**2.7. Obesity, diabetes and nonalcoholic fatty liver disease (NAFLD)**

Obesity represents an important public health problem, with a massive increase in the past years and with staggering estimations of approximately 300 million obese worldwide. Obesity elevates the risk of all types of cancer, including HCC [40]. One study performed in Denmark on a cohort of 43.965 obese patients estimated the relative risk of liver cancer to 1.9 in comparison to the general population [41]. Two Swedish population-based cohort studies also showed an increased risk of HCC among obese [42, 43].

In another US study, Nair et al. evaluated the importance of obesity in over 19,000 patients diagnosed with cirrhosis and liver transplants, with an overall incidence for HCC of 3.5%. The study suggested obesity as a statistically independent risk factor for liver cancer in patients with alcoholic and cryptogenic cirrhosis [44]. Furthermore, a recent case–control study indicated synergy between increased alcohol intake, smoking, and obesity [45]. In 2014, an American study regarding the incidence of hepatocellular carcinoma in Texas Latinos concluded that the incidence of liver cancer is somehow higher than other regions in the US, suggesting risk factors related to increased obesity and diabetes rates, as well as environmental, cultural and socioeconomic factors, and possibly genetic predisposition [46].

isolated [31]. A recent meta-analysis concluded that the risk of HCC is much lower for patients with autoimmune hepatitis and cirrhosis than for patients with cirrhosis from viral hepatitis or primary biliary cholangitis [32, 33]. Development of HCC from autoimmune hepatitis with corticosteroid-therapy should mainly impose searching for associated viral chronic hepatitis

Tobacco and alcohol abuse represent important HCC risk factors and exposure to both risk factors can increase HCC susceptibility. The mechanism involves generation of reactive oxy-

Alcohol chronic intake is associated with HCC development due to the several mechanisms such as creation of acetaldehyde-DNA; formation of cytochrome P450E1-associated ROS species; iron overload, which can lead to further ROS formation and p53 gene mutation or activation of factor-KappaB-involved in the promotion of inflammatory response; oxidative stress promotion; and decreased metabolism of vitamin A, which determines the promotion of hepatocyte proliferation as well as initiation and development of liver fibrosis [36]. Alcohol interferes with hepatocarcinogenesis by inducing an already demonstrated precancerous lesion, such as liver cirrhosis or by modifying carcinogenesis initiated by other agents such as HBV or HCV or environmental carcinogens following hepatic enzyme induction or by

Aflatoxin b1 derived from a fungus (Aspergillus flavus) is a major risk factor in some tropical and subtropical regions. Aspergillus flavus is ubiquitous and contaminates cereals (corn, rice, and sorghum), hazelnuts, etc., stored in humidity conditions. Epidemiological data have shown a strong correlation between aflatoxin intake and HCC incidence in some countries in Asia and Africa. Since 1993, the International Agency for Research on Cancer recognized aflatoxins as a human carcinogen (group IA) [38]. Advanced age, smoking, alcohol, and HBV

Obesity represents an important public health problem, with a massive increase in the past years and with staggering estimations of approximately 300 million obese worldwide. Obesity elevates the risk of all types of cancer, including HCC [40]. One study performed in Denmark on a cohort of 43.965 obese patients estimated the relative risk of liver cancer to 1.9 in comparison to the general population [41]. Two Swedish population-based cohort studies also

In another US study, Nair et al. evaluated the importance of obesity in over 19,000 patients diagnosed with cirrhosis and liver transplants, with an overall incidence for HCC of 3.5%. The study suggested obesity as a statistically independent risk factor for liver cancer in patients with alcoholic and cryptogenic cirrhosis [44]. Furthermore, a recent case–control study

gen species (ROS) and a decrease of antioxidants, which induces oxidative stress [35].

or any other HCC risk factors that can promote carcinogenesis [34].

6 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

infection may increase the carcinogenic risk of aflatoxin [39].

showed an increased risk of HCC among obese [42, 43].

**2.7. Obesity, diabetes and nonalcoholic fatty liver disease (NAFLD)**

**2.5. Tobacco and alcohol abuse**

altering cell membranes [37].

