5-Fluorouracil Poisoning

Complex MONDO:0016312 Pathograph 18 Show in embeddings browser Drug Toxicity Poisoning

5-Fluorouracil poisoning is the systemic toxicity syndrome produced by excess exposure to the antimetabolite chemotherapeutic 5-fluorouracil (5-FU) or its oral prodrug capecitabine. Excess exposure arises in two broad settings: accidental overdose (most often an infusion-pump programming error delivering a multi-day dose in hours) and, at standard doses, deficient activity of dihydropyrimidine dehydrogenase (DPD, encoded by DPYD), the rate-limiting catabolic enzyme that clears the great majority of administered drug. 5-FU is a uracil analogue that is anabolically activated to cytotoxic nucleotides. FdUMP forms a stable ternary complex with thymidylate synthase and the folate cofactor, arresting de novo thymidylate synthesis and causing "thymineless" DNA damage; fluoronucleotides are also misincorporated into DNA and into RNA. The tissues with the highest proliferative turnover fail first, producing mucositis, diarrhoea and myelosuppression, while non-proliferative toxicities - cardiotoxicity (most often myocardial ischaemia), a cerebellar/encephalopathic neurotoxicity, and hyperammonaemia - are attributed to the drug and its catabolites. A specific antidote, uridine triacetate, floods the pathway with uridine and markedly improves survival when given within about 96 hours of overexposure. Pre-treatment DPYD genotyping and phenotyping identify patients at risk and are the principal preventive measure. No GeneReviews or StatPearls chapter indexes this entity; it is curated from pharmacogenetic guidelines, clinical reviews and case reports.

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8
Pathophys.
8
Phenotypes
18
Pathograph
2
Genes
3
Medical Actions
2
Differentials
1
Models
1
Deep Research
⚙

Pathophysiology

8
Systemic 5-Fluorouracil Overexposure
Excess circulating 5-FU accumulates either from an absolute overdose (classically an ambulatory-infusion-pump error compressing a multi-day dose into hours) or from a standard dose in a patient whose catabolic clearance is impaired. 5-FU and its oral prodrug capecitabine both converge on the same circulating active drug.
Downstream
Anabolic Activation to Cytotoxic Nucleotides
Myocardial Toxicity The administered drug and its fluorinated catabolites drive the cardiac arm of the non-proliferative toxicity.
Central Neurotoxicity The administered drug and its fluorinated catabolites drive the neurologic arm of the non-proliferative toxicity.
Deficient DPD-Mediated Catabolism
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of pyrimidine catabolism and clears the large majority of administered 5-FU to inactive dihydrofluorouracil. Partial or complete DPD deficiency, usually from DPYD variants, markedly raises and prolongs 5-FU exposure so that a standard dose behaves as an overdose and shunts more drug into the anabolic pathway.
Downstream
Systemic 5-Fluorouracil Overexposure Reduced DPD activity is one of the two routes to overexposure, raising and prolonging circulating 5-FU for a given dose.
Show evidence (2 references)
PMID:29152729 SUPPORT REVIEW SYNTHESIS Other
"DPYD, the gene encoding dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme for fluoropyrimidine catabolism"
Establishes DPD as the rate-limiting catabolic enzyme for fluoropyrimidines, the node's central claim.
PMID:33283204 SUPPORT REVIEW SYNTHESIS Other
"DPYD gene encodes DPD, the rate-limiting enzyme responsible for catabolism of 5-FU and is responsible for >85% of 5-FU elimination."
Quantifies the catabolic share DPD carries, so its deficiency produces the overexposure this node describes.
Anabolic Activation to Cytotoxic Nucleotides
5-FU is converted through phosphoribosylation and kinase steps to cytotoxic fluoronucleotides, principally FdUMP (which inhibits thymidylate synthase) and the fluoro-ribonucleotide FUTP (which is misincorporated into RNA). These metabolites mediate the drug's cytotoxicity and, in overexposure, its toxicity.
Downstream
Thymidylate Synthase Inhibition
RNA Misincorporation
Thymidylate Synthase Inhibition
FdUMP forms a stable ternary complex with thymidylate synthase and the folate cofactor 5,10-methylenetetrahydrofolate, blocking de novo synthesis of dTMP. The resulting dTTP depletion and nucleotide-pool imbalance drive uracil misincorporation, futile excision-repair cycling and DNA strand breaks ("thymineless death"). Thymidylate synthase is the sole de novo source of thymidylate and the principal target of 5-FU.
Downstream
Proliferating-Tissue Cytotoxicity
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Other
"TYMS catalyzes methylation of dUMP to dTMP. As the sole de novo source of thymidylate in the cell it is an important target for 5-flurouracil (5-FU) and capecitabine (CAP)."
Identifies thymidylate synthase as the de novo thymidylate source and the 5-FU target, the basis of this node.
RNA Misincorporation
FUTP is incorporated into cellular RNA in place of UTP, disrupting RNA processing and function. This RNA-directed toxicity is largely independent of the thymidylate pathway; that uridine triacetate, which delivers competing uridine, rescues toxicity is clinical evidence for an RNA-directed component, though the point is inferred from the antidote's effect rather than shown directly here.
Downstream
Proliferating-Tissue Cytotoxicity
Proliferating-Tissue Cytotoxicity
Tissues with the highest proliferative turnover - gastrointestinal mucosa and bone marrow - sustain the earliest and most severe injury, producing mucositis/stomatitis, diarrhoea and myelosuppression.
Downstream
Oral mucositis
Diarrhea
Bone marrow suppression
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rare toxicities, such as hepatitis, encephalopathy and acute cardiac ischemia following first or second dose of 5-FU"
Lists the proliferative-tissue toxicities (diarrhoea, mucositis/stomatitis, myelosuppression) that define this node.
Myocardial Toxicity
5-FU and its fluorinated catabolites injure the myocardium, producing myocardial ischaemia through proposed mechanisms including coronary artery spasm, endothelial injury with thrombosis, and oxidative energetic failure of cardiomyocytes. No single mechanism is established.
Experimental models
H9c2 rat cardiocyte 5-FU apoptosis assay CELL LINE Reproduces a candidate cellular mechanism (oxidative-stress-driven apoptosis) of 5-FU cardiotoxicity in a rodent cardiomyocyte line.
Downstream
Myocardial ischemia
Show evidence (1 reference)
PMID:25186061 SUPPORT REVIEW SYNTHESIS Human Clinical
"the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in..."
A systematic review of the candidate mechanisms of 5-FU cardiotoxicity this node summarizes.
Central Neurotoxicity
5-FU produces a central neurotoxicity that includes a cerebellar syndrome and a hyperammonaemic encephalopathy occurring without hepatic failure. The hyperammonaemia is incompletely understood; a proposed route is catabolite (fluoroacetate/fluorocitrate) inhibition of the Krebs cycle driving ammonia accumulation.
Downstream
Hyperammonemia
Hyperammonemic encephalopathy
Cerebellar ataxia
Show evidence (2 references)
PMID:32082663 SUPPORT Human Clinical
"Hyperammonemia is associated with fluorouracil though the mechanism is unclear."
Supports the hyperammonaemic arm and that its mechanism is not settled.
PMID:32082663 SUPPORT Human Clinical
"Another possible etiology is inhibition of the Krebs cycle by fluoroacetate or fluorocitrate, metabolites of 5-FU, leading to excess urea and the subsequent accumulation of ammonia"
Gives the postulated catabolite mechanism (Krebs-cycle inhibition) for the ammonia accumulation in this node.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 5-Fluorouracil Poisoning Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Blood 1
Bone marrow suppression Abnormality of multiple cell lineages in the bone marrow HP:0012145 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelosuppression, annotated with Abnormality of multiple cell lineages in the bone marrow (HP:0012145). HP:0012145 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression"
Myelosuppression is a core manifestation of fluoropyrimidine toxicity.
Cardiovascular 2
Palmar-plantar erythrodysesthesia Palmoplantar erythema HP:0025493 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palmoplantar erythrodysesthesia, annotated with Palmoplantar erythema (HP:0025493). HP:0025493 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36160401 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most patients experience adverse effects from these drugs, including fatigue, oral mucositis, abdominal pain, diarrhea, myelosuppression, palmoplantar erythrodysesthesia and rarely central nervous system toxicity or cardiomyopathy."
Lists palmoplantar erythrodysesthesia among fluoropyrimidine adverse effects.
Myocardial ischemia Angina pectoris HP:0001681 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial ischemia, annotated with Angina pectoris (HP:0001681). HP:0001681 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25186061 SUPPORT REVIEW SYNTHESIS Human Clinical
"A severe side effect to 5-FU and capecitabine-based treatment is cardiotoxicity, which often presents as myocardial ischemia, but to a lesser extent cardiac arrhythmias, hyper- and hypotension, left ventricular dysfunction, cardiac arrest and sudden death"
Myocardial ischaemia (anginal presentation) is the dominant cardiotoxic phenotype; the term captures the ischaemic chest-pain presentation.
Digestive 1
Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014). HP:0002014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression"
Diarrhoea is a core manifestation of fluoropyrimidine toxicity.
Head and Neck 1
Oral mucositis Stomatitis HP:0010280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral mucositis, annotated with Stomatitis (HP:0010280). HP:0010280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression"
Mucositis/stomatitis is a core manifestation of fluoropyrimidine toxicity.
Metabolism 1
Hyperammonemia HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987). HP:0001987 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32082663 SUPPORT Human Clinical
"found to have hyperammonemia (84 mcmol/L), without hepatic failure"
Documents the hyperammonaemia (without hepatic failure) that defines this node.
Nervous System 2
Hyperammonemic encephalopathy HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Encephalopathy (HP:0001298). HP:0001298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32082663 SUPPORT Human Clinical
"she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure"
Documents 5-FU-associated hyperammonaemic encephalopathy without hepatic failure.
Cerebellar ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar ataxia, annotated with Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36160401 SUPPORT Human Clinical
"He had rapidly worsening encephalopathy and ataxia."
Documents ataxia as part of severe 5-FU central neurotoxicity.
🧬

