Understanding the association between developing a fatty liver and subsequent cardio-metabolic complications

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is also predicted to become the most frequent indication for liver transplantation by 2030. In the last decade, it has become evident that the clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, but there is now compelling evidence that NAFLD is a multisystem disease, affecting many extra-hepatic organs. In this article, we discuss the evidence linking NAFLD with important cardiometabolic complications (mainly Type 2 diabetes and cardiovascular disease) and the putative underlying mechanisms by which NAFLD may contribute to the development of these complications.

Keywords:

• cardiovascular disease
• metabolic syndrome
• NAFLD
• NASH
• Type 2 diabetes

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver diseases worldwide, causing considerable liver-related morbidity and mortality [1]. Over the past decade, it has also become increasingly clear that NAFLD is a multisystem disease that affects a variety of extra-hepatic organ systems [2]. Convincing evidence now substantiates a strong link between NAFLD and the development of important cardiometabolic complications, mainly cardiovascular diseases (CVD) and Type 2 diabetes mellitus (T2DM) [1–4].

Abundant data link NAFLD with subclinical CVD markers. A recent systemic review and meta-analysis involving 27 cross-sectional studies clearly showed that NAFLD was associated with increased carotid wall thickness, impaired flow-mediated vasodilation, increased arterial stiffness and coronary artery calcification [5]. All these associations were independent of traditional cardiovascular risk factors and metabolic syndrome (MetS) across a wide range of patient populations [5]. Recent results from the Framingham Heart study further confirmed this notion, showing that there was a significant association between NAFLD and subclinical CVD outcomes, independent of many metabolic diseases/traits [6]. Numerous hospital- and population-based studies have shown that the prevalence of clinically manifest CVD is also remarkably increased in NAFLD patients [2–4]. Again, in patients referred for clinically indicated coronary angiography, the presence of NAFLD was associated with a greater severity of coronary atherosclerosis, independently of traditional risk factors [7,8]. Notably, some recent cross-sectional studies also suggested that NAFLD patients are not only more prone to develop coronary atherosclerosis, but they are also more likely to have high-risk atherosclerotic plaques that are more susceptible to rupture [9,10].

Most importantly, there are now about 20 retrospective and prospective studies that have assessed the relationship between NAFLD and the risk of developing future CVD events [2]. Most of these studies showed that NAFLD is associated with increased CVD mortality and morbidity, independently of traditional risk factors and MetS traits. With regard to the published studies that included patients with biopsy-confirmed NAFLD, some of these cohort studies with a reasonably long follow-up period have shown that the all-cause mortality rate is greater in patients with NAFLD than in matched control populations, and that this increase is largely due to CVD and liver-related causes [11–13]. These studies have also shown that the histologic severity of liver fibrosis is the main determinant of all-cause and cause-specific mortality. The latest analyses of the Third National Health and Nutrition Examination Survey database have also confirmed that ultrasonographic NAFLD with advanced hepatic fibrosis (as estimated by non-invasive scoring systems) is independently associated with increased all-cause mortality, and that this increase in mortality is largely due to CVD causes [14].

To date, accumulating evidence also supports a link of NAFLD with functional and structural cardiac alterations both in adults and in children with, or without, co-existing MetS features [2,3]. For example, in a recent cross-sectional analysis of 2713 participants from the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study, VanWagner LB et al. showed that NAFLD was independently associated with systolic and diastolic dysfunction, higher cardiac output and myocardial remodeling and provided further insight into a possible link between NAFLD and heart failure [15].

NAFLD is now increasingly diagnosed in individuals who do not have T2DM or MetS. This supports the assertion that the conventional paradigm of NAFLD representing the ‘hepatic manifestation’ of the MetS is outdated, and it is now becoming increasingly evident that NAFLD is also a pathogenic determinant of the MetS [1,2]. With regard to this evolving concept, there is now convincing evidence suggesting that NAFLD may precede the development of T2DM and MetS. There are now approximately 30 retrospective and prospective studies that provided strong evidence for NAFLD as an independent predictor of the development of T2DM or MetS [16]. Notably, in a cohort of over 12,000 Korean individuals, Sung et al. examined the impact of resolution of fatty liver on the risk of T2DM at the 5-year follow-up to establish whether NAFLD improvement was associated with T2DM risk reduction [17]. These data demonstrated that there was a significant T2DM risk reduction in those subjects in whom fatty liver on ultrasonography resolved over time. Conversely, the individuals in whom the severity of fatty liver worsened over 5 years showed a marked increase in T2DM risk, further supporting the notion that more severe forms of NAFLD are associated with a higher risk of incident T2DM [17]. More recently, another large retrospective cohort study showed that NAFLD improvement was significantly associated with reduced T2DM incidence [18].

From the above-mentioned published data, it is important to understand how mechanistically pre-existent NAFLD may lead to the development of T2DM, CVD and other cardiac alterations.

The molecular mechanisms by which NAFLD may contribute to the development of these cardio-metabolic complications are not been fully elucidated. Improved understanding of these mechanisms would enable us to better tailor a treatment for this expanding clinical challenge. It is plausible to assume that the mechanisms linking NAFLD to T2DM and CVD/cardiac diseases are multifactorial, involve both genetic and acquired factors and often overlap with metabolic disorders, which may frequently coexist in NAFLD patients. However, increasing evidence suggests that, with the exception of cases where NAFLD results from either patatin-like phospholipase domain-containing 3 (PNPLA3) gene polymorphisms or familial hypobetalipoproteinemia in which NAFLD is usually dissociated from insulin resistance, NAFLD directly causes hepatic insulin resistance in most cases [16,19]. Experimental data indicate that the pathogenetic mechanisms that contribute to intra-hepatocytic lipid compartmentation are determinants of whether NAFLD is or is not associated with insulin resistance and T2DM [20]. Proposed mechanisms by which NAFLD causes hepatic insulin resistance implicate various lipid species, inflammatory signaling and other cellular modifications [20]. Recent evidence also supports a key role for hepatic diacylglycerol activation of protein kinase Cϵ in triggering hepatic insulin resistance. Dysregulation of intrahepatic lipid droplet metabolism may influence the intracellular compartmentation of diacylglycerol, which dictates whether or not protein kinase Cϵ will translocate to the plasma membrane, thereby promoting lipotoxicity and hepatic insulin resistance [21]. NAFLD may also contribute to T2DM development through the release of some circulating mediators, such as fetuin-A, selenoprotein P, FGF-21 and other specific hepatokines, which are involved in glucose metabolism and insulin sensitivity [1,2,16].

In addition, there is now compelling evidence indicating that NAFLD, especially its necro-inflammatory form, may induce atherogenic dyslipidemia and release a variety of pro-inflammatory markers, pro-coagulant factors and thrombogenic molecules that may promote the development and progression of CVD and other structural and functional myocardial alterations [1–4]. Although all these mechanisms plausibly link NAFLD with CVD/cardiac diseases, no studies to date have proven a cause–effect relationship and further research is needed to gain mechanistic insights into the pathophysiology that links NAFLD to CVD/cardiac diseases.

Collectively, from the data available in the literature, it is possible to speculate that the histological features and severity of NAFLD might differently affect the risk of developing T2DM and CVD/cardiac diseases. Indeed, the amount of liver fat appears to be a key pathogenic factor for the development of insulin resistance, atherogenic dyslipidemia and T2DM, independently of visceral adipose tissue [22]. As reported above, there is now a recent body of evidence that the development of, or resolution of, liver fat influences the risk of incident T2DM [17,18]. Conversely, we believe that the question of whether the prognostic role of NAFLD in the development of CVD is confined to NASH or is already present in simple steatosis remains still unresolved. Although some biochemical and histological data give an indication that the risk of major CVD events is mainly confined to NASH, or is at least most pronounced in NASH compared with simple steatosis (thus suggesting that hepatic necro-inflammation and fibrosis per se might be causative factors in the development of CVD), further methodologically stringent prospective studies in larger cohorts of patients with biopsy-proven NAFLD are needed to answer this question. Furthermore, uncertainty still remains about the prognostic role of NAFLD in CVD risk stratification. Future prospective studies are needed to assess whether the addition of NAFLD to conventional risk factors will improve CVD risk prediction [4]. Finally, more research is also needed to elucidate whether genetic-related NAFLD (e.g., PNPLA3-related NAFLD) carries the same risk as NAFLD occurring with the MetS for the development of both T2DM and CVD/cardiac diseases [19].

In the meantime, from the perspective of clinical practice, it is essential that specialists and practicing clinicians be aware of the strong link between NAFLD, CVD and T2DM, especially because of the high and growing prevalence of NAFLD. A multidisciplinary approach to the treatment of NAFLD patients based on a careful evaluation of coexisting risk factors and monitoring for CVD and liver complications is warranted. In particular, health care providers, who manage patients with NAFLD, should not only focus on liver disease but also recognize the increased risk of CVD and T2DM and undertake early, aggressive risk factor modifications.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.