Dubin-Johnson综合征的临床特点分析
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摘要
Dubin-Johnson综合征(DJS)是一种少见的常染色体隐性遗传病,是由于毛细胆管上特异性有机阴离子转运蛋白基因缺陷,导致结合胆红素排泄障碍,血液中结合胆红素升高,黑色色素在肝细胞内沉着,大体表现为黑肝。该疾病预后良好,不需特殊治疗,但容易被误诊导致患者反复就诊治疗,承担不必要的精神和经济负担。近年来有报道本病可合并多种疾病,诊断较困难,从而对持续性黄疸难以解释,并且患者可在中老年时期就诊,而不是在青少年好发时期,容易遗漏该疾病导致误诊。本文对DJS的发病机制、临床特点及近年来的诊断方法等作一综述。
Dubin-Johnson syndrome(DJS) is a rare autosomal recessive disease caused by deficiency of the canalicular multi-specific organic anionic transporter(CMOAT) protein.The consequent impairment of conjugated bilirubin secretion into the bile results in hyperbilirubinemia,and the manifestation is black pigment depositing in liver cells under microscope and black liver from macroscopy.However,DJS appears to be a benign disease and no specific treatment has been developed.Misdiagnosis of DJS is common and patients frequently experience repeated visits to physicians during which they undergo a battery of unnecessary clinical testing.This situation may be further complicated by concomitant diseases,which are only recently being recognized and may be the primary etiology or a promoting factor for the patient's prolonged jaundice.Moreover,the patients who tend to present to clinic during middle and old age which is the rare morbidity age can be easily misdiagnosed.As the disease can be easily ignored.In this review,we summarize the known information regarding DJS pathogenesis,clinical characteristics,and diagnostic methods in order to improve physicians' awareness of the disease.
Dubin-Johnson syndrome(DJS) is a rare autosomal recessive disease caused by deficiency of the canalicular multi-specific organic anionic transporter(CMOAT) protein.The consequent impairment of conjugated bilirubin secretion into the bile results in hyperbilirubinemia,and the manifestation is black pigment depositing in liver cells under microscope and black liver from macroscopy.However,DJS appears to be a benign disease and no specific treatment has been developed.Misdiagnosis of DJS is common and patients frequently experience repeated visits to physicians during which they undergo a battery of unnecessary clinical testing.This situation may be further complicated by concomitant diseases,which are only recently being recognized and may be the primary etiology or a promoting factor for the patient's prolonged jaundice.Moreover,the patients who tend to present to clinic during middle and old age which is the rare morbidity age can be easily misdiagnosed.As the disease can be easily ignored.In this review,we summarize the known information regarding DJS pathogenesis,clinical characteristics,and diagnostic methods in order to improve physicians' awareness of the disease.
引文
[1]Dubin I,Johnson F.Chronic idiopathic jaundice with unidentifiedpig-ment in liver cells:a new clinicopathologic entity with a reportof 12 cases[J].Medicine(Baltimore),1954,33(3):155-197.
[2]Paulusma CC,Kool M,Bosma PJ,et al.A mutation in the humancanalicular multispecific organic anion transporter gene causes theDubin-Johnson syndrome[J].Hepatology,1997,25(6):1539-1542.
[3]Gan Y,Zheng HF,Zhu SR,et al.Clinical features of Dubin-Johnson syndrome[J].Chin Gen Pract,2011,14(18):2089-2090.(in Chinese)甘雨,张鸿飞,朱世殊,等.Dubin-Johnson综合征临床特点分析[J].中国全科医学,2011,14(18):2089-2090.
[4]Strassburg CP.Hyperbilirubinemiasyndromes(Gilbert-Meulen-gracht,Crigler-Najjar,Dubin-Johnson,and Rotor syndrome)[J].Best Pract Res Clin Gastroenterol,2010,24(5):555-571.
[5]Guo CJ,Lin SR,LI YN.Diagnosis and differential diagnosis of Du-bin-Johnson syndrome[J].J Beijing Med Univ,2000,32(2):128-130.(in Chinese)郭长吉,林三仁,李益农.腹腔镜和肝活检对Dubin-Johnson综合征诊断的价值[J].北京医科大学学报,2000,32(2):128-130.
[6]Uchiumi T,Tanamachi H,Kuchiwaki K.Mutation and functionalanalysis of ABCC2/multidrug resistance protein 2 in a Japanese pa-tient with Dubin-Johnson syndrome[J].Hepatol Res,2012,Oct10.[Epub ahead of print]
[7]Paumgartner G.Biliary physiology and disease:reflections of a phy-sician-scientist[J].Hepatology,2010,51(4):1095-1106.
[8]Benz-de Bretagne I,Respaud R,Vourc'h P,et al.Urinary elimi-nation of coproporphyrins is dependent on ABCC2 polymorphismsand represents a potential biomarker of MRP2 activity in humans[J].J Biomed Biotechnol,2011,2011:498757.
