Attribution of Nonalcoholic Steatohepatitis as an Etiology of Cirrhosis for Clinical Trials Eligibility: Recommendations From the Multi-stakeholder Liver Forum

Abstract

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major public health threat and it is dynamic in its natural history of disease progression. The burden of end-stage liver disease due to this condition is projected to increase by 200% to 300% over the next 2 decades.1Estes C. Razavi H. Loomba R. et al.Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.Hepatology. 2018; 67: 123-133Crossref PubMed Scopus (959) Google Scholar This has led to intense drug development efforts to establish effective therapy for this condition.2Rotman Y. Sanyal A.J. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.Gut. 2017; 66: 180-190Crossref PubMed Scopus (286) Google Scholar Two major approaches are being taken to treat nonalcoholic steatohepatitis (NASH): (1) targeting the metabolic underpinning of the disease and other upstream drivers of disease activity,2Rotman Y. Sanyal A.J. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.Gut. 2017; 66: 180-190Crossref PubMed Scopus (286) Google Scholar and (2) targeting downstream elements of disease course, such as fibrosis, to reduce disease progression.2Rotman Y. Sanyal A.J. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.Gut. 2017; 66: 180-190Crossref PubMed Scopus (286) Google Scholar The greatest and most urgent unmet need is to develop effective therapy for those patients who already have developed cirrhosis and are thus at the highest risk of liver-related adverse outcomes. A major challenge, however, in conducting clinical trials for NASH cirrhosis is an accurate case definition for eligibility into such trials. It may be straightforward in clinical practice to attribute NASH as the likely cause of cirrhosis in patients without competing etiologies; however, the stringent case definitions required to standardize trial enrollment across clinical trials of investigational drugs or lifestyle interventions are currently lacking for NASH-related cirrhosis. NASH is a histological diagnosis and yet many patients with NASH-related cirrhosis do not have histological confirmation at the time of their clinical presentation. If a liver biopsy is performed in patients with NASH cirrhosis, liver histology may not display typical histological lesions such as steatosis and hepatocyte ballooning in approximately 40% of patients.3Younossi Z. Stepanova M. Sanyal A.J. et al.The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.J Hepatol. 2018; 69: 1365-1370Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar The Liver Forum has identified the development of consensus definitions for NASH cirrhosis as an important step toward developing effective therapies for this condition. The Liver Forum is a multi-stakeholder group including academic investigators from around the world, members of professional organizations (American Association for the Study of Liver Diseases and European Association for Study of the Liver), representatives from regulatory agencies (US Food and Drug Administration and European Medicines Agency), drug developers from the pharmaceutical industry, and patient advocates. This article summarizes the work of the NASH Cirrhosis Working Group to specifically focus on case definitions that would allow attribution of NASH as the etiology for compensated cirrhosis. This document summarizes the current consensus of the working group, which will revisit this topic and update recommendations as new data become available. The general diagnosis of cirrhosis was addressed in a previous document of the Liver Forum4Siddiqui M.S. Harrison S.A. Abdelmalek M.F. 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: 2001-2012Crossref PubMed Scopus (85) Google Scholar and thus will not be addressed here. A formal and consistent methodology was followed to reach consensus recommendations. First, the literature, existing guidelines, and previous and ongoing clinical trials were all reviewed by the Working Group (Appendix). A standardized discussion format was established, and data summarized in an objective and measurable fashion. Multiple conference calls and correspondence were held to establish consensus when there was divergence of opinion. The steps involved in developing these consensus-based recommendations are described in Supplementary Table 1. These steps were in line with what has been used by other internationally regarded organizations,5World Health OrganizationWHO handbook for guideline development. World Health Organization, Geneva2014Google Scholar and by the Liver Forum to develop recommendations for baseline parameters,6Patel Y.A. Imperial J.C. Muir A.J. et al.Baseline parameters in clinical trials for nonalcoholic steatohepatitis: recommendations from the Liver Forum.Gastroenterology. 2017; 153: 621-625.e7Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar case definitions,4Siddiqui M.S. Harrison S.A. Abdelmalek M.F. 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: 2001-2012Crossref PubMed Scopus (85) Google Scholar endpoints,7Cheung A. Neuschwander-Tetri B.A. Kleiner D.E. et al.Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the Liver Forum.Hepatology. 2019; 70: 1841-1855Crossref PubMed Scopus (50) Google Scholar and pediatric trials.8Vos M.B. Dimick-Santos L. Mehta R. et al.Factors to consider in development of drugs for pediatric nonalcoholic fatty liver disease.Gastroenterology. 