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Cell injuryadaptation 5


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for Undergraduate medical students (MBBS)

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Cell injuryadaptation 5

  1. 1. Cell injury & Adaptation-5Cell injury & Adaptation-5 Pathologic CalcificationPathologic Calcification Dr.CSBR.Prasad, M.D.
  2. 2. CalcificationCalcification Def:Def: Precipitation of calcium salts Types:Types: 1-Physiological (Eg: Bones, Teeth, OtolithsBones, Teeth, Otoliths) 2-Pathological SDUMC-Path-CSBRP
  3. 3. 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
  4. 4. Pathologic CalcificationPathologic Calcification There are 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. 5. Pathologic CalcificationPathologic Calcification DYSTROPHIC CALCIFICATIONDYSTROPHIC 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. 6. Pathologic CalcificationPathologic Calcification DYSTROPHIC CALCIFICATIONDYSTROPHIC 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. 7. Pathologic CalcificationPathologic Calcification DYSTROPHIC CALCIFICATIONDYSTROPHIC 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. 8. This is papillary carcinoma of thyroid. Note the small psammoma body in the center.
  9. 9. Psammoma bodies Thyroid Papillary carcinoma & Meningioma SDUMC-Path-CSBRP
  10. 10. DYSTROPHIC CALCIFICATION Pathogenesis. The final common 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. 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. 12. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION NOTE:NOTE: It must 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. 13. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION Salient features: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. 14. Can you name some 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. 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. 16. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION Metastatic calcification 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. 17. METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION Metastatic calcification 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. 18. Pathologic CalcificationPathologic Calcification 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 SDUMC-Path-CSBRP
  19. 19. Pathologic CalcificationPathologic Calcification Stains to 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. 20. SDUMC-Path-CSBRP IMAGES IN CLINICAL MEDICINE Metastatic Pulmonary Calcification
  21. 21. Nephrocalcinosis Plain abdominal x ray, including kidneys, ureters, and bladder Student BMJ 2008;16:205 -17 SDUMC-Path-CSBRP
  22. 22. Gastric calcification: Prominent scattered irregular, 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. 23. Patient with dystrophic calcification in the Achilles tendon due to recurrent trauma and tendinitis SDUMC-Path-CSBRP
  24. 24. Patient with multiple "rice-grain" calcifications in muscles about knees due to cysticercosis SDUMC-Path-CSBRP
  25. 25. Ovarian papillary serous cystadenocarcinomas may contain small concretions called psammomma bodies SDUMC-Path-CSBRP
  26. 26. Breast carcinoma - Central necrosis with dystrophic calcifications SDUMC-Path-CSBRP
  27. 27. Radiographs of the right (A) and left (B) humeri demonstrate extensive calcified soft tissue deposits (arrows). SDUMC-Path-CSBRP
  28. 28. Meningioma – Psammoma bodies SDUMC-Path-CSBRP
  29. 29. Calcinosis Cutis - Metastatic Calcification SDUMC-Path-CSBRP
  30. 30. Calciphylaxis SDUMC-Path-CSBRP
  31. 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. 32. SDUMC-Path-CSBRP
  33. 33. E N D SDUMC-Path-CSBRP
  34. 34. • 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
  35. 35. • Hypercalcemia of malignancy 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. 36. • The advent of 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. 37. Immediate control of blood 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. 38. • Osteoblasts (or stromal 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. 39. • 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. SDUMC-Path-CSBRP
  40. 40. • 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. SDUMC-Path-CSBRP
  41. 41. • The ionized fraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion SDUMC-Path-CSBRP
  42. 42. • 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. SDUMC-Path-CSBRP
  43. 43. • 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. SDUMC-Path-CSBRP
  44. 44. • 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. SDUMC-Path-CSBRP
  45. 45. • 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. • 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. 46. • 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. SDUMC-Path-CSBRP
  47. 47. • 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. SDUMC-Path-CSBRP
  48. 48. • 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. SDUMC-Path-CSBRP
  49. 49. • if an asymptomatic 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. 50. • When the calcium 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. 51. • 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. SDUMC-Path-CSBRP
  52. 52. • 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.SDUMC-Path-CSBRP
  53. 53. • 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.SDUMC-Path-CSBRP
  54. 54. • 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 <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. 55. • 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'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