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doi:10.1111/jgh.13030
H E PAT O L O G Y
Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan Kiyoaki Ito,*,‡‡‡,1 Hiroshi Yotsuyanagi,†,1 Masaya Sugiyama,* Hiroshi Yatsuhashi,‡ Yoshiyasu Karino,§ Yasuhiro Takikawa,¶ Takafumi Saito,** Yasuji Arase,†† Fumio Imazeki,‡‡ Masayuki Kurosaki,§§ Takeji Umemura,¶¶ Takafumi Ichida,*** Hidenori Toyoda,††† Masashi Yoneda,‡‡‡ Yasuhito Tanaka,§§§ Eiji Mita,¶¶¶ Kazuhide Yamamoto,**** Kojiro Michitaka,†††† Tatsuji Maeshiro,‡‡‡‡ Junko Tanuma,§§§§ Masaaki Korenaga,* Kazumoto Murata,* Naohiko Masaki,* Kazuhiko Koike,† Masashi Mizokami,*,1 and The Japanese AHB CHB Study Group2 *The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, †Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, ††Department of Hepatology, Toranomon Hospital, §§Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, §§§§AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, ‡Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, §Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, ¶Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, **Department of Gastroenterology, Yamagata University School, Yamagata, ‡‡Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, ¶¶Department of Medicine, Shinshu University School of Medicine, Matsumoto, ***Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, †††Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, ‡‡‡Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, §§§Nagoya City University Graduate School of Medical Sciences, Nagoya, ¶¶¶National Hospital Organization Osaka National Hospital, Osaka, ****Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Okayama, ††††Department of Gastroenterology, Ehime University Graduate School of Medicine, Toon, and ‡‡‡‡ First Department of Internal Medicine, University Hospital, Faculty of Medicine, University of the Ryukyu, Okinawa, Japan
Key words acute hepatitis B, chronic hepatitis B, distribution, genotype, human immunodeficiency virus. Accepted for publication 2 June 2015. Correspondence Masashi Mizokami, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Konodai, Ichikawa 272–8516, Japan. Email: [email protected] 1
These authors contributed equally to this work. Japanese AHB and CHB Study Group including Yasuharu Imai (Ikeda Municipal Hospital), Norie Yamada, Hideaki Takahashi (St Marianna University School of Medicine), Koji Ishii (Toho University School of Medicine), Hideyuki Nomura (Shin-Kokura Hospital), Jiro Nishida (Tokyo Dental Collage Ichikawa General Hospital), Shigeru Mikami (Kikkoman Hospital), Tsuneo Kitamura (Juntendo University Urayasu Hospital), Akihito Tsubota (Kashiwa Hospital Jikei University School of Medicine), Noritomo Shimada (Shinmatsudo Central General Hospital), Tetsuya Ishikawa (Nagoya University Graduate School of Medicine), Yoshiyuki Ueno (Tohoku University Graduate School of Medicine), Tomoyoshi Ohno (Social Insurance Chukyo Hospital), Etsuro Orito (Nagoya Daini Red Cross Hospital), Michihiro Suzuki 2
180
Abstract Background and Aims: The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. Methods: Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. Results: Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. Conclusions: The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients.
Journal of Gastroenterology and Hepatology 31 (2016) 180–189 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
K Ito et al.
