1. Introduction

Hepatocellular carcinoma (HCC) is one of the dominant histopathological types of liver cancer, accounting for almost 90% of primary liver cancers worldwide, it is the sixth most common cancer and it is the third cause of cancer-related deaths worldwide [1]. Despite the decreasing incidence of HCC related to viral hepatitis, an increase in the incidence of HCC was observed especially in Europe and America [2]. The global burden of hepatocellular carcinoma in 2012 was of 14 million cases and it is predicted to grow to 22 million over the next two decades.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 viral hepatitis.

2. Natural history: Progression from hepatic steatosis to HCC

cryptogenic cirrhosis or with unknown HCC etiology has been proposed.

tomatic nature and can be underestimated and poorly treated.

related cirrhosis may progress to HCC within 6 years [31].

patients (11% vs 2% in patients with fatty liver without NASH) [35].

gression to HCC.

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 pro-

Metabolic Risk Factors in Hepatocellular Carcinoma http://dx.doi.org/10.5772/intechopen.80527 99

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

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 asymp-

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 NASH-

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 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

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

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

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].
