Intracellular accumulation.pdf

Different agents can injure the various structural & functional components of the cell. INTRACELLULAR ACCUMULATIONS One of the manifestations of metabolic derangements in cells ➢ Cytoplasm Sites of accumulations ➢ within organelles (typically lysosomes) ➢ in the nucleus Four main mechanisms le...

Different agents can injure the various structural & functional components of the cell. INTRACELLULAR ACCUMULATIONS One of the manifestations of metabolic derangements in cells ➢ Cytoplasm Sites of accumulations ➢ within organelles (typically lysosomes) ➢ in the nucleus Four main mechanisms leading to abnormal intracellular accumulations Inadequate removal of a normal substances secondary to defects in packaging & transport Failure to degrade a metabolite due to inherited enzyme deficiencies, typically lysosomal enzymes Accumulation of an endogenous substance Deposition of an abnormal exogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites Four main mechanisms leading to abnormal intracellular accumulations Inadequate removal of a normal substances Accumulation of an endogenous substance Failure to degrade a metabolite Deposition of an abnormal exogenous substance Accumulation of Lipids in Cells All major classes of lipids can accumulate in cells ✓ Triglycerides ✓ Cholesterol/cholesterol esters ✓ Phospholipids Phospholipids are components of the myelin figures found in necrotic cells Abnormal complexes of lipids & carbohydrates accumulate in the lysosomal storage diseases Steatosis (Fatty Change) The terms steatosis & fatty change describe ➢ abnormal accumulations of triglycerides within parenchymal cells Fatty change occurs in ➢ Liver: it is the major organ involved in fat metabolism ➢ also occurs in the heart, muscle, & kidney ▪ normal liver in situ in the upper abdomen, as seen at autopsy ▪ Normal liver lies below the diaphragm & the Normal liver chest cavity is above with the heart & lungs ▪ liver is the largest parenchymal organ fatty liver is pale yellow-brown because of the increased lipid content within hepatocytes The capsule is smooth, & the cut surface has a uniform texture It is two to three times normal size—hepatomegaly Fatty liver Fatty liver Model of liver anatomy In the hexagonal lobular model, the terminal hepatic vein (CV) is at the center of a “lobule,” while the portal tracts are at the periphery; these landmarks serve to identify “periportal” and “pericentral” parenchyma. In the acinar model, on the basis of blood flow, three zones can be defined, zone 1 being the closest to the blood supply and zone 3 being the farthest. BD, Bile duct; HA, hepatic artery; PV, portal vein Normal liver Normal liver zones, microscopic The liver is functionally divided into lobules with a central vein and peripheral triads. Hepatic cords radiate from the central vein as single plates of one hepatocyte thickness sandwiching a bile canaliculus flowing toward the triad Fatty liver Many hepatocytes have cytoplasm filled with large, clear lipid droplets This process is potentially reversible in weeks to months with cessation of alcohol abuse or discontinuation of a toxic drug Fatty change (or steatosis ) Causes of Steatosis (Fatty Change) ➢ Alcohol abuse (Most common) ➢ Toxins ➢ Protein malnutrition causes fatty liver ➢ Diabetes mellitus ➢ Obesity ➢ Anoxia (severe hypoxia) ➢ Non-alcoholic fatty liver disease which is often associated with diabetes & obesity Cholesterol and Cholesterol Esters cellular metabolism of cholesterol is tightly regulated such that ➢ most cells use cholesterol for the synthesis of cell membranes without intracellular accumulation of cholesterol or cholesterol esters ➢ Accumulations manifested histologically by intracellular vacuoles are seen in several pathologic processes Accumulations of Cholesterol & Cholesterol Esters- pathologic processes ➢ Atherosclerosis: formation of atherosclerotic plaque due to deposition within the intimal layer of the aorta & arteries ➢ Xanthomas: Clusters of foamy cells (Intracellular accumulation of cholesterol within macrophages) in the subepithelial connective tissue of the skin and in tendons ➢ Cholesterolosis: focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder ➢ Niemann-Pick disease, type C: lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs Proteins ▪ Excesses of proteins within the cells sufficient to cause morphologically visible accumulation ▪ Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm ▪ By electron microscopy, they can be amorphous, fibrillar, or crystalline in appearance ▪ In some disorders, such as certain forms of amyloidosis, abnormal proteins deposit primarily in extracellular spaces Proteins ▪ Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria) ▪ increased reabsorption of the protein into vesicles, & the protein appears as pink hyaline droplets within the cytoplasm of the tubular cell Protein reabsorption droplets in the renal tubular epithelium Proteins ▪ Accumulation of secreted protein within the ER due to excessive secretion & active synthesis of immunoglobulins in the plasma cells ▪ The ER becomes hugely distended, producing large, homogeneous eosinophilic inclusions called Russell bodies Normal plasma cells Plasma cell with Russell bodies Cytoskeleton ➢ ability of cells to adopt a particular shape, maintain polarity, organize intracellular organelles ➢ migrate depends on an intracellular scaffold of structural proteins that form the cytoskeleton ➢ cytoskeleton can have an appearance similar to the beams & supports of a building ➢ cytoskeletal structures are constantly elongating & shrinking ➢ microfilaments & microtubules are most active, & their assembly and disassembly can drive cell migration Cytoskeletal elements & cell-cell interactions ➢ Interepithelial adhesion involves several different surface protein interactions at tight junctions, adherens junctions, & desmosomes ➢ Adhesion to the extracellular matrix involves cellular integrins (& associated proteins) within hemidesmosomes ➢ various adhesion proteins within the plasma membrane associate with actin microfilaments & intermediate filaments to provide a mechanical matrix for cell structure & signaling ➢ Gap junctions do not impart structural integrity but allow cell-cell communication by the movement of small molecular weight and/or charged species