Intracellular Accumulations - Pathology Lecture Notes PDF

Intracellular Accumulations Pathological Calcification Cell Aging MED301 Pathology Wk 2 11.10.24 Intracellular Accumulations Metabolic derangements in cells, accumulation of substances- harmless or cause further injury May be located in cytoplasm, organelles, or nu...

Intracellular Accumulations Pathological Calcification Cell Aging MED301 Pathology Wk 2 11.10.24 Intracellular Accumulations Metabolic derangements in cells, accumulation of substances- harmless or cause further injury May be located in cytoplasm, organelles, or nuclei Mechanisms of intracellular accumulation: 1. Inadequate removal 2. Endogenous substance-defects in folding, packaging, transport or secretion 3. Failure to degrade 4. Decomposition and accumulation of exogenous substance Mechanisms of intracellular accumulations Intracellular accumulations- lipids Triglycerides; cholesterol/cholesterol esters; phospholipids (components of myelin figures in necrotic cells. Abnormal complexes of lipids and carbohydrates in lysosomal storage diseases Steatosis (Fatty change): Abnormal accumulation of triglycerides within parenchymal cells. (liver- major organ for fat metabolism, but also in heart, muscle and kidney) Causes: toxins, protein malnutrition, diabetes mellitus, obesity, anorexia, alcohol abuse Intracellular lipid accumulations- fatty liver (left) and cholesterolosis (right) Intracellular accumulations- cholesterol and cholesterol esters Cholesterol metabolism regulated, cell use for synthesis of cell membranes Accumulations in intracellular vacuoles seen in several pathological processes: Atherosclerosis- atherosclerotic plaques (smooth muscle cell and macrophages within intimal layer of aorta and large arteries)- foam cells, yellow cholesterol laden atheromas in intima. Some such cells may rupture and release cholesterol and cholesterol esters into extracellular space, forming crystals (long needles clefts in tissue sections; small crystals phagocytosed by macrophages and activate inflammasome Intracellular accumulations- cholesterol and cholesterol esters Xanthomas- cholesterol accumulation within macrophages; characteristic of acquired or hereditary hyperlipidemic states. Clusters of foamy cells in the subepithelial connective tissue of skin and tendons, producing tumorous masses known as xanthomas. Cholesterolosis – Focal accumulations of cholesterol- laden macrophages in the lamina propria of the gallbladder. Niemann-Pick disease, type C – Lysosomal storage disease caused by mutations affecting enzyme involved in cholesterol trafficking; cholesterol accumulations in Intracellular accumulations- proteins Appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm. EM- amorphous, fibrillar, or crystalline In some disorders (certain forms of amyloidosis), abnormal proteins deposit primarily in extracellular spaces Intracellular accumulations- proteins Excess protein accumulations- causes: Reabsorption droplets in proximal renal tubules (renal diseases, proteinuria) Distended ER, produce large homogenous eosinophilic inclusions called Russel bodies Defective intracellular transport and secretion of critical proteins (alpha-1-antitrypsin deficiency- emphysema Accumulation of cytoskeletal proteins- Alcoholic hyaline- eosinophilic cytoplasmic inclusion in liver cells, predominantly keratin intermediate filaments. Neurofibrillary tangle – in brain in Alzheimer disease, containing neurofilaments and other proteins Aggregation of abnormal (or misfolded) proteins- intracellular, extacellular or both (amyloidosis- proteinopathies or protein- aggregation diseases) Protein reabsorption droplets in renal tubular epithelium Intracellular accumulations- hyaline change Hyaline- alteration within cells or in extracellular space giving homogenous, glassy, pink appearance in H&E sections. Not a representation of a specific pattern of accumulation, a histological term. Intracellular hyaline accumulations of proteins – reabsorption droplets, Russell bodies, alcoholic hyaline. Extracellular hyaline – collagenous fibers in old scars may appear hyalinized; in long-term hypertension and diabetes mellitus, walls of arterioles, especially in kidney, become hyalinized- result from extravasated plasma protein and deposition of basement membrane Intracellular accumulations- glycogen Excessive intracellular deposits of glycogen- abnormality in either glucose or glycogen metabolism. Glycogen masses appear as clear vacuoles within cytoplasm, Diabetes mellitus- glycogen in renal tubular epithelial cells, liver cells, beta-cells of islets of Langerhans within pancreas, and heart muscle cells. Also accumulates within select cells in a group of related genetic disorders- glycogen storage diseases, or glycogenoses. Due to enzymatic defect in the synthesis or breakdown of glycogen resulting in massive accumulation, causing cell injury and death Intracellular accumulations- pigments Exogenous- carbon (coal dust)- air pollutant- inhalation, uptake by macrophages in lung, transported via lymphatic channels to lymph nodes in tracheobronchial region. Blacken tissues of lungs (anthracosis) and involved lymph nodes May