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*USMLE Step 1, General Principles > Growth Adaptations, Cellular Injury, and Cell Death > Flashcards

Growth Adaptations, Cellular Injury, and Cell Death Flashcards

1
Q

Hypertrophy - Mechanism

A

Gene activation, protein synthesis, production of organelles

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2
Q

Hyperplasia - Mechanism

A

Production of new cells from stem cells or resting cells

  1. Labile (stem) cells - Continuously divide
  2. Stable cells - Resting cells in Go phase of cell cycle that may be stimulated to enter cell cycle
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3
Q

Atrophy - Mechanism (2)

A
  1. Decrease in cell size
    a. Increased catabolism of cell organelles and reduction of cytosol via autophagy in which autophagic vacuoles fuse with lysosomes
    b. Increased catabolism of proteins by ubiquitin-proteasome pathway and decreased protein synthesis
  2. Decrease in cell number by apoptosis
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4
Q

Metaplasia - Mechanism

A

Reprogramming of stem cells to utilize progeny cells with a different pattern of gene expression

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5
Q

Metaplasia - Barrett esophagus

A

Squamous epithelium –> Non-ciliated columnar epithelium with mucus-secreting cells and goblet cells

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6
Q

Metaplasia - Mainstem bronchus (smoking)

A

Pseudostratified columnar epithelium –> Squamous epithelium

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7
Q

Metaplasia - Schistosoma haematobium infection (urinary bladder)

A

Transitional (urogenital) epithelium –> Squamous epithelium

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8
Q

Metaplasia - Myositis ossificans

A

Mesenchymal tissue –> Bone

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9
Q

Metaplasia - Keratomalacia

A

Specialized epithelium (conjunctivae) –> Keratinizing, stratified squamous epithelium

(Vitamin A deficiency)

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10
Q

Dysplasia - Mechanism

A

Disorderly proliferation of cells

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11
Q

Dysplasia - Microscopic features (2)

A
  1. Increased mitotic activity with NORMAL mitotic spindles

2. Increased nuclear size and chromatin

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12
Q

Pathologic metaplasia without risk of progression to dysplasia and neoplasia?

A

Apocrine metaplasia of the breast (fibrocystic change)

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13
Q

Reversibility

  • Metaplasia
  • Dysplasia
  • Neoplasia
A
  • Metaplasia and dysplasia reversible

- Neoplasia irreversible

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14
Q

Hypoxia

A

Inadequate oxygenation of tissue

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15
Q

PaO2 - Contributing factors (4)

A
  1. Percent O2 in inspired air
  2. Atmospheric pressure
  3. Ventilation (PAO2 in the lungs)
  4. Perfusion and diffusion (Normal O2 exchange in the lungs through the alveolar-capillary membrane)
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16
Q

SaO2 - Contributing factors (5)

A
  1. Percent O2 in inspired air
  2. Atmospheric pressure
  3. Ventilation (PAO2 in the lungs)
  4. Perfusion and diffusion (Normal O2 exchange in the lungs through the alveolar-capillary membrane)
  5. Valence of heme iron in Hb

Fe2+ (ferrous, reduced) binds O2
Fe3+ (ferric, oxidized) does NOT bind O2

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17
Q

Hypoxia - Clinical findings (4)

A
  1. Cyanosis - Bluish discoloration of the skin and mucuous membranes (SaO2 < 80%)
  2. Confusion
  3. Cognitive impairment
  4. Lethargy
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18
Q

Oxidative phosphorylation (electron transport chain) - Cellular location

A

Inner mitochondrial membrane

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19
Q

Causes of tissue hypoxia (3)

A
  1. Ischemia
  2. Hypoxemia
  3. Decreased O2 carrying capacity
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20
Q

Ischemia - Definition

A

Decreased arterial blood flow to tissue or venous outflow from tissue

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21
Q

Hypoxemia - Definition

A

Decrease in PaO2 (PaO2 < 60 mm Hg, SaO2 < 90%)

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22
Q

Causes of hypoxemia (6)

A
  1. Decreased inspired PO2 (PiO2)
  2. Respiratory acidosis
  3. Ventilation defect
  4. Perfusion defect
  5. Diffusion defect
  6. Cyanotic congenital heart disease
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23
Q

Hypoxemia: Causes of decreased PiO2 (2)

A
  1. Breathing at high altitude

2. Breathing reduced %O2 mist

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24
Q

Hypoxemia: Respiratory acidosis - Definition

A

Retention of CO2 in the lungs

Increased PACO2 always produced decreased PAO2 (Dalton’s law - PO2 + PCO2 + PN2 = 760 mm Hg)

