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Mappings

MONDO

MONDO:0800385 iron poisoning

Primary MONDO disease identifier for iron poisoning.

ICD-10-CM

ICD10CM:T45.4 Poisoning by, adverse effect of and underdosing of iron and its compounds

semapv:ManualMappingCuration

Injury, poisoning and certain other consequences of external causes (S00-T88)
Poisoning by, adverse effects of and underdosing of drugs, medicaments and biological substances (T36-T50)
Poisoning by, adverse effect of and underdosing of primarily systemic and hematological agents, not elsewhere classified
Poisoning by, adverse effect of and underdosing of iron and its compounds

ICD10CM:T45.4X1A Poisoning by iron and its compounds, accidental (unintentional), initial encounter

semapv:ManualMappingCuration

ICD10CM:T45.4X2A Poisoning by iron and its compounds, intentional self-harm, initial encounter

semapv:ManualMappingCuration

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Discussions and Knowledge Gaps

5

In acute iron poisoning, which better identifies the patient who will develop toxicity — the serum iron concentration, or the suspected ingested dose of elemental iron? The cited literature does not agree. Two paediatric cohorts answer in opposite directions, and a third series finds a timed serum-iron cutoff with complete negative predictive value inside the mild-symptom stratum.

CONTROVERSY OPEN serum_iron_versus_ingested_dose

Attached to

diagnosis#Serum iron concentration biochemical#Serum iron concentration pathophysiology#Ingestion of Iron in Excess of Absorptive and Binding Capacity

How to read the enums here, first, because they are counter-intuitive. Every evidence item on this discussion is marked SUPPORT, including items on opposite sides of the question, because what each supports is the claim that the literature disagrees, and that is this discussion's only claim. There is no schema slot for which side a source is on; the explanations carry it. The polarity that takes a side lives on the serum-iron diagnosis entry instead, where the claim being supported or refuted is that the serum iron is informative. This is a live disagreement between published positions rather than a gap, and both positions are curated on the serum-iron diagnosis entry with their own evidence. PMID:14722368, a 21-patient Indian cohort with four deaths, found the ingested dose and clinical signs guided management while the serum iron did not help. PMID:34121325, a 54-patient Australian cohort of unintentional exposures with no severe toxicity, found the reverse on both counts: peak serum iron separated symptomatic from asymptomatic children at P < 0.001, while suspected dose did not differ between them. The cohorts are not interchangeable and the difference may be the answer rather than a contradiction. One is a referral series containing deaths; the other is a poisons-information-service series of unintentional exposures in which nobody became severely toxic. A measurement can discriminate mild toxicity from none and still fail to guide management once a child is already shocked, and an ingested dose reported by a parent may be estimated very differently in the two settings. Nothing cited here resolves which explanation holds. A third series, PMID:39509998, narrows the disagreement without settling it, and narrows it along the axis the proposed experiment below names. It analysed the serum iron inside a severity stratum rather than pooled and found it discriminating in the mild one: among patients whose symptoms stayed minor, a concentration at or below 300 microg/dL drawn 2 to 4 hours after ingestion was followed by no subsequent toxic concentration, giving complete negative predictive value. That is the mild-range half of the stratified prediction below, arriving from a study that was run without reference to it. It is not the whole of that prediction: no severe stratum was analysed, the ingested dose was not compared against the concentration, and the abstract does not report the age distribution of its 75 patients, so it does not stand as a third paediatric cohort. Its specificity of 54% also bounds what it licenses, since a rule for whom to stop watching is not a rule for whom to chelate. The practical consequence has changed in one respect and not in the other. This entry now curates the conventional serum-iron thresholds, on the biochemical entry, because PMID:39509998 states them quotably and they are curated as what its own sentence calls them, a tradition, rather than as validated cutoffs. The elemental-iron dose bands remain curated nowhere: no source this entry can quote states them, and unlike the serum concentration the ingested dose has now failed to discriminate outright in one cohort.

Proposed experiments

Test both predictors against outcome, stratified by severity stratum

serum_iron_versus_dose_discrimination_by_severity_stratum

In a cohort spanning both settings - unintentional exposures and referred severe poisonings - record suspected ingested dose and timed serum iron against a hard outcome, and analyse within severity strata rather than pooled. The specific question is whether serum iron discriminates in the mild range while dose discriminates in the severe range, which would make both cited findings correct in their own populations and would explain the disagreement without either being wrong. Report how the ingested dose was ascertained, since parental estimate and pharmacy reconciliation are not the same measurement. PMID:39509998 is a partial instance of this design and is the reason it is worth running in full: it stratified by symptom severity and found the serum iron discriminating in the mild stratum, but analysed no severe stratum and did not put the ingested dose alongside the concentration in the same comparison.

Show evidence (5 references)

PMID:34121325 SUPPORT Human Clinical

"Suspected dose ingested is a poor predictor of toxicity."

The Australian cohort's own conclusion, and one half of the disagreement this discussion records.

PMID:34121325 SUPPORT Human Clinical

"The median suspected dose of elemental iron ingested was 72 mg/kg (IQR 41-140 mg/kg). Seventeen (31%) children were symptomatic. There were no cases of severe toxicity."

Characterises that cohort as unintentional exposures without severe toxicity, which is the population difference that may explain why its finding diverges from the referral series with four deaths.

PMID:14722368 SUPPORT Human Clinical

"Dose of ingested iron and clinical signs were most useful guide to iron toxicity and management decisions; serum iron did not help."

The opposing position, from the referral cohort, and the reason there is a controversy to record at all. Marked SUPPORT like every other item on this discussion, because what it supports is the disagreement itself rather than either side of it; marking one side of a two-sided question REFUTE would make the other read as this discussion's thesis. Curated alongside the other cohorts rather than beneath them.

