Association between serum homocysteine levels and mortality stratified by liver fibrosis index: a retrospective cohort study of US adults

Background: Elevated serum homocysteine (Hcy) levels have been associated with increased mortality; however, whether this association varies with the liver fibrosis burden remains unclear. Methods: We analyzed 16,541 adults from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2006 with mortality follow-up through December 31, 2019, via the National Death Index linkage. Serum Hcy levels were categorized as <10, 10-15, or >15 μmol/L. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. Cox proportional hazard regression models, accounting for the complex survey design, were used to estimate the associations. Results: During a mean follow-up of 182.4 months, 3,740 deaths occurred. Hcy >15 μmol/L was associated with increased all-cause mortality regardless of liver fibrosis status. In contrast, moderate elevations (10-15 μmol/L) were associated with higher mortality only among participants with a higher FIB-4 index (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.19-1.42), but not among those with a lower FIB-4 index (HR, 1.24; 95% CI, 0.92-1.67). Kaplan-Meier curves showed greater separation across Hcy categories in the high FIB-4 group. Natural cubic spline analyses demonstrated nonlinear associations between Hcy and mortality that differed according to fibrosis status. Cause-specific analyses indicated that these associations were primarily driven by metabolic and other nonmalignant deaths, rather than malignant mortality. The findings were consistent across fibrosis quartiles, subgroup analyses, and sensitivity analyses. Conclusion: The association between serum Hcy levels and mortality differed across liver fibrosis strata. These findings suggest that stricter Hcy thresholds are warranted in populations with a higher risk of liver fibrosis.