Flashcards in Cellular Injury and Adaptation Deck (174):
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Homeostasis
balance of physiologic and biochemical functions within the body
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Alteration of homeostasis results in
stress to cell, cellular injury or adaptive changes to survive altered environment
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Reversible injury
injury is corrected prior to destruction of cellular repair mechanisms; severity of injury does not exceed the cells ability to repair itself
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Irreversible injury
repair mechanisms are destroyed (removal from altered environment will be insufficient) cell cannot repair itself --> DEATH; injury exceeds the cell's ability for self-repair, resulting in cell death
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Cellular Injury
Hypoxia, Physical agents, chemicals, infectious agents, immune reactions, genetic derangements, nutritional imbalance
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Hypoxia
Decreased supply of O2 to cell or inability to use O2
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Anoxia
Complete absence of O2
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Causes of Hypoxia
Ischemia (decreased BF), decreased oxygenation of blood, decreased O2 carrying capacity, inability to utilize O2
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Examples of Physical injury to cell
mechanical trauma, temperature extremes, atmospheric pressure variation, radiation, electrical injury
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Examples of Chemical Injury to cell
Simple agents (electrolytes, glucose), Poisons, Pollutants, Insecticides, herbicides, industrial products, drugs (therapeutic or recreational), alcohol
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Infectious Causes of cell injury
bacteria, rickettsia, fungi, virus, parasite
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Immune Response Causes of cell injury
Hypersensitivity reaction
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4 Key Signs of REVERSIBLE cell injury
Decreased aerobic respiration, cellular edema, ribosome detachment from RER, ultrastructural morphological changes
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Reversible Injury - Decreased Aerobic Respiration Results in
Decreased ATP production, increased AMP and anaerobic glycolysis, Increased lactate (decreased pH), decreased cellular glycogen, clumping of nuclear chromatin, decreased protein synthesis
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Examples of nutritional variations that cause cellular injury
deficits, excess, malabsorption, altered use
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Sites that are altered in cellular injury
cell membrane integrity, aerobic respiration, enzyme/protein synthesis, genetic apparatus
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What causes cellular edema in reversible cell injury?
Suppression of Na+ pump with increased [Na+] retention; increased intracellular Na+
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Ultrastructural Morphological Changes in reversible cellular injury
Phospholipid membrane alteration, loss of microvilli, myelin figure formation, mitochondrial swelling, RER swelling
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Key Signs of IRREVERSIBLE cellular injury
ATP Depletion, Cell Membrane Damage
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Cell Membrane Damage as a result of irreversible damage
Phospholipid Depletion, Cytoskeletal breakdown, toxic ROS, Lipid breakdown products, amino acid loss
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Structural changes in IRREVERSIBLE cell injury include
vacuolization of mitochondria, PM damage, Lysosomal swelling, Loss of proteins, enzymes, and RNA
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What characterizes cell injure as irreversible?
ATP depletion, cellular edema -> PM tears and damage, mitochondrial dysfunction (high [Ca2+] intracellularly), Membrane phospholipid depletion, cytoskeleton changes, ROS, lipid breakdown products, and amino acid loss
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Irreversible Cellular Damage - What is the determining/most important factor?
Cellular Membrane Dysfunction
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Irreversible Cellular Damage - What results from mitochondrial dysfunction?
ATP depletion -> increased cytosolic [Ca2+] -> mitochondrial phospholipase activation -> phospholipid breakdown + accumulation of FFA -> altered permeability of PM
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Myelin figures are characteristic of
reversible injury
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cellular edema is characteristic of
reversible injury
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Irreversible Cellular Damage - What causes membrane phospholipid depletion?
increase [Ca2+] intracellular activation of phospholipase AND ATP-dependent maintenance and production of phospholipids
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Irreversible Cellular Damage - What causes cytoskeletal abnormalities?
Hypoxia AND activation of proteases by high intracellular levels of [Ca2+]
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Irreversible Cellular Damage - What causes Toxic oxygen radical production?
sudden repercussion of hypoxic tissue
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Irreversible Cellular Damage - What produces Toxic oxygen radicals?
segmented neutrophils
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Reperfusion Injury
sudden reperfusion of ischemic tissue causes toxic oxygen radical production by segmented neutrophils
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Irreversible Cellular Damage - What produces lipid breakdown products?
phospholipase breakdown of pospholipids, high [FFA]
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Irreversible Cellular Damage - What amino acid is protective?
GLYCINE
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GLYCINE's protective feature
allows ATP depleted cells to resist high Ca2+ levels
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decreased aerobic respiration is a characteristic of
reversible injury
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increased intracellular pH is a characteristic of
reversible injury
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Increased intracellular AMP is a characteristic of
reversible injury
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Decreased glycogen stores v
reversible injury
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clumping of nuclear chromatin is a characteristic of
reversible injury due to decreased pH
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Ribosome detachment from RER is a characteristic of
reversible injury
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decreased function of sodium pump is a characteristic of
reversible injury
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Increased intracellular sodium is a characteristic of
reversible injury
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decreased protein synthesis is a characteristic of
reversible injury
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swelling of mitochondria is a characteristic of
reversible injury
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loss of microvilli is a characteristic of
reversible injury
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accumulation of lactate metabolites and phosphate is a characteristic of
reversible injury
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blebs is a characteristic of
reversible edema; due to structural alterations in phospholipid membranes
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myelin figures is a characteristic of
reversible injury
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ATP depletion reversible injury
irreversible injury; suppression of ATP-dependent repair mechanisms
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vacuolization of mitochondria is a characteristic of
irreversible injury
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lysosomal swelling is a characteristic of
irreversible injury
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loss proteins/enzymes and RNA is a characteristic of
irreversible injury
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PM tearing/damage is a characteristic of
irreversible injury
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Increased cytosolic [Ca2+] is a characteristic of
irreversible injury
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Increased [Ca2+] causes
activation of mitochondrial phospholipase and lysosomal proteases, ATPases, endonucleases
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Phospholipase
mitochondrial ([Ca2+] activated) breaks down phospholipids of PM
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Accumulation of FFA's is a characteristic of
irreversible injury
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Permeability changes in PM is a characteristic of
irreversible injury
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Membrane phospholipid depletion is a characteristic of
irreversible injury
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Damage to intermediate cytoskeletal filaments is a characteristic of
irreversible injury; hypoxia induced
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Separation of PM and cytoskeleton is a characteristic of
irreversible injury
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Proteases
lysosomal proteases released and activated by high intracellular [Ca2+]
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Toxic oxygen radicals is a characteristic of
irreversible injury
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reperfusion injury is a characteristic of
irreversible injury
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accumulation of lipid breakdown products is a characteristic of
irreversible injury
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loss of glycine and other amino acids is a characteristic of
irreversible injury
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Glycine
allows ATP depleted cells to resist high Ca2+ levels
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Reason for decreased protein synthesis in cellular injury?
detachment of ribosomes from RER
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Reason for nuclear clumping in cellular injury?
increased anaerobic glycolysis and decreased pH
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Intracellular release of lysosomal enzymes is a characteristic of
irreversible injury
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What is a free radical?
Activated oxygen or carbon species that cause cell damage (ROS, COS)
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Unstable free radicals react with?
inorganic and organic chemicals in membrane lipids and nucleic acids
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What generates free radicals?
autocatalytic reactions within the cell, O2 therapy, radiation, oxidative injury, reperfusion, chemicals, inflammation, microbes, gases, aging
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Free radicals can result in
lipid peroxidation, oxidative protein modification, DNA damage
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Examples of Free radicals
Hydrogen Peroxide (H2O2), Superoxide (O2-), Hydroxyl ions (-OH)
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Superoxide dismutase
converts superoxide (O2-) to hydrogen peroxide (H2O2)
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Radiation creates free radicals by
radiolysing H2O into hydroxyl ions (-OH)
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Aging and free radicals
continuous free radical production, decreased anti-oxidant production, decreased anti-oxidant activity
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Agents that are protective against free radicals
Antioxidants: Vitamin E, Glutathione, D-Penicillamine, serum proteins, flavonoids
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Catalase enzyme converts
H2O2 --> H2O and O2
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Glutathione peroxidase
H2O2 --> H20
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Free radical production increases with
AGE
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Direct acting chemicals induce chemical injury by
DIRECTLY combining with critical components of cellular organelle
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By-products of glycolysis
H2O2 and O2-
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Toxic metabolites of chemicals induce chemical injury by
metabolism of drugs create toxic active metabolites that can either directly bind critical components of cellular organelle or induce freed radical formation
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Lipid peroxidation in the liver due to drug metabolites free radical production result in
lipid peroxidation causing damage to RER and PM -> ribosome detachment and decreased protein synthesis (Fatty liver) OR -> PM damage and increased permeability, cell swelling, influx of Ca, necrosis
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Viral infections cause cell injury by
causing cytolysis or cytopathic changes (degenerative changes)
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How does a virus directly damage the cell?
viral replication interferes with cellular mechanisms
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How does a virus inadvertently cause cell damage?
induces immunologic response: viral tropism (supporting growth of virus) result in phagocytosis, endocytosis or direct fusion of host cell
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Viral infections may cause host cell
lysis, cytoskeletal alterations, syncytial/giant cell formation, or inclusion formation
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Physiologic and biochemical mechanisms resulting in cellular injury may cause
morphological alterations in the cell
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Ultrastructural morphological changes include
PM alterations: swelling, blood formation, microvilli destruction, myelin figures;
Mitochondria: swelling, densities and granule formation
ER: swelling
Lysosome: swelling, rupture
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What morphological changes may be seen with the LIGHT microscope?
Reversible Injuries: Cellular swelling and intracellular accumulations
Irreversible Injuries: cell death
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Cell Death morphologic changes result from
Progressive degradation: enzyme digestion of cellular components and denaturation of proteins
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Autolysis
cellular digestion and denaturation cause by enzymes produced by necrotic cell
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Heterolysis
cellular digestion and denaturation cause by enzymes produced by cells other than the one affected
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General morphologic appearance of necrotic cell cytoplasm under the microscope?
eosinophilic (pink with H&E), glassy (loss of glycogen), and vacuolated
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General morphologic appearance of necrotic cell nucleus under the microscope?
clumped chromatin, pyknosis (shrunken nucleus), karyolysis (degraded nucleus), karyorrhexis (breakup of nucleus)
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Pyknosis
shrunken nucleus (as seen with necrotic cells)
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Karyolysis
degraded nucleus (as seen with necrotic cells)
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Karyorrhexis
breakup of nucleus (as seen with necrotic cells)
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Apoptosis
type of necrosis of an individual cell death by fragmentation and phagocytosis of fragments
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Coagulation Necrosis
Lose of nucleus due to denaturation of nuclear proteins and lysosomal enzymes (thus preventing proteolysis); cell shape maintained, eosinophila prominent
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Organs typically with coagulation necrosis
heart, kidney, and skeletal muscle
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Liquefeaction Necrosis
affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus
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Liquefeaction Necrosis hydrolytic enzymes are produced by
autolysis (self) or heterolysis (others)
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Liquefeaction Necrosis occurs primarily in the
brain, abdominal viscera and tissues infected with bacteria
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Liquefeaction Necrosis may result in _________ formation
abscess
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coagulation necrosis may progress to
Liquefeaction Necrosis
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Fat Necrosis
lipases cause saponification of fat -> resultant chalky white consistency
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Fat necrosis may result in ______
calcification
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Fat necrosis primarily occurs in
pancreas (after lipase and amylase release) and trauma to adipose tissue
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Caseation Necrosis is a combination of
coagulation and liquefaction necrosis
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Caseation Necrosis leads to ____ formation
granuloma
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Caseation Necrosis is characterized by
soft, granular, "cheesy" proteinacious material, surrounded by multinucleate giant cells, lymphocytes, and macrophages
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Caseation Necrosis primarily occurs in
any tissue infected with Mycobacterium tuberculosis and certain fungal infections
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Gangrenous Necrosis occurs primarily in
ISCHEMIC necrotic tissues, subsequently infected by anaerobic bacteria (Clostridium)
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Dry Gangrene
ISCHEMIA + necrosis and drying of the tissue -> black, mummified appearance
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Dry gangrene is typically caused by
arterial occlusion
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Dry gangrene microscopically shows ___________ necrosis
COAGULATION
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Wet gangrene is characterized by
soft, green-black, foul smelling purulent consistency
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Wet gangrene microscopically shows ___________ necrosis
Liquefaction following the release of autolytic, heterlytic, and bacterial enzymes
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Wet gangrene is typically caused by
arterial occlusion or traumatic injury
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Intracellular accumulations include
normal substances, abnormal substances, pigments; accumulation within the cell
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Intracellular accumulations may be:
harmful or harmless, within the cytoplasm or nucleus, produced by cell or elsewhere
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Types of intracellular accumulations
lipid, protein, glycogen, complex lipids, complex carbohydrates, pigments
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Lipid intracellular accumulations are characterized by
fatty change (fatty degeneration/infiltration)
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Lipid intracellular accumulations occur in
liver, heart, kidney, or skeletal muscle
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Lipid intracellular accumulations may be composed of
triglycerides, cholesterol, or both
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Protein intracellular accumulations may occur
in any tissue as HYALINE or plasma cells as RUSSELL BODIES
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Russell bodies
protein accumulation in plasma cells
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Protein intracellular accumulations often occur in
kidney, liver, or joints
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Glycogen intracellular accumulations
Common in diabetics (many tissues) and in glycogen storage diseases (specific or many tissues)
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Fatty liver
Fat accumulation in hepatocytes due to metabolic abnormality
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Lysosomal storage disease
accumulation in cells due to lack of enzyme
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Pigment intracellular accumulation
Normal or abnormal, produced endogenously or exogenously (uptake of indigestible material)
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Exogenous pigment accumulation include:
carbon (tattoo, anthracosis)
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Endogenous pigment accumulation include:
melanin, lipofuscin, hemosiderin, bilirubin and carotene
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Subcellular Alterations
changes occurring in the cell at the level of organelle
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Lysosome mechanism
vesicle from RER - Golgi - cytoplasm as primary lysosome fuses with phagosome to become secondary lysosome; hydrolytic enzymes digest phagosome particles
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Heterophagocytosis
type of phagocytosis of a compound outside the cell begin brought into the cell
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Heterophagocytosis is carried out by
neutrophils and macrophages
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Autophagocytosis
type of phagocytosis where lysosomes phagocytose damaged organelle originate ding within the same cell
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SER subcellular alterations due to injury
SR is broken down after PM damage
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Mitochondrial subcellular alterations due to injury
mitchondrial permeability transition pore -> loss of mitochondrial membrane potential -> loss of OXphos and ATP
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Lipofuscin pigment granules
finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion (aging process)
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What causes mitchondrial permeability transition pore formation?
increased Ca2+, free radicals, toxins, hypoxia
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Cytoskeleton/Cell membrane sub cellular alteration due to injury are characterized by
changes in the filaments and microtubules
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Damage to cytoskeletal filaments and MT's result in
altered cellular structure, impaired phagocytosis, impaired mitosis, impaired sperm motility
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Mallory Bodies
characteristic cytoskeletal change (twisted rope appearance) indicative of alcoholic liver disease
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Neurofibrillary tangles
characteristic cytoskeletal change - aggregates of hyperphosphorylated tau protein that are a primary marker of Alzheimer's Disease
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Atrophy - cellular adaptation
decreased cell size due to loss of cell substance
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Atrophy may be caused by
decreased workload (disuse), loss of innervation, decreased blood supply, inadequate nutrition, loss of endocrine stimulation, aging, pressure
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Hypertrophy
increase in cell size; increased demands of cell or increased stimulation by hormones
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Physiologic hypertrophy
uterine and breast enlargement during pregnancy
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Pathologic hypertrophy
cardiac hypertrophy in HTN or valvular incompetence
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Hyperplasia
increase in cell number (with hypertrophy depending on stimulus)
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Hyperplasia cannot occur in
nerve, skeletal, or cardiac muscle
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Physiologic Hyperplasia
Hormonal: epithelium of breast during puberty
Compensatory: to account for damaged tissue
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Pathologic Hyperplasia
Abnormal hormonal stimulation (endometrium, breast, adrenal)
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Metaplasia
Reversible change in cell type as a result of stress, divergent differentiation
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Metaplasia may lead to
pre-malignant (dysplastic) changes
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Dysplasia
Deranged development due to stimulation to proliferate with atypical cytological alterations
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Dysplasia may be
precursor to cancer
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Calcification
Calcium salt + other ions precipitate and deposit in tissues
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Dystrophic calcification
deposition of calcium as a sequelae to necrosis or tissue injury and inflammation; intra- or extracellular
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Examples of Dystrophic calcification
arteriosclerosis, fat necrosis
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Metastatic Calcification
Systemic hypercalcemia -> deposition of calcium in viable tissue
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What condition is known for systemic increased levels of Ca?
Hyperparathyroidism -> systemic metastatic calcification deposition
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Hyaline
translucent, albuminoid protein which is the product of amyloid degeneration
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Intracellular hyaline deposition may occur
in plasma cells + viral infection, hepatocytes + chronic alcohol abuse
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Extracellular hyaline deposition may occur
arterial walls and in scar tissue following chronic inflammatory processes
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Desmoplasia
associated with malignant neoplasms, which can evoke a fibrosis response by invading healthy tissue.
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