The results of this prospective cohort study, which included a long follow-up period, indicate that patients who are O(−)AO(+)NAFLD(+) are at a relatively high risk of CVD, and their level of risk is similar to that of patients who are O(+)AO(+)NAFLD(+). Interestingly, we found that participants who were O(+)AO(−)NAFLD(−) in the present study were at the lowest risk of developing CVD. The proportion of the participants who were O(−)AO(+)NAFLD(+) was high among those who were ³65 years old or those who had diabetes mellitus, whereas the proportion of participants who were O(+)AO(+)NAFLD(+) was high among those who had hypertension or diabetes mellitus. To our knowledge, this is the first study to compare the risks of CVD among patients with combinations of obesity, AO, and NAFLD in Korea.
NAFLD, obesity, and AO in South Korea
The prevalence of NAFLD, obesity, and AO varies between ethnic groups. NAFLD affects up to 30% of the adult population in the United States and Europe (1-3), and around 25% in Asia (28). By contrast, in South Korea, the prevalence of NAFLD, assessed using the controlled attenuation parameter of transient elastography, a non-invasive tool that estimates the severity of liver fibrosis and steatosis, is 42.9% in the healthy population (29). In the present study, the prevalence of NAFLD, obesity, and AO was 48.8%, 42.5%, and 29.8%, respectively. These discrepancies in the estimated prevalence of NAFLD may be the result of variations in the definitions and inclusion criteria used for NAFLD in each study population. However, the prevalence of NAFLD, obesity, and AO is increasing because of the aging population, obesity, low physical activity, and Westernization of the lifestyle in South Korea (28, 30, 31). Indeed, the Korea National Health and Nutrition Examination Survey (KNHANES) has shown that the prevalence of NAFLD, defined as a hepatic steatosis index >36, increased from 18.6% in 1998−2001 to 21.5% in 2016−2017, and during the same period the prevalence of obesity and AO also increased (from 27.0% to 35.1% for obesity, and from 29.4% to 36.0% for AO) (32). Therefore, the prevalence of NAFLD, obesity, and AO in Korea is expected to increase further, and these conditions will represent a significant public health burden in the near future.
Relationships between NAFLD, obesity, and AO, and cardiovascular risk
NAFLD is a chronic disease that is characterized by fat accumulation and inflammation in the liver; therefore, individuals who are obese and/or have AO are at the greatest risk of developing NAFLD. In addition, the majority of NAFLD patients die from cardiovascular disease (33). Obesity is generally defined as a state of abnormal or excessive accumulation of adipose tissue, which predisposes to a variety of health problems that are associated with cardio-metabolic abnormalities. BMI is the measure that is normally used to define obesity in clinical and public health guidelines, and high BMI has served as a proxy for general overweight and obesity for many years (16-19). However, AO, defined using WC, more effectively reflects visceral fat content, and this is more strongly associated with the risk of CVD (34, 35). In the present study, participants with NAFLD and/or AO had a significantly higher risk of CVD, independent of obesity (Additional file 2). Recent studies have also shown that central obesity in individuals with a normal BMI is strongly associated with a higher risk of all-cause and CVD mortality (36-38). In contrast to individuals with obesity, the relationship between NAFLD and the risk of CVD in people with a normal BMI remains to be fully elucidated. In Japan, normal-weight individuals with NAFLD have a higher risk of incident CVD than overweight individuals (27); however, in Korea, non-obese NAFLD is not significantly associated with a higher risk of incident CVD (39). Based on these results, obesity defined by BMI criteria does not always entail metabolic abnormalities and CVD risk. Indeed, a previous study reported a subgroup of obese individuals who lacked relevant cardio-metabolic risk factors had a reduced risk of CVD (40, 41). Therefore, a novel indicator is needed to access cardio-metabolic abnormalities including diabetes and CVD risk in individuals regardless of their BMI, particularly in Asian subjects, who tend to have a low BMI. Abdominal obesity is closely associated with NAFLD and can easily be assessed by measuring waist circumference (WC), an anthropometric measure of obesity. Abdominal obesity is now considered a potential prognostic indicator of development of NAFLD, diabetes, and CVD; and metabolically classification of obesity defined by WC criteria could provide more accurate information for predicting incident CVD risk. However, information on CVD risk according to combinations of BMI, WC and NAFLD is limited and to the best of our knowledge, this is the first study to compare the risk of CVD incidence according to the combination of abdominal obesity and NAFLD between obese and non-obese subjects, in particular, Koreans.
