Takeji Umemura

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. 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. K. The Liver Cancer Study of and treatment for hepatocellular carcinoma a and nationwide survey in PubMed Scopus Google Scholar, K. M. Kojiro M. Kobayashi K. Nakanuma Y. S. Makuuchi M. Yamaoka Y. of the survey of primary liver PubMed Scopus Google Scholar A total of patients have been in this between and the 95% were as HCC and indicating that the of primary liver cancer in Japan is between and 1999 have that most patients with HCC are for hepatitis B to hepatitis C virus for in 1975 and for in of HCC of in of in In of HCC have accounted for more that of in the last years. In HCC accounted for of in of in 1990, and of in K. Y. A. Y. S. The of blood transfusion in chronic liver disease in PubMed Scopus Google Scholar, K. T. Y. K. Y. S. Y. K. Alter H.J. of blood B hepatitis and hepatocellular carcinoma analysis by detection of to hepatitis C PubMed Scopus Google Scholar Although was in HCC of in in 1990, and in Thus, HCV-related HCC has an increasing of Thus, the increased rates of death because of primary liver cancer in Japan to the increase in numbers of HCV-related Although Japan is a relatively with a the incidence of HCC different The of Japan for 2001 in by the Japanese of and on the incidence of deaths as a of HCC in a increase of death rates for HCC the of Japan from to of Japan and of and and Scholar The average age-adjusted death rate of HCC the was 27.3 per 100,000 with death rates than 30 per 100,000 people were on the the and the western of Nationwide health screening for and in the over years of age population has been since and prevalence rates for have been by prefecture in Japan. The average prevalence was in the total Japanese population. Although prevalence rates of are in a as and rates of are most of Japan. In is in the prevalence of in different rates are in and on the western of There were between death rates from in each prefecture and prevalence of correlation correlation with the prevalence of correlation For although and have prevalence rates of and death rates from HCC in and were and per 100,000 people, both of which are below the average In with rates of as and death rates for primary liver and per 100,000 people, were higher than the Thus, although rates of HBV infection in the population correlates with rates of HCC in most countries of the in Japan, this is the and HCV to be the major to rates of primary liver between age-adjusted annual death rates from primary liver cancer and prevalence of and the general population over years of age in Figure of of HCC conducted at are shown in K. Y. A. Y. S. The of blood transfusion in chronic liver disease in PubMed Scopus Google Scholar, K. T. Y. K. Y. S. Y. K. Alter H.J. of blood B hepatitis and hepatocellular carcinoma analysis by detection of to hepatitis C PubMed Scopus Google Scholar accounted for the of of both and HCV-related HCC for all age The of of HCC in men was in in 1990, in indicating a recent increase in women in recent years. The average age of of HCC was in all 3 In the average age of patients with HCV-related HCC rose from years in to years in and years in The of a history of blood transfusion was in in 1990, and in and patients with For the between of blood transfusion and of HCC were and years, from onset of infection to of HCC has also been by in reported the average between blood transfusion and of chronic hepatitis as years, of as years, and HCC as after hepatitis PubMed Scopus Google Scholar The for the increasing between transfusion and of HCC in recent years is a is the recent of therapy of hepatitis which to is a in of HCV infection The correlation of age at the of blood transfusion and from transfusion to of HCC is shown in Figure These results an between age of to HCV and of liver cancer results that to and HCC is more with age of onset of hepatitis have been reported by the between the age of blood transfusion and age of of HCC in Japanese K. T. K. K. S. H. H. S. T. M. Mizokami M. T. T. T. M. H. K. S. Study of of hepatitis C virus in Japanese patients with C chronic liver a Scholar The average was years, and it with increasing at the of years for patients the age of 30 years, years for between the of 30 and years, and years for the age of years. reported a correlation between the from HCV infection to the development of HCC and the age at of infection indicating that the age of than the duration of HCV was more for development of HCC in patients with hepatitis H. H. K. M. K. Inoue M. K. K. M. of on the development of hepatocellular carcinoma in patients with chronic hepatitis 2002; PubMed Scopus Google Scholar In a a the of by age of onset of HCV T. Rates and risk of liver in patients with chronic hepatitis PubMed Scopus Google Scholar Among patients the age of 20 years, were during the first years of infection. Among patients aged 20 to 30 years and 30 to years, was an increase in of after 30 years of infection. In patients between and 50 years, was a increase in of after years of infection. patients after 50 years of were rates of for all of These that age has a major on rate of of hepatitis development of and of of and Hepatocellular in 1990, and in of between and more than blood of hepatocellular more than K. Y. A. Y. S. The