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

Abstract

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.

Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

“…It is conceivable that the Axl feedback regulatory pathway as induced by excessive IFN-α/β signaling during early stage of HBV infection sets the stage for relaying subsequent HBVtolerant immune responses. The immune tolerizing machinery following Axl signaling that maintains the HBV-tolerant state at later stage is currently open for further investigation.Our findings seem contradictory to current clinical practice where IFN-α is used for treating chronic HBV infection [32][33][34]. The paradox can be reconciled by the fact that enhanced IFN-α/β expression of the young mice in our model occurs at an early stage of HBV infection.…”

Integrated Analysis of Gene Expression Profiles Reveals Deregulation of the Immune Response Genes during Different Phases of Chronic Hepatitis B Infection

“…In addition, DEG-GO network obtained from IT-IA patients revealed that most important GO terms were involved in immune response ( Figure 5). Spontaneous hepatitis flare (acute exacerbations) with sudden elevation of serum ALT over five times the upper limit of normal or a greater than 3-fold increase in ALT are often hallmarks of the immune clearance phase (30,31). Previous studies have revealed that immune response against HBV antigens mediated by HLA-class I antigen-restricted, cytotoxic T lymphocyte (CTL) and its downstream mechanisms can cause the hepatitis flares.…”

Serum progranulin levels are elevated in patients with chronic hepatitis B virus infection, reflecting viral load

“…A large body of studies have demonstrated that a variety of regulatory molecules participate in immune response, contributing to chronic HBV infection, dysregulated liver inflammation and disease progression [10,11]. A better understanding of the role of immune factors in the pathogenesis of HBV infection will shed new light on the mechanisms of HBV-infected liver diseases and provide new therapeutic target for anti-HBV treatment.…”