Circulating total bilirubin and risk of non-alcoholic fatty liver disease in the PREVEND study: observational findings and a Mendelian randomization study

Abstract

The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28-75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73-0.92; p = 0.001) per 1 standard deviation (SD) change in log e total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78-0.97; p = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69-1.38; p = 0.900) for FLI and 1.14 (0.81-1.59; p = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.

Association of Serum Bilirubin Level with Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study of 1672 Obese Children

“…Despite this evidence, the relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. Recently, two different studies were performed in China [42] and the Netherlands [43], aiming to assess the association of total bilirubin with the risk of new-onset NAFLD, and investigate the causal nature of their association using a Mendelian randomization approach. Multivariable analysis showed that elevated levels of total bilirubin were not causally associated with NAFLD.…”

Systematic Influence of Circulating Bilirubin Levels on Osteoporosis

“…Circulating bilirubin level is one robust indicator of hepatic dysfunction, and in vitro study reveals that bilirubin from jaundiced patients can inhibit the proliferative capacity of osteoblast (11,33,34). Total bilirubin has a detrimental effect on cell viability, cell differentiation and mineralization of primary human osteoblasts in a dose-dependent manner (11).…”

A Nomogram Model Based on Noninvasive Bioindicators to Predict 3-Year Risk of Nonalcoholic Fatty Liver in Nonobese Mainland Chinese: A Prospective Cohort Study

“…A number of prospective cohort studies have shown that DBIL levels are significantly associated with a reduction in the risk of NAFLD, providing a protective biomarker for NAFLD [ 52 ]. More importantly, this association is independent of classic risk factors including liver enzymes, coronary heart disease, Mets, diabetes, and other classic metabolic risk factors [ 53 ].…”

“…However, the relationship between TB and indirect bilirubin and the risk of NAFLD was not significant. This may be partly due to DBIL, which is more soluble in serum and acts in an active form before indirect bilirubin [ 52 , 53 ]. This conflicts with our research results.…”