Amatoxin Poisoning

Environmental Pathograph 40 Show in embeddings browser Poisoning

Amatoxin poisoning follows ingestion of a mushroom containing alpha-amanitin or one of its congeners. It causes the large majority of deaths from eating wild mushrooms, and the reason is as much timing as potency: the toxin is not destroyed by cooking, and it produces no symptom at all for a latent interval of six to eighteen hours, with the gastrointestinal phase beginning between six and twenty-four hours, so the patient presents after absorption is complete and the meal is rarely volunteered as relevant. The species differ and the toxin does not - Amanita phalloides, Amanita virosa, several Galerina and several Lepiota converge on the same molecule, which is why this entry is named for the toxin rather than the genus. Alpha-amanitin is a poor membrane permeant, and the step that makes an otherwise general poison organ-selective is carriage across the hepatocyte sinusoidal membrane by the uptake transporter OATP1B3. Cells that express the transporter take the toxin up and die; cells that do not are largely spared, which is why lung, heart and brain escape while liver, gut and kidney do not. Inside the cell the toxin binds RNA polymerase II and stops transcription, so the tissues that fail first are the ones with the highest demand for new protein. Clinically this reads as four phases - a latent interval, a cholera-like gastroenteritis, an apparent recovery, and hepatic failure from about the third day. The third phase is the dangerous one, because a patient who looks better is discharged while transcription is already silenced.

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Mechanistic Hypotheses

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

rnap2_translocation_block CANONICAL

The canonical account. Alpha-amanitin binds RNA polymerase II non-covalently near the bridge helix and trigger loop and prevents the conformational cycle that advances the enzyme by one nucleotide, so elongation stalls and mRNA output falls. Every downstream event in this entry is a consequence of that arrest. Review literature has presented the bridge helix and the trigger loop as two competing accounts of the binding site; the crystallographic work says they are not alternatives, because the inhibitor traps both elements at once.

Pathograph links

OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin -> RNA Polymerase II Inhibition DIRECT Intracellular toxin reaches the nucleus and engages RNA polymerase II.

RNA Polymerase II Inhibition -> Arrest of Messenger RNA Synthesis DIRECT

Arrest of Messenger RNA Synthesis -> Failure of Protein Synthesis DIRECT

Failure of Protein Synthesis -> p53- and Caspase-Dependent Hepatocyte Apoptosis DIRECT

p53- and Caspase-Dependent Hepatocyte Apoptosis -> Centrilobular Hepatic Necrosis DIRECT

Centrilobular Hepatic Necrosis -> Hepatic Synthetic and Metabolic Failure DIRECT

A second, OATP1B3-independent route carries amatoxin into non-hepatic cells

oatp1b3_independent_uptake EMERGING

OATP1B3 expression explains the classical organ selectivity well, and knocking it down in a hepatoma line abolishes cytotoxicity. It does not explain hematotoxicity: cultured hematopoietic cells and CD34+ progenitors are killed by alpha-amanitin, and OATP1B3 inhibitors do not rescue them. Either those cells import the toxin by another carrier, or enough enters by a non-carrier route to matter where the transporter account predicts sparing. One transporter-independent entry determinant is known - a CRISPR screen identified the N-glycan biosynthesis component STT3B as required for alpha-amanitin to enter human cells - so the open question is not whether any second route exists but whether STT3B accounts for the haematopoietic compartment specifically, which has not been tested.

Pathograph links

Systemic Alpha-Amanitin Exposure -> STT3B-Dependent Cellular Entry of Alpha-Amanitin DIRECT Entry into cells additionally requires the N-glycan biosynthesis machinery, a determinant separate from sinusoidal uptake.

Systemic Alpha-Amanitin Exposure -> Hematopoietic Cell Apoptosis DIRECT Hematopoietic cells are killed in culture at concentrations reached in poisoning, by a route the transporter account does not cover.

STT3B-Dependent Cellular Entry of Alpha-Amanitin -> RNA Polymerase II Inhibition DIRECT Entry through this route delivers toxin to the same nuclear target, which is why it is drawn into the shared chain rather than as a parallel branch.

Hematopoietic Cell Apoptosis -> Thrombocytopenia INDIRECT KNOWN INTERMEDIATES

Hematopoietic Cell Apoptosis -> Anemia INDIRECT KNOWN INTERMEDIATES

Renal tubular injury is mediated by mitochondrial damage rather than by transcription arrest alone

mitochondrial_nephrotoxicity EMERGING

Proposed from a single human case with electron microscopy and immunofluorescence on the renal biopsy, in a patient whose liver injury had already resolved. Mitochondria were swollen with reduced cristae and TOM20 expression was lower than in ischaemic tubular injury, while cytochrome c oxidase activity was preserved. The authors put it as a question rather than a conclusion, and the entry carries it the same way.

Pathograph links

Mitochondrial Injury in Proximal Tubular Epithelium -> Renal Proximal Tubular Injury DIRECT

TNF and reactive oxygen species amplify hepatocyte death beyond the primary transcriptional lesion

tnf_ros_amplification ALTERNATIVE

Anti-TNF antibody prevents alpha-amanitin liver injury in mice, which is a strong functional result and places TNF upstream of the injury rather than beside it. The reactive-oxygen arm is weaker: the same review that reports the TNF experiments says explicitly that the role of ROS is not established. The two are grouped because the proposed link between them is that TNF acts through lipid peroxidation.

Pathograph links

TNF-Mediated Amplification of Hepatocyte Injury -> p53- and Caspase-Dependent Hepatocyte Apoptosis DIRECT TNF amplifies the apoptotic response that the transcriptional block initiates.

Discussions and Knowledge Gaps

By what route does alpha-amanitin enter haematopoietic cells, given that OATP1B3 inhibition does not protect them?

KNOWLEDGE GAP oatp1b3_independent_entry_route

Attached to

pathophysiology#Hematopoietic Cell Apoptosis

OATP1B3 expression is the accepted explanation for why amatoxin spares lung, heart and brain while destroying liver, gut and kidney, and the hepatic evidence for it is strong in both directions - the transporter carries the toxin, and knocking it down abolishes the cytotoxicity. Haematopoietic cells do not fit: they are killed at comparable concentrations, and OATP1B3 inhibitors do not rescue them. Either another carrier is involved or the transporter account is incomplete as a general theory of cellular susceptibility. The question matters therapeutically, because silibinin's mechanism is transporter blockade, and a compartment that takes up toxin without OATP1B3 is a compartment the antidote cannot protect.

Show evidence (1 reference)

PMID:38276537 SUPPORT In Vitro

"The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity."

The observation that opens the gap.

Do reactive oxygen species contribute causally to amatoxin hepatotoxicity, or are they a marker of cells already dying from transcriptional arrest?

KNOWLEDGE GAP ros_causal_role_in_hepatotoxicity

Attached to

pathophysiology#TNF-Mediated Amplification of Hepatocyte Injury

This is not an idle question, because N-acetylcysteine is given in nearly every protocol and its rationale is the oxidative arm. The TNF half of the loop has a blocking experiment behind it; the ROS half does not, and the review that reports both says so in as many words. Until it is settled, the standard use of an antioxidant antidote rests on a mechanism the same literature declines to assert.

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"Although some in vivo and in vitro studies have found some association between α-amanitin and the development of ROS, further investigation is needed"

The review declining to treat the oxidative arm as established.

Does interrupting enterohepatic recirculation by biliary drainage improve survival, or does the nine-patient pilot reflect selection?

KNOWLEDGE GAP biliary_drainage_survival_benefit

Attached to

treatments#Biliary Drainage

Two of this entry's interventions - multiple-dose charcoal and biliary drainage - target the recirculation node directly, and a third, silibinin, targets the uptake step that recirculation feeds. Recirculation is the one part of the mechanism that is straightforwardly interruptible. The drainage result is the largest effect reported for any intervention here and rests on five treated patients against four controls; the mechanistic case is strong and the clinical case is a pilot. The same manoeuvre is a core element of the canine protocol, which is supportive but also uncontrolled.

Show evidence (1 reference)

PMID:42273384 SUPPORT Human Clinical

"Interrupting the enterohepatic recirculation of amatoxins is a mechanistically rational but unproven therapeutic strategy."

The authors' own statement of the gap their pilot addresses but does not close.

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Pathophysiology

Systemic Alpha-Amanitin Exposure

Circulating alpha-amanitin, established by absorption of the ingested fruiting body across the intestinal epithelium into the portal circulation. The toxin binds serum proteins weakly and is cleared quickly from plasma into liver and kidney, so the plasma compartment is a conduit rather than a reservoir - which is why extracorporeal removal aimed at the blood has a narrow window. The ingestion event itself is modelled once, as the `environmental:` entry that TRIGGERS this node, rather than duplicated as a pathophysiology node; that follows Arsenic_Poisoning, whose exposure entries likewise point at the systemic-exposure node.

A second, OATP1B3-independent route carries amatoxin into non-hepatic cells

Downstream

OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin The liver is the first organ reached from the portal circulation, and the sinusoidal transporter OATP1B3 carries the toxin into the hepatocyte.

Enterohepatic Recirculation of Alpha-Amanitin A substantial fraction of absorbed toxin is excreted in bile and reabsorbed, returning to the liver instead of leaving the body.

Intestinal Epithelial Injury Enterocytes have a high protein-synthesis rate and are injured directly, producing the gastrointestinal phase before any hepatic sign appears.

Renal Proximal Tubular Injury Filtered toxin is reabsorbed by the proximal tubule, which concentrates it in the tubular epithelium.

STT3B-Dependent Cellular Entry of Alpha-Amanitin Entry into cells additionally requires the N-glycan biosynthesis machinery, a determinant separate from sinusoidal uptake.

Hematopoietic Cell Apoptosis Hematopoietic cells are killed in culture at concentrations reached in poisoning, by a route the transporter account does not cover.

OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin

Carriage of alpha-amanitin across the sinusoidal membrane into the hepatocyte by the organic anion transporting polypeptide OATP1B3, encoded by SLCO1B3. This is the step that converts a poorly permeant peptide into a hepatocyte poison, and it is the reason the disease is a hepatopathy rather than a generalised cytotoxicity. It is also the step the first-line antidote targets.

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

hepatocyte CL:0000182

SLCO1B3 hgnc:10961

Experimental models

HepG2 hepatoma line with OATP1B3 knockdown CELL LINE Knockdown abolishes cytotoxicity, establishing the uptake step as necessary.

Downstream

RNA Polymerase II Inhibition Intracellular toxin reaches the nucleus and engages RNA polymerase II.

Show evidence (3 references)

PMID:16495352 SUPPORT DIRECT In Vitro

"we have identified OATP1B3 as the human hepatic uptake transporter for amatoxins"

The identification of the transporter, from uptake assays in cells stably expressing each candidate OATP.

PMID:16495352 SUPPORT DIRECT In Vitro

"Under our conditions, only OATP1B3 was able to transport amanitin"

A specificity result rather than a positive one: of the three sinusoidal OATPs tested, the other two did not transport the toxin.

PMID:38641045 SUPPORT DIRECT In Vitro

"knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity"

The loss-of-function control for this node: removing the transporter removes the toxicity, which makes uptake necessary rather than merely associated.

STT3B-Dependent Cellular Entry of Alpha-Amanitin

A requirement for the N-glycan biosynthesis component STT3B for alpha-amanitin to enter human cells, identified by CRISPR screening. It is a separate determinant from sinusoidal uptake: OATP1B3 explains which organs are reached, while STT3B is required for entry at the cellular level, and depleting it reduces toxin entry. It also nominated a repurposable inhibitor, which is why it appears here as a node with a treatment attached rather than as a note.

A second, OATP1B3-independent route carries amatoxin into non-hepatic cells

Downstream

RNA Polymerase II Inhibition Entry through this route delivers toxin to the same nuclear target, which is why it is drawn into the shared chain rather than as a parallel branch.

Show evidence (2 references)

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"Depletion of STT3B significantly decreased the entrance of α-amanitin in human cells"

The loss-of-function result establishing STT3B as required for cellular entry, restated by this review from the CRISPR screen it cites.

PMID:39684738 SUPPORT REVIEW SYNTHESIS In Vitro

"The N-glycan biosynthesis pathway and its main component, STT3B, were found to play a crucial role in α-amanitin toxicity"

Names the pathway and the screen that identified it.

RNA Polymerase II Inhibition

Non-covalent binding of alpha-amanitin to RNA polymerase II, trapping the bridge helix and trigger loop so the enzyme cannot complete the conformational cycle that adds a nucleotide and advances along the template. The enzyme is not destroyed; it is held, which is why the effect is a progressive decay of existing transcripts rather than an instantaneous stop.

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

POLR2A hgnc:9187

transcription elongation by RNA polymerase II GO:0006368 ↓ DECREASED

DNA-directed RNA polymerase activity GO:0003899 ↓ DECREASED

Downstream

Arrest of Messenger RNA Synthesis

Show evidence (2 references)

PMID:18552824 SUPPORT DIRECT In Vitro

"suggest that alpha-amanitin impairs nucleotide incorporation and translocation by trapping the trigger loop and bridge helix"

The structural result behind this node, from elongation-complex crystals soaked with the inhibitor. It also settles the bridge-helix-versus-trigger-loop question in favour of both.

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"The primary mechanism of liver toxicity is considered to be the inhibition of RNA polymerase II with consequent hepatocyte apoptosis."

Places polymerase inhibition as the accepted primary lesion.

Arrest of Messenger RNA Synthesis

Progressive loss of cellular mRNA as existing transcripts are degraded and not replaced. The lag between exposure and injury is largely the half-life of the transcripts and proteins already present.

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

mRNA synthesis GO:0009299 ↓ DECREASED

Downstream

Failure of Protein Synthesis

Collapse of new protein production in cells that cannot tolerate it. This is the point at which the lesion becomes tissue-selective: the transcriptional block is universal, but only cells with a high protein-synthesis demand fail on the timescale of the poisoning.

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

translation GO:0006412 ↓ DECREASED

Downstream

p53- and Caspase-Dependent Hepatocyte Apoptosis

Show evidence (1 reference)

PMID:33803263 SUPPORT INDIRECT In Vitro

"four subunits in the T-complex protein 1-ring complex protein decreased depending on the α-AMA concentration"

A dose-dependent fall in specific chaperonin subunits in treated hepatoma cells, which is a measured consequence of the synthesis block. Graded INDIRECT because the proteomic readout shows depletion of particular proteins rather than global synthesis rate.

p53- and Caspase-Dependent Hepatocyte Apoptosis

Programmed death of hepatocytes downstream of the transcriptional block, requiring p53 and executed through caspases. The genetic evidence is subtractive rather than correlative, which is what makes this node a mechanism rather than a description.

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

hepatocyte CL:0000182

TP53 hgnc:11998

apoptotic process GO:0006915 ↑ INCREASED

Downstream

Centrilobular Hepatic Necrosis

Show evidence (2 references)

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"Knock-out p53/BAK mice also showed significant resistance to hepatotoxicity from α-amanitin exposure, and wild-type mice under the same conditions exhibited significant liver cell death"

A knockout-versus-wild-type comparison making p53 and BAK necessary for the hepatotoxicity. Graded MODEL_ORGANISM because the quoted experiment is in mice, and REVIEW_SYNTHESIS because this review is restating it rather than reporting its own experiment.

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"In vitro studies have shown that liver injury in mammals by α-amanitin is driven by p53- and caspase-3-dependent apoptosis in hepatocytes"

Evidences the caspase half of this node's name, which the knockout quote above does not cover.

TNF-Mediated Amplification of Hepatocyte Injury

An amplification loop in which alpha-amanitin raises hepatic TNF and TNF in turn increases hepatocyte death. Blocking TNF prevents the liver injury in mice, which places it in the causal path rather than alongside it.

TNF and reactive oxygen species amplify hepatocyte death beyond the primary transcriptional lesion

TNF hgnc:11892

Downstream

p53- and Caspase-Dependent Hepatocyte Apoptosis TNF amplifies the apoptotic response that the transcriptional block initiates.

Show evidence (1 reference)

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism

"However, in mice treated with anti-TNF antibodies, liver injury caused by α-amanitin was prevented"

A blocking experiment: removing TNF signalling removes the injury, which is why this is modelled as a node in the chain rather than a correlate.

Centrilobular Hepatic Necrosis

Confluent loss of hepatocytes concentrated in zone 3 around the central vein, the histological lesion of amatoxin poisoning, commonly preceded by steatosis.

Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery

centrilobular region hepatocyte CL:0019029

Downstream

Hepatic Synthetic and Metabolic Failure

Elevated hepatic transaminases Transaminase release from dying hepatocytes, which is the biochemical signature of the necrosis rather than of the synthetic failure that follows.

Show evidence (2 references)

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Biopsies of explanted livers have demonstrated massive centrilobular hemorrhagic necrosis and vacuolar degeneration of hepatocytes"

Human explant histology, which is the direct observation of this node. Graded HUMAN_CLINICAL because the quoted material is patient tissue, with quote_role REVIEW_SYNTHESIS because the citing paper is summarising it.

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"Steatosis often precedes the appearance of centrilobular necrosis"

Sources the sequence this node's description states.

Hepatic Synthetic and Metabolic Failure

Loss of hepatic synthetic and metabolic function - clotting factors, gluconeogenesis, ammonia clearance - presenting from about the third day and driving the systemic phenotypes. This is the node transplant decisions are made against. It is deliberately named for the mechanism rather than for the clinical syndrome, so that it does not collide with the `Acute liver failure` phenotype in the flat bare-name target namespace.

Downstream

Acute liver failure The clinical syndrome these synthetic and metabolic failures constitute.

Prolonged prothrombin time Loss of hepatic clotting-factor synthesis.

Hypoglycemia Loss of hepatic gluconeogenesis and glycogen reserve.

Hepatic encephalopathy Failure of hepatic ammonia clearance.

Jaundice

Hyperbilirubinemia

Enterohepatic Recirculation of Alpha-Amanitin

Biliary excretion of absorbed toxin followed by intestinal reabsorption, which returns the toxin to the liver rather than eliminating it and so extends the hepatic exposure well beyond the plasma half-life. This node is the target of multi-dose activated charcoal and of biliary drainage, and it is why an intervention aimed only at the blood has limited reach.

Animal models

Canine natural amatoxin poisoning treated on an adapted Santa Cruz protocol Dog perturbs Percutaneous biliary drainage was used to interrupt recirculation, and all five dogs survived.

Downstream

OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin Reabsorbed toxin re-enters the portal circulation and is taken up again.

Intestinal Epithelial Injury

Direct injury to enterocytes, whose high protein-synthesis rate makes them an early target. This produces the gastrointestinal phase, which begins six to twenty-four hours after the meal and can itself be severe enough to cause hypovolaemic collapse before any hepatic sign appears.

enterocyte CL:0000584

Downstream

Profuse watery diarrhea

Vomiting

Abdominal pain

Dehydration Fluid and electrolyte loss from the gastrointestinal phase.

Hypotension Hypovolaemia from the gastrointestinal losses, which the source names as a consequence of this phase rather than of the later hepatic failure.

Metabolic acidosis Acid-base disturbance from the gastrointestinal fluid and electrolyte losses.

Renal Proximal Tubular Injury

Injury to the proximal tubular epithelium, which reabsorbs filtered toxin and so concentrates it. The renal lesion can run independently of the hepatic one and may outlast it, which is why acute kidney injury is not simply hepatorenal syndrome in this poisoning.

epithelial cell of proximal tubule CL:0002306

Downstream

Acute kidney injury

Oliguria

Mitochondrial Injury in Proximal Tubular Epithelium

Swollen mitochondria with reduced cristae and lowered TOM20 in tubular epithelium, with cytochrome c oxidase activity preserved. Proposed as the proximate mechanism of the renal lesion, on the strength of one human biopsy.

Renal tubular injury is mediated by mitochondrial damage rather than by transcription arrest alone

epithelial cell of proximal tubule CL:0002306

mitochondrion organization GO:0007005 ↓ DECREASED

Downstream

Renal Proximal Tubular Injury

Show evidence (1 reference)

PMID:39967828 SUPPORT DIRECT Human Clinical

"Immunofluorescence for the key mitochondrial protein TOM20 found significantly decreased expression compared with ischemic acute tubular injury."

The measurement behind this node, with ischaemic tubular injury as the comparator, from a renal biopsy in a patient whose liver injury had resolved.

Hematopoietic Cell Apoptosis

Caspase-dependent death of haematopoietic cells and CD34+ progenitors on direct exposure to alpha-amanitin. This is the part of the disease the transporter account does not explain, because OATP1B3 inhibitors do not protect these cells.

A second, OATP1B3-independent route carries amatoxin into non-hepatic cells

hematopoietic stem cell CL:0000037

apoptotic process GO:0006915 ↑ INCREASED

Experimental models

Cultured hematopoietic cell lines and primary CD34+ progenitors PRIMARY CELL CULTURE Direct amanitin exposure kills haematopoietic cells and progenitors by a caspase-dependent route that OATP1B3 inhibitors do not block.

Downstream

Thrombocytopenia

Anemia

Show evidence (2 references)

PMID:38276537 SUPPORT DIRECT In Vitro

"α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism"

The paper's own conclusion, from caspase-3/7 activity and pan-caspase-inhibitor rescue.

PMID:38276537 SUPPORT DIRECT In Vitro

"The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity."

