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.
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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