[9]FranK M,Doss MO.Relevance of urinarycoproporphyrin isomers inhereditary hyperbilirubinemias[J].Clin Biochem,1989,22(3):221-222.
[10]Sun YL,Zhao JM,Xin SJ.Chinical and patologilal features of pa-tients with hereditary disorders of bilirubin metabolism[J].InfectDis Inf,2008,21(5),287-290.(in Chinese)孙艳玲,赵景民,辛绍杰.几种主要的先天性胆红素代谢障碍性肝病的临床及病理研究[J].传染病信息,2008,21(5):287-290.
[11]Cebecauerova D,Jirasek T,Budisova L,et al.Dual hereditaryjaundice:simultaneous occurrence of mutations causing gilbert’sand dubin-Johnson syndrome[J].Gastroenterology,2005,129(1):315-320.
[12]Bosia JD,D'Ascenzo MV,Borzi S.The Dubin-Johnson syn-drome:case report and review of literature[J].Acta GastroenterolLatinoam,2008,38(3):194-198.
[13]Nies AT,Keppler D.The apical conjugate efflux pump ABCC2(MRP2)[J].Pflugers Arch,2007,453(5):643-659.
[14]Swartz HM,Chen K,Roth JA.Further evidence that the pigment inthe DubinJohnson syndrome is not melanin[J].Pigment Cell Res,1987,1(2):69-75.
[15]Fabris L,Cadamuro M,Okolicsanyi L.The patient presenting withisolated hyperbilirubinemia[J].Dig Liver Dis,2009,41(6):375-381.
[16]Kobayashi Y,Ishihara T,Wada M,et al.Dubin-Johnson-likeblack liver with normal bilirubin level[J].J Gastroenterol,2004,39(9):892-895.
[17]Kazama-Saegusa S,Kazama JJ,Sugaya H,et al.A case of lateonset primary hyperoxaluria type I(PH-I)presented with blackliver[J].Clin Nephrol,1998,50(3):184-187.
[18]Mahtab MA,Karim MF,Rahman S,et al.Dubin-Johnson syn-drome with systemic lupus erythematosus:a case report[J].Hepa-tobiliary Pancreat Dis Int,2006,5(4):617-619.
[19]Bosia JD,D'Ascenzo MV,Borzi S,et al.The Dubin-Johnsonsyndrome:case report and review of literature[J].Acta Gastroen-terol Latinoam,2008,38(3):194-198.
[20]Ra SH,Sung SY,Jung HY,et al.A case of sustained cholestasiscaused by acute a viral hepatitis in Dubin-Johnson Syndrome[J].Korean J Gastroenterol,2012,59(4):313-316.
[21]Korkmaz U,Duman AE,Og¨u¨tmen KoζD,et al.Severe jaundicedue to coexistence of Dubin-Johnson syndrome and hereditaryspherocytosis:a case report.[J].Turk J Gastroenterol,2011,22(4):422-425.
[22]Zuo LY.Dubin-Johnson syndrome complicated with chronic hepa-titis B:a report of one case[J].J Clin Hepatol,2007,23(4):320.(in Chinese)左凌云.Dubin-Johnson综合征合并慢性乙型肝炎1例[J].临床肝胆病杂志,2007,23(4):320.
[23]Hrebícek M,Jirásek T,HartmannováH,et al.Rotor-type hyper-bilirubinaemia has no defect in the canalicular bilirubin export pump[J].Liver Int,2007,27(4):485-491.
[24]Yan YD,Li J.Clinical analysis of seven cases of Dubin-Johnsonsyndrome[C].Proceedings of the 9th National Academic Confer-ence on Infectious Diseases organized by Chinese Medical Associa-tion,2006.(in Chinese)严友德,李军.Dubin-Johnson综合征7例临床分析[C].中华医学会全国第九次感染病学学术会议论文汇编,2006.
[2]Paulusma CC,Kool M,Bosma PJ,et al.A mutation in the humancanalicular multispecific organic anion transporter gene causes theDubin-Johnson syndrome[J].Hepatology,1997,25(6):1539-1542.
[3]Gan Y,Zheng HF,Zhu SR,et al.Clinical features of Dubin-Johnson syndrome[J].Chin Gen Pract,2011,14(18):2089-2090.(in Chinese)甘雨,张鸿飞,朱世殊,等.Dubin-Johnson综合征临床特点分析[J].中国全科医学,2011,14(18):2089-2090.
[4]Strassburg CP.Hyperbilirubinemiasyndromes(Gilbert-Meulen-gracht,Crigler-Najjar,Dubin-Johnson,and Rotor syndrome)[J].Best Pract Res Clin Gastroenterol,2010,24(5):555-571.
