ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos ETM-0-0-09219 10.3892/etm.2020.9219 Articles Gilbert syndrome with systemic lupus erythematosus presenting with persistent unconjugated hyperbilirubinemia: A case report YeNaifang 1 * ZhouZhuochao 2 * GongHuiyun 3 TengJialing 2 HanYue 4 YangChengde 2 YeJunna 2 Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui 230601, P.R. China Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China Department of Clinical Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China Correspondence to: Professor Junna Ye or Dr Chengde Yang, Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai 200025, P.R. China yjn0912@qq.com yangchengde@sina.com

*Contributed equally

 11 2020 14 09 2020 20 5 91 26 11 2019 03 06 2020 Copyright: © Ye et al. 2020 This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited, the use is non-commercial and no modifications or adaptations are made.

Gilbert syndrome (GS) is a hereditary unconjugated hyperbilirubinemia that results from mutations in the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene. To the best of our knowledge, there are currently no reports that focus on patients with systemic lupus erythematosus (SLE) coexisting with GS. The present study aimed to evaluate the clinical characteristics and genotype of UGT1A1 in a Chinese patient with SLE and GS. Complete medical records and laboratory data were reviewed for a patient with SLE referred to Ruijin Hospital (Shanghai, China) for treatment between March 2016 and January 2020. Genetic analysis of the UGT1A1 gene was performed by PCR amplification and Sanger sequencing. The serum total bilirubin and unconjugated bilirubin concentrations on admission were 96.2 and 86.8 µmol/l, respectively. The homozygous mutation c.1456T>G (p.Y486D) in exon 5 was detected in this patient. The patient had a good response to phenobarbital orally at a dose of 30 mg/day and a decrease in serum bilirubin was observed. Elevated unconjugated hyperbilirubinemia in SLE needs to be differentiated from other diseases, such as GS, which can be diagnosed by UGT1A1 genetic sequencing.

 systemic lupus erythematosus Gilbert syndrome genotype hyperbilirubinemia Introduction

Gilbert syndrome (GS) is a common autosomal dominant disorder that results in intermittent hyperbilirubinemia in the absence of any signs or symptoms of liver disease (1). GS usually manifests in decreased activity of the uridine diphosphate-glucuronosyltransferase (UGT1A1) gene with an incidence of ~5-10% in the global population from 2018 (1,2). UGT1A1 gene encodes a UDP-glucuronosyltransferase, which transforms small lipophilic molecules, including bilirubin into water-soluble, excretable metabolites. Several variations in the UGT1A1 gene have been described, including UGT1A1*28, UGT1A1*60 and UGT1A1*93 (3,4). GS in combination with diseases, such as thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, spherocytosis and acute lymphoblastic leukemia may potentiate severe hyperbilirubinemia (5-9). In addition, GS may decrease plasma oxidation and affect drug metabolism, such as irinotecan hydrochloride by decreasing the ability to conjugate drugs (10). However, to the best of our knowledge, there are currently no reports about patients with systemic lupus erythematosus (SLE) coexisting with GS.

SLE is a chronic multisystem inflammatory disease characterized by the production of various autoantibodies, such as anti-double-stranded DNA antibodies (anti-dsDNA antibodies), anti-Sm antibodies and anti-SSA/SSB antibodies. Fang et al (11) indicated that hepatic manifestation triggered by SLE itself is controversial and usually asymptomatic. This is due to the fact a variety of causes need to be differentiated, such as i) an overlap of SLE with autoimmune hepatitis (AIH) or primary biliary cirrhosis; ii) an overlap of SLE with non-autoimmune hepatopathy; iii) the existence of liver injury that only relates to SLE. And elevated liver parameters seem to be common, accounting for 25-50% patients with SLE (11); however, the etiology of hepatic damage remains unclear (12). A study by Vitek et al (13) that involved 259 patients with SLE revealed that SLE disease activity was accompanied by very low serum bilirubin levels, which were caused by severe oxidative stress. Patients with GS may be protected from the development of SLE. The present study aimed to summarize the clinical characteristics, genetic type and treatment of a patient with SLE coexisting with GS.