Genetic Associations

2
DPYD
Gene: DPYD hgnc:3012 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DPYD (hgnc:3012). hgnc:3012 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR
Show evidence (2 references)
PMID:29152729 SUPPORT REVIEW SYNTHESIS Other
"four decreased function DPYD variants are of primary relevance due to their population frequency and established impact on enzyme function and toxicity risk"
CPIC names the clinically actionable decreased-function DPYD variants.
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"DPYD mutations are found in 50% of severe 5-FU toxicity cases"
Quantifies the share of severe toxicity attributable to DPYD variation.
TYMS
Gene: TYMS hgnc:12441 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TYMS (hgnc:12441). hgnc:12441 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"polymorphisms in 5 and 3 untranslated regions (5UTR and 3UTR) of TYMS gene have been described previously and these are suggested to be both predictive to toxicity and prognostic to efficacy with fluoropyrimidines"
Supports TYMS variation as a reported modifier of fluoropyrimidine toxicity.
💊

Medical Actions

3
Uridine triacetate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: uridine triacetate CHEBI:90914 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses uridine triacetate (CHEBI:90914). CHEBI:90914 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Specific antidote for 5-FU/capecitabine overdose or early-onset severe toxicity, approved for use within 96 hours of the last fluoropyrimidine dose; it delivers uridine that competes with the toxic fluoronucleotides. In pooled analysis survival was approximately 96% versus 16% in a historical cohort.
Show evidence (2 references)
PMID:36160401 SUPPORT REVIEW SYNTHESIS Human Clinical
"Uridine triacetate (UTA) is an emergency treatment for overdoses and early onset, severe or life-threatening toxicities from fluoropyrimidines. It is approved for use in adults and children within 96 h of last fluoropyrimidine administration."
States the indication and 96-hour window for the antidote.
PMID:36160401 SUPPORT REVIEW SYNTHESIS Human Clinical
"The use of the drug resulted in approximately 96% survival (compared to 16% survival in a historic cohort), and about half the patients resumed their chemotherapy regimens within 3 weeks of overexposure."
Quantifies the survival benefit of timely uridine triacetate.
DPYD genotype-guided dosing
Action: genetic testingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic testing (NCIT:C15709). NCIT:C15709 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Testing NCIT:C15709
Pre-treatment DPYD genotyping/phenotyping to identify deficient metabolisers and reduce or avoid fluoropyrimidine dosing - the principal preventive measure.
Mechanism Target:
Deficient DPD-Mediated Catabolism — Identifies reduced-function DPYD carriers before exposure so dose can be lowered or the drug avoided, pre-empting the overexposure step.
Show evidence (1 reference)
PMID:29152729 SUPPORT REVIEW SYNTHESIS Other
"the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine)"
CPIC's stated purpose - using DPYD genotype to guide fluoropyrimidine dosing.
Supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Management of febrile neutropenia, fluid/electrolyte support for diarrhoea, and cardiac monitoring with drug cessation for cardiotoxicity.
🌍

