The Association of the Steatosis Severity in Fatty Liver Disease With Coronary Plaque Pattern in General Population

Pai-Feng Hsu; Ying-Wen Wang; Chung-Chi Lin; Yuan-Jen Wang; Yaw-Zon Ding; Teh-Ling Liou; Shao-Sung Huang; Tse-Min Lu; Wan-Leong Chan; Shing-Jong Lin; Hsin-Bang Leu

Disclosures

Liver International. 2021;41(1):81-90. 

In This Article

Discussion

Our current study demonstrates the association of coronary atherosclerosis plaques characteristics and liver steatosis severity. People with increased severity of liver steatosis had higher coronary plaque burden involvement. Furthermore, liver steatosis severity especially correlated with mixed coronary plaque pattern independently after adjusting for traditional cardiovascular risk factors, suggesting an association between liver steatosis and the possible plaques vulnerability in coronary arteries. In subgroup analysis, there was a trend showing higher coronary atherosclerotic disease associated with steatosis severity and overall and mixed type plaques, especially among the lower risk populations, such as those who were younger, male, non-smoking, had low BMI and those without metabolic syndrome.

Vascular atherosclerosis severity correlated with multiple traditional risk factors, such as high blood pressure, diabetes, dyslipidemia, cigarette smoking and obesity. Fatty liver disease, which is frequently observed in high CV risk patients, has been linked to atherosclerosis. There are many studies that justify this association,[21,22] and these two disorders have been shown to share several common cardiometabolic risk factors. Systemic inflammation, endothelial dysfunction, hepatic insulin resistance, increased oxidative stress and altered lipid metabolism were some of the mechanisms by which NAFLD steatosis severity increased the risk of CVD.[10] Our previous study showed that the severity of NAFLD significantly correlated with increasing Framingham risk score and C-reactive protein (CRP) values,[2] indicating that NAFLD is an important risk factor for CVD, and inflammation may play an important role in connecting NAFLD and an increase in the risk of CVD. Now, our study results further confirm the association between increasing liver steatosis severity and the prevalence of cardiometabolic risk factors, including hyperlipidemia, diabetes and hypertension.

Previous studies[18–20,23] have shown that NAFLD is independently associated with vascular atherosclerosis such as carotid intimal thickness and coronary artery calcification (CIMT and CAC respectively). One meta-analysis evaluating CAC in 16,433 NAFLD patients and 41,717 control subjects demonstrated that NAFLD is significantly associated with both a CAC score >0 and a CAC score >100.[24] Furthermore, another meta-analysis[25] involving 85,395 participants, 29,493 of whom had NAFLD, also showed an increased risk of subclinical atherosclerosis in NAFLD (odds ratio [OR]: 1.60; 95% CI: 1.45–1.78) and had an increase in the risk towards higher CIMT (OR: 1.74; 95% CI: 1.47–2.06), arterial stiffness (OR: 1.56; 95% CI: 1.24–1.96), CAC (OR: 1.40; 95% CI: 1.22–1.60), and endothelial dysfunction as measured by flow-mediated dilation (OR: 3.73; 95% CI: 0.99–14.09). In our current study, subjects with moderate to severe liver steatosis tended to have higher CAC scores. CAC score has important predictive value for future events.[26] However, recent data provides new information to elucidate the role of coronary calcium. Coronary calcium is the product of CAC volume and CAC density.[16] CAC volume has a positive association with the occurrence of CV events, but CAC density is inversely associated with future CV risk,[27] suggesting not all CAC score share same future risk.[16] Both calcium volume and density may affect clinical significance[16] and considering various plaque patterns could provide additional prediction value. Although the association of CAC and liver steatosis does not achieve statistically significance in our study, subjects with moderate to severe steatosis still have higher CAC score, and the APRI tertile (new Supplement Table S1) significantly associated with CAC score, suggesting that a trend toward an association still existed between liver steatosis and CAC score.

