Title: Long-Term Outcomes of Nonalcoholic Fatty Liver Disease: From Nonalcoholic Steatohepatitis to Nonalcoholic Steatofibrosis
Abstract: The following commentary discusses a landmark article published in CGH and is part of a series that celebrates the journal's 15th year of publication. Landmark articles were chosen by the CGH Board of Editors and represent discoveries that advanced the science and practice of gastroenterology.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Although the term nonalcoholic steatohepatitis (NASH) was coined in 1989, it took another decade to recognize that NASH is a part of the clinicopathologic spectrum of nonalcoholic fatty liver disease (NAFLD) with subtypes with differential potential for progression.1Matteoni C.A. Younossi Z.M. Gramlich T. et al.Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Google Scholar In 2009, we published one of the first long-term outcomes study of NAFLD subjects in Clinical Gastroenterology and Hepatology.2Rafiq N. Bai C. Fang Y. et al.Long-term follow-up of patients with nonalcoholic fatty liver.Clin Gastroenterol Hepatol. 2009; 7: 234-238Google Scholar In this study, subjects with biopsy-proven NAFLD with long-term outcomes data from the National Death Index were followed for a maximum of 28.5 years.2Rafiq N. Bai C. Fang Y. et al.Long-term follow-up of patients with nonalcoholic fatty liver.Clin Gastroenterol Hepatol. 2009; 7: 234-238Google Scholar Although the study showed that the most common cause of death in the NAFLD cohort was cardiac related, subjects with biopsy-proven NASH experienced significantly increased liver-related mortality as compared with NAFLD subjects whose liver biopsies did not indicate steatohepatitis. This and other subsequent studies also documented that presence of type II diabetes in NAFLD is an independent predictor of liver-related and overall mortality.3Younossi Z.M. Gramlich T. Matteoni C.A. et al.Nonalcoholic fatty liver disease in patients with type 2 diabetes.Clin Gastroenterol Hepatol. 2004; 2 (erratum in Clin Gastroenterol Hepatol 2004;2:522): 262-265Google Scholar, 4Stepanova M. Rafiq N. Makhlouf H. et al.Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).Dig Dis Sci. 2013; 58: 3017-3023Google Scholar This long-term study was followed by several other similar studies reporting almost identical results. Although our original findings still hold true today, there are several other advances in the field of NAFLD that are worthy of a commentary. In this context, we believe that the burden of NAFLD should be assessed in a comprehensive manner including its impact on clinical, economic, and patient-reported outcomes. The clinical impact of NAFLD relates to its prevalence, incidence, and progression. The global prevalence of NAFLD is estimated to be around 25%.5Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease: meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Google Scholar Although fewer studies are available regarding the incidence of NAFLD and NASH, they seem to follow the same trends as the rates for obesity.5Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease: meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Google Scholar In terms of progressiveness, there is now consensus that NASH is the subtype of NAFLD that can progress to cirrhosis and its complications.1Matteoni C.A. Younossi Z.M. Gramlich T. et al.Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Google Scholar, 2Rafiq N. Bai C. Fang Y. et al.Long-term follow-up of patients with nonalcoholic fatty liver.Clin Gastroenterol Hepatol. 2009; 7: 234-238Google Scholar, 3Younossi Z.M. Gramlich T. Matteoni C.A. et al.Nonalcoholic fatty liver disease in patients with type 2 diabetes.Clin Gastroenterol Hepatol. 2004; 2 (erratum in Clin Gastroenterol Hepatol 2004;2:522): 262-265Google Scholar, 4Stepanova M. Rafiq N. Makhlouf H. et al.Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).Dig Dis Sci. 2013; 58: 3017-3023Google Scholar, 5Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease: meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Google Scholar, 6Younossi Z.M. Stepanova M. Rafiq N. et al.Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality.Hepatology. 2011; 53: 1874-1882Google Scholar, 7Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397Google Scholar, 8Dulai P.S. Singh S. Patel J. et al.Increased risk of mortality by fibrosis stage in non-alcoholic fatty liver disease: systematic review and meta-analysis.Hepatology. 