 Materials and methods <sec> <title>Patient characteristics, examination and treatment

A 27-year-old Chinese female patient was referred to Ruijin Hospital (Shanghai, China) displaying jaundice in March 2016. The jaundice began 6 years prior to admission. The patients parents did not have jaundice, and she denied the use of potential cholestasis-inducing medication. The patient presented with a malar rash, arthritis, thrombocytopenia and decreased hemoglobin, but without kidney and nervous system involvement. The patient had no symptoms of photosensitivity, alopecia or oral ulcers. Autoantibody testing revealed that the patient had a titer of 1:100 for antinuclear antibody and that anti-Sjogren's syndrome A and B antibodies were positive as well. On this basis, the patient was diagnosed with SLE according to the 2011 classification criteria of the Systemic Lupus International Collaborating Clinics (14). The patient's laboratory findings were as follows: Hemoglobin, 80 g/l (reference value: 110-150 g/l); white blood cell count, 9.0x109/l (reference value: 4.0-10.0x109/l); and platelet (PLT) count, 50.0x109/l (reference value: 100-300x109/l). The liver function test revealed that serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase were normal and total bilirubin (TB) was 91.1 µmol/l (3.4-20.5 µmol/l), and direct bilirubin (DB) was 12.5 µmol/l (0.0-6.8 µmol/l). Therefore, the patient was characterized with persistent elevated indirect (unconjugated) bilirubin (IB). For the immunosuppressive therapy, hydroxychloroquine at a dose of 200 mg twice/day, prednisone 40 mg/day and cyclosporine 50 mg twice/day orally were used. The patient was in a stable condition with regard to the SLE disease activity. However, jaundice still existed. TB, DB, erythrocyte sedimentation rate (ESR) and PLT were detected in Ruijin Hospital (Shanghai, China), consecutively. The Coombs test was negative, which excluded hemolytic anemia. Transaminases and serological tests for hepatitis B and C were negative, which excluded virus hepatitis. There was no obvious abnormality on the abdominal ultrasound or bone marrow biopsy. Informed written consent and consent for publication were obtained from the patient. This study was approved by the Ethics Committee of Ruijin Hospital (ID: 2016-62).

 PCR amplification and sequencing

A total of 2 ml patient peripheral blood was collected in a tube containing ethylenediaminetetraacetic acid (EDTA). Genomic DNA was extracted from the peripheral blood sample using the membrane-based QIAamp DNA extraction kit (Qiagen GmbH) according to the manufacturer's instructions. DNA concentration and purity were measured with a spectrophotometer (NanoDrop 2000; Thermo Fisher Scientific, Inc.). Primer pairs were the same as used in a previous study (15). The promoter, exons 1-5, adjacent intronic regions and the phenobarbital response enhancer module of the UGT1A1 gene were analyzed by polymerase chain reaction (PCR). PCR mixtures were initially denatured at 95˚C for 5 min, followed by 35 cycles of 30 sec 95˚C denaturation, 30 sec 54-64˚C annealing according to the primer pair being used and 45 sec extension at 72˚C, with a final extension at 72 for 10 min. PCR products (5 µl) were sequenced with the Big-Dye Terminator Sequencing kit and an ABI 377 automated DNA sequencer (Applied Biosystems, Thermo Fisher Scientific Inc.).

 Follow-ups

The follow-up of this patient including clinical symptoms, signs and laboratory examinations, such as ESR, PLT, liver function tests was conducted every 1 to 3 months. In addition, the SLEDAI score was evaluated each time (16,17). The total follow-up period was 46 months.

 Results <sec> <title>Laboratory data and treatment

Laboratory data were recorded consecutively and were presented in Table I. TB, IB and ESR levels were elevated at admission. Then, TB and IB levels remained stable from June 2016 to October 2016. Treatment using phenobarbital at a dose of 30 mg/day was started on November 4, 2016 until November 10, 2016.

