High levels of circulating HMGB1 as a biomarker of acute liver failure in patients with viral hepatitis E

Background: Viral hepatitis E clinically ranges between acute self-limiting hepatitis (AVH) and acute liver failure (ALF). The varied clinical course of the disease possibly thought to be immune-mediated. High-mobility group box 1 (HMGB1) is a non-histone chromosomal nuclear protein with recently discovered pro-inflammatory and immunomodulatory action. Its presence in abundance within hepatocytes is thought provoking in patients with hepatitis. Aim: The present study was designed to elucidate the role of circulating HMGB1 and its gene expression in patients with viral hepatitis E. Methods: Blood samples were obtained from AVH (n = 38), ALF (n = 34) and healthy controls (HC, n = 30). The HMGB1 levels were estimated in serum by quantitative-micro-ELISA. Gene expression levels were studied in the patient's PBMCs by real-time PCR. Lymphocyte proliferation was estimated by colorimetric-MTT assay. Results: Mean circulating HMGB1 levels in HC, AVH and ALF patients were found to be 12.04 +/- 2.23, 112.6 +/- 13.33 and 225.3 +/- 15.04 ng/ml respectively. The levels were significantly higher in ALF than AVH and HC (P < 0.0001). Moreover, 88.2% of ALF patients with >= 250 ng/ml of circulating HMGB1 had a fatal outcome. The gene expression of HMGB1 in the PBMCs of ALF and AVH patients were comparable. A positive correlation was observed between HMGB1 level and INR. A significantly low lymphocyte proliferation was observed in ALF patients (P = 0.008). Conclusion: Massive necrosis of hepatocytes in ALF patients might predispose to excessive accumulation of extracellular HMGB1 leading to suppression of T-cell proliferation. Therefore, it is proposed that excessive circulating HMGB1 might play an important role in immunosuppression and fulminant course of the disease following HEV infection.