Alanine aminotransferase (ALT) flares are a common feature of hepatitis B (HBV) and are a sensitive indicator of liver injury. Yet not all flares are injurious, according to speakers during the Hepatitis B Special Interest Group session on Sunday.
“There are good flares and bad flares,” said Marc G. Ghany, MD, MHSc, FAASLD, Clinical Tenure Track Investigator in the Liver Disease Branch of the National Institute of Diabetes and Digestive and Kidney Diseases. “But for now, we have no biomarkers to tell us whether any particular flare is good or bad.”
In patients with chronic HBV, ALT levels are used to trigger diagnostic testing, as a surrogate marker of disease severity, to monitor disease activity and progression, as a criterion to assess the need for treatment and as a treatment endpoint.
Flares are a part of the natural history of untreated HBV and chronic HVB, said Dr. Ghany. Flares are more frequent in patients who are older, male, Asian, HBeAg positive and infected with HBV genotype C. Expect flares during antiviral therapy, after the withdrawal of antiviral therapy, during or after immunosuppression or chemotherapy and post-partum, he said.
“Most flares resolve within two months,” Dr. Ghany said. “Virtually all should be resolved within six months.”
But what is a flare? Most definitions focus on abrupt or intermittent elevations in serum ALT. Dr. Ghany proposed a standardized definition as an abrupt elevation in serum ALT greater than five times the upper limit of normal and more than twice the patient’s baseline value.
Identifying a flare can be challenging, he added. Only about a third of flares produce clinical symptoms, usually acute hepatitis-like symptoms, hepatic decompensation with or without cirrhosis or death.
At the same time, ALT flares can be confused with a superinfection of other hepatotrophic viruses including hepatitis A, C, D and E, drug toxicity, alcoholic hepatitis and autoimmune hepatitis.
“You need to exclude all these other diagnoses,” Dr. Ghany cautioned.
Good flares can improve HBeAg seroconversion, and elevated ALT level is associated with higher levels of spontaneous HBeAg seroconversion. Bad flares can produce jaundice, lead to recurrent or multiple flares and sometimes both.
Patients should be monitored weekly or biweekly during a flare for clinical deterioration or hepatic decompensation, Dr. Ghany advised. Patients who are over 30, have stable or increasing HBV DNA or are HBeAg negative/anti-HBe positive may be candidates for early treatment.
“Patients with cirrhosis or decompensation should be treated immediately with a first line nucleoside analogue,” he added.
The mechanisms by which flares mediate liver damage are emerging, said Kyong-Mi Chang, MD, Professor and Associate Director of the Penn Center for Viral Hepatitis, University of Pennsylvania. ALT flares suppress both T-cells and B cells but upregulate NK activation. Cytokines produced during the flare promote NK-mediated liver damage via t TRAIL and TRAIL receptor pathways.
Flares associated with treatment also alter the NK phenotype, noted Dr. Chang. The altered phenotype is associated both with improved HBV-specific T-cell response and HBsAg loss. That suggests NK cells may regulate T-cell activity and predict the loss of HBsAg.