Background & Aims: Dubin- Johnson syndrome is recessively inherited, conjugated hyperbilirubinemia induced by mutations in the ABCC2/MRP2 gene encoding the canali- cular transporter for conjugated bilirubin. Gilb...Background & Aims: Dubin- Johnson syndrome is recessively inherited, conjugated hyperbilirubinemia induced by mutations in the ABCC2/MRP2 gene encoding the canali- cular transporter for conjugated bilirubin. Gilbert’ s syndrome is recessively inherited, unconjugated hyperbilirubinemia caused by decreased conjugation rate of bilirubin associated mostly with homozygous A(TA)7TAA variant of the TATAA- box in the UGT1A1 gene promoter. Our aim was to establish the molecular diagnosis in a 3- year- old male with atypical, intermittent, predominantly unconjugated, hyperbilirubinemia. Methods: 99mTc- HIDA cholescintigraphy was used for imaging the biliary tree. Expression of ABCC2/MRP2 protein in hepatocytes was investigated immunohistochemically. UGT1A1 and ABCC2/ MRP2 genes were sequenced from genomic DNA, and the mutations were verified by fragment analysis, sequencing the cloned exons, and restriction fragment length polymorphism. Results: Cholescintigraphy revealed delayed visualization of the gallbladder. A brown granular lipopigment differing from melanin- like pigment reported in Dubin- Johnson syndrome was present in hepatocytes, but, otherwise, liver histology was normal. ABCC2/MRP2 protein was not detected on the canalicular membrane of hepatocytes, and 2 novel mutations were found in the ABCC2/MRP2 gene: a heterozygous in- frame insertion deletion mutation 1256insCT/delAAACAGTGAACCTGATG in exon 10 inherited from the father and a heterozygous deletion 4292delCA in exon 30 inherited from the mother. In addition, the patient was homozygous for - 3279T > G and A(TA)7TAA mutations in the UGT1A1 gene promoter. Conclusions: Our patient represents a case of digenicmixed hyperbilirubinemia - a distinct type of constitutive jaundice resulting from coinherited defects in ABCC2/MRP2 and UGT1A1 genes.展开更多
Background/Aims: Artificial liver support represents a potentially useful option for the treatment of severe liver failure. A sufficient ‘ dose’ might be crucial for such treatments to provide a survival benefit. Th...Background/Aims: Artificial liver support represents a potentially useful option for the treatment of severe liver failure. A sufficient ‘ dose’ might be crucial for such treatments to provide a survival benefit. The aim of this study was to compare in vivo efficiency and resulting delivered treatment dose of two commercially available devices that use different therapeutic principles: albumin dialysis (AD, MARS ) and fractionated plasma separation (FPS, Prometheus ). Methods: Eight patients with acute-on-chronic liver failure were treated alternately with AD and FPS. Thirty-two treatments at identical blood and dialysate flow rates were evaluated. Clearance and reduction ratio (a measure of delivered treatment dose)were compared for bilirubin subfractions, ammonia and urea. Results: FPS achieved significantly higher clearance for all measured protein-bound and water-soluble markers. This resulted in significantly higher reduction ratios for FPS compared to AD. Unconjugated bilirubin, a marker for strongly albumin-bound toxins, was influenced only by FPS. Conclusions: FPS provided a higher delivered treatment dose than a matching treatment with AD. Reduction ratios of bilirubin and urea should be reported in clinical studies on liver dialysis, since delivered dose is likely to be linked to the clinical effectiveness of extracorporeal liver support therapies.展开更多
文摘Background & Aims: Dubin- Johnson syndrome is recessively inherited, conjugated hyperbilirubinemia induced by mutations in the ABCC2/MRP2 gene encoding the canali- cular transporter for conjugated bilirubin. Gilbert’ s syndrome is recessively inherited, unconjugated hyperbilirubinemia caused by decreased conjugation rate of bilirubin associated mostly with homozygous A(TA)7TAA variant of the TATAA- box in the UGT1A1 gene promoter. Our aim was to establish the molecular diagnosis in a 3- year- old male with atypical, intermittent, predominantly unconjugated, hyperbilirubinemia. Methods: 99mTc- HIDA cholescintigraphy was used for imaging the biliary tree. Expression of ABCC2/MRP2 protein in hepatocytes was investigated immunohistochemically. UGT1A1 and ABCC2/ MRP2 genes were sequenced from genomic DNA, and the mutations were verified by fragment analysis, sequencing the cloned exons, and restriction fragment length polymorphism. Results: Cholescintigraphy revealed delayed visualization of the gallbladder. A brown granular lipopigment differing from melanin- like pigment reported in Dubin- Johnson syndrome was present in hepatocytes, but, otherwise, liver histology was normal. ABCC2/MRP2 protein was not detected on the canalicular membrane of hepatocytes, and 2 novel mutations were found in the ABCC2/MRP2 gene: a heterozygous in- frame insertion deletion mutation 1256insCT/delAAACAGTGAACCTGATG in exon 10 inherited from the father and a heterozygous deletion 4292delCA in exon 30 inherited from the mother. In addition, the patient was homozygous for - 3279T > G and A(TA)7TAA mutations in the UGT1A1 gene promoter. Conclusions: Our patient represents a case of digenicmixed hyperbilirubinemia - a distinct type of constitutive jaundice resulting from coinherited defects in ABCC2/MRP2 and UGT1A1 genes.
文摘Background/Aims: Artificial liver support represents a potentially useful option for the treatment of severe liver failure. A sufficient ‘ dose’ might be crucial for such treatments to provide a survival benefit. The aim of this study was to compare in vivo efficiency and resulting delivered treatment dose of two commercially available devices that use different therapeutic principles: albumin dialysis (AD, MARS ) and fractionated plasma separation (FPS, Prometheus ). Methods: Eight patients with acute-on-chronic liver failure were treated alternately with AD and FPS. Thirty-two treatments at identical blood and dialysate flow rates were evaluated. Clearance and reduction ratio (a measure of delivered treatment dose)were compared for bilirubin subfractions, ammonia and urea. Results: FPS achieved significantly higher clearance for all measured protein-bound and water-soluble markers. This resulted in significantly higher reduction ratios for FPS compared to AD. Unconjugated bilirubin, a marker for strongly albumin-bound toxins, was influenced only by FPS. Conclusions: FPS provided a higher delivered treatment dose than a matching treatment with AD. Reduction ratios of bilirubin and urea should be reported in clinical studies on liver dialysis, since delivered dose is likely to be linked to the clinical effectiveness of extracorporeal liver support therapies.
