Navigating the Nomenclature of Liver Steatosis: Transitioning from NAFLD to MAFLD and MASLD - Understanding Affinities and Differences

Apichat Kaewdech, M.D., Pimsiri Sripongpun, M.D.

Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand.

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition affecting approximately one-quarter of individuals of the global population.1–4 In a large prospective study in the US employing magnetic resonance imaging (MRI) and liver elastography, an estimated prevalence of NAFLD was 38%, with 14% categorized as non-alcoholic steatohepatitis (NASH).5 Similarly, a pooled analysis among European countries revealed a 26.9% NAFLD prevalence,6 whereas in Asia, the overall prevalence was approximately 30% which increased to

33.9% in 2017.7 Notably, a predicted model anticipated a further 18.3% increase in the global prevalence, with China exhibiting the highest rise owing to its aging population and diabetes.8 Moreover, the number of liver transplants due to hepatocellular carcinoma (HCC) from fatty liver without significant alcohol consumption between 2002 to 2012 increased by nearly 4-fold, becoming the third leading indication for liver transplantation in the US.9 Given the enormous burden and rapid growth of NAFLD, prevention strategies and NASH therapy are imperative.10 The spectrum of disease is heterogeneous;

Corresponding author: Pimsiri Sripongpun E-mail: spimsiri@medicine.psu.ac.th

Received 31 January 2024 Revised 22 March 2024 Accepted 23 March 2024 ORCID ID:http://orcid.org/0000-0003-0007-8214 https://doi.org/10.33192/smj.v76i4.267556

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

from simple steatosis, steatohepatitis, cirrhosis, and eventually HCC development, particularly in patients having advanced fibrosis and cirrhosis.11 The majority of HCC in patients with NAFLD occurred in the cirrhotic background, however, a substantial proportion of up to 38% had arisen from non-cirrhosis.12 Importantly, patients with fatty liver disease are at risk of developing not only hepatic but also extrahepatic cancers, including endometrial cancer, gastric cancer, pancreatic cancer, and colon cancer.13

In the past, fatty liver disease was classified into 2 groups: alcohol-associated liver disease (ALD) and NAFLD, based on the amount of alcohol consumption in individuals with evidence of hepatic steatosis.14–19 In 2020, an international consensus proposed a new terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD).20 This change carries potential benefits in increasing awareness and in accordance with pathophysiologic aspects, as metabolic dysfunction results in a wide range of systemic derangement, including liver disease. More recently, in June 2023, the new nomenclature with the overarching term of steatotic liver disease (SLD) comes with the new subclassifications of metabolic dysfunction-associated fatty liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and ALD has been introduced and endorsed by the international liver societies.21–23 This review focuses on the transition of nomenclature from NAFLD to MAFLD to MASLD/ MetALD, and its impacts.

Naming change from NAFLD to MAFLD

In 2020, a group of international experts proposed a new nomenclature of NAFLD to MAFLD, using positive criteria (metabolic dysfunction) rather than a negative one (non-alcoholic), and did not exclude patients with significant alcohol consumption or concomitant with other chronic liver diseases.20 Table 1 depicts the comparisons between NAFLD and MAFLD. The diagnostic criteria included evidence of hepatic steatosis along with one of the following: 1) overweight or obesity (≥23 kg/m2 in Asians or ≥25 kg/m2 in Caucasians), 2) diagnosis with type 2 diabetes, or 3) presence of at least 2 criteria of cardiometabolic and MAFLD risks. Metabolic risks from physical examination included the presence of an increase in waist circumference (WC: ≥90 cm or ≥80 cm in Asian men and women, respectively or ≥102 cm and ≥88 cm in Caucasian men and women, respectively), high blood pressure (≥130/85 mmHg) or use of antihypertensive drug.20 Evidence of elevated triglycerides level (TG) (≥150 mg/dL), low level of HDL-cholesterol (<40 mg/dL in men or <50 mg/dL in women), prediabetes status (defined as fasting plasma glucose (FPG) levels 100-125 mg/dL or hemoglobin (Hb) A1c 5.7-6.4% or 2-hour post prandial plasma glucose levels 140-199 mg/dL), homeostasis model assessment of insulin resistance (HOMA-IR) score ≥2.5, high sensitivity C-reactive protein (CRP) level >2 mg/L were considered essential metabolic risk factors for the diagnostic criteria in individuals who are non-overweight/obese and absence of diabetes mellitus.20

TABLE 1. Comparisons between NAFLD and MAFLD.

Reasons for the name change

While the term NAFLD has been widely used for a long-term, it appears to have certain significant drawbacks. NAFLD is a term with a negative connotation (non-) and can stigmatize those with alcohol use issues. Additionally, NAFLD fails to encapsulate the primary pathogenesis of the disease, which is metabolic derangement. Contrarily, the new term, MAFLD, provides greater mechanistic insight into metabolic dysregulation including inflammatory markers such as highly sensitive CRP, and uses the positive criteria to establish the diagnosis. Furthermore, other causes of chronic liver disease (CLD) need to be excluded in the diagnosis of NAFLD, while MAFLD, covers patients with dual liver pathology e.g., MAFLD with hepatitis C virus, MAFLD with autoimmune hepatitis, or when associated with ALD. Additionally, NAFLD studies often rely on histology for eligibility, potentially impeding trial endpoints. Using the term MAFLD and understanding its multiple phenotypes may be beneficial for clinical trial design and developing therapies targeted to different subtypes of MAFLD. Lastly, renaming NAFLD to MAFLD could improve public recognition and increase the chance of receiving funds, as it acknowledges that fatty liver can be associated with metabolic dysregulation rather than just liver disease alone.

Diagnosis of MAFLD with other etiologies

MAFLD can coexist with other CLDs, accelerating the progression of liver fibrosis and cancer development. The most common etiology that is associated with MAFLD is ALD.24 In the presence of dual causes, the patients were more likely to be younger, with male sex preponderance, elevated liver enzymes, and higher Aspartate Aminotransferase (AST) to Platelet Ratio Index.25 The positive criteria for the diagnosis of MAFLD reflect the real situation in clinical practice where many etiologies of CLD might coexist in a single patient. The NAFLD criteria allowed the alcohol intake with certain cutoff levels (<3 drinks/ day in men and <2 drinks/day in women).14–16 Currently, there is no longer a so-called ‘safe amount’ of alcohol intake.26 A large database study that included 28 million individuals globally indicated that the level of alcohol consumption that can minimize the harm of alcohol is zero.27 Similarly, a 4.9-year follow-up study of 58,927 Korean patients with NAFLD reported that light and moderate drinkers were also associated with worsening fibrosis scores.28 Another study also supported alcohol abstinence to minimize the risk of fibrosis progression, particularly in patients with metabolic syndrome.29

However, MAFLD in combination with chronic hepatitis B (CHB) infection, still exhibited controversial

results for the long-term outcomes when compared with those associated with CHB alone. The presence of hepatic steatohepatitis has been shown to be a strong predictor of having significant fibrosis (odds ratio [OR] 10.0, 95% confidence interval [CI], 2.08–48.5) and advanced fibrosis (OR 3.45, 95% CI, 1.11–10.7).30 Hepatic steatosis was also significantly associated with a 4-fold increased risk of all- cause mortality and cancer.31 Another long-term cohort study, including more than a thousand patients from 2 tertiary centers in Canada and Netherlands, demonstrated that 27.5% of patients with CHB were concomitant with MAFLD, and was proven histologically,32 while those with MAFLD had an increased risk of decompensation (adjusted hazard ratio [HR] 2, 95% CI 1.26–3.19) and HCC (adjusted HR 1.93, 95%CI 1.17–3.21). Recently, a study from Rugivarodom et al, reported that patients with CHB with concomitant hepatic steatosis on liver biopsy were at a higher risk of developing liver-related mortality (HR 3.7).33 Contradictorily, few studies also demonstrated that the liver-related complications were not statistically significantly different between patients with CHB with and without hepatic steatosis.34

Hepatitis C infection, particularly in genotype 3, is directly associated with causing hepatic steatosis.35 Other genotypes were associated with steatosis via the mechanism of insulin resistance.36 Overall, the prevalence of dual chronic hepatitis C (CHC) infection and fatty liver was approximately 27%-44.8%.37,38 Concomitant hepatic steatosis and CHC accelerated fibrosis progression and extrahepatic events including cardiovascular, renal events and cancer development.39,40

In summary, a combination of other causes of CLD with MAFLD was generally associated with poor outcomes, as well as both hepatic and extrahepatic complications. Nonetheless, it has been concluded that virological suppression and sustained virological response in individuals with CHB and CHC can improve hepatic fat.31,41

Comparisons of NAFLD and MAFLD

Table 2 illustrates studies comparing NAFLD and MAFLD. The vast majority of patients with fatty liver can be included by either using the NAFLD or MAFLD criteria. Although some studies showed the same producibility and characteristics of patients in the diagnosis of fatty liver between NAFLD and MAFLD criteria42–44, several others reported the advantages of MAFLD criteria over NAFLD, including enhanced detection of patients with significant or advanced hepatic fibrosis, cardiovascular risk,25,32,45–50 as well as a higher all-cause mortality.51 Interestingly, non-obese MAFLD may be overlooked due

TABLE 2. Summarized comparative studies between MAFLD and NAFLD.

TABLE 2. Summarized comparative studies between MAFLD and NAFLD. (Continue)

TABLE 2. Summarized comparative studies between MAFLD and NAFLD. (Continue)

Abbreviations: ALD, alcoholic associated liver disease; CAP, controlled attenuation parameter; FAST, FibroScan-aspartate aminotransferase score; FIB-4, Fibrosis-4; HBV, hepatitis B virus; HCV, hepatitis C virus; MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, non-alcoholic fatty liver disease; NAS score, non-alcoholic fatty liver disease activity score; NFS, NAFLD fibrosis score; NHANES III, the third National Health and Nutrition Examination Surveys of the United States

to the absence of any obvious metabolic dysregulation under the new criteria.52 This drawback might stem from the lack of inflammatory or insulin resistance markers in retrospective studies, which are now incorporated in the new MAFLD criteria if the patients are non-obese or non-diabetic.

Most recent nomenclature: MASLD and MetALD

More recently, in June 2023, the newest nomenclature of the MASLD under the overarching term of SLD, was introduced in the International Liver Congress held in Vienna. This nomenclature was derived from the Delphi consensus process and endorsed by the major hepatology societies.21–23 In this updated nomenclature, not only is the term “MASLD” introduced, but for the first time, another unique category of MetALD was established.

In the transition from NAFLD to MAFLD, the authors proposed replacing the term “nonalcoholic” with “metabolic dysfunction” to better reflect the etiology of the disease rather than merely excluding significant alcohol consumption in patients with hepatic steatosis. However, the term “fatty” in MAFLD is considerably stigmatizing for the patients, whereas “steatotic” in MASLD is more neutral and medically inclined.21–23 The term “steatotic” may cause confusion for patients regarding the disease due to its medical nature. Nevertheless, the impact of potentially stigmatizing terms in non-English speaking countries, such as Thailand, where both “fatty” and “steatotic” translate to the same word in Thai, remains unknown, potentially leading to uniform communication regarding the nomenclature of the disease between doctors and patients.

Furthermore, beyond the distinction between “fatty” and “steatotic”, there are differences in the diagnostic criteria for MAFLD and MASLD.20–23 The variations in the definitions of MAFLD and MASLD are depicted in Table 3. The most significant differences are the alcohol threshold and the number of cardiometabolic risks required for the diagnosis under each terminology. While MAFLD emphasizes the number of cardiometabolic risks and categorizes patients into obese, lean/normal weight, and type 2 diabetes MAFLD, the diagnosis of MASLD mandates the exclusion of significant alcohol consumption. For MASLD, if patients exhibit both cardiometabolic risk(s) and alcohol consumption >20/30 gm in women/ men but less than 50/60 gm/day in women/men, they would be categorized as MetALD, and if the alcohol consumption exceeds 50/60 gm/day in women/men, regardless of cardiometabolic risk presence, they would be categorized as ALD.

Clinical evidence of the MASLD and MetALD nomenclature Given that the alcohol intake threshold for diagnosing MASLD is the same as the previous criterion for diagnosing NAFLD, a clinical question arises regarding the potential utilization of existing NAFLD data under the new MASLD definition. Recent studies conducted in the US, Korea, and Hong Kong have demonstrated that the characteristics of individual patients with NAFLD and MASLD are nearly identical, with an overlap of up to 98% to 99% of patients.56–58 Therefore, in general, the term MASLD can be used interchangeably with the previous term NAFLD. A study from India reported that the MASLD criteria is superior to MAFLD in diagnosing the disease in patients with normal weight/lean. Nevertheless, the major caveat is that this study was retrospective, and the HOMA-IR and the hs-CRP were unavailable for the majority of patients in that cohort.59 The data regarding the comparisons between the MAFLD and MASLD criteria in both patients’ characteristics and longitudinal

outcomes are very limited, at this point.

MetALD, introduced for the first time, has its own definition due to concerns regarding the potential impact of varying alcohol intake on clinical outcomes in patients with cardiometabolic risk and the presence of hepatic steatosis. For instance, in patients with type 2 diabetes and fatty liver, it is unclear whether no/minimal alcohol intake or consuming moderate amounts would have different effects. The usefulness of determining this MetALD subcategory is yet to be explored. Some studies have indicated a higher risk of long-term overall and cardiovascular mortality in individuals with MASLD and MetALD compared to those without SLD.57,60 However, specifical comparisons between MASLD and MetALD groups to assess the effect of alcohol consumption in patients with cardiometabolic features, using the same dataset of NHANES III dataset, have yielded a non-significantly higher risk of long-term overall mortality compared to the MASLD group at an adjusted hazard ratio of 1.11 (95%CI: 0.90-1.38, p=0.337), after adjusting the age, sex, smoking status, race-ethnicity, and liver fibrosis category level using a noninvasive biomarker. [unpublished data, the results of our analysis were presented at the EASL SLD summit in September 2023.]

Lastly, there are some challenges associated with the transition from the nomenclature NAFLD to MAFLD and MASLD. First, these terms may confuse patients because there are two terms, MAFLD and MASLD. Second, it is unclear whether the clinical trial endpoints for new drugs are the same for or differ between these two terms. Lastly, there is inconsistency in the adoption of the new term

TABLE 3. The differences in the definitions of MAFLD and MASLD.

by international liver societies; for example, MASLD is endorsed by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), whereas MAFLD is endorsed by the Asian Pacific Association for the Study of the Liver (APASL).

CONCLUSION

In conclusion, efforts to improve disease nomenclature based on the underlying pathophysiology, as well as raising awareness among doctors, patients, and the public awareness on fatty liver disease, have been made substantial in recent years. Emphasizing the role of metabolic dysfunction as a cause of disease and acknowledging its significant long-term cardiometabolic morbidity and mortality risk is crucial. Nonetheless, further investigation is necessary to determine whether the MASLD and MetALD definitions offer superior diagnostic and prognostic value compared to the MAFLD definition.

ACKNOWLEDGMENT

This study was supported by the Faculty of Medicine, Prince of Songkla University, Thailand.

Conflict of interest

Kaewdech A. and Sripongpun P. declare no conflicts of interest.

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