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Abstract Details
Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score
Hepatology. 2022 Mar 25. doi: 10.1002/hep.32475. Online ahead of print.
1Department of Laboratory Medicine & Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
2Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, Ontario, Canada.
3Alimentiv Inc., London, Ontario, Canada.
4Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada.
5Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
6Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
7Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
8NIHR Newcastle Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
9Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, Arizona, USA.
10Pacific Rim Pathology, San Diego, California, USA.
11Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
12Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
13Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.
14Harvard Medical School, Boston, Massachusetts, USA.
15Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
16Division of Gastroenterology & Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
17Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
18Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
19Institute of Cardiometabolism and Nutrition, Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France.
20Department of Pathology, University of California at San Diego, La Jolla, California, USA.
21Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia, USA.
22Department of Medicine, Center for Liver Diseases, Inova Fairfax Medical Campus, Falls Church, Virginia, USA.
23Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
24Medical Director, Pinnacle Clinical Research, San Antonio, Texas, USA.
25NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA.
Abstract
Background and aims: The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS).
Approach and results: Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87.
Conclusions: After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.