1. What are the basic principles of growth adapdations?
    An organ is in homeostasis with the physiologic stress placed on it. An increase, decrease, or change in stress on an organ can result in growth adaptations.
  2. What leads to an increase in organ size?
    An increase in stress
  3. Hypertrophy occurs via what?
    an increase in the size
  4. Hyperplasia occurs via what?
    the number of cells
  5. What does hypertrophy involve?
    gene activation, protein synthesis, and production of organelles.
  6. What does Hyperplasia involve?
    the production of new cells from stem cells.
  7. Permanent tissues are... Do they undergo hypertrophy or hyperplasia?
    cardiac muscle, skeletal muscle, and nerve, cannot make new cells and undergo hypertrophy only.
  8. Pathologic hyperplasia leads to what?
    (e.g., endometrial hyperplasia) can progress to dysplasia and,eventually cancer.
  9. What is an exception to pathologic hyperplasia leading to cancer?
    benign prostatic hyperplasia (BPH), which does notincrease the risk for prostate cancer,
  10. What leads to a decrease in organ size?
    A decrease in stress (e.g., decreased hormonal stimulation, disuse, or decreased nutrients/blood supply) (atrophy).
  11. Atrophy occurs via?
    a decrease in the size and number of cells
  12. How does a decrease in cell number occur?
    via apoptosis.
  13. Decrease in cell size occurs via what?
    ubkjuitin-proteosome degradation of the cyloskeleton and autophagy of cellular components.
  14. What happens in ubiquitin-proteosome degradation?
    intermediate filaments of the cytoskeleton are tagged with ubiquitin and destroyed by proteosomes.
  15. What does autophagy of cellular components involve?
    generation of autophagic vacuoles that fuse with lysosomes whose hydrolytic enzymes breakdown cellular components.
  16. What happens in METAPLASIA?
    change in stress on an organ leads to a change in cell type
  17. Metaplasia most commonly involves?
    change of one type of surface epithelium (squamous, columnar, or urothelial) to another
  18. How do metaplastic cells handle the new stress?
    they are better able to handle the new stress.
  19. Esophagus is normally lined by what?
    nonkeratinizing squamous epithelium (suited to handle friction of a food bolus)
  20. Barrett esophagus
    Acid reflux from the stomach causes metaplasia to nonciliated mucin-producing columnar cells (better able to handle the stress of acid
  21. Metaplasia occurs via what?
    programming of stem cells, which then produce the new cell type.
  22. Is Metaplasia reversible?
    with removal of the driving stressor.
  23. Can metaplasia progress to cancer?
    Under persistent stress, can progress to dysplasia and eventually result in cancer.
  24. What is an exception to metaplasia leading to cancer?
    apocrine metaplasia of breast, which carries no increased risk for cancer.
  25. Vitamin A deficiency can result in what?
  26. Vitamin A is necessary for what?
    differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye.
  27. Keratomalacia
    In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium.
  28. Myositis Ossificans
    Mesenchymal (connective) tissues can undergo metaplasia. A classic example is myositis ossificans in which muscle tissue changes to bone during healing after trauma
  29. DYSPLASIA is?
    Disordered cellular growth
  30. Dysplasia most often refers to?
    proliferation of precancerous cells
  31. Cervical intraepithelial neoplasia (CIN)
    represents dysplasia and is a precursor to cervical cancer
  32. Dysplasia often arises from?
    longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus)
  33. Is dysplasia is reversible?
    yes, with alleviation of inciting stress.
  34. In dysplasia what happens if stress persists?
    dysplasia progresses to carcinoma irreversible)
  35. What is aplasia?
    it is failure of cell production during embryogenesis (e.g., unilateral renal agenesis)
  36. What is hypoplasia?
    it is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome)
  37. When does cellular injury occur?
    when a stress exceeds the cells ability to adapt
  38. The likelihood of injury depends on what?
    the type of stress, its severity, and the type of cell affected.
  39. What are highly susceptible to ischemic injury? As opposed to?
    neurons whereas, skeletal muscle is relatively more resistant.
  40. Slowly developing ischemia
    eg: renal artery atherosclerosis, results in ATROPHY
  41. acute ischemia
    eg: renal artery embolus, results in INJURY
  42. What are common causes of cellular injury?
    inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.
  43. What is HYPOXIA?
    Low oxygen delivery to tissue; important cause of cellular injury
  44. What is the final electron acceptor in the electron transport chain of oxidative phosphorylation?
  45. Decreased oxygen results in what?
    impairs oxidative phosphorylation, resulting in decreased ATP production
  46. What does a lack of ATP leads to?
    cellular injury
  47. What are some causes of hypoxia?
    include ischemia, hypoxemia, and decreased 02 - carrying capacity of blood.
