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. 2023 Sep 10;6(9):e1554. doi: 10.1002/hsr2.1554

Association of nonalcoholic fatty liver disease and carotid media‐intima thickness: A systematic review and a meta‐analysis

Manouchehr Khoshbaten 1, Sepideh H Maleki 2, Sara Hadad 1, Amrit Baral 3, Ana V Rocha 3, Laxmi Poudel 4, Alireza Abdshah 3,5,✉
PMCID: PMC10493365  PMID: 37701352

Abstract

Introduction

The relationship between cardiovascular disorders and nonalcoholic fatty liver disease (NAFLD) has been extensively studied. To better pool this data and make a more definite conclusion, we performed a meta‐analysis to evaluate the association between NAFLD and the thickness of media and intima of carotid artery (CIMT) and cardiovascular disorders.

Methods

We searched PubMed, Ovid, Scopus, ProQuest, Web of Science, and the Cochrane Library, and analyzed the pooled data using R studio and the “metafor” package.

Results

The final analysis included a total of 59 studies with 16,179 cases and 26,120 control individuals. NAFLD was shown to be associated with an increase of 0.1231 mm (20.6%) in carotid artery intima‐media thickness (CIMT) (p = 0.002, 95% confidence interval [CI]: 0.0462–0.2000) in individuals with NAFLD. The prevalence of atherosclerotic plaques in the carotid arteries and the occurrence of NAFLD are significantly correlated, according to a meta‐analysis based on 17 distinct studies (p = 0.001, 1.28–1.43, 95% CI, odds ratio = 1.356).

Conclusion

Patients with increased CIMT are considerably more likely to have NAFLD. Large prospective investigations are required to corroborate these findings and their prognostic significance, along with the effectiveness of the available interventions.

Keywords: atherosclerosis, cardiovascular diseases, carotid arteries, meta‐analysis, NAFLD

Key Points

  • Nonalcoholic fatty liver disease (NAFLD) is associated with increased carotid intima media thickness.

  • NAFLD is associated with increased prevalence of atherosclerotic plaques in the carotid arteries.

1. INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is a liver condition marked by an excessive accumulation of fat and is brought on by causes other than alcohol and other particular liver‐damaging variables. 1 Its prevalence is rising in parallel with obesity and metabolic illness rates. 2 The prevalence of NAFLD varies by country and ranges from 10% to 24%, while obese patients show a frequency of 57% to 74%. 2.6% of children are also impacted, ranging from 22.5% to 52.8% among obese children. 3 In Asia, its prevalence has been increased; a 3–20‐fold increase in nations such as Japan in last two decades. 4 Obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome are among the main risk factors for NAFLD. 5 It is believed that NAFLD is likely a liver manifestation of metabolic syndrome, and clinical, epidemiological, and biochemical studies strongly support this hypothesis. 5 Moreover, recent studies have shown that NAFLD is associated with a variety of classic and non‐classic risk factors for cardiovascular disease disorders. In this case, different epidemiological studies have shown that cardiovascular disease is the primary cause of mortality in NAFLD patients. 6

One of the subclinical indicators of atherosclerosis is carotid intima‐media thickness (CIMT), which is strongly associated with coronary heart disease. 7 Numerous studies have been conducted to demonstrate the connection between NAFLD and atherosclerosis, and these studies show that there is a connection between NAFLD and an increase in the intima and media of carotid arteries. Aside from being strongly correlated with obesity and other elements of the metabolic syndrome, increased CIMT, plaque, and impaired endothelial flow‐mediated vasodilatation are additional indicators of subclinical atherosclerosis in nonalcoholic fatty liver patients. 8 , 9 A variety of chemicals are also released from fatty and inflamed liver in nonalcoholic fatty liver patients, particularly if they also have nonalcoholic steatohepatitis (NASH), which may have a pathogenic role in accelerating atherosclerosis. 10 Validation of these findings can turn NAFLD into a prognostic and therapeutical target for cardiovascular disorders. Despite several studies, this association has not yet been investigated in a systematic review approach. As a result, we aimed to conduct a systematic and comprehensive review on the association between NAFLD and cardiovascular disorders.

