Non-alcoholic fatty liver disease and risk of cardiovascular disease

doi:10.1016/j.metabol.2015.09.017

Metabolism

Volume 65, Issue 8, August 2016, Pages 1136-1150

https://doi.org/10.1016/j.metabol.2015.09.017 Get rights and content

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. During the past decade, it has also become increasingly evident that NAFLD is a multisystem disease that affects many extra-hepatic organ systems, including the heart and the vascular system. In this updated clinical review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong association of NAFLD with cardiovascular diseases (CVDs) and other functional and structural myocardial abnormalities. We also discuss some recently published data that correlate NAFLD due to specific genetic polymorphisms with the risk of CVDs. Finally, we briefly examine the assessment tools for estimating the global CVD risk in patients with NAFLD as well as the conventional and the more innovative pharmacological approaches for the treatment of CVD risk in this group of patients.

Introduction

Non-alcoholic fatty liver disease (NAFLD) describes the alcohol-like liver disease that occurs in the absence of alcohol abuse, and spans simple steatosis, non-alcoholic steatohepatitis (NASH) with/without cirrhosis and hepatocellular carcinoma (HCC). NAFLD is the most common cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity [1], [2]. However, over the past decade, it has become increasingly clear that NAFLD is also strongly associated with an increased risk of cardiovascular disease (CVD) [2], [3], [4], [5], [6], [7], which represents the leading cause of mortality among NAFLD patients [1], [2], [3]. While most NAFLD cases are strongly associated with obesity and other metabolic syndrome (MetS) traits, an as yet unknown proportion of NAFLD cases are associated with specific genetic polymorphisms among which the variant (G) allele at rs738409 of the patatin-like phospholipase domain containing-3 (PNPLA3) gene is probably the most common and best characterized [2].

Despite emerging evidence which suggests that NAFLD is also linked to other chronic diseases [7], [8], [9], [10], it is the adverse impact of NAFLD on CVD risk which deserves particular attention owing to the epidemics of obesity/MetS leading to a dramatic surge in the proportion of NAFLD patients in the general population.

Thus, in this clinical review we provide an update on the current evidence for a strong association of NAFLD with CVD and other structural and functional cardiac complications. As a novelty of this updated review that was not previously reviewed elsewhere, we also discuss in-depth the role of some genetic polymorphisms in the development and progression of both NAFLD and CVD. Indeed, it is uncertain whether genetic-related NAFLD (e.g., PNPLA3-related NAFLD) carries the same risk as NAFLD occurring with the MetS for the development of CVD/cardiac diseases. Finally, we also discuss how the CVD risk should be currently estimated and managed in patients with NAFLD.

Section snippets

NAFLD and CVD

As shown in Fig. 1, patients with NAFLD have a myriad of traditional and non-traditional risk factors for CVD [2], [3], [11]. This finding is the basis for therapeutic actions in preventing the development of CVD events in patients with NAFLD.

Abundant data link NAFLD with subclinical CVD markers [2], [3], [4]. In their meta-analytic review involving 7 cross-sectional studies, Sookoian et al. have firstly shown that NAFLD was associated with increased carotid-artery intimal medial thickness and

PNPLA-3 and TM6SF2 Genetic Variants

The genetic risk of NAFLD is strongly influenced by the nonsynonymous 738409 variant encoding an amino acid substitution p.Ile148Met and located in the PNPLA3 gene [55], [56]. After the first description of the association by a genome wide association study (GWAS) on NAFLD [55], this missense variant was associated not only with increased intra-hepatic triglyceride content but also with the histological severity and progression of disease [56], [57]. Overall, the PNPLA3-rs738409 was responsible

Estimation of CVD Risk in NAFLD

Presently, estimation of the global CVD risk in patients with NAFLD should be performed using the same methods used for individuals without NAFLD in primary prevention of CVD [2], [3], [4], [5]. The Framingham risk score (FRS) is currently the most practical tool to calculate the 10-year risk of developing a CVD event in adults aged ≥ 20 years, who do not have a prior history of CVD or diabetes. This risk score accurately predicted the CVD risk in a cohort of United States patients with NAFLD,

Conclusions

In this updated review of the published studies assessing the association between NAFLD and the risk of CVD and other functional and structural heart diseases, we provide further support to the assertion that there is a clear association of NAFLD with CVD and structural/functional cardiac abnormalities, though causality remains to be proven in well-controlled prospective and intervention studies. In the meantime, from the perspective of clinical practice, the notion that NAFLD is a powerful

Author Contributions

All authors researched the data, contributed to the discussion and wrote the manuscript.

Funding

GT is supported in part by grants from the University School of Medicine of Verona. SS and CJP are supported in part by grants from the Agencia Nacional de Promoción Científica y Tecnológica (PICT 2010-0441 and PICT 2012-0159).

Disclosure Statement

The authors have no potential conflicts of interest to disclose.

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Citation Excerpt :
The liver is a transducer of cardiovascular risk, through its central regulation of lipid and glucose metabolism, insulin signalling and the production of inflammatory and thrombogenic factors. As a consequence, ectopic fat accumulation within the liver leads to the release of pro-inflammatory, diabetogenic and atherogenic signals which may contribute to the development of atherosclerotic cardiovascular disease (ASCVD) [1–3]. Previous studies have demonstrated that ASCVD is the most common cause of death in individuals with hepatic steatosis (HS), however, an independent impact on ASCVD still needs to be confirmed [4–7].
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Non-alcoholic fatty liver disease and risk of cardiovascular disease

Abstract

Introduction

Section snippets

NAFLD and CVD

PNPLA-3 and TM6SF2 Genetic Variants

Estimation of CVD Risk in NAFLD

Conclusions

Author Contributions

Funding

Disclosure Statement

J Hepatol

Dig Liver Dis

Am J Kidney Dis

J Hepatol

Atherosclerosis

J Hepatol

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Clin Gastroenterol Hepatol

J Hepatol

Am J Cardiol

Nutr Metab Cardiovasc Dis

Metabolism

J Lipid Res

J Hepatol

J Hepatol

J Hepatol

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Clin Liver Dis

J Hepatol

Atherosclerosis

Adv Clin Chem

Ann Hepatol

Gastroenterology

J Hepatol

Gastroenterology

Atherosclerosis

The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

Am J Gastroenterol

Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis

Nat Rev Gastroenterol Hepatol

Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease

N Engl J Med

Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

World J Gastroenterol

Extra-hepatic complications of nonalcoholic fatty liver disease

Hepatology

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

Endocrine

Nonalcoholic fatty liver disease and decreased bone mineral density: is there a link?

J Endocrinol Invest

Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications

Semin Thromb Hemost

Liver: an alarm for the heart?

Liver Int

Presence of coronary plaques in patients with nonalcoholic fatty liver disease

Radiology

Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease

Gut

High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial

Radiology

Association between nonalcoholic fatty liver disease and carotid artery inflammation evaluated by 18F-fluoro-deoxyglucose positron emission tomography

Angiology

Long term prognosis of fatty liver: risk of chronic liver disease and death

Gut

Long-term follow-up of patients with NAFLD and elevated liver enzymes

Hepatology

Decreased survival of subjects with elevated liver function tests during a 28-year follow-up

Hepatology

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up

Hepatology

Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study

Hepatogastroenterology

Non-alcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients

Diabetes Care

Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease