References:

Robbins pathology textbook

Teacher's handout
Gohjan Review
FA 2011
Cecil essential of med

LVER OBJECTVES

1. DEFNE CRRHOSS AND DESCRBE THE ROLES OF NECROSS, FBROSS, REGENERATVE
NODULES, VASCULAR REORGANZATON N TS PATHOGENESS. LST THE COMMON CLNCAL
SGNS AND SYMPTOMS OF CRRHOSS.
a. CIRRHOSIS
i. rreversible diffuse fibrosis of the liver w/ formation of regenerative nodules
ii. Most common cause: alcoholic liver disease
1. May also be due to postnecrotic cirrhosis, autoimmune disease (primary biliary
cirrhosis, autoimmune hepatitis), or metabolic diseases (hemochromatosis,
wilson's disease, alpha-1 antitrypsin deficiency, galactosemia)
iii. End stage of liver disease defined by 3 characteristics:
1. Bridging fibrous septae
a. bands or scars linking portal tracts w/ one another and portal tracts w/
terminal hepatic veins
2. Parenchymal nodules
a. proliferating hepatocytes encircled by firbosis
3. Disruption of architecture of entire liver
iv. Features ---
1. Parenchymal injury and fibrosis are diffuse
a. Fibrosis varies from thin bands to thick massive scars
2. Must have noduIarity (regenerative noduIes)
a. Reflects the balance b/w regenerative activity and constrictive scarring;
hepatocyte reaction to injury
b. Micronodular:
i. nodules < 3mm, uniform size
ii. Due to metabolic insult (alcohol, hemochromatosis, wilson's
disease)
c. Macronodular:
i. nodules > 3mm, varied size
ii. Usually due to significant Iiver injury Ieading to hepatic
necrosis
iii. ncreased risk of hepatocellular carcinoma
iv. Due to postinfectious or drug induced hepatitis
d. compress sinusoids and central veins leading to intrasinusoidal
hypertension
3. VascuIar architecture is reorganized
a. formation of abnormal connections b/w vascular inflow and hepatic vein
outflow channels. This causes less blood supply to the taken tot he
functional hepatocytes (they are bypassed).
b. Pathogenesis:
i. Progressive fibrosis and reorganization of the liver vascular architecture
1. Excess collagen deposition in the lobules, creating delicate or broad septal
tracts. New vascular channels in the septae connect the vascular structures
in the portal region and terminal hepatic veins, shunting blood around the
parenchyma.
a. Source of excess collagen = perisinusoidal stellate cells (TO cell)
i. Normally store vit. A during cirrhosis they become activated to
produce collagen (fibroblast like cell)
ii. Collagen and are diffusely deposited throughout the lobule
disrupting blood flow and impairing diffusion of solutes b/w
hepatocytes and plasma.
iii. These are located in the space of disse; fibrosis of the space of
disse is accompanied by loss of fenestrations in the sinusoidal
endothelial cells. This impairs movement of proteins (albumin,
clotting factors, lipoproteins) b/w hepatocytes and plasma)
2. Throughout process of fibrosis, remaining hepatocytes are stimulated to
regenerate and proliferate as spherical nodules w/in the confines of the fibrous
septae.
ii. Net outcome: fibrotic, nodular liver in which delivery of blood to hepatocytes is severely
compromised, as is the ability of hepatocytes to secrete substances into plasma.
Disruption of the interface b/w the parenchyma and portal tractsobliterates biliary channels
as well.Thus, may develop jaundice and even hepatic failure despite having a liver of
normal mass.
c. CIinicaI signs and symptoms
i. Jaundice!
ii. May be clinically silent
iii. When symptomatic: anorexia, weight loss, weakness, osteoporosis, frank debilitation
(non-specific signs)
d. CompIications:
i. Liver failure
ii. Portal hypertension
iii. Hepatocellular carcinoma
iv. *n these we will have additional signs and symptoms (FA pg. 330)

