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Association between nonalcoholic fatty liver disease and carotid intima-media thickness according to the presence of metabolic syndrome
Atherosclerosis 204 (2009) 521–525
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Association between nonalcoholic fatty liver disease and carotid intima-media thickness according to the presence of metabolic syndrome Hyeon Chang Kim a,b , Dae Jung Kim c,∗ , Kap Bum Huh d a
Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States c Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South Korea d Huh’s Diabetes Center and the 21 Century Diabetes and Vascular Research Institute, Seoul, South Korea b
a r t i c l e
i n f o
Article history: Received 10 July 2008 Received in revised form 8 September 2008 Accepted 9 September 2008 Available online 19 September 2008 Keywords: Nonalcoholic fatty liver disease Liver steatosis Metabolic syndrome Atherosclerosis Intima-media thickness
a b s t r a c t Objective: Controversy exists as to whether the association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis is independent of other metabolic disorders. We examined the association between NAFLD and carotid intima-media thickness (IMT) according to the presence of metabolic syndrome (MetS). Methods: A cross-sectional analysis was performed among 556 men and 465 women, ages 30–79 years. The presence of NAFLD was evaluated ultrasonographically. Carotid IMT was determined ultrasonographically by the average of the maximal IMT at each common carotid artery. Independent associations between NAFLD and IMT were assessed using multiple linear and logistic regression models, after adjusting for age, sex, waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol consumption. Results: After adjusting for major risk factors, subjects with NAFLD had greater carotid IMT than subjects without NAFLD (difference 0.034 mm, p = 0.016). However, the difference in IMT was significant only in subjects with MetS (0.060 mm, p = 0.015) and not in subjects without MetS (0.015 mm, p = 0.384). Similarly, the NAFLD-associated adjusted odds ratio for increased IMT, defined as the sex-specific top quintile, was 1.63 (95% CI, 1.10–2.42) in all subjects and 2.08 (95% CI, 1.19–3.66) in subjects with MetS, but 1.18 (95% CI, 0.64–2.19) in subjects without MetS. When the analysis was performed according to the number of metabolic abnormalities, the NAFLD–IMT association was observed only in subjects with four or more abnormalities. Conclusion: These results suggest that NAFLD is independently associated with carotid atherosclerosis only in people who have multiple metabolic abnormalities. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that is characterized by significant lipid deposition within the hepatocytes in people with no history of excessive alcohol consumption [1]. The best diagnostic test for confirming NAFLD is a liver biopsy, but medical and ethical considerations limit its use in patients with nonprogressive fatty liver diseases [2,3]. Elevated levels of liver enzymes, such as aspartate aminotransferase, alanine aminotransferase (ALT), and ␥-glutamyl transferase (␥GT), are common laboratory abnormalities found in patients
∗ Corresponding author at: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San-5, Wonchon-dong, Yeongtong-gu, Suwon 443721, South Korea. Tel.: +82 31 219 5128; fax: +82 31 219 4497. E-mail address: [email protected] (D.J. Kim). 0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.09.012
with NAFLD, but the specificity of these tests is low [1,4]. Consequently, the clinical evaluation of NAFLD is commonly based on a combination of ultrasonographic findings and laboratory tests [3,5]. Liver ultrasonography results, although not sufficiently sensitive to detect liver inflammation and fibrosis, correlate well with the histological finding of fatty infiltration. In addition, international guidelines have been proposed for the diagnosis of different degrees of steatosis [3,5,6]. NAFLD is associated with various metabolic abnormalities, including central obesity, type 2 diabetes, dyslipidemia, high blood pressure [7,8], and metabolic syndrome (MetS) [9,10]. Fatty liver can develop as the result of various metabolic conditions that promote fat accumulation and inflammation in the liver [9–11]; otherwise, NAFLD may contribute to the development of MetS [12,13]. Previously, we reported that NAFLD measured ultrasonographically is closely associated with metabolic abnormalities and MetS among apparently healthy Korean adults [14,15]. Recently, NAFLD has been reported to be associated
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with carotid artery atherosclerosis, which is evaluated using the intima-media thickness (IMT) [16–22]. However, whether NAFLD has a direct impact on atherosclerosis independent of other metabolic risk factors is unclear. Therefore, we investigated the association between NAFLD measured ultrasonographically and carotid IMT in the presence of multiple metabolic abnormalities. 2. Methods 2.1. Study design and participants This cross-sectional study was performed as part of the Korean Metabolic Syndrome Study, which was undertaken to evaluate the role of MetS as a risk for cardiovascular disease in Korean adults. The institutional review board of Severance Hospital at Yonsei University approved the study protocol, and informed consent was obtained from each participant. We measured metabolic profiles, evaluated cardiovascular risk factors, and performed abdominal and carotid artery ultrasonography scans on 1244 men and women. All measurements were taken over a 3-month period (April–June 2001) at a health-screening center in Seoul, Korea. All participants were apparently healthy and independently functioning individuals who visited the health center for general health screening. Among the 1244 initial volunteers, 1142 people who were aged from 30 to 79 years completed anthropometric measurements, serum biochemistry profiles, and liver and carotid artery ultrasound scans. We excluded 121 people who had a history of coronary heart disease or stroke, had hepatitis B virus surface antigens (HBsAg), or consumed alcoholic drinks four times per week or more. In total, 1021 subjects (556 men and 465 women) were included in the analyses. 2.2. Measurements Trained nurses interviewed all participants and obtained their medical history and health-related behaviors using a standardized questionnaire. Weight and height were measured while the participant was clothed in a light gown. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2 ). Waist circumference was measured midway between the lowest rib margin and the iliac crest in a standing position. Resting blood pressure was measured twice, and the mean value was used for the analyses. Blood samples were obtained after a fasting period of at least 8 h. Total serum cholesterol, high-density lipoprotein (HDL)–cholesterol, and triglyceride levels were measured using enzymatic colorimetric methods. Fasting plasma glucose levels were measured using the glucose oxidase method. Serum insulin levels were measured using a radioimmunoassay. Insulin resistance was determined by the homeostasis model assessment of insulin resistance (HOMA-IR). The serum ALT and ␥GT levels were measured using enzymatic methods. Liver ultrasound scans were performed to assess the presence and severity of NAFLD. The same operator performed all ultrasound scans using a high-resolution B-mode scanner (SSD-5500; Aloka, Tokyo, Japan). The operator was unaware of the participants’ medical histories and laboratory findings. The degree of steatosis was assessed semiquantitatively (absent, mild, moderate, and severe) on the basis of abnormally intense, high-level echoes arising from the hepatic parenchyma, liver–kidney differences in echo amplitude, echo penetration into the deep portion of the liver, and clarity of the blood vessel structure in the liver [5]. The carotid arteries were evaluated using a high-resolution B-mode scanner (SSA-270A; Toshiba, Tokyo, Japan) and a 7.5-MHz probe. Both com-
mon carotid arteries were scanned proximal to distal up to the bifurcation. Frozen photocopies of the end-diastolic images were captured in a longitudinal view that showed the bifurcation. The IMT was measured at the far wall of both common carotid arteries approximately 1 cm proximal to the carotid bulb. Measurements of IMT (i.e. the distance between the leading edge of the first and second echogenic lines) were performed using calipers (Digimatic; Mitutoyo, Kawasaki, Japan). The carotid IMT was defined as the mean of the maximal IMT of each common carotid artery. A single examiner took all measurements. The intra-observer coefficient of variation was 2.1% [23]. The metabolic syndrome was defined according to the criteria established by the National Cholesterol Education Program Adult Treatment Panel III using the adjusted waist circumference for Asians [24]. Accordingly, participants with three or more of the following five criteria were defined as having MetS: abdominal obesity by waist circumference (men/women >90/80 cm), high blood pressure (≥130/85 mmHg) or on antihypertensive medication, elevated fasting blood glucose (≥5.6 mmol/l) or on antidiabetic medication, hypertriglyceridemia (≥1.7 mmol/l), and low serum HDL–cholesterol (men/women <1.0/1.3 mmol/l). 2.3. Statistical analysis Clinical and biochemical characteristics are shown according to the presence of NAFLD, separately in men and women. For each variable, differences according to the presence of NAFLD were tested using Student’s t-test, the Wilcoxon rank-sum test, or 2 test. Simple and partial (adjusting for age and sex) correlation coefficients were used to assess correlations between IMT and selected metabolic risk factors. Independent associations between NAFLD and continuous form of carotid IMT were assessed using two multiple linear regression models. The first model adjusted for age and sex, and the second model additionally adjusted for waist circumference, systolic blood pressure, fasting plasma glucose, total/HDL–cholesterol ratio, cigarette smoking, and alcohol consumption. Logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) for increased IMT according to the presence of NAFLD. Increased IMT in this analysis was defined using the sex-specific highest quintile: >0.86 mm for men and >0.83 mm for women. Similarly, two serial models (age- and sex-adjusted, and multivariate-adjusted) were used for the logistic regression analyses. To determine whether the association between NAFLD and carotid IMT is independent of other metabolic abnormalities, the above-mentioned analyses were performed separately in subjects with and without MetS, and again according to the number of metabolic abnormalities. To examine possible sex differences in the associations among NAFLD, MetS, and carotid IMT, analyses were also performed separately in men and women. SAS System version 9.13 (SAS Institute, Cary, NC, USA) was used to perform all statistical analyses. All statistical tests were two-tailed, and p-values less than 0.05 were considered significant. 3. Results Among the 556 men and 465 women examined, ultrasound scans revealed NAFLD in 317 men (133 mild, 165 moderate, and 19 severe) and 190 women (87 mild, 93 moderate, and 10 severe). Age was positively associated with NAFLD in women, but not in men. BMI, waist circumference, and systolic and diastolic blood pressures were significantly and positively associated with NAFLD. Total cholesterol and triglyceride levels were positively associated with NAFLD; however, HDL–cholesterol level was negatively associated with NAFLD. Consequently, there was a strong positive associa-
H.C. Kim et al. / Atherosclerosis 204 (2009) 521–525
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Table 1 Clinical and biochemical characteristics of 556 men and 465 women according to NAFLD. Characteristics
Age (years) BMI (kg/m2 ) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Total cholesterol (mmol/l) HDL–cholesterol (mmol/l) Total/HDL–cholesterol ratio Triglyceride (mmol/l) Fasting glucose (mmol/l) HOMA-IR ALT (IU/l) ␥GT (IU/l) Current smoking Alcohol intake ≥1/week Carotid IMT (mm) Increased carotid IMT
Men
p
No NAFLD (n = 239)
NAFLD (n = 317)
51.6 ± 11.0 23.2 ± 2.5 83.0 ± 6.9 126.6 ± 16.8 78.1 ± 11.5 5.03 ± 0.84 1.19 ± 0.27 4.38 ± 1.04 1.53 [1.12–2.48] 5.17 [4.78–5.56] 1.84 [1.45–2.56] 20 [16–28] 32 [22–51] 115 (48.1) 132 (55.5) 0.71 ± 0.19 35 (14.6)
50.7 ± 10.4 25.1 ± 2.5 88.8 ± 6.5 132.0 ± 17.4 81.8 ± 11.6 5.26 ± 0.87 1.10 ± 0.23 4.96 ± 1.14 2.42 [1.69–3.26] 5.44 [5.00–6.11] 2.83 [2.04–3.80] 30 [22–40] 47 [32–75] 140 (44.2) 176 (55.7) 0.77 ± 0.23 77 (24.3)
Women
0.302 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.354 0.956 <0.001 0.005
p
No NAFLD (n = 275)
NAFLD (n = 190)
51.5 ± 9.4 23.6 ± 2.7 79.0 ± 7.0 128.4 ± 20.3 78.2 ± 13.2 5.21 ± 0.85 1.37 ± 0.35 4.01 ± 1.09 1.30 [0.94–1.86] 4.94 [4.72–5.28] 1.95 [1.38–2.35] 17 [13–21] 17 [14–23] 14 (5.1) 36 (13.2) 0.70 ± 0.21 38 (13.8)
54.2 ± 8.7 26.2 ± 3.1 86.7 ± 7.7 134.4 ± 18.0 81.8 ± 11.8 5.52 ± 0.95 1.22 ± 0.32 4.78 ± 1.30 1.82 [1.42–2.76] 5.28 [4.89–5.89] 3.01 [2.15–4.71] 21 [16–27] 25 [19–35] 5 (3.7) 24 (12.6) 0.78 ± 0.23 56 (29.5)
0.002 <0.001 <0.001 0.001 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.472 0.849 <0.001 <0.001
Data are expressed as the mean ± S.D., median [inter-quartile range], or number (%).
tion between the total/HDL–cholesterol ratio and NAFLD. Fasting glucose, insulin resistance, liver enzyme levels, and carotid IMT were also positively associated with NAFLD. Current smoking and alcohol consumption were not associated with NAFLD (Table 1). Among cardiovascular risk factors, age was the most strongly correlated with carotid IMT. After adjusting for age and sex, carotid IMT was strongly correlated with BMI, waist circumference, systolic and diastolic blood pressure, total/HDL–cholesterol ratio, and insulin resistance. In addition, carotid IMT was also significantly associated with total cholesterol, triglycerides, fasting glucose, and ALT (Table 2). When we adjusted for age and sex, mean carotid IMT values were significantly higher in subjects with NAFLD than in subjects without (0.772 vs. 0.706 mm, difference = 0.066 mm, p < 0.001). Among the subjects with NAFLD, the severity of steatosis was not significantly associated with IMT (p = 0.634). After additional adjustment for waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol intake, the subjects with NAFLD still had a greater IMT (0.756 vs. 0.722 mm, p = 0.016). However, this association differed depending on the presence or absence of MetS. NAFLD was significantly and independently associated with higher IMT values in people with MetS (difference = 0.060 mm, p = 0.015), but not in people without MetS (p = 0.384). Similar relationships were observed for the dichotomous form of carotid IMT. The NAFLD-associated odds ratios for increased IMT were 2.32 (95% CI, 1.65–3.27) in the age- and
sex-adjusted model and 1.63 (95% CI, 1.10–2.42) in the multivariateadjusted model. However, the association was significant only in people with MetS (odds ratio, 2.08; 95% CI, 1.19–3.66), and not in people without MetS (odds ratio, 1.18; 95% CI, 0.64–2.19). When we performed the subgroup analysis according to the number of metabolic abnormalities, an independent association was observed only between NAFLD and increased IMT among the subjects with four or five metabolic abnormalities (odds ratio, 2.64, 95% CI, 1.04–6.70; Table 3). The association between NAFLD and carotid IMT also differed according to the presence of MetS in the sex-specific analyses (Table 4). However, a significant association was observed only in female subjects with MetS (adjusted difference = 0.071 mm, p = 0.045; adjusted odds ratio for increased IMT = 2.38, p = 0.027). The association in male subjects with MetS did not reach significance (adjusted difference = 0.066 mm, p = 0.055; adjusted odds ratio increased IMT = 2.03, p = 0.114). 4. Discussion There is increasing evidence for an association between NAFLD and an increased risk of cardiovascular morbidity and mortality [25–27]. The association between NAFLD and cardiovascular risk factors can largely explain the higher risk of cardiovascular disease among people with NAFLD [2,15,27]. Recent case–control studies [16,17,21] and cross-sectional studies [18–20,22] have reported
Table 2 Correlations between IMT and metabolic risk factors. Variable
Age BMI Waist circumference Systolic blood pressure Diastolic blood pressure Total cholesterol HDL–cholesterol Total/HDL–cholesterol ratio Triglyceridea Fasting glucosea HOMA-IRa ALTa ␥GTa a
Log-transformed.
Simple Spearman correlation
Partial Spearman correlation adjusted for age and sex
Coefficient
p
Coefficient
p
0.4071 0.1140 0.2079 0.3033 0.2276 0.1004 −0.0731 0.1274 0.0471 0.1454 0.1407 0.0011 −0.0055
<0.001 <0.001 <0.001 <0.001 <0.001 0.001 0.020 <0.001 0.133 <0.001 <0.001 0.973 0.863
0.1186 0.1595 0.2104 0.1544 0.0820 −0.0823 0.1227 0.0652 0.0924 0.1298 0.0655 0.0287
<0.001 <0.001 <0.001 <0.001 0.012 0.014 <0.001 0.046 0.005 <0.001 0.045 0.379
524
H.C. Kim et al. / Atherosclerosis 204 (2009) 521–525
Table 3 Association between NAFLD and IMT according to the presence of multiple metabolic abnormalities. NAFLD-associated mean difference in IMT (mm). Characteristics
All subjects
No. of people
No. (%) of people with NAFLD
NAFLD-associated mean difference in IMT (um)a
NAFLD-associated odds ratio (95% CI) for increased IMT*
Age- and sex-adjusted
Multivariate-adjusteda
Age- and sex-adjusted
Multivariate-adjusteda
1,021
507 (49.7)
0.066 (p < 0.001)
0.034 (p = 0.016)
2.32 (1.65–3.27)
1.63 (1.10–2.42)
Metabolic syndrome No 593 Yes 428
207 (34.9) 300 (70.1)
0.035 (p = 0.028) 0.071 (p = 0.003)
0.015 (p = 0.384) 0.060 (p = 0.015)
1.41 (0.84–2.38) 2.42 (1.42–4.14)
1.18 (0.64–2.19) 2.08 (1.19–3.66)
No. of metabolic abnormalities 0 or 1 304 2 289 3 245 4 or 5 183
72 (23.7) 135 (46.7) 160 (65.3) 140 (76.5)
0.046 (p = 0.016) 0.014 (p = 0.589) 0.049 (p = 0.075) 0.094 (p = 0.028)
0.034 (p = 0.075) 0.006 (p = 0.842) 0.041 (p = 0.137) 0.087 (p = 0.066)
1.55 (0.69–3.48) 1.28 (0.69–2.60) 2.09 (1.03–4.25) 2.71 (1.15–6.35)
1.55 (0.57–4.22) 1.14 (0.51–2.56) 1.86 (0.90–3.87) 2.64 (1.04–6.70)
a
Adjusted for age, sex, waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol intake.
