Test your medicine knowledge with the MKSAP challenge, in partnership with the American College of Physicians.

A 58-year old woman is evaluated for a 3-week history of fatigue and weight loss. The patient has no significant medical history and takes no prescription medication, but she does take a daily over-the-counter multivitamin and a calcium supplement. She has a 50-pack-year smoking history.

Physical examination reveals a lethargic, ill-appearing woman. Temperature is 37.3 °C (99.1 °F), blood pressure is 136/78 mm Hg, pulse rate is 95/min, and respiration rate is 12/min. Other physical examination findings are unremarkable.

Laboratory studies:

Hemoglobin	8.3 g/dL (83 g/L)
Albumin	4.6 g/dL (46 g/L)
Blood urea nitrogen	43 mg/dL (15.4 mmol/L)
Calcium	14.5 mg/dL (3.6 mmol/L)
Creatinine	2.4 mg/dL (212 µmol/L)
Sodium	145 mEq/L (145 mmol/L)

A chest radiograph shows a 5-cm mass in the right lower lobe of the lung but is otherwise unremarkable.

Which of the following is the most likely cause of her hypercalcemia?

A: Malignancy
B: Primary hyperparathyroidism
C: Sarcoidosis
D: Vitamin D intoxication

MKSAP Answer and Critique

The correct answer is A: Malignancy.

This patient has severe hypercalcemia in the setting of a lung mass. This scenario is highly suggestive of humoral hypercalcemia of malignancy (HHM), which results from tumor production of a circulating factor, parathyroid hormone (PTH)–related protein (PTHrP), that acts on skeletal calcium release, calcium handling by the kidney, and intestinal calcium absorption. Tumors that cause HHM by secreting PTHrP are typically squamous cell carcinomas (often of the lung). Rarely, this disorder can be caused by unregulated production of 1,25-dihydroxyvitamin D (as in B-cell lymphomas) or other mediators that interfere with calcium homeostasis. Although PTHrP assays are now available commercially, results may not be available for up to 10 days. Because endogenous PTH secretion is suppressed in the setting of hypercalcemia, a low PTH level provides indirect but strong evidence of the nature of this patient’s hypercalcemia. Because HHM results in a fairly rapid rise in the serum calcium level, patients tend to be more symptomatic than patients with hypercalcemia from other, more chronic causes.

Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting and typically presents at an asymptomatic stage. This disorder is usually due to a benign parathyroid adenoma and not to a lung mass.

Hypercalcemia is frequently associated with sarcoidosis, with 30% to 50% of patients with the disease demonstrating some degree of abnormal calcium metabolism. However, this patient has no history or physical examination findings suggestive of sarcoidosis, and her lung mass would be an atypical manifestation of primary pulmonary sarcoidosis.

The patient takes a daily multivitamin and calcium supplement in over-the-counter dosages. The recommended daily allowance of vitamin D is 600 units. Although the point at which toxicity occurs is not clear, the Institute of Medicine’s recommended tolerable intake of vitamin D is 4,000 units daily, although substantially greater amounts are usually needed for clinically significant hypervitaminosis to occur. It is unlikely that the amount of vitamin D in her daily multivitamin is enough to cause acute toxicity and hypercalcemia.

Key Point

• Humoral hypercalcemia of malignancy results from tumor production of a circulating factor (parathyroid hormone–related protein [PTHrP]) that acts on skeletal calcium release, calcium handling by the kidney, or intestinal calcium absorption and often involves squamous cell carcinomas of the lung.

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