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Hypercalcemic Disorders

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  1. Hypercalcemic Disorders Hasan AYDIN, MD Yeditepe University Hospital Endocrinology and Metabolism

  2. Etiologies of Hypercalcemia Decreased Bone Mineralization Elevated PTH Aluminum toxicity Decreased Urinary Excretion Thiazide diuretics Elevated calcitriol Elevated PTH Increased GI Absorption Milk-alkali syndrome Elevated calcitriol Vitamin D excess Excessive dietary intake Granulomatous diseases Elevated PTH Hypophosphatemia Increased Loss From Bone Increased net bone resorption Elevated PTH Hyperparathyroidism Malignancy Osteolytic metastases PTHrP secreting tumor Increased bone turnover Paget’s disease of bone Hyperthyroidism

  3. ETIOLOGY Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism • T Thiazide, other drugs - Lithium • R Rabdomyolysis • A AIDS • P Paget’s disease, Parental nutrition, Pheochromocytoma, Parathyroid disease • V Vitamins • I Immobilization • T Thyrotoxicosis • A Addison’s disease • M Milk-alkali syndrome • I Inflammatory disorders • N Neoplastic related disease • S Sarcoidosis

  4. CLASSIFICATION PTH-Dependent Hypercalcemia • Primary hyperparathyroidism • Tertiary hyperparathyroidism • Familial hypocalciuric hypercalcemia • Lithium-asociated hypercalcemia

  5. CLASSIFICATION PTH-Independent Hypercalcemia • Neoplasms • PTHr-P dependent • Other humoral syndromes • Osteolytic metastases and multiple myeloma • ExcessVitamin D/1,25(OH)2D • Vitamin D ingestion • 1,25(OH)2D intoxication • Toicaşl vitamin D analogues • Sarcoidosis and other granulomatous diseases • Williams syndrome • Hyperthyroidism • Adrenal insufficiency • Renal failure • İmmobilization • Jansen’s metapyseal chondrodysplasia • Drugs • Vitamin A intoxication • Milk alkali syndrome • Thiazide diuretics • Theophylline

  6. CLINICAL MANIFESTATIONS • GI-Anorexia, Nausea, Vomiting, Constipation and rarely acute Pancreatitis. • CVS- Hypertension, shortened QT interval • RENAL- Thirst, Polyuria, Polydipsia, and occasionally Nephrocalcinosis. • CNS-Cognitive difficulties, Apathy, Drowsiness, Obtundation, or even Coma. -Anxiety, Depression, Psychosis • Ectopic Calcifications-Nephrocalcinosis, calcifications of blood vessels, band keratopathy

  7. SYMPTOMS More than 50% of all patients with primary hyperparathyroidism are asymptomatic when hypercalcemia is first discovered.

  8. COMPLICATIONS • Sinus bradycardia • Increase in the degree of a heart block • Cardiac arrhythmia • Hypertension • Pancreatitis • Peptic ulcer disease • Nephrolithiasis • Accelerated vascular calcification

  9. Diagnostic Yield in Hypercalcemia

  10. HYPERCALCEMIA SERUM CALCIUM > 10.6 Determine wheather hypercalcemia is real, measure ionized Ca adjust for change in serum albumin level, careful drug hx Li, Vit D or A, Measure PTH PTH high PTH - N or Low Hyperparathroidism Malig- prim. or mets If cause remain unclear measure Vit D Vit high Consider other consider Sarcoidosis *Hyperthyroidism CXR *Milk-alkali syndrome *Familial hypocalciuric hypercalcemia

  11. MANAGEMENT OF SYMPTOMATIC HYPERCALCEMIA • General measures • Saline diuresis • Specific measures • Glucocorticoids • Phosphate infusion • Bisphosphonates • Calcitonin • Dialysis

  12. LOOP DIURETICS • Facilitate urinary excretion of calcium • By inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle. • Guard against volume overload • Volume expansion must precede the administration of furosemide, because the drug’s effect depends on delivery of calcium to the ascending limb. Needs frequent measurement of lytes and water

  13. CALCITONINNot as effective as bisphosphonate, tachyphylaxis quickly occurs and limits therapeutic efficacy • MITHRAMYCIN Toxic effect limits it’s use, reserved for difficult cases of hypercalcemia that are related to malignancy • GALLIUM NITRATENeed to infuse it over 5 days, nephrotoxity limits it’s use, not used frequently • CORTICOSTEROIDSFor myeloma, lymphoma, Sarcoidosis, or vit D toxicity decrease GI absorption, 200-300mg hydrocort for upto 5 days, slow response limits it’s use • HEMODIALYSISZero or low calcium bath, In selected condition, eg-hypercalcemia complicated byrenal failure

  14. BISPHOSPHONATES • Structurally related to pyrophosphate. • P-C-P bound is a back bone that renders them resistant to phosphates. • They bind to hydroxyapatite in bone and inhibit the dessolution of crystals. • Their great affinity for bone and their resistance to degradation account for their extremely long half life in bone. • Poor GI absorption- <10% • ETIDRONATEPAMIDRONATECLODRONATE

  15. CHOICE OF AGENT • Mild (<12 mg/dl)-Hydration with saline. • Moderate(>15mg/dl) with moderate symptoms- Bisphosphonate. • Severe life threatening( >15mg/dl) - Saline + Calcitonin + mithramycin, alternatively bisphosphonate, if steroids sensitive + steroids. • Hypercalcemia secondary to malignancy- survival after the appearance of hypercalcemia is very poor - median of 3 months.

