Case Presentation: A 75-year-old man presents with altered mental status for one day. On exam, patient was nonverbal, opening eyes spontaneously, and responsive to painful stimuli. CT head, chest x-ray, urinalysis, blood cultures, urine cultures, metabolic panel, blood counts, and toxicology screen were all not significant for acute findings.The patient has a history of stage IIa proximal gastric adenocarcinoma (TxN1M0) and currently receiving 5-fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT) chemotherapy. Patient had received 5-fluorouracil the day prior to admission. Two weeks earlier, he had a similar clinical presentation with lactic acidosis (12.4 mmol/L) one day after receiving 5-fluorouracil. CT head, lumbar puncture, metabolic panel, and blood counts were all unremarkable. Toxicology screen was positive for cocaine two weeks ago and encephalopathy was attributed to cocaine toxicity after spontaneously resolving over several hours. During this admission, his labs were notable for hyperammonemia (153 μmol/L) and lactic acidosis (12.1 mmol/L). Patient was given a lactulose enema and he responded well with ammonia decreasing to 15 μmol/L and lactic acid to 1.2 mmol/L with resolution of encephalopathy. No metabolic, infectious, toxic, ischemic, or structural causes explained the encephalopathy and presence of hyperammonemia without liver disease. He was diagnosed with 5-fluorouracil-induced hyperammonemia and discharged with a plan for a 50% dose reduction of 5-fluorouracil for his fourth cycle of chemotherapy.
Discussion: We present a case of 5-fluorouracil hyperammonemic encephalopathy following FLOT chemotherapy. Fluorouracil is a commonly used chemotherapeutic agent for a variety of malignancies including breast, colon and rectal, gastric, and pancreatic cancer. 5-fluorouracil hyperammonemia encephalopathy is a very rare, but an increasingly well-known complication of fluoropyrimidine therapy. Neurotoxicity occurs in an estimated 0.7% of 5-fluorouracil patients and is characterized by an abrupt alteration in mental status[1]. Similar presentations can also occur following cytoreductive therapy or bone marrow transplantation in hematologic malignancies[2]. 5-fluorouracil is thought to result in hyperammonemia via direct inhibition of the Krebs cycle and subsequent inhibition of the urea cycle[3,4]. 5-fluorouracil produces the metabolite fluoroacetate which inhibits citrate use and results in decreased ATP production. This results in inhibition of the ATP-depending carbamoyl phosphate synthetase I (CPS I) in the first step of the urea cycle, resulting in a buildup of ammonium ions. ATP inhibits the ATP-dependent urea cycle[3,4]. Furthermore, the inhibition of ATP production is believed to be the cause of lactic acidosis often seen in 5-fluorouracil toxicity[3].
Conclusions: Workup for altered mental status in a patient receiving 5-fluorourail should include evaluation of ammonia levels. Recommended treatment is immediate discontinuation or reduction of chemotherapy, supportive hydration, and lactulose. Proper identification and diagnosis of 5-fluorouracil hyperammonemia encephalopathy is critical as recovery is rapid with treatment.