Association of Circadian Rhythms with the Risk of Chronic Liver Disease: Findings from a Large Prospective Study

Objectives: The liver clock of hepatocytes is actively involved in regulating their proliferation, metabolism, oxidative stress response, and chronic liver disease (CLD) progression. However, the relationship between circadian rhythms and CLD remains poorly understood. This study aims to examine the associations of circadian rhythms with metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and hepatocellular carcinoma. Methods: This study included 94,006 participants from the UK Biobank. Circadian rhythms were assessed by a 7-day accelerometer via relative amplitude (RA), which indicates the difference between the most and least active periods. Cox regression and restricted cubic splines were employed to evaluate the associations between circadian rhythms and CLD. Liver fat content and hepatic inflammation were additionally assessed via magnetic resonance imaging (MRI)-measured proton density fat fraction (PDFF) and cT1 scores. Results: During the follow-up of 9.8 years, individuals in the lowest quartile of RA had higher hazard ratios (HRs) of 1.54 (95% CI: 1.32–1.78) for MASLD, 1.79 (95% CI: 1.38–2.32) for cirrhosis, and 1.65 (95% CI: 1.02–2.76) for hepatocellular carcinoma than those in the highest third quartile did. A dose‒response relationship between RA and CLD was observed (P<0.001). Furthermore, there was a joint and independent relationship between polygenic risk scores, relative amplitude and the CLD. RA was negatively correlated with PDFF and cT1 scores, demonstrating a dose‒response pattern (P<0.001). Conclusions: Abnormal circadian rhythm is significantly associated with the risk of CLD, potentially due to increased liver fat content and hepatic inflammation. Therefore, disrupted circadian rhythms may be a risk factor for liver disease and represent a potential target for intervention.