induce fibroblastic reaction or emphysema- coal worker’s pneumoconiosis Intracellular accumulations- pigments Endogenous – Lipofuscin/lipochrome/wear-and-tear pigment- polymers of lipids and phospholipids in complex with protein. Not injurious but indicator of free radical injury and lipid peroxidation. Prominent in liver and heart of aged; severe malnutrition and cancer cachexia Melanin – brown-black pigment formed when tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes. Homogentisic acid, black pigment in alkaptonuria (rare metabolic disease)- pigment deposited in skin, connective tissue, cartilage- ochronosis Lipofuscin granules in cardiac myocytes CELLULAR AGING Result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage –due to effects of exposure to exogenous influences Influenced by a limited number of genes Associated with definable mechanistic alterations Several mechanisms- intrinsic to cells or environmentally induced. Cellular ageing DNA Damage- exogenous (physical, chemical, biological); endogenous (ROS) DNA repair enzymes- role in aging process Accumulating damage (14 new mutations per year) Most common hematological malignancies are diseases of the aged Werner syndrome- premature aging, defective gene product DNA helicase (protein involved in DNA replication and repair, other functions requiring DNA unwinding); rapid accumulation of chromosomal damage Bloom syndrome, ataxia-telangiectasia- mutated genes encode proteins involved in d/s breaks in DNA Cellular ageing Cellular senescence – all normal cells have limited capacity for replication- replicative senescence Aging associated with progressive replicative senescence Two mechanisms underlie cellular senescence: Telomere attrition –progressive shortening of telomeres-cell cycle arrest Activation of tumor suppressor genes (CDKN2A locus-encodes p16 or INK4a protein - pushes cells along senescence pathway Defective protein homeostasis – maintenance of proteins in correctly folded confirmations (via chaperones of the HSP family); degradation of misfolded, damaged, or unneeded proteins by autophagy-lysosome system and ubiquitin proteasome system Role telomere length in replicative senescence Cellular ageing Dysregulated nutrient sensing – Eating less (caloric restriction) increases longevity. Two major neurohormonal circuits regulate metabolism: 1. Insulin and IGF-1 signaling pathway p.68 2. Sirtuins- family of NAD-dependent protein deacetylases-promote expression of genes whose products include proteins that inhibit metabolic activity, reduce apoptosis, stimulate protein folding, counteract harmful effects of ROS. Also increase insulin sensitivity and glucose metabolism. Intracellular accumulations- pigments Endogenous- Hemosiderin- hemoglobin-derived, golden yellow-to-brown, granular, or crystalline, one of major storage forms of iron Aggregates of ferritin micelles- in mononuclear phagocytes of bone marrow., spleen, liver Local excess of iron from hemorrhage (localized hemosiderosis)- common bruise Systemic iron overload- hemosiderin deposited in many organs and tissues –hemosiderosis due to: increased absorption of dietary iron –inborn error of metabolism- hemochromatosis; hemolytic anemias; repeated blood transfusions PATHOLOGICAL CALCIFICATION Abnormal tissue deposition of calcium salts, + small amounts of iron, magnesium and other mineral salts/ Two forms: A) deposition locally in dying tissues – dystrophic calcification B) deposition in normal tissues- metastatic calcification – results from hypercalcemia secondary to disturbance in calcium metabolism Pathological calcification Dystrophic calcification: In areas of necrosis and in foci of enzymatic necrosis of fat Atheromas of advanced atherosclerosis Aging Damaged heart valves Microscopically – fine, white granules or clumps, felt as gritty deposits. Sometimes, tuberculous lymph node converted to stone. Often cause of organ dysfunction. E.g. calcific valvular disease and atherosclerosis Serum calcium is normal in dystrophic calcification Pathological calcification Metastatic calcification- in normal tissues whenever hypercalcemia. Four principal causes of hypercalcemia- increased secretion of TD, subsequent bone resorption (hyperparathyroidism) Resorption of bone tissue (multiple myeloma, leukemia; diffuse skeletal metastasis e.g. breast cancer; accelerated bone turnover e.g. Paget’s disease; immobilisation) Vitamin D –related disorders (Vit D intoxication, sarcoidosis, idiopathic hypercalcemia of infancy- Williams syndrome) Renal failure- retention of phosphate, leading to secondary hyperparathyroidism. Also Aluminium intoxication; milk-alkali syndrome Pathological calcification Metastatic calcification – may occur widely throughout body but principally interstitial tissues of gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins. Common characteristic- all excrete acid, have an internal alkaline compartment predisposing them to metastatic calcification. Non-crystalline amorphous deposits or as hydroxyapatite crystals. Cause no clinical dysfunction but on occasion, massive involvement of lungs preduce respiratory compromise. Mechanisms that cause and counteract cellular ageing