MSACL 2025 Abstract

Mass Spectrometric Evalaution of the Comparative Efficacy of Cholic and Chenodeoxycholic Acids in the Treatment of Cerebrotendinous xanthomatosis

Kenneth DR Setchell PhD, FAASLD (1), Wujuan Zhang PhD (1), Jian-she Wang MD (2).
(1) Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA and (2) Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University and Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China

Kenneth Setchell, PhD (Presenter) Cincinnati Children’s Hospital Medical Center

Presenter Bio: Kenneth Setchell is Professor of Pediatrics and the Director of Clinical Mass Spectrometry in the Division of Pathology and Laboratory Medicine at the Cincinnati Children’s Hospital Medical Center and Department of Pediatrics of the University of Cincinnati College of Medicine. His expertise is in clinical and biomedical applications of mass spectrometry and allied techniques, primarily in small molecules and in the area of bile acids, steroids, sterols, lipids and small molecules with a focus on liver disease, gastroenterology and nutrition. Moving from the Medical Research Center’s Clinical Resarch Center in 1984 he established a mass spectrometry facility that provides clinical diagnostic testing, therapeutic drug monitoring and biomedical research support to investigators within CCHMC and the University of Cincinnati College of Medicine. This academic facility uniquely operates under GLP standards, is CAP/CLIA accredited, and consequently has provided analytical support for numerous Phase 1-3 clinical trials for the pharmaceutical industry, leading to 2 new drugs (Cholbam and Maralixibat) being FDA approved. He has published >430 peer-reviewed publications, is the inventor of 13 patents. He was awarded the 2004 Adolf Windaus Prize for research on bile acids following the discovery with mass spectrometry of 6 genetic defects in the cholesterol-bile acid synthetic pathway that cause liver disease in infants and children and is an internationally recognized center for the diagnosis of these defects. With the late James E. Heubi MD, they developed a successful therapy using oral cholic acid to reverse the disease in otherwise fatal forms of liver disease that was approved in 2015 by the FDA - the first drug to gain FDA approval in over 40 years for cholestatic liver disease. He is also recognized in the field of nutrition, specifically related to soy and isoflavones, having discovered the intestinally derived metabolite, S-(-)equol in human urine and making the association with soy food intake that has driven much of the interest in soy foods. He has received awards for his discoveries and in 2014 was listed by Thomson-Reuters as one of “The World’s Most Influential Scientific Minds” based on highly cited publications. He received the Distinguished Contributor Award 2016 at the Mass Spectrometry Applied to the Clinical Laboratory (MSACL) for lifetime contributions to the application of mass spectrometry to the clinical research. In 2023, named as one of the leading national and international medical researchers with 36,663 citations from 302 publications (from a total of >400 publications) with a 92 D-Index.

Relevant Financial Disclosures (within past 24 months, reported on Apr 05, 2025) Other Potential Conflicts Asklepion Pharmaceuticals / Stock Aliveris s.r.l, Italy / Stock Mirum Pharmaceuticals / Consultant Discussing Products? YES, presenter will present educational content related to products/services of one or more ineligible company(ies) listed above. All relevant financial relationships have been MITIGATED.

INTRODUCTION:
A deficiency in the activity of sterol 27-hydroxylase (CYP27A1) manifests as the rare lipid-storage disease of Cerebrotendinous xanthomatosis (CTX). This autosomal recessive disease presents with neurological abnormalities, xanthomas in tendons, premature atherosclerosis, dementia, diarrhea, and cataracts. In infancy, CTX presents with transient, severe, or even fatal cholestasis. Early diagnosis is critical to being able to initiate treatment to prevent the progression of the symptomology. Diagnosis of CTX has been performed in our facility for almost 40 years by analysis of urine using fast atom bombardment ionization mass spectrometry (FAB-MS) and the findings of elevated levels of bile alcohol glucuronides and an absence of the primary bile acid conjugates, particularly of chenodeoxycholic acid. More recently, we have established a stable-isotope dilution LC-MS assay for the accurate measurement of bile alcohols in urine, applicable to monitoring of the therapy. Administration of chenodeoxycholic acid has been the standard of care for CTX, but cholic acid therapy was approved by the FDA a decade ago. CDCA has been favored because of the long-standing track record of its effectiveness in adults with CTX but there have been no comparative studies reported. CDCA is intrinsically hepatotoxic and cathartic. Cholic acid, is more hydrophilic and is approved for treatment of bile acid synthesis disorders (BASD), including CTX, yet despite its superior safety profile has not been the first treatment choice. The argument against its use has been that it does not bind well to the nuclear receptor FXR to suppress CYP7A1 expression, the ultimate target of therapy. However, the in vivo ability of cholic acid to activate FXR is unquestionable based on its clinical effectiveness in suppressing atypical bile acids and improving liver function in patients with BASD. Following the development of a targeted mass spectrometry assay to accurately measure the key bile alcohol in CTX we present the first comparative data on the effectiveness of both primary bile acids on the primary endpoint of biochemical efficacy.

METHODS:
A quantitative stable-isotope dilution LC-MS assay was developed for the measurement in urine of the major bile alcohol glucuronide, 5β-cholestane-3α,7α,12α,25-tetrol-3-O-β-glucuronide which is a biomarker for CTX. In a study of 26 patients with biochemically and genetically confirmed CTX the effects of treatment with either cholic acid (n=16) or CDCA (n=10) on key biochemical endpoints of efficacy was compared.

RESULTS:
Treatment with either cholic acid (n=16) or CDCA (n=26) resulted in a clinically meaningful lowering from baseline of the bile alcohol 5β-cholestane-3α,7α,12α,25-tetrol-3-O-β-glucuronide in urine. The average % reduction from baseline was 70% for cholic and 90% for CDCA, indicating both bile acids effectively reduce bile acid/alcohol synthesis with the difference unlikely to be clinically significant. Cholic acid reduces 5-cholestanol levels, and in CTX patients with neonatal cholestasis led to normalization of liver histology and resolution of the inflammatory activity observed pre-treatment.

DISCUSSION/CONCLUSION:
We confirm that cholic acid is as effective as CDCA on the key biochemical endpoints in CTX. In conclusion, based on its safety profile, and its biochemical effectiveness, cholic acid should be considered in the treatment pediatric CTX patients, especially those presenting with neonatal cholestasis.