HEREDITARY UNCONJUGATED HYPERBILIRUBINEMIA
Abstract
Congenital hereditary non-conjugate hyperbilirubinemias include Gilbert’s syndrome, Crigler-Najjar type 1 and Crigler-Najjar type 2 syndromes (or Arias’ disease). They are caused by a hereditary deficiency of the enzyme - bilirubinuridine-5’-diphosphate glucuronosyltransferase (UGT1A1), involved in the glucuronization of bilirubin. The enzyme deficiency is due to mutations in the UGT1A1 gene, which provides UGT1A1 activity. Complete or almost complete loss of (Crigler-Najjar syndrome type 1) or decreased UGT1A1 activity (Gilbert’s syndrome and Crigler-Najjar syndrome type 2) lead to impaired conversion of bilirubin in the liver with the accumulation of unconjugated bilirubin in the blood. Syndromes are distinguished by the level of bilirubin in blood plasma, the reaction to the introduction of phenobarbital, the presence or absence of bilirubin glucuronides in bile.
References
Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146(7):1625-1638. https://doi.org/10.1053/j.gastro.2014.03.047.
Strassburg CP. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics. 2008;9(6):703-715. https://doi.org/10.2217/14622416.9.6.703.
Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury NR. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N. Engl. J. Med. 1995;333(18):1171-1175. https://doi.org/10.1056/NEJM199511023331802.
Burchell B, Hume R. Molecular genetic basis of Gilbert’s syndrome. J. Gastroenterol. Hepatol. 1999;14(10):960-966. https://doi.org/10.1046/j.1440-1746.1999.01984.x.
Strassburg CP. Hyperbilirubinemia syndromes (GilbertMeulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract. Res. Clin Gastroenterol. 2010;24(5):555-571. https://doi.org/10.1016/j.bpg.2010.07.007.
Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum. Mutat. 2000;16(4):297-306. https://doi.org/10.1002/1098-1004(200010)16:4(297::AIDHUMU2)3.0.CO;2-Z.
Crigler JFJr, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics. 1952;10(2):169-180.
Arias IM, Gartner LM, Cohen M, Ezzer JB, Levi AJ. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency. Clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am. J. Med. 1969;47(3):395-409. https://doi.org/10.1016/0002-9343(69)90224-1.
Kumar P, Sasmal G, Gupta S, Saxena R, Kohli S. Crigler Najjar syndrome type 2 (CNS type 2): An unwonted cause of jaundice in adults. J. Clin. Diagn. Res. 2017;11(7):OD05-OD06. https://doi.org/10.7860/JCDR/2017/28195.10221.
Nair KM, Lohse P, Nampoothiri S. Crigler-Najjar syndrome type 2: Novel UGT1A1 mutation. Indian J. Hum. Gen. 2012;18(2):233-234. https://doi.org/10.4103/0971-6866.100776.
Nilyanimit P, Krasaelap A, Foonoi M, Chongsrisawat V, Poovorawan Y. Role of a homozygous A(TA) 7TAA promoter polymorphism and an exon 1 heterozygous frameshift mutation UGT1A1 in Crigler-Najjar syndrome type II in a Thai neonate. Genet. Mol. Res. 2013;12(3):3391-3397. https://doi.org/10.4238/2013.September.4.5.
Nakagawa T, Mure T, Yusoff S, Ono E, Harahap ISK, Morikawa S, Morioka I, Takeshima Y, Nishio Н, Matsuo M. A homozygous mutation in UGT1A1 exon 5 may be responsible for persistent hyperbilirubinemia in a Japanese girl with Gilbert’s syndrome. Kobe J. Med. Sci. 2011;57(1):E26-31.
Strassburg CP. Gilbert-Meulengracht’s syndrome and pharmacogenetics: is jaundice just the tip of the iceberg? Drug Metab. Rev. 2010;42(1):168-181. https://doi.org/10.3109/03602530903209429.
King D, Armstrong MJ. Overview of Gilbert’s syndrome. Drug Ther. Bull. 2019;57(2):27-31. https://doi.org/10.1136/dtb.2018.000028.
Marques SC, Ikediobi ON. The clinical application of UGT1A1 pharmacogenetic testing: gene-environment interactions. Hum. Genomics. 2010;4(4):238-249. https://doi.org/10.1186/1479-7364-4-4-238.
Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur. J. Pediatr. 2012;171(1):11-15. https://doi.org/10.1007/s00431-011-1641-0.
Haque MA, Sharmin LS, Harun or Rashid M, Alim MA, Ekram ARMS, Chulam S. Mowla SGM. Crigler-Najjar syndrome type 2 in a young adult. J. Med. 2011;12(1):86-88. https://doi.org/10.3329/jom.v12i1.6359.
Rossi F, Francese M, Iodice RM, Falcone E, Vetrella S, Punzo F, De Vita S, Perrottaet S. Inherited disorders of bilirubin metabolism. Minerva Pediatr. 2005;57(2):53-63.