increased carotid IMT among patients with NAFLD. Possible biological mechanisms linking the effects of NAFLD to atherosclerosis development include endothelial dysfunction, oxidative stress, inflammation, inflammatory cytokines, and abnormal lipid and glucose metabolism [27]. However, these mechanisms are also closely related to other risk factors for atherosclerosis. Therefore, it is unclear whether NAFLD contributes to the development of atherosclerosis directly. Several studies have reported independent associations between NAFLD and atherosclerosis after adjusting for cardiovascular risk factors and MetS [16–18,20,22]. In our analyses, NAFLD was significantly associated with IMT after adjusting for major cardiovascular risk factors. In the subgroup analysis, however, the independent association between NAFLD and IMT was limited to subjects with MetS or multiple metabolic abnormalities. Among metabolically healthy people, the NAFLD–IMT association was not significant after adjusting for cardiovascular risk factors. In a previous study, NAFLD was associated with carotid IMT, even in the absence of MetS [16]. However, only age and sex were controlled for in the subgroup analysis of that study [16]. Given the close relationship between metabolic disorders and both NAFLD and carotid IMT, a potential for residual confounding effects exists in the relationship between NAFLD and IMT, even after adjusting for MetS and individual metabolic disorders. Our findings suggest that the effects of NAFLD on carotid IMT are mediated or explained by the presence of multiple metabolic abnormalities. NAFLD can be a marker of severe metabolic disorders and can exaggerate the adverse effects of metabolic disorders on the development of atherosclerosis [2,9,28]. The severity of NAFLD might be another cause of our findings. The spectrum of NAFLD varies from benign simple steatosis to a more progressive form of disease, nonalcoholic steatohepatitis (NASH), which can progress to liver fibrosis and even cirrhosis [2,4,26]. Metabolic disorders have been repeatedly reported to be associated with NAFLD, but their simultaneous presence can
increase the risk of NASH. Among the NAFLD patients, the presence of MetS was associated with NASH and with more severe necroinflammatory activity and fibrosis [10]. NASH was also reported to be associated with greater disturbances of insulin sensitivity, adipocytokines, and inflammatory cytokines [11,29,30]. Therefore, not simple steatosis, but NASH, may contribute to the development of atherosclerosis. We acknowledge certain limitations of this study. First, this study could not assess the temporal nature of the relationships among NAFLD, MetS, and carotid atherosclerosis because of its cross-sectional design. Prospective studies are required to confirm our findings and to assess potential interactions between NAFLD and MetS. Second, the diagnosis of NAFLD in this study was based on ultrasound examinations and the exclusion of other common causes of fatty liver. However, these diagnoses were not confirmed by liver biopsy, which is the only diagnostic method that can confirm NAFLD [1,2,6]. In a prospective comparative study of 85 patients confirmed with liver biopsy, ultrasound examination had 94% sensitivity and 84% specificity in the identification of steatosis [5]. Another study observed no difference between biopsy-confirmed NAFLD and ultrasonographically diagnosed NAFLD in relation to cardiovascular risk factors and carotid IMT [17]. Third, the possibility exists of confounding effects of other types of liver disease. We excluded individuals who were positive for HBsAg and who had a history of excessive alcohol consumption, since hepatitis B virus infection and alcoholic liver diseases account for the majority of chronic liver diseases in Korea. In a further analysis, the association between liver steatosis and the MetS was not greatly affected by the alcohol intake. However, the possibility of residual confounding still exists because we measured alcohol intake using a simple questionnaire and did not have any objective index for alcohol intake. In addition, we did not exclude hepatitis C virus (HCV) infection, which is another common cause of chronic liver disease. The estimated prevalence of anti-HCV among
Table 4 Sex-specific association between NAFLD and IMT according to the presence of metabolic syndrome. Characteristics
No. of people
No. (%) of people with NAFLD
Men All subjects No metabolic syndrome Metabolic syndrome
556 336 220
317 (57.0) 147 (43.8) 170 (77.3)
0.040 (p = 0.032) 0.030 (p = 0.175) 0.066 (p = 0.055)
1.62 (0.94–2.81) 1.42 (0.65–3.10) 2.03 (0.84–4.89)
Women All subjects No metabolic syndrome Metabolic syndrome
465 257 208
190 (40.9) 60 (23.4) 130 (62.5)
0.029 (p = 0.180) –0.020 (p = 0.476) 0.071 (p = 0.045)
1.70 (0.95–3.04) 0.82 (0.28–2.40) 2.38 (1.10–5.15)
a
NAFLD-associated mean difference in IMT (mm)a
Adjusted for age, waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol intake.
NAFLD-associated odds ratio (95% CI) for increased IMTa
H.C. Kim et al. / Atherosclerosis 204 (2009) 521–525
Koreans aged 40 years or older from 1995 to 2000 was 1.29% (95% CI, 1.12–1.48) [31]. Moreover, we cannot rule out other less common liver diseases, although all of the enrolled participants stated that they had no previously diagnosed liver disease. Finally, an inadequate statistical power due to a small sample size might be a source of false-negative findings in the subgroup analysis. However, we observed a strong association between NAFLD and IMT in the presence of MetS, although the MetS subgroup was smaller than the non-MetS subgroup. We also observed consistent findings from the pooled and sex-specific analyses, and from the linear and logistic regression analyses. Therefore, the study findings were unlikely to have been caused mainly by the small sample size. In summary, NAFLD was positively associated with carotid IMT among middle-aged Koreans, but the association between NAFLD and IMT was limited to the people with multiple metabolic abnormalities or MetS. These results suggest that the relationship between NAFLD and carotid IMT reflects adverse effects of MetS, rather than a direct contribution of NAFLD to the development of atherosclerosis. Conflict of interest None. Acknowledgment This work was supported by grants from the Korean Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A040152 and A050463). References [1] Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–31. [2] Angelico F, Del Ben M, Conti R, et al. Non-alcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases. J Gastroenterol Hepatol 2003;18:588–94. [3] Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol 2003;15:539–43. [4] Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960–7. [5] Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 1986;292:13–5. [6] Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–50. [7] Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450–5. [8] Luyckx FH, Lefebvre PJ, Scheen AJ. Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes Metab 2000;26:98–106.
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Association between nonalcoholic fatty liver disease and carotid intima-media thickness according to the presence of metabolic syndrome Hyeon Chang Kim a,b , Dae Jung Kim c,∗ , Kap Bum Huh d a
Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States c Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South Korea d Huh’s Diabetes Center and the 21 Century Diabetes and Vascular Research Institute, Seoul, South Korea b
a r t i c l e
i n f o
Article history: Received 10 July 2008 Received in revised form 8 September 2008 Accepted 9 September 2008 Available online 19 September 2008 Keywords: Nonalcoholic fatty liver disease Liver steatosis Metabolic syndrome Atherosclerosis Intima-media thickness
a b s t r a c t Objective: Controversy exists as to whether the association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis is independent of other metabolic disorders. We examined the association between NAFLD and carotid intima-media thickness (IMT) according to the presence of metabolic syndrome (MetS). Methods: A cross-sectional analysis was performed among 556 men and 465 women, ages 30–79 years. The presence of NAFLD was evaluated ultrasonographically. Carotid IMT was determined ultrasonographically by the average of the maximal IMT at each common carotid artery. Independent associations between NAFLD and IMT were assessed using multiple linear and logistic regression models, after adjusting for age, sex, waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol consumption. Results: After adjusting for major risk factors, subjects with NAFLD had greater carotid IMT than subjects without NAFLD (difference 0.034 mm, p = 0.016). However, the difference in IMT was significant only in subjects with MetS (0.060 mm, p = 0.015) and not in subjects without MetS (0.015 mm, p = 0.384). Similarly, the NAFLD-associated adjusted odds ratio for increased IMT, defined as the sex-specific top quintile, was 1.63 (95% CI, 1.10–2.42) in all subjects and 2.08 (95% CI, 1.19–3.66) in subjects with MetS, but 1.18 (95% CI, 0.64–2.19) in subjects without MetS. When the analysis was performed according to the number of metabolic abnormalities, the NAFLD–IMT association was observed only in subjects with four or more abnormalities. Conclusion: These results suggest that NAFLD is independently associated with carotid atherosclerosis only in people who have multiple metabolic abnormalities. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that is characterized by significant lipid deposition within the hepatocytes in people with no history of excessive alcohol consumption [1]. The best diagnostic test for confirming NAFLD is a liver biopsy, but medical and ethical considerations limit its use in patients with nonprogressive fatty liver diseases [2,3]. Elevated levels of liver enzymes, such as aspartate aminotransferase, alanine aminotransferase (ALT), and ␥-glutamyl transferase (␥GT), are common laboratory abnormalities found in patients
∗ Corresponding author at: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San-5, Wonchon-dong, Yeongtong-gu, Suwon 443721, South Korea. Tel.: +82 31 219 5128; fax: +82 31 219 4497. E-mail address: [email protected] (D.J. Kim). 0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.09.012
with NAFLD, but the specificity of these tests is low [1,4]. Consequently, the clinical evaluation of NAFLD is commonly based on a combination of ultrasonographic findings and laboratory tests [3,5]. Liver ultrasonography results, although not sufficiently sensitive to detect liver inflammation and fibrosis, correlate well with the histological finding of fatty infiltration. In addition, international guidelines have been proposed for the diagnosis of different degrees of steatosis [3,5,6]. NAFLD is associated with various metabolic abnormalities, including central obesity, type 2 diabetes, dyslipidemia, high blood pressure [7,8], and metabolic syndrome (MetS) [9,10]. Fatty liver can develop as the result of various metabolic conditions that promote fat accumulation and inflammation in the liver [9–11]; otherwise, NAFLD may contribute to the development of MetS [12,13]. Previously, we reported that NAFLD measured ultrasonographically is closely associated with metabolic abnormalities and MetS among apparently healthy Korean adults [14,15]. Recently, NAFLD has been reported to be associated
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with carotid artery atherosclerosis, which is evaluated using the intima-media thickness (IMT) [16–22]. However, whether NAFLD has a direct impact on atherosclerosis independent of other metabolic risk factors is unclear. Therefore, we investigated the association between NAFLD measured ultrasonographically and carotid IMT in the presence of multiple metabolic abnormalities. 2. Methods 2.1. Study design and participants This cross-sectional study was performed as part of the Korean Metabolic Syndrome Study, which was undertaken to evaluate the role of MetS as a risk for cardiovascular disease in Korean adults. The institutional review board of Severance Hospital at Yonsei University approved the study protocol, and informed consent was obtained from each participant. We measured metabolic profiles, evaluated cardiovascular risk factors, and performed abdominal and carotid artery ultrasonography scans on 1244 men and women. All measurements were taken over a 3-month period (April–June 2001) at a health-screening center in Seoul, Korea. All participants were apparently healthy and independently functioning individuals who visited the health center for general health screening. Among the 1244 initial volunteers, 1142 people who were aged from 30 to 79 years completed anthropometric measurements, serum biochemistry profiles, and liver and carotid artery ultrasound scans. We excluded 121 people who had a history of coronary heart disease or stroke, had hepatitis B virus surface antigens (HBsAg), or consumed alcoholic drinks four times per week or more. In total, 1021 subjects (556 men and 465 women) were included in the analyses. 2.2. Measurements Trained nurses interviewed all participants and obtained their medical history and health-related behaviors using a standardized questionnaire. Weight and height were measured while the participant was clothed in a light gown. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2 ). Waist circumference was measured midway between the lowest rib margin and the iliac crest in a standing position. Resting blood pressure was measured twice, and the mean value was used for the analyses. Blood samples were obtained after a fasting period of at least 8 h. Total serum cholesterol, high-density lipoprotein (HDL)–cholesterol, and triglyceride levels were measured using enzymatic colorimetric methods. Fasting plasma glucose levels were measured using the glucose oxidase method. Serum insulin levels were measured using a radioimmunoassay. Insulin resistance was determined by the homeostasis model assessment of insulin resistance (HOMA-IR). The serum ALT and ␥GT levels were measured using enzymatic methods. Liver ultrasound scans were performed to assess the presence and severity of NAFLD. The same operator performed all ultrasound scans using a high-resolution B-mode scanner (SSD-5500; Aloka, Tokyo, Japan). The operator was unaware of the participants’ medical histories and laboratory findings. The degree of steatosis was assessed semiquantitatively (absent, mild, moderate, and severe) on the basis of abnormally intense, high-level echoes arising from the hepatic parenchyma, liver–kidney differences in echo amplitude, echo penetration into the deep portion of the liver, and clarity of the blood vessel structure in the liver [5]. The carotid arteries were evaluated using a high-resolution B-mode scanner (SSA-270A; Toshiba, Tokyo, Japan) and a 7.5-MHz probe. Both com-
mon carotid arteries were scanned proximal to distal up to the bifurcation. Frozen photocopies of the end-diastolic images were captured in a longitudinal view that showed the bifurcation. The IMT was measured at the far wall of both common carotid arteries approximately 1 cm proximal to the carotid bulb. Measurements of IMT (i.e. the distance between the leading edge of the first and second echogenic lines) were performed using calipers (Digimatic; Mitutoyo, Kawasaki, Japan). The carotid IMT was defined as the mean of the maximal IMT of each common carotid artery. A single examiner took all measurements. The intra-observer coefficient of variation was 2.1% [23]. The metabolic syndrome was defined according to the criteria established by the National Cholesterol Education Program Adult Treatment Panel III using the adjusted waist circumference for Asians [24]. Accordingly, participants with three or more of the following five criteria were defined as having MetS: abdominal obesity by waist circumference (men/women >90/80 cm), high blood pressure (≥130/85 mmHg) or on antihypertensive medication, elevated fasting blood glucose (≥5.6 mmol/l) or on antidiabetic medication, hypertriglyceridemia (≥1.7 mmol/l), and low serum HDL–cholesterol (men/women <1.0/1.3 mmol/l). 2.3. Statistical analysis Clinical and biochemical characteristics are shown according to the presence of NAFLD, separately in men and women. For each variable, differences according to the presence of NAFLD were tested using Student’s t-test, the Wilcoxon rank-sum test, or 2 test. Simple and partial (adjusting for age and sex) correlation coefficients were used to assess correlations between IMT and selected metabolic risk factors. Independent associations between NAFLD and continuous form of carotid IMT were assessed using two multiple linear regression models. The first model adjusted for age and sex, and the second model additionally adjusted for waist circumference, systolic blood pressure, fasting plasma glucose, total/HDL–cholesterol ratio, cigarette smoking, and alcohol consumption. Logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) for increased IMT according to the presence of NAFLD. Increased IMT in this analysis was defined using the sex-specific highest quintile: >0.86 mm for men and >0.83 mm for women. Similarly, two serial models (age- and sex-adjusted, and multivariate-adjusted) were used for the logistic regression analyses. To determine whether the association between NAFLD and carotid IMT is independent of other metabolic abnormalities, the above-mentioned analyses were performed separately in subjects with and without MetS, and again according to the number of metabolic abnormalities. To examine possible sex differences in the associations among NAFLD, MetS, and carotid IMT, analyses were also performed separately in men and women. SAS System version 9.13 (SAS Institute, Cary, NC, USA) was used to perform all statistical analyses. All statistical tests were two-tailed, and p-values less than 0.05 were considered significant. 3. Results Among the 556 men and 465 women examined, ultrasound scans revealed NAFLD in 317 men (133 mild, 165 moderate, and 19 severe) and 190 women (87 mild, 93 moderate, and 10 severe). Age was positively associated with NAFLD in women, but not in men. BMI, waist circumference, and systolic and diastolic blood pressures were significantly and positively associated with NAFLD. Total cholesterol and triglyceride levels were positively associated with NAFLD; however, HDL–cholesterol level was negatively associated with NAFLD. Consequently, there was a strong positive associa-
H.C. Kim et al. / Atherosclerosis 204 (2009) 521–525
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Table 1 Clinical and biochemical characteristics of 556 men and 465 women according to NAFLD. Characteristics
Age (years) BMI (kg/m2 ) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Total cholesterol (mmol/l) HDL–cholesterol (mmol/l) Total/HDL–cholesterol ratio Triglyceride (mmol/l) Fasting glucose (mmol/l) HOMA-IR ALT (IU/l) ␥GT (IU/l) Current smoking Alcohol intake ≥1/week Carotid IMT (mm) Increased carotid IMT
Men
p
No NAFLD (n = 239)
NAFLD (n = 317)
51.6 ± 11.0 23.2 ± 2.5 83.0 ± 6.9 126.6 ± 16.8 78.1 ± 11.5 5.03 ± 0.84 1.19 ± 0.27 4.38 ± 1.04 1.53 [1.12–2.48] 5.17 [4.78–5.56] 1.84 [1.45–2.56] 20 [16–28] 32 [22–51] 115 (48.1) 132 (55.5) 0.71 ± 0.19 35 (14.6)
50.7 ± 10.4 25.1 ± 2.5 88.8 ± 6.5 132.0 ± 17.4 81.8 ± 11.6 5.26 ± 0.87 1.10 ± 0.23 4.96 ± 1.14 2.42 [1.69–3.26] 5.44 [5.00–6.11] 2.83 [2.04–3.80] 30 [22–40] 47 [32–75] 140 (44.2) 176 (55.7) 0.77 ± 0.23 77 (24.3)
Women
0.302 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.354 0.956 <0.001 0.005
p
No NAFLD (n = 275)
NAFLD (n = 190)
51.5 ± 9.4 23.6 ± 2.7 79.0 ± 7.0 128.4 ± 20.3 78.2 ± 13.2 5.21 ± 0.85 1.37 ± 0.35 4.01 ± 1.09 1.30 [0.94–1.86] 4.94 [4.72–5.28] 1.95 [1.38–2.35] 17 [13–21] 17 [14–23] 14 (5.1) 36 (13.2) 0.70 ± 0.21 38 (13.8)
54.2 ± 8.7 26.2 ± 3.1 86.7 ± 7.7 134.4 ± 18.0 81.8 ± 11.8 5.52 ± 0.95 1.22 ± 0.32 4.78 ± 1.30 1.82 [1.42–2.76] 5.28 [4.89–5.89] 3.01 [2.15–4.71] 21 [16–27] 25 [19–35] 5 (3.7) 24 (12.6) 0.78 ± 0.23 56 (29.5)
0.002 <0.001 <0.001 0.001 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.472 0.849 <0.001 <0.001
Data are expressed as the mean ± S.D., median [inter-quartile range], or number (%).
