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The indications for duct-to-duct (DD) biliary reconstruction in living donor liver transplantation (LDLT) for small children are still controversial. In this study, the feasibility of DD biliary reconstruction versus Roux-en-Y (RY) biliary reconstruction was investigated in terms of long-term outcomes. Fifty-six children who consecutively underwent LDLT with a weight less than or equal to 10.0 kg were enrolled. Biliary reconstruction was performed in a DD fashion for 20 patients and in an RY fashion for 36 patients. During a minimum follow-up of 2 years, the incidence of biliary strictures was 5.0% in the DD group and 11.1% in the RY group. Cholangitis during the posttransplant period was observed in the RY group only. There were no deaths related to biliary problems. This study shows that DD reconstruction in LDLT for small children (weighing 10.0 kg or less) is a feasible option for biliary reconstruction.
© 2014 American Association for the Study of Liver Diseases.
UNLABELLED - Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and bile duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in bile duct development compared to control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the phenotype seen with Notch signaling loss alone. This phenotype is associated with significant intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to ductular proliferation and a decrease in the density of communicating peripheral bile duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1β and Sox9 (sex determining region Y-related HMG box transcription factor 9).
CONCLUSION - HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to intrahepatic bile duct development and their effect on cholestatic liver disease phenotypes.
Copyright © 2011 American Association for the Study of Liver Diseases.
Biliary obstruction in the setting of hepatic bacterial infection has great morbidity and mortality. We developed a novel murine model to examine the effect of biliary obstruction on the clearance of hepatic Escherichia coli infection. This model may allow us to test the hypothesis that biliary obstruction itself adversely affects clearance of hepatic infections even if the bacteria are introduced into the liver by a nonbiliary route. We ligated the bile ducts of C57BL/6 mice on days -1, 0, or +1, relative to a day 0 portal venous injection of E. coli. We monitored survival, hepatic bacterial growth, pathology, and IL-10 protein levels. The role of IL-10 in this model was further examined using IL-10 knockout mice. Mice with bile duct ligation at day +1 or 0, relative to portal venous infection at day 0, had decreased survival compared with mice with only portal venous infection. The impaired survival was associated with greater hepatic bacterial growth, hepatic necrosis, and increased production of IL-10. Interestingly, the transgenic knockout of IL-10 resulted in impaired survival in mice with bile duct ligation and portal venous infection. Biliary obstruction had a dramatic detrimental effect on hepatic clearance of portal venous E. coli infection. This impaired clearance is associated with increased IL-10 production. However, transgenic knockout of IL-10 increased mortality after hepatic infection.
Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD(50)) for E. coli injected into the bile duct was 50 CFU/animal; the LD(50) for E. coli injected into the portal vein was 5 x 10(7) CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.
Some liver allograft recipients with hepatitis C virus (HCV) infection develop hyperbilirubinemia, which might be the result of a cholestatic variant of hepatitis C. We evaluated all liver biopsy samples from 6 liver transplant recipients who had polymerase chain reaction-positive HCV infection and histologic evidence of hepatitis and jaundice and compared them with liver biopsy samples from a control group of transplant recipients with HCV hepatitis without jaundice. Patients with known ductopenic rejection, biliary obstruction, or co-infection with hepatitis A or B were excluded from the study. Measurement of viral titers and genomic typing were performed when possible. Six patients developed hepatitis and jaundice, with maximum bilirubin levels ranging from 5.8 to 47.6 mg/dL. In this group, 5 (83%) had moderate interface hepatitis (control group, 15%), 6 (100%) had confluent necrosis (control group, 12%), 5 (83%) had bridging fibrosis (control group, 18%), 4 (67%) had significant hepatocyte swelling (control group, 9%), 4 (67%) had prominent ductular proliferation (control group, 3%), and 6 (100%) had mild duct damage and inflammation (control group, 53%). All 6 of the patients with cholestasis had allograft failure. Of these, three allografts were available for review, which did not reveal occult obstruction, rejection, or duct loss. All patients in the control group have retained their allografts. In 4 patients with cholestasis, the median HCV RNA titer was 93.97 mEq/mL, with a mean of 54.19 mEq/mL (control mean = 5.2 mEq/mL). Five patients also underwent viral genomic typing: 2 with type 1a, 2 with type 1b, and 1 with mixed type 1a and 1b. Cholestasis in patients with posttransplantation hepatitis C may be caused by an aggressive HCV infection that exhibits histologic features of confluent necrosis, hepatocyte swelling, and/or ductular proliferation. Viral titers are often increased in such patients.
Copyright 1998 W.B. Saunders Company.
Acute self-limited liver disease has been associated with tetracycline use. However, severe prolonged cholestatic hepatitis and bile duct paucity have not been previously attributed to tetracyclines. Hepatitis, characterized by prolonged jaundice, severe pruritus, and moderate increased transaminase values, occurred within 2 months of ingesting tetracyclines in two female patients. Serum bilirubin levels normalized 12 and 34 months after tetracycline ingestion. Liver histology revealed bile duct paucity, severe cholestasis, and minimal necrosis and inflammation. Tetracyclines may infrequently induce bile duct paucity and prolonged, severe, and reversible cholestasis.
The kinetics and urinary excretion of etoposide and etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered etoposide dose was excreted in the urine as etoposide compared with 35% in controls (P = .15). Urinary excretion of etoposide glucuronide accounted for 29% of an administered etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.