Pathoma

Chapter 1

1. Growth Adaptations

 Basic principles:
o Organ is in homeostasis with physiologic stress placed on it
o Increase, decrease, or change in stress on an organ can result in
growth adaptations
 Hyperplasia and hypertrophy
o Increase in stress leads to increase in organ size - if it has to do more
work, it will become bigger
o Occurs via increase in size and/or number of cells
o Hypertrophy
 Involves gene activation, protein synthesis, and production of
organelles
 Increase production of cytoskeleton to increase size of the cell
 Permanent tissues cannot make new cells so can only undergo
hypertrophy
 Cardiac muscle
 Skeletal muscle
 Nerve
o Hyperplasia
 Involves production of new cells from stem cells
 Example of physiological hyperplasia is pregnancy
 Pathologic hyperplasia can progress to dysplasia and cancer
 Example: endometrial hyperplasia
 Grows with exposure to estrogen and sheds
with progesterone so if overexposed to estrogen it can
cause hyperplasia and progress to dysplasia
 Exemption: benign prostatic hyperplasia
 Is a pathologic hyperplasia but there is no
cancer risk
o Hyperplasia and hypertrophy generally occur together
 Example: uterus during pregnancy
 Atrophy
o Decrease in stress leads to a decrease in organ size
o Occurs via a decrease in the size and number of cells
o Decrease in cell number occurs via apoptosis
o Decrease in cell size occurs via two mechanisms:
 Ubiquitin-proteosome degradation of the cytoskeleton
 Ubiquitin posted on intermediate filaments and this is
recognized by the proteosome
 Autophagy of cellular components
  Cellular components consumed into vacuoles and they
are fused with lysosomes (contain hydrolytic enzymes to
destroy into building blocks)
 Metaplasia
o Change in stress on an organ leads to change in the cell type
o Most commonly involves surface epithelium
o Metaplastic cells are better able to handle the new stress
o Remember 3 types of epithelium: squamous (keratinizing or non
keratinizing), columnar, transitional (urothelium)
o Barrett oesophagus is a classic example
 Squamous epithelium in oesophagus and stomach is columnar
non-ciliated mucinous
o Metaplasia occurs via reprogramming of stem cells
 Reversible with removal of the driving stressor
 Example: treatment of GORD
o Metaplasia can progress to dysplasia and cancer
 Example: Barrett oesophagus
 Exception: Apocrine metaplasia
 One of the changes seen with fibrocystic change in the
breast
 Does not increase the risk of future breast cancer
o Vitamin A deficiency can result in metaplasia
 Example: keratomalacia
 Night blindness with vitamin A deficiency
 Another feature of vitamin A deficiency is immunodeficiency
 15-17 translocation (involves retinoic acid receptor) is
called acute Promyelocytic Leukaemia (PML)
 Disrupts the vitamin A receptor causes the cells to stay
trapped in blast state so they accumulate resulting in this
leukaemia
 One of the treatments for PML is Atra (all trans retinoic
acid - derivative of vitamin A that can bind the mutated
receptor so they cells can mature to neutrophils)
 Third consequence of vitamin A deficiency is metaplasia
 Vitamin A is involved in maintaining specialized
epithelium of the body (example: conjunctiva of the eye)
 In deficiency there is metaplasia of these cells resulting
in a thickening of the surface (keratomalacia)
o Mesenchymal tissues can undergo metaplasia
 Example: myositis ossificans
 Inflammation of skeletal muscle (from trauma usually)
results in metaplastic production of bone in the skeletal
muscle
 Dysplasia
o Disordered cellular growth
o Refers to proliferation of precancerous cells (example: cervical
intraepithelial neoplasia)
  Remember it can be divided into CIN 1, 2, and 3
o Arises from longstanding pathologic hyperplasia (endometrial
hyperplasia) or metaplasia (Barrett's oesophagus)
o Dysplasia is reversible with alleviation of inciting stress
o If stress persists, dysplasia progresses to carcinoma (irreversible)
 Aplasia
o Failure of cell production during embryogenesis
o Example: unilateral renal agenesis
 Hypoplasia
o Decrease in cell production during embryogenesis
o Results in relatively small organ
o Example: streak ovary in Turner syndrome

