# The role of hypothyroidism in cirrhosis pathogenesis: A retrospective cohort study and multi-omics integration analysis

## TL;DR

This study finds that hypothyroidism may increase the risk of cirrhosis and identifies immune molecules and potential drugs for treatment.

## Contribution

This is the first study to establish a causal link between hypothyroidism and cirrhosis using multi-omics and genetic methods.

## Key findings

- Hypothyroidism is causally linked to cirrhosis, likely through immune dysregulation involving HLA-DQA1 and CD27.
- Glycyrrhizic acid and levothyroxine sodium are candidate drugs targeting HLA-DQA1 and CD27.
- HLA-DQA1 and CD27 are key in macrophage and T cell functions, making them potential therapeutic targets.

## Abstract

Liver cirrhosis is a progressive chronic disease with high morbidity and mortality, thereby posing a major challenge to global health. Evidence suggests that thyroid dysfunction, particularly hypothyroidism, is linked to liver diseases. Hypothyroidism disrupts metabolism, immune homeostasis, and inflammatory pathways, processes central to cirrhosis pathophysiology. However, its causal role and molecular mechanisms remain unclear.

The study initiated by analyzing the association between thyroid dysfunction and cirrhosis through retrospective analysis of longitudinal data obtained from the Medical Information Mart for Intensive Care clinical database. To assess genetic correlation, we applied linkage disequilibrium score regression, followed by bidirectional Mendelian randomization to explore potential causal relationships. Through transcriptome-wide association studies, we identified candidate genes, which were then prioritized using a combination of weighted gene co-expression network analysis and differential gene expression data integration. To interpret the biological relevance of these genes, we conducted functional enrichment analyses. We further explored gene function at the cellular level by leveraging single-cell RNA sequencing (scRNA) to map cell-specific expression patterns, analyze intercellular communication, and simulate gene knockouts. Finally, we performed molecular docking and phenome-wide Mendelian randomization to identify potential therapeutic compounds targeting the prioritized genes.

Through a combination of observational and genetic insights, we established a causal relationship between hypothyroidism and cirrhosis, identifying hypothyroidism as a risk factor for cirrhosis. Subsequent multi-omics analyses highlighted HLA-DQA1 and CD27 as potential therapeutic targets. ScRNA revealed key roles of these molecules in macrophages and CD8 ⁺ T cells, and simulated knockouts confirmed their importance in T cell activation and lymphocyte proliferation. Finally, molecular docking analysis identified glycyrrhizic acid and levothyroxine sodium as candidate drugs targeting HLA-DQA1 and CD27, while phenome-wide Mendelian randomization analysis revealed potential adverse effects associated with these targets.

This study is the first to reveal a causal relationship between hypothyroidism and cirrhosis, potentially driven by immune dysregulation mediated by HLA-DQA1 and CD27. These findings offer novel insights into disease progression and identify HLA-DQA1 and CD27 as potential therapeutic targets, with glycyrrhizic acid and levothyroxine sodium as promising candidate drugs.

Liver cirrhosis is a life-threatening condition with limited treatment options, and understanding its risk factors is essential for early prevention. In this study, we investigated the causal relationship between hypothyroidism—a disorder in which the thyroid gland fails to produce sufficient hormones—and cirrhosis. Using a combination of retrospective and multi-omics studies, we found that hypothyroidism may increase the risk of developing cirrhosis. We also identified two immune-related molecules, HLA-DQA1 and CD27, that may mediate this effect and serve as potential targets for future therapies. Furthermore, our analysis revealed a set of candidate drugs that could help treat patients with both conditions. These findings highlight an overlooked link between thyroid dysfunction and liver disease and offer new directions for clinical intervention and drug development.