Abstract
Gilbert syndrome is a common autosomal dominant hereditary condition with incomplete penetrance and characterized by intermittent unconjugated hyperbilirubinemia in the absence of hepatocellular disease or hemolysis. In patients with Gilbert syndrome, uridine diphosphate–glucuronyl transferase activity is reduced to 30% of the normal, resulting in indirect hyperbilirubinemia. In its typical form, hyperbilirubinemia is first noticed as intermittent mild jaundice in adolescence. However, Gilbert syndrome in combination with other prevailing conditions such as breast feeding, G-6-PD deficiency, thalassemia, spherocytosis, or cystic fibrosis may potentiate severe hyperbilirubinemia and/or cholelithiasis. It may also reduce plasma oxidation, and it may also affect drug metabolism. Although in general the diagnosis of the syndrome is one of exclusion, molecular genetic tests can now be performed when there is a diagnostic problem. The most common genotype of Gilbert syndrome is the homozygous polymorphism A(TA)7TAA in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), which is a TA insertion into the promoter designated UGT1A1*28. No specific management is necessary as Gilbert syndrome is a benign condition. Conclusion: Gilbert genotype should be kept in the clinician’s mind, at least as a contributor factor, in cases with unexplained indirect hyperbilirubinemia.
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Arnold JC, Otto G, Kraus T, Kommerell B, Theilmann L (1992) Gilbert’s syndrome—a possible cause of hyperbilirubinemia after orthotopic liver transplantation. J Hepatol 14:404
Bancroft JD, Kreamer B, Gourley GR (1998) Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 132:656–660
Billing BH, Black M (1969) Bilirubin metabolism. Gut 10:250–254
Black M, Billing BH (1969) Hepatic bilirubin UDP-glucuronyl transferase activity in liver disease and Gilbert’s syndrome. N Engl J Med 280:1266–1271
Bosma PJ, Roy Chowdhury J, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GNJ, Jansen PLM, Oude Elferink RPJ, Roy Chowdhury N (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:1171–1175
Bulmer AC, Blanchfield JT, Toth I, Fassett RG, Coombes JS (2008) Improved resistance to serum oxidation in Gilbert’s syndrome: a mechanism for cardiovascular protection. Atherosclerosis 199:390–396
Claridge LC, Armstrong MJ, Booth C, Gill PS (2011) Gilbert’s syndrome. BMJ 342:d2293. doi:10.1136/bmj.d2293
Davidson AR, Rojas-Bueno A, Thompson RP, Williams R (1975) Reduced caloric intake and nicotinic acid provocation tests in the diagnosis of Gilbert’s syndrome. Br Med J 2(5969):480
del Giudice EM, Perrotta S, Nobili B, Specchia C, d'Urzo G, Iolascon A (1999) Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis. Blood 94:2259–2262
Dickey W, McAleer JJ, Callender ME (1991) The nicotinic acid provocation test and unconjugated hyperbilirubinaemia. Ulster Med J 60:49–52
Gilbert A, Lereboullet P (1901) La cholemie simple familiale. Semaine Med 21:241
Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK, Kubota S, Carvalho S, Pennington MW, Owens IS, Popescu NC (2001) Thirteen UDP-glucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 11:357–368
Haverfield EV, McKenzie CA, Forrester T, Bouzekri N, Harding R, Serjeant G, Walker T, Peto TE, Ward R, Weatherall DJ (2005) UGT1A1 variation and gallstone formation in sickle cell disease. Blood 105:968–972
Hirschfield GM, Alexander JG (2006) Gilbert’s syndrome: an overview for clinical biochemists. Ann Clin Biochem 43:340–343
Iolascon A, Faienza MF, Giordani L, Perrotta S, Ruggiu G, Meloni GF, del Giudice EM (1999) Bilirubin levels in the acute hemolytic crisis of G6PD deficiency are related to Gilbert’s syndrome. Eur J Haematol 62:307–310
Iolascon A, Faienza MF, Moretti A, Perrotta S, Miraglia del Giudice E (1998) UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis. Blood 91:1093
Kaplan M, Hammerman C, Renbaum P, Klein G, Levy-Lahad E (2000) Gilbert’s syndrome and hyperbilirubinaemia in ABO-incompatible neonates. Lancet 356(9230):652–653
Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E (1997) Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A 94:12128–12132
Kitsiou-Tzeli S, Kanavakis E, Tzetis M, Kavazarakis E, Galla A, Tsezou A (2003) Gilbert’s syndrome as a predisposing factor for idiopathic cholelithiasis in children. Haematologica 88:1193–1194
Koiso H, Kin Y, Narahara N, Tamura J, Naruse T, Karasawa M, Murakami H, Hattori Y, Oba Y, Sato H (1998) Alpha-thalassemia accompanied with Gilbert’s syndrome. Rinsho Ketsueki 39:703–708
Laforgia N, Faienza MF, Rinaldi A, D'Amato G, Rinaldi G, Iolascon A (2002) Neonatal hyperbilirubinemia and Gilbert’s syndrome. J Perinat Med 30:166–169
Lankisch TO, Moebius U, Wehmeier M, Behrens G, Manns MP, Schmidt RE, Strassburg CP (2006) Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology 44:1324–1332
Lankisch TO, Schulz C, Zwingers T, Erichsen TJ, Manns MP, Heinemann V, Strassburg CP (2008) Gilbert’s syndrome and irinotecan toxicity: combination with UDP-glucuronosyltransferase 1A7 variants increases risk. Cancer Epidemiol Biomark Prev 17:695–701
Lin J-P, Cupples LA, Wilson PWF, Heard-Costa N, O’Donnell CJ (2003) Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham Study. Am J Hum Genet 72:1029–1034
Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Belanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magalou J, Roy Chowdhury J, Ritter JK, Schachter H, Tephly TR, Tipton KE, Nebert DW (1997) The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7:255–269
Meulengracht E (1939) Icterus interminus juvenilis. Klin Wchnschr 818:118
Miyake H, Tashiro S, Yogita S, Ishikawa M, Fukuda Y, Harada M, Wada D, Ito S, Yasuda M (1998) Can the liver with Gilbert’s syndrome be used as graft of living-related liver transplantation? J Med Invest 44:219–221
Monaghan G, McLellan A, McGeehan A, Li Volti S, Mollica F, Salemi I, Din Z, Cassidy A, Hume R, Burchell B (1999) Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr 134:441–446
Murthy GD, Byron D, Shoemaker D, Visweswaraiah H, Pasquale D (2001) The utility of rifampin in diagnosing Gilbert’s syndrome. Am J Gastroenterol 96:1150–1154
Origa R, Galanello R, Perseu L, Tavazzi D, Domenica Cappellini M, Terenzani L, Forni GL, Quarta G, Boetti T, Piga A (2009) Cholelithiasis in thalassemia major. Eur J Haematol 82(1):22–25
Preisig D, Bircher J, Preisig R (1982) Positive diagnosis of Gilbert syndrome. Retrospective analysis of 59 cases with special reference to the nicotinic acid test. Schweiz Med Wochenschr 112:1122–1129, Article in German
Ritter JK, Crawford JM, Owens IS (1991) Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells. J Biol Chem 266:1043–1047
Sampietro M, Lupica L, Perrero L, Comino A, Martinez di Montemuros F, Cappellini MD, Fiorelli G (1997) The expression of uridine diphosphate glucuronosyltransferase gene is a major determinant of bilirubin level in heterozygous beta-thalassaemia and in glucose-6-phosphate dehydrogenase deficiency. Br J Haematol 99:437–439
Schmid R (1995) Gilbert’s syndrome—a legitimate genetic anomaly? N Engl J Med 333:1217–1218
Sleisenger MH (1967) Nonhemolytic unconjugated hyperbilirubinemia with hepatic glucuronyl transferase deficiency: a genetic study in four generations. Trans Assoc Am Physicians 80:259–266
Strassburg CP (2010) Hyperbilirunemia syndromes (Gilbert-Meulengracht, Grigler-Najjar, Dubin-Johnson and Rotor syndrome). Best Pract Res Clin Gastroenterol 24:555–571
Tan TC (1967) Gilbert’s disease. Sing Med J 8:123–125
Te HS, Schiano TD, Das S, Kuan SF, DasGupta K, Conjeevaram HS, Baker AL (2000) Donor liver uridine diphosphate (UDP)-glucuronosyltransferase-1A1 deficiency causing Gilbert’s syndrome in liver transplant recipients. Transplantation 69:1882–1886
Thomsen HF, Hardt F, Juhl E (1981) Diagnosis of Gilbert’s syndrome. Reliability of the caloric restriction and phenobarbital stimulation tests. Scand J Gastroenterol 16:699–703
Tsezou A, Tzetis M, Giannatou E, Spanos I, Roma E, Fretzayas A, Kanavakis E, Kitsiou-Tzeli S (2009) Gilbert syndrome as a predisposing factor for cholelithiasis risk in the Greek adult population. Genet Test Mol Biomark 13:143–146
Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P (2002) Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 160:449–456
Wasmuth HE, Keppeler H, Herrmann U, Schirin-Sokhan R, Barker M, Lammert F (2006) Coinheritance of Gilbert syndrome-associated UGT1A1 mutation increases gallstone risk in cystic fibrosis. Hepatology 43:738–741
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Fretzayas, A., Moustaki, M., Liapi, O. et al. Eponym. Eur J Pediatr 171, 11–15 (2012). https://doi.org/10.1007/s00431-011-1641-0
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DOI: https://doi.org/10.1007/s00431-011-1641-0