J o u r n a l o f C a r d i o v a s c u l a r C o m p u t e d T o m o g r a p h y 7 ( 2 0 1 3 ) 3 1 1 e3 1 8
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Original Research Article
Relation of nonalcoholic fatty liver disease to the metabolic syndrome: The Multi-Ethnic Study of Atherosclerosis Irfan Zeb MDa,*, Ronit Katz DPhilb, Khurram Nasir MDc,d,e,f,g, Jingzhong Ding MDh, Panteha Rezaeian MDg, Matthew J. Budoff MDg a
Bronx-Lebanon Hospital Center, 1650 Grand Concourse, Bronx, NY 10457, USA University of Washington, Seattle, WA, USA c Center for Prevention and Wellness Research, Baptist Health Medical Group, Miami Beach, FL, USA d Department of Epidemiology, Robert Stempel College of Public Health, Florida International University, Miami, FL, USA e Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA f The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA g Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA h Wake Forest University, Winston-Salem, NC, USA b
article info
abstract
Article history:
Background: An overlap exists between risk factors for metabolic syndrome (MetS) and
Received 7 April 2013
nonalcoholic fatty liver disease (NAFLD).
Received in revised form
Objectives: We studied the association of MetS and its components with NAFLD in a multi-
11 August 2013
ethnic population.
Accepted 16 August 2013
Methods: Cross-sectional study was designed, including 6814 participants from the MultiEthnic Study of Atherosclerosis. Liver fat content was measured with cardiac CT scans
Keywords:
by using liver-to-spleen ratio of 14 drinks/week for men and >7 drinks/week for women), self-reported
Metabolic syndrome
history of cirrhosis, and missing information were excluded. A total of 4140 participants
MESA
met the criteria for inclusion in the study. Results: The odds ratios (ORs) for presence of NAFLD were highest for persons with diabetes (OR, 4.16; 95% CI, 3.24e5.33), followed by presence of MetS (OR, 3.97; 95% CI, 3.26e4.83). Among components of MetS central obesity was associated with higher odds for presence (OR, 3.41; 95% CI, 2.77e4.20) and severity (OR, 5.58; 95% CI, 3.86e8.06) of NAFLD . The ORs for moderate-to-severe NAFLD were higher for presence of MetS (OR, 5.92; 95% CI, 4.29e8.19)] by using 14 drinks/week for men and >7 drinks/week for women).24,25 For these analyses, we excluded persons with no available liver and spleen images on CT scan (N ¼ 2425), persons with heavy alcohol intake defined by >14 drinks/week for men and >7 drinks/week for women (N ¼ 220), and selfreported cirrhosis (N ¼ 7). We further excluded participants with missing MetS components (N ¼ 22), leaving a total sample size of 4140 persons. Medical history, anthropometric measurements, and CT scans for the present study were taken from the first examination of the MESA cohort (July 2000 to August 2002) as previously described. Information about demographic data, tobacco usage, alcohol consumption, medical conditions, and current use of prescription and nonprescription medications and supplements was obtained through a questionnaire at the baseline visit of the study. Alcohol consumption was defined according to the number of drinks per week. DM was defined as fasting blood glucose 126 mg/dL or use of insulin or oral hypoglycemic medications. Resting blood pressure was measured 3 times with participants in the seated position with a Dinamap model Pro 100 automated oscillometric sphygmomanometer (Critickon; General Electric, Madison, WI). The average of the last 2 measurements was used for analysis. Height and weight were measured with participants wearing light clothing and no shoes, and body mass index (BMI) was calculated (as weight divided by height squared; kg/m2). Waist and hip circumference data were also collected. Waist circumference at the umbilicus was measured to the nearest 0.1 cm with the use of a steel measuring tape (standard 4-ounce tension). For the present study, we used cardiac CT scans that covered images of the liver and spleen. MetS was defined by using criteria modified from the Third Adult Treatment Panel of the National Cholesterol Education Program, that is, 3 or more of the following: large waist circumference (women >88 cm and men >102 cm), elevated triglycerides (150 mg/dL), low HDL cholesterol (men 100 mm2 in area. Two ROIs were placed in the right liver lobe anterioposteriorly, one ROI in the left liver lobe, and one ROI in the spleen. ROIs with larger areas were used, whenever possible, to include a greater area of the liver and spleen while taking care to exclude regions of nonuniform parenchymal attenuation, including hepatic vessels (Fig. 1). Liver-to-spleen ratio was calculated by taking mean Hounsfield unit measurement of both right liver lobe ROIs and dividing it by the spleen Hounsfield unit measurement. Liverto-spleen ratio < 1.0 was taken as the cutoff for the diagnosis of presence of liver fat. As another parameter, liver attenuation < 40 HU was used as a cutoff of >30% liver fat content. Reproducibility of liver and spleen attenuation measurements were performed on 100 randomly selected participant scans measured by a single reader. The same reader repeated the measurements on those 100 scans for intrareader variability. The second reader performed measurements on the same 100 participant scans for inter-reader variability.
2.4.
Statistical analysis
NAFLD was defined by using liver-to-spleen ratio < 1.0 and liver attenuation < 40 HU. Comparisons among MetS, diabetes, and neither condition with demographic measures and cardiovascular risk factors are expressed with means and proportions. We used the c2 test for proportions and analysis of variance for comparing levels of continuous risk factors. We used multiple logistic regression to examine the prevalence of liver-to-spleen ratio < 1.0 and liver attenuation < 40 HU (ie, participants with NAFLD present at baseline) among the 3 disease groups (MetS, diabetes, and neither condition), adjusted for age, sex, and ethnicity and additionally for other
Fig. 1 e Prevalence of NAFLD by diabetes, MetS, or neither condition defined by L/S < 1.0 and liver attenuation > 40 HU. L/S, liver-to-spleen ratio; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease.
non-MetS risk factors (low-density lipoprotein [LDL] cholesterol, smoking, and lipid-lowering medications). We further examined the number of MetS risk factors (from none to all 5) and their association with prevalence of NAFLD, and we also examined the risk of NAFLD by number of MetS risk factors by using participants with 0 or 1 MetS risk factors as the reference group, because of the relatively small numbers. Statistical analyses were performed with SPSS 16.0.2 software for Windows (SPSS Inc, Chicago, IL). A P value < .05 was considered statistically significant. Confidence intervals are expressed as 95% CIs.
