Oral Cholic Acid in Zellweger Spectrum Disorders: A Word of Caution

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To the Editor:
We read with interest the article by Heubi et al (1), which describes the use of cholic acid (CA) in patients with bile acid synthesis disorders due to a single enzyme deficiency and Zellweger spectrum disorder (ZSD). We believe that the design and presentation of the data importantly affect the interpretation of the authors on the reported effect and safety of CA, particularly in patients with ZSD. First, single enzyme deficiencies and ZSDs are 2 distinct disorders, and we strongly feel that results in patients with ZSD should be reported separately. The choice of a worst-to-best analysis (comparing the least favorable outcome before intervention with the best favorable outcome after intervention) is to the best of our knowledge an unacceptable statistical method in biomedical studies. We have found no references that validate its use in biomedical research. Type 1 statistical errors, detecting an effect that is not present, are likely to occur, particularly in the patients with ZSD who have a great natural variability of biochemical markers.
Our suggestion of a type I error is supported by a lack of significant effect of CA in patients with ZSD on all primary outcomes in the sensitivity analysis presented in the supplementary material. Another unaddressed aspect is the well-known phenomenon in ZSD of biochemical normalization in patients without intervention (2), a bias which cannot be ruled out since the interval of measurements is not specified.
The conclusion that CA is safe and well tolerated in patients with ZSD is in our view insufficiently supported by the provided data, as data on safety were registered in a nonstructured fashion and retrospectively. In a previous study, not discussed by Heubi et al (1), we systematically studied the effect of CA for 9 months in a well-defined cohort of 19 patients with ZSD (3). Although CA resulted in lower C27-bile acid intermediates in plasma and urine, no clinical benefit could be observed. Rather, CA could even be harmful in patients with cirrhosis (3).
In conclusion, the beneficial effects of CA in ZSD still remain to be proven, while caution is required when initiating this treatment, particularly in those with advanced liver disease.
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