Hepatocellular carcinoma: Recent trends in Japan
2004; Elsevier BV; Volume: 127; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2004.09.012
ISSN1528-0012
AutoresKendo Kiyosawa, Takeji Umemura, Tetsuya Ichijo, Akihiro Matsumoto, Kaname Yoshizawa, Amal Gad, Eiji Tanaka,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoDuring the past 20 years, primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. The numbers of deaths and death rate from HCC showed a sharp increase beginning in 1975. Although both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important causes, HCV-related HCC has accounted for most of the recent increase and now represents 75% of all HCC in Japan. Geographically, HCC is more frequent in western than eastern Japan, and the death rate of HCC in each prefecture correlates with prevalence of anti-HCV. Among patients with HCV-related HCC, a history of blood transfusion was a relatively important source of infection in the 1990s, whereas community-acquired infections increased after 2000. There was a negative correlation between the duration from onset of infection to development of HCC and the age at onset. Interferon therapy for chronic hepatitis C has reduced the risk for HCC, indicating that early detection of HCV carriers and better treatment will contribute to improved outcomes. Nationwide screening for HCV and HBV began in 2002 in Japan, and reduction of HCC is anticipated. Further research should focus on mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and treatment approaches. Better understanding of HCC unrelated to HCV and HBV and possibly because of steatohepatitis and diabetes should also be a major concern in future studies. During the past 20 years, primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. The numbers of deaths and death rate from HCC showed a sharp increase beginning in 1975. Although both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important causes, HCV-related HCC has accounted for most of the recent increase and now represents 75% of all HCC in Japan. Geographically, HCC is more frequent in western than eastern Japan, and the death rate of HCC in each prefecture correlates with prevalence of anti-HCV. Among patients with HCV-related HCC, a history of blood transfusion was a relatively important source of infection in the 1990s, whereas community-acquired infections increased after 2000. There was a negative correlation between the duration from onset of infection to development of HCC and the age at onset. Interferon therapy for chronic hepatitis C has reduced the risk for HCC, indicating that early detection of HCV carriers and better treatment will contribute to improved outcomes. Nationwide screening for HCV and HBV began in 2002 in Japan, and reduction of HCC is anticipated. Further research should focus on mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and treatment approaches. Better understanding of HCC unrelated to HCV and HBV and possibly because of steatohepatitis and diabetes should also be a major concern in future studies. On a global scale, the Japanese have one of the longest average life expectancies, and the size of the aged population has been rising rapidly. These trends have led to a rising demand for improved health and quality of life in the elderly population. The 3 leading causes of death in Japan are malignant neoplasms, cardiovascular diseases, and cerebrovascular diseases. Death rates because of malignant neoplasms and cardiovascular disease have been increasing rapidly in recent decades. The age-adjusted death rate because of maligant neoplasms in 1960 was 100.4 per 100,000 people, and the total number of deaths was 93,773. The death rates from malignant neoplasms subsequently increased to 116.3 in 1970, 139.1 in 1980, 177.2 in 1990, and 235.6 per 100,000 people in 2000 (greater than a 2-fold increase). In 2001, the death rate because of malignant neoplasms was 238.8 per 100,000 people, and total deaths were 300,658. Since 1981, malignant neoplasms have been the leading cause of death in Japan. Among causes of death from malignant neoplasms, primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), 4% cholangiocarcinoma, and 1% other have been particularly prominent. For the last 30 years, liver cancer has been the third leading cause of death from malignant neoplasms in men (following stomach and lung cancer). In women, liver cancer has ranked fifth during the past decade, following stomach, colon, lung, and breast cancer. In 2001, the death rates per 100,000 people for the leading causes of cancer mortality in men were 45.6 for lung, 37.1 for stomach, and 27.3 for primary liver cancer; rates in women have been 14.6 for stomach, 13.6 for colon, 12.2 for lung, 11.1 for breast, and 8.8 for primary liver cancer. There are 2 major causes of HCC in Japan: hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The increase in incidence of HCC in Japan, however, has largely been attributable to HCV infection and the increase of this disease in the general population during the last 50 to 60 years.1Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan projection to other countries in the foreseeable future.Oncology. 2002; 62: 8-17Crossref PubMed Scopus (194) Google Scholar Using a molecular clock analysis based on sequencing of HCV isolates, it has been hypothesized that genotype 1 HCV first appeared in Japan in the 1880s and that a major spread of infection in the population began in the 1930s and peaked between 1940 and 1970.2Tanaka Y. Hanada K. Mizokami M. Yeo A.E. Shih J.W.K. Gojobori T. Alter H.J. A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades.Proc Nat Acad Sci U S A. 2002; 99: 15584-15589Crossref PubMed Scopus (294) Google Scholar Thus, an understanding of recent trends in HCC in Japan depend on an understanding of the epidemiology and natural history of HCV infection. Changes in annual death totals of primary liver cancer in different age groups between 1958 and 2001 are shown in Figure 1. The total number of deaths from HCC was stable and less than 10,000 people per year until 1975 when numbers increased sharply. The increase in 1995 was probably due to the change in International Classification of Disease (ICD) codes from ICD9 to ICD10. Peak numbers of deaths from HCC were in patients below the age of 69 years until 1999, when the peak age rose to over 70 years. Death rates from liver cancer by gender are shown in Figure 2. Rates were consistently higher in men than women. Total age-adjusted death rates per 100,000 people were 9.4 in 1960, 8.7 in 1965, 9.2 in 1970, 9.3 in 1975, 12.0 in 1980, 15.8 in 1985, 19.7 in 1990, 25.5 in 1995, and 27.1 in 2000. A sharp rise in death rates for primary liver cancer in men began in 1975 and a more gradual rise in women in 1980. Since 1995, the rate of rise in men has slowed, although total numbers are still increasing. A nationwide survey of primary liver cancer has been conducted every 2 years since 1968 by the Liver Cancer Study Group of Japan. The results of survey up to 1999 have been reported in several publications.3The Liver Cancer Study Group of JapanPrimary liver cancer in Japan, sixth report.Cancer. 1987; 60: 1400-1411Crossref PubMed Scopus (213) Google Scholar, 4Arii S. Yamaoka Y. Futagawa S. Inoue K. Kobayashi K. Kojiro M. Makuuchi M. Nakanuma Y. Okita K. Yamada R. The Liver Cancer Study GroupResults of surgical and non-surgical treatment for small-sized hepatocellular carcinoma a retrospective and nationwide survey in Japan.Hepatology. 2000; 32: 1224-1229Crossref PubMed Scopus (708) Google Scholar, 5Ikai I. Okita K. Omata M. Kojiro M. Kobayashi K. Nakanuma Y. Fujiwara S. Makuuchi M. Yamaoka Y. Report of the 15th follow-up survey of primary liver cancer.Hepatol Res. 2004; 28: 21-29Crossref PubMed Scopus (131) Google Scholar A total of 99,196 patients have been entered in this registry between 1980 and 1999. Of the total, 95% (93,901) were diagnosed as HCC histologically and clinically, indicating that the majority of primary liver cancer in Japan is HCC. Five serologic surveys performed between 1990 and 1999 have documented that most patients with HCC are positive for either hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV). Tests for HBsAg became available in 1975 and those for anti-HCV in 