Growth Adaptations, Cellular Injury and Cell Death

Question 1

Mechanism of cellular hypertrophy

Answer 1

Increased cellular stress -> increased gene activation -> increased protein synthesis and production of organelles

Question 2

Permanent tissues that can only undergo hypertrophy

Answer 2

Cardiac myocytes, skeletal muscle and nerve

Question 3

Pathologic hyperplasia that does NOT have an increased risk for progression to dysplasia and cancer

Answer 3

Benign prostatic hyperplasia

Question 4

Mechanisms of cellular atrophy

Answer 4

Apoptosis decreases cell number and decreased cell size occurs via ubiquitin-proteosome degradation of cytoskeletal proteins and vacuole autophagy of organelles.

Question 5

Mechanism of metaplasia

Answer 5

Change in type of stress -> reprogramming of stem cells -> change in cell type to better hand stress. This most commonly occurs in surface epithelium.

Question 6

3 types of epithelium

Answer 6

Squamous (keratinizing vs. non-keratinizing), columnar and transitional (urothelium).

Question 7

Barrett esophagus metaplasia. What happens if the patient is treated and acid exposure decreases?

Answer 7

Esophageal non-keratinized squamous epithelium changes to columnar, non-ciliated, mucinous epithelium in response to increased gastric acid exposure in the esophagus. Remember that metaplasia is reversible and the epithelium can return to normal if the exposure is eliminated.

Question 8

Type of metaplasia that does not increase the risk for cancer?

Answer 8

Apocrine metaplasia associated with fibrocystic changes in the breast.

Question 9

Vitamin A deficiency metaplasia

Answer 9

Vitamin A is necessary for maintenance of the specialized squamous epithelium of the eye (conjunctiva). When vitamin A is deficient, the epithelium undergoes metaplasia

Question 10

Myositis ossificans metaplasia

Answer 10

Inflammation of the skeletal muscle from trauma that results in metaplasia to bone within the muscle.

Question 11

Consequence of longstanding pathologic hyperplasia or metaplasia?

Answer 11

Dysplasia, which is a disordered cellular growth pattern.

Question 12

What is the distinction between dysplasia and cancer?

Answer 12

Cancer is irreversible and dysplasia is reversible.

Question 13

Classic example of aplasia

Answer 13

Unilateral renal genesis from failure of cell production during embryogenesis.

Question 14

Classic example of hypoplasia?

Answer 14

Streak ovary in Turner syndrome from decreased cell production during embryogenesis.

Question 15

When does cellular injury occur vs. adaptation?

Answer 15

Injury occurs when the insult exceeds the cell’s ability to adapt. This is determined by the type of stress, its severity and the type of cell affected.

Question 16

Hypoxemia vs. hypoxia

Answer 16

Hypoxemia = low PaO2. Hypoxemia = low O2 delivery to tissue, leads to decreased ATP and cellular injury.

Question 17

3 major causes of hypoxia

Answer 17

Ischemia (ACS, shock and Budd-Chiari syndrome), hypoxemia (PaO2

Question 18

PaO2 and SaO2 in anemia

Answer 18

Both are normal in anemia

Question 19

PaO2 and SaO2 in CO poisoning

Answer 19

PaO2 in normal, SaO2 will be decreased.

Question 20

A patient is found dead in his house with a cherry red appearance to the skin. What symptom would have been the earliest sign of illness?

Answer 20

Headache -> confusion -> coma -> death in CO poisoning.

Question 21

PaO2 and SaO2 in methemoglobinemia

Answer 21

PaO2 normal, SaO2 decreased to due oxidation of Fe2+ to Fe3+ and inability to bind O2.

Question 22

A patient presents with cyanosis and chocolate-colored blood. What are risk factors for the condition he had.

Answer 22

Oxidant stressors such as sulfa drugs and nitrates can cause methemoglobinemia. Newborns can also develop methemoglobinemia due to immature machinery that reduces Fe3+ back to Fe2+.

Question 23

Treating methemoglobinemia?

Answer 23

IV methylene blue reduces Fe3+ back to Fe2+ (Fe2 binds O2)

Question 24

How does low ATP from hypoxia result in cellular injury?

Answer 24

ATP is necessary for Na-K pump. Lack of ATP results in Na accumulation in the cell, cellular swelling and cellular injury. ATP is necessary for the Ca pump. Lack of ATP results in Ca accumulation in the cell and enzyme activation. Finally, lack of ATP results in increased production of lactic acid via aerobic glycolysis. This reduces intracellular pH and causes precipitation of DNA and proteins.

Question 25

Hallmark findings in reversible cellular injury.

Answer 25

1 = cellular swelling. This manifests as loss of microvilli, membrane blebbing and swelling of the rough endoplasmic reticulum leading to the ribosomes falling off and reducing protein synthesis.

