Serum lipidomic signatures in patients with varying histological severity of metabolic-dysfunction associated steatotic liver disease

Background & aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Patients with metabolic associated steatohepatitis (MASH) with fibrosis are at greatest risk of liver and cardiovascular complications. To identify such at-risk MASLD patients, physicians are still reliant on invasive liver biopsies. This study aimed to identify circulating lipidomic signatures to better identify patients with MASH in a multi-ethnic Asian cohort. Approach & results: A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures for MASLD, at-risk MASH and advanced fibrosis were identified. 210 lipids showed significant differences for varying histological subtypes of MASLD. Majority of these lipids were associated with liver steatosis (198/210). We identified a panel of 13 lipids associated with lobular inflammation, ballooning and significant fibrosis. Of note, dihexosylceramides were novel markers for significant fibrosis. Using the serum lipidome alone, we could stratify patients with MASLD (AUROC 0.863), as well as those with at-risk MASH (AUROC 0.912) and advanced fibrosis (AUROC 0.95). The lipidomic at-risk MASH predictor, using 14 markers, was independently validated (n = 105) with AUROC 0.76. Conclusions: The dynamic shift in serum lipid profile was associated with progressive histological stages of MASLD, providing surrogate markers for distinguishing stages of MASLD as well as identifying novel pathways in the pathogenesis.