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Hepatology
Original article
Non-alcoholic fatty liver disease and progression of coronary artery calcium score: a retrospective cohort study
  1. Dong Hyun Sinn1,
  2. Danbee Kang2,
  3. Yoosoo Chang3,4,5,
  4. Seungho Ryu3,4,5,
  5. Seonhye Gu6,
  6. Hyunkyoung Kim6,
  7. Donghyeong Seong2,
  8. Soo Jin Cho7,
  9. Byoung-Kee Yi2,8,
  10. Hyung-Doo Park9,
  11. Seung Woon Paik1,
  12. Young Bin Song1,10,
  13. Mariana Lazo10,
  14. Joao A C Lima10,
  15. Eliseo Guallar10,
  16. Juhee Cho2,3,5,10,
  17. Geum-Youn Gwak1
  1. 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
  2. 2Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
  3. 3Center for Cohort Studies, Total Healthcare Screening Center, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, South Korea
  4. 4Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, South Korea
  5. 5Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
  6. 6Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
  7. 7Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
  8. 8Department of Medical Informatics, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
  9. 9Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
  10. 10Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, USA
  1. Correspondence to Professor Geum-Youn Gwak, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul 06351, South Korea; gy.gwak{at}samsung.com or Professor Juhee Cho, Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-Gu, 06351, Seoul, South Korea; jcho{at}skku.edu

Abstract

Background and aim Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, was associated with subclinical atherosclerosis in many cross-sectional studies, but the prospective association between NAFLD and the progression of atherosclerosis has not been evaluated. This study was conducted to evaluate the association between NAFLD and the progression of coronary atherosclerosis.

Methods This retrospective cohort study included 4731 adult men and women with no history of cardiovascular disease (CVD), liver disease or cancer at baseline who participated in a repeated regular health screening examination between 2004 and 2013. Fatty liver was diagnosed by ultrasound based on standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls. Progression of coronary artery calcium (CAC) scores was measured using multidetector CT scanners.

Results The average duration of follow-up was 3.9 years. During follow-up, the annual rate of CAC progression in participants with and without NAFLD were 22% (95% CI 20% to 23%) and 17% (16% to 18%), respectively (p<0.001). The multivariable ratio of progression rates comparing participants with NAFLD with those without NAFLD was 1.04 (1.02 to 1.05; p<0.001). The association between NAFLD and CAC progression was similar in most subgroups analysed, including in participants with CAC 0 and in those with CAC >0 at baseline.

Conclusions In this large cohort study of adult men and women with no history of CVD, NAFLD was significantly associated with the development of CAC independent of cardiovascular and metabolic risk factors. NAFLD may play a pathophysiological role in atherosclerosis development and may be useful to identify subjects with a higher risk of subclinical disease progression.

  • CARDIOVASCULAR DISEASE
  • FATTY LIVER
  • FIBROSIS
  • ULTRASONOGRAPHY

https://doi.org/10.1136/gutjnl-2016-311854

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    Significance of this study

    What is already known on this subject?

    • Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome.

    • NAFLD is associated with an increased risk of diabetes and metabolic syndrome, both established risk factors for cardiovascular disease.

    • In cross-sectional studies, NAFLD is associated with subclinical atherosclerosis, but the prospective association between NAFLD and the progression of atherosclerosis has not been evaluated.

    What are the new findings?

    • NAFLD is associated with the progression of coronary atherosclerosis, independent of cardiovascular and metabolic risk factors.

    • The association was evident in most subgroups analysed, including in participants with coronary artery calcium (CAC) 0 and in those with CAC >0 at baseline.

    How might it impact on clinical practice in the foreseeable future?

    • NAFLD may be useful to identify subjects with a higher risk of subclinical coronary atherosclerosis progression.

    • Interventions that reduce the prevalence of NAFLD may reduce the progression of CAC.

    Introduction

    Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic abnormality tightly linked to the overweight and obesity epidemic.1 ,2 NAFLD can progress to liver cirrhosis and liver cancer, but its clinical burden is not confined to the liver. NAFLD is considered a hepatic manifestation of the metabolic syndrome, and the presence and severity of NAFLD are associated with an increased prevalence and incidence of cardiovascular disease (CVD).3 ,4 Several large retrospective and prospective studies have shown that NAFLD is associated with increased risk of CVD morbidity and mortality, independent of established CVD risk factors.5–7 A meta-analysis of 16 observational prospective and retrospective studies demonstrated that NAFLD is significantly associated with an increased risk of fatal and non-fatal cardiovascular events.8 Furthermore, a meta-analysis of 27 cross-sectional studies reported a strong independent association between NAFLD and several markers of subclinical atherosclerosis,9 but no prospective data are available evaluating the association between NAFLD and the progression of subclinical markers of atherosclerosis.

    In this study we thus aimed to assess the longitudinal independent association of NAFLD with the progression of coronary atherosclerosis measured as coronary artery calcium (CAC) scoring with CT. CAC scores are strongly associated with the extent of coronary atherosclerosis and independently predict future risk of CVD events.10 CAC progression is associated with worsening coronary atherosclerosis and may help predict future coronary events.11 Indeed, progression of CAC is strongly associated with the development of incident coronary heart disease and all-cause mortality with an approximately linear dose–response relationship, even after adjusting for traditional cardiovascular risk factors.12 ,13 Therefore, we compared the progression of CAC scores in participants with and without NAFLD at baseline in a large sample of apparently healthy Korean men and women who participated in a health screening examination programme.

    Methods

    Study population

    We conducted a retrospective cohort analysis of men and women of 18 years of age or older who underwent a comprehensive health screening examination at the Samsung Medical Center Health Promotion Center in Seoul, South Korea, from 1 March 2004 to 31 December 2013 (figure 1). As our objective was to evaluate the association between NAFLD and the change in CAC score, the analysis was restricted to subjects who underwent at least two screening examinations including both a coronary CT scan and an abdominal ultrasound (US) (n=9271). We then excluded participants who had any of the following conditions: alcohol intake ≥30 g/day in men or ≥20 g/day in women (n=2942), history of liver cirrhosis or positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies (n=564), history of CVD (n=470) or cancer (n=205), use of aspirin (n=1425), warfarin (n=21) or antithrombotic medications (n=21), or having missing information on body mass index (BMI) or blood pressure (n=304). As study participants could have more than one exclusion criteria, the final sample size was 4731 (4307 men and 424 women). The Institutional Review Board of the Samsung Medical Center approved this study and waived the requirement for informed consent as we used only deidentified data routinely collected during health screening visits.

    Figure 1
    Figure 1

    Flow chart of study participants (n=4731).

    Data collection

    At each visit, demographic characteristics, smoking status, alcohol consumption, medical history and medication use were collected through standardised, self-administered questionnaires. Smoking status was categorised into never, former or current smoker. Alcohol consumption was categorised into none or moderate (<30 g/day in men and <20 g/day in women). Height, weight, waist circumference and sitting blood pressure were measured by trained nurses. BMI was calculated as weight in kilograms divided by height in metres squared. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, a self-reported history of hypertension, or current use of antihypertensive medications. Diabetes mellitus was defined as a fasting serum glucose ≥126 mg/dL, a self-reported history of diabetes or self-reported use of insulin or antidiabetic medications.

    Serum total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were determined with an enzymatic colorimetric method. Serum glucose was measured by the hexokinase/glucose-6-phosphate dehydrogenase method. Haemoglobin A1c (HbA1C) was measured by high-performance liquid chromatography. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyltransferase were measured following the International Federation of Clinical Chemistry method. Insulin was measured by immunoradiometric assay. Serum creatinine levels were measured with the kinetic alkaline picrate method (Jaffe method) in an automated chemistry analyser. Diabetes mellitus was defined as a fasting serum glucose ≥126 mg/dL, a self-reported history of diabetes or self-reported use of insulin or antidiabetic medications. We also calculated NAFLD fibrosis score as an index of liver fibrosis. The NAFLD fibrosis score was calculated as −1.675+0.037×age (years)+0.094×BMI (kg/m2)+1.13×impaired fasting glucose/diabetes (yes=1, no=0)+0.99×AST/ALT ratio−0.013×platelet count (×109/L)−0.66×albumin (g/dL).14 A low NAFLD fibrosis score (<−1.455) is a strong predictor of the absence of liver fibrosis.14 The Department of Laboratory Medicine and Genetics at Samsung Medical Center has participated in several proficiency testing programmes operated by the Korean Association of Quality Assurance for Clinical Laboratory, the Asian Network of Clinical Laboratory Standardization and Harmonization and the College of American Pathologists.

