Targeting Calcitriol Metabolism in Acute Vitamin D Toxicity-A Comprehensive Review and Clinical Insight

Abstract

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

Keywords: CYP polymorphism; calcitriol; drug toxicity; nutrients; pharmacogenetics; vitamin D.

Figure 1

Key enzymes of calcitriol metabolism. Scheme of calcitriol metabolism, including key enzymatic steps of activation and degradation and their respective regulatory mechanisms. Red arrows indicate an increase or upregulation of respective elements.

Figure 2

Genetic conditions affecting calcitriol metabolism. Gain/loss-of-function mutations in the genes of key enzymatic steps of calcitriol metabolism can cause vitamin D-dependent rickets (VDDR), and defective calcitriol degradation by CYP24A1’s loss of function can cause idiopathic infantile hypercalcemia (IHH).

Figure 3

Pharmacological targets of calcitriol metabolism in renal and extrarenal tissue. The inhibition and induction of key enzymatic steps in the activation and degradation of vitamin D metabolites, leading to a decrease in 1,25(OH)₂D₃. Red arrows indicate a decrease or downregulation of respective elements.

Figure 4

Case report: total serum calcium and 25(OH)D₃ levels over time. Total serum calcium levels (red) in mmol/L (normal range 2.2–2.65 mmol/L, red dotted lines) and 25-hydroxy-vitamin-D-levels (blue) in ng/mL (normal range 30–80 ng/mL, blue dotted lines) are shown over the time in days. Timeframes of treatment with normal saline, furosemide, calcitonin and zoledronate (gray), subsequent use of prednisone (green) and follow-up (pink) are shown. Conversion of 25(OH)D₃ is 1 ng/mL = 2.5 nmol/L.