Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine

To report the occurrence of fatal acute liver failure following addition of levothyroxine to a regimen of sunitinib and acetaminophen.

A 57-year-old woman who started sunitinib treatment for relapsed metastatic gastrointestinal stromal tumor after imatinib failure had disease stabilization and normal liver function through 8 cycles of sunitinib 50 mg/day for 4 weeks, followed by 2 weeks off treatment. Her continuing medications included acetaminophen approximately 4.5 g/wk, as well as standard medications for asthma. In cycle 8, she received oral levothyroxine 50-150 microg/day for approximately 30 days to control hypothyroidism before beginning cycle 9 of sunitinib. On day 4 of cycle 9, she was hospitalized with progressively rising circulating liver enzyme levels. She died 4 days postadmission despite discontinuation of sunitinib and initiation of intensive supportive treatment. At autopsy, her liver showed severe centrilobular necrosis with moderate-to-severe steatosis and minimal parenchymal invasion by the neoplasm. Viral stains were negative.

Hepatic failure has been reported rarely in patients receiving sunitinib. Autopsy results excluded neoplastic disease progression and viral infection in the etiology of the event, and the patient may have died of the combined interaction of sunitinib, acetaminophen, and levothyroxine. Although sunitinib was not more than a possible hepatotoxin (Roussel Uclaf Causality Assessment Method) and may even have been hepatoprotective over a 48-week period against chronic intake of acetaminophen (probable hepatotoxin) by producing regional hypothyroidism within the liver, it is hypothesized that correction of the putative hepatic hypothyroidism with oral levothyroxine (possible hepatotoxin) and reinitiation of sunitinib treatment may have triggered hepatic necrosis.

Acetaminophen should be used with particular caution in patients receiving sunitinib. In sunitinib-treated patients who also require levothyroxine therapy, increased caution in restarting subsequent sunitinib treatment and discontinuation of acetaminophen, if possible, is advisable. Further evaluation of this potential interaction is warranted.