Acetaminophen Hepatotoxicity

Complex MONDO:0005359 Pathograph 5 Show in embeddings browser Liver Disease Iatrogenic condition

Acetaminophen (paracetamol, APAP) hepatotoxicity is the archetypal dose-dependent drug-induced liver injury and the leading cause of acute liver failure in the United States. At therapeutic doses APAP is safe, but in overdose the cytochrome P450-generated reactive metabolite NAPQI depletes glutathione, binds mitochondrial proteins, and triggers oxidative stress and centrilobular hepatocyte necrosis. It is the intrinsic (predictable, dose-dependent) end of the drug-induced liver injury spectrum and conforms to the conserved DILI mechanism module.

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1
Mappings
5
Pathophys.
5
Phenotypes
5
Pathograph
3
Medical Actions
🔗

Mappings

MONDO
MONDO:0005359 drug-induced liver injury
skos:closeMatch MONDO
MONDO drug-induced liver injury is the closest available parent; this entry specializes it to the acetaminophen/NAPQI dose-dependent (intrinsic) form.
⚙

Pathophysiology

5
NAPQI reactive metabolite formation and glutathione depletion
In overdose, cytochrome P450 metabolism of acetaminophen generates the reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI), which depletes hepatocyte glutathione and binds cellular and mitochondrial proteins — the proximal toxic trigger that the DILI module's reactive-metabolite node represents.
hepatocyte CL:0000182
xenobiotic metabolic process GO:0006805 ↑ INCREASED
Downstream
Mitochondrial oxidative stress and dysfunction NAPQI-protein adducts and glutathione depletion converge on mitochondrial injury.
Show evidence (1 reference)
PMID:36670547 SUPPORT Other
"APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)"
Directly identifies NAPQI as the reactive metabolite that drives acetaminophen hepatotoxicity, matching the DILI trigger node this disease conforms to. Evidence source is OTHER because this is a review article.
Mitochondrial oxidative stress and dysfunction
NAPQI adduct formation and glutathione depletion provoke mitochondrial oxidative stress, impaired respiration, and the mitochondrial permeability transition — the major cellular event linking acetaminophen exposure to hepatocyte death.
hepatocyte CL:0000182
response to oxidative stress GO:0006979 ↑ INCREASED
mitochondrion GO:0005739
Downstream
Centrilobular hepatocyte necrosis Mitochondrial failure precipitates hepatocyte death.
Show evidence (2 references)
PMID:36670547 SUPPORT Other
"Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury."
Names mitochondrial oxidative stress and dysfunction as the major cellular events in acetaminophen injury, matching the DILI amplifier node. Evidence source is OTHER because this is a review article.
PMID:36738840 SUPPORT In Vitro
"On-chip HLOs were able to predict the synergistic hepatotoxicity of tenofovir-inarigivir and displayed steatosis and mitochondrial perturbation, via phenotypic and transcriptomic analysis, on exposure to fialuridine and acetaminophen, respectively."
A New Approach Methodology (NAM): an iPSC-derived human liver organoid adapted to a liver-on-chip microphysiological system. On acetaminophen exposure the on-chip organoids displayed mitochondrial perturbation by phenotypic and transcriptomic analysis, recapitulating in vitro the mitochondrial dysfunction that this node assigns to APAP hepatotoxicity.
Centrilobular hepatocyte necrosis
Mitochondrial failure and oxidative stress precipitate predominantly necrotic death of centrilobular hepatocytes, the central effector lesion of acetaminophen hepatotoxicity and of the DILI module.
hepatocyte CL:0000182
cell death GO:0008219 ↑ INCREASED
Downstream
Sterile inflammatory amplification Necrotic hepatocytes release damage-associated signals that recruit inflammatory cells.
Acute liver failure Massive hepatocyte loss produces acute liver failure.
Show evidence (2 references)
PMID:24099014 SUPPORT Other
"the most common manifestation is hepatocyte death following drug intake"
Hepatocyte death is the most common manifestation of DILI and the central lesion of acetaminophen toxicity, matching the module effector node. Evidence source is OTHER because this is a review article.
PMID:35024303 SUPPORT Other
"the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response"
Names necrotic cell death as a critical mechanism in the acetaminophen hepatotoxicity model, supporting the necrosis effector. Evidence source is OTHER because this is a review article.
Sterile inflammatory amplification
Necrotic hepatocytes release damage-associated molecular patterns that drive a sterile inflammatory response, recruiting innate immune cells that amplify and extend the hepatocellular injury.
hepatocyte CL:0000182 Kupffer cell CL:0000091 neutrophil CL:0000775
inflammatory response GO:0006954 ↑ INCREASED
Downstream
Acute liver failure Sustained inflammatory injury extends hepatocyte loss toward liver failure.
Show evidence (1 reference)
PMID:35024303 SUPPORT Other
"the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response"
Names the sterile inflammatory response as a critical mechanism in acetaminophen hepatotoxicity, matching the DILI amplification node. Evidence source is OTHER because this is a review article.
Acute liver failure
Accumulated centrilobular necrosis and inflammation can produce fulminant hepatic failure; acetaminophen is the single leading cause of acute liver failure in the United States.
hepatocyte CL:0000182
cell death GO:0008219 ↑ INCREASED
Show evidence (1 reference)
PMID:24099014 SUPPORT Other
"Acetaminophen (APAP) alone accounts for the half of the overall cases of acute liver failure in USA"
Documents acetaminophen as the leading cause of acute liver failure, matching the DILI consequence node. Evidence source is OTHER because this is a review article.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acetaminophen Hepatotoxicity 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

