Downloaded 122 times
![Pathologic CalcificationPathologic Calcification
Pathologic calcification is the abnormal
tissue deposition of calcium salts
[together with smaller amounts of iron,
magnesium, and other mineral salts]
SDUMC-Path-CSBRP](https://image.slidesharecdn.com/cellinjuryadaptation-5-151101071849-lva1-app6891/85/Cell-injuryadaptation-5-3-320.jpg)
![Pathology pearlsPathology pearls
• Calcification in lung fields usually
indicates benign process [Inflammatory
process]
• Calcification in breast usually indicates
malignant process [Carcinoma]
SDUMC-Path-CSBRP](https://image.slidesharecdn.com/cellinjuryadaptation-5-151101071849-lva1-app6891/85/Cell-injuryadaptation-5-31-320.jpg)
![• PTH acts directly on bone, where it
induces calcium resorption, and on the
kidney, where it stimulates calcium
reabsorption and synthesis of 1,25-
dihydroxyvitamin D [1,25(OH)2D], a
hormone that stimulates gastrointestinal
calcium absorption.
SDUMC-Path-CSBRP](https://image.slidesharecdn.com/cellinjuryadaptation-5-151101071849-lva1-app6891/85/Cell-injuryadaptation-5-34-320.jpg)
Uploaded byPrasad CSBR
Cell injuryadaptation 5
Pathologic calcification involves the abnormal deposition of calcium salts in tissues. There are two main types: dystrophic calcification occurs in dead or damaged tissues and is associated with normal calcium levels, while metastatic calcification occurs in normal living tissues and is associated with high calcium levels. Dystrophic calcification results from calcium deposition in areas of tissue damage or necrosis. Metastatic calcification is usually caused by hypercalcemia from conditions like hyperparathyroidism or certain cancers. The lungs, kidneys, and gastric mucosa are especially susceptible to metastatic calcification.
More Related Content
Similar to Cell injuryadaptation 5
Cell injuryadaptation 5
- 1. Cell injury &Adaptation-5Cell injury & Adaptation-5 Pathologic CalcificationPathologic Calcification Dr.CSBR.Prasad, M.D.
- 2. CalcificationCalcification Def:Def: Precipitation ofcalcium salts Types:Types: 1-Physiological (Eg: Bones, Teeth, OtolithsBones, Teeth, Otoliths) 2-Pathological SDUMC-Path-CSBRP
- 3. Pathologic CalcificationPathologic Calcification Pathologiccalcification is the abnormal tissue deposition of calcium salts [together with smaller amounts of iron, magnesium, and other mineral salts] SDUMC-Path-CSBRP
- 4. Pathologic CalcificationPathologic Calcification Thereare two forms of pathologic calcification:There are two forms of pathologic calcification: Dystrophic calcification Metastatic calcification Site Dead tissue Normal tissue Serum calcium Normal Hypercalcemia Calcium metabolism Normal Deranged Examples Abscess wall Skin SDUMC-Path-CSBRP
- 5. Pathologic CalcificationPathologic Calcification DYSTROPHICCALCIFICATIONDYSTROPHIC CALCIFICATION:: Salient features:Salient features: Dead tissuesDead tissues NormocalcemiaNormocalcemia Seen in areas of necrosis Occurs in all forms necrosis Calcification is almost inevitable in the atheromas Develops in aging or damaged heart valves Microscopically:Microscopically: fine, white granules or clumps often felt as gritty deposits
- 6. Pathologic CalcificationPathologic Calcification DYSTROPHICCALCIFICATIONDYSTROPHIC CALCIFICATION:: Morphology:Morphology: •In H&E sections, the calcium salts have a basophilic, amorphous granular, sometimes clumped, appearance •They can be intracellular, extracellular, or both •Heterotopic bone may be formed in the focus of calcification •Psammoma bodies: progressive acquisition of outer layers may create lamellated configurations SDUMC-Path-CSBRP
- 7. Pathologic CalcificationPathologic Calcification DYSTROPHICCALCIFICATIONDYSTROPHIC CALCIFICATION:: Morphology:Morphology: •Psammoma bodies: progressive acquisition of outer layers may create lamellated configurations in tumors The following tumors may show these structuresThe following tumors may show these structures 1-Papillary carcinoma of ovary 2-Papillary carcinoma of thyroid 3-Meningioma SDUMC-Path-CSBRP
- 8. This is papillarycarcinoma of thyroid. Note the small psammoma body in the center.
