Gilbert’s syndrome is the common cause of non hemolytic unconjugated hyperbilirubinemia with a prevalance of 3～7%. Gilbert’s syndrome may introduce a selection of potential liver donors from brain death patients. We present a case of living-related liver transplantation (LRLT) from a donor with Gilbert’s syndrome. A 22-year-old woman had been diagnosed as having liver cirrhosis at the age of 5. She underwent liver transplantation with the donor’s left lobe as the graft. The donor, who was the father of the patient, had been diagnosed with Gilbert’s syndrome. Although the recipient was well until 11 months after surgery, she died of subacute fulminant hepatitis 16 months after surgery. However, it was clear that the liver with Gilbert’s syndrome could be used as a graft of living-related liver transplantation for adult recipients

Fukuda, Yo

Harada, Masamitsu

Ishikawa, Masashi

Ito, Susumu

Miyake, Hidenori

Tashiro, Seiki

Wada, Daisuke

Yasuda, Mitsugu

Yogita, Shiro

Tokushima University Institutional Repository

INTRODUCTIONGilbert's syndrome is a common cause of benign hyper-bilirubinemia in the general population. It was first describedby Augustin Nicolas Gilbert and co-workers in 1900 (1).Clinically manifest Gilbert's syndrome with a stableelevated serum unconjugated hyperbilirubinemia, or withunconjugated hyperbilirubinemia after a 24-h fast, occurswith a frequency varying between 2% and 12% (2-6).Although there are various possible causes of hyper-bilirubinemia after liver transplantation, for example, duringepisodes of rejection, cholestasis, cholangitis or hemolysis,Gilbert's syndrome should be considered an additionalpotential cause. However, in case of liver transplantationfrom a cadaveric body, it is impossible to diagnose thedonor as Gilbert's syndrome. We have not been able toidentify any report in which donor was diagnosed asGilbert's syndrome before liver trnasplantation. We onlyfound reports in which the donor was suspected as Gilbert'ssyndrome after diagnosis as Gilbert's syndrome for arecipient after cadaveric liver transplantation (7-10). Thereis no information on whether a liver with Gilbert's syndromecan be used as a graft of living-related liver transplan-tation. We describe the clinical course of an adult patientwho underwent living-related liver transplantation (LRLT)from a donor who was diagnosed as Gilbert's syndromebefore operation.CASE REPORTDonor : The patient's 57-year-old father was the candidatefor LRLT. Although histological findings in the preoperativeliver biopsy specimens showed slight fatty infiltration, hisefforts to reduce caloric intake resulted in successfulimprovement fatty infiltration of the liver within 6 months.Preoperative his hepatic function was normal exceptfor hyperbilirubinemia. Laboratory data showed alanineaminotransferase(ALT) 10 international units(IU)/L (normal,3-30IU/L), aspartate aminotransferase(AST) 12IU/L (normal,10-30 IU/L), alkaline phosphatase(ALP) 147 IU/L (normal,81-231 IU/L), lactic dehydrogenase(LDH) 270 IU/L (normal,237-454 IU/L), γ-glutamyl transpeptidase(γ-GTP) 37 IU/L(normal, 7-22 IU/L), cholinesterase 349 IU/L (normal, 200-460 IU/L), total bilirubin 2.3 mg/dl (normal, 0.1-1.0 mg/dl), conjugated bilirubin 0.3 mg/dl (normal, 0-0.4 mg/dl),total protein 6.7g/dl (normal, 6.3-8.2g/dl) and serumalbumin 4.0 g/dl (normal, 3.5-5.1 g/dl). He was diagnosedas Gilbert's syndrome because of an increase of unconjugatedserum bilirubin during low caloric intake (Fig.1) andnicotinic acid test (Fig.2). The standard liver volume forthe patient was calculated to be 900 ml on the basis ofbody weight. Volumetric analysis with computed tomographyrevealed that the left lobe volume of the donor's liver was512 ml, corresponding to 56% of the recipient standardliver