Pathophysiology revision

1 - Pathophysiology of the cell – causes and mechanisms of cell injury

1) Define the term homeostasis and describe how cells undergo this
process

Homeostasis = Maintenance of a constant internal environment

inside the body by co-ordinated physiological mechanisms

 Cells exist in homeostasis. Where they are subject to

stress they attempt to adapt. When they are unable to
adapt = injured cells.
 Injurious stimuli also causes cell injury
 If cell injury is mild = reversible injury = homeostasis
 If cell injury is severe = irreversible injury = cell death
(necrosis/apoptosis)

2) Describe the 5 major types of cellular adaptation

Adaptation refers to changes made by a cell in response to adverse environmental

changes.

 Atrophy = decrease in cell size.

 Physiologic atrophy = thymus atrophy
during childhood.
 Pathologic atrophy = Skeletal muscle
atrophy
 Hypertrophy = increase in cell size.
 Physiologic hypertrophy = in skeletal
muscle w/sustained weight bearing
exercise.
 Pathologic hypertrophy = in cardiac muscle
due to hypertension
 Hyperplasia = increase in the number of cells – due to increased cell mitosis
 Physiologic = compensatory (allows tissue and organ regeneration –
liver hepatocytes, bone marrow cells) and hormonal (in organs that
depend on estrogen – uterine cells undergo hyperplasia and
hypertrophy during pregnancy)
 Metaplasia = reversible transformation of one mature cell type into another.
 E.g. changes associated w/respiratory tract in smokers – bronchial
cells convert from mucus secreting, ciliated, columnar to non-ciliated,
squamous epithelium incapable of secreting mucus. The transformed
cells may become dysplastic or cancerous if the stimulus isn’t removed
  E.g. Barrett’s oesophagus = non-keratinising squamous epithelium
undergoes Metaplasia to become mucinous columnar cells, protecting
the oesophagus form acid reflux originating in the stomach.
 Dysplasia = abnormal changes in cellular shape, size, and/or organisation –
not considered a true adaptation; it is thought to be related to hyperplasia

3) Describe some common causes of cell injury

 The most common cause is hypoxia (O2 deficiency) – prevents aerobic
oxidative respiration and conversion of carbs to ATP
 Hypoxia can often be caused by ischemia (lack of blood supply to an
affected area), pneumonia, anaemia, and CO poisoning
 Injuries from physical agents – mechanical forces, temperature extremes,
electrical injuries
 Radiation – ionising (releases free radicals), UV (causes DNA damage by
ROS)
 Chemical injury – lead and mercury toxicity
 Biological injuries – infectious agents (viruses, bacteria)
 Nutritional imbalances
 Genetic defects
 Aging

4) Describe the different mechanisms of cell injury

The 3 major mechanisms of cell injury:

 Free radical formation – cause damage by:

 Lipid peroxidation – OH radicals attach
the lipids in the cell membrane and cause
a chain rxn which causes damage to the
cell membrane
 Protein cross-linking – protein misfolding
 DNA fragmentation – can cause
oncogenesis
 Hypoxia and ATP depletion
 Failure of Na+/K+ pump (needs ATP –
usually 3 Na+ out for 2 K+ in) = water and
Na+ accumulate in the cell = cell swelling
and decreased mitochondrial function
 Increased anaerobic glycolysis = > lactate
= lactic acidosis
 Disruption of intracellular Ca2+ homeostasis
 Failure of membrane associated Ca2+/Mg2+ ATPase exchange systems
= hypercalcaemia (increased Ca2+) = activates phospholipases (destroy
membrane), proteases, ATPases, and endonucleases
2 - Pathophysiology of the cell injury – effects and responses (refer to picture
in Q1 of point 1)

1) Define the term adaptation and explain the 4 main types

When cells are subjected to stress they attempt to adapt. If they are unable to adapt
they become injured cells. Adaptation refers to changes made by a cell in response
to adverse environmental changes.

 Atrophy = decrease in cell size.

 Hypertrophy = increase in cell size.
 Hyperplasia = increase in the number of cells – due to increased cell mitosis
 Metaplasia = reversible transformation of one mature cell type into another.

2) Describe the 2 types of reversible cell injury

Reversible cell injury consists of 2 primary morphological changes:

 Cellular swelling – due to hypoxia, failure of ATP dependent Na/K pump

occurs leading to water and Na entering the cell = swelling
 Fatty changes = intracellular accumulation of fat. When it occurs, small
vacuoles of fat disperse throughout the cytoplasm.

3) Explain the result of irreversible injury

If the cell injury is sever and progressive = irreversible injury = cell death – either
necrosis (unplanned cell death) or apoptosis (programmed cell death), 2 processes
which are morphologically distinct

NB! For this Q you must use info from Qs 1, 3-5.

3 - Pathophysiology of the cell injury – apoptosis

1) Define the term apoptosis

Apoptosis = programmed cell death, which does not produce inflammation. It is a

highly regulated process that functions to remove damaged, unwanted or diseased
cells. It is an E dependant process

Apoptosis is triggered by TNF-α, ischemia, lack of growth factors, radiation, poisons

 2) What are caspases? Describe the caspase cascade

Caspases (Cys dependant Asp directed proteases) = a family of protease enz.

playing essential roles in programmed cell death and inflammation.

In the caspase cascade one caspase upstream will activate many molecules of
another caspase which will do the same to other molecules of caspases down-
stream. The 3 broad categories of caspases are:

 Inflammatory – involved in maturation of pro-inflammatory cytokines

 Initiator – kick off the caspase cascade = are at the top and activate the
effector caspase
 Effector caspase – cleavage of cellular substrates = mediate the killing

3) Describe the effects of initiation of the caspase cascade

As the caspases start to break down the cell, it shrinks and sends out distress
signals which attract macs to degrade the shrunken cells leaving no trace and
preventing any inflammatory response. We can view apoptosis in the following
stages:

 Loss of mitochondrial function and caspase activation

 Fragmentation of DNA by endonucleases
 Shrinkage of nuclear and cell volumes due to destruction of cytoskeleton
 Cell membrane undergoes blebbing where proteins are degraded
 Formation and phagocyte removal

4) Describe the extrinsic and intrinsic apoptosis pathways

 Extrinsic pathway = cells instructed to die from the
outside – the death receptors on the cell surface
induce death when ligand binds
 In the image, the Fas Ligand binds to the Fas death
receptor causes the procaspases to come together
and to bind to the FADD adaptor protein. They are
cleaved and activated (initiator caspases are
activated) = activation of executioner caspases =
apoptosis
 Intrinsic pathway = when cells are stressed, damaged, or abnormal, pro-
apoptotic signals are released which induce mitochondria to release
cytochrome c into the cytosol, where it binds to the Apaf-1. Apaf-1 will
aggregate and procaspase 9 binds to the
cytochrome c/adaptor complex which leads to
their activation = active caspase 9 = triggers
the caspase cascade = apoptosis
 5) Explain the clinical significance of apoptosis
 Crucial for development, maintenance, and control
 Increased apoptosis = liver failure, immune deficiency, aplastic anaemia,
transplant rejection, diabetes mellitus, neuronal degeneration (Parkinson’s,
Alzheimer’s)
 Decreased apoptosis = persistent infections, tumours, autoimmune diseases,
development abnormalities
 In neonates, during development, tissue present between the digits is
removed by apoptosis
 Furthermore, to prevent cancers and malformations, damaged cells must be
successfully removed. However, AIDS and Alzheimer’s are examples of
conditions that disrupt the apoptosis process and cause increased apoptosis,
leading to pathology

6) Describe how apoptosis is regulated

 Bcl-2 = family of interactive proteins. There are pro survival (protect from
apoptosis) and pro death (suppress protection) members
 Anti-apoptotic (pro survival) = Bcl-2 and Bcl-XL
 Pro apoptotic (pro death) = Bax, Bak (both lack BH4 domain – form pores in
mitochondria so cytochrome c can be released) and Bad (BH3 only protein)
 For life there is a Bcl-2 (survival) and Bax (death) balance – the Bcl-2 mops
up the Bax so there is no death

4 - Pathophysiology of the cell injury – free radicals

1) Define the terms free radicals and ROS and list some common examples

Free radicals = highly reactive chemical species w/an unpaired e - in the outer shell of
the molecule. This unpaired e- causes free radicals to be unstable and highly
reactive.

Reactive Oxygen Species (ROS) = O2-containing molecules that include free radicals
such as:

 Superoxide anion (O2.)

 Hydroxyl radical (OH.)
 Nitric oxide (NO)
 Alkoxy radicals (RO.)
 Peroxyl radicals (ROO.)
 2) Describe how free radicals are formed

They are produced endogenously by normal metabolic processes or cell activities

such as cellular respiration, and the metabolic burst that accompanies phagocytosis.
Exogenous causes:

 Ionising and UV radiation – splits H2O into an e- and OH.

 Chemical cell injury – metabolism of exogenous chemicals can result in free
radical formation
 Metals – Fe can (via Fenton rxn) be converted to a OH . Free radical

Oxidative stress = a condition that occurs when the generation of ROS exceeds the
ability of the body to neutralise and eliminate ROS

3) Describe the 3 main mechanisms of damage

 Lipid peroxidation – OH radicals attach the lipids in the cell membrane and
cause a chain rxn which causes damage to the cell membrane
 Protein cross-linking – protein misfolding
 DNA fragmentation – can cause oncogenesis

4) Describe the defences against free radicals

Antioxidants = natural and synthetic molecules that inhibit the rxns of ROS w/biologic
structures or prevent the uncontrolled formation of ROS. Include enzymatic and non-
enzymatic compounds:

 Enzymatic = catalase catalyses the decomposition of H 2O2 to H2O and O2.

Also superoxide dismutase (nullifies superoxide), and glutathione peroxidase
 Non-enzymatic = vitamins A, E and C – all donate e -s

5 - Pathophysiology of the cell injury – mechanisms of cell death

1) What is necrosis?

Unplanned, messy cell death due to toxic injury,

ischaemia and lack of nutrients – cytoplasm
swells and organelles fragment, nucleus is
damaged and cell dies.

2) Describe the process of necrosis

 ATP deficiency (ischemia, hypoxia,
hypoglycaemia) → failure of Na+/K+ pump
= ↑ in intracellular Na+ = cell swelling
  Also intracellular K+ ↓ as a result, extracellular K+ ↑, and cell membrane is
depolarised → Cl- enters and cell = cell swelling
 Lack of O2 = anaerobic glycolysis = formation of lactic acid → lactic acidosis
 If E deficiency rises, cell is > likely to be exposed to oxidative damage →
membrane destruction → cellular enz. leak out and cause damage →
inflammation

3) List the key cellular changes that occur during necrosis

 Karyolysis = chromatin fades due to the loss of DNA by degradation
 Pyknosis = nucleus shrinks and chromatin condenses
 Karyorrhexis = shrunken nucleus fragments
 Plasma membrane appears discontinuous caused by cell blebbing

4) List the different types of necrosis

 Coagulative = due to hypoxia
 Liquefactive = enz. digestion of necrotic cells, hypoxic damage of CNS
 Caseous = specific bacterial diseases – e.g. TB, caseous lymphadenitis
 Gangrenous = usually ischemic necrosis of extremities
 Fat = necrosis is a product of inflammation, vit E deficiency, trauma

5) Compare apoptosis and necrosis

Apoptosis Necrosis
Energy dependent Energy independent
Induced by physiological/pathological stimuli Induced by ischaemia, hypoxia, poisoning
Cell shrinkage Cell swelling
Organelle integrity Organelle don’t maintain integrity
Chromatin condensation Nuclear swells and fragments
Plasma membrane integrity Loss of plasma membrane integrity (rupture)

6 - Disturbances of peripheral circulation – arterial hyperaemia

1) Describe the 3 mechanisms for regulation of microcirculation

 Nervous system = SNS generates impulses acting w/different receptors on
smooth muscle of vessels – α and β adrenergic and cholinergic
 α = vasoconstriction (VC)
 β = vasodilation (VD)
 Humoral = different hormones and hormone like substances
 VC = vasopressin (ADH), adrenaline and noradrenaline
(catecholamines), angiotensin II
 VD = ANP, VIP (both stimulate activity of endothelial NO synthetase);
histamine, prostaglandins, bradykinin
  Metabolic:
 VC = endothelin (acts only over adjacent cells); ↑ Ca 2+, ↑ pO2
 VD = ↑ K+, ↑ Mg2+; ↑ pCO2, ↑ H+, ↑ lactic acid, ↑ ADP (acidosis)

2) Define the term arterial (active) hyperaemia

↑ blood supply in a given place due to VD of incoming entering arterial vessel

3) Describe physiological hyperaemia

 Working/functional hyperaemia = ↑ activity → ↓ O2 and nutrients → anaerobic
glycolysis → ↑ lactate → acidosis → VD to meet ↑ requirements of working
muscle/organ
 Reactive post-ischemic = after ischemia/↓ blood flow, aa. compensate by VD
to get ↑ O2 to affected areas
 Emotional/neurotonic = SNS generates impulses to cause VD of aa. of face –
when you have a red face due to stress/worry/fear/anger
 Neuroparalitic = lack of vasoconstrictive n. impulses – aa. remain dilated

4) Describe pathological hyperaemia

Result of trauma (burn) or inflammation. Damaged tissue at injured site synthesises

bio active substances (inflammatory mediators, cytokines) = causes VD followed by
↑ arterial blood and ↑ permeability of vessels (swelling, oedema)

5) List the clinical manifestations of arterial hyperaemia

 Reddening of the skin
 ↑ temp. – due to influx of warm arterial blood and ↑ in metabolic rate
 ↑ size of organ/tissue - ↑ in volume due to ↑ in blood and lymphatic filling
 Pulsatile movement of blood in the affected area synchronous w/heart
contraction
 ↑ turgor pressure (skin becomes > tight)

6) List the consequences of arterial hyperaemia

 Physiological hyperaemia = activation of a specific function of the organ/tissue
– e.g. activation of local immunity, ↑ lymphocyte formation and lymphatic
drainage from tissues
 Pathological hyperaemia = overgrowth and micro-rupture of the walls of the
vessels of the microcirculatory bed → bleeding
7 - Venous hyperaemia. Stasis

1) Define the term venous (passive) hyperaemia

↑ in the blood supply of the organ/tissue due to a ↓ in the outflow of blood through
venous vessels (venules, vv., and venous type capillaries)

2) Explain the causes of venous hyperaemia

 Mechanical obstacle to flow of venous blood = may be due to narrowing of
lumen when its compressed (swelling, oedematous tissue, scar, tourniquet)
and obturation (thrombus, embolus, tumour)
 Physical = the effect of a changed temp
 Chemical = hormonal contraceptives contribute to development of
thrombophlebitis
 Biological = clogging of vessels w/helminths and others
 Social = professions associated w/prolonged standing - surgeons,
hairdressers etc.

3) List the clinical manifestations of venous hyperaemia

 Cyanosis (blue skin) due to ↓ Hb
 ↓ temp of organs/tissues in the zone of venous stasis
 Oedema in the legs – due to ↑ intravascular pressure in capillaries,
postcapillaries, and venules
 Overgrowth and micro-rupture of the walls of the vessels of the
microcirculatory bed → bleeding and haemorrhages in the tissue
 Burning sensation

4) List the pathogenic effects of venous hyperaemia

 Hypoxia
 Oedema of the tissue
 Haemorrhages in the tissue
 ↓ of specific and nonspecific functions of organs and tissues
 Hypotrophy and hypoplasia of structural elements of tissues and organs
 Necrosis of parenchymal cells and development of CT in organs

5) Define the term stasis

It is a significant slowing/stopping of the flow of blood and/or lymph in the vessels of

the organ/tissue. It is the final stage of venous hyperaemia

6) Describe the pathogenesis of stasis

Etiologic factors → activation and/or ↑ in blood levels → proaggregants, large

molecule proteins → adhesion, aggregation, agglutination of blood elements →
slowing/stopping the flowing of blood and/lymph in the vessels → stasis
 7) What are the 2 types of stasis?
 Primary (true) stasis = activation of blood elements which aggregate,
agglutinate, and attach to the wall of the microvessel → stasis (explained
above)
 Secondary stasis = ischemic and congestive

8) List the consequences of stasis

 Oedema
 Tight calves
 Pain during walking
 Brown-coloured skin
 Varicose vv.
 Leg ulcers very resistant to treatment

8 - Ischaemia. Infarction

1) Define the term ischemia

A restriction/↓ in blood supply to tissues, causing a shortage of O 2 that’s needed for

cellular metabolism

2) Explain the causes of ischemia

 Compression of the arterial vessels - tumour, scar, oedematous tissue or
tourniquet
 ↓ in lumen of the a. (obstruction which blocks the vessel) – embolus,
thrombus, or atherosclerotic plaque
 Rupture of the vessel by trauma causing a loss of bp downstream of the
rupture
 Vasoconstriction

3) List some important types of ischemia

 Acute = sudden O2 deficit. If acute ischemia continues = local ischemic
necrosis (infarction)
 Cardiac ischemia = myocardium receives insufficient blood flow and can lead
to a myocardial infarction
 Brain ischemia = can lead to an ischemic stroke (cerebral infarction), where
part of the brain dies from hypoxia

4) List the clinical manifestations of ischemia

 Pain
 Pale skin
  Feel cold
 Paresthesia = local numbness and tingly feeling

5) What is reperfusion injury?

 Reintroduction of blood flow brings O2 back to the tissues = greater production
of free radicals and ROS that damage cells
 It also brings > Ca2+ to the tissues causing further Ca2+ overloading and can
result in potentially fatal cardiac arrhythmias and also accelerates cellular self-
destruction
 Also exaggerates the inflammation response of damages tissues, causing
WBCs to destroy damaged cells that may otherwise still be viable

6) Give examples of disorders that involve ischemia

Coronary heart disease, vascular brain disease, Raynaud’s syndrome

7) Define the term infarction

Tissue death (necrosis) due to inadequate blood supply to the affected area.

8) What is the cause of infarction

May be caused by a. blockages, rupture, mechanical compression or VC (prolonged

ischemia)

9) Describe the classification of infarction

By histopathology

 Red infarcts (haemorrhagic infarcts) = affect the lungs or other loose organs.
The occlusion consists > of RBCs and fibrin strands; occlusion in a v.
 White infarcts (anaemic infarcts) = affect solid organs (spleen, heart and
kidneys) where the solidity of tissue limits the amount of nutrients that can
flow into the area of ischaemic necrosis. Can occur due to VC of an a. and
there is < blood in the infarct

By localisation

 Heart = myocardial infarction. Commonly due to occlusion of a coronary a.

 Brain = cerebral infarction. Due to a disturbance in the blood vessels
supplying blood to the brain
 Lung = pulmonary/lung infarction
 Spleen = splenic infarction. Occurs when the splenic a. or one of its branches
are blocked
 Limb = limb infarction. Due to arterial embolism and skeletal muscle infarction
(prolonged standing, and poorly controlled DM)
9 - Thrombosis

1) Define the term thrombosis

Formation of a blood clot inside a blood vessel, obstructing the flow of blood through
the circulatory system

2) Describe the causes of thrombosis

The main causes of thrombosis are given in Virchow’s triad:

 Haemodynamic changes – stasis, turbulence

 Endothelial injury/dysfunction
 Hypercoagulability

Some risk factors for thrombosis include:

 Previous episodes of thrombosis

 VC
 Stroke
 Heart failure
 Shock
 Obesity
 Varicose vv.
 Trauma
 Surgery

3) List the signs and symptoms of thrombosis

Thrombosis may occur in the vv., aa. or heart

Venous thrombosis

 RBCs, platelets and fibrin make up the venous thrombosis, which attaches
itself to the endothelium
 The valves of vv. are a recognised site of VT initiation
 Leads to congestion w/in the affected part of the body, can also cause
pulmonary embolism
 DVT/PE = refers to a venous thromboembolism (VTE) where a deep v.
thrombosis (DVT) has moved to the lungs (PE – pulmonary embolism)
 Can develop in deep v. in the lower extremity (DVT), or in the super.
saphenous, hepatic, and renal vv.

Arterial thrombosis

 Caused by damage to the vessel wall (often rupture of atheroma, a fat-rich

deposit in the blood vessel wall)
  Can lead to hypoxia of the tissue, embolisation, dissolution/organisation
(induce inflammation and re-establish physiological flow)
 Can occur as a consequence of embolism of blood clots originating from the
heart (cardiogenic emboli). The most common cause of this is atrial fibrillation

Heart = MI due to obstruction of a coronary a. by a thrombus

Hepatic a. thrombosis usually occurs as a complication after liver transplantation.

10 - Embolism

1) Define the terms embolus and embolism

Embolus = an unattached mass that travels through the bloodstream and is capable
of clogging arterial capillary beds at a site distant from its point of origin

Embolism = lodging of an embolus inside a blood vessel

2) Explain the cause of embolism

99% = thromboembolism. Rarer types include:

 Fat globule (fat embolism)

 Air bubble (gas embolism)
 Foreign material
 Tumour fragments
 Atherosclerotic debris
 Amniotic fluid embolism

The consequence of an embolism depends on the location, however can include

ischemic necrosis (infarction) of downstream tissue due to occlusion of the vessel

3) Describe the direction of the embolus

 Anterograde = movement of emboli is in the direction of blood flow
 Retrograde = movement of emboli is in the opposite direction of the blood
flow. Usually in vv. or w/emboli of high weight

4) Describe the classification of embolism

Arterial embolism

 Can cause blockage in any part of the body. It is a major cause of infarction
 Can travel through the systemic circulation
 Strokes = embolus lodging in the brain
  Arterial embolus may originate in the heart

Venous embolism

 Formed in a systemic v. which may then travel to the lungs to form a

pulmonary embolism
 Systemic embolism can come from thrombi from the left side of the heart and
travel throughout the body, causing tissue ischemia
 Most common site of origin of pulmonary emboli = femoral vv.

Paradoxical embolism (venous to arterial)

 Embolus from the vv. crosses to the arterial blood system

 People w/heart problems such as septal defects between the atria and
ventricles

11 - The molecular and biochemical basis of neoplasia. Genetic changes,

oncogenes and tumour suppressor genes. Hormones; growth factors and
inhibitors; and stromal, adhesive and proteolytic proteins

1) Define the terms neoplasia and anaplasia

Neoplasia = the presence/formation of new, abnormal growth of tissue. Can be

benign or malignant

Anaplasia = lack of structural and functional differentiation of a cell – could be a

malignant cell (malignant tumour cells are characterised by high levels of anaplasia)

2) Describe the differences between benign and malignant

Benign tumour Malignant tumour

Doesn’t invade surrounding tissue or spread May invade surrounding tissue or spread
around the body around the body (metastasis)
Grow slowly Grow quickly
Encapsulated (have a capsule) Un-encapsulated (don’t have a capsule)
Well-circumscribed (edges are distinct and Irregular shape
demarcated in a certain shape)
Well differentiated Poorly differentiated
Freely moveable w/in or on the tissue > difficult to move around
Minimal anaplasia Anaplasia is typical
 3) Describe the molecular and biochemical basis of neoplasia

Main cause of neoplasia = DNA damage, impacting 1/> genes that control the cell
cycle, apoptosis, response to growth factors, or other cellular functions that control
the cell cycle. DNA damage can be caused by a n.o of factors (carcinogens):

 Environment = radiation, food, smoking, pollution

 Age
 Hereditary
 Acquired preneoplastic disorders – precancerous conditions that predispose
to cancer

4) Describe the genetic changes that occur in neoplasia

DNA damage results in genetic changes which impact one of two classes of normal
regulatory genes:

 Growth promoting proto-oncogenes = genes that encourage normal cell

division. E.g. RAS protein
 Growth-inhibiting tumour suppressor genes = prevent uncontrolled cell growth
either by apoptosis, DNA repair or cell cycle regulation. 2 classes:
 Governors
 Guardians (sense genome damage and force apoptosis). E.g. p53

5) Define the terms tumour suppressor genes, proto-oncogenes, and

oncogenes

Tumour suppressor genes = genes suppressing tumour formation by stopping

mitosis. E.g. p53, BRCA1, BRCA2

Proto-oncogenes = normal genes that can become oncogenes due to

mutations/increased expression – they code for proteins that regulate cell cycle, cell
growth and cell differentiation. E.g. HER2, RAS, WNT

Oncogenes = genes, that due to mutation/increased expression, can turn a normal

cell into a tumour cell. E.g. Bcr-Abl gene in CML

6) List the different types of mutations

Mutation = changes in the DNA sequence of a cells genome.

 Point mutation = changes to a single nucleotide

 Substitution = replacing one nucleotide w/another – due to degeneracy of
genetic code this may lead to same AA = silent mutation
 Missense mutations = substitutions that result in a codon for another AA
  Nonsense mutations = substitutions that result in a stop codon. By causing
premature termination they destroy the function of the polypeptide >
effectively than missense mutations.
 Deletion = removal of a nucleotide. Insertion = adding a nucleotide. Both are
frameshift mutations. After the point of mutation there will be many AA
different from the old ones

7) Describe the role of growth factors in neoplasia

 Normal cells require growth factors that encourage them to divide
 E.g. Mitogen-activated protein kinase (MapK) pathway = a ligand binds to the
tyrosine kinase receptor, which goes on to stimulate cell division.
 Cancer cells however don’t require growth factors to encourage them to
proliferate. They can either use Autocrine signalling to produce their own
growth factors, or damage to MapK pathway means no growth factors are
required at all
 Furthermore apoptosis
doesn’t occur properly. In
neoplasms there is often
an over expression of
anti-apoptotic inhibitors
(survivin) which prevent
the caspases from doing
their job successfully
 The over expression
stems from the ubiquitin-
proteasome pathway,
which in turn activates the transcription and translation of these anti-apoptotic
molecules

12 - Pathogenesis of neoplasia

There are 3 stages for tumour development:

 Initiation – via carcinogens

 Promotion (mutagens/mitogen activating
signals – causes uncontrollable division)
 Progression
Initiation phase results in irreversible DNA damage, affecting either growth promoting
proto-oncogenes or growth inhibiting tumour suppressors, leading to a cancerous
cell.

Promotion = unregulated, accelerated growth (activation of oncogenes by promoter

agents). This stage is reversible is the promoter substance is removed.

Progression = over a period of time, many tumours become > aggressive and have
greater malignant potential (tumour progression).

As tumour cells divide, they undergo a form of natural selection, w/the most antigenic
being destroyed by the host’s immune system, and the most successful undergoing
clonal expansion, w/additional mutations. In effect, this means that the tumour now
consists of many different types of tumour cell variants, all of which have been
naturally selected to require fewer growth factors and non-antigenic to the host.

13 - Cellular changes in neoplasia. Differences between normal and cancer

cell.

There are 6 key “Hallmarks of cancer cells”:

1. Self sufficiency in growth signals (cancer cells stimulate their own

growth)
 Cancer cells don’t need stimulation from external signals (growth factors) to
multiply – they can stimulate their own growth
 They can do this by autocrine signalling; by permanently activating the
signalling pathway that respond to these signals; or by destroying ‘off
switches’ that prevents excessive growth from these signals (-ve feedback)
 Additionally cell division is not controlled because the proteins that control the
process are altered → ↑ growth and cell division w/in the tumour

2. Insensitivity to anti-growth signals (they resist inhibitory signals that

might otherwise stop their growth)
 Tumour suppressor proteins are altered in cancer ∴ they don’t effectively
prevent cell division
 Contact inhibition = normal cells will stop dividing when the cells fill up the
space they are in and touch other cells
 Cancer cells do not have contact inhibition ∴ will continue to grow and divide,
regardless of their surroundings.

3. Evading/escaping apoptosis
 Normal cells undergo apoptosis, either via the intrinsic/extrinsic mechanism,
in order to grow and develop properly and also when the cell is
damaged/injured
 Cancer cells evade apoptosis by altering the mechanism that detect the
damage/abnormalities = proper signalling cant occur = apoptosis can’t be
activated
 Cancer cells also ↑ the n.o of anti-apoptotic proteins = no apoptosis

4. Limitless replicative potential (they can multiply indefinitely)

 Non-cancer cells die after a certain n.o of divisions due to chromosome
telomeres (Hayflick limit – 60-70 divisions)
 Cancer cells upregulate expression of the enz. telomerase = elongation of the
telomeres = allowing for indefinite cellular growth and division (immortality)

5. Sustained angiogenesis (they stimulate the growth of blood vessels to

supply nutrient to tumours)
 Angiogenesis = process by which new blood vessels are formed
 Tumours are a very dense collection of cells, meaning a large amount of
blood is required.
 Hypoxia w/in cancer cells triggers the transcription of Vascular Endothelial
Growth Factor (VEGF), a pro-angiogenic factor
 Transcription of VEGF is usually controlled by VHL (tumour suppressor).
However mutations in the VHL gene = ↑ risk of neoplasia

6. Tissue invasion and metastasis (they invade local tissue and spread to
distant sites)
 Invasion = the direct extension and penetration by cancer cells into
neighbouring tissues
 Metastasis = spread of cancer cells from their site/organ of origin to invade
surrounding tissue and spread to distant body parts
 Multistep process = starts w/local invasion of the cells into the surrounding
tissues. They then have to invade blood vessels, survive in the harsh
environment of the circulatory system, exit this system and then start dividing
in the new tissue
14 - Tumour/organism relationships

1) Describe the effects of tumours on the body

Tumour cahexia = a wasting

syndrome characterised by weight
loss, anorexia, asthenia (abnormal
physical weakness/lack of E), and
anaemia.

Paraneoplastic syndromes = rare

disorders that are triggered by an
altered immune system response to a
neoplasm. They most commonly
present w/cancers of the lung, breast,
ovaries, or lymphatic system
(lymphoma)

2) Describe the relationship of

tumours and the immune
system

NK cells and cytotoxic lymphocytes

both recognise MHC receptors on the
surface of tumour cells and trigger an
immune response, while TH cells
support this process by releasing cytokines to recruit > NK cells and lymphocytes

However since tumour cells grow rapidly and their DNA is rapidly altering, a form of
natural selection occurs, w/some tumour cells evolving to avoid the detection of
these immune cells. this creates a heterogeneous collection of cells w/in the tumours
which is harder for the immune system to deal with

Furthermore, the tumour cells can evolve to include inhibitory molecules which
suppress T cells, such as PLD1 which binds to a PD1 receptor on the T cell making
it inactive. They can also attract regulatory T cells and certain myeloid cells which
help to reduce the activity of the immune system in the region

Tumour cells can express the ligand for the CD95 receptor on their surface and thus
driving lymphocytes to apoptosis. A compromised immune response (e.g. HIV) also
helps tumour cells to survive.
15 - Epithelial neoplasia

1) Define the term intraepithelial neoplasia

Abnormal growth (dysplasia) of cells w/in the epithelial layer – is considered a

precancerous condition. There are different localisations = anal intraepithelial
neoplasia (AIN), biliary, cervical, endometrial, GI, vaginal, vulvar.

2) Explain the most common intraepithelial neoplasia

Cervical IN = abnormal growth of cells on the surface of the cervix that could
potentially lead to cervical cancer. HPV (human papilloma virus) infection is
necessary for the development of CIN, but not all w/this infection develop cervical
cancer

CIN is classified in 3 grades:

 CIN 1 (grade I) = low-grade squamous intraepithelial lesion – mild dysplasia

confined to the basal 1/3 of the epithelium
 CIN 2 (grade II) = moderate dysplasia confined to the basal 2/3 of the
epithelium
 CIN 3 (grade III) = severe dysplasia w/undifferentiated neoplastic cells that
span > 2/3 of the epithelium

3) Define the term carcinoma

A type of cancer that develops from the epithelial cells of the body – severe cases of
intraepithelial neoplasia develop into carcinomas. (Malignant tumours of epithelial
origin)

4) Describe the classification of carcinomas

According to the cell type from which they start

 Epithelial cells → carcinoma

 Non-hematopoietic mesenchymal cells → sarcoma
 Hematopoietic cells
 Bone marrow-derived cells that normally mature in the bloodstream →
leukemia
 Bone marrow-derived cells that normally mature in the lymphatic
system → lymphoma
 Germ cells → germinoma
Histological types

 Adenocarcinoma = a malignant tumour formed from glandular structures in

epithelial tissue
 Squamous cell carcinoma = cancer that result from squamous cells – these
cells from the surface of the skin and lining of hollow organs in the body and
line the respiratory and digestive tracts
 Adenosquamous carcinoma = mixed tumour containing both adenocarcinoma
and squamous cell carcinoma
 Anaplastic carcinoma = heterogeneous group of high-grade carcinomas that
feature cells lacking distinct histological or cytological evidence of any of the
more specifically differentiated neoplasms
 Small and large cell carcinomas
 Basal cell carcinoma = most common form of all cancers, occurs in the basal
cell layer of the skin, very rarely spreads

16 – Mesenchymal, neuroendocrine & germ cell neoplasia. Carcinoid tumours,

testicular cancer & sarcomas

1) Define the term sarcoma (mesenchymal neoplasia)

A malignant tumour of mesenchymal (non-epithelial) origin. This contrasts

w/carcinomas which are of epithelial origin. Human sarcomas are quite rare.

2) Describe the classification of sarcomas

Classification according to the type of tissue that they most closely resemble

 Osteosarcoma = resembles bone

 Chondrosarcoma = resembled cartilage
 Liposarcoma = resembles fat
 Leiomyosarcoma = resembles smooth muscle

Classification according to grade

Grading = degree of differentiation of tumour cells. it is the most important prognostic

factor and indicator of metastatic risk. As the grade goes up (the tumour cells don’t
look like the tissue they are derived from), the prognosis worsens

 G1 = well differentiated
  G2 = moderately differentiated
 G3 = poorly differentiated
 G4 = undifferentiated/anaplastic

3) What are neuroendocrine neoplasms (carcinoid tumours)?

Neoplasms (tumours) that arise from cells of the endocrine and nervous system.
many are benign whilst some are malignant. They most commonly occur in the
intestine (carcinoid tumours), but they are also found in the pancreas, lungs and the
rest of the body. neuroendocrine tumours are often small, yellow, and located in the
submucosa

4) Describe the classification of neuroendocrine neoplasms

The WHO places neuroendocrine tumours into 3 main categories, which emphasizes
tumour grade rather than the anatomical origin:

 Well differentiated
 Low grade, but well differentiated
 High grade, but poorly differentiated

Classification according to anatomic origin

They are often located in the intestine (carcinoids), pancreas or lungs, as well as the
pituitary gland, thyroid (medullary carcinoma), adrenal glands - medulla
(pheochromocytoma)

 Pheochromocytoma = begins in the chromaffin cells of the adrenal glands.

Most often occurs in the adrenal medulla. This tumour ↑ production of
adrenaline and noradrenaline = ↑ bp and HR
 Merkel cell cancer = neuroendocrine carcinoma of the skin. Highly aggressive
and rare cancer that begins in the hormone-producing cells just beneath the
skin and in the hair follicles

5) Explain the cause of neuroendocrine neoplasia

The causes are poorly understood, but highly increased based on a n.o of different
genetic conditions:

 Multiple endocrine neoplasia (MEN) type 1 and 2 (MEN1 and MEN2)

 Von Hippel-Lindau (VHL) disease
 Neurofibromatosis type 1

6) Define the term germ cell neoplasia and explain their cause

Neoplasia derived from the germ cells (eggs/sperm)

Germ cell tumours that originate outside the gonads may be birth defects resulting
from errors during development of the embryo. They are found in the head, neck,
mediastinum, and pelvis

Research suggests this distribution (outside the gonads) is due to abnormal

migration of germ cells during embryogenesis.

7) Describe the classification of germ cell neoplasia

Germinomatous

 Tumours comprised solely from germ cells

 They don’t produce tumour markers and have a homogenous cellular
composition of gonadal origin
 E.g. germinoma, dysgerminoma, and seminoma

Non-germinomatous

 Include all other germ-cell tumours, pure and mixed (e.g. choriocarcinoma)
 They produce tumour markers that are detected in the blood/CSF

8) Describe the symptoms of testicular cancer

 1st sign of testicular cancer = enlargement of the testicle and discomfort.
Aches in the abdomen/groin or sensation of heaviness in the scrotum occur
 Signs of metastatic spread = swelling of lower extremities, back pain,
hemoptysis (cough w/blood), or dizziness
 Gynecomastia can occur from hCG-producing tumours

9) List the tumour markers that can be found in testicular cancer

 Alpha fetoprotein = normally present in the fetal serum in high levels and
should be present in trace amounts after 1 year
 Beta-hCG = produced by the placenta in pregnancy and shouldn’t be present
in high levels in the normal M
 LDH = enz. found in the muscle, liver, kidney, and brain and has shown to
correlate w/the mass of tumour cells. They are often ↑ in metastatic testicular
cancer
17 - Systemic effects of neoplasia

 Fever = especially in Hodgkin’s disease, renal cell carcinoma, and osteogenic

sarcoma. Due to release of pyrogens by tumour cells
 Endocrine syndromes = Cushing’s, inappropriate antidiuresis,
hypercalcaemia, hypoglycaemia
 Neurological syndromes = spinal cord motor neuropathy and sensorimotor
peripheral neuropathy
 Skeletal muscle = dermatomyositis
 Haematological syndromes = erythrocytosis (↑ RBC mass)
 Malabsorption
 Renal syndromes = nephritic syndrome

Anaemia

 Drugs to treat cancer are cytotoxic = ↓ RBC production

 RBC production is impaired in people w/malignancies including nutritional
deficiencies, bone marrow failure and iron deficiency
 Inflammatory cytokines released due to tumours cause a ↓ in erythropoietin
synthesis
 Hypoxia → solid tumours; promote tumour resistance to chemo and
radiotherapy
 Cancer-related anaemia is treated w/Fe supplements and epoetin alfa

Anorexia and cahexia

 Cancer anorexia-cahexia syndrome = wasting syndrome → weightloss,

wasting of body fat and muscle and profound weakness and anorexia
 Cause = due to inflammatory response = TNF-alpha secreted by macs in
response to tumour cell growth → cahexia and wasting, suppress satiety
centres in hypothalamus and ↑ synthesis of lipoprotein lipase (releases FAs
from lipoproteins so that they can be used by tissues.

Fatigue and sleep disorders

 Cancer-related fatigue = tiredness, weakness, lack of E that isn’t relived by

rest/sleep
 Due to cancer and effect of cancer treatment
 Peripheral fatigue = originates in NMJ and muscles → lack of ATP and build
up of lactic acid
  Central fatigue = difficulty in initiating and maintaining voluntary activities →
cancer and cancer treatments results in dysregulation of brain serotonin level
and function. TNF-alpha can also influence 5-HT metabolism

18 - Immune disorders - essence and classification. Antibody mediated

hypersensitivity reaction type I

1) Define the term hypersensitivity rxns

Exaggerated/inappropriate immune responses against an Ag/allergen

2) Define the term type I (immediate) hypersensitivity (HS) rxn

Type I HS rxn = IgE mediated/anaphylactic rxn

It is an allergic rxn provoked by re-exposure to a specific type of Ag referred to as an

allergen. Exposure may be by ingestion, inhalation, injection, or direct contact

Allergens = insect venom, food, pollen, dust mites

AB = IgE

3) Describe the pathogenesis of type I HS rxn

HS is a 2 step process, w/a first exposure (sensitisation) phase, where the body is
primed to react to the Ag, and secondly a subsequent exposure phase, where the
actual allergic rxn occurs. Type I HS rxn is a result of a genetic defect that makes T
cells over sensitive to a certain allergen.

First exposure (sensitisation)

 Allergen enters the body and the Ag is phagocytosed by dendritic cells

 Dendritic cell (APC) expresses the Ag to naive T cells → T H2 activated
 TH2 (CD4+ cells) releases IL-4, 5, and 6 which activate B cells → plasma cells
→ release of IgE
 IgE AB binds to FcεRI receptors on mast cells which act as specific receptors
 Mast cells are now sensitised and remain in the body, ready to attack the Ag

Subsequent exposure

 Ag enters the body once more. Mast cells w/IgE AB now bind to the Ag
 This causes mast cell degranulation and release of inflammatory mediators
 Release of histamine → VD, bronchoconstriction, ↑ permeability of vessel
walls = early response
 Cytokine release = recruitment and activation of inflammatory cells.
 Leads to secondary late response = mucosal oedema, leukocyte
infiltration, epithelial damage, bronchospasm
 4) What are the 2 types of type I HS rxn?
 Local = atopic form – allergic rhinitis, atopic dermatitis, asthma, and
gastroenteropathy
 General = anaphylaxis (systemic effects)
 Anaphylactic shock = bronchoconstriction, cardiac arrest (main
problem) → leads to difficulty in breathing
 Rapid ↓ in bp due to VD = rapid ↓ in cardiac output = aorta doesn’t
pump enough blood = ↓ flow through coronary a. = acute cardiac arrest
– cardiogenic shock (heart suddenly can’t pump enough blood to meet
the body’s needs)

5) Describe the treatment options

 Adrenaline = VC → ↑ bp = restores circulation to normal
 Antihistamines
 Corticosteroids

6) Give some examples of type I HS rxn

 Allergic asthma
 Allergic rhinitis (“hay fever”)
 Anaphylactic shock
 Food allergy
 Urticaria (hives)

19 - Immune disorders - essence and classification. Antibody mediated

hypersensitivity reaction type II

1) Define the term type II hypersensitivity (HS) rxn

Type II HS rxn = tissue-specific/cytotoxic HS

In type II HS rxn the ABs produced by the immune response bind to Ag’s on the
patient’s own cell surfaces. The Ag’s recognised may either be intrinsic or extrinsic

Ag = often drugs such as penicillin. Can also be an endogenous molecule

AB = IgM and IgG

2) Define the term hapten

Small molecules which, when attached to a

large carrier such as a protein, can elicit the
production of ABs which bind specifically to it
 3) Describe the pathogenesis of type II HS rxn
 Ag enters the body and binds to an APC → activation of B cells
 Subsequent exposure = plasma cells are activated and large amounts of
allergen-specific IgM and IgG are formed and are densely bound to the
allergenic cell surface (opsonification)
 This forms an Ag-AB complex on the cell surface → activates complement
system
 The complement system then triggers the hemolysis of the cell, leading to
tissue damage

4) Describe the complement system

Classical pathway

 Triggered by activation of the C1-complex (C1qr 2s2)

 This occurs when C1q binds to IgM/IgG complexed w/Ag's → conformational
changes in the C1q molecule
 This causes cleavage and activation of the serine protease C1r → cleavage
and activation of serine protease C1s
 C1s cleaves C4 into C4a and C4b, then C2 into C2a and C2b
 C4b + C2a = classical pathway C3 convertase (C4b2a) → splits C3 into C3a
and C3b
 C3b later joins w/C4b2a = C5 convertase (C4b2a3b complex)

Alternate pathway

 C3 → C3a and C3b

 C3b + Factor B = C3bB
 Factor D cleaves Factor B → C3bBb (alternate pathway C3 convertase)
 C3bBb cleaves C5 → C5a and C5b
 C5b + C6 – C9 = MAC (membrane attack complex) – inserts into the cell
membrane. Fluid rushes in which causes the cell to swell and burst

5) What is ADCC?
 ADCC = AD-dependent cell-mediated cytotoxicity
 Low conc. of IgM/IgG coat target cells.
 NK cells bind to the Fc receptors and release perforins (make pores in the cell
membrane) and granzymes, which causes the lysis of the cell
 E.g. of ADCC = transplant rejection, immune rxns against neoplasms and
parasites
 6) Describe some effects of type II HS rxn
 Haptens binding to endogenous RBCs results in haemolytic anaemia
 Hapten + granulocyte = agranulocytosis
 Hapten + thrombocyte = thrombocytopenia
 Goodpasture’s syndrome = basement membrane in the lung and kidney is
attacked by one’s own ABs

20 - Immune disorders - essence and classification. Antibody mediated

hypersensitivity reaction type III

1) Define the term type III HS rxn

Type III HS rxn = immune complex mediated type of HS

Type III occurs when there is an accumulation of immune complexes (Ag-AB

complexes) that have not been adequately cleared by innate immune cells, giving
rise to an inflammatory response and attraction of leukocytes.

Ag = can be drugs, endogenous or exogenous molecules or proteins

AB = IgM and IgG

2) Describe the pathogenesis of type III

HS rxn
 Occur when there is an excess of Ag
leading to small immune complexes being
formed that fix complement and are not
cleared from the circulation
 It involves soluble Ag’s that aren’t bound
to cell surfaces (as opposed to those in
type II HS.
 When these Ag’s bind ABs, immune
complexes of different sizes form. Large
complexes can be cleared by macs but
they have difficulty in the disposal of small immune complexes.
 These immune complexes insert themselves into small blood vessels, joints,
and glomeruli → activation of classical pathway
 Such depositions can induce an inflammatory response and can cause
damage when they precipitate
 Damage is to anaphylotoxins (C3a and C5a) which mediate the induction of
granule release from mast cells, and recruitment of inflammatory cells into the
tissue → tissue damage (vasculitis) → serum sickness
 3) Give some examples of type III HS rxn
 Vasculitis
 Serum sickness
 Glomerulonephritis
 Urticaria
 Arthritis

21 - Immune disorders – cell-mediated hypersensitivity reaction type IV

1) Define the term type IV HS rxn

Type IV HS rxn = delayed type/T-cell mediated HS

Unlike the other types, type IV is cell mediated and is a delayed response (1 st 3 HS
rxns are AB mediated and are immediate)

Ag = some metals (e.g. nickel, chromium), cosmetics, detergents, organ transplants

MNEMONIC to remember the HS rxns = ACID = Allergic (I), Cytotoxic (II), Immune
complex deposition (III), and Delayed (IV)

2) Describe the pathogenesis of type

IV HS rxn
 Sensitisation = Ag enters the body
and is taken up by APCs which
present them to TH cells. This
process takes > than 5 days
 On subsequent exposure, many T
cells are activated into TH cells
 These stimulate monocyte formation
in the bone marrow via IL-3 and
granulocyte-mac colony stimulating factor (GM-CSF), attract monocytes and
macs via chemokines, activate them via IFN-γ and w/them cause a strong
inflammatory rxn (this occurs after 1-3 days)
 This causes release of pro-inflammatory cytokines (TNF, IL-1) → oedema,
redness, fever
 Additionally, lysosomal enz. released, ROS and complement components →
tissue damage
Summary = initial contact of Ag’s → sensitisation – sensitised T cells → T H1 →
release of chemokines = ↑ phagocytosis by macs → inflammation after 1-3 days and
tissue damage

3) Give some examples of type IV HS rxn

 Contact dermatitis (inflammation of skin) – in response to nickel, hair dyes,
topical drugs
 Tuberculin rxns – mycobacterium TB is injected into the skin; if person has
been exposed to TB previously, TH1 cells migrate to injection site →
inflammatory response → induration (skin thick and hard)
 Host vs. Graft rxns & vice versa

22 - Autoimmune response – essence and mechanism of generation

1) Define the terms autoimmunity, autoimmune disease, and self-tolerance

 Autoimmunity = the ability of the immune system to identify its own healthy
cells
 Autoimmune disease = when the body’s immune system attacks its own cells
– inability of the immune system to differentiate between self and non-self
Ag’s
 Self-tolerance = the capacity of the immune system to differentiate self from
non-self (central or peripheral)

2) Describe some of the causes of autoimmune diseases

 Genetic predisposition – mainly HLA-II phenotypes
 Hormonal influences → sex prevalence
 Cancellation of immunological ignorance of auto Ag’s from immunologically
privileged regions e.g. eye, brain, uterus, sperm, thyroglobulin
 Infections – cross rxn of anti-foreign ABs – e.g. anti-streptococcal ABs against
endocardium and myocardium
 Mutation of immunocompetent cells

3) Give some examples of tissue/organ specific and systemic autoimmune

diseases

Tissue/organ specific Systemic

DM type I Rheumatoid arthritis
Grave’s disease Systemic lupus
Goodpasture syndrome Mixed CT diseases
Atrophic gastritis and pernicious anaemia
 Myasthenia gravis

4) Define the terms central and peripheral tolerance

 Central tolerance (AKA –ve selection) = elimination of self-reactive T and B
cells (in thymus or bone marrow)
 Peripheral tolerance = deletion/inactivation of autoreactive T/B cells that
escaped elimination in central lymphoid organs (thymus/bone marrow)

5) Describe the mechanisms of central and peripheral tolerance

Central tolerance

B cell tolerance

Immature B cells in bone marrow undergo –ve selection when they bind self
peptides. Main outcomes of autoreactivity of BCRs:

 Apoptosis (clonal deletion)

 Receptor editing = the self-reactive B cell changes specificity by rearranging
genes and develops a new BCR that doesn’t respond to self – gives the B
cells a change for editing the BCR before its signalled to apoptose or become
anergic
 Induction of anergy (functionally inactivated – a state of non-reactivity)

T cell tolerance

T cell tolerance occurs in the thymus. They undergo +ve and –ve selection. TCRs
must have the ability to recognise self MHC molecules w/bound non-self peptide.

 If the maturing T cell is able to bind to a surface MHC molecule in the thymus,
it undergoes +ve selection i.e. evades apoptosis, and depending on whether
the T cell binds MHC I or II, it will become a CD8+ or CD4+ T cell,
respectively
 -ve selection = during –ve selection, T cells are tested for their affinity to self.
If they bind a self peptide, then they are signalled to apoptose
 T cells that don’t bind self, but do recognise Ag/MHC complexes, and are
either CD4+/CD8+, migrate to secondary lymphoid organs as mature naïve T
cells

Peripheral tolerance

 Clonal deletion and Treg conversion = immature dendritic cells acquire an Ag

from the peripheral tissues and present it to the naïve T cells in the secondary
 lymphoid organs. If the T cell recognises the Ag, it is either deleted or
converted to Treg
 Suppression = suppression of self-reactive effector T cells by Tregs. Those
generated in the thymus are natural Tregs and those generated in the
periphery are induced Tregs
 Induced anergy = T-cells can be made non-responsive to Ag’s presented if
the T-cell engages an MHC molecule on an APC (signal 1) w/out engagement
of co-stimulatory molecules (signal 2)

6) What are Treg cells?

