Lecture 4 Intracellular Accumulations PDF

Lecture 4 Intracellular Accumulations Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1 Learning Outcomes By the end of this lecture, the students will be able to 1. Name the substances which can accumulate within cells 2. Describe the pathways of abnormal intracellular accumulations 3...

Lecture 4 Intracellular Accumulations Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1 Learning Outcomes By the end of this lecture, the students will be able to 1. Name the substances which can accumulate within cells 2. Describe the pathways of abnormal intracellular accumulations 3. Enumerate the causes and discuss the mechanisms of fatty liver 4. List the various endogenous and exogenous pigments 5. Describe the terms hemosiderosis, jaundice, anthracosis, brown atrophy 6. Define pathological calcification and discuss its causes and pathogenesis 2 Overview of Intracellular Accumulations: Under some circumstances cells may accumulate abnormal amounts of various substances. They may be harmless or associated with varying degrees of injury The substance may be located in: The cytoplasm. Within organelles (typically lysosomes) In the nucleus. It may be synthesized by: The affected cells. or may be produced elsewhere. Intracellular Accumulations Three categories: 1. Normal cellular constituents: Lipid, proteins, carbohydrates 2. Abnormal substances: exogenous/ endogenous. 3. Pigments: exogenous/ endogenous. Pathways of Abnormal Intracellular Accumulations: 1) Abnormal metabolism. 2) Alterations in protein folding and transport. 3) Deficiency of critical enzymes. 4) Inability to degrade phagocytosed particles. (1) Abnormal metabolism. A normal substance is produced at a normal or increased rate of production of a normal substance, but metabolic rate is inadequate to remove it (e.g., fatty change in liver). (2) Alterations in protein folding and transport: A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion. Mutations that cause defective folding and transport may lead to accumulation of proteins (e.g., α1-antitrypsin deficiency). (3) Deficiency of critical enzymes. An inherited defect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases. (4) Inability to degrade phagocytosed particles. An abnormal exogenous 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) Intracellular Accumulations Include the Following: 1) Hydropic change (Water). 2) Fatty change. 3) Proteins: abnormal protein accumulation is often irreversible. 4) Glycogen: glycogen storage diseases. 5) Complex carbohydrates: mucopolysaccharidoses and other complex carbohydrate diseases. 6) Minerals: Iron, as hemosiderin, or carbon, as anthracotic pigment. 7) Pigments. 8) Calcium. 9) Amyloid. Fatty change (Steatosis) Abnormal accumulation of triglycerides within parenchymal cells. Caused by an imbalance between the uptake, utilization, & secretion of fat. Commonly seen in the liver. May also occur in heart, kidney, skeletal muscle and other organs. Depending upon the cause and amount of accumulation, fatty change may be mild and reversible or severe producing irreversible cell injury and cell death. Major causes of fatty liver Alcoholic liver disease(most common). Protein malnutrition (starvation). Diabetes Mellitus. Obesity. Hepatotoxins. Hypoxia (anemia, cardiac failure). Drugs. Starvation will increase this Hepatotoxins (e.g. alcohol) by disrupting mitochondria and SER ; anoxia Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation. CCl4 and protein malnutrition Lipid accumulation Morphology of Fatty Liver. Grossly: enlarged, yellow and/or greasy. Note/ Gross morphology in liver depends on severity. Increased size is observed and liver becomes yellow and greasy when severe. Microscopically: Fat is seen as small, fatty, cytoplasmic droplets or as large vacuoles. Fat vacuoles displace the nucleus to the periphery of the cell. Vacuoles appear clear, with well-defined edges. Note/ Lipid accumulations must be distinguished from accumulations of water or glycogen, using special preparation and stain – Oil Red-O. FATTY LIVER Conditions Association with Cholesterol and Cholesterol Esters Accumulation Atherosclerosis. Acquired and heredity hyperlipidemia. Inflammation and necrosis. Atherosclerosis: Smooth muscle cells and macrophages are filled with lipid vacuoles composed of cholesterol and cholesteryl esters in the wall of arteries. These give atherosclerotic plaques their characteristic → yellow color and contribute to the pathogenesis of the lesion. The Accumulations of Pigments Pigments can be exogenous or endogenous. Exogenous pigments include carbon. Endogenous pigments include melanin, bilirubin, hemosiderin, & lipofuscin. These