Background/Aims The histologic status of the immune-tolerant (IT) phase of chronic hepatitis B relative to long-term outcomes is unclear. This study aimed to discover how the serological criteria currently in use correspond to histologic criteria in determining the IT phase and indication for liver biopsy.
Methods Patients in the serological IT phase determined by positive hepatitis B e antigen, hepatitis B virus (HBV) DNA ≥106 IU/mL, and normal or minimally elevated alanine aminotransferase (ALT) ≤60 IU/L, who underwent liver biopsy at three different hospitals were included. The distribution of the histologic IT phase, defined as fibrosis of stage 1 or less and inflammation of grade 1 or less, was compared with that of the serological IT phase. The risk factors for the incidence of liver-related events, such as hepatocellular carcinoma, liver cirrhosis, liver transplantation, and death, were also analyzed.
Result s: Eighty-two (31.7%) out of 259 clinically suspected IT phase patients belonged to the histologic IT phase. Age over 35, high AST, and low albumin were useful for ruling out the histologic IT phase. Risk factors predicting liver-related events were age and significant fibrosis stage. There was no significant difference in the proportion of histologic IT phase and clinical prognosis between normal ALT and mildly elevated ALT groups. However, even in patients with normal ALT, age was an important factor in predicting the presence of the histologic IT phase.
Conclusions A significant number of patients who belonged to the serological IT phase were not in the histologic IT phase. Patients over 35 years and those with high AST, low albumin, and low HBV DNA levels were more likely to experience poor long-term clinical outcomes. Therefore, additional histologic assessment should be considered.
Citations
Citations to this article as recorded by
Higher level of HBsAg associated with delayed development of HCC in immune-tolerant patients Tai-Chung Tseng, Tetsuya Hosaka, Mei-Hung Pan, Chun-Jen Liu, Fumitaka Suzuki, Chien-Jen Chen, Tung-Hung Su, Hiromitsu Kumada, Wan-Ting Yang, Hung-Chih Yang, Chen-Hua Liu, Pei-Jer Chen, Hwai-I. Yang, Jia-Horng Kao Hepatology.2026; 83(1): 142. CrossRef
Risk of Hepatocellular Carcinoma Decreases After Antiviral Therapy–Induced HBsAg Seroclearance Han Ah. Lee, Hyun Woong Lee, Yeon Seok Seo, Dong Hyun Sinn, Sang Hoon Ahn, Beom Kyung Kim, Seung Up Kim Journal of Gastroenterology and Hepatology.2025; 40(7): 1675. CrossRef
Unraveling Demographic Patterns in Hepatitis B Clinical and Laboratory Profiles: Insights From a Ghanaian Cohort: A Retrospective Study Napoleon Bellua Sam, Saeed Folorunsho Majeed, Adams Dramani Health Science Reports.2025;[Epub] CrossRef
Cost‐Effectiveness of Antiviral Therapy in Patients With High Viremic Indeterminate Phase Chronic Hepatitis B Suk‐Chan Jang, Won‐Mook Choi, Gi‐Ae Kim, Gwang Hyeon Choi, Yun Bin Lee, Dong Hyun Sinn, Hye‐Lin Kim, Young‐Suk Lim Liver International.2025;[Epub] CrossRef
Comparison of the efficacy and action mechanism of Chinese patent medicines for liver fibrosis and cirrhosis Lingping Fu, Jin Xie, ZeXin Wang, Tao Jiang, Yi Zeng, Jing Yan, Rong Sun, Mengshuang Huang, Shengyi Du, Xiaobao Wang, Yuyang Liu, Kailai Xi, Ailin Chen, Xiao Ma, Jinhao Zeng, Thomas Efferth Phytomedicine.2025; 148: 157246. CrossRef
Longitudinal observation of chronic domestic cat hepadnavirus infection in cats with evidence of extrahepatic involvement Sabrina Wahyu Wardhani, Sitthichok Lacharoje, Tanit Kasantikul, Chutchai Piewbang, Somporn Techangamsuwan Journal of Feline Medicine and Surgery.2025;[Epub] CrossRef
Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”? Yen-Chun Liu, Wen-Juei Jeng Current Hepatology Reports.2024; 23(1): 11. CrossRef
Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation Jinglin Tang, Jiaxuan Zhang, Gaoli Zhang, Wenhui Peng, Ning Ling, Yingzhi Zhou, Hongmei Xu, Hong Ren, Min Chen, Marthandan Mahalingam, Swati Jain mBio.2024;[Epub] CrossRef
Noninvasive Models to Assess Liver Inflammation and Fibrosis in Chronic HBV Infected Patients with Normal or Mildly Elevated Alanine Transaminase Levels: Which One Is Most Suitable? Shasha Ma, Lian Zhou, Shutao Lin, Mingna Li, Jing Luo, Lubiao Chen Diagnostics.2024; 14(5): 456. CrossRef
Lack of association between early on-treatment HBeAg seroclearance and development of hepatocellular carcinoma or decompensated cirrhosis Hyunjae Shin, Won-Mook Choi, Seung Up Kim, Yunmi Ko, Youngsu Park, Jeayeon Park, Moon Haeng Hur, Min Kyung Park, Yun Bin Lee, Yoon Jun Kim, Jung-Hwan Yoon, Jeong-Hoon Lee, Fabien Zoulim JHEP Reports.2024; 6(7): 101089. CrossRef
Inverse relationship between HBV DNA levels and liver histopathological changes in immune‐tolerant CHB patients Deliang Huang, Huiyi Lai, Zhibin Zhu, Hong Yu, Jinghan Peng, Yuanyuan Chen, Xuejiao Liao, Jun Chen Journal of Viral Hepatitis.2024; 31(7): 363. CrossRef
Editorial: High qHBsAg—is it a good or bad signal? Beom Kyung Kim Alimentary Pharmacology & Therapeutics.2024; 59(12): 1616. CrossRef
Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase Jian Wang, Li Zhu, Zhiyi Zhang, Shaoqiu Zhang, Yifan Pan, Yuanyuan Li, Fei Cao, Chao Jiang, Tao Fan, Ye Xiong, Jiacheng Liu, Yuxin Chen, Shengxia Yin, Xin Tong, Chuanwu Zhu, Xingxiang Liu, Jie Li, Chao Wu, Rui Huang Virology Journal.2024;[Epub] CrossRef
Estimating the key outcomes and hepatocellular carcinoma risk in patients in immune‐tolerant phase of chronic hepatitis B virus infection: A systematic review and meta‐analysis Min Liu, Taixue Zhao, Jinyang Zhang, Bing Bu, Ruyi Zhang, Xueshan Xia, Jiawei Geng Reviews in Medical Virology.2024;[Epub] CrossRef
Significant liver histological change is common in HBeAg-positive chronic hepatitis B with normal ALT Menghui Duan, Huanming Xiao, Meijie Shi, Yubao Xie, Pengtao Zhao, Sheng Li, Xiaoling Chi, Xueen Liu, Hui Zhuang BMC Infectious Diseases.2024;[Epub] CrossRef
Preface Seung Up Kim Clinical and Molecular Hepatology.2024; 30(Suppl): S3. CrossRef
Vibration-controlled transient elastography for significant fibrosis in treatment-naïve chronic hepatitis B patients: A systematic review and meta-analysis Mi Na Kim, Jihyun An, Eun Hwa Kim, Hee Yeon Kim, Han Ah Lee, Jung Hwan Yu, Young-Joo Jin, Young Eun Chon, Seung Up Kim, Dae Won Jun, Ji Won Han, Miyoung Choi Clinical and Molecular Hepatology.2024; 30(Suppl): S106. CrossRef
HBeAg-positive CHB patients with indeterminate phase associated with a high risk of significant fibrosis Yuanyuan Li, Yijia Zhu, Dongmei Gao, Yifan Pan, Jian Wang, Shaoqiu Zhang, Xiaomin Yan, Li Zhu, Chuanwu Zhu, Xingxiang Liu, Zhaoping Zhang, Jie Li, Yuxin Chen, Rui Huang, Chao Wu Virology Journal.2024;[Epub] CrossRef
