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

  • Hypercalciuria usually precedes hypercalcemia.

  • Asymptomatic, mild hypercalcemia (above 10.5 mg/dL [2.6 mmol/L]) is usually due to primary hyperparathyroidism; symptomatic, severe hypercalcemia (above 14 mg/dL [3.5 mmol/L]) is usually due to hypercalcemia of malignancy.


Important causes of hypercalcemia are listed in Table 21–9. 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) is the most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients (see eTable 39–1). The neoplasm is clinically apparent in nearly all cases when the hypercalcemia is detected, and the prognosis is poor. Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia via overproduction of active vitamin D3 (1,25 dihydroxyvitamin D3).

Table 21–9.Causes of hypercalcemia.

Milk-alkali syndrome has had a resurgence due to calcium ingestion for prevention of osteoporosis. Heavy calcium carbonate intake causes hypercalcemic acute kidney injury, likely from renal vasoconstriction. The decreased GFR impairs bicarbonate excretion, while hypercalcemia stimulates proton secretion and bicarbonate reabsorption. Metabolic alkalosis decreases calcium excretion, maintaining hypercalcemia.

Hypercalcemia causes nephrogenic DI through activation of calcium-sensing receptors in collecting ducts, which reduces ADH-induced water permeability. Volume depletion further worsens hypercalcemia.


A. Symptoms and Signs

The history and physical examination should focus on the duration of hypercalcemia and evidence for a neoplasm. Hypercalcemia may affect gastrointestinal, kidney, and neurologic function. Mild hypercalcemia is often asymptomatic. Symptoms usually occur if the serum calcium is higher than 12 mg/dL (3 mmol/L) and tend to be more severe if hypercalcemia develops acutely. Symptoms include constipation and polyuria, except in hypocalciuric hypercalcemia, in which polyuria is absent. Other symptoms include nausea, vomiting, anorexia, peptic ulcer disease, renal colic, and hematuria from nephrolithiasis. Polyuria from hypercalciuria-induced nephrogenic DI can result in volume depletion and acute kidney injury. Neurologic manifestations range from mild drowsiness to weakness, depression, lethargy, stupor, and coma in severe hypercalcemia. Ventricular ectopy and idioventricular rhythm occur and can be accentuated by digitalis.

B. Laboratory Findings


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