[5]Guo CJ,Lin SR,LI YN.Diagnosis and differential diagnosis of Du-bin-Johnson syndrome[J].J Beijing Med Univ,2000,32(2):128-130.(in Chinese)郭长吉,林三仁,李益农.腹腔镜和肝活检对Dubin-Johnson综合征诊断的价值[J].北京医科大学学报,2000,32(2):128-130.
[6]Uchiumi T,Tanamachi H,Kuchiwaki K.Mutation and functionalanalysis of ABCC2/multidrug resistance protein 2 in a Japanese pa-tient with Dubin-Johnson syndrome[J].Hepatol Res,2012,Oct10.[Epub ahead of print]
[7]Paumgartner G.Biliary physiology and disease:reflections of a phy-sician-scientist[J].Hepatology,2010,51(4):1095-1106.
[8]Benz-de Bretagne I,Respaud R,Vourc'h P,et al.Urinary elimi-nation of coproporphyrins is dependent on ABCC2 polymorphismsand represents a potential biomarker of MRP2 activity in humans[J].J Biomed Biotechnol,2011,2011:498757.
[9]FranK M,Doss MO.Relevance of urinarycoproporphyrin isomers inhereditary hyperbilirubinemias[J].Clin Biochem,1989,22(3):221-222.
[10]Sun YL,Zhao JM,Xin SJ.Chinical and patologilal features of pa-tients with hereditary disorders of bilirubin metabolism[J].InfectDis Inf,2008,21(5),287-290.(in Chinese)孙艳玲,赵景民,辛绍杰.几种主要的先天性胆红素代谢障碍性肝病的临床及病理研究[J].传染病信息,2008,21(5):287-290.
[11]Cebecauerova D,Jirasek T,Budisova L,et al.Dual hereditaryjaundice:simultaneous occurrence of mutations causing gilbert’sand dubin-Johnson syndrome[J].Gastroenterology,2005,129(1):315-320.
[12]Bosia JD,D'Ascenzo MV,Borzi S.The Dubin-Johnson syn-drome:case report and review of literature[J].Acta GastroenterolLatinoam,2008,38(3):194-198.
[13]Nies AT,Keppler D.The apical conjugate efflux pump ABCC2(MRP2)[J].Pflugers Arch,2007,453(5):643-659.
[14]Swartz HM,Chen K,Roth JA.Further evidence that the pigment inthe DubinJohnson syndrome is not melanin[J].Pigment Cell Res,1987,1(2):69-75.
[15]Fabris L,Cadamuro M,Okolicsanyi L.The patient presenting withisolated hyperbilirubinemia[J].Dig Liver Dis,2009,41(6):375-381.
[16]Kobayashi Y,Ishihara T,Wada M,et al.Dubin-Johnson-likeblack liver with normal bilirubin level[J].J Gastroenterol,2004,39(9):892-895.
[17]Kazama-Saegusa S,Kazama JJ,Sugaya H,et al.A case of lateonset primary hyperoxaluria type I(PH-I)presented with blackliver[J].Clin Nephrol,1998,50(3):184-187.
[18]Mahtab MA,Karim MF,Rahman S,et al.Dubin-Johnson syn-drome with systemic lupus erythematosus:a case report[J].Hepa-tobiliary Pancreat Dis Int,2006,5(4):617-619.
[19]Bosia JD,D'Ascenzo MV,Borzi S,et al.The Dubin-Johnsonsyndrome:case report and review of literature[J].Acta Gastroen-terol Latinoam,2008,38(3):194-198.
[20]Ra SH,Sung SY,Jung HY,et al.A case of sustained cholestasiscaused by acute a viral hepatitis in Dubin-Johnson Syndrome[J].Korean J Gastroenterol,2012,59(4):313-316.
[21]Korkmaz U,Duman AE,Og¨u¨tmen KoζD,et al.Severe jaundicedue to coexistence of Dubin-Johnson syndrome and hereditaryspherocytosis:a case report.[J].Turk J Gastroenterol,2011,22(4):422-425.
[22]Zuo LY.Dubin-Johnson syndrome complicated with chronic hepa-titis B:a report of one case[J].J Clin Hepatol,2007,23(4):320.(in Chinese)左凌云.Dubin-Johnson综合征合并慢性乙型肝炎1例[J].临床肝胆病杂志,2007,23(4):320.
[23]Hrebícek M,Jirásek T,HartmannováH,et al.Rotor-type hyper-bilirubinaemia has no defect in the canalicular bilirubin export pump[J].Liver Int,2007,27(4):485-491.
[24]Yan YD,Li J.Clinical analysis of seven cases of Dubin-Johnsonsyndrome[C].Proceedings of the 9th National Academic Confer-ence on Infectious Diseases organized by Chinese Medical Associa-tion,2006.(in Chinese)严友德,李军.Dubin-Johnson综合征7例临床分析[C].中华医学会全国第九次感染病学学术会议论文汇编,2006.