5
Blood 1
Coagulopathy Abnormality of the coagulation cascade HP:0003256
Show evidence (1 reference)
PMID:35615243 SUPPORT Human Clinical
"Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy"
Defines acute liver failure as comprising a coagulopathy of liver origin, the basis of the rising INR in severe acetaminophen toxicity.
Digestive 2
Acute liver failure Hepatic failure HP:0001399
Show evidence (1 reference)
PMID:24099014 SUPPORT Other
"Acetaminophen (APAP) alone accounts for the half of the overall cases of acute liver failure in USA"
Establishes acute liver failure as the defining severe outcome of acetaminophen hepatotoxicity. Evidence source is OTHER because this is a review article.
Jaundice Jaundice HP:0000952
Show evidence (1 reference)
PMID:35615243 SUPPORT Human Clinical
"Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy"
Defines acute liver failure (the severe paracetamol outcome) as comprising jaundice alongside coagulopathy and encephalopathy.
Metabolism 1
Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910
Show evidence (1 reference)
PMID:28421844 SUPPORT Human Clinical
"acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L"
Human cohort study defining acetaminophen acute liver injury by alanine aminotransferase (ALT) elevation, directly supporting elevated transaminases as the biochemical phenotype.
Nervous System 1
Hepatic encephalopathy Encephalopathy HP:0001298
Show evidence (1 reference)
PMID:35615243 SUPPORT Human Clinical
"Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy"
Defines acute liver failure as comprising encephalopathy, the neurological hallmark of severe acetaminophen toxicity.
💊

