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The global distribution of hepatocellular carcinoma correlates with the geographic prevalence of chronic carriers of HBV, who number 400 million worldwide. The highest rates are in Southeast Asia and sub-Saharan Africa. In these areas the rates of HBV infection range from 10 to 25 percent and are maintained by vertical transmission of the virus from mothers to infants or infection of children under the age of 10 years by horizontal spread within families. (2) With persistent HBV infection, the risk of hepatocellular carcinoma increases by a factor of 100. (3) Indeed, among those who become infected with HBV at birth, men have an estimated lifetime risk of hepatocellular carcinoma of 50 percent, and women have a risk of 20 percent. (2) These tumors have a poor prognosis, with five-year survival rates of less than 5 percent.
Persistent infection with HCV is also an important risk factor for hepatocellular carcinoma. Four million persons in the United States have chronic HCV infection. The virus is usually transmitted by the parenteral route in adults, (4) and chronic infection develops in approximately 80 percent of persons who are exposed to the virus. Well-known and common modes of transmission include transfusion (before 1991, when screening of blood products for the virus began) and the use of intravenous drugs. The U.S. blood supply is currently safe, because all donors are now screened for antibodies to structural and nonstructural proteins of HCV. Since universal screening began, the risk of HCV infection after transfusion has been substantially reduced -- probably to 1 per 100,000 units of blood transfused. (5)
It is noteworthy that up to 50 percent of persons with chronic HCV infection report no exposure to any known risk factor, and the route of infection in these persons is unknown. As is true for HBV, the relative risk of hepatocellular carcinoma among persons with chronic HCV infection and cirrhosis is approximately 100 times the risk in uninfected persons. Persistent HCV infection is the cause of 70 percent of the cases of hepatocellular carcinoma in Japan (4) and approximately 30 to 50 percent of the cases in the United States, with a shift in the peak incidence toward a younger age group. The important role of HCV infection in the development of hepatocellular carcinoma is discussed by El-Serag and Mason.
Some factors in the pathogenesis of hepatocellular carcinoma have recently been defined. Almost all tumors occur in the context of chronic liver-cell injury, inflammation, and increased turnover of hepatocytes. The subsequent regenerative response and fibrosis lead to cirrhosis, which is followed by mutations in hepatocytes and the eventual development of hepatocellular carcinoma. HBV may be involved at multiple steps in this oncogenic process. For example, persistent viral infection causes inflammation, increased cell turnover, and cirrhosis. Furthermore, during the typically long period of infection (10 to 40 years), the HBV genome may be integrated into the chromosomes of hepatocytes. This event causes or contributes to genomic instability as a result of point mutations, deletions, translocations, and rearrangements at multiple sites where the viral genome is randomly inserted into the DNA of the hepatocyte. One of the viral gene products, the HBx protein, activates transcription, and during persistent viral infection, it may increase the expression of growth-regulating genes involved in the malignant transformation of hepatocytes. (2)
How HCV induces hepatocellular carcinoma is unknown. Like persistent HBV infection, persistent HCV infection also initiates inflammation, cellular injury, regeneration, and cirrhosis, all of which may contribute to the oncogenic process. Important to clinical practice was the unexpected and striking finding that 20 to 85 percent of persons with alcoholism -- whether or not they have liver disease -- have antibodies to structural and nonstructural proteins of HCV, indicating past or ongoing infection. The use of the reverse-transcription-polymerase-chain-reaction assay to detect HCV RNA revealed that 15 to 50 percent of persons with alcoholism and liver disease, particularly those with cirrhosis, were infected with HCV. (4) A study of 7000 persons in northern Italy demonstrated that in people with alcoholism and HCV infection, rapid worsening of the chronic liver disease was followed in turn by cirrhosis and hepatocellular carcinoma. (6) Alcohol abuse impairs cellular immunity and inhibits the efficacy of antiviral therapy with interferon. There is no doubt that patients with chronic HCV infection should not drink alcohol, which will accelerate the liver disease caused by the virus.
Aflatoxins also contribute to the development of hepatocellular carcinoma. These toxic compounds are produced by Aspergillus flavus and A. parasiticus and contaminate food supplies such as corn, peanuts, milo, sorghum, and rice in some regions of the world. The liver metabolizes aflatoxins to reactive intermediates that bind selectively to guanine residues in the DNA of hepatocytes. Several studies have demonstrated that aflatoxin B1 induces a specific guanine-to-thymine point mutation in codon 249 of the p53 tumor-suppressor gene. (7) This mutation inactivates the p53 protein, allowing unregulated cellular proliferation, and thereby contributes to the pathogenesis of hepatocellular carcinoma.
Cirrhosis is a very important risk factor for hepatocellular carcinoma. In patients with hemochromatosis, the risk of hepatocellular carcinoma increases by a factor of approximately 200 with the onset of cirrhosis. However, the occurrence of cirrhosis in patients with autoimmune chronic hepatitis, Wilson's disease, primary biliary cirrhosis, or alcohol abuse without coexisting HCV infection increases the risk of hepatocellular carcinoma by a factor of only 2 to 5. The cause of these differences is unknown. Patients with chronic HBV and HCV infection and cirrhosis should be monitored with serum alpha-fetoprotein determinations and ultrasonography of the liver to detect these tumors at an early stage, when surgical resection may be possible. However, it is unclear how often these tests should be performed and whether early detection actually prolongs survival in patients with cirrhosis.
Can we prevent hepatocellular carcinoma? In Taiwan, vaccination of children against hepatitis B reduced the rate of chronic infection from 10 percent to less than 1 percent, and follow-up revealed a striking reduction in the incidence of hepatocellular carcinoma. (8) These results further strengthen the evidence of the role of HBV in the pathogenesis of the disease and indicate that vaccination is essential for its primary prevention. The incidence of hepatocellular carcinoma may be further reduced by eliminating aflatoxin from the food supply in areas of the world where agricultural products are stored under conditions that favor the growth of A. flavus and A. parasiticus.
Any antiviral treatment that eradicates HBV or HCV infection or inhibits the progression of chronic liver disease to cirrhosis should, in principle, help prevent hepatocellular carcinoma. Treatment with interferon alfa and ribavirin has eradicated chronic HCV infection in some patients, (9,10) and it may lead to a reduction in the incidence of hepatocellular carcinoma in such patients. One study reported a decreased incidence of hepatocellular carcinoma associated with chronic HCV infection after treatment with interferon alfa (11); however, another recent, prospective trial found no reduction in risk after such therapy. (12) Large, prospective studies are needed before we can draw firm conclusions about the possible protective effects of antiviral treatment against hepatocellular carcinoma. With the development of new and more effective antiviral therapies and the implementation of preventive approaches, it is highly likely that the incidence of one of the most common and devastating tumors in the world can be reduced.
Nedim Ince, M.D.
Jack R. Wands, M.D.
Massachusetts General
Hospital Cancer Center
Charlestown, MA 02129
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