Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates

Hiroki Kawai; Shigeo Takashima; Akiko Ohba; Kayoko Toyoshi; Kazuo Kubota; Hidenori Ohnishi; Nobuyuki Shimozawa

doi:10.1016/j.braindev.2022.10.001

Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates

Brain Dev. 2023 Jan;45(1):58-69. doi: 10.1016/j.braindev.2022.10.001. Epub 2022 Oct 29.

Authors

Hiroki Kawai¹, Shigeo Takashima², Akiko Ohba², Kayoko Toyoshi², Kazuo Kubota³, Hidenori Ohnishi³, Nobuyuki Shimozawa⁴

Affiliations

¹ Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan; Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan; Kibogaoka Medical and Support Center for Children, Gifu, Japan. Electronic address: kawaih@gifu-u.ac.jp.
² Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan.
³ Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan; Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan.
⁴ Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan; Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan.

PMID: 36511274
DOI: 10.1016/j.braindev.2022.10.001

Abstract

Objective: Bile acid intermediates, 3α,7α,12α-trihydroxycholestanoic acid (THCA) and 3α,7α-dihydroxycholestanoic acid (DHCA), are metabolized in peroxisomes. Some peroxisomal disorders (PDs), such as Zellweger spectrum disorder (ZSD), show an accumulation of bile acid intermediates. In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities. In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness. Here, we established a method for the quantitative determination of bile acid intermediates (THCA/DHCA) for differentiating PDs and assessing bile acid treatment.

Methods: Serum samples, obtained from patients with several forms of ZSD as well as peroxisomal β-oxidation enzyme deficiencies, were deproteinized and analyzed using liquid chromatography-mass spectrometry.

Results: Levels of the bile acid intermediates increased significantly in patients with Zellweger syndrome (ZS) and slightly in patients with neonatal adrenoleukodystrophy and infantile Refsum disease (IRD), reflecting the severity of these diseases. One patient with ZS treated with primary bile acids for 6 months showed slightly decreased serum DHCA levels but significantly increased serum THCA levels. One patient with IRD who underwent living-donor liver transplantation showed a rapid decrease in serum THCA and DHCA levels, which remained undetected for 6 years. In all controls, THCA and DHCA levels were below the detection limit.

Conclusion: The analytical method developed in this study is useful for diagnosing various PD and validating bile acid treatment. Additionally, it can help predict the prognosis of patients with PD and support treatment strategies.

Keywords: 3α,7α,12α-Trihydroxycholestanoic acid (THCA); 3α,7α-Dihydroxycholestanoic acid (DHCA); Bile acid intermediate; Peroxisomal disorder.

MeSH terms

Bile Acids and Salts
Humans
Infant, Newborn
Liver Transplantation*
Living Donors
Peroxisomal Disorders* / diagnosis
Zellweger Syndrome* / diagnosis

Substances

Bile Acids and Salts

Supplementary concepts

Peroxisomal ACYL-COA oxidase deficiency