2. METHODS

2.1. Search strategy and eligibility criteria

This systematic review was conducted upon studies indexed in the PubMed, Ovid, Scopus, ProQuest, Web of science, and the Cochrane Library until July 2, 2023. Searching strategy to find the most relevant studies was (“hepatic steatosis” or “non‐alcoholic fatty liver disease” or “fatty liver”) and (“atherosclerosis” or “intima and media thickness” or “carotid artery” or “carotid plaque” or “cardiovascular disease”). In addition, our detailed search strategy is summarized in Table 1. The inclusion criteria were English‐language descriptive and cohort studies examining the association between adult patients with NAFLD and carotid artery atherosclerosis (over 18 years old). Moreover, studies that have not yet been published, or did not report the variables considered in this study as well as inclusion of patients with hepatic steatosis due to secondary causes (including alcoholic patients, intravenous nutrition, hepatitis B or C, or drugs) were excluded from our repertoire. Our Patient Intervention Comparator Outcome (PICO) was as follows: (1) P: patients with NAFLD, (2) I: ultrasound examination of the carotid artery, (3) C: normal control individuals, and (4) carotid‐intima thickness and its plaque amount. Two separate reviewers screened all the studies, and another investigator entered all the endpoints and measures obtained in the chosen studies in Excel. The data was then prepared and analyzed as explained in the statistical analysis section. No automation tool was used in this process.

Table 1.

Search strategy in PubMed database and keywords used for search.