2. Cellular injury

 Injury occurs when stress exceeds cell's ability to adapt

o Likelihood of injury depends on type of stress (inflammation more
likely to cause adaptation), severity (slowly cutting off blood supply versus
sudden thrombus formation), and type of cell affected (neurons very
susceptible to hypoxia compared to skeletal muscle which can handle
hypoxia for very long time)
 Common causes of injury
o Inflammation
o Nutritional deficiency or excess
o Hypoxia
o Trauma
o Genetic mutations
 Hypoxia
o Low oxygen delivery to tissues
o Low oxidative phosphorylation so low ATP therefore cellular injury
o 3 causes:
 Ischaemia
 Decreased blood flow through an organ via 3
mechanisms
 Block in arterial flow into the organ (example:
atherosclerosis)
 Decreased flow through vein
 Block flow of fresh blood across capillary bed
 Example: Budd Chiari syndrome
 Thrombosis in hepatic vein so block flow
of blood to liver leading to infarction
 Most common cause is polycythaemia
vara - high RBC count due to overproduction of
RBCs - thickened blood leading to thrombosis - one
place is the hepatic vein causing Budd Chiari
syndrome
  Another cause of Budd Chiari syndrome
is Lupus who has Lupus anticoagulant -
hypercoaguable state in these patients
 Shock can also cause ischaemia - generalized decreased
perfusion to organs due to many causes
 Hypoxemia
 Low partial pressure of O2 in the blood (PaO2 < 60
mmHg, SaO2 < 90%)
 Remember FiO2 (O2 in the atmosphere), PAO2 (O2 in
alveoli), PaO2 (O2 in arteriole), SaO2 (O2 loaded to
haemoglobin)
 FiO2 common cause of it to go down is high altitude
 PAO2 most common cause of it to go down is anything
that increases PACO2 (cause nitrogen is a constant and O2 and
CO2 must balance to a particular pressure) - COPD,
hypoventilation, etc.
 If you thicken interstitium (fibrosis) cannot get O2 from
alveoli to arteriole so can also cause hypoxemia
 If PaO2 goes down, the SaO2 will go down
 Decreased O2 carrying capacity of the blood
 Arises with Hb loss or dysfunction
 Anaemia
 Decrease in RBC mass
 PaO2 normal, SaO2 normal
 SaO2 is just what percentage of Hb is bound by
O2
 CO poisoning
 CO binds Hb more avidly than O2
 PaO2 normal, SaO2 decreased
 Exposures include smoke from fires and exhaust
from cars or gas heaters
 Classic finding is cherry red appearance of skin
 Hb so tightly bound so it reflects the red
light
 Early sign of exposure is headache
 Significant exposure can load to coma and
death
 Methemoglobinemia
 Iron in haem is oxidized to Fe3+ which cannot
bind O2 (Fe2+ binds O2)
 PaO2 normal, SaO2 decreased
 Seen in oxidant stress (example: sulfa and
nitrate drugs) or in newborns
 Newborns: we are always oxidizing a bit
of haemoglobin in our blood but we have enzymes
that reduce iron back to its 2+ state but in
 newborns this machnery is immature so they are
susceptible
 Classic finding is cyanosis with chocolate
coloured blood
 Treatment is IV methylene blue to generate
mediators to reduce iron back down to 2+ state
o Hypoxia impairs oxidative phosphorylation resulting in decreased ATP
o Low ATP disrupts key cellular functions:
 Na/K pump (sodium will build up in cell, water follows, cell
swells)
 Ca pump (cell wants a super low concentration of Ca in
cytosol, high cytosolic Ca can activate enzymes that we would not
want to be activated in the cell)
 Aerobic glycolysis (now will switch to anaerobic glycolysis,
production of lactic acid)
o Initial phase of injury is reversible:
 Hallmark is cellular swelling leading to
 Loss of microvilli
 Membrane blebbing
 Swelling causes blebbing of membrane from
cytoskeleton
 Swelling of RER
 Ribosomes attached via loose association so
they actually pop off when swelling of RER happen
 Therefore decrease in protein synthesis is
another sign
o Eventually, damage becomes irreversible:
 Hallmark is membrane damage (3 in particular):
 Plasma membrane
 Enzymes will leak out into the blood
 Example: cardiac enzymes (troponin) to look for
irreversible damage
 Calcium outside of the cell can now rush in so
intracellular Ca will increase
 Mitochondrial membrane
 ETC is on the inner mitochondrial membrane
 Cytochrome C is also in the mitochondria and if
it leaks into cytoplasm is can activate apoptosis
 Lysosome
 Contains lytic enzymes
 Lytic enzymes can leak with lysosome damage
and can cause digesting of the cell itself (especially since
calcium has leaked into cytosol and will activate the
enzymes)
o End result of irreversible injury is cell death

