Pathoma Lecture Notes

385 Pages·2017·10.45 MB·English

Pathoma Lecture Notes
Chapter 1: Growth Adaptations,
Cellular Injury, and Cell Death
1.1 Growth adaptations
Hyperplasia Metaplasia Dysplasia
- Increase in cell number - Change in cell type due to - Proliferation of pre-
reprogramming of stem cell cancerous cells
- Reversible - Reversible - Reversible
- Pathologic hyperplasia - Can progress to dysplasia - Can progress to cancer
can progress to cancer and cancer
- BPH don't increase risk - Apocrine metaplasia don't
of cancer increase risk of breast cancer
- Etiology: - Etiology: - Etiology:
• Physiologic (ex- • Vit A deficiency • Long standing
pregnancy) (keratomalacia, pathologic hyperplasia
• Pathologic (ex - …) myositis ossificans) or metaplaisa
• Cellular stress (barret's
esophagus)
Processes Properties
Hyperplasia •Usually, hyperplasia and hypertrophy occur together
and • Permanent cell undergro hypertrophy only– cardiac myocytes, skeletal
Hypertrophy cells, and nerves.
• Pathologic hyperplasia (not physiologic ex- pregnancy) can progress to
dysplasia and cancer.
• Exception is benign prostatic hyperplasia (is pathologic but does not
increase risk of cancer).
Atrophy • can occur by decrease in cell number (apoptosis) or decrease in cell size.
• Decrease in cell size occurs by – ubiquitin-proteosome degradation of
cytoskeleton and autophagy of cellular components
Metaplasia • change in cell type.
•Mostly affects surface epithelium. Ex – barret’s esophagus (change from
squamous to columnar)
•MOA: occurs by reporgramming of stem cells
• Reversible
• Can progress to dysplasia and cancer. Ex – Barret’s. Exception –
Apocrine metaplasia doesn’t increase risk of breast cancer. Apocrine
metaplasia seen when fibrocystic changes in breast occur.
• Vitamin A deficiency can result in metaplasia. Ex – keratomalacia and
myositis ossificans.
•Mesenchymal tissue can undergo metaplasia (ex – bone, blood vessel,
fat etc). ex – myositis ossificans – inflammation of skeletal muscle reads
to metaplasia to bony tissue.
Cellular injury Page 1.1
Fig – myositis ossificans
Dysplasia • disordered cell growth; proliferation of precancerous cells. Ex - Cervical
intraepithelial neoplasia
•Arises from longstanding pathologic hyperplasia or metaplasia
• Reversible
• If dysplasia persists, it can progress to cancer.
Aplasia • Failure of cell production during embryogenesis. Ex – unilateral renal
agenesis (failure to make 1 kidney)
Hypoplasia • decrease in cell production in embryogenesis. Results in relatively small
organ. Ex – streak ovary in Turner syndrome.
Extras – Vitamin A is necessary for maturation of immune system. 15-17 translocation in
pt genome causes acute promyelocytic leukemia. The translocation causes mutation in vit-
A receptor – retinoic acid receptor. Mutation of receptors cause immune cells to be
trapped in blast stage. Treatment for Promyelocytic leukemia is all trans retinoic acid
(drug) which can bind to mutated receptor. Cells can mature and be neutrophil.
• Vitamin A is necessary for maintainence of special epithelial tissue in body – ex –
conjucitva of eye. Conjuctiva is a thin delicate membrane that covers eye. Deficiency
of vit A can result in metaplasia of cells in conjucitva where cells thicken which is
called keratomalacia.
• Fig – keratomalacia.
Cellular injury Page 1.2
1.2 Cellular injury
1. What is cellular injury?
- If cellular stress overcomes cell's ability to adapt, then cell gets injured.
2. What does cellular injury depend on?
- Type of stress
- Severity
- Type of cell - neurons can withstand hypoxia only for 3-5mins. Skeletal muscle can withstand for a
very long time.
3. What are causes of hypoxia(low O2 delivery to tissue)?
- ischemia,
- hypoxemia (PaO2<60 mm Hg),
- low O2 carrying capacity (ex - anaemia, CO poisoning, methmeglobinemia)
4. What is shock? What are it's causes?
- Shock is a generalized decreased perfusion of a vital organ. Can occur by hypovolemia,
cardiogenic, spetic, neurogenic, anaphylactic causes
5. What is Budd chiari syndrome?
- Blockade of hepatic vein can result in hepatic infraction, aka budd chiari syndrome.