Effects of combinations of obesity and NAFLD on cardiovascular risk
In the present study, participants who had AO but not generalized obesity were at significantly higher risk of CVD than those who were obese, but did not have AO, although the statistical significance disappeared in multivariable analysis with adjustment for covariates including NAFLD (Additional file 2F). In addition, the effect of NAFLD on cardiovascular risk depended on body shape: it was associated with a 1.67-fold higher risk of CVD in the O(−)AO(+)NAFLD(+) group, but not in the O(−)AO(+)NAFLD(−) group, when they were compared with the O(−)AO(−)NAFLD(−) group. Interestingly, being O(+)AO(−)NAFLD(−) was significantly associated with a lower risk of developing CVD. Although the reasons for the higher risk in the O(−)AO(+)NAFLD(+) group and the lower risk in the O(+)AO(−)NAFLD(−) group are unclear, we can speculate that (1) AO, but not generalized obesity, is associated with both excess visceral fat and low muscle mass (42, 43), which are associated with risk factors for CVD such as insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation (44-46); (2) NAFLD plays a crucial role in the pathogenesis of CVD via the systemic release of several proinflammatory, prothrombotic, and oxidative stress mediators (33).
Conversely, individuals who are O(+)AO(−)NAFLD(−) may have a larger amount of gluteofemoral adipose tissue, which is associated with a favorable metabolic and cardiovascular risk profile, and it could partially explain the obesity paradox (47, 48). In general, individuals who are determined to have a normal weight on the basis of BMI are considered to be normal, regardless of whether they have central obesity, in clinical practice. However, the present findings indicate that WC should also be measured and used in conjunction with BMI in the assessment of obesity to improve the assessment and prediction of potential cardio-metabolic risks and to provide an accurate prognosis with regard to the risk of CVD. In addition, individuals at high risk for CVD can be identified by considering which combination of obesity, AO, and NAFLD they have. Furthermore, the present results suggest that efforts aimed at reducing the incidences of AO and NAFLD in both non-obese and obese individuals might delay or prevent the development of CVD. We hope that the present findings could lead to the establishment of a comprehensive and accurate strategy for the appropriate management of patients in the early stages of cardio-metabolic derangement to prevent the development of CVD.
Strengths and limitations
This study had several limitations that need to be addressed. First, NAFLD was defined on the basis of FLI, which may have led to some exposure misclassification. Liver biopsy, and non-invasive techniques such as ultrasonography, magnetic resonance spectroscopy (MRS), and computed tomography (CT), for the assessment of fatty liver were not available in the present study; therefore, we used FLI, which is a well-validated tool for the diagnosis of NAFLD (23). The Asian population tends to have a higher prevalence of NAFLD and metabolic syndrome than other populations despite having low BMIs. This has been reported to be due to the high prevalence of central adiposity in this population (49, 50). Therefore, the optimal cut-off values for FLI in Asian people remain controversial. To overcome these limitations, we used FLI cut-offs (≥35 for men and ≥20 for women) for the diagnosis of NAFLD that were suggested to be suitable for use in Asian people in a previous study (24). However, we also compared the findings obtained using these cut-off values with those obtained using other FLI cut-off values (both ≥30 and ≥60) that have been previously reported (23) and generated similar results (Additional file 5). Second, it is possible that there were additional confounders that were not accounted for in the study, despite the fact that we adjusted for numerous variables, including demographic characteristics, drinking status, smoking status, medical history, blood pressure, and laboratory parameters. Third, CVD mortality information could not be obtained for this analysis; therefore, we may have underestimated the risk of CVD.
However, the study had several strengths. The main strengths were its community-based prospective design and the long follow-up period. In addition, to our knowledge, this is the first study to investigate the long-term impact of combinations of obesity, AO, and NAFLD on the risk of CVD in South Korea.