Several epidemiological studies suggested that NAFLD may be both a consequence and a cause of metabolic syndrome and its individual features, and that the link of NAFLD/NASH with type 2 diabetes, hypertension and cardiovascular disease is more complex than previously believed.
ReviewHypertension, diabetes, atherosclerosis and NASH: Cause or consequence?
Introduction
Non-alcoholic fatty liver disease (NAFLD) defines the hepatic consequences of over-nutrition in individuals without secondary causes of hepatic steatosis, and encompasses a spectrum of pathologic conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), with or without cirrhosis and hepatocellular carcinoma (HCC).[1], [2]
NAFLD represents a major public health problem.3 The prevalence of the disease is increasing in parallel with the pandemic of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS), and is as high as 25% in the general adult population in Western countries.4 NAFLD is also significantly associated with increased long-term morbidity and mortality, primarily owing to cardiovascular disease (CVD).[1], [5], [6]
Traditionally considered as the simple “hepatic manifestation” of MetS, owing to its strong association with abdominal obesity, atherogenic dyslipidaemia, T2DM and hypertension (HTN), NAFLD has even closer mutual interrelationships with T2DM and other MetS components than previously thought.[2], [7], [8], [9] Indeed, on the one hand, MetS and its individual components predict the development and progression of NAFLD;[10], [11], [12], [13], [14] on the other hand, NAFLD is a precursor for the future development of MetS components.[6], [9], [15], [16], [17], [18], [19], [20], [21], [22], [23] Accordingly, it has also been suggested that ultrasonographic changes in NAFLD status over time may affect the risk of incident T2DM, HTN and other MetS components.[24], [25], [26]
Collectively, these findings have fuelled a “chicken and egg” dilemma regarding the temporal and causal relationship between NAFLD and cardiometabolic risk: is NAFLD a consequence or a cause of MetS and its individual components? Some recent community-based studies have developed this research question further by suggesting the existence of a bi-directional relationship and reciprocal causality relating NAFLD to T2DM and MetS.[22], [27], [28], [29], [30]
Herein, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and MetS components (especially T2DM and HTN), whilst also reviewing current knowledge surrounding the strong link between NAFLD and increased risk of incident CVD. Special attention will be paid to prospective studies that used imaging methods or biopsies to diagnose NAFLD. Finally, we also briefly discuss the putative pathophysiological mechanisms linking NAFLD to the risk of incident HTN, T2DM and CVD.
Section snippets
NAFLD and hypertension
Blood pressure has a continuous and consistent relationship with the risk of incident CVD. As such, HTN, affecting around 30% of the general population, is one of the strongest risk factors for CVD.[31], [32]
Up to 50% of hypertensive patients have NAFLD and several studies reported a strong association between blood pressure and NAFLD in both hypertensive and normotensive individuals.[33], [34], [35] Presence and severity of NAFLD have also been associated with increased arterial stiffness and
Diabetes increases risk of NAFLD
Patients with established T2DM display a high prevalence of NAFLD. Indeed, in these patients, NAFLD ranges from approximately 45% to 75% in large hospital-based studies and from 30% to 70% in population-based studies.57 For example, in the Valpolicella Heart Diabetes Study, involving nearly 3,000 Italian outpatients with T2DM, the prevalence of NAFLD on ultrasonography was 69.5%.58
Substantial evidence also indicates that people with T2DM are at high risk of developing NASH, and a twofold to
NAFLD and cardiovascular disease
NAFLD typically exists in a “milieu” of altered metabolism, including central obesity, dysglycaemia, atherogenic dyslipidaemia and HTN. Cumulatively, these aetiological factors increase the risk of CVD, so it is rational that CVD is the leading cause of death in patients with NAFLD.
Several authors have investigated the possible association between NAFLD and the risk of prevalent and incident CVD.[59], [83], [84], [85], [86] Whilst the association between NAFLD and increased CVD prevalence seems
Arterial hypertension
HTN has been associated with increased fibrosis progression in NAFLD.[126], [127] Experimentally, it has been shown that the renin-angiotensin-aldosterone (RAA) system may influence the development of HTN and hepatic fibrosis in rat models,128 as well as the occurrence of albuminuria in human NAFLD.51 Moreover, specific genetic polymorphisms encoding angiotensinogen are more common in patients with NASH than in control subjects,129 and a specific single nucleotide polymorphism of angiotensin II
Conclusions
This review reinforces the notion that NAFLD is a multisystem disease, which plays an important role in the development of atherosclerosis/CVD, T2DM and other cardiometabolic diseases by disrupting the regulation of multiple metabolic and inflammatory pathways.
Strong evidence indicates that the global health burden of NAFLD is not only confined to progressive liver disease, but also embraces major extra-hepatic complications. Indeed, the leading causes of mortality among patients with NAFLD are
Financial support
GT is supported in part by grants from the University School of Medicine of Verona, Verona, Italy.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
Study concept and design: AL, FN, AM, GT; acquisition of data: AL, FN, AM, GT; analysis and interpretation of data: AL, FN, AM, GT; drafting of the manuscript: AL, FN, AM, GT.
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