Young-Gyun Seo MD., PhD. ¹, Stergios A. Polyzos MD., PhD. ², Kyung-Hee Park MD., PhD. ¹, Christos S. Mantzoros MD., PhD. ^3,4

¹Department of Family Medicine, Hallym University Sacred Heart Hospital, Anyang, Gyeonggi-do, Korea
²First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
³Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
⁴Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA

Corresponding Author: Christos S. Mantzoros, MD, DSc, PhD hc

Background and aims: Associations between hepatic fibrosis and mortality remain to be fully elucidated in large population-based studies. This study aimed to evaluate the associations of fibrosis-4 index (FIB-4) with all-cause, cardiovascular, cancer and liver-related mortality in the adult Korean population without viral hepatitis.

Methods: Baseline data were retrieved from the Korea National Health and Nutrition Examination Survey (KNHANES) and mortality data were retrieved from the Korean Cause of Death data registry. Adults (≥19 years) without viral hepatitis B or C, liver cirrhosis, any cancer, stroke, myocardial infarction, angina pectoris, or renal failure at baseline were eligible. Presumed hepatic fibrosis was evaluated with FIB-4. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariable Cox regression analysis, and Kaplan-Meier estimates of the cumulative mortality were evaluated.

Results: There were 46,456 individuals with median follow-up of 8.6 years (interquartile range 6.3-10.6 years). Kaplan-Meier curves for cumulative mortality showed that participants with FIB-4≥2.67 (versus FIB-4<2.67) had higher cumulative all-cause, cardiovascular, cancer and liver-related mortality. In the fully adjusted model, Cox regression analysis revealed that presumed advanced hepatic fibrosis (FIB-4≥2.67) remained associated with all-cause mortality (HR 1.64, 95%CI 1.23-2.18), cardiovascular mortality (HR 2.96, 95%CI 1.60-5.46), and liver-related mortality (HR 10.50, 95%CI 4.70-23.44), but not cancer mortality, after adjusting for confounders including central obesity and insulin resistance. Excluding participants with estimated alcohol intake ≥30 gr for males and ≥20 gr for females did not affect the results.

Conclusions: At the population level, liver fibrosis estimated by FIB-4 was associated with increased cumulative all-cause, cardiovascular and liver-related mortality.