volume.Recipient : A 22-year-old woman had been diagnosed ashaving liver cirrhosis at the age of 5. She had undergonedevascularization and transection of the esophagus, andsplenectomy for esophageal varices at the age of 8.Complications such as spontaneous bacterial peritonitisCan the liver with Gilbert's syndrome be used as graft ofliving-related liver transplantation?Hidenori Miyake＊, Seiki Tashiro＊, Shiro Yogita＊, Masashi Ishikawa＊, Yo Fukuda＊,Masamitsu Harada＊, Daisuke Wada＊, Susumu Ito†, and Mitsugu Yasuda†*First Department of Surgery, and †Second Department of Internal Medicine, The University of Tokushima Schoolof Medicine, Tokushima, JapanAbstract: Gilbert’s syndrome is the common cause of non hemolytic unconjugated hyperbilirubinemiawith a prevalance of 3～7%. Gilbert’s syndrome may introduce a selection of potential liver donorsfrom brain death patients. We present a case of living-related liver transplantation (LRLT) from adonor with Gilbert’s syndrome. A 22-year-old woman had been diagnosed as having liver cirrhosis atthe age of 5. She underwent liver transplantation with the donor’s left lobe as the graft. The donor,who was the father of the patient, had been diagnosed with Gilbert’s syndrome. Although therecipient was well until 11 months after surgery, she died of subacute fulminant hepatitis 16 monthsafter surgery. However, it was clear that the liver with Gilbert’s syndrome could be used as a graft ofliving-related liver transplantation for adult recipients. J. Med. Invest. 44 : 219-221, 1998Key Words : Gilbert's syndrome, hyperbilirubinemia, unconjugated bilirubin, living-ralated liver transplantationReceived for publication December 17, 1997 ; accepted January 5, 1998.１ Address correspondence and reprint requests to Hidenori Miyake, M.D.,Ph.D., First Department of Surgery, The University of Tokushima School ofMedicine, Kuramoto-cho, Tokushima 770-8503, Japan and Fax : +81-886-31-9698.The Journal of Medical Investigation Vol.44 1998２１９and nonspecific colitis sometimes appeared from 17 yearsold, and icterus and ascites had appeared on all suchoccasions. These complications frequently occured from22 years old. Laboratory data before liver transplantationshowed ALT 129 IU/L (normal, 3-30 IU/L), AST 141 IU/L(normal, 10-30 IU/L), ALP 1316 IU/L (normal, 81-231 IU/L), LDH 457 IU/L (normal, 237-454 IU/L), γ-GTP 446 IU/L (normal, 7-22 IU/L), cholinesterase 137 IU/L (normal,200-460IU/L), total bilirubin 6.5mg/dl (normal, 0.1-1.0mg/dl), conjugated bilirubin 4.2 mg/dl (normal, 0-0.4 mg/dl),total protein 8.0 g/dl (normal, 6.3-8.2 g/dl) and serumalbumin 2.8 g/dl (normal, 3.5-5.1 g/dl).The patient and her family members were informed thatLRLT might be possible, and they indicated that thepatient's 57-year-old father was willing to act as the donor.This proporsal was submitted to the ethical committee ofThe University of Tokushima, School of Medicine and wasaccepted.On March 28 th, 1995, the patient underwent LRLT withthe donor's left lobe as the graft. The graft weight was440g and the graft corresponded to 49% of the recipient'sstandard liver volume. Volumetric analysis showed rapidenlargement of graft to 683ml as early as one week afterthe operation. Although the recipient had acute rejectionand stenosis of hepaticojejunostomy within 6months,unconjugated bilirubin-dominant hyperbilirubineia neverappeared. The recipient was well until 11 months aftersurgery. Changes of ALP, ALT, AST and bilirubin in therecipient within 4 weeks after operation are shown inFigures 3 and 4. Although she suffered from acute hepatitisdue to Hepatitis B virus and died of subacute fulminanthepatitis 16 months after liver transplantation, the recipienthad kept good liver function up to 1 year. Postoperativecourse of the donor was