Genotype A HBV in Japanese AHB and CHB
(Kawasaki Municipal Tama Hospital), Hitoshi Takagi (Gunma University Graduate School of Medicine), Eiichi Tomita (Gifu Municipal Hospital), Kumada Takashi (Ogaki Municipal Hospital), Toshihiko Mizuta (Saga University Faculty of Medicine), Tetsuya Mine (Tokai University School of Medicine), Jong-Hon Kang (Teine-Keijinkai Hospital), Katsuji Hirano (Juntendo University Shizuoka Hospital), Hirohito Tsubouchi (Kagoshima University Graduate School of Medical and Dental Sciences), Akito Nozaki (Yokohama City University Medical Center), Akito Sakai (Kanazawa University Graduate School of Medical Science), Shuhei Nishiguchi (Hyogo College of Medicine), Akihiro Tamori (Osaka City University Graduate School of Medicine), Satoru Hagiwara (Kinki University School of Medicine), Takahide Nakazawa (University of Kitasato East Hospital), Michio Sata (Kurume University School of Medicine), Toshiro Kamoshida (Hitachi General Hospital) Atsushi Takahashi (Fukushima Medical University School of Medicine), Satoshi Kakizaki (Gunma University Graduate School of Medicine), Yoshimasa Kobayashi (Hamamatsu University School of Medicine), Shigeru Sasaki (Sapporo Medical University), Tadashi Ikegami (Tokyo Medical University Ibaraki Medical Center), Yoichi Hiasa (Ehime University Graduate School of Medicine), Kenji Nagata (University of Miyazaki), Tomoyuki Kubota (Saiseikai Niigata Daini Hospital), Hiroshi Mitsui (Tokyo Teishin Hospital), Norihiko Yamamoto (Mie University School of Medicine), Masataka Tsuge (Hiroshima University), Shuichi Sato (Shimane University Hospital), Yoshito Ito (Kyoto Prefectural University of Medicine), Wataru Sato (Akita University School of Medicine), Shigeharu Uchida (Japanese Red Cross Society), Yuki Tada (National Institute of Infectious Diseases), Toshiaki Mizuochi (National Institute of Infectious Diseases), Norihiro Furusho (Kyushu University), and Shuhei Hige (Hokkaido University Graduate School of Medicine), Masaaki Korenaga, Kazumoto Murata and Naohiko Masaki (National Center for Global Health and Medicine), University of Tokyo, NHO Nagasaki Medical Center, Yoshiyasu Karino (Sapporo Kosei General Hospital), Yasuhiro Takikawa (Iwate Medical University), Takafumi Saito (Yamagata University School), Yasuji Arase (Toranomon Hospital), Fumio Imazeki (Chiba University), Masayuki Kurosaki (Musashino Red Cross Hospital), Takeji Umemura (Shinshu University School of Medicine), Hidenori Toyoda (Ogaki Municipal Hospital), Masashi Yoneda (Aichi Medical University School of Medicine), Eiji Mita (National Hospital Organization Osaka National Hospital), Kazuhide Yamamoto (Okayama University Graduate School of Medicine), Takafumi Ichida (Juntendo University Shizuoka Hospital), University of the Ryukyu, Yasuhito Tanaka (Nagoya City University Graduate School of Medical Sciences), Kojiro Michitaka (Ehime Prefectural Central Hospital), Saga University Hospital, Minoru Kobayashi, Norie Yamada (Kiyokawa Hospital), Keiko Hosho (Tottori University School of Medicine), Tetsuya Mine (Tokai University School of Medicine), Satoshi Yamagiwa (Niigata University School of Medicine), Isao Sakaida (Yamaguchi University School of Medicine), and Kunio Nakane (Akita City Hospital). Conflict of interest: The authors have no conflicts of interest to disclose.
Introduction Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections among humans. Approximately two billion people worldwide have been exposed to HBV, and 350 million of them remain chronically infected.1 The incidence of HBV infection and patterns of transmission vary greatly among different population subgroups throughout the world.2 In Western countries, chronic HBV infection is relatively rare and is acquired primarily in adulthood via sexual transmission or the use of injectable drugs, whereas in Asia and most of Africa, the infection is transmitted from an infected mother to her newborn. In Japan, approximately 1.1–1.4 million people are infected with HBV. Hepatitis B virus genomic sequences vary worldwide and have been classified into at least nine genotypes (A through J) on the basis of an intergroup divergence of ≥8% over the complete nucleotide sequence.3,4 HBV genotypes differ in their clinical manifestations5 and responses to therapy (e.g. interferon therapy). HBV genotypes also have distinct geographic distributions6–8 and, in particular, genotype A is predominant in Northwestern Europe, the USA, Central Africa, and India.9,10 The Japanese have been infected with genotypes B and C since prehistoric times.6 However, many lines of recent evidence have revealed an increase in the prevalence of acute infection with HBV genotype A after sexual transmission among Japanese individuals.11,12 Moreover, we previously reported that acute infection with HBV genotype A is associated with an increased risk of progression to persistent infection.13 Therefore, we hypothesized that the distribution of genotype A chronic hepatitis B (CHB) has also increased.
