Vitamin D Sufficiency Revisited: Evidence of a Dose-Response Effect for MASLD in Adults at Risk

Background and Aims: Vitamin D plays a pivotal role in liver health, influencing multiple steps in the development of steatosis, fibrosis, and extrahepatic complications in metabolic dysfunction-associated steatotic liver disease (MASLD). However, serum vitamin D concentrations that confer optimal hepatic protection in MASLD remain unclear. We therefore aimed to investigate the association between vitamin D status and MASLD and to explore whether higher vitamin D concentrations confer incremental protection beyond current sufficiency cut-offs. Method: We conducted a multicenter cross-sectional study of 1039 adults with at least one cardiometabolic risk factor for MASLD diagnosis, recruited between 2022 and 2024. Participants that reported excessive alcohol intake (>30 g/day for men, >20 g/day for women) and other etiologies of liver disease were excluded. Serum vitamin D levels were measured, with ≥20 ng/mL defined as sufficiency. MASLD (controlled attenuation parameter [CAP] ≥ 248 dB/m) and significant fibrosis (liver stiffness measurement [LSM] ≥ 8 kPa) were assessed using vibration-controlled transient elastography. Missing vitamin D values were imputed with multiple imputation. Associations between vitamin D status, MASLD and fibrosis were examined using multivariable logistic regression models adjusted for potential confounders. Results: Participants had a mean age of 52.2 ± 13.0 years; 51.6% were male and mean BMI was 30.1 ± 5.8 kg/m². Vitamin D sufficiency and obesity were present in 81.2% (95% CI: 78.4-84.9) and 54.7% (95% CI: 51.3-58.0), respectively. Vitamin D sufficiency was associated with lower odds of MASLD (crude OR = 0.47, 95% CI: 0.33-0.67) and significant fibrosis (crude OR = 0.46, 95% CI: 0.28-0.76). After adjusting for potential confounders, the association between Vitamin D sufficiency and MASLD remained clinically relevant but did not reach statistical significance (adjusted OR = 0.60, 95% CI: 0.36-1.03, p = 0.06). In contrast, the association between Vitamin D sufficiency and significant fibrosis was both clinically relevant and statistically significant (adjusted OR = 0.48, 95% CI: 0.246-0.916, p = 0.03). When Vitamin D was categorized into quartiles, participants in the highest quartile (≥44 ng/dL) had 61% lower odds of MASLD in the adjusted model (adjusted OR = 0.39, 95% CI: 0.21-0.71) compared with participants in the lowest quartile (≤22 ng/mL). No significant dose-dependent associations were observed for fibrosis. Conclusions: Vitamin D levels showed a dose-dependent decrease in the odds of MASLD among at-risk adults. While the protective effect on fibrosis was not dose-dependent, these findings collectively suggest vitamin D as a potentially modifiable factor in MASLD prevention and management.