Fatal 5-Fluorouracil Toxicity With Hyperammonemic Encephalopathy, Lactic Acidosis, and Pneumatosis Intestinalis Despite Uridine Triacetate Rescue: A Case Report

5-Fluorouracil (5-FU) is among the most widely prescribed chemotherapeutic agents worldwide, yet severe toxicity can produce a life-threatening metabolic syndrome, most commonly associated with dihydropyrimidine dehydrogenase (DPD) deficiency. We report a fatal case of early-onset fluoropyrimidine toxicity characterized by severe metabolic derangements followed by severe myelosuppression. A 56-year-old male patient with stage III (primary tumor (T4), regional lymph nodes (cN2), distant metastasis (cM0), human papillomavirus (HPV)-16-positive) squamous cell carcinoma of the right tonsil developed intractable vomiting within 24 hours of initiating continuous 5-FU infusion as part of a TPF regimen (docetaxel, cisplatin, 5-FU). He presented with severe lactic acidosis (lactate 14.8 mmol/L, rising to >17), hyperammonemia (ammonia 462 µmol/L), high anion gap metabolic acidosis (anion gap 30 mmol/L), and acute kidney injury. DPYD genotyping was ordered on the day of treatment, but the results were not available during hospitalization. The 5-FU infusion was discontinued before the completion of the planned four-day course. The patient was intubated for airway protection and transferred to a tertiary care center, and uridine triacetate was initiated approximately 24 hours after the discontinuation of 5-FU. Over 48 hours, the metabolic derangements improved (lactate 4.2 mmol/L, ammonia <10 µmol/L), though acute kidney injury continued to worsen. Subsequent myelosuppression developed by hospital day 3, with profound cytopenia (absolute neutrophil count (ANC) 0.02 × 10³/µL, platelets 26 × 10³/µL). The patient developed Escherichia coli bacteremia, vasopressor-dependent shock, and CT findings of extensive pneumatosis intestinalis with free intraperitoneal air. Surgical consultation estimated an 80% complication risk and 70% mortality for exploratory laparotomy. The family elected comfort care, and the patient died shortly after. Three weeks later, DPYD testing returned negative for all 12 variants analyzed (activity score 2.0, normal metabolizer). This case documents severe fluoropyrimidine toxicity presenting with hyperammonemic encephalopathy, lactic acidosis, and myelosuppression, findings biologically consistent with fluorocitrate-mediated mitochondrial dysfunction supported by preclinical evidence. Resolution of the initial metabolic crisis should not be interpreted as resolution of overall toxicity, as the myelosuppressive component must be anticipated. DPYD genotyping results should be available prior to the initiation of fluoropyrimidines. Genotyping in this patient returned negative for all tested variants, demonstrating that fatal fluoropyrimidine toxicity can occur in patients classified as normal metabolizers by current testing panels. The predisposing factor underlying this patient's sensitivity to 5-FU remains unexplained.