A newly published study in the December 23, 2025 issue of the journal Oncoscience has brought to light a rare but serious neurological complication associated with the widely used chemotherapy agent 5-fluorouracil (5-FU). This report, authored by Areti Kalfoutzou and colleagues at the National and Kapodistrian University of Athens, describes a case of hyperammonemic encephalopathy induced by 5-FU, underscoring the critical need for heightened vigilance among clinicians treating cancer patients with this drug. The condition, characterized by elevated ammonia levels in the blood and resultant acute neurocognitive disturbances, poses a diagnostic challenge as it can manifest even when standard liver function tests remain normal.
Hyperammonemic encephalopathy is a rapidly progressive neurotoxic syndrome caused by the accumulation of ammonia in the bloodstream. Ammonia, a byproduct of protein metabolism, is typically cleared efficiently by the liver. However, disruptions in its clearance can lead to elevated systemic concentrations, which readily cross the blood-brain barrier, disrupting neurotransmission and cellular metabolism within the central nervous system. This results in acute symptoms such as confusion, disorientation, lethargy, and potentially coma. While this syndrome is often associated with hepatic failure or inborn metabolic disorders, the case presented identifies 5-FU as a precipitating factor in a patient without evident hepatic impairment.
The patient in question was a 63-year-old woman undergoing chemotherapy for pancreatic cancer. Her treatment regimen included 5-FU in combination with other agents. Following multiple cycles, the patient experienced recurrent episodes of confusion and decreased consciousness. Intriguingly, despite comprehensive laboratory workups revealing normal liver enzyme levels and biochemistry, serum ammonia concentrations were found to be significantly elevated during the symptomatic episodes. This dissociation between liver function and ammonia elevation is particularly noteworthy and suggests a direct or indirect impairment of ammonia metabolism induced by 5-FU.
Mechanistically, 5-FU is a fluorinated pyrimidine analog widely utilized in oncology for gastrointestinal and various solid tumors. Beyond its cytotoxic effects targeting DNA synthesis, 5-FU may disrupt hepatic energy metabolism and enzyme systems critical for ammonia clearance, such as the urea cycle. This interference can impair the detoxification pathways, allowing systemic ammonia accumulation. Moreover, 5-FU metabolites may exert mitochondrial toxicity leading to altered hepatocyte function and further compromise of nitrogen clearance. This case underscores the complexity of 5-FU-induced toxicities, extending beyond classical myelosuppression and mucositis into metabolic and neurologic domains.
The diagnosis of 5-FU-induced hyperammonemic encephalopathy was further supported by employing the Naranjo adverse drug reaction probability scale, a validated tool used to assess the likelihood of drug-related adverse events. The temporal association between each 5-FU administration and the onset of neurological symptoms, followed by resolution after drug withdrawal and supportive therapy, strongly implicated 5-FU as the causative agent. Importantly, other medications, including antiepileptics and irinotecan, which the patient was also receiving and are known to be associated with hyperammonemia, were ruled out based on symptom patterns and response.
Therapeutic intervention focused on prompt discontinuation of 5-FU alongside administration of lactulose and intravenous fluids aimed at reducing systemic ammonia levels and supporting hepatic clearance mechanisms. Lactulose, a non-absorbable disaccharide, acidifies the gut lumen, promoting trapping of ammonia in its ionized form and enhancing fecal nitrogen excretion. This combined approach led to rapid neurological improvement and full resolution of the encephalopathy, confirming the diagnosis and reinforcing the reversibility of this drug-induced toxicity if promptly identified.
This case shines a spotlight on the necessity for oncologists and healthcare professionals to maintain a high index of suspicion for hyperammonemic encephalopathy in patients receiving 5-FU, particularly when new neurological symptoms arise. Routine liver function tests may not sufficiently predict or detect this complication, thus advocating for timely serum ammonia measurements in relevant clinical contexts. Early recognition and treatment are crucial to prevent potentially irreversible neurological damage or fatal outcomes.
Furthermore, these findings raise important considerations regarding the reintroduction of 5-FU in patients who have experienced hyperammonemia. The authors recommend cautious deliberation and consultation with specialists in metabolic disorders or clinical toxicology when considering rechallenge, as recurrence can be life-threatening. Alternative chemotherapeutic regimens or supportive care may be warranted to balance oncologic efficacy with patient safety.
In the broader context of cancer pharmacotherapy, this report expands understanding of 5-FU’s toxicity profile, emphasizing that adverse effects extend beyond conventional cytotoxicity to include metabolic dysfunction and neurotoxicity. It signals a pressing need for further research into the mechanisms by which 5-FU alters ammonia metabolism and for developing predictive biomarkers to identify susceptible individuals. The case also encourages exploration of prophylactic or adjunctive strategies to mitigate hyperammonemia risk during 5-FU treatment.
As cancer treatment protocols continue to evolve towards personalized medicine, the identification and management of rare but severe adverse events like 5-FU-induced hyperammonemic encephalopathy become paramount. Clinicians are urged to adopt a multidisciplinary approach encompassing oncology, neurology, hepatology, and pharmacology to optimize therapeutic outcomes and minimize toxicity. Patient education regarding early symptom reporting and monitoring for subtle neurocognitive changes is equally vital.
In light of this novel report, professional societies and guideline committees may consider incorporating recommendations for ammonia monitoring in specific clinical scenarios involving 5-FU. The clinical community is reminded that vigilance for silent toxicities—those not immediately evident through standard laboratory parameters—is essential to enhance patient safety and treatment success. This case exemplifies how rare adverse reactions can reveal critical insights into drug mechanisms, ultimately guiding improved cancer care.
The contribution by Kalfoutzou et al. opens an important dialogue in oncology and toxicology fields. By disseminating such findings in an open-access platform, the authors facilitate rapid knowledge translation to the global medical community. This transparency and accessibility are crucial in accelerating awareness, research, and clinical adaptation to safeguard patients undergoing chemotherapy worldwide.
Subject of Research: People
Article Title: Silent toxicity: A rare case of 5-fluorouracil-induced hyperammonemic encephalopathy
News Publication Date: December 23, 2025
Web References: http://dx.doi.org/10.18632/oncoscience.638
Image Credits: Copyright © 2025 Kalfoutzou et al. Licensed under CC BY 4.0
Keywords: oncology, hyperammonemia, encephalopathy, fluorouracil, neurotoxicity
