Editorial: Lipidomics in MASLD and MetALD—Authors' Reply

Abstract

We appreciate the insightful editorial [1] highlighting the significance of our lipidomic findings for detecting higher alcohol consumption in steatotic liver disease (SLD) [2]. When looking at SLD on a population level, one key challenge is that MetALD remains so rare that it is likely underreported [3]. This raises concerns about misclassification, particularly in cohorts relying on self-reported alcohol intake [4]. Biomarkers such as carbohydrate-deficient transferrin (CDT) in serum or ethylglucuronid (ETG) may serve as objective measures of alcohol intake and could be particularly useful in individuals with advanced SLD [5], where accurate assessment of alcohol exposure is crucial for prognosis and management. While previous studies have demonstrated the utility of CDT in detecting chronic alcohol consumption, its role in distinguishing moderate drinkers from those with excessive intake in the setting of SLD remains uncertain [6].

HDL might be a starting point to differentiate MASLD from MetALD but, while lipidomics has provided key discriminatory markers, the next logical step is integrating proteomics to refine the distinction between these subtypes further. Beyond biochemical markers, the interaction between alcohol intake in SLD and emerging pharmacological interventions remains an area of critical importance. With the advent of novel therapies for MASLD/MASH, including Resmetirom [7], GLP-1 receptor agonists [8] and agents targeting relevant metabolic pathways, for example, FGF21 [9], their potential interaction with alcohol metabolism warrants further scrutiny. Additionally, the interplay between lifestyle factors, genetic risk variants and alcohol consumption remains poorly understood. Given that alcohol intake is highly variable across populations, differs over time and is influenced by socioeconomic, cultural and behavioural factors, future studies should aim to integrate multiomic data, including lipidomics, proteomics and metabolomics, to dissect these complex interactions.

Moving forward, a comprehensive approach combining lipidomics, proteomics and metabolomics will be essential to uncover non-linear relationships that may remain hidden when analysing a single omics layer. We propose developing a multi-omics-based score to differentiate MASLD and MetALD more effectively, ultimately aiding in personalised risk assessment and therapeutic decisions.

Lastly, lipidomic differences between MASLD and MetALD further validate the new nomenclature's attempt to differentiate subgroups within SLD [10]. The distinct lipid profiles observed in MetALD—particularly the elevation of HDL-centric lipidomic markers and ketone body metabolites—suggest that these two entities are biologically distinct rather than merely reflecting a continuum of alcohol exposure. This supports the concept that the classification of MetALD as a separate entity within SLD is not arbitrary but rather underpinned by measurable metabolic and lipidomic alterations.