Over the past 100 years, cardiovascular disease (CVD) has become a leading cause of mortality and morbidity in developed countries, and similar trends have occurred for chronic liver disease. Subsequent research also indicated that people with non-alcoholic fatty liver disease (NAFLD) had a twofold increased risk of CV events and that this risk was doubled in those with liver fibrosis. However, no validated CVD risk score specific for NAFLD patients has yet been validated, as traditional risk scores tend to underestimate the CV risk in NAFLD patients. From a practical perspective, identifying NAFLD patients and assessing severity of liver fibrosis when concurrent atherosclerotic risk factors are already established may serve as an important criterion in new CV risk scores. The current review aims to assess current risk scores and their utility for the prediction of CV events among patients with NAFLD. Obesity is a multifactorial relapsing disease, as defined by the International Classification of Disease . AccordiBeing overweight or obese is among the main risk factors for developing non-alcoholic fatty liver disease (NAFLD), which is considered to be the most prevalent chronic liver disease worldwide . NAFLD iHowever, a new concept is emerging that is known as metabolic-associated fatty liver disease (MAFLD), which is a heterogenous clinical entity. The diagnostic criteria of MAFLD requires the presence of metabolic risk factors in the setting of hepatic steatosis, includes individuals with other concomitant liver diseases, and excludes those with hepatic steatosis who do not fulfill the metabolic risk criteria . Large cThe majority of people with NAFLD will not develop liver fibrosis or cirrhosis, yet some studies argue that by 2030, NASH will become the leading cause of liver transplant in the USA . An analAs previously reported, chronic liver disease (CLD) and cardiovascular diseases (CVDs) are stealing the spotlight in current epidemiological trends concerning morbidity and mortality rates. CVDs, which include ischemic heart disease, acute myocardial infarction, and stroke, are the most common non-communicable diseases globally, responsible for an estimated 17.8 million deaths in 2017 ,17. As tIn this manuscript, we aimed to review current risk scores and their utility for the prediction of cardiovascular events among patients with NAFLD. In light of more recent discoveries, we performed a literature search between January 2012 and January 2023 on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org, and ClinicalTrials.gov for English articles. The search terms used included, but were not limited to, “NAFLD”, “non-alcoholic fatty liver disease”, “risk scores”, “cardiovascular risk scores”, “cardiovascular risk factors”, “mortality prediction scores”, “cardiovascular risk assessment”, and “prediction models”. The cited articles were selected based on their relevance to the review objective.Whether liver disease in NAFLD confers any additional CV risk, or whether an increase in CV risk in NAFLD is due to associated CVD risk factors, is still a matter of avid discussion. Understanding whether the liver disease in NAFLD contributes to additional CVD risk is important, as it is plausible that treatment of the liver disease may reduce the overall risk of CVD above the treatment of NAFLD-associated risk factors . Recent Risk factors for NAFLD are quite diverse. Beginning with alterations of hepatic microvasculature, increased arterial stiffness, and distortion of sinusoidal patterns which leads to intrahepatic endothelial dysfunction  and activation of angiogenesis and vascular remodeling via VEGF, we can better understand the complex pathophysiological mechanisms behind an otherwise benign affliction . SystemiFurthermore, mitochondrial malfunction and disruption is one of the main mechanisms of liver and heart damage. This should not come as a surprise since mitochondria are crucial organelles involved in cellular metabolism and homeostasis of energy . Many elThere are multiple intricate underlying mechanisms by which NAFLD increases the risk of CVD . NAFLD iSystemic inflammation, endothelial dysfunction, plaque instability, IR, oxidative stress, and altered lipid metabolism are some of the mechanisms involved in the complex pathogenesis of NAFLD-CVD . The livVisceral adipose fat appears to have a strong independent positive correlation with liver fat. However, the mechanism linking visceral fat to CVD is related to IR, which is also associated with an increased CV risk and atherosclerosis . BesidesApolipoprotein-B-containing lipoproteins operate as damage-associated molecular patterns (DAMPs) that activate Toll-like receptors (TLRs) after being transported and oxidized within the subendothelial vascular wall . TriglycAs previously reported, vascular abnormalities and endothelial dysfunction are recognized as initial steps in disease progression in both CLD and CHD. Endothelial dysfunction is a complex process and is the foundation for atherosclerosis before plaque inflammation ,43. In aIR is another key metabolic feature of both cardiovascular and hepatic injury. Patients who have IR have a suppression of insulin’s effects, which causes the liver to continuously produce glucose . AdiposeThe genetic profile also contributes to disease outcome. Changes in the polymorphism of patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2 are linked to an increased risk of liver steatosis, fibrosis, and cancer ,54. HoweWhile some cohort studies revealed that NAFLD patients may have increased cardiovascular mortality, other research was unable to support this idea. For instance, a