In this study, we conducted a national survey of acute and chronic HBV infections to determine the geographic distribution, clinical, and virologic characteristics of genotype A HBV infection in acute hepatitis B (AHB) and CHB patients in Japan.
Patients and methods Patients with acute hepatitis B. Between 2005 through 2010, AHB patients were recruited from 48 liver centers throughout Japan. The diagnosis of AHB was based on the rapid onset of clinical symptoms accompanied by elevated serum alanine aminotransferase (ALT) levels in addition to the detection of serum hepatitis B surface antigen (HBsAg) and a high-titer antibody to hepatitis B core antigen of the immunoglobulin M class. Patients with initial high-titer antibody to hepatitis B core antigen of the immunoglobulin G class (>10.0 S/CO) were diagnosed with an exacerbation of CHB and were excluded. Patients with acute hepatitis A, hepatitis C, or drug-induced or alcohol-induced acute hepatitis were also excluded; hepatitis D virus infection was not determined because of its extreme rarity in Japan. The study protocol conformed to the 1975 Declaration of Helsinki and was approved by the Ethics Committees of the institutions involved. Every patient provided informed consent for participation in this study. Patients with chronic hepatitis B. We recruited 3682 patients with CHB treated at 36 liver centers spread across Japan between 2010 and 2011. In all cases, the diagnosis had been established after a follow up of at least 12 months. The patients were classified into one of the following four clinical categories:
Journal of Gastroenterology and Hepatology 31 (2016) 180–189 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
181
K Ito et al.
Genotype A HBV in Japanese AHB and CHB
asymptomatic carrier state, defined by the presence of HBsAg with normal ALT levels for 1 year (examined at least four times at 3-month intervals) and without evidence of portal hypertension; chronic hepatitis, defined by elevated serum ALT levels (>1.5 times the upper limit of the normal range [35 IU/L]) persisting for 6 months; cirrhosis, diagnosed principally by ultrasonography (coarse liver architecture, nodular liver surface, blunt liver edges, and hypersplenism); platelet counts
doi:10.1111/jgh.13030
H E PAT O L O G Y
Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan Kiyoaki Ito,*,‡‡‡,1 Hiroshi Yotsuyanagi,†,1 Masaya Sugiyama,* Hiroshi Yatsuhashi,‡ Yoshiyasu Karino,§ Yasuhiro Takikawa,¶ Takafumi Saito,** Yasuji Arase,†† Fumio Imazeki,‡‡ Masayuki Kurosaki,§§ Takeji Umemura,¶¶ Takafumi Ichida,*** Hidenori Toyoda,††† Masashi Yoneda,‡‡‡ Yasuhito Tanaka,§§§ Eiji Mita,¶¶¶ Kazuhide Yamamoto,**** Kojiro Michitaka,†††† Tatsuji Maeshiro,‡‡‡‡ Junko Tanuma,§§§§ Masaaki Korenaga,* Kazumoto Murata,* Naohiko Masaki,* Kazuhiko Koike,† Masashi Mizokami,*,1 and The Japanese AHB CHB Study Group2 *The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, †Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, ††Department of Hepatology, Toranomon Hospital, §§Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, §§§§AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, ‡Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, §Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, ¶Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, **Department of Gastroenterology, Yamagata University School, Yamagata, ‡‡Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, ¶¶Department of Medicine, Shinshu University School of Medicine, Matsumoto, ***Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, †††Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, ‡‡‡Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, §§§Nagoya City University Graduate School of Medical Sciences, Nagoya, ¶¶¶National Hospital Organization Osaka National Hospital, Osaka, ****Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Okayama, ††††Department of Gastroenterology, Ehime University Graduate School of Medicine, Toon, and ‡‡‡‡ First Department of Internal Medicine, University Hospital, Faculty of Medicine, University of the Ryukyu, Okinawa, Japan
Key words acute hepatitis B, chronic hepatitis B, distribution, genotype, human immunodeficiency virus. Accepted for publication 2 June 2015. Correspondence Masashi Mizokami, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Konodai, Ichikawa 272–8516, Japan. Email: [email protected] 1
These authors contributed equally to this work. Japanese AHB and CHB Study Group including Yasuharu Imai (Ikeda Municipal Hospital), Norie Yamada, Hideaki Takahashi (St Marianna University School of Medicine), Koji Ishii (Toho University School of Medicine), Hideyuki Nomura (Shin-Kokura Hospital), Jiro Nishida (Tokyo Dental Collage Ichikawa General Hospital), Shigeru Mikami (Kikkoman Hospital), Tsuneo Kitamura (Juntendo University Urayasu Hospital), Akihito Tsubota (Kashiwa Hospital Jikei University School of Medicine), Noritomo Shimada (Shinmatsudo Central General Hospital), Tetsuya Ishikawa (Nagoya University Graduate School of Medicine), Yoshiyuki Ueno (Tohoku University Graduate School of Medicine), Tomoyoshi Ohno (Social Insurance Chukyo Hospital), Etsuro Orito (Nagoya Daini Red Cross Hospital), Michihiro Suzuki 2
180
Abstract Background and Aims: The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. Methods: Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. Results: Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. Conclusions: The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients.
Journal of Gastroenterology and Hepatology 31 (2016) 180–189 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
K Ito et al.
Genotype A HBV in Japanese AHB and CHB
(Kawasaki Municipal Tama Hospital), Hitoshi Takagi (Gunma University Graduate School of Medicine), Eiichi Tomita (Gifu Municipal Hospital), Kumada Takashi (Ogaki Municipal Hospital), Toshihiko Mizuta (Saga University Faculty of Medicine), Tetsuya Mine (Tokai University School of Medicine), Jong-Hon Kang (Teine-Keijinkai Hospital), Katsuji Hirano (Juntendo University Shizuoka Hospital), Hirohito Tsubouchi (Kagoshima University Graduate School of Medical and Dental Sciences), Akito Nozaki (Yokohama City University Medical Center), Akito Sakai (Kanazawa University Graduate School of Medical Science), Shuhei Nishiguchi (Hyogo College of Medicine), Akihiro Tamori (Osaka City University Graduate School of Medicine), Satoru Hagiwara (Kinki University School of Medicine), Takahide Nakazawa (University of Kitasato East Hospital), Michio Sata (Kurume University School of Medicine), Toshiro Kamoshida (Hitachi General Hospital) Atsushi Takahashi (Fukushima Medical University School of Medicine), Satoshi Kakizaki (Gunma University Graduate School of Medicine), Yoshimasa Kobayashi (Hamamatsu University School of Medicine), Shigeru Sasaki (Sapporo Medical University), Tadashi Ikegami (Tokyo Medical University Ibaraki Medical Center), Yoichi Hiasa (Ehime University Graduate School of Medicine), Kenji Nagata (University of Miyazaki), Tomoyuki Kubota (Saiseikai Niigata Daini Hospital), Hiroshi Mitsui (Tokyo Teishin Hospital), Norihiko Yamamoto (Mie University School of Medicine), Masataka Tsuge (Hiroshima University), Shuichi Sato (Shimane University Hospital), Yoshito Ito (Kyoto Prefectural University of Medicine), Wataru Sato (Akita University School of Medicine), Shigeharu Uchida (Japanese Red Cross Society), Yuki Tada (National Institute of Infectious Diseases), Toshiaki Mizuochi (National Institute of Infectious Diseases), Norihiro Furusho (Kyushu University), and Shuhei Hige (Hokkaido University Graduate School of Medicine), Masaaki Korenaga, Kazumoto Murata and Naohiko Masaki (National Center for Global Health and Medicine), University of Tokyo, NHO Nagasaki Medical Center, Yoshiyasu Karino (Sapporo Kosei General Hospital), Yasuhiro Takikawa (Iwate Medical University), Takafumi Saito (Yamagata University School), Yasuji Arase (Toranomon Hospital), Fumio Imazeki (Chiba University), Masayuki Kurosaki (Musashino Red Cross Hospital), Takeji Umemura (Shinshu University School of Medicine), Hidenori Toyoda (Ogaki Municipal Hospital), Masashi Yoneda (Aichi Medical University School of Medicine), Eiji Mita (National Hospital Organization Osaka National Hospital), Kazuhide Yamamoto (Okayama University Graduate School of Medicine), Takafumi Ichida (Juntendo University Shizuoka Hospital), University of the Ryukyu, Yasuhito Tanaka (Nagoya City University Graduate School of Medical Sciences), Kojiro Michitaka (Ehime Prefectural Central Hospital), Saga University Hospital, Minoru Kobayashi, Norie Yamada (Kiyokawa Hospital), Keiko Hosho (Tottori University School of Medicine), Tetsuya Mine (Tokai University School of Medicine), Satoshi Yamagiwa (Niigata University School of Medicine), Isao Sakaida (Yamaguchi University School of Medicine), and Kunio Nakane (Akita City Hospital). Conflict of interest: The authors have no conflicts of interest to disclose.
