Non-linear Associations of Circulating Total Bilirubin Concentration with NAFLD Risk and All-Cause Mortality

Introduction

Over the past decades, nonalcoholic fatty liver disease (NAFLD) has become the most prevalent hepatic disease worldwide, affecting 25% of the adult population. NAFLD, a major cause of cirrhosis and hepatocellular carcinoma, leads to considerable liver-related and extrahepatic morbidity and mortality. Conventional methods of diagnosing NAFLD, such as liver biopsy and imaging technologies like CT and MRI, have significant shortcomings. Recently, noninvasive diagnostic methods based on clinical parameters with routine laboratory tests have been developed, including the fatty liver index (FLI) and United States FLI (USFLI), which are reliable tools with high diagnostic accuracy for NAFLD.

Study Objectives

This study aimed to explore the association of circulating total bilirubin concentration with NAFLD risk and all-cause mortality, examining potential nonlinear relationships between them. Accumulating evidence suggests that mildly elevated total bilirubin exerts antioxidant and anti-inflammatory properties in multiple metabolic diseases.

Materials and Methods

We used nationally representative data from the National Health and Nutrition Examination Survey (NHANES). NAFLD was assessed using the FLI and USFLI. A total of 35,912 and 17,329 participants were included in the FLI-NAFLD and USFLI-NAFLD groups, respectively. The mean age of the total population was 46.25 years, and 48.51% were male.

Results

Compared to participants with the lowest quintile of total bilirubin concentration, those with the highest quintile had a lower risk of NAFLD in both FLI-NAFLD (OR: 0.48, 95% CI: 0.40, 0.59) and USFLI-NAFLD (OR: 0.55, 95% CI: 0.43, 0.70) groups. The association between total bilirubin concentration and all-cause mortality was not significant among those with the highest quintile of total bilirubin concentration (HR: 0.89, 95% CI: 0.66, 1.20).

Nonlinear Associations

The restricted spline curves showed a nonlinear U-shaped association of total bilirubin concentration with NAFLD risk and all-cause mortality. The segmented linear regression analysis showed negative associations between total bilirubin concentration and risk of NAFLD in both FLI-NAFLD (OR: 0.94, 95% CI: 0.93, 0.95) and USFLI-NAFLD (OR: 0.95, 95% CI: 0.93, 0.96) groups when total bilirubin concentration was below the turning point (FLI-NAFLD: 18.81 mmol/L; USFLI-NAFLD: 15.39 mmol/L). These associations were not significant when total bilirubin concentration was higher than the turning point. Furthermore, all-cause mortality decreased (OR: 0.97, 95% CI: 0.95, 1.00) with increased total bilirubin concentration up to the turning point (11.97 mmol/L), and then all-cause mortality increased with increasing total bilirubin concentration (OR: 1.03, 95% CI: 1.02, 1.04).

Discussion

Our study demonstrated that higher circulating total bilirubin concentration within the physiological range was associated with decreased risk of NAFLD and all-cause mortality among NAFLD patients. These findings suggest that mildly elevated total bilirubin concentration may play an antioxidant and anti-inflammatory role in NAFLD. The mechanisms underlying this association might be attributed to the antioxidant and anti-inflammatory properties of bilirubin, which can protect various proteins, lipid membranes, and cells from damage.

Conclusion

In conclusion, our study provides evidence that higher circulating total bilirubin concentration within the physiological range is associated with a decreased risk of NAFLD and all-cause mortality. These findings highlight the potential of bilirubin as a biomarker for NAFLD and a predictor of mortality among NAFLD patients.

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