Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the p...Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates,mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes.Several inherited disorders characterised by impaired bilirubin conjugation(Crigler-Najjar syndrome typeⅠand typeⅡ,Gilbert syndrome)or transport(Dubin-Johnson and Rotor syndrome)result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type.Moreover,disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders.In this review,we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome.The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood,from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3.OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs,such as the intestine and kidney,and for a number of endogenous compounds,xenobiotics and drugs.Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins,sartans,methotrexate or rifampicin.The liverblood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.展开更多
Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress.Dubin-Johnson syndrome is a rare,autosomal recessive,inherited disorder characteriz...Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress.Dubin-Johnson syndrome is a rare,autosomal recessive,inherited disorder characterized by biphasic,predominantly conjugatedhyperbilirubinemia with no progression to end-stage liver disease.The molecular basis in Dubin-Johnson syndrome is absence or deficiency of human canalicular multispecific organic anion transporter MRP2/cMOAT caused by homozygous or compound heterozygous mutation(s) in ABCC2 located on chromosome 10q24.Clinical onset of the syndrome is most often seen in the late teens or early adulthood.In this report,we describe a case of previously unrecognized Dubin-Johnson syndrome caused by two novel pathogenic mutations (c.2360_2366delCCCTGTC and c.3258+1G>A),coinciding with cholestatic liver disease in an 82-year-old male patient.The patient,suffering from advanced atherosclerosis with serious involvement of coronary arteries,developed colorectal cancer with nodal metastases.The subsequent findings do not support the protective role of Dubin-Johnson type hyperbilirubinemia.展开更多
AIM: To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.METHODS: The sustained virological response(SVR) rate, IL28 B geno...AIM: To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.METHODS: The sustained virological response(SVR) rate, IL28 B genotype, IFNL4 genotype, initial viral load(IVL) and other pretreatment variables in 39 endstage renal disease patients(ESRD) on maintenance haemodialysis(HD) infected with hepatitis C virus(HCV), genotype 1b, were compared with a control group of 109 patients with normal kidney function treated within the same period. All the patients were treatment nave and had well compensated liver disease. The ESRD patients received 135 μg of PEGylated interferon α-2a(Peg IFN-α) weekly and a reduced dose of ribavirin(RBV) was administered to 23/39 patients with an initial haemoglobin level > 10 g/d L. Control group patients were given standard doses of Peg IFN-α and RBV. SVR was assessed as HCV RNA negativity 24 wk post-treatment. A t-test or ANOVA were used for comparisons of the means and a χ2 testcompared the frequencies.Logistic regression was used to determine significant predictors of SVR.Cutoff values for continuous variables were obtained from Receiver Operating Characteristic analysis.RESULTS:The distribution of IL28B rs12979860 CC,CT and TT genotypes in the ESRD group was 28.2%,64.1%and 7.7%,respectively,and 19.3%,62.4%and18.3%in the controls.The IFNL4 genotype was in almost absolute linkage disequlibrium with IL28B.The proportion of patients with a low IVL(<600000 IU/m L)was significantly higher in the ESRD group than in the controls(28/39,71.8%vs 51/109,46.8%,P=0.009),as was the proportion of patients with low IVL in IL28B CC carriers compared with non-CC carriers in the ESRD group(10/11,90.9%vs 18/28,64.3%,P=0.0035).This difference was not found in the controls(7/22,31.8%vs 44/87,50.6%,P=0.9).The overall SVR rate was 64.1%(25/39)in the ESRD group and 50.5%(55/109)in the control group(P=0.19).11/11(100%)and 19/22(86.4%)IL28B CC patients achieved SVR in the ESRD and control groups,respectively.A statistically significant association between SVR and IL28B and IFNL4 variants was found in both groups.The ESRD patients who achieved SVR showed the lowest IVL[median 21000,interquartile range(IQR):6000-23000IU/m L],compared with ESRD individuals without SVR(1680000,IQR:481000-6880000,P=0.001),controls with SVR(387000,IQR:111000-1253000)and controls without SVR(905000,IQR:451000-3020000).In ESRD,an IVL<600000 IU/m L was strongly associated with SVR:24/28(85.7%)patients who achieved SVR had viraemia below this threshold.CONCLUSION:Haemodialysis decreases the viral load,especially in IL28B CC genotype carriers.A low IVL was the strongest predictor of SVR in ESRD patients identified in multivariate analysis.展开更多
