Intractable itch relieved by 4-phenylbutyrate therapy in patients with progressive familial intrahepatic cholestasis type 1

Abstract

BackgroundProgressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1.MethodsThe therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected.Results4PB therapy had no beneficial effect on the patients’ liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy.Conclusions4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families.

Successful treatment with 4‐phenylbutyrate in a patient with benign recurrent intrahepatic cholestasis type 2 refractory to biliary drainage and bilirubin absorption

“…Therefore, it is conceivable that 4PB therapy could relieve the cholestatic episodes in patients with BRIC1 who retain protein activity of ATP8B1 per se. Furthermore, even in the BRIC1 patients whose liver functions are barely improved by treatment with 4PB, intractable itching, the main complaint in the cholestatic attacks of patients with BRIC1, should disappear, because the antipruritic potency of 4PB on cholestatic itching was indicated in our previous study . In PFIC1 patients, regardless of the lack of improvement in liver functions assessed by biochemical and histological analysis, therapy with 4PB significantly relieved sustained refractory pruritus, made it possible for the patients to sleep well, and thereby helped improve their quality of life and that of their families .…”

“…Furthermore, even in the BRIC1 patients whose liver functions are barely improved by treatment with 4PB, intractable itching, the main complaint in the cholestatic attacks of patients with BRIC1, should disappear, because the antipruritic potency of 4PB on cholestatic itching was indicated in our previous study . In PFIC1 patients, regardless of the lack of improvement in liver functions assessed by biochemical and histological analysis, therapy with 4PB significantly relieved sustained refractory pruritus, made it possible for the patients to sleep well, and thereby helped improve their quality of life and that of their families . The relief of intractable itching by 4PB therapy in the patient in this study might have been achieved by not only the improvement in liver function but also by its antipruritic effect, because the itching resolved prior to the improvement in liver function tests and to the decrease in the factors suspected to be causally associated with cholestatic pruritus.…”

“…d), showed that the transport activity of [ 3 H]‐TC mediated per unit mass of HA‐BSEP D404G molecules did not differ significantly from that mediated by HA‐BSEP WT . Treatment for 24 h with 1 mM 4PB, a clinically relevant concentration in patients with OTCD, increased the cell surface expression of HA‐BSEP WT and HA‐BSEP D404G by 2.6‐ and 2.1‐times, respectively, in HEK293T cells (Fig. b), without significantly changing the expression level of either mRNA (Fig.…”

Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4‐phenylbutyrate

“…Recently, 4‐PB therapy was reported to decrease itching in 3 patients with PFIC1. In these patients, BSEP protein‐level expression increased with 4‐PB, but serum levels of BA and of ATX were not altered . The mechanisms underlying the improvement of itching observed with 4‐PB in PFIC1 and in PFIC2 patients remain to be identified.…”

Impaired Hepatic Uptake by Organic Anion-Transporting Polypeptides Is Associated with Hyperbilirubinemia and Hypercholanemia in Atp11c Mutant Mice

“…We have published experimental and clinical evidence that 4-phenylbutyrate, a drug used to treat ornithine transcarbamylase deficiency, has an additional pharmacological effect that increases the expression of BSEP on the CM (Hayashi and Sugiyama, 2007) and improves liver function and/or pruritus in these PFIC patients (Hasegawa et al, 2014;Naoi et al, 2014). The development of therapeutic methods to treat other PFIC patients and understanding of the mechanism underlying intrahepatic cholestasis caused by inherited genetic defects require the identification of other genes that are causally associated with PFIC in the remaining 30% of patients with a normal GGT level.…”