INTRODUCTION: Zellweger spectrum disorders (ZSDs) are characterized by a failure in peroxisome formation, caused by autosomal recessive mutations in different PEX genes. At least some of the progressive and irreversible clinical abnormalities in patients with a ZSD, particularly liver dysfunction, are likely caused by the accumulation of toxic bile acid intermediates. We investigated whether cholic acid supplementation can suppress bile acid synthesis, reduce accumulation of toxic bile acid intermediates and improve liver function in these patients. METHODS: An open label, pretest-posttest design study was conducted including 19 patients with a ZSD. Participants were followed longitudinally during a period of 2.5 years prior to the start of the intervention. Subsequently, all patients received oral cholic acid and were followed during 9 months of treatment. Bile acids, peroxisomal metabolites, liver function and liver stiffness were measured at baseline and 4, 12 and 36 weeks after start of cholic acid treatment. RESULTS: During cholic acid treatment, bile acid synthesis decreased in the majority of patients. Reduced levels of bile acid intermediates were found in plasma and excretion of bile acid intermediates in urine was diminished. In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates. CONCLUSIONS: Oral cholic acid therapy can be used in the majority of patients with a ZSD, leading to at least partial suppression of bile acid synthesis. However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects.

Department of Gastroenterology and Hepatology Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Pediatric Gastroenterology Emma Children's hospital Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pediatric Neurology Emma Children's Hospital Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Department of Pediatric Neurology Emma Children's Hospital Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam The Netherlands Laboratory Genetic Metabolic Diseases Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pharmacy Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Surgery Maastricht University Amsterdam The Netherlands

Laboratory Genetic Metabolic Diseases Academic Medical Center University of Amsterdam Amsterdam The Netherlands

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