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Antibody to Hepatitis B Core Antigen and Risk for Hepatitis C–Related Hepatocellular Carcinoma: A Prospective Study

Kazuki Ikeda, MD; Hiroyuki Marusawa, MD, PhD; Yukio Osaki, MD; Takefumi Nakamura, MD, PhD; Naoto Kitajima, MD, PhD; Yukitaka Yamashita, MD, PhD; Masatoshi Kudo, MD, PhD; Tosiya Sato, PhD; and Tsutomu Chiba, MD, PhD
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From Kyoto University, Kyoto, Japan; Osaka Red Cross Hospital, Kitano Hospital, and Kinki University, Osaka, Japan; Kasai Municipal Hospital, Hyogo, Japan; and Wakayama Red Cross Medical Center, Wakayama, Japan.

Acknowledgments: The authors thank the following physicians for their continued dedication: Y. Yamashita, MD, and K. Kaneshiro, MD, Miki City Hospital; S. Morishita, MD, Shimada Municipal Hospital; T. Eguchi, MD, Kitano Hospital; Y. Kimura, MD, T. Kurokami, MD, K. Matsumura, MD, Y. Kokuryu, MD, K. Kojima, MD, and K. Ito, MD, Shizuoka General Hospital; K. Mizuta, MD, and Y. Toda, MD, Shiga Medical Center for Adults; Y. Matsumori, MD, and Y. Yamamoto, MD, Takatsuki General Hospital; Y. Tanaka, MD, and K. Kajimura, MD, Kishiwada City Hospital; J. Shimamura, MD, and H. Shimomura, MD, Kurashiki Central Hospital; Y. Okabe, MD, and A. Orino, MD, Kobe City General Hospital; H. Azechi, MD, and O. Nishida, MD, Ohtsu Red Cross Hospital; T. Tamada, MD, Takatsuki Red Cross Hospital; K. Miura, MD, Kyoto Katsura Hospital; S. Ono, MD, Ako Municipal Hospital; T. Aoi, MD, M. Nabeshima, MD, and K. Mori, MD, Kyoto University Hospital.

Grant Support: By a Grant-in-Aid for Scientific Research (15209024 and 16790378) from the Japan Society for the Promotion of Science.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Tsutomu Chiba, MD, PhD, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; e-mail, chiba@kuhp.kyoto-u.ac.jp.

Current Author Addresses: Drs. Ikeda, Marusawa, and Chiba: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

Dr. Osaki: Osaka Red Cross Hospital, 5-30 Fudegasaki, Tennoji-ku, Osaka 543-8555, Japan.

Dr. Nakamura: Kitano Hospital, 2-4-20 Ogimachi, Kita-ku, Osaka 530-8480, Japan.

Dr. Kitajima: Kasai Municipal Hospital, 1-13 Yokoo, Hojyo-cho, Kasai 675-2393, Japan.

Dr. Yamashita: Japan Red Cross Society Wakayama Medical Center, 4-20 Komatsubaradori, Wakayama 640-8558, Japan.

Dr. Kudo: Kinki University School of Medicine, 377-2 Ohno-Higashi-cho, Osaka-Sayama 589-8511, Japan.

Dr. Sato: Department of Biostatistics, Kyoto University School of Public Health, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Author Contributions: Conception and design: K. Ikeda, H. Marusawa, T. Chiba.

Analysis and interpretation of the data: K. Ikeda, H. Marusawa, T. Sato, T. Chiba.

Drafting of the article: K. Ikeda, H. Marusawa, T. Chiba.

Critical revision of the article for important intellectual content: K. Ikeda, H. Marusawa, M. Kudo, T. Sato, T. Chiba.

Final approval of the article: K. Ikeda, H. Marusawa, T. Sato, T. Chiba.

Provision of study materials or patients: K. Ikeda, H. Marusawa, Y. Osaki, T. Nakamura, N. Kitajima, Y. Yamashita, M. Kudo, T. Chiba.

Statistical expertise: T. Sato.

Obtaining of funding: H. Marusawa, T. Chiba.

Administrative, technical, or logistic support: K. Ikeda, H. Marusawa, Y. Osaki, T. Chiba.

Collection and assembly of data: K. Ikeda, H. Marusawa, Y. Osaki, T. Nakamura, N. Kitajima, Y. Yamashita, T. Chiba.

Ann Intern Med. 2007;146(9):649-656. doi:10.7326/0003-4819-146-9-200705010-00008
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In a previous study, we retrospectively showed that anti-HBc is detectable in approximately 50% of patients with HCV-related chronic liver disease who lacked HBsAg (28). Of note, the proportion of patients who were positive for anti-HBc increased in association with the progression of liver disease, and accordingly the prevalence of anti-HBc was substantially higher in patients with HCC than in those with chronic hepatitis or cirrhosis. Many published reports support our observation that the presence of anti-HBc in the serum of patients with HCV-related HCC is a common clinical finding, which suggests that previous exposure to HBV may be a risk factor for HCC in patients with HCV-related chronic liver disease (3435). However, all of those findings were obtained from retrospective studies and were not confirmed prospectively.