3.
Results
3.1.
Participant characteristics
Among the 4140 MESA participants 1859 (45%) were men; 10% self-identified as Chinese, 30% as black, and 23% as Hispanic; and mean age was 63 10 years. Overall, 1958 (47%) had hypertension, 554 (13%) had diabetes, and 1154 (28%) had MetS. Table 1 represents clinical information of the participants according to the presence of MetS, diabetes, or neither of these conditions and according to the individual components of the MetS. The prevalence of positive criteria for the MetS was highest for abdominal obesity and high blood pressure (85% and 82%, respectively), whereas IFG was the least prevalent (37%) among the MetS components.
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Table 1 e Characteristics of participants with diabetes, the ATP III MetS, or neither condition and individual components, in the MESA population.
Age, y, mean SD Female, n (%) Ethnicity White, n (%) Chinese American, n (%) African American, n (%) Hispanic, n (%) Income < $40,000, n (%) Glucose, mg/dL, mean SD BMI, mean SD Total cholesterol, mg/dL, mean SD HDL, mg/dL, mean SD LDL, mg/dL, mean SD Triglycerides, mg/dL, mean SD Lipid-lowering medications, n (%) Diastolic BP, mm Hg, mean SD Systolic BP, mm Hg, mean SD Antihypertensive medications, n (%) Current smoker, n (%) MetS components Abdominal obesity (large waist), n (%) High blood pressure, n (%) Low HDL, n (%) High triglycerides, n (%) Impaired fasting glucose, n (%)
Neither condition (n ¼ 2432)
MetS (n ¼ 1154)
Diabetes (n ¼ 554)
62 11 1292 (53)
64 10 709 (61)
65 10 280 (51)
973 (40) 251 (10) 720 (30) 488 (20) 1085 (47) 87 9 27.0 4.8 194 34 55 15 119 30 103 58 313 (13) 71 10 123 21 660 (27) 277 (11)
446 (39) 102 (9) 303 (26) 303 (26) 625 (57) 96 12 30.8 5.1 196 37 43 10 117 32 180 93 210 (18) 73 10 134 21 618 (54) 131 (11)
108 (20) 49 (9) 220 (40) 177 (32) 336 (65) 150 57 30.9 5.7 190 41 46 13 113 34 163 151 155 (28) 72 10 133 22 335 (64) 66 (12)
977 (40) 1073 (44) 417 (17) 268 (11) 144 (6)
982 (85) 943 (82) 861 (75) 734 (64) 432 (37)
397 (72) 435 (79) 294 (53) 241 (44) 554 (100)
ATP III, Third Adult Treatment Panel of the National Cholesterol Education Program; BMI, body mass index (calculated as weight divided by height squared; kg/m2); BP, blood pressure HDL, high-density lipoprotein; LDL, low-density lipoprotein; MESA, Multi-Ethnic Study of Atherosclerosis; MetS, metabolic syndrome.
3.2. Relationship of MetS and diabetes to NAFLD defined as liver-to-spleen ratio < 1.0 The prevalence of liver-to-spleen ratio < 1.0 in persons with MetS (28%) was similar to persons with diabetes (29%), and both were significantly different from persons with neither condition (P < .001) (Fig. 1). A graded linear relationship was found between the presence of liver-to-spleen ratio < 1.0 and the number of components of MetS. The liver-to-spleen ratio < 1.0 prevalence ranged from 6% in persons with none or 1 metabolic risk factor to 15%, 24%, 34%, and 41% in persons with 2, 3, 4, or 5 components, respectively (P < .001 for trend; Fig. 2). From the regression analyses, the odds ratio (OR) of liver-to-spleen ratio < 1.0 (compared with participants with neither condition) adjusted for age, sex, race, LDL, smoking, and use of lipid-lowering medications was significantly higher among participants with MetS and diabetes (OR, 3.97; 95% CI, 3.26e4.83 and OR, 4.16; 95% CI, 3.24e5.33, respectively; Table 2). When we looked at the components of the MetS, central obesity (OR, 3.41; 95% CI, 2.77e4.20) was associated with the highest OR for the presence of NAFLD, followed by IFG/DM (OR, 2.99; 95% CI, 2.49e3.59), high triglycerides (OR, 2.70; 95% CI, 2.27e3.23), low HDL (OR, 2.36; 95% CI, 1.99e2.80), and elevated blood pressure (OR, 1.97; 95% CI, 1.62e2.39) (Table 2). The OR for the presence of NAFLD increased with the increasing number of MetS components. The OR for the presence of NAFLD for 3 components of MetS was 5.22 (95% CI, 3.99e6.83) which increased to 13.29 (95% CI, 8.92e19.79) for the
presence of all 5 components of MetS components (Table 2). These results were adjusted for age, sex, ethnicity, LDL, smoking, and use of lipid-lowering medications.
3.3. Relationship of MetS and diabetes to NAFLD defined as liver attenuation < 40 HU When defining NAFLD as liver attenuation < 40 HU (a cutoff that represents presence of moderate-to-severe hepatic steatosis), the prevalence in persons with MetS (12%) was similar to persons with diabetes (11%), and both were significantly different from persons with neither condition (P < .001; Fig. 1). Again, we observed a graded linear relationship between the presence of liver attenuation < 40 HU and the number of components of MetS. The liver attenuation < 40 HU prevalence ranged from 1% in participants with none or 1 metabolic risk factor to 4%, 9%, 16%, and 18% in those with 2, 3, 4, or 5 components, respectively (P < .001 for trend; Fig. 2). Table 3 shows the results of the multivariable logistic regression analysis that looked at the association of NAFLD with MetS, diabetes, and components of MetS by using liver attenuation < 40 HU. The ORs for moderate-to-severe NAFLD were similar for the presence of MetS (OR, 5.92; 95% CI, 4.29e8.19) and diabetes (OR, 5.35; 95% CI, 3.57e8.01). Central obesity was associated with the highest OR for moderate-tosevere NAFLD (OR, 5.58; 95% CI, 3.86e8.06) followed by high triglycerides (OR, 3.34; 95% CI, 2.54e4.39), IFG (OR, 3.20; 95% CI, 2.42e4.23), elevated blood pressure (OR, 2.75; 95% CI,
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and 0.99, respectively) and spleen attenuation measurement (0.99 and 0.99, respectively).33
4.
