Gilbert综合征UGT1A1基因突变特征及对肝脏和肝外系统的影响

梁晨; 白丽; 郑素军

doi:10.3969/j.issn.1001-5256.2019.07.046

Gilbert综合征UGT1A1基因突变特征及对肝脏和肝外系统的影响

DOI: 10.3969/j.issn.1001-5256.2019.07.046

首都医科大学附属北京佑安医院疑难肝病及人工肝中心肝衰竭与人工肝治疗研究北京市重点实验室

基金项目:

北京市医院管理局消化内科学科协同发展中心项目(XXZ0503),北京市医院管理局“登峰”人才培养计划基金资助项目(DFL20151601);北京市医院管理局临床医学发展专项经费资助(ZYLX201806)；科技创新服务能力建设-高精尖学科建设项目(市级)(11920703)；十三五国家科技重大专项(2012ZX10002004-006,2017ZX10203201-005,2017ZX10201201,2017ZX10202203-006-001,2017ZX10302201-004-002)；国家重点研发计划资助(2017YFA0103000)；

详细信息

中图分类号: R596.1
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出版历程
- 收稿日期: 2019-01-15
- 出版日期: 2019-07-20

Research advances in mutation characteristics of the UGT1A1 gene in Gilbert syndrome and its influence on intrahepatic and extrahepatic systems

Intractable Hepatic Diseases and Artificial Liver Treatment & Training Center, Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You An Hospital, Capital Medical University

Research funding:

摘要

摘要: Gilbert综合征是最常见的遗传性高胆红素血症,发病率较高。简述了Gilbert综合征的流行病学特征、常见的尿苷二磷酸葡萄糖醛酸转移酶(UGT) 1A1基因突变位点以及Gilbert综合征对肝脏本身及肝外疾病的影响进展,并认为这对Gilbert综合征的诊疗及某些肝脏及肝外疾病的防治具有重要意义。
- 吉尔伯特病 /
- 高胆红素血症 /
- 突变 /
- 尿苷二磷酸葡萄糖醛酸转移酶
Abstract: Gilbert syndrome is the most common type of hereditary hyperbilirubinemia with a high incidence rate. This article briefly describes the research advances in epidemiological characteristics of Gilbert syndrome, common UGT1 A1 gene mutation sites, and the influence of Gilbert syndrome on intrahepatic and extrahepatic diseases. It is pointed out that an understanding of these aspects plays an important role in the diagnosis and treatment of Gilbert syndrome and the prevention and treatment of intrahepatic and extrahepatic diseases.
- Gilbert disease /
- hyperbilirubinemia /
- mutation /
- UGT

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参考文献(45)

[1]KAMAL S, ABDELHAKAM S, GHORABA D, et al.The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome:A longitudinal study[J].BMCGastroenterol, 2019, 19 (1) :22.

[2]GAMMAL RS, COURT MH, HAIDAR CE, et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing[J].Clin Pharmacol Ther, 2016, 99 (4) :363-369.

[3]GOEL A, AGGARWAL R.Unconjugated hyperbilirubinemia:Ablessing in disguise?[J].J Gastroenterol Hepatol, 2013, 28 (11) :1687-1689.

[4]GENTILE S, TIRIBELLI C, BALDINI G, et al.Sex differences of nicotinate-induced hyperbilirubinemia in Gilbert's syndrome.Implication of bilitranslocase function[J].J Hepatol, 1985, 1 (4) :417-429.

[5]BOSMA PJ, CHOWDHURY JR, BAKKER C, et al.The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome[J].N Engl J Med, 1995, 333 (18) :1171-1175.

[6]HORSFALL LJ, NAZARETH I, PEREIRA SP, et al.Gilbert's syndrome and the risk of death:A population-based cohort study[J].J Gastroenterol Hepatol, 2013, 28 (10) :1643-1647.

[7]STRASSBURG CP.Gilbert-Meulengracht's syndrome and pharmacogenetics:Is jaundice just the tip of the iceberg?[J].Drug Metab Rev, 2010, 42 (1) :168-181.

[8]SUN L, LI M, ZHANG L, et al.Differences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome typeⅡ[J].Medicine (Baltimore) , 2017, 96 (45) :e8620.