  48. Ischemia is?
    decreased blood flow through an organ
  49. Ischemia arises with?
    1. Decreased arterial perfusion (eg atherosclerosis) 2. Decreased venous drainage (eg Budd-Chiari syndrome) 3. Shock—generalized hypotension resulting in poor tissue perfusion
  50. Hypoxemia is?
    a low partial pressure of oxygen in the blood (Pao2< 60 mm Hg, SaO2<90%).
  51. Hypoxemia arises with
    1. High altitude 2. Hypoventilation 3. Diffusion defect 4. V/Q mismatch
  52. High altitude to hypoxemia, how?
    Decreased barometric pressure results in decreased PaO2
  53. Hypoventilation to hypoxemia, how?
    Increased Paco, results in decreased PaO2
  54. Diffusion defect to hypoxemia, how?
    PAO2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis)
  55. V/Q mismatch to hypoxemia, how?
    Blood bypasses oxygenated lung (circulation problem, eg: right-to-left shunt), or oxygenated air cannot reach blood (ventilation problem, eg: atelectasis)
  56. Decreased O2-carrying capacity arises with what?
    hemoglobin (Hb) loss or dysfunction
  57. What are some examples of Decreased O2-carrying capacity?
    1. Anemia 2. Carbon monoxide poisoning 3. Methemoglobinemia
  58. Anemia leading to decreased O2 carrying capacity.
    (decrease in RBC mass) PaO2 normal; SaO2 normal
  59. Carbon monoxide poisoning
    CO binds hemoglobin more avidly than oxygen
  60. What is the PaO2 and SaO2 for carbon monoxide poisoning?
    PaO2 normal; SaO2 decreased
  61. Exposures for Carbon monoxide poisoning
    include smoke from fires and exhaust from cars or gas heaters.
  62. Classic finding for Carbon monoxide poisoning
    cherry-red appearance of skin.
  63. Early sign of exposure for Carbon monoxide poisoning
    headache; significant exposure leads to coma and death.
  64. What is Methemoglobinemia?
    Iron in heme is oxidized to Fe3+ which cannot bind oxygen
  65. PaO2 and SaO2 for Methemoglobinemia?
    PaO2 normal; SaO2 decreased
  66. Methemoglobinemia is Seen with?
    oxidant stress (eg sulfa and nitrate drugs) or in newborns
  67. Classic finding for Methemoglobinemia?
    cyanosis with chocolate-colored blood.
  68. Treatment for Methemoglobinemia?
    intravenous methylene blue, which helps reduce Fe3+ back to Fe2+ state.
  69. Hypoxia results in low ATP how?
    impairs oxidative phosphorylation resulting in decreased ATP.
  70. Low ATP disrupts what?
    key cellular functions including 1. Na/K pump 2. Ca2+ pump 3. Aerobic glycolysis
  71. Disruption of Na/K pump results in what?
    sodium and water buildup in the cell
  72. Disruption of Ca2+ pump results in what?
    Ca2+ buildup in the cytosol of the cell
  73. Disruption of Aerobic glycolysis results in what?
    switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DMA.
  74. The hallmark of reversible injury is
    cellular swelling.
  75. Cytosol swelling results in
    loss or microvilli and membrane blebbing.
  76. Swelling of the rough endoplasmic reticulum (RER) results in
    dissociation of ribosomes and decreased protein synthesis.
  77. The hallmark of irreversible injury is
    membrane damage.
  78. Plasma membrane damage results in
    1. Cytosolic enzymes leaking into the serum {e.g cardiac troponin) 2. Additional calcium entering into the cell
  79. Mitochondrial membrane damage results in
    1. Loss of the electron transport chain (inner mitochondrial membrane) 2. Cytochrome c leaking into cytosol (activates apoptosis)
  80. Lysosome membrane damage results in
    hydrolytic enzymes leaking into the cytosol, which in turn, are activated by the high intracellular calcium.
  81. The end result of irreversible injury is
    cell death.
  82. The morphologic hallmark of cell death is
    loss of the nucleus,
  83. loss of the nucleus occurs via
    nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis)
  84. The two mechanisms of cell death are
    necrosis and apoptosis.
