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  • Cells are active participants in their environment, constantly adjusting their structure and function to accommodate changing demands and extracellular stresses. Cells tend to maintain their intracellular milieu within a fairly narrow range of physiologic parameters; that is, they maintain normal homeostasis. As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation, achieving a new steady state and preserving viability and function. The principal adaptive responses are hypertrophy, hyperplasia, atrophy, and metaplasia. If the adaptive capability is exceeded or if the external stress is inherently harmful, cell injury develops (Fig. 1-1). Within certain limits injury is reversible, and cells return to a stable baseline; however, severe or persistent stress results in irreversible injury and death of the affected cells. Cell death is one of the most crucial events in the evolution of disease in any tissue or organ. It results from diverse causes, including ischemia (lack of blood flow), infections, toxins, and immune reactions. Cell death is also a normal and essential process in embryogenesis, the development of organs, and the maintenance of homeostasis.
  • The term “hyaline” is the most commonly confused concept in pathology. ANY eosinophilic staining, amorphic substance, can be correctly called hyaline, especially necrosis, amyloid, various proteinaceous secretions, fibrin are the most common.
  • The slit-like spaces are cholesterol clefts, a classic feature of atherosclerosis.
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    1. 1. Reversible cellular injury Part 1 Cellular swelling- vacuolar and hydropic degeneration Intracellular accumulation of lipids -atherosclerosis. Lipidoses.
    2. 2. Reversible cellular injury 1  Disorders in the cellular water balance.  Lipid accumulation within the parenchymal cells /lipid degeneration/.  Lipid accumulation within the mesenchymal cells. Lipid phagocytosis.  Lysosomal storage diseases / tesaurismoses/.  Abnormal accumulation of complex lipids in the cell - lipidosis.
    3. 3. CELLULAR RESPONSES TO STRESS AND PATHOGENIC FACTORS hypertrophy, hyperplasia, atrophy metaplasia
    4. 4. REVERSIBLE CELL INJURY  Morphologic changes in early stages or mild forms of injury  reversible if the damaging stimulus is removed  Some injuries can lead to death if prolonged and or severe enough  In the past  Degeneration (degenerare – changing)  Dystrophia (dys+trophe –abnormal feeding)
    5. 5. REVERSIBLE CELL INJURY  Two groups morphologic changes  Disorders in the cellular water balance  Cellular swelling  Abnormal intracellular accumulations  Lipids  Glycogen, mucopolysacharides  Proteins  Pigments
    6. 6. Disorders in the cellular water balance Cellular swelling  The first manifestation of almost all forms of injury to cells – hypoxia, infections, poisons  Increased cellular water content  Due to failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis.
    7. 7. Disorders in the cellular water balance Cellular swelling  It is difficult to appreciate with the light microscope  It may be more apparent at the level of the whole organ-macroscopy  it causes some pallor, increased turgor, and increase in weight of the organ.  Site of localization  Renal tubular cells  Hepatocytes  Myocardial cells
    8. 8. Disorders in the cellular water balance Cellular swelling  Microscopic examination  Cells are swollen, deformed, pale  hydropic change or vacuolar degeneration –the presense of small, clear vacuoles within the cytoplasm  they represent distended and pinched-off segments of the ER.  Swelling of cells is reversible.
    9. 9. Degeneratio parenchymatosa renis The epithelial cell of the proximal convoluted tubules are swollen and deformed, with pale and dull cytoplasm
    10. 10. Abnormal intracellular accumulations  Under some circumstances cells may accumulate abnormal amounts of various substances  They may be harmless or associated with varying degrees of injury.  may be located in the cytoplasm, within organelles (lysosomes), or in the nucleus
    11. 11. Abnormal intracellular accumulations 3 main pathways of intracellular accumulations  A normal substance is produced at a normal or an increased rate, but the metabolic rate is inadequate to remove it.  fatty change in the liver  A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion.  accumulation of proteins - α1-antitrypsin deficiency  defect in an enzyme results to failure to degrade a metabolite – storage diseases  An abnormal exogenous substance is deposited and accumulates because the cells has no enzymatic machinery to degrade the substance nor the ability to transport it to other sites  Accumulations of carbon or silica particles
    12. 12. Intracellular accumulations  Lipids  Neutral Fat  Cholesterol  Proteins  “Hyaline” = any “proteinaceous” pink “glassy” substance  Glycogen  Pigments  Endogenous  exogenous
    13. 13. Intracellular lipid accumulations  Sites of localization  within the parenchymal cells -lipid degeneration  within the fat cells – obesitas, lipomatosis  within the macrophages -lipid phagocytosis.
