JILBER’S SYNDROME: CLINICAL AND PHARMACOLOGICAL ASPECTS. Review
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Keywords

Gilbert’s syndrome, drugs, metabolism, pharmacogenetics

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Khaitovych , M., & Turchak , D. (2020). JILBER’S SYNDROME: CLINICAL AND PHARMACOLOGICAL ASPECTS. Review. Medical Science of Ukraine (MSU), 16(4), 58-64. https://doi.org/10.32345/2664-4738.4.2020.9

Abstract

Relevance. At present, the metabolism of drugs in patients with Gilbert's syndrome will be actively studied, as it may be associated with both the risk of dose-dependent adverse reactions and treatment ineffectiveness.

Objective: to summarize the information of various authors on the peculiarities of the use of drugs in patients with Gilbert's syndrome.

Methods. Analysis of scientific publications in the international electronic scientometric database PubMed by keywords. Search depth - 10 years (2010-2019).

Results. Gilbert’s syndrome is observed in 3-10% of the population and is characterized by an isolated increase of bilirubin in the blood to moderate values without changes in other biochemical parameters of liver function and without damage to its structure. Gilbert's syndrome is inherited autosomal recessively and is mainly due to the presence of an additional dinucleotide thymine-adenine (TA) in the promoter region A(TA)6TAA gene encoding the enzyme UGT1A1. Elongation of the promoter sequence reduces the formation of UGT1A1. Invariant A(TA)7TAA, the level of enzyme production can be reduced to 80% of the norm in hetero- and up to 20% in homozygotes, respectively. Gilbert’s syndrome is manifested by increased levels of indirect bilirubin in the blood, jaundice of the skin and mucous, abdominal pain, as well as dyspepsia, and asthenovegetative syndrome. Intermittent icteric sclera and skin occur against the background of exogenous and endogenous factors such as starvation, dehydration, infectious diseases, emotional and physical stress, hemolysis, menstruation, alcohol consumption, hormonal contraception, etc., usually at a bilirubin concentration exceeding 40-45 μmol/l. Complications of hyperbilirubinemia with Gilbert’s syndrome include the development of gallstone disease, including in children and adolescents. Gilbert’s syndrome is associated with impaired metabolism of some drugs – aglucones. These include anabolic steroids, glucocorticoids, androgens, rifampicin, cimetidine, chloramphenicol, streptomycin, sodium salicylate, ampicillin, caffeine, Ethinyl estradiol, paracetamol, ibuprofen, The clinical feature of Gilbert’s syndrome is the appearance or aggravation of jaundice associated with the use of such drugs. In conditions of UGT1 deficiency, drugs compete with bilirubin for the enzyme, which leads to an increase of indirect bilirubin in the serum. Therefore, to prevent liver damage, it is necessary to assess the risk and benefit of drug treatment of patients with Gilbert’s syndrome in each case.

Conclusions. Gilbert’s syndrome is a common pathological condition and therefore it is important to diagnose it as early as possible. Given that the use of aglucones in patients with Gilbert's syndrome may cause the development of drug-induced liver damage, it is necessary to assess the risk and benefit of drug treatment of patients with Gilbert’s syndrome in each case.

https://doi.org/10.32345/2664-4738.4.2020.9
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References

Ipatova M.G., Shumilov P.V., Shagalova D.L., Nesterova T.A., Ivanova A.S. [Features of pharmacotherapy in patients with Gilbert’s syndrome]. Pediatrics. 2015; 94(6): 92-6. [in Russian] URL: https://pediatriajournal.ru/files/upload/mags/349/2015_6_4484.pdf

Rejzis, A.R., Hohlova, O.N., Nikitina, T.S. [Gilbert's syndrome. Contemporary views, outcomes and therapy]. Internet Doktor.ru. 2012; 3 (71): 42-5. URL: https://internist.ru/publications/detail/sindrom-zhilbera.-sovremennye-vozzreniya,-ishody-i-terapiya/

Berrueco R., Alonso-Saladrigues A., Martorell-Sampol L., Català-Temprano A., Ruiz-Llobet A., Toll T., Torrebadell M., Naudó M., Camós M., Rives S. Outcome and toxicities associated to chemotherapy in children with acute lymphoblastic leukemia and Gilbert syndrome. Usefulness of UGT1A1 mutational screening. Pediatr Blood Cancer. 2015 Apr; 62(7): 1195-201. DOI: https://doi.org/10.1002/pbc.25457

Botvin’ev K., Kolotilina A.I., Turina, I.E., Dubrovina G.M. [Effect of anti-helicobacter therapy on the hepatic glucuronyl transferase system of adolescents with Gilbert’s syndrome]. Klin Med (Mosk). 2014; 92(12), 55-8. [in Russian] https://pubmed.ncbi.nlm.nih.gov/25980300/

Buch S., Schafmayer C., Volzke H. et al. Loci from a genome-wide analyses of bilirubin levels are associated with gallstone risk and composition. Gastroenterology. 2010; 139(6): 1942-51. DOI: https://doi.org/10.1053/j.gastro.2010.09.003.

