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

Abstract

As in adults, obesity also plays a central role in the development of metabolic syndrome (MS) in children. Non-alcoholic fatty liver disease (NAFLD) is considered a manifestation of MS. Not only MS but also NAFLD seem to be inversely associated with serum bilirubin concentrations, an important endogenous tissue protector when only mild elevated. The aim of the study was to evaluate the association between serum bilirubin levels and the prevalence of MS and NAFLD in Italian obese children and adolescents. A retrospective cross-sectional study was performed in 1672 patients aged from 5 to 18 years. Clinical and laboratory parameters were assessed. NAFLD was measured by liver ultrasonography. The study was approved by the Ethical Committee of the Istituto Auxologico Italiano (research project code 1C021_2020, acronym BILOB). MS was present in 24% and fatty liver (FL) in 38% of this population. Bilirubin was not associated with FL and MS as a whole, but it was inversely associated only with selected components of MS, i.e., large WC, high blood pressure and high triglycerides. Our data suggest that bilirubin is not protective against MS and NAFLD in the presence of severe obesity.

Association of Serum Bilirubin and Functional Variants of Heme Oxygenase 1 and Bilirubin UDP-Glucuronosyl Transferase Genes in Czech Adult Patients with Non-Alcoholic Fatty Liver Disease

“…It has been reported repeatedly that individuals with Gilbert syndrome and increased bilirubin levels have a lower frequency of cardiovascular diseases, cancer, as well as various metabolic diseases compared to normobilirubinemic subjects [ 35 , 39 ]. However, as described above, the epidemiological data on the association of serum bilirubin and NAFLD/NASH reported so far are controversial [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The results from our clinical study did not find any such association, as was similarly found in recently published studies [ 22 , 23 , 24 , 25 , 26 ].…”

“…However, as described above, the epidemiological data on the association of serum bilirubin and NAFLD/NASH reported so far are controversial [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The results from our clinical study did not find any such association, as was similarly found in recently published studies [ 22 , 23 , 24 , 25 , 26 ]. The major confounding factor might be NAFLD-induced liver dysfunction, which might even lead to a certain elevation of serum bilirubin concentration.…”

“…In fact, serum bilirubin concentrations have been reported to be negatively associated with NAFLD/NASH in adults [ 18 , 19 , 20 ] as well as in pediatric patients [ 21 ]. On the other hand, two recent Mendelian randomization studies from China [ 22 ] and the Netherlands [ 23 ] did not prove any causal association of systemic bilirubin concentrations and NAFLD; and in the recent Italian study, no association of serum bilirubin with liver steatosis was observed either [ 24 ]. Moreover, in another study by Tarantino et al, serum bilirubin concentrations were higher across all stages of NAFLD [ 25 ], and NASH patients were shown to have higher serum bilirubin concentrations compared to those with simple steatosis [ 26 ].…”

Serum Bilirubin Levels in Overweight and Obese Individuals: The Importance of Anti-Inflammatory and Antioxidant Responses

“…In this regard, large amounts of data have been obtained from several observational epidemiological studies, whereas there is a lack of controlled clinical trials offering the highest clinical evidence. Second, a recent large retrospective cross-sectional study on severely obese children showed that bilirubin is inversely associated only with some components of MetS, such as high blood pressure, high triglycerides, waist circumference, waist–height ratio, CRP levels, and HOMA-IR index; interestingly, no association between serum bilirubin and MetS or fatty liver was found [ 131 ]. This study showed that bilirubin is not protective in the presence of severe obesity (BMI > 95th percentile), whereas there is a greater number of published studies focused on the whole spectrum of individuals from overweight to obese.…”

Association of Serum Bilirubin With Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

“…Both MetS and NAFLD seem to be associated with serum bilirubin, including total bilirubin (TBIL), DBIL, and IBIL. And the increase in bilirubin levels has been demonstrated to be negatively correlated with the prevalence of NAFLD (8,(13)(14)(15)(16). Nevertheless, the alternative study based on Mendelian randomization analysis did not find a causal relationship between bilirubin levels and the risk of NAFLD (17,18).…”