+ 2 more references

This entry models the coagulopathy of acute iron poisoning as reversible iron inhibition of the coagulation serine proteases, leaving fibrinogen itself undamaged. A separate literature reports the opposite kind of effect, in which ferric iron generates hydroxyl radicals that convert fibrinogen into fibrinolysis-resistant fibrin. Do both happen in acute iron poisoning, and if the second does, is the coagulopathy still correctable by removing the iron?

KNOWLEDGE GAP OPEN iron_effects_on_fibrinogen_versus_proteases

Attached to

pathophysiology#Reversible Iron Inhibition of Coagulation Serine Proteases

The two reported effects are not variants of one another. PMID:6421970, the source this entry's coagulation node is built on, found iron inactivating thrombin, factor Xa and kallikrein reversibly while leaving the zymogens and fibrinogen intact, which is an anticoagulant effect and matches the bleeding seen clinically. PMID:23170793 reports ferric ions generating hydroxyl radicals that convert fibrinogen into dense matted deposits with permanent resistance to enzymatic degradation, which is a prothrombotic effect on the substrate the first paper found undamaged. Three things keep this a gap rather than a contradiction to resolve. The second finding comes from a chronic degenerative disease frame, atherosclerosis and diabetes, where the iron burden and its time course are nothing like an overdose. The two describe different iron species and different targets, so they can both be true without meeting. And no cited source looks for fibrinogen structural change in acute iron poisoning at all. What makes it worth recording is that the entry's node carries a therapeutic implication which the second mechanism would not share. Protease inhibition is reversible, so the node states the coagulopathy is in principle correctable by chelation rather than only by factor replacement. A structural conversion of fibrinogen described as permanently resistant to degradation would not be undone by removing the iron. If both operate, chelation would correct one arm of the coagulopathy and not the other, and the node's framing is incomplete rather than wrong.

Proposed experiments

Look for fibrinogen structural change in acute iron poisoning plasma

fibrinogen_structure_in_acute_iron_poisoning_plasma

In plasma from patients with acute iron poisoning, sampled before and after chelation, assay both arms in the same specimens: protease activity for the reversible inhibition arm, and clot ultrastructure with fibrinolytic susceptibility for the fibrinogen arm. The discriminating result is what chelation does to each. Recovery of protease activity without recovery of clot architecture would show the two arms coming apart and would qualify the claim that this coagulopathy is correctable by removing the iron. Benchmark against plasma from a non-iron coagulopathy so that any change is attributable to iron rather than to critical illness.

Show evidence (2 references)

PMID:23170793 SUPPORT In Vitro

"We have recently shown that trivalent iron (ferric ions) generates hydroxyl radicals, which subsequently convert FBG into abnormal fibrin clots in the form of DMDs."

The competing effect, on the molecule PMID:6421970 reported as undamaged. PARTIAL because the work is framed on chronic degenerative disease rather than acute poisoning, so it establishes that ferric iron can do this to fibrinogen and not that it does so in this disease.

PMID:23170793 SUPPORT In Vitro

"A characteristic feature of DMDs is their remarkable and permanent resistance to the enzymatic degradation."

The property that gives this gap its therapeutic edge. The node's claim that the coagulopathy is correctable by removing the iron rests on the inhibition being reversible; a fibrin deposit described as permanently resistant to enzymatic degradation would not be reversed by chelation. PARTIAL on the same disease-frame grounds.

The diagnostic and management claims in this entry rest on case series, expert consensus, animal studies and adult volunteer studies rather than on controlled human trials in acute iron poisoning. Which of them would survive a trial-grade evidence base, and which are conventions that have persisted for want of better data?

KNOWLEDGE GAP OPEN evidence_base_quality_for_diagnosis_and_management

Attached to

diagnosis#Serum iron concentration diagnosis#Abdominal radiography for retained iron tablets treatments#Whole Bowel Irrigation treatments#Oral Deferiprone (investigational for acute poisoning)

This is a standing limitation on the entry rather than a gap in one mechanism, and it is stated by a review of the field rather than inferred here: diagnosis and management of iron poisoning have minimally evolved, and the evidence for them remains principally case series, expert consensus, animal studies and adult volunteer studies. That is visible throughout this entry, and recording it once in sourced form is more honest than repeating the caveat at every node. It is why the serum iron concentration is curated with a REFUTE beside its SUPPORT items rather than resolved; why oral deferiprone is investigational on rat data with its own HUMAN_MODEL_MISMATCH; why abdominal radiography rests on a single case report; why the Phase 3 mortality association is noted as a four-death series and not a prognostic rule; and why the commonly taught serum-iron chelation threshold and elemental-iron dose bands are curated nowhere in this entry at all. A curator who finds any of those thin should read this first: the thinness is the field's, not an artefact of what was reachable here.

Proposed experiments

Prospective multicentre registry of acute iron ingestion

prospective_registry_of_acute_iron_ingestion

Enrol consecutive acute iron ingestions across multiple poison centres with a common dataset — ingested preparation and estimated elemental dose, timed serum iron, abdominal radiograph findings, decontamination given, chelation timing and dose, and outcome. That is the design that would let the conventions in this entry be tested rather than inherited: whether serum iron predicts outcome once dose and clinical signs are accounted for (the disagreement between PMID:2870463 and PMID:14722368), whether radiographic tablet burden changes management, and what elemental-iron dose actually separates benign from severe. A registry rather than a trial because withholding chelation from a severely poisoned child is not randomisable.

