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

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

  • Symptomatic, severe hypercalcemia (> 13 mg/dL [3.2 mmol/L]) is usually due to hypercalcemia of malignancy.


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. Hypercalcemia above 14 mg/dL is most often associated with malignancy and is rare with primary hyperparathyroidism. 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 D (1,25 dihydroxyvitamin D3). Patients with mild hypercalcemia and normal to slightly elevated PTH levels should be assessed for familial hypocalciuric hypercalcemia.

Table 21–7.Causes of hypercalcemia.

Milk-alkali syndrome has had a resurgence due to calcium ingestion for prevention of osteoporosis and treatment of dyspepsia. 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 directly affects the NKCC2 channel in the loop of Henle and downregulates the aquaporin 2 channels in the collecting duct, which impairs the kidney's concentrating ability and can cause dehydration.


A. Symptoms and Signs

The history and physical examination should focus on the duration of hypercalcemia and evidence for a neoplasm. Hypercalcemia may affect GI, kidney, and neurologic function. Mild hypercalcemia (below 12 mg/dL) is often asymptomatic. Moderate hypercalcemia (12–14 mg/dL) may be tolerated if it is longstanding yet tends to be symptomatic if acute. Severe hypercalcemia (above 14 mg/dL) is frequently symptomatic. Common symptoms include anxiety, lethargy, constipation, anorexia, and cognitive changes, which can progress to lethargy and stupor in severe cases. Pancreatitis from calcium deposition in the pancreatic duct is a rare complication. Polyuria and dehydration may occur from impaired renal concentrating ability. Other symptoms include renal colic and hematuria from nephrolithiasis. ...

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