of blood transfusion in chronic liver disease in PubMed Scopus Google Scholar K. T. Y. K. Y. S. Y. K. Alter H.J. of blood B hepatitis and hepatocellular carcinoma analysis by detection of to hepatitis C PubMed Scopus Google Scholar in a blood of hepatocellular There are 3 major of risk that to the incidence of and of liver diabetes and rates of and with other as and and are 2 to 3 more to HCC than women, although this to be in patients with HCV-related HCC in Japan. The average age of of HCC in Japan is years, an average that has in the last 20 years. In the average age of of HCC has increased in recent years with HCV as There are in rates of HCC in different and groups of primary liver Liver PubMed Scopus Google Scholar of and have higher age-adjusted death rates than the although this largely to higher rates of hepatitis B the incidence of HCC patients with HCV-related has been reported to be in the United to 4% in and to in M. A. M. A. Hepatocellular carcinoma in patients with PubMed Scopus Google Scholar whereas the reported incidence in Japanese patients with because of HCV is to H. T. S. for hepatocellular carcinoma patients with chronic liver PubMed Scopus Google Scholar and in rates of HCC be due to in of HBV and HCV infections and particularly the age of onset and duration of infection. the for and the of is an important risk for reported that and were associated with a higher risk of HCC, both in the patients and in the patients showed to H. M. S. S. H. Y. M. of therapy in hepatocellular carcinoma for patients with chronic hepatitis PubMed Scopus Google Scholar of have shown that the risk of and HCC in patients with hepatitis C in Japan. this is due to a higher rate of in patients with HCV per has a has been S. H. K. H. T. T. T. of hepatocellular carcinoma in patients with hepatitis C PubMed Scopus Google Scholar, Y. Y. M. of the of hepatocellular carcinoma in patients with chronic hepatitis C a after PubMed Scopus Google Scholar, T. Y. M. T. T. analysis of risk for hepatocellular carcinoma in patients with hepatitis C liver PubMed Scopus Google Scholar 2 diabetes and have been to be increased in in patients with hepatitis C and liver disease in and studies. a of United States to from to 2000 and that diabetes was an risk for chronic liver disease and T. the risk of chronic disease and hepatocellular PubMed Scopus Google Scholar There have been on the between hepatitis and HCC from Japan. HCV have shown that to of the and of have been in HCV K. H. Y. H. K. Y. T. K. C virus in PubMed Scopus Google Scholar, Y. H. H. T. K. S. K. K. C virus infection and diabetes of the virus in the development of PubMed Scopus Google Scholar Although has been as a of HCC in HCV the between 2 diabetes and HCC has been are to a in development of a was to that are in Y. S. M. Kobayashi K. of in hepatocellular carcinoma with PubMed Scopus Google Scholar and chronic liver M. Y. A. molecular in the of patients with PubMed Scopus Google Scholar were to be associated for In and Japan, the most of HBV are B and which are in the United States and of patients of In conducted by the of of chronic hepatitis B because of genotype B was and the because of genotype C was These are to patients with HCC, because of genotype B and because of genotype T. H. M. K. K. T. S. K. H. S. Mizokami M. of hepatitis B virus (HBV) in patients with chronic HBV infection in PubMed Scopus Google Scholar In the patients with genotype the age of of HCC was 70 years, which was higher than that of genotype C which was years. These that both of HBV were of leading to HCC that the was more in patients with genotype In genotype B is more than genotype C in patients with HCC, the age of with genotype B was 50 years and than with genotype C B with in patients with chronic hepatitis PubMed Scopus Google Scholar These be by a of of genotype B between the 2 In as as in most the is whereas the of Japanese patients have the Mizokami M. 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Scholar have HBV of which have been associated with in important and HBV infection is by of HBV in of patients are M. hepatitis 2002; PubMed Scopus Google Scholar HBV infection has been reported in HCV-related and HCC by several groups of Japanese T. Y. K. H. H. T. S. C virus is with hepatitis B virus of the by the as by in PubMed Scopus Google Scholar, K. Kobayashi M. M. T. S. B virus is in liver from hepatitis C chronic hepatitis PubMed Scopus Google Scholar, Y. H. K. H. T. T. Makuuchi M. S. K. The of hepatitis B virus in hepatocellular carcinoma of patients with hepatitis PubMed Scopus Google Scholar T. A. A. B virus in the of HBV PubMed Scopus Google Scholar from patients and the liver from of patients with HCC for HBV and results with from patients with chronic hepatitis HBV was in of of HCC and in of of chronic hepatitis 95% The of HBV with HCC was of and of HCV infection. and HBV were in patients with Thus, that HBV is a risk for development of Although HCV is at different HCV 1 and 2 for most of infection in Japan. K. T. K. K. S. H. H. S. T. M. Mizokami M. T. T. T. M. H. K. S. Study of of hepatitis C virus in Japanese patients with C chronic liver a Scholar conducted of the HCV genotype in Japanese patients with chronic liver disease from in Japan in patients with chronic HCV infection from the of Japan, chronic and The prevalence of HCV 1 and 2 was on the HCV genotype 1 in each disease from to HCV genotype 1 was relatively more in patients with more disease and HCC whereas genotype 2 was less with HCV genotype 1 2 with to and history of blood A of genotype 1 with more disease was reported from at M. T. A. A. K. The natural of chronic hepatitis C a comparison between patients with 1 and 2 hepatitis C PubMed Google Scholar the of HCV genotype 1 and disease has been in and is still a of There is that are associated with development of There was that the HCV is infection with HBV has been associated with HCC, and Japanese patients with HCV-related HCC have a relatively prevalence of to hepatitis B indicating HBV infection. of of HCV and HBV in HCC has been other than the that the 2 infections are more to to than research is with virus in HCV-related HCC in Japan is and is that is a cause of this cancer in Japan. as increase liver cancer risk and have been to a on of the risk of hepatocellular carcinoma in hepatitis B carriers with chronic hepatitis have PubMed Scopus Google Scholar is in Japan, and is of other to the increasing rates of HCC in Japan. The of the survey of primary liver cancer conducted by the Liver Study Group of Japan on the rates of patients therapy and therapy K. M. Kojiro M. Kobayashi K. Nakanuma Y. S. Makuuchi M. Yamaoka Y. of the survey of primary liver PubMed Scopus Google Scholar patients were between and 1999, were after The rates of the are shown in Figure for HCC were of and The rates at and years were and These were higher than of other rates have been to with numbers of of and early therapy during this in Japan. liver for HCC with has been by since Thus, for HCC have been In 1999, the Japan of the Cancer at a to liver cancer. The and better on to hepatitis virus screening for and of the general population as as in a history of blood major and to carriers of HCV and and of therapy with and for hepatitis C and therapy for hepatitis chronic hepatitis at of disease to and and of a between and to and HCC K. for liver 2002; Google Scholar The nationwide by the Japan of to HCC was in of the in a in the last of each in each prefecture Japan. 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M. Y. K. Interferon therapy the rate of to hepatocellular carcinoma in chronic hepatitis C in a in PubMed Scopus Google Scholar The reduction of of HCC was more shown in patients with as with and The of from that treatment the risk of HCC in patients with hepatitis H. M. S. S. H. Y. M. of therapy in hepatocellular carcinoma for patients with chronic hepatitis PubMed Scopus Google of the in on the of HCC Among and Interferon in M. for hepatitis C virus infection a of the for the PubMed Scopus Google S. T. S. H. T. S. S. S. Kobayashi K. S. of of on incidence of hepatocellular carcinoma in chronic hepatitis C with PubMed Scopus Google A. K. M. K. S. A. A. K. M. K. K. for hepatocellular carcinoma and incidence after treatment in patients with chronic hepatitis PubMed Scopus Google Y. S. S. S. M. Y. Y. T. H. Y. M. K. Y. of therapy and hepatocellular carcinoma in patients with chronic hepatitis PubMed Scopus Google K. S. K. K. Y. Kobayashi M. A. H. M. of therapy on hepatocellular carcinogenesis in patients with chronic hepatitis C a of patients with PubMed Scopus Google H. Y. M. Y. T. M. Inoue M. M. S. S. T. S. M. Interferon therapy the risk for hepatocellular carcinoma of and patients with chronic hepatitis C in PubMed Scopus Google hepatocellular in a HCC, hepatocellular The of the of of HCC in Japan is HBV and HCV infection. 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Autoimmune pancreatitis (AIP) is characterized by high serum immunoglobin (Ig) G4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Since liver dysfunction is frequently seen in AIP patients, we investigated hepatic histopathology and its clinical significance in patients with AIP. We examined the clinical features, histology, and immunoglobin G (IgG)4-bearing plasma cell infiltration of liver biopsies from 17 patients with AIP and 63 patients with either autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or chronic viral hepatitis and histological changes in the 7 of 17 livers before and after glucocorticoid therapy. The liver histology of AIP was classified into 5 patterns: evident portal inflammation with or without interface hepatitis (6 cases), large bile-duct obstructive features (8 cases), portal sclerosis (8 cases), lobular hepatitis (5 cases), and canalicular cholestasis (4 cases); some of the histological features coexisted in the same liver. The number of IgG4-bearing plasma cells was significantly higher in AIP patients than controls (P < 0.01), and was significantly correlated with serum IgG4 concentration (P = 0.0014, r = 0.709). Glucocorticoid therapy reduced IgG4-bearing plasma cell infiltration in the liver (P = 0.031) and ameliorated other histological findings. In conclusion, virtually all AIP liver biopsies showed evidence of various pathological changes and infiltration of IgG4-bearing plasma cells. These features were ameliorated by steroid therapy, suggesting that the liver is concurrently affected in AIP, and that liver biopsies can provide significant information in the clinical evaluation and diagnosis of AIP.

Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.