenesis is now known to occur in limited regions of adult mammalian nervous systems (thus representing a potential but as yet unrealized possible therapy for neuron loss), including human, the nervous system cannot replace most mature neurons and clinically significant regeneration does not occur. 2. astrocytes historically thought analogous to fibroblasts in connective tissue (form "scar tissue", but no collagen synthesis); proliferation and enlargement is called (reactive) gliosis (or astrogliosis); function as
bipolar:

pseudo

metabolic buffers and detoxifiers in the CNS; new physiological functions of astrocytes are being rapidly discovered in development, maintenance of homeostasis, blood brain barrier, even neuronal function brightly eosinophilic structures of variable shape (rounded, elongated, carrot-shaped) in astrocyte processes are called Rosenthal fibers (containing B crystallin and hsp 27) in Alexander disease (a leukodystrophy associated with mutations in the GFAP gene), abundant Rosenthal fibers are found in periventricular, perivascular, and subpial locations corpora amylacea (polyglucosan bodies) are round, PAS positive, lamellated, indigestible structures in the end processes that are mainly composed of glycosaminoglycans but contain hsps and ubiqutin Alzheimer type II astrocyte has no visible cytoplasm, nuclear enlargement (2-3X) possibly with scalloping of the nuclear membrane, loss of central chromatin, and the presence of a prominent nucleolus and sometimes a pseudo intranuclear glycogen droplet, although the latter may not be in the plane of section. Most commonly seen with hyperammonemic states (chronic liver disease, urea cycle disorders) 3. microglia Small cell with modest processes in resting state When stimulated, hypertophy occurs (activation); nuclear hypertrophy produces rod cells (eg neurosyphilis) May form aggregates called microglial nodules; these may represent the end-stage of congregation around cell bodies of dying neurons (neuronophagia) If destructive lesion of CNS occurs, can assume phenotype of lipid-laden macrophage (gitter cell, foam cell). Macrophages derived from monocytes that enter from the bloodstream generally outnumber the microglia derived cells after common destructive insults like infarcts.
163. Cerebral

edema, herniations, and hydrocephalus edema (most of increased fluid is in white matter) 1. major threats to CNS by cerebral edema are brain herniations and decreased cerebral perfusion pressure 2. types of cerebra edema: vasogenic (fluid from "leaky vessels" enlarges extracellular space, ie around focal lesions like tumors, abscesses, etc) cytotoxic (hypoxic-ischemic damage causes cellular swelling and decreases extracellular space) interstitial (transependymal, ie hydrocephalus) B. increased intracranial pressure causes include mass lesions in the brain (tumors, blood, or abscess); excess CSF (hydrocephalus); cerebral edema results include headaches and vomiting; papilledema (swelling of optic disk); herniation of parts of brain C. hydrocephalus: enlargement of ventricles 1. causes excess production of CSF (rare): choroid plexus papilloma decreased absorption of CSF: for example, due to dural sinus thrombosis blockage of normal flow of CSF: obstructive hydrocephalus (more common) communicating hydrocephalus: diffuse enlargement of entire ventricular system due to obstruction in the subarachnoid space sufficient to prevent return of CSF to venous system; examples: inflammation, hemorrhage of scarring of the subarachnoid space non-communicating hydrocephalus: focal enlargement of a part of the ventricular system implying a focal obstruction (examples: aqueductal stenosis; mass of the third ventricle obstructing the foramen of Munro) 2. functional classification of hydrocephalus a) high pressure (obstruction): before fusion of sutures causes enlarged head; after fusion of sutures causes increased intracranial pressure pseudotumor cerebri (benign intracranial hypertension): causes headaches, blurred vision, papilledema (but no mass is found with MRI) b) low or normal pressure normal pressure hydrocephalus: a treatable cause of dementia; ventricular enlargement without cortical atrophy, persistent activity of radionuclide in lateral ventricles 3. therapy: may need surgical shunts (ventriculocaval, ventriculocisternal, spinoperitoneal) 4. hydrocephalus ex vacuo is an old term; not really a hydrocephalus but a compensatory enlargement of ventricles due to loss of brain parenchyma D. brain herniations
A. cerebral

1. subfalcine

herniations of medial aspect of cerebral hemisphere (cingulate gyrus) under falx usually no specific sx. but may compress anterior cerebral artery 2. tentorial herniation (transtentorial = central) a) medial part of temporal lobe (uncus) herniates over free edge of tentorium b) compression of CN III (oculomotor nerve) causes ipsilateral ocular motor paralysis (affected eye "looks down and out") ptosis and ipsilateral dilated, fixed pupil with no accommodation c) compression of the cerebral peduncles ipsilateral compression causes motor paralysis contralateral to the side of the lesion sometimes contralateral cerebral peduncle compression (Kernohan's notch) causes paralysis ipsilateral to the lesion (when there are localizing signs that point to opposite sides of brain, the oculomotor paralysis and "blown" pupils are the more reliable findings) d) compression of posterior cerebral artery may produce infarct of occipital lobe (primary visual cortex) 3. caudal displacement of entire brain stem Compression of medullary centers disrupts cardiac and respiratory function tearing of penetrating arteries from basilar to midbrain produces secondary brain stem hemorrhages (also called Duret hemorrhages), a terminal event 4. tonsillar (cerebellar) herniation causes include lesions in posterior fossa (such as cerebellar masses) may occur if lumbar puncture in patient with increased intracranial pressure (therefore, focal mass lesions and raised ICP need to be considered before performing LP; eye exam, scan) cerebellar tonsils herniate into foramen magnum and compress medulla, including cardiac and respiratory centers (often a terminal event)
herniation 164. Malformations A. neural

and developmental diseases tube defects 1. some combination of abnormality of CNS, meninges, overlying bone and soft tissue 2. encephalocele is diverticulum of malformed CNS tissue throught a defect in the skull. 3. cranial end defect = anencephaly incompatible with life all that remains is disorganized glial tissue with vessels called the cerebrovasculosa 4. caudal defects = spina bifida (abnormal fusion of lowest (posterior) vertebral arches) a) spina bifida occulta is the mildest form (affects 10% of population) failure of vertebral fusion only (spinal cord and meninges are normal) evaluate child with recurrent meningitis for spina bifida occulta with dermal sinus tract b) spina bifida cystica (highly variable incidence around the world; about 1 birth in 1000 in the U.S.A.; 90% are myelomeningocele and myeloschisis, i.e., the bad ones) c) meningocele protrusion of meningeal sac filled with CSF through vertebral defect spinal cord is normal and there are minimal or no neurologic defects surgical closure is necessary and curative to prevent recurrent leptomeningitis d) myelomeningocele herniation of spinal cord and meningeal sac through vertebral defect severe neurologic defects involving lower extremities, bladder, and rectum (basically a complete cord lesion at the level of the cele) e) myeloschisis (spina bifida aperta) complete failure of fusion of caudal end of neural plate with a flat mass of spinal tissue on surface of back. Same severe neurologic deficit as myelomeningocele 5. increased alpha-fetoprotein (AFP) in maternal serum and amniotic fluid (note that decreased AFP is associated with Down syndrome) 6. associated with decreased folate during pregnancy (folate supplementation in diet decreases the incidence of these defects) 7. cranium bifidum: ossification defects of the occipital bone; somewhat analogous to spina bifida may produce protrusion of meninges (cranial meningocele), meninges and brain (meningoencephalocele), or meninges, brain, and ventricles (meningohydroencephalocele)

B. forebrain

anomalies (brain abnormally small)(more common) or megalencephaly (brain abnormally large) 2. lissencephaly: absence of gyri (agyria) leaving a smooth-surfaced brain; numerous distinct causes including mutations in LIS-1 (microtubule associated protein) and -dystroglycan (Miller-Dieker syndrome) 3. polymicrogyria: unusually numerous, irregularly formed cerebral convolutions; "cobblestone" appearance; may be genetically determined or acquired in utero before the end of the 4th month of gestation often around a focal destructive lesion 4. heterotopias are neuronal migration disorders associated with seizure disorders; often periventricular; associated with Filamin1, a gene that endoces actin binding proteins involved in the extension of filopodia 5. holoprosencephaly single frontal lobe and single ventricle (due to failure of brain to cleave into two hemispheres); also associated with single eye milder forms down to agenesis of olfactory nerves and associated structures exist associated with fetal-alcohol syndrome or trisomy 13 (Pataus syndrome) some cases have mutation in Sonic hedgehog gene 6. agenesis of corpus callosum: radiologic studies reveal misshapen lateral ventricles ("bat-wing" deformity); may be isolated or associated with numerous other malformations. Affected individuals may have MR or may be normal 7. hydranencephaly congenital absence of cerebral hemispheres; replaced by large, dilated ventricles causes include bilateral hemispheric infarction and necrotizing encephalitis (in utero TORCH infections: toxoplasmosis, rubella, CMV, herpes) C. posterior fossa 1. Arnold-Chiari malformation (aka Chiari type 2 malformation) (Chiari type 1 consists of low-lying tonsils without other structural abnormality in the posterior fossa. This abnormality may be asymptomatic or may cause hydrocephalus that is treatable by neurosurgery.) small posterior fossa (thought to be causative) with extension of vermis through foramen magnum, elongation of medulla (S-shaped deformity), "beak-shaped" tectum, abnormal upwardly angled course of the first 4 to 6 cervical nerve roots towards their intervertebral foramina also highly associated with meningomyelocele, hydrocephalus (both almost invariably present), and syringomyelia 2. Dandy-Walker malformation enlarged posterior fossa due to large cyst (the cysts represents the expanded, roofless fourth ventricle in the absence of a normally formed vermis) also associated with severe hypoplasia or absence of cerebellar vermis and possibly other brainstem abnormalities D. spinal cord 1. syringomyelia a) cleft-like cavity (syrinx) found in the inner portion of spinal cord (location is usually C5-T5) lacking an ependymal lining b) hydromyelia if ependymal-lined c) associated with Arnold-Chiari malformation d) also occurs in association with spinal cord tumors, trauma e) initially the syrinx involves crossing fibers found in ventral white commissure so presentation is: bilateral loss of pain and temperature (crossing spinothalamic tracts) sensation at level of lesion (both arms) preservation of touch and proprioception (posterior columns are not affected initially) f) later the syrinx involves anterior (ventral) horn (motor symptoms) or descending sympathetic fibers (Horner's syndrome) E. perinatal brain injury 1. The term cerebral palsy refers to a non-progressive motor neurologic deficit which may be complex (spasticity, dystonia, chorea/athetosis) due to insults during the pre- and/or perinatal periods Signs and symptoms may not be immediately apparent Early intra-uterine insults may not elicit classic or much of any reactive changes in the brain Postmortem examination shows a wide range of destructive lesions 2. Various common pre- and perinatal lesions that can give rise to this syndrome
1. microcephaly

 Intraparenchymal

hemorrhage (usually in the germinal matrix region which may then extend to the ventricular system) Damage up to and including infarcts in the periventricular white matter (periventricular leukomalacia) If involve the grey and white matter, multicystic (leuko)encephalopathy Ischemic damage to gyri (cortex) preferentially damages cortical ribbon at base of gyrus, producing ulegyria Basal ganglia and thalamus are selectively prone to damage (neuron loss), and aberrant myelinization can later occur in these structures (status marmoratus) which can be the underlying substrate of movement disorders such as choreoathetosis.
165. Trauma A. skull

fractures if the fractured bone is moved into the cranial cavity by a distance greater than its thickness. 2. fractures often stop at suture where energy causing fracture is dissipated; if fracture crosses suture line, termed diastatic 3. signs: fluid through nose = CSF rhinorrhea; fluid though ears = CSF otorrhea; to dx CSF note characteristic composition (low protein with glucose; in contrast mucus has high protein content with no glucose) 4. base of skull fracture involving anterior cranial fossa: cribriform plate fracture; bloody nasal discharge (spreading yellow halo with central blood stain) and loss of smell middle cranial fossa (petrous temporal bone): associated with CSF otorrhea, bruise over ear and mastoid ("battle sign") and injury of CN VII-VIII B. terms concussion is transient loss of consciousness without grossly evident structural damage and may have memory loss (retrograde or post-traumatic) contusion is a "brain bruise" (wedge-shaped zone of small hemorrhages +/- necrosis at crest of gyrus) on brain surface from blunt head trauma a brain lesion is designated a coup lesion if it underlies the place where something hit the skull, as contrecoup if the lesion is on opposite side from where skull struck. There are plenty of exceptions to this, and there are no rules that work if the skull is fractured as part of the head trauma (which can produce a fracture contusion underneath), but in general the coup lesion is larger than the contrecoup if the head is not moving and is struck by a moving object (e.g., head struck by a bat), and the opposite pattern (contrecoup>coup) if the the head is in motion and strikes a fixed object (e.g., person falls backwards off a porch onto a hard surface) Old traumatic lesions on the surface of the brain have a characteristic macroscopic appearance: they are depressed, retracted, yellowish brown patches involving the crests of gyri. These are called plaque jaune. C. diffuse axonal injury diffuse axonal injury (DAI) typically occurs after MVA (motor vehicle accident) brain trauma patients may have many different pathologies, but pure DAI often involves a rotational head injury, no increase in ICP, only minor findings by MRI (like petechial hemorrhages) and coma due to diffuse transection of axons (animal studies suggest this starts about 6 hours after injury) microscopy reveals axon retraction balls (spheroids) with degeneration of the axon distal to the transaction; these can be seen with H&E but are more sensitively demonstrated with silver stains or ihc for transported proteins, one of the most sensitive of which is amyloid precursor protein (APP) D. epidural hematoma hemorrhage above dura (potential space) cause is severe trauma (falls, MVA, assaults) that tears middle meningeal artery and fractures of temporal bone; there is usually loss of consciousness at the time of injury symptoms occur within hours (patient may appear normal for several hours = lucid interval); during this time, patient appears to have had a clinically uncomplicated concussion bleeding causes increased intracranial pressure, which produces headaches, vomiting, papilledema, tentorial herniation, and if untreated, coma and death CT shows hyper dense convex lens-shaped (lenticular) extra-axial fluid collection E. subdural hematoma 1. acute subdural: severe trauma, no lucid interval, higher mortality than epidural 2. chronic subdural bleeding from torn bridging veins causes blood to accumulate in subdural space typical patient is elderly with minimal trauma (cortical atrophy with aging makes bridging veins fragile)
1. displaced

in young child think child abuse is slow (venous origin) and symptoms develop over days to months (membranous capsule may form [better formed superficially] and increase in size due to repeated bleeding from abnormal capillaries in granulation tissue forming capsule) slowly increased intracranial pressure causes headaches, vomiting, papilledema compression of underlying brain causes focal epileptic convulsions and neurologic symptoms (contralateral spastic paralysis) treatment is surgical evacuation F. spinal cord trauma: symptoms depend on level of injury thoracic vertebra of T1 and below: paraplegia (paralysis of lower body and legs); dysfunction of bladder and rectum cervical lesions: quadriplegia (paralysis of all four limbs) above C4: respiratory compromise (phrenic nerve comes from cervical roots 3,4, and 5: "C3, 4, and 5 keep the diaphragm alive")
bleeding 166. Hypoxic

if

and/or Ischemic damage Purely hypoxic insults are said not to cause irreversible neuronal damage, but purely hypoxic insults (without superimposed cardiac arrest) are relatively rare A. probably the most common example of pure hypoxic insult involves episodes of near-drowning. B. global ischemia imbalance between delivery of blood and oxygen and utilization of oxygen everywhere in the brain 1. generalized decreased blood flow (cardiac arrest, shock, severe hypotension): diffuse hypoxic/ischemic encephalopathy 2. hypoperfusion: watershed (border-zone) infarcts occur at border of area supplied by major vessels (anterior and middle cerebral artery border most at risk) 3. pseudolaminar necrosis (uneven destruction within the neocortical band) occur at ends of short penetrating vessels from pial arteries (hypoperfusion); can develop with post-arrest coma 4. order of susceptibility of different cell types (think NOAM): neurons > oligos > astrocytes > mesenchyme (microglia and vasculature) 5. the most vulnerable neurons are large neurons of the hippocampus (pyramidal cells of Sommer sector, CA1 (plus to a lesser degree neurons in CA4),Purkinje cells of the cerebellum, and larger neurons (pyramidal neurons) in the cerebral cortex. This selective neuronal necrosis is thought to be due to: The presence of relatively more glutamate receptors of the NMDA type (excitotoxic amino acid) receptors on these neurons. These receptors gate calcium into the cytoplasm of the neuron. The relatively lower concentration of calcium-binding proteins in the cytoplasm of these neurons, thus making them more vulnerable to unregulated calcium fluxes (recall that Ca++ is maintained in the range of 10-7 to 10-6 M intracellularly as compared with mM concentrations in the bloodstream, and that numerous enzymes, including proteases, phospholipases and endonucleases are activated when Ca++ reaches the uM range.) C. focal ischemia localized (focal) ischemia = cerebral infarction, which usually results from either thrombosis or emboli occlusive thrombosis is usually the result of atherosclerosis and usually produces nonhemorrhagic (white, pale) infarcts emboli can originate from cardiac mural thrombi (predisposing: MI, valvular disease or atrial fib), thromboemboli (most often arising from atherosclerotic lesions in the carotid system) and can produce hemorrhagic (red) infarcts (don't anticoagulate) because emboli lyse quickly and re-expose the damaged distal vessels to arterial pressures vasculitis can lead to infarcts; examples used to be associated with infections such as TB, syphilis, now more commonly associated with infections in immunosuppressed (aspergillus, CMV) Other vasculitides that affect the brain are PAN, primary angiitis of the CNS, Wegeners D. TIA's transient ischemic attacks (TIAs) are associated with symptoms that last less than 24 hours; warning sign for stroke result from either decreased blood flow from severe atherosclerosis of cerebral arteries or emboli from ulcerated atherosclerotic plaques of carotid arteries transient vision loss in one eye (like a shade dropping) = amaurosis fugax (think carotid artery disease)

that amaurosis fugax plus any sign referable to a structure supplied by the middle cerebral artery = carotid artery disease (note middle cerebral artery signs plus anterior cerebral signs are also suggestive of carotid artery disease) E. Infarct: microscopic changes (liquefactive necrosis). An infarct can be characterized as acute, subacute, resolving or remote. 1. early changes first changes (greater than 1 hour) = swollen mitochondria and swollen astrocytic processes (only demonstrable in animal research setting) 12 hours = formation of red neurons first 48 hours = neutrophil leukocyte infiltration (generally not as prominent as it is in MI) falls off rapidly after this; endothelial and astroglial cells swell 2. subacute changes 2-3 days = macrophages (foam cells) appear 3-4 days = edema is maximal (and can cause death) 5 days = neutrophils disappear around 1 week = proliferation of astrocytes begins as does neovascularization 3. resolution macrophages phagocytose dead brain. This can take months or years if the infarct is large. The infarcted brain becomes liquefied. astrocytes and vessels proliferate around the periphery and to some extent into the infarcted area. 4. remote: The area of infarction becomes a cystic cavity containing a few gliovascular strands.
167. Cerebrovascular

note

syndromes ("stroke" is any sudden non-traumatic irreversible neurologic impairment by implication cerebrovascular) A. middle cerebral artery (MCA) infarct (note: almost all right-handed individuals have speech lateralized to the left, as do a clear majority of left-handed individuals, but a minority use the right hemisphere or both) 1. frontal lobe contralateral hemiparesis (face = arm > leg) ipsilateral conjugate eye deviation (frontal eye fields out) Brocas speech area (inferior frontal gyrus) causes nonfluent (motor or expressive) aphasia = inability to form words, but patients know what they want to say (often associated with contralateral hemiparesis of face or hand) 2. temporal lobe deafness (if bilateral destruction) (very rare) Wernickes speech area (superior temporal gyrus) causes fluent (receptive) aphasia = no problem forming words and speaking, but nonsense and inappropriate words (note that in contrast to Broca's aphasia, Wernicke's aphasia is not necessarily associated with hemiparesis) 3. parietal lobe a) cortical sensory loss (face = arm > legs) b) involvement of optic radiations cause homonymous hemianopia c) inferior parietal lobe syndromes = unilateral sensory neglect is usually due to lesion of contralateral parietal lobe d) dominant side = apraxia (failure to carry out learned movements, eg. can't salute to command, but can copy a salute) impaired ability to calculate is due to parietal lobe lesion in dominant hemisphere Gerstmanns syndrome = left-right confusion, finger agnosia, dysgraphia, dyscalculia e) non-dominant side (contralateral to the side controlling language, usually the right side in a right-handed person) produces hemineglect, anosognosia (denial of defect), and constructional apraxia (unable to draw simple designs; may leave off side) f) a lesion of the arcuate fasciculus (which connects Wernicke's and Broca's areas) produces a conduction aphasia (impairment of repetition) B. anterior cerebral artery (ACA) infarct (uncommon in isolation); can affect medial portion of hemispheres contralateral paralysis of leg with increased reflexes and positive Babinski's contralateral cortical sensory loss (leg only) incontinence, abulia (lack of ability to act or make decisions), and deviation of eyes toward lesion no hemianopia or aphasia

C. posterior 1.

cerebral artery occipital lobe produces contralateral homonymous hemianopia with macula sparing (often only finding) 2. temporal lobe hippocampus produces memory defects loss of amygdala (if bilateral) produces Klver-Bucy syndrome = placid, hyperoral, hypersexual, psychic blindness (visual objects treated inappropriately, eg. monkey approaches snake without concern) penetrating branches (thalamogeniculates): thalamic syndromes (due to thalamic infarcts) D. lacunar syndromes 1. lacunes are infarcts less than 15 mm in diameter (see effects of hypertension on the brain) that can occur in multiple locations. 2. One of the most common is in the basal ganglia. When they affect the internal capsule (ic) or specific thalamic nuclei, even a small infarct can produce obvious deficits pure motor symptoms = lesions of posterior limb of internal capsule pure sensory = lesions of ic or VPL of thalamus (mixed sensory + motor symptoms = both) 3. Other common locations are cerebellar hemisphere, pons E. brain stem syndromes 1. medulla a) lowest portion of the brain stem (extends from the pyramidal decussation to the inferior pontine sulcus) b) contains autonomic centers that regulate respiration, circulation, and gastrointestinal motility c) gives rise to CN IX - CN XII and contains the caudal portion of CN V and CN VIII d) medial medullary syndrome (inferior alternating hemiplegia) results from occlusion of the anterior spinal artery and affects the corticospinal tract (contralateral hemiparesis of trunk and extremities) the medial lemniscus (contralateral loss of proprioception, discriminative tactile, vibration sense from trunk and extremities) hypoglossal nerve roots (ipsilateral flaccid paralysis of tongue) 2. lateral medullary syndrome (Wallenbergs syndrome) results from occlusion of the (most common) vertebral artery or occlusion of the posterior inferior cerebellar artery. The deficits are all referable to tissues supplied by the PICA (hence the other name PICA syndrome) and affects the vestibular nuclei (nystagmus, nausea, vomiting, vertigo) inferior cerebellar peduncle (ipsilateral cerebellar signs) nucleus ambiguus (ipsilateral laryngeal, pharyngeal, and palatine paralysis) glossopharyngeal nerve roots (loss of gag reflex) vagal nerve roots (same signs as the nucleus ambiguus) spinothalamic tracts (contralateral loss of pain and temperature from trunk and extremities) spinal trigeminal nucleus (ipsilateral loss of pain and temperature from face) descending sympathetic tract, which passes through the lateral aspects of the medulla in the dorsal longitudinal fasciculus (ipsilateral Horners syndrome: ipsilateral ptosis, miosis, and anhidrosis) 3. pons (pinpoint pupils + coma = pontine lesion [differential diagnosis is opiate overdose]) a) middle portion of the brain stem b) medial inferior pons syndrome results from occlusion of the paramedian branches of the basilar artery which affects the corticospinal tracts (producing contralateral spastic paralysis) medial lemniscus (contralateral loss of proprioception, tactile sensation, and vibration from the trunk and extremities) c) cranial nerve VI (abducens) (producing ipsilateral lateral rectus palsy) 4. lateral inferior pons syndrome results from occlusion of a branch of the basilar artery (AICA) which affects: facial nerve nucleus (ipsilateral facial paralysis, etc) cochlear and vestibular nuclei spinothalamic tracts (contralateral loss of pain and temperature sense from the trunk and extremities) spinal trigeminal nucleus (ipsilateral loss of pain and temperature from the face) sympathetics (ipsilateral Horner syndrome) 5. midbrain a) lesions of the midbrain in general produce partial ophthalmoplegia and contralateral hemiplegia b) dorsal midbrain syndrome (Parinaud syndrome) (frequently the result of a pineal tumor; eg pinealoma or a germinoma) affects:

colliculus and pretectal areas (producing paralysis of upward and downward gaze) aqueduct (obstruction produces a noncommunicating hydrocephalus) c) medial midbrain syndrome (Weber's syndrome; due to occlusion of median or paramedian perforating branches of the basilar artery) affects: ipsilateral oculomotor nerve roots: dilated pupil that does not react to light corticobulbar tracts (producing contralateral weakness of the lower face (CN VII), tongue (CN XII), and palate (CN X)) corticospinal tracts (producing contralateral spastic paralysis of the trunk and extremities) F. cerebellar syndromes 1. superior cerebellar artery = nystagmus, +/- vertigo, ipsilateral Horner's, ataxia, contralateral hypalgesia and thermoanesthesia 2. vermis syndromes anterior vermis syndrome: most common cause is chronic alcoholism; result in truncal ataxia posterior vermis syndrome: cause is brain tumor in children (medulloblastomas); result in truncal (?)dystaxia G. thalamus: Dejerine-Roussy syndrome: results from infarction of the thalamus contralateral loss of sensory and contralateral dysthesia (pain) with vasomotor disturbances and movement abnormalities; pain is unique to this stroke syndrome
cerebral 168.

superior

Intracranial hemorrhage, non-traumatic common cause of spontaneous intraparenchymal hemorrhage is hypertension (see below for other effects of hypertension on the brain) four typical locations in decreasing order of frequency: basal ganglia, pons, cerebellum, and lobar white matter. arteriolar wall damage due to deposition of lipid and hyaline material in walls (hyaline arteriolosclerosis; aka, lipohyalinosis) may proceed to frank necrosis hypertension aggravates and extends atherosclerosis into distal, smaller branches (note: diabetes mellitus also does this) it seems likely that basal ganglia hematomas are due to a rupture of lenticulostriate arteries (branch of middle cerebral artery) historically, hypertensive hemorrhages have been ascribed to Charcot-Bouchard microaneurysms, which are dilated attenuated arterioles (<300 m diam) found in hypertensive brains rupture of vessels produces small (lacunar) hemorrhages or large hemorrhages centered in lateral or medial neostriatum (putamen or thalamus) B. cerebral amyloid angiopathy (CAA) amyloid angiopathy is a high probability explanation for a significant lobar hemorrhage in the non-hypertensive elderly deposition of the pathogenic fragment beta A4 (same fragment as the one discussed in the Alzheimer section below) with conformational change to produce amyloid in walls of medium to small arteries of brain and meninges results in segmental dilations and microaneurysms, which can produce thrombosis and hemorrhage C. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoenceophalopathy) (whew!) rare hereditary disorder due to mutation in gene encoding Notch3 receptor HAs, strokes (less often hemorrhages), dementia concentric thickening of the media and adventitia of many vessels in the body (dx by skin biopsy) but especially leptomeningeal and CNS arterioles which contain distinctive basophilic, PAS(+) punctate material on LM, osmiophilic granular material on EM D. subarachnoid hemorrhage 1. when not associated with trauma, cause is most often due to rupture of a saccular (berry) aneurysm unruptured aneurysm is present in 2% of adults these aneurysms have collagen in the wall but lack the internal elastic lamina or smooth muscle of normal intracranial arteries typically berry aneurysms occur at arterial bifurcations in the circle of Willis most common site is junction of anterior communicating artery and anterior cerebral artery increase in size with age (not found in childhood); risk of rupture increases with increasing size associated with adult polycystic kidney disease, Ehlers-Danlos type IV, Marfan, NF1 2. signs and symptoms of subarachnoid hemorrhage
A. most

onset of severe headache (typically described as "worse headache ever") often followed by loss of conscious and coma pain and stiffness of neck due to blood causing meningeal irritation bloody or xanthochromic CSF; CT shows blood in cisterns and sulci E. Hypertensive cerebrovascular disease 1. Intracerebral hemorrhage: see above 2. Lacunar infarcts: see above 3. Slit hemorrhages small hemorrhages often at grey white junction possibly related to arteriolar damage as previously described. 4. Encephalopathy Acute: Seen in context of highly elevated BP (malignant hypertension): HA, confusion, vomiting leading to convulsions, coma, death if not treated. Pathology: edematous brain and fibrinoid necrosis of arterioles Chronic: May develop sufficiently numerous infarcts and other changes to lead to dementia, gait disturbance, pseudobulbar signs (vascular ischemic dementia or multi-infarct dementia); if involves the white matter preferentially, sometimes referred to as Binswanger disease F. Other hypercoagulable states (anticoagulants), vascular malformation (ie arterio-venous malformations (AVM's) and cavernous hemangiomas), tumors, drugs (ie cocaine, which can produce any type of cerebral hemorrhage and infarction, except epidural hemorrhage)
169. Infections

sudden

(meningitis is inflammation of the leptomeninges and the CSF within the subarachnoid space, not the brain parenchyma) A. bacterial meningitis (acute, pyogenic) 1. CSF findings = increased neutrophils (may be grossly purulent), increased protein, increased pressure, and decreased glucose 2. cause varies according to age neonates (0-6months) = group B streptococci, E. coli children (6 months to 6 years) = strep pneumonia (gram(+) lancet-shaped diplococci); N. meningitidis; H. influenzae (greatly decreased in developed world due to vaccine) 6 years to 60 years = Neisseria meningitidis (meningococcus; gram-negative diplococci); gets to brain from pharynx by hematogenous route older than 60 years = Streptococcus pneumoniae, Listeria epidemics due to Neisseria meningitidis Gram positive, catalase positive hemolytic rods (with tumbling motility) in CSF = Listeria monocytogenes (found in all age groups) 3. signs and symptoms fever and signs of meningeal irritation (irritability, headache, photophobia, stiff neck, clouding of consciousness) (but not in neonates) positive Kernig sign = cant straighten raised leg because of pain positive Brudzinski neck sign = passive flexion of neck causes flexion of legs and thighs 4. complications death may due to increased cerebral pressure from cerebral edema cranial nerve palsies (because all cranial nerves transverse subarachnoid space) leptomeningeal fibrosis can lead to chronic adhesive arachnoiditis sensorineural deafness, hydrocephalus (secondary to arachnoiditis); decreased IQ in childhood cases B. acute, aseptic (misnomer, since typically viral) meningitis same presentation as above, but no recognizable organism CSF findings = increased lymphocytes, normal to moderately elevated protein, normal glucose (but note that due to the stereotyped nature of the inflammatory response, during the first 24 hours neutrophils may predominate) failure to culture an etiologic agent in a majority of cases differential includes true aseptic meningitis, e.g., chemical meningitis C. chronic, bacterial meningoencephalitis 1. tuberculosis causes chronic meningitis that is localized to base of brain around circle of Willis

tends to show lymphocytic pleocytosis although some neutrophils may be present, protein is elevated, often dramatically; glucose normal or decreased granulomatous meningoencephalitis; arteries running through the inflammation may show obliterative endarteritis that can produce brain infarcts; cranial nerves may be encased in process; with chronicity a dense adhesive arachnoiditis may evolve and produce hydrocephalus tuberculoma may occur, a large mass-like granuloma in the brain differential diagnosis of base of brain leptomeningeal processes = chronic meningitis (TB or fungal), sarcoid, arteritis (vasculitis) D. spirochetes 1. treponema pallidum (plasma cells around blood vessels); lab test is positive VDRL or RPR (rapid plasma reagin) a) secondary syphilis may have meningitis (syphilitic meningitis, also called meningovascular syphilis) and cranial nerve palsies another base of brain meningitis obliterative endarteritis (Heubners) b) tertiary syphilis may include neurosyphilis (1) paretic neurosyphilis is due to invasion of brain mental deterioration (sometimes with delusions of grandeur) resulting in severe dementia eventually Argyll Robertson pupils = pupils constrict with accommodation, but they don't constrict to light neuron loss, gliosis, microglial cell (rod cell) proliferation, iron deposits, organisms may be demonstrable (2) tabes dorsalis = degeneration of dorsal columns and dorsal roots, loss of dorsal root ganglion neurons, organisms not demonstable (a) impaired joint position sensation (proprioception) and ataxia (b) loss of pain sensation causes skin and joint damage (Charcot joints) and characteristic shooting "lightning" pains (c) positive Romberg sign is used to distinguish lesions of posterior columns and midline (vermis) cerebellum in patient with postural instability positive Romberg sign = patient falls to side when standing with eyes closed (lesion of posterior columns or dorsal roots) negative Romberg sign = postural instability doesn't worsen with eyes closed (indicates cerebellar problem) 2. borrelia burgdorferi (spread by ixodes ticks and causes Lyme disease) first stage = erythema chronicum migrans of skin second stage (weeks to months) = cardiac or neurologic disease (meningitis, cranial neuritis, or radiculoneuritis, such as Bells palsy) third stage (years) = ill-defined arthritis or encephalopathy; pathology not well-delineated; rare autopsy cases have shown microglial proliferation and scattered organisms 3. leptospira interrogans exposure to contaminated water (access through mucous membranes) biphasic disease = initial infection (acute febrile illness with meningitis +/- cranial neuritis) then later is autoimmune reaction E. abscess sx: headaches, seizures, altered mental status focal signs related to where the abscess arises CSF findings: markedly increased pressure; clear gross appearance; increased protein; normal glucose; variable but lymphocytes and polys may be present MRI reveals ring-enhancing lesion of brain ddx of ring-enhancing lesion (which is due to central necrosis with peripheral new blood vessel formation) = abscess, tumor, infarct and MS abscess can cause fibrous proliferation with capsule formation (formed better toward surface, therefore abscess can extend centrally [daughter abscesses] and possibly rupture into ventricle) F. viral meningoencephalits 1. arthropod-born viruses (arboviruses): transmitted by blood-sucking vectors, mostly by mosquito but some by tick heterogenous (many different viruses) group of diseases responsible for most outbreaks of epidemic encephalitis

CSF

hemisphere, most common are: eastern and western equine encephalitis, West Nile, Venezuelan, St. Louis and LaCrosse encephalitis seizures, confusion, delirium, coma focal deficits CSF findings same as viral meningitis; again, neutrophils may be present early (~first 24h) with rapid conversion to lymphocytes mx: lymphocytic meningoencephalitis, microglial nodules, neuronophagia, with foci of necrosis; severity and distribution of lesions varies with the virus involved 2. HSV type 1 is most common cause of sporadic viral encephalitis Commonly presents with alterations in mood, memory and behavior latent in trigeminal (Gasserian) ganglion (only 10% have any history of herpes, but studies have shown that around 80% of adults have Herpes latent in the trigeminal ganglion) and may produce hemorrhagic necrotizing encephalitis of inferior and medial aspects of temporal lobe and inferior aspects of frontal lobe in adults CSF findings include mixed inflammation with neutrophils (because a necrotizing process) and lymphocytes, red blood cells, and increased protein; CSF analysis by PCR for virus detective the most sensitive way to make the dx Mx: hemorrhagic, necrotizing, lymphocytic meningoencephalitis and Cowdry type A inclusions may be found in both neurons and glia may result in severe sequalae, (antiviral treatment reduces m&m) memory difficulties, (rare Kluver-Bucy syndrome (bilateral necrosis amygdalar region; sx = placidity, hypersexual, hyperoral, psychic blindness), or death 3. HSV type 2: mainly a severe necrotizing encephalitis of neonates born through the birth canal of a mother with active, primary HSV genital infection 4. CMV infects fetus (periventricular necrosis and calcification) and immunocompromised patients (AIDS); tendency to infect brain near the ventricular surfaces; both intracytoplasmic and intranuclear inclusions 5. poliomyelitis is an enterovirus (fecal-oral transmission); most patients get a mild or subclinical gastroenteritis; a small percentage of patients experience infection of the CNS by the virus; this may progress no further than previously described aseptic meningitis in more severe cases, virus invades anterior horn motor neurons of spinal cord (microscopy reveals neuronophagia of anterior horn neurons); anterior roots atrophic, dorsal roots OK produces LMN signs (flaccid muscle weakness, atrophy, fasciculations, fibrillation, hyporeflexia) postpolio syndrome: occurs > 25 years later with progressive weakness, decreased muscle mass, and pain 6. rabies is due to a single-stranded RNA rhabdovirus (uniformly fatal without vaccine and once symptoms appear) transmission is through the bite of a rabid animal (dog (rare now in the US), bat, raccoon, and skunk) bite may not be necessary or history elicited with bat (solitary silver-eared bat) virus travels retrogradely through peripheral nerves to brain (trans-synaptically) and forms inclusions within neurons called Negri bodies (cytoplasmic, round to oval eosinophilic inclusions in pyramidal neurons of the hippocampus and Purkinje cells of the cerebellum) virus then returns to periphery, including salivary glands, by peripheral nerves signs include irritability, ascending paralysis, difficulty swallowing, spasms of throat (resulting in "hydrophobia"), seizures and delirium 7. HIV infects macrophages and microglial cells in CNS (which form multinucleated giant cells) primary infection can cause a self-limited aseptic meningitis soon after exposure, then HIV encephalitis (with cognitive dysfunction, motor impairment, and behavioral disturbances), demyelination, and vacuolar myelopathy (posterior and lateral areas of spinal cord similar to changes of B12 deficiency) mx: microglial nodules, some reactive gliosis, macrophages in the perivascular spaces; multinucleated giant cell (often without an accompanying granuloma) is distinctive; changes tend to be subcortical; white matter pallor or damage sometimes seen secondary opportunistic infections include CMV, toxoplasmosis, cryptococcus 8. progressive multifocal leukoencephalopathy (PML) ("opathy" meaning infection without inflammation) complication in immunosuppressed individuals due to infection by JC polyomavirus (not related to Creutzfeldt-Jakob agent) reactivation disease; most have (+) JC serology by adolescence, no clinical syndrome known from primary infection Unless immunocompromise can be reversed, focal, relentlessly progressive sx and signs

western

of oligodendrocytes causes rapidly coalescing foci of demyelination and produce dementia and ataxia multifocal lesions in white matter without mass effect (no shift in hemispheres); demyelination; oligos may show glassy intranuclear inclusions; bizarre giant astrocytes 9. subacute sclerosing panencephalitis (SSPE): seen in childhood due to infection with a defective measles virus G. fungal 1. CSF findings: increased pressure, protein, decreased glucose 2. 3 patterns: base of brain meningoencephalitis, vasculitis (often produces septic infarcts that are markedly hemorrhagic), brain invasion; these may overlap 3. three angioinvasive fungi that produce septic necrotizing lesions in the brains of immunosuppressed individuals: candida, aspergillus, and phycomycetes (mucor), the latter affects neutropenic and diabetic patients preferentially 4. cryptococcosis (fungus) is seen in immunosuppressed individuals (AIDS); may also occur in apparently immunocompetent individuals tends to produce chronic base of brain meningitis stain is India ink (negative staining of capsule); may see narrow-neck budding (compare to broad-based budding of blastomyces) H. other 1. toxoplasma gondii (protozoan) causes extensive necrosis and periventricular calcification in immunocompromised patients (AIDS) or infants subacute disorder produces multiple ring enhancing lesions mx: necrotizing process leading to abscess, generally not well-formed; marked vascular proliferation/reaction; organisms may be demonstrated; old treated lesions small glial scar with central macrophages (non-specific) 2. amebiasis Nagleria species cause a rapidly fatal necrotizing encephalitis Acanthmoeba causes a chronic granulomatous meningoencephalitis 3. cerebral malaria is due to Plasmodium falciparum (Plasmodium is a protozoan transmitted by Anopheles mosquitos) infected red blood cells preferentially plug cerebral vessels 4. African trypanosomiasis is transmitted by tsetse fly (Glossinia palpalis) causes "sleeping sickness" = lethargy, headache, drowsiness, painless lymphadenopathy Trypanosoma rhodesiense in East Africa and Trypanosoma gambiense in West Africa 5. taenia solium (pork tapeworm) "correct" life cycle is when man ingests pork containing larval forms in muscle and gets tapeworm cysticercosis occurs when man replaces pig as intermediate host and ingests ova, then larva hatch and disseminate hematogenously, particularly muscle and brain severe headaches (ring-enhancing intracranial cysts with calcifications) with peripheral eosinophilia; "Swiss cheese" gross appearance of brain very common disease in Latin America (> 2% of population) 6. hydatid cyst is due to larval form of Echinococcus granulosus I. spongiform encephalopathies (used to be called "slow virus" infections) 1. general pathology sc CJD due to an abnormal prion protein (PrP or PrP ), "prion" stands for proteinaceous and infectious and was coined by Prusiner c arise from alternate folding (normal alpha helix to abnormal beta-pleated sheet) of the normally present PrP the conformational change can occur spontaneously at a very slow rate sc c sc once formed PrP can combine with PrP to much more quickly form many more PrP particles, which can crystallize and form plaques c sc c PrP can also form PrP at much higher rates if mutations are present in PrP ; can result from mutations in c the gene that codes for PrP (called PRNP) mutations in this gene have been identified in patients with the familial forms of CJD, GSS, and fatal familial insomnia patients develop rapidly progressive dementia and death within several months characteristic spongiform change ("cluster of grapes" vacuolation) in brain (gray matter) plus neuron loss and gliosis (no inflammation)

infection

2. disease

(for the most part these are transmissible by gross contamination or are hereditary, but they are not infectious in the usual sense) a) kuru is confined to New Guinea due to cannibalism ("kuru plaques" are amyloid bodies with radially arranged spicules) sc b) scrapie is the best understood animal form of disease seen in sheep and goats; hence the terminology PrP c) Creutzfeldt-Jakob disease (CJD) cause rapidly progressive dementia (1) may see startle myoclonus early (myoclonus is sudden contraction of muscles) (2) case report from corneal transplant, depth electrodes, improperly autoclaved surgical instruments (3) familial CJD has mutated PrP Gerstmann-Staussler-Schenker syndrome has cerebellar abnormalities and plaques fatal familial insomnia: need point mutation in codon 178 and polymorphism at 129 of PrP (4) new variant CJD has symptoms starting earlier (average age of 28) and amyloid plaques d) mad cow disease (bovine spongiform encephalopathy) appears related to new variant CJD in humans (bad hamburger meat consumed by humans in England)

170. Demyelinating

disorders A. Multiple Sclerosis (MS) 1. MS is the most common CNS demyelinating disease, worldwide in distribution with variable prevalence (about 1 in 1000 in US) immunologically mediated demyelination; both environmental and genetic factors come into play; (incidence 150 fold higher with an affected monozygotic twin) SNPs in IL-2 and IL-7 receptor genes linked to susceptibility T cell autoimmunity (CD4+, Th1, Th17 T cells implicated in initiation) has long been the focus of pathogenetic research However, a recent result (N Engl J Med 358:676, February 14, 2008 : B-Cell Depletion with Rituximab in Relapsing-Remitting Multiple Sclerosis) shows efficacy of antibody therapy directed at (non-plasma cell) B cells 2. M:F::1:2 (average age of presentation 30) 3. relative risk related to environment; there is a gradient of increasing risk in populations at increasing latitudes (risk of population living in temperate latitude>risk of living in tropical or subtropical latitude; there are other environmental risk factors) 4. signs and symptoms are highly variable, but the disease is characterized by a fluctuating course of relapses and remissions. The dx until relatively recently was purely clinical. Lab tests may be helpful, and MRI findings have been incorporated recently (Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the McDonald Criteria Ann Neurol 2005;58:840846) These are difficult to summarize, but the historical, clinical criteria are still valid: neurological deficits separated in "time and space" meaning clinical attacks occurring at differing times and referable to different areas of the nervous system. Roughly speaking, MRI evidence may now be used to supply evidence of dissemination in time or space. Rarely, MS may be continuously progressive and different diagnostic criteria apply. 5. sx initially tend to be those of white matter disease rather than gray (e.g.,long tract sx rather than presentation with seizure or cognitive dysfunction) 6. early findings may include weakness of lower extremities, visual abnormalities with retrobulbar pain classic Charcot triad (mnemonic is SIN) = scanning speech, intention tremor, and nystagmus internuclear ophthalmoplegia (INO) (aka MLF syndrome) is due to demyelination of medial longitudinal fasciculus sign is medial rectus palsy on attempted lateral gaze with monocular nystagmus in abducting eye with convergence INO is essentially pathognomonic for MS (because INO in conscious individual rules out destructive lesion of MLF) optic neuritis is a common presentation (not everyone with ON goes on to develop MS, however) and produces a Marcus-Gunn (afferent) pupil (shine light in normal eye, both constrict; then shine light in abnormal eye and both dilate paradoxically) Lhermitte's sign = flexion of neck produces electric sensation down back into legs (intramedullary disease of cervical cord near dorsal root entry zone) 7. variants

Optica (Devic disease): Formerly considered a type of MS, this is a disease that is now clearly distinguishable from MS. An autoimmune humoral (antibody) attack on aquaporin 4 molecule localized to foot processes of astrocytes results in syndrome of bilateral optic neuritis and prominent spinal cord involvement acute MS (Marburg form): fulminant, relentlessly progressive course (months) in young individuals 8. clinical tests MRI is highly sensitive for detecting lesions, many of which come and go without clinical correlate; MRI has made its way into the clinical criteria for classification of probability of MS. CSF examination reveals normal glucose with increased protein, either no cells or mild pleocytosis CSF protein electrophoresis reveals oligoclonal bands (2 or more separate bands not found in serum) These are due to clonal expansion of different B cells inside the CNS with production of Abs, often directed against various childhood viruses. It has not been possible to show that the virus epitopes or the parent viruses targeted by the antibodies are the cause of MS, nor that the Abs are mechanistically involved in producing the MS lesions. various (visual, auditory, sensory) evoked potentials may be delayed if lesions involve the relevant white matter tracts 9. pathology lesions are called plaques and when evident at gross examination represent focal areas of demyelination acute plaque shows indistinct margin, hypercellularity, perivascular lymphocyte, edema, loss of myelin and axons, macrophages, reactive astrocytes, no glial scar, remyelination chronic active: sharp edge, perivascular cuffs of lymphs, lipid (myelin)-laden macs, deposition of Ig, hypocellular center chronic silent: sharp edge, astroglial scar, reduced numbers of demyelinated axons, few or no oligos, hyalinized vessels myelin is lost to a greater extent than axons, although axons are lost (compare to Wallerian degeneration with equal loss of axons and myelin) B. ADEM ADEM = acute disseminated encephalomyelitis (aka acute perivenous encephalomyelitis). The hyperacute form is known as acute, necrotizing hemorrhagic encephalomyelitis or the acute hemorrhagic leukoencephalitis of Weston-Hurst (pathology of ADEM plus fibrinoid necrosis of vessels, esp capillaries leading to actual tissue necrosis). Seen in a couple of settings: post-infectious (measles most important but can happen after a variety of viral illnesses) and post-vaccinal (smallpox and rabies vaccine used in past; smallpox vaccine no longer used at all, and the modern rabies vaccine has zero incidence of this complication due to the fact that the antigens are created by molecular methods, not raised in brain) pathology = demyelination around veins (multifocal small zones of demyelination that can coalesce into larger ones) animal model recapitulates the disease almost exactly: inject white matter, myelin, or myelin components into guinea pig, the pig forms antibodies (not thought to be significant), then cell-mediated delayed type hypersensitivity reaction in 4-7 days The disease is due to similarity of antigenic stretch of amino acids in some myelin proteins to those expressed on the outside of viruses (molecular mimicry) with resultant T cellmediated destruction of myelin/oligos. monophasic illness; most patients (80%) recover completely or nearly completely; the remainder may have severe sequelae or death
171. Degenerative A. Alzheimers

Neuromyelitis

CNS diseases disease (AD) 1. most common cause of dementia in elderly (second most common is vascular or multi-infarct dementia, third is diffuse Lewy body disease) incidence of dementia increases with age; prevalence doubles every five years after 60 (incidence x duration = prevalence) multi-infarct dementia may also have signs of previous CVA's 2. slow progressive mental deterioration that begins with impairment of higher intellectual functions alterations in mood and behavior loss of recent memory (early sign) severity correlates with degeneration of medial temporal lobe over time, progressive loss of memory and decrease in all higher cognitive functions

3. etiology

is not well understood (age is a main risk factor), but it is clear that AD is multifactorial in origin and that there are multiple molecular pathways to this disease state 4. multifactorial disease a) beta-amyloid (aka A) amyloid hypothesis of AD: A deposition is necessary but not sufficient for the development of Alzheimer's disease gene of the amyloid precursor protein (APP) is located on chromosome 21 nearly all individuals with trisomy 21, (Down syndrome) show the pathological changes of Alzheimer's disease past a relatively early age cleavage of APP by alpha secretase precludes A formation cleavage of APP by beta-secretase (also known as beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) and then gamma-secretase produces pathogenic fragment (A; the cleavage results in a protein fragment that has either 40 and 42 aas (A40 and A42), so you sometimes see this protein referred to as A40-42; A42 is the more pathogenic of the two.) As properties are not completely worked out. A is toxic to neurons and is deposited in the extracellular space as the disease progresses. At first soluble and monomeric, it then forms oligomers and it can undergo a conformational change to adopt a -pleated sheet configuration and thus become an amyloid. early-onset familial Alzheimer is related to mutations in presenilins or APP. The amyloid hypothesis has unquestionably been proven in kindreds that have APP mutations and familial AD. presenilin 1 (PS1) gene and presenilin 2 (PS2) gene contribute their protein products to the gamma secretase complex that also contains other enzymes and that processes Notch and other membrane proteins b) apolipoprotein E (normal component of VLDL, HDL, chylomicrons; mediates lipid uptake into various tissue); there are 3 isotypes common in the population, 2, 3, 4. sporadic AD (the vast majority of AD) associated with the presence of the 4 isotype of ApoE 4 is most important factor besides age identified in general population, conveys about 25% of the risk of developing sporadic AD (also present in some late onset familial cases) 4 allele promotes A generation and deposition, possibly by competing with soluble A at the level of a receptor that can clear the A from the brain c) genetic factors beta-APP mutations (chromosome 21), presenilin 1 mutations (chromosome 14), and presenilin 2 mutations (chromosome 1) all lead to increased A production apoE polymorphism specifically 4 (chromosome 19) leads to increased A deposition 5. gross pathology: non-specific, but may show atrophy of cerebral cortex (wide sulci and narrow gyri), especially frontal and temporal with compensatory ventricular enlargement; white matter frequently attenuated (lobar, corpus callosum) 6. microscopic pathology senile (neuritic) plaques are spherical aggregate of swollen neuritic processes often with a central amyloid core (A from APP). Plaques are generally seen only in AD and, in more limited numbers, in ageing. Therefore, plaques if present in sufficient numbers in the neocortex are more specific for the diagnosis of AD than tangles are (see below). Deposition of A without the neuritic reaction leads to the formation of diffuse plaques, felt to be an earlier stage in plaque development. neurofibrillary tangles are intracytoplasmic bundles of paired helical filaments with abnormal phosphorylated tau and numerous other proteins (neurofibrillary tangles also seen in numerous other diseases, such as progressive supranuclear palsy, see below) note disorders associated with tau cytopathology (tauopathies) (the affected tau differs slightly at the molecular level): AD, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) 7. therapeutic possibilities and trials: inhibit the gamma-secretase that produces the abnormal A-beta facilitate clearance of soluble A from parenchyma (immunization against A40-42 is one particularly intriguing possibility under current active investigation) inhibit polymerization of A into amyloid augmenting central cholinergic function (loss of cholinergic neurons in the basal forebrain is the earliest and most severe neurochemical loss in Alzheimer disease; these same neurons are heavily implicated in

learning and memory) is the only real therapy in current use, but quite limited in its therapeutic effect and does not prevent progression of the disease 8. differential is long, but for neurodegenerations includes Pick disease, diffuse Lewy body disease and many other rare, subcortical neurodegenerative conditions. Clinical dx is ~90% accurate. The only way to make the dx with certainty at present is brain examination at autopsy. The amyloid binding agent PiB may provide a premortem way to dx the disease. B. Lewy body dementia: see under Parkinson syndrome below C. frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) 1. FTDP-17: frontotemporal dementia with tau pathology and a mutation on chromosome 17 where the Tau gene is located. Tau is a microtubule associated protein (MAP) with 3 or 4 (splice variants) microtubule binding domains Tau(+) tangles in frontal, temporal and SN neurons as well as glia; tendency towards more 4R 2. FTDP-U: frontotemporal dementia without tau pathology growing recognition that most FTDPs do not have tau pathology ubiquitin (+) tau(-) cytoplasmic inclusions progranulin gene mutation identified as major cause of autosomal dominant FTDP-U D. Pick's disease rare cause of dementia with prominent early personality and language alterations characteristic location of atrophy = frontal and temporal lobes (posterior two-thirds of superior temporal gyrus is spared); frontotemporal dementia atrophy so marked as to produce "knife edge" frontotemporal atrophy microscopy shows Pick cells in the cortex, which are swollen cells without well-defined inclusions and Pick bodies, which are well-defined, argyrophilic and positive for ubiquitin, tau (3R), and neurofilaments (best found in hippocampus) E. progressive supranuclear palsy (PSP) supranuclear palsy = loss of function at a level above the cranial nuclei that direct the extraocular muscles (3,4,6) abnormal vertical eye movements (due to abnormality of the tectal region of the posterior midbrain) is key other signs include dystonia ("Donald Duck" dysarthria), dementia, and variable extrapyramidal (Parkinson-like) sx and cerebellar dysfunction may see emotional lability with explosive outbursts of laughter (pseudobulbar affect) widespread (subthalamic n., substantia nigra, globus pallidus many other) neuronal loss and gliosis with taupositive (4R) neurofibrillary tangles Mutation of MAP not demonstrated, but certain polymorphisms over-represented in those with PSP F. corticobasal degeneration (CBD) sx: extrapyramidal rigidity, asymmetric motor problems (jerking movements of limbs, "alien hand" syndrome), sensory cortical dysfunction (apraxias) and dementia microscopic pathology: ballooned neurons similar to Pick cells, tau positive astrocytes (tufted) and oligodendroglia (coiled bodies), astrocytic plaques (tau positive processes arrayed around an astrocyte) G. remember that vascular dementia is more likely explanation of dementia than all of these but AD.
172. Degenerative

diseases of the basal ganglia A. nomenclature caudate (which underlies the lateral wall of the lateral ventricle) + putamen = neostriatum putamen + globus pallidus = lentiform nucleus (globus pallidus is medial, the putamen is lateral) caudate+ putamen + globus pallidus = corpus striatum B. Parkinsons syndrome 1. older adults (after 50) 2. signs and symptoms due to extrapyramidal dysfunction (requires two out of first three listed below) difficulty initiating movement (bradykinesia) pill-rolling tremor at rest increased muscle rigidity (in contrast to spasticity); "cogwheel" rigidity expressionless (masked or flat) facies postural instability or gait disturbance also often present; typical posture is stooped forward with shuffling gait 3. group of disorders producing parkinsonism syndrome

disease (PD) is Parkinson syndrome with Lewy bodies (and not secondary to any of the below (ie., "idiopathic")) Responsiveness to L-DOPA at least early is one factor favoring Parkinsons disease chronic, repetitive head trauma (especially boxers) multiple system atrophy, one component of which is nigro-striatal degeneration secondary to drugs, such as MPTP (1-methyl-4-phenyl-tetrahydrobiopteridine), an illicit drug contaminant PSP and corticobasal degeneration, discussed previously post (Von Economos) encephalitis = postencephalitic (1915-1918 influenza pandemic whether influenza virus or a separate one continues to be a historical controversy) 4. pathology of PD a) decreased dopaminergic input from substantia nigra to neostriatum b) gross exam may show depigmentation (pallor) of substantia nigra (dopamine) and locus ceruleus (norepinephrine) c) microscopy shows neuron loss with gliosis, pigment incontinence, Lewy bodies in neurons in substantia nigra pars compacta Lewy bodies are intracytoplasmic eosinophilic inclusions that are composed of fine filaments densely packed in the core but loose at their rim these filaments are composed of neurofilament antigens, parkin, and ubiquitin, but the major component of the Lewy body in sporadic PD is alpha-synuclein note that extra-lysosomal degradation is mediated by ubiquitin (binds to damaged protein and marks them for destruction by proteosome) d) genetic abnormalities rare cases have mutations in alpha-synuclein a juvenile autosomal recessive form of PD linked to gene coding for parkin (an E3 ubiquitin ligase) one family has abnormal gene coding for deubiquitination enzyme UCH-L1 e) compare Lewy body disorders (there may be clinical overlap, particularly as disease progresses): classic Parkinson disease = Lewy bodies in pars compacta neurons of the substantia nigra (produces extrapyramidal movement disorder) Lewy body dementia = Lewy bodies in cerebral cortex (produces dementia, third most common cause of dementia) autonomic failure = = Lewy bodies in IML (sympathetic) neurons in thoracic spinal cord cause autonomic dysfunction, including orthostatic hypotension, impotence, abnormal sweat and salivary gland secretion, pupillary abnormalities Lewy body dysphagia = Lewy bodies in dorsal vagal nuclei 5. treatment L-dopa (a dopamine precursor, which does not halt progression of disease) used with carbidopa (a peripheral dopamine decarboxylase inhibitor that does not cross the blood-brain barrier, therefore inhibits peripheral metabolism of L-dopa) side-effects of L-dopa include other movement disorders and on-off phenomenon bromocriptine (a postsynaptic dopamine agonist) is used in end-stage Parkinson's amantadine (simulates presynaptic dopamine release) benztropine (an anticholinergic that reduces central cholinergics); note that cholinergic agonists make symptoms worse deprenyl (selegiline) (a selective MAO-B inhibitor) C. Huntingtons disease autosomal dominant inheritance due to trinucleotider repeat disorder (on chromosome 4) in HD gene (codes for protein huntingtin); the trinucleotide, CAG, codes for glutamine; stretches of CAG repeats greater than 35 result in the disease The glutamine repeats confer a toxic effect on the protein (gain of function disorder) hyperkinetic movement disorder = chorea (aka Huntington's chorea) = athetoid movement (uncontrolled jerky movements); compare to hemiballismus, which is uncontrolled flailing of an arm (may be seen with lesion of the subthalamic nucleus) depression and progressive dementia (average survival is ~ 12 to 15 yrs.) onset of symptoms anytime, but usually between 30 and 40 (signs of juvenile form are similar to Parkinson's) disease shows "anticipation" (presents earlier in life with worse symptoms in subsequent generations); this correlates with longer stretches of CAG repeats in each subsequent generation