Environmental Factors

1
Therapeutic fluoropyrimidine administration
exposure to 5-fluorouracil ECTO:9000261 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to 5-fluorouracil (ECTO:9000261). ECTO:9000261 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
The exposure is iatrogenic: 5-FU, or capecitabine (its oral prodrug), is given as cancer chemotherapy to large numbers of patients. Poisoning follows when that administration is excessive (an overdose or infusion-pump error) or when a standard dose is not cleared because of DPD deficiency.
Show evidence (1 reference)
PMID:36160401 SUPPORT REVIEW SYNTHESIS Human Clinical
"5-Fluorouracil (5FU) or capecitabine, a prodrug enzymatically converted to 5-FU, is prescribed to thousands of patients with gastrointestinal, breast, and other cancers in the United States (US) (Ison et al., 2016)."
Establishes the iatrogenic chemotherapeutic exposure that underlies this entry.
Mechanism Target:
TRIGGERS Systemic 5-Fluorouracil Overexposure — Administered fluoropyrimidine is the source of the circulating drug that, in overdose or with deficient clearance, becomes the systemic overexposure that drives toxicity.
Show evidence (1 reference)
PMID:36160401 SUPPORT REVIEW SYNTHESIS Human Clinical
"Uridine triacetate (UTA) is an emergency treatment for overdoses and early onset, severe or life-threatening toxicities from fluoropyrimidines."
Names overdose and severe toxicity from administered fluoropyrimidines as the overexposure state this exposure triggers.
🔬

Diagnosis

2
Clinical recognition from chemotherapy exposure and toxidrome
Diagnosis rests on a recent fluoropyrimidine exposure together with a characteristic toxicity pattern - severe mucositis, diarrhoea and myelosuppression, and sometimes cardiac or neurologic involvement. An overdose or infusion-pump error may be evident from the administration record.
Show evidence (1 reference)
PMID:33283204 SUPPORT REVIEW SYNTHESIS Human Clinical
"manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rare toxicities, such as hepatitis, encephalopathy and acute cardiac ischemia following first or second dose of 5-FU"
The toxidrome that, with an exposure history, establishes the clinical diagnosis.
Serum ammonia and lactate in acute neurotoxicity
When a patient on 5-FU develops acute encephalopathy, serum ammonia (with lactate) identifies 5-FU hyperammonaemic encephalopathy, which occurs without hepatic failure, and separates it from other causes of altered mental status.
Serum ammonia LOINC:1841-6 Logical Observation Identifiers Names and Codes (LOINC) Lactate LOINC:2524-7 Logical Observation Identifiers Names and Codes (LOINC)
LOINC:1841-6 is bound specifically to Serum rather than Plasma: LOINC has no combined Serum-or-Plasma ammonia code (ammonia assays are frequently specimen-sensitive, which may be why), and this row's own name specifies serum ammonia. Lactate is bound to the method-less Serum-or-Plasma code.
Show evidence (1 reference)
PMID:32082663 SUPPORT Human Clinical
"found to have hyperammonemia (84 mcmol/L), without hepatic failure"
Supports measuring ammonia to identify 5-FU hyperammonaemic encephalopathy without hepatic failure.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from 5-Fluorouracil Poisoning:

Hyperammonaemic encephalopathy from other causes
Overlapping Features Hepatic failure and inherited urea-cycle or hyperammonaemia disorders also cause hyperammonaemic encephalopathy and overlap with the neurologic presentation of 5-FU toxicity.
Distinguishing Features
  • 5-FU hyperammonaemic encephalopathy occurs without hepatic failure and resolves on stopping the drug.
  • Onset within days of a fluoropyrimidine dose points to drug toxicity rather than a chronic metabolic cause.
Show evidence (1 reference)
PMID:32082663 SUPPORT Human Clinical
"found to have hyperammonemia (84 mcmol/L), without hepatic failure"
The absence of hepatic failure distinguishes 5-FU encephalopathy from hepatic causes.
Acute coronary syndrome Not Yet Curated MONDO:0005542
Overlapping Features 5-FU cardiotoxicity most often presents as myocardial ischaemia and can mimic a primary acute coronary syndrome.
Distinguishing Features
  • 5-FU cardiotoxicity is temporally linked to the infusion and is typically vasospastic, often resolving on drug cessation, rather than fixed obstructive coronary disease.
Show evidence (1 reference)
PMID:25186061 SUPPORT REVIEW SYNTHESIS Human Clinical
"A severe side effect to 5-FU and capecitabine-based treatment is cardiotoxicity, which often presents as myocardial ischemia, but to a lesser extent cardiac arrhythmias, hyper- and hypotension, left ventricular dysfunction, cardiac arrest and sudden death"
Establishes that 5-FU cardiotoxicity presents as myocardial ischaemia, the overlap with acute coronary syndrome.
🧫

Experimental Models

1
H9c2 rat cardiocyte 5-FU apoptosis assay CELL_LINE
Cultured H9c2 rat cardiocytes exposed to 5-FU, used to probe the oxidative, apoptotic mechanism of 5-FU cardiotoxicity.
Pathograph links
Myocardial Toxicity partially recapitulates fidelity: low observes: cellular Reproduces a candidate cellular mechanism (oxidative-stress-driven apoptosis) of 5-FU cardiotoxicity in a rodent cardiomyocyte line.
Limitations: A rat-derived immortalized cell line at supratherapeutic concentrations cannot reproduce the coronary-spasm and endothelial components of the tissue-scale Myocardial Toxicity node, so it models only the cellular oxidative-injury arm one step below that node.
Show evidence (1 reference)
PMID:22812382 SUPPORT In Vitro
"The apoptosis induced by 5-FU and LF in cardiocytes was paralleled by the activation of caspases 3, 9 and 7 and by the intracellular increase of O(2-) levels."
Shows 5-FU drives caspase-mediated apoptosis with increased superoxide in cardiocytes, the oxidative arm of the cardiotoxicity node.
{ }

