Growth Adaptations, Cellulary Injury, and Cell Death

Question 1

Which 3 permanent tissue types only undergo hypertrophy?

Answer 1

Cardiac, skeletal, nerve

Question 2

One exception to the pathologic hyperplasia – > dysplasia – > cancer rule

Answer 2

Benign Prostatic Hyperplasia

Question 3

Describe the pathophys behind a decrease in cell size.

Answer 3

Ubiquitin proteosome degradation –intermediate filaments of the cytoskeleton are tagged with ubiquitin and destroyed by proteosomes. Following this is autophagy, which involves generation of autophagic vacuoles. These vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellular components.

Question 4

Exception to metaplasia which progresses to dysplasia and eventually result in cancer

Answer 4

Apocrine metaplasia of breast – no increased risk for cancer.

Question 5

Answer 5

This is keratomalacia. Vitamin A is necessary for the differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. In Vit A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium.

Question 6

Classic example of mesenchymal tissue undergoing metaplasia

Answer 6

Myositis ossificans, in which CT within muscle changes to bone during healing after trauma.

Question 7

Describe relationship between Vitamin A and immune system.

Answer 7

Vit A deficiency can also lead to immune system issues also as it is necessary for proper maturation of cells of immune system. For example, a 15;17 translocation disrupts the vitamin A receptor, causing cells to remain trapped in “blast” state – > PML.

Question 8

Which types of cells are more susceptible to ischemic injury? Less?

Answer 8

More susceptible: neurons

More resistant: skeletal muscle

Question 9

How does low oxygen delivery to tissue cause cellular injury?

Answer 9

Oxygen is the final electron acceptor in the ETC of oxidative phosphorylation. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production. The lack of ATP (essential energy source) leads to cellular injury.

Question 10

3 causes of hypoxia

Answer 10

Ischemia, hypoxemia, and decreased oxygen carrying capacity of blood.

Question 11

Causes of ischemia

Answer 11

Decreased venous drainage (e.g. Budd Chiari syndrome)

Shock –generalized hypotension results in poor tissue perfusion

Decreased arterial perfusion (e.g. atherosclerosis)

Question 12

Causes of hypoxemia

Answer 12

Hypoxemia is a low partial pressure of oxygen in the blood (PaO2 <60, SaO2 <90%):

Hypoventilation–increased PACO2 results in decreased PAO2

Diffusion defect–PAO2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis)

V/Q mismatch –blood bypasses oxygenated lung (circulation problem like a right to left shunt) or oxygenated air cannot reach blood (ventilation problem, e.g. atelectasis)

High altitude –decreased barometric pressure results in decreased PAO2

Question 13

Causes of decreased O2 carrying capacity

Answer 13

Hb loss or dysfunction such as:

Anemia: decrease in RBC mass; PaO2 normal and SaO2 normal

CO poisoning–CO binds Hb more avidly than oxygen causing PaO2 to be normal and SaO2 decreased.

Methemoglobinemia – Iron in heme is oxidized to Fe3+ which cannot bind oxygen; PaO2 normal, SaO2 decreased. Seen with both oxidant stress (e.g., sulfa and nitrate drugs) or in newborns. Classically find cyanosis with chocolate colored blood. Tx with IV methylene blue, which helps reduce Fe3+ back to Fe2+ state.

Question 14

How does low ATP disrupt key cellular functions?

Answer 14

Na-K pump resulting in sodium and water buildup in the cell – > swelling

Ca2+ pump, resulting in Ca buildup int he cytosol of the cell.

Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH which denatures proteins and precipitates DNA.

Question 15

Describe irreversible cell injury.

Answer 15

Hallmark: membrane damage.

Plasma membrane damage resulting in cytosolic enzymes leaking into teh serum (e.g., cardiac trops) and additional calcium entering the cell.

Mtc membrane damage results in both loss of the ETC (inner MTC membrane) and cytochrome c leaking into cytosol which activates apoptosis.

Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which, in turn, are activated by high intracellular calcium.

Question 16

Pyknosis

Answer 16

Nuclear condensation

Question 17

Karyorrhexis

Answer 17

Fragmentation

Question 18

Karyolysis

Question 19

Define necrosis.

Answer 19

Death of large groups of cells followed by acute inflammation due to some underlying pathologic process** never physiologic!

Question 20

Coagulative necrosis

Answer 20

Necrotic tissue that remains firm; cell shape and organ structure are preserved by coagulation of proteins but the nucelus disappears. Characteristic of ischemic infarction of any organ EXCEPT brain. Areas of infarcted tissue often wedge shaped and pale. Red infarction arises if blood re-enters a loosely organized tissue.

Question 21

Liquefactive necrosis

Answer 21

Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction. Characteristic of brain infarction (proteolytic enzymes from microglial cells); abscesses (proteolytic enzymes from neutrophils) and pancreatitis (proteolytic enzymes from pancreas liquefy PARANCHYMAL tissue of pancreas).

Question 22

Gangrenous necrosis

Answer 22

Coag necrosis that resembles mummified tissue (Dry gangrene). Characteristic of ischemia of lower limb and GI tract. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).

Question 23

Caseous necrosis

Answer 23

Soft and friable necrotic tissue with cottage cheese like appearance. Combination of coagulative and liquefactive necrosis characteristic of granulomatous ifnlammation due to TB or fungal infections.

