Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management

J Hepatol. 2014 Dec;61(6):1407-17. doi: 10.1016/j.jhep.2014.08.033. Epub 2014 Aug 29.


Hepatitis B flare, defined as an event with abrupt rise of alanine aminotransferase (ALT) levels to >5 times the upper limit of normal during chronic hepatitis B virus (HBV) infection, is considered to be the result of a human leukocyte antigen-I restricted, cytotoxic T lymphocyte mediated immune response against HBV and its downstream mechanisms. It may occur spontaneously, during or after antiviral therapy and in the setting of immunosuppression and/or chemotherapy. The clinical spectrum of hepatitis B flares varies from asymptomatic to symptomatic and typical overt acute hepatitis, even with hepatic decompensation or failure. Flares may also occur in viraemic patients with cirrhosis with higher incidence of decompensation/mortality, hence requiring immediate antiviral therapy. An upsurge of serum HBV DNA and hepatitis B surface antigen levels usually precedes the abrupt rise of ALT levels. Rising or stable and high HBV DNA during flares represent ineffective immune clearance and further hepatocytolysis, even hepatic decompensation, may occur. Such patients require immediate antiviral therapy. In contrast, bridging hepatic necrosis and/or alpha-fetoprotein levels >100 ng/ml or decreasing HBV DNA during flares represent a more effective immune clearance and frequently leads to seroclearance of HBV DNA and/or hepatitis B e antigen with remission. If patients are non-cirrhotic and there is no concern of developing decompensation, patients may be observed for 3-6 months before deciding on the need of antiviral therapy. Severe and repeated flares are prone to develop into decompensation or lead to the development of cirrhosis, thus a timely treatment to prevent the hepatitis B flare is better than to cope with the flare. Screening, monitoring and prophylactic or pre-emptive antiviral therapy is mandatory for patients who are going to receive immunosuppressants or chemotherapy.

Keywords: Alpha-fetoprotein; Chemotherapy; Cirrhosis; Hepatitis B virus; Hepatocellular carcinoma; Immune clearance; Immune restoration; Interferon-α; Nucleos(t)ide analogue; Pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alanine Transaminase / metabolism
  • Antiviral Agents / therapeutic use
  • DNA, Viral / metabolism
  • Disease Management*
  • Disease Progression*
  • Hepatitis B / drug therapy*
  • Hepatitis B / metabolism
  • Hepatitis B / physiopathology*
  • Hepatitis B e Antigens / metabolism
  • Hepatitis B virus / metabolism
  • Hepatitis B, Chronic / drug therapy*
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / physiopathology*
  • Humans
  • Mass Screening


  • Antiviral Agents
  • DNA, Viral
  • Hepatitis B e Antigens
  • Alanine Transaminase