Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver dysfunction worldwide. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is strongly associated with fibrosis, cardiovascular risk, and liver-related morbidity. However, non-invasive methods for reliably detecting MASH remain lacking. We hypothesize that the 13C-methionine breath test (MeBT), a simple, non-invasive assay of hepatic mitochondrial function, can identify individuals with advanced MASLD. This hypothesis is grounded in emerging evidence that mitochondrial dysfunction is not merely a feature but a central driver of MASH pathogenesis. Methionine metabolism, culminating in 13CO2 production via mitochondrial sarcosine oxidase, is impaired in MASH and may be detectable through reduced breath 13CO2 exhalation. Prior studies support the diagnostic value of MeBT in distinguishing advanced fibrosis and cirrhosis with high sensitivity and specificity. Moreover, we propose that methionine metabolism itself may play a causative role in disease progression through redox imbalance and epigenetic instability. If validated, MeBT could serve as both a sensitive functional biomarker and a mechanistic readout, enabling earlier detection, guiding risk stratification, and reframing MASH as a disorder of mitochondrial failure. This may help shift diagnostic paradigms from structural staging to metabolic dysfunction, paving the way for novel interventions and non-invasive monitoring tools.