Search Query Items found
#1 Search: “Atherosclerosis”[Mesh] Sort by: Most Recent 56,032
#2 Search: ((Atherosclerosis[Title/Abstract]) OR (Atheroscleroses[Title/Abstract])) OR (Atherogenesis[Title/Abstract]) 142,274
#3 Search: (“Atherosclerosis”[Mesh]) OR (((Atherosclerosis[Title/Abstract]) OR (Atheroscleroses[Title/Abstract])) OR (Atherogenesis[Title/Abstract])) 163,244
#4 Search: “Carotid Arteries”[Mesh] Sort by: Most Recent 62,693
#5 Search: (“Carotid Artery”[Title/Abstract]) OR (“Carotid Arteries”[Title/Abstract]) 79,303
#6 Search: (“Carotid Arteries”[Mesh]) OR ((“Carotid Artery”[Title/Abstract]) OR (“Carotid Arteries”[Title/Abstract])) 108,219
#7 Search: ((“Atherosclerosis”[Mesh]) OR (((Atherosclerosis[Title/Abstract]) OR (Atheroscleroses[Title/Abstract])) OR (Atherogenesis[Title/Abstract]))) AND ((“Carotid Arteries”[Mesh]) OR ((“Carotid Artery”[Title/Abstract]) OR (“Carotid Arteries”[Title/Abstract]))) 13,290
#8 Search: “Carotid Artery Diseases”[Mesh] 52,225
#9 Search: ((((((“Carotid Atherosclerosis”[Title/Abstract]) OR (“Carotid Atheroscleroses”[Title/Abstract])) OR (“Carotid Artery Disease*“[Title/Abstract])) OR (“Carotid Artery Disorder*“[Title/Abstract])) OR (“Carotid Arterial Disease*“[Title/Abstract])) OR (“Carotid artery atherosclerosis”[Title/Abstract])) OR (“Carotid Atherosclerotic Disease*“[Title/Abstract]) 8489
#10 Search: (“Carotid Artery Diseases”[Mesh]) OR (((((((“Carotid Atherosclerosis”[Title/Abstract]) OR (“Carotid Atheroscleroses”[Title/Abstract])) OR (“Carotid Artery Disease*“[Title/Abstract])) OR (“Carotid Artery Disorder*“[Title/Abstract])) OR (“Carotid Arterial Disease*“[Title/Abstract])) OR (“Carotid artery atherosclerosis”[Title/Abstract])) OR (“Carotid Atherosclerotic Disease*“[Title/Abstract])) 54,602
#11 Search: ((“Carotid Artery Diseases”[Mesh]) OR (((((((“Carotid Atherosclerosis”[Title/Abstract]) OR (“Carotid Atheroscleroses”[Title/Abstract])) OR (“Carotid Artery Disease*“[Title/Abstract])) OR (“Carotid Artery Disorder*“[Title/Abstract])) OR (“Carotid Arterial Disease*“[Title/Abstract])) OR (“Carotid artery atherosclerosis”[Title/Abstract])) OR (“Carotid Atherosclerotic Disease*“[Title/Abstract]))) OR (((“Atherosclerosis”[Mesh]) OR (((Atherosclerosis[Title/Abstract]) OR (Atheroscleroses[Title/Abstract])) OR (Atherogenesis[Title/Abstract]))) AND ((“Carotid Arteries”[Mesh]) OR ((“Carotid Artery”[Title/Abstract]) OR (“Carotid Arteries”[Title/Abstract])))) 61,111
#12 Search: “Non‐alcoholic Fatty Liver Disease”[Mesh] 23,321
#13 Search: ((((((NAFLD[Title/Abstract]) OR (“Non‐alcoholic Fatty Liver*“[Title/Abstract])) OR (“Nonalcoholic Steatohepatitis”[Title/Abstract])) OR (“Nonalcoholic Steatohepatitides”[Title/Abstract])) OR (“Nonalcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non alcoholic Fatty Liver Disease*“[Title/Abstract]) 36,568
#14 Search: (“Nonalcoholic Fatty Liver Disease”[Mesh]) OR (((((((NAFLD[Title/Abstract]) OR (“Nonalcoholic Fatty Liver*“[Title/Abstract])) OR (“Nonalcoholic Steatohepatitis”[Title/Abstract])) OR (“Nonalcoholic Steatohepatitides”[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non alcoholic Fatty Liver Disease*“[Title/Abstract])) 39,599
#15 Search: ((“Non‐alcoholic Fatty Liver Disease”[Mesh]) OR (((((((NAFLD[Title/Abstract]) OR (“Nonalcoholic Fatty Liver*“[Title/Abstract])) OR (“Nonalcoholic Steatohepatitis”[Title/Abstract])) OR (“Nonalcoholic Steatohepatitides”[Title/Abstract])) OR (“Nonalcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract]))) AND (((“Carotid Artery Diseases”[Mesh]) OR (((((((“Carotid Atherosclerosis”[Title/Abstract]) OR (“Carotid Atheroscleroses”[Title/Abstract])) OR (“Carotid Artery Disease*“[Title/Abstract])) OR (“Carotid Artery Disorder*“[Title/Abstract])) OR (“Carotid Arterial Disease*“[Title/Abstract])) OR (“Carotid artery atherosclerosis”[Title/Abstract])) OR (“Carotid Atherosclerotic Disease*“[Title/Abstract]))) OR (((“Atherosclerosis”[Mesh]) OR (((Atherosclerosis[Title/Abstract]) OR (Atheroscleroses[Title/Abstract])) OR (Atherogenesis[Title/Abstract]))) AND ((“Carotid Arteries”[Mesh]) OR ((“Carotid Artery”[Title/Abstract]) OR (“Carotid Arteries”[Title/Abstract]))))) 184