  16. SPECIFIC CAUSES OF HYPERCALCEMIA

  17. FAMILIAL HYPOCALCIURIC HYPERCALCEMIA • Autosomal dominant • Inactivating mutation of calcium sensing receptor • Shift in the set point for suppression of PTH • Starts at birth • Serum Ca mild/moderately elevated • Urinary calcium excretion low/normal • Urinary CCa/CCr <0,1 • PTH normal/Slightly elevated • Multiple, slightly enlarged, policlonal glands • Usually asymptomatic • Surgery not effective

  18. Lithium Toxicity • 5% of cases • Due to: • Increse in the set-point for PTH secretion • Increase in tubular reabsorption of calcium • After years of treatment • Elevation in calcium and PTH • Enlargement of parathyroids • After withdrawal, Ca and PTH returns normal within several months

  19. Hypercalcemia of Malignancy • Most common cause in hospitalized patients • Most common in Sq. Cell Ca., Breast. Renal Bladder Ca, MM, Lymphoma • Uncommon in colon and prostate ca. • Occurs in the late course of malignancy • Dehydration, immobilization and treatment with certain drugs contribute to or potentiate development of hypercalcemia

  20. Hypercalcemia of Malignancy • Specific causes of hypercalcemia • Direct invasion of bone (local osteolysis)-20-40% • Tumor production of circulating factors (PTHrP) that osteoclastic resorption of bone (humoral hypercalcemia of malignancy)-40-50% • Ectopic production of 1,25 (OH)2D3 (lymphomas) • Ectopic production of PTH (Lung, Ovary, Thyroid) • Concomitant malignancy and PHP or granulomatous disease • Treatment with estrogen and antiestrogen (tamoxifen)

  21. Vitamin D Intoxication • >100,000 units/day • 25(OH)D level 5-10x high despite N/slightly elevated 1,25(OH)2D3 • Hypercalcemia and hypercalciuria • N/V, weakness, altered consciousness • Persist for weeks to months after discontinuation of medication • Use of steroids (prednisone 40-60 mg/day)

  22. Granulomatous Diseases • Hypercalcemia in 10%, hypercalciuria 50% of sarcoidosis • Correlate with degree of severity and level of ACE • Causes • High level of 1,25(OH)2D3 • Overproduction of bone resorbing cytokines • Production of PTHrP • Treatment with steroids (prednisone 40-60 mg/d)

  23. Hyperthyroidism • 15-50% of cases • By direct stimulation of ostoclastic bone resorption • Ca levels rarely exceed 11 mg/dL • Low PTH, Low 1,25(OH)2D3, Hypercalciuria • Β-Blockers (propronalol 20-40 qid)

  24. Vitamin A Intoxication • >50,000 IU/day • Treatment with cis-retinoic acid or all-transretinoic acid • Dry skin, pruritus, headache, bone pain • By direct stimulation of bone resorption • Treatment with hydration and steroids

  25. Adrenal Insufficiency • Causes • Volume depletion with hemoconcentration • Increased tubular reabsorption of calcium, • Increased skeletal release of calcium • Treatment • Correction of volume depletion • Steroids

  26. Thiazide Diuretics • Rarely cause hypercalcemia by themselves • Causes • ↑ renal tubular reabsorption of Ca • ↑ bone resorption activity • Diuretic-induced volume depletion

  27. Milk Alkali Syndrome • Ingestion of excessive amounts of milk (calcium supplements) or soluble alkali (antacids) • Acute form • Triad of hypercalcemia, metabolic alkalosis, renal failure • Treatment with rehydration and if necessary dialysis • Chronic form (Burnett syndrome) • Soft tissue calcifications in kidney and nephrocalcinosis • Progressive renal insufficiency

  28. Immobilization • Increased bone resorption • Hypercalciuria, ↓ PTH and 1,25(OH)2D3 • Bisphosphonates ± Calcitonin

  29. Williams Syndrome • Supravalvular aortic stenosis, elfin facies, mental retardation • Hypercalcemia in infancy (↑ 1,25(OH)2D3) Jansen’s Metaphyseal Chondrodisplasia • Short stature, hypercalcemia • Similar to PHP • PTH-R activating mutation

  30. HEREDITARY PRIMARY HYPERPARATHYROIDISM SYNDROMES • MEN 1 • Familial Hypocalciuric Hypercalcemia • Neonatal Severe Hyperparathyroidism • MEN 2a • Hyperparathyroidism-Jaw Tumor Syndrome

  31. MEN 1 • Parathyroid, enteropancreatic, pituitary and other tumors (85 % HP, 35 % Z-E, 25 % Prolactinoma) • Otosomal dominant • Inactivating MEN 1 gene germ-line mutation • Starting age : 25 • Urinary calcium excretion normal-high • High PTH • Multiple abnormal glands • 90 % cure after PTX

  32. MEN 2A • Pheochromocytoma, medullary thyroid CA, mild hyperparathyroidism • Activating mutation of the RET proto-oncogene • Otosomal dominant