Detection of metabolic signatures implicated in the progression from hepatitis to cirrhosis to hepatocellular carcinoma

Abstract

Background and aims

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The mechanisms driving the transition from hepatitis to cirrhosis, and eventually, to HCC are unclear. This study aimed to clarify the metabolic changes that underly the progression of HCC and identify potential prognostic and therapeutic biomarkers.

Methods

This prospective study collected serum samples from patients with chronic hepatitis, cirrhosis, or HCC, hospitalized at the Fifth Medical Center of the PLA General Hospital, from December 2022 to December 2023. The samples were analyzed using non-targeted, ultra-high-performance liquid chromatography and mass spectrometry. Partial least squares-discriminant analysis modeling and t-tests were used to identify key differentially expressed metabolites associated with the progression from hepatitis to cirrhosis to HCC. Pathway enrichment analysis was conducted to determine the key metabolic pathways involved, while machine learning models were applied to identify the metabolite signatures.

Results

We identified 153 differentially expressed metabolites in the progression from hepatitis to cirrhosis to HCC, many of which were involved in ammonia cycling or the metabolism of methylhistidine, alanine, arginine, proline, or betaine. We also identified L-histidine and adenosine as the metabolites that demonstrated significant sensitivity and specificity for distinguishing among the hepatitis, cirrhosis, and HCC stages.

Conclusions

Our study comprehensively characterized the metabolic profiles of the different stages of the hepatitis-cirrhosis-HCC transition. We showed that serum metabolite detection is a viable diagnostic tool for identifying and monitoring high-risk individuals, which could potentially be used to halt the development of HCC.