title: Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors.
abstract: OBJECTIVE
  To report 2 cases of hyperammonemic encephalopathy induced by sunitinib in patients with metastatic gastrointestinal stromal tumor (GIST).
  
  
  METHODS
  A 58-year-old man with imatinib-resistant metastatic GIST presented to the emergency department with confusion that developed 17 days after the initiation of sunitinib 50 mg/day. His serum ammonia level was markedly elevated (210 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. His neurologic status normalized within 24 hours and his serum ammonia level decreased to 64 μg/dL. A 68-year-old woman with imatinib-resistant metastatic GIST was admitted into the emergency department with confusion and irritability that developed 10 days after the start of sunitinib therapy. Her serum ammonia level was markedly elevated (389 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. Within 24 hours, her mental status was improved and her serum ammonia level was decreased to 116 μg/dL. Sunitinib was reintroduced, and the same symptoms occurred after day 7 of administration. Sunitinib was not prescribed afterward and the woman did not experience any further encephalopathic symptoms.
  
  
  CONCLUSIONS
  Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases such as stem cell factor receptor, vascular endothelial growth factor, and platelet-derived growth factor. It is used as second-line therapy for patients with imatinib-resistant GIST. Hyperammonemic encephalopathy is an uncommon fatal complication of chemotherapy. According to the Naranjo probability scale, sunitinib was a probable cause of hyperammonemic encephalopathy in the patients described here. Although the mechanism of hyperammonemia is unclear, hyperammonemic encephalopathy might be caused by a vascular disorder related to the antiangiogenic properties of sunitinib, and it has ethnic differences associated with genetic polymorphisms.
  
  
  CONCLUSIONS
  Sunitinib may induce hyperammonemic encephalopathy in some patients. Although further studies are warranted, clinicians should be aware of this severe adverse event when using sunitinib for treatment of GIST.
authors.affiliation: Division of Hematology/Oncology, Research Institute of Clinical Medicine, Advanced Research Cancer Center, Chonbuk National University, Jeonbuk, South Korea.
authors.forename: Na-Ri
authors.initials: NR
authors.lastname: Lee
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Yhim
authors.forename: Chang-Yeol
authors.initials: CY
authors.lastname: Yim
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Kwak
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Song
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001928:Brain Diseases, Metabolic / Q000209:etiology*; D003221:Confusion / Q000209:etiology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000556:secondary; D006801:Humans; D022124:Hyperammonemia / Q000139:chemically induced* / Q000503:physiopathology / Q000628:therapy; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib