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

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

doi:10.1007/s10545-018-0194-z

Cited by 6 publications

(17 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 .…”

Section: Discussionmentioning

confidence: 89%

“…However, short-and long-term follow-up showed, besides significant increase in weight, no improvement of clinical symptoms or liver phenotype. 4,31 Long-term follow-up did show stabilization of liver function/enzymes. 4 However, if the stabilization of liver function was caused by cholic acid supplementation and not by natural course of disease is unknown due to missing data of natural history of liver phenotype in ZSDs.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

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

Berendse

Koot

Klouwer

et al. 2019

J of Inher Metab Disea

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 97%

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

Berendse

Koot

Klouwer

et al. 2019

J of Inher Metab Disea

Self Cite

View full text Add to dashboard Cite

show abstract

“…[ 17 ] Open-label, pretest-postest study 19 patients with ZSD (mean age 14 years) 15 mg/kg/day (with dose adjustments, as needed) 36 weeks Signficant increases in plasma CA levels Signficant decreases in plasma levels of C 27 -bile acid intermediates No changes in: AST, ALT, or conjugated bilirubin Fibroscan® liver stiffness values Concentrations of fat-soluble vitamins Weight Subset of patients with advanced liver disease at baseline (n = 4) showed evidence of increased liver damage with CA therapy CA therapy can be used in the majority of patients with ZSD, leading to at least partial supression of bile acid synthesis Caution is needed in patients with advanced liver disease because of possible hepatotoxic effects Small size of the cohort Short duration of treatment Mild disease severity at start of treatment Klouwer et al . [ 20 ] Extension of Berendse et al . 2016 pretest–posttest study 22 patients with ZSD (mean age 13 years) 15 mg/kg/day (with dose adjustments, as needed) Additional 12 months (total duration 21 months) Significant decreases in plasma C 27 -bile acid intermediates No changes in: AST, ALT, or conjugated bilirubin Liver elasticity Concentrations of fat-soluble vitamins Weight Subset of patients with advanced liver disease at baseline (n = 6) had progressive increases in conjugated bilirubin levels with CA therapy Although CA therapy resulted in lower C 27 -bile acid intermediate levels in plasma and urine, no clincial benefit was observed CA therapy can be harmful to ZSD patients with cirrhosis Small size of the cohort Short duration of treatment Mild disease severity at start of treatment Heubi et al .…”

Section: Clinical Studies Demonstrating Efficacy Of Ca Therapy In Patients With Zsdmentioning

confidence: 99%

“…An extension of this study was conducted for an additional 12 months in 22 patients with ZSD [ 20 ]. The 19 patients continuing from the initial study were maintained on the same dose that they were on at the conclusion of the 9-month treatment phase.…”

Section: Clinical Studies Demonstrating Efficacy Of Ca Therapy In Patients With Zsdmentioning

confidence: 99%

Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Anderson

Ammous²,

Eroğlu³

et al. 2021

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system. Main body Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population. Conclusions Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.

show abstract

“…49 Cholic acid therapy reduces the production of bile acid intermediates in patients with ZSD; however, its use may be limited due to possible hepatotoxicity. 51,52 Patients with X-ALD and cerebral involvement can benefit from hematopoietic stem cell transplantation (HSCT) if performed prior to significant involvement. 53,54 HSCT is associated with up to a 20% mortality rate due to transplantrelated complications.…”

Section: Peroxisomal Disorders Treatmentmentioning

confidence: 99%

Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Biase

Tortorelli

Kratz

et al. 2020

Genetics in Medicine

View full text Add to dashboard Cite

Disclaimer: This technical standard is designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to this standard is voluntary and does not necessarily assure a successful medical outcome. This standard should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this standard. They also are advised to take notice of the date any particular standard was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Peroxisomal disorders are a clinically and genetically heterogeneous group of diseases caused by defects in peroxisomal biogenesis or function, usually impairing several metabolic pathways. Peroxisomal disorders are rare; however, the incidence may be underestimated due to the broad spectrum of clinical presentations. The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform Screening Panel for newborn screening programs in the United States may increase detection of this and other peroxisomal disorders. The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells. Molecular testing can confirm biochemical findings and identify the specific genetic defect, usually utilizing a multiple-gene panel or exome/genome approach. When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction. This document provides a resource for laboratories developing and implementing clinical biochemical genetic testing for peroxisomal disorders, emphasizing technical considerations for sample collection, test performance, and result interpretation. Additionally, considerations on confirmatory molecular testing are discussed.

show abstract

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

Cited by 6 publications

References 28 publications

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

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

Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Contact Info

Product

Resources

About