A 38-year-old woman with pulmonary sarcoidosis presents with fatigue, polyuria, and constipation. Serum calcium is 12.8 mg/dL, PTH is suppressed, and 1,25-dihydroxycholecalciferol level is elevated despite low 25-hydroxyvitamin D. The mechanism of her hypercalcemia is:

• A Primary overactivity of parathyroid glands increasing bone resorption
• B Unregulated expression of 1-alpha hydroxylase by activated macrophages within granulomas ✓
• C Reduced renal degradation of 25-hydroxyvitamin D due to nephrocalcinosis
• D Ectopic secretion of calcitonin by granuloma cells

Explanation

Activated macrophages in granulomas express 25-hydroxyvitamin D 1-alpha hydroxylase extrarenally. Unlike the renal enzyme, this activity is not subject to feedback suppression by calcium, PTH, or fibroblast growth factor 23, so calcitriol production continues autonomously, increasing intestinal calcium absorption and producing hypercalcemia with suppressed PTH. Glucocorticoids suppress this extrarenal hydroxylase and are used therapeutically. Suppressed PTH excludes primary hyperparathyroidism, and calcitonin lowers rather than raises calcium.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.