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Intracellular accumulations 1
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- 2. LEARNING OBJECTIVES Enlistintracellular accumulations Describe the mechanism of intracellular accumulations. Identify microscopically different types of intracellular accumulations
- 3. Overview Under somecircumstances cells may accumulate abnormal amounts of various substances. They may be harmless or associated with varying degrees of injury .
- 4. Overview Intracellular maybe found: in the cytoplasm within organelles (typically lysosomes) in the nucleus Come to the cell through: Synthesis by affected cells (endogenous) Produced elsewhere (exogenous)
- 5. ENLIST INTRACELLULAR ACCUMULATIONS TRIGLYCERIDE ACCUMULATION Fatty change CHOLESTROL AND CHOLESTRYL ESTER Atherosclerosis Atheroma Cholesterolosis PROTIEN ACCUMULATION Amyloidosis (Protien accumalation in renal tubules in Nephrotic syndrome ) Hyaline change 1- Russell bodies (multiple myeloma) 2- Mallory bodies (alcoholic liver disease)
- 6. Glycogen accumulation(Diabetes mellitus, glycogen storage disease) Pigmentations 1- Exogenous (air pollutants, silica, carbon, tattooing) 2- Endogenous 1. Lipofuscin 2. Hemosiderin 3. Bilirubin 4. Melanin
- 7. MECHANISM 1. Normal orincreased rate of production of a normal substance, but metabolic rate is inadequate to remove it (e.g. fatty change in liver)
- 8. MECHANISM 2. A normalor an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion.
- 9. MECHANISM 3. An inheriteddefect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases.
- 10. MECHANISM 4. An abnormalexogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. (e.g. Accumulations of carbon or silica particles)
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- 15. Fatty Change Fattychange refers to abnormal accumulation of triglycerides within parenchymal cells. Site: liver, most common site it may also occur in heart, skeletal muscle, kidney, and other organs. MORPHOLOGY Most common site: the liver and the heart. With increasing accumulation, the organ enlarges and becomes progressively yellow, soft, and greasy.
- 20. microscopy fatty change Early: small fat vacuoles in the cytoplasm around the nucleus. Later stages: the vacuoles coalesce to create cleared spaces that displace the nucleus to the cell periphery Occasionally contiguous cells rupture (fatty cysts)
- 23. Cholesterol and CholesterylEsters Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation
- 24. CHOLESTEROL AND CHOLESTEROL ESTERS a)Atherosclerosis : In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made of cholesterol and cholesterol esters. These cells have a foamy appearance ( foam cells)and aggregates produce yellow cholesterol-laden atheromas. b) Xanthomas: clusters of foamy cells are found in the sub epithelial connective tissue of the skin and in tendons .
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- 27. ATHEROSCLEROSIS: These give atherosclerotic plaquestheir characteristic yellow color and contribute to the pathogenesis of the lesion
- 28. CHOLESTEROLOSIS There is focalaccumulation of cholesterol-laden macrophages in the lamina propria of the gall-bladder. (foam cells)
- 30. Morphologically visibleprotein accumulations are much less common than lipid accumulations They may occur because excesses are presented to the cells or because the cells synthesize excessive amounts
- 31. AMYLOIDOSIS Amyloid lightchain AL (Ig light chains, derived from plasma cells) Primary amyloidosis – M Myeloma Amyloid associated chain AA(non-Ig protein from liver) secondary amyloidosis – TB, R. arthritis Beta amyloid precurson proteins AB form (in cerebral lesions like Alzeihemer diseases) Histologically: Eosinophilic hyaline extracellular substance causes pressure atrophy in deposition area.
- 32. Protein accumulations Example: 1. Nephroticsyndrome: 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
- 33. The process isreversible; if the proteinuria abates, the protein droplets are metabolized and disappear.
- 34. Protein accumulations MALLORY BODY,OR "ALCOHOLIC HYALINE," is an eosinophilic intra-cytoplasmic inclusion in liver cells that is highly characteristic of ALCOHOLIC LIVER DISEASE hepatocytes of alcoholic liver disease primary biliary cirrhosis hepatocellular carcinoma.
- 35. Protein accumulations Example: 2. Multiplemyeloma. Russell bodies are eosinophilic, large, homogenous immunoglobulin-containing inclusions usually found in a plasma cell undergoing excessive synthesis of immunoglobulin the Russell body is characteristic of the distended endoplasmic reticulum. This is one cell variation found in multiple myeloma.