**2.6. Environmental toxins**

The mechanism by which obesity leads to cancer is unclear; insulin resistance and its subsequent inflammatory cascade, and insulin growth factor (IGF)-1 seem to be implicated [47]. In a study published in 2010, Michael Karin's team addressed the mechanism by which the obesity can lead to cancer by studying the development of HCC induced by diethylnitrosamine (DEN) or fat diet in mice [48, 49].

Although this is not entirely proven, a number of studies indicate that NAFLD is the link between obesity, diabetes, and HCC. In time, NAFLD can lead to fibrosis and finally, cirrhosis. Approximately 60% of patients with obesity have simple steatosis or steatosis with mild inflammation and around 25–30% have nonalcoholic steatohepatitis (NASH) [50].

Further mechanisms involved in the development of HCC at obese patients were addressed by Villanueva et al. by studying the molecular links between inflammation and liver cancer uncovering the reported role of lymphotoxin signaling in HCC development. The involvement of oxidative stress in developing HCC in obese patients was studied by Zhang, Kaufman et al., who underlined that the accumulation of intracellular lipids increases the demand on the endoplasmic reticulum (ER), which integrates several metabolic processes, therefore inducing ER dysfunction that leads to the production of ROS, provoking oxidative stress and activation of inflammatory pathways (NF-kB and JNK signaling). Another effect of oxidative stress is that can also induce DNA damage that leads to genomic instability that prompts the mutations that favor the development of neoplastic cells [51–53]. Carbohydrate metabolism alterations are frequently encountered at patients with cirrhosis [54].

Since 1986 at least 10 case-control and 5 prior cohort studies from seven different countries reported a connection between diabetes and HCC, promoting the idea that diabetes is an important and consistent risk factor for HCC [55–57]. However, the current studies have not established if diabetes precedes HCC.

The association among obesity, diabetes, NAFLD, and HCC has been assessed by El-Serag et al. in two large studies that substantiated the increased risk of HCC by obtaining results, which showed a doubling number of cases with HCC in patients with diabetes in contrast with nondiabetic patients in a 10–15 year observation period, explaining that the rising incidence of HCC in the US in the past 30 years is connected to an ever-growing prevalence of obesity and diabetes [58, 59].

Since the incidence of obesity and diabetes is in a continuous growth in the world, Kelly, and co. study demonstrated a direct established relationship between diabetes and HCC risk. The biological mechanism of diabetes implicated in hepatocarcinogenesis is not entirely established. Increased serum levels of insulin are at this point the most researched mechanism for the link between diabetes and cancer, though only high levels of insulin are not enough to cause HCC. Levels of insulin-like growth factor-1 (IGF-1) have been linked with increased risk for pancreatic cancer [60–62]. Most studies indicate that serum IGF-1 levels were linked with the high-risk of HCC, and also that IGF-1 can promote tumor cell growth [63–66]. This was often linked to cell proliferation in pancreatic cancer and similar effects could be observed in HCC [62, 67].

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As diabetes and obesity continue to be an ever-growing worldwide concern, we can anticipate a near future increase in the prevalence of NAFLD-related HCC [68]. If liver cirrhosis is present, NAFLD patients have a substantially higher risk to develop HCC [69]. Obesity is linked with a low-grade inflammatory status and also an increased production of cytokines like IL-6 or TNF-alpha [70]. Multiple potential carcinogenic mechanisms are also involved, such as reduced levels of adiponectin [71, 72], hepatic lipid accumulation with possible energy support required for massive tumor growth [73] or normal intracellular signaling means affected by lipotoxicity [74].

#### **2.8. Iron overload**

Almost two thirds of the total iron pool is present in hemoglobin while the rest of it is stored, mostly inside the liver, with the help of an intracellular protein called ferritin, which can bind up to 4500 molecules of iron per molecule of ferritin. Transferrin is a glycoprotein responsible for binding the circulating iron within the plasma [75]. Iron overload has been mainly associated with hereditary hemochromatosis (HH) and dietary iron overload (DIO).

Iron overload is frequently linked with an abnormal secretion of hepcidin [76, 77]. Recent studies performed on rats, which underwent a high-iron diet also confirm the possibility to develop HCC in the absence of liver cirrhosis, therefore, excessive iron is capable to generate oxidative tissue damage alone by accelerating the development of free radicals [78, 79]. DIO has been reported in some countries located in the southern and central part of Africa, mainly in the rural parts and highlights the link between the consumption of large volumes of homebrewed alcohol using iron containers, and development of iron overload [79].
