**2.1. Cirrhosis**

Cirrhosis is the main underlying cause for most HCC cases, with HBV, and HCV infection often involved in the development of cirrhosis. Approximately 70–90% of liver cancers occur on cirrhosis, and in Western countries, the HCC ratio on cirrhosis exceeds 90%. The likelihood of developing HCC in viral B cirrhosis is 2.4% per year, and viral C cirrhosis is 5–7% per year. In Europe, HCC incidence is 1.5–3/100 cirrhosis per year. Male gender, advanced age, long duration of the disease and the severity of the disease are the main risk factors for developing cancer in cirrhosis alongside etiology of cirrhosis [3].

is found in 9% HIV-infected patients, resulting in an increased risk of developing HCC compared to chronic HBV infection alone [15]. At the time of writing, there are 10 genotypes of human HBV named from A to J. The last genotype (J) was described in 2009 by Tatematsu K

Introductory Chapter: Etiology and Pathogenesis of Hepatocellular Carcinoma

http://dx.doi.org/10.5772/intechopen.78328

5

The prevalence of HBV carriers associates geographically with the distribution of HCC. Epidemiological studies indicated a 200-fold increase in HCC risk in Taiwanese HVB men compared to HBV-negative men [18]. Cirrhosis developed from chronic HBV infection is

Hepatocarcinogenesis generated by chronic HBV infection is a multistep process that implies rearrangement of the intracellular DNA leading to inflammation of the hepatocytes, accompanied by an increased rate of proliferation [19]. After the integration of viral DNA into the host's genome, the telomerase reverse transcriptase is altered and multiple genes involved in the malignant process suffer various insertional mutations [20]. If the inflammation process continues to affect the hepatocytes, the liver will respond to injury with necrosis of the affected areas, followed by compensatory regeneration and hepatic fibrosis, therefore, altering the entire hepatic architecture, leading to cirrhosis [21]. Recent studies enhance the importance of HBV X protein, suggesting that pathways like p38MAPK and PI-3 K/AKT are used in order to increase the invasive potential of HBV infection [22, 23]. The association of HBV infection with HCV or HVD or with increased alcohol intake or aflatoxin consumption increases the

Chronic hepatitis C infection is a major risk factor for developing HCC. In developed countries, HCV is the important risk factor for HCC. HCV-associated HCC patients are usually

The evolution over time of the viral infection in a few countries is pledged for the massive increase of HCC incidence. The major spread of HCV infection took place in Japan around the 1930s and in the US in the 1960s. These assessments are consistent with epidemiological observations and allow the estimate that HCC prevalence will increase in the US over the next 2–3 decades when it is likely to match that in Japan [25]. HBV co-infection, present in 3–13% of patients with viral hepatitis C, is associated with a HCC risk of 3–4 times the incidence of each infection [26]. It is considered that the survivors of the Hiroshima and Nagasaki nuclear bombs that were HCV-positive had a much higher risk of developing HCC in the absence of cirrhosis. It was suggested that the radiation had a mutagenic effect and C virus stimulated cell proliferation in these patients [27]. Almost all HCV-related hepatocarcinomas occur due to cirrhosis or chronic inflammation. It is therefore, believed that HCV is an indirect carcinogenic agent by induced inflammatory and necrotic lesions. Core protein influences various

The risk of developing HCC for patients with underlying autoimmune hepatitis still remains unclear. Development of HCC in the absence of cirrhosis or viral hepatitis is rather rare or

significantly older than those with HCC associated with HBV infection [16].

cellular functions, including apoptosis, and suppresses p53 activity [28–30].

et al. [16], while the highest risk of developing HCC is linked with genotype C [17].

globally the most important etiologic factor of HCC.

carcinogenic risk of HBV [24].

