Nonlinear associations of serum vitamin D levels with advanced liver disease and mortality: a US Cohort Study.

Abstract

Background: Vitamin D deficiency is prevalent and linked to chronic diseases; its association with advanced liver disease progression requires clarification.

Objectives: To investigate the association between vitamin D levels and risks of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality, and assess risk changes after achieving sufficiency post-supplementation.

Design: This was a retrospective cohort study.

Methods: Utilized TriNetX US data (3,905,594 patients, 2000-2024). Adults with vitamin D deficiency (20.00-30.00 ng/mL) were compared with those with sufficient levels (30.01-80.00 ng/mL). Follow-up was initiated from the first vitamin D test or start of supplementation to minimize immortal time bias. Propensity score matching (1:1) balanced >20 baseline confounders.

Results: After matching, 1,204,760 patients with vitamin D deficiency and 1,204,760 with sufficient vitamin D levels were included. Vitamin D deficiency was associated with an increased risk of liver cirrhosis (hazard ratio (HR), 1.30; 95% confidence interval (CI), 1.25-1.36), HCC (HR, 1.22; 95% CI, 1.08-1.37), and all-cause mortality (HR, 1.14; 95% CI, 1.13-1.16). Achieving sufficient vitamin D levels reduced the risk of all-cause mortality (HR, 0.93; 95% CI, 0.88-0.99) and aligned HCC outcomes (HR, 1.16; 95% CI, 0.68-2.00). However, it did not significantly reduce the risk of liver cirrhosis (HR, 2.05; 95% CI, 1.69-2.50). Dose-response analysis showed a U-shaped relationship for liver cirrhosis and HCC, with the lowest risks at 40-60 ng/mL.

Conclusion: Serum vitamin D levels showed a nonlinear association with liver cirrhosis and HCC risk; deficiency independently increased the risks for cirrhosis, HCC, and mortality. Supplementation achieving sufficiency reduced mortality and normalized HCC risk but not cirrhosis risk, potentially reflecting limitations in reversing established disease. The lowest liver disease risk was associated with vitamin D levels of 40-60 ng/mL in this cohort, although causality and the clinical benefit of targeting this specific range require confirmation.