- Most common cause of budd chiari syndrome is polycythemia vera. Polycythemia vera is a disease
with too much RBC which leads to clot formation. Another cause is lupus.
6. What will PaO2 and O2 sat be in anaemia?
- PaO2 and O2 sat will be normal in anaemia
7. What will PaO2 and O2 sat be in CO poisoning?
- PaO2 will be the same and O2 sat will reduce. CO binds to Hb 100 times stronger than O2.
8. What are signs/symptoms of CO poisoning?
- Early sign is headache (ask a pt if he has headache if you suspect CO poisoning). Pt may have
cherry red color skin.
9. What is methemoglobinemia?
- Normally, Fe in hemoglobin is in 2+ state and can bind to O2. If it gets oxidized to 3+, it can't bind
to O2 and this is methemoglobinemia.
10. What will PaO2 and O2 sat be in methemoglobinemia?
- PaO2 will be the same and O2 sat will reduce.
11. What are causes of methemoglobinemia?
- Oxidative stress - sulfa drugs, nitrate drugs. Also seen in newborns because their machinery to
reduce Fe 3+ isn't good.
12. What are signs/symptoms of methemoglobinemia?
- Cyanosis with chocolate colored blood.
13. What is treatment of methemoglobinemia?
Cellular injury Page 2.1
13. What is treatment of methemoglobinemia?
- IV methylene blue - it generates moderators that will reduce Fe3+
14. What are consequences of low ATP in cell?
- Lactic acidosis due to lots of glycolysis
- Disrupted Na/K pump result in Na accumulation and resulting water retention in cell
- Disrupted Ca pump result in Ca accumulation and random enzyme activation in cytosol
15. What are reversible finding in cell of low ATP?
- Hallmark is cellular swelling - loss of microvilli, membrane blebing as it pulls away from the
cytoskeleton, swelling of RER and ribosomes fall off (low protein synthesis)
16. What are irreversible finding in cell of low ATP?
- Hallmark is membrane damage. End result is cell death.
- Cellular enzymes leak out (liver enzyme in hepatitis and cardiac enzyme in MI) and intracellular Ca
increases.
- Cytochrome C from mitochondria leaks out to cytosol and activates apoptosis
- Lysozome enzymes will leak out and digest the cells. Ca in cytosol activates them.
Cellular injury Page 2.2
1.3 Cell death
1. What is morphologic hallmark of cell death?
- Loss of nucleus
2. What are the steps by which nucleus is lost?
• Pyknosis - shrinking of nucleus
• Karyorrhexis - breaking of nucleus to big pieces
• Karyolysis - big nuclear pieces broken down to molecular building blocks
3. Explain necrosis
• Necrosis occurs as a result of acute inflammation to a large group of cells and is always pathologic
• Types
1. Coagulative necrosis
2. Liquefactive necrosis
3. Gangrenous necrosis - dry and wet
4. Caseous necrosis
5. Fat necrosis
6. Fibrinoid necrosis
4. Describe coagulative necrosis
- Cell and organ structure is preserved by coagulation of cellular proteins
- Characteristic of ischemic infarction of any organ except brain
Cellular injury Page 3.1
Fig - right is normal glomerulus and left is coagulative necrosis of glomerulus. Note cellular
and organization structure is preserved with loss of nucleus.
- Area of infracted tissue is often wedge shaped and pale. Wedge points to the blocked blood
vessel.
5. When does red infraction (hemorrhagic infraction) occur?
• Red infraction occurs when blood reenters a loosely organized tissue. Ex- ischemia of testis, lungs.
(is red infraction a type of coagulative necrosis?)
6. Describe liquefactive necrosis
- Necrosis in which enzymatic lysis of cells and proteins result in liquefaction
- Characteristic of brain (microglial cells destroy the tissue), abscess (neutrophils contain hydrolytic
enzyme that destroy the tissue), and pancreatitis (pancreatic enzyme digest the pancreas and
liquify; however surrounding fat will have fat necrosis)
7. Describe gangrenous necrosis
- It is coagulative necrosis that resembles mummified tissue (dry gangrene). If infection occurs on
dry gangrene, liquifactive necrosis occurs and is called wet gangrene.