2019; 157: 1448-1456.e1Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Liver biopsy is currently the reference standard to determine NASH as the cause for cirrhosis based on specific histological features including steatosis, inflammation, and hepatocyte ballooning, in addition to the presence of cirrhosis. In the context of NASH clinical trials, an NAFLD Activity Score (NAS) of 4 points or higher has been used to identify patients with clinically significant disease activity9Kleiner D.E. Brunt E.M. Van Natta M. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (7113) Google Scholar; however, some of the histological features indicating disease activity may not always be readily apparent or easily identified in patients with NASH with cirrhosis, and thus, the NAS can be lower than 4. This may lead to a higher percentage of screen failures in NASH cirrhosis trials because of the inability to detect active steatohepatitis in such patients.10Kleiner D.E. Makhlouf H.R. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children.Clin Liver Dis. 2016; 20: 293-312Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar In clinical practice, when a patient presents with clinically evident cirrhosis, there is less enthusiasm to recommend a liver biopsy when the clinical picture is consistent with fatty liver disease, either because of concern for heightened risk of complications or because of the patient’s reluctance. If a patient currently presenting with cirrhosis (but without a recent liver biopsy) has previously documented NAFLD, it is reasonable to consider NASH as the likely etiology, as long as other possible etiologies are comprehensively excluded. Some histological features (eg, steatosis) disappear as cirrhosis develops and progresses, making identification of the underlying etiology of cirrhosis difficult (cryptogenic cirrhosis is considered in more detail below).10Kleiner D.E. Makhlouf H.R. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children.Clin Liver Dis. 2016; 20: 293-312Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar The working group’s consensus was that the case definition of NASH-related cirrhosis for inclusion in clinical trials may be qualitatively categorized according to a hierarchy based on the degree of certainty of NASH as the cause of cirrhosis, for example, definitive, probable, and possible categories (see definitions that follow and Table 1). Within each category, the definitions are listed by decreasing order of confidence (eg, 2a is considered more robust than 2b). When some of the histological evidence is absent, the presence of concomitant metabolic risk factors (history of type 2 diabetes mellitus [T2DM], hypertension, dyslipidemia, or obesity) strengthens the likelihood that NASH is the cause of cirrhosis. A diagnosis of NASH cirrhosis can be made only in the absence of other etiologies, such as excessive alcohol intake, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alpha-1-antitrypsin deficiency, and autoimmune hepatitis.4Siddiqui M.S. Harrison S.A. Abdelmalek M.F. 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: 2001-2012Crossref PubMed Scopus (85) Google Scholar,9Kleiner D.E. Brunt E.M. Van Natta M. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (7113) Google Scholar,11Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.Gastroenterology. 2012; 142: 1592-1609Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar1.Definite NASH cirrhosisThe attribution of NASH as a definite cause of cirrhosis includes1a.Patients with current liver biopsy showing cirrhosis with steatohepatitis.1b.Patients with a previous biopsy showing steatohepatitis, but now with evidence of cirrhosis, either by clinical history or current features, imaging, noninvasive tests, or biopsy.Among individuals with a current biopsy, histological findings consistent with active steatohepatitis may have disappeared. In such instances, there should be at least 1 metabolic risk factor to support the likelihood of NASH as the underlying cause of cirrhosis.1c.Patients with a current biopsy showing cirrhosis with steatosis (but no findings of active steatohepatitis) together with at least 2 coexisting or historical features of metabolic comorbidities including obesity and/or T2DM to corroborate a diagnosis of NASH as the cause of cirrhosis (Table 1).Table 1NASH Cirrhosis: Liver Forum Consensus Definitions for Clinical TrialsDefinitiveProbablePossible1a.Current biopsy shows cirrhosis with steatohepatitis. There is no evidence for a competing etiology.aCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis.1b.Previous biopsy showed steatohepatitis, but now with cirrhosis either by clinical history or current features, imaging, noninvasive tests, or biopsy. If there is a current biopsy, it does not show evidence of steatosis or steatohepatitis, as these histological findings may have disappeared (burn-out). There is no evidence for a competing etiology.aCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis. There is at least one coexisting or history of metabolic comorbiditybComorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol. to corroborate a diagnosis of NAFLD.1c.Current biopsy shows cirrhosis with steatosis. There is no evidence for a competing etiology.aCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis. There are at least 2 coexisting or history of metabolic comorbidities,bComorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol. including obesitycBody mass index ≥30 kg/m2 or central obesity per consensus guidelines. and/or T2DM to corroborate a diagnosis of NAFLD.2a.Previous biopsy shows steatosis, but now with cirrhosis, either by clinical