#16 Search: “Carotid Stenosis”[Mesh] 18,014
#17 Search: (((((“Carotid Stenosis”[Title/Abstract]) OR (“Carotid plaques”[Title/Abstract])) OR (“Carotid Stenoses”[Title/Abstract])) OR (“Carotid Ulcer*“[Title/Abstract])) OR (“Intima media thickness”[Title/Abstract])) OR (“Carotid intimal thickness”[Title/Abstract]) 22,959
#18 Search: (“Carotid Stenosis”[Mesh]) OR ((((((“Carotid Stenosis”[Title/Abstract]) OR (“Carotid plaques”[Title/Abstract])) OR (“Carotid Stenoses”[Title/Abstract])) OR (“Carotid Ulcer*“[Title/Abstract])) OR (“Intima media thickness”[Title/Abstract])) OR (“Carotid intimal thickness”[Title/Abstract])) 35,063
#19 Search: ((“Non‐alcoholic Fatty Liver Disease”[Mesh]) OR (((((((NAFLD[Title/Abstract]) OR (“Nonalcoholic Fatty Liver*“[Title/Abstract])) OR (“Nonalcoholic Steatohepatitis”[Title/Abstract])) OR (“Nonalcoholic Steatohepatitides”[Title/Abstract])) OR (“Nonalcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non alcoholic Fatty Liver Disease*“[Title/Abstract]))) AND ((“Carotid Stenosis”[Mesh]) OR ((((((“Carotid Stenosis”[Title/Abstract]) OR (“Carotid plaques”[Title/Abstract])) OR (“Carotid Stenoses”[Title/Abstract])) OR (“Carotid Ulcer*“[Title/Abstract])) OR (“Intima media thickness”[Title/Abstract])) OR (“Carotid intimal thickness”[Title/Abstract]))) 268
#20 Search: “Cerebrovascular Disorders”[Mesh] 427,170
#21 Search: ((((((((“Cardiovascular risk marker*“[Title/Abstract]) OR (“Surrogate markers of cardiovascular disease*“[Title/Abstract])) OR (“Cerebrovascular Disorder*“[Title/Abstract])) OR (“Intracranial Vascular Disease*“[Title/Abstract])) OR (“Intracranial Vascular Disorder*“[Title/Abstract])) OR (“Cerebrovascular Disease*“[Title/Abstract])) OR (“Brain Vascular Disorder*“[Title/Abstract])) OR (“Cerebrovascular Occlusion*“[Title/Abstract])) OR (“Cerebrovascular Insufficienc*“[Title/Abstract]) 32,706
#22 Search: (“Cerebrovascular Disorders”[Mesh]) OR (((((((((“Cardiovascular risk marker*“[Title/Abstract]) OR (“Surrogate markers of cardiovascular disease*“[Title/Abstract])) OR (“Cerebrovascular Disorder*“[Title/Abstract])) OR (“Intracranial Vascular Disease*“[Title/Abstract])) OR (“Intracranial Vascular Disorder*“[Title/Abstract])) OR (“Cerebrovascular Disease*“[Title/Abstract])) OR (“Brain Vascular Disorder*“[Title/Abstract])) OR (“Cerebrovascular Occlusion*“[Title/Abstract])) OR (“Cerebrovascular Insufficienc*“[Title/Abstract])) 441,976
#23 Search: ((“Non‐alcoholic Fatty Liver Disease”[Mesh]) OR (((((((NAFLD[Title/Abstract]) OR (“Nonalcoholic Fatty Liver*“[Title/Abstract])) OR (“Nonalcoholic Steatohepatitis”[Title/Abstract])) OR (“Nonalcoholic Steatohepatitides”[Title/Abstract])) OR (“Nonalcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non‐alcoholic Fatty Liver Disease*“[Title/Abstract])) OR (“Non alcoholic Fatty Liver Disease*“[Title/Abstract]))) AND ((“Cerebrovascular Disorders”[Mesh]) OR (((((((((“Cardiovascular risk marker*“[Title/Abstract]) OR (“Surrogate markers of cardiovascular disease*“[Title/Abstract])) OR (“Cerebrovascular Disorder*“[Title/Abstract])) OR (“Intracranial Vascular Disease*“[Title/Abstract])) OR (“Intracranial Vascular Disorder*“[Title/Abstract])) OR (“Cerebrovascular Disease*“[Title/Abstract])) OR (“Brain Vascular Disorder*“[Title/Abstract])) OR (“Cerebrovascular Occlusion*“[Title/Abstract])) OR (“Cerebrovascular Insufficienc*“[Title/Abstract]))) 220
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2.2. Ethical considerations

