v
Search
Advanced Search

Publications > Journals > Journal of Translational Gastroenterology > Article Full Text

  • Review Article
  • OPEN ACCESS

Liver Fibrosis as an Independent Cardiovascular Risk Factor in Non-alcoholic Fatty Liver Disease

  • Dmitry Victorovich Garbuzenko* 
 Author information
Journal of Translational Gastroenterology   2024;2(1):21-29

doi: 10.14218/JTG.2023.00071

Abstract

This review summarizes the current investigations that confirm the significance of liver fibrosis (LF) as an independent cardiovascular risk factor in non-alcoholic fatty liver disease (NAFLD). PubMed, Google Scholar, Web of Science platform, Reference Citation Analysis, and Cochrane Systematic Reviews were searched for articles published between 2008 and 2023. Relevant articles were identified using the following keywords: “cardiovascular diseases”, “cardiovascular risk factors”, “non-alcoholic fatty liver disease”, “nonalcoholic steatohepatitis”, and “liver fibrosis”. The reference lists of the identified articles were also searched for other relevant publications. The investigations that described LF as a cardiovascular risk factor in NAFLD met the inclusion criteria. NAFLD occupies a leading position among liver diseases worldwide. Cardiovascular disorders are the most significant cause of unfavorable outcomes in NAFLD patients. Currently, the relationship between them is well established. The pathophysiological mechanisms predisposing to the development of cardiovascular disorders in NAFLD include atherogenic dyslipidemia, impaired glucose metabolism and liver insulin resistance, low-grade systemic inflammation, endothelial dysfunction, cardiovascular remodeling, as well as gut dysbiosis, which are influenced by numerous genetic and epigenetic factors. Identification of cardiovascular risk factors in NAFLD is an important public health issue. At present, there is evidence that the presence of advanced LF may be a strong independent predictor and risk factor for cardiovascular disorders in NAFLD. It is obvious that early diagnosis of LF will allow to stratify NAFLD patients by cardiovascular risk groups and thereby determine the most optimal therapeutic interventions.

Keywords

Cardiovascular diseases, Cardiovascular risk factors, Non-alcoholic fatty liver disease, Nonalcoholic steatohepatitis, Liver fibrosis

Introduction

Non-alcoholic fatty liver disease (NAFLD) occupies a leading position among liver diseases worldwide. The ubiquitous NAFLD incidence increased from 25.26% in 1990–2006 to 38.00% in 2016–2019.1 NAFLD is described as a condition in which ≥5% of hepatocytes accumulate fat in patients who do not abuse alcohol. There are two main manifestations: simple steatosis without liver fibrosis (LF) (nonalcoholic fatty liver) and nonalcoholic steatohepatitis (NASH). NASH, in addition to steatosis, is characterized by lobular inflammation, hepatocyte ballooning, and various LF stages.2

The correlation between NAFLD and cardiovascular diseases (CVDs) is established by numerous clinical studies.3 NAFLD and NASH are accompanied by an increase in the frequency of cardiovascular events, particularly coronary artery disease, hypertension, atherosclerosis,4 myocardial infarction, ischemic stroke, atrial fibrillation, and heart failure.5 The risk of these events escalates with the progression of NAFLD, especially in advanced LF.6,7 As a result, CVDs are currently the predominant cause of death in NAFLD patients.8 This problem is compounded by an increase in the number of NAFLD patients with CVDs, who may have cardiovascular risk factors.9 Therefore, the most commonly used assessment systems, such as the Framingham risk score for hard coronary heart disease, may underestimate the cardiovascular risk associated with NAFLD.10 Nevertheless, serious cardiovascular disorders can occur in all clinical forms of NAFLD regardless of established cardiovascular risk factors.11 For example, the relationships between NAFLD, insulin resistance, metabolic syndrome, and CVDs have been well established.12 It is known that the metabolic syndrome is characterized by a combination of signs such as abdominal obesity, dyslipidemia, glucose metabolism disorders and hypertension.13 However, even normoponderal NAFLD patients have an increased risk of CVDs.14 This is likely due to the presence of other independent cardiovascular risk factors in NAFLD patients. At present, there is evidence that the presence of advanced LF may be a strong independent predictor and risk factor for cardiovascular disorders in NAFLD.15,16

This review summarizes the current investigations that confirm the significance of LF as an independent cardiovascular risk factor in NAFLD.

Literature search

PubMed, Google Scholar, Web of Science platform, Reference Citation Analysis, and Cochrane Systematic Reviews were searched for articles published between 2008 and 2023. Relevant articles were identified using the following keywords: “cardiovascular diseases”, “cardiovascular risk factors”, “non-alcoholic fatty liver disease”, “nonalcoholic steatohepatitis”, and “liver fibrosis”. The reference lists of the identified articles were also searched for other relevant publications. The investigations that described LF as a cardiovascular risk factor in NAFLD met the inclusion criteria.

