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Mrs. D is a 60-year-old, African American 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).

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

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 or in at-risk patients, such as those with malignancy. In fact, most cases of hypercalcemia are diagnosed in asymptomatic persons. Second, hypercalcemia may be found during evaluation of patients with certain 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, renal failure, and the milk-alkali syndrome) the complete differential diagnosis is extensive. What follows is a somewhat abbreviated list organized by etiology.

  1. Parathyroid hormone (PTH)–related

    1. Primary hyperparathyroidism

    1. Secondary hyperparathyroidism (due to renal insufficiency and calcium or vitamin D supplementation)

    1. Tertiary hyperparathyroidism

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

    1. Familial hypocalciuric hypercalcemia

  2. Hypercalcemia of malignancy

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

      1. Squamous cell carcinomas

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

    1. Osteolytic metastasis

      1. Breast cancer

      1. Multiple myeloma

    1. Production of calcitriol (Hodgkin disease)

  3. Vitamin D related

    1. Hypervitaminosis D

    1. Granulomatous diseases

  4. Other relatively common causes of hypercalcemia

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

    1. Hyperthyroidism

    1. Thiazide diuretics

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

      1. Hyperalbuminemia

      1. Multiple myeloma

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 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 directed 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 it inhibitory effects on PTH levels.

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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 5 years. Evaluation with colonoscopy had been normal. Results of laboratory tests, drawn over the last few years by previous physicians, show normal results (including TSH), with the exception of calcium levels in the ...

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