Sarcoidosis Extrarenal 1-Alpha-Hydroxylase Hypercalcaemia — ESENeph MCQ

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ModerateElectrolyte DisordersSarcoidosis Extrarenal 1-Alpha-Hydroxylase HypercalcaemiaESENeph

A 62-year-old woman with CKD G4 (eGFR 18 mL/min/1.73m2) presents with painful erythematous nodules on both shins. Biopsy shows non-caseating granulomas in the dermis. She has bilateral hilar lymphadenopathy on chest X-ray, elevated serum ACE levels, and calcium 3.05 mmol/L. What is the mechanism of hypercalcaemia in this condition?

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Correct answer: A — Extrarenal 1-alpha-hydroxylase activity in granulomatous tissue

In sarcoidosis, activated macrophages within granulomas express 1-alpha-hydroxylase (CYP27B1), which converts 25-OH vitamin D to 1,25-dihydroxy vitamin D (calcitriol) independently of renal 1-alpha-hydroxylase and PTH regulation. This unregulated extrarenal calcitriol production increases intestinal calcium absorption and bone resorption, causing hypercalcaemia. Unlike CKD-related 1-alpha-hydroxylase deficiency (where renal calcitriol production falls), in sarcoidosis the granulomatous tissue bypasses this deficiency. PTH is suppressed by the hypercalcaemia. Treatment involves glucocorticoids (which suppress macrophage 1-alpha-hydroxylase), low-calcium diet, avoidance of vitamin D supplements, and adequate hydration. In CKD, this mechanism is particularly important because exogenous active vitamin D should be stopped.

Reference: Iannuzzi et al 2007 – Sarcoidosis NEJM; JRCPTB 2022 – Nephrology Curriculum