The liver, a vital organ responsible for metabolism, detoxification, and biochemical synthesis, is essential for maintaining overall health (1). Approximately 2 million deaths occur each year due to liver diseases (2). Liver function can be impaired by various factors such as viral infections, excessive alcohol consumption, drug-induced hepatotoxicity, and metabolic disorders (3). Liver function parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), the ALT/AST ratio, gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) are essential indicators for assessing liver health. Moreover, they are involved in metabolic processes that link liver health to other bodily systems. For example, within the Framingham Heart Study cohort, higher GGT levels were associated with increased plasma triglycerides, body mass index (BMI), and blood pressure (4). Given these connections, the relationship between liver function and cardiovascular health (CVH) has attracted increasing attention.

In 2010, the American Heart Association (AHA) introduced Life’s Simple 7 (LS7), a set of metrics for assessing CVH (5). However, the LS7 did not account for individual variations and changes over time, prompting the AHA to develop Life’s Essential 8 (LE8) in 2022 (6). The LE8 score includes eight key measures: diet, physical activity, nicotine exposure, sleep health, BMI, lipids, blood glucose, and blood pressure. The LE8 score has shown promise in predicting a range of health outcomes beyond CVD. Higher LE8 scores are inversely associated with several non-communicable diseases, including biological aging (7), testosterone deficiency (8), and depression (9), and is associated with increased longevity (10). Emerging evidence also suggests a connection between CVH, as measured by LE8, and liver diseases (11, 12). It is worth noting that the components of LE8 are not only important for CVH, but also have potential effects on liver function. For instance, poor sleep health has been associated with metabolic dysregulation, which can lead to liver fat accumulation and increased liver enzymes. Nicotine exposure has been linked to oxidative stress, which may contribute to liver injury and inflammation. Elevated blood glucose levels are a known risk factor for non-alcoholic fatty liver disease (NAFLD), which in turn can elevate liver enzymes such as ALT and AST. Similarly, high BMI and poor lipid profiles are associated with liver fat deposition and hepatocyte damage, potentially increasing liver enzyme levels. Given these associations, the LE8 score may be an effective tool for assessing overall liver function. While some studies have shown associations between poor CVH and adverse liver outcomes (13–15), few have explored the role of comprehensive CVH measures like LE8 in relation to specific liver function parameters. In addition, most studies assume a linear relationship between CVH and liver outcomes without considering potential non-linear associations.

The National Health and Nutrition Examination Survey (NHANES) is a nationally representative dataset. NHANES includes detailed demographic, lifestyle, and clinical data, making it ideal for examining the association between LE8 scores and liver function. The purpose of this study is to examine the association between LE8 scores and liver function parameters in a representative sample of US adults. Additionally, through nonlinear curve fitting and subgroup analysis, we aim to reveal complex, age-dependent associations between CVH and liver function, providing novel insights into how improving CVH might protect liver function.

In this large cross-sectional study, we observed significant inverse associations between the LE8 score and liver function parameters, including ALT, AST, ALP, GGT, and the ALT/AST ratio. The relationship between LE8 scores and ALT and ALT/AST ratio showed nonlinear patterns, with significant decreases occurring at LE8 scores above 50.625 and 61.875, respectively. These findings underline the potential utility of the LE8 score in liver health monitoring, particularly for early identification of individuals at higher risk of liver dysfunction.

One of the key findings of this study was that the LE8 score was significantly associated with liver function parameters. A cross-sectional study by Labayen et al. recruiting 637 adolescents in 9 European countries found a positive association between ideal CVH and lower GGT and ALT (13). In a separate cross-sectional study of 1,084 European adolescents, they found that a lower AST/ALT ratio was also associated with higher cardiometabolic risk factors (16). A landmark study in 1995 first identified a significant association between GGT levels and mortality from coronary heart disease (17). Recent systematic reviews and meta-analyses have confirmed this association, showing a 60% increased relative risk of all-cause mortality in the highest tertile of GGT levels and a 7% increased risk per 5 U/L increase in GGT levels (18). In a cohort study of Austrian adults, high GGT was found to be significantly associated with CVD mortality in a dose–response relationship (19). In men and women, the hazard ratios for GGT were 1.66 and 1.64, respectively, with a stronger association in younger participants. In addition, the Rotterdam Study found that individuals in the top 5% of GGT levels had a 55% higher risk of all-cause mortality (20). Another meta-analysis showed a 56% increase in all-cause mortality for the highest versus lowest GGT quartile (21). Our study shows a negative association between LE8 scores and GGT levels, suggesting that better CVH, as reflected by higher LE8 scores, is associated with lower GGT levels. This finding is consistent with previous research and supports the role of GGT as a potential biomarker of CVH and mortality risk. The relationship between serum aminotransferases, particularly ALT and AST, with CVD risk has been extensively studied, though with varying degrees of association. However, when considering the LE8 score, which is designed to assess CVH, the interaction between these liver enzymes and LE8 components requires careful interpretation. Existing evidence suggests that the association between ALT and CVD risk is not as strong or consistent as that observed for GGT. For example, while the Framingham Offspring Heart Study found that elevated ALT levels were initially associated with a higher risk of CVD events, this association was attenuated after adjustment for multiple variables, suggesting that ALT may not independently predict CVD risk (22). However, an independent association between ALT levels and increased CVD mortality was found in a cohort study of 37,085 Korean participants (23). This nuanced relationship may extend to its association with LE8 scores, where ALT might correlate with some LE8 components, such as BMI and blood lipids, but not necessarily with overall cardiovascular risk. Similar trends are observed with AST, where its association with CVD events remains inconclusive. A meta-analysis of prospective cohort studies found no significant link between AST levels and increased risk of CVD mortality (24). Our results suggest a weak relationship between AST and LE8 score, which may reflect the limited role of CVH as an independent marker of AST. In contrast, ALP has shown a more consistent association with CVD risk. Higher levels of ALP have been associated with an increased risk of CHD and all-cause mortality, even after adjusting for traditional risk factors and excluding individuals with chronic kidney disease (25). This consistent association suggests that ALP may have a more direct relationship with CVH and, by extension, LE8 scores. The LE8 score, which includes several CVH factors, may interact with ALP levels in a way that reflects the enzyme’s role in vascular calcification and other cardiovascular processes.

