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Original article
Serum metabolites detect the presence of advanced fibrosis in derivation and validation cohorts of patients with non-alcoholic fatty liver disease
  1. Cyrielle Caussy1,2,
  2. Veeral H Ajmera1,
  3. Puneet Puri3,
  4. Cynthia Li-Shin Hsu1,
  5. Shirin Bassirian1,
  6. Mania Mgdsyan1,
  7. Seema Singh1,
  8. Claire Faulkner1,
  9. Mark A Valasek4,
  10. Emily Rizo1,
  11. Lisa Richards1,
  12. David A Brenner1,5,
  13. Claude B Sirlin6,
  14. Arun J Sanyal3,
  15. Rohit Loomba1,5,7
  1. 1NAFLD Research Center, Department of Medicine, La Jolla, California, USA
  2. 2Université Lyon 1, Hospices Civils de Lyon, Lyon, California, France
  3. 3Virginia Commonwealth University, Richmond, Virginia, USA
  4. 4Department of Pathology, University of California at San Diego, La Jolla, California, USA
  5. 5Division of Gastroenterology, Department of Medicine, La Jolla, California, USA
  6. 6Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, California, USA
  7. 7Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California, USA
  1. Correspondence to Professor Rohit Loomba, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla 92093-0063, US; roloomba{at}ucsd.edu

Abstract

Objective Non-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis.

Design This is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling.

Results In the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively.

Conclusion A combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.

  • nonalcoholic steatohepatitis
  • hepatic fibrosis
  • magnetic resonance imaging

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Footnotes

  • CC, VHA and PP contributed equally.

  • Contributors CC: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, approved final submission. VA: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, approved final submission. PP: collection, analysis and interpretation of data, critical revision of the manuscript, approved final submission C-H: statistical analysis, critical revision of the manuscript, approved final submission SB: data collection, critical revision of the manuscript, approved final submission. MM: data collection, critical revision of the manuscript, approved final submission SS: data collection, critical revision of the manuscript, approved final submission Claire Faulkner: data collection, critical revision of the manuscript, approved final submission MAV: data collection, critical revision of the manuscript, approved final submission ER: patient visits, critical revision of the manuscript, approved final submission LR: patient visits, critical revision of the manuscript, approved final submission DAB: study concept and design, critical revision of the manuscript, study supervision, approved final submission CBS: analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, obtained funding, study supervision, approved final submission AJS: critical revision of the manuscript, approved final submission RL: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, obtained funding, study supervision, approved final submission

  • Funding RL is supported in part by the American Gastroenterological Association (AGA) Foundation – Sucampo – ASP Designated Research Award in Geriatric Gastroenterology and by a T. Franklin Williams Scholarship Award; Funding provided by: Atlantic Philanthropies, Inc, the John A. Hartford Foundation, OM, the Association of Specialty Professors, and the American Gastroenterological Association and grant K23-DK090303. CS and RL serve as co-PIs on the grant R01-DK106419. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. VA is supported by the AASLD Foundation Clinical and Translational Research Award. CC is supported by grants from the Société Francophone du Diabète (SFD), the Philippe Foundation and Monahan Foundation under the Fulbright program.

  • Competing interests CBS consults, advises and is on the speakers’ bureau for Bayer. He received grants from GE Healthcare

  • Patient consent Not required.

  • Ethics approval This study was Health Insurance Portability and Accountability Act (HIPAA) compliant and was approved by the UCSD Institutional Review Board 111282.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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