Supports this node's own statement that OATP1B3 inhibitors do not protect these cells. The claim it cuts against - that transporter-mediated uptake explains entry into every susceptible cell - is made by the oatp1b3_independent_uptake hypothesis and its discussion, not by this node, so the REFUTE is carried there rather than here.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 3

Prolonged prothrombin time HP:0008151

Show evidence (1 reference)

PMID:15664245 SUPPORT Human Clinical

"Prediction of fatal outcome had an optimum, if a prothrombin index less than 25% was combined with a serum creatinine greater than 106 micromol/l from day 3 after ingestion onwards"

A 198-patient series in which the prothrombin index, combined with creatinine, predicted death - which both evidences the coagulopathy and grounds the transplant criteria recorded under diagnosis.

Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:38393145 SUPPORT Human Clinical

"A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets."

The retrospective series that identified hematotoxicity as a feature of the poisoning rather than an incidental finding.

Anemia HP:0001903

Show evidence (1 reference)

PMID:38393145 SUPPORT Human Clinical

"A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets."

Records the falling haemoglobin and haematocrit in the same series.

Cardiovascular 1

Hypotension HP:0002615

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"

Names hypotension as a consequence of the gastrointestinal phase.

Digestive 5

Profuse watery diarrhea HP:0002014

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"a gastrointestinal phase occurring 6–24 h after ingestion characterized by symptoms of abdominal pain, nausea, vomiting, and watery diarrhea"

Names watery diarrhea within the defined gastrointestinal phase. The binding is the genus HP:0002014 Diarrhea because HPO has no watery-diarrhea term; the character is carried in preferred_term.

Vomiting HP:0002013

Show evidence (1 reference)

PMID:34143367 SUPPORT Human Clinical

"hospitalized in a peripheral hospital because of nausea, vomiting, watery diarrhea, and oliguria"

A human case in which vomiting is named as a presenting feature. The previous quote here recorded the onset interval and meal size and did not mention vomiting.

Jaundice HP:0000952

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"Acute liver failure with sudden derangement in transaminases and jaundice are the main pathophysiologic features of amatoxin intoxication."

Names jaundice as a defining feature.

Acute liver failure Acute hepatic failure HP:0006554

Show evidence (1 reference)

PMID:38393145 SUPPORT Human Clinical

"Six out of twenty-eight patients developed acute liver failure (ALF)."

A counted rate in a 28-patient single-centre series. Not used to set a frequency band, because the denominator is patients admitted with suspected poisoning of any severity rather than confirmed amatoxin ingestion.

Ulcerating ileocolitis Enterocolitis HP:0004387

Show evidence (2 references)

PMID:26357578 SUPPORT DIRECT Human Clinical

"Ulcerating ileocolitis was identified by computed tomography identifying a thickening of the bowel wall of the entire ileum and biopsies taken from the ileum and large bowel revealing distinct ileitis and proximally accentuated colitis."

The imaging and histology behind this phenotype. Bound to the genus HP:0004387 Enterocolitis because HPO has no ileocolitis term and the case names both ileitis and colitis, so Colitis alone would understate it.

PMID:26357578 SUPPORT Human Clinical

"only very few descriptions of late gastrointestinal complications of amatoxin poisoning exist worldwide"

Records that this is a rare complication, which is why no frequency is set on it. No causal edge is drawn to it either: the report argues the association is likely from the absence of alternative causes, which is not an attribution to a mechanism this entry models.

Genitourinary 2

Acute kidney injury HP:0001919

Show evidence (1 reference)

PMID:39967828 SUPPORT Human Clinical

"the patient subsequently developed KDIGO stage 3 acute kidney injury"

A staged human case of acute kidney injury following amatoxin exposure, developing after the liver injury had subsided.

Oliguria HP:0100520

Show evidence (1 reference)

PMID:34143367 SUPPORT Human Clinical

"he showed progressive decline of urine output"

Records falling urine output in a human case of amatoxin nephrotoxicity.

Metabolism 5

Dehydration HP:0001944

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"

Names the volume-depletion consequences of the gastrointestinal phase. Cited here for the hypovolaemic state rather than for a named dehydration finding.

Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"Acute liver failure with sudden derangement in transaminases and jaundice are the main pathophysiologic features of amatoxin intoxication."

Names transaminase derangement as a defining feature.

Hyperbilirubinemia HP:0002904

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"The final phase is progression to acute liver failure with a dramatic rise in transaminases and bilirubin associated with coagulopathy, hypoglycemia, acidosis, renal failure"

Names the bilirubin rise in the hepatic phase.

Hypoglycemia HP:0001943

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"The final phase is progression to acute liver failure with a dramatic rise in transaminases and bilirubin associated with coagulopathy, hypoglycemia, acidosis, renal failure"

Names hypoglycemia in the hepatic phase.

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"

Names metabolic acidosis as a consequence of the gastrointestinal phase.

Nervous System 1

Hepatic encephalopathy HP:0002480

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"renal failure (potentially hepatorenal syndrome), and hepatic encephalopathy"

Names hepatic encephalopathy in the final phase.

Constitutional 1

Abdominal pain HP:0002027

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"a gastrointestinal phase occurring 6–24 h after ingestion characterized by symptoms of abdominal pain, nausea, vomiting, and watery diarrhea"

Names abdominal pain within the defined gastrointestinal phase.

💊

Medical Actions

Intravenous Fluid Resuscitation and Supportive Care

Action: fluid therapy Ontology label: Fluid Therapy NCIT:C116537

Platform: Other

Volume replacement and correction of electrolytes and glucose, begun on presentation. Beyond treating hypovolaemia it maintains the urine output on which renal elimination of the toxin depends.

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"Aggressive IV rehydration maintains renal function, corrects metabolic acidosis and electrolyte abnormalities, and is beneficial in mitigating irreversible hepatotoxicity"

States the rationale and claimed benefit of fluid resuscitation.

Multiple-Dose Activated Charcoal

Action: multiple-dose activated charcoal Ontology label: Therapeutic Procedure NCIT:C49236

Agent: activated charcoal CHEBI:91090

Platform: Other

Repeated enteral activated charcoal, aimed not only at unabsorbed toxin in the gut but at toxin re-secreted in bile, which is what makes repeat dosing rational rather than merely cautious.

Mechanism Target:

INHIBITS Enterohepatic Recirculation of Alpha-Amanitin — Charcoal binds biliary-excreted toxin in the small intestine and prevents its reabsorption.

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"Given the enterohepatic circulation of amatoxins, activated charcoal should bind toxins excreted via bile into the small intestine, and multiple doses of charcoal should reduce toxin absorption from the gastrointestinal tract"

States the mechanism this edge asserts. Note the source's own modal verb - "should bind", "should reduce" - which is a rationale rather than a measured effect, and the explanation does not upgrade it.

Silibinin

Action: Pharmacotherapy NCIT:C15986

Agent: silibinin CHEBI:9144

Platform: Small molecule

The first-line antidote where available, given intravenously. Its mechanistic claim is precise: it competes with amatoxin for OATP1B3 and so blocks the uptake step. Its clinical claim is weaker than that precision suggests - see the treatments discussion.

Mechanism Target:

INHIBITS OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin — Silibinin inhibits OATP1B3-mediated amanitin transport, which is the mechanistic basis for giving it.

Show evidence (1 reference)

PMID:16495352 SUPPORT DIRECT In Vitro

"as well as by some antidotes used in the past for the treatment of human amatoxin poisoning (silibinin dihemisuccinate, penicillin G, prednisolone phosphate, and antamanide)"

The transport assay result, quoted far enough to name silibinin itself. The shorter form of this quote established only that some inhibitors worked.

INHIBITS Enterohepatic Recirculation of Alpha-Amanitin — Blocking hepatic re-uptake also interrupts the recirculating loop, so silibinin acts on the loop as well as on the uptake step that feeds it.

Show evidence (1 reference)

PMID:22352731 SUPPORT DIRECT Other

"has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin"

States both effects in one sentence, and is why silibinin carries a second target_mechanisms link rather than only the uptake one.

Show evidence (4 references)

PMID:22352731 SUPPORT INDIRECT Human Clinical

"In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin."

The efficacy claim for the intravenous formulation, which the oral-silymarin study below does not address. Graded INDIRECT because it aggregates uncontrolled case reports, and the source is a review advocating for the product it names.

PMID:22352731 SUPPORT Other

"There are no controlled clinical studies available due to ethical reasons"

Records why the evidence base for the first-line antidote is uncontrolled, which is why the item above is graded INDIRECT rather than treated as settled.

PMID:41378447 REFUTE DIRECT Human Clinical

"After adjusting for potential confounders, silymarin was not associated with a decrease in mortality."

Scoped to the claim that this treatment reduces mortality, and to the oral silymarin formulation studied here rather than to intravenous silibinin. It does not refute the uptake-inhibition mechanism above, which is an in-vitro transport result.

+ 1 more reference

Benzylpenicillin

Action: Pharmacotherapy NCIT:C15986

Agent: benzylpenicillin CHEBI:18208

Platform: Small molecule

High-dose intravenous penicillin G, historically the most widely used agent for this poisoning and mechanistically a competitor at the same transporter silibinin blocks. It is included because the entry's primary source calls it the most widely used agent, not because it is preferred: where the two have been compared, silibinin did better.

Mechanism Target:

INHIBITS OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin — Benzylpenicillin inhibits OATP1B3 and so limits amatoxin entry into the hepatocyte, the same node silibinin acts on.

Show evidence (2 references)

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"In vitro studies with human hepatocytes demonstrated that benzylpenicillin limited the cytotoxicity of amatoxins through potent inhibition of the OATP1B3 transporter"

The transport-inhibition result behind this edge, in human hepatocytes.

PMID:16495352 SUPPORT DIRECT In Vitro

"as well as by some antidotes used in the past for the treatment of human amatoxin poisoning (silibinin dihemisuccinate, penicillin G, prednisolone phosphate, and antamanide)"

Independent confirmation from the transporter-identification study, which names penicillin G among the antidotes that inhibited amanitin uptake.

Show evidence (3 references)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"Benzylpenicillin is the most widely used agent against A. phalloides poisoning"

Establishes the agent's place in practice, which is why omitting it would have given a distorted picture of how this poisoning is actually treated.

PMID:12475187 REFUTE DIRECT Human Clinical

"Benzylpenicillin (Penicillin G) alone and in association was the mostfrequently utilized chemotherapy but showed little efficacy"

Scoped to the claim that this agent is effective, not to the claim that it is widely used, which the item above makes and this one independently confirms. From a compilation of 2108 hospitalised exposures. The source's run-together "mostfrequently" is reproduced exactly, since a snippet never corrects its source.

PMID:22352731 REFUTE DIRECT Human Clinical

Scoped to the claim that benzylpenicillin should be preferred: where the two were compared, mortality was roughly twice as high with penicillin. The source is a review advocating for the silibinin product it names, which is why this is recorded as comparative evidence rather than as a settled result.

N-Acetylcysteine

Action: Pharmacotherapy NCIT:C15986

Agent: acetylcysteine CHEBI:22198

Platform: Small molecule

Given intravenously on acetaminophen-style regimens, as a glutathione precursor aimed at the oxidative arm of the injury. It is standard in most protocols; the oxidative arm it targets is itself not firmly established.

Show evidence (3 references)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"drug therapies including antibiotics, N-acetylcysteine, and silibinin"

Records N-acetylcysteine as part of standard drug therapy.

PMID:39684738 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"NAC was associated with higher survival in patients with amatoxin poisoning"

The human efficacy signal, from a retrospective multivariate analysis. Graded INDIRECT because it is an association in observational data; no randomised or controlled trial of N-acetylcysteine in this poisoning exists.

PMID:39684738 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"In experimental studies, NAC has demonstrated protective effects in human hepatocytes from α-amanitin-induced apoptosis"

The mechanistic counterpart in human hepatocytes, which is what makes the observational survival signal biologically plausible rather than incidental.

Therapeutic Plasma Exchange

Action: therapeutic plasma exchange Ontology label: Plasmapheresis NCIT:C15304

Platform: Other

Extracorporeal plasma exchange, used as an adjunct in established liver failure. The largest series to date missed its primary endpoint overall but found a benefit confined to patients with grade 2 or worse encephalopathy.

Show evidence (2 references)

PMID:41163058 SUPPORT DIRECT Human Clinical

"PEX was independently associated with reduced risk of the combined endpoint death or liver transplantation within 28 days from inclusion in patients with HE grade ≥ 2"

The positive subgroup result, in patients with hepatic encephalopathy of grade 2 or worse, from a 111-patient multi-centre retrospective study.

PMID:41163058 REFUTE DIRECT Human Clinical

"the primary outcome of 28-day LTX-free survival in all patients was not different between the SOC and PEX-groups"

Scoped to the claim that plasma exchange benefits unselected patients. The study's primary endpoint was negative, and recording only the subgroup result would misstate what it found.

Biliary Drainage

Action: percutaneous or endoscopic biliary drainage Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Surgery

Percutaneous or endoscopic drainage of bile, diverting re-secreted toxin out of the body instead of returning it to the gut. Mechanistically the most direct attack on enterohepatic recirculation, and supported so far only by very small prospective and veterinary series.

Mechanism Target:

INHIBITS Enterohepatic Recirculation of Alpha-Amanitin — External diversion of bile removes re-secreted toxin from the recirculating pool.

Show evidence (1 reference)

PMID:42273384 SUPPORT DIRECT Human Clinical

"Interrupting the enterohepatic recirculation of amatoxins is a mechanistically rational but unproven therapeutic strategy."

States the mechanism this edge asserts, and states in the same sentence that it is unproven, which is the honest strength of the edge.

Show evidence (1 reference)

PMID:42273384 SUPPORT DIRECT Human Clinical

"All five patients who underwent BD (performed at a median of three days after ingestion) survived (100%), whereas only one of the four non-BD patients survived (25%; P = 0.048)."

The whole of the human efficacy evidence: nine patients, five treated. The effect size is large and the sample is too small to settle the question, which is why the description says so.

Liver Transplantation

Action: Liver Transplantation NCIT:C15271

Platform: Surgery

Definitive treatment for established fulminant hepatic failure, with listing guided by prothrombin index and creatinine from day three.

Show evidence (1 reference)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"Liver transplantation is required in those with acute liver failure and poor prognostic features."

States the indication for transplantation.

🌍

Environmental Factors

Ingestion of foraged amatoxin-containing mushrooms

Bound to the genus ECTO:0000537 exposure to toxin rather than to ECTO:0000524 exposure to mycotoxin, on positive grounds rather than for want of searching. Searched the pinned local build (`uv run runoak -i sqlite:obo:ecto search 'l~mushroom'`, `'l~amanit'`, `'l~fungal toxin'`, `'l~mycotoxin'`, `'l~toxin'`, `'l~exposure to fung'`, `'l~poisonous'`) on 2026-09-19: ECTO has no mushroom, Amanita or amatoxin exposure class, and the only fungal-toxin hit is ECTO:0000524. That term is defined as `RO:0002309` involving CHEBI:25442 mycotoxin, and `uv run runoak -i sqlite:obo:chebi ancestors CHEBI:37415 -p i` shows alpha-amanitin is not a descendant of CHEBI:25442 - it sits under cyclic peptide, not under mycotoxin - so binding it would assert a classification CHEBI does not make. This also matches how the KB already splits the two: Ergotism, a genuine mould mycotoxicosis, binds ECTO:0000524, while Ciguatera_Fish_Poisoning and Acute_Ackee_Fruit_Intoxication bind ECTO:0000537 and carry the agent in preferred_term, which is what this entry does.

Consumption of wild-collected mushrooms of Amanita, Galerina or Lepiota mistaken for edible species. The exposure is dietary, the dose is set by the quantity of fruiting body eaten, and no method of preparation reduces it.

Show evidence (2 references)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"Amatoxins have good heat stability and are not destroyed by cooking or drying"

Supports treating the ingested mushroom as the exposure regardless of preparation, since cooking does not reduce the dose.

PMID:12475187 SUPPORT Human Clinical

"This mushroom intoxication is ascribed to 35 amatoxin-containing species belonging to three genera: Amanita, Galerina, and Lepiota."

Sources the species scope, which is this entry's stated reason for being named after the toxin rather than after a genus.

Mechanism Target:

TRIGGERS Systemic Alpha-Amanitin Exposure — The foraged meal is the route by which systemic amatoxin exposure is established; there is no other meaningful route of human exposure.

Show evidence (1 reference)

PMID:17503263 SUPPORT Human Clinical

"more than 90% of deaths resulting from ingestion of amatoxin-containing species"

Attributes the great majority of mushroom-poisoning deaths to ingestion of amatoxin-containing species, which is the exposure this link models.

🔬

Diagnosis

Urinary amatoxin detection

The only specific confirmatory test. Urine is the correct matrix; the window is narrow, and a negative result late after ingestion does not exclude poisoning.

urinary amatoxin assay NCIT:C217459

Bound to NCIT:C217459 Diagnostic Toxicology Testing, whose OLS hierarchicalAncestors include both NCIT:C25218 Clinical Intervention or Procedure (so it satisfies the dynamic enum) and NCIT:C18020 Diagnostic Procedure (so it is a strict specialisation of the generic term). The assay methods named in the source were searched first and rejected on positive grounds: NCIT:C17156 Mass Spectrometry and NCIT:C16435 Liquid Chromatography have no NCIT:C25218 ancestor, because they are technique concepts rather than clinical actions, and would fail the enum. NCIT:C17241 Urinalysis is reachable from NCIT:C25218 but not from NCIT:C18020 and names the specimen rather than the analysis, so it was not preferred.

Show evidence (4 references)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"The only specific laboratory test available is the detection of amatoxins in urine"

Establishes urinary detection as the specific test.

PMID:39684738 SUPPORT REVIEW SYNTHESIS Other

"After 36 h from the time of ingestion, the accuracy of the analysis is unreliable, and a negative result does not rule out amatoxin toxicity"

The limitation that matters clinically, since patients typically present late.

PMID:30565383 SUPPORT DIRECT Human Clinical

"Urinary amatoxin and prothrombin were independent predictors of hepatotoxicity"

The dedicated study of this assay, in 32 patients, showing it carries prognostic information and not only diagnostic confirmation.

+ 1 more reference

Prothrombin index and creatinine from day three

Prognostic assessment rather than diagnosis of the poisoning itself, used to decide transplant listing. A prothrombin index below 25 per cent together with a raised creatinine from day three onward predicted death with high accuracy in the derivation series.

prognostic laboratory assessment for transplant listing NCIT:C18020

Show evidence (1 reference)

PMID:15664245 SUPPORT DIRECT Human Clinical

"Prediction of fatal outcome had an optimum, if a prothrombin index less than 25% was combined with a serum creatinine greater than 106 micromol/l from day 3 after ingestion onwards"

The derivation of the amatoxin-specific transplant criteria, in 198 patients of whom 23 died.

📊

Prevalence

Patients treated for amatoxin poisoning at a single Italian toxicology unit, 1988-2002

Unknown Not yet documented

Not a population rate. Recorded because it is the best available statement of case fatality under a defined treatment protocol: 2 deaths among 111 patients, both admitted more than 60 hours after ingestion.

Show evidence (2 references)

PMID:17503263 SUPPORT Human Clinical

"all patients treated within 36 hours after mushroom ingestion were cured without sequelae"

The series' own summary of outcome by time to treatment, which is the variable this record exists to capture.

PMID:17503263 SUPPORT Human Clinical

"Two patients died; both were admitted to the hospital more than 60 hours after mushroom ingestion."

Carries the death count and the late-presentation detail that this record's notes state, so neither figure rests on prose alone.

Amanita phalloides poisoning, pooled across published series

Unknown Not yet documented

A case-fatality range quoted by a review, not a prevalence. Kept as a range rather than a point estimate because the underlying series differ in era, access to intensive care and case definition; two other sources in this entry give 10-40% and "over 90% of fatalities due to mushrooms", which are answering different questions.

Show evidence (2 references)

PMID:39684738 SUPPORT REVIEW SYNTHESIS Human Clinical

"The mortality rate of A. phalloides poisoning is 10–20%"

The review's pooled case-fatality statement.

PMID:38393145 SUPPORT Human Clinical

"Amanita phalloides poisoning is a serious health problem with a mortality rate of 10-40%."

A wider case-fatality range from a different source, quoted so that the disagreement this record's notes describe is visible rather than asserted.

🔬

Clinical Trials

ChiCTR2300073442 NOT_APPLICABLE UNKNOWN

Prospective pilot cohort of biliary drainage in amatoxin-induced pre-acute liver failure, registered with the Chinese Clinical Trial Registry and reported in PMID:42273384. The registry record still reads "Recruiting" and "Phase 0", but its last refresh predates the published nine-patient result, so `status` is recorded as UNKNOWN rather than copying a stale registry field, and `phase` as NOT_APPLICABLE because a non-randomised interventional pilot does not follow the FDA phase scheme the enum encodes.

Show evidence (1 reference)

ICTRP:ChiCTR2300073442 SUPPORT Other

"| Main ID | ChiCTR2300073442 |"

WHO ICTRP registration record establishing the trial's identity.

🧫

Experimental Models

HepG2 hepatoma line with OATP1B3 knockdown CELL_LINE

Human hepatoma cells in which OATP1B3 is knocked down, used to test whether transporter-mediated uptake is necessary for amatoxin cytotoxicity. The panel of eight organ-derived lines in the same study is what connects transporter expression to the organ selectivity seen clinically.

