Metabolic dysfunction-associated steatotic liver disease (MASLD) with increased alcohol intake (MetALD): a nonsensical concept and unwanted confusion

Introduction

While hepatitis C is on its way to being controlled, liver disease continues to pose a significant medical challenge globally. Two major concerns are metabolic dysfunction-associated steatotic liver disease (MASLD) (1) and alcohol-related liver disease (ALD), for which there is currently no specific treatment. The diagnostic criteria for fatty liver disease have been revised several times (2). In this context, various attempts have been made to exclude ALD, but these have not proved helpful in clinical practice. This mini-review discusses the possibility and meaning of a strict differentiation between MASLD and ALD from a practitioner’s view point.

Evolution of diagnostic criteria for MASLD and ALD

The diagnosis of fatty liver disease has been fluid and quite unstable because the rough binary classification was made as those by alcohol toxicity and those by other factors (2), despite the tremendous variety of etiologies. Recently, attempts have been made to rename the disease to clearly state the etiology in the name, as the term ‘nonalcoholic fatty liver disease’ (NAFLD) has been considered inappropriate (3). Finally, in the previous year, the American Association for the Study of Liver Diseases (AASLD) designated metabolic disorder-related NAFLD as MASLD (1), which is the most common form of NAFLD. The purpose of this proposal was to define MASLD as a liver condition that can coexist with any liver disease, including ALD. Inconsistently, however, the proposal still obsesses over the upper limit of alcohol consumption to diagnose MASLD and introduces a complex definition of MASLD with increased alcohol intake (MetALD), which is fatty liver with a double factor, both moderate alcohol consumption and metabolic disorders (Figure 1) (1). Presumably the AASLD Fatty Liver Team would like to make a strict differentiation between MASLD and ALD, but the current proposal is afraid of causing confusion. As a practitioner, I must comment that their fundamental theory might not fully consider the actual situation. The reasons for my concern are explained from the next section.

Figure 1 A schematic diagram of the definition of MASLD-MetALD-ALD. MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; MetALD, metabolic dysfunction-associated steatotic liver disease with increased alcohol intake; ALD, alcohol-related liver disease; EtOH, ethanol.

Complexity of the etiology of fatty liver in heavy drinkers

Heavy drinking is often associated with obesity and metabolic disorders (4-6). According to U.S. data, while heavy drinkers have a lower risk of obesity than nondrinkers (7), obese individuals report a higher lifetime prevalence of alcohol use disorders than non-obese individuals (8). It is widely accepted that alcohol and metabolic syndrome are a dangerous combination, and there are serious interactions between them that can initiate and exacerbate liver damage (4-6,9,10). Therefore, the pathogenesis of fatty liver in heavy drinkers cannot be attributed solely to alcohol toxicity, and the differentiation between MASLD and ALD is almost impossible. The concept of MetALD (1) seems further nonsensical. Figure 2 shows a case in point: a 62-year-old obese, diabetic woman who was a heavy drinker beyond the definition of MetALD. She presented with liver damage, and a biopsy revealed cirrhosis associated with steatohepatitis. In this case, it is difficult to determine whether the liver lesions are caused by metabolic abnormalities or alcohol-related injury. Both factors must be considered simultaneously, given the extensive clinical and pathologic findings. In short, this case should be interpreted as a combination of MASLD and ALD, but the current definition of MASLD does not allow for such a diagnosis. Rather, the earlier concept of MAFLD (11,12), which was defined as a possible complication with any liver disease, including ALD, but denied and abandoned, was more in line with reality.

Figure 2 The photomicrographs of liver biopsies obtained from an ALD patient with metabolic syndrome (A,B) and a patient with MASLD and no history of alcohol consumption (C,D) showing histological similarities. As demonstrated by this example, it is not possible to differentiate between ALD, MetALD and MASLD based on morphological findings alone. (A,C) Hematoxylin-eosin stain, ×100; (B,D) Azan-Mallory stain, ×100. MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic dysfunction-associated steatotic liver disease with increased alcohol intake; ALD, alcohol-related liver disease.

Ambiguity in standards for healthy alcohol consumption

In East Asia, particularly in Japan, there is a long-standing belief that drinking alcohol is beneficial for health, often referred to as the ‘King of Medicine’ (13). This cultural attitude towards alcohol consumption is generally more tolerant than in the West. Small amounts of alcohol were also believed to have health benefits in the West due to the low incidence of cardiovascular diseases (14-16). However, the criteria for the amount of alcohol that does not affect health are vague (10,17). It is unclear whether the upper limit of alcohol consumption in the diagnostic criteria for MASLD completely eliminates the harmful effects of alcohol (10,18). Therefore, it can be concluded that adding the amount of alcohol consumption as one of the diagnostic criteria for MASLD was a mistake. It is challenging to ascertain the precise quantity of alcohol consumed by each MASLD patient, given the limitations of the current methodology.

Difficulties in histological differentiation between MASLD and ALD

As a pathologist, I would like to introduce some histological trials. Currently, there is an attempt to differentiate MASLD and ALD histologically using artificial intelligence (19). However, it is important to note that only a few cases of both disorders are pure. In most cases, as shown in Figure 2, they are affected to some extent by alcohol consumption and metabolic abnormalities. Mallory-Denk bodies and megamitochondria, once thought to be specific to ALD, have been shown to be cellular alterations that are not exclusive to ALD but are also present in MASLD (20). Therefore, establishing typical histological findings for each is difficult. Even with multiple iterations of machine learning on such an insufficient dataset, achieving a useful level of differentiation seems unlikely. It seems to be impossible establishing a reliable differentiating system as expected. Many experimental studies of fatty liver pathology have been performed in alcohol-fed animal models (13). This suggests that the histologic features of MASLD and ALD are largely identical.

Conclusions

As discussed above, the traditional approach to differentiating between MASLD and ALD has insurmountable limitations. A strict differentiation between MASLD/MetALD/ALD is impossible, unconstructive, and even pointless. MASLD and ALD are often intertwined, and their complex nature makes simple classifications and diagnostic criteria inadequate for real-world clinical use. The management of patients with fatty liver requires sufficient consideration of the individual situation and risk to achieve a balanced response from a comprehensive perspective. For this purpose, it seems prudent to abolish MetALD and define MASLD and ALD as completely independent entities, with the potential for comorbidity between them. Now, it is not too late to reconsider.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://dmr.amegroups.com/article/view/10.21037/dmr-24-4/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://dmr.amegroups.com/article/view/10.21037/dmr-24-4/coif). Y.I. serves as an unpaid editorial board member of Digestive Medicine Research from August 2022 to July 2024. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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