Fluorouracil-induced Hyperammonemia in a Patient with Colorectal Cancer

Case Report

A 40-year-old male with a history of chronic kidney failure, with a stable creatinine baseline of around 1.5 mg/dl, started showing polycythemia on his blood counts with eventual bleeding per the rectum, which led to colonoscopy. Upon results of the colonoscopy, the diagnosis of colonic cancer and staging soon followed. The patient was found to have metastases to the liver, as well as the pelvic bone. A few months following the diagnosis, he underwent colonic resection and was started on adjuvant chemotherapy. The patient was started on FOLFIRI plus Avastin. The standard regimen consists of irinotecan i.v. at 180 mg/m² over 90 min on day 1; leucovorin i.v. at 400 mg/m² over 2 h on day 1; fluorouracil i.v. bolus at 400 mg/m² on day 1 followed by 2,400 mg/m² continuous i.v. infusion over 46 h beginning on day 1; cycle repeated every 14 days until disease progression or unacceptable toxicity and Avastin i.v. at 7.5 mg/kg every 3 weeks.

Following the first two cycles, the patient presented with intractable nausea and vomiting after completion of chemotherapy sessions, but after three to four days of the nausea and vomiting his symptoms usually improved. On the third cycle, he did not experience the same results. The day after the patient underwent his third round of chemotherapy with FOLFIRI and Avastin, he presented to the emergency room (ER) with altered mental status. At home, by mid-afternoon his wife had noticed he was slowly starting to become more obtunded and lethargic than he had been in the morning or after previous chemotherapy, hence prompting his wife to bring him to the ER. In the ER, he was barely responsive, although his eyes were open, but his gaze did not track. He was also retching intermittently. He had vomited yellowish-colored fluid multiple times since the chemotherapy. He also had a small brown semi-liquid bowel movement whilst in the ER. He had not complained of any pain earlier when he had been more alert. He had no shortness of breath, chest pain, fever, rigors or chills. He had not had any such presentation after his previous two chemotherapy sessions, except for the moderate somnolence due to an antiemetic dose of lorazepam (Ativan) after those episodes, but this time he had not taken any Ativan and his mental status was much worse. No seizure-like activity was noted and no falls were reported. Patient himself was unable to provide any history due to his mental state and all history was obtained from his wife and other family members. The patient was not known to have drug allergies and there was no history of smoking, alcohol or illicit drug use.

Upon physical examination, the patient's eyes were open, but did roll upwards. He did have rolling eye movements but without any gaze preference. He spontaneously moved all four extremities and retched intermittently, but apart from that, he did not respond to painful stimuli or any other verbal instructions. The patient was intubated for airway protection.

His most recent vital signs at the time were blood pressure of 130/70 mmHg, oxygenating 99% on room air, respiratory rate of 22, heart rate of 90 bpm and temperature of 98.4°F. His chest was clear to auscitation with slightly increased effort. The patient's heart rate was slightly tachycardic with regular rhythm. The complete blood complete blood count (CBC) showed an elevated white blood cell count of 21,000/μl (normal range: 5,200-12,400/μl) with blood and urine negative for infection. The remainder of the CBC values were within normal limits. Some of his panel results were as follows: sodium 151 mEq/l (normal range: 135-146 mEq/l), potassium was normal, calcium 10.3 mg/dl (8.6-10 mg/dl), blood urea nitrogen 48 mmol/l (normal range: 9-23 mmol/l), creatinine 2.5 mg/dl (normal range: 0.7-1.1 mg/dl). Arterial blood gas levels were abnormal, the pH was 7.08 mol/L, and pCO₂ was 29 mmHg, bicarbonate was less than 10 mmol/, pO₂ was 250 mmHg. Liver function tests were as follows: aspartate aminotransferase 49 IU/I (normal range: 10-49 IU/I); alanine transaminase 82 IU/I (normal range: 0-33 IU/I); alkaline phosphatase 269 IU/I (normal range: 45-129 IU/I). The shocking value was the elevated ammonia level which upon arrival at the ER was 611.1 mmol/l (normal range: 11-35 mmol/l). His lactic acid level was 12.2 mg/dl (normal range: 4.5 to 19.8 mg/dl), phosphorus 10.1 mmol/l (normal range: 2.4-5.1 mmol/l) and uric acid was 14 mmol/l (normal range: 3-7 mmol/l).

The patient was admitted in order to rule out tumor lysis syndrome. Upon patient presentation, physicians were perplexed as to the potential diagnoses. Some of the ideas initially proposed included liver failure, tumor lysis syndrome or even a combination of both.

At presentation, the patient was started on hemodialysis to potentially help with the metabolic acidosis and hyperammonemia. Meanwhile, supportive care was started in the hope that it was an acute process which was somehow precipitated by his chemotherapy. The patient was kept on a ventilator while he battled acute encephalopathy and severe metabolic derangements.

After hydration, the patient's ammonia level was 611.1 mmol/l, dropping to 515 mmol/l within several hours of presentation then to 59.9 mmol/l by the next day. Moreover, the lactic acid level started to drop by the following day. This prompted the addition of lactulose, and after two days, the patient's ammonia level had dropped to 28.4 μmol/l, returning to within the normal range. The patient was alert and oriented at this point, which was 3 days after the 5-FU dose, and was discharged from the hospital on the fourth day.

The patient reported to the oncologist for follow-up and his 5-FU dose was reduced by 50% a week later when he underwent the second cycle and he did not experience hyperammonemia induced by 5-FU again.