3. Cell death
 Morphologic hallmark of cell death is loss of nucleus
o Occurs via pyknosis (nucleus shrinks down into what looks like an ink
dot), kayorrhexis (nucleus breaks up into pieces), and karyolysis (broken
down further into building blocks)
 Two mechanisms of cell death: necrosis and apoptosis
 Necrosis
o Death of a large group of cells followed by acute inflammation
 Remember two things cause acute inflammation: infection and
necrosis
o Due to underlying pathologic process; never physiologic
o Divided into several types based on gross features
 Coagulative necrosis
 Necrotic tissue that remains firm
 Cell shape and organ structure are preserved by
coagulation of cellular proteins
 Nucleus disappears - example from text shows kidney
but the cells have lost their nuclei
 Characteristic of ischaemic infarction of any organ
except the brain
 Area of infarcted tissue is wedge shaped and pale
 Wedge points to the area of occlusion
 Red infarction arises if blood re-enters a loosely
organized tissue
 Classic example is testicular haemorrhagic
infarction
 When testicle twists around spermatic
cord blood is still entering via the artery since it is
thick walled but the vein collapses
 So the tissue dies but blood will still be
entering
 Liquefactive necrosis
 Necrotic tissue that becomes liquefied
 Enzymatic lysis of cells and proteins results in
liquefaction
 Characteristic of
 Brain infarction
 Brain contains microglia cells (derivative
of monocytes) which contain hydrolytic enzymes
that destroys the tissue when it dies
 Abscess
 Neutrophils contain hydrolytic enzymes
that destroys the tissue
 Pancreatitis
 Pancreatic enzymes will become
activated in the pancreas it will result in liquefactive
necrosis in the pancreas itself
  In pancreatitis there will also be "fat
necrosis" of the peripancreatic fat
 Gangrenous necrosis
 Coagulative necrosis that resembles mummified tissue
(dry gangrene)
 Characteristic of ischemia of lower limb and GI tract
 If superimposed infection occurs, then liquefactive
necrosis ensues (wet gangrene)
 Caseous necrosis
 Soft, friable necrotic tissue with "cottage cheese-like"
appearance
 Basically liquefactive necrosis with something
mixed in (bacteria or fungus thickens up the soup to
make it cottage cheese like)
 Combination of coagulative and liquefactive necrosis
 Characteristic of granulomatous inflammation due to
TB or fungal infection
 Fat necrosis
 Necrotic adipose tissue with chalky-white appearance
due to deposition of calcium
 When fat dies, fatty acids are released which have the
ability to bind with calcium (called saponification)
 Remember in pancreatitis there is liquefactive necrosis
of pancreas and fat necrosis of peripancreatic fat
 Also characteristic of trauma to fat
 Breast: if a woman is in a car accident and the
breast gets forced against steering wheel
 When fat necrosis occurs there is usually a giant
cell reaction cause of inflammatory response to fat (so
might say on an exam that a biopsy shows giant cells, fat,
and calcification)
 Calcification can sometimes mean there is
ductal carcinoma in situ but can also be seen in benign
situation like fat necrosis
 Woman might not remember any trauma really:
like getting hit with a baseball could also cause fat
necrosis
 Saponification
 Fatty acids released by trauma or lipase join
with calcium (how soap is made)
 Dystrophic calcification
 Dead or dying tissue and calcium
deposits (serum calcium and phosphate is normal
level)
 Saponification is one example
 Psammoma bodies is another example
of dystrophic calcification
  Papillary carcinoma of thyroid,
meningioma, papillary carcinoma of ovary
 Metastatic calcification (does not mean they have metastatic
cancer!)
 Elevated serum calcium OR phosphate leading to
calcification of multiple tissues
 However, metastatic cancer to the bone could cause
elevated serum calcium leading to metastatic
calcification
 Fibrinoid necrosis
 Necrotic damage to blood vessel wall
 Leaking proteins into vessel wall results in bright pink
staining
 Characteristic of:
 Malignant hypertension
 Hypertension can be divided into benign
and malignant
 Benign hypertension is a low grade
hypertension leading to long term progressive
damage to organs
 Malignant hypertension is very high
blood pressure that presents with headache, renal
failure, papilledema and is a medical emergency
 Can cause the blood vessel wall
to undergo fibrinoid necrosis due to the high
pressure
 Vasculitis
 In a subset of vasculitis
 A 30 year old woman would not normally have
malignant hypertension or vasculitis so a reason a 30 year old
woman may have fibrinoid necrosis is pre-eclampsia
 Presents in third trimester with elevated BP and
proteinuria and the consequence is fibrinoid necrosis of
the placenta
 Apoptosis
o Energy dependant, genetically programmed cell death
o Involves single cells or small groups of cells
o Examples
 Endometrial shedding during the menstrual cycle
 Removal of cells during embryogenesis
 Syndactyly can result from lack of apoptosis
 CD8+ cell mediated killing of virally infected cells
 Proteins from virus get made by host machinery and
will presented on MHC class 1 (on all nucleated cells and
platelets and presents endogenous protein) which is
recognized by CD8+ T cells which induce apoptosis of the
infected cell
 o Morphology
 Dying cell shrinks (becomes eosinophilic since cytoplasm is
more concentrated)
 Nucleus condenses and fragments (apoptosis means falling
leaves)
 Apoptotic bodies fall from cell and are removed by
macrophages
 Not followed by acute inflammation
o Apoptosis is mediated by caspases
 Activate proteases (breakdown of cytoskeleton)
 Activate endonucleases (break down DNA)
o Caspases are activated by 3 major pathways
 Intrinsic mitochondrial pathway
 Cellular injury, DNA damage, or decreased hormonal
stimulation (endometrial cycle when the oestrogen is removed
we have shedding of endometrium) inactivates Bcl2
 Bcl2 normally stabilizes mitochondrial
membrane so that cytochrome C does not leak out
 Cytochrome C leaks from inner mitochondrial matrix
into the cytoplasm
 Extrinsic receptor-ligand pathway
 FAS ligand binds FAS death receptor (CD95) on target
cell
 T cells are born in bone marrow and get
educated in thymus
 Undergo positive selection: do you have the
ability to bind self antigen and MHC? If so can survive
 Negative selection: do you have ability to bind
self antigen too tightly? If so have to die.
 For negative selection the way the T
cells die is they undergo the extrinsic receptor-
ligand pathway via FAS
 TNF binds TNF receptor on target cell
 Cytotoxic CD8+ T cell pathway
 Antigen presented on MHC class 1 to CD8+ T cells and
the T cells produce perforins and granzyme
 Perforins create pores in membrane of target cell
 Granzyme enters pores and activate caspases

