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 low-dose, 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 5β-reductase (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 7α-hydroxylase 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 5β-reductase 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.

Prognosis and clinical characteristics of patients with 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency diagnosed in childhood

“…These all suggested CA is an effective, well-tolerant therapy option without hepatotoxic and embryotoxic/teratogenic [27] . Prolonged oral CDCA therapy is considered to be safe and lifesaving as it leads to normalization of clinical features, serum liver biochemistry and liver imaging, together with a substantial improvement of mass spectrometry BA profiles and liver histology [24] . Despite the similar treatment mechanism with CA, CDCA is not recommended when patients have live cirrhosis because it can be hepatotoxic at that stage [28] .…”

“…Additionally, CDCA is contraindicated during pregnancy. Unfortunately, CDCA is used instead of CA in some areas such as Japan and China, since the latter is not available for clinical use [24] . Although UDCA relieves cholestasis, UDCA is not optimal because it does not reduce and may enhance the production of hepatotoxic abnormal BA.…”

“…[15] Renal cyst is because the unusual BAs were excreted via the kidneys and high concentrations of BA can be toxic to renal tubules and may generate or initiate renal lesions. [22,24] What' more, the recognition of this rare condition may be influenced by its description in the regional medical journals and therefore more cases come to attention, which could possibly explain why there are many differences in regions.…”

“…CA is the only primary BA having a marketing authorization in the USA and in Europe and is the first-line therapy for patients with 3b-HSD deficiency. [24,27] One study described the long-term effects of CA. With CA therapy, patients have survived to adulthood with a mean age of 24.3 y (range: 15.3-37.2 year) and a normal quality of life at last follow-up, which lasted 21.4 years by average (range: 14.6-24.1 years).…”

“…Unfortunately, CDCA is used instead of CA in some areas such as Japan and China, since the latter is not available for clinical use. [24] Although UDCA relieves cholestasis, UDCA is not optimal because it does not reduce and may enhance the production of hepatotoxic abnormal BA. UDCA could improve the liver dysfunction of patients in the short term but not decrease the production of atypical BA.…”