Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score

Rish K Pai; Vipul Jairath; Malcolm Hogan; Guangyong Zou; Oyedele A Adeyi; Quentin M Anstee; Bashar A Aqel; Cynthia Behling; Elizabeth J Carey; Andrew D Clouston; Kathleen Corey; Brian G Feagan; David E Kleiner; Christopher Ma; Stefanie C McFarlane; Mazen Noureddin; Vlad Ratziu; Mark A Valasek; Zobair M Younossi; Stephen A Harrison; Rohit Loomba

doi:10.1002/hep.32475

Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score

Hepatology. 2022 Oct;76(4):1150-1163. doi: 10.1002/hep.32475. Epub 2022 Apr 6.

Authors

Rish K Pai¹, Vipul Jairath^{2

3

4}, Malcolm Hogan³, Guangyong Zou^{3

4

5}, Oyedele A Adeyi⁶, Quentin M Anstee^{7

8}, Bashar A Aqel⁹, Cynthia Behling^{10

11}, Elizabeth J Carey⁹, Andrew D Clouston¹², Kathleen Corey^{13

14}, Brian G Feagan^{2

3

4}, David E Kleiner¹⁵, Christopher Ma^{3

16

17}, Stefanie C McFarlane³, Mazen Noureddin¹⁸, Vlad Ratziu¹⁹, Mark A Valasek²⁰, Zobair M Younossi^{21

22}, Stephen A Harrison^{23

24}, Rohit Loomba²⁵

Affiliations

¹ Department of Laboratory Medicine & Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
² Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, Ontario, Canada.
³ Alimentiv Inc., London, Ontario, Canada.
⁴ Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada.
⁵ Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
⁷ Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
⁸ NIHR Newcastle Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
⁹ Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, Arizona, USA.
¹⁰ Pacific Rim Pathology, San Diego, California, USA.
¹¹ Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
¹² Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
¹³ Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁴ Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
¹⁶ Division of Gastroenterology & Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁷ Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁸ Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹⁹ Institute of Cardiometabolism and Nutrition, Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France.
²⁰ Department of Pathology, University of California at San Diego, La Jolla, California, USA.
²¹ Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia, USA.
²² Department of Medicine, Center for Liver Diseases, Inova Fairfax Medical Campus, Falls Church, Virginia, USA.
²³ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
²⁴ Medical Director, Pinnacle Clinical Research, San Antonio, Texas, USA.
²⁵ NAFLD 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.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Biopsy
Fibrosis
Humans
Liver / pathology
Non-alcoholic Fatty Liver Disease* / pathology
Reproducibility of Results
Severity of Illness Index

Grants and funding

U01 DK061734/DK/NIDDK NIH HHS/United States