2. CLASSFY THE DFFERENT TYPES OF CRRHOSS AND KNOW THER NCDENCE ACCORDNG TO
ETOLOGY, GROSS MORPHOLOGY, MCROSCOPC ASPECT.
a. AIcohoIic Liver Disease (60-70%)
i. Fatty Liver (completely reversible!)
1. Morphology:
a. Macroscopically: large, soft, yellow and greasy.
b. Microscopically: macrovesicular steatosis involving most regions of the
hepatic lobule. The intracytoplasmatic fat is seen as clear vacuoles. No
fibrosis.
2. Pathogenesis:
a. Shunting of normal substrates away from catabolism and toward lipid
biosynthesis, owing to generation of excess reduced NAD
b. mpaired assembly and secretion of lipoproteins
c. ncreased peripheral catabolism of fat
3. Clinical freatures:
a. Hepatomegaly
b. Mild elevation of bilirubin and APL (maybe)
ii. Alcoholic Hepatitis (reversible)
1. Etiology:
a. Appears acutely following a bout of heavy drinking.
2. Morphology:
a. Hepatocyte swelling and necrosis
b. Mallory bodies; visible as eosinophilic cytoplasmic inclusions in
degenerating hepatocytes. (cytokeratin filaments)
c. Neutrophilic rxn (inflammation)
d. Fibrosis ; splits apart the parenchyma
e. Macroscopically: liver is mottled red w/ bile stained areas. Visible
nodules and fibrosis.
3. Pathogenesis:
a. Alcohol is directly toxic to the liver and there is an association b/w level
and duration of alcohol intake and cirrhosis.
b. At the cellular level, it produces alterations of mitochondrial and
microtubular fxn and membrane fluidity. t induces cytochrome P450
which leads to increased xsformation of other drugs to toxic metabolites.
We also have generation of free radicals which react w/ membrane and
proteins. Acetyldehyde induces lipid peroxidation and acetyldehyde
protein adduct formation, further disrupting microtubular fxn. Also
immunologic attack and can displace other nutrients.
i. Wernicke's Syndrome: Due to thiamine deficiency.
ii. Ataxic gate and occulomotor alterations due to demylenation
and degeneration of thalamus, hypothalamus, mammillary
bodies and nuclei of cranial nerves supplying extraoccular
muscles. This coupled to a psychotic component.
4. Clinical features:
a. Painful hepatomegaly
b. Hyperbilirubinemia, elevated APL, neutrophilic infiltrate
iii. Cirrhosis (not reversible)
1. Morphology
a. Macroscopically: brown, shrunken, nonfatty organ. Scattered larger
nodules create a hobnail appearance.
i. slamic necrosis and fibrous obliteration of nodules create
broad expanses of tough, pale scar tissue --- Laennec cirrhosis
ii. Bile statis
b. Microscopically: fibrosis, hyperplastic nodules
2. Clinical features
a. Those of cirrhosis on FA; portal hypertension, ascites and varices.
There may be hepatic encephalopathy.
b. Labs: elevated serum aminotransferase, hyperbilirubinemia(direct and
indirect), elevation of serum APL, hypoproteinemia, anemia.
c. Death due to hematemesis, infection, liver failure, hepatoma,
hepatorenal syndrome.
b. Postnecrotic Cirrhosis (10-15%)
i. Cirhossis resulting from chronic viral hepatitis
1. Chronic hepatitis due to HBV and HCV
ii. Morphology:
1. rregularly sized nodules w/ broad scars
iii. ncreased risk of hepatocellular carcinoma
c. BiIiary (10%)
i. Secondary Biliary Cirrhosis
1. Complication of chronic extrahepatic bile duct obstruction.
a. Obstruction: gallstones > malignancies of biliary tree or head of
pancreas > strictures
2. Pathogenesis:
a. Secondary inflammation resulting from biliary obstruction initiate
periportal fibrosis, which eventually leads to hepatic scarring and
nodule formation, generating secondary biliary cirrhosis. Subtotal
obstruction may promote secondary bacterial infections of the biliary
tree (ascending cholangitis), which aggravates the inflammatory injury.
3. Morphology:
a. Micronodular cirrhosis
b. bile duct and ductular injury proliferation and regeneration and
reduplication
c. Mononuclear infiltration
d. n cases of extrahepatic obsturction bile stasis is present
e. Cholangitis may also be seen
ii. Primary Biliary Cirrhosis
1. nflammatory autoimmune disease mainly affecting the intrahepatic bile ducts.
Accompanied by portal inflammation, scarring, and eventual development of
cirrhosis and liver failure.
2. Common in women 40 - 50 yrs
3. Pathogenesis:
a. Unknown, various theories out
b. Damage to mitochondrial proteins by CD8 T cells, antimitochondrial
antibodies....
4. Clinical presentation:
a. Pruritus (early finding, b/f jaundice)
b. Hepatosplenomegaly
c. Jaundice (late finding)
d. Xanthelasma
i. eyelid; as a result of infiltration of the nasal area of the eyelid
by cholesterol rich macrophages
e. Kayser-Fleischer ring in cornea (due to retention of cooper)
f. Association w/ other autoimmune disorders: RA, Hashimotos, Sjogren's,
celiac disease
5. Laboratory:
a. Cholesterol elevated
b. Hyperbilirubinemia
c. Antimitochondrial antibodies (AMA) -essential for diagnosis
d. Elevated APL and GGT (markers of cholestasis)
e. ncreased gM
f. ANA may be seen
6. Morphology:
a. Destructive cholangitis (inflammation of bile duct)
b. Portal solid granulomata
c. Portal chronic inflammatory infiltrate
d. Fibrosis w/ cirrhosis
7. Complications:
a. ncreased risk for hepatocellular carcinoma
d. Hemochromatosis (5%)
i. Excessive accumulation of body iron
ii. Hereditary
1. Regulation of intestinal absorption of dietary iron is abnormal, leading to a net
iron accumulation which is toxic to the tissue.
2. Etiology:
a. North Europeans
b. Male predominance
3. Pathogenesis:
a. Defect may reside in the RE cell's inability to synthesize the regulatory
signal for the intestinal mucosa or may be the inability of the RE cell to
store iron, or defect may be at the level of the intestinal mucosa. High
degree of iron accumulation >> cell injury.
b. Mechanism of the disease is direct iron toxicity. The mechanisms
include lipid peroxidation via iron catalyzed free radical reactions, iron
stimulation of collagen formation, and direct interactions of iron with
DNA leading to predisposition to hepatocellular carcinoma.
4. Morphology:
a. ron deposits in multiple organs (liver, pancreas, heart, joints, skin)
i. dark brown in H&E
ii. blue in persian-blue stained section
iii. Review where it accumulates in each organ from the teachers
ppt.
5. Clinical course
a. Skin pigmentation
b. Hepatomegaly
c. Diabetes
d. Gonadal insuficiency
e. Heart failure, arrythmias
6. Laboratory:
a. High serum iron, ferritin, and percent saturation
b. Decreased total iron binding capacity
c. Urinary iron increased
d. Liver biopsy shows increased iron
iii. Acquired / Secondary
1. Caused by multiple blood xsfusions, alcohol abuse, and well water.... refer to
teachers ppt.
2. ron deposits are more prevalent in marcorphages than in parenchymal tissue.
e. WiIson's Disease (rare)
i. Epidemiology:
1. AR due to
2. men > women
3. Genetic defect in chromosome 13
ii. Problem:
1. Copper absorption and xsport to iver are normal
2. Absorbed copper however fails to enter circulation in the form of ceruloplasmin
and biliary excretion of copper is deminished.
3. Copper accumulates in the liver
4. Unbound copper accumulates in blood, thereby depositing in other tissues
especially the liver, brain, cornea, kidney and joints
iii. Pathogenesis: (theories)
1. Poisoning of hepatic enzymes
2. Copper binding to cytosolic proteins such as tubulin
a. This leads to the mallory bodies
3. Free radical formation
iv. Morphology (progression)
1. Fatty change (mildest form) >
2. Acute hepatitis (mallory bodies prominent) >
3. Chronic hepatitis >
a. Moderate to severe inflammation and hepatocyte necrosis
b. Macrovesicular steatosis, vacuolated hepatocellular nuclei, mallory
bodies
4. Cirrhosis
5. Massive liver necrosis (rare)
v. Diagnosis
1. Decrease in serum ceruloplasmin
2. ncrease in hepatic copper
3. ncreased urinary excretion of copper
vi. Clinical findings
1. Kayser-Fleischer ring (copper deposition in descement's membrane of the
cornea)
a. also present in primary biliary cirrhosis
2. CNS disease
a. Copper deposition in putamen (basal ganglia) > movement disorder
(parkinsonian like, psychosis)
3. Hepatosplenomegaly
4. Hemolytic anemia
5. Renal disease
f. AIpha one anti-trypsin deficiency (rare)
i. Misfolded gene product protein accumulates in hepatocellular ER.
ii. Autosomal dominant (codominant)
iii. Pathogenesis:
1. Mutant polypeptide is abnormally folded and polymerizes, creating endoplasmic
reticulum stress and leading to apoptosis. The accumulated polypeptide
triggers a series of events, including an autophagocytic response, mitochondrial
dysfunction and possible activation of pro-inflammatory NF-kB causing
hepatocyte damage.
iv. Morphology:
1. Round to oval cytoplasmic globular inclusions in hepatocytes, in H&E are
acidophilic and indistinctly demarcated from the surrounding cytoplasm.
2. PAS; red cytoplasmic granules
3. EM; dilation of the ednoplasmic reticulum
v. Associations:
1. Panacinar emphysema (decreased elastic tissue in lungs)
2. Cirrhosis of liver
a. AAT deficiency is most common cause of cirrhosis in children
3. ncreased risk of hepatocellular carcinoma
g. Cryptogenic (10-15%)
i. Unknown!

3. DEFNE AND KNOW THE DFFERENCE OF THE FOLLOWNG:
*Bilirubin is the end product of heme degradation.
*Bilirubin is complexed with albumin in the blood and is delivered to the liver. Hepatocellular update and
glucoroidation in the endoplasmic reticulum generate bilirubin monoglycuronides and diglucuronides, which
are water soluble and readily excreted into bile. Gut bacteria deconjugate the bilirubin and degrade it to
colorless urobilinoens. The urobilinogens and the residue of intact pigments are excreted in the feces, with
some reabsorption and excretion into urine.
*FA: normally, liver cells convert unconjugated (indirect) bilirubin into conjugated (direct) bilirubin. Direct
bilirubin is water soluble and can be excreted into urine and by the liver into bile to be converted by gut
bacteria to urobilinogen (some of which is reabsorbed).

a. DRECT/ CONJUNGATED BLRUBN
i. Characteristics:
1. Water soluble
2. Loosely bound to albumin
3. Excess can be excreted in urine (non-toxic)
ii. ncrease in urobilinogen
iii. ndirect Vanden Bergh Reaction
b. NDRECT/ UNCONJUGATED BLRUBN
i. Characteristics:
1. nsoluble in water (lipid soluble) at physiologic pH
2. Tightly complexed to albumin in plasma
3. Not excreted in urine even when blood levels are high
ii. Unbound plasma fraction may increase in severe hemolytic disease or when protein
binding drugs displace bilirubin from albumin.
1. Hemolytic disease of newborn (erythroblastosis fetalis) ---
a. accumulation of unconjugated bilirubin in brain, leading to severe
neurologic damage (kernicterus)
iii. Decrease in urinary urobilinogen
iv. Direct Vanden Bergh Reaction

Van Den Bergh test: chemical reaction used to measure bilirubin levels in blood.
Determines the amt. of conjugated bilirubin in blood.
Reaction of bilirubin w/ erlich diazo reagent
Direct: reaction w/o adding alcohol
ndirect: reaction w/ addition of alcohol

c. HYPERBLRUBNEMA
i. ncreased levels of bilirubin in blood


4. COMPARE AND CONTRAST THE MAJOR PATHOGENC CATEGORES OF JAUNDCE N TERMS OF:

Jaundice occurs when the equilibrium b/w bilirubin production and clearance is disturbed.

*Normal bilirubin metabolism: Process up to UBG production already discussed..... A small percentage of UBG is
reabsored into the blood. Most of it enters the liver and a small percentage enters the urine. All the normal bilirubin in
blood is UCB primarily derived from macrophage destruction of senescent RBCs. UCB does not enter urine, because
it is attached to albumin in the blood and is lipid, not water soluble. CB is never a normal finding in urine b/c it does
not have contact w/ blood in its metabolism.