Show evidence (2 references)

PMID:21975503 SUPPORT Other

"Despite these changes, diagnosis and management of iron poisoning have minimally evolved, and the current evidence for iron poisoning is yet based principally on case series, expert consensus, animal studies, and adult volunteer studies."

States the evidence base of the field directly, which is what makes this a sourced limitation rather than a curator's impression of one.

PMID:21975503 SUPPORT Other

"Although seen less frequently than acetaminophen or salicylate poisoning, acute iron poisoning remains a dangerous threat, particularly to pediatric patients."

Establishes that the thin evidence base attaches to a disease that is still dangerous, which is why the gap matters rather than being merely academic.

Which route carries the hepatocellular and mucosal cell death of acute iron poisoning: ferroptosis (iron-dependent, GPX4-restrained lethal lipid peroxidation), lysosomal destabilisation ending in apoptotic or necrotic death, or unregulated oxidative organelle damage requiring no death programme at all? The three are not mutually exclusive, and none has been demonstrated in this disease.

KNOWLEDGE GAP OPEN ferroptosis_in_acute_iron_poisoning

Attached to

pathophysiology#Iron-Catalysed Oxidative Organelle Injury pathophysiology#Periportal Hepatocellular Necrosis

Ferroptosis is a well-characterised, iron-dependent regulated cell-death pathway, and acute iron poisoning is the most extreme iron load a human tissue encounters — so the pathway is an obvious candidate for the cell death in this disease. But that inference runs from the general mechanism to this disease, not from evidence in it: the acute-iron-poisoning literature is a clinical toxicology literature of case series and poison-centre surveillance, and it predates the description of ferroptosis. No ferroptosis marker has been demonstrated in human acute iron poisoning tissue. The distinction is not academic, because a regulated pathway is druggable in ways that Fenton-chemistry damage is not: if ferroptosis carries a meaningful share of the hepatocyte death, a ferroptosis inhibitor becomes a candidate adjunct to chelation. This entry therefore curates the oxidative organelle injury it has evidence for, and records ferroptosis as an untested possibility rather than annotating GO:0097707 on the pathograph. The gap is wider than ferroptosis alone. PMID:11978485 proposes a separate, explicitly non-exclusive route in which iron-catalysed oxidative destabilisation of lysosomes spills digestive enzymes into the cytoplasm and ends in apoptotic or necrotic death. So there are at least two mechanistically distinct candidate death routes on offer — lipid-peroxidative ferroptosis and lysosomal rupture — and the acute iron poisoning literature demonstrates neither. Both are drawn from chronic iron-overload and general iron-toxicity biology. Establishing which, if either, carries the hepatocyte death in acute poisoning is the question; the experiments below should discriminate between them rather than test ferroptosis in isolation. A third literature bears on this without being about it, and it argues for restraint rather than for ferroptosis. Acetaminophen hepatotoxicity is the best-studied iron-dependent drug-induced liver injury, and a critical review of it warns in general terms against applying death mechanisms across cell types and disease states without validation, then concludes from the published data that hepatic antioxidant defences normally hold lipid peroxidation below pathophysiological relevance, so that ferroptosis becomes a significant mode of drug-induced cell death only where those defences are severely compromised. Acute iron poisoning is a plausible candidate for exactly that compromised state, which is the argument for testing it, not a demonstration that it holds. The same literature also supplies a specific route that would connect the two organelles this entry annotates on one node: lysosomal damage releasing iron that the mitochondrial calcium uniporter then takes up, making the lysosome the source and the mitochondrion the site. Whether that relay operates in iron poisoning, where the iron arrives from outside the cell rather than from a damaged lysosome, is untested and is worth distinguishing in the experiments below.

Proposed experiments

Discriminate the ferroptotic and lysosomal death routes in poisoned liver

death_route_discrimination_in_poisoning_liver

In explanted or post-mortem liver from acute iron poisoning, benchmarked against liver injured by a non-iron hepatotoxin, assay both candidate routes in the same tissue: lipid-peroxidation products and ferroptosis-associated transcriptional signatures for the ferroptotic route, and lysosomal membrane permeabilisation — cathepsin release into the cytosol, LAMP staining — for the lysosomal route. The point is to discriminate between them, so a design that assays only one cannot answer the question. The non-iron comparator is what separates an iron-specific death signature from generic oxidative necrosis.

Validate GPX4 abundance as a ferroptosis readout against selenium status

gpx4_readout_validation_against_selenium_status

Before GPX4 abundance is used as an index of ferroptotic pressure in poisoned tissue, establish what it is measuring. GPX4 is a selenoprotein whose expression tracks intracellular selenium utilisation and selenoprotein-synthesis capacity, so a low GPX4 in poisoned liver may reflect selenium status rather than iron-driven consumption. Measure selenium status and selenoprotein-synthesis capacity alongside GPX4 in the same specimens and test whether GPX4 varies with iron exposure once selenium status is accounted for. If it does not, the lipid hydroperoxide products should be the primary ferroptosis readout in the discrimination experiment above.

Ferroptosis inhibition in the rat acute oral iron model

ferroptosis_inhibition_rat_acute_iron_model

Add a ferroptosis inhibitor to the established rat acute oral iron LD50 model, alone and with chelation, and measure mortality, transaminases and hepatic histology. A survival benefit beyond chelation alone would establish a regulated-death contribution and a therapeutic target.

Show evidence (7 references)

PMID:32165281 SUPPORT Other

"Ferroptosis (FPT) is a form of cell death due to missed control of membrane lipid peroxidation (LPO)."

Defines the candidate pathway and situates it as a failure of control over lipid peroxidation — the process iron catalyses — which is why it is a plausible but as yet untested contributor here.