Pathophysiological mechanisms of cardiovascular disorders in NAFLD

The pathophysiological mechanisms predisposing to the development of cardiovascular disorders in NAFLD are complex and multifactorial.17 These mechanisms include atherogenic dyslipidemia, impaired glucose metabolism, liver insulin resistance, low-grade systemic inflammation, endothelial dysfunction, as well as gut dysbiosis, all of which are influenced by numerous genetic and epigenetic factors.18 In addition, advanced LF/cirrhosis in NASH may contribute to cardiovascular disorders as a result of cardiovascular remodeling in response to the hyperdynamic circulatory state associated with portal hypertension. The term “remodeling” began to be used in cardiology in the 1980s, and in strict interpretation, means the process of reorganization of the existing structure, during which new material is attached to it, or it is completely changed (Fig. 1).19 In particular, left ventricular concentric remodeling, which was an unfavorable prognostic sign, was revealed in NASH patients.20 LF in NASH may also be associated with CVDs by a more expressed profile of systemic inflammation affecting various organs and systems and the interactions between them, leading to further inflammation and immune response activation.21

Potential pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver disease.
Fig. 1  Potential pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver disease.

NAFLD, non-alcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Noninvasive tests of liver fibrosis to assess cardiovascular risk in NAFLD

Given the known limitations of performing a liver biopsy, noninvasive tests of LF have been used in most investigations to assess cardiovascular risk in NAFLD (Table 1).22,23,24–44 The Fibrosis-4 (FIB-4) score is an index based on aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, platelet count, and age to evaluate LF. When evaluating LF in NAFLD patients, a FIB-4 score <1.3 is categorized as low risk, while a FIB-4 score ≥2.67 is categorized as high risk of LF.45 The NAFLD fibrosis score (NFS) is a combined assessment of age, hyperglycemia, body mass index, platelet count, albumin, and the AST/ALT ratio to evaluate LF. The following NFS thresholds for evaluating LF are proposed: <−1.455 - predictor of absence of significant LF (F0-F2); ≤−1.455 to ≤0.675 - indeterminate score; >0.675 - predictor of presence of significant LF (F3-F4).46 The BARD score includes three variables: AST/ALT ratio ≥0.8–2 points; a body mass index ≥28—1 point; and the presence of type 2 diabetes mellitus (T2DM)—1 point. The possible score ranges from 0 to 4 points. A total score of ≥2 is associated with advanced LF.47 The APRI index is calculated by using the formula AST/upper limit of normal × 100/platelet count. APRI index values of ≤0.3 and ≤0.5 rule out significant LF and cirrhosis, respectively, and a value of ≥ 1.5 rules out significant LF.48 The Forns index, calculated based on the following four parameters: patient age, total cholesterol, gamma-glutamyl transferase, and platelet count, has the cut-off points for the LF assessment <4.2 and >6.9.49 Transient elastography is the most commonly used imaging-based LF assessment method. To exclude advanced LF in NAFLD patients, the recommended values of liver stiffness measured by transient elastography are <8 kPa. The general limitations of noninvasive tests include insufficient verification accuracy for mild and moderate LF and inadequate differences in adjacent LF stages; in addition, there are not enough noninvasive tests to diagnose subclinical hepatic inflammation and ballooning, as well as to accurately determine the severity of portal hypertension in compensated advanced chronic liver disease. There are also specific advantages and limitations of individual noninvasive tests. Finally, the test-retest reliability of noninvasive tests has not been fully studied, warranting future research. Nevertheless, the use of noninvasive tests in scientific research for evaluating liver disease severity and prognosis is supported by the current guidelines.50

Table 1

Main characteristics of investigations on the significance of liver fibrosis as an independent cardiovascular risk factor in non-alcoholic fatty liver disease

