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Association of Coronary Artery Calcification With Hepatic Steatosis in Asymptomatic Individuals

  • Rajiv Chhabra
    Affiliations
    Department of Gastroenterology and Hepatology, Saint Luke's Hospital of Kansas City, Kansas City, MO

    Liver Disease Management Center and Division of Gastroenterology, Department of Medicine, Saint Luke's Hospital, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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  • James H. O’Keefe
    Affiliations
    Department of Gastroenterology and Hepatology, Saint Luke's Hospital of Kansas City, Kansas City, MO

    Saint Luke's Mid America Heart Institute, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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  • Harshal Patil
    Affiliations
    Saint Luke's Mid America Heart Institute, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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  • Evan O’Keefe
    Affiliations
    Saint Luke's Mid America Heart Institute, Kansas City, MO
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  • Randall C. Thompson
    Affiliations
    Department of Gastroenterology and Hepatology, Saint Luke's Hospital of Kansas City, Kansas City, MO

    Saint Luke's Mid America Heart Institute, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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  • Shaya Ansari
    Affiliations
    Department of Gastroenterology and Hepatology, Saint Luke's Hospital of Kansas City, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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  • Kevin F. Kennedy
    Affiliations
    Saint Luke's Mid America Heart Institute, Kansas City, MO
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  • Linda W. Lee
    Affiliations
    Department of Gastroenterology and Hepatology, Saint Luke's Hospital of Kansas City, Kansas City, MO

    Liver Disease Management Center and Division of Gastroenterology, Department of Medicine, Saint Luke's Hospital, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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  • John H. Helzberg
    Correspondence
    Correspondence: Address to John H. Helzberg, MD, Saint Luke's Transplant Specialists, 4320 Wornall Rd, Ste 240, Kansas City, MO 64111.
    Affiliations
    Department of Gastroenterology and Hepatology, Saint Luke's Hospital of Kansas City, Kansas City, MO

    Liver Disease Management Center and Division of Gastroenterology, Department of Medicine, Saint Luke's Hospital, Kansas City, MO

    School of Medicine, Department of Medicine, University of Missouri–Kansas City, Kansas City, MO
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Published:October 18, 2013DOI:https://doi.org/10.1016/j.mayocp.2013.06.025

      Abstract

      Objective

      To determine the association of coronary artery calcification with hepatic steatosis in asymptomatic volunteers.

      Patients and Methods

      The study group comprised 400 asymptomatic volunteers, enrolled from April 1, 2011, to September 30, 2012, without known coronary artery disease who were self-referred for screening noncontrast computed tomography to determine coronary calcium score (CCS). Computed tomographic images were used to determine the presence of hepatic steatosis. An a priori model was created to predict a CCS of 100 Agatston units (AU) or higher on the basis of Framingham risk factors, diabetes mellitus, and metabolic syndrome. Hepatic steatosis was then added to this model. Computation of the odds ratio (OR) for hepatic steatosis predicting a CCS of 100 AU or higher was performed. Finally, the OR for a CCS of 100 AU or higher being associated with hepatic steatosis was calculated.

      Results

      When hepatic steatosis was added to traditional coronary risk factors, it was independently associated with a CCS of 100 AU or higher (OR, 2.85). This was greater than the OR of Framingham factors, diabetes mellitus, or metabolic syndrome. A CCS of 100 AU or higher was independently associated with an increased risk for hepatic steatosis (OR, 2.4). This OR was higher than traditional hepatic steatosis risk factors or metabolic syndrome.

      Conclusion

      Hepatic steatosis is a strong independent predictor of a CCS of 100 AU or higher in asymptomatic patients. It is associated with an increased risk of coronary artery disease beyond that expected from traditional coronary risk factors and/or metabolic syndrome. Additional studies are needed to clarify the role of hepatic steatosis as a possible independent risk factor for the development of coronary artery disease.

