Posted by • December 3rd, 2010

A 61-year-old man was admitted with a week-long history of nausea, vomiting, nocturia, and polyuria. During the previous 6 months, he had noted progressive fatigue and a 7-kg (15-lb) weight loss.  Read more about this case in our latest Clinical Problem Solving article, In Search of…

Mild-to-moderate hypercalcemia (defined as a serum calcium level below 13.5 mg per deciliter [3.4 mmol per liter]) is commonly due to primary hyperparathyroidism and is typically diagnosed in the outpatient setting. Other possible causes are familial hypocalciuric hypercalcemia, granulomatous diseases, and in rare cases medications, including thiazide diuretics and, less frequently, calcium-containing antacids resulting in the milk alkali syndrome. Patients may be asymptomatic or have nonspecific symptoms, including nausea, vomiting, and constipation. On the other hand, severe hypercalcemia (defined as a serum calcium level greater than or equal to 13.5 mg per deciliter) is often the result of a malignant condition. Symptoms are generally more pronounced than those in mild-to-moderate cases, with neuropsychiatric manifestations and other symptoms that develop over a period of weeks to months, including polyuria and polydipsia due to defects in the ability of the distal tubule to concentrate urine. Acute renal failure may result from a combination of volume contraction and hypercalcemia-induced renal vasoconstriction.

Clinical Pearls

What are the mechanisms of hypercalcemia of malignancy?

Hypercalcemia of malignancy typically occurs through the following mechanisms: a humoral effect mediated by PTHrP, osteolytic metastases, or ectopic 1-alpha-hydroxylation of 25-hydroxyvitamin D resulting in increased calcitriol levels. This last mechanism is characteristic of Hodgkin’s lymphoma; the extrarenal production of calcitriol by the lymphoma or tumor-infiltrating macrophages substantially increases absorption of calcium from the intestine, raising the serum calcium level. In patients with myeloma, tumor-induced osteolysis causes hypercalcemia.

How should severe hypercalcemia be managed?

Intravenous fluid resuscitation is the mainstay of short-term treatment for hypercalcemia. Bisphosphonates are also warranted for severe hypercalcemia; although their potential nephrotoxicity in a patient with renal failure is a concern, no dose adjustment is recommended for initial treatment in a patient with hypercalcemia of malignancy if the serum creatinine level is less than 4.5 mg per deciliter (397.8 micromoles per liter). Furosemide results in calciuresis, but its use should be limited to patients with signs of volume overload.

Morning Report Questions

Q: How should calcitriol-mediated hypercalcemia be treated?

A: In patients with calcitriol-mediated hypercalcemia, corticosteroids are the therapy of choice, reducing calcitriol production by macrophages and typically correcting the serum calcium within 3 to 5 days after the initial dose.

Q: What is the principal treatment for hypercalcemia of malignancy?

A: For hypercalcemia of malignancy, bisphosphonates are the principal treatment — in particular, the potent agent zoledronic acid.

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