3. Metabolic risk factors, NAFLD and HCC

It is established that HCC and NAFLD share many risk factors and the development of HCC in NAFLD/NASH patients is probably multifactorial and involves low grade chronic systemic inflammatory response, excessive fat accumulation and insulin resistance [40, 46].

#### 3.1. Obesity

There is more evidence that overweight and obesity and metabolic syndrome have reached a epidemic proportion over the last decades, and there are evident data that show that 80% of NAFLD patients are overweight or obese [42]. According to the World Health Organization, in 2008, more than 35% of adults worldwide are overweight, and of these, 13% are obese [29] and if overweight and obesity rates continue at their current ascending trend, it is estimated that more than 3.3 billion adults will become overweight or obese by year 2030 [43].

Overweight and obesity are leading risk factors for overall mortality, accounting for more than 3.4 million adult deaths every year, and are considered risk factors for 44% of the diabetes, 23% of the ischemic heart disease, and between 7 and 40% of certain cancer [42].

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].

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 and alteration of intestinal flora [46].

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 have been related to NAFLD and progression to liver cancer.

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 cell growth, angiogenesis and metastasis [31].

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 progression to HCC [45].

#### 3.2. Insulin resistance

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 HCV-

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 investi-

It is established that HCC and NAFLD share many risk factors and the development of HCC in NAFLD/NASH patients is probably multifactorial and involves low grade chronic systemic

There is more evidence that overweight and obesity and metabolic syndrome have reached a epidemic proportion over the last decades, and there are evident data that show that 80% of NAFLD patients are overweight or obese [42]. According to the World Health Organization, in 2008, more than 35% of adults worldwide are overweight, and of these, 13% are obese [29] and if overweight and obesity rates continue at their current ascending trend, it is estimated that

Overweight and obesity are leading risk factors for overall mortality, accounting for more than 3.4 million adult deaths every year, and are considered risk factors for 44% of the diabetes, 23%

inflammatory response, excessive fat accumulation and insulin resistance [40, 46].

more than 3.3 billion adults will become overweight or obese by year 2030 [43].

of the ischemic heart disease, and between 7 and 40% of certain cancer [42].

related HCC [29].

100 Liver Cancer

3.1. Obesity

gated the relation between these diseases [46].

3. Metabolic risk factors, NAFLD and HCC

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 resistance is also related to oxidative stress, which has the most important role in carcinogenesis in the presence of NAFLD and NASH.

3.3. Lipotoxicity

[58–61].

the liver [65, 66].

3.4. Microbiota: Intestinal flora dysregulation

Increased lipid accumulation in the liver arises from lipolysis within peripheral adipose tissue, dietary sources and de novo hepatic lipogenesis, and this increased lipid accumulation causes hepatic lipotoxicity resulting in the excessive production of saturated and monounsaturated free fatty acids (FFAs) [40, 46, 56]. These FFAs undergo β-oxidation leading to formation of reactive oxygen species that will further induce mitochondrial damage, endothelial reticulum

Metabolic Risk Factors in Hepatocellular Carcinoma http://dx.doi.org/10.5772/intechopen.80527 103

As a result of the hepatic insulin resistance an increase in the liver of free fatty acids (FFAs) is observed, mainly due to dysregulation of the lipolysis and lipogenesis balance, resulting lipotoxicity that will determine chronic damage to hepatic tissue [51]. But, lipotoxicity is not due only as consequence of the excessive accumulation of FFAs in the liver, and the modification of lipid composition is another contributor to lipotoxicity, and recent studies are aimed at searching for specific metabolic changes as potential signatures of development of HCC in patients with NAFLD [57]. For example, some studies show that, during natural history of progression from normal liver to NAFLD or NASH, the ratio of polyunsaturated fatty acids (PUFAs) is increased in NASH, and phosphatidylcholine (PC) levels are reduced in both NAFLD and NASH, and based on these observations, it has been suggested that the LPA signaling axis may be one of the mechanism that is connecting hepatic steatosis to HCC

The basis for the ongoing interest on the role of gut microbiota in progression of NAFLD was the observation of fatal NASH that occurred in patients undergoing jejunoileal bypass in bariatric surgery and the reversal after metronidazol therapy [62]. There are several evidences that demonstrate a high prevalence of small intestinal bacterial overgrowth in patients with NAFLD/NASH and that also demonstrate the role of microbiota modifications in the development of NAFLD and NASH [45]. Specific microflora changes may play an important role in progression of hepatic steatosis, especially in obese patients. In patients with NAFLD and NASH was observed a difference in microbiota composition compared with healthy population [63, 64]. The mechanisms implicated in the progression of gut microbiota-related NAFLD and NASH and HCC are: alteration of intestine permeability, persistent activation of innate immune system with consequent chronic inflammation, changes in bile acid metabolism [65]. Patients with NAFLD or NASH show increased levels of lipopolysaccharides (LPS), a known innate immune system activator, on serum confirming the inflammatory state associated with this conditions and alteration in gut permeability with disruption of intercellular tight junctions observed in patients with NAFLD can contribute directly to lipopolysaccharides action to

All these findings were confirmed in human study wherein increased LPS-binding protein (LBP) levels were observed in obese patients with NAFLD and even more in obese patients

with NASH, correlating with liver TNFα increased expression [67].

stress, and gene transcription promoting inflammatory cell signaling pathways.

Epidemiologic studies show that diabetes is associated with an increased risk of developing HCC compared with non-diabetics patients, regardless of other HCC risk factors and also seems to be independent of obesity [47]. In a large study conducted on patients with and without diabetes, with a follow-up period of 10–15 years, NAFLD incidence was significantly higher among patients with diabetes and a significantly higher incidence of HCC among patients with diabetes was observed [7]. Meta-analysis published over the years, revealed a 2 to 3-fold greater risk of HCC in patients with diabetes compared with non-diabetic patients, and this significant association was reported independent of alcohol abuse or chronic viral hepatitis in studies that examined these factors [48, 49].

Epidemiologic data demonstrate that both obesity and type 2 diabetes mellitus have increases the risk for HCC, and NAFLD, which is present in up to 90% of obese persons and up to 70% of type 2 diabetes mellitus patients [24], appears to play an important role in HCC development. NAFLD is nowadays considered the most common risk factor for HCC, followed by type 2 diabetes and it is exceeding the incidence of chronic viral infections and alcoholic liver disease [48, 50]. These can be explained by effective measures to reduce HCV infection incidence, which was the major cause of HCC in the United States and in other developed countries, and also can be explained by the increasing prevalence of NAFLD in these areas [51].

The strong relationship between visceral obesity and insulin resistance (IR) is well known, but insulin resistance is not related only to adipose tissue, in fact, liver accumulation of fatty acid metabolites can induce hepatic insulin resistance. One of the main fatty acid metabolite involved in hepatic insulin resistance is diacylglycerol (DAG) and it has been proposed as a predictor for hepatic insulin resistance [52]. The consequent hyperinsulinemia downregulates s expression of IRS2 in the hepatic cells increasing hepatic insulin resistance and in addition, insulin stimulates lipogenesis through activation of SREBP-1c, inducing, in a vicious circle with further fat accumulation and insulin resistance [31]. The liver microenvironment may induce insulin resistance also in other tissues, in fact, an increase in liver fat content may be considered a very strong predictor of insulin resistance in skeletal muscles, hepatic and adipose tissue, regardless of adiposity. In conclusion, liver fat content may predict the development of metabolic syndrome or diabetes, and the underlying mechanism may be the altered gene expression and protein synthesis and secretion also observed in NAFLD [53]. It is known that hyperinsulinemia occurs as a response to insulin resistance, and that is considered a risk factor for liver fibrosis and HCC development by activation of hepatic stellate cells, by dysregulation in the proliferation-apoptosis balance in hepatic cells, and by stimulation of angiogenesis. The most studied mechanism involved in NAFLD-related HCC is the IGF signaling axis that has a growth factor-like activity on hepatic cells and also a pro-angiogenic activity on the hepatic vascular system. Dysregulation of the IGF signaling axis has an important role in hepatic carcinogenesis and it is represented by the low levels of IGF1 in serum and overexpression of IGF-II. Insulin receptors (IRS) bind to insulin or IGF and share the same prooncogenic pathways with IGF1 receptor (IGF1R), including the activation of P13K/Akt and MAPK [54, 55].