Regulatory T cells (Treg or Tregs) modulate the immune system, maintain tolerance to
self Ag’s, and prevent autoimmune disease. They are immunosuppressive and
general suppress/downregulate induction and proliferation of effector T cells

23 - Immunodeficient states. Primary immunodeficiency diseases

1) Define the term immunodeficiency and differentiate between primary

and secondary types
 Immunodeficiency = when the immune response is compromised or entirely
absent
 Primary immunodeficiency = congenital/inherited
 Secondary = acquired, due to another disease/syndrome

2) Describe B cell deficiency

 Affects AB production and humoral immunity
 Clinical manifestations = ↑ risk of pyogenic infections, including those cause
by S.pneumoniae, H. influenza, S. aureus; respiratory infections; otitis

Transient hypoagammaglobulinaemia of infancy

 IgG is the only Ig passed through the placenta to the fetus. After birth IgG
levels gradually ↓, however they start to build back up throughout the first
months of life
 In this disease, infants >6 months have significantly low IgG due to delayed
maturation of B cells.
 This isn’t severe as IgA and IgM are normal and thus provide protection.
Transient condition = usually resolves by 2-4 years of age

X-linked agammaglobulinaemia (Bruton’s disease)

 XR inheritance
 B cell maturation is halted early due to mutations in a tyrosine kinase enz. = Ig
light chains are not produced
  Disease becomes apparent after 6 months when IgG levels are ↓ → ↑ in
bacterial infections
 Lab results show Ig’s are absent. Treatment = systemic application of gamma
globulin

Selective IgA deficiency

 Lack of IgA in the body due to blocking in the pathway that promotes
differentiation of mature B cells to IgA-secreting plasma cells
 IgM and IgG levels are normal
 Infections of respiratory tract and GI tract occur
 Most sufferers are asymptomatic, however weakened defence can lead to
predisposition to recurrent sinopulmonary infections and diarrhoea

Hyper IgM immunodeficiency

 High IgM levels, low IgG and IgA

 XR inheritance
 Results in recurrent pyogenic infections, otitis media, sinusitis, pneumonia

3) Describe T cell deficiency

T cell populations (mainly CD4+ helper and CD8+ killer T cells) are responsible for:

 Protection against fungal, protozoan, viral, and intracellular bacterial infections

 Control of malignant cell proliferation
 Coordinating the overall immune response

Clinical manifestations = severe infections; defects in TCRs, activation of T cell

process or secretion of cytokines

DiGeorge syndrome

 Due to microdeletion on chromosome 22 during 12 th month of gestation

 Failure in development of thymus and parathyroid glands, and congenital
defects of the head, neck, and/or heart
 T cells are absent in lymph nodes, spleen, and peripheral blood
 Transplant of thymus tissue can be helpful

4) Describe combined immunodeficiency (B and T cells)

 Occurs due to mutations in 1/> genes that regulate lymphocyte proliferation
and/or maturation. It includes genes that affect TCRs, cytokine production and
MHCs
 Result = altered communication between T and B cells and of immune
response e.g. ADA mutation: gene which encodes for adenosine deaminase –
involved in purine metabolism
 5) Describe defects of the complement system

Hereditary angioneurotic oedema

 Deficit of C1 esterase inhibitor – enz. that inhibits the protein cleavage

cascade
 Uncontrolled activation of complement = liberation of kinins → VD → oedema
of airways and face → asphyxia → death

6) Describe defects of phagocytes

 Defect in phagocyte oxidase (NADPH oxidase) enz. = can cause chronic
granulomatous disease
 Defects in integrins and selectin ligands = causes leukocyte adhesion
deficiencies

24 - Immunodeficient states. Acquired immunodeficiency syndrome (AIDS)

1) Explain secondary B cell immune deficiencies

 Chronic loss of Ig’s from the body
 This may be due to = nephritic syndrome (Ig’s lost in urine – generally not the
heavier IgM); enteropathies (Ig’s lost from the intestinal tract)

2) Explain secondary T cell immune deficiencies

 More common than primary T cell immune deficiencies
 Etiology = viral infections (HIV, cytomegalovirus), malignancies (Hodgkin’s
and non-Hodgkin’s lymphoma)
 Pathogenesis = direct infection of T cells
 Clinical manifestations = ↑ incidence of opportunistic infections, delayed HS
rxns

3) Define the term AIDS

Acquired Immune Deficiency Syndrome (AIDS) is an infectious disease caused by

HIV (human immunodeficiency virus) and is characterised by profound
immunosuppression w/associated opportunistic infections, malignancies, wasting,
and CNS degeneration
 4) Describe the mechanism of action of
HIV
 HIV is a ssRNA retrovirus
 HIV-1 is highly virulent, highly infective,
and has global prevalence. In
comparison HIV-2 has lower virulent
and infectivity, and is prevalent in W
Africa.
 HIV is mainly transmitted via sexual
intercourse. Women infected w/HIV
can transmit the virus to their offspring
in utero, during labour and delivery, or
through breast milk
 The virus works by entering a CD4+
cell (dendritic cells, TH, macs) and
replicating. It integrates the proviral
genome into the host, triggering viral
gene expression, creating > copies of
the virus to continue on to infect more of the organisms T cells
 This leads to systematic destruction of T cells → AIDS

5) Describe the phases in HIV infection

 Acute phase = flu-like symptoms occur; fever, fatigue, myalgia, headaches.
The high ↑ in viral replication = viral overload, ↓ CD4+ T cell count
 Chronic phase/latent period = asymptomatic; ~10 years; CD4+ T cells decline
from normal range; lymphadenopathy occurs
 Final crisis stage = CD4+ T cell levels drop too low, immune system becomes
severely compromised and causes:
 Development of opportunistic infections – recurrent bacterial
pneumonia, fungal infections
 Malignancies
 Wasting syndrome – involuntary weightloss, diarrhoea, chronic
weakness, and fever.
 Metabolic disorders – insulin resistance and diabetes; hyperlipidemia,
mitochondrial disorders

6) Describe the diagnosis and treatment of AIDS

Diagnosis = AB test – ABs against HIV

Treatment = no cure. Anti-retroviral therapy = combo of meds to slow HIV replication

and help immune system recover and fight off other infections
25 - Inflammation – etiology, phases, and main clinical signs

1) Define the term inflammation

Defense rxn of the organism and its tissues to harmful stimuli – Local activation of
innate defences caused by injury/infection.

2) Describe the etiology of inflammation

Exogenous = mechanical, physical (radiation, UV, temp.), chemical damage,

biological (viruses, bacteria)

Endogenous = immune rxns, necrosis, metabolic disorders (e.g. gout)

3) Compare acute and chronic inflammation (see Q31 for table)

Acute = initial response of the body to harmful stimuli and is achieved by the ↑
movement of plasma and leukocytes (especially granulocytes) from the blood into
the injured tissues.

Chronic = prolonged inflammation which leads to a progressive shift in the type of

cells present at the site of inflammation, such as mononuclear cells, and is
characterised by simultaneous destruction and healing of the tissue from the
inflammatory process

4) Describe the 3 phases of inflammation

Vascular phase

 Momentary VC followed rapidly by VD = ↑ vascular permeability → ↑ blood

flow causes heat and redness, and outpouring of protein-rich fluid (exudate)
into extravascular spaces
 This is a result of ↑ histamines, kinins, prostaglandins and other cytokines

Cellular phase = phagocyte migration and phagocytosis

 This phase involves delivery of leukocytes (mainly

neutrophils) to site of injury so they can perform
their normal functions
 Delivery and activation of leukocytes = adhesion
and margination, transmigration, and chemotaxis
 Margination =inflammatory cells move close
to vascular wall i.e. endothelial cells
 Rolling = on the vascular wall
 Adhesion = to the vascular wall (IL-1)
 Transmigration = diapedesis (between
endothelial cells)
  After extravasation, leukocytes (inflammatory cells) migrate to site of injury by
chemotaxis
 Once at the sight of injury = phagocytosis and cell killing
 Purulent inflammation = results in large amount of pus, consisting of
neutrophils, dead cells, and fluid.
 Abscesses = large, localised collections of pus enclosed by surrounding
tissues

Tissue repair and regeneration

5) List the main clinical signs of inflammation

 Redness = rubor
 Swelling = tumour
 Heat = calor
 Pain = dolor
 Loss of function = functio laesa

26 - Vascular changes in inflammation (phase 1 of inflammation)

1) What are the 2 vascular changes that occur?

 Changes in vascular flow and vascular diameter (calibre)
 Increased vascular permeability of microvasculature
 Outpouring of protein-rich fluid (exudate) into extravascular space
 Loss of proteins = ↓ capillary osmotic pressure and ↑ interstitial osmotic
pressure. This, couples w/an ↑ in capillary hydrostatic pressure, causes
a marked outflow of fluid and its accumulation in the tissue spaces =
swelling, pain, and impaired function
 As fluid moves out of vessels, stasis (slow blood flow) → leukocytes
emigrate and clotting of blood occurs

2) Describe the process of increased vascular flow and diameter

 Damage triggers release of pathogen/damage associated molecular proteins
(PAMPs or DAMPs)
 PAMPs or DAMPs are detected by immune cells (mainly macs, dendritic cells,
histocytes, Kupffer cells and mast cells) w/pattern recognition receptors
(PRRs)
 The immune cells then release chemicals such as histamine and serotonin
 Histamine triggers VD which ↑ blood flow → heat and redness
 This ↑ VD reduces the speed of blood flow through the aa. leading to stasis
 3) Describe the four mechanisms of increased vascular permeability

Endothelial cell contraction

 Most common cause of ↑ permeability

 Stimulated by release of histamine, serotonin, and other chemical mediators
released by immune cells that have been activated by PAMPs or DAMPs
 Instant rxn which is short lived

Direct damage to endothelium

 In cases of burns or toxins we see damage to the endothelial layer

 Effect is sustained for several hours until damage is repaired

Endothelial injury due to leukocytes

 Neutrophils adhering to the endothelium may injure it

 Effect is sustained for several hours until damage is repaired

Transcytosis

 This is the ↑ transport of fluids and

proteins through intracellular channels
 Such movement is triggered by vascular
endothelial growth factor (VEGF) which
promotes leakage

27 - Cell response in inflammation (phase 2 of inflammation)

1) Describe the process of leukocyte delivery and activation

 Margination = leukocytes accumulate and move nearer to the vascular wall
(endothelial cell) due to stasis of blood flow and dilation of blood vessels
 Rolling = cytokine release causes endothelial cells lining the vessels to
express adhesion molecules that bind to CHOs on the leukocytes. This
interaction (‘tethering’) slows their flow and causes leukocytes to roll along the
endothelial cell surface
 Adhesion = leukocytes adhere onto the vascular wall – facilitated by
complementary adhesion
molecules on the
leukocyte and endothelial
surfaces
  Transmigration (diapedesis) = a set of proteins known as PECAM-1
(platelet endothelial cell adhesion molecule 1) are responsible for helping the
leukocyte/platelets to migrate across the endothelial border and into the
interstitial fluid
 Chemotaxis = cell migration to site of tissue injury. They are guided by a
gradient of secreted chemoattractants = exogenous (bacterial Ag’s) or
endogenous (C5a, cytokines, interleukins, TNF)

2) Describe what happens after leukocyte activation

Once at the site of injury, neutrophils, monocytes, and tissue macs are activated to
perform phagocytosis

 Opsonisation of microbes by C3b and AB facilitate recognition by neutrophil

C3b and AB Fc receptor
 Receptor is activated and triggers intracellular signalling → formation of
pseudopods that engulf the microbe w/in the phagosome
 Phagosome fuses w/intracellular lysosome → phagolysosome into which
lysosomal enz. are released to kill and degrade the microbe

3) List some types of adhesion molecules

Selectins = endothelial selectins bind carbs on leukocyte transmembrane

glycoproteins. In normal cells, they aren’t expressed – only when they are activated,
by chemical mediators such as IL-1/TNF. They mediate rolling phase of
extravasation:

 P-selectins (on plasma cells)

 E-selectins (on endothelium)
 L-selectin (on leukocytes)

Integrins = involved in cellular adhesion and primarily expressed on leukocytes. They

are transmembrane adhesion glycoproteins w/α and β chains.

 LFA-1 = found on circulating leukocytes, and binds ICAM-1 and ICAM-2 on

endothelial cells
 Mac-1 = found on circulating leukocytes, and binds ICAM-1 on endothelial
cells
 VLA-4 = found on leukocytes and endothelial cells, and facilitates chemotaxis;
also binds VCAM-1

Immunoglobulins (endothelial adhesion molecules), bind to integrins on WBCs

 ICAM-1 = intercellular adhesion molecule (adhesion and transmigration)

 VCAM-1 = vascular cellular adhesion molecule (adhesion)
28 - Mediators of inflammation

1) Define the term inflammatory mediators and describe their classification

Inflammatory mediators = substances that initiate and regulate inflammatory rxns

Classification:

 Cell or plasma derived

 Based on mechanism of action = VD, VC, ↑ vascular permeability, chemotaxis
and leukocyte adhesion

2) List the cell derived inflammatory mediators

I) Vasoactive mediators (amines)

 Histamine and serotonin = cause VD, ↑ vascular permeability and swelling

 Sources = mast cells, basophils, and platelets

II) Metabolites of arachidonic acid (eicosanoids)

 Prostaglandins = induce VD and

bronchoconstriction (source = leukocytes,
platelets, and endothelial cells)
 Leukotrienes = induce smooth muscle
contraction in bronchioles,
bronchoconstriction, and ↑ vascular
permeability (source = leukocytes)
 Lipoxins = factors which inhibit inflammation =
regulatory factor of inflammation
 Eicosanoid synthesis has 2 pathways

III) Platelet activating factor (PAF) = universal

mediator

 Activates platelet aggregation

 Causes VD; ↑ venous permeability; stimulates and activates leukocyte
adhesion; involved in chemotaxis of leukocytes; activates degranulation and
production of ROS; stimulates production of prostaglandins and leukotrienes

IV) Reactive Oxygen Species (ROS)

Free radicals are released intra- and extracellularly as a result of existence of

bacterial products, chemokines (chemotaxic factors), immune complexes, and
phagocytosis
 V) Lysosomal enz. of leukocytes

 Acidic proteolytic enz. which are found in phagolysosome

 Neutral proteases released extracellularly in order to destroy pathogens
(tissue structure of organism is also destroyed due to these enz.)
 Neutrophilic elastase destroys elastic fibers of CT

VI) Cytokines and chemokines

 TNFα/TNF (Tumour necrosis factor α), IL-1 (interleukin), IL-6, IFN γ (interferon
gamma)
 TNF and IL-1 = chemokines – activate leukocytes, control migration of
inflammatory cells, activate endothelial cells to express adhesive molecules ,
activate synthesis of other cytokines from immune cells. They also deactivate
synthesis of eicosanoids and NO; and are involved in pathogenesis of fever
 IL-8 = attracts and activates
neutrophils
 MIP-1α (mac inflammatory
protein) = activates and
attracts basophils and
eosinophils (granulocytes)

VII) Neuropeptides

Substance P is a potent vasodilator

and initiates expression of almost all
cytokines.

3) List the plasma derived

inflammatory mediators

Name Produced by Description

Bradykinin Kinin system Vasoactive
C3a Complement system Cleaved to produce C3a and C3b. C3a
stimulates histamine release → VD. C3b is
able to bind to bacterial cell walls and acts as
an opsonin, which marks the invader as a
target for phagocytosis
C5a Complement system Stimulates histamine release → VD. Also acts
as a chemoattractant to direct cells via
chemotaxis to the site of inflammation
Factor XII (Hageman Liver Activated by collagen, platelets or exposed
factor) basement membranes. Upon activation, it is
able to activate kinin, fibrinolysis, and
coagulation systems (all involved in
inflammation)
MAC Complement system MAC = C5b + C6-C9. It inserts into bacterial
cell walls and causes cell lysis
Plasmin Fibrinolysis system Able to break down fibrin clots, cleave C3, and
activate factor XII
Thrombin Coagulation system Cleaves fibrinogen to produce fibrin, which
aggregates to form a blood clot.

29 - Metabolic changes and proliferative processes during inflammation

1) Describe the metabolic changes that occur during inflammation

Metabolic acidosis

 Through inflammatory process

 Worn-out tissue damaged by trauma/infection is broken down and recycle for
replacement w/fresh tissue
 Increasing levels of harmful MOs caused by acidosis can lead to inflammation
 Corrosive nature of acids can damage tissue and organs thus causing
inflammation
 Acidosis also ↑ free radical production which makes inflammation worse

Hyperkalaemia

Leakage of K+ → hyperkalaemia at site of inflammation due to tissue damage =

abnormal ↑ levels of K+ in blood → abnormal heart rhythms.

Catabolic effects = breakdown of proteins

Metabolism of leukocytes generates free radicals

2) Describe the proliferative processes during inflammation

The stages in wound healing = haemostasis (blood clotting), inflammation,

proliferation (growth of new tissue), and maturation (remodelling).

About 2/3 days after the wound occurs, fibroblasts begin to enter the wound site,
marking the onset of the proliferative phase even before the inflammatory phase has
ended.

Angiogenesis (AKA neovascularisation)

Formation of new blood vessels in the region by endothelial cells, which are attracted
to the wound area by fibronectin

Fibroplasia and granulation tissue formation

 Fibroblasts proliferate and migrate towards the wound, forming granulation

tissue (a rudimentary tissue that appears 2-5 days post wound)
 Controlled by growth factors PDGF and TGF-β (transforming growth factor β)
  These fibroblasts synthesise and deposit collagen (type III). Collagen
deposition is important because it increases the strength of the wound.

Epithelialisation

 This occurs after granular tissue has been laid down

 Basal keratinocytes are responsible for the epithelialisation phase
 Occurs above granular tissue, but below a scab, if one was formed

Contraction

The wound contracts upon itself due to the action of myofibroblasts (differentiated
fibroblasts) contraction. It occurs 5-15 days post wounding, can last for several
weeks, and continues even after the wound in completely reepithelialised

30 - Types of inflammation. Development, going out, and biological

significance of inflammation

1) Describe the classification of inflammation

Based on the duration of inflammation = acute or chronic

Based on the morphologic patterns:

 Granulomatous = formation of granulomas; result of TB, leprosy, sarcoidosis,

and syphilis
 Fibrinous = exudate w/fibrin and fibrinogen
 Purulent = exudate has pus (consists of neutrophils, dead cells, and fluid);
infection is by pyogenic bacteria (staphylococci)
 Serous = clear-fluid exudate, no protein mass
 Haemorrhagic = exudate contains blood

2) Describe the development of inflammation

Development takes the form of resident immune cells (macs, dendritic cells,
histocytes, and mast cells) which initiate inflammation via their pattern recognition
receptors (PRRs) which recognise the pathogen-associated molecular patterns
(PAMPs) and damage-associated molecular patterns (DAMPs).

 At the onset of an infection, burn, or other injuries, these cells undergo

activation (one of the PRRs recognize a PAMP or DAMP) and release
inflammatory mediators responsible for the clinical signs of inflammation.
 VD and its resulting ↑ blood flow cause the redness (rubor) and ↑ heat (calor).
  ↑ Permeability of the blood vessels results in an exudation (leakage) of
plasma proteins and fluid into the tissue (oedema), which manifests itself as
swelling (tumour).
 Some of the released mediators such as bradykinin ↑ the sensitivity to pain
(hyperalgesia, dolor).
 The mediator molecules also alter the blood vessels to permit the migration of
leukocytes, mainly neutrophils and macs, outside of the blood vessels
(extravasation) into the tissue. The neutrophils migrate along a chemotactic
gradient created by the local cells to reach the site of injury.

3) Explain the biological significance of inflammation

 It is a typical pathological process – body’s response to injury and is
characterised by the elaboration of chemical mediators and movement of fluid
and leukocytes from the vascular compartment into the extravascular tissue
space
 By increasing blood flow to the region, ensuring macs move into the interstitial
when the injurious agent is found, and is simultaneously activating the body’s
immune response at a systemic level, inflammation can be seen as an
efficient and effective mechanism for healing

4) Describe the systemic effects of inflammation

 Sepsis = when the body’s response to infection causes injury to its own
tissues and organs. Causative agent is infection
 Bacteremia = bacterial sepsis
 Viremia = viral sepsis
 VD and organ dysfunction are serious problems associated w/widespread
infection that may lead to septic shock and death

Acute phase proteins

Inflammation also induces high systemic levels of acute-phase proteins. In acute

inflammation, these proteins prove beneficial; however, in chronic inflammation they
can contribute to amyloidosis. These proteins include C-reactive protein (CRP),
serum amyloid A, and serum amyloid P, which cause a range of systemic effects
including fever, ↑ bp, ↓ sweating, malaise (general discomfort/pain), loss of appetite,
and drowsiness

Leukocyte numbers

Leukocytosis is often seen during inflammation induced by infection, where it results

in a large increase in the amount of leukocytes in the blood, especially immature
cells. Bacterial infection usually results in an ↑ of neutrophils (neutrophilia) whereas
diseases such as asthma, hay fever, and parasite infestation result in an ↑ in
eosinophils, (eosinophilia)
 31 - Chronic inflammation

1) Define the term chronic inflammation

Prolonged inflammation which is characterised by simultaneous destruction and

healing of the tissue from the inflammatory process

2) Describe the etiology and characteristics of chronic inflammation

Etiology = persisting infection, prolonged exposure to toxic stimuli, and altered

immune tolerance (autoimmune disorders)

Characteristics:

 Infiltration w/mononuclear cells (macs, lymphocytes, plasma cells)

 Tissue destruction (caused by inflammatory cells)
 Proliferative process (CT repair involving angiogenesis and fibrosis)

3) Which cells predominate in chronic inflammation

 Macs are the main cells. they are derived from circulating monocytes in the
blood → move into tissues where they differentiate into macs
 They perform phagocytosis; initiate process of tissue repair; involved in scar
formation and fibrosis
 They secrete inflammatory mediators – TNF, IL-1, chemokines
 They display Ag’s to T lymphocytes and respond to signals from T cells.
activated T cells will then produce cytokines that activate macs, ↑ Ag
presentation and further cytokine production
 Other cells include = lymphocytes, mast cells, and eosinophils

4) Compare acute and chronic inflammation

Acute Chronic
Causative agent Bacterial pathogens, injured tissues Persistent acute inflammation due
to non-degradable pathogens,
viral infection, persistent foreign
bodies, or autoimmune rxns
Major cells Neutrophils (primarily), basophils Mononuclear cells (monocytes,
involved (inflammatory response), and macs, lymphocytes, plasma cells),
eosinophils (response to helminths fibroblasts
and parasites), mononuclear cells
(monocytes and macs)
Primary mediators Vasoactive amines, eicosanoids IFNγ and other cytokines, growth
factors, ROS, hydrolytic enz.
Onset Immediate Delayed
Duration Few days Up to many months/years
Outcomes Resolution, abscess formation, chronic Tissue destruction, fibrosis,
inflammation necrosis
32 - Fever – etiology and pathogenesis

1) Define the term fever

↑ in body temp due to a higher set point of the thermoregulatory centre in the
hypothalamus caused by pyrogens

2) What is the body’s normal thermoregulatory set point?

The thermoregulatory centre is in the preoptic area of the hypothalamus – it

regulates heat production and heat loss so that a normal body temperature is
maintained.

The thermoregulatory set point = level at which body temp is regulated so the core
temp is maintained w/in normal range (normal = 36.5 – 37.5°C).

3) List some features that can affect body temp

 Place of measurement = measurement from the rectum can be up to 0.6°
higher than the axillary temp
 Ovulation – 2 weeks before ovulation, temp is lower, temp ↑ during ovulation
 Seasonal variations – associated w/metabolic changes
 Postprandial (after meal) elevation
 Pregnancy

4) Describe the etiology of fever

Fever is caused by pyrogens (a substance that induces fever). These can be either
endogenous (internal) or exogenous (external). Pyrogenicity can vary: In extreme
examples, some bacterial pyrogens known as super-Ag’s can cause rapid and
dangerous fevers. Depyrogenation may be achieved through filtration, distillation,
chromatography, or inactivation

Endogenous

 Endogenous pyrogens are cytokines, molecules that are a part of the immune
system. They are produced by activated immune cells and cause the ↑ in the
thermoregulatory set point
 Major = IL-1 and IL-6
 Minor = IL-8, TNF, IFNγ, and MIP1α and MIP1β (mac inflammatory protein)
 Cytokines are released into general circulation → migrate to brain → bind
w/endothelial receptors on vessel walls, or interact w/local microglial cells.
 When these cytokines bind, the arachidonic acid pathway is then activated
Exogenous

 Examples = LPS (lipopolysaccharide) lipoproteins, bacterial endotoxins

 Lipopolysaccharide-binding protein (LBP) binds to LPS → this complex then
binds to CD14 receptor of a nearby mac → results in synthesis and release of
various endogenous cytokines such as IL-1, IL-6, and TNF α
 In other words, exogenous pyrogens cause release of endogenous pyrogens,
which, in turn, activate the arachidonic acid pathway.

5) Describe the pathogenesis of fever

 Exogenous factors will trigger the release of the endogenous factors.
 Endogenous factors travel through the blood stream to the ant. hypothalamus
(preoptic area) and induce prostaglandin E 2 (PGE2), which is a metabolite of
arachidonic acid
 PGE2 binds to receptors in the hypothalamus to induce ↑ in thermoregulatory
set point through cAMP.
 The arachidonic acid pathway (which produces PGE 2) is mediated by
the enz. phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and
PGE2 synthase. These enz. ultimately mediate synthesis and release
of PGE2
 In response to ↑ in set point, hypothalamus initiates shivering and VC that
raise the body’s core temp to the new set point, and fever is established
 Exogenous pyrogens, via vagus n., can activate solitary tract nucleus →
activates noradrenergic n. fibers → activated COX enz. → ↑ set point

6) Describe the mechanisms of fever

 Release of PGE2 from inflammatory cells
 Resetting of thermoregulatory set point in hypothalamus to a higher level
 Generation of hypothalamic-mediated responses to raise body temp =
shivering (mechanical thermogenesis), VC (< heat loss), piloerection (hairs
stand up), ↑ metabolism
 Development of fever w/elevation of body to new thermostatic set point
 Produce of temp reducing-responses (VD, sweating, ↑ ventilation) and return
of body temp to lower level
33 - Stages of fever. Types of temperature curves

1) Describe the stages of fever

Prodrome stage

Non-specific complaints = mild headache, fatigue, malaise (general discomfort), and

fleeting aches and pains

Increment stage (AKA chill)

 VC and piloerection → goosebumps

 Feeling cold and onset of generalised shaking (rigors), even though ↑ in body
temp (PGE2 mediated)
 Heat production > heat loss

Fastigial stage (AKA stable stage, or flush)

 Cutaneous VD occurs and the skin becomes warm and flushed

 Body temp reaches the new set point
 Heat production = heat loss, but the set point is higher
 ↑ α waves in electro-encephalogram – brain functions are inhibited
 Hallucination/fever delirium – due to ↑ permeability of the BBB and ↑ levels of
endorphins in CSF
 Febrile fits (young children and infants) = headache, arthralgia, continued
tachycardia, tachypnoea but ventilation rate remains the same, ↑ utilisation of
vit C and B vitamins (only 5% develop – need genetic disposition)

Decrement stage

 Endogenous pyrogens ↓, set point returns to normal, ↓ PGE 2 = body temp ↓

 Heat loss > heat production
 VD, sweating, ↓ bp, heart rate returns to normal
 2 types of decrement:
 Lytic = slow ↓ of temp, takes days, gradual = > favourable
 Crisis = rapid ↓ of temp (hours), achieved by severe peripheral dilation
and excessive sweating.
 Dangers of crisis = causes rapid ↓ in bp which can cause people to
collapse (dangerous for those w/congestive heart failure). If coupled
w/dehydration, the blood becomes > viscous
 2) Describe the different types of temperature curves

Type Description Etiology

Intermittent Temp returns to normal every day
Remittent Temp doesn’t return to normal and
fluctuates > 1°C in 24h
Continuous/sustained Temp doesn’t return to normal
BUT doesn’t fluctuate > 1°C in 24h
Relapsing Temp returns to normal for a few
days before ↑ again
Pyogenic infection, lymphoma,
malaria,
Infective endocarditis,
Typhoid, meningitis, UTI, lobar
pneumonia
Malaria (3 day pattern),
Hodgkin’s lymphoma

34 -
Metabolic and functional changes during fever. Biological significance of fever

1) Describe the metabolic changes during fever

 Carb metabolism = ↑ glycogenolysis → ↓ of glycogen stores = hypoglycaemia,
loss of appetite due to TNF (normal glycogen in muscles and liver = 150-
160g)
 Hypoglycaemia leads to hyperlipidaemia and activation of β oxidation and
excess production of ketone bodies → acetone in urine → metabolic
acidosis/ketosis
 Protein metabolism = ↑ breakdown of proteins due to TNF and IL-1
 Dehydration due to excess sweating, loss of Na + (electrolyte imbalance)

2) Describe the functional changes during fever

General:

 Loss of appetite (TNF), fatigue, insomnia

 ↑ leukocyte, along w/↑ in acute phase proteins (CRP, fibrinogen, SAA)
  Herpes = caused by type 1 HSV that established latency in regional ganglia
and is reactivated by ↑ in body temp

Systemic effects:

 CVS = tachycardia (w/each ↑ of temp by 1°C = ↑ heart rate at 10 bpm);

hypotension (especially during stage 3 due to VD)
 Respiratory system = hyperventilation → dehydration occurs due to water loss
(evaporation from lungs)
 GI system = loss of appetite (due to ↑ temp), nausea, vomiting,
diarrhoea/constipation (due to ↓ motility of GI tract)
 CNS = somnolence (drowsiness), insomnia (due to headache), at very high
temps = seizures due to endogenous pyrogens (especially in children and
epilepsy patients)
 Urinary system = oliguria (↓ urine output) or polyuria
 Endocrine = ↑ in catecholamines (adrenaline and noradrenaline) shifts body
metabolism to heat production rather than E generation; ↑ thyroid hormones
(T3 and T4) = ↑ heat production

3) Describe the biological significance of fever

Favourable (adaptive):

 ↑ in temp makes the body a < favourable host for viruses and bacteria
 Stimulates immune system - ↑ immune response = ↑ phagocytosis. This
inhibits bacterial and tumour cell growth
 ↑ elimination of pathogenic agents causing fever due to ↑ phagocytosis and
inhibited bacterial growth

Unfavourable:

 ↑ O2 consumption
 ↓ body mass (due to ↑ catabolic effects)
 General and systemic disorders
 Hyperpyrexia = fever > 40/41 – due to severe infections e.g. sepsis.
Antipyretics are effective (< production of PGE2, cold wraps can cause VC
and decrease dissipation and heat loss

4) What are cryogens?

Endogenous cryogens = substances that ↓ body temp – ADH, α-MSH (melanocyte

stimulating hormone), lipocortin, CRH (corticotropin releasing hormone)

5) Describe the therapeutic approach to fever

Etiological approach = antibiotics (treat infections), and steroids (suppress immune
response)

Systematic approach:

 NSAIDs (Non-Steroidal Inflammatory Drugs) = inhibit COX enz. – involved in

synthesis of PGE2 which causes ↑ in body temp e.g. = aspirin, ibuprofen
 Corticosteroids = inhibit PLA2 → < PGE2. They also block transcription of
mRNA of pyrogenic cytokines
 Glucose infusions prevent metabolic acidosis

6) Define the term hyperthermia and describe its pathogenesis

 Hyperthermia = ↑ in body temp w/no change of set point. Temp ranges
between 37.5-38.3°C
 Cause = ↑ heat production and ↓ heat loss; excessive environmental heat
 Heat stroke = core temp > 40.5, brain temp ↑, cerebral oedema, death
 Heat collapse = VD, sweating → dehydration, ↓ cardiac output and bp →
weak and nausea

7) What is malignant hyperthermia? Describe its pathogenesis

Genetic mutation of sarcoplasmic Ca2+ transport (ryanodine receptor) = uncontrolled

muscle contraction → ↑ E consumption → lactic acidosis → VD, ↑ bp, ↑ temp → ↑
core temp → irreversible brain damage (acidosis)

35 - Red blood cell disorders. Classification of anaemias

Function of bone marrow = hematopoiesis and

maturation of blood cells. also has emission
function – release of mature RBCs into
peripheral circulation

All blood cells are derived from pluripotent

stem cells, which undergo differentiation into:

 Common myeloid progenitors = RBCs,

platelets, mast cells, granulocytes
(leukocytes), macs/monocytes
 Common lymphoid progenitors = NK
cells, T lymphocyte, plasma cells
(differentiated B lymphocytes)
 1) Describe the term anaemia

Anaemia = a ↓ in the total amount of RBCs or Hb in the blood – lowered ability of the
blood to carry O2. Main causes are due to blood loss, ↓ RBC production, and ↑ RBC
destruction

2) Describe the signs and symptoms of anaemia

 Eyes = yellowing (jaundice - ↑ breakdown of Hb which leads to ↑ levels of
unconjugated bilirubin)
 Skin = pale, cold, yellow (jaundice)
 Respiratory = SOB
 CVS = palpitations, tachycardia, hypotension.
In severe anaemia = chest pain, angina, MI
 Central = fatigue, dizziness. In severe
anaemia = fainting
 Spleen = splenomegaly
 Muscular = weakness
 GI = achlorhydria (↓ levels of gastric acid),
changed stool colour

3) Describe the 3 RBC parameters

Hb conc .
 MCH (mean cell Hb) = mean Hb mass/RBC. (g/ RBC )
N . o RBC
 Normal = 30 pg; < 30 = hypochromic; > 30 = hyperchromic
Hct
 MCV (mean cell vol.) = mean volume of 1 RBC). (L/ RBC)
N . o RBC
 Normal = 90 fl; < 90 = microcytic; > 90 = macrocytic
Hbconc .
 MCHC (mean cell Hb conc.) = mean Hb conc. in RBCs. ( g /L RBC )
Hct
 Normal = 320 g/L
 MCHC = MCH/MCV

4) Describe how we classify anaemia based on cell morphology

 Size - Anisocytosis = different sizes of the RBCs
 Normocytes = 5-7 μm
 Microcytic = < 5 μm
 Macrocytic = > 7 μm
 Shape – Poikilocytosis = different shapes of the RBCs
 Normal shape = biconcave disc
 Acanthocyte = hedge-hog shaped RBC – seen in haemolytic anaemia
 Keratinocytes (horn) seen in G6PD anaemia
  Spherocytes = spherocytic anaemia
 Dacrocyte = tear drop cells – seen in leukaemia
 Schistocyte/schizocyte = fragmented RBC – haemolytic anaemia
 Colour – Polychromasia = different colours of the RBCs
 Hypochromic
 Hyperchromic

5) Describe the other ways to classify anaemia

Anaemia can also be classified by the underlying pathophysiological mechanism

Haemorrhagic anaemia

 Acute = caused by sudden blood loss (trauma), may see ↓ Hct hours after the
event. Reticulocytes (immature RBCs) are released in the coming days to ↑
RBC numbers
 Chronic = caused by chronic blood loss from locations such as GI and
urogenital tracts. Body is unable to produce Hb at the required level due to
insufficient Fe

Deficiency anaemia

 Vitamin B12
 Iron deficiency

Aplastic anaemia (bone marrow defect)

 Bone marrow defect leads to a ↓ of levels of all blood cells

 Etiology = ionising radiation, viral infections, toxic factors, metastasis
 Symptoms = tiredness, pale skin, tachycardia, ↑ risk of bleeding (low
platelets), ↑ risk of infections (low WBCs)
 Diagnosis = patient has pancytopenia (↓ RBC, leukocyte, and thrombocyte
count). Confirmed on bone marrow biopsy/aspiration

Haemolytic anaemia (↑ RBC destruction)

 Can be intravascular or extravascular (in the spleen)

 Can be intrinsic to the RBC (e.g. genetic defect) or extrinsic (e.g. viral)
 Sickle cell anaemia = e.g. of intrinsic RBC membrane defect. Genetic defect
leads to cells being sickle shaped - ↓ O2 carrying capacity
 G6PD = e.g. of enz. defects. This enzymopathy results in higher levels of free
radical production w/in RBCs, leading to intra- and extravascular haemolysis
 Etiology = membrane defects (often leads to spherocytic anaemia),
haemoglobinopathies, enz. defects
 Symptoms = often have jaundice and hepatosplenomegaly
  With intravascular haemolysis we may see haemoglobinuria, as bits of
destroyed RBCs are filtered in the glomeruli – this may lead to secondary
renal failure

36 - Iron deficiency anaemia

1) What is iron-deficiency anaemia? List the symptoms

Iron-deficiency anaemia = caused by a lack of iron. Symptoms include:

 Non-specific symptoms – pallor, fatigue, weakness, headache

 ↓ appetite, dysphagia
 Koilonychias (spoon-shaped nails) or brittle nails
 SOB, angina, palpitations

2) Describe the etiology

 Blood loss – GI bleeding or ↑ menstrual bleeding (heavy periods)
 Diet = Fe uptake is too low (↓ Fe intake) – malnutrition
 Iron malabsorption = reduced due to achlorhydria; and malabsorption in
diseases of the upper SI or in the presence of Fe-binding food components
(phytamine in cereals and veg)
 ↑ Fe requirement = growth (children), pregnancy, breast feeding
 Parasitic disease = helminths, specifically hookworms

3) Describe the pathophysiological mechanism

 When the body has enough Fe to meet its needs, it stores the rest in the bone
marrow and liver in ferritin complexes
 Fe is an important component of Hb. 70% of the Fe is bound to Hb. It is
mainly absorbed in SI and certain factors ↑ (vit C)/↓ (drugs – antacids) its
absorption
 After being absorbed, it travels through the blood, bound to transferrin, and
ends up in the bone marrow, where it’s involved in RBC formation. When
RBCs are degraded, the Fe is recycled by the body and stored.
 However small amounts of Fe are lost in faeces and need to be replaced by
dietary intake. Fe balance is maintained by absorption of 0.5-1.5 mg daily to
replace 1 mg lost in faeces
 When the amount of Fe needed by the body is > than the amount that’s
available, the body can use Fe stores (ferritin) for a short period of time and
RBC formation continues normally.
 As these stores are used up, Fe is eventually depleted to the point that RBC
formation is abnormal → anaemia

4) Describe the diagnosis

 Change Parameter
↓ Ferritin, Hb, MCV, MCH, serum Fe
↑ Total Fe-binding capacity, transferrin, RBC distribution width

 Microcytic hypochromic anaemia develops - ↓ n.o of RBCs (microcytic) and ↓

Hb present (hypochromic)
 The RBCs have irregular shape (poikilocytosis) and size (anisocytosis)

37 - Pernicious anaemia

1) Define the term pernicious anaemia. List the symptoms

Megaloblastic anaemias are caused by impaired DNA synthesis that results in

enlarged RBCs due to impaired maturation and division. Vit B 12 and folic acid
deficiencies are the most common conditions associated w/megaloblastic anaemias.

Pernicious anaemia = anaemia that results from a lack of intrinsic factor (required for
the absorption of vit B12)

Symptoms are similar to the ones mentioned in the above syllabus points.
Additionally paresthesia (tingling in hands and feet) and polished tongue may be
present.

2) Describe the etiology

 Atrophic gastritis = destruction of gastric mucosa and loss of parietal cells.
Also production of AB to intrinsic factor and parietal cells
 Vit B12 must be obtained from the diet. It is absorbed in the ileum after
binding to intrinsic factor. Intrinsic factor is produced by parietal cells of
the gastric mucosa and the intrinsic factor-B12 complex is absorbed by
receptors on the ileum epithelial cells
 Pernicious anaemia is characterised by B12 deficiency caused by the
absence of intrinsic factor
 Impaired B12 absorption following gastrectomy or gastric bypass surgery –
parts of the stomach that produce gastric secretions are removed/bypassed =
intrinsic factor isn’t available
 However B12 deficiency following gastric surgery isn’t usually a clinical
issue because the body stores many years’ worth of B 12 in the liver and
patients are adequately supplemented w/the vitamin
 Ileal resection
 Inflammation or neoplasms in ileum

3) Describe the pathophysiological mechanism

 Vit B12 (AKA cobalamin) = serves as a cofactor

 DNA synthesis and nuclear maturation, which in turn leads to normal RBC
maturation and division. Lack of B12 → abnormally large RBCs produced due
to excess cytoplasmic growth and structural proteins. The cells have
immature nuclei, flimsy membranes and are oval = short life span (weeks)
 Myelin synthesis (prevents abnormal FAs from being incorporated into
neuronal lipids) → impairment of myelinisation of n. fibers – neurological
disorders (loss of vibration and position sense, spastic ataxia)

4) Describe the diagnosis

 Megaloblastic (big size), hyperchromic (↑ Hb) anaemia develops
 Blood smear shows large, fragile, immature RBCs (megaloblasts). Ovalocytes
are also seen and a characteristic feature of megaloblastic anaemias is
hypersegmented neutrophils
 ↓ serum levels of vit B12, detection of parietal cell and intrinsic factor ABs
 Treatment w/i.m injections of cobalamin in the forms of cyano-, hydroxo- or
methylcobalamin

38 - White blood cell disorders. Leukocytosis and leucopenia. Cyclic

neutropenia

WBCs = granulocytes and agranulocytes

 Granulocytes = neutrophils (phagocytes), eosinophils, and basophils –

polymorphic nuclei w/2/> lobes
 Agranulocytes = monocytes (large, round nucleus – tissue macs) and
lymphocytes (B and T)

Normal WBC range = 4-11 x 109/L

1) Define the term leukocytosis and leukopenia

Leukocytosis = ↑ in the n.o of WBCs (leukocytes) found in the blood

Leucopenia = ↓ in the n.o of WBCs (leukocytes) found in the blood

2) Describe the etiology of these diseases

Leukocytosis

Type Cause
Neutrophilic leukocytosis  Acute bacterial infections, esp. pyogenic infections
(neutrophilia)  Sterile inflammation
  Tissue necrosis (infiltration w/inflammatory cells) – e.g. MI
or burns
Eosinophilic leukocytosis  Allergic disorders = asthma, hay fever, drug allergies,
(eosinophilia) allergic skin diseases
 Parasitic infections
 Some forms of malignancy = Hodgkin’s lymphoma, and
some forms of Non-Hodgkin’s lymphoma
 Systemic autoimmune diseases
 Some forms of vasculitis
Basophilic leukocytosis Rare. Often indicative of myeloproliferative diseases – e.g. CML
(basophilia)
Monocytosis  Chronic infections = TB, bacterial endocarditis,
rickettsiosis, malaria
 Systemic autoimmune diseases
 Inflammatory bowel diseases = ulcerative colitis
Lymphocytosis  Chronic infections = TB, brucellosis
 Viral infections = hepatitis, cytomegalovirus
 Pertussis
 Some forms of malignancy – lymphocytic leukaemias

Certain meds, including corticosteroids, lithium, and β agonists, may cause

leukocytosis.

The mechanism that causes leukocytosis can be of several forms:

 ↑ release of leukocytes from bone marrow storage pools

 ↓ margination of leukocytes onto vessel walls
 ↓ extravasation of leukocytes from the vessels into tissues
 ↑ in number of precursor cells in the marrow

Leucopenia

Divided into lymphopenia and neutropenia (AKA agranulocytosis)

 Lymphopenia = ↓ n.o of lymphocytes, can be congenital or acquired, very

rare, immune deficiency states – e.g. Bruton’s disease , HIV
 Neutropenia = can be congenital (primary) or acquired (secondary)

Causes

 Acute viral infections – influenza, cold

 Has been associated w/chemo, radiation therapy, myelofibrosis, aplastic
anaemia, stem cell and bone marrow transplants, HIV/AIDS, and steroid use
 Certain meds – certain anti-psychotics, anti-convulsants, immunosuppressive
drugs, chemo.

↓ /ineffective production ↑ destruction

Suppression of myeloid stem cells – e.g. in aplastic
anaemia, infiltrative disease of bone marrow → results
in anaemia, thrombocytopenia, agranulocytosis
Suppression of granulocyte precursors, drugs
Ineffective granulopoiesis (myelodysplastic syndromes)
Rare inherited syndromes (Kostman’s syndrome –
defect in specific genes = altered differentiation and
maturation of granulocytes)
Immune mediated destruction (idiopathic)
– e.g. type 2 HS rxn
↑ sequestration in spleen (splenomegaly)
↑ peripheral consumption (severe
bacterial, fungal infection)
↑ transmigration (blood → perivascular
space)

3) What is cyclic neutropenia?

 It is a form of congenital (childhood onset) neutropenia that tends to occur
every 3 weeks and lasts 3-6 days at a time due to changing rates of cell
production by the bone marrow
 It is often present among several members of the same family
 AD inheritance of mutations in ELA2 gene – encodes neutrophil elastase
 Treatment = G-CSF (granulocyte colony-stimulating factor) and usually
improves after puberty

39 - Lymphoma and acute myelogenous leukaemia

1) Define the term lymphoma and describe the classification

Lymphoma = malignant proliferation of lymphoid cells in the lymph nodes.

Classification systems generally classify lymphoma according to:

 Whether or not it is a Hodgkin lymphoma

 Whether the replicating cell is a T or B cell
 The site from which the cell arises

Hodgkin lymphoma (HL)

 Accounts for about 15% of lymphomas

 Presence of distinctive neoplastic ‘Reed-Sternberg cells’
 Occurs in early childhood or late adulthood
 Arises from a single node/chain of nodes → spreads to contiguous
(bordering/touching) lymphoid tissues
 Has distinctive morphological features = large, atypical, mononuclear tumour
cells (Reed-Sternberg cells) – release factors that induce accumulation of
reactive lymphocytes, macs, and granulocytes
 Etiology = largely unknown, but exposure to carcinogens and viruses, as well
as genetic predisposition
  Classification:
 Nodular lymphocyte-predominant HL = nodular growth pattern,
localised, slow progression, high survival rate (80%)
 Classic HL = clonal proliferation of mononuclear Hodgkin’s cells and
multinucleated Reed-Sternberg cells. 4 types = nodular sclerosing
(most common in adolescent and young adult F), mixed cellularity,
lymphocyte rich, and lymphocyte depleted.

Non-Hodgkin’s lymphoma (NHL)

 Accounts for 95% of lymphomas. General onset = >65

 Etiology = largely unknown, but impairment of immune system and infectious
agents play a role
 Can start in almost any body part (unlike HL which starts in a single node) and
spreads early to various lymph tissue throughout the body
 They can originate from malignant transformations of either T or B cells during
their differentiation in peripheral lymphoid tissues
 B and T cell lymphomas can spread to various lymphoid tissue throughout the
body, especially the liver, spleen, and bone marrow
 Mature B cell lymphomas are the most common type of lymphoma in the west
 There are many subtypes but generally they are aggressive and have slow
development

Hodgkin’s lymphoma Non-Hodgkin’s lymphoma

Localised to a single group of nodes
Starts in a single node
Orderly, stepwise spread
Mesenteric nodes and Waldeyer’s ring are
rarely involved
Frequent involvement of multiple nodes
Can start in almost any body part
Non-orderly spread
Mesenteric nodes and Waldeyer’s ring are
commonly involved

2) Describe the symptoms and diagnosis of lymphomas

Symptoms

 Lymphadenopathy (swelling of lymph nodes)

 B symptoms (systemic symptoms) – can be associated w/both HL and NHL =
fever, night sweats, weight loss
 Other symptoms = loss of appetite/anorexia, fatigue, respiratory
disease/dyspnoea, and itching

Diagnosis = lymph node biopsy. After diagnosis, tests can be carried out to look for
specific features characteristic of different types of lymphoma = immunophenotyping,
flow cytometry, FISH

3) Describe the staging of lymphomas

  Stage I = cancer located in a single region
 Stage II = cancer located in 2 separate regions, and both areas are confined
to one side of the diaphragm (both above/both below)
 Stage III = cancer has spread to both sides of the diaphragm
 Stage IV = diffuse involvement of 1/> extralymphatic organs – including liver,
bone marrow, or nodular involvement of the lungs

4) Define the term leukaemia and describe its classification

Leukaemia = neoplastic proliferation of WBCs in peripheral blood

 Derived from precursor myeloid or lymphoid tissue cells

 Exact cause = unknown. A combo of genetic factors and environmental
factors are believed to play a role
 Lymphocytic leukaemias involve immature lymphocytes and their progenitors
that originate in the bone marrow but infiltrate the spleen, lymph node, CNS,
and other tissue
 Myelogenous leukaemias involve myeloid stem cell in bone marrow and
interfere w/maturation of all blood cells, including granulocytes, RBCs and
thrombocytes

Origin Acute Chronic

Lymphoid ALL CLL
Myelogenous AML CML

ALL

 Overproduction of immature WBCs (lymphoblasts) occurring in the bone

marrow, and we see a ↓ in lymphoblast quality
 Most common occurrence in childhood = 2-5 years
 Symptoms = ↑ risk of bacterial infection, dyspnoea, chest pain, tendency to
bleed and general anaemic symptoms
 Thought to be a cancerous gene affecting the lymphoblast

CLL

 Most common type of leukaemia affecting adults

 B-cells grow in uncontrolled manner and accumulate in bone marrow where
they crowd out healthy blood cells
 Results in swollen lymph nodes, spleen, and liver, eventually develop
anaemia and infections
 5 year survival rate

AML
  Cancer of myeloid line w/rapid growth of cells that build up in bone marrow
and effect other normal cell production
 Rare, treated w/bone marrow replacement therapy
 Symptoms = recurrent infections, anaemia, and frequent bleeding
 Onset = > 20 years

CML

 Gradual proliferation of myeloid cells in the bone marrow

 Linked w/genetic abnormality known as Philadelphia chromosome (due to
translocation between chromosome 9 and 22)
 Has a chronic (slow onset, nn-specific symptoms), accelerated and blast crisis
phase
 Life expectancy = 2-5 years

40 - Platelet disorders. Drug-associated immune thrombocytopenia

Hemostasis is designed to maintain the integrity of the vascular compartment. The

process is divided into 3 phases—vessel VC (reduces blood flow); platelet
adherence and formation of the platelet plug; and formation of the fibrin clot, which
cements the platelet plug together. Clot retraction, which pulls the edges of the
injured vessel together, and clot dissolution, which involves the action of plasmin to
dissolve the clot and allow blood flow to be re-established and tissue healing to take
place, are also important processes of hemostasis. Blood coagulation requires the
stepwise activation of coagulation factors, carefully controlled by activators and
inhibitors.

There are 3 broad categories of platelet disorders:

 Thrombocytopenia
 Altered platelet function = congenital (disorders of adhesion, activation, and
aggregation) and acquired (disorders of adhesion)
 Thrombocytosis = reactive, myeloproliferative neoplasms, other myeloid
neoplasms, congenital

1) Describe thrombocytopenia
 Definition = abnormally low/↓ levels of platelets (thrombocytes) in the blood
 Normal platelet count = 150,000 – 450,000 platelets/μL of blood. For
thrombocytopenia requiring emergency treatment = 50,000 platelets/μL
 Usually has no symptoms and is picked up on routine full blood count
  Signs include = external bleeding (nosebleeds, and/or bleeding gums);
bruising, particularly purpura in the forearms and petechiae in the feet, legs,
and mucous membranes
 Non-specific = malaise, fatigue, and general weakness (w/or w/out
accompanying blood loss)
 Diagnosis = full blood count, liver enz., kidney function, vit B 12 levels, folic acid
levels, RBC sedimentation rate, and peripheral blood smear. If cause remains
unclear = bone marrow biopsy
 Treatment = corticosteroids (↑ platelet production), lithium carbonate/folate
(stimulate platelet production in the bone marrow)
 Thrombocytopenia may be inherited/acquired

Cause Examples
↓ production  Dehydration, vit B12/folic acid deficiency
 Leukaemia or aplastic anaemia
 ↓ production of thrombopoietin by the liver in liver failure
 Sepsis, systemic viral or bacterial infection
 Hereditary syndrome = Fanconi anaemia, Wiskott-Aldrich
syndrome, congenital amegakaryocytic thrombocytopenia
↑ destruction  Immune thrombocytopenic purpura
 Thrombotic thrombocytopenic purpura
 Disseminated intravascular coagulation (DIC)
 Systemic lupus erythematosus
 Hypersplenism
 Dengue fever
 Gaucher’s disease
 Zika virus
Medication induced Can induce thrombocytopenia through direct myelosuppression:
 Valproic acid
 Methotrexate
 Carboplatin
 H2 blockers and PPIs
Other causes  Lab errors – possibly due to anti-coagulant EDTA in CBC
specimen tubes
 Snakebite
 Niacin toxicity
 Lyme disease

2) Describe altered platelet function

 Often congenital, includes diseases where platelets fail to adhere, activate, or
aggregate
 Severe examples would be the genetic disorder Glanzmann’s thrombasthenia
where platelets contain defective/low glycoprotein IIb/IIIa (this is a fibrinogen
receptor, meaning no fibrinogen bridging of platelets can occur)
 3) Describe thrombocytosis (AKA thrombocythemia)
 Definition = high/↑ platelet levels in the blood. It can be either primary
(essential, caused by a myeloproliferative disease) or secondary (reactive,
due to inflammation, splenectomy, Fe deficiency)
 Usually no symptoms and picked up on routine full blood count. It often occurs
in tandem w/an inflammatory disease, as thrombopoietin is elevated in these
clinical states as part of the acute phase rxn. Can also occur in patients
w/polycythemia vera (↑ RBC count), and is an additional risk factor for
complications.
 Small amount of patients report symptoms of erythromelalgia, a burning
sensation and redness of the extremities that resolves w/cooling and/or
aspirin use
 Reactive (secondary) accounts for 88-97% of thrombocytosis in adults, and
100% in children. Acute infection, tissue damage, chronic inflammation and
malignancy are the common causes of reactive thrombocytosis. Other causes
= post surgery, Fe deficiency, drugs, and rebound effect after bone marrow
suppression

4) Describe drug-associated immune thrombocytopenia

 Aspirin (an NSAID) irreversibly disrupts platelet function by inhibiting COX-1,
and hence normal hemostasis. The resulting platelets are unable to produce
new cyclooxygenase because they have no DNA
 Normal platelet function will not return until the use of aspirin has ceased and
enough of the affected platelets have been replaced by new ones, which can
take over a week.
 Ibuprofen, another NSAID, doesn’t have such a long duration effect, w/platelet
function usually returning w/in 24 h, and taking ibuprofen before aspirin
prevents the irreversible effects of aspirin
 Drugs that stimulate platelet production = thrombopoietin mimetics,
desmopressin, factor VIIa

41 - Coagulation disorders

1) Define the term coagulopathy and describe the signs and symptoms

Coagulopathy (AKA bleeding disorder) = condition in which the blood’s ability to

coagulate (form clots) is impaired. Left untreated = damage to joints, muscles, or
internal organs
Signs and symptoms = uncontrolled internal/external bleeding; blood in urine/stool,
double vision, severe head/neck pain, repeated vomiting, difficulty walking,
convulsions, or seizures.