      Abbreviations and Acronyms:

      AU (Agatston units), BMI (body mass index), CAC (coronary artery calcium), CAD (coronary artery disease), CCS (coronary calcium score), CT (computed tomography), DM (diabetes mellitus), IDI (integrated discrimination improvement), LDL-C (low-density lipoprotein cholesterol), NAFLD (nonalcoholic fatty liver disease), OR (odds ratio)
      Nonalcoholic fatty liver disease (NAFLD) has histologic features similar to alcoholic liver disease, although it is found in patients who consume little or no alcohol. Approximately 34% of adults in the United States have NAFLD, although most affected individuals are unaware of their liver disease.
      • Adams L.A.
      • Angulo P.
      • Lindor K.D.
      Nonalcoholic fatty liver disease.
      Up to 70% to 90% of patients with the metabolic syndrome have NAFLD as assessed by cardiometabolic risk factors, including obesity, type 2 diabetes mellitus (DM), hypertension, and atherogenic dyslipidemia.
      • Targher G.
      • Bertolini L.
      • Padovani R.
      • et al.
      Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes.
      Nonalcoholic fatty liver disease is considered to be the hepatic manifestation of the metabolic syndrome. Most cases of NAFLD are discovered in individuals between the ages of 30 and 60 years, although NAFLD is also described with increasing frequency in obese children and adolescents. Often NAFLD is unrecognized clinically, and thus substantial time often elapses until the diagnosis is established. The spectrum of NAFLD ranges from simple steatosis to steatohepatitis with associated fibrosis, cirrhosis, and occasionally development of hepatocellular carcinoma. The pathogenesis of NAFLD is incompletely understood, but postprandial hypertriglyceridemia and insulin resistance have been implicated as likely major pathogenic mechanisms that lead to steatosis. However, a second hit from additional oxidative injury is possibly required to manifest the necroinflammatory component of steatohepatitis.
      • Marchesini G.
      • Brizi M.
      • Morselli-Labate A.M.
      • et al.
      Association of nonalcoholic fatty liver disease with insulin resistance.
      • Marchesini G.
      • Bugianesi E.
      • Forlani G.
      • et al.
      Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.
      The association between NAFLD and metabolic syndrome is increasingly recognized. Given the strong association between NAFLD and metabolic syndrome risk factors, patients with NAFLD would be expected to have an increased risk of coronary artery disease (CAD). Furthermore, NAFLD may be not only a marker but also a causal mediator of CAD, generating systemic inflammation that triggers an increased CAD risk beyond that expected from conventional metabolic syndrome risk factors.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • et al.
      Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients.
      • Targher G.
      • Arcaro G.
      Non-alcoholic fatty liver disease and increased risk of cardiovascular disease.
      • Adibi P.
      • Sadeghi M.
      • Mahsa M.
      • Rozati G.
      • Mohseni M.
      Prediction of coronary atherosclerotic disease with liver transaminase level.
      • Targher G.
      • Day C.P.
      • Bonora E.
      Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
      Computed tomography (CT) is an accurate imaging modality to detect and characterize hepatic steatosis. The CT diagnosis of hepatic steatosis is confirmed by measuring the difference in liver and spleen attenuation values. A liver density that is 10 or more Hounsfield units less than splenic density defines the CT validation of hepatic steatosis.
      • Piekarski J.
      • Goldberg H.I.
      • Royal S.A.
      • Axel L.
      • Moss A.A.
      Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease.
      A meta-analysis that compared the diagnostic accuracy of ultrasonography, CT, magnetic resonance imaging, and magnetic resonance spectroscopy for the evaluation of hepatic steatosis compared with liver biopsy revealed CT to have a sensitivity of 72% and specificity of 95%.
      • Bohte A.E.
      • van Werven J.R.
      • Bipat S.
      • Stoker J.
      The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis.
      Coronary artery calcification, as quantified by cardiac CT, is a highly sensitive marker of coronary atherosclerosis that also is a strong independent predictor of future cardiac events.
      • Budoff M.J.
      • Achenbach S.
      • Blumenthal R.S.
      • et al.
      Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology.
      • Budoff M.J.
      • Shaw L.J.
      • Liu S.T.
      • et al.
      Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.
      Cardiac CT with multidetector row CT has enabled the acquisition of thin sections of the heart and coronary arteries gated to diastole to minimize coronary motion. The total coronary calcium score (CCS) is a precise surrogate for the overall coronary plaque burden. Multiple studies have found an incremental predictive value of the CCS over the Framingham risk score in both symptomatic and asymptomatic patients.
      • Budoff M.J.
      • Shaw L.J.
      • Liu S.T.
      • et al.
      Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.
      It has been recently reported that among all the novel coronary risk markers, coronary artery calcium (CAC) as assessed by CT was the most accurate for predicting risk of future adverse coronary events.
      • Yeboah J.
      • McClelland R.L.
      • Polonsky T.S.
      • et al.
      Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.
      The aims of this study were to determine the association of CAC with NAFLD in asymptomatic individuals and to determine whether NAFLD confers additional predictive risk of CAC beyond conventional cardiac risk factors.