Publication

PMID:38641045

Pathograph links

OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin recapitulates fidelity: moderate observes: cellular Knockdown abolishes cytotoxicity, establishing the uptake step as necessary.

Limitations: A transformed hepatoma line rather than primary hepatocyte, and cytotoxicity over hours in culture rather than the multi-day staged human course. The model speaks to the uptake step only.

Show evidence (1 reference)

PMID:38641045 SUPPORT In Vitro

"knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity"

The loss-of-function result this model contributes.

Cultured hematopoietic cell lines and primary CD34+ progenitors PRIMARY_CELL_CULTURE

Haematopoietic lines and primary CD34+ cells exposed to alpha- and beta-amanitin with and without caspase inhibition, antidotes and OATP1B3 inhibitors. This is the model that exposed the gap in the transporter account.

Publication

PMID:38276537

Pathograph links

Hematopoietic Cell Apoptosis recapitulates fidelity: moderate observes: cellular Direct amanitin exposure kills haematopoietic cells and progenitors by a caspase-dependent route that OATP1B3 inhibitors do not block.

Limitations: An in-vitro exposure at defined concentrations, which does not establish that marrow reaches those concentrations in poisoned patients; the human evidence for hematotoxicity is a separate 28-patient retrospective series.

Show evidence (1 reference)

PMID:38276537 SUPPORT In Vitro

"The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity."

The negative rescue result that makes this model informative about an OATP1B3-independent route.

🐁

Animal Models

Canine natural amatoxin poisoning treated on an adapted Santa Cruz protocol

Dogs are poisoned naturally by foraged Amanita and reproduce the human course closely, including the oral route and the hepatic failure. This series treated five dogs with a protocol adapted from human practice, with biliary drainage as a core intervention.

Species

Dog

Publication

PMID:33458945

Pathograph links

Enterohepatic Recirculation of Alpha-Amanitin perturbs fidelity: moderate observes: organism Percutaneous biliary drainage was used to interrupt recirculation, and all five dogs survived.

Limitations: An uncontrolled case series of five animals with no comparison group, so survival cannot be attributed to any one component of a multi-part protocol. Species differences in amatoxin absorption are also substantial.

Show evidence (1 reference)

PMID:33458945 SUPPORT Model Organism

"Core interventions included percutaneous biliary drainage, use of octreotide, and early nil per os orders."

Names biliary drainage as a core element of the protocol applied.

Show evidence (1 reference)

PMID:33458945 SUPPORT Model Organism

"All dogs survived to discharge with this treatment strategy."

The outcome of the series, and the reason the canine setting is treated as informative for human management rather than only as comparative toxicology.

{ }

Source YAML

click to show

name: Amatoxin Poisoning
creation_date: '2026-09-19T19:00:00Z'
description: >-
  Amatoxin poisoning follows ingestion of a mushroom containing alpha-amanitin or
  one of its congeners. It causes the large majority of deaths from eating wild
  mushrooms, and the reason is as much timing as potency: the toxin is not
  destroyed by cooking, and it produces no symptom at all for a latent interval of
  six to eighteen hours, with the gastrointestinal phase beginning between six and
  twenty-four hours, so the patient presents after absorption is complete and the
  meal is rarely volunteered as relevant. The species differ and the toxin does
  not - Amanita phalloides, Amanita virosa, several Galerina and several Lepiota
  converge on the same molecule, which is why this entry is named for the toxin
  rather than the genus.

  Alpha-amanitin is a poor membrane permeant, and the step that makes an
  otherwise general poison organ-selective is carriage across the hepatocyte
  sinusoidal membrane by the uptake transporter OATP1B3. Cells that express the
  transporter take the toxin up and die; cells that do not are largely spared,
  which is why lung, heart and brain escape while liver, gut and kidney do not.
  Inside the cell the toxin binds RNA polymerase II and stops transcription, so
  the tissues that fail first are the ones with the highest demand for new
  protein.

  Clinically this reads as four phases - a latent interval, a cholera-like
  gastroenteritis, an apparent recovery, and hepatic failure from about the third
  day. The third phase is the dangerous one, because a patient who looks better is
  discharged while transcription is already silenced.
categories:
- Toxic Exposure Disorder
- Foodborne Toxin Exposure
- Acute Liver Failure
category: Environmental
parents:
- Poisoning
synonyms:
- Amanita phalloides poisoning
- death cap poisoning
- amatoxin syndrome
- cyclopeptide mushroom poisoning
- phalloides syndrome
notes: >-
  No disease_term is bound because MONDO has no amatoxin or mushroom-poisoning
  concept. Searched via the OLS MONDO index on 2026-09-19 for "mushroom
  poisoning", "mycetism", "amatoxin", "amanita", "amanitin", "phalloides",
  "toxic mushroom" and "hepatotoxic mushroom": the only returns were unrelated
  (MONDO:0005865 mushroom workers' lung, an occupational hypersensitivity
  pneumonitis, and MONDO:0016028 erythromelalgia). The nearest MONDO poisoning
  terms are agent-specific for other agents (MONDO:0017859 colchicine poisoning,
  MONDO:0042496 ergotism), and binding any of them would misname the agent. The
  deep-research report reached the same conclusion independently and offered
  MeSH:D009145 Mushroom Poisoning as the closest controlled heading; MeSH is not
  an ontology dismech binds disease_term to, and that heading is in any case the
  genus (all mushroom poisoning) rather than this toxin syndrome. Thirty-five other
  disorder entries already carry no disease_term.

  Thirteen further references were fetched and are committed because the
  deep-research report cites them, but are not cited by this entry. They divide
  into three groups: duplicates of mechanism or clinical content already sourced
  here from a primary or more specific paper (PMID:26375431, PMID:8370055,
  PMID:22811920, PMID:42188618, PMID:34208167 and
  DOI:10.1080/15563650.2022.2098139); case reports and regional series whose
  content is epidemiological or descriptive rather than mechanistic
  (PMID:28570504, PMID:41050366, PMID:41441612, PMID:42523156, PMID:40645529 and
  the canine DOI:10.1177/104063870701900317, a second dog case report beside the
  five-dog series already cited); and none that were screened out as wrong-entity
  or contradicted. They are kept rather than pruned because the committed report
  cites them, which is the repository's rule for what a reference cache may hold.

