Calcium levels in the body are tightly regulated through the actions of parathyroid hormone (PTH), vitamin D, and other factors. Disorders can cause either hypercalcemia (high calcium levels) or hypocalcemia (low calcium levels). Primary hyperparathyroidism, where the parathyroid glands overproduce PTH, is a common cause of hypercalcemia and may require parathyroid surgery. Malignancy is another major cause through the action of PTH-related peptide. Severe hypercalcemia requires rehydration and drugs to reduce bone resorption and calcium levels. Hypocalcemia can result from hypoparathyroidism or resistance to PTH/vitamin D

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 ECF CALCIUM GUT KIDNEY BONE (1 kg) Net 175 mg Net 175 mg 500 mg 500 mg 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 Other PTH low PTH high 25-OHD low Alk phos Normal Normal High High

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