Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 10 2023
01 10 2023
Historique:
received:
30
05
2023
accepted:
23
06
2023
medline:
25
9
2023
pubmed:
22
9
2023
entrez:
22
9
2023
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37738404
doi: 10.1097/HC9.0000000000000245
pii: 02009842-202310010-00024
pmc: PMC10519483
pii:
doi:
Substances chimiques
Bilirubin
RFM9X3LJ49
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Références
Trends Mol Med. 2023 Apr;29(4):315-328
pubmed: 36828710
Commun Med (Lond). 2021 Aug 27;1:28
pubmed: 35602215
Hum Mol Genet. 2022 Aug 17;31(15):2548-2559
pubmed: 35225327
Int J Epidemiol. 2008 Apr;37(2):234-44
pubmed: 18381398
BMC Gastroenterol. 2011 Apr 14;11:39
pubmed: 21492460
N Engl J Med. 1995 Nov 2;333(18):1171-5
pubmed: 7565971
Am J Hum Genet. 2022 Oct 6;109(10):1727-1741
pubmed: 36055244
Clin Chem. 1994 Jan;40(1):18-23
pubmed: 8287538
J Biol Chem. 1994 Jul 8;269(27):17960-4
pubmed: 8027054
J Clin Exp Hepatol. 2018 Dec;8(4):362-366
pubmed: 30563996
Crit Rev Clin Lab Sci. 2018 Mar;55(2):129-139
pubmed: 29390925
Gastroenterology. 2010 Dec;139(6):1942-1951.e2
pubmed: 20837016
Hepatology. 2016 Apr;63(4):1170-83
pubmed: 26663021
Hypertension. 2018 Oct;72(4):788-795
pubmed: 30354722
PLoS One. 2022 Jun 24;17(6):e0269713
pubmed: 35749402
Lancet. 2012 Jul 7;380(9836):37-43
pubmed: 22579043
Clin Mol Hepatol. 2023 Feb;29(Suppl):S196-S206
pubmed: 36472050
Science. 1957 Sep 20;126(3273):563-4
pubmed: 13467249
Br J Cancer. 2015 May 12;112(10):1709-16
pubmed: 25880011
Clin Pharmacol Ther. 2022 Feb;111(2):435-443
pubmed: 34625956
Sci Rep. 2020 May 26;10(1):8689
pubmed: 32457304
Clin Gastroenterol Hepatol. 2022 Mar;20(3):641-650
pubmed: 33524594
Cancers (Basel). 2021 Mar 29;13(7):
pubmed: 33805415
Nat Rev Dis Primers. 2016 Apr 28;2:16024
pubmed: 27121416
J Clin Lab Anal. 1999;13(6):273-9
pubmed: 10633294
Clin Chem. 1984 Aug;30(8):1380-2
pubmed: 6744591
PLoS One. 2014 Apr 11;9(4):e94479
pubmed: 24728477
N Engl J Med. 1967 Nov 23;277(21):1108-12
pubmed: 6054997
J Med Genet. 2001 Apr;38(4):244-9
pubmed: 11370628
Arch Biochem Biophys. 2019 Sep 15;672:108062
pubmed: 31376369
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Lancet. 1977 Apr 30;1(8018):931-3
pubmed: 67389
BMC Endocr Disord. 2013 Oct 04;13:39
pubmed: 24090309
Front Genet. 2022 Jul 25;13:920390
pubmed: 35983412
JAMA Intern Med. 2013 Jul 8;173(13):1222-8
pubmed: 23753274
Pharmaceutics. 2022 Sep 29;14(10):
pubmed: 36297516
Cardiovasc Diabetol. 2022 Apr 18;21(1):54
pubmed: 35436955
PLoS Med. 2015 Mar 31;12(3):e1001779
pubmed: 25826379
Hepatology. 2004 Oct;40(4):827-35
pubmed: 15382174
JAMA. 2018 May 15;319(19):1981-1982
pubmed: 29710130
Am J Physiol Endocrinol Metab. 2021 Feb 1;320(2):E191-E207
pubmed: 33284088
Am J Gastroenterol. 2017 May;112(5):740-751
pubmed: 27725647
Lancet Public Health. 2018 Jul;3(7):e323-e332
pubmed: 29908859
Antioxidants (Basel). 2022 Jul 18;11(7):
pubmed: 35883877
J Hepatol. 2023 Aug;79(2):277-286
pubmed: 37088311