      Patients and Methods

      A cross-sectional study was performed with enrollment of 400 asymptomatic volunteers, enrolled from April 1, 2011, to September 30, 2012, who were self-referred for routine screening coronary CT scans to determine the CCS. Written informed consent was obtained from all participants. The protocol was approved by the Institutional Review Board of Saint Luke’s Hospital of Kansas City, Missouri (protocol 10-515; principal investigator: J.H.H.). A total of 22 patients were excluded for failing to obtain the required blood procurement. One patient who tested positive for hepatitis C was also excluded.
      The coronary scans were interpreted by experienced cardiologists specializing in coronary CT imaging. The CT scans of the liver and spleen were interpreted by a masked abdominal imaging radiologist (S.A.), who determined the presence of hepatic steatosis by measuring the difference in liver and spleen attenuation values. Portions of the liver and spleen were included on the CT scans. Hepatic steatosis was defined by liver density that was 10 or more Hounsfield units less than splenic density. Statistical analysis of coronary calcium scans, blood tests, and CT liver attenuation values was performed to determine the association of CAC in patients with NAFLD.

      Inclusion and Exclusion Criteria

      Asymptomatic consecutive patients undergoing screening cardiac CT for coronary risk assessment were asked whether they would like to enroll in a study that assessed fatty liver as a possible cardiac risk factor. Volunteers older than 18 years with no history of liver disease were allowed to enroll after written informed consent to participate in the study protocol was obtained. Body mass index (BMI) (calculated as the weight in kilograms divided by the height in meters squared) was calculated at the time of the enrolling visit. Patients with any history of underlying liver disease, positive hepatitis B or C serologic test results, or those with consumption of more than one alcoholic beverage daily were excluded.
      Patients who agreed to participate in the study were asked to complete a questionnaire (Supplemental Appendix, available online at http://www.mayoclinicproceedings.org) and undergo a single blood procurement to evaluate liver enzymes and fasting lipid profile and to determine past exposure to hepatitis B or C.
      All studies were performed on a definition dual–source CT scanner (Siemens Corporation). The CT protocol was as follows: sequential sections 3 mm in thickness, tube voltage of 120 kV, and scan length from the carina to just distal to the inferior edge of the left ventricle (including the upper portion of the liver and spleen), with automatically adjusted tube current. Section thickness reconstructions of 3 mm were viewed for CCS and clinical cardiology review. The inferior portion of the CT scan field was reconstructed at 6-mm section thickness for measurement of liver and spleen density. The mean ± SD radiation dose was 0.96±0.20 mSv.