Fig. 2 e Prevalence of NAFLD by number of components of MetS. L/S, liver-to-spleen ratio; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease.
2.02e3.75), and low HDL (OR, 2.55; 95% CI, 1.95e3.34). The ORs for presence of moderate-to-severe NAFLD increased with increasing numbers of components of MetS. The ORs were higher for presence of moderate-to-severe NAFLD: 9.49 (95% CI, 5.67e15.90) for the presence of 3 components and 24.05 (95% CI, 12.73e45.45) for the presence of all 5 components. The results were adjusted for age, sex, ethnicity, LDL, smoking, and used of lipid-lowering medications. Excellent correlation was observed for inter-reader and intrareader variability of liver attenuation measurement (0.96
Discussion
The present study highlights the increased likelihood of NAFLD with the presence of MetS and diabetes, as well as with the number of components of MetS. DM was associated with higher OR for the presence of NAFLD, followed by the MetS, whereas for moderate-to-severe NAFLD, MetS had the higher OR, followed by DM. This finding may imply that presence of moderate-to-severe NAFLD may require the presence of more MetS risk factors than DM alone. Marchesini et al19 assessed the prevalence of the MetS in 304 consecutive patients with NAFLD without overt diabetes and showed that hyperglycemia/DM was the only criteria among components of MetS that was significantly associated with nonalcoholic steatohepatitis (NASH) after adjustment for age, sex, and obesity. They also showed that MetS carried a high risk of NASH among subjects with NAFLD (OR, 3.2; 95% CI, 1.2e8.9; P ¼ .026) after correction for sex, age, and body mass, and the MetS was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1e11.2; P ¼ .032). When we assessed the association of individual components of MetS with the presence of NAFLD, central obesity was associated with the highest odds for NAFLD, followed by IFG/DM. Marceau et al20 showed waist-tohip ratio as the only anthropometric continuous variable to predict steatosis in severely obese subjects. Central obesity has been shown to play a major role in the pathogenesis of the MetS.34 The current therapeutic recommendations also recommend management of weight as one of the prime targets for treatment of NAFLD. We used waist circumference as a measure of central obesity rather than using BMI. BMI may not be a true indicator of central obesity. Marchesini et al10 found in their study that the waist circumference and
Table 2 e Cross-sectional associations of the MetS, components, and number of components of the MetS with L/S < 1. No.
Model 1* OR (95% CI)
Model 2y OR (95% CI)
Model 3z OR (95% CI)
226 (9) 325 (28) 160 (29)
1.00 (ref) 3.72 (3.07e4.49) 3.79 (3.00e4.79)
1.00 (ref) 3.95 (3.25e4.81) 4.19 (3.27e5.35)
1.00 (ref) 3.97 (3.26e4.83) 4.16 (3.24e5.33)
471 (19) 407 (26) 368 (30) 325 (29) 528 (22)
1.42 (1.20e1.69) 2.49 (2.11e2.95) 3.00 (2.53e3.55) 2.69 (2.26e3.19) 2.60 (2.16e3.13)
2.01 2.32 2.69 3.01 3.42
(1.66e2.44) (1.96e2.75) (2.26e3.20) (2.51e3.61) (2.78e4.21)
1.97 (1.62e2.39) 2.36 (1.99e2.80) 2.70 (2.27e3.23) 2.99 (2.49e3.59) 3.41 (2.77e4.20)
1.00 (ref) 2.49 (1.90e3.26) 4.48 (3.45e5.81) 7.19 (5.43e9.51) 10.59 (7.25e15.47)
1.00 2.84 5.18 8.59 13.22
(ref) (2.15e3.75) (3.96e6.78) (6.41e11.51) (8.90e19.66)
1.00 (ref) 2.86 (2.16e3.77) 5.22 (3.99e6.83) 8.68 (6.47e11.65) 13.29 (8.92e19.79)
Patients with LSR < 1, n (%)
MetS and DM Neither condition 2432 MetS 1154 DM 554 Components of the MetS Elevated BP 2451 Low HDL 1572 High TG 1243 IFG (100 mg/dL) 1130 Abdominal obesity 2356 No. of components of the MetS 0þ1 1490 2 1048 3 901 4 527 5 174
94 152 212 181 72
(6) (15) (24) (34) (41)
BP, blood pressure; DM, diabetes mellitus; IFG, impaired fasting glucose; HDL, high-density lipoprotein; L/S, liver-to-spleen ratio; LSR, liver-tospleen ratio; MetS, metabolic syndrome; OR, odds ratio; TG, triglyceride. * Unadjusted. y Adjusted for age, sex, ethnicity. z Adjusted for age, sex, ethnicity, LDL, smoking, and use of lipid-lowering medications.
