The present study evaluated the association between liver fibrosis assessed using noninvasive fibrosis markers and CAC progression in subjects with NAFLD. We observed that CAC progression occurred more frequently in the group with NAFLD and higher fibrosis scores than in the group without NAFLD. In addition, baseline NAFLD and noninvasively assessed liver fibrosis stage were positively associated with the risk of CAC score progression. Individuals with NAFLD and a more advanced fibrosis stage with a higher FIB-4 score were at a significantly higher risk of CAC progression (OR, 1.70; 95% CI, 1.12–2.58) than individuals without NAFLD. Moreover, in the sensitivity analysis, similar results were obtained for the association between fibrosis stage stratified by the NFS and CAC progression.
Although the baseline CAC score measured by MDCT has been represented as a surrogate marker for CAC17,18, previous studies reported that CAC progression is significantly associated with incident cardiovascular events and mortality15,18. Because atherosclerosis progression is a dynamic and ongoing process, CAC progression may be a more effective predictor of future cardiovascular events than the baseline CAC score19. Therefore, here we evaluated CAC score progression using serial MDCT scans. Interestingly, we found that subjects with an advanced liver fibrosis stage determined using liver fibrosis markers were at a significantly higher risk for CAC progression after adjustment for known metabolic factors as confounders.
To our knowledge, the present study is the first to investigate the association between noninvasive liver fibrosis score and CAC progression. Advanced liver fibrosis stage assessed using a noninvasive fibrosis marker increased the risk of CAC progression in subjects with NAFLD. However, subjects with a low probability of liver fibrosis did not show an increased risk of CAC progression. Similarly, a long-term follow-up study of NAFLD with biopsy-proven fibrosis stage showed that subjects with advanced fibrosis were at an increased risk of CVD death (stage 3, 4; hazard ratio [HR], 1.55), whereas subjects at an early liver fibrosis stage were not6.
Although the mechanisms responsible for the association between liver fibrosis and CAC progression remain unclear, several possibilities have been suggested. Endothelial dysfunction triggered by persistent chronic inflammation and oxidative stress was shown to induce coronary atherosclerosis and liver fibrosis in patients with NAFLD/NASH20,21. NASH was also reportedly associated with prothrombotic factors22. This coagulation factor imbalance resulted in a positive link between CVD and liver fibrosis in subjects with NAFLD4. Moreover, pro-inflammatory cytokines were shown to induce abnormal lipid metabolism, chronic inflammation, and oxidative stress in subjects with NAFLD and liver fibrosis, suggesting that this pathogenic mechanism may be involved in the systemic inflammation that leads to CVD21,23,24,25. Pathophysiological evidence has helped establish a strong correlation between an emerging prevalence of NAFLD/NASH and an increased risk of CVD26. Thus, therapeutic candidates based on the pathogenesis of NAFLD/NASH probably exert beneficial effects against CVD events4,26. In this respect, noninvasive biomarkers of liver fibrosis would have clinical value for assessing liver fibrosis severity and future CVD risk.
The present study found that the noninvasive assessment of liver fibrosis in subjects with NAFLD was not significantly associated with the baseline CAC score after adjustment for confounding factors. One possible explanation for this discrepancy is that our study included participants who underwent routine health check-ups and excluded those with a history of CVD. In two previous studies, patients at high risk of CVD (baseline CAC score > 100) has been reported to correlate with high liver fibrosis score in subjects with NAFLD7,8. In addition, a previous study reported that patients with CAC progression combined with moderate to severe CAC scores (> 100) have an increased the risk of all-cause mortality16. However, only 11.3% of subjects in the present study had a baseline CAC score > 100, and 57.7% had a baseline CAC score = 0. Therefore, the assessment of a low-risk population in our study may have reduced the association between noninvasive liver fibrosis markers and the baseline CAC score. However, a positive association was obtained between CAC score progression and liver fibrosis markers for the low-risk population in this study. Thus, CAC score progression, not baseline CAC, could be a good prognostic marker for assessing the correlation with noninvasive liver fibrosis score, even in low-risk populations. These results also suggest that biomarker-based liver fibrosis stage can predict long-term dynamic changes in coronary atherosclerosis, rather than the baseline CAC score.
In the present study, NAFLD was diagnosed by ultrasonography instead of liver biopsy. Although the overall sensitivity and specificity of ultrasonography are approximately 85% and 94%27, respectively, it is considered to have a relatively low sensitivity for small hepatic steatosis28. Therefore, the true incidence of NAFLD could be underestimated in our study. However, ultrasonography is a widely accessible imaging technique for the diagnosis of fatty liver owing to its high safety, noninvasive nature, low cost, and ease of use. Recent studies reported that ultrasonography has adequate accuracy for detecting hepatic steatosis in as little as 10–20% of the liver29,30. Therefore, the use of ultrasonography is reliable for diagnosing fatty liver and has relatively few limitations compared with biopsy.
Noninvasive fibrosis scoring systems including the FIB-4 score and NFS are widely used to identify liver fibrosis severity. These noninvasive fibrosis assessments yield a high sensitivity and negative predictive value but a low positive predictive value, suggesting that it is better to exclude than detect advanced liver fibrosis13,31. False positive results of the intermediate/high fibrosis stage assessed with the FIB-4 score or NFS could have occurred in the present study, possibly diluting the association between liver fibrosis score and CAC progression. However, previous data indicated that the NFS could be an effective biomarker for predicting cardiovascular risk and mortality32,33. Although other noninvasive diagnostic techniques for predicting liver fibrosis, such as ultrasound elastography, could enable a better estimation of liver fibrosis, this technique is not always available in clinical practice31. Thus, noninvasive fibrosis scoring systems have diagnostic efficacy for identifying liver fibrosis in patients with NAFLD.
This study had several limitations. First, our subjects were recruited during general health examinations, so they did not represent the general population and laboratory test of chronic liver disease were conducted only for hepatitis B and C. Therefore, we were unable to collect data for other etiologies of chronic liver disease (e.g., tests for antinuclear, antimitochondrial, smooth muscle, and liver kidney microsome type-1 antibodies). Second, patients at a high risk of CAC progression may have undergone repeated MDCT during follow-up; thus, there was a high prevalence of NAFLD and male patients. This might have further contributed to our cohort not representing the general population. Third, since an alcohol consumption history could not be obtained quantitatively, it was impossible to fully discriminate between alcoholic fatty liver disease and NAFLD. However, the relative contribution of alcohol consumption to the development of NAFLD is controversial34. Finally, information on lipid-lowering agents other than statins was not obtained; such other drugs may have affected the calcification in subjects with coronary atherosclerosis.
In conclusion, to our knowledge, the present study is the first to show that advanced liver fibrosis stage assessed using a noninvasive fibrosis marker is an independent and significant contributor to CAC progression in subjects with NAFLD. Our findings suggest that noninvasive assessment of liver fibrosis degree is a useful indicator for predicting an increased risk of the development of CVD among subjects with NAFLD.