2) Describe the mechanism (etiology)

 ↓ levels/absence of clotting/coagulation factors in the blood
 Genetic disorders such as haemophilia and Von Willebrand’s disease
 Acquired = deficit of vit K, liver disease
 Anti-coagulants (warfarin) will also prevent clots from forming properly
 Dysfunction/↓ levels of platelets

Genetic disorders

 Haemophilia A (lack of factor VIII) and haemophilia B (lack of factor XI) – both
X recessive)
 Von Willebrand’s disease (AD) = deficiency in quality/quantity of von
Willebrand factor, a protein required for platelet adhesion

Disseminated intravascular coagulation (DIC)

 DIC = condition in which blood clots form throughout the body, blocking small
blood vessels
 Formation of these blood clots obstructs the tissue blood flow → multiple
organ damage
 Additionally, the coagulation process uses up clotting factors and platelets →
disruption of normal clotting and severe bleeding occurs
 Symptoms = chest pain, SOB, leg pain, problems speaking/problems moving
parts of the body
 Etiology = solid tumours and blood cancers, massive tissue injury, sepsis,
snakebite, large aortic aneurysms.

42 – Static properties (compliance and elastic recoil) and dynamic properties

(flow and resistance) of lungs – pathological changes

1) Define the term compliance and describe the pathological changes

 Lung/pulmonary compliance = a measure of the lung’s ability to stretch and
expand (distensibility of elastic tissue)
 It is determined by elastic properties of the lung (distensibility and stiffness)
and alveolar surface tension
 Separated into static and dynamic compliance
 Static compliance = represents lung compliance during periods w/out
gas flow, such as during an inspiratory pause.
  Dynamic compliance = represents lung compliance during periods of
gas flow, such as during active inspiration. It is always ≤ static
compliance
 Pulmonary surfactant ↑ compliance by ↓ the surface tension of water
 Low compliance indicates a stiff lung = extra work required to bring in a
normal volume of air. This occurs when the lungs become fibrotic, lose their
distensibility and become stiffer
 High compliance = in emphysema – elastic tissue is damaged by enz.
secreted by WBCs in response to a variety of inhaled irritants. Patients have
high compliance due to poor elastic recoil. They have extreme difficulty
exhaling air = extra work is required to get air out of the lungs. Also often have
difficulties inhaling air = due to collapsed alveoli which makes inhalation
difficult
 Compliance is ↓ in: supine position, hydrothorax, pneumothorax, high
standing of a diaphragm, severe and chronic restrictive pathologies
 Summary = low compliance = fibrosis; high compliance = emphysema/COPD
 Compliance is inversely correlated w/their elastic properties/elastance → high
compliance = low elastance

2) Define the term elastic recoil and describe the pathological changes
 Elastic recoil = ability of an inflated lung to return to original position after
being stretched (the ease w/which the lung rebounds after inhalation)
 Overstretching of the lungs occurs w/emphysema (elastic components of the
lungs lose their recoil)
 Disorders of lung inflation are caused by conditions that:
 Obstruct airways
 Cause lung compression → accumulation of fluid in interpleural space
 Produce lung collapse → pneumothorax, atelectasis

3) Define the term surface tension

 Surface tension (ST) = the elastic sheet like property of the surface of a liquid
that allows it to resist an external force, due to the cohesive nature of its
molecules OR it is the elastic tendency of a fluid surface which makes it
acquire the least SA possible
 ST opposes lung expansion and reduces the efficiency of gas diffusion = if ST
is reduced, the lungs can expand more easily.
 Surfactant (produced by type II pneumocytes – alveolar epithelial cells) ↓ ST
in the lungs, thus ↑ lung compliance and ease of inflation
 Atelectasis = collapse of the lung – can be caused by poor surfactant
spreading during inspiration, causing ST to be at its highest which tends to
collapse smaller alveoli
 Synthesis of impaired surfactant can occur due to severe injury/infection and
can contribute to acute respiratory distress syndrome (fluid build up in alveoli)
 4) Describe the airway resistance and flow
 Airway resistance = the resistance to airflow during inhalation and expiration.
It depends on the diameter of the airways and whether airflow is lamina or
turbulent
8 ηl
 Poieseuille’s law ( 4 ) shows that airway resistance in inversely proportional
πr
to the radius to the power of 4. Hence a small change in diameter has a huge
effect on the resistance of any airway – halving the radius would cause
resistant increase 16-fold
 Therefore smaller airways all individually have much higher flow resistance
than larger airways like the airways.
 However, the branching of the airways means that the total resistance is ↓ in
the smaller airways because they are connected in parallel. The highest total
resistance is actually in the trachea and larger bronchi
 Resistance ↓ as lungs expand and pull airways open during inspiration and ↑
as the lungs deflate during exhalation → this is why people w/conditions that ↑
airway resistance (bronchial asthma) have < difficulty during inspiration than
expiration
 Laminar flow = air is flowing through the tube in parallel layers, w/no
disruption between layers, constant velocity (bit air in centre moves faster)
 Turbulent flow = air isn’t flowing in parallel layers, but direction, velocity and
pressure w/in the flow of air become chaotic. If airflow becomes turbulent, the
pressure difference required to maintain airflow will need to be increased,
which in turn would increase turbulence and therefore resistance.

43 – Changes in ventilation/perfusion ratio

1) Define the terms ventilation, perfusion and ventilation/perfusion ratio

(V/Q)

Gas transfer in the lungs depends on both pulmonary ventilation and perfusion:

 Ventilation = the air that reaches the alveoli for gas exchange (V)
 Perfusion = the blood that reaches the alveoli for gas exchange (Q)
 The ratio defines the amount of air reaching the alveoli per min/the amount of
blood reaching the alveoli per min
 Gas diffusion is most efficient at optimal ventilation/perfusion ratio (V/Q).
Optimal V/Q = 0.8, because V = 4L and Q = 5L (CO)

2) Describe how the ratio is affected

  V is affected by gravity in the lungs, but it affects Q more (blood flow)
 There is a higher PP of O2 and CO2 towards the apex and a lower PP towards
the base. Base also has max blood flow (Q)
 V/Q ratio is higher at apex of lung because of lower Q – V/Q = 3.6
 Further down the lung V/Q becomes optimal = 0.8
 At the base V/Q isn’t optimal but it is optimal at around V/Q = 0.6
 During high altitude hypoxia of the whole lung occurs – causes VC in the
pulmonary blood vessels. But the hypoxic VC can work in our favour when the
↑ pulmonary pressure can recruit unused capillaries to ↑ the SA for gas
diffusion

3) Describe what causes ↑/↓ ventilation and perfusion

 ↑ V = physiologically (during work), pathophysiologically (in metabolic
acidosis) ↑ demand, or due to an inappropriate hyperactivity of the respiratory
neurons
 ↓ V = ↓ demand, damaged respiratory cells, neural transmission is abnormal,
diseases of the respiratory muscles, ↓ thoracic mobility, enlargement of
pleural space by pleural effusion/pneumothorax, restrictive/obstructive lung
diseases
 ↑ Q = during physical work
 ↓ Q = heart/circulatory failure, constriction/occlusion of pulmonary vessels

4) What causes V/Q mismatch?

Gas exchange requires matching V and Q so that equal amounts of air and blood
enter the respiratory portions of the lungs. Both dead air space and shunt produce
V/Q mismatch.

Revision of dead space:

 Dead space = volume of inhaled air that doesn’t participate in gas exchange
(150ml) i.e. its ventilated but not perfused
 Anatomical DS = air in the conducting zone/airways that doesn’t take part in
gas exchange
 Alveolar dead space = air in the respiratory zone/airways that doesn’t take
part in gas exchange i.e. alveoli that are ventilated but not perfused

Dead air space

 There is ventilation w/out perfusion i.e. there is lack of capillary blood flow to
pick up O2 and drop off CO2 → ↑ V/Q
 E.g. pulmonary embolism – impaired blood flow due to clot
 Emphysema = enlarged alveoli w/↓ SA and fewer capillaries
 Cardiovascular shock = blood flow to lungs is ↓
Shunt

 (cardiac) Shunt = when blood follows a pattern that deviates from the
systemic circulation – e.g. R-L shunt = blood that moves from R side to the L
side of circulation w/out being oxygenated
 Anatomic shunt = due to congenital heart defects = blood moves from
venous to arterial side of circulation w/out moving through the lungs
 Physiologic shunt = mismatch in V/Q → there is insufficient V to
provide O2 needed to oxygenate blood flowing through the alveolar
capillaries → due to destructive lung disease or from heart failure
 There is Q w/out V, so blood flowing past poorly ventilated alveoli doesn’t pick
up additional O2 and total O2 content of arterial blood is lowered and we get
hypoxemia → low V/Q
 E.g. atelectasis; pneumonia and pulmonary oedema (some alveoli filled
w/fluid); mucous plugging (air can’t get into alveoli)

44 – Disturbances in the control of breathing

1) Explain how breathing is regulated

 Under normal conditions PCO2 controls the respiratory rate
 Respiratory centre = located in MO – regulates breathing. It contains dorsal
(inspiration) and ventral (inspiration and expiration) respiratory neurons
 Additionally, it contains the apneustic center – has an excitatory effect on
inspiration, tending to prolong inspiration; and a pneumotaxic center –
switches inspiration off, assisting in the control of respiratory rate and
inspiratory volume
 Control of breathing has automatic and voluntary components
 Automatic regulation is controlled by input from chemoreceptors and
lung receptors
 Chemoreceptors = peripheral (in carotid bodies; respond to partial gas
pressures and pH) and central (respond to changes in pH due to
changes in gas conc. in CSF) – monitor blood levels of gases, and pH
and adjust ventilation to meet changing metabolic needs
 Lung receptors = monitor breathing patterns and lung functions =
stretch, irritant, and Juxtacapillary receptors
 Voluntary regulation integrates breathing w/voluntary acts such as
speaking, blowing, and singing.
 Dorsal and ventral respiratory neurons communicate w/lower respiratory
motor neurons → stimulate phrenic and intercostal nerves → respiratory
muscles → pulmonary ventilation
  Excitation of respiratory neurons = acidosis (↓ pH), hypercapnia (↑ CO 2),
hypoxia (↓ O2), ↓ Ca2+ & Mg2+ in CSF, ↑ body temp
 Inhibition of respiratory neurons = alkalosis (↑ pH), hypocapnia (↓ CO 2),
central hypoxia, ↑ Ca2+ & Mg2+ in CSF, ↑ bp, severe hypothermia

2) Describe the quantitative changes associated w/breathing

 Tidal volume = the air inspired during normal/relaxed breathing - 500ml
 Respiratory rate = 10-24 breaths/min (12-16 bpm at rest)
 Respiratory minute volume = TV x RR = volume of air inhaled/exhaled/min.
Calculation: 0.5 L (TV) X 12 bpm (RR at rest) = 6 L/min

Term Definition
Hypopnoea ↓ breathing movements – shallow breathing
Eupnoea Normal breathing movements
Hyperpnoea ↑ breathing movements – rapid/deep breathing
Apnoea Cessation (stopping) of breathing
Bradypnoea ↓ breathing rate (<10 bpm)
Tachypnoea ↑ breathing rate (>24 bpm)
Dyspnoea Difficulty breathing; SOB
Asphyxia Inability to breather
Orthopnoea Dyspnoea that occurs when lying flat (need to sit upright)

3) Describe the qualitative changes associated w/breathing

Qualitative changes = pathological patterns of breathing (abnormal or uneven

rhythm) – Cheyne-Stokes, Biot’s, and Kussmaul’s breathing

Dyspnoea = SOB due to problems

associated w/respiratory system/due
to cardiac problems

 Inspiratory dyspnoea = if
dyspnoea occurs during
inhalation = during obstruction
of upper airways – observe
hyperpnoea and ↓ RR
 Expiratory dyspnoea = during
obstruction of lower airways –
asthma, bronchitis
 Mixed form = dyspnoea during
both inhalation and exhalation
= COPD
 Euler-Liljestrand mechanism or
hypoxic pulmonary VC =
physiological response to
 alveolar hypoxia – VC of small pulmonary aa. to redirect blood flow from
poorly-ventilated to well-ventilated lung regions

45 – Obstruction of airflow in respiratory passageways. Pathophysiology of

asthma

1) What are obstructive pulmonary disorders?

Obstructive pulmonary disorders = characterised by an ↑ resistance to flow. It is

generally characterised by inflamed and easily collapsible airways, obstruction to
airflow, problems exhaling and frequent medical clinic visits and hospitalizations.

2) Describe the pathophysiology of asthma

Asthma is the result of chronic inflammation of the conducting zone (bronchi and
bronchioles), which results in ↑ contractibility of the surrounding smooth muscles →
narrowing of the airway. Typical changes in the airways include ↑ in eosinophils and
thickening of the reticular CT

Definition = asthma is a long-term inflammatory disease of the airways

There are 2 types of asthma:

 Atopic asthma = most common, e.g. of type 1 HS rxn (IgE mediated) – is

associated w/exposure to specific allergen
 Non-atopic asthma = is associated w/some non-specific stimulants

Etiology = genetic (family history – childhood asthma) and environmental factors

(later onset asthma)

Triggering substances = air pollution (cigarette smoke, car exhaust), allergens (dust,
mould)

Symptoms = chest tightness, cough, dyspnea,

wheezing, sputum

Classification of asthma = intermittent → mild

persistent → moderate persistent → severe
persistent

Treatment

 Avoid contact w/triggering substances

  Meds = bronchodilators (anti-cholinergics, β-agonists) → relax smooth
muscles in the lungs and dilate airways
 More severe forms = corticosteroids, long acting β- or leukotrienes agonists
 Very severe forms = IV corticosteroids, MgSO4, O2 therapy

Pathophysiology

 In asthma there is an allergy to inhaled Ag’s (e.g. pollen) → cause an

inflammation of the bronchial mucosa leading to the release of histamine and
leukotrienes
 Bronchial muscles contract, mucus secretion and vessel permeability
(mucosal oedema) are ↑
 This leads to ↑ resistance to breathing = ↑ work of breathing

46 – Obstruction of airflow in respiratory passageways. Pathophysiology of

chronic obstructive pulmonary disease (chronic bronchitis and emphysema)

The term COPD encompasses 2 types of obstructive airway disease: emphysema,

w/enlargement of airspaces and destruction of lung tissue, and chronic (obstructive)
bronchitis, w/↑ mucous production, obstruction of small airways, and a chronic
productive cough. People w/COPD often have overlapping features of both disorders

 Chronic bronchitis → productive cough (defined by clinical features)

 Emphysema → defined by structural changes i.e. enlargement of airspace

Chronic bronchitis

 Chronic bronchitis represents airway obstruction of the major and small

airways
 Exposure to chemicals and irritants (smoking) stimulates mucous production
in airways → productive cough lasting ≥ 3 months each year for ≥ 2 years
 Mucosa of lungs = epithelium + lamina propria. Submucosa = smooth muscle
and CT – it contains bronchial mucous glands that secrete mucous into the
lumen of the bronchi
 How is there excess mucous production:
 Smoking → exposure to irritants and chemicals → hypertrophy and
hyperplasia of bronchial mucinous glands (main bronchi) and goblet
cells (bronchioles) → ↑ mucous production → airway obstruction
 Smoking = cilia are < mobile = hard to move mucous
 Mucous hypersecretion + poor cilia function = productive cough

Emphysema
  Emphysema is characterised by a loss of lung elasticity and abnormal
enlargement of the airspaces distal to the terminal bronchioles, w/destruction
of the alveolar walls and capillary beds
 Enlargement of the airspaces → hyperinflation of the lungs and produces an ↑
in total lung capacity
 Causes = smoking (incites lung injury) and inherited α 1-antitrypsin (enz.
protecting the lung from protease enz. such as
neutrophil elastase) deficiency
 Emphysema is due to breakdown of elastin and
other alveolar wall components by proteases.
Normally anti-protease enz. (e.g. α1-antitrypsin)
protect the lung. In emphysema:
 Cigarette smoke/other irritants → attraction
of inflammatory cells → release of elastase
(usually inhibited by α1-antitrypsin) – in
smokers anti-protease production and
release may be inadequate to neutralise
the excess protease production →
destruction of elastic fibers in lung →
emphysema

Types of emphysema:

 Centriacinar/centrilobular = most common (due to smoking), mainly affects

prox. respiratory bronchioles in upper lobes of lungs
 Panacinar emphysema = entire acinus is affected (> common in α 1-antitrypsin
deficiency), affects lower lobes of lungs

Symptoms

 Productive cough, SOB, and sputum production – present for a prolonged

period of time
 Prolonged exhalation (> work needed to exhale)
 Wheezing
 Barrel chest is characteristic sign of COPD (> common in emphysema)
 Advanced COPD = pulmonary HT → R sided heart failure (cor pulmonale) –
symptoms include peripheral oedema and bulging neck vv.
 “Pink puffer” – for people w/predominant emphysema = lack of cyanosis, the
use of accessory muscles, and pursed-lip (“puffer”) breathing
 “Blue bloaters” – for people w/predominant chronic bronchitis = cyanosis (due
to hypercapnia) and fluid retention associated w/R sided heart failure

Treatment
  Stop smoking
 Supplemental O2
 Meds = bronchodilators, corticosteroids, anti-B

47 – Restrictive disturbances of breathing. Idiopathic pulmonary fibrosis

1) What are restrictive pulmonary disorders?

Restive pulmonary disorder = anatomical or functional loss of gaseous exchange

area.

 Anatomic loss = removal (resection) or displacement (e.g. by a tumour) of

lung tissue. Atelectasis may also lead to a ↓ in diffusion area
 Functional loss = pulmonary oedema or in inflammation

They are a category of diseases that restrict lung expansion, resulting in a ↓ lung
volume, an ↑ work of breathing, and inadequate ventilation and/or oxygenation

2) Describe the pathophysiology of idiopathic pulmonary disorders

Definition = a type of chronic lung disease characterised by a progressive and

irreversible ↓ in lung function.

Pathophysiology

 Damage to alveolar epithelium → type I pneumocytes release transforming

growth factor β 1 (TGF-β1)
 This stimulates type II pneumocytes to trigger fibroblast proliferation to
myofibroblasts → they secrete reticular and elastic fibers
 Problem is that type II pneumocytes over proliferate = too many
myofibroblasts and collagen and myofibroblasts don’t undergo apoptosis →
collagen thickens the interstitial layer between the alveoli and capillaries →
problems w/ventilation and oxygenation, and stiffening of the lungs occurs →
restricted lung expansion due to fibrosis of the interstitium = restrictive lung
disease

Etiology = unknown. Risk factors include family history, cigarette smoke, and certain
viral infections.

Symptoms

 Problems w/oxygenation and ventilation = dry, non-productive cough

 SOB w/exercise
 Cyanosis
 Clubbing of the digits
 Can progress to respiratory failure – lungs lose functional tissue
Manifestations of restrictive lung disease

 ↓ total lung capacity (max amount of air the lungs can hold)
 ↓ forced vital capacity (amount of air expelled w/max effort after a deep
breath)
 ↓ forced expiratory volume in 1 sec (the air exhaled w/max effort in the 1 st sec)
 Loss of alveoli → fluid filled spaces ‘cysts’ – honeycomb appearance

Diagnosis = chest CT scan – honeycomb appearance and thickening of interstitial

walls; spirometry

Treatment = supplemental O2, lung transplant

48 – Pulmonary oedema

Definition = build up of fluid in the lungs including the airways (alveoli) and
interstitium (lung tissue between the alveoli and capillaries). It leads to impaired gas
exchange and may cause respiratory failure

Movement of fluids into the interstitial space in normal [physiological conditions are
governed by 3 factors:

1) Hydrostatic pressure = pressure of fluids in a confined space

2) Oncotic pressure = type of osmotic pressure exerted by cells and proteins that
can’t cross the capillary membrane, and ∴ attract fluid. It is higher in the
capillaries than the interstitial fluid
3) Capillary permeability = affects how easily fluid gets through

Normally, the sum of these 3 factors is slightly in favour of movement of fluid out of
the capillaries and into the interstitial space → lymphatics → lungs free of excess
fluid.

Cause of pulmonary oedema

Cardiogenic i.e. due to heart disease

 L sided heart failure → L ventricle cant pump effectively → blood backs up in

L atrium → blood backs up in pulmonary vv. and capillaries → pulmonary HT
= ↑ in pulmonary hydrostatic pressure → > fluid pushed into interstitial space
of the lungs → pulmonary oedema
 Hypertensive crisis = severe systemic HT (>180/110) → L ventricle is healthy
but cant effectively pump blood due to high afterload → this prevents forward
flow of blood and same situation as above occurs (L atrium → pulmonary vv.
and capillaries etc.)
Non-cardiogenic i.e. damage to pulmonary capillaries or alveoli

 Pulmonary infections, inhalation of toxic substances, chest trauma → direct

injury to alveoli → inflammation of lungs causing nearby capillaries to become
> permeable → proteins and fluids enter the interstitial space
 Sepsis → inflammation through the body → pulmonary oedema + extra fluid
in interstitial space of tissue throughout the body
 Low oncotic pressure - e.g. not making enough proteins (malnutrition or liver
failure) or loosing protein too quickly (nephritic syndrome) → fluid goes from
capillaries to interstitium

Clinical manifestations

 Gas exchange is difficult = O2 and CO2 have to diffuse through a wide layer of
interstitial fluid to get from the alveoli to the pulmonary capillaries and vice
versa → difficult to fully oxygenate blood
 Severe SOB = in L heart failure → orthopnoea
 Other symptoms may be = haemoptysis (coughing up blood), excessive
sweating, anxiety, and pale skin

Diagnosis = chest X-ray/CT → shows fluid in interstitial space

Treatment = supplemental O2; if due to cardiogenic cause = meds to lower bp

49 – Pulmonary embolism

Definition = blockage of the pulmonary a.

It is typically a thromboembolism (90%) = blood clot from DVT lodges itself in the
pulmonary aa.

Pathogenesis

Development of thrombosis is due to a group of causes – Virchow’s triad:

 Alterations in blood flow = immobilisation (after surgery, long-haul flight),

injury, pregnancy, obesity, and cancer
 Factors in the vessel wall = surgery, catheterisations causing direct injury
 Factors affecting the properties of the blood = estrogen-containing hormonal
contraceptions, genetic or acquired thrombophilia, cancer

Process of embolism development:

 Damage to endothelium → VC → primary hemostasis

  Activation of coagulation cascade = clotting factors, fibrinogen → fibrin clot →
secondary hemostasis. As the clot grows, ↓ blood flow and ↑ bp
 Usually clot is broken down via plasmin. Sometimes the high bp causes part
of the clot to break free → thromboembolus → travels to heart → R atrium →
R ventricle → lungs → pulmonary thromboembolism
 This results in ↓ blood flow to lung tissue → V/Q mismatch (getting enough air
but not enough blood flow) → hyperventilation → release of CO 2 →
respiratory alkalosis

Symptoms

 Small emboli = asymptomatic (no symptoms)

 Large emboli = sudden and severe chest pain, SOB (dyspnoea), tachypnoea,
fatigue, cough.
 More severe cases = cyanosis, collapse, and circulatory instability
 Saddle PE = thrombi at the bifurcation of the pulmonary a. = blocks both lungs
= sudden death
 Multiple emboli occurring over time causes pulmonary HT or R ventricular
failure

Diagnosis = CT pulmonary angiogram – dye injected into blood vessels to identify

blockages; V/Q scan

Treatment = small clots resolve on their own; thrombolytic enz.; surgically remove
clots (pulmonary thrombectomy); long term prevention = warfarin, heparin

50 – Hypoxia – definition, essence, and classification. Hypoxic hypoxia

1) What is hypoxia? Describe the pathogenesis

Hypoxia = when the body/body part has inadequate O 2 supply (↓ O2). It can be
classified as general or local depending on if it affects the body or a specific tissue.

O2 is required for oxidative phosphorylation which provides the cells w/E. At a

cellular level, lack of O2 → ↓ ATP → Na/K pump begins to fail → influx of Na+ and
H2O. Failure of Ca2+ pump = ↑ intracellular Ca2+ → triggers internal proteolysis

Causes = hypoventilation (reduces the diffusion gradient to venous blood and thus
impairs O2 uptake); ↓ diffusing capacity; ↓ O2 uptake capacity of the blood; circulatory
failure; impaired tissue diffusion; poisons.

Symptoms include:
  Generalised = fatigue, numbness, nausea. Severe hypoxia = ataxia,
confusion, hallucinations, unconsciousness, breathlessness, pallor,
tachycardia, and pulmonary HT → cyanosis, bradycardia, hypotension, heart
failure, death
 Localised = cyanosis. Severe hypoxia = tissue may become gangrenous and
extreme pain may be felt
2) Differentiate between the causes of acute and chronic hypoxia

Acute = trauma, stroke, MI, acute lung injury and primary hypoxic brain tumours

Chronic = congestive heart failure, and chronic respiratory disease

3) Describe the classification of hypoxia

 Hypoxemic hypoxia = ↓ O2 in blood and tissues. It can be due to ↓ pO2 at
altitude or cardiopulmonary failure (lungs unable to efficiently transfer O 2 from
alveoli to the blood)
 Anaemic hypoxia = blood is unable to transport O 2 sufficiently. Due to blood
loss, CO poisoning, or diseases such as SCA
 Stagnant (circulatory) hypoxia = insufficient blood flow through the capillaries.
May be due to heart failure, ↓ circulatory volume (hypovolaemia), or VD
 Histotoxic (histologic) hypoxia = cells are unable to use the O 2, although the
amount in the blood may be normal. May be due to cyanide poisoning, alcohol
consumption, or narcotics

4) List the 4 clinical stages of hypoxia

 Asymptomatic = no effect
 Compensatory = O2 saturation is 80-90% but no visible symptoms
 Deterioration or disturbance = unable to compensate ∴ symptoms begin to
show e.g. SOB and cyanosis
 Critical = O2 saturation < 70% and patient is generally incapacitated

5) What is hypoxic hypoxia?

Hypoxic hypoxia = insufficient O2 available to lungs (O2 deficiency in the lungs). It is

characterised by a ↓ in pO2 - < 60 mmHg. This results in V/Q mismatch → ↓
oxygenation of blood and ↓ Hb saturation → hypoxemia and tissue hypoxia

Exogenous factors Endogenous factors

Low O2 in atm air (hypobaric
conditions – high altitude)
Pulmonary disorders
 ↓ alveolar ventilation
 Impaired diffusion of gases (pulmonary oedema,
pneumothorax, interstitial fibrosis of the lungs)
 Impaired perfusion (pulmonary embolism,
emphysema, fibrosis of lungs)
Suppression of respiratory centre
 Head trauma
  Tumours

51 – Haemic (blood) hypoxia

1) Define the term hypoxemia. Describe the causes

Hypoxemia = ↓ O2 in the blood

 Anaemia (acute/chronic) = ↓ RBC and Hb content

 Inactivation hypoxia = due to inactivation of Hb and thus it cannot bind and
release O2

2) What is carboxyhemoglobinemia?
 Presence of carboxy Hb in the blood = CO binds to Hb instead of O 2 – CO has
a higher affinity to Hb than O2 (dissociation curve shifts to L)
 Colour of blood is red
 Sources of CO = gas stoves, cars, cigarette smoke
 CO also has a higher affinity for myoglobin in cardiomyocytes → severe
arrhythmias, infarction (necrosis)
 In skeletal muscle we get severe hypoxia, necrosis, acute tubular necrosis,
and acute renal failure

3) What is methemoglobinemia (MetHb)?

 Condition caused by ↑ levels of MetHb in blood (Hb containing Fe 3+ form of
iron instead of Fe2+)
 Fe3+ (ferric) form of Fe has lower affinity for O2 = impairs binding and transport
of O2, Hb carries O2 but isn’t able to release it effectively → hypoxia
 Dissociation curve shifts to L, blood is chocolate-brown coloured
 Cause = congenital (deficiency of NADH-cytochrome b5 reductase) and
acquired (meds – N containing nitroglycerine; chemicals – nitrites, thiols,
dyes)
 Clinical manifestations:
 MetHb 15-20% of whole Hb content = asymptomatic, cyanosis
 MetHb >20% = dyspnoea, fatigue, vertigo, weakness, syncope
(temporary loss of consciousness)
 MetHb >70% = death
 Treatment = vit C ampoules (converts Fe3+ to Fe2+); remove blood containing
MetHb and give blood w/Fe2+

4) What is sulfhaemoglobinaemia?
  Excess sulfhaemoglobin in the blood.
 Pigment is a greenish derivative of Hb which can’t be converted back to
normal, functional Hb → causes cyanosis
 Cause = meds containing sulphonamides, sulphur poisoning

52 – Circulatory hypoxia

Circulatory (AKA stagnant) hypoxia = ↓ blood flow preventing adequate blood supply
to tissues. In this form the lung are working just fine and the blood can carry
sufficient O2. However, the tissue isn’t receiving sufficient O2 because the heart can’t
pump the blood to the tissue (or the aa. leading to the tissue have been blocked)

Types include:

 Ischemic i.e. ischemic heart disease

 ↓ perfusion to tissues
 Can be local (MI, occlusion of a single a.) or systemic (shock)
 Congestive i.e. congestive heart failure = can be local (thrombus) or systemic
(R heart failure). Basic features include:
 Venous hypoxemia = ↓ saturation of venous blood → ↑ obstruction,
stasis
 Lactic acidosis (anaerobic glycolysis)
 Cyanosis (lips, hands, nose tip)

Treatment = cardiovascular drugs (↑ cardiac output), supplemental O 2

53 – Tissue hypoxia

Tissue (AKA histotoxic) hypoxia = inability of the tissue/cell to use/take up O 2. There

is no problem getting O2 to the tissues – lungs and circulatory system are working
just fine, however the tissue is unable to use the O 2

 Cell unable to use O2 = ↓ ATP production by mitochondria → uncoupling of

oxidative phosphorylation
 Causes = cyanide poisoning – binds to complex IV → by blocking the enz., O 2
use is ↓ = pO2 in venous blood is ↑ → stops oxidative phosphorylation and
prevents ATP formation
 In some cases, histotoxic hypoxia can be a result of ischaemia. During a
stroke, there is an interruption in blood supply followed by reperfusion which
leads to histotoxic hypoxia because of ROS accumulation. Where cellular
 stress has triggered inflammation, ROS are released w/in the cell →
mitochondrial damage → prevents oxidative phosphorylation

Treatment = reversal of cyanide poisoning/cyanide antidote kit (the nitrites act w/Hb
→ MetHb which binds cyanide. Cyanide has a preference for Fe 3+ on MetHb over the
Fe2+ on complex IV and causes it to be drawn out of the mitochondria →
mitochondria can produce ATP again)

54 – Metabolic changes during hypoxia

O2 is required in oxidative phosphorylation which occurs in inner mitochondrial

membrane. It accepts e- to produce H2O, which allows the process to finish and
produce ATP ∴ w/out O2 we can’t complete oxidative phosphorylation and produce
ATP.

 Lack of ATP = Na/K pump fails → water flows into the cell → cell swelling
 Causes ↓ SA and absorption of cell membrane
 Causes cell to bleb/bulge out w/water = cytoskeleton is beginning to fail
 RER swells = ribosomes detach → ↓ protein synthesis
 Lack of ATP also causes failure of Ca2+ pump = ↑ Ca2+ in the cell → activates
several enz. = proteases, endonucleases, hydrolytic enz. (from lysosomes),
and phospholipases.
 Ca2+ can also enter the mitochondria making its membrane > permeable.
Cytochrome C leaks out of mitochondria → activates apoptosis

When oxidative phosphorylation fails:

 Anaerobic glycolysis → lactic acid is produced → ↓ pH of the cell → acidosis

→ proteins and enz. denature

55 – Adaptation to hypoxia

1) Describe adaptations that occur in the different systems

Adaptations that occur in:

 Respiratory system = hyperventilation, ↑ gas diffusion and perfusion of the

lungs
 CVS = tachycardia, ↑ cardiac output, ↑ vascularisation in chronic hypoxia
 Blood = ↑ RBC (erythropoietin) and/or Hb production
 Tissue = ↑ n.o of mitochondria, ↑ vascularisation (VEGF)

2) Describe the detailed studies of Tibetan and Andean populations

Certain populations that live significantly above sea level have undergone
physiological adaptation in order to live in their specific areas.

 Tibetan populations inhale more air w/each breath, and breathe more rapidly
than other populations, w/ enlarged lung volumes and ↑ cerebral blood flow .
 Andean populations, who have been living in their high altitude homes for
>11,000 years, have a different pattern of Hb adaptation , w/↑ Hb
concentrations , enabling them to make > effective transport of O 2
 It should be clear, both of these cases look to correct the imbalance in V/Q in
the lungs, the Tibetans by altering the V (ventilation), the Andeans the Q
(perfusion)

3) Explain the function of hypoxia-inducible factors (HIF)

 HIFs are TFs that respond to ↓ in available O2 in the cellular environment
(hypoxia)
 HIF is a heterodimer and has 2 subunits
 They are activated when there is hypoxia. they are responsible for activation
of TFs
 Effects:
 Stimulates VEGF → neovascularisation and angiogenesis
 Production of erythropoietin → activated erythropoiesis (RBC
production)
 Regulates vascular tone → ↑ perfusion
 Remodelling and vascularisation

56 – Cardiac arrhythmias. Bradycardia. Atrioventricular block

1) What are cardiac arrhythmias? List the 4 categories

 Cardiac arrhythmia = group of conditions in which the heart rate is irregular,
too fast, or too slow.
 Normal HR = 60-100 bpm - <60 = bradycardia, >100 = tachycardia
 Clinical manifestations = palpitations, light-headedness, loss of consciousness
(syncope), dyspnoea, angina

There are 4 categories:

 Extra beats = premature atrial or ventricular contractions

 Supraventricular tachycardias (SVT) = abnormally fast heart rhythm arising
from improper electrical activity in the upper part of the heart – includes atrial
fibrillation, atrial flutter, paroxysmal SVT, and Wolff-Parkinson-White
syndrome.
  Ventricular arrhythmias
 Bradyarrhythmias

2) Describe the 2 basic mechanisms of arrhythmias

Altered impulse formation:

 ↓ SA automaticity (i.e. sinus bradycardia) (↓ sympathetic stimulation)

 ↑ SAN automaticity (↑ sympathetic stimulation)
 ↑ automaticity of latent pacemakers (AVN and Purkinje fibers intrinsically
depolarise faster than SAN)
 Abnormal automaticity (ectopic pacemakers in atrial and/or ventricular
myocytes – dye to myocyte injury)
 Triggered activity

Altered impulse conduction:

 Conduction block (AV block, BB block – delayed propagation of impulse often

due to ischaemia, fibrosis, inflammation)
 Re-entry loops (impulse travels in continuous loop around the heart

3) Describe the pathophysiology of bradycardia

 Bradycardia = < 60 bpm
 Asymptomatic until < 50 bpm. Typical symptoms = fatigue, weakness,
dizziness, sweating, syncope

Four classifications:

 Sinus bradycardia – 3 subtypes

 Respiratory sinus arrhythmia = usually found in young and healthy
adults. HR ↑ during inhalation and ↓ during exhalation – thought to be
caused by changes in the vagal tone during respiration.
 Sinus bradycardia = sinus rhythm of <60 bpm – common in healthy
individuals and well-conditioned athletes
 Sick sinus syndrome = includes SA block, sinus arrest, and severe
sinus bradycardia
 AV nodal (AV junctional rhythm) = caused by the absence of the electrical
impulse from the SAN – impulse from AVN only which controls pace at a
lower rate
 Ventricular bradycardia (AV block) = HR < 50 bp, occurs when there is a lack
of impulse from AVN/SAN. Impulse originates from bundle of His
 Infantile = defined as < 100 bpm, found in premature babies

Etiology = cardiac or non-cardiac

 Cardiac = IHD, vascular heart disease, valvular heart disease

  Non-cardiac = recreational drug use, metabolic disorder, endocrine disorder
(especially thyroid)

4) Describe the pathophysiology of atrioventricular (AV) block

 AV block = conduction between the atria and ventricles is impaired.
 Usually SAN generates an impulse which travels down to ventricles. In AV
block, this message doesn’t reach the ventricles, or is impaired along the way
 Etiology = ischaemia, infarction, fibrosis, drugs (digoxin, β-blockers, Ca 2+
channel blockers, class 1a anti-arrhythmic drugs)

There are 3 types:

 1st degree AV block = impulse conduction from atria to ventricles through AVN
is delayed and travels slower than normal – PR > 0.2 s
 2nd degree AV block = not all impulses generated in SAN can pass to AVN to
cause ventricular contraction – i.e. some impulses don’t pass to ventricles
(absence of QRS complex sometimes in the ECG)
 3rd degree/complete AV block = no impulses reach the ventricles, signal
blocked completely

Treatment = meds to ↑ HR (atropine); transcutaneous pacing through electrodes on

skin; permanent pacemaker

57 – Tachyarrhythmias. Wolf-Parkinson-White syndrome

1) What are tachyarrhythmias? Describe the pathophysiology

 Tachycardia = HR >100 bpm
 Causes = congenital heart defects, anaemia, exercise, stress, hypo-/HT,
smoking, certain meds, caffeine, hyperthyroidism, fever, anxiety, etc.
 Symptoms = heart palpitations, SOB, light-headedness, ↑ pulse, chest pain,
syncope – these symptoms are a result of < blood being pumped around the
body, as the heart doesn’t have the chance to properly fill in between each
beat

There are 2 types of tachycardia:

Supraventricular tachycardia (SVT)

SVT is an abnormally fast HR arising from improper electrical activity in the upper
part of the heart. There are 3 main types:
  Atrial flutter = caused by a re-entry rhythm in the atria, w/a regular atrial rate
often of about 300 beats per minute. The AVN will not usually conduct 300
bpm so the P:QRS ratio is usually 2:1 or 4:1 pattern
 Atrial fibrillation = abnormal heart rhythms characterised by rapid and irregular
beating of the atria. Often it starts as brief periods of abnormal beating which
become longer and possibly constant over time. In A-fib, the normal regular
electrical impulses generated by the SAN are overwhelmed by disorganized
electrical impulses usually originating in the roots of the pulmonary vv. →
irregular conduction of ventricular impulses that generate the heartbeat
 Wolff-Parkinson-White syndrome (WPW syndrome) = see Q2

Ventricular tachycardia

 Premature ventricular contractions = heartbeat is initiated by Purkinje fibers in

the ventricles rather than the SAN, meaning the ventricles begin to contract
prior to atrial contraction
 Accelerated idioventricular rhythm = ↑ rate of myocardial repolarisation
 Ventricular fibrillation = when the heart quivers instead of pumping due to
disorganised electrical activity in the ventricles. It is thought to be a result of
stress or damage to the heart, and can quickly lead to death

2) Describe the pathophysiology of Wolf-Parkinson-White syndrome (WPW

syndrome)
 In the normal heart the only route from the atria to the ventricles is through the
AV bundle.
 However, in some individuals there exists an accessory pathway (bundle of
Kent) through which conduction is able to travel. This is usually on the L side
of the heart.
 Conduction is able to travel through this accessory pathway, and is not
delayed by the AVN, and thus there is pre-excitation of the ventricles.
 Risk of sudden death in 0.6% of patients
 This sudden death can occur when there is paroxysmal tachycardia. When
this occurs, the signal from the atria, travels down through the accessory
pathway, and then back up the bundle of His, and back into the atria. This
sets off a loop of depolarisation, sometimes called a re-entry circuit

58 – Congestive heart failure. Left ventricular failure

1) Define the term heart failure (HF) and describe its etiology

HF = heart is unable to pump sufficiently to maintain blood flow to meet the body’s
needs.
Etiology:

 Mechanical = aortic stenosis, arterial HT, mitral/tricuspid stenosis

 Myocardial abnormalities and loss of cardiomyocytes = myocarditis,
cardiomyopathy, COPD, inflammation
 Altered cardiac rhythm/conduction disturbances = extreme brady-/tachycardia
 Meds = NSAIDs, anesthetic agents like ketamine, some cancer meds,
salbutamol
2) Describe the classification of HF

There are many different ways to categorise HF:

 According to the side of the heart involved – R vs. L HF

 According to whether the abnormality is due to insufficient contraction
(systolic dysfunction), or due to insufficient relaxation of the heart (diastolic
dysfunction), or to both.
 Whether the problem is primarily ↑ venous back pressure (preload), or failure
to supply adequate arterial perfusion (afterload).
 According to the degree of co-existing illness i.e. HF/systemic HT,
HF/diabetes
 According to the degree of functional impairment conferred by the abnormality

3) Differentiate between systolic and diastolic HF

Systolic HF

 When the ventricles cant pump enough blood out

 It is defined by the ejection fraction – stroke volume/total volume
 <50% ejection fraction suggests systolic HF

Diastolic HF

 Defined by the preload (amount of blood at the end of diastole)

 A low preload = ↓ contractility of the heart (Frank-Starling law) and ∴ ↓ CO

4) Define the term L HF and describe its etiology

L HF = insufficiency of the L ventricle to pump enough blood via systemic circulation

Etiology:

 Damage to myocardium (due to IHD or coronary atherosclerosis); ∴ heart cant

contract as forcefully or pump blood as efficiently
 Long-standing HT = high arterial pressure in systemic circulation, making it
harder for the L ventricle to pump blood out of to the hypertensive systemic
circulation.
  To compensate, the muscles of the L ventricle undergo hypertrophy so the
ventricle can contract w/more force. Hypertrophy leads to ↑ O2 demand and
the coronary aa. are also squeezed i.e. < blood to the heart → weaker
contractions= systolic failure
 Dilated cardiomyopathy = i.e. heart chamber grows in size/dilates so the
ventricle fills up w/more blood (preload) and to ↑ the contraction strength.
Over time, muscle walls get thinner and weaker → systolic L HF

So, when L ventricle cant pump enough blood to systemic circulation, there is <
blood to kidneys → RAAS activated → fluid retention → leaks from blood vessels →
fluid build up in lungs and other parts of the body

5) Describe the clinical signs of L HF

L HF causes blood to back up into the lungs → ↑ pressure in pulmonary aa. →

pulmonary oedema. The extra fluid in the alveoli makes gas exchange harder (longer
time for diffusion) → dyspnoea (SOB), orthopnoea, crackles in auscultation. Due to
impaired gas exchange we also get cyanosis and hypoxia. ↓ cardiac output = fatigue

6) Describe the treatment of HF (R and L)

ACE inhibitors (dilate blood vessels to improve blood flow), diuretics (↓ fluid build up
in the body)

59 - Congestive heart failure. Right ventricular failure

1) Define the term R HF and describe its etiology

R HF = insufficiency of the R ventricle to pump blood to the pulmonary circulation

Etiology:

 Usually occurs as a result of L HF. When the L ventricle fails, ↑ fluid pressure
is transferred back through the lungs, ultimately damaging the heart’s R side.
 L→R cardiac shunts can also cause R HF, w/> blood filling the R ventricle,
leading to concentric hypertrophy
 Cor pulmonale (pulmonary heart disease) = enlargement and failure of the R
ventricle as a response to ↑ vascular resistance (e.g. pulmonary stenosis) or
pulmonary HT.
 Chronic pulmonary heart disease usually results in R ventricular
hypertrophy.
 Hypertrophy is an adaptive response to a long-term increase in
pressure. Individual muscle cells grow larger (in thickness) and change
 to drive the increased contractile force required to move the blood
against greater resistance

2) Describe the clinical signs of R HF

 Backward failure of the R ventricle
leads to congestion of systemic
capillaries. This generates excess
fluid accumulation in the body.
This causes swelling under the
skin (peripheral oedema).
Because of the effects of gravity,
the oedema is most pronounced
in the dependant parts of the body
(lower extremities when upright,
sacrum when supine) – known as
pitting oedema
 Nocturia (frequent night time
urination) may occur when fluid
from the legs is returned to the bloodstream while lying down at night.
 Blood backs up to the body in R HF → systemic v. congestion → jugular
venous distension
 When blood backs up to the liver and spleen → fluid moves into interstitial
spaces w/in those organs = hepatosplenomegaly
 If the liver is congested for a long period of time = cardiac cirrhosis and liver
failure
 Excess interstitial fluid near surface of liver and spleen can move to peritoneal
spaces → ascites (build up of fluid in peritoneal space)

60 – Endocarditis and myocarditis

1) Define the term endocarditis and describe its etiology

Endocarditis = inflammation of the endocardium (inner layer of the heart), which

affects mainly the valves but also the interventricular septum, chordae tendinae, and
the mural endocardium. Most often valves in the L side of the heart are affected
Classification = infective and non-infective

Etiology:

 Mostly bacterial infection (fungi is < common) – i.e. infective endocarditis

 Risk factors include valvular heart disease including rheumatic disease, CHD,
artificial valves, haemodialysis, i.v drug use (open wounds), and electronic
pacemakers
 Streptococci and staphylococci are the most commonly involved bacteria
 Non-infective endocarditis = usually occurs during a hypercoagulable state
such as system-wide bacterial infection, or pregnancy; and can occur in
cancer patients. The inflammation causes formation of vegetations which may
cause thromboembolism

2) Describe the pathogenesis of endocarditis

 Damage to the endothelial lining of the valves = underlying collagen and
tissue exposed; platelets + fibrin adhere → thrombosis (blood clot) forms
 Bacteraemia
 Implantation and growth at the site of the clot = bacteria attaches to the blood
clot via adhesin → vegetation

3) Describe the clinical symptoms of endocarditis

 Fever
 Petechia (small areas of bleeding into the skin)
 Heart murmur
 Fatigue
 Complications = valvular insufficiency, HF, stroke, and kidney failure.

4) Describe the diagnosis and treatment of endocarditis

Diagnosis = blood culture; ↑ WBC w/neutrophilia; ↓ Hb, RBC; ECG; abdominal

ultrasound

Treatment = identifying and eliminating causative MO – prolonged cause of anti-B. In

severe cases (valve dysfunction leads to HF) = surgery

5) Define the term myocarditis and describe its etiology

Myocarditis = infectious or immune inflammation of the myocardium (middle,

muscular layer of the heart)

Etiology:

 Infective myocarditis is usually caused by a viral infection (coxsackie virus,

EBV, HCV); bacterial infection (C. diphtheriae, brucella, borrelia, H.
influenzae); or parasitic (T. cruzi → Chagas disease)
  Non-infective myocarditis is usually found in patients w/rheumatic fever or
autoimmune diseases such as lupus.
 Other = toxins (drugs, alcohol), rejection after heart transplant, electric shock,
heavy metals

6) Describe the pathogenesis of myocarditis

 Most forms of myocarditis involve the infiltration of heart tissues by one or two
types of pro-inflammatory blood cells, lymphocytes and macs
 Myocardial inflammation causes swelling → damage to cardiac myocytes
ability to contract → ↓ contractility → ↓ CO. tachycardia also occurs in order to
↑ the contractility of the heart
 Severe myocarditis → fibrosis of myocardium → long-term problems w/heart
contraction → HF

7) Describe the clinical symptoms of myocarditis

 Chest pain (often described as “stabbing” in character)
 Congestive HF → oedema, SOB, and liver congestion
 Palpitations (due to arrhythmias)
 Fever (especially when infectious cause – e.g. in rheumatic fever)

8) Describe the diagnosis

 Blood = ↑ troponin and CK
 ECG = sinus tachycardia, T wave inversion, saddle shape ST elevations
 Chest X-ray = enlarged heart
 Echography = inflamed heart muscle walls

61 – Valvular heart disease. Aortic stenosis

1) Define the term aortic stenosis and describe its etiology

Aortic stenosis = narrowing of the opening of the aortic valve

Etiology:

 Age-related progressive calcification (mean age 65-70 years)

 Congenital defect = bicuspid aortic valve – 2 of the leaflets fuse during
development resulting in a 2 leaflet valve (instead of the normal 3 leaflets)
 Acute rheumatic fever post inflammation
 2) Describe the pathophysiology of aortic stenosis
 Aortic valve normally consists of 3 leaflets/cusps and has an opening of 3-4
cm2. In aortic stenosis, the opening of the aortic valve becomes narrowed
(<1cm2)
 As a consequence of this stenosis, the L ventricle needs to generate a higher
pressure w/each contraction to effectively move blood forward into the aorta
→ concentric hypertrophy – walls of L ventricle are equally thickened;
sarcomeres are added in parallel to existing ones
 In the later stages, the L ventricle dilates, the wall thins, and the systolic
function deteriorates → ↓ CO and ↑ risk of HF
 Syncope (momentary loss of consciousness/fainting) = ↓ blood to brain
 Angina pectoris = ↓ blood to coronary aa.
 Congestive HF can occur
 If the valve doesn’t open properly, as the L ventricle contract → high pressure
created until valve eventually snaps open = ‘ejection click’
 Auscultation = systolic murmur (appears when L ventricle pushes blood to
aorta) due to turbulence (blood must flow through narrow opening)
 The murmur gets louder (as > blood passes through the opening) and
then gets quieter (as amount of blood flow ↓ as < blood is in the
ventricles) = crescendo-decrescendo murmur

3) Describe the clinical symptoms of aortic stenosis

 People w/mild-moderate aortic stenosis are usually asymptomatic
 3 main symptoms = syncope, angina pectoris, and SOB w/activity or other
symptoms of HF such as SOB while laying flat, episodes of SOB at night, or
oedema

62 - Valvular heart disease. Aortic regurgitation

1) Define the term aortic regurgitation and describe its etiology

Aortic regurgitation/insufficiency = incomplete closing of the aortic valve during

diastole, leading to regurgitation of blood from the aorta back to the L ventricle
(backflow of blood)

Etiology:

 Aortic root dilation – idiopathic in 80% of cases, but also may result from
aging, syphilitic aortitis (syphilis), osteogenesis imperfecta, aortic dissection,
and systemic HT
 Congenital abnormalities
  Other = Marfan syndrome, Ehlers-Danlos syndrome, ankylosing spondylitis,
and lupus
 In acute cases the main causes are infective endocarditis, aortic dissection or
trauma

2) Describe the pathophysiology of aortic regurgitation

 Due to incomplete closure of the aortic valve during diastole there is a
regurgitation of a large portion of blood from the aorta back to the L ventricle.
This regurgitant blood flow, plus the blood normally coming from the L atrium
during ventricular filling → dilation of the L ventricle; eccentric L ventricular
hypertrophy (sarcomeres added in series to existing ones)
 ↑ blood volume of the L ventricle → ↑ stroke volume → ↑ systolic blood
pressure
 During diastole there is < volume in the aorta (some has leaked back to L
ventricle) → ↓ diastolic blood pressure
 ↑ systolic + ↓ diastolic bp = ↑ pulse pressure (the difference between them) →
hyperdynamic circulation – i.e. ‘water-hammer’ pulse (blood slams like a
hammer against walls of a. in each heart beat)
 Regurgitation of blood flow causes ↑ L ventricular end-diastolic pressure →
transmitted to L atrium and pulmonary vv. → pulmonary oedema
 ↓ CO → sympathetic stimulation → ↑ in heart rate and peripheral vascular
resistance – cause the regurgitation to worsen
 Auscultation = early diastolic decrescendo murmur can be heard over the
base of the heart, as well as a click and a systolic murmur due to the forced
large-volume ejection

3) Describe the clinical symptoms of aortic regurgitation

Symptoms are similar to those of HF and include the following:

 SOB on exertion
 Orthopnoea
 Paroxysmal nocturnal dyspnoea (SOB at night)
 Palpitations
 Angina pectoris
 Cyanosis (acute cases)

63 - Valvular heart disease. Mitral stenosis

 1) Define the term mitral stenosis and describe its etiology

Mitral stenosis = narrowing of the opening of the mitral valve

Etiology:

 Rheumatic fever (most common)

 Calcification and congenital defects are < common
2) Describe the pathophysiology of mitral stenosis
 The normal mitral valve opening is 4-6 cm2 (mitral stenosis = 2 cm2)
 Symptoms develop as the gradient across the valve becomes worse so that
the L atrial pressure is > L ventricular pressure
 ↑ volume of L atrium → ↑ pressure in L atrium → dilation of L atrium → blood
backs up into pulmonary circulation → pulmonary congestion (L HF) and
oedema
 Extra blood volume in pulmonary circulation → pulmonary HT → hard for R
ventricle to pump blood to lungs → R ventricle hypertrophy → R HF
 Dilation of L atrium also causes muscle wall to stretch → pacemaker cells
become > irritable → atrial fibrillation → stopping of blood flow → thrombus
formation

3) Describe the clinical symptoms of mitral stenosis

 HF symptoms = SOB on exertion, orthopnoea, paroxysmal nocturnal
dyspnoea
 Palpitations
 Angina pectoris
 Haemoptysis
 Thromboembolism – in later stages when the L atrial volume is ↑ (i.e. dilation)
 Ascites and oedema – if R HF develops

64 - Valvular heart disease. Mitral regurgitation

1) Define the term mitral regurgitation and describe its etiology

Mitral regurgitation/insufficiency = incomplete closing of the mitral valve during

systole, leading to regurgitation of blood from the L ventricle back to the L atrium

Etiology:

 Mitral valve prolapse = displacement of an abnormally thickened mitral valve

leaflet into the L atrium during systole.
 IHD
  Rheumatic fever and Marfan syndrome
 Secondary mitral regurgitation – due to dilation of the L ventricle that causes
stretching of the mitral valve annulus (ring) and displacement of the papillary
muscles)

2) Describe the pathophysiology of mitral regurgitation

 The mitral valve is made of an annulus (ring) to which an ant. and a post.
leaflet are attached. These are connected by chordae tendinae to papillary
muscles that arise from the ventricular wall
 In mitral valve prolapse the chordae tendinae are too long → the leaflets
bulge like a parachute into the L atrium, where they open
 Damage to papillary muscle from MI → papillary muscles cant anchor
chordae tendinae → mitral valve prolapse
 The regurgitant volume causes a volume and pressure overload of both L
atrium and ventricle → ↓ CO and eccentric hypertrophy → L HF
 Forward stroke volume (that moving through the aorta into the systemic
circulation) is ↓
 Auscultation = heart murmur → mid-systolic click (leaflet folded into the atrium
and suddenly stopped by chordae tendinae). Little bit of blood flows back from
L ventricle to the L atria. The murmur is holosystolic – lasts for the duration of
systole

3) Describe the clinical symptoms of mitral regurgitation

 Acute = typically have symptoms of acute decompensated congestive HF
(SOB, pulmonary oedema, orthopnoea, and paroxysmal nocturnal dyspnoea),
as well as cardiogenic shock (SOB at rest)
 Chronic = asymptomatic (compensated mitral insufficiency). Over time they
may be decompensation and patient can develop congestive HF

65 – Coronary artery disease. Angina pectoris

1) Define the term coronary a. disease (CAD) and describe its etiology and
pathogenesis

CAD/ischemic heart disease (IHD) = ↓ blood flow to the heart muscle due to build up
of plaque in coronary aa.

