Partial external biliary diversion in bile salt export pump deficiency: Association between outcome and mutation

To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency. METHODSMutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [3H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays. RESULTSA girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients’ native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute, respectively. CONCLUSIONIn summary, our findings suggest that residual function of BSEP as well as substrate specificity influence the therapeutic effectiveness of PEBD in progressive familial intrahepatic cholestasis type 2 (PFIC-2).

Vitamin E treatment for children with chronic hepatitis B:A randomized placebo controlled trial

AIM:To evaluate the safety and efficacy of vitamin E in children with chronic hepatitis B.METHODS:We randomly assigned patients with chronic hepatitis B,positive for hepatitis B e antigen(HBeAg),to receive either vitamin E or placebo once daily for 6 mo in a 3:1 ratio and double-blind manner.The primary end point was HBeAg seroconversion,defined as the loss of HBeAg,undetectable levels of serum hepatitis B virus DNA,and the appearance of antibodies against HBeAg 12 mo after therapy.RESULTS:At baseline visit,49 patients had normal and 43 had increased serum aminotransferase levels.Twenty-nine patients did not respond to previous treatment with interferon-α or lamivudine.Seventy-six children completed the study;16 were non-compliant(n = 7),lost to follow-up(n = 7),or started another antiviral treatment(n = 3).Intention-to-treat analysis showed HBeAg seroconversion in 16 children(23.2%) treated with vitamin E and two(8.7%) in the placebo group(P = 0.13).Vitamin E was well tolerated.CONCLUSION:There is only a tendency that vitamin E may promote HBeAg seroconversion.Therefore larger studies are needed to clarify the role of antioxidants in the therapy of chronic hepatitis B.