Tag Archives: BSEP

Dr. William Balistreri: Whatever Happened to Neonatal Hepatitis (Part 2)

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Recently Dr. Balistreri gave our group an excellent lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

Key Points:

  • Producing enough bile acids and recycling bile acids in enterohepatic circulation is crucial for bile acid flow. In addition, there are ‘good’ bile acids like cholic acid that have trophic properties and ‘bad’ bile acids like lithocholic acid that cause liver toxicity
  • In addition to defects in the metabolic pathway of bile acids, discoveries identified defects in the membrane transporters (eg. FIC1, BSEP, MDR3), trafficking proteins (eg. MYO5B, VPS33B), nuclear control receptors (eg. FXR), and tight junction proteins (eg. TJP2). Tight junction protein defects are associated with bile leakage from bile canaliculus
  • Alagille syndrome, a disorder of embryogenesis, related to JAG1-NOTCH2 signaling pathways affects organs throughout the body
  • Many of these genetic mutations are now being identified in adults with unexplained liver diseases (eg. intrahepatic cholestasis of pregnancy and cryptogenic cirrhosis)
  • Cholestasis panels and whole exome sequencing are important tools
  • Ileal bile acid transporter (IBAT) inhibitors have emerged as important therapies for conditions like Alagille which were previously treated with biliary diversion

Cholestasis Evaluation:

See blog post: Identifying Biliary Atresia in Infants: New Guidelines

Baby with Carbamoyl-phosphate synthetase 1 (CPS1) deficiency (urea cycle defect)

My take: This lecture really shows how the field of pediatric liver disease has been a puzzle. Now one can see how almost all of the pieces of the puzzle work together.

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How Progressive Familial Intrahepatic Cholestasis (PFIC) Recurs After Liver Transplantation

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A recent case-report study (D Krebs-Schmitt et al. JPGN 2019; 68: 169-74) describes how progressive familial intrahepatic cholestasis (PFIC) due to bile salt export pump (BSEP) deficiency can recur after liver transplantation.

BSEP deficiency due to mutations in ABCB11 gene causes the development of PFIC type 2.  In this case report, the authors describe recurrence of BSEP-deficiency following liver transplantaion in 3 patients.

Key points:

  • Following liver transplantation, patients with PFIC 2 can develop antibodies to BSEP as this antigen was not present in the pretransplant period.  Since initial reports, more than 20 patients have been described. “In most of these cases, intensifying the immunosuppression led to normalization of graft function.”
  • In this case report, the 3 patients ultimately required retransplantation due to recurrent disease and one patient died (following retransplantation). One patient also received stem cell transplantation after a complicated course.

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Georgia Aquarium

Emerging Treatment for PFIC-2

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A great example of “bench to bedside” research was recently published (J Pediatr 2014; 164: 1219-27). While this research involved treatment of a rare condition, progressive familial intrahepatic cholestasis type 2 (PFIC2), the way the authors used a series of convincing experiments to determine the effect of a new medication shows how important a single patient can be in advancing medical treatment.  For PFIC2, the implications of this study are more direct since there are no established medications.

Previous experimental evidence has indicated that 4-phenylbutyrate (4PB), a drug used to treat ornithine transcarbamylase deficiency (OTCD), can increase the expression of the bile salt export pump (BSEP). Since BSEP, encoded by ABCB11 gene, is defective in PFIC2, the authors sought to determine whether 4PB would be effective for patients with PFIC2 who showed a reduced (but not absent) BSEP expression.

They identified a jaundiced infant female at 2 months of age with normal GGT who was diagnosed with PFIC2 due to the presence of the c.3692G>A (p.R1231Q) mutation in both alleles of ABCB11.

The authors then treated this infant with 200 mg/kg/day (into 4 doses a day) with 4PB; gradually the dosage was increased to 500 mg/kg/day.  The authors performed elegant in vitro studies from genomic DNA from peripheral leukocytes along with histologic studies from liver biopsy specimens.

Key Findings:

At the 500 mg/kg/day dosage, BSEP expression at the canalicular membrane was partially restored and this coincided with improved liver tests, improved liver histology, and relief of pruritus.

Conclusion: 4PB retards degradation of the canalicular BSEP which resulted in biochemical and histologic improvement.  This study involved only one patient; thus, further studies will be needed.

Related blog post:

BRIC, PFIC, and nasobiliary drainage | gutsandgrowth