    14. 14. Lipid accumulation within the parenchymal cells Lipid degeneration  = Fatty Change (Steatosis)  refers to any abnormal accumulation of triglycerides within parenchymal cells.  It is most often seen in the liver, since this is the major organ involved in fat metabolism  It may also occur in heart, skeletal muscle, kidney, and other organs.  Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia.
    15. 15. Pathogenesis of fatty liver  Fat metabolism  Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes  they are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies  Some fatty acids are synthesized from acetate within the hepatocytes as well.  Secretion of the triglycerides from the hepatocytes requires the formation of complexes with apoproteins to form lipoproteins, which are able to enter the circulation  Excess accumulation of triglycerides may result from defects at any step from fatty acid entry to lipoprotein exit, thus accounting for the occurrence of fatty liver after diverse hepatic insults.  Overfeeding, obesitas, diabetes mellitus - ↑ FFA income  Starvation- ↑ fatty acid mobilization from peripheral stores.  Hypoxia and Hepatotoxins (e.g., alcohol) - ↓fatty acid oxidation (alter mitochondrial, SER function)  CCl4 and protein malnutrition - ↓ synthesis of apoproteins
    16. 16. Morphology of fatty changes  In any site, fatty accumulation appears as clear vacuoles within parenchymal cells.  Special staining techniques are required to distinguish fat from intracellular water or glycogen, which can also produce clear vacuoles but have a different significance.  To identify fat microscopically, tissues must be processed for sectioning without the organic solvents typically used in sample preparation - frozen sections, by staining with Sudan IV or oil red O (stain fat orange-red).  Glycogen may be identified by staining for polysaccharides using the periodic acid-Schiff stain (stains glycogen red- violet).  If vacuoles do not stain for either fat or glycogen, they are presumed to be composed mostly of water.
    17. 17. LIPID LAW  ALL Lipids are YELLOW grossly and WASHED out (CLEAR)
    18. 18. FATTY LIVER  Gross appearance  Mild fatty change in the liver may not affect the gross appearance.  With increasing accumulation, the organ enlarges and becomes progressively yellow  it may weigh 3 to 6 kg (1.5-3 times the normal weight)  bright yellow, soft, and greasy.
    19. 19. FATTY LIVER  Microscopic features  Microvesicular steatosis  Macrovesicular steatosis  mixed
    20. 20. Degeneratio Adiposa Hepatis (HE, Sudan III)
    21. 21. Lipid degeneration of myocardium  In the heart, lipid is found in the form of small droplets, occurring in one of two patterns  In prolonged moderate hypoxia (anemia)- focal intracellular fat deposits (papillary muscles)  creating grossly apparent bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved heart ("tigered effect").  In more profound hypoxia or by some forms of toxic injury (e.g., diphtheria) – diffuse pattern of fatty change  uniformly affected myocytes.
    22. 22. Lipid degeneration of the ren  In the ren, lipid is found in the form of small droplets, occurring in the epithelial cells of convoluted tubules  In severe hypoxia  In nephrotic syndrome  Increases reabsorption of lipoproteins
    23. 23. FATTY CHANGES  The significance of fatty change depends on the cause and severity of the accumulation.  When mild it may have no effect on cellular function.  More severe fatty change may transiently impair cellular function - fatty change is reversible.  In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis
    24. 24. Lipid accumulations within the fat cells  General obesitas  within the fat cells of adipose tissue  Lipomatosis (local obesitas)  within the fat cells of connective tissue of different organs, no functional disturbances  Heart – subepicardium of right chamber  Pancreas – interlobular connective tissue
    25. 25. Lipid accumulations within the macrophages Lipid phagocytosis.  Phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesterol esters) in several different pathologic processes.  Macrophages in contact with the lipid debris of necrotic cells or abnormal (e.g., oxidized) forms of lipoproteins may become stuffed with phagocytosed lipid.  foam cells - macrophages filled with minute, membrane-bound vacuoles of lipid, imparting a foamy appearance to their cytoplasm.  In atherosclerosis - smooth muscle cells and macrophages are filled with lipid vacuoles composed of cholesterol and cholesteryl esters  these give atherosclerotic plaques their characteristic yellow color and contribute to the pathogenesis of the lesion  Xantomas – fibromas (benign tumors, where tumor cells accumulate cholesterol esters)  xanthos – yellow,  Xantelasmas  clusters of these foamy macrophages present in the subepithelial connective tissue of skin  In hereditary hyperlipidemic syndromes macrophages accumulate intracellular cholesterol - lipidoses
    26. 26. Arteriosclerosis  Endothelial cell damage of muscular and elastic arteries  Abdominal aorta  coronary artery,  popliteal artery  Internal carotid artery  Causes of endothelial cell injury  Hypertension, smoking, LDL  Cell response to endothelial injury  Macrophages and platelets adhere to damaged endothelium.  Released cytokines cause hyperplasia of medial smooth muscle cells.  Smooth muscle cells migrate to the tunica intima.  Cholesterol enters smooth muscle cells and macrophages (foam cells).  Smooth muscle cells release cytokines that produce extracellular matrix.  collagen, proteoglycans, and elastin  Development of fibrous cap (plaque)  Smooth muscle, foam cells, inflammatory cells, extracellular matrix  Fibrous cap overlies a necrotic center.  Cellular debris, cholesterol crystals (slit-like spaces), foam cells  Disrupted plaques may extrude underlying necrotic material leading to vessel thrombosis  Fibrous plaque becomes dystrophically calcified and ulcerated.