recent meta-analysis by Targher et al. revealed that people with NAFLD had a 64% higher likelihood than those without NAFLD of having fatal or nonfatal cardiovascular events. Non-fatal events included myocardial infarctions requiring coronary revascularization, strokes, and angina pectoris. The findings of Wu et al. differ from those of Tagher et al. in that they did not find a clear connection between the presence of NAFLD and an increase in cardiovascular mortality .A distinct risk group can be identified in patients with NAFLD who also have concurrent T2DM, NASH, or advanced fibrosis (F3–F4) . NAFLD pHs-CRP is a non-specific and sensitive marker for detecting inflammation that was proposed for its potential to add predictive value in several chronic diseases . A folloThe prevalence of arterial hypertension in NAFLD patients ranges from 40 to 70%, and recent research has demonstrated that NAFLD is closely linked to an elevated risk of incident prehypertension and hypertension . People Patients with NAFLD are more likely to develop both clinical and subclinical atherosclerosis. Patients with NAFLD may also be more susceptible to the development of atherosclerotic CVD due to an imbalance in procoagulant factors . In addiPatients with NAFLD/NASH are more likely to have subclinical CVD and several other cardiovascular risk factors . A summaBecause of the inherent limitations of using risk scores based on conventional CV risk-factor-derived multivariable statistical models to identify at-risk patients, the current global risk prediction studies are imperfect even though they may contribute to describing, at least in part, the relationship between NAFLD and increased CV risk ,31. AddiWith varying degrees of severity in each stage of simple steatosis and NASH, NAFLD progresses differently . Except for more severe cases of NASH+ fibrosis, these stages are typically reversible ,16,19. CTo diagnose the NAFLD stage and the degree of NASH and fibrosis by histological examination, as well as to track the course of the illness, liver biopsy is currently the “gold standard” (accounting for possible errors caused by sampling variability) . CurrentNAFLD can develop in individuals who are not overweight. In recent years, emerging evidence has demonstrated that lean NAFLD is a progressive condition and that predominantly male patients with lean NAFLD exhibited some features of MetS and might have worse outcomes than obese-NAFLD . WhetherThe NAFLD Liver Fat Score has its origins in a Finnish population . InsulinThe fatty liver index is based on BMI, the AST/ALT ratio, and the existence of T2DM, and this measure evaluates MAFLD/NAFLD ,85,86,87The APRI (AST-to-Platelet Ratio Index) is another easy-to-use tool to quickly assess the presence of fibrosis. It has been validated for the identification of NAFLD and can identify advanced fibrosis in those with viral infection. APRI is regarded as a good predictor of progressive fibrosis in patients with NAFLD . NeverthAnother widely used score is the NAFLD fibrosis score. Age, glucose levels, BMI, albumin and platelet count, and AST/ALT ratio are the parameters used. This score is widely used to predict advanced fibrosis. Particularly, patients with NAFLD have reduced levels of albumin and albumin-binding function. A high score (>0.68) significantly increased the probability of death in MAFLD/NAFLD patients by four times . Even thIn addition to risk-stratifying methods based on fibrosis for the MAFLD/NAFLD spectrum, many authors have proposed non-invasive scoring systems as screening tools for liver disease. However, some healthcare experts continue to emphasize liver biopsy as the gold standard for diagnosis while arguing for a thorough characterization of biopsy indications. However, fatty liver index, APRI, fibrosis-4 index, and NAFLD fibrosis score, in contrast to other available risk scores, depend on commonly requested parameters, making them easier to utilize in daily clinical practice . AdditioAlthough NAFLD is a common disease, there are no approved therapies. As previously reported, the leading causes of death in patients with NAFLD are complications of cardiometabolic disease. Therefore, efforts are directed toward developing drugs that target both NAFLD and cardiometabolic risk factors. Currently, several therapeutic agents have been proposed and are under assessment . Given tThe causal bidirectional relationship between CVD and NAFLD is more tangible nowadays. Early clinical intervention in at risk patients could alter the disease course. Moreover, patients who share multiple cardiometabolic risk factors who are at risk for developing CV events should benefit from early clinical and therapeutic intervention. Current guidelines do not recognize NAFLD as an independent risk factor for CVD, despite recent research indicating NAFLD’s involvement in incident CVD. Improving patient safety requires a greater understanding of the biopsy-free scores that are available for staging. Both NAFLD and CVD are silent pandemics, which are constantly expanding, and they compel clinicians to look for alternate methods of screening, early detection, and follow-up. Prospective long-term studies with homogeneous diagnostic criteria, considering not only the presence but also the severity of NALFD, are necessary to test if this diagnosis can improve cardiovascular disease risk stratification. New and inclusive risk scores are needed to address complex patients who are at risk of developing either CV events or progression toward more advanced and irreversible liver disease with overall poor outcome. Emerging new therapies could change the face of NAFLD patients.


