1. Introduction
Nonalcoholic fatty liver disease (NAFLD) refers to the fatty degeneration of liver cells exceeding 5% in the absence of other liver-damaging factors. NAFLD is the most prevalent chronic liver disease globally and the leading cause of liver-related morbidity and mortality, accounting for around 30% of cases [
1]. NAFLD-related cirrhosis and hepatocellular cancer are the primary reasons for liver transplantation [
2]. NAFLD is a multisystem disease that increases the risk of extrahepatic organ diseases [
3]. A meta-analysis showed that NAFLD was independently related to the occurrence of coronary artery disease (CAD) (relative risk = 1.21, 95% CI: 1.07–1.38) [
4]. Coronary heart disease is the leading cause of mortality in China, and a notable epidemiological aspect of the country is the sharp increase in the atherosclerotic cardiovascular disease (CVD) burden [
5]. Recent research has revealed a strong association between metabolism and the aetiology and symptoms of fatty liver. An international expert consensus recommends substituting the term “metabolic dysfunction-associated fatty liver disease (MAFLD)” for “NAFLD” [
6]. Whether patients have MAFLD or NAFLD, CVD is the leading cause of death for them [
7,
8].
Although a liver biopsy is the most reliable method for identifying chronic liver disease, it is not appropriate for large-scale population screening because of its invasiveness, sampling variability, and uncommon complications. Owing to changes in contemporary living environments and lifestyles and advancements in diagnostic and treatment techniques, fatty liver disease (FLD) has been identified as a global pandemic affecting hundreds of millions of people. Hepatic fat degeneration is a prerequisite for diagnosing NAFLD/MAFLD. The development of non-invasive liver disease assessment tools, including imaging methods and laboratory indicators, has improved FLD diagnosis and prognosis [
9]. A study investigating the relationship between hepatic steatosis and CAD showed that patients with CAD and hepatic steatosis had a worse prognosis than those without hepatic steatosis [
10]. In this study, hepatic steatosis was evaluated using CT. However, the disadvantages of CT, such as radioactivity and high price, limit its promotion among the general public. Ultrasound is an inexpensive, quick, and safe diagnostic technique with 89% sensitivity and 93% specificity for identifying FLD [
11]. Building on liver biopsy as the gold standard in their research, Ballestri et al. developed the ultrasonographic fatty liver indicator (US-FLI), a semiquantitative index, to assess the degree of liver steatosis [
12], wherein a higher US-FLI value indicates a higher degree of liver steatosis. With US-FLI ≥ 2, the sensitivity and specificity of detecting mild fatty liver were 90.1% and 90%, respectively. One study found that US-FLI as a continuous variable could predict the occurrence of NAFLD in children [
13]. The SYNTAX score (SS) is a risk model that stratifies CAD risk based on the invasive coronary angiography (ICA) according to the anatomical morphological characteristics of lesions, such as the number and location of diseased vessels, involved coronary arteries, calcification, coronary artery course, degree of occlusion, and thrombosis, to determine the best revascularization strategy and predict prognosis [
14]. The higher the SS, the more complicated the disease, indicating considerable treatment challenges and a worse prognosis.
Since the term “MAFLD” is relatively new, most clinical research is focused on the non-invasive diagnosis of NAFLD, while there are relatively few non-invasive diagnostic studies based on MAFLD. This study used US-FLI to determine the level of hepatic fatty degeneration in patients with MAFLD and examined its correlation with SS.
4. Discussion
Our results showed that the new semiquantitative ultrasound liver steatosis index, US-FLI, was an independent predictor for CAD and positively associated with the severity of CAD after adjusting for confounders. For each increase of 1 unit of US-FLI, the probability of MS CAD increased by 1.262 times. In addition, we demonstrated that T2DM was an independent risk factor for MS CAD, and the risk of MS CAD in T2DM patients increased by 3.337 times compared with those without T2DM. US-FLI combined with T2DM showed better predictive performance in the prediction model of MS CAD risk than US-FLI alone. Consistent with prior research, our results indicated that male and patients with lower values of EF and TBIL, higher values of ApoA1, and less than 150 min of physical activity per week were more likely to have MS CAD, even though these were not statistically significant. To our knowledge, few studies have examined the correlation between steatosis and the severity of CAD in MAFLD using US-FLI.
