Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

Abstract

Background: We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) over 21 years between 1996 and 2017. Diagnoses were made by bile acid and genetic analyses. We gave lowdose, long-term chenodeoxycholic acid (CDCA) treatment to 5 of the patients, who had 3β-hydroxy-Δ 5 -C 27 -steroid dehydrogenase/isomerase (3β-HSD) deficiency (n=3) or Δ 4 -3-oxosteroid 5βreductase (5β-reductase) deficiency (n=2). Another patient with the latter diagnosis whose bile acid analyses had mitigating features was maintained on ursodeoxycholic acid according to parental preferences and now remains healthy after discontinuation of treatment. A patient with oxysterol 7αhydroxylase deficiency developed liver failure and fully recovered after successful liver transplantation. We used clinical records to clarify long-term outcome and value of CDCA in the other patients. Efficacy of CDCA treatment was evaluated in the 5 patients given a low dose (5 to 10 mg/kg/day) for a long term.Results: Medians with ranges of current patient ages and duration of CDCA treatment are10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7 , SRD5B1 , or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted.Conclusions: We concluded that low-dose CDCA treatment is effective in 3β-HSD deficiency and 5βreductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term, low-dose CDCA treatment.We have no financial support.

Special FX: Harnessing the Farnesoid-X-Receptor to Control Bile Acid Synthesis

“…Since CYP7A1 is important for bile acid homeostasis, it is likely that FXR/ FGF19/FGFR4 signaling represents the major physiological 1 Dipartimento di Medicina E Chirurgia, Università di Perugia, Piazza L. Severi 1, 06100 Perugia, Italy 2 SC di Gastroenterologia Ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy mechanism for the negative feedback regulation of bile acid synthesis. When bile acid concentrations increase in the liver, the FXR/SHP pathway is also activated in order to prevent further bile acid synthesis [9].…”

“…In this issue of Digestive Disease and Sciences, Kimura et al [9] report a small series of seven Japanese patients with bile acid synthesis disorders caused by homozygous or compound heterozygous loss-of-function mutations of the 3β-HSD, the 5β-reductase (AKR1D1), and the oxysterol 7α-hydroxylase (Cyp7B1) ( Fig. 1, yellow boxes).…”

“…The seven patients were identified over 21 years (1996-2017) with diagnosis achieved by measuring atypical bile acids in the blood and urine by fast atom bombardment mass spectrometry (FAB-MS). The 3β-HSD deficiency is the most common bile acid disorder in Europe and the USA, accounting for ≈ 40% of inborn errors of bile acid metabolism in western populations, though it is less prevalent in Japan [9]. On the other hand, the deficiency of oxysterol-7α hydroxylase (Cyp7B1) is a very rare inborn error of bile acid synthesis, slightly more prevalent in East Asia, that can eventuate in liver failure requiring liver transplantation, although there are reports showing long-term survival with CDCA treatment [2].…”

“…As mentioned above both CA and CDA are FXR ligands, whereas UDCA is neutral toward the receptor. In this Japanese series [9], three patients with 3β-HSD deficiency and two patients with 5β-reductase deficiency were administered CDCA due to a lack of availability of CA in Japan. The patient with oxysterol 7α hydroxylase deficiency underwent a liver transplantation that was curative, with no evidence of liver fibrosis 10 years after the procedure.…”

“…One patient with 5β-reductase (AKR1D1) deficiency was administered UDCA only for the first 12 months of life due to the parents refusing further therapy; the patient was healthy at 16-year follow-up. The doses of CDCA used by Kimura et al [9] ranged from 4 to 7.8 mg/kg/day with the median duration of therapy 10 years. CDCA treatment improved hepatic biochemistries with follow-up imaging showing no evidence of liver cirrhosis, liver tumor, or biliary stones.…”