Types include stable angina, unstable angina, MI, and sudden cardiac death.

Etiology/predisposition factors:
  HT
 Smoking
 Diabetes; obesity; poor diet; high blood cholesterol; lack of exercise
 Depression, stress
 Family history
 Excessive alcohol

Pathogenesis:

 Narrowing/obstruction of the lumen of the coronary aa. – atherosclerosis;

thrombosis/embolism (very rare); spasm; inflammation
 ↑ O2 demand due to hypertrophy of the myocardium and/or
tachycardia/tachyarrhythmia
 ↓ CO; aortic valve diseases

2) Describe the 3 types of angina

Stable angina (AKA classic angina)

 Definition = chest pain/discomfort that often occurs w/activity or emotional

stress – most common
 Patient usually has > 70% stenosis i.e. 70% of the a. is blocked by plaque
build up
 The small opening that blood flows through is enough to supply the
heart during rest = no pain
 Exercise/stress = ↑ O2 demand = heart needs to work harder and thus
needs > blood and O2 → chest pain – blood flow cant meet metabolic
demands of myocardium

Symptoms include:

 Pain, tightness, or discomfort in chest. It is often retrosternal, but also be in

precordial area, in epigastrium, back, or even in the shoulder, arm or jaw. If
often propagates to last 2 fingers of L arm
 Symptoms usually last 20 mins and subsides w/rest Provoking factors =
physical exercise, stress, HT, tachycardia or extreme bradycardia,
hypoglycaemia, cold weather (↑ need of O 2 by the myocardium)

Unstable angina

Definition = angina pectoris that is irregular – a pattern of angina that occurs

randomly/unpredictably and is unrelated to any obvious trigger such as
exercise/stress

It has at least 1 of the 3 features:

1. It occurs at rest (or w/minimal exertion), usually lasting > 10 mins

 2. It is severe and of new onset
3. It occurs w/a crescendo pattern (i.e. distinctly > severe, prolonged, or frequent
than before)

Stable vs. unstable:

 What differentiates them (other than symptoms) is the pathophysiology of the

atherosclerosis
 The pathophysiology of unstable angina is the ↓ of coronary flow due to
transient platelet aggregation on apparently normal endothelium, coronary a.
spasms, or coronary thrombosis
 The process starts w/atherosclerosis, progresses through inflammation to
yield an active unstable plaque, which undergoes thrombosis and results in
acute myocardial ischemia, which, if not reversed, results in cell necrosis
(infarction)

Variant (Prinzmetal) angina

Definition = angina that commonly occurs in individuals at rest or even sleep (unlike
classical angina which is triggered by exercise/stress)

 It is caused by vasospasm, a narrowing of the coronary aa. due to contraction

of the smooth muscle tissue in the vessel walls. This contrasts w/classical
type which is due to permanent occlusion of the aa. by atherosclerosis
 Vasoconstrictors = thromboxane A2, histamine and endothelin
 People w/variant angina are generally younger and have fewer risk factors for
CAD except for smoking, which is a common and significant risk for both
types of angina
 Symptoms = repeated episodes of unexplained chest pain, light-headedness,
excessive sweating, and/or ↓ exercise tolerance that, unlike classic angina,
typically doesn’t progress to MI

66 – Coronary artery disease. Myocardial infarction

Myocardial infarction (MI) (AKA heart attack) = death (irreversible ischemic necrosis)
of the myocardium due to lack of blood flow and complete blockage of the coronary
aa.

The complete blockage of a coronary a. caused by a rupture of an atherosclerotic

plaque is usually the underlying mechanism of an MI. They are < commonly caused
by coronary a. spasms, which may be due to cocaine, significant emotional stress,
and extreme cold, among others.

Blockage of a. → myocardium becomes ischemic → ↓ contractility of muscle → ↓

stroke volume, HR, and CO → acute heart failure and even death. After 20-40 mins
of ischaemia, the damage becomes irreversible

Coronary aa. most commonly blocked: (NB! All of the below supply the L ventricle)

 L ant. descending – supplies blood to ant. wall and septum of L ventricle

 R coronary a. – supplies post. wall, septum, papillary muscles of L ventricle
 L coronary a. – supplies the lat. wall of the L ventricle

In MI there are 3 zones:

 Ischemic zone = inverted T wave

 Lesion/injury zone = elevated ST
 Zone of infarction/necrosis = deep Q wave

Symptoms:

 Chest pain; can radiate to L arm/jaw (referred pain); doesn’t change

w/position and lasts for > 30 mins
 Sweating, nausea, fatigue, vomiting, and syncope (fainting)
 SOB (dyspnoea)
 Tachycardia EXCEPT for septal infarction (location of AVN → AV block →
bradycardia)
 Cardiac arrest, and atypical symptoms such as palpitations, occur > frequently
in F, the elderly, those w/diabetes, in people who have just had surgery, and
in critically ill patients

Diagnosis:

 ↑ Troponin I and T in blood 2-4 h after MI, peak at 48 h and stay ↑ for 7-10
days
 Other tests, such as CK-MB or myoglobin, are discouraged. CK-MB is not as
specific as troponins for acute myocardial injury, and may be ↑ w/ past cardiac
surgery, inflammation or electrical cardioversion; it rises w/in 4–8 hours and
returns to normal w/in 2–3 days
 ECG = elevated ST wave segment, inverted T wave, new Q wave

Complications:

 w/in 24 hours = arrhythmias, cardiogenic shock – heart unable to pump

enough blood to body
 1-3 days = tissue around infracted area becomes inflamed and invaded by
neutrophils → pericarditis
  3-14 days = macs invade tissues → begins healing process (formation of
granulation tissue) – at this stage, tissue is most sensitive to myocardial
rupture
 After 2 weeks – months = scarring process finishes, tissue becomes white.
Scarred tissue doesn’t help pump blood and overtime the remaining heart
muscle can grow/change shape to compensate and pump harder → ultimately
leads to HF

Treatment:

 Pain management = nitroglycerine or morphine

 Anticoagulation therapy = aspirin is given to ↓ the size of the clot and ↓ further
the clotting in the affected a.
 Angioplasty = surgical removal of blockage
 Stent can be placed in coronary a. to physically open the blood vessels

67 – Pericardial diseases. Pericarditis, pericardial effusion and tamponade

1) Describe the pathophysiology of pericarditis

Definition = inflammation of the pericardium (the fibrous sac that surrounds the
heart).

Classification:

 Acute (< 6 weeks), subacute (6 weeks 6 months), and chronic (> 6 months)
 Serous, purulent, fibrinous, caseous, and haemorrhagic

Etiology:

 Viral (coxsackie, HIV, herpes), bacterial (M. tuberculosis), or fungal infection

 Idiopathic
 Autoimmune disease = lupus, rheumatic fever
 Dressler’s syndrome – post MI syndrome
 Paraneoplastic – in patients w/tumours
 Uremic – in patients w/end stage chronic renal failure
 Postpericardiotomy syndrome – after heart surgery
 Trauma to the heart
 Radiation induced
 Hypothyroidism

Pathophysiology:
  Local VD, ↑ capillary permeability, accumulation of WBC
 Capillaries that supply the serous pericardium become permeable → plasma
proteins (including fibrinogen) exit the capillaries and enter the pericardial
space → fibrosis – over time, it becomes harder for heart to relax/expand → ↓
stroke volume and ↑ HR

Symptoms:

 Chest pain = sharp; retrosternal; exertion doesn’t change the pain; pain is
worse in supine position or upon inspiration; sudden pain, that lasts for hours
or sometimes days
 Fever

Diagnosis:

 Laboratory = can show ↑ urea (BUN) or ↑ blood creatinine in cases of uremic

pericarditis. Generally however, lab values are normal
 ECG = ST segment elevation, PR segment depression, inverted T wave

2) Describe the pathophysiology of pericardial effusion

Definition = abnormal accumulation of fluid in the pericardial cavity

Etiology:

 Pericarditis
 Cancer
 Heart surgery (postpericardiotomy syndrome)
 Trauma
 Hypothyroidism

Pathophysiology:

 Usually results from a disturbed equilibrium between the production and re-
absorption of pericardial fluid, or from a structural abnormality that allows fluid
to enter the pericardial cavity (normal levels = 15-50 ml)
 Significant accumulation of fluid in pericardium results in ↑ adrenergic
stimulation → tachycardia and ↑ cardiac contractility
 There is ↑ central venous pressure, jugular v. distension, ↓ systolic bp,
narrowed pulse pressure, and signs of circulatory shock
 Systolic hypotension can result (due to ↓ ejection fraction) → ↓ CO and ↑
venous pressure
Symptoms:

Small effusions may be asymptomatic. Large effusions (>100 ml) = ↓ heart sounds,
CO, and bp; SOB; light-headedness

Diagnosis:

 ECG = low QRS complex voltage (differing heights of QRS complex due to
heart swinging back and forth in a pool of pericardial fluid)
 Chest X-ray = silhouette that pools at bottom of heart – looks like a water
bottle
 Echocardiogram = heart looks like it’s ‘dancing’ w/in the pericardium

Treatment:

Depends on the extent of effusion

 Small = diuretics to remove fluid and NSAIDs/corticosteroids to minimise fluid

accumulation
 Large = pericardiocentesis – insert needle into pericardial cavity and draining
the excess fluid

3) Describe the pathophysiology of tamponade

Definition = compression of the heart due to the accumulation of fluid, pus, or blood
in the pericardial sac

Etiology = caused by a large/uncontrolled pericardial effusion. This occurs as a result

of chest trauma, myocardial rupture, cancer, uremia, pericarditis, or cardiac surgery

Pathophysiology:

 Accumulation of fluid in pericardium puts pressure on the outside of the heart

 ↑ Intracardiac pressure → heart cant stretch out fully between contractions →
chambers don’t fill properly → ↓ CO (< blood squeezed out w/each heartbeat)
→ hypotension - < blood leaving the heart and reaching organs and tissues →
tachycardia (heart tries to compensate by beating faster
 Normally, inhalation creates a –ve pressure which pulls blood into the heart →
↑ in R heart volume → R ventricle expands into pericardial space
 In cardiac tamponade however, during inhalation, the R ventricle can’t move
into the pericardial space and the extra volume pushes the intraventricular
septum to the L → ↓ ventricular diastolic volume → ↓ stroke volume → ↓
systolic bp – results in ‘pulsus paradoxus’ (when systolic bp is < 10 mmHg)

Symptoms:
  Distended jugular vv. = atria cant distend enough to accommodate venous
blood returning to the heart ∴ blood backs up into the v.
 Tachycardia, coughing, SOB, weakness, light-headedness
 If severe, the heart can become ischemic – may stop beating

Diagnosis:

 Beck’s triad = hypotension (due to 2191 (due to ↓ stroke volume); jugular

venous distension; and muffled heart sounds (due to fluid build up inside the
pericardium)
 ECG = tachycardia, low QRS complex voltage, different heights of QRS
complex
 Echocardiography = shows excess fluid, heart ‘swinging’ inside pericardial
cavity

68 – Primary hypertension

HT = long-term medical condition in which the bp in the aa. is persistently elevated.

Can lead to CAD, stroke, heart failure, peripheral vascular disease, vision loss.

Blood pressure = cardiac output X peripheral resistance.

Category Systolic pressure (mmHg) Diastolic pressure (mmHg)

Normal <120 <80
High normal/pre-HT 120-139 80-89
Stage I 140-159 90-99
Stage II 160-179 100-109
Stage III ≥180 ≥110
Isolated systolic HT ≥160 < 90-110

Primary/essential HT = form of HT that has no identifiable cause. It is the most

common type, affecting 95% of hypertensive patients, it tends to be familial and is
likely to be the consequence of an interaction between environmental and genetic
factors.

Etiology:

 Family predisposition, atherosclerosis

 Hyperlipidaemia (essential or symptomatic – diabetes, hypothyroidism);
obesity; lack of exercise; ↑ intake of salt
 Stress; smoking; excess alcohol consumption
 Hyperactivity of the SNS
  High renin levels predispose to HT by causing Na retention through the
following mechanism = ↑ renin → ↑ angiotensin II → ↑ VC, thirst/ADH and
aldosterone → ↑ Na reabsorption in kidneys → ↑ bp
 Old age

Pathophysiology:

 CO and peripheral resistance are the 2 determinants of arterial pressure

 CO is determined by SV and HR (CO = SV X HR); SV is related to myocardial
contractility and to the size of the vascular compartment
 Peripheral resistance is determined by functional and anatomic changes in
small aa. and arterioles
 CO is ↑ early in the disease
course, w/total peripheral
resistance (TPR) normal; over
time CO drops to normal levels but
TPR is ↑. 3 theories have been
proposed to explain this:
 Overactive RAAS leads to
VC and retention of Na and
H2O. The ↑ in blood volume leads to HT
 An overactive SNS, leading to ↑ stress responses
 Polygenic cause

Symptoms:

For all types of arterial HT = pain/tightness at the back of the head, tiredness,
fatigue, vertigo, drowsiness, nausea. There are also asymptomatic cases of arterial
HT

Treatment = vasodilators to 21 = vasodilators to

↓ peripheral resistance; ACE inhibitors, ARBs

69 – Secondary hypertension

Secondary HT = type of HT which by definition

is caused by an identifiable underlying primary
cause. It is much < common than primary HT,
affecting only 5% of hypertensive patients

Renovascular HT

 The most common form of secondary HT

  Etiology = 2 main causes are fibromuscular dysplasia and renal a. stenosis
(atherosclerosis). Other causes are chronic parenchymal renal diseases –
chronic glomerulonephritis, chronic pyelonephritis, glomerulopathies,
hereditary diseases, and chronic renal failure
 Pathophysiology = they cause renal ischaemia → renin → angiotensin II (↑
TPR) → aldosterone release, ↑ Na retention → ↑ CO = renal HT
 Symptoms = age 30-50, w/significantly ↑ diastolic values; in some cases
hypokalemic alkalosis is present

Hormonal/endocrine HT

 Adrenogenital syndrome = cortisol formation is blocked, and thus ACTH

release isn’t inhibited → ↑ amounts of mineralcorticoid active precursors are
produced and released → Na+ retention → ↑ ECV → ↑ CO and HT
 Primary hyperaldosteronism (Conn’s syndrome) = adrenal cortical tumour
releases large amounts of aldosterone w/out regulation → Na + retention etc.
(same as above)
 Cushing’s syndrome = excessive secretion of glucocorticoids causes the HT –
due to ↓ amounts of ACTH
 Hyper- and hypothyroidism

Neurogenic HT

 Excessive secretion of adrenaline and noradrenaline → VC → ↑ bp

 Pheochromocytoma = adreno-medullary tumour which results in excessive
secretion of adrenaline and noradrenaline which promotes VC – results in
both CO HT and TPR HT

Hypertensive crisis

 Blood pressure = > 180/120

 Divided into hypertensive emergency (damage to end organs) and
hypertensive urgency (no damage yet to end organs – brain, kidney, heart,
lungs)

70 – Circulatory insufficiency. Shock

Circulatory shock = acute failure of the circulatory system to supply the peripheral
tissues and organs of the body w/an adequate blood supply → cellular hypoxia i.e.
hypoperfusion of tissues and organs

Cell response = see image

Compensatory mechanisms:

 ↑ SNS = ↑ HR and VC – adrenaline and noradrenaline activate the α (VC) and

β1 (HR) receptors
 Renin release → angiotensin II → VC, Na+ and H2O retention
 Other vasoconstrictors = noradrenaline, vasopressin, endothelin

Shock

Hypovolemic shock

 Most common type, cause by insufficient circulating volume (intravascular

volume)
 Non-haemorrhagic = not from bleeding –
e.g. severe dehydration = low fluid = low
blood volume = shock
 Haemorrhagic = loss of blood volume from
ruptured blood vessels. Loss of 20% blood
volume (1L) can induce this type.
 Pathophysiology of haemorrhagic shock = ↓
end diastolic volume → ↓ SV → ↓ CO → ↓
bp → compensatory mechanisms (see
image)
 Symptoms = depends on severity – thirst,
tachycardia, cool and clammy skin - ‘cold
shock’ (due to intense VC via ↑ SNS), ↓ bp,
oliguria

Cardiogenic shock

 Caused by failure of the heart to pump blood effectively to meet the body’s
demands – due to dysfunction of the ventricles
 Clinically, it is defined as ↓ CO, hypotension, hypoperfusion, and indications of
tissue hypoxia, despite adequate intravascular volume
 Causes = MI (most common), myocardial contusion (blunt cardiac injury),
sustained arrhythmias, cardiac surgery, end stage of CAD or cardiomyopathy
 Pathophysiology = MI → muscle cells die → weaker contraction → ↓ stroke
volume and CO; vasoconstrictors are released to ↑ vascular resistance and
bp
 Symptoms = hypotension; cool, clammy skin (due to VC); distended jugular
vv. (due to ↑ jugular venous pressure); oliguria; hyperventilation; fatigue (due
to hyperventilation and hypoxia); cyanosis; pulmonary oedema

Obstructive shock
  Form of shock associated w/physical obstruction of the great vessels or the
heart itself
 Causes = cardiac tamponade, pulmonary embolism, aortic stenosis,
constrictive pericarditis
 R heart pressure is ↑ due to R ventricular dysfunction → distension of jugular
vv.
 Treat via removing/correcting the obstruction – pericardiocentesis; fibrinolytic
drugs

Distributive shock

Definition = abnormal distribution of blood flow in the microvasculature which results

in inadequate blood supply to the tissues and organs. The types include

Septic shock

 It is a serious condition that occurs when a body-wide infection leads to

dangerously low bp – it is the most common type
 LPS (endotoxins) in outer membrane of G –ve bacteria damage endothelial
cells (also release PAF and ROS) → release of vasodilators (NO) → LPS also
activate complement that stimulates mast cells to release histamine; macs
and neutrophils are also activated (release TNF, IL-1)
 ↑ vascular permeability = vessels become leaky
 The endothelium also releases tissue factor (↑ blood clotting) = further ↓ in
perfusion
 Widespread VD = very low vascular resistance = blood moves too fast to
unload O2 (blood comes back to the R side of the heart w/left over O 2)
 Signs and symptoms = tachypnoea; tachycardia; WBC either significantly ↑/↓;
fever/hypothermia

Anaphylactic shock

 Caused by a severe anaphylactic rxn to an allergen, Ag or drug causing the

release of histamine → widespread VD → hypotension and ↑ capillary
permeability
 Symptoms = abdominal cramps, warm/burning sensation of skin, hives,
respiratory distress, hypotension, weak pulse
 Treatment = adrenaline – acts on α and β receptors → VC and relaxation of
bronchi. Can also use antihistamines and bronchodilators

Neurogenic shock

 Loss of sympathetic vasomotor tone

 Rare; may occur when, for e.g., brain stem/spinal cord trauma or intoxication
disturb ANS regulation of the heart and circulation, and the venous return is
markedly reduced
  Symptoms = hypotension (due to VD); warm, flushed skin; heart rate slower
than normal
 If injury below C5 = diaphragmatic breathing due to loss of nervous control of
the intercostal muscles (which are required for thoracic breathing)
 If injury above C3 = respiratory arrest after injury, due to loss of nervous
control of the diaphragm

71 – Hypotension

Hypotension = low bp - <90/60

Causes = hypovolemia (most common), hormonal changes, VD, side effects of

meds, anaemia, heart or endocrine problems

Orthostatic hypotension (AKA postural hypotension)

 Abnormal ↓ in bp that occurs when a person stands up after having been

seated/supine position
 Normally this ↓ is transient because the baroreceptors in the thorax and
carotid sinus sense the ↓ pressure and initiate reflex VC of vv. and arterioles
and an ↑ in HR → bp returns to normal
 Pathophysiology = happens when gravity causes blood to pool in the lower
extremities → compromised venous return → ↓ CO and ↓ bp
 E.g. changing from a lying position to standing loses about 700 ml of blood
from the thorax, w/a ↓ in systolic and diastolic blood pressures. The overall
effect is an insufficient blood perfusion in the upper part of the body
 Symptoms = light-headedness, difficulty concentrating, blurred vision, vertigo,
palpitations, nausea
 Diagnosis = measure bp after lying flat for 5 mins, then 1 min after standing,
and 3 mins after standing. It is defined as a ↓ in systolic bp of at least 20
mmHg and/or in the diastolic bp of at least 10 mmHg between the supine and
upright readings

Causes:

 Hypovolemia = due to excessive use of diuretics, excessive diaphoresis

(sweating), vomiting or diarrhoea. Result = vascular compartment is partially
filled; weakness and fainting
 Drug-induced hypotension = anti-HT drugs, psychotropics
 Aging
 > 70 years = ↑ tendency towards arterial pressure instability and
orthostatic hypotension
  Diminished ability to ↑ HR, ventricular SV, or peripheral resistance
 ↓ function of skeletal muscle pump
 Bed rest and immobility = promotes ↓ in plasma volume, ↓ in venous tone;
failure of peripheral VC and weakness of skeletal muscles that support vv.
and assist in returning blood to the heart
 Disorders of the ANS function

72 – Overview of gastrointestinal disorders

Disorders of the GI system generally present w/1/> of the following classic signs:

 Pain in abdomen or chest

 Indigestion, possibly w/dysphagia, odynophagia (pain when swallowing) or
anorexia
 Altered bowel movements
 GI bleeding

GI disorders can lead to complications such as dehydration or sepsis acutely and

malabsorption in chronic conditions, as such, they should be treated with caution.

GI diseases may be limited to the GI tract (e.g. reflux oesophagitis, peptic ulcer),
may be a manifestation of a systemic disorder (e.g. inflammatory bowel disease) or
present as a systemic disease, resulting from a primary GI pathologic process (e.g.
malabsorption).

We can divide the disorders of the GI system into upper GI complains and Lower GI
complaints , each w/their more commonly associated symptoms.

Upper GI:

 Chest pain
 Chronic and recurrent abdominal pain
 Dyspepsia
 Lump in throat
 Halitosis (bad breath)
 Nausea and vomiting

Lower GI:

 Constipation
 Diarrhoea
 Gas/bloating
 Abdominal pain
  Rectal pain/bleeding

73 – Oesophageal achalasia

Review of the anatomy of the oesophagus

 A fibromuscular tube (25 cm) through which food passes (aided by peristaltic
contractions) from the pharynx to the stomach.
 Lined w/non-keratinised stratified epithelium
 Submucosal layer = mucous secreting (lubrication)
 Muscularis layer = peristalsis
 The muscular layers of the oesophagus = internal circular and external
longitudinal layers.
 The external layer is composed of different muscle types in each 1/3 of the
oesophagus:
 Sup. third = voluntary striated muscle
 Middle third = voluntary striated and smooth muscle
 Inf. third = smooth muscle
 2 functional sphincters = upper (pharynx → oesophagus) and lower
(oesophagus → stomach) oesophageal sphincters
 Opening of upper sphincter is triggered by the swallowing reflex – it is usually
closed to prevent air from entering the oesophagus.
 Lower sphincter = during peristalsis it is relaxed to allow food to enter the
stomach. Otherwise at rest it is closed to prevent the reflux of acid

Oesophageal achalasia

 Definition = failure of smooth muscle fibers to relax, which causes the lower
oesophageal sphincter (LES) to remain closed, thus preventing food passing
into the stomach and the oesophagus above the LES becomes enlarged
 It is an oesophageal motility disorder involving the smooth muscle layer of the
oesophagus and the LES
 It is characterized by incomplete LES relaxation, increased LES tone, and
lack of peristalsis of the oesophagus (inability of smooth muscle to move food
down the oesophagus) in the absence of other explanations like
cancer/fibrosis

Etiology

 LES pressure and relaxation are regulated by excitatory (e.g., ACh, substance
P) and inhibitory (e.g. NO, VIP) NTs. People w/achalasia lack noradrenergic,
non-cholinergic, inhibitory ganglion cells, causing an imbalance in excitatory
and inhibitory neurotransmission. The result is a hypertensive non-relaxed
esophageal sphincter
  ↑ pressure in LES → obstruction and dilation of oesophagus → accumulation
of food can cause growth of bacteria and inflammation → oesophagitis and
pneumonia

Symptoms

 Dysphagia – tends to become progressively worse over time and to involve

both fluids and solids
 Regurgitation of undigested food
 Pulmonary aspiration – oesophageal contents into the lungs when the person
lies down → pneumonia
 Cough
 Chest pain behind the sternum
 Weight loss

Diagnosis and treatment

 Barium swallow and oesophageal manometry (oesophageal motility study)

 Can also do oesophagogastroduodenoscopy (EGD), w/or w/out endoscopic
ultrasound to rule out possibility of cancer
 Can ↓ pressure at LES via:
 Nifedipine (Ca2+ channel blocker) – has side effects such as headaches
and swollen feet
 Surgical myotomy of LES – cut muscle of LES
 Balloon dilation of LES – balloon inflates and opens the LES and
allows relaxation that can hopefully be sustained over time

74 – Reflux oesophagitis

 Definition = long-term condition in which there is reflux of stomach contents

into the oesophagus, resulting in either symptoms or complications.
 Clinically, it is referred to as gastroesophageal reflux disease (GERD)
 GERD is thought to be associated w/temporary/brief relaxations of
weak/incompetent LES (i.e. LES isn’t closed properly). This allows reflux to
occur and, in addition, decreased clearance of the refluxed acid from the
oesophagus from the oesophagus after it has occurred
 Delayed gastric emptying also may contribute to reflux by increasing gastric
volume and pressure w/greater chance for reflux
 Oesophageal mucosal injury is related to the destructive nature of the
refluxate and the amount of time it is in contact w/mucosa
Etiology

Factors that can contribute GERD include:

 Hiatal hernia - ↑ the likelihood of GERD due to mechanical and motility factors
 Obesity
 Zollinger-Ellison syndrome – can be present w/↑ gastric acidity due to gastrin
production
 Hypercalcaemia – can ↑ gastrin production → ↑ acidity
 Visceroptosis or Génard syndrome – stomach has sunk in the abdomen
upsetting the motility and acid secretion of the stomach.
 Alcohol, heavy smoking, chocolate, caffeine, fatty foods

Symptoms

 Heartburn = 30-60 min after eating, relived by sitting upright, often occurs at
night
 Chest pain (epigastric/retrosternal area) = radiates to throat, shoulder, or back
 Sour metallic taste in the mouth
 Dysphagia
 Dry cough, sore throat, hoarseness = acid damaging the larynx
 Regurgitation of food or sour liquids

Complications

 Erosion of mucosal surface of oesophagus

 Ulcers
 Bleeding
 Oesophageal strictures – caused by combo of scar tissue, spasm, and
oedema, and produce narrowing of the oesophagus → dysphagia
 Barrett’s oesophagus = intestinal metaplasia (changes of the epithelial cells
from squamous to intestinal columnar epithelium) of the distal oesophagus
 Oesophageal adenocarcinoma

Diagnosis and treatment

 Diagnosis is usually made clinically. Other investigations may include EGD

and oesophageal pH monitoring but not barium swallow and oesophageal
manometry
 Treatment = PPIs (omeprazole), H2 receptor antagonists (cimetidine) – inhibit
gastric acid production, antacids – inhibit gastric acid secretion; avoid
caffeine, fatty food, chocolate, spicy food; sit up and sleep w/head elevated
  Surgery for severe GERD is Nissen fundoplication = upper part of stomach is
wrapped around LES to strengthen it and prevent acid reflux and to repair a
hiatal hernia – recommended only for those who don’t improve w/PPIs

75 – Acid-peptic disease. Acute erosive gastritis and chronic atrophic gastritis

 Gastritis = inflammation of the lining of the stomach

 The stomach lining is usually impermeable to the acid it secretes which allows
the stomach to contain acid and pepsin w/out having its walls digested
 The gastric mucosal barrier includes an impermeable epithelial cell surface
covering, coupled secretion of hydrogen and bicarbonate ions and the
characteristics of gastric mucus
 Epithelial layer of the stomach are connected by tight junctions → prevent
acid penetration, and are covered by a hydrophobic lipid layer that prevents
diffusion of water soluble molecules.

Acute erosive gastritis

 Characterised by an acute inflammation of the inner mucosal lining of the

stomach wall which is usually brief in nature
 Inflammation may be accompanied by haemorrhage into the mucosa of the
stomach and, in severe cases, acute gastric bleeding

Etiology

 NSAIDs
 Ischaemia
 Stress – multiorgan failure, burns, surgery, CNS trauma
 Alcohol abuse, corrosive chemicals
 Trauma – gastroscopy, swallowed foreign body, retching, vomiting, radiation
 Bacterial infections – e.g. H. pylori – typically starts as an acute gastritis in the
antrum, causing inflammation and over time, it may extend to involve the
entire gastric mucosa resulting in chronic gastritis
 The major mechanism of injury is the reduction of prostaglandin synthesis –
prostaglandins are responsible for maintaining the mechanisms that result in
the protection of the mucosa from injurious effects of gastric acid

Symptoms

 Complaints vary
 People w/aspirin (NSAID) related gastritis can be totally unaware of the
condition or may complain only of heartburn/sour stomach
 Gastritis associated w/excessive alcohol consumption = causes temporary
gastric distress, which may lead to vomiting; > severe = bleeding and
haematemesis
  Gastritis caused by bacterial infections = abrupt and violent onset, w/gastric
distress and vomiting
 Acute gastritis is usually a self limiting disorders, w/complete regeneration and
healing occurring w/in several days of removal of the causative agent

Chronic atrophic gastritis

Definition = chronic inflammation which eventually leads to atrophy of the stomach

mucosa, causing significantly reduced n.o’s of parietal and main cells followed by ↓
secretion of HCl, intrinsic factor, and pepsin.

There are 3 types of chronic gastritis

H. pylori gastritis

 Chronic inflammatory disease of the antrum and body of the stomach caused
by H pylori
 H pylori colonize the mucus-secreting epithelial cells of the stomach. They
have flagella, which allow them to move through the mucous layer of the
stomach
 H pylori secrete urease (breaks down urea → ammonia and CO 2). The
alkaline ammonia neutralizes gastric acid ; why it is able to survive the acidic
environment in the stomach.
 H pylori produces enzymes and toxins that interfere w/the local protection of
the gastric mucosa against acid and produce continuous inflammatory
response (Neutrophils, B and T lymphocytes recruited)
 The inflammation can extend deeper into the gastric glands resulting in
atrophy → atrophic gastritis, and metaplasia (gastric epithelium → intestinal
epithelium)
 Treatment: combo of 2 anti-B (clarithromycin + amoxicillin) w/PPI

Chronic autoimmune gastritis

 Associated with other autoimmune disorders e.g. DM1

 Autoantibodies to the gastric parietal cells and intrinsic factor → defective
gastric acid secretion and vit. B12 deficiency
 Affects the body and fundus, sparing the antrum
 Lack of intrinsic factor → defect in vit B12 absorption →deficiency and slow-
onset megaloblastic anemia. Also get atrophic glossitis (smooth and beefy red
tongue), malabsorptive diarrhoea, neuropathies.
 Slow onset and progression

Chemical gastropathy

 Chronic gastric injury resulting from reflex of alkaline duodenal contents,

pancreatic secretions, and bile into the stomach
  Will enter through the pyloric valve of the stomach if it has been removed
during surgery or doesn’t work properly
 Most commonly seen in people who have had gastroduodenostomy or
gastrojejunostomy surgery

Symptoms for gastritis

 Many people are asymptomatic

 Upper central abdominal pain
 Nausea, vomiting, belching, bloating
 Early satiety, loss of appetite, weight loss

Diagnosis

 Blood tests = blood cell count, presence of H. pylori

 Urine analysis
 Endoscopy (to check for inflammation of stomach lining and mucous erosion)
and stomach biopsy
 Stool sample – to look for blood in stool

76 – Acid-peptic disease. Gastric ulcer & 77 – Duodenal ulcer

 Definition = a break in the lining of the stomach (gastric ulcer) or the

duodenum (duodenal ulcer) or both, which may be acute or chronic

Review of GI system

 Review of GI mucosa
 Epithelial layer = absorbs and secretes mucous and digestive enz.
 Lamina propria = blood and lymph vessels
 Muscularis mucosa = smooth muscles
 4 regions:
 Cardia = epithelial cells mostly secreting mucous
 Fundus and body = mostly parietal cells which secrete HCl; chief cells
which secrete pepsinogen
 Pylorus = G cells which secrete gastrin (stimulates parietal cells to
secrete HCl
 Prostaglandins are also secreted in the stomach and duodenum – stimulate
mucous and bicarbonate secretion (to neutralise the acid and protect the
mucosa); VD of nearby blood vessels → epithelial cell growth and acid
secretion

Etiology
  H. pylori bacteria
 NSAIDs (mostly gastric ulcers) = inhibit COX enz. which synthesise
prostaglandins → ↓ prostaglandins = gastric mucosa is susceptible to damage
 Zollinger-Ellison syndrome/gastrinoma (duodenal ulcers) = a disease in which
tumours release abnormal amounts of gastrin which stimulates excess
secretion of HCl from parietal cells → damage to stomach mucosa → peptic
ulcers
 Alcohol, tobacco, spicy foods, and caffeine worsen peptic ulcers
 Stress (shock, burns, operation)

Pathogenesis

 Gastric ulcers typically form in the lesser curvature of the antrum

 Gastric ulcer is caused by inadequate natural defence of the stomach’s
mucosa against pepsin and HCl
 Duodenal ulcers typically occur right after the pyloric sphincter. Brunner gland
(secrete mucous rich in bicarbonate ions) hypertrophy occurs
 Duodenal ulcer = pathologically excessive secretion of HCl

Symptoms

 Gastric ulcer = pain in epigastrium (often in L epigastrium) provoked by food,

which appears during a meal or shortly after (30 mins)
 Duodenal ulcer = pain in epigastrium (often in R epigastrium) on empty
stomach, which is relieved by food and antacids. It also appears late after
meals (3 hours)
 Bloating and abdominal fullness (heaviness in the abdomen)
 Belching
 Nausea and vomiting
 Loss of appetite and weight loss
 Haematemesis = can occur due to bleeding directly from a gastric ulcer, or
from damage to the oesophagus from severe/continuous vomiting

Diagnosis

 EGD
 Biopsy is performed to check for signs of malignant cells of H. pylori infection
 Diagnosis of H. pylori can also be made by urea breath test or stool Ag test

Treatment = combo of anti-B and PPIs for H. pylori infection

Complications

 Very deep ulcers can erode into underlying blood vessels → bleeding →
haemorrhage into GI tract can happen → rapid loss of blood → shock
  Perforation = ulcer erodes all the way through the wall of the stomach or
duodenum → GI contents enter the peritoneal space
 Duodenal ulcer = perforation on ant. wall of duodenum → air collects under
diaphragm → irritating phrenic n. → referred pain up to the shoulder
 Long standing duodenal ulcers near pyloric sphincter = much scarring or
oedema → obstructs normal passage of gastric contents → gastric outlet
obstruction → nausea and vomiting

78 – Disorders of the gallbladder. Cholelithiasis

Review of gallbladder anatomy

 A hollow organ that sits in a shallow depression below the R lobe of the liver.
 Pear-shaped sack w/its tip opening into the cystic duct, lying on the inf.
surface of the liver in a fossa
 Makes contact w/the duodenum and transverse colon
 Function = receive bile from the liver, concentrate it, store and release it -
contracts to expel bile as a result of stimulation by CCK hormone

Cholelithiasis (AKA gallstones)

 Definition = metabolic disease characterised by the formation of stones in the

gallbladder and/or the bile ducts (choledocholithiasis)
 Gallstones = small, round stones found inside the gallbladder. Types =
cholesterol, bilirubin, and mixed
 3 factors contribute to formation of gallstones
 Abnormalities in composition of the bile
 Stasis of bile
 Inflammation of the gallbladder
 Cholesterol stones = made of cholesterol that has precipitated out of the bile
as a solid and forms stones (80%)
 Not enough salts/acid or phospholipids in the bile to keep cholesterol in
solution
 Gall bladder stasis – if the bile just sits in the gallbladder it can cause
the cholesterol to separate and precipitate out as a solid
 Bilirubin stones (20%) = made mostly of unconjugated bilirubin and thus are
pigmented; formed when there is too much bilirubin in the bile and combines
w/Ca2+ to form a solid precipitate → visible on X-ray (unlike cholesterol
stones)

Predisposition factors
  ↑ level of cholesterol – familial hypercholesterolemia, diabetes,
hyperthyroidism, treatment w/hormonal contraceptive and other causes of ↑
estrogen levels; impaired cholesterol metabolism in the liver due to hereditary
enz. deficiency, or consequence of hepatitis and cirrhosis
 Obesity and F sex - ↑ risk of gallstones
 Indirect bilirubin in the bile – haemolytic anaemia, Gilbert’s disease
 ↑ Ca2+ levels – hyperparathyroidism
 Rapid weight loss = ↓ lipids = imbalance in bile composition = ↑ risk of
gallstone formation
 Obstructed drainage of the gallbladder or bile ducts – dyskinesia, atonia,
stenosis
 Chronic cholecystitis

Clinical forms and symptoms

1) Latent form = no symptoms; the stone is discovered accidentally by

abdominal ultrasound or on X-ray
2) Dyspeptic form = main symptoms are nausea, sometimes vomiting, bitter
taste in the mouth, heaviness/dull pain in the R hypogastrium which is usually
provoked by fatty and fried foods, eggs, chocolate, coffee, alcohol
3) Biliary colic (gallstone attack – when the stone is obstructing the cystic duct or
common bile duct)
 Severe pain in the R hypogastrium which propagates towards the back
and R shoulder (the attack often occurs in the night)
 Nausea, vomiting of green fluid (bile) w/bitter taste (but not in total
obstruction of common bile duct)
 Brownish urine and jaundice (if common bile duct is obstructed)
 Possible intermittent fever even w/out concomitant infection

Diagnosis

 Diagnosis is typically confirmed by abdominal ultrasound.

 Other imaging techniques include ERCP (endoscopic retrograde
cholangiocholecystopancreatography) or MRCP (magnetic resonance CP)

79 – Disorders of the small intestine. Diarrhoea

Intestinal motility is controlled by neurons located in the submucosal and myenteric

plexuses of the gut. As a general rule, PNS ↑ motility of the bowel, whereas SNS
stimulation tends to ↓/slow its activity
Definition = excessive, frequent passage of stool – it is the condition of having at
least 3 loose, liquid, or watery bowel movements each day. It often

Types of diarrhoea:

 Acute diarrhoea = abnormally frequent discharge of semisolid or fluid faecal

matter from the bowel, lasting <14 days. Usually due to infection
 Secretory = means that there is an ↑ in the active secretion, or there is an
inhibition of absorption. Most common cause is cholera toxin that stimulates
secretion of anions (especially Cl-). Therefore, to maintain a charge balance in
the GI tract, Na+ is carried w/it along w/water
 Osmotic = occurs when too much water is drawn into the bowels. If a person
drinks solutions w/excessive sugar or salt, these can draw water from the
body into the bowel and cause this type. Maldigestion or osmotic laxatives
also cause this type
 Exudative = occurs w/the presence of blood and pus in the stool. Occurs
w/IBDs such as Crohn’s disease or ulcerative colitis, and food poisoning
 Inflammatory = occurs when there is damage to the mucosal lining/brush
border, which leads to a passive loss of protein-rich fluids and a ↓ ability to
absorb these lost fluids. Can be caused by infections or autoimmune
problems
 Chronic = when symptoms persist for 3-4 weeks

Etiology

 Acute diarrhoea = most commonly due to viral gastroenteritis w/rotavirus,

which accounts for 40% of cases in children under five.

 In travellers, however, bacterial infections predominate. Various toxins such

as mushroom poisoning and drugs can also cause acute diarrhoea.

 Chronic diarrhoea can be the part of the presentations of a number of chronic

medical conditions affecting the intestine. Common causes include ulcerative
colitis, Crohn's disease, microscopic colitis, celiac disease, IBS and bile acid
malabsorption

Health effects

 Electrolyte imbalances
 Renal impairment
 Dehydration
 Weight loss
  Defective immune system responses

Diagnosis and treatment

 Diagnosis is based on complaints of frequent stools

 For chronic diarrhoea = stool tests, colonoscopy (check for cancer)
 Acute diarrhoea is self-limiting and requires no treatment
 Treatment = replacement of fluids and electrolytes.

80 – Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon

and SI. Crohn’s disease and ulcerative colitis (UC) are the main types of IBD. The
cause

Etiology

 Exact cause is unknown, it arises as a result of the interaction of

environmental and genetic factors leading to immunological responses and
inflammation in the intestine
 Diet = gluten sensitivity is common in IBD and associated w/having flare-ups.
Diet high in protein, particularly animal protein, may be associated w/↑ risk of
IBD and relapses
 Microbiota = alterations in the microbiome may contribute to IBD
 Breach of intestinal barrier = loss of integrity of the intestinal epithelium plays
a key pathogenic role in IBD

Crohn’s disease

 Definition = a type of IBD that may affect any part of the GI tract from mouth to
anus
 In 50% of cases it affects mainly the ileum and cecum

Clinical manifestations

 Sharp, demarcated granulomatous lesions that are surrounded by normal-

appearing mucosal tissue
 All the layers of the bowel are involved – submucosal layer affected to the
greatest extent – inflammatory and fibrotic changes
 Surface of inflamed bowel has a cobblestone appearance (fissures and
crevices develop)
 After time the bowel becomes thickened and inflexible
 Main symptoms = diarrhoea, abdominal pain, weight loss, fluid and
electrolyte disorders, malaise, and low-grade fever
 Diarrhoea is < bloody than UC (submucosal layer is mostly affected in
Crohn’s)
Complications = fistula and abdominal abscess formation, intestinal obstruction

Diagnosis and treatment

 History and physical examination; endoscopy and biopsy

 CT scan = detects inflammatory mass, fistula or abscess
 Treatment = anti-B (effective in long term), maintain adequate nutrition (high
in cals, vits, and proteins, low in fats).
 Surgical resection of damage bowel, drainage of abscesses or repair of fistula
tracts may be necessary

Ulcerative colitis

 Definition = long-term condition that results in inflammation and ulcers of the

colon and rectum
 Mainly affects the mucosal layer
 May involve the rectum alone (ulcerative proctitis), rectum and sigmoid colon,
or the entire colon (pancolitis)
 Lesions form in the crypts of Lieberkuhn in the base of the mucosal layer
 Inflammatory lesions can become necrotic and ulcerate
 Mucosal layer develops tongue-like projections called pseudopolyps

Clinical manifestations

 Attacks of diarrhoea (can persist for days, weeks or months and then subside
and recur again after several months to years)
 Because it affects the mucosal layer → stools typically contain blood and
mucus
 Abdominal cramping, fecal incontinence, anorexia, weakness, fatigue
 Mild form → intermittent rectal bleeding, liquid stools
 Moderate form → severe diarrhoea and bleeding, abdominal pain
 Severe form → bloody stools resulting in severe anaemia, hypovolemia,
impaired nutrition.
 Complications = cancer of the colon

Diagnosis and treatment

 History and physical examination

 Sigmoidoscopy, colonoscopy, biopsy. DON’T perform colonoscopy in persons
w/severe form → danger of perforation
 Avoid caffeine, lactose, spicy foods. Take fibre supplements
 Medications:
 5-aminosalicylic acid (5-ASA)
 Corticosteroids
 Anti TNF therapies
  Probiotics

Comparison between Crohn’s and UC

Characteristic Crohn’s disease UC

Type of inflammation Granulomatous Ulcerative and exudative
Level of involvement Mainly submucosal Mainly mucosal
Areas of involvement Mainly ileum, secondarily ileum Mainly rectum and L colon
Diarrhoea Common Common
Rectal bleeding Rare Common
Fistulas and strictures Common Rare
Perianal abscesses Common Rare
Development of cancer Uncommon Relatively common

Management (treatment)

Crohn’s disease UC
5-ASA (Mesalazine) < useful > useful
Anti-B Effective in long term Generally not useful
Surgery Often returns following Usually cured by removal
removal of affected part of colon

81 – Diverticular disease. Constipation

Diverticular disease

 Diverticulosis = the condition of having multiple pouches (diverticula) in the

colon that are not inflamed.
 Diverticula = outpockets of the colonic mucosa and submucosa through
weaknesses of muscle layers in the colon wall. They typically cause no
symptoms.
 Diverticular disease = occurs when diverticula become inflamed
(diverticulitis), or bleed
 Sometimes the diverticula/pouch includes all of the colon layers = ‘true
diverticula’
 Or the mucosa and submucosa layer poke through the muscle layer →
‘pseudo diverticula’ i.e. no muscle layer, pseudo = false
 Colonic diverticula = result from high pressures in the colon due to
exaggerated or abnormal contraction of smooth muscles (as diameter ↓, the
pressure ↑)
 Sigmoid colon is where most diverticula form (has the smallest lumen
diameter and higher pressures)
  Additionally, diverticula forms in spots where the blood vessels that supply the
intestinal walls travel through the muscle layer → blood vessel can rupture →
blood in stool
 ↑ stress or ↓ strength of intestinal walls → diverticula
 Risk factors = advanced age, constipation, diet low in fiber, CT disorders
(Marfan, EDS) – may cause weakness in the colon wall, genetic
predisposition, extreme weight loss, heavy meat consumption

Symptoms and complications

 Most people remain asymptomatic

 Some people complain of cramping, bloating, flatulence, and irregular
defecation – could be attributed to coexistent IBS
 Diverticulitis = due to erosion of diverticular wall from higher luminal pressures
→ pain in L lower quadrant, not associated w/bleeding (blood vessels become
scarred from inflammation)
 If the diverticula becomes distended enough → it might rupture and form a
fistula (connection w/nearby organ) e.g. fistula connecting LI and bladder may
form; ‘colovesicular fistula’; result in air or stool in the urine

Diagnosis and treatment

 Abdominal X-ray – may show signs of a thickened wall, ileus, constipation,

small bowel obstruction or free air in the case of perforation
 Contrast CT; colonoscopy – will show diverticulum and rule out malignancy
 Treatment = anti-B, high fiber diet, surgical removal

Constipation

 Definition = bowel movements that are infrequent or hard to pass.

