Glycerol Phenylbutyrate Therapy in Progressive Familial Intrahepatic Cholestasis Type 2

To the Editor: In vitro studies have shown that sodium phenylbutyrate (PBA) can partially correct the misstrafficking of some endoplasmic reticulum–retained bile salt export pump missense mutants (1,2). In vivo studies in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients carrying such mutants and treated orally with PBA (Ammonaps) have provided encouraging results with evidence for cholestasis improvement (1,2). Because of poor palatability and presentation, PBA administration and long-term adherence may be difficult (3). In addition, caution was made regarding possible hepatotoxicity due to interactions between PBA and rifampicin (4). After in vitro studies showing that the p.G982R endoplasmic reticulum–retained bile salt export pump missense mutant was partially retargeted to the canalicular membrane with PBA, a PFIC2 girl carrying heterozygous compound ABCB11 mutations (p.A257 V; p.G982R) was treated with PBA from 10 to 14.5 years (PBA: 275 mg · kg−1 · day−1; 12 g/day, 24 tablets/day) (1). PBA treatment allowed disappearance of pruritus and normalization of serum bile acid (sBA) concentration (patient 2 (1)). Rifampicin was progressively tapered down then stopped and no evidence for PBA hepatotoxicity was found (4). Between 15 and 17 years she took PBA very intermittently due to difficulties with its administration, the consequence being periods with pruritus and cholestasis recurrence (sBA: 4–252 μmol/L; N < 10). Then, the patient decided to totally stop PBA. She experienced unremitting pruritus with sBA being permanently >250 μmol/L. At 18 years we proposed her to start a treatment with glycerol phenylbutyrate (GPB) (Ravicti, not labeled for the use under discussion) at the dose of 11 g/day (10 mL/day) of GPB (8 g · m−2 · day−1, in 2 divided doses) (5). GPB, a triglyceride consisting of 3 molecules of sodium phenylbutyrate joined to glycerol has no sodium burden, and offers palatability and pharmacokinetic advantages over PBA (5,6). Because of a better flavor and a convenient liquid presentation compared to PBA, full adherence to GPB treatment was obtained. After 1 month, pruritus disappeared and sBA normalized (4.6 μmol/L). Follow-up at 3 and 8 months confirmed the absence of pruritus and cholestasis (sBA: 1.9 and 5 μmol/L). Serum liver tests, alpha-fetoprotein level, and liver elastography value (Supersonic Shear Imaging: 6 kPa) were normal. This report shows that in our PFIC2 patient GPB is as efficient as PBA to improve pruritus and cholestasis and allows good oral tolerance and therapeutic adherence.