    A. Death of large groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features
    A. Coagulative necrosis, B. liquefactive necrosis, C. Gangrenous necrosis D. Caseous necrosis E. Fat necrosis F. Fibrinoid necrosis
  87. What is Coagulative necrosis?
    Necrotic tissue that remains firm, cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears
  88. Coagulative necrosis is Characteristic of?
    ischemic infarction of any organ except the brain
  89. Area of infarcted tissue for Coagulative necrosis?
    It is often wedge-shaped (pointing to focus of vascular occlusion) and pale.
  90. What is Red infarction
    arises if blood re-enters a loosely organized tissue (e.g. pulmonary or testicular infarction)
  91. What is Liquefactive necrosis?
    Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction.
  92. Liquefactive necrosis is Characteristic of?
    Brain infarction, abscess, pancreatitis
  93. What type of necrosis for brain infarction?
    Liquefactive necrosis - Proteolytic enzymes from microglial cells liquefy the brain.
  94. What type of necrosis for abscess?
    Liquefactive necrosis - proteolytic enzymes from neutrophils liquefy tissue
  95. What type of necrosis for pancreatitis?
    Liquefactive necrosis - Proteolytic enzymes from pancreas liquefy parenchyma.
  96. What is Gangrenous necrosis?
    Coagulative necrosis that resembles mummified tissue (dry gangrene)
  97. Gangrenous necrosis is characteristic of?
    ischemia of lower limb and GI tract
  98. What is wet gangrene?
    superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).
  99. What is Caseous necrosis?
    Soft and friable necrotic tissue with cottage cheese-like appearance. It's a combination of coagulative and liquefactive necrosis
  100. What is caseous necrosis characteristic of?
    granulomatous inflammation due to tuberculous or fungal infection
  101. What is fat necrosis?
    Necrotic adipose tissue with chalky-white appearance due to deposition of calcium
  102. What is fat necrosis characteristic of?
    trauma to fat (eg. breast) and pancreatitis-mediated damage of peripancreatic fat
  103. Fat necrosis and saponification
    Fatty acids released by trauma (eg to breast) or lipase (eg pancreatitis) join with calcium via a process called saponification which is an example of dystrophic calcification in which calcium deposits on dead tissues.
  104. dystrophic calcification
    the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate
  105. Dystrophic calcification vs metastatic calcification
    high serum calcium or phosphate levels lead to calcium deposition in normal tissues (eg. hyperparathyroidism leading to nephrocalcinosis)
  106. Fibrinoid necrosis
    Necrotic damage to blood vessel wall, Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically
  107. What is fibrinoid necrosis characteristic of?
    malignant hypertension and vasculitis
  108. What is apoptosis?
    Energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells.
  109. Examples of apoptosis include
    1. Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. CD8+ T cell-mediated killing of virally infected cells
  110. Morphology of apoptosis
    1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink) 2. Nucleus condenses (pyknosis) and fragments (karyorrhexis).
  111. Apoptotic bodies
    fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation
  112. Apoptosis is mediated by
    caspases that activate proteases and endonucleases
  113. Proteases
    break down the cytoskeleton.
  114. Endonucleases
    break down DNA,
  115. How are caspases activated?
    1. Intrinsic mitochondrial pathway 2. Extrinsic receptor-ligand pathway 3. Cytotoxic CD8+ Tcell-mediated pathway
  116. What is the main molecule in the intrinsic mitochondrial pathway?
  117. What happens to Bcl2 in the intrinsic mitochondrial pathway?
    Cellular injury, DNA damage, or loss of hormonal stimulation leads to inactivation of Bcl2
  118. In the intrinsic mitochondrial pathway lack of Bcl 2 results in what?
    allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases.
  119. What is the extrinsic receptor-ligand pathway?
    FAS ligand binds to (CD95) FAS death receptor and TNF binds TNF receptor (both activate caspases)
  120. What is an example of FAS ligand binding to FAS death receptor (CD95) on the target cell activating caspases
    negative selection of thymocytes in thymus
  121. Cytotoxic CD8+ T cell-mediated pathway releases what?
    perforins and granzyme ex CD8+ T-cell killing of virally infected cells is an example.
  122. Perforins
    secreted by CD8+ T cell create pores in membrane of target cell
  123. Granzyme
    secreted from CD8+ T cell enters pores and activates caspases
  124. Free radicals are what?
    chemical species with an unpaired electron in their outer orbit.
  125. When does physiologic generation of free radicals occur?
    it occurs during oxidative phosphorylation
  126. How are free radicals generated physiologically?
    Cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of O2 yields superoxide (O2.) hydrogen peroxide (H202), and hydroxyl radicals (OH.)
  127. Pathologic generation of free radicals arises with?
    Ionizing radiation, inflammation, metals, drugs and chemicals
  128. Ionizing radiation and Pathologic generation of free radicals
    water hydrolyzed to hydroxyl free radical
  129. Inflammation and Pathologic generation of free radicals
    NADPH oxidase generates superoxide ions during oxygen dependent killing by neutrophils.
  130. Metals and Pathologic generation of free radicals
    (e.g., copper and iron) Fe generates hydroxyl free radicals (Fenton reaction).
  131. Drugs and chemicals and Pathologic generation of free radicals
    P450 system of liver metabolizes drugs (e.g acetaminophen), generating free radicals.
  132. Free radicals cause
    cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis.
  133. Elimination of free radicals occurs via what?
    Antioxidants, Enzymes, Metal carrier proteins
  134. Elimination of free radicals via Antioxidants
    glutathione and vitamins A , C, and E
  135. Elimination of free radicals via Enzymes
    SOD, glutathione peroxidase, catalase
  136. Superoxide dismutase
    (in mitochondria) superoxide (O2.—>H202)
  137. Glutathione peroxidase
    (in mitochondria) GSH + free radical GSSH and H202
  138. Catalase
    (in peroxisomes) H2O2 —> O2 and H202
  139. Elimination of free radicals via Metal carrier proteins
    transferrin and ceruloplasmin
  140. Free Radical Injury
    Carbon tetrachloride (CCl4) and Reperfusion Injury
  141. Carbon tetrachloride - What is it used for?
    Organic solvent used in the dry cleaning industry
  142. How is CCl4 metabolized?
    Converted to CC14 free radicals by P450 system of hepatocytes
  143. CCl4 results in what?
    cell injury with swelling of RER, ribosomes detach, impairing protein synthesis. Decreased apolipoproteins lead to fatty change in the liver
  144. Reperfusion injury
    Return of blood to ischemic tissue results in production of O2-derived free radicals, which further damage tissue. Leads to a continued rise in cardiac enzymes (troponin) after reperfusion of infarcted myocardial tissue
  145. What is an amyloid?
    It is a misfolded protein that deposits in the extracellular space, thereby damaging tissues.
  146. What are the shared features of amyloid proteins?
    beta-pleated sheet configuration, Congo red staining and apple-green birefringence when viewed microscopically under polarized light Deposition can be systemic or localized,
  147. What is primary amyloidosis?
    It is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain
  148. What is primary amyloidosis associated with?
    plasma cell dyscrasias (e.g multiple myeloma)
  149. Secondary amyloidosis is?
    systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA).
  150. What is SAA?
    It is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean Fever (FMF).
  151. What is FMF due to?
    a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin.
  152. What does FMF present with?
    episodes of fever and acute serosal inflammation
  153. FMF can mimic what?
    appendicitis, arthritis, or myocardial infarction
  154. How does FMF result in AA amyloid deposition in tissues?
    High SAA during attacks deposits as AA amyloid in tissues
  155. What is the most common organ involved in systemic amyloidosis?
  156. What are the clinical findings of systemic amyloidosis?
    Nephrotic syndrome, Restrictive cardiomyopathy or arrhythmia, Tongue enlargement, malabsorption, and hepatosplenomegaly
  157. Diagnosis of systemic amyloidosis requires what?
    tissue biopsy, Abdominal fat pad and rectum are easily accessible biopsy targets.
  158. Damaged organs of systemic amyloidosis must be...
    transplanted. Amyloid cannot be removed.
  159. What is localized amyloidosis?
    Amyloid deposition that is usually localized to a single organ
  160. What is senile cardiac amyloidosis?
    Non-mutated serum transthyretin deposits in the heart. Usually asymptomatic; present in 25% of individuals > 80 years of age
  161. Familial amyloid cardiomyopathy
    Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy, 5% of African Americans carry the mutated gene.
  162. Non-insulin-dependent diabetes mellitus (type II)
    Anylin (derived from insulin) deposits in the islets of the pancreas,
  163. Alzheimer disease
    amyloid beta (derived from J-amyloid precursor protein) deposits in the brain forming amyloid plaques
  164. Gene for J-APP is present on...
    chromosome 21.
  165. Downs syndrome and Alzheimers?
    Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset).
  166. Dialysis-associated amyloidosis
    B-microglobulin deposits in joints,
  167. Medullary carcinoma of the thyroid
    Calcitonin (produced by tumor cells) deposits within the tumor ('tumor cells in an amyloid background').
Card Set