  No GeneReviews chapter exists for this disease, which is expected: GeneReviews
  covers Mendelian disorders and this is an acute toxic exposure with no genetic
  cause. `just check-genereviews` reports GeneReviews NO_CHAPTER against the
  committed Bookshelf index. It also reports StatPearls CITED_UNTAGGED, naming
  PMID:28613706 - and that finding is triggered by this very sentence, because the
  checker reads the chapter identifier written here as a citation. No StatPearls
  chapter is cited as evidence anywhere in the entry. StatPearls is never a
  baseline in any case, and the deep-research report's StatPearls quotations were
  not reused: the report's own reference validation found 11 of its 12 quoted
  claims absent from the cited source, so none of its quotations was treated as
  usable without re-derivation from a cached record.
mechanistic_hypotheses:
- hypothesis_group_id: rnap2_translocation_block
  hypothesis_label: Alpha-amanitin arrests transcription by trapping the RNA polymerase II translocation machinery
  status: CANONICAL
  description: >-
    The canonical account. Alpha-amanitin binds RNA polymerase II non-covalently
    near the bridge helix and trigger loop and prevents the conformational cycle
    that advances the enzyme by one nucleotide, so elongation stalls and mRNA
    output falls. Every downstream event in this entry is a consequence of that
    arrest. Review literature has presented the bridge helix and the trigger loop
    as two competing accounts of the binding site; the crystallographic work says
    they are not alternatives, because the inhibitor traps both elements at once.
- hypothesis_group_id: oatp1b3_independent_uptake
  hypothesis_label: A second, OATP1B3-independent route carries amatoxin into non-hepatic cells
  status: EMERGING
  description: >-
    OATP1B3 expression explains the classical organ selectivity well, and
    knocking it down in a hepatoma line abolishes cytotoxicity. It does not
    explain hematotoxicity: cultured hematopoietic cells and CD34+ progenitors are
    killed by alpha-amanitin, and OATP1B3 inhibitors do not rescue them. Either
    those cells import the toxin by another carrier, or enough enters by a
    non-carrier route to matter where the transporter account predicts sparing.
    One transporter-independent entry determinant is known - a CRISPR screen
    identified the N-glycan biosynthesis component STT3B as required for
    alpha-amanitin to enter human cells - so the open question is not whether any
    second route exists but whether STT3B accounts for the haematopoietic
    compartment specifically, which has not been tested.
- hypothesis_group_id: mitochondrial_nephrotoxicity
  hypothesis_label: Renal tubular injury is mediated by mitochondrial damage rather than by transcription arrest alone
  status: EMERGING
  description: >-
    Proposed from a single human case with electron microscopy and
    immunofluorescence on the renal biopsy, in a patient whose liver injury had
    already resolved. Mitochondria were swollen with reduced cristae and TOM20
    expression was lower than in ischaemic tubular injury, while cytochrome c
    oxidase activity was preserved. The authors put it as a question rather than a
    conclusion, and the entry carries it the same way.
- hypothesis_group_id: tnf_ros_amplification
  hypothesis_label: TNF and reactive oxygen species amplify hepatocyte death beyond the primary transcriptional lesion
  status: ALTERNATIVE
  description: >-
    Anti-TNF antibody prevents alpha-amanitin liver injury in mice, which is a
    strong functional result and places TNF upstream of the injury rather than
    beside it. The reactive-oxygen arm is weaker: the same review that reports the
    TNF experiments says explicitly that the role of ROS is not established. The
    two are grouped because the proposed link between them is that TNF acts
    through lipid peroxidation.
pathophysiology:
- name: Systemic Alpha-Amanitin Exposure
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Circulating alpha-amanitin, established by absorption of the ingested fruiting
    body across the intestinal epithelium into the portal circulation. The toxin
    binds serum proteins weakly and is cleared quickly from plasma into liver and
    kidney, so the plasma compartment is a conduit rather than a reservoir - which
    is why extracorporeal removal aimed at the blood has a narrow window. The
    ingestion event itself is modelled once, as the `environmental:` entry that
    TRIGGERS this node, rather than duplicated as a pathophysiology node; that
    follows Arsenic_Poisoning, whose exposure entries likewise point at the
    systemic-exposure node.
  chemical_entities:
  - preferred_term: alpha-amanitin
    term:
      id: CHEBI:37415
      label: alpha-amanitin
    modifier: INCREASED
  downstream:
  - target: OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin
    causal_link_type: DIRECT
    description: >-
      The liver is the first organ reached from the portal circulation, and the
      sinusoidal transporter OATP1B3 carries the toxin into the hepatocyte.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In the liver, amanitins are transported by Organic Anion Transporting Polypeptides (OATP) into hepatocytes, causing extensive centrolobular necrosis."
      explanation: States the transporter-mediated hepatic uptake step and the lesion it produces.
  - target: Enterohepatic Recirculation of Alpha-Amanitin
    causal_link_type: DIRECT
    description: >-
      A substantial fraction of absorbed toxin is excreted in bile and reabsorbed,
      returning to the liver instead of leaving the body.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Approximately 60% of absorbed α-amanitin is excreted into bile and then returned to the liver via enterohepatic circulation."
      explanation: Quantifies the recirculating fraction, which is the rationale for charcoal and biliary drainage.
  - target: Intestinal Epithelial Injury
    causal_link_type: DIRECT
    description: >-
      Enterocytes have a high protein-synthesis rate and are injured directly,
      producing the gastrointestinal phase before any hepatic sign appears.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Metabolically active tissues dependent on high rates of protein synthesis, such as cells of the gastrointestinal tract, hepatocytes, and proximal convoluted tubules of the kidney, are disproportionately affected"
      explanation: >-
        Names the three high-turnover tissues that bear the injury, and is the
        source for treating the gut as a primary target rather than a bystander.
  - target: Renal Proximal Tubular Injury
    causal_link_type: DIRECT
    description: >-
      Filtered toxin is reabsorbed by the proximal tubule, which concentrates it in
      the tubular epithelium.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In the kidneys, after glomerular filtration, amanitins are reabsorbed in the renal tubules, resulting in acute tubular necrosis"
      explanation: States the renal route of exposure and the resulting lesion.
  - target: STT3B-Dependent Cellular Entry of Alpha-Amanitin
    causal_link_type: DIRECT
    hypothesis_groups:
    - oatp1b3_independent_uptake
    description: >-
      Entry into cells additionally requires the N-glycan biosynthesis machinery,
      a determinant separate from sinusoidal uptake.
  - target: Hematopoietic Cell Apoptosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - oatp1b3_independent_uptake
    description: >-
      Hematopoietic cells are killed in culture at concentrations reached in
      poisoning, by a route the transporter account does not cover.
    evidence:
    - reference: PMID:38276537
      reference_title: Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In CD34+ stem cells, α-amanitin decreased the number of colonies and cells."
      explanation: >-
        Shows direct toxicity to primary human progenitors, establishing the
        hematopoietic compartment as a target rather than a consequence of liver failure.
- name: OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin
  biological_scale: CELLULAR
  description: >-
    Carriage of alpha-amanitin across the sinusoidal membrane into the hepatocyte
    by the organic anion transporting polypeptide OATP1B3, encoded by SLCO1B3.
    This is the step that converts a poorly permeant peptide into a hepatocyte
    poison, and it is the reason the disease is a hepatopathy rather than a
    generalised cytotoxicity. It is also the step the first-line antidote targets.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  genes:
  - preferred_term: SLCO1B3
    term:
      id: hgnc:10961
      label: SLCO1B3
  evidence:
  - reference: PMID:16495352
    reference_title: Molecular characterization and inhibition of amanitin uptake into human hepatocytes.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "we have identified OATP1B3 as the human hepatic uptake transporter for amatoxins"
    explanation: >-
      The identification of the transporter, from uptake assays in cells stably
      expressing each candidate OATP.
  - reference: PMID:16495352
    reference_title: Molecular characterization and inhibition of amanitin uptake into human hepatocytes.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Under our conditions, only OATP1B3 was able to transport amanitin"
    explanation: >-
      A specificity result rather than a positive one: of the three sinusoidal
      OATPs tested, the other two did not transport the toxin.
  - reference: PMID:38641045
    reference_title: Amanitin-induced variable cytotoxicity in various cell lines is mediated by the different expression levels of OATP1B3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity"
    explanation: >-
      The loss-of-function control for this node: removing the transporter removes
      the toxicity, which makes uptake necessary rather than merely associated.
  notes: >-
    The node is bound to CL:0000182 hepatocyte rather than to a zonal subtype
    because the uptake step is not reported as zone-restricted; the zonation
    appears downstream, at the necrosis node, which binds CL:0019029.
  downstream:
  - target: RNA Polymerase II Inhibition
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnap2_translocation_block
    description: Intracellular toxin reaches the nucleus and engages RNA polymerase II.
    evidence:
    - reference: PMID:16495352
      reference_title: Molecular characterization and inhibition of amanitin uptake into human hepatocytes.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "CCK-8, a substrate specific for OATP1B3, prevented the fragmentation of nucleoli, a lesion typical for amanitin action"
      explanation: >-
        Blocking the transporter prevents the nucleolar lesion, which links uptake
        to the nuclear target. Graded INDIRECT because nucleolar fragmentation is a
        morphological readout of transcriptional arrest rather than a measurement of
        polymerase activity.
- name: STT3B-Dependent Cellular Entry of Alpha-Amanitin
  biological_scale: CELLULAR
  description: >-
    A requirement for the N-glycan biosynthesis component STT3B for alpha-amanitin
    to enter human cells, identified by CRISPR screening. It is a separate
    determinant from sinusoidal uptake: OATP1B3 explains which organs are reached,
    while STT3B is required for entry at the cellular level, and depleting it
    reduces toxin entry. It also nominated a repurposable inhibitor, which is why
    it appears here as a node with a treatment attached rather than as a note.
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Depletion of STT3B significantly decreased the entrance of α-amanitin in human cells"
    explanation: >-
      The loss-of-function result establishing STT3B as required for cellular
      entry, restated by this review from the CRISPR screen it cites.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "The N-glycan biosynthesis pathway and its main component, STT3B, were found to play a crucial role in α-amanitin toxicity"
    explanation: Names the pathway and the screen that identified it.
  downstream:
  - target: RNA Polymerase II Inhibition
    causal_link_type: DIRECT
    hypothesis_groups:
    - oatp1b3_independent_uptake
    description: >-
      Entry through this route delivers toxin to the same nuclear target, which is
      why it is drawn into the shared chain rather than as a parallel branch.
- name: RNA Polymerase II Inhibition
  biological_scale: MOLECULAR
  description: >-
    Non-covalent binding of alpha-amanitin to RNA polymerase II, trapping the
    bridge helix and trigger loop so the enzyme cannot complete the conformational
    cycle that adds a nucleotide and advances along the template. The enzyme is not
    destroyed; it is held, which is why the effect is a progressive decay of
    existing transcripts rather than an instantaneous stop.
  molecular_functions:
  - preferred_term: DNA-directed RNA polymerase activity
    term:
      id: GO:0003899
      label: DNA-directed RNA polymerase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: transcription elongation by RNA polymerase II
    term:
      id: GO:0006368
      label: transcription elongation by RNA polymerase II
    modifier: DECREASED
  genes:
  - preferred_term: POLR2A
    term:
      id: hgnc:9187
      label: POLR2A
  evidence:
  - reference: PMID:18552824
    reference_title: Structural basis of transcription inhibition by alpha-amanitin and implications for RNA polymerase II translocation.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "suggest that alpha-amanitin impairs nucleotide incorporation and translocation by trapping the trigger loop and bridge helix"
    explanation: >-
      The structural result behind this node, from elongation-complex crystals
      soaked with the inhibitor. It also settles the bridge-helix-versus-trigger-loop
      question in favour of both.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The primary mechanism of liver toxicity is considered to be the inhibition of RNA polymerase II with consequent hepatocyte apoptosis."
    explanation: Places polymerase inhibition as the accepted primary lesion.
  downstream:
  - target: Arrest of Messenger RNA Synthesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnap2_translocation_block
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "This inhibits transcription, causing a progressive decrease in messenger ribonucleic acid (mRNA) levels, leading to deficient protein synthesis and, eventually, cell apoptosis and necrosis"
      explanation: >-
        States the whole intracellular chain in one sentence - transcription arrest,
        falling mRNA, failed protein synthesis, cell death - and is cited on each of
        the three edges it covers.
- name: Arrest of Messenger RNA Synthesis
  biological_scale: MOLECULAR
  description: >-
    Progressive loss of cellular mRNA as existing transcripts are degraded and not
    replaced. The lag between exposure and injury is largely the half-life of the
    transcripts and proteins already present.
  biological_processes:
  - preferred_term: mRNA synthesis
    term:
      id: GO:0009299
      label: mRNA transcription
    modifier: DECREASED
  downstream:
  - target: Failure of Protein Synthesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnap2_translocation_block
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "This inhibits transcription, causing a progressive decrease in messenger ribonucleic acid (mRNA) levels, leading to deficient protein synthesis and, eventually, cell apoptosis and necrosis"
      explanation: Covers the step from falling mRNA to deficient protein synthesis.
- name: Failure of Protein Synthesis
  biological_scale: CELLULAR
  description: >-
    Collapse of new protein production in cells that cannot tolerate it. This is
    the point at which the lesion becomes tissue-selective: the transcriptional
    block is universal, but only cells with a high protein-synthesis demand fail on
    the timescale of the poisoning.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  evidence:
  - reference: PMID:33803263
    reference_title: Identification of Decrease in TRiC Proteins as Novel Targets of Alpha-Amanitin-Derived Hepatotoxicity by Comparative Proteomic Analysis In Vitro.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "four subunits in the T-complex protein 1-ring complex protein decreased depending on the α-AMA concentration"
    explanation: >-
      A dose-dependent fall in specific chaperonin subunits in treated hepatoma
      cells, which is a measured consequence of the synthesis block. Graded INDIRECT
      because the proteomic readout shows depletion of particular proteins rather
      than global synthesis rate.
  downstream:
  - target: p53- and Caspase-Dependent Hepatocyte Apoptosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnap2_translocation_block
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "This inhibits transcription, causing a progressive decrease in messenger ribonucleic acid (mRNA) levels, leading to deficient protein synthesis and, eventually, cell apoptosis and necrosis"
      explanation: Covers the final step, from deficient protein synthesis to cell death.
- name: p53- and Caspase-Dependent Hepatocyte Apoptosis
  biological_scale: CELLULAR
  description: >-
    Programmed death of hepatocytes downstream of the transcriptional block,
    requiring p53 and executed through caspases. The genetic evidence is
    subtractive rather than correlative, which is what makes this node a mechanism
    rather than a description.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Knock-out p53/BAK mice also showed significant resistance to hepatotoxicity from α-amanitin exposure, and wild-type mice under the same conditions exhibited significant liver cell death"
    explanation: >-
      A knockout-versus-wild-type comparison making p53 and BAK necessary for the
      hepatotoxicity. Graded MODEL_ORGANISM because the quoted experiment is in
      mice, and REVIEW_SYNTHESIS because this review is restating it rather than
      reporting its own experiment.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "In vitro studies have shown that liver injury in mammals by α-amanitin is driven by p53- and caspase-3-dependent apoptosis in hepatocytes"
    explanation: >-
      Evidences the caspase half of this node's name, which the knockout quote
      above does not cover.
  downstream:
  - target: Centrilobular Hepatic Necrosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnap2_translocation_block
- name: TNF-Mediated Amplification of Hepatocyte Injury
  biological_scale: CELLULAR
  description: >-
    An amplification loop in which alpha-amanitin raises hepatic TNF and TNF in
    turn increases hepatocyte death. Blocking TNF prevents the liver injury in
    mice, which places it in the causal path rather than alongside it.
  genes:
  - preferred_term: TNF
    term:
      id: hgnc:11892
      label: TNF
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, in mice treated with anti-TNF antibodies, liver injury caused by α-amanitin was prevented"
    explanation: >-
      A blocking experiment: removing TNF signalling removes the injury, which is
      why this is modelled as a node in the chain rather than a correlate.
  downstream:
  - target: p53- and Caspase-Dependent Hepatocyte Apoptosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnf_ros_amplification
    description: TNF amplifies the apoptotic response that the transcriptional block initiates.
- name: Centrilobular Hepatic Necrosis
  biological_scale: TISSUE
  description: >-
    Confluent loss of hepatocytes concentrated in zone 3 around the central vein,
    the histological lesion of amatoxin poisoning, commonly preceded by steatosis.
  cell_types:
  - preferred_term: centrilobular region hepatocyte
    term:
      id: CL:0019029
      label: centrilobular region hepatocyte
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Biopsies of explanted livers have demonstrated massive centrilobular hemorrhagic necrosis and vacuolar degeneration of hepatocytes"
    explanation: >-
      Human explant histology, which is the direct observation of this node.
      Graded HUMAN_CLINICAL because the quoted material is patient tissue, with
      quote_role REVIEW_SYNTHESIS because the citing paper is summarising it.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Steatosis often precedes the appearance of centrilobular necrosis"
    explanation: Sources the sequence this node's description states.
  downstream:
  - target: Hepatic Synthetic and Metabolic Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - rnap2_translocation_block
  - target: Elevated hepatic transaminases
    causal_link_type: DIRECT
    description: >-
      Transaminase release from dying hepatocytes, which is the biochemical
      signature of the necrosis rather than of the synthetic failure that follows.
- name: Hepatic Synthetic and Metabolic Failure
  biological_scale: ORGANISM
  description: >-
    Loss of hepatic synthetic and metabolic function - clotting factors,
    gluconeogenesis, ammonia clearance - presenting from about the third day and
    driving the systemic phenotypes. This is the node transplant decisions are made
    against. It is deliberately named for the mechanism rather than for the
    clinical syndrome, so that it does not collide with the `Acute liver failure`
    phenotype in the flat bare-name target namespace.
  downstream:
  - target: Acute liver failure
    causal_link_type: DIRECT
    description: >-
      The clinical syndrome these synthetic and metabolic failures constitute.
  - target: Prolonged prothrombin time
    causal_link_type: DIRECT
    description: Loss of hepatic clotting-factor synthesis.
  - target: Hypoglycemia
    causal_link_type: DIRECT
    description: Loss of hepatic gluconeogenesis and glycogen reserve.
  - target: Hepatic encephalopathy
    causal_link_type: DIRECT
    description: Failure of hepatic ammonia clearance.
  - target: Jaundice
    causal_link_type: DIRECT
  - target: Hyperbilirubinemia
    causal_link_type: DIRECT
- name: Enterohepatic Recirculation of Alpha-Amanitin
  biological_scale: ORGANISM
  description: >-
    Biliary excretion of absorbed toxin followed by intestinal reabsorption, which
    returns the toxin to the liver rather than eliminating it and so extends the
    hepatic exposure well beyond the plasma half-life. This node is the target of
    multi-dose activated charcoal and of biliary drainage, and it is why an
    intervention aimed only at the blood has limited reach.
  downstream:
  - target: OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin
    causal_link_type: DIRECT
    description: Reabsorbed toxin re-enters the portal circulation and is taken up again.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Approximately 60% of absorbed α-amanitin is excreted into bile and then returned to the liver via enterohepatic circulation."
      explanation: States the recirculating fraction returning to the liver.
- name: Intestinal Epithelial Injury
  biological_scale: TISSUE
  description: >-
    Direct injury to enterocytes, whose high protein-synthesis rate makes them an
    early target. This produces the gastrointestinal phase, which begins six to
    twenty-four hours after the meal and can itself be severe enough to cause
    hypovolaemic collapse before any hepatic sign appears.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  downstream:
  - target: Profuse watery diarrhea
    causal_link_type: DIRECT
  - target: Vomiting
    causal_link_type: DIRECT
  - target: Abdominal pain
    causal_link_type: DIRECT
  - target: Dehydration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Fluid and electrolyte loss from the gastrointestinal phase.
  - target: Hypotension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hypovolaemia from the gastrointestinal losses, which the source names as a
      consequence of this phase rather than of the later hepatic failure.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"
      explanation: >-
        Attributes hypotension and acidosis to the gastrointestinal symptoms, which
        is what these two edges assert.
  - target: Metabolic acidosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Acid-base disturbance from the gastrointestinal fluid and electrolyte losses.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"
      explanation: Attributes metabolic acidosis to the gastrointestinal phase.
- name: Renal Proximal Tubular Injury
  biological_scale: TISSUE
  description: >-
    Injury to the proximal tubular epithelium, which reabsorbs filtered toxin and so
    concentrates it. The renal lesion can run independently of the hepatic one and
    may outlast it, which is why acute kidney injury is not simply hepatorenal
    syndrome in this poisoning.
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  downstream:
  - target: Acute kidney injury
    causal_link_type: DIRECT
  - target: Oliguria
    causal_link_type: DIRECT
- name: Mitochondrial Injury in Proximal Tubular Epithelium
  biological_scale: CELLULAR
  description: >-
    Swollen mitochondria with reduced cristae and lowered TOM20 in tubular
    epithelium, with cytochrome c oxidase activity preserved. Proposed as the
    proximate mechanism of the renal lesion, on the strength of one human biopsy.
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: DECREASED
  evidence:
  - reference: PMID:39967828
    reference_title: Is Amanita phalloides Nephrotoxicity due to Mitochondrial Toxicity?
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence for the key mitochondrial protein TOM20 found significantly decreased expression compared with ischemic acute tubular injury."
    explanation: >-
      The measurement behind this node, with ischaemic tubular injury as the
      comparator, from a renal biopsy in a patient whose liver injury had resolved.
  downstream:
  - target: Renal Proximal Tubular Injury
    causal_link_type: DIRECT
    hypothesis_groups:
    - mitochondrial_nephrotoxicity
    evidence:
    - reference: PMID:39967828
      reference_title: Is Amanita phalloides Nephrotoxicity due to Mitochondrial Toxicity?
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings suggest that Amanita phalloides elicits acute tubular injury via mitochondrial damage, possibly through a pathway that spares COX function."
      explanation: >-
        The authors' own reading of the biopsy, stated as a suggestion. Graded
        INDIRECT because a single cross-sectional biopsy shows the two findings
        together rather than showing that one produces the other.
- name: Hematopoietic Cell Apoptosis
  biological_scale: CELLULAR
  description: >-
    Caspase-dependent death of haematopoietic cells and CD34+ progenitors on direct
    exposure to alpha-amanitin. This is the part of the disease the transporter
    account does not explain, because OATP1B3 inhibitors do not protect these cells.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:38276537
    reference_title: Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism"
    explanation: The paper's own conclusion, from caspase-3/7 activity and pan-caspase-inhibitor rescue.
  - reference: PMID:38276537
    reference_title: Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity."
    explanation: >-
      Supports this node's own statement that OATP1B3 inhibitors do not protect
      these cells. The claim it cuts against - that transporter-mediated uptake
      explains entry into every susceptible cell - is made by the
      oatp1b3_independent_uptake hypothesis and its discussion, not by this node,
      so the REFUTE is carried there rather than here.
  downstream:
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - oatp1b3_independent_uptake
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - oatp1b3_independent_uptake
phenotypes:
- category: Gastrointestinal
  name: Profuse watery diarrhea
  description: >-
    Cholera-like watery diarrhea beginning six to twenty-four hours after the meal,
    part of the gastrointestinal phase and a major source of volume loss.
  phenotype_term:
    preferred_term: profuse watery diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "a gastrointestinal phase occurring 6–24 h after ingestion characterized by symptoms of abdominal pain, nausea, vomiting, and watery diarrhea"
    explanation: >-
      Names watery diarrhea within the defined gastrointestinal phase. The binding
      is the genus HP:0002014 Diarrhea because HPO has no watery-diarrhea term; the
      character is carried in preferred_term.
- category: Gastrointestinal
  name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:34143367
    reference_title: 'Extensive proximal tubular necrosis without recovery following the ingestion of Amanita phalloides: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hospitalized in a peripheral hospital because of nausea, vomiting, watery diarrhea, and oliguria"
    explanation: >-
      A human case in which vomiting is named as a presenting feature. The
      previous quote here recorded the onset interval and meal size and did not
      mention vomiting.
- category: Gastrointestinal
  name: Abdominal pain
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "a gastrointestinal phase occurring 6–24 h after ingestion characterized by symptoms of abdominal pain, nausea, vomiting, and watery diarrhea"
    explanation: Names abdominal pain within the defined gastrointestinal phase.
- category: Constitutional
  name: Dehydration
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"
    explanation: >-
      Names the volume-depletion consequences of the gastrointestinal phase. Cited
      here for the hypovolaemic state rather than for a named dehydration finding.
- category: Cardiovascular
  name: Hypotension
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"
    explanation: Names hypotension as a consequence of the gastrointestinal phase.
- category: Hepatic
  name: Elevated hepatic transaminases
  description: >-
    Transaminase rise beginning during the apparent-convalescence phase, often
    while the patient feels better, and reaching several thousand units per litre
    in severe poisoning.
  phenotype_term:
    preferred_term: elevated serum aminotransferases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Acute liver failure with sudden derangement in transaminases and jaundice are the main pathophysiologic features of amatoxin intoxication."
    explanation: Names transaminase derangement as a defining feature.
- category: Hepatic
  name: Jaundice
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Acute liver failure with sudden derangement in transaminases and jaundice are the main pathophysiologic features of amatoxin intoxication."
    explanation: Names jaundice as a defining feature.
- category: Hepatic
  name: Hyperbilirubinemia
  phenotype_term:
    preferred_term: Hyperbilirubinemia
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The final phase is progression to acute liver failure with a dramatic rise in transaminases and bilirubin associated with coagulopathy, hypoglycemia, acidosis, renal failure"
    explanation: Names the bilirubin rise in the hepatic phase.
- category: Hematologic
  name: Prolonged prothrombin time
  description: >-
    Coagulopathy from loss of hepatic clotting-factor synthesis. The prothrombin
    index is the most discriminating single laboratory parameter in the derivation
    series, though it was not shown to beat creatinine, and the rule that came out
    of that series uses the two together.
  phenotype_term:
    preferred_term: prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  evidence:
  - reference: PMID:15664245
    reference_title: Indication of liver transplantation following amatoxin intoxication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prediction of fatal outcome had an optimum, if a prothrombin index less than 25% was combined with a serum creatinine greater than 106 micromol/l from day 3 after ingestion onwards"
    explanation: >-
      A 198-patient series in which the prothrombin index, combined with
      creatinine, predicted death - which both evidences the coagulopathy and
      grounds the transplant criteria recorded under diagnosis.
- category: Neurologic
  name: Hepatic encephalopathy
  phenotype_term:
    preferred_term: Hepatic encephalopathy
    term:
      id: HP:0002480
      label: Hepatic encephalopathy
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "renal failure (potentially hepatorenal syndrome), and hepatic encephalopathy"
    explanation: Names hepatic encephalopathy in the final phase.
- category: Metabolic
  name: Hypoglycemia
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The final phase is progression to acute liver failure with a dramatic rise in transaminases and bilirubin associated with coagulopathy, hypoglycemia, acidosis, renal failure"
    explanation: Names hypoglycemia in the hepatic phase.
- category: Metabolic
  name: Metabolic acidosis
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The clinical and metabolic consequences of these symptoms include hypotension, electrolyte disturbances, impaired renal function, and metabolic acidosis"
    explanation: Names metabolic acidosis as a consequence of the gastrointestinal phase.
- category: Hepatic
  name: Acute liver failure
  description: >-
    Fulminant hepatic failure developing from about day three, the cause of death
    in fatal cases and the indication for transplantation.
  phenotype_term:
    preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
  evidence:
  - reference: PMID:38393145
    reference_title: Unexpected Amanita phalloides-Induced Hematotoxicity-Results from a Retrospective Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six out of twenty-eight patients developed acute liver failure (ALF)."
    explanation: >-
      A counted rate in a 28-patient single-centre series. Not used to set a
      frequency band, because the denominator is patients admitted with suspected
      poisoning of any severity rather than confirmed amatoxin ingestion.
- category: Renal
  name: Acute kidney injury
  description: >-
    Acute tubular injury from proximal tubular reabsorption of filtered toxin, which
    may be severe and, in at least one reported case, irreversible after the
    hepatic injury had resolved.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:39967828
    reference_title: Is Amanita phalloides Nephrotoxicity due to Mitochondrial Toxicity?
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient subsequently developed KDIGO stage 3 acute kidney injury"
    explanation: >-
      A staged human case of acute kidney injury following amatoxin exposure,
      developing after the liver injury had subsided.
- category: Renal
  name: Oliguria
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  evidence:
  - reference: PMID:34143367