Source YAML

click to show 
name: 5-Fluorouracil Poisoning
creation_date: "2026-10-05T00:00:00Z"
category: Complex
categories:
- Treatment Toxicity
- Toxic Exposure Disorder
parents:
- Drug Toxicity
- Poisoning
synonyms:
- 5-FU poisoning
- 5-FU toxicity
- fluorouracil toxicity
- fluoropyrimidine toxicity
- 5-fluorouracil overdose
- capecitabine toxicity
description: >-
  5-Fluorouracil poisoning is the systemic toxicity syndrome produced by excess
  exposure to the antimetabolite chemotherapeutic 5-fluorouracil (5-FU) or its
  oral prodrug capecitabine. Excess exposure arises in two broad settings:
  accidental overdose (most often an infusion-pump programming error delivering a
  multi-day dose in hours) and, at standard doses, deficient activity of
  dihydropyrimidine dehydrogenase (DPD, encoded by DPYD), the rate-limiting
  catabolic enzyme that clears the great majority of administered drug. 5-FU is a
  uracil analogue that is anabolically activated to cytotoxic nucleotides. FdUMP
  forms a stable ternary complex with thymidylate synthase and the folate
  cofactor, arresting de novo thymidylate synthesis and causing "thymineless"
  DNA damage; fluoronucleotides are also misincorporated into DNA and into RNA.
  The tissues with the highest proliferative turnover fail first, producing
  mucositis, diarrhoea and myelosuppression, while non-proliferative toxicities -
  cardiotoxicity (most often myocardial ischaemia), a cerebellar/encephalopathic
  neurotoxicity, and hyperammonaemia - are attributed to the drug and its
  catabolites. A specific antidote, uridine triacetate, floods the pathway with
  uridine and markedly improves survival when given within about 96 hours of
  overexposure. Pre-treatment DPYD genotyping and phenotyping identify patients at
  risk and are the principal preventive measure. No GeneReviews or StatPearls
  chapter indexes this entity; it is curated from pharmacogenetic guidelines,
  clinical reviews and case reports.
disease_term:
  preferred_term: 5-fluorouracil poisoning
  term:
    id: MONDO:0016312
    label: 5-fluorouracil poisoning
pathophysiology:
- name: Systemic 5-Fluorouracil Overexposure
  description: >-
    Excess circulating 5-FU accumulates either from an absolute overdose
    (classically an ambulatory-infusion-pump error compressing a multi-day dose
    into hours) or from a standard dose in a patient whose catabolic clearance is
    impaired. 5-FU and its oral prodrug capecitabine both converge on the same
    circulating active drug.
  biological_scale: ORGANISM
  downstream:
  - target: Anabolic Activation to Cytotoxic Nucleotides
    causal_link_type: DIRECT
  - target: Myocardial Toxicity
    causal_link_type: DIRECT
    description: >-
      The administered drug and its fluorinated catabolites drive the cardiac arm
      of the non-proliferative toxicity.
  - target: Central Neurotoxicity
    causal_link_type: DIRECT
    description: >-
      The administered drug and its fluorinated catabolites drive the neurologic
      arm of the non-proliferative toxicity.
- name: Deficient DPD-Mediated Catabolism
  description: >-
    Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme
    of pyrimidine catabolism and clears the large majority of administered 5-FU to
    inactive dihydrofluorouracil. Partial or complete DPD deficiency, usually from
    DPYD variants, markedly raises and prolongs 5-FU exposure so that a standard
    dose behaves as an overdose and shunts more drug into the anabolic pathway.
  biological_scale: MOLECULAR
  downstream:
  - target: Systemic 5-Fluorouracil Overexposure
    causal_link_type: DIRECT
    description: >-
      Reduced DPD activity is one of the two routes to overexposure, raising and
      prolonging circulating 5-FU for a given dose.
    evidence:
    - reference: PMID:36160401
      reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Dihydropyridine deaminase (DYPD) deficiency due to genetic variations predispose patients to the toxic effects of 5-FU and capecitabine by reducing deactivation which increases blood levels of the drug."
      explanation: >-
        States the causal step from impaired DPD-mediated deactivation to raised
        circulating drug levels.
  evidence:
  - reference: PMID:29152729
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "DPYD, the gene encoding dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme for fluoropyrimidine catabolism"
    explanation: >-
      Establishes DPD as the rate-limiting catabolic enzyme for fluoropyrimidines,
      the node's central claim.
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "DPYD gene encodes DPD, the rate-limiting enzyme responsible for catabolism of 5-FU and is responsible for >85% of 5-FU elimination."
    explanation: >-
      Quantifies the catabolic share DPD carries, so its deficiency produces the
      overexposure this node describes.
- name: Anabolic Activation to Cytotoxic Nucleotides
  description: >-
    5-FU is converted through phosphoribosylation and kinase steps to cytotoxic
    fluoronucleotides, principally FdUMP (which inhibits thymidylate synthase) and
    the fluoro-ribonucleotide FUTP (which is misincorporated into RNA). These
    metabolites mediate the drug's cytotoxicity and, in overexposure, its
    toxicity.
  biological_scale: MOLECULAR
  downstream:
  - target: Thymidylate Synthase Inhibition
    causal_link_type: DIRECT
  - target: RNA Misincorporation
    causal_link_type: DIRECT
- name: Thymidylate Synthase Inhibition
  description: >-
    FdUMP forms a stable ternary complex with thymidylate synthase and the folate
    cofactor 5,10-methylenetetrahydrofolate, blocking de novo synthesis of dTMP.
    The resulting dTTP depletion and nucleotide-pool imbalance drive uracil
    misincorporation, futile excision-repair cycling and DNA strand breaks
    ("thymineless death"). Thymidylate synthase is the sole de novo source of
    thymidylate and the principal target of 5-FU.
  biological_scale: MOLECULAR
  downstream:
  - target: Proliferating-Tissue Cytotoxicity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "TYMS catalyzes methylation of dUMP to dTMP. As the sole de novo source of thymidylate in the cell it is an important target for 5-flurouracil (5-FU) and capecitabine (CAP)."
    explanation: >-
      Identifies thymidylate synthase as the de novo thymidylate source and the
      5-FU target, the basis of this node.
- name: RNA Misincorporation
  description: >-
    FUTP is incorporated into cellular RNA in place of UTP, disrupting RNA
    processing and function. This RNA-directed toxicity is largely independent of
    the thymidylate pathway; that uridine triacetate, which delivers competing
    uridine, rescues toxicity is clinical evidence for an RNA-directed component,
    though the point is inferred from the antidote's effect rather than shown
    directly here.
  biological_scale: MOLECULAR
  downstream:
  - target: Proliferating-Tissue Cytotoxicity
    causal_link_type: DIRECT
- name: Proliferating-Tissue Cytotoxicity
  description: >-
    Tissues with the highest proliferative turnover - gastrointestinal mucosa and
    bone marrow - sustain the earliest and most severe injury, producing
    mucositis/stomatitis, diarrhoea and myelosuppression.
  biological_scale: TISSUE
  downstream:
  - target: Oral mucositis
  - target: Diarrhea
  - target: Bone marrow suppression
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rare toxicities, such as hepatitis, encephalopathy and acute cardiac ischemia following first or second dose of 5-FU"
    explanation: >-
      Lists the proliferative-tissue toxicities (diarrhoea, mucositis/stomatitis,
      myelosuppression) that define this node.
- name: Myocardial Toxicity
  description: >-
    5-FU and its fluorinated catabolites injure the myocardium, producing
    myocardial ischaemia through proposed mechanisms including coronary artery
    spasm, endothelial injury with thrombosis, and oxidative energetic failure of
    cardiomyocytes. No single mechanism is established.
  biological_scale: TISSUE
  downstream:
  - target: Myocardial ischemia
  evidence:
  - reference: PMID:25186061
    reference_title: "A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia."
    explanation: >-
      A systematic review of the candidate mechanisms of 5-FU cardiotoxicity this
      node summarizes.
- name: Central Neurotoxicity
  description: >-
    5-FU produces a central neurotoxicity that includes a cerebellar syndrome and
    a hyperammonaemic encephalopathy occurring without hepatic failure. The
    hyperammonaemia is incompletely understood; a proposed route is catabolite
    (fluoroacetate/fluorocitrate) inhibition of the Krebs cycle driving ammonia
    accumulation.
  biological_scale: ORGANISM
  downstream:
  - target: Hyperammonemia
  - target: Hyperammonemic encephalopathy
  - target: Cerebellar ataxia
  evidence:
  - reference: PMID:32082663
    reference_title: "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperammonemia is associated with fluorouracil though the mechanism is unclear."
    explanation: >-
      Supports the hyperammonaemic arm and that its mechanism is not settled.
  - reference: PMID:32082663
    reference_title: "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Another possible etiology is inhibition of the Krebs cycle by fluoroacetate or fluorocitrate, metabolites of 5-FU, leading to excess urea and the subsequent accumulation of ammonia"
    explanation: >-
      Gives the postulated catabolite mechanism (Krebs-cycle inhibition) for the
      ammonia accumulation in this node.
phenotypes:
- name: Oral mucositis
  description: Painful inflammation and ulceration of the oral mucosa.
  phenotype_term:
    preferred_term: Oral mucositis
    term:
      id: HP:0010280
      label: Stomatitis
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression"
    explanation: Mucositis/stomatitis is a core manifestation of fluoropyrimidine toxicity.
- name: Diarrhea
  description: Severe secretory/mucosal diarrhoea from intestinal epithelial injury.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression"
    explanation: Diarrhoea is a core manifestation of fluoropyrimidine toxicity.
- name: Bone marrow suppression
  description: >-
    Myelosuppression, the dose-limiting haematologic toxicity, presenting as
    neutropenia (predisposing to febrile neutropenia) and other cytopenias.
  phenotype_term:
    preferred_term: Myelosuppression
    term:
      id: HP:0012145
      label: Abnormality of multiple cell lineages in the bone marrow
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression"
    explanation: Myelosuppression is a core manifestation of fluoropyrimidine toxicity.
- name: Palmar-plantar erythrodysesthesia
  description: Hand-foot syndrome - painful erythema and dysaesthesia of palms and soles, most associated with capecitabine.
  phenotype_term:
    preferred_term: Palmoplantar erythrodysesthesia
    term:
      id: HP:0025493
      label: Palmoplantar erythema
  evidence:
  - reference: PMID:36160401
    reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most patients experience adverse effects from these drugs, including fatigue, oral mucositis, abdominal pain, diarrhea, myelosuppression, palmoplantar erythrodysesthesia and rarely central nervous system toxicity or cardiomyopathy."
    explanation: Lists palmoplantar erythrodysesthesia among fluoropyrimidine adverse effects.
- name: Myocardial ischemia
  description: >-
    Myocardial ischaemia from coronary vasospasm is the dominant cardiotoxic
    presentation; the broader cardiotoxicity spectrum (arrhythmia, left
    ventricular dysfunction, cardiac arrest, sudden death) is described on the
    Myocardial Toxicity pathophysiology node.
  phenotype_term:
    preferred_term: Myocardial ischemia
    term:
      id: HP:0001681
      label: Angina pectoris
  evidence:
  - reference: PMID:25186061
    reference_title: "A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A severe side effect to 5-FU and capecitabine-based treatment is cardiotoxicity, which often presents as myocardial ischemia, but to a lesser extent cardiac arrhythmias, hyper- and hypotension, left ventricular dysfunction, cardiac arrest and sudden death"
    explanation: >-