The information about the patients was kept confidential since this research was done as a review. Only studies that addressed ethical concerns and were published in credible journals were included in this analysis. The findings of this research were disclosed without hindrance, in accordance with the confidentially principle, and by citing the relevant sources. The investigation was carried out with the greatest care to ensure that the conclusions are supported by the available scientific data. To prevent plagiarism, the scientific writing rules were also followed.

2.3. Statistical analysis

We have listed the studies that we utilized in along with their details in Table 2. After importing the data, and defining the effects as “the difference between carotid intima‐media thickness of subjects with NAFLD versus those without NAFLD; we performed the analysis using R. 79 The preparation was done using the “tidyverse” 80 package, and the meta‐analysis and visualizations were done using the “metafor” 81 package. For the meta‐analysis, we used the random‐effects model, and we checked for heterogeneity and ran sensitivity analysis. We performed the meta‐analysis both with the overall effect and by using sample number of the studies as weights. We then generated the forest plots and funnel plot to visualize the effects.

Table 2.

Summary of data obtained from articles.

Carotid atherosclerosis plaque CIMT(mm) Number of NAFLD Number of control patients Total sample NAFLD diagnosis Published year First author
NAFLD CONTROL NAFLD CONTROL
Count % Count % Mean SD Mean SD
0.46 0.04 0.41 0.03 320 687 1007 Sonography 2017 Xia Li 11
35 31 0.78 0.15 0.75 0.15 636 484 898 Sonography 2020 Hyeok‐Hee Lee 12
7 14.2 0 0 0.9 (no SD reported) 0.6 (no SD reported) 50 30 80 Biopsy 2014 Nicoleta V. Leach 13
32.0% (high) 22.10% (high) 290 290 580 Sonography 2013 Kamran B. Lankarani 14
0.4 0.19 0.27 0.18 117 44 161 Sonography 2013 Metin Kucukazman 15
0.818 0.006 0.818 0.008 747 464 1211 Sonography 2014 Soo‐Kyung Kim 16
0.75 0.06 0.74 0.08 180 1105 1285 CT 2014 Nan Hee Kim 17
0.72 0.06 0.619 0.04 103 50 153 Sonography 2019 Cemal Kemaloglu 18
0.68 0.1 0.65 0.1 40 26 66 Sonography 2009 F. Karakurt 19
109 34.1 59 18.8 0.79 0.18 0.73 0.13 320 313 633 Sonography 2012 Ji Hoon Kang 20
0.09 0.19 0.8 0.1 29 22 51 CT 2013 Pikkel Josef 21
357 13.8 865 14.3 0.59 0.1 0.57 0.1 2590 6042 8632 Sonography 2012 Yun Huang 22
0.66 0.04 0.64 0.04 342 613 955 Sonography 2016 Ho Cheol Hong 23
1.09 0.15 0.88 0.05 196 100 296 Sonography 2018 Amr Shaaban Hanafy 24
2452 56.5 1883 44.5 0.82 0.3 0.85 0.39 4349 4231 8571 Sonography 2017 Kaifeng Guo 25
0.83 0.21 0.76 0.14 106 909 1015 CT 2018 Anders Gummesson 26
0.6 0.11 0.54 0.08 113 57 170 Biopsy 2013 Halil Genc 27
46 50 95 52 0.96 0.22 0.79 0.18 91 182 273 Sonography/biopsy 2016 Anna Ludovica Fracanzani 28
0.89 0.26 0.64 0.14 125 350 375 sonography/biopsy 2008 Anna Ludovica Fracanzani 29
0.83 0.16 0.77 0.016 49 33 82 Sonography 2018 Reza Fadaei 30
0.6 0.13 0.5 0.08 67 35 102 Biopsy 2012 Teoman Dogru 31
0·60 0·50 115 74 189 Sonography/biopsy 2013 Teoman Dogru 32
0.67 0.09 0.52 0.11 51 21 72 biopsy 2012 Yasar Colaka 33
0.68 0.15 0.68 0.14 93 37 130 Sonography/biopsy 2017 Ibrahim Cetindaglı 34
20 50 10 25 0.70 0.2 0.54 0.13 40 40 80 Sonography 2005 Angel Brea 35
0.64 0.17 0.43 0.14 34 35 69 Sonography 2013 Ö. Başar 36
0.1 0.02 0.08 0.02 50 50 100 Sonography 2021 Maha Assem 37
0.64 0.1 0.52 0.10 57 30 87 Sonography/biopsy 2012 Yasar Colak 38
9 92.52 58 52.73 110 107 217 Sonography 2015 Florin Casoinic 39
0.646 0.091 0.544 0.067 40 40 80 Biopsy 2007 Cem Aygun 40
60 30.4 70 35.2 0.6 0 0.6 0 148 129 277 Sonography 2017 Clarence Gill 41
31 24 0.79 0.22 0.73 0.15 452 453 905 Sonography 2012 Xiaoming Li 42
0.81 0.14 0.58 0.15 250 85 335 Sonography 2011 Afshin Mohammadi 43
0.65 0.09 0.55 0.07 84 65 149 Sonography 2011 Afshin Mohammadi 44
38 25.3 8 5.3 0.62 0.19 0.5 0.13 150 150 300 Sonography 2019 Ali Mohammadzadeh 45
0.56 0.11 0.45 0.13 99 52 151 Sonography 2014 Maryam Zaare Nahandi 46
0.44 0.07 0.4 0.05 61 41 102 Biopsy 2015 Kadir Ozturk 47
0.63 0.17 0.54 0.1 45 45 90 Sonography 2020 Vijay Rampally 48
0.79 0.18 0.67 0.13 23 28 51 Biopsy 2010 Charalambos Vlachopoulos 49
1.14 0.20 0.82 0.12 85 160 245 Biopsy 2006 Giovanni Targher 50
0.8 0.1 0.6 0.03 109 109 218 Sonography 2016 Hafsa Riaz 51
0.82 0.15 0.58 0.1 200 100 300 Sonography 2017 Abid Rasool 52
1.10 0.20 0.84 0.13 50 40 90 Biopsy 2005 Giovanni Targher 53
0.6 0.11 0.6 0.23 654 2770 3433 Sonography 2019 Zhuojun Xin 54
0.6 0.12 0.49 0.1 40 40 80 Sonography 2012 Manik Lal Thakur 55
1.2 0.14 0.9 0.12 37 35 72 Sonography 2016 Radojica V. Stolic 56
29.3 33.6 0.82 0.16 0.76 0.15 92 128 220 Sonography 2010 Paolo Salvi 57
0.88 0.18 0.87 0.2 729 3394 4123 Sonography 2019 Ebenezer Oni 58
0.71 0.17 0.69 0.31 107 43 150 Sonography 2020 Nurazam omar 59
19.2 2.2 0.592 0.1 0.489 0.13 101 544 645 Sonography 2013 Sandhya Mishra 60
57.8 37.5 0.84 0.1 0.72 0.1 90 64 154 Sonography 2009 Stefano Ramilli 61
34.50% (high) 19.10% (high) 144 107 251 Sonography 2018 Eugene Choon‐Li Tan 62
1.18 0.14 0.94 0.12 45 40 85 Sonography 2004 Giovanni Targher 63
1.09 0.77 0.98 0.68 38 18 56 Sonography 2011 Laura I. Poanta 64
31.6 40.1 0.82 0.2 0.64 0.14 73 51 124 Sonography 2018 Sivabal Vanjiappan 65
27 71.1 4 8 1.1 0.1 0.8 0.1 38 50 88 CT 2014 Ivana Mikolasevic 66
0.75 0.23 0.66 0.15 24 28 52 Biopsy 2012 Binnur Pinarbasi 67
0.67 0.15 0.63 0.13 394 421 815 Sonography 2015 Seung Hwan Moon 68
0.75 0.15 0.74 0.13 61 40 101 CT 2009 Jean Michel Petit 69
1 0.6 0.98 0.11 289 47 336 Sonography 2015 Cristina Alina Silaghi 70
20.4 0 0.75 0.15 0.58 0.09 77 15 92 Biopsy 2015 Josep Puig 71
21.5 6 0.72 0.15 0.46 0.13 117 32 149 Biopsy 2015 Josep Puig 71
645 40 967 59.9 43.84% (high) 56.15% (high) 1571 2541 4112 Sonography 2018 Jilin Zheng 72
28.9 16.9 0.81 0.25 0.69 0.18 123 599 722 Sonography 2016 Lie Zhang 73
21.9 15 30% (high) 21.1% (high) 1375 1237 2612 Sonography 2018 Yu Chen Guo 74
0.712 0.150 0.5875 0.088 76 24 100 Sonography 2022 Shabbirhussain 75
0.78 0.145 0.75 0.15 456 396 852 Sonography 2023 Cho 76
0.64 0.1 0.8 0.2 63 35 98 Sonography 2023 Zhang 77
31.8% high 19.7% high 384 506 890 Sonography 2022 Bessho 78
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Abbreviations: CT, computed tomography; NAFLD, nonalcoholic fatty liver disease; SD, standard deviation.