4. Free radical injury

 
 Free radicals
o Chemical species with unpaired electron in outer orbit
o Can induce damage within cell
o Free radicals are made physiologically and pathologically
 Physiologic generation occurs during oxidative phosphorylation
 o Cytochrome C oxidase transfers electrons to O2 during oxidative
phosphorylation
 O2 accepts two electrons to make water
o Partial reduction yields O2- (super oxide), H2O2 (hydrogen peroxide),
and OH (hydroxyl ion) radicals
 Pathologic generation
o Ionizing radiation
 OH is generated because radiation hits water in the tissues
 OH is the most damaging free radical
o Inflammation
 Oxygen dependant and independent ways of killing microbes
 Oxygen dependant starts out with oxidative burst where O2 is
taken and acted on by an enzyme called NAPH oxidase and converts
it to superoxide and then superoxide dismutase converts it to H2O2
which is then converted by myeloperoxidase to HOCl (bleach)
 The first reaction generates superoxide which is a free
radical
o Metals (example: copper and iron)
 Copper and iron are usually bound
 If iron is left free it can generate free radicals: fenton reaction
allows iron to generate OH (most dangerous of all free radicals)
 Haemochromatosis
 Results in tissue damage because of free radical
formation
 Wilson's disease (excess copper)
 Also tissue damage from free radical formation
o Drugs and chemicals
 Acetaminophen goes to liver and converted by P450 system
and free radicals generated in process and can be damaging to
tissues
 High dose acetaminophen may be taken for suicide or
can just overdose accidentally causing liver cirrhosis
 CCl4 (carbon tetrachloride) is a chemical that can cause free
radical formation
 Free radical damage
o Peroxidation of lipids
 Damaging particularly the lipid membrane
o Oxidation of DNA and proteins
 Protein oxidation can cause damage to cell
 DNA oxidation can result in damage to cell and oncogenesis
cause it can introduce mutations
 Elimination of free radicals via 3 mechanisms
o Antioxidants
 Vitamin A, C, E
o Enzymes
 Superoxide dismutase (handles O2-)
  Glutathione peroxidase (handles OH with the help of
glutathione)
 Catalase (handles H2O2)
o Metal carrier proteins
 Transferrin in blood tightly binds iron to bring to liver and
macrophages (in liver and macrophages the iron is bound to ferritin)
 Free radical injury examples:
o CCL4
 Dry cleaning industry
 CCL4 gets into the blood and gets converted to CCl3 (free
radical) in the P450 system in the liver
 CCl3 damages hepatocytes
 First sign of reversible injury will be cell swelling - RER
will also swell and the ribosomes will pop off and protein
synthesis will be reduced
 Loss of apolipoprotein production (carry fat and
cholesterol) so if you have this then you will have the
classic histological finding of fatty change to the liver
o Reperfusion injury
 When cells are irreversibly damaged from infarction for
example, you will have enzymes that leak into the blood
 If blood is returned to the organ, for example, via the cath lab,
once blood returns now O2 and inflammatory cells have returned to
the tissue
 The inflammatory cells react with the dead tissue and the
presence of O2 can generate free radicals
 Free radicals will further damage the cardiac myocytes
 So after cath lab, the cardiac enzymes will continue to
rise