First author, year, ref.DesignLiver fibrosis assessmentMain findings*
Impact of liver fibrosis on the cardiovascular risk in NAFLD
Park, 202122A prospective cross-sectional studyLiver biopsyNASH or advanced LF was independently associated with a higher risk of atherosclerotic CVDs.
Baratta, 202023A prospective cohort studyFIB-4 score, NFSFIB-4 score >2.67, and NFS >0.676 in NAFLD patients were independently associated with risk of incident cardiovascular events.
Vieira Barbosa, 202224A prospective cohort studyFIB-4 scoreFIB-4 score ≥2.67 in NAFLD patients was the strongest predictor of major adverse cardiovascular events overall and was consistently associated with myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, coronary artery bypass graft, and percutaneous coronary intervention.
Pennisi, 202125A prospective cohort studyTransient elastographyLF severity in NAFLD patients were independent factors for a higher atherosclerotic cardiovascular risk after adjusting for obesity.
Long, 202126A prospective cohort studyTransient elastographyLF in NAFLD patients was associated with multiple cardiovascular risk factors, including increased odds of obesity, metabolic syndrome, T2DM, hypertension, and low high-density lipoprotein cholesterol.
Impact of liver fibrosis on the cardiovascular outcome in NAFLD
Kim, 201327A retrospective cohort studyNFS, APRI index, FIB-4 scoreCompared to NAFLD patients without LF, those with a high probability of advanced LF had a 69% increase in mortality after adjustment for other known predictors of mortality. These increases in mortality were almost entirely from cardiovascular causes.
Park, 202128A prospective cohort studyBARD scoreNAFLD patients with advanced LF demonstrated a significantly higher incidence of heart failure, hospitalized heart failure, all–cause mortality and cardiovascular mortality compared to NAFLD patients without advanced LF.
Impact of liver fibrosis on the cardiovascular comorbidities in NAFLD Subclinical coronary atherosclerosis
Jamalinia, 202329Systematic review and meta-analysisNo data availableA significant association of subclinical atherosclerosis with LF in NAFLD patients was revealed, as well as its correlation with LF stages.
Song, 201930A retrospective, cross-sectional studyNFS, FIB-4 score, Forns index, APRI indexAn association of coronary atherosclerosis with LF in NAFLD patients was revealed.
Tsai, 202231A retrospective cohort studyNFS, FIB-4 score, Forns index, APRI indexThe male gender, diastolic blood pressure, and NFS in NAFLD patients were independently associated with coronary segment stenosis score progression.
Chen, 201532A prospective cross-sectional studyNFSCompared to NAFLD patients without advanced LF, presence of advanced LF associated with a 303% increased risk for elevated carotid intima-media thickness, a 398% increased risk of prevalence of carotid plaque, and a 456% increased risk for prevalence of arterial stiffness.
Kim, 202233A retrospective, cross-sectional studyNFS, BARD scorePatients with lean NAFLD and advanced LF had a significantly higher risk for atherosclerotic CVDs than those with obese NAFLD with or without advanced LF.
Coronary artery disease
Sinn, 202034A retrospective cohort studyNFS, FIB-4 scoreNAFLD patients with advanced LF may have an increased risk of myocardial infarction.
Higashiura, 202235A prospective cohort studyFIB-4 scoreLF stage in NAFLD patients correlated with new onset of ischemic heart disease in the group with “fatty liver”, but not in the group without “fatty liver”.
Subclinical cardiac structural and functional abnormalities
Lee, 201836A prospective cohort studyTransient elastography, NFSCompared to those without NAFLD, NAFLD patients had alterations in cardiac remodeling, manifested by increased left ventricular mass index, left ventricular end-diastolic diameter, and left atrial volume index. NAFLD patients with advanced LF demonstrated higher values of left ventricular filling pressure and tended to increase it.
Chung, 201837A prospective cross-sectional studyNFSThe risk of diastolic dysfunction in NAFLD patients gradually increases according to the LF severity.
Canada, 201938A prospective cross-sectional studyLiver biopsyOn stress echocardiography in NAFLD patients a significant stepwise increase in stress left ventricular filling pressure with increasing LF stage was noted. A trend between impaired left ventricular relaxation with exercise and increasing LF stages was also noted.
Lee, 202039A retrospective cohort studyNFSLF in NAFLD patients was independently associated with diastolic dysfunction after adjusting for insulin resistance and cardiometabolic risk factors.
Sunbul, 201540A prospective cohort studyLiver biopsyNAFLD patients with LF had significantly lower RV function assessed by GLS compared to patients without LF. NASH CRN score ≥5 was associated with lower RV-GLS. NASH CRN score inversely correlated with RV-GLS such as patients with impaired RV-GLS (<19%) showed significantly higher NASH CRN score compared to normal RV-GLS group.
Cardiac arrhythmias
Käräjämäki, 201741A prospective cross-sectional studyTransient elastography, NFSLF severity was highest in NAFLD patients with atrial fibrillation.
Park, 202042A retrospective cohort studyFIB-4 scoreLF severity in NAFLD patients had a significant correlation with atrial fibrillation.
Kang, 202043A retrospective, cross-sectional studyNFS, FIB-4 scoreLF severity in NAFLD patients was associated with atrial fibrillation.
Cardiac conduction defects
Mantovani, 201744A retrospective cross-sectional studyFIB-4 score, APRI indexNAFLD patients with advanced LF had a substantially greater prevalence of heart block as compared to NAFLD patients with mild and moderate LF or persons without NAFLD.

*The research results are statistically significant. APRI, AST to Platelet Ratio; CRN, Clinical Research Network; CVDs, cardiovascular diseases; FIB-4, fibrosis-4; GLS, global longitudinal strain; LF, liver fibrosis; NAFLD, non-alcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NFS, NAFLD fibrosis score; RV, right ventricular; T2DM, Type 2 Diabetes Mellitus.