1990. HBsAg-positive cases of HCC constituted 42% of cases in 1977–1978, but only 16% of cases in 1998–1999. In contrast, anti-HCV-positive cases of HCC have accounted for more that 70% of cases diagnosed in the last 10 years. In cross-sectional studies, HBV-related HCC accounted for 51% of cases in 1982, 23% of cases in 1990, and 14% of cases in 2003.6Kiyosawa K. Akahane Y. Nagata A. Koike Y. Furuta S. The significance of blood transfusion in non-A, non-B chronic liver disease in Japan.Vox Sang. 1982; 43: 45-52Crossref PubMed Scopus (66) Google Scholar, 7Kiyosawa K. Sodeyama T. Tanaka E. Gibo Y. Yoshizawa K. Nakano Y. Furuta S. Akahane Y. Nishioka K. Purcell R.H. Alter H.J. Interrelationship of blood transfusion, non-A, non- B hepatitis and hepatocellular carcinoma analysis by detection of antibody to hepatitis C virus.Hepatology. 1990; 12: 671-675Crossref PubMed Scopus (1199) Google Scholar Although anti-HCV was not available in 1982, non-HBV-related HCC or anti-HCV-positive cases represented 49% of cases in 1982, 61% in 1990, and 81% in 2003. Thus, HCV-related HCC has become an increasing majority of cases. Thus, the increased rates of death because of primary liver cancer in Japan appear to reflect the increase in numbers of HCV-related HCC. Although Japan is a relatively small country with a homogenous population, the incidence of HCC varies greatly among different regions. The Vital Statistics of Japan for 2001 published in 2003 by the Japanese Ministry of Health, Labor, and Welfare on the incidence of deaths as a result of HCC in its 48 prefectures shows a gradient increase of death rates for HCC along the axis of Japan from east to west (Figure 3).8Vital Statistics of Japan 2001Statistics and Information Department, Minister's Secretariat, Ministry of Health, Labor and Welfare.Health and Welfare Statistics Association. Ohwa Sogo Insatsu. Co, Tokyo2003Google Scholar The average age-adjusted death rate of HCC among the 48 prefectures was 27.3 per 100,000 people. Prefectures with death rates greater than 30 per 100,000 people were found chiefly on the Kyushu Islands, the Shikoku Islands, and the western area of Honshu Island. Nationwide health screening for HBsAg and anti-HCV in the over 40 years of age population has been performed since 2002, and prevalence rates for these markers have been analyzed by prefecture in Japan. The average HBsAg prevalence was 1.2% in the total Japanese population. Although high prevalence rates of HBsAg are found in a few areas, such as Okinawa (3.1%), Hokkaido (2.4%), and Shimane (2.1%), rates of HBsAg are generally evenly distributed throughout most of Japan. In contrast, there is considerable variation in the prevalence of anti-HCV in different geographic areas. Highest rates are found in Kyushu Island, Shikoku Island, and on the western side of Honshu Island (∼1.5%). There were highly significant associations between death rates from HCiC in each prefecture and prevalence of anti-HCV (Figure 4B, correlation coefficient = 0.616; P = .01, Y = 18.1 + 8.752X), but no correlation with the prevalence of HBsAg (Figure 4A, correlation coefficient = 0.093; P = .533). For instance, although Hokkaido and Okinawa have high prevalence rates of HBsAg (2.4% and 3.1%, respectively), death rates from HCC in Hokkaido and Okinawa were 22.7 and 10.6 per 100,000 people, respectively, both of which are below the national average (23.7). In contrast, areas with high rates of anti-HCV, such as Saga (3.9%), Hiroshima (1.8%), Fukuoka (1.7%), and Kagawa (1.7%), had high death rates for primary liver cancer—43.1, 39.6, 39.8, and 31.9 per 100,000 people, respectively—which were higher than the national average. Thus, although rates of HBV infection in the population correlates best with rates of HCC in most countries of the world, in Japan, this is not the case, and HCV appears to be the major contributor to rates of primary liver cancer.Figure 4Relationship between age-adjusted annual death rates from primary liver cancer and prevalence of HBsAg (A) and anti-HCV (B) among the general population over 40 years of age in 2002.View Large Image Figure ViewerDownload (PPT) Results of cross-sectional studies of HCC conducted at Shinshu University are shown in Table 1.6Kiyosawa K. Akahane Y. Nagata A. Koike Y. Furuta S. The significance of blood transfusion in non-A, non-B chronic liver disease in Japan.Vox Sang. 1982; 43: 45-52Crossref PubMed Scopus (66) Google Scholar, 7Kiyosawa K. Sodeyama T. Tanaka E. Gibo Y. Yoshizawa K. Nakano Y. Furuta S. Akahane Y. Nishioka K. Purcell R.H. Alter H.J. Interrelationship of blood transfusion, non-A, non- B hepatitis and hepatocellular carcinoma analysis by detection of antibody to hepatitis C virus.Hepatology. 