- 36. Russell bodies areeosinophilic, large, homogeneous immunoglobulin-containing inclusions usually found in a plasma cell undergoing excessive synthesis of immunoglobulin; the Russell ... Multiple aggregates of Russell bodies create what are known as Mott cells. This is one cell variation found in multiple myeloma.
- 40. GLYCOGEN Associated withabnormalities in the metabolism of either 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. Glycogen accumulates within cells in a group of closely related genetic disorders collectively referred to as glycogen storage diseases, or glycogenoses In these diseases, enzymatic defects in the synthesis or breakdown of glycogen result in massive stockpiling, with secondary injury and cell death.
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- 44. Exogenous pigment Themost common is carbon When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. Tattooing is a form of localized exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages, in which they reside for the remainder of the life of the bearer. The pigments do not usually evoke any inflammatory response.
- 45. Exogenous pigment Aggregatesof the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).
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- 48. COAL WORKERS' PNEUMOCONIOSIS Heavy accumulations may induce emphysema or a fibroblastic reaction that can result in a serious lung disease called coal workers' pneumoconiosis
- 49. ENDOGENOUS PIGMENTS Endogenouspigments include: Endogenous pigments are characterized as hematogenous and nonhematogenous. Hematogenous pigments originate from blood and nonhematogenous pigments originate from non-blood, fat or fatlike, and non-fatlike substances lipofuscin, melanin certain derivatives of hemoglobin Hemosiderin bilirubin
- 50. LIPOFUSCIN "Wear-and-tear pigment" isan insoluble brownish-yellow granular intracellular material that seen in a variety of tissues (the heart, liver, kidney, retina, adrenals, nerve cells and ganglion cells in brain) as a function of age or atrophy. Consists of complexes of lipid and protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids of sub cellular membranes. The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.
- 52. Lipofuscin By electronmicroscopy, the pigment appears as perinuclear electron-dense granules
- 54. Melanin is anendogenous, brown-black pigment produced in melanocytes Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment (dermal macrophages)
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- 58. Hemosiderosis is systemicoverload of iron, hemosiderin is deposited in many organs and tissues is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs. With progressive accumulation, parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected
- 59. Hemosiderin Local excessesof iron, and consequently of hemosiderin, result from hemorrhage. Bruise: The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and bilirubin (red bile) from the heme
- 60. Hemosiderin The iron ionsof hemoglobin accumulate as golden-yellow hemosiderin. The iron can be unambiguously identified by the Prussian blue histochemical reaction
- 61. Hemosiderosis Hemosiderosis occursin the setting of: 1. increased absorption of dietary iron 2. impaired utilization of iron 3. hemolytic anemias 4. Repeated blood transfusions (the transfused red cells constitute an exogenous load of iron). .
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- 64. Endogenous Accumulations BilirubinKernicterus: fat-soluble unconjugated bilirubin derived from Rh hemolytic disease of newborn; bilirubin enters basal ganglia nuclei of brain, causing permanent damage Cholesterol Xanthelasma: yellow plaque on eyelid; cholesterol in macrophages Atherosclerosis: cholesterol-laden smooth muscle cells and macrophages (i.e., foam cells); components of fibrofatty plaques Glycogen Diabetes mellitus: increased glycogen in proximal renal tubule cells (cells are insensitive to insulin and become overloaded with glycogen Von Gierke's glycogenosis: deficiency of glucose-6-phosphatase; glycogen excess in hepatocytes and renal tubular cells
- 65. Hemosiderin andferritin Iron overload disorders (e.g., hemochromatosis): excess hemosiderin deposition in parenchymal cells, leading to free radical damage and organ dysfunction (e.g., cirrhosis); increase in serum ferritin Melanin; Addison's disease: destruction of the adrenal cortex; hypocortisolism leads to an increase in ACTH causing excess synthesis of melanin and diffuse pigmentation of the skin and mucosal membranes Triglyceride Fatty liver: triglyceride in hepatocytes pushes the nucleus to the periphery
- 66. Exogenous Accumulations Lead poisoning: lead deposits in nuclei of proximal renal tubular cells (acid-fast inclusion) contribute to nephrotoxic changes in the proximal tubule