Non-alcoholic fatty liver disease affects up to a quarter of the adult population in many developed and developing countries. This disease has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of hepatocarcinoma varies between patients with cirrhosis and noncirrhotic patients. In this review, HCC associated with non-alcoholic fatty liver disease will be described, considering its epidemiology, risk factors, and management, including preventive strategies and therapeutic approaches.Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. The incidence of NASH is projected to increase by up to 56% over the next 10 years. There is growing epidemiological evidence that NAFLD has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of HCC varies between patients with NASH cirrhosis and patients with noncirrhotic NAFLD. In this review, NAFLD/NASH-associated HCC will be described, including its epidemiology, risk factors promoting hepatocarcinogenesis, and management of HCC in patients with obesity and associated metabolic comorbidities, including preventive strategies and therapeutic approaches to address this growing problem. Non-alcoholic fatty liver disease (NAFLD) is becoming the most common cause of chronic liver disease and cirrhosis. The condition encompasses a spectrum of conditions ranging from non-alcoholic fatty liver (NAFL) or simple steatosis, characterized by hepatic triglyceride accumulation in the hepatocytes without inflammation, to non-alcoholic steatohepatitis (NASH), which is represented by steatosis plus liver inflammation, and finally hepatic fibrosis and cirrhosis and/or hepatocellular carcinoma (HCC) .The incidence and prevalence of NAFLD have had a rapid and significant rise in recent decades worldwide ,3. A recRegarding the incidence of NAFLD, even if the data on it are more scarce, because of the lack of methodologically correct studies on this matter, the abovementioned meta-analysis reported an increase of about 58% from 1994–2006 to 2010–2014, with an estimation of 28.9 cases per 1000 person-years, with a strong correlation with older age (>50 years) and obesity, which is closely related to the increased incidence of insulin resistance, metabolic syndrome, and type 2 diabetes (T2DM) in the general population  and incidence [incidence rate ratio of 0.28 (95% CI: 0.18–0.42)] with respect to those (in matched cohorts) who did not undergo this procedure [Patients with NAFLD and a BMI ≥ 35 kg/m surgery . These r surgery . Moreoverocedure When lifestyle changes are not sufficient, pharmacological therapy should be indicated. Several drugs have been proposed, targeting directly or indirectly the major components of the pathophysiology of inflammation and fibrosis in NAFLD . A comprStatins, HMG-CoA reductase inhibitors, are the major lipid-lowering drugs prescribed; they act by reducing the endogenous production of cholesterol with partial resolution of the liver histology, but also by their anti-inflammatory, anti-proliferative, and anti-angiogenic effects . A recenAmong antidiabetic drugs, thiazolidinediones, and Pioglitazone in particular, showed good results in terms of liver histology of diabetic patients with NAFLD . They acRecent studies are evaluating the effects of GLP-1 agonists on the liver. Liraglutide appears to be able to inhibit de novo lipogenesis in the liver and to improve the sensitivity of cells to insulin ,100. SimOther studies have demonstrated a reduction in necroinflammation and ballooning degeneration, with resolution of NASH in a proportion of cases after the intake of high doses (800 IU/day) of vitamin E, which has an antioxidant action ,103. HowFurthermore, recent studies in mouse models on Nicotinamide N-methyltransferase, an enzyme mainly expressed in the liver , report Finally, very recently, other studies have reported on a new class of drugs which is the “dual agonist drugs”, such as Efinopegdutide and Tirzepatide, in patients with NAFLD, obesity, and/or type 2 diabetes ,115. ThiObeticholic acid, a farnesoid X receptor agonist, is the only drug shown to improve fibrosis without worsening NASH; however, it is necessary to point out that its use has also been related to the side effect of LDL hypercholesterolemia which further increases the cardiovascular risk of these patients . HoweverCenicriviroc, a dual antagonist of the chemokine receptors CCR2 and CCR5, localized on stellate and Kuppfer’s cells, has been tested in NASH subjects. The pathophysiological basis was that the antagonization of these receptors blocks hyperinflammation and fibrogenesis . AccordiIn conclusion, at the time of this review, no pharmacological therapy has been approved precisely for the cure of NAFLD/NASH, and, whereas several molecules are at various levels of experimental development, just as many promising therapies have failed at the interim analyses of the phase 3 studies by not achieving the primary endpoints proposed by FDA and EMA for