uneventful and he returned towork after dischraging from the hospital.DISCUSSIONEstimates of the prevalence of Gilbert's syndrome rangefrom 3% to 7% in the general population, and up to 12% inthe male population (11, 12). Gilbert's syndrome can betransferred from the donor to a recipient. The reason whyit seems that the prevalence of Gilbert's syndrome in thepost liver-transplant population is significantly lower thanin the general population is that in case of cadaveric livertransplantation, an unexplained hyperbilirubinemia in apotential donor may cause the transplant team to reject apotential donor (10). Furthermore, because brain deathdonors at the time of organ donation usually are onventilators and have many complications in intensive careFig.1. Low caloric intake test : Bilirubin levels after 3 days under400 kcal diet. Total bilirubin levels increased within 72 hours up to2.8 mg/dl due to increase of unconjugated bilirubin.Fig.２. Nicotinic acid test : IV administration of 50mg nicotinic acid.Unconjugated bilirubin levels increased within 2 hours up to 2.2 mg/dl due to increase of unconjugated bilirubin.Fig.3. Changes of ALP, ALT and AST : Alkaline phosphatase (ALP),alanine aminotransferas(ALT) and aspartate aminotransferase(AST)levels in serum gradually decreased, but not within normal range in1 month after LRLT.Fig.4. Changes of bilirubin : Bilirubin levels in serum decreasedafter LRLT and unconjugated hyperbilirubinemia never appeared.H. Miyake et al. LRLT from a donor with Gilbert’s Syndrome２２０units, it is very difficult for the transplant team to diagnosedonors as Gilbert's syndrome.In case of cadaveric liver transplantation, the diagnosisthat the donor was Gilbert's syndrome is only speculationfrom the fact that the recipient was diagnosed as Gilbert'ssyndrome after liver transplantation. However, in case ofLRLT, the donor can be diagnosed as Gilbert's syndromebefore the operation from an increase in unconjugatedbilirubin levels during low caloric intake and nicotinic acidtest. But now, it is not clear whether the liver with Gilbert'ssyndrome can be used as a graft or not. Gates reportedthat those recipients who did seem to have Gilbert's syn-drome had excellent long term survival and completelynormal graft function by analysis of 3 patients with Gilbert'ssyndrome out of their 229 post-transplant patients (10). How-ever, a report in which one case whose total and conjugatedbilirubin levels were 1.5 and 0.6 mg/dl, respectively, wasdiagnosed as having Gilbert's syndrome, which eliminatedhim as a candidate (13). They also mentioned that inaccordance with their policy to make every effort to avoidany possible postoperative increase in serum bilirubin level,even though the other liver function tests for the donorcandidate were completely normal, they were compelledto pass over the primary candidate for the secondary one(13). However, they are changing their opinion to relaxingtheir guidelines for donor selection, because slight elevationof serum bilirubin poses little direct hazard to theliving-related liver transplantation from their experiences.In our case, if possible, we selected the patient's motherinstead of the father as a donor. But the mother could notbe a donor because she sufferred from primary biliarycirrhosis. We think that intermittent hyperbilirubinemiacaused by Gilbert's syndrome in the recipient does notlead to poor outcome of LRLT because patients withGilbert's syndrome have no damage in the liver, as in ourpatient's donor. Furthermore, hyperbilirubinemia due toGilbert's syndrome does not always appear in the recipient,as in our case.In a recent study, it was shown that patients with Gilbert'ssyndrome had an A(TA)7 TAA instead of an A(TA)6 TAAsequence in the bilirubin UDP-glucuronosyltransferase-genepromotor