Medical Actions

3
N-acetylcysteine
Action: Pharmacotherapy NCIT:C15986
Agent: N-acetylcysteine NCIT:C200
N-acetylcysteine (NAC) is the standard antidote for acetaminophen poisoning, replenishing glutathione to detoxify NAPQI; it is most effective when given early after overdose.
Show evidence (1 reference)
PMID:36670547 SUPPORT Other
"N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning"
Identifies N-acetylcysteine as the standard antidote for acetaminophen poisoning. Evidence source is OTHER because this is a review article.
Activated charcoal
Action: Pharmacotherapy NCIT:C15986
Single-dose activated charcoal given to patients presenting early after acute overdose reduces gastrointestinal absorption of acetaminophen.
Show evidence (1 reference)
PMID:34053705 SUPPORT Other
"Patients who present early should be offered activated charcoal"
Identifies early activated charcoal as standard management of acute acetaminophen overdose. Evidence source is OTHER because this is a review.
Liver transplantation
Action: liver transplantation Ontology label: Liver Transplantation NCIT:C15271
Emergency liver transplantation is reserved for patients with acetaminophen- induced acute liver failure unlikely to survive with medical therapy alone.
Show evidence (1 reference)
PMID:35615243 SUPPORT Human Clinical
"Liver transplant is reserved for those patients unlikely to survive with medical treatment alone."
Establishes liver transplantation as the rescue therapy for paracetamol acute liver failure refractory to medical management.
🌍

Environmental Factors

1
Acetaminophen overdose
Ingestion of acetaminophen in excess of the metabolic capacity to safely conjugate it (intentional or unintentional overdose) is the proximal exposure that precipitates hepatotoxicity.
Show evidence (1 reference)
PMID:36670547 SUPPORT Other
"is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury."
Establishes acetaminophen overdose as the exposure that converts a safe drug into a cause of fatal liver injury. Evidence source is OTHER because this is a review article.
🔬

Biochemical Markers

2
Serum acetaminophen concentration (INCREASED)
Context: The serum acetaminophen concentration plotted against time since ingestion on the acetaminophen (Rumack-Matthew) nomogram guides the decision to treat with N-acetylcysteine after an acute overdose.
Show evidence (1 reference)
PMID:34053705 SUPPORT Other
"The acetaminophen nomogram is used to assess the need for treatment"
The acetaminophen nomogram interprets the serum acetaminophen level against time since ingestion to guide treatment. Evidence source is OTHER because this is a review article.
International normalized ratio (INR) (INCREASED)
Context: A rising INR reflects the hepatic coagulopathy of acetaminophen-induced acute liver failure and is a central prognostic and transplant-criteria marker.
Show evidence (1 reference)
PMID:35615243 SUPPORT Human Clinical
"Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy"
The coagulopathy of liver origin that defines acetaminophen acute liver failure is quantified clinically by a rising INR.
{ }

Source YAML

click to show 
name: Acetaminophen Hepatotoxicity
creation_date: "2026-06-24T00:00:00Z"
category: Complex
categories:
- Treatment-Related Disorder
- Hepatic Toxicity
- Adverse Drug Reaction
synonyms:
- acetaminophen-induced liver injury
- paracetamol hepatotoxicity
- APAP hepatotoxicity
- acetaminophen poisoning
description: >-
  Acetaminophen (paracetamol, APAP) hepatotoxicity is the archetypal
  dose-dependent drug-induced liver injury and the leading cause of acute liver
  failure in the United States. At therapeutic doses APAP is safe, but in
  overdose the cytochrome P450-generated reactive metabolite NAPQI depletes
  glutathione, binds mitochondrial proteins, and triggers oxidative stress and
  centrilobular hepatocyte necrosis. It is the intrinsic (predictable,
  dose-dependent) end of the drug-induced liver injury spectrum and conforms to
  the conserved DILI mechanism module.
parents:
- Liver Disease
- Iatrogenic condition
disease_term:
  preferred_term: acetaminophen hepatotoxicity
  term:
    id: MONDO:0005359
    label: drug-induced liver injury
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005359
      label: drug-induced liver injury
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO drug-induced liver injury is the closest available parent; this entry
      specializes it to the acetaminophen/NAPQI dose-dependent (intrinsic) form.
environmental:
- name: Acetaminophen overdose
  description: >-
    Ingestion of acetaminophen in excess of the metabolic capacity to safely
    conjugate it (intentional or unintentional overdose) is the proximal exposure
    that precipitates hepatotoxicity.
  evidence:
  - reference: PMID:36670547
    reference_title: "The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      is relatively safe at therapeutic doses; however, APAP overdose may lead to
      fatal acute liver injury.
    explanation: >-
      Establishes acetaminophen overdose as the exposure that converts a safe
      drug into a cause of fatal liver injury. Evidence source is OTHER because
      this is a review article.
pathophysiology:
- name: NAPQI reactive metabolite formation and glutathione depletion
  conforms_to: "drug_induced_liver_injury#Reactive Drug Metabolite Formation and Hepatocellular Stress"
  description: >-
    In overdose, cytochrome P450 metabolism of acetaminophen generates the
    reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI), which depletes
    hepatocyte glutathione and binds cellular and mitochondrial proteins — the
    proximal toxic trigger that the DILI module's reactive-metabolite node
    represents.
  role: trigger
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: xenobiotic metabolic process
    term:
      id: GO:0006805
      label: xenobiotic metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:36670547
    reference_title: "The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite
      N-acetyl-p-benzoquinone imine (NAPQI)
    explanation: >-
      Directly identifies NAPQI as the reactive metabolite that drives
      acetaminophen hepatotoxicity, matching the DILI trigger node this disease
      conforms to. Evidence source is OTHER because this is a review article.
  downstream:
  - target: Mitochondrial oxidative stress and dysfunction
    description: >-
      NAPQI-protein adducts and glutathione depletion converge on mitochondrial
      injury.
- name: Mitochondrial oxidative stress and dysfunction
  conforms_to: "drug_induced_liver_injury#Mitochondrial Dysfunction and Oxidative Stress"
  description: >-
    NAPQI adduct formation and glutathione depletion provoke mitochondrial
    oxidative stress, impaired respiration, and the mitochondrial permeability
    transition — the major cellular event linking acetaminophen exposure to
    hepatocyte death.
  role: amplifier
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:36670547
    reference_title: "The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mitochondrial oxidative stress and dysfunction are the major cellular events
      associated with APAP-induced liver injury.
    explanation: >-
      Names mitochondrial oxidative stress and dysfunction as the major cellular
      events in acetaminophen injury, matching the DILI amplifier node. Evidence
      source is OTHER because this is a review article.
  - reference: PMID:36738840
    reference_title: "A human liver organoid screening platform for DILI risk prediction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      On-chip HLOs were able to predict the synergistic hepatotoxicity of
      tenofovir-inarigivir and displayed steatosis and mitochondrial
      perturbation, via phenotypic and transcriptomic analysis, on exposure to
      fialuridine and acetaminophen, respectively.
    explanation: >-
      A New Approach Methodology (NAM): an iPSC-derived human liver organoid
      adapted to a liver-on-chip microphysiological system. On acetaminophen
      exposure the on-chip organoids displayed mitochondrial perturbation by
      phenotypic and transcriptomic analysis, recapitulating in vitro the
      mitochondrial dysfunction that this node assigns to APAP hepatotoxicity.
  downstream:
  - target: Centrilobular hepatocyte necrosis
