From NAFLD to MASLD: Promise and pitfalls of a new definition†
Authors: Kenneth Cusi, Zobair Younossi, Michael Roden
Journal: Hepatology (2023)

To the editor, As members of the nomenclature steering committee, we recognize the significant effort involved by all stakeholders in the procedures leading to the proposal of a nomenclature change from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD). The new name could potentially remove stigma, which has been highlighted by patient representatives, and bring awareness to the critical role of insulin resistance in the pathophysiology of "metabolic dysfunction" and liver disease. As highlighted below, we are hopeful that this accomplishment will encourage future research and a continued dialogue to address remaining caveats regarding the definition of steatotic liver diseases and its clinical implications. The MASLD definition change (steatosis plus ≥1 cardiometabolic risk factor) was understandably driven, at least in part, by a need for a "positive" diagnosis rather than a "negative" one, i.e. by exclusion of excessive alcohol use and any other liver disease (NAFLD). Future work should validate the hypothesis that MASLD supports the intended pathophysiological mechanism that steatosis is driven by insulin resistance and "metabolic dysfunction". This is important because liver-related mortality in NAFLD appears closely related to insulin resistance, as recently reported in 12,878 individuals followed for a median of 22.8 years.1 Two recent studies show encouraging concordance between NAFLD and MASLD: one study on 3,173 middle-age US adults participating in the National Health and Nutrition Examination Survey 2017–2020 who were screened by transient elastography,2 and another study from Hong Kong in 1,016 randomly selected community participants screened by proton-magnetic resonance spectroscopy.3 However, one must keep in mind that the prevalence of ≥1 cardiometabolic risk factor is very high (>90%) in the general population aged ≥45 and ≥1 of these cardiovascular risk factors are already present in 85% of individuals without steatosis.2 In contrast, only ~50% of individuals with MASLD who are overweight have insulin resistance by HOMA-IR,2 suggesting a significant discordance and relative low specificity for these clinical comorbidities as surrogates for insulin resistance. Discordance may be inevitable when a metabolic outcome of insulin resistance (steatosis) is asked to translate into at least one clinical comorbidity (hypertension, atherogenic dyslipidemia, overweight/obese or prediabetes/type 2 diabetes), and when these comorbidities are caused by multiple and incompletely understood mechanisms beyond insulin resistance. Another consideration is that repurposing cardiometabolic risk factors developed for the prediction of cardiovascular disease and type 2 diabetes,4 for the diagnosis of MASLD, potentially transfers to the liver field unresolved issues long debated surrounding the metabolic syndrome.5 Finally, clinicians must be aware that many people with prediabetes or different forms of diabetes may have steatosis and hyperglycemia but not necessarily insulin resistance or MASLD (e.g., after pancreatectomy, cystic fibrosis, type 1 diabetes and certain diabetes endotypes).6 MASLD may assist non-specialists and people with the disease to link insulin resistance and metabolic abnormalities to steatosis, but use of the term may invalidate some prior epidemiological work. While the population identified by the new definitions (e.g., MASLD, MASH) will overlap well in individuals attending tertiary care centers or registries, or participating in NASH/MASH clinical trials, more work is needed to validate MASLD across different populations, as recently performed.2,3 Instead of assuming that MASLD, despite its new definition, is identical to NAFLD, we need to generate outcomes evidence with carefully designed research. A new, better definition needs to encompass steatosis in all settings, even if having a low risk of advanced fibrosis, as in primary care. More research is urgently needed to validate the proposed definition of MASLD in terms of its sensitivity, specificity, positive predictive value and negative predictive value for insulin resistance compared to steatosis alone (NAFLD). We propose that individuals without ≥1 cardiometabolic risk factor criteria would be better classified as having "early" MASLD rather than "cryptogenic steatosis" when all secondary causes have been ruled out. Steatosis without comorbidities may be more common in young adults (age 18-44), where ~40% are estimated to have insulin resistance but are often not obese.7 Mislabeling steatosis linked to insulin resistance as "cryptogenic steatosis" may have important clinical consequences as it may favor clinical inertia and downplay an emphasis on lifestyle changes to avoid liver disease progression. Depending on resources, assessment of insulin resistance (e.g., HOMA-IR) and/or oral glucose tolerance test would be helpful in this setting, as prediabetes or diabetes are the most insulin-resistant states and, among metabolic comorbidities, have the greatest negative impact on the development and progression of steatohepatitis. Of note, the decision to change the definition of MASLD was supported by a slim majority (53% for a change vs. 47% for no change) and would have benefited from a broader debate of the above issues before adoption. Future work and scientific debate may reconsider the "forced" definition that now directly links a biological event (insulin resistance) with the above common clinical cardiometabolic risk factors. The disease is steatosis or steatohepatitis (with its associated risk of fibrosis), without the need to impose upon it a clinical comorbidity to define it, diagnose it, or make it more worthy of our clinical attention. While cardiometabolic risk factors are potentially valuable aids in the diagnosis of insulin resistance and "metabolic dysfunction", they cannot be strictly forced into a relationship with steatosis against their (biological) will.