Burchell B., Soars M., Monaghan G., Cassidy A., Smith D., Ethell B. Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol Lett. 2000; 112-113: 333-340. DOI: https://doi.org/10.1016/S0378-4274(99)00209-X

Dekker D., Dorresteijn M.J., Pijnenburg M., Heemskerk S., Rasing-Hoogveld A., Burger D.M., Wagener F., Smits P. The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2011 Feb; 31(2): 458-63. DOI: https://doi.org/10.1161/atvbaha.110.211789

Erlinger S., Ariasm I.M., Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014 Jun; 146(7): 1625-38. DOI: https://doi.org/10.1053/j.gastro.2014.03.047

Esteban A., Pérez-Mateo M. Heterogeneity of paracetamol metabolism in Gilbert's syndrome. Eur J Drug Metab Pharmacokinet. 1999; 24(1): 9-13. DOI: 10.1007/BF03190005

Farrar J.S., Palais R.A., Wittwer C.T. Snapback primer genotyping of the Gilbert syndrome UGT1A1 (TA)(n) promoter polymorphism by high-resolution melting. Clin Chem. 2011; 57(9): 1303-10. DOI: https://doi.org/10.1373/clinchem.2011.166306

Feinberg S. Correction of venlafaxine- and duloxetine-induced transaminase elevations with desvenlafaxine in a patient with Gilbert’s syndrome. CNS Spectr. 2010; 15(1): 53-5. DOI: https://doi.org/10.1017/s1092852900000304

Fernández-Crehuet P., Fernández-Crehuet J.F., Allam M.F., Navajas R.F-C. Hepatotoxicity of isotretinoin in patients with acne and Gilbert’s syndrome: a comparative study. BMJ Open. 2014; 4(3): e004441. DOI: http://dx.doi.org/10.1136/bmjopen-2013-004441

Fretzayas A., Moustaki M., Liapi O., Karpathios T. Gilbert syndrome. Eur J Pediatr. 2012 Jan; 171(1): 11-5. DOI: https://doi.org/10.1007/s00431-011-1641-0

Horsfall L.J., Nazareth I., Pereira S.P., Petersen I. Gilbert's syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol. 2013; 28(10): 1643-7. DOI: https://doi.org/10.1111/jgh.12279

Huang M-J., Chen Y-C., Huang Y-Y., Yang S-S., Chen P-L., Huang C-S. Effect of UDP-glucuronosyltransferase 1A1 activity on risk for developing Gilbert's syndrome. Kaohsiung J Med Sci. 2019; 35(7): 432-9. DOI: https://doi.org/10.1002/kjm2.12077

Jiang J., Wang H.G., Wu W.L., Peng X.X. Mixed Dubin-Gilbert Syndrome: A Compound Heterozygous Phenotype of Two Novel Variants in ABCC2 Gene. Chin Med J (Engl). 2017 Apr; 130(8): 1003-5. DOI: https://doi.org/10.4103/0366-6999.204108

Kabícek P., Barnincová L. Juvenile hyperbilirubinaemia and its early manifestation in adolescence. Cas Lek Cesk. 2007; 146(6): 528-32. PMID: 17650591. URL: https://pubmed.ncbi.nlm.nih.gov/17650591/

Kamal S., Abdelhakam S., Ghoraba D., Massoud Y., Aziz K.A., Hassan H., Hafez T., Sallam A.A. The frequency, clinical course, and health related quality of life in adults with Gilbert’s syndrome: a longitudinal study. BMC Gastroenterology. 2019; 19. URL: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-019-0931-2

Kurtipek G.S., Sarı N., Akyurek F.T. Significant reduction in bilirubin levels in a patient with Gilbert's Syndrome under isotretinoin treatment for acne vulgaris: A new area of use for isotretinoin? Dermatol Ther. 2019 Mar; 32(3): e12884. DOI: https://doi.org/10.1111/dth.12884