      Myocardial ischaemia (anginal presentation) is the dominant cardiotoxic
      phenotype; the term captures the ischaemic chest-pain presentation.
- name: Hyperammonemia
  description: Elevated serum ammonia without hepatic failure, the metabolic abnormality underlying 5-FU hyperammonaemic encephalopathy.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:32082663
    reference_title: "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found to have hyperammonemia (84 mcmol/L), without hepatic failure"
    explanation: Documents the hyperammonaemia (without hepatic failure) that defines this node.
- name: Hyperammonemic encephalopathy
  description: Acute encephalopathy with hyperammonaemia in the absence of hepatic failure, typically within days of starting 5-FU.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:32082663
    reference_title: "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure"
    explanation: Documents 5-FU-associated hyperammonaemic encephalopathy without hepatic failure.
- name: Cerebellar ataxia
  description: Acute cerebellar syndrome with gait and limb ataxia, part of the central neurotoxicity of 5-FU.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36160401
    reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had rapidly worsening encephalopathy and ataxia."
    explanation: Documents ataxia as part of severe 5-FU central neurotoxicity.
genetic:
- name: DPYD
  notes: >-
    Loss-of-function and reduced-function DPYD variants lower DPD activity and are
    the principal pharmacogenomic risk factor for severe fluoropyrimidine
    toxicity. CPIC identifies four decreased-function variants of primary
    relevance (c.1905+1G>A/DPYD*2A, c.1679T>G, c.2846A>T, and the HapB3 intronic
    variant).
  relationship_type: RISK_FACTOR
  gene_term:
    preferred_term: DPYD
    term:
      id: hgnc:3012
      label: DPYD
  evidence:
  - reference: PMID:29152729
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "four decreased function DPYD variants are of primary relevance due to their population frequency and established impact on enzyme function and toxicity risk"
    explanation: CPIC names the clinically actionable decreased-function DPYD variants.
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "DPYD mutations are found in 50% of severe 5-FU toxicity cases"
    explanation: Quantifies the share of severe toxicity attributable to DPYD variation.
- name: TYMS
  notes: >-
    Variation in TYMS, the drug's direct target, is a reported but less firmly
    established modifier of fluoropyrimidine toxicity risk.
  relationship_type: MODIFIER
  gene_term:
    preferred_term: TYMS
    term:
      id: hgnc:12441
      label: TYMS
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "polymorphisms in 5 and 3 untranslated regions (5UTR and 3UTR) of TYMS gene have been described previously and these are suggested to be both predictive to toxicity and prognostic to efficacy with fluoropyrimidines"
    explanation: Supports TYMS variation as a reported modifier of fluoropyrimidine toxicity.
experimental_models:
- name: H9c2 rat cardiocyte 5-FU apoptosis assay
  experimental_model_type: CELL_LINE
  description: >-
    Cultured H9c2 rat cardiocytes exposed to 5-FU, used to probe the oxidative,
    apoptotic mechanism of 5-FU cardiotoxicity.
  modeled_mechanisms:
  - target: Myocardial Toxicity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Reproduces a candidate cellular mechanism (oxidative-stress-driven
      apoptosis) of 5-FU cardiotoxicity in a rodent cardiomyocyte line.
    limitations: >-
      A rat-derived immortalized cell line at supratherapeutic concentrations
      cannot reproduce the coronary-spasm and endothelial components of the
      tissue-scale Myocardial Toxicity node, so it models only the cellular
      oxidative-injury arm one step below that node.
    evidence:
    - reference: PMID:22812382
      reference_title: "5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The apoptosis induced by 5-FU and LF in cardiocytes was paralleled by the activation of caspases 3, 9 and 7 and by the intracellular increase of O(2-) levels."
      explanation: >-
        Shows 5-FU drives caspase-mediated apoptosis with increased superoxide in
        cardiocytes, the oxidative arm of the cardiotoxicity node.
environmental:
- name: Therapeutic fluoropyrimidine administration
  exposure_term:
    preferred_term: exposure to 5-fluorouracil
    term:
      id: ECTO:9000261
      label: exposure to 5-fluorouracil
  description: >-
    The exposure is iatrogenic: 5-FU, or capecitabine (its oral prodrug), is given
    as cancer chemotherapy to large numbers of patients. Poisoning follows when
    that administration is excessive (an overdose or infusion-pump error) or when a
    standard dose is not cleared because of DPD deficiency.
  evidence:
  - reference: PMID:36160401
    reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "5-Fluorouracil (5FU) or capecitabine, a prodrug enzymatically converted to 5-FU, is prescribed to thousands of patients with gastrointestinal, breast, and other cancers in the United States (US) (Ison et al., 2016)."
    explanation: Establishes the iatrogenic chemotherapeutic exposure that underlies this entry.
  influences_mechanisms:
  - target: Systemic 5-Fluorouracil Overexposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Administered fluoropyrimidine is the source of the circulating drug that, in
      overdose or with deficient clearance, becomes the systemic overexposure that
      drives toxicity.
    evidence:
    - reference: PMID:36160401
      reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Uridine triacetate (UTA) is an emergency treatment for overdoses and early onset, severe or life-threatening toxicities from fluoropyrimidines."
      explanation: >-
        Names overdose and severe toxicity from administered fluoropyrimidines as
        the overexposure state this exposure triggers.
treatments:
- name: Uridine triacetate
  description: >-
    Specific antidote for 5-FU/capecitabine overdose or early-onset severe
    toxicity, approved for use within 96 hours of the last fluoropyrimidine dose;
    it delivers uridine that competes with the toxic fluoronucleotides. In pooled
    analysis survival was approximately 96% versus 16% in a historical cohort.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: uridine triacetate
      term:
        id: CHEBI:90914
        label: uridine triacetate
  evidence:
  - reference: PMID:36160401
    reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Uridine triacetate (UTA) is an emergency treatment for overdoses and early onset, severe or life-threatening toxicities from fluoropyrimidines. It is approved for use in adults and children within 96 h of last fluoropyrimidine administration."
    explanation: States the indication and 96-hour window for the antidote.
  - reference: PMID:36160401
    reference_title: "Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The use of the drug resulted in approximately 96% survival (compared to 16% survival in a historic cohort), and about half the patients resumed their chemotherapy regimens within 3 weeks of overexposure."
    explanation: Quantifies the survival benefit of timely uridine triacetate.
- name: DPYD genotype-guided dosing
  description: >-
    Pre-treatment DPYD genotyping/phenotyping to identify deficient metabolisers
    and reduce or avoid fluoropyrimidine dosing - the principal preventive measure.
  treatment_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  target_mechanisms:
  - target: Deficient DPD-Mediated Catabolism
    description: >-
      Identifies reduced-function DPYD carriers before exposure so dose can be
      lowered or the drug avoided, pre-empting the overexposure step.
    evidence:
    - reference: PMID:29152729
      reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine)"
      explanation: CPIC's stated purpose - using DPYD genotype to guide fluoropyrimidine dosing.
- name: Supportive care
  description: >-
    Management of febrile neutropenia, fluid/electrolyte support for diarrhoea,
    and cardiac monitoring with drug cessation for cardiotoxicity.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
diagnosis:
- name: Clinical recognition from chemotherapy exposure and toxidrome
  description: >-
    Diagnosis rests on a recent fluoropyrimidine exposure together with a
    characteristic toxicity pattern - severe mucositis, diarrhoea and
    myelosuppression, and sometimes cardiac or neurologic involvement. An overdose
    or infusion-pump error may be evident from the administration record.
  evidence:
  - reference: PMID:33283204
    reference_title: "Pharmacogenetic Variants in the DPYD and TYMS Genes are Clinically Significant Predictors of Fluoropyrimidine Toxicity: Are We Ready for Use in our Clinical Practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rare toxicities, such as hepatitis, encephalopathy and acute cardiac ischemia following first or second dose of 5-FU"
    explanation: The toxidrome that, with an exposure history, establishes the clinical diagnosis.
- name: Serum ammonia and lactate in acute neurotoxicity
  description: >-
    When a patient on 5-FU develops acute encephalopathy, serum ammonia (with
    lactate) identifies 5-FU hyperammonaemic encephalopathy, which occurs without
    hepatic failure, and separates it from other causes of altered mental status.
  measurements:
  - preferred_term: Serum ammonia
    term:
      id: LOINC:1841-6
      label: Ammonia [Moles/volume] in Serum
  - preferred_term: Lactate
    term:
      id: LOINC:2524-7
      label: Lactate [Moles/volume] in Serum or Plasma
  notes: >-
    LOINC:1841-6 is bound specifically to Serum rather than Plasma: LOINC has
    no combined Serum-or-Plasma ammonia code (ammonia assays are frequently
    specimen-sensitive, which may be why), and this row's own name specifies
    serum ammonia. Lactate is bound to the method-less Serum-or-Plasma code.
  evidence:
  - reference: PMID:32082663
    reference_title: "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found to have hyperammonemia (84 mcmol/L), without hepatic failure"
    explanation: Supports measuring ammonia to identify 5-FU hyperammonaemic encephalopathy without hepatic failure.
differential_diagnoses:
- name: Hyperammonaemic encephalopathy from other causes
  description: >-
    Hepatic failure and inherited urea-cycle or hyperammonaemia disorders also
    cause hyperammonaemic encephalopathy and overlap with the neurologic
    presentation of 5-FU toxicity.
  distinguishing_features:
  - 5-FU hyperammonaemic encephalopathy occurs without hepatic failure and resolves on stopping the drug.
  - Onset within days of a fluoropyrimidine dose points to drug toxicity rather than a chronic metabolic cause.
  evidence:
  - reference: PMID:32082663
    reference_title: "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found to have hyperammonemia (84 mcmol/L), without hepatic failure"
    explanation: The absence of hepatic failure distinguishes 5-FU encephalopathy from hepatic causes.
- name: Acute coronary syndrome
  description: >-
    5-FU cardiotoxicity most often presents as myocardial ischaemia and can mimic a
    primary acute coronary syndrome.
  distinguishing_features:
  - 5-FU cardiotoxicity is temporally linked to the infusion and is typically vasospastic, often resolving on drug cessation, rather than fixed obstructive coronary disease.
  disease_term:
    preferred_term: acute coronary syndrome
    term:
      id: MONDO:0005542
      label: acute coronary syndrome
  evidence:
  - reference: PMID:25186061
    reference_title: "A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A severe side effect to 5-FU and capecitabine-based treatment is cardiotoxicity, which often presents as myocardial ischemia, but to a lesser extent cardiac arrhythmias, hyper- and hypotension, left ventricular dysfunction, cardiac arrest and sudden death"
    explanation: Establishes that 5-FU cardiotoxicity presents as myocardial ischaemia, the overlap with acute coronary syndrome.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: 5-Fluorouracil Poisoning · 2026-10-05T14:09:30Z · View source

