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Association of life’s essential 8 with mortalities in patients with alcohol-related liver disease

BMC Gastroenterology volume 24, Article number: 326 (2024) Cite this article

Abstract

Background

Alcohol-related liver disease (ALD) and cardiovascular diseases share some common risk factors. This study aims to investigate the associations between Life’s Essential 8 (LE8), a comprehensive measure of cardiovascular health (CVH), and outcomes of ALD.

Methods

Data were obtained from the 2011–2018 National Health and Nutrition Examination Survey (NHANES). Cox proportional hazards models were employed to assess the relationships between LE8 and all-cause and cardiovascular mortality in patients with ALD. Additionally, restricted cubic splines (RCS), piecewise regression, and subgroup analyses were conducted.

Results

A total of 5321 ALD patients were included in this study with a mean LE8 score of 67.38. During a median follow-up period of 63 months, 228 all-cause deaths were recorded. After adjusting for potential confounders, the risk of all-cause mortality in the high CVH group decreased by 53.7% compared to the low CVH group (HR = 0.463, 95%CI = 0.223–0.965). The result was robust in subgroup analyses. The RCS analysis indicated a non-linear relationship between LE8 and cardiovascular mortality, showing that the risk of cardiovascular mortality decreased with increasing LE8 scores for values below 71.12 (HR = 0.949, 95% CI = 0.915–0.984).

Conclusions

LE8 score is inversely and linearly linked to all-cause mortality in ALD patients. Promoting adherence to optimal cardiovascular health may unveil additional strategies for the effective management of ALD patients and contribute to reducing their long-term mortality.

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Background

Alcohol-related liver disease (ALD) is the most common type of chronic liver disease worldwide. Cirrhosis caused by alcohol consumption accounts for 25% of all cirrhosis deaths, and ALD-related cancer deaths account for 30% of all liver cancer deaths [1]. ALD initially progresses from alcoholic fatty liver disease to alcoholic steatohepatitis, ultimately leading to fibrosis and cirrhosis. In some cases, it can also lead to hepatocellular carcinoma [2, 3]. Unfortunately, patients with ALD often remain asymptomatic until the development of severe and advanced disease, making early diagnosis extremely difficult. Currently, effective medical treatments for ALD are lacking, with abstinence from alcohol being the most common strategy for preventing disease progression [4]. Compared to the latest advances in viral hepatitis, there has been almost no pharmacological progress in the treatment of ALD patients [4]. Therefore, additional strategies are urgently needed.

In recent decades, cardiovascular diseases were the main reason for the stagnation of life expectancy growth in the United States [5]. The American Heart Association (AHA) recently released an updated algorithm for evaluating cardiovascular health (CVH)—Life’s Essential 8 (LE8) score, which measures adherence to a set of lifestyle behaviors and health factors, including a healthy diet, physical activity, avoidance of nicotine, healthy sleep, healthy weight, as well as healthy levels of blood lipids, blood glucose, and blood pressure [6]. The comprehensive measurement of multiple metrics can effectively represent the full range of CVH. A study found that individuals with higher LE8 score had an average lifespan increase of 8.9 years compared to those with the lowest score [7]. A study from the UKB database, involving 137,794 individuals, revealed a significant association between elevated CVH levels, as defined by LE8, and a decreased risk of coronary heart disease, stroke, and cardiovascular disease [8]. For young people, there is also an inverse gradient association of baseline and long-term CVH with the risk of premature cardiovascular disease and all-cause mortality [9].

Furthermore, LE8 score has been shown to be strongly associated with various diseases, such as diabetes, cancer, dementia, and depression [10,11,12]. Recent studies have confirmed that LE8 score is closely associated with the risk of non-alcoholic fatty liver disease [13, 14]. ALD and cardiovascular diseases share some common risk factors. Excessive and frequent alcohol consumption has significant adverse effects on both the liver and the heart [15]. Obesity, hyperglycemia, hypertension, and hyperlipidemia are definite risk factors for cardiovascular disease and are closely related to metabolic disorders in the liver [16, 17]. Meanwhile, previous studies have mostly focused on individual factors affecting prognosis, neglecting the overall impact of healthy lifestyles. Therefore, heart protection recommendations, represented by LE8 score, may also be effective in reducing the risk of long-term mortality in ALD patients.

In order to address this knowledge gap, we investigated the association between LE8 score, an updated CVH indicator, and both all-cause mortality and cardiovascular mortality in adults with ALD.

Methods

Study design and participants

The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional survey, which combines interviews and physical examinations to provide a comprehensive picture of the health and nutritional status of the U.S. population [18]. The protocol of NHANES was approved by the National Centre for Health Statistics ethics review board, and all participants had provided written informed consent.

A total of 39,156 individuals were identified from four survey cycles (2011–2018) of NHANES data. According to our study objective, adults with ALD were included in the study. Therefore, 15,331 (39.2%) participants under the age of 18 were first excluded, followed by 16,764 (42.8%) participants without diagnosed ALD and missing follow-up data. We further excluded 1740 (4.4%) participants with missing data for LE8 or covariates. Finally, a total of 5321 (13.6%) adults with ALD were included in this study. The diagnostic criteria for ALD are shown in Table S1.

Definitions of exposure, covariates, and outcomes

LE8 score is a new measure of CVH proposed by the AHA, which includes four health behaviors (diet, physical activity, nicotine exposure, and sleep health) and four health factors (body mass index, blood lipids, blood glucose, and blood pressure). Each metric is scored using a scoring algorithm ranging from 0 to 100 points, with LE8 score being the unweighted average of all components. This study followed the AHA’s published scoring criteria for calculating LE8 score and classified participants with LE8 score > 80 as high CVH, those with LE8 score of 50–79 as moderate CVH, and those with LE8 score < 50 as low CVH [6]. The covariates included age, sex, race, marital status, education, and the ratio of family income to poverty (RIP). The definitions are detailed in Table S1. All-cause mortality was derived from National Death Index (NDI) records linked to NHANES data through December 31, 2019.

Statistic analysis

NHANES used a complex multistage sampling design, so all analyses in this study used appropriate weighting procedures. Baseline characteristics were described using weighted means ± standard errors for continuous variables and frequencies and percentages for categorical variables. Participants were divided into low CVH, moderate CVH, and high CVH groups based on LE8 score. Intergroup differences were compared using one-way ANOVA test, Kruskal-Wallis H test, or Chi-squared test. Multivariate Cox regression was used to explore the associations between LE8 score and all-cause mortality and cardiovascular mortality. The Schoenfeld residuals method was used to test the proportional hazards assumption. We developed three different models to represent the stratified adjustment of the regression model (Model 1: unadjusted; Model 2: adjusted for sex, age, and race; Model 3: adjusted for sex, age, and race, marital status, education, and RIP). LE8 score was included in the model as a continuous and categorical variable, respectively, to verify the robustness of the results. In addition, restricted cubic spline (RCS) regression was used to explore the potential nonlinear relationship between LE8 score and mortality, with the number of nodes determined based on the minimum value of the Akaike Information Criterion (AIC). Nonlinearity was evaluated using the likelihood ratio test. If nonlinearity was detected, two segmented Cox proportional hazards regression models were constructed. The Kaplan-Meier method was used to estimate survival probability, and different groups were compared by the log-rank test. To eliminate the confounding influence of viral hepatitis, we excluded patients with this condition to reassess the relationship between LE8 and mortality. In participants without ALD, we also evaluated the relationship between LE8 and all-cause mortality using Cox regression models. We further investigated the independent association of the LE8 components with all-cause mortality using Cox regression models. Stratified analyses were performed based on sex, age, race, marital status, and education. Additionally, potential interactions were examined by multiplying the relevant variables. Statistical significance was assumed to be two-side P < 0.05. All analyses were conducted using R version 4.3.1 software (R Core Team (2023). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org/).

Results

Baseline characteristics of study participants

5321 adults were finally enrolled in this study, and the recruiting process was illustrated in Fig. 1. Characteristics according to LE8 score and all-cause mortality were shown, respectively, in Table 1 and Table S2. The mean age of the study population was 47.21 years old, of which 1789 (34.53%) participants were women. The mean LE8 score was 67.38, and the frequencies and percentages for low, moderate, and high CVH were 3698 (69.50%), 928 (17.44%), and 695 (13.06%), respectively. After a median follow-up duration of 63 months (interquartile range: 39–85 months), 228 participants were reported as having died from all causes. The incidences of all-cause death for low, moderate, and high CVH groups were 7.30%, 3.30%, and 2.13%, respectively. As shown in Fig. 2, the Kaplan–Meier survival curves stratified by CVH groups also demonstrated that the low CVH group had higher all-cause mortality (log-rank test, p < 0.01). People in the low CVH group tend to be older, obese and have lower RIP and education levels.

Fig. 1
figure 1

Flow diagram for inclusion of the study population

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Table 1 Baseline characteristics of participants
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Fig. 2
figure 2

The Kaplan–Meier curve for the study population with different Life’s Essential 8

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Associations between LE8 score and mortality

Results from the fully adjusted multiple Cox regression in Table 2 demonstrated a significant association between LE8 score and all-cause mortality (HR = 0.979, 95%CI = 0.964–0.994). In model 1, 2, and 3, compared to the low CVH group, all-cause mortality was decreased by 73.3%, 68.3%, and 53.7% in the high CVH group (all P < 0.05). The multivariable-adjusted RCS revealed that there was inverse dose-response association between LE8 score and all-cause mortality (P for nonlinearity = 0.762; Fig. 3).

Table 2 Association between LE8 score and all-cause mortality
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Fig. 3
figure 3

Restricted cubic spline fitting for the association between LE8 score with all-cause mortality

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However, the results in Table S3 showed that the association between LE8 score and cardiovascular mortality was not statistically significant. As shown in Figure S1, the association between LE8 score and cardiovascular mortality was detected as U-shaped with a threshold value of 71.12 for LE8 score, although this association was not statistically significant (P for nonlinearity > 0.05). Table S4 demonstrated that for values below this threshold, the risk of cardiovascular death decreased as the LE8 score increased (HR = 0.949, 95%CI = 0.915–0.984, P < 0.01). Conversely, values exceeding the threshold were not significantly associated with cardiovascular mortality. As shown in Table S5, LE8 was still associated with an increased risk of all-cause mortality after excluding participants with viral hepatitis. Table S6 indicated that the relationship between LE8 and all-cause mortality remains statistically significant among participants without ALD. Table S7 demonstrated the relationship between the components of LE8 and all-cause mortality, with nicotine exposure, blood glucose, and blood pressure being significantly associated with the risk of all-cause mortality.

Subgroup analyses

The results of the subgroup analyses in Fig. 4 indicated that the association between LE8 score and all-cause mortality is consistent and reliable after being stratified by sex, age, race, marital status, and education (all P for interaction > 0.05). The inverse association between LE8 score and ALD was more significant in participants under 65 years old, female, married or with partner, and those with education level higher than high school.

Fig. 4
figure 4

Forest plot for subgroup analysis

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Discussion

This cross-sectional study included ALD patients in the United States, in which the risk of all-cause mortality was reduced sequentially across the low, moderate, and high CVH groups. After adjusting for confounding factors, LE8 score was associated with the risk of all-cause mortality in ALD patients. Stratified analysis confirmed that the findings were consistent and reliable. At the same time, when the LE8 score was below 71.12, there was also a significant negative association between the LE8 score and the risk of cardiovascular mortality.

To our knowledge, this is the first study to evaluate the relationship between CVH defined by LE8 score and the all-cause and cardiovascular mortalities of ALD. Previous studies have reported that ALD is one of the major causes of chronic liver disease worldwide, accounting for 48% of liver cirrhosis-related deaths in the United States [4]. Due to the lack of early symptoms, most ALD patients present with advanced cirrhosis at their first visit [19]. Epidemiological studies have shown that only 30% of heavy drinkers will develop advanced ALD, suggesting that alcohol dependence is not a prerequisite for developing advanced ALD [20]. Therefore, we still need other means to improve the long-term mortality of ALD.

Although LE8 score was primarily proposed to assess CVH, studies have shown that LE8 score is significantly associated with the risk of stroke, chronic kidney disease, diabetes, NAFLD, and many other diseases [13, 14, 21,22,23,24]. A prospective multicenter cohort study based on the UK Biobank (UKB) showed that LE8 scores for most patients with chronic liver disease were in the low to moderate CVH group, and the inverse dose-response association between LE8 score and chronic liver disease was significant [25]. At the same time, the health behaviors and health factors included in LE8 score also have influences on the development of ALD. Many studies have shown that alcohol consumption in patients with metabolic syndrome leads to a significant increase in the risk of advanced liver disease, even within acceptable ranges [26,27,28]. Obesity not only worsens the prognosis of ALD, but also plays a synergistic role with metabolic syndrome in disease progression in ALD patients [26]. A mendelian randomization study demonstrated a causal relationship between obesity and a poor prognosis in ALD [29]. A meta-analysis of 10 cohort studies involving 1,005,339 participants showed that smoking significantly increases the risk of ALD [30].

