How does granulomatous disease cause hypercalcemia?

• A. Activated macrophages express 1α-hydroxylase, increasing calcitriol independent of PTH.
• B. Increased PTH secretion from parathyroid glands.
• C. Renal failure reduces phosphate excretion.
• D. Decreased vitamin D activation due to liver disease.

Answer: (A)

Granulomatous disease raises calcium mainly through extrarenal production of active vitamin D. In granulomas, activated macrophages express 1α-hydroxylase, converting 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) without needing PTH. The increased calcitriol boosts intestinal calcium absorption (and can enhance bone resorption), driving hypercalcemia even when PTH levels are low or suppressed. This mechanism is distinct from PTH-driven hypercalcemia and from problems like kidney failure or liver disease, which affect calcium and vitamin D metabolism in different ways.