Calcium Disorders

1. Calcium Disorders William E. Clutter, M.D. Associate Professor of Medicine Department of Internal Medicine Division of Endocrinology, Metabolism & Lipid Research

2. Calcium regulation • Albumin binding – ionized vs total calcium • Corrected Ca = Ca (mg/dl) + 0.8 (4 – albumin in g/dl) • Parathyroid hormone • 1,25 (OH)2 Vitamin D • PTH-related peptide (PTHrP) • Cytokines

3. Calcium balance BONE (1 kg) 500 mg 500 mg Net 175 mg Net 175 mg GUT ECF CALCIUM KIDNEY 1000 mg

4. Hypercalcemia: clinical signs • GI: • Nausea, vomiting, abdominal pain • Constipation • Renal: • Polyuria, dehydration • Renal failure • Neurological • Fatigue • Confusion • Stupor, coma

5. Hypercalcemia: major causes • Primary hyperparathyroidism (PHPT) • Malignancy • Others

6. Hyperparathyroidism: causes • Primary • Adenoma (90%) • Multiple gland enlargement (10%) • MEN 1 • MEN 2A • Familial hyperparathyroidism • Carcinoma (<1%) • Familial benign hypercalcemia (FBH) • Secondary (normo- or hypocalcemic) • Renal failure • Vitamin D deficiency

7. Malignant hypercalcemia: major causes • PTHrP - mediated • Breast carcinoma • Squamous carcinoma (lung, head & neck, esophagus) • Renal carcinoma • Cytokine - mediated • Myeloma (lymphoma, leukemia)

8. Hypercalcemia: other causes • Drugs: • Vitamin D • Calcium carbonate (milk alkali syndrome) • Lithium • PTH • Vitamin A • Sarcoidosis, other granulomatous disorders • Hyperthyroidism

9. Hypercalcemia: presentations • Chronic, mild-moderate • Often asymptomatic • Cause: primary hyperparathyroidism • Issues: parathyroidectomy or not • Acute, severe • Symptomatic • Cause: malignant hypercalcemia (rarely others) • Issues: treat hypercalcemia, find & treat cause

10. Primary hyperparathyroidism • F:M 3:1 • Usually > 50 y/o • Presentation: • Asymptomatic hypercalcemia (>50%) • Renal stones (20%) • Decreased bone density • Symptoms of hypercalcemia (<5%)

11. Hypercalcemia: evaluation • Duration >6 months or renal stones: PHPT • Signs of malignancy, other rare causes • Medications (including OTC, supplements) • Family history • Plasma PTH • Normal or elevated: primary hyperpararthyroidism • Low: other causes

12. Primary hyperparathyroidism: Rx • Indications for parathyroidectomy: • symptomatic hypercalcemia • kidney stones • bone density T-score < -2.5 SD • plasma calcium >(ULN + 1) mg/dl • age <50 years • (urine calcium >400 mg/24 hr) NIH consensus Panel JCEM 87:5353, 2002

13. Parathyroid Localization Sestamibi scans Left lower parathyroid adenoma Mediastinal parathyroid adenoma

14. Primary hyperparathyroidism: pitfalls • Positive family history: • Evaluate for MEN 1 or 2A • Evaluate for FBH • FE Ca <0.01 • Evaluate family • CaSR gene analysis • Concomitant vitamin D deficiency • PTH disproportionately high • More severe post-op hypocalcemia • Replete if 25-OH vitamin D <20 ng/dl

15. Primary hyperparathyroidism: pitfalls • Diagnose before imaging! • False positive and negative sestamibi scans • Normal ionized calcium: • Primary vs secondary hyperparathyroidism

16. Primary Hyperparathyroidism • Follow-up of unoperated: • Normal calcium intake • Annual calcium, creatinine • Biannual bone mass • Bisphosphonate for osteoporosis • Cinacalcet (calcimimetic) ? • Indications for surgery • Declining bone mass or renal function • Worsening hypercalcemia

17. Nonparathyroid hypercalcemia • Repeat history (especially drugs) • Vitamin D toxicity suspected: 25 (OH) vitamin D • Sarcoidosis suspected: 1,25 (OH)2 vitamin D • Malignancy suspected: • SPEP, UPEP • Bone scan • Chest & abdominal CT • Biopsy • PTHrp

18. Severe hypercalcemia: • Principles of therapy • Expand ECF volume • Increase urinary calcium excretion • Decrease bone resorption • Indications for therapy • Symptoms of hypercalcemia • Plasma [Ca] >12 mg/dl

19. Severe hypercalcemia: therapy • Restore ECF volume • Normal saline rapidly • Positive fluid balance >2 liters in first 24 hr • Saline diuresis • Normal saline 100-200 ml/hr (replace potassium) • Zoledronic acid 4 mg IV over 15 min • if plasma [Ca] >14 mg/dl or >12 mg/dl after rehydration • Monitor plasma calcium QD • Myeloma or vitamin D toxicity: • prednisone 30 mg BID

20. Hypocalcemia: clinical signs • Paresthesias • Tetany (carpopedal spasm) • Trousseau’s, Chvostek’s signs • Seizures • Chronic: cataracts, basal ganglia Ca

21. Trousseau’s sign

22. Hypocalcemia: causes • Hypoparathyroidism • Surgical • Autoimmune • Magnesium deficiency • PTH resistance (pseudohypoparathyroism) • Vitamin D deficiency • Vitamin D resistance • Other: renal failure, pancreatitis, tumor lysis

23. Hypocalcemia: evaluation • Confirm low corrected & ionized calcium • History: • Neck surgery • Other autoimmune endocrine disorders • Causes of Mg deficiency • Malabsorption • Family history

24. Hypocalcemia: evaluation • Physical exam: • Signs of tetany • Signs of pseudohypoparathyroidism • Short metacarpals • Short stature, round face • Lab • PTH • Creatinine, Mg, P, alkaline phosphatase • 25-OH vitamin D

25. Hypocalcemia: evaluation Cause Hypoparathyroidism PTH resistance Vitamin D deficiency Vitamin D resistance Phosphate High High Low Low Alk phos Normal Normal High High Other PTH low PTH high 25-OHD low

26. Hypocalcemia: acute therapy • IV calcium infusion • 1-2 gm Ca gluconate (10-20 ml) IV over 10 min • 6 gm Ca gluconate/500 cc D5W over 6 hr • Follow plasma Ca & P Q 4-6 hr & adjust rate • IV or oral calcitriol 0.25-2 mcg/day • Oral calcium carbonate 1-2 gm BID-TID

27. Hypocalcemia: chronic therapy • Oral calcitriol 0.25-2 mcg/day • Calcium carbonate 1-2 gm BID-TID