Approach to Hypercalcemia

DeWalt, 6/00

Signs and symptoms of elevated calcium: Fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urination, short QT interval, arrhythmias Symptoms more common with Ca > 11.5-12 If Ca > 13, start getting calcification If Ca > 15, medical emergency Differential Diagnosis Hyperparathyroidism and hypercalcemia of malignancy account for 90% of diagnoses 1. Parathyroid related A. Primary hyperparathyroidism 1) solitary adenomas 2) MEN B. Lithium therapy C. Familial hypocalciuric hypercalcemia 2. Malignancy related A. Solid tumor with metastases (breast) B. Solid tumor with humoral mediation of hypercalcemia (lung, kidney) C. Hematologic malignancies (multiple myeloma, lymphoma, leukemia) 3. Vitamin D related A. Vitamin D intoxication B. increased 1,25(OH)2D; sarcoidosis and other granulomatous diseases C. Idiopathic hypercalcemia of infancy 4. Associated with high bone turnover A. Hyperthyroidism B. Immobilization C. Thiazides D. Vitamin A intoxication 5. Associated with renal failure A. Severe secondary hyperparathyroidism B. Aluminum intoxication C. Milk-alkali syndrome Pathophysiology 1. Hyperparathyroidism elevated Ca, low phos annual incidence 0.2% in patients over 60, prevalence is 1% peak age is 20s to 40s 80% are solitary adenoma can occur as part of MEN 1 or MEN 2A more than half are asymptomatic Manifestations 1. Kidney: calcium oxalate or calcium phosphate stones or calcinosis 2. Bone: osteitis fibrosa cystica, osteopenia 3. GI: vague abdominal complaints, duodenal ulcers if part of MEN 1 with Z-E syndrome 4. MS: pseudogout Laboratory: PTH level 2. Lithium therapy Elevated Ca in 10% of patients PTH is elevated Complete reversal when stopped

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3. Familial Hypocalciuric Hypercalcemia Autosomal dominant trait Excessive secretion of PTH (abnormal sensing of blood Ca by parathyroid gland and renal tubule) 4. Jansens Disease short stature, bowed legs, multiple cystic resorptive areas in bones, elevated Ca, decreased phos PTH undetectable Constitutive activation of PTH receptor 5. Malignancy related hypercalcemia Common and sometimes the presenting abnormality Diagnosis: Low PTH, elevated PTHrP Presence of other symptoms: weight loss, fatigue, muscle weakness, unexplained rash Other studies: bone scan, CT of chest and abdomen. Consider BM biopsy A. Bony metastases: 1) creation of a microenvironment of bone resorption 2) paracrine action of cytokines and lymphokines 3) PTHrP probably a paracrine molecule in breast CA 4) Myeloma secretes IL-6, IL-1 and TNF-B B. Humoral Hypercalcemia of Malignancy (HHM) 1) solid tumor without extensive bony metastases 2) Squamous cell and renal tumors are classic 3) Most HHM is associated with PTHrP (80%) 4) May be related to 1,25(OH)2D (B cell lymphomas) 6. Excessive Vitamin D ingestion need chronic ingestion of 50-100 times the normal dose measure the 25(OH)D level (the 1,25(OH)2D level will be low or normal) may take weeks to resolve due to fat stores responsive to glucocorticoids 7. Abnormal Vitamin D metabolism (Sarcoid and granulomatous disease) Unregulated production of 1,25(OH)2D by macrophages in the granuloma Responds to glucocorticoids Block excessive production and the response to vit D in organs 8. Idiopathic Hypercalcemia of Infancy Williams syndrome: supravalvular aortic stenosis, mental retardation, Elfin faces Excessive intestinal absorption of Ca Treatement: limit Ca intake, steroids Abnormality disappears after the first year of life 9. Abnormalities of high bone turnover hyperthyroidism immobilization- more common in children/adolescents than adults thiazides vitamin A intoxication 10. Tertiary hyperparathyroidsim 11. Aluminum intoxication Abnormal incorporation of Ca into bone Hypercalcemia precipitated by Vitamin D administration 12. Milk-Alkali Syndrome Hypercalcemia, alkalosis, renal failure Ingestion of milk and or calcium carbonate Failure to reduce Ca absorption in presence of high intake of Ca Hypercalcemia bicarbonate retention alkalosis renal calcium retention severe hypercalcemia Reduced renal concentrating ability, tubular dysfunction

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Approach to diagnosis A. Look for signs and symptoms of disease (90% of hyperparathyroidism are asymptomatic) B. Chronicity: if >1yr, not malignancy C. Ask about ingestion: vitamin D and A, Tums D. Labs: PTH 1,25(OH)2D helpful in sarcoid, B cell lymphomas If FHx of endocrine neoplasia, screen for the other tumors and also family members If PTH low: CXR, CT of chest and abdomen, bone scan, SPEP, UPEP Differential Diagnosis Of Hypercalcemia Criterion Clinical issues alone >90% caused by hyperparathyroidism or cancer If asymptomatic or chronic: Level of PTH measured by PTH assay Increased or normal (despite hypercalcemia): Decreased or undetectable: Conclusion

Hyperparathyroidism most likely Hyperparathyroidism confirmed Acute presentation with or without symptoms screen carefully for malignancy Chronicmalignancy unlikely, sarcoidosis or other rarer cause

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Treatment 1. Restore normal hydration (hours) Almost all hypercalcemic patients are dehydrated due to vomiting, inanition, defect in urinary concentrating ability 2. Forced diuresis (saline and furosemide) (hours) Increased Ca excretion Monitor for Mg and K depletion Monitor for pulmonary edema Furosemide should be reserved for patients in danger of fluid overload 3. Bisphosphonates (2-4 days) Inhibit osteoclast action Pamidronate 60-90mg IV over 4-24 hours (low grade fever in up to 20% of patients) 4. Calcitonin (hours) 2-8 units/kg SQ or IM every 6-12 hours tachyphylaxis is a problem Less commonly used methods: 5. Glucocorticoids (days) increased urinary excretion, decreased intestinal absorption helpful in malignancies due to antitumor effect, action against cytokines helpful in vitamin D intoxication and sarcoidosis Prednisone 40-100 mg divided qid 6. Dialysis 7. Phosphate therapy Goal to restore phosphate to normal levels if low

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 Low phosphate increases intestinal Ca absorption and decreases Ca uptake into bone 8. Plicamycin (3-4 days) Rarely usedsevere toxicities (thrombocytopenia, hepatocellular necrosis, lactic acidosis, etc) 9. Gallium Nitrate (days) Rarely used--5 day infusion, nephrotoxicity References Harrisons On-Line Mundy GR, Guise TA. Hypercalcemia of Malignancy. Am J Med 103:134-45, 1997. Grill V, Rankin W, Martin TJ. Parathyroid Hormone-related Protein (PTHrP) and Hypercalcaemia. Europ J Cancer 34:222-29, 1998. Kakizaki S, Ohya N, Yoshinaga T, et al. Undifferentiated pancreatic cancer associated with humoral hypercalcemia of malignancy. Jpn J Clin Oncol 28: 563-66, 1998

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