Growth Adaptations, Cellular Injury, and Cell Death (Pathoma)

Question 1

Hypertrophy

Answer 1

Increase in size of cells (i.e. cardiac muscle cells in HTN)

Involves: Gene actiation, protein synthesis, and production of organelles.

Often occures w/ hyperplasia (i.e. pregnant uterus)

Permanent tissues can only undergo hypertrophy (i.e. cardiac myocytes, skeletal muscle, and nerves)

Question 2

Hyperplasia

Answer 2

Increase in number of cells

Involves production of new cells from stem cells (i.e. Benign Prostatic Hyperplasia)

Often occures w/ hypertrophy (i.e. pregnant uterus)

Cannot occur in permanent tissues.

Pathologic hyperplasia can progress to dysplasia and cancer (i.e. endometrial hyperplasia; exception is BPH)

Question 3

Atrophy

Answer 3

Decrease in stress –> decrease in size.

Occurs via size or number of cells (both called atrophy and occur together)

Decrease in number occurs via apoptosis

Decrease in size occurs via Ubiquitin proteosome degredation of cytoskeleton or autophagy of cellular components

Question 4

Decrease in cell number occurs via?

Answer 4

Apoptosis

Question 5

Decrease in cell size occurs via

Answer 5

Ubiquitin proteosome degredation of cytoskeleton or autophagy of cellular components

Question 6

Metaplasia

Answer 6

Change in stress on organ leads to change cell type.

Most commonly involves surface eptithelium.

Metaplastic cells are better able to handle the new stress

Example: Barrert esophagus changing from squamous to columnar non ciliated mucinous epithelium in response to GERD to better handle stomach acid)

Occurs via reprogramming of stem cells which then produce the new cell type (this is reversible –> i.e. treating GERD –> reverses Barrett’s esophagous)

Under persistent stress metaplasia can progress to dysplasia and eventually cancer (i.e. Barrett’s; key exception is apocrine metaplasia of the breast)

Vitamin A deficiency can result in metaplasia (keratomalacia or M3 leukemia).

Mesenchymal tissues can undergo metaplasia (i.e. myositis ossificans)

Question 7

Deficiency of what can result in metaplasia?

Answer 7

Vitamin A.

I.e. keratomalacia or Acute Promyelocytic Leukemia (M3))

Thus Rx for M3 is All-Trans-Retinoic-Acid (ATRA) is a Vit. A derivative.

Question 8

Keratomalacia

Answer 8

Vit. A deficiency causes goblet cell/columnar epithelium of conjunctiva to undergo metaplasia into keratinizing squamous epithelium. Becomes thick and causes blindness

Think Nick Kristof –> Helen Keller International –> Vitamin A capsules and GMO sweet potatoes

Dry eyes (xeroopthalmia) can also lead to destruction of the cornea (keratomalacia) and blindness

Question 9

Myositis ossificans

Answer 9

Inflammation of skeletal muscle (i.e. after trauma) can cause skeletal muscle to undergo metaplasia into bone.

Don’t be tricked into picking osteosarcoma (myositis ossificans is not connected to bone)

Question 10

Dysplasia

Answer 10

Disordered cellular growth

Proliferation of precancerous cells

Arises from longstanding pathologic hyperplasia or metaplasia

Key is REVERSIBLE

If stress persists, dysplasia progresses to carcinoma (irreversible –> key distinction)

Question 11

Aplasia

Answer 11

Failure of cell production during embryogenesis

I.e. Renal agenesis

Question 12

Hypoplasia

Answer 12

Decrease in cell production during embryogenesis

Results in relatively small organ

I.e. streak ovary in Turner Syndrome

Question 13

Cellular injury

Answer 13

Stress exceeds cell’s ability to adapt

Likelihood depends on type of stress, its severity, and type of cell affected

Neurons are highly susceptible to ischemic injury vs. skeletal muscle is resistant

Slowly developing ischemia results in atrophy (Renal Artery Stenosis) vs. Acute ischemia (renal artery embolus) results in injury

Common causes of injury: inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.

Question 14

Hypoxia

Answer 14

Low oxygen delivery to tissue

Oxygen needed to run ETC and make ATP.

