Causal pathways of plasma metabolites: unveiling metabolic associations in liver diseases

TL;DR

This study identifies causal links between plasma metabolites and liver diseases, highlighting the role of glucose metabolism in conditions like fibrosis and liver cancer.

Contribution

The study uses Mendelian randomization to uncover novel causal associations between specific metabolites and chronic liver diseases.

Findings

252 potential causal associations were identified between plasma metabolites and liver diseases, with 13 showing strong effects.

An elevated glucose-to-mannose ratio was significantly linked to fibrosis/cirrhosis, metabolic liver disease, and hepatoma.

Six metabolites increased fibrosis/cirrhosis risk, while three were associated with liver cancer.

Abstract

This study aimed to explore the causal relationships between 1,400 plasma metabolites and various chronic liver conditions, including liver fibrosis or cirrhosis, liver carcinoma, hepatic failure, and metabolic liver disorders.

This study used a two-sample Mendelian randomization (MR) method. Forward analysis focused on associations with four liver disease categories, whereas reverse analysis examined links with specific metabolites or ratios. Five MR methods were applied, primarily the inverse variance weighted (IVW) method. The IVW, Egger, and Weighted Median analyses showed p-values < 0.05 with positive directions, suggesting strong positive effects. The IVW analysis alone indicated a potential positive effect with p-value < 0.05. Sensitivity analyses ensured the results’ robustness and validity.

In the forward causal analysis, we identified 252 potential causal associations, 13 of which were notably strong. Specifically, six plasma metabolites and metabolic ratios were found to increase the risk of fibrosis/cirrhosis, while the other three were associated with an increased likelihood of liver cancer. Additionally, three were positively correlated with metabolic liver disease risk and one was inversely related to liver failure risk. In contrast, reverse causal analysis revealed that fibrosis/cirrhosis was linked to ten plasma metabolites and metabolic ratios, whereas liver cancer was associated with three plasma metabolites and metabolic ratios.

Our findings underscore the significant association between an elevated glucose-to-mannose ratio and a range of liver conditions, including fibrosis/cirrhosis, metabolic liver disease, and hepatoma, thereby highlighting the crucial role of glucose metabolism in liver disease.

The online version contains supplementary material available at 10.1186/s12986-025-01017-9.

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