Parkinson's

 atrophy

of neostriatum (caudate nucleus and putamen) and frontal lobes; ubiquitin and huntingtin positive intranuclear inclusions atrophy of caudate may cause "bat-wing" appearance of lateral ventricles spiny projection neurons including GABA-ergic are preferentially lost early in the disease treatment with haloperidol and pheonthiazines to block dopamine receptors ameliorates some symptoms, but this doesn't halt progression of the disease
173. Spinocerebellar

and motor neuron degenerations ataxia: large group of disorders sx and neuron loss referable to the cerebellum, brainstem, spinal cord, and peripheral nerve many have CAG trinucleotide repeat expansions, similar to HD another group of disease are due to expansion of non-coding region repeats, somewhat mysterious but see lecture on myotonic dystrophy miscellaneous other mutations B. Friedreich's ataxia Widespread neuronal degenerations (Clarkes column, Betz cells, CN 8, 10, 12, both Purkinje and dentate gyrus neurons) degeneration of spinocerebellar tracts, dorsal columns, lateral corticospinal tracts, and cerebellum fibers in these tracts show a "dying-back" axonopathy in which fiber loss is more evident in the axon farther from the neuronal cell body initial symptom is ataxia of gait followed by hand clumsiness defect is trinucleotide repeat expansion in gene that codes for protein called frataxin cardiac involvement common and life-threatening diabetes in about 10% C. ataxia-telangiectasia ATM gene mutation results in failure to respond to DNA damage appropriately (double strand breaks) patients sensitive to ionizing radiation increased susceptibility to cancer (esp. breast) cerebellar abnormalities not well understood, loss of Purkinje and granular cells; other cells lost as well (degen of dorsal columns, spinocerebellar tracts, corticospinal tracts) D. subacute combined degeneration: seen in patients with vitamin B12 deficiency degeneration of both posterior and lateral areas: posterior (dorsal) columns, the corticospinal pathways, and the spinocerebellar tracts (mainly the dorsal spinocerebellar tract) abnormality initially of myelin sheaths but axons eventually lost discontinuous abnormalities of the involved tracts at various levels of the neuraxis (not an orderly tract degeneration) E. ALS 1. ALS = amyotrophic lateral sclerosis aka Lou Gehrigs disease (death due to respiratory failure or pneumonia) 2. most common form of motor neuron disease, 10% are familial (AD) 3. onset in middle age with both lower motor neurons (LMN) disease and upper motor neurons (UMN) disease (no sensory abnormality) 4. LMN disease = weakness and fasciculation ("amyotrophic" = myo-atrophic) 5. UMN disease = spasticity, hyperreflexia ("lateral sclerosis") 6. due to degeneration of upper and motor neurons due possibly to: abnormalities of glutamate or related neurotransmitters (excitotoxicity) antibodies affecting ion channels defects involving free radicals, a familial form has been localized to a form of superoxide dismutase (SOD) genes, but this appears to be a gain of function mutation whose role in pathogenesis has not been worked out (SOD is a scavenger for oxygen free radicals) gross reveals degeneration and atrophy of lateral corticospinal tracts and anterior motor neurons (anterior horn) of spinal cord; anterior nerve roots are thin F. bulbospinal atrophy (Kennedy syndrome) expansion of a CAG repeat region in the androgen receptor on X chromosome sx: androgen insensitivity with gynecomastia, testicular atrophy, and oligospermia; neurological syndrome largely LMN G. spinal muscular atrophy
A. spinocerebellar

 onset

in infancy (type 1 or Werdnig-Hoffman) or childhood (type 2 or 3) by mutations in SMN1 gene, often a deletion; number of copies of a nearby homologous SMN2 gene modifies the clinical phenotype muscle pathology characteristic: panfascicular marked atrophy, round not angular atrophy, scattered markedly hypertrophic type 1 fibers CNS pathology shows depopulated anterior horn regions type 1 presents often at birth with a floppy baby or within a few months of birth; relentlessly progressive loss of motor function, death within a few years type 2&3 presents in early childhood (3 to 15 months), death usually occurs within a few years in type 2, and type 3 may survive to adulthood
caused 174. Inborn

metabolic disorders

A. General

storage disorders: usually AR; deficiency in ability to catabolize sphingolipids, mucopolysacharides, or mucolipids; failure to catabolize results in accumulation of the substrate of the enzyme in the neuron with ballooning and eventual loss; when neocortical neurons involved, loss of cognitive function and seizure disorders likely Leukodystrophies: abnormal myelin synthesis or turnover; usually AR (adrenoleukodystrophy exception: Xlinked) usually present in early childhood after a period of normal milestone acquisition; usually with sparing of superficial subarcuate fibers, also referred to as U-fiber sparing) B. Neuronal storage disorders 1. Neuronal Ceroid Lipofuscinosces (NCL): neurons accumulate excess lipofuscin, an autofluorescent, indigestible lysosomal product with a variety of ultrastructural appearances 8 gene mutations identified so far; products generally involved in protein modificatin/degradation Multiple clinical presentations at different ages with different eponyms: infantile, INCL; late infantile, LINCL; juvenile, JNCL or Batten disease; adult, ANCL or Kuf disease Mental and motor deterioration, blindness, seizures 2. Tay-Sachs disease: hexosaminidase alpha subunit deficiency (with ganglioside accumulation) with developmental delay, progressive neurological deterioration C. Leukodystrophies 1. Krabbes disease AR disorder due to mutation in and decreased galactocerbrosidebeta-galactosidase function (turnover of myelin is abnormal) increased galactocerebroside in brain ; CNS demyelination with multinucleated macrophages (globoid cells) growth retardation, long tract problems, loss of milestones, rigidity or spasticity with hyperactive reflexes 2. metachromatic leukodystrophy AR disorder due to mutation in and decreased arylsulfatase function (cerebroside sulfatase) metachromatic granules in oligodendrocytes and neurons (metachromatic material causes the stain to change color, ie material stains brown with toluidine blue); metachromatic material may be found in nerve or urine. microscopy shows loss of myelin and prismatic bodies in macrophages both central and peripheral demylination; increased CSF protein 3. adrenoleukodystrophy (ALD) adrenoleukodystrophy is the disorder in "Lorenzos oil" (XR disorder) adrenal insufficiency with peripheral and CNS demyelination (typically demyelination starts occipitally and moves anteriorly) mutations of the ALD gene which codes for a member of the ATP-binding cassette transporter family of proteins increased serum VLCFA (very long chain fatty acids) due to problem with transporter into peroxisomes the early onset form features central demyelination; later onset form termed adrenomyeloneuropathy and shows mainly peripheral nerve and spinal cord changes. Interestingly, kindreds with a single mutation show members with both types of disease, implying the existence of disease-modifying alleles. 4. Pelizaeus-Merzbacher disease: defect in gene on X chromosome that codes for proteolipid protein (PLP), a major protein of CNS myelin "tigroid" appearance of brain sections stained for myelin D. Canavan disease: mutations and deletions of gene coding for aspartoacylase (spongy degeneration in white matter)

Neuronal

E. Alexander

F. Mitochondrial 175. CNS

disease: mutation in GFAP gene; innumerable Rosenthal fibers in the brain encephalomyopathies affect both muscle and brain; see muscle notes

tumors A. general 1. most frequent primary tumor location in adults is supratentorial; in children, infratentorial 2. CNS tumors may be malignant biologically or "malignant by position" ie., benign but unresectable (craniopharyngioma, ependymoma even meningioma sometimes) 3. the single most important prognostic consideration in primary intraparenchymal tumors is whether the tumor is well-circumscribed (potentially resectable) or infiltrating (generally not resectable) 4. tumors by location: supratentorial (adults) = meningioma, glioblastoma, astrocytoma, oligodendroglioma cerebellopontine angle = schwannoma, meningioma, epidermoid cyst medial temporal lobe = ganglioglioma, oligodendroglioma posterior fossa (kids) = medulloblastoma, pilocytic astrocytoma, ependymoma B. astrocytomas 1. most common type of primary brain tumor in adults (located in cerebral hemispheres) 2. produce seizures and headaches (mass effect) 3. WHO grade I = pilocytic astrocytoma (clinicopathologic entity, ie circumscribed often cystic tumor in characteristic location usually in young person) a benign (well demarcated) tumor of the cerebellum of children and young adults; may occur in other locations does not progress in grade (in contrast, grades II and III may progress to worse tumors) microscopy reveals Rosenthal fibers and may be either monophasic or biphasic with fibrillary and microcystic areas (this pattern has been termed "juvenile pilocytic astrocytoma") 4. WHO grade II = infiltrating astrocytoma with low cellularity, mild atypia, no mitoses, no necrosis 5. WHO grade III = anaplastic (malignant) astrocytoma that is infiltrating with atypia, increased cellularity, some mitoses, no necrosis 6. WHO grade IV = glioblastoma (formerly glioblastoma multiforme) is highly aggressive (very high grade), very poor prognosis, and most common intrinsic brain tumor gross reveals hemorrhage and necrosis, commonly extends in corpus callosum across midline ("butterfly" tumor) histology reveals foci (serpentine) of necrosis with pseudopalisading of tumor cells and proliferation of blood vessels can be subdivided into primary (95% of cases) or secondary (5%) on clinical grounds with distinctive molecular findings secondary is when occurs in younger pt with progression from lower grade astrocytoma ; ~60% of these have p53 mutations as quite early events while only 8% have EGFr amplificaton primary form occurs in patient typically in 50s with short clinical history; ~40% have EGFr amplification, ~25% have p53 mutations Numerous other molecular differences; one similarity is that mutations in PTEN are about equally common in the two forms (60-70%) C. oligodendroglioma slow-growing, infiltrating, high recurrence rate (more sensitive to chemotherapy); commonly presents with seizure(s) microscopy reveals sheets of tumor cells with round regular nuclei and clear perinuclear haloes ("fried-egg" appearance) calcification common (seen with x-ray) when clinical history is long cytogenetic abnormalities have diagnostic, prognostic and therapeutic significance: relatively large co-deletions of up to the entire arms 19q and 1p are present in 80% or more of classic oligodendrogliomas, indicate a tumor that will respond well to all standard therapies (temozolamide is current chemotherapy of choice; also responds well to radiation) with long median survival (on the order of 10 years) D. ependymoma tumor of childhood and adolescence; well circumscribed tumor, slow growth but prognosis is poor (4 yr survival) because of location location is ventricular system (fourth ventricle is most common location in young)

obstruction of 4th ventricle causes hydrocephalus and signs of increased intracranial pressure reveals true rosettes (blepharoplasts are rod-shaped structures [basal bodies of cilia]) and perivascular pseudorosettes E. medulloblastoma highly malignant infiltrative tumor with neuronal and glial markers (5 year survival is 75%) of children, but is very radiosensitive tumor cells are small with hyperchromatic nuclei and scant cytoplasm sometimes forming Homer-Wright (true) rosettes many variants: classic, desmoplastic (with "pale islands" or nodularity), large cell/anaplastic similar, probably identical conceptually, to PNET (primitive neuroectodermal tumor) cells elsewhere a clinicopathologic entity; that is, by definition a small blue cell tumor primarily arising in the posterior fossa = medulloblastoma F. Schwannoma 1. a benign nerve sheath tumor (aka neurilemmoma) which is the classic benign tumor (encapsulated, well circumscribed, slow-growing) 2. in contrast to neurofibroma, does not infiltrate nerve to which it is attached (ie eccentric gross appearance), therefore surgical resection can spare nerve 3. occurs in mixed nerves peripherally and preferentially affects sensory (dorsal) roots 4. most common intracranial location is cerebellopontine angle (frequently referred to as an acoustic neuroma or acoustic tumor) signs due to involvement of CN VIII: a) tinnitus and sensorineural hearing loss due to involvement of cochlear portion of VIII (tuning fork on top of skull [Weber test] lateralizes to normal side) b) vertigo (dizziness) due to involvement of vestibular portion of VIII (positive Romberg sign = patient falls to side when standing with eyes closed) may affect by expansion and impingement other CN's such as VII (ipsilateral facial [Bell's] palsy), IX (decreased gag reflex, decreased taste to posterior 1/3rd tongue), V (facial pain) may also occur peripherally or on dorsal roots (note all central structures commonly involved are sensory) 5. histology Antoni A areas are cellular spindle cell areas that have palisading cellular areas with adjacent nuclear free zone (called Verocay bodies) Antoni B are less cellular areas with round nuclei, microcysts and myxoid change G. meningioma tumor of adults (after 40) slowly growing, well circumscribed tumor (but rapid growth possible during pregnancy due to progesterone receptors) atypical meningiomas are defined by somewhat elevated mitotic rate (4 or more per 10 HPF), certain architectures (clear cell, chordoid), certain cytological findings and/or brain invasion malignant meningiomas are unusual and are defined by anaplasia (resemblance to sarcoma), high mitotic rate (20 or more per 10 HPF or certain architectures (papillary, rhabdoid) origin is meningothelial cell of arachnoid (external to brain, therefore surgical removal) many histologic patterns including whorled pattern (may calcify and form psammoma bodies) (the tumor cells like to wrap around things) H. primary CNS lymphoma (PCNSL) B cell neoplasm, generally diffuse large cell (high grade) that displays angiotropism (infiltrative through blood vessels and into brain) increasing incidence, partly due to immunosuppression (especially after renal transplant) and AIDS (most common focal cerebral process in some AIDS series), partly for unexplained reasons in the immunocompetent associated with EBV in immunosuppressed (test for EBV-DNA in CSF using PCR is sensitive and almost completely specific) immunocompetent individuals develop diffusely infiltrating lesion; immunosuppressed individuals develop multiple ring-enhanced lesions truly "primary" = no evidence of lymphoma elsewhere in over 90% of cases, even at autopsy quite responsive to steroids initially (not responsive to toxoplasmosis therapy) other signs favoring PCNSL over toxoplasmosis in AIDS pt: solitary lesion, periventricular lesion(s), "fingerlike" extensions from mass subventricularly, lesion in the corpus callosum I. spinal cord
microscopy

progressive

(inside of the cord) are rare compared to brain tumors; two most common are ependymoma (~60%), and astrocytoma(30%), be aware of hemangioblastoma intradural but extramedullary = meningioma, nerve sheath tumors [schwannoma and neurofibromas] extradural = metastases, lymphoma, myeloma or plasmacytoma J. germ cell tumors occur near midline, typically suprasellar or pineal region, and in the young pineal region germ cell neoplasms show strong predilection males; not true of suprasellar lesions similar appearance and biology to the testicular tumors; the appearance knows as seminoma in testis is called germinoma in brain germ cell tumors have high propensity to metastasize to brain, thus must exclude primary outsided of brain K. pinealoma pinealocytes normally synthesize melatonin and serotonin, therefore pineal gland tumor is associated with abnormal sleep-wake cycle large tumors may cause noncommunicating hydrocephalus or compress upper midbrain and pretectal areas to produce Parinaud's syndrome (impaired conjugate vertical gaze, pupillary abnormality, absence of accommodation reflex). Malignant form is a PNET termed pineoblastoma L. chordoma derived from notochord; location is clivus or sacrococcygeal region gross: lobulated midline mucoid mass; mx: cells with extensive vacuolaton due to droplets of mucus in cytoplasm (called physaliphorous cells) and shorts strands of epithelial cells floating in a mucoid ground substance M. Metastases common; 25% to 50% of intracranial tumors in hospitalized patients lung, breast, melanoma, kidney and GI tract most common sources gross: sharply demarcated masses often near the grey-white border micro: also sharply demarcated (melanoma may infiltrate microscopically), often with zones of necrosis one other pattern is meningeal carcinomatosis, with tumor lining or studding the subarachnoid space
176. Seizures A. general

intramedullary

epilepsy = recurrent seizures; affects 1 to 2 % of population; EEG is the most important diagnostic test seizures are not epilepsy; criteria for febrile seizures include: convulsion associated with an elevated temperature greater than 38C; 2) pt < six years of age 3) No central nervous system infection or inflammation; 4) No acute systemic metabolic abnormality that may produce convulsions; 5) No history of previous afebrile seizures. simple febrile seizures last less than 15 minutes, have no focal features, and, if they occur in a series, the total duration is less than 30 minutes complex febrile last more than 15 minutes, have focal features or postictal paresis, and occur in a series with a total duration greater than 30 minutes febrile seizures especially complex ones, are associated with a greater tendency to develop epilepsy in later life 3. seizure disorders are associated with a higher rate of (often unexplained) death than in age-matched cohort B. partial seizures by far the most common type of seizure (1/3rd of afflicted individuals not controlled by medication and might benefit from surgery) involves one area of the brain; temporal lobe is most common simple partial has awareness intact, while complex partial has impaired awareness (partial complex seizures originate in the temporal lobe or the frontal lobe) anatomical abnormalities are now being demonstrated in the vast majority (80-95%) of cases of partial seizures example of anatomic abnormality is hippocampal (Ammon's horn) sclerosis, which refers to loss of neurons in CA1 and CA4 areas of hippocampus, (see selective neuronal necrosis in foregoing) C. generalized seizures absence (petit mal) = blank stare; child may present because of "daydreaming" in class; EEG shows classic three-per-second "spike-and-dome" discharges tonic-clonic (grand mal) = alternating stiffening and movement; EEG shows generalized high-voltage spikes myoclonic = quick repetitive jerks
1. 2. febrile

tonic = stiffening atonic = "drop" seizures

177. Neurocutaneous

syndromes (phakomatoses) A. neurofibromatosis (very specific criteria for the clinical diagnosis of either NF1 or NF2 have been elaborated) 1. neurofibromatosis Type 1 (NF1) = von Recklinghausen's disease (AD inheritance) gene located on chr 17 codes for neurofibromin which is a type of GAP that down regulates the p21 ras oncoprotein highest spontaneous mutation rate known (one possible reason is because it is a very large gene) multiple neural tumors including neurofibromas, plexiform neurofibromas, meningiomas, astrocytomas pigmented nodules of iris (Lisch nodules) and caf-au-lait spots of skin neurofibromas are within nerve (multiple types of cells that support neurons proliferate), therefore can't be removed surgically without removing axons plexiform neurofibromas are pathognomonic and have involvement of all the fascicles of a nerve variable expressivity with 100% penetrance sarcomatous degeneration is a relatively common event in NF1 (malignant peripheral nerve sheath tumor (MPNST) often referred to in old literature as "neurofibrosarcoma") 2. neurofibromatosis Type 2 (NF2) has multiple meningiomas or bilateral acoustic neuromas (no skin lesions); mutation located on chr 22 in the same region as a common cytogenetic abnormality of meningtiomas. B. tuberous sclerosis autosomal dominant with variable penetrance mutations at several loci including the TSC1 locus, which codes for hamartin, and the TSC2 locus, which codes for tuberin these proteins inhibit mTOR, which is the mammalian target of rapamycin.; mTOR plays a central role in the regulation of cell growth dysregulation of mTOR activity is associated with several hamartoma syndromes, including tuberous sclerosis, von Hippel-Lindau syndrome, Peutz-Jeghers syndrome, and the PTEN-related hamartoma syndromes triad = angiofibromas (clinical misnomer is "adenoma sebaceum"), seizures and mental retardation hamartomas in CNS ("tubers" are firm areas with haphazardly arranged neurons and glia with stout processes) only TS patients get a benign CNS tumor descriptively named subependymal giant cell tumor (located subventricle with projection into ventricle) grossly some hamartomas that project into ventricles are described as "candle-gutterings" other hamartomatous tumors include rhabdomyoma of heart and angiomyolipoma of kidney other skin lesions include hypopigmented areas (in kids may need to use Wood's lamp to see well) C. Von Hippel-Lindau disease autosomal dominant inheritance due to deletion of VHL (tumor suppressor) on chromosome 3 (normally codes for pVHL, which regulates transcription of a number of transcription factors that are activated by hypoxia. defined by hemangioblastomas (mx shows lots of vessels and lots of neutral fat) of cerebellum and retina (associated with paraneoplastic polycythemia), but these may occur anywhere in neural axis in large numbers also develop renal cell carcinoma (multiple and bilateral) and cysts of pancreas and kidneys D. Sturge-Weber syndrome capillary-venous malformation of leptomeninges and superficial cortex of one cerebral hemisphere with ipsilateral port-wine stain (nevus flammeus) in trigeminal region of face characteristic "railroad track" calcification in superficial brain with time

PERIPHERAL NERVE/MUSCLE
178. Normal A. peripheral

nerve bundles of nerve fibers surrounded by CT (white grossly due to myelin); types of CT include epineurium: dense CT (fascia) on outside of nerve perineurium: dense CT surrounding each bundle of nerve fibers (fascicle) endoneurium: reticular fibers surrounding individual nerve fibers 2. nerve fiber: individual axon with its Schwann cell with or without myelin myelinated fiber (axon): single Schwann cell per internode several unmyelinated fibers may be ensheathed by a single Schwann cell over some extent
1. nerves:

of peripheral nerve myelin protein zero (major protein) myelin basic protein (second most abundant protein) there are other proteins B. skeletal muscle 1. terms sarcoplasm = cytoplasm of muscle fiber sarcolemma = plasma membrane of muscle fiber endomysium: relatively inconspicuous connective tissue (CT) surrounding individual skeletal muscle cells perimysium: CT surrounding small bundles (fascicles) of muscle cells epimysium: CT surrounding entire muscle 2. sarcomere: functional unit Z bands: ends of sarcomere; location where actin (thin) filaments are anchored A (anisotropic) band: formed by myosin filaments (also contains some actin filaments) M line: center of A band H band: middle of A band; no actin filaments I (isotropic) band: between A bands; contains mainly thin filaments T tubules (transverse tubule): invaginations of sarcolemma; open to extracellular space; located at junction of A band and I band; triad = one T tubule and 2 sarcoplasmic reticuli 3. functional types of skeletal muscle fibers : determined by LMN a) slow-twitch fibers (type I or red fibers) increased myoglobin (a red pigment); increased mitochondria (oxidative enzymes); decreased ATPase (lesser ATPase staining) function: long, slow, aerobic (oxidative) exercise; not easily fatigued (good for marathon) b) fast-twitch fibers (type II or white fibers) increased glycolytic enzymes (Embden-Meyerhof pathway); increased glycogen; increased phosphorylase; darker ATPase stain function: fast, very short (anaerobic) exercise; easily fatigued c) ATPase staining: normal is checkerboard pattern because there is a random mixture of both type I and type II fibers
myelin 179. Peripheral A. When

3. components

nerve abnormalities (neuropathies, polyneuropathies) a pathological condition causes loss of a neuron that projects to the periphery, the term neuronopathy is sometimes used; when the insult affects the axon peferentially, axonopathy; in either instance the axon is lost, myelin lost secondarily sensory system (e.g.,paraneoplastic diseases) or motor system (example is amyotrophic lateral sclerosis) autonomic system (e.g., Shy-Drager syndrome = male impotence, anhidrosis, orthostatic hypotension, more) B. When an insult affects primarily the axon or neuronal soma, the main pathological response in the axon is referred to as axonal degeneration 1. degeneration of distal end of axons with secondary degeneration of myelin sheath 2. A focal lesion at one point in the axon (causing transaction) results in a process known as Wallerian degeneration distal to the injury within a day, axon starts to break down chwann cells start to catabolize myeline and phagocytose axonal debris; form myelin ovoids macrophages are recruited in to aid in phagocytosis entire process happens relatively quickly (days); all axonal profiles appear to be at about the same stage of degeneration with a transected or crushed nerve if basal lamina intact, axonal regeneration begins quickly (and can proceed at about 1mm/day) 3. When slowly evolving neuronopathies or axonopathies cause disease, axonal degeneration is present in a fraction of fibers in a nerve and the degeneration appears to be at various stages 4. motor axonal degeneration causes denervation atrophy of muscle (see below) 5. regeneration (reinnervation) is characterized by axonal sprouting and by muscle type grouping, because the fiber type is dictated by the innervating neuron, and sprouting will reinnervate adjacent muscle fibers 6. possible causes are legion and include toxic (drugs, alcohol, heavy metals), trauma, ischemia (diabetes), and metabolic derangements

common pattern is for the longest peripheral fibers to be affected first (most metabolically demanding), which produces a "stocking and glove" distribution of sensory loss and muscle abnormalities C. When an insult affects primarily the Schwann cell or myelin sheath the pathological response is loss of myelin often referred to as segmental demyelination. 1. repeated segmental demyelination followed by remyelination produces concentrically arranged proliferating Schwann cell processes ("onion bulbs") 2. NCV (nerve conduction velocity): critical test that may help distinguish demyelinating from axonal degeneration In axonal degeneration, the NCV is maintained until very late in the course (when almost all axons are lost) In segmental demyelination, NCVs are decreased D. Inflammatory neuropathies 1. Guillain-Barr syndrome (acute inflammatory demyelinating polyradiculoneuropathy) a) ascending paralysis that often follows recovery from acute viral URI epidemic form in China follows campylobacter jejuni infection CMV, EBV, M. pneumoniae have all been associated epidemiologically post-vaccinial b) initial weakness in distal extremities then rapidly involves proximal muscles; DTRs lost early c) sensory abnormalities common, but not the clinical problem, and patients may have autonomic dysfunction (cardiac or BP abnormalities) d) histology reveals inflammation and demyelination of peripheral nerves and spinal nerve roots (radiculoneuropathy) perivenular and endoneurial lymphocytes, macrophages, possibly plasma cells macrophages insert at node of Ranvier,strip away myelin from axon in severe cases axons are lost Remyelination occurs during recovery e) pathogenesis animal model uses immunization of a myelin protein T cell-mediated disease ensues; T cells if transferred from immunized animal to a naive host produce the disease f) CSF reveals increased protein (due to altered permeability of microcirculation in spinal roots in subarachnoid space) with normal cell count because cells are held within roots/nerves (cytoalbuminologic dissociation) g) With proper cardiorespiratory support mortality has decreased from 25% to less than 5%; about 20% have residual deficit, rest recover comletely; rx with plasmapheresis or IV immunoglobulin 2. chronic example is chronic inflammatory demyelinating polyneuropathy (CIDP) clinically similar to Guillain-Barr except for chronic course (more than 12 weeks); may have remissions and relapses usually presents with symmetric proximal and distal weakness in extremities (+/- sensory defects); CN's may be involve CSF reveals elevated CSF protein and cytoalbuminologic dissociation as in GBS sural nerve biopsy (when dx is in question): inflammation is present in a minority of cases and may be mild; segmental demyelination and remyelination with occasional onion bulb formation rx: steroid responsive; may use IV immunoglobulin or plasmapheresis E. Diabetic neuropathy 1. common, important, related to duration of disease; up to 80% who have had the disease for 15 years 2. several patterns distal symmetric sensory or sensorimotor neuropathy: classic glove and stocking distribution, abnormalities of nonenzymatic glycation or polyol pathways implicated; loss of distal sensation sets patients up for local injury leading to diabetic ulcers with poor repair due to microvascular disease autonomic neuropathy: often present at the same time as the distal pattern, hypotension, sexual dysfunction, disorders of gastric or bladder emptying or GI motility focal or multifocal asymmetric neuropathy (mononeuropathy (eg cranial nerve III) or mononeuropathy multiplex) mx axonal degeneration predominantly but with a bit of segmental demyelination thrown in; thickened endoneurial arteriolar walls with hyalinization and prominent reduplication of the basement membrane

7. one

F. Metabolic

and nutritional neuropathies distal, symmetric, cramps, diminished DTRs and dysesthesias; improves with dialysis liver disease, thyroid disease and chronic respiratory insufficiency thiamine deficiency; also B2, B6 and vit E deficiency chronic EtOH (thiamine deficiency a strong component of this, but EtOH may have toxic effect on its own) G. Associated with malignancy 1. direct compression by a tumor (e.g., brachial plexopathy from a carcinoma in the apex of the lung) 2. paraneoplastic: distal sensorimotor slowly progressive neuropathy associated with an occult malignancy, most commonly small cell carcinoma of the lung inflammation within DRG frequently IgG Ab that binds a protein expressed both by neurons and tumor severity of the syndrome depends on titer of the Ab H. Toxic: long list, including heavy metals and numerous organic compounds I. Traumatic 1. lacerations=cut by sharp object 2. avulsion= tension pulls nerve apart 3. regeneration occurs if distal nerve sheaths still intact, aligned in absence of aligned nerve sheaths, axons attempt regeneration in a tangled mass of neurites all elements of the nerve proliferate, axons, Schwann cells, fibroblasts to produce a traumatic neuroma within the mass the nerve fibes are randomly oriented but properly formed 4. compression neuropathy carpal tunnel syndrome, entrapment of median nerve in the wrist, due to numerous causes: repetitive stress, diabetes, amyloid, acromegaly, hypothyroidism, edema, pregnancy ulnar, peroneal, radial nerves also can show compression/entrapment neuropathy interdigital nerve compression at intermetatarsal sites leads to pain, nodule at site known as Mortons neuroma
uremic: 180. Infections A. leprosy

(Hansen disease) due to Mycobacterium leprae host does not respond to invasion of Schwann cells by M. leprae; orgs proliferate, widespread nerve involvement, invade other cells, distal nerves affected preferentially because orgs prefer cool environment, pain fibers preferentially involved leading to injury distally with ulcer formation tuberculoid: granulomatous response to orgs, more focal nerve involvement B. diphtheria exotoxin-produced disease enters sensory ganglia (incomplete blood nerve barrier) first with production of parasthesias, loss of proprio, vibratory; then weakness produces demyelination C. botulism due to Clostridium botulinum exotoxin, which is a heat-labile zinc metalloprotease that inhibits release of acetylcholine at synaptic cleft of cholinergic nerve terminals causes generalized muscle weakness, diplopia, dysphagia, pupils mydriatic and don't respond to light or accommodation associated with home-canned food (infants can also ingest C. botulinum spores in honey) D. tetanus due to Clostridium tetani (gram-positive, motile, nonencapsulated, anaerobic, spore-bearing bacillus) produces tetanospasmin, a neurotoxin that blocks the release of the inhibitory neurotransmitter glycine in anterior horn cells signs include stiffness of jaw (trismus), muscle spasms of face, abdomen, back (opisthotonos) associated with puncture wounds, can also grow in umbilical stump of newborns tetanus toxoid (DPT vaccination) effectively reduces incidence E. varicella-zoster virus following chickenpox infection, virus remains latent in sensory ganglia reactivation leads to painful,vesicular skin eruption in the distribution of the sensory dermatomes (shingles) factors leading to reactivation are complex; decreased cell-mediated immunity is implicated ganglia show neuronal destruction and loss with lymphocytic infiltration and sometimes hemorrhage
lepromatous:

181. Hereditary

neuropathies motor and sensory neuropathy (HMSN) 1. Charcot-Marie-Tooth disease, hypertrophic form (HMSN type I), the most common hereditary peripheral neuropathy AD; very slowly progressive; mostly distal sensorimotor deficits; normal life span typical characteristic progressive muscular atrophy of calf clinically called peroneal muscular atrophy signs include distal muscle weakness and atrophy of calf; pes cavus duplication of region for PMP22 myelin protein(HMSN1A) or mutation in myelin protein MPZ (HMSN1B); numerous other molecular causes described mx: classic onion bulb neuropathy, in distal nerves (individual enlarged nerves may be palpable=hypertrophic neuropathy) 2. HMSN II similar clinically, probably more of an axonopathy than a segmental demyelination 3. Dejerine-Sottas diseas (HMSN III) AR; genetically heterogeneous but comes from mutations in same molecules as HMSN I earlier onset, not limited to distal peripheral nerves, failure to gain milestones hypertrophic neuropathy B. hereditary sensory and autonomic neuropathies (HSAN) (see table 27-2) C. familial amyloid polyneuropathies (FAP): most have mutations of the transthyretin gene D. peripheral neuropathy accompanying inherited metabolic disorders eg, porphyria, adrenoleukodystrophy, Refsum disease (see table 27-3)
A. hereditary

182. Muscle

atrophy atrophy (due to muscle denervation, ie LMN) fibers shrink and are small and angular on cross section may form target fibers, which have central light area surrounded by dark rim with normal peripheral zone on oxidative stain with reinnervation will develop fiber-type grouping B. spinal muscular atrophy (SMA)- discussed in neurodegeneration notes
A. denervation

183. Muscular

dystrophies muscular dystrophy (DMD) 1. XR (male children before 5 years of age), but sporadic cases are common (high rate of spontaneous mutations because gene is one of the largest, 2.3 million base pairs) 2. mutation, often significant deletion of dystrophin gene (demonstrate with muscle biopsy) leads to a lack of dystrophin, both by immunohistochemistry and by Western blot a protein found on the inner surface on the sarcolemma links to cytoplasmic actin dystrophin and the dystrophin associated protein complex (mutations in other members of which can give rise to other dystrophies) form an interface between the intracellular contractile apparatus and the extracellular connective tissue matrix 3. most common and most severe muscular dystrophy (1 in 3500 live male births) 4. proximal weakness (pelvic girdle muscles); positive Gowers maneuver (child uses stronger arm and shoulder muscles to rise from floor, but not specific) 5. pseudohypertrophy of calf muscles (firm, rubbery calves) is due to increased fibrous tissue and adipose tissue (not increased muscle tissue) 6. histology shows rounded atrophic fibers, necrosis, degeneration, myophagocytosis and (clumps of) regenerating fibers, and increased connective tissue mixed with hypertrophied fibers 7. lab findings: increased serum creatine kinase, aldolase, LDH B. Becker muscular dystrophy similar clinically to Duchennes muscular dystrophy (XR inheritence), but less severe and weakness begins later in life (second to third decade) abnormal, rather than absent, dystrophin due to mutations of dystrophin gene C. other muscular dystrophies 1. numerous others 2. limb girdle dystrophies are dystrophies affecting proximal muscles in a similar fashion to Duchenne/Becker
A. Duchenne

AD or AR; 17 of them so far involve proteins that interact with dystrophin D. myotonic dystrophy due to expansion of CTG trinucleotide repeat in DM kinase gene, which codes for myotonin protein kinase onset in 2nd or 3rd decade of weakness and myotonia (inability to relax a strongly contracted muscle, seen as difficulty releasing grip with handshake) with normal serum muscle enzymes mx shows greatly increased central nuclei and other findings of dystrophy: ring fibers, necrosis, degeneration, myophagocytosis and (clumps of) regenerating fibers, and increased connective tissue mixed with hypertrophied fibers other signs include cataracts, frontal baldness, hypogonadism, cardiac problems
four 184. Other

either

muscular disorders channel myopathies (channelopathies) 1. periodic paralysis: recurrent episodes of weakness or paralysis: induced by cold, after vigorous exercise, or high carbohydrate meals 2. May be associated with hyper, hypo or normokalemia hyperkalemic periodic paralysis: gene coding for a skeletal muscle sodiumchannel protein (SCN4A) hypokalemic: gene encodes a voltage gated L type calcium channel 3. malignant hyperthermia may occur after giving succinylcholine or inahalational agents as part of induction of general anesthesia hypermetabolic state that can occur in a variety of muscle diseases One genetic defect is in the ryanodine receptor, a voltage gated L type calcium channel; uncontrolled release of calcium from muscle SER appears to be important; dx is confirmed with muscle bx sx (within 30 minutes): fever, tachycardia, muscle rigidity, metabolic acidosis with hyperkalemia B. congenital myopathies 1. general infantile hypotonia causes floppy infant syndrome (marked hypotonia at birth) proximal muscle weakness 2. central core disease central core disease has loss of mitochondria and other organelles in center of type I muscle fibers many cases are due to mutation in ryanodine receptor (a calcium channel) some cases are associated with a susceptibility to malignant hyperthermia 3. nemaline myopathy: has numerous short rods or granules predominately in type I fibers (arise from z-discs) C. myopathies associated with inborn errors of metabolism 1. lipid myopathies: accumulation of lipid within muscle (oil red O positive intracytoplasmic vacuoles) due to carnitine deficiency (muscle weakness only) or decreased carnitine palmitoyl transferase (recurrent myoglobinuria and rhabdomyolysis after prolonged exercise; in contrast to the muscle cramps associated with defects in glycolysis which occur quickly with intense exercise) decreased carnitine palmitoyl transferase is the most common cause of recurrent myoglobinuria 2. mitochondrial myopathies a) recall that mitochondria derive their proteins 20% from mitochondrial DNA and that mtDNA also codes for 22 mitochondrial specific transfer RNAs and 2 ribosomal RNA species. The rest of mitochondrial protein complexes are coded from nuclear DNA. Mutations in either nuclear or mt DNA can cause mitochondrial myopathies (or encephalomyopathies, since other neurologic sx may occur; cardiomyopathy also possible). b) histology reveals numerous fibers with peripheral red-staining areas of cytoplasm ("ragged-red fibers") on trichrome c) EM shows subsarcolemmal collections of mitochondria with "parking lot" inclusions d) many of these diseases show cytochrome oxidase negative fibers on cytochemistry e) point mutations in mtDNA; these show maternal inheritance myoclonic epilepsy with ragged red fibers (MERRF) Leber hereditary optic neuropathy (LHON) mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) f) mutations in nuclear DNA AR or AD
A. ion

cases of subacute necrotizing encephalopathy (Leigh syndrome), exertional myoglobinuria, and Xlinked cardioskeletal myopathy (Barth syndrome) g) deletions or duplications of mtDNA progressive external opthalmoplegia Kearns-Sayre syndrome has external ophthalmoplegia plus pigmentary retinopathy (night blindness), ataxia, heart block D. inflammatory myopathies 1. proximal muscle weakness, sometimes with pain 2. laboratory findings = increased serum muscle enzymes (increased CK); EMG findings may be supportive (mixed neurogenic and myopathic changes) 3. polymyositis affects proximal muscles (cell-mediated injury by CD8 positive lymphocytes in endomysium) mx: necrosis, myophagocytosis, and endomysial inflammatory infiltrates (lymphocytes plus macrophages) no skin findings 4. dermatomyositis (associated with autoantibodies against capillaries of muscle) bimodal age groups, especially children (adult disease is associated with increased risk of visceral malignancies) proximal muscles involved (symmetric bilateral) eyelids have lilac (heliotrope) discoloration with periorbital edema, while red rash on knuckles = Groton lesion) microscopy shows inflammation (typically perimysial and perivascular; the disorder is an antibody plus complement mediated attack on vessels), perifascicular atrophy (atrophic fibers at periphery of muscle fiber fascicles, a pattern reflective of ischemia) 5. inclusion-body myositis age > 50 years (most frequent form of myositis in elderly) insidious onset that begins with distal muscles (extensors of knee and flexors of wrists and fingers) with slow progression to proximal muscle weakness histology reveals changes similar to those of PM plus numerous rimmed vacuoles (contain cytoplasmic filamentous inclusions and amyloid deposits that have A and/or hyperphosphorylated tau in them) does not respond to steroids or immunosuppression E. toxic myopathies 1. thyroid related: acute or chronic muscle weakness that may precede other sx; hypothyroid may produce cramping or aching reflected in bx as atrophy, increased internal nuclei, glycogen aggregates & sometimes deposition of mucopolysaccharides hyperthyroid produces muscle fiber necrosis, regeneration and lymphocytosis; exopthalmic ophthalmoplegia limited to extraocular muscles 2. ethanol binge drinking: rhabdomyolysis, myoglobinuria chronic may present with complicated combination of myopathy and neuropathy 3. drug-induced steroid myopathy, characterized by proximal muscle weakness and type 2 atrophy (not specific) on bx chloroquine, proximal weakness with vacuolar myopathy that my progress to necrosis statins: myopathy most common side effect (1.5%), unrelated to statin used, dose, duration. Bx may not show any abnormality, but either a metabolic/toxic picture (scattered individual myofibers undergoing necrosis/myophagocytosis) or a mitochondrial pattern (ragged red fibers) may be demonstrated
185. Neuromuscular

some

junction (NMJ) A. myasthenia gravis more common in females) when presenting before 40; equal incidence after 40 associated with thymic hyperplasia (65%) or thymoma (15%); thymectomy usually improves clinical situation in these due to autoantibodies against acetylcholine receptors at neuromuscular junction; AChR are lost muscle weakness due to abnormal neuromuscular transmission (weakness is worse with use, better with rest) decremental response to repetitive electrical stimulation on EMG (electromyography); nerve conduction studies are normal involvement of extraocular muscles and eyelids causes ptosis or diplopia

improved with anticholinesterase drugs (Tensilon), which increase levels of ACh at the muscle end plates therapy with anticholinesterase drugs and immunosuppression B. Eaton-Lambert syndrome paraneoplastic syndrome (usually associated with small cell carcinoma of lung) autoantibody against calcium channels on motor nerve terminals signs and symptoms are similar to myasthenia gravis (except not aggravated by effort and not improved with Tensilon) enhanced neurotransmission with repetitive stimulation BONE
186. Normal A. composition 1. cells a) osteoprogenitor b) osteoblasts located

symptoms

of bone cells: located in periosteum and endosteum; differentiate into osteoblasts

in line along surface of bone; mx resemble plasma cells contain alkaline phosphatase and surface receptors for PTH, calcitriol, IL-1,6, TNF-beta (not calcitonin) osteocalcin is a unique serum marker for osteoblastic activity functions: synthesize osteoid (uncalcified bone matrix); local control of bone remodeling c) osteoclasts located on surface of bones in small depressions (Howship's lacunae); contain lysosomes mx: large multinucleated cells (similar to megakaryocytes) with ruffled border (site of active bone resorption) function: bone resorption; secretion of acid hydrolases and collagenases d) osteoclast formation origin is from granulocyte-monocyte precursor (in bone marrow) RANK (receptor activator for nuclear factor kappa-beta) is expressed on preosteoclasts osteoblast/stromal cell membrane-associated RANK ligand (RANKL) binds to RANK on cell surface of osteoclast precursors when RANK binds to RANK ligand (RANKL), osteogenesis is initiated; this can be inhibited by osteoprotegrin (OPG) stromal cells can secrete osteoprotegerin (OPG) which is a decoy receptor for RANKL (preventing it from binding), which decreases osteoclast formation osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis and in patients with lytic bone metastases e) osteocytes mature cells within bone origin is from osteoblasts; can not synthesize protein 2. mineralized matrix: hydroxyapatite (calcium and phosphate); note that unmineralized bone = osteoid 3. organic matrix: type I collagen, which is secreted by osteoblasts B. types of bone 1. woven bone (aka primary or immature bone) irregular arrangement of type I collagen; numerous osteocytes formed rapidly, first compact bone formed during fetal development and bone repair; pathologic in adult skeleton remodeled and replaced by secondary bone 2. lamellar bone (aka secondary or mature) a) parallel arrangement of type I collagen b) consist of haversian system (osteon) (1) many lamellae surrounding central haversian canal lamellae: calcified matrix arranged in regular concentric layers haversian canal: contains blood vessels, nerves, CT (2) interconnected by Volkmann's canals, which carry neurovascular supply c) few osteocytes; formed slowly, compact bone of adults; normal in adult skeleton

layers of bone: compact bone outer (cortical) layer and cancellous bone, the inner layer composed of bony trabeculae C. bone growth and development 1. control: Homeobox genes 2. formation a) intramembranous: does not involve cartilage formation; location is flat bones (calvarium, mandible, maxilla, sternum, pelvis) b) endochondral (1) does involve hyaline cartilage; location is long tubular bones (e.g. femur) (2) process stages first is development of primary ossification center; forms at epiphyseal plate (modified cartilage between diaphysis and epiphysis) layers (zones): reserve (resting) zone; proliferating zone; hypertrophy zone; zone of calcification; zone of ossification.
187. Congenital

3. gross

bone disorders A. achondroplasia autosomal dominant inheritance, defect is point mutation in gene coding for FGF receptor 3 that keeps this gene in its active state (normally activation of FGF3 inhibits cartilage production) dec cartilage cell proliferation at epiphysial plates of long bones causes narrow epiphyseal plate membranous ossification is OK, therefore skull, facial bones, axial skeleton are normal appositional growth is OK, therefore width of bone not affected result in dwarfism (short limbs with normal-size head and trunk) B. osteogenesis imperfecta multiple fractures with minimal trauma AD inherited defect (mutation in genes coding for alpha1 and alpha2 chains of collagen) gene mutations cause defective collagen synthesis (type I procollagen) signs include "brittle bones" (brittle bone disease) with blue sclera (due to thin sclera) and hearing loss selected clinical types (although there are many): type I associated with postnatal fractures, while type II with death in utero C. Stickler syndrome (esoteric): abnormal gene for alpha 1 type 2 collagen; sx: myopia, hypoplasia of jaw, dysplasia of epiphysis (early onset arthritis) D. osteopetrosis "marble bone disease" (Albers-Schnberg disease), because bone is brittle like chalk (therefore multiple fractures) dec osteoclastic activity (osteoclasts lack normal ruffled border) cause inc density of skeleton (dec marrow space) one form is due to a deficiency of carbonic anhydrase II (which is normally needed by osteoclasts and tubular cells to excrete H+ ions); gene is CA2 long bone are wider at metaphysis and diaphysis ("Erlenmeyer flask" appearance) dec neural foramina causes cranial nerve problems such as blindness, deafness, and facial paralysis grossly bones lack medullary canal; mx there is persistence of primary spongiosa causes myelophthisic anemia with extramedullary hematopoiesis treatment with bone marrow transplant to provide monocyte stem cells, which can form osteoclasts E. Waardenburg syndrome: abnormal PAX3; hearing loss, abnormal pigmentation, craniofacial abnormalities bone disorders A. osteoporosis 1. dec bone mass (osteopenia) despite normal bone mineralization; normal numbers of osteoclasts and osteoblasts; normal osteoid formation 2. x-ray shows radiolucency ; result is thin bone cortex and trabeculae that causes inc risk of fractures (bone pain and fractures with minimal trauma) 3. serum lab shows normal serum calcium, normal phosphorus, normal alkaline phosphatase 4. type I = postmenopausal (10-15 years after menopause) due to dec estrogen (which is due to decreased functioning of ovaries; treat with estrogen) which inc osteoclast activators IL-1 and IL-6

188. Metabolic

cytokines increase RANK and RANKL and decrease OPG vertebral fractures (acute back pain), kyphosis, decreased height Teriparatide, a portion of human parathyroid hormone, has recently been approved for the treatment of osteoporosis; it stimulates new bone formation 5. type II = senile osteoporosis men and women older than 70 causes vertebral wedge fractures and distal wrist (Colles') fractures 6. other causes include endocrine disorders (hyperthyroidism, Cushings syndrome, acromegaly) B. Pagets disease of bone; localized disorder of bone remodeling (note: not other Paget disease) 1. typically seen in older patients (1% of US population over 50) 2. may effect only one bone (monostotic) or multiple bone (polyostotic) 3. signs are bone pain and inc bone size; collagen breakdown products (eg hydroxyproline and hydroxylysine) are increased in amount in the serum and urine 4. complications fractures (multiple microfractures) cause bone pain high output cardiac failure because there are functional AV shunts early hearing loss due to narrowing of auditory foramen inc risk of malignancy (osteosarcoma) 5. etiology is unknown but may be viral (possibly slow virus infection by a paramyxovirus which induces secretion of IL-6) 6. aka osteitis deformans 7. stages are characterized by inc osteoblastic and osteoclastic activity (inc alkaline phosphatase dut to high bone turnover) osteolytic phase = osteoclastic resorption (giant osteoclasts with >100 nuclei are pathognomonic) mixed phase = both osteoblastic and osteoclastic activity (mosaic patterns of cement lines microscopically) late phase = sclerotic phase (osteoblastic activity >> osteoclastic resorption causes inc bone density) C. rickets etiology is dec vitamin D in children results in dec calcification, inc osteoid, and inc thickness of epiphyseal plates serum lab reveals low calcium, low phosphorous, high alkaline phosphatase D. osteomalacia (soft bones) etiology is dec vitamin D in adults; may be secondary to renal disease (eg. chronic renal failure with decreased 1-alpha hydroxylase) dec calcification of osteoid matrix (failure of bone mineralization); seams of uncalcified osteoid (inc osteoid) trabeculae normal size, but partially calcified soft bones, which cause deformity and fracture E. scurvy etiology is dec ascorbic acid (vitamin C) impaired collagen formation results in impaired osteoid matrix formation (dec osteoid with normal mineralization) F. hyperparathyroidism (primary or secondary) 1. aka Von Recklinghausens disease of bone (don't confused with the other Von Recklinghausen disease) 2. most common is secondary to renal disease (ie renal osteodystrophy) 3. multiple osteolytic lesions due to marked proliferation of osteoclasts ("tunneling"; "dissecting osteitis") and fibroblasts 4. osteitis fibrosa cystica = fibrous replacement of bone with focal nodular masses (brown tumors) masses of osteoclastic giant cells, fibroblasts, and collagen brown color due to hemorrhage and hemosiderin 5. if due to renal insufficiency may treat with calcitriol (to increase intestinal uptake of calcium)
causes 189. Other

these

non-neoplastic bone disorders

complete closed

A. fracture 1. terms

or incomplete (simple): overlying tissue is intact; compound: fracture site communicates with skin surface comminuted: bone is splintered; displaced: ends of bone at fracture site are not aligned

 stress 2. phases initial

fracture: slowly developing fracture due to increased physical activity

inflammatory phase (lasting a few days) phase (lasting a few weeks; formation of a cartilaginous callus) remodeling phase (which lasts for months to years) 3. types Colles fracture: MC wrist fracture; results from a fall onto outstretched hand; irregularity of lower end of radius with "dinner fork" deformity scaphoid (carpal navicular) fracture: most common carpal bone fractured; assume this fracture is there is tenderness in the anatomical snuff box clavicular fracture: most common long bone that is fractured in children; usually involves the middle third of the clavicle greenstick fracture: incomplete fracture involving the cortex of only one side of a bone nursemaid's elbow: radial head subluxation in child after being pulled or lifted by the hand B. congenital hip dislocation: varying displacement of the proximal femur from the acetabulum more often seen in females, firstborn children, and breech presentations C. avascular necrosis (osteonecrosis) note blood supply to head of femur (3 sources): retinacular vessels in capsule (main source); medullary vessels in femoral neck; via the ligamentum teres gross of femoral head: wedge-shaped yellow infarct causes are many, including trauma, steroids, embolism Legg-Calve-Perthes disease = avascular necrosis of femoral head in children (pain in groin that radiates to knee) Osgood-Schlatter's disease = avascular necrosis of anterior tibial tuberosity where patellar tendon inserts (intermittent swelling and pain below knee at tibial tuberosity) D. osteomyelitis 1. acute pyogenic site of infection varies with age (kids at metaphysis; adults at epiphysis and subchondral) signs include fever, chills, peripheral leukocytosis, throbbing bone pain (x-ray shows lytic bone surrounded by sclerosis) new osteoblastic periosteal bone = involucrum; trapped necrotic bone = sequestrum; localized abscess = Brodie's abscess most common cause is Staphylococcus aureus (but sickle cell is associated with Salmonella osteomyelitis; cat bites are associated with Pasteurella multocida; human bites are associated with anaerobes; foot puncture wound with pseudomonas; hip replacement with staph epidermidis) 2. tuberculous osteomyelitis tuberculosis (with caseous necrosis) of vertebrae is called Pott's disease 3. skeletal syphilis both syphilis (Treponema pallidum) and yaws (Treponema pertenue) can involve bone with congenital syphilis the spirochetes localize in active enchodral ossification (osteochondritis) and periosteum (periostitis) saber shins results from massive reactive periosteal bone deposition on the medial and anterior surfaces of the tibia bloody mucopurulent nasal discharge with saddle-nose deformity also generalized rash and V-shaped incisors (Hutchinson's teeth)
reparative 190. Bone

forming tumors

A. osteoma

is the skull and facial bones; appearance is circumscribed mass of dense sclerotic bone is Gardners syndrome (familial colonic adenomatous polyposis with multiple with multiple osteomas) B. osteoid osteoma location is cortex of metaphysis of femur, tibia, humerus severe pain characteristically at night due to excess production of prostaglandin E2 characteristically relieved by aspirin histology reveals central nidus of uncalcified osteoid with rim of sclerotic bone
association

location

C. osteoblastoma:

similar to osteoid osteoma, but larger (> 2cm), no surrounding sclerotic bone, arises in medulla of metaphysis (not cortex), lack of pain, no response to aspirin D. osteosarcoma aka osteogenic sarcoma (most common primary malignant tumor of bone) males age 10-20 (second peak occurs in the sixth decade, which is associated with Pagets disease of bone) childhood form associated with retinoblastoma; other associations include Paget's disease, fibrous dysplasia and osteochondromatosis location is the metaphysis of long bones signs include pain and swelling, inc alkaline phosphatase x-ray findings: Codmans triangle (lifting of periosteum by expanding tumor) and "sunburst" appearance aggressive malignancy with early hematogenous spread (lungs) histology reveals malignant anaplastic osteoblasts, numerous mitoses, and production of osteoid by tumor cells (which is diagnostic) expression of MDR1 gene product p-glycoprotein is associated with multidrug resistance
191. Cartilage

forming tumors A. osteochondroma most common benign bone neoplasm (considered to be a form of exostosis) associated with inactivation of the EXT gene in the growth plate chondrocytes location is cortex of metaphysis of long bones (lower end of femur or upper end of tibia) histology reveals mature bone with cap of hyaline cartilage B. chondroma diaphysial medulla (enchondromas) of small bones of hands and feet, and long bones, such as femur and humerus (not pelvis or ribs) histology reveals lobules of hyaline cartilage with few cells characteristic x-ray sign is O-ring sign (well-circumscribed oval lucency surrounded by thin rim of radiodense bone) solitary lesions have no risk of malignant transformation Olliers disease = multiple enchondromas (not hereditary) Maffucci's syndrome = multiple enchondromas (familial form, that is associated with multiple skin hemangiomas + inc risk chondrosarcoma C. chondroblastoma location is epiphyseal region, distal femur and proximal tibia or humerus histology: numerous cells, rare mitoses; cartilage and calcification in background of "chicken-wire" mineralization D. chondromyxoid fibroma: stellate and spindle cells surrounded by myxoid matrix E. chondrosarcoma (malignancy of cartilage) 1. location (dec frequency) = pelvic girdle, ribs, shoulder girdle, long bones (not distal extremities like enchondroma) 2. most cases are solitary, while multiple forms are associated with Olliers disease 3. histologic types conventional (hyaline and/or myxoid) clear cell: sheets of large malignant chondrocytes with clear cytoplasm, numerous osteoclast-type giant cells, intralesional reactive bone formation dedifferentiated: has second high-grade component of a poorly differentiated sarcoma mesenchymal: islands of well-differentiated hyaline cartilage surrounded by sheets of small round cells (can mimic Ewing sarcoma) and fibro-osseous tumors cortical defect extremely common (upto 50% of children older than 2 years of age) developmental defects (rather than true neoplasms) asymptomatic; detected incidentally with x-ray; usually undergo spontaneous resolution nonossifying fibroma: fibrous cortical defects that grow to 5 cm in size (usually detected at adolescence) B. fibrous dysplasia 1. monostotic (single lesion) form (the most common form)
A. fibrous

192. Fibrous

form without endocrine dysfunction form with endocrine dysfunction = McCure-Albright syndrome young girls with short stature, precocious puberty, and unilateral pigmented skin lesions (cafe-au-lait spots) somatic (not familial) mutation of GNAS gene that causes excess cAMP which leads to hyperthyroidism, pituitary adenomas secreting growth hormone, primary adrenal hyperplasia compare to dec cAMP mutation 4. histology of fibrous dysplasia reveals replacement of marrow by proliferating fibroblasts and haphazard arrangement of immature (woven) bony trabeculae ("Chinese letters") C. fibrosarcoma (herringbone pattern) and malignant fibrous histiocytoma (storiform pattern)
3. polyostotic 193. Miscellaneous A. aneurysmal

2. polyostotic

tumors bone cyst: composed of multiple blood filled spaces (not lined by endothelial cells) B. Ewings sarcoma 1. males age < 15; usually located in the diaphysis or metaphysis of the long bones (not the epiphysis) 2. cell of origin is a neuroectodermal cell that is positive for NSE 3. t(11;22) forms EWS-FLI1 fusion gene 4. histology reveals sheets of small round cells with cytoplasmic glycogen that are PAS positive 5. positive for Mic-2 (CD99) 6. reactive new bone formation causes concentric "onionskin" layering 7. responsive to chemotherapy 8. similar to another PNET = primitive neuroectodermal tumor: medulloblastoma (see the neuro notes) highly malignant infiltrative tumor with neuronal and glial markers (5 year survival is 75%) of children, but is very radiosensitive tumor cells are small with hyperchromatic nuclei and scant cytoplasm forming Homer-Wright (true) rosettes a clinicopathologic entity; that is, by definition is a PNET-like tumor occurring in the posterior fossa = medulloblastoma C. giant cell tumor (osteoclastoma) location is the epiphyseal end of long bones (about the knee) characteristic x-ray appearance is "soap bubble" appearance histology reveals numerous osteoclast-like multinucleated giant cells locally aggressive and many recur after curettage (10% metastasize) D. metastatic disease joint diseases A. osteoarthritis (degenerative joint disease) 1. chronic noninflammatory joint disease that is due to mechanical trauma ("wear and tear"), primarily weightbearing joints 2. degeneration of articular cartilage with subchondral new bone formation x-ray: loss of joint space associated with increased water in cartilage with loss of proteoglycans 3. eburnation = polished ivory appearance of articular surface 4. osteophyte formation (such as bony spur and joint mice) Heberdens nodes = osteophytes at DIP of fingers Bouchards nodes = osteophytes at PIP of fingers 5. seen in older patients who develop pain, stiffness, swelling, usually worse in evening (after use) and better with rest 6. crepitus is a characteristic grating sound (friction between adjacent exposed subchondral bone) B. rheumatoid arthritis 1. pathology nonsuppurative, proliferative (hyperplastic) synovitis (synovium proliferates and forms pannus with cartilage destruction) associated with rheumatoid factor, which is an autoantibody, mostly IgM, against the Fc portion of IgG (anti-IgG antibody) antibodies to citrulline-modified peptides (anti-cyclic citrullinated peptide [CCP] antibodies) have been recently shown to be present in many people with rheumatoid arthritis initiator may be a microbial agent (EBV is suspect)

194. Inflammatory

associated with HLA-DR4 painful, stiff joints (symptoms worse in morning; last > 1 hour) 4. symmetric involvement of small joints of hands and feet metacarpophalangeal (MCP) involvement causes ulnar deviation (classic sign); DIP joints are spared involvement of metatarsophalangeal (MTP) may form "hammer toe" "swan-neck" deformity 5. rheumatoid nodules may develop at pressure points (elbows) in skin; mx shows central fibrinoid necrosis surrounded by peripheral palisading epithelioid histiocytes 6. associated with systemic signs including fever, fatigue, pleuritis and pericarditis 7. variants a) juvenile idiopathic arthritis ( previously called juvenile rheumatoid arthritis) (1) general: <16 years old; joint aspiration: leukocytosis, inc protein, dec glucose, dec complement (2) subtypes (all may have fever, nodules, erythematous rashes, pericarditis, fatigue; RF usually negative) systemic acute febrile (Still's disease): high spiking fevers, evanescent salmon-colored rash, arthritis, hepatosplenomegaly polyarticular: multiple, symmetric inflamed joints; may have iridocyclitis oligoarticular (pauciarticular): chronic arthritis; 1/3rd may have iridocyclitis, which can cause blindness b) Feltys syndrome = rheumatoid arthritis, splenomegaly, neutropenia (inc #'s of large granular lymphocytes in peripheral blood) C. seronegative spondyloarthropathies (think "PAIR") 1. psoriasis (psoriatic arthritis) 2. ankylosing spondylitis (Marie-Strumpell disease) = low back pain and stiffness in young adult male ("bamboo" spine x-ray); most common extraskeletal manifestation is acute iritis 3. inflammatory bowel disease (enteropathic arthritis) 4. Reiter syndrome (males): now called reactive arthritis (Hans Reiter was a German physician who committed war crimes during World War II) non-gonococcal urethritis (or cervicitis), conjunctivitis, arthritis (seronegative spondyloarthropathy) associated with chlamydia (GU) infections and shigella, salmonella, yersinia (GI) infections D. suppurative arthritis hematogenous seeding of joints during bacteremia (with gonococcus, staph, strep or salmonella in sickle cell anemia) acute development of tender, red, swollen joint with restricted range of movement usually monoarticular involvement; cloudy synovial fluid (clots easily) with high neutrophil count Lyme disease (caused by the spirochete Borrelia burgdorferi)
3. swollen, 195. Metabolic

2. females,

joint disease (ochronosis) autosomal recessive disorder; degeneration of cartilage (occurs earlier than other classic arthritis and may cause juvenile osteoarthritis) dec homogentisic acid oxidase causes inc homogentisic acid black (radiopaque) collagen and cartilage urine is initially colorless, then darkens with exposure to air (infants: black discoloration of diapers) B. gout 1. precipitation of monosodium urate crystals (negatively birefringent needle-shaped crystals) associated with hyperuricemia negatively birefringent means the crystals are birefringent (two colors) only the colors are different than crystals that have positive birefringence 2. severe pain of joints (arthritis) and bursa (bursitis); asymmetric distribution of involvement 3. more common in men 4. attacks may be precipitated by large meal or alcohol 5. common site is MTP (metatarsophalangeal) joint of great toe (podagra) 6. formation of tophi (urate crystals in protein matrix) can occur outside of joints (external ear and Achilles tendon) 7. causes of hyperuricemia (secondary gout)
A. alkaptonuria

urate excretion due to chronic renal disease or certain drugs (thiazide diuretics competitively inhibit secretion of uric acid) b) leukemia/lymphoma with treatment cause cell necrosis, which inc release of nucleic acid and inc uric acid formation (also P. vera) c) Lesch-Nyhan syndrome (XR inheritance) dec HGPRT (hypoxanthine-guanine phosphoribosyltransferase); severe neurologic signs and symptoms including self-mutilation d) glucose-6-phosphatase deficiency 8. treatment for gout is allopurinol (inhibits xanthine oxidase), probenecid (uricosuric agent), colchicine (inhibitor of microtubule formation; useful in acute attacks to inhibit leukocytes), NSAIDs C. pseudogout (chondrocalcinosis) deposits of calcium pyrophosphate dihydrate crystals (short rhomboid shaped crystals) affects large joints, classically the knee (metatarsophalangeal joint is usually not affected)
196. Tumors

a) dec

of joints

A. ganglion

common cyst of tendon sheath or joint capsule (wrist is common location) from cystic or myxoid degeneration of connective tissue; cell wall does not have a true lining B. synovial cyst herniation of synovium through a joint capsule or massive enlargement of a bursa a synovial cyst of the popliteal space is called a Baker cyst C. villonodular synovitis pigmented villonodular synovitis (PVNS) giant tumor of tendon sheath (localized nodular tenosynovitis) D. synovial sarcoma fourth most common sarcoma; 3rd-5th decades; occur aroundlarge joints; most lower extremity (esp the knee) t(X;18) produces SYT-SSX1 (or SSX2) fusion genes biphasic histology: spindle cells/epithelial cells
results

small

HIGH-YIELD NOTES OF PATHOLOGY 2009-10 PART 5 SKIN

197. Normal A. epidermis 1. cells

produce keratin cells: found in lowest levels; epidermal stem cells (2) prickle (spinous) cells: found in middle layers; contain keratin and desmosomes (3) granular cells found in superficial layers contain numerous intracytoplasmic basophilic keratohyaline granules (non membrane-bound granules rich in histidine and cystine) b) melanocytes dendritic cells that originate from neural crest synthesize melanin (enzyme is tyrosinase) positive stains: dopa reaction; S100 (nonspecific); MART-1 (Melan-A; specific), HMB45 (specific; abnormal cells) c) Langerhans cells dendritic cells that process antigen contain Birbeck granules (racquet-shape) d) Merkel cells: attach to keratinocytes; contain distinctive membrane-bound, dense-core granules 2. layers stratum germinativum (basale): deepest layer; contains basal cells (the stem cells for other keratinocytes), melanocytes, Merkel cells stratum spinosum: contains prickle cells (polyhedral keratinocytes) and Langerhans cells (process antigens and have Birbeck granules) Malpighian layer = stratum germinativum + stratum spinosum stratum granulosum: contains granular keratinocytes (have keratohyaline granules) stratum lucidum: found only in palms and soles stratum corneum: contains anucleate keratinized cells and cornified cells B. basement zone 1. innermost portion of the basal keratinocytes: contain cytoplasmic tonofilaments; attach to the attachment plate of the hemidesmosome 2. plasma membrane of the basal keratinocytes 3. basal lamina lamina lucida: subdesmosomal dense plate; anchoring filaments; contains bullous pemphigoid antigen lamina densa: type IV collagen subbasal lamina densa zone: collagen rootlets; anchoring fibrils C. glands eccrine (merocrine) sweat glands: innervated by cholinergic fibers; secretory unit: dark cells, clear cells, myoepithelial cells apocrine sweat glands: innervated by adrenergic fibers; specialized locations: axilla, areola, perianal sebaceous glands: holocrine glands; secrete sebum into the neck of the hair follicle D. dermis papillary dermis: forms papillary papillae; contains capillary loops and Meissner's corpuscles (receptors for fine touch) reticular dermis: major portion of dermis; contains dense collagen bundles; Pacinian corpuscles (pressure receptors); Krause's end bulbs (cold and pressure receptors)
(1) basal 198. Terms A. clinical flat,

a) keratinocytes:

(macroscopic) terms non palpable lesion of different color than surrounding skin: <1cm = macule; >1cm = patch small elevated skin lesion: <1cm = papule; >1cm = plaque fluid-filled blister: <0.5cm = vesicle; >0.5cm = bulla

containing pus = pustule; itchy, elevated areas of skin due to dermal edema are wheals breaks in the skin (such as produced by deep scratching) = excoriations lichenification: thick rough skin with prominent skin markings, usually due to repeated rubbings B. pathologic (microscopic) terms acanthosis: hyperplasia of the entire epidermis acantholysis: loss of connections between keratinocytes hyperkeratosis: hyperplasia of the stratum corneum parakeratosis: retention of nuclei in the stratum corneum dyskeratosis: premature keratinization below the stratum granulosum papillomatosis: hyperplasia of the papillary dermis spongiosis: epidermal edema (as seen with sunburn) lentiginous: linear proliferation of melanocytes within the basal layer of the epidermis exocytosis: infiltration of epidermis by inflammatory or circulating blood cells
traumatic 199. Melanocytic A. abnormal

blister

lesions of the skin pigmentation 1. vitiligo acquired loss of melanocytes; depigmented white patches (symmetrical) unknown etiology (possibly autoimmune) koebnerization: lesions develop primarily at sites of repeated trauma associations: pernicious anemia, thyroid disease (especially Hashimoto's thyroiditis) 2. albinism: no pigment production by melanocytes a) ocular albinism: x-linked disorder limited to eyes b) oculocutaneous albinism: autosomal recessive disorder predisposes to actinic keratosis and skin cancers (basal and squamous cell carcinoma, malignant melanoma) subtypes: tyrosinase-negative albinism (abnormal conversion of tyrosine to DOPA) and tyrosinasepositive albinism (unknown defect) 3. freckle (ephelis): increased melanin pigment in basal keratinocytes of epidermis; fades without sun exposure 4. chloasma (melasma) brown patches on forehead and cheeks; worse with sun exposure associations: pregnancy (mask of pregnancy), menopause, and birth control pills 5. lentigo: pigmented macule due to melanocytic hyperplasia in epidermis lentigo simplex (young); slight elongation of rete ridges lentigo senilis (elderly) or solar lentigo; elongation of rete ridges ("liver spots") LEOPARD syndrome = lentigos, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness B. pigmented nevi 1. nevocellular nevus (common mole) appear in childhood (hamartomas) junctional nevus = nests of nevus cells at epidermal-dermal junction; no atypia is present intradermal (dermal) nevus = nevus cells in clusters within dermis compound nevus = nevus cells at epidermal-dermal junction and dermis 2. blue nevus = non nested spindle nevus cells located in mid to deep dermis and are highly pigmented with long thin "dendritic" processes 3. halo nevus = nevus surrounded by regular depigmented halo due to lymphocytic inflammation 4. Spitz nevus (juvenile melanoma) occurs in kids and is always benign mx shows large, plump and fusiform nevus cells that grow in bundles (spindle-shaped cells may be confused with malignant melanoma) 5. congenital nevus ("birth mark") large lesions (>1cm in "bathing suit" distribution) associated with increased risk of forming malignant melanoma mx shows nests of round nevus cells in the deep dermis into subcutaneous fat 6. dysplastic nevi (occur on both non-sun exposed and sun exposed skin) some cases are familial (dysplastic nevus syndrome) increased risk of forming malignant melanoma mx shows fusion of adjacent junctional nests + cytologic atypia

C. malignant

junctional dysplastic nevus; compound dysplastic nevus melanoma 1. etiology and clinical de novo or arise from melanocytes or nevus cells of pre-existing nevi clinical warning signs include enlargement of preexisting mole, itching or pain in mole, development of new pigmented lesion in adult, irregular colors or borders in nevus; think ABCD = asymmetry, border irregularity, color variation, diameter (large) increased incidence in patients with dysplastic nevi; also associated with blistering sunburns during childhood in fair-skinned persons associated gene abnormalities include CDKN2A (also seen with dysplastic nevus syndrome) and increases in RAS and PI-3K/AKT signaling (see below) treatment is surgery (wide local excision +/- regional node dissection often guided by sentinel node analysis) 2. growth phases a) initial phase is the radial growth phase (lateral growth within epidermis only = melanoma in-situ, no risk of metastasis) b) later phase is the vertical growth phase (1) growth into reticular dermis and beyond (metastasis occur) (2) prognosis depends upon thickness (depth) of lesion (most important prognostic indicator) (a) Breslow's measurement: measure granular cell layer to deepest tumor cell; breakpoints at 0.75, 1.5, and 3.0mm (b) Clark's levels I: intraepidermal ("in-situ") II: into papillary dermis III: filling papillary dermis IV: into reticular dermis V: into subcutaneous tissue 3. general histology melanocytic cells located high in the epidermis (pagetoid cells) lack of maturation of melanocytes at base of lesion; possible lymphocytic infiltrate cytologic atypia of melanocytes with presence of mitoses special stains: melanoma cells positive for S-100 and HMB-45 (the latter is specific for melanoma) 4. clinical types a) superficial spreading melanoma (the most common type) located on trunk and extremities prominent radial growth phase = melanoma cells scattered within epidermis (Pagetoid cells; "buckshot" appearance) b) nodular melanoma has a very short radial growth phase (mainly vertical growth phase) and has the poorest prognosis c) lentigo malignant melanoma located on sun-exposed skin in older patients, mean age of 70 years (mx will also show atrophic epidermis and invasion into dermis) preexisting lentigo maligna (Hutchinson freckle); mx: many atypical melanocytes in basal layer with atrophic epidermis and sun-damage dermis d) acral lentiginous melanoma is a less common type of melanoma found on palm, sole, or subungual areas of dark-skinned individuals

types:

200. Benign

skin tumors A. seborrheic keratosis (SK) "stuck-on", often pigmented, lesion of trunk and face (increased number with age) sudden development of large numbers (Leser-Trelat sign) may be associated with another malignancy mx shows hyperkeratosis with many keratin-filled cysts within epidermis (horn and pseudohorn cysts) B. acanthosis nigricans (dark pigmented skin) location: axilla, groin, neck, palms, soles forms: benign (80%) in children; malignant (20%) in adults (may be associated with visceral malignancy, eg gastric adenocarcinoma) histology: hyperkeratosis, papillomatosis, mild hyperpigmentation

C. acrochordons D. epidermal

are skin tags (fibroepithelial polyps); mx shows a large polyp lined by squamous epithelium (epithelial) inclusion cyst (epidermoid cyst) clinical name is "sebaceous cyst" but this is a misnomer (not sebaceous) keratin-filled cyst lined by stratified squamous epithelium having a granular cell layer if no granular cell layer and amorphous keratin (not laminated) = pilar cyst (trichilemmal cyst), which typically is found on scalp if adnexal structures present = dermoid cyst E. adnexal tumors 1. origin from hair: trichoepithelioma: proliferation of basaloid cells that form primitive structures resembling hair follicles trichilemmoma: localized proliferation of pale pink glassy cells that resemble the uppermost portion of the hair follicle (infundibulum) pilomatrixoma: has characteristic "shadow" ("ghost") cells 2. origin from sweat (eccrine) glands: eccrine poroma, eccrine spiradenoma, syringoma (eyelids; mx: multiple small ducts some having a comma-like shape) 3. origin from apocrine glands: cylindroma: location is scalp; mx shows islands of basaloid cells forming a "jigsaw" pattern; if multiple called "Turban" tumors hidradenoma papilliferum (vulva): composed of ducts lined by apocrine-type cells having characteristic decapitation secretion 4. origin from sebaceous glands: nevus sebaceous and sebaceous adenoma F. keratoacanthoma (KA) grows quickly over weeks and resolves (may be a form of squamous cell carcinoma that regresses) mx shows cup-shaped lesion with central keratin-filled "crater"
201. Premalignant A. actinic

and malignant skin tumors keratosis (AK) is a small scaly erythematous lesion due to sun exposure (may produce a "cutaneous horn") found on sun-exposed areas need to biopsy AK to rule out skin cancer dermis has solar degeneration of collagen (solar elastosis) while epidermis has atypia of squamous epidermal cells note that arsenic ingestion (well water) causes arsenical keratosis; "actinic" is caused by sun by definition B. Bowens disease = carcinoma in situ of skin (full thickness epithelial dysplasia but no invasion through basement membrane) C. squamous cell carcinoma most are caused by sun exposure and arise from actinic keratosis rare causes include chronic infection (sinus tracts and ulcers), extensive burns, or chemical carcinogens (arsenic); also seen with xeroderma pigmentosa tumors not sun-associated are more aggressive clinically (especially those associated with immunosuppression) histology reveals irregular groups of atypical squamous cells with intercellular bridges, abundant pink cytoplasm and keratin formation ("keratin pearls") D. basal cell carcinoma 1. most common type of skin cancer (but almost never metastasize) 2. sun-induced (ie actinic damage), therefore usual location is sun-exposed areas (face and neck) 3. central ulceration with peripheral pearly margins ("rodent ulcer") 4. mx shows groups of "basaloid" cells with peripheral palisading of cells and peritumoral clefting (between tumor and adjacent stroma) 5. variants of basal cell carcinomas: a) superficial basal cell (often multifocal); superficial means still attach to bottom of epidermis b) morphea-like (sclerosing) basal cell clinically resembles scar margins are difficult to determine (locally aggressive) marked fibrosis histologically (thin invasive groups of cells within marked fibrosis) c) pigmented basal cell clinically confused with melanoma E. Merkel cell carcinoma (neuroendocrine) small cells with little cytoplasm (similar to small cell carcinoma of lung) electron microscopy reveals neurosecretory granules

F. molecular 1. basal

genetics of skin caners cell carcinoma: basal cell nevus syndrome (Gorlin syndrome) rare AD syndrome, which is associated with mutations in tumor-suppressor gene PTCH PTCH codes for a receptor for the protein product of the sonic hedgehog gene (SHH) in the absence of SHH PTCH inactivates SMO and keeps it from activating downstream transcription factors mutations of PTCH signaling pathway are also seen in sporadic basal cell carcinoma 2. squamous cell carcinoma not associated with an inherited single gene defect high rate of mutations in p53 in actinic keratoses 3. melanoma familial syndromes main association is with deletion of p16INK4A, which leads to unrestricted phosphorylation of RB, release of E2F, and uncontrolled cell growth other genes: CDK4 and BRAF (the product being a component of the RAS/RAF/MAP kinase signal transduction pathway)

202. Other

tumors A. dermatofibroma mixture of fibroblast, collagen, capillaries, and histiocytes if lots of histiocytes = fibrous histiocytoma if lots of capillaries = sclerosing hemangioma B. dermatofibrosarcoma protuberans (DFSP) slowly growing, locally infiltrative (surgically needs wide excision) spindle cells in a storiform (cartwheel) pattern; extension into the subcutaneous fat produces a characteristic "honeycomb" pattern C. xanthoma yellow papules found eyelids (xanthelasma) or over tendons or joints that are associated with hypercholesterolemia focal dermal aggregates of lipid-laden histiocytes D. hemangioma strawberry hemangioma is found in children and regress spontaneously (no need for excision) cherry hemangioma is a small red papule E. pyogenic granuloma contains inflammatory cells and proliferating small blood vessels (proliferating endothelial cells) in edematous stroma F. mastocytosis (urticaria pigmentosa) has dermal proliferation of mast cells (cells stain with metachromatic toluidine blue stain) release of histamine and heparan causes itching (pruritus), flushing, and wheal formation with rubbing (dermatographism) positive Darier sign (a wheal forms when the skin lesion is rubbed) inflammatory dermatoses

203. Acute

A. urticaria

pruritic red wheals (dermal edema) that are also called hives (a type I hypersensitivity reaction) shows dermal edema with mild superficial perivascular mixed inflammation some cases are chronic (unknown cause, but 1/3rd are associated with circulating IgE receptor antibodies) B. acute eczematous dermatitis in general acute eczematous dermatitis are red, oozing, crusted lesions histology show spongiotic dermatitis (edema in intercellular spaces in epidermis = spongiosis) or chronic perivascular inflammation may be caused by atopic dermatitis, contact dermatitis, lichen simplex chronicus (leathery skin caused by chronic rubbing), or exfoliative dermatitis C. erythemas 1. erythema multiforme hypersensitivity reaction (usually to drugs, such as penicillin, sulfonamides, phenytoin, or infections) characteristic lesion is target lesion (but many different types of lesions are present, hence the name) severe form of disease is Stevens-Johnson syndrome (severe crusted hemorrhagic lesions involving eyes and oral cavity)
histology

raised

epidermal spongiosis and necrosis with dermal vasculitis and edema infectiosum: fifth disease; infection by parvovirus B19; "slapped cheek" appearance in kids 3. erythema (chronicum) migrans: rash (active red, flat border with central clearing) associated with Lyme disease 4. erythema marginatum: serpiginous, flat, nonscarring, painless rash associated with acute rheumatic fever 5. erythema nodosum and erythema induratum: types of panniculitis (see next)
2. erythema 204. Chronic

mx:

inflammatory dermatoses dermatitis classically involves areas with a high density of sebaceous glands may be due in part to the lipophilic yeast Malassezia furfur B. psoriasis red plaques covered by silver scales that are located on the extensor surfaces of elbows and knees, also scalp and sacrum scratching causes new lesions = Koebner phenomenon removing scale produces tiny bleeding points = Auspitz sign associated with rheumatoid arthritis-like lesions of fingers; nails can have deep, scattered pits with papules the etiology is unknown, but is associated with faster turn-over time of epidermal cells (3 days instead of normal 28 days) microscopy reveals parakeratosis, loss of granular cell layer, regular elongation of rete ridges, subcorneal microabscesses treatment is with topical steroids and ultraviolet irradiation (severe disease treated with methotrexate) C. lichen planus "pruritic purple polygonal papules and plaques" that are located on the flexor surfaces of extremities, oral lesions, and external genitalia scratching causes new lesions = Koebner phenomenon the etiology is unknown (occasionally drug reaction) slower rate of cellular proliferation causes increased retention of cells in epidermis causes increased keratin microscopy reveals lymphocytic inflammation at basal cell layer (band-like) "saw-tooth" appearance of rete ridges; Civatte bodies are dead keratinocytes (death due to apoptosis) D. SLE malar "butterfly" rash; mx reveals liquefactive degeneration of the basal layers of the epidermis IgG and complement are deposited at the dermal-epidermal junction; granular IF pattern
A. seborrheic

205. Vesiculobullous

skin diseases A. pemphigus vulgaris chronic disease (but may be fatal due to extensive skin involvement) flaccid bullae (large blisters) and erosions with large denuded areas pressure extends bulla = Nikolskys sign autoimmune disorder with IgG autoantibodies against desmoglein 3 of the epidermal intercellular cement substance (type II hypersensitivity reaction) IF reveals IgG deposits in a uniform intercellular "chicken-wire" appearance acantholytic intraepidermal bullae (acantholysis = destruction of intercellular attachments of keratinocytes) treatment includes steroids, methotrexate, gold salts B. bullous pemphigoid tense bullae of skin (mucosal lesions are rare) chronic recurring disorder that is self-limited (less severe than pemphigus vulgaris) autoantibodies against bullous pemphigoid antigen in hemidesmosomes IgG at epidermal basement membrane (type II hypersensitivity reaction with linear immunofluorescence) IF reveals linear deposits of IgG and C3 in the lamina lucida nonacantholytic subepidermal bullae with eosinophilic infiltrate in surrounding dermis Nikolskys sign is negative treatment is with steroids C. dermatitis herpetiformis (DH) chronic recurring lesions that are self-limited grouped erythematous extremely pruritic vesicles and bullae

 results

from formation of antibodies against gliadin, a protein found in the gluten fraction of wheat; cross-react with reticulin, a component of the anchoring fibrils of the epidermal basement membrane associated with gluten-sensitive enteropathy (celiac disease), and the skin lesions may improve with gluten-free diets) granular deposits of IgA at tips of dermal papillae with subepidermal vesicles (early lesions show microabscesses at tips of dermal papillae) necrotizing papillitis (dermal microabscesses with neutrophils and eosinophils at tips of dermal papillae)
206. Other

dermatoses bullosa 1. blisters that develop at sites of pressure, trauma, or rubbing (minor trauma); lesions heal normally, but the resultant scarring can be severe 2. histology: vesicle formation at varying levels of epidermis 3. antibodies to basal cells (epidermolytic (simple) form); mutations in genes coding for keratins 14 and 5 lamina lucida of basement membrane (junctional form) anchoring fibrils of basement membrane: dermolytic (dystrophic) form; mutations in gene that codes for type VII collagen B. porphyrias may have subepidermal vesicles with marked thickening of superficial dermal vessels C. acne acne vulgaris has formation of comedo (blackhead or whitehead) and may be related to propionibacterium acnes or androgens affects pilosebaceous apparatus; may treat with 13-cis-retinoic acid D. panniculitis 1. erythema nodosum most common form of panniculitis; inflammation of subcutaneous adipose tissue causes include idiopathic; infections: beta-hemolytic strep, TB, fungi, leprosy; drugs: sulfonamides; sarcoidosis, and inflammatory bowel disease appearance: multiple tender red nodules (anterior tibia) mx: vasculitis and inflammation (lymphocytes and histiocytes) of connective tissue septa between the lobules of the subcutaneous adipose tissue prognosis: heal in 3-4 weeks without scarring 2. lobular inflammation without vasculitis: Weber-Christian disease (relapsing febrile nodular nonsuppurative panniculitis) with vasculitis: erythema induratum (most patients have tuberculosis) E. ichthyosis: hyperkeratosis; fish-like scales; X-linked form has a deficiency of steroid sulfatase F. Darier's disease (keratosis follicularis) slowly progressive skin eruptions of crusted papules histology: acanthosis, hyperkeratosis, dyskeratosis, and suprabasal acantholysis G. benign familial pemphigus (Hailey-Hailey disease) localized eruption of vesicles; axilla and groin histology: acantholysis and vesicle formation (no immunoglobulin formation) H. pityriasis rosea presents with "Herald patch" followed by crops of small, pink, oval patches along flexural lines; Christmas-tree pattern I. rosacea is characterized by erythema and telangiectasis of central face J. rhinophyma has an enlarged nose ("W.C. Field's nose") with hyperplasia of nasal soft tissue K. pseudoxanthoma elasticum abnormal elastic fibers; soft yellow-orange plaques of neck, axilla, groin, eye ("angioid streaks") histology: accumulation of abnormal elastic fibers in dermis
A. epidermolysis

207. Bacterial A. viral

and viral skin infections

1. verruca

vulgaris (common wart) is due to HPV (human papillomavirus): several types of HPV, including types 2 and 4 microscopy reveals squamous papilloma (papillomatosis) with koilocytes and prominent granular cell layer of epidermis (keratohyaline granules)

warts (hyperkeratotic lesions on the soles similar to a callus) are associated with HPV type 1 plana (found on the face) are associated with HPV type 3 2. molluscum contagiosum (DNA poxvirus) gross lesions are small discrete dome-shaped papules (found in perigenital and perianal areas in adults; may be on face in kids) microscopically reveal epidermal cells with intracytoplasmic inclusions (molluscum bodies) 3. herpes simplex oral lesions are due to herpes simplex type 1, while genital lesions (clear vesicles on red base) are due to herpes simplex type 2 mx shows intraepidermal vesicles, giant cells, and Cowdry A inclusions (seen with Tzanck prep, which is a smear from opened skin vesicle) 4. chickenpox is due to varicella-zoster virus child with recurrent crops of skin lesions every 3-5 days (no rx necessary in healthy kids because disease is self-limited) skin lesions include macules, papules, vesicles ("dew drops on a rose petal"), pustules, and scabs all present at same time microscopy reveals intraepidermal vesicle with giant cells and Cowdry A intranuclear inclusions (similar to herpes simplex) 5. shingles is due to varicella-zoster virus in adults cause painful eruptions along dermatomes corresponding to affected dorsal root ganglia virus remain latent for years in dorsal root ganglia 6. roseola infantum (exanthem subitum): caused by human herpesvirus 6; infant with very high fever that resolves with generalized rash of rose-pink macules and papules 7. smallpox caused by variola virus; eliminated in 1980, but now possible use as bioterrorist weapon incubation: 12-14 days; highly contagious during first week of illness sx: high fever, fatigue, headache, rash (begins in 2-3 days; develops pus-filled lesions that crust into scabs; feel like "BB pellets" in the skin) fatal in perhaps 30% of cases B. bacterial 1. impetigo is due to superficial epidermal infection with Staphylococcus aureus (gram-positive cocci in clusters) or Streptococcus pyogenes (group A strep) pustules (blisters filled with pus) found on the face of children that can rupture to form thick yellow (honeycolored) crust neonatal impetigo is due to staph producing epidermolytic toxin that leads to bullae formation and denuded skin ("scalded skin syndrome") 2. hidradenitis suppurativa is due to staphylococcal (staph aureus) infection of apocrine glands of axilla and anogenital region pt presents with painful lump in axilla draining purulent material; rx is incise and drain (I&D) the abscess in contrast, miliaria (heat rash or prickly heat) involves eccrine glands and is associated with excess sweating and obstruction of these eccrine glands 3. furuncle: a boil or pimple; carbuncle: an infection of the deep hair follicle that develops subcutaneous extension 4. erysipelas is due to dermal streptococci infection of the face or scalp sx: rapidly spreading, erythematous swelling that usually begins on face ("butterfly" distribution) characteristically there is a sharp demarcation between affected and unaffected skin; due to degradation of hyaluronic acid in ground substance in contrast, cellulitis is deeper infection of the subcutaneous tissue; usual organism is streptococcus pyogenesis 5. Borrelia burgdorferi (spread by ixodid ticks and causes Lyme disease) first stage = erythema chronicum migrans of skin: active red, flat border with central clearing second stage (weeks to months) = cardiac (hear block, heart failure, carditis) or neurologic disease (meningitis, cranial neuritis, or radiculoneuritis) third stage (years) = ill-defined arthritis or neurologic disease 6. syphilis is due to Treponema pallidum 7. anthrax is due to Bacillus anthracis (a spore-forming gram-positive bacillus) associated with industries involving animal products (or biological warfare); may form "malignant pustule"
verruca

plantar

reveals severe acute necrotizing hemorrhagic inflammation secondary to vasculitis grow colonies of bacteria that grossly are tangled having a "medusae head" appearance; gram stains reveal parallel chains of boxcar-shaped gram-positive organisms 8. Mandura foot: multiple draining sinuses; may have yellow flecks grossly; may be due to nocardia (grampositive filamentous rod; partially acid-fast); mx shows chronic suppurative inflammation
cultures 208. Skin

histology

fungi and parasites

A. fungi

mycoses to outermost skin and hair hyper or hypopigmented lesions of trunk KOH prep reveals long septate hyphae that fluorescence under Woods light hyphae ("spaghetti and meatball") can be seen in tissue sections (possibly with routine H&E stains or better with fungal stains) b) tinea (pityriasis) versicolor is caused by Malassezia globosa or Malassezia furfur, which are yeast rather than dermatophytes (usually are not pruritic) c) tinea (ringworm): infection of the stratum corneum: primarily by dermatophytes Microsporum (eg microsporum canis) has macroconidia that are spindled with rough thick wall, few microconidia present Trichophyton (eg trichophyton rubrum) has few smooth wall, cigar shape macroconidia, many microconidia present Epidermophyton has macroconidia that are club-shape, thin smooth wall (microconidia) clinically called tinea ("ringworm"): scalp infection is tinea capitis, while infection of feet ("athlete's foot") is tinea pedis, infection of groin ("jock itch") is tinea cruris, and infection of trunk is tinea corporis sx: red pruritic annular skin lesions with central clearing 2. subcutaneous mycoses a) dermis and subcutaneous tissue b) sporothrix schenckii (dimorphic fungus) cause sporotrichosis round or cigar-shaped yeast (may form asteroid body in tissue) inoculation from thorns and splinters, therefore individuals at risk are gardeners (rose growers) c) chromoblastomycosis causes verrucous (warty, cauliflower-like) lesion (mx see brown pigmented organisms "copper pennies") B. parasites 1. scabies cause is itch mite Sarcoptes scabiei serpiginous burrows causing pruritus variant is Norwegian scabies: immunosuppressed patients; numerous mites 2. leishmania: amastigotes are 2-5 microns in size with bar-shaped kinetoplasts a) vector is the sandfly (phlebotomus) b) clinical types L. tropica: cutaneous (oriental sore, Baghdad boil); itchy papule that becomes an expanding ulcer L. braziliensis: mucocutaneous L. donovani: kala-azar ("black sickness"; due to pigmentation of the skin): deep visceral; parasites in macrophages (increased size liver, spleen, lymph nodes); sx: fever, weight loss, pancytopenia 3. filaria: onchocerca volvulus vector is simulian (black fly); need running water for breeding (rivers) microfilaria migrate to eyes: "river blindness"
a) limited

1. superficial

BREAST
209. Normal/developmental A. anatomy/histology ducts

(basal layer has myoepithelial cells and does not proliferate) and stroma (fibrous and adipose tissue) terminal duct lobular unit (females only): terminal ducts and lobules (not fully developed until pregnancy when secretory acini are formed)

B. life

cycle changes female breast and male breast: large duct system ending in terminal ducts with minimal to no lobule formation 2. adolescent breast: large and intermediate size ducts; no lobules 3. adult female a) non pregnant (1) prior to menopause: cycle changes (a) follicular phase: due to estrogen; ductal cells proliferate; terminal lobular units are inactive (b) luteal phase: due to progesterone proliferation of terminal ducts; mitoses present basal epithelial cells are vacuolated stroma cells proliferate; increased stromal edema (c) menstruation (dec estrogen and progesterone) desquamation of epithelial cells (apoptosis) dec stromal edema; dec size of ducts and lobules (2) after menopause: absent terminal duct lobular units; dec fibrous tissue (mainly fat) b) pregnant (lactating breast) terminal ductules within the lobules proliferate and enlarge form secretory acini, which consist of cuboidal alveolar cells with cytoplasmic vacuoles C. developmental disorders mammary hypoplasia: ipsilateral with Becker's nevus; Turner syndrome; congenital adrenal hyperplasia acquired mammary hypoplasia: radiation and excision of breast tissue supernumerary nipples and breast: persistence of epidermal thickening along the milk line (due to failure of the milk line to involute) congenital inversion of the nipple: difficulty in nursing; mistaken for nipple retraction accessory axillary breast tissue: misidentified as lymph nodes; source of tumors
1. prepuberal 210. Clinical

presentations A. symptoms 1. pain (mastalgia or mastodynia) most common breast symptom diffuse cyclic pain has no pathologic correlate noncyclic pain is usually associated with focal disease 2. discrete palpable masses 3. nipple discharge milky discharge (galactorrhea): increased prolactin (pituitary adenoma) blood discharge: usually benign lesions (nipple papillomas) B. mammography densities: invasive carcinoma, fibroadenomas, cysts (not ductal carcinoma in situ; DCIS) calcifications: associated with secretory material, necrotic debris, hyalinized stroma; DCIS is the most common malignancy associated with calcification
acute

211. Inflammations

mastitis is due to bacterial infection (staph or strep) that is related to nursing mastitis has squamous metaplasia of lactiferous ducts with keratin debris in lumen (presents as painful red subareolar mass in smoker) plasma cell mastitis (mammary duct ectasia) has dilated ducts filled with granular, necrotic, acidophilic debris (cheesy nipple discharge) fat necrosis is uncommon but results from trauma (possibly running); mx reveals fat necrosis with foreign body reaction lymphocytic mastopathy (sclerosing lymphocytic lobulitis): most common in women with type I DM or autoimmune thyroid disease leaking silicone implant could histologically reveal granulomatous reaction with multinucleated macrophages
periductal 212. Benign

A. nonproliferative

epithelial lesions breast changes (fibrocystic changes)

common (so common that fibrocystic change is not "fibrocystic disease") typically are bilateral and may vary with menstrual cycle or regress with pregnancy sx: cyclic pain, tenderness, enlargement ("lumpiness"); sx may improve with reduction in dietary caffeine, salt, fat, or dairy products 3. simple changes (due to hormonal imbalance with excess estrogens) fibrosis with cysts, which may appear blue grossly (blue dome cyst) epithelial cells may form apical snouts (process is called apocrine metaplasia) B. proliferative breast disease without atypia 1. epithelial hyperplasia: presence of more than two cell layers (hyperplasia is moderate to florid if more than four cell layers) 2. sclerosing adenosis florid proliferation of small ductal structures in fibrous stroma (ducts have two cell layers including myoepithelial cells) easily confused with cancer, but from low-power has a nodular pattern (cancer is stellate) 3. complex sclerosing lesion (radial scar): steallate lesions with central nidus of entrapped glands in hyalinized stroma 4. papillomas (intraductal papilloma) usually near nipple (subareolar papilloma), cause nipple discharge and bleeding mx shows papillary structures lined by a layer of epithelial and myoepithelial cells 5. juvenile papillomatosis ("Swiss cheese" disease) distinct form of ductal hyperplasia usually seen in young individuals presents as localized multinodular masses simulating fibroadenoma C. proliferative breast disease with atypia: atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) D. clinical significance: epithelial hyperplasia may be associated risk of carcinoma (note: family history of breast cancer increases risk in all categories) types with no inc risk = pure fibrosis, cystic changes, apocrine metaplasia, mild hyperplasia (<4 cells thick) slight inc risk (1.5-2 times) = sclerosing adenosis, moderate to florid epithelial hyperplasia (>4 cells thick) significant inc risk (5 times) = atypical hyperplasia
2. changes 213. Carcinoma

1. very

of the breast and epidemiology 1. risk factors inc age (greatest risk factor) length of reproductive life (ie, early menarche or late menopause) parity (inc risk with nulliparity) and age at first pregnancy, that is, after age 30 inc estrogens: associated with obesity (synthesis of estrogen in fat depots) or exogenous estrogens (no increased risk with usual birth control pills) 2. signs and symptoms most common location is the upper outer quadrant tumors may have calcification, which can be seen with mammography nipple retraction (due to tumor invading into the main excretory ducts) B. etiology and pathogenesis 1. hereditary breast cancer genetic predisposition (other than age, greatest risk factor is positive family history), examples are abnormalities of BRCA1 and BRCA2 2. sporadic breast cancer: major risk factors are related to hormone exposure; majority occur in postmenopausal women and overexpress estrogen receptors 3. mechanisms of carcinogenesis C. prognostic factors 1. major prognostic factors invasion versus in situ disease metastases (axillary lymph node status is the most important factor for invasive disease) tumor size inflammatory carcinoma = marked infiltration of dermal lymphatics (not true inflammatory response), which is a very bad prognosis edema and thickening of overlying skin (called peau dorange because it looks somewhat like an orange)
A. incidence

 fixation 2. minor

to chest wall or ulceration prognostic factors histologic type and histologic grade (better histologic types include tubular, colloid, medullary, lobular, and papillary) status of hormone receptors (estrogen and progesterone): estrogen receptor-positive tumors may regress with anti-estrogen therapy (such as tamoxifen, which is a weak estrogen agonist) lymphovascular invasion proliferation rate of tumor (high proliferation rates are associated with worse prognosis) oncogene amplification, such as c-erb B2 (Her2/neu), which is associated with worse prognosis presence of cathepsin D, which is a proteolytic enzyme associated with metastasis of breast carcinoma

214. Classification A. general

are divided into in situ carcinomas and invasive carcinomas the descriptive terms "ductal" and "lobular" are still used, breast cancers are thought to originate from the terminal duct lobular unit B. carcinoma in situ 1. ductal carcinoma in situ (DCIS) cells look monotonous subtypes: comedocarcinoma (central necrosis), solid, cribriform, papillary, micropapillary 2. Pagets disease clinical see dermatitis of nipple invasion of epidermis by individual large tumor cells with clear halo (positive for mucin) underlying carcinoma always present (invasive ductal carcinoma or DCIS) 3. lobular carcinoma in situ (LCIS) lobular carcinoma in situ microscopically reveals proliferation of bland cells that fill and distend terminal ducts and lobules may be multifocal in one breast or bilateral LCIS is a marker lesion of patients who are at high risk for developing an invasive mammary carcinoma (ductal NOS, lobular, or ductal variants) C. invasive (infiltrating) carcinoma 1. invasive carcinoma, no special type (ductal carcinoma) a) general gross reveals stellate with chalky streaks (calcification) fibrous stromal reaction (desmoplasia) = scirrhous carcinoma b) newer classification "luminal A": (largest group) ER positive and HER2/neu negative; slow growing, respond well to hormonal rx "luminal B":ER positive, higher grade, higher proliferative rate, overexpressess HER2/neu (triple positive); more likely to have lymph node mets "normal breast-like": well-differentiated ER-positive and HER2/neu-negative; most similar to normal breast tissue "basal-like": absence of ER, PR, and HER2/neu but express markers typical of myoepithelial cells (one of group of triple-negative carcinomas) "HER2 positive": ER-negative with overexpression of HER2/neu; usually poorly-differentiated with high frequency of brain mets note: Herceptin is a monoclonal antibody specific to HER2/neu 2. invasive lobular carcinoma associated with bilateral disease infiltrating lobular carcinoma shows single file infiltration ("Indian-filing") or around ducts ("target" or "bulls eye" pattern) 3. medullary carcinoma (not related to medullary carcinoma of the thyroid) better prognosis than ductal carcinoma microscopically see sheets of undifferentiated cells with lymphocyte at margin of tumor especially associated with mutations of BRCA1 gene; have a basal-like gene expression 4. mucinous (colloid) carcinoma
although

carcinomas

prognosis than ductal carcinoma mucinous carcinoma, the histology reveals malignant cells in lakes of mucin 5. tubular carcinoma best prognosis of breast cancers well-differentiated carcinoma that microscopically shows pointed or comma-shaped small glands 6. invasive papillary carcinoma 7. metaplastic carcinoma
aka 215. Other

better

tumors tumors 1. fibroadenoma most common benign breast tumor; typically occurs in the upper outer quadrant of the breast in women between the ages of 20 and 35 gross reveals firm rubbery nodule (sphere), well-circumscribed with uniform tan color; estrogen-sensitive, frequently enlarge during pregnancy microscopic reveals irregular benign ducts in loose stroma (no inc # of stromal cells or mitoses) 2. phyllodes tumor old name is cystosarcoma phyllodes (phyllodes is Greek for leaf like; gross appearance has bulbous protrusions) histology similar to fibroadenoma but inc stromal cellularity (benign phyllodes tumor has few mitoses; malignant phyllodes tumor has many mitoses) recurrence is common; rx is excision or mastectomy (lymph node dissection is not necessary) B. lactating adenoma: seen in pregnant female microscopic reveals lots of benign glands; don't misdiagnose as malignant
A. stromal

216. Male

breast

A. gynecomastia

of male breast may be seen with Klinefelter's syndrome, testicular feminization, testicular tumors (such as Leydig cell tumor), inc sensitivity to estrogen (such as with cirrhosis), or at puberty (could be normal finding) or obesity microscopy reveals dense hyaline collagenous connective tissue around ducts which may have hyperplasia of the ductal epithelial cells B. carcinoma risk factors and pathology of male breast cancer is similar to breast cancer in women gynecomastia does not appear to be a risk factor associated with BRCA2 gene in familial cases FEMALE
217. Normal A. embryology 1. internal

enlargement

genitalia

a) gonads

gonads: develop from gonadal ridge covering epithelium: forms primitive sex cords which form medullary sex cords male: form seminiferous tubules females: degenerate; secondary sex (cortical) cords form follicle cells (3) primordial sex (germ) cells develop (ie derived from) wall of yolk sac in male form testis; in female form ovary b) mesonephros (1) tubules (a) male: regresses forming appendix epididymis and paradidymis (b) female: regresses (forms vestigial structures) epoophoron: cranial group of tubules; location is broad ligament above ovary paroophoron: caudal group of tubules; location is broad ligament beside ovary
(2) coelomic

(1) indifferent

ducts = Wolffian ducts epididymis, vas deferens, seminal vesicles female: regresses forming Gartner's duct (abnormality = Gartner's duct cyst of vagina or mesonephric cysts of cervix or vulva) c) paramesonephric ducts = Mullerian ducts (lateral and parallel to Wolffian ducts) (1) male: regresses (appendix testes) (2) female: forms fallopian tubes, uterus, hydatid of Morgagni (3) developmental abnormalities of uterus uterine agenesis = abnormal development of paired paramesonephric (Mullerian) ducts double uterus = abnormal development of inferior portion of Mullerian ducts bicornuate uterus (may cause infertility) = abnormal development of superior portion of Mullerian ducts (paramesonephric ducts) bicornuate uterus with rudimentary horn = abnormal development of Mullerian ducts (paramesonephric ducts) d) metanephros (mesoderm) metanephric diverticulum (uteric bud): outgrowth of mesonephric duct forms ureter, pelvis, calyces, collecting tubules metanephric mass (mesoderm): from caudal portion of nephrogenic cord; nephron 2. external genitalia genital tubercle: develops at cranial end of cloacal membrane during fourth week gestation; males forms penis; females forms clitoris genital swellings (labioscrotal swellings): male forms scrotum; female forms labia majora urogenital sinus: both sexes forms urinary bladder and urethra; male forms prostate; female forms vagina B. histology 1. ovary a) medulla b) cortex (1) surface epithelial cells: may form epithelial neoplasms (2) stromal cells: one type are hilar cells, similar to interstitial cells of testes (Leydig cells); may produce steroids (androgens and estrogens) (3) follicles (a) primordial follicles: oocyte (ovum) arrested in prophase I of meiosis I; follicular cells surround oocyte (b) developing follicles i. primary follicle i) not dependent upon FSH; surrounded by zona pellucida ii) types: unilaminar or multilaminar several layers of follicular cells = granulosa cells surrounded by two layers of stromal cells: inner = theca interna; outer = theca externa ii. secondary follicle liquor follicule accumulates in intercellular spaces between granulosa cells dependent upon FSH iii. Graafian follicle oocyte found on mound of granulosa cells (cumulus oophorus) granulosa cells (may form Call-Exner bodies) theca interna theca externa iv. ovulation: forms corpus hemorrhagicum; Mittelschmerz = pain associated with ovulation (due to peritoneal irritation by blood from the site of the ruptured follicle) v. luteal phase: corpus luteum has luteinized granulosa cells and luteinized theca cells vi. no pregnancy: corpus luteum atrophies (luteolysis) vii. corpus albicans: remnants of corpus luteum form scar 2. fallopian tubes: infundibulum (fimbriated end); ampulla (most common site of fertilization); isthmus; intramural portion 3. uterus a) endometrium
male:

(2) mesonephric

= functional layer = basal layer (3) blood supply: endometrial arteries spiral arteries: long and coiled; supply superficial two-thirds of endometrium (stratum functionale) basilar arteries: long and straight; supply deep one-third (stratum basale) (4) menstrual cycle (histology) (a) menses = days 1-4: foci of necrosis; crumbling glands; condensed stroma; inflammation (neutrophils are present, but no plasma cells) (b) proliferative phase = days 5-14: straight glands; many mitoses; stratification of glandular epithelium (c) ovulation = day 15 (d) secretory phase = days 15-28 (length is more constant than proliferative phase) early secretory: glandular vacuoles; subnuclear vacuoles = post-ovulatory days 2-3 late secretory: glandular secretions; stroma has edematous with decidual changes (abundant eosinophilic cytoplasm) b) uterine cervix transition zone = between ectocervix (stratified squamous epithelium) and endocervix (columnar epithelium and mucus-secreting glands) transformation zone = zone of squamous metaplasia 4. vaginal mucosa a) types of cells superficial squamous cells (SCC): mature with estrogen stimulation intermediate squamous cells (ISC): mature with progesterone stimulation parabasal cells (PBC): absence of estrogen and progesterone stimulation b) maturation index normal = 70% SCC, 30% ISC, 0% PBC (endocervical cells should be present in normal adequate PAP smear) increased SCC may be due to increased unopposed estrogen increased ISC may be seen with pregnancy or prepuberty increased PBC = atrophic smears in postmenopausal women (may need to repeat PAP after treatment with estrogen) 5. pregnancy: placenta: has cytotrophoblasts, syncytiotrophoblasts; decidual layer C. physiology 1. ovarian cycle: dependent on developing follicles a) follicular phase due to dominant follicle (1) primary follicle: not dependent on FSH (2) secondary follicle: dependent on FSH (3) Graafian follicle granulosa cells secrete: estrogen (majority of estrogen in follicular fluid); inhibin, folliostatin, activin regulate FSH secretion theca interna secretes estrogen (primary source circulating estrogen) and testosterone (granulosa cells convert it to estradiol) theca externa b) luteal phase is due to presence of corpus luteum; luteinized granulosa cells: decreased secretion of estradiol; increased secretion of progesterone c) no pregnancy: corpus luteum atrophies (luteolysis) 2. endometrium a) menstrual cycle = uterine cycle (only upper two-thirds of endometrium cycles) (1) menses = days 1-4 first day on menses = first day of cycle disintegration of functionalis average blood loss is 30ml vasospasm due to local release of prostaglandins (2) proliferative phase = days 5-14 corresponds to follicular phase of ovary
(2) basalis

