Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Abstract

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.

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review

“…Oral cholic acid is an efficacious therapy in bile acid synthesis disorders and adjunctive treatment of peroxisomal disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat‐soluble vitamin absorption without liver fibrosis 22 . Unfortunately, our patient died before the effects of this medication could be ascertained.…”

Acute Late-Onset Cirrhosis in Zellweger Spectrum Disorder

“…In rat models, C 27bile acid intermediates have been shown to be particularly cytotoxic in hepatoma cell lines [6]. Cholic acid is hypothesized to reduce levels of cytotoxic C 27 -bile acid intermediates via Case Reports in Gastroenterology restoration of the negative feedback loop, restore C 24 -bile acid levels to facilitate biliary excretion of bile acids, improve cholestasis, and increase intraluminal bile acid concentration which improves absorption of dietary fat and fat-soluble vitamins [5]. In fact, the use of bile acid supplementation as a proposed treatment has been suggested for many years with noted improvements to liver function and overall growth in patients [7].…”

Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review

“…Variability in biochemical parameters was suggested as a contributing factor in the lack of measurable effectiveness of oral betaine supplementation on biochemical function in ZSD patients (Plourde et al, unpublished results). Moreover, in both DHA and cholic acid therapy studies, baseline symptom presentation was discussed as a factor to consider when evaluating the effectiveness of therapy [ 36 , 149 ]. Our findings may be useful to further characterize clinical presentation and severity in ZSD, which may serve as an important consideration in the design of future clinical trials.…”