De novo curation of 5-Fluorouracil Poisoning (MONDO:0016312). Deep research via the claude_code provider (research/5-Fluorouracil_Poisoning-deep-research-claude_code.md). Built a 7-node pathophysiology chain (deficient DPD catabolism -> systemic overexposure -> anabolic activation -> thymidylate synthase inhibition / RNA misincorporation -> proliferating-tissue cytotoxicity; overexposure also -> a fluorinated-catabolite/drug toxicity node for cardiotoxicity and hyperammonaemic encephalopathy). Proliferating-tissue cytotoxicity wires to stomatitis/diarrhoea/marrow suppression and the toxicity node to the cardiac/neuro phenotypes (6/7 phenotypes connected; palmoplantar erythrodysesthesia left unwired as its mechanism is not modelled). Phenotypes: stomatitis, diarrhoea, bone marrow suppression, palmoplantar erythrodysesthesia, myocardial ischaemia, hyperammonaemic encephalopathy, cerebellar ataxia. Genetic risk via DPYD (RISK_FACTOR) and TYMS (MODIFIER). Treatments: uridine triacetate antidote (CHEBI:90914), DPYD genotype-guided dosing, supportive care. One H9c2 rat-cardiocyte in-vitro experimental model linked to the cardiotoxicity node. Evidence from CPIC 2017 (PMID:29152729), Saif review (PMID:33283204), Jacob UTA case/review (PMID:36160401), cardiotoxicity systematic review (PMID:25186061), hyperammonaemic encephalopathy case (PMID:32082663), and rat cardiocyte study (PMID:22812382). No GeneReviews/StatPearls chapter exists. Validated: just validate (21/21 snippets, 21 titles), validate-terms, validate-disorders (CI gate), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes all pass. preflight-dr returned SKIP (no MONDO causal gene for a poisoning entity); report top genes DPYD/TYMS confirm correct entity. Follow-up in the same session added environmental (iatrogenic 5-FU exposure, ECTO:9000261, TRIGGERS the overexposure node), diagnosis (toxidrome recognition; serum ammonia/lactate for neurotoxicity), and differential_diagnoses (other hyperammonaemic encephalopathy; acute coronary syndrome, MONDO:0005542); re-validated (27/27 snippets). Review round 1 (ai4c-reviewer, CHANGES_REQUESTED): split the bundled toxicity node into Myocardial Toxicity (TISSUE) and Central Neurotoxicity (ORGANISM); bound hyperammonaemia to HP:0001987 as its own phenotype; renamed the cardiac phenotype to Myocardial ischemia so name/preferred_term/binding agree; added the postulated Krebs-cycle catabolite mechanism (PMID:32082663) to the CNS node; regraded the DPD rate-limiting snippet to OTHER for consistency with the TYMS enzyme-biochemistry grading; repointed the H9c2 model link to Myocardial Toxicity (now a 1-step, caveated upward extrapolation). Kept the DPYD genotype-guided-dosing treatment bound to NCIT:C15709 Genetic Testing: no dose-modification action term is reachable from the TreatmentTerm root (NCIT:C25218).

Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-sonnet-5-5 15 citations 2026-10-05T14:00:42.140922

1. Disease Information

  • 5-FU poisoning is toxicity from fluorouracil overdose, or from severe early-onset toxicity at standard doses. Capecitabine, a 5-FU prodrug, behaves the same way.
  • Overdose: dosing or infusion-pump errors.
  • Standard-dose toxicity: reduced detoxification, usually DPD deficiency.
  • The only approved antidote is uridine triacetate. In pooled studies it was started within 96 h of overdose or early-onset severe toxicity. 30-day survival was 94% overall (96% in overdose, 81% in early-onset severe toxicity), against 16% in a historical best-supportive-care cohort. Ison et al., Clin Cancer Res 2016 (FDA approval summary), via JHU Pure, Drugs & Therapy Perspectives guide. Treat the 16% comparator as a historical control, not a randomized one.
  • Synonyms: fluorouracil overdose or toxicity, capecitabine toxicity, fluoropyrimidine toxicity.
  • Data level: disease-level, aggregated from case reports and trials. This is not EHR-derived.

2. Etiology

  • Causal factors (environmental/iatrogenic): overdose, or standard dosing in a patient who cannot clear the drug.
  • Genetic risk factors:
  • DPYD variants reduce DPD activity. Poor metabolizers have complete DPD deficiency and risk severe or fatal toxicity. CPIC advises avoiding fluoropyrimidines in them and using reduced starting doses in partial deficiency. CPIC 2017 update, PMID:29152729 (URL as returned by search: Wiley); earlier guideline PMID:23988873.
  • The Dutch Pharmacogenetics Working Group has a parallel guideline: PMC7080718.
  • TYMS variation is also implicated: PMC7713499, and uridine triacetate in a TYMS-variant patient, PubMed 30013790.
  • Specific alleles such as DPYD2A, c.1679T>G, c.2846A>T and HapB3 are [background, unverified]*. Quote them from the CPIC table.
  • Other risk factors [background, unverified]: renal impairment, drug interactions (for example with capecitabine or brivudine/sorivudine), and dosing errors.
  • Protective factors: none well established. Normal DPD activity is the default state.
  • Gene–environment: DPYD genotype determines how a given dose or exposure behaves. This is a pharmacogenetic interaction, not a classic GxE one.

3. Phenotypes (suggested HP terms; verify each before binding)

Frequencies are not sourced, so I give none. - Diarrhea (HP:0002014) and mucositis/stomatitis. - Myelosuppression: neutropenia, pancytopenia. - Hyperammonemic encephalopathy. It presents as sudden altered mental status, lactic acidosis and respiratory alkalosis with high ammonia. Onset is 0.5–5 days after starting 5-FU. French national survey, case report PMC7013286. - Cardiotoxicity. It often presents as myocardial ischemia, with less common arrhythmia, hypo- or hypertension, LV dysfunction, cardiac arrest and sudden death. Systematic review PMC4170068. - Hand-foot syndrome, nausea/vomiting and alopecia [background, unverified]. - Onset is acute: early-onset severe toxicity, and delayed-onset cases are also reported (PMC9490183). Quality-of-life data were not searched.