Produce unconjugated hyperbiIirubinemia
*Jaundice type: Hemolytic
*Urine bilirubin: Absent (acholuria)
*Urine urobilinogen: ncreased
Excess production of bilirubin (most common)
Ex. hemolytic anemias, resorption of major hemorrhages, ineffective
erythropoiesis syndromes
Reduced hepatocyte uptake
Ex. drug interference w/ membrane carrier system, Gilbert syndrome
mpaired conjugation
Physiologic jaundice of newborn, breask milk jaundice, crigler najjar syndrome,
gilbert syndrome, diffuse hepatocellular disease

*There is an increased macrophage production of UCB causing an increase in serum UCB. There is a
corresponding increase in uptake and conjugation of UCB, conjugation to CB, and conversion of CB in the bowel to
UBG. This causes darkening of the stool. There is a greater percentage of UBG recycled back to the liver and urine.
The increase in urine UBG, darkens the color of the urine.
*Because RBCs contain the enzyme aspartate aminotransferase (AST), hemolysis of RBCs causes an increase in
serum AST.
*ALT, ALP, and GGT levels are normal.

Produce conjugated hyperbiIirubinemia
*Jaundice type: Obstructive
*Urine bilirubin: ncreased
*Urine urobilinogen: Decreased
Extrahepatic (bile flow decreased)
Common duct obstruction (gallstone, carcinoma of head of pancreas)
ntrahepatic (bile flow decreased)
Drug induced cholestasis, primarybiliary cirrhosis
Hereditary (decreased intrahepatic bile flow)
Dubin-Johnson syndrome (disorder in secretion into intrahepatic bile ducts, black
pigment in hepatocytes
Rotor's syndrome (disorder in secretion into intrahepatic bile ducts, NO black
pigment in hepatocytes)

*ncrease in serum and urine CB is due to obstruction of intrahepatic or extrahepatic bile flow. (no bile reaches
duodenum and no UBG is formed). This causes increased pressure in the intrahepatic bile ductules leading to rupture
and egress of CB into sinusoidal blood. There is absence of UBG in the stool (light colored, gray-white) and urine. CB
backs up into liver and some escapes into blood stream. Serum conjugated levels increase and it also increases in
urine.
*There is a marked increase in serum ALP and GGT and only a slight increase in serum AST adn ALT.

Produce conjugated/unconjugated hyperbiIirubinemia
*Jaundice type: Hepatocellular
*Urine bilirubin: ncreased
*Urine urobilinogen: normal or decreased
Viral Hepatitis
Alcoholic Hepatitis

*There is generalized liver dysfunction involving uptake an conjugation of UCB, secretion of CB into bil ducts, and
recycling of UBG. Serum UCB is owing to decrease in uptake and conjugation. Serum and urine CB are increased
because of liver cell necrosis and disruption of bile ductules b/w hepatocytes. Urine UBG is increased b/c
UBG is redirected from the liver to the kidneys. Because there is an increase in serum UCB, and CB, there is a mixed
hyperbilirubinemia.
*ALT is higher than AST and there is a sliht increase in ALP and GGT.
*n alcoholic hepatitis, AST is greater than ALT, b/c alcohol damages mitochondria, which is where AST is normally
located.

NOTE: Refer to teacher handout slide 27 (patterns of liver fxn abnormalities)

5. DESCRBE THE BASC DEFECT, PREDOMNANT FORM OF BLRUBN, AND CLNCAL MPLCATONS
OF THE FOLLOWNG HEREDTARY HYPERBLRUBNEMAS:
a. CRGGLER/ NAJJAR
i. Defect: Absent UDP-glucoronyl xsferase
ii. Bilirubin form: Unconjugated hyperbilirubinemia (problem w/ conjugation)
iii. Findings: jaundice, kernicterus
iv. mplications: Presents early in life, patients die w/in a few yrs.
b. GLBERT SYNDROME
i. Defect: Decreased UDP-glucoronyl xsferase or decreased bilirubin uptake
ii. Bilirubin form: Unconjugated hyperbilirubinemia (problem w/ uptake)
1. Bilirubin increases w/ fasting and stress
iii. Findings: Asymptomatic
iv. mplications: No clinical consequences
c. DUBN-JOHNSON
i. Defect: Defective liver excretion
ii. Bilirubin form: Conjugated hyperbilirubinemia (problem w/ excretion of conjugated)
iii. Findings: Grossly black liver
iv. mplications: Benign
d. ROTOR SYNDROME
i. **Similar to Dubin-Johnson but milder
ii. Findings: Does NOT cause black liver

6. DEFNE CHOLESTASS AND LST THE CLNCAL AND MORPHOLOGC FEATURES OF NTRAHEPATC
AND EXTRAHEPATC CHOLESTASS

ChoIestasis:
mpaired bile formation and flow, leading to accumulation of bile pigment in the hepatic
parenchyma. Can be caused by intra or extra hepatic obstruction of bile channels.
Clinical presentation:
Jaundice
Pruritus (due to bile salts deposited in skin)
Skin xanthomas
Malabsorption: nutritional deficiencies (bile salts do not enter the small intestine)
Light colored stools (lack of urobilin)
Labs:
Elevated serum APL and GGT
Morphology:
Accumulation of bile pigment w/in the hepatic parenchyma
Green brown plugs of bile visible in dilated canaliculi. Rupture of
canaliculi leads to extravasation of bile, which is quickly phagocytosed
by Kupffer cells.
Droplets of bile pigment also accumulate w/in hepatocytes, causing the
cells to take on a wispy appearance (feathery or foamy degeneration).
Bile duct proliferation (characteristic feature)
obstruction of the biliary tree induces distention of upstream bile ducts
by bile, the bile stasis and back pressure induces proliferation of the
duct epithelial cells.
Prolonged obstruction ----
leads not only to foamy change of centrilobular hepatocytes but to focal
destruction of the parenchyma.
Coalescence of necrotic foci generates bile lakes (filled w/ cellular
debris and pigment).
Unrelieved obstruction ---
portal tract fibrosis
biliary cirrhosis
Intrahepatic choIestasis
*Blockage of the intrahepatic bile ducts
Can result from a wide range of conditions, including those that impair canicular xsport
(drugs) and those that cause destruction of the small intrahepatic bile ductules (pirmary
biliary cirrhosis).
Causes: drugs (oral contraceptives, anabolic steroids), neonatal hepatitis,
pregnancy induced cholestasis (estrogen)
Characterized by the destruction and subsequent disappearance of small lobular bile
ducts. The decrease in bile ducts leads to progressive cholestasis, portal inflammation,
and scarring and eventually to cirrhosis.
Not benefited by surgery
Extrahepatic choIestasis
*Blockage of common bile duct
Due to a variety of causes that can obstruct the biliary system at any level, from its outlet
at the duodenum and ampulla of vater to the intrahepatic ducts.
Causes: gallstone (most common), primary sclerosing cholangitis, extrahepatic
biliary atresia, carcinoma head of pancreas
Responsive to surgery thus, prompt diagnosis is imperative

7. LST THE MAJOR CLNCAL FEATURES OF HEPATC FALURE AND THE PATHOPHYSOLOGC BASS
FOR EACH
*Hepatic failure is the end stage of progressive chronic damage.
a. Jaundice
i. total bilirubin metabolism is deranged, but hepatocyte excretion is rate-limiting so
conjugated hyperbilirubinemia predominates.
ii. Reduced synthesis and secretion of albumin
b. Hypoalbuminemia / Coagulopathy
i. Predisposes to peripheral edema (hypoalbuminemia)
ii. Reduced synthesis and secretion of clotting factors (, V, X, X) worsened by
malabsorption of vit.. Activation of hageman factor, inadequate clearance of activated
factors.
iii. **Bleeding occurs and thus, we lose these important factors
c. DC / Hyperammonemia / Fector hepaticus / ncreased serum levels of hepatic enzymes
i. Defective urea cycle fxn
ii. nconstant formation of mercaptans in gut
iii. Seen only w/ active liver cell necrosis, level of increase correlates w/ extent of liver
destruction
iv. LDH is relatively non-specific
v. Plays a role in cerrebral dysfunction (hyperammonemia)
vi. Formation of mecaptans by the action of gastrointestinal bacteria on the sulfurcontaining
amino acid methionine, and shunting of splanchnic blood from the portal into the systemic
circulation (fetor hepaticus, musty or sweet body odor)
d. LDH, ALT/GTP, AST/GOT / Gynecomastia, testicular atrophy, palmar erythema, spider angiomas
of the skin / hepatic encephalopathy / hepatorenal syndrome
i. putatively related to impaired estrogen metabolism and consequent hyperestrogonism
ii. hepatic encephalopathy --- seems to be associated w/ elevated ammonia levels in blood
and the CNS, which impair neuronal fxn and promote generalized brain edema.
iii. hepatorenal syndrome --- appearance of renal failure in individuals with severe chronic
liver disease in whom there are no intrinsic morphologic or functional causes for the renal
failure.
1. Sodium retention, impaired free-water excretion, and decreased renal perfusion
and glomerular filtration rate are the main renal functional abnormalities.
2. Several factors are involved in its development, including decreased renal
perfusion pressure due to systemic vasodilation, activation of the renal
sympathetic nervous system with vasoconstriction of the afferent renal arterioles,
and increased synthesis of renal vasoactive mediators, which further decrease
glomerular filtration.
e. Coma
i. usually follows encephalopahty, preceeds death

