Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Nov;50(10):1100-1111.
doi: 10.1111/apt.15503. Epub 2019 Oct 3.

Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials

Rish K Pai  1 , David E Kleiner  2 , John Hart  3 , Oyedele A Adeyi  4 , Andrew D Clouston  5 , Cynthia A Behling  6 , Dhanpat Jain  7 , Sanjay Kakar  8 , Mayur Brahmania  9 , Lawrence Burgart  10 , Kenneth P Batts  10 , Mark A Valasek  11 , Michael S Torbenson  12 , Maha Guindi  13 , Hanlin L Wang  13 , Veeral Ajmera  11 , Leon A Adams  14 , Claire E Parker  9 , Brian G Feagan  9 , Rohit Loomba  11 , Vipul Jairath  9
Affiliations

Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials

Rish K Pai et al. Aliment Pharmacol Ther. 2019 Nov.

Abstract

Background: There is substantial variation in how histologic definitions and scoring systems of non-alcoholic fatty liver disease (NAFLD) are operationalised.

Aim: To develop a consensus-based framework for standardising histologic assessment of liver biopsies in clinical trials of NAFLD.

Methods: An expert panel of 14 liver pathologists and three hepatologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 130 items derived from literature review and expert opinion were rated by each panel member on a 1-9 scale. Disagreement was defined as ≥5 ratings in the lowest (1-3) and highest (7-9) categories. Items were classified as inappropriate (median 1-3.5 without disagreement), uncertain (median 3.5-6.5 or any median with disagreement) or appropriate (median 6.5-9 without disagreement). Survey results were discussed as a group before voting.

Results: Current measures of disease activity and fibrosis may not fully capture important features of non-alcoholic steatohepatitis (NASH). Alternative methods to evaluate ballooning degeneration are needed. Panellists were uncertain whether portal inflammation, degree of steatosis and Mallory-Denk bodies are important measures of disease activity. Furthermore, it was felt that current staging systems do not capture the full spectrum of fibrosis in NASH. A consensus definition and sub-stages for bridging fibrosis are needed. The severity of perisinusoidal fibrosis should be captured at all stages. Lastly, a method to evaluate features of fibrosis regression should be developed.

Conclusion: The operating properties of the modifications proposed should be evaluated prospectively to determine reliability and responsiveness.

PubMed Disclaimer

Conflict of interest statement

STATEMENT OF INTERESTS

Authors’ declaration of personal interests:

RL has received funding support from NIEHS (5P42ES010337), NCATS (5UL1TR001442), and NIDDK (R01DK106419); RKP has received consulting income from Genentech, Eli Lilly, and Robarts Clinical Trials Inc.; DEK has no relevant conflicts of interest to disclose; JH has no relevant conflicts of interest to disclose; OAA has no relevant conflicts of interest to disclose; ADC has no relevant conflicts of interest to disclose; CAB has received consulting fees from ICON and Covance through Pacific Rim Pathology Group; DJ has no relevant conflicts of interest to disclose; SK has no relevant conflicts of interest to disclose; MB has received speaker fees from Merck; LB has no relevant conflicts of interest to disclose; KPB has no relevant conflicts of interest to disclose; MAV has no relevant conflicts of interest to disclose; MST has no relevant conflicts of interest to disclose; MG has no relevant conflicts of interest to disclose; HLW has no relevant conflicts of interest to disclose; VA has no relevant conflicts of interest to disclose; LAA has no relevant conflicts of interest to disclose; CEP is an employee of Robarts Clinical Trials, Inc; BGF has received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG and UCB; consulting fees from Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestle, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd. and Zyngenia; speakers bureau fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts and UCB Pharma; is a scientific advisory board member for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestle, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma; and is the Senior Scientific Officer of Robarts Clinical Trials Inc; RL serves as a consultant or advisory board member for Arrowhead Pharmaceuticals, AstraZeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol-Myer Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed, Gemphire, Gilead, Glympse bio, GNI, GRI Bio, Intercept, Ionis, Janssen Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus, Sanofi, Siemens, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt, Pfizer, Prometheus, and Siemens. He is also co-founder of Liponexus, Inc; VJ has received consulting fees from AbbVie, Takeda, Eli Lilly, Pfizer, Janssen, Ferring, Shire, Merck, GSK, Celltrion, and Robarts Clinical Trials Inc; serves as an advisory board member for AbbVie, Takeda, Janssen, Arena, GSK, Eli Lilly and Ferring; and has received speakers’ bureau fees from Takeda, AbbVie, Janssen, Pfizer, Shire and Ferring.

Comment in

References

    1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328–357. - PubMed
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84. - PubMed
    1. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11–20. - PubMed
    1. Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol 2018;69:896–904. - PubMed
    1. Siddiqui MS, Harrison SA, Abdelmalek MF, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology 2018;67:2001–2012. - PMC - PubMed

Publication types

MeSH terms