(1) functionalis

by estrogen from ovarian follicle (estrogen levels peak around day 12, about 2 days prior to ovulation) endometrial glands proliferate (3) ovulation = day 15; indicators of ovulation: biopsy with secretory endometrium (most reliable); post-ovulatory day (POD) 2-3 see subnuclear vacuoles in endometrial cells thick, cellular cervical mucus that does not fern (progesterone causes thick mucus; just prior to ovulation mucus is thin due to estrogen) rise in basal body temperature (4) secretory phase = days 15-28 (length is more constant than proliferative phase) corresponds to luteal phase of ovary influence by progesterone from granulsa cells of corpus luteum (progesterone levels peak around day 21) 3. hormone levels review a) follicular phase (proliferative endometrium) (1) early proliferative FSH and LH: slow increase due to decreased inhibition by estrogen and progesterone FSH rise will induce maturation of ovarian follicles; LH will stimulate estrogen release from theca interna estrogen and progesterone: low due to luteolysis of corpus luteum (2) mid proliferative FSH and LH: both decreased due to feedback inhibition by estrogen estrogen: markedly increased from theca interna; with time will become stimulatory instead of inhibitory to LH progesterone: low (3) late proliferative into ovulation at midcycle FSH: increased (small peak due to decreased estrogen levels); induces LH receptors on granulosa cells LH: increased (large peak); stimulates primary oocytes to complete meiosis I; causes ovulation estrogen: decreased progesterone: low but starts to increase b) luteal phase (secretory endometrium) (1) early secretory FSH and LH: both decreased due to feedback inhibition by estrogen and progesterone LH: decrease causes corpus luteum to involute estrogen: increased from corpus luteum progesterone: markedly increased (2) late secretory FSH and LH: both start to increase due to decreased inhibition of estrogen and progesterone estrogen and progesterone: both decreased from death of corpus luteum (luteolysis) c) if no pregnancy: decreased corpus luteum decreases estrogen, progesterone, inhibin --> increases GnRH, which increases FSH and LH 4. uterine cervix a) mucosa: no cyclic desquamation b) cervical mucus (1) effects of estrogen makes mucus thinner and more alkaline; promotes survival and transport of sperm thinnest at time of ovulation dries in arborizing, fern-like pattern elasticity = spinnbarkeit; greatest at ovulation (2) progesterone: makes mucus thick, tenacious, cellular; no fern pattern (sort of indicates that ovulation has occurred) 5. vaginal mucosa: estrogen increases glycogen
218. Infections

influenced

A. normal:

vagina contains a mixed bacterial flora in an acidic (pH 3.5-4.5) environment due to lactic acid-producing lactobacilli B. lower genital tract only 1. herpes simplex virus type 2 clinical: clear vesicles on red (erythematous) base Tzanck smear reveals intranuclear inclusions (Cowdry A bodies) and giant cells with ground glass nuclei transmission to the newborn during delivery is a feared complication that may be fatal to the infant 2. candida (the most common form of vaginitis) produces thick white vaginal discharge ("cottage-cheese") with pruritus; mx shows spores and pseudohyphae 3. trichomoniasis is due to Trichomonas vaginalis causes severe vaginal itching with dysuria and a thick, yellow-gray discharge; gross reveals red "strawberry" vaginal mucosa PAP stain reveals pear shaped, eccentric nucleus, red granules (wet prep shows large, pear-shaped motile organism with single flagellum) infection is often associated with loss of acid-producing Doderlein bacilli 4. Mycoplasma species (M. hominis, M. genitalium, U. urealyticum) cause some cases of vaginitis and also cause spontaneous abortions 5. bacterial vaginosis most common cause of vaginal discharge clinicallly may have "fishy" smell replacement of normal vaginal flora (lactobacillus sp) by overgrowth of polymicrobe group that includes Gardnerella vaginallis (pleomorphic gram variable coccobacillus) lose normal acidic vaginal environment presence of clue cells (squamous epithelial cells whose borders are obscured by bacteria and appear fuzzy) gram stain: squamous epithelial cells covered by small gram variable rods C. lower and upper genital tract 1. gonorrhea is due to N. gonorrhoeae gram-negative intracellular diplococci (culture on Thayer-Martin media); oxidase-positive and ferment glucose, but not maltose or sucrose also causes PID (pelvic inflammatory disease), characterized by adnexal tenderness (acute salpingitis: neutrophils in fallopian tubes) with cervical pain (motion of cervix produces pain; "chandelier sign" is cervical motion tenderness makes pt "jump for the chandelier") Fitz-Hugh-Curtis syndrome is perihepatic inflammation following PID; pt with recent PID presents with RUQ abdominal pain 2. Chlamydia causes lymphogranuloma venereum due to C. trachomatis L1, L2, or L3 enlarged groin lymph nodes and painful genital ulcers (positive complement fixation test = Frei test) drains to perirectal nodes and produces scarring and rectal strictures classic clinical is the double genitocrural fold, or "groove sign", a depression between groups of inflamed nodes C. trachomatis is most common STD in US and can produce PID (subacute, often undiagnosed) D. other 1. syphilis is due to Treponema pallidum primary syphilis causes painless firm genital ulcer (hard chancre) secondary syphilis has local or generalized rash tertiary syphilis: condyloma lata may occur in moist areas such as anus, vagina, axilla positive VDRL, FTA-ABS, and treponemes on dark-field examination rx with penicillin (Jarisch-Herxheimer reaction = fever and flulike symptoms upon penicillin rx in pt with syphilis) 2. chancroid (the "third venereal disease") is due to Haemophilus ducreyi (gram negative coccobacillus; "school of fish" appearance) which produces a painful "soft" chancre and regional lymphadenopathy 3. granuloma inguinale is due to Calymmatobacterium donovani (Calymmatobacterium granulomatis) multiple cutaneous nodules in genital area with superficial ulcers; lymph nodes not involved (therefore no strictures) mx: combined stellate suppurative (microabscesses) and granulomatous inflammation (similar to cat-scratch fever)

 histiocytes 219. Vulva A. non-neoplastic

may be present with intracytoplasmic Donovan bodies

glands (analogous to male bulbourethral glands): lateral wall of vestibule; obstruction can from a cyst, lined by transitional epithelium vulvar vestibulitis: chronic recurrent inflammation of the mucosal and vestibular glands of the vulvar; causes pain (vulvodynia) leukoplakia = clinical white patch; may be caused by vitiligo (loss of pigment in the epidermis); lichen sclerosis, epithelial hyperplasia and hyperkeratosis, and epidermal atypia or dysplasia (which may also produce erythroplakia or clinical red patch) lichen sclerosis (chronic atrophic vulvitis) refers to atrophy of epidermis with sclerosis (fibrosis) of upper dermis (seen in older females) lichen simplex chronicus (squamous hyperplasia, hyperplastic dystrophy) may produce leukoplakia clinically (need biopsy to rule out neoplasia) B. neoplasms 1. papillary hidradenoma is a benign adnexal skin tumor most common benign tumor of vulva (originates from apocrine sweat glands) mx: multiple finger-like projections formed by tubular ducts that are lined underneath by a flattened layer of myoepithelial cells same histologic appearance as intraductal papilloma of the breast 2. condyloma acuminatum due to HPV (human papillomavirus) types 6 and 11 gross reveals cauliflower-like lesion; mx reveals papillomatous proliferation of epithelial cells with condensed nuclei and perinuclear vacuolization koilocytes ("raisin-like" condensed nucleus surrounded by clear space) are characteristic microscopic change of HPV infection 3. VIN (vulvar intraepithelial neoplasia) = epithelial atypia and dysplasia due to HPV (human papillomavirus) types 16 and 18 squamous carcinoma in-situ = Bowens disease 4. squamous cell carcinoma; most common vulvar malignancy HPV-positive lesions: basaloid and warty carcinomas HPV-negative lesions: keratinizing squamous cell carcinomas 5. verrucous carcinoma is a localized malignancy that may become aggressive with radiation therapy 6. extramammary Pagets disease gross reveals red, crusty scaly, maplike lesion of labia majora large atypical cells in the epidermis; cytoplasm looks like a halo and contains mucopolysaccharide (stains positive for mucin with mucicarmine stain) may be associated with underlying adenocarcinoma of apocrine sweat glands (but uncommon in contrast to Pagets disease of nipple) differential diagnosis is vulvar malignant melanoma but this tumor has intraepidermal cells positive for S100, negative for mucin
220. Vagina A. congenital

Bartholin's

duct cyst is fluid-filled submucosal cyst in anterolateral portion of vagina or vulva (mesonephric (Wolffian) duct origin) B. neoplasms 1. squamous cell carcinoma extremely uncommon; may be preceded by vaginal intraepithelial neoplasia (VIN) most cases associated with HPV infection 2. adenocarcinoma (clear cell carcinoma) preceded by vaginal adenosis (glands within vaginal stroma); derived from Mullerian glandular epithelium histology reveals cells with clear cytoplasm (cytoplasmic glycogen) and "hobnail" appearance associated with DES (diethylstilbestrol) therapy in mother (DES has estrogen activity; inhibits mullerian differentiation)

Gartner

with DES include vaginal adenosis, cervical ectropion, adenocarcinoma of the vagina, and clear cell carcinoma of the vagina 3. sarcoma botryoides a variant of rhabdomyosarcoma (embryonal rhabdomyosarcoma ) that is found in children < 5 years of age (most common vaginal tumor in children) gross reveals "bunch of grapes" protruding from vagina; cross-striations seen microscopically (stain with anti-myosin immunoperoxidase) a hallmark is relatively denser accumulation of neoplastic cells under the surface (cambium layer)
221. Cervix A. inflammation

associations

cysts are endocervical glands blocked by squamous metaplasia over opening cervicitis has polymorphonuclear leukocytes (neutrophils); chronic cervicitis has mononuclear cells (mainly lymphocytes and plasma cells) microglandular hyperplasia: gross shows polyp protruding into endocervical canal; mx shows endocervical glands with numerous inflammatory cells (especially in the center of abnormal aggregates of endocervical glands); associated with the use of birth control pills B. endocervical polyp: mx shows dense fibrous stroma lined by endocervical columnar epithelium C. CIN (cervical intraepithelial neoplasia) 1. CIN is the precursor lesion for squamous cell carcinoma begins at transformation zone, which is squamous metaplasia at the transition zone between ectocervix and endocervix endocervical ectropion is prolapse of endocervix past the cervical os 2. clinically can use Schiller test = paint cervix with aqueous iodine dysplastic epithelium appears pale (no glycogen) normal epithelium stains dark mahogany brown (has glycogen) 3. cause is HPV HPV types 16 and 18 are associated with more aggressive disease HPV types 32, 33, 35 are associated with intermediate disease 4. mechanisms of HPV viral (E6 and E7) genes of high-risk HPV disrupt cell cycle by binding to RB (E7 protein binds to the Rb protein preventing it from binding to the host transcription factor E2F) and upregulating cyclin E (with increased p16INK4) E6 can interupt cell death pathways by binding to p53; also induces rapid degradation of p53 via ubiquitindependent proteolysis E6 can up-regulate telomerase D. histology 1. features of dysplasia (can be seen with PAP smear or cervical biopsy) increased nuclear to cytoplasmic ratio (N/C ratio) and increased mitoses koilocytosis (condensed, shriveled "raison-like" nucleus surrounded by clear space) is due to HPV 2. grade of dysplasia depends on thickness of abnormal cells from basal layer (note where mitoses are found) basal one-third = mild dysplasia (CIN I) middle one-third = moderate dysplasia (CIN II) upper one-third = severe dysplasia (CIN III) full thickness = carcinoma in situ (CIS), which is irreversible (also CIN III) 3. new "Bethesda" system; used for PAP smears (cytology) a) low grade squamous intraepithelial lesion Human Papillomavirus (HPV) infection mild dysplasia (CIN I) b) high grade squamous intraepithelial lesion moderate dysplasia (CIN II) severe dysplasia (CIN III) CIS (CIN III) E. squamous cell carcinoma risk factors include early sexual activity, multiple sex partners, lower socioeconomic group histology reveals microinvasive or invasive squamous cell carcinoma
acute

Nabothian

222. Menstrual A. terms

abnormalities

= inc amount of regular bleeding (may result from submucosal leiomyomas) 2. dysmenorrhea = severe pain during menstruation (inc PGF2 in menstrual fluid) primary dysmenorrhea is not associated with organic disease secondary dysmenorrhea is associated with organ lesions, such as endometriosis (most common cause), ovarian cysts, PID, adenomyosis, leiomyomas, cervical stenosis treatment is with oral contraceptives or NSAIDs (which inhibit cyclooxygenase and dec prostaglandin F levels) 3. metrorrhagia = bleeding at irregular intervals (cervical carcinoma may produce metrorrhagia) 4. menometrorrhagia = excessive bleeding at irregular intervals 5. postmenopausal bleeding = bleeding > 1 year after menopause (think endometrial hyperplasia or endometrial cancer) 6. oligomenorrhea = bleeding at intervals > 35 days apart (may be due to polycystic ovarian syndrome or weight too low) 7. polymenorrhea = bleeding at intervals < 22 days apart (think anovulatory cycles) B. DUB (dysfunctional uterine bleeding) is abnormal bleeding due to a functional disturbance rather than an organic lesion, such as a leiomyoma 1. anovulatory cycles (persistence of the graafian follicle without ovulation) typically around menarche or menopause (also polycystic ovary disease); inc estrogen and dec progesterone; no corpus luteum formed biopsy after ovulation by clinical dates reveals proliferative endometrium with mild hyperplasia (should see secretory changes) may see stromal breakdown (anovulatory menstruation) 2. inadequate luteal phase dec progesterone from corpus luteum (also decreased LH and FSH) biopsy after ovulation by clinical dates reveals asynchrony between chronologic dates and histologic dates 3. irregular shedding prolonged corpus luteum; sx: prolonged heavy bleeding at the time of menses histology of biopsy after ovulation by clinical dates reveals mixture of secretory glands and proliferative glands C. amenorrhea 1. primary amenorrhea = absence of menses by age 16 a) general: constitutional delay in puberty has normal response to progesterone challenge; otherwise classify based on gonadotropin levels progesterone challenge: give progesterone and then stop; if bleeding results (positive test), then endometrium was primed by estrogen and the problem is anovulation estrogen-progesterone challenge: if bleeding occurs in pt with amenorrhea, then problem is with follicle or hypothalamic-pituitary axis; absence of bleeding indicates Asherman's syndrome b) hypergonadotropic hypogonadism = primary ovarian disease Turner syndrome is the most common genetic cause of primary amenorrhea (may need to perform chromosomal study) c) hypogonadotropic hypogonadism = hypothalamic or pituitary disease delayed onset of puberty is the most common cause acquired abnormalities include excessive weight loss Kallmann's syndrome is primary amenorrhea, lack of secondary sex characteristics, and dec sense of smell (hyposmia) (dec GnRH, dec LH and FSH) due to lack of embryonic migration of cells from olfactory bulb to hypothalamus d) normal gonadotropin levels = end-organ abnormality such as imperforate hymen and developmental abnormalities 2. secondary amenorrhea = absent menses for 3 months in woman who previously had menses a) pregnancy is the most common (other than menopause); diagnosis with hCG levels b) hypothalamic/pituitary abnormalities (dec FSH and LH) weight loss syndromes include anorexia nervosa or too much exercise and weight loss (decreased total body adipose tissue)

1. menorrhagia

with anorexia nervosa = serum FSH decreased; serum LH decreased; no bleeding after progesterone challenge c) ovarian disorders (such as surgical removal of ovaries: serum FSH increased; serum LH increased; no bleeding after progesterone challenge) d) end-organ (uterus) disease such as Asherman syndrome = removal of stratum basalis with excessive endometrial curettage; causes amenorrhea; normal serum FSH and serum LH; no bleeding after progesterone challenge
D. other 1. menopause signs

findings

of menopause include fatigue, insomnia, hot flashes, and amenorrhea (mx of endometrium shows atrophy of glands and stroma) think HAVOC: hot flashes, atrophy of vagina, osteoporosis, coronary artery disease dec estrogen and inc FSH (best clinical indicator), inc LH; no bleeding after progesterone challenge 2. exogenous hormones (birth control pills) microscopy shows discordance between glands and stroma (inactive glands with decidual change of stromal cells)
223. Endometrial 1. acute

abnormalities

A. inflammation

endometritis infection of endometrium (rare but associated with childbirth or abortion; group B strep is grampositive, catalase-negative, positive CAMP test and sodium hippurate hydrolysis) toxic shock syndrome is caused by staph aureus and is associated with the use of tampons microscopically see neutrophils (but neutrophils are also normal finding in menstrual endometrium) 2. chronic endometritis associated with postpartum, post abortion, or IUD (actinomyces infection); sx: irregular periods microscopically see plasma cells (all it takes is one plasma cell to diagnose chronic endometritis) B. ectopic tissue 1. adenomyosis = endometrial tissue is located in wall of uterus (myometrium); gross shows brown or red hemorrhagic area histology reveals endometrial glands and stroma within myometrium note: if only stroma and no glands is present is called benign stromal nodule 2. endometriosis = endometrial tissue is located outside of uterus (may cause menstrual-related pain) a) gross reveals repeated hemorrhage ("chocolate cysts") b) histology reveals endometrial glands and stroma outside of uterus c) etiology (theories) metaplastic theory = abnormal differentiation of coelomic epithelium implantation theory = endometrium "spills out" of fallopian tubes during menses vascular theory = lymphatic or hematogenous spread C. hyperplasia 1. cause is excess unopposed estrogen stimulation a) mechanism inactivation of PTEN tumor suppressor gene makes endometrial cells more sensitive to estrogen stimulation PTEN codes for a lipid phosphatase the blocks Akt phosphorylation in the P13K pathway b) associations polycystic ovarian disease (Stein Leventhal syndrome) functional ovarian tumors that secrete estrogen excess adrenocortical function prolonged estrogenic substances (unopposed by progesterone) 2. classification simple hyperplasia without atypia = histological appearance is similar to proliferative endometrium (but in post-menopausal woman; tell hyperplasia in premenopausal female but amount of tissue present, not by histology) cystic hyperplasia = simple hyperplasia with some dilated glands ("Swiss cheese" appearance) complex hyperplasia without atypia = crowded glands with budding (no cytologic atypia)
bacterial

 atypical 3. result:

hyperplasia = complex hyperplasia with atypia (greatest risk of developing adenocarcinoma) endometrial bleeding (endometrial hyperplasia and neoplasia are important causes of post-menopausal bleeding)

224. Uterine

tumors

A. benign

polyps: microscopically see characteristic thick-walled blood vessels in the polyp, which is lined by epithelium on at least three sides 2. leiomyoma ("fibroids") most common tumor in women (inc incidence in blacks) historically demonstrated monoclonality of neoplasms by using G6PD isoenzyme levels within leiomyomas of heterozygous females most are asymptomatic, but may cause pain, bleeding, or infertility subperitoneal on the anterior surface of the uterine corpus may cause urinary frequency estrogen-sensitive, therefore there may rapid inc size with pregnancy and dec size after menopause (natural course is to regress after menopause) gross reveals sharply circumscribed round, firm, gray white nodules with whorled ("watered silk") appearance on cut surface mx = whorling interlacing bundles of elongated cells having spindle-shaped nuclei (smooth muscle cells), uniform size and shape, no atypia, and few to no mitoses B. malignant 1. endometrial carcinoma (the most common histologic type is adenocarcinoma) a) type I endometrial carcinoma (age group 55-65 yrs) stromal invasion by malignant glands (may have areas of squamous differentiation, called adenoacanthoma; benign = adenoacanthoma; malignant = adenosquamous carcinoma) patients present with vaginal bleeding; eg post-menopausal bleeding preceded by endometrial hyperplasia most often risk factor for endometrial adenocarcinoma is prolonged unopposed estrogen stimulation (including nulliparity, early menarche, late menopause), obesity, diabetes, hypertension molecular genetics: PTEN b) type II endometrial carcinoma (age group 65-75 yrs; thin physique) worse prognosis histology includes papillary serous carcinoma, clear cell carcinoma, and mixed mullerian tumor preceded by endometrial intraepithelial carcinoma in atrophic endometrium molecular genetics: p53 2. sarcomas a) leiomyosarcoma: usually de novo; mx shows increased cellularity with varying cellular atypia <5 mitoses/10 HPF (high power field) + atypia = atypical leiomyoma 5 10 mitoses/10 HPF + atypia = malignant >10 mitoses/10 HPF = malignant b) mixed mesodermal = mixed mllerian sarcoma (carcinosarcomas) malignant epithelial cells (usually adenocarcinoma) malignant stroma (usually leiomyosarcoma) c) endometrial stromal sarcoma: has "worm-like" appearance grossly; mx shows lymphatic invasion by endometrial stroma
225. Ovarian

1. endometrial

cysts A. follicular cysts (cystic follicles) distention of unruptured graafian follicle, which are lined by flattened layer of granulosa cells most common cause of ovarian enlargement B. corpus luteum cyst (luteal cyst) hemorrhage into persistent mature corpus luteum lined by luteinized granulosa cells C. theca-lutein cyst secondary to gonadotropin stimulation, such as with pregnancy, hydatidiform mole, choriocarcinoma excessive luteinization of theca interna (cells with abundant cytoplasm)

D. luteoma

of pregnancy: dont resect surgically (will regress following pregnancy) cyst: hemorrhage from endometriosis F. polycystic ovarian disease (PCOD, aka Stein-Leventhal syndrome) cause is abnormal hypothalamus-pituitary-ovarian axis (basically think as autonomous inc LH) inc LH stimulates theca interna to inc androgens, which then stimulate adrenals to inc estrogen, which then inhibit FSH and stimulate GnRH, which then stimulates LH (viscous circle) insulin levels are also increased (glucose levels may be normal), which may act with LH to increase ovarian androgen production markedly thickened ovarian capsule with multiple follicular cysts (granulosa cell layer and luteinized theca interna) young women with obesity, hirsutism, and amenorrhea inc androgens causes hirsutism, dec ovarian follicle maturation (dec numbers of corpora lutea), amenorrhea inc estrogens causes inc risk endometrial hyperplasia and carcinoma summary of lab findings = inc LH, dec FSH (high LH:FSH ratio), normal prolactin, inc serum testosterone, inc estrogen, dec progesterone (anovulation) first-line conservative therapy is weight loss; may also try clomiphine citrate (induces ovulation and may cause multiple pregnancies)
E. chocolate 226. Ovarian

surface tumors (tumors of Mullerian epithelium)

A. general

incidence with number of ovulations (repeated tearing and regrowth of surface epithelium) with mutations of BRCA1 and BRCA2 (especially serous cystadenocarcinomas) risk of malignancy increases as a function of the amount of solid epithelial growth B. serous tumors histology reveals ciliated columnar epithelial that are similar to fallopian tubes (may be papillary and form psammoma bodies) serous cystadenoma is a benign tumor that is frequently bilateral (cystadenofibroma) borderline serous tumor (borderline tumors do not have stromal invasion but may have epithelial stratification, mild cytologic atypia, papillary ingrowths, and calcification serous cystadenocarcinoma are malignant, frequently bilateral (stromal invasion is diagnostic microscopic feature) C. mucinous tumors (histology reveals nonciliated mucinous columnar epithelial cells similar to endocervix) have been associated with Brenner tumors mucinous cystadenoma borderline mucinous tumor mucinous cystadenocarcinoma can rupture and cause widespread abdominal dissemination of mucinous material = pseudomyxoma peritonei D. endometrioid tumors histology reveals nonciliated, non mucinous columnar epithelial cells similar to endometrium usually malignant and are called endometrioid carcinoma E. Brenner tumor (histology reveals transitional-like epithelial cells similar to urinary bladder with "coffee-bean" nuclei having longitudinal groove) F. clear cell carcinoma (histology is similar to renal cell carcinoma)
associated 227. Ovarian

inc

germ cell tumors

A. dysgerminomas

to seminoma of testis (and germinomas of mediastinum and pineal gland); sensitive to radiotherapy microscopy reveals sheets of large cells with distinct cell border and fibrous stroma infiltrated by lymphocytes positive for PLAP (placental alkaline phosphatase) and HCG (10% cases) B. teratomas contain elements from multiple embryonic layers mature teratomas = cystic (dermoid cysts) tumors contain mature skin, bone, cartilage, teeth immature teratomas are malignant and aggressive (they contain immature elements, such as neural tissue) monodermal teratomas contain one type of tissue, and example is struma ovarii, which contains thyroid tissue C. choriocarcinoma (ovarian choriocarcinomas are less responsive to chemotherapy than are gestational choriocarcinomas) malignant cytotrophoblasts and syncytiotrophoblasts (giant cells), which secrete beta-HCG

homologous

beta-HCG (human chorionic gonadotropin) sinus tumor (yolk sac tumor) inc APF (alpha fetoprotein) primitive cells form structures similar to immature glomeruli (glomeruloid or Schiller-Duval bodies) E. gonadoblastoma histology reveals mixture of germ cells (usually dysgerminoma) and stromal cells (usually Sertoli-Leydig cells) found in streak ovaries of patients with Turners syndrome and Y chromosome (XX/XY mosaics)
D. endodermal 228. Ovarian

inc

sex cord-stromal or other tumors tumors 1. thecomas gross reveals yellow tumors, while histology reveals spindle-cells with vacuolated cytoplasm (oil red O positive) may secrete steroid hormones (estrogen) and may cause endometrial hyperplasia and carcinoma 2. fibromas spindle-cells (oil red O negative), ie well-differentiated fibroblasts may be associated with Meigs syndrome (ovarian fibroma, ascites, and hydrothorax) or basal cell-nevus syndrome 3. granulosa cell tumors (considered to be potentially malignant) contain Call-Exner bodies (tumor cells around central space) nuclei are often grooved (another "coffee-bean" type nucleus) estrogen secretion can cause endometrial hyperplasia and carcinoma occasional tumors produce androgens, which can cause masculinization tumor marker is inhibin 4. Sertoli-Leydig cell tumors (androblastoma, arrhenoblastoma) may be androgen-secreting and cause masculinization; MC virulizing tumor in women; sx: abrupt cessation of menses coincident with signs of maculization mx of Leydig cell tumor: abundant eosinophilic cytoplasm with rare rhomboid bodies B. other: Krukenberg tumor = metastatic gastric signet ring carcinoma to ovary (mucicarmine positive)
A. sex-cord-stromal

229. Pregnancy A. normal

intrauterine pregnancy placenta has cytotrophoblasts and syncytiotrophoblasts forming chorionic villi a) villous maturation early: two layers of trophoblasts, loose irregular stroma, capillaries, stellate mesenchymal cells, Hofbauer histiocytes early second trimester: loss of two layered trophoblast; cytotrophs aggregate into groups third trimester: irregular trophoblast; inapparent cytotrophs last two months: syncytial knots, vasculosyncytial membranes, prominent vasculature 2. most common cause of secondary amenorrhea; diagnose with elevated beta-human chorionic gonadotropin B. gestational diabetes: due to human somatomammotropin (hCS) ; opposes the actions of insulin; increases maternal lipolysis and serum glucose levels C. spontaneous abortion: nonelective termination of a pregnancy at < 20 weeks gestation or fetal weight < 500 gms threatened ab: no products of conception expelled; membranes intact; internal cervical os is closed; uterine bleeding inevitable ab: no products of conception expelled; membranes ruptured; internal cervical os open; uterine bleeding and cramps complete ab: all products of conception expelled; internal cervical os closed; uterine bleeding incomplete ab: some products of conception expelled; internal cervical os open; uterine bleeding missed ab: fetal demise (no cardiac activity); no products of conception expelled; retained fetal tissue; internal cervical os closed; no uterine bleeding D. ectopic pregnancy location is most often the fallopian tube (bleeding causes hematosalpinx); rupture may cause massive bleeding and shock mx reveals fetal parts and chorionic villi
1. normal

cavity reveals the effects of progesterone, such as hypersecretory endometrium (Arias-Stella reaction) with decidualized stroma but no fetal parts or chorionic villi are present E. disorders of the placenta 1. twin placentas (placental membranes covering the fetus consist of an inner amnion and an outer chorion) monozygotic = monochorionic diamniotic or monochorionic monoamniotic (eg identical twins or Siamese twins) monozygotic (identical) twins may be dichorionic diamnionic (if splitting occurred at two-cell stage), monochorionic diamnionic (if splitting produced a blastocyst with two inner cell masses), or monochorionic monoamniotic (if splitting occurred after the formation of the inner cell mass) dizygotic = dichorionic diamnionic, fused or unfused; dizygotic (fraternal) twins always have two chorions and two amnions (fused or unfused) dichorionic monoamnionic is not possible 2. abnormalities of placentas abruptio placenta = premature separation of placenta causes continuous antepartum painful vaginal bleeding and fetal death placenta accreta = placenta attaches directly to myometrium (dec decidual layer) and causes impaired placental separation following delivery, which results in extensive post-partum hemorrhage placenta previa = placenta attaches to lower uterine segment; painless self-limited bright red bleeding; do NOT do vaginal exam placenta increta = attachment of anchoring villi pass deeper into myometrium placenta percreta = chorionic villi penetrate muscle wall to reach serosa F. hypertension pre-eclampsia = hypertension, proteinuria, edema, abnormal coagulation eclampsia = signs of pre-eclampsia plus hyper-reflexia and convulsions abnormal placental vasculature with endothelial dysfunction toxemic hypertension is due to dec PGE2 by placenta (normally placental PGE counteracts hypertensive effects of angiotensin) increased vasoconstrictors (thromboxane, angiotensin, endothelin); decreased vasodilators (prostacyclin, PGE2, nitric oxide) deliver fetus ASAP (until then bed rest, salt restriction) treat eclampsia with IV magnesium sulfate and diazepam (medical emergency); cure for preeclampsia/eclampsia is delivery G. gestational trophoblastic disease 1. hydatidiform mole a) clinical presents with abnormally rapid inc size of uterus with inc inc human chorionic gonadotropin (hCG); "snowstorm" appearance with ultrasound preeclampsia in the first trimester is pathognomonic for hydatidiform mole b) high incidence in Asia c) 2% (mainly complete mole) will develop into choriocarcinoma (moles are most common precursor of choriocarcinoma) d) gross reveals grape-like mass (swollen chorionic villi) e) partial mole some, not all, villi are effected (edematous, nonvascular and swollen) and fetal parts are present karyotypes = triploidy (69XXY) and tetraploidy (92XXXY) due to fertilization of ovum by two or more sperm (two haploid sperm fertilizing a haploid ovum) f) complete (classic) mole all villi are effected (edematous, avascular, and swollen) and no fetal parts karyotype = 46XX (all from sperm (paternal = androgenesis) due to fertilization of "empty" ovum) p57 is a strongly paternally imprinted gene that can identify molar villi (not expressed since both X chromosomes derived from father) 2. invasive mole is locally invasive or may embolize (but not true mets because they won't grow at these sites) 3. gestational choriocarcinoma histology reveals malignant cytotrophoblasts and syncytiotrophoblasts (no chorionic villi) preceded by most often by hydatidiform mole (50%) aggressive tumor with inc incidence in Asia and Africa

endometrial

 inc

human chorionic gonadotropin (also used to test effectiveness of treatment) hematogenous spread (most often to lung) gestational choriocarcinomas are responsive to chemotherapy (in contrast to ovarian choriocarcinomas) with almost 100% cures
early

MALE
230. Penis A. congenital

anomalies urethral opening clinically may produce obstruction, urinary tract infection, or sterility hypospadias (more common) = urethral opening on ventral (inferior) surface of penis (due to failure of urethral folds to close) epispadias = urethral opening on dorsal (superior) surface (due to faulty positioning of the genital tubercle) 2. phimosis orifice of prepuce too small; unable to retract foreskin causes: abnormal development of prepuce; inflammatory scarring B. inflammation inflammation of glans = balanitis (rare in circumcised males) inflammation of glans and prepuce = balanoposthitis gonorrhea: mucopurulent penile discharge; urethral swab reveals gram-negative diplococci in leukocytes syphilis: treponema pallidum lichen sclerosus (balanitis xerotica obliterans): more frequent in foreskin; may have autoimmune etiology; mx: orthokeratotic hyperkeratosis with epidermal atrophy and sclerosis C. other abnormalities Peyronies disease is subcutaneous fibrosis of the dorsum of the penis priapism is intractable painful erection (may be a complication of sickle cell anemia) D. tumors 1. condyloma acuminatum (the cause is HPV subtypes 6 and 11) gross appearance is warty papillary mass microscopic reveals papillary squamous epithelium with koilocytosis (no invasion) 2. carcinoma-in-situ (associated with HPV subtype 16) a) Bowens disease location is shaft and scrotum; solitary thick gray-white opaque with shallow ulceration and crusting histology reveals full-thickness carcinoma-in situ (CIS) b) erythroplasia of Queyrat (erythroplasia = red plaques) location is glans and prepuce; single or multiple shining or velvety red plaques histology reveals dysplasia (mild to CIS) c) Bowenoid papulosis (associated with HPV subtype 16, ?sexually transmitted) multiple red-brown verrucoid (wart-like) lesions (earlier in life) histology reveals CIS (but almost never develops into an invasive carcinoma; may spontaneously regress) 3. squamous cell carcinoma: rare in circumcised men; associated with HPV subtypes 16 and 18 4. verrucous carcinoma (old name is giant condyloma of Buschke-Lowenstein) gross is locally aggressive exophytic lesion (rarely metastasizes except with radiotherapy) microscopic reveals papillary tumor with koilocytosis and invasion along a broad, pushing front 5. embryonal rhabdomyosarcoma: grape-like mass in child
1. abnormal 231. Testes A. congenital

anomalies

1. cryptorchidism failure inc

of normal descent of intra-abdominal testes (unilateral in most cases) risk of germ cell tumors of testes (therefore, with unilateral cryptorchidism, remove the affected testis) the higher the location of the undescended testicle, eg. intra-abdominal, the greater the risk of developing cancer histology: atrophy and hyalinization of the seminiferous tubules (decreased number of sperm) with interstitial cell hyperplasia

B. regressive

changes seen in many conditions, including aging, cryptochidism, Klinefelter syndrome findings associated with decreased fertility: hypospermatogenesis, maturation arrest, etc C. inflammation (orchitis) 1. suppurative (acute inflammation with neutrophils): secondary to urinary tract infections or prostatitis if < 35 years of age: N. gonorrhea and chlamydia trachomatis if >35 years of age: E. coli and pseudomonas 2. granulomatous: caseating (tuberculosis; arises within the epididymis and spreads to the testis) or non-caseating (autoimmune) 3. viral: think mumps virus; mx shows interstitial edema and mononuclear inflammatory infiltrate 4. compare to epididymitis (caused by chlamydia trachomatis subtypes D-K and N. gonorrhea) adult male develops scrotal swelling and pain (elevation of scrotum relieves pain = Prehn's sign) D. torsion obstruction of venous drainage (thick-walled arteries are patent) produces venous infarction clinical: severe sudden scrotal pain with swelling; may produce gangrene; needs urgent surgical exploration E. tumors 1. spermatic cord and paratesticular tumors lipomas adenomatoid tumor: a slow growing benign tumor that arise from mesothelial cells of tunica vaginalis 2. germ cell tumors a) genomic change: isochromosome of 12p virtually all testicular germ cell tumors have an isochromosome of the short arm of chromosome 12 b) seminoma (the most common germ cell tumor) gross: absence of hemorrhage or necrosis (if hemorrhage is present, think mixed tumor) uniform population of large polygonal cells with distinct borders and clear cytoplasm (lymphocytes infiltrate stroma) very radiosensitive same lesion in ovaries is called a dysgerminoma, while the same lesion in pineal is germinoma cells are positive for c-KIT and placental alkaline phosphatase (PLAP) 10% of seminomas secrete hCG (due to syncytiotrophoblastic cells being present) a subtype is spermatocytic seminoma; a distinct clinical entity (older age, much better prognosis); mx shows maturation of the tumor cells, some resemble secondary spermatocytes c) embryonal carcinoma (secretes AFP) grossly see areas of hemorrhage and necrosis histology is poorly-differentiated (may have glandular differentiation) d) yolk sac tumors (secrete AFP): most common malignant testicular tumor in children; characteristic SchillerDuval bodies seen histologically e) choriocarcinoma malignant cytotrophoblasts and syncytiotrophoblasts (giant cells) inc HCG (human chorionic gonadotropin) f) teratoma mature (benign) teratoma (cystic tumor) are quite rare in adult males immature (malignant) teratoma (solid tumor) are more common in adult males g) mixed tumors (contain mixtures from multiple germ cell types) are common h) chemicals use for diagnosis and clinical follow-up inc inc inc human choriogonadotropin = choriocarcinoma (note slight increase in some seminomas) inc inc AFP = yolk sac tumor and embryonal carcinoma note: many overlaps except pure seminomas never inc AFP (therefore would be a mixture of types and not radiosensitive) 3. sex cord-gonadal stroma a) Leydig cell (interstitial cell) tumors (often associated with precocious puberty) gross reveals distinctive golden-brown homogenous cut surface microscopically may find intracytoplasmic rod-shape pink crystalloids of Reinke b) Sertoli cell tumors (androblastoma) may elaborate estrogens or androgens; mx: immature cord-like tubular structures (like seminiferous tubules) 4. other tumors
atophy:

a) gonadoblastoma b) testicular

lymphoma is most common type of testicular malignancy in elderly men (usual histology is large cell NHL) c) cysts (1) hematocele (2) hydrocele most common cause of scrotal enlargement; dx with imagin ultrasound (to tell cyst from a solid tumor) clear serous fluid in tunica vaginalis (transilluminates) due to problem with processes vaginalis (3) varicocele is due to dilated veins (increased temperature may cause infertility) (4) spermatocele (may develop following a vasectomy)
232. Prostate A. regions

zone (70% of prostate; lateral and posterior lobes): simple glands; loose stroma ; empty into the urethra distal to the verumontanum central zone (25% of the prostate; aka middle lobe): these glands lie between the ejaculatory ducts and end near the verumontanum transition zone (5% of the prostate): two small lobes lateral to the proximal urethral segment verumontanum is an elevation in the wall of the urethra where the seminal ducts enter B. inflammation: signs and symptoms: dysuria, frequency and urgency, low back pain, fever, malaise 1. acute bacterial most common are gram-negative organisms; same organisms that cause urinary tract infections (E. coli) signs and symptoms: pain associated with urination or ejaculation; marked tenderness with rectal examination 2. chronic bacterial: recurrent infections with the same organism 3. chronic abacterial: possibly related to chlamydia trachomatis or ureaplasma urealyticum C. BPH (benign prostatic hyperplasia) typical location is the transition zone (previously called the anterior and lateral lobes) and verumontanum (previously the median lobe) development is thought to be due to age-related increase estradiol with pre-sensitization by DHT (dihydrotestosterone), which is formed from testosterone by 5alpha-reductase in stromal cells therapy with 5alpha-reductase inhibitors (such as finasteride) may dec DHT levels gross (digital exam) reveals firm, rubbery consistency histology reveals a mixture of benign glands and stroma (not premalignant) enlarged prostate causes urinary obstruction clinical signs include frequency, dysuria, hesitancy (difficulty initiating urination) complications of BPH include urinary tract infections, hydroureter and hydronephrosis (does not cause neurogenic bladder) D. prostate cancer (adenocarcinoma) typical location is peripheral zone (previously called the posterior lobe), which is the area most sensitive to changes in androgen levels development is androgen dependent, therefore therapy may involve orchiectomy associated with hypermethylation of glutathione S-transferase (GSTP1) gene promoter may be preceded by prostatic intraepithelial neoplasia (PIN) which mx shows cellular crowding, variation in nuclear size, hyperchromatism, nucleoli, and two distinct epithelial cell layers (basal layer and luminal layer) gross (digital exam) reveals hard, irregular nodule histology reveals small glands "back-to-back" appearance with single cell layer and one or more enlarged nucleoli; may see perineural invasion grading system involves the Gleasons score, which is the combination of the two most common histologic patterns, varying from 1 (well-differentiated) to 5 (poorly-differentiated); Gleason's scores range from 2 (1+1), ie well-differentiated, to 10 (5+5), ie, poorly-differentiated stages of prostate cancer: A = incidental microscopic lesions, clinically not apparent; B = clinically palpable, but still confined to the prostate; C = local extension beyond the capsule of the prostate, but no metastases; and D = metastases (D1 is regional pelvic lymph node metastases, while D2 is distant metastases)

peripheral

 bony

metastasis (which may be osteoblastic) cause inc serum alkaline phosphatase and bone pain (vertebral) or leukoerythroblastosis inc PSA (prostate specific antigen, but not specific) and inc PAP (prostatic acid phosphatase) positive for AMACR (alpha-methyacyl-CoA-racemase) LOWER URINARY TRACT
233. Ureters A. inflammations: aggregates

uretitis, if long term: of lymphocytes can produce granular surface (ureteritis follicularis) fine cysts may develop on the suface (ureteritis cystica) B. tumors (rare) benign tumors: fibroepithelial polyps and leiomyomas malignant tumors: majority are transitional cell carcinomas
234. Urinary

bladder: review/congenital

A. review

urinary bladder is derived from endoderm epithelium: transitional epithelium (5 to 7 cells in thickness, umbrella (dome) cells on surface) lamina propria: may have Brunn's nests (downgrowths of nests of transitional epithelium in the lamina propria) wall: smooth muscle B. congenital diverticula: due to defect of muscle in wall (may also be aquired); produces urinary stasis leading to infection and bladder calculi extrophy: due to developmental failure of anterior wall (persistence of the cloacal membrane); produces chronic infections and inc risk for adenocarcinoma (also associated with epispadias in males) absence of bladder urachus: formed from allantois (in adult forms median umbilical ligament, which goes from the umbilicus to the apex of the bladder); incomplete attenuation of the urachus produces cysts, sinuses, fistulas; results in urine leaking from umbilicus (also inc risk to develop adenocarcinoma)
235. Inflammation A. acute

embryology:

of the urinary tract (bladder = cystitis) cystitis (urinary tract infection = UTI) microscopically see stromal edema with neutrophils signs and symptoms = frequency, pain, dysuria; more common in women (possibly due to shorter urethra) predisposing conditions include obstruction (tumors, calculi, BPH) and catheterization complications include pyelonephritis and septicemia diagnosis with urine culture (>100,000 colonies/ml); E. coli is the most common cause, Staphylococcus saprophyticus is second UTI in child less than 5 years of age: may indicate genitourinary malformation (eg vesicoureteral reflux of posterior urethral valves) B. chronic changes 1. cystitis cystica Brunns nests are downgrowths of nests of transitional epithelium if glandular spaces develop with mucin secretions, similar in appearance to colonic mucosa = cystitis glandularis 2. interstitial cystitis: inflammation (with eosinophils) and fibrosis involving entire bladder wall (aka Hunners interstitial cystitis) 3. radiation cystitis: may see atypical fibroblasts 4. nephrogenic metaplasia: see many small benign tubules in the lamina propria C. malakoplakia soft yellow plaques (may occur in other sites such as prostate, kidney, colon, lung) histology has sheets of macrophages with granular cytoplasm (digested bacteria) and laminated calcifications (Michaelis-Gutmann bodies) of the urinary bladder papillomas

236. Tumors

A. benign:

papilloma: papillary fronds containing delicate fibrovascular cores lined by less than 7 layers of cytologically and architecturally normal urothelium; prominent cytoplasmic vacuoles are seen inverted papilloma has intertwining cords of cells with minimal atypia and characteristic endophytic growth pattern (not exophytic like papillary TCC) B. malignant 1. urothelial carcinomas (transitional cell carcinoma; TCC) a) risk factors include industrial chemicals (beta-naphthylamine, an aniline dye), dietary factors (cyclamates and saccharin), cigarettes, and alcohol b) molecular theory of pathogenesis deletion involving tumor suppressor gene p16 on chromosome 9 produces superficial papillary lesions mutations involving p53 produce invasive tumors c) classic clinical sign is painless hematuria (most common neoplastic cause of painless hematuria in an adult living in the United States) d) papillary urothelial carcinomas (papillary TCC) inc epithelial thickness (> 7 layers) +/- atypia +/- invasion (note: non-invasive papillary TCC is not referred to as TCC in-situ) types: papillary urothelial neoplasms of low malignant potential (PUNLMP), low-grade papillary urothelial carcinoma, high-grade papillary urothelial carcinoma e) nonpapillary urothelial carcinomas are flat lesions noninvasive = carcinoma in-situ invasive (into either lamina propria or smooth muscle) 2. squamous cell carcinoma is associated with schisosoma haematobium infection in Egypt and Middle East 3. adenocarcinoma is associated with urachal epithelial remnants, glandular metaplasia, cystitis glandularis
237. Urethra A. inflammation

urothelial

= urethritis urethritis 2. non-gonococcal urethritis dysuria with yellow-green urethral discharge and no prostate pain (if prostate pain then prostatitis) discharge reveals numerous neutrophils, no bacteria (is due to Chlamydia trachomatis or Ureaplasma urealyticum) 3. Reiter syndrome: arthritis, urethritis (mx shows nonspecific inflammation), conjunctivitis B. caruncle: painful lesion of urethral meatus in females (mx shows inflammed granulation tissue) C. tumors benign: inverted papilloma malignant: squamous cell carcinoma (most common) and transitional cell carcinoma
1. gonococcal

HIGH-YIELD NOTES OF PATHOLOGY 2009-2010 PART 6a IMMUNOLOGY

238. Anatomy/histology A. lymph

nodes 1. cortex primary follicles secondary follicles: mantle zone and germinal centers, which contain transforming B cells (the most numerous cell type in germinal centers), dendritic reticulum cells (antigen presenting cells), and tingiblebody macrophages (macrophages containing ingested intracytoplasmic debris) 2. paracortex T cells are the most numerous cell type in the paracortex (and also the interfollicular areas) histiocytes, interdigitating reticulum cells (antigen presenting cells), and post-capillary venules post-capillary venules have high endothelial cells, which express ICAM-1, ICAM-2, VCAM, E-selectin, and P-selectin; lymphs in circulating blood adhere to HEV and enter lymph node by migrating between these cells 3. medulla: cords (plasma cells and small lymphocytes) and sinuses (lymphocytes and histiocytes; macrophages being the predominate cell) 4. antigen path: enter via afferent lymphatics; into subcapsular sinuses; through cortex and paracortex; leave via efferent lymphatics at the hilum B. spleen 1. red pulp: contains splenic cords of Billroth (macrophages, which destroy old red cells) and splenic sinuses;"barrel ribs" appearance of reticulin fibers in longitudinal sinusoids 2. white pulp a) PALS (periarteriolar lymphoid sheath) contains T cells b) lymphoid nodules (contain germinal centers, B cells, and mantle zones) c) marginal zone (area where T and B cells first enter spleen) marginal zone also found in tonsiles and Peyer's patches of small bowel; less evident in lymph nodes (except some reactive conditions like toxoplasmosis) the nodal counterpart of spleen marginal zone B-cells are monocytoid B-cells 3. arteries trabecular artery central artery (in white pulp) penicillar artery: composed of pulp arterioles, macrophage-sheathed arterioles, and terminal capillaries; closed circulation into sinusoids and open circulation into red pulp C. thymus derived from pharyngeal pouches 3 and 4 contains thymocytes (T lymphocytes), epithelial cells, antigen presenting cells (interdigitating cells and macrophages), and Hassalls corpuscles D. mucosal lymphoid system mucosal lymphocytes: IEL (intraepithelial lymphocytes) and LPL (lamina propria lymphocytes) MALT (mucosa associated lymphoid tissue) in GI tract, lung, GU tract, eye, etc
239. B

lymphocytes (occurs in the bone marrow) of immunoglobulin genes seen only in B cells (heavy chain first, then light chain) note: chromosome 14 has genes for immunoglobulin heavy chains and T cell receptor; chromosome 2 has kappa genes; chromosome 22 has lamda genes sequence: lymphoid stem cell; pro B cell (pre-pre B cell); pre B cell; immature B cell; mature B cell lymphoid stem cells have Tdt, Ia, CD34 and CD38; pro-B cells also have rearrangement of the only heavy chain D gene with J gene pre-B cell have cytoplasmic mu (and no surface immunoglobulin) and Tdt, Ia, CD10, CD19, CD20, and CD22 (heavy chain V rearranged) immature B cells have sIgM and Ia, CD19, CD20, CD21, and CD22 (light chain genes rearranged; kappa before lambda)
rearrangement

A. development

(virgin) B cells (which have not yet been exposed to the appropriate antigen) have surface IgM and IgD and Ia, CD19, CD20, CD21, and CD22 isotype switching (from IgM to other immunoglobulins): DNA for the Cmu region of H chains is excised B. locations: germinal centers of lymph nodes and spleen; 10-20% of circulating peripheral lymphocytes C. functioning and markers B cells form plasma cells, which secrete immunoglobulin the surface receptor for antigen on B cells is composed of immunoglobulin additional components of the B cell surface receptor for Ig are CD79a (aka Ig-alpha) and CD79b (aka Ig-beta, B29) D. two main subsets of B lymphocytes CD5-positive cells (aka B-1 cells) make IgM antibody to soluble polysaccharides and self-antigens (T-cell independent antigens); found predominately in peritoneal and pleural cavities CD5-negative cells (aka conventional or B-2 cells) make IgG, IgA, or IgE antibody to protein or cellular antigens or bacterial lipopolysaccharides (need specific helper T cells)
240. T

mature

lymphocytes A. T cell development and maturation occurs in thymus rearrangement of genes for T cell receptor is seen only in T cells (no rearrangement of immunoglobulin genes, which are in germline configuration) sequence: pre-thymus (lymphoid stem cell); thymus (stage I, II and III); post-thymus thymic cortex has stage I (early) thymocytes (double negative) and stage II (intermediate or common) thymocytes (double positive) stage I thymocytes have Tdt, CD2, CD5, CD7, CD34, CD38, and CD71 (TCR in germline configuration) stage II thymocytes have Tdt, CD1, CD2, CD4, CD5, CD7, CD8, and CD38 (TCR beginning to be rearranged) thymic medulla has stage III (mature) thymocytes (single positive, either CD4 or CD8 and CD2, CD3, CD5, CD38, CD44, and TCR) post-thymic T cells are CD4 (helper) T cells or CD8 (cytotoxic) T cells (lose CD38); in peripheral blood 60% lymphocytes are T cells (2:1 ratio CD4:CD8) B. T cell locations lymph nodes = paracortex and interfollicular areas (in spleen also located in periarteriolar lymphoid sheath, aka PALS) 60-70% of circulating peripheral lymphocytes C. functioning 1. secrete lymphokines 2. surface receptor for antigen is TCR (T cell receptor), which is attached to CD3 TCR-1 has gamma-delta chains (these cells home to mucosal epithelia and do not need MHC I, II, or antigen presenting cells) TCR-2 has alpha-beta chains (these cells are CD4 and CD8 lymphocytes) (about 95% of T cells) 3. T cell activation needs 2 signals signal 1 = binding of TCR to appropriate MHC-bound antigen signal 2 = interaction of CD28 on T cells to B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells D. subsets of helper T lymphocytes 1. Th1 cells (intracellular pathogens) secrete IL-2 and gamma-IFN and stimulate proliferation and cytotoxic responses involved in delayed type hypersensitivity, macrophage activation, and inc synthesis of IgG2b 2. Th2 cells (extracellular pathogens) secrete IL-4, 5, 6, 10 stimulate B-cell maturation, differentiation, antibody formation (particularly IgE, mediated by IL-4 and IL13), class switching activation of eosinophils (mediated by IL-5) 3. Th17 found in skin and GI tract; secrete IL-17 and IL-22; target neutrophils inc in some autoimmune diseases (eg, psoriasis, Crohn disease, ulcerative colitis, and multiple sclerosis) 4. Tfh (follicular B helper): found in germinal centers; secrete IL-21; help B cells to develop into plasma cells E. other T cells 1. Th3: prevalent in the intestines; main lymphokine is TGF-beta

2. Treg

(regulatory): one type of suppressor T cells CD4, CD25 (receptor for IL-1); and FOXP3 (forkhead box P3) secrete IL-10; inhibit Th1, Th2, and Th17 cells mutated FOXP3 in x-linked disorder IPEX (immune dysfunction, polyendocrinopathy, and enteropathy, Xlinked), a type of autoimmune polyendocrine syndrome
express

241. Other

review presenting cells (APC) 1. interdigitating cells: APC's of paracortex of lymph nodes (T cell area) (aka dendritic cells) 2. Langerhan's cells are the antigen-presenting cells of the skin (have long thin cell processes) they migrate in the lymph as "veiled cells" and form the interstitial (interdigitating) reticulum cells in lymph nodes contain Birbeck granules (pentilaminar bodies) 3. follicular dendritic cells: APC's of primary and secondary lymphoid follicles; have abundant Fc receptors; don't phagocytize, no class II antigens B. NK cells natural killer cells are large granular lymphocytes do not need previous sensitization (participate in ADCC type II hypersensitivity reactions) have CD16 and CD56 activity is regulated by balance between activating receptors and inhibitory receptors activating receptors include members of the NKG2D family and some Ig-like receptors inhibitory receptors (aka killer inhibitory receptors) inhibit the activation of NK cells by recognition of self-class I MHC molecules NK cells also secrete cytokines, such as IFN-, TNF, and granulocyte macrophage colony-stimulating factor (GM-CSF) C. cytokines 1. general IL-1 from macrophages, APC's, other somatic cells; many acute inflammatory effects IL-2: from activated Th1 cells; autocrine effects to increase its own receptor; stimulates cell-mediated immunity by stimulating cytokine-driven proliferation of CD8+ cytotoxic T cells (promotes the clonal expansion of T lymphocytes) IL-3 is multi-colony stimulating factor (multi-CSF); stimulates pluripotential stem cells IL-4: from TH2 cells; inhibits TH1 cells (cell-mediated immunity), stimulates TH2 cells, and regulates heavy chain class switching to IgE IL-5 from Th2; increases the number and function of eosinophils IL-6 from TH2 cells; a chemoattractant for neutrophils, T cells, and basophils IL-8: from macrophages; a chemokine that is a chemoattractant for neutrophils, T cells, and basophils IL-10: from Th2, CD8 cells, and more; suppresses cell-mediated immune reactions IL-12: from NK cells, B cells, and macrophages; stimulates cell-mediated immunity by stimulating TH1 cells and inhibits humoral immunity by inhibiting TH2 cells IL-13 is similar to IL-4 gamma interferon: from TH1 cells and macrophages; stimulates cell-mediated immunity (by cytokineinduced production of cytotoxic granules by CD8+ T cells), induces the formation of high endothelial venules, is the most potent activator of macrophages (forming epithelioid cells); inc expression of MHCII on macrophages 2. may classify into functional classes: mediate innate (natural) immunity: IL-1, TNF, type 1 interferons, IL-6 regulate lymphocyte growth, activation, and differentiation: IL-2, IL-4, IL-10, IL-12, IL-15, TGF-beta activate inflammatory cells: IL-5, interferon-gamma, TNF, lymphotoxin (aka TNF-beta) chemokines stimulate hematopoiesis: IL-3 D. CD's (defined by the use of monoclonal antibodies) CD1 is on cortical thymocytes CD2 = receptor for sheep erythrocyte (E rosette) on T lymphocytes CD3 = attached to T cell receptor (stimulates PLC to inc IP3 and intracellular calcium) CD4 = helper T cells, binds with MHC class II antigens
A. antigen

 CD5 CD8

and 7 = pan-T cell markers = cytotoxic T cells, binds with MHC class I antigens CD10 (CALLA) is on pre B cells CD14 is on monocytes CD15 (leuM1, aka Lewis X) and CD30 (Ki-1) are found on the malignant cells (Reed-Sternberg cells) in most forms of Hodgkin's disease CD16 is the receptor for Fc portion of IgG (NK cells can lyse IgG-coated target cells) CD18 is beta2 integrin (combines with forms of CD11) CD markers for B cells (pan-B cell markers) = CD19, CD20 (aka L26), CD21 (receptor for EBV), and CD22 (aka pan-B cell markers) CD25 is the receptor for IL-2; CD35 is complement receptor 1 (for C3b) CD28 binds to B7 to provide second signal in T cell activation CD40 binding of antigen to this receptor on B lymphocytes induces isotype switching; defective functioning can lead to hyper-IgM syndrome CD41a is GpIIb/IIIa, which is the receptor for fibrinogen CD45 is the leukocyte common antigen (LCA); CD55 is DAF (decay accelerating factor) CD56 is found on NK cells (large granular lymphocytes) CD62 forms are the selectins (CD62E is E-selectin; CD62P is P-selectin; CD62L is L-selectin) CD79a (aka Ig-alpha) and CD79b (aka Ig-beta, B29): part of antigen receptor on B cells CD80 (B7-1) and CD86 (B7-2): part of signal 2 in CD4 T cell activation CD95 is Fas receptor for Fas ligand CD117 is c-KIT
242. Immunoglobulins A. general

chains: kappa (chromosome 2) and lambda (chromosome 22); heavy chains (on chromosome 14) fragment (antibody-binding region; has the hypervariable regions) and Fc fragment (crystallizable, carboxy terminal, complement-binding region) papain digestion forms 2 Fab + 1 Fc, while pepsin digestion forms 1 F(ab')2 + 1 Fc antigen: a substance that can both elicit and combine with an immune response epitote (antigenic determinant): a portion of an antigen that can combine directly with an antigen binding region of an antibody hapten: a molecule that can bind to an immunoglobulin or T cell receptor, but is not big enough to elicit an immune response superantigen: a protein that activates T cells directly by binding to V beta region of a T cell and an MCH antigen on a T cell; example is toxic shock syndrome paratope: the antigen-binding region of an immunoglobulin idiotope: an antigenic determinant on a variable domain of an immunoglobulin molecule idiotype: 3D structure of the variable region of an immunoglobulin or T cell receptor (a set of one or more idiotopes); responsible for antigen specificity anti-idiotype: an immunoglobulin that reacts with the idiotype on a particular immunoglobulin molecule isotype is the subclass of Ig determined by heavy chain B. IgM large molecule (pentamer) that is secreted early in immune response (primary response) and is the surface receptor for developing (nave) B cells 5-10% of immunoglobulin in blood can not cross the placenta (think IgM is too big to cross, but actually the placenta lacks transport receptors for IgM) can activate complement directly (because it is so big) contains a J chain C. IgG most abundant immunoglobulin in serum (80%) secreted during second antigen exposure (secondary) half-life is about 23 days can cross the placenta (small monomer, and placenta has transport receptors for IgG) can activate complement (but it takes several) and can function as opsonin
Fab

light

 Fc D. IgE

portion of IgG can bind to PMN's, monocytes, splenic macrophages, and some B lymphocytes attached to the surface of basophils and mast cells in type I hypersensitivity reactions such as allergies, asthma, parasitic infection

found E. IgA

participates secretory can

immunoglobulin that is found along GI tract and respiratory tract (glandular secretions) activate alternate complement pathway usually a dimer with a J chain and a secretory component F. IgD receptor for B cells that is found on the surface of mature (virgin) B cells; also involved in B cell activation
243. Major

histocompatibility complex (MHC) I antigens (determined in the lab by serologic techniques) found on all nucleated cells (coded for by codominant genes at HLA-A, B, and C loci) transmembrane polymorphic alpha glycoprotein heavy chain with nonpolymorphic, nontransmembrane beta2 microglobulin extracellular region of heavy chain has three domains: alpha1, alpha2, alpha3; antigens sit in groove between alpha1 and alpha2 react with antibodies (serologically defined) and CD8-positive lymphocytes (second messenger is Gq linked to CD3 activating PLC to inc calcium) bind to proteins made within the cell (endogenous route) and transported by TAP (transporter associated with antigen processing) peptide transporter complex react with CD8+ lymphocytes (against virus infected cells and transplants) B. Class II antigens (determined in lab by mixed lymphocyte reaction: mix donor lymphocytes and recipient lymphocytes) 1. general found on antigen-presenting cells, B cells, and T cells (coded for by genes located at HLA-D loci) HLA-DR are most important antigens in determining success or failure of organ transplantation transmembrane polymorphic alpha chain and beta chain (which are transported to the surface after combining with invariant chain) react with CD4-positive lymphocytes (second messenger is Gq linked to CD3 activating PLC to inc calcium) fight exogenous antigens that have been processed by antigen-presenting cells (exogenous route) 2. superantigens certain bacterial toxins, an example is staph aureus that has TSST-1 and causes toxic shock syndrome superantigens binds both class II MHC and TCR not processed, instead reacts outside binding groove reacts with up to 10% peripheral T cells (CD4 cells) and causes massive T cell activation (and shock)
A. Class

244. HLA

associations seronegative spondyloarthropathies (think "PAIR") 1. psoriasis: pustular form; has characteristic "sausage-shaped" fingers 2. ankylosing spondylitis (Marie-Strumpell disease) = low back pain and stiffness in young adult male due to fusion of vertebrae ("bamboo" spine x-ray, negative RF) 3. inflammatory bowel disease 4. Reiter syndrome (males): now called reactive arthritis (Hans Reiter was a German physician who committed war crimes during World War II) non-gonococcal urethritis (or cervicitis), conjunctivitis, arthritis (seronegative spondyloarthropathy) ("can't see, can't pee, can't climb a tree") associated with chlamydia (GU) infections and shigella, salmonella, yersinia (GI) infections B. other rheumatoid arthritis and HLA-DR4; insulin-dependent diabetes mellitus and HLA-DR3 and DR4 hemochromatosis and HLA-A3; 21-hydroxylase deficiency and HLA-BW47
A. HLA-B27

245. Type

I hypersensitivity reactions exposure = antigen binds to antigen presenting cell and causes TH2 cells to secrete

A. pathology 1. first

which stimulates plasma cells to secrete IgE (reagin) which increases production of eosinophils IL-13, which promotes IgE production and mucus secretion from epithelial cells IgE binds to high-affinity Fc epsilon receptor on mast cells and basophils (cells are "armed" and ready) 2. second and subsequent exposures: binding of antigen to previously bound IgE causes release from mast cells and basophils of primary mediators (histamine) and new synthesis of secondary mediators (leukotrienes C4 and D4, prostaglandin D2, and more) B. clinical 1. localized reactions (atopy = constellation of multiple symptoms; better definition = predisposition to develop localized immediate hypersensitivity reactions to a variety of allergens) urticaria or hives on skin (multiple large pruritic red plaque-like wheals on skin with edema) nose (allergic rhinitis or nasal polyps), eye (conjunctivitis), lung (asthma), and GI tract (food allergy) Prausnitz-Kustner reaction (passive cutaneous anaphylaxis): inoculate skin with serum having antibodies then give antigen (Prausnitz was the professor allergic to fish and Kustner was the normal medical student that got the injection) 2. systemic reaction = reaction to wasp sting, drug (eg penicillin), etc; anaphylaxis (can die due to marked laryngeal edema) 3. treatment includes antihistamines, steroids, epinephrine (stimulates adenyl cyclase), cromolyn sodium (stabilizes mast cell membranes), theophylline (inhibits phosphodiesterase, which converts cAMP to AMP)
IL-5, 246. Type

IL-4,

II hypersensitivity reactions (IgG or IgM) binds to antigens in-situ and produces linear immunofluorescence (IF) B. complement involved or not involved, the latter is called ADCC (antibody-dependent cell mediated cytotoxicity) = cell lysis without phagocytosis (seen with NK cells, monocytes, neutrophils, eosinophils) C. may destroy blood cells, as seen with transfusion reactions, autoimmune hemolytic anemia, and erythroblastosis fetalis D. may produce connective tissue disorders (linear immunofluorescence) disorders involving antibodies against antigens in skin include pemphigus and pemphigoid antibodies against basement membrane (lungs and kidneys) antigens = Goodpastures disease E. may also cause cell dysfunction (hyper or hypofunction) 1. hyperfunction Graves disease (antibody that stimulates TSH receptor) chronic urticaria: one-third have autoantibodies against the normal receptor on mast cells for the Fc portion of IgE (causes mast cells to degranulate) 2. hypofunction (blocking) myasthenia gravis (antibody against the acetylcholine receptor) pernicious anemia (antibody against intrinsic factor or gastric parietal cells) autoimmune thyroiditis: e.g. Hashimoto's thyroiditis (antibody that blocks TSH receptor) F. therapy includes suppression (cyclophosphamide), plasmapheresis
A. antibody

247. Type

III hypersensitivity reactions A. antibody (IgG or IgM), binds antigens and forms immune complexes, which can cause: vasculitis (microscopically seen as fibrinoid necrosis, which consitis of fibrin + necrosis) glomerulonephritis (granular immunofluorescence seen as granular ("lumpy") deposits) complement activation in tissue decreases serum complement levels and neutrophil aggreation in tissue B. serum sickness is the classic example of generalized type III reaction occurs 5-7 days after large amount of foreign antigen injection usually repeated injections (such as treatment for rabies) C. Arthus reaction is the classic example of focal type III reaction (due to preformed antibodies) 4-10 hours after injection; sx include red, hot, warm, and ulceration at site fibrinoid necrosis (vasculitis) at the site of injection D. drugs (examples include foreign serum causing serum sickness, heroin causing glomerulonephritis, quinidine causing hemolytic anemia) E. certain infections (examples include post-streptococcal glomerulonephritis and hepatitis B associated with polyarteritis nodosa) F. certain endogenous antigens, such as nuclear antibodies (SLE) and immunoglobulin (rheumatoid arthritis)

G. therapy 248. type

includes aspirin, antihistamines, steroids, immunosuppression (cyclophosphamide), plasmapheresis

IV hypersensitivity reactions hypersensitivity 1. involves class II antigens (HLA-D) and CD4-helper T lymphocytes 2. antigen binds to antigen presenting cell (macrophages) which secretes IL-12; activates CD4+ TH1 cells which then secrete: gamma interferon which activates macrophages to form epithelioid cells (granulomas) IL-2 which activates CD4 cells (autocrine effect) 3. examples contact dermatitis (involves Langerhans cells), especially a reaction to nickel (in jewlery) poison ivy and poison oak (antigenic component is ursiol) granulomas are seen with mycobacteria, fungi, parasites, foreign material sarcoid tuberculin (PPD) skin test (Mantoux) for TB and lepromin test for leprosy B. T-cell mediated cytotoxicity 1. involves class I antigens (HLA-A, B, C) and CD8 cytotoxic T lymphocytes CD8 cells produce perforins and serine proteases (CTL granules also have granzymes, which enter target cell via perforin holes to activate caspases and induce apoptosis) CD8 cells controlled through apoptosis (they express Fas which binds to Fas ligand and causes FADD to activate caspase 8) 2. important in viral infections, transplants, and possibly destruction of certain tumors
A. delayed-type

249. Transplants A. terms

(autologous) is self to self (graft accepted); eg storing one's own blood for future transfusions is between identical twins (graft accepted) allograft is from person to person (not identical twins) (variable acceptance) xenograft (heterologous) is from species to species (strong rejection) B. host versus graft disease 1. hyperacute begins within minutes due to preformed anti-HLA antibodies (humoral) that attack the blood vessels of the graft this is sort of an example of a classic Arthus reaction (microscopically see lots of neutrophils) 2. acute reactions begin days to months after transplant (but progresses quickly after it begins) humoral reaction: immune complexes cause necrotizing vasculitis cellular reaction: mononuclear cells invade the interstitium (in kidneys also invades the tubules causing "tubulitis") cellular reaction is reversible with immunosuppression (OKT3 and cyclosporin, which inhibits activation of gene for IL-2) 3. chronic is the type IV reaction: progressive, slow loss of parenchymal cells (irreversible) microscopically see vascular changes (intimal fibrosis) with interstitial inflammation C. graft versus host disease (GVH) due to transplantation of immunocompetent T lymphocytes; seen with bone marrow transplants and liver transplants biopsy skin, mucosa, or colon (microscopically will see epithelial invasion by T lymphocytes from donor)
isograft 250. Autoantibodies A. lab

autograft

tests

sensitivity

= true positives/people with disease = true positives/(true positives + false negatives) (screening test needs high sensitivity) specificity = true negatives/people without disease = true negatives/(true negatives + false positives) (confirmatory test needs high specificity) predictive value of a positive test = true positives/(true positives + false positives) predictive value of a negative test = true negatives/(true negatives + false negatives) both positive and negative predictive values are affected by the prevalence of the disease

risk is disease risk in exposed group/disease risk in unexposed group; used for cohort studies ratio approximates the relative risk if the prevalence is not too high; used for retrospective studies (casecontrol) precision is the consistency and reproducibility of a test (reliability); random error reduces precision accuracy is the trueness of the test measurements; systemic error reduces accuracy B. nuclear 1. diffuse (homogenous) = DNA (many diseases), histones (drug-induced SLE) 2. rim (peripheral) = double-stranded DNA (SLE) 3. speckled (nonDNA extractable nuclear proteins) Smith (Sm)= SLE SS-A and SS-B = Sjgren's syndrome) Scl-70 = progressive systemic sclerosis 4. nucleolar (RNA) = many (e.g. progressive systemic sclerosis) 5. centromere = CREST syndrome C. cytoplasmic: mitochondria = primary biliary cirrhosis D. cells 1. smooth muscle = lupoid hepatitis (autoimmune chronic active hepatitis) 2. neutrophils = antineutrophil cytoplasmic antibodies (ANCA) c-ANCA (cytoplasmic against proteinase 3) = Wegeners granulomatosis p-ANCA (perinuclear against myeloperoxidase) = microscopic polyarteritis, primary sclerosing cholangitis, and Wegener's 3. parietal cell and intrinsic factor = pernicious anemia 4. microvasculature of muscle = dermatomyositis E. proteins immunoglobulin: anti-IgG (rheumatoid factor) = rheumatoid arthritis thyroglobulin = Hashimotos thyroiditis F. structural antigens lung and glomerular basement membranes = Goodpastures disease intercellular space of epidermis = pemphigus vulgaris epidermal basement membrane = bullous pemphigoid G. receptors acetylcholine receptor = myasthenia gravis thyroid hormone receptor = Graves disease insulin receptor = diabetes mellitus
odds 251. SLE

relative

(lupus) females with fever, fatigue, weight loss (classic skin rash = photosensitive malar "butterfly" rash, i.e. worse with sunlight) B. autoimmune disorder associated with the development of numerous autoantibodies specific antibodies are anti-double stranded DNA (rim) and anti-Smith sensitive, but not specific antibodies are ANA antibodies immune complexes deposited in tissue as LE bodies (hematoxylin bodies) (eaten by phagocytes form LE cells); eg type III hypersensitivity reaction antibodies against cardiolipin (phospholipid) = lupus anticoagulant (misnomer because it causes thrombosis and spontaneous abortions) autoantibodies against cells in blood (eg anti-platelet antibodies) may cause cytopenias (a type II hypersensitivity reaction) autoantibodies may cause false positive test for syphilis (RPR and VDRL) C. inflammation of small blood vessels (small vessel vasculitis) with fibrinoid necrosis (type III hypersensitivity reaction) D. inflammation of joints = synovitis and arthritis (arthritis is the most common symptom) E. inflammation of serous membranes = pleural effusions and pleuritis F. involvement of kidney = many different abnormalities but wire loop lesions (subendothelial deposits) is most characteristic G. involvement of heart = Libman-Sacks endocarditis and pericarditis H. involvement of CNS may be life-threatening
A. young

I. skin

biopsy reveals liquefactive degeneration of basal layer of epidermis with numerous inflammatory cells (IF shows granular deposits of immune complex of involved and uninvolved skin = lupus band test) J. variants 1. chronic discoid lupus (changes are confined to skin and pts have no antibodies to ds-DNA) 2. drug-induced lupus (in these pts anti-histone antibodies are characteristic) associated with certain drugs, especially procainamide (anti-arrythmia), hydralazine (anti-hypertensive), INH (anti-TB), phenytoin multi-system disease (but no CNS or renal involvement) that is reversible treatment is by removing drug (symptoms improve when drug is removed)
252. Other

autoimmune disorders syndrome CD4+ T cell destruction of salivary glands (enlargement of parotid most often); microscopic shows numerous lymphocytes dry eyes (keratoconjunctivitis) and dry mouth (xerostomia) inc risk of B-cell lymphoma (immunoblastic non-Hodgkin's lymphoma or marginal zone lymphoma) autoantibodies that are specific for Sjogren's are SS-A and SS-B (antibodies against RNP antigens) sicca syndrome is isolated (primary) form without other autoimmune disease; pts have dry eyes, dry mouth, dry nose and vagina, chronic bronchitis, reflux esophagitis Mikulicz syndrome is any enlargement of the lacrimal or major salivary glands (need lip biopsy to rule out Sjgren's syndrome, then look at minor salivary glands for characteristic changes) B. scleroderma 1. autoimmune disorder of females (20-50 years of age) 2. diffuse disease = progressive systemic sclerosis (PSS); specific autoantibody is against DNA topoisomerase (anti-Scl 70), while less specific autoantibody is anticentromere antibody (also found in CREST syndrome) blood vessels develop fibrinoid necrosis and intimal fibrosis = "onion-skinning" (renal involvement may produce malignant hypertension; renovascular hypertension is the MC cause of death) skin has sclerotic atrophy with loss of adnexal structures GI involvement is diffuse (involvement of esophagus produces dysphagia) lung involvement produces interstitial fibrosis (restrictive lung disease) 3. limited disease = CREST syndrome (a more benign disease that is associated with anticentromere antibodies) calcinosis, Raynauds phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia C. other polyarteritis (see under blood vessels) polymyositis and dermatomyositis (see under muscle) rheumatoid arthritis (see under bone and joints)
A. Sjgren's

253. Defects

in inflammation or immunity

A. general

of cellular immunity (involving T cells) cause recurrent infections with viruses, fungi, and mycobacteria of humoral (antibodies) immunity (involving B cells) cause recurrent infections with bacteria decreased peripheral lymphocyte count seen with disorders that dec T cells (such as SCIDs and DiGeorge syndrome) B. X-linked agammaglobulinemia of Bruton (XLA) x-linked recessive disorder (effects males) having mutation involving cytoplasmic Bruton tyrosine kinase (btk) defective maturation of B lymphocytes past the pre-B stage due to defect in a tyrosine-kinase gene pre-B cells are present (cytoplasmic mu), but not mature B cells (no germinal centers, no plasma cells, and dec serum Ig) recurrent bacterial infections (especially respiratory because of dec IgA) begin at age 9 months (when maternal antibodies are gone) inc incidence of autoimmune disorders (especially rheumatoid arthritis) treatment is with immunoglobulin injections from random pooled donors C. severe combined immunodeficiency (SCID) 1. decrease involves both T cells and B cells 2. inc incidence of infections, including viruses, fungi, and bacteria (prolonged diarrhea may be due to rotavirus and bacteria)
defects

defects

death in first year of life NOT vaccinate 3. types (inheritance) x-linked type is due to defect in gamma chain of IL-2 receptor (also in receptors for IL-4, 7, 9, 15) IL-7 receptor is most important autosomal recessive (Swiss type) lacks adenosine deaminase (inc dATP inhibits ribonucleotid reductase); prenatal diagnosis and gene therapy possible D. common variable immunodeficiency (aka adult-onset agammaglobulinemia) variable clinical presentation but all have dec immunoglobin (IgG, IgA, IgE) with hyperplastic B cell areas and no plasma cells recurrent infections (especially bacteria and Giardia) and inc incidence of autoimmune diseases and lymphoid malignancies E. isolated deficiency of IgA selective IgA deficiency is most common primary immune deficiency; may have concomitant IgG2 deficiency most patients are asymptomatic, but may have sinopulmonary infections, diarrhea (giardia infection), autoimmune diseases (especially SLE, RA), allergies, dental caries, inflammatory bowel disease may develop antibodies against IgA, which is associated with a risk of anaphylaxis with transfusions F. hyper-IgE (Jobs syndrome) recurrent bacterial infections (especially recurrent cold staph aureus abscesses) chronic pruritic eczematoid dermatitis with hyperkeratotic fingernails and growth retardation G. hyper-IgM immunodeficiency paradoxically is basically a T-cell disorder (defect in CD40L of TH or CD40 on B cells) defect prevents T lymphocytes inducing isotype switching in B lymphocytes, therefore dec IgG, IgE, IgA levels with inc IgM (causes cytopenias) most common form is X-linked (XLM) H. DiGeorge's syndrome developmental failure of pharyngeal pouches 3 and 4 due to deletion of chromosome 22 no thymus = no T cells = no cell-mediated immunity, which causes severe infections with viruses, mycobacteria, fungi no parathyroids = dec calcium (causes tetany) and inc phosphorous typical face (hypertelorism with low set ears) and congenital heart defects think "CATCH-22": Cardiac abnormalities, Abnormal facies (hypertelorism, low set ears, prominent nose), T cell defects (secondary to abnormal development of the thymus), Cleft palate, Hypocalcemia (secondary to primary hypoparathyroidism) I. Wiskott-Aldrich syndrome XR disorder that involves both B cells and T cells abnormal gene that codes for Wiskott-Aldrich syndrome protein (WASP) defect in IgM response to capsular polysaccharides of bacteria, which leads to recurrent bacterial infections serum levels of IgM are low with elevated IgA and normal IgE, normal IgG triad of signs = recurrent pyogenic infections, eczema, thrombocytopenia (causes epistaxis, petechia, purpura) J. other bare lymphocyte syndrome: AR disorder with lack of either class I or class II antigens on the surface of lymphocytes Omenn syndrome: AR disorder due to mutations of RAG1 and 2 (recombination activating genes); sx are similar to graft-versus-host disease
do 254. Acquired

severe,

immunodeficiency syndrome (AIDS) A. pathology 1. due to HIV (human immunodeficiency virus) which is an RNA envelop retrovirus; doesn't tolerate being outside of fluids (sensitive to drying) a) general restricted host range (no arthropod vector) contains reverse transcriptase, which is an RNA-dependent DNA polymerase that makes HIV provirus cell receptors for HIV: CD4 is the high-affinity receptor; chemokine receptors are co-receptors M-tropic strains infect macrophages/monocytes and T cells via CCR5 (beta-chemokine receptor) T-tropic strains infect only T cells (both fresh and cultured) via CXCR4 (alpha-chemokine receptor)

infection is M-tropic strain, later is more virulent T-tropic (T-tropic strains accumulate with time) layer is membrane obtained from host (has glycoproteins, such as gp120, gp41); inner layer is matrix (with p17matrix); then inside is capsid (with p24); then inside capsid are RNA genome and key proteins (reverse transcriptase, protease, integrase) b) genes: just a few genes, but it is very mutable gag codes for core protiens (eg p24) pol codes for reverse transcriptase env codes for envelope proteins c) proteins core protein: p24 transmembrane protein: gp41 (holds gp120 in place) surface spike: gp120 inner membrane protein: p17 2. mechanism a) first HIV gp120 binds to CD4, which is found on CD4+ T lymphocytes other CD4+ cells (which may be reservoirs of HIV) include monocytes, macrophages, microglial cell of CNS, follicular dendritic cells of lymph nodes, and Langerhans cells of skin (have CCR5, not CXCR4) b) second (after conformational change) gp41 fuses into cell membrane homozygous individuals for defective CCR5 are resistant to infection with HIV (heterozygous individuals get delayed AIDS) B. clinical 1. general high risk populations: homosexuals or bisexual men, IV drug abusers, heterosexual partners of high risk groups, recipients of multiple blood transfusions (such as hemophiliacs), and infants of high risk mothers the largest increase in the rate of AIDS is now occuring in heterosexuals, women, and minorities routes of infection: sexual contact, parenteral inoculation, and passage of the virus from infected mothers to their newborn infants bi-directional venereal heterosexual transmission is the predominant mode of transmission worldwide 2. early (acute phase) initial: lots of virus; modest decrease in CD4 cells; no symptoms (or flu-like) self-limited illness (acute seroconversion illness) with sore throat, fever, rash HIV seropositivity within 3 months 3. middle phase is the chronic phase (lasts 7-10 years) during which there is widespread seeding of lymphoid tissue; CD4 numbers gradually decrease clinical latency as low level HIV replication in reservoirs (lymph nodes, spleen, tonsils), not peripheral blood persistent generalized lymphadenopathy (PGL): microscopically may show progressive transformation of germinal centers ARC (AIDS-related complex) is an old term that is out of date (don't use) 4. final phase is the crisis phase: immunosuppression; lots and lots of viruses; marked decrease in CD4 cells a) it begins about 7 to 10 years after infection and individuals die within 3 years b) apoptosis of T lymphs: shed gp120 interacts with CD4 cells and cross-reacts with antibody against gp120, then when it gets a normal signal to activate, the T lymph instead undergoes apoptosis c) criteria for diagnosis of "full-blown" AIDS CD4+ cells < 200/microliter (prognosis is related to CD4 count) certain opportunistic infections, such as candida (most common), pneumocystis jiroveci, atypical mycobacteria (AIC), toxoplasma ("ring enhancing lesion" of CNS with MRI), CMV chorioretinitis certain malignancies, such as multifocal Kaposis sarcoma (HHV-8 associated) and non-Hodgkin's lymphoma (immunoblastic lymphoma) cryptococcus, blastomycosis, giant cells in the brain d) lab tests dec CD4+ causes dec CD4:CD8 ratio (inversion of normal ratio of 0.5:1) antibody to gp120 monitors course of infection, while level of p24 measures virus load in the blood anti-HIV antibody by ELISA (screen); may have false positives
outer

early

antibody by Western blot (confirm test) rarely used 5. treatment includes nucleoside analogs (zidovudine or AZT), protease inhibitors reverse transcriptase inhibitors or protease inhibitors; newer drugs fight integrase, CD4 binding, and membrane fusion lamivudine (3TC) is a dideoxynucleoside that terminates the synthesis of proviral DNA and is used clinically to treat infections with viruses that contain an RNA-dependent DNA polymerase, namely HIV and hepatitis B
culture: 255. Amyloidosis A. general

anti-HIV

means "starch-like" because amyloid in fresh tissue + iodine stains brown is any protein having beta-pleated sheet tertiary configuration (amyloid depositis are always extracellular) special unique staining properties = apple-green birefringence with Congo red stain B. systemic deposition multiple myeloma: may have deposits of amyloid light protein (in kidney = amyloid nephropathy) chronic inflammatory diseases: may have deposits of amyloid associated protein (which is derived from SAA in blood made in liver) long-term hemodialysis: may have deposits of beta2-microglobulin (a component of MHC class I antigens) because it doesn't filter through cuprophane dialysis membranes C. localized deposition senile cardiac disease: deposits of amyloid transthyretin (ATTR); normally TTR transports thyroxine and retinol (trans-thy-retin) Alzheimer's disease: deposits of beta-amyloid (aka A-beta) protein (which is derived from amyloid precursor protein) medullary carcinoma of thyroid: deposits of procalcitonin non-insulin dependent diabetes mellitus (type II): amyloid deposits in islets of Langerhans of pancreas (AIAPP from islet amyloid peptide, aka amylin)
amyloid

amyloid

HIGH-YIELD NOTES OF PATHOLOGY 2009-2010 PART 6b RED BLOOD CELLS

256. normal A. general

development 1. first site of hematopoiesis in fetus is yolk sac; at 12-24 wks is liver; after that is bone marrow 2. stem cells and committed stem cells (stem cells are capable of self-renewal) pluripotential stem cell (hematopoietic stem cell): gives rise to tri-lineage myeloid stem cell and lymphoid stem cell (common lymphoid progenitor) tri-lineage myeloid stem cell (CFU-S) (common myeloid progenitor): gives rise to 3 types of committed stem cells, called colony-forming units (CFUs): CFU-Eo, CFU-G/M, and E/Mega CFU-Eo forms eosinophiloblast; CFU-G/M forms CFU-M (which forms monoblasts) and CFU-G (which forms myeloblasts); E/Mega forms CFU-Mega (which forms megakaryoblasts) and BFU-E (which forms CFU-E and then proerythroblasts) notes: granulocytes and macrophages have a common precursor called CFU-GM; in the erythroid development there are two primitive stages, the more primitive being a BFU-E (burst-forming uniterythroid), and the later stage being a CFU-E 3. blasts: immature cells (immature chromatin) with nucleolus; erythroblasts have dark blue cytoplasm B. growth factors: colony stimulating factors (CSF) multi-CSF (aka interleukin-3), produced by T cells, causes proliferation of all progenitor cells (except lymphoid) leading to the proliferation of granulocytes, monocytes, erythrocytes, and megakaryocytes GM-CSF (granulocyte-macrophage colony-stimulating factor) acts on CFU-GM to produce granulocyte/macrophage colonies M-CSF (not to be confused with multi-CSF) causes CFU-M proliferation and differentiation G-CSF causes CFU-G proliferation and differentiation erythropoietin, produced by the peritubular cells in the kidney, is essential for the differentiation of erythroid precursors C. red blood cell development 1. bone marrow: erythroblastic island is found around macrophage (nurse cell), which provides iron to developing erythroid precursors a) normal development = normoblastic maturation; stimulated by erythropoietin (megaloblastic maturation is abnormal) (1) pronormoblast (rubriblast) (2) polychromatophilic erythroblast (rubricyte); takes 3 mitoses to get here maximal amount of mitochondria hemoglobin production starts (stains pink) (3) orthochromatophilic erythroblast (metarubricyte): has condensed nucleus (4) reticulocyte (time of maturation from erythroblast to bone marrow reticulocyte is about 5 days; time reticulocyte in marrow is about 1 day) (a) characteristics larger cell that is spherical and has bluish color (polychromasia) due to free ribosomal RNA (pink color is due to hemoglobin) no nucleus (first cell in erythroid maturation not to have nucleus) note that any rbc with nucleus (nRBC) in peripheral blood is abnormal shift cells are bone marrow reticulocytes that are present in the peripheral blood (indicates bone marrow is releasing cells early) (b) clinical tests for reticulocytes i. reticulocyte count equals percent of red cells present in peripheral blood (normal = 1.5%) absolute number of red blood cells present ii. corrected reticulocyte count (which corrects for degree of anemia) = (patient's hct/45) times reticulocyte count <2% = poor bone marrow response > 3% = good bone marrow response

iii. reticulocyte use

index = corrected reticulocyte count/2 if shift cells are present (polychromasia), which are bone marrow reticulocytes divide by 2 because shift cells take twice as long as reticulocytes to mature (2 days vrs 1 day)

2. peripheral

blood

maturation to mature erythrocyte takes about one day erythrocyte biconcave disk; 7 microns in diameter (similar to size of lymphocyte nucleus) pink cytoplasm (due to high levels of hemoglobin) central pallor about one-third diameter of RBC = normochromic no RNA or mitochondria (therefore no oxidative-phosphorylation for energy); energy production for red cells is from glycolysis life span = 120 days (removed by macrophages of the RES, especially within the spleen) D. structure of membrane 1. integral proteins a) protein 3 (protein C): anion exchange channel for Cl- and HCO3b) glycophorins: example is glycophorin A responsible for red blood cell types MN binding site for P. falciparum and influenza virus; absence of glycophorin A is associated with resistance to these infections 2. peripheral proteins: ankyrin, actin, spectrin (found on the inner surface of the rbc membrane), protein 4.1 E. function (physiology and biochemistry) 1. metabolism a) glycolysis: metabolism of glucose (the only major source of ATP in red cells, because they lack mitochondria) muscle and red blood cells obtain more glucose for use as fuel from liver conversion of lactate into pyruvate as a substrate for gluconeogenesis conversion of pyruvate into glucose by the liver by liver is called the Cori cycle b) pentose phosphate (hexosemonophosphate) shunt (1) glucose 6 phosphate dehydrogenase glucose-6-phosphate to 6 phosphogluconate NADP (oxidized) to NADPH (reduced) (2) glutathione reductase (needs FAD) NADPH (reduced) to NADP (oxidized) oxidized glutathione to reduced glutathione (3) glutathione peroxidase (needs selenium) reduced glutathione to oxidized glutathione something oxidized (methemoglobin) to hemoglobin 2. hemoglobin (heme and globin) a) heme = 4 protoporphyrin groups with iron (1) synthesis: occurs in 8 steps, the first (rate-limiting) and the last 3 occur in the mitochondria; the intermediate steps occur in the cytoplasm (a) succinyl-coenzyme A (from the TCA cycle) + glycine forms delta-aminolevulinic acid (d-ALA) needs pyridoxal phosphate (vitamin B6); catalyzed by the rate-limiting enzyme ALA synthetase; inhibited by hemin (b) 2 molecules of ALA condense to form porphobilinogen, catalyzed by ALA-dehydrase (c) 4 molecules of porphobilinogen form uroporphyrin III or I; the III isomer is converted to protoporphyrin (d) iron is inserted into protoporphyrin by the mitochondrial enzyme ferrochelatase (aka. heme synthetase) to form heme if iron is inadequately available, free erythrocyte protoporphyrin (FEP) increases and zincprotoporphyrin accumulates Fe++ = reduced hemoglobin (if oxygen added = oxyhemoglobin) Fe+++ = methemoglobin (hemiglobin): oxidized hemoglobin; forms Heinz bodies; does not carry oxygen well at high O2 b) globin = 2 pairs of chains (total of 4 = tetramer)
b) mature

a) reticulocyte:

genes on chromosome 16: alpha (two genes on each chromosome; total of 4 genes) and zeta (in utero) (2) beta-like genes on chromosome 11 (epsilon, gamma, delta, beta): sequence from the 5 end to the 3 end is epsilon-gamma-delta-beta (3) different types of normal hemoglobins (a) note: sequence of gene expression is same as the gene sequence on their respective chromosomes from the 5' to 3' direction (b) hemoglobin A (alpha2-beta2): 5 % of hemoglobin A is glycosylated (increased in patients with diabetes mellitus) (c) hemoglobin A2 (alpha2-delta2) (d) hemoglobin F (alpha2-gamma2) (e) hemoglobin percentages birth: hemoglobin F = 75%; hemoglobin A2 <2%; hemoglobin A <25% adult: hemoglobin F <1%; hemoglobin A2 = 2-3%; hemoglobin A >95% c) biochemical structure of hemoglobin (1) primary structure = amino acid sequence (2) secondary structure: mostly alpha helix (3) tertiary structure folds between alpha helical segments; forms 7-8 helical regions, named A to H pocket: hydrophobic nonpolar amino acids); contains heme surface: hydrophilic (4) quaternary structure (a) due to inter-relationship between 4 globin chains (b) responsible for oxygen-dissociation curve (c) sigmoidal shape of oxygen-dissociation curve i. note: myoglobin is hyperbolic ii. P50 = PO2 where hemoglobin is 50% saturated with oxygen (inversely proportional to oxygen affinity) iii. RIGHT shift of curve (seen in tissue: increased CO2) i) dec affinity for oxygen (increasing P50); eg abnormal hemoglobins with decreased oxygen affinity ii) dec pH (increased [H+]) = the Bohr effect (may be seen with strenuous (anaerobic) exercise) iii) increased 2,3 DPG (source of 2,3-DPG in erythrocytes is 1,3 bisphosphoglycerate, part of the glycolysis pathway) stabilizes beta chain of deoxyhemoglobin and decreases pH gamma chain (Hb F) lacks beta143 histidine: less affinity for 2,3 DPG than Hb A results: Hb F has greater affinity for oxygen than Hb A; will also increase hct in newborn iv) increased temperature v) increased pCO2 iv. LEFT shift of curve (seen in lungs): inc affinity for oxygen; inc pH; inc CO d) breakdown products of hemoglobin include bilirubin, hemosiderin, ferritin, and hematin
257. Red

(1) alpha-like

cell morphology and terms abnormal shape = poikilocytosis (poikilo means various; eg poikilotherm), abnormal size = anisocytosis (aniso means unequal; eg anisocoria) B. shape 1. elliptocytes: seen with hereditary elliptocytosis 2. spherocytes hereditary spherocytosis (lab test is increased osmotic fragility) autoimmune hemolytic anemia (AIHA) (lab test is positive DAT, aka direct Coombs) 3. target cells (due to increased RBC membrane): hemoglobinopathies, thalassemia, and liver disease 4. acanthocytes (irregular spicules on RBC surface): abetalipoproteinemia 5. echinocytes or burr cells (smooth undulations on RBC surface): uremia or artifact 6. schistocytes (fragments or helmet cells): DIC or traumatic hemolysis (eg microangiopathic hemolytic anemia)
A. terms:

cells: G6PD deficiency cells (dacrocytes): thalassemia and myelofibrosis 9. stomatocytes: "mouth"-like central pallor 10. sickle cells (drepanocytes): sickle cell anemia 11. rouleaux ("stack of coins"): multiple myeloma C. inclusions 1. basophilic stippling (due to remnants of RNA): inc reticulocytes (reticulocytosis) and lead poisoning (coarse granules) 2. Howell-Jolly bodies (due to remnants of nuclear chromatin); seen with severe anemias and patients without spleen (splenectomy) 3. Pappenheimer bodies (iron): splenectomy (triad of Howell-Jolley bodies, target cells, and reticulocytosis suggests splenectomy) 4. ring sideroblasts (iron in mitochondria forming ring around nucleus): sideroblastic anemia 5. Heinz bodies (due to denatured hemoglobin): seen with G6PD deficiency; not seen with routine Wright-Giemsa stain; need supravital stain
8. teardrop 258. Classification A. signs

7. bite

of anemia of anemia include: cardiovascular changes (inc cardiac output, heart rate, stroke volume, wide pulse pressure) include palpitations, dizziness, angina pallor of skin and nails; hypoxia produces weakness, claudication, fatigue, lethargy B. lab tests hematocrit = ratio of volume of erythrocytes to the volume of whole blood MCV (mean cell volume) is the average volume of a red blood cell (eg hematocrit/RBC count) MCH (mean cell hemoglobin) is the average content (mass) of hemoglobin per RBC (eg hemoglobin concentration/RBC count) MCHC (mean cell hemoglobin concentration) is the average concentration of hemoglobin in a given volume of packed RBC's (eg Hb concentration/hct) RDW (red cell distribution width) is the coefficient of variation of red blood cell volume (RDW is the best lab measure of anisocytosis) C. size 1. dec size (dec MCV) = microcytic anemia = iron deficiency, thalassemia, anemia of chronic disease (AOCD), or sideroblastic anemia 2. inc size (inc MCV) = macrocytic megaloblastic anemia (due to dec B12 or folate): has oval macrocytes inc reticulocytes (many causes); has round macrocytes 3. normal size (normal MCV) = normocytic (all of the rest of the causes of anemia cause normocytic anemias) D. color dec color (inc central pallor of rbc's) = hypochromic (dec MCHC): same 4 microcytic anemias (iron deficiency, thalassemia, AOCD, sideroblastic anemia) inc color (loss of central pallor of rbc's) is NOT called hyperchromic but is called spherocytic (inc MCHC) normal color (central pallor of about 1/3rd the diameter of the RBC) = normochromic (normal MCHC) E. blood loss 1. acute, such as secondary to trauma at first there is proportional decrease in plasma and RBC's: normal hemoglobin concentration, normal hematocrit, normal MCV then over a couple of days there is albumin and fluid shifts into the intravascular space: dec hematocrit with normal MCV about five days later: reticulocytosis (causes increased MCV) 2. chronic: blood loss from GI tract or GYN; causes iron deficiency anemia

259. Hemolysis A. intravascular

hemolysis (example: severe calcific aortic stenosis) release of hemoglobin (causes hemoglobinemia and hemoglobinuria; increased urine hemosiderin); also increased LDH inc bilirubin (unconjugated) release causes jaundice (and inc risk of pigment (bilirubin) gallstones)

oxidized to methemoglobin (methemoglobinemia and methemoglobinuria) hemoglobin-binding proteins such as haptoglobin and hemopexin no splenomegaly (because no extravascular hemolysis in spleen) B. extravascular hemolysis splenomegaly (if extravascular hemolysis occurs in spleen) or hepatomegaly (if extravascular hemolysis occurs in liver) inc bilirubin and dec haptoglobin (but not as much as IV hemolysis) absence of the following: hemoglobinemia, hemoglobinuria, and methemoglobin formation
dec 260. Hereditary

hemoglobin

intrinsic red cell defects A. hereditary spherocytosis 1. autosomal dominant inheritance due to defect involving rbc membrane (dec rbc surface membrane formation) defects in ankyrin are most common (other defects involve spectrin, band 3 protein, protein 4.1) similar defect in hereditary elliptocytosis (also autosomal dominant inheritance) 2. spherocytes are not flexible and are removed in spleen by macrophages (ie, EV hemolysis), which causes mild to moderate hemolytic anemia which causes inc bilirubin (jaundice and risk of pigment gallstones) splenomegaly chronic hemolysis (pts are at risk for acute red cell aplasia due to parvovirus B19 infection) 3. differential diagnosis of spherocytes includes warm autoimmune hemolytic anemia (but AIHA has positive DAT (direct Coombs); HS has negative DAT) 4. inc osmotic fragility (note: dec osmotic fragility with target cells, such as seen with thalassemia and sickle cell anemia) 5. characteristic lab finding = normal MCH with inc MCHC 6. treatment is splenectomy (will cause increase in hematocrit and produce Howell-Jolly bodies in peripheral smear) B. dec G6PD 1. G6PD (glucose 6 phosphate dehydrogenase) is rate-limiting enzyme in HMP (pentose phosphate) shunt; makes NADPH to keep glutathione reduced 2. deficiency is not due to dec synthesis but is due to defective protein folding; deficiency decreases levels of reduced glutathione 3. X-linked inheritance; patient populations: a) African-Americans hemolysis secondary to acute oxidative stress, such as oxidative drugs (primaquine, sulfonamides, antiTB drugs, anti-malarial drugs) intermittent hemolysis (even if drug is continued) because only older rbc's have dec levels of G6PD b) Mediterranean type has more severe hemolysis because all RBCs have dec G6PD (associated with favism due to ingestion of fava beans) 4. oxidation of hemoglobin forms Heinz bodies (lab test is Heinz body preparation) not seen with normal stains, instead need supravital stains (methylene blue and crystal violet) "eaten" by splenic macrophages (ie extravascular hemolysis) forming bite cells C. dec pyruvate kinase: catalyzes the conversion of phosphoenolpyruvate to pyruvate; most common enzyme deficiency of glycolytic pathway (seen in Amish) decreased production of ATP decreases ATPase-dependent sodium-potassium membrane pump red cells become dehydrated and form spherocytes; results in extravascular hemolysis in spleen increased 2,3 DPG (shifts hemoglobin-oxygen curve to right), mild jaundice symptoms are mild because of increased production of 2,3 diphosphoglycerate increases oxygen delivery to the tissue D. abetalipoproteinemia (defect in the synthesis of apolipoprotein B) increased sphingomyelin in RBC membrane; very low cholesterol and triglyceride levels in blood with acanthocytosis sx: steatorrhea, ataxia, atypical form of retinitis pigmentosa (progressive, bilateral, concentric contraction of visual fields with loss of central vision) E. pyropoikilocytosis: RBCs lyse at lower temperatures than normal; result in marked poikilocytosis and anisocytosis (small microspherocytes to large cells)

261. Hemoglobinopathies

A. hemoglobin 1. genetics

S (AR inheritance) heterozygous (AS) = trait (associated with resistance to P. falciparum infection, malaria), patients have less symptoms than disease homozygous (SS) = disease (sickle cell anemia) single nucleotide change in codon causes valine (neutral) to replace normal glutamic acid (acidic) at beta 6 position 2. pathology: deoxyhemoglobin S polymers forms tactoids (fluid crystals) in RBCs which will form irreversibly sickled red blood cells 3. some factors affecting formation of sickled cells increased hemoglobin F makes symptoms better (increased by therapy with hydroxyurea); therefore no symptoms at birth presence of hemoglobin C (SC = double-heterozygote) makes symptoms better inc concentration (dehydration) makes symptoms worse while dec concentration (with thalassemia) makes symptoms better dec pH decreases oxygen affinity and makes symptoms worse 4. inc RBC destruction causes a severe hemolytic anemia inc erythroid series in bone marrow ("crew-cut" appearance with skull x-ray) inc bilirubin leads to jaundice and gallstone (pigment) formation risk of aplastic crisis (with parvovirus B19 infection) peripheral blood shows inc reticulocytes (inc polychromasia) and inc target cells with a normocytic, normochromic anemia 5. capillary thrombi, which cause autosplenectomy: seen in older kids and adults (Howell-Jolly bodies in peripheral blood after autosplenectomy) results in increased incidence of infections (encapsulated organisms); eg Salmonella osteomyelitis and pneumococcal infections leg ulcers several type of crises, which include vaso-occlusive (pain), aplastic, splenic sequestration (sx: acute LUQ abd mass with dec hemoglobin) 6. inc incidence of infections, such as pneumococcal and Salmonella osteomyelitis (leg pain) 7. hand-foot syndrome (swelling) in children; typical triad of fever, pallor, and symmetric swelling of hands and feet 8. lab tests for hemoglobin S sickling test = metabisulfite test (cant tell disease from trait); metabisulfite is a reducing substance that enhances the process of deoxygenation direct gene diagnosis (such as using MstII endonuclease sites) 9. therapy includes hydroxyurea (increases hemoglobin F) and bone marrow transplantation B. hemoglobin C single nucleotide change in codon causes lysine (basic) to replace normal glutamic acid (acidic) at beta 6 position mild normochromic normocytic anemia, splenomegaly, target cells and rod-shaped crystals in RBCs C. hemoglobin M = methemoglobin (ferric heme), which is oxidized hemoglobin oxidation of hemoglobin causes decreased cooperation between the globin chains, so at high O2 levels hemoglobin M is relatively unsaturated, causing cyanosis (low arterial oxygen saturation, eg SaO2) brown blood (doesn't turn red with air), brown color is due to ferric iron (process is like rust) may be caused by an amino acid substitution
262. Thalassemias A. general thalassemias thalassemias

are quantitative, not qualitative, abnormalities of hemoglobin (cause abnormal alpha:beta ratio) are the most common single-gene disorder world-wide (provide protective advantage to carriers, such as with malaria) note composition of hemoglobins: HbA (alpha2beta2), HbA2 (alpha2delta2), HbF (alpha2gamma2), Hb Barts (gamma4), Hb H (beta4)

folate as dietary supplement for therapy but not iron (patients can develop iron overload from multiple transfusions in severe cases) B. alpha thalassemia 1. basics there are a total of 4 alpha genes and alpha thalassemia is due to gene deletions = 4 clinical diseases (with decreased alpha globin production) alpha chains are expressed prenatally and postnatally, therefore have prenatal and post natal disease 2. genetics = alpha thalassemia is mainly due to gene deletions abnormal genotypes on single chromosome (2 genes per chromosome) -- --/ (alpha thal 1) found in Southeast Asia and Mediterranean, while -- alpha/ (alpha thal 2) found in Africans (therefore less risk of severe disease in children) 3. clinical a) normal = 4 alpha genes (alpha alpha/alpha alpha) and 100 % alpha chains b) silent carrier = one deletion # of alpha genes = 3 (-- alpha/alpha alpha) which produces 75% alpha chains completely asymptomatic and all lab tests normal (infer from pedigrees) c) alpha-thal trait = two deletions (1) # of alpha genes = 2 (2) genotypes cis (-- --/alpha alpha) heterozygous alpha thal 1 is seen in Asians trans (-- alpha/-- alpha) homozygous alpha thal 2 is seen in blacks (offspring's dont develop H disease or hydrops) (3) % alpha chain = 50% (4) differential diagnosis of mild anemia and microcytosis iron deficiency: determine iron levels (thal also has inc numbers of microcytes, while dec iron has dec number of microcytes) beta thal has inc hemoglobins A2 and F d) Hb H = 3 deletions # of alpha genes = 1 (-- --/ -- alpha) which produces 25% alpha chains; one parent needs to have two deletions on one chromosome (ie alpha thal 1) inc Hb H (beta4,) forms Heinz bodies (visualize with crystal blue) e) hydrops fetalis = 4 deletions and is lethal in utero alpha thal major; # of alpha genes = 0 (-- --/ -- --), ie homozygous alpha thal 1, and 0% alpha chains inc gamma4 = Barts both parents needs to have two deletions on one chromosome (ie alpha thal 1) C. beta thalassemia 1. basics there are a total of 2 beta genes (because they are expressed postnatally only postnatal disease) beta thalassemia is due mainly to point mutations, which forms either some beta chains (beta+) or none (beta 0) splicing mutations may result in either beta-0 or beta-+ thalassemia promoter region mutations result in some (but decreased) production of beta-globin (called beta+ thalassemia) chain terminator mutations generally produce beta0 thalassemia; result from either nonsense mutations or frameshift mutations 2. beta-thal minor is asymptomatic except for inc hemoglobin A2 (8%) and inc hemoglobin F (5%) but note: RBC count is normal or inc; that is, dec MCV with inc RBC count = thal minor compare to iron deficiency which has a dec RBC count 3. beta-thal intermedia has a severe anemia, but no transfusions needed 4. beta-thal major (Cooleys anemia) a) patients normal at birth, but symptoms develop at about 6 months as hemoglobin F levels decline b) severe hemolytic anemia because dec RBC life span transfusions required, which results in inc iron accumulation (hemochromatosis) CHF (due to hemochromatosis) is the most common cause of death in these pts c) jaundice (unconjugated hyperbilirubinemia) and inc risk of pigment (bilirubin) gallstones d) intramedullary destruction (ineffective erythropoiesis)

give

e) inc

erythroid precursors in the bone marrow (red marrow), which causes "crew-cut" skull x-ray and inc size of maxilla ("chipmunk face") f) peripheral blood reveals microcytic/hypochromic anemia, numerous target cells (dec osmotic fragility), inc reticulocytes g) hemoglobin electrophoresis reveals inc hemoglobin F (90%) and inc hemoglobin A2 (dec hemoglobin A) h) compared to iron deficiency: beta-thal also has normal RDW (red cell distribution width), low MCV with increased red cell count
263. Paroxysmal

hemoglobinuria (PNH vrs PCH) nocturnal hemoglobinuria (PNH) 1. episodes (paroxysms) of hemolysis at night 2. dec GPI-linked proteins (glycosyl phosphatidyl inositol) especially DAF (decay accelerating factor), aka CD55 normally inc the degradation of C3 convertase deficiency decreases the inhibition of complement (therefore inc complement activity) all cells in blood have inc sensitivity to the lytic actions of complement (lysis of all cell lines) PNH results from acquired mutations in phosphatidylinositol glycan A (PIGA), which is X-linked and is essential for the synthesis of the GPI anchor three GPI-linked proteins that regulate complement are deficienct in PNH: DAF (CD55), membrane inhibitor of reactive lysis (CD59), and a C8 binding protein; CD59 is most important 3. acquired clonal stem cell disorder, therefore effects all cell lines 4. pancytopenia in peripheral blood = anemia, leukopenia, thrombocytopenia 5. inc risk for aplastic anemia, leukemia, venous thrombosis 6. acidosis in vivo, which occurs during sleep (breathing slowly retains CO2) and exercise (lactic acidosis) 7. positive lab tests include acidosis in vitro (Hams test) and sucrose in vitro (sucrose lysis test) B. paroxysmal cold hemoglobinuria (PCH) disease is also called cold hemolysin disease due to biphasic IgG Antibody called Donath-Landsteiner Antibody (anti-P) biphasic means fixes complement in cold and causes RBC lysis in warm (body temp) acute PCH due to viral or mycoplasma, while chronic PCH associated with congenital syphilis symptoms (associated with cold exposure) include chills/fever, muscle pain, and hemoglobinuria
A. paroxysmal

264. Autoimmune A. general

hemolytic anemia (AIHA)

is anti-RBC antibodies 2. lab test is the Coombs test, which is also called the direct antiglobulin test (DAT) anti-globulin antibodies agglutinate antibody-coated RBCs note: indirect Coombs is used to detect antibodies in patients serum 3. peripheral blood shows microspherocytes, which are formed secondary to dec in amount of membrane and are eaten by splenic macrophages 4. inc LDH (glycolytic enzyme released from RBC's) and dec haptoglobin (hemoglobin-binding protein) B. warm AIHA 1. antibodies are IgG that are usually against Rh antigens (not monoclonal) and are active at 37 degrees C (hence "warm") 2. rbc's are removed by splenic macrophages (with Fc receptors) which results in splenomegaly 3. most cases are idiopathic 4. secondary causes include a) autoimmune diseases (such as SLE) b) WDLL/CLL (which is associated with CD5 (T cell) antigen in B cell CLL and SLL) c) drugs (1) hapten model drug binds to RBC membrane and results in formation of IgG antibodies penicillin and cephalosporins (2) immune complexes (type III hypersensitivity reaction) drug binds to plasma proteins which then together combine with antibodies to form immune complexes that are deposited on RBC membranes (RBCs have complement receptor (CR) 1 which bind to C3b)

1. etiology

 quinidine (3) autoAbs

and phenacetin (type II hypersensitivity reaction) IgG antibodies are directed against normal RBC membrane antigens (usually Rh antigens) classic example is alpha-methyl DOPA (Aldomet)

C. cold

AIHA agglutinins a) antibodies are IgM (monoclonal antibodies that are active < 30 degrees C and fix complement) complete activation of complement causes IV hemolysis incomplete activation of complement to C3 causes rbc's to be destroyed by Kupffer cells in liver; therefore hepatomegaly but no splenomegaly b) associations: anti-I (found on all adult RBCs) antibody is associated with mycoplasma pneumonia anti-i (found on cord red blood cells) antibody is associated with infectious mononucleosis Raynauds phenomenon (ischemia with cold exposure causes blanching and numbness followed by cyanosis and red color) 2. cold hemolysins (IgG) = paroxysmal cold hemoglobinuria (PCH), but dont confuse with PNH (see previous)
1. cold

