title: Drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase.
abstract: OBJECTIVE
  To identify the proportion, causes and the nature of drug-induced liver injury (DILI) in patients with notably elevated alanine aminotransferase (ALT).
  
  
  METHODS
  All the inpatients with ALT levels above 10 times upper limit of normal range (ULN) were retrospectively identified from a computerized clinical laboratory database at our hospital covering a 12-mo period. Relevant clinical information was obtained from medical records. Alternative causes of ALT elevations were examined for each patient, including biliary abnormality, viral hepatitis, hemodynamic injury, malignancy, DILI or undetermined and other causes. All suspected DILI cases were causality assessed using the Council for International Organizations of Medical Sciences scale, and only the cases classified as highly probable, probable, or possible were diagnosed as DILI. Comments related to the diagnosis of DILI in the medical record and in the discharge letter for each case were also examined to evaluate DILI detection by the treating doctors.
  
  
  RESULTS
  A total of 129 cases with ALT > 10 ULN were identified. Hemodynamic injury (n = 46, 35.7%), DILI (n = 25, 19.4%) and malignancy (n = 21, 16.3%) were the top three causes of liver injury. Peak ALT values were lower in DILI patients than in patients with hemodynamic injury (14.5 ± 5.6 ULN vs 32.5 ± 30.7 ULN, P = 0.001). Among DILI patients, one (4%) case was classified as definite, 19 (76%) cases were classified as probable and 5 (20%) as possible according to the CIOMS scale. A hepatocellular pattern was observed in 23 (92%) cases and mixed in 2 (8%). The extent of severity of liver injury was mild in 21 (84%) patients and moderate in 4 (16%). Before discharge, 10 (40%) patients were recovered and the other 15 (60%) were improved. The improved patients tended to have a higher peak ALT (808 ± 348 U/L vs 623 ± 118 U/L, P = 0.016) and shorter treatment duration before discharge (8 ± 6 d vs 28 ± 12 d, P = 0.008) compared with the recovered patients. Twenty-two drugs and 6 herbs were found associated with DILI. Antibacterials were the most common agents causing DILI in 8 (32%) cases, followed by glucocorticoids in 6 (24%) cases. Twenty-four (96%) cases received treatment of DILI with at least one adjunctive drug. Agents for treatment of DILI included anti-inflammatory drugs (e.g., glycyrrhizinate), antioxidants (e.g., glutathione, ademetionine 1,4-butanedisulfonate and tiopronin), polyene phosphatidyl choline and herbal extracts (e.g., protoporphyrin disodium and silymarin). Diagnosis of DILI was not mentioned in the discharge letter in 60% of the cases. Relative to prevalent cases and cases from wards of internal medicine, incident cases and cases from surgical wards had a higher risk of missed diagnosis in discharge letter [odds ratio (OR) 32.7, 95%CI (2.8-374.1), and OR 58.5, 95%CI (4.6-746.6), respectively].
  
  
  CONCLUSIONS
  DILI is mostly caused by use of antibacterials and glucocorticoids, and constitutes about one fifth of hospitalized patients with ALT > 10 ULN. DILI is underdiagnosed frequently.
authors.affiliation: Department of Pharmacy, the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood*; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000209:etiology; D016009:Chi-Square Distribution; D003951:Diagnostic Errors; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D005938:Glucocorticoids; D000410:Alanine Transaminase
keywords: Abnormal liver enzyme; Adjunctive drugs; Alanine aminotransferase; Drug-induced liver injury; Underdiagnosis