Constipation is a syndrome, not a disease

Etiology

 Primary/functional constipation = not due to an underlying cause such as

meds or underlying medical condition. Causes include = low fiber diet,
dehydration, ↓ physical activity
 Secondary causes = side effects of meds such as opiates, diuretics;
endocrine and metabolic disorders such as hypothyroidism, diabetes,
hypercalcaemia, celiac disease; and obstruction such as from colorectal
cancer

Pathophysiology classes into 3 broad categories:

  Normal-transit constipation = difficulty in defecation and usually responds to
fluid ↑ and fibre intake
 Slow-transit constipation = infrequent bowel movements due to alteration in
intestinal movements
 Defecatory disorders = dysfunction of pelvic floor or anal sphincters

Complaints w/constipation

 Straining w/bowel movement = stools are hard and dry

 Pain w/bowel movements secondary to straining
 Abdominal pain and bloating
 Tenesmus = a feeling of incomplete defecation

Treatment

 ↑ intake of water and fiber (either dietary or supplements)

 Laxatives – routine use is discourages

82 – Etiology and pathogenesis of liver diseases

 The liver is the largest and most versatile organ in the body.
 It is located between the GIT and systemic circulation
 Venous blood from the intestine flows through the liver before it is returned to
the heart

The main functions of the liver include:

 Synthesis of plasma proteins

 Maintenance of blood glucose levels
 Regulation of circulating lipoprotein levels and vitamins, mineral storage
 Metabolism and elimination of harmful toxins and drugs
 Conversion of ammonia to urea
 Removal of bilirubin (product of haemoglobin breakdown) from the blood
 Liver disease can be acute or chronic, focal or diffuse, mild or severe, and
reversible or irreversible.
 75% of liver cells have to be affected before decrease in function occurs

Etiology
  Liver disease can be inherited (genetic) or caused by a variety of factors that
damage the liver
 Infection: Hepatitis A, B, C
 Immune system abnormality (autoimmune liver diseases): autoimmune
hepatitis, biliary cirrhosis
 Genetics: Alpha-1 antitrypsin deficiency
 Cancer
 Chronic alcohol abuse, fat accumulating in the liver (non-alcoholic fatty liver
disease)
 Over time, damage to the liver causes scarring (cirrhosis), which can lead to
liver failure

Symptoms

 Jaundice
 Abdominal pain and swelling
 Swelling in legs and ankles
 Dark urine colour
 Pale stool or bloody or tar coloured stool
 Chronic fatigue
 Nausea or vomiting
 Loss of appetite
 Tendency to bruise easily

83 – Types of liver dysfunction

Defects in amino acid metabolism:

 AAs are delivered to the liver from the gut or from general circulation
 In the liver AAs undergo 2 types of metabolism = oxidative deamination
(removal of amino group to form keto acid and ammonia) and transamination
(conversion of ammonia to urea)
 Since oxidative deamination results in the production of ammonia, any
impairment of AA metabolism results in the ↓ of blood urea nitrogen level and
an ↑ in the amount of circulating ammonia.
 ↑ levels of ammonia can be toxic especially to the brain → hepatic coma
 This can occur in hepatic parenchymal disease, severe acute hepatic failure,
hepatocyte failure

Defects in protein synthesis

 Hepatocytes synthesise albumin and some Ig’s

  In chronic diffuse liver disease or in severe acute liver disease = ↓ levels of
circulating albumin and Ig’s
 ↓ levels of albumin leads to decreased plasma binding of drugs, it can also
lead to oedema formation

Defects in carb metabolism

 Hepatocytes actively stores glucose by converting it to glycogen. Glycogen

can then be later broken down to release glucose in the general circulation (if
blood sugar level falls)
 Impaired CHO metabolism due to liver disease results in hyperglycemia or
hypoglycaemia; when food is ingested they tend to become hyperglycaemic
because the hepatocytes cannot store glycogen while, as dietary intake is
decreased or absent, the hepatocytes cannot mobilize glucose from what little
stored glycogen there is = hypoglycaemia → ‘hepatic diabetes’

Defects in lipid metabolism:

2 main manifestations of liver failure is associated w/lipid metabolism;

 Deposition of triglycerides w/in the organ itself → ‘fatty liver’ (a result of

chronic alcoholism)
 Reduction in rate of synthesis of cholesterol

Impaired production of clotting factors:

 Fibrinogen, prothrombin, factors V, VII and X are all produced in the liver.
Impaired production = coagulation defects
 NOTE: measuring prothrombin time is a good indicator of the progress of
acute hepatitis

Impaired detoxification function:

 The liver is responsible for detoxifying substances from the gut, drugs and
circulating hormones and alcohol
 In liver disease, some drugs are not degraded properly for excretion →
hepatotoxicity

84 – Manifestations of liver dysfunction

Function Manifestation of altered function

Production bile salts Malabsorption of fat and fat-soluble vitamins
Elimination of bilirubin ↑ in serum bilirubin and jaundice
Metabolism of steroid hormones:  Disturbance in gonadal function,
 Steroid hormones gynecomastia
 Glucocorticoids  ↑ cortisol levels – e.g. Cushing’s
  Aldosterone
Metabolism of drugs
Carb metabolism
Stores glycogen and synthesises glucose from
AAs, lactic acid and glycerol
Fat metabolism:
 Formation of lipoproteins
 Conversion of carbs and proteins to fat
 Synthesis, recycling and elimination of
cholesterol
 Formation of ketones from FAs
Protein metabolism:
 Deamination of proteins
 Formation of urea from ammonia
 Synthesis of plasma proteins
Synthesis of clotting factors – fibrinogen,
prothrombin, factors V, VII. IX, and X
Storage of minerals and vitamins
Filtration of blood and removal of bacteria and
toxins by Kupffer cells
syndrome
 Hyperaldosteronism – Na+ retention and
hypokalaemia
 ↓ drug metabolism
 ↓ plasma binding of drugs due to ↓ in
albumin
Hypoglycaemia may develop when
glycogenolysis and gluconeogenesis are
impaired
Abnormal glucose tolerance curve due to
impaired uptake and release of glucose by liver
 Impaired synthesis of lipoproteins
 Altered cholesterol levels
 ↑ blood ammonia levels
 ↓ levels of plasma proteins (especially
albumin) → oedema formation
↑ tendency to bleed
Signs of deficiency in fat-soluble and other
vitamins that are stored in the liver
↑ exposure of the body to colonic bacteria and
other foreign matter

85 – Acute hepatitis

Hepatitis is the inflammation of the liver parenchyma (tissue). It may be acute or

chronic. Acute hepatitis can be self-limiting (resolve on its own), progress to chronic
hepatitis, or rarely result in acute liver failure

Causes:

 Viruses = the most common cause of hepatitis worldwide – Hep A, B, C, D

and E
 Alcoholism – excessive alcohol consumption
 Certain medications
 Toxins
 Autoimmune diseases
 Non-alcoholic steatohepatitis (NASH)
  Genetic = α1-antitrypsin deficiency, hemochromatosis, and Wilson’s disease
 Ischaemic hepatitis (shock liver) - ↓ blood flow to liver as in shock, HF, or
vascular insufficiency

Viral hepatitis

 Definition = inflammation of the liver due to viral infection

 It may present in acute form as a recent infection w/relatively rapid onset, or in
chronic form
 Most common causes are hepatitis A, B, C, D and E. Other viruses like EBV,
CMV and yellow fever virus can also cause hepatitis
 Viruses target hepatocytes, they get inside and infect the cells → hepatocytes
present abnormal proteins on their cell surface via MHC I molecules → CD8+
T cells recognise the abnormal proteins → cytotoxic killing of hepatocytes →
cell apoptosis → liver inflammation and liver damage

Symptoms of acute viral hepatitis

 In the initial prodromal stage = flu like symptoms – fatigue, nausea, vomiting,
poor appetite, arthralgia, headaches, malaise
 Jaundice
 Hepatomegaly
 ↑ blood transaminases – ALAT and ASAT leak into the blood from the liver
 Atypical lymphocytosis – abnormally large lymphocytes from Ag stimulation

Hepatitis A (HAV)

 Transmission = faecal-oral
 Acute form, no chronic
 IgM AB = during acute illness
 IgG AB = old infection or reinfection
 A vaccine is available that will prevent HAV infection for up to 10 years

Hepatitis B (HBV)

 Transmission = blood, sex, mother-to-child (breastfeeding), I.V drug use

 Can cause both acute and chronic hepatitis
 Patients w/HBV have ABs against the virus, but not enough to clear the
infected liver cells
 HBV surface Ag → IgG formed against them
 Core Ag (inside virus) → IgM formed against them
 “E” Ag is secreted by infected cells = marker of active infection
 A vaccine is available to prevent infection for life

Hepatitis C (HCV)
  Transmission = blood, sex, mother-to-child (placenta, childbirth), I.V drug use
 Can progress to chronic hepatitis
 HCV IgG AB

Hepatitis D (HDV)

 Same transmission as HBV and HCV

 Can only propagate in the presence of HBV. It has no independent life cycle,
but can survive and replicate as long as HBV infection persists in the host
body. It can only cause infection when encapsulated by HBV surface Ag’s

Hepatitis E (HEV)

 Transmission = faecal oral route (contaminated water, undercooked sea food)

 Acute, no chronic
 HEV IgM AB = active infection
 HEV IgG AB = protective and signals recovery
 No vaccination available

Autoimmune hepatitis

 Definition = inflammation of the liver due to autoimmune disease that occurs

when the body’s immune system attacks liver cells
 Cause = unknown. Can be due to environmental triggers, genetic
predisposition. Occurs mainly in young F
 Genetics = HLA system located on chromosome 6 that regulates our immune
system → they control the proteins that are encoded and used on the cells
surface to present foreign molecules to the immune system
 Can be associated w/Hashimoto’s thyroiditis → immune cells attack the
thyroid
 Individuals often have no initial symptoms and the disease is detected by
abnormal liver function tests
 Common symptoms = fatigue, weakness, weight loss, malaise, nausea,
jaundice, arthralgia
 For symptomatic patients there is an ↑ in transaminases in the blood – 2
types:
 Type 1 = most common, characterised by ↑ levels of antinuclear auto-
ABs → these ABs fail to tell the difference between self and non-self.
Also anti-smooth muscle ABs are present. There is ↓ albumin and ↑
prothrombin time
 Type 2 = rare disorder, characterised by presence of ABs to the
microsomes of the liver or kidney, or ABs to the liver cytosol
  Treatment = immunosuppressants (corticosteroids), azathioprine (inhibits B
and T cells), liver transplant

Fulminant hepatitis

 Definition = a rare syndrome of massive necrosis of liver parenchyma and a ↓

in liver size that usually occurs after infection w/certain hepatitis viruses,
exposure to toxic agents, or drug-induced injury – acute liver failure
 It most commonly occurs in HBV, HDV and HEV infections.
 About 1–2% of cases of hepatitis E can lead to fulminant hepatitis, but
pregnant women are particularly susceptible, occurring in up to 20% of cases.
 GI symptoms, systemic inflammatory response, haemorrhage, jaundice can
be absent or minimal. ↑ blood ammonia → encephalopathy and cerebral
oedema

86 – Chronic hepatitis

 Definition = inflammation of the liver that lasts at least 6 months

 The course of illness resembles chronic viral hepatitis w/↑ serum
aminotransferases w/out jaundice and w/mild if any symptoms.
 Symptoms = usually minimal if present at all and include non-specific
symptoms of weakness, fatigue, intermittent nausea, and abdominal
discomfort
 It is the principal cause of chronic liver disease, cirrhosis, and hepatocellular
cancer
 Of the hepatotropic viruses, only 3 causes chronic hepatitis: HBV, HDV and
HCV
 In both HBV and HCV → fibrosis and clinical manifestations of the disease
result from the host immune responses directed against viral Ag’s; the hosts
immune system directs cytotoxic T lymphocytes and cytokines to inhibit viral
replication → inflammation and liver injury

Criteria for diagnosis:

 Persistent ↑ ALT above the upper limit on at least 3 occasions

 Alkaline phosphatase levels of <2 times the upper limit
 Minimal and non-specific symptoms
 Mild or minimal bilirubin elevations
  Liver biopsy changes of chronic hepatitis w/portal inflammation and spotty
lobular inflammation and necrosis w/variable degrees of interface hepatitis
and portal fibrosis

Treatment = recombinant human interferon-2 alpha and peginterferon. Liver

transplantation is for more advanced decompensated cirrhosis from viral hepatitis
but viral hepatitis often reoccurs again after transplantation

87 – Cirrhosis. Etiology and pathogenesis

Definition = severe scarring of the liver and poor liver function seen at the terminal
stages of chronic liver disease (chronic disease of the liver marked by degeneration
of cells, inflammation, and fibrous thickening of tissue)

Etiology

 Infectious – mainly due to chronic hepatitis B and C

but also due to TB, malaria, and other infections
 Alcoholic
 Hepatotoxic drugs or toxins
 Primary biliary cirrhosis = autoimmune disease of
the liver. Results from a slow, progressive
destruction of the small bile ducts of the liver,
causing bile to build up in the liver (cholestasis).
 Secondary biliary cirrhosis = develops due to
cholestasis caused by chronic obstruction of the
bile ducts by stones, inflammations, tumours
 Autoimmune hepatitis
 Metabolic – hereditary diseases including Wilson’s
disease, hemochromatosis, galactosemia, α 1-
antitrypsin deficiency
 Cardiac cirrhosis – due to R side heart failure or
severe venous congestion in the liver due to other
causes

Classification

 Clinical = compensated and decompensated (w/ascites)

  Histological = macronodular (due to hepatitis), micronodular (alcoholic), mixed
(Wilson’s disease)

Pathogenesis

 Liver injury results in chronic inflammation and activation of Kupffer cell, and
other endogenous liver cells w/the production of cytokines. These, together
w/disruption of the ECM activates hepatic stellate cells (HSC).
 These transform into myofibroblasts which produce collagen and constrict
sinusoids.
 Collagen in the space of Disse leads to “capillarisation” of the sinusoids and
loss of endothelial fenestrations, hindering exchange of solutes.
 The fibrous tissue forms constrictive bands that disrupt flow in vascular
channels and biliary duct systems in the liver
 Disruption of vascular channels → portal HT, obstruction of biliary channels,
loss of liver cells and liver failure

Summary = Hepatocyte injury triggers release of paracrine factors → activate stellate

cells which transform into myofibroblasts and produce collagen → disruption of
vascular channels → portal HT, obstruction of biliary channels, and liver failure

Clinical manifestations (see image above)

88 – Cirrhosis. Clinical manifestations – portal hypertension, ascites and

hepatic encephalopathy

Clinical manifestations (mentioned above)

Portal HT

 Characterised by ↑ resistance to flow in

the portal venous system (HT in hepatic
portal system)
 Portal circulation = blood from GI tract,
spleen and pancreas travels to the liver
through the portal v. before moving into
the IVC for return to the heart
 The most common cause is cirrhosis
 Other causes are grouped into prehepatic, hepatic, and posthepatic
 Prehepatic causes = portal v. thrombosis, splenomegaly, arteriovenous
fistula
 Hepatic causes = cirrhosis, chronic pancreatitis, fatty liver disease,
toxicity, congenital hepatic fibrosis etc.
  Posthepatic causes = IVC obstruction, R HF, Budd-Chiari syndrome
(hepatic v. thrombosis)
 Diagnosis = ultrasonography – dilated portal v. (diameter > 13/15mm) is a
sign of portal HT
 Effects of portal HT = splenomegaly, oesophageal varices, caput medusae

Ascites

 Definition = abnormal build up of fluid in the abdomen (at least 500ml of fluid
accumulates – technically it is >25 ml of fluid in peritoneal cavity)
 It is a late stage manifestation of cirrhosis and portal HT
 Portal HT leads to ↑ hydrostatic pressure and we have ↓ colloidal osmotic
pressure due to impaired synthesis of albumin by the liver (as fibrotic tissue
builds up, we get compression of the central v. and sinusoids → portal HT →
fluid gets pushed into peritoneal cavity → ascites)
 Treatment = dietary restriction of Na+ and use of diuretics

Hepatic encephalopathy

 Definition = an altered level of consciousness as a result of liver failure. Onset

may be gradual or sudden
 Other symptoms include mood changes, personality changes and movement
problems. In the advanced stages it can result in a coma
 Occurs in those w/acute or chronic liver disease. Episodes can be triggered
by infections, GI bleeding, constipation, electrolyte problems or certain meds
 Can be exogenic (in patients w/liver cirrhosis) or endogenic
 Etiology = excessive N load, electrolyte/metabolic disturbance, drugs and
meds, infections (exogenic); toxic endogenic metabolites, which are
consequence of acute necrosis of the liver due to infections or toxicity
(endogenic)

Pathogenesis:

 Circulatory system starts diverting blood away from the liver due to high liver
pressure → portosystemic shunt (blood follows the path of least resistance
and shunts away from the portal system and towards the systemic circulation)
 Fibrosis → ↑ pressure → blood diversion → ↓ liver function → ↓ detoxification
→ toxins enter the brain causing mental deficits = hepatic encephalopathy
 ↑ levels of ammonia are especially toxic to the brain → hepatic coma

89 – Jaundices

Review on bilirubin formation

  Bile is the substance that gives bile its colour. It is formed from ageing RBCs
 Hb is phagocytosed by macs → heme + globin.
 Globin is degraded into AA and plays no role in jaundice
 Heme → biliverdin (green) – catalysed by heme oxygenase
 Biliverdin → bilirubin (yellow) (unconjugated, free, or indirect bilirubin) –
catalysed by biliverdin reductase
 Unconjugated bilirubin travels to the liver through the bloodstream, bound to
serum albumin (since it is not soluble)
 In the liver it is conjugated w/glucuronic acid to become > water soluble →
conjugated bilirubin – catalysed by UDP-glucuronyl transferase
 This conjugated bilirubin is excreted from the liver into the biliary and cystic
ducts as part of bile.
 Intestinal bacteria convert the bilirubin into urobilinogen.
 From here urobilinogen can take two pathways. It can either be further
converted into stercobilinogen, which is then oxidized to stercobilin and
passed out in the faeces, or it can be reabsorbed by the intestinal cells,
transported in the blood to the kidneys, and passed out in the urine as the
oxidised product urobilin.
 Stercobilin and urobilin are the products responsible for the coloration of feces
and urine, respectively.

Jaundice (AKA icterus)

 Definition = a yellowish pigmentation of the skin and sclera (whites of the

eyes) due to ↑ bilirubin.
 It is commonly associated w/itching. The faeces may be pale and the urine
dark
 The sclera themselves are not icteric, however, but rather the conjunctival
membranes that overlie them

Types

 Pre-hepatic/hemolytic = caused by anything that causes an ↑ rate of

hemolysis (breakdown of RBCs)
 Hepatic/hepatocellular = caused due to parenchymal cells of liver
 Post-hepatic/cholestatic/obstructive = caused due to obstruction of biliary
passage
 Neonatal

Pre-hepatic/hemolytic jaundice

 Unconjugated bilirubin comes from the breakdown of heme

 The ↑ breakdown of RBCs → ↑ unconjugated bilirubin present in the blood
and deposition of it into various tissues can lead to a jaundiced appearance
 In tropical countries, severe malaria can cause jaundice in this manner
  Certain genetic diseases, such as SCA, spherocytosis, thalassemia, PKD,
and G6PD deficiency can lead to ↑ RBC lysis and ∴ hemolytic jaundice
 In jaundice secondary to hemolysis, the ↑ production of bilirubin → ↑
production of urine-urobilinogen.
 Bilirubin isn’t usually found in the urine because unconjugated bilirubin isn’t
water-soluble, so, the combo of ↑ urine-urobilinogen w/no bilirubin (since it’s
unconjugated) in urine is suggestive of hemolytic jaundice
 Lab findings = no bilirubin in urine, ↑ unconjugated bilirubin in serum,
kernicterus is associated w/↑ unconjugated bilirubin not carried by albumin –
newborns are especially vulnerable to this due to ↑ permeability of the BBB

Hepatocellular jaundice

 Can be caused by acute or chronic hepatitis, hepatotoxicity, cirrhosis, and

alcohol liver disease
 Cell necrosis ↓ the liver’s ability to metabolise and excrete bilirubin → build-up
of unconjugated bilirubin in blood
 Other causes include primary biliary cirrhosis → ↑ plasma conjugated bilirubin
because there is impairment of its excretion into the bile → excreted into urine
 Interferes w/all phases of bilirubin metabolism (uptake, conjugation, and
excretion) → ↑ levels of both conjugated and unconjugated bilirubin, dark
urine, ↑ serum alkaline phosphatase

Post-hepatic/cholestatic/obstructive jaundice

 Most common causes are gall stones in the common bile dust
(choledocholithiasis), and pancreatic cancer in the head of the pancreas
 Also liver flukes can live in the common bile duct, causing obstructive jaundice
 In complete obstruction of the bile duct, no urobilinogen is found in the urine,
since bilirubin has no access to the intestine and it is in the intestine that
bilirubin gets converted to urobilinogen, w/the urobilinogen later being partially
reabsorbed from the intestine into the general circulation, and then excreted
into the urine.
 In this case, presence of bilirubin (conjugated) in the urine w/out urine-
urobilinogen suggests obstructive jaundice, either intra-hepatic or post-
hepatic.
 The presence of pale stools and dark urine suggests an obstructive or post-
hepatic cause as normal feces get their colour from bile pigments

Neonatal jaundice

 In newborns, jaundice tends to develop because of 2 factors – the breakdown

of fetal Hb as it is replaced w/adult Hb and the relatively immature metabolic
pathways of the liver, which are unable to conjugate and so excrete bilirubin
as quickly as an adult
  This causes an accumulation of bilirubin in the blood (hyperbilirubinaemia),
leading to the symptoms of jaundice
 Breastfeeding jaundice = caused by insufficient breast milk intake →
inadequate quantities of bowel movements to remove bilirubin from the body
→ ↑ enterohepatic circulation → ↑ reabsorption of bilirubin from the intestines
 Treatment w/phototherapy

90 – Disorders of the exocrine pancreas. Pancreatitis

Review of pancreas

 Pancreas is endocrine and exocrine gland

 Endocrine = α (glucagon) and β (insulin) cells – blood sugar control
 Exocrine = made up of lobules that consist of acinar cells.
 They secrete digestive enz. into the ducts → main pancreatic duct →
duodenum along w/bile duct
 Acinar cells secrete proteolytic enz. (trypsin, pancreatic amylase,
lipase) in their inactive form – become activated in the intestines
 Acinar cells also secrete trypsin inhibitor

Acute pancreatitis

Pathogenesis

 Occurs when there is abnormal activation of digestive enzymes w/in the

pancreas (usually activated in the duodenum).
 This occurs through inappropriate activation of inactive enzyme precursors
(zymogens) inside the pancreas, most notably trypsinogen → leads to
inflammation, oedema, vascular injury, and even cellular death.
 The death of pancreatic cells occurs via necrosis (creates necrotic lesions) or
apoptosis
 Pancreatic destruction results from proteases and the inflammatory response
→ blood vessels leak and rupture → causes swelling. Lipases also destroy
the fat around the pancreas → liquefactive haemorrhagic necrosis

Etiology

 Main causes are alcohol abuse and gallstones

 Biliary pancreatitis due to gallstones or constriction of ampulla of Vater
 Toxicity – alcohol or drugs (steroids, sulphonamides, diuretics), causing
inflammation and oedema of the gland and premature activation of the enz.
  Alcohol stimulates pancreatic secretions from acinar cells and ↓ fluid
and bicarbonate from the ductal epithelial cells → thick pancreatic
juices → blocks ducts → pancreatic juices back up → ↑ pressure →
trypsinogen turns to active trypsin → activation of other enz. →
autodigestion of the pancreas
 Infection – viral or bacterial (mumps, Coxsackie virus, Mycoplasma
pneumoniae)
 Inflammation of adjacent organs – mainly cholecystitis or penetration of
duodenal ulcer
 Abdominal trauma
 Idiopathic

Symptoms

 Severe pain in the epigastrium, w/encircling propagation towards both

hypogastria and the back but mostly on the L side
 Nausea and vomiting
 Fever, possibly w/rigors
 Severe weakness and possibly shock
 Appearance of jaundice is frequent

Complications

 Formation of pancreatic pseudocysts (fibrous tissue surrounds the liquefactive

necrotic tissue around the pancreas) → cavity fills w/pancreatic juice → can
rupture and release pancreatic enzymes into abdominal cavity → massive
inflammation
 The pseudocyst can become infected e.g. E. coli → pancreatic abscess →
high fever & WBC count
 Haemorrhage from damaged blood vessels → hypovolemic shock
 Systemic activation of blood coagulation factors (DIC)
 Acute respiratory distress syndrome (massive inflammation) → leaky blood
vessels throughout the body → difficulty breathing

Diagnosis and treatment

 Specific for diagnosis = ↑ alpha-amylase, lipase, and ↓ Ca 2+; blood sugar is

slightly ↑ and glycosuria is often present
 Liver enz. and bilirubin are usually ↑ as is the urobilinogen in the urine
 Treatment = pain management, hydration, electrolytes, I.V fluids

Chronic pancreatitis

Definition
Chronic pancreatitis is a long-standing inflammation of the pancreas that alters the
organ’s normal structure and functions

Pathogenesis

Fibrous changes in the gland possibly w/formation of pseudocysts causing

impairment of its exocrine function and eventually endocrine functions

Hereditary = AD disease beginning in childhood – mutation to gene encoding

trypsinogen

Etiology

 Acute/relapsing pancreatitis
 Toxicity – alcohol and drugs
 Autoimmune disorders
 Hereditary cause – genetics – AD disease
 Metabolic and hormonal disorders – hypercholesterolaemia,
hyperparathyroidism
 Infections of adjacent organs – usually chronic cholecystitis
 Idiopathic

Symptoms

 Upper abdominal pain = ↑ after drinking/eating, lessens when fasting/sitting

and leaning forward.
 Nausea and vomiting
 Steatorrhoea = frequent, oily, foul-smelling bowel movements
 Damage to the pancreas reduces the production of pancreatic enz. that aid
digestion, which can result in malnutrition. Fats and nutrients are not
absorbed properly, leading to steatorrhoea
 Weight loss even when eating habits and amounts are normal
 DM1 = chronic pancreatitis can affect the ability of the IOL to produce insulin
to regulate glucose levels, leading to DM1.

Diagnosis and treatment

 Specific for diagnosis = stool tests for steatorrhoea and creatorrhoea

 Blood sugar is ↑ in patients w/secondary diabetes
 Treatment = pancreatic enz. replacement therapy, surgery
91 – Disorders of the exocrine pancreas. Pancreatic insufficiency

Definition = inability to properly digest food due to a lack of digestive enz. made by
the pancreas

Pathogenesis

PI is caused by a progressive loss of the pancreatic cells that make digestive enz. →
maldigestion and malabsorption of nutrients → weak bones, vision problems, easy
bruising, skin rashes, difficulty gaining weight

Etiology

 Most common causes = chronic pancreatitis and cystic fibrosis

 In children, another common cause is Shwachman-Diamond syndrome, a rare
AR genetic disorder resulting from mutation in SBDS gene

Symptoms

 Anaemia (vit B12, iron, folate deficiency)

 Bleeding disorders (vit K malabsorption)
 Oedema (hypoalbuminaemia)
 Fatigue
 GI disturbances = flatulence and abdominal distension (bacterial fermentation
of unabsorbed food); steatorrhoea; bloating; abdominal pain
 Metabolic bone diseases (vit D deficiency)
 Weight loss

Diagnosis and treatment

 3 main tests = faecal elastase test, faecal fat test, and a direct pancreatic
function test
 Treatment = no cure; use pancreatic enz. replacement products

92 – Disturbances in lipid digestion and absorption in the gastro-intestinal

tract

Fat malabsorption

 Steatorrhea = fatty stool; foul

smelling, pale and greasy
  Gas and bloating, sometimes diarrhoea

Cholestasis

 Stop/slowdown in bile flow (bile = emulsifies fat) from the liver to the SI by an
obstruction e.g. gallstones or inflammation from liver disease
 Since the bile cannot get to the SI, it can’t assist to digest fat → malabsorption
 Lack of bile also affects absorption of Ca, Vit D and Vit K (increase risk of
bleeding)

Pancreatitis

 Inflammation of the pancreas → fat malabsorption

 May be due to gallstones
 Chronic inflammation of the pancreas makes it difficult for the pancreas to
secrete enough lipase to digest fat

Cystic fibrosis

 Genetic disorder that affects epithelial cells that line the lungs, digestive
system, liver and pancreas, thus causing a thick viscous mucous.
 In the pancreas the thick mucus prevents secretion of digestive enzymes into
the intestines leading to malabsorption of nutrients, especially fats.

Zollinger-Ellison syndrome

 Rare condition characterized by formation of tumours in the duodenum and

pancreas that release high amounts of gastrin (hormone that stimulates
stomach to release > acid)
 The high acidity causes ulcers in the duodenum and also obstructs the action
of lipase → poor fat digestion

93 – Disturbances in lipid transport. Hyperlipidemia. Fatty liver

Review of lipid transport

 Due to their hydrophobic nature, lipids must be bound to plasma lipoproteins

to be transported through the bloodstream
 Composition = hydrophobic core (cholesterol esters and triglycerides).
Surrounded by hydrophilic outer shell (phospholipid, cholesterol, and
apolipoproteins – stabilise the complex and give it functional identity)

Type Composition Site of production Function

Chylomicron 90% dietary TAG Assembled in intestinal Degradation of TAG to
s Apo B-48 mucosa glycerol in liver
VLDL 60% endogenous TAG Liver Carry lipids from liver to
Apo B-100 peripheral tissues
LDL 50% cholesterol When VLDL is modified in Carry cholesterol from
Apo B-100 plasma liver → peripheral tissue
HDL Cholesterol ester and Blood Carry cholesterol from
phospholipid peripheral tissues → liver
Apo A-1

Hyperlipidaemia

 Definition = abnormally ↑ levels of any or all lipids/lipoproteins in the blood.

 They are divided into primary (familial) and secondary (acquired) subtypes
 They are also classified according to which types of lipids are elevated –
hypercholesterolaemia, hypertriglyceridaemia, or both in combined
hyperlipidaemia

Primary (familial)

Type Synonym Defect Increased Notes

lipoprotein
Familial ↓ lipoprotein Chylomicrons All can lead to acute
a hyperchylomicronaemi lipase (LPL) pancreatitis, lipemia
Type a retinas, xanthomas and
I hepatosplenomegaly
b Altered Apo Chylomicrons
C-2
c LPL inhibitor Chylomicrons
in blood
Familial LDL receptor LDL Lack of LDL receptor =
a hypercholesterolaemia deficiency LDL remains in blood
Type stream
II b Familial combined ↓ LDL LDL and
hyperlipidaemia receptor and VLDL
↑ Apo B
Type III Familial Defect in IDL Can cause xanthomas
dysbetalipiproteinaemia Apo E-2
synthesis
Type IV Familial ↑ VLDL VLDL Can cause pancreatitis at
hypertriglyceridaemia production high VLDL levels
and ↓
elimination
Type V Mixed ↑ VLDL VLDL and Similar to type I but w/high
hyperlipoproteinaemia production chylomicrons VLDL as well. Associated
and ↓ LPL w/glucose intolerance and
hyperuricaemia
Secondary (acquired)

 Result from another underlying disorder that leads to alterations in plasma

lipid and lipoprotein metabolism
 The most common causes are DM and use of drugs such as thiazide
diuretics, β blockers and oestrogens.
 Other causes include hypothyroidism, kidney failure, nephrotic syndrome,
alcohol consumption.
 They may result in ↑ risk of premature atherosclerosis or, when associated
w/marked hypertriglyceridaemia, may lead to pancreatitis.
 Treatment of the underlying condition, when possible, or discontinuation of the
offending drugs usually leads to an improvement in the hyperlipidaemia

Fatty liver (AKA hepatic steatosis)

 Definition = a condition where excess fat builds up in the liver

 There are 2 types = alcoholic liver disease and non-alcoholic fatty liver
disease (NAFLD)
 Pathogenesis = defects in FA metabolism – may be due to imbalance in E
consumption and its combustion, resulting in lipid storage, or can be a
consequence of peripheral resistance to insulin, whereby the transport of FAs
from adipose tissue to the liver is increased
 Alcoholism is known to damage mitochondria and other cellular structures,
further impairing cellular E mechanism
 NAFLD may begin as excess of unmetabolized E in liver cells
 Fatty liver is considered reversible if the underlying cause is reduced or
removed

Alcoholic liver disease

 Fatty liver disease = accumulation of fat in hepatocytes → steatosis; liver

becomes yellow and enlarged; ingestion of large amounts of alcohol
 Alcoholic hepatitis = inflammation and necrosis of liver cells caused by excess
alcohol consumption
 Signs = jaundice, fever, hepatic tenderness, pain, anorexia, nausea,
liver failure
 Severe alcoholic hepatitis → encephalopathy
 If the person survives yet continues to drink → cirrhosis
 Alcoholic cirrhosis = end result of repeated bouts of drinking-related
hepatocytes injury and regeneration
 Gross = uniform nodules on liver surface → micronodular
  In advanced cirrhosis, regeneration process causes nodules to become
larger and > irregular in shape and size and new portal tracts and
venous outflow channels form
 Nodules may compress hepatic vv., obstructing blood flow out of the
liver → portal HT, extrahepatic portosystemic shunts, and cholestasis

NAFLD

 2 types = non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis

(NASH)
 NAFL usually doesn’t progress to liver damage or NASH
 NASH includes both a fatty liver and hepatitis. It may lead to complications
such as cirrhosis, liver cancer, liver failure, or cardiovascular disease
 Risk factors = obesity, DM2, diet high in fructose, old age
 Pathogenesis = lipid accumulation w/in hepatocytes and formation of free
radicals
 Obesity = ↑ synthesis and ↓ oxidation of free FAs
 DM2 = ↑ adipose tissue lipolysis and subsequent production of free FAs
 Excess FAs → steatosis → fatty liver disease
 NAFLD is usually asymptomatic → fatigue and discomfort in upper R
quadrant of abdomen.
 Diagnosis = ↑ ASAT and ALAT

94 – Disturbances in lipid metabolism in fat tissue. Obesity. Metabolic

syndrome

Obesity – refer to Q121

Metabolic syndrome

Definition

 It is a clustering of at least 3 of the 5 following medical conditions: central

obesity, HT, hyperglycaemia, hypertriglyceridaemia, and low serum HDL.
 It is associated w/the risk of developing cardiovascular disease and DM2
 The syndrome is thought to be caused by an underlying disorder of E
utilisation and storage

Etiology

 The exact mechanisms of the complex pathway of the metabolic syndrome

are not understood
 Pathophysiology is very complex and has only been partially explained
  Most patients are old, obese, sedentary, and have a degree of insulin
resistance. Stress can also be a contributing factor
 The most important risk factors = diet (especially sugar-sweetened beverage
consumption), genetics, ageing, sedentary behaviour (low physical activity),
disrupted sleep, mood disorders, and excessive alcohol use

Signs and symptoms

 Key sign is central obesity (AKA abdominal, visceral, M pattern or apple-

shaped). It is characterised by adipose tissue accumulation mainly around the
waist and trunk
 Other signs = HT, hyperglycaemia, insulin resistance/prediabetes,
hypertriglyceridaemia, and low serum HDL
 Associated conditions include hyperuricaemia; fatty liver progressing to
NAFLD; PCOS in F and erectile dysfunction in M; and acanthosis nigricans

Diagnosis

To diagnose metabolic syndrome, a person must have at least 3 of the following:

 Abdominal obesity = waist circumference >35” in F and >40” in M

 Hypertriglyceridaemia = > 1.7 mmol/L
 ↓ HDL = < 1.3 mmol/L in F and < 1 mmol/L in M
 HT = ≥ 130/85 mmHg
 Fasting plasma glucose = ≥ 6.1 mmol/L (110 mg/dl)

Management and prevention

 Generally, the individual disorders that compose the metabolic syndrome are
treated separately. Diuretics and ACE inhibitors may be used to treat HT.
Various cholesterol drugs may be used if LDL, triglycerides, and/or HDL is
abnormal
 Dietary carb restriction reduces blood glucose levels, contributing to weight
loss and reduces the use of several meds that may be prescribed for
metabolic syndrome
 Prevention = ↑ physical activity (walking 30mins every day) and a healthy,
reduced calorie diet

95 – Disturbances in intermediary lipid metabolism. Ketosis

Review of ketone bodies

  Ketone bodies are 3 water-soluble molecules that are produced by the liver
from FAs during periods of low food intake (fasting), carb restricted diets,
starvation, prolonged intense exercise, alcoholism or untreated/poorly treated
DM1
 They are produced by the liver as a result of intense gluconeogenesis, which
is the production of glucose from non-carb sources
 Ketogenesis = synthesis and breakdown of HMG-CoA by HMG-CoA synthase
and HMG-CoA lyase
 Ketone bodies = acetoacetate, β-hydroxybutyrate, and acetone
 Significance of ketone bodies = alternate sources to glucose for E; produced
under conditions of cellular E deprivation; and utilisation of ketone bodies by
brain, heart, kidney, skeletal muscles
 Ketone can be used as fuel in the heart, brain and muscle, but not the liver (it
lacks an enz. required for ketone body utilisation – β-ketoacyl-CoA
transferase)
 Ketone bodies are transported to peripheral tissues and converted into
acetyl-CoA, which then enters Krebs cycle and is oxidised in the mitochondria
for E = yields 2 GTP and 22 ATP per acetoacetate molecule when oxidised

Ketosis

 Definition = a metabolic state in which some of the body's E supply comes

from ketone bodies in the blood, in contrast to a state of glycolysis in which
blood glucose provides E. Generally, ketosis occurs when the body is
metabolizing fat at a high rate and converting FAs into ketones.
 Ketonemia = the presence of ketone bodies in the blood plasma, while
ketonuria = the presence of ketone bodies in the urine. Both states are
brought about by the physiological state of ketosis.
 Causes = prolonged starvation, uncontrolled DM (insulin deficiency leads to
release of FAs from adipose cells w/subsequent production of ketone bodies),
chronic alcoholism
 Biochemical findings = ketonemia, ketonuria, acetone breath, hyperkalaemia,
metabolic acidosis

Ketoacidosis = a conditions referring to low blood pH which can occur when

ketogenesis produces > ketone bodies than what can be utilised by the peripheral
tissues (these are both carboxylic acids). It is most common in untreated DM1, when
the liver breaks down fat, as it is unable to successfully store sugar. Symptoms:

 Polyuria, polydipsia
 Dehydration
 Abdominal pain – nausea and vomiting
 Fruity breath – acetone
 Kussmaul breathing
  Mental status changes – combative, drunk, coma

96 – Lipoprotein metabolism and pathobiochemistry. Atherosclerosis

Atherosclerosis

Definition

 It is a condition where the aa. become narrowed and hardened due to the
buildup of plaque around the a. wall.
 When severe, it can result in CAD, stroke, peripheral a. disease, or kidney
problems, depending on which aa. are being affected. Symptoms, if they
occur, generally do not begin until middle age

Etiology

 Modifiable = diabetes, hypercholesterolaemia, smoking, trans fat, abdominal

obesity, Western diet, insulin resistance, HT
 Non-modifiable = advanced age, M sex, family history, genetic abnormalities

Pathogenesis and mechanism of development

 Vascular endothelium consists of a single layer of cells w/cell-to-cell

attachments, which normally protects the subendothelial layers from
interacting w/blood cells and other blood components
 Agents such as smoking, ↑ LDL, immune mechanisms and mechanical stress
associated w/HT → endothelial injury w/adhesion of monocytes and
phagocytes
 Migration of inflammatory cells (monocytes) between the endothelial cells to
localise in the intima, transform into macs and engulf lipoproteins, largely LDL
 Although the ingestion of lipids by transformed macs (become foam cells) is
protective in that it removes excess lipids from circulation, progressive
accumulation eventually leads to lesion progression
  Activated macs release free radicals to oxidise LDLs, which is toxic to the
endothelium → exposure of subendothelial tissue to blood components →
platelet adhesion and fibrin deposition
 They also produce growth factors that contribute to the migration and
proliferation of smooth muscle cells (SMCs) and the elaboration of the ECM

3 different stages or subtypes of lesions:

 Fatty streaks
 Thin, yellow lines running
along major aa.
 Consists of SMCs filled
w/cholesterol and macs
 Doesn’t cause symptoms but
overtime can develop into
atheromatous plaque
 Fibrous atheromatous plaque
 Accumulation of lipids,
proliferation of vascular smooth muscle, formation of scar tissue and
calcification
 Fibrous cap of CT and smooth muscle tissue
 As the lesions ↑ in size, they can occlude a vessel or thrombus
formation occurs → ↓ blood flow
 Complicated atherosclerotic plaque
 Develops when the fibrous plaque breaks down → haemorrhage,
ulceration and scar tissue deposits
 Thrombosis → slowing and turbulence of blood flow

Clinical manifestations

 Atherosclerosis is asymptomatic for decades because the aa. enlarge at all

plaque locations, thus there is no effect on blood flow.
 Signs and symptoms only occur after severe narrowing or closure impedes
blood flow to different organs enough to induce symptoms – e.g. MI or stroke
 Atherosclerotic lesions produce their effects by:
 Narrowing of the vessel and ischaemia
 Sudden vessel obstruction due to plaque haemorrhage or rupture
 Thrombosis and formation of emboli resulting from damage to the
vessel endothelium
 Aneurysm formation due to weakening of the vessel wall
 Narrowing of coronary aa. = angina, SOB, sweating, nausea, dizziness,
breathlessness, or palpitations
 Narrowing of carotid aa. = weakness, difficulty thinking and speaking,
dizziness, difficulty walking/standing, blurred vision, numbness of face, arms
and legs, severe headache and losing consciousness → stroke
  Narrowing of peripheral aa. (supplying to arms, legs, and pelvis) = numbness
w/in arms/legs and pain.
 Narrowing of renal aa. = ↓ kidney blood flow and chronic kidney disease

97 – Disturbances in carbohydrates digestion, absorption and transport.

Hyper- and hypoglycaemia

Disturbances in carb digestion, absorption and transport

Metabolic processes in the carb metabolism

 Glycolysis = oxidation of glucose to obtain ATP and pyruvate, pyruvate enters

Krebs cycle to produce e- carriers for ETC and ATP production
 Pentose phosphate pathway = converts hexoses into pentoses and NADPH.
Pentoses used for nucleotide synthesis, NADPH for lipid synthesis
 Glycogenesis = conversion of excess glucose into glycogen as cellular E
storage
 Glycogenolysis = breakdown of glycogen stores into glucose
 Gluconeogenesis = formation of glucose from common metabolites such as
pyruvate, lactate, glycerol, glucogenic AA (e.g. Gly, Ala, Pro), and all KC
intermediates

Blood glucose levels are an indication of the glucose in the blood. Control of this is
governed by the pancreatic hormones insulin and glucagon , as well as the adrenal
hormones adrenaline and cortisol .

When blood glucose is high, insulin is released by β cells of the pancreas. This
encourages the conversion of glucose into glucagon. Insulin acts on Protein Kinase
which causes the phosphorylation of protein phosphatases which activate glycogen
synthase.

Glycogen synthase then allows for the conversion of glucose into glycogen, reducing
glucose in the blood to normal levels. Glucagon acts in the opposite way =
dephosphorylation of protein phosphatase, inactivating glycogen synthase, blocking
glycogen synthase, while simultaneously activating glycogen phosphorylase which
activates glycogen degradation.
Digestion of carbs

Food intake Enzymes End products

 Polysaccharides  Salivary amylase  Glucose
 Disaccharides  Disaccharidases (lactase)  Fructose
 Monosaccharides  Pancreatic amylase  Galactose

Absorption and transport of carbs

 Monosaccharides are absorbed into capillaries through villi

 Shuttled into the cells via secondary AT – glucose enters w/Na + via
Na/glucose symporter. Na+ then leaves the enterocyte via Na+/K+ pump
 To get into the cells, the sugars use different protein pores:
 Fructose = GLUT-5
 Glucose = SGLT protein transporter
 All sugars exit the enterocyte via GLUT-2

Disorders of digestion and absorption

Etiology = pancreatitis, disaccharidase insufficiency

Clinical manifestations = diarrhoea, bloating, gases; ↑ osmolarity of intestinal

content; fermentation

Disturbances

 Intestinal lactase deficiency = lactose can’t be digested and is oxidised by

bacteria in the gut. Gas is produced, bloating, and watery diarrhoea
 G6PD deficiency = causes insufficient amount of NADPH to be produced. As
a result, glutathione is not adequately reduced. G6PD helps RBCs work
properly and too little G6PD → hemolysis → hemolytic anaemia. XR disease
 Glycogen storage diseases = glycogen accumulates mainly in liver or muscle
(or both). Enz deficiencies occur mainly in glycogen degradation or
conversion to glucose. In liver, glycogen storage diseases can produce
conditions from mild hypoglycaemia to liver failure. In muscle = difficulty to
perform strenuous exercise to cardiorespiratory failure

Hyperglycaemia

Definition = ↑ blood glucose – >11.1 mmol/L (200 mg/dL)

Etiology

 Postprandial (occurring after a meal)

 Diabetes mellitus
 Drugs = corticosteroids, β-blockers, adrenaline, niacin/nicotinic acid, thiazide
diuretics etc.
  Stress
 Endocrinopathies (dysfunction of thyroid, adrenal, pituitary glands)
 In all cases, the mechanism sees the bodies inability to take in glycogen into
the cells, meaning it remains in the bloodstream

Symptoms

 Polyphagia, polydipsia, polyuria

 Blurred vision, fatigue, restlessness, weight loss
 Poor wound healing, xerostomia, dry/itchy skin, paresthesia

Extremely high blood glucose = hyperglycaemia coma – loss of blood volume, low
bp, impaired CNS function

Hormones

 Steroid hormones = stimulate gluconeogenesis, cause post-receptor insulin

resistance and ↓ glucose utilisation
 Thyroid hormones = ↑ glycemising effect of catecholamines, ↓ insulin
secretion of β-cells
 Somatostatin = ↓ insulin secretion

Hypoglycaemia

Definition = ↓ blood glucose – < 3.9 mmol/L (70 mg/dL)

Etiology

 Meds used to treat DM such as insulin, sulfonylureas, and biguanides

 ↓ glucose intake = starvation, disorders of card digestion and absorption,
disorders of AT
 Liver disorders = ↓ gluconeogenesis (excess alcohol consumption) and
glycogenolysis
 Hormone deficiency = Addison’s disease (↓ cortisol), not enough glucagon, or
not enough adrenaline → hypoglycaemia

Symptoms

 Mild hypoglycaemia = hunger, fatigue, tremor, rapid pulse, anxiety →

‘sympathoadrenal symptoms’ due to activation of SNS (SNS activation
increases blood glucose by mobilizing liver glycogen in liver and muscle)
 More severe hypoglycaemia = blurred vision, impaired thinking, confusion,
seizures and coma due to glucose deprivation in the brain (‘neruoglycopenic
symptoms’)
98 – Disturbances in protein digestion and absorption. Changes in serum
protein levels

Digestion and absorption of proteins

Digestion

Protein digestion begins in the stomach (broken into polypeptides) and is completed
in the small intestine (by endo and exopeptidases). Proteins are broken down into
AA, dipeptides and Tripeptides. The key enzymes include:

 Pepsin = the gastric chief cells secrete the inactive precursor of pepsin,
pepsinogen. Pepsinogen is activated to pepsin at low gastric pH.
 Endopeptidases = hydrolyse the interior peptide bonds of proteins. The
endopeptidases of the GI tract: pepsin, trypsin, chymotrypsin, and elastase.
 Exopeptidases = hydrolyse one AA at a time from the C terminal ends of
proteins and peptides. The exopeptidases of the GI tract: carboxypeptidases
A and B.

Absorption

L AA are transported similar to glucose and galactose, meaning its via Na + AA co-
transporters on the apical side of enterocytes and facilitated diffusion on the
basolateral side.

Dipeptides and Tripeptides = most proteins are absorbed in these forms, via H +
dependent co-transporters on the apical side. Inside the cell cytosolic peptidases
break them down to AA which are then transported via facilitated diffusion into blood

Disturbances in protein digestion and absorption

Stomach: Consequences:
 Gastritis  ↑ N loss w/faeces
 Atrophic gastritis  Creatorrhea (excretion of muscle fibre in faeces)
Pancreas:  Hypoproteinaemia
 Chronic pancreatitis  Hypoalbuminaemia and oedema
 Biogenic amines = phenol, cadaverin
 Intestinal intoxication
Motility = slow/fast

Celiac disease

 Coeliac disease = chronic autoimmune disorder that mainly affects the SI.
 It is caused by a rxn to gluten found in wheat, barley, rye
 Usually gluten gets broken down in the stomach to gliadin, however gliadin
resists degradation by enz. and enters the SI → binds to IgA (gliadin-IgA
complex) which binds to a transferrin receptor and crosses the enterocyte into
 the lamina propria. Here, gliadin gets converted into a deaminated form and
gets taken up by the macs
 Macs then present deaminated gliadin via MHC II → T H bind to it and release
inflammatory cytokines → damage and destroy epithelial cells in the villi
 Symptoms = steatorrhoea, weight loss, bloating, abdominal pain and
cramping

Changes in serum protein levels

 Serum proteins = serum albumin, α-1 and 2 globulins, β-1 and 2 globulins, γ
globulins
 Albumin (55% of blood proteins) = maintains osmotic pressure of plasma to
assist in transport of lipids and steroid hormones
 Globulins = help fight infection and transport nutrients
 Basic functions of plasma proteins include:
 Transport proteins = lipids, Hb, Fe, Cu, bilirubin, Ca, hormones
 Defensive function = Ig, complement system, protease inhibitors
 Buffer function
 Coagulation

Hypoproteinemia

 Definition = abnormally low level of protein in the blood

 Causes include:
 Nutritional hypoproteinemia = severe limitation of protein intake in diet
– e.g. Kwashiorkor
 Malabsorption
 Liver disease = ↓ synthesis of plasma proteins like albumin
 Renal diseases (nephrotic syndrome) = plasma proteins lost in urine
 Sepsis = macs activated in liver and spleen secrete TNFα into the
bloodstream resulting in hypoproteinemia
 Pathophysiology = ↓ serum protein ↓ the osmotic pressure of the blood → loss
of fluid from intravascular compartment, or the blood vessels, to the interstitial
tissue → oedema

Hyperproteinemia

 Definition = excess levels of protein in the blood

 Causes = monoclonal gammopathies (e.g. multiple myeloma) and after I.V Ig
has been given
  Signs = loss of appetite, diarrhoea, nausea, severe fatigue, unexplained
weight loss

99 – Disturbances in intermediary protein metabolism and amino acid

catabolism

Phenylketonuria (PKU)

 Classical PKU is caused by a deficiency of Phe hydroxylase (PAH) = leads to

↑ Phe levels in the blood and various tissue, including the brain. Usually Phe
is converted to Tyr which is involved in production of thyroxine (produces
NTs) and melanin – these metabolic pathways will be deregulated = lower
levels of them
 AR disorder, caused by mutation to the PAH gene

Symptoms:

 Mental retardation
 Fair hair, eyes, and skin – due to low melanin levels
 Musty odour of the urine – due to excretion of phenylacetate in the sweat and
urine
 Vomiting
 Eczema

Treated patients are asymptomatic if the disease is detected early by neonatal

screening. Treatment w/dietary restriction of Phe

There are 3 other forms of PKU:

 Maternal PKU = develops if a pregnant woman w/PKU doesn’t follow a

special diet at least 3 months before and during pregnancy
 The fetus has no PKU but can be damaged by the high levels of Phe –
can lead to congenital defects
 Pregnant woman must maintain low Phe levels throughout the
pregnancy by doing regular blood tests and keeping a strict diet
 Diagnosis = elevated levels of Phe in blood and urine – Guthrie test
 Mild hyperphenylalaninemia
 Tetrahydrobiopterin deficiency-mediated PKU
  Tetrahydrobiopterin is a cofactor necessary for activity of PAH and Tyr
hydroxylase (L-Tyr > L-DOPA > dopamine)

Alkaptonuria

 Definition = a rare inherited genetic disorder in which the body cant process
Phe and Tyr, which occur in protein.
 Cause = mutation to HGD gene (homogentisic acid oxidase)
 This results in an accumulation of homogentisic acid (HA) which is an
intermediate in the degradation of Tyr
 Symptoms = blue, speckled discoloration of skin; large joint arthritis; urine
darkens when exposed to air (HA in urine)
 Treatment = dietary restriction of Phe and Tyr; daily intake of 1g of ascorbic
acid to accelerate HA excretion

Homocystinuria

A disorder of methionine metabolism, leading to abnormal accumulation of

homocysteine and its metabolites in blood and urine.

 Classical homocystinuria = caused by deficiency of cystathionine β-synthase,

which catalyses the formation of cystathionine from homocysteine and Ser.
 Symptoms = subluxation of the lens, osteoporosis, neurologic symptoms,
mental retardation, and predisposition to thrombosis
 Diagnosis = increased levels of Met in serum and homocysteine in urine
 Treatment = low Met diet and drugs (pyridoxine)

100 – Disturbances in the final steps of protein metabolism

The final stages of protein metabolism are the whole set of transformations leading
to the formation of terminal nitrogen-containing products excreted from the body
(ammonia, urea, uric acid, creatinine), and also the process of their excretion

 Ammonia is formed from oxidative deamination of glutamate in all tissues

 Detoxification of ammonia = 2 metabolic cycles in the liver
 Ornithine cycle (periportal hepatocytes) → urea
 Glutamine synthetase (perivenous hepatocytes) → glutamine
 Elimination though the kidneys

Urea (ornithine cycle)

The urea cycle involves taking ammonia (NH 3) and converting it to the less toxic
urea. It mainly occurs in the liver w/2 stages in the mitochondria and 3 stages in the
cytosol.

