Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction
- Jayanta Roy-Chowdhury, MD, MRCP
Jayanta Roy-Chowdhury, MD, MRCP
- Professor of Medicine and Genetics
- Albert Einstein College of Medicine
- Namita Roy-Chowdhury, PhD
Namita Roy-Chowdhury, PhD
- Professor of Medicine and Genetics
- Albert Einstein College of Medicine
- Xia Wang, MD, PhD
Xia Wang, MD, PhD
- Research Associate
- Albert Einstein College of Medicine
The metabolism of bilirubin by the liver is comprised of four distinct but interrelated stages (see "Bilirubin metabolism"):
●Uptake from the circulation
●Conjugation with glucuronic acid
- http://mghlabtest.partners.org/MGH_Reference_Intervals_August_2011.pdf (Accessed on March 29, 2013).
- Berk PD, Jones EA, Howe RB, et al. Disorders of bilirubin metabolism. In: Metabolic Control and Disease, 8th ed, Bondy PK, Rosenberg LE (Eds), Saunders, Philadelphia 1980. p.1009.
- Muraca M, Fevery J, Blanckaert N. Relationships between serum bilirubins and production and conjugation of bilirubin. Studies in Gilbert's syndrome, Crigler-Najjar disease, hemolytic disorders, and rat models. Gastroenterology 1987; 92:309.
- Muraca M, Blanckaert N. Liquid-chromatographic assay and identification of mono- and diester conjugates of bilirubin in normal serum. Clin Chem 1983; 29:1767.
- Gilbert A, Lereboullet P. La cholamae simple familiale. Sem Med 1901; 21:241.
- Thompson RP. Genetic transmission of Gilbert's syndrome. In: Familial Hyperbilirubinemia, Okolicsanyi L (Ed), Wiley, New York 1981. p.91.
- Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr 2012; 171:11.
- Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333:1171.
- Borlak J, Thum T, Landt O, et al. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 2000; 32:792.
- Sieg A, Arab L, Schlierf G, et al. [Prevalence of Gilbert's syndrome in Germany]. Dtsch Med Wochenschr 1987; 112:1206.
- Monaghan G, Ryan M, Seddon R, et al. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996; 347:578.
- Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998; 95:8170.
- Biondi ML, Turri O, Dilillo D, et al. Contribution of the TATA-box genotype (Gilbert syndrome) to serum bilirubin concentrations in the Italian population. Clin Chem 1999; 45:897.
- Lampe JW, Bigler J, Horner NK, Potter JD. UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics 1999; 9:341.
- Raijmakers MT, Jansen PL, Steegers EA, Peters WH. Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J Hepatol 2000; 33:348.
- Roy-Chowdhury N, Deocharan B, Bejjanki HR, et al. Presence of the genetic marker for Gilbert syndrome is associated with increased level and duration of neonatal jaundice. Acta Paediatr 2002; 91:100.
- Muraca M, Fevery J. Influence of sex and sex steroids on bilirubin uridine diphosphate-glucuronosyltransferase activity of rat liver. Gastroenterology 1984; 87:308.
- Black M, Billing BH. Hepatic bilirubin udp-glucuronyl transferase activity in liver disease and gilbert's syndrome. N Engl J Med 1969; 280:1266.
- Auclair C, Hakim J, Boivin P, et al. Bilirubin and paranitrophenol glucuronyl transferase activities of the liver in patients with Gilbert's syndrome An attempt at a biochemical breakdown of the Gilbert's syndrome. Enzyme 1976; 21:97.
- Fevery J, Blanckaert N, Heirwegh KP, et al. Unconjugated bilirubin and an increased proportion of bilirubin monoconjugates in the bile of patients with Gilbert's syndrome and Crigler-Najjar disease. J Clin Invest 1977; 60:970.
- Cobelli C, Ruggeri A, Toffolo G. BSP vs bilirubin kinetics in Gilbert's syndrome. In: Familial Hyperbilirubinemia, Okolicsanyi L (Ed), Wiley, New York 1981. p.121.
- Felsher BF, Rickard D, Redeker AG. The reciprocal relation between caloric intake and the degree of hyperbilirubinemia in Gilbert's syndrome. N Engl J Med 1970; 283:170.
- Barrett PV. Hyperbilirubinemia of fasting. JAMA 1971; 217:1349.
- Gollan JL, Bateman C, Billing BH. Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome. Gut 1976; 17:335.
- Cowan RE, Thompson RP, Kaye JP, Clark GM. The association between fasting hyperbilirubinaemia and serum non-esterified fatty acids in man. Clin Sci Mol Med 1977; 53:155.
- Felsher BF, Carpio NM, VanCouvering K. Effect of fasting and phenobarbital on hepatic UDP-glucuronic acid formation in the rat. J Lab Clin Med 1979; 93:414.
- Kotal P, Vítek L, Fevery J. Fasting-related hyperbilirubinemia in rats: the effect of decreased intestinal motility. Gastroenterology 1996; 111:217.
- Brink MA, Méndez-Sánchez N, Carey MC. Bilirubin cycles enterohepatically after ileal resection in the rat. Gastroenterology 1996; 110:1945.
- Aono S, Adachi Y, Uyama E, et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Lancet 1995; 345:958.
- Koiwai O, Nishizawa M, Hasada K, et al. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol Genet 1995; 4:1183.
- Chalasani N, Chowdhury NR, Chowdhury JR, Boyer TD. Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect. Gastroenterology 1997; 112:2099.
- Kadakol A, Sappal BS, Ghosh SS, et al. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet 2001; 38:244.
- SAGILD U, DALGAARD OZ, TYGSTRUP N. Constitutional hyperbilirubinemia with unconjugated bilirubin in the serum and lipochrome-like pigment granules in the liver. Ann Intern Med 1962; 56:308.
- Powell LW, Hemingway E, Billing BH, Sherlock S. Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). A study of 42 families. N Engl J Med 1967; 277:1108.
- Ellis E, Wagner M, Lammert F, et al. Successful treatment of severe unconjugated hyperbilirubinemia via induction of UGT1A1 by rifampicin. J Hepatol 2006; 44:243.
- Ohkubo H, Okuda K, Iida S. Effects of corticosteroids on bilirubin metabolism in patients with Gilbert's syndrome. Hepatology 1981; 1:168.
- Black M, Sherlock S. Treatment of Gilbert's syndrome with phenobarbitone. Lancet 1970; 1:1359.
- Kutz K, Kandler H, Gugler R, Fevery J. Effect of clofibrate on the metabolism of bilirubin, bromosulphophthalein and indocyanine green and on the biliary lipid composition in Gilbert's syndrome. Clin Sci (Lond) 1984; 66:389.
- Powell LW, Billing BH, Williams HS. An assessment of red cell survival in idiopathic unconjugated hyperbilirubinaemia (Gilbert's syndrome) by the use of radioactive diisopropylfluorophosphate and chromium. Australas Ann Med 1967; 16:221.
- Blueger AF, Krupnikova EZ, Sondore VY, Semushina EP. Study of the etiology and pathogenesis of low grade nonhemolytic unconjugated hyperbilirubinemia (Gilbert's disease). Acta Hepatogastroenterol (Stuttg) 1977; 24:140.
- Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101:847.
- Burchell B, Soars M, Monaghan G, et al. Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol Lett 2000; 112-113:333.
- de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology 1992; 102:577.
- Carulli N, Ponz de Leon M, Mauro E, et al. Alteration of drug metabolism in Gilbert's syndrome. Gut 1976; 17:581.
- Ullrich D, Sieg A, Blume R, et al. Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert's syndrome. Eur J Clin Invest 1987; 17:237.
- Rauchschwalbe SK, Zühlsdorf MT, Wensing G, Kuhlmann J. Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype. Int J Clin Pharmacol Ther 2004; 42:73.
- Lankisch TO, Moebius U, Wehmeier M, et al. Gilbert's disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology 2006; 44:1324.
- Deterding K, Grüngreiff K, Lankisch TO, et al. Gilbert's syndrome and antiviral therapy of hepatitis C. Ann Hepatol 2009; 8:246.
- Xu CF, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer 2010; 102:1371.
- del Giudice EM, Perrotta S, Nobili B, et al. Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis. Blood 1999; 94:2259.
- Origa R, Galanello R, Perseu L, et al. Cholelithiasis in thalassemia major. Eur J Haematol 2009; 82:22.
- Haverfield EV, McKenzie CA, Forrester T, et al. UGT1A1 variation and gallstone formation in sickle cell disease. Blood 2005; 105:968.
- Roda A, Roda E, Sama C, et al. Serum primary bile acids in Gilbert's syndrome. Gastroenterology 1982; 82:77.
- Vierling JM, Berk PD, Hofmann AF, et al. Normal fasting-state levels of serum cholyl-conjugated bile acids in Gilbert's syndrome: an aid to the diagnosis. Hepatology 1982; 2:340.
- Douglas JG, Beckett GJ, Nimmo IA, et al. Bile salt measurements in Gilbert's syndrome. Eur J Clin Invest 1981; 11:421.
- Okolicsanyi L, Fevery J, Billing B, et al. How should mild, isolated unconjugated hyperbilirubinemia be investigated? Semin Liver Dis 1983; 3:36.
- Fromke VL, Miller D. Constitutional hepatic dysfunction (CHD; Gilbert's disease); a review with special reference to a characteristic increase and prolongation of the hyperbilirubinemic response to nicotinic acid. Medicine (Baltimore) 1972; 51:451.
- GYDELL K. Nicotinic acid induced hyperbilirubinemia and hypersideremia. I. Observations in hemolytic disease and allied conditions. Acta Med Scand 1959; 164:305.
- Gentile S, Tiribelli C, Persico M, et al. Dose dependence of nicotinic acid-induced hyperbilirubinemia and its dissociation from hemolysis in Gilbert's syndrome. J Lab Clin Med 1986; 107:166.
- Monaghan G, McLellan A, McGeehan A, et al. Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr 1999; 134:441.
- Lin YC, Chang PF, Hu FC, et al. Variants in the UGT1A1 gene and the risk of pediatric nonalcoholic fatty liver disease. Pediatrics 2009; 124:e1221.
- Guillemette C, Millikan RC, Newman B, Housman DE. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans. Cancer Res 2000; 60:950.
- Guillemette C, De Vivo I, Hankinson SE, et al. Association of genetic polymorphisms in UGT1A1 with breast cancer and plasma hormone levels. Cancer Epidemiol Biomarkers Prev 2001; 10:711.
- Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert's syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol 2013; 28:1643.
- REFERENCE RANGES
- BILIRUBIN OVERPRODUCTION
- GILBERT SYNDROME
- - Impaired bilirubin glucuronidation
- - Increased bilirubin production
- - Genetic defect
- - Histology
- Clinical manifestations
- - Symptoms
- - Physical examination findings
- - Laboratory tests
- - Drug interactions
- - Cholelithiasis
- - Neonatal jaundice
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS