Correspondence

Hepatitis B e Antigen and the Risk of Hepatocellular Carcinoma

N Engl J Med 2002; 347:1721-1722November 21, 2002

Article

To the Editor:

Yang et al. (July 18 issue)1 report that the detection of hepatitis B e antigen (HBeAg) at a single point in time during the course of chronic hepatitis B predicts the development of hepatocellular carcinoma. As noted in the article and the accompanying editorial,2 there are no hints of the direct involvement of HBeAg in the mutagenicity in the liver. On the other hand, HBeAg represents a surrogate marker of viral replication and necroinflammatory activity. The authors discuss both direct mechanisms of carcinogenicity (hepatitis B x antigen [HBxAg]–related effects) and indirect mechanisms of carcinogenicity (chronic hepatic inflammation as indicated by the monitoring of alanine aminotransferase levels). However, data on these primary markers are not reported by the authors, and this weakens the implications for clinical practice. If there is a significant difference in alanine aminotransferase levels between patients with hepatocellular carcinoma and patients without hepatocellular carcinoma, the alanine aminotransferase level represents a better and even less expensive marker. If this is not the case, as shown previously,3 direct carcinogenic mechanisms should be monitored with a marker related directly to carcinogenicity (e.g., HBxAg) rather than with a surrogate marker.

Do the authors mean to imply that the sole detection of HBeAg serves as an indication for treatment to prevent hepatocellular carcinoma? We think that at present no clear change in the existing guidelines4 for the evaluation and treatment of patients with hepatitis B virus (HBV) is warranted on the basis of the data presented by Yang et al.

Andreas Geier, M.D.
Carsten Gartung, M.D.
Christoph G. Dietrich, M.D.
Aachen University, D-52074 Aachen, Germany
ageier@ukaachen.de

4 References

1. 1

   Yang H-I, Lu S-N, Liaw Y-F, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168-174
   Full Text | Web of Science | Medline

2. 2

   Liang TJ, Ghany M. Hepatitis B e antigen -- the dangerous endgame of hepatitis B. N Engl J Med 2002;347:208-210
   Full Text | Web of Science | Medline

3. 3

   Sato A, Kato Y, Nakata K, et al. Relationship between sustained elevation of serum alanine aminotransferase and progression from cirrhosis to hepatocellular carcinoma: comparison in patients with hepatitis B virus- and hepatitis C virus-associated cirrhosis. J Gastroenterol Hepatol 1996;11:944-948
   Web of Science | Medline

4. 4

   Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-1241
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Geier et al. suggest that both HBxAg and the serum alanine aminotransferase level may be more appropriate than HBeAg as the primary markers for the prediction of the risk of hepatocellular carcinoma. Per their suggestion, we further analyzed the risk of hepatocellular carcinoma according to the serum alanine aminotransferase level and the presence or absence of seropositivity for HBsAg and HBeAg at the time of recruitment for our long-term follow-up study. The findings are shown in Table 1Table 1Adjusted Relative Risk of Hepatocellular Carcinoma According to the Results of HBV Antigen Tests and Serum Alanine Aminotransferase (ALT) Level.. In addition to seropositivity for HBsAg and HBeAg, an elevated serum alanine aminotransferase level (greater than or equal to 45 IU per liter) was also significantly associated with an increased risk of hepatocellular carcinoma. These three markers are independent risk factors for hepatocellular carcinoma. Men who were seropositive for HBsAg and HBeAg and who had an elevated serum alanine aminotransferase level were at highest risk for hepatocellular carcinoma (multivariate-adjusted relative risk, 109; 95 percent confidence interval, 51 to 233), as compared with those who were seronegative for HBsAg and HBeAg and who had a normal serum alanine aminotransferase level. A more interesting finding was that the adjusted relative risk for those who were seropositive for HBsAg and HBeAg and who had a normal serum alanine aminotransferase level was 61 (95 percent confidence interval, 34 to 112). Our findings provide strong evidence that HBeAg is an important marker, in addition to the serum alanine aminotransferase level, for the evaluation and treatment of patients with chronic HBV infection.

The HBxAg test is not performed routinely in most laboratories. We did not test for this marker in our study. However, an elevated rate of seropositivity for HBxAg has been found in patients with replicative markers of HBV (seropositivity for HBeAg, HBV DNA, or both), indicating that the expression of HBxAg is closely correlated with viral replication.1-3 HBeAg is thus considered an appropriate surrogate marker for HBxAg.

Chien-Jen Chen, Sc.D.
Hwai-I Yang, M.Sc.
San-Lin You, Ph.D.
National Taiwan University, Taipei 10018, Taiwan
cjchen@ha.mc.ntu.edu.tw

3 References

1. 1

   Feitelson MA, Clayton MM. X antigen polypeptides in the sera of hepatitis B virus-infected patients. Virology 1990;177:367-371
   CrossRef | Web of Science | Medline

2. 2

   Wu Z. Seroepidemiological study of hepatitis B virus x antigen (HBxAg) and anti-HBx antibodies in patients with hepatitis B. Zhonghua Liu Xing Bing Xue Za Zhi 1992;13:205-207
   Medline

3. 3

   Huang Y, Wu G, Wang X. Analysis of hepatitis B virus X antigen expression in chronic hepatitis B and cirrhosis. Zhonghua Nei Ke Za Zhi 1995;34:235-238
   Medline

Citing Articles (5)

Citing Articles

1. 1

   Lifeng Liu, Jinjian Yao, Jin Li, Jinliang Zhang, Jinling Yu, Xiaorui Jiang, Shuzhen Sun, Qing Liu, Ying Chang, Yongwen He, Jusheng Lin. (2011) Effects of variant rs346473 in ARHGAP24 gene on disease progression of HBV infection in han Chinese population. Journal of Huazhong University of Science and Technology [Medical Sciences] 31:4, 482-487
   CrossRef

2. 2

   Naoky C. S. Tsai, Peter S. Holck, Linda L. Wong, Aldrich A. Ricalde. (2008) Seroepidemiology of hepatitis B virus infection: analysis of mass screening in Hawaii. Hepatology International 2:4, 478-485
   CrossRef

3. 3

   Mark A Feitelson, Marcia M Clayton, Helena MGPV Reis, Guoyi Wu, Eva Ping Lu. (2008) Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma. Expert Opinion on Pharmacotherapy 9:13, 2233-2245
   CrossRef

4. 4

   Chih-Lin Lin, Li-Ying Liao, Chun-Jen Liu, Ming-Whei Yu, Pei-Jer Chen, Ming-Yang Lai, Ding-Shinn Chen, Jia-Horng Kao. (2007) Hepatitis B viral factors in HBeAg-Negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology 45:5, 1193-1198
   CrossRef

5. 5

   Robert Perrillo. (2006) Management of chronic hepatitis B virus infection: Current perspectives for the nurse practitioner. Journal of the American Academy of Nurse Practitioners 18:5, 203-215
   CrossRef