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

Abstract

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.

Hepatic symptoms and histology in 13 patients with a Zellweger spectrum disorder

“…It was hypothesis that cholic acid therapy could prevent disease progression and progression of liver disease. However, short‐ and long‐term follow‐up showed, besides significant increase in weight, no improvement of clinical symptoms or liver phenotype . Long‐term follow‐up did show stabilization of liver function/enzymes .…”

Ophthalmic Diagnosis and Novel Management of Infantile Refsum Disease with Combination Docosahexaenoic Acid and Cholic Acid

“…While some studies suggest a beneficial effect of DHA supplementation in patients with Zellweger spectrum disorders, a randomized double-blind placebo-controlled trial showed no improvement of visual function and growth [ 21 , 22 ]. Similarly, despite FDA approval, studies surrounding cholic acid supplementation have not demonstrated improved growth and development or reduced urinary excretion of toxic intermediates in these patients [ 23 , 24 ]. Additional research is needed to evaluate efficacy of DHA and cholic acid as combination therapy for IRD.…”

Product Validation and Stability Testing of Pharmacy Compounded Cholic Acid Capsules for Dutch Patients with Rare Bile Acid Synthesis Defects

“…Abnormally elevated bile acid intermediates are thought to be toxic for the brain [ 8 , 9 ], potentially causing neurological disease. Despite the paucity of clinical evidence, bile acid supplementation with 5–15 mg/kg cholic acid (CA) for the treatment of different types of BASDs has been available for many years [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. It has been hypothesized that cholic acid supplementation decreases endogenous bile acid production, stimulates bile secretion, and improves bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression [ 2 , 7 , 19 , 20 ].…”