1990; 12: 671-675Crossref PubMed Scopus (1199) Google Scholar Men accounted for the majority of cases of both HBV- and HCV-related HCC for all age groups. The proportion of cases of HCC in men was 81% in 1982, 90% in 1990, but only 72% in 2003, indicating a recent relative increase in cases among women in recent years. The average age of diagnosis of HBV-related HCC was similar in all 3 time periods. In contrast, the average age of patients with HCV-related HCC rose from 61.6 years in 1982 to 63.1 years in 1990 and 67.8 years in 2003. The proportion of cases reporting a history of blood transfusion was 13% in 1982, 42% in 1990, and 36% in 2003 innon-HBV (HBsAg-negative) and anti-HCV positive patients with HCC. For these time periods, the intervals between date of blood transfusion and diagnosis of HCC were 23.4, 29.0, and 36.6 years, respectively. This estimated incubation period from onset of infection to clinical diagnosis of HCC has also been found by Tong et al in Los Angeles, who reported the average interval between blood transfusion and diagnosis of chronic hepatitis as 13.7 years, diagnosis of cirrhosis as 20.6 years, and HCC as 28.3 years.9Tong M.J. El-Farra N. Reikes A.R. Co R.L. Clinical outcomes after transfusion-associated hepatitis C.N Engl J Med. 1995; 332: 1463-1466Crossref PubMed Scopus (1197) Google Scholar The reason for the increasing interval between transfusion and diagnosis of HCC in recent years is not known, but a possible explanation is the recent introduction of therapy of hepatitis C, which may prolong survival or time to HCC. Another explanation is a delay in diagnosis of HCV infection and/or HCC. The correlation of age at the time of blood transfusion and interval from transfusion to diagnosis of HCC is shown in Figure 5. These results demonstrate an inverse relationship between age of exposure to HCV and appearance of liver cancer (correlation coefficient = 0.753; P < .001; Y = 59.0 − 0.728X). Such results suggest that progression to cirrhosis and HCC is more rapid with older age of onset of hepatitis C. Similar findings have been reported by others. Tanaka et al analyzed the interval between the age of blood transfusion and age of diagnosis of HCC in 115 Japanese patients.10Tanaka E. Kiyosawa K. Matsushima T. Ishikawa K. Hino K. Tanaka S. Nose H. Kimada H. Iino S. Kamimura T. Unohara M. Mizokami M. Okanoue T. Kuroki T. Yamada G. Miura T. Yano M. Tsubouchi H. Kohara K. Sato S. Hattori N. Genotyping Elisa Study GroupEpidemiology of genotypes of hepatitis C virus in Japanese patients with type C chronic liver diseases a multi-institute analysis.J Gastroenterol Hepatol. 1995; 10: 535-545Google Scholar The average interval was 30.6 years, and it decreased with increasing ages at the time of transfusion: 34.8 years for patients transfused before the age of 30 years, 30.4 years for those transfused between the ages of 30 and 40 years, and 24.7 years for those transfused above the age of 40 years. Hamada et al reported a significant inverse correlation between the interval from HCV infection to the development of HCC and the age at time of infection (correlation coefficient = 0.702; P < .0001; Y = 61.1 − 0.82X), indicating that the age of patients, rather than the duration of HCV infection, was more significant for development of HCC in patients with posttransfusion hepatitis C.11Hamada H. Yatsuhashi H. Yano K. Daikoku M. Arisawa K. Inoue O. Koga M. Nakata K. Eguchi K. Yano M. Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C.Cancer. 2002; 95: 331-339Crossref PubMed Scopus (61) Google Scholar In a similar fashion, Poynard et al found a large difference among the probabilities of fibrosis progression by age of onset of HCV infection.12Poynard T. Ratziu V. Chalotte F. Goodman Z. McHutchison J. Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C.J Hepatol. 2001; 34: 730-739Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar Among patients infected before the age of 20 years, there were few if any events during the first 10 years of infection. Among patients aged 20 to 30 years and 30 to 40 years, there was an increase in progression of fibrosis after 30 years of infection. In patients infected between ages 40 and 50 years, there was a clear increase in progression of fibrosis after 10 years of infection. Finally, among patients infected after 50 years of age, there were rapid rates of progression for all stages of fibrosis. These findings indicate that age has a major effect on rate of progression of hepatitis C, development of cirrhosis, and HCC.Table 1Comparison of Clinical Features of HBV- and HCV-Related Hepatocellular Carcinoma in 1982, 1990, and 2003 in Shinshu University HospitalHBV relatedHCV related1982 (n = 55)1990 (n = 29)2003 (n = 27)1982 (n = 53)1990 (n = 50)2003 (n = 108)Male78%83%81%81%90%72%Age (y)55.4 ± 11.154.8 ± 9.853.8 ± 9.061.6 ± 10.163.1 ± 7.367.8 ± 7.8Family clustering33%45%44%1.8%4%2.7%History of BT8.3%6.9%3.7%13%42%26%Interval between BT and DX23.4 ± 7.029.0 ± 13.636.6 ± 10.1Heavy drinkeraHeavy drinker: more than 80 g ethanol daily, 1982,6 1990.73.6%6.9%3.7%7.5%10%7.4%BT, blood transfusion; Dx, diagnosis of hepatocellular carcinoma.a Heavy drinker: more than 80 g ethanol daily, 1982,6Kiyosawa K. Akahane Y. Nagata A. Koike Y. Furuta S. The significance of blood transfusion in non-A, non-B chronic liver disease in Japan.Vox Sang. 1982; 43: 45-52Crossref PubMed Scopus (66) Google Scholar 1990.7Kiyosawa K. Sodeyama T. Tanaka E. Gibo Y. Yoshizawa K. Nakano Y. Furuta S. Akahane Y. Nishioka K. Purcell R.H. Alter H.J. Interrelationship of blood transfusion, non-A, non- B hepatitis and hepatocellular carcinoma analysis by detection of antibody to hepatitis C virus.Hepatology. 1990; 12: 671-675Crossref PubMed Scopus (1199) Google Scholar Open table in a new tab BT, blood transfusion; Dx, diagnosis of hepatocellular carcinoma. There are 3 major categories of risk factors that appear to influence the incidence of HCC: host, viral, and environmental factors. Host factors include gender, age, ethnicity, stage of liver disease, diabetes mellitus, and hepatic steatosis. Viral factors include genotype, viral levels, DNA integration, rates of mutation, and coinfection with other agents. Environmental factors include toxins such as aflatoxin B1, medications and hormones, and nicotine or smoking. Men are 2 to 3 times more likely to develop HCC than women, although this proportion appears to be decreasing recently in patients with HCV-related HCC in Japan. The average age of diagnosis of HBV-related HCC in Japan is approximately 53 years, an average that has not changed in the last 20 years. In contrast, the average age of diagnosis of HCC has increased progressively in recent years among persons with HCV infection, as discussed previously. There are marked differences in rates of HCC in different ethnic and racial groups worldwide.13Bosch X. Ribes J. Borras J. Epidemiology of primary liver cancer.Semin Liver Dis. 1999; 19: 271-285Crossref PubMed Scopus (862) Google Scholar Persons of Asian and African decent have higher age-adjusted death rates than the white population, although this may relate largely to higher rates of underlying hepatitis B or C. Importantly, the incidence of HCC among white patients with HCV-related cirrhosis has been reported to be 1.2% in the United States, 3% to 4% in France, and 1.6% to 3% in Italy,14Colombo M. de Francis R. Del Ninno E. Sangiovanni A. De Fazio C. Tommasini M. Donato M.F. Piva A. Di Carlo V. Dioguardi N. Hepatocellular carcinoma in Italian patients with cirrhosis.N Engl J Med. 1991; 325: 675-680Crossref PubMed Scopus (808) Google Scholar whereas the reported incidence in Japanese patients with cirrhosis because of HCV is 6% to 7%.15Tsukuma