- Characterstic of ischemia of lower limb and GI tract
8. Describe caseous necrosis
- It is soft, friable necrosis with 'cottage cheese' like appearance
- It's liquefactive necrosis with debris that thickens the soup to make it cheese like
- Characteristic of granulomatous inflammation of TB or fungal infection (fungal cell wall and
micobacterium thickens the soup).
Cellular injury Page 3.2
Fig - caseous necrosis
9. Describe fat necrosis
- Necrotic fat with Chalky white appearance due to deposition of Ca. MOA- When fat cells die by
trauma or when fat is broken down by lipase, fatty acids are released. In presence of Ca,
saponification occurs which gives it the chalky white apperance. Ca accumulation happens by
dystropic calcification.
- Characteristic cases - trauma to fat (ex - as in car accident trauma in breast), pancreatitis mediated
damage of peripancreatic fat
Fig - fat necrosis around pancreas
10. What is fibrinoid necrosis
- Necrotic damage to blood vessel
- Proteins leak into vessel wall which results in bright pink staining of vessel wall in H&E
- Characteristic of malignant hypertension and vasculitis. Pre-eclampsia can cause fibrinoid necrosis
of placenta. (benign HTN is chronic low increase in BP that cause slow damage. Malignant
hypertension is sudden super elevated BP that is a medical emergency- findings such as
headache, renal failure, papilledema). Super high BP in malignant HTN can kill vessel wall cells.
11. What are mechanism by which calcium can deposit in human tissue?
- Dystropic calcification
- Metastatic calcification
12. What is dystropic calcification?
- It's a mechanism by which Ca deposits in a human body (it's abnormal as calcium is not supposed
to just randomly accumulate). Mechanism - when there's a dead tissue, calcium can accumulate
even if serum Ca is normal. Ex - in fat necrosis, in tumor as center of tumor might not get enough
blood supply and die.
13. What is metastatic calcification?
Cellular injury Page 3.3
13. What is metastatic calcification?
- Serum Ca or PO4 is elevated. This elevated stuff can force Ca to accumulate on tissue. It doesn't
mean that pt has metastatic cancer.
Apoptosis
14. Explain apoptosis. (apoptosis means falling of leaves)
- It is purposeful, energy dependent killing of small group of cells
- Examples - Endometrial shredding during menstruation, removal of cells in embryogenesis, CD8
cell mediated killing of virally infected cells
15. What is mechanism of apoptosis?
- Cell shrinks (and becomes eosinophilic due to concentration of cytoplasm) and nucleus also
shrinks and fragments.
- Apoptotic bodies fall from cell like leaves fall from tree. Then they are eaten bym acrophage. No
inflammation occurs
Fig - compare the pink apoptotic cell to it's surrounding neighbors
16. What is biochemical pathway leading to apoptosis?
- Caspase activation is the key step.
○ Caspases activate proteases that break down cytoskeleton.
○ Caspases also activate endonucleases that break down nucleus.
17. What 3 pathways lead to caspase activation? (HY)
- Intrinsic mitochondrial pathway - Bcl2 is a protein whose function is to stabilize mitochondrial
membrane so that cytochrome C from mitochondria can't leak out. Due to membrane damage
(cellular injury), DNA damage, or decreased hormonal stimulation of cell (ex- endometrial cells in
lack of estrogen), Bcl2 can be inactivated. Leakage of cytochrome C will then activate caspase.
- Extrinsic receptor-ligand pathway -
○ Example- FAS ligand binds to FAS death receptor(CD95) on target cell and target cell dies
via activation of caspases. Case report - new CD8+ T cells from bone marrow undergo
positive selection (I.e., if they can bind to self antigen on MHC-I molecule, they get to live)
and negative selection (i.e., if they bind to self antigen on MHC-I molecule very strongly,
they die) in thymus. The killing of these young T-cells in negative selection happens by
binding of FAS ligand to FAS death receptor on T-cells.
○ Another example - TNF binds to TNF receptor on target cell and cell dies.
- Cytotoxic CD8+ T-cell pathway - When CD8+ cells recognize foreign antigen on MHC-I receptors,
they release perforins that make holes on target cell. Then, they release granzyme that enter
target cell and activate caspases.
Cellular injury Page 3.4