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Editorial-NEJM

Volume 347:208-210 July 18, 2002 Number 3
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Hepatitis B e Antigen � The Dangerous Endgame of Hepatitis B

 

The external pernicious influences of wind and dampness cause liver Qi to stagnate, and excess damp heat in liver and weakness of spleen Qi result.

 

� From the teachings of traditional Chinese medicine

 

Just as traditional Chinese medicine teaches us to respect the external forces that may affect the liver, modern Western medicine continues to uncover the maleficence of these influences in the forms of viral hepatitis. Viral hepatitis is the leading cause of hepatocellular carcinoma, which is the eighth most common cancer in the world. In developing countries, liver cancer is one of the three leading causes of morbidity and mortality. In developed countries, the incidence of hepatocellular carcinoma is lower, but recent studies have projected an alarming increase in its incidence over the next 10 years.1 Although this projected increase is attributed mostly to hepatitis C, hepatitis B will continue to account for a major part of the burden of liver cancer in the foreseeable future. Liver cancer develops insidiously in patients with chronic liver disease, and by the time it becomes symptomatic, cure is usually not possible. The ratio of mortality from hepatocellular carcinoma to its incidence, even in developed countries, is close to 1:1, and most patients do not survive for more than one year after the diagnosis has been made.

Shortly after the discovery of hepatitis B virus (HBV), the striking epidemiologic association between HBV infection and hepatocellular carcinoma was noted. This association was firmly established by the prospective study of Beasley et al. in Taiwan, reported more than 20 years ago.2 In the ensuing years, studies in animals have shown a causal relation between HBV infection and the development of hepatocellular carcinoma. In this issue of the Journal, Yang et al. report the results of another study conducted in Taiwan,3 which underscore the importance of this association. In their prospective, population-based study, Yang et al. followed 11,893 men for the development of hepatocellular carcinoma from 1991 to 2000. About 20 percent of the men were HBV carriers � that is, they were positive for hepatitis B surface antigen (HBsAg). The men were also tested for hepatitis B e antigen (HBeAg) at the start of the study to determine the role of this serologic marker in the development of hepatocellular carcinoma (Figure 1).



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 		 Figure 1. Genome of Hepatitis B Virus.

The viral genome is partially double-stranded (wavy black lines). The genome encodes four genes: the surface (S), core (C), polymerase (P), and X genes, shown as large arrows. The S and C genes give rise to various overlapping proteins (three for the S gene and two for the C gene). The longer core gene product is processed into the e antigen (red segment).

 
 
The risk of hepatocellular carcinoma was increased by a factor of 10 among the men who were positive for HBsAg alone and by a factor of 60 among those who were positive for both HBsAg and HBeAg, as compared with the reference group of men who were negative for both markers. An older age, the presence of antibodies against hepatitis C virus, cigarette smoking, and use of alcohol were also identified as independent risk factors for the development of hepatocellular carcinoma. Perhaps the most interesting finding was revealed by analysis of data from a nested case�control study, in which HBV DNA was measured in a subgroup of men with hepatocellular carcinoma and a subgroup of matched controls who were positive for HBsAg but negative for HBeAg. In this analysis, the presence of HBV DNA (as determined with the use of an assay for which the threshold of detection was 2.5 pg per milliliter) was significantly associated with the development of hepatocellular carcinoma.

Ostensibly, the striking increase in cases of hepatocellular carcinoma in men who were positive for HBeAg might suggest a role of HBeAg in the carcinogenesis associated with HBV infection. Is such a role consistent with our understanding of the biology of HBV infection? The answer is probably no. HBeAg is the alternative protein product of the core gene, one of the four genes encoded by the HBV genome.4 Its translation is initiated from the precore region, which contains a leader sequence that directs the protein to the secretory pathway. Before the introduction of DNA testing, HBeAg was used as a marker for active HBV replication and infectivity and as a criterion for treatment.5