- 9. Psammoma bodies Thyroid Papillarycarcinoma & Meningioma SDUMC-Path-CSBRP
- 10. DYSTROPHIC CALCIFICATION Pathogenesis. The finalcommon pathway is the formation of crystalline calcium phosphate Process - two major phases: InitiationInitiation (or nucleation) and PropagationPropagation • Both can occur intracellularly and extracellularly • Initiation of intracellular calcification occurs in the mitochondria • Initiators of extracellular dystrophic calcification include phospholipids found in membrane-bound vesicles - matrix vesicles SDUMC-Path-CSBRP
- 11. DYSTROPHIC CALCIFICATION Pathogenesis:Pathogenesis: Membrane-facilitated calcification--- has several steps: (1) calcium ion binds to the phospholipidsbinds to the phospholipids present in the vesicle membrane, (2) this generates more phosphate groupsgenerates more phosphate groups with more binding of calcium (3) the cycle of calcium and phosphate binding is repeated – ↑↑ local concentrationlocal concentration (4) a structural change occurs in the arrangement of calcium and phosphate groups, generating a microcrystalmicrocrystal which can then propagate and perforatepropagate and perforate the membrane Propagation of crystal formation depends on the concentration of Ca 2+ and PO4 SDUMC-Path-CSBRP
- 12. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION NOTE:NOTE: Itmust not be confused with the process ofIt must not be confused with the process of metastasis of tumorsmetastasis of tumors It’s entirely a different conditionIt’s entirely a different condition Here ‘Metastasis’ only means ‘Here ‘Metastasis’ only means ‘widespreadwidespread’’ SDUMC-Path-CSBRP
- 13. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION Salientfeatures:Salient features: Normal tissuesNormal tissues HypercalcemiaHypercalcemia There are fourfour principal causes of hypercalcemia: 1. Hyperparathyroidism (↑ PTH) 2. Destruction of bone tissue 3. Vitamin D-related disorders 4. Renal failure 1-Primary tumors of BM 2-Diffuse skeletal mets 3-↑Bone turnover 4-Immobilization 1-Vit-D intoxication 2-Sarcoidosis 3-Pri.Hypercalcemia of infancy SDUMC-Path-CSBRP
- 14. Can you namesome bone seekingCan you name some bone seeking tumors?tumors? B.K.PATIL B- Breast K- Kidney P- Prostate A- Adrenal T- Thyroid I – Intestine L- Lung SDUMC-Path-CSBRP
- 15. Hypercalcemia - causesHypercalcemia- causes Vitamin D intoxication Aluminium intoxication Sarcoidosis Milk-alkali syndrome Thiazide diuretics PrimaryPrimary hyperparathyroidismhyperparathyroidism ** Immobilization MalignancyMalignancy ** Vitamin A intoxication Secondary hyperparathyroidism Adrenal insufficiency William's syndrome ** These categories account for 90 percent of cases ofThese categories account for 90 percent of cases of hypercalcemia in adultshypercalcemia in adults
- 16. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION Metastaticcalcification may occur widelyMetastatic calcification may occur widely throughout the bodythroughout the body But it mainly affects:But it mainly affects: • Gastric mucosa • Kidneys • Lungs • Systemic arteries & • Pulmonary veins SDUMC-Path-CSBRP
- 17. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION Metastaticcalcification may occur widelyMetastatic calcification may occur widely throughout the bodythroughout the body But it mainly affects:But it mainly affects: • Gastric mucosa • Kidneys • Lungs • Systemic arteries & • Pulmonary veins Why it affects mainly these tissue? or What is common to all these three structures? SDUMC-Path-CSBRP
- 18. Pathologic CalcificationPathologic Calcification Figure1-42 View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. The semilunar cusps are thickened and fibrotic. Behind each cusp are seen irregular masses of piled-up dystrophic calcification SDUMC-Path-CSBRP
- 19. Pathologic CalcificationPathologic Calcification Stainsto demonstrate calciumStains to demonstrate calcium:: von Kossa method: Ca – Deep black Alizarin red – S: Ca – Bright red Purpurin method: Ca – Red SDUMC-Path-CSBRP
- 20. SDUMC-Path-CSBRP IMAGES IN CLINICALMEDICINE Metastatic Pulmonary Calcification
- 21. Nephrocalcinosis Plain abdominal x ray,including kidneys, ureters, and bladder Student BMJ 2008;16:205 -17 SDUMC-Path-CSBRP
- 22. Gastric calcification: Prominent scatteredirregular, amorphous basophilic substances are present in small deposits in the superficial lamina propria, abutting the gastric epithelium. These irregular, basophilic, amorphous material is positive by von Kossa stain. von Kossa stain
- 23. Patient with dystrophiccalcification in the Achilles tendon due to recurrent trauma and tendinitis SDUMC-Path-CSBRP
- 24. Patient with multiple"rice-grain" calcifications in muscles about knees due to cysticercosis SDUMC-Path-CSBRP
- 25. Ovarian papillary serouscystadenocarcinomas may contain small concretions called psammomma bodies SDUMC-Path-CSBRP
- 26. Breast carcinoma -Central necrosis with dystrophic calcifications SDUMC-Path-CSBRP
- 27. Radiographs of theright (A) and left (B) humeri demonstrate extensive calcified soft tissue deposits (arrows). SDUMC-Path-CSBRP
- 28. Meningioma – Psammomabodies SDUMC-Path-CSBRP
- 29. Calcinosis Cutis -Metastatic Calcification SDUMC-Path-CSBRP
- 30.
