Nonalcoholic Fatty Liver Disease Gets Renamed as Metabolic Dysfunction–Associated Steatotic Liver Disease: Progress But With Challenges

Alcohol, viral hepatitis, and metabolic dysfunction (characterized by any 1 of the following criteria: abdominal obesity, hypertension, elevated fasting serum glucose, elevated plasma triglycerides, and low plasma high-density-lipoprotein cholesterol; Figure 1) are the major etiologies for chronic liver diseases worldwide.1Devarbhavi H. Asrani S.K. Arab J.P. et al.Global burden of liver disease: 2023 update.J Hepatol. 2023; 79: 516-537Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Liver disease secondary to metabolic dysfunction is encountered in up to 30% of the world's adult population, with a heterogeneous distribution in different countries based on the prevalence of metabolic risk factors, ethnicity, country income, diet, and lifestyle. The highest prevalence is reported in Europe and in the Americas and the lowest prevalence in African countries.2Younossi Z.M. Golabi P. Paik J.M. et al.The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.Hepatology. 2023; 77: 1335-1347Crossref PubMed Scopus (230) Google Scholar,3Riazi K. Azhari H. Charette J.H. et al.The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar Because of the increase in metabolic risk factors in teenagers and young adults, it is expected that the prevalence of liver disease associated with metabolic dysfunction will dramatically increase in the next decades.4Estes C. Anstee Q.M. Arias-Loste M.T. 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: 896-904Abstract Full Text Full Text PDF PubMed Scopus (1092) Google Scholar The rising trend in the body mass index (BMI) of children and adolescents has plateaued at high levels in many high-income countries but is accelerating in the 2 most populous countries, India and China, where one-third of the Earth's inhabitants live.5NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.Lancet. 2017; 390: 2627-2642Abstract Full Text Full Text PDF PubMed Scopus (4821) Google Scholar Alcohol consumption is the leading cause of advanced liver disease in the world1Devarbhavi H. Asrani S.K. Arab J.P. et al.Global burden of liver disease: 2023 update.J Hepatol. 2023; 79: 516-537Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and has the highest economic burden and social impact. Alcohol-related liver disease (ALD) is associated with the highest number of liver disease–attributable deaths in the Western World and is currently the leading indication for liver transplantation in Europe and the United States.6Wong R.J. Singal A.K. Trends in liver disease etiology among adults awaiting liver transplantation in the United States, 2014-2019.JAMA Netw Open. 2020; 3e1920294Crossref Scopus (125) Google Scholar The burden and prevalence of ALD runs in parallel with the amount of alcohol consumed per capita in the different regions and countries of the world7Stein E. Cruz-Lemini M. Altamirano J. et al.Heavy daily alcohol intake at the population level predicts the weight of alcohol in cirrhosis burden worldwide.J Hepatol. 2016; 65: 998-1005Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar; in this regard, European countries with higher rates of heavy alcohol consumption have a higher percentage of cirrhosis attributable to alcohol.8Karlsen T.H. Sheron N. Zelber-Sagi S. et al.The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar Other cofactors, such as genetic predisposition, smoking, and pattern of alcohol consumption, have also been shown to play a role in the prevalence and severity of ALD.9Huang D.Q. Mathurin P. Cortez-Pinto H. et al.Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors.Nat Rev Gastroenterol Hepatol. 2023; 20: 37-49Crossref PubMed Scopus (64) Google Scholar The burden of ALD is anticipated to increase if no interventions are implemented at the global level.10Julien J. Ayer T. Bethea E.D. et al.Projected prevalence and mortality associated with alcohol-related liver disease in the USA, 2019-40: a modelling study.Lancet Public Health. 2020; 5: e316-e323Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Because of the high prevalence of both alcohol consumption and metabolic risk factors, it is not surprising that these coexist as causes of liver disease in a high percentage of the world's population.10Julien J. Ayer T. Bethea E.D. et al.Projected prevalence and mortality associated with alcohol-related liver disease in the USA, 2019-40: a modelling study.Lancet Public Health. 2020; 5: e316-e323Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Also, considering the coincident geographic distribution of these risk factors, Europe and the Americas are expected to be the world regions that will be more severely affected by coexistence of both causes of liver disease. Although the effect of the combination of both obesity and alcohol on the incidence, progression, and severity of liver disease has not yet been completely understood, it appears that the factors may have synergistic effects in increasing liver disease risk when present in the same individual.11Chang Y. Ryu S. Kim Y. et al.Low levels of alcohol consumption, obesity, and development of fatty liver with and without evidence of advanced fibrosis.Hepatology. 2020; 71: 861-873Crossref PubMed Scopus (45) Google Scholar This synergistic effect of the combination of alcohol and obesity in increasing hepatic risk may have specific implications for public policy.8Karlsen T.H. Sheron N. Zelber-Sagi S. et al.The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.Lancet. 2022; 399: 61-116Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar Taking all this into account, the scientific community and stakeholder organizations associated with liver diseases determined there was a need for new terminology to cover liver disease related to alcohol alone, metabolic risk factors (until recently termed nonalcoholic fatty liver disease [NAFLD]/nonalcoholic steatohepatitis [NASH]) alone, the combination of alcohol and metabolic risk factors, and hepatic steatosis due to other specific etiologies. The new terminology more precisely describes the various causes of hepatic steatosis, and the clinical impact of this change needs to be determined. The term "nonalcoholic steatohepatitis (NASH)" was coined by Dr Jurgen Ludwig and colleagues12Ludwig J. Viggiano T.R. McGill D.B. et al.Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar to describe changes in liver pathology similar to those seen in what was then called alcoholic hepatitis but in patients not known to be consuming alcohol. That such an entity even existed was met with considerable skepticism. Thus, as stated in a personal communication by Dr Ludwig, a major medical journal and a satellite working group at a Falk liver meeting in Basel rejected the paper describing NASH under the assumption that alcohol use in these patients had not been detected. After multiple discussions with the editor, the manuscript was ultimately published in 1980 in the Mayo Clinic Proceedings,12Ludwig J. Viggiano T.R. McGill D.B. et al.Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar the journal associated with the institution where Dr Ludwig worked. The NASH entity took years to be accepted by the medical community, with only a few publications on NASH/NAFLD per year through 1990 but with a rapid increase to 5388 publications in 2022. Despite this wide acceptance of terminology, there had been several attempts to change the nomenclature, including to "metabolic dysfunction–associated fatty liver disease" (MAFLD).13Eslam M. Sanyal A.J. George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology. 2020; 158: 1999-2014Abstract Full Text Full Text PDF PubMed Scopus (1730) Google Scholar The need for nomenclature change stemmed from several reasons, but the main reason was the necessity to update the name from an exclusionary term of "nonalcoholic" to one that recognized metabolic dysfunction as the underlying disease pathogenesis. Moreover, NASH was not applicable to the pediatric population where alcohol use is hardly prevalent. The exclusion of alcohol use, as the name "nonalcoholic" implies, did not allow accurate diagnosis of people with metabolic comorbidities who use alcohol in moderate amounts but do not meet strict criteria for ALD. The term "fatty" was also perceived as stigmatizing for some patients who lived with the disease. Through an iterative process of online surveys and 2 hybrid meetings including 236 panelists across different specialties, from 56 countries, the term "fatty liver disease" was changed to "steatotic liver disease" (SLD) as an umbrella term to include all conditions with evidence of hepatic steatosis on imaging or biopsy.14Rinella M.E. Lazarus J.V. Ratziu V. et al.A multi-society Delphi consensus statement on new fatty liver disease nomenclature.Hepatology. 2023; 78: 1966-1986Crossref PubMed Scopus (166) Google Scholar SLD can now be further defined into specific subtypes to refine the cause of steatosis (Figure 1). Under this new definition, the disease previously known as NAFLD is now metabolic dysfunction–associated steatotic liver disease (MASLD), defined as steatosis in the presence of at least 1 component of metabolic syndrome in a person with no or low alcohol use (<1 standard drink a day in women, <2 standard drinks a day in men). The metabolic criteria for adults are listed in Figure 1. A specific disease type has been created for those with identical metabolic criteria but with moderate alcohol use (2–3 standard drinks a day in women, 3–4 standard drinks a day in men): metabolic dysfunction–associated and alcohol-related liver disease (MetALD). This is an important addition that reflects real-world experiences and allows differentiating the disease on a spectrum that may have different clinical progression trajectories. Currently, those with moderate alcohol use are not captured accurately in research studies of longitudinal outcomes. ALD is diagnosed in the presence of hepatic steatosis when the average consumption of alcohol is more than 3 drinks (∼40 g) per day for women and 4 drinks (∼50–60 g) per day for men. It is important to note that the disease previously known as "lean NAFLD," which affects 10%–20% of those with NAFLD,15Long M.T. Noureddin M. Lim J.K. AGA Clinical Practice Update: diagnosis and management of nonalcoholic fatty liver disease in lean individuals: expert review.Gastroenterology. 2022; 163: 764-774Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar is now classified under "cryptogenic SLD" in those with a BMI in the normal range and in the absence of prediabetes/diabetes, hypertension, and dyslipidemia. However, because waist circumference is part of the definition of MASLD, accurate classification of these individuals would require systematic measurement of this parameter in all clinics. In a cohort of patients previously diagnosed as lean NAFLD, the new nomenclature would capture 83.5% as MASLD when BMI and/or waist circumference are available, whereas 16.5% of them would not fit the MASLD criteria and would be characterized as cryptogenic SLD.16De A. Bhagat N. Mehta M. et al.Metabolic dysfunction-associated steatotic liver disease (MASLD) definition is better than MAFLD criteria for lean patients with NAFLD [published online ahead of print August 7, 2023]..J Hepatol. 2023; https://doi.org/10.1016/j.jhep.2023.07.031Abstract Full Text Full Text PDF Scopus (8) Google Scholar The implications of this nomenclature change should be addressed from different viewpoints: the patient, the primary care physician and the practicing gastroenterologist, drug development, and public policy. It is uncertain whether the new terminology removes the stigma perceived to be associated with "fatty." Initial experience in adopting the new terminology in the clinic suggests that patients find the term MASLD rather complicated and do not understand "steatosis"; the term "fatty" invariably sneaks back into the conversation when trying to explain steatosis. Because stigma is culturally sensitive, it is likely that the new name impacts stigma in the English-speaking world more than in many other countries, such as India and China, where alternative terminology may define this disease and "fat" may even be interpreted as being healthy. Only time will tell whether the new terminology will be considered less stigmatizing by patients globally. The major gaps in clinical practice relate to lack of awareness, suboptimal screening, and disease identification before advanced hepatic fibrosis develops. Moreover, unlike many other liver diseases in which the hepatologist has a leading role (eg, autoimmune or viral hepatitis), MASLD requires multidisciplinary care of the underlying determinants of metabolic dysfunction, such as obesity, diabetes, hypertension, and dyslipidemia. Recognizing the important role of these comorbidities in the naming of the disease and the updated definition should increase diagnosis and hopefully strengthen the multidisciplinary models of care that are yet to be universally implemented for ideal management of MASLD.17Allen A.M. Younossi Z.M. Tsochatzis E.A. et al.Measuring NAFLD models of care.Nat Rev Gastroenterol Hepatol. 2023; 20: 626-627Crossref PubMed Scopus (1) Google Scholar As the role of the gastroenterologist expands in the treatment of obesity in patients presenting with gastrointestinal diseases,18Camilleri M. El-Omar E.M. Ten reasons gastroenterologists and hepatologists should be treating obesity.Gut. 2023; 72: 1033-1038Crossref PubMed Scopus (5) Google Scholar screening and risk-stratifying for MASLD in these patients should also become the norm. Risk stratification, which should be applied in primary care or gastroenterology, includes 2 levels of noninvasive testing: Fibrosis-4 index followed by elastography or enhanced liver fibrosis (ELF).19Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. et al.AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (238) Google Scholar Specifically, patients with type 2 diabetes mellitus, obesity with metabolic complications, MetALD, and first-degree relatives of patients with cirrhosis secondary to MASLD should be screened for hepatic fibrosis. Patients with minimal or stage 0–1 fibrosis should return to primary care because the major cause of mortality in these patients is nonhepatic. Less than 3% of patients with MASLD will die of complications of cirrhosis or require liver transplantation over a clinical course of 15 years.20Allen A.M. Therneau T.M. Ahmed O.T. et al.Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design.J Hepatol. 2022; 77: 1237-1245Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar More patients die of complications of cardiovascular disease, diabetes, and cancer than they do of liver disease. With a worldwide prevalence of SLD of almost 30%, there is clearly not enough specialist workforce to look after such patients. Thus, the role of the gastroenterologist is to determine whether patients have other causes of liver disease and confirm whether they have at least F2 hepatic fibrosis; if they have F3–F4 hepatic fibrosis, the gastroenterologist should initiate surveillance for high-risk esophageal varices and hepatocellular carcinoma. When such patients have hepatic decompensation, they should be referred to a hepatologist, especially if they are candidates for liver transplantation. Meanwhile, all physicians caring for patients with MASLD need to take measures to treat obesity and be aware that nonhepatic outcomes include malignancy, cardiovascular, endocrine, and neurologic manifestations. There are possible implications in drug development, already challenged by many factors.21Harrison S.A. Allen A.M. Dubourg J. et al.Challenges and opportunities in NASH drug development.Nat Med. 2023; 29: 562-573Crossref PubMed Scopus (36) Google Scholar Individuals with moderate alcohol use are currently excluded from clinical trials and the potential benefit of upcoming therapies for metabolic dysfunction–associated steatohepatitis, diagnosed definitively when inflammation and hepatocyte ballooning are seen in addition to steatosis on liver biopsy. A current challenge in identifying patients with MetALD is the reliance on clinical history of alcohol consumption and the high likelihood of under-reporting.22Stockwell T. Zhao J. Greenfield T. et al.Estimating under- and over-reporting of drinking in national surveys of alcohol consumption: identification of consistent biases across four English-speaking countries.Addiction. 2016; 111: 1203-1213Crossref PubMed Scopus (71) Google Scholar Development and validation of accurate biomarkers that discriminate between low and moderate alcohol use and effective implementation of validated questionnaires have become even more important research priorities.23Szabo G. Kamath P.S. Shah V.H. et al.Alcohol-related liver disease: areas of consensus, unmet needs and opportunities for further study.Hepatology. 2019; 69: 2271-2283Crossref PubMed Scopus (52) Google Scholar Seminal work by Lazarus et al24Lazarus J.V. Mark H.E. Anstee Q.M. et al.Advancing the global public health agenda for NAFLD: a consensus statement.Nat Rev Gastroenterol Hepatol. 2022; 19: 60-78Crossref PubMed Scopus (298) Google Scholar has uncovered the global lack of public health and systems preparedness, and a consensus of recommendations related to multiple perspectives (awareness, treatment and care, patient and community, leadership, human and economic burden, etc) was developed by a multidisciplinary group of health experts to address the challenges posed by MASLD. However, this complex response requires collaboration between multiple sectors beyond health care to address measures of prevention and care of this disease (healthy food availability, education, inequalities, green public spaces, health policy, among others) using the Sustainable Development Goal framework adopted by all UN member states.25Lazarus J.V. Han H. Mark H.E. et al.The global fatty liver disease Sustainable Development Goal country score for 195 countries and territories.Hepatology. 2023; 78: 911-928Crossref PubMed Scopus (6) Google Scholar It is hoped that the nomenclature change that recognizes metabolic dysfunction as the underlying determinant of the disease will enhance the attention to the threats of this liver disease in communities26Lazarus J.V. Kopka C.J. Younossi Z.M. et al.It is time to expand the fatty liver disease community of practice.Hepatology. 2023; 78: 1325-1328Crossref PubMed Scopus (5) Google Scholar and public health responses, similar to the recognition given to diabetes, cardiovascular disease, and obesity. To summarize, while renaming and redefining the disease was needed, the implementation is not without challenges (Table 1). A more complex classification may add confusion in the mind of nonhepatology providers when awareness and understanding of the implications of SLD are already suboptimal. Differentiation of MetALD from ALD may also be challenging because the cutoffs that determine the amount of alcohol that contributes to liver damage in those with metabolic syndrome require further study. In addition, it is unclear how exactly patients with hepatic steatosis and moderate alcohol use (2–3 standard drinks a day in women, 3–4 standard drinks a day in men) but without any metabolic risk factors should be characterized: ALD or cryptogenic SLD? Educational efforts and implementation strategies are currently planned by hepatology societies, but it will take time for the medical community to become familiar with and accept these changes. There will also be some delay until regulatory agencies such as the US Food and Drug Administration and European Medicines Agency implement these changes in the drug approval process, and until then progress in the trial design and enrollment may be hindered. Updating the International Classification of Diseases coding system to reflect these changes is a necessary step for implementation in the next few years.Table 1Advances and Practical Challenges of Nomenclature Change to MASLDAdvancesChallengesMASLD terminology more accurately captures pathophysiology of the spectrum of disease.Proposed nomenclature challenging for the busy practitioner to readily understand and adopt in practice. More complicated than prior nomenclature, increasing risk of diagnostic misclassification.Nomenclature and classification more granular when compared with previous definitions.Practitioners might find it difficult to explain terminology to patients.Provides guidance on distinct categorization of SLD.Patients may not readily understand and accept the new nomenclature; therefore, the need for considerable education.Provides guidance on thresholds of alcohol consumption to separate out MASLD from MetALD and ALD.Alcohol thresholds in the presence or absence of metabolic dysfunction are uncertain. Alcohol consumption is generally underestimated.Creates a specific category of SLD not associated with metabolic syndrome and/or excess alcohol consumption.Major implications in comparing future studies with previously published data because of differences between diagnostic criteria for NAFLD and MASLD as relates to new studies on global epidemiology, natural history, outcomes, and disease burden trends.Attempts to eliminate stigmatization associated with "fatty" liver disease.Global acceptance of the new nomenclature by journals, scientific bodies, and regulatory agencies may take time.Creates a distinction between pediatric and adult SLD.Currently, there is no International Classification of Diseases code based on new nomenclature.Helps in granular guidance for inclusion and exclusion of patients in clinical trials.The new nomenclature questions the validity of previous clinical as well as ongoing therapeutic trials where the inclusion and exclusion criteria are not synchronous with new proposed criteria.Adoption by US Food and Drug Administration and other regulatory agencies of MASLD criteria for clinical trials will take time. Additionally, assessment of ongoing clinical trials that use NAFLD criteria may be problematic.ALD, alcohol-related liver disease; MASLD, metabolic dysfunction–associated steatotic liver disease; MetALD, metabolic dysfunction–associated and alcohol-related liver disease; NAFLD, nonalcoholic fatty liver disease; SLD, steatotic liver disease. Open table in a new tab