Ultrasonography is now widely accepted as a useful screening tool to detect carotid artery plaque and predict cardiovascular events.[27, 28] With serial carotid ultrasonography of patients with type 2 diabetes at intervals of 6–8 years, this study demonstrated that hepatic steatosis with significant fibrosis was strongly associated with progression of carotid artery atherosclerosis, even in relatively metabolically-healthy patients. It also showed that the association between hepatic fibrosis and risk of atherosclerosis progression increased with higher numbers of factors defining metabolic syndrome.
NAFLD was reported as an independent risk factor for cardiovascular disease in general population.[7, 29] In several efforts to prove this relationship via carotid ultrasonography, it was discovered that NAFLD was associated with increased carotid IMT in type 2 diabetes patients with insulin resistance and a higher prevalence of carotid plaque. In the present study, we focused on the long-term effect of NAFLD with or without significant fibrosis on atherosclerosis by repeated carotid ultrasonography. The results showed that progression of carotid atherosclerosis after 6–8 years occurred more frequently among patients with NASH. Like previous studies, the association between hepatic fibrosis and progression of carotid atherosclerosis became weaker as it was adjusted for metabolic factors including BMI,[31, 32] but it still remained significant after the adjustment.
To our knowledge, this is the first report demonstrating that hepatic fibrosis is significantly associated with progression of carotid artery atherosclerosis in subjects with type 2 diabetes. It indicates that not only presence of - but also severity of - metabolic liver disease can affect risk of cardiovascular complications. Previous long-term studies showed that risk of coronary artery disease-related mortality was much higher in patients with NASH (12–16%)[9, 33] compared to NAFLD (1–3%),[10, 34] and these findings are consistent with recent meta-analysis in which increased NAFLD severity produced higher risk of cardiovascular complications.
NAFLD is considered a ‘hepatic manifestation of metabolic syndrome.’ It is very closely related with type 2 diabetes or metabolic syndrome, and the main pathophysiology underlying this relationship is known to be insulin resistance.[35, 36] NAFLD and metabolic syndrome can be thought to have similar effects on arteries, which accelerate atherogenesis via inflammation,[37, 38] increased oxidative stress, atherogenic dyslipidemia, imbalance of adipokines, and hypercoagulable status. In this study, we found that hepatic fibrosis accompanied by several metabolic syndrome factors synergistically increases the risk of atherosclerosis progression. Altered lipidomics and increased hepatic production of prothrombogenic factors, including fetuin-A in patients with fibrosing NASH, can be potential contributors to the link between NASH and cardiovascular diseases.
In addition, the association between hepatic fibrosis and risk of atherosclerosis progression was significant in all metabolic subgroups, regardless of age, BMI, presence of metabolic syndrome, or insulin sensitivity. It indicates that hepatic fibrosis may serve as a predictive marker for increased susceptibility to atherosclerosis progression even with less evidence of systemic metabolic alterations, implicating the possible presence of systemic profibrogenic stimuli that accelerate atherogenesis in patients with hepatic fibrosis. We suggest that hepatic fibrosis can be an independent risk factor for atherogenesis acceleration and its identification by clinical indicators may be helpful to predict the risk of atherosclerosis progression.
Conversely, there was no incremental risk of atherosclerosis progression in hepatic steatosis without fibrosis in type 2 diabetes patients. This finding is in similar with that of a previous study in which patients with hepatic steatosis and no additional feature of liver injury were found to follow a relatively benign clinical course, with mortality similar to the general population. Although steatosis without fibrosis was not associated with increased risk of atherosclerosis progression in this study, repeat ultrasonography was not performed beyond 8 years, making it difficult to predict longer-term effect of steatosis without fibrosis on risk of atherosclerosis progression. Since high rates of fibrosis progression have been demonstrated in patients with steatosis, it would be important to consider its clinical significance and to manage it appropriately without overlooking risk of cardiovascular complication.
This study has several distinguishing strengths. First, we analyzed long-term results of carotid ultrasonography in a large number of subjects with type 2 diabetes. Most previous studies using carotid ultrasonography were cross-sectional and were insufficient to determine a causal relationship. In addition, this study was a hospital-based cohort study conducted in a single institution, so participants were managed and evaluated under standardized conditions and practices.
A limitation of this study is the fact that a biochemical scoring system rather than liver biopsy was used to evaluate hepatic fibrosis. However, the FIB-4 index was initially validated by comparing results to that of liver biopsy, and they were shown to have fairly high accuracy to predict hepatic fibrosis.[47, 48] This study analyzed the findings of carotid deterioration using ultrasonography, one of the major surrogate markers of cardiovascular disease. However, our methods did not allow for investigation of cardiovascular events that could represent a direct outcome of atherosclerosis progression. Finally, this was a cohort-based study of Koreans and is likely to include biases based on dietary patterns and characteristics of type 2 diabetes. Therefore, further study is needed to confirm whether the results of this study can be generalized to other ethnic populations.