Is liver biopsy essential to identifying the immune tolerant phase of chronic hepatitis B? Joo Hyun Oh, Dong Hyun Sinn Clinical and Molecular Hepatology.2023; 29(2): 367. CrossRef
Letter regarding “Long-term prognosis and the need for histologic assessment of chronic hepatitis B in the serological immune-tolerant phase” Chia-Ming Chu, Yun-Fan Liaw Clinical and Molecular Hepatology.2023; 29(2): 510. CrossRef
The imitator of immune-tolerant chronic hepatitis B: A killer in disguise Moon Haeng Hur, Jeong-Hoon Lee Clinical and Molecular Hepatology.2023; 29(2): 363. CrossRef
Correspondence on Letter regarding “Long-term prognosis and the need for histologic assessment of chronic hepatitis B in the serological immune tolerant phase” Jeong-Ju Yoo, Sang Gyune Kim Clinical and Molecular Hepatology.2023; 29(2): 513. CrossRef
Research Progress in Histological Features and Related Influencing Factors of Chronic Hepatitis B Patients with Persistent Normal ALT 宇行 刘 Advances in Clinical Medicine.2023; 13(05): 8702. CrossRef
Core indicators related to the elimination of hepatitis B and C virus infection in South Korea: A nationwide study Chang Hun Lee, Gwang Hyeon Choi, Hwa Young Choi, Sojung Han, Eun Sun Jang, Young Eun Chon, Young Chang, Kyung-Ah Kim, Do Young Kim, Hyung Joon Yim, Hye-Lin Kim, Sook-Hyang Jeong, In Hee Kim Clinical and Molecular Hepatology.2023; 29(3): 779. CrossRef
Yu Rim Lee, Min Kyu Kang, Jeong Eun Song, Hyun Jung Kim, Young Oh Kweon, Won Young Tak, Se Young Jang, Jung Gil Park, Changhyeong Lee, Jae Seok Hwang, Byoung Kuk Jang, Jeong Ill Suh, Woo Jin Chung, Byung Seok Kim, Soo Young Park
Clin Mol Hepatol 2020;26(4):562-576. Published online October 1, 2020
Background/Aims Although coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, the implication of pre-existing liver disease on the outcome of COVID-19 remains unresolved.
Methods A total of 1,005 patients who were admitted to five tertiary hospitals in South Korea with laboratory-confirmed COVID-19 were included in this study. Clinical outcomes in COVID-19 patients with coexisting liver disease as well as the predictors of disease severity and mortality of COVID-19 were assessed.
Result s: Of the 47 patients (4.7%) who had liver-related comorbidities, 14 patients (1.4%) had liver cirrhosis. Liver cirrhosis was more common in COVID-19 patients with severe pneumonia than in those with non-severe pneumonia (4.5% vs. 0.9%, P=0.006). Compared to patients without liver cirrhosis, a higher proportion of patients with liver cirrhosis required oxygen therapy; were admitted to the intensive care unit; had septic shock, acute respiratory distress syndrome, or acute kidney injury; and died (P<0.05). The overall survival rate was significantly lower in patients with liver cirrhosis than in those without liver cirrhosis (log-rank test, P=0.003). Along with old age and diabetes, the presence of liver cirrhosis was found to be an independent predictor of severe disease (odds ratio, 4.52; 95% confidence interval [CI], 1.20–17.02;P=0.026) and death (hazard ratio, 2.86; 95% CI, 1.04–9.30; P=0.042) in COVID-19 patients.
Conclusions This study suggests liver cirrhosis is a significant risk factor for COVID-19. Stronger personal protection and more intensive treatment for COVID-19 are recommended in these patients.
Citations
Citations to this article as recorded by
Global geographic and socioeconomic disparities in COVID-associated acute kidney injury: a systematic review and meta-analysis Danyang Dai, Pedro Franca Gois, Digby Simpson, Souhayel Hedfi, Sally Shrapnel, Jason Donald Pole Journal of Global Health.2025;[Epub] CrossRef
Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors Levente Zsichla, Viktor Müller Viruses.2023; 15(1): 175. CrossRef
SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups George D Liatsos World Journal of Gastroenterology.2023; 29(16): 2397. CrossRef
COVID-19 and severity of liver diseases: Possible crosstalk and clinical implications Mohammad T. Imam, Ziyad S. Almalki, Abdullah R. Alzahrani, Saeed S. Al-Ghamdi, Alaa H. Falemban, Ibrahim M. Alanazi, Naiyer Shahzad, Munira Muhammad Alrooqi, Qaiser Jabeen, Imran Shahid International Immunopharmacology.2023; 121: 110439. CrossRef
Clinical Effect of Hepatitis B Virus on COVID-19 Infected Patients: A Nationwide Population-Based Study Using the Health Insurance Review & Assessment Service Database Jung Wan Choe, Young Kul Jung, Hyung Joon Yim, Gi Hyeon Seo Journal of Korean Medical Science.2022;[Epub] CrossRef
Heterogeneity and Risk of Bias in Studies Examining Risk Factors for Severe Illness and Death in COVID-19: A Systematic Review and Meta-Analysis Abraham Degarege, Zaeema Naveed, Josiane Kabayundo, David Brett-Major Pathogens.2022; 11(5): 563. CrossRef
COVID-19 Severity and Mortality Among Chronic Liver Disease Patients: A Systematic Review and Meta-Analysis Ramya Nagarajan, Yuvaraj Krishnamoorthy, Sathish Rajaa, Vishnu Shankar Hariharan Preventing Chronic Disease.2022;[Epub] CrossRef
Forms of cholangitis to be considered after SARS-CoV-2 infection Ju-Yeon Cho, Young-Sun Lee, Soon Sun Kim, Do Seon Song, Jeong-Hoon Lee, Ji Hoon Kim Clinical and Molecular Hepatology.2022; 28(4): 929. CrossRef
A systems biology approach for investigating significantly expressed genes among COVID-19, hepatocellular carcinoma, and chronic hepatitis B Babak Sokouti Egyptian Journal of Medical Human Genetics.2022;[Epub] CrossRef
Autoimmune liver disease represented as primary biliary cholangitis after SARS-CoV-2 infection: A need for population-based cohort study Soon Kyu Lee, Jung Hyun Kwon, Nara Yoon, Soon Woo Nam, Pil Soo Sung Clinical and Molecular Hepatology.2022; 28(4): 926. CrossRef
Prognostic Impact of Myosteatosis on Mortality in Hospitalized Patients with COVID-19 Min-Kyu Kang, Yu-Rim Lee, Jeung-Eun Song, Young-Oh Kweon, Won-Young Tak, Se-Young Jang, Jung-Gil Park, Soo-Young Park Diagnostics.2022; 12(9): 2255. CrossRef
The association of chronic liver disorders with exacerbation of symptoms and complications related to COVID‐19: A systematic review and meta‐analysis of cohort studies Maryam Afraie, Pardis Mohammadzedeh, Mobin Azami, Sorour Khateri, Kamran Zamani, Farhad Moradpour, Yousef Moradi The Clinical Respiratory Journal.2022; 16(12): 777. CrossRef
COVID-19 With Preexisting Hypercoagulability Digestive Disease Mingshan Jiang, Jingxi Mu, Silan Shen, Hu Zhang Frontiers in Medicine.2021;[Epub] CrossRef
