Which cells are primarily responsible for extrarenal production of 1,25(OH)2D in granulomatous disease?

• A. Macrophages
• B. Osteoblasts
• C. Hepatocytes
• D. Erythrocytes

Answer: (A)

Extrarenal activation of vitamin D by activated macrophages in granulomas is the key concept. These macrophages express the enzyme 1-alpha-hydroxylase, which converts 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D outside the kidney. Unlike the renal enzyme, this extrarenal activity is not properly regulated by PTH or calcium levels, so it can produce excess active vitamin D. The result is increased intestinal calcium absorption and potential hypercalcemia, a classic feature in granulomatous diseases like sarcoidosis. Other cell types don’t carry out this final activation step: osteoblasts are involved in bone formation, hepatocytes mainly produce 25-hydroxyvitamin D in the liver, and erythrocytes do not participate in vitamin D metabolism.