Question 26

Hallmark findings in irreversible cellular injury.

Answer 26

Membrane damage. Plasma membrane (cardiac enzymes in MI, LFTs in hepatitis, increased intracellular Ca), mitochondrial membrane (ETC damage, cytochrome C-induced apoptosis) and lysosomal membrane (release of lytic enzymes into cytosol).

Question 27

Hallmark findings in cellular death.

Answer 27

Hallmark = loss of the nucleus. The nucleus is lost by pyknosis (shrinks), karyorrhexis (breaks up) and karyolysis (broken down).

Question 28

Mechanisms of cell death

Answer 28

Necrosis (involves a large group of cells, is followed by ACUTE INFLAMMATION and is never physiologic) and apoptosis.

Question 29

Subtypes of necrosis

Answer 29

Coagulative, liquefactive, gangrenous, caseous, fat and fibrinoid necrosis.

Question 30

Coagulative necrosis

Answer 30

Necrotic tissue that remains firm due to protein coagulation. Cellular architecture is preserved and nucleus is gone. This is the classic type of necrosis seen in ischemic infarction. Note the loss of nuclei and preserved architecture in the image on the left.

Question 31

Gross appearance of tissue that underwent coagulative necrosis?

Answer 31

Wedge-shaped and pale, with the edge pointing to the area of occlusion.

Question 32

When might you see red infarction?

Answer 32

Testicular torsion. This occurs because the torsion allows blood in, but not out due to venous occlusion. The tissue dies and presents as red infarction.

Question 33

Liquefactive necrosis. Where is this commonly seen?

Answer 33

Enzymatic lysis of the cells results in liquefaction. This is commonly seen in brain infarction (because it have high amounts of microglial cells with lytic enzymes that liquefy the brain tissue after infarction), abscess (PMNs have hydrolytic enzymes that liquefy the tissue) and pancreatitis (pancreatic enzymes are activated and liquefy the surrounding parenchyma).

Question 34

Gangrenous necrosis. Where is it seen? When is it wet?

Answer 34

Coagulative necrosis that resembles mummified tissue (dry gangrene). This is classically seen in the lower limbs and GI tract. It is wet gangrene when there is superimposed infection resulting in liquefactive necrosis.

Question 35

Caseous necrosis.

Answer 35

Soft, friable necrotic tissue with a cheese-like appearance. This is liquefactive necrosis that gets thickened by the wall of fungi and Tb.

Question 36

Fat necrosis

Answer 36

Necrotic adipose tissue with chalky-white appearance due to saponification of FA with Ca. This is seen in the peri-pancreatic fat in pancreatitis and in breast trauma (may present as a breast mass with a biopsy showing giant cells, fat and calcification)

Question 37

Aside from peri-pancreatic fat necrosis, what are other examples of saponification in the body?

Answer 37

Dystrophic calcification onto dying tissue in psammoma bodies. Note that in this condition serum Ca and PO4 will be NORMAL, as opposed to metastatic calcification with elevated Ca and/or PO4 which forces Ca into tissues and causes calcium deposition in tissue.

Question 38

Fibrinoid necrosis

Answer 38

Necrotic damage to the blood vessel wall from wall damage that causes protein leakage into the wall. This is characteristic of malignant hypertension, pre-eclampsia and vasculitis.

Question 39

Examples of apoptosis

Answer 39

Menstruation, embryogenesis (formation of fingers/toes) and CD8+ T-cell mediated killing of virally infected cells.

Question 40

How can you tell microscopically that a cell is undergoing apoptosis?

Answer 40

The dying cell shrinks, becomes eosinophilic, the nucleus condenses and fragments. Then apoptotic bodies fall from the cell and are removed by macrophages WITHOUT ACUTE INFLAMMATION.

Question 41

What causes apoptosis?

Answer 41

Caspases activate proteases to break down the cytoskeleton and endonucleases to break down the DNA.

Question 42

How are caspases activated?

Answer 42

1) INTRINSIC MITOCHONDRIAL PATHWAY: Bcl2 gets inactivated and cytC leaks out to activate caspases. 2) EXTRINSIC RECEPTOR-LIGAND PATHWAY: FAS ligand binds the FAS death receptor (CD95) on the target cell. TNF binds TNF receptor on the target cell. 3) CYTOTOXIC CD8+ T-CELL PATHWAY: CD8+ T-cells bind MHC I antigen, secrete perforins and granzyme. The perforins create pores in the membrane of the target cell and granzymes enter the pores to activates caspases.

Question 43

Classic example of extrinsic receptor-ligand pathway of apoptosis?

Answer 43

T-cell negative selection in the thymus.

Question 44

Free radical. When are they physiologic? When are they pathologic?

Answer 44

Chemical species with an unpaired electron in the outer orbit. They are physiologic during oxidative phosphorylation: cytC oxidase transfers e- to O2 as the final e- acceptor to make ATP. Ionizing radiation (OH), inflammation (oxidative burst), metals (Wilson’s and Hemochromatosis), drugs & chemicals (acetaminophen -> NAPQI and CCl4) are pathologic causes.

Question 45

How oxygen changes as it accepts electrons?

Answer 45

O2 -> O2- -> H2O2 -> OH -> H2O

Question 46

Most damaging free radical?

Answer 46

OH

Question 47

Oxygen dependent killing of microbes by PMNs.

Answer 47

NADPH oxidase takes O2 -> O2-. Then superoxide dismutase takes O2- -> H2O2. Finally myeloperoxidase take H2O2 to HOCl.

Question 48

How does Fe generate free radicals?

Answer 48

The Fenton reaction generates OH.

Question 49

Why are free radicals so bad?

Answer 49

They result in the peroxidation of lipids, oxidation of DNA (leading to cancer) and oxidation of proteins.

Question 50

How does the body eliminate free radicals?

Answer 50

Antioxidants (vitamins A,E & C), enzymes (SOD, glutathione peroxidase and catalase) and metal carrier proteins (transferrin and ferritin bind Fe, ceruloplasmin binds Fe).

Question 51

What enzymes in the body eliminate free radicals?

Answer 51

Superoxide dismutase removes O2-. Hydrogen peroxide is removed by catalase. Hydroxyl radicals are removed by glutathione peroxidase.

Question 52

How does carbon tetrachloride cause fatty liver changes.?

Answer 52

When CCl4 gets into the blood, it is converted to CCl3 in the liver and the free radical damages hepatocytes. This results in decreased hepatic synthesis of apolipoproteins, fat gets into the liver, can’t get out and steatosis follows.

Question 53

Mechanism of reperfusion injury after MI?

Answer 53

When blood is returned to the organ after ischemia, the combination of inflammatory cells reacting against dead tissue and oxygen generates free radicals that can further damage the cardiac myocytes.

Question 54

What is amyloid?

Answer 54

Misfolded protein that deposits in the extracellular space in a beta-pleated sheet configuration.

Question 55

Different types of systemic amyloidosis?

Answer 55

Primary: systemic deposition of AL amyloid from Ig light chain associated with plasma cell dycrasias. Secondary: systemic deposition of AA amyloid derived from SAA amyloid, which is an acute phase reactant. This is associated with chronic inflammation, malignancy and Familial Mediterranean Fever.

Question 56

How does Familial Mediterranean Fever cause amyloidosis?

Answer 56

It is a dysfunction of PMNs that presents with episodes of fever and acute serosal inflammation (pericarditis, GI pain) resulting in high levels of SAA during attacks that deposit as AA amyloid.

Question 57

Classic clinical findings in amyloidosis

Answer 57

Nephrotic syndrome, restricted cardiomyopathy, arrhythmias, tongue enlargement, malabsorption and hepatosplenomegaly.

Question 58

How to diagnose amyloidosis? How to treat?

Answer 58

Tissue biopsy of abdominal fat pad and rectum. Only treatment is transplantation.

Question 59

What type of amyloid deposits in the cardiac muscle of 25% of individuals over 80 years old?

Answer 59

Senile cardiac amyloidosis is due to deposition of non-mutated drum transthyretin (second most common protein in the blood) deposits in the heart. Note that these patients are typically asymptomatic

Question 60

What type of amyloid deposits in patients with familial amyloid cardiomyopathy?

Answer 60

Mutated serum transthyretin. This typically is symptomatic and results in restrictive cardiomyopathy. Note that 5% of African Americans carry the mutated gene.

Question 61

How do diabetics get amyloidosis?

Answer 61

Insulin insensitivity results in excess production of insulin and amylin. Amylin deposits in the islets of the pancreas.

Question 62

Why do Down’s patients get Alzheimer disease?

Answer 62

Alzheimer’s disease is due to deposition of A-beta amyloid. This comes from the beta-amyloid precursor protein on chromosome 21, which is produced in excess in trisomy 21.

Question 63

Type of amyloid that deposits in patients with dialysis-associated amyloidosis?

Answer 63

Beta2-microglobulin deposits in joints. Remember beta2-microglobulin provides structural support for MHC I. When patients go on dialysis, this protein is not filtered well, it builds up and deposits in joints.

Question 64

Amyloidosis in the thyroid

Answer 64

Medullary carcinoma of the thyroid involves neuroendocrine-derived C-cells that produce calcitonin. Overproduction of calcitonin can deposit and present as tumor cells with an amyloid background.