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  • br Emerging metabolic risk factors Metabolic syndrome has be


    Emerging metabolic risk factors Metabolic syndrome has been associated with an increased risk of HCC. In particular, each feature of this syndrome may increase cancer risk and a synergic effect has been described [2], [3]. Overweight and obesity are well-recognized risk factors for HCC [4]. However, visceral adiposity shows a stronger association with HCC risk than general body weight [5]. Furthermore, obesity may influence HCC prognosis. For example, in a large study, Body Mass Index (BMI) was predictor of microvascular invasion and worsened prognosis [6], whereas visceral adiposity correlated with HCC recurrence after treatment in another study [7]. Diabetes mellitus type 2 (DM II) has been proposed as an important independent predictor of HCC regardless of alcohol consumption [8]. Hyperlipidemia and hyperthension are two additional features of metabolic syndrome that have been studied in relation to HCC. In particular, hyperthension seems to be related to a higher risk of HCC, whereas the relation between HCC and hyperlipidemia is quite controversial [2], [3]. Also, synergism between traditional and new risk factors has to be considered. For example, a strong synergic effect of alcohol abuse and DM II has been described [9]. Moreover, diabetes and obesity have been reported to enhance the risk of HCC in cohorts of chronic hepatitis patients, even more if both metabolic risk factors were present [10]. Metabolic risk factors affecting the natural history of NAFLD towards HCC are illustrated in Fig. 1.
    NAFLD and NASH as emerging precancerosis Although NAFLD diagnosis can be made by means of imaging (i.e. ultrasound or magnetic resonance), biopsy and the consequent histology still remain the gold standard. Histology generally displays the accumulation of triglycerides in hepatocytes, usually in mixed macrovesicular or microvesicular droplets, in the absence of alcohol abuse, steatogenic medication or hereditary disorders. Based on the increasing incidence of NAFLD in the general population, this condition is becoming the most common underlying risk factor for HCC. In particular, in histology-based studies, carried out in apparently healthy candidates for liver donation, the authors reported that the prevalence of NAFLD was 12–18% in Europe and 27–38% in the United States. The prevalence of steatosis was significantly higher in patients with metabolic risk factors, up to 94% in obese patients, 67% in overweight patients and 40–74% in diabetic patients [11]. The association between NAFLD and each component of the metabolic syndrome is well recognized and some authors have proposed hepatic steatosis itself as a feature of metabolic syndrome [12]. With regard to the prevalence of NASH, about 6–15% of cases were reported in non-selected samples, whereas prevalence was higher in patients with obesity or DM II (25–30%) and in severely obese with DM II (35%). Nevertheless, the prevalence of NASH is difficult to determine because biopsy is required, including specific criteria such as steatosis, hepatocellular injury, mainly in the form of ballooning, and lobular inflammation. Liver fibrosis may be present in noncirrhotic NASH, initially in perisinusoidal acinar zone 3 [11]. However, NASH is probably underdiagnosed because it Ko 143 may be misclassified with cryptogenic cirrhosis (CC), which shares the same risk factors including diabetes and obesity [13], [14]. Therefore, to better estimate the prevalence of NASH, a novel NASH category including obese patients with cryptogenic cirrhosis or with unknown HCC etiology has been proposed. As a consequence, NASH resulted as the second leading cause of HCC in patients undergoing liver transplantation [15].
    Natural history: Transition from steatosis to hepatocellular carcinoma About 20% of NAFLD patients may have NASH, which may progress to cirrhosis in 20–45% of cases, a known precancerosis for HCC [16]. About 7% of patients with NASH-related cirrhosis may progress to HCC within 6.5years [11]. The different long-term prognosis between NAFLD and NASH patients has been explained based on the presence (and the degree) of fibrosis, which has been described as a crucial prognostic factor. In fact, fibrosis stage strongly predicts liver disease-related and overall mortality in NAFLD patients [17]. Interestingly, a recent meta-analysis reported a rate of fibrosis progression of 0.07 stages per annum in patients with steatosis but without fibrosis at baseline, and a doubled rate for NASH patients. However, the proportion of patients whose liver fibrosis progressed from stage 0 to stage 3 or 4 was comparable in the two subgroups [18]. Based on the reported older age of patients with NASH compared with those with NAFLD and on the median 8-years interval between the two conditions, the higher stages of fibrosis observed in NASH may reflect only a longer length of liver disease [19]. In addition, in one study, although fibrosis stage was significantly more advanced at stage of HCC when compared to the stage of NASH, 28% of patients showed stage 1 or stage 2 fibrosis at the time of HCC diagnosis [20]. Therefore, advanced fibrosis and cirrhosis is not a necessary step for HCC development in the presence of steatosis, as shown by cases of HCC developing in non-cirrhotic livers, mainly in old male and obese patients or with criteria of metabolic syndrome [21]. In another study, by analyzing a wide healthcare claims database, the authors reported that NAFLD/NASH was the most common underlying risk factor for HCC (59%) and the majority of these tumors that developed on NAFLD had no International Classification of Diseases code for cirrhosis [22]. The same findings were reported analyzing the SEER-Medicare database. The authors showed that 36% of NAFLD-related HCCs developed in non-cirrhotic livers and 18% in absence of steatohepatitis. Non-cirrhotic NAFLD was the only etiology in 5.8% of HCC patients and isolated fatty liver was the only etiology in about 1% of the total cohort [23]. Since HCC may occur in NAFLD patients even in the absence of progression to NASH, steatosis itself may be considered a precancerous condition. Several genetic and environmental factors influence progression of NAFLD to liver cancer and can be considered as modifiers of the natural history of liver steatosis. Patients with NAFLD or NASH have a much higher risk for developing cirrhosis and HCC in the presence of one or more metabolic syndrome features [2], [3]. Recent studies have shown the role of specific gene polymorphisms as determinants of NAFLD susceptibility and progression. One of the most studied nucleotide polymorphisms in this field is rs738409 C/G resulting in an isoleucine to methionine substitution at residue 148 (I148M) in human patatinlike phospholipase domain containing 3 (PNPLA3) leading to alteration of TAG remodeling in lipid droplets. This variant has been associated with increased fat content, NAFLD susceptibility and progression, and with a higher risk for liver fibrosis and NAFLD-related HCC [16]. Other genetic modifiers of natural history of NAFLD include glucokinase regulator (GCKR) and transmembrane 6 superfamily 2 (TM6SF2). TM6SF2 E167K and GCKR rs780094 gene variants are associated with an increased risk for fatty liver and liver fibrosis. Therefore, the combined evaluation of clinical comorbidities and specific gene variants may be useful in clinical practice and for risk stratification in NAFLD patients [11].