**2.4. Autoimmune hepatitis**

**2.3. HCV infection**

The progression from cirrhosis to HCC is a complex process. Cirrhosis is the outcome of any chronic hepatic illness and it is outlined by debilitation of regenerative capacity of the liver through declining proliferation of the hepatocytes [4]. Telomere dysfunction and alterations of cellular micro- and macroenvironment have been proven to enhance cellular proliferation [5]. Telomerase dysfunctions determine chromosomal instability and reduced regenerative liver capacity with decreased hepatocyte regeneration. It has been proven that telomeres are shorter in hepatocytes from a cirrhotic liver compared to a normal liver. Also, shorter telomeres are associated with the progression of liver fibrosis [6].

Several mouse models studies have suggested that telomerase dysfunctions have been associated with early-stage liver cancers but not with high-grade HCCs, which tends to indicate that telomere dysfunction cannot determine alone the development and progression of HCC in cirrhotic livers [7]. Van Gijssel et al. supported this idea by using a rat model in which they decreased hepatocyte proliferation with various hepatotoxic compounds that also increased carcinogen-induced tumor forming [8]. Activation of stellate cells in liver cirrhosis can increase products of oxidative stress, several growth factors as well as cytokines with further roles in reducing hepatocyte regeneration, and development of HCC [9]. Outbreaks of dysplasia occur in regeneration nodules, followed by neoplastic transformation. HCC rarely develops on the noncytotoxic liver and this is particularly common in HBV infection, hemochromatosis or HCV infection. The existence of viral infection or portal hypertension can increase the odds of developing HCC for patients with primary biliary cirrhosis [10].

### **2.2. HBV infection**

HBV is regarded as the main etiological factor that generates multiple pathological changes inside the liver structure, being responsible for the development of HCC over time [11]. However, in order to correctly assess the risk of carcinogenesis triggered by chronic HBV infection, multiple variables need to be considered, like a virus or host-related factors and also the patient's lifestyle [12]. A major study published Chen CJ et al. evaluated the risk of developing HCC in 3653 patients who were positive HBV infection and negative for hepatitis C antibodies. The authors concluded that recorded serum levels of HBV DNA higher or equal to 10,000 copies/mL are a significant risk predictor for the development of HCC, no matter the Hepatitis B antigen level and liver cirrhosis [13].

In highly endemic regions, HBV is mainly transmitted from mother to child during birth (perinatal exposure). In developed countries, HBV infection is primarily contracted through parental contact with infected blood or through sexual contact [14]. Co-infection with HBV is found in 9% HIV-infected patients, resulting in an increased risk of developing HCC compared to chronic HBV infection alone [15]. At the time of writing, there are 10 genotypes of human HBV named from A to J. The last genotype (J) was described in 2009 by Tatematsu K et al. [16], while the highest risk of developing HCC is linked with genotype C [17].

The prevalence of HBV carriers associates geographically with the distribution of HCC. Epidemiological studies indicated a 200-fold increase in HCC risk in Taiwanese HVB men compared to HBV-negative men [18]. Cirrhosis developed from chronic HBV infection is globally the most important etiologic factor of HCC.

Hepatocarcinogenesis generated by chronic HBV infection is a multistep process that implies rearrangement of the intracellular DNA leading to inflammation of the hepatocytes, accompanied by an increased rate of proliferation [19]. After the integration of viral DNA into the host's genome, the telomerase reverse transcriptase is altered and multiple genes involved in the malignant process suffer various insertional mutations [20]. If the inflammation process continues to affect the hepatocytes, the liver will respond to injury with necrosis of the affected areas, followed by compensatory regeneration and hepatic fibrosis, therefore, altering the entire hepatic architecture, leading to cirrhosis [21]. Recent studies enhance the importance of HBV X protein, suggesting that pathways like p38MAPK and PI-3 K/AKT are used in order to increase the invasive potential of HBV infection [22, 23]. The association of HBV infection with HCV or HVD or with increased alcohol intake or aflatoxin consumption increases the carcinogenic risk of HBV [24].