Due to: ischemia (poor blood flow due to atherosclerosis, venous thrombosis, or shock), hypoxemia (i.e. COPD), or decreased O2 carrying capacity (i.e. severe anemia).

Question 15

Budd-Chiari Syndrome

Answer 15

Thrombus forms in Hepatic Vein causing ischemia of liver. and infarction in liver parenchyma and death.

MCC is Polycythemia Vera

Another classic example is Lupus anticoagulant.

Question 16

Ischemia causes?

Answer 16

Atherosclerosis (i.e. angina)

Venous Thrombosis (i.e. Budd-Chiari Syndrome)

Shock (hypoperfusion in hypovolemia etc.)

Question 17

Hypoxemia

Answer 17

Low partial pressure of O2 in blood (PaO2 PAO2–> PaO2 –> SaO2

Thus any change of FiO2 such as altitude; or PA02 decrease due to increased PACO2 in hypoventilation or COPD, would cause hypoxemia and thus eventually SaO2

Causes: Altitude, hypoventilation, diffusion defect, and V/Q mismatch

Question 18

Decreased O2 carrying capacity

Answer 18

Arises w/ Hb loss (anemia –> normal PaO2 and SaO2!) or dysfunciton (CO poisoning or methemoglobinemia)

Question 19

CO poisoning

Answer 19

Binds Hb more avidly than O2

PaO2 nromal, SaO2 decreased (not on pulse-oximeter however)

Exposures include smoke from fires and exhaust from cars or gas heaters.

Classic finding is cherry red appearance of skin.

Early sign is headache (key sign in taking hx), significant exposure can lead to coma and death.

Question 20

Methemoglobinemia

Answer 20

Iron in heme is oxidized to Fe3+ which cannot bind O2 (Fe2+ binds O2!)

PaO2 normal, Sa02 is decreased

Seen w/ oxidant stress (i.e. sulfa and nitrate drugs or in newborns

Classic finding is cyanosis w/ chocolate-covered blood.

Rx: I.V. Methylene Blue (reduces Fe3+ back to Fe2+)

Question 21

Low ATP disrupts what key cellular functions?

Answer 21

Na/K pump –> cellular swelling
Ca++ pump –> activates unwanted enzymes –> apoptosis
Aerobic glycolysis –> poor ATP production and lactic acid buildup –> DNA and protein denaturation at low pH’s

Question 22

Reversible Injury

Answer 22

Cellular Swelling! due to loss of Na/K pump.

Leads to loss of microvilli (key in small bowel), membrane blebbing (loss of integrity of cytoskeleton due to swelling) , and swelling of RER (loss of loosely associated ribosomes)

Question 23

Irreversible injury

Answer 23

Long standing

Hallmark is Membrane Damage
1.) Plasma membrane –> enzymes from inside cell –> i.e. cardiac troponin test in M.I. or AST/ALT in liver damage

2. ) Mitochondrial Membrane –> disrupts ETC on inner mitochondrial membrane and releases cytochrome C –> activation of apoptosis
3. ) Lysosome membrane –> release of lytic enzymes and join w/ intracellular Ca++ and causes damage of cellular organelles

End result is cell death

Question 24

Morphologic hallmark of cell death?

Answer 24

Loss of nucleus!!!

Occurs via pyknosis (shrinking into ink dot), karyorrhexis (breaking of nucleus into big pieces) and karyolysis (broken into small building blocks)

Question 25

Two mechanisms of cell death

Answer 25

Necrosis (Cellular homicide) and Apoptosis (Cellular suicide)

Question 26

Necrosis

Answer 26

Death of a large group of cells followed by ACUTE INFLAMMATION (i.e. neutrophilia following MI)

Due to underlying pathologic process; never physiologic

Severeal Types:

1. ) Coagulative Necrosis - tissue remains firm. Characteristic of ischemic infarction in any organ except brain.
2. ) Liquefactive Necrosis - tissue becomes liquified by enzymatic degredation (brain infarction, abscess, pancreatitis)
3. ) Gangrenous Necrosis - (resembles mumified tissue –> lower limb and GI; wet or dry)
4. )Caseous Necrosis - Soft and friable (cottage-cheese) from combo of liquifactive and coagulative. Granulomas (TB vs. Fungal)
5. ) Fat Necrosis - Chalky white appearance due to calcium deposition. Due to damage to tissue and subsequent saponificaiton.
6. ) Fibrinoid necrosis - damage to blood vessel wall. Bright pink. Malignant HTN or vasculitis.