2017; 65: 1557-1565Google Scholar There is also significant evidence suggesting that subjects with NAFLD are at increased risk for hepatocellular carcinoma,9Younossi Z.M. Otgonsuren M. Henry L. et al.Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.Hepatology. 2015; 62: 1723-1730Google Scholar and a small proportion of these cases of hepatocellular carcinoma can occur in the absence of cirrhosis.10Mittal S. Sada Y.H. El-Serag H.B. et al.Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population.Clin Gastroenterol Hepatol. 2015; 13: 594-601Abstract Full Text Full Text PDF Scopus (176) Google Scholar Furthermore, there is substantial indirect evidence that most cases of cryptogenic cirrhosis in the United States are related to NASH and NASH can recur after liver transplantation.11Ong J. Younossi Z.M. Non-alcoholic fatty liver disease after liver transplantation: a case of nurture and nature.Am J Gastroenterol. 2010; 105: 621-623Google Scholar In the context of increasing trends in its prevalence, NASH has now become the second most common indication for liver transplantation.12Wong R.J. Cheung R. Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.Hepatology. 2014; 59: 2188-2195Google Scholar In addition to the increasing prevalence in the general population, NAFLD prevalence rates are much higher in those with diabetes and severely obese subjects undergoing weight reduction surgery. Furthermore, the risk of NAFLD and NASH can vary by ethnicity.13Saab S. Manne V. Nieto J. et al.Nonalcoholic fatty liver disease in Latinos.Clin Gastroenterol Hepatol. 2016; 14 (quiz e9–e10): 5-12Abstract Full Text Full Text PDF Scopus (64) Google Scholar In the United States, NAFLD has been found to be more common in Mexican Americans as compared with non-Hispanic whites and non-Hispanic blacks.13Saab S. Manne V. Nieto J. et al.Nonalcoholic fatty liver disease in Latinos.Clin Gastroenterol Hepatol. 2016; 14 (quiz e9–e10): 5-12Abstract Full Text Full Text PDF Scopus (64) Google Scholar Even within an ethnic group, there are differences according to the country of origin.13Saab S. Manne V. Nieto J. et al.Nonalcoholic fatty liver disease in Latinos.Clin Gastroenterol Hepatol. 2016; 14 (quiz e9–e10): 5-12Abstract Full Text Full Text PDF Scopus (64) Google Scholar However, African Americans have the lowest prevalence of NAFLD despite having higher prevalence rates of the risk factors associated with NAFLD (obesity, type 2 diabetes mellitus, and hypertension).13Saab S. Manne V. Nieto J. et al.Nonalcoholic fatty liver disease in Latinos.Clin Gastroenterol Hepatol. 2016; 14 (quiz e9–e10): 5-12Abstract Full Text Full Text PDF Scopus (64) Google Scholar These variations suggest that development of NAFLD is influenced by both nature (genetics) and nurture (environment, diet). The exact contribution of these factors to the development of NAFLD and NASH may be different throughout the world and is not well understood. One interesting and intriguing issue is that about 18% of all NAFLD cases in the United States are lean according to body mass index threshold.14Younossi Z.M. Stepanova M. Negro F. et al.Nonalcoholic fatty liver disease in lean individuals in the United States.Medicine (Baltimore). 2012; 91: 319-327Google Scholar In contrast, there is higher prevalence of lean NAFLD in certain Asian countries with a higher to lower gradient of lean NAFLD from rural to urban areas. These data suggest that NAFLD and NASH are really just phenotypes reflecting several different underlying pathogenic mechanisms in different regions of the world. It is important to note that not all subjects with NASH progress to cirrhosis. A small proportion of NASH subjects may even regress spontaneously.15McPherson S. Hardy T. Henderson E. et al.Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.J Hepatol. 2015; 62: 1148-1155Google Scholar Nevertheless, it has become important to determine which pathologic features seen in the liver biopsy of subjects with NASH can predict long-term outcomes of mortality. In this context, our group was the first to show that presence of significant hepatic fibrosis was the only independent predictor of liver-related mortality in NASH.6Younossi Z.M. Stepanova M. Rafiq N. et al.Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality.Hepatology. 2011; 53: 1874-1882Google Scholar This was subsequently confirmed in another multicenter study and a recent meta-analysis.7Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397Google Scholar, 8Dulai P.S. Singh S. Patel J. et al.Increased risk of mortality by fibrosis stage in non-alcoholic fatty liver disease: systematic review and meta-analysis.Hepatology. 2017; 65: 1557-1565Google Scholar In addition to the importance of hepatic fibrosis in predicting liver-related mortality, it is also the most reliable pathologic feature assessed by pathologists. In contrast, hepatocyte ballooning, Mallory-Denk bodies, and lobular inflammation that are key components of histologic diagnosis of NASH suffer from higher interobserver and intraobserver variability and are less reliable.16Younossi Z.M. Gramlich T. Liu Y.C. et al.Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations.Mod Pathol. 1998; 11: 560-565Google Scholar This makes the histologic outcome of "NASH resolution" quite problematic and emphasizes the superiority of "fibrosis improvement" as the most relevant and reliable histologic outcome. Finally, most efforts to develop the noninvasive radiologic and serum biomarkers for subjects with NASH (wet and dry biomarkers) are focused on determining stage of hepatic fibrosis. Although the current generation of noninvasive biomarkers is unable to replicate the accuracy the liver biopsy, future tests are highly likely to be quite accurate. While awaiting the availability of new (more accurate) markers, it is prudent to focus on NAFLD with fibrosis as the most clinically relevant and reliable disease entity. In this context, we recently classified our NAFLD cohort as having either nonalcoholic steatofibrosis (steatosis with fibrosis with or without other features) or NASH.17Younossi Z.M. Stepanova M. Rafiq N. et al.Non-alcoholic steatofibrosis is independently associated with both overall mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).Hep Communication. June 2017; (http://dx.doi.org/10.1002/hep4.1054)Google Scholar The long-term data from this study show that both NASH and nonalcoholic steatofibrosis diagnostic categories are associated with increased liver-related mortality with almost identical fit statistics. In contrast, only steatofibrosis is associated with increased overall mortality.17Younossi Z.M. Stepanova M. Rafiq N. et al.Non-alcoholic steatofibrosis is independently associated with both overall mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD).Hep Communication. June 2017; (http://dx.doi.org/10.1002/hep4.1054)Google Scholar Entering a new era of developing treatment regimens for subjects with NASH, it is important to focus on the type of liver disease that is most clinically relevant. Furthermore, one must choose clinical trial endpoints that represent the best surrogate for mortality in NAFLD and are also most robust and reliable. In this context, subjects with steatofibrosis may be the most clinically relevant and improvement of fibrosis in NASH may be the most robust endpoint. To capture the comprehensive impact of NAFLD, it is important to assess its economic impact and its burden on patient experience. Studies have shown that patients with NAFLD experience impairment of their health-related quality of life with significant impairment in physical functioning and vitality.18Golabi P. Otgonsuren M. Cable R. et al.Non-alcoholic fatty liver disease (NAFLD) is associated with impairment of health related quality of life (HRQOL).Health Qual Life Outcomes. 2016; 14: 18Google Scholar Although these assessments have generally been performed using the generic PRO instruments, a disease-specific health-related quality of life tool was recently developed.19Younossi Z.M. Stepanova M. Henry L. et al.A disease-specific quality of life instrument for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: CLDQ-NAFLD.Liver Int. 2017 Feb 17; (http://dx.doi.org/10.1111/liv.13391)Google Scholar The disease-specific CLDQ-NAFLD has been fully validated and is currently being used in clinical trials for treatment of NAFLD. Finally, the economic burden of NAFLD can be enormous. In recent studies using the Medicare database, a growing inpatient and outpatient cost trend for Medicare subjects with NAFLD was documented.20Sayiner M. Otgonsuren M. Cable R. et al.Variables associated with inpatient and outpatient resource utilization among Medicare beneficiaries with nonalcoholic fatty liver disease with or without cirrhosis.J Clin Gastroenterol. 