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Oncoscience, Volume 12, 2025
Case Report
Silent toxicity: A rare case of 5-fluorouracil-induced
hyperammonemic encephalopathy
Areti Kalfoutzou
1
, Cleopatra Rapti
2
, Eleftheria Bagiokou
3
, Vasileios Kolintzikis
4
and Vasileios Ramfidis
2
1
Second Propaedeutic Department of Internal Medicine, Attikon General Hospital, National and Kapodistrian University of
Athens, Athens, Greece
2
Department of Medical Oncology, 251 Air Force General Hospital, Athens, Greece
3
Oncology Unit, 3rd Department of Internal Medicine, Athens General Hospital of Thoracic Diseases “Sotiria”, National and
Kapodistrian University of Athens, Athens, Greece
4
Second Department of Medical Oncology, Agios Savvas Cancer Hospital, Athens, Greece
Correspondence to
: Areti Kalfoutzou,
Keywords
: hyperammonemia; encephalopathy; fluorouracil; neurotoxicity
Received
: July 22, 2025
Accepted
: December 12, 2025
Published
: December 23, 2025
Copyright:
© 2025 Kalfoutzou et al. This is an open access article distributed under the terms of the
and source are credited.
ABSTRACT
Hyperammonemic encephalopathy (HE) is a rare but serious neurological
condition characterized by an acute alteration in mental status due to elevated serum
ammonia levels, occurring in the absence of known liver disease. The build-up of
ammonia, a by-product of protein metabolism, in the bloodstream leads to its crossing
of the blood-brain barrier, where it acts as a neurotoxin, causing potentially reversible
brain damage. Chemotherapeutic agents such as 5-fluorouracil (5-FU) are known
to cause drug-induced HE. Our case reports a 63-year-old woman who presented
with several episodes of reduced consciousness shortly after 5-FU administration,
highlighting the necessity of monitoring serum ammonia levels in patients treated
with 5-FU who develop neurological symptoms, and the need for expert consultation
in attempting a 5-FU rechallenge.
INTRODUCTION
Hyperammonemic encephalopathy is characterized
by a sudden alteration in mental status caused by
elevated levels of ammonia, occurring in the absence
of any known liver disease [1]. Most common causes
of HE are metabolic disorders, particularly urea cycle
disorders (UCD) and certain drugs. Hyperammonemic
encephalopathy due to 5-FU is a rare but serious
adverse event, with an incidence of 1% and a reported
mortality rate of 17% [2, 3]. This case describes a
middle-aged female with pancreatic adenocarcinoma
treated with FOLFIRINOX, who experienced multiple
episodes of mental status change shortly after 5-FU
administration. Serum ammonia levels were found
significantly elevated, while the liver function tests
(LFT) and neuroimaging scans were unremarkable. The
patient’s symptoms resolved after permanently stopping
5-FU and administering lactulose and intravenous fluids,
therefore supporting the diagnosis of hyperammonemic
encephalopathy due to 5-FU.
CASE PRESENTATION
A 63-year-old Caucasian female was diagnosed with
pancreatic adenocarcinoma in 2012. Her past medical
history included epileptic seizures, diabetes mellitus and
hypothyroidism. She underwent a Whipple pancreatectomy
along with 6 cycles of adjuvant chemotherapy with
gemcitabine.
Four years later, a follow-up MRI scan of the
abdomen demonstrated a suspicious lesion measuring 25
mm in the pancreatic tail, strongly indicative of disease
recurrence. Computed Tomography (CT) scans of the
brain and chest were insignificant, and the patient was
submitted to a total pancreatectomy and splenectomy,
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and “adjuvant-like” chemotherapy with FOLFIRINOX
(5-Fluouracil, leucovorin, irinotecan and oxaliplatin).
At this point, the patient’s medication list included the
following: levetiracetam, lacosamide, pancrelipase,
glucagon, long-acting insulin and insulin lispro.
Two days after the 4th cycle of chemotherapy, the
patient was admitted due to an acute change in mental
status. The patient’s daughter reported similar episodes of
confusion and somnοlence in the patient, which typically
occurred 3–4 days following each chemotherapy cycle and
resolved spontaneously within a few days. On admission,
the patient was afebrile, with no clinical signs of sepsis
or dehydration. Neurological examination revealed
a lethargic patient who barely responded to verbal
commands (Glasgow Coma Scale – GCS: 11/15). No focal
neurological deficits or signs of meningeal irritation were
observed.
Laboratory examinations demonstrated normocytic
normochromic anemia, along with normal liver function
tests (LFT) (Table 1). Serum ammonia levels were
markedly elevated (120 μg/mL, normal range: 0–32).
