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

Setor K Kunutsor,Stephan J L Bakker,Robin P F Dullaart,Lyanne M Kieneker,Niek Verweij,Monika Frysz

doi:10.1007/s10654-019-00589-0

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 loge 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.

Highlights

Circulating total bilirubin has been consistently shown to be inversely and independently associated with adverse cardiometabolic outcomes such as cardiovascular disease (CVD), hypertension and type 2 diabetes [1,2,3]
Though a causal association has been demonstrated for total bilirubin and type 2 diabetes [4], there is no strong evidence for a causal association between total bilirubin levels and CVD [5, 6]
The levels were lower by 12% in the combined group of current and former smokers compared with non-current smokers (Table 2)

Summary

Introduction

Circulating total bilirubin has been consistently shown to be inversely and independently associated with adverse cardiometabolic outcomes such as cardiovascular disease (CVD), hypertension and type 2 diabetes [1,2,3]. Nonalcoholic fatty liver disease (NAFLD), emerging as the most common cause of chronic liver disease in the developed world [7], is a cardiometabolic condition which is characterized by hepatic steatosis with varying degrees of necroinflammation and fibrosis [7]. In the absence of the reference standard—liver biopsy [8], the diagnosis of NAFLD is commonly based on (1) imaging techniques [i.e., ultrasonography, computed tomography (CT) scan, or. Due to the high costs associated with these imaging techniques and their unsuitability for use in large-scale population-based studies, a number of biomarker-based algorithms have been developed to aid the diagnosis of NAFLD. The fatty liver index (FLI) [10] and the hepatic steatosis index (HSI) [11] are based on accessible variables and have been reported to have good diagnostic accuracies for NAFLD [10,11,12]

Objectives

Methods

Results

Conclusion