265. isoimmune A. review

hemolytic anemia (antibodies from one person react with RBCs from another person) blood types 1. Rh antigens: five major Rh antigens, called CDEce (Fisher-Race theory); there is no d antigen (called "small d" instead) Rh-positive means the person is D-antigen positive, and Rh-negative means that no D-antigen is present (which is usually indicated by two "d") Rh antigens are inherited in groups of three on each chromosome in a codominant fashion an individual inherits a group of 3 antigens from each parent (somewhat analogous to the HLA antigens) 2. ABO type O: genotype is OO; has no antigens but anti-A, anti-B, anti-AB antibodies; universal donor type A: genotype is either AA or AO; hasA antigen and anti-B antibodies type B: genotype is either BB or BO; has B antigen and anti-A antibodies type AB: genotype is AB; has A and B antigens but no antibodies; universal recipient; can't have an O child B. blood transfusions (type II hypersensitivity reactions involving antibodies against in-situ antigens) 1. acute immune hemolysis (positive DAT) a) acute intravascular hemolysis: involve ABO antigens; severe reactions are due to anti-ABO antibodies (complement-fixing) symptoms (secondary to vasoactive substances) include flushing, hyperventilation, tachycardia, and urticaria (risk of shock and death) b) acute extravascular hemolysis: involve non-ABO antigens; less severe reactions are due to anti-Rh antibodies (not-complement-fixing) EV hemolysis in spleen (splenomegaly) symptoms include chills/fever develop about one hour after transfusion 2. delayed hemolytic usually within two weeks (can occur months to years later though) positive DAT; sx similar to EV hemolysis 3. febrile nonhemolytic transfusion reaction: fever, headache, and facial flushing (negative direct and indirect Coombs) due to preformed anti-leukocyte antibodies C. hemolytic disease of the newborn (HDN) 1. signs anemia, severe jaundice (unconjugated hyperbilirubinemia), and CHF edema due to dec synthesis of albumin (hypoproteinemia); if marked is called hydrops fetalis; if widespread is anasarca risk of kernicterus = unconjugated BR deposition in basal ganglia of brain due to immaturity of blood-brain barrier normoblasts (erythroblasts) in peripheral blood = erythroblastosis (hence the other name erythroblastosis fetalis) 2. anti-Rh antibody (against the D antigen, ie anti-D antibody): Rh negative mother whose first child is Rh positive and second child is Rh positive

depends upon the dose of the antigen (> 1 ml at the time of delivery) response (first pregnancy) is IgM antibody, which can NOT cross the placenta (therefore NO disease with 1st pregnancy) c) subsequent response (subsequent pregnancies) produce IgG antibodies these antibodies can cross the placenta and cause hemolysis in utero (hydrops fetalis) and fetal death d) treatment is Rh- moms (prevent formation of anti-Rh antibodies) give anti-D globulin (RhoGAM) to mom at birth of Rh+ infant (and during pregnancy) binds to and masks D antigen on the fetal RBCs so mothers immune system doesnt see them note: ABO incompatibility also helps to mask RBCs 3. anti-ABO (usually less severe than Rh incompatibility) a) ABO incompatibility in 20% of pregnancies, but only about 10% develop HDN (because ABO antigens are not well expressed prenatally and most ABO antibodies are IgM) b) O moms anti-A, anti-B (usually is IgM, which can NOT cross placenta, but some with IgG antibodies, which can cross the placenta) can have antibodies without prior sensitization, therefore disease is possible with first pregnancy
b) initial 266. Megaloblastic A. general 1. due

a) formation

anemia

to impaired DNA synthesis (delayed mitoses) while RNA is OK asynchrony effects ALL rapidly proliferating cell lines, including cells of bone marrow, GI tract, GYN (can see changes with PAP smear!) 2. enlarged proliferating cells a) RBCs have megaloblastic maturation megaloblasts in bone marrow form macro-ovalocytes in peripheral blood autohemolysis in bone marrow (ineffective erythropoiesis) will cause inc bilirubin and LDH b) WBC changes include giant metamyelocytes in bone marrow and hypersegmented neutrophils (> 5 lobes) in peripheral blood c) note that platelets are not increased in size B. dec vitamin B12 1. biochemistry a) normal biochemical steps involving B12 (cyanocobalamin): methylmalonyl-CoA converted to succinyl-CoA homocysteine converted to methionine b) note: in breakdown of fatty acids with odd numbers of carbons, carbon dioxide, biotin, and carboxylase are involved in converting propionyl-CoA to methylmalonyl-CoA 2. causes of B12 deficiency include: a) dietary deficiency rare because it takes years to develop dietary deficiency (because B12 is stored in the liver, the only non-fat soluble vitamin stored) dietary deficiency seen only in strict vegetarians (diet with no animal proteins, milk, or eggs) b) dec absorption normal: dietary B12 binds to salivary R-binders; B12-R complex broken by pancreatic proteases; free B12 binds to intrinsic factor (IF is secreted by gastric parietal cells); B12-IF complex absorbed by ileal mucosal epithelial cells; B12 transported in blood bound to transcobalamin II dec IF is associated with gastrectomy or pernicious anemia, an autoimmune disorder against gastric parietal cells (increased risk gastric cancer) pancreatic insufficiency (pancreatic proteases normally breakdown R-vit B12 complexes in duodenum) intestinal malabsorption due to parasites (fish tapeworm aka Diphyllobothrium latum), bacteria (blindloop syndrome), or Crohn's disease of ileum (regional enteritis) 3. signs and symptoms a) weakness due to anemia (megaloblastic) b) sore ("beefy") tongue due to generalized epithelial atrophy c) subacute combined degeneration of the spinal cord (SCDSD) = demyelination of the: posterior (sensory) tracts cause loss of vibration and position
nuclear-cytoplasmic

involves dorsal spinocerebellar tracts (arm and leg dystaxia) and corticospinal tracts (spastic paralysis) d) inc methyl malonic acid in urine 4. Schilling test = intramuscular vitamin B12, then give oral radioactive vitamin B12, and measure urine for radioactive vitamin B12 5. for therapy give vitamin B12, which will cause an inc reticulocytes in about 5 days (but symptoms of SCDSC are not reversed with therapy) C. dec folate (tetrahydrofolate (FH4) acts as an intermediate in the transfer of one-carbon units from compounds such as formiminoglutamic acid) 1. causes include: dec intake = dietary (only takes months) deficiency seen in chronic alcoholics and elderly ("tea and toast" diet) dec absorption due to intestinal malabsorption (folate is absorbed in the upper small intestines) inc requirement for folate, such as pregnancy dec utilization = folate antagonists used in chemotherapy (eg methotrexate, which inhibits the reduction of dihydrofolate to tetrahydrofolate; leucovorin is an active form of folate that "rescues" these toxic effects) or anticonvulsants (especially phenytoin) 2. signs and symptoms megaloblastic anemia but NO neurologic symptoms (NO SCDSC) inc FIGLU (formiminoglutamate) in urine D. esoteric causes orotic aciduria (dec orotidylic pyrophosphorylase-orotidylic decarboxylase) causes abnormal growth and megaloblastic anemia in child with normal B12 and folate levels
267. microcytic/hypochromic A. iron

lateral

anemias deficiency 1. forms of iron a) functional iron is found in hemoglobin, myoglobin, enzymes (eg, catalase and cytochromes) b) ferritin is the physiologic storage form (plasma ferritin = total body Fe); good indicator of total body stores c) hemosiderin = degraded ferritin + lysosomal debris (Prussian blue positive) d) iron is transport by transferrin transferrin levels = TIBC (total iron binding capacity) (normal = 300 micrograms/dl) % saturation (normal = one-third saturation, as normal serum iron is 100 micrograms/dl) in many cells transferrin is the surface receptor for the transport of iron into cells, therefore the level of transferrin receptors is inversely proportional to the amount of iron and TIBC is inversely proportional to serum ferritin levels e) dietary forms: heme iron (such as hemoglobin and myoglobin; found in meats) and non-heme iron (found in plants) primary site for absorption is the duodenum (a Billroth II procedure, which connects distal stomach to the jejunum, decreases iron absorption) iron must be in the ferrous state (Fe++) to be absorbed; vitamin C is the most important factor for reducing iron to this ferrous state gastric acid releases iron from heme and non-heme sources, but it does not reduce iron to the reduced state absorption regulated by the Divalent Metal Transporter 1 (DMT1), the product of HFE gene (transports Fe2+ from the intestinal lumen to the cytosol of enterocytes), ferroportin (a transmembrane protein that transports iron from the inside to the outside of a cell), and hephaestin (converts Fe2+ to Fe3+ and mediates iron efflux with ferroportin) hepcidin: master regulator of iron metabolism in humans; directly inhibits ferroportin high hepcidin levels inhibit irons absorption into the blood (hepcidin not only reduces iron uptake from enetrocytes but also suppresses iron release from macrophages) 2. causes of deficiency a) dietary deficiency is seen in elderly, kids, poor b) dec absorption (1) generalized malabsorption (2) s/p gastrectomy

acid production (because acid is needed for ferrous absorption) small intestinal transit time = dumping syndrome, which causes signs of hypoglycemia (lightheadedness, sweating, palpitations) after eating (due to rapid passage of high-osmolarity food into the jejunum) after vagotomy and Billroth II anastomosis (gastrojejunostomy) c) inc demand is seen in kids and pregnant women d) chronic blood loss due to GYN (menstrual bleeding) or GI causes (in United States think carcinoma, in the rest of the world think hookworm) hookworns: decator americanis and ancyclostoma duodenale; the larval form of ancyclostoma duodenale can cause cutaneous larval migrans 3. sequence of events a) first is dec storage iron; patients are not clinically anemic dec serum ferritin (but ferritin is an acute phase reactant and may be artificially elevated, such as with inflammatory disorders) dec stainable iron in the bone marrow b) next is dec circulating iron which causes dec serum iron, inc TIBC, and dec % saturation; patients are still not clinically anemic c) then forms microcytic/hypochromic anemia ( dec MCV and dec MCHC); anisopoikilocytosis with pencil/cigar cells 4. other symptoms inc FEP (free erythrocyte protoporphyrin) epithelial atrophy is seen in Plummer-Vinson syndrome = dec iron, atrophic glossitis (no papillae), dysphagia, and esophageal webs koilonychia = concave nails (spoon nails) with abnormal ridging and splitting; pica = eating unusual things (eg., dirt) 5. treatment: ferrous sulfate B. AOCD anemia of chronic disease is characterized by iron being trapped in bone marrow macrophages (inc serum ferritin with dec TIBC) in some chronic disorders inflammatory mediators, particularly IL-6 increase hepatic production of hepcidin hepcidin inhibits ferriportin function in macrophages (traps iron in bone marrow macrophages) note: anemia associated with chronic renal failure is due to dec erythropoietin (normocytic/normochromic); may need to rx with erythropoietin C. thalassemia: see previous section D. sideroblastic anemia associated with ring sideroblasts in bone marrow (erythroid precursors that have ring of iron in mitochondria around nucleus) may be either pyridoxine (vitamin B6) responsive or pyridoxine unresponsive, which is a form of myelodysplastic syndrome (refractory anemia with ring sideroblasts); may also be associated with certain drugs (INH), lead poisoning, and alcoholism peripheral blood may show dimorphic RBC population (also seen with blood transfusions and treated iron deficiency anemia) lab tests show inc serum iron, inc ferritin, inc FEP, and inc % saturation of TIBC with dec TIBC E. Lab for microcytic/hypochromic anemias iron deficiency: dec serum iron; inc serum TIBC; dec % saturation; decreased serum ferritin; decreased BM sideroblasts; decreased BM iron; increased FEP thal: normal serum iron; normal serum TIBC; normal% saturation; normal/inc serum ferritin; normal BM sideroblasts; normal/inc BM iron; normal FEP AOCD: dec serum iron; dec serum TIBC; normal/dec % saturation; inc serum ferritin; decreased BM sideroblasts; increased BM iron; increased FEP SA: inc serum iron; dec serum TIBC; increased% saturation; increased serum ferritin; increased BM sideroblasts; increased BM iron; increased FEP
dec 268. Other

dec

causes of anemia A. marrow failure (normal marrow has cellularity of about 50% (decreases with age past 50) and a myeloid to erythroid ratio of about 3:1) 1. aplastic anemia (due to failure of multipotential stem cells, which will cause hypocellular marrow)

blood reveals pancytopenia (anemia, neutropenia, and thrombocytopenia), and there is no reticulocytosis or splenomegaly causes include radiation, benzene, certain infections (hepatitis C), Fanconi's syndrome (hypoplasia of kidney, spleen, thumbs, and radii) treatment with allogenic BM transplant, transfusion, G-CSF or GM-CSF 2. pure red cell aplasia may be associated with thymoma, myasthenia gravis, or parvovirus infection (parvovirus B19, which causes "slapped cheek" disease can also cause acute red cell aplasia in child with chronic hemolytic anemia, such as thalassemia or sickle cell) or drugs (eg AZT rx for AIDS) 3. myelophthisic anemia = space occupying lesion in the marrow causes include mets to marrow (think prostate primary in older male), granulomas (TB or sarcoid), and fibrosis (myelofibrosis) peripheral blood show immature RBC's (nucleated red blood cells) and immature WBC's (myelocytes), which is called leukoerythroblastosis B. trauma trauma = microangiopathic anemia (which causes IV hemolysis) peripheral blood shows schistocytes, helmet cells, and increased polychromasia causes include DIC, HUS/TTP, vasculitis, prosthetic or calcified cardiac valves, and march hemoglobinuria C. porphyria 1. porphyrias are due to dec heme synthesis (which result from deficiencies of the enzymes involved in heme synthesis) 2. general signs and symptoms skin changes include photosensitivity and hypertrichosis; neurologic changes include psychosis and seizures other abnormalities include red fluorescent urine, hemolytic anemia, and erythrodontia (?werewolves vrs vampires) 3. AIP (acute intermittent porphyria) is due to dec PBG deaminase (URO-I synthase) (AD inheritance) inc delta-ALA (amino-levulinic acid) and PBG in liver and urine (differential diagnosis of inc ALA is lead poisoning) signs include episodic abdominal colic and neuropsychiatric changes (hallucinations and manic-depressive episodes) 4. CEP (congenital erythropoietic porphyria) is due to dec URO-III cosynthase (AR inheritance) inc URO-I in RBC's and urine signs include skin damage (due to severe photosensitivity), hypertrichosis, hemolytic anemia with red urine and red teeth (erythrodontia) 5. PCT (porphyria cutanea tarda) is the most common porphyria and is due to dec hepatic URO decarboxylase (AD inheritance) inc UPG-I and UPG-III in liver and urine signs include photosensitivity (causing scaring), skin pigmentation, and facial hypertrichosis signs are worse with alcohol ingestion, estrogens, iron supplements 6. VP (variegate porphyria) is due to dec PROTO oxidase (AD inheritance found in Afrikaner whites of South Africa and "Royal Malady" of George III) inc PROTO in liver and feces signs include episodic abdominal colic, skin changes, and neuropsychiatric changes signs are precipitated by barbiturates (phenobarb), sulfonamides, alcohol (which are metabolized by hepatic cytochrome P450, causing hyperplasia of cytochrome P450, which causes dec synthesis of heme and dec formation of hemin, which is normally an important inhibitor of ALA synthetase) treat acute attacks with IV hemin D. lead 1. lead inhibits enzymes in heme synthesis (lead has a high affinity for sulfhydryl groups) including ALA dehydratase (results in increased ALA in urine) ferrochelatase (aka heme synthetase) which normally causes iron chelation to protoporphyrin (results in increased FEP) ?? some say ALA synthase too (but wouldn't increase ALA) 2. anemia (hypochromic microcytic) basophilic stippling of red cells (clusters of ribosomes) inc FEP (free erythrocyte protoporphyrin), inc urinary ALA, inc zinc protoporphyrin 3. neurologic effects:

peripheral

characterized by dec mental abilities (dec IQ in children) and convulsions (if severe) neuropathy due to demyelination (foot drop and wrist drop) 4. GI findings include lead colic ("painters cramps" or abdominal colic) due to severe contraction of smooth muscle of intestinal wall lead line in gingiva 5. treatment: either BAL (dimercaprol) or a chelating agent, such as EDTA
peripheral 269. Polycythemia A. relative: B. absolute 1. primary 2. secondary

encephalopathy

= inc # of red cells due to dec plasma volume (hemoconcentration) as seen with dehydration or vomiting/diarrhea

= polycythemia rubra vera (a myeloproliferative syndrome that is associated with dec EPO) (is due to increased EPO) appropriate inc RBC's can be due to lung disease, cyanotic heart disease, and high altitude inappropriate is due paraneoplastic secretion of EPO by tumors such as renal cell carcinoma, hepatic carcinoma, and cerebellar hemangioblastoma

WHITE BLOOD CELLS

270. Leukopenia A. dec

= decreased numbers (hypoplasia) of white blood cells (primarily neutropenia) production (bone marrow shows decreased precursors in the marrow) dec stem cells: seen with aplastic anemia, leukemias/lymphomas, megaloblastic anemia drugs (most common); suppression may be predictable (dose-related) (eg chemotherapeutic agents or chloramphenicol), or unpredictable (idiosyncratic) cyclic neutropenia (stem cell defect; rx with G-CSF) infections (Ehrlichia chaffeensis invades neutrophils and monocytes and causes fever, headache, myalgia with "asterisk-shaped" inclusion in WBCs) therapy may include GM-CSF and GSF B. inc destruction (bone marrow shows increased precursors (hyperplasia) in the marrow) 1. immune induced destruction due to drugs (antibodies against white blood cells; may cause destruction in the spleen with hyperplasia of the myeloid series in the bone marrow) Feltys syndrome (rheumatoid arthritis, splenomegaly, and neutropenia), which is due to a proliferation of large granular lymphocytes 2. sequestration in spleen (splenomegaly) 3. inc utilization of neutrophils may result from viruses, rickettsia, or overwhelming sepsis blood leukocytosis neutrophils (neutrophilia) inc bone marrow production seen with acute inflammation associated with pyogenic bacterial infection, tissue necrosis, or acute inflammation inc release from bone marrow storage pool caused by corticosteroids, stress, or endotoxin demargination of neutrophils in peripheral blood seen with acute infection, exercise (eg running a marathon), epinephrine increased LAP (leukocyte alkaline phosphatase, which is found in neutrophils) is useful to differentiate from neoplastic CML (which has dec LAP) Dohle bodies (aggregates of RER), toxic granulations (prominent granules), and cytoplasmic vacuoles of neutrophils (May-Hegglin abnormality consists of numerous large Dohle bodies, giant platelets, and variable dec # platelets leading to purpura) inc bands ("left shift") in peripheral blood; very high numbers of neutrophils in a reactive process = leukemoid reaction B. inc eosinophils (eosinophilia) allergies and asthma (type I hypersensitivity reaction) parasites and drugs (especially in hospital) certain skin diseases and certain cancers (adenocarcinomas) C. inc monocytes (monocytosis) certain chronic diseases, such as some collagen vascular diseases and inflammatory bowel disease (IBD) certain infections, especially TB
A. inc

271. Peripheral

D. inc

lymphocytes (lymphocytosis) (viral diseases) or chronic inflammatory processes (not usually increased with bacterial infections, except for diphtheria) may see plasmacytoid lymphocytes and atypical lymphocytes (abundant deep blue cytoplasm and may be indented by adjacent erythrocytes producing a "ballerina-skirt" appearance) E. basophils/mast cells: associated with type I hypersensitivity reactions basophilia seen with allergic reactions, myeloproliferative syndromes
acute 272. Non-neoplastic A. acute 1. focal

proliferations of lymph nodes

involvement is seen with bacterial lymphadenitis (acute suppurative lymphadenitis) see neutrophils within the lymph node note: cat-scratch fever (most cases due to Bartonella henslae; rare cases caused by Afipia felis) causes combined stellate suppurative (microabscesses) and granulomatous inflammation (similar to granuloma inguinale) 2. generalized involvement is seen with viral infections (see reactive T cells immunoblasts in lymph nodes and peripheral blood) B. chronic follicular hyperplasia (involves B lymphocytes) and may be seen with rheumatoid arthritis, toxoplasmosis, and early HIV infections toxoplasma in lymph nodes: follicular hyperplasia, monocytoid B cell proliferation, and epithelioid histiocytes infiltrating lymphoid follicles monocytoid B cells are now called marginal cells AIDS: initially show follicular hyperplasia with loss of mantle zones, intrafollicular hemorrhage ("follicle lysis"), and monocytoid B cell proliferation; later there is depletion of lymphocytes (CD4+ lymphocytes) in both the follicles and the interfollicular areas paracortical and interfollicular lymphoid hyperplasia: involves T cell immunoblasts and may be seen with viral, drugs (Dilantin), and SLE sinus histiocytosis (involves macrophages) in most cases are nonspecific, an example is lymph nodes draining cancers; exceptions include sinus histiocytosis with massive lymphadenopathy (found in Jamaican children) and lymph nodes draining chronic skin infections which may contain melanin pigment and hemosiderin (dermatopathic lymphadenopathy)
may 273. Acute

leukemias A. general 1. peripheral blood has dec mature forms and inc immature forms (blasts, which have immature chromatin with nucleoli) 2. bone marrow has inc immature cells (blasts); the WHO diagnostic criteria is > 20% blast in bone marrow (FAB criteria is > 30%, see below) 3. acute symptoms are secondary to marrow failure causing dec RBC (anemia and fatigue), dec WBC (infections and fever), dec platelets (bleeding) 4. myelodysplastic syndromes (MDS) are classified based on number of blasts in marrow (2 major classifications: FAB and WHO (world health org)) a) general characteristics inc risk of developing acute leukemia (preleukemias) dysplastic changes include Pelger-Huet cells ("aviator glasses" nuclei), ring sideroblasts, nuclear budding, "pawn ball" megakaryocytes, hypersegmented neutrophils, hypogranular neutrophils b) FAB (French-American-British) classification <5% blasts = refractor anemia (with or without ring sideroblasts) 5-20% blasts = refractory anemia with excess blasts (RAEB) 20-30% blasts = refractory anemia with excess blasts in transformation (RAEB-IT); note more than 30% blasts = acute leukemia c) WHO: reduced blast requirement for AML from 30% to 20%, eliminated RAEB-IT, added multilineage dysplasia and 5q- syndrome refractory anemia with or without ring sideroblasts refractory cytopenia with multilineage dysplasia

type 1 (5-9% blasts in blood/marrow), type 2 (10-19% blasts in blood/marrow) syndrome, or therapy related MDS, or MDS, unclassified B. ALL (acute lymphocytic leukemia) 1. lymphoblasts: positive for TdT (terminal deoxytransferase, a nuclear stain), PAS, and acid phosphatase (myeloperoxidase negative; no Auer rods) 2. ALL is associated with CNS infiltration (give prophylactic radiation to head because malignant cells in brain are protected from chemotherapy by blood-brain barrier) 3. increased risk of ALL in first few years of life in individuals with Down syndrome 4. FAB classification (French-American-British) of ALL (not used today) L1 = small homogenous blasts with immature chromatin and nucleoli (85% of cases of ALL) L2 = larger, heterogenous (pleomorphic) blasts with nuclear clefts L3 = (<1% of cases) large blasts with cytoplasmic vacuoles that stain with oil red O (leukemic form of Burkitts lymphoma) 5. immunologic classification of ALL a) T-cell lineage (T-ALL is similar to T lymphoblastic lymphoma) is associated with mediastinal mass (think T = thymus = mediastinal) in young (adolescent) adult male up to 70% of T-ALLs have gain-of-function mutations in NOTCH1, a gene that is essential for T-cell development negative DR (Ia); negative surface Ig; negative cytoplasmic mu; negative CD10 b) B-cell lineage surface immunoglobulin (sIg) present = mature B-ALL (aka FAB L3, the leukemic form of Burkitts lymphoma) cytoplasmic mu present = pre-B-ALL; associated with translocation t(1;19); express Tdt, CD19, CD10, and CD22 early pre B-ALL: seen primarily in children; may be CALLA (CD10) positive (most common type of ALL) or negative presence of CALLA in early pre B-ALL makes prognosis very good 6. prognosis with translocations t(12;21), which is TEL-AML-1 fusion, has excellent prognosis t(4;11) and t(11;19), which involve the MLL gene product, have poor prognosis t(1;19) has neutral prognosis t(9;22) has bad prognosis C. AML (acute myelocytic leukemia) 1. myeloblasts may have intracytoplasmic rods (stain red) called Auer rods (rarely found except for M3 AML) abnormal lysosomes (primary granules) that are pathognomonic of myeloblasts and NOT found in ALL they also stain positive with myeloperoxidase (MPO) or sudan black B stain (this stain is used to tell AML from ALL, as lymphoblasts do not stain) 2. tissue form of AML is called granulocytic sarcoma (chloroma; old term, indicates green color grossly; remember myeloperoxidase can produce a green color) 3. FAB classification (French-American-British) of AML a) M0 = undifferentiated b) M1 = myeloblastic leukemia without maturation; markers of immature myeloid cells include CD34 and CD33 c) M2 = myeloblastic leukemia with maturation (some promyelocytes) d) M3 = hypergranular (microgranular) promyelocytic leukemia (1) numerous cytoplasmic granules and numerous Auer rods (2) may develop DIC due to release of thromboplastic substances in granules (especially when therapy kills the leukemic cells) (3) characteristic translocation = t(15;17) 15 has the PML unit (promyelocytic), while 17 has the retinoic acid receptor alpha (RAR-alpha) forms an abnormal retinoic acid receptor, therefore therapy with all-trans-retinoic acid is possible e) M4 = myelomonocytic leukemia has both myeloblasts and monoblasts staining pattern shows mixture of cells, some positive and others negative for staining with nonspecific esterase (NSE) f) M5= monocytic leukemia (may have gingival infiltrates); staining pattern of monoblasts: positive for myeloperoxidase, sudan black B, nonspecific esterase (inhibited by fluoride)
5q-

RAEB,

for TdT and PAS = erythroleukemia (DiGuglielmos disease) has abnormal erythroid precursors (binucleate and megaloblastic changes) h) M7 = acute megakaryocytic leukemia is associated with acute myelofibrosis due to release of PDGF (stain positively for GPIIb/IIIa or vWF)
g) M6 274. Chronic

negative

leukemia lymphocytic leukemia (CLL) 1. very similar to WDLL (well-differentiated lymphocytic lymphoma), which is aka SLL (small lymphocytic lymphoma) lymph node involvement common (50%) patient presents with blood findings = CLL, while patient presents with lymph node findings = SLL 2. classification a) B-CLL (95% of cases) have B-cell markers (eg CD19, 20, 21) one T-cell marker is also present = CD5, which is thought to be related to AIHA also important is that the cells are CD23 positive and CD10 negative b) T-CLL (5% of cases) have T cell markers 3. peripheral blood has inc inc lymphocytes which are normal-appearing, but numerous smudge cells are present ("parachute cells") 4. bone marrow has numerous of these normal-appearing lymphocytes 5. clinical most indolent of all of the leukemias mean age at time of diagnosis is 60; sx include anemia, fatigue, and generalized, non-tender lymphadenopathy malignant cells are non-functional and pts develop hypogammaglobulinemia (therefore inc risk of infections) associated with warm AIHA (10% of cases), which will cause spherocytes to be in peripheral blood rarely transform into worse disease, such as prolymphocytic leukemia (prolymphocytes are large lymphocytes with prominent nucleoli and mature (coarse) chromatin) or Richters syndrome (large cell lymphoma) CLL is associated with trisomy 12 in leukemic cells B. chronic myelocytic leukemia (CML) 1. one of the four MPS (myeloproliferative syndromes) 2. clonal proliferation of pluripotent stem cells 3. hypercellular bone marrow (all cell lines inc in number) 4. unique chromosomal translocation = Ph (Philadelphia) chromosome, which has t(9;22) 9 has c-abl (an oncogene), while 22 has bcr (breakpoint cluster region), which is not an oncogene forms new protein P210 that has tyrosine kinase activity (ie, non-receptor associated tyrosine kinase) 5. insidious onset (chronic) 6. peripheral leukocytosis inc inc inc neutrophils (and bands and metamyelocytes) inc eosinophils and basophils (like the other MPS) 7. dec dec LAP (leukocyte alkaline phosphatase): compare with leukemoid reaction which has inc LAP 8. prognosis/therapy a) previous therapy: control with hydroxyurea slow progression (1/2 develop accelerated phase <5 years; characterized by increasing anemia and thrombocytopenia) then blast crisis (very bad prognosis); 2/3 myeloid blasts and 1/3 lymphoid blasts b) new therapy: Glivec (formerly known as STI571): an inhibitor of the tyrosine kinase produced by the Philadelphia chromosome also used to treat GIST, gastrointestinal stromal tumors
A. chronic

275. Non-Hodgkin's

lymphoma (Working Formulation) (non-Hodgkin's lymphomas in the marrow are typically paratrabecular; ie next to the bone spicules) A. low grade lymphomas 1. small lymphocytic lymphoma (SLL); previously well-differentiated lymphocytic lymphoma (WDLL)

diffuse pattern (not nodular) of small B lymphocytes, which have B cell markers and one T cell marker (CD5), like B-CLL frequently has a leukemic phase and has a propensity for metastasis to the bone marrow 2. follicular small cleaved (<20% large cells in follicles) small cleaved cells are also called centrocytes (small cells with irregular or cleaved nuclear contours and scant cytoplasm) small cleaved cells in peripheral smear are called "buttock cells" 3. follicular mixed small and large cell (20-50% large cells, which are also called centroblasts: larger cells with open nuclear chromatin, several nucleoli, and modest amounts of cytoplasm) 4. notes for follicular lymphomas a) all follicular lymphomas are derived from B lymphocytes of germinal centers; follicular lymphomas lack the tingible-body macrophages seen in reactive germinal centers of follicular hyperplasia b) associated with characteristic translocation t(14;18) 14 has immunoglobulin heavy chain genes, 18 has bcl-2 (activation of bcl-2 inhibits apoptosis by blocking bax channel; bcl-2 is not activated in reactive germinal centers) c) commonly present with disseminated disease (more advanced stage) but better prognosis than diffuse lymphomas, but dont respond to therapy (unlike the more aggressive diffuse lymphomas) d) up to 1/2 of cases will progress to a diffuse large cell NHL B. intermediate grade lymphomas follicular large cell (>50% large cells) diffuse lymphomas, which include diffuse small cleaved, diffuse mixed small cleaved and large cell, and diffuse large cell (some body-cavity large B-cell lymphomas are associated with HHV-8; diffuse large B-cell lymphomas are associated with dysregulation of bcl-6) C. high grade lymphomas 1. immunoblastic lymphoma (immunoblasts that have prominent central nucleoli are usually B immunoblasts) most are B-immunoblastic lymphoma and may be associated with autoimmune diseases (such as Sjgren's syndrome or Hashimoto's thyroiditis) or immunosuppression (such as AIDS and renal transplant) aka immunodeficiency-associated B-cell lymphomas (and are often infected with EBV) 2. lymphoblastic lymphoma (majority of cases are T cells which are aggressive and rapidly progressive) leukemic phase of lymphoblastic lymphoma is similar to T-ALL young males with mediastinal mass (think thymus) mx shows diffuse proliferation of immature lymphocytes with convoluted nuclei 3. small noncleaved lymphoma (not the same as SLL) a) non-Burkitts type b) Burkitts type cytoplasmic lipid vacuoles that are ORO positive (leukemic form is L3 ALL) "starry-sky" appearance histologically due to numerous reactive tingible-body macrophages (which are the "stars") African type is the endemic form (involvement of mandible or maxilla is characteristic) that is associated with EBV and characteristic t(8;14) translocation where 14 has immunoglobulin heavy chain and 8 has oncogene c-myc American type is non-endemic from that commonly involve abdomen (such as bowel, retroperitoneum, or ovaries)
proliferation 276. Other

only

heme malignancies cell lymphoma not in original Working classification (aka intermediate differentiated lymphocytic lymphoma, "intermediate" does not refer to grade) arise from mantle zone B lymphocytes (positive for CD19, CD20, CD5, negative for CD23) most cases of small cleaved NHL are in fact mantle cell lymphoma associated with characteristic translocation t(11;14): 11 has bcl-1 (cyclin D) while 14 has immunoglobulin heavy chain genes B. marginal zone lymphoma may arise inside or outside lymph nodes (extranodal) begins as reactive polyclonal reaction and may be associated with previous autoimmune disorders
A. mantle

localized for long periods of time (associated with mucosa-associated lymphoid tissue = MALT lymphomas) MALT lymphomas are often associated with translocations involving either the MALT1 or the BCL10 gene C. hairy cell leukemia indolent disease of older males lymphocytes have "hair-like" cytoplasmic projections ("dry tap" with bone marrow aspiration) diagnostic staining pattern is TRAP (tartrate-resistant acid phosphatase) positive typically express the pan-B-cell markers CD19 and CD20, surface Ig (usually IgG), and certain relatively distinctive markers, such as CD11c, CD25, and CD103 markedly enlarged spleen (splenomegaly) due to malignant infiltrate of red pulp treatment with 2-chlorodeoxyadenosine (2CdA) which inhibits adenosine deaminase (ADA) and inc's toxic deoxyadenosine D. anaplastic large cell lymphoma T lymphocytes that are CD30 (Ki-1) positive = Ki-1 lymphoma clinical: aggressive with extranodal involvement (skin (usual), lungs, CNS) "hallmark" cells with horseshoe-like or "embryo-like" nuclei; some have rearrangement of ALK E. ATLL (adult T-cell leukemia/lymphoma) malignant T cell disorder (CD4-T cells) due to HTLV-1 found in Southern Japan or Caribbean skin lesions, hypercalcemia, enlarged lymph nodes, liver, and spleen (hyperlobated "4-leaf clover" lymphocytes in peripheral blood) F. mycosis fungoides malignant T cell disorder (post-thymic CD4 cells), but better prognosis than ATLL generalized pruritic erythematous rash (no hypercalcemia) sequence of skin changes (stages): first is inflammatory eczematous, second is plaque stage, third is tumor nodules stage mx reveals atypical PAS-positive lymphs in epidermis (epidermotropism) (aggregates of these cells are called Pautrier microabscesses) cerebriform Szary cells in peripheral blood = Szary syndrome (which is also associated with a generalized exfoliative skin rash)
277. REAL

remain

classification (revised European-American classification of lymphomas) B-cell neoplasms (immature B cells): precursor B-cell ALL B. peripheral B-cell neoplasms (mature B cells) SLL/CLL follicular lymphoma diffuse large B-cell lymphoma Burkitt lymphoma mantle cell lymphoma extranodal marginal zone lymphoma hairy cell leukemia multiple myeloma C. precursor T-cell neoplasms (immature T cells): precursor T-cell ALL D. peripheral T-cell neoplasms (mature T cells) ATLL anaplastic large cell lymphoma mycosis fungoides/Sezary syndrome
A. precursor

278. Hodgkin's

disease with NHL bimodal age group distribution (late 20s and > 50) clinically may present similar to infection (fever) spread is contiguous to adjacent node groups (unlike non-Hodgkin's lymphomas) classification based on inflammatory response and not malignant cell no leukemic state, but involvement of spleen and liver is common (nodal disease precedes splenic disease which precedes hepatic disease which precedes bone marrow disease which precedes extranodal disease) B. malignant cell
A. differences

(Reed-Sternberg) cell appearance = symmetric (mirror image) bilobed nucleus with prominent central nucleoli surrounded by clear space in most cases the Ig genes of Reed-Sternberg cells have undergone both V(D)J recombination and somatic hypermutation; probable origin from a germinal center or post-germinal-center B cell 2. variants mononuclear cells may be found in any of the subtypes L-H cells = "popcorn" cells (are seen only in LP HD) lacunar cells (clear space surrounding) are seen only in NS HD pleomorphic cells are seen in LD HD 3. markers positive for CD15 (Leu-M1) and CD30 (Ki-1) except for LP HD in which the malignant cells stain for B cells markers typical of germinal-center B cells, such as CD20 and BCL6, and have negative CD15 and CD30 C. classification LP (lymphocyte predominant) type has L-H cells (popcorn cells) and are negative for CD15 and CD30 (cells may originate from follicular B-cells and transform into diffuse large cell B cell lymphoma) LP (lymphocyte-rich) type has lots of lymphocytes, frequent RS cells, which are CD15 and CD30 positive mixed cellularity has eosinophils and plasma cells (inc eosinophils is related to IL-5 secretion) LD (lymphocyte depleted); few lymphocytes and numerous RS cells, many of which are pleomorphic in appearance (pleomorphic variants) NS (nodular sclerosis) has lacunar cells and broad collagen bands (this is the most common subtype and is the only type more common in females) types associated with EBV: mixed cellularity, lymphocyte-rich, lymphocyte depleted; not: nodular sclerosis or lymphocyte predominate D. staging B symptoms = fever (that come and go = Pel-Epstein fever), weight loss, night sweats (A = asymptomatic) I = one lymph node involved; II = multiple lymph nodes involved (same side of diaphragm); III = multiple lymph nodes involved (both sides of diaphragm); IV = extranodal involvement E. clinical usually patients present with painless enlargement of lymph nodes a bad prognosis is directly proportional to the # of R-S cells present and inversely proportional to the # of lymphocytes rx with radiation +/- combination chemotherapy, particularly MOPP (mechlorethamine, vincristine, procarbazine, prednisone) or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) survivors of chemotherapy and radiotherapy have inc risk for non-Hodgkins lymphoma or acute leukemia years later
"owl-eye" 279. MPS

1. RS

(myeloproliferative syndromes)

A. general

are clonal neoplastic proliferation of multipotential myeloid stem cells 2. bone marrow is markedly hypercellular (hence the name myeloproliferative) all cell lines (erythroid, myeloid, and megakaryocytes) can not tell MPS apart by histologic appearance of the bone marrow B. P. vera (polycythemia rubra vera) incerythroid precursors with inc red cell mass (primary), inc hematocrit, inc blood viscosity (deep vein thromboses and infarcts) dec EPO (erythropoietin), but red blood cells have inc sensitivity to EPO and proliferate too much associated with mutations in JAK2 (makes hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin) inc basophils and inc eosinophils (like all of the MPS) inc LAP (leukocyte alkaline phosphatase) plethora (redness) and cyanosis (blue) histamine release from basophils and mast cells causes intense pruritus and gastric ulcers (bleeding may cause iron deficiency) high cell turnover can cause hyperuricemia (gout)

1. MPS's

develop into "spent phase" with myelofibrosis (also inc risk for acute leukemia) (myelofibrosis with myeloid metaplasia) 1. etiology is unknown (agnogenic) 2. bone marrow aspiration may be "dry tap", but biopsy specimen shows hypocellular marrow with fibrosis (inc reticulin) fibroblasts are polyclonal proliferation (not neoplastic) fibrosis is secondary to factors released from megakaryocytes, such as PDGF (platelet-derived growth factor) 3. inc spleen due to extramedullary hematopoiesis (myeloid metaplasia): spleen is most common site for extramedullary hematopoiesis 4. peripheral smear reveals leukoerythroblastosis (immature white cells and nucleated red cells) plus teardrop RBCs (which is associated with extramedullary hematopoiesis in spleen) 5. high cell turnover causes hyperuricemia (gout) D. ET (essential thrombocythemia); not the same as thromobytosis, which is reactive inc numbers of platelets inc megakaryocytes (and other cell lines) in bone marrow peripheral blood shows inc number of platelets (> 1,000,000) some with abnormal shapes (also inc numbers of leukocytes) signs include excessive bleeding and occlusion of small vessels associated with mutations in JAK2 E. CML: see previous
C. MF 280. Plasma

may

cell dyscrasias A. multiple myeloma 1. most common primary tumor arising in bone of adults 2. clinical triad: hypercalcemia, multiple lytic bone lesions, and increased plasma cells in the bone marrow 3. M spike = monoclonal immunoglobulin spike (lab shows inc serum protein with normal serum albumin) most common is IgG (60%) or IgA (20%), but note that IgM myeloma is not the same as Waldenstrom's macroglobulinemia 20% have Bence-Jones proteins, which are light chains that are small and can be filtered into urine (therefore, no M spike) 4. bone marrow has inc #s plasma cells (>20% is characteristic) 5. peripheral blood may show rouleaux ("stack of coins") 6. multiple lytic bone lesions due to release of RANKL by bone marrow stromal cells, which activates osteoclasts IL-6 is an important cytokine (inc amounts of IL-6 are associated with a worse prognosis because survival of myeloma cells is dependent on IL-6) lytic bone lesions cause hypercalcemia and bone pain 7. increased risk infection, which is the most common cause of death 8. renal disease, such as myeloma nephrosis 9. amyloidosis (10% of patients) due to amyloid light (AL) chains 10. solitary aggregates of plasma cells (plasmacytomas) may be within bone (and are precursor lesions to later develop myeloma) outside bone (extramedullary), which are found usually within upper respiratory tract and are not precursor lesions for myeloma B. Waldenstrm's macroglobulinemia 1. aka lymphoplasmacytic lymphoma or small lymphocytic lymphoma with plasmacytic differentiation 2. Waldenstrom's is a cross between multiple myeloma and small lymphocytic lymphoma (SLL) like myeloma has M spike (IgM) like SLL (unlike myeloma) the neoplastic cells infiltrate many organs, such as lymph nodes, spleen, and bone marrow (plasma cells, lymphocytes and plasmacytoid lymphocytes, called p lymphs, are increased in numbers, but there are no tumor masses in bone, and therefore there is no inc serum calcium); may also see Dutcher bodies (intranuclear immunoglobulin) 3. hyperviscosity syndrome because IgM is pentamer (large) visual abnormalities, may see vascular dilatations and hemorrhages in retina neurologic symptoms include headaches and confusion

 bleeding C. other 1. MGUS

and cryoglobulinemia (abnormal globulins precipitate at low temperature and may cause Raynauds phenomenon or cold urticaria)

(monoclonal gammopathy of undetermined significance) (old name was benign monoclonal gammopathy) M protein is found in 1-3% of asymptomatic individuals over the age of 50 (the incidence increases with increasing age) about 20% of these individuals will develop a plasma cell dyscrasia in 10-15 years 2. heavy chain disease (only heavy chains are produced and not the entire immunoglobulin) alpha heavy chain disease involves sites of normal IgA production (respiratory tract and small intestines, involvement of the latter site being called Mediterranean lymphoma, which is associated with previous bacterial infection and IPSID (immunoproliferative small intestinal disease)) gamma heavy chain disease is found in older patients and is similar to lymphoma and produces diffuse lymphadenopathy mu heavy chain disease is a very rare complication of CLL
281. Infectious A. cause:

mononucleosis most common is EBV (a herpesvirus) but less commonly due to other viruses (heterophile-negative IM is most likely due to CMV) B. sequence of events EBV invades B lymphocytes via CD21 (CR2) receptor cytotoxic (CD8) T lymphocytes respond against invaded B cells and form atypical lymphocytes (Downey cells), which are enlarged lymphocytes that have abundant cytoplasm that is condensed peripherally ("ballerinaskirt" appearance); similar in appearance to monocytes, hence the name "mononucleosis" atypical lymphocytes are found in the peripheral blood and T cell areas of lymph nodes (paracortex) and may cause misdiagnosis as Hodgkins disease histologically ( therefore, dont biopsy a lymph node!) C. antibody production heterophil antibodies (antibodies against other species such as red cells of sheep and horses) are the basis of the Paul-Bunnell reaction which is used as the Monospot test (may be negative first week, so need to repeat test in about one week) D. clinical age groups ("kissing disease") include adolescents and young adults symptoms (classic triad) = fever, sore throat (see gray-white membrane on tonsils), and lymphadenitis (posterior auricular nodes) (4th sign is hepatosplenomegaly) acute, self-limited disease (resolves in 4 to 6 weeks) complications include hepatic dysfunction, splenic rupture, and rash if treated with ampicillin cell histiocytosis/spleen cell histiocytosis (old name is histiocytosis X) 1. general proliferation of cells similar to the antigen-presenting dendritic Langerhans cells of the epidermis cytoplasmic granules (diagnostic) are rod-shaped organelles that look like tennis rackets; called LC (Langerhans cell) granules, pentilaminar bodies, or Birbeck granules a bad prognosis is indirectly proportional to age (young is bad) and directly proportional to dissemination (diffuse is bad) 2. acute disseminated Letterer-Siwe disease (affects children < 3 years of age) seborrhea-like lesions of skin with hepatosplenomegaly and lymphadenopathy involvement of bone marrow causes anemia, thrombocytopenia, and leukopenia (recurrent infections) prognosis is poor (usually rapidly fatal without chemotherapy) 3. multifocal Hand-Schuller-Christian disease (affects children aged 2-6) triad of signs due to tumor masses = lytic bone lesions of skull, exophthalmos, and diabetes insipidus (dec ADH causes polydipsia and polyuria with inc serum osmolality and dec urine osmolality) prognosis is good 4. unifocal

282. Langerhans

A. Langerhans

 focal

granuloma-like B. spleen splenic

skeletal lesion (ribs) found in adults; prognosis is excellent lesions contain lipid-laden Langerhans cells (think oil red O stain), macrophages, lipidladen lymphocytes, and eosinophils = eosinophilic granuloma

rupture = severe abdominal pain radiating to left scapula, hypotension, peritoneal tap grossly bloody after trauma no spleen (or autoinfarction with sickle cell): increased risk of infection with encapsulated organisms; about 50% due to strep pneumonia; also H. influenzae and neisseria meningitidis causes of enlarged spleen (splenomegaly) include hypersplenism, infections, congestive splenomegaly (due to portal hypertension), extramedullary hematopoiesis (with myelofibrosis), leukemias (CLL, CML, hairy cell leukemia) hypersplenism can cause destruction of any of the cells in the blood (causing anemia, leukopenia, thrombocytopenia) PLATELETS AND BLEEDING
283. Bleeding A. types

of bleeding 1. petechiae are < 2 mm; purpura are 2 mm to 1 cm; ecchymoses are > 1 cm 2. clinical classification of purpura non-palpable purpura may be due to excess corticosteroids (Cushing's), dec vitamin C (scurvy), infections (meningococcemia, septicemia, rickettsia), abnormal connective tissue (Ehlers-Danlos) palpable purpura may be due to cutaneous vasculitis (collagen vascular diseases or Henoch-Schonlein purpura) B. signs abnormalities of blood vessels produce small, spontaneous hemorrhages (skin and mucus membranes) namely petechiae and purpura abnormalities of platelets produce petechia and purpura abnormalities of coagulation factors produce ecchymoses and hematomas C. tests platelet tests include platelet count (number) and morphology bleeding time tests for abnormalities of blood vessels or platelets (not the coagulation cascade); does not predict surgical bleeding; replaced by platelet function analyzer; pointless to do bleeding time if platelet count is less than 100,000 prothrombin time (PT) tests for components of the extrinsic coagulation pathway (V, VII, X, prothrombin, fibrinogen) PT/INR = international normalized ratio; want 2-3 for stable coumadin therapy partial thromboplastin time (PTT) tests for components of the intrinsic coagulation pathway (XII, XI, IX, VIII, X, V, prothrombin, fibrinogen) PTT is sensitive to heparin (unfractionated); not sensitive to low molecular weight heparin (for this use antifactor Xa assay) thrombin time (TT) tests for adequate fibrinogen levels fibrin degradation products (FDP) tests fibrinolysis system (inc with DIC and PE) anti-factor Xa assay: used to evaluate new heparin tourniquet test: not routinely used
284. platelet

abnormalities (signs of platelet abnormalities are petechiae (minute pin-sized hemorrhages) and purpura (large red, nonblanching)) A. ITP (immune thrombocytopenic purpura) 1. antiplatelet antibodies (against platelet antigens such as Gp IIb/IIIa and Gp Ib/IX) (antibodies are made in the spleen) 2. platelets destroyed peripherally in spleen (macrophages with Fc receptors bind IgG-coated platelets) 3. bone marrow reveals inc #s megakaryocytes (some immature) note that drug-induced thrombocytopenia has dec #s megakaryocytes in bone marrow 4. peripheral blood shows decreased numbers of platelets (thrombocytopenia) and may see enlarged platelets too 5. lab reveals prolonged bleeding time; normal PT and PTT 6. forms of ITP

ITP is seen in children following viral infection (self-limited disorder; therefore therapy not usually needed) chronic ITP is usually seen in women (childbearing years) and may be first manifestation of SLE 7. therapy corticosteroids, which decrease antibody production and also inhibit reticuloendothelial function immunoglobulin therapy, which floods Fc receptors on splenic macrophages making them less likely to bind to antibody-coated platelets splenectomy, which removes site of platelet destruction and antibody production 8. note isoimmune thrombocytopenia clinical forms: neonatal (moms antibodies destroy baby's platelets) and post-transfusion antibodies against platelet isoantigens (such as PLA1) B. drug-induced thrombocytopenia drug-induced thrombocytopenia has dec #s megakaryocytes in bone marrow implicated drugs include heparin (especially important; called HIT for heparin-induce thrombocytopenia; fewer complications and more predictable response with low molecular weight heparin), quinine, penicillins, thiazide diuretics, methyldopa 1. heparin-induce thrombocytopenia (HIT) a) incidence: 5% of patients treated with heparin b) cause: autoantibody directed against heparin in association with platelet factor 4 c) sx: >50% reduction in platelet count beginning 5 or more days after starting heparin therapy d) note: bleeding is uncommon with HIT, instead the main complications of HIT are venous or arterial thrombosis (HITT = HIT with thrombosis syndrome) e) thrombosis due to platelet activation caused by immune complexes on the surface of the platelets f) fewer complications and more predictable response with low molecular weight (LMW) heparin (1) low molecular weight (LMW) heparin note heparin is an anticoagulant proteoglycan in mast cells, but heparan is a proteoglycan found in the extracellular matrix heparin (unfractionated) molecular weight = 15,000 LMW heparin molecular weight = 5,000 LMW heparin is preparation of choice (enoxoparin or dalteparin) heparin inhibits coagulation by stimulating antithrombin III (ATIII inactivates XIIa, XIa, IXa, Xa; this prolongs the PTT) and inhibiting thrombin LMW heparins have greater relative activity in inactivating factor Xa by antithrombin than inactivation of thrombin LMW heparins have more predictable anticoagulant response than unfractionated heparin LMW heparins also have decreased binding to platelets: this probably accounts for decreased incidence of HIT with LMW heparins note: still don't use LMW heparins for patients with HIT!! indications for use of LMW heparins: DVT prophylaxis, rx of unstable angina (2) thrombin (a) formation of thrombin (II) from prothrombin (b) formation is stimulated by Xa, V, calcium, PF3 (c) thrombin functions can be either pro-coagulation or anti-coagulation pro-coagulation functions include stimulating platelet aggregation and formation of fibrin anti-coagulation (when modulated by thrombomodulin) functions include activation of protein C g) rx: stop heparin; may use danaparoid sodium (mixture of heparan sulfate, dermatan sulfate, chondroitin sulfate, and LMW heparin) or direct thrombin inhibitor (hirudin or argatroban) h) don't give Warfarin, which can cause skin necrosis or increased risk of thromboembolism (1) Warfarin: Warfarin inhibits vitamin K dependent factors (II, VII, IX, X, factor C and factor S) by blocking gamma-carboxylation of glutamate residues factor C and factor S have shorter half-lives than coagulation factors II, VII, IX, and X, so may have transient increased risk of thrombosis when starting Warfarin therapy incidence of warfarin skin necrosis: 0.1% of patients treated with warfarin (most commonly obese women in their sixth decade) sx: necrosis of skin of buttocks, thighs, and breasts that begins 3 to 5 days after starting therapy

acute

 mx: thrombosis of capillaries and small veins; arteries are spared Willebrand disease deficiency of von Willebrand factor (which is made by endothelial cells and megakaryocytes); most common hereditary coagulation deficiency (AD) spontaneous bleeding from mucosal membranes and excessive wound bleeding (menorrhagia in young female) bleeding into joints is uncommon prolonged bleeding time and PTT with normal platelet count and normal PT; secondary deficiency of VIII leads to a prolonged PTT decreased platelet response to ristocetin (adhesion defect) is important diagnostic test treat mild cases (type I) with desmopressin (ADH analog) which releases vWF from Weibel Palade bodies of endothelial cells type I vWD (most common subtype) is mild disease with proportional decrease in all vWF multimers type II vWD is mild to moderate disease with absence of high molecular weight multimers type III vWD is severe disease with marked decrease in all multimers D. TTP (thrombotic thrombocytopenic purpura); together TTP and HUS are called thrombotic microangiopathies (TMA) 1. most often effects adult females 2. pentad (characteristic) of signs: (think FAT RN = fever, anemia, thrombocytopenia, renal dysfunction, neurologic abnormality) a) fever b) thrombocytopenia (with increased numbers of bone marrow megakaryocytes) c) microangiopathic hemolytic anemia: PAS+ microthrombi (no vasculitis); very little thrombin peripheral blood with large platelets (macrothrombocytes), schistocytes, and increased reticulocytes no activation of clotting cascade (unlike DIC); normal PT and PTT d) neurologic defects e) renal failure 3. cause: problem with vWF processing enzyme, which normally processes large multimers into small multimers; therefore, with TTP there are too many large multimers, which activate platelets (deficient enzyme is ADAMTS 13, a metalloprotease) 4. treatment: use plasma exchange, large-volume plasmapheresis, steroids; don't give platelets, because this makes it worse (possibility of death) E. HUS (hemolytic uremic syndrome) found primarily in kids (clinically see acute onset of bloody diarrhea and oliguria following gastroenteritis) due to Verotoxin-producing E. coli (bad hamburger) which is similar to shiga toxins produced by Shigella associated with predominance of unusually large vWF multimers in plasma similar symptoms as TTP except no neurologic symptoms (dec platelet count, microangiopathic HA with schistocytes and inc serum LDH) F. qualitative disorders 1. abnormal adhesion (abnormal response to ristocetin) a) von Willebrand disease (see above) b) Bernard-Soulier syndrome is due to a deficiency of Gp Ib/IX, which is the receptor for vWF on platelets signs are similar to von Willebrand disease = bleeding (petechiae) lab tests show normal vWF, factor VIII, PT, PTT, and platelet count, but abnormal platelet response to ristocetin cryoprecipitate (contains vWF) corrects defect in vWD, but not Bernard-Soulier syndrome (since that defect involves the receptor for vWF) 2. abnormal aggregation (primary wave defects); normal response to ristocetin; normal secondary wave a) Glanzmann's thrombasthenia is due to a deficiency of GpIIb/IIIa on platelets bleeding (petechiae), with normal vWF, factor VIII, PT, PTT, platelet count abnormal platelet response (no primary wave) to collagen and other substances; normal response to ristocetin b) afibrinogenemia = bleeding, normal platelet count, no primary wave but prolonged PT, PTT 3. abnormal activation (secondary wave defects) disorders are storage pool disorders a) abnormal alpha granules = gray platelet syndrome b) abnormal dense bodies C. von

syndrome (see inflammation and repair notes) syndrome (see immunology notes) TAR (thrombocytopenia with absent radii) 4. acquired defects in platelet functioning drugs: eg aspirin inhibits the formation of thromboxane A2; platelets will have normal response to exogenous ADP (normal phase I), but no phase II uremia: a toxin interferes with platelet factor III
Wiskott-Aldrich 285. Coagulation

Chediak-Higashi

abnormalities A (note: hemophilia B, also XR, is due to dec factor IX and has symptoms similar to hemophilia A) 1. x-linked recessive (seen primarily in males) hereditary deficiency of factor VIII (which is normally made in endothelial cells) 2. symptoms are variable due to variable decrease in the level of VIII massive hemorrhage after trauma or surgery and "spontaneous" hemorrhages (hemarthroses); no petechiae 3. clinical tests normal bleeding time, tourniquet test, platelet count, and PT abnormal PTT (prolonged) 4. therapy fresh plasma or factor VIII concentrates (cryoprecipitate); no longer used because lack of safe viral elimintation (risk of viral hepatitis and AIDS) treat mild cases with DDAVP B. dec vitamin K dec of coagulation factors II, VII, IX, X, factor C; recall that Warfarin blocks gamma-carboxylation of glutamate residues in these coag factors normal bleeding time, tourniquet test, platelet count abnormal (prolonged) PTT and PT C. circulating anticoagulants (eg coagulation inhibitors) think of this if abnormal PT or PTT does not correct if patient's plasma is mixed with normal plasma D. DIC 1. disseminated intravascular coagulation is always secondary to another disorder (never primary disorder) such as OB complications (from placental tissue factor) M3 AML (cytoplasmic granules) adenocarcinomas (mucin) gram negative sepsis (TNF- alpha) micro-organisms (meningococcus and rickettsia) 2. widespread fibrin deposition in microcirculation (microthrombi) 3. excessive clotting causes inc FDP (fibrin degradation products) (aka fibrin split products) (also inc D-dimers) 4. consumption of platelets and clotting factors causes hemorrhages 5. clinical tests find abnormal bleeding time, platelet count (dec), PTT (inc), PT (inc), and inc FDP (especially inc D-dimers)
A. hemophilia

286. Lab

tests for bleeding disorders vessel disease: positive tourniquet test; increased bleeding time; normal platelet count; normal PTT; normal PT thrombocytopenia: positive tourniquet test; increased bleeding time; decreased platelet count; normal PTT; normal PT abnormal platelet function: positive tourniquet test; increased bleeding time; normal platelet count; normal PTT; normal PT hemophilia A or B: normal tourniquet test; normal bleeding time; normal platelet count; increased PTT; normal PT vWD: positive/normal tourniquet test; increased bleeding time; normal platelet count; increased PTT; normal PT decreased vitamin K (Coumadin (Warfarin)): normal tourniquet test; normal bleeding time; normal platelet count; increased PTT; increased PT DIC: positive tourniquet test; increased bleeding time; decreased platelet count; increased PTT; increased PT
blood

ADRENAL
328. Review A. cortex 1. embryology: 2. anatomy:

derived from mesoderm yellow outer layer of adrenal gland 3. histology: layers from outside inward are zona glomerulosa: secretes mineralocorticoids, eg aldosterone (and some deoxycorticosterone); part of RAA system (not controlled by pituitary) zona fasciculata: largest zone (80%); secretes glucocorticoids cortisol and corticosterone); controlled by ACTH from pituitary; has the enzymes 3-beta-hydrogenase, 11-hydroxylase, 17-hydroxylase, 21hydroxylase (but not 18-hydroxylase) zona reticularis: secretes androgens, eg DHEA (dehydroepiandrosterone) and androstenedione; controlled by ACTH from pituitary mnemonic: "salt, sugar, sex, the deeper you go, the sweeter it gets" 4. physiology a) aldosterone (1) secretion: controlled by renin-angiotensin system (not pituitary) (a) renin produced by juxtaglomerular cells of renal afferent arteriole (compare to macula densa cells, which are specialized distal tubular epithelial cells located at the juxtaglomerular apparatus) renin converts angiotensinogen (an alpha2-globulin produced by the liver) to angiotensin I; release stimulated by dec blood volume (b) angiotensin converting enzyme (ACE) location is endothelial cells of the lung converts angiotensin I to angiotensin II (c) angiotensin II: stimulates production of aldosterone (2) mechanism of action: binds to cytosolic receptor, then binds to DNA, then increased mRNA (3) function: regulate sodium excretion and intravascular volume (a) kidney (distal tubule and collecting ducts): exchange of sodium for potassium and hydrogen ions increased sodium resorption (decreased renal secretion of sodium); increased potassium excretion; increased hydrogen ion excretion increased intravascular volume; decreased renin secretion b) glucocorticoids: cortisol (1) secretion (a) controlled by ACTH (precursor substance is POMC): from pituitary; activates adenyl cyclase to increase cAMP CRH (corticotropin-releasing hormone): from hypothalamus (b) components of control diurnal (circadian) rhythm: peak levels early morning prior to awakening; nadir at midnight stress response: emotional stress (fear and anxiety), body injury (surgery and hypoglycemia) negative inhibition: cortisol inhibits pituitary and hypothalamus (2) exogenous corticosteroids: produce adrenal atrophy; risk for acute adrenal insufficiency if stopped (3) mechanism of action: binds to cytosolic receptor, which then enhance transcription of selected genes in the nucleus then increased mRNA (4) function (a) regulate metabolism of CHO, proteins, fats; overall catabolic effect i. liver: increased synthesis (anabolic) increased gluconeogenesis is due to increased protein catabolism (increased amino acids); dec glucose utilization; increased lipolysis (increased) glycerol increased glycogen synthesis increased blood glucose (helps to prevent hypoglycemia with fasting)

catabolic resulting in dec synthesis, increased muscle breakdown lipolytic (increased lipolysis) (b) immune system induce lipocortin: inhibits phospholipase A2 then dec prostaglandins and leukotrienes decreased IL-2 production by T cells decreased histamine and serotonin release from mast cells and platelets decreased peripheral lymphocytes, monocytes, eosinophils, basophils increased neutrophil release from marrow, causes neutrophilia; dec leukocyte migration (c) cardiovascular: increased cardiac output; increased peripheral vascular tone (d) renal: increased GFR; dec renal reabsorption: calcium, phosphorus (e) other actions counteracts insulin (decreased insulin sensitivity); stimulates appetite; stimulates erythropoietin; dec GI absorption of calcium inhibits fibroblasts, which impairs wound healing
iii. fat: B. medulla 1. embryology:

ii. muscle:

arises from ectoderm neural crest 2. anatomy: note that similar cells are found outside of adrenal gland = paraganglia branchiomeric: associated with parasympathetic system of the head and neck; common carotid artery (carotid body) intravagal; within the urinary bladder aorticosympathetic: bifurcation of aorta (organ of Zuckerkandl) 3. histology: chromaffin cells stain positive with chromium salts; synthesize epinephrine and norepinephrine; innervated by preganglionic sympathetic (cholinergic) fibers 4. biochemistry a) synthesis tyrosine converted to DOPA by tyrosine hydroxylase DOPA converted to dopamine by DOPA decarboxylase dopamine converted to norepinephrine by dopamine hydroxylase methylation of norepinephrine to form epinephrine by PNMT (phenylethanolamine-Nmethyltransferase) b) metabolism (1) enzymes: COMT (catechol-O-methyltransferase); MAO (monoamine oxidase) (2) metabolites DA: HVA (homovanillic acid) Epi: metanephrine and VMA (vanillylmandelic acid) NE: normetanephrine and VMA
329. Congenital

adrenal hyperplasia (CAH) (which can cause adrenal virilism) deficiency (the product of CYP21A2) 1. most common from of CAH 2. salt-wasting form due to decreased or no aldosterone inc sodium excretion in urine causes dec sodium in blood (hyponatremia): hypotension with increased renin dec potassium excretion causes inc potassium in blood (hyperkalemia) dec hydrogen ion excretion causes inc hydrogen ions in blood (acidosis) 3. no cortisol causes inc ACTH, which stimulates adrenal cortex (causing hyperplasia) 4. inc 17-hydroxyprogesterone converted to testosterone which causes virilism in females 5. summary of lab findings = dec aldosterone, dec DOC, dec cortisol, inc ACTH, inc sex steroids (dec LH, dec FSH), dec sodium, inc K+, inc H+ (hyperkalemic acidosis) B. 11-hydroxylase deficiency decreased aldosterone and decreased cortisol, which increases ACTH increased DOC (deoxycorticosterone) and 11-deoxycortisol, which are both strong mineralocorticoids (increased mineralocorticoid effects) salt (sodium) retention (this is the hypertensive form of CAH); hypokalemic alkalosis inc androgens (sex steroids) may cause virilism in females; dec LH
A. 21-hydroxylase

of lab findings: dec aldosterone, inc DOC, dec cortisol, inc ACTH, inc sex steroids (dec LH, dec FSH), inc sodium, dec K+, dec H+ (hypokalemic alkalosis) C. 17-hydroxylase deficiency decreased cortisol (which increases ACTH and subsequently increases DOC, which increase blood pressure); dec renin no increased aldosterone (final step is controlled by renin-angiotensin system) decreased sex hormones (with subsequent inc LH) causes primary amenorrhea in females and pseudohermaphrodites in males note ddx of primary amenorrhea in females: primary amenorrhea with no sense of smell = Kallman's primary amenorrhea, short, web neck, etc = Turner's young female with metromenorrhagia, mucosal bleed = vWD young female with infertility, fat, hairy, etc = PCOD young female with inc BP and amenorrhea = 17OHase deficiency young female with inc BP and normal menses = RAS lab summary: inc DOC (dec aldosterone), dec renin, dec cortisol, inc ACTH, dec sex steroids, inc LH and FSH, inc sodium, dec potassium, dec H+ (hypokalemic alkalosis)
330. Excess

summary

aldosterone hyperaldosteronism = Conns syndrome 1. hypertension with low renin (hypertension does not respond to ACE inhibitors) 2. sodium and water retention leads to hypernatremia (but no edema because of the effects of ANF, atrial natriuretic factor) 3. hypokalemic alkalosis hypokalemia causes muscle weakness, fatigue, paralysis, paresthesias alkalosis causes dec serum ionized calcium (seen clinically as tetany, similar to sx of hyperventilation) 4. causes include cortical adenoma (most common) and bilateral hyperplasia of zona glomerulosa 5. lab summary: inc aldosterone, dec renin, inc sodium, dec potassium, dec H+ (hypokalemic alkalosis), normal cortisol, normal ACTH, normal sex steroids 6. rx with aldosterone antagonist spironolactone prior to possible surgery B. secondary hyperaldosteronism is due to inc renin from juxtaglomerular cells of kidney (increased angiotensin II increases aldosterone); results from: tumors and renal ischemia (renal artery stenosis causes hypernatremia, hypokalemic alkalosis, and inc renin) dec plasma volume juxtaglomerular cell hyperplasia = Bartters syndrome, which is characterized by normal BP with hyponatremia, hypokalemia (weakness), metabolic alkalosis, inc renin, inc PG's due to renal defect of sodium resorption C. treatment with spironolactone (aldosterone antagonist)
A. primary

