Growth Adaptations, Cellular Injury and Cell Death

Question 1

Hypertrophy vs. Hyperplasia

Answer 1

Hypertrophy is an increase in size. Involves gene activation, protein synthesis, and production of organelles (need to increase cytoskeleton to expand)

Hyperplasia is an increase in the number of cells. Involves the production of new cells from stem cells

Generally occur together (ex/uterus during pregnancy)

Question 2

What permanent tissues undergo hypertrophy only?

Answer 2

Cardiac muscle, skeletal muscle and nerve - cannot make new cells

Question 3

Pathologic hyperplasia can progress to dysplasia and eventually cancer - give an example and an exception

Answer 3

Example: endometrial hyperplasia
Exception: BPH

Question 4

How does atrophy occur? Mechanism

Answer 4

Decrease in size and number of cells

Decrease in cell number occurs by apoptosis
Decrease in size occurs via ubiquitin-proteosome degradation of the cytoskeleton (IF) and autophagy of cellular components (autophagic vacuoles fuse with lysosomes)

Question 5

What is metaplasia? Classic example?

Answer 5

A change in cell type - metaplastic cells are better able to handle a new stress. Most commonly involves change of one type of surface epithelium (squamous, columnar, or urothelial) to another

Ex/ Barrett esophagus

Question 6

Barrett esophagus

Answer 6

A classic example of metaplasia - the esophagus is normally lined by nonkeratinizing squamous epithelium (suited to handle the friction of a bolus). Acid reflux from the stomach causes metaplasia to non-ciliated, mucin-producing columnar cells (better able to handle the stress of acid)

Question 7

What type of epithelium is the nonkeratinizing squamous epithelium in Barretts esophagus converted to?

Answer 7

non-ciliated, mucin-producing columnar cells

Question 8

How does metaplasia occur?

Answer 8

Via reprogramming of stem cells - reversible with removal of the driving stressor

Question 9

Under persistent stress, metaplasia can progress to dysplasia and eventually result in cancer - Barrett esophagus may progress to adenocarcinome of the esophagus. What is one notable exception?

Answer 9

Apocrine metaplasia of the breast (fibrocystic change of the breast), carries no increased risk for cancer

Question 10

What vitamin deficiency can result in metaplasia/

Answer 10

Vitamin A - necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. In vitamin A deficiency, the goblet cell/columnar epithelium of the conductive undergoes metaplasia into keratinizing squamous epithelium. Dry eyes (xerophthalmia) can lead to destruction of the cornea (keratomalacia) and blindness

Question 11

What is a classic example of mesenchymal metaplasia?

Answer 11

Myositis ossificans - CT within muscle changes to bone during healing after trauma

Question 12

What is dyplasia? Example?

Answer 12

Disordered cell growth, most often refers to proliferation of precancerous cells
ex/ CIN (cervical intrapeithelial neoplasia) represents dysplasia and is a precursor to cervical cancer
Often arises from longstanding pathologic hyperplasia (endometrial hyperplasia) and metaplasia (Barrett esophagus)
Reversible

Question 13

What is aplasia? Hypoplasia?

Answer 13

Failure of cell production during embryogenesis (ex/ unilateral renal agenesis)
Hypoplasia is a decrease in cell production during embryogenesis, resulting in a relatively small organ (ex/streak ovary in Turner syndrome)

Question 14

Slow ischemia results in… whereas, acute ischemia results in…

Answer 14

Slow developing ischemia (renal artery athersclerosis) results in atrophy

Acute ischemia (renal artery embolus) results in injury

Question 15

Hypoxia is…Mechanism of injury?

Answer 15

Low oxygen delivery to tissue - oxygen is the final electron acceptor in the ETC of oxidative phosphorylation. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production. Lack of ATP leads to cellular injury

Question 16

Ischemia in Budd-Chiari syndrome occurs how?