- 31. Pathology pearlsPathology pearls •Calcification in lung fields usually indicates benign process [Inflammatory process] • Calcification in breast usually indicates malignant process [Carcinoma] SDUMC-Path-CSBRP
- 32.
- 33.
- 34. • PTH actsdirectly on bone, where it induces calcium resorption, and on the kidney, where it stimulates calcium reabsorption and synthesis of 1,25- dihydroxyvitamin D [1,25(OH)2D], a hormone that stimulates gastrointestinal calcium absorption. SDUMC-Path-CSBRP
- 35. • Hypercalcemia ofmalignancy is also common and is usually due to the overproduction of parathyroid hormone– related peptide (PTHrP) by cancer cells. The similarities in the biochemical characteristics of hyperparathyroidism and hypercalcemia of malignancy, first noted by Albright in 1941, are now known to reflect the actions of PTH and PTHrP through the same G protein–coupled PTH/PTHrP receptor.SDUMC-Path-CSBRP
- 36. • The adventof new drugs, including bisphosphonates and selective estrogen receptor modulators (SERMs), offers new avenues for the treatment and prevention of metabolic bone disease. PTH analogues are promising therapeutic agents for the treatment of postmenopausal or senile osteoporosis, and calcimimetic agents, which act through the calcium-sensing receptor, may provide new approaches for PTH suppression. SDUMC-Path-CSBRP
- 37. Immediate control ofblood calcium is due to PTH effects on bone and, to a lesser extent, on renal calcium clearance. Maintenance of steady-state calcium balance, on the other hand, probably results from the effects of 1,25(OH)2D on calcium absorption SDUMC-Path-CSBRP
- 38. • Osteoblasts (orstromal cell precursors), which have PTH receptors, are crucial to this bone- forming effect of PTH; osteoclasts, which mediate bone breakdown, lack PTH receptors. PTH-mediated stimulation of osteoclasts cytokines is believed to be indirect, acting in part through released from osteoblasts to activate osteoclasts; in experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone (Chap. 346). SDUMC-Path-CSBRP
- 39. • Continuous exposureto elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast-mediated bone resorption. However, the intermittent administration of PTH, elevating hormone levels for 1–2 h each day, leads to a net stimulation of bone formation rather than bone breakdown. Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. PTH as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial. SDUMC-Path-CSBRP
- 40. • Hypocalcemia increasestranscriptional activity within hours. 1,25(OH)2D3 strongly suppresses PTH gene transcription. In patients with renal failure, IV administration of supraphysiologic levels of 1,25(OH)2D3 or analogues of the active metabolite can dramatically suppress PTH overproduction, which is sometimes difficult to control due to severe secondary HPT. SDUMC-Path-CSBRP
- 41. • The ionizedfraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion SDUMC-Path-CSBRP
- 42. • Stimulation ofthe receptor by high calcium levels suppresses PTH secretion. The receptor is present in parathyroid glands and the calcitonin-secreting cells (C cells) of the thyroid, as well as in other sites such as brain and kidney. Genetic evidence has revealed a key biologic role for the calcium-sensing receptor in parathyroid gland responsiveness to calcium and in renal calcium clearance. Point mutations associated with loss of function cause a syndrome FHH resembling hyperparathyroidism but with hypocalciuria. SDUMC-Path-CSBRP
- 43. • The paracrinefactor termed PTHrP is responsible for most instances of hypercalcemia of malignancy. • Many different cell types produce PTHrP, including brain, pancreas, heart, lung, mammary tissue, placenta, endothelial cells, and smooth muscle. SDUMC-Path-CSBRP
- 44. • In adultsPTHrP (human PTH-related peptide ) appears to have little influence on calcium homeostasis, except in disease states, when large tumors, especially of the squamous cell type, lead to massive overproduction of the hormone. SDUMC-Path-CSBRP