Our study revealed the connection between mixed type plaque and liver steatosis severity. In a study (25) investigating plaque patterns and NAFLD, high-risk plaque features (positive remodelling, napkin-ring sign, spotty calcium, CT attenuation <30 HU) were more frequently observed in NAFLD patients than non-NAFLD patients (59.3% vs 19.0%; P < .001). The association between NAFLD and high-risk plaque feature (OR: 2.13; 95% CI: 1.18–3.85) persisted after adjusting for the severity of coronary atherosclerosis and traditional risk factors. Hou et al compared CTA features and future outcomes and estimated that the 3-year probability of major cardiovascular events was 6% for a calcified plaque, 23% for a non-calcified plaque and 38% for a mixed plaque,[15] indicating that mixed plaques are associated with the worst prognosis.[15,16] Our previous study reported elevated C-reactive protein values in subjects with liver steatosis, suggesting that an increase in inflammation status in liver steatosis and inflammation may play a crucial role in determining plaque vulnerability in the atherosclerosis process.

Previous studies of the relationship between NAFLD and coronary atherosclerosis revealed that both NAFLD and coronary atherosclerosis are most likely related to metabolic syndrome. NAFLD is associated with visceral adiposity, which is also a known cardiovascular risk factor.[28] At present, it still remains unclear whether the association between NAFLD and coronary atherosclerosis reflects the existence of underlying metabolic syndrome risk factors that also produce the development of coronary atherosclerosis or whether the NAFLD itself is an independent risk factor for the development of high-risk coronary atherosclerosis. Many studies clearly demonstrated an association of NAFLD with coronary artery wall calcification, CAD and atherosclerosis in the carotid arteries.[29–31] Interestingly, a previous study suggested that coronary artery atherosclerosis was associated with NAFLD, independent of cardiovascular risk factors and visceral adiposity.[31] An extensive review article also concluded that the association between NAFLD and subclinical atherosclerosis appears to be independent of traditional cardiovascular risk factors and metabolic syndrome.[32] After co-variants including age, gender, hypertension, diabetes, smoking status, WC and LDL were adjusted, our current study still found an independent association between mixed plaques and liver steatosis, suggesting a significant connection between liver steatosis and coronary atherosclerosis. Although liver steatosis is associated with mixed type plaques after co-variant adjustment, it was not stronger than the above established risk factors. Therefore, it is not surprising that the significance with liver steatosis was found among the highest risk group (mixed type plaque). Furthermore, this association could be seen in the subgroup analysis. The severity of liver steatosis has an obvious trend association with plaque burden in low risk population. Age, gender, hypertension, smoking status and hyperlipidemia are all well-established and potent risk factors for coronary artery disease. Even after all risks were modified, some residual risk factors still remain. Recent studies trying to elucidate possible residual risk factors have reported that even normal LDL levels are associated with subclinical atherosclerosis in absence of risk factors.[33] Therefore, it is worthy to extend our knowledge for possible etiology exploration for atherosclerosis. Our currents study indicates that less confounding factors may clarify the effects of liver steatosis on coronary atherosclerosis plaque burden and cause it to worsen. With advancing age and other traditional risk factors, this association maybe obscures because of other more potent coronary atherosclerosis risk factors. It has extended our understanding about the importance of liver steatosis in subclinical atherosclerosis, especially among those without risk factors. Therefore, in addition to traditional risk factors, including hypertension, smoking status, obesity, higher LDL and modifiable risk factors, such as liver steatosis, should be avoided to prevent atherosclerosis progression.

This study has limitations that should be discussed. First, our study is a cross-sectional design study that does not allow establishment of a causal relationship between liver steatosis and coronary plaque formation. Second, we use the ultrasound method to quantify the amount of liver steatosis, although we had good kappa statistics for agreement between experienced US specialists. Finally, because all participants were enrolled from those who received annual check-up in our healthcare centre, not all received medical treatment in same hospital and out-patient clinic visit. Therefore, detailed complete medication history were not available for every participants.

In conclusion, an increase in NAFLD severity appears to be associated with higher coronary artery atherosclerosis burden and CV risk factors. Furthermore, NAFLD severity correlated with the risk of presence of high-risk mixed type plaques. In the subgroup analysis, this association was more obvious in lower risk populations, such as younger people, males and those without metabolic syndrome.

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