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Calcification Dr. Terezia Laszlo Calcification • Pathologic calcification is the abnormal tissue deposition of calcium salts, • It is a common process occurring in a variety of pathologic conditions. Calcification • Pathologic calcification: – Dystrophic calcification – Metastatic calcification • Dystrophic calcification – May occur at any serum calcium level – Usually occurs in previously injured tissue • Metastatic calcification – Occurs at high serum calcium levels – in normal tissue, during periods of hypercalcemia Dystrophic Calcification • • • • Location: intracellular extracellular Both calcification of injured cells • in areas of necrosis, – coagulative, caseous or liquefactive type, – and in foci of enzymatic necrosis of fat • in the atheromas of advanced atherosclerosis • in aging or damaged heart valves • Heterotopic bone may be formed in the focus of calcification • single necrotic cells may constitute seed crystals that become encrusted by the mineral deposits – psammoma bodies Dystrophic calcification, Pathogenesis • the final common pathway is the formation of crystalline calcium phosphate mineral in the form of an apatite similar to the hydroxyapatite of bone phases: 1. initiation (or nucleation) and 2. propagation • both can occur • intracellularly and extracellularly. Dystrophic calcification Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that accumulate calcium. of extracellular dystrophic calcification • include phospholipids found in membranebound vesicles about 200 nm in diameter • known as matrix vesicles Dystrophic calcification • calcium is concentrated in these vesicles by a process of membrane-facilitated calcification, which has several steps: • (1) calcium ion binds to the phospholipids present in the vesicle membrane, • (2) phosphatases associated with the membrane generate phosphate groups, which bind to the calcium, • (3) the cycle of calcium and phosphate binding is repeated, raising the local concentrations and producing a deposit near the membrane, • (4) a structural change occurs in the arrangement of calcium and phosphate groups, generating a microcrystal, which can then propagate and perforate the membrane Dystrophic calcification Propagation • depends on – the concentration of Ca2+ and PO4 and – the presence of inhibitors and other proteins in the extracellular space, such as the connective tissue matrix proteins. Dystrophic calcification • Although dystrophic calcification may be simply a telltale sign of previous cell injury, it is often a cause of organ dysfunction. • calcific valvular disease and • atherosclerosis Morphology • Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits. • Sometimes a tuberculous lymph node is virtually converted to stone. Calcium salts • stain dark blue on H&E. • Von Kossa (Silver nitrate solution +Calcium-phosphateform Silver- Phosphate under UV light - black silver precipit) Examples for Dystrophic calcification: • Certain tumors contain "psammoma bodies", little spherules of basement membrane that calcify – thyroid cancer, ovarian cancer, meningioma • Calcium help mammographers recognize breast cancer – Calcified „Comedo” necrosis • Advanced atherosclerotic plaques undergo calcification. • Malformed or damaged cardiac valves tend to calcify: – congenitally bicuspid aortic valves – aortic valve stenosis - post endocarditis - ATS • Caseous granulomas (tuberculosis) • Scars (surgical, myocardial) • Little spherical calcifications associated with giant cells in granulomas are called "Schaumann bodies" in Sarcoidosis • Uterine smooth muscle tumors may calcify Myoma petrificata utery • If a fetus dies and calcifies, it may be retained for years as a "lithopedion" ("stone child"). • Precipitation of calcium stearate in pancreatitisassociated fat necrosis. • Celiac plexus calcification (causes pain syndromes) • Low Plasma Calcium: stimulates PTH release, and PTH acts to resorb Ca2+ from the pool in bone and to enhance renal reabsorption of Ca2+ • High Plasma Calcium: stimulates CT secretion which lowers plasma calcium by inhibiting bone resorption • Parathyroid Hormone: • functions to raise plasma calcium – bone resorption – renal calcium reabsorption • stimulates the metabolism of Vitamin D to its active hormonal form, 1,25(OH)2 / D3 Vitamin D: Functions • promotes calcium absorption from the gut • promotes calcium reabsorption from the kidney • promotes calcium mobilization from bone via resorption • enhances phosphate absorption by the intestine Metastatic calcification when apparently normal tissue undergoes calcification because of hypercalcemia / altered Ca2+ metabolism There are four principal causes of hypercalcemia: • (1) increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, – parathyroid tumors, • (2) destruction of bone tissue, – – – – primary tumors of bone marrow (e.g., multiple myeloma, leukemia) metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease) immobilization; • (3) vitamin D-related disorders, including vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor) • (4) renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism. Clinical Correlate(s): Hyperparathyroidism• Excessive PTH usually due to a Parathyroid Adenoma, breaks the feedback loops • Symptoms– renal stones, – bone pain (due to increased bone resorption) – Metastatic calcification Hypoparathyroidism• Lack of PTH (usually due to removal of the parathyroid gland along w/ the thyroid) • Symptoms: - hypocalcemia/convulsion Metastatic calcification sites: many sites can be affected, especially gastric and intestinal mucosa, walls of blood vessels, Basal lamina of lung, kidney, etc Metastatic calcification • affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins. • Although quite different in location, all of these tissues lose acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification. • noncrystalline amorphous deposits or • hydroxyapatite crystals. • Usually, the mineral salts cause no clinical dysfunction, but, on occasion, massive involvement of the lungs produces remarkable xray films and respiratory deficits. • Massive deposits in the kidney (nephrocalcinosis) may in time cause renal damage