      Outcome Variable

      Significant CAD was defined as a CCS of 100 Agatston units (AU) or higher.
      • Rumberger J.A.
      • Brundage B.H.
      • Rader D.J.
      • Kondos G.
      Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons.
      The anticipated frequency in our population was 30%. In similar studies, the event rate of a CCS of 100 AU or greater was 30%.
      • Bybee K.A.
      • Lee J.
      • Markiewicz R.
      • et al.
      Diagnostic and clinical benefit of combined coronary calcium and perfusion assessment in patients undergoing PET/CT myocardial perfusion stress imaging.

      Traditional Predictor Variables

      Six a priori traditional risk factors for CAD were selected: age, sex, smoking, low-density lipoprotein cholesterol (LDL-C), hypertension, and DM, in addition to metabolic syndrome. Metabolic syndrome was defined using the Adult Treatment Panel III or World Health Organization criteria.
      • Wilson P.W.
      • D'Agostino R.B.
      • Levy D.
      • Belanger A.M.
      • Silbershatz H.
      • Kannel W.B.
      Prediction of coronary heart disease using risk factor categories.

      Statistical Analyses

      Continuous data are given as mean ± SD and compared with the t test, and categorical data are given as number (percentage) and compared with a χ2 test. Two a priori analyses were conducted. The first analysis was predicting a CCS of 100 AU or higher after adjusting for the traditional predictor variables with hepatic steatosis as the primary independent variable. The second analysis was deriving predictors of hepatic steatosis after forcing in the model age, LDL-C, DM, BMI, and metabolic syndrome. From the first aim, we tested the incremental utility of hepatic steatosis by computing odds ratios (ORs) from a logistic regression model and by calculating the integrated discrimination improvement (IDI) index.
      • Pencina M.J.
      • D'Agostino Sr, R.B.
      • D'Agostino Jr., R.B.
      • Vasan R.S.
      Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
      The second aim also used a logistic regression model, and output is reported with ORs and 95% CIs. Using estimates from prior studies, the sample size of approximately 300 would have 80% power to detect an OR of 2.5 in the primary predictor variable. All analyses were conducted with SAS statistical software, version 9.3 (SAS Institute Inc).