3. RESULTS

3.1. Data collection

PubMed, Ovid, Scopus, ProQuest, Web of Science, and the Cochrane Library databases were used in our study in which 495, 546, 566, 80, 683, and 4 articles were screened out, respectively. Strategy search for PubMed database is provided in Table 1. Consequently, a total of 2865 articles were screened out in which 1024 articles remained after eliminating duplicates from the total articles, while 159 items remained after initial screening using titles and abstracts. The whole texts of 159 articles were meticulously examined in the next stage. Then, 90 items were eliminated as being irrelevant and the data from 69 remained articles was collected, which is summarized in Table 2. There was a total of 56,582 patients in these studies, comprising 26,689 NAFLD cases and 38,584 control subjects. Finally, 10 articles were excluded due to reporting mean and percentage values rather than mean and standard deviation, and 59 articles remained for meta‐analysis. The details of included and excluded data can be shown in illustrated PRISMA flowchart (Figure 1).

Figure 1.

Figure 1

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PRISMA flow diagram showing the selection process of studies in the systematic review and meta‐analysis.

3.2. Relationship between NAFLD and CIMT

The findings of the meta‐analysis based on 59 studies (after weighing based on their sample size) revealed that NAFLD was linked to an increase in CIMT associated with an increase of 0.1231 mm (20.6%) in CIMT (p = 0.002, 95% CI: 0.0462, 0.2000) in individuals with NAFLD. The forest plot in Figure 2 shows our pooled estimate, and the funnel plot in Figure 3 shows that the studies were symmetrically distributed.

Figure 2.

Figure 2

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Results of a meta‐analysis of studies on the association of carotid artery intima‐media diameter (CIMT) with nonalcoholic fatty liver disease (NAFLD).

Figure 3.

Figure 3

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Funnel plot publication bias in the studies conducted on the relationship between carotid artery intima‐media diameter (CIMT) and nonalcoholic fatty liver disease (NAFLD).

At first we noted a significant heterogeneity among the studies, but after further exploration, we noted that one of the studies was causing a significant heterogeneity, and because of the lower sample size and the wide confidence interval in the study, 21 we excluded the study from the meta‐analysis. In the final analysis, using the sample size of the studies as weights, we noted no significant heterogeneity among the studies (Q = 67.49, and p = 0.18).