Impact of liver fibrosis on cardiovascular risk in NAFLD

It has been shown that patients with NASH or advanced LF are at a higher risk of atherosclerotic CVDs compared to non-LF NAFLD patients, independent of established cardiovascular metabolic risk factors.22 In a study by Labenz et al.,51 the overall 10-year CVDs risk, according to the Framingham risk scale, was high among patients with histologically confirmed NAFLD, with the highest risk observed in those with advanced LF. Noninvasive LF markers in NAFLD patients may be predictors of an increased risk of cardiovascular events, regardless of metabolic syndrome.23 For example, a FIB-4 score ≥2.67 was found to be a strong independent prognostic criterion for major adverse cardiovascular events in NAFLD and was invariably associated with unstable angina, myocardial infarction, heart failure, percutaneous coronary intervention, and coronary artery bypass grafting in addition to known cardiovascular risk factors.24 In a study by Hanson et al.,52 the NFS in NAFLD patients with advanced LF without prior CVDs was found to be an independent predictor of cardiovascular events, even after adjusting for the relevant covariates, which included cardiovascular risk indicators such as the Framingham risk score and atherosclerotic CVDs indicators. In the Alimentazione, Benessere Cardiovascolare e Diabete study, the LF severity assessed by transient elastography was an independent factor for a higher atherosclerotic CVDs risk in addition to steatosis after adjusting for obesity.25 Multivariate adjusted logistic regression models that were used in 3,276 adult participants of the Framingham Heart Study showed a significant association between advanced LF assessed by transient elastography and obesity-related signs, namely, hypertension, low high-density lipoprotein cholesterol and most notably, T2DM. This association persisted with a 2.5-fold increase even after accounting for controlled attenuation parameters. This suggests a link between LF and cardiometabolic diseases in addition to an association with liver steatosis.26

Impact of liver fibrosis on the cardiovascular outcome in NAFLD

Although liver-related complications are a significant cause of mortality in NAFLD, CVDs accounts for at least 40% of the total number of deaths in NAFLD, making it the predominant cause of mortality.53 According to a meta-analysis by Younossi et al.,1 the pooled CVDs-related mortality rate in NAFLD patients was 4.2 per 1,000 person-years. The NAFLD severity is the main factor determining the increased risk of CVDs. Therefore, patients with NASH and progressive LF can be classified as a special risk group.54 In a large study involving 11,154 patients, 34% of whom were diagnosed with NAFLD, higher values of noninvasive LF tests, such as the APRI index, FIB-4 score, and NFS, were associated with a progressive increase in CVDs mortality after correction for other predictors of death.27 In a study by Mann et al.,55 NAFLD patients with liver cirrhosis had higher mortality regardless of known cardiovascular risk factors. Additionally, liver steatosis and/or advanced LF in NAFLD patients assessed by the fatty liver index as well as the BARD score and NFS significantly correlated with the risk of heart failure and mortality.28,56

Impact of liver fibrosis on cardiovascular comorbidities in NAFLD

NAFLD can negatively affect both the coronary arteries and other heart anatomical structures, contributing to an increase in morbidity and mortality from CVDs among NAFLD patients.57 In particular, there is strong evidence linking NAFLD with the risk of developing coronary atherosclerosis and coronary artery disease, cardiac structural and functional abnormalities, cardiac valvular calcification, cardiac arrhythmias, and conduction defects.58

Subclinical coronary atherosclerosis

For a long time, NAFLD was not considered a probable cause of atherosclerosis but was recognized as a valuable indicator of the early stages of its development.59 Moreover, well-planned and controlled studies conducted in recent years have provided very valuable information that allows one to take a fresh look at the relationships among these pathological conditions.60 In particular, the association of LF in NAFLD with subclinical atherosclerosis was shown, and LF severity aggravated this relationship.29

Coronary artery calcium scoring via computerized tomography is usually used to determine the degree of coronary atherosclerosis. In a study involving 665 NAFLD patients, noninvasive LF markers, such as APRI index, NFS, and FIB-4 score, made it possible to reliably predict the values of the coronary calcium index >100 via computerized tomography.30 In a study by Tsai et al.,31 NAFLD patients with basal coronary plaques had higher NFSs, FIB-4 scores and Forns index, suggesting the possibility of their use for early identification of coronary plaques and prediction of the risk of adverse cardiovascular events. According to a study by Chen et al.,32 NAFLD patients with advanced LF assessed by the NFS had a higher probability of carotid artery intima-media thickening, the presence of carotid plaque and arterial stiffness, regardless of known metabolic factors, prior cardiovascular events, or insulin resistance. It was found that NASH patients have higher carotid artery intima-media thickness than nonalcoholic fatty liver patients. In addition, NASH patients had high levels of high-sensitivity C-reactive protein, and the levels of high-sensitivity C-reactive protein were significantly correlated with LF. It is known that high levels of highly sensitive C-reactive protein are associated with an increased risk of heart attack.61 Interestingly, lean NAFLD patients with advanced LF are more likely to have atherosclerotic CVDs than obese subjects.33

Coronary artery disease

The presence, severity and prevalence of coronary artery disease may be associated with NAFLD, regardless of well-known risk factors. In addition, the relationship between coronary artery disease and NAFLD may be attributed to the formation of atherosclerotic coronary plaques characteristic of both diseases. Their calcium content according to computerized tomography data is a clinically significant sign of subclinical coronary artery disease.62 In a study by Wong et al.,63 NAFLD patients prevailed among those with significant coronary artery stenosis. An association between NAFLD and an increased risk of acute myocardial infarction has also been shown, regardless of known risk factors.34 An independent correlation was shown between the FIB-4 score in NAFLD patients and the risk of coronary artery disease.35 In a study by Ghoneim et al.,64 it was found that NASH is associated with acute myocardial infarction regardless of the established risk factors. The probability of acute myocardial infarction in young NASH patients was higher than that in older subjects. Acute myocardial infarction is a frequent outcome in NASH patients.