PMID:11978485 SUPPORT Other

"An alternative-and not mutually exclusive-mechanism for cellular iron toxicity involves iron-catalyzed oxidative destabilization of lysosomes, leading to leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death."

Supplies the competing lysosomal death route that widens this gap. PARTIAL because, like the ferroptosis proposal, it is drawn from chronic iron-overload biology and has not been shown in acute iron poisoning.

PMID:39649034 SUPPORT Other

"However, concerns arise when such mechanisms are applied across different cell types and disease states without sufficient validation."

Makes this discussion's central caution a sourced one rather than a curator's assertion. The gap recorded here is precisely that ferroptosis is being carried into acute iron poisoning from other cell types and disease states, and a critical review of the ferroptosis literature in drug-induced liver injury names that move as the thing to be wary of.

+ 4 more references

Does the mortality benefit of oral deferiprone seen in the rat acute oral-iron model translate to human acute iron poisoning, where the chelator must be given after ingestion rather than coadministered with the iron?

HUMAN MODEL MISMATCH OPEN deferiprone_human_translation_acute_poisoning

Attached to

treatments#Oral Deferiprone (investigational for acute poisoning) pathophysiology#Ingestion of Iron in Excess of Absorptive and Binding Capacity

The rat result is a real, dose-responsive survival benefit, but its design limits what it can say about the clinical problem: deferiprone was coadministered with the iron or given two hours later, whereas a poisoned child presents hours after an ingestion of unknown size, often already vomiting — which is both the reason an oral agent is attractive and the reason it may not be retained. The authors state plainly that oral efficacy in acute poisoning had not been tested in humans. The stakes are access rather than superiority: deferoxamine's cost and parenteral route put it out of reach in much of the world, so an oral alternative would change who can be treated at all. Until human data exist, deferiprone is curated here as investigational and deferoxamine remains the antidote. This discussion attaches to the ingested-burden node rather than to plasma non-transferrin-bound iron, matching where this treatment's target_mechanisms edge points and for the same reason: the only measurement supporting oral deferiprone in the acute setting is gastrointestinal tissue iron, not a plasma iron species. A systemically absorbed chelator plausibly also acts on plasma NTBI, but nothing in the cited evidence measures that, so both links are drawn where the evidence is rather than where the pharmacology is assumed to reach.

Proposed experiments

Delayed-administration oral chelation in the rat model

delayed_oral_chelation_rat_model

Repeat the rat acute oral iron model with deferiprone given at intervals matching realistic human presentation delays, and in animals made to vomit or with delayed gastric emptying, to test whether the benefit survives the timing and retention conditions of a real poisoning.

Registry-based human comparative cohort

deferiprone_registry_human_cohort

In settings where parenteral deferoxamine is unavailable and oral deferiprone is used, assemble a poison-centre registry cohort comparing chelated and unchelated acute iron poisonings on mortality, peak serum iron and hepatic injury, with severity adjustment.

Show evidence (1 reference)

PMID:10674529 SUPPORT Model Organism

"Its efficacy, by oral administration, in acute iron poisoning has not been tested."

The authors state that human oral efficacy in acute poisoning is untested, which is precisely the translational gap recorded here.

⚙

Pathophysiology

10

Ingestion of Iron in Excess of Absorptive and Binding Capacity

Ingestion of a supratherapeutic dose of an iron salt delivers elemental iron to the gastrointestinal lumen in amounts that exceed the tightly regulated physiological control of iron entry. Under normal conditions systemic iron is held within narrow limits by the hepcidin-ferroportin axis acting on absorptive enterocytes; an overdose bypasses that control both by sheer mass and by corroding the mucosal barrier that enforces it.

Animal models

Rat oral iron LD50 model of acute iron overdose Rat recapitulates Reproduces the defining exposure of human iron poisoning — a single acute oral iron load large enough to kill — and the gastrointestinal iron accumulation that follows it.

Downstream

Direct Corrosive Injury to Gastrointestinal Mucosa Iron salts in the lumen are directly toxic to the gastrointestinal mucosa they contact.

Non-Transferrin-Bound Iron in Plasma Iron absorbed in excess of what transferrin can bind circulates in an unbound, redox-active form.

Show evidence (2 references)

PMID:31949017 SUPPORT Other

"Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload."

Establishes that iron's safety depends on tight homeostatic control, which is the control an overdose defeats.

PMID:31949017 SUPPORT Other

"The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive enterocytes and iron-recycling macrophages."

Identifies the enterocyte hepcidin-ferroportin checkpoint that normally sets systemic iron entry.

Direct Corrosive Injury to Gastrointestinal Mucosa

Iron salts in contact with gastric and small-intestinal mucosa produce erosion, ulceration, haemorrhage and, at the severe end, mucosal necrosis and infarction. Injury is typically greatest in the stomach and proximal small bowel, but enteric-coated preparations can carry the injury distally and spare the proximal gut entirely — evidence that the lesion tracks where the preparation dissolves rather than following a fixed anatomical distribution.

intestinal epithelial cell CL:0002563 gastric mucosal epithelial cell CL:0002178

stomach UBERON:0000945 small intestine UBERON:0002108

Downstream

Hypovolaemia and Circulatory Shock Blood and fluid lost through the corroded mucosa can by itself depress the circulation.

Fibrotic Healing of Corrosive Injury and Gastric Outlet Obstruction The acute ulcers heal by scarring, and the scar contracts the lumen weeks after the poisoning has otherwise resolved.

Show evidence (2 references)

PMID:2231830 SUPPORT Human Clinical

"They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation."

Describes the severity range of the acute corrosive lesion and its delayed stricturing sequel.

