Characterization of erythrovirus B19 genomes isolated in liver tissues from patients with fulminant hepatitis and biliary atresia who underwent liver transplantation.
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BACKGROUND: Fulminant hepatitis and biliary atresia are serious problems and their causes have not been explained well. We investigated whether or not erythrovirus B19 is a candidate etiologic agent in such liver disease patients who had undergone liver transplantation. METHODS: Liver tissues from 47 patients consisted of 28 fulminant hepatitis and 19 biliary atresia were examined to detect B19 genes by PCR and further analyzed their genomic characterization. RESULTS: B19 DNA was detected by nested PCR in 10 of 28 cases (35.7%) livers in the fulminant hepatitis group and 7 of 19 (36.8%) livers in the biliary atresia group, respectively (statistically not significant). Importantly, among the 8 hepatic B19 DNA-positive patients who had paired samples of liver and serum, the serum B19 genome was detectable in only one case. B19 mRNA was identified in all of 10 fulminant hepatitis cases with hepatic B19 DNA, but only 1 out of 7 (14.3%) cases in biliary atresia tested. Furthermore, we obtained ten isolates having the B19 genome with nearly full-length sequences. Interestingly, phylogenetic analysis based on the NS1 gene revealed three different clusters: two for isolates from fulminant hepatitis and the other for isolates from biliary atresia. CONCLUSIONS: Our results presented here suggested that B19 may be an etiologic agent of fulminant hepatitis. (+info)
Living donor liver transplantation for biliary atresia.
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Biliary atresia is the most common cause of chronic cholestasis in infants and children. The incidence is estimated at 3.7:10,000 among Taiwanese infants. Kasai hepatoportoenterostomy helps children survive beyond infancy. Liver transplantation is indicated when the Kasai procedure fails to work or when patients develop progressive deterioration of liver function despite an initially successful Kasai operation. Living donor liver transplantation was developed to alleviate organ shortage from deceased donors. It has decreased the waiting time for transplantation and, therefore, improves patient survival. One hundred living donor liver transplantations have been performed for biliary atresia at Chang Gung Memorial Hospital-Kaohsiung Medical Center with both 98% 1-year and 5-year actual recipient survival. (+info)
Management of biliary atresia: experience in a single institute.
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BACKGROUND: The management of biliary atresia (BA) has evolved with time. The outcome of BA treatment in the Chang Gung Memorial Hospital-Kaohsiung Medical Center had not been recorded and we addressed this issue in this study. METHODS: Medical records of the 93 patients with BA who underwent Kasai portoenterostomy (KP) in the Chang Gung Memorial Hospital-Kaohsiung Medical Center from 1986 to 2005 were reviewed retrospectively. There were 46 male and 47 female patients included in this study. Sixty patients received KP before 60 days of age and 33 patients received KP after 60 days of age. RESULTS: Jaundice-free survival with native liver was accomplished in 29 of 60 patients who received KP before 60 days of age but in only 9 of 33 after that age (p = 0.048). Cholangitis developed in 56 patients (60.2%). Incidence of cholangitis was not significantly different between the patients free of jaundice (22/38) and those with persistent jaundice (34/55) (p = 0.704). Seven patients had single cysts and 1 had multiple cysts, with 4 being jaundice-free. Five out of 9 were free of jaundice after re-do KP. Among the 62 patients followed for more than 5 years, 32 (51.6%) survived with native liver. CONCLUSION: This study revealed that half of the patients with BA survived with their native liver for more than 5 years. Age at operation, not post-KP cholangitis or liver cysts, was the most determinant factor of BA outcome. (+info)
Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling.
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Patients with Alagille syndrome (AGS), a genetic disorder of Notch signaling, suffer from severe ductopenia and cholestasis, but progression to biliary cirrhosis is rare. Instead, in biliary atresia (BA) severe cholestasis is associated with a pronounced "ductular reaction" and rapid progression to biliary cirrhosis. Given the role of Notch in biliary development, we hypothesized that defective Notch signaling would influence the reparative mechanisms in cholestatic cholangiopathies. Thus we compared phenotype and relative abundance of the epithelial components of the hepatic reparative complex in AGS (n = 10) and BA (n = 30) using immunohistochemistry and computer-assisted morphometry. BA was characterized by an increase in reactive ductular and hepatic progenitor cells, whereas in AGS, a striking increase in intermediate hepatobiliary cells contrasted with the near absence of reactive ductular cells and hepatic progenitor cells. Hepatocellular mitoinhibition index (p21(waf1)/Ki67) was similar in AGS and BA. Fibrosis was more severe in BA, where portal septa thickness positively correlated with reactive ductular cells and hepatic progenitor cells. AGS hepatobiliary cells failed to express hepatic nuclear factor (HNF) 1beta, a biliary-specific transcription factor. These data indicate that Notch signaling plays a role in liver repair mechanisms in postnatal life: its defect results in absent reactive ductular cells and accumulation of hepatobiliary cells lacking HNF1beta, thus being unable to switch to a biliary phenotype. (+info)
Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia.
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BACKGROUND & AIMS: Lymphocytes populate the livers of infants with biliary atresia, but it is unknown whether neonatal lymphocytes regulate pathogenesis of disease. Here, we investigate this question by examining the role of T lymphocytes in the destruction of extrahepatic bile ducts of neonatal mice using an experimental model of biliary atresia. METHODS: Inoculation of neonatal mice with rhesus rotavirus followed by multistaining flow cytometry to quantify expression of interferon-gamma by hepatic lymphocytes, and real-time polymerase chain reaction for mRNA expression of pro-inflammatory cytokines. This was followed by determining the consequences of antibody-mediated depletion of lymphocyte subtypes on the development of biliary obstruction, and coculture and cell transfer experiments to investigate the effector role of lymphocyte subtypes on neonatal biliary disease. RESULTS: Rotavirus infection results in overexpression of interferon-gamma by neonatal hepatic T cells. Among these cells, depletion of CD4(+) cells did not change the course of inflammatory injury and obstruction of neonatal bile ducts. In contrast, loss of CD8(+) cells remarkably suppressed duct injury, prevented luminal obstruction, and restored bile flow. Coculture experiments showed that rotavirus-primed, but not naive, CD8(+) cells were cytotoxic to cholangiocytes. In adoptive transfer experiments, we found that primed CD8(+) cells preferentially homed to extrahepatic bile ducts of neonatal mice and invaded their epithelial lining. CONCLUSIONS: Primed neonatal CD8(+) cells can activate a pro-inflammatory program, target diseased and healthy duct epithelium, and drive the phenotypic expression of biliary atresia, thus constituting a potential therapeutic target to halt disease progression. (+info)
Oligoclonal expansions of CD4+ and CD8+ T-cells in the target organ of patients with biliary atresia.
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BACKGROUND & AIMS: Biliary atresia is an inflammatory, fibrosclerosing neonatal cholangiopathy, characterized by a periductal infiltrate composed of CD4(+) and CD8(+) T cells. The pathogenesis of this disease has been proposed to involve a virus-induced, subsequent autoreactive T cell-mediated bile duct injury. Antigen-specific T-cell immunity involves clonal expansion of T cells expressing similar T-cell receptor (TCR) variable regions of the beta-chain (Vbeta). We hypothesized that the T cells in biliary atresia tissue expressed related TCRs, suggesting that the expansion was in direct response to antigenic stimulation. METHODS: The TCR Vbeta repertoire of T cells from the liver, extrahepatic bile duct remnants, and peripheral blood of biliary atresia and other cholestatic disease controls were characterized by fluorescent-activated cell sorter analysis, and TCR junctional region nucleotide sequencing was performed on expanded TCR Vbeta regions to confirm oligoclonality. RESULTS: FACS analysis revealed Vbeta subset expansions of CD4(+) and CD8(+) T cells from the liver or bile duct remnant in all patients with biliary atresia and only 1 control. The CD4(+) TCR expansions were limited to Vbeta3, -5, -9, and -12 T-cell subsets and the CD8(+) TCR Vbeta expansions were predominantly Vbeta20. Each Vbeta subset expansion was composed of oligoclonal populations of T cells. CONCLUSIONS: Biliary atresia is associated with oligoclonal expansions of CD4(+) and CD8(+) T cells within liver and extrahepatic bile duct remnant tissues, indicating the presence of activated T cells reacting to specific antigenic stimulation. Future studies entail identifying the specific antigen(s) responsible for T-cell activation and bile duct injury. (+info)
Evidence of immune tolerance to blood group antigens in a case of ABO-incompatible pediatric liver transplantation.
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In a 12-year-old patient with blood group O, who had received a partial liver graft 10 years ago from his father with blood group A, the levels of anti-A-specific antibodies (Abs) were persistently undetectable after the transplantation, while the levels of anti-B-specific Abs gradually increased and attained a plateau. Peripheral blood mononuclear cells (PBMCs) from this patient were engrafted into NOD/SCID mouse in order to investigate the immune response to donor-type blood group antigens. Even after sensitization with blood group-A erythrocytes, no anti-A Abs were detected in the serum samples of the mouse that received PBMCs from the blood group-O recipient of group-A liver allograft, however, immunoglobulins specific for antigens other than the A antigens were produced. Thus, we provide a possible evidence of immune tolerance to blood group antigens in this ABO-incompatible pediatric liver transplantation. (+info)
Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop.
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Biliary atresia is the most common cause of end-stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30-45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune-mediated fibro-obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the center's experience, the presence of associated congenital anomalies, and the postoperative occurrence of cholangitis. A number of screening strategies in infants have been studied. The most promising are early measurements of serum conjugated bilirubin and a stool color card given to new parents that alerts them and their primary care provider to alcholic stools. This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006, in Bethesda, MD, that addressed the issues of outcomes, screening, and pathogenesis of biliary atresia. (+info)