Intracellular accumulation BCw .pdf

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 ➢ v...

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 Cytoskeletal Proteins ▪ types of cytoskeletal proteins: microtubules (20 to 25 nm in diameter), thin actin filaments (6 to 8 nm), thick myosin filaments (15 nm) & intermediate filaments (10 nm) ▪ Intermediate filaments: provide a flexible intracellular scaffold that organizes the cytoplasm & resists forces applied to the cell, are divided into five classes: i. ii. iii. iv. v. keratin filaments (characteristic of epithelial cells) neurofilaments (neurons) desmin filaments (muscle cells) vimentin filaments (connective tissue cells) glial filaments (astrocytes) Accumulation of cytoskeletal proteins Accumulations of keratin filaments & neurofilaments are associated with certain types of cell injury ➢ Alcoholic hyaline : an eosinophilic cytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease & is composed predominantly of keratin intermediate filaments ➢ Neurofibrillary tangle: found in the brain in Alzheimer disease contains neurofilaments & other proteins Alcoholic hepatitis, microscopic A case of acute alcoholic hepatitis has prominent intracellular deposits of red globular Mallory-Denk bodies (alcoholic hyalin) This hyalin represents an intracellular accumulation of cytoskeletal elements, including cytokeratins, seen in liver cell injury from chronic alcohol abuse Defective intracellular transport and secretion of critical proteins α 1 -antitrypsin deficiency Protein mutation slow folding resulting in the buildup of partially folded intermediates , which aggregate in the ER of the hepatocyte & are not secreted results ➢ loss of protein function ➢ ER stress caused by the misfolded proteins Aggregation of abnormal proteins Amyloidosis ▪ Amyloidosis results from abnormal folding of proteins, which become insoluble, aggregate, and deposit as fibrils in extracellular tissues ▪ The deposits can be intracellular extracellular, or both, and the aggregates may either directly or indirectly cause the pathologic changes Amyloidosis Amyloidosis is a condition associated with a number of inherited & inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise Three most common forms of amyloid ➢ Amyloid light chain (AL) protein: made up of complete immunoglobulin light chains, associated with certain plasma cell tumors ➢ Amyloid-associated (AA) protein: increased in inflammatory states as part of the acute phase response ➢ β-amyloid (Aβ) protein: constitutes the core of cerebral plaques found in Alzheimer disease Hyaline Change A descriptive histologic term refers to ➢ a homogeneous, glassy, pink appearance in routine histologic sections stained with H&E ➢ Intracellular hyaline: seen in accumulations of protein reabsorption droplets, Russell bodies, & alcoholic hyaline ➢ Extracellular hyaline: in long-standing hypertension & diabetes mellitus, the walls of arterioles in the kidney become hyalinized, resulting from extravasated plasma protein & deposition of basement membrane materials Glycogen ➢ Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism ➢ Glycogen accumulates within select cells in a group of related genetic disorders that are collectively referred to as the glycogen storage diseases , or glycogenoses Pigments colored substances: Exogenous or Endogenous Exogenous Pigments ➢ most common exogenous pigment is carbon (coal dust) ➢ Accumulations of this pigment blacken the tissues of the lungs (anthracosis) & the involved lymph nodes ➢ In coal miners, the aggregates of carbon dust may induce a fibroblastic reaction or even cause a serious lung disease known as coal worker's pneumoconiosis Normal lung Pulmonary anthracosis silicosis Endogenous Pigments Lipofuscin: referring to brown lipid ➢ In tissue sections, it appears as a yellow-brown, finely granular cytoplasmic, often perinuclear, pigment ➢ an insoluble pigment, also known as lipochrome or wear-and-tear pigment ➢ composed of polymers of lipids & phospholipids in complex with protein, suggesting that it is derived through lipid peroxidation of polyunsaturated lipids of intracellular membranes Endogenous Pigments Lipofuscin ➢ not injurious to the cell or its functions ➢ Its importance lies in its being a telltale sign of free radical injury and lipid peroxidation ➢ It is seen in cells undergoing slow, regressive changes ➢ particularly prominent in the liver and heart of aging patients or patients with severe malnutrition and cancer cachexia Endogenous Pigments Lipofuscin granules in cardiac myocytes shown light microscopy deposits indicated by arrow ) electron microscopy note the perinuclear, intralysosomal location) Endogenous Pigments Hemosiderin ➢ a hemoglobin-derived, golden yellow-to-brown, granular, or crystalline pigment ➢ one of the major storage forms of iron ➢ Local or systemic excesses of iron cause hemosiderin to accumulate within cells ➢ Local excesses (localized hemosiderosis) result from hemorrhages in tissues - bruise Endogenous Pigments-Hemosiderin When there is systemic iron overload , hemosiderin deposited in many organs & tissues, a condition called hemosiderosis 1. increased absorption of dietary iron due to an inborn error of metabolism called hemochromatosis causes of hemosiderosis 2. hemolytic anemias, in which excessive lysis of red blood cells leads to release of abnormal quantities of iron 3. blood transfusions, because transfused red blood cells constitute an exogenous iron load Pathologic Calcification Abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, & other mineral salts Two forms of pathologic calcification Dystrophic Calcification Metastatic Calcification ➢ deposition locally in dying tissues ➢ deposition in normal tissues ➢ occurs despite normal serum levels of calcium & in the absence of derangements in calcium metabolism ➢ results from hypercalcemia secondary to some disturbance in calcium metabolism Dystrophic Calcification ➢ in areas of necrosis ➢ advanced atherosclerosis ➢ aging or damaged heart valves, further hampering their function ➢ sometimes a tuberculous lymph node is virtually converted to stone ▪ Gross: appear as fine, white granules or clumps, often felt as gritty deposits ▪ Histologically: a basophilic, amorphous granular, sometimes clumped appearance ▪ lamellated configurations of calcification- psammoma bodies Dystrophic calcification ➢ atheromatous plaques ➢ congenitally bicuspid aortic valves ➢ calcification of mitral valve ring ➢ old tuberculous lesions ➢ fat necrosis ➢ breast lesions Dystrophic calcification in fat necrosis focal areas of fat destruction Fat necrosis in acute pancreatitis Normal areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells surrounded by basophilic calcium deposits & an inflammatory reaction Dystrophic calcification of the aortic valve, unopened aortic valve in a heart with calcific aortic stenosis. It is markedly narrowed (stenosis). The semilunar cusps are thickened and fibrotic, & behind each cusp are irregular masses of piled-up dystrophic calcification. Metastatic Calcification occur in normal tissues whenever there is hypercalcemia four principal causes of hypercalcemia ▪ Increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, as in hyperparathyroidism due to parathyroid tumors, & ectopic secretion of PTH-related protein by malignant tumours ▪ Resorption of bone tissue, secondary to primary tumours of bone marrow (e.g., multiple myeloma, leukaemia) or diffuse skeletal metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease), or immobilization ▪ Vitamin D–related disorders , including vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor), & idiopathic hypercalcemia of infancy (Williams syndrome), characterized by abnormal sensitivity to vitamin D ▪ Renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism Metastatic Calcification occur widely throughout the body but principally affects interstitial tissues of ➢ gastric mucosa ➢ Kidneys ➢ Lungs ➢ systemic arteries ➢ pulmonary veins