Sorafenib-Induced Hepatic Encephalopathy

Abstract

The multikinase inhibitorsorafenibwas recentlyapproved inEurope forthetreatment of advanced hepatic carcinoma (AHC). We reporta case of hepaticencephalopathy inducedby sorafenib,with positive rechallenge. Case Report. A 63-year-old patientwasdiagnosed with AHCassociated with Child-Pugh Class A alcohol-relatedcirrhosis (prothrombin 61%; bilirubin 13 mg/dL,albumin 2.9 g/dL,no ascitesor encephalopathy).There was no portalthrombosis and the patienthad not used alcohol since 2006. Chronic medical therapy consisted of propranolol 40 mg/day(for esophagealvarices),paroxetine20 mg/day,zopiclone7.5 mg/day, andoxybutynin 5 mg/day. In November 2008,sorafenib 400 mg twicedaily(approved dosing) was introduced.since chemoembolization had not succeeded.There were no complicationsfor 20 days after sorafenib initiation,except blood pressurevalues of 160/90mm Hg. The patientwas admittedto the hospital on day 21 due to confusion and asterixis. Results of an electroencephalogram revealed no lesionand computedtomography scan of the brainshoweddiffusesubcortical atrophy appropriate for age.There was no hemorrhage, infection, or renalinsufficiency. Drug-inducedhepatic encephalopathy was suspected and sorafenibwas discontinued. Within 24 hours,all neurologic symptoms resolved. The patient was discharged5 days later and sorafenib 200 mg twicedaily was reintroduced. Eightdays later,the patientpresented with a new episode of confusionand asterixis,as severe as the first one despite the dose reduction. Sorafenib was stopped,the symptoms resolved within 24 hours, and the patient no longerpresented hepatic encephalopathy. Discussion.The most commonadverseeffectsof sorafenibare liver dysfunction,diarrhea, and hand-footskin reaction.To our knowledge, this is thefirstpublished reportof hepatic encephalopathy induced by sorafenib. Use of the Naranjo probability scale indicates the role of sorafenib in hepaticencephalopathyto be probable.' The delay between sorafenib initiation and onset of neurotoxicity for both consecutive episodes is suggestive.The rapid improvementof symptomsafter sorafenib withdrawal and the positive rechallengestrengthenthe role of this drug in this case. Finally,comprehensive medicalexams and tests ruledout common causesof hepatic encephalopathy. This adverse effectis not clearlyidentified. Hepatic encephalopathy is not reported in the safetydata from pivotal studies in patients with AHC treated with sorafenib.There is only one case mentioned in a Phase I clinical trial evaluating the doxorubicin/sorafenib combination in patients with AHC. 1 However,preliminary results from a French study (unpublished results) reported 2 casesof hepatic encephalopathy in 2 patients with relapsed hepatocellular carcinoma associated with Child-Pugh Class A cirrhosis. 3 In addition, we found 5 cases of hepatic encephalopathy associated with sorafenib reported by medical professionals to an independent drug database," None of these cases is well described, but 3 patients required hospitalizationand 2 patients died. Lastly, a recentstudysuggestst...

Regorafenib-induced hyperammonemic encephalopathy

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“…9 The authors of the case series suspected that sorafenib may have direct neuronal action, which could have triggered the onset of metabolic encephalopathy. 9 Marks et al 10 reported another isolated case of sorafenib-induced encephalopathy in a patient with advanced hepatocellular carcinoma. The encephalopathy resolved when sorafenib was withheld but then recurred when the drug was recommenced.…”

Acute Hyperammonemic Encephalopathy in a Non-Cirrhotic Patient With Hepatocellular Carcinoma Reversed by Arginine Therapy

“…In these case reports and in a third report involving a closely related drug, sorafenib, drug discontinuation leads to resolution of elevated ammonia levels. 6,7 Our patient had HCC without portal hypertension and had intact hepatic synthetic function. The patient's age and lack of prior symptoms made the possibility of a dominant genetic disorder such as OTC deficiency extremely small.…”

Severe hepatic encephalopathy and decrease in enhancement of hepatocellular carcinoma treatedwith sorafenib

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