**4.2. Hepatitis C virus (HCV) infection**

HCV infection is also one of the frequent risk factors in developing HCC in the word. The risk of HCC is very high in patients chronically infected with HCV [19]. Coinfection with HIV or HBV increased this risk further. The high majority of coinfected patients with either HIV or HBV precipitate chronic hepatitis, leading to HCC. Suppression of HCV load by IFN therapy, apparently, participates in reducing the onset of HCC [20]. However, concerns regarding the impact of HCV direct-acting agents (DAAs) on the incidence of HCC continue to be raised in clinic [21]. The potential increased risk of HCC in HCV patients under DAAs therapy has been reported [22]. Therefore, interferon therapy should not be discontinued at least for HCV patients with high risk of HCC.

#### **4.3. Alcohol abuse**

Evidence shows that long-term alcohol use is responsible for alcoholic liver disease (ALD) and a high risk of developing HCC [23]. ALD is well characterized; however, little progress has been made for its treatment. It is well established that alcohol is highly toxic to hepatocytes. By causing continuous cell necrosis, it induces perpetual regeneration of hepatocytes and paves the way to carcinogenesis [24]. In addition, alcohol causes liver damage by promoting inflammation that precipitates cirrhosis and leads to HCC [23]. The effect of alcohol on liver disease is boosted in people with viral hepatitis [25].

#### **4.4. Nonalcoholic steatohepatitis (NASH)**

NASH is a condition of fatty liver disease in which liver has abnormal fat accumulation and increased inflammation. Although the exact etiology of NASH remains unknown, the risk factors include obesity, type II diabetes, and related metabolic dysfunctions. NASH patients with no cirrhosis have no increased risk of HCC, indicating that induction of liver cirrhosis is a leading cause of HCC. However, the outcome of NASH is much similar as other chronic hepatitis such as HCV infection [26]. Although the risk of developing HCC might be lower in NASH patients than HCV patients, the severity of HCC and patient survival in both cases remain similar.