    reference_title: 'Extensive proximal tubular necrosis without recovery following the ingestion of Amanita phalloides: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he showed progressive decline of urine output"
    explanation: Records falling urine output in a human case of amatoxin nephrotoxicity.
- category: Gastrointestinal
  name: Ulcerating ileocolitis
  description: >-
    A rare late gastrointestinal complication, distinct from the day-one
    gastroenteritis: bowel-wall thickening with biopsy-proven ileitis and colitis
    appearing around day eight, after the hepatic injury has begun to reverse.
  phenotype_term:
    preferred_term: ulcerating ileocolitis
    term:
      id: HP:0004387
      label: Enterocolitis
  evidence:
  - reference: PMID:26357578
    reference_title: Ulcerating Ileocolitis in Severe Amatoxin Poisoning.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ulcerating ileocolitis was identified by computed tomography identifying a thickening of the bowel wall of the entire ileum and biopsies taken from the ileum and large bowel revealing distinct ileitis and proximally accentuated colitis."
    explanation: >-
      The imaging and histology behind this phenotype. Bound to the genus
      HP:0004387 Enterocolitis because HPO has no ileocolitis term and the case
      names both ileitis and colitis, so Colitis alone would understate it.
  - reference: PMID:26357578
    reference_title: Ulcerating Ileocolitis in Severe Amatoxin Poisoning.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only very few descriptions of late gastrointestinal complications of amatoxin poisoning exist worldwide"
    explanation: >-
      Records that this is a rare complication, which is why no frequency is set
      on it. No causal edge is drawn to it either: the report argues the
      association is likely from the absence of alternative causes, which is not
      an attribution to a mechanism this entry models.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Falling platelet count during the course of poisoning. Reported as part of a
    time-dependent haematological decline rather than only as a consequence of
    liver failure.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:38393145
    reference_title: Unexpected Amanita phalloides-Induced Hematotoxicity-Results from a Retrospective Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets."
    explanation: >-
      The retrospective series that identified hematotoxicity as a feature of the
      poisoning rather than an incidental finding.
- category: Hematologic
  name: Anemia
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:38393145
    reference_title: Unexpected Amanita phalloides-Induced Hematotoxicity-Results from a Retrospective Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets."
    explanation: Records the falling haemoglobin and haematocrit in the same series.
environmental:
- name: Ingestion of foraged amatoxin-containing mushrooms
  description: >-
    Consumption of wild-collected mushrooms of Amanita, Galerina or Lepiota
    mistaken for edible species. The exposure is dietary, the dose is set by the
    quantity of fruiting body eaten, and no method of preparation reduces it.
  exposure_term:
    preferred_term: dietary exposure to amatoxins in foraged mushrooms
    term:
      id: ECTO:0000537
      label: exposure to toxin
  food_source:
    preferred_term: mushroom fruitbody
    term:
      id: FOODON:00003528
      label: mushroom fruitbody
  influences_mechanisms:
  - target: Systemic Alpha-Amanitin Exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The foraged meal is the route by which systemic amatoxin exposure is
      established; there is no other meaningful route of human exposure.
    evidence:
    - reference: PMID:17503263
      reference_title: 'Amatoxin poisoning: a 15-year retrospective analysis and follow-up evaluation of 105 patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "more than 90% of deaths resulting from ingestion of amatoxin-containing species"
      explanation: >-
        Attributes the great majority of mushroom-poisoning deaths to ingestion of
        amatoxin-containing species, which is the exposure this link models.
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Amatoxins have good heat stability and are not destroyed by cooking or drying"
    explanation: >-
      Supports treating the ingested mushroom as the exposure regardless of
      preparation, since cooking does not reduce the dose.
  - reference: PMID:12475187
    reference_title: 'Treatment of amatoxin poisoning: 20-year retrospective analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mushroom intoxication is ascribed to 35 amatoxin-containing species belonging to three genera: Amanita, Galerina, and Lepiota."
    explanation: >-
      Sources the species scope, which is this entry's stated reason for being
      named after the toxin rather than after a genus.
  notes: >-
    Bound to the genus ECTO:0000537 exposure to toxin rather than to
    ECTO:0000524 exposure to mycotoxin, on positive grounds rather than for want
    of searching. Searched the pinned local build
    (`uv run runoak -i sqlite:obo:ecto search 'l~mushroom'`, `'l~amanit'`,
    `'l~fungal toxin'`, `'l~mycotoxin'`, `'l~toxin'`, `'l~exposure to fung'`,
    `'l~poisonous'`) on 2026-09-19: ECTO has no mushroom, Amanita or amatoxin
    exposure class, and the only fungal-toxin hit is ECTO:0000524. That term is
    defined as `RO:0002309` involving CHEBI:25442 mycotoxin, and
    `uv run runoak -i sqlite:obo:chebi ancestors CHEBI:37415 -p i` shows
    alpha-amanitin is not a descendant of CHEBI:25442 - it sits under cyclic
    peptide, not under mycotoxin - so binding it would assert a classification
    CHEBI does not make. This also matches how the KB already splits the two:
    Ergotism, a genuine mould mycotoxicosis, binds ECTO:0000524, while
    Ciguatera_Fish_Poisoning and Acute_Ackee_Fruit_Intoxication bind ECTO:0000537
    and carry the agent in preferred_term, which is what this entry does.
treatments:
- name: Intravenous Fluid Resuscitation and Supportive Care
  description: >-
    Volume replacement and correction of electrolytes and glucose, begun on
    presentation. Beyond treating hypovolaemia it maintains the urine output on
    which renal elimination of the toxin depends.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: fluid therapy
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Aggressive IV rehydration maintains renal function, corrects metabolic acidosis and electrolyte abnormalities, and is beneficial in mitigating irreversible hepatotoxicity"
    explanation: States the rationale and claimed benefit of fluid resuscitation.
- name: Multiple-Dose Activated Charcoal
  description: >-
    Repeated enteral activated charcoal, aimed not only at unabsorbed toxin in the
    gut but at toxin re-secreted in bile, which is what makes repeat dosing
    rational rather than merely cautious.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: multiple-dose activated charcoal
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
    therapeutic_agent:
    - preferred_term: activated charcoal
      term:
        id: CHEBI:91090
        label: charcoal
  target_mechanisms:
  - target: Enterohepatic Recirculation of Alpha-Amanitin
    treatment_effect: INHIBITS
    description: Charcoal binds biliary-excreted toxin in the small intestine and prevents its reabsorption.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Given the enterohepatic circulation of amatoxins, activated charcoal should bind toxins excreted via bile into the small intestine, and multiple doses of charcoal should reduce toxin absorption from the gastrointestinal tract"
      explanation: >-
        States the mechanism this edge asserts. Note the source's own modal verb -
        "should bind", "should reduce" - which is a rationale rather than a measured
        effect, and the explanation does not upgrade it.
- name: Silibinin
  description: >-
    The first-line antidote where available, given intravenously. Its mechanistic
    claim is precise: it competes with amatoxin for OATP1B3 and so blocks the
    uptake step. Its clinical claim is weaker than that precision suggests - see
    the treatments discussion.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: silibinin
      term:
        id: CHEBI:9144
        label: silibinin
  target_mechanisms:
  - target: OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin
    treatment_effect: INHIBITS
    description: >-
      Silibinin inhibits OATP1B3-mediated amanitin transport, which is the
      mechanistic basis for giving it.
    evidence:
    - reference: PMID:16495352
      reference_title: Molecular characterization and inhibition of amanitin uptake into human hepatocytes.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "as well as by some antidotes used in the past for the treatment of human amatoxin poisoning (silibinin dihemisuccinate, penicillin G, prednisolone phosphate, and antamanide)"
      explanation: >-
        The transport assay result, quoted far enough to name silibinin itself. The
        shorter form of this quote established only that some inhibitors worked.
  - target: Enterohepatic Recirculation of Alpha-Amanitin
    treatment_effect: INHIBITS
    description: >-
      Blocking hepatic re-uptake also interrupts the recirculating loop, so
      silibinin acts on the loop as well as on the uptake step that feeds it.
    evidence:
    - reference: PMID:22352731
      reference_title: 'Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning.'
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: "has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin"
      explanation: >-
        States both effects in one sentence, and is why silibinin carries a second
        target_mechanisms link rather than only the uptake one.
  evidence:
  - reference: PMID:22352731
    reference_title: 'Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin."
    explanation: >-
      The efficacy claim for the intravenous formulation, which the oral-silymarin
      study below does not address. Graded INDIRECT because it aggregates
      uncontrolled case reports, and the source is a review advocating for the
      product it names.
  - reference: PMID:22352731
    reference_title: 'Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are no controlled clinical studies available due to ethical reasons"
    explanation: >-
      Records why the evidence base for the first-line antidote is uncontrolled,
      which is why the item above is graded INDIRECT rather than treated as settled.
  - reference: PMID:41378447
    reference_title: 'Effect of oral silymarin in patients with acute hepatotoxic mushroom poisoning: an analysis of poison center data.'
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "After adjusting for potential confounders, silymarin was not associated with a decrease in mortality."
    explanation: >-
      Scoped to the claim that this treatment reduces mortality, and to the oral
      silymarin formulation studied here rather than to intravenous silibinin. It
      does not refute the uptake-inhibition mechanism above, which is an in-vitro
      transport result.
  - reference: PMID:41378447
    reference_title: 'Effect of oral silymarin in patients with acute hepatotoxic mushroom poisoning: an analysis of poison center data.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "the incidence of acute kidney injury was reduced"
    explanation: >-
      The same study's positive secondary outcome. Recorded as a separate item
      because one evidence item cannot carry a negative primary and a positive
      secondary result at once.
- name: Benzylpenicillin
  description: >-
    High-dose intravenous penicillin G, historically the most widely used agent for
    this poisoning and mechanistically a competitor at the same transporter
    silibinin blocks. It is included because the entry's primary source calls it
    the most widely used agent, not because it is preferred: where the two have
    been compared, silibinin did better.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: benzylpenicillin
      term:
        id: CHEBI:18208
        label: benzylpenicillin
  target_mechanisms:
  - target: OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin
    treatment_effect: INHIBITS
    description: >-
      Benzylpenicillin inhibits OATP1B3 and so limits amatoxin entry into the
      hepatocyte, the same node silibinin acts on.
    evidence:
    - reference: PMID:39684738
      reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "In vitro studies with human hepatocytes demonstrated that benzylpenicillin limited the cytotoxicity of amatoxins through potent inhibition of the OATP1B3 transporter"
      explanation: >-
        The transport-inhibition result behind this edge, in human hepatocytes.
    - reference: PMID:16495352
      reference_title: Molecular characterization and inhibition of amanitin uptake into human hepatocytes.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "as well as by some antidotes used in the past for the treatment of human amatoxin poisoning (silibinin dihemisuccinate, penicillin G, prednisolone phosphate, and antamanide)"
      explanation: >-
        Independent confirmation from the transporter-identification study, which
        names penicillin G among the antidotes that inhibited amanitin uptake.
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Benzylpenicillin is the most widely used agent against A. phalloides poisoning"
    explanation: >-
      Establishes the agent's place in practice, which is why omitting it would
      have given a distorted picture of how this poisoning is actually treated.
  - reference: PMID:12475187
    reference_title: 'Treatment of amatoxin poisoning: 20-year retrospective analysis.'
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Benzylpenicillin (Penicillin G) alone and in association was the mostfrequently utilized chemotherapy but showed little efficacy"
    explanation: >-
      Scoped to the claim that this agent is effective, not to the claim that it is
      widely used, which the item above makes and this one independently confirms.
      From a compilation of 2108 hospitalised exposures. The source's run-together
      "mostfrequently" is reproduced exactly, since a snippet never corrects its source.
  - reference: PMID:22352731
    reference_title: 'Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning.'
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin."
    explanation: >-
      Scoped to the claim that benzylpenicillin should be preferred: where the two
      were compared, mortality was roughly twice as high with penicillin. The source
      is a review advocating for the silibinin product it names, which is why this is
      recorded as comparative evidence rather than as a settled result.
- name: N-Acetylcysteine
  description: >-
    Given intravenously on acetaminophen-style regimens, as a glutathione precursor
    aimed at the oxidative arm of the injury. It is standard in most protocols; the
    oxidative arm it targets is itself not firmly established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetylcysteine
      term:
        id: CHEBI:22198
        label: acetylcysteine
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "drug therapies including antibiotics, N-acetylcysteine, and silibinin"
    explanation: Records N-acetylcysteine as part of standard drug therapy.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "NAC was associated with higher survival in patients with amatoxin poisoning"
    explanation: >-
      The human efficacy signal, from a retrospective multivariate analysis.
      Graded INDIRECT because it is an association in observational data; no
      randomised or controlled trial of N-acetylcysteine in this poisoning exists.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "In experimental studies, NAC has demonstrated protective effects in human hepatocytes from α-amanitin-induced apoptosis"
    explanation: >-
      The mechanistic counterpart in human hepatocytes, which is what makes the
      observational survival signal biologically plausible rather than incidental.
- name: Therapeutic Plasma Exchange
  description: >-
    Extracorporeal plasma exchange, used as an adjunct in established liver failure.
    The largest series to date missed its primary endpoint overall but found a
    benefit confined to patients with grade 2 or worse encephalopathy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: therapeutic plasma exchange
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  evidence:
  - reference: PMID:41163058
    reference_title: Therapeutic plasma exchange in amatoxin associated acute liver failure-results from the multi-center Amanita-PEX study.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "PEX was independently associated with reduced risk of the combined endpoint death or liver transplantation within 28 days from inclusion in patients with HE grade ≥ 2"
    explanation: >-
      The positive subgroup result, in patients with hepatic encephalopathy of
      grade 2 or worse, from a 111-patient multi-centre retrospective study.
  - reference: PMID:41163058
    reference_title: Therapeutic plasma exchange in amatoxin associated acute liver failure-results from the multi-center Amanita-PEX study.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "the primary outcome of 28-day LTX-free survival in all patients was not different between the SOC and PEX-groups"
    explanation: >-
      Scoped to the claim that plasma exchange benefits unselected patients. The
      study's primary endpoint was negative, and recording only the subgroup result
      would misstate what it found.
- name: Biliary Drainage
  description: >-
    Percutaneous or endoscopic drainage of bile, diverting re-secreted toxin out of
    the body instead of returning it to the gut. Mechanistically the most direct
    attack on enterohepatic recirculation, and supported so far only by very small
    prospective and veterinary series.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: percutaneous or endoscopic biliary drainage
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Enterohepatic Recirculation of Alpha-Amanitin
    treatment_effect: INHIBITS
    description: External diversion of bile removes re-secreted toxin from the recirculating pool.
    evidence:
    - reference: PMID:42273384
      reference_title: 'Bile Drainage Improves Survival in Amatoxin-induced Severe Liver Injury: A Prospective Pilot Cohort Study.'
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Interrupting the enterohepatic recirculation of amatoxins is a mechanistically rational but unproven therapeutic strategy."
      explanation: >-
        States the mechanism this edge asserts, and states in the same sentence
        that it is unproven, which is the honest strength of the edge.
  evidence:
  - reference: PMID:42273384
    reference_title: 'Bile Drainage Improves Survival in Amatoxin-induced Severe Liver Injury: A Prospective Pilot Cohort Study.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five patients who underwent BD (performed at a median of three days after ingestion) survived (100%), whereas only one of the four non-BD patients survived (25%; P = 0.048)."
    explanation: >-
      The whole of the human efficacy evidence: nine patients, five treated. The
      effect size is large and the sample is too small to settle the question,
      which is why the description says so.
- name: Liver Transplantation
  description: >-
    Definitive treatment for established fulminant hepatic failure, with listing
    guided by prothrombin index and creatinine from day three.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Liver transplantation is required in those with acute liver failure and poor prognostic features."
    explanation: States the indication for transplantation.
diagnosis:
- name: Urinary amatoxin detection
  description: >-
    The only specific confirmatory test. Urine is the correct matrix; the window is
    narrow, and a negative result late after ingestion does not exclude poisoning.
  diagnosis_term:
    preferred_term: urinary amatoxin assay
    term:
      id: NCIT:C217459
      label: Diagnostic Toxicology Testing
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The only specific laboratory test available is the detection of amatoxins in urine"
    explanation: Establishes urinary detection as the specific test.
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "After 36 h from the time of ingestion, the accuracy of the analysis is unreliable, and a negative result does not rule out amatoxin toxicity"
    explanation: >-
      The limitation that matters clinically, since patients typically present late.
  - reference: PMID:30565383
    reference_title: Potential value of urinary amatoxin quantification in patients with hepatotoxic mushroom poisoning.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urinary amatoxin and prothrombin were independent predictors of hepatotoxicity"
    explanation: >-
      The dedicated study of this assay, in 32 patients, showing it carries
      prognostic information and not only diagnostic confirmation.
  - reference: PMID:30565383
    reference_title: Potential value of urinary amatoxin quantification in patients with hepatotoxic mushroom poisoning.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In positive amatoxins patients, urinary concentrations > 55 ng/ml (or a baseline prothrombin ≤ 83%), were associated to hepatotoxicity"
    explanation: The concentration threshold the same study derived.
  notes: >-
    Bound to NCIT:C217459 Diagnostic Toxicology Testing, whose OLS
    hierarchicalAncestors include both NCIT:C25218 Clinical Intervention or
    Procedure (so it satisfies the dynamic enum) and NCIT:C18020 Diagnostic
    Procedure (so it is a strict specialisation of the generic term). The assay
    methods named in the source were searched first and rejected on positive
    grounds: NCIT:C17156 Mass Spectrometry and NCIT:C16435 Liquid Chromatography
    have no NCIT:C25218 ancestor, because they are technique concepts rather than
    clinical actions, and would fail the enum. NCIT:C17241 Urinalysis is reachable
    from NCIT:C25218 but not from NCIT:C18020 and names the specimen rather than
    the analysis, so it was not preferred.
- name: Prothrombin index and creatinine from day three
  description: >-
    Prognostic assessment rather than diagnosis of the poisoning itself, used to
    decide transplant listing. A prothrombin index below 25 per cent together with a
    raised creatinine from day three onward predicted death with high accuracy in the
    derivation series.
  diagnosis_term:
    preferred_term: prognostic laboratory assessment for transplant listing
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:15664245
    reference_title: Indication of liver transplantation following amatoxin intoxication.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prediction of fatal outcome had an optimum, if a prothrombin index less than 25% was combined with a serum creatinine greater than 106 micromol/l from day 3 after ingestion onwards"
    explanation: >-
      The derivation of the amatoxin-specific transplant criteria, in 198 patients
      of whom 23 died.
prevalence:
- population: Patients treated for amatoxin poisoning at a single Italian toxicology unit, 1988-2002
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Not a population rate. Recorded because it is the best available statement of
    case fatality under a defined treatment protocol: 2 deaths among 111 patients,
    both admitted more than 60 hours after ingestion.
  evidence:
  - reference: PMID:17503263
    reference_title: 'Amatoxin poisoning: a 15-year retrospective analysis and follow-up evaluation of 105 patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients treated within 36 hours after mushroom ingestion were cured without sequelae"
    explanation: >-
      The series' own summary of outcome by time to treatment, which is the
      variable this record exists to capture.
  - reference: PMID:17503263
    reference_title: 'Amatoxin poisoning: a 15-year retrospective analysis and follow-up evaluation of 105 patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients died; both were admitted to the hospital more than 60 hours after mushroom ingestion."
    explanation: >-
      Carries the death count and the late-presentation detail that this record's
      notes state, so neither figure rests on prose alone.
- population: Amanita phalloides poisoning, pooled across published series
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    A case-fatality range quoted by a review, not a prevalence. Kept as a range
    rather than a point estimate because the underlying series differ in era,
    access to intensive care and case definition; two other sources in this entry
    give 10-40% and "over 90% of fatalities due to mushrooms", which are answering
    different questions.
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mortality rate of A. phalloides poisoning is 10–20%"
    explanation: The review's pooled case-fatality statement.
  - reference: PMID:38393145
    reference_title: Unexpected Amanita phalloides-Induced Hematotoxicity-Results from a Retrospective Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Amanita phalloides poisoning is a serious health problem with a mortality rate of 10-40%."
    explanation: >-
      A wider case-fatality range from a different source, quoted so that the
      disagreement this record's notes describe is visible rather than asserted.
animal_models:
- name: Canine natural amatoxin poisoning treated on an adapted Santa Cruz protocol
  species: Dog
  description: >-
    Dogs are poisoned naturally by foraged Amanita and reproduce the human course
    closely, including the oral route and the hepatic failure. This series treated
    five dogs with a protocol adapted from human practice, with biliary drainage as
    a core intervention.
  publication: PMID:33458945
  modeled_mechanisms:
  - target: Enterohepatic Recirculation of Alpha-Amanitin
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Percutaneous biliary drainage was used to interrupt recirculation, and all
      five dogs survived.
    limitations: >-
      An uncontrolled case series of five animals with no comparison group, so
      survival cannot be attributed to any one component of a multi-part protocol.
      Species differences in amatoxin absorption are also substantial.
    evidence:
    - reference: PMID:33458945
      reference_title: Clinical recovery of 5 dogs from amatoxin mushroom poisoning using an adapted Santa Cruz protocol for people.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Core interventions included percutaneous biliary drainage, use of octreotide, and early nil per os orders."
      explanation: Names biliary drainage as a core element of the protocol applied.
  evidence:
  - reference: PMID:33458945
    reference_title: Clinical recovery of 5 dogs from amatoxin mushroom poisoning using an adapted Santa Cruz protocol for people.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "All dogs survived to discharge with this treatment strategy."
    explanation: >-
      The outcome of the series, and the reason the canine setting is treated as
      informative for human management rather than only as comparative toxicology.
experimental_models:
- name: HepG2 hepatoma line with OATP1B3 knockdown
  experimental_model_type: CELL_LINE
  description: >-
    Human hepatoma cells in which OATP1B3 is knocked down, used to test whether
    transporter-mediated uptake is necessary for amatoxin cytotoxicity. The panel
    of eight organ-derived lines in the same study is what connects transporter
    expression to the organ selectivity seen clinically.
  publication: PMID:38641045
  modeled_mechanisms:
  - target: OATP1B3-Mediated Hepatocyte Uptake of Alpha-Amanitin
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Knockdown abolishes cytotoxicity, establishing the uptake step as necessary.
    limitations: >-
      A transformed hepatoma line rather than primary hepatocyte, and cytotoxicity
      over hours in culture rather than the multi-day staged human course. The model
      speaks to the uptake step only.
    evidence:
    - reference: PMID:38641045
      reference_title: Amanitin-induced variable cytotoxicity in various cell lines is mediated by the different expression levels of OATP1B3.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity"
      explanation: The loss-of-function result this model contributes.
- name: Cultured hematopoietic cell lines and primary CD34+ progenitors
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Haematopoietic lines and primary CD34+ cells exposed to alpha- and beta-amanitin
    with and without caspase inhibition, antidotes and OATP1B3 inhibitors. This is
    the model that exposed the gap in the transporter account.
  publication: PMID:38276537
  modeled_mechanisms:
  - target: Hematopoietic Cell Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Direct amanitin exposure kills haematopoietic cells and progenitors by a
      caspase-dependent route that OATP1B3 inhibitors do not block.
    limitations: >-
      An in-vitro exposure at defined concentrations, which does not establish that
      marrow reaches those concentrations in poisoned patients; the human evidence
      for hematotoxicity is a separate 28-patient retrospective series.
    evidence:
    - reference: PMID:38276537
      reference_title: Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity."
      explanation: >-
        The negative rescue result that makes this model informative about an
        OATP1B3-independent route.
discussions:
- discussion_id: oatp1b3_independent_entry_route
  kind: KNOWLEDGE_GAP
  prompt: >-
    By what route does alpha-amanitin enter haematopoietic cells, given that
    OATP1B3 inhibition does not protect them?
  attaches_to:
  - pathophysiology#Hematopoietic Cell Apoptosis
  rationale: >-
    OATP1B3 expression is the accepted explanation for why amatoxin spares lung,
    heart and brain while destroying liver, gut and kidney, and the hepatic evidence
    for it is strong in both directions - the transporter carries the toxin, and
    knocking it down abolishes the cytotoxicity. Haematopoietic cells do not fit:
    they are killed at comparable concentrations, and OATP1B3 inhibitors do not
    rescue them. Either another carrier is involved or the transporter account is
    incomplete as a general theory of cellular susceptibility. The question matters
    therapeutically, because silibinin's mechanism is transporter blockade, and a
    compartment that takes up toxin without OATP1B3 is a compartment the antidote
    cannot protect.
  evidence:
  - reference: PMID:38276537
    reference_title: Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity."
    explanation: The observation that opens the gap.
- discussion_id: ros_causal_role_in_hepatotoxicity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do reactive oxygen species contribute causally to amatoxin hepatotoxicity, or
    are they a marker of cells already dying from transcriptional arrest?
  attaches_to:
  - pathophysiology#TNF-Mediated Amplification of Hepatocyte Injury
  rationale: >-
    This is not an idle question, because N-acetylcysteine is given in nearly every
    protocol and its rationale is the oxidative arm. The TNF half of the loop has a
    blocking experiment behind it; the ROS half does not, and the review that
    reports both says so in as many words. Until it is settled, the standard use of
    an antioxidant antidote rests on a mechanism the same literature declines to
    assert.
  evidence:
  - reference: PMID:39684738
    reference_title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although some in vivo and in vitro studies have found some association between α-amanitin and the development of ROS, further investigation is needed"
    explanation: The review declining to treat the oxidative arm as established.
- discussion_id: biliary_drainage_survival_benefit
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does interrupting enterohepatic recirculation by biliary drainage improve
    survival, or does the nine-patient pilot reflect selection?
  attaches_to:
  - treatments#Biliary Drainage
  rationale: >-
    Two of this entry's interventions - multiple-dose charcoal and biliary drainage
    - target the recirculation node directly, and a third, silibinin, targets the
    uptake step that recirculation feeds. Recirculation is the one part of the
    mechanism that is straightforwardly interruptible. The drainage result is the
    largest effect reported for any intervention here and rests on five treated
    patients against four controls; the mechanistic case is strong and the clinical
    case is a pilot. The same manoeuvre is a core element of the canine protocol,
    which is supportive but also uncontrolled.
  evidence:
  - reference: PMID:42273384
    reference_title: 'Bile Drainage Improves Survival in Amatoxin-induced Severe Liver Injury: A Prospective Pilot Cohort Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interrupting the enterohepatic recirculation of amatoxins is a mechanistically rational but unproven therapeutic strategy."
    explanation: The authors' own statement of the gap their pilot addresses but does not close.
clinical_trials:
- name: ChiCTR2300073442
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    Prospective pilot cohort of biliary drainage in amatoxin-induced pre-acute liver
    failure, registered with the Chinese Clinical Trial Registry and reported in
    PMID:42273384. The registry record still reads "Recruiting" and "Phase 0", but
    its last refresh predates the published nine-patient result, so `status` is
    recorded as UNKNOWN rather than copying a stale registry field, and `phase` as
    NOT_APPLICABLE because a non-randomised interventional pilot does not follow the
    FDA phase scheme the enum encodes.
  evidence:
  - reference: ICTRP:ChiCTR2300073442
    reference_title: Clinical study of interruption of toxin enterohepatic circulation by bile drainage for the treatment of liver failure due to amatoxin-containing mushrooms
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Main ID | ChiCTR2300073442 |"
    explanation: WHO ICTRP registration record establishing the trial's identity.
references:
- reference: PMID:39684738
  title: 'Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.'
- reference: PMID:16495352
  title: Molecular characterization and inhibition of amanitin uptake into human hepatocytes.
- reference: PMID:18552824
  title: Structural basis of transcription inhibition by alpha-amanitin and implications for RNA polymerase II translocation.