    description: >-
      Mitochondrial failure precipitates hepatocyte death.
- name: Centrilobular hepatocyte necrosis
  conforms_to: "drug_induced_liver_injury#Hepatocyte Cell Death"
  description: >-
    Mitochondrial failure and oxidative stress precipitate predominantly necrotic
    death of centrilobular hepatocytes, the central effector lesion of
    acetaminophen hepatotoxicity and of the DILI module.
  role: central_effector
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: cell death
    term:
      id: GO:0008219
      label: cell death
    modifier: INCREASED
  evidence:
  - reference: PMID:24099014
    reference_title: "Mechanisms of drug-induced liver injury."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the most common manifestation is hepatocyte death following drug intake
    explanation: >-
      Hepatocyte death is the most common manifestation of DILI and the central
      lesion of acetaminophen toxicity, matching the module effector node.
      Evidence source is OTHER because this is a review article.
  - reference: PMID:35024303
    reference_title: "Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the critical roles of drug metabolism, mitochondrial dysfunction, necrotic
      cell death, autophagy and the sterile inflammatory response
    explanation: >-
      Names necrotic cell death as a critical mechanism in the acetaminophen
      hepatotoxicity model, supporting the necrosis effector. Evidence source is
      OTHER because this is a review article.
  downstream:
  - target: Sterile inflammatory amplification
    description: >-
      Necrotic hepatocytes release damage-associated signals that recruit
      inflammatory cells.
  - target: Acute liver failure
    description: >-
      Massive hepatocyte loss produces acute liver failure.
- name: Sterile inflammatory amplification
  conforms_to: "drug_induced_liver_injury#Sterile and Immune-Mediated Inflammatory Amplification"
  description: >-
    Necrotic hepatocytes release damage-associated molecular patterns that drive
    a sterile inflammatory response, recruiting innate immune cells that amplify
    and extend the hepatocellular injury.
  role: amplifier
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:35024303
    reference_title: "Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the critical roles of drug metabolism, mitochondrial dysfunction, necrotic
      cell death, autophagy and the sterile inflammatory response
    explanation: >-
      Names the sterile inflammatory response as a critical mechanism in
      acetaminophen hepatotoxicity, matching the DILI amplification node.
      Evidence source is OTHER because this is a review article.
  downstream:
  - target: Acute liver failure
    description: >-
      Sustained inflammatory injury extends hepatocyte loss toward liver failure.
- name: Acute liver failure
  conforms_to: "drug_induced_liver_injury#Liver Injury and Acute Liver Failure"
  description: >-
    Accumulated centrilobular necrosis and inflammation can produce fulminant
    hepatic failure; acetaminophen is the single leading cause of acute liver
    failure in the United States.
  role: consequence
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: cell death
    term:
      id: GO:0008219
      label: cell death
    modifier: INCREASED
  evidence:
  - reference: PMID:24099014
    reference_title: "Mechanisms of drug-induced liver injury."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acetaminophen (APAP) alone accounts for the half of the overall cases of
      acute liver failure in USA
    explanation: >-
      Documents acetaminophen as the leading cause of acute liver failure,
      matching the DILI consequence node. Evidence source is OTHER because this
      is a review article.
phenotypes:
- name: Elevated hepatic transaminases
  description: >-
    Marked transaminase elevation (often into the thousands of IU/L) reflecting
    centrilobular hepatocyte necrosis.
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:28421844
    reference_title: "Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L
    explanation: >-
      Human cohort study defining acetaminophen acute liver injury by alanine
      aminotransferase (ALT) elevation, directly supporting elevated transaminases
      as the biochemical phenotype.
- name: Acute liver failure
  description: >-
    Fulminant hepatic failure from massive hepatocyte loss, the most severe
    outcome of acetaminophen overdose.
  phenotype_term:
    preferred_term: Acute liver failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:24099014
    reference_title: "Mechanisms of drug-induced liver injury."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acetaminophen (APAP) alone accounts for the half of the overall cases of
      acute liver failure in USA
    explanation: >-
      Establishes acute liver failure as the defining severe outcome of
      acetaminophen hepatotoxicity. Evidence source is OTHER because this is a
      review article.
- name: Jaundice
  description: >-
    Jaundice from impaired bilirubin handling is a defining feature of the acute
    liver failure that can follow acetaminophen overdose.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:35615243
    reference_title: "Acute liver failure following paracetamol overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute liver failure is a rare syndrome comprising a coagulopathy of liver
      origin, jaundice and encephalopathy
    explanation: >-
      Defines acute liver failure (the severe paracetamol outcome) as comprising
      jaundice alongside coagulopathy and encephalopathy.
- name: Coagulopathy
  description: >-
    Coagulopathy of hepatic origin (prolonged INR) reflecting loss of hepatic
    synthetic function in acetaminophen-induced acute liver failure.
  phenotype_term:
    preferred_term: Coagulopathy
    term:
      id: HP:0003256
      label: Abnormality of the coagulation cascade
  evidence:
  - reference: PMID:35615243
    reference_title: "Acute liver failure following paracetamol overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute liver failure is a rare syndrome comprising a coagulopathy of liver
      origin, jaundice and encephalopathy
    explanation: >-
      Defines acute liver failure as comprising a coagulopathy of liver origin,
      the basis of the rising INR in severe acetaminophen toxicity.
- name: Hepatic encephalopathy
  description: >-
    Hepatic encephalopathy marks progression to severe acute liver failure and is
    a key transplant-criteria feature.
  phenotype_term:
    preferred_term: Hepatic encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:35615243
    reference_title: "Acute liver failure following paracetamol overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute liver failure is a rare syndrome comprising a coagulopathy of liver
      origin, jaundice and encephalopathy
    explanation: >-
      Defines acute liver failure as comprising encephalopathy, the neurological
      hallmark of severe acetaminophen toxicity.
biochemical:
- name: Serum acetaminophen concentration
  presence: INCREASED
  context: >-
    The serum acetaminophen concentration plotted against time since ingestion on
    the acetaminophen (Rumack-Matthew) nomogram guides the decision to treat with
    N-acetylcysteine after an acute overdose.
  evidence:
  - reference: PMID:34053705
    reference_title: "Acetaminophen Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The acetaminophen nomogram is used to assess the need for treatment
    explanation: >-
      The acetaminophen nomogram interprets the serum acetaminophen level against
      time since ingestion to guide treatment. Evidence source is OTHER because
      this is a review article.
- name: International normalized ratio (INR)
  presence: INCREASED
  context: >-
    A rising INR reflects the hepatic coagulopathy of acetaminophen-induced acute
    liver failure and is a central prognostic and transplant-criteria marker.
  evidence:
  - reference: PMID:35615243
    reference_title: "Acute liver failure following paracetamol overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute liver failure is a rare syndrome comprising a coagulopathy of liver
      origin, jaundice and encephalopathy
    explanation: >-
      The coagulopathy of liver origin that defines acetaminophen acute liver
      failure is quantified clinically by a rising INR.
treatments:
- name: N-acetylcysteine
  description: >-
    N-acetylcysteine (NAC) is the standard antidote for acetaminophen poisoning,
    replenishing glutathione to detoxify NAPQI; it is most effective when given
    early after overdose.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-acetylcysteine
      term:
        id: NCIT:C200
        label: Acetylcysteine
  evidence:
  - reference: PMID:36670547
    reference_title: "The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      N-acetylcysteine (NAC) is clinically used as the main antidote for APAP
      poisoning
    explanation: >-
      Identifies N-acetylcysteine as the standard antidote for acetaminophen
      poisoning. Evidence source is OTHER because this is a review article.
- name: Activated charcoal
  description: >-
    Single-dose activated charcoal given to patients presenting early after acute
    overdose reduces gastrointestinal absorption of acetaminophen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:34053705
    reference_title: "Acetaminophen Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients who present early should be offered activated charcoal
    explanation: >-
      Identifies early activated charcoal as standard management of acute
      acetaminophen overdose. Evidence source is OTHER because this is a review.
- name: Liver transplantation
  description: >-
    Emergency liver transplantation is reserved for patients with acetaminophen-
    induced acute liver failure unlikely to survive with medical therapy alone.
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  evidence:
  - reference: PMID:35615243
    reference_title: "Acute liver failure following paracetamol overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver transplant is reserved for those patients unlikely to survive with
      medical treatment alone.
    explanation: >-
      Establishes liver transplantation as the rescue therapy for paracetamol
      acute liver failure refractory to medical management.