Mitochondrial stages

(1) Formation of Carbamoyl phosphate – catalysed by carbamoyl phosphate

synthetase I. The enz. requires N-acetylglutamate as a +ve allosteric activator
(2) Formation of citrulline – catalysed by ornithine transcarbamoylase (OTC). The
rxn product, citrulline, is transported to the cytosol

Cytosolic stages

(3) Synthesis of arginosuccinate – catalysed by arginosuccinate synthetase

(4) Cleavage of arginosuccinate – catalysed by argininosuccinate lyase (AKA
arginosuccinase) and yields arginine and fumarate. Fumarate is hydrated to
malate providing a link w/several metabolic pathways
(5) Cleavage of arginine to ornithine and urea – catalysed by arginase. Ornithine
re-enters the mitochondria
(6) Fate of urea = urea diffuses from the liver, and is transported in the blood to
the kidneys, where it is filtered and excreted in the urine. Urea can be cleaved
by bacterial urease to CO2 + NH3. This NH3 is partly lost in the feces, and is
partly reabsorbed into the blood

Urea cycle disorders

 Genetic defects in the enzymes involved in the cycle can occur.

 Mutations lead to deficiencies of the various enzymes and transporters
involved in the urea cycle and cause urea cycle disorders.
 If affected individuals ingest AAs beyond what is necessary for the min daily
requirements, the ammonia that is produced will not be able to be converted
to urea → hyperammonemia
 Hyperammonemia = excess ammonia in the blood. Can lead to hepatic
encephalopathy and coma
 Types:
 Primary = caused by several IEMs that are characterised by ↓ activity
of any of the enz. in the urea cycle. Most common = OTC deficiency
 Secondary = caused by IEMs, which are characterised by ↓ activity of
enz. that are not part of the urea cycle (propionic academia,
methylmalonic academia), or dysfunction of cells that make major
contributions to metabolism (acute liver failure, hepatic cirrhosis)
 Acquired = caused by diseases that result in either acute liver failure,
or cirrhosis of the liver w/chronic liver failure.
 Congenital = due to genetic defects in one of the enz. in the urea cycle
Azotemia (excess nitrogenous matter in blood)

Types:

 Pre-renal azotemia = caused by a ↓ in blood flow (hypoperfusion) to the

kidneys. However, there is no inherent kidney disease. It can occur following
haemorrhage, shock, hypovolemia, congestive HF, and narrowing of the renal
a. etc.
 Primary renal azotemia (acute kidney failure) = typically leads to uremia. It
is an intrinsic disease of the kidney, generally the result of parenchymal
damage. Causes include kidney failure, glomerulonephritis, acute tubular
necrosis, or any other kind of kidney disease
 Post-renal azotemia = due to blockage of urine flow in an area below the
kidney → can cause hydronephrosis (build-up of urine in kidney). Can be
caused by congenital abnormalities, blockage of ureters by kidney stones,
pregnancy, compression of the ureters by cancer, prostatic hyperplasia, or
blockage of the urethra by kidney or bladder stones.

Symptoms = oligo-/anuria, fatigue, ↓ alertness, confusion, pale skin, tachycardia,

xerostomia, thirst, oedema, uremic frost

Creatinine

 Creatinine = breakdown product of creatine phosphate in muscle, and is

usually produced at a fairly constant rate by the body.(form of creatine)-
derived from glycine and arginine and formed due to transamination.
 Creatinine is filtered and secreted w/little or no reabsorption - ∴ if the filtration
in the kidney is deficient, blood creatinine conc. ↑ (↑ creatinine in blood)
 Creatinine conc. in the blood and urine may be used to calculate the
creatinine clearance (CrCl), which correlates approximately w/the GFR
 Creatinuria is characteristic of newborns and pregnancy
 ↑ excretion of creatine in urine occurs with muscle atrophy, myodystrophy,
myasthenia, myositis

101 – Disturbances in purine metabolism. Gout

Definition = a form of inflammatory arthritis characterised by recurrent attacks of a

red, tender, hot, and swollen joint.

Etiology

 Hyperuricemia = too much uric acid in the blood

  The crystallisation of uric acid, often related to high levels in the blood, is the
underlying cause of gout.
 This can occur because of diet, genetic predisposition, or ↓ excretion of
urate.
 Diet = consumption of alcohol, fructose-sweetened drink, meat and seafood.
Food rich in purines yield high amounts of uric acid – dried anchovies, shrimp,
organ meat, seaweed.
 Phosphoribosyl pyrophosphate synthetase (PRPS) = enz. that converts ribose
5-phosphate into phosphoribosyl pyrophosphate. In a mutation that leads to
super activity of the enz., we can produce excess purine and uric acid.
 Medical conditions = gout frequently occurs in combo w/other medical
problems = metabolic syndrome (combo of abdominal obesity, HT, insulin
resistance, and abnormal lipid levels), kidney failure, haemolytic anaemia,
lead poisoning, and myeloproliferative diseases such as polycythemia
 Medication = diuretics have been associated w/attacks of gout;
immunosuppressive drugs cyclosporine and tacrolimus; β blockers, aspirin,
and niacin
 Risk factors = BMI ≥ 35 ↑ M risk of gout threefold; chronic lead exposure ;
alcohol; diet (food rich in purines); recent surgery or trauma

Pathogenesis

 Urate levels can be ↑ because of: ↓ excretion (most common), ↑ production, or

↑ purine intake
 Gout is a disorder of purine metabolism, and occurs when its final metabolite,
uric acid, crystallizes in the form of monosodium urate, precipitating and
forming deposits (tophi) in joints, on tendons, and in the surrounding tissues.
 Microscopic tophi are usually encased in a fibrous matrix, which blocks
interaction of the crystals w/cells and therefore avoids inflammation
 Naked crystals may break off due to minor physical damage to the joint,
medical or surgical stress, or rapid changes in uric acid levels. When they
break through the tophi, they trigger a local immune-mediated inflammatory
rxn in macs → causes inflammatory cascade

Symptoms

 Acute inflammatory arthritis = a red, tender, hot, swollen joint. the MTP joint at
the base of the big toe is affected most often. Other joints = heels, knees,
wrists, and fingers. Pain usually begins over 2-4 h and during the night.
 Fever, fatigue, tachycardia, chills, and malaise may sometimes occur
 Hyperuricemia may result in other symptoms, including hard, painless,
deposits of uric acid crystals (tophi). Extensive tophi may lead to chronic
arthritis due to bone erosion; crystals precipitating in kidneys → stone
formation and subsequent urate nephropathy
  Limited range of motion

Diagnosis

 Synovial fluid analysis = identification of monosodium urate crystals in

synovial fluid or a tophus. Under polarised light microscopy, they have a
needle-like morphology.
 Blood test = may be hyperuricemia – ½ the time gout occurs w/out
hyperuricemia and most people w/↑ uric acid levels never develop gout; may
be ↑ WBCs and sedimentation rate; kidney function (GFR, creatinine, and
creatinine clearance)
 Complete blood count (CBC) helps differentiate between septic arthritis
and gout
 Rheumatoid factor (RF) or antinuclear AB (ANA) may be ordered to rule out
other causes of arthritis symptoms. A blood culture may also be done if septic
arthritis is suspected
 Ultrasound = can detect urate crystals in a joint/tophus
 X-ray = joint X-rays can be useful in ruling out other causes of joint
inflammation

Treatment

 NSAIDs = ↓ pain and swelling

 Diet modification = keep well hydrated; avoid alcohol, red meat and seafood;
physical exercise
 Meds to ↓ uric acid levels = xanthine oxidase inhibitors (allopurinol)
 Probenecid = ↑ excretion of uric acid by the kidneys

102 – Alterations of kidney structure and function in disease. Manifestations of

altered kidney function

Kidney structure and function

Structure

The kidney is composed of 2 main regions – the cortex (outside) and the medulla
(inside). Medulla is further divided into:

 Renal pyramids separated by renal columns. Pyramids consist of minor calyx

which drain into the major calyx which drains through the renal pelvis into the
ureter which then drains to the bladder
 Nephrons – functions unit of the kidney, located in the renal pyramids.
Function

 Excretory = excretes urine which contains: Na+, H2O, H+, K+, urea/uric acid,
creatinine and nitrogen waste products
 Homeostatic = the kidney helps keep homeostasis by removing excess
products from the blood/if something is low don’t excrete it (keep it in blood)
 Endocrine = kidney produces rennin, erythropoietin, activates vitD 3,
prostaglandins, kinins, endothelin, e.t.c
 Metabolic

Alterations of kidney structure and function

Nephrotic syndrome

 Definition = it is a collection of symptoms due to kidney damage. This includes

proteinuria, hypoproteinemia, hyperlipidaemia and peripheral oedema. Other
symptoms include weight gain, fatigue, and foamy urine.
 Causes = primary glomerulonephrosis – usually described by their histology
(minimal change disease, membranous glomerulonephritis,
membranoproliferative glomerulonephritis) and secondary glomerulonephrosis
– usually described by their underlying cause (diabetic nephropathy, lupus,
syphilis, hep B, Sjogren’s syndrome)
 Pathophysiology = glomeruli are affected by an inflammation or a hyalinisation
(formation of homogenous crystalline material w/in cells) that allows proteins
such as albumin, antithrombin, or the Ig’s to pass through the cell membrane
and appear in urine
 As a response to hypoproteinemia the liver begins a compensatory
mechanism involving the synthesis of proteins, such as α-2 macroglobulin and
lipoproteins. An ↑ in the latter can cause hyperlipidaemia associated w/this
syndrome

Nephritic syndrome

 Definition = a collection of symptoms that occur due to nephritis. It often

occurs in glomerulonephritis, which is characterised by a thin glomerular
basement membrane and small pores in the podocytes of the glomerulus,
large enough to permit proteins and RBCs to pass into the urine
 Symptoms include = hematuria, oliguria, azotemia, and HT
 Cause = caused by inflammation of glomerulus; can be infectious,
autoimmune, or thrombotic.
 Pathophysiology = it is dependent on where damage is done by AB-Ag
complexes (in the glomerulus). In the case of IgA nephropathy, the
glomerulus can’t filter IgA AB-Ag complexes, and this causes an inflammatory
 response, then release of cytokines (and growth factors), and finally results in
glomerular scarring

Manifestations of altered kidney function

 ↓ kidney function leads to accumulation of urea, inability to maintain

electrolyte, water and acid-base balance
 Failure to properly excrete urea → ↑ blood urea nitrogen (BUN), serum
creatinine → uraemia (vomiting/diarrhoea, nausea, weight loss, poly-/oliguria,
hematuria)
 Inorganic phosphate build up in blood = itching, bone damage, muscle
cramps
 Hyperkalaemia = arrhythmias, muscle paralysis
 Failure of water balance = oedema, SOB (fluid in lungs)
 Lack of EPO = anaemia – fatigue, dizziness, hypotension

103 – Acute renal failure

Definition = sudden reversible impairment of the renal function causing retention of

N-containing substances, hypervolemia, electrolyte and acid-base misbalance. AKA
acute kidney injury (AKI)

Classification = pre-renal, intrinsic, post-renal (retention of urine); oliguric and non-

oliguric; w/slow or rapid ↓ of GFR

Etiology and pathogenesis

Pre-renal causes

 Pre-renal causes are those that ↓ effective renal blood flow and cause a ↓ in
the GFR (glomerular filtration rate). Both kidneys need to be affected as one
kidney is still > than adequate for normal kidney function
 Notable causes = hypovolemia, hypotension, HF, liver cirrhosis, and local
changes to the blood vessels supplying the kidney (renal a. stenosis and renal
v. thrombosis)
 ↓ blood flow → < blood to glomerulus → < blood is filtered → ↓ in GFR (how
much blood the kidneys filter through their glomeruli per minute)
 As a result, < urea and creatinine are filtered out (i.e. > stays in the blood) →
azotemia (high levels of N-containing substances in the blood)
 Oliguria
 Kidneys activate RAAS → aldosterone released from adrenal glands →
reabsorption of Na+ back into the blood (water follows Na+)
Intrinsic/intra-renal

Due to disease processes which directly damage the kidney itself. Damage to the:

 Tubules = acute tubular necrosis (epithelial cells that line the tubules die) due
to ischaemia, and nephrotoxins (aminoglycosides, lead) → the dead epithelial
cells accumulate and block the tubule → ↑ pressure in the tubules → ↓ GFR
→ oliguria, azotemia, hyperkalaemia, metabolic acidosis
 Glomerulus = glomerulonephritis – AB-Ag complexes deposit into glomerular
tissue → activation of complement → macs, Neu release lysosomal enz. →
inflammation and damage to podocytes → ↑ membrane permeability; proteins
filtered into urine = proteinuria, hematuria
 Interstitium = acute interstitial nephritis

Other causes include rhabdomyosis and tumour lysis syndrome. Certain med
classes such as calcineurin inhibitors (e.g. tacrolimus) can also directly damage the
tubular cells of the kidney and result in the a form of intrinsic AKI

Post-renal

 Caused by retention of urine due to obstruction of the urinary tract:

 Kidney stones
 Compression of ureter (intra-abdominal tumours)
 Compression of urethra (benign prostatic hyperplasia)
 Unilateral obstruction (1 ureter affected) = renal function preserved
 Bilateral obstruction (both affected) → acute renal failure → buildup of urine
and pressure that backs up into kidney (hydronephrosis) → ↓ GFR →
azotemia, oliguria. High pressure in the tubules forces Na + and water to be
reabsorbed back into the blood

Symptoms

 Main symptom is oligo-anuria

 The clinical picture is often dominated by the
underlying cause – symptoms of the disease
that caused the AKI
 Azotemia leads to = fatigue, loss of appetite,
headache, nausea and vomiting
 Hyperkalaemia = arrhythmias
 Hypervolemia = SOB, pulmonary oedema
 In severe cases = anxiety, confusion,
drowsiness

Diagnosis
AKI can be diagnosed if any of the following is present:

 ↑ in serum creatinine by ≥0.3 mg/dl (≥26.5 μmol/l) w/in 48 hours; or

 ↑ in serum creatinine to ≥1.5 times baseline, which has occurred w/in the prior
7 days; or
 Urine volume < 0.5 ml/kg/h for 6 hours

104 – Chronic renal failure. Uraemia

Definition = progressive irreversible impairment of the renal function causing

progressively ↓ clearance of nitrogen and other products including hormones,
leading to general intoxication, misbalance in the electrolyte and acid-base
homeostasis, etc; ↑ protein catabolism w/its consequences (loss of muscular mass, ↓
immunity, hemorrhagic diathesis, etc); lack of EPO, causing impaired erythropoiesis
(AKA chronic kidney disease – CKD) (kidney damage or a GFR < 60 ml/min for 3
months/>)

Etiology

 Most common = DM, HT, glomerulonephritis

 Diabetes = excess glucose in the blood sticks to proteins (non-
enzymatic glycation) which affects the efferent arteriole (becomes stiff
and narrow) → difficult for blood to leave the glomerulus → ↑ pressure
in glomerulus → hyperfiltration
 HT = renal a. wall thickens → narrow lumen → < blood and O 2 to the
kidney → ischemic injury
 Idiopathic
 Mesangial cells secrete structural matrix which expands the size of the
glomerulus. Glomerulosclerosis results and in time it diminishes the nephrons
ability to filter the blood → CKD
 Systemic diseases = lupus, rheumatoid arthritis
 Infections = HIV
 Medications = NSAIDs
 Smoking

Symptoms

 HT = due to fluid overload and production of vasoactive hormones created by

the kidney via the RAAS → ↑ risk of suffering from congestive HF
  Uremia = symptoms include pericarditis, impaired immune function, skin
disorders (itching, gout), GI manifestations (nausea/vomiting), neurologic
manifestations (encephalopathy) and sexual dysfunction
 Uremic frost = crystallised urea deposits that can be found on the skin
of those affected by CKD.
 In CKD, the high level of urea in the bloodstream leads to high levels of
urea secreted by eccrine sweat glands as a component of sweat. As
water evaporates off of the skin, it results in a crystallisation of the
remaining urea
 Is > common in severe, untreated uremia and is associated w/serum
BUN levels >200.
 Hyperkalemia = malaise, arrhythmias. Usually it doesn’t develop until GFR
falls to < 20-25 ml/min/1.73 m2, at which point the kidneys have ↓ ability to
excrete K. Hyperkalemia in CKD can be exacerbated by acidosis (which
leads to extracellular shift of K) and from lack of insulin
 ↓ EPO synthesis = anaemia
 Fluid balance overload = symptoms range from mild oedema to pulmonary
oedema
 Hyperphosphatemia = ↑ CV risk, neuropathy, gastroenteropathy,
susceptibility to infection, coagulopathies. It also ↓ plasma Ca 2+ →
demineralisation
 Hypocalcaemia = due to calcitriol deficiency and resistance to calcemic action
of parathyroid hormone. Later, this progresses to secondary
hyperparathyroidism, renal osteodystrophy, and vascular calcification that
further impairs cardiac function.
 Metabolic acidosis (due to accumulation of sulphates, phosphates, uric acid)
may cause altered enz. activity by excess acid acting on enz.; and also ↑
excitability of cardiac and neuronal membranes by the promotion of
hyperkalaemia due to excess acid (acidosis)

Grades

CKD stage GFR level (ml/min/1.73 m2)

Grade 1 ≥ 90
Grade 2 60 – 89
Grade 3 30 – 59
Grade 4 15 – 29
Grade 5 < 15
Treatment

Manage the underlying cause, dialysis, transplantation

105 – Glomerulonephritis

Classification = acute, rapidly progressive (subacute) and chronic

Acute (proliferative) glomerulonephritis (AKA post-streptococcal glomerulonephritis)

Definition = acute, diffuse immune inflammation of both kidneys affecting the

glomerular basement membrane, the mesangium and the capillary endothelium;

Etiology and pathophysiology

 Infection w/β-hemolytic streptococci group A. The usual sources of infection

are pharynx and the skin
 Formation of immune complexes of streptococci Ag and ABs which are
deposited or formed in situ on the glomerular basement membrane (hunch-
like sub-epithelial depositions) and in the mesangium causing local
inflammation w/stasis and proliferation of endothelial and mesangial cells and
infiltration w/polymorphonuclear leukocytes and monocytes

Symptoms

 Usually appear 10-14 days after initial infection

 Signs = hematuria, oliguria (diuresis < 500 ml/24 hr), oedema, HT, fever
(headache, malaise, anorexia, nausea)

Phases:

 Initial phase = when symptoms start to appear – after 10-14 days

 Oligo-anuric phase (lasts for a week) – oliguria or anuria (diuresis < 100 ml/24
hours) due to ↓ GFR. The consequences are:
 Hypervolemia = causes oedema (due to water and Na retention and ↑
capillary permeability) and arterial HT which is usually mild/moderate.
Complications include possible L HF w/cardiac asthma and pulmonary
or cerebral oedema
 Impaired clearance function and regulation of electrolytes and acid-
base balance = retention of N substances, hyperkalaemia, and
metabolic acidosis (fatigue, exhaustion, confusion, drowsiness)
 Polyuric phase (lasts 7-10 days) = characterized w/polyuria and gradual
disappearance of all symptoms of the oligo-anuric phase; however the
excessive polyuria may cause dehydration and hypokalaemia, the later may
provoke cardiac arrhythmias
 Recovery phase (lasts 3-6 months) = during which the changes in the urine
(proteinuria, hematuria) disappear completely and the GFR is normalized

Diagnosis
  Urine (specific for the diagnosis) = usually high specific gravity; moderate
proteinuria (usually between 1 and 2 g/l) and hematuria
 Abdominal ultrasound = kidneys are slightly enlarged w/diffuse structural
changes
 ECG and chest X-ray are usually required and possible echocardiography;
opthalmoscopy, CT and consultation w/neurologist are required in patients
w/suspected cerebral oedema
 Renal biopsy is performed only in prolonged and atypical cases for DDx

Rapidly progressive glomerulonephritis (RPGN) (AKA sub-acute glomerulonephritis)

Definition = rapidly progressive autoimmune kidney disease usually caused by auto-

ABs against the glomerular basement membrane

Etiology

 Infections = viral (hep B and C, HIV), bacterial (syphilis), fungal, parasitic

(malaria, schistosomiasis)
 Tumours = lymphoma
 Leukaemia, autoimmune diseases
 Idiopathic

Pathogenesis

 Epithelial cell proliferation occurs in the bowman’s space → develop a

crescent shape = obliteration of the bowman’s space
 Goodpasture syndrome = anti-glomerular basement membrane ABs
(anti-GBM ABs) target the BM causing glomerular damage
 Cell mediated immunity and macs are involved

Symptoms

 Specific for diagnosis = excessive arterial HT, severe nephrotic syndrome and
rapidly progressive chronic renal failure; hematuria and proteinuria
 Other symptoms = fatigue, loss of appetite and weight loss, nausea/vomiting,
pain in lumbar region, arthralgias, myalgias, and fever
 In Goodpasture syndrome = cough w/blood in the sputum (hemoptysis)
(autoimmune pulmonitis – auto-AB against the alveolar membrane)

Diagnosis

 Specific for diagnosis = presence of anti-GBM ABs

 Ultrasound = slightly enlarged kidney w/diffuse structural changes
 Renal biopsy = w/signs of extracapillary proliferation crescent type, linear
depositions of the ABs on the BM, depositions of fibrin
106 – Nephrotic syndrome

Definition = it is a collection of symptoms due to kidney damage. This includes

proteinuria, hypoproteinemia, hyperlipidaemia and peripheral oedema. Other
symptoms include weight gain, fatigue, and foamy urine.

Etiology

Primary glomerulonephrosis = usually described by their histology:

 Minimal change disease

 Lipid nephrosis = diffuse loss of podocytes of the glomeruli
 Focal segmental glomerulosclerosis = ↑ collagen deposition
(sclerosis/scarring) in some, but not all, glomeruli
 Membranous glomerulonephritis = thickening of the BM due to deposition of
immune complexes

Secondary glomerulonephrosis = due to changes caused by systemic disease

(usually described by their underlying cause):

 Diabetic nephropathy. Lupus, syphilis, hep B, Sjogren’s syndrome

Pathophysiology

Glomeruli are affected by an inflammation or a hyalinisation (formation of

homogenous crystalline material w/in cells) that allows proteins such as albumin,
antithrombin, or the Ig’s to pass through the cell membrane and appear in urine

Albumin is the main protein in the blood that is able to maintain an oncotic pressure,
which prevents the leakage of fluid into the extracellular medium and the subsequent
formation of oedemas

As a response to hypoproteinemia the liver begins a compensatory mechanism

involving the synthesis of proteins, such as α-2 macroglobulin and lipoproteins. An ↑
in the latter can cause hyperlipidaemia associated w/this syndrome

Symptoms

 Large amounts of proteinuria (>3.5 g/1.73 m2 body surface area/day)

 Hypoalbuminaemia (<2.5 g/dl) → hypervolemia → oedema:
 Puffiness around the eyes, characteristically in the morning
 Pitting oedema over the legs
 Pleural effusion (fluid in pleural cavity)
 Ascites (fluid in peritoneal cavity)
 Anasarca (generalised oedema throughout the body)
 Hyperlipidaemia → ↑ risk for atherosclerosis. It is caused by 2 factors:
  Hypoproteinaemia stimulates protein synthesis in the liver, resulting in
the overproduction of lipoproteins
 Lipid catabolism is ↓ due to lower levels of lipoprotein lipase
 Anaemia = may be present due to transferrin loss
 Dyspnoea = may be present due to pleural effusion or due to diaphragmatic
compression w/ascites
 Thrombophilia/hypercoagulability = greater disposition for formation of blood
clots that is caused by a ↓ in antithrombin III levels in the blood due to its loss
in urine → risk for DVT, pulmonary emboli, renal v. thrombosis
 Lipiduria = indicative of glomerular pathology due to an ↑ in the filtration of
lipoproteins
 Loss of Ig’s = ↓ resistance to infections

107 – Renal stones (nephrolithiasis)

Definition = formation of stones in the pyelon, calices in 1/both kidneys, or in the

bladder. If the stone grows to >5 mm it can cause blockage of the ureter → severe
pain in lower back or abdomen. They form when solids in the urine precipitate out
and crystallise.

Classification of stones

Kidney Incidenc Circumstances Colour Description

stone type e
Calcium 80% When urine is Black/dark Some of the oxalate in the urine is
oxalate acidic brown produced by the body. Ca and
oxalate in the diet play a role in
stone formation. Ca from bone
may also play a role in stone
formation
Uric acid 5 – 10 % When urine is Yellow/reddish Diets rich in animal proteins and
persistently acidic brown purines = organ meats, fish and
shellfish
Calcium 5 – 10 % When urine is Dirty white Tends to grow in alkaline urine,
phosphate alkaline especially when proteus bacteria
are present
Struvite 10 – 15 % Infections in the Dirty white Diet hasn’t been shown to affect
kidney struvite stone formation
Cysteine 1–2% Rare genetic Pink/yellow Cysteine leaks through the
disorder kidneys and into the urine to form
crystals
Xanthine Extremely rare Brick red

Predisposition factors
  Dehydration = ↓ water intake, climate, professional environment
 Obesity
 High dietary intake of animal protein, sodium, sugars including honey, refined
sugars, fructose and high fructose corn syrup, oxalate, grapefruit juice and
apple juice
 Crohn’s disease = associated w/hyperoxaluria and malabsorption of Mg
 Metabolic disorders = hyperuricemia and hyperuricosuria; hyperoxaluria;
cysteinuria
 Endocrine disorders = hyperparathyroidism
 Infections of the kidney and the bladder
 Obstruction of the urine flow
 Family predisposition
 Endemic predisposition = usually regions where water contains > CaCO 3

Pathophysiology

Hypocitraturia

 Hypocitraturia/low urinary-citrate excretion (< 320 mg/day) can cause kidney

stones in up to 2/3 of cases.
 The protective role of citrate is linked to several mechanisms – e.g. citrate
reduces urinary supersaturation of calcium salts by forming soluble
complexes w/Ca2+ and by inhibiting crystal growth and aggregation.
 The therapy w/K/Mg K citrate is commonly prescribed in clinical practice in
order to ↑ urinary citrate and to ↓ stone formation rates

Supersaturation of urine

 When the urine becomes supersaturated (when the urine solvent contains
more solutes than it can hold in solution) w/1 or more calculogenic (crystal-
forming) substances, a seed crystal may form through the process of
nucleation.
 Heterogeneous nucleation (where there is a solid surface present on which a
crystal can grow) proceeds > rapidly than homogeneous nucleation (where a
crystal must grow in a liquid medium with no such surface), because it
requires < E.
 Adhering to cells on the surface of a renal papilla, a seed crystal can grow
and aggregate into an organized mass. Depending on the chemical
composition of the crystal, the stone-forming process may proceed > rapidly
when the urine pH is unusually high or low
 Supersaturation is likely the underlying cause of uric acid and cysteine stones,
but calcium-based stones (especially calcium oxalate stones) may have a
more complex cause
Symptoms

 Renal colic = sudden harsh pain usually in one of the lumbar regions,
propagating towards the bladder and the groin.
 Hematuria
 Nausea and vomiting, fatigue, sweating, restlessness
 Urinary urgency
 Pain and burning during urination are possible especially when the stone is in
the bladder or in the case of cystitis
 In some cases the colic may provoke hypertonic crisis w/its symptoms
 Presence of fever indicates concomitant infection

Complications

 Hydronephrosis in some cases followed by pyelonephrosis; in prolonged

hydronephrosis (>1 month) the renal function may be irreversibly damaged
and even the kidney may be totally lost
 Infections
 In rare cases, when both ureters are obstructed → urinary retention and acute
renal failure

108 – Disturbances in water-electrolyte balance. Oedema

Total body water (TBW) = 50-70% of body weight – F have a higher % of adipose,
thus have lower TBW = 50% of body weight

Distribution of TBW:

 Intracellular fluid (ICF) = w/in the cells (2/3 of TBW)

 Extracellular fluid (ECF) = outside the cells (1/3 of TBW). It is further divided
into:
 Plasma (1/4) = non-cellular component of blood, contains proteins
 Interstitial fluid (3/4) = fluid actually bathing the cells
 Transcellular fluid = formed from the transport activities of cells (1.5% of TBW)
e.g. of this fluid = synovial fluid, CSF, intraocular fluid, joint fluid

Electrolytes are substances that dissociate in solution to form charged particles

(ions). e.g. NaCl → Na+ (cations) and Cl- (anions)

Major cations Major anions

ECF K+ Cl-
High conc. of Ca2+ HCO3-
ICF K+ Proteins, organic phosphates (> acidic)
Mg2+
Low conc. of Ca2+

Oedema

Definition = abnormal accumulation of fluid in the interstitium, located beneath the

skin and in the cavities of the body, which can cause severe pain.

Classifications

 Cutaneous/pitting oedema = after pressure is applied to a small area, the

indentation persists after the release of the pressure. Due to water retention;
can be caused by systemic disease, pregnancy, HF, or local conditions like
varicose vv., thrombophlebitis, insect bites, and dermatitis
 Non-pitting oedema = observed when the indentation doesn’t persist.
Associated w/lymphedema, lipedema, and myxedema
 Generalised oedema/anasarca = causes include congestive HF, liver failure,
renal failure, and severe malnutrition.
 Organ-specific:
 Pedal oedema = ECF accumulation in the legs. Can occur due to
hypervolemia, congestive HF, ↑ hydrostatic/↓ oncotic pressure,
obstruction of lymphatic/venous vessels draining the lower extremity.
Some drugs (amlodipine) can also cause it
 Cerebral oedema = ECF accumulation in the brain. Can occur in toxic
or abnormal metabolic states and conditions such as lupus or ↓ O 2 at
high altitudes
 Pulmonary oedema = due to L HF
 Periorbital oedema (eye puffiness)
 Myxedema = caused by ↑ tendency of the tissue to hold water w/in its
extracellular space. This is because of an ↑ in hydrophilic carb-rich
molecules deposited in the tissue matrix

Pathophysiology

6 factors can contribute to the formation of oedema:

↑ hydrostatic pressure

 Hydrostatic pressure w/in blood vessels tends to cause water to filter out of
the tissue. This leads to a difference in protein conc. between blood plasma
and tissue. As a result, the colloidal/oncotic pressure tends to draw water
back into the blood vessels from the tissue.
  ↑ hydrostatic pressure = pushes > water out of the capillary into the interstitial
space
 Causes = hypervolemia (HF, kidney disease), venous obstruction, liver
disease w/portal v. obstruction

↓ colloidal/oncotic pressure w/in blood vessels

 Capillary oncotic pressure = plasma proteins (mainly albumin) exert the

osmotic force needed to pull fluid back into the capillary from tissue spaces
 ↓ production of plasma proteins (severe liver failure), malnutrition, ↑ loss of
plasma proteins

↑ tissue colloidal/oncotic pressure

↑ capillary permeability (e.g. inflammation)

 Capillary pores enlarged or integrity of capillary wall damaged → plasma

proteins and other osmotically active particles leak into the interstitial spaces
(fluid from capillary → interstitium)
 Causes = burn injury, inflammation

Obstruction of fluid clearance in the lymphatic system (lymphedema)

 Lymphedema may be due to obstruction from, for e.g., pressure from a

cancer/enlarged lymph nodes, destruction of lymph vessels by radiotherapy,
or infiltration of the lymphatics by infection

Changes in the water retaining properties of the tissues themselves. Raised

hydrostatic pressure often reflects retention of water and Na + by the kidneys

Treatment

 Involves resolving the underlying cause

 Treatment may also involve positioning the affected body parts to improve
drainage. For e.g., swelling in feet or ankles may be ↓ by having the person lie
down in bed or sit w/the feet propped up on cushions.
 Intermittent pneumatic compression can be used to pressurize tissue in a
limb, forcing fluids—both blood and lymph—to flow out of the pressurized
area
 Drugs = diuretics (severe oedema)

109 – Disturbances in mineral metabolism – Na, K, Cl

Sodium (normal 135 – 145 mmol/L)

Hyponatraemia (↓ serum Na – < 135 mmol/L)

Causes

In those w/hypovolemia:

 Prolonged vomiting, ↓ oral intake, severe diarrhoea

 Use of diuretics
 Addison’s disease and congenital adrenal hyperplasia in which the adrenal
glands don’t produce enough steroid hormones
 Pancreatitis
 Prolonged exercise and sweating, combined w/drinking water w/out
electrolytes (exercise-associated hyponatraemia)

In those w/normal volume:

 Syndrome of inappropriate ADH secretion

 Hypothyroidism
 Not enough ACTH
 Normal physiologic change of pregnancy

In those w/hypervolemia:

 Liver cirrhosis
 Congestive HF
 Nephrotic syndrome
 Polydipsia

Symptoms

Nausea and vomiting, headache, short-term memory loss, confusion, lethargy,

fatigue, loss of appetite, irritability, muscle weakness, spasms or cramps, seizures,
and ↓ consciousness or coma

Hypernatraemia (↑ serum Na – > 145 mmol/L)

Causes

In those w/hypovolemia:

 Dehydration = inadequate intake of water

 Excessive losses of water from the urinary tract = may be caused by
glycosuria
 Water losses associated w/extreme sweating
 Severe watery diarrhoea
In those w/normal volume or euvolemia:

 Excessive excretion of water caused by diabetes insipidus, which involves

either inadequate production of ADH from the pituitary gland, or impaired
responsiveness of the kidneys to ADH

In those w/hypervolemia:

 Intake of a hypertonic fluid (a fluid w/a higher concentration of solutes than the
remainder of the body) w/restricted free water intake. Ingesting seawater also
causes hypernatremia because seawater is hypertonic and free water is not
available
 Mineralcorticoid excess due to a disease such as Crohn’s usually doesn’t lead
to hypernatraemia unless free water intake is restricted
 Salt poisoning is the most common cause in children

Symptoms

 Compensatory mechanisms = ↑ thirst, 2191ADH w/oliguria

 ↓ ICF = dry skin and mucous membranes; ↓ salivation and lacrimation; ↑ body
temp.
 Hyperosmolarity and movement of water out of neural tissue = headache,
disorientation, agitation, ↓ reflexes, seizures, and coma (severe
hypernatraemia)

Potassium (normal 3.5 – 5 mmol/L)

Hypokalaemia (↓ serum K – < 3.5 mmol/L)

Causes

 Inadequate K intake
 Excessive loss of K – diarrhoea, excessive sweating, vomiting, adenoma
 Urinary loss = diuretics (thiazide and loops), metabolic alkalosis, trauma,
stress, ↑ aldosterone
 Shift between ICF and ECF compartment e.g. decongestant and
bronchodilators cause intracellular shift in K

Symptoms

 Mild hypokalaemia is w/out symptoms, though it may cause ↑ bp, and can
provoke the development of arrhythmias.
 ↑ thirst, polyuria, metabolic alkalosis
 Severe hypokalaemia = muscle weakness, myalgia, tremor, muscle cramps,
and constipation
  With > severe hypokalaemia = flaccid paralysis and ↓ reflexes

Hyperkalaemia (↑ serum K – > 5.5 mmol/L)

Causes

 Ineffective elimination = ↓ kidney function, meds that inhibit RAAS,

mineralcorticoid (aldosterone) deficiency/resistance
 Excessive release from cells = metabolic acidosis (↑ in H + in cells can displace
K+ out of the cells); insulin deficiency (insulin ↑ the uptake of K + into the cells);
β-blockers (they can ↑ K= levels by blocking β2 receptors); exercise (can cause
a release of K+ into the bloodstream by ↑ the n.o of K+ channels in the cell
membrane)
 Excessive intake = isn’t a primary cause of hyperkalaemia because the body
usually can adapt to the ↑ in K+ by ↑ its excretion into the urine through
aldosterone secretion and ↑ the n.o of K+ secreting channels in kidney
tubules. Usually develops when there are other co-morbidities such as
hyperaldosteronism and CKD

Pathophysiology

 ↑ extracellular K+ levels result in depolarisation of the membrane potentials of

cells due to the ↑ in the equilibrium potential of K +.
 This depolarisation opens some voltage-gated Na + channels, but also ↑ the
inactivation at the same time.
 Since depolarisation due to conc. change is slow, it never generates an AP by
itself; instead, it results in accommodation.
 Above a certain level of K+ the depolarisation inactivates Na+ channels, opens
K+ channels, thus the cells become refractory.
 This leads to the impairment of neuromuscular, cardiac, and GI organ
systems. Of most concern is the impairment of cardiac conduction, which can
cause ventricular fibrillation, bradycardia, or asystole

Symptoms

 Mild hyperkalaemia usually doesn’t produce any symptoms. When it does,

they are non-specific – malaise, palpitations, and muscle weakness
 GI = nausea, vomiting, diarrhoea, intestinal cramps
 Neuromuscular = weakness, paralysis (severe hyperkalaemia)
 CV = cardiac arrhythmias or sudden cardiac death

Chlorine (normal 96 – 106 mEq/L)

Hypochloremia (↓ serum Cl – < 96 mEq/L)

  Rarely occurs in the absence of other abnormalities. It’s sometimes
associated w/hypoventilation.
 It can be associated w/chronic respiratory acidosis
 It is usually the result of hyponatraemia

Hyperchloremia (↑ serum Cl – > 110 mEq/L)

Causes

 Loss of electrolyte-free fluid = sweating, skin burns, lack of adequate water

intake, hyper-metabolic state, and diabetes insipidus. Losing fluid →
dehydration and dry mucous membrane
 Loss of hypotonic fluid = due to diuretic use, diarrhoea, vomiting, burns, renal
disease, renal failure, and renal tubular acidosis
 ↑ salt intake → HT, oedema, CV dysfunction

Pathophysiology

One suggested mechanism leading to hyperchloremia, there is a ↓ in Cl - transporter

proteins along the nephron. These proteins may include sodium-potassium-2
chloride co-transporter, Cl- anion exchangers, and Cl- channels. As a result of the
reduced activity in these transporters, another suggested mechanism is a depletion
in concentration gradient which would allow for the passive diffusion of Cl - in and out
the tubule

Symptoms

 Dehydration, thirst, weakness

 HT, CV dysfunction, oedema
 Kussmaul breathing
 Hyperglycaemia
 Respiratory alkalosis

110 – Disturbances in calcium and phosphate metabolism

Calcium (normal 2.1 – 2.6 mmol/L)

Hypocalcaemia (↓ serum Ca – < 2.1

mmol/L)

Causes
  Hypoparathyroidism = in the setting of absent, ↓, or ineffective PTH, the body
loses the regulatory function of Ca levels
 Hyperphosphatemia
 Abnormal loss of Ca2+ from the kidney
 Renal failure = ↓ production of active vit D
 Mg deficiency = inhibits PTH release
 Drugs = loop diuretics ↑ urinary excretion of Ca2+, PPIs ↓ absorption

Symptoms

 Petechiae – later develop into purpura

 Oral, perioral, and acral paresthesias (pins and needles)
 Carpopedal and generalised tetany (unrelieved and strong contractions of the
hands, and in the large muscles of the rest of the body) are seen
 Latent tetany:
 Trousseau sign of latent tetany (eliciting carpal spasm by inflating the
bp cuff and maintaining the cuff pressure above systolic)
 Chvostek’s sign (tapping of the inf. portion of the cheekbone will
produce facial spasms)
 Hyperactive tendon reflexes
 Effects on CO = -ve Chronotropic effect (↓ HR) and –ve inotropic effect (↓
contractility)
 ECG changes = QT prolongation, or intermittent prolongation of QTc
(corrected QT interval)
 Skeletal effects = osteomalacia and bone pain

Hypercalcaemia ( ↑ serum Ca – > 2.6 mmol/L)

Causes

 Primary hyperparathyroidism – causes ↑ bone resorption

 Cancer = solid tumour w/metastasis (breast cancer), solid tumour w/humoral
mediation of hypercalcaemia (lung cancer), haematological cancers
 Vit D disorders = hypervitaminosis D (vit D intoxication)
 Kidney failure

Symptoms

There is a general mnemonic for remembering the effects of hypercalcaemia:

"Stones, Bones, Groans, Thrones and Psychiatric Overtones"

 Stones (kidney/biliary)
 Bones (bone pain)
 Groans (abdominal pain, nausea, vomiting)
  Thrones (polyuria) resulting in dehydration due to nephrogenic diabetes
insipidus from nephrocalcinosis
 Muscle tone (hypotonicity, muscle weakness, hyporeflexia)
 Psychiatric overdose (depression, anxiety, cognitive dysfunction, insomnia,
coma)

Hypercalcaemia can result in an ↑ in HR (+ve Chronotropic effect) and ↑ in

contractility (+ve inotropic effect)

Other symptoms include arrhythmias, fatigue, anorexia, constipation, and paralytic

ileus.

Phosphate (normal 2.5 – 4.5 mg/dL OR 0.81 – 1.46 mmol/L)

Hypophosphatemia (↓ serum phosphate – < 2.5 mg/dL or 0.81 mmol/L)

Causes

 Inadequate intake
 ↑ excretion – hyperparathyroidism, hypophosphatemic rickets
 Insufficient intestinal absorption = glucocorticoids, high dietary Mg 2+, antacids
 Shift of phosphorus from extracellular to the intracellular space. This can be
seen in treatment of diabetic ketoacidosis, refeeding, short-term ↑ in cellular
demand and acute respiratory alkalosis

Symptoms

 Muscle dysfunction and weakness – this occurs in major muscles, but also
may manifest as: diplopia, low CO, dysphagia, and respiratory depression due
to respiratory muscle weakness.
 Mental status changes – This may range from irritability to gross confusion,
delirium, and coma.
 WBC dysfunction, causing worsening of infections.
 Instability of cell membranes due to low ATP levels – this may cause
rhabdomyolysis w/↑ serum levels of creatine phosphokinase, and also
hemolytic anemia
 ↑ affinity for O2 in the blood caused by ↓ production of 2,3-bisphosphoglyceric
acid
 Large pulp chambers in the teeth

Hyperphosphatemia (↑ serum phosphate – > 4.5 mg/dL or 1.46 mmol/L)

Causes
  Impaired renal phosphate excretion = renal insufficiency, hypoparathyroidism,
parathyroid suppression, acromegaly, heparin therapy
 Massive extracellular fluid phosphate loads = rapid administration of
exogenous phosphate, extensive cellular injury or necrosis (crush injuries,
hyperthermia, rhabdomyolysis, fulminant hepatitis), transcellular phosphate
shifts (metabolic and respiratory acidosis)

Symptoms

Many of the signs and symptoms are related to Ca deficit because of the reciprocal
relationship between Ca and phosphate (> serum phosphate = < serum Ca levels)

 Neuromuscular = paresthesias, tetany

 CV = hypotension, cardiac arrhythmias

111 – Disturbances in trace elements metabolism

Trace elements are needed in small amounts for normal growth

Iron

Free iron Fe2+ is absorbed across the apical side via enterocytes, binds to apoferitin
→ basolateral membrane → blood → Fe2+ binds to transferrin in the blood → liver →
bone marrow; released and reused for Hb synthesis. Fe deficiency = anaemia

Trace element Function Deficiency Excess

Zinc (7-11 mg) Protein, lipid, Stomatitis, glossitis, Acute = nausea, vomiting,
carb, and bone abdominal symptoms abdominal pain, melena,
metabolism (diarrhoea, nausea, diarrhoea, jaundice
vomiting), delayed wound
healing, dwarfism, growth Chronic = ↓ reproductive
retardation, mental function, anaemia
symptoms, anorexia
Copper (1-4 mg) Hemopoiesis Anaemia, leucopenia, Nausea, vomiting,
Bone and CT neutropenia diarrhoea, jaundice,
metabolism oliguria, coma, melena
Cobalt Hemopoiesis Pernicious anaemia Cobalt poisoning
Iodine (200-30,000 μg) Tissue Goitre, hypothyroidism Goitre; burning of the
metabolism mouth, throat, and
Formation of stomach; fever, nausea,
thyroid vomiting, diarrhoea
hormones

112 – Basic disturbances in acid-base equilibrium. Acidosis

 Acidosis = a process that causes a low pH in blood and tissues

  Academia = when arterial pH falls below 7.35

Symptoms of acidosis

 Central = headache, sleepiness, confusion, loss of consciousness, coma

 Respiratory = SOB, coughing. Those w/metabolic acidosis may exhibit
Kussmaul breathing (deep, rapid breathing classically associated w/diabetic
ketoacidosis)
 Heart = arrhythmia, ↑ HR
 Muscular = seizures, weakness
 GI = nausea, vomiting, diarrhoea

Nervous system involves occurs > often w/respiratory acidosis than w/metabolic
acidosis.

Metabolic acidosis

 ↓ plasma pH (< 7.35) and HCO3- (bicarbonate)

Causes

 ↑ production of metabolic acids = accumulation of lactic acid, and

overproduction of ketoacids (DM, starvation)
 ↓ renal function = renal tubular acidosis – tubular secretion of H + or
reabsorption of HCO3- is abnormal
 ↑ HCO3- loss = in urine (tubular defect), diarrhoea

Compensatory mechanisms

Metabolic acidosis is either due to increased generation of acid or an inability to

generate sufficient bicarbonate. The body regulates the acidity of the blood by four
buffering mechanisms:

 Bicarbonate buffering system

 Intracellular buffering by absorption of H atoms by various molecules,
including proteins, phosphates and carbonate in bone.
 Respiratory compensation = hyperventilation will cause > CO 2 to be removed
from the body and thereby ↑ pH.
 Kidney compensation

Respiratory acidosis

 Definition = medical emergency in which hypoventilation ↑ the conc. of CO 2 in

the blood and ↓ the blood’s pH (acidosis)
 ↓ plasma pH and ↑ pCO2 (hypercapnia)

Causes
  Acute = abrupt failure of ventilation – depression of central respiratory center
by cerebral disease or drugs, inability to ventilate adequately due to
neuromuscular disease, or airway obstruction related to asthma or COPD
exacerbation
 Chronic disorders of ventilation → hypoxia → acute respiratory distress
syndrome e.g. COPD
 Hypoventilation
 Excess CO2 production (exercise, fever, sepsis, burns)

Compensatory mechanisms

In acute respiratory acidosis, compensation occurs in 2 steps:

 The initial response is cellular buffering (plasma protein buffers) that occurs
over minutes to hours. Cellular buffering elevates plasma bicarbonate (HCO 3−)
only slightly
 The 2nd step is renal compensation that occurs over 3–5 days. W/renal
compensation, renal excretion of carbonic acid is ↑ and HCO 3- reabsorption is
↑

113 – Basic disturbances in acid-base equilibrium. Alkalosis

 Alkalosis = a process that causes a high pH in blood and tissues

 Alkalemia = when arterial pH rises above 7.45

Metabolic alkalosis

 ↑ plasma pH and HCO3-

Causes

 Retention of HCO3-
 Excess bicarbonate levels = excess intake of HCO3- containing antacids
(Alka-Seltzer), exogenous input (infusion to compensate for acidosis)
 Loss of H+
 Vomiting = loss of HCl w/the stomach contents.
 Severe vomiting also causes loss of K+ (hypokalemia) and Na+
(hyponatremia). The kidneys compensate for these losses by retaining
 Na+ in the collecting ducts at the expense of H + (sparing Na/K pumps to
prevent further loss of K+), leading to metabolic alkalosis
 Shift of H+ into intracellular space = seen in hypokalaemia. Due to a low
extracellular K+ conc., K+ shifts out of the cells. In order to maintain electrical
neutrality, H+ shifts into the cells, raising pH

Compensatory mechanism

Compensation occurs mainly in the lungs, which retain CO 2 through hypoventilation

(respiratory compensation). CO2 is then consumed toward the formation of the
carbonic acid intermediate, thus decreasing pH. Respiratory compensation, though,
is incomplete. The ↓ in [H+] suppresses the peripheral chemoreceptors, which are
sensitive to pH. But, because respiration slows, there's an increase in pCO 2 which
would cause an offset of the depression because of the action of the central
chemoreceptors which are sensitive to the partial pressure of CO 2 in the CSF. So,
because of the central chemoreceptors, respiration rate would be ↑

Renal compensation, < effective than respiratory compensation, consists of ↑

excretion of HCO3−, as the filtered load of HCO3− exceeds the ability of the renal
tubule to reabsorb it

Symptoms

 Mild cases of often causes no symptoms.

 Moderate to severe = paresthesia, neuromuscular irritability, tetany, cardiac
arrhythmias (usually due to hypokalaemia), coma, seizures, and temporary
waxing and waning confusion

Respiratory alkalosis

 Definition = medical condition in which ↑ respiration elevates the blood pH

beyond the normal range w/a concurrent ↓ pCO 2 (amount of CO2 dissolved in
the blood)
 ↑ plasma pH and ↓ pCO2 (hypocapnia)

Causes

Hyperventilation due to:

 Central stimulation of medullary respiratory centres = anxiety, pain,

pregnancy, encephalitis
 Stimulation of peripheral chemoreceptors (carotid chemoreceptors) =
hypoxemia, exposure to high altitudes
 May also be due to fever, pulmonary disorder, vocal cord paralysis, liver
disease
Mechanism

Respiratory alkalosis generally occurs when some stimulus makes a person

hyperventilate → ↑ alveolar respiration, expelling CO2 from circulation → altered
dynamic chemical equilibrium of CO2 in circulatory system

Circulating H+ and HCO3- are shifted through the carbonic acid (H2CO3) intermediate
to make > CO2 via the enzyme carbonic anhydrase. This causes ↓ circulating H+
conc., and ↑ pH (alkalosis)

Compensatory mechanism = renal compensation – alkaline urine (↑ H + excretion

and ↓ HCO3- reabsorption)

Symptoms

 Palpitations
 Tetany
 Convulsion
 Sweating

Classification

 Acute = occurs rapidly, have a high pH because the response of the kidney is
slow
 Chronic = > long-standing condition, here one finds the kidneys have time to ↓
the HCO3- level

114 – Interrelationships between intracellular and extracellular pH

A buffer is a mixture of a weak acid and its conjugate base or a weak base and its
conjugate acid. A buffered solution resists a change in pH

Normal blood pH is regulated between 7.35 – 7.45. The 3 major mechanisms

involved in regulating the pH of body fluids are:

 Chemical (blood buffer system)

 Physiological (the respiratory rate can help w/pH control)
 Renal secretion (where we can get rid of H+ via urine).

Chemical acid-base buffer system

Bicarbonate buffer system

Definition = it is an acid-base homeostatic mechanism involving the balance of

carbonic acid (H2CO3), bicarbonate ion (HCO3-), and CO2 in order to maintain the pH
in the blood to support proper metabolic function

 Catalysed by carbonic anhydrase, CO2 reacts w/H2O to form carbonic acid

(H2CO3)
 H2CO3 rapidly dissociates to H+ and HCO3- and the latter is transported to the
lungs
 In the lungs the rxns occur in reverse = HCO 3- enters the cell in exchange for
Cl- and reacts w/H+ (that dissociates from Hb) to form H2O and CO2 and is
expired by the lungs
 Rxn = CO2 + H2O ⇌ H2CO3 ⇌ HCO3- + H+
 pH is balanced by the presence of both a weak acid (H 2CO3) and its conjugate
base (HCO3-) so that any excess acid or base introduced to the system is
neutralised
 HCO3- (conjugate base) serves to neutralise acid introduced to the
blood thorugh other metabolic processes (lactic acid, ketone bodies)
 H2CO3 (weak acid) serves to neutralise bases introduced to the blood
(urea from catabolism of proteins)

Phosphate buffer system

Phosphate buffer system is the 2nd most important. It works in the same principle as
the bicarbonate buffer system and operates in the ICF – H 2PO4- ⇌ H+ + HPO42-

 H2PO4- acts as the H+ donor (acid) = if additional OH- enter the cellular fluid,
they are neutralised by H2PO4-
 HPO42- acts as the H+ acceptor (base) = if additional H+ enter the cellular fluid,
they are neutralised by HPO42-

Protein buffer system

 They are the largest buffer system in the body

 Proteins are amphoteric – they contain many ionisable groups that can
release/bind H+
 They are largely located w/in cells – albumin and plasma globulins are the
main protein buffers

Respiratory regulation of acid-base balance

Central chemoreceptors are located on the ventral surface of the medulla, near the
exit point of CN 9 and 10 and only a short distance from the DRG – thus they
communicate directly w/the inspiratory center.
The brain stem chemoreceptors are sensitive to changes in pH of CSF. Decrease in
pH of CSF = increase in breathing rate (hyperventilation) and increase in pH of CSF
= decrease in breathing rate (hypoventilation).