2017; 51: 254-260Google Scholar, 21Younossi Z.M. Zheng L. Stepanova M. et al.Clinical outcomes and resource utilization in Medicare patients with chronic liver disease: a historical cohort study.BMJ Open. 2014; 4: e004318Google Scholar Furthermore, a formal economic analysis estimated the economic burden of NAFLD in the United States and Europe (Germany, France, Italy, and United Kingdom) to be approximately $103 billion and €35 billion, respectively. Most of this cost is driven by the clinical care of NAFLD subjects without NASH. In contrast, if one focuses only on NAFLD subjects with clinically relevant liver disease (NAFLD with fibrosis), the annual expenditures in the United States are estimated to be between $10–$15 billion.22Younossi Z.M. Blissett D. Blissett R. et al.The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe.Hepatology. 2016; 64: 1577-1586Google Scholar In this context, we believe this is the group of subjects with NAFLD who are at the greatest risk for adverse outcomes and should be the target of treatment interventions with more manageable economic burden. Despite these advancements in the understanding of NAFLD, several challenges remain. First, there is a tremendous lack of appreciation of the clinical importance of NAFLD in the primary care setting and among the policy makers and payers. Second, despite the increasing global epidemic of NAFLD, there seems to be differences in pathogenic mechanisms of this disease which makes a "single pill" approach to this disease challenging and probably impossible. Third, the current gold standard for NASH and fibrosis is a liver biopsy with its potential flaws. Although several noninvasive diagnostic methods are being developed, none have been fully validated and accepted in clinical practice. Nevertheless, given the importance of fibrosis in NAFLD and NASH, the most promising technologies focus on fat and fibrosis (ie, steatofibrosis). Finally, in terms of treatment, currently there are limited options. In this context, weight loss through lifestyle modification is effective but is hard to achieve and sustain. Nevertheless, many new treatments are being evaluated for treatment of NASH in phase 2 and 3 clinical trials. Although it is too early to determine their efficacy and safety, treatments that focus on reducing fibrosis seem to hold the most promise. Nevertheless, it is important to recognize that future treatment of NASH or steatofibrosis may include an initial phase of combination of drugs targeting different relevant pathways followed by a maintenance long-term phase. This phase is necessary because NASH, like other manifestations of metabolic syndrome (eg, dyslipidemia), may not be "cured" but managed with chronic treatment similar to the use of statins for hypercholesterolemia. In this context, not only the efficacy but also the safety of these regimens will be of paramount importance. In summary, since our publication of long-term outcomes of NAFLD patients in 2009,2Rafiq N. Bai C. Fang Y. et al.Long-term follow-up of patients with nonalcoholic fatty liver.Clin Gastroenterol Hepatol. 2009; 7: 234-238Google Scholar there is substantial evidence supporting the tremendous and comprehensive impact of NAFLD on the individual patients and the society. It is now known that presence of significant fibrosis in NAFLD is the strongest independent predictor of mortality. In this context, development of wet or dry noninvasive biomarkers to accurately determine the stage of fibrosis in NAFLD is of greatest clinical importance. Furthermore, safe and effective drug regimens (possibly combination regimens) that reduce fibrosis should have an important impact on liver-related outcomes and patient-reported outcomes. Long-Term Follow-Up of Patients With Nonalcoholic Fatty LiverClinical Gastroenterology and HepatologyVol. 7Issue 2PreviewNonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) convincingly. NASH is the only subtype of NAFLD that has been shown to progress relatively, although these findings were reported from studies with short follow-up periods. We assessed the long-term outcomes of a NAFLD cohort. Full-Text PDF