Hepatitis C Virus and Hepatocellular Carcinoma

As early as the days of Hippocrates, hepatitis has been described as a disease that occurs in the young and shows the cardinal symptom of jaundice, which sometimes develops into a critical condition. Ironically, research on hepatitis progressed rapidly during World War II because injuries and the terrible sanitary conditions of the battlefields caused serious hepatitis epidemics. People recognized that hepatitis could be classified into two types: infectious and serumal. The former became known as hepatitis A and the latter as hepatitis B. After the war, the hunt for hepatitis viruses had begun. First, the hepatitis B virus (HBV) was identified in 1967 by Blumberg, who was awarded a Nobel Prize in recognition of his discovery. Next, the hepatitis A virus (HAV) was discovered in 1973. These discoveries were thought to have clarified the causes of hepatitis, but by the following year, it was acknowledged that many cases of hepatitis were not caused by either HAV or HBV (Prince et al., 1974). Later, the hepatitis D virus (HDV) and the hepatitis E virus (HEV) were discovered in 1977 and 1983, respectively, but they were not the cause of hepatitis non-A, non-B, which is associated with blood transfusion. In 1989, HCV was identified by a molecular biological method where researchers induced the expression of cDNAs obtained from the blood plasma of a chimpanzee with hepatitis non-A, non-B and screened them with convalescent serum (Choo et al., 1989). HCV was the first virus to be discovered not by the previously used virological methods, but by a molecular biological method.

The discovery of HCV had a great impact on the treatment and prevention of liver diseases (Hayashi & Takehara, 2006). It turned out that not only did most patients who had been diagnosed as hepatitis non-A, non-B actually have hepatitis C, but also that there were quite a few hepatitis C patients among those who had been thought to have alcoholic liver disease or autoimmune hepatitis. As the natural history of hepatitis C was clarified, it became clear that the disease is a major risk factor for hepatocellular carcinoma (HCC) (Figure 1). The infection route of HCV is via the blood. Some patients who are exposed to the virus develop overt liver disease, but most of them remain in a latent state. Within six months of being infected, 30% of the patients expel the virus naturally while the remaining 70% enter a phase of persistent infection. Once patients enter in this latter phase, it is very rare for the

Annual rate 0.5%^

Annual rate 0.5%^

Eliminating virus

Fig. 1 Natural history of HCV infection and its incidence of HCC according to liver fibrosis stage

Eliminating virus

Fig. 1 Natural history of HCV infection and its incidence of HCC according to liver fibrosis stage virus to be expelled naturally, with the estimated annual rate being less than 0.2% at most. Many of the patients with persistent infection show the medical conditions of chronic hepatitis and develop cirrhosis in 20 to 30 years. Patients with cirrhosis develop HCC at a very high annual rate of 8%, while patients with early chronic hepatitis do so at an annual rate of only 0.5%. The estimated number of patients with HCV is about 1.7 million in Japan and about 1.7 billion in the world. It is a serious public health problem as many of these patients belong to a high-risk group for HCC.

HCV does not fit into the classical definition of a tumor virus. The mechanism of carcinogenesis in patients with persistent infection of HCV is not fully understood, but it is usually explained from the virus and the inflammation viewpoints. From the virus viewpoint, the HCV core protein has an effect on the mitochondrial electron transport system and prompts the production of reactive oxygen species (ROS) (Moriya et al., 1998; Okuda et al., 2002). This process is thought to cause damage to the host gene. It has also been reported that the expression of HCV core protein activates bcl-xL transcription via the MAP kinase pathway as well as the activation of STAT3 (Otsuka et al., 2002). We have shown that high expression of bcl-xL, observed in about one-third of HCC cases, is involved in the apopto-sis resistance of cancer cells (Takehara et al., 2001; Takehara & Takahashi, 2003). From the inflammation viewpoint, it is thought that the inflammation itself induces oxidative stress and that hepatic regeneration in patients with hepatic disorder has an influence on the fixation of accumulated mutations (Kato et al., 2003). In any case, the larger clone size of the transformed hepatic cells caused by these factors leads to overt HCC. Generally, the innate immune system recognizes abnormality in autologous cells in vivo, and the immunological expulsion mechanism starts to function. Increasing evidence supports the possible involvement of innate immunity in the carcinogenesis of HCC and its development in patients with HCV infection.

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