The biologic function of HBeAg in the life cycle of HBV remains controversial. It is not required for viral replication, but it appears to be necessary for the establishment of chronic infection in animal models.6 Naturally occurring variants of HBV that are defective in the production of HBeAg have provided intriguing insights into the role of this protein.7 The most common of these variants contains a stop-codon mutation in the precore sequence that abrogates the synthesis of HBeAg; acute infection with this variant has been associated, but not invariably, with acute fulminant hepatitis.5 These findings suggest that the antigen has an immunomodulatory role, the mechanism of which remains largely unknown.5,8

Although this proposed role of HBeAg may contribute to the development of liver cancer, it is most likely that its role as a marker of active viral replication is associated with the increased risk of hepatocellular carcinoma. The finding, reported by Yang et al., of an association between positivity for HBV DNA and hepatocellular carcinoma in a subgroup of men who were seronegative for HBeAg supports this interpretation. This study would have been more informative if the HBV DNA level had been measured in all the HBV carriers in the cohort, regardless of their HBeAg status, in order to determine whether there was an association between the HBV DNA level and the development of hepatocellular carcinoma.

Does this epidemiologic study shed any light on the pathogenesis of HBV-associated hepatocellular carcinoma? The development of hepatocellular carcinoma is probably multifactorial. The chronic inflammatory changes provide a highly carcinogenic environment for hepatocytes. The production of inflammatory cytokines with the generation of reactive oxygen species can induce chromosomal mutations. In addition, the liver is the main organ that detoxifies xenobiotics and toxic byproducts from either the environment or the body's metabolism. Chronic hepatitis can result in aberrant processing and accumulation of these compounds, which are often potent DNA mutagens. The host immune response causes a large number of infected hepatocytes to die, and new hepatocytes are generated in great numbers, with a cell turnover rate that is 100 to 1000 times the rate in the normal state.9 The proliferating hepatocytes accumulate mutations and eventually become transformed. Many genetic alterations have been described in hepatocellular carcinoma, and the cumulative consequence of these changes underlies the multistage development of the disorder.10

Specific environmental hepatotoxins, such as aflatoxin and alcohol, probably contribute to the increased incidence of liver cancer in many regions of the world. This model of recurrent injury and regeneration is consistent with the emerging concept that many chronic inflammatory conditions, such as inflammatory bowel disease and gastroesophageal reflux, confer a predisposition to cancer. The model points to a correlation between the severity of the cellular injury and the risk of cancer. Yang et al. could have examined the veracity of this correlation if they had obtained information on the severity of liver disease, such as aminotransferase levels or the grade and stage of hepatitis, at the beginning of their study. Despite this shortcoming, the conventional wisdom and circumstantial evidence in the literature suggest that persons with more active liver disease are at higher risk for the development of hepatocellular carcinoma.

Does HBV play a direct part in the development of hepatocellular carcinoma other than being the causative agent in the process of recurrent injury and regeneration? Although the preponderance of evidence suggests that none of the HBV gene products function as classic oncogenes, viral factors may contribute to the oncogenic potential of the virus by altering the extent and severity of the injury.5 HBV may behave like a direct mutagen through the mechanism of chromosomal integration.4,11 In addition, the HBx protein has been shown to interact with a variety of cellular functions,4,12 many of which have direct implications for malignant transformation. HBV has seven genotypes, and recent data suggest that the spectrum of liver disease, including hepatocellular carcinoma, may differ among the genotypes,13 an observation that is supported by studies in animals.11 The reason for these differences is not known.

In the past two decades, we have made great strides in addressing this global health problem. The successful implementation of HBV vaccination in many parts of the world has dramatically reduced the prevalence of HBV infection and, consequently, of hepatocellular carcinoma.14,15 HBV infection can probably be eliminated throughout the world by means of universal vaccination, but accomplishment of this goal will require the collective efforts of national governments, public health agencies, philanthropic organizations, and pharmaceutical companies. We are making headway in the development of successful treatments for HBV infection. The currently approved drugs, interferon and lamivudine, are effective in 30 to 40 percent of HBV-infected people, and more effective anti-HBV drugs are being developed in both laboratories and clinics.16 The success of these efforts will depend on our resolve to make the elimination of HBV infection a top priority on the public health agenda for this new century, as we did with smallpox in the 1970s.

 


T. Jake Liang, M.D.
Marc Ghany, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases
Bethesda, MD 20892

References

 

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