As a multisystem disease, NAFLD/MAFLD is characterized by an increased risk of extrahepatic events, the most significant of which are cancer and CVD [
16]. A large cohort study involving 5671 subjects found that patients with hepatic steatosis had an increased risk of early atherosclerosis [
17]. A meta-analysis found the risk of CVD in patients with NAFLD increased by 57–69% after correcting for other common risk factors [
18]. Even without T2DM or hypertension, patients with NAFLD showed a bias towards developing CAD in the next 10 years, revealing that NAFLD may pose an independent risk factor for CVD or that there are other undetermined risk factors. In addition, Toh et al., in a meta-analysis of 38 included articles, reported that the prevalence of CAD in patients with MS hepatic steatosis was 37.5%, which was significantly higher than that in patients with mild hepatic steatosis [
7]. These findings coincide with those of this study. Metabolic syndrome (MetS) is a general term used to describe multiple CVD-related risk factors, including IR, atherosclerotic dyslipidaemia, central obesity, and HBP. A study using systems biology models showed a large overlap in the disease mechanisms of NAFLD and MetS [
19]. Some studies have pointed out that NAFLD is a liver manifestation of MetS, and the term “MAFLD” was based on this concept. Although many studies have shown that MAFLD/NAFLD, as a multisystem disease, is strongly associated with CVD, the fundamental mechanism is still not fully elucidated. However, the following possibilities still exist.
Given the strong association between MetS and NAFLD/MAFLD, as well as their link to CVD, it is crucial to explore how shared risk factors contribute to these interactions. Among these, obesity stands out as a central factor influencing the development and progression of both conditions. As lifestyle changes, obesity has become a global epidemic and has shown a continuous upward trend over the past 50 years. According to estimates by the World Health Organization, 1.9 billion adults worldwide are overweight or obese, which brings with it an increased social burden and disease risks such as CVD, T2DM, and fatty liver [
20]. Obesity is the abnormal accumulation of fat that can impair health, leading to metabolic changes in white adipose tissue and the induction of inflammation through adipokines, which promotes the progression of many chronic metabolic diseases. Adipokines such as adiponectin, leptin, and omentin are bioactive molecules secreted by adipose tissue. They influence MAFLD and CAD through mechanisms such as inflammation, IR, oxidative stress, and lipid metabolism, potentially leading to mutual influence between the two conditions. There are several methods for assessing obesity, including visceral fat accumulation and anthropometric indicators. Although BMI, as a measurement indicator of peripheral obesity, has been confirmed to be associated with CAD, some studies have reported that it is not the most appropriate indicator for predicting the severity of CAD, which may be related to the close correlation between central obesity and CAD [
21,
22,
23]. This study explored the association of FLD, which is closely related to central obesity, with CAD. Although unclear, possible mechanisms by which obesity causes coronary atherosclerosis include the fact that the liver is exposed to elevated levels of NEFA due to the tendency of abdominal fat cells to excrete NEFA straight into the portal vein [
24]. Increased NEFA levels lead to atherogenic lipid synthesis in the liver. Additionally, low-grade inflammation in the liver and fat caused by NEFA may lead to cardiovascular events. Systemic inflammation is associated with the onset and progression of atherosclerosis, while persistent chronic low-grade inflammation also indicates the risk of complications arising from atherosclerosis [
25]. Even at the initial stages of lipid accumulation in the arterial wall, inflammatory cells such as leukocytes begin to localize and aggregate at the lesion site by binding to adhesion molecules expressed by endothelial cells of the artery [
26]. The CAD is fundamentally a chronic immune-inflammatory fibroproliferative disorder induced by lipids [
27]. In a large cohort study from the multi-ethnic study of atherosclerosis, the NAFLD group exhibited higher serum levels of inflammatory markers [
28]. NAFLD induces systemic inflammation through complex interactions between the gut microbiota, liver, and adipose tissue. The pro-inflammatory cytokines released in this process may contribute to plaque formation and endothelial dysfunction, ultimately leading to CAD [
29].
