title: High-dose frequency beta-interferons increase the risk of liver test abnormalities in multiple sclerosis: a longitudinal study.
abstract: BACKGROUND
  Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist.
  
  
  OBJECTIVE
  We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT).
  
  
  METHODS
  Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥ 2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤ 35, >35-40, >40-45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤ 5, >5-15, >15-40, >40 months) on de novo liver enzyme abnormality.
  
  
  RESULTS
  Over a mean treatment period of 38.7 months (SD=34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR=3.8(95% CI: 1.6-9.2) for IFNβ-1a 44 µg SC, and OR=3.4 (95% CI: 1.5-7.9) for IFNβ-1b 250 µg SC compared with the lower frequency IFNβ-1a 30 µg IM. Younger age (≤ 40 years), male gender, and ≤ 15 months of IFNβ exposure were also independent predictors.
  
  
  CONCLUSIONS
  A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated.
authors.affiliation: Faculty of Medicine, School of Population and Public Health, University of British Columbia, Vancouver, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Chan
authors.forename: E
authors.initials: E
authors.lastname: Kingwell
authors.forename: J
authors.initials: J
authors.lastname: Oger
authors.forename: E
authors.initials: E
authors.lastname: Yoshida
authors.forename: H
authors.initials: H
authors.lastname: Tremlett
mesh_terms: D000328:Adult; D000367:Age Factors; D000410:Alanine Transaminase / Q000097:blood*; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D001955:British Columbia; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects*; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008111:Liver Function Tests; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy*; D016017:Odds Ratio; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D007155:Immunologic Factors; D016899:Interferon-beta; D000410:Alanine Transaminase