title: Serum markers for mitochondrial dysfunction and cell death are possible predictive indicators for drug-induced liver injury by direct acting antivirals.
abstract: OBJECTIVE
  We prospectively screened patients treated with direct-acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug-induced liver injury (DILI).
  
  
  METHODS
  The levels of various serum markers among DILI, non-DILI and control groups were compared. The DILI group consisted of eight patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non-DILI group via a matched-group design based on age, sex and disease severity. Additionally, eight healthy volunteers were employed as the controls. Serum measurements of cytokines/chemokines, cytokeratin-18 fragment (CK-18F) and super oxidase dismutase-2 (SOD2) were evaluated on the date at which hepatitis C virus RNA was absent (baseline). For patients with DILI, serum measurements taken before treatment, 1 week before pronounced transaminase elevation (prominence-1 W) and on the date at which pronounced elevation of transaminase occurred (prominence) were also evaluated.
  
  
  RESULTS
  All patients treated with DAA had normalized transaminase levels at baseline. In patients with DILI, interferon-inducible protein-10 (IP-10) levels were higher at prominence-1 W than at baseline. Those patients also had significantly higher levels of SOD2 and CK-18F at prominence-1 W than at baseline.
  
  
  CONCLUSIONS
  Elevated IP-10 may be a preconditioning chemokine for DAA-induced liver injury, and damage markers associated with cell death and mitochondrial dysfunction are potential predictive serum markers for DILI.
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kakisaka
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Miyasaka
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takikawa
keywords: cytokeratin-18 fragment; drug-induced liver injury; interferon-inducible protein-10; super oxidase dismutase-2