Cholic acid therapy in Zellweger spectrum disorders

Berendse, Kevin; Klouwer, Femke C. C.; Koot, Bart; Kemper, E. Marleen; Ferdinandusse, Sacha; Koelfat, K.V.; Leníček, Martin; Schaap, Frank G.; Waterham, Hans R.; Vaz, Frédéric M.; Engelen, Marc; Jansen, Petér L. M.; Wanders, Ronald J. A.; Poll-Thé, Bwee Tien

doi:10.1007/s10545-016-9962-9

Cited by 41 publications

(48 citation statements)

References 35 publications

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“…The individual patient characteristics are presented in Table . The study numbers of the included patients correspond to the data from the initial paper . A total of 22 ZSD patients were included in the 9 months treatment phase (median age 9.5 years).…”

Section: Resultsmentioning

confidence: 99%

“…A total of 22 ZSD patients were included in the 9 months treatment phase (median age 9.5 years). Nineteen of these were previously reported . Seventeen completed the 21 months treatment phase (median age 15 years).…”

Section: Resultsmentioning

confidence: 99%

“…This study is an extension study of a previously conducted pretest‐posttest design study in which 19 ZSD patients were treated with CA for 9 months after a run‐in period of 2 years. The results of this study have been previously published . The initial treatment phase took place between April 2014 and January 2015 and was extended till January 2016 (trial registry: http://www.isrctn.com/ISRCTN96480891).…”

Section: Methodsmentioning

confidence: 99%

“…ZSD patients who were not included in the initial study or were born after April 2014 (i.e. the start of the 9 months treatment phase of the initial study), were included for 9 months of CA treatment when they met the previously described inclusion and exclusion criteria . The frequency and characteristics of the study visits for these patients were identical to those in the initial study.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we performed a systematic study of the effects of 9 months of oral CA treatment in 19 patients with a ZSD . Bile acid synthesis was, indeed, suppressed in most patients during treatment, and consequently led to decreased C 27 ‐bile acid intermediates in plasma and urine of those patients.…”

Section: Introductionmentioning

confidence: 99%

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

Klouwer

Koot

Berendse

et al. 2019

J of Inher Metab Disea

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Klouwer

Koot

Berendse

et al. 2019

J of Inher Metab Disea

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

Berendse

Koot

Klouwer

et al. 2019

J of Inher Metab Disea

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Patients with a Zellweger spectrum disorder (ZSD) have a defect in the assembly or maintenance of peroxisomes, leading to a multisystem disease with variable outcome. Liver disease is an important feature in patients with severe and milder phenotypes and a frequent cause of death. However, the course and histology of liver disease in ZSD patients are ill‐defined. We reviewed the hepatic symptoms and histological findings of 13 patients with a ZSD in which one or several liver biopsies have been performed (patient age 0.2‐39 years). All patients had at least some histological liver abnormalities, ranging from minor fibrosis to cirrhosis. Five patients demonstrated significant disease progression with liver failure and early death. In others, liver‐related symptoms were absent, although some still silently developed cirrhosis. Patients with peroxisomal mosaicism had a better prognosis. In addition, we show that patients are at risk to develop a hepatocellular carcinoma (HCC), as one patient developed a HCC at the age of 36 years and one patient a precancerous lesion at the age of 18 years. Thus, regular examination to detect fibrosis or cirrhosis should be included in the standard care of ZSD patients. In case of advanced fibrosis/cirrhosis expert consultation and HCC screening should be initiated. This study further delineates the spectrum and significance of liver involvement in ZSDs.

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Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics

Minegishi,

Kobayashi,

Fujikura

et al. 2024

Pharmacology Res & Perspec

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Human cytochrome P450 3A4 (CYP3A4) is a drug‐metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human‐like regulation of the coding genes. A normal diet (ND, CE‐2), CE‐2 with 1% cholesterol and 0.5% cholic acid (HCD) or CE‐2 with 0.5% cholic acid was given to the mice. The plasma concentrations of cholesterol, cholic acid and its metabolites in HCD mice were higher than those in ND mice. In this condition, the expression levels of hepatic CYP3A4 and the hydroxylation activities of triazolam, a typical CYP3A4 substrate, in liver microsomes of HCD mice were higher than those in liver microsomes of ND mice. Furthermore, plasma concentrations of triazolam in HCD mice were lower than those in ND mice. In conclusion, our study suggested that hepatic CYP3A4 expression and activity are influenced by the combination of cholesterol and cholic acid in vivo.

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Cholic acid therapy in Zellweger spectrum disorders

Cited by 41 publications

References 35 publications

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

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

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

Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics

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