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25
Q

Hypoxemia: Ventilation defect - Definition

A
  • Lung perfused but not ventilated

- Impaired O2 delivery to alveoli

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26
Q

Hypoxemia: Perfusion defect - Definition

A

Lung ventilated but not perfused

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27
Q

Hypoxemia: Diffusion defect - Definition

A

Decreased diffusion of O2 through the alveolar-capillary interface

Examples - Interstitial pulmonary fibrosis, pulmonary edema

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28
Q

Hypoxemia: Cyanotic congenital heart defect - Definition

A

Shunting of venous blood into arterial blood causes a drop in PaO2

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29
Q

Causes of decreased O2-carrying capacity (4)

A
  1. Anemia
  2. Methemoglobinemia (metHb)
  3. Carbon monoxide (CO) poisoning
  4. Factors causing a left-shifted Hb-O2 dissociation curve
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30
Q

Methemoglobinemia - Definition

A

Hb with oxidized Fe3+ (ferric iron) groups

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31
Q

Methemoglobinemia - Causes (3)

A
  1. Oxidant stress - Nitrite- or sulfur-containing drugs
  2. Congenital deficiency of cytochrome b5 reductase
  3. Decreased levels of cytochrome b5 reductase (newborns, until approx. 4 months of age)
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32
Q

Methemoglobinemia - Mechanism of hypoxia (2)

A
  1. metHb decreases the number of O2-binding sites, since O2 cannot bind Fe3+ in metHb
  2. metHb impairs O2 unloading (left-shifts Hb-O2 dissociation curve) by stabilizing R state
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33
Q

Methemoglobinemia - Pathognomonic clinical finding

A

Chocolate-colored blood (increased deoxy-Hb)

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34
Q

Methemoglobinemia - Treatment (2)

A

IV methylene blue, vitamin C

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35
Q

Cytochrome b5 reductase system

A

Cytochrome b5 reductase catalyzes the enzymatic reduction of metHb and the enzymatic oxidation of NADH

Fe3+ reduced to Fe2+
NADH oxidized to NAD+

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36
Q

NADPH-methemoglobin reductase system

A

NADPH-methemoglobin reductase catalyzes the enzymatic reduction of metHb and the enzymatic oxidation of NADPH
- Located in the pentose phosphate shunt

Fe3+ reduced to Fe2+
NADPH oxidized to NADP+

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37
Q

Methemoglobinemia - IV methylene blue (MOA)

A

Accelerates the enzymatic reduction of metHb by NADPH-methemoglobinemia reductase
- NOT normally operational in reducing metHb

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38
Q

Carbon monoxide poisoning - Mechanism of hypoxia (3)

A
  1. CO-Hb decreases the number of O2-binding sites, since binds Hb with 200x affinity versus O2
  2. CO-Hb impairs O2 unloading (left-shifts Hb-O2 dissociation curve) by stabilizing R state
  3. CO-Hb inhibits cytochrome oxidase in ETC, thereby preventing O2 consumption and ATP production
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39
Q

CO poisoning - Pathognomonic clinical finding

A

Cherry-red skin

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40
Q

CO poisoning - Early sign of exposure

A

Headache

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41
Q

CO poisoning - Treatment

A

100% O2 therapy

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42
Q

Factors causing a left-shifted Hb-O2 dissociation curve (6)

A
  1. metHb
  2. CO
  3. HbF
  4. Increased 2,3-BPG
  5. Decreased temperature
  6. Decreased H+ / increased pH / alkalosis
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43
Q

Anemia

  • PaO2
  • SaO2
  • Hb-O2 dissociation curve
  • Cytochrome oxidase
A

Anemia

  • PaO2 - NORMAL
  • SaO2 - NORMAL
  • Hb-O2 dissociation curve - NORMAL
  • Cytochrome oxidase - NORMAL
44
Q

Methemoglobinemia

  • PaO2
  • SaO2
  • Hb-O2 dissociation curve
  • Cytochrome oxidase
A

Methemoglobinemia

  • PaO2 - NORMAL
  • SaO2 - DECREASED
  • Hb-O2 dissociation curve - LEFT-SHIFTED
  • Cytochrome oxidase - NORMAL
45
Q

Carbon monoxide poisoning

  • PaO2
  • SaO2
  • Hb-O2 dissociation curve
  • Cytochrome oxidase
A

Carbon monoxide poisoning

  • PaO2 - NORMAL
  • SaO2 - DECREASED
  • Hb-O2 dissociation curve - LEFT-SHIFTED
  • Cytochrome oxidase - INHIBITED
46
Q