Subclinical cardiac structural and functional abnormalities

Recent studies have identified NAFLD as a risk factor not only for premature coronary artery disease and cardiovascular events but also for early cardiac structural and functional abnormalities. For example, in a study by Lee et al.,36 it was demonstrated that advanced LF in NAFLD patients without a history of CVDs correlates with an increase in left ventricular filling pressure, which is associated with diastolic dysfunction associated with impaired myocardial glucose uptake. It was noted that left ventricular diastolic dysfunction in advanced LF was significant only in NAFLD patients without obesity.37 Alterations in myocardial structure and in the load dependence of left ventricular diastolic function parameters were also observed in NASH patients without a history of CVDs.65 Another study revealed that NASH patients with liver cirrhosis had an increased prevalence of diastolic dysfunction compared with patients with other causes of liver cirrhosis.66 Diastolic dysfunction in NASH patients leads to a decrease in physical performance. The severity of these disorders correlates with the LF stage.38 In a study by Lee et al.39 including T2DM patients aged ≥50 years, participants with NAFLD had changes in left ventricular structure and diastolic dysfunction compared to non-NAFLD patients. Advanced LF significantly correlated with left ventricular diastolic dysfunction after correction for cardiovascular risk factors, especially in patients without insulin resistance. Although NASH is accompanied by a higher frequency of left ventricular diastolic dysfunction, this does not affect the immediate post-transplant outcome or 30-day mortality from all causes.67 Sunbul et al.40 have shown that NAFLD patients with LF have significantly lower right ventricular function compared to patients without LF. They used the NASH CRN histological scoring system as an independent predictor. It turned out that the NASH CRN score ≥5 was associated with lower right ventricular global longitudinal strain. The NASH CRN score inversely correlated with right ventricular global longitudinal strain. Patients with impaired right ventricular global longitudinal strain had a higher NASH CRN score than did those with normal right ventricular global longitudinal strain. Cardiac structural and functional abnormalities contribute to the development of heart failure, which, in NAFLD, occurs with a preserved ejection fraction. The relationship between more advanced heart failure and LF stage was evident in NAFLD patients. Left atrial dilatation and more pronounced diastolic dysfunction were observed in NAFLD patients with advanced LF.68

Cardiac arrhythmias

Atrial fibrillation is an extremely important social problem due to its large prevalence and high morbidity and mortality rates.69 Atrial fibrillation often occurs in NAFLD patients, in whom it usually has a permanent (chronic) form.70 In a study by Whitsett et al.,71 atrial fibrillation was found to be twice as common in NASH patients than in the general population. An Oulu Project Elucidating the Risk of Atherosclerosis study revealed a link between atrial fibrillation and liver stiffness measured by transient elastography in elderly NAFLD patients.41 A number of studies have shown an independent association between atrial fibrillation and advanced LF assessed by NFS and FIB-4 score in NAFLD patients.42,43

Cardiac conduction defects

Cardiac conduction defects are a well-established risk factor for general and cardiac mortality in NAFLD patients.72 In a study by Mantovani et al.,43 persistent heart block was found to be most common in NAFLD patients with T2DM in the presence of advanced LF, assessed by the FIB-4 score.

Conclusions

NAFLD occupies a leading position among liver diseases worldwide. Given that cardiovascular disorders are the most significant cause of unfavorable outcomes in NAFLD patients, identifying cardiovascular risk factors is an important public health issue. There is much evidence that LF can considerably increase morbidity and mortality from CVDs in NAFLD patients. Early diagnosis of LF will allow to stratify NAFLD patients by cardiovascular risk groups and thereby determine the most optimal therapeutic interventions.

Abbreviations

ALT: 

alanine aminotransferase

APRI: 

AST to Platelet Ratio

AST: 

aspartate aminotransferase

CRN: 

Clinical Research Network

CVDs: 

cardiovascular diseases

FIB-4: 

fibrosis-4

GLS: 

global longitudinal strain

LF: 

liver fibrosis

NAFLD: 

non-alcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

NASH: 

nonalcoholic steatohepatitis

NFS: 

NAFLD fibrosis score

RV: 

right ventricular

T2DM: 

type 2 diabetes mellitus

Declarations

Acknowledgement

None.

Funding

None.

Conflict of interest

The author has no conflict of interests related to this publication.

References

  1. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 2023;77(4):1335-1347 View Article PubMed/NCBI
  2. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023;77(5):1797-1835 View Article PubMed/NCBI
  3. Bisaccia G, Ricci F, Khanji MY, Sorella A, Melchiorre E, Iannetti G, et al. Cardiovascular Morbidity and Mortality Related to Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Curr Probl Cardiol 2023;48(6):101643 View Article PubMed/NCBI
  4. Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z. Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: A systematic review and meta-analysis. Sci Rep 2016;6:33386 View Article PubMed/NCBI
  5. Alon L, Corica B, Raparelli V, Cangemi R, Basili S, Proietti M, et al. Risk of cardiovascular events in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Prev Cardiol 2022;29(6):938-946 View Article PubMed/NCBI
  6. Mantovani A, Csermely A, Petracca G, Beatrice G, Corey KE, Simon TG, et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021;6(11):903-913 View Article PubMed/NCBI
  7. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016;65(3):589-600 View Article PubMed/NCBI
  8. European Association for the Study of the Liver (EASL)., European Association for the Study of Diabetes (EASD)., European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  9. Polyzos SA, Kechagias S, Tsochatzis EA. Review article: non-alcoholic fatty liver disease and cardiovascular diseases: associations and treatment considerations. Aliment Pharmacol Ther 2021;54(8):1013-1025 View Article PubMed/NCBI
  10. Chiriac S, Stanciu C, Girleanu I, Cojocariu C, Sfarti C, Singeap AM, et al. Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases: The Heart of the Matter. Can J Gastroenterol Hepatol 2021;2021:6696857 View Article PubMed/NCBI
  11. Byrne CD, Targher G. Non-alcoholic fatty liver disease-related risk of cardiovascular disease and other cardiac complications. Diabetes Obes Metab 2022;24(Suppl 2):28-43 View Article PubMed/NCBI
  12. Muzurović E, Mikhailidis DP, Mantzoros C. Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk. Metabolism 2021;119:154770 View Article PubMed/NCBI
  13. Godoy-Matos AF, Silva Júnior WS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr 2020;12:60 View Article PubMed/NCBI
  14. Yoshitaka H, Hamaguchi M, Kojima T, Fukuda T, Ohbora A, Fukui M. Nonoverweight nonalcoholic fatty liver disease and incident cardiovascular disease: A post hoc analysis of a cohort study. Medicine (Baltimore) 2017;96(18):e6712 View Article PubMed/NCBI
  15. Mullish BH, Forlano R, Manousou P, Mikhailidis DP. Non-alcoholic fatty liver disease and cardiovascular risk: an update. Expert Rev Gastroenterol Hepatol 2018;12(12):1175-1177 View Article PubMed/NCBI
  16. Tamaki N, Kurosaki M, Takahashi Y, Itakura Y, Inada K, Kirino S, et al. Liver fibrosis and fatty liver as independent risk factors for cardiovascular disease. J Gastroenterol Hepatol 2021;36(10):2960-2966 View Article PubMed/NCBI
  17. Garbuzenko DV, Belov DV. Non-alcoholic fatty liver disease as an independent factor of cardiometabolic risk of cardiovascular diseases. Exp Clin Gastroenterol 2021;194:22-34 View Article
  18. Garbuzenko DV. Pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver disease. Gastroenterol Hepatol Bed Bench 2022;15(3):194-203 View Article PubMed/NCBI
  19. Garbuzenko DV, Arefyev NO, Belov DV. Restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. World J Hepatol 2016;8(36):1602-1609 View Article PubMed/NCBI
  20. Styczynski G, Kalinowski P, Michałowski Ł, Paluszkiewicz R, Ziarkiewicz-Wróblewska B, Zieniewicz K, et al. Cardiac Morphology, Function, and Hemodynamics in Patients With Morbid Obesity and Nonalcoholic Steatohepatitis. J Am Heart Assoc 2021;10(8):e017371 View Article PubMed/NCBI
  21. Campos-Murguía A, Ruiz-Margáin A, González-Regueiro JA, Macías-Rodríguez RU. Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease. World J Gastroenterol 2020;26(39):5919-5943 View Article PubMed/NCBI
  22. Park JH, Koo BK, Kim W, Kim WH, Innovative Target Exploration of NAFLD (ITEN) Consortium. Histological severity of nonalcoholic fatty liver disease is associated with 10-year risk for atherosclerotic cardiovascular disease. Hepatol Int 2021;15(5):1148-1159 View Article PubMed/NCBI
  23. Baratta F, Pastori D, Angelico F, Balla A, Paganini AM, Cocomello N, et al. Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study. Clin Gastroenterol Hepatol 2020;18(10):2324-2331.e4 View Article PubMed/NCBI
  24. Vieira Barbosa J, Milligan S, Frick A, Broestl J, Younossi Z, Afdhal N, et al. Fibrosis-4 Index Can Independently Predict Major Adverse Cardiovascular Events in Nonalcoholic Fatty Liver Disease. Am J Gastroenterol 2022;117(3):453-461 View Article PubMed/NCBI
  25. Pennisi G, Di Marco V, Buscemi C, Mazzola G, Randazzo C, Spatola F, et al. Interplay between non-alcoholic fatty liver disease and cardiovascular risk in an asymptomatic general population. J Gastroenterol Hepatol 2021;36(9):2389-2396 View Article PubMed/NCBI
  26. Long MT, Zhang X, Xu H, Liu CT, Corey KE, Chung RT, et al. Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study. Hepatology 2021;73(2):548-559 View Article PubMed/NCBI
  27. Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013;57(4):1357-1365 View Article PubMed/NCBI
  28. Park J, Kim G, Kim H, Lee J, Lee YB, Jin SM, et al. The association of hepatic steatosis and fibrosis with heart failure and mortality. Cardiovasc Diabetol 2021;20(1):197 View Article PubMed/NCBI
  29. Jamalinia M, Zare F, Lankarani KB. Systematic review and meta-analysis: Association between liver fibrosis and subclinical atherosclerosis in nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2023;58(4):384-394 View Article PubMed/NCBI
  30. Song DS, Chang UI, Kang SG, Song SW, Yang JM. Noninvasive Serum Fibrosis Markers are Associated with Coronary Artery Calcification in Patients with Nonalcoholic Fatty Liver Disease. Gut Liver 2019;13(6):658-668 View Article PubMed/NCBI
  31. Tsai TY, Hsu PF, Wu CH, Huang SS, Chan WL, Lin SJ, et al. Association between Coronary Artery Plaque Progression and Liver Fibrosis Biomarkers in Population with Low Calcium Scores. Nutrients 2022;14(15):3163 View Article PubMed/NCBI
  32. Chen Y, Xu M, Wang T, Sun J, Sun W, Xu B, et al. Advanced fibrosis associates with atherosclerosis in subjects with nonalcoholic fatty liver disease. Atherosclerosis 2015;241(1):145-150 View Article PubMed/NCBI
  33. Kim Y, Han E, Lee JS, Lee HW, Kim BK, Kim MK, et al. Cardiovascular Risk Is Elevated in Lean Subjects with Nonalcoholic Fatty Liver Disease. Gut Liver 2022;16(2):290-299 View Article PubMed/NCBI
  34. Sinn DH, Kang D, Chang Y, Ryu S, Cho SJ, Paik SW, et al. Non-alcoholic fatty liver disease and the incidence of myocardial infarction: A cohort study. J Gastroenterol Hepatol 2020;35(5):833-839 View Article PubMed/NCBI
  35. Higashiura Y, Tanaka M, Mori K, Mikami T, Hosaka I, Ohnishi H, et al. High fibrosis-4 index predicts the new onset of ischaemic heart disease during a 10-year period in a general population. Eur Heart J Open 2022;2(3):oeac030 View Article PubMed/NCBI
  36. Lee YH, Kim KJ, Yoo ME, Kim G, Yoon HJ, Jo K, et al. Association of non-alcoholic steatohepatitis with subclinical myocardial dysfunction in non-cirrhotic patients. J Hepatol 2018;68(4):764-772 View Article PubMed/NCBI
  37. Chung GE, Lee JH, Lee H, Kim MK, Yim JY, Choi SY, et al. Nonalcoholic fatty liver disease and advanced fibrosis are associated with left ventricular diastolic dysfunction. Atherosclerosis 2018;272:137-144 View Article PubMed/NCBI
  38. Canada JM, Abbate A, Collen R, Billingsley H, Buckley LF, Carbone S, et al. Relation of Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease to Left Ventricular Diastolic Function and Exercise Tolerance. Am J Cardiol 2019;123(3):466-473 View Article PubMed/NCBI
  39. Lee H, Kim G, Choi YJ, Huh BW, Lee BW, Kang ES, et al. Association between Non-Alcoholic Steatohepatitis and Left Ventricular Diastolic Dysfunction in Type 2 Diabetes Mellitus. Diabetes Metab J 2020;44(2):267-276 View Article PubMed/NCBI
  40. Sunbul M, Kivrak T, Durmus E, Akin H, Aydin Y, Ergelen R, et al. Nonalcoholic Steatohepatitis Score is an Independent Predictor of Right Ventricular Dysfunction in Patients with Nonalcoholic Fatty Liver Disease. Cardiovasc Ther 2015;33(5):294-299 View Article PubMed/NCBI
  41. Käräjämäki AJ, Kettunen O, Lepojärvi S, Koivurova OP, Kesäniemi YA, Huikuri H, et al. Presence of atrial fibrillation is associated with liver stiffness in an elderly Finnish population. PLoS One 2017;12(3):e0173855 View Article PubMed/NCBI
  42. Park HE, Lee H, Choi SY, Kim HS, Chung GE. The risk of atrial fibrillation in patients with non-alcoholic fatty liver disease and a high hepatic fibrosis index. Sci Rep 2020;10(1):5023 View Article PubMed/NCBI
  43. Kang MK, Park JG, Kim MC. Association between Atrial Fibrillation and Advanced Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease. Yonsei Med J 2020;61(10):860-867 View Article PubMed/NCBI
  44. Mantovani A, Rigolon R, Pichiri I, Bonapace S, Morani G, Zoppini G, et al. Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus. PLoS One 2017;12(10):e0185459 View Article PubMed/NCBI
  45. Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. J Gastroenterol 2021;56(11):951-963 View Article PubMed/NCBI
  46. Blond E, Disse E, Cuerq C, Drai J, Valette PJ, Laville M, et al. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease in severely obese people: do they lead to over-referral?. Diabetologia 2017;60(7):1218-1222 View Article PubMed/NCBI
  47. Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008;57(10):1441-1447 View Article PubMed/NCBI
  48. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Cárdenas E, Sánchez-Avila F, Vargas-Vorácková F. AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis. Ann Hepatol 2008;7(4):350-357 PubMed/NCBI
  49. European Association for Study of Liver., Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015;63(1):237-264 View Article PubMed/NCBI
  50. European Association for the Study of the Liver, Clinical Practice Guideline Panel; Chair:; EASL Governing Board representative:; Panel members. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis—2021 update. J Hepatol 2021;75(3):659-689 View Article PubMed/NCBI
  51. Labenz C, Prochaska JH, Huber Y, Nagel M, Straub BK, Wild P, et al. Cardiovascular Risk Categories in Patients With Nonalcoholic Fatty Liver Disease and the Role of Low-Density Lipoprotein Cholesterol. Hepatol Commun 2019;3(11):1472-1481 View Article PubMed/NCBI
  52. Henson JB, Simon TG, Kaplan A, Osganian S, Masia R, Corey KE. Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2020;51(7):728-736 View Article PubMed/NCBI
  53. Przybyszewski EM, Targher G, Roden M, Corey KE. Nonalcoholic Fatty Liver Disease and Cardiovascular Disease. Clin Liver Dis (Hoboken) 2021;17(1):19-22 View Article PubMed/NCBI
  54. Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology 2018;155(2):443-457.e17 View Article PubMed/NCBI
  55. Mann JP, Carter P, Armstrong MJ, Abdelaziz HK, Uppal H, Patel B, et al. Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors. PLoS One 2020;15(10):e0241357 View Article PubMed/NCBI
  56. Yoshihisa A, Sato Y, Yokokawa T, Sato T, Suzuki S, Oikawa M, et al. Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction. ESC Heart Fail 2018;5(2):262-270 View Article PubMed/NCBI
  57. Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73(8):948-963 View Article PubMed/NCBI
  58. Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut 2020;69(9):1691-1705 View Article PubMed/NCBI
  59. Trovato GM. Non-alcoholic fatty liver disease and Atherosclerosis at a crossroad: The overlap of a theory of change and bioinformatics. World J Gastrointest Pathophysiol 2020;11(3):57-63 View Article PubMed/NCBI
  60. VanWagner LB. New insights into NAFLD and subclinical coronary atherosclerosis. J Hepatol 2018;68(5):890-892 View Article PubMed/NCBI
  61. Ozturk K, Uygun A, Guler AK, Demirci H, Ozdemir C, Cakir M, et al. Nonalcoholic fatty liver disease is an independent risk factor for atherosclerosis in young adult men. Atherosclerosis 2015;240(2):380-386 View Article PubMed/NCBI
  62. Patil R, Sood GK. Non-alcoholic fatty liver disease and cardiovascular risk. World J Gastrointest Pathophysiol 2017;8(2):51-58 View Article PubMed/NCBI
  63. Wong VW, Wong GL, Yip GW, Lo AO, Limquiaco J, Chu WC, et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 2011;60(12):1721-1727 View Article PubMed/NCBI
  64. Ghoneim S, Dhorepatil A, Shah AR, Ram G, Ahmad S, Kim C, et al. Non-alcoholic steatohepatitis and the risk of myocardial infarction: A population-based national study. World J Hepatol 2020;12(7):378-388 View Article PubMed/NCBI
  65. Simon TG, Bamira DG, Chung RT, Weiner RB, Corey KE. Nonalcoholic Steatohepatitis is Associated with Cardiac Remodeling and Dysfunction. Obesity (Silver Spring) 2017;25(8):1313-1316 View Article PubMed/NCBI
  66. Izzy M, Soldatova A, Sun X, Angirekula M, Mara K, Lin G, et al. Cirrhotic Cardiomyopathy Predicts Posttransplant Cardiovascular Disease: Revelations of the New Diagnostic Criteria. Liver Transpl 2021;27(6):876-886 View Article PubMed/NCBI
  67. Marella HK, Kamal F, Peravali R, Jacob J, Nair SP. Left ventricular diastolic dysfunction in liver transplantation: a stronger association with non-alcoholic steatohepatitis. Clin Exp Hepatol 2020;6(2):158-162 View Article PubMed/NCBI
  68. Miller A, McNamara J, Hummel SL, Konerman MC, Tincopa MA. Prevalence and staging of non-alcoholic fatty liver disease among patients with heart failure with preserved ejection fraction. Sci Rep 2020;10(1):12440 View Article PubMed/NCBI
  69. Essien UR, Kornej J, Johnson AE, Schulson LB, Benjamin EJ, Magnani JW. Social determinants of atrial fibrillation. Nat Rev Cardiol 2021;18(11):763-773 View Article PubMed/NCBI
  70. Anstee QM, Mantovani A, Tilg H, Targher G. Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2018;15(7):425-439 View Article PubMed/NCBI
  71. Whitsett M, Wilcox J, Yang A, Zhao L, Rinella M, VanWagner LB. Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis. Liver Int 2019;39(5):933-940 View Article PubMed/NCBI
  72. Wijarnpreecha K, Panjawatanan P, Kroner PT, Cheungpasitporn W, Ungprasert P. Association between cardiac conduction defect and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Ann Gastroenterol 2020;33(6):661-666 View Article PubMed/NCBI
Copyright © 2024 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Translational Gastroenterology
  • eISSN 2994-8754

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2047033
  • Visits today : 790
Back to Top

Liver Fibrosis as an Independent Cardiovascular Risk Factor in Non-alcoholic Fatty Liver Disease

Dmitry Victorovich Garbuzenko
  • Reset Zoom
  • Download TIFF