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cohort·epidemiology, gastroenterology, internal medicine, observational study, public health·PMC10519483

Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia

Hepatology Communications · 11 authors, 5 centres

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TL;DR

This cohort study defined stratified total bilirubin reference intervals for Gilbert syndrome (GS) and hypobilirubinemia in 138,125 apparently healthy middle-aged UK Biobank participants, correcting a historical underestimation of GS in women.

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The study analyzed 138,125 apparently healthy middle-aged adults from the UK Biobank to define stratified total bilirubin reference intervals for Gilbert syndrome (GS) and hypobilirubinemia based on sex, age, and UGT1A1*28 genotype. In women, the stratified definition identified 10% with GS compared to 3.7% using the historical ≥1 mg/dL cutoff. Limitations include the study's restriction to middle-aged Europeans, potential for residual confounding despite adjusting for 17 factors, and the focus on total rather than unconjugated bilirubin. The findings suggest that stratified definitions improve GS diagnosis, especially in women, and support a personalized cholelithiasis risk score for men with GS.

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cohort

SPECIALTY

epidemiology

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ORIGINAL PAPER

PMC10519483

Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia

Hepatology Communications

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ABSTRACT

Background and Aims: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1 *28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1 *28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival. Methods: UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations. Results: In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL ( P <0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3–1.7], P =0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin ( P =0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia. Conclusions: In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization.

CITATION EXPORT

Thierry Poynard, Olivier Deckmyn, Valentina Peta et al.. Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia. Hepatology Communications. (2023). https://doi.org/10.1097/HC9.0000000000000245

AUTHORS

11 · 5 CENTRES

Thierry Poynard, Olivier Deckmyn, Valentina Peta, Mehdi Sakka, Pascal Lebray, Joseph Moussalli, Raluca Pais, Chantal Housset, Vlad Ratziu, Eric Pasmant, Dominique Thabut

1Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
2BioPredictive, Paris, France
3Department of Biochemistry, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
4Department of Hepato-Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
5Department of Genetic, Assistance Publique-Hôpitaux de Paris (AP-HP), Cochin Hospital, Paris, France