Magnetic Resonance Imaging (MRI) scan of the brain and
abdomen with intravenous contrast was unremarkable. An
electroencephalogram (EEG) was negative for signs of
epileptic activity. Lactulose was administered at a dose of
30mL per os daily, leading to a subsequent improvement
in the patient’s mental status and serum ammonia levels
(34 μg/mL) after 2 days. The Naranjo probability score
was 7 (Table 2), classifying our case as a probable adverse
drug reaction. The patient was discharged after 4 days
in excellent clinical condition. Key clinical points are
summarized in Figure 1.
A comprehensive review of the patient’s
medication was conducted, and 5-Fluouracil (5-FU)
was considered the primary cause of hyperammonemic
encephalopathy, as the symptoms emerged shortly after
the initiation of the 46-hour 5-FU infusion pump and
resolved rapidly after its extraction. Notably, irinotecan,
levetiracetam and lacosamide could have contributed to
the patient’s symptoms since they are associated with
hyperammonemia. Applying the Naranjo algorithm
yielded scores of 3 (possible) for irinotecan, 1 (possible)
for levetiracetam, and 1 (possible) for lacosamide,
thereby identifying 5-FU as the most likely cause of HE.
Permanent discontinuation of 5-FU and irinotecan was
decided, and the patient will be closely monitored for
hyperammonia related to levetiracetam or lacosamide. A
detailed molecular analysis is currently being processed to
identify actionable gene alterations for potential treatment
options.
DISCUSSION
Hyperammonemic encephalopathy (HE) is defined
as the sudden onset of neurological manifestations due to
the elevation of serum ammonia, in the absence of known
Table 1: Laboratory examinations of the patient upon admission and discharge
Laboratory examination
Patient values (Day 1)
Patient values (Day 4)
Reference range
White Blood Cells
12.5
8.7
4–10 K/μL
Neutrophils
19.8
6.8
1.5–7 K/μL
Hemoblobin
10.2
9.4
12–16 g/dL
Hematocrit
34
31.2
36–46%
Platelets
435
374
140–440 K/μL
Blood Urea Nitrogen
28
34
15–54 mg/dL
Creatinine
0.6
0.7
0.55–1.2 mg/dL
Glucose
102
112
75–110 mg/dL
ALT
44
31
5–45 IU/L
AST
36
34
10–40 IU/L
γGT
59
55
10–60 IU/L
ALP
112
103
35–116 IU/L
Total bilirubin
1.09
1.07
0–1.3 mg/dL
Direct bilirubin
0.3
0.3
0–0.3 mg/dL
Albumin
3.5
3.3
3.5–5.5 g/dL
Na
138
135
137–150 mEq/L
K
4.1
3.7
3.5–5.3 mEq/L
Serum Ammonia
120
44
11–32 μg/mL
Abbreviations: ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; γ-GT: Gamma-Glutamyl Transferase; ALP:
Alkaline Phosphatase.
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hepatotoxicity [1]. Excess ammonia in the bloodstream
can cross the blood-brain barrier and act as a neurotoxin,
leading to rapid onset of neurological symptoms by
disrupting neurotransmission and causing astrocyte
edema [3]. Physiologically, ammonia is detoxified in the
liver via the urea cycle, while astrocytes convert ammonia
to glutamine via glutamine synthetase [4]. Metabolic
disorders, particularly urea cycle disorders, and certain
drugs are among the most common causes of excess
ammonia in the body [5].
Drug-induced hyperammonemic encephalopathy
(HE) has been linked to several medications, including
anticonvulsants like valproic acid, levetiracetam, and
lacosamide, as well as chemotherapeutic agents including
5-fluorouracil, capecitabine, gemcitabine, irinotecan,
and tyrosine kinase inhibitors such as sunitinib, imatinib,
sorafenib, and regorafenib [1, 2, 6, 7]. 5-fluouracil,
in particular, yields catabolites (fluoro-β-alanine,
monofluoroacetate) that depress tricarboxylic acid
(TCA) cycle flux, reduce adenosine triphosphate (ATP),
and secondarily impair the urea cycle, predisposing to
hyperammonemia [8]. A study published by Balcerac in
2022 demonstrated that, among 2924 reported cases of
drug-induced hyperammonemia from 1967 to 2020, 5-FU
was the second most common agent, accounting for 301
cases globally [2].
Additionally, it has been hypothesised that
chemotherapy-induced diarrhea caused has a protective
effect against the risk of hyperammonemic encephalopathy
by promoting to the rapid excretion of ammonia [9].
Furthermore, gene alterations that affect the metabolism
of 5-FU, such as dihydropyrimidine dehydrogenase (DPD)
deficiency and TYMS gene polymorphisms, are suspected
to play a role in HE-pathogenesis caused by 5-FU [4].
