Association of circadian syndrome with nonalcoholic fatty liver disease and liver fibrosis: A cross-sectional study based on NHANES 2017 to 2020.03 data

Nonalcoholic fatty liver disease (NAFLD), affecting approximately 25% of the global population, is a persistent liver disorder strongly associated with metabolic dysfunctions.NAFLD can progress to liver fibrosis, and although liver biopsy is currently considered the most definitive method for diagnosing both conditions, its invasive nature makes it unsuitable for repeated use within a short timeframe, posing significant limitations in clinical practice.Liver ultrasound transient elastography (LUTE) offers a noninvasive technique to quantify liver steatosis and fibrosis, frequently serving as a standard tool for monitoring therapeutic outcomes and tracking disease progression. [,] ^{1 2} [,] ^{3 4} [] ⁵

The circadian rhythm is a biological process regulated by light/dark cycles, typically following a 24-hour cycle in humans. It governs sleep, mood, feeding, metabolism, immunity, and nearly all other physiological processes, allowing the body to maintain rhythmic behaviors even in the absence of light.Circadian rhythm disruption occurs when the body’s internal biological clock is desynchronized, often caused by changes in light exposure or behavioral shifts such as shift work or jet lag.These disturbances can disrupt cellular functions at the molecular level, leading to metabolic dysregulation and the development of metabolic diseases.Research using animal models has demonstrated that disturbances in circadian rhythms contribute to the development of insulin resistance, impaired glucose tolerance, obesity, and NAFLD.Clinically, NAFLD is often associated with irregular sleep patterns, shift work, jet lag, and insufficient sleep. [] ⁶ [] ⁷ [,] ^{8 9} [] ¹⁰ [,] ^{11 12}

Circadian syndrome (CircS) is defined by the presence of at least 4 persistent health issues, such as lipid metabolism disorders, depression, abdominal obesity, hypertension, reduced sleep duration, and diabetes.Although our knowledge of circadian rhythm-related health problems has expanded, no previous studies have explored the relationships of CircS with NAFLD and liver fibrosis. [] ¹³

To better understand the potential association of CircS with NAFLD and liver fibrosis, we analyzed data from multiple cycles of the National Health and Nutrition Examination Survey (NHANES). This research aims to provide fresh insights into the management and treatment of NAFLD and liver fibrosis.

This cross-sectional study examined the associations of CircS with NAFLD and liver fibrosis, using data from the NHANES database covering 2017 to 2020.03. The findings suggest that CircS is significantly linked to an increased prevalence of NAFLD or liver fibrosis, especially among individuals younger than 60. Furthermore, the presence of diabetes intensified the connection between CircS and NAFLD.

The circadian rhythm system plays a critical role in maintaining metabolic health by regulating gut microbiota, hormones, and inflammation, which are vital for disease prevention and treatment.With the growing prevalence of modern lifestyle factors such as light pollution, shift work, and dietary changes, the impact of circadian rhythm disruption on health has become increasingly apparent.For example, shift workers with similar body mass index as daytime workers are more likely to develop metabolic disorders.CircS is a clinical syndrome characterized by circadian rhythm disruption and several associated chronic conditions, making it easier to apply in clinical practice. Previous research has found positive correlations between CircS and chronic diarrhea, kidney stones, frailty, and stroke. [–] ^{20 23} [–] ^{24 26} [] ²⁷ [–] ^{28 31}

The liver is a crucial metabolic organ, and its functions are closely tied to circadian rhythms. Circadian regulation ensures that liver metabolic activities are synchronized with physiological timing by modulating the expression of key metabolic enzymes and transcription factors. Many major liver functions, particularly those related to energy balance and nutrient metabolism, exhibit rhythmic fluctuations. For example, glucose transporters and glucagon receptors involved in glucose metabolism show rhythmic expression throughout the day.Similarly, key enzymes involved in lipid metabolism, such as glycerol-3-phosphate acyltransferase, exhibit circadian rhythmicity.In this study, we observed the association of CircS with NAFLD and liver fibrosis. However, the relationship between sleep duration and NAFLD or liver fibrosis remains controversial. Some studies have found that NAFLD patients experience poor sleep quality and delayed sleep onset,similar to findings in cirrhosis patients.A study by Um YJ et al, which followed 86,530 adults without baseline NAFLD or fibrosis over 3.6 years, found that reduced sleep duration or poor sleep quality increased the risk of developing NAFLD.Conversely, some studies have reported no significant association between sleep duration and the risk of NAFLD.This discrepancy may be because sleep duration, as part of CircS diagnosis, does not fully capture the complexity of circadian rhythm disruption. [,] ^{32 33} [] ³⁴ [] ³⁵ [] ³⁶ [] ³⁷ [] ³⁸

The association between age and NAFLD has also been debated. For example, a retrospective study of 1509 NAFLD patients found a “U-shaped” relationship between age and NAFLD prevalence, with a peak in men aged 40 to 49 and women aged 60 to 69.A meta-analysis on global NAFLD prevalence found that the rate increases continuously across all age groups from 30 to 79 years.Moreover, studies suggest that aging may accelerate the progression of liver fibrosis.In our subgroup analysis, we found that CircS was more strongly associated with NAFLD and liver fibrosis in participants younger than 60 years, possibly due to greater social stress, unhealthy dietary habits, and shift work.Additionally, we found a stronger correlation between CircS and NAFLD in participants with diabetes, consistent with previous findings. For instance, a cohort study of 18,503 participants reported that approximately 30% of diabetic patients also had NAFLD, highlighting the positive association between the 2. [] ³⁹ [] ⁴⁰ [] ⁴¹ [–] ^{42 44}

This study has several notable strengths, such as the use of a large, nationally representative sample and a multistage random sampling approach, which improves the reliability and generalizability of the findings. To our knowledge, CircS, as a newly emerging concept related to metabolism, has not been previously examined in relation to NAFLD and liver fibrosis using a representative sample of U.S. adults. However, a few limitations should be acknowledged. The cross-sectional nature of the study prevents us from establishing causal relationships between CircS and NAFLD or liver fibrosis. Furthermore, the limitations of the NHANES database restricted our ability to include all potential factors that could influence NAFLD and liver fibrosis. Future research is necessary to confirm the causal links between CircS and these liver conditions.

In U.S. adults, CircS shows significant positive associations with both NAFLD and liver fibrosis. Our findings suggest that individuals under 60 years old and those with diabetes may represent high-risk populations requiring greater attention to liver health. However, as this is a cross-sectional study, these observed associations do not imply causation, and the potential bidirectional relationships between circadian dysfunction and liver diseases warrant further investigation through longitudinal studies.

We would like to thank all participants in this study.

Guanhua Lv. Conceptualization:

Wenzhao Guo, Sijia Li. Investigation:

Wenzhao Guo, Yuhang Gao, Meng Mi. Writing – original draft:

Bingjiu Lu, Xinghai Yue, Wenting Zhao, Ran Zhao. Writing – review & editing: