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, as a major cause of cirrhosis and hepatocellular carcinoma, has been determined to cause considerable liver-related and extrahepatic morbidity and mortality. The conventional methods of diagnosing NAFLD have shortcomings. Liver biopsy is invasive, and imaging technologies such as ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) are expensive and not suitable for large-scale population-based studies. Recently, noninvasive diagnostic methods based on clinical parameters with routine laboratory tests have been developed. Of these, the fatty liver index (FLI) and United States FLI (USFLI) are simple and reliable tools with high diagnostic accuracy for NAFLD.
Study Objectives
Accumulating evidence has supported that mildly elevated total bilirubin exerts antioxidant and anti-inflammatory properties in multiple metabolic diseases. This study aimed to explore the association of circulating total bilirubin concentration with NAFLD risk and all-cause mortality and examine the potential nonlinear relationships between them.
Materials and Methods
We used nationally representative data from the National Health and Nutrition Examination Survey (NHANES). NAFLD was assessed using the fatty liver index (FLI) and United States fatty liver index (USFLI), respectively.
A total of 35,912 and 17,329 participants were included in FLI-NAFLD (cases diagnosed by FLI) and USFLI-NAFLD (cases diagnosed by USFLI) groups, respectively. The mean age of the total population was 46.25 years, and 48.51% were male. 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. Compared to participants with the lowest quintile of total bilirubin concentration, 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).
Results
The restricted spline curves showed the 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) and 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).
Subgroup Analysis
The subgroup analysis results showed that participants with the highest quintile of total bilirubin concentration were negatively associated with the risk of FLI-NAFLD across strata of age, sex, race, educational status, BMI, smoking status, alcohol drinking, leisure time physical activity, and ALP, AST, ALT, and GGT levels. Furthermore, the results for the risk of USFLI-NAFLD were similar in all subgroups (P interaction > 0.05). Sensitivity analyses were also conducted by excluding participants with diabetes, hypertension, and hypercholesterolemia, respectively, and the associations did not appreciably change.
Discussion
In this large cross-sectional analysis of a representative sample of US adults, we found that participants with a higher circulating total bilirubin concentration had a lower risk of NAFLD. The significant negative association was robust across multiple subgroups and sensitivity analyses. In addition, this study is the first to examine the nonlinear association of total bilirubin concentration with the risk of NAFLD and all-cause mortality by fitting a restricted cubic spline, and the results indicated a U-shaped relationship. These findings suggest that mildly elevated circulating total bilirubin concentrations were associated with a decreased risk of NAFLD and all-cause mortality.
Conclusion
Our study demonstrated that higher elevated circulating total bilirubin concentration within the physiological range may play an antioxidant and anti-inflammatory role and was associated with a decreased risk of NAFLD and all-cause mortality.
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