The cholic acid extension study in Zellweger spectrum disorders: Results and implications for therapy

Femke C. C. Klouwer, Bart G. P. Koot, Kevin Berendse, Elles M. Kemper, Sacha Ferdinandusse, Kiran V. K. Koelfat, Martin Lenicek, Frederic M. Vaz, Marc Engelen, Peter L. M. Jansen, Ronald J. A. Wanders, Hans R. Waterham, Frank G. Schaap, Bwee Tien Poll-The*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

IntroductionCurrently, no therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes. In a previous study, we showed that oral cholic acid (CA) treatment can suppress bile acid synthesis in ZSD patients and, thereby, decrease plasma levels of toxic C-27-bile acid intermediates, one of the biochemical abnormalities in these patients. However, no effect on clinically relevant outcome measures could be observed after 9 months of CA treatment. It was noted that, in patients with advanced liver disease, caution is needed because of possible hepatotoxicity.

MethodsAn extension study of the previously conducted pretest-posttest design study was conducted including 17 patients with a ZSD. All patients received oral CA for an additional period of 12months, encompassing a total of 21months of treatment. Multiple clinically relevant parameters and markers for bile acid synthesis were assessed after 15 and 21months of treatment.

ResultsBile acid synthesis was still suppressed after 21months of CA treatment, accompanied with reduced levels of C-27-bile acid intermediates in plasma. These levels significantly increased again after discontinuation of CA. No significant changes were found in liver tests, liver elasticity, coagulation parameters, fat-soluble vitamin levels or body weight.

ConclusionsAlthough CA treatment did lead to reduced levels of toxic C-27-bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21months of treatment. We discuss the implications for CA therapy in ZSD based on these results.

Original languageEnglish
Pages (from-to)303-312
Number of pages10
JournalJournal of Inherited Metabolic Disease
Volume42
Issue number2
DOIs
Publication statusPublished - Mar 2019

Keywords

  • GROWTH-FACTOR 21
  • PEROXISOME BIOGENESIS DISORDERS
  • FATTY LIVER-DISEASE
  • BILE-ACIDS
  • CLINICAL-MANIFESTATIONS
  • MASS-SPECTROMETRY
  • INBORN-ERRORS
  • HEPATOTOXICITY
  • DIAGNOSIS

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