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Mrs. D is a 60-year-old, woman who complains of long-standing constipation. Initial laboratory evaluation reveals a normal TSH, normal electrolytes, and a calcium level of 10.8 mg/dL (nl 8.4–10.2).

image What is the differential diagnosis of hypercalcemia? How would you frame the differential?


Figure 22-1.

Diagnostic approach: hypercalcemia.

Hypercalcemia is generally detected in 1 of 3 clinical circumstances: asymptomatic patients without risk factors for hypercalcemia; during evaluation of symptoms or findings that can be related to hypercalcemia, such as constipation, weakness, fatigue, depression, nephrolithiasis, or osteopenia; and in patients presenting with severe hypercalcemia and resulting 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 (FHH)

  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. Plasma cell myeloma (formerly 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

    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 (25-hydroxyvitamin D) 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 levels. Calcitonin lowers calcium by suppressing calcium release from bones by inhibiting the function of osteoclasts.


Mrs. D comes to your office for an initial visit. Her constipation has been long-standing and severe enough to lead to physician visits over the past ...

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