Introduction Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections among humans. Approximately two billion people worldwide have been exposed to HBV, and 350 million of them remain chronically infected.1 The incidence of HBV infection and patterns of transmission vary greatly among different population subgroups throughout the world.2 In Western countries, chronic HBV infection is relatively rare and is acquired primarily in adulthood via sexual transmission or the use of injectable drugs, whereas in Asia and most of Africa, the infection is transmitted from an infected mother to her newborn. In Japan, approximately 1.1–1.4 million people are infected with HBV. Hepatitis B virus genomic sequences vary worldwide and have been classified into at least nine genotypes (A through J) on the basis of an intergroup divergence of ≥8% over the complete nucleotide sequence.3,4 HBV genotypes differ in their clinical manifestations5 and responses to therapy (e.g. interferon therapy). HBV genotypes also have distinct geographic distributions6–8 and, in particular, genotype A is predominant in Northwestern Europe, the USA, Central Africa, and India.9,10 The Japanese have been infected with genotypes B and C since prehistoric times.6 However, many lines of recent evidence have revealed an increase in the prevalence of acute infection with HBV genotype A after sexual transmission among Japanese individuals.11,12 Moreover, we previously reported that acute infection with HBV genotype A is associated with an increased risk of progression to persistent infection.13 Therefore, we hypothesized that the distribution of genotype A chronic hepatitis B (CHB) has also increased.
In this study, we conducted a national survey of acute and chronic HBV infections to determine the geographic distribution, clinical, and virologic characteristics of genotype A HBV infection in acute hepatitis B (AHB) and CHB patients in Japan.
Patients and methods Patients with acute hepatitis B. Between 2005 through 2010, AHB patients were recruited from 48 liver centers throughout Japan. The diagnosis of AHB was based on the rapid onset of clinical symptoms accompanied by elevated serum alanine aminotransferase (ALT) levels in addition to the detection of serum hepatitis B surface antigen (HBsAg) and a high-titer antibody to hepatitis B core antigen of the immunoglobulin M class. Patients with initial high-titer antibody to hepatitis B core antigen of the immunoglobulin G class (>10.0 S/CO) were diagnosed with an exacerbation of CHB and were excluded. Patients with acute hepatitis A, hepatitis C, or drug-induced or alcohol-induced acute hepatitis were also excluded; hepatitis D virus infection was not determined because of its extreme rarity in Japan. The study protocol conformed to the 1975 Declaration of Helsinki and was approved by the Ethics Committees of the institutions involved. Every patient provided informed consent for participation in this study. Patients with chronic hepatitis B. We recruited 3682 patients with CHB treated at 36 liver centers spread across Japan between 2010 and 2011. In all cases, the diagnosis had been established after a follow up of at least 12 months. The patients were classified into one of the following four clinical categories:
Journal of Gastroenterology and Hepatology 31 (2016) 180–189 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
181
K Ito et al.
Genotype A HBV in Japanese AHB and CHB
asymptomatic carrier state, defined by the presence of HBsAg with normal ALT levels for 1 year (examined at least four times at 3-month intervals) and without evidence of portal hypertension; chronic hepatitis, defined by elevated serum ALT levels (>1.5 times the upper limit of the normal range [35 IU/L]) persisting for 6 months; cirrhosis, diagnosed principally by ultrasonography (coarse liver architecture, nodular liver surface, blunt liver edges, and hypersplenism); platelet counts