region on both alleles. It is possible that a liverfrom a donor with the A(TA)7TAA/A(TA)7TAA genotypecauses clinically manifest Gilbert's syndrome in the recipient(14). Jansen also mentioned that a liver with Gilbert'ssyndrome genotype usually has few consequences for therecipient and an isolated unconjugated bilirubin serumlevel in the donor is no reason not to use that liver fororgan donation (14). Although, in our case, the donor wasdiagnosed as Gilbert's syndrome by both 3-day low calorictest and nicotinic acid test, our recipient did not clinicallymanifest Gilbert's syndrome, probably because the expressionof Gilbert's syndrome is influenced by food intake, cigarettesmoking, alcohol consumption, medication and the fatcontent of the diet in addition to the promotor regionabnormality.We conclude that the liver with Gilbert's syndrome canbe used as a graft of living-related liver transplantation.However, it is very important for the transplant surgeons tobe aware that Gilbert's syndrome can be transferred fromthe donor to a recipient because unexplained post-transplanthyperbilirubinemia causes confusion and gives a compli-cated evaluation to the recipient.REFERENCES1. Gilbert A, Castaigne MJ, Lereboullet P : De I'eicterefamilial : Contribution a I'etude de la diathese biliare.Semaine Medicale 20 : 281, 19002. Owens D, Evans J : Population studies on Gilbert'ssyndrome. J Med Genet 12 : 152-156, 19753. Bailey A, Robinson D, Dawson AM : Does Gilbert'ssyndrome Exist ? Lancet : 931-933, 19774. Sieg A, Arab L, Achlierf G, Stiehl A, Kommerell B :Die Pravalenz des Gilbert-syndroms in Deutschland.Dtsch Med Wochenschr 112 : 1206-1208, 19875. Fevery J : Pathogenesis of Gilbert's syndrome. Eur JClin Invest 11 : 417-418, 19816. Watson KJR, Gollan JL : Gilbert's syndrome. Balliere'sClin Gastroenterol 3 : 337-355, 19897. Arnold JC, Otto G, Kraus T, Kommerell B, ThielmannL : Gilbert's syndrome-a possible cause of hyper-bilirubinemia after orthotopic liver transplantation. JHepatol 14 : 404, 19928. Henne-Bruns D, Kremer B : Manifestation of a Gilbert'sSyndrom after orthotopic Liver Transplantation:Rare cause of Postoperative Hyperbilirubinemia. KlinWochenschr 66 : 596-598, 19889. Henne-Bruns D, Kremer B : What's your diagnosis ?Part II Hepato-gastroenterol 37 : 85, 199010. Gates LK, Wiesner RH, Krom RA, Steers J, Gores GJ,Hay JE, Porayko MK : Etiology and Incidence ofUnconjugated Hyperbilirubinemia after OrthotopicLiver Transplantation. Am J Gastroenterol 89 : 1541-1543, 199411. Foulk WT, Butt HR, Owen CA : Constitutional hepaticdysfunction(Gilbert's syndrome) : Its natural historyand related syndromes. Medicine (Baltimore) 38 : 25-46, 195912. Powell LW, Hemingway E, Billing BH : Idiopathicunconjugated hyperbilirubinemia (Gilbert's syndrome).A study of 42 families. N Engl J Med 277 : 1108-1112,196713. Morimoto T, Awane M, Tanaka A, Ikai I, Yamamoto Y,Takada Y, Honda K, Inamoto T, Uemoto S, InomataY, Tanaka K, Yamaoka Y, Shimahara Y, Ozawa K :Analysis of functional abnormalities uncovered duringpreoperative evaluation of donor candidates forliving-related liver transplantation. Clin Transplan-tation 9 : 60-64, 199514. Jansen PL, Bosma PJ, Bakker C, Lems SP, Slooff MJ,Haagsma EB : Persistent unconjugated hyperbilirubinemiaafter liver transplantation due to an abnormal bilirubinUDP-glucuronosyltransferase gene promotor sequencein the donor. J Hepatol 27 : 1-5, 1997２２１The Journal of Medical Investigation Vol.44 1998

Can the liver with Gilbert's syndrome be used as graft of living-related liver transplantation?

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Can the liver with Gilbert's syndrome be used as graft of living-related liver transplantation?

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