22: Hypercalcemia

CHIEF COMPLAINT

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

In general, hypercalcemia is detected in 1 of 3 clinical circumstances. First, hypercalcemia may be discovered during routine laboratory work-ups in patients with no symptoms. These patients may or may not have a risk factor for hypercalcemia, such as malignancy. Most cases of hypercalcemia are diagnosed in these asymptomatic people. Second, hypercalcemia may be found during evaluation of patients with symptoms or findings that can be related to hypercalcemia, such as constipation, weakness, fatigue, depression, nephrolithiasis, or osteopenia. Third, severe hypercalcemia may present as altered mental status.

Although most cases of hypercalcemia are due to only a handful of conditions (primary hyperparathyroidism, hypercalcemia of malignancy, chronic kidney disease (CKD), and the milk-alkali syndrome), the complete differential diagnosis is extensive. The most commonly used framework for the differential is organized by pathophysiology. What follows is a somewhat abbreviated list organized by etiology.

1. Parathyroid hormone (PTH)–related

   1. Primary hyperparathyroidism

   2. Secondary hyperparathyroidism (with calcium supplementation)

   3. Tertiary hyperparathyroidism

   4. Lithium therapy (causes hypercalcemia in about 10% of patients)

   5. Familial hypocalciuric hypercalcemia

2. Hypercalcemia of malignancy

   1. Secretion of parathyroid hormone–related protein (PTHrP)

      1. Squamous cell carcinomas

      2. Adenocarcinoma of lung, pancreas, kidney, and others

   2. Osteolytic metastasis

      1. Breast cancer

      2. Multiple myeloma

   3. Production of calcitriol (Hodgkin disease)

3. Vitamin D–related

   1. Hypervitaminosis D

   2. Granulomatous diseases

4. Other relatively common causes of hypercalcemia

   1. Milk-alkali syndrome (mainly seen in patients with CKD who are taking calcium carbonate)

   2. Hyperthyroidism

   3. Thiazide diuretics

   4. Falsely elevated serum calcium (secondary to increased serum binding protein)

      1. Hyperalbuminemia

      2. Hypergammaglobulinemia

Clinically, the differential diagnosis is most commonly organized by the pivotal findings of whether or not the PTH is elevated and whether the patient has a known malignancy. A useful clinical algorithm is presented in Figure 22-1.

Before returning to the case, it is worthwhile to briefly review the basics of calcium metabolism. Calcium levels are dictated by the actions of PTH, calcitonin, and calcitriol (1,25-dihydroxyvitamin D). PTH levels rise and fall in response to serum calcium levels. High levels of PTH stimulate a rise in serum calcium by increasing both renal tubular calcium reabsorption and bone resorption. PTH also stimulates the conversion of calcidiol to calcitriol in the kidneys. Calcitriol leads to a further increase in serum calcium via increased absorption of calcium in the small intestine. Phosphate metabolism is also controlled by PTH and calcitriol; PTH generally lowers phosphate levels through its effects on the kidney, while calcitriol generally raises phosphate levels through its effects on the intestine and inhibitory effects on PTH ...