[Survey of anti-tuberculosis drug-induced severe liver injury in Japan].
OBJECTIVE
To clarify the incidence and clinical significance of anti-tuberculosis drug-induced liver injury.


METHODS
Questionnaire was sent out by mail to 114 hospitals, to ask whether there were patient(s) from 1994 to 2003 with liver injury induced by anti-tuberculosis drugs with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of more than 1000 IU/l and/or total bilirubin level of more than 2 mg/dl. As for the cases of severe hepatic injury, their backgrounds and clinical courses were investigated.


RESULTS
Seventy cases were reported from 24 out of 68 hospitals which treated at least 8095 tuberculosis patients in 2003. Incidence rate of severe liver injury by anti-tuberculosis drugs was 0.50 to 0.59 percent in three hospitals with good surveillance system, and overall incidence was estimated to be between 0.1 to 0.5 percent. We could analyze 33 cases; one was HB antigen positive, one had HCV positive liver cirrhosis, 2 had other hepatic disease, and 17 had other underlying disease including diabetes mellitus. Twenty-three were treated by regimens with isoniazid (INH), rifampicin (RFP) and pyrazinamide (PZA), and 8 by regimens without PZA but with INH and RFP and one was a multidrug-resistant case and was treated by regimen with ethionamide and PZA. The onset of liver injury was within 2 months after starting anti-tuberculosis chemotherapy in 28 (85%) cases. In twenty-eight cases which both ALT and total bilirubin level are known, total bilirubin level at the onset of liver injury was more than 2 mg/dl in 14 cases and most of the cases were hepatocellular type of liver injury. Six out of 10 cases with total bilirubin level more than 5 mg/dl died by liver failure. Total birilubin was less than 2 mg/gl in two of the dead cases; in one case antituberculosis drug were continued despite elevated level of ALT and another case complicated with gastric bleeding. Treatment for liver injury was conservative in most cases, 6 were treated by plasmapheresis and no liver transplantation was carried out. Eight cases died of liver failure, one died of tuberculosis and only 15 were treated successfully for tuberculosis.


CONCLUSIONS
Incidence rate was high comparared with that by other drugs reported previously. The risk factor of liver injury by antituberculosis drugs was not detected, but elevated total bilirubin level more than 5 mg/dl was an alarming sign for poor prognosis.
Shigeto
Eriko
E
Department of Respiratory Medicine, National Hospital Organization, Higashihiroshima Medical Center, Hiroshima, Japan. shigetou_eriko@hiro-hosp.jp
D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000009:adverse effects*; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008107:Liver Diseases / Q000175:diagnosis / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011795:Surveys and Questionnaires
D000995:Antitubercular Agents; D015415:Biomarkers; D001663:Bilirubin