 Mutation in the UGT1A1 gene

A direct sequencing analysis was conducted to identify the mutation in the UGT1A1 gene of the patient. The analysis revealed a homozygous mutation from a T to G at nucleotide position 1456 in UGT1A1 exon 5 (c.1456T>G), resulting in the substitution of aspartate to tyrosine at position 486 of the UGT1A1 protein (p.Y486D) (Fig. 1).

 Outcome and follow-up period

SLE activity indicators, such as ESR, high-sensitivity C-reactive protein and anti-dsDNA antibody remained normal during the follow-up period. SLEDAI score varied from 0 to 1. Following phenobarbital treatment for 1 week, there was a rapid decrease in bilirubin levels (Fig. 2). TB and IB were decreased and therapy was well tolerated without any side effects. After 46 months of follow up, the patient remained stable on low-dose oral prednisone (10 mg/day) and cyclosporin (50 mg twice/day). The latest TB and IB values were 81.5 and 71.7 µmol/l, respectively (Table I).

 Discussion

GS is caused by a mutation in the UGT1A1 gene resulting in impairment of glucuronidation of unconjugated bilirubin within hepatocytes. Several studies have reported the coexistence of GS and hereditary spherocytosis, G6PD deficiency, gallstone disease and other diseases (8,18,19). The reports were summarized in Table II for UGT1A1 genetic mutations and related diseases during the past 4 years. Butorac et al (7) reported the coexistence of hereditary spherocytosis and GS in a 21-month-old girl with unconjugated hyperbilirubinemia. Li et al (20) reported the combination of myeloproliferative neoplasms and the presence of the insertion mutation with the (TA)6TAA box and the missense mutation (G→A) at 211 bp of exon 1 in the UGT1A1 gene. Recently, over 130 genetic variants in the UGT1A1 gene were associated with GS after assessing the presence of genetic polymorphisms among different ethnicities (21). East Asian individuals had a prevalence of ~2% for the genetic variants in the UGT1A1 gene, while Caucasian individuals had a prevalence of 2-10%, and Southern Asian and Middle Eastern individuals demonstrated a significantly increased prevalence of 20% (22-24). A TA insertion mutation in the TATA box [A (TA) 7TAA] (UGT1A1*28) and c0.211 G>A (p.G71R) in exon 1 (UGT1A1*6) were common (25-27). A(TA)7TAA was the most common mutation in the UGT1A1 gene seen in Caucasian individuals, accounting for ~35-40% (28). A study from a Romanian cohort demonstrated that the polymorphism with the highest frequency was the UGT1A1 7TA (UGT1A1*28) (29). However, a Chinese study revealed that 36.3% of patients with GS had the c.3279T>G mutation (30). And the frequency of A (TA) 7TAA was 30.6%, which was lower compared with Caucasians (21). To the best of our knowledge, the present study demonstrated the first patient diagnosed as SLE with GS who had the homozygous mutation c.1456 T>G (p.Y486D) in the UGT1A1 gene. The patient in the present study presented with persistent unconjugated hyperbilirubinemia and had a good response to phenobarbital with a decrease in bilirubin, which confirmed the diagnosis of GS. Low-dose phenobarbital can be used continuously in patients with GS who tolerate it well. During the 46 month follow-up period, the patient exhibited stable SLE activity and serum bilirubin level. A limitation of the present study was lack of family gene verification, as the parents of the patient did not have jaundice and refused gene testing.