- 45. • Calcitonin isa hypocalcemic peptide hormone that in several mammalian species acts as an antagonist to PTH. Calcitonin seems to be of limited physiologic significance in humans. • In humans, even extreme variations in calcitonin production do not change calcium and phosphate metabolism; no definite effects are attributable to calcitonin deficiency (totally thyroidectomized patients receiving only replacement thyroxine) or excess (patients with medullary carcinoma of the thyroid, a calcitonin-secreting tumor) • It is of medical significance because of its role as a tumor marker in sporadic and hereditary cases of medullary carcinoma and its medical use as an adjunctive treatment in severe hypercalcemia and in Paget's disease of bone. SDUMC-Path-CSBRP
- 46. • The hypocalcemicactivity of calcitonin is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance. These effects are mediated by receptors on osteoclasts and renal tubular cells. SDUMC-Path-CSBRP
- 47. • Before undertakinga diagnostic workup, it is essential to be sure that true hypercalcemia, not a false-positive laboratory test, is present. A false-positive diagnosis of hypercalcemia is usually the result of inadvertent hemoconcentration during blood collection or elevation in serum proteins such as albumin. Hypercalcemia is a chronic problem, and it is cost-effective to obtain several serum calcium measurements; these tests need not be in the fasting state. SDUMC-Path-CSBRP
- 48. • Hypercalcemia fromany cause can result in fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urination, a short QT interval in the electrocardiogram, and, in some patients, cardiac arrhythmias. SDUMC-Path-CSBRP
- 49. • if anasymptomatic individual has had hypercalcemia or some manifestation of hypercalcemia, such as kidney stones, for >1 or 2 years, it is unlikely that malignancy is the cause. SDUMC-Path-CSBRP
- 50. • When thecalcium level is >3.2 mmol/L (13 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal function. • Severe hypercalcemia, usually defined as 3.7–4.5 mmol/L (15–18 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.SDUMC-Path-CSBRP
- 51. • Adenomas aremost often located in the inferior parathyroid glands, but in 6–10% of patients, parathyroid adenomas may be located in the thymus, the thyroid, the pericardium, or behind the esophagus. SDUMC-Path-CSBRP
- 52. • Parathyroid carcinomais often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule. • It may be difficult to appreciate initially that a primary tumor is carcinoma; increased numbers of mitotic figures and increased fibrosis of the gland stroma may precede invasion. The diagnosis of carcinoma is often made in retrospect.SDUMC-Path-CSBRP
- 53. • Hyperparathyroidism froma parathyroid carcinoma may be indistinguishable from other forms of primary hyperparathyroidism but is usually more severe clinically. A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5– 3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with care to avoid capsular rupture.SDUMC-Path-CSBRP
- 54. • Manifestations ofhyperparathyroidism involve primarily the kidneys and the skeletal system. • Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970. With earlier detection, renal complications occur in <20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients, repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.SDUMC-Path-CSBRP
- 55. • The distinctivebone manifestation of hyperparathyroidism is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago. Histologically, the pathognomonic features are an increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship's lacunae) and a replacement of the normal cellular and marrow elements by fibrous tissue. X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption). SDUMC-Path-CSBRP
Editor's Notes
- #2 Prepared in June, 2007.
- #5 There are two forms of pathologic calcification. When the deposition occurs locally in dying tissues, it is known as dystrophic calcification; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism. In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification, and it almost always results from hypercalcemia secondary to some disturbance in calcium metabolism.
- #6 DYSTROPHIC CALCIFICATION Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost inevitable in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves, further hampering their function ( Fig. 1-42 ). 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.
- #7 DYSTROPHIC CALCIFICATION Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost inevitable in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves, further hampering their function ( Fig. 1-42 ). 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.
- #8 DYSTROPHIC CALCIFICATION Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost inevitable in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves, further hampering their function ( Fig. 1-42 ). 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.
- #11 Pathogenesis. In the pathogenesis of dystrophic calcification, the final common pathway is the formation of crystalline calcium phosphate mineral in the form of an apatite similar to the hydroxyapatite of bone. The process has two major phases: initiation (or nucleation) and propagation; both can occur intracellularly and extracellularly. Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that accumulate calcium. Initiators of extracellular dystrophic calcification include phospholipids found in membrane-bound vesicles about 200 nm in diameter; in cartilage and bone, they are known as matrix vesicles, and in pathologic calcification, they are derived from degenerating or aging cells. It is thought that 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, and (4) a structural change occurs in the arrangement of calcium and phosphate groups, generating a microcrystal, which can then propagate and perforate the membrane. Propagation of crystal formation 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. Although dystrophic calcification may be simply a telltale sign of previous cell injury, it is often a cause of organ dysfunction. Such is the case in calcific valvular disease and atherosclerosis, as becomes clear in further discussion of these diseases.
- #12 Pathogenesis. In the pathogenesis of dystrophic calcification, the final common pathway is the formation of crystalline calcium phosphate mineral in the form of an apatite similar to the hydroxyapatite of bone. The process has two major phases: initiation (or nucleation) and propagation; both can occur intracellularly and extracellularly. Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that accumulate calcium. Initiators of extracellular dystrophic calcification include phospholipids found in membrane-bound vesicles about 200 nm in diameter; in cartilage and bone, they are known as matrix vesicles, and in pathologic calcification, they are derived from degenerating or aging cells. It is thought that 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, and (4) a structural change occurs in the arrangement of calcium and phosphate groups, generating a microcrystal, which can then propagate and perforate the membrane. Propagation of crystal formation 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. Although dystrophic calcification may be simply a telltale sign of previous cell injury, it is often a cause of organ dysfunction. Such is the case in calcific valvular disease and atherosclerosis, as becomes clear in further discussion of these diseases.
- #14 METASTATIC CALCIFICATION Metastatic calcification may occur in normal tissues whenever there is hypercalcemia. Hypercalcemia also accentuates dystrophic calcification. There are four principal causes of hypercalcemia: (1) increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, as in hyperparathyroidism due to parathyroid tumors, and ectopic secretion of PTH-related protein by malignant tumors ( Chapter 7 ); (2) destruction of bone tissue, occurring with primary tumors of bone marrow (e.g., multiple myeloma, leukemia) or diffuse skeletal metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease), or immobilization; (3) vitamin D-related disorders, including vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor), and idiopathic hypercalcemia of infancy (Williams syndrome), characterized by abnormal sensitivity to vitamin D; and (4) renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism. Less common causes include aluminum intoxication, which occurs in patients on chronic renal dialysis, and milk-alkali syndrome, which is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate.
- #16 *These categories account for 90 percent of cases of hypercalcemia. Chronic symptomatic hypercalcemia is more likely related to primary parathyroid disease, while patients with hypercalcemia secondary to malignancies are often asymptomatic and have hypercalcemia for a much shorter duration in the course of their disease. SARCOIDOSIS: Isolated macrophages from patients with sarcoidosis have been reported to synthesize 1,25(OH)2 vitamin D from 25(OH) vitamin D as do normal macrophages when stimulated by gamma interferon. William&apos;s syndrome: is a rare developmental disorder associated with supravalvular aortic stenosis, elfin facies, and mental retardation. Hypercalcemia may develop during the first few years of life due to increased intestinal absorption of calcium and elevated levels of 1,25(OH)2 vitamin D. The molecular basis of this disease has been localized to deletion or translocation of the distal portion of the elastin gene. Less common causes include : aluminum intoxication, which occurs in patients on chronic renal dialysis, and milk-alkali syndrome, which is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. *Although hyperparathyroidism, a frequent cause of asymptomatic hypercalcemia, is a chronic disorder in which manifestations, if any, may be expressed only after months or years, hypercalcemia can also be the earliest manifestation of malignancy, the second most common cause of hypercalcemia in the adult. The causes of hypercalcemia are numerous (Table 347-1), but hyperparathyroidism and cancer account for 90% of cases. *if an asymptomatic individual has had hypercalcemia or some manifestation of hypercalcemia, such as kidney stones, for &gt;1 or 2 years, it is unlikely that malignancy is the cause.
- #17 Metastatic calcification may occur widely throughout the body put principally 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. In all these sites, the calcium salts morphologically resemble those described in dystrophic calcification. Thus, they may occur as noncrystalline amorphous deposits or, at other times, as hydroxyapatite crystals.
- #18 Metastatic calcification may occur widely throughout the body put principally 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. In all these sites, the calcium salts morphologically resemble those described in dystrophic calcification. Thus, they may occur as noncrystalline amorphous deposits or, at other times, as hydroxyapatite crystals.
- #19 Figure 1-42 View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. The semilunar cusps are thickened and fibrotic. Behind each cusp are seen irregular masses of piled-up dystrophic calcification.
- #20 DYSTROPHIC CALCIFICATION Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost inevitable in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves, further hampering their function ( Fig. 1-42 ). 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.
- #21 IMAGES IN CLINICAL MEDICINE Metastatic Pulmonary Calcification Sophie Timmins, M.D., and Michael Hibbert, M.D. N Engl J Med 2010; 363:2547 ------------------------------ A chest radiograph of a 47-year-old woman with a dry cough and mild exertional dyspnea showed poorly defined bilateral nodular opacities in the superior lung fields (Panel A). The patient had undergone renal transplantation at 23 years of age for an unspecified glomerulonephritis. She had no history of exposure to tobacco or occupational aerosols. An axial computed tomographic scan of the chest showed centrilobular ground-glass nodules and heterogeneous attenuation, features that were suggestive of calcium deposition (Panel B). Results of serum tests revealed increased serum creatinine (285 μmol per liter [3.2 mg per deciliter]), a normal calcium level (2.3 mmol per liter [9.2 mg per deciliter], corrected for the serum albumin level), a normal phosphate level (1.4 mmol per liter [4.3 mg per deciliter]), increased parathyroid hormone (1571 ng per liter), and a low vitamin D level (calcidiol, 13.4 nmol per liter [5.4 ng per milliliter], and calcitriol, 20 pmol per liter [7.7 ng per milliliter]). Bronchoalveolar washings were negative for mycobacterial and fungal infection. On the basis of these findings, the patient received a diagnosis of metastatic pulmonary calcification due to chronic renal impairment and secondary hyperparathyroidism. Results of pulmonary-function tests, which showed mild restriction and moderate diffusion impairment, were consistent with the diagnosis. The patient&apos;s lung function and symptoms have remained stable for 18 months while she has been treated with phosphate binders, vitamin D supplementation, and cinacalcet, a calcimimetic agent. Sophie Timmins, M.D.Michael Hibbert, M.D.Royal North Shore Hospital, Sydney, NSW, Australia [email_address]
- #22 Flank pain radiating to the suprapubic region A 33 year old woman presented at the urology department with a two year history of intermittent flank pain radiating to the suprapubic region. She had no medical or family history of note. Examination showed that she had microscopic haematuria and proteinuria. Radiological investigations were carried out (figs 1 and 2). Questions (1) What abnormality is shown in fig 1? (2) What are the predisposing conditions to this abnormality? (3) What investigation is being performed in fig 2? (4) What is the diagnosis? Answers (1) Bilateral renal calcification as a result of stones or nephrocalcinosis. (2) Metabolic and anatomical abnormalities can predispose patients to bilateral formation of kidney stones. Anatomical problems—Renal calculi are more common where there are structural anomalies in the kidney, such as tubular ectasia, ureteric obstruction, renal papillary necrosis, and medullary sponge kidney. Metabolic problems—Hypercalciuria can be idiopathic or occurs secondary to hypercalcaemia, in hyperparathyroidism, for example, sarcoidosis, and hypervitaminosis D. High urinary oxalate usually arises from dietary excess or secondary to a malabsorption syndrome. It is rarely associated with a severe congential defect or primary hyperoxaluria. Hypocitraturia and distal renal tubular acidosis are also implicated in the formation of renal calculi. (3) Intravenous urogram. (4) Medullary sponge kidney. Discussion Medullary sponge kidney is a renal malformation characterised by dilation of the collecting ducts. This is associated with the formation of cysts that may be microscopic or visible to the naked eye. These are diffuse and bilateral but do not involve the cortex, although in some patients involvement may be limited to one kidney or only some calyces.w1 Stones may develop in the renal parenchyma or more diffuse calcification (nephrocalcinosis) may be present at the corticomedullary junction or both.w2 Medullary sponge kidney affects one person in 5000w3 and is also known as tubular ectasia or Cacchi-Ricci disease.w4 Although medullary sponge kidney is autosomal dominant, most cases are sporadic, and in less than 5% of cases is there family history.w5 Unlike in autosomal dominant polycystic kidney disease, cysts are not seen elsewhere in the body, and renal failure is uncommon. Diagnosis The diagnosis of medullary sponge kidney is normally made by intravenous urogram. Changes seen depend on the severity of the pathological changes. This can be as mild as a “blush” (a faint white border on the inside of the kidney outline), to more obvious linear radiation, to unmistakable cystic dilation in the collecting ducts communicating with the calyces (as in fig 1).w6 The kidneys are either normal in size (9-12 cm in length) or mildly enlarged. Magnetic resonance imaging is a useful alternative diagnostic tool in patients with allergy to contrast media.w7 Many patients with medullary sponge kidney are asymptomatic and are discovered incidentally when an abdominal x ray is performed for another indication. The key clinical manifestations of the disorder are related to urine stasis and associated tubular defects, most commonly stone formation and urinary tract infections.w8 Medullary sponge kidney accounts for 12-20% of calcium stones. Haematuria (gross and microscopic) is the second most common symptom. The bleeding is typically painless unless clots lead to ureteric obstruction and subsequent renal colic. Urinary tract infection also occurs more often. Most patients have a near normal life expectancy. Complications, such as infection, haematuria, and stones affect 10% of patients, and progression to end stage renal disease is rare. Tubular defects are associated with metabolic abnormalities, which are associated with other malformations.w9 Management The disease has no specific treatment, and management aims to prevent complications. High fluid intake may prevent stones forming and infection, and prophylactic antibiotics are used to treat recurrent infections. If possible, any metabolic abnormalities that predispose a patient to stone formation should be tackled. Although small calculi may be passed spontaneously, larger calculi need active intervention, such as lithotripsy or surgical removal of stones. Renal abscesses are a rare complication that may require intensive antimicrobial therapy and surgical drainage. Learning points A diagnosis of medullary sponge kidney diagnosis can be made on intravenous urogram or computed tomogram When uncomplicated the condition has no symptoms and no effect on renal function The main complications arise from urine stasis and tubular defects. Stone formation leads to colic and infection. Renal tubular acidosis causes a metabolic acidosis. End stage renal disease is rare Management is focused towards complications
- #23 CalcificationIf you look at the gastric mucosa, we see some calcification. Why should there be calcification in the gastric mucosa? Think about the physiology of the gastric mucosa. Why do you often see calcification there? Someone said pH, I think, or maybe they said phosphate. As you secrete hydrogen ions into the lumen, you put out bicarbonate on the basolateral side. That bicarbonate will raise the pH. We know calcium phosphate is not as soluble in an alkaline milieu, and the patient calcifies the gastric mucosa. -----------------------------------------
- #26 Ovarian papillary serous cystadenocarcinomas may contain small concretions called psammomma bodies, seen here as purplish rounded and laminated objects. They are essentially just a form of dystrophic calcification in neoplasms.
- #30 Metastatic Calcification Rare manifestation of metastatic calcification that may accompany hypercalcemia associated with: primary or secondary hyperparathyroidism destructive lesions of bone55 hypervitaminosis D other rare causes56–58 Deposits in: deep dermis subcutaneous tissue, particularly of: axillae abdomen medial aspect of thighs flexural areas
- #31 Calcific uraemic arteriolopathy or calciphylaxis as it is frequently called is a syndrome of medial calcification of small arteries leading to painful ischaemia, usually of the skin, almost exclusively found in patients with chronic kidney disease (CKD). Mortality in reported case series is 60-80% with no effective treatment known.The pathophysiology remains poorly understood but recent advances in vascular biology have demonstrated that vascular calcification is a highly regulated process. If this process can therefore be comprehensively examined through phenotypic, genotypic and proteomic analysis, the opportunity to identify therapeutic targets within or without the current therapeutic armamentarium and design intervention studies in calciphylaxis may become feasible. ================ Microscopically, calciphylaxis is seen here to be characterized by small arterial calcification. The calcium levels are not necessarily elevated, though phosphorus levels are. Secondary hyperparathyroidism as a consequence of chronic renal failure may be present, and parathyroidectomy may be helpful.