Answer 16

Decreased venous drainage - thrombosis of hepatic vein - infarction in liver (other causes include polycythemia vera and lupus anticoagulant)

Question 17

Causes of hypoxemia (low partial pressure of oxygen in the blood, PaO2<90%)

Answer 17

High altitude
Hypoventilation (incrased PACO2 decreases PAO2)
Diffusion defect (thicker diffusion barrier - interstitial pulmonary fibrosis)
V/Q mismatch (circulation or ventilation problem)

Question 18

Causes of hypoxia

Answer 18

Ischemia, hypoxemia, decreased O2 carrying capacity of blood

Question 19

Ischemia causes

Answer 19

Decreased arterial perfusion (athersclerosis)
Decreased venous perfusion (Budd-Chiaria)
Shock

Question 20

Decreased O2 carrying capacity arises with hemoglobin loss or dysfunction - three examples

Answer 20

Anemia (decreased RBC mass - PaO2 and SaO2 are normal)
CO poisoning (displaces oxygen because it binds more avidly to hemoglobin, SaO2 decreased)
Methemoglobin (iron in heme is oxidized to Fe3+, cannot bind oxygen, SaO2 decreased)

Question 21

CO poisoning - classical finding? Early sign of exposure? PaO2, SaO2?

Answer 21

Cherry-red skin
Headache
PaO2 - normal, SaO2 - decreased

Question 22

Methemoglobinemia:

Cause, classic finding and treatment

Answer 22

Iron in heme is oxidized to Fe3+, which cannot bind oxygen - PaO2 is normal, SaO2 is decreased
Seen with oxidant stress (sulfa and nitrate drugs) or in newborns
Classic finding is cyanosis with chocolate-colored blood
Treatment: IV methylene blue, helps reduce Fe3+ back to Fe2+

Question 23

What cellular functions are disrupted by low ATP?

Answer 23

Na+-K+ pump, resulting in water and sodium build up in the cell
Ca++ pump, resulting in Ca++ buildup in the cytosol of the cell
Aerobic glycolysis, resulting in a switch to anaerobe glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DNA

Question 24

What is the hallmark of reversible injury?

Answer 24

Cellular swelling - cytosol swelling results in a loss of microvilli and membrane blabbing. Swelling of the RER results in dissociation of ribosomes and decreased protein synthesis

Question 25

What is the hallmark of irreversible injury?

Answer 25

Membrane damage - Plasma membrane damage results in cytosolic enzymes leaking into the serum (cardiac troponin), additional calcium enters the cell. Mitochondrial membrane damage results in the loss of ETC (inner mitochondrial membrane) and cytochrome C leaking into cytosol (activates apoptosis). Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which in turn, are activated by high intracellular calcium.

Question 26

Morphologic hallmark of cell death: What do pyknosis, karyorrhexis and karyolysis mean?

Answer 26

Loss of nucleus - occurs via nuclear condensation (pyknosis), fragmentation (karyorrhexis) and dissolution (karyolysis)

Question 27

What follows necrosis?

Answer 27

*Acute inflammation

Question 28

Coagulative necrosis: What is it? Characteristic of what type of damage?

Answer 28

Necrotic tissue that remains firm; cell shape and organ structure are preserved by coagulation of proteins but the nucleus disappears Characteristic of ischemic infarction of any organ except the brain Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale *Red infarction arises if blood re-enters a loosely organized tissue (pulmonary or testicular infarction)

Question 29

When does a red infarction occur?

Answer 29

When blood re-enters a loosely organized tissue (pulmonary or testicular infarction)

Question 30

Liquefactive necrosis: What is it? Characteristic of what three pathologies (*where are the enzymes coming from)?

Answer 30

Necrotic tissue that becomes liquified; enzymatic lysis of cells and protein results in liquefaction Characteristic of: Brain infarction - proteolytic enzymes from *microglial cells liquefy the brain Abscess - proteolytic enzymes from neutrophils liquefy tissue Pancreatitis - proteolytic enzymes from pancreas liquefy parenchyma

Question 31

Gangrenous necrosis: What is it? Characteristic of ischemia where?

Answer 31

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

Question 32

Caseous necrosis: What is it? Characteristic of what?

Answer 32

Soft and friable necrosis tissue with "cottage cheese-like" appearance Combination of coagulative and liquefactive necrosis Characteristic of granulomatous inflammation due to tuberculosis or fungal infection

Question 33

Fat necrosis: What is it? Characteristic of damage where?

Answer 33

Necrotic adipose tissue with chalky-white appearance due to deposition of calcium Characteristic of trauma to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat

Question 34

What is saponification?

Answer 34

Occurs when FA released by trauma (to the breast) or lipase (from pancreatitis) join with calcium It is an example of dystrophic calcification in which calcium deposits on dead tissue, the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate (ex/ psammoma bodies)

Question 35

Fibrinoid necrosis: What is it? Characteristic of what?

Answer 35

Necrotic damage to blood vessel wall Leaking of proteins (including fibrin) into vessel wall result in bright pink staining of the wall microscopically Characteristic of malignant HTNN and vasculitis

Question 36

Malignant vs. dystrophic calcification

Answer 36

Metastatic calcification occurs when high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis) Dystrophic calcification occurs when necrotic tissue acts as a nidus for calcification in the setting of a normal serum calcium and phosphate

Question 37

What is apoptosis? Examples?

Answer 37

ATP-dependent, genetically programmed cell death involving a single cell or small groups of cells. Ex/ endometrial shedding during menstruation, removal of cells during embyrogenesis, CD8+ T cell killing of virally infected cells

Question 38

Morphology of apoptotic cells

Answer 38

Dying shell shrinks, cytoplasm becomes more concentrated/eosinophilic Nucleus condenses and fragments in an organized manner Apoptotic bodies fall from the cell and are removed by macrophages *not followed by inflammation

Question 39

What mediates apoptosis?

Answer 39

Caspases that activate proteases (break down the cytoskeleton) and endonucleases (break down DNA)

Question 40

What are the three pathways that activate caspases?

Answer 40

* Intrinsic mitochondrial pathway: cellular injury, DNA damage or decreased hormonal stimulation leads to inactivation of Bcl2. Lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases * Extrinsic receptor-ligand pathway: FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (e.g., negative selection of thymocytes in thymus). TNF binds TNF receptor on the target cell, activating caspases * Cytotoxic CD8+ T cell-mediated pathway: Perforins secreted by CD8+ T cell create pores in membrane of target cell. Granzyme from CD8+ T cell enters pores and activates caspases (e.g., CD8+ killing of virally infected cells)

Question 41

Describe the cytotoxic CD8+ T cell-mediated pathway of caspase activation

Answer 41

*Cytotoxic CD8+ T cell-mediated pathway: Perforins secreted by CD8+ T cell create pores in membrane of target cell. Granzyme from CD8+ T cell enters pores and activates caspases (e.g., CD8+ killing of virally infected cells)

Question 42

Describe the intrinsic mitochondrial pathway of caspase activation

Answer 42

*Intrinsic mitochondrial pathway: cellular injury, DNA damage or decreased hormonal stimulation leads to inactivation of Bcl2. Lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases

Question 43

Describe the extrinsic receptor-ligand pathway of caspase activation

Answer 43

*Extrinsic receptor-ligand pathway: FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (e.g., negative selection of thymocytes in thymus). TNF binds TNF receptor on the target cell, activating caspases

Question 44

Physiological generation of free radicals occurs during...

Answer 44

Oxidative phosphorylation: cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of O2 yields superoxide, hydrogen peroxide and hydroxyl radicals

Question 45

Pathologic generation of free radicals occurs with (4)

Answer 45

1) Ionizing radiation - water hydrolyzed to hydroxyl free radical (most damaging) 2) Inflammation - *NADPH oxidase generates superoxide ions during oxygen-dependant killing by neutrophils 3) Metals (copper and iron) - Fe2+ generates hydroxyl radicals (Fenton reaction) 4) Drugs and chemicals - P450 system of liver metabolizes drugs (acetaminophen), generating free radicals

Question 46

What is the most damaging free radical?

Answer 46

Hydroxyl radical

Question 47

How does inflammation produce free radicals?

Answer 47

*NADPH oxidase generates superoxide ions during oxygen-dependant killing by neutrophils

Question 48

How do free radicals cause cellular injury?

Answer 48

Peroxidation of lipids and oxidation of DNA and proteins

Question 49

How does elimination of free radicals occur? (3)

Answer 49

1) Antioxidants (glutathione, vitamins A, C and E) 2) Enzymes (superoxide dismutase, glutathione peroxidase, catalase) 3) Metal carrier proteins (transferrin and ceruloplasmin)

Question 50

Where are the enzymes that eliminate free radicals located?

Answer 50

Superoxide dismutase (SOD) - mitochondria (superoxide) Glutathione peroxidase - mitochondria (free radical) Catalase - peroxisomes (hydrogen peroxide)

Question 51

What are two examples of free radical injury?

Answer 51

Carbon tetrachloride (CCl4): organic solvent used in the *dry cleaning business. Converted to CCL3 free radical by *P450 system. Results in cell injury with swelling of RER, ribosomes detach impairing protein synthesis -> decreased apolopoproteins lead to fatty changes in the liver (fat gets in but can't get out) Reperfusion injury: return of blood to ischemic tissues results in production of O2 derived free radicals (return of inflammatory cells), which further damages tissues. Leads to a continued rise in cardiac enzymes (troponin) after reperfusion of infarcted myocardial tissue

Question 52

What is amyloid? What is it characterized by?

Answer 52

Misfolded protein that deposits in extracellular space -> damaging tissues - B-pleated sheet configuration - Congo red staining and apple-green birefringence when viewed microscopically under polarized light

Question 53

Primary amyloidosis: What is being deposited? What is it associated with?

Answer 53

Systemic deposition of *AL amyloid, derived from *immunoglobulin LC Associated with *plasma cell dyscrasia (e.g., multiple myeloma) - overproduction of LC, leaks out into blood and deposits in tissues

Question 54

Clinical findings of systemic amyloidosis

Answer 54

Nephrotic syndrome (*kidney is most commonly involved organ) Restrictive cardiomyopathy or arrhythmia Tongue enlargement, malabsorption and hepatosplenomegaly

Question 55

How do you diagnose primary amyloidosis?

Answer 55

Tissue biopsy (abdominal fat pad and rectum easily accessible)

Question 56

Senile cardiac amyloidosis: | What is being deposited? Where?

Answer 56

*Nonmutated serum transthyretin deposits in the heart | Usually asymptomatic; present in 25% of individuals > 80 years of age

Question 57

Familial amyloid cardiomyopathy: | What is being deposited? Where?

Answer 57

*Mutated serum transtheyretin deposits in the heart leading to restrictive cardiomyopathy 5% of African Americans carry the mutated gene

Question 58

Non-insulin-dependent DM (Type II): | What is being deposited? Where?

Answer 58

*Amylin (derived from insulin) deposits in the islets of the pancreas

Question 59

Alzheimer disease: | What is being deposited? Where? Genetic association?

Answer 59

*AB amyloid (derived from B-amyloid precursor protein) deposits in the brain forming amyloid plaque Gene for B-APP is present on *chromosome 21. Most individuals with *Down syndrome (trisomy 21) develop AD by age 40 (early-onset)

Question 60

Dialysis-associated amyloidosis: | What is being deposited? Where?

Answer 60

*B2-microglobulin deposits in joints

Question 61

Medullary carcinoma of the thyroid: | What is being deposited? Where?

Answer 61

Calcitonin (overproduced by tumor cells - C cells) deposits within the tumor "tumor cells in an amyloid background"

Question 62

Secondary amyloidosis: What is being deposited? What is it associated with?

Answer 62

Systemic deposition of AA amyloid derived from serum amyloid-associated protein (SAA) SAA is an *acute phase reactant that is increased in chronic inflammatory states, malignancy and Familial Mediterranean Fever (FMF)

Question 63

``` Familial Mediterranean Fever (FMF): Due to a dysfunction of what? AD or AR? How does it present? What type of amyloid? ```

Answer 63

Dysfunction of neutrophils AR Presents w/ episodes of fever and acute serosal inflammation (can mimic appendicitis, arthritis, MI) SAA (acute phase reactant) deposits as AA amyloid

Question 64

What is the amyloid and where does it deposit? ``` Primary amyloidosis Secondary amyloidosis Senile cardiac amyloidosis Familial amyloid cardiomyopathy Non-insulin-dependent DM (Type II) Alzheimer disease Dialysis-associated amyloidosis Medullary carcinoma of the thyroid ```

Answer 64

Primary amyloidosis: AL derived from immunoglobulin LC, systemic Secondary amyloidosis: AA derived from serum amyloid-associated protein (SAA), systemic Senile cardiac amyloidosis: Non-mutated serum transthyretin, heart Familial amyloid cardiomyopathy: Mutated serum transthyretin, heart Non-insulin-dependent DM (Type II): Amylin (derived from insulin), islets of the pancreas Alzheimer disease: AB amyloid, brain Dialysis-associated amyloidosis: B2-microglobulin, joints Medullary carcinoma of the thyroid: Calcitonin, tumor