Author information

• ¹Liver Consulting LLC, Dix Hills, New York, USA.
• ²Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
• ³Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA.
• ⁴Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
• ⁵Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
• ⁶Eli Lilly, Indianapolis, Indiana, USA.
• ⁷Division of Hepatology and Nutrition, Food and Drug Administration, Silver Spring, Maryland, USA.
• ⁸Division of Gastroenterology, Georgetown University Hospital, Washington, District of Columbia, USA.
• ⁹Center for Drug Evaluation and Research Office of New Drugs, Office of Inflammation and Immunity, Division of Hepatology and Nutrition, US Food and Drug Administration, Silver Spring, Maryland, USA.
• ¹⁰Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
• ¹¹Fatebenefratelli Gemelli Isola - Rome, Sacred Heart Catholic Univesity, Rome, Italy.
• ¹²Research and Development, CymaBay Therapeutics, Inc., Newark, California, USA.
• ¹³Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
• ¹⁴Pacific Rim Pathology Group, San Diego, California, USA.
• ¹⁵University of California Berkeley, School of Public Health, Forum for Collaborative Research, Washington, District of Columbia, USA.
• ¹⁶Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana, USA.
• ¹⁷Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
• ¹⁸Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.

Abstract

Background: Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology.

Aim: To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting.

Methods: From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment.

Results: Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified.

Conclusions: Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.