tion between the total/HDL–cholesterol ratio and NAFLD. Fasting glucose, insulin resistance, liver enzyme levels, and carotid IMT were also positively associated with NAFLD. Current smoking and alcohol consumption were not associated with NAFLD (Table 1). Among cardiovascular risk factors, age was the most strongly correlated with carotid IMT. After adjusting for age and sex, carotid IMT was strongly correlated with BMI, waist circumference, systolic and diastolic blood pressure, total/HDL–cholesterol ratio, and insulin resistance. In addition, carotid IMT was also significantly associated with total cholesterol, triglycerides, fasting glucose, and ALT (Table 2). When we adjusted for age and sex, mean carotid IMT values were significantly higher in subjects with NAFLD than in subjects without (0.772 vs. 0.706 mm, difference = 0.066 mm, p < 0.001). Among the subjects with NAFLD, the severity of steatosis was not significantly associated with IMT (p = 0.634). After additional adjustment for waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol intake, the subjects with NAFLD still had a greater IMT (0.756 vs. 0.722 mm, p = 0.016). However, this association differed depending on the presence or absence of MetS. NAFLD was significantly and independently associated with higher IMT values in people with MetS (difference = 0.060 mm, p = 0.015), but not in people without MetS (p = 0.384). Similar relationships were observed for the dichotomous form of carotid IMT. The NAFLD-associated odds ratios for increased IMT were 2.32 (95% CI, 1.65–3.27) in the age- and
sex-adjusted model and 1.63 (95% CI, 1.10–2.42) in the multivariateadjusted model. However, the association was significant only in people with MetS (odds ratio, 2.08; 95% CI, 1.19–3.66), and not in people without MetS (odds ratio, 1.18; 95% CI, 0.64–2.19). When we performed the subgroup analysis according to the number of metabolic abnormalities, an independent association was observed only between NAFLD and increased IMT among the subjects with four or five metabolic abnormalities (odds ratio, 2.64, 95% CI, 1.04–6.70; Table 3). The association between NAFLD and carotid IMT also differed according to the presence of MetS in the sex-specific analyses (Table 4). However, a significant association was observed only in female subjects with MetS (adjusted difference = 0.071 mm, p = 0.045; adjusted odds ratio for increased IMT = 2.38, p = 0.027). The association in male subjects with MetS did not reach significance (adjusted difference = 0.066 mm, p = 0.055; adjusted odds ratio increased IMT = 2.03, p = 0.114). 4. Discussion There is increasing evidence for an association between NAFLD and an increased risk of cardiovascular morbidity and mortality [25–27]. The association between NAFLD and cardiovascular risk factors can largely explain the higher risk of cardiovascular disease among people with NAFLD [2,15,27]. Recent case–control studies [16,17,21] and cross-sectional studies [18–20,22] have reported
Table 2 Correlations between IMT and metabolic risk factors. Variable
Age BMI Waist circumference Systolic blood pressure Diastolic blood pressure Total cholesterol HDL–cholesterol Total/HDL–cholesterol ratio Triglyceridea Fasting glucosea HOMA-IRa ALTa ␥GTa a
Log-transformed.
Simple Spearman correlation
Partial Spearman correlation adjusted for age and sex
Coefficient
p
Coefficient
p
0.4071 0.1140 0.2079 0.3033 0.2276 0.1004 −0.0731 0.1274 0.0471 0.1454 0.1407 0.0011 −0.0055
<0.001 <0.001 <0.001 <0.001 <0.001 0.001 0.020 <0.001 0.133 <0.001 <0.001 0.973 0.863
0.1186 0.1595 0.2104 0.1544 0.0820 −0.0823 0.1227 0.0652 0.0924 0.1298 0.0655 0.0287
<0.001 <0.001 <0.001 <0.001 0.012 0.014 <0.001 0.046 0.005 <0.001 0.045 0.379
524
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Table 3 Association between NAFLD and IMT according to the presence of multiple metabolic abnormalities. NAFLD-associated mean difference in IMT (mm). Characteristics
All subjects
No. of people
No. (%) of people with NAFLD
NAFLD-associated mean difference in IMT (um)a
NAFLD-associated odds ratio (95% CI) for increased IMT*
Age- and sex-adjusted
Multivariate-adjusteda
Age- and sex-adjusted
Multivariate-adjusteda
1,021
507 (49.7)
0.066 (p < 0.001)
0.034 (p = 0.016)
2.32 (1.65–3.27)
1.63 (1.10–2.42)
Metabolic syndrome No 593 Yes 428
207 (34.9) 300 (70.1)
0.035 (p = 0.028) 0.071 (p = 0.003)
0.015 (p = 0.384) 0.060 (p = 0.015)
1.41 (0.84–2.38) 2.42 (1.42–4.14)
1.18 (0.64–2.19) 2.08 (1.19–3.66)
No. of metabolic abnormalities 0 or 1 304 2 289 3 245 4 or 5 183
72 (23.7) 135 (46.7) 160 (65.3) 140 (76.5)
0.046 (p = 0.016) 0.014 (p = 0.589) 0.049 (p = 0.075) 0.094 (p = 0.028)
0.034 (p = 0.075) 0.006 (p = 0.842) 0.041 (p = 0.137) 0.087 (p = 0.066)
1.55 (0.69–3.48) 1.28 (0.69–2.60) 2.09 (1.03–4.25) 2.71 (1.15–6.35)
1.55 (0.57–4.22) 1.14 (0.51–2.56) 1.86 (0.90–3.87) 2.64 (1.04–6.70)
a
Adjusted for age, sex, waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol intake.
increased carotid IMT among patients with NAFLD. Possible biological mechanisms linking the effects of NAFLD to atherosclerosis development include endothelial dysfunction, oxidative stress, inflammation, inflammatory cytokines, and abnormal lipid and glucose metabolism [27]. However, these mechanisms are also closely related to other risk factors for atherosclerosis. Therefore, it is unclear whether NAFLD contributes to the development of atherosclerosis directly. Several studies have reported independent associations between NAFLD and atherosclerosis after adjusting for cardiovascular risk factors and MetS [16–18,20,22]. In our analyses, NAFLD was significantly associated with IMT after adjusting for major cardiovascular risk factors. In the subgroup analysis, however, the independent association between NAFLD and IMT was limited to subjects with MetS or multiple metabolic abnormalities. Among metabolically healthy people, the NAFLD–IMT association was not significant after adjusting for cardiovascular risk factors. In a previous study, NAFLD was associated with carotid IMT, even in the absence of MetS [16]. However, only age and sex were controlled for in the subgroup analysis of that study [16]. Given the close relationship between metabolic disorders and both NAFLD and carotid IMT, a potential for residual confounding effects exists in the relationship between NAFLD and IMT, even after adjusting for MetS and individual metabolic disorders. Our findings suggest that the effects of NAFLD on carotid IMT are mediated or explained by the presence of multiple metabolic abnormalities. NAFLD can be a marker of severe metabolic disorders and can exaggerate the adverse effects of metabolic disorders on the development of atherosclerosis [2,9,28]. The severity of NAFLD might be another cause of our findings. The spectrum of NAFLD varies from benign simple steatosis to a more progressive form of disease, nonalcoholic steatohepatitis (NASH), which can progress to liver fibrosis and even cirrhosis [2,4,26]. Metabolic disorders have been repeatedly reported to be associated with NAFLD, but their simultaneous presence can
increase the risk of NASH. Among the NAFLD patients, the presence of MetS was associated with NASH and with more severe necroinflammatory activity and fibrosis [10]. NASH was also reported to be associated with greater disturbances of insulin sensitivity, adipocytokines, and inflammatory cytokines [11,29,30]. Therefore, not simple steatosis, but NASH, may contribute to the development of atherosclerosis. We acknowledge certain limitations of this study. First, this study could not assess the temporal nature of the relationships among NAFLD, MetS, and carotid atherosclerosis because of its cross-sectional design. Prospective studies are required to confirm our findings and to assess potential interactions between NAFLD and MetS. Second, the diagnosis of NAFLD in this study was based on ultrasound examinations and the exclusion of other common causes of fatty liver. However, these diagnoses were not confirmed by liver biopsy, which is the only diagnostic method that can confirm NAFLD [1,2,6]. In a prospective comparative study of 85 patients confirmed with liver biopsy, ultrasound examination had 94% sensitivity and 84% specificity in the identification of steatosis [5]. Another study observed no difference between biopsy-confirmed NAFLD and ultrasonographically diagnosed NAFLD in relation to cardiovascular risk factors and carotid IMT [17]. Third, the possibility exists of confounding effects of other types of liver disease. We excluded individuals who were positive for HBsAg and who had a history of excessive alcohol consumption, since hepatitis B virus infection and alcoholic liver diseases account for the majority of chronic liver diseases in Korea. In a further analysis, the association between liver steatosis and the MetS was not greatly affected by the alcohol intake. However, the possibility of residual confounding still exists because we measured alcohol intake using a simple questionnaire and did not have any objective index for alcohol intake. In addition, we did not exclude hepatitis C virus (HCV) infection, which is another common cause of chronic liver disease. The estimated prevalence of anti-HCV among
Table 4 Sex-specific association between NAFLD and IMT according to the presence of metabolic syndrome. Characteristics
No. of people
No. (%) of people with NAFLD
Men All subjects No metabolic syndrome Metabolic syndrome
556 336 220
317 (57.0) 147 (43.8) 170 (77.3)
0.040 (p = 0.032) 0.030 (p = 0.175) 0.066 (p = 0.055)
1.62 (0.94–2.81) 1.42 (0.65–3.10) 2.03 (0.84–4.89)
Women All subjects No metabolic syndrome Metabolic syndrome
465 257 208
190 (40.9) 60 (23.4) 130 (62.5)
0.029 (p = 0.180) –0.020 (p = 0.476) 0.071 (p = 0.045)
1.70 (0.95–3.04) 0.82 (0.28–2.40) 2.38 (1.10–5.15)
a
NAFLD-associated mean difference in IMT (mm)a
Adjusted for age, waist circumference, systolic blood pressure, fasting glucose, total/HDL–cholesterol ratio, smoking, and alcohol intake.
NAFLD-associated odds ratio (95% CI) for increased IMTa
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Koreans aged 40 years or older from 1995 to 2000 was 1.29% (95% CI, 1.12–1.48) [31]. Moreover, we cannot rule out other less common liver diseases, although all of the enrolled participants stated that they had no previously diagnosed liver disease. Finally, an inadequate statistical power due to a small sample size might be a source of false-negative findings in the subgroup analysis. However, we observed a strong association between NAFLD and IMT in the presence of MetS, although the MetS subgroup was smaller than the non-MetS subgroup. We also observed consistent findings from the pooled and sex-specific analyses, and from the linear and logistic regression analyses. Therefore, the study findings were unlikely to have been caused mainly by the small sample size. In summary, NAFLD was positively associated with carotid IMT among middle-aged Koreans, but the association between NAFLD and IMT was limited to the people with multiple metabolic abnormalities or MetS. These results suggest that the relationship between NAFLD and carotid IMT reflects adverse effects of MetS, rather than a direct contribution of NAFLD to the development of atherosclerosis. Conflict of interest None. Acknowledgment This work was supported by grants from the Korean Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A040152 and A050463). References [1] Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–31. [2] Angelico F, Del Ben M, Conti R, et al. Non-alcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases. J Gastroenterol Hepatol 2003;18:588–94. [3] Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol 2003;15:539–43. [4] Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960–7. [5] Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 1986;292:13–5. [6] Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–50. [7] Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450–5. [8] Luyckx FH, Lefebvre PJ, Scheen AJ. Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes Metab 2000;26:98–106.
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