      Results

      A total of 400 patients were enrolled in the study; 22 patients were excluded because they did not complete the laboratory blood procurement. One patient was excluded after his serologic test found circulating hepatitis C antibody. Thus, 377 patients were included in the final analysis (Table). The mean ± SD age of the patients was 57.1±9.7 years. Whites were the major ethnic group, representing 88.3% of the patients, and 196 (52%) of patients were male. Sixty-eight of the 377 patients (18.0%) enrolled had a CCS of 100 AU or higher. Hepatic steatosis was present on CT scans in 43 patients (11.4%). Metabolic syndrome was present in 56 patients (14.9%). The mean CCS was 108.8 AU.
      TableCharacteristics of the Study Population
      ALT = alanine aminotransferase; AST = aspartate aminotransferase; AU = Agatston units; BMI = body mass index; CCS = coronary calcium score; LDL-C = low-density lipoprotein cholesterol.
      ,
      SI conversion factors: To convert ALT, AST, and alkaline phosphatase values to μkat/L, multiply by 0.0167; to convert bilirubin values to μmol/L, multiply by 17.104; to convert total cholesterol and LDL-C values to mmol/L, multiply by 0.0259; and to convert triglyceride values to mmol/L, multiply by 0.0113.
      CharacteristicTotal patients
      Data are presented as No. (percentage) of patients or mean +/− SD unless otherwise indicated.
      (N=377)
      CCS ≥100 AU
      Data are presented as No. (percentage) of patients or mean +/− SD unless otherwise indicated.
      P value
      Yes (n=68)No (n=309)
      Age (y)57.09±9.7162.37±8.5155.95±9.59<.001
      Dyslipidemia135 (35.8)38 (55.9)97 (31.4)<.001
      BMI29.28±6.8530.59±8.0328.99±6.54.08
      Male196 (52.0)46 (67.6)150 (48.5).004
      White333 (88.3)62 (91.2)271 (87.7).42
      Metabolic syndrome56 (14.9)19 (27.9)37 (12.0)<.001
      Prior coronary artery disease000
      Hypertension139 (36.9)36 (52.9)103 (33.3).002
      History of liver disease6 (1.6)1 (1.5)5 (1.6).93
      History of viral hepatitis1 (0.3)01 (0.3).64
      Alcohol use233 (61.8)46 (67.6)187 (60.5).27
      Diabetes mellitus41 (10.9)14 (20.6)27 (8.8).005
      Smoking116 (30.8)27 (39.7)89 (28.8).09
      AST (U/L)29.76±11.8532.29±10.1229.20±12.14.051
      ALT (U/L)38.21±99.5235.84±15.1538.74±109.73.83
      Alkaline phosphatase (U/L)76.18±21.0876.79±21.8876.04±20.93.79
      Bilirubin (mg/dL)0.75±0.330.81±0.390.73±0.31.08
      Total cholesterol (mg/dL)197.83±38.78195.26±40.70198.40±38.39.55
      LDL-C (mg/dL)112.20±34.65108.70±36.87112.96±34.16.36
      Triglycerides (mg/dL)148.84±116.68171.10±98.35143.94±119.92.08
      Hepatic steatosis43 (11.4)15 (22.1)28 (9.1).002
      CCS ≥100 AU108.81±392.63554.39±785.4710.75±22.35<.001
      ALT >30 U/L175 (46.4)42 (61.76)133 (43.0).005
      LDL-C >70 U/L329 (87.3)55 (80.9)274 (88.7).08
      Triglycerides >150 U/L131 (34.7)34 (50.0)97 (31.4).004
      a ALT = alanine aminotransferase; AST = aspartate aminotransferase; AU = Agatston units; BMI = body mass index; CCS = coronary calcium score; LDL-C = low-density lipoprotein cholesterol.
      b SI conversion factors: To convert ALT, AST, and alkaline phosphatase values to μkat/L, multiply by 0.0167; to convert bilirubin values to μmol/L, multiply by 17.104; to convert total cholesterol and LDL-C values to mmol/L, multiply by 0.0259; and to convert triglyceride values to mmol/L, multiply by 0.0113.
      c Data are presented as No. (percentage) of patients or mean +/− SD unless otherwise indicated.
      When hepatic steatosis was added to the traditional cardiac risk factor model, it was independently associated with greater risk of a CCS of 100 AU or higher (OR, 2.85; 95% CI, 1.26-6.44; P=.01). This OR was greater than the OR of all Framingham risk factors or from DM or metabolic syndrome (Figure 1). Compared with the model that used only traditional coronary risk factors, the addition of hepatic steatosis nonsignificantly increased the C statistic (0.776 vs 0.789; P=.31), although the C statistic of 0.789 implies good discrimination. However, the IDI index was significant (absolute IDI index, 0.17; relative IDI index, 13.6%; P=.04). This finding indicated that the spread in predicted probabilities between a CCS of 100 AU or higher and a CCS of 100 AU or lower was separated by an additional 14% after inclusion of hepatic steatosis. In addition, a CCS of 100 AU or higher was independently associated with an increased risk of the presence of hepatic steatosis (OR, 2.45; 95% CI, 1.08-5.54; P=.03), with a good discriminant C statistic of 0.761. This OR was higher than that from metabolic syndrome, DM, BMI, increased age, or dyslipidemia (Figure 2).
      Figure thumbnail gr1
      Figure 1Odds ratios of age, sex, traditional Framingham risk factors, metabolic syndrome, and hepatic steatosis with coronary artery disease. Coronary artery disease was defined by a coronary calcium score of 100 Agatston units or higher on noncontrast computed tomography screening. LDL-C = low-density lipoprotein cholesterol.
      Figure thumbnail gr2
      Figure 2Odds ratios of coronary artery disease, age, dyslipidemia, diabetes, metabolic syndrome, and body mass index (BMI) with hepatic steatosis. Hepatic steatosis was defined by liver density that was 10 or more Hounsfield units less than splenic density. LDL-C = low-density lipoprotein cholesterol.

      Discussion

      To our knowledge, this is the first study in a US population to report hepatic steatosis, or NAFLD, to be an independent predictor of CAC in asymptomatic patients in a cross-sectional multivariate analysis. Moreover, our OR of 2.85 was significantly higher than that reported in a large retrospective study from Korea, in which the OR was 1.84.
      • Kim D.
      • Choi S.Y.
      • Park E.H.
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      Nonalcoholic fatty liver disease is associated with coronary artery calcification.
      Additional studies from Taiwan, Brazil, and Korea have reported lesser OR associations of 1.24, 1.68, and 2.46, respectively.
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      Hepatic steatosis is associated with a greater prevalence of coronary artery calcification in asymptomatic men.
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      The presence of hepatic steatosis and CAD may be linked because both represent severe end-organ damage related to metabolic syndrome. However, NAFLD and particularly steatohepatitis are likely to promote a proinflammatory milieu that is often highly pathogenic. In addition to being predictive for the prevalence of CAD, NAFLD, steatohepatitis, and steatocirrhosis have all been associated with an increased risk of liver cancer and exogenous malignant tumors outside the liver.
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      The prevalence of NAFLD is considerably higher in patients with acute myocardial infarction compared with the general population. In addition, the presence of NAFLD has been associated with a greater severity of CAD in patients previously undergoing coronary angiography. The findings appear to be independent of patients’ age, sex, and BMI.
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      In addition, increased oxidative stress and chronic, subclinical inflammation may be responsible for the progression from simple steatosis to steatohepatitis and cirrhosis. Reactive oxygen species generated by steatosis stimulate fatty acid oxidation, attendant hepatocyte injury, and cytokine release. The ensuing proinflammatory milieu is likely to perpetuate the liver damage of NAFLD and add further atherogenic stimuli to the baseline high oxidative stress and proinflammatory status conferred by the metabolic syndrome.
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      Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?.
      We attempted to eliminate bias by masking the results of the presence of NAFLD and CCS of 100 AU or higher computations by separate groups of specialized coronary imaging cardiologists and one abdominal imaging radiologist, who interpreted the CT scans. The clinical data were collected separately and given to the hepatologists. Results were then analyzed independently, after delivery of the data to the statistician for analysis.
      Finally, this study also found that a CCS of 100 AU or higher in multivariate analysis is a risk factor for the presence of hepatic steatosis (Figure 2). The OR of a CCS of 100 AU or higher was, in fact, greater than age, LDL-C, BMI, or the presence of DM or metabolic syndrome for the presence of NAFLD. Therefore, in patients with CAD and especially those with obesity, metabolic syndrome, or type 2 DM, screening for hepatic steatosis, steatohepatitis, and cirrhosis should be considered.

      Conclusion

      Hepatic steatosis is a strong independent predictor for the presence of calcified plaque in the coronary arteries of asymptomatic patients. In this analysis, it was a stronger predictor for CAC than age, sex, smoking history, LDL-C, DM, or the metabolic syndrome. Therefore, NAFLD is associated with a significantly increased risk of a CCS of 100 AU or higher, beyond that expected from traditional coronary risk factors or metabolic syndrome. Additional studies are needed to clarify the role of hepatic steatosis in comprehensive coronary heart disease risk assessment and possible pathogenesis of CAD.

      Acknowledgment

      We thank Lori J. Wilson for her support in the preparation of the submitted manuscript. Drs Chhabra and Helzberg are coauthors who contributed equally in the manuscript production.

      Supplemental Online Material

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