Metabolic syndrome (MetS) has greatly increased in prevalence, along with the exponential increase of obesity worldwide [1]. Metabolic syndrome encompasses a group of metabolic disorders such as hypertension, central obesity, insulin resistance (IR), and atherogenic dyslipidemia and is strongly associated with an increased risk of developing diabetes and atherosclerotic and non-atherosclerotic cardiovascular disease (CVD), as well as liver fibrosis and hepatocarcinoma [2]. Genetic and acquired factors both contribute to MetS’ pathogenesis, as well as to the inflammation pathway leading to CVD and liver fibrosis [3]. Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer and is the third leading cause of cancer death worldwide [4]. HCC predisposing factors include liver cirrhosis, hepatitis B and C infections (HBV-HCV), non-alcoholic fatty liver disease (NAFLD), and, particularly, Type 2 diabetes mellitus (T2DM) [5]. This evidence has been confirmed by several studies, which reported an increased risk of developing HCC in T2DM patients, even in the absence of alcoholism, obesity, and chronic hepatitis ^[6][7][6,7]. By contrast, NAFLD plays an important role in the increased incidence of T2DM and its complications [8], through the development of IR, which is a key linking factor between these two diseases [9]. In recent years, vaccinations and newer highly effective oral antiviral therapies, including direct-acting antivirals, have reduced the risk of viral hepatocellular carcinoma [10]. However, a current analysis predicts an increase in HCC incidence driven by NAFLD, leading to a total of 12,240 cases per year by 2030 in the United States [11]. In fact, about 35% of non-alcoholic steatohepatitis (NASH) cases progress to liver fibrosis and potentially to end-stage liver disease or HCC ^[12][13][12,13].

NAFLD includes a large spectrum of diseases ranging from hepatic steatosis, fibrosis, NASH, to end-stage liver cirrhosis [14]. It has recently been described that up to 20% of individuals with NAFLD and T2DM will develop clinically significant liver fibrosis [15]. In the year 2020, a consensus of international experts proposed going beyond the current nomenclature “non-alcoholic fatty liver disease” (NAFLD) and change it to the acronym MAFLD, “metabolic dysfunction associated with fatty liver disease”, to further enhance the underlying condition of systemic metabolic dysfunction [16]. The diagnosis of MAFLD is based on the detection of hepatic steatosis (diagnosed by imaging, biomarkers, or histology) and at least one characteristic of overweight/obesity, T2DM, or metabolic dysregulation [17]. The last criterion is met when at least two features are present, including increased waist circumference, hypertension, hypertriglyceridemia, low HDL-C, prediabetes, IR, and inflammation or subclinical inflammation ^[16][18][16,18]. The MAFLD definition represents a paradigm shift that is able to identify a more homogeneous group of patients with fatty liver disease secondary to metabolic impairment. However, the impact of the new classification in clinical practice is not yet known. MAFLD patients with advanced fibrosis and cirrhosis have a higher risk of developing HCC, although HCC can occur even in the absence of advanced fibrosis [19]. Furthermore, it has been observed that patients with MAFLD-HCC have less severe liver damage and dysfunction than patients with HCV-related HCC, as indicated by higher serum albumin, lower serum bilirubin, and lower rates of ascites.

Phenotypically, MAFLD-HCCs appear to be different from other forms of HCCs, as the lesions are generally well-differentiated, solitary, with a greater inflammatory infiltration, lower likelihood of extrahepatic metastasis [20], and a greater size than HCC originating from other chronic liver diseases [21].

2. NAFLD and NASH

Liver lipid storage is associated with visceral obesity, IR, and dyslipidemia in the complex picture of metabolic syndrome. NAFLD presents an accumulation of triglycerides (TG) within hepatocytes in the form of intracellular lipid droplets. TG are formed by esterification of free fatty acids (FA) and glycerol. Thus, the development of NAFLD is caused by an imbalance in hepatocellular FA metabolism ^[22][23][22,23]. The increased hepatic availability of FA is due to increased dietary intake, decreased inhibition of lipolysis at the level of adipose tissue caused by IR, as well as increased de novo hepatic lipogenesis [24]. Free fatty acids can undergo beta oxidation or TG esterification. Hepatic expression of CD36 fatty acid translocase is markedly increased in individuals with NAFLD. Furthermore, hepatic expression of adipocyte fatty acid-binding proteins (FABP), FABP-4 and FABP-5, is associated with an increase in intrahepatic TG ^[25][26][25,26]. An important accumulation of FA is due to de novo lipogenesis (DNL), a metabolic process that synthesizes new FA from excess glucose [27]. This pathway is an important contributor to hepatic lipid accumulation in the pathogenesis of NAFLD ^[28][29][28,29]. The activation of two transcription factors, sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate-responsive element binding protein (ChREBP), which are boosted by insulin and glucose responses to dietary carbohydrates [30], play a synergistically important role in the regulation of hepatic DNL. Additionally, in patients with NAFLD, a small amount of the FA pool is derived from dietary TG, which is associated with chylomicrons [31]. The most evocative theory in the pathogenesis of NAFLD is the “two-shot” hypothesis [32]. The first blow is insulin resistance caused by excessive FA flow in the liver. The second blow is inflammation associated with gut-derived endotoxin, oxidative stress, and mitochondrial dysfunction. It is closely related to the progression of NAFLD to NASH, which is characterized by excessive triglyceride accumulation (steatosis), inflammation, injury, and hepatocytes apoptosis that can lead to cirrhosis and HCC [33]. The remarkable prevalence of NAFLD and NASH could, in a short time, make both entities the most common predisposing factors of HCC in the coming years. The notion that HCC develops only in patients with cirrhotic NAFLD has long been challenged, as HCC has been increasingly recognized in non-cirrhotic patients with NASH [34]. Mohamad et al. observed in a small sample size that patients with NAFLD-HCC in the absence of cirrhosis had larger tumor diameters at diagnosis, higher rates of tumor recurrence, and worse survival outcomes than NAFLD-HCC patients with cirrhosis [35]. An Italian multicenter study enrolled 145 patients with NAFLD-related HCC between 2010 and 2012. An amount of about 50% of patients had no cirrhosis and all patients enrolled had NASH with advanced fibrosis rather than simple steatosis without fibrosis, suggesting that the stage of fibrosis might be relevant in the future risk of HCC in the absence of cirrhosis [36]. Furthermore, in a Japanese multicenter cohort of 87 patients with histologically proven NAFLD-related HCC diagnosed between 1993 and 2010, 72% of them had advanced fibrosis (F3 and F4), while 65% had at least moderate to severe necro-inflammatory activity [37].