cell injuryadaptation 5

Cell injury & Adaptation-5Cell injury & Adaptation-5Pathologic CalcificationPathologic Calcification

Dr.CSBR.Prasad, M.D.

Calcification Calcification

Def:Def: Precipitation of calcium salts

Types:Types: 1-Physiological (Eg: Bones, Teeth, OtolithsBones, Teeth, Otoliths)2-Pathological

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Pathologic Calcification Pathologic Calcification

Pathologic calcification is the abnormal tissue deposition of calcium salts [together with smaller amounts of iron, magnesium, and other mineral salts]

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Pathologic Calcification Pathologic 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

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Pathologic Calcification Pathologic Calcification DYSTROPHIC CALCIFICATIONDYSTROPHIC CALCIFICATION::

Salient features:Salient features: Dead tissuesDead tissues Normocalcemia Normocalcemia

Seen in areas of necrosisOccurs in all forms necrosisCalcification is almost inevitable in the atheromas Develops in aging or damaged heart valves

Microscopically:Microscopically:fine, white granules or clumpsoften felt as gritty deposits


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

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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 thyroid3-Meningioma

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This is papillary carcinoma of thyroid.

Note the small psammoma body in the center.

Psammoma bodiesThyroid Papillary carcinoma & Meningioma

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DYSTROPHIC CALCIFICATIONPathogenesis. 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

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DYSTROPHIC CALCIFICATIONPathogenesis: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 membranePropagation of crystal formation depends on the concentration of Ca 2+ and PO4

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METASTATIC CALCIFICATIONMETASTATIC CALCIFICATIONNOTE:NOTE:

It must not be confused with the process of It must not be confused with the process of metastasis of tumorsmetastasis of tumors

It’s entirely a different conditionIt’s entirely a different conditionHere ‘Metastasis’ only means ‘Here ‘Metastasis’ only means ‘widespreadwidespread’’

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METASTATIC CALCIFICATIONMETASTATIC CALCIFICATION

Salient features:Salient features: Normal tissuesNormal tissues Hypercalcemia Hypercalcemia

There are fourfour principal causes of hypercalcemia:

1. Hyperparathyroidism (↑ PTH)2. Destruction of bone tissue3. Vitamin D-related disorders4. Renal failure

1-Primary tumors of BM 2-Diffuse skeletal mets3-↑Bone turnover 4-Immobilization

1-Vit-D intoxication 2-Sarcoidosis3-Pri.Hypercalcemia of infancy

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Can you name some bone seeking Can you name some bone seeking tumors?tumors?

B.K.PATILB- BreastK- KidneyP- ProstateA- AdrenalT- ThyroidI – IntestineL- Lung

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Hypercalcemia - causesHypercalcemia - causesVitamin D intoxication

Aluminium intoxication

Sarcoidosis Milk-alkali syndrome

Thiazide diuretics Primary Primary hyperparathyroidism hyperparathyroidism **

Immobilization MalignancyMalignancy ** Vitamin A intoxication Secondary

hyperparathyroidismAdrenal insufficiency William's syndrome

** These categories account for 90 percent of cases of These categories account for 90 percent of cases of hypercalcemia in adultshypercalcemia in adults


Metastatic calcification may occur widely Metastatic calcification may occur widely throughout the body throughout the body

But it mainly affects:But it mainly affects:

• Gastric mucosa • Kidneys • Lungs• Systemic arteries &• Pulmonary veins

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Metastatic calcification may occur widely Metastatic calcification may occur widely throughout the body throughout 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?

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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

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Stains to demonstrate calciumStains to demonstrate calcium::

von Kossa method: Ca – Deep blackAlizarin red – S: Ca – Bright redPurpurin method: Ca – Red

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IMAGES IN CLINICAL MEDICINEMetastatic Pulmonary Calcification

Nephrocalcinosis

Plain abdominal x ray, including

kidneys, ureters, and bladder

Student BMJ 2008;16:205 -17

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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

Patient with dystrophic calcification in the Achilles tendon due to recurrent trauma and tendinitis

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Patient with multiple "rice-grain" calcifications in muscles about knees due to cysticercosis

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Ovarian papillary serous cystadenocarcinomas may contain small concretions called psammomma bodies

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Breast carcinoma - Central necrosis with dystrophic calcifications

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Radiographs of the right (A) and left (B) humeri demonstrate extensive calcified soft tissue deposits (arrows).

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Meningioma – Psammoma bodies

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Calcinosis Cutis - Metastatic Calcification

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Calciphylaxis

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Pathology pearlsPathology pearls

• Calcification in lung fields usually indicates benign process [Inflammatory process]

• Calcification in breast usually indicates malignant process [Carcinoma]

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• 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.

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• 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.

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• 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.

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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

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• 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).

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• 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.

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• 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.

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• The ionized fraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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).

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