title: High levels of circulating HMGB1 as a biomarker of acute liver failure in patients with viral hepatitis E.
abstract: 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.
  
  
  OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Virology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
authors.forename: Manasi
authors.initials: M
authors.lastname: Majumdar
authors.forename: Radhakanta
authors.initials: R
authors.lastname: Ratho
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Chawla
authors.forename: Mini P
authors.initials: MP
authors.lastname: Singh
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D003124:Colorimetry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D024243:HMGB1 Protein / Q000097:blood*; D016751:Hepatitis E / Q000150:complications*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017114:Liver Failure, Acute / Q000097:blood / Q000175:diagnosis* / Q000209:etiology*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue
keywords: acute liver failure; cell-mediated immunity; hepatitis E virus; high-mobility group box 1; proliferation index