    Abdominal US

    The written reports for fatty liver of abdominal US were used for this study. Abdominal US were performed using LogiQ E9 (GE Healthcare, Milwaukee, Wisconsin, USA), iU22 xMatrix (Philips Medical Systems, Cleveland, Ohio, USA) or ACUSON Sequoia 512 equipments (Siemens, Issaquah, Washington, USA) by experienced radiologists unaware of the study aims. Images were captured in a standard fashion with the patient in the supine position with the right arm raised above the head. An US diagnosis of fatty liver was made based on standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls.15 ,16 Since we had already excluded participants with excessive alcohol use (≥30 g/day for men and ≥20 g/day for women) as well as other identifiable causes of fatty liver at baseline as described in the exclusion criteria, fatty liver was considered NAFLD.

    Coronary CT scans

    Imaging data for the evaluation of CAC were acquired using Brilliance 40 (Philips Medical Systems), VCT LightSpeed 64 (GE Healthcare) or Discovery 750HD (GE Healthcare) multidetector CT scanners. The analysis of the scans was performed on Extended Brilliance Workspace (Philips Medical Systems) or Advantage (GE Healthcare) workstations. CAC scores were calculated as described by Agatston et al.17

    Statistical analysis

    We compared the quantitative progression of CAC scores in participants with and without NAFLD at baseline using linear mixed models for longitudinal data with random intercepts and random slopes.18 Since CAC scores are markedly right skewed, the primary analysis used loge-transformed (CAC+1) as the outcome and estimated the ratio of the annual progression rates of CAC scores (with 95% CIs) comparing participants with NAFLD with those without NAFLD at baseline. As a secondary analysis, we used untransformed CAC scores (natural scale) to estimate the average difference in the annual progression of CAC scores in Agatston units (with 95% CI) comparing participants with and without NAFLD at baseline.18

    We used four models with increasing degrees of adjustment to account for potential confounding factors at baseline. Model 1 was adjusted for age and sex. Model 2 was further adjusted for smoking and alcohol consumption. In addition, to evaluate potential mediation of the association between NAFLD and CAC progression by metabolic factors, model 3 was further adjusted for BMI, systolic blood pressure, total and HDL cholesterol, triglycerides (loge transformed), presence of diabetes, use of antihypertensive medication, use of lipid-lowering drugs, HbA1C and estimated glomerular filtration rate. Model 4 was further adjusted for time-dependent BMI, antihypertensive medications and lipid-lowering drugs. Interaction analysis was used to evaluate if the association of NAFLD with CAC progression differed in prespecified subgroups.

    Since participants in our analyses had to have at least two screening visits, we used inverse probability weights (IPWs) to correct for potential selection bias in this group. IPWs reweight study participants so that participants who are similar to those lost to follow-up after the first coronary CT are given a higher weight. IPWs were obtained from a logistic regression model including all screenees with at least one coronary CT scan and similar selection criteria to those used in this analysis (n=12 097). All analyses reported were corrected for IPWs (weighted and unweighted results were very similar). As an additional sensitivity analysis, we repeated the analysis based on the sample of participants with at least one coronary CT scan using the same mixed models as described above, but the results were also very similar (not shown).18

    All reported p values were two-sided and the significance level was set at 0.05. All analyses were performed using STATA V.13 (StataCorp LP, College Station, Texas, USA).

    Results

    The baseline characteristics of study participants are shown in table 1. The mean (SD) age of study participants was 52.2 (7.1) years, and the prevalence of NAFLD at baseline was 44.1% (n=2088). Compared with participants without NAFLD, those with NAFLD were more likely to be males, smokers, metabolically unhealthy and to have a higher BMI and total cholesterol levels. The median CAC score at baseline was 2.0 (54.2% participants had a CAC score >0). CAC scores at baseline were higher in participants with NAFLD compared with those without NAFLD at baseline (median values: 4.0 vs 1.0, p<0.001). The multivariable adjusted CAC score ratio comparing participants with NAFLD with those without NAFLD was 5.0 (95% CI 2.9 to 7.1, p<0.001).

    View this table:
    Table 1

    Characteristics of study participants by non-alcoholic fatty liver status at baseline (n=4731)

    The average duration of follow-up was 3.9 years (maximum 9.5 years; average number of visits per participant 3.1). During follow-up, the annual rates of CAC progression (95% CI) in participants with and without NAFLD at baseline were 22% (20% to 23%) and 17% (16% to 18%), respectively (p<0.001; table 2). The multivariable adjusted ratio of progression rates comparing participants with NAFLD with those without NAFLD was 1.04 (1.02 to 1.05; p<0.001) (table 2 and figure 2). The results did not materially change after adjusting for potential metabolic mediators.

    View this table:
    Table 2

    Ratio of annual progression rates of CAC scores in participants with and without NAFLD at baseline (n=4731)

    Figure 2
    Figure 2

    Average trajectories of CAC scores in participants with and without non-alcoholic fatty liver at baseline. Trajectories were obtained from mixed linear models for longitudinal data with random intercepts and random slopes using loge (CAC+1) as outcome. Models were adjusted for age, sex, smoking status (never, former, current and missing), alcohol intake (none, moderate and missing), systolic blood pressure, total and high-density lipoprotein cholesterol, triglycerides (loge-transformed), diabetes, use of antihypertensive medications, and use of statins at baseline. CAC, coronary artery calcium; NAFLD, non-alcoholic fatty liver disease.

    When we used natural scale CAC score as an outcome, the average annual progression of CAC in participants with and without NAFLD was 17.8 (16.0 to 19.5) and 12.8 (11.5 to 14.0) Agatston units, respectively (p<0.001; table 3). The multivariable adjusted average difference in annual progression of CAC scores comparing participants with NAFLD with those without NAFLD was 5.0 Agatston units (2.9 to 7.1; p<0.001).

    View this table:
    Table 3

    Average difference in annual progression rates of CAC scores (Agatston units) in participants with and without NAFLD at baseline (n=4731)

    Progression of CAC scores increased across categories of NAFLD severity as defined by the NAFLD fibrosis score (table 4). The association between NAFLD and CAC progression was also observed both in participants with CAC 0 and in those with CAC >0 at baseline (tables 2 and 3). We also evaluated if the association between NAFLD and CAC progression differed in prespecified subgroups defined by age (<50, ≥50 years), sex, smoking (current, non-current), alcohol drinking (none, moderate), elevated blood pressure (defined as a systolic blood pressure ≥130 mm Hg, a diastolic blood pressure ≥85 mm Hg or self-reported use of antihypertensive medication), reduced HDL cholesterol (defined as HDL cholesterol levels <40 mg/dL in men and <50 mg/dL in women), elevated triglycerides (defined as triglyceride levels ≥150 mg/dL), elevated fasting glucose (defined as fasting serum glucose levels ≥100 mg/dL, a self-reported history of diabetes or self-reported use of insulin or antidiabetic medications), elevated ALT (defined as ALT levels ≥30 U/L for men and ≥19 U/L for women) or baseline CAC score (0, >0) (figure 3). The positive association between NAFLD and annual rate of CAC progression was consistently observed in all subgroups analysed except in participants with elevated blood pressure (p for interaction=0.034).

    View this table:
    Table 4

    Ratio of annual progression rates and average difference in annual progression of CAC scores in participants with and without NAFLD at baseline by NAFLD severity (n=4731)

    Figure 3
    Figure 3

    Ratios of annual progression rates of CAC scores comparing non-alcoholic fatty liver disease status in predefined subgroups at baseline. *Models were adjusted for age, sex, smoking status (never, former, current and missing) and alcohol intake (none, moderate and missing) at baseline. †Elevated waist circumference: ≥90 cm in men or ≥85 cm in women; elevated triglycerides: ≥150 mg/dL; reduced HDL-C: <40 mg/dL in men or <50 mg/dL in women; elevated blood pressure: ≥130/85 mm Hg or use of antihypertensive medications; elevated fasting glucose: ≥100 mg/dL or use of antidiabetic medications; elevated ALT: ≥30 U/L in men or ≥19 U/L in women. ALT, alanine aminotransferase; CAC, coronary artery calcium; HDL-C, high-density lipoprotein cholesterol.

    Discussion

    In this large longitudinal study, we found that the progression of coronary atherosclerosis was faster in participants with NAFLD at baseline compared with those without NAFLD. The association between baseline NAFLD and progression of CAC scores persisted after adjusting for traditional risk factors and for potential metabolic mediators, and was progressive across categories of NAFLD fibrosis score. This association was evident in most subgroups analysed, including in participants with and without CAC at baseline. The present study is the first report to demonstrate a longitudinal association between NAFLD and CAC progression and provides strong support to the hypothesis that NAFLD is an independent risk factor contributing to the progression of atherosclerosis.

    Several cross-sectional studies have reported an association between NAFLD and CAC independent of traditional cardiovascular and metabolic risk factors.19–23 In the largest study, Lee et al22 analysed 21 335 male participants in a health screening programme, and showed that NAFLD was more closely associated with CAC than abdominal obesity. The association between NAFLD and CAC, however, has not been consistent across all studies. McKimmie et al24 reported no significant association between hepatic steatosis and CAC in a sample enriched with patients with type 2 diabetes. Similarly, in a study of 213 participants with diabetes, NAFLD was associated with CAC in patients with HbA1C <7%, but not in those with HbA1C ≥7%.25 Finally, a study of 919 postmenopausal women showed an association between NAFLD with the prevalence of CAC, but this association was attenuated and no longer statistically significant after adjusting for insulin resistance.26 All these studies were cross-sectional and thus had inherent limitations including the temporal ambiguity of the associations and the possibility of selection bias in participants with prevalent disease. Our longitudinal data provide a strong support for a role of NAFLD in the progression of coronary atherosclerosis, independent of traditional and metabolic risk factors.

    Although the pathophysiological mechanisms linking NAFLD to atherosclerosis are not completely understood, several pathways are plausible. NAFLD is considered an early hepatic manifestation of the metabolic syndrome, with insulin resistance as a common pathophysiological mechanism.27–29 The metabolic syndrome is associated with subclinical inflammation, a prothrombotic state, and endocrine and hemodynamic alterations that may increase the risk of atherosclerosis.30 ,31 NAFLD is also associated with oxidative stress,32 with macrophage activation,33 and with endothelial dysfunction, all major mechanisms for atherosclerosis development.34 ,35 NAFLD may accelerate atherosclerosis through increased levels of atherogenic, triglyceride-rich, cholesterol-rich particles and small dense LDL particles.36 Finally, improvement of NAFLD has been associated with reduced progression of carotid intima-media thickness,37 whereas persistent NAFLD was associated with an increased risk of subclinical carotid atherosclerosis development.38 These mechanisms further support the case that NAFLD is not just an epiphenomenon, but an active mediator directly contributing to the progression of atherosclerosis.

    Several limitations need to be considered in the interpretation of our findings. First, our study was based on repeated participation in health screening examinations, and participants who did not receive a second CT scan for CAC scoring were excluded. IPW correction for this type of selection bias did not appreciably modify the results. Similarly, including participants with only one CAC score in the mixed models also resulted in identical findings (data not shown). Furthermore, the association between baseline NAFLD and CAC progression was similar in participants with CAC 0 and with CAC >0 at baseline. Second, we defined NAFLD by US after exclusion of secondary causes for steatosis. NAFLD encompasses a spectrum of diseases ranging from simple steatosis to steatohepatitis and fibrosis, which cannot be differentiated with a standard US.28 US also may lead to an incorrect diagnosis of NAFLD in 10% to 30% of cases.39 Third, because of the long study duration, different CT scanners and radiology technicians were involved in performing CAC score measurements over time. Study personnel collecting the data, however, were unaware of the study aims, and equipment changes were independent of participant characteristics. As a consequence, measurement error in the exposure and outcome variables in this study likely resulted in an underestimation of the association between NAFLD and CAC score progression. Fourth, the retrospective study design might have led to inevitable biases including selection or misclassification bias. Finally, our study was conducted in asymptomatic Korean men and women attending regular health screening examinations and our findings may not be generalisable to other populations, particularly in other age or race/ethnicity groups.

    In addition to the longitudinal design, our study had multiple strengths, including the large sample size and the availability of detailed information on multiple cardiovascular and metabolic parameters. The use of high-quality clinical, imaging, and laboratory procedures, and the availability of carefully phenotyped participants are major additional strengths of our data.

    In summary, NAFLD was associated with the progression of coronary atherosclerosis, independent of established risk factors. Our findings suggest that NAFLD may play a pathophysiological role in atherosclerosis development and may be useful to identify subjects with a higher risk of subclinical disease progression. Future clinical trials should test if interventions that reduce the prevalence of NAFLD also reduce the progression of CAC.

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    Footnotes

    • DHS and DK contributed equally.

    • Correction notice This article has been corrected since it published Online First. Professor Cho has been added as co-corresponding author.

    • Contributors DHS and G-YG designed the study. DK, SG, HK, DS, SJC and B-KY collected the data. DK, SG, HK, EG and JC performed the data analysis. DHS, DK, YC, SR, H-DP, SWP, YBS, ML, JL, EG, JC and G-YG wrote the final report. All authors contributed to critical revision of the final report. JC and G-YG are guarantors. All the authors had full access to all of the data and can take responsibility for the integrity of the data and the accuracy of the data analysis.

    • Competing interests None declared.

    • Ethics approval Methods, Study population.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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