Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers.
OBJECTIVE
Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis.


METHODS
251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case-control study, which included 184 patients with biopsy-proven liver fibrosis stages.


RESULTS
In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to <45% in the longitudinal cohort; this finding was validated by the case-control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67).


CONCLUSIONS
A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.
Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan School of Medicine, Tzu Chi University, Hualien, Taiwan.
Tai-Chung
TC
Tseng
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Chun-Jen
CJ
Liu
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
Hung-Chih
HC
Yang
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Chi-Ling
CL
Chen
Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Master of Public Health Degree Program, National Taiwan University, Taipei, Taiwan.
Wan-Ting
WT
Yang
Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan.
Cheng-Shiue
CS
Tsai
St Vincent's Hospital, Melbourne, Victoria, Australia.
Stephanie Fang-Tzu
SF
Kuo
Medisch centrum haaglanden, The Hague, The Netherlands.
Femke Carolien
FC
Verbree
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Tung-Hung
TH
Su
Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan.
Chia-Chi
CC
Wang
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Chen-Hua
CH
Liu
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Pei-Jer
PJ
Chen
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Genomics Research Center, Academia Sinica, Taiwan.
Ding-Shinn
DS
Chen
Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Jia-Horng
JH
Kao
D000328:Adult; D002353:Carrier State; D016022:Case-Control Studies; D004279:DNA, Viral / Q000097:blood; D005260:Female; D006509:Hepatitis B / Q000150:complications / Q000821:virology*; D006512:Hepatitis B Core Antigens / Q000097:blood / Q000235:genetics*; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D008103:Liver Cirrhosis / Q000821:virology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors
D004279:DNA, Viral; D006512:Hepatitis B Core Antigens