331. Excess

cortisol = Cushing syndrome redistribution of body fat seen clinically as central obesity, moon face, and dorsal "buffalo hump" diabetes mellitus (due to cortisol antagonist to insulin) with hyperglycemia inc protein metabolism causes muscle wasting (selective atrophy of fast-twitch type II myofibers) with thin extremities, dec bone matrix of bone (osteoporosis), and thinning of skin (striae with easy bruising) delayed wound healing cortisol inhibits lymphocytes, macrophage, and neutrophils (therefore inc risk of infections) psychiatric effects include euphoria, mania, psychosis inc androgens cause hirsutism, acne, infertility, menstrual abnormalities excess cortisol causes Crooke hyaline change in normal pituitary cells = basophilic granular cytoplasm of ACTH-producing cells becomes homogenous (composed of intermediated keratin filaments) B. pathology 1. primary = adrenal abnormality inc cortisol, dec ACTH, and no suppression with high dose dexamethasone (note that high dose dexamethasone suppresses pituitary release of ACTH) causes include functioning adrenocortical adenoma (remainder of cortex is atrophic) and adrenocortical carcinoma
A. clinical

2. secondary

= non adrenal abnormality (that is, inc ACTH causes bilateral adrenal hyperplasia) = Cushings disease (seen with ACTH-secreting pituitary adenoma) inc cortisol, inc ACTH, (normal aldosterone), and suppression by high dose dexamethasone (seen as dec urinary steroid secretion) b) ectopic production of ACTH (seen with paraneoplastic syndrome, such as small cell carcinoma of lung) inc cortisol, inc ACTH, with no suppression by high dose dexamethasone 3. exogenous cortisol (causes adrenal cortical atrophy) inc cortisol, dec ACTH, with no suppression by high dose dexamethasone
a) pituitary 332. Hypofunctioning A. acute acute may

of adrenals (primary disorders of the adrenal gland)

weakness and fever that develops into vascular collapse and coma be due to too rapid withdrawal of steroid therapy or Waterhouse-Friderichsen syndrome = bilateral hemorrhagic necrosis of adrenal cortex due to meningococcemia (gram-negative diplococcus) B. chronic 1. primary adrenocortical insufficiency = Addisons disease (effects all three layers of adrenal cortex) a) dec mineralocorticoid (aldosterone) causes (1) weakness and fatigue (2) inc sodium excretion in renal tubules with retention of potassium and hydrogen ions dec sodium (hyponatremia) with dec plasma volume and hypotension (hyponatremic volume contraction) inc potassium (hyperkalemic acidosis) causes muscular weakness and EKG changes dec chloride, glucose, bicarbonate b) compensatory inc ACTH, which causes inc skin pigmentation due to MSH (melanin stimulating hormone; don't confuse MSH with melatonin) effect of POMC (precursor to ACTH) c) patients unable to respond to stress and are at risk of developing life-threatening shock (addisonian crisis) d) summary of lab = dec aldosterone (inc renin), dec sodium, inc potassium, inc H+, dec cortisol, dec glucose, inc ACTH, dec sex steroids, inc LH, FSH e) causes of Addison's disease autoimmune (microscopy reveals diffuse infiltrate of lymphocytes) is the most common cause of Addison's disease today part of polyglandular autoimmune syndromes (PGA) type I and II (see pituitary notes) other causes of Addison's include TB, metastases (from the lung), amyloidosis, other infections 2. secondary adrenocortical insufficiency is due to defects involving the hypothalamus or anterior pituitary dec ACTH, dec cortisol (dec glucose), dec androgens, normal aldosterone (no hyperpigmentation with normal potassium and normal BP)
333. Multiple

endocrine syndromes

A. hypofunctioning

endocrine hypofunctioning due to autoimmune destruction = polyglandular autoimmune syndromes (PGA) type I = decreased adrenal (Addison's), decreased parathyroid, mucocutaneous candidiasis (2 of these 3), +/diabetes, premature ovarian failure type 1 is now called autoimmune polyendocrine syndrome type 1 (APS1), aka autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED), and is caused by mutations in the autoimmune regulator (AIRE) gene, the product of which is expressed mainly in the thymus type II (Schmidt's syndrome) = decreased adrenal (Addison's), decreased thyroid (Hashimoto's thyroiditis) (but possibly Graves), +/- diabetes, premature ovarian failure type 2 is now called autoimmune polyendocrine syndrome type 2 (APS2) and lacks mucocutaneous candidiasis, ectodermal dysplasia, and hypoparathyroidism type III = polyglandular without adrenal involvement B. hyperfunctioning 1. multiple endocrine hyperfunctioning due to multiple neoplasias = multiple endocrine neoplasia (MEN) 2. type I (Wermer's syndrome) is due to mutant MEN 1 gene (tumor suppressor gene) parathyroid (hyperplasia or adenoma) pituitary adenoma

multiple

islet cell neoplasms, such as gastrinoma (Zollinger-Ellison syndrome) and insulinoma II (type IIa or Sipple's syndrome) is due to mutant RET gene (point mutation in extracellular domain) parathyroid tumors medullary carcinoma of thyroid pheochromocytoma 4. type III (MEN IIb) is due to mutant RET gene (point mutation in intracellular domain) medullary carcinoma of thyroid and pheochromocytoma multiple mucocutaneous neuromas with Marfanoid habitus, but no hyperparathyroidism
3. type 334. Adrenal

pancreatic

medullary tumors A. pheochromocytoma 1. most common tumor of adrenal medulla in adults 2. cell of origin is chromaffin cells of adrenal medulla (paraganglioma) which secrete catecholamines histology is not specific, but EM shows membrane-bound dense core neurosecretory granules 3. "10% tumor" = 10% malignant, 10% bilateral (multiple), 10% extra adrenal (intra-abdominal, mediastinum, carotid body of neck, bladder), 10% calcify, 10% kids, 10% familial (associated with MEN types II and III) 4. inc catecholamine secretion (inc epinephrine and norepinephrine, not serotonin) a) episodic hyperadrenergic symptoms (5 P's) pressure (episodic elevated blood pressure due to peripheral vasoconstriction (alpha1 receptors) and inc cardiac output (beta1 receptors) pain (headaches) perspiration palpitations and tachycardia pallor and diaphoresis (sweating) b) laboratory tests inc catecholamines and their metabolites, such as metanephrine, normetanephrine, and VMA (best screening test is urinary VMA) also inc blood glucose (epinephrine increases blood glucose levels) 5. treatment surgical treatment is to remove tumor (beware of hypertension during surgery) medical treatments is with alpha antagonists, such as phenoxybenzamine (nonselective, irreversible alpha blocker) or prazosin B. neuroblastoma most common tumor of adrenal medulla in children (median age is 2 years); child presents with enlarging abdomen screening test is inc urinary metanephrine and VMA associated with amplification of N-myc (the number of N-myc genes is proportional to the aggressiveness of the tumor) Trk gene expression (encodes nerve growth factor for neuroblast differentiation) is associated with a good prognosis mx: small round cells with formation of Homer-Wright rosettes (groups of cells arranged in a ring around a central mass of pink neural filaments) EM: neurosecretory granules; immunohistochemical stains are positive for neuron-specific enolase (NSE) highly malignant; prognostic factors include age (<1 year of age has excellent prognosis) and ploidy of tumor cells (hyperdiploid or near-triploid is good) occasionally differentiates into benign ganglioneuroma (this change is associated with marked reduction in gene amplification)

THYROID
320. Hypothyroidism A. clinical

signs (in general gradual onset of signs due to dec rate of metabolism) dec T3 and T4: if primary thyroid failure will have inc TSH; if due to pituitary (secondary hypothyroidism) or hypothalamic (tertiary hypothyroidism) failure will have dec TSH and negative thyrotropin-releasing hormone (TRH) stimulation test (a definitive test) decreased basal metabolic rate; cold-intolerant; weight gain; hoarseness lethargy, fatigue, apathy, depression, paranoia ("myxedema madness"), prolonged relaxation phase in deep tendon reflexes ("hung-up" reflexes) myxedema due to inc interstitial mucopolysaccharides and inc water retention dry (orange) skin with coarse and brittle hair (hair loss) constipation; decreased EPO causes anemia; increased cholesterol (type IV secondary hyperlipidemia; increased risk of atherosclerosis) treat with L-thyroxine B. cretinism seen in children with growth retardation and mental retardation dry, rough skin, with puffy face (periorbital edema) and flattened, broad nose large, protuberant tongue and protuberant abdomen (pot-bellied) due to enzyme deficiency (sporadic) or dietary causes (endemic): severe iodine deficiency or goitrogens in diet that block hormone synthesis rx with thyroxine C. causes 1. primary causes dietary, such as severe iodine deficiency or goitrogens that block hormone synthesis drugs (lithium, amiodarone, etc), iatrogenic causes (surgery, medical, or radiation) or immune abnormalities (thyroiditis) 2. secondary cause is pituitary failure (which will have dec TSH) 3. tertiary hypothyroidism is due to hypothalamic causes; the TRH stimulation test: separates secondary from tertiary hypothyroidism TRH injection result in no increase in thyroid hormone nor TSH with secondary hypothyroidism TRH injection results in increased thyroid hormone production with tertiary hypothyroidism
321. Thyroiditis A. Hashimotos

thyroiditis 1. associated with multiple types of antibodies (autoimmune disorder) including anti-thyroglobulin thyroidal peroxidase antibody (old name is antimicrosomal antibody) TSH-R[block] Ab (old name is anti-TSH receptors) 2. lab: decreased T4, decreased free T4, and increased TSH 3. histology diffuse lymphoplasmacytic infiltrate (forming germinal centers) Hurthle cells which are oncocytes (large cells with abundant pink cytoplasm) 4. more common in females (painless enlargement of thyroid with some hypothyroidism) 5. associated with HLA-DR5 and other autoimmune diseases (combination with Addisons disease = Schmidts syndrome) 6. inc risk of lymphoma B. subacute thyroiditis aka deQuervain's thyroiditis (granulomatous thyroiditis) etiology is probably viral, often history of URI (mumps, coxsackie, measles, adenovirus) more common in females and is associated with HLA-B35 histology reveals granulomatous inflammation with giant cells around fragments of colloid patients develop acute onset of fever with painful enlargement of thyroid mild hyperthyroidism early (due to gland damage), but may develop hypothyroidism late self-limited disorder that lasts weeks to months with full recovery C. subacute lymphocytic thyroiditis

non-painful enlargement of thyroid +/- fibrosis (no pain is in contrast to subacute thyroiditis) reveals changes similar to Hashimotos but no Hurthle cells are present seen most often in women during postpartal period may develop hyperthyroidism (inc T3, inc T4, dec TSH with dec radioactive iodine uptake), but is self-limited disorder D. Reidels thyroiditis etiology is unknown rock-hard enlarged thyroid (clinical is due to mass effect, such as feelings of suffocation that may mimic carcinoma) histology reveals fibrous destruction of thyroid with extension into adjacent soft tissue in these individuals similar fibrosis may occur in the retroperitoneum and mediastinum
histology 322. Hyperthyroidism A. clinical

modest

(thyrotoxicosis) signs free thyroxine index: increased (inc T3 and T4) increased basal metabolic rate; nervousness and hyperactivity; warm skin with fine hair heat-intolerant; weight loss; pretibial myxedema = Graves diarrhea; increased reflexes (with tremor); menstrual abnormalities, such as amenorrhea or oligomenorrhea cardiac changes include rapid pulse and palpitations (may lead to high-output cardiac failure) exophthalmos seen with Graves disease B. primary = Grave's disease 1. triad of: hyperthyroidism (secondary to diffuse toxic goiter) with inc T3, inc T4, dec TSH and inc uptake of radioactive iodine ophthalmopathy (eye changes) includes exophthalmus (protrusion of the eyes causing wide staring gaze and lid lag) dermopathy = pretibial myxedema (due to localized accumulation of mucopolysaccharide) causing scaly thickened skin 2. females 20-30, associated with HLA-DR3 3. due to autoimmune antibodies (autoimmune disorder) IgG antibodies to portions of the TSH receptor (may cross placenta and cause neonatal hyperthyroidism) TSH-R [stim] Ab (TSH-receptor stimulating antibody); cause increased intracellular cAMP levels old names include TSI (thyroid stimulating immunoglobulins) and LATS (long-acting thyroid stimulator) TBII (thyroid-binding inhibitor immunoglobulin) 4. diffuse uniform enlargement of thyroid (appears meaty on cut section; red because of increased vascularity) is called diffuse toxic goiter 5. microscopic reveals inc cellularity with scalloping of colloid and lymphocytic infiltrate (may produce germinal centers) 6. thyroid storm (thyrotoxic crisis) has mental changes, fever, tachycardia after surgery or infection (medical emergency) 7. hypertensive crisis = acute severe hypertension (headache, ringing in ears, retinal hemorrhages); rx with nitroprusside (but beware cyanide toxicity) 8. other autoimmune diseases have increased incidence, especially Hashimoto's thyroiditis; thyroid cancer is not increased in incidence C. secondary (increased TSH with increased T3 and T4) pituitary hyperfunction (inc TSH secretion) or hypothalamus hyperfunction (increased secretion of TRH) struma ovarii (thyroid tissue in ovary) may become hyperfunctioning general term for any enlargement of the thyroid gland (usually due to dec synthesis of thyroid hormone causing inc TSH) A. simple goiter aka diffuse nontoxic (euthyroid) goiter mx: initial diffuse hyperplasia of follicles (resembles Graves disease); then repeated episodes of involution and hyperplasia endemic goiter is due to iodine deficiency or goitrogens, such as cabbage, cauliflower, Brussels sprouts, turnips, and cassava

323. Goiter:

goiter may be due to substances that inhibit thyroid synthesis (goitrogens) or hereditary enzyme deficiencies note: the toxic effects of eating too many brussels sprouts (a member of the brassica family of vegetables) is due to the presence of glucosinolates (aka isothiocyanates), substances that also have anti-cancer effects; these toxic effects can occur with the ingestion of more than 10oz of brussel sprouts/day for years, or more acutely with the ingestion of more than 30oz [about 2 pounds] of brussel sprouts note that hyperthyroidism with focal enlargement of thyroid (solitary hyperfunctioning nodule = Plummer's nodule) B. multinodular goiter may arise from simple goiter that has repeated periods of enlargement and involution (most patients are euthyroid); may form large colloid nodule histology may reveal large colloid nodules (colloid goiter)
324. Neoplasms

sporadic

of the thyroid adenoma benign tumor of thyroid (most are solitary and are usually "cold" (nonfunctioning) on scan) may be associated with somatic mutations of the TSH receptor (which is a Gs receptor that causes inc cAMP) FNA cant tell benign follicular adenoma from malignant follicular carcinoma by FNA (with cytology call both "follicular neoplasm") histology reveals variable sized small follicles with dec colloid that appear different from surrounding thyroid parenchyma and complete fibrous capsule without invasion B. follicular carcinoma histology similar to follicular adenoma (may have well-defined capsule) but capsular or blood vessel invasion (best histologic criteria) immunohistochemistry: positive for thyroglobulin and TTF-1 (thyroid transcription factor) spread is via blood vessels (vascular) to lung and bones (rather than lymph node mets seen with papillary thyroid carcinoma) prognosis is less than papillary carcinoma either mutations in the RAS family of oncogenes (NRAS mutations being the most common) or unique translocation between PAX8 and the peroxisome proliferator-activated receptor gamma (PPAR gamma1) C. papillary carcinoma most common type of thyroid cancer (associated with previous exposure to radiation and abnormalities of RET proto-oncogene) either rearrangements of the tyrosine kinase receptors RET or NTRK1 (neurotrophic tyrosine kinase receptor 1); activating mutations in the BRAF oncogene; or RAS mutations multifocal disease in thyroid and spread via lymphatic to lymph nodes papillary projections (may form microcalcifications called psammoma bodies) nuclear changes include ground glass nuclei ("Orphan Annie eyes"), nuclear grooves, and intranuclear inclusions (cytoplasmic invaginations into nucleus) follicular variant: well formed follicles with characteristic vesicular, optically clear (empty) appearing nuclei (better px than follicular carcinoma) prognosis is good (better than any other form of thyroid cancer) D. medullary carcinoma cell of origin is parafollicular C cells (which produce calcitonin; can be used as a serum marker) microscopy reveals groups of poorly differentiated cells in stroma with amyloid (calcitonin fragments), which is seen as apple-green birefringence with Congo Red stain electron microscopy reveals membrane-bound dense core granules in neoplastic cells associated with abnormalities of RET proto-oncogene and multiple endocrine neoplasia (MEN) syndrome type II and III E. undifferentiated (anaplastic) carcinoma rare (found in elderly) histology reveals anaplastic with giant cells prognosis is poor because of rapid growth (anaplasia = poor prognosis)
A. follicular

PARATHYROID
325. Calcium

A. review

serum: total serum calcium = calcium bound to albumin+ calcium complexed to citrate and phosphate + free calcium; active form = free ionized calcium factors affecting serum levels: PTH increases calcium; D3 increases calcium; calcitonin decreases calcium in general, phosphorous and calcium levels go in opposite directions; with chronic renal failure should try to raise calcium and restrict phosphorous B. hypocalcemia 1. signs include numbness and tingling of hands, feet, and lips and tetany (muscle spasms) 2. causes of hypocalcemia include either a) parathyroid causes (primary hypoparathyroidism) b) non-parathyroid causes hypoalbuminemia causes decreased serum calcium without tetany (because serum ionized calcium levels are normal) hypomagnesemia (cofactor for adenyl cyclase), which causes dec cAMP and dec calcium (total and ionized) dec vitamin D and chronic renal failure hyperventilation (respiratory alkalosis causes inc bound calcium and dec free calcium with normal total calcium) C. hypercalcemia 1. signs of hypercalcemia (mnemonic is "stones, bones, abdominal groans, and psychiatric moans") nephrocalcinosis and calcium stones in urine soft tissue (metastatic) calcification peptic ulcer disease (increased gastrin causes increased acid secretion) psychiatric changes (with acute psychiatric mental changes always check serum calcium levels) 2. causes ("chimps"); basically due to PTH or not PTH cancer (paraneoplastic secretion of PTHrP, which will decrease PTH and cause all parathyroid glands to be atrophic) and ATLL hyperparathyroidism (primary) iatrogenic (drugs) or immobilization (bone is reabsorbed) multiple myeloma (calcium is released from bone by IL-6 [osteoclast stimulating factor] stimulating osteoclasts) primary = inc vitamin D or inc milk consumption (milk-alkali syndrome) notes about milk-alkali syndrome: more than 2 g/day of elemental calcium with alkali (tolerable upper daily limit may be 2.5g); normal daily calcium is about 500-1000 mg; recommendation for daily intake: 10001200mg; helpful in preventing and treating osteoporosis; source: milk and OTC calcium supplements; one 8-oz glass of milk has about 300 mg calcium; OTC calcium supplements: eg, Tums: regular strength = 200mg calcium/tablet; extra strength = 500mg/tablet; Mylanta chewable = 400mg/tablet sarcoid (and other granulomatous diseases because sometimes the epithelioid cells of granulomas may secrete vitamin D)
326. Hypoparathyroidism

in

and pseudohypoparathyroidism A. clinical: signs of hypoparathyroidism are due to dec calcium (numbness and tingling of hands, feet, and lips and tetany) Trousseaus sign = blood pressure cuff producing carpal spasms Chvosteks sign = tapping facial nerve produces facial twitching (can be seen in normal individuals) B. primary hypoparathyroidism 1. primary hypoparathyroidism may be due to: idiopathic or iatrogenic causes (such as surgical accident during thyroidectomy) congenital thymic hypoplasia (DiGeorges syndrome) immune abnormality: part of type I polyglandular autoimmune syndrome which is characterized by hypoadrenalism (Addison's disease) + hypoparathyroidism + mucocutaneous candidiasis 2. lab values: decreased plasma PTH; decreased plasma(OH)2 vitD; increased serum phosphate; decreased serum calcium C. secondary hypoparathyroidism: secondary to non-parathyroid causes of hypercalcemia D. pseudohypoparathyroidism (characteristically has decreased calcium with increased PTH) an X-dominant disorder that is due to a defect in Galphas proteins (PTH, TSH, glucagon, FSH, LH)

 results lab:

in end-organ unresponsiveness to PTH (causes serum PTH to be normal to inc) increased plasma PTH; decreased plasma(OH)2 vitD; increased serum phosphate associated with Albrights osteodystrophy, which is characterized by short stature with shortened fourth and fifth fingers
327. Hyperparathyroidism A. primary

hyperparathyroidism and symptoms a) bone has characteristic changes subperiosteal bone resorption of distal phalanges brown tumors of bone with fibrous replacement of marrow (brown color due to hemorrhage and hemosiderin); with osteoclasts cystic changes called osteitis fibrosa cystica (von Recklinghausens disease) pain and inc serum alkaline phosphatase b) additional signs due to inc calcium (see above); not hyperphosphatemia c) increased 24-hour urinary excretion of calcium and phosphate 2. causes include: a) adenoma most common cause of primary hyperparathyroidism (90%) benign solitary neoplasm (characteristically only one gland is affected and enlarged) gross shows inc size while the other glands are normal or smaller than normal b) hyperplasia affects all four glands equally (weight of each gland > 40 mg) to tell from adenoma biopsy 2nd parathyroid gland and if abnormal then it's hyperplasia, but if it's normal then it's an adenoma c) carcinoma (very rare, but grossly will see invasion into adjacent tissue) d) chromosomal defects associated with primary hyperparathyroidism is MEN 1gene and PRAD 1 (codes for cyclin D1) B. secondary hyperparathyroidism secondary to dec serum calcium (see above for causes of hypocalcemia); therefore PTH is increased and calcium is low or low-normal chronic renal disease is by far the most common (another is dec vitamin D, possibly due to dec 1 alpha hydroxylase activity in the kidneys) pathology shows hyperplasia of all 4 glands secondary hyperparathyroidism that becomes autonomous (with hypercalcemia) is called tertiary hyperparathyroidism; usually seen with chronic renal failure (hypercalcemia persists in spite of treatment with dialysis or transplantation)
1. signs

HIGH-YIELD NOTES OF PATHOLOGY 2009-2010 PART 7a GENETICS

287. Mutations A. point

(cause permanent change in DNA) mutations 1. exons (transcribed into mRNA; largest known gene is dystrophin gene on X chromosome; may have spontaneous mutations) transitions: either pyrimidine is changed to the other pyrimidine or a purine is changed to the other purine transversions: either a purine is changed to either pyrimidine or a pyrimidine is changed to either purine silent mutations usually involve the 3rd nucleotide in codon with no change in amino acid sequence of protein (no detectable effect) missense mutations result in replacement of one amino acid by another (example is sickle cell anemia) nonsense mutations usually produce stop codons (example is beta-thalassemia) note severity: nonsense > missense > silent 2. introns (noncoding sequence between two exons for a single protein) a) spliced out from heterogenous RNA; splicing begins at 5' end with sequence GT (splice donor) ends at 3' end with sequence AG (splice acceptor) b) many effects, such as defective splicing at donor site (GT) or acceptor site (AG) B. deletions and insertions non-multiples of 3 produce frameshift mutations which are very damaging (example is Tay-Sachs disease) multiples of 3 result in missing amino acids (example is cystic fibrosis resulting from a 3 base deletion, which causes a single amino acid deletion) C. chemicals and radiation frameshift mutations: intercalating agents insert themselves between stacked base pairs in DNA; eg acridine orange and acridine dyes helix distortion mutations: ultraviolet light forms thymine dimers point mutations: base analogs; eg bromodeoxyuridine and 2-aminopurine transition mutations: deaminating agent and nitrous acid terms terms alleles = alternate forms of a gene at a particular locus anticipation = subsequent generations have more severe disease developing earlier (seen with trinucleotide expansion disorders) expressivity = extent of phenotypic expression gene dosage = amount of a gene product is proportional to the number of gene copies (ie - with trisomy) genetic drift = a gene frequency varies substantially from one generation to the next in small populations (eg variegate porphyria in the Afrikaner population of South Africa) gene flow = the slow diffusion of genes across population barriers genetic load = frequency of bad recessive mutations in a population (high load in most humans, therefore inbreeding causes defects) genomic imprinting = phenotype depends upon which parent contributes the abnormal gene (eg. chrom 15 with Angelman and Prader-Willi) haplotype = a defined combination of alleles in a specific region of a chromosome heterogeneity = same phenotypic effect can be produced by mutations at multiple sites (eg., hemophilia, OI, albinism, Leigh's syndrome) heterozygous = a variation in genes between the two chromosomes of a single individual (normal = "wild" type) homozygous = same genes on both chromosomes locus = gene's location on a chromosome penetrance = an all-or-none phenomenon describing the percent of individuals who express a certain disease (usually an AD condition) phenotype = the clinical expression of the genes of an individual pleiotropism = genes that have more one effect (Marfan's, cystic fibrosis, OI)

288. Genetic

A. basic

expressivity = degree of expression of gene is different in different individuals (eg phenotypic difference in patients with neurofibromatosis) B. confusing terms association = pattern of nonrandom anomalies with unknown mechanism (VATER association) deformation = an alteration of a normally formed body part by mechanical forces disruption = defect that results from interference of a normally developing process dysplasia = abnormal organization of cells into tissue (different meaning from precancerous epithelial dysplasia) dysraphic = defects caused by failure of apposed structures to fuse (spina bifida) dystopia = retention of an organ at a site during development (dystopic testes in inguinal canal) malformation malformation = morphologic defect that results from an intrinsically abnormal developmental process (ie. cleft lip or polydactyly) sequence = a pattern of cascade anomalies that can be explained by a single, localized aberration in organogenesis (ie. oligohydramnios sequence) syndrome = pathologically related constellation of congenital anomalies that cannot be explained by a single, localized, initiating defect (?in organogenesis) (ie. Down's syndrome)
289. Autosomal

variable

dominant (AD) (note: tips for evaluating a pedigree: O = female; = male; think "males are square"; no skipped generations = dominant; no male-to-male transmission = x-linked) A. characteristics disease produced in heterozygous state (therefore an affected child usually has one effected, eg heterozygous, parent and one normal parent) no skipped generations, therefore parents affected (unless new mutation, reduced penetrance, delayed age of onset, germ line mosaicism) father to son transmission possible males and females affected equally recurrence risk is 50% (vertical transmission) B. examples (think adult or abnormal structural proteins) fibrillin = Marfans syndrome collagen = EDS and OI neurofibromin = NF1 beta-myosin = hypertrophic cardiomyopathy spectrin or ankyrin = hereditary spherocytosis; hereditary elliptocytosis LDL receptor = familial hypercholesterolemia (type II hyperlipidemia) vWF = von Willebrands disease adult polycystic renal disease recessive (AR)

290. autosomal

A. characteristics

produce in homozygous state; heterozygous individuals are carriers an affected child usually has two carrier, eg heterozygous, parents skipped generations father to son transmission possible males and females affected equally pedigree may show only one individual with disease (also think new mutation (NF-1 or achondroplasia), except if weird AD disorder recurrence risk is 25% B. examples think young kid (eg childhood polycystic renal disease) or enzyme deficiency regulatory proteins, such as sickle cell anemia and thalassemia enzymes (usually catabolic), such as storage diseases, PKU other disorders, such as cystic fibrosis, Wilsons disease, hemochromatosis, alpha1AT deficiency
therefore 291. X-linked

disease

disorders A. X-linked dominant (XD) no skipped generations (eg dominant inheritance) no male to male transmission (eg X-linked)

affected twice as often as males pseudohypoparathyroidism, Alports, hypophosphatemic rickets, ornithine-transcarbamylase deficiency (hyperammonemia) B. X-lined recessive (XR) 1. characteristics skipped generations (eg recessive inheritance) no male to male transmissions (eg X-linked) affected males more frequent than affected females (rare, but may be homozygous for the disease or may have an unfavorable Lyonization) all daughters of affected males are carriers oblique transmission (maternal uncles and male cousins from mother's sisters) 2. diseases a) hematology disease G6PD deficiency hemophilia A (dec VIII) and hemophilia B (dec IX) b) immunodeficiency diseases Brutons agammaglobulinemia (defect in B cell maturation at pre-B stage) SCID's due to abnl IL-2 receptor chronic granulomatous disease (abnormal NADPH oxidase) Wiskott-Aldrich syndrome c) storage diseases Fabrys disease (dec alpha-galactosidase A) Hunters syndrome (dec L-Iduronosulfate sulfatase) d) muscle diseases Duchennes and Becker's muscular dystrophy (abnormal dystrophin) e) metabolic diseases diabetes insipidus (dec ADH) Lesch-Nyhan syndrome (dec HGPRT) f) other red-green color blindness fragile X syndrome (actually weird inheritance) weird disease = Menkes "kinky hair" syndrome: due to dec copper (dec lysine oxidase) (think "kink" in copper metabolism and "steely hair" that is easily broken)
examples: 292. Mitochondrial/other A. Y-transmission: B. mitochondrial 1. normal

females

only males affected; all males affected; only male to male transmission

include outer membrane, intermembranous space, inner membrane, matrix within mitochondria include: beta-oxidation of fatty acids, oxidation of pyruvate, synthesis of urea, TCA cycle genes mainly code for oxidative phosphorylation enzymes, such as NADH dehydrogenase, cytochrome c oxidase, and ATP synthase 2. characteristics males and females affected only females transmit the disease (think mitochondrial DNA in cytoplasm of ovum, but not sperm); females transmit disease to all offspring's heteroplasmy = mixture of mutant and normal DNA homoplasmy = mutant DNA only severity correlates with the amount of mutant mtDNA 3. examples a) LHON (Leber hereditary optic neuropathy) = sudden loss of central vision in young adult b) mitochondrial myopathies (1) mx reveals "ragged-red fibers"; EM reveals "parking lot" inclusions in mitochondria (2) Kearns-Sayre syndrome = external ophthalmoplegia, pigmentary retinopathy (night blindness), ataxia, heart block
process

components

(3) decreased

cytochrome oxidase (a mitochondrial enzyme) is seen in MERRF (myoclonic epilepsy with ragged red fibers) and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and Leigh syndrome (4) Leigh syndrome subactue necrotizing encephalopathy fatal disease; onset in first year of hypotonia, CNS symptoms (central hypoventilation syndrome), ophthalmoplegia, lactic acidemia, etc. defect: multiple, including mtDNA mutation, pyruvate dehydrogenase complex deficiency, complex I (NADH dehydrogenase) deficiency, complex IV (cytochrome c; COX) deficiency, complex V (ATPase) deficiency (defects involve mitochondrial pathway converting pyruvate to ATP).
293. Calculations A. basic

probability of independent events: multiply probability of each event (like tossing two coins and getting two heads) if the probability of 2 dependent events (such as tossing a coin, heads or tails) equal 1 then the probability of not producing an event (such as tails) in multiple occurrences = 1 minus all other possible combinations chance that a child inherits a particular gene on one chromosome of one parent = 50% usually with AD disorder in child one parent is normal and the other is abnormal (heterozygous) and 1/2 children normal, 1/2 affected (eg chance that both of 2 children affected would be 1/2 times 1/2 = 1/4) usually with AR disorder in child both parents are carriers (heterozygous) and 3/4 are phenotypically normal (with 1/4 normal and 1/2 carriers) and 1/4 with disease (eg with 2 children chance that both with disease = 1/4 times 1/4; chance that both without disease = 3/4 times 3/4) if both parents are homozygous for an autosomal recessive disorder then the risk of transmission is 100% if status of both parents is unknown then the risk of transmission = (carrier rate times 1/2) times (carrier rate times 1/2) if one parent is a known carrier and the other parent status is not known then the risk of transmission = 1/2 times (carrier rate times 1/2) prevalence of a disease (number of affected individuals in a population); for a AR disorder prevalence = the carrier rate (mom) times the carrier rate (dad) times 1/4 B. coefficient of relation parent-child = 1/2; siblings = 1/2 first cousins = 1/8; first cousins once removed = 1/16; second cousins = 1/32 C. Hardy-Weinberg principle 1. predicts population genotype frequencies based on gene frequencies assume random mating and assume gene frequencies p (for A) and q (for a) then aa genotype (homozygous) = qxq and Aa genotype (heterozygotes carriers) = 2xpq
probability 294. Diseases

of structural/receptor/regulator proteins (examples)

A. structural 1. Marfans

syndrome abnormal fibrillin gene (fibrillin is "scaffold" for elastin); inheritance is autosomal dominant (AD) fibrillin occurs in two homologous forms, fibrillin-1 and fibrillin-2 (encoded by two separate genes, FBN1 and FBN2) mutations of FBN1 underlie Marfan syndrome; mutations of the related FBN2 gene give rise to congenital contractural arachnodactyly very tall with long arms and arachnodactyly (spider fingers); arm span is characteristically greater than height vascular abnormalities include cystic medial necrosis of aorta (produces dissecting aneurysms and AR) and MV prolapse high arched palate and bilateral subluxed lens into anterior chamber of the eye (usually outward and upward) 2. Ehlers-Danlos syndrome defect is in formation of collagen (10 types) most common type is type VI [kyphoscoliosis type], which results from abnormal lysyl hydroxylase classical type (types I/II) is due to mutations in the genes for type V collagen vascular type (type IV) results from abnormalities of type III collagen

IX is abnormal copper metabolism is fragile and hyperextensible ("India rubber man") joints are hypermobile (contortionist), can produce recurrent dislocated shoulder complications include colon rupture (EDS type IV), cornea rupture (EDS type VI), and diaphragmatic hernia (EDS type I) 3. osteogenesis imperfecta (OI) defect in synthesis of type I collagen "brittle bones" result in multiple fractures with minimal trauma (confused with child abuse) blue sclera (due to thin sclera) and hearing loss the severe fatal type may be seen in offspring's of parents with gonadal mosaicism 4. Stickler syndrome abnormal type II collagen (found in cartilage) due to abnormal gene for alpha1 type 2 collagen dysplasia of epiphysis produces early-onset arthritis other signs include myopia and hypoplasia of the jaw B. receptor: one example is primary (familial) hyperlipidemia (Fredrickson phenotypic classification of hyperlipoproteinemias) 1. type I hyperlipoproteinemia increased chylomicrons (increased triglyceride) due to mutation in lipoprotein lipase gene or deficiency of apo-CII serum electrophoresis shows increased band at origin (where chylomicrons are located) 2. type II hyperlipoproteinemia (familial hypercholesterolemia) = increased LDL (increased cholesterol; increased beta band) a) mutation involving LDL receptor (more important) or apo B gene b) classification of LDL defects class I, the most common defect, involves decreased transcription of genes for the LDL receptor class II involves trapping of the LDL receptor in the endoplasmic reticulum class III involves decreased binding of LDL to the LDL receptor class IV results from the inability of the LDL receptor to localize in clathrin-coated pits class V is related to the inability of the LDL receptor to dissociate from LDL in the CURL) c) clinical severe atherosclerosis early in life with early MI's (homozygotes in 20's, heterozygotes in 30's) tendon xanthomas (lipid deposits) especially in Achilles tendon 3. type III hyperlipidemia (aka floating or broad beta disease) increased IDL and chylomicron remnants (increased cholesterol and triglycerides) due to mutation in apolipoprotein E 4. type IV hyperlipidemia = increased VLDL (increased triglyceride) due to mutation in lipoprotein lipase gene (increased pre-beta band); eg decreased catabolism of VLDL 5. type V hyperlipidemia = increased chylomicrons and VLDL (increased triglyceride) due to mutation in apolipoprotein CII (rarely due to deficiency of lipoprotein lipase) C. regulators: one example is neurofibromatosis 1. neurofibromatosis Type 1 (NF1) = von Recklinghausen's disease (AD inheritance) gene located on 17 codes for neurofibromin which is a type of GAP that down regulates the p21 ras oncoprotein highest spontaneous mutation rate known (one reason is because it is a very large gene) multiple neural tumors including neurofibromas, plexiform neurofibromas, meningiomas, astrocytomas pigmented nodules of iris (Lisch nodules) and caf-au-lait spots of skin plexiform neurofibromas are pathognomonic and have involvement of all the fascicles of a nerve variable expressivity with 100% penetrance sarcomatous degeneration is a relatively common event in NF1 ("neurofibrosarcoma") 2. neurofibromatosis Type 2 (NF2) multiple meningiomas or bilateral acoustic neuromas (no skin lesions) abnormal NF-2 gene, a tumor-suppressor gene, the product of which is merlin merlin shows structural similarity to the ezrin, radixin, moesin family of proteins, hence the name (MoesinEzrin-Radixin-Like Protein) it is thought that merlin regulates contact inhibition and proliferation of Schwann cells
skin

type

295. Carbohydrate

disorders review 1. glycogen synthesis a) glucose to G-6-P (glucose-6-phosphate) by glucokinase (hexokinase) hexokinase: throughout body glucokinase: lower affinity, but higher capacity; only in liver b) G-6-P to G-1-P (glucose-1-phosphate) to UDPG (uridine diphosphoglucose) to glycogen not glucose-6-phosphatase or G6PD glycogen synthetase a (active) forms alpha 1,4 bonds (glycogen synthetase a is converted to glycogen synthetase b (inactive) by protein kinase from inc cAMP) branching enzyme: alpha 1,6 bonds 2. glycogen breakdown a) lysosomal: acid maltase (aka alpha 1,4-glucosidase) b) cytoplasmic: glycogen phosphorylase a formed from (active) phosphorylase kinase a (which is formed from the inactive phosphorylase kinase b by protein kinase from inc cAMP) two enzyme forms: liver form and muscle form produces G-1-P and limit dextrin 3. storage liver: maintains blood glucose levels; abnormality produces hypoglycemia and convulsions muscle: provides energy during exercise; abnormality produces muscle symptoms with exercise 4. histologic staining: PAS-positive, diastase-sensitive B. glycogen storage disorders 1. type I = von Gierke disease (severe sx), which is due to dec glucose-6-phosphatase inc glycogen (cytoplasmic) in liver (hepatomegaly) and kidneys recurrent severe fasting hypoglycemia, which causes dizziness and sweating (due to epinephrine secretion) and convulsions also see inc lipids (xanthomas) and inc uric acid (gout); rx with frequent meals 2. type V = McArdles, which is due to dec muscle phosphorylase inc glycogen in muscle exercise causes cramps and myoglobulinemia (dark color grossly), but no inc lactate 3. type II = Pompes disease (intermediate sx), which is due to dec acid maltase (alpha-1,4-glucosidase) inc glycogen (lysosomal storage disorder, therefore found throughout body) deposition in heart causes cardiomegaly and CHF which leads to death not hypoglycemic because cytoplasmic enzymes OK 4. type IV = Anderson's (deficiency is branching enzyme) accumulation of abnormal glycogen (amylopectin) with long outer chains; death before age 2 from cirrhosis; rx is liver transplant C. other carbohydrates 1. review a) lactose (carbohydrate in milk): converted to glucose and galactose by lactase in gut b) sucrose (found in table sugar; composed of fructose and glucose): major source of fructose in diet c) fructose (found in fruits and fruit juices) absorbed in gut; travels to liver via portal vein phosphorylated to fructose-1-phosphate in liver by fructokinase F-1-phosphate converted to glyceraldehyde and dihydroxyacetone phosphate (DHAP) by aldolase B (liver aldolase) d) galactose converted to glucose in 3 steps galactose converted to gal-1-phosphate by galactokinase gal-1-phosphate converted to UDP-gal by gal-1-phosphate uridyl transferase (GALT) UDP-gal converted to UDP-glu (and vice-versa) by epimerase 2. fructose intolerance dec fructokinase is a benign, asymptomatic disease dec liver aldolase B produces a severe disease: inc fructose-1-phosphate in hepatocytes, dec phosphate, severe hypoglycemia (because dec phosphate inhibits gluconeogenesis and glycogenolysis), cirrhosis, hyperlactic acidemia
A. metabolism

 rx:

dietary restriction of fructose, sorbitol, and sucrose sources, such as fruits and table sugar

3. galactosemia more

common variant is dec GALT which causes inc galactose-1-phosphate in liver (hepatomegaly) and spleen (splenomegaly) signs include cataracts and mental retardation (accumulation of galactitol in lens and neural tissue), failure to thrive, vomiting and diarrhea treatment is dec dietary galactose and lactose for at least the first 2 years of life
296. mucopolysaccharidoses A. terms

= sugars + amino acids (peptides/proteins) = proteins + GAGs (very long heteropolysaccharide chains) a) carbohydrates predominate (little protein) = mucopolysaccharide (aka GAG = glycosaminoglycans) (1) acidic sugars (all GAGs except keratan sulfate) D-glucuronic acid: hyaluronic acid, heparan sulfate, chondroitin sulfate L-iduronic acid: dermatan sulfate and heparin (but some also in heparan sulfate) (2) amino sugars D-glucosamine (available as tablets for joint therapy): heparin, hyaluronic acid, keratin sulfate, heparan sulfate D-galactosamine: dermatan sulfate, chondroitin sulfate B. clinical 1. general: metabolites accumulate in: macrophages, endothelial cells, and leukocytes (Alder-Reily bodies) neurons (zebra bodies) causing mental retardation hepatocytes (hepatomegaly) chondrocytes causing arthritis (joint stiffness) and skeletal deformities smooth muscle cells causing aortic stenosis and cardiac lesions 2. IH = Hurlers ("gargoylism"), which is due to dec alpha-L-iduronidase inc heparan sulfate (HS) and dermatan sulfate (DS) in lysosomes and excreted in urine short individuals with coarse facial features ("gargoylism"), corneal clouding, and mental retardation 3. II = Hunters syndrome (x-linked recessive), which is due to dec L-iduronosulfate sulfatase (iduronate sulfatase) milder disease than Hurlers (clear corneas and large tongue) inc DS and HS in lysosomes and excreted in urine 4. IV = Morquio's inc KS (excreted in urine) dwarves with bad AV (aortic valve), normal intelligence; abnormalities of vertebra C2 can cause subluxation of spine and quadriplegia
2. proteoglycans 297. mucolipidoses A. aka

1. glycoproteins

(ML)/other glycoprotein storage diseases (oligosaccharidoses) B. similar to MPS with abnormal bone development (dysostosis), but no urinary excretion of acid mucopolysaccharides C. I-cell disease (inclusions in cultured fibroblasts) mental retardation, skeletal dysplasia, increased serum lysosomal enzymes (acid hydrolases) can't form mannose-6-phosphate (lack N-acetylglucosamine phosphotransferase) and therefore lysosomal enzymes can't go to lysosomes

298. sphingolipidoses A. review 1. lysosomes

enzymatic digestion; acid hydrolases (think acid pH) modification: terminal mannose-6-phosphate (necessary for many lysosomal enzymes to be transferred from golgi to lysosomes) 2. sphingolipids: sphingosine (ceramide) + fatty acids (rather than glycerol + fatty acids) phosphosphingolipids (contain phosphoric acid), ie sphingomyelin location: myelin and RBC membranes increased sphingomyelin causes acanthocytes (abetalipoproteinemia)
post-translational

intracellular

3. glycosphingolipids

characteristics: essential components of membranes (especially nerves); regulate cell interactions; very antigenic (such as blood groups) b) classification based on ceramide (1) neutral (uncharged) = cerebrosides: ceramide + one sugar (either galactose or glucose) (2) sulfatides: contain sulfuric acid ester (3) globosides: ceramide + two or more sugars (4) gangliosides contain sialic acid (NANA = N-acetylneuramininc acid); provides negative charge found in outer leaflet plasma membrane: receptors for toxins: cholera (peptide B binds to the carbohydrate of GM1 ganglioside on intestinal epithelial cells), tetanus, and influenza types: GM1 and GM2 c) classification based on sugars galactoceramides: gal-ceramide and sulfatide glucoceramides: glu-ceramide, gal-glu-ceramide, gal-gal-glu-ceramide, NAG-gal-gal-glu-ceramide (globoside), and gangliosides B. clinical 1. Niemann-Pick disease (dec sphingomyelinase) most common type is type A (infantile) = mental retardation, seizures, ataxia, and death by age 3 (seen in Ashkenazi Jews) macrophages filled with lipid (sphingomyelin) form foam cells (see myelin figures or Zebra bodies with EM) cherry red spot of retina 2. leukodystrophies (dysmyelination) a) ALD (adrenoleukodystrophy) is the disorder in "Lorenzos oil" peripheral and CNS demyelination with adrenal insufficiency increased serum VLCFA (very long chain fatty acids) due to problem with peroxisomes b) MLD (metachromatic leukodystrophy), which is due to dec arylsulfatase (cerebroside sulfatase); inc sulfatide (cerebroside sulfatase) demyelination signs (spasticity) and increased CSF protein metachromatic granules (brown material with toluidine blue) in oligodendrocytes and neurons c) Krabbes disease (dec galactosylceramide beta-galactosidase) increased galactocerebroside in brain ; CNS demyelination with multinucleated macrophages (globoid cells) around blood vessels growth retardation, rigidity or spasticity with hyperactive reflexes 3. Tay-Sachs disease (dec hexosaminidase A, alpha subunit); inc GM2-ganglioside (think "Tay-SaX" sounds like "Xosaminidase") cherry red macula and blindness (amaurosis) infants of Ashkenazi Jews (Eastern Europe) develop mental retardation, fixed gaze, and seizures ("amaurotic familial idiocy") mx shows foamy macrophages; EM shows whorled lamellar bodies in lysosomes 4. Sandhoffs disease (dec hexosaminidase A and B, beta subunits); inc GM2-ganglioside and globoside same symptoms as Tay-Sach's (mental retardation, seizures, and blindness with a cherry red macula) 5. Gauchers disease (the most common lysosomal storage disease), which is due to dec glucocerebrosidase (betaglucosidase) increased glucocerebroside from catabolism of membranes (not lipid, therefore no foam cells) macrophages filled with glucocerebroside = Gaucher cells ("crumpled tissue paper") the most common type is the adult type (type I), which is found primarily in Ashkenazi Jews type 2 usually presents in infancy with severe neurologic sxs (seizures, ataxia, paralysis, etc) inc ACE (angiotensin converting enzymes) and inc acid phosphatase (liver, lymph nodes, blood) 6. Fabrys disease ( x-linked recessive), which is due to dec alpha-galactosidase A; inc ceramide trihexosidase paresthesias (burning and tingling) of palms and soles purple hyperkeratotic genital lesions (cutaneous angiokeratomas) thickened blood vessels cause myocardial infarction and stroke 7. Farber's disease (disseminated lipogranulomatosis): AR disorder due to deficiency of ceramidase; increased ceramide

a) general

 sx:

hoarseness, painful swollen joints, skin nodules, usually death by age 2

299. Abnormalities A. review:

of amino acids tyrosine metabolism phenylalanine converted to tyrosine by liver enzyme phenylalanine hydroxylase (PAH) tyrosine is converted to: melanin, thyroxine, catecholamines, and homogentisic acid biopterin: tetrahydrobiopterin (BH4) converted to quinoid dihydrobiopterin associated with phenylalanine converted to tyrosine and tryptophan converted to serotonin B. hyperphenylalaninemia 1. classic phenylketonuria (PKU) a) dec phenylalanine hydroxylase causes inc phenylalanine and dec melanin (pt are usually blond and blue-eyes) tyrosine and tyrosine products are normal (but tyrosine becomes an essential amino acid and must be obtain form diet) urine has increased phenylketone, phenylpyruvate, phenylacetate b) normal at birth but mental deterioration and retardation soon afterwards; "Flowers for Algernon" (also develops musty odor due to phenylacetic acid) c) screening test at birth is the Guthrie test (incubate blood with a special bacterial strain, Bacillus subtilis) d) treatment is restrict phenylalanine (no Nutrisweet, aspartame) and increase dietary tyrosine 2. maternal PKU homozygous female treated early then stopped has heterozygous children who can develop mental retardation due to maternal inc phenylalanine during pregnancy 3. dec BH4 (tetrahydrobiopterin) can also cause hyperphenylalaninemia untreated will cause dec monoamine neurotransmitters (DOPA, NE, E, serotonin) control phenylalanine levels and give products of tyrosine hydroxylase (DOPA) and tryptophan hydroxylase (serotonin) if treatment is only dietary phenylalanine restriction patients will still develop mental retardation C. alkaptonuria dec homogentisic oxidase (causes inc homogentisic acid); normal biochemical step is conversion of homogentisic acid to methylacetoacetate urine turns dark with standing (black diapers in infants); due to oxidation of excess homogentisic acid ochronosis = black cartilage (ears), tendons, and sclera arthritis in younger individual that is not juvenile rheumatoid arthritis (negative RF) D. albinism may have deficiency of tyrosinase (or lack of migration of neural crest cells) white hair, pink skin, blue iris, red pupils inc incidence of squamous cell carcinoma of skin due to lack of melanin pigment E. maple syrup urine disease branched-chain ketoaciduria (think "cutting branches of maple tree") branched chain amino acids are leucine, isoleucine, valine block is due to deficiency of branched-chain alpha ketoacid dehydrogenase signs = mental retardation, hypoglycemia, spasticity, and death treatment is dec protein intake F. Hartnup's disease abnormal transport of neutral amino acids in kidneys and intestines (think "hard neutral uptake") dec tryptophan causes dec niacin which can produce pellagra-like (dermatitis, diarrhea, dementia) G. Lesch-Nyhan syndrome x-recessive disorder due to dec HGPRT (hypoxanthine-guanine phosphoribosyl transferase) causes abnormal purine salvage (HGPRT normally salvages (recycles) hypoxanthine and guanine); increased 5phosphoribosyl-1-pyrophosphate (PRPP) inc uric acid (hyperuricemia) causes gout other signs include mental retardation, spasticity, involuntary movements, self-mutilation, and aggressive behavior H. homocystinuria

 deficiency

of cystathionine synthetase or pyridoxal phosphate (vitamin B6), which also causes inc serum methionine increased risk of atherosclerosis and thrombosis other signs (reminiscent of Marfan's) include long fingers (arachnodactyly), subluxed lens, osteoporosis
300. Chromosome A. karyotypes 1. routine

basics

karyotyping material via cell culture, amniotic fluid, chorionic villus sampling arrest mitosis at metaphase with colchicine, which inhibits microtubule formation staining produces banding patterns; G-banding (giemsa) is most commonly used major limitation: applicable only to cells that are dividing or can be induced to divide in vitro 2. FISH (fluorescence in situ hybridization) FISH uses DNA probes labeled with fluorescent dyes that recognize chromosome-specific sequences these probes are applied to interphase nuclei and bind to its complementary sequence on the chromosome FISH is not limited to interphase nuclei; can use DNA probes that are specific for defined regions of the chromosomes can determine trisomies, microdeletions, etc. chromosome painting is an extension of FISH, whereby whole chromosomes can be labeled with a series of fluorescent DNA probes spectral karyotyping (SKY) (aka "spectacular karyotyping") can visualize the entire human genome 3. normal karyotype = 23 pairs of chromosomes (each pair of autosomes are homologs) centromere divides chromosome into p = short arm (petite) and q = long arm telomere is at distal end of each chromosome B. terms 1. haploid = number of chromosomes in germ cells (23 or n) 2. diploid = number of chromosomes found in non-germ cells (46 or 2n) 3. euploid = any exact multiple of the haploid number 4. aneuploid = any non-multiple of the haploid number (cause may be due to nondisjunction or anaphase lag) 5. triploid = three times the haploid number (69 or 3n) 7% of miscarriages usually due to double fertilization of haploid ovum (two haploid sperm fertilizing a haploid ovum) paternal dominant triploidy (paternal disomy of all chromosomes) is associated with partial hydatidiform mole 6. tetraploid = four times the haploid number (92 or 4n) 7. trisomy = three copies of same chromosome (ie., trisomy 21) C. mechanisms of abnormalities 1. nondisjunction (failure of homologous chromosomes or paired chromatids to separate) can be during meiosis or mitosis 2. translocations can be a) balanced (no material is gained or loss) b) centric fusion = Robertsonian translocation involves 2 acrocentric chromosomes; individual may be balanced or unbalanced carrier of translocation is clinically normal (balanced) but offspring may have trisomy (ie familial form of Downs); unbalanced 3. isochromosomes transverse separation (instead of normal longitudinal); one arm of a chromosome is lost and the remaining arm is duplicated autosome isochromosomes are usually lethal (isochromosome 12 seen in testicular germ cell tumors) x chromosome isochromosome may cause Turners syndrome
obtain 301. Trisomies A. trisomy