📚

References & Deep Research

References

PMID:39684738

Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management.

No top-level findings curated for this source.

PMID:16495352

Molecular characterization and inhibition of amanitin uptake into human hepatocytes.

No top-level findings curated for this source.

PMID:18552824

Structural basis of transcription inhibition by alpha-amanitin and implications for RNA polymerase II translocation.

No top-level findings curated for this source.

Deep Research

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 (2)

Record notes

No disease_term is bound because MONDO has no amatoxin or mushroom-poisoning concept. Searched via the OLS MONDO index on 2026-09-19 for "mushroom poisoning", "mycetism", "amatoxin", "amanita", "amanitin", "phalloides", "toxic mushroom" and "hepatotoxic mushroom": the only returns were unrelated (MONDO:0005865 mushroom workers' lung, an occupational hypersensitivity pneumonitis, and MONDO:0016028 erythromelalgia). The nearest MONDO poisoning terms are agent-specific for other agents (MONDO:0017859 colchicine poisoning, MONDO:0042496 ergotism), and binding any of them would misname the agent. The deep-research report reached the same conclusion independently and offered MeSH:D009145 Mushroom Poisoning as the closest controlled heading; MeSH is not an ontology dismech binds disease_term to, and that heading is in any case the genus (all mushroom poisoning) rather than this toxin syndrome. Thirty-five other disorder entries already carry no disease_term. Thirteen further references were fetched and are committed because the deep-research report cites them, but are not cited by this entry. They divide into three groups: duplicates of mechanism or clinical content already sourced here from a primary or more specific paper (PMID:26375431, PMID:8370055, PMID:22811920, PMID:42188618, PMID:34208167 and DOI:10.1080/15563650.2022.2098139); case reports and regional series whose content is epidemiological or descriptive rather than mechanistic (PMID:28570504, PMID:41050366, PMID:41441612, PMID:42523156, PMID:40645529 and the canine DOI:10.1177/104063870701900317, a second dog case report beside the five-dog series already cited); and none that were screened out as wrong-entity or contradicted. They are kept rather than pruned because the committed report cites them, which is the repository's rule for what a reference cache may hold. No GeneReviews chapter exists for this disease, which is expected: GeneReviews covers Mendelian disorders and this is an acute toxic exposure with no genetic cause. `just check-genereviews` reports GeneReviews NO_CHAPTER against the committed Bookshelf index. It also reports StatPearls CITED_UNTAGGED, naming PMID:28613706 - and that finding is triggered by this very sentence, because the checker reads the chapter identifier written here as a citation. No StatPearls chapter is cited as evidence anywhere in the entry. StatPearls is never a baseline in any case, and the deep-research report's StatPearls quotations were not reused: the report's own reference validation found 11 of its 12 quoted claims absent from the cited source, so none of its quotations was treated as usable without re-derivation from a cached record.

Create: Amatoxin_Poisoning (no MONDO term) · 2026-09-19T20:46:40Z · View source

New entry for amatoxin poisoning, created because the concept had zero footprint anywhere in kb/ - no disorder entry, no module, no stub, not a single mention - despite causing the large majority of fatal mushroom poisonings. Named for the toxin rather than the genus, because Amanita, Galerina and Lepiota species converge on the same molecule. This follows the existing toxin-named entries Aconitine_Poisoning, Colchicine_Poisoning and Ricin_Poisoning. No disease_term. MONDO was searched through the OLS index for eight spellings of the concept and has no amatoxin or mushroom-poisoning term; the searches and the two unrelated hits are recorded in the entry's own notes. No GeneReviews chapter exists and `just check-genereviews` confirms NO_CHAPTER, correct for an acute toxic exposure with no genetic cause. Deep research: `just research-disorder claude_code Amatoxin_Poisoning` (366s, 23 web searches, 32 citations). The run exited 3 on a network timeout resolving MeSH:D009145 during term validation, so it wrote neither validation block. Both were retro-fitted afterwards - references with `just validate-research-reference`, and terms with the underlying `scripts/run_deep_research_client.sh validate-terms` with `--skip-prefix MeSH` added alongside the recipe's default `--skip-prefix HGNC`, since MeSH does not resolve through the OLS adapter and is not an ontology this repo binds to. The report is unusually unreliable and nothing was copied from it. Its reference validation resolves 27/27 identifiers but finds 11 of 12 quoted claims absent from the cited source - the exact case where confabulation_rate reads 0.0 and the report is still not quotable. Its term validation names four CURIEs that are different terms: CHEBI:2828 offered as alpha-amanitin is Arnebinone; NCBITaxon:33397 offered as Amanita phalloides is Chironomus plumosus, a midge; CL:1001016 offered as proximal convoluted tubule epithelium is loop-of-Henle ascending limb epithelial cell; and GO:0006919 and GO:0070265 are obsolete. Every snippet here was re-derived by reading the cached reference, and every CURIE by a live OLS or local-OAK lookup performed while writing the line. The correct values are CHEBI:37415 and NCBITaxon:67723. Snippet verification was run as a pre-pass before the YAML was written: 44 candidate quotes checked as exact substrings of references_cache/, 42 passed, and both failures were exotic whitespace - a thin space around the >= in PMID:41163058, and non-breaking spaces in "6 h" and "200 g" in PMID:34143367. Those two were extracted from the cache files by regex rather than retyped. Every reference_title was likewise read from cache frontmatter programmatically and re-checked after assembly: 15 distinct pairs, 0 mismatches. Pathophysiology is a single connected chain of 15 atomic nodes - ingestion, systemic exposure, OATP1B3-mediated hepatocyte uptake, RNA polymerase II inhibition, mRNA arrest, protein-synthesis failure, p53/caspase-dependent apoptosis, centrilobular necrosis and acute liver failure, plus the enterohepatic recirculation loop and the intestinal, renal, mitochondrial-renal, TNF and haematopoietic branches. 13 of 17 phenotypes are causally connected (76.5%). Four hypothesis groups, all wired to edges: rnap2_translocation_block (CANONICAL), oatp1b3_independent_uptake (EMERGING), mitochondrial_nephrotoxicity (EMERGING), tnf_ros_amplification (ALTERNATIVE). Three deliberate REFUTE items, each scoped to a claim rather than to a mechanism. PMID:38276537 refutes extending the OATP1B3 uptake account to haematopoietic cells, where inhibitors do not rescue, without touching the hepatocyte evidence where knockdown is protective. PMID:41378447 refutes a mortality benefit for oral silymarin, while a separate SUPPORT item from the same paper records its positive acute-kidney-injury secondary outcome. PMID:41163058 refutes a plasma-exchange benefit in unselected patients, while a SUPPORT item records the positive subgroup result in encephalopathy grade 2 or worse. The ECTO binding is the genus ECTO:0000537 exposure to toxin, rejected from ECTO:0000524 exposure to mycotoxin on positive grounds: that term is defined as involving CHEBI:25442 mycotoxin, and an ancestors query on the pinned CHEBI build shows alpha-amanitin is not a descendant of it. This matches how the KB already splits the two, with Ergotism on ECTO:0000524 and Ciguatera_Fish_Poisoning and Acute_Ackee_Fruit_Intoxication on ECTO:0000537. Two corrections made during validation, both caught by `just validate`: NCIT:C77524 Activated Charcoal is not reachable from the ChemicalEntityTerm roots and was replaced by CHEBI:91090 charcoal with the specificity carried in preferred_term; and the first draft's environmental block carried an `organism:` slot that does not exist on Environmental, so the Amanita phalloides taxon binding was dropped rather than relocated. Eleven evidence items quoting the review PMID:39684738 for human clinical features were regraded from evidence_source OTHER to HUMAN_CLINICAL with quote_role REVIEW_SYNTHESIS, since OTHER asserts nothing about a quote describing the patient picture. The ChiCTR-registered trial behind the biliary-drainage pilot is recorded as a clinical_trials entry keyed on ICTRP:ChiCTR2300073442, with the WHO ICTRP record fetched and committed, rather than left in prose. A pre-PR red-team review by a fresh-context subagent against `dismech-pr-review` returned 22 findings; every one was acted on before the first push. The two blocking ones were both content the entry's own committed cache supported and the entry either omitted or contradicted. First, the oatp1b3_independent_uptake hypothesis asserted "the route has not been identified" while the entry's most-cited reference describes a CRISPR screen identifying STT3B/N-glycan biosynthesis as required for cellular entry; a STT3B node was added to the chain and the hypothesis reworded to the question that is actually open. Second, benzylpenicillin was absent although the same source calls it the most widely used agent for this poisoning, so it was added with its OATP1B3 mechanism and with two REFUTE items carrying the comparative evidence against its efficacy. Other corrections of note. The N-acetylcysteine explanation claimed no controlled efficacy evidence "was found in the sources screened", which the same cache disproves; the efficacy statements were added and the wording narrowed to the true claim, that no randomised or controlled trial exists. An OATP1B3-dependent hepatic edge had been opted into the OATP1B3-INDEPENDENT hypothesis group - the tag was removed. Three snippets did not name the thing they were attached to: the Vomiting quote recorded an onset interval, the diarrhea quote never said diarrhea, and the silibinin transport quote was truncated just before silibinin is named. All three were replaced with sentences that do, already exact in the cache. A node-level REFUTE was refuting a claim made by the hypothesis rather than by the node, and was corrected to SUPPORT at the node. The lead description conflated the 6-18 h asymptomatic latency with the 6-24 h symptom-onset window, and contradicted the entry's own phenotype text. The GeneReviews note asserted a `just check-genereviews` verdict the tool contradicts - and the note itself is what triggers the contradiction, because naming NBK431052 in prose makes the checker read it as a citation; the note now says so. "Thirty-four" entries without disease_term was wrong; the count is 36 including this one. The pathophysiology node `Acute Liver Failure` and the phenotype `Acute liver failure` differed only in case, so they were two graph nodes for one concept and the phenotype rendered isolated. The mechanism node was renamed `Hepatic Synthetic and Metabolic Failure`, which is what it actually describes, and the phenotype wired from it. With three further edges added from nodes already present, phenotype connectivity went from 13/17 to 17/17. The diagnosis binding moved from the bare root NCIT:C18020 to NCIT:C217459 Diagnostic Toxicology Testing, after confirming via OLS hierarchicalAncestors that it descends from both NCIT:C25218 and NCIT:C18020. `GO:0016071` mRNA metabolic process was replaced by `GO:0009299` mRNA transcription, since the former subsumes mRNA degradation and so carries the wrong sign for a node about synthesis failing. The duplicate `Ingestion of Amatoxin-Containing Mushroom` pathophysiology node was dropped and the environmental link retargeted at the systemic-exposure node, following Arsenic_Poisoning. Six previously uncited references were consumed, including the species-scope source that the entry's own naming rationale depends on, the intravenous silibinin evidence, the dedicated urinary-quantification study, and the ulcerating-ileocolitis phenotype. The thirteen that remain uncited are listed in the entry's notes with the reason each was not used. One process failure to record: the benzylpenicillin CHEBI identifier was written from memory rather than from a lookup, in the middle of a fix pass that was itself correcting reviewer-surfaced defects. It happened to be right - CHEBI:18208 is benzylpenicillin - and it was checked immediately afterwards against OLS, but it was right by luck and not by process, which is the same failure the rest of this entry was built to avoid. Validation: `just validate-disorders` reports 89/89 snippets verified, with schema and term validation passing. Clean: check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-snippet-grading, check-title-snippets, check-snippet-length, check-folded-hyphens, check-environmental-evidence, check-case-collisions, check-reference-titles, check-not4curation, validate-history.

Claude Code ▸

Amatoxin Poisoning — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 32 citations 2026-09-19T20:08:15.056604

Amatoxin Poisoning — Comprehensive Research Report

1. Disease Information

Overview. Amatoxin poisoning is an acute, dose-dependent toxic hepatonephropathy caused by ingestion of amatoxin-containing mushrooms — most notably Amanita phalloides ("death cap"), but also A. virosa, A. verna, A. exitialis, A. fuliginea, Galerina spp., and some Lepiota spp. More than 35 mushroom species across the genera Amanita, Galerina, and Lepiota contain amatoxins (StatPearls NBK431052). It is the leading cause of fatal mushroom poisoning worldwide: "amatoxin-containing mushrooms cause 95% of worldwide mushroom ingestion deaths" (StatPearls). The disease is not a genetic/Mendelian disorder but an environmental/toxic-exposure disease entity — it has no OMIM phenotype number and, to my knowledge, no dedicated Orphanet ID (Orphanet is oriented to rare genetic disease and does not carry a specific entry for amatoxin poisoning). It is indexed in PubMed/MeSH and coded administratively via ICD-10-CM toxicology codes.

Key identifiers: - MeSH: Mushroom Poisoning, Unique ID D009145 (MeSH Browser) — the broader indexing term under which amatoxin-specific literature is filed; there is no separate amatoxin-specific MeSH descriptor, so curation should cite D009145 as the closest controlled heading. - ICD-10-CM: T62.0X1- (Toxic effect of ingested mushrooms, accidental/unintentional), with A/D/S 7th-character extensions for initial encounter, subsequent encounter, and sequela (ICD10Data). ICD-11 places it under Chapter 22 (Injury, poisoning or certain other consequences of external causes) without an amatoxin-specific leaf code identified in this search. - MONDO / OMIM / Orphanet: no amatoxin-specific MONDO term or OMIM phenotype number was identified — as an acute environmental toxidrome rather than an inherited disease, this is expected; if a MONDO/HPO-style knowledge base entry is created, this would be modeled as an environmental/toxic exposure entity rather than a Mendelian disease. - Wikidata: "mushroom poisoning" Q852186; the causal toxin class is described on Wikidata's "poisoning by drugs" superclass Q387175. - CHEBI (toxin chemistry, see §4/§6): α-amanitin, β-amanitin, phalloidin are indexed compounds (structural details below).

Synonyms / alternative names: Amatoxin mushroom poisoning; amatoxin syndrome; Amanita phalloides poisoning; death-cap poisoning; phalloides syndrome; cyclopeptide mushroom poisoning; hepatotoxic mushroom poisoning.

Data provenance. The evidence base is almost entirely aggregated disease-level and cohort/case-series data — national poison-center registries, retrospective multi-center cohorts (e.g., a Slovak cohort of 698 patients; a Chinese cohort of 105 and another of 567 patients; a Turkish liver-transplant cohort of 26 patients), case reports/series, and animal/in-vitro mechanistic studies — rather than individual EHR-linked genomic data, consistent with an acute toxic-exposure disease rather than a genetically characterized disorder.

2. Etiology

Disease causal factor: ingestion of amatoxins — a family of bicyclic octapeptide toxins (α-amanitin, β-amanitin, γ-amanitin, ε-amanitin) — present in fruiting bodies of Amanita phalloides and related species. This is a purely environmental/toxicological etiology; there is no genetic cause of the disease itself.

Risk factors: - Environmental/behavioral: wild-mushroom foraging, misidentification of A. phalloides for edible species (e.g., paddy-straw mushroom, Volvariella volvacea, in Asian contexts) (StatPearls); toxic species entering food-distribution/market chains through "misidentification during collection, unintentional mixing of edible and toxic species" (PMC13211627); amatoxin is heat-stable and survives cooking, drying, and freezing, so no culinary preparation is protective (StatPearls). - Age: children absorb proportionally higher toxin doses and have substantially higher morbidity/mortality than adults; "most unintentional mushroom exposures occur in children younger than 6 years," and historic mortality series report ~50% in adults vs ~33% in children in that era, though absolute pediatric case-fatality for hepatotoxic species has been reported >80% in some series (PMC12488608). - Dose/quantity ingested: the single most important determinant of severity — a single A. phalloides cap can contain a lethal dose (estimated human oral LD50 for α-amanitin ≈ 0.1 mg/kg) (StatPearls; veterinary sources). - Delay to treatment: time from ingestion to initiation of decontamination/antidotal therapy is a major modifiable prognostic factor. - Putative genetic/transporter variation (not established as a validated risk factor): hepatic uptake of amatoxin is mediated by the OATP1B3 transporter, encoded by SLCO1B3 (HGNC gene). Common SLCO1B3 SNPs (rs4149117 c.334T>G; rs7311358 c.699G>A) alter transporter activity for other OATP1B3 substrates in pharmacogenomic studies, but a direct, validated association between SLCO1B3 genotype and inter-individual amatoxin susceptibility was not found in the literature searched — this should be treated as a plausible but unproven gene–toxin interaction rather than a confirmed risk factor. - Familial clustering: shared-meal ingestion produces simultaneous, sometimes markedly heterogeneous, outcomes within families/households ("Family and the Fungi" case series, family of eight, PMID search; a Vietnamese familial case series with "markedly heterogeneous outcomes," PMID 42523156).

Protective factors: none intrinsic (no known protective genetic variant or diet identified in the literature searched); the only true "protective factor" is avoidance of ingestion (education) or early decontamination/antidotal treatment after exposure.

Gene–environment interaction: the leading candidate is SLCO1B3/OATP1B3 transporter expression level, which mechanistically determines cellular amatoxin influx (see §6) — cell lines with low OATP1B3 expression show markedly reduced amanitin cytotoxicity (PubMed 38641045, Amanitin-induced variable cytotoxicity in various cell lines is mediated by the different expression levels of OATP1B3). Whether inherited human SLCO1B3 polymorphism modulates clinical severity in patients remains an open research question, not yet answered in a clinical cohort.

3. Phenotypes

Amatoxin poisoning produces a time-staged, multi-organ phenotype set, classically described in four (or, in condensed schemes, three) phases.

Phase 1 — Latent phase

Type: absence of symptoms (asymptomatic interval)
Onset: 6–24 h post-ingestion (mean ~10–12.3 h; rarely up to 36–48 h) (PMC13211627; StatPearls)
Clinical significance: this delay — longer than the near-immediate onset of most non-amatoxin mushroom toxidromes — is itself a diagnostic clue and the reason patients rarely link symptoms to the meal.
HPO: no positive finding to bind (asymptomatic interval); could be modeled as a temporal qualifier rather than a phenotype node.

Phase 2 — Gastrointestinal phase (~6–24 h onward, lasting 1–3 days)

Phenotype	HPO term	Notes
Watery/profuse diarrhea	HP:0002014 Diarrhea	Cholera-like, can be severe
Recurrent vomiting	HP:0002013 Vomiting
Abdominal pain / cramps	HP:0002027 Abdominal pain
Dehydration	HP:0001944 Dehydration	Risk of hypovolemic shock
Hypotension / shock	HP:0002615 Hypotension	Severe cases
Tachycardia	HP:0001649 Tachycardia	Reflex to volume loss

Severity: variable, moderate to severe; can itself cause death from hypovolemic shock/electrolyte derangement in the most severe cases before hepatic phase manifests.
Progression: transient, self-limited over 1–3 days, masking ongoing occult hepatic injury.

Phase 3 — "Apparent convalescence" / latent hepatotoxic phase (day 2–3)

Symptomatic relief with ongoing subclinical rise in transaminases; this is the most dangerous phase for missed diagnosis, described as "a significant diagnostic challenge" because of "the transient improvement phase preceding severe organ toxicity" (PMC13211627).

Phase 4 — Hepatic/multiorgan failure phase (day 3–7+)

Phenotype	HPO term	Notes
Elevated hepatic transaminases	HP:0002910 Elevated hepatic transaminase	AST/ALT frequently >1000–5000 U/L
Jaundice	HP:0000952 Jaundice
Coagulopathy	HP:0001928 Abnormal bleeding (or HP:0031956 Elevated prothrombin time / INR)	Loss of clotting factor synthesis
Hepatic encephalopathy	HP:0002480 Hepatic encephalopathy	Graded I–IV
Hypoglycemia	HP:0001943 Hypoglycemia	Loss of hepatic gluconeogenesis
Metabolic acidosis	HP:0001942 Metabolic acidosis
Acute liver failure	HP:0006554 Acute hepatic failure	Fulminant hepatic failure
Acute kidney injury / hepatorenal syndrome	HP:0001919 Acute kidney injury; consider HP:0000083 Renal insufficiency	Acute tubular necrosis, proximal tubule injury
Elevated bilirubin	HP:0002904 Hyperbilirubinemia
Elevated LDH	(no dedicated HP term; lab finding)
Elevated ammonia	(no dedicated HP term commonly used; correlates with encephalopathy)	Plasma ammonia >95.1 μmol/L independently associated with mortality (PMC13211627)

Additional / less common phenotypes reported in recent literature: - Hematotoxicity — unexpectedly reported in a retrospective cohort ("Unexpected Amanita phalloides-Induced Hematotoxicity," PMC10891511); direct amanitin cytotoxicity to hematopoietic cell lines has been separately demonstrated in vitro (PMC10820516, Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells). - Elevated CK-MB and impaired consciousness — identified as independent mortality risk factors reflecting extrahepatic organ involvement, beyond conventional liver parameters (PMC13211627, citing a Chinese cohort study, PMID 40645529). - Ulcerating ileocolitis — a distinct, less common GI manifestation described in a dedicated case report (PMC4555452). - Proximal tubular necrosis without recovery — a nephrotoxic phenotype that can be irreversible even after hepatic recovery (PMC8610939).

Frequency/severity data: In a Chinese cohort of 105 patients, INR > 3.6 (AUC 0.941) and plasma ammonia > 95.1 μmol/L (AUC 0.805) independently predicted mortality; a Chronic Liver Failure–Organ Failure (CLIF-OF) score >9 within 24 h "demonstrated excellent predictive performance and outperformed the other evaluated scoring systems" (PMC13211627).

Quality-of-life impact: acute survivors without transplant generally recover full hepatic/renal function; those with irreversible proximal tubular necrosis or those requiring liver transplantation face long-term morbidity (immunosuppression, chronic kidney disease risk) — dedicated EQ-5D/SF-36 outcome studies specific to amatoxin poisoning were not identified in this search.

4. Genetic/Molecular Information

Amatoxin poisoning is not a Mendelian/inherited disease — there is no causal gene, no pathogenic germline variant, and no chromosomal abnormality that causes it. The relevant "genetic/molecular" information is instead about (a) the toxin's own molecular identity and target, and (b) transporter genetics that may modulate host susceptibility.

Molecular target (host): - POLR2A (RNA polymerase II largest subunit) — the direct, non-covalent binding target of amanitins. α-Amanitin binds in the "bridge helix" region of RNAP II via hydrogen bonding, blocking translocation and transcription elongation (PMC11640968). HGNC: POLR2A. - SLCO1B3 (OATP1B3) — hepatic sinusoidal uptake transporter for amanitin; HGNC gene SLCO1B3. Knockdown of OATP1B3 in HepG2 cells abolishes α-amanitin cytotoxicity, and cell-line susceptibility correlates with OATP1B3 expression level (PubMed 38641045; PubMed 16495352, Letschert et al., Molecular characterization and inhibition of amanitin uptake into human hepatocytes, Toxicol Sci 2006). - SLC10A1 (NTCP, sodium-taurocholate cotransporting polypeptide) — contributes secondarily to hepatocyte amanitin uptake alongside OATP1B3. - STT3B — a subunit of the oligosaccharyltransferase (N-glycan biosynthesis) complex, recently identified via CRISPR screening as required for cellular amanitin entry; STT3B depletion sharply reduces α-amanitin uptake, and indocyanine green was identified as a candidate STT3B inhibitor with in vivo protective effect (PMC11640968). - TP53 / BAK — p53- and caspase-3-dependent apoptosis mediates hepatocyte death; p53/BAK-knockout mice show resistance to α-amanitin hepatotoxicity (PMC11640968). - TNF (TNF-α) — amplifies hepatocyte apoptosis and lipid peroxidation after amanitin exposure; anti-TNF antibody pretreatment prevents liver injury in mice (PMC11640968).

Toxin molecular identity (chemical entities): - α-Amanitin — CHEBI-indexed bicyclic octapeptide, Wikipedia/CHEBI entry ("α-Amanitin"); a highly modified bicyclic octapeptide with an outer peptide-bond loop and an inner loop closed by a tryptathionine (Trp–Cys) crossbridge between 6-hydroxytryptophan and cysteine; carries hydroxylated/modified residues including (2S,3R,4R)-4,5-dihydroxyisoleucine and trans-4-hydroxyproline, conferring high-affinity RNAP II binding. - β-Amanitin, γ-amanitin, ε-amanitin — structural congeners differing at side-chain positions, all sharing the amatoxin bicyclic scaffold and RNAP II mechanism. - Phalloidin / phallacidin — related bicyclic heptapeptide "phallotoxins," biosynthesized by the same Amanita gene cluster but acting on filamentous actin rather than RNAP II; contribute to the early GI-phase symptoms, though they are poorly absorbed orally and are not the lethal principle. - CHEBI suggestions: CHEBI:2828 (α-amanitin) and related CHEBI entries for β-amanitin/phalloidin (exact CHEBI IDs should be confirmed via OAK/CHEBI lookup at curation time rather than asserted from memory).

Variant classification / population frequency: not applicable in the ClinVar/gnomAD sense, since this is a toxin-exposure disease. No ACMG/AMP pathogenicity classification, no somatic/germline distinction, and no allele-frequency data for a "causal variant" exist. The nearest genetic-variation data relevant to the entry are the SLCO1B3 transporter SNPs discussed in §2, which are pharmacogenomic modifiers of a xenobiotic transporter, not disease-causing variants.

Epigenetics / chromosomal abnormalities: none identified as relevant; not applicable to this disease category.

5. Environmental Information

Environmental/toxic factor: amatoxins (α-, β-, γ-amanitin) synthesized by Amanita phalloides and related fungi — this is itself the disease's entire environmental etiology (see §2). CHEBI/ECTO exposure-term candidates: "exposure to Amanita phalloides toxin" / "dietary exposure to mushroom toxin" (exact ECTO CURIE should be confirmed at curation via OAK lookup).

Lifestyle factors: wild-mushroom foraging as a recreational/subsistence activity is the dominant behavioral risk factor; regional foraging culture explains most of the geographic difference in case burden — "this difference in frequency reflects the relative popularity of mushroom foraging in Europe and Asia rather than significant differences in intrinsic toxicity or prevalence of harmful mushroom species across the regions" (search synthesis from epidemiology sources above). Restaurant/market contamination (toxic species entering food-distribution chains) is a second, distinct lifestyle-adjacent exposure route, especially documented in China/Southeast Asia (PMC13211627).

Infectious agents: not applicable — amatoxin poisoning is a toxidrome, not an infection.

6. Mechanism / Pathophysiology

Ordered causal chain

Ingestion of amatoxin-containing mushroom material → amatoxins (heat-stable; survive cooking) are released and rapidly absorbed from the small-intestinal mucosa into the portal circulation. This step also directly injures enterocytes (high protein-synthesis-rate cells), contributing to the early diarrhea/vomiting phase (Phase 2, §3). Inferred/demonstrated: demonstrated in humans and animal models.
Absorbed amatoxin travels via the portal vein to the liver, where it is taken up across the hepatocyte sinusoidal membrane predominantly by the organic anion-transporting polypeptide OATP1B3 (gene SLCO1B3), with a secondary contribution from the bile-salt transporter NTCP (SLC10A1) (PubMed 16495352; PubMed 38641045). This leads to → hepatocyte-selective toxin accumulation, explaining the liver's role as principal target organ.
Within the hepatocyte, entry into the cytosol/nucleus additionally requires the N-glycan biosynthesis machinery (STT3B), recently identified via CRISPR screening as necessary for α-amanitin uptake at the cellular level — depleting STT3B sharply reduces toxin entry (PMC11640968). This leads to →
Non-covalent, high-affinity binding of α-amanitin to RNA polymerase II at the bridge-helix region (hydrogen-bond interaction with RNAP II residues), which blocks the enzyme's translocation step during transcription elongation (PMC11640968). This leads to →
Progressive, global inhibition of mRNA synthesis, and consequently → failure of new protein synthesis in cells with the highest transcriptional/translational turnover (hepatocytes, enterocytes, and renal proximal tubular epithelial cells) — the mechanistic basis for the tissue tropism of the disease (StatPearls; PMC11640968). This leads to →
Cellular stress response and mitochondrial dysfunction: p53 accumulates in the cytosol and translocates to mitochondria (a process reported as Bcl-2–mediated), reducing TOM20 expression and triggering mitochondrial reactive oxygen species (ROS) generation (PubMed 39967828 / PMC11835023, Is Amanita phalloides Nephrotoxicity due to Mitochondrial Toxicity?). Branch: cytosolic ROS may also directly activate the caspase cascade independent of the mitochondrial route.
p53- and caspase-3-dependent apoptosis of hepatocytes ensues; this is genetically demonstrated — p53/BAK-knockout mice are resistant to α-amanitin hepatotoxicity (PMC11640968). In parallel, →
TNF-α upregulation amplifies hepatocyte apoptosis and lipid peroxidation; anti-TNF antibody pretreatment in mice prevents α-amanitin liver injury, establishing this as a mechanistically necessary (not merely correlated) amplification loop (PMC11640968).
At the tissue level, the combination of direct transcriptional shutdown, oxidative/mitochondrial injury, and apoptosis/necrosis produces centrilobular (zone 3) hepatic necrosis with nucleolar disintegration, corresponding clinically to the rapid rise in transaminases and progression toward fulminant hepatic failure (Phase 4).
In parallel to the hepatic branch, the same RNAP II-inhibition/oxidative-stress/mitochondrial-dysfunction cascade occurs in renal proximal tubular epithelial cells, producing acute tubular necrosis, cell vacuolization, tubular dilatation, and interstitial edema — this can occur independently of, and sometimes outlasts, hepatic recovery (PubMed 39967828; PMC8610939, a case of irreversible proximal tubular necrosis).
Systemic consequences of hepatic failure — loss of clotting-factor synthesis (coagulopathy), loss of gluconeogenesis (hypoglycemia), impaired ammonia clearance (hyperammonemia → hepatic encephalopathy), and metabolic acidosis — converge with renal failure to produce multiorgan failure, the terminal common pathway leading to death without liver transplantation.
A separately reported extrahepatic branch: direct amanitin cytotoxicity to hematopoietic cells ([PMC10820516]) and possible cardiac involvement (elevated CK-MB as an independent mortality predictor, [PMC13211627]) suggest the RNAP II-inhibition mechanism is not confined to the classic three target tissues, though the mechanistic detail of cardiac/hematologic injury is less well characterized than hepatic/renal injury — this is an area of ongoing investigation rather than an established branch.

Molecular pathways / GO terms

RNA polymerase II transcription inhibition: GO:0006366 (transcription by RNA polymerase II); target protein POLR2A.
Apoptotic process: GO:0006915 (apoptotic process); GO:0097194 (execution phase of apoptosis); GO:0006919 (activation of cysteine-type endopeptidase activity involved in apoptotic process) for caspase-3 activation.
Response to oxidative stress: GO:0006979 (response to oxidative stress); GO:0072593 (reactive oxygen species metabolic process).
Mitochondrial dysfunction/mitophagy: GO:0000422 (mitophagy); GO:0007005 (mitochondrion organization).
TNF signaling: GO:0033209 (tumor necrosis factor-mediated signaling pathway).
Necrosis: GO:0070265 (necrotic cell death).

Cell types (CL terms)

Hepatocyte — CL:0000182
Enterocyte — CL:0000584
Kidney proximal tubule epithelial cell — CL:1001016 (or CL:0002306 epithelial cell of proximal tubule)
Hepatic stellate cell / Kupffer cell — potential secondary responders in the inflammatory amplification loop (not directly evidenced above but biologically plausible; do not bind without a specific citation)

Anatomical/tissue targets (UBERON, see also §7)

Liver (UBERON:0002107), specifically the centrilobular/zone 3 hepatic lobule region
Kidney proximal convoluted tubule (UBERON:0004134 / UBERON:0001225 renal tubule)
Small intestine mucosa/enterocyte layer (UBERON:0002108/UBERON:0000160)

Omics / advanced technologies

Metabolomics: an untargeted metabolomics study of 61 amatoxin poisoning patients identified 33 differential metabolites, with 11-oxo-androsterone glucuronide, glucose-6-phosphate, and glycochenodeoxycholate-3-sulfate positively correlating with hepatic injury severity (PMC13211627, citing PMID-referenced study [34]).
Functional genomics/CRISPR screen: identified STT3B/N-glycan biosynthesis as a novel amanitin-entry dependency, nominating indocyanine green as a candidate inhibitor (PMC11640968).
Proteomics: comparative proteomic analysis in vitro identified decreased TRiC chaperonin proteins as a novel correlate of α-amanitin hepatotoxicity (PMC7999322, Identification of Decrease in TRiC Proteins as Novel Targets of Alpha-Amanitin-Derived Hepatotoxicity by Comparative Proteomic Analysis In Vitro).
Machine learning models: a retrospective ML study of 567 critically ill mushroom-poisoning patients found extreme gradient boosting achieved AUC 0.83 (cross-validation) / 0.90 (test set), sensitivity 0.93, specificity 0.79, outperforming physician gestalt for outcome prediction (PMC13211627).

7. Anatomical Structures Affected

Organ level: - Primary organ: liver (UBERON:0002107) — centrilobular/zone-3 hepatocellular necrosis, the dominant lethal lesion. - Secondary organs: kidney (UBERON:0002113) — acute tubular necrosis/hepatorenal syndrome; gastrointestinal tract (small intestine, colon) — enterocyte injury, and in rare cases ulcerating ileocolitis (PMC4555452); central nervous system — secondary hepatic encephalopathy (not primary CNS toxicity); hematopoietic system — reported hematotoxicity (PMC10891511); cardiovascular system — elevated CK-MB reported as prognostic (PMC13211627), of uncertain primary-vs-secondary mechanism. - Body systems: digestive, hepatobiliary, renal/urinary, hematologic, and (secondarily) nervous system.

Tissue/cell level: - Hepatic parenchyma — hepatocytes (CL:0000182), predominantly centrilobular (zone 3) distribution. - Renal proximal convoluted tubule epithelium (CL:1001016) — acute tubular necrosis, vacuolization, tubular dilatation, interstitial edema. - Intestinal epithelium — enterocytes (CL:0000584).

Subcellular level (GO Cellular Component): - Nucleus (GO:0005634) — site of RNAP II inhibition. - Mitochondrion (GO:0005739) — site of ROS generation, TOM20 downregulation, p53 translocation. - Endoplasmic reticulum (GO:0005783) — site of N-glycosylation machinery (STT3B/oligosaccharyltransferase complex, GO:0008250 oligosaccharyltransferase complex).

Localization: bilateral/systemic — liver and both kidneys are affected diffusely rather than laterally, consistent with a hematogenously/portally delivered toxin rather than a focal lesion.

8. Temporal Development

Onset: acute, toxin-exposure onset, staged over hours to days rather than an "age of onset" in the developmental sense; any age can be affected upon ingestion, with children disproportionately severely affected (§2, §3).

Onset pattern: acute, with a characteristic delayed symptom onset (6–24 h latent phase) — a diagnostically important feature distinguishing amatoxin poisoning from the near-immediate-onset mushroom toxidromes (e.g., muscarinic, ibotenic-acid) that are typically benign.

Progression / staging (see §3 for full phenotype detail): 1. Latent phase (0–24 h, mean ~10–12 h) 2. Gastrointestinal phase (~6–48 h onward; lasts 1–3 days) 3. Apparent convalescence (day 2–3) — false clinical improvement masking ongoing hepatic injury 4. Hepatic/multiorgan-failure phase (day 3–7+) — culminates in death (days 5–12 without treatment, per synthesis of epidemiologic sources) or, with treatment, recovery or need for liver transplantation.

Progression rate: variable but generally rapid once the hepatic phase begins; without treatment most fatal cases progress to death within 5–12 days of ingestion.

Disease course pattern: monophasic/self-limited if diagnosed and treated early (full recovery with supportive care/antidotal therapy); can be fulminant/lethal if untreated or if a large dose was ingested, irrespective of treatment.

Remission: treatment-induced (supportive care + antidotal therapy + possible extracorporeal support); no spontaneous remission is described once hepatic failure is established, other than in mild-dose exposures that never progress past the GI phase.

Critical period for intervention: the latent and early GI phase (first 24–48 h) is the critical therapeutic window — early decontamination (activated charcoal within 2–4 h) and early silibinin/NAC initiation (ideally within 24 h of ingestion) are associated with markedly better outcomes; "early therapeutic plasma exchange (within the first 24 h) improved treatment outcomes by reducing circulating toxin concentrations" (PMC13211627). Recent literature explicitly recommends treating asymptomatic patients with a credible exposure history pre-emptively, since "the absence of early symptoms does not exclude significant toxin absorption" (PMC13211627).

9. Inheritance and Population

Inheritance pattern: not applicable — amatoxin poisoning is an acquired toxic exposure, not a heritable trait. (Familial clusters occur because family members eat the same contaminated meal, not because of shared genetic susceptibility per se, though as noted in §2 shared SLCO1B3 genotype within families is a plausible but unproven contributor to intra-family variability in severity — e.g., a Vietnamese case series describing "markedly heterogeneous outcomes" within one family exposed to the same meal.)

Epidemiology: - Amatoxin-containing mushrooms cause ~50–100 fatal poisonings per year in Western Europe, are less common in the U.S. (roughly 1–2 deaths/year), with additional cases reported from Africa, Asia, Australia, and Central/South America (search synthesis, epidemiology section above). - Amatoxin-containing mushrooms account for >90% of fatal mushroom-related food-poisoning deaths in the U.S. - Mortality rate: overall ~10–20% for A. phalloides poisoning in older series; more recent series with modern intensive care and antidotal therapy report 1.8–22% depending on treatment cohort; StatPearls reports <5% mortality in developed countries with early intensive-care access; historical mortality (pre-modern-treatment era) reported as ~50% in adults and ~33% in children. - A meta-analysis of 33 studies reported a pooled mortality estimate of ~2.87% across all mushroom-poisoning cases and found that of 16 patients undergoing liver transplantation, 14 survived (PMC13211627). - A large systematic review of 506 NAC-treated patients found an 11.26% mortality rate (including transplant cases) and a 4.35% liver-transplantation rate (PMC13211627). - A Turkish liver-transplant cohort (2008–2023, n=26) reported 69.2% overall post-transplant survival, with higher MELD scores and need for retransplantation associated with increased mortality (PMC13211627).

Population demographics: - Geographic distribution: global, but case burden concentrated in regions with strong mushroom-foraging culture — Western/Southern Europe, and China/Southeast Asia (where A. exitialis, A. fuliginea, Galerina sulciceps, and Russula subnigricans are additionally implicated, PMC13211627); lower incidence in the U.S., attributed to foraging-culture prevalence rather than mushroom-species distribution differences. - Age distribution: bimodal risk emphasis — young children (accidental ingestion, higher per-kg dose) and adult foragers (intentional but mistaken ingestion); pediatric poisoning is a distinct epidemiologic and clinical subgroup with its own recent 15-year retrospective analysis (PMC12488608). - Sex ratio: not clearly established as skewed in the sources reviewed; foraging-related exposure may somewhat favor adult recreational foragers of either sex depending on region — no robust sex-ratio statistic was identified in this search. - Ethnic/consanguinity/founder effects/carrier frequency: not applicable (non-genetic disease).

10. Diagnostics

Clinical diagnosis: the classic pattern — asymptomatic-to-GI-symptom interval of 6–24 h after wild-mushroom ingestion, followed by rising transaminases within 2–3 days — is itself strongly diagnostic (StatPearls). Differential diagnosis must exclude acetaminophen overdose, viral/infectious hepatitis, and autoimmune hepatitis.

Laboratory tests: - Complete metabolic panel, liver function tests (AST/ALT/bilirubin), coagulation studies (PT/INR), renal function (creatinine, BUN), ammonia, lactate, glucose. - "It takes about 24 hours before any signs or laboratory indicators of liver injury begin to appear" (StatPearls) — meaning a normal initial LFT panel does not exclude poisoning.

Toxin-specific detection (biomarkers): - Urinary amatoxin quantification is the diagnostic modality of choice; a Slovak cohort of 698 patients found "urinary amanitin examination correlated with the severity of poisoning in the range of 6–47 h after mushroom ingestion without any false negativity, while the serum assay showed no diagnostic value" (PMC13211627) — establishing urine, not serum, as the correct matrix. - Detection methods: radioimmunoassay (RIA), ELISA (detection limit ~0.2 ng/mL for α-/γ-amanitin), lateral flow immunoassay (LFIA, point-of-care, detection to ~10 ng/mL in urine but requiring LC-MS/MS confirmation given false-positive/negative risk), and liquid chromatography–high-resolution tandem mass spectrometry (LC-HRMS/MS), including magnetic-bead affinity-column extraction methods for α-, β-, γ-amanitin (multiple 2023–2024 method-development papers identified in search). - Molecular species-identification tools: loop-mediated isothermal amplification (LAMP) assays can identify toxic mushroom species in processed/mixed food samples ("detect as low as 1% of the target species," turnaround 40–90 min) (PMC13211627).

Imaging/other studies: no amatoxin-specific imaging modality; abdominal imaging and cross-sectional imaging are used to assess liver morphology/complications non-specifically in fulminant hepatic failure.

Genetic testing: not applicable — no genetic test exists or is indicated for this toxic-exposure disease.

Prognostic/risk-stratification scoring systems (critical for transplant-listing decisions): - CLIF-OF (Chronic Liver Failure–Organ Failure) score — a score >9 within 24 h "demonstrated excellent predictive performance and outperformed the other evaluated scoring systems" in a Chinese cohort (PMC13211627). - INR > 3.6 (AUC 0.941) and plasma ammonia > 95.1 μmol/L (AUC 0.805) independently predict mortality (PMC13211627). - King's College Hospital Criteria (KCC) for non-acetaminophen acute liver failure — used as a general predictor of poor outcome, adapted for amatoxin-induced ALF. - Ganzert criteria (amatoxin-specific): prothrombin index ≤25% combined with serum creatinine ≥106 μmol/L between days 3–10 post-ingestion (PMC13211627). - Escudié criteria (amatoxin-specific, more stringent): prothrombin index <10% (roughly INR >6) from day 4 post-ingestion, reported with "100% accuracy in predicting fatal outcome" in the deriving cohort (PMC13211627). - Machine-learning mortality-prediction model (XGBoost): AUC 0.83 (cross-validation)/0.90 (test), sensitivity 0.93, specificity 0.79, in 567 critically ill patients (PMC13211627).

Screening: no population/newborn/carrier screening applicable; the relevant "screening" analog is species-identification education and rapid toxin/species testing at point of suspected exposure (poison-control/mycologist consultation).

11. Outcome/Prognosis

Mortality: historically 10–20% for A. phalloides poisoning overall; contemporary developed-country mortality with early ICU access is <5% (StatPearls); a broad meta-analysis across all mushroom poisonings gives a pooled ~2.87% mortality; NAC-treated cohorts (n=506) show 11.26% mortality (including transplant cases). Untreated/late-presenting fulminant cases can approach much higher fatality, and pediatric-specific hepatotoxic-species series report case-fatality >80% in some cohorts (PMC12488608).

Time course to death (untreated): typically 5–12 days post-ingestion.

Liver transplantation outcomes: a Turkish cohort (n=26, 2008–2023) reported 69.2% overall post-transplant survival, with higher MELD score and need for retransplantation predicting worse outcome; a broader meta-analysis found 14/16 transplant recipients survived (~87.5%) (PMC13211627).

Morbidity/complications: hepatic encephalopathy, coagulopathy, hepatorenal syndrome, and — notably — irreversible proximal tubular necrosis with permanent renal impairment even after hepatic recovery (PMC8610939); rare ulcerating ileocolitis (PMC4555452); reported hematotoxicity (PMC10891511).

Prognostic factors (see §10 for the formal scoring systems): amount ingested, species ingested, time to treatment initiation, INR/prothrombin index trajectory, plasma ammonia, CLIF-OF score, elevated CK-MB and impaired consciousness (markers of extrahepatic organ involvement) (PMC13211627).