4. Genetic/Molecular

  • DPYD (the lowercase hgnc: CURIE must be looked up; I did not verify one). Loss of function of the catabolic enzyme. Classification and allele frequencies: CPIC and gnomAD, not retrieved.
  • TYMS is a modifier, as the TYMS-variant case above shows.
  • Germline origin. Epigenetic and chromosomal data: none sought.

5. Environmental

The exposure is iatrogenic. In the KB, environmental would be the drug exposure, and an ECTO term needs a re-run search (for example l~fluorouracil) before binding. There are no lifestyle or infectious factors.

6. Mechanism / Pathophysiology

Causal chain (inferred steps are marked): 1. Excess 5-FU exposure follows overdose, or standard dosing with deficient DPD clearance. DPD normally catabolizes most of a dose. 2. High exposure produces more active metabolites and thymidylate synthase inhibition ([background, unverified]; classic mechanism). 3. Metabolites are incorporated into RNA and DNA ([background, unverified]). This injures rapidly dividing cells, causing mucositis, diarrhea and myelosuppression. 4. Uridine triacetate works because uridine competes with the toxic metabolites. Its efficacy in this setting supports an RNA-directed toxicity component. This is inferred from the antidote's clinical effect, not directly demonstrated here. 5. Branch, neurologic: catabolites (fluoro-β-alanine, monofluoroacetate) depress TCA-cycle flux and ATP. This secondarily impairs the urea cycle, leading to hyperammonemia and then encephalopathy (PMC7013286). The fluoroacetate/fluorocitrate step is postulated, not proven. 6. Branch, cardiac: proposed mechanisms are endothelial injury with thrombosis, energy depletion and ischemia, oxidative stress, coronary spasm, and reduced red-cell oxygen transfer. There is no evidence for a single mechanism. One source: rat cardiocyte oxidative stress and apoptosis, PMC3461434 (in vivo/in vitro rat data). - Suggested GO/CL terms (verify): apoptotic process, response to oxidative stress, the citrate cycle and urea cycle. Cell types: intestinal epithelial cell, hematopoietic progenitor, cardiac muscle cell, hepatocyte.

7. Anatomical Structures

  • Primary: GI tract mucosa, bone marrow.
  • Secondary: heart and brain; liver (the site of DPD detoxification).
  • Suggested UBERON terms: look up small intestine, bone marrow, heart, brain, liver. The condition is bilateral and systemic.

8. Temporal Development

Acute. The encephalopathy appears at 0.5–5 days. Early-onset severe toxicity and delayed onset are both described. Recovery with prompt antidote is substantial per the figures above. Stages and critical periods: the 96-hour antidote window is the key one.

9. Inheritance and Population

  • Inheritance: DPD deficiency is autosomal recessive for complete deficiency. Partial deficiency is intermediate [background, unverified]; confirm against CPIC.
  • Prevalence, incidence, sex ratio and ancestry: not retrieved. I did not find numbers, so none are stated.

10. Diagnostics

  • Clinical: history of exposure plus toxicity pattern. Check ammonia and lactate if neurologic changes appear.
  • Genetic: DPYD genotyping before therapy (CPIC, DPWG). Universal pre-treatment testing is promoted by some groups (NCODA). Other approaches (phenotyping, uracil levels) are [background, unverified].
  • Differential: sepsis, other chemotherapy toxicities, and other causes of encephalopathy. Nothing in the sources retrieved distinguishes these.

11. Outcome/Prognosis

With uridine triacetate started within 96 h, 30-day survival was 94% versus 16% for historical controls. Complete DPD deficiency risks fatal toxicity (CPIC). Other prognostic data were not retrieved.

12. Treatment

  • Antidote: uridine triacetate (Vistogard), FDA-approved for overdose and early-onset severe toxicity (Ison 2016). Delayed-onset use was reported in PMC9490183. Its use in a TYMS-variant patient is described in PubMed 30013790. The CHEBI/NCIT agent CURIE needs lookup.
  • Supportive care: fluids, antiemetics, antidiarrheals, G-CSF, transfusion, ICU care [background, unverified]. Suggested NCIT action terms (verify): NCIT:C15986 Pharmacotherapy and NCIT:C15747 Supportive Care. These appear in the CLAUDE.md list and should still be looked up.
  • Prevention-linked dosing: DPYD-guided dose reduction or avoidance (CPIC).
  • Trials: none retrieved. NCT07158164 surfaced, a DPYD-guided dosing study. I did not read it, so check it before citing.

13. Prevention

  • Primary: pre-treatment DPYD genotyping with dose adjustment, plus pump and dosing safeguards (the latter [background, unverified]).
  • Secondary: early recognition of toxicity within the antidote window.
  • No vaccine or public-health program applies.

14. Other Species

Not researched. Fluoropyrimidine toxicity in dogs and cats (topical 5-FU is especially toxic to them) is [background, unverified]. Check OMIA and PubMed before adding it.

15. Model Organisms

  • Rat cardiocyte oxidative-stress and apoptosis data (PMC3461434). Grade these MODEL_ORGANISM or IN_VITRO depending on the quoted sentence.
  • Dpyd-deficient mouse models are [background, unverified]. Search MGI before adding any.

Gaps and next steps

  1. Fetch the PMIDs for the Ison 2016 paper, the French national survey and the cardiotoxicity review. I did not retrieve them, so I give no numbers.
  2. Take allele frequencies and CPIC tier tables from the CPIC supplement.
  3. Take epidemiology from a primary source.
  4. Look up every suggested CURIE.
  5. Run just preflight-dr on this report.

Sources used: CPIC 2017 (Wiley), DPWG, PMC7713499, NCODA, Ison 2016 record, uridine triacetate guide, delayed-onset case PMC9490183, TYMS case 30013790, French survey, PMC7013286, cardiotoxicity review PMC4170068, PMC3461434.

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 2
Off topic 2

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMC:PMC7013286 (7 mentions) - A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine.
  • shared terms: encephalopathy
  • PMC:PMC4170068 (5 mentions) - A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity.
  • shared terms: none

Weighed against this report's own most characteristic terms: toxicity, unverified, cpic, dpd, uridine, triacetate, dosing, severe, antidote, dose, overdose, deficiency, dpyd, early-onset, exposure, curie, appear, check, encephalopathy, verify.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 4
Resolved 4
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 1
Terms named as a different term 0

Every term resolved, and every label the report gave matched.