Targeted Therapy for PFIC type 2

Progressive Familial Intrahepatic Cholestasis, type 2, (PFIC2) is due to decrease (or absent) function of the bile salt export pump (BSEP) encoded by ABCB11 has been treated mainly in a symptomatic manner with medicines like ursodeoxycholic acid and sometimes biliary diversion.  PFIC2 has been associated with increased risk for hepatocellular carcinoma (HCC).

A recent study (E Gonzales, et al. Hepatology 2015; 62: 558-66) indicates that newer therapies targeting the specific mutation may be effective.

In this study, treatment with oral 4-phenylbutyrate (4-PB) in four patients improved pruritus, serum bile acid concentrations, and liver function tests. 4-PB is considered a chaperone drug and may partially correct mistrafficking.

The associated editorial (pg 349-50) notes that 4-PB has an unpleasant taste and requires ingestion of a large number of pills. In addition, patients with complete loss of BSEP, 4-PB will not be effective. Finally, even in patients with a clinical response, it is unclear if this will lower the risk of HCC.

A second study (S Varma et al. Hepatology 2015; 62: 198-206) retrospectively studied 22 children with PFIC2.  “Children with late-onset presentation, lower ALT, and intracellular BSEP expression are likely to respond, at least transiently, to nontransplant treatment.”  Nontransplant treatment in this cohort included ursodeoxycholic acid in 19 (10 mg/kg thrice daily) and partial biliary diversion in 3.  Higher ALT values were considered to be >165 IU/L. Another point in this study: response to treatment can be slow and take many months.

My take: These studies provide useful information about which patients with PFIC2 respond medically and introduce a new therapy, 4-PB.

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Is this really newsworthy? Perhaps next week: man with venomous snakes says they make great pets?

Perhaps next week the story will be: man with venomous snakes says they make great pets?

Emerging Treatment for PFIC-2

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.

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BRIC, PFIC, and nasobiliary drainage | gutsandgrowth