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Table 3 e Cross-sectional associations of the MetS, components, and number of components of the MetS with liver attenuation < 40 HU. N
Model 1* OR (95% CI)
Model 2y OR (95% CI)
Model 3z OR (95% CI)
59 (2) 139 (12) 59 (11)
1.00 (ref) 5.34 (3.90e7.33) 4.40 (3.00e6.46)
1.00 (ref) 5.84 (4.23e8.06) 5.20 (3.49e7.74)
1.00 (ref) 5.92 (4.29e8.19) 5.35 (3.57e8.01)
180 160 155 126 212
(7) (10) (13) (11) (9)
1.64 (1.24e2.17) 2.76 (2.12e3.60) 3.78 (2.90e4.92) 2.65 (2.04e3.44) 3.91 (2.78e5.48)
2.74 2.52 3.30 3.16 5.53
2.75 (2.02e3.75) 2.55 (1.95e3.34) 3.34 (2.54e4.39) 3.20 (2.42e4.23) 5.58 (3.86e8.06)
19 43 81 83 31
(1) (4) (9) (16) (18)
1.00 (ref) 3.32 (1.92e5.73) 7.65 (4.61e12.71) 13.25 (7.91e22.19) 16.59 (9.02e30.51)
1.00 3.96 9.27 17.13 23.33
Patients with LSR < 1, n (%)
MetS and DM Neither condition 2432 MetS 1154 DM 554 Components of the MetS Elevated BP 2451 Low HDL 1572 High TG 1243 IFG (100 mg/dL) 1130 Abdominal obesity 2356 No. of components of the MetS 0þ1 1490 2 1048 3 901 4 527 5 174
(2.01e3.72) (1.92e3.29) (2.51e4.33) (2.39e4.16) (3.83e7.99) (ref) (2.28e6.88) (5.54e15.52) (10.09e29.08) (12.39e43.95)
1.00 (ref) 4.03 (2.32e7.00) 9.49 (5.67e15.90) 17.91 (10.52e30.49) 24.05 (12.73e45.45)
BP, blood pressure; DM, diabetes mellitus; IFG, impaired fasting glucose; HDL, high-density lipoprotein; LSR, liver-to-spleen ratio; MetS, metabolic syndrome; OR, odds ratio; TG, triglyceride. * Unadjusted. y Adjusted for age, sex, ethnicity. z Adjusted for age, sex, ethnicity, LDL, smoking, and use of lipid-lowering medications.
waist-to-hip ratio was higher for subjects with NAFLD than for subjects with diabetes despite similar BMI. They also found that in subjects with NAFLD, subjects with normal body weight had similar waist-to-hip ratio as those of overweight persons and larger than control subjects. This shows that subjects with NAFLD may have relatively increased visceral adiposity despite the normal body weight. The prevalence of MetS is increasing with increasing prevalence of obesity,35 and it may add to the overall burden to cardiovascular disease because of its association with cardiovascular disease. It would be important to look at the association of MetS and NAFLD in age groups in which the prevalence of MetS is higher. The persons included in the present study were 45 to 84 years of age (mean age, 64 10 years). The higher burden of cardiometabolic risk factors associated with MetS in this population put them at a higher risk of NAFLD. The importance for identifying NAFLD in this population group in 2-fold: First, NAFLD in the presence of necroinflammatory changes (NASH) is a progressive liver disease, resulting in liver failure and cirrhosis. In fact, a large percentage of cryptogenic cirrhosis cases are identified as being caused by NASH. The increasing prevalence of NAFLD in the presence of increased components of MetS, as is seen in the middle-to-old age population, would increase the number of cases of liver failure and cirrhosis caused by NAFLD. Second, a significant overlap exists between risk factors for atherosclerosis and NAFLD, supporting the role of NAFLD in cardiovascular disease.36 Studies have shown NAFLD as an independent risk factor for cardiovascular disease events.37,38 The present study shows that, in the presence of all 5 components of the MetS, the risk of NAFLD may increase by as much 24 times compared with participants with no presence of Mets components. On the basis of these observations, it would be prudent to look for the presence of NAFLD in patients undergoing noncontrast CT
scans whenever images of liver and spleen are available on the scans.
4.1.
Limitations
First, this is a cross-sectional study that looked at the association of NAFLD with the components of MetS; this cannot be used to determine causality. Second, we used CT scan criteria of liver-to-spleen ratio and liver attenuation to determine the presence and severity of NAFLD. We did not perform liver biopsies to confirm the diagnosis of fatty liver. However, these criteria have been studied in comparison with histologic analyses for accuracy.28,31,32,39 We used liver attenuation values to define the presence and severity of liver fat content. There may be overlap present between the attenuation values of normal liver and mild steatosis. However, liver attenuation values < 40 HU can be reliably used to define the presence of moderate-to-severe steatosis.31
5.
Conclusion
NAFLD is rapidly gaining attention as a component of the MetS, as an independent risk factor for cardiovascular disease events, and as a possible cause for liver failure and cirrhosis. The present study shows that the prevalence of NAFLD may increase multiple folds with the presence of increasing components of the MetS in the middle-to-old age population, increasing their overall disease burden and also putting them at an increased risk of future adverse cardiovascular events and liver complications. This study also highlights the importance of central obesity in increasing the risk of developing NAFLD and the need to optimize weight for reducing the risk of NAFLD. It would be prudent to look for the presence of
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fatty liver on CT scans if the images for liver and spleen are available.
Acknowledgments We thank the Multi-Ethnic Study of Atherosclerosis publications and presentations committee (http://www.mesa-nhlbi. org) for their continued support in the preparation of the manuscript. This research was supported by the National Heart, Lung, and Blood Institute grant R01 HL071739 and contracts N01-HC95159 through N01-HC-95165 and N01-HC-95169.
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14. Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433e438. 15. Meigs JB. Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol. 2000;152:908e911. discussion 912. 16. James PT, Rigby N, Leach R. The obesity epidemic, metabolic syndrome and future prevention strategies. Eur J Cardiovasc Prev Rehabil. 2004;11:3e8. 17. Shirai K. Obesity as the core of the metabolic syndrome and the management of coronary heart disease. Curr Med Res Opin. 2004;20:295e304. 18. Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003;144:5159e5165. 19. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917e923. 20. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab. 1999;84:1513e1517. 21. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356e359. 22. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124e131. 23. Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol. 2002;156:871e881. 24. Becker U, Deis A, Sorensen TI, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996;23:1025e1029. 25. Coates RA, Halliday ML, Rankin JG, Feinman SV, Fisher MM. Risk of fatty infiltration or cirrhosis of the liver in relation to ethanol consumption: a case-control study. Clin Invest Med. 1986;9:26e32. 26. Carr JJ, Nelson JC, Wong ND, et al. Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology. 2005;234:35e43. 27. Lee SS, Park SH, Kim HJ, et al. Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations. J Hepatol. 2010;52:579e585. 28. Piekarski J, Goldberg HI, Royal SA, Axel L, Moss AA. Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease. Radiology. 1980;137:727e729. 29. Bydder GM, Chapman RW, Harry D, Bassan L, Sherlock S, Kreel L. Computed tomography attenuation values in fatty liver. J Comput Tomogr. 1981;5:33e35. 30. Kawata R, Sakata K, Kunieda T, Saji S, Doi H, Nozawa Y. Quantitative evaluation of fatty liver by computed tomography in rabbits. AJR Am J Roentgenol. 1984;142: 741e746. 31. Kodama Y, Ng CS, Wu TT, et al. Comparison of CT methods for determining the fat content of the liver. AJR Am J Roentgenol. 2007;188:1307e1312.
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32. Park SH, Kim PN, Kim KW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006;239:105e112. 33. Zeb I, Li D, Nasir K, Katz R, Larijani VN, Budoff MJ. Computed tomography scans in the evaluation of fatty liver disease in a population based study: the multi-ethnic study of atherosclerosis. Acad Radiol. 2012;19:811e818. 34. Maison P, Byrne CD, Hales CN, Day NE, Wareham NJ. Do different dimensions of the metabolic syndrome change together over time? Evidence supporting obesity as the central feature. Diabetes Care. 2001;24:1758e1763. 35. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004;27:2444e2449.
36. Omagari K, Kadokawa Y, Masuda J, et al. Fatty liver in nonalcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol. 2002;17:1098e1105. 37. Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13:1579e1584. 38. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341e1350. 39. Longo R, Ricci C, Masutti F, et al. Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography. Invest Radiol. 1993;28:297e302.
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Original Research Article
Relation of nonalcoholic fatty liver disease to the metabolic syndrome: The Multi-Ethnic Study of Atherosclerosis Irfan Zeb MDa,*, Ronit Katz DPhilb, Khurram Nasir MDc,d,e,f,g, Jingzhong Ding MDh, Panteha Rezaeian MDg, Matthew J. Budoff MDg a
Bronx-Lebanon Hospital Center, 1650 Grand Concourse, Bronx, NY 10457, USA University of Washington, Seattle, WA, USA c Center for Prevention and Wellness Research, Baptist Health Medical Group, Miami Beach, FL, USA d Department of Epidemiology, Robert Stempel College of Public Health, Florida International University, Miami, FL, USA e Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA f The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA g Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA h Wake Forest University, Winston-Salem, NC, USA b
article info
abstract
Article history:
Background: An overlap exists between risk factors for metabolic syndrome (MetS) and
Received 7 April 2013
nonalcoholic fatty liver disease (NAFLD).
Received in revised form
Objectives: We studied the association of MetS and its components with NAFLD in a multi-
11 August 2013
ethnic population.
Accepted 16 August 2013
Methods: Cross-sectional study was designed, including 6814 participants from the MultiEthnic Study of Atherosclerosis. Liver fat content was measured with cardiac CT scans
Keywords:
by using liver-to-spleen ratio of 14 drinks/week for men and >7 drinks/week for women), self-reported
Metabolic syndrome
history of cirrhosis, and missing information were excluded. A total of 4140 participants
MESA
met the criteria for inclusion in the study. Results: The odds ratios (ORs) for presence of NAFLD were highest for persons with diabetes (OR, 4.16; 95% CI, 3.24e5.33), followed by presence of MetS (OR, 3.97; 95% CI, 3.26e4.83). Among components of MetS central obesity was associated with higher odds for presence (OR, 3.41; 95% CI, 2.77e4.20) and severity (OR, 5.58; 95% CI, 3.86e8.06) of NAFLD . The ORs for moderate-to-severe NAFLD were higher for presence of MetS (OR, 5.92; 95% CI, 4.29e8.19)] by using 14 drinks/week for men and >7 drinks/week for women).24,25 For these analyses, we excluded persons with no available liver and spleen images on CT scan (N ¼ 2425), persons with heavy alcohol intake defined by >14 drinks/week for men and >7 drinks/week for women (N ¼ 220), and selfreported cirrhosis (N ¼ 7). We further excluded participants with missing MetS components (N ¼ 22), leaving a total sample size of 4140 persons. Medical history, anthropometric measurements, and CT scans for the present study were taken from the first examination of the MESA cohort (July 2000 to August 2002) as previously described. Information about demographic data, tobacco usage, alcohol consumption, medical conditions, and current use of prescription and nonprescription medications and supplements was obtained through a questionnaire at the baseline visit of the study. Alcohol consumption was defined according to the number of drinks per week. DM was defined as fasting blood glucose 126 mg/dL or use of insulin or oral hypoglycemic medications. Resting blood pressure was measured 3 times with participants in the seated position with a Dinamap model Pro 100 automated oscillometric sphygmomanometer (Critickon; General Electric, Madison, WI). The average of the last 2 measurements was used for analysis. Height and weight were measured with participants wearing light clothing and no shoes, and body mass index (BMI) was calculated (as weight divided by height squared; kg/m2). Waist and hip circumference data were also collected. Waist circumference at the umbilicus was measured to the nearest 0.1 cm with the use of a steel measuring tape (standard 4-ounce tension). For the present study, we used cardiac CT scans that covered images of the liver and spleen. MetS was defined by using criteria modified from the Third Adult Treatment Panel of the National Cholesterol Education Program, that is, 3 or more of the following: large waist circumference (women >88 cm and men >102 cm), elevated triglycerides (150 mg/dL), low HDL cholesterol (men 100 mm2 in area. Two ROIs were placed in the right liver lobe anterioposteriorly, one ROI in the left liver lobe, and one ROI in the spleen. ROIs with larger areas were used, whenever possible, to include a greater area of the liver and spleen while taking care to exclude regions of nonuniform parenchymal attenuation, including hepatic vessels (Fig. 1). Liver-to-spleen ratio was calculated by taking mean Hounsfield unit measurement of both right liver lobe ROIs and dividing it by the spleen Hounsfield unit measurement. Liverto-spleen ratio < 1.0 was taken as the cutoff for the diagnosis of presence of liver fat. As another parameter, liver attenuation < 40 HU was used as a cutoff of >30% liver fat content. Reproducibility of liver and spleen attenuation measurements were performed on 100 randomly selected participant scans measured by a single reader. The same reader repeated the measurements on those 100 scans for intrareader variability. The second reader performed measurements on the same 100 participant scans for inter-reader variability.
2.4.
Statistical analysis
NAFLD was defined by using liver-to-spleen ratio < 1.0 and liver attenuation < 40 HU. Comparisons among MetS, diabetes, and neither condition with demographic measures and cardiovascular risk factors are expressed with means and proportions. We used the c2 test for proportions and analysis of variance for comparing levels of continuous risk factors. We used multiple logistic regression to examine the prevalence of liver-to-spleen ratio < 1.0 and liver attenuation < 40 HU (ie, participants with NAFLD present at baseline) among the 3 disease groups (MetS, diabetes, and neither condition), adjusted for age, sex, and ethnicity and additionally for other
Fig. 1 e Prevalence of NAFLD by diabetes, MetS, or neither condition defined by L/S < 1.0 and liver attenuation > 40 HU. L/S, liver-to-spleen ratio; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease.
non-MetS risk factors (low-density lipoprotein [LDL] cholesterol, smoking, and lipid-lowering medications). We further examined the number of MetS risk factors (from none to all 5) and their association with prevalence of NAFLD, and we also examined the risk of NAFLD by number of MetS risk factors by using participants with 0 or 1 MetS risk factors as the reference group, because of the relatively small numbers. Statistical analyses were performed with SPSS 16.0.2 software for Windows (SPSS Inc, Chicago, IL). A P value < .05 was considered statistically significant. Confidence intervals are expressed as 95% CIs.
3.
Results
3.1.
Participant characteristics
Among the 4140 MESA participants 1859 (45%) were men; 10% self-identified as Chinese, 30% as black, and 23% as Hispanic; and mean age was 63 10 years. Overall, 1958 (47%) had hypertension, 554 (13%) had diabetes, and 1154 (28%) had MetS. Table 1 represents clinical information of the participants according to the presence of MetS, diabetes, or neither of these conditions and according to the individual components of the MetS. The prevalence of positive criteria for the MetS was highest for abdominal obesity and high blood pressure (85% and 82%, respectively), whereas IFG was the least prevalent (37%) among the MetS components.
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Table 1 e Characteristics of participants with diabetes, the ATP III MetS, or neither condition and individual components, in the MESA population.
Age, y, mean SD Female, n (%) Ethnicity White, n (%) Chinese American, n (%) African American, n (%) Hispanic, n (%) Income < $40,000, n (%) Glucose, mg/dL, mean SD BMI, mean SD Total cholesterol, mg/dL, mean SD HDL, mg/dL, mean SD LDL, mg/dL, mean SD Triglycerides, mg/dL, mean SD Lipid-lowering medications, n (%) Diastolic BP, mm Hg, mean SD Systolic BP, mm Hg, mean SD Antihypertensive medications, n (%) Current smoker, n (%) MetS components Abdominal obesity (large waist), n (%) High blood pressure, n (%) Low HDL, n (%) High triglycerides, n (%) Impaired fasting glucose, n (%)
Neither condition (n ¼ 2432)
MetS (n ¼ 1154)
Diabetes (n ¼ 554)
62 11 1292 (53)
64 10 709 (61)
65 10 280 (51)
973 (40) 251 (10) 720 (30) 488 (20) 1085 (47) 87 9 27.0 4.8 194 34 55 15 119 30 103 58 313 (13) 71 10 123 21 660 (27) 277 (11)
446 (39) 102 (9) 303 (26) 303 (26) 625 (57) 96 12 30.8 5.1 196 37 43 10 117 32 180 93 210 (18) 73 10 134 21 618 (54) 131 (11)
108 (20) 49 (9) 220 (40) 177 (32) 336 (65) 150 57 30.9 5.7 190 41 46 13 113 34 163 151 155 (28) 72 10 133 22 335 (64) 66 (12)
977 (40) 1073 (44) 417 (17) 268 (11) 144 (6)
982 (85) 943 (82) 861 (75) 734 (64) 432 (37)
397 (72) 435 (79) 294 (53) 241 (44) 554 (100)
ATP III, Third Adult Treatment Panel of the National Cholesterol Education Program; BMI, body mass index (calculated as weight divided by height squared; kg/m2); BP, blood pressure HDL, high-density lipoprotein; LDL, low-density lipoprotein; MESA, Multi-Ethnic Study of Atherosclerosis; MetS, metabolic syndrome.
3.2. Relationship of MetS and diabetes to NAFLD defined as liver-to-spleen ratio < 1.0 The prevalence of liver-to-spleen ratio < 1.0 in persons with MetS (28%) was similar to persons with diabetes (29%), and both were significantly different from persons with neither condition (P < .001) (Fig. 1). A graded linear relationship was found between the presence of liver-to-spleen ratio < 1.0 and the number of components of MetS. The liver-to-spleen ratio < 1.0 prevalence ranged from 6% in persons with none or 1 metabolic risk factor to 15%, 24%, 34%, and 41% in persons with 2, 3, 4, or 5 components, respectively (P < .001 for trend; Fig. 2). From the regression analyses, the odds ratio (OR) of liver-to-spleen ratio < 1.0 (compared with participants with neither condition) adjusted for age, sex, race, LDL, smoking, and use of lipid-lowering medications was significantly higher among participants with MetS and diabetes (OR, 3.97; 95% CI, 3.26e4.83 and OR, 4.16; 95% CI, 3.24e5.33, respectively; Table 2). When we looked at the components of the MetS, central obesity (OR, 3.41; 95% CI, 2.77e4.20) was associated with the highest OR for the presence of NAFLD, followed by IFG/DM (OR, 2.99; 95% CI, 2.49e3.59), high triglycerides (OR, 2.70; 95% CI, 2.27e3.23), low HDL (OR, 2.36; 95% CI, 1.99e2.80), and elevated blood pressure (OR, 1.97; 95% CI, 1.62e2.39) (Table 2). The OR for the presence of NAFLD increased with the increasing number of MetS components. The OR for the presence of NAFLD for 3 components of MetS was 5.22 (95% CI, 3.99e6.83) which increased to 13.29 (95% CI, 8.92e19.79) for the
presence of all 5 components of MetS components (Table 2). These results were adjusted for age, sex, ethnicity, LDL, smoking, and use of lipid-lowering medications.
3.3. Relationship of MetS and diabetes to NAFLD defined as liver attenuation < 40 HU When defining NAFLD as liver attenuation < 40 HU (a cutoff that represents presence of moderate-to-severe hepatic steatosis), the prevalence in persons with MetS (12%) was similar to persons with diabetes (11%), and both were significantly different from persons with neither condition (P < .001; Fig. 1). Again, we observed a graded linear relationship between the presence of liver attenuation < 40 HU and the number of components of MetS. The liver attenuation < 40 HU prevalence ranged from 1% in participants with none or 1 metabolic risk factor to 4%, 9%, 16%, and 18% in those with 2, 3, 4, or 5 components, respectively (P < .001 for trend; Fig. 2). Table 3 shows the results of the multivariable logistic regression analysis that looked at the association of NAFLD with MetS, diabetes, and components of MetS by using liver attenuation < 40 HU. The ORs for moderate-to-severe NAFLD were similar for the presence of MetS (OR, 5.92; 95% CI, 4.29e8.19) and diabetes (OR, 5.35; 95% CI, 3.57e8.01). Central obesity was associated with the highest OR for moderate-tosevere NAFLD (OR, 5.58; 95% CI, 3.86e8.06) followed by high triglycerides (OR, 3.34; 95% CI, 2.54e4.39), IFG (OR, 3.20; 95% CI, 2.42e4.23), elevated blood pressure (OR, 2.75; 95% CI,
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and 0.99, respectively) and spleen attenuation measurement (0.99 and 0.99, respectively).33
4.
Fig. 2 e Prevalence of NAFLD by number of components of MetS. L/S, liver-to-spleen ratio; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease.
2.02e3.75), and low HDL (OR, 2.55; 95% CI, 1.95e3.34). The ORs for presence of moderate-to-severe NAFLD increased with increasing numbers of components of MetS. The ORs were higher for presence of moderate-to-severe NAFLD: 9.49 (95% CI, 5.67e15.90) for the presence of 3 components and 24.05 (95% CI, 12.73e45.45) for the presence of all 5 components. The results were adjusted for age, sex, ethnicity, LDL, smoking, and used of lipid-lowering medications. Excellent correlation was observed for inter-reader and intrareader variability of liver attenuation measurement (0.96
Discussion
The present study highlights the increased likelihood of NAFLD with the presence of MetS and diabetes, as well as with the number of components of MetS. DM was associated with higher OR for the presence of NAFLD, followed by the MetS, whereas for moderate-to-severe NAFLD, MetS had the higher OR, followed by DM. This finding may imply that presence of moderate-to-severe NAFLD may require the presence of more MetS risk factors than DM alone. Marchesini et al19 assessed the prevalence of the MetS in 304 consecutive patients with NAFLD without overt diabetes and showed that hyperglycemia/DM was the only criteria among components of MetS that was significantly associated with nonalcoholic steatohepatitis (NASH) after adjustment for age, sex, and obesity. They also showed that MetS carried a high risk of NASH among subjects with NAFLD (OR, 3.2; 95% CI, 1.2e8.9; P ¼ .026) after correction for sex, age, and body mass, and the MetS was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1e11.2; P ¼ .032). When we assessed the association of individual components of MetS with the presence of NAFLD, central obesity was associated with the highest odds for NAFLD, followed by IFG/DM. Marceau et al20 showed waist-tohip ratio as the only anthropometric continuous variable to predict steatosis in severely obese subjects. Central obesity has been shown to play a major role in the pathogenesis of the MetS.34 The current therapeutic recommendations also recommend management of weight as one of the prime targets for treatment of NAFLD. We used waist circumference as a measure of central obesity rather than using BMI. BMI may not be a true indicator of central obesity. Marchesini et al10 found in their study that the waist circumference and
Table 2 e Cross-sectional associations of the MetS, components, and number of components of the MetS with L/S < 1. No.
Model 1* OR (95% CI)
Model 2y OR (95% CI)
Model 3z OR (95% CI)
226 (9) 325 (28) 160 (29)
1.00 (ref) 3.72 (3.07e4.49) 3.79 (3.00e4.79)
1.00 (ref) 3.95 (3.25e4.81) 4.19 (3.27e5.35)
1.00 (ref) 3.97 (3.26e4.83) 4.16 (3.24e5.33)
471 (19) 407 (26) 368 (30) 325 (29) 528 (22)
1.42 (1.20e1.69) 2.49 (2.11e2.95) 3.00 (2.53e3.55) 2.69 (2.26e3.19) 2.60 (2.16e3.13)
2.01 2.32 2.69 3.01 3.42
(1.66e2.44) (1.96e2.75) (2.26e3.20) (2.51e3.61) (2.78e4.21)
1.97 (1.62e2.39) 2.36 (1.99e2.80) 2.70 (2.27e3.23) 2.99 (2.49e3.59) 3.41 (2.77e4.20)
1.00 (ref) 2.49 (1.90e3.26) 4.48 (3.45e5.81) 7.19 (5.43e9.51) 10.59 (7.25e15.47)
1.00 2.84 5.18 8.59 13.22
(ref) (2.15e3.75) (3.96e6.78) (6.41e11.51) (8.90e19.66)
1.00 (ref) 2.86 (2.16e3.77) 5.22 (3.99e6.83) 8.68 (6.47e11.65) 13.29 (8.92e19.79)
Patients with LSR < 1, n (%)
MetS and DM Neither condition 2432 MetS 1154 DM 554 Components of the MetS Elevated BP 2451 Low HDL 1572 High TG 1243 IFG (100 mg/dL) 1130 Abdominal obesity 2356 No. of components of the MetS 0þ1 1490 2 1048 3 901 4 527 5 174
94 152 212 181 72
(6) (15) (24) (34) (41)
BP, blood pressure; DM, diabetes mellitus; IFG, impaired fasting glucose; HDL, high-density lipoprotein; L/S, liver-to-spleen ratio; LSR, liver-tospleen ratio; MetS, metabolic syndrome; OR, odds ratio; TG, triglyceride. * Unadjusted. y Adjusted for age, sex, ethnicity. z Adjusted for age, sex, ethnicity, LDL, smoking, and use of lipid-lowering medications.
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Table 3 e Cross-sectional associations of the MetS, components, and number of components of the MetS with liver attenuation < 40 HU. N
Model 1* OR (95% CI)
Model 2y OR (95% CI)
Model 3z OR (95% CI)
59 (2) 139 (12) 59 (11)
1.00 (ref) 5.34 (3.90e7.33) 4.40 (3.00e6.46)
1.00 (ref) 5.84 (4.23e8.06) 5.20 (3.49e7.74)
1.00 (ref) 5.92 (4.29e8.19) 5.35 (3.57e8.01)
180 160 155 126 212
(7) (10) (13) (11) (9)
1.64 (1.24e2.17) 2.76 (2.12e3.60) 3.78 (2.90e4.92) 2.65 (2.04e3.44) 3.91 (2.78e5.48)
2.74 2.52 3.30 3.16 5.53
2.75 (2.02e3.75) 2.55 (1.95e3.34) 3.34 (2.54e4.39) 3.20 (2.42e4.23) 5.58 (3.86e8.06)
19 43 81 83 31
(1) (4) (9) (16) (18)
1.00 (ref) 3.32 (1.92e5.73) 7.65 (4.61e12.71) 13.25 (7.91e22.19) 16.59 (9.02e30.51)
1.00 3.96 9.27 17.13 23.33
Patients with LSR < 1, n (%)
MetS and DM Neither condition 2432 MetS 1154 DM 554 Components of the MetS Elevated BP 2451 Low HDL 1572 High TG 1243 IFG (100 mg/dL) 1130 Abdominal obesity 2356 No. of components of the MetS 0þ1 1490 2 1048 3 901 4 527 5 174
(2.01e3.72) (1.92e3.29) (2.51e4.33) (2.39e4.16) (3.83e7.99) (ref) (2.28e6.88) (5.54e15.52) (10.09e29.08) (12.39e43.95)
1.00 (ref) 4.03 (2.32e7.00) 9.49 (5.67e15.90) 17.91 (10.52e30.49) 24.05 (12.73e45.45)
BP, blood pressure; DM, diabetes mellitus; IFG, impaired fasting glucose; HDL, high-density lipoprotein; LSR, liver-to-spleen ratio; MetS, metabolic syndrome; OR, odds ratio; TG, triglyceride. * Unadjusted. y Adjusted for age, sex, ethnicity. z Adjusted for age, sex, ethnicity, LDL, smoking, and use of lipid-lowering medications.
waist-to-hip ratio was higher for subjects with NAFLD than for subjects with diabetes despite similar BMI. They also found that in subjects with NAFLD, subjects with normal body weight had similar waist-to-hip ratio as those of overweight persons and larger than control subjects. This shows that subjects with NAFLD may have relatively increased visceral adiposity despite the normal body weight. The prevalence of MetS is increasing with increasing prevalence of obesity,35 and it may add to the overall burden to cardiovascular disease because of its association with cardiovascular disease. It would be important to look at the association of MetS and NAFLD in age groups in which the prevalence of MetS is higher. The persons included in the present study were 45 to 84 years of age (mean age, 64 10 years). The higher burden of cardiometabolic risk factors associated with MetS in this population put them at a higher risk of NAFLD. The importance for identifying NAFLD in this population group in 2-fold: First, NAFLD in the presence of necroinflammatory changes (NASH) is a progressive liver disease, resulting in liver failure and cirrhosis. In fact, a large percentage of cryptogenic cirrhosis cases are identified as being caused by NASH. The increasing prevalence of NAFLD in the presence of increased components of MetS, as is seen in the middle-to-old age population, would increase the number of cases of liver failure and cirrhosis caused by NAFLD. Second, a significant overlap exists between risk factors for atherosclerosis and NAFLD, supporting the role of NAFLD in cardiovascular disease.36 Studies have shown NAFLD as an independent risk factor for cardiovascular disease events.37,38 The present study shows that, in the presence of all 5 components of the MetS, the risk of NAFLD may increase by as much 24 times compared with participants with no presence of Mets components. On the basis of these observations, it would be prudent to look for the presence of NAFLD in patients undergoing noncontrast CT
scans whenever images of liver and spleen are available on the scans.
4.1.
Limitations
First, this is a cross-sectional study that looked at the association of NAFLD with the components of MetS; this cannot be used to determine causality. Second, we used CT scan criteria of liver-to-spleen ratio and liver attenuation to determine the presence and severity of NAFLD. We did not perform liver biopsies to confirm the diagnosis of fatty liver. However, these criteria have been studied in comparison with histologic analyses for accuracy.28,31,32,39 We used liver attenuation values to define the presence and severity of liver fat content. There may be overlap present between the attenuation values of normal liver and mild steatosis. However, liver attenuation values < 40 HU can be reliably used to define the presence of moderate-to-severe steatosis.31
5.
Conclusion
NAFLD is rapidly gaining attention as a component of the MetS, as an independent risk factor for cardiovascular disease events, and as a possible cause for liver failure and cirrhosis. The present study shows that the prevalence of NAFLD may increase multiple folds with the presence of increasing components of the MetS in the middle-to-old age population, increasing their overall disease burden and also putting them at an increased risk of future adverse cardiovascular events and liver complications. This study also highlights the importance of central obesity in increasing the risk of developing NAFLD and the need to optimize weight for reducing the risk of NAFLD. It would be prudent to look for the presence of
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fatty liver on CT scans if the images for liver and spleen are available.
Acknowledgments We thank the Multi-Ethnic Study of Atherosclerosis publications and presentations committee (http://www.mesa-nhlbi. org) for their continued support in the preparation of the manuscript. This research was supported by the National Heart, Lung, and Blood Institute grant R01 HL071739 and contracts N01-HC95159 through N01-HC-95165 and N01-HC-95169.
references
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