2. Natural history: Progression from hepatic steatosis to HCC

The most common and known risk factor for HCC are viral infection, virus B or C, toxic factors - alcohol and aflatoxin and immune diseases like primary biliary cirrhosis. There is an increasing number of HCC developed on liver metabolic diseases, including NAFLD and NASH, based on epidemiological evidence that shows a relationship of these diseases with an incident of HCC, regardless of the common known risk factors like alcohol consumption or chronic

It is not surprising the growing interest in the last few years on the mechanisms underlying the transition from liver metabolic disorders to HCC that is involving these new metabolic risk factors that include inflammation, insulin resistance, lipid and bile acids metabolism and the gut microbiota. A better understanding of the impact of these factors on the liver microenvi-

Metabolic syndrome has been associated with an increased risk of HCC and each component of this syndrome may increase cancer risk and also a synergic effect has been described [4, 5]. Overweight and obesity are well recognized independent risk factors for HCC, visceral adiposity showing stronger association with HCC risk than general body weight [6, 7]. Studies demonstrated that obesity may also influence HCC prognosis, Body Mass Index (BMI) seems to be a predictor of microvascular invasion and poor prognosis, while visceral adiposity is associated with HCC recurrence after treatment [8, 9]. Type 2 diabetes mellitus has been recognized in various studies as an important independent risk factor for HCC regardless of alcohol consumption [10]. Hyperlipidemia and hypertension are two additional components of metabolic syndrome that have been studied as risk factors for HCC, and hypertension seems to be related to a higher risk of HCC, whereas the relation between HCC and hyperlipidemia remains controversial [4, 5]. Also, synergism between the new risk factors and traditional risk factors has to be considered, for example, a strong synergic effect of alcohol abuse and type 2 diabetes mellitus has been described, also diabetes and obesity have been reported to enhance

Non alcoholic fatty liver disease (NAFLD) is one of the most common cause of chronic liver disease and include a large spectrum of chronic liver disorders ranging from simple hepatic steatosis with no evidence of hepatocellular injury to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and liver failure and currently, all guidelines agree that NAFLD is associated with the increasing percentage of obesity, type 2 diabetes mellitus, hypertension and dyslipidemia in our population [13, 14]. Several studies have demonstrated a strong association between NAFLD and each components of metabolic syndrome and there is enough evidence to define NAFLD itself as a liver component of metabolic syndrome [15–19, 46].

The rising incidence of NAFLD/NASH worldwide led to an important rise in HCC incidence related to these chronic liver diseases [3]. Many studies have demonstrated over the years that NAFLD can lead to hepatic fibrosis and cirrhosis, increasing therefore the risk for developing HCC [20, 21]. Among these patients with Non alcoholic fatty liver disease or non-alcoholic steatohepatitis, studies show that the third cause of death is liver disease, and HCC represents the main cause of death in these patients [20–23]. The incidence rate for developing HCC in patients with NASH related hepatic cirrhosis is up to 27% in retrospective studies [24]. Increased incidence of HCC was also been reported in patients with NAFLD in the absence of hepatic cirrhosis, and several risk factors for HCC development have been identified [6, 25–29].

ronment may have potential benefit on the management of liver disease [3].

the risk of HCC in patients with chronic hepatitis [11, 12].

viral hepatitis.

98 Liver Cancer

The term nonalcoholic fatty liver refers to a variety of liver disease that ranges from simple isolated hepatic steatosis, to non-alcoholic steatohepatitis with or without cirrhosis, and progression to HCC.

Although NAFLD diagnosis can be made by imaging (ultrasound or magnetic resonance), biopsy still remain the gold standard for diagnosis. 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 [30].

The prevalence of NASH is difficult to determine because biopsy is required, with specific criteria such as steatosis, hepatocellular injury, mainly in the form of ballooning, and lobular inflammation, and once cirrhosis is present, NASH may be difficult to evaluate because often the fatty deposition disappear. Liver fibrosis may be present in non-cirrhotic NASH, initially in perisinusoidal acinar zone 3 [31]. Because of the need of histopathologic confirmation, NASH is most likely underdiagnosed and it may be misclassified as cryptogenic cirrhosis, which shares the same risk factors including diabetes and obesity [32, 33, 46]. Therefore, to estimate correctly the prevalence of NASH, a novel NASH category including obese patients with cryptogenic cirrhosis or with unknown HCC etiology has been proposed.

The prevalence of NAFLD and NASH is variable and it is depended on the method of diagnostic used to confirm the disease, and it is usually underreported because of the asymptomatic nature and can be underestimated and poorly treated.

NAFLD is present in more than 25% of adult population and about 10 to 20% of NAFLD patients may progress to NASH, which may progress to cirrhosis in 20–45% of cases, and cirrhosis is a well-known risk factor for HCC, and approximately 7% of patients with NASHrelated cirrhosis may progress to HCC within 6 years [31].

Patients with nonalcoholic steatohepatitis are more susceptible to develop progressive advanced liver disease when compared to benign course of simple hepatic steatosis. In a study that included 420 patients with NAFLD/NASH, it was demonstrated a higher mortality in these patients when compared to the general population and also liver-related deaths occurred in 13% compared to 1% in general population, and 3% of patients with NAFLD developed hepatic cirrhosis. [34] Another study showed increased rates of hepatic cirrhosis in patients with nonalcoholic steatohepatitis (25%) compared to patients with fatty liver without non-alcoholic steatohepatitis (3%), and also showed an increased risk of liver disease related death in these patients (11% vs 2% in patients with fatty liver without NASH) [35].