pigments can accumulate inside cells in different situations. Exogenous Pigment: Carbon Introduced into the body from outside by ingestion, inhalation or inoculation. Most common inhaled pigment is carbon (coal dust), When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional lymph nodes. Anthracosis (in lung) - Accumulation of carbon, black pigment. Anthracosis Exogenous Pigments: Tattooing Inoculated/injected pigment : tattooing. Tattooing is a form of localized, exogenous pigmentation of the skin. Pigments inoculated are phagocytosed by dermal macrophages, in which they reside for the remainder of the life. The pigments do not usually evoke any inflammatory response. (a) Melanin Brownish-black pigment produced by melanocytes located in the epidermis. Acts as a screen against harmful ultraviolet radiation. (a) Melanin Increased melanin pigmentation is caused by: - Sun tanning. - Certain diseases e.g., nevus, or malignant melanoma. Decreased melanin pigmentation is seen in: -Vitiligo - Albinism (c) Hemosiderin Hemoglobin-derived. Golden yellow-to-brown, granular pigment. One of the major storage forms of iron. Hemosiderin pigment represents aggregates of ferritin micelles. Identified by its staining reaction (blue color) with the Prussian blue dye. Accumulates in tissues when there is a local or systemic excess of iron. Hemosiderin accumulation is usually pathologic. (c) Hemosiderin This excess accumulation is divided into 2 types: (1) Hemosiderosis: hemosiderin when is accumulation primarily within of tissue macrophages & is not associated with tissue damage. (2) Hemochromatosis: when there is more extensive accumulation of hemosiderin (Iron), often within parenchymal cells, which leads to tissue damage, scarring & organ dysfunction, including liver fibrosis, heart failure, and diabetes mellitus. Hemosiderin Granules in Liver Cells. The iron ions of hemoglobin accumulate as golden-yellow hemosiderin. A The iron can be unambiguously identified by the Prussian blue histochemical reaction B Hemosiderin granules in liver cells. A, H&E section showing golden-brown, finely granular pigment. B, Prussian blue reaction, specific for iron. (d) Lipofuscin Lipofuscin (“wear and tear” pigment) is an insoluble brownish-yellow granular intracellular material. Consists of lipids and phospholipids in complex with protein. Derived from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. Not injurious to the cell or its functions, but is important as a marker of past freeradical injury. (d) Lipofuscin Seen in a variety of tissues (the heart, liver, and brain) as a function of age or atrophy. The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy. In tissue sections, it appears as a: - Yellow-brown. - Finely granular intracytoplasmic - Often perinuclear pigment. Lipofuscin Granules in a Cardiac Myocyte. A B Lipofuscin granules in a cardiac myocyte. A, Light microscopy (deposits indicated by arrows). B, Electron microscopy. Note the perinuclear, intralysosomal location. By electron microscopy, the pigment appears as perinuclear electron-dense granules Pathologic Calcification A common process in a wide variety of disease states. Abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals. Two forms: (1) Dystrophic calcification. (2) Metastatic calcification. (1) Dystrophic Calcification Deposition of calcium salts in dead or degenerated tissues. Occurs with normal calcium metabolism and normal serum calcium. Seen in : ▪ Arteries in Atherosclerosis. ▪ Damaged heart valves. ▪ Necrosis Dystrophic Calcification in the Wall of the Stomach. At the far left is an artery with calcification in its wall. There are also irregular bluish-purple deposits of calcium in the submucosa. Calcium is more likely to be deposited in tissues that are damaged. (2) Metastatic Calcification. Deposition of calcium salts is in vital tissues. Calcium metabolism is abnormal. Serum calcium is high (hypercalcemia), usually a consequence of parathyroid hormone excess. May occurs in normal tissues. Seen in interstitial tissues of blood vessels, stomach, kidneys, lungs. Morphology similar to that in dystrophic Calcification. Metastatic Calcification: Principle Causes 1. Increased secretion of parathyroid hormone, as occurs in hyperparathyroidism resulting from parathyroid tumors. 2. Destruction of bone tissue, as occurs with primary tumors of bone narrow (e.g., multiple myeloma). 3. Vitamin D-related disorders, including Vitamin D intoxication and systemic sarcoidosis. 4. Associated with renal failure, which cause secondary hyperparathyroidism. References 1. Robbins and Cotran Pathologic Basis of Disease; 10th ed. 2021 2. HarshMohan Textbook of Pathology. 7th edition. 34 Thank You 35