Intracellular Accumulations and Pathologic Calcification PDF

INTRACELLULAR ACCUMULATIONS AND PATHOLOGIC CALCIFICATION ABUAD MBBS 400 LEVEL BLOCK 1 LECTURE DELIVERED BY DR. UCHIME K.E.  INTRODUCTION One of the manifestations of metabolic derangements in cells is the intracellular accumulation of abnormal amounts o...

INTRACELLULAR ACCUMULATIONS AND PATHOLOGIC CALCIFICATION ABUAD MBBS 400 LEVEL BLOCK 1 LECTURE DELIVERED BY DR. UCHIME K.E.  INTRODUCTION One of the manifestations of metabolic derangements in cells is the intracellular accumulation of abnormal amounts of various substances that may be harmless or associated with varying degrees of injury. The substance may be located in the cytoplasm, within the organelles, or in the nucleus  INTRODUCTION Cells can accumulate abnormal amounts of various substances. These may be: A. Normal endogenous substances which are produced at normal or increased rate, with the metabolic rate inadequate for their removal (e.g., fat accumulation in liver cells) B. Abnormal endogenous substances (product of a mutated gene)- may accumulate because of defective folding or transport and inadequate degradation (e.g., α1-antitrypsin disease)  INTRODUCTION C. A normal substance can accumulate due to genetic or acquired defects in its metabolism (e.g., lysosomal storage disease) D. Abnormal exogenous substances may accumulate in normal cells because they lack the machinery to degrade such substances (e.g., macrophages laden with environmental carbon). Mechanism of intracellular accumulations  INTRACELLULAR ACCUMULATIONS Common intracellular accumulations include: Lipids Proteins Hyaline changes Glycogen Pigments  LIPIDS Lipids including triglycerides, cholesterol and cholesterol esters, and phospholipids can accumulate in cells. 1. Steatosis(fatty changes): accumulation of TGs within parenchymal cells either due to excessive entry or defective metabolism and export. It can occur in the heart, muscle, kidney and especially the liver causing fatty liver. Causes of fatty liver include alcohol abuse, protein malnutrition, DM, obesity, toxins and anoxia. FATTY LIVER A. Gross picture of a fatty liver showing pale yellow parenchyma with rounded borders. B. Photomicrograph of liver steatosis  LIPIDS 2. Cholesterol and cholesterol esters: Accumulation of cholesterol seen as intracellular cytoplasmic vacuoles can be seen in the following conditions – Atherosclerosis Xanthomas Cholesterolosis Niemann-Pick disease, type C Cholesterolosis. Cholesterol-laden macrophages (foam cells, arrow) in a focus of gallbladder cholesterolosis.  PROTEINS Intracellular protein accumulation may be due to excessive synthesis, absorption, or defects in cellular transport. Microscopically, visible accumulation appear as rounded, eosinophilic cytoplasmic droplets. In some disorders, abnormal proteins deposit primarily in the extracellular space (e.g., amyloidosis)  PROTEINS Example of intracellular protein accumulation are: 1. Reabsorption droplets of proteins accumulate in proximal renal tubules in the setting of chronic proteinuria. 2.Immunoglobulin in plasma cells, when produced in excessive amounts, producing Russell bodies.  PROTEINS 3. Defective intracellular transport and secretion (e.g. α1-antitrypsin deficiency, where partially folded intermediates or mutated proteins accumulate in hepatocytes ER) 4. Accumulated cytoskeletal proteins: e.g. keratin in alcoholic hyaline, neurofibrillary tangles containing neurofilaments in Alzheimer disease.  PROTEINS Aggregates of abnormally folded proteins (e.g in genetic mutations, aging) can accumulate in either intracellular and/or extracellular space and cause pathologic change (e.g. amyloid) Protein reabsorption droplets in the renal tubular epithelium. Amyloidosis spleen. A, The pink acellular amyloid material is seen in the red pulp causing atrophy of while pulp. B, Congo red staining shows Congophilia as seen by red-pink colour. C, When viewed under polarising microscopy the corresponding area shows apple-green birefringence. Amyloidosis kidney, Congo red stain. A, The amyloid deposits are seen mainly in the glomerular capillary tuft stained red-pink (Congophilia). B, Viewing the same under polarising microscopy, the congophilic areas show apple-green birefringence.  HYALINE CHANGE Hyaline change refers to any deposit that imparts a homogenous, glassy pink appearance in H&E-stained histologic sections. Examples: Intracellular hyaline change – proximal tubule epithelial protein droplets, Russell bodies, viral inclusions and alcoholic hyaline Extracellular hyaline change- occurs in damaged arterioles (e.g. due to chronic hypertension), presumably due to extravasated proteins. Hyaline degeneration inLeiomyomas. Microscopy shows whorls of smooth muscle cells which are spindle-shaped, having abundant cytoplasm and oval nuclei and mixed with fibrous tissue. The hyaline material appears homogeneous, pink and glassy  GLYCOGEN Glycogen is commonly stored within the cells as a ready energy source Excessive intracellular deposits (seen as clear vacuoles) are seen with abnormalities of: -  Glycogen storage – glycogenoses, or