Patients with compensated liver cirrhosis related to non-alcoholic steatohepatitis present with better survival outcomes compared to patients with HCV related cirrhosis, but in the presence of uncompensated liver cirrhosis poor prognosis was observed in both populations [36, 37], and currently, both, the American and European Associations for the Study of Liver Diseases, recommend screening for HCC in all patients with non-alcoholic steatohepatitis related cirrhosis [38].

Evidence from studies suggests that an important proportion of patients with NAFLDassociated HCC, do not have histologic evidence of liver cirrhosis. In one study from 1168 patients that underwent hepatic surgery for HCC, 6 out of 8 patients with NASH-related HCC did not had any histopathological evidence of liver cirrhosis and also the study suggested that the presence of hepatic cirrhosis in NASH-related HCC patients is lower compared to HCVrelated HCC [29].

Body Mass Index is the most commonly used index in epidemiologic studies, but body fat topography, and especially central obesity, seems to be more important in pathophysiologic mechanisms that connect obesity to cancer. Central obesity, is the key feature in most metabolic syndrome definitions, and has also been directly correlated with insulin resistance [44, 46].

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Obesity have been associated with disproportion between visceral and subcutaneous adipose tissue and with chronic inflammatory state due to adipokine imbalance that is defined as increased levels of leptin and decreased levels of adiponectin. Furthermore, obesity has been associated with other risk factors including insulin resistance, increased hepatic lipid storage

Adipokine imbalance as mentioned before occurs with simultaneous increased leptin and decreased adiponectin levels resulting in a pro-inflammatory and pro-oncogenic state. Both leptin and adiponectin are hallmarks of obesity, and have been extensively studied and both

Leptin is secreted by adipose tissue and acts as a hormone and it is involved in the process of satiety. High levels of leptin and resistance to its action are observed in obese persons. Leptin has been demonstrated to be implicated in NAFLD progression, liver fibrosis, NASH and eventually in the carcinogenesis process of HCC through multiple molecular mechanisms. And these mechanisms are the activation of JAK2/STAT3, PI-3 K/Akt, ERK pathways and the inhibition of the TGFβ1-induced apoptotic pathway [24]. For example, the activation of Akt pathway was observed in about 40% of HCC patients. Leptin's role is to have growth factorlike activities on hepatic cells and HCC cells, and also have proinflammatory, profibrogenic and proangiogenic role on liver microenvironment and also it is implicated in the process of

Adiponectin is the most abundant hormone of adipose tissue and has well known metabolic functions, having anti-inflammatory, antifibrotic, antiangiogenic, and antiproliferative activities on the liver microenvironment. Adiponectin exerts antifibrotic effects on hepatic cells through activation of the signaling AMPK axis and inhibition of TGFβ-mediated profibrogenic gene expression, and in addition, adiponectin may also induce apoptosis of hepatic cells. The anti-inflammatory activity of adiponectin is mostly related to inhibition of NFkB signaling axis [31]. A direct effect of adiponectin on HCC cells has also been described, induces apoptosis and inhibits HCC cell proliferation and migration. In addition, adiponectin prevents HCC development by activation of the AMPK signaling pathway and consequent modulation of mTOR and JNK/caspase 3 axis, resulting in growth cell inhibition and enhanced apoptosis [4]. A number of observations support the reduced adiponectin levels observed in obese patients and were associated to increased incidence of hepatic steatosis, fibrosis and accelerated pro-

Insulin resistance it is another important component of the metabolic syndrome, and along with obesity, is involved in the chronic inflammatory state directly linked to NAFLD. Insulin

and alteration of intestinal flora [46].

cell growth, angiogenesis and metastasis [31].

gression to HCC [45].

3.2. Insulin resistance

have been related to NAFLD and progression to liver cancer.

In another study that analyzed 128 patients with HCC recruited over a period of 12 years, it was reported that a significant number of patients with NASH developed HCC in the absence of fibrosis when compared to HCC of other etiology [39]. To explain this phenomenon in noncirrhotic NAFLD patients, one proposed hypothesis is the malignant transformation of liver cell adenoma, and there are some published reports that have suggested that in the presence of metabolic syndrome features, liver cell adenoma may incur a malignant transformation [40, 41].

In the last years, many studies tried to establish the relationship between NAFLD and NASH, cryptogenic cirrhosis and HCC. The true prevalence of NASH and NASH-related HCC is probably underestimated due to the asymptomatic nature of the disease, and in up to 29% of HCC cases, the underlying etiology of liver disease remains unknown or are considered as cryptogenic cirrhosis [40]. Histopathological features that are suggestive for non-alcoholic steatohepatitis are more frequently observed in patients with HCC of unknown etiology than in patients with HCC related to chronic viral hepatitis or alcoholic etiology [32]. Even if the true prevalence of NAFLD/NASH-related HCC is not yet well defined, the increasing incidence of obesity and diabetes, suggests that the incidence NAFLD/NASH-related HCC will continue to grow in the next years, and there are already numerous studies that are investigated the relation between these diseases [46].