PMID:2231830 SUPPORT Human Clinical

"Damage to distal areas of the bowel can occur with complete sparing of proximal portions particularly if the iron is an enteric-coated preparation."

Shows the injury follows where the iron preparation dissolves, supporting a direct contact-corrosive mechanism rather than a fixed anatomical susceptibility.

Non-Transferrin-Bound Iron in Plasma

Once absorbed iron exceeds the binding capacity of transferrin, iron circulates unbound to its physiological carrier. This non-transferrin-bound fraction is redox-active and enters cells outside transferrin-receptor control, so the cellular iron-handling machinery that would normally throttle uptake is bypassed. It is the species to which the systemic, as opposed to corrosive, manifestations of iron poisoning are attributed.

iron ion transport GO:0006826 ↑ INCREASED

Downstream

Iron-Catalysed Oxidative Organelle Injury Redox-active unbound iron catalyses free-radical chemistry inside the cells it enters.

Reversible Iron Inhibition of Coagulation Serine Proteases Non-transferrin-bound iron acts directly on the serine proteases of the coagulation cascade.

Show evidence (3 references)

PMID:6421970 SUPPORT In Vitro

"Although nontransferrin-bound Fe3+ is thought to initiate the disorder, little is known about how it interferes with blood coagulation."

Names non-transferrin-bound Fe3+ as the initiating circulating species in acute iron toxicity.

PMID:40650208 SUPPORT Other

"The pathophysiological significance of NTBI and LPI lies in their ability to enter cells via alternative transport pathways that are not regulated by the transferrin receptor system or by cellular iron levels."

States the transferrin-receptor bypass that this node's description asserts, and why it matters pathophysiologically.

PMID:40650208 SUPPORT Other

"The redox-active and chelatable fraction of NTBI is referred to as labile plasma iron (LPI)."

Identifies the redox-active fraction, and — being by definition chelatable — the fraction the antidote acts on.

Iron-Catalysed Oxidative Organelle Injury

Redox-active iron entering cells catalyses Fenton-type generation of reactive oxygen species, peroxidising membrane lipids and damaging intracellular organelles. The affected cells are those exposed to the highest iron flux — the mucosa in contact with the ingested salt and, through the portal circulation, the hepatocyte. Two organelles are proposed as the proximate targets: mitochondria, which may make cells with high mitochondrial activity preferentially vulnerable, and lysosomes, whose iron-catalysed oxidative destabilisation releases digestive enzymes into the cytoplasm. Both routes are described in the cellular iron-toxicity literature rather than demonstrated in acute poisoning — see this node's notes.

iron-catalysed reactive oxygen species generation GO:0072593 ↑ INCREASED cellular response to oxidative stress GO:0034599 ↑ INCREASED

mitochondrion GO:0005739 lysosome GO:0005764

Downstream

Metabolic Acidosis Interference with intermediary metabolism, compounded by reduced tissue perfusion, generates an acidosis.

Periportal Hepatocellular Necrosis The hepatocyte, receiving absorbed iron first through the portal vein, sustains the oxidative injury at the highest local concentration.

Show evidence (6 references)

PMID:3784842 SUPPORT Human Clinical

"They also cause metabolic acidosis by interfering with intermediary metabolism and producing shock and reduced tissue perfusion."

Attributes the metabolic derangement of iron poisoning to interference with intermediary metabolism, the clinical expression of this node.

PMID:37629109 SUPPORT Other

"Based on its role as the major biological catalyst of free radical reactions and the Fenton reaction, iron has also been implicated in all diseases associated with free radical pathology and tissue damage."

Identifies iron as the catalyst of Fenton free-radical chemistry, which is the molecular event this node asserts.

PMID:40650208 SUPPORT Other

"This unregulated uptake can lead to iron accumulation in vulnerable tissues such as the liver and the heart."

Names the liver as a tissue in which unregulated iron uptake accumulates, supporting the organ selectivity this node describes.

+ 3 more references

Reversible Iron Inhibition of Coagulation Serine Proteases

Non-transferrin-bound iron reversibly inactivates the serine proteases of the coagulation cascade — thrombin, factor Xa and kallikrein — without damaging the zymogens or fibrinogen itself. This produces a coagulopathy that is mechanistically distinct from the coagulopathy of hepatic synthetic failure, an attribution the authors state as likely rather than established; the two may coexist in severe poisoning. Because the inhibition is relieved by removing the iron, it is in principle correctable by chelation rather than only by factor replacement.

serine-type endopeptidase activity of the coagulation cascade GO:0004252 ↓ DECREASED

Show evidence (3 references)

PMID:6421970 SUPPORT In Vitro

"Studies of the mechanism by which iron prevents a normal plasma coagulation revealed that the proenzymes of the coagulation cascade and fibrinogen were not damaged by iron."

Excludes zymogen and fibrinogen damage, localising the defect to the active proteases.

PMID:6421970 SUPPORT In Vitro

"Because the amidolytic activity of human thrombin as well as factor Xa, kallikrein, and bovine trypsin was also reversibly suppressed by ferrous sulfate as well as ferric citrate, we consider it likely that the coagulopathy occurring in iron poisoning is the consequence of a general,..."

Identifies the general susceptibility of coagulation serine proteases to non-transferrin-bound iron as the mechanism of the coagulopathy.

PMID:6421970 SUPPORT In Vitro

"At iron concentrations comparable to those of previous animal investigations, we reproduced the coagulopathy, in other words, the dose-related prolongation of the prothrombin, thrombin, and partial thromboplastin time, in human plasma in vitro."

Shows the clotting-time prolongation is reproduced in human plasma by iron alone, without any hepatic contribution.