Maladaki A., Yavropoulou M.P., Kotsa K., Tranga T., Ventis S., Yovos J.G. Non tumoral hyperserotoninaemia responsive to octreotide due to dual polymorphism in UGT1A1 and UGT1A6. Hormones (Athens). 2012; 11(1): 104-8. doi:https://doi.org/10.1007/BF03401544

McDonald G.B., Evans A.T., McCune J.S., Schoch G., Ostrow J.D., Gooley T.A. Mortality outcomes after busulfan-containing conditioning treatment and haemopoietic cell transplantation in patients with Gilbert's syndrome: a retrospective cohort study. Lancet Haematol. 2016; 3(11): e516-e525. DOI: https://doi.org/10.1016/S2352-3026(16)30149-1

Nakagawa T., Mure T., Yusoff S., Ono E., Harahap I.S.K., Morikawa S. et al. Acetaminophen administration in a patient with Gilbert’s syndrome. Pediatr Int. 2012; 54(6): 934-6. DOI: https://doi.org/10.1111/j.1442-200X.2012.03602.x

Pasha Y.Z., Kacho M.A., Niaki H.A., Tarighati M., Alaee E. The Association between Prolonged Jaundice and TATA Box Dinucleotide Repeats in Gilbert's Syndrome. J Clin Diagn Res. 2017; 11(9): GC05-GC07. DOI: https://doi.org/10.7860/jcdr/2017/19376.10597

Radoi V.E., Ursu R.I., Poenaru E., Arsene C., Bohiltea C.L., Bohiltea R. Frequency of the UGT1A1*28 polymorphism in a Romanian cohort of Gilbert syndrome individuals. J Gastrointestin Liver Dis. 2017 Mar; 26(1): 25-8. DOI: https://doi.org/10.15403/jgld.2014.1121.261.ugt URL: https://pubmed.ncbi.nlm.nih.gov/28338110/

Rasool A., Sabir S., Ashlaq M., Farooq U., Khan M.Z., Khan F.Y. Gilbert’s syndrome – a concealed adversity for physicians and surgeons. J Ayub Med Coll. 2015; 27(3): 707-10. https://www.sid.ir/en/journal/ViewPaper.aspx?ID=561260

Rauchschwalbe S.K., Zühlsdorf M.T., Wensing G., Kuhlmann J. Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype. Int J Clin Pharmacol Ther. 2004 Feb; 42(2): 73-7. DOI: https://doi.org/10.5414/cpp42073

Simondsen K.A., Kolesar J.M. Lenalidomide-induced elevated bilirubin. J Oncol Pharm Pract. 2012; 18(4): 402-5. DOI: https://doi.org/10.1177%2F1078155212439492

Singh A., Jialal I. Unconjugated hyperbilirubinemia. StatPearls [Internet]. 2020. https://www.ncbi.nlm.nih.gov/books/NBK562172/

Spraggs C.F., Parham L.R., Hunt C.M., Dollery C.T. Lapatinib-induced liver injury characterized by class II HLA and Gilbert’s syndrome genotypes. Clin Pharmacol Ther. 2012; 91(4): 647-52. DOI: https://doi.org/10.1038/clpt.2011.277

Strassburg C.P. Gilbert-Meulengracht’s syndrome and pharmacogenetics: is jaundice just the tip of the iceberg? Drug Metab Rev. 2010; 42(1): 168-81. DOI: https://doi.org/10.3109/03602530903209429

Strassburg C.P. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics. 2008; 9(6): 703-15. DOI: https://doi.org/10.2217/14622416.9.6.703

Tolomeo M., Colomba C., Meli M., Cascio A. Hepatotoxicity caused by mebendazole in a patient with Gilbert’s syndrome. J Clin Pharm Ther. 2019; 44(6): 985-7. DOI: https://doi.org/10.1111/jcpt.13033

Vitek L., Bellarosa C., Tiribelli C. Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity? Clin Pharmacol Ther. 2019; 106(3): 568-75. DOI: https://doi.org/10.1002/cpt.1341

Wagner K-H., Shiels R.G., Lang C.A., Khoei N.S. Bulmer A.C. Diagnostic criteria and contributors to Gilbert's syndrome. Crit Rev Clin Lab Sci. 2018; 55(2): 129-39. DOI: https://doi.org/10.1080/10408363.2018.1428526

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