No abstract

Combination therapy with PEG-IFN-alpha2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-alpha2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.

Severe bile salt export pump (BSEP) deficiency is a hereditary cholestatic condition that starts in infancy and leads to end-stage liver disease. Three children who underwent orthotopic liver transplantation for severe BSEP deficiency had post-transplantation episodes of cholestatic dysfunction that mimicked the original disease. Remission of all episodes was achieved by intensifying the immunosuppressive regimen. The phenotypic recurrence of the disease correlated with the presence of circulating high-titer antibodies against BSEP that inhibit transport by BSEP in vitro. When administered to rats, these antibodies targeted the bile canaliculi and impaired bile acid secretion.

No abstract

Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and bile salt export pump (BSEP) disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.