13 (Patau syndrome) ; karyotype is 47, XY, +13 or 47, XX, +13 severe mental retardation with forebrain abnormalities such as holoprosencephaly (no olfactory bulbs, fused frontal lobes); associated with abnormalities of sonic hedgehog gene; most cases of holoprosencephaly have normal karyotypes, but most characteristic abnormality is trisomy 13 and 15

facial abnormalities including cleft lip/palate, single eye ("cyclops") rocker bottom feet, and congenital heart defects B. trisomy 18 (Edward's syndrome) (think "E" in "Edward's" and "eighteen"); karyotype is 47, XY, +18 or 47, XX, +18 severe mental retardation characteristic clenched fist with overlapping fingers micrognathia (tiny jaw), low-set ears, rocker-bottom feet, congenital heart defects, and polyhydramnios with a single umbilical artery C. trisomy 21 (Down's syndrome) ; karyotype is 47, XY, +21 or 47, XX, +21 1. causes a) 95% due to nondisjunction (parent will have normal karyotype) 95% due to maternal nondisjunction associated with increasing maternal age (eg age 30 = 1/900; age 40 = 1/100) during meiosis: 75% meiosis I; 25% meiosis II b) 3-5% due to translocation = Robertsonian (balanced) translocation (familial form of Down's) (1) parent (carrier) = 14, 21, 14/21 (ie 14/21 Robertsonian translocation) then there are 6 possible gametes: normal gamete (14, 21) produces normal offspring 14/21 gamete produces offspring with Robertsonian translocation 21, 14/21 gamete produces offspring with Down's 14 gamete produces non-viable offspring with monosomy 21 14, 14/21 gamete produces non-viable offspring with trisomy 14 21 gamete produces non-viable offspring with monosomy 14 (2) parent (carrier) = 14, 14, 21/21 (ie 21/21 Robertsonian translocation) then progeny are either trisomy 21 or monosomy 21 (not viable) c) 1-3% are mosaic (nondisjunction early during somatic mitosis) 2. recurrence risk a) overall after one child with Down's = 1% b) based on parent karyotype: (1) normal parent karyotype then risk is associated with increasing maternal age (2) parent with Robertsonian translocation: 14/21: mother = 10-15% (theoretical is 1/3); father <2% 21/21: mother = 100%; father = 100% 3. clinical mental retardation (most common familial cause) oblique palpebral fissures, epicanthal folds, flat facial profile ("mongolism"), and horizontal palmar ("Simian") crease heart defects (endocardial cushion defect is most common) acute lymphoblastic leukemia (first 2 years of life) Alzheimer's disease (almost 100% incidence after age 35) duodenal atresia (double-bubble sign on x-ray = air in stomach and duodenum) maternal serum alpha-fetoprotein (MSAFP) testing should be done at 16-18 weeks gestation; a triple screen includes AFP, estriol, and hCG: all three are low with trisomy 18; hCG is high and AFP and estriol are low with trisomy 21 D. excess # of sex chromosomes excess Y (XYY) associated with tall with cystic acne (antisocial behavior and criminals is controversial); normal IQ (but learning problems) excess X (XXX, XXXX, etc) individuals are phenotypically normal but inc mental retardation with inc'ing number of X
polydactyly, 302. Chromosomal A. 5p-

midline

deletions (eg 46 XX, 5p- or 46XY, 5p-) cri du chat (high pitched mewing cry like a cat) severe mental retardation, microcephaly, and heart defects B. 11p-: associated with Wilms tumor and absence of iris (WAGR syndrome = Wilm's tumor, aniridia, GU abnormalities, mental retardation) C. 13q-: retinoblastoma

D. 15q1. terms imprinting uniparental normal

means inactivation and may be due to DNA methylation disomy = two parental chromosomes of same type from same parent (normal is biparental

disomy) maternal chromosome 15 has imprinted Prader-Willi genes and active Angelman genes normal paternal chromosome 15 has active Prader-Willi genes and imprinted Angelman genes 2. abnormal maternal deletion (with normal paternal imprinting) causes Angelman syndrome stiff ataxic gait with jerky movements and inappropriate laughter ("happy puppets") may be due to two copies of paternal 15 chromosome (paternal uniparental disomy) affected gene is UBE3A, which is a ubiquitin protein-ligase 3. abnormal paternal deletion (with normal maternal imprinting) causes Prader-Willi syndrome mental retardation, short, obese (eats a lot) with small hands and feet and hypogonadism may be due to two copies of maternal 15 chromosome (maternal uniparental disomy) E. 22q11.2 deletion syndrome 1. DiGeorge's syndrome is due to developmental failure of pharyngeal pouches 3 and 4 due to deletion of chromosome 22: think "CATCH 22" C = cardiac (congenital) abnormalities A = abnormal face (hypertelorism with low set ears) T = thymus defect (no T cells) = no cell-mediated immunity, which causes severe infections with viruses, mycobacteria, fungi C = cleft palate H = hypocalcemia (due to absence of parathyroids) 2. also associated with a high risk for psychotic illness, such as schizophrenia and bipolar disorders 3. includes so-called velocardiofacial syndrome
303. Hypogonadism A. review 1. chromatin

open chromatin (lighter areas); transcriptionally active (darker areas) = transcriptionally inactive; highly condensed chromatin (1) constitutive heterochromatin always condensed and inactive in all cells (not transcribable) genes at centromere and telomere (2) facultative heterochromatin may be either condensed and inactive or decondensed and active example is the X chromosome 2. Lyon hypothesis about X inactivation (which forms the Barr body) only one X is active in each cell and the other X is inactive inactivation of X occurs early in female embryonic development (and is complete by 2nd week) inactivation is random (maternal or paternal X, except for abnormal X), incomplete, and reversible note that the number of Barr bodies, which are facultative heterochromatin, = the number of X chromosomes minus one 3. recent studeis many genes escape X inactivation; some of the genes that are expressed from both X chromosomes are important for normal growth and development B. Turner's syndrome 1. cause 45XO is cause in 55-60%: no Barr body; most are paternal error (nondisjunction during paternal meiosis) remainder 40% are due to isochromosome, mosaics (one Barr body; inc risk for seminoma and gonadoblastoma), and xp implicated genes are many, including SHOX (short stature homeobox) 2. female hypogonadism = ovarian dysgenesis hypermaturing ovaries ("menopause before menarche") leads to streak ovaries decreased estrogen leads to decreased secondary female characteristics with increased LH, FSH
b) heterochromatin

a) euchromatin:

female = Mllerian duct develops (due to lack of MIF) and Wolffian duct regresses (due to lack of testosterone) 3. primary amenorrhea (no menarche); Turner's is an important cause of primary amenorrhea 4. skeletal abnormalities short stature due to growth retardation (no adolescent growth spurt) inc carrying angle of forearm with elbow out (cubitus valgus); 'shield-shaped' chest, and a high-arched palate 5. web neck due to lymphedema (also associated with cystic hygroma) 6. no mental retardation 7. 1/2 of patients develop hypothyroidism due to autoantibodies against thyroid hormone C. Klinefelter's syndrome 1. most common genotype is 47XXY (single Barr body), which is due to nondisjunction during meiosis 2. male hypogonadism = testicular dysgenesis small firm atrophic testes no sperm (Klinefelter's is a principle cause of male infertility) decreased testosterone, which causes decreased secondary male characteristics (eunuchoidism) but no abnormalities until puberty increased FSH, LH, estradiol; decreased 17-ketosteroids 3. tall because no testicular (androgen) induced fusion of epiphyses 4. gynecomastia (inc risk of breast cancer) and female distribution of hair (patients rarely go bald) 5. slight dec IQ, but pts are not severe mental retardation
304. Ambiguous

ductal

sexual development A. sexual development 1. terms genetic sex: determined by Y chromosome; TDF (testicular determining factor) thought to be SRY (sexdetermining region of Y chromosome) gonadal sex: determined by histologic appearance of gonads ductal sex: determined by presence of mullerian duct and wolffian duct phenotypic (genital) sex: determined by appearance of external genitalia 2. normal a) XY (1) Y produces TDF: testes (gonadal sex) (a) Sertoli cells produce MIF (mullerian inhibiting substance) causing the Mullerian to regresses (b) Leydig cells produce testosterone forms wolffian duct (ductal sex): epididymis, vas deferens, seminal vesicles forms DHT (via 5 a reductase): prostate and male external genitalia (phenotypic sex): penis, scrotum, urethra b) XX (1) no Y therefore no TDF (2) XX = ovaries (gonadal sex) no testosterone therefore wolffian regresses no MIF therefore Mullerian forms (ductal sex): fallopian tubes, uterus, hydatid no DHT therefore female external genitalia (phenotypic sex): clitoris, labia, lower vagina B. pseudohermaphroditism 1. general (Hermes was the male messenger of the gods; Aphrodite was the goddess of love) true hermaphrodites has both ovarian and testicular tissue (may result of a chimera, which refers to cells being from different zygotes) pseudohermaphrodite is a disagreement between the phenotypic and gonadal sex female 46,XY individuals may have deletions or mutations involving SRY (sex-determining region of Y) 2. male pseudohermaphrodite (XY) a) androgen insensitivity syndrome (testicular feminization) (XR) is due to mutation of gene for androgen receptor (1) gonadal sex = testes (because of Y in XY individual), but in inguinal canal (2) ductal sex = both ductal types regress Mllerian duct regresses (due to MIF) Wolffian duct regresses (due to lack of testosterone receptors)

sex is phenotypic female (due to lack of receptors for DHT) develop blind-end vagina ("primary amenorrhea") and inc breast tissue b) 5 alpha reductase deficiency; 5-alpha reductase normally converts testosterone to dihydrotestosterone (DHT) (1) gonadal sex = testes (because of Y in XY individual) (2) ductal sex is male Mllerian duct regresses (due to MIF) Wolffian duct develops (due to testosterone) (3) phenotypic sex is variable: variable external genitalia (due to decreased DHT due to lack of 5alpha reductase) with micropenis, hypospadias, and cryptorchid testis (testes or penis may enlarge at puberty) c) abnormal SRY (quite rare): phenotypically female with primary amenorrhea, 46,XY karyotype, external and internal female genitalia, no testes 3. female pseudohermaphrodite (XX) a) XO = Turner's (1) no XX: streak gonads; decreased estrogen and decreased secondary sex characteristics (2) no Y no testosterone: Wolffian regresses no MIF: Mullerian develops (ductal female) no DHT: external female b) congenital adrenal hyperplasia (is due to deficiency of adrenal cortex enzymes, such as 11-hydroxylase or 21-hydroxylase) (1) gonadal sex = ovaries (XX individual) (2) ductal sex is female Mllerian duct develops (due to lack of MIF) Wolffian duct regresses (due to lack of local testosterone production) (3) phenotypic sex is external male (due to excess systemic formation of DHT) C. summary ductal male with external male = normal male ductal female with external female = normal female no ducts (with testes) and external female = testicular feminization (no androgen receptors) ductal male with external female = 5-alpha-reductase deficiency ductal female with external male = congenital adrenal hyperplasia
pts 305. Disorders A. fragile

(3) phenotypic

of trinucleotide repeats X syndrome 1. abnormal trinucleotide ((CGG)x) repeat involving FMR1 gene (which is expressed mainly in brain and testes) increased numbers (amplification) of repeats (>230) causes FMR1 methylation and inhibits expression of FMR1 expansion (amplification) in females only = parental imprinting transmitting males = premutation is 50-230 repeats anticipation = with subsequent generations the disease is earlier and more severe Sherman's paradox = incidence of mental retardation is greater in grandsons than brothers of transmitting males 2. hereditary mental retardation (second most common familial cause; most common is Down syndrome) and autism 3. long face with large everted ears 4. large testes (macro-orchidism); think "CGG = see giant gonads" B. Huntington's syndrome: see neuropathology C. myotonic dystrophy: see muscular dystrophies and childhood is most susceptible to teratogens at 3-9 weeks when organs are being created out of germ cell layer morphogenesis a) homeobox genes (HOX genes)

306. Infancy

A. malformations 1. embryo 2. normal

in temporal or spatial combinations in patterning of limbs, vertebrae, craniofacial structures mutations of HOX may cause extra digits (synpolydactyly) or short digits (brachydactyly) vitamin A is an upstream regulator of HOX genes (retinoic acid during pregnancy may produce retinoic acid embryopathy) b) PAX genes (paired box genes) mutations of PAX-3 is seen in Waardenburg syndrome (congenital pigment abnormalities (white forelocks of hair; eye colors don't match) and deafness) other PAX mutations may be seen with aniridia and Wilm's syndrome B. teratogens 1. ACE inhibitors can cause renal damage 2. DES can cause clear cell carcinoma of vagina in subsequent generations 3. iodide can cause congenital goiter or hypothyroidism 4. 13-cis-retinoic acid extremely high risk for birth defects including CNS, cardiac, and craniofacial defects may interfere with HOX genes 5. thalidomide causes limb defects (underdeveloped limbs which are short stumps without fingers or toes = "seal flippers" called phocomelia) 6. alcohol most common cause of congenital malformations in US (may be due to inhibition of cell migration) pre (low birth weight) and postnatal developmental retardation (mental retardation) microcephaly, facial abnormalities (maxillary hypoplasia and microphthalmos), short palpebral fissures 7. tetracycline can cause pigmentation of bone and teeth C. infections TORCH = toxoplasma, other, rubella, CMV, herpesvirus: signs of this group include fever, encephalitis, chorioretinitis, etc congenital rubella findings: purpuric "blueberry muffin" rash, cataracts, hearing loss, and PDA D. SIDS sudden infant death syndrome is a heterogeneous, multifactorial disorder definition is "sudden death of infant under 1 year of age that is unexplained after thorough examination" most SIDS occurs between 2 and 4 months of life child usually dies during sleep (= crib death or cot death) risk factor is sleeping in a prone position (healthy infants should sleep on their back or side) E. physical child abuse clinical: multiple bruises (without a bleeding disorder), fractures (at different stages of healing), retinal hemorrhages ("shaken baby syndrome) law requires reporting of any suspicion of child abuse or neglect F. tumors 1. benign hemangioma lymphangioma teratoma 2. malignant: small round blue cell tumors neuroblastoma nephroblastoma (Wilms tumor) retinoblastoma medulloblastoma Ewing sarcoma/PNET rhabdomyosarcoma
role

act

HIGH-YIELD NOTES OF PATHOLOGY 2009-2010 PART 7b NUTRITION/ENVIRONMENT

307. Nutritional A. energy

states from food carbohydrates = 4 kcal/g (brain neurons use glucose as primary source for fuel) fats = 9 kcal/g (myocardial cells burn fats for primary source of fuel) proteins = 4 kcal/g alcohol = 7 kcal/g B. feeding 1. carbohydrates (glucose) increased diet carbohydrates cause increased insulin/decreased glucagon (anabolic state) blood glucose = about 20 grams (80 kcal) insulin increases glycogen (glycogenesis) in liver and muscle, activates glycogen synthase, increased glycolysis inactivates glycogen phosphorylase 2. fats (trigylcerides): insulin increases adipose tissue (lipogenesis); in liver increases VLDL 3. protein (amino acids): insulin increases protein synthesis in muscle C. fasting (not eating for several hour): decreased diet carbohydrates causes decreased insulin/increased glucagon 1. glycogenolysis (glycogen is converted to glucose): occurs with overnight fast source of glycogen is liver (100g = 400 kcal) and muscle (400 g =1600 kcal), but muscle glycogen is used by muscle only (no glucose 6-phosphatase) 2. gluconeogenesis: occurs in liver with longer fasting (12 to 24 hours) source for gluconeogenesis includes amino acids (from protein breakdown in muscle and alanine cycle), and glycerol, and lactate (Cori cycle) Cori cycle: lactate from skeletal muscle glycolysis is transported to the liver and kidney where it re-forms glucose 3. lipolysis: releases triglycerides to form glycerol (for gluconeogenesis) and free fatty acids muscle metabolizes FFA while liver uses they to form ketone bodies (which can used by muscle and brain) D. starvation (not eating for several days) 1. no diet carbohydrates and no glycogen causes decreased insulin/increased glucagon 2. no glycogenolysis 3. starvation is similar to fasting with increased protein loss and formation of ketone bodies (ketosis) by liver (used by brain for fuel) 4. steps for ketone body formation formation of acetoacetyl CoA from beta-oxidation of acyl-CoA formation of HMG-CoA from acetoacetyl-CoA and acetyl-CoA (enzyme is HMG-CoA synthase) cleave HMG-CoA to form acetoacetate and CoA reduce acetoacetate to form 3-hydroxybutyrate and acetone 5. diabetes is similar to starvation (except diabetes also has glycogen stores and increased blood fatty acid levels) and diet A. very short term (seconds) muscles use ATP and creatine phosphate B. short term (anaerobic) muscles use glycolysis (forms lactate, which makes muscles sore and diffuses into the blood) and glycogenolysis (muscle and liver glycogen) C. long term (aerobic) 1. glucose "old" glucose is from glycogen (stimulated by glucagon) "new" glucose (gluconeogenesis) is from glycerol (TG from fat breakdown), alanine (from protein breakdown), and lactate (from Cori cycle) 2. aerobic exercise is similar to fasting (only telescoped in time) a) induces fat burning enzymes which increases lipolysis at rest, but results of increased lipolysis depend on ratio of alpha2/beta3 (alpha2's decrease lipolysis; beta3's increase lipolysis): alpha2's in women found on hips, thighs, and butt, in men found around abdomen b) when glycogen stores depleted then it is similar to starvation

308. Exercise

supply of CHO = 20 g blood glu (80 kcal), 100 g liver glycogen (400 kcal), 400 g muscle glycogen (1600 kcal) = about 2080 kcal total 1 mile burns about 100 kcal, therefore glycogen depleted at about 20 miles ("hitting the wall") decreased glucose and insulin and increased free fatty acids and glucagon c) exercise decreases insulin secretion (insulin is the "anti-exercise" hormone) via alpha2 on beta islet cells; therefore no insulin-induced hypoglycemia or inhibition of lipolysis during exercise (note catecholamines are primary regulators of serum glucose during exercise) d) "runner's high": thought to be due to secretion of endorphins (ed note: definitely a bogus myth!) D. appetite 1. neurohumoral mechanisms that regulate appetite and energy balance can be subdivided into three components a) peripheral (afferent) system (1) appetite suppressants (a) leptin synthesized by fat cells (the product of the ob gene) to signal fat storage reserves in the body the leptin receptor (OB-R) is the product of the diabetes (db) gene acts on hypothalamus to decrease hunger and food intake weight loss decreases leptin causing increased food intake (i.e. to eat more when fat storages are low) weight gain increases leptin causing decreased food intake (i.e. to eat less when fat storages are high) mice genetically deficient in leptin (ob/ob mice) or leptin receptors (db/db mice) overeat and gain weight leptin also regulates energy expenditure an abundance of leptin stimulates physical activity, heat production, and energy expenditure in the hypothalamus: leptin stimulates POMC/CART neurons that produce anorexigenic neuropeptides (primarily melanocyte-stimulating hormone, alpha-MSH, an appetite suppressant) and stimulates catabolic circuits inhibits NPY/AgRP neurons that produce feeding-inducing (orexigenic) neuropeptides and inhibits anabolic circuits (inhibit energy production) in individuals with stable weight, the activities of the opposing POMC/CART and NPY/AgRP pathways are properly balanced a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity most obese individuals are thought to be leptin resistant and have been found to have high levels of leptin this resistance is thought to explain in part why administration of leptin has not been shown to be effective in suppressing appetite in most obese people (b) peptide YY (PYY) secreted from endocrine cells in the ileum and colon inhibits gastric motility and increases water and electrolyte absorption in the colon a meal-regulated anorexigenic signal (inhibits food intake); counters the appetite-stimulant effects of ghrelin plasma levels of PYY are low during fasting and increase shortly after food intake levels generally increase after gastric bypass surgery obese people secrete less PYY than non-obese people levels generally decrease in individuals with the Prader-Willi syndrome (c) obestatin potentially from stomach and small intestine encoded by the same gene that also encodes ghrelin, a peptide hormone that increases appetite the protein product of that gene breaks into two smaller peptides, ghrelin and obestatin (d) amylin secreted with insulin from pancreatic -cells that reduces food intake and weight gain being evaluated for the treatment of obesity and diabetes both PYY and amylin act centrally by stimulating POMC/CART neurons in the hypothalamus, causing a decrease in food intake

body

from -cells of the pancreas stimulants (a) ghrelin produced in the stomach and in the arcuate nucleus only known gut hormone that increases food intake most likely stimulates NPY/AgRP neurons to increase food intake leptin and ghrelin are considered to be complementary in their influence on appetite, with ghrelin produced by the stomach modulating short-term appetitive control levels rise sharply before meals and fall between 1 and 2 hours after eating (short-term mediator) when stomach is "filled" (gastric bypass surgery may suppress ghrelin levels) in obese individuals the postprandial suppression of ghrelin is attenuated, leading to maintenance of the obesity (3) other (a) adiponectin produced mainly by adipocytes (probably has no effect on appetite) levels inversely correlate with body fat (lower in obese than in lean individuals) has been called a "fat-burning molecule" and the "guardian angel against obesity," directs fatty acids to muscle for their oxidation adiponectin is an insulin-sensitizing hormone with anti-diabetic, anti-inflammatory and antiatherogenic properties (diabetes risk decreases as adiponectin levels increase) decreases the influx of fatty acids to liver, decreases glucose production in the liver, causing an increase in insulin sensitivity and a protection against the metabolic syndrome (b) other substances from fat cells adipose tissue also produces cytokines such as TNF, IL-6, IL-1, and IL-18, chemokines, and steroid hormones increased production of cytokines and chemokines by adipose tissue in obese patients creates a chronic sub-clinical (asymptomatic) inflammatory state that includes high levels of circulating C-reactive protein adipose tissue participates in the control of energy balance and energy metabolism, functioning as a link between lipid metabolism, nutrition, and inflammatory responses b) arcuate nucleus in the hypothalamus: (1) an area of the hypothalamus that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively (2) contains two subsets of first-order neurons: POMC (pro-opiomelanocortin) and CART (cocaine and amphetamine-regulated transcripts) neurons; stimulatory inputs to the VMH and inhibitory inputs to the LH NPY (neuropeptide Y, an extremely potent stimulator of feeding behavior) and AgRP (agoutirelated peptide); has stimulatory inputs to the LH and inhibitory inputs to the VMH POMC/CART neurons enhance energy expenditure and weight loss (catabolic) through the production of the anorexigenic -melanocyte-stimulating hormone (MSH), and the activation of the melanocortin receptors 3 and 4 NPY/AgRP neurons promote food intake (orexigenic [increasing or stimulating the appetite] effect) and weight gain end result: NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group c) efferent system: carries the signals generated in the second order neurons of the hypothalamus to control food intake and energy expenditure E. obesity defined as an accumulation of adipose tissue that is of sufficient magnitude to impair health associated with type 2 diabetes, dyslipidemias, cardiovascular disease, hypertension, breathing difficulties during sleep, certain types of cancer, cholesterol gallstones, osteoarthritis (and more) excess weight can be assessed by the body mass index BMI makes blanket assumptions and gives inaccurate information with above-average lean muscle mass can measure triceps skinfold thickness, mid-arm circumference, and the ratio between waist and hip circumferences
(e) insulin (2) appetite

or visceral, obesity, is associated with a much higher risk than is excess accumulation of fat diffusely in subcutaneous tissue F. dietary stuff 1. weight-loss programs (a brief subset) a) Atkins: low CHOs, high protein, high fat; people eventually eat less (decreased calories) b) Scarsdale diet: short-term low CHO fad diet while eating grapefruit and taking diet pills c) Pritikin: vegetarian very low fat, high fiber diet d) Dr. Phil (McGraw): 7 keys based on lifestyle modification and high-response cost, high-yield nutrition principle (eg eat food that takes a long time to prepare) e) low glycemic: remove refined CHO's, which cause greatest post-prandial increased blood glu, which increases insulin and stimulates hunger glycemic index (GI): speed at which a CHO enters the blood as glucose (fiber content and fat content will decrease glycemic index); low index: fruits, veggies, nuts; highest index: starches (pasta, rice, bagels, potatoes) glycemic load (GL): glycemic index times the amount of available CHO per serving low GI and low GL: all-bran cereal, beans, oranges, peaches, peanutes... high GI and high GL: baked potatoes, cornflakes f) commercial plans Weight watchers: balanced low fat with exercise and group counseling Nutrisystem: reduced calorie with balanced nutrition based of food pyramid using pre-packaged meals Jenny Craig: reduced calorie diet, about 1200 cal/day, with balanced nutrition based on food pyramid and pre-packaged meals Richard Simmons: basically follows food pyramid with 1200 cal/day and exercise South Beach diet: a diet based on the glycemic index, by Dr. Agastston, a cardiologist; he says you can lose 10 pounds in the first two weeks... 2. diet foods and pills (a brief subset) a) ephedrine (aka Ma Hunag herb): component of many diet pills (somewhat synergestic with caffeine) and "herbal ecstasy" sympathomimetic: stimulates alpha1, beta1, and beta2 adrenoreceptors; potentially fatal adrenergic effects b) phenylpropanolamine (PPA): found in cough medicine and appetite suppressantes; can cause severe high BP (and stroke) sympathomimetic: stimulates alpha1, beta1, and beta2 adrenoreceptors; similar to pseudoephedrine c) orlistat: blocks lipase in gut; side effects include loose fatty stools (similar to olestra, a fat substitute) d) serotonin-releasing: fen-phen, redux: can cause pulmonary hypertension and cardiac disease e) Yohimbine; a naturally-occurring indole alkaloid with alpha2-adrenergic blocking activity (therefore, increases norepinephrine) has been used as a mydriatic agent, aphrodisiac, and weight loss chemical increases lipolysis (increased plasma free fatty acids); may be due to a direct effect of alpha2-adrenergic blockage or increased adrenergic stimulation of beta-3 receptors found on adipocytes f) aspartame (NutraSweet, Equal, Spoonful, and Equal-Measure) = phenylalanine, aspartic acid, and methanol 3. sports drinks, etc Sports Drinks: calories per 8oz: Gatorade 50 (110mg sodium; 30mg potassium); Powerade 70; AllSport 70 Energy Gels: Power Gel double caffeine 110cal, 50mg caffeine/package; GU 100 cal, ~20mg caffeine; Ultra Gel 133 cal, 0 caffeine
309. Protein-energy A. kwashiorkor

central,

malnutrition (PEM)

protein (calories may be OK) in older child (during weaning) albumin causes generalized edema (anasarca) and ascites (increased size of belly) defective enzyme formation leads to malabsorption due to decreased intestinal enzymes (therefore hard to treat orally); mx shows villous atrophy fatty liver (due to decreased apoproteins and decreased VLDL synthesis) abnormal skin and hair, such as fine, brittle, red hair with light bands ("flag sign") lethargy (won't eat), anemia, recurrent infections B. marasmus
decreased

decreased

 decreased younger

calories (protein may be OK) than one year of age normal albumin (therefore no edema) generalized wasting (individuals are emaciated and are "skin and bones") digestion is OK and individuals are easy to treat alert and ravenous, but anemia is present
310. Fat

soluble vitamins (fat soluble vitamins (ADEK) are stored and may cause symptoms if in excess; malabsorption can cause a deficiency fat soluble vitamins) A. vitamin A 1. normal group of related compounds called "retinoids", which includes retinal, retinol, and retinoic acid retinal is the aldehyde form of vit A, is converted from beta-carotene and acts as visual pigment retinol is the alcohol form of vitamin A, and is stored in Ito cells in liver retinoic acid can be used in therapy for some skin diseases (retinol and retinoic acid can function as steroid hormones and bind nuclear proteins vitamin A is a steroid hormone (binds to nuclear protein) functions include maintenance of epithelium (particularly mucus-secreting), part of retinal visual pigments (rhodopsin in rods, idopsin in cones), antioxidant, increased immunity to infections 2. deficiency causes night blindness (decreased rhodopsin production in rods) dry eyes (xerophthalmia), soft cornea (keratomalacia), and Bitot's spots (plaques of keratin debris) dry skin and recurrent infections (pulmonary) note that some retinoids are used for treatment, eg. all-trans retinoic acid used to treat psoriasis and acute promyelocytic leukemia and 13-cis retinoic acid used to treat severe acne 3. excess (vitamin A is normally stored in Ito lipocytes in liver) acute (eating polar bear livers) toxic effects include cerebral edema and death chronic (excess ingestion of cod-liver oil) causes cerebral dysfunction (pseudotumor cerebri), dry skin, alopecia (hair loss), liver damage is a teratogen (dont use in pregnancy) B. vitamin D 1. normal a) synthesis:7 dehydrocholesterol in skin + UV light forms previtamin D3 which in liver is converted to 25hydroxy-D3 (calcifidiol) by cytochrome P-450 mixed function oxidase and then is converted in kidney to 1,25-dihydroxy-vit D3 (calcitriol, the most potent metabolite) by a renal tubular mitochondrial hydroxylase b) function: increase calcium and phosphorus (mechanism is binding to receptors in cytoplasm and nucleus) intestines: increased calcium binding proteins increases absorption of calcium and phosphorous bone: increased bone resorption and increased mineralization of osteoid kidneys: increased renal tubular resorption of calcium and phosphate 2. deficiency a) causes include dietary deficiency, decreased synthesis (northern latitudes or decreased 1-alpha hydroxylase in kidney), malabsorption, liver or renal disease, drugs b) results in decreased serum calcium (1) rickets (bending bones) in children increased osteoid with decreased mineralization (histologically see thick osteoid seams) epiphyses are wide (wrist and knees) and pts develop growth retardation craniotabes (push in skull, it pops back) "rachitic rosary results from increased osteoid and cartilage at costochondral junction Harrisons groove = transverse line across lower rib cage bowing of legs is secondary to soft bones (2) osteomalacia in adults: osteopenia (bone pain) with increased thickness osteoid seams (which are not calcified due to decreased calcium) 3. excess vitamin D in adults may cause hypercalcemia, hypercalciuria and nephrocalcinosis (renal calculi) possibly secondary to sarcoid as the epithelioid macrophages may convert vit D to active form

C. vitamin

function includes anti-oxidant (protects red blood cells from hemolysis) (seen in premature infants or malabsorption disorders) causes spinocerebellar degeneration of posterior columns of spinal cord (loss of position and vibration) with loss of nerve cells in dorsal root ganglia weakness of skeletal muscle (eg ophthalmoplegia) hemolytic anemia (infants) due to increased fragility of erythrocytes (vit E is normally an antioxidant) D. vitamin K normal function is post-translational gamma-carboxylation of glutamic acid involving vit K-dependent factors II, VII, IX, X and protein C and protein S source is dietary (leafy green foods and dairy products) and intestinal bacteria (main source) vitamin K is given to protect against hemorrhagic disease of the newborn causes of deficiency include fat malabsorption, broad spectrum antibiotics, diffuse liver disease deficiency results in decreased synthesis of vitamin K-dependent factors Warfarin (Coumadin) is a vitamin K antagonist because warfarin inhibits epoxide reductase and interferes with gamma-carboxylation (which normally provides calcium-binding sites for clotting factors) increased bleeding with prolonged PT and PTT (use PT as a screening test for Coumadin) and normal bleeding time
2. deficiency 311. Water

1. normal

soluble vitamins B1 (thiamine) 1. normal functions oxidative decarboxylation of alpha ketoacids (such as pyruvate and alpha-ketoglutarate) cofactor for transketolase in pentose phosphate shunt (especially in erythrocytes) maintenance of neural membranes (provides ATP) 2. thiamine deficiency (seen in alcoholics or individuals with diets high in polished rice or white flour) causes a) wet beriberi = cardiovascular involvement vasodilation may cause AV shunting and lead to "high output cardiac failure) flabby heart due to dilated cardiomyopathy heart failure will lead to generalized edema (hence the name "wet") b) dry beriberi = nerve involvement (polyneuropathy) numbness and tingling in feet and lower legs c) lesions (hemorrhages) of mammillary bodies and periventricular areas of thalamus (seen in alcoholics and severe malnutrition) Wernicke syndrome = acute syndrome with ataxia, ophthalmoplegia (abducens nerve palsy), and progressive dementia Korsakoffs psychosis (chronic thought disorder): retrograde and antegrade amnesia, memory gaps filled with improbable stuff (confabulation) Wernicke's is reversible with thiamine; Korsakoff is permanent note: giving IV glucose to alcoholics without first giving thiamine may precipitate Wernicke's encephalopathy B. vitamin B2 (riboflavin) part of flavoproteins FMN and FAD, each can reversibly accept 2 hydrogen atoms (involved in electron transfer in respiratory chain; complexes I and II) deficiency causes cheilosis (inflammation and fissuring of lips), angular stomatitis (cheilosis at corners of mouth), glossitis (atrophy of mucosa of tongue), vascularization of cornea, and seborrheic dermatitis of face and genitalia (scrotum and vulva) C. vitamin B3 (niacin) normal function is part of NAD and NADP (coenzymes for redox reactions) source is dietary (also made from tryptophan) niacin deficiency causes pellagra (D's = dermatitis, dementia, diarrhea, and death) deficiency may be caused by Hartnup disease, carcinoid tumors, INH, eating lots of maize (where niacin is bound and can't be absorbed) niacin can be used to treat hyperlipidemia (niacin inhibits lipolysis and stimulates lipoprotein lipase, which causes decreased free fatty acids to be delivered to the liver, which causes decreased VLDL production) D. vitamin B5 (pantothenate)
A. vitamin

precursor to CoA, part of fatty acid synthesis, and cofactor for acyl transfers, which is part of fatty acid degradation deficiency causes dermatitis, enteritis, alopecia, and adrenal hypofunction E. vitamin B6 (pyridoxine) normally found in pyridoxal 5-phosphate: synthesis of delta-ALA (in heme synthesis) and synthesis of GABA cofactor in transaminases (ALT and AST), decarboxylations, and transsulfuration deficiency causes sideroblastic anemia (a myelodysplastic syndrome) and non-specific symptoms including angular stomatitis and glossitis deficiency may due to prolonged therapy with isoniazid (especially in young people); therefore may need to give pyridoxine with INH rx for tb neurologic symptoms (due to decreased synthesis of GABA) include convulsions (infants) and polyneuropathy (adults) F. vitamin B12 1. cobalamin deficiency causes megaloblastic (macrocytic) anemia with oval macrocytes and hypersegmented neutrophils, which have more than 5 lobes subacute combined degeneration of the spinal cord (degeneration of posterior and lateral portions) G. vitamin C normal functions include anti-oxidant, cofactor for hydroxylation of proline and lysine, necessary for normal synthesis of collagen deficiency of vitamin C (ascorbic acid) is called scurvy defective collagen formation (decreased lysyl oxidase) causes poor wound healing (wounds reopen) bone has decreased osteoid (which is composed of type I collagen), mineralization is normal (in contrast to vit D deficiency) perifollicular hemorrhages ("bruising on butt") and "cork-screw" hair bleeding gums and loose teeth "pithed frog" appearance (due to painful subperiosteal hemorrhages) H. folate deficiency causes megaloblastic (macrocytic) anemia = macro-ovalocytes and hypersegmented neutrophils deficiency associated with neural tube defects in utero (drink orange juice and eat green leaves)
312. Other

normally

disorders and more 1. biotin normal function is cofactor for carboxylations (not decarboxylations); eg catabolizing fatty acids to carbon dioxide and water and converting pyruvate to oxaloacetate deficiency causes dermatitis and enteritis (may be caused by eating too much raw egg whites, which contains avidin which binds biotin) 2. zinc normal function includes cofactor for enzymes involved in collagen metabolism deficiency causes acrodermatitis enteropathica (which has a distinctive rash on face, anus, and extremities) 3. selenium normal function is anti-oxidant and part of glutathione peroxidase (in red cells and white cells) deficiency causes myopathy and cardiomyopathy 4. chromium = component of glucose tolerance factor, which potentiates insulin 5. iron deficiency causes a hypochromic/microcytic anemia 6. iodine deficiency causes goiter and hypothyroidism 7. magnesium = cofactor for adenylate cyclase 8. copper = component of lysyl oxidase, cytochrome c oxidase, ferroxidase, and superoxide dismutase B. eating disorders 1. anorexia nervosa = self-induced starvation in previously healthy young female clinical findings are similar to severe PEM amenorrhea (decreased GnRH, decreased LH, decreased FSH), decreased thyroid hormone (cold intolerance, bradycardia, constipation, skin and nail changes), osteoporosis (decreased estrogen), cardiac arrhythmias (due to hypokalemia) may cause sudden death 2. bulimia = binge eating followed by induced vomiting in previously healthy young female
A. minerals

 menstrual 313. Environmental A. burns 1. first

irregularities, electrolyte abnormalities (hypokalemia), aspiration of gastric contents

general

degree thickness (only part of epidermis involved) that heals without scarring erythema due to dermal capillary dilation example is sunburn (microscopically would see epidermal edema with focal necrosis of epidermal cells) 2. second degree = partial thickness (full-thickness necrosis of epidermis but partial necrosis of dermis and no adnexal necrosis) a) superficial partial thickness burns characterized by injury to the epidermis and superficial dermis clinical: ruptured red, weeping, painful blisters; usually heal in 1-3 weeks without scarring b) deep partial thickness burns more injury to the deeper dermis (but no necrosis of the adnexal structures ) clinical: whiter and less erythematous than superficial second degree burns; heal after 3-4 weeks, and scarring may occur 3. third degree full thickness (necrosis of epidermis, dermis, and adnexa, hair follicles, etc) that needs skin graft high risk of infection; destruction of nerve endings may result in lack of pain sensation heals with severe scarring (and contractions) 4. complications: inhalation (ARDS), loss of fluids and electrolytes (hypovolemia), infection (pseudomonas aeruginosa, a gram-negative oxidase positive rod that produces bluish-green pigment), acute gastritis (Curling ulcer) B. gunshot wounds handgun injuries from close range (< 1 foot) produce gray-black discoloration around entrance (fouling) due to heat, smoke, and burned powder handgun injuries from 1 to 3 feet may produce stippling without fouling, while injuries > 3 feet have neither entrance wounds are slightly smaller than diameter of bullet exit wounds are more irregular ("cookie cutter" appearance) than entrance wounds and can be larger C. thermal injuries hypothermia causes vasoconstriction and increased viscosity of blood; causes ischemic injury and nerve damage (frostbite); may have cherry red skin color hyperthermia causes heat cramps (loss of electrolytes through sweating), heat exhaustion, and heat stroke (marked peripheral vasodilation; fever) D. electrical injury depends on the resistance of the tissue; resistance of tissue is inversely proportional to water content (wet skin is worse) lightning may produce linear arborizing burns E. mechanical force abrasion: a "scrape" in which the superficial epidermis is torn off by friction or force laceration: an irregular tear in the skin produced by overstretching (bridging strands of fibrous tissue typically present; not in incisions) contusion: blunt force trauma the causes interstitial bleeding usually without disruption of the continuity of the tissue
partial 314. Toxins A. lead 1. lead

inhibits enzymes in heme synthesis (lead has a high affinity for sulfhydryl groups) including dehydratase (results in increased ALA in urine) ferrochelatase (aka heme synthetase) which normally causes iron chelation to protoporphyrin (results in increased FEP) 2. anemia (hypochromic microcytic) basophilic stippling of red cells (clusters of ribosomes) increased FEP (free erythrocyte protoporphyrin) and increased urinary ALA 3. neurologic effects:
ALA

characterized by decreased mental abilities (decreased IQ in children) and convulsions (if severe) peripheral neuropathy due to demyelination (foot drop and wrist drop) 4. GI findings include lead colic ("painters cramps or abdominal colic) due to severe contraction of smooth muscle of intestinal wall; "lead line" on gingiva 5. treatment with BAL (dimercaprol) or chelating agent (EDTA) B. mercury mercury found in some industry (such as hat makers, ie. "mad hatter disease) and coastal areas (mercury in fish) neurologic findings include dementia and cerebellar signs kidney findings include acute renal tubular necrosis (which produces acute renal failure) C. arsenic (rx with dimercaprol or penicillamine) 1. acute poisoning causes severe abdominal pain, renal tubular necrosis, and death 2. chronic effects include arsenical keratosis (thick skin, due to hyperkeratosis) with increased pigmentation, nail abnormalities and increased risk skin cancers demyelinating symmetric polyneuropathy ("stocking and glove" distribution) angiosarcoma of liver D. nickel can cause contact dermatitis (type IV hypersensitivity reaction) and cancer E. cobalt can cause a cardiomyopathy (dilated) F. methyl alcohol (methanol, wood alcohol; may be added intentionally or unintentionally to "moonshine") converted by alcohol dehydrogenase to formaldehyde and formic acid; high-anion gap metabolic acidosis, photophobia, and blindness treatment is with IV ethyl alcohol (competes with methanol for alcohol dehydrogenase) G. ethylene glycol found in antifreeze (ethylene glycol tastes sweet so cats and dogs will ingest and die) metabolized to calcium oxalate, which causes renal tubular necrosis and acute renal failure ethylene glycol poisoning is a cause of metabolic acidosis with increased anion gap H. carbon tetrachloride found in industry such as solvent and dry-cleaning causes centrilobular necrosis and fatty change of liver (due to decreased formation of apoprotein), convulsions, and coma I. carbon monoxide colorless, odorless gas found in car exhaust, natural gas heaters, and cigarette smoke binds tightly to oxygen (shifts dissociation curve to left); cherry-red color to blood and skin (increased carboxyhemoglobin) headaches, hyperreflexia, death J. cyanide found in amygdalin (found in pits of peaches and apricots) and laetrile (a drug used outside of USA) inhibits cytochrome oxidase (final enzyme in respiratory chain) cherry-red color to skin and bitter-almond breath or body odor treat with nitrite (forms methemoglobin)
315. Other A. ethanol

encephalopathy

(alcohol) effects increased NADH/NAD ratio causes increased lactate/pyruvate ratio (can't convert lactate to pyruvate) because of increased NADH (inhibits gluconeogenesis and produces hypoglycemia) increased free fatty acid delivery to liver; increased lipid synthesis and decreased lipid oxidation in liver; decreased export of VLDL from liver 2. pathologic results alcoholic hepatitis (Mallory bodies and fibrosis around central vein), alcoholic steatosis (reversible), and cirrhosis acute and chronic pancreatitis; dilated cardiomyopathy decreased synthesis of testosterone; increased synthesis of gamma-glutamyltransferase in liver hyperuricemia (gout)
1. metabolic

syndrome (longitudinal lacerations at GEJ due to excess vomiting without relaxation of LES sphincter) peripheral polyneuropathy, degeneration of cerebellum and pons, Wernicke-Korsakoff syndrome (with decreased thiamine) fetal alcohol syndrome 3. symptoms with withdrawal include tremor, tachycardia, hypertension, malaise, delirium tremens, formication 4. treatment with disulfiram B. caffeine 1. actions: a methylxanthine block adenosine receptors (adenosine inhibits the release of most CNS excitatory neurotransmitters); probably most important in vivo mechanism increases intracellular calcium release from sarcoplasmic reticulum of skeletal muscle increases cyclic AMP by blocking phosphodiesterase effects membrane Na-K ATPase pump (???stimulation my attenuate exercise-induced hyperkalemia) 2. affect on prolonged exercise (ergogenic effects): a) improves preformance, possible mechanisms: influence on psychologic state: CNS stimulant, by blocking adenosine receptors increased fat utilization (increased free fatty acids) with sparing of muscle glycogen stores; caffeine may increase adipose tissue lipolysis via increased catecholmaine secretion b) side effects: diuresis; insomnia c) withdrawal: causes headaches (possibly due to excessive cerebral vasodilatation, as caffeine is a cerebral vasoconstrictor) 3. content in drinks/foods/pills soft drinks (legal limit is 72mg/12oz of a carbonated drink): Diet Mountain Dew (55mg/12oz); Coke (45mg/12oz); Pepsi (37mg/12oz); Sprite/7 Up (0mg) coffees/teas: brewed (varies, ~100mg/7oz); tea (varies, ~50mg/7oz); Starbucks coffee (quite variable, from 60 to 125+mg/4oz: ie Starbucks grande 500mg/16oz; Starbucks tall coffee 375mg/12oz); Starbucks Frappuccino (90 mg/9.5oz); Starbucks DoubleShot (141mg/6.5oz) "energy" drinks: Amp (75mg/250ml, which is about 8.4oz); Red Bull (80mg/250ml); Sobe adrenaline rush (86mg/250ml) pills: Vivarin (200mg/pill); NoDoz regular (100mg/tablet); cold tablet (~30mg/pill) food: chocolate bar (~30mg/bar; eg Hershey Chocolate Bar has 10mg/1.5oz); note: a methylxanthine in cocoa beans is theobromine, which can be toxic to some animals, particularly dogs, which metabolize theobromine very slowly 4. intake: limit/day of 100mg (???); for atheletic performance: 2.5mg/kg body weight (eg 350mg for a 175-pound person) 5. note: International Olympic Committee limits on caffeine (may be dropped): 12micrograms/ml urine (equal to about 600-800mg of dietary caffeine over an hour); NCAA limit is 15micrograms/ml urine 6. sx of toxicity: nevousness, palpitations, anxiety, muscle tightness and twitching, insomnia, arrhythmias (sx similar to anxiety neurosis) C. other ergogenic substances: anabolic steroids (and growth hormone, insulin-like growth factor, human chorionic gonadotropin, etc) EPO creatine: not of use for distance runners glycerol: acute increase in plasma volume; no ergogenic effect (but may hide effects of EPO) branched chain amino acids: no effect, may be harmful (theory is that increased serotonin in brain causes feeling of fatigue; serotonin made from free tryptophan, which is released from binding to albumin by increased free fatty acids during exercise; branched chain amino acids (valine, leucine, isoleucine) compete with transport receptor for tryptophan in the brain) D. miscellaneous birth control pills: contraindications include past history of thrombophlebitis, history of systemic vascular disease, hypertension, pregnancy (not family history of ovarian cancer) cocaine can cause sudden cardiac death (arrhythmias or coronary artery vasospasm), MI, hypertension, premature labor, brain hemorrhage effects of cigarette smoking include coronary artery disease, lung disease (emphysema, chronic bronchitis, etc), cancer (lung, esophagus, etc), OB complications (abruptio placentae, etc), etc

Mallory-Weis

DIABETES MELLITUS
316. Hormone A. insulin

review

is in beta cells of islets of Langerhans in pancreas is preproinsulin: proinsulin; insulin b) notes about C peptide (1) cleaved from proinsulin to form insulin; not present in exogenous (manufactured) insulin (2) useful in diagnosis of patient with decreased glucose and increased insulin increased C peptide = increased endogenous insulin (pancreatic islet cell tumor) decreased C peptide = increased exogenous insulin (factious injection, eg Munchausen syndrome), murder 2. regulation of secretion increased release by glucose, amino acids (especially arginine), fatty acids decreased release by decreased glucose, somatostatin, alpha-2 receptor stimulation (epinephrine) 3. mechanism of action of insulin receptor tetramer composed of 2 glycoproteins (alpha and beta) alphas are extracellular and bind insulin; betas span membrane and have tyrosine kinase activity (autophosphorylates itself) down regulates its own receptor; eg starvation increases receptors; obesity decreases receptors (important in type II diabetes mellitus) 4. function a) general: increased anabolism (increased synthesis of glycogen, fat, protein); decreased catabolism b) liver stimulates glycogen synthesis, glycolysis (increases precursors for fatty acid synthesis), lipogenesis (increased VLDL production by liver) inhibits gluconeogenesis, glycogenolysis, fatty acid oxidation (no ketone body formation) c) muscle: stimulates glycogen synthesis and protein synthesis; inhibits glycogenolysis d) adipose tissue stimulates lipoprotein lipase insulin inhibits hormone-sensitive lipase by inhibiting adenyl cyclase (this lipase liberates free fatty acids from adipocytes) B. glucagon 1. formation is in alpha cells of islets of Langerhans in pancreas 2. regulation of secretion increased release by catecholamines (via beta-adrenergic receptors), cortisol, amino acids, decreased serum glucose (hypoglycemia) decreased release by glucose, fatty acids, ketones 3. function in liver it stimulates glycogenolysis, gluconeogenesis, fatty acid oxidation, ketogenesis, uptake of amino acids in adipose tissue it stimulates hormone-sensitive lipase in muscle there is less effect
a) sequence 317. Diabetes

1. formation

mellitus (types)

A. general

definition: fasting glucose > 126mg/dl (previous level was 140 mg/dl) or plasma glucose > 200 mg/dl at two points during glucose tolerance test (one within two hours of glucose ingestion); normal fasting glucose is < 110mg/dl note: impaired glucose tolerance = fasting glucose < 126 mg/dl but plasma glucose between 140 and 200 during glucose tolerance test; while impaired fasting glucose = fasting glucose between 110 and 125 with normal glucose tolerance test B. secondary DM: secondary in certain disorders (eg, diseases of the exocrine pancreas, such as pancreatitis, hemochromatosis, cystic fibrosis, or tumors) or excess hormones, such as cortisol (Cushing's), ACTH (Cushing's), growth hormone (acromegaly), glucagon (glucagonoma) C. primary DM

clinical

1. Type

= 15%; age = kids (under 30) dependent (IDDM = insulin dependent diabetes mellitus) c) treat with insulin; dont treat with oral hypoglycemics d) not associated with obesity e) moderate (polygenic) genetic predisposition f) associated with HLA-DR3 and DR4 g) autoimmune disorder (islet cell autoantibodies such as antibodies against glutamic acid decarboxylase) h) histology reveals lymphocytes within islets ("insulitis) and decreased numbers of beta cells i) signs and symptoms polyuria due to osmotic diuresis (glycosuria) polydipsia due to increased serum osmolality stimulates thirst polyphagia due to gluconeogenesis stimulates protein breakdown j) acute complications = DKA (diabetic ketoacidosis), see below 2. Type 2 a) incidence = 85%; age = adults (over 40); note: adults can get type 1 DM (about 5% of pts with type 1 DM) b) not insulin dependent (NIDDM = noninsulin dependent diabetes mellitus) c) treat with oral hypoglycemics (sulfonylureas) d) associated with obesity (obesity causes insulin resistance) e) strong genetic predisposition (but not associated with HLA) f) cause (1) major factors (a) peripheral insulin resistance: causes include obesity (more than 80% of type 2 DM individuals are overweight; obesity down regulates number of insulin receptors) and nuclear PPAR (peroxisome proliferator-activator receptor) modulation PPAR-alpha (found in liver): stimulates genes for fatty acid and lipoprotein metabolism PPAR-delta: regulates serum lipids PPAR-gamma (found in adipose tissue; involved in adipocyte differentiation): increases insulin sensitivity, decreases free fatty acids, decreases blood pressure (b) beta cell dysfunction: causing impaired insulin secretion; due to: glucotoxicity: prolonged increased serum glucose inhibits beta cells lipotoxicity: insulin secretion is inhibited by increased serum free fatty acids or increased cellular fat in liver, muscle (both have GLUT-4 receptors), and islet cells; causes include obesity, dietary habits, stress, genetic factors, more... (c) excessive hepatic glucose production (d) treat post-prandial hyperglycemia with oral hypoglycemia, such as sulfonylureas (2) phases of type 2 DM (usually) obesity nuclear PPAR modulation insulin resistance, leading to hyperinsulinemia beta cell dysfunction, leading to decreased insulin secretion impaired glucose levels (postprandial and fasting) (3) stages (World Health Organization, aka WHO): normoglycemia with normal glucose tolerance hyperglycemia with impaired glucose tolerance and/or impaired fasting glycemia diabetes mellitus with hyperglycemia not requiring insulin diabetes mellitus with hyperglycemia requiring insulin for control diabetes mellitus with hyperglycemia requiring insulin for survival g) histology = amyloid (islet amyloid polypeptide) in islets (late change) h) signs and symptoms hyperosmolar coma serum insulin levels are normal to high i) acute complications = hyperosmolar coma 3. maturity-onset diabetes of the young (MODY) heterogenous group of disorders (AD inheritance) characterized by defective beta-cell function without betacell loss
b) insulin

a) incidence

onset is before age 25 and individuals are of normal weight and lack GAD antibodies and lack insulin resistance syndrome most common clinical presentation of MODY: mild increase in blood glucose in asymptomatic young person with a familial history of diabetes MODY type 3 (most common form of MODY) is associated with a mutation for transcription factor hepatocyte nuclear factor 1alpha MODY2 is caused by mutations involving the glucokinase gene; sx: hyperglycemia at birth, complications rare D. metabolic syndrome (aka dysmetabolic syndrome X) 1. clinical findings: abdominal obesity (waist size: in men > 40 in; in women >35 in), with increased free fatty acids atherogenic dyslipidemia: increased triglyceride, small LDL, decreased HDL increased blood pressure insulin resistance (with or without glucose intolerance); possibly caused by PPAR deactivation prothrombotic/proinflammatory states 2. acquired causes: overweight, physical inactivity, increased CHO in diet, genetic factors (such as PPAR modulation)
318. Diabetes

clinically

mellitus (general pathology) insulin causes hyperglycemia B. "starvation in the midst of plenty" 1. stimulation of glycogenolysis, gluconeogenesis (protein breakdown causes muscle wasting, weight loss, and polyphagia), lipolysis (forms ketone bodies) 2. increased serum glucose (hyperglycemia) causes increased urine glucose (glycosuria) which causes osmotic diuresis, which increases serum osmolarity lose water (polyuria) and electrolytes which stimulates thirst (polydipsia) 3. hypertriglyceridemia due to decreased lipoprotein lipase and increased lipolysis causing increased fatty acid delivery to the liver with increased production of VLDL C. organ involvement in muscle there is increased glycogenolysis and proteolysis in liver there is increased glycogenolysis, lipolysis, gluconeogenesis (mx: glycogen inclusions in nuclei) in fat there is increased lipolysis in kidney there is glycosuria and polyuria (which leads to polydipsia) D. mechanisms for long term complications 1. nonenzymatic glycosylation: example is glycosylated hemoglobin (used clinically to evaluate long-term glucose control) a) glucose + protein (amino groups) --> Schiff base (unstable) --> Amadori product (unstable) --> AGE (advanced glycosylation end products); irreversible protein-to-protein cross-linking in basement membrane; can trap LDL and increase atherosclerosis albumin binds to glycosylated products in basement membrane; increased thickness basement membrane (structural defect) and increased endothelial permeability 2. abnormal polyol pathway: found in tissues that do not need insulin for glucose uptake (nerve, lens, kidney, vessels) glucose + aldose reductase--> sorbitol; sorbitol + dehydrogenase--> fructose; increases osmolality; increases water influx examples: lens--> cataracts; damage to Schwann cells--> neuropathy; damage to pericytes of retinal capillaries--> microaneurysms (retinopathy)
A. decreased

319. Diabetes A. acute

mellitus (complications) complications 1. DKA (diabetic ketoacidosis) is seen in type 1 DM increased lipolysis causes increased free fatty acid delivery to liver, which leads to increased ketone body formation (acetoacetate, beta-hydroxybutyrate, acetone, the latter produces "fruity" smell of breath) ketone bodies produces metabolic acidosis (decreased pH, decreased HCO3-) and Kussmaul breathing (deep and rapid)

glucagon also causes increased ketone bodies and increased gluconeogenesis (epinephrine also increases serum glucose) hypovolemia (due to polyuria) with decreases total potassium (but serum is increased due to acidosis) and decreased total sodium; therapy therefore involves giving fluids MC cause of DKA is non-compliance with insulin therapy; second is infection; mortality rate of DKA is about 10% therapy with insulin can decrease hydrogen ion concentration (which move into cells) which can also produce hypokalemia (insulin and decreased hydrogen ion concentration cause potassium to go into cells) summary of lab findings: decreased sodium, decreased bicarbonate, increased H+, increased glucose, increased ketones, increased anion gap (high anion gap metabolic acidosis with hyperkalemia) in comatose patient with type 1 DM need to rule out hypoglycemic coma due to excess insulin 2. hyperosmolar coma (seen in type 2 DM): increased glucose, increased serum and urine osmolality, no acidosis, glycosuria without ketonuria increased glucose will increase osmolality (estimated serum osmolality = (2[Na] + [glucose/18] + [BUN]/2.8)) B. chronic complications 1. nonenzymatic glycosylation causes: small vessel disease = thickening of basement membrane (characteristic finding with diabetes) large vessel disease = atherosclerosis (increased lipids) and increased incidence of gangrene, MI, stoke 2. abnormal polyol pathway (increased sorbitol causes increased osmolarity and infusion of water) affects lens causing cataracts damage to Schwann cells causing peripheral neuropathy ("stocking and glove" distribution) damage to pericytes of retinal capillaries causes microaneurysms and leads to diabetic retinopathy and blindness 3. kidney nodular glomerulosclerosis = Kimmelstiel-Wilson disease (differentiate form amyloid because amyloid is Congo red positive) glycogen nephrosis (glycogen in renal tubular epithelial cells) = Armanni-Ebstein lesion capsular drops are round eosinophilic masses attached to capsule of Bowman's space increased renal infections such as acute pyelonephritis and acute papillary necrosis hyaline arteriolosclerosis (benign nephrosclerosis) affecting both afferent and efferent arterioles note: diabetics are prone to developing acute renal failure from IV contrast materials for radiologic imaging studies 4. increased susceptibility to infections, such as UTI, candida, mucor of nasal sinuses, and malignant otitis externa due to pseudomonas aeruginosa 5. delayed wound healing C. tests include fasting serum glucose, glucose tolerance test, HbA1c (glycosylated hemoglobin), which measures long-term control

increased