From NAFLD to MAFLD: A “Redefining” Moment for Fatty Liver Disease
The term non-alcoholic fatty liver disease (NAFLD) was first introduced in 1980 to describe a condition resembling alcoholic fatty liver disease but occurring in individuals without a history of excessive alcohol consumption. Morphologically, NAFLD is characterized by excessive fat accumulation in the liver, in the absence of other known causes of liver disease such as alcohol, autoimmune liver disease, or viral hepatitis. The clinical manifestations of NAFLD, both hepatic and extrahepatic, arise from complex interactions between primary drivers including poor lifestyle habits, diet, dysfunctional microbiota, genetic predisposition, and environmental factors, all of which contribute to metabolic dysfunction and liver disease. However, the term NAFLD has been increasingly criticized for its oversimplification of a highly heterogeneous disease. By grouping all patients under the NAFLD umbrella, the term implies a homogeneous disease state, which negatively impacts clinical management and the understanding of its pathogenesis. Advances in the understanding of fatty liver diseases have made it clear that the term NAFLD, now four decades old, is outdated and no longer adequately describes the complexity of the disease. Today, it is recognized that fatty liver disease not only affects those who consume alcohol and those who do not, but also potentially impacts all patients with any form of liver disease by acting as a disease modifier.
NAFLD is inherently defined by the exclusion of excessive alcohol intake. However, this exclusion is problematic because the definition of “excessive alcohol” remains uncertain and is largely based on expert opinion rather than empirical data. Recent evidence suggests that there are no safe limits for alcohol consumption, and even low levels of alcohol intake can increase the risk of liver disease over the long term. Additionally, emerging research indicates that some gut microbiota produce alcohol, which can contribute to liver damage. The requirement to rule out other etiologies such as viral hepatitis or immune-mediated liver diseases further complicates the diagnostic process. This approach implicitly suggests that metabolic dysfunction does not contribute to the progression of diseases like viral hepatitis once they are diagnosed, which is contradicted by substantial evidence showing that metabolic dysfunction accelerates disease progression in conditions such as alcohol-associated liver disease, hepatitis C, and hepatitis B. Furthermore, the varied diagnostic thresholds for alcohol ingestion in published studies blur the distinction between non-alcoholic fatty liver (NAFL) and alcoholic fatty liver. Beyond these scientific issues, the term “alcoholic” in NAFLD carries stigmatizing social connotations, which can negatively impact patients.
To address these issues, an international expert panel recently reached a consensus to rename NAFLD as metabolic associated fatty liver disease (MAFLD). This change was accompanied by the proposal of new diagnostic criteria that better reflect current knowledge of the disease. The new criteria are based on the presence of hepatic steatosis in conjunction with one or more of the following: overweight/obesity, type 2 diabetes mellitus, or evidence of metabolic dysregulation. This redefinition marks a significant shift in hepatology, offering a new framework for understanding liver diseases associated with fat deposition and metabolic dysfunction. Importantly, MAFLD aligns liver disease more closely with our current understanding of obesity, metabolic syndrome, and systems biology. For clinicians, the new definition simplifies the diagnostic process by using positive criteria rather than exclusionary ones and establishes a scientific framework for considering other etiologies that may contribute to fatty liver diseases. This approach allows for the recognition of the heterogeneity of MAFLD, not only in patients where metabolic dysfunction is the primary driver but also in those with other liver diseases where metabolic dysfunction can alter disease outcomes. Within the broader concept of “metabolic dysfunction,” it is now possible to move toward greater disease subtyping, which could lead to precision medicine based on a systems narrative.
Another key difference between NAFLD and MAFLD is that the former term encompassed only simple steatosis and non-alcoholic steatohepatitis (NASH). In contrast, MAFLD is viewed as a disease process that includes the full spectrum of the condition, from simple steatosis (MAFLD with no inflammation and fibrosis) to more advanced stages (e.g., MAFLD with grade 1 inflammation and stage 2 fibrosis, or MAFLD with grade 0 inflammation and stage 4 fibrosis). This broader definition also allows for the diagnosis of conditions such as “cryptogenic cirrhosis” and lean MAFLD based on physiological and metabolic criteria, rather than treating them as entirely separate entities. Additionally, the new nomenclature avoids the stigmatization associated with the term “alcoholic” by reducing the etiological competition between purely alcohol-related and metabolic dysfunction-related liver diseases.
MAFLD is now recognized as a highly prevalent disease, affecting one in four people globally and is the leading cause of chronic liver disease in the United States and Europe. The prevalence of MAFLD is following a similar trajectory in the Middle East and Asia, with China projected to have the highest incidence and future burden, estimated at 314 million cases by 2030. If left unaddressed, MAFLD has the potential to become the most common cause of liver cancer, liver failure, and liver transplantation in China, posing a significant societal and economic burden. Outside of China, the direct annual medical costs of MAFLD are substantial, exceeding $100 billion in the United States and €35 billion in Europe (including the United Kingdom, France, Germany, and Italy).
Despite the clear need to reduce the disease burden, public health responses to MAFLD have been suboptimal. For example, a 2019 cross-sectional survey of 29 European countries (including Norway, Switzerland, and all European Union countries except Malta) revealed that none had written strategies or action plans for addressing MAFLD. This lack of response can be partially attributed to differences in the perception of the disease due to outdated nomenclature and definitions. In Europe, for instance, alcohol is often regarded as the primary cause of chronic liver disease. Similarly, while deaths due to non-communicable diseases are 30 times higher than those due to human immunodeficiency virus (HIV), funding for non-communicable diseases is 17 times lower. Public health strategies are understandably focused on these more recognized conditions, which is further complicated by the overlapping features of MAFLD and other liver diseases. Effectively managing MAFLD could significantly reduce the health burden and societal costs of alcohol-associated liver disease, as the two conditions frequently coexist and synergistically contribute to adverse hepatic and extrahepatic outcomes.
The renaming of NAFLD to MAFLD represents a defining moment in hepatology and serves as a catalyst for action, driving improvements in disease awareness, advocacy, research, and clinical management. Widespread adoption of the new definition by patients, practitioners, medical organizations, the pharmaceutical industry, and regulatory agencies is essential to maximize its impact. Already, momentum is building, as evidenced by numerous editorials published on the topic and efforts by national and regional societies worldwide to develop guidelines based on the new terminology and definition. While global endorsement of MAFLD may take time, it is a necessary step toward effectively addressing the disease.
In conclusion, the transition from NAFLD to MAFLD reflects a paradigm shift in the understanding and management of fatty liver disease. By moving away from exclusionary criteria and embracing a more inclusive and scientifically grounded definition, MAFLD offers a clearer framework for diagnosing and treating a highly heterogeneous disease. This change not only simplifies the diagnostic process but also opens the door to precision medicine and more effective public health strategies. As MAFLD continues to rise in prevalence globally, the adoption of this new terminology is crucial for reducing the disease burden and improving outcomes for patients worldwide.
doi.org/10.1097/CM9.0000000000000981
Was this helpful?
0 / 0