A narrative review on characterization of acute respiratory distress syndrome in COVID-19-infected lungs using artificial intelligence Jasjit S. Suri, Sushant Agarwal, Suneet K. Gupta, Anudeep Puvvula, Mainak Biswas, Luca Saba, Arindam Bit, Gopal S. Tandel, Mohit Agarwal, Anubhav Patrick, Gavino Faa, Inder M. Singh, Ronald Oberleitner, Monika Turk, Paramjit S. Chadha, Amer M. Johri, J. M Computers in Biology and Medicine.2021; 130: 104210. CrossRef
COVID‐19 in hospitalized liver transplant recipients: An early systematic review and meta‐analysis Kumar Jayant, Isabella Reccia, Francesco Virdis, Jordan S. Pyda, Piotr J. Bachul, Diego di Sabato, Rolf N. Barth, John Fung, Talia Baker, Piotr Witkowski Clinical Transplantation.2021;[Epub] CrossRef
Management of Patients with Chronic Liver Disease: The Era of the COVID-19 Pandemic Yu Rim Lee The Korean Journal of Gastroenterology.2021; 77(4): 156. CrossRef
Patients with cirrhosis during the COVID-19 pandemic: Current evidence and future perspectives Hung-Yuan Su, Yin-Chou Hsu World Journal of Clinical Cases.2021; 9(13): 2951. CrossRef
Italian association for the study of the liver position statement on SARS-CoV2 vaccination Francesco Paolo Russo, Salvatore Piano, Raffaele Bruno, Patrizia Burra, Massimo Puoti, Mario Masarone, Sara Montagnese, Francesca Romana Ponziani, Salvatore Petta, Alessio Aghemo Digestive and Liver Disease.2021; 53(6): 677. CrossRef
Angiotensin-converting enzyme 2 receptors, chronic liver diseases, common medications, and clinical outcomes in coronavirus disease 2019 patients Wattana Leowattana World Journal of Virology.2021; 10(3): 86. CrossRef
Impact of COVID-19 on liver Yu-Jang Su, Chen-Wang Chang, Ming-Jen Chen, Yen-Chun Lai World Journal of Clinical Cases.2021; 9(27): 7998. CrossRef
Update on liver disease management during the pandemic of coronavirus disease 2019 (COVID-19): 2021 KASL guideline Ju-Yeon Cho, Young-Sun Lee, Soon Sun Kim, Do Seon Song, Jeong-Hoon Lee, Ji Hoon Kim Clinical and Molecular Hepatology.2021; 27(4): 515. CrossRef
Clinical outcomes in COVID-19 and cirrhosis: a systematic review and meta-analysis of observational studies Paul Middleton, Catherine Hsu, Mark P Lythgoe BMJ Open Gastroenterology.2021; 8(1): e000739. CrossRef
Multicenter Analysis of Clinical Features and Prognosis of COVID-19 Patients with Hepatic Impairment Jeong Eun Song, Min Kyu Kang, Yu Rim Lee, Chang Hyeong Lee, Jung Gil Park, Young Oh Kweon, Won Young Tak, Soo Young Park, Se Young Jang, Jae Seok Hwang, Byoung Kuk Jang, Won Young Jang, Jeong Ill Suh, Woo Jin Chung, Byung Seok Kim Gut and Liver.2021; 15(4): 606. CrossRef
Critical Update on the Diagnosis and Management of COVID-19 in Advanced Cirrhosis and Liver Transplant Recipients Cyriac Abby Philips, Mohamed Rela, Arvinder Singh Soin, Subhash Gupta, Sudhindran Surendran, Philip Augustine Journal of Clinical and Translational Hepatology.2021; 000(000): 000. CrossRef
Red rice bran polyphenols suppress invasive properties of HepG2 cells, possibly through Wnt/β-catenin-mediated EMT reversal Nattawan Thaolipo, Worawat Surarit, Pintusorn Hansakul F1000Research.2025; 14: 407. CrossRef
