In this study, non-obese NAFLD was associated with an increased risk of early LV diastolic dysfunction, independent of well-identified cardiovascular risk factors.
Previously, several studies have suggested that NAFLD was an independent risk factor affecting cardiac structure and function, but there are few studies on the correlation between non-obese NAFLD and LV function or structure in Chinese population. Therefore, this paper studied the changes of LV structure and function in hospitalized non-obese NAFLD patients, and discussed the correlation between non-obese NAFLD and early LV diastolic dysfunction, aiming to provide scientific evidence for clinicians to pay attention to the cardiac structure and function of non-obese NAFLD patients.
Our study showed that compared with the control group, non-obese NAFLD patients had higher BMI, BSA, levels of liver enzymes, blood lipids, proportion of DM, and worse glucose metabolism, which were consistent with previous reports. Although BMI of non-obese NAFLD patients is within the normal range, the visceral fat index is still high[13, 28]. Obesity is related to higher all-cause mortality[29], so both obese and non-obese NAFLD patients can benefit from losing weight[30]. For non-obese NAFLD patients, losing weight by 5–10% through lifestyle intervention can also benefit significantly[31].
In this study, LV structure and function are mainly evaluated by echocardiographic parameters, among which E/A is an important index to evaluate early LV diastolic function. E/A > 1 generally indicates the normal early LV diastolic function[32], while in dysfunction, the E value decreases due to the decrease of the maximum mitral blood flow velocity in the early LV diastole, which leads to E/A < 1[33]. Therefore, we used E/A<1 to determine early LV diastolic dysfunction. We compared the LV structure and function indexes between non-obese NAFLD group and control group, and the results showed that non-obese NAFLD patients had smaller LVEDD and worse early LV diastolic function. In non-obese people, subjects with non-obese NAFLD had a 4-fold increased risk for early LV diastolic dysfunction. The above results were consistent with many previous research on NAFLD[23, 34–36].
Non-obese NAFLD is similar to obese NAFLD in pathophysiology. A previous study based on liver biopsy showed that compared with obese NAFLD patients, non-obese NAFLD patients had lighter degree of hepatocytic steatosis, lobular inflammation and advanced liver fibrosis, and lower prevalence of NASH (54.1% vs 71.2%, p < 0.001)[37], and it also believed that liver fibrosis in non-obese NAFLD patients was obviously related to metabolic disorders. Another meta-analysis including 493 non-obese NAFLD patients and 2209 obese NAFLD patients compared the liver histological features between the two groups, which also showed that pathological changes of non-obese NAFLD were mild[38]. Insulin resistance is universal in NAFLD patients[12, 39, 40]. Non-obese NAFLD patients generally had higher prevalence of DM and glucose intolerance than healthy subjects, while there was no statistical difference between non-obese and obese NAFLD patients[41]. The changes of intestinal microbiota are also associated with the progress of NAFLD and liver fibrosis[42, 43]. A previous report about gut microbiota composition showed that Eubacterium abundance was significantly decreased in non-obese NAFLD patients compared with that in obese NAFLD patients and healthy subjects, then the results demonstrated a negative correlation between Eubacterium and hepatic fibrosis and that the decrease in the abundance of Eubacterium producing butyric acid may play an important role in the development of non-obese NAFLD[44]. It was found that a variety of gene sites are related to the risk, disease severity, hepatic steatosis and advanced fibrosis of NAFLD, including PNPLA3, TM6SF2, GCKR, MBOAT7, APOC3, HSD17B13, etc[45–50]. Among them, PNPLA3 is one of the earliest genes related to NAFLD in genome-wide association studies. the PNPLA3 rs738409 GG genotype was found in 13–19% of the general population in Asian, which is higher than that in other regions[12]. PNPLA3 not only plays a role in increasing the susceptibility to NAFLD, but also is related to abdominal visceral fat accumulation[51], and this gene has been proved to be one of the risk factors for NAFLD in non-obese people[52]. TM6SF2 has a protective effect on cardiovascular system, but it participates in hepatic steatosis and increases the susceptibility to NASH and hepatic fibrosis[53]. Compared with obese NAFLD patients, TM6SF2 E167K mutation is more common in non-obese NAFLD patients[54]. At present, it is considered that NAFLD is not only related to systemic insulin resistance, but also related to endothelial dysfunction, oxidative stress, plaque formation, vascular tone change, systemic inflammatory response, metabolic disorders of blood lipid and so on[55–57]. Previous studies have shown that compared with healthy people, non-obese NAFLD patients also have a higher risk of coronary heart disease[58], and there is no statistical difference between non-obese NAFLD patients and obese NAFLD patients in the risk of cardiovascular diseases and malignant tumors, and they all have a higher risk of all-cause mortality. The main causes of death of non-obese NAFLD patients are malignant tumors and cardiovascular diseases[59].
Despite the fact that NAFLD is usually associated with obesity, it has also been noted that the prevalence of NAFLD is increasing in non-obese individuals. Non-obese NAFLD is similar to the obese NAFLD in pathophysiological mechanism and influence on other related diseases. Compared with the healthy individuals, the non-obese NAFLD patients have a higher risk of liver cirrhosis, hypertension, DM, coronary heart disease and other diseases, as well as the risk of all-cause death, which needs to be confirmed by more studies in the future. The results of this study indicated that non-obese NAFLD was an independent risk factor for early LV diastolic dysfunction, which was consistent with the current research results. This research is meaningful for clinicians and patients because the results can remind clinicians to pay more attention to cardiac structure and function of non-obese NAFLD patients, and early intervention on non-obese NAFLD to delay its progress may be helpful to prevent or improve myocardial dysfunction.
However, this study has several limitations. First, the cross-sectional design of this study is difficult to explore the causal relationship between NAFLD and early LV diastolic dysfunction. Second, imaging examination were used to diagnose NAFLD and we were unable to obtain liver histological samples, the gold standard for the diagnosis of NAFLD. Third, we used E/A<1 to determine early LV diastolic dysfunction, while subjects with E/A ≥ 1 may have middle and late LV diastolic dysfunction. However, the above situation is extremely impossible because all the subjects enrolled in this study excluded heart disease patients and all of them had normal LV size and ejection fraction, and there was no evidence of heart failure. More accurate methods are needed to evaluate the LV structure and function in the future. Fourth, this study's cohort is a selected population, so may not be representative of the general population. In addition, this study only included subjects of East Asian ethnicity, so the conclusions may not be generalizable to other ethnic groups. Further studies are needed to validate our results.
In conclusion, non-obese NAFLD is associated with increased risk of early LV diastolic dysfunction. Therefore, intervention of non-obese NAFLD may be beneficial to improve early LV diastolic dysfunction.