Response of central chemoreceptors:

1) In the blood CO2 combines reversibly w/H2O to form H+ and HCO3-. However
the BBB is impermeable to these ions, which remain trapped in the vascular
compartment and don’t enter the brain. CO2, however, is permeable across
the BBB and enters the ECF of the brain
2) CO2 is also permeable across the brain-CSF barrier and enters the CSF
3) In the CSF, CO2 is converted to H+ and HCO3-. ∴ ↑ in arterial PCO2 = ↑ in
PCO2 of CSF → ↑ in H+ conc. of CSF (↓ in pH)
4) Central chemoreceptors detect the change – signals the inspiratory center to
stimulate hyperventilation

There are peripheral chemoreceptors for O2, CO2 and H+ in the carotid bodies and in
the aortic bodies. Information about arterial PO 2, PCO2 and pH is relayed to the DRG
via CN 9 and 10, which manage an appropriate change in breathing rate

Renal regulation of acid-base balance

 The kidneys maintain acid-base balance through reabsorption of HCO 3-,

regulation of H+ secretion, and generation of new HCO3-
 When the pH in the ECF tends to fall (i.e. becomes > acidic) H + is excreted
into the urine, while the HCO3- is secreted into the blood plasma, causing the
plasma pH to ↑ (correcting the initial fall).
 The converse happens if the pH in the ECF tends to rise: HCO 3- is excreted
into the urine and H- into the blood plasma.

115 – Primary and secondary hyperparathyroidism. Familial hypocalciuric

hypercalcaemia

Parathyroid hormone revision

 Parathyroid hormone (PTH) is secreted by parathyroid glands

 It regulates the serum calcium through its effects on bone, kidney and
intestines
 Released when there is low Ca2+ in the blood – stimulates efflux of Ca2+ from
bone, ↓ loss of Ca2+ in urine, and enhanced absorption of Ca 2+ from intestines
 Hyperparathyroidism = ↑ PTH levels in the blood

Primary hyperparathyroidism
Causes

 Caused by a tumour w/in the parathyroid gland (parathyroid adenoma)

 Less common causes = parathyroid hyperplasia, parathyroid carcinoma, and
adenomas in >1 gland
 It is also a feature of several familial endocrine disorders – multiple endocrine
neoplasia 1 and 2a (MEN1, MEN2A), and familial hyperparathyroidism

Clinical manifestations

 Hypercalcaemia and ↑ Ca2+ in the urine filtrate, resulting in hypercalciuria and

the potential for development of kidney stones
 Most people are asymptomatic and disease is discovered during routine
biochemical testing

If symptoms are present they are those of hypercalcaemia. They are classically
summarised by “stones, bones, abdominal groans, thrones, and psychiatric
overtones”

 “Stones” = kidney stones → renal failure

 “Bones” = bone-related complications – osteitis fibrosa (loss of bone mass,
weakening of the bones) osteoporosis, osteomalacia, arthritis
 “Abdominal groans” = GI symptoms of constipation, indigestion, nausea, and
vomiting. hypercalcaemia can lead to peptic ulcers and acute pancreatitis
 “Thrones” = polyuria and constipation
 “Psychiatric overtones” = effects on the CNS – lethargy, fatigue, depression,
memory loss, psychosis, ataxia, coma.

Diagnosis and treatment

 Diagnosis = blood tests - ↑ Ca2+ and PTH

 Treatment = surgical removal of the gland (parathyroidectomy)
 Meds = oestrogen replacement therapy in postmenopausal F and
bisphosphonates which may improve bone turnover

Secondary hyperparathyroidism

Cause

 Chronic kidney failure is the most common cause.

 Failing kidneys don’t convert enough vit D to its active form, and they don’t
adequately excrete phosphate.
 When this happens, insoluble calcium phosphate forms in the body and
removes Ca2+ from the circulation. Both processes lead to hypocalcaemia and
hence secondary hyperparathyroidism
  It can also result from malabsorption (chronic pancreatitis, small bowel
disease)

Clinical manifestations

 Bone and joint pain are common, as are limb deformities

 In the early stage = ↓ Ca2+ and activated vit D levels = ↑ PTH
 As the disease progresses = ↓ in vit D and Ca2+ receptors, and the parathyroid
gland becomes > resistant to feedback regulation = ↑ phosphate levels induce
hyperplasia of the parathyroid gland independent of Ca 2+ and vit D = chronic
kidney disease-mineral bone disorder (CKD-MBD)

Treatment

Calcitriol and other vit D analogs = control parathyroid hyperplasia

Familial hypocalciuric hypercalcaemia (FHH)

 It is an AD inherited condition that causes hypercalcaemia associated

w/inappropriate levels of PTH and urinary Ca2+ excretion

Classified into 3 types depending on which gene is involved:

 FHH types 1-3

 FHH type 1 = most common, due to mutation in CASR gene which codes for
Ca2+-sensing receptor (CaSR) protein that Ca2+ molecules bind to in order to
regulate Ca2+ levels in the blood
 In the parathyroid gland, the CaSR mediates –ve feedback mechanisms
relating to PTH secretion. In normal individuals, PTH secretion ↓ w/↑ Ca 2+
 Loss of CaSR function = ↓ sensitivity of parathyroid and renal cells to Ca 2+
levels (i.e. inhibition of PTH release doesn’t occur) → hypercalcaemia

Clinical manifestations

 Most cases are asymptomatic

 General symptoms may include fatigue, weakness, excess thirst
 Some can suffer from relapsing pancreatitis – if this occurs parathyroidectomy
is recommended
 Usually treatment is unnecessary due to FHH being asymptomatic

Diagnosis

Lab signs of FHH include:

 Hypercalcaemia
 ↓ Ca2+ excreted in the urine (low urine Ca2+)
  Hypermagnesemia
 High normal to mildly ↑ PTH

116 – Hypoparathyroidism and pseudohypoparathyroidism

Hypoparathyroidism

 ↓ function of the parathyroid glands w/underproduction of PTH →

hypocalcaemia

Etiology

 Congenital = absence of parathyroid glands (DiGeorge syndrome)

 Acquired = removal of, or trauma to, the parathyroid glands due to thyroid
surgery (thyroidectomy), parathyroid surgery (parathyroidectomy) or other
surgical interventions in the central part of the neck (such as operations on
the larynx and/or pharynx)
 Autoimmune = antiparathyroid ABs associated w/DM1 or Grave’s disease
 Mg deficiency (Mg is required for PTH secretion)
 Idiopathic

Clinical manifestations

 Hypocalcaemia interferes w/normal muscle contraction and n. conduction →

paresthesia, tetany (severe spasms) w/muscle cramps, convulsion
 Patients also report fatigue, headaches, bone pain, hypotension and
insomnia.

Treatment

 Severe hypocalcaemia = IV Ca2+

 Mg supplements if there is a Mg deficiency
 Chronic disease = oral Ca2+ and vit D

Pseudohypoparathyroidism

 It is a condition associated primarily w/resistance to PTH

 It is a familial disorder
 Patients have low serum Ca2+ and high phosphate, but PTH is appropriately
high (due to low level of Ca2+ in the blood)
 Its pathogenesis has been linked to dysfunctional G proteins
 Variants of the disorder = pseudohypoparathyroidism + congenital defects, or
congenital defects + normal Ca2+ and phosphate levels

Clinical manifestations
  Hypocalcaemia → tetany, paresthesia, cramping, muscle spasms
 ↑ parathyroid function (hyperparathyroidism)
 Hyperphosphatemia
 Congenital defects in growth and development of the skeleton, including short
stature and short metacarpal and metatarsal bones

Treatment = Ca2+ and calcitriol supplements

117 – Osteoporosis and osteomalacia

Osteoporosis

 Definition = a metabolic bone disease characterised by a loss of mineralised

bone mass causing ↑ porosity of the skeleton and susceptibility to fractures
 Bones that commonly break include the vertebrae, bones of the forearm, and
the hip.

Risk factors

Non-modifiable:

 Advanced age and F sex; oestrogen deficiency is correlated w/a rapid ↓ in

bone mineral density, while in M, a ↓ in testosterone levels has a comparable
(but < pronounced) effect
 Ethnicity = EU and Asian ancestry predisposes for osteoporosis
 Family history
 Those who have already had a fracture are at least 2x likely to have another
fracture
 Build = small stature is associated w/the development of osteoporosis
 Early menopause/hysterectomy

Potentially modifiable:

 Excessive alcohol and tobacco smoking

 Malnutrition, vit D deficiency, high dietary protein

Medical disorders:

 Immobilisation – bedridden, wheelchair, space flight, fractured limb in a cast

  Hypogonadal states = Turner syndrome, Klinefelter syndrome, anorexia
nervosa
 Endocrine disorders = Cushing’s, hyperparathyroidism, hyper/hypothyroidism,
DM 1 and 2
 Malnutrition, parenteral nutrition, and malabsorption – Crohn’s, ulcerative
colitis, CF, surgery, severe liver disease
 Rheumatologic disorders = rheumatoid arthritis, ankylosing spondylitis, lupus

Medication = glucocorticoids and anti-epileptics

Pathogenesis

 Underlying mechanism is an imbalance between bone resorption and bone

formation
 3 main mechanisms by which osteoporosis develops are = an inadequate
peak bone mass (the skeleton develops insufficient mass and strength during
growth), excessive bone resorption, and inadequate formation of new bone
during remodelling

Clinical manifestations

 Predisposition to fractures – vertebral compression fracture, fracture of hip,

pelvis, humerus (caused by fall, sudden movement, lifting, jumping)
 ↓ in height (wedging and collapsing of vertebrae)
 Loss of height in vertebral column + kyphosis (excessive convex curvature of
spine) = Dowager hump

Diagnosis and treatment

 Diagnosis = X-ray, bone mineral density (BMD)

 Regular exercise and intake of Ca2+ and vit D are important for prevention
 Lifestyle management = weight-bearing endurance exercise and/or exercises
to strengthen muscles improves bone strength in those w/osteoporosis
 Meds = bisphosphonates – bind to hydroxyapatite and prevent bone
resorption by inhibiting osteoclast activity
 Selection oestrogen receptor modulators – Raloxifene
 Recombinant PTH = Teriparatide – treat F w/postmenopausal osteoporosis

Osteomalacia

 Definition = softening of the bones resulting from inadequate mineralisation of

bone
 Rickets = the disorder in children; osteomalacia = disorder in adults

Etiology
  Insufficient Ca2+ absorption from the intestine because of a lack of dietary Ca 2+
OR a deficiency of or resistance to the action of vit D
 Phosphate deficiency caused by ↑ renal losses or ↓ intestinal absorption
 Renal rickets is a form of osteomalacia in people w/chronic renal failure – the
kidney can’t activate vit D
 Vit D resistant rickets = XD disorder, renal tubular defects that cause excess
phosphate loss
 Also primary hyperparathyroidism can cause ↑ Ca2+ resorption from the bone
which can lead to osteomalacia

Clinical manifestations

 Diffuse bone and joint pain (especially of spine, pelvis, and legs)
 Muscle weakness
 Difficulty walking, often w/waddling gait
 Hypocalcaemia (+ve Chvostek sign) (compensated/secondary
hyperparathyroidism)
 Compressed vertebrae and diminished stature
 Pelvic flattening

Diagnosis and treatment

 Diagnosis = X-ray – pseudofractures called looser zones; bone biopsy

 Prevention = adequate intake of vit D and Ca 2+
 Treatment = oral vit D3

118 – Diabetes mellitus. Pathology and pathogenesis

Diabetes is a group of metabolic diseases in which there are high blood sugar levels
over a prolonged period. The 3 types of diabetes mellitus are:

 Type 1 DM (“insulin-dependent DM”, IDDM, or “juvenile

diabetes”) – results from the body’s failure to produce
enough insulin
 Type 2 DM (“non insulin-dependent DM”, NIDDM, or “adult
onset diabetes”) – begins w/insulin resistance, a condition in
which cells fail to respond to insulin properly. As the disease
progresses a lack of insulin may also develop. The primary
cause is excessive body weight and not enough exercise
 Gestational diabetes – occurs when pregnant women w/out
a previous history of diabetes develop a high blood glucose
level
Insulin is the main hormone that regulates the uptake of glucose from the blood into
most cell of the body. Therefore, deficiency of insulin or the insensitivity of its
receptors play a central role in all forms of DM.

Insulin is released by β cells of the IOL in response to ↑ blood glucose, typically after
eating. lower glucose levels result in ↓ insulin release and in the breakdown of
glycogen to glucose. This process is mainly controlled by glucagon (α cells), which
acts in the opposite manner to insulin

DM 1

 Characterised by loss of the insulin-producing β cells, leading to insulin

deficiency
 This type can be further classified as immune-mediated or idiopathic.
 It is thought to be an autoimmune disorder resulting from a genetic
predisposition; an environmental triggering event (infection); and a T-cell-
mediated HS rxn (type 4 HS) against some β cell Ag
 The major susceptibility gene for DM 1 is located in the human leukocyte Ag
(HLA) region on chromosome 6. This gene encodes MHC, which is extremely
important for recognising foreign molecules and maintaining self-tolerance
 Self-tolerance = ability of the immune system to recognise self-Ag’s as a non-
threat whilst responding to foreign substances. In DM 1, T cells lose their self-
tolerance, i.e. they respond to self-Ag’s
 There is also production of auto-ABs against insulin and the IOL

Symptoms = polyphagia, polyuria, polydipsia, xerostomia, glycosuria, weight loss

Treatment = life-long insulin therapy

DM 2

 DM 2 is due to insufficient insulin production in the setting of insulin resistance

 The metabolic abnormalities that lead to DM 2 include:
 Insulin resistance
 Deranged secretion of insulin by the pancreatic β cells
 ↑ glucose production by the liver
 Insulin resistance is the ↓ ability of insulin to act effectively on target tissue,
especially muscle, liver, and fat.
 In the liver, insulin normally suppresses glucose release. However, in the
setting of insulin resistance, the liver inappropriately releases glucose into the
blood.
 Insulin resistance initially stimulates an ↑ in insulin secretion, often to a level
of modest hyperinsulinemia, as the β cells attempt to maintain a normal blood
glucose level → leads to β cell hyperplasia and hypertrophy
 In time, the ↑ demand for insulin secretion leads to β cell exhaustion and
failure (leads to hypoplasia and hypotrophy).
  This results in ↑ postprandial blood glucose levels and an eventual ↑ in
glucose production by the liver.
 Since people w/DM 2 do not have an absolute insulin deficiency, they are <
prone to ketoacidosis compared to people w/DM 1

Diagnosis of DM

 Fasting plasma glucose level at/> 7 mmol/L (126 mg/dL). Patients w/fasting
glucose levels from 5.6 to 6.9 mmol/L (100-125 mg/dL) are considered to
have impaired fasting glucose (a pre-diabetic state)
 Glucose tolerance test = 2 hours after a 75 g oral dose, a plasma glucose at/>
11.1 mmol/l (200 mg/dL)
 Islet autoreactivity, measured by the presence of autoantibodies directed
towards the β cells (DM 1)
 Glycated haemoglobin of > 48 mmol/l

119 – Pathobiochemistry of diabetes mellitus

Insulin synthesis

 Preproinsulin – has a signal sequence that is only needed

at the beginning and is then removed
 Proinsulin – has C chain in the structure. 3 disulfide
bridges are established – 2 DSB between the A and B
chains, and 1 DSB w/in the A chain. The DSB are
established because if C chain is removed A and B chains
would be separated, therefore DSB need to be made
here.
 Insulin = once the C chain has been removed

Insulin secretion

 Insulin secretion from β cells is triggered by rising

blood glucose levels.
 Starts w/uptake of glucose by the GLUT2 transporter
 Glucose released from glycolysis results in a rise of
the ATP/ADP ratio. This rise inactivates the K+
channel
 This results in depolarisation of the membrane,
causing the Ca2+ channel to open up, allowing Ca2+
ions to flow inward.
  The rise in intracellular Ca2+ levels leads to exocytotic release of insulin from
their storage granules.
 Usually the GLUT4 transporter is in the cytoplasm – insulin binding to the
insulin receptor causes GLUT4 to be deposited in the membrane so a channel
can form and glucose can enter the cell. w/out a signal from insulin, GLUT1 is
deposited in the membrane; however it has a low affinity for glucose.
 GLUT2 doesn’t rely on insulin for facilitated diffusion

Insulin transduction pathway

It is a biochemical pathway by which insulin ↑ the uptake of glucose into fat and
muscle cells and ↓ the synthesis of glucose in the liver.

 Insulin binding to the α subunit activates receptor tyrosine kinase activity of

the intracellular domain of the β subunit of the insulin receptor
 Tyrosine residues of the β subunit are auto-phosphorylated
 Receptor tyrosine kinase also phosphorylates insulin receptor substrate
(IRS1)

 IRS1 acts as an adapter protein, allowing phosphoinositide 3-kinase (PI3K) to
bind. PI3K is responsible for the phosphorylation of a phospholipid in the
bilayer, phosphatidylinositol-4,5,diphosphate (PIP 2), and converts it into PIP3
 PIP3 then moves along the membrane and
binds to PIP3-dependant protein kinase
(PDK1) in order to activate it.
 Active PDK1 then activates protein kinase B
(AKT)
 Once AKT is activated, it can then move
anywhere w/in the cytoplasm, as well as
diffuse across the membrane. It catalyses
phosphorylation of key proteins, leading to
an increase in glycogen synthase activity
(glycogenesis) and recruitment of GLUT4 to
the membrane (to bring glucose into the cell)

Symptoms of diabetes

 Polyphagia, polydipsia, polyuria, glycosuria weight loss

 Blurred vision
 Fatigue, slow healing of cuts, itchy skin
 Acetone breath, Kussmaul breathing (hyperventilation) (> common w/DM 1)
 GI = nausea, vomiting, abdominal pain
120 – Complications in diabetes mellitus

Acute complications

Diabetic ketoacidosis (DKA)

Definition = life-threatening complication of uncontrolled diabetes and mainly affects

people w/DM 1

Pathogenesis

 DKA arises because of a lack of insulin in the body

 This lack of insulin leads to the release of FFAs (free FA) from adipose tissue
(lipolysis), which are converted via β-oxidation into ketone bodies
(acetoacetate and β-hydroxybutyrate)
 The ketone bodies can initially be used for E in cells in cases of starvation
 However, they have a low pKa and ∴ ↑ the acidity of the blood (metabolic
acidosis)
 The body initially buffers the change w/the bicarbonate buffering system, but
this system is quickly overwhelmed
 Compensatory mechanism = hyperventilation to lower the CO 2 levels. This
hyperventilation, in its extreme form, may be observed as Kussmaul breathing

Symptoms

 Osmotic diuresis = ↑ in urination rate. Glucose enters tubules and can’t be

reabsorbed → ↑ in osmotic pressure w/in the tubule → retention of eater w/in
the lumen, and thus ↓ reabsorption of water, ↑ urine output
 Osmotic diuresis results in dehydration from polyuria, and polydipsia
 Abdominal pain – nausea and vomiting
 Fruity breath
 Kussmaul breathing
  Hypotension, tachycardia
 Complication of cerebral oedema which may cause headache, coma, loss of
pupillary light reflex, and can progress to death

Treatment = fluids for dehydration, insulin for hyperglycaemia, and replacement of

electrolytes (K+)

Hyperosmolar hyperglycaemia state (HHS)

Definition = a complication of DM in which hyperglycaemia results in high osmolarity

w/out significant ketoacidosis. It is > common in DM 2

Pathogenesis

 It is usually provoked by an infection, MI, stroke, or another acute illness

 ↑ in plasma osmolarity due to extreme dehydration and ↑ conc. in the blood
 Glucose is polar = can’t pass through the cell membrane, ∴ it acts as a solute
 When glucose levels are really high in the blood (hyperosmolar state), water
leaves the cells and enters blood vessels, which leaves the cells dry and
shrivelled
 Blood vessels full of water = ↑ urination = total body dehydration
 Dehydration of body cells, particularly in the brain, causes mental status
change
 Ketosis is absent because the presence of some insulin inhibits hormone-
sensitive lipase mediated lipolysis

Chronic complications

Microangiopathy

Definition = disease of blood vessels affecting small blood vessels in the body.

Pathogenesis

 Thickening of the basement membrane in the vessel wall causing the wall to
become weaker
 As a result, they bleed, leak protein, and slow the flow of blood throughout the
body.

Complications

Microangiopathy can cause one or more of the following:

 Diabetic nephropathy = damage to the kidney which can lead to chronic renal
failure, eventually requiring dialysis.
 Diabetic neuropathy = abnormal and ↓ sensation, usually stating w/the feet
but potentially in other nn., later often fingers and hands. When combined
 w/damaged blood vessels this can lead to diabetic foot. Diabetic amyotrophy
is muscle weakness due to neuropathy
 Diabetic retinopathy = growth of growth of friable and poor-quality new blood
vessels in the retina as well as macular oedema, which can lead to severe
vision loss or blindness
 Diabetic encephalopathy = ↑ cognitive decline and risk of dementia
 Diabetic cardiomyopathy = damage to the heart muscle, leading to impaired
relaxation and filling of the heart (diastolic dysfunction) and eventually HF.
 Erectile dysfunction

Macrovascular diseases

Definition = it is a disease of any large blood vessel in the body. Fat and blood clots
build up in the large blood vessels and stick to the vessel walls (atherosclerosis)

 Coronary a. disease = leading to angina or MI

 Stroke (mainly the ischemic type)
 Diabetic myonecrosis (muscle wasting)
 Peripheral vascular disease = contributes to intermittent claudication
(exertion-related leg and foot pain) as well as diabetic foot
 Diabetic foot = often due to a combo of sensory neuropathy (numbness or
insensitivity) and vascular damage, increases rates of skin ulcers (diabetic
foot ulcers) and infection and, in serious cases, necrosis and gangrene
 F infertility = > common w/DM 1

121 – Body weight control by the hypothalamus. Obesity

Body weight control by the hypothalamus

 Hunger = a want to seek food

 Appetite = desire for a particular type of food
 Satiety = feeling of fullness or ↓ desire for food
 The arcuate nucleus of the hypothalamus has been identified as the center for
hunger and satiety
 Short-term regulation of hunger and food intake includes:
  Neural signals from GI tract = stretch receptors inhibit appetite upon
distension of the GI tract by sending signals along the vagus n. afferent
pathway and inhibiting the hunger center
 Nutrient signals = nutrient signals that indicate fullness, and ∴ inhibit
hunger include rising blood glucose levels, ↑ blood levels of AA, and
blood conc. of FA
 Hormone signals = insulin and cholecystokinin (CCK) are released
from the GI tract during food absorption and act to suppress feeling of
hunger

Short-term messengers that promote orexigenic effects (↑ feeding/stimulates

appetite):

 Ghrelin = released mainly from the stomach (especially during fasting),

stimulates appetite
 Neuropeptide Y (NPY)
 Agouti-related protein (AGRP)

Short-term messengers that promote anorexigenic effects (↓ feeding/suppresses

appetite):

 CCK = released in response to fat in duodenum, suppresses appetite

 Glucagon-like peptide-1 (GLP-1) = released from SI in response to carbs,
mainly has a strong suppressant effect on the hypothalamic feeding centre
 Leptin = suppresses release of NPY, which in turn prevents release of
appetite enhancing orexins from the lat. hypothalamus. This decreases
appetite and food intake, promoting weight loss

Obesity

Definition = excess body fat accumulation w/multiple organ-specific pathologic

consequences. Clinically, it is defined as BMI ≥ 30 [BMI = weight (kg)/height 2 (m)]

Classification

2 types of obesity based on distribution of fat have been described:

 Upper body obesity – AKA central, abdominal, visceral, or M (android) obesity

 Individuals are often referred to as being “apple” shaped
 Absolute waist circumference = >40 in (M) or >35 in (F)
 Waist-hip ratio = >0.9 (M) or >0.85 (F)
 Lower body obesity – AKA peripheral, gluteal-femoral, or F (gynoid) obesity
 Individuals are often referred to as being “pear” shaped

Causes
  Combo of excessive food intake and a lack of physical activity is thought to
explain most cases of obesity
 A limited n.o of cases are due mainly to genetics, medical reasons, or
psychiatric illnesses
 Environmental factors causing obesity = ↑ consumption of sugary, fatty foods;
↑ portion sizes; lack of exercise (sedentary lifestyle); insufficient sleep;
ethnicity (Asian population); geriatric pregnancy; genetics (family history)

Pathophysiology

 Leptin is a hormone produced by adipose tissue that acts on leptin receptors

on peripheral tissue and brain (hypothalamus)
 Leptin levels rise after food intake, stimulating sensation of satiety, and fall
during fasting, stimulating the sensation of appetite
 A deficiency in leptin signalling, either via leptin deficiency or leptin resistance,
leads to overfeeding and may account for some genetic and acquired forms of
obesity

Morbidity

Obesity ↑ the risk of many physical and mental conditions. These comorbidities are
most commonly shown in metabolic syndrome, a combo of medical disorders which
includes DM 2, HT, hypercholesterolemia, and hypertriglyceridemia.

Medical field Conditions Medical field Conditions

Cardiology CAD (angina and MI);
CHF; HT; dyslipidemia;
DVT and PE
Endocrinolog DM; PCOS; menstrual
y disorders; infertility;
complications during
pregnancy; birth defects
Neurology Stroke; migraines; carpal
tunnel syndrome;
dementia; MS
Psychiatry Depression in F; social
stigmatisation
Rheumatology Gout; poor mobility;
and osteoarthritis; low back
orthopaedics pain
Dermatology Stretch marks; acanthosis
nigricans; lymphedema;
hirsutism
Gastroenterology GERD; fatty liver disease;
gallstones
Oncology Oesophageal; colorectal;
pancreatic; gallbladder;
endometrial; kidney;
leukaemia; hepatocellular
carcinoma
Respirology COPD; asthma; sleep apnoea
Urology and Erectile dysfunction; urinary
nephrology incontinence; chronic renal
failure; hypogonadism
 122 – Pituitary adenoma

Definition = benign tumour arising from the ant. pituitary. It is the most common
cause of hyperpituitarism

Review of pituitary hormones

Hormone Target organ Effect

Adrenocorticotropic Adrenal cortex Stimulates production of glucocorticoids and
hormone (ACTH) androgens
Thyroid stimulating Thyroid Stimulates production of thyroid hormones by
hormone (TSH) thyroid follicular cells
Follicle stimulating Testes/ovaries Stimulates development of ovarian follicles/regulate
hormone (FSH) spermatogenesis in testes
Leutinising hormone Testes/ovaries Ovulation, formation of corpus luteum in ovary;
(LH) stimulates oestrogen and progesterone production
Prolactin Mammary glands Milk secretion and production
Growth hormone Stimulates body growth; secretes ILGF-1; lipolysis;
inhibit insulin action on carb and lipid metabolism

Classification

Unlike tumours of the posterior Pituitary, Pituitary adenomas are classified as

endocrine tumours (not brain tumours). Pituitary adenomas are classified based
upon anatomical, histological and functional criteria

Anatomical = anatomically pituitary tumours are classified by their size based on

radiological findings; either microadenomas (<10 mm) or macroadenomas (≥10 mm)

Histological = historically they were classed as either basophilic, acidophilic, or

chromophobic on the basis of whether or not they took up H&E stain. This
classification has fallen into disuse, in favour of a classification based on what type
of hormone is secreted by the tumour

Functional = is based upon the tumours endocrine activity as determined by serum

hormone levels and pituitary tissue cellular hormone secretion detected via
immunohistochemical staining. Adenomas can be non-functional tumours or
functional tumours that secrete pituitary hormones (cause signs and symptoms)

Type of adenoma Secretion Description % of hormone

production cases
Lactotrophic Prolactin  They are usually benign 30%
adenomas tumours composed of prolactin-
(prolactinomas) secreting cells →
hyperprolactinemia
 This inhibits secretion of LH,
 which in turn ↓ oestrogen levels
→ amenorrhoea, galactorrhoea,
hypogonadism, infertility, and
impotence
 In M the symptoms are > vague
and can include ED,
gynecomastia, and loss of libido
Somatotrophic Growth Acromegaly in adults; gigantism in 15%
adenomas hormone children
Corticotrophic ACTH Cushing’s disease
adenomas
Gonadotropic LH and FSH Usually asymptomatic 10%
adenomas
Thyrotrophic TSH Occasionally hyperthyroidism, usually <1%
adenomas (rare) asymptomatic
Null cell Don’t 25% of pituitary
carcinomas secrete adenomas are non-
hormones secretive

Causes = multiple endocrine neoplasia 1 (MEN1), Carney complex, familial isolated

pituitary adenoma

Signs and symptoms

 Hormone secreting pituitary adenomas cause one of several forms of

hyperpituitarism. Some tumours secrete >1 hormone, the most common
combo being GH and prolactin → acromegaly and unexpected lactation
 May present w/visual field defects (bitemporal hemianopsia) due to
compression of the optic n. (at the optic chiasm) by the tumour.
 Pituitary adenomas can cause symptoms of ↑ intracranial pressure =
headache, vomiting w/out nausea, ocular palsies, altered level of
consciousness, back pain, papilledema
 In some cases they can extend beyond the sella turcica into the base of the
brain → seizures
 Sometimes, acute haemorrhage into the adenoma can occur causing
enlargement of the pituitary → pituitary apoplexy

123 – Hypopituitarism

Definition = ↓ secretion of pituitary hormones

 Selective hypopituitarism = ↓ secretion of 1 specific pituitary hormone

 Panhypopituitarism = ↓ secretion of most/all pituitary hormones
  Typically, 70-90% of the ant. pituitary must be destroyed before
hypopituitarism becomes clinically evident.
 The clinical manifestations usually occur gradually but it can present as an
acute and life-threatening condition.

Etiology

 Tumours and mass lesions – pituitary adenomas, cysts, metastatic cancer

 Pituitary surgery or radiation – radiation mainly affects GH, FSH, and LH
 Infiltrative lesions and infections – hemochromatosis, lymphocytic
hypophysitis (immune system attacks pituitary)
 Empty sella syndrome – an enlarged sella turcica that is not entirely filled
w/pituitary tissue
 Hypothalamic disorders – tumours and mass lesions, hypothalamic radiation,
infiltrative lesions (sarcoidosis), trauma, infections
 Genetic diseases – rare congenital defects of 1/> pituitary hormones
 Pituitary infarction – infarction after substantial blood loss during childbirth
(Sheehan syndrome)
 Pituitary apoplexy – sudden haemorrhage into the pituitary gland

Symptoms

Ant. pituitary hormone loss tends to follow a typical sequence. The sequence of loss
of pituitary hormones can be remembered by the mnemonic “Go Look For The
Adenoma”:

 GH = GH secretion is typically 1st to be lost. GH deficiency leads to ↓ in

muscle mass, central obesity, and impaired attention and memory. Children
experience growth retardation and short stature
 LH = results in sex hormone deficiencies. Oligo- or amenorrhoea; M lose
facial hair, scrotal and trunk hair, as ↓ muscle mass and anaemia; both – ↓
libido and loss of sexual function, ↑ risk of osteoporosis
 FSH = causes infertility
 TSH = leads to secondary hypothyroidism. Symptoms include fatigue,
intolerance to cold, constipation, weight gain, hair loss, bradycardia and
hypotension.
 ACTH = usually the last to become deficient, results in secondary adrenal
insufficiency. Symptoms include fatigue, weight loss, failure to thrive, delayed
puberty, hypoglycaemia, anaemia, and hyponatremia.

Diagnosis and treatment

 Diagnosis = blood tests. 2 types are used to confirm the presence of a

hormone deficiency:
  Basal levels, where blood samples are taken, usually in the morning,
w/out any form of stimulation
 Dynamic tests, where blood tests are taken after injection of a
stimulating substance
 Measurement of ACTH and GH usually requires dynamic testing,
whereas the other hormones (LH/FSH, prolactin, TSH) can typically be
tested w/basal levels
 Treatment is threefold = removing the underlying cause, treating the hormone
deficiencies, and addressing any other repercussions that arise from the
hormone deficiencies

124 – Diabetes insipidus

Diabetes insipidus (DI) = it is condition characterised by polyuria and polydipsia. It

is caused by a deficiency of or a ↓ response to ADH. People w/DI are unable to
concentrate their urine during periods of water restriction, and they excrete large
volumes of urine, usually 3-20 L/day, depending on the degree of ADH deficiency or
renal insensitivity to ADH. This large urine output is accompanied by excessive thirst

ADH

 ADH is made in the hypothalamus and stored in the pituitary. It helps regulate
the amount of fluid in the body i.e. controls water retention
 > ADH in the blood = retain fluid. < ADH in the blood = excrete fluid
 During dehydration, pituitary will release ADH
 ADH usually acts by ↑ water permeability in the collecting ducts and DCT.
 It binds to receptors on the DCT which stimulate translocation of aquaporins
into the apical membrane.
 These channels allow water into the collecting duct cells.
 The ↑ in permeability allows for reabsorption of water into the bloodstream,
thus concentrating urine (↓ urine volume and ↑ urine conc.)

Etiology and pathogenesis

Central = due to a lack of ADH. Cause may be idiopathic, malignant/benign tumours

of the brain/pituitary, cranial surgery, or head trauma

Nephrogenic = ↓ response to ADH. It results from a lack of aquaporins channels in

the dist. collecting duct (↓ surface expression and transcription). It is seen in lithium
toxicity, hypercalcaemia, hypokalaemia, or release of ureteral obstruction.
Dipsogenic = results from the excessive intake of fluids as opposed to deficiency of
ADH. It may be due to a defect or damage to the thirst centre, located in the
hypothalamus, or due to mental illness.

Gestational = occurs only during pregnancy and the postpartum period. During
pregnancy, women produce vasopressinase in the placenta, which breaks down
ADH. It is thought to occur w/excessive production and/or impaired clearance of
vasopressinase.

Treatment

 Central and gestational = Desmopressin

 Nephrogenic = thiazide diuretic can be used to create mild hypovolemia which
encourages water and salt uptake in PCT and thus improves nephrogenic DI.

125 – Syndrome of inappropriate vasopressin secretion

Syndrome of inappropriate ADH secretion (SIADH) = is characterised by

excessive unsuppressible release of ADH either from the post. pituitary, or an
abnormal non-pituitary source. Unsuppressed ADH causes an ↑ in solute-free water
being returned by the tubules of the kidney to the venous circulation.

Classification

 Type A = erratic and unregulated release of ADH. No relation to plasma

osmolality
 Type B = constant release of a moderate amount of ADH
 Type C = unique because plasma Na+ conc. is stable (the baseline plasma
Na+ conc. is set lower than normal)
 Type D = rare, normal ADH secretion but urine osmolality is still high

Etiology

 CNS diseases that directly stimulate the hypothalamus

 Infections = meningitis, encephalitis, brain abscesses, AIDS
 Perinatal asphyxia
  Mass/bleed = trauma, subarachnoid haemorrhage, subdural
haematoma
 Hydrocephalus
 Multiple sclerosis (MS)
 Various cancers that synthesise and secrete ectopic ADH
 Carcinomas = lung cancers, GI cancers, genitourinary cancers
 Lymphoma
 Sarcomas (Ewing’s sarcoma)
 Various lung diseases
 Infection = pneumonia, lung abscesses
 Asthma
 Cystic fibrosis (CF)
 Numerous drugs that chemically stimulate the hypothalamus – e.g.
SSRIs, MDMA, morphine, carbamazepine, cyclophosphamide, valproic acid
 Inherited mutations
 Miscellaneous largely transient conditions – e.g. endurance exercise,
general anaesthesia

Pathophysiology

 Excessive ADH causes an inappropriate ↑ in the reabsorption in the kidneys

of solute-free water ("free water") – excess water moves from the DCT and
collecting ducts (CD) back into the circulation.
 This has two consequences. First, in the ECF space, there is a dilution of
blood solutes, causing hypoosmolality, including hyponatremia.
 Also the ICF volume expands. This is because the osmolality of the ECF is
(transiently) < than that of the ICF; and since water is readily permeable to cell
membranes, solute-free water moves from the ECF to the ICF compartment
by osmosis

Symptoms

 GI = anorexia and nausea

 Musculoskeletal = muscle aches, generalised muscle weakness
 Neuro-muscular = ↓ reflexes, ataxia, tremor
 Respiratory = Cheyne-Stroked respiration
 Neurological = lethargy, confusion, delirium; cerebral oedema can result in
seizures, coma, and death

Diagnosis and treatment

 Diagnosis = based on clinical and lab findings of low serum osmolality and low
serum Na+ (hyponatremia)
 Treatment = treating the underlying cause
  Management includes restriction of daily intake of fluids, starting a high salt
and high protein diet
 In chronic SIADH = drugs to inhibit ADH

126 – Hyperthyroidism

Definition = ↑ synthesis and secretion of thyroid hormones causing ↑ metabolism

affecting all systems.

Thyroid hormones are necessary for normal growth and development, and they
regulate cellular metabolism; excess causes an ↑ in the metabolic rate that is
associated w/↑ total body heat production and cardiovascular activity (↑ heart
contractility, heart rate, VD)

Classification

 Diffuse toxic goiter (Graves’ disease), toxic multinodular goiter (Plummer’s

disease), toxic adenoma, and subacute thyroiditis are the most common
causes – 90%
 Secondary hyperthyroidism (very rare) = caused by pituitary tumours
producing TSH or TTH or due to pituitary resistance to thyroid hormones

Graves’ disease

 It is an autoimmune disease that affects the thyroid

 Exact cause is unclear – combo of genetic and environmental factor
 It is an immune-mediated disorder that results from the production of thyroid-
stimulating immunoglobulins (TSI) by stimulated B lymphocytes.
 These immunoglobulins bind to the thyroid-stimulating hormone (TSH)
receptor to mimic the action of TSH and stimulate thyroid growth and thyroid
hormone overproduction (phenomenon = antigenic mimicry)
 Thyroxine (T4) receptors in the pituitary gland are activated by the surplus
hormone, suppressing additional release of TSH in a -ve feedback loop. The
result is very high levels of circulating thyroid hormones and a low TSH level
 Predisposition factors = family predisposition, F sex, endemic region (> iodine
in water)
 Provoking factors = stress, infection (EBV is a
potential trigger), meds (e.g. amiodarone), toxic
environment
Symptoms

 Rapid weight loss despite ↑ appetite

 Excessive sweating, intolerance to heat
 Hand tremor, hyperactivity, anxiety, irritability, restlessness, emotional
instability, insomnia
 Hair loss, itching
 Tachycardia w/premature beats or absolute arrhythmia, systolic arterial HT
 Frequent defecation w/soft stool, diarrhoea
 Menstrual disturbances, sexual impotence in M
 Exophthalmos (bulging of the eye) = occurs specifically and uniquely in
hyperthyroidism caused by Graves’ disease
 If thyroid gland becomes very large, it may cause pressure symptoms and
signs, including dysphagia (difficulty swallowing), tightness in neck, and
hoarseness
 Thyroid storm is a severe form of thyrotoxicosis characterized by rapid and
often arrhythmias, high temp, vomiting, diarrhoea, and mental agitation
 Hyperthyroidism due to certain types of thyroiditis can eventually lead to
hypothyroidism, as the thyroid gland is damaged

Diagnosis and treatment

 Specific for the disease = ↓ cholesterol and triglycerides, slightly ↑ glucose;

often slightly/moderately ↑ liver enz., total protein and albumin may be slightly
↓
 Crucial for diagnosis = hormonal tests - ↑ FT3 (free triiodothyronine) and FT4
(free thyroxin), and ↓ TSH and TTH (thyrotropin hormone); TSIs (auto-ABs –
specific for Grave’s disease) are ↑
 Treatment = thyrostatics (anti-thyroid drugs) inhibit the production of thyroid
hormones, such as carbimazole and methimazole.
 Use of β-blockers to offset the effects of palpitations, trembling, and anxiety
(all these symptoms are mediated by ↑ in β-adrenergic receptors on cell
surfaces)
 Eating a diet low in iodine

127 – Hypothyroidism
Definition

↓ synthesis and secretion of thyroid hormones which causes cretinism in children

(mentally retarded dwarfs) and in adults ↓ metabolism, accelerated atherosclerosis
and myxedematous infiltration (accumulation of GAGs in the tissues)

Classification

 Primary = caused by diseases directly affecting the thyroid gland, most

common cause is Hashimoto disease
 Secondary = lack of thyroid hormone secretion due to inadequate stimulation
by TSH from the pituitary gland
 Tertiary = inadequate release of TRH (thyrotropin releasing hormone) from
the hypothalamus
 Other common causes are panhypopituitarism (Simonds-Sheehan syndrome)
or pituitary adenoma

Etiology and pathogenesis of primary hypothyroidism

 Autoimmune – the most common cause is by the autoimmune disease

Hashimoto thyroiditis; a chronic immune reaction w/production of ABs against
the thyroid Ag’s, resulting in lymphocytic infiltration of the gland and
progressive destruction of functional thyroid tissue (TSH receptor–blocking
ABs in Hashimoto disease – chronic lymphocytic thyroiditis); postpartum
thyroiditis and subacute granulomatous thyroiditis are relatively rare cases
 ↓ intake of iodine which is essential for the synthesis of the thyroid hormones
(causing goiter and ↓ hormonal secretion)
 Infections; partial or total resection of the gland (due to cancer or toxic
adenoma); complication of radioiodine therapy; drugs such as amiodarone,
interferon alpha, thalidomide, lithium etc; postpartum thyroiditis; idiopathic
 Predisposition factors = family predisposition, F sex, endemic region w/lack of
iodide
 Provoking factors = stress, infections, toxic environment

Symptoms

 General = fatigue, somnolence, feeling cold,

weight gain despite ↓ appetite, hypoglycaemia
 Psychological = poor memory and conc.,
bradylalia and bradypsychia (slowed talking and
thinking), confusion
 Poor hearing, hair loss, hoarseness
 Heart = slow pulse rate, pericardial effusion, chest
pain
 Lungs = SOB, pleural effusion
  Skin = paresthesia; pale, dry, skin; myxedema
 GI = ascites, constipation, often hypoacidity due to atrophic gastritis
 Reproductive = amenorrhea, ↓ libido
 More specific to Hashimoto’s disease = feeling of fullness in the throat or
painless thyroid enlargement; sometimes neck pain, sore throat, or both

Diagnosis and treatment

 Specific for the disease = ↑ cholesterol and ↓ blood glucose

 Crucial for the diagnosis = ↑ TSH and TRH w/↓ FT3 and FT4 – reverse
feedback; however in patients w/secondary hypothyroidism all hormones are
↓; antimicrosomal or antithyroid peroxidase (anti-TPO) ABs are found >
commonly than anti-thyroglobulin (anti-Tg) ABs in patients w/Hashimoto’s
disease
 Treatment = hormone replacement therapy w/synthetic preparations of T 3 and
T4 - levothyroxine

128 – Goiter

Definition = swelling in the neck resulting from an enlarged thyroid gland. It can be
associated w/a thyroid that is not functioning properly

Classification

A goitre may be classified either as nodular or diffuse

Growth pattern:

 Uninodular goitre = one thyroid nodule; can be either inactive, or active (toxic)
– autonomously producing thyroid hormones
 Multinodular goitre = multiple nodules can likewise be inactive or toxic, the
latter is called toxic multinodular goitre and associated w/hyperthyroidism
 Diffuse goitre = the whole thyroid appearing to be enlarged due to hyperplasia

Size:

 Class I = the goitre in normal posture of the head cannot be seen; it is only
found by palpation
 Class II = the goitre is palpable and can be easily seen.
 Class III = the goitre is very large and is retrosternal (partially or totally lying
below the sternum), pressure results in compression marks.
Etiology

Worldwide, the most common cause for goitre is iodine deficiency, usually seen in
countries that do not use iodized salt. Selenium deficiency is also considered a
contributing factor. In countries that use iodized salt, Hashimoto's thyroiditis is the
most common cause. Goitre can also result from cyanide poisoning; this is
particularly common in tropical countries where people eat the cyanide-rich cassava
root as the staple food

Symptoms

A goiter can present as a palpable or visible enlargement of the thyroid gland at the
base of the neck. A goiter, if associated w/hypo-/hyperthyroidism, may be present
w/symptoms of the underlying disorder.

When enlarged enough, goiters can compress the oesophagus and trachea →
difficulty swallowing, choking. Also compression of the SVC can occur, causing
distension of vv. of the neck and upper extremities, oedema of the eyelids and
conjunctiva, and syncope when coughing

129 – Excessive secretion of adrenal glucocorticoid hormones. Cushing’s

syndrome

Review of adrenal glands

 The adrenal glands are paired, pyramid shaped structures in the

retroperitoneal space.
 Outer cortex = glucocorticoids (mainly cortisol), mineralcorticoids (mainly
aldosterone), and androgens (sex hormones)
 Inner medulla = adrenaline and noradrenaline
 Hypothalamic-pituitary-adrenal (HPA) feedback system regulates cortisol
levels
 Corticotropin releasing hormone (CRH) controls the release of ACTH from the
ant. pituitary. ↑ cortisol levels elicit a –ve feedback inhibition of ACTH release

Cushing’s syndrome

Definition = ↑ synthesis and secretion of cortisol due to hyperplasia or tumours

(adenoma/carcinoma) of the suprarenal (adrenal) glands

Etiology

 Primary hypercorticism (Cushing’s syndrome) = hyperplasia/tumours of the

cortex of the adrenal glands
  Secondary hypercorticism (Cushing’s disease) usually adenoma of the frontal
part of the pituitary gland w/↑ production of ACTH → hyperplasia of the cortex
of both adrenal glands w/↑ cortisol secretion. Other causes for secondary
hypercorticism are:
 Iatrogenic Cushing’s syndrome = prolonged treatment w/corticosteroids
(glucocorticoids) (bronchial asthma, CT disorders, other autoimmune
diseases)
 Ectopic ACTH syndrome caused by non-pituitary ACTH-secreting
tumour (oat cell carcinoma, small-cell lung carcinoma, or carcinoid
tumour)

Symptoms

 Generalised = weight gain (often w/oedema), slow healing of cuts, ↑ risk of

infections, fatigue, glucose intolerance
 Muscular = prox. muscle weakness
 Skin = thinning, fragility, acne prone, hirsutism, striae
 Vascular = arterial HT (new or worsened)
 Bones = ↑ risk of fractures, bone pain due to osteoporosis
 Psychological = depression, anxiety, irritability, loss of emotional control,
cognitive difficulties, ↓ libido
 Reproductive = menstrual irregularities, amenorrhea (F); erectile dysfunction
(M)
 Headaches, moon face, buffalo hump, drowsiness, double vision (diplopia),
restricted vision perimeters
 Often chest pain, rhythm disorders, SOB especially in patients w/severe
arterial HT, susceptibility to infections is common
 Hyperacidity and epigastrial pain due to gastritis or ulcers

Diagnosis and treatment

 Diagnosis = dexamethasone suppression test, saliva cortisol level

 Treatment = stopping meds that cause the symptoms; removal of tumours

130 – Adrenocortical insufficiency. Addison’s disease

There are 3 types of adrenal insufficiency:

 Primary adrenal insufficiency (AKA Addison’s disease) = due to destruction of

the adrenal gland
 Secondary adrenal insufficiency = caused by impairment of the pituitary gland
or hypothalamus
  Tertiary adrenal insufficiency = due to hypothalamic disease and a ↓ release
of CRH

Primary adrenal insufficiency (Addison’s disease)

Definition = ↓ synthesis and secretion of corticosteroids and mineralcorticoids

(aldosterone) from the adrenal glands

Etiology

 Autoimmune destruction of the adrenal cortex. Adrenal destruction can also

be due to metastasis, haemorrhage, particular infections (TB), or the
deposition of abnormal proteins in amyloidosis
 Adrenal dysgenesis = the gland has not formed adequately during
development
 Impaired steroidogenesis = the gland is present but is biochemically unable to
produce cortisol. Congenital adrenal hyperplasia is the most common
synthesis problem.

Symptoms

 Not apparent until 90% of the gland has been destroyed

 Excessive weakness, easy tiredness, vertigo, drowsiness
 Low bp (systolic <110 mmHg) w/orthostatic hypotension (sudden drop of bp
when the patient is standing upright)
 Nausea, abdominal pain, sometimes vomiting and diarrhoea
 Loss of appetite and weight loss
 Menstrual disturbances
 In some cases depression, irritability, and ↓ concentration
 Hyperpigmentation

Diagnosis

 Specific for the disease = ↑ K+, ↓ Na+, ↓ blood glucose, usually slight anaemia
is present
 Crucial for diagnosis = ↓ levels of cortisol and aldosterone w/↑ ACTH in
primary hypocorticism but ↓ if the pituitary gland is damaged

Addisonian crisis

It is a constellation of symptoms that indicates severe adrenal insufficiency. This may

be the result of either previously undiagnosed Addison's disease, a disease process
suddenly affecting adrenal function (such as adrenal hemorrhage), or an intercurrent
problem (e.g., infection, trauma) in someone known to have Addison's disease. It is a
medical emergency and potentially life-threatening situation requiring immediate
emergency treatment. Symptoms include:
  Sudden penetrating pain in the legs, lower back, or abdomen
 Severe vomiting and diarrhoea → dehydration
 Hypotension
 Hypoglycaemia, hyponatremia, hyperkalaemia, hypercalcaemia
 Syncope (loss of consciousness and ability to stand)
 Confusion, psychosis, slurred speech, severe lethargy, convulsions

Secondary adrenal insufficiency

It is caused by impairment of the pituitary gland or hypothalamus. Its principal

causes include pituitary adenoma (which can suppress production of ACTH and lead
to adrenal deficiency unless the endogenous hormones are replaced); and
Sheehan's syndrome, which is associated w/impairment of only the pituitary gland.

131 – Hyperaldosteronism. Conn’s syndrome

Definition = it is a medical condition wherein too much aldosterone is produced by

the adrenal glands, which can lead to hypokalaemia and ↑ H + excretion (alkalosis)

Aldosterone is essential for Na+ conservation in the kidney, salivary glands, sweat
glands, and colon. It promotes Na+ retention by acting on mineralcorticoid receptors
in principal cells of the DCT and the CT. Simultaneously, it stimulates secretion of K +
into the lumen, ↑ its excretion

Etiology

Primary hyperaldosteronism = adrenal hyperplasia and adrenal adenoma (Conn's

syndrome). These cause hyperplasia of aldosterone-producing cells of the adrenal
cortex resulting in primary hyperaldosteronism. Also have familial
hyperaldosteronism

Secondary hyperaldosteronism = excess aldosterone production in response to high

levels of renin (overactivity of RAAS) – during chronic low bp e.g. congestive HF,
cirrhosis, L ventricular failure

Symptoms

Can be asymptomatic, but they symptoms may be present:

  Fatigue, headache
 HT, hypokalaemia, hypernatraemia, hypomagnesemia
 Metabolic alkalosis
 Intermittent/temporary paralysis
 Muscle spasms, muscle weakness, numbness
 Polyuria, polydipsia

Treatment

 K+ sparing diuretic (spironolactone) = acts as an aldosterone antagonist

 Treat underlying cause – e.g. Conn’s syndrome → remove the tumour

132 – Disorders of adrenal and androgen production

Hyperandrogenism

Definition = high levels of androgens in F

Etiology

 Polycystic ovary syndrome (PCOS) = endocrine disorder characterised by an

excess of androgens produced by the ovaries.
 Cushing’s syndrome = develops due to long-term exposure to cortisol
 Congenital adrenal hyperplasia (CAH) = consists of a group of AR disorders
that cause a lack of an enz. needed for producing cortisol and/or aldosterone.
Defect in synthesis of cortisol → ↑ levels of ACTH → overstimulates the
pathways for production of adrenal androgens
 Tumours = adrenocortical carcinomas, adenoma of the adrenal gland,
arrhenoblastoma (tumour of ovary)
 Drug-induced = can happen according to 1 of 5 major mechanisms:
 Direct introduction of androgens into the body
 Binding of the drug to androgen receptors and subsequent participation
in androgenic action
 Reduction of sex hormone-binding globulin plasma conc. that leads to
a resulting ↑ in free testosterone
 Interference w/ and alteration of the hypothalamic-pituitary-ovarian axis
  ↑ in release of adrenal androgens
 Menopause = during menopause the body slows down the release of
oestrogen at a faster rate than androgens, but in some cases the oestrogen
levels drop enough that there is substantially higher androgen levels leading
to hyperandrogenism
 Heredity

Symptoms

 Hirsutism (M-pattern hair growth), alopecia (balding)

 Oligomenorrhea (menstrual irregularities), infertility
 Acne, oily skin
 Obesity, DM 2
 Deepening of voice
 Libido - ↑ sex drive

Hypoandrogenism

Definition = ↓ levels of androgens in the body

Etiology

 Caused mainly by dysfunction, failure, or absence of the gonads

(hypergonadotropic); or impairment of the hypothalamus or pituitary gland
(hypogonadotropic)
 Can also be caused by androgen insensitivity syndrome of hyperestrogenism

Symptoms

 M = loss of libido, impotence, infertility, shrinkage of testicles, penis and

prostate, diminished masculinisation (↓ facial and body hair growth), low
muscle mass, anxiety, depression, fatigue, vasomotor symptoms (hot
flashes), insomnia, headaches, and osteoporosis. Also may have symptoms
of hyperestrogenism, such as gynecomastia and feminisation
 F = loss of libido, ↓ body hair growth, depression, fatigue, vaginal
vasocongestion (can result in cramps), vasomotor symptoms (hot flashes and
palpitations), insomnia, headaches, osteoporosis, ↓ muscles mass.

133 – Disorders of the female reproductive tract. Menstrual disorders. Infertility

Review of F reproductive tract and menstrual cycle

 Oestrogen = stimulates growth in ovaries, fallopian tubes, uterus, and vagina;

thickens the endometrium; growth of breasts and milk-producing apparatus;
skeletal growth by stimulation of osteoblasts
 Progesterone = produced after ovulation and in the placenta during
pregnancy, prepares the uterus for implantation of zygote, ↓ excitability of
uterine smooth muscles
 External genitalia = labia majora, labia minora, clitoris
 Internal genitalia = vagina, cervix, uterus, fallopian tubes, ovaries

Proliferative phase of menstrual cycle

 Low estrogen and progesterone stimulates GnRH to stimulate FSH and LH

release
 FSH stimulates production of primary ovarian follicles
 Primary follicles secrete estrogen in response to FSH & LH.
 Estrogen thickens the endometrium
 Negative feedback = oestrogen inhibits GnRH→ inhibits LH and FSH →no
more development of
 follicles
 Ovulation (day 14) = 2 days before ovulation surge of LH secretion and thecal
cells secrete progesterone. Follicle ruptures, oocyte is released and remaining
follicle is called the corpus luteum (CL)

Secretory phase

 After ovulation, CL secretes progesterone (lots) and estrogen (not so much)

 Progesterone prepares the endometrium for implantation

Menstruation

 Degeneration of CL stops secretion of oestrogen and progesterone

 Endometrium involutes
 Ischemia & necrosis
 ↓progesterone levels = uterine contraction, expel blood and tissue

Disorders of the F reproductive tract

Disorders of external genitalia

 Bartholin cysts are a result of occluded ducts in Bartholin glands. It can

become large (up to 5cm) and produce pain and discomfort. Infection of the
cyst can cause acute inflammation within the gland and result in abscess
  Vulvodynia is a syndrome of unexplained vulvar pain and is characterized by
sensation of burning, stinging, irritation, soreness or rawness. It can be
localized or generalized

Disorders of the vagina

The normal vaginal ecology depends on a delicate balance of hormones and

bacterial flora. pH of the vagina is 3.8-4.5 (due to certain bacilli that metabolize
glycogen to produce lactic acid)

 Vaginitis = inflammation of the vagina and is characterized by vaginal

discharge, burning, itching, redness, and swelling of vaginal tissue. C.
albicans and T. vaginalis are the most common causes of bacterial vaginosis.
 Cancers of the vagina = extremely rare accounting for 1% of all cancers of
the F reproductive system. Like vulvar carcinoma it is largely a disease in
older women (60-70y). Mostly squamous cell carcinomas

Disorders of the cervix and uterus

 Cervicitis = acute or chronic inflammation of the cervix primarily due to

streptococcus, staphylococcus, enterococcus, C. albicans
 Cervical cancer = pathogenesis is linked to HPV infections and arises from
precursor lesions that can be detected by Pap smear, if detected early it is the
most easily cured cancers of the F reproductive system.
 Endometritis = can be acute or chronic. Chronic inflammation of the
endometrium is due to intrauterine devices, pelvic inflammatory disease, and
retained products of conception after delivery or abortion. Vaginal bleeding,
uterine tenderness, fever, malaise, foul smelling discharge.
 PID (pelvic inflammatory disease) = inflammation of the upper reproductive
tract that involves the uterus (endometritis), fallopian tubes (salpingitis), or
ovaries (oophoritis). Gonococcus, staphylococcus, streptococcus, Chlamydia,
trichomonas etc. Ascend though the cervical canal and enter the endometrial
cavity, then to the fallopian tubes and ovaries. The organisms multiply rapidly
in the favourable environment.
 Symptoms = lower abdominal pain and tenderness; back pain; purulent
cervical discharge; fever; elevated WBCs and CRP.
 Diagnosis = laparoscopy
 Treatment = I.V antibiotics
 Endometriosis = functional endometrial tissue is found in ectopic sites
outside the uterus e.g. ovaries, vagina, vulva or intestines. Cause = unknown.
Risk factors = early menstruation and late menopause, short menstrual cycle
(<28days), longer duration (>5 days) or heavier flow cycles, ↑ menstrual pain.
 Implantation theory= menstrual blood containing fragments of
endometrium is forced upward into fallopian tubes into the peritoneal
cavity
  Vascular/lymphatic theory= endometrial tissue may metastasize
through lymphatics or vascular system
 In the ovaries, endometrial tissue can form cysts = ‘chocolate cysts’ →
rupture → peritonitis
 Diagnose = laparoscopy
 Treatment = pain relief, endometrial suppression and surgery. NSAIDs,
use of oral contraceptives to induce physiologic amenorrhea.
 Endometrial cancer = most frequent cancer of the F reproductive tract,
typically in postmenopausal women – abnormal postmenopausal bleeding =
early detection and cure.
 Type I = estrogen excess- endometroid carcinoma; risk factor =
endometrial hyperplasia
 Type II = endometrial atrophy
 Diagnosis = D&C, endometrial biopsy

Disorders of the ovaries

 Polycystic ovary syndrome (PCOS) = a disorder characterized by hirsutism

& acne (hyperandrogenism), obesity, infertility, and is often associated
w/hyperinsulinemia and insulin resistance (amplified by obesity)
 Chronic anovulation causes amenorrhea or irregular menstruation
 Altered gonadotropin levels → ↑ LH release → ↑ androgen production
 Ovarian cancer = most deadly cancer of the F reproductive tract. Family
history of cancer, particularly breast and ovarian cancer ↑ the risk of
developing ovarian cancer (BRCA1 and BRCA2 tumour suppressor genes).
Oral contraceptive use, pregnancy and lactation ↓ the risk. Most ovarian
cancers are of epithelial origin

Menstrual disorders

Disorders of ovulation

 Oligoovulation = infrequent or irregular ovulation (cycles of ≥36 days or <8

cycles a year)
 Anovulation = absence of ovulation when it would be normally expected (post-
menarchal, premenopausal F). Usually manifests as irregularity of menstrual
periods.

Disorders of cycle length

 Polymenorrhea = frequent menstruation w/<21 days apart

 Irregular menstruation = where there is variation in menstrual cycle length of
more than approximately 8 days for a woman.
 Oligomenorrhea =infrequent, often light menstrual periods (intervals
exceeding 35 days).
  Amenorrhea = absence of a menstrual period in a F of reproductive age.
Physiologic states of amenorrhoea are seen during pregnancy and lactation.
Outside of the reproductive years there is absence of menses during
childhood and after menopause.

Disorders of flow

 Hypomenorrhea = abnormally light menstrual periods

 Menorrhagia = abnormally heavy and prolonged menstrual period
 Metrorrhagia = bleeding between periods
 Dysmenorrhea = painful menstruation
 Primary = excess production of prostaglandin released from the
endometrium whilst it shed, which stimulates smooth muscles and
causes intense uterine contractions
 Secondary = structural abnormalities – e.g. endometriosis, PID. Pain
often begins before menstruation and becomes worse during
 Menopause = cessation of menstrual cycle – usually occurs between 45 & 55
 1 full year w/out menstruation = menopause
 Cessation of ovarian function and diminished levels of estrogen:
decline in sexual characteristics, vasomotor instability (hot flashes,
palpitations, dizziness, and headaches).
 Long-term estrogen deprivation include osteoporosis and heart disease

All these disorders are most often due to lack of ovulation and disturbance pattern of
ovarian hormone secretion

 Estrogen and progesterone deficiencies are associated w/absence of

ovulation – anovulatory bleeding
 Dysfunctional bleeding can be primary (disorder of uterus or ovaries), or
secondary (hypothalamic-pituitary stimulation leads to defect in ovary
function).
 Non-hormonal causes of irregular menstruation = endometrial polyps, cancer,
bleeding disorders e.g. platelet dysfunction

Infertility

Definition = inability of a person to reproduce by natural means.

Causes = acquired (age, smoking, STDs, body weight, radiation and chemo,
immune infertility), genetic factors, PCOS, menopause, ovarian cancer, anovulation

134 – Disorders of the male reproductive tract. Male infertility. Benign prostatic
hyperplasia
Disorders of the M reproductive tract

Disorders of the penis

 Balanitis = acute or chronic inflammation of the glans penis

 Balanoposthitis = inflammation of the glans and prepuce (foreskin)
 Both can be due to trauma, irritation or infection by C. albicans and other
anaerobic bacteria
 Peyronie’s disease = growth of a fibrous band on top of the penile shaft.
Fibrous tissue prevents lengthening of the penis during erection → bent
erection, painful erection.
 Priapism = abnormal, painful, sustained erection (>4h) that can result in
ischemia and fibrosis of erectile tissue. It can occur at any age and one of the
complications can be sickle cell disease (secondary cause). Primary cause =
idiopathic. Due to impaired blood flow of the penis.

Disorders of the scrotum and testes

After descent of the testes, the inguinal canal closes almost completely – failure to
close → inguinal hernia (protrusion of parietal peritoneum and part of the intestine
through an abnormal opening from the abdominal cavity)

The testes and the epididymis are completely surrounded by tunica vaginalis
(serous pouch):

 Hydrocele = collection of fluid in the tunica vaginalis. Can be unilateral or

bilateral and can be as a primary congenital defect or secondary condition
 Hematocele = accumulation of blood in the tunica vaginalis causing the
scrotal skin to be dark red or purple
 Spermatocele = accumulation of sperm in the tunica vaginalis.
 Varicocele = enlargement of the vv. (pampiniform plexus) w/in the scrotum
 Testicular torsion = twisting of the spermatic cord resulting in compromise in
blood flow to the testis → obstruction of venous drainage → oedema,
haemorrhage, arterial obstruction. Can be intravaginal or extravaginal
(spermatic cord twists inside the tunica vaginalis)
 Epididymitis = inflammation of the epididymis (transport and stores sperm).
From STIs (Chlamydia, gonorrhoea) or urinary tract pathogens (E.coli,
pseudomonas)

Male infertility

Definition = refers to a M inability to cause pregnancy in a fertile F

Etiology

Immune fertility (10-30%)

Anti-sperm ABs (ASA) production are directed against surface Ag’s on sperm, which
can interfere w/sperm motility and transport through the F reproductive tract,
inhibiting capacitation and acrosome rxn, impaired fertilisation, influence on the
implantation process, and impaired growth and development of the embryo.

Risk factors = breakdown of blood-testis barrier, trauma, surgery, orchitis, varicocele,

infections, prostatitis, testicular cancer.

Genetics (10-15%)

Klinefelter syndrome (XXY) directly affects sexual development before birth and
during puberty. The reduction of testosterone in the M body normally results in an
overall ↓ in the production of viable sperm for these individuals thereby forcing them
to turn to fertility treatments to father children

Y chromosomal infertility = M can exhibit azoospermia (no sperm production),

oligospermia (small n.o of sperm production), or they will produce abnormally
shaped sperm.

Pre-testicular causes

Pre-testicular factors refer to conditions that impede adequate support of the testes
and include situations of poor hormonal support and poor general health including

 Varicocele
 Drug, alcohol
 Meds, including those that affect spermatogenesis such as chemo, anabolic
steroids, Cimetidine, spironolactone; those that ↓ FSH production such as
phenytoin; those that ↓ sperm motility such as nitrofurantoin
 Genetic abnormalities
 Tobacco smoking
 DNA damage

Post-testicular causes

Post-testicular factors ↓ M fertility due to conditions that affect the M genital system
after testicular sperm production and include defects of the genital tract as well as
problems in ejaculation:

 Vas deferens obstruction

 Lack of vas deferens, often related to genetic markers for CF
 Infection e.g. prostatitis
 Retrograde ejaculation (semen is redirected back to the urinary bladder)
 Ejaculatory duct obstruction
 Hypospadias (urethra doesn’t open from its usual location)
 Impotence
Benign prostatic hyperplasia (BPH)

Definition (AKA prostate enlargement) = non-cancerous ↑ in size of the prostate

gland

 It is characterised by the formation of large, discrete lesions in the periurethral

region of the prostate rather than the peripheral zones, which are commonly
affected by prostate cancer
 The exact cause is unknown. Risk factors = age, family history, race, ethnicity,
dietary fat and meat consumption, and hormonal factors
 The incidence of BPH ↑ w/↑ age and is highest in African Americans and
lowest in native Japanese.
 Both androgens (testosterone and dihydrotestosterone/DHT) and oestrogens
appear to contribute to the development of BPH.
 DHT, the biologically active metabolite of testosterone is thought to be the
ultimate mediatory of prostatic hyperplasia, oestrogen sensitises the prostate
to the growth-producing effects of DHT
 The nodules/lesions compress and distort the urethra → partial/complete
obstruction of urinary outflow → dysuria, acute retention of urine
w/overdistension of the bladder → ↑ frequency of urination and constant
desire to empty the bladder
 Obstruction of urinary outflow may also give rise to UTIs, destructive changes
of the bladder, hydroureter, and hydronephrosis → eventual renal failure
 Diagnosis = digital rectal examination shows an enlarged prostate.
 Treatment = 5-α reductase inhibitors – ↓ prostate size by blocking effect of
androgen on the prostate, causing atrophy of the prostate epithelial cells.
surgical removal of the enlarged prostate

135 – Motor disturbances: lower and upper motor neurons. Motor neuron
disease

Upper and lower motor neurons

Motor function consists of upper motor neurons (UMN) and lower motor neurons
(LMN). Upper motor neurons project from the motor cortex to the brain stem or
spinal cord, where they innervate with LMNs of the contracting muscles.

UMNs

 Project from the motor cortex down to the brainstem or spinal cord
 Glutamate transmits nerve impulses from upper to lower motor neurons
 UMNs synapse w/LMNs and are unable to leave the CNS
Disturbances:

 Loss of dexterity: stiffness, slowness and clumsiness in performing motor

actions
 Loss of muscle strength (weakness)
 Spasticity
 Pathological hyperflexia → Babinski sign; extension of the great toe in
response to stroking the outer edge of the sole upward from the heel

LMNs

 Receive impulses from UMNs and connect the spinal cord and brain stem to
muscle fibres (cranial and spinal nerves)
 Cell bodies of LMNs are located in the grey matter of spinal cord and brain
stem and their axons leave and synapse with muscles in the body
 Alpha motor neurons → large and innervate muscle fibres for contraction
and force generation
 Beta motor neurons → innervate extrafusal and intrafusal (muscle spindle)
fibres to control basic muscle tone
 Gamma motor neurons → innervate only spindle muscle fibres

Disturbances:

 Muscle weakness
 Muscle atrophy = due to muscle fibre denervation
 Muscle Flaccidity
 Fasciculations = spontaneous contraction of muscle fibres
 Muscle cramps

Motor neuron disease

Motor neuron diseases (MNDs) are a group of neurodegenerative disorders that

selectively affect motor neurons (controls voluntary muscles). They are characterised
by progressive muscle weakness and the degeneration of the motor neuron on
electrophysiological testing.

Classification

All types of MND can be differentiated by 2 defining characteristics:

1. Is the disease sporadic or inherited?

2. Is there involvement of the UMN, the LMN, or both?

Sporadic/acquired MNDs occur in patients w/no family history of degenerative motor

neuron disease. Inherited/genetic MNDs adhere to one of the following inheritance
patterns: AD, AR, or X-linked. Some disorders, like ALS, can occur sporadically
(85%) or can have a genetic cause (15%) w/the same clinical symptoms and
progression of disease

The following disorders are counted among motor neuron diseases:

 Amyotrophic lateral sclerosis (ALS) = causes death of neurons controlling

voluntary muscles. It is the most common type affecting muscles of arms,
legs, mouth, and respiratory system. affects LMN in spinal cord and UMN in
brain stem and cerebral cortex
 Progressive bulbar palsy (PBP) = involves the brain stem. Frequent choking,
difficulty speaking, eating, and swallowing
 Pseudobulbar palsy = characterised by the inability to control facial
movements
 Progressive muscular atrophy (PMA) = slow and progressive muscle wasting
especially in arms, legs, and mouth. It affects only the LMN
 Primary lat. sclerosis (PLS) = affects only the UMN. It is characterised by
progressive muscle weakness in the voluntary muscles

Symptoms

 Symptoms come on slowly, and worsen over the course of >3 months.
Various patterns of muscle weakness are seen, and muscle cramps and
spasms may occur.
 One can have difficulty breathing w/climbing stairs (exertion), difficulty
breathing when lying down (orthopnea), or even respiratory failure if breathing
muscles become involved.
 Bulbar symptoms = difficulty speaking (dysarthria), difficulty swallowing
(dysphagia), and excessive saliva production (sialorrhea)
 Sensation, or the ability to feel, is typically not affected.
 Emotional disturbance (e.g. pseudobulbar affect) and cognitive and
behavioural changes (e.g. problems in word fluency, decision-making, and
memory) are also seen.
 There can be LMN findings (e.g. muscle wasting, muscle twitching), UMN
findings (e.g. brisk reflexes, Babinski reflex, Hoffman's reflex, ↑ muscle tone),
or both

136 – Motor disturbances: cerebellum and basal ganglia. Parkinson’s disease

Disturbances of the cerebellum

 Removal or damage to the cerebellum causes movements to become highly

abnormal
 The cerebellum is vital during rapid muscular activities e.g. running, typing
even talking. Loss of cerebellar function can result in total incoordination of
these functions even though paralysis doesn’t occur
 Functions of the cerebellum are integrated into afferent and efferent pathways
 Important afferent pathway = corticopontocerebellar pathway
 Other afferent pathways link cerebellum to input from basal ganglia, muscle
and joint information from stretch receptors, visual input from eyes, balance
and equilibrium from vestibular system in the inner ear

Important efferent pathways:

 Vestibulocerebellar pathway = equilibrium and posture

 Spinocerebellar pathway = coordinating movements in distal portion of limbs
(hands, fingers)
 Cerebrocerebellar pathway = transmits info to cerebral cortex to coordinate
sequential body and limb movements

Signs of cerebellar dysfunction

 Cerebellar gait ataxia = staggering, lurching, and uncontrolled gait

 Cerebellar tremor = rhythmic back and forth movement of a finger/toe that
worsens as the target is approached
 Nystagmus = involuntary eye movement which affects the ability to fix eyes on
a target
 Motor skills of chewing, swallowing, and speech are affected

Disorders of the basal ganglia

The basal ganglia/basal nuclei are large masses of grey matter located w/in the
central core of white matter of the cerebral hemispheres.

The main components are = caudate nucleus (+ putamen = striatum);

lentiform nucleus (globus pallidus + putamen); subthalamic nucleus; and
substantia nigra

The basal ganglia plays an important role in starting, stopping, and

monitoring movement executed by the cortex. They also help regulate the
intensity of movements and are involved in cognitive and perceptual
function
  Cognitive function = monitor sensory information coming into the brain and
apply it to info stored in memory as a means of planning and sequencing
motor movements.
 The basal ganglia have input structures that receive afferent info from the
cerebral cortex and thalamus and output structures that deliver information
to other brain centers.
 Disorders of the basal ganglia consist of a complex group of motor
disturbances: tremor and other involuntary movements, changes in posture
and muscle tone, poverty and slowness of movement, tics, hypo-/hyperkinetic
disorders.
 Lesions of the basal ganglia disrupt movement but don’t cause paralysis

Parkinson disease

Definition = a degenerative disorder of basal ganglia function that results in variable

combos of tremor, rigidity, akinesia/bradykinesia, and postural changes

The disorder is characterised by degeneration of the dopamine producing neurons in

the substantia nigra → tremor, rigidity, bradykinesia

It is the 2nd most common neurological disorder after Alzheimer’s and it is

progressive; adult-onset (>50)

Etiology

 Cause is still unknown – most cases are caused by an

interaction of environmental and genetic factors
 Environmental factors = pesticides, trauma,
inflammation, impaired circulation, tumours.
 Genetics = genetic mutation in PINK1, PRKN
(encodes Parkin) genes. Rarely, it is due to MPTP
(synthetic opioid) which destroys dopaminergic
neurons of the substantia nigra
 The parkin protein acts as an enz. (i.e. ubiquitin
ligase) in the ubiquitin-conjugating system that targets
defective and abnormally folded proteins for
destruction. Loss of normal parkin function = abnormal proteins aggregate
and cause neurodegenerative changes
 In Parkinson’s, the substantia nigra gradually disappears and Lewy bodies
(eosinophilic) are observed under a microscope in the affected neurons
before they die

Symptoms

 Tremor = involuntary shaking most noticeably in the hands → ‘resting tremor’

i.e. present and rest and diminishes w/movement
  Bradykinesia (slow movement), hypokinesia (lessened movement), akinesia
(absence of movement) → legs freeze up → shuffling gait
 Stiffness/rigidity → stooped posture, mask-like expression
 Postural instability (unsteady when standing/walking)
 There is NO weakness (unlike diseases of motor cortex/corticospinal
pathway)

Treatment

 ↑ dopamine signalling the brain – dopamine cant cross BBB but its precursor,
levodopa, can
 Levodopa + carbidopa (carbidopa inhibits peripheral dopa decarboxylase
 Dopamine agonists (bromocriptine)

137 – Disturbances of the somatosensory system

The somatosensory system relays info for touch, temp, pain and body position:

 Mechanoreceptors = for touch and proprioception

 Thermoreceptors = detect changes in skin temp
 Nociceptors = respond to harmful/noxious stimuli

Information is transmitted over 3 types of neurons:

 1st order neurons = transmit info from receptors to dorsal horn neurons in the
spinal cord
 2nd order neurons = in the spinal cord/brainstem, transmits info to the
thalamus
 3rd order neurons = forward info from the thalamus to the somatosensory
cortex (precentral gyrus)

There are 2 ascending pathways for

transmission of somatosensory info:

 Dorsal column system = fine touch,

pressure, proprioception
 Anterolateral system = pain, temp, light
touch

Somatosensory disorder
  Definition = impairment of the somatosensory system
 The absence of proprioception or two-point tactile discrimination on one side
of the body suggests injury to the contralateral side of the primary
somatosensory cortex.
 However, depending on the extent of the injury, damage can range in loss of
proprioception of an individual limb or the entire body.
 A deficit known as cortical astereognosis of the receptive type describes an
inability to make use of tactile sensory info for identifying objects placed in the
hand

Symptoms of somatosensory impairment:

 Hyperalgesia = HS to pain
 Hyperpathia = pain that lasts beyond the irritating stimulus
 Hyperthesia = ↑ sensitivity to somatosensory stimuli
 Dysesthesia = impaired sensation, experience of pain to non-noxious stimuli
or abnormal sensation in absence of sensory stimuli
 Allydynia = pain in response to a stimulus that is not normally painful
 Paresthesia = prickling/tingling/numb sensations w/no apparent physical
cause
 Thalamic syndrome = thrombotic blockade of blood flow to the somatosensory
thalamus → ataxia and loss of sensations from opposite side of the body

138 – Pain

 Pain = a physiological response associated w/tissue damage. Activation of

nociceptive fibers is what elicits pain. Different types of nociceptors will elicit
different types of pain.
 Pain can be either nociceptive or neuropathic in origin.
 The receptors for pain (nociceptors) are free nerve endings. When
nociceptors are activated in response to actual or impending tissue injury,
nociceptive pain is the consequence.
 Neuropathic pain arises from direct injury or dysfunction of the sensory axons
of peripheral or central nerves
 Nociceptors transmit impulses to the dorsal horn neurons in the spinal cord
using chemical NTs. They are activated by different stimuli – mechanical,
thermal, and chemical
 Mechanical and thermal stimuli elicit fast pain via Aδ fibres (myelinated) →
neospinothalamic tract
 Chemical stimuli elicit slow pain transmitted via C-fibres (unmyelinated) →
paleospinothalamic tract
Central processing of pain info includes transmission to:

 Somatosensory cortex = pain info is received and interpreted

 Limbic system = emotional components of pain are experienced
 Brain stem centers = ANS responses are recruited

Pain pathway

 The nn. that supply nociceptors are Aδ and C fibers. These then synapse on
the dorsal root ganglion, before decussating into the spinothalamic tract.
 From here the 2nd order neurons ascend to the thalamus, from where it
synapses to the ventrolateral complex and post. nuclear group of the
thalamus, before going to the somatosensory areas of the cortex via their 3 rd
order neuron
 2nd order neurons send their info via 2 pathways to the thalamus – dorsal
column medial-lemniscus system and the anterolateral system. the 1 st is
reserved more for regular non-painful sensation, while the latter is reserved
for pain sensation

Anterolateral system

 Transmits somatosensory info about pain (nociception) and temp – info from
nociceptors and thermoreceptors
 Consists mainly of group III and IV fibers (group IV fibers have the slowest
conduction velocities of all the sensory nn.) – fibers are small, myelinated or
unmyelinated, w/slower conduction velocities.
 The 1st order neurons have their cell bodies in the dorsal horn and synapse on
thermoreceptors and nociceptors in the skin. They synapse on 2 nd order
neurons in the spinal cord, which cross the midline and ascend to the
contralateral thalamus – cross in the spinal cord segment
 In the thalamus, 2nd order neurons synapse on 3rd order neurons, which
ascend to the somatosensory cortex and synapse on 4 th order neurons.

Mechanism of pain suppression (analgesia) is mediated by opiate receptors:

descending pathway

 Periaqueductal grey (mesencephalon) = receives input from ascending pain

pathway
 Nucleus raphe magnus (medulla) receives input from the periaqueductal grey
and projects neurons to the dorsal horn
 Enkephalin interneurons receive input from the raphe magnus axons for pre-
and postsynaptic inhibition of incoming signal

Types of pain:

 Can arise from cutaneous, deep somatic or visceral nociceptors

  Referred pain- pain perceived at a site different from its origin
 Acute pain
 Chronic pain

Alterations in pain sensitivity and special types of pain:

 Analgesia = absence of pain

 Hyper- & hypoalgesia = ↑/↓ sensitivity to pain
 Hyper- & hypoesthesia = abnormal ↑/↓ in sensitivity to pain sensation
 Allodynia = pain due to stimuli that doesn’t usually cause pain
 Neuropathic pain = due to trauma or in a disease of neurons.
 Neuralgia → severe, brief, repetitive lightning-like pain
 Trigeminal neuralgia → facial tics or spasms
 Phantom limb pain = follows amputation of a limb/part of limb; pain sensations
as though the limb were still present

139 – Sensory disturbances – vision, hearing, and balance

Vision

 Conjunctiva lines the inner surface of the eyelids and covers the eyeball to the
junction of the cornea and sclera. Conjunctivitis (pink eye) is due to
bacterial/viral infections, allergic reaction, chemical/physical agents
 Keratitis = inflammation of the cornea
 Lens = changes shape to allow focusing of light onto the retina. Refraction =
ability of the lens to bend light rays to focus an object onto the retina
 Myopia (near-sightedness) = occurs when the eye grows too long,
resulting in the lens focusing the image in front of the retina. Corrected
w/a concave lens
 Hyperopia (long-sightedness) = occurs when the eyeball is shorter than
normal, resulting in the lens focusing the image behind the retina.
Corrected w/a convex lens
 Presbyopia = occurs usually w/older age. it is long-sightedness caused
by loss of elasticity of the lens (hardening of the lens)
 Cataract = clouding of the lens in the eye which leads to a ↓ in vision
 The retina covers the inner aspect of the posterior 2/3rds of the eyeball and is
continuous w/the optic n.
 It contains photoreceptors for vision: rods (black and white
discrimination) and cones (colour vision)
 Retinopathies = visual disorders involving the small blood vessels of
the retina (DM, hypertension)
  Retinal detachment = separation of sensory receptors from their blood
supply causing blindness
 Macular degeneration = destructive changes in central fovea – leading
cause of blindness in elderly
 Glaucoma = chronic, degenerative visual field loss associated w/↑ intraocular
pressure
 Eye movement is controlled by extraocular muscles, provides alignment of
eyes and binocular vision.
 Strabismus = condition in which eyes don’t properly align w/each other
when looking at an object. Paretic strabismus is due to paralysis of
1/several extraocular muscles
 Non-paretic strabismus is not due to paralysis of extraocular muscles
 Concomitant strabismus is a deviation that is the same magnitude
regardless of gaze position.
 Non-comitant strabismus has a magnitude that varies as the person
shifts his or her gaze up, down, or to the sides.

Esotropia Eyes crossed

Exotropia Eyes diverge
Hypertropia Eyes vertically misaligned (upward deviation)
Hypotropia Eyes vertically misaligned (downward deviation)
Cyclotropia Torsional deviation

 Amblyopia = diminished vision due to underdeveloped CNS

Hearing

 The outer ear collects sound vibrations and channels them to the tympanic
membrane (separates the outer ear from middle ear)
 The middle ear is an air-filled cavity in the temporal bone that amplifies sound
waves and transmits them to the fluid-filled inner ear
 The middle ear is connected to the nasopharynx via the eustachian tube,
which opens briefly during swallowing to allow for equalization of air pressures
on either sides of the tympanic membrane
 The Eustachian tube is lined w/a mucous membrane that is continuous w/the
nasopharynx allowing for infections to travel along the eustachian tube to the
middle ear
 Otitis media (OM) = inflammation of the middle ear;
 Acute otitis media (AOM) = bacterial infection (H.influenzae,
S.pneumoniae), abrupt onset
 Otitis media effusion (OME) = fluid in the middle ear → ear pain,
hearing loss, fever
 The inner ear contains the auditory and vestibular systems. The auditory
system contains the cochlea whose receptors convert sound waves to nerve
impulses that are transmitted to the cochlear nerve to the auditory cortex
Hearing loss or deafness can be caused by:

 Conductive disorders = auditory stimuli are not transmitted through outer and
middle ears to sensory receptors on the inner ear
 Sensorineural disorders = affect the inner ear, auditory n., or auditory
pathway. Sound waves are conducted to the inner ear but abnormalities of the
cochlea or auditory nerve ↓/distort transfer of information to the brain.
 Combo of conductive and sensorineural disorders

Balance

 Receptors of the vestibular system respond to changes in rotational and linear

acceleration of the head and are located in the fluid-filled semicircular ducts of
the inner ear
 Signals from the vestibular system initiate head and eye movement to
stabilize the visual field and make adjustments in the posture muscles that
maintain balance
 Vertigo = a symptom where a person feels as if they or the objects around
them are moving when they are not.

Disorders of vestibular function can result from:

 Repeated stimulation of the vestibular system e.g. car, air and boat travel
(motion sickness)
 Acute infections of the vestibular pathways → acute vestibular neuritis;
inflammation of the vestibular n. characterized by vertigo, nausea and
vomiting
 Dislodgement of otoliths (calcium carbonate particles from the utricle become
dislodged and float in the endolymph) that participate in the receptor function
for the vestibular system → benign paroxysmal positional vertigo; pathologic
vertigo that usually develops after 4th decade of life. Brief episodes of vertigo
(<1min) due to a change in head position e.g. when you get out of bed,
bending over and straightening up.
 Distension of the endolymphatic compartment of the inner ear – Meniere
disease → hearing loss, tinnitus, vertigo. Trauma, infections (syphilis),
hypothyroidism, and vascular disorders can cause this.

140 – Disturbances in consciousness, arousal, and cognition

 Consciousness = the state of being aware of one self and environment

 Arousal = the state of responsiveness to sensory stimulation or excitability
 Cognition = mind process by which we become aware of thought and
perception, including aspects of perceiving, thinking, and remembering →
cerebral cortex
 Reticular activating system (RAS)

 System of interlacing nerve cells and fibers in the brain stem that receives
input from multiple sensory pathways
 Ascending sensory tracts send axon fibers to reticular formation. These give
rise to fibers that synapse to nuclei of the thalamus and from the thalamus,
thalamic projections influence widespread areas of the cerebral cortex and
limbic system.
 Basically, RAS acts as a ‘gate-keeper’, evaluating the incoming information
and prioritizing that info in the form of messages that need your attention. The
RAS is like a filter between your conscious mind and unconscious mind.
 Ascending RASs travel from the medulla through the midbrain, so lesions of
the brainstem can interrupt RAS activity → altered levels of consciousness
and coma
 Any deficit in the level of consciousness indicates injury to either RAS or to
both cerebral hemispheres. E.g. metabolic derangements that affect both
hemispheres, head trauma causing injuries to both RAS and cerebral
hemisphere.

Levels of consciousness

Levels of consciousness reflect the awareness and response to the environment.

Descending levels of consciousness and their characteristics:

Level of Characteristics
consciousness
Full consciousness Awake, alert, and oriented to time, place, and person; comprehends
spoken and written word and is able to express ideas
Confusion Disoriented to time, place, or person; memory difficulty; difficulty
following commands
Lethargy Oriented to time, place, and person; very slow in mental processes,
motor activity, and speech; responds to pain appropriately
Obtundation Responds verbally w/a word; arousable w/stimulation; responds
appropriately to painful stimuli; follows simple commands; appears
very drowsy
Stupor Unresponsive except to vigorous and repeated stimuli; responds
appropriately to painful stimuli; lies quiet w/minimal spontaneous
movement; may have incomprehensible sounds and/or eye opening
Coma Doesn’t respond appropriately to stimuli; sleeplike state w/eyes
closed; doesn’t make any verbal sounds

Glasgow Coma Scale (GCS)

The degree of consciousness is measured by

standardised behaviour observation scales
such as the GCS. A person is assessed against
the criteria of the scale, and the resulting points give a person's score between 3
(indicating deep unconsciousness – worst possible score) and 15 (best possible
score

Coma= state of profound unconsciousness from which the patient cannot be

aroused, even by powerful stimuli

 Alcoholic coma = stupor accompanying severe alcoholic intoxication

 Diabetic coma = severe diabetic acidosis
 Hepatic coma = coma accompanying hepatic encephalopathy
 Irreversible coma = brain death
 Uremic coma = uremia

Confusional states:

 Hallucinations = a sense of perception (sight, touch, sound, smell or taste)

that has no basis in external stimulation.
 Delusion = idiosyncratic false belief that is firmly maintained in spite of
obvious proof or evidence to the contrary

141 – Epilepsy

Definition = a group of neurological disorders characterised by epileptic seizures.

Epileptic seizures are episodes that can vary from brief and nearly undetectable
periods to long periods of vigorous shaking.

Etiology

 60% of cases, the cause is unknown (idiopathic)

 Epilepsy can have both genetic and acquired causes, w/interaction of these
factors in many cases.
 Genetics is believed to be involved in the majority of cases. Some are due to
a single gene defect; most are due to the interaction of multiple genes and
environmental factors. Most genes involved affect ion channels, either directly
or indirectly
 Epilepsy may occur as a result of a number of other conditions including
tumours, strokes, head trauma, previous infections of the CNS, genetic
abnormalities, and as a result of brain damage around the time of birth

Pathophysiology

 Seizures may be caused by alteration in cell membrane permeability or

distribution of ions across the neuronal cell membranes.
 Seizures occur when neurons are synchronously active when they’re not
supposed to be i.e. neurons are firing (sending a message) using electrical
signals relayed from neuron to neuron
  Each electrical signal that passes through a neuron are ions flowing in and out
through protein channels
 The flow of ions is controlled by NTs and receptors → NTs bind to receptors
→ open up the ion channels and relay the electrical message (excitatory NTs)
or close the ion channels and stop the electrical message (inhibitory NTs)

In epilepsy there is either too much excitation or too little inhibition:

 Glutamate is an excitatory NT that binds to NMDA receptors to allow Ca 2+ to

enter the neuron → patients w/epilepsy can have fast or long-activation of
NMDA receptors
 GABA is the main inhibitory NT, which binds to GABA receptors and tells the
cell to inhibit the signal by opening channels that let in Cl- ions → patients
w/epilepsy can have dysfunctional GABA receptors → unable to inhibit signals

Classification of seizures

Focal seizures = seizures begin in a specific or focal area of 1 cerebral hemisphere

 Simple partial = w/out impairment of consciousness or awareness

 Symptoms depend on the area of the brain where the abnormal
electrical activity occurs
 Strange sensations e.g. hearing/tasting something
 Can be preceded by aura which is a warning sign of an impending
seizure
 Person usually knows the seizure is happening and often remembers
the seizure afterwards
 Complex partial = w/impairment of consciousness or awareness
 Arises from the temporal lobe.
 Psychomotor seizures
 Lip smacking, grimacing, rubbing clothing
 May not remember what happens after the seizure occurs → confusion
during postictal period (altered state of consciousness after an epileptic
seizure)
 Déjà vu and hallucinations can occur

Generalised seizures = begin simultaneously in both cerebral hemispheres

 Tonic-clonic seizures = most common generalised seizure; loss of

consciousness occurs; incontinence of bowel and bladder contents is
common
  Absence seizures = generalised, non-convulsive epileptic events and are
expressed mainly as disturbances in consciousness
 Myoclonic seizures = short muscle twitches (brief involuntary muscle
contractions)
 Clonic seizures = begin w/loss of consciousness and sudden hypotonia,
followed by limb jerking that may/may not be symmetrical
 Tonic seizures = sudden onset of ↑ tone, which is maintained in the extensor
muscles. It is often associated w/falling
 Atonic seizures = sudden, short loss of muscle tone leading to slackening of
the jaw, drooping of the limbs, or falling to the ground (drop attacks)

Status epilepticus

 Definition = seizures that don’t stop spontaneously or occur in succession

w/out recovery
 Usually tonic-clonic type
 Medical emergency = treat w/IV benzodiazepines to enhance GABA

Diagnosis and treatment

 Diagnosis = electroencephalogram (EEG) to look for abnormal pattern of brain

waves, CT/MRI to look at the structure of the brain
 Treatment = anti-epileptic drugs (phenytoin, carbamazepine, valproate,
phenobarbital)
 Nerve stimulation (stimulation of vagus n.), ketogenic diet

142 – Dementia and Alzheimer’s disease

Dementia = a broad category of brain diseases that cause a long-term and often
gradual ↓ in the ability to think and remember that is great enough to affect a
person’s daily functioning.

Alzheimer’s disease

 Alzheimer’s is a neurodegenerative disorder that accounts for 60-80% of all

cases of dementia
 Alzheimer’s is characterised by cortical atrophy and loss of neurons,
particularly in the parietal and temporal lobes. w/significant atrophy, there is
ventricular enlargement (i.e. hydrocephalus) from the loss of brain tissue
 Major microscopic features = amyloid plaques and neurofibrillary tangles
Amyloid plaques

 They are patches or flat areas composed of clusters of degenerating n.

terminals arranged around a central amyloid core
 In the cell membrane of a neuron, there is an amyloid precursor protein (APP)
– it helps neurons grow and repair after injury
 Since APP is a protein, it gets used, broken down and recycled. Normally, it
gets broken down by α-secretase and γ-secretase → left over fragment is
soluble
 If β-secretase combines w/γ-secretase instead of α-secretase → left over
fragment is insoluble → creates monomer called amyloid β (Aβ) → chemically
sticky and bond together outside the neurons and form β amyloid plaques
 These plaques can get between the neurons → disrupts signalling → brain
function impaired
 The plaques may also cause an inflammatory rxn → damage surrounding
neurons
 They can deposit in blood vessels of the brain = amyloid angiopathy →
weakens the walls of the vessels → haemorrhage

Neurofibrillary tangles

 Found in cytoplasm of abnormal neurons, consist of fibrous proteins that are

wound around each other in a helical fashion.
 They are resistant to chemical/enzymatic breakdown, and persist in the brain
tissue long after the neuron has died and disappeared
 Major component is an abnormally hyperphosphorylated form of the protein
tau, an axonal MT-associated protein that enhances MT assembly
 Kinase enz. transfers phosphate groups to the tau protein → tau protein
changes shape → stops supporting the MT and clumps up w/other tau
proteins and gets tangled → forms neurofibrillary tangles → neuron
undergoes apoptosis

Alzheimer disease can be:

 Sporadic = late onset type, cause isn’t well known, 90% of cases. Risk ↑
significantly w/age
 Gene: e4 allele of Apo E (Apo e4) → if a patient inherits 1 e4 allele the
risk of Alzheimer’s ↑ and if they inherit 2 e4 alleles the risk ↑ even more
 [NOTE: Apo E helps break down Aβ
 Familial = early onset Alzheimer’s, 5-10% of cases due to several gene
mutations
 E.g. PSEN-1 or PSEN-2 gene mutations (encode for presinilin 1 and 2
respectively = protein subunits of γ-secretase)
  Trisomy 21 (down syndrome) because the gene responsible for
producing APP is located on chromosome 21 i.e. they have an extra
APP gene

Symptoms = correlate w/the amount of plaques and tangles that build up (arrows
indicate the progression of Alzheimer’s)

No detectable symptoms → patients lose short-term memory → loss of some motor

skills, language affected → loss of long-term memory → disorientation → bedridden
→ death due to pneumonia

Other types of dementia

Reversible causes of dementia = hypothyroidism, vit B12 deficiency, lyme disease,

and neurosyphilis.

Vascular dementia

 The cause of at least 20% of dementia cases

 It is caused by brain injury resulting from ischemic or haemorrhagic damage
 The incidence is closely associated w/HT, arrhythmias, MI, peripheral
vascular disease, lipid abnormalities, DM, autoimmune and infectious
vasculitis
 Symptoms depend on where in the brain the injury occurred and whether the
affected vessels are large or small

Frontotemporal dementia (FTD)

 Atrophy of frontal and anterior temporal lobes of the brain- known as ‘Pick
disease’
 Most common cause of dementia of persons younger than 65 years
 Behaviour and language affected
 Unlike Alzheimer’s, FTD begins w/very disruptive behaviours – impulsive
actions, apathy, inappropriate social behaviours
 Language – understanding or expressing language

Creutzfeldt-Jakob disease (CJD)

 It is one of the 3 prion diseases (transmissible spongiform encephalopathies)

 Extremely rare, it causes severe degenerative dementia
 4 categories = sporadic, hereditary, acquired, and new variant CJD
 It causes degeneration of the pyramidal and extrapyramidal systems and is
distinguished by its rapid course – 6 months

Huntingdon disease
  It is a hereditary disorder characterised by chronic progressive chorea,
psychological changes, and dementia.
 AD disorder, onset most commonly 4th/5th decade
 Due to trinucleotide expansion in HD gene that codes for huntingtin protein
 The longer repeats = earlier onset
 It produces localised death of brain cells – it mostly effects neurons of basal
ganglia that modulate motor output

143 – Stroke

Blood supply of the brain

The circle of Willis (CoW) = circulatory anastomoses that supplies blood to the brain
and surrounding structures. It is part of the cerebral circulation and is composed of
the following aa.:

 Ant. cerebral a. (L and R) = arise from the ICA.

Forms the anterolateral portion of the CoW
 Ant. communicating a. = connects the L and R ant.
cerebral aa.
 Internal carotid a. (L and R) = arise from the L and
R common carotid aa.
 Post. cerebral a. (L and R) = arise from the basilar
a., which is formed by the L and R vertebral aa.
which arise from the subclavian aa.
 Post. communicating a. (L and R) = arise from ICA
just before it divides into its terminal branches (ant.
and middle cerebral aa.)

All the aa. involved give off cortical and central branches. The central branches
supply the interior of the CoW, > super., the interpeduncular fossa.

The arrangement of the brain’s aa., into the CoW creates redundancy for collateral
circulation in the cerebral circulation. If one part of the circle/an a. becomes
blocked/narrowed, blood flow from other blood vessels can soften preserve the
cerebral perfusion well enough to avoid the symptoms of ischemia.

The full branches, starting anteriorly:

ant. cerebral, middle sup., post. communicating, post. cerebral, sup. cerebellar,
basilar, pontine, ant. inf. cerebellar, vertebral, post. inf. cerebellar aa.

Stroke

Definition = medical condition in which poor blood flow to the brain (cerebral
circulation) results in cell death. (focal neurological deficit due to a vascular induced
disorder that injures brain tissue)

Risk factors

Modifiable Non-modifiable
 HT  Age – risk ↑ w/age
 Hyperlipidaemia  Gender – M and postmenopausal
 Heart disease – atrial fibrillation F
 Carotid a. disease  Race – African Americans have
 Coagulation disorders higher risk
 Obesity/inactivity  Hereditary – family history
 Heavy alcohol use
 Smoking
 Cocaine use

Classification and pathophysiology

Ischaemic stroke

It is caused by interruption of the blood supply to the brain → dysfunction of the brain
tissue in that area. There are 4 reasons why this might happen:

 Thrombosis (obstruction of a blood vessel by a blood clot forming locally)

 Embolism (obstruction due to an embolus from elsewhere in the body)
 Systemic hypoperfusion (general ↓ in blood supply, e.g. in shock)
 Cerebral venous sinus thrombosis

Cryptogenic stroke = stroke w/out an obvious explanation. This constitutes 30-40%

of all ischaemic strokes

Brain tissue ceases to function if deprived of oxygen for more than 60 to 90 secs,
and after approximately 3 hours will suffer irreversible injury possibly leading to the
death of the tissue, i.e., infarction

When blood vessels in the brain get blocked, the brain becomes low in E →
anaerobic metabolism w/in the region of brain tissue affected by ischaemia → ↑
lactic acid → destroys cells due to its acidic nature and disrupts the normal acid-
base balance in the brain

As oxygen or glucose becomes depleted in ischemic brain tissue, the production

ATP fails → failure of E-dependent processes (such as ion pumping) necessary for
tissue cell survival → cellular injury and death.

A major cause of neuronal injury is the excitatory NT glutamate. The conc. outside
the cells is normally kept low due to uptake carriers. Failure of these = glutamate
acts on receptors in n. cells → influx of Ca2+ which activates enz. that digest the
cells’ proteins, lipids, and nuclear material

Ischaemia also induces production of ROS → react w/ and damage cells

Ischemia produces loss of structural integrity of brain tissue and blood vessels →
breakdown of the protective BBB → cerebral oedema

Haemorrhagic stroke

It is caused by rupture of a blood vessel or an abnormal vascular structure. There

are 2 main types:

 Intracerebral haemorrhage = bleeding w/in the brain itself (when a. in the

brain bursts, flooding the surrounding tissue w/blood), due to either
intraparenchymal haemorrhage (bleeding w/in the brain tissue) or
intraventricular haemorrhage (bleeding w/in the ventricular system)
 Subarachnoid haemorrhage = bleeding that occurs outside the brain tissue
but still w/in the skull (between pia and arachnoid mater)

Some causes of haemorrhagic stroke are hypertensive haemorrhage, ruptured

aneurysm, ruptured arteriovenous (AV) fistula, transformation of prior ischaemic
infarction, and drug induced bleeding.

They result in tissue injury by causing compression of tissue from an expanding

haematoma (s). in addition, the pressure may lead to a loss of blood supply to the
affected tissue w/resulting infarction, and the blood released by the brain
haemorrhage appears to have direct toxic effects on brain tissue and vasculature.

They cause specific symptoms (e.g. subarachnoid haemorrhage causes severe

headache known as a thunderclap headache) or reveal evidence of a previous head
injury.

Symptoms
Symptoms typically start suddenly, over seconds to minutes, and in most cases do
not progress further. The symptoms depend on the area of the brain affected. The
more extensive the area of the brain affected, the more functions that are likely to be
lost.

Warning signs of stroke = FAST – Facial droop, Arm weakness, Speech difficulty,
and Time to call emergency services

If the area of the brain affected includes one of the 3 prominent CNS pathways
(spinothalamic tract, corticospinal tract, and the DCML pathway) symptoms may
include:

 Hemiplegia (unilateral paresis – weakness of one entire side of the body) and
muscle weakness of the face
 Numbness
 ↓ in sensory or vibratory sensation
 Initial flaccidity (↓ muscle tone), replaced by spasticity (↑ muscle tone),
excessive reflexes, and obligatory synergies.

In most cases, the symptoms affect only one side of the body (unilateral). Depending
on the part of the brain affected, the defect in the brain is usually on the opposite
side of the body

A brainstem stroke can produce symptoms relating to deficits in the CNs that arise
from the brainstem:

 Altered smell, taste, hearing, or vision (total or partial)

 Drooping of eyelid (ptosis) and weakness of ocular muscles
 ↓ reflexes: gag, swallow, pupil reactivity to light
 ↓ sensation and muscle weakness of the face
 Balance problems and nystagmus
 Altered breathing and heart rate
 Weakness in SCM w/inability to turn head to one side
 Weakness in tongue (inability to stick out the tongue or move it from side to
side)

If the cerebellum is involved, ataxia might be present and this includes altered
walking gait, altered movement coordination, and vertigo and/or disequilibrium

144 – Stress and distress. Stress-induced diseases

Stress = an organism’s response to a stressor such as an environmental condition. It
is the body’s method of reacting to a condition such as a threat, challenge or
physical and psychological barrier.

Eustress vs. distress

 Eustress = beneficial stress – either psychological, physical (exercise), or

biochemical/radiological (hormesis)
 Distress = an aversive state in which a person is unable to completely adapt
to stressors and their resulting stress and shows maladaptive behaviours.

The stress response involves activation of = SNS, hypothalamic pituitary adrenal

(HPA) axis and the immune system.

Seyle, referred stress response as the general adaptation syndrome, divided it into 3
stages:

 Alarm stage = activation of SNS and HPA axis → release of catecholamines

and cortisol
 Resistance stage = the body selects the most effective defences
 Exhaustion stage = physiologic resources are depleted and signs of systemic
damage appear

Adaptation = a person can balance between stressors and his/her ability to deal with
it. It is affected by a number of factors:

 Age (a child has an immature renal structure and has difficulty conc. urine so
they are < able than an adult to cope w/↓ water intake)
 Gender (postmenopausal F have lower activation of SNS than M in response
to stressors)
 Nutrition, sleep-wake cycles (sleep disorders can lead to stress), psychosocial
factors.

Prolonged activation of the stress response due to overwhelming or chronic

stressors can be damaging to health

Acute stress disorder occurs in individuals w/out any other apparent psychiatric
disorder, in response to exceptional physical or psychological stress. While severe,
such rxns usually subside w/in hours or days. The stress may be an overwhelming
traumatic experience (e.g. accident, battle, physical assault, rape) or unusually
sudden change in social circumstances of the individual, such as multiple
bereavements.

Autonomic signs of “panic anxiety” = tachycardia, sweating, hyperventilation. The

symptoms usually appear w/in minutes of the impact of the stressful stimulus and
disappear w/in 2-3 days
PTSD = e.g. of chronic activation of the stress response due to a traumatic event;
flashbacks, emotional numbing, intense activation of the neuroendocrine system

Treatment of stress should be aimed at helping people avoid coping behaviours that
can affect their health and providing them with other ways to reduce stress. Music
therapy, massage therapy

The 5 R’s of stress and anxiety reduction:

 Recognition of the causes and sources of the threat or distress; education and
consciousness raising.
 Relationships identified for support, help, reassurance
 Removal from (or of) the threat or stressor; managing the stimulus.
 Relaxation through techniques such as meditation, massage, breathing
exercises, or imagery.
 Re-engagement through managed re-exposure and desensitization.