INTRODUCTION: Currently, 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 C27 -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. METHODS: An 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 12 months, encompassing a total of 21 months of treatment. Multiple clinically relevant parameters and markers for bile acid synthesis were assessed after 15 and 21 months of treatment. RESULTS: Bile acid synthesis was still suppressed after 21 months of CA treatment, accompanied with reduced levels of C27 -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. CONCLUSIONS: Although CA treatment did lead to reduced levels of toxic C27 -bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21 months of treatment. We discuss the implications for CA therapy in ZSD based on these results.

• MeSH
• aplikace orální MeSH
• biologické markery krev   MeSH
• dítě MeSH
• dospělí MeSH
• játra metabolismus   MeSH
• kyselina cholová krev   terapeutické užití   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci jater farmakoterapie   metabolismus   MeSH
• peroxizomy metabolismus   MeSH
• předškolní dítě MeSH
• Zellwegerův syndrom krev   farmakoterapie   metabolismus   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• bilirubin krev   MeSH
• dítě MeSH
• dospělí MeSH
• játra metabolismus   MeSH
• kyselina cholová krev   terapeutické užití   MeSH
• lidé MeSH
• longitudinální studie MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci jater farmakoterapie   metabolismus   MeSH
• neutrální endopeptidasa regulující fosfáty metabolismus   MeSH
• předškolní dítě MeSH
• transaminasy krev   MeSH
• Zellwegerův syndrom krev   farmakoterapie   metabolismus   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH