Nonalcoholic Fatty Liver Disease Is Associated With Increased Risk of Atrial Fibrillation

Xiaoyan Cai; Sulin Zheng; Ying Liu; Yan Zhang; Jianhua Lu; Yuli Huang


Liver International. 2020;40(7):1594-1600. 

In This Article


In this meta-analysis among 614 673 participants with median follow-up duration of 10 years, we found that compared with non-NAFLD, NAFLD was associated with a 19% higher risk of incident AF, independent of multiple cardiovascular risk factors, and about 5% of incident AF in the population can be attributed to NAFLD.

Previous meta-analyses investigating the association between NAFLD and the risk of AF reported inconsistent results. Wijarnpreecha et al included 5 studies (2 cross-sectional studies and 3 cohort studies) and reported that the risk of AF in patients with NAFLD was significantly higher than those without NAFLD (RR 2.06, 95% CI 1.10–3.85).[10] Another meta-analysis included 3 studies observed that patients with NAFLD had 2.5 times significantly higher chance (OR = 2.47, CI = 1.30–4.66,) of developing AF.[28] However, inclusion of cross-sectional studies in these meta-analyses may overestimate the association between NAFLD and risk of AF. In contrast, a recent meta-analysis by Mantovani et al combined data from 5 cross-sectional and 4 prospective cohort studies. Their results found that in cross-sectional studies, NAFLD was associated with an increased risk of prevalent AF (OR 2.07, 95% CI 1.38–3.10), while data from 4 longitudinal studies showed that NAFLD was independently associated with an increased risk of incident AF only in type 2 diabetic patients (HR 4.96, 95% CI 1.42–17.28), but not in pooled analysis of all prospective cohorts (HR 1.34, 95% 0.92–1.95).[9] Therefore, they proposed that NAFLD is associated with an increased risk of AF in high-risk individuals, especially in patients with type 2 diabetes. However, the observational design of the included studies cannot interpret the causality.[9] Compared with those previous meta-analyses, our study has several strengths. First, we excluded studies with case-control or cross-sectional design, or cohort studies did not adjust for other cardiovascular risk factors, which mitigated the possibility of influencing the association between NAFLD and prognosis by other confounding factors. Actually, our results showed that the strength of the association between NAFLD and AF (19% increased of RR) was obviously weaker than previously reported. Second, several included studies with large sample size in our review were recently published and thus were not included in previous studies, which constituted the latest evidence in the field.

We also found that there was significant heterogeneity for the risk of AF in minimally adjusted model (unadjusted or age and gender adjusted) compared with maximal confounders adjusted model, which demonstrated that the risk of AF in patients with NAFLD is at least partially attributed to co-exiting risk factors. However, it should be noted that even after adjustment for multiple conventional cardiovascular risk factors, the risk of AF still remained higher in patients with NAFLD, indicating that other potential mechanisms may be involved in the link between NAFLD and development of AF. Several mechanisms may contribute to the risk of AF in NAFLD. First, in patients with NAFLD, fat accumulation is not restricted in the liver tissue, but also other tissues including pericardium or myocardium, resulting in atrial stiffness and diastolic dysfunction,[29,30] both of them are significant risk factor for AF. Second, emerging evidence has showed that NAFLD is a status of metabolic inflammation and should be considered as a low-grade inflammatory disorder.[31] Inflammation is associated with adverse atrial structural and electrical remodelling, which can lead to the onset and maintenance of AF.[32] Therefore, the inflammatory pathways may be involved in the pathogenesis of NAFLD-associated AF. Third, NAFLD is associated with cardiac autonomic dysfunction,[33] which may influence cardiac electrical remodelling and play an important role in initiation and maintenance of AF.

Considering the high prevalence of NAFLD, effective intervention in these large populations could have major impacts on clinical outcomes and public health. Lifestyle change to effect weight loss and reduce obesity the cornerstone of treatment for NAFLD.[5] Control of the cardiometabolic risk factors should be recommended in patients with NAFLD.[11] Further studies are needed to clarify whether treatment for NAFLD can decrease the risk of AF.

There are several limitations in this study. First, NAFLD was defined with different methods in included studies, which was an underlying factor for the heterogeneity among the studies. However, the risk of AF did not show significant heterogeneity among subgroup analysis according to methods of defining NAFLD. Second, no association between AF and NAFLD confirmed by biopsy had been reported. NAFLD is a heterogeneous disease, including "simple steatosis", nonalcoholic steatohepatitis (NASH) and hepatic fibrosis based on histologically findings. The inflammatory activation is more obvious in patients with NASH and advanced hepatic fibrosis.[34] Whether patients with more severe histologically findings based on biopsy or noninvasive markers of fibrosis (eg NAFLD fibrosis score, fibrosis-4 score) carried a higher risk of AF is not available in the study. Third, the diagnosis of AF in the included studies was based only on standard electrocardiogram and no data were available on 24-h electrocardiogram monitoring. Therefore, some patients with paroxysmal AF may be not diagnosed. Fourth, subgroup analysis showed that patients with type 2 diabetes seem to carry a higher risk of AF than general population. However, only one prospective study was available for analysis of the risk of AF in patients with diabetes.[27] Further studies are needed to explore whether diabetes and NAFLD have a synergistic effect on the risk of incident AF.

In conclusion, NAFLD is associated with a moderate increased risk of AF. The increased risk of AF is partly attributed to co-exiting cardiometabolic risk factors. Screen and proper management of NAFLD may reduce the incidence and morbidity of AF.