10 Questions Answered About New Liver Disease Term 'MASLD'

Citing several limitations inherent to the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), an international multisociety panel significantly revised its nomenclature and definition recently. The reassessment is timely, given that NAFLD and NASH are the most common forms of chronic liver disease worldwide.

The panel's primary objective was to link the replacement nosology to the underlying presumed pathophysiology, thereby highlighting that metabolic dysfunction is a defining characteristic of these diseases. However, concerns have been raised among some that inclusion of the word "metabolic" along with some of the other suggested elements may be confusing for both clinicians and patients.

Let's review some of the key questions surrounding these changes, to better understand their possible impact.

What Is the New Nomenclature?

The panel reached a consensus on adopting these new and updated terms:

Steatotic liver disease (SLD): the all-encompassing term for the various etiologies of steatosis
Metabolic dysfunction–associated steatotic liver disease (MASLD): the term chosen to replace NAFLD
Metabolic dysfunction–associated steatohepatitis (MASH): the term chosen to replace NASH
MetALD: persons with MASLD and who consume alcohol at 140-350 g/wk for women and 210-420 g/wk for men
Cryptogenic SLD: person without metabolic dysfunction and no known cause

Notably, the overarching term SLD serves as an umbrella for the entire spectrum of causes of hepatic steatosis and allows for precise classification once a specific etiology has been identified.

Although change is never a smooth process, the concept behind the revision makes sense. I recall an analogous situation, whereby for years we labeled a form of transmissible hepatitis as "non-A, non-B," describing what was not the cause. With the discovery of the hepatitis C virus, the term thankfully disappeared.

Similarly, NAFLD stated that the liver injury is not alcohol-related but did not capture its causality.

What Was the Composition of the Decision-Making Panel?

This was a multi-stakeholder effort, empaneled jointly by the American Association for Study of Liver Disease (AASLD) and the European Association for Study of the Liver (EASL), in collaboration with the Asociación Latinoamericana para el Estudio del Hígado (ALEH).

The diverse panel (236 panelists from 56 countries) also solicited input from hepatologists, gastroenterologists, pediatricians, endocrinologists, and hepatopathologists; public health and obesity experts; and colleagues from industry, regulatory agencies, and patient advocacy organizations.

This globally representative cadre of diverse professionals was charged with addressing key concerns regarding the terms NAFLD and NASH and developing consensus on a new nomenclature and diagnostic criteria.

Why Did They Feel a Change Was Needed?

The panel sought to create a unified global approach to nomenclature and disease definition, which they viewed as "critical for increasing disease awareness, driving policy change, identifying those at risk, [and] facilitating diagnosis and access to care."

They emphasized that the term "nonalcoholic" does not depict the etiology of the liver injury and that both "nonalcoholic" and "fatty" have been considered to be pejorative. Such language might "create or exacerbate stigma, marginalize segments of the affected population and, ultimately, contribute to health inequalities."

They also focused on the fact that there are people with metabolic risk factors for NAFLD (eg, type 2 diabetes) who consume amounts of alcohol that exceed the thresholds used to define "nonalcoholic," and they cited overlapping biological processes that may contribute to both NAFLD and alcohol-related liver disease.

In short, the panel believed that the proposed nomenclature improves upon the prior terminology and assigns a metabolic basis for a liver disease long recognized as "the hepatic manifestation of the metabolic syndrome."

What Process Did They Follow to Obtain a Consensus?

The methodology used was a modified, multistep Delphi process. The panel was generated through an iterative, inclusive process involving the diverse liver organizations mentioned above.

The steering committee was composed of two co-chairs representing AASLD and EASL and 34 other members nominated by their respective associations. Their consensus-building process incorporated input from a literature review and from content experts, practitioners, and patient advocates.

Five issues were considered to be key to a revised nomenclature:

What are the issues with current nomenclature, and can they be addressed?
What is the importance of steatohepatitis in disease definition and endpoints?
How should the role of alcohol be accounted for?
How might a name change impact disease awareness, clinical trials, and regulatory approval pathways?
Can an alternative name reduce heterogeneity and allow for future advances?

The top three choices for names and acronyms that emerged from the output of the Delphi process were submitted to an external committee that served to refine the definition, including metabolic parameters for both adult and pediatric disease. The proposal from this external committee was discussed and approved by the NAFLD Nomenclature Steering Committee. Leadership of the societies (ie, AASLD, EASL, and ALEH) then reviewed and subsequently approved the proposed nomenclature.

Why MASLD?

The panel cited the well-established epidemiologic and pathogenic linkage between NAFLD, metabolic dysfunction, and insulin resistance. Therefore, the ultimate diagnosis should "be based on affirmative rather than exclusionary criteria such as nonalcoholic."

They agreed that the criteria must be defined broadly enough to identify individuals with both obesity and cardiometabolic risk factors and in the context of regional/ethnic differences. According to the panel, the chosen parameters had to be simple, readily available, and easily measurable in order to allow integration of the terminology into clinical practice.

The selected diagnostic criteria had to align with cardiometabolic risk factors associated with insulin resistance. Thus, the panel included patients with steatosis and any one of the cardiometabolic criteria (ie, elevated body mass index, impaired glycemic control, elevated blood pressure, or elevated triglycerides). Specific adult and pediatric cardiometabolic criteria can be referenced in the consensus statement.

The group emphasized due diligence during clinical evaluation, purposely stating that "making a diagnosis of MASLD does not imply that other causes of SLD do not need to be considered, which is particularly relevant in children where it is imperative to exclude other causes of hepatic steatosis prior to applying the MASLD diagnostic criteria to ensure that dual pathology is not missed."

Did the Panel Identify Any Limitations to Adopting the Term MASLD?

Yes. Because this definition is based on specific, primarily cardiometabolic, risk factors, there are inherent limitations that they recognized.

They cited the fact that the key metabolic dysfunction underlying MASLD is insulin resistance. However, the chosen metabolic risk factors do not equally predict insulin resistance (eg, diastolic blood pressure and high-density lipoprotein cholesterol levels are only weakly associated).

In addition, insulin resistance and steatosis may be present in the absence of cardiometabolic risk factors; thus, the panel recommended that these cases with steatosis but without overt cardiometabolic risk factors or another discernible cause be labeled as "cryptogenic."

What Is the Perceived Role of Alcohol in These Proposed Definitions?

The strong consensus of the panel was to "continue to limit alcohol intake (as previously limited for NAFLD) in the context of steatosis." They also stated that "MetALD patients should be classified in a category distinct from MASLD, mainly because of the added pathogenic value of alcohol consumption and consequential prognostic implications."

Although this process was focused on NAFLD, not alcohol-related liver disease, they deemed it relevant to address situations where there was overlap. They created a separate category outside of pure MASLD — MetALD — for people with alcohol intake greater than that allowed for NAFLD/MASLD. They envisioned that the group of patients with MetALD may be composed of individuals in whom MASLD is the perceived dominant driver and others in whom ALD predominates.

In fact, Diaz and colleagues recently proposed that regardless of the presumed etiology, patients with SLD should be evaluated for both metabolic syndrome and alcohol consumption to enable better prognostication and allow a personalized medicine approach.

What About 'Lean NAFLD'?

Because the proposed nomenclature focuses on a positive diagnosis based on the presence of cardiometabolic risk factors, this will allow for a "rational reclassification of most cases of the condition formerly known as "lean NASH" into the regular MASLD category, as long as currently defined metabolic risk factors are present."

Did the Panel Discuss Genetic Factors?

It is known that various genetic variants influence the prevalence and/or severity of MASLD. These include PNPLA3, TM6SF2, HSD17B13, and other genetic risk variants common in the general population.

The panel did not consider them to be a distinct nosologic entity, concluding that "these variants are disease modifiers for both MASLD and ALD rather than causative factors, in contrast to rare variants responsible for monogenic diseases."

What Are the Implications and Next Steps?

Clearly, creation of a new nomenclature and diagnostic criteria for the common entities of NAFLD/NASH was a major challenge and a daunting process. We congratulate the panel members for their obvious diligent labors. They established a robust, representative, patient-centric Delphi process in order to systematically resolve the concerns that had been raised. They have offered an affirmative, nonstigmatizing description of the condition to replace what had been a diagnosis of exclusion. They also included patient advocacy groups throughout the process to ensure that the chosen nomenclature raises awareness and reduces the stigma associated with use of the replaced terms.

There is much work to be done. "Buy-in" from clinicians must be secured. That may involve further fine-tuning of the proposed terms and definitions. The panel stated that the "proposed nomenclature is not intended to be static, but rather allows the flexibility for refinement as new evidence emerges about underlying pathophysiology and risk factors." The panel also made clear that the name change does not invalidate data from prior NAFLD/NASH clinical trials, emphasizing a high concordance between MASLD and NAFLD.

It will remain to be seen whether the new proposed terminology sufficiently addresses the perceived weakness of the existing nomenclature. It also remains to be seen how the terms are incorporated into general practice, and whether they truly enhance disease awareness, improve understanding of pathophysiology, and foster research and drug/biomarker development.

The AASLD has developed a comprehensive and collaborative phased implementation strategy that includes conversations with stakeholders, a detailed technical implementation plan, and the development of comprehensive resources for practitioners.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; Director Emeritus, Pediatric Liver Care Center; Medical Director Emeritus, Liver Transplantation; and Professor, University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center. He has served as director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for Medscape. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

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