As most clinicians working in the field of metabolic (dysfunction) associated fatty liver disease (MAFLD) are aware, a significant proportion, up to 40% of patients, are of healthy weight by standard ethnic-specific BMI criteria. This phenomenon of healthy-weight individuals developing metabolic diseases has also been observed in patients with Type 2 diabetes and with cardiovascular disease, the main extrahepatic morbidities associated with MAFLD. Over the last decade there have been numerous publications assessing the prevalence and in some cases the longitudinal history of MAFLD (formerly termed non-alcoholic fatty liver disease [NAFLD]). There have also been numerous reviews that have synthesised this data or conducted meta-analyses on the topic. However, what to us has been lacking is that all these data are observational in nature and descriptive. There has previously been no rigorous attempt of sufficient quality that tries to both integrate the clinical knowledge that is available from the studies and integrates them into an overall pathophysiological framework to better understand why MAFLD develops in healthy weight individuals.

We were particularly interested in undertaking this review after our earlier work in 2020 suggested that a more appropriate term for NAFLD would be metabolic dysfunction associated fatty liver disease (MAFLD) since metabolic dysfunction is the sine qua non for progressive disease. Having first suggested a name, the international panel of experts subsequently proposed a conceptual framework to define MAFLD in terms of a set of positive criteria rather than being merely a disease of exclusion. Since then over 1000 papers have used the term MAFLD suggesting that not only is this a useful terminology and but also an excellent overarching framework to understand the disease and its subgroups. The success of this endeavour led us to interrogate the problem of MAFLD in normal weight individuals - not so much from a clinical and descriptive perspective, but rather to try and integrate new knowledge in the field to come up with a framework to understand the evelopment of MAFLD in healthy weight individuals. We were encouraged that MAFLD in normal weight people might have unique pathophysiological features after our earlier paper (Hepatology, VOL . 71, NO. 4, 2020) suggesting that lean MAFLD is a distinct pathophysiological entity shaped by differential metabolic adaptation.

From these insights, we decided to delve deeply into all the literature both descriptive and pathophysiological on MAFLD in normal weight, overweight and obese individuals. We thought it critical that the entire hepatology community and the wider medical research community be provided with a potential framework through which lens the disease could be interrogated. Our ultimate goal was to spur both basic and clinical research to understand the disease entity. Our thought was that through this process, new insights could be gained and perhaps that the therapeutic approaches we use for patients with lean fatty liver disease verses their obese and overweight counterparts, might be different. Our key insight from the literature and the epidemiological data was understanding the importance of the overall metabolic health of an individual. From this arose the concepts of metabolic flexibility and metabolic adaptation which we felt best provides a wider conceptual framework for the development of MAFLD in lean people.

Not only does our work provide an overall schema to understand fatty liver disease development and progression in lean individuals, but it also does so for MAFLD development in their overweight or obese counterparts. We believe that while this is particularly informative for the fields of hepatology and gastroenterology, it fits equally well for understanding the diverse adverse impacts that can occur in individuals who are normal weight with regards to cardiovascular disease or Type 2 diabetes. Thus, while all of these diseases have excess adiposity including peripheral adiposity at their core, the pathophysiological mechanisms that shape the clinical phenotype will depend on an individuals metabolic flexibility and adaptive capacity in responding to relative nutritional excess, dietary composition and physical activity levels among others. We are hopeful that through this framework, unique translational opportunities will emerge both in terms of pathophysiology and treatment. One of the big lacunae in the clinical trials arena for MAFLD is that most of the studies focus on patients who are overweight or obese. At a pathophysiological level, we believe that our review will provide the impetus for in-depth studies of patients with MAFLD who are of healthy weight including of body composition measurements, microbiota richness as well as of metabolic flexibility. Through this understanding we suspect that there will be differences in the way different drugs work in obese individuals versus those who are of healthy weight. This is not to say that the same therapy used for overweight and obese steatohepatitis would not work for patients with lean disease. Rather what we are suggesting is that the magnitude and extent of benefit of the various drug classes used in overweight and obese MAFLD may be quantifiably different in patients with lean disease. In turn this would give rise ultimately to a more personalised and precision medicinecentred approach to treatment.

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