H. Hiyama T. Tanaka S. Risk factors for hepatocellular carcinoma among patients with chronic liver disease.N Engl J Med. 1993; 328: 1797-1801Crossref PubMed Scopus (1082) Google Scholar Ethnic and racial variation in rates of HCC may be due to differences in distribution of HBV and HCV infections and particularly the age of onset and duration of infection. Nevertheless, the real reason for these discrepancies and the possible role of racial differences remains unclear. Advanced hepatic fibrosis is an important risk factor for developing HCC. Yoshida et al reported that male sex, older age, and advanced fibrosis were associated with a higher risk of HCC, both in the interferon-untreated patients and in the patients who showed nonsustained response to interferon therapy.16Yoshida H. Tateishi R. Sata M. Fujiyama S. Nishiguchi S. Ishibashi H. Yamada G. Yokosuka O. Shiratori Y. Omata M. Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C.Gut. 2004; 53: 425-430Crossref PubMed Scopus (145) Google Scholar Several of studies have shown that heavy alcohol intake increases the risk of cirrhosis and HCC in patients with hepatitis C in Japan. Whether this is due to a higher rate of cirrhosis in patients with HCV who drink alcohol or whether alcohol per se has a carcinogenic effect has not been adequately assessed.17Kubo S. Kinoshita H. Hirohashi K. Tanaka H. Tsukamoto T. Shunto T. Kuroki T. High malignancy of hepatocellular carcinoma in alcoholic patients with hepatitis C virus.Surgery. 1997; 121: 425-429Abstract Full Text PDF PubMed Scopus (44) Google Scholar, 18Aizawa Y. Shibamoto Y. Takagi I. Zeniya M. Toga G. Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C a long-term follow-up study after histologic diagnosis.Cancer. 2000; 89: 53-59Crossref PubMed Scopus (102) Google Scholar, 19Chiba T. Matsuzaki Y. Abei M. Shoda J. Aikawa T. Tanaka N. Osuga T. Multivariative analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis.J Gastroenterol. 1996; 31: 552-558Crossref PubMed Scopus (81) Google Scholar Type 2 diabetes and hepatic steatosis have been found to be increased in frequency in patients with hepatitis C and advanced liver disease in case series and epidemiologic studies. El-Serag et al analyzed a large cohort study of United States veterans admitted to Veterans Administration Hospitals from 1985 to 2000 and found that diabetes was an independent risk factor for chronic liver disease and HCC.20El-Serag H.B. Tran T. Everhart J.E. Diabetes increases the risk of chronic disease and hepatocellular carcinoma.Gastroenterology. 2004; 126: 460-468Abstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar There have been no reports on the relationship between diabetes, hepatitis C, and HCC from Japan. However, studies using HCV core gene transgenic mice have shown that hepatic steatosis related to presence of the transgene and direct evidence of insulin resistance have been found in human HCV infection.21Moriya K. Yotsuyanagi H. Shintani Y. Fujie H. Ishibashi K. Matsuura Y. Miyamura T. Koike K. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice.J Gen Virol. 1997; 78: 1527-1531Crossref PubMed Scopus (589) Google Scholar, 22Shintani Y. Fujie H. Miyoshi H. Tsutsumi T. Tsukamoto K. Kimura S. Moriya K. Koike K. Hepatitis C virus infection and diabetes direct involvement of the virus in the development of insulin resistance.Gastroenterology. 2004; 126: 840-848Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar Although hepatic steatosis has been recognized as a preconditioning status of HCC in HCV core transgenic mouse, the causal association between type 2 diabetes and HCC has not yet been clarified. Oncogenes are believed to play a role in development of HCC. Recently, a complementary DNA (cDNA) microarray approach was used to identify unique gene sets that are abnormally expressed in HCC23Shirota Y. Kaneko S. Honda M. Kawai H.F. Kobayashi K. Identification of differentially expressed genes in hepatocellular carcinoma with cDNA microarrays.Hepatology. 2001; 33: 832-840Crossref PubMed Scopus (175) Google Scholar and preneoplastic chronic liver diseases.24Kim J.W. Ye Q. Forgues M. Chen Y. Budhu A. Sime J. Hofseth L.J. Kaul R. Wang X.W. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis.Hepatology. 2004; 39: 518-527Crossref PubMed Scopus (130) Google Scholar However, no specific host genes or mutations were found to be associated for HCC. In southern Asia and Japan, the most common genotypes of HBV are B and C, which are found rarely in the United States and Western Europe outside of patients of Asian descent. In large surveys conducted by Orito et al, the proportion of cases of chronic hepatitis B because of genotype B was 12% and the proportion because of genotype C was 85%. These proportions are similar to those among patients with HBV-related HCC, 13% because of genotype B and 86% because of genotype C.25Orito E. Ichida T. Sakugawa H. Sata M. Horiike N. Hino K. Okita K. Okanoue T. Iino S. Tanaka E. Suzuki K. Watanabe H. Hige S. Mizokami M. G[e]ographic distribution of hepatitis B virus (HBV) genotypes in patients with chronic HBV infection in Japan.Hepatology. 2001; 34: 590-594Crossref PubMed Scopus (391) Google Scholar In the patients with genotype B, the mean age of diagnosis of HCC was 70 years, which was higher than that of genotype C patients, which was 55 years. These findings suggested that both genotypes of HBV were capable of leading to HCC but that the process was more rapid in patients with genotype C. In Taiwan, where genotype B is more common than genotype C (61% vs. 31%, respectively) in patients with HBV-related HCC, the mean age of those with genotype B was 50 years and younger than those with genotype C (59 years).26Kao J.H. Chen P.J. Lai M.Y. Chen D.S. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology. 2000; 118: 554-559Abstract Full Text Full Text PDF PubMed Scopus (878) Google Scholar These differences may be explained by a distinct distribution of subtypes of genotype B between the 2 countries. In Taiwan as well as in most Asian countries, only the subtype Ba is found, whereas the majority of Japanese patients have the subtype Bj.27Orito E. Mizokami M. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan.Intervirology. 2003; 46: 408-412Crossref PubMed Scopus (59) Google Scholar Mutations in either the precore or the core promoter regions of HBV account for the finding of HBeAg-negative chronic hepatitis B, a common form of chronic HBV infection in Asia and Japan. Orito et al found that precore mutations (at nucleotide [nt] 1896) were responsible for the majority of patients with genotype B who had HBeAg-negative chronic hepatitis B and HCC. In contrast, the frequency of the core promoter double mutation at nt 1762 and nt 1764, which may regulate the transcriptional activity of precore/core RNA and pregenomic RNA, was significantly more frequent in patients with HBV genotype C than B and was independent of HBeAg status. The double mutation in the core promoter was also found frequently in patients with HCC, thereby suggesting its association with hepatocarcinogenesis. Natural history studies suggest that patients infected with HBV genotype B are often negative for HBeAg and have lower average ALT levels and a better prognosis those patients with genotype C. Patients with genotype C tend to remain HBeAg positive for a longer time and are more likely to have elevated ALT levels and more advanced liver disease than patients with genotype B. These findings indicate that HBV genotype, along with associated clinical features of disease, may be an important factor in development of HBV-related HCC. HBV DNA is known to become integrated into host DNA during chronic infection. There does not appear to be a specific or prominent site in host DNA at which HBV DNA is integrated at a high rate, and the link of these integration sites to HCC is not well established.28Kew M.C. Hepatitis B virus in the etiology of hepatocellular carcinoma.in: Tabor E. Viruses and liver cancer. Elsevier Science, Amsterdam2000: 17-30Google Scholar Nevertheless, many HBVrelated HCCs have clonal HBV DNA integrations, some of which have been associated with mutations in important growth factors and oncogenes. Occult HBV infection is char
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