8. DESCRBE THE PATHOGENESS AND CLNCAL CONSEQUENCE OF
a. HEPATIC ENCEPHALOPATHY
i. Pathogenesis
1. Regarded as a disorder of neuroxsmission in the CNS and neuromuscular
system, and seems to be associated w/ elevated ammonia levels in blood and te
CNS, which impairs neuronal fxn and promote generalized brain edema.
a. ncrease in aromatic amino acids which are converted into false
neuroxsmitters
b. ncrease in serum ammonia
i. defective urea cycle, cannot metabolize ammonia
ii. factors that aggravate:
1. dietary or blood in G increases bacterial conversion
of urea into ammonia
2. portasystemic shunts, shunt ammonia away from liver
which would normally metabolize ammonia
3. ncreased protein, alkalosis, sedatives
ii. CIinicaI outcome
1. Alterations in the mental status
2. Somnolence and disordered sleep rhythms
3. Asterixis (inability to sustain posture)
4. Coma and death in late stages
b. PORTAL HYPERTENSION
i. *Due to compression of central vein by fibrous tissue. There is also perisinusoidal fibrosis,
along w/ reduced splenic valvular resistance w/ increases portal flow
ii. Pathogenesis
1. ncreased resistance to intrahepatic blood flow due to intrasinusoidal
hypertension from regenerative nodule compression
2. ncrease in portal venous flow resulting from hyperdynamic circulation
a. Due to arterial vasodilation in splanchnic circulation
iii. CIinicaI outcome
1. Ascites
2. Esophageal varices (formation of of portosystemic venous shunts)
3. Congestive splenomegaly
4. Hepatic encephalopathy
c. ESOPHAGEAL VARICES
i. Pathogenesis:
1. Dilated submucosal left gastric vein
2. Complication of portal hypertension from cirrhosis
ii. CIinicaI outcome
1. Rupture w/ massive hematemesis
d. BUDD-CHIARI SYNDROME
i. Pathogenesis:
1. Any obstruction of the venous vasculature of the liver is referred to as Budd
Chiari syndrome, from the venules to the right atrium. This leads to increased
portal vein and hepatic sinusoid pressures as the blood flow stagnates. The
increased portal pressure causes: 1) increased filtration of vascular fluid with the
formation of protein-rich ascites in the abdomen; and 2) collateral venous flow
through alternative veins leading to gastric varices and hemorrhoids. Obstruction
also causes centrilobular necrosis and peripheral lobule fatty change due to
ischemia.
2. f this condition persists chronically what is known as Nutmeg liver will develop.
ii. CIinicaI outcome: (cIassic triad)
1. Abdominal pain
2. Ascites
3.
Hepatomegaly
e. ASCITIS
i. ntra-abdominal fluid (transudate)
ii. Due to xsudation of plasma due to increase in hydrostatic pressure secondary to scarring.
The scarring produces sinusoidal hypertension draining fluid into the space of disse.
There is also decrease in albumin synthesis which decreases plasma oncotic pressure.
There is also secondary aldosteronism w/ retention of sodium and water. There is also
increased formation of lymph w/in liver which leaks through the liver capsule.
iii. Pathogenesis
1. Sinusoidal hypertension
a. Fluid is driven into the space of disse due to alterations in starling's
forces. Fluid is removed by hepatic lymphatics
2. Percolation of hepatic lymph into the peritoneal cavity
a. w/ cirrhosis lymphatic flow exceeds thoracic duct capacity
3. Splanchnic vasodilation and hyperdynamic circulation
a. arterial vasodilation in the splanchnic circulation tends to reduce
arterial blood pressure. W/ increased vasodilaiton the heart is unable to
compensate > activation of RAAS
b. Combination of portal hypertension, vasodilation, and sodium and
water retention increases the perfusion pressure of intestinal capillaries,
causing extravasation of fluid into the abdominal cavity
iv. CIinicaI outcome
1. Abdominal distention w/ a fluid wave
2. ncreased risk for spontaneous bacterial peritonitis
f. HEPATORENAL SYNDROME
i. Reversible renal failure w/o renal parenchymal disease
ii. Pathogenesis:
1. Theory: Reduction in renal blood flow due to vasoconstriction which decreases
glomerular filtration rate and renal retention of sodium.
iii. CIinicaI outcome:
1. Liver transplantation only curative treatment
2. n males ---
a. gynocomastia, spider telangiectasia, female distribution of hair
g. PORTAL VEIN THROMBOSIS
i. Pathogenesis:
1. thrombus that affects the hepatic portal vein leading to portal hypertension and
reduction in the blood supply to the liver.
2. Causes:
a. Polycythemia vera (most common)
b. Hypercoagulable state
c. Hepatocellular carcinoma
ii. CIinicaI outcome:
1. Enlarged, painful liver
2. Portal hypertension, ascites, splenomegaly
3. High mortality rate

9. OUTLNE THE PATHOGENESS OF THE HEPATC LESONS SEEN ASSOCATED WTH CONGESTVE
HEART FALURE AND THE MORPHOLOGC PATTERNS WHCH ARE PRESENT
a. Cardiac ScIerosis
i. Chronic, severe CHF may lead to fibrosis of the liver
1. complication of sustained increased venous backpressure and centrilobular
hypoxia
ii. Morphology
1. Fibrosis is centrilobular (destinctive)
2. Macro: Liver is reduced in size and has a fine pigskin grain on its external
surface
3. Micro: fibrous tissue about the central vein, delicate strands fan out into the
surrounding liver substance.
a. extreme cases or those associated with tricuspid insufficiency ---
i. interconnection of fibrous stands produce bridging tracts
iii. Clinical consequences
1. Doesn't meat criteria for cirrhosis
2. Consequences are negligible or identical to those of centrilobular hemorrhagic
necrosis

10. LST AND DESCRBE THE MAJOR PRNCPAL PATTERNS OF LVER CELL NECROSS AND EXAMPLE
OF A CONDTON ASSOCATED WTH EACH OF THE PATTERNS
a. Centrilobular necrosis
Necrosis restricted to the hepatocytes immediately surrounding the central vein (zone 3)
Seen in ischemic injury and drug (tylenol, alcohol) and toxic reactions
schemia: This zone is most susceptible to ischemia b/c it has the least amt. of
oxygen
Drugs and alcohol: Susceptible to drugs b/c it has most P450 cytochrome
b. Periportal necrosis
Necrosis restricted to the hepatocytes immediately surrounding the portal vein (zone 1)
Rare. Seen in eclampsia, viruses damage this zone
Zone one contains a lot of glutathione
c. Focal necrosis
Scattered cells w/in the lobules
Minute areas of necrosis scarcely visible to the naked eye occur, particularly in the lymph-
follicles and the liver in various forms of severe infection.
May be due to minute thrombi or to alterations in the endothelium of the capillaries.
d. nterface hepatitis (piecemeal necrosis)
interface b/w periportal parenchyma and inflammed portal tracts
observed in hepatitis of viral or autoimmune origin. The term describes the piecemal
removal of hepatocyte cytoplasm, which is mediated by lymphocytes binding to
hepatocytesand repetitive steps of endocytosis, which removes parts of the hepatocyte
cytoplasm and the nucleus
e. Bridging necrosis
*Term given to confluent necrosis linking terminal venules to portal tracts. Necrosis of
zone 3. There are various types ---
Portal to portal
Linking of portal tracts to each other (portal-portal bridging necrosis) is common
in conditions in which portal tracts are widened, for example by chronic
hepatitis or biliary tract disease; this is partly because the chance of obtaining
a longitudinal section of a widened portal tract is greater than for one of normal
width.
Portal to central
Bridging of terminal hepatic venules to portal tracts (central-portal bridging
necrosis) is a fairly common feature of acute hepatitis of viral type, when the
bridges contain few or no elastic fibres. t is also seen in exacerbations of chronic
hepatitis. Old bridges contain elastic fibres as well as collagen fibres.
Central to central
Linking of perivenular areas to each other (central-central bridging necrosis) by
is found in some examples of parenchymal hypoperfusion and venous outflow
obstruction.
f. Submassive necrosis
Necrosis of the entire lobule
seen in fulminant hepatic failure
g. Massive necrosis
Necrosis of most of the liver
Seen in fulminant hepatic failure
Seen in Wilson's disease (due to copper accumulation)
ndistinguishable from that caused by viruses or drugs
h. Abscesses
Disseminated bacterial or fungal infection