- #40 Continuous exposure to elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast-mediated bone resorption. However, the intermittent administration of PTH, elevating hormone levels for 1–2 h each day, leads to a net stimulation of bone formation rather than bone breakdown. Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. PTH as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.
- #41 Hypocalcemia increases transcriptional activity within hours. 1,25(OH)2D3 strongly suppresses PTH gene transcription. In patients with renal failure, IV administration of supraphysiologic levels of 1,25(OH)2D3 or analogues of the active metabolite can dramatically suppress PTH overproduction, which is sometimes difficult to control due to severe secondary HPT.
- #42 The ionized fraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion
- #43 Stimulation of the receptor by high calcium levels suppresses PTH secretion. The receptor is present in parathyroid glands and the calcitonin-secreting cells (C cells) of the thyroid, as well as in other sites such as brain and kidney. Genetic evidence has revealed a key biologic role for the calcium-sensing receptor in parathyroid gland responsiveness to calcium and in renal calcium clearance. Point mutations associated with loss of function cause a syndrome FHH resembling hyperparathyroidism but with hypocalciuria.
- #44 The paracrine factor termed PTHrP is responsible for most instances of hypercalcemia of malignancy. Many different cell types produce PTHrP, including brain, pancreas, heart, lung, mammary tissue, placenta, endothelial cells, and smooth muscle.
- #45 In adults PTHrP (human PTH-related peptide ) appears to have little influence on calcium homeostasis, except in disease states, when large tumors, especially of the squamous cell type, lead to massive overproduction of the hormone.
- #46 Calcitonin is a hypocalcemic peptide hormone that in several mammalian species acts as an antagonist to PTH. Calcitonin seems to be of limited physiologic significance In humans, even extreme variations in calcitonin production do not change calcium and phosphate metabolism; no definite effects are attributable to calcitonin deficiency (totally thyroidectomized patients receiving only replacement thyroxine) or excess (patients with medullary carcinoma of the thyroid, a calcitonin-secreting tumor). in humans, however, at least in calcium homeostasis. It is of medical significance because of its role as a tumor marker in sporadic and hereditary cases of medullary carcinoma and its medical use as an adjunctive treatment in severe hypercalcemia and in Paget&apos;s disease of bone.
- #47 The hypocalcemic activity of calcitonin is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance. These effects are mediated by receptors on osteoclasts and renal tubular cells.
- #48 Before undertaking a diagnostic workup, it is essential to be sure that true hypercalcemia, not a false-positive laboratory test, is present. A false-positive diagnosis of hypercalcemia is usually the result of inadvertent hemoconcentration during blood collection or elevation in serum proteins such as albumin. Hypercalcemia is a chronic problem, and it is cost-effective to obtain several serum calcium measurements; these tests need not be in the fasting state.
- #49 Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urination, a short QT interval in the electrocardiogram, and, in some patients, cardiac arrhythmias.
- #50 if an asymptomatic individual has had hypercalcemia or some manifestation of hypercalcemia, such as kidney stones, for &gt;1 or 2 years, it is unlikely that malignancy is the cause.
- #51 When the calcium level is &gt;3.2 mmol/L (13 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal function. Severe hypercalcemia, usually defined as 3.7–4.5 mmol/L (15–18 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.
- #52 Adenomas are most often located in the inferior parathyroid glands, but in 6–10% of patients, parathyroid adenomas may be located in the thymus, the thyroid, the pericardium, or behind the esophagus.
- #53 Parathyroid carcinoma is often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule. It may be difficult to appreciate initially that a primary tumor is carcinoma; increased numbers of mitotic figures and increased fibrosis of the gland stroma may precede invasion. The diagnosis of carcinoma is often made in retrospect.
- #54 Hyperparathyroidism from a parathyroid carcinoma may be indistinguishable from other forms of primary hyperparathyroidism but is usually more severe clinically. A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with care to avoid capsular rupture.
- #55 Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970. With earlier detection, renal complications occur in &lt;20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients, repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.
- #56 The distinctive bone manifestation of hyperparathyroidism is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago. Histologically, the pathognomonic features are an increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship&apos;s lacunae) and a replacement of the normal cellular and marrow elements by fibrous tissue. X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption).