Association between cardiac conduction defect and nonalcoholic fatty liver disease: a systematic review and meta-analysis

Introduction

Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of more than 5% of hepatic fat accumulation without a history of excessive alcohol consumption or any secondary causes of liver disease [1]. A recent meta-analysis has estimated the pooled incidence of NAFLD to be approximately 50 per 1000 person-years in Asia and approximately 25 per 1000 person-years in Europe [2-4]. Several metabolic disorders, such as diabetes mellitus, obesity, dyslipidemia, hypertension and hyperuricemia, are more common among patients with NAFLD [5-9]. The relationship between NAFLD and these disorders is bidirectional and is linked by insulin resistance and chronic inflammation [10].

Cardiovascular disease is another common associated disorder among patients with NAFLD [11,12], particularly coronary artery disease and congestive heart failure, as has been observed by several epidemiologic studies [13-16]. Patients with NAFLD may also be at an increased risk of cardiac conduction defects, although the evidence for this particular type of cardiovascular disease is still relatively limited [17-19]. This systematic review and meta-analysis was conducted to identify all observational studies that investigated the risk of cardiac conduction defects among patients with NAFLD versus those without and to summarize their results together to better characterize this risk.

Materials and methods

Results

Two hundred twenty-nine articles were initially identified using the described search strategy (95 articles from Medline and 134 articles from EMBASE). After the exclusion of 90 duplicated articles, 139 articles underwent title and abstract review. One hundred and twenty articles were excluded at this stage since they were case reports, case series, correspondence, review articles, in vitro studies, animal studies or interventional studies, leaving 19 articles for full-text review. Sixteen of these were excluded after the full-length review as they did not report the association of interest. Finally, 3 cross-sectional studies [17-19] with 3651 participants were included in the final analysis. A flowchart showing the literature search, review and selection process is shown in Fig. 1. The study characteristics and quality assessment using the modified Newcastle-Ottawa scale are presented in Table 1. It should be noted that the inter-observer reliability for the quality assessment was high, with a kappa statistics of 0.77.

Figure 1 Literature review process

Table 1 Main characteristics of the studies included in this meta-analysis

Association between NAFLD and cardiac conduction defect

The pooled analysis found a significantly greater risk of a cardiac conduction defect among patients with NAFLD, with a pooled OR of 5.17 (95%CI 1.34-20.01), as demonstrated in Fig. 2. The heterogeneity between the studies was high, with an I2 of 96%.

Figure 2 Forest plot of all studies

NAFLD, nonalcoholic fatty liver disease; CI, confidence interval; df, degrees of freedom

Discussion

This study is the first systematic review and meta-analysis that comprehensively combined the data from all available studies on the association between NAFLD and cardiac conduction defect. The pooled analysis found an approximately 5-fold greater risk of cardiac conduction defects among patients with NAFLD compared to individuals without. The reasons behind this increased risk are not well understood but there are some possible explanations.

The first explanation is related to the increased level of inflammatory cytokines among patients with NAFLD [23,24]. Deposition of adipose tissue in the liver induces low-grade systemic inflammation through the release of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor, and transforming growth factor (TGF)-β. These cytokines are arrhythmogenic, as demonstrated by several studies [25,26]. For instance, in a rodent study, IL-1β was shown to prolong the repolarization phase and interfere with potassium and calcium fluxes, causing disturbance of cardiac conduction [27]. Another in vitro study found that an increased level of TGF-β can induce fibrotic changes in cardiomyocytes, causing arrhythmias and conduction defects [28].

Second, fatty accumulation in the liver could be a marker of fatty deposition in other organ tissues, including myocardium and pericardium [29]. This ectopic fatty tissue acts as an electrical insulator, which may cause heart block and arrhythmia if it infiltrates the conduction system [18,30,31]. Moreover, this fatty infiltration can subsequently transform into fibrous tissue, which would further increase the severity of a conduction defect [32].

It is also possible that NAFLD does not directly cause conduction defects. The observed association could be a consequence of the increased risk of coronary artery disease [33] and heart failure [34] among patients with NAFLD, as both conditions can cause structural changes of the heart [35,36]. The current systematic review and meta-analysis could not exclude the role of these potential confounders, as the primary studies did not comprehensively adjust their effect estimates for them.

Even though we conducted a comprehensive literature search and retrieved high quality studies, as suggested by the high Newcastle-Ottawa scores, the study had some limitations and our results should be interpreted with caution. First, the statistical heterogeneity was high in this meta-analysis. We believe that the differences in the study population, the definition of cardiac conduction abnormality, and the variables used for adjustment in the multivariate analysis across the studies were the main source of the between-study variation. For instance, the study by Iscen et al [17] found only right bundle-branch block, a finding without any clinical significance in young adults. On the other hand, the other 2 studies included patients with cardiac conduction defects that are severe and need special cardiological management (i.e., first-degree block, Mobitz type 1 block, left bundle-branch block, bifascicular block and nonspecific intraventricular block in the study by Mangi et al [18], and first-degree atrioventricular block, second-degree block, third-degree block, left bundle-branch block, right bundle-branch block, left anterior hemiblock and left posterior hemiblock in the study by Mantovani et al [19]). This would also make it difficult to determine the clinical implications of the observed association. Second, the temporal relationship between NAFLD and cardiac conduction defect could not be clearly established, given the cross-sectional nature of the included studies. It is still possible that the association between NAFLD and cardiac conduction is confounded by comorbidities, such as diabetes mellitus and other cardiovascular diseases, given that one of the 3 included studies did not adjust its effect estimate for any potential confounders. Further prospective cohort studies with comprehensive adjustment for potential confounders are still required. Third, we could not perform a publication bias analysis because of the limited number of studies included. Thus, publication bias in favor of studies with positive results may have been present. Fourth, none of the included studies provided data on subgroups of patients with nonalcoholic steatohepatitis. Further studies are still needed to investigate the risk in this specific subgroup.

In summary, the current study demonstrated a significantly greater risk of cardiac conduction defects among patients with NAFLD compared with individuals without. Physicians who provide care to patients with NAFLD should be aware of this association, since cardiovascular mortality is their most common cause of death. Nonetheless, further studies are still required to investigate whether the association is causal and to determine the role of screening and preventative measures in clinical practice.