5. Amyloidosis
 
o Misfolded protein that deposits in extracellular space
o Damages tissues
 Multiple proteins can deposit as amyloid
o Beta pleated sheet configuration
o Congo red staining and apple-green birefringence under polarized
light
o Tends to deposit around blood vessels
 Deposition can be systemic or localized
o Systemic amyloidosis is divided into primary and secondary types
 Primary
 Systemic deposition of AL amyloid, derived from Ig light
chain
 Remember Ig light chain is a part of Ig
 Associated with plasma cell dyscrasias
  Plasma cell dyscrasia is any problem with the
plasma cells
 Plasma cells usually make sure that they
produce an equal amount of heavy chain and light chain
so that they can bind together to make Ig
 In dyscrasias, there is an overproduction of Ig
light chain which will leak into the blood and the light
chain becomes misfolded and deposit into the tissues
 Secondary
 Systemic deposition of AA amyloid derived from SAA
 SAA is an acute phase reactant that is increased in
chronic inflammatory states (Crohn's, UC, RA, chronic
osteomyelitis, etc.), malignancy (can result in low grade
chronic inflammatory state), and in Familial Mediterranean
fever (rare)
 Familial Mediterranean fever is a autosomal
recessive dysfunction of neutrophils that occurs in
people of Mediterranean origin
 Presents with episodes of fever and acute
serosal inflammation
 Can mimic MI, acute appendicitis, etc.
(serosal inflammation)
 High SAA during attacks deposits as AA amyloid
 Classic clinical findings (systemic)
 Nephrotic syndrome (greater than 3.5g of protein lost
in urine over 24h); kidney is the most common organ involved
 Restrictive cardiomyopathy (cannot fill heart properly
so cannot pump well so can lead to HF or arrhythmia)
 Tongue enlargement, malabsorption (bowel wall
thickened), and hepatosplenomegaly
 Diagnosis
 Requires tissue biopsy
 Abdominal fat pad and rectum are easily accessible
targets
 Damaged organs must be transplanted
 Amyloid cannot be removed
o Localized amyloidosis
 Amyloid deposition usually localized to single organ
 Senile cardiac amyloidosis
 Non-mutated serum transthyretin (this is the amyloid
in this case) deposits in heart
 Transthyretin is the second most common
protein in the blood
 Usually asymptomatic
 Present in 25% of individuals >80 years of age
 Familial amyloid cardiomyopathy
 Mutated serum transthyretin deposits in the heart
  Leads to restrictive cardiomyopathy
 5% of African Americans carry this mutated gene
 Type 2 diabetes
 Resistance to insulin in skeletal muscle and adipose
tissue
 Pancreas put out extra insulin until it burns out
 Amylin (byproduct of insulin) deposits in islets of
pancreas
 Histological finding in type 2 diabetes is deposition of
amyloid in the islets of the pancreas
 Alzheimer's disease
 A-beta amyloid deposits in the brain, forming amyloid
plaques
 Derived from beta-amyloid precursor protein (on
chromosome 21)
 Most individuals with Downs syndrome develop
AD by the age of 40 (early onset AD)
 Dialysis associated amyloidosis
 B2-microglobulin deposits in joints of patients who are
on dialysis
 MHC class 1 has an extracellular domain and a
transmembrane domain
 B2-microglobulin provides support to MHC class
1
 For patients on dialysis, B2-microglobulin is not
filtered well in the blood so it builds up in the blood
 Medullary carcinoma of the thyroid
 Tumour derived from C cells (neuroendocrine cells)
 Calcitonin deposits within the tumour since there is
overproduction of calcitonin
 Classic histologic description is tumour cells in an
amyloid background
 Fine needle aspiration is how we biopsy thyroid