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Appendix Figure.
Cumulative incidence of hepatocellular carcinoma among patients with hepatitis treated with interferon and untreated patients.
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Figure. .
Occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis who had or did not have interferon therapy

The number and proportion of patients who developed HCC in each group is shown in the bottom boxes. All CIs are 95% CIs. Anti-HBc = antibody to hepatitis B core antigen.

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Submit a Comment/Letter
Association of BMI and Diabetes With Development of Hepatocellular Carcinoma
Posted on May 15, 2007
Rohit Loomba
Liver Diseases Branch, NIDDK, NIH
Conflict of Interest: None Declared

We read with interest the article by Ikeda and colleagues suggesting an association between antibody to core antigen (anti-HBc) and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C(1). The investigators conducted a careful multivariable analysis using a Cox proportional hazard model and included several of the recognized risk factors for the development of HCC such as age, sex, smoking, alcohol consumption, and response to interferon therapy in addition to anti-HBc status.

However, several epidemiologic studies and a meta-analysis including patients from Asia and the West have shown an association between body mass index (BMI) and diabetes mellitus with the development of HCC(2-4). Obesity and diabetes have been closely linked to the development of HCC perhaps through their association with nonalcoholic steatohepatitis, which is a progressive liver disease(5). The authors do not provide any information regarding the contribution of metabolic factors such as BMI and diabetes in assessing the risk of HCC in this population. Data on BMI and a history of diabetes should be available from the patient charts. Therefore, it will be of interest to readers whether risk factors such as BMI and diabetes mellitus contribute to the development of HCC in this population and modify the association between anti-HBc positivity and the development of HCC in individuals with HCV related cirrhosis.


1. Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, Kudo M, et al. Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study. Ann Intern Med 2007;146:649-656.

2. Kusakabe A, Tanaka Y, Orito E, Sugauchi F, Kurbanov F, Sakamoto T, Shinkai N, et al. A weak association between occult HBV infection and non- B non-C hepatocellular carcinoma in Japan. J Gastroenterol 2007;42:298- 305.

3. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4:369-380.

4. Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 2005;42:218-224.

5. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology 2004;127:S97-103.

Conflict of Interest:

None declared

In response
Posted on June 23, 2007
Kazuki Ikeda
Kyoto university
Conflict of Interest: None Declared

We thank Dr.Loomba and Dr.Ghany for their comments regarding the obesity as a possible risk for liver cancer, and we appreciate the opportunity to respond. As they pointed out, obesity is widely recognized as a significant risk factor for the development of many types of human cancers including hepatocellular carcinoma (HCC) (1). In our current paper, we prospectively analyzed the various clinical factors including positivity for antibody to hepatitis B core antigen, smoking and alcohol intake as risks for the occurrence of HCC in Japanese patients with hepatitis C virus (HCV) infection (2). We found that the incidence of HCC in our patients with body mass index (BMI) > 30 kg/m2 was not significantly different compared with those with BMI <25 kg/m2 (16.7 percent vs. 22.1 percent, respectively; p=0.85). However, the prevalence of obese people among Japanese is not so high compared to that in USA and European population. In fact, we observed that only 3.0 percent of the HCV-positive patients analyzed in our study had a BMI greater than 30.0 kg/m2. In contrast, it was shown that the prevalence of obese with a BMI greater than 30.0 kg/m2 in US was ranged from 13 percent to 27 percent (3). The recent US study revealed that the relative risk of HCC was 1.68 times higher among women with a BMI>35 kg/m2, and was 4.52 times higher for men with a similarly increased BMI compared with the reference groups with baseline BMIs of 18.5 to 25.0 kg/m2 (4). Thus, it seems reasonable to assume that the number of cases with high BMI value was not enough among Japanese patients with HCV-related chronic liver disease to evaluate the risk for HCC occurrence. Similarly, several epidemiological data showed an increased risk of HCC among patients with diabetes, a condition closely associated with obesity (5). However, only 5.7 percent of our Japanese patients with HCV-related chronic liver disease had a diagnosis with diabetes defined by use of insulin or oral diabetic medication. Therefore, it was also difficult to analyze the statistical difference of the incidence of HCC between patients with and without diabetes enrolled in our prospective study. In conclusion, we believe that further prospective study should be carried out in the epidemic area of overweight to ask whether high BMI and diabetes could be the risk for incidence of HCC.

Kazuki Ikeda Hiroyuki Marusawa Tsutomu Chiba

References 1. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology. 2004;127:S97-103.

2. Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, et al. Antibody to hepatitis B core antigen and risk for hepatitis C- related hepatocellular carcinoma: a prospective study. Ann Intern Med. 2007; 146: 649-656.

3. McTigue KM, Garrett JM, Popkin BM. The natural history of the development of obesity in a cohort of young U.S. adults between 1981 and 1998. Ann Intern Med. 2002; 136: 857-864.

4. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Eng J Med 2003; 348: 1625-1638.

5. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States veterans. Am J Gastroenterol. 2001; 96: 2462-2467.

Coflict of Interest: None declared.

Conflict of Interest:

None declared

Occult Hepatitis B and Risk of Hepatitis C - Related Hepatocellular Carcinoma - A Hidden Menace?
Posted on June 26, 2007
Tung-Hung Su
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital
Conflict of Interest: None Declared

Dear Editor,

We read with interest the article Antibody to Hepatitis B Core Antigen and Risk for Hepatitis C - Related Hepatocellular Carcinoma: A Prospective Study. It provides evidence that occult hepatitis B virus (HBV) may contribute to HCC development in HCV-related cirrhosis patients, even in those with sustained response to previous interferon-based therapy. However, several issues need to be further clarified.

First, the definition of occult HBV infection is seronegativity of HBsAg but positivity of HBV DNA in serum or liver tissue. In this study, more stringent criteria were adopted to exclude individuals positive for serum HBV DNA which could be detected in up to 50% of those positive for isolated anti-HBc (1). Accordingly, a significant proportion of occult HBV carriers might be excluded, therefore, the contribution of occult HBV infection to HCC development may be underestimated. Besides, the authors used a less sensitive branched DNA assay with limit of detection around 700,000 copies/mL. It is believed that serum HBV DNA level in subjects with occult HBV infection is less than 1,000 copies/mL (1). Thus, their patients with serum HBV DNA levels ranging from 1,000 to 700,000 copies/mL might be included for analysis. A prospective study revealed a higher baseline serum HBV DNA level (> 10,000 copies/mL) is a strong predictor of HCC development, regardless of cirrhosis (2). In summary, the authors should re-analyze their data by a more sensitive real-time PCR assay and subdivide their patients according to serum HBV DNA level.

Second, although anti-HBc-positive and -negative patients had similar bilirubin level and prothrombin time, the severity (e.g. Child-Turcotte- Pugh score) and duration of cirrhosis was not compared, which were known to contribute to the development of HCC (3). Moreover, individuals positive for anti-HBc and anti-HBs have a lower prevalence of serum HBV DNA than those with isolated anti-HBc (4). Therefore, in addition to status of anti-HBs, the authors should include cirrhosis into analysis to make the comparisons more informative.

Third, the authors failed to stratify patients receiving interferon- based therapy by genotype and viral load, which are associated with sustained response and HCC development (5) . Besides, the use of interferon-alpha or interferon-beta treatment was not standardized. Therefore, although anti-HBc-positive HCV carriers seemed to have a higher risk of HCC development, whether anti-HBc itself, HCV viral factors (genotype and viral load) or treatment regimen contribute more to hepatocarcinogenesis remains to be established. Taken together, the pathogenesis of HCC could not be over-simplified to either viral factor, and more complex mechanisms involve the interplay between HBV and HCV should be considered.

In conclusion, whether occult hepatitis B is a hidden menace to HCV- related hepatocarcinogenesis needs further confirmation by using more sensitive molecular assays and delicate study design.


1.Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis. 2002;2(8):479-86.

2.Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65-73.

3.Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35-50.

4.Kao JH, Chen PJ, Lai MY, Chen DS. Occult hepatitis B virus infection and clinical outcomes of patients with chronic hepatitis C. J Clin Microbiol. 2002;40(11):4068-71.

5.Ishikawa T, Ichida T, Yamagiwa S, et al. High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. J Gastroenterol Hepatol. 2001;16(11):1274-81.

Conflict of Interest:

None declared

Submit a Comment/Letter

Summary for Patients

Does Exposure to Hepatitis B Virus Increase the Risk for Liver Cancer in Patients with Hepatitis C Infection?

The summary below is from the full report titled “Antibody to Hepatitis B Core Antigen and Risk for Hepatitis C–Related Hepatocellular Carcinoma: A Prospective Study.” It is in the 1 May 2007 issue of Annals ofInternal Medicine (volume 146, pages 649-656). The authors are K. Ikeda, H. Marusawa, Y. Osaki, T. Nakamura, N. Kitajima, Y. Yamashita, M. Kudo, T. Sato, and T. Chiba.


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