Nakagawa et al (31) described a single homozygote for the p.Y486D mutation in UGT1A1 exon 5, one of the shared exons, and predicted that the p.Y486D mutation may disturb the metabolization of the antipyretic and acetaminophen. This may affect the activity of the UGT1A1, UGT1A6 and UGT1A9 genes, which catalyze acetaminophen glucuronidation (32). Acetaminophen (~85%) is metabolized by conjugation, mainly glucuronidation through UDP-glucuronosyltransferase (33). Ha et al (10) revealed that UGT1A1 genetic polymorphisms, particularly the UGT1A1*28 allele of GS may alter the metabolism of drugs, such as irinotecan hydrochloride by decreasing the ability to conjugate drugs. Attention should be paid to the use of these drugs in patients with GS.

The coexistence of SLE and GS requires further investigation. The association between serum bilirubin and SLE activity remains unclear. Serum bilirubin is the final product of hemoglobin metabolism (34). Severe hyperbilirubinemia could lead to cholestasis and neurological impairments (neurotoxicity or kernicterus), which have considerable morbidity and mortality risks (35). It was revealed that bilirubin has potent cytoprotective action due to its anti-inflammatory, anti-oxidant and immunosuppressive roles at low concentrations, and mild hyperbilirubinemia prevents the development of ischemic heart disease by increasing the serum antioxidant capacity (36-39). Patients with GS had low levels of oxidative stress associated with hyperbilirubinemia (40). In addition, GS was associated with a decreased prevalence of cardiovascular disease, diabetes, endometrial cancers and with a better prognosis for Hodgkin's lymphoma (1,39,41-43). In the present study, unconjugated bilirubin levels were elevated, while the SLE activity indicators remained normal and stable, such as the SLEDAI score. dos Santos et al (44) reported that unconjugated bilirubin level in SLE was negatively correlated with disease activity, which is consistent with the present study. Although the activity of SLE increases oxidative stress, serum bilirubin plays an important role in controlling it (45). Patients with GS can be treated with phenobarbital or no medication. When a patient experiences any other factors, such as menstruation, infection, surgery or overexertion, the degree of jaundice could be aggravated.

To conclude, the present study identified a homozygous mutation, c.1456T>G, in a patient with SLE with persistent hyperbilirubinemia coexisting with GS. It is pivotal that elevated unconjugated hyperbilirubinemia in SLE should be differentiated from other diseases, such as GS.

 Acknowledgements

Not applicable.

 Funding

The present study was supported by grants from the National Natural Science Foundation of China (grant no. 81801592), Shanghai Sailing Program (grant no. 18YF1414100), and Excellent Youth B Project (grant no. GCQN-2017-B05) and Innovative Research Team of high-level local universities in Shanghai.

 Availability of data and materials

All data generated or analyzed during this study are included in this published article.

 Authors' contributions

NY and ZZ drafted the manuscript. HG performed the laboratory tests. YH performed the PCR amplification and sequencing. JT performed the follow-up task and analysed clinical data. The experiments were designed by JY and CY. All authors read and approved the final manuscript.

 Ethics approval and consent to participate

The present study was approved by the Ethics Committee of Ruijin Hospital (ID: 2016-62) and signed informed consent was obtained from the patient.

 Patient consent for publication

The patient referred to in this study provided consent for the publication of her information.

 Competing interests

The authors declare that they have no competing interests.

 References WagnerKHShielsRGLangCASeyed KhoeiNBulmerACDiagnostic criteria and contributors to Gilbert's syndromeCrit Rev Clin Lab Sci5512913920182939092510.1080/10408363.2018.1428526 SiegAArabLSchlierfGStiehlAKommerellBPrevalence of Gilbert's syndrome in GermanyDtsch Med Wochenschr112120612081987360884510.1055/s-2008-1068222(In German) MaruoYNakaharaSYanagiTNomuraAMimuraYMatsuiKSatoHTakeuchiYGenotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndromeJ Gastroenterol Hepatol3140340820162625042110.1111/jgh.13071 D'AngeloRRinaldiCDonatoLNicociaGSidotiAThe combination of new missense mutation with [A(TA)7TAA] dinucleotide repeat in UGT1A1 gene promoter causes Gilbert's syndromeAnn Clin Lab Sci45202205201525887876 FretzayasAMoustakiMLiapiOKarpathiosTGilbert syndromeEur J Pediatr171111520122216000410.1007/s00431-011-1641-0 BerruecoRAlonso-SaladriguesAMartorell-SampolLCatala-TempranoARuiz-LlobetATollTTorrebadellMNaudoMCamosMRivesSOutcome and toxicities associated to chemotherapy in children with acute lymphoblastic leukemia and Gilbert syndrome. Usefulness of UGT1A1 mutational screeningPediatr Blood Cancer621195120120152585541310.1002/pbc.25457 Butorac AhelIBaraba DekanicKPalcevskiGRoganovicJAn infant with unusually high unconjugated hyperbilirubinemia due to coexistence of hereditary spherocytosis and gilbert syndromeJ Pediatr Hematol Oncol40e127e12820182920015710.1097/MPH.0000000000001025 ZahedpashaYAhmadpourMNiakiHAAlaeeERelation between neonatal icter and gilbert syndrome in gloucose-6-phosphate dehydrogenase deficient subjectsJ Clin Diagn Res8636520142478308310.7860/JCDR/2014/6674.4108 TzetisMKanavakisETsezouALadisVPaterakiEGeorgakopoulouTKavazarakisEMaragoudakiEKarpathiosTKitsiou-TzeliSGilbert syndrome associated with beta-thalassemiaPediatr Hematol Oncol1847748420011176409610.1080/088800101753328439 HaVHJuppJTsangRYOncology drug dosing in gilbert syndrome associated with UGT1A1: A summary of the literaturePharmacotherapy3795697220172849410910.1002/phar.1946 FangXZamanMHGuoXDingHXieCZhangXDengGMRole of hepatic deposited immunoglobulin G in the pathogenesis of liver damage in systemic lupus erythematosusFront Immunol9145720182998850010.3389/fimmu.2018.01457 ChowdharyVRCrowsonCSPoteruchaJJModerKGLiver involvement in systemic lupus erythematosus: Case review of 40 patientsJ Rheumatol352159216420081879300210.3899/jrheum.080336 VitekLMuchovaLJancovaEPesickovaSTegzovaDPeterovaVPavelkaKTesarVSchwertnerHAssociation of systemic lupus erythematosus with low serum bilirubin levelsScand J Rheumatol3948048420102060467310.3109/03009741003742748 PetriMOrbaiAMAlarconGSGordonCMerrillJTFortinPRBruceINIsenbergDWallaceDJNivedODerivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosusArthritis Rheum642677268620122255307710.1002/art.34473 EhmerUKalthoffSFakundinyBPabstBFreibergNNaumannRMannsMPStrassburgCPGilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidationHepatology551912192120122221312710.1002/hep.25561 BombardierCGladmanDDUrowitzMBCaronDChangCHDerivation of the SLEDAI: A disease activity index for lupus patients. The Committee on Prognosis Studies in SLEArthritis Rheum356306401992159952010.1002/art.1780350606 GladmanDDIbañezDUrowitzMBSystemic lupus erythematosus disease activity index 2000J Rheumatol29288291200211838846 KumarDParakhASharmaSGilbert syndrome increasing unconjugated hyperbilirubinemia in a child with hereditary spherocytosisJ Pediatr Hematol Oncol34545620122213461110.1097/MPH.0b013e318228fdd1 BaleGAvanthiUSPadakiNRSharmaMDuvvurNRVishnubhotlaVRKIncidence