Summary: Virtually any significant insult to the liver may cause hepatocyte necrosis.
n ischemic necrosis, poorly stained mummified hepatocytes remain (coagulative
necrosis). n necrosis that is toxic or immunologically mediated, isolated hepatocytes
round up to form shrunken, pyknotic, and intensely eosinophil councilman bodies (a
process known as apoptosis). Alternatively, hepatocytes may osmotically swell and
rupture, so called hydrophobic degeneration. Necrosis may be limited to scattered cells
w/in the hepatic lobules (focal necrosis) or involve particular regions of the lobule (zonal
necrosis), either lobules (submassive necrosis) or the whole liver (massive necrosis).
Focal necrosis is most characteristic of microbial infections, particularly viral hepatitis.
Centrilobular necrosis is characteristic of ischemic injury and many drug and toxic
chemical reactions. Midzonal necrosis is a rare pattern, seen in yellow fever. Periportal
necrosis is seen primarily in phosphorus poisoning and eclampsia. Massive necrosis
is most commonly caused by severe chemical and drug toxicity or viral hepatitis. n
other conditions such as typhoid fever, tularemia brucellosis, and herpes or adenovirus
infection, expanding regions of the parenchyma are destroyed (geographic necrosis). With
disseminated candidal or bacterial infection, macroscopic abscesses may occur.

11. LST THE VRUSES WHCH ARE NOT GENERALLY DENTFED AS HEPATTS VRUSES, BUT WHCH
PRODUCE HEPATTS DURNG THE COURSE OF THE VRAL LLNESS
EBV (infectious mono)
May cause a mild hepatitis during the acute phase
CMV
Particularly in the newborn or immunosuppressed
Yellow Fever Virus
Major cause in tropical areas
Rubella, adenovirus, herpesvirus, enterovirus infections
mmunocompromised

12. DESCRBE THE MPORTANCE OF THE FOLLOWNG TESTS N RELATONSHP TO THE PRESENCE
FOR ACTVTY OF HEPATC DSEASE
a. HEPATTS SURFACE ANTGEN
A surface coat lipoprotein antigen of the hepatitis B virus, peaking w/in the first
appearance of clinical disease symptoms. Tests for serum HBsAg are used in the
diagnosis of acute or chronic hepatitis B and in testing blood products for infectivity.
b. HEPATTS CORE ANTGEN
An antigen of the DNA core of the hepatitis B virus, indicating the presence of replicating
hepatitis B virus
Found on the dane particle and also in hepatocyte nuclei in hepatitis B infections
c. HEPATTS SURFACE ANTBODY
Protective antibody that is produced in response to an infection.
Appears when a person has recovered from an acute infection and cleared the virus or
responded successfully to the hep B vaccine shot
d. HEPATTS CORE ANTBODY
An antibody produced in response to the core antigen.
Not protective
Presents in those infected with hepatitis B.
ts appearance w/ the protective surface antibody indicates prior infection and
recovery
ts appearance w/ the HBsAg (virus) indicated chronically infected person
e. DANE PARTCLE
The complete hepatitis B viron
t's a DNA virus of the hepadna family and consist of an outer envelope and core.
Core (formed in the hepatocyte nucleus)
partially double stranded circular DNA
Core antigen
e antigen
Envelope (formed in hepatocyte cytoplasm)
contains the surface antigen
f. e ANTGEN
Viral protein that is secreted by hepatitis B infected cells
Used as a marker of active viral disease and patients degree of infectiousness
g. HEPATTS D ANTGEN
h. ANT-HCN ANTBODY
i. ANT HAB ANTBODY
j. ANTMALARAL ANTBODY (???) Could be ANTMTOCHONDRAL
Primary biliary cirrhosis
k. ANT SMOOTH MUSCLE ANTBODY
Antibodies formed against smooth muscle
Found in autoimmune hepatitis
l. ANTNUCLEAR ANTBODY
Antibodies against contents of the cell nucleus
Found in autoimmune hepatitis

13. OUTLNE THE PATHOGENESS, MORPHOLOGY, CLNCAL EFFECTS, FREQUENCY AND LONG TERM
COMPLCATON OF THE FORMS OF ALCOHOLC LVER DSEASE
a. AIcohoIic Liver Disease (60-70%)
i. Fatty Liver (completely reversible!)
1. Morphology:
a. Macroscopically: large, soft, yellow and greasy.
b. Microscopically: macrovesicular steatosis involving most regions of the
hepatic lobule. The intracytoplasmatic fat is seen as clear vacuoles. No
fibrosis.
2. Pathogenesis:
a. Shunting of normal substrates away from catabolism and toward lipid
biosynthesis, owing to generation of excess reduced NAD
b. mpaired assembly and secretion of lipoproteins
c. ncreased peripheral catabolism of fat
3. Clinical freatures:
a. Hepatomegaly
b. Mild elevation of bilirubin and APL (maybe)
ii. Alcoholic Hepatitis (reversible)
1. Etiology:
a. Appears acutely following a bout of heavy drinking.
2. Morphology:
a. Hepatocyte swelling and necrosis
b. Mallory bodies; visible as eosinophilic cytoplasmic inclusions in
degenerating hepatocytes. (cytokeratin filaments)
c. Neutrophilic rxn (inflammation)
d. Fibrosis ; splits apart the parenchyma
e. Macroscopically: liver is mottled red w/ bile stained areas. Visible
nodules and fibrosis.
3. Pathogenesis:
a. Alcohol is directly toxic to the liver and there is an association b/w level
and duration of alcohol intake and cirrhosis.
b. At the cellular level, it produces alterations of mitochondrial and
microtubular fxn and membrane fluidity. t induces cytochrome P450
which leads to increased xsformation of other drugs to toxic metabolites.
We also have generation of free radicals which react w/ membrane and
proteins. Acetyldehyde induces lipid peroxidation and acetyldehyde
protein adduct formation, further disrupting microtubular fxn. Also
immunologic attack and can displace other nutrients.
i. Wernicke's Syndrome: Due to thiamine deficiency.
ii. Ataxic gate and occulomotor alterations due to demylenation
and degeneration of thalamus, hypothalamus, mammillary
bodies and nuclei of cranial nerves supplying extraoccular
muscles. This coupled to a psychotic component.
4. Clinical features:
a. Painful hepatomegaly
b. Hyperbilirubinemia, elevated APL, neutrophilic infiltrate
iii. Cirrhosis (not reversible)
1. Morphology
a. Macroscopically: brown, shrunken, nonfatty organ. Scattered larger
nodules create a hobnail apperance.
i. schemic necrosis and fibrous obliteration of nodules create
broad expanses of tough, pale scar tissue --- Laennec cirrhosis
ii. Bile statis
b. Microscopically: fibrosis, hyperplastic nodules
2. Clinical features
a. Those of cirrhosis on FA; portal hypertension, ascites and varices.
There may be hepatic encephalopathy.
b. Labs: elevated serum aminotransferase, hyperbilirubinemia(direct and
indirect), elevation of serum APL, hypoproteinemia, anemia.
c. Death due to hematemesis, infection, liver failure, hepatoma,
hepatorenal syndrome.

