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For further information, see CMDT Part 21-08: Hypercalcemia

Key Features

Essentials of Diagnosis

  • Serum calcium level > 10.5 mg/dL (> 2.6 mmol/L)

  • Serum ionized calcium > 5.3 mg/dL (> 1.32 mmol/L)

  • Most common causes: primary hyperparathyroidism and malignancy-associated hypercalcemia

  • Asymptomatic, mild hypercalcemia (≥ 10.5 mg/dL [or 2.6 mmol/L]) is usually due to primary hyperparathyroidism; symptomatic, severe hypercalcemia (≥ 13 mg/dL [or 3.2 mmol/L]) is due to hypercalcemia of malignancy

General Considerations

  • Primary hyperparathyroidism and malignancy account for 90% of cases

  • Chronic hypercalcemia (over 6 months) or some other manifestations such as nephrolithiasis suggests a benign cause

  • Tumor production of parathyroid hormone–related proteins (PTHrP) is the most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients

  • Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia from production of active vitamin D3 (1,25 dihydroxyvitamin D3) by the granulomas

  • Patients with mild hypercalcemia and normal to slightly elevated PTH levels should be assessed for familial hypocalciuric hypercalcemia

  • Milk-alkali syndrome has had a resurgence related to calcium ingestion for prevention of osteoporosis and treatment of dyspepsia

  • Hypercalcemia can cause nephrogenic diabetes insipidus and volume depletion, which further worsen hypercalcemia


  • Increased intake or absorption (Table 21–7)

    • Milk-alkali syndrome

    • Vitamin D or A excess

  • Endocrine disorders

    • Primary and secondary hyperparathyroidism

    • Acromegaly

    • Adrenal insufficiency

    • Pheochromocytoma

    • Thyrotoxicosis

  • Neoplastic diseases

    • Tumor production of PTHrP (ovary, kidney, lung)

    • Plasma cell myeloma

    • Lymphoma

  • Miscellaneous causes

    • Thiazide diuretics

    • Granulomatous diseases

    • Paget bone disease

    • Hypophosphatasia

    • Immobilization

    • Familial hypocalciuric hypercalcemia

    • Complications of kidney transplantation

    • Lithium intake

Table 21–7.Causes of hypercalcemia.

Clinical Findings

Symptoms and Signs

  • History and physical examination should focus on the duration of hypercalcemia and evidence for a neoplasm

  • May affect gastrointestinal, kidney, and neurologic function

  • Mild hypercalcemia (< 12 mg/dL) is often asymptomatic

  • Moderate hypercalcemia (12–14 mg/dL) may be tolerated if longstanding yet tends to be symptomatic if acute

  • Severe hypercalcemia (> 14 mg/dL) is frequently symptomatic, including

    • Anxiety

    • Lethargy

    • Constipation

    • Anorexia

    • Cognitive changes

    • Lethargy

    • Stupor

  • Polyuria and dehydration may occur from impaired renal concentrating ability

  • Renal colic and hematuria may result from nephrolithiasis

  • Acute hypercalcemia can shorten the QT interval, though clinically relevant arrhythmias are rare


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