Metabolic Acidosis

A metabolic acidosis develops from impaired intermediary metabolism together with the reduced tissue perfusion of evolving shock. With coma and shock it is one of the three features conventionally accepted as marking severe poisoning.

Downstream

Hypovolaemia and Circulatory Shock Acidosis and circulatory failure reinforce each other in the decompensated phase.

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning."

Establishes metabolic acidosis as one of the accepted markers of severe iron poisoning.

Periportal Hepatocellular Necrosis

Extensive hepatocellular necrosis develops early in severe poisoning and carries a high mortality. Its periportal distribution is unusual among hepatotoxins and matters prognostically: the periportal zone is the principal site of hepatic regeneration, so injury concentrated there removes the liver's own capacity to recover. Hepatotoxicity appears to be dose-related, the lowest associated acute serum iron concentration reported greatly exceeding the reference range.

hepatocyte CL:0000182

liver UBERON:0002107

Show evidence (3 references)

PMID:11778670 SUPPORT Other

"Review of this literature and of experimental animal studies demonstrates that it occurs early in the clinical course and has a relatively high mortality."

Establishes the early onset and high mortality of the hepatic injury.

PMID:11778670 SUPPORT Human Clinical

"As this is the principle sitefor hepatic regeneration, this accountsfor the relatively high mortality rate."

Gives the mechanistic reason the periportal localisation is prognostically important. Quoted verbatim, including the source's spacing errors.

PMID:11778670 SUPPORT Human Clinical

"The lowest acute serum iron concentration associated with hepatotoxicity was 1700 microg/dL (304 micromol/L). Since this greatly exceeds the reference range of 50-150 microg/dL (9-27 micromol/L), it supports a dose-related etiology."

Supports a dose-related aetiology for the hepatotoxicity and gives the lowest reported associated serum iron concentration.

Hypovolaemia and Circulatory Shock

Circulatory failure in iron poisoning is multifactorial: gastrointestinal fluid and blood loss through the corroded mucosa, acidosis, and reduced tissue perfusion reinforce one another. Shock recurring or developing in the later phase, together with acidosis, marks the decompensation in which most deaths occur, and maintaining the intravascular volume is correspondingly central to management.

Downstream

Acute Kidney Injury Renal failure appears in the decompensated phase alongside shock and hepatocellular necrosis.

Show evidence (3 references)

PMID:3784842 SUPPORT Human Clinical

"Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop."

States directly that shock recurs or develops in the decompensated phase, which is what this node asserts.

PMID:2870463 SUPPORT Human Clinical

"In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume."

Indirect: a management statement about maintaining intravascular volume, from which the hypovolaemia is inferred rather than reported.

PMID:2870463 SUPPORT Human Clinical

"Iron poisoning continues to be a major toxicologic problem, with major impact on the gastrointestinal and circulatory systems."

Identifies the circulatory system, alongside the gastrointestinal tract, as a principal target of iron poisoning.

Acute Kidney Injury

Renal failure develops in the decompensated phase of severe poisoning, alongside recurrent shock, acidosis and hepatocellular necrosis.

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop."

Reports renal failure as a feature of the third phase of severe iron poisoning.

Fibrotic Healing of Corrosive Injury and Gastric Outlet Obstruction

Weeks after the acute event, the iron-induced mucosal ulcers heal by fibrous scarring that narrows the lumen, most often at the gastric outlet or duodenum, and the patient returns with recurrent vomiting. This delayed structural complication is unusual among acute poisonings and is the reason iron ingestion requires follow-up well beyond the acute admission. In adults, and particularly after enteric-coated preparations, the stricture may instead form in the distal small bowel.

pyloric antrum UBERON:0001165

Show evidence (2 references)

PMID:3784842 SUPPORT Human Clinical

"The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers."

Establishes the timing, mechanism and presentation of the late stenosis.

PMID:2231830 SUPPORT Human Clinical

"We describe an adult example of both, each occurring in the distal portion of the small intestine."

Documents that the acute injury and the late stricture can both occur distally in adults, extending the lesion beyond the classical gastric and proximal small-bowel sites.

✶

Histopathology

2

Gastric mucosal necrosis with superficial stainable iron

At autopsy after fatal acute ingestion, stainable iron lies superficially over areas of mucosal necrosis, with fibrin thrombi in the submucosa beneath — the histological form of the corrosive injury, with the iron sitting where it was in contact rather than distributed through the tissue.

Show evidence (1 reference)

PMID:33729557 SUPPORT Human Clinical

"Superficial deposits of stainable iron were present overlying areas of mucosal necrosis with underlying submucosal fibrin thrombi."

Describes the histology of the corrosive gastric lesion and the superficial, contact distribution of the iron.

Absent significant hepatic stainable iron despite fatal poisoning

In the same fatal case, no significant stainable iron was found in the liver, even though the clinical course showed hepatic compromise with markedly elevated serum iron. Stainable hepatic iron is therefore not a reliable post-mortem marker of acute iron poisoning, and its absence does not exclude the diagnosis.

Show evidence (2 references)

PMID:33729557 SUPPORT Human Clinical

"No significant stainable iron was present in the liver."

Reports the negative hepatic iron stain in a fatal acute iron poisoning.

PMID:33729557 SUPPORT Human Clinical

"His clinical course and laboratory findings demonstrated hepatic and renal compromise with markedly elevated serum iron levels."

Establishes that hepatic compromise and high serum iron were present in the same patient whose liver showed no significant stainable iron.

