title: Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.
abstract: BACKGROUND
  Emergence of elevated liver function tests (LFTs) during a clinical trial may be due to underlying disease factors of the participants, thus cofounding safety assessments of therapies. Limited data exist addressing the frequency of elevated LFTs in the chronic disease setting of cystic fibrosis (CF). The objectives of this study were to characterize emergence rates of elevated LFTs in CF trials and their association with clinical outcomes.
  
  
  METHODS
  The cohort was comprised of participants of three completed multicenter CF trials. LFTs were collected as safety endpoints, and hospitalization rates and changes in pulmonary function and weight were used to assess the association between elevated LFTs and clinical outcome.
  
  
  RESULTS
  93/376 (25%) participants had ≥1 emergent elevated LFT exceeding the normal reference range over an average 8.3 month follow-up, and only 12/93 (13%) had a value determined by the physician as clinically significant. The emergence of an elevated LFT was not significantly associated with a greater rate of decline in pulmonary function or weight as compared to participants with normal LFTs. The emergence of an elevated LFT value was however associated with a higher hospitalization risk (relative risk:1.67, 95% confidence interval:1.11, 2.53).
  
  
  CONCLUSIONS
  Elevated LFTs are common among CF trials, although in most cases they are not deemed clinically significant. These elevated LFTs are associated with more frequent hospitalizations, but additional studies are needed to determine the causality of this association. Therapeutic trials in CF must define a priori criteria for clinical significance of elevated LFTs to enable unbiased safety assessments.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98101-9300, USA. nicole.hamblett@seattlechildrens.org
authors.forename: Nicole
authors.initials: N
authors.lastname: Mayer-Hamblett
authors.forename: Margaret
authors.initials: M
authors.lastname: Kloster
authors.forename: Bonnie W
authors.initials: BW
authors.lastname: Ramsey
authors.forename: Michael R
authors.initials: MR
authors.lastname: Narkewicz
authors.forename: Lisa
authors.initials: L
authors.lastname: Saiman
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Goss
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects*; D054316:Biomarkers, Pharmacological / Q000097:blood; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000097:blood* / Q000150:complications; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007223:Infant; D008111:Liver Function Tests; D008297:Male; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy*; D012129:Respiratory Function Tests; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D054316:Biomarkers, Pharmacological; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase