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Pathoma > Growth Adaptations, Cellular Injury and Cell Death > Flashcards

Growth Adaptations, Cellular Injury and Cell Death Flashcards

1
Q

Hypertrophy vs. Hyperplasia

A

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)

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2
Q

What permanent tissues undergo hypertrophy only?

A

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

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3
Q

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

A

Example: endometrial hyperplasia
Exception: BPH

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4
Q

How does atrophy occur? Mechanism

A

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)

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5
Q

What is metaplasia? Classic example?

A

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

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6
Q

Barrett esophagus

A

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)

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7
Q

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

A

non-ciliated, mucin-producing columnar cells

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8
Q

How does metaplasia occur?

A

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

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9
Q

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?

A

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

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10
Q

What vitamin deficiency can result in metaplasia/

A

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

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11
Q

What is a classic example of mesenchymal metaplasia?

A

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

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12
Q

What is dyplasia? Example?

A

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

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13
Q

What is aplasia? Hypoplasia?

A

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)

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14
Q

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

A

Slow developing ischemia (renal artery athersclerosis) results in atrophy

Acute ischemia (renal artery embolus) results in injury

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15
Q

Hypoxia is…Mechanism of injury?

A

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

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16
Q

Ischemia in Budd-Chiari syndrome occurs how?

A

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

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17
Q

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

A

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

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18
Q

Causes of hypoxia

A

Ischemia, hypoxemia, decreased O2 carrying capacity of blood

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19
Q

Ischemia causes

A

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

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20
Q

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

A

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)

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21
Q

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

A

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

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22
Q

Methemoglobinemia:

Cause, classic finding and treatment

A

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+

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23
Q

What cellular functions are disrupted by low ATP?

A

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

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24
Q

What is the hallmark of reversible injury?

A

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

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25
Q

What is the hallmark of irreversible injury?

A

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.

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26
Q

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

A

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

27
Q

What follows necrosis?

A

*Acute inflammation

28
Q

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

A

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)

29
Q

When does a red infarction occur?

A

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

30
Q

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

A

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

31
Q

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

A

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)

32
Q

Caseous necrosis:
What is it?
Characteristic of what?

A

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

33
Q

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

A

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

34
Q

What is saponification?

A

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)

35
Q

Fibrinoid necrosis:
What is it?
Characteristic of what?

A

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

36
Q

Malignant vs. dystrophic calcification

A

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

37
Q

What is apoptosis? Examples?

A

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

38
Q

Morphology of apoptotic cells

A

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

39
Q

What mediates apoptosis?

A

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

40
Q

What are the three pathways that activate caspases?

A
  • 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)
41
Q

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

A

*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)

42
Q

Describe the intrinsic mitochondrial pathway of caspase activation

A

*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

43
Q

Describe the extrinsic receptor-ligand pathway of caspase activation

A

*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

44
Q

Physiological generation of free radicals occurs during…

A

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

45
Q

Pathologic generation of free radicals occurs with (4)

A

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

46
Q

What is the most damaging free radical?

A

Hydroxyl radical

47
Q

How does inflammation produce free radicals?

A

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

48
Q

How do free radicals cause cellular injury?

A

Peroxidation of lipids and oxidation of DNA and proteins

49
Q

How does elimination of free radicals occur? (3)

A

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

50
Q

Where are the enzymes that eliminate free radicals located?

A

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

51
Q

What are two examples of free radical injury?

A

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

52
Q

What is amyloid? What is it characterized by?

A

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
53
Q

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

A

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

54
Q

Clinical findings of systemic amyloidosis

A

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

55
Q

How do you diagnose primary amyloidosis?

A

Tissue biopsy (abdominal fat pad and rectum easily accessible)

56
Q

Senile cardiac amyloidosis:

What is being deposited? Where?

A

*Nonmutated serum transthyretin deposits in the heart

Usually asymptomatic; present in 25% of individuals > 80 years of age

57
Q

Familial amyloid cardiomyopathy:

What is being deposited? Where?

A

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

58
Q

Non-insulin-dependent DM (Type II):

What is being deposited? Where?

A

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

59
Q

Alzheimer disease:

What is being deposited? Where? Genetic association?

A

*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)

60
Q

Dialysis-associated amyloidosis:

What is being deposited? Where?

A

*B2-microglobulin deposits in joints

61
Q

Medullary carcinoma of the thyroid:

What is being deposited? Where?

A

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

62
Q

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

A

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)

63
Q 
Familial Mediterranean Fever (FMF): 
Due to a dysfunction of what?
AD or AR?
How does it present?
What type of amyloid?
A

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

64
Q

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
A

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

Pathoma (6 decks)

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