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

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Abstract

Background

We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21 years between 1996 and 2017.

Aim

We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency.

Methods

Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography–mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems.

Results

Medians with ranges of current patient ages and duration of CDCA treatment are 10 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 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 CDCA treatment.

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Abbreviations

BASD:

Bile acid synthesis disorders

3β-HSD:

3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase

5β-reductase:

Δ4-3-Oxosteroid 5β-reductase

oxysterol 7α:

Oxysterol 7α-hydroxylase

GGT:

γ-Glutamyltransferase

TBA:

Total bile acids

US:

United States

CA:

Cholic acid

CDCA:

Chenodeoxycholic acid

SD:

Standard deviation

ALT:

Alanine aminotransferase

D. Bil:

Direct bilirubin

Cr:

Creatinine

GC-MS:

Gas chromatography–mass spectrometry

UDCA:

Ursodeoxycholic acid

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Acknowledgments

The authors thank Dr. Hajime Uchida at National Center for Child Health and Development, Dr. Mitsuyoshi Suzuki at Juntendo University, all participating patients, their families, and all physicians and surgeons for collaborating in data collection.

Funding

The authors have no financial support.

Author information

Author notes

  1. Akihiko Kimura, Tatsuki Mizuochi, and Hiroshi Nittono have contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan

    Akihiko Kimura & Tatsuki Mizuochi

  2. Kumamoto-Ashikita Medical Center for the Severely Disabled, Kumamoto, Japan

    Akihiko Kimura

  3. Junshin Clinic Bile Acid Institute, Tokyo, Japan

    Hajime Takei & Hiroshi Nittono

  4. Department of Pediatrics and Clinical Genomics, Faculty of Medicine, Saitama Medical University, Saitama, Japan

    Akira Ohtake

  5. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Jun Mori

  6. Department of Pediatrics, Gifu Municipal Hospital, Gifu, Japan

    Kunihiro Shinoda

  7. Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan

    Takuji Hashimoto

  8. Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan

    Mureo Kasahara

  9. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Takao Togawa

  10. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan

    Tsuyoshi Murai

  11. Department of Chemistry, College of Humanities and Science, Nihon University, Tokyo, Japan

    Takashi Iida

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  1. Akihiko Kimura
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Contributions

AK, TMi, and HN conceived and designed the study; AK, TMi, HT, AO, JM, TH, MK, and HN acquired the samples and data; HT and HN performed the bile acid analysis; TMi and TT performed the genetic analysis; TMu and TI synthesized the standard bile acid samples; AK and TMi interpreted the data and drafted the article; all authors contributed to critical review and approval of the draft.

Corresponding author

Correspondence to Tatsuki Mizuochi.

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Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

This study was approved by the ethics committees at Kurume University and Nagoya City University Graduate School of Medical Sciences. Written informed consent was obtained from enrolled patients or their parents.

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Electronic supplementary material

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10620_2020_6722_MOESM1_ESM.jpg

Supplementary Figure S1. Schematic representation of bile acid biosynthetic pathways and location of enzymatic defects. The two major synthetic pathways for synthesis of primary bile acids from cholesterol are shown, indicating sites of HSD3B7, SRD5B1, and CYP7B1, where genetic defects cause severe neonatal cholestasis. HSD3B7, 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase; SRD5B1, Δ4-3-oxosteroid 5β-reductase; CYP7B1, oxysterol 7α-hydroxylase. (JPG 147 kb)

10620_2020_6722_MOESM2_ESM.jpg

Supplementary Figure S2. Effect of CA or CDCA treatment in patients with HSD3B7 and SRD5B1 deficiencies. If primary bile acids are not synthesized due to HSD3B7 and SRD5B1 deficiencies, toxic bile acids such as 3β-hydroxy-Δ5 and 3-oxo-Δ4 accumulate in hepatocytes, resulting in liver damage. Administration of cholic acid (CA) or chenodeoxycholic acid (CDCA), which are primary bile acids, suppresses synthesis of toxic bile acids by exerting negative feedback upon CYP7A1 activity via the farnesoid X receptor. HSD3B7, 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase; SRD5B1, Δ4-3-oxosteroid 5β-reductase. (JPG 113 kb)

10620_2020_6722_MOESM3_ESM.jpg

Supplementary Figure S3. Effect of UDCA treatment on serum D. Bil and ALT concentrations in a patient with 5β-reductase deficiency (Patient 4). Serum direct bilirubin (D. Bil) and alanine aminotransferase (ALT) decreased with ursodeoxycholic acid (UDCA) administration. (JPG 136 kb)

Supplementary Material 4. (DOCX 18 kb)

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Kimura, A., Mizuochi, T., Takei, H. et al. Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment. Dig Dis Sci 66, 3885–3892 (2021). https://doi.org/10.1007/s10620-020-06722-4

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