Lecture 5 Intracellular Accumulations PDF

Lecture 5 Intracellular accumulations Year/Level: D2 / Semester 1 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...

Lecture 5 Intracellular accumulations Year/Level: D2 / Semester 1 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 2  Lecture Outline Overview of intracellular accumulations. Accumulation of Lipids. Accumulation of Cholesterol.  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..etc 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 1) Hydropic change (Water). Following: 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.  Lipids Triglycerides (most common form of accumulation). Cholesterol and Cholesterol Esters.  Fatty change (Steatosis) Refers to any abnormal accumulation of triglycerides within parenchymal cells. Caused by an imbalance between the uptake, utilization, & secretion of fat. Defects in fat metabolism are often induced by alcohol consumption, and also associated with diabetes, obesity, and toxins. 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.  Conditions with Excess Fat: 1. Obesity. 2. Diabetes mellitus. 3. Congenital hyperlipidemia: conditions with excess fat → exceeding the capacity of liver to metabolize it. 4. Liver cell damage, when fat cannot be metabolized in it.  Fatty Liver. Most common cause- Alcohol abuse. Free fatty acids– esterified in liver to triglycerides & converted into cholesterol/ phospholipids or oxidized to ketone bodies. Triglycerides + Apoproteins= Lipoproteins. Fatty change in the liver is reversible, but when excessive it may lead to → cirrhosis.  Major Causes of Fatty Liver. Alcoholic liver disease(most common). Protein malnutrition (starvation). Diabetes Mellitus. Obesity. Hepatotoxins. Hypoxia (anemia, cardiac failure). Drugs.  Mechanisms of Fatty Liver. The condition of fatty liver is caused by one of the following: 1) Excessive entry of free fatty acids into the liver (e.g., starvation). 2) Enhanced fatty acid synthesis. 3) Decreased catabolism of triglycerides (↓ fatty acid oxidation). 4) Increased esterification of fatty acids to triglycerides as a result of an increase in a-glycerophosphate (alcohol). 5) Decreased apoprotein synthesis (carbon tetrachloride poisoning). 6) Impaired lipoprotein secretion from the liver (e.g., alcohol). Starvation will increase this Hepatotoxins (e.g. alcohol) by disrupting mitochondria and SER ; anoxia Defects in any of the steps of uptake, CCl4 and protein malnutrition catabolism, or secretion can lead to lipid accumulation. 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 Normal  Cholesterol and Cholesterol Esters. Cholesterol is used for the synthesis of cell membranes. Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation. However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes. Cholesterol & esters accumulate in macrophages (foam cells) and foreign body giant cells. Accumulations of cholesterol is manifested by intracellular vacuoles.  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.  References 1. Robbins and Cotran Pathologic Basis of Disease; 10th ed. 2021 2. HarshMohan Textbook of Pathology. 7th edition. 25  Thank You Any questions? [email protected] 26