TY - JOUR
T1 - The cholic acid extension study in Zellweger spectrum disorders
T2 - Results and implications for therapy
AU - Klouwer, Femke C. C.
AU - Koot, Bart G. P.
AU - Berendse, Kevin
AU - Kemper, Elles M.
AU - Ferdinandusse, Sacha
AU - Koelfat, Kiran V. K.
AU - Lenicek, Martin
AU - Vaz, Frederic M.
AU - Engelen, Marc
AU - Jansen, Peter L. M.
AU - Wanders, Ronald J. A.
AU - Waterham, Hans R.
AU - Schaap, Frank G.
AU - Poll-The, Bwee Tien
N1 - Funding Information:
The authors thank the patients and their families for their cooperation. This work was supported in part by grants from Metakids, Hersenstichting (grant F 2012(1)-102), Axel Foundation and Stichting Steun Emma Kinderziekenhuis AMC, the Netherlands. Furthermore, we thank prof. dr. A.K. Groen from the Academic Medical Center in Amsterdam for the helpful discussions.
Publisher Copyright:
© 2018 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
KW - GROWTH-FACTOR 21
KW - PEROXISOME BIOGENESIS DISORDERS
KW - FATTY LIVER-DISEASE
KW - BILE-ACIDS
KW - CLINICAL-MANIFESTATIONS
KW - MASS-SPECTROMETRY
KW - INBORN-ERRORS
KW - HEPATOTOXICITY
KW - DIAGNOSIS
U2 - 10.1002/jimd.12042
DO - 10.1002/jimd.12042
M3 - Article
C2 - 30793331
SN - 0141-8955
VL - 42
SP - 303
EP - 312
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 2
ER -