From NAFLD to MASLD: 2023 Brings New Liver Disease Nomenclature

Three years ago, a global committee dubbed the Nomenclature Development Initiative launched a process to consider whether the names for some of the most common liver diseases in the world were actually accurate.

A modified Delphi process led by the American Association for the Study of Liver Disease (AASLD), the European Association for the Study of the Liver (EASL), and the Latin American Association for the Study of the Liver (ALEH) confirmed this was the case in the 2020 survey, with 74% of respondents reporting they felt the nomenclature for nonalcoholic fatty liver disease (NAFLD)—estimated to affect up to 25% of US adults and 30% of the total global population—was sufficiently flawed enough to warrant a name change.^1,2

Now coined as metabolic dysfunction-associated steatotic liver disease (MASLD), the newly named condition comes alongside several changes in the revised nomenclature for liver disease, including a transition from nonalcoholic steatohepatitis (NASH) to metabolic dysfunction-associated steatohepatitis (MASH) and the addition of a new disease category called MetALD for patients with MASLD who consume increased amounts of alcohol.³

Given the rising prevalence and pressing impact of the diseases on multiple facets of clinical and public health care strategy, it comes as no surprise that the change in NAFLD nomenclature was the top news in hepatology in 2023.

Out With NAFLD…

The term “fatty liver” dates back to 1836 with a report of alcohol-induced liver histology changes from Thomas Addison. A full 144 years later in 1980, the term NASH was coined by Ludwig et al. to describe a progressive form of fatty liver disease observed in patients who denied any alcohol abuse qualifying them for alcoholic steatohepatitis, and NAFLD was introduced shortly thereafter in a 1986 review article.⁴

“When you start to think about what it means to treat fatty liver disease, you immediately set up an expectation that has a stigma associated with it: obesity,” Mark Sulkowski, MD, senior associate dean for clinical trials and professor of medicine at Johns Hopkins University told HCPLive. “It's counterproductive—if you're trying to make progress in terms of helping people suffering from medical disease, using a name that is stigmatizing isn't a good way to go about that.”

Mazen Noureddin, MD, MHSc, medical director of the Houston Research Institute, added to HCPLive that many hepatologists have expressed concern around the stigmatizing nature of the NAFLD and NASH nomenclature—”especially the word ‘fatty’ as well as the word ‘alcoholic’.”

“Although it's specific for nonalcoholic, the patient's first reaction is alcoholic, and you sit down and try to emphasize with them that this isn’t alcoholic, and yet it doesn't sit well with them,” Noureddin said.

Indeed, during the Delphi process from the Nomenclature Development Initiative, the terms “nonalcoholic” and “fatty” were felt to be stigmatizing by 61% and 66% of respondents, respectively. Beyond their stigmatizing nature, experts also pointed out they did not accurately describe the etiology of the disease.¹

“There are really 2 causes of steatosis. One is metabolic, and the other is alcohol. By not distinguishing those two or recognizing that sometimes the same person who had metabolic risk factors also drank alcohol in an unhealthy manner, not recognizing the need to potentially approach those patients differently created the problem clinically,” Sulkowski explained.

Jamile Wakim-Fleming, MD, director of the Center for Metabolic Steatosis of the Liver at Cleveland Clinic, also explained to HCPLive that, “[Fat] does not reflect on the underlying pathology or disease from which the patient is suffering but it is rather a descriptive adjective that does not reflect the medical disorder.”

Prior to the Delphi consensus, another consensus-driven proposed change in nomenclature led by an international panel of experts suggested the term “metabolic dysfunction-associated fatty liver disease” (MAFLD), which was deemed a more appropriate overarching term that better reflected the disease pathogenesis than NAFLD.^5,6 Although the name was accepted by some, others pointed out problems with mixed etiologies, continued use of the stigmatizing term “fatty,” and contradictions to natural history with the proposed new disease definition.⁷

“A lot of people brought up the fact that it may be long and complicated for patients and you might end up using the word ‘fatty liver’ at the end no matter what to simplify it for them. The answer is, yeah, sure, you still can use the word fatty in your description to the patient. But, you shouldn’t just be leaving them with that,” Noureddin explained.

Returning to the drawing board, multiple global hepatology and gastroenterology societies, patients and patient advocacy organizations, regulatory experts, and industry representatives came together to form the Delphi panel tasked with developing and finalizing new nomenclature accounting for stigmatization and the role of metabolic factors in liver disease pathology.¹

…In With MASLD

To address various concerns related to the NAFLD and MAFLD nomenclature, a multi-stakeholder effort was set forth to develop a consensus on a change in nomenclature and diagnostic criteria. Invitation to participate on the Delphi panel included 7 pan-national societies and organizations, with 29% from EASL, 27% from AASLD, 13% from the Asian Pacific Association for the Study of the Liver (APASL), 12% from ALEH, 7% from other societies, and 11% from patient advocacy organizations. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings.¹

The consensus process used a modified Delphi method to incorporate input from the literature and a diverse group of content experts, practitioners, and patient advocates. They sought to address issues with the NAFLD nomenclature, the importance of steatohepatitis in disease definition and endpoints, how to properly account for the role of alcohol, the impact of a name change on treatment development, and the reduction of heterogeneity to allow for future advances.¹

Results showed clear support for a name change (74%) and the use of an overarching term for accommodating the evolution of disease understanding (78%), namely, steatotic liver disease (95%). The use of a metabolic descriptor in the new nomenclature was preferred by 67% of respondents. In total, 75% of respondents from the external expert committee chose MASLD as the replacement term for NAFLD, and 88% supported MASH as the replacement term for NASH.¹

Whereas NAFLD was based on the exclusion of any other liver disease, MASLD encompasses patients who have hepatic steatosis and at least 1 of 5 cardiometabolic risk factors. Additionally, the updated nomenclature added a new classification, MetALD, to represent a separate group of patients with MASLD who consume alcohol at a rate of 140–350 g/wk for females and 210–420 g/wk for males.³

Making Waves in Hepatology

When considering the potential impact of a change in name, definition, or both, 56% of respondents felt a change in nomenclature would positively impact disease awareness. Others expressed concerns about the potential impact on clinical trial results and the regulatory approval of biomarkers.1

Addressing these concerns, AASLD noted the new nomenclature does not alter natural history, clinical trials, or biomarkers, and will not impede development or change the previous staging and severity of the disease.7 Additionally, an analysis of the European NAFLD Registry, part of the LITMUS consortium, showed 98% of the existing registry cohort of patients with NAFLD would fulfill the new criteria for MASLD.1

“With new names, sometimes people are not updated on time or they're confused. This is the nature of any change, and we hope it's just for the better,” explained Noureddin, calling the change in nomenclature “the right thing to do” and noting he has not observed any major complications as a result of the new nomenclature thus far.

Juan Pablo Arab, MD, associate professor of medicine in the department of epidemiology and biostatistics at Schulich School of Medicine at Western University, added the main difference with the new nomenclature is the availability of a “positive diagnosis,” encouraging clinicians to account for cardiovascular risk and metabolic dysfunction while allowing them to diagnose liver disease “based on what it is and not by what it is not.”

“We've seen changes in nomenclature before. PBC, for example—we went from primary biliary cirrhosis to primary biliary cholangitis. It took a little bit of time, and maybe that shift wasn't as big as this one, but I think that eventually this will settle in,” said Anthony Martinez, MD, medical director of hepatology at Erie County Medical Center, who also described concerns about public understanding of the new nomenclature and potential causes for delay in its implementation.

Wakim-Fleming noted the Cleveland Clinic was already embracing the new name, renaming their clinic to the Center for Metabolic Steatosis of the Liver within a month of the nomenclature change’s publication. Like many of her peers, she has hope what reads like a simple shift in a few letters means focused research, better disease management, more treatment referrals, and more patients seeking help as the burden of stigma and misclassification disappears.

References

1. ^{Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79(6):1542-1556. doi:10.1016/j.jhep.2023.06.003}
2. ^{American Liver Foundation. NASH Definition & Prevalence. Liver Diseases. November 1, 2023. Accessed December 12, 2023. https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-definition-prevalence/}
3. ^{American Association for the Study of Liver Diseases. New MASLD Nomenclature. Accessed December 12, 2023. https://www.aasld.org/new-masld-nomenclature}
4. ^{Lonardo A, Leoni S, Alswat KA, Fouad Y. History of Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2020;21(16):5888. Published 2020 Aug 16. doi:10.3390/ijms21165888}
5. ^{Eslam M, Sanyal AJ, George J, et al. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. https://doi.org/10.1053/j.gastro.2019.11.312}
6. ^{Gofton C, Upendran Y, Zheng MH, George J. MAFLD: How is it different from NAFLD?. Clin Mol Hepatol. 2023;29(Suppl):S17-S31. doi:10.3350/cmh.2022.0367}
7. ^{American Association for the Study of Liver Diseases. Multinational Liver Societies Announce New “Fatty” Liver Disease Nomenclature That Is Affirmative And Non-Stigmatizing. June 24, 2023. Accessed December 12, 2023. https://www.aasld.org/news/multinational-liver-societies-announce-new-fatty-liver-disease-nomenclature-affirmative-and}