An Ethanolic Extract of Sulfur Polypore Mushroom Laetiporus sulphureus (Agaricomycetes) Mycelium Inhibits Cell Cycle Progression, Survival, and Migration in Human Hepatocarcinoma Cell Lines
Martina De Mattheis, Alberto Massimi, Lara Lizzi, Marco Leonardi, Mirco Iotti, Mara Massimi International Journal of Medicinal Mushrooms.2025; 27(12): 67. CrossRef
Novel pyrano[2,3-c]pyrazolopyrimidines as promising anticancer agents: Design, synthesis, and cell cycle arrest of HepG2 cells at S phase David S. A. Haneen, Mohamed H. Hekal, Wael S. I. Abou-Elmagd, Wael M. El-Sayed Synthetic Communications.2024; 54(8): 655. CrossRef
Ribonucleotide reductase subunit switching in hepatoblastoma drug response and relapse Anthony Brown, Qingfei Pan, Li Fan, Emilie Indersie, Cheng Tian, Nikolai Timchenko, Liyuan Li, Baranda S. Hansen, Haiyan Tan, Meifen Lu, Junmin Peng, Shondra M. Pruett-Miller, Jiyang Yu, Stefano Cairo, Liqin Zhu Communications Biology.2023;[Epub] CrossRef
An Efficient 5-Aminolevulinic Acid Photodynamic Therapy Treatment for Human Hepatocellular Carcinoma Abhishek Kumar, Florian Pecquenard, Martha Baydoun, Alexandre Quilbé, Olivier Moralès, Bertrand Leroux, Lynda Aoudjehane, Filomena Conti, Emmanuel Boleslawski, Nadira Delhem International Journal of Molecular Sciences.2023; 24(13): 10426. CrossRef
Glycidamide and cis-2-butene-1,4-dial (BDA) as potential carcinogens and promoters of liver cancer - An in vitro study Sofia Gouveia-Fernandes, Armanda Rodrigues, Carolina Nunes, Catarina Charneira, João Nunes, Jacinta Serpa, Alexandra M.M. Antunes Food and Chemical Toxicology.2022; 166: 113251. CrossRef
Alpinumisoflavone Impairs Mitochondrial Respiration via Oxidative Stress and MAPK/PI3K Regulation in Hepatocellular Carcinoma Cells Hyewon Jang, Jiyeon Ham, Jisoo Song, Gwonhwa Song, Whasun Lim Antioxidants.2022; 11(10): 1929. CrossRef
A meta-learning approach to improving radiation response prediction in cancers Yuening Zhang, Li Qiu, Yongyong Ren, Zhiwei Cheng, Leijie Li, Siqiong Yao, Chengdong Zhang, Zhiguo Luo, Hui Lu Computers in Biology and Medicine.2022; 150: 106163. CrossRef
In Vitro Cell Toxicity and Intracellular Uptake of Doxorubicin Exposed as a Solution or Liposomes: Implications for Treatment of Hepatocellular Carcinoma Fredrik Kullenberg, Oliver Degerstedt, Carlemi Calitz, Nataša Pavlović, David Balgoma, Johan Gråsjö, Erik Sjögren, Mikael Hedeland, Femke Heindryckx, Hans Lennernäs Cells.2021; 10(7): 1717. CrossRef
Entrainment of superoxide rhythm by menadione in HCT116 colon cancer cells Uma Kizhuveetil, Meghana V. Palukuri, Priyanshu Sharma, Devarajan Karunagaran, Raghunathan Rengaswamy, G. K. Suraishkumar Scientific Reports.2019;[Epub] CrossRef
Krüppel‐like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway JinBo Lin, Huifang Tan, Yingjie Nie, Dongwen Wu, Weiji Zheng, Wensong Lin, Zheng Zhu, Bing Yang, Xiaoliang Chen, Tao Chen Cancer Science.2019; 110(4): 1220. CrossRef
CMA down-regulates p53 expression through degradation of HMGB1 protein to inhibit irradiation-triggered apoptosis in hepatocellular carcinoma Jing-Hua Wu, Jia-Pei Guo, Jun Shi, Hui Wang, Lei-Lei Li, Bin Guo, Dian-Xing Liu, Qing Cao, Zhi-Yong Yuan World Journal of Gastroenterology.2017; 23(13): 2308. CrossRef
First
Prev