and risk of gallstone disease in gilbert's syndrome patients in Indian populationJ Clin Exp Hepatol836236620183056399610.1016/j.jceh.2017.12.006 LiXXShiJHuangZDShaoYQNieNZhangJGeMLHuangJBZhengYZClinical characteristics and gene mutations of gilbert syndrome complicated with myeloproliferative neoplasmZhongguo Shi Yan Xue Ye Xue Za Zhi2556757120172844631210.7534/j.issn.1009-2137.2017.02.046(In Chinese) CanuGMinucciAZuppiCCapoluongoEGilbert and crigler najjar syndromes: An update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation databaseBlood Cells Mol Dis5027328020132340325710.1016/j.bcmd.2013.01.003 MendezLLagoaMQuirogaTMargozziniPAzocarLMolinaHRVeraAVillarroelLArreseMHampeJPrevalence of Gilbert syndrome and its genetic determinants in ChileRev Med Chil1411266127420132452235410.4067/S0034-98872013001000005(In Spanish) GweeKAKoayESKangJYThe prevalence of isolated unconjugated hyperbilirubinaemia (Gilbert's syndrome) in subjects attending a health screening programme in SingaporeSingapore Med J3358858919921488666 HemmatiFSakiFSakiNHaghighatMGilbert syndrome in Iran, fars provinceAnn Saudi Med308420102010396510.4103/0256-4947.59376 BosmaPJChowdhuryJRBakkerCGantlaSde BoerAOostraBALindhoutDTytgatGNJansenPLOude ElferinkRPThe genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndromeN Engl J Med333117111751995756597110.1056/NEJM199511023331802 SatoHAdachiYKoiwaiOThe genetic basis of Gilbert's syndromeLancet3475575581996859631310.1016/s0140-6736(96)91266-0 BurchellBHumeRMolecular genetic basis of Gilbert's syndromeJ Gastroenterol Hepatol1496096619991053049010.1046/j.1440-1746.1999.01984.x HsiehTYShiuTYHuangSMLinHHLeeTCChenPJChuHCChangWKJengKSLaiMMChaoYCMolecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoterPharmacogenet Genomics1722923620071749672210.1097/FPC.0b013e328012d0da RadoiVEUrsuRIPoenaruEArseneCBohilteaCLBohilteaRFrequency of the UGT1A1*28 polymorphism in a Romanian Cohort of gilbert syndrome individualsJ Gastrointestin Liver Dis26252820172833811010.15403/jgld.2014.1121.261.ugt SunLLiMZhangLTengXChenXZhouXMaZQiLWangPDifferences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome type IIMedicine (Baltimore)96e862020172913709510.1097/MD.0000000000008620 NakagawaTMureTYusoffSOnoEKusuma HarahapISMorikawaSMoriokaITakeshimaYNishioHMatsuoMA homozygous mutation in UGT1A1 exon 5 may be responsible for persistent hyperbilirubinemia in a Japanese girl with Gilbert's syndromeKobe J Med Sci57E26E31201122169899 CourtMHDuanSXvon MoltkeLLGreenblattDJPattenCJMinersJOMackenziePIInterindividual variability in acetaminophen glucuronidation by human liver microsomes: Identification of relevant acetaminophen UDP-glucuronosyltransferase isoformsJ Pharmacol Exp Ther2999981006200111714888 GelotteCKAuilerJFLynchJMTempleARSlatteryJTDisposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adultsClin Pharmacol Ther8184084820071737752810.1038/sj.clpt.6100121 LesterRSchmidRBilirubin MetabolismN Engl J Med27077978619641410731810.1056/NEJM196404092701507 WatchkoJFTiribelliCBilirubin-induced neurologic damage-mechanisms and management approachesN Engl J Med3692021203020132425638010.1056/NEJMra1308124 VitekLJirsaMBrodanovaMKalabMMarecekZDanzigVNovotnyLKotalPGilbert syndrome and ischemic heart disease: A protective effect of elevated bilirubin levelsAtherosclerosis16044945620021184967010.1016/s0021-9150(01)00601-3 IlzeckaJStelmasiakZSerum bilirubin concentration in patients with amyotrophic lateral sclerosisClin Neurol Neurosurg10523724020031295453710.1016/s0303-8467(03)00031-3 YuceSCureECicekYCumhur CureMYilmazAKizilkayaBEvaluation of aortic stiffness in Gilbert syndrome patients: A protective effect of elevated bilirubin levelsTurk Kardiyol Dern Ars4359960620152653698410.5543/tkda.2015.44457 McCartyMF‘Iatrogenic Gilbert syndrome’-a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubinMed Hypotheses6997499420071782549710.1016/j.mehy.2006.12.069 MaruhashiTSogaJFujimuraNIdeiNMikamiSIwamotoYKajikawaMMatsumotoTKiharaYChayamaKHyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndromeCirculation12659860320122277345410.1161/CIRCULATIONAHA.112.105775 DuguayYMcGrathMLépineJGagnéJFHankinsonSEColditzGAHunterDJPlanteMTêtuBBélangerAThe functional UGT1A1 promoter polymorphism decreases endometrial cancer riskCancer Res641202120720041487185810.1158/0008-5472.can-03-3295 StrassburgCPHyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome)Best Pract Res Clin Gastroenterol2455557120102095595910.1016/j.bpg.2010.07.007 RibragVKoscielnySCasasnovasOCazeneuveCBricePMorschhauserFGabarreJStamatoullasALenoirGSallesGGroupe d'Etude des Lymphomes agressifs group, Laboratoire de Génétique et de recherche translationnelle, Institut Gustave RoussyPharmacogenetic study in Hodgkin lymphomas reveals the impact of UGT1A1 polymorphisms on patient prognosisBlood1133307331320091876878410.1182/blood-2008-03-148874 dos SantosBHde R AlmeidaCMSkareTLSystemic Lupus Erythematosus activity and serum bilirubinsActa Reumatol Port38242246201324435028 LozovoyMASimaoANPanisCRotterMAReicheEMMorimotoHKLavadoECecchiniRDichiIOxidative stress is associated with liver damage, inflammatory status, and corticosteroid therapy in patients with systemic lupus erythematosusLupus201250125920112181359210.1177/0961203311411350 JamwalMAggarwalAKumarVSharmaPSachdevaMUBansalDMalhotraPDasRDisease-modifying influences of coexistent G6PD-deficiency, Gilbert syndrome and deletional alpha thalassemia in hereditary spherocytosis: A report of three casesClin Chim Acta458515420162710820110.1016/j.cca.2016.04.020 SingerSPilpelNPinhas-HamielOGilbert syndrome in patients with type 1 diabetes-prevalence, glycemic control, and microalbuminuriaPediatr Diabetes1880380720172809384210.1111/pedi.12488 MoyerAMSkierkaJMKotzerKEKlugeMLBlackJLBaudhuinLMClinical UGT1A1 genetic analysis in pediatric patients: Experience of a reference laboratoryMol Diagn Ther2132733520172821380610.1007/s40291-017-0265-0 AisoMYagiMTanakaAMiuraKMiuraRArizumiTTakamoriYNakaharaSMaruoYTakikawaHGilbert Syndrome with concomitant hereditary spherocytosis presenting with moderate unconjugated hyperbilirubinemiaIntern Med5666166420172832106610.2169/internalmedicine.56.7362 PashaYZKachoMANiakiHATarighatiMAlaeeEThe association between prolonged jaundice and TATA box dinucleotide repeats in Gilbert's syndromeJ Clin Diagn Res11GC05GC0720172920773310.7860/JCDR/2017/19376.10597 HaddadFTrabelsiNChaouchLDarragiIOueslatiMBoudrigaIChaouachiDEl-BorgiWHafsiaRAbbesSOuraginiHHomozygous mutation on the β-globin polyadenylation signal in a Tunisian patient with β-Thalassemia intermedia and coinheritance of Gilbert's syndromeHemoglobin4114715020172859216810.1080/03630269.2017.1322610 QianJDHouFQWangTLShaoCWangGQGilbert syndrome combined with prolonged jaundice caused by contrast agent: Case reportWorld J Gastroenterol241486149020182963242910.3748/wjg.v24.i13.1486 KamalSAbdelhakamSGhorabaDMassoudYAzizKAHassanHHafezTAbdel SallamAThe frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: A longitudinal studyBMC Gastroenterol192220193071770310.1186/s12876-019-0931-2

Mutation in the UGT1A1 gene in the patient. Sequencing analysis revealed a homozygous mutation from a T to G at nucleotide position 1456 in UGT1A1 exon 5 (c.1456T>G), resulting in the substitution of aspartate for tyrosine at position 486 of the UGT1A1 protein (p.Y486D). Tyr, tyrosine; Asp, aspartate.

Variations in serum bilirubin during follow up. The figure presents the variations in serum bilirubin during follow up. The patient was treated with phenobarbital on November 4, 2016. After 1 week, there was a rapid decrease in total and indirect bilirubin levels. TB, total bilirubin; DB, direct bilirubin; IB, indirect bilirubin.

Variation of laboratory data during follow-ups for the patient with systematic lupus erythematosus and coexisting Gilbert syndrome.

Time, day/month/year ESR, mm/h PLT, x109/l TB, µmol/l DB, µmol/l IB, µmol/l
28/03/2016 23 106 96.2 9.4 86.8
29/06/2016 9 108 87.2 11.4 75.8
19/07/2016 13 90 90.7 10.5 80.2
10/08/2016 5 88 89.5 12.4 77.1
11/10/2016 6 75 90.7 10.5 80.2
04/11/2016 8 54 77.2 8.7 68.5
10/11/2016 7 50 54.2 8.9 45.3
29/11/2017 22 15 80.2 9.0 71.2
30/05/2018 7 43 66.5 8.8 57.7
01/03/2019 13 27 67.6 9.1 58.5
06/01/2020 12 32 81.5 9.8 71.7

ESR, erythrocyte sedimentation rate; PLT, platelet; TB, total bilirubin; DB, direct bilirubin; IB, indirect bilirubin.

UGT1A1 genetic mutations and related diseases during the 4 year follow up period.

First author, year Number of patients Country Disease Mutations (Refs.)
Maruo, et al 2016 121 Japan GS p.G71R,p.P229Q, c.-3279T>G:A(TA)7TAA (3)
Jamwal, et al 2016 3 India GS, G6PD-deficiency, HS (TA)7/7 repeats (46)
Singer, et al 2016 43 Israel GS, type I diabetes Not mentioned (47)
Radoi, et al 2017 292 Romania GS UGT1A1 (7TA), UGT1A1 (8TA) (29)
Moyer, et al 2017 54 England GS, neonatal jaundice Novel variants: c.337T>G (p.Y113D), c.1469A>C(p.D490A) (48)
Li, et al 2017 1 China GS, MPN (TA)6TAA, c.-211G>A (20)
Sun, et al 2017 59 China GS c.-3279T>G, A(TA)7TAA, p.G71R, p.P229Q, p.P364L, p.Y486D (30)
Aiso, et al 2017 1 Japan GS, HS A(TA)7TAA, c.211G>A:p.G71R (49)
Pasha, et al 2017 51 Iran GS UGT1A1 (7TA) (50)
Haddad, et al 2017 1 Tunisia GS, β-thalassemia (TA)6/(TA)7 (51)
Butorac, et al 2018 1 Croatia GS, HS UGT1A1 (7TA) (7)
Qian, et al 2018 1 China GS, gallstone disease A(TA)7TAA, c.-364C>T, c.-1352A>C (52)
Bale, et al 2018 1,191 India GS, gallstone disease UGT1A1(TA)n (19)
Kamal, et al 2019 110 Egypt GS A(TA)7TAA (53)

GS, Gilbert syndrome; G6PD-deficiency, glucose-6-phosphate dehydrogenase deficiency; HS, hereditary spherocytosis; MPN, myeloproliferative neoplasm; ALL, acute lymphoblastic leukemia.