considering them efficacious in NAFLD/NASH: (i) resolution of NASH by histology without worsening of fibrosis and/or (ii) improvement in fibrosis without worsening of NASH. The causes of these failures are complex and multifaceted and are related to the complexity of the pathophysiology of NAFLD itself, together with the uncertainties on the assessment of its diagnosis and progression/regression. These aspects make difficult to identify the right therapy for the right patients, thus dooming potentially promising drugs to failure .Treatment options for HCC can be classified into surgical resection and non-surgical therapies . As descIn a such scenario, in which any novel therapy for NAFLD has failed the abovementioned endpoints on fibrosis and/or steatohepatitis or it is still in a preliminary phase of study, it is difficult to report on any noticeable effect on HCC occurrence of these drugs. However, it is logical to infer, even if without any evidence so far, that the development of any therapy that could be efficacious in improving steatohepatitis and/or fibrosis progression could lead to a reduction in HCC incidence, also because of several pathophysiological mechanisms they have in common .As a proof of this fact, Metformin, the drug used in the first line in the pharmacological therapy of TD2M, has not demonstrated benefits on liver histology; however, this drug would potentially be able to reduce the incidence of HCC in patients with NASH as, through AMP, it activates the protein kinase that downregulates c-Myc as demonstrated in a mouse model . Even ifWith regard specifically to HCC pharmacological chemotherapy, recent findings suggest that immunotherapy is promising to reduce the recurrence of HCC and provides treatment options for advanced HCC that is not suitable for surgical resection. The U.S. Food and Drug Administration (FDA) in recent years has approved several drugs for systemic HCC treatment, such as Sorafenib, a multi-kinase inhibitor , LenvatiTo date, the main management strategy in the case of cirrhosis and fibrosis is identical to the chronic liver diseases of other etiologies. In particular, it is aimed at controlling the underlying condition and secondary prevention of complications. Patients with cirrhosis will have to undergo periodic control esophagogastroduodenoscopy (EGDS) to evaluate esophageal varices and to eventually proceed with their ligation; in these subjects, the use of non-selective β-blockers to prevent their enlargement is also indicated . In the International guidelines suggest that, in the presence of liver cirrhosis of any etiology, which is considered the major driver of hepatocarcinogenesis, an active surveillance ultrasound is indicated every 4–6 months, aimed at the early identification of potentially neoplastic nodules. Nodules smaller than 1 cm should be followed with a closer ultrasound check (every 3 months) to monitor the growth more accurately. If the nodule is larger than 1 cm, more in-depth examinations such as contrast enhanced ultrasonography (CEUS) or CT/MRI with contrast are indicated. For a definitive diagnosis, liver biopsy is indicated ,137. HowThe BCLC (Barcelona Clinic Liver Cancer) system used for staging liver cancer, takes into account the number and size of the tumor, the stage of the underlying liver disease  and the patient’s condition, dividing them into five stages: stages 0 and A, B, C, and D .In stages 0 and A, it is possible to conduct therapy with curative intent by resection and ablation. Liver transplantation is the best option for patients who meet the Milan criteria: single tumor <5 cm or less than three tumors each <3 cm. In stage B, transarterial chemoembolization (TACE) is indicated; it blocks the hepatic artery to deliver massive doses of chemotherapy with minimal systemic toxicity; it is not applicable in the presence of cirrhosis and portal hypertension due to the vascular consequences induced by these stages. In the advanced stage (BCLC C), systemic therapy with VEGF inhibitors and, recently, with immune checkpoint inhibitors is indicated. However, there are several concerns regarding the literature data that seem to indicate that precisely NAFLD-related HCC is less chemosensitive to these new treatments with respect to those related to viral etiologies . TerminaIn conclusion, the fat accumulation in the hepatocytes (namely liver steatosis) associated with lipid and sugar metabolism derangements, a condition which went under the name of non-alcoholic fatty liver disease (NAFLD) and now has been categorized as metabolic-associated steatotic liver disease (MASLD), represents a continuously increasing challenge for physicians and researchers who are facing (and more and more in future they will) several issues related to its increasing epidemiology and diffusion, diagnostic and management issues, therapeutical problems, and, finally, the problematic HCC surveillance, diagnosis, and management.