Renal proximal tubule: 1-alpha-hydroxylase

Target organ · CYP27B1 Rate-limiting step

The rate-limiting and tightly regulated step of vitamin D activation. Mitochondrial CYP27B1 in the proximal tubular cell converts 25(OH)D to 1,25-dihydroxyvitamin D. PTH and a low phosphate stimulate it; FGF23, calcitriol itself and a high phosphate shut it down.

Traced from the start

Detail

Enzyme: CYP27B1, mitochondrial, in the proximal convoluted tubule; substrate arrives by megalin-mediated endocytosis of the 25(OH)D-binding protein complex
Stimulated by: PTH (the dominant drive), hypophosphataemia and hypocalcaemia
Inhibited by: FGF23, calcitriol itself as negative feedback, and hyperphosphataemia
Counter-enzyme: CYP24A1, the 24-hydroxylase, inactivates both 25(OH)D and calcitriol to calcitroic acid, and is induced by calcitriol and FGF23
Extrarenal source: Activated macrophages in granulomas and in lymphoma express CYP27B1 that is not subject to this feedback

When it goes wrong

Chronic kidney disease with loss of functioning proximal tubule

Calcitriol falls, gut calcium absorption drops, calcium falls and PTH rises; treat with an active analogue such as calcitriol, alfacalcidol or paricalcitol, because plain cholecalciferol cannot be activated

Sarcoidosis, tuberculosis or lymphoma

Unregulated macrophage 1-alpha-hydroxylation: hypercalcaemia and hypercalciuria with a raised calcitriol and a suppressed PTH, responsive to corticosteroids

Vitamin D-dependent rickets type 1 (CYP27B1 mutation)

Normal 25(OH)D with a low calcitriol, hypocalcaemia and rickets; responds to calcitriol but not to cholecalciferol

Loss-of-function CYP24A1 mutation

Idiopathic infantile hypercalcaemia: calcitriol cannot be cleared, giving hypercalcaemia, nephrocalcinosis and stones

Practise this structure

1 question in the bank tagged Vitamin D.

A 63-year-old woman reports several months of bone pain and difficulty climbing stairs. She has no focal neurological deficit. Serum calcium is 2.19 mmol/L (2.1…

Clinical rotations · common