14. DESCRBE ACUTE VRAL HEPATTS WTH TYPES A, B, C, DELTA, G, E, AUTOMMUNE:
Viral Hepatitis
Epidemiology
Can be self limiting or progress to fibrosis and cirrhosis
Acute < 6 months / chronic > 6 months
Causes
Acute
Viral: Hep A, B, C, D, E (Will cover below!)
Herpes virus, cytomegalovirus, EBV, yellow fever, adenovirus
Non-viral: Toxoplasma, leptospira, alcohol, drugs and toxins, ischemic
hepatitis..
Chronic
Viral: B, D, C (Hep A and E DO NOT cause chronic hep)
Non-viral: autoimmune, alcohol and drugs, primary biliary cirrhosis and
primary sclerosis cholangitis (can mimic)
Phases
Prodrome
Fever
Painful hepatomegaly; distaste for alcohol/cigarrett
Serum xsaminases increase steadily (peak just b/f jaundice)
Jaundice
Variable depending on the type of hepatitis
ncreased urine bilirubin and urine UBG
Recovery
Jaundice resolves
Microscopic findings
Lymphocytic infiltrate w/ destruction of hepatocytes
Apoptosis of hepatocytes (councilman bodies)
Persistent inflammation and fibrosis is an unfavorable sign
Sign of chronic hepatitis progressing to postnecrotic cirrhosis

a. Hepatitis A: "nfectious Hepatitis"
Epidemiology
Virus: ssRNA, hepatovirus (related to picornavirus)
Route of xsmission: Fecal - Oral (contaminated food or water)
May also be contracted by consumption
ncubation period: 2-6 wks
More common in children, travelers, low socioeconomic status, rural areas
Higher mortality in those > 50yrs
**Most common viral cause of jaundice
Pathogenesis
Following ingestion, HAV enters the bloodstream and is carried to the liver. n the
liver it multiplies w/in hepatocytes and kupffer cells. Virons are secreted into bile
and released in stool. W/in the hepatocyte the RNA genome is released from the
protein coat and is xslated by the cell's own ribosome.
Unlike other picornaviruses this virus requires and intact eukaryote
initiating factor 4G for the initiation of xslation. The requirement for
this factor results in an inability to shut down host protein synthesis.
The virus must then inefficiently compete for the cellular xslational
machinery. There is no apparent virus mediated cytotoxicity presumably
b/c of the virus own requirement for an intact eukaryotic initiation factor
and liver pathology is likely immune mediated.
Virus alters antigenic structure of membrane of cells
mmune rxn of T and B cells occurs. The T cell response is responsible
for cell necrosis. Severity and necrosis depends on level of immune
response - the more severe the hepatitis, the greater the immune
response, the less probability of survival of virus infected cells or the
development of chronic carrier state.
Viremia is transient; shed in the stool 2-3 wks b/f and 1 wk after the onset of
jaundice.
B/c viremia is xsient, blood-borne xsmission occurs only rarely
Clinical Manifestations
Acute viral hepatitis - may be anicteric (similar to viral disease) or icteric (consist
of 3 phases)
Pre-icteric (days to weeks)
Follows incubation period.
Pyresia, myalgias, malaise, headache, anorexia, rashes,
utricaria, migratory arthritis
cteric
Anorexia, nausea, vomiting, RUQ discomfort, jaundice
Convalescent (weeks to months)
Tiredness, malaise
Laboratory
Diagnosis: detection of serum gM antibodies
Anti HAV gM indicated infection
Fecal shedding of the virus ends as the gM titers rises
gM response begins to decline in a few months and this is
followed b the appearance of gG anti-HAV
Anti HAV gG indicates recovery/ vaccination
Persists for years, could confer lifelong immunity
Leukopenia, lymphocytosis (atypical lymphocytes)
ncreased urinary urobilinogen and bilirubin in early icteric period; serum bilirubin
increases and urinary urobilinogen decreases at the peak of the jaundice
cteric period
both direct and indirect increased w/ predominance of direct
Liver fxn
AST 500 - 1,000 .U. (late pre-icteric and icteric)
ALT - increased
**Both decrease and return to normal in late icteric period
Alkaline phosphatase minimally elevated
Slight decrease in albumin, increase in gamma globulins
Clinical course
Frequency of chronic liver disease: never
Does not cause chronic hepatitis or a carrier state and only rarely
causes fulminant hepatitis
Prevention
Passive immunization
immune serum globulin given to travelers and household members of
infected pts.
passive xsfer of antibodies
Active immunization (inactivated Havrix)
inactivated cell culture derived vaccine
protective antibodies in 1 month

a. Hepatitis B
Epidemiology
Virus: partially dsDNA (hepadnavirus)
Route of xsmission: parenteral, sexual contact, perinatal
ncubation period: 1-4 months
Pathogenesis
The host immune response to the virus is the main determinant of the outcome
of the infection. The mechanism of innate immunity protect the host during the
initial phases of the infection, and a strong response by virus specific CD4+ and
CD8+ interferon gamma producing cells is associated w/ the resolution of acute
infection. These are several reasons to believe that HBV does not cause direct
hepatocyte injury. Most importantly, many chronic carriers have irons in their
hepatocytes w/ no evidence of cell injury. Hepatocyte damage is believed to
result from damage to the virus infected cells by CD8+ cytotoxic T cells.
Clinical Presentation
Variable fever, profound malaise, painful hepatomegaly, jaundice
Serum sickness prodrome: immunocomplex disease, vasculitis, utricaria,
polyarthritis, membranous glomerulopathy
Laboratory
Diagnosis: Detection of HBsAG or antibody to HBcAG
Serology
Hepatitis B surface antigen (HBsAG)
Appears w/in 4-12 wks (first marker of infection)
Persists up to 3 months in acute hepatitis, if longer than 6
months this defines chronic HBV
*Used for diagnosis of hepatitis
Hepatitis B e antigen (HBeAg)
nfective particles
Appear 3-5 days after HBsAg and disappear in 2-6wks b/f
HBsAg
Among chronic carriers its presence indicates greater
likelihood of progressive liver disease
Anti-HBV core antibody gM (anti-HBc-gM)
*Confirms diagnosis
Nonprotective antibody (remains positive in acute infections)
Appears 5-14 days after e antigen
Persists during window phase or serologic gap
HBsAG, HBV DNA, and HBeAg are absent during
that time
Converts entirely to anti-HBc-gG by 6 months
Anti-HBV surface antibody (anti-HBs)
Protective antibody (marker of immunization)
Appears at the recovery phase
Even though it indicated immunity, these individuals are not
accepted as blood donors
Anti- e antigen
Appears when e antigen begins to disappears
Appearance means that acute viremic stage is ending. Good
prognosis. Low infectivity and benign liver disease is present
Chronic HBV
Persistence of HBsAg longer than 6 months
Healthy chronic carrier ---
HBsAg and HBc-gG
No DNA nor e antigen
Contagious but at a lower risk
nfective chronic carrier ---
HBsAg, anti-HBc-gG, infective particles (DNA and e
antigen)
ncreased risk for postnecrotic cirrhosis and
hepatocellular carcinoma
Xsaminase and bilirubin elevated
Microscopy
*Refer to teacher handout and pictures as each stage has a diff appearance
Clinical Course
HBV can produce ---
Acute hepatitis w/ recovery and clearance of the virus
Non-progressive chronic hepatitis
Progressive chronic disease ending in cirrhosis
Fulminant hepatitis w/ massive liver necrosis
Asymptomatic carrier state
Clinical Outcome
Frequency of chronic liver disease: 10%
Fulminant hepatitis especially if connected w/ HDV
Hepatocellular carcinoma secondary to postnecrotic cirrhosis (complication)
Prevention
mmunization w/ recombinant vaccine
Treatment
There is no evidence that early therapy for acute hepatitis B w/ interferon alpha
or antiviral agents decreases the rate of chronicity or speeds recovering.
Most patients w/ acute, icteric HB recover w/o residual injury or chronic
hepatitis.
f progress to chronic hepatitis treatment is 4-6 months of alpha interferon (to
decrease HBeAg and HBV DNA --- infective particles).