The inverse relationship between the LE8 score and liver enzyme levels, particularly GGT, may be explained by several potential mechanisms. A healthier lifestyle, as reflected by a higher LE8 score, may reduce inflammatory stress, improve insulin sensitivity, and prevent excess adiposity (14). These factors contribute to a more favorable cardiovascular risk profile and may also reduce pathways leading to liver enzyme elevation. For example, adherence to dietary patterns such as the Mediterranean or DASH diets, which are characterized by a high intake of monounsaturated fatty acids, phytochemicals, fiber, and antioxidants, has been demonstrated to reduce inflammation and improve insulin resistance (26, 27). Participants who performed physical activity improved insulin sensitivity by decreasing immune cell activation and increasing glucose transporter type 4 translocation (28, 29). In addition, recent evidence indicates physical activity can directly affect lipogenesis and/or hepatic oxidation, thereby affecting hepatic lipid content (30). Avoiding obesity plays a critical role in preventing the release of inflammatory cytokines and free fatty acids from dysfunctional adipose tissue, which are known to contribute to lipotoxicity and hepatic steatosis (13, 31). Moreover, GGT has been implicated in promoting the oxidation of low-density lipoprotein (LDL) through redox reactions within atherosclerotic plaques, contributing to plaque development and progression (32). These mechanistic insights suggest that GGT is more strongly associated with LE8 scores than other liver enzymes, such as ALT, AST, and ALP, which may be due to its multifaceted role in oxidative stress and inflammation.

A key takeaway from this study is that the LE8 score can serve as an integrated measure for monitoring liver health and guiding CVH promotion. Given that CVD and liver dysfunction are often interconnected and share common risk factors, the LE8 score could serve as a dual marker to assess the overall health status of patients. Integrating LE8 scoring into routine clinical practice could be particularly beneficial in identifying individuals at high risk for both cardiovascular and liver diseases. By providing a holistic assessment of lifestyle factors, LE8 scores can help clinicians screen for early signs of liver dysfunction, such as elevated liver enzymes, while simultaneously monitoring cardiovascular risk. Furthermore, the use of the LE8 score in clinical practice could enhance personalized treatment strategies. For example, clinicians could tailor interventions to improve both cardiovascular and liver health based on a patient’s LE8 score. Interventions could include lifestyle modifications such as improved diet, increased physical activity, and smoking cessation. In this way, the LE8 score could contribute to a more integrated approach to managing patients’ overall health, potentially reducing the burden of both CVD and liver disorders. However, the feasibility of incorporating LE8 scoring into routine clinical practice would depend on the availability of relevant data in electronic health records and the development of standardized assessment tools for LE8 scoring. Training healthcare providers to interpret LE8 scores and use them to guide clinical decisions would also be necessary. Therefore, we call for future guidelines to consider incorporating the LE8 scores as part of routine health assessments to better understand its impact on patient outcomes and healthcare efficiency.

The strengths of our study are noteworthy. A key strength is the innovative use of the LE8 score, a comprehensive metric that integrates multiple lifestyle factors to provide a holistic assessment of CVH. This comprehensive approach may provide valuable insights into identifying individuals at higher risk for liver function abnormalities who may benefit from targeted interventions. In addition, our study used the WQS regression model, a novel methodological approach that allowed us to identify the most influential components of the LE8 score on liver enzyme levels. The use of data from the NHANES, a large-scale, nationally representative cross-sectional survey, further strengthens the generalizability of our findings to the broader U.S. population. The multistage probability sampling design of NHANES ensures that our results are applicable to different demographic groups. Furthermore, our study included detailed subgroup and interaction analyses, which provided a deeper understanding of how different population characteristics may influence the relationship between the LE8 score and liver enzyme levels. This approach highlights the necessity of adapting interventions to particular subgroups, thereby increasing the likelihood of developing more personalized and effective prevention strategies.

This study has several limitations. First, the cross-sectional design of the study limits the ability to infer causality. Although we observed correlations between LE8 scores and liver function, causal relationships cannot be established. Second, despite adjustment for numerous potential confounders, it is not possible to completely eliminate all sources of bias. For example, dietary recall data based on 24-h recall methods may be susceptible to recall or reporting bias, potentially affecting the accuracy of dietary intake data. Finally, because the NHANES database does not provide exact dates for dietary recall interviews and blood sample collection, we are unable to directly analyze the temporal relationship between these variables, which limits the assessment of time-dependent effects of dietary intake and blood biomarkers on liver function parameters.

The present study reveals a significant inverse relationship between the LE8 scores and liver enzyme levels. This finding indicates that higher LE8 scores, which reflect better CVH, are associated with improved liver function. Nonlinear analyses identified key inflection points for ALT and the ALT/AST ratio, indicating that the advantages of elevated LE8 scores on liver function may be more pronounced above specific thresholds. Given the potential of the LE8 score to guide early identification of individuals at risk for liver diseases, future guidelines could incorporate the LE8 score as part of routine screening and preventive measures. However, given the limitations of the current study, future prospective studies are needed to confirm these associations and explore the underlying mechanisms further.