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

Yasuhiro Hasegawa, Hisamitsu Hayashi, Sotaro Naoi, Hiroki Kondou, Kazuhiko Bessho, Koji Igarashi, Kentaro Hanada, Kie Nakao, Takeshi Kimura, Akiko Konishi, Hironori Nagasaka, Yoko Miyoshi, Keiichi Ozono, Hiroyuki Kusuhara, Yasuhiro Hasegawa, Hisamitsu Hayashi, Sotaro Naoi, Hiroki Kondou, Kazuhiko Bessho, Koji Igarashi, Kentaro Hanada, Kie Nakao, Takeshi Kimura, Akiko Konishi, Hironori Nagasaka, Yoko Miyoshi, Keiichi Ozono, Hiroyuki Kusuhara

Abstract

Background: Progressive 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.

Methods: The 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.

Results: 4PB 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.

Conclusions: 4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families.

Figures

Figure 1
Figure 1
Studies of liver biopsy specimens obtained from the patients before and after 4PB therapy. (D) Histological characteristics of liver sections. Liver sections prepared from the liver biopsy specimens of the patients before and after the 4PB therapy were subjected to HE staining as described in Patients and Methods. A typical image under each condition is shown. Original magnification; 200×. (A-C) Analysis of mRNA and protein expression levels. cDNA (A), crude membrane fractions (B), and nuclear and cytosolic fractions (C) were prepared from liver biopsy specimens from the patients and then analyzed by qPCR (A) and immunoblotting (B and C) as described in Materials and Methods. In (A), the data were obtained from triplicate determination. Each bar represents the mean ± SE of individual specimens. In (B and C), the signal intensity of ATP8B1, BSEP, and FXR relative to that of NaKα1, LaminA, and EEA1 is presented below each panel. AU, arbitrary unit; P-gp, P-glycoprotein; P1, patient 1; P2, patient 2; P3, patient 3; 4PB(-), before 4PB treatment; 4PB(+), after 4PB treatment.
Figure 2
Figure 2
Liver function testing before, during and after the course of 4PB therapy in the patients. Serum AST, ALT, GGT (A), total bilirubin, direct bilirubin, and bile acids (B) levels were monitored before, during and after the 4PB therapy. T-Bil, total bilirubin; D-Bil, direct bilirubin; BA, bile acids.
Figure 3
Figure 3
Itching intensity in the patients before, during, and after the course of 4PB therapy. (A, B) Correlation diagram of itching scores for the PFIC1 patients with serum ATX activity (A) and ATX level (B) in the patients before, during, and after 4PB therapy. Pruritus severity was scored ranging from 0 (no pruritus) to 4 (cutaneous mutilation, with bleeding and scarring) as described in Patients and Methods. (C) Skin of the patients before and after the 4PB therapy.

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