Also, we looked in several studies on patients suffering from diabetes, which had contributed to their NAFLD, and the outcome of a subgroup meta‐analysis of 7 studies that only involved diabetic patients—both the NAFLD group and the control group—showed us that the presence of NAFLD, while slightly increasing the odds, was not significantly correlated with increase in CIMT (p value = 0.557; 1.089–0.955 confidence interval [CI] 95%; odds ratio [OR] = 1.020). This analysis can be observed in Figure 4.

Figure 4.

Figure 4

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Subgroup results of meta‐analysis of studies conducted on diabetic patients regarding the relationship between carotid artery intima‐media diameter (CIMT) and nonalcoholic fatty liver disease (NAFLD). CI, confidence interval.

We also assessed for the effect of the method of diagnosis (ultrasound vs. CT scan vs. biopsy) and noticed that there was no significant effect of method of diagnosis on the association between NAFLD and increase in CIMT (CT vs. biopsy: p = 0.72; ultrasound vs. biopsy: p = 0.22).

3.3. Association between NAFLD and atherosclerotic plaque in carotid arteries

A meta‐analysis based on 17 separate studies revealed a significant association between the incidence of atherosclerotic plaques in the carotid arteries and the presence of NAFLD. They noted that in the patients with plaques, there was 1.35 times odds of having NAFLD versus those without plaques (p < 0.001, 1.28–1.43, 95% CI, OR = 1.356). The summary of this analysis can be viewed in Figure 5.

Figure 5.

Figure 5

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Results of a meta‐analysis of studies on the association of atherosclerotic plaque with NAFLD. CI, confidence interval; NAFLD, nonalcoholic fatty liver disease.

4. DISCUSSION

NAFLD has become a global public health issue since it is linked to metabolic risk factors such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome, along with genetic, socioeconomic, and lifestyle components. 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 Increased endothelial dysfunction, 91 , 92 ischemic heart disease, 93 cardiovascular events, 93 , 94 , 95 peripheral vascular disease, cardiovascular morbidity, and cardiovascular mortality are all medical issues, which may be caused by NAFLD. 87 , 96 Other research has shown an independent link between NAFLD and cardiovascular disease, regardless of other metabolic risk factors. 97 This finding raises the possibility that NAFLD is a direct contributor to the pathogenesis of atherosclerosis rather than just a sign of cardiovascular disorder. 98 Numerous pathogenic mechanisms, including elevated levels of oxidative stress brought on by steatosis‐stimulated fatty acid oxidation, 87 systemic release of pro‐atherogenic molecules like tumor necrosis factor‐alpha, interleukin‐6, and oxidized low‐density lipoprotein cholesterol, 99 elevated insulin resistance, 100 and macrophage activation, 101 have been proposed as potential causes for the acceleration of atherosclerosis and the rise in the prevalence of cardiovascular diseases in NAFLD patients. The atherogenic impact of liver inflammation is further confirmed by the fact that NASH (nonalcoholic steatohepatitis) patients had more atherosclerosis than steatosis patients. 102 , 103

In the present study, 59 observational studies were reviewed and the association between NAFLD and increased CIMT as well as prevalence of atherosclerotic plaque in the carotid artery (both subclinical indicators of atherosclerosis) was evaluated. In a pooled analysis of 59 studies, NAFLD was shown to be linked with a higher CIMT rate. In a pooled analysis of 59 studies, NAFLD was shown to be linked with higher CIMT. Of note, CIMT was 0.12 mm more (20.6%) in those with NAFLD than in controls (without NAFLD). Meanwhile, this value was about 18.7% in a meta‐analysis conducted by Madan et al. on 20 observational studies examining the influence of NAFLD on CIMT in adults, 104 and 13% in a meta‐analysis performed by Sookoian et al. on 7 studies. 105 In addition, a meta‐analysis of 17 studies revealed that NAFLD was related with a higher incidence of carotid plaque found by ultrasonography. 104 In concordance to our findings, NAFLD was related with an elevated risk of carotid plaque (detected by ultrasonography) in the meta‐analysis of Madan et al. 104 (of 13 studies). However, in a subgroup meta‐analysis of seven studies comparing diabetic individuals with NAFLD to diabetic patients without NAFLD, the presence of NAFLD was not significantly correlated with elevated CIMT rate in these patients. NAFLD seemed to be connected with an elevated risk of cardiovascular disease in both diabetic and nondiabetic individuals (T2DM). 106 , 107 Despite the fact that multiple research projects have shown that NAFLD is substantially correlated with higher CIMT in nondiabetic individuals, the association between fatty liver and atherosclerosis in patients with T2DM is less obvious, and there are contradictory findings across investigations. 16 , 50 , 69 , 108 , 109 Targher et al. found that NAFLD measured by ultrasonography in T2DM patients on a restricted diet was related with an increased incidence of cardiovascular disease and CIMT. 109 However, in agreement with our findings, Petit et al. did not demonstrate a link between NAFLD and elevated CIMT in T2DM patients. 69 Similar to our investigation, Guo et al. also did not find correlation between NAFLD and elevated CIMT in T2DM patients in a Chinese hospitalized population controlling for multiple confounding factors. 25 In contrast to our findings, Kim et al. observed that NAFLD is related to higher CIMT in individuals with T2DM but is impacted by insulin resistance. 16 Guo et al., revealed that after controlling cardiovascular risk factors, there was an independent correlation between NAFLD and carotid and lower limb atherosclerotic plaques, which is indicative of the independent association between NAFLD and advanced atherosclerotic lesions in T2DM patients. 25 The association between NAFLD and carotid atherosclerosis may be obscured by diabetes, which is regarded as one of the most significant risk factors for cardiovascular disease and the progression of atherosclerosis in the body. Other possible explanations for this contradiction include the techniques for detecting fatty liver (using ultrasound, CT, or magnetic resonance spectroscopy), ethnic disparities, and sample size.

Although increased CIMT has been shown to be associated with an increased risk of stroke, 93 myocardial infarction, 93 , 94 and peripheral vascular disease, 93 a recent meta‐analysis study suggested that carotid plaques may be a better predictor of cardiovascular risk than CIMT. 110 In addition, comprehensive research revealed that carotid plaque area is a more accurate predictor of ischemic stroke in the first year than CIMT. Consequently, instead of CIMT, it is necessary to study the influence of NAFLD on the carotid plaque area in the next investigations. 111

A recent meta‐analysis by Madan et al. 104 of 28 studies revealed an increased risk of carotid atherosclerosis in adult and pediatric populations with NAFLD compared to groups without NAFLD. However, a number of other research have evaluated the connection between NAFLD and carotid disease. 11 , 23 , 24 , 25 , 26 , 28 , 30 , 34 , 41 , 45 , 48 , 51 , 52 , 56 , 58 , 65 , 73 As a result, we did an updated meta‐analysis to incorporate new research done in Asia and Europe over the last years on the connection between NAFLD and carotid atherosclerosis through measurements of the CIMT in millimeters.

The constraints of any meta‐analysis research, by its nature, include its effect on the reviewed papers' texts, the risk of publication bias (publication bias), and the comprehensive search approach. To prevent this, we conducted the meta‐analysis using a comprehensive search approach and unambiguous inclusion and exclusion criteria. In addition, owing to the inclusion of observational studies in the analysis, unmeasured and underreported confounding factors and errors are possible. However, one of the most important strengths of our study was the focus on the amount of difference, along with percentage of difference, in the thickness of carotid intima‐media, instead of just describing the association or the odds of difference.

5. CONCLUSION

Through this systematic review and meta‐analysis, we concluded that NAFLD is correlated with an increase of 20.6% (0.12 mm) in CIMT. We also observed that NAFLD is correlated with an increase in atherosclerotic plaques.

AUTHOR CONTRIBUTIONS

Manouchehr Khoshbaten: Conceptualization; data curation; formal analysis; writing—original draft. Sepideh Hadi Maleki: Data curation; formal analysis; writing—original draft. Sara Hadad: Data curation; formal analysis; validation; writing—original draft. Amrit Baral: Data curation; writing—original draft; writing—review & editing. Ana Vitoria Rocha: Data curation; investigation; writing—review & editing. Laxmi Poudel: Data curation; writing—original draft; writing—review & editing. Alireza Abdshah: Visualization; writing—original draft; writing—review & editing.

CONFLICTS OF INTEREST STATEMENT

The authors declare no conflicts of interest.

TRANSPARENCY STATEMENT

The lead author Alireza Abdshah affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

ACKNOWLEDGMENTS

This study was funded by the authors.

Khoshbaten M, Maleki SH, Hadad S, et al. Association of non‐alcoholic fatty liver disease and carotid media‐intima thickness: a systematic review and a meta‐analysis. Health Sci Rep. 2023;6:e1554. 10.1002/hsr2.1554

DATA AVAILABILITY STATEMENT

The data set of the extracted measurements, along with R codes for analysis and plotting, can be made available upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data set of the extracted measurements, along with R codes for analysis and plotting, can be made available upon request.

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