This case illustrates that malakoplakia may exhibit ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase activity and cause severe hypercalcemia upon vitamin D supplementation.
Mutations of the activating enzymes CYP2R1 and CYP27B1 cause lack of normal 1,25-(OH)<sub>2</sub>D<sub>3</sub> synthesis and result in rickets whereas mutations of the inactivating enzyme CYP24A1 cause build-up of excess 1,25-(OH)<sub>2</sub>D<sub>3</sub> and result in hypercalcemia, nephrolithiasis, and nephrocalcinosis.
The ingestion of excessive amounts of vitamin D<sub>3</sub> (or vitamin D<sub>2</sub>) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)<sub>2</sub>D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)<sub>2</sub>D.