In macrophages of patients with defects in lysosomal enzymes that break down glycogen (glycogen storage diseases), and  Glucose metabolism – diabetes mellitus  PIGMENTS Pigments are coloured substances that can be exogenous or endogenous. Exogenous pigments: e.g., carbon or coal dust (anthracosis), tattoo pigments Endogenous pigments: e.g., - Lipofuscin (yellow-brown intracytoplasmic granules) - Melanin (brown-black pigment in melanocytes) - Homogentistic acid (black pigment in patients with alkaptonuria causing ochronosis) - Hemosiderin (golden-brown granular intracellular pigment composed of aggregated ferritin) Compound naevus showing clusters or lobules of benign naevus cells in the dermis as well as in lower epidermis. These cells contain coarse, granular, brown black melanin pigment. Anthracosis lung. There is abundant coarse black carbon pigment in the septal walls and around the respiratory bronchiole. Brown atrophy of the heart. The lipofuscin pigment granules are seen in the cytoplasm of the myocardial fibres, especially around the nuclei. PATHOLOGIC CALCIFICATION Pathologic calcification is an abnormal tissue deposition of calcium salts in tissues other than osteoid or enamel. It is also associated with deposition of small amounts of iron, magnesium, and other minerals. Two types: Dystrophic and Metastatic DYSTROPHIC CALCIFICATION Dystrophic calcification arises in non- viable tissues in the presence of normal calcium serum levels It can be a marker of prior cellular injury It can also be a source of significant pathology (e.g. psammoma bodies) Can be intracellular or extracellular Deposition ultimately involves precipitation of a crystalline calcium phosphate similar to bone hydroxyapatite. DYSTROPHIC CALCIFICATION Example of dystrophic calcification include ABCDE: -Atherosclerosis -Psammoma Bodies -Caseous necrosis -Damaged heart valves, Dead eggs/parasites -Enzymatic fat necrosis Others: Mockenberg’s medial calcific sclerosis  DYSTROPHIC CALCIFICATION: MECHANISM The mechanism of dystrophic calcification involves two phases: initiation and propagation phases. A. INITIATION (NUCLEATION) PHASE: Occurs extracellularly or intracellularly Extracellular initiation occurs on membrane-bound vesicles form dead or dying cells that concentrate calcium due to their content of charged phospholipids. DYSTROPHIC CALCIFICATION: MECHANISM INITIATION (NUCLEATION) PHASE CONTINUES… Membrane-bound phosphatases then generate phosphates that form calcium-phosphate complexes. The cycle of calcium and phosphate binding is repeated and eventually produce a deposit. Initiation of intracellular calcification occurs in mitochondria of dead or dying cells. DYSTROPHIC CALCIFICATION: MECHANISM PROPAGATION PHASE B. PROPAGATION PHASE: Here, there is propagation of crystal formation depending on - the concentration of calcium and phosphates, - The presence of inhibitors - The structural components of the extracellular matrix DYSTROPHIC CALCIFICATION Dystrophic calcification of the aortic valve. View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. It is markedly narrowed (stenosis). The semilunar cusps are thickened and fibrotic, and behind each cusp are irregular masses of piled-up dystrophic calcification. DYSTROPHIC CALCIFICATION: PSAMMOMA BODIES METASTATIC CALCIFICATION Metastatic calcification results form systemic hypocalcaemia. Calcium deposits occur as amorphous basophilic densities that can be present widely throughout the body. Typically, they have no clinical sequelae, although massive deposition can cause renal or lung deficits.  METASTATIC CALCIFICATION: CAUSES Four principle causes of metastatic calcification are: 1. Elevated parathyroid hormone (e.g. hyperparathyroidism) 2. Bone destruction: due to primary tumor of the bone (e.g. multiple myeloma), by diffuse skeletal metastasis, by accelerated bone turnover(Paget disease), or immobilization  METASTATIC CALCIFICATION: CAUSES 3. Vitamin D-related disorders, including vitamin D intoxication 4. Renal failure: causes retention of phosphates, leading to secondary hyperparathyroidism 5. Others: Sarcoidosis and milk alkali syndrome.  SUMMARY Abnormal deposits of materials in cells and tissues are the result of excessive intake or defective transport or catabolism. It includes the deposition of lipids(TGs, cholesterol and cholesterol esters), proteins, and glycogen in tissue cells. Exogenous or endogenous pigments can also be deposited within a cell. They are typically indigestible pigments, such as carbon, lipofuscin (breakdown product of lipid peroxidation), or iron (usually due to overload, as in hemosiderosis)  SUMMARY Pathologic calcifications Dystrophic calcification: Deposition of calcium at sites of cell injury and necrosis Metastatic calcification: Deposition of calcium in normal tissues, caused by hypercalcemia (usually a consequence of parathyroid hormone excess)  Source: Aster. Robbins and Cotran Pathologic Basis of Disease. Ninth edition. Philadelphia, PA: Elsevier/Saunders, 2015. Mohan, Harsh. Pathology Practical Book. Ed. 3, cet. 1 New Delhi: Jaypee Brothers Medical, 2013 THANK YOU ANY QUESTIONS?