Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad

Abstract

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares might occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and might mark transitions to inactive disease or clearance of infection, but in certain scenarios they might also lead to hepatic decompensation or death. As such, understanding of the clinical significance of flares in different patient populations and different scenarios is important for optimal management. In this Review, we summarise what is known about flares in different stages of chronic HBV infection; describe flares in the context of the natural history of chronic infection; summarise the immunological mechanisms underlying flares, and describe flares in different clinical scenarios. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve the understanding of flares, hopefully providing insights into their pathogenesis that can be used to improve current clinical management and ideally to further develop new curative therapeutic approaches for HBV infection. We also propose a working definition of an ALT flare to facilitate future research.

Figure 1a:. Course of ALT flare in an HBeAg Positive Patient

Figure 1b:. Course of ALT flare in an HBeAg Negative / anti-HBe Positive Patient

ALT alanine aminotransferase; HBV hepatitis B virus

Figure 2:. Proposed adaptive and innate immune components in CHB flare.

A. Adaptive immune dysregulation in CHB. HBV persists with global and virus-specific dysfunction in adaptive immune cells, with the induction of immune regulatory pathways. B. Activation of innate immune components in CHB Flare. In CHB flare, innate immune cells in the liver may be activated by a threshold level of HBV, leading to increased cytokines that activate NK cells and promote inflammation while promoting hepatocyte death (e.g. via TRAIL/TRAIL-R). C. Immune response with antiviral therapy. Therapeutic control of HBV DNA and ALT as well as loss of HBeAg or HBsAg have been associated with changes in immune parameters.

Figure 3:. Outcomes Following Withdrawal of Nucleoside Analogues among HBeAg Negative Patients.

HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, nucleos(t)ide analog. Figure reproduced with permission from Wiley.