    27. 27. Arteriosclerosis  Complications of atherosclerosis  Vessel weakness (e.g., abdominal aortic aneurysm)  Vessel thrombosis  acute MI (coronary artery),  Stroke (internal carotid artery, middle cerebral artery),  Small bowel infarction (superior mesenteric artery),  Hypertension  Renal artery atherosclerosis may activate the renin-angiotensin- aldosterone system.  Peripheral vascular disease  Increased risk of gangrene  Pain in the buttocks and when walking (claudication)  Cerebral atrophy  circle of Willis vessels or internal carotid artery
    28. 28. Atheromatosis Aortae (HE, SUDANIII)
    29. 29. Atheromatosis Aortae The slit-like spaces are cholesterol clefts, a classic feature of atherosclerosis
    30. 30. Tesaurismoses Lysosomal Storage Diseases  There is an inherited lack of a lysosomal enzyme, catabolism of its substrate remains incomplete, leading to accumulation of the partially degraded insoluble metabolites within the lysosomes  Lysosomes, contain a variety of hydrolytic enzymes that are involved in the breakdown of complex substrates into soluble end products.  Approximately 40 lysosomal storage diseases, divided into broad categories based on the biochemical nature of the substrates and the accumulated metabolites  Lipidosis  Glycogenosis  Mucopolysaccharidoses  Within each group are several entities, each resulting from the deficiency of a specific enzyme.  Despite this complexity, certain features are common to most diseases in this group
    31. 31. LIPIDOSIS  Autosomal recessive transmission of enzyme defects for lipid metabolism, leading to accumulation of undegraded lipid metabolites in the cells of different organs  Gaucher Disease  Tay-Sachs disease  Niemann-Pick Disease, Types A and B
    32. 32. LIPIDOSIS Gaucher Disease  The disease results from mutation in the gene that encodes glucosylceramidase (glucocerebrosidosis)  an accumulation of glucosylceramide in the mononuclear phagocytic cells (liver, lien, bone marrow) and their transformation into so-called Gaucher cells  derived from the breakdown of senescent blood cells, particularly erythrocytes  Gaucher cells  enlarged, (100 μm), because of the accumulation of distended lysosomes,  a pathognomonic cytoplasmic appearance characterized as "wrinkled tissue paper“  EM –lysosomes with tubular structures and fibrils  Clinical features  hepatosplenomegaly  Bones-osteopenia  ± neurologic disorders
    33. 33. LIPIDOSIS Tay-Sachs disease  Characterized by a mutation in and consequent deficiency of the α subunit of the enzyme hexosaminidase A, involving in the degradaytion of gangliosides  CNS –neurons, ganglia, retina  Neurologic disturbances, amaurosis  Affected cells - swollen, possibly foamy  EM- a whorled configuration within lysosomes
    34. 34. LIPIDOSIS Niemann-Pick Disease  A primary deficiency of acid sphingomyelinase and the resultant accumulation of sphingomyelin  Affected cells and organs  phagocytic cells of spleen, liver, bone marrow, lymph nodes, lungs  stuffed with droplets or particles of the complex lipid, imparting a fine vacuolation or foaminess to the cytoplasm  Neurons of CNS  enlarged and vacuolated as a result of the storage of lipids.  2 types  Type A –manifests itself in infancy with massive visceromegaly and severe neurologic deterioration  Type B – no neurologic disorders