Question 27

Area of infarcted tisse is often what shape?

Answer 27

Wedge shaped and pale

Due to anatomy of branching vessels being most common thrombus point.. Wedge points to area of occlusion.

Question 28

Red infarction arises if?

Answer 28

Blood reenters the tissue and a loosely organized tissue.

Classic example is testicular torsion causing venous collapse and subsequent ischemia. Artery remains patent causing red infarction.

Question 29

Coagulative necrosis

Answer 29

Necrotic tissue remains firm –> cell shape and organ structure are preserved but nucleus dissapears.

Characteristic of ischemic infarction anywhere except brain.

Area is often pale and wedge shaped.

Red infarction if reperfused and loose tissue.

Question 30

Liquefactive Necrosis

Answer 30

Necrotic tissue becomes liquified due to enzymatic lysis of cells and protein

Characteristic of:

1. )Brain Infarction - proteolytic enzymes from microglial cells
2. ) Abscess - proteolytic enzymes of neutrophils
3. ) Pancreatitis - proteolytic enzymes of the pancreas

Question 31

Gangrenous Necrosis

Answer 31

Coagulative necrosis that resembles mummified tissue (dry gangrene)

Characteristic of ischemia of lower limb (diabetics –> popliteal atherosclerosis –>ischemia –> gangrenous necrosis ) and small bowel.

Wet gangrene if there is a superimposed infection of dead tissue causing concurrent liquefactive necrosis.

Question 32

Caseous Necrosis

Answer 32

Soft and friable tissue w/ cottage cheese appearance

Combination of coagulative and liquefactive necrosis

Characteristic of granulomatous inflammation due to TB or fungal infections

Question 33

Fat Necrosis

Answer 33

Necrotic adipose tissue w/ chalky-white appearance due to calcium.

Characteristic of trauma to fat (i.e. big boobed runner –> important for masses and mammogram ddx), or pancreatitis-mediated damage of peripancreatic fat.

Occurs via saponification –> fatty acids released by trauma or lipase join w/ calcium. (example of dystrophic calcification)

Question 34

Two mechanisms of calcium deposition in tissue

Answer 34

Dystrophic calcification - Damaged tissue serves as nidus w/ subsequent calcium depositon. Normal serum calcium and phosphate.

Metastatic calcification –> High serum Ca or PO4 causes deposit of calcium throughout body (doesn’t have to be metastatic cancer, i.e. hyperparathyroidism!)

Question 35

Fibrinoid Necrosis

Answer 35

Damage to blood vessels

Has bright pink staining.

Indicative of malignant HTN or vasculitis.

Know that fibrinoid necrosis of placenta is common in preecclampsia (along w/protienuria). Common test question.

Caused by leaking of proteins (i.e. fibrin) into vessel wall

Question 36

Apoptosis

Answer 36

Energy-dependent, genetically programmed cell death.

Ivolves single cells or small groups.

Examples: Endometrial shedding, removal of cells during embryogenesis, CD8+ T cell-mediated killing in virally infected cells.

Morphology: (translation is falling of leaves)

• Dying of cell shrinks (becomes eosinophillics)
• Apoptotic bodies fall from cell are removed by macrophages; NO INFLAMMATION

Mediated by caspases –> activate proteases (break down cytoskeleton) and endonucleases (break down DNA)

2 Pathways:

Intrinsic mitochondrial pathway. Cellular injury, DNA damage, decreased hormonal stimulation inactivates Bcl2. Cytochrome C leads from inner mitochondrial matrix into cytoplasm.

Extrinsic receptor-ligand pathway. FAS ligand binding FAS death receptor (CD95). (This is key for negative selection of T cells in Thymus )or TNF binds TNF receptor on target cell.

Cytotoxic CD8+ T-cell mediated pathway. CD8’s release perforin to form holes and granzymes to activate caspases. (i.e. CD8 killing virally infected cell.)

Question 37

Generation of free radicals

Answer 37

Physiologic:
Oxidative phosphorylation

Pathologic
Ionizing Radiation

Inflammation (Neutrophils w/ oidative burst using NADPH oxidase making superoxide)

Metals (copper and Iron –> fenton reaction if left unbound. Wilson’s disease or hemochromatosis –> mechanism of pathology)

Drugs and Chemicals (Acetaminophen and CCl4)

Question 38

Free radical damage

Answer 38

Peroxidation of lipids

Oxidation of DNA (oncogenesis!) and proteins

Question 39

Elimination of free radicals

Answer 39

Antioxidants (Vitamin A,C, and E)

Enzymes (Superoxide Dismutase, Glutathione peroxidase, and Catalase)

Metal carrier proteins (i.e. transferrin to carry iron in blood)

Question 40

Enzymes that neutralize free radicals

Answer 40

Superoxide dismutase (O2- –> H202)

Glutathione peroxidase (in mitochondria) 2GSH + free radical –> GS-SG and H202

Catalase (in peroxisome) H202 –> 02 and H20

Question 41

CC:l4 Free radical injury

Answer 41

CCL4 is converted to the free radical CCL3 in the p450 system of the liver.

This damage causes cellular swelling and ribosomes to be kicked off the RER thus decreasing protein sythesis causing lack of apoliproteins –> fats to accumulate in the liver –> fatty liver.

Think dry cleaner.

Question 42

Reperfusion injury

Answer 42

I..e Post MI

Irreversible injury to cells –> cellular contents released (troponins rise) –> reperfusion –> inflammatory cells along with reperfused O2 –> reperfusion injury –> cardiac troponins continue to rise

Question 43

Amyloid

Answer 43

Misfolded protein that can be deposited in extracellular space thereby damaging tissues.

Multiple proteins can deposit as amyloid

Beta-sheet configuration

Congo red staining and apple-green birefringence under polarized light.

Often around blood vessels

Deposition can be systemic or localized.

Question 44

Primary Amyloidosis

Answer 44

Systemic deposition of AL amyloid which is derived from immunoglobin light chain.

Associated w/ plasma cell dyscrasias (i.e. MM)

Classic clinical findings:

Kidney is most common affected organ (usually nephrotic syndrome).

Restrictive cardiomyopathy, or arrhythmias

Tongue enlargement, malabsorbtion, and h/smegaly

Dx: biopsy –> esp. abdominal fat pad and rectum

Damaged organs must be tranplanted –> can’t be removed.

Question 45

Secondary Amyloidosis

Answer 45

Systemic deposition of AA amyloid derived from SAA

SAA is an acute phase reactant that is increased in chronic inflammatory states (i.e. SLE, RA, etc.), malignancy, and Familial Mediterranean Fever.

Classic clinical findings:

Kidney is most common affected organ (usually nephrotic syndrome).

Restrictive cardiomyopathy, or arrhythmias

Tongue enlargement, malabsorbtion, and h/smegaly

Dx: biopsy –> esp. abdominal fat pad and rectum

Damaged organs must be tranplanted –> can’t be removed.

Question 46

Familial Mediterranean Fever

Answer 46

Dysfunction of neutrophils (AR); occurs of Mediterranean origin

Presents w/ episodes of fever and acute serosal inflammaiton (i.e.pericarditis, arthritis)

High SAA during attacks depostis AA

Question 47

Senile cardiac amyloidosis

Answer 47

Non-mutated serum transthyretin deposits in heart

Usually asymptomatic

Present in 25% of individuals >80y.o.

Question 48

Familial Amyloid Cardiomyopathy

Answer 48

Mutated serum transthyretin deposits in heart

Leads to restrictive cardiomyopathy

5% of AA carry mutated gene

Question 49

Non-insulin dependent DM II

Answer 49

Amylin deposits in the islets of the pancreas

Derived from insulin

Question 50

Alzheimer’s disease

Answer 50

Abeta deposits in brain, forming amyloid plaques

Derived from Beta-amyloid precursor protein (on chromosome 21 –> early onset alzheimer’s in Down’s

Question 51

Dialysis-associated amyloidosis

Answer 51

Beta2-microglobulin deposits in joints in dialysis patients.

Question 52

Medullary carcionoma of thyroid

Answer 52

Calcitonin deposits within tumor

Tumor of C-cells

i.e. fine needle biopsy of thyroid mass will show tumor cells w/ amyloid background.