Associations Between Liver Histology and Early Carotid Atherosclerosis in Subjects With Nonalcoholic Fatty Liver Disease *

I read with interest the article by Villanova et al.1 regarding the significant associations between liver histology and endothelial dysfunction, as measured by flow-mediated vasodilation (FMV), in patients with nonalcoholic fatty liver disease (NAFLD). They reported that NAFLD patients had a significant decrease in percent FMV when compared to age- and sex-matched controls, and that the severity of NAFLD strongly correlated with a low FMV, independently of age, sex, body mass index, and homeostasis model assessment (HOMA)-IR insulin resistance score. Additionally, the 10-year estimated probability of cardiovascular events was moderately higher in those with NAFLD.1 These findings confirm and extend the observations of some recent cross-sectional studies documenting that patients with NAFLD, as diagnosed by ultrasonography, had a markedly greater carotid artery intima-media thickness (IMT) and increased prevalence of carotid plaques compared with controls.2-4 More recently, we enrolled 50 consecutive NAFLD patients and 40 healthy controls with normal liver ultrasonography and normal liver enzymes who were matched for sex (M/F 30/20 vs. 26/14), age (46 ± 4 vs. 46 ± 3 years) and BMI (26.6 ± 1.6 vs. 26.2 ± 1.8 kg/m2). The diagnosis of NAFLD was based on liver biopsy and the exclusion of known etiological factors of chronic liver disease. According to classification of Brunt et al.,5 liver histopathology results were steatosis alone in 7 patients, NASH with fibrosis score of 0 in 14 patients, NASH/fibrosis score 1 in 16 patients, NASH/fibrosis score 2 in 8 patients, and NASH/fibrosis score 3 in 5 patients. None had cirrhosis (a fibrosis score of 4). Compared with controls, NAFLD patients had a significantly higher prevalence of the metabolic syndrome (MetS)6 (54% vs. 2.5%) and higher values of liver enzymes (AST 48 ± 21 vs. 22 ± 3 U/L; ALT 102 ± 50 vs. 24 ± 4 U/L) and HOMA-IR score (4.14 ± 2 vs. 1.73 ± 1). Smoking history and low-density lipoprotein (LDL) cholesterol concentration did not differ between the groups. Importantly, NAFLD patients had a markedly greater carotid IMT (1.10 ± 0.2 vs. 0.84 ± 0.13 mm; P < .001), with no differences between sexes. The significant differences in carotid IMT that were observed between the groups were little affected by adjustment for age, sex, HOMA-IR score, and presence of MetS (P = .005 by analysis of covariance). Among NAFLD patients there was a strong association between the degree of hepatic fibrosis and carotid IMT (P < .001). By logistic regression analysis, hepatic fibrosis score independently predicted (P < .001) carotid IMT after adjustment for age, sex, HOMA-IR score, and MetS. Overall, therefore, the evidence from this and other studies1-4 supports the possibility that NAFLD is atherogenic beyond its close relationship to the MetS phenotype, possibly through increased oxidative stress, subclinical inflammation, postprandial lipemia, and decreased adiponectin concentrations.7-10 These findings might have important clinical and public health implications. Since NAFLD patients are at increased cardiovascular risk, the casual detection of NAFLD on an ultrasound examination should alert to the possible coexistence of multiple underlying cardiovascular risk factors warranting evaluation and treatment as much as the risk for advancing liver disease. Prospective studies are clearly needed to validate these findings and better estimate the individual cardiovascular risks associated with the presence of MetS and NAFLD. Giovanni Targher M.D.*, * Division of Internal Medicine, “Sacro Cuore–don G. Calabria” Hospital of Negrar, Verona, Italy.