Our study also revealed the dose-response relationship between LE8 score and the risk of long-term mortality in ALD patients using restricted cubic splines (RCS), which has not been previously reported. LE8 score was linearly related to the risk of all-cause mortality in ALD patients, which confirmed that implementing health behaviors and health factors can continuously reduce the risk of all-cause mortality. However, the association between LE8 score and cardiovascular mortality was not consistent. Previous studies have reported that ALD has a significant impact on the cardiovascular system and hemodynamics by increasing heart rate, cardiac output, reducing systemic vascular resistance, arterial pressure, and dilating plasma volume, thus increasing the risk of alcoholic cardiomyopathy, arterial hypertension, atrial arrhythmias, and hemorrhagic and ischemic stroke [31]. In patients with biopsy-proven ALD, there is a two-fold increased short-term risk for cardiovascular disease [32]. Therefore, there may be a more complex link between ALD and cardiovascular disease. The relationship between LE8 score, as a composite indicator, and cardiovascular mortality in patients with ALD needs to be further explored.

Subgroup analyses demonstrated a strong negative association between LE8 score and all-cause mortality in younger, female, coupled participants, and those with a higher education level than high school. Several studies have shown that women have a higher risk of ALD than men with the same amount of alcohol, possibly due to sex-specific hormones that cause alcoholic behavior to produce more pro-inflammatory cytokines, leading to liver damage [33]. Smoking cessation and healthy diet included in LE8 have been confirmed to directly improve inflammatory status [34, 35]. Therefore, female ALD patients may benefit more from high CVH levels than men. Additionally, several studies have shown that marriage can alleviate disease progression by promoting a healthier lifestyle or providing social support [36,37,38]. A study based on the large cohort ChinaHEART, which analyzed data on 1,283,774 Chinese people born in the 1940s, 1950s, 1960s, and 1970s, found that mortality rates decreased with higher levels of education [39]. Therefore, we must be aware in clinical practice that the potential beneficial value of LE8 score for ALD patients varies across different populations.

However, there are several limitations to this study. Firstly, most assessments of health indicators were based on questionnaires, which are susceptible to recall bias. This bias can compromise the validity of the data collected and exaggerate or diminish the perceived relationships between LE8 score and mortality. Secondly, the relationship between health behaviors or factors and outcomes can be multifactorial. Despite model adjustments and subgroup analyses, we could not rule out potential confounders that might influence the results. Thirdly, the nature of cross-sectional research prevented us from establishing a causal relationship between LE8 score and the mortality of ALD patients, highlighting the need for future studies that employ longitudinal designs. Finally, the results of this study were obtained only from US adults, and further research is needed to determine if they are applicable to populations in other countries.

Conclusion

Among adult ALD patients in the United States, the LE8 score was significantly associated with the risk of all-cause mortality. When the LE8 score was in the lower range, it was also significantly negatively associated with the risk of cardiovascular mortality. These associations vary among different populations. It is suggested that LE8 score can be applied clinically as a meaningful indicator to assist in the comprehensive management of ALD patients and to improve long-term mortality risk.

Data availability

The datasets analyzed in this study are publicly available and can be found at https://www.cdc.gov/nchs/nhanes/.

Abbreviations

ALD:

Alcohol-related liver disease

LE8:

Life’s Essential 8

CVH:

Cardiovascular health

NHANES:

National Health and Nutrition Examination Survey

RCS:

Restricted cubic spline

AHA:

The American Heart Association

RIP:

Family income to poverty

NDI:

National Death Index

AIC:

Akaike Information Criterion

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Acknowledgements

The authors thank the staf and the participants of the NHANES study for their valuable contributions.

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Authors and Affiliations

  1. Department of General Surgery, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China

    Xiaohui Zhang & Zhen Liu

  2. Guangning County People’s Hospital, Zhaoqing, China

    Shimou Wu

  3. Department of Cardiology, The 963 Hospital of the PLA Joint Logistics Support Force, Jiamusi, Heilongjiang, China

    Yang Cao

  4. Southern medical university, Guangzhou, China

    Sicong Ma

  5. Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China

    Hongfei Sun

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Contributions

ZL and XHZ designed the research. SMW, SCM, YC and HFS collected, analyzed the data. XHZ drafted the manuscript. ZL and YC revised the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Zhen Liu.

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The protocol of NHANES was approved by the National Centre for Health Statistics ethics review board, and all participants had provided written informed consent.

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Zhang, X., Wu, S., Cao, Y. et al. Association of life’s essential 8 with mortalities in patients with alcohol-related liver disease. BMC Gastroenterol 24, 326 (2024). https://doi.org/10.1186/s12876-024-03432-3

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  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12876-024-03432-3

Keywords

BMC Gastroenterology

ISSN: 1471-230X

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