the end of September 2008. The day after completion, the patient complained of nausea and vomiting. On the following day, he developed generalized jaundice. At the beginning of October 2008, laboratory Trichostatin A TSA investigations revealed a markedly increased serum level of alanine aminotransferase : 639 U/L, a moderately increased AST: 109 U/L, and increased alkaline phosphatase : 261 U/L, with an ALT/AP ratio of 1.75, indicating cholestatic hepatitis. Total bilirubin was markedly increased at 12.77 mg/dL. During follow up care, serum levels of hepatic enzymes and of bilirubin were determined by the general practitioner. Because of persisting jaundice, the patient was referred to a hepatologist for further diagnosis. Sonographic examination of the abdomen did not reveal pathologies of the liver or of the biliary tract.
By the end of October 2008, the patient went to the neurosurgery outpatient clinic for a postoperative follow up. Because the liver injury was considered as possibly drug induced, it was recommended not to proceed with the adjuvant TZM as monotherapy. One week later, the patient returned to the neurosurgery outpatient department and an MRT of the brain did not reveal a recurrence of the tumor. At the beginning of December 2008, the patient was again referred to the neurosurgery department because of progressive visual disturbances. A tumor relapse was excluded by MRT. At this time point, the physical examination revealed generalized jaundice and the ultrasound examination showed a modestly enlarged liver without signs ofOur analysis of the FDA AERS database for the years 2007 2010 retrieved 198 single adverse event reports of TZM associated hepatotoxicity corresponding to 154 single cases.
In these 154 unique cases, 110 had a single hepatic adverse event reported and 44 had more than one. Our above described case was also included in the FDA AERS database. The MedDRA preferred terms of hepatic adverse events reported in association with TZM as the primary suspect drug are described in Table 1. The most frequent adverse hepatic event related to TZM was hepatic function abnormal, with 48 single reports. Discussion Here, we describe the case of a severe sustained cholestatic liver injury that occurred in close temporal relation to TZM treatment in a GBM patient. Importantly, this liver injury was not associated with a previous or concurrent liver disease.
The patient did not have a previous history of drug allergy or elevated bilirubin values in the past. The onset of clinical symptoms coincided with the end of the administration of TZM. Early clinical symptoms presented by the patient were consistent with acute liver disease. Hepatic injury was confirmed by the results of laboratory tests that revealed significantly elevated serum levels of liver enzymes and bilirubin. The pattern of liver enzyme levels strongly suggested cholestatic hepatitis. This diagnosis was confirmed by histopathological examination of a liver biopsy that did not suggest an autoimmune, viral, or biliary etiology. We consider that the liver injury in this case is probably causally related to TZM exposure. First of all, the manifestation of liver disease was in a close temporal relation to preceding drug treatment. Second, previous liver disease was excluded as well a