{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T10:58:10Z","timestamp":1789556290848,"version":"build-2803163510"},"reference-count":97,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Retrophin, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Bile acid synthesis disorders (BASDs) represent a distinct category of progressive familiar cholestatic liver disease. A novel targeted mass spectrometry assay was developed for the accurate measurement of the major urinary atypical bile acids and bile alcohols that are biomarkers for HSD3B7, AKR1D1, CYP7B1 and CYP27A1 deficiencies, the four most common BASDs. Methods: Stable-isotope dilution UPLC tandem mass spectrometry was used for the simultaneous quantification of 12 key atypical bile acid biomarkers in urine from patients with BASD. Typical concentration ranges for these metabolites were established from urine samples from patients with biochemically and\/or genetically confirmed BASD and compared with non-cholestatic and cholestatic controls. Results: The separation of major 3\u03b2-hydroxy-\u03945-bile acid sulfates, taurine- and glycine-conjugated 3-oxo-\u03944-bile acids, and bile alcohol glucuronides was achieved in a 20 min chromatographic run with intra- and inter-batch imprecisions of &lt;15% for all metabolites. The mean \u00b1 SEM urinary concentration of total 3\u03b2-sulfated-\u03945-cholenoic acids in patients with HSD3B7 deficiency was 704 \u00b1 204 \u00b5mol\/L (n = 22), approximately 2000-fold higher than in cholestastic patients (n = 168) or non-cholestatic controls (n = 127). Similarly, the concentration of 5\u03b2-cholestane-3\u03b1,7\u03b1,12\u03b1,24,25-pentol-glucuronide, the major bile alcohol, in patients with CYP27A1 deficiency was 95 \u00b1 17 \u00b5mol\/L (n = 12). For CYP7B1 deficiency, two confirmed cases showed elevated levels (average, 7.5 \u00b5mol\/L) of the glycine conjugate of 3\u03b2-sulfooxy-\u03945-bile acid. In AKR1D1 deficiency, total 3-oxo-\u03944-bile acids in urine were elevated (81 \u00b1 16 \u00b5mol\/L, n = 48), but concentrations showed overlap with cholestatic and non-cholestatic controls. Conclusions: A novel quantitative tandem mass spectrometry assay is described for the measurement of the major atypical metabolites and biomarkers in urine applicable to the accurate monitoring of treatment responses, and for the first time typical concentration ranges are established for each of these BASDs.<\/jats:p>","DOI":"10.3390\/metabo16070436","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T01:03:23Z","timestamp":1782263003000},"page":"436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Monitoring Atypical Metabolite Biomarkers in Patients with Bile Acid Synthesis Disorders by a Novel Targeted Tandem Mass Spectrometry Assay"],"prefix":"10.3390","volume":"16","author":[{"given":"Kenneth D. R.","family":"Setchell","sequence":"first","affiliation":[{"name":"Clinical Mass Spectrometry, Division of Pathology and Laboratory Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4156-3294","authenticated-orcid":false,"given":"Xueheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Clinical Mass Spectrometry, Division of Pathology and Laboratory Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Reed","sequence":"additional","affiliation":[{"name":"Clinical Mass Spectrometry, Division of Pathology and Laboratory Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wujuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Mass Spectrometry, Division of Pathology and Laboratory Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1097\/01.mpg.0000226386.79483.7b","article-title":"Defects in bile acid biosynthesis\u2014Diagnosis and treatment","volume":"43","author":"Setchell","year":"2006","journal-title":"J. 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