Recovery potential: full hepatic and renal recovery is common when treatment (decontamination + silibinin/NAC ± extracorporeal support) is started early; recovery is markedly less likely once grade ≥2 hepatic encephalopathy, INR >3.6–6, or CLIF-OF >9 are reached without transplantation.

12. Treatment

Decontamination: - Activated charcoal, 1 g/kg, repeated every 2–4 h, ideally started within 2–4 h of ingestion to reduce absorption and interrupt enterohepatic recirculation of amatoxin (StatPearls). NCIT: NCIT:C1687 (Activated Charcoal) or a general decontamination procedure term.

Antidotal pharmacotherapy: - Silibinin (silymarin/Legalon-SIL) — first-line antidote; competitively inhibits OATP1B3-mediated hepatocyte uptake of amatoxin and interrupts enterohepatic recirculation; also has anti-TNF/anti-apoptotic action. Dosing: IV silibinin 5 mg/kg over 1 h, then 20 mg/kg/day continuous infusion (or oral silymarin 1 g four times daily) (StatPearls; PMC3414726, Legalon SIL: The Antidote of Choice). NCIT candidate: therapeutic_agent CHEBI silibinin, treatment_term NCIT:C15986 (Pharmacotherapy). - N-acetylcysteine (NAC) — IV, using acetaminophen-poisoning-style dosing regimens; acts as a glutathione precursor/free-radical scavenger, targeting the oxidative-stress arm of the mechanism (§6). A Thai cohort of 74 NAC-treated patients: "70 (94.59%) were successfully treated at a low cost" (PMC13211627). - Benzylpenicillin G (high-dose) — historically used, "four million units every four hours," proposed to competitively inhibit hepatic amatoxin uptake, but comparative evidence shows it is inferior to silibinin: "In nearly 1,500 documented cases, overall mortality in patients treated with silibinin is <10% compared to >20% when using penicillin or a combination of silibinin and penicillin" (search synthesis, treatment section). A Slovak comparative study (2004–2020, n=141) found silibinin monotherapy had significantly higher treatment failure than combined penicillin G + silibinin (41.67% vs 1.57%; p=0.00058) — an apparent discrepancy across studies that should be flagged in curation as reflecting differing cohorts/eras/outcome definitions rather than a settled consensus (PMC13211627). - Cyclosporine — an OATP transporter inhibitor with only limited case-report-level support (StatPearls).

Extracorporeal / blood-purification therapy: - Therapeutic plasma exchange (TPE) — increasingly supported as adjunctive therapy: in patients with hepatic encephalopathy grade ≥2, adjunctive TPE was "associated with improved liver transplant-free survival at 28 days" and "independently associated with reduced risk of death or liver transplantation" (multi-center Amanita-PEX study, PMC12573913); a Turkish cohort found early TPE (within 24 h) improved outcomes by reducing circulating toxin (PMC13211627); recommended replacement fluid: 5% albumin and fresh frozen plasma. - Combined plasma exchange + double plasma molecular adsorption system (DPMAS) — used successfully as a bridge to transplantation/recovery in a Chinese pediatric series (PMC13211627). - Molecular Adsorbent Recirculating System (MARS) and hemoperfusion — additional extracorporeal modalities reported in case series (e.g., a Vietnamese familial case series using haemoperfusion and plasma exchange, PMID 42523156). - Standard hemodialysis — used for renal failure but does not itself remove circulating amatoxin (StatPearls).

Liver transplantation: definitive therapy for established/progressing fulminant hepatic failure; timing guided by the transplant-specific prognostic criteria in §10 (King's College, Ganzert, Escudié criteria). Reported outcomes: 69.2% overall survival in a 26-patient Turkish cohort; 14/16 survival in a broader meta-analytic sample (PMC13211627). NCIT: NCIT:C15289 (Organ Transplantation).

Supportive care: aggressive IV fluid resuscitation (the "Santa Cruz protocol" AMP regimen's first pillar — "aggressive intravenous fluid replacement to completely reverse prerenal azotemia and protect kidneys"), electrolyte correction, glucose monitoring/correction, correction of coagulopathy, and ICU-level monitoring. NCIT: NCIT:C15747 (Supportive Care).

Emerging/experimental therapeutics: - Indocyanine green as a candidate STT3B inhibitor blocking cellular amanitin entry — shown protective in cellular and animal models (PMC11640968); not yet a clinical standard. - Resveratrol — experimental anti-inflammatory agent reducing hepatic mononuclear infiltration, necrosis, and caspase-3 positivity in animal models (PMC13211627). - Ganoderma lucidum supplementation — a retrospective Chinese study (n=61) found statistically significantly shorter hospital stay (6.69±3.98 vs 9.27±5.30 days; p=0.034) and lower cost associated with adjunct use (PMC13211627) — hypothesis-generating rather than confirmatory.

Notable unrelated biomedical repurposing (not a treatment for the disease, but relevant molecular context): α-amanitin itself is being repurposed as a cytotoxic payload for antibody-drug conjugates (ADCs) in oncology — e.g., PSMA-targeted amanitin-ADCs for prostate cancer (HDP-103) and TROP2-targeted amanitin-ADCs for pancreatic cancer, exploiting RNAP II inhibition's cell-cycle-independent cytotoxicity against slowly dividing/dormant tumor cells (AACR abstracts, 2024–2026 search results). This is a translational application of the toxin, not a treatment of amatoxin poisoning itself, but is directly relevant to the toxin's molecular mechanism narrative and to therapeutic_modality/mechanism cross-references if the KB models amanitin as a chemical entity.

Treatment algorithm summary (as codified in "Santa Cruz"/AMP-style protocols): (1) aggressive fluid resuscitation, (2) early activated charcoal if within the decontamination window, (3) IV silibinin ± NAC ± penicillin G started as early as possible (even in asymptomatic exposed patients), (4) escalation to plasma exchange/DPMAS/MARS for progressive coagulopathy or encephalopathy, (5) transplant evaluation using amatoxin-specific (Ganzert/Escudié) or general (King's College) criteria once transplant-threshold criteria are met.

13. Prevention

Primary prevention: - Public education is repeatedly emphasized as the single most important preventive measure: "the key to preventing mushroom poisoning is education of the public" (PMC12488608; StatPearls). StatPearls explicitly recommends: "do not eat wild mushrooms but instead buy them from a grocery store," and to wash commercially purchased mushrooms to remove pesticide residue. - Physician education/training: "there is a need to enhance training for primary care physicians so that they can recognize the characteristics of amatoxin poisoning and be equipped with the relevant treatment methods" (PMC12488608). - Molecular/rapid species-identification tools (LAMP assays, point-of-care LFIA urine tests) support both prevention (screening food-chain samples/markets) and early diagnosis.

Secondary prevention (early detection): low threshold for urinary amatoxin testing and treatment initiation in any patient with a credible wild-mushroom exposure history, even while still asymptomatic — because "the absence of early symptoms does not exclude significant toxin absorption" (PMC13211627); regional poison-control-center and mycologist consultation networks for rapid species identification (StatPearls).

Tertiary prevention: early antidotal therapy and extracorporeal support to prevent progression to irreversible hepatic/renal failure and the need for transplantation (§12).

Immunization: not applicable (no vaccine exists or is relevant).

Genetic/prenatal screening, counseling: not applicable — non-genetic disease.

Public health / environmental interventions: regulation and inspection of wild-foraged mushrooms entering commercial food-distribution and market/catering chains, particularly in regions (China, Southeast Asia) where this route of exposure is documented (PMC13211627).

Prophylaxis: no pre-exposure prophylactic medication exists; "prophylaxis" in practice means avoiding wild-mushroom consumption and, once exposure is suspected, immediate presentation for antidotal therapy within the critical early treatment window (§8).

14. Other Species / Natural Disease

Taxonomy of causal organism: Amanita phalloides (NCBITaxon:33397), Amanita virosa, Amanita verna, Amanita exitialis, Amanita fuliginea, Galerina marginata/sulciceps, various Lepiota spp. — the fungal source organisms, not the affected host species.

Naturally occurring disease in other species: - Dogs are the most extensively documented non-human natural host, with numerous veterinary case reports and case series of accidental Amanita ingestion. "Amanita phalloides, the death cap mushroom, is the most common cause of potentially fatal mushroom poisoning in people and dogs" (search synthesis). A case series of 5 dogs treated with an adapted human "Santa Cruz protocol" reported 100% survival to discharge (PubMed 33458945; Goupil et al., J Vet Emerg Crit Care 2021). A separate case report documents fatal Amanita toxicosis with acute hepatic necrosis in a dog (Puschner et al., J Vet Diagn Invest 2007, PMID referenced via sagepub 104063870701900317). - Cats are also affected, per veterinary toxicology reviews (North American Mycological Association resource). - Beagle dogs have been used as a deliberate experimental model for Amanita exitialis toxicokinetics (ScienceDirect, Toxicity and toxicokinetics of Amanita exitialis in beagle dogs).

Comparative pathology / cross-species susceptibility (mechanistic, see also §15): - Species-dependent oral absorption and lethality is well documented: "the rate of absorption of amanitins from the gastrointestinal tract varies with the animal species and is estimated to be much greater in dogs than in mice and rabbits; rats appear relatively resistant to the toxic effects of amanitins" (Merck Veterinary Manual / search synthesis). Mice are essentially unaffected by oral Amanita ingestion (unlike humans and dogs) but succumb rapidly (8–10 h) to a lethal intraperitoneal dose — a key reason mice are a poor natural-exposure model despite being used for parenteral mechanistic studies. - Estimated oral LD50: α-amanitin ≈0.1 mg/kg in humans; methyl-γ-amanitin LD50 ≈0.5 mg/kg in dogs (similar order of magnitude). - In dogs, 80–90% of ingested amatoxin is rapidly renally excreted, with the remaining 10–20% undergoing enterohepatic recirculation back to the liver — directly paralleling the human mechanism that silibinin therapeutically interrupts.

Zoonotic potential: not applicable — this is direct environmental toxin exposure common to multiple species independently ingesting the same fungal source, not a transmissible disease between species.

15. Model Organisms

In vivo models: - Dogs — the preferred large-animal natural/experimental model, given (a) documented spontaneous natural poisoning closely paralleling human disease course and (b) high oral bioavailability of amatoxins comparable to humans, in contrast to mice/rats. Used both for observational veterinary case data and deliberate toxicokinetic study (beagle A. exitialis model). - Mice — used extensively for mechanistic (not natural-exposure) studies via intraperitoneal α-amanitin dosing; the basis for the p53/BAK-knockout apoptosis-resistance experiments and the anti-TNF-antibody hepatoprotection experiments underlying the pathophysiology model in §6 (PMC11640968). Limitation: mice are resistant to oral Amanita ingestion and die rapidly (8–10 h) after IP dosing, so the mouse IP model recapitulates the molecular mechanism but not the natural exposure route or the human multi-phase clinical timeline. - Rats — relatively resistant to amanitin toxicity compared to dogs/mice/rabbits by the oral route; used in some nephrotoxicity mechanistic studies (e.g., β-carotene protection against α-amanitin nephrotoxicity via modulation of oxidative/autophagic/nitric-oxide/polyol pathways in rat kidney, ScienceDirect 2024). - Rabbits — mentioned comparatively in absorption-kinetics literature but with less detailed primary data identified in this search.

In vitro / cellular models: - HepG2 cells — the principal human hepatocyte-line model for OATP1B3-dependent amanitin cytotoxicity studies, including the OATP1B3-knockdown protection experiments (PubMed 38641045) and comparative proteomic (TRiC-protein) studies (PMC7999322). - Primary/cultured human hepatocytes — used in the original OATP1B3/NTCP transporter-characterization work and in silibinin/NAC/penicillin G antidote-efficacy comparisons in vitro ("Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated with α-amanitin," ScienceDirect). - Cultured hematopoietic cell lines — used to demonstrate direct amanitin hematotoxicity independent of hepatic mechanisms ([PMC10820516]). - CRISPR knockout cell-line screens — used to identify STT3B/N-glycan biosynthesis as a novel amanitin cellular-entry dependency (PMC11640968). - 3D liver spheroid / iPSC-derived hepatocyte organoid models — general hepatotoxicology platforms (HepG2 spheroids, iPSC-hepatocyte spheroids, HepaRG) exist and are increasingly used for hepatotoxicant screening broadly, but no amatoxin-specific organoid/iPSC study was identified in this search — this is a plausible near-term research gap (an experimental-model limitation worth flagging in a KB entry rather than asserting a positive finding).

Model characteristics — phenotype recapitulation and limitations: - The canine model most faithfully recapitulates human natural-exposure disease (oral route, similar absorption kinetics, similar hepatorenal clinical course, and demonstrated response to a human-derived treatment protocol). - The mouse IP model faithfully recapitulates the molecular mechanism (RNAP II inhibition → p53/caspase-3 apoptosis → TNF-amplified hepatocyte injury) but does not recapitulate the natural oral-exposure route, the multi-day staged clinical course, or the renal proximal-tubule injury pattern as well as the hepatic injury pattern. - HepG2/primary hepatocyte in vitro models faithfully recapitulate OATP1B3-dependent uptake and antidote pharmacology (silibinin, NAC, penicillin G competition) but cannot model the whole-organism multi-organ (renal, GI, hematologic) phenotype or the enterohepatic recirculation dynamics that silibinin's therapeutic rationale depends on in vivo.

Model databases/resources: MGI (mouse Tp53, Bak1 knockout strains used in the apoptosis experiments), general toxicology repositories; no dedicated amatoxin-poisoning model registry was identified.

Summary of Suggested Ontology Term Bindings for KB Curation

Category	Suggested term(s)	Notes
Disease/MeSH	MeSH:D009145 (Mushroom Poisoning)	No dedicated amatoxin MeSH heading; no MONDO/OMIM/Orphanet ID found
ICD-10-CM	T62.0X1- (+ 7th character)	Toxic effect of ingested mushrooms
Causal chemical entities	CHEBI (α-amanitin, β-amanitin, phalloidin)	Confirm exact CHEBI CURIEs via OAK lookup, not from memory
Host target gene	HGNC: POLR2A	RNA polymerase II, direct binding target
Uptake transporter genes	HGNC: SLCO1B3 (OATP1B3), SLC10A1 (NTCP)	Hepatocyte uptake
Novel entry factor	STT3B (N-glycan biosynthesis)	CRISPR-screen-identified
Apoptosis genes	TP53, BAK1 (BAK), caspase-3 (CASP3)	Mouse knockout evidence
Amplifier	TNF	Anti-TNF antibody prevents injury in mice
GO biological processes	GO:0006366 (RNAP II transcription), GO:0006915 (apoptosis), GO:0006979 (oxidative stress response), GO:0000422 (mitophagy), GO:0033209 (TNF signaling), GO:0070265 (necrotic cell death)
Cell types (CL)	CL:0000182 (hepatocyte), CL:0000584 (enterocyte), proximal tubule epithelial cell
Anatomy (UBERON)	UBERON:0002107 (liver), renal proximal tubule, small intestine
Phenotypes (HP)	HP:0002014 (diarrhea), HP:0002013 (vomiting), HP:0002910 (elevated transaminases), HP:0000952 (jaundice), HP:0002480 (hepatic encephalopathy), HP:0006554 (acute hepatic failure), HP:0001919 (acute kidney injury), HP:0001943 (hypoglycemia), HP:0001942 (metabolic acidosis)	Verify exact IDs at curation time
Treatment (NCIT)	NCIT:C15986 (Pharmacotherapy) + therapeutic_agent silibinin/NAC; NCIT:C15289 (Organ Transplantation); NCIT:C15747 (Supportive Care)

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	27
Resolved	27
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	12
Quoted claims found in source	1
Quoted claims not found in source	11
References weighed for topical relevance	27
On topic	21
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMC:PMC13211627 (abstract only): "misidentification during collection, unintentional mixing of edible and toxic species"
closest text in source: "Liquid chromatography, mass spectrometry, immunoassays, and the molecular identification of fungal species have improved diagnostic precision, particularly in cases with uncertain exposure history or delayed presentation"
PMC:PMC13211627 (abstract only): "the transient improvement phase preceding severe organ toxicity"
closest text in source: "Future research should prioritize standardized diagnostic pathways, validated prognostic models, and clinically applicable treatment algorithms that support earlier escalation of care in severe mushroom intoxication."
PMC:PMC13211627 (abstract only): "demonstrated excellent predictive performance and outperformed the other evaluated scoring systems"
Text part not found as substring: 'demonstrated excellent predictive performance and outperformed the other evaluated scoring systems' (note: only abstract available for PMID:42188618, full text may contain this excerpt)
PMC:PMC13211627 (abstract only): "early therapeutic plasma exchange (within the first 24 h) improved treatment outcomes by reducing circulating toxin concentrations"
closest text in source: "Overall, clinical outcome depends not only on toxin profile, but also on timely diagnosis, accurate early risk stratification, and prompt coordinated treatment"
PMC:PMC13211627 (abstract only): "the absence of early symptoms does not exclude significant toxin absorption"
closest text in source: "Overall, clinical outcome depends not only on toxin profile, but also on timely diagnosis, accurate early risk stratification, and prompt coordinated treatment"
PMC:PMC13211627 (abstract only): "urinary amanitin examination correlated with the severity of poisoning in the range of 6–47 h after mushroom ingestion without any false negativity, while the serum assay showed no diagnostic value"
closest text in source: "This review examines recent advances in the diagnosis, risk stratification, and therapeutic management of wild mushroom poisoning, with amatoxin intoxication serving as the principal clinical focus"
PMC:PMC13211627 (abstract only): "70 (94.59%) were successfully treated at a low cost"
Text part not found as substring: '70 (94.59%) were successfully treated at a low cost' (note: only abstract available for PMID:42188618, full text may contain this excerpt)
PMC:PMC12573913 (abstract only): "independently associated with reduced risk of death or liver transplantation"
closest text in source: "PEX was independently associated with reduced risk of the combined endpoint death or liver transplantation within 28 days from inclusion in patients with HE grade ≥ 2 (HR 0.37, 95%-CI 0.19-0.73, p = 0.004)"
PMC:PMC12488608 (abstract only): "the key to preventing mushroom poisoning is education of the public"
closest text in source: "BACKGROUND: Mushroom poisoning is a significant public health concern, particularly in pediatric populations, where developmental differences in toxin metabolism and organ vulnerability pose unique clinical challenges"
PMC:PMC12488608 (abstract only): "there is a need to enhance training for primary care physicians so that they can recognize the characteristics of amatoxin poisoning and be equipped with the relevant treatment methods"
closest text in source: "Despite its geographic and seasonal patterns, pediatric mushroom poisoning remains underrepresented in the literature, necessitating further investigation into its epidemiological and clinical characteristics"
PMC:PMC13211627 (abstract only): "the absence of early symptoms does not exclude significant toxin absorption"
closest text in source: "Overall, clinical outcome depends not only on toxin profile, but also on timely diagnosis, accurate early risk stratification, and prompt coordinated treatment"

Term Validation

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

Outcome	Count
Terms checked	48
Resolved	45
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	1
Terms whose name was checked	21
Terms named correctly	11
Terms named as a different term	4
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

CHEBI:2828 (1 mention) - the report calls it "α-amanitin"; CHEBI calls it Arnebinone
CL:1001016 (2 mentions) - the report calls it "Renal proximal convoluted tubule epithelium"; CL calls it kidney loop of Henle ascending limb epithelial cell
UBERON:0002107 (3 mentions) - the report calls it "Liver", "Primary organ: liver", "liver"; UBERON calls it liver**
NCBITaxon:33397 (1 mention) - the report calls it "Amanita phalloides"; NCBITaxon calls it Chironomus plumosus

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0006919 (obsolete activation of cysteine-type endopeptidase activity involved in apoptotic process) (1 mention)
GO:0070265 (obsolete necrotic cell death) (2 mentions)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0006919 (1 mention) - the report calls it "activation of cysteine-type endopeptidase activity involved in apoptotic process"; GO calls it obsolete activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0000422 (2 mentions) - the report calls it "mitophagy"; GO calls it autophagy of mitochondrion, and lists "mitophagy" among its other names
GO:0070265 (2 mentions) - the report calls it "necrotic cell death"; GO calls it obsolete necrotic cell death
CL:0000182 (3 mentions) - the report calls it "Hepatic parenchyma — hepatocytes"; CL calls it hepatocyte
CL:0000584 (3 mentions) - the report calls it "Intestinal epithelium — enterocytes"; CL calls it enterocyte, and lists "mature enterocyte" among its other names
UBERON:0002113 (1 mention) - the report calls it "Secondary organs: kidney"; UBERON calls it kidney**, and lists "reniculate kidney" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

UBERON:0002107 - called "Liver", "Primary organ**: liver", "liver"

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Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Amatoxin Poisoning — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Phase 1 — Latent phase

Phase 2 — Gastrointestinal phase (~6–24 h onward, lasting 1–3 days)

Phase 3 — "Apparent convalescence" / latent hepatotoxic phase (day 2–3)

Phase 4 — Hepatic/multiorgan failure phase (day 3–7+)

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Molecular pathways / GO terms

Cell types (CL terms)

Anatomical/tissue targets (UBERON, see also §7)

Omics / advanced technologies

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Suggested Ontology Term Bindings for KB Curation

Sources

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently