Gen Path L5

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  1. Characteristics of Intracellular Accumulations:
    • origin - endogenous or exogenous
    • substance- normal or abnormal
    • synthesis by cell or produced elsewhere
    • accumulate in organelles, cytosol or nucleus
    • significance - completely harmless and indicators of pathology or the primary cause of disease
  2. The nature of accumulated intracellular substances
    • normal cellular constituent in excess - Water, proteins, lipids, carbohydrates, or complexes
    • abnormal substance: faulty synthesis or metabolism (endogenous) or Foreign and originates from outside the body (exogenous)
    • Pigments: endogenous (lipofuscin and hemosiderin) or exogenous
  3. Pathways of intracellular accumulations
    • Normal or increased rate of production of a normal substance, inadequate metabolic rate to remove it (e.g. fatty change in liver)
    • normal or abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion (e.g. α-1-antitrypsin deficiency)
    • Inherited defect in enzyme -> failure to degrade a metabolite; storage diseases
    • abnormal exogenous substance is deposited and accumulates, w/o enzymatic machinery to degrade or transport ability
  4. Fatty Change (Steatosis)
    • any abnormal accumulation of triglycerides within parenchymal cells.
    • Sites: liver, heart, kidney, skeletal muscle, and other organs.
    • Causes: Toxins (alcohol), diabetes mellitus, protein malnutrition (starvation), obesity, anoxia.
  5. Defects in any step of lipid metabolism can lead to lipid accumulation
    • Uptake, catabolism, secretion
    • Starvation -> increased free fatty acid uptake
    • CCl4 , protein malnutrition -> affect apoprotein which combines w/ triglyceride to form lipoprotein
    • Hepatotoxins (eg alcohol), anoxia -> affect oxidation of fatty acid to ketone bodies and CO2.
  6. Morphology of fatty change
    With increasing accumulation, the organ enlarges and becomes progressively yellow, soft, and greasy.
  7. Fatty change is reversible except if
    some vital intracellular process is irreversibly impaired (e.g., in CCl4 poisoning).
  8. Alcoholic liver disease
    • alcoholic steatosis - fatty change, periventricular fibrosis
    • alcoholic hepatitis - mallory bodies, inflammation, fatty change, necrosis
    • alcoholic cirrhosis (irreversible) - fibrosis, hyperplastic nodules
  9. Cellular cholesterol metabolism is tightly regulated to ensure ________ synthesis without significant intracellular accumulation.
    normal cell membrane
  10. Foam cells:
    Lipid-laden macrophages
  11. Atherosclerosis:
    • Intimal layer of aorta & large arteries
    • deposition of cholesterol, phagocytosed by macrophage cells to form different kinds of foam cells
    • triggers inflammatory process
    • enlarges the deposition
    • Causes narrowing of the vessels
    • High incidence of myocardial and cerebral infarction
  12. Xanthomas:
    • Fats build up under the surface of the skin.
    • foam cells
    • subepithelial connective tissue of skin or in tendons
  13. Cholesterolosis:
    Abnormal deposits of cholesterol esters (foam cells) in Gallbladder
  14. protein accumulations
    • much less common than lipid accumulations
    • excesses are presented to the cells or the cells synthesize excessive amounts
    • Reabsorption droplets in proximal renal tubules – proteinuria
    • Immunoglobulin in plasma cells - Marked accumulation of newly synthesized immunoglobulins in the RER of some plasma cells, forming rounded,
    • eosinophilic Russell bodies
    • Defective protein folding - Alpha-1 Antitrypsin deficiency; Neurodegenerative diseases
  15. Nephrotic syndrome:
    • In the kidney trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules
    • After heavy protein leakage, pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink, hyaline cytoplasmic droplets
  16. Mallory body
    • "alcoholic hyalin"
    • eosinophilic cytoplasmic inclusion in liver cells highly characteristic of alcoholic liver disease
    • composed predominantly of aggregated intermediate filament proteins
  17. alpha-1 antitrypsin deficieny (A1AT)
    • made in liver, released into blood, ultimately protects the lungs from attack by antibacterial elastase made by neutrophil
    • When mutated, A1AT is stuck in liver, the lungs are attacked by neutrophil elastase w/o the protection, and the accumulation of A1AT can damage the liver.
  18. Pathogenesis of emphysema
    • Oxidative stress, increased apoptosis and senescence
    • Inflammatory cells and mediators
    • Protease-antiprotease imbalance (can be induced by A1AT deficiency)
    • All lead to alveolar wall destruction
  19. Glycogen accumulations
    • abnormalities in the metabolism of glucose or glycogen
    • Examples:
    • 1. In poorly controlled diabetes mellitus, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. high glucose inhibits metabolism of glycogen.
    • 2. Glycogen accumulates within cells in a group of closely related genetic disorders - glycogen storage diseases, or glycogenoses
  20. Pompe disease (glycogen storage disease type II)
    • shows myocardial fibers full of glycogen seen as clear spaces.
    • alpha-1,4-glucosidase deficiency which breaks down the glycogen that accumulates in autophagosomes
  21. Pigments
    • colored substances
    • exogenous or endogenous
  22. Exogenous pigment - Carbon or coal dust
    • inhaled, phagocytosed by alveolar macrophages, and transported through lymphatic channels to the
    • regional tracheobronchial lymph nodes
    • anthracosis (blackening of lung)
    • also asbestosis, silicosis, and pneumoconiosis.
  23. Exogenous pigment - Tattooing
    • Pigments inoculated
    • phagocytosed by dermal macrophages
  24. Endogenous pigments
    • lipofuscin
    • melanin
    • certain derivatives of hemoglobin (hemosiderin)
  25. Lipofuscin
    • "wear-and-tear pigment"
    • insoluble brownish-yellow granular intracellular material
    • seen in a variety of tissues (heart, liver, and brain) as a function of age or atrophy
    • Mechanism of formation: product of lipid peroxidation, accumulates in lysosomes as the cell ages.
    • Not injurious
    • important marker of past free-radical injury.
    • when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.
  26. Melanin
    • endogenous, brown-black pigment
    • the pigment primarily responsible for skin color
    • only produced in melanocytes
    • accumulates in adjacent basal keratinocytes in the skin (dermal macrophages)
  27. Hemosiderin
    • hemoglobin-derived granular pigment
    • golden yellow to brown
    • accumulates when there is a local or systemic excess of iron, result from hemorrhage
    • represents large aggregates of ferritin (Ferrin plus iron) micelles, can be seen by light and electron microscopy
  28. Bruise:
    • Extravasated red cells at the site of injury are phagocytosed over several days by macrophages, which break down the hemoglobin and recover the iron.
    • The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and then bilirubin (red bile) from the heme, after removal of iron
    • iron released from heme is incorporated into ferritin and eventually hemosiderin, the iron can be unambiguously identified by the Prussian blue histochemical reaction
Card Set:
Gen Path L5
2016-09-05 18:06:06
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