Cyanide poisoning

  • PaO2
  • SaO2
  • Hb-O2 dissociation curve
  • Cytochrome oxidase
A

Cyanide poisoning

  • PaO2 - NORMAL
  • SaO2 - NORMAL
  • Hb-O2 dissociation curve - NORMAL
  • Cytochrome oxidase - INHIBITED

Cyanide inhibits cytochrome oxidase (complex IV) in the electron transport chain, which prevents O2 consumption. Shutdown of the ETC prevents the diffusion from blood to tissue 2/2 loss of the diffusion gradient.

47
Q

Hallmark of reversible cell injury

A

Cellular swelling with loss of microvilli and membrane blebbing

48
Q

Reversible cell injury - Decreased ATP synthesis in the mitochondria 2/2 hypoxia causes (2)

A
  1. Anaerobic glycolysis
    - Net gain of 2 ATP
  2. Na-K ATPase dysfunction
49
Q

Reversible cell injury - Anaerobic glycolysis causes (3)

A
  1. Lactic acidosis
  2. Low pH denatures structural/enzymatic proteins
  3. Low pH precipitates DNA (chromatin clumping)
50
Q

Reversible cell injury - Na-K ATPase dysfunction causes

A

Na+ and water to buildup in the cell –> Cellular swelling

51
Q

Reversible cell injury - Swelling of the cytosol causes (2)

A
  1. Loss of microvilli

2. Membrane blebbing

52
Q

Reversible cell injury - Swelling of the endoplasmic reticulum (ER) causes (2)

A
  1. Dissociation of ribosomes, leading to decreased protein synthesis
  2. Fatty change 2/2 decreased synthesis of apolipoproteins
53
Q

Hallmark of irreversible cell injury

A

Membrane damage

54
Q

Irreversible cell injury - Prolonged decreased ATP synthesis in the mitochondria 2/2 hypoxia causes

A

Ca2+ ATPase pump dysfunction, thereby increasing cytosolic [Ca2+]

55
Q

Irreversible cell injury - Increased cytosolic [Ca2+] activates enzymes (4)

A
  1. Phospholipase - Increases cell and organelle membrane permeability
  2. Proteases - Damages cytoskeleton
  3. Endonucleases - Degrades nuclear chromatin (karyolysis)
  4. Caspases - Triggers apoptosis
56
Q

Irreversible cell injury - Increased cytosolic [Ca2+] activates phospholipase, which damages cell and organelle membranes (4)

A
  1. Plasma membrane
  2. Inner mitochondrial membrane
  3. Outer mitochondrial membrane
  4. Lysosomal membrane
57
Q

Irreversible cell injury - Consequences of mitochondrial membrane permeability/damage (3)

A
  1. Cytochrome c in the ETC (inner mitochondrial membrane), is released into the cytosol, where it activates caspases, thereby triggering apoptosis
  2. Pro-apoptotic proteins sequestered in the mitochondrial matrix (b/w inner and outer mitochondrial membranes) are released into the cytosol (activate apoptosis)
  3. Mitochondrial conductance channels (pores) are opened, leading to loss of H+ ions and loss of the membrane potential, eliminating oxidative phosphorylation function
58
Q

Hallmark of cell death

A

Loss of nucleus

59
Q

Mechanism of nuclear loss (3)

A
  1. Pyknosis (condensation)
  2. Karyorrhexis (fragmentation)
  3. Karyolysis (dissolution)
60
Q

Cell death - Types (2)

A

Apoptosis and necrosis

61
Q

Coagulative necrosis - Definition

A

Necrosis with preservation of the structural/architectural outline of dead cells

62
Q

Coagulative necrosis - Mechanism (2)

A
  1. Denaturation of enzymes and structural proteins

2. Inactivation of intracellular enzymes, including lysosomal enzymes, prevents autophagy

63
Q

Gross manifestation of coagulative necrosis

A

Infarction

- Exception is cerebral infarction

64
Q

Pale (ischemic) infarction - Mechanism

A

Increased density of tissue prevents RBCs released from damaged vessels from diffusing through the necrotic tissue
- Heart, kidney, spleen

65
Q

Hemorrhagic (red) infarction - Mechanism

A

Loose-textured tissue allows RBCs released from damaged vessels to diffuse through the necrotic tissue
- Lung, bowel, testicle