⬡

Pathograph

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

●

Phenotypes

14

Blood 2

Gastrointestinal haemorrhage FREQUENT Gastrointestinal hemorrhage HP:0002239

Show evidence (3 references)

PMID:14722368 SUPPORT Human Clinical

"Three patients were asymptomatic, others had vomiting (n =15, 83%), diarrhoea (n =13, 72%), malena (n = 8, 44%), and hemetemesis (n=6, 33%) generally within 6 hours of ingestion."

Overt gastrointestinal bleeding was common: melaena in 8 of 21 poisoned children (38%) and haematemesis in 6 of 21 (29%). The band is derived from melaena alone because the paper does not report how far the two overlap; that does not matter here, since the true union is bounded between 38% (complete overlap) and 67% (disjoint) and both ends fall inside FREQUENT. A single-centre retrospective paediatric cohort of 21 iron poisonings; the band is derived against all 21 patients, since three were asymptomatic and the paper's own percentages use the 18 symptomatic patients as denominator.

PMID:3784842 SUPPORT Human Clinical

"Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss."

Reports significant blood loss as a direct gastrointestinal effect of iron salts.

PMID:2870463 SUPPORT Human Clinical

"Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage."

Gastrointestinal haemorrhage is severe enough in iron poisoning to warrant blood component replacement.

Coagulopathy Abnormality of coagulation HP:0001928

Show evidence (2 references)

PMID:6421970 SUPPORT In Vitro

"Coagulopathy is a hallmark of severe ferrous sulfate poisoning in humans and laboratory animals."

Establishes coagulopathy as a hallmark feature of severe iron poisoning.

PMID:2870463 SUPPORT Human Clinical

"Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage."

Disorders of coagulation are a management target in iron poisoning, supporting them as a clinical feature.

Cardiovascular 2

Hypotension HP:0002615

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"Rarely, blood loss may be sufficient to cause hypotension."

Reports hypotension as a consequence of gastrointestinal blood loss in iron poisoning.

Shock HP:0031273

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning."

Establishes shock as an accepted marker of severe iron poisoning.

Digestive 4

Vomiting FREQUENT HP:0002013

Show evidence (2 references)

PMID:14722368 SUPPORT Human Clinical

"Three patients were asymptomatic, others had vomiting (n =15, 83%), diarrhoea (n =13, 72%), malena (n = 8, 44%), and hemetemesis (n=6, 33%) generally within 6 hours of ingestion."

Vomiting in 15 of 21 poisoned children (71%), which is the FREQUENT band. A single-centre retrospective paediatric cohort of 21 iron poisonings; the band is derived against all 21 patients, since three were asymptomatic and the paper's own percentages use the 18 symptomatic patients as denominator.

PMID:3784842 SUPPORT Human Clinical

"Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss."

Lists vomiting as a direct consequence of the gastrointestinal toxicity of iron salts.

Diarrhoea FREQUENT Diarrhea HP:0002014

Show evidence (2 references)

PMID:14722368 SUPPORT Human Clinical

"Three patients were asymptomatic, others had vomiting (n =15, 83%), diarrhoea (n =13, 72%), malena (n = 8, 44%), and hemetemesis (n=6, 33%) generally within 6 hours of ingestion."

Diarrhoea in 13 of 21 poisoned children (62%), which is the FREQUENT band. A single-centre retrospective paediatric cohort of 21 iron poisonings; the band is derived against all 21 patients, since three were asymptomatic and the paper's own percentages use the 18 symptomatic patients as denominator.

PMID:3784842 SUPPORT Human Clinical

"Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss."

Lists diarrhoea among the direct gastrointestinal effects of iron salts.

Acute hepatic failure OCCASIONAL HP:0006554

Show evidence (2 references)

PMID:14722368 SUPPORT Human Clinical

"Nine progressed to shock and/or impaired consciousness; two had acute liver failure."

Acute liver failure in 2 of 21 poisoned children (10%), the OCCASIONAL band. Note the shock figure in the same sentence is deliberately NOT used as a frequency for the Shock phenotype, because it counts shock and impaired consciousness together and cannot be split.

PMID:11778670 SUPPORT Human Clinical

"From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation."

Frames the hepatotoxicity as severe enough to warrant transplant consideration, i.e. as hepatic failure.

Gastric outlet obstruction from stricture Gastrointestinal obstruction HP:0004796

Show evidence (2 references)

PMID:2231830 SUPPORT Human Clinical

"They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation."

Reports delayed obstruction from stricture formation as a gastrointestinal consequence of iron overdose.

PMID:3784842 SUPPORT Human Clinical

"The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers."

Gives the timing and presentation of the delayed gastric or duodenal stenosis.

Genitourinary 1

Acute kidney injury HP:0001919

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop."

Reports renal failure as a feature of the third phase.

Metabolism 1

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning."

Establishes metabolic acidosis as an accepted marker of severe iron poisoning.

Nervous System 2

Impaired consciousness and coma HP:0001259

Show evidence (2 references)

PMID:3784842 SUPPORT Human Clinical

"Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis."

Reports impaired consciousness as a feature of severe iron poisoning.

PMID:3784842 SUPPORT Human Clinical

"The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning."

Names coma specifically, which is what the HP term on this phenotype asserts; the preceding snippet covers the milder impairment of consciousness on the same continuum.

Convulsions Seizure HP:0001250

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis."

Reports convulsions as a feature of severe iron poisoning.

Constitutional 1

Abdominal pain HP:0002027

Show evidence (2 references)

PMID:3784842 SUPPORT Human Clinical

"Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss."

Lists abdominal pain among the direct gastrointestinal effects of iron salts.

PMID:2231830 SUPPORT Human Clinical

"Significant protracted abdominal pain should alert the clinician of its possibility."