Pre-existing liver disease, dehydration, sepsis, cachexia,
renal failure, chronic constipation and several drug-drug
interactions are known patient-related risk factors for
5-FU induced HE [9–11].
Table 2: Naranjo causality assessment for 5-fluorouracil (5-FU) [16]
Question
Score
1. Are there previous conclusive reports on this reaction?
Yes (+1)
2. Did the adverse event appear after the suspected drug was administered?
Yes (+2)
3. Did the adverse event improve when the drug was discontinued or a specific antagonist was administered?
Yes (+1)
4. Did the adverse event reappear when the drug was readministered?
Yes (+2)
5. Are there alternative causes that could on their own have caused the reaction?
Yes (−1)
6. Did the reaction reappear when a placebo was given?
Unknown (0)
7. Was the drug detected in blood or other fluids in concentrations known to be toxic?
Unknown (0)
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? Unknown (0)
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
Yes (+1)
10. Was the adverse event confirmed by any objective evidence?
Yes (+1)
Figure 1: Timeline of key clinical events and management.
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Clinical presentation of 5-FU induced HE includes
a wide range of symptoms such as loss of appetite,
nausea/vomiting, confusion, seizures, or psychiatric
disorders [12]. Subtle manifestations including
agitation, loss of concentration, or urinary incontinence
may occur [13]. The symptoms usually emerge 2 days
after the drug initiation and resolve within 2–10 days,
whereas few patients experience long-term neurologic
sequelae [12].
Agents known to reduce ammonia reabsorption,
such as lactulose, antibiotics that lower the ammonia-
producing bacteria in the intestinal flora, particularly
rifaximin, along with dietary protein restriction and
intravenous fluids, are indicated for the treatment
of hyperammonemic encephalopathy [5, 6, 14].
Intravascular volume expansion improves renal
perfusion, GFR, urine flow, and distal sodium delivery,
thereby enhancing ammonium trapping and excretion
[15]. Branched amino acids may also be indicated,
while hemodialysis is reserved for more severe cases
[9]. Additionally, uridine triacetate has been proposed
as an antidote to severe 5-FU toxicity; however, it has
not been explored as a treatment option for HE [12].
Recent literature, including the 2023 case report and
review by Kurniawan et al., similarly emphasizes prompt
recognition, discontinuation of 5-FU, supportive care,
and careful consideration of rechallenge in selected
cases, but only with close collaboration with an expert in
metabolic diseases [12].
In our case, the clinical presentation in the absence
of known liver disease or acute hepatotoxicity, as indicated
by the normal laboratory and imaging tests, as well as the
elevated serum ammonia levels, raised the suspicion of
drug-induced hyperammonemic encephalopathy. The
patient’s symptoms emerged soon after the initiation and
resolved rapidly after discontinuing the 5-FU infusion.
The recurrence of symptoms with each chemotherapy
cycle, along with the lack of an alternative explanation,
further supported our presumed diagnosis. Interestingly, in
a study by Boilève et al. including 30 patients with 5-FU
induced HE, serum ammonia levels were measured in
50% of patients, despite the lack of an alternate differential
diagnosis [12]. This highlights the need for routinely
measuring serum ammonia in any patient treated with
5-FU presenting with acute neurological manifestations
[12].
CONCLUSIONS
Hyperammonemia caused by chemotherapeutic
or targeted agents, while rare, is a recognized adverse
event in cancer patients and should be considered in
any patient with neurological symptoms following 5-FU
administration. Clinicians should be particularly aware of
this potentially fatal adverse event, remain vigilant when
administering chemotherapeutic agents such as 5-FU and
capecitabine, and be prepared to discontinue therapy if
clinically indicated.
AUTHOR CONTRIBUTIONS
A.K. contributed to the conception, design, and
drafting of the manuscript. C.R. participated in the clinical
data collection and literature review. V.K. was involved in
patient management and critical manuscript revision. E.B.
assisted in data interpretation and manuscript editing. V.R.
supervised the case report and provided final approval of
the version to be published.
CONFLICTS OF INTEREST
Authors have no conflicts of interest to declare.
ETHICAL STATEMENT
This case report was conducted in accordance with
institutional ethical standards. Approval was obtained
from the Institutional Review Board (IRB) on 2025-07-10
under approval number 254/10-07-2025. Written informed
consent was obtained from the patient for publication of
all relevant clinical details and images.
CONSENT
Written informed consent for publication was
obtained from the patient prior to the submission of this
case report.
FUNDING
The authors declare that they received no financial
support for the research, authorship, and/or publication of
this article.
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