Steatotic liver disease, a useful construct in primary care that doesn’t upset the apple cart

The field of hepatology recently adapted new nomenclature for what was previously known as NAFLD. Under the umbrella term of steatotic liver disease (SLD), metabolic dysfunction–associated steatotic liver disease (MASLD) replaces the historical term "NAFLD." The new nomenclature emphasizes the underpinnings of the disease by recognizing its strong association with metabolic dysfunction and minimizing stigma related to the terms "nonalcoholic" and "fatty."1 The new nomenclature also introduces a new category for those with MASLD, who consume more alcohol than allowed by the definition, termed metabolic and alcohol-associated liver disease (MetALD).1 A global Delphi consensus process co-led by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL), in collaboration with the Latin American Association for the Study of the Liver (ALEH), several other societies, academic experts, and patient advocacy groups recommended a new nomenclature inclusive of updated definitions for the conditions formerly encompassed by the term NAFLD.1 It was anticipated that the overlap between the population defined by NAFLD would have near complete overlap using the MASLD criteria; however, this needed to be demonstrated across practice settings. Further, based on significant data showing the synergistic impact of alcohol in the setting of central obesity and other cardiometabolic risk factors (CMRFs), it is logical to conclude that the population defined by MASLD would have a distinct natural history and disease severity, compared to the MetALD population. However, the utility of these subcategories requires validation in terms of prognostic relevance and response to therapeutics. Recent publications demonstrate almost complete overlap between the population historically identified as NAFLD and the population defined by the new MASLD diagnostic criteria, which requires the presence of at least 1 CMRF in the setting of steatosis.2 Data from the AFEF Group for the Study of Liver Fibrosis on 2187 patients with liver biopsy performed for NAFLD and concomitant noninvasive test measurements demonstrated that at least 98% of patients with NAFLD would qualify as having MASLD.2 Further, among 261 patients from a community cohort in Hong Kong with NAFLD determined by proton-magnetic resonance spectroscopy,3 only 6 (2.3%) did not fulfill the metabolic criteria of MASLD. Further, of those patients with biopsy-proven NAFLD (n=414), only 0.2% did not meet the criteria of MASLD.3 Thus far, it appears that there is a high level of concordance between NAFLD and MASLD from the community and academic cohorts2,3; however, more data are needed to better understand the prevalence, distribution, and clinical characteristics of SLD subgroups across populations, including primary care. Data specifically in Asian patients are needed given the higher prevalence of lean disease in these populations. In this issue of Hepatology, Lee et al4 evaluated the presence of CMRFs according to the predefined criteria for MASLD from 2535 individuals who had undergone magnetic resonance elastography (MRE) and proton density fat fraction (MRI-PDFF) as part of routine health check-ups in 5 different primary care clinics in South Korea. The use of magnetic resonance-based imaging lends added strength given the high level of sensitivity for hepatic steatosis.5 The prevalence of SLD on MRI-PDFF was 39.13%, and 29.39%, 5.64%, and 2.68% were characterized as MASLD, MetALD, and ALD, respectively. 95.80% previously characterized as NAFLD fulfilled the new criteria for MASLD. Further, 94.5% of patients who were currently classified as MASLD met the criteria of previous NAFLD definition. This high level of agreement between the newly defined MASLD population and the historically defined NAFLD population provides reassurance that the terms are superimposable, even in a large cohort of Asian patients, more likely to have steatosis in the absence of being overweight, as this was a concern with the previously proposed MAFLD definition.6 An Indian cohort also demonstrated the new nomenclature/criteria of MASLD better captures of lean patients with NAFLD compared to the previously suggested MAFLD criteria.7 In this study by Lee et al,4 the high concordance of NAFLD and MASLD was noted despite a body mass index of 24.64±3.12 kg/m2. In keeping with the milder disease severity typical of NAFLD/MASLD in the primary care setting, the majority of this Korean primary care cohort had early disease (mean MRI-PDFF value was 7.31±6.14%, and the mean MRE value was 2.24±0.54 kPa). The prevalence of significant hepatic fibrosis (≥F2) among the patients with MASLD was 2.4%, and that of advanced hepatic fibrosis (≥F3) was only 1.6%. Of the 2535 participants, 82.88% had one or more CMRFs, and 39.13% had hepatic steatosis on MRI-PDFF. The distribution of SLD subtypes was MASLD 75.10%, MetALD 14.41%, cryptogenic 3.33%, and ALD 6.85%. Of the MetALD subjects, 70.63% were classified as MASLD-predominant and 29.37% as ALD-predominant. However, in a recent analysis of NHANES data, the prevalence of SLD in the United States was estimated to be 34.2%, with MASLD accounting for the majority (31.3%), followed by MetALD (2.8%), and ALD and etiology-specific/cryptogenic SLD both <0.1% of the population, using new consensus nomenclature.8 It is anticipated that those with MetALD would have more advanced disease or have a steeper trajectory of disease progression.2,8 Thus, it was unsurprising that the MetALD group had significantly higher FIB-4 index and mean MRE values than the MASLD group (p values=0.048 and 0.025, respectively). This underscores the importance of obtaining an alcohol history from patients with MASLD. While the cutoff for allowable alcohol limits was carried over from the NAFLD-defined limits of <20 g/30 g daily for females and males, respectively, even this quantity is thought to be potentially harmful as outlined by NIAAA. Specifically, the alcohol consumption threshold of ≥20/30 g/d (women/men) defining "moderate" alcohol use for MASLD definition may be too high as the NIAAA definition for "heavy drinking" is defined as ≥14/21 g/d (women/men).9 Early counseling to abstain or minimize alcohol use could decrease the risk for progressive hepatic fibrosis and future adverse clinical outcomes of advanced liver disease. Much needs to be learned about the natural history and response to therapeutics in the context of MetALD across its spectrum. While the authors comment on potential distinguishing features of ALD versus MASLD-predominant MetALD, the sample size may have limited the ability to discern a dose-dependent effect of alcohol use within the spectrum of MetALD. While the prevalence of patients with cryptogenic SLD was low (<2%), further characterization of this cohort of patients, including their natural history, is needed. It remains unknown what proportion of "cryptogenic" SLD could otherwise be reclassified as MASLD with longitudinal follow-up as hepatic insulin resistance may precede the development of more overt CMRFs. Although selection bias could have been introduced by the inclusion of participants willing to pay to undergo MRI-PDFF and MRE as additions to the health check-up, the characteristics of the study cohort likely resemble the characteristics of patients encountered in primary care settings in Asia, though a significant majority of the cohort was male.10 Although the use of noninvasive approaches for defining disease severity may be a limitation, noninvasive tests such as MRE and FIB-4 are effective in risk-stratifying patients with mild versus advanced hepatic fibrosis.11 Data presented by Lee et al4 add to a growing body of literature providing assurance that the overlap between NAFLD and the new nomenclature (MASLD) is nearly universal. It is critical that the global use of the new nomenclature across practice settings increase to enable the identification of patients at risk for disease progression.12 While historically excluded from observational and interventional clinical studies, patients with MetALD warrant further investigation, particularly in light of their higher risk of advanced liver disease. While this study lends reassurance to the concordance of NAFLD and MASLD in Korea, further investigation of the clinical course and outcomes of MASLD and MetALD among different ethnic groups and underlying genetic variants are needed.