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. 2024 Dec 19;19(1):466.
doi: 10.1186/s13023-024-03449-7.

The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review

Yasmin Polak  1   2 , Laura van Dussen  2 , E Marleen Kemper  1   2 , Frédéric M Vaz  3   4   5   6 , Femke C C Klouwer  7 , Marc Engelen  7 , Carla E M Hollak  8   9
Affiliations

The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review

Yasmin Polak et al. Orphanet J Rare Dis. .

Abstract

Background: Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C27-bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients.

Methods: A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms.

Results: From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1-35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders (n = 73), 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n = 62), cerebrotendinous xanthomatosis (n = 22), Δ4-3-oxosteroid 5β-reductase deficiency (n = 13), and α-methylacyl-CoA racemase deficiency (n = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies).

Conclusion: More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.

Keywords: Bile acid synthesis defects; Cholic acid; Single enzyme defects; Toxic bile acid intermediates; Zellweger spectrum disorders.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Conflict of interest: EK: Board member of the Dutch Hospital Pharmacist Association for which no personal fees are received. The association has no involvement in the preparation of this manuscript or interest in the product or patients described. FV: Consulting for Scenic Biotech, board member of the European Metabolic Group (EMG), secretary of the SSIEM Education and Training Advisory Committee (ETAC), inventor of a patent for a screening method of cerebrotendinous xanthomatosis (PCT/EP2018/055236). CH: Received grants from Sanofi, Idorsia and Protalix to perform clinical studies in the field of lysosomal storage disorders, these clinical studies are outside the scope of this manuscript and CH received no personal fees. All other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
PICOS chart detailing inclusion criteria for systematic review. Abbreviations RCT, randomized controlled trial; PICOS, ‘population, interventions, comparators, outcomes, and study designs’. Clinical outcomes: Liver disease, kidney dysfunction, neurological disease, hearing impairment, vision impairment, skeletal disease or growth retardation, psychiatric symptoms. Biochemical outcomes: Primary bile acids and bile acid intermediates (toxic metabolite) plasma levels, liver chemistries, fat-soluble vitamins, plasma cholestanol and cholesterol levels. Safety outcomes: Dose-response relationship, adverse effects and side effects
Fig. 2
Fig. 2
PRISMA flow diagram [25]
Fig. 3
Fig. 3
Types of (serious) adverse events and number of times reported
Fig. 4
Fig. 4
Risk of bias assessment of included studies using Murad tool. This represents the review authors judgements on each risk of bias item
See this image and copyright information in PMC

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