Clinical Trials Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2017; 23(5): 876-884
Published online Feb 7, 2017. doi: 10.3748/wjg.v23.i5.876
Effects of sex and generation on hepatitis B viral load in families with hepatocellular carcinoma
Ai-Ru Hsieh, Cathy SJ Fann, Chau-Ting Yeh, Hung-Chun Lin, Shy-Yi Wan, Yi-Cheng Chen, Chia-Lin Hsu, Jennifer Tai, Shi-Ming Lin, Dar-In Tai
Ai-Ru Hsieh, Graduate Institute of Biostatistics, China Medical University, Taichung 40402, Taiwan
Cathy SJ Fann, Chia-Lin Hsu, Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 11529, Taiwan
Chau-Ting Yeh, Hung-Chun Lin, Shy-Yi Wan, Yi-Cheng Chen, Shi-Ming Lin, Dar-In Tai, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
Jennifer Tai, Kaohsiung Medical University, College of Medicine, Kaohsiung 807, Taiwan
Author contributions: Hsieh AR and Tai DI contributed equally; Hsieh AR, Fann CSJ and Hsu CL contributed to the statistical analysis; Tai DI contributed to developing the study protocol, interpreting the data, and writing the manuscript; Yeh CT contributed to HBV DNA and HBV genotyping assays; Lin HC, Wan SY and Tai J contributed to carried out the survey and collecting the data; Chen YC and Lin SM contributed to collecting the cases.
Supported by grants from the Chang Gung Memorial Hospital (No. CMRPG3C0701); the National Science Council (No. NSC101-2314-B-182A-025-MY3); and China Medical University (No. CMU103-N-15).
Institutional review board statement: This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan (IRB: 91-124).
Informed consent statement: Written informed consent was obtained from all participants before study participation. All experiments and data comparisons were carried out in compliance with relevant laws and guidelines and in accordance with the ethical standards of the Declaration of Helsinki.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: No additional data are available for this study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Dar-In Tai, MD, Professor, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No 5, FuXing Street, Guishan Dist., Taoyuan 333, Taiwan.
Telephone: +886-3-3281200 Fax: +886-3-3272236
Received: October 12, 2016
Peer-review started: October 14, 2016
First decision: December 1, 2016
Revised: December 14, 2016
Accepted: January 4, 2017
Article in press: January 4, 2017
Published online: February 7, 2017

To explore factors associated with persistent hepatitis B virus (HBV) infection in a cohort of hepatocellular carcinoma (HCC)-affected families and then investigate factors that correlate with individual viral load among hepatitis B surface antigen (HBsAg)-positive relatives.


We evaluated non-genetic factors associated with HBV replication in relatives of patients with HCC. Relatives of 355 HCC cases were interviewed using a structured questionnaire. Demographics, relationship to index case, HBsAg status of mothers and index cases were evaluated for association with the HBV persistent infection or viral load by generalized estimating equation analysis.


Among 729 relatives enrolled, parent generation (P = 0.0076), index generation (P = 0.0044), mothers positive for HBsAg (P = 0.0007), and HBsAg-positive index cases (P = 5.98 × 10-8) were associated with persistent HBV infection. Factors associated with HBV viral load were evaluated among 303 HBsAg-positive relatives. Parent generation (P = 0.0359) and sex (P = 0.0007) were independent factors associated with HBV viral load. The intra-family HBV viral load was evaluated in families clustered with HBsAg-positive siblings. An intra-family trend of similar HBV viral load was found for 27 of 46 (58.7%) families. Male offspring of HBsAg-positive mothers (P = 0.024) and older siblings were associated with high viral load.


Sex and generation play important roles on HBV viral load. Maternal birth age and nutritional changes could be the reasons of viral load difference between generations.

Keywords: Familial generation, Sex, Hepatitis B virus, Perinatal infection, Viral replication

Core tip: Familial clustering of chronic hepatitis B infection is identified in this study. Most of the hepatitis B surface antigen (HBsAg) carriers in this cohort are in families of an HBsAg-positive index case. A high prevalence of HBsAg is found in the siblings’ generation and in offspring of an HBsAg-positive mother. The HBsAg status of index cases and HBsAg status of the mother are important factors for determining the persistence of hepatitis B virus (HBV) infection in hepatocellular carcinoma families. Sex and generation are factors associated with HBV replication. Perinatal infection has a great influence on male offspring’s HBV replication.