Editorial: Breath Profiling in MASLD—A Step Towards Better Risk Stratification

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become a major global health concern, affecting approximately 25%–30% of adults worldwide [1]. Although recent reclassification efforts have clarified its diagnostic criteria [2], identifying patients at the highest risk of disease progression using simple, non-invasive methods remains a major unmet need [3, 4].

In a proof-of-concept study, Sinha et al. [5] investigated exhaled breath analysis using an electronic nose (eNose) to address this challenge. They showed that volatile organic compound (VOC) profiles could distinguish MASLD patients from healthy controls with 100% sensitivity (96% cross-validation), independent of age or sex. Critically, the authors applied unbiased clustering of breath profiles—without relying on clinical assumptions—to identify three distinct MASLD subgroups with different 5-year outcomes. Among these, Cluster 2 was associated with a markedly worse prognosis: 42% developed cirrhosis progression or liver-related complications, 67% showed evidence of portal hypertension and 12.5% died from liver-related causes. Despite similar baseline characteristics, Cluster 2 patients had significantly higher serum hyaluronic acid levels and poorer glycaemic control compared to other groups. These findings suggest that breath-based signatures may detect latent metabolic derangements not captured by conventional markers.

While eNose technology has gained traction in respiratory medicine, being applied to diseases such as asthma, COPD and lung cancer [6, 7], its use in liver disease remains in its infancy. The current study represents an important early step in translating breathomics—a broader field encompassing eNose approaches—into hepatology, where existing non-invasive biomarkers often lack precision.

The study's strengths include the use of a well-characterised MASLD cohort, standardised breath collection protocols and long-term clinical follow-up. Notably, the risk stratification emerged solely from exhaled VOC patterns, rather than traditional fibrosis scores or clinical comorbidities, highlighting the biological relevance of breath profiles. However, certain limitations should be acknowledged. The cohort size was small, and external validation in larger and more diverse populations is essential. Comparative studies with established non-invasive tools such as transient elastography or serum-based fibrosis markers would also help position eNose technology within clinical workflows. Nonetheless, the results are compelling. Conventional metabolic markers—such as those used to define MASLD—may predict cardiovascular outcomes but are less reliable for forecasting liver-specific risks [8, 9]. Recent large-scale studies confirm that MASLD patients, including those who are lean or only mildly overweight, can silently progress to advanced liver disease [10]. Breathomics offers a promising new dimension of risk detection that transcends simple anthropometric or biochemical assessments.

In conclusion, Sinha et al. demonstrate that exhaled breath profiling, combined with unbiased clustering, can uncover high-risk MASLD phenotypes invisible to traditional clinical evaluation. With further validation, this non-invasive approach could reshape early risk stratification and support more personalised management in MASLD.

Takefumi Kimura: conceptualization, formal analysis, writing – original draft.

The author declares no conflicts of interest.

This article is linked to Sinha et al paper. To view this article, visit https://doi.org/10.1111/apt.70176.