[9]MARUO Y, NAKAHARA S, YANAGI T, et al.Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome typeⅡand Gilbert syndrome[J].J Gastroenterol Hepatol, 2016, 31 (2) :403-408.

[10]BOSMA PJ.Inherited disorders of bilirubin metabolism[J].JHepatol, 2003, 38 (1) :107-117.

[11]THOGULUVA CHANDRASEKAR V, JOHN S.Gilbert syndrome[DB/OL].StatPearls, Treasure Island (FL) , StatPearls Publishing, 2019.

[12]VUKOVIC M, RADLOVIC N, LEKOVIC Z, et al.UGT1A1 (TA) n promoter genotype:Diagnostic and population pharmacogenetic marker in serbia[J].Balkan J Med Genet, 2018, 21 (1) :59-68.

[13]TAKANO M, SUGIYAMA T.UGT1A1 polymorphisms in cancer:Impact on irinotecan treatment[J].Pharmgenomics Pers Med, 2017, 10:61-68.

[14]BURCHELL B, HUME R.Molecular genetic basis of Gilbert's syndrome[J].J Gastroenterol Hepatol, 1999, 14 (10) :960-966.

[15]SUGATANI J, KOJIMA H, UEDA A, et al.The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR[J].Hepatology, 2001, 33 (5) :1232-1238.

[16]SAMPIETRO M, IOLASCON A.Molecular pathology of CriglerNajjar type I and II and Gilbert's syndromes[J].Haematologica, 1999, 84 (2) :150-157.

[17]NAKAGAWA T, MURE T, YUSOFF S, et al.A homozygous mutation in UGT1A1 exon 5 may be responsible for persistent hyperbilirubinemia in a Japanese girl with Gilbert's syndrome[J].Kobe J Med Sci, 2011, 57 (1) :e26-e31.

[18]CHIDDARWAR AS, D'SILVA SZ, COLAH RB, et al.Genetic variations in bilirubin metabolism genes and their association with unconjugated hyperbilirubinemia in adults[J].Ann Hum Genet, 2017, 81 (1) :11-19.

[19]SALOMONE F, LI VOLTI G, ROSSO C, et al.Unconjugated bilirubin, a potent endogenous antioxidant, is decreased in patients with non-alcoholic steatohepatitis and advanced fibrosis[J].J Gastroenterol Hepatol, 2013, 28 (7) :1202-1208.

[20]TIAN J, ZHONG R, LIU C, et al.Association between bilirubin and risk of non-alcoholic fatty liver disease based on a prospective cohort study[J].Sci Rep, 2016, 6:31006.

[21]HJELKREM M, MORALES A, WILLIAMS CD, et al.Unconjugated hyperbilirubinemia is inversely associated with non-alcoholic steatohepatitis (NASH) [J].Aliment Pharmacol Ther, 2012, 35 (12) :1416-1423.

[22]CHANG Y, JUNG HS, YUN KE, et al.Metabolically healthy obesity is associated with an increased risk of diabetes independently of nonalcoholic fatty liver disease[J].Obesity (Silver Spring) , 2016, 24 (9) :1996-2003.

[23]JANG BK.Elevated serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease[J].Clin Mol Hepatol, 2012, 18 (4) :357-359.

[24]YESILOVA Z, SERDAR M, ERCIN CN, et al.Decreased oxidation susceptibility of plasma low density lipoproteins in patients with Gilbert's syndrome[J].J Gastroenterol Hepatol, 2008, 23 (10) :1556-1560.

[25]YANG H, WANG Q, ZHENG L, et al.Clinical significance of UGT1A1 genetic analysis in Chinese neonates with severe hyperbilirubinemia[J].Pediatr Neonatol, 2016, 57 (4) :310-317.

[26]LONGHI MS, VUERICH M, KALBASI A, et al.Bilirubin suppresses Th17 immunity in colitis by upregulating CD39[J].JCI Insight, 2017, 2 (9) :e92791.

[27]ZHU L, WANG L, CAO F, et al.Modulation of transport and metabolism of bile acids and bilirubin by chlorogenic acid against hepatotoxicity and cholestasis in bile duct ligation rats:Involvement of SIRT1-mediated deacetylation of FXR and PGC-1alpha[J].J Hepatobiliary Pancreat Sci, 2018, 25 (3) :195-205.

[28]KAWAMOTO R, NINOMIYA D, SENZAKI K, et al.Mildly elevated serum total bilirubin is negatively associated with hemoglobin A1c independently of confounding factors among community-dwelling middle-aged and elderly persons[J].JCirc Biomark, 2017, 6:1849454417726609.

[29]LIU J, DONG H, ZHANG Y, et al.Corrigendum:Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPARgamma levels[J].Sci Rep, 2016, 6:19170.

[30]HAMOUD AR, WEAVER L, STEC DE, et al.Bilirubin in the liver-gut signaling axis[J].Trends Endocrinol Metab, 2018, 29 (3) :140-150.

[31]FUJIWARA R, HAAG M, SCHAEFFELER E, et al.Systemic regulation of bilirubin homeostasis:Potential benefits of hyperbilirubinemia[J].Hepatology, 2018, 67 (4) :1609-1619.

[32]IDELMAN G, SMITH DL, ZUCKER SD.Bilirubin inhibits the upregulation of inducible nitric oxide synthase by scavenging reactive oxygen species generated by the tol-like receptor 4-dependent activation of NADPH oxidase[J].Redox Biol, 2015, 5:398-408.

[33]LI J, QI LL, WU J.Research advances in the diagnosis of nonalcoholic fatty liver disease in children[J].J Clin Hepatol, 2017, 33 (10) :2025-2029. (in Chinese) 李靖, 戚伶俐, 吴捷.儿童非酒精性脂肪性肝病的诊断进展[J].临床肝胆病杂志, 2017, 33 (10) :2025-2029.

[34]LUO L, AN P, JIA X, et al.Genetically regulated bilirubin and risk of non-alcoholic fatty liver disease:A mendelian randomization study[J].Front Genet, 2018, 9:662.

[35]HAHN RZ, ANTUNES MV, VERZA SG, et al.Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity[J].Curr Med Chem, 2018.[Epub ahead of print]

[36]EHMER U, KALTHOFF S, FAKUNDINY B, et al.Gilbert syndrome redefined:A complex genetic haplotype influences the regulation of glucuronidation[J].Hepatology, 2012, 55 (6) :1912-1921.

[37]STRASSBURG CP.Hyperbilirubinemia syndromes (GilbertMeulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome) [J].Best Pract Res Clin Gastroenterol, 2010, 24 (5) :555-571.

[38]BOON AC, HAWKINS CL, COOMBES JS, et al.Bilirubin scavenges chloramines and inhibits myeloperoxidase-induced protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum[J].Free Radic Biol Med, 2015, 86:259-268.

[39]BULMER AC, BLANCHFIELD JT, TOTH I, et al.Improved resistance to serum oxidation in Gilbert's syndrome:A mechanism for cardiovascular protection[J].Atherosclerosis, 2008, 199 (2) :390-396.

[40]STEC DE, JOHN K, TRABBIC CJ, et al.Bilirubin binding to PPARalpha inhibits lipid accumulation[J].PLo S One, 2016, 11 (4) :e0153427.

[41]GUPTA N, SINGH T, CHAUDHARY R, et al.Bilirubin in coronary artery disease:Cytotoxic or protective?[J].World JGastrointest Pharmacol Ther, 2016, 7 (4) :469-476.

[42]MCGRATH M, LEPINE J, LEE IM, et al.Genetic variations in UGT1A1 and UGT2B7 and endometrial cancer risk[J].Pharmacogenet Genomics, 2009, 19 (3) :239-243.

[43]GIL J, SASIADEK MM.Gilbert syndrome:The UGT1A1*28promoter polymorphism as a biomarker of multifactorial diseases and drug metabolism[J].Biomark Med, 2012, 6 (2) :223-230.

[44]TSEZOU A, TZETIS M, GIANNATOU E, et al.Genetic polymorphisms in the UGT1A1 gene and breast cancer risk in Greek women[J].Genet Test, 2007, 11 (3) :303-306.

[45]GIRARD H, THIBAUDEAU J, COURT MH, et al.UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver[J].Hepatology, 2005, 42 (2) :448-457.

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