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

Key Features

Essentials of Diagnosis

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

  • Hypercalciuria usually precedes hypercalcemia

  • Asymptomatic, mild hypercalcemia (≥ 10.5 mg/dL [or 2.6 mmol/L]) is usually due to primary hyperparathyroidism

  • Symptomatic, severe hypercalcemia (≥ 14 mg/dL [or 3.5 mmol/L]) is due to hypercalcemia of malignancy

General Considerations

  • Important causes of hypercalcemia are listed in Table 21–7

  • Primary hyperparathyroidism and malignancy account for 90% of cases

  • Primary hyperparathyroidism is the most common cause of hypercalcemia (usually mild) in ambulatory patients

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

  • Tumor production of PTH-related proteins (PTHrP)

    • Most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients

    • The neoplasm is clinically apparent in nearly all cases when the hypercalcemia is detected

  • Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia via overproduction of active vitamin D3 (1,25 dihydroxyvitamin D3)

  • Milk-alkali syndrome has had a resurgence due to calcium ingestion for prevention of osteoporosis

  • Hypercalcemia causes nephrogenic DI through activation of calcium-sensing receptors in collecting ducts, which reduces ADH-induced water permeability

  • Volume depletion further worsens hypercalcemia

Table 21–7.Causes of hypercalcemia.

Clinical Findings

History and physical examination

  • Should focus on the duration of hypercalcemia and evidence for a neoplasm

Symptoms and Signs

  • May affect gastrointestinal, kidney, and neurologic function

  • Mild hypercalcemia is often asymptomatic

  • Symptoms usually occur if the serum calcium is > 12 mg/dL (or > 3 mmol/L) and tend to be more severe if hypercalcemia develops acutely

  • Constipation and polyuria

  • Polyuria is absent in hypocalciuric hypercalcemia

  • Polyuria from hypercalciuria-induced nephrogenic diabetes insipidus can result in volume depletion and acute kidney injury

  • Other abdominal symptoms include

    • Nausea

    • Vomiting

    • Anorexia

    • Peptic ulcer disease

    • Renal colic

    • Hematuria from nephrolithiasis

  • Neurologic manifestations may range from mild drowsiness to weakness, depression, lethargy, stupor, and coma in severe cases

  • Ventricular ectopy and idioventricular rhythm occur and can be accentuated by digitalis


Laboratory Tests

  • The ionized calcium exceeds 1.32 mmol/L

  • A high serum chloride concentration and a low serum phosphate concentration in a ratio ...

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