Studies have shown that NAFLD is one of the groups with the highest risk of developing T2DM [
30]. The American Diabetes Association found that T2DM is an independent risk factor for NAFLD [
31]. Brar et al. showed that a reduction in fatty liver degeneration could prevent diabetes mellitus [
32]. High blood sugar levels, IR, and impaired pancreatic islet cell function are characteristics of T2DM. Although the mechanism remains unclear, it seems that IR is a key factor and has a bidirectional relationship with NAFLD. A study by FU C-P et al. showed that the blood glucose level 2 h after an oral glucose tolerance test was positively correlated with SS in patients with angina pectoris, which is consistent with the conclusion of our study [
33]. Our study further combined US-FLI with T2DM and found that the combined index was more valuable for diagnosing the severity of CAD. IR is characterized by an abnormal cellular response to insulin, manifested as elevated NEFA, impaired blood glucose regulation, and hyperinsulinemia, indicative of metabolic dysfunction. It contributes to the development of NAFLD by altering glucose, lipid, and protein metabolism. Additionally, inflammation and visceral fat accumulation may further exacerbate IR. The study by Song J et al. reported that IR increases the risk of more severe CAD in patients with T2DM [
34]. The connection between IR and coronary endothelial dysfunction is closely linked to inflammation and obesity, which intersect through various metabolic pathways, ultimately leading to atherosclerosis [
35]. However, the precise mechanisms involved are still under investigation.
In a previous study, we found that the causes of MAFLD/NAFLD and CVD are intertwined and interrelated through metabolism-related mechanisms, thereby promoting their development. These findings highlight the complexity of chronic diseases. Fatty liver not only affects liver metabolism and causes liver damage but is also directly or indirectly linked with coronary atherosclerosis, ultimately damaging heart function. Conversely, the presence of coronary atherosclerosis also implicates the risk of MAFLD, thus confirming the hypothesis of a liver–heart axis. Any of these circumstances may lead to difficulties in disease diagnosis and treatment. Currently, the annual rates of morbidity and mortality for NAFLD/MAFLD and CVD are increasing. What we see now is just the tip of the iceberg; what lies beneath the surface is closer to the truth. However, early detection of the disease is equally important for identifying its pathophysiological mechanisms. Therefore, our study used fast, convenient, and harmless ultrasound examinations to assess liver fatty degeneration through new indicators to explore their relationship with the severity of CAD and to find a simple method to screen MS groups.
However, our study had certain restrictions. This was a small cross-sectional study, and we did not assess the prognostic value of US-FLI. Although ultrasound indicators have good diagnostic efficacy and can accurately assess the degree of fatty liver degeneration, a liver biopsy remains the most accurate method. As a result, the diagnostic sensitivity of US-FLI for MS CAD may be compromised. We were unable to completely rule out the influence of potential confounders, even after adjusting for a number of pertinent confounding variables, potentially affecting the study’s validity. Owing to data limitations, our study did not evaluate a range of inflammatory markers, including interleukin-6, a detailed medication history, and nutritional status, which may have implications for the observed associations. Since this study used manual measurements to evaluate fatty liver and coronary heart disease, this may also explain why the ultrasound fatty liver index was not sensitive enough to diagnose MS CAD. The results of this study are likely to be regionally limited in terms of population generalization. The evolving terminology and diagnostic criteria differences between metabolic dysfunction-associated steatotic liver disease and MAFLD also present challenges, indicating that future research could benefit from incorporating metabolic dysfunction-associated steatotic liver disease criteria to better understand its implications [
36]. Therefore, further large-scale prospective studies are warranted.