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. 2025 May 8:18:17562848251338669.
doi: 10.1177/17562848251338669. eCollection 2025.

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

Yuan-Tsung Tseng  1   2 , Chun-Hsiang Wang  3 , Jung-Der Wang  1 , Kow-Tong Chen  1   4 , Chung-Yi Li  5   6   7
Affiliations

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

Yuan-Tsung Tseng et al. Therap Adv Gastroenterol. .

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.

Keywords: hepatocellular carcinoma; liver cirrhosis; mortality; vitamin D deficiency; vitamin D supplementation.

Plain language summary

How vitamin D levels impact liver health and risk of death: a US Study Vitamin D is an important nutrient that our bodies need to stay healthy, but both too little and too much may be harmful. This study explored whether having low vitamin D levels increases the risk of serious liver diseases “such as liver cirrhosis and liver cancer” and the risk of death, and whether improving vitamin D levels can make a difference. Researchers analyzed the health records of millions of adults from various US hospitals between 2000 and 2024. They compared patients with low vitamin D levels to those with normal levels. In addition, they looked at a group of patients who had low vitamin D levels but later improved their levels through supplementation. The study found that people with low vitamin D levels had a higher risk of developing advanced liver diseases and were more likely to die compared to those with normal vitamin D levels. Interestingly, even after improving vitamin D levels, the risk of liver cirrhosis remained high, although the risk of death was reduced and liver cancer risk was similar to those with normal levels. The researchers also discovered that the relationship between vitamin D and liver health was not straightforward both very low and very high vitamin D levels were associated with greater risks, suggesting that an optimal balance is key. In simple terms, maintaining the right amount of vitamin D appears important for protecting liver health and reducing the risk of serious illness and death, although more research is needed to confirm the ideal levels and the benefits of aiming for them.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
Flowchart of stratification of the study population from the TriNetX US Database based on vitamin D levels.
Figure 2.
Figure 2.
Cumulative risk of liver cirrhosis, hepatocellular carcinoma, and all-cause mortality by vitamin D status: (a) continuous deficiency versus vitamin D sufficiency and (b) recovery from deficiency versus vitamin D sufficiency. The x-axis represents follow-up time in years, while the y-axis represents the cumulative risk of each outcome. Shaded areas around the lines indicate the 95% confidence intervals. Log-rank tests were conducted to determine the statistical significance of the differences between groups.
Figure 3.
Figure 3.
Risk of liver cirrhosis, HCC, and mortality stratified by demographic and clinical factors in continuous vitamin D deficiency and sufficiency groups. This figure illustrates the adjusted hazard ratios and 95% confidence intervals for liver cirrhosis, HCC, and mortality outcomes between the continuous vitamin D deficiency and vitamin D sufficiency groups stratified by various subgroups and comorbidities. The analysis is stratified by demographic factors (age groups: 20–39, 40–59, 60–79, >80 years; gender: male/female; race: White, Black, Asian) and various comorbidities, including MASLD, NAFLD, viral hepatitis (including separate analyses for HBV and HCV), DM, CLD, and CKD. The analysis compared the risk associated with continuous vitamin D deficiency with a vitamin D-sufficient state in both the comorbid and non-comorbid populations. Propensity score matching was performed based on age at index, sex, race, socioeconomic status, lifestyle, medications, comorbidities, and laboratory data. CKD, chronic kidney disease; CLD, chronic liver disease; DM, diabetes mellitus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MASLD, metabolic associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease.
Figure 4.
Figure 4.
Association between 25-hydroxyvitamin D levels and risks of liver cirrhosis, HCC, and all-cause mortality. This figure illustrates the nonlinear association between 25-hydroxyvitamin D levels and HRs for liver cirrhosis (a), HCC (b), and all-cause mortality (c). The solid line represents the estimated HR, while the dashed lines indicate the 95% confidence intervals. The black dots represent spline knots used in the restricted cubic spline regression model. HCC, hepatocellular carcinoma; HR, hazard ratios.
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