Gives protracted abdominal pain diagnostic weight as a marker of severe gastrointestinal complications.

Other 1

Hepatocellular necrosis Hepatic necrosis HP:0002605

Show evidence (2 references)

PMID:3784842 SUPPORT Human Clinical

"Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop."

Reports extensive hepatocellular necrosis in the decompensated phase.

PMID:11778670 SUPPORT Human Clinical

"Unlike most other hepatotoxins, the periportal areas of the hepatic lobule are the primary sites of injury."

Specifies the periportal distribution of the hepatic necrosis.

💊

Medical Actions

6

Deferoxamine Chelation

Action: Pharmacotherapy NCIT:C15986

Agent: deferoxamine CHEBI:4356

Intravenous deferoxamine is the specific antidote, indicated in severe intoxication on the basis of estimated body iron burden, clinical features and serum iron concentration. It binds circulating iron so that it can be excreted, and is given alongside supportive care with particular attention to intravascular volume.

Mechanism Target:

INHIBITS Non-Transferrin-Bound Iron in Plasma — Chelation removes the unbound circulating iron that drives the systemic arm of the poisoning.

Show evidence (1 reference)

PMID:2870463 SUPPORT Human Clinical

"By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine."

Establishes that chelation is directed at the body iron burden, i.e. at the circulating iron this node represents.

Show evidence (4 references)

PMID:2870463 SUPPORT Human Clinical

"In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume."

States the indication and route for deferoxamine in severe iron poisoning.

PMID:12503657 SUPPORT Human Clinical

"Whole bowel irrigation in addition to gastric lavage with an iron dose of over 50 mg/kg as well as deferoxamine treatment for patients in whom clinical and laboratory indications are present."

Reports deferoxamine given on clinical and laboratory indications in a paediatric case series.

PMID:14722368 SUPPORT Human Clinical

"Desferrioxamine infusion and supportive care of shock was the mainstay."

Confirms deferoxamine infusion, with shock support, as the mainstay of management in a real paediatric cohort.

+ 1 more reference

Whole Bowel Irrigation

Action: gastrointestinal decontamination by whole bowel irrigation Ontology label: Therapeutic Procedure NCIT:C49236

Whole bowel irrigation with polyethylene glycol solution is used to clear unabsorbed iron tablets from the gut. It is specifically endorsed for substantial iron ingestions because the morbidity is high and other decontamination options are lacking — activated charcoal does not absorb iron and gastric lavage is a questionable intervention.

Mechanism Target:

INHIBITS Ingestion of Iron in Excess of Absorptive and Binding Capacity — Removing unabsorbed tablets from the lumen limits the iron burden still available for absorption and for continued mucosal corrosion.

Show evidence (1 reference)

PMID:15533024 SUPPORT Human Clinical

"WBI should be considered for patients who have ingested substantial amounts of iron as the morbidity is high and there is a lack of other options for gastrointestinal decontamination."

Endorses whole bowel irrigation specifically for iron ingestion, acting on the unabsorbed luminal burden.

Show evidence (3 references)

PMID:15533024 SUPPORT Human Clinical

"Although some volunteer studies have shown substantial decreases in the bioavailability of ingested drugs, no controlled clinical trials have been performed and there is no conclusive evidence that WBI improves the outcome of the poisoned patient."

Records the honest limit of the evidence base: whole bowel irrigation is recommended for iron on grounds of high morbidity and absent alternatives, not on demonstrated outcome benefit.

PMID:1754488 SUPPORT Human Clinical

"Ipecac and gastric lavage are questionable interventions for the overdose patient, and activated charcoal does not absorb iron."

Sources the claim that the usual decontamination alternatives do not work for iron, which is why whole bowel irrigation is reached for.

PMID:1754488 SUPPORT Human Clinical

"Because less than half of the iron was removed during surgery, and because the chelation requirement was modest, it is likely that whole bowel irrigation removed a significant amount of iron."

A single-case inference that irrigation removed substantial iron; suggestive of the mechanism, not a demonstration of outcome benefit.

Fluid Resuscitation and Supportive Care

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

Maintenance of intravascular volume, correction of acidosis and of coagulation disorders, and replacement of blood components when there is gastrointestinal haemorrhage. Prompt recognition and initiation of management is the single most critical element in reducing morbidity and mortality.

Mechanism Target:

INHIBITS Hypovolaemia and Circulatory Shock — Volume replacement counters the hypovolaemia produced by gastrointestinal fluid and blood loss.

Show evidence (1 reference)

PMID:2870463 SUPPORT Human Clinical

"In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume."

Identifies maintenance of intravascular volume as a specific supportive care target in severe iron poisoning.

Show evidence (3 references)

PMID:2870463 SUPPORT Human Clinical

"Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage."

Lists the supportive measures beyond chelation in iron poisoning.

PMID:2870463 SUPPORT Human Clinical

"The prompt recognition and initiation of management of children with acute iron poisoning is the single most critical element in decreasing the morbidity and mortality associated with these products."

Establishes timeliness of management as the dominant determinant of outcome.

PMID:14722368 SUPPORT Human Clinical

"Shock responded to normal saline (33 +/- 15 mL/kg) and dopamine (10 +/- 4 microg/kg/min) within 4-24 hours in 7 of 9 patients."

Shock in iron poisoning responded to volume replacement plus an inotrope in 7 of 9 affected children, direct support for fluid resuscitation acting on the hypovolaemia node.

Surgical Removal of Retained Iron and Correction of Stricture

Action: Surgical Procedure NCIT:C15329

Surgical removal of iron may be indicated when large numbers of tablets remain in the gastrointestinal tract and cannot be cleