Commentary Non-alcoholic fatty liver disease as driving force in coronary heart disease? Giovanni Targher Non-alcoholic fatty liver disease (NAFLD) has emerged as an imperative public health problem worldwide. NAFLD is now the most common chronic liver disease in high-income countries, and is estimated to affect at least 25%?30% of the general population.1 NAFLD typically exists in a ¡®milieu¡¯ of altered metabolism, including abdominal obesity, insulin resistance, dysglycaemia and atherogenic dyslipidaemia.1 Cumulatively, these aetiological factors increase the risk for cardiovascular disease (CVD), and so it is, perhaps, not surprising that CVD is the leading cause of mortality in patients with NAFLD. The challenge over the past decade has been to tease apart the complex inter-relationships between NAFLD and these aetiological factors, to establish whether NAFLD per se increases the risk of developing CVD. The validation of NAFLD as an independent risk factor would have direct relevance for primary preventative strategies against CVD. A prior narrative review published in 2010 by Ghouri et al2 concluded that a diagnosis of NAFLD was not sufficient to consider patients as being at high risk for CVD, and that the evidence base for CVD risk screening based on the presence of NAFLD was weak. However, over the years increasing evidence supports the existence of a strong association between NAFLD and increased CVD risk. Several cross-sectional studies have consistently demonstrated that NAFLD was associated with both clinically manifest CVD and various markers of subclinical atherosclerosis (including also increased coronary artery calcium (CAC) score).3 All these associations were independent of conventional CVD risk factors across a wide range of patient populations. Moreover, NAFLD was also associated with an increased prevalence of high-risk and vulnerable coronary artery plaques, independently of the extent and severity of coronary atherosclerosis.3 Convincing evidence now also substantiates the existence of a link of NAFLD with subclinical myocardial remodelling and dysfunction, valvular heart diseases (ie, aortic-valve sclerosis and mitral annulus calcification) and increased risk of cardiac arrhythmias (mainly atrial fibrillation).3 Although the cross-sectional associations of NAFLD with CVD and other cardiac complications are strong and consistent across different patient populations, the data on whether NAFLD per se is a new driving force in the development of CVD events remains an issue of debate. A recent systematic review and meta-analysis of 16 unique, observational studies, involving approximately 34?000 individuals (36.3% of whom with NAFLD as detected by imaging or histology) followed-up over a median period of 6.9?years, has confirmed that patients with NAFLD had a higher risk of fatal and non-fatal CVD events than those without NAFLD (random effect OR 1.64, 95% CIs 1.26 to 2.13).4 Patients with more ¡®severe¡¯ NAFLD (defined either by presence of hepatic steatosis on imaging plus either increased serum gamma-glutamyltransferase concentrations or high NAFLD fibrosis score or high 18F-fluoro-2-deoxyglucose uptake on positron emission tomography, or by increasing fibrosis stage on liver biopsy) were also more likely to develop fatal and non-fatal CVD events (OR 2.58; 95% CI 1.78 to 3.75).4 Although the results of this updated meta-analysis provide robust evidence of the association between NAFLD and risk of developing major CVD events; however, it is important to underline that the quality of published studies was not always high and that causality remains to be proven in high-quality intervention studies. Moreover, the key question of whether the prognostic role of NAFLD in CVD development is restricted to non-alcoholic steatohepatitis (NASH) or is also associated with simple steatosis still remains unresolved. More research is needed to address this issue. On this background of evidence, the longitudinal findings of Sinn et al5 add a further critical piece of information by confirming that patients with NAFLD are more likely to develop coronary atherosclerosis over time. In a large retrospective cohort of 4731 South Korean individuals with no history of CVD, the authors have examined, for the first time, the association between NAFLD and the progression of CAC score over a mean follow-up period of 3.9?years. Notably, they found that NAFLD diagnosed on ultrasonography was associated with an increased risk of CAC progression, independently of multiple established risk factors and potential confounders (including also the temporal changes in body weight, antihypertensive and lipid-lowering medications). The association between NAFLD and risk of CAC progression was also observed both in participants with CAC=0 and in those with CAC>0 at baseline, and was progressive across categories of NAFLD fibrosis score.5 These findings are clinically relevant and provide further support for the view that NAFLD is useful to identify subjects with a higher risk of subclinical coronary atherosclerosis progression and, therefore, CVD. These findings are in line with those recently published by the same authors on this cohort of Korean individuals showing that persistent NAFLD significantly increased the risk of carotid atherosclerosis, and that the HR, comparing subjects with regression of NAFLD versus those with persistent NAFLD, was 0.82 (95% CI 0.69 to 0.96; p=0.013).6 These findings are also in line with those of two recent studies7 ,8 Bhatia et al7 recently documented a significant association between an improvement in NAFLD severity, both in terms of markers of simple steatosis and steatohepatitis, and attenuation of carotid intima-media thickness progression during a 18-month randomised double-blind, placebo-controlled trial. Finally, in a longitudinal analysis of 1872 individuals attending a CVD primary prevention clinic who were followed-up for a mean period of 8?years, Pais et al8 reported that incident hepatic steatosis (as estimated by the fatty liver index) was associated with a greater increase in carotid intima-media thickness, and baseline hepatic steatosis predicted the development of carotid atherosclerotic plaques after adjustment for several cardiometabolic risk factors. Currently, there is a growing body of evidence suggesting that NAFLD is not only a simple marker of CVD but is also actively implicated in its pathogenesis.1 ,3 ,4 When NAFLD develops and hepatic fat, inflammation and fibrosis progress (NASH), many important alterations occur in the liver, resulting in the worsening of systemic/hepatic insulin resistance, the production of atherogenic lipids and the systemic release of a myriad of pro-inflammatory, pro-oxidant, prothrombogenic and vasoactive mediators.9 All these NAFLD-related alterations may influence the risk of CVD, contributing to the development of vascular, cardiac and arrhythmic complications. Collectively, therefore, the findings from the study by Sinn et al5 and other recently published studies (as discussed above) clearly indicate that a diagnosis of NAFLD identifies a subset of the general population, which is exposed to at higher risk of CVD. This also implies that patients with NAFLD should undergo careful cardiovascular surveillance. In line with this implication, given that CVD complications frequently dictate the outcome(s) of NAFLD, the recent European clinical practice guidelines have recommended screening of cardiovascular system in all patients with NAFLD, at least by detailed risk factor assessment.10 However, it is not yet established whether addition of NAFLD to the currently available risk assessment calculators improves CVD risk prediction.3 Moreover, randomised controlled trials with CVD outcomes that focus on treatments for liver disease in NAFLD are also needed in order to definitely establish a causal relationship between NAFLD and risk of CVD events. Finally, since NAFLD is heterogeneous and may also be caused by common genetic variants (eg, patatin-like phospholipase domain-containing 3 (PNPLA-3) variant, which is associated with increased liver fat content, but not with features of the metabolic syndrome),3 it will be also interesting to ascertain whether metabolic syndrome-related NAFLD and PNPLA-3-related NAFLD produce the same risk of developing CVD. Currently, there are no approved pharmacological agents for the treatment of NAFLD. Nevertheless, NAFLD and CVD share many cardiometabolic risk factors, and treatment strategies for NAFLD and CVD are similar, sharing the specific aims of modifying all the coexisting risk factors.1 Thus, clinicians who manage patients with NAFLD should focus on liver disease and also should recognise the increased risk of CVD of these patients, screen them for conventional risk factors and undertake early, aggressive risk factor modification(s).