a. Hepatitis C
Epidemiology
Virus: ssRNA (flaviridae)
Route of xsmission: parenteral
Risk factors: intranasal cocaine use
ncubation period: 2-26 wks
Most common blood borne infection
Pathogenesis
Persistent infection and chronic hepatitis are hallmark
Virus develops multiple strategies to evade host antiviral immunity.
HCV is able to actively inhibit the interferon mediated cellular antiviral
response at multiple steps, including tool like receptors signaling in
response to viral RNA recognition and signaling downstream of FN
receptors that confers on cells an anti viral state.
Clinical Manifestations
Majority is asymptomatic thus, easily missed in acute stage
Chronic > cirrhosis
Laboratory
Screen w/ enzyme immunoassay (EA)
Presence of anti-HCV gG indicates active infection or recovery
Doesn't differentiate b/w acute, chronic or resolved
This antibody is not protective
Confirmatory tests
Recombinant immunoblot assay (RBA)
HCV RNA PCR (gold standard) --- detectable in blood for 1-3 wks
(+) RBA and PCR indicate active infection
(+) RBA and (-) PCR indicate recent recovery
Anti-HCV is present
Characteristic for HCV is episodic elevations in serum aminoxsferases
Clinical Course
Frequency of chronic liver disease: 80%
Progression to chronic disease occurs in the majority of HCV individuals and
cirrhosis eventually occurs
Elevated titers of anti HCV gG do not confer effective immunity. Thus,
we have repeated bouts of hepatic damage, the result of reactivation of
a preexisting infection or emergence of an endogenous, newly mutated
strain. This leads to the cirrhosis.
Circulating HCV RNA persists despite the presence of neutralizing
antibodies.
Prevention
No vaccine available

a. Hepatitis D
Epidemiology
Virus: circular defective ssRNA (subviral particle in deltaviridae family)
Route of xsmission: parenteral
ncubation period: 1-4 months
Laboratory
Diagnosis: detection of gM and gG antibodies; HDV RNA serum; HDAg in liver
Serology:
Presence of anti-HDV-gM or gG indicates active infection
gG is not protective
Clinical Course
Causes infection if encapsulated by HBsAg or in the presence of HBV. Thus, we
have delta hepatitis in 2 settings:
Acute confection by HDV and HBV
The HBV infection must occur first to provide the HBsAg
necessary for HDV
Superinfection of a chronic carrier of HBV with HDV
Coinfection may produce mild to fulminant hepatitis
Superinfection will lead to 3 possibilities;
Acute severe hepatitis in an HBV carrier
Mild HBV hepatitis may turn into fulminant
Chronic progressive disease may develop >> cirrhosis
Clinical outcome
Frequency of chronic liver disease: 5% (coinfection), 70% (superinfection)
Prevention
mmunization w/ recombinant vaccine for HBV
Treatment
Prolonged course of alpha interferon has shown improvements

a. Hepatitis E
Epidemiology
Virus: ssRNA (calicivirus)
Route of xsmission: fecal-oral
ncubation period: 4-5 wks
Laboratory
Diagnosis: PCR for HEV RNA; detection of serum gM and gG antibodies
Serology
Anti-HEV gM indicates active infection
Anti-HEV gG indicates recovery (protective)
Clinical Course
Self limited and does not progress
Frequency of chronic liver disease: never

a. Hepatitis G
Epidemiology
Virus: flavivirus
Xsmission: contaminated blood or blood products, sexually
Laboratory
DOES NOT cause elevations in serum aminoxsferases; virus replicates in the
bone marrow and spleen
Clinical Course
Not associated w/ chronic liver disease
n individuals also infected w/ HV, this virus can be protective against HV

a. Autoimmune Hepatitis
Epidemiology
Female predominance (type )
Children 2-14 yrs (type )
Pathogenesis
T cell mediated autoimmunity, hepatocyte injury is caused by FN-gamma
produced by CD4+ and CD8+ T cells mediated cytotoxicity.
mmune rxn may be triggered by viral infections, drugs, herbal products
Commonly occurs w/ other autoimmune disorders
Classifications (based on the patterns of circulating antibodies)
Type 1
Antinuclear (ANA)
Anti-smooth muscle (SMA)
Anti-actin (AAA)
Anti-soluble liver antigen/liver pancreas antigen (anti SLA/LP)
Type 2
Anti-liver kidney microsome-1 (ALKM-1)
Anti-liver cytosol-1 (ACL-1)
Histology
Similar to chronic hepatitis but marked by prominent inflammatory infiltrates of
lymphocytes and plasma cells
Clusters of plasma cells in the interface of portal tracts and hepatic lobules =
characteristic
Laboratories
Absent serologic markers but presence of elevated gG levels and the antibodies
listed above depending on the type
Clinical course
Symptomatic w/ increased xsaminases
Fulminant hepatitis
Progress to cirrhosis
Treatment
mmunosupression has a good response
Corticosteorids

15. DESCRBE THE CLNCAL TESTS OF MOST VALUE N THE DAGNOSS OF ACUTE VRAL HEPATTS,
LVER FALURE, BLARY TRACT OBSTRUCTON, CHRONC HEPATTS, PRMARY BLARY
CRRHOSS, WLSON'S DSEASE

DISEASE DIAGNOSTIC TEST
Acute Viral Hepatitis 1. Serum Aspartate Aminoxsferase (AST)
a. Will be elevated
2. Serum Alanine Aminoxsferase (ALT)
a. Will be more elevated than AST
3. GGT
a. elevated to same extent as AST

Lab results:
Serology
HAV - detection of serum gM antibodies.
HBV - detection of HBsAg or antibody to HBcAg
HCV - PCR for HCV RNA, ELSA for antibody dectection
HDV - detetion of gM and gG antibodies, HDV RNA serum, HDAg in liver
HEV - PCR for HEV RNA, detection of serum gM and gG antibodies

Mixed hyperbilirubinemia
ncreased urine UBG and urine bilirubin
ncreased serum xsaminases (ALT higher)
Liver Failure Decrease in xsaminases (liver parenchyma destroyed)
Elevated ammonia
ncrease in PT
Biliary Tract Obstruction 1. Alkaline Phosphatase
a. Will be elevated
2. Gamma glutamyl xsferase (GGT)
a. will be elevated
3. ALT
a. elevated to same extent as GGT
Chronic hepatitis Serology (as indicated above)
*Hepatitis A and E DO NOT lead to chronic

n hepatitic cirrhosis will see elevated alpha feto protein
Primary biliary Cirrhosis 1. Alkaline Phosphatase
a. Will be elevated
2. AST
a. Mildly elevated w/ active cirrhosis
Antimitochondrial antibodies
Serum ANA positive
ncrease in serum gM
ncrease in serum ALP and GGT
ncrease serum cholesterol
Wilson's disease Decreased total serum copper
Decreased serum ceruloplasmin
ncreased serum and urine free copper
*Kayser-Fleischer ring (copper pigment in cornea)

16. LST THE MAJOR TESTS USED N THE LABORATORY AS SCREENNG TESTS FOR HEPATC
DSEASE AND THE MEANNG OF THE ABNORMLTES ASSOCATED WTH EACH OF THESE TESTS
a. AIkaIine Phosphatase
i. Found in liver, biliary tract epithelium, bone, intestinal mucosa, placenta
ii. High
1. Children (b/c of bone growth) --- normal finding
2. Biliary tract obstruction (elevation reflects degree of obstruction)
3. Space occupying lesions
a. Metastatic liver disease
b. Hepatoma
c. Liver abscess
d. Granulomata
4. Bliary cirrhosis
5. Third trisemester pregnancy --- normal finding
6. Other:
a. Hyperthyroidism, tissue damage and infarction, bone diseases
b. Serum Aspartate Aminoxsferase (AST)
i. Found in liver, heart, skeletal muscle, red cells
ii. High
1. Acute hepatitis
2. Active cirrhosis
3. Liver metastases
4. EBV infection
5. Drug induced injury
6. Liver congestion
7. Others: M, hypothyroidism, muscle disease, trauma, burns, renal infact
c. Serum AIanine Aminoxsferase (ALT)
i. Found in liver, heart, skeletal muscle, kidney
ii. High
1. Viral hepatitis (increased more than AST)
2. EBV infection
3. Drug induced liver injury
d. Lactic Dehydrogenase
i. Found in heart, skeletal muscle, red cells, lungs, lymphoid tissue, liver, kidney
ii. High
1. Metastatic tumor to liver
2. Neoplasms w/o liver involvement - leukemias, lymphomas...
a. Thus, insensitive test
e. Gamma GIutamyI Xsferase (GGT)
i. Found mostly in liver
ii. High
1. Liver damage, biliary tract obsturction
2. Acute liver injury (elevated same as AST)
3. Obstructive disease or liver damage (equal or greater than ALP)
4. Heavy drinkers
iii. Normal
1. Childhood, pregnancy, bone disease (serves to differentiate)!
f. BIood Ammonia
i. High
1. W/ normal blood flow; in liver decompensation
2. W/ altered blood flow; in cirrhosis
3. Directly dependent on presence of hepatic failure
4. Best correlation w/ hepatic coma
g. AIpha Feto Protein
i. High
1. Fetal liver --- normal finding
2. Hepatoma
3. Embryonal cell carcinoma and teratomas of the testes
4. Hepatitis
5. Alcoholic cirrhosis
h. Serum BiIirubin
i. High
1. Hemolysis
2. Extrahepatic biliary tract obstruction
3. Liver damage