66
Q

Liquefactive necrosis - Definition

A

Necrosis with degradation of tissue that softens and becomes liquified

67
Q

Coagulative necrosis - Mechanism

A

Release of lysosomal enzymes by necrotic cells and/or the release of hydrolytic enzymes by neutrophils entering the tissue

  • Note that the release of lysosomal enzymes occurs prior to the denaturation of structural and enzymatic proteins, opposite that of coagulation necrosis
68
Q

Gross manifestation of liquefactive necrosis (2)

A
  1. Cerebral infarction
    - Autocatalytic effect of hydrolytic enzymes released by neuroglial cells
  2. Bacterial abscess
    - Hydrolytic enzymes released by neutrophils liquefy dead tissue, producing a cavity filled with purulent material
69
Q

Caseous necrosis - Infections (3)

A
  1. Mycobacterium tuberculosis (TB)
  2. Nocardia
  3. Fungal infections
70
Q

Caseous necrosis - Mechanism

A

Caseous material is produced by the release of lipid from the cell walls (mycolic acid) of M. tuberculosis, Nocardia, and systemic fungi after immune destruction by macrophages in the granulomas

71
Q

Enzymatic fat necrosis

  • Pathologic condition
  • Mechanism
A
  • Enzymatic fat necrosis of the peripancreatic fat 2/2 acute pancreatitis
  • Pancreatic lipase and phospholipase hydrolyze triacylglycerols in fat cells with release of fatty acids
  • Ca2+ combines with the fatty acids to produce soap (saponification –> dystrophic calcification)
72
Q

Traumatic fat necrosis

  • Pathologic condition
  • Mechanism
A
  • Non-enzymatic fat necrosis in fatty 2/2 blunt trauma or surgery (e.g., breast trauma)
  • Ca2+ combines with the fatty acids released 2/2 blunt trauma to produce soap (saponification –> dystrophic calcification)
73
Q

Necrosis types a/w the pancreas (2)

A
  1. Liquefactive necrosis of the pancreatic parenchyma

2. Enzymatic fat necrosis of the peripancreatic fat

74
Q

Dystrophic calcification

A

Abnormal deposition of Ca2+ in NONVIABLE TISSUES in the setting of NORMAL Ca2+/phosphate levels

75
Q

Metastatic calcification

A

Abnormal deposition of Ca2+ in VIABLE TISSUES in the setting of ABNORMAL (ELEVATED) Ca2+ and/or phosphate
- Elevated phosphate drives Ca2+ into tissues

76
Q

Fibrinoid necrosis - Definition/mechanism

A

Deposition of pink-staining proteinaceous material (fibrin) in damaged tissue

77
Q

Fibrinoid necrosis - Conditions (3)

A
  1. Malignant hypertension
  2. Immune vasculitis
  3. Pre-eclampsia (fibrinoid necrosis of the placental vessels)
78
Q

Free radicals - Targets (2)

A
  1. Nucleic acids (oxidation of DNA)

2. Cell membranes (lipid peroxidation)

79
Q

Brown atrophy

A

Undigested lipids derived from lipid peroxidation of autophagized organelle membranes are stored as RESIDUAL BODIES (LIPOFUSCIN/LIPOCHROME) in PRIMARY LYSOSOMES

  • Brown/yellow “wear and tear” pigment
80
Q 
Reactive oxygen species (ROS):
O2 + 1e = 
O2 + 2e =
O2 + 3e = 
O2 + 4e =
A

O2 + 1e = superoxide (O2•-)
O2 + 2e = hydrogen peroxide (H2O2)
O2 + 3e = hydroxyl radical (OH•)
O2 + 4e = 2H2O

81
Q

Most destructive free radical

A

Hydroxyl radical (OH•)

82
Q

Antioxidants (4)

A

Vitamin A, vitamin C, vitamin E, glutathione

83
Q

Glutathione - Oxidized and reduced forms

A

Oxidized form - GSSG

Reduced form - 2GSH

84
Q

Antioxidant that best neutralizes hydroxyl radical (OH•)

85
Q

Reactive oxygen species - Superoxide dismutase (SOD)

  • Cellular location
  • Catalyzed reaction
A 
Superoxide dismutase (mitochondria)
4 O2•- + (4H+)  --> 2H2O2 + 2O2
86
Q

Reactive oxygen species - Glutathione reductase

  • Cellular location
  • Catalyzed reaction
A

Glutathione reductase (mitochondria)

  1. H2O2 (generated from SOD) is reduced to form 2H20
  2. Reduced glutathione (2GSH) is oxidized to form oxidized glutathione (GSSG)
87
Q

Reactive oxygen species - Catalase

  • Cellular location
  • Catalyzed reaction
A

Catalase (peroxisomes)

2H2O2 –> 2H2O + O2

88
Q

Acetaminophen - Metabolism in normal doses

A

CYP450 system - Smooth ER of hepatocytes

- Metabolized to glucuronate or sulfate conjugates that are excreted by the kidneys

89
Q

Acetaminophen - Metabolism in toxic doses

A

CYP450 isoenzyme CYP2E1 - Smooth ER of hepatocytes

- Metabolized to toxic intermediate NAPQI

90
Q

Acetaminophen - Metabolism in normal doses in alcoholics

A
  • Alcohol induces CYP2E1 synthesis, causing a
91
Q

Acetaminophen poisoning - Liver cell necrosis

- Initial site

A

Centrilobar zone III around the central venules

- Greatest concentration of CYP2E1 in zone III

92
Q

Amyloidosis - Mechanism of injury

A

Amyloid deposits in interstitial tissue, which results in organ dysfunction 2/2 pressure atrophy of adjacent cells

93
Q

Amyloidosis - Congo red stain with polarizing microscopy

A

Amyloid stains red with Congo red stain and exhibits apple green birefringence under polarizing microscopy 2/2 beta-pleated sheet configuration of misfolded proteins

94
Q

Primary amyloidosis is the systemic deposition of ___ amyloid which is derived from ___

A

Primary amyloidosis is the systemic deposition of AL AMYLOID which is derived from Ig light chains synthesized in plasma cells

95
Q

Primary amyloidosis a/w (1)

A

Plasma cell dyscrasias

96
Q

Secondary amyloidosis is the systemic deposition of ___ amyloid which is derived from ___

A

Secondary amyloidosis is the systemic deposition of AA AMYLOID which is derived from SERUM AMYLOID A (SAA), an acute phase reactant synthesized by the liver

97
Q

Secondary amyloidosis a/w (3)

A
  1. Chronic inflammatory states
  2. Malignancy
  3. Familial Mediterranean fever
98
Q

Familial Mediterranean fever

  • Inheritance
  • Pathology
  • Clinical findings (3)
A

FMF is an AR “auto-inflammatory” disorder characterized by excess IL-1 production a/w systemic AA amyloid deposition, fever, and inflammation of serosal surfaces (pleura, peritoneum, synovium)

99
Q

Systemic amyloidosis

  • Organ most commonly targeted with amyloid deposition
  • Diagnosis
A
  • Amyloid deposition most commonly in kidney
  • Diagnosis with abdominal fat pad or rectal biopsy
  • End-organ failure 2/2 amyloidosis must be transplanted
100
Q

Senile cardiac amyloidosis

  • Amyloid protein
  • Amyloid protein derivation
  • Clinical findings
A
  • Amyloid derived from TTR (ATTR)
  • Transthyretin (TTR) - T4 and retinoic acid carrier protein
  • Usually asymptomatic; present in 25% of patients > 80y/o
101
Q

Familial amyloid cardiomyopathy

  • Amyloid protein
  • Amyloid protein derivation
  • Clinical findings
A
  • Amyloid derived from mutated TTR (ATTR)
  • Mutated transthyretin (TTR)
  • Restrictive cardiomyopathy
102
Q

Type II diabetes mellitus

  • Amyloid protein
  • Amyloid protein derivation
A
  • Amyloid derived from islet amyloid polypeptide (AIAPP)
  • Islet amyloid polypeptide (IAPP), also called amylin
  • IAPP/amylin co-secreted with insulin
103
Q

Alzheimer disease

  • Amyloid protein
  • Amyloid protein derivation
A
  • Aβ amyloid

- β-amyloid precursor protein (β-APP), chromosome 21

104
Q

Dialysis-associated amyloidosis

  • Amyloid protein
  • Amyloid protein derivation
  • Clinical findings
A
  • Amyloid derived from β2M (Aβ2M)
  • β2-microglobulin (MHC class I light chain)
  • Amyloid deposition in joints, synovial membranes, and tendon sheaths –> Carpal tunnel syndrome, joint pathology
105
Q

Medullary carcinoma of the thyroid

  • Amyloid protein
  • Amyloid protein derivation
  • Clinical findings
A
  • Amyloid derived from calcitonin (A-Cal)
  • Calcitonin produced by neoplastic parafollicular C cells of the thyroid
  • Tumor in an amyloid background

*USMLE Step 1, General Principles (3 decks)

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