Frailty is a multidimensional clinical syndrome characterised by reduced physiological reserve and increased vulnerability to stressors. It is common in ageing populations and in patients with chronic diseases, and has been linked to adverse outcomes including hospitalisation and mortality. Emerging evidence suggests that frailty is associated with chronic liver disease (CLD), but the biological mechanisms remain poorly understood. In particular, it is unclear whether circulating proteins related to frailty are predictive of incident liver disease and whether they correspond to early subclinical imaging features of hepatic injury.
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Research questions:
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Which plasma proteins are associated with frailty status in the general population?
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Do frailty-related proteins predict incident liver outcomes, including cirrhosis, hepatocellular carcinoma and liver-related mortality?
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Are frailty-related proteins linked to subclinical imaging markers of liver injury, such as hepatic fat fraction and iron derived from MRI?
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Objectives:
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To identify frailty-related plasma proteins through cross-sectional association analyses.
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To determine the prognostic value of frailty-related proteins for incident liver disease in longitudinal analyses.
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To integrate imaging-derived liver phenotypes to explore whether frailty-related proteins reflect early hepatic pathology.
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Scientific rationale:
Frailty reflects systemic biological vulnerability driven by chronic inflammation, metabolic dysregulation and impaired repair mechanisms. Plasma proteomics provides an opportunity to capture these biological processes at scale, while MRI-derived imaging markers offer objective assessment of subclinical liver injury. By integrating these data, our study will provide novel insights into the molecular pathways linking frailty to liver disease, and identify potential biomarkers for early detection, risk stratification and prevention.