17. DESCRBE CHRONC HEPATTS WTH REGARDS TO CAUSES, MORPHOLOGY OF LVER
HSTOLOGY, COMPLCATONS, CLNCAL MANFESTATONS, EXTRAHEPATC LESONS,
MORBDTY, AND MORTALTY
a. Chronic viraI hepatitis - symptomatic, biochemical, or serologic evidence of continuing or
relapsing hepatic disease for more than 6 months with histologically documented inflammation and
necrosis.
i. HBV an HCV lead to chronic viral hepatitis
1. Contribute to the development of primary hepatocellular carcinoma
ii. HDV (superinfection) also leads to chronic
b. Classifications
i. Chronic persistent hepatitis
1. inflammation confined to portal tracts
ii. Chronic active hepatitis
1. portal tract inflammation spills into the parenchyma and surrounds regions of
necrotic hepatocytes
iii. Chronic lobular hepatitis
1. persistent inflammation is confined to the lobule
c. Morphology
i. Mild - inflammatory infiltrate limited to portal tracts
ii. Histologic hallmark of progressive disease is piecemeal necrosis
1. chronic inflammatory infiltrate spills out from portal tracts into adjacent
parenchyma, with associated necrosis of hypatocytes in the limiting plate
iii. Bridging necrosis (as w/ acute) may connect adjacent portal-portal, central-central, and
portal-central zones.
iv. Continued loss of hepatocytes results in fibrous septum with accompanied by hepatocyte
regeneration, results in cirrhosis.
v. n HCV
1. also see lymphoid aggregates in portal tracts, mild fatty change, bile duct
damage
vi. n HBV
1. Ground-glass hepatocytes
d. Clinical
i. Elevation of xsaminases
ii. Fatigue (common)
iii. Spider angiomas (common), palmar erythema, mild hepatomegaly, hepatic tenderness,
mild splenomegaly.
iv. mmune complexes
e. Complications
i. Causes of death include ---
1. cirrhosis with liver failure and hepatic encephalopathy
2. massive hematemesis from esophageal varices
3. f HBV or HCV; hepatocellular carcinoma
---------------------------
Aside: Acute ViraI Hepatitis for comparison (also refer to Fig. 18-19)

Any of the Hep viruses can cause this
Phases
ncubation period
Symptomatic preicteric phase
Non-specific symptoms: malaise, fatigue, nausea....
Serum sickness like syndrome (HBV)
fever, rash, arthralgias (attributed to circulating immune complexes)
Symptomatic icteric phase
conjugated hyperbilirubinemia
urine turns darker and stools become lighter
pruritus (due to retention of bile acids)
Convalescence
Morphology
Liver is enlarged and green
Necrosis of random, isolated liver cells or small cell clusters
necrotic hepatocytes may be evident as fragmented, eosinophilic councilman bodies
confluent necrosis may lead to bridging necrosis
Diffuse liver cell injury
lobular disarray due to cellular swelling, necrosis, and regeneration of cells producing
compression of the vascular sinusoids and loss of the normal, more or less radial array
bile stasis w/in the lobule
Reactive changes in kupffer cells and sinusoidal lining cells and an inflammatory infiltrate in portal
tracts
kupffer cells and sinusoidal lining cells undergo hypertrophy and hyperplasia
Evidence of hepatocytic regeneration during the recovery phase
regenerating hepatocytes lack uniformity in size and are pale

18. KNOW THE DFFERENCES BETWEEN CHOLANGTS, SLEROSNG CHOLANGTS,
PERCHOLANGTS

ChoIangitis nflammation of the bile duct
Most commonly due to bacterial infections >> Ascending cholangitis
caused by bacteria, and causes pain, jaundice, and fever. The bacteria usually
originate from a precedingcholedocholithiasis and is ascending from the
intestines.
ScIerosing ChoIangitis The bile ducts inside and outside the liver become narrowed and scarred (intra and
extra hepatic)
Primary - autoimmune origin
Secondary - obstruction
PerichoIangitis An inflammatory condition of the tissues surrounding the bile ducts in the liver.
Pericholangitis is a complication of ulcerative colitis and portal hypertension

19. COMPARE THE FOLLOWNG: ALCOHOLC CRRHOSS, POST HEPATC NECROSS, SECONDARY
BLARY CRRHOSS, PRMARY BLARY CRRHOSS, HEMOCHROMATOSS, CARDAC SCLEROSNG,
N TERMS OF PREDSPOSNG FACTORS OR CONDTONS, DSTNGUSHNG MORPHOLOGY,
MAJOR CLNCAL FEATURES NCLUDNG LABORATORY CHANGES, COURSE AND PROGNOSS
NCLUDNG RELATONSHP TO NEOPLASA.


AIcohoIic Cirrhosis Postnecrotic Secondary BiIiary Cirrhosis
Cirrhosis (same
as post hepatic
necrosis)
Predisposing
Factors
Alcohol chronic hepatitis due
to HBV and HCV
Prolonged obstruction to the extrahepatic
biliary tree
Morphology rreversible diffuse
fibrosis w/ formation of
regenerative nodules
rregularly sized
nodules w/ broad
scars
nitiation of periportal fibrosis secondary
to inflammation leads to secondary biliary
cirrhosis
liver exhibits yellow-green
pigmentation
large and small bile ducts are
distended and frequently contain
inspissated bile
portal tracts are interconnected by
inflammed fibrous septa and appear
edematous
cytoplasmic and canalicular
accumulation of bile, extensive
feathery degeneration of
heptocytes, and formation of bile
lakes
ascending bacterial infections >
cholangitis abscesses
Clinical
Features
Hepatic failure
Portal hypertension
Ascites
Hepatorenal syndrome

Jaundice
Labs Decreased serum BUN
ncreased serum
ammonia
Fasting hypoglycemia
Lactic acidosis
Hyponatremia
Hypokalemia
ncreased PT
Hypoalbuminemia
Hypocalcemia

Clinical Course Death due to
hematemesis, infection,
liver failure, hepatoma,
hepatorenal syndrome.
ncreased risk of
hepatocellular
carcinoma




Primary BiIiary Cirrhosis Hemochromatosis Cardiac ScIerosing
Predisposing
Factors
Autoimmune
Female predominance (40-
50yr)
Common genetic disorder in
North European ancestry
AR
Male predominance
CHF
Morphology 1. Florid duct lesions
(granulomatous
destruction of
interlobular bile
ducts)
2. Ductal proliferation
w/ periportal hepatitis
3. Scarring, w/ bridging
necrosis and septal
fibrosis
4. Cirrhosis

*Damage restricted to portal
tracts followed by progressive
damage to the parenchyma
Prussian blue stain:
hepatocytes filled w/ blue iron
granules
Late stage - parenchyma
damage and fibrosis
Subtle increase in fibrous
tissue about the central veins,
from which delicate strands
fan out into the surrounding
liver substance
Clinical
Features
Pruritus (b/f jaundice)
Hepatosplenomegaly
Jaundice (late)
Xanthelasma
ron deposits in multiple organs
Cirrhosis
Bronze diabetes (DM T1
destruction of beta cells, and
hyperpigmentation)
Malabsorption
Restrictive cardiomyopathy
Hypogonadism

Labs Anti-mitochondrial antibodies*
ANA positive
ncreased gM, ALP, GGT
ncreased cholesterol
ncreased serum iron, percent
saturation and ferritin
Decreased total iron binding
capacity

Clinical
Course
ncreased risk for
hepatocellular carcinoma
ncreased risk for hepatocellular
carcinoma (if cirrhosis)