Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity.
OBJECTIVE
Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians and patients adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Centers for Disease Control's (CDC) isoniazid severe adverse events program.


METHODS
We analyzed Drug-Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities.


RESULTS
Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 of these met inclusion criteria. The median age of cases was 49 years (range, 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range, 0-99 days). Thirty-three cases (55%) continued taking isoniazid for more than 7 days after the ATS criteria for stopping were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting criteria for stopping. A delay in stopping was associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for more than 7 days after meeting criteria for stopping. Only 1 of 25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC was reported.


CONCLUSIONS
Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the United States, and its hepatotoxicity is under-reported significantly.
Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina. Electronic address: paul_hayashi@med.unc.edu.
Paul H
PH
Hayashi
Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan.
Robert J
RJ
Fontana
Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana.
Naga P
NP
Chalasani
Division of Gastroenterology, University of Southern California, Los Angeles, California.
Andrew A
AA
Stolz
Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota.
Jay A
JA
Talwalkar
Division of Gastroenterology, Einstein Healthcare Network and University of Pennsylvania, Philadelphia, Pennsylvania.
Victor J
VJ
Navarro
Division of Gastroenterology, University of Texas, Southwestern Medical Center, Dallas, Texas.
William M
WM
Lee
Division of Gastroenterology, California Pacific Medical Center, San Francisco, California.
Timothy J
TJ
Davern
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
David E
DE
Kleiner
Duke Clinical Research Institute, Duke University, Durham, North Carolina.
Jiezhun
J
Gu
Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Jay H
JH
Hoofnagle
D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology* / Q000473:pathology; D005260:Female; D019983:Guideline Adherence; D006302:Health Services Research; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D014481:United States; D055815:Young Adult
D000995:Antitubercular Agents; D007538:Isoniazid
Adverse Reaction; Antibiotics; Drug-Induced Liver Injury; Hepatotoxicity; Tuberculosis