Progressive familial intrahepatic cholestasis （PFIC） type 2 is caused by mutations in ABCB11, which encodes bile salt export pump （BSEP）. We report a Thai female infant who presented with progressive cholestatic j...Progressive familial intrahepatic cholestasis （PFIC） type 2 is caused by mutations in ABCB11, which encodes bile salt export pump （BSEP）. We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum y-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11, a four-nucleotide deletion in exon 3, c.90_93delGAAA, and a single-nucleotide insertion in exon 5, c.249_250insT, were identified, with confirmation in her parents. These mutations were predicted to lead to synthesis of truncated forms of BSEP. Immunostaining and mutation analysis thus established the diagnosis of PFIC type展开更多
AIM:To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficie...AIM:To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency.METHODS:Mutational analysis of ABCB4,screening for copy number variations by multiplex ligation-dependent probe amplification,genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome(LPAC,OMIM#600803)and in 5young females with suspected LPAC and their families(5 probands,15 additional family members).The probands came to medical attention for contraceptiveassociated intrahepatic cholestasis.RESULTS:A possibly pathogenic variant of ABCB4was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4.Among these 16,however,none developed gallstones in childhood.In 5index patients,all young females carrying at least one pathogenic mutation in one allele of ABCB4,manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives.Variants ABCB11c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC.CONCLUSION:Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied topediatric patients with idiopathic gallstones.Sexual immaturity even prevents manifestation of LPAC.展开更多
基金Supported by The Project(Ministry of Health,Czech Republic)for Development of Research Organization 00023001(IKEM,Prague,Czech Republic),Institutional support
文摘Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates,mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes.Several inherited disorders characterised by impaired bilirubin conjugation(Crigler-Najjar syndrome typeⅠand typeⅡ,Gilbert syndrome)or transport(Dubin-Johnson and Rotor syndrome)result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type.Moreover,disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders.In this review,we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome.The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood,from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3.OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs,such as the intestine and kidney,and for a number of endogenous compounds,xenobiotics and drugs.Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins,sartans,methotrexate or rifampicin.The liverblood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
基金Supported by The Project(Ministry of Health,Czech Republic)for Development of Research Organization00023001(IKEM,Prague,Czech Republic)-Institutional supportthe grant SVV-2012-264502
文摘Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress.Dubin-Johnson syndrome is a rare,autosomal recessive,inherited disorder characterized by biphasic,predominantly conjugatedhyperbilirubinemia with no progression to end-stage liver disease.The molecular basis in Dubin-Johnson syndrome is absence or deficiency of human canalicular multispecific organic anion transporter MRP2/cMOAT caused by homozygous or compound heterozygous mutation(s) in ABCC2 located on chromosome 10q24.Clinical onset of the syndrome is most often seen in the late teens or early adulthood.In this report,we describe a case of previously unrecognized Dubin-Johnson syndrome caused by two novel pathogenic mutations (c.2360_2366delCCCTGTC and c.3258+1G>A),coinciding with cholestatic liver disease in an 82-year-old male patient.The patient,suffering from advanced atherosclerosis with serious involvement of coronary arteries,developed colorectal cancer with nodal metastases.The subsequent findings do not support the protective role of Dubin-Johnson type hyperbilirubinemia.
基金Supported by The Internal Grant Agency of Ministry of Health of the Czech Republic,No.NT/11235-5
文摘AIM: To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.METHODS: The sustained virological response(SVR) rate, IL28 B genotype, IFNL4 genotype, initial viral load(IVL) and other pretreatment variables in 39 endstage renal disease patients(ESRD) on maintenance haemodialysis(HD) infected with hepatitis C virus(HCV), genotype 1b, were compared with a control group of 109 patients with normal kidney function treated within the same period. All the patients were treatment nave and had well compensated liver disease. The ESRD patients received 135 μg of PEGylated interferon α-2a(Peg IFN-α) weekly and a reduced dose of ribavirin(RBV) was administered to 23/39 patients with an initial haemoglobin level > 10 g/d L. Control group patients were given standard doses of Peg IFN-α and RBV. SVR was assessed as HCV RNA negativity 24 wk post-treatment. A t-test or ANOVA were used for comparisons of the means and a χ2 testcompared the frequencies.Logistic regression was used to determine significant predictors of SVR.Cutoff values for continuous variables were obtained from Receiver Operating Characteristic analysis.RESULTS:The distribution of IL28B rs12979860 CC,CT and TT genotypes in the ESRD group was 28.2%,64.1%and 7.7%,respectively,and 19.3%,62.4%and18.3%in the controls.The IFNL4 genotype was in almost absolute linkage disequlibrium with IL28B.The proportion of patients with a low IVL(<600000 IU/m L)was significantly higher in the ESRD group than in the controls(28/39,71.8%vs 51/109,46.8%,P=0.009),as was the proportion of patients with low IVL in IL28B CC carriers compared with non-CC carriers in the ESRD group(10/11,90.9%vs 18/28,64.3%,P=0.0035).This difference was not found in the controls(7/22,31.8%vs 44/87,50.6%,P=0.9).The overall SVR rate was 64.1%(25/39)in the ESRD group and 50.5%(55/109)in the control group(P=0.19).11/11(100%)and 19/22(86.4%)IL28B CC patients achieved SVR in the ESRD and control groups,respectively.A statistically significant association between SVR and IL28B and IFNL4 variants was found in both groups.The ESRD patients who achieved SVR showed the lowest IVL[median 21000,interquartile range(IQR):6000-23000IU/m L],compared with ESRD individuals without SVR(1680000,IQR:481000-6880000,P=0.001),controls with SVR(387000,IQR:111000-1253000)and controls without SVR(905000,IQR:451000-3020000).In ESRD,an IVL<600000 IU/m L was strongly associated with SVR:24/28(85.7%)patients who achieved SVR had viraemia below this threshold.CONCLUSION:Haemodialysis decreases the viral load,especially in IL28B CC genotype carriers.A low IVL was the strongest predictor of SVR in ESRD patients identified in multivariate analysis.
文摘Progressive familial intrahepatic cholestasis （PFIC） type 2 is caused by mutations in ABCB11, which encodes bile salt export pump （BSEP）. We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum y-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11, a four-nucleotide deletion in exon 3, c.90_93delGAAA, and a single-nucleotide insertion in exon 5, c.249_250insT, were identified, with confirmation in her parents. These mutations were predicted to lead to synthesis of truncated forms of BSEP. Immunostaining and mutation analysis thus established the diagnosis of PFIC type
基金The project (Ministry of Health,Czech Republic) for development of research organization 00023001 (IKEM,Prague,Czech Republic) - Institutional support PRVOUK-P24/LF1/3 and MH CZ - DRO VFN64165 to Dvorakova L and Hrebicek M
文摘AIM:To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency.METHODS:Mutational analysis of ABCB4,screening for copy number variations by multiplex ligation-dependent probe amplification,genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome(LPAC,OMIM#600803)and in 5young females with suspected LPAC and their families(5 probands,15 additional family members).The probands came to medical attention for contraceptiveassociated intrahepatic cholestasis.RESULTS:A possibly pathogenic variant of ABCB4was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4.Among these 16,however,none developed gallstones in childhood.In 5index patients,all young females carrying at least one pathogenic mutation in one allele of ABCB4,manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives.Variants ABCB11c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC.CONCLUSION:Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied topediatric patients with idiopathic gallstones.Sexual immaturity even prevents manifestation of LPAC.