history or current features, imaging, noninvasive tests, or biopsy. If there is a current biopsy, it does not show evidence of steatosis or steatohepatitis as histological findings may have disappeared (burn-out). There is no evidence for a competing etiology.aCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis. There are at least 2 coexisting or history of metabolic comorbidities,bComorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol. including obesitycBody mass index ≥30 kg/m2 or central obesity per consensus guidelines. and/or T2DM to corroborate a diagnosis of NAFLD.2b.Patient with cirrhosis with current or previous imaging showing steatosis. There is no liver histology available. There is no evidence for a competing etiology.aCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis. There are at least 2 coexisting or history of metabolic comorbidities,bComorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol. including obesitycBody mass index ≥30 kg/m2 or central obesity per consensus guidelines. and/or T2DM to corroborate a diagnosis of NAFLD.2c.“Cryptogenic cirrhosis” without current or previous evidence of steatosis by imaging or steatosis/steatohepatitis by histology. There is no evidence for a competing etiologyaCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis. but there are at least 2 coexisting or history of metabolic comorbidities,bComorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol. including obesitycBody mass index ≥30 kg/m2 or central obesity per consensus guidelines. and/or T2DM to corroborate a diagnosis of NAFLD.3a.“Cryptogenic cirrhosis” without current or previous evidence of steatosis by imaging or steatosis/steatohepatitis by histology. There is no evidence for a competing etiologyaCompeting etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis. but there is at least 1 coexisting or history of metabolic comorbidity,bComorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol. including obesitycBody mass index ≥30 kg/m2 or central obesity per consensus guidelines. and/or T2DM.3b.Patients with previously eradicated HCV, or remote history of heavy alcohol consumption, but currently have evidence of cirrhosis and histological evidence of steatohepatitis.HCV, chronic hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus.a Competing etiology: including alcohol, viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Alpha-1-Antitrypsin deficiency and autoimmune hepatitis.b Comorbidities: History of type 2 diabetes mellitus, hypertension, dyslipidemia or obesity. We suggest a duration of at least 5 years; however, this can be discussed with regulators for each study protocol.c Body mass index ≥30 kg/m2 or central obesity per consensus guidelines. Open table in a new tab HCV, chronic hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus. The 1a definition has the highest degree of certainty, whereas criteria for metabolic comorbidities were added to both 1b and 1c to increase the likelihood of diagnosing NASH cirrhosis in the absence of a recent biopsy demonstrating cirrhosis and steatohepatitis. In the case where there is less histological evidence for NASH (eg, 1c vs 1b), requiring more than 1 comorbidity may increase the certainty of NASH diagnosis, a plausible conclusion that is supported by recent data from NASH cirrhosis studies (see Table 1 for a list of comorbidities).3Younossi Z. Stepanova M. Sanyal A.J. et al.The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.J Hepatol. 2018; 69: 1365-1370Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar,12Harrison S.A. Abdelmalek M.F. Caldwell S. et al.Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis.Gastroenterology. 2018; 155: 1140-1153Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Further, when individuals meeting such criteria undergo liver transplantation, there is approximately 88% recurrence of NAFLD over time, compared with approximately 20% incidence of NAFLD among those with cirrhosis due to other etiologies.13Bhati C. Idowu M.O. Sanyal A.J. et al.Long-term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis-related cirrhosis.Transplantation. 2017; 101: 1867-1874Crossref PubMed Scopus (83) Google Scholar NASH is strongly associated with metabolic syndrome, the definition of which has been harmonized across several academic societies.14Alberti K.G. Eckel R.H. Grundy S.M. et al.Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (9986) Google Scholar However, both hypertension and dyslipidemia may be less evident once patients develop cirrhosis because of the dynamic nature and pathophysiological changes associated with cirrhosis.15Iwakiri Y. Shah V. Rockey D.C. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions.J Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar example, associated with cirrhosis Y. Shah V. Rockey D.C. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions.J Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar and history of T2DM and obesity has not only been associated with NAFLD but with of the S. et of NAFLD from steatosis to for and clinical Hepatol. Full Text Full Text PDF PubMed Scopus Google S. R. et and in patients with nonalcoholic fatty liver disease, and with Hepatol. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar It is currently the duration of these comorbidities the disease to cirrhosis. it is likely that the the duration of these obesity and T2DM, the the likelihood of cirrhosis development. a on this topic was not suggest that a of 5 duration is reasonable to support that coexisting metabolic to NASH however, this will validation and may as data NASH with a previous biopsy with steatosis but not steatohepatitis, and current cirrhosis, either by a clinical history or current features, imaging, noninvasive tests, or biopsy. If there is a current biopsy, it may not show evidence of steatosis or steatohepatitis, as these histological features may have disappeared. There be at least 2 coexisting or history of metabolic comorbidities including obesity and/or T2DM to support NASH as an underlying cause of with cirrhosis by a clinical history or current features, imaging, or noninvasive with current or previous imaging showing evidence of steatosis. There is no liver histology available. There are at least 2 coexisting or historical metabolic comorbidities including obesity and/or T2DM to support NASH as an underlying cause of with cirrhosis” by a clinical history or current features, imaging, noninvasive tests, or biopsy) without current or previous evidence of steatosis by imaging or steatosis/steatohepatitis by histology. There are at least 2 coexisting or historical metabolic comorbidities including obesity and/or T2DM to support NASH as an underlying cause of cirrhosis. cirrhosis and its to NASH is an of ongoing In a recent clinical Younossi et Z. Stepanova M. Sanyal A.J. et al.The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.J Hepatol. 2018; 69: 1365-1370Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar that 40% of patients with cryptogenic cirrhosis steatosis on their biopsy, their baseline biopsy no features to suggest NAFLD or to patients with NASH, patients with cryptogenic cirrhosis of metabolic the of including metabolic comorbidities in these case Z. Stepanova M. Sanyal A.J. et al.The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.J Hepatol. 2018; 69: 1365-1370Abstract Full Text Full Text PDF PubMed Scopus (33) Google J.C. et cirrhosis: clinical and risk factors for underlying disease.Hepatology. PubMed Scopus Google Scholar it has been that many of these patients will have a recurrence of NAFLD liver C. Idowu M.O. Sanyal A.J. et al.Long-term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis-related cirrhosis.Transplantation. 2017; 101: 1867-1874Crossref PubMed Scopus (83) Google M.S. et of non-alcoholic steatohepatitis and cryptogenic cirrhosis liver transplantation in the context of the metabolic 2012; PubMed Scopus Google Scholar In Younossi et Z. Stepanova M. Sanyal A.J. et al.The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.J Hepatol. 2018; 69: 1365-1370Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar showed that the cryptogenic cirrhosis group higher fibrosis more on and a higher risk of liver-related than patients with NASH cirrhosis. This that these patients are in the of their disease and likely in most need for effective NASH with cirrhosis” by a clinical history or current features, imaging, noninvasive tests, or biopsy) without current or previous evidence of steatosis by imaging or steatosis/steatohepatitis by histology. There is 1 coexisting or history of metabolic comorbidity including obesity and/or T2DM.3b.Patients with previously eradicated hepatitis C or a remote history of heavy alcohol consumption, but who currently have evidence of cirrhosis and histological evidence of steatohepatitis. with a remote history of heavy alcohol should not have evidence of cirrhosis at the time of with cryptogenic cirrhosis may have metabolic comorbidities (see Table which the likelihood of NASH as the cause of cirrhosis less this this as and recommend regulatory and such patients into a NASH cirrhosis clinical It is that the duration of a condition can be in of as as in diagnosis due to of to or a history of a patient’s may increase confidence in the duration of these however, in (eg, duration of is not always available. discussion with regulatory agencies development for the trial is patient history be considered as from being the cause of cirrhosis and for liver transplantation, many patients has been eradicated treatment with active have metabolic in M. et liver in hepatitis C patients with 2018; PubMed Scopus Google M. A. C. et cause of liver in analysis of for liver and and 2018; PubMed Scopus Google Scholar If these patients not have cirrhosis at the time of and develop cirrhosis, this can be to NASH, time has However, these patients were to have cirrhosis at the time of it is plausible that cirrhosis developed due to both and the as to what the recommendations are that the of evidence to support is not at this drugs in patients with previous a time of et fibrosis from to for hepatitis 2018; PubMed Scopus Google Scholar be to the of on those who currently have evidence of cirrhosis and histological evidence of steatohepatitis. A duration be in the case of drugs are being other of chronic liver disease should be excluded. The of NASH and other coexisting chronic liver and is the of this accurate case definition of NASH cirrhosis is for patients into clinical trials as as to across clinical trials. there are no criteria for NASH cirrhosis. This the Liver Forum to develop consensus case definitions for NASH cirrhosis for clinical trial that patients with cirrhosis may no have evidence of active steatohepatitis on biopsy at the time of enrollment and may not have a historical biopsy to establish the diagnosis, these case definitions based on of on to a of clinical and determine the likelihood that NASH is the etiology of cirrhosis. The of probable, for inclusion into a specific clinical trial in this patient should be discussed with regulatory agencies the study