Question 24

Fat necrosis

Answer 24

Necrotic adipose tisseu with chalky white appearance due to deposition of calcium charactersitic of trauma to fat and pancreatitis mediated damage of peripancreatic fat. Fatty acids released by trauma or lipase joins with calcium via process called SAPONIFICATION. Saponification is an example of dystrophic calcification i nwhich calcium deposits on dead tissues. The necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate. Metastatic calcification occurs when high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis.)

Question 25

Fibrinoid necrosis

Answer 25

Necrotic damage to blood vessel wall –leaking of proteins including fibrin into vessel wall results in bright pink staining of the wall microscopically, characteristic of malignant HTN and vasculitis. Could also occur in PREECLAMPSIA d/t fibrinoid necrosis of placenta.

Question 26

Intrinsic MTC pathway and caspases

Answer 26

Cellular injury, DNA damage, or decreased hromonal stimulation (e.g., menstruation) leads to inactivation of Bcl2. The lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases.

Question 27

Extrinsic receptor ligand pathway and caspases

Answer 27

FAS ligand binds FAS death receptor (CD95) on the target cel, activating caspases (e.g., negative selection of thymocytes in thmus). TNF then binds TNF receptor on the target cell, activating caspases.

Question 28

Cytotoxic CD8 T cell-mediated pathway

Answer 28

Perforins secreted by CD8+ T cell create pores in membrane of target cell. Granzyme from CD8+ T cell enters pores and activates caspases. CD9 T cell killing of virally infected cells is an example.

Question 29

How does inflammation generate free radicals?

Answer 29

NADPH oxidase generates superoxide ions during oxygen-dependent killing by neutrophils

Question 30

Describe CCl4 free radical injury.

Answer 30

Carbon tetrachloride is an organic solvent used in the dry cleaning industry that is converted to CCl3 free radical by P450 system of hepatocytes. This results in cell injury with swelling of the RER; consequently, ribosomes detach which imapirs protein synthesis. Decreased apolipoproteins leads to fatty change in the liver.

Question 31

What is amyloid?

Answer 31

Amyloid is a misfolded protein that deposits in the extracellular space, thereby damaging tissues. Multiple proteins can deposit as amyloid. Shared features include beta-pleated sheet ocnfiguration and congo red staining and apple green birefringence when viewed under polarized light.

Question 32

Most common organ involved in systemic amyloidosis

Answer 32

Kidney – results in nephrotic syndrome. Can also be heart causing restrictive cardiomyopathy or arrhythmia. Additionally, tongue enlargement, malabsorption and hepatosplenomegaly.

Question 33

Clinical findings of systemic amyloidosis

Answer 33

SAA is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever. FMF is due to a dysfunction of neutrophils (AR) and occurs in persons of Mediterranean origin. This presents with episodes of fever and acute serosal inflammation which can mimic appendicitis, arthritis, or MI. High SAA during attacks deposits as AA amyloid in tissues.

Question 34

Senile cardiac amyloidosis

Answer 34

Non-mutated serum transthyretin deposits in the heart. This is usually asymptomatic and present in 25% of individuals >80 y.o.

Question 35

Familial amyloid cardiomyopathy

Answer 35

Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy (which leads to heart failure since it cant pump as well). 5% of African Americans carry teh mutated gene.

Question 36

Dialysis-associated amyloidosis

Answer 36

B2 microglobulin deposits in joints. B2 microglobulin is a structural component of MHC Class I.

Question 37

Which tumor is associated with amyloidosis?

Answer 37

Medullary CA of the thyroid. Calcitonin, produced by C cells, deposits within the tumor.

Question 38

Which free radical is the most damaging?

Answer 38

Hydroxyl (OH)

Question 39

How does ionizing radiation generate free radicals?

Answer 39

Water gets hydrolyzed to hydroxyl free radical.

Question 40

Explain the pathophys behind Hemochromatosis.

Answer 40

The buildup of Fe2+ generates hydroxyl free radicals via the Fenton reaction. These free radicals are what deposit in the various body tissues, causing the damage seen in hemochromatosis.

Question 41

Explain the pathophys behind Wilson’s disease.

Answer 41

The buildup of copper generates free radicals which deposit in the body tissues, causing the damage seen.

Question 42

How do free radicals cause cellular injury?

Answer 42

Peroxidation of lipids (esp lipid membranes) and oxidation of DNA and proteins. DNA damage is implicated in aging and oncogenesis.

Question 43

What 3 ways does the body get rid of free radicals?

Answer 43

Antioxidants (e.g., glutathione and vitamins A, C, and E)

Enzymes: SOD in mtc converts O2 to H202

Glutathione peroxidase in mtc: 2GSH + free radical –> GS-SG and H2O

Catalase in peroxisomes converts hydrogen peroxide to oxygen and water.

Metal carrier proteins such as transferrin and ceruloplasmin

Question 44

Why might you see an increase in cardiac enzymes after an MI has already occurred and the pt is being treated?

Answer 44

Reperfusion injury –the return of blood (which contains oxygen) to ischemic tissue results in the production of oxygen-derived free radicals, which further damages tissue.