To the Editor:
We kindly thank Drs. Chimakurthi and Rowe for their thoughtful comments. Waist circumference, an anthropometric measure of abdominal obesity, is known to be associated with cardiovascular (CV) risk, independent of classical risk factors, as suggested by a recent analysis of the Emerging Risk Factors Collaboration [
], but do not significantly add to the prediction accuracy of CV risk models. As waist circumference is a surrogate of hepatic steatosis, the authors suggest that the association between steatosis and increased CV risk only reflects the impact of visceral adiposity on the CV risk.
- Wormser D.
- Kaptoge S.
- Di Angelantonio E.
- Wood A.M.
- Pennells L.
- Thompson A.
- et al.
Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies.
Lancet. 2011; 377: 1085-1095
Overall, we agree that it is difficult to determine the specific contribution of NAFLD to the increase in CV risk because NAFLD patients have cardiometabolic risk factors that confound this association. Waist circumference is an imperfect clinical marker of visceral adiposity, as it can be influenced by sex, race [
- Camhi S.M.
- Bray G.A.
- Bouchard C.
- Greenway F.L.
- Johnson W.D.
- Newton R.L.
- et al.
The relationship of waist circumference and BMI to visceral, subcutaneous, and total body fat: sex and race differences.
Obesity. 2011; 19: 402-408
3] and subcutaneous fat. It correlates poorly with visceral fat, when measured by CT-scan, in different ethnic groups [
- Mongraw-Chaffin M.
- Golden S.H.
- Allison M.A.
- Ding J.
- Ouyang P.
- Schreiner P.J.
- et al.
The sex and race specific relationship between anthropometry and body fat composition determined from computed tomography: evidence from the multi-ethnic study of atherosclerosis.
PLoS One. 2015; 10e0139559
- Goncalves F.B.
- Koek M.
- Verhagen H.J.
- Niessen W.J.
- Poldermans D.
Body-mass index, abdominal adiposity, and cardiovascular risk.
Lancet. 2011; 378 ([Author reply 228]): 227
5]. Interestingly, in our cohort, waist circumference was an independent predictor of CV risk in patients without steatosis, but not in patients with steatosis (Table 1A, transversal cohort). When adjusting for classical CV risk factors, steatosis was still an independent predictor of CV risk in patients with BMI ⩽25 kg/m2 (beta = 0.051, p = 0.035) or with normal waist (beta = 0.067, p = 0.003). Moreover, in our longitudinal cohort, steatosis, but not waist circumference, predicted the occurrence of carotid plaques during follow-up (Table 1B, longitudinal cohort).
- Ng A.C.
- Wai D.C.
- Tai E.S.
- Ng K.M.
- Chan L.L.
Visceral adipose tissue, but not waist circumference is a better measure of metabolic risk in Singaporean Chinese and Indian men.
Nutr Diab. 2012; 2e38
Table 1Cardiovascular risk factors. (A) Transversal cohort: Independent predictors of C-IMT in patients with and without steatosis. (B) Longitudinal cohort: Independent predictors of the occurrence of carotid plaques in Cox multivariate models.
Model 2∗ – FLI was replaced by its components.
An argument in favor of NAFLD as an independent contributor to accelerated atherosclerosis, is the recent demonstration that resolution of NAFLD resulted in regression or a lower progression rate of atherosclerosis. In a sub-analysis of the Welcome trial, Bhatia et al., demonstrated that regression of steatosis (assessed by magnetic resonance spectroscopy) and steatohepatitis (as assessed by serum CK18 fragments) were independently associated with lower carotid intima-media thickness (C-IMT) progression rate, even after adjustment for confounders, including standard CV risk factors, weight changes and specific medication use [
]. Conversely, a recent study of 8020 healthy Korean men has shown that persistent NAFLD (defined by ultrasound) during follow-up was associated with a higher risk of developing carotid plaques even after adjustment for smoking, alcohol, BMI and weight change [
- Bhatia L.
- Scorletti E.
- Curzen N.
- Clough G.F.
- Calder P.C.
- Byrne C.D.
Improvement in non-alcoholic fatty liver disease severity is associated with a reduction in carotid intima-media thickness progression.
Atherosclerosis. 2016; 246: 13-20
- Sinn D.H.
- Cho S.J.
- Gu S.
- Seong D.
- Kang D.
- Kim H.
- et al.
Persistent nonalcoholic fatty liver disease increases risk for carotid atherosclerosis.
Gastroenterology. 2016; 151: 481-488
Our results favor screening for CV disease in patients with NAFLD, a recommendation made by the recent European Association for the Study of the Liver (EASL) clinical practice guidelines. Whether adding NAFLD to existent CV risk scores will improve prediction remains to be proven by long-term, prospective, follow-up studies. A relevant question will then be to determine which of the histological lesions defining NAFLD (steatosis, steatohepatitis or fibrosis) adds significantly to the prediction value of established CV risk models. While hepatic steatosis seems to be associated with early atherosclerosis but not with clinical CV events [
], liver fibrosis impacts long-term CV outcomes [
- Mellinger J.L.
- Pencina K.M.
- Massaro J.M.
- Hoffmann U.
- Seshadri S.
- Fox C.S.
- et al.
Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham heart study.
J Hepatol. 2015; 63: 470-476
- Perazzo H.
- Munteanu M.
- Ngo Y.
- Lebray P.
- Seurat N.
- Rutka F.
- et al.
Prognostic value of liver fibrosis and steatosis biomarkers in type-2 diabetes and dyslipidaemia.
Aliment Pharmacol Ther. 2014; 40: 1081-1093
10]. Since current guidelines do not recommend that patients at risk of CV disease should be screened for NAFLD, these issues deserve to be explored thoroughly in future studies.
- Angulo P.
- Kleiner D.E.
- Dam-Larsen S.
- Adams L.A.
- Bjornsson E.S.
- Charatcharoenwitthaya P.
- et al.
Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease.
Gastroenterology. 2015; 149: 389-397
Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
- Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies.Lancet. 2011; 377: 1085-1095
- The relationship of waist circumference and BMI to visceral, subcutaneous, and total body fat: sex and race differences.Obesity. 2011; 19: 402-408
- The sex and race specific relationship between anthropometry and body fat composition determined from computed tomography: evidence from the multi-ethnic study of atherosclerosis.PLoS One. 2015; 10e0139559
- Body-mass index, abdominal adiposity, and cardiovascular risk.Lancet. 2011; 378 ([Author reply 228]): 227
- Visceral adipose tissue, but not waist circumference is a better measure of metabolic risk in Singaporean Chinese and Indian men.Nutr Diab. 2012; 2e38
- Improvement in non-alcoholic fatty liver disease severity is associated with a reduction in carotid intima-media thickness progression.Atherosclerosis. 2016; 246: 13-20
- Persistent nonalcoholic fatty liver disease increases risk for carotid atherosclerosis.Gastroenterology. 2016; 151: 481-488
- Hepatic steatosis and cardiovascular disease outcomes: an analysis of the Framingham heart study.J Hepatol. 2015; 63: 470-476
- Prognostic value of liver fibrosis and steatosis biomarkers in type-2 diabetes and dyslipidaemia.Aliment Pharmacol Ther. 2014; 40: 1081-1093
- Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397
Published online: August 04, 2016
© 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.