Tcaciuc E, Podurean M, Tcaciuc A. Management of Crigler-Najjar syndrome. Med. Pharm Rep. 2021;94(Suppl 1):S64-S67. https://doi.org/10.15386/mpr-2234.
Sun L, Li M, Zhang L, Teng X, Chen X, Zhou X, Ma Z, Qi L, Wang P. Differences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome type II. Medicine. 2017;96(45):e8620. https://doi.org/10.1097/MD.0000000000008620.
D’Angelo R, Rinaldi C, Donato L, Nicocia G, Sidoti A. The combination of new missense mutation with [A(TA)7TAA] dinucleotide repeat in UGT1A1 gene promoter causes Gilbert’s syndrome. Ann. Clin. Lab. Sci. 2015;45(2):202-205.
Xiang GQ, Sun FR, Wang BY. Gilbert’s syndrome: hyperbilirubinemia enemy or friend. Zhonghua Gan Zang Bing Za Zhi. 2021;29(10):1024-1027. https://doi.org/10.3760/cma.j.cn501113-20200212-00041.
Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr. Res. 2016;79(3):378-386. https://doi.org/10.1038/pr.2015.247.
Nag DS, Sinha N, Samaddar DP, Mahantyet PR. General Anesthesia in a patient with Gilbert’s syndrome. J. Anaesthesiol. Clin. Pharmacol. 2011;27(2):253-255. https://doi.org/10.4103/0970-9185.81836.
Maruo Y, Nakahara S, Yanagi T, Nomura A, Mimura Y, Matsui K, Sato H, Takeuchi Y. Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome. J. Gastroenterol. Hepatol. 2016;31(2):403-408. https://doi.org/10.1111/jgh.13071.
Ilchenko LYu, Fedorov IG, Totolyan GG, Tsvetkova AG, Gavrilenko EG, Mironov KO, Nikitin IG. Nasledstvennaja nekonjugirovannaja giperbilirubinemija (sochetanie sindroma Kriglera-Najjara II tipa i sindroma Zhilbera) [Hereditary unconjugated hyperbilirubinemia (combination of Crigler-Najjar syndrome type II and Gilbert’s syndrome)]. Gepatologija i gastrojenterologija [Hepatology and Gastroenterology]. 2021;5(1):79-84. https://doi.org/10.25298/2616-5546-2021-5-1-79-84. https://elibrary.ru/kjlteu. (Russian).
Canu G, Minucci A, Zuppi C, Capoluongo E. Gilbert and Crigler Najjar syndromes: an update of the UDPglucuronosyltransferase 1A1 (UGT1A1) gene mutation database. Blood Cells Mol. Dis. 2013;50(4):273-280. https://doi.org/10.1016/j.bcmd.2013.01.003.
Gorbunova O, Chernysheva E. A new look at gilbert syndrome (literature review). Georgian Med. News. 2019;296:75-81.
Li L, Deng C, Tang YM, Mao Q. Spectrum of UGT1A1 variations in Chinese patients with Crigler-Najjar syndrome type II. PLOS ONE. 2015;10(5):e0126263. https://doi.org/10.1371/journal.pone.0126263.
Muchová L, Kráslová I, Lenícek M, Vítek L. Gilbert’s syndrome--myths and reality. Cas. Lek. Cesk. 2004;143(6):375-380.
Rawa K, Adamowicz-Salach A, Matysiak M, Trzemecka A, Burzynska B. Coexistence of Gilbert syndrome with hereditary haemolytic anaemias. J. Clin. Pathol. 2012;65(7):663-665. https://doi.org/10.1136/jclinpath-2011-200580.
Saif MW, Smith MH, Maloney A, Diasio RB. Imatinibinduced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor. Ann. Gastroenterol. 2016;29(4):551-556. https://doi.org/10.20524/aog.2016.0053.
Wagner K-H, Shiels RG, Lang CA, Khoei NS, Bulmer AC. Diagnostic criteria and contributors to Gilbert’s syndrome. Crit. Rev. Clin. Lab. Sci. 2018;55(2):129-139. https://doi.org/10.1080/10408363.2018.1428526.
Bulmer AC, Verkade HJ, Wagner K-H. Bilirubin and beyond: a review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog. Lipid Res. 2013;52(2):193-205. https://doi.org/10.1016/j.plipres.2012.11.001.
Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Kihara Y, Chayama K, Noma K, Nakashima A, Tomiyama H, Takase B, Yamashina A, Higashiet Y. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation. 2012;126(5):598-603. https://doi.org/10.1161/CIRCULATIONAHA.112.105775.
Horsfall LJ, Nazareth I, Pereira SP, Petersenet I. Gilbert’s syndrome and the risk of death: a population-based cohort study. J. Gastroenterol. Hepatol. 2013;28(10):1643-1647. https://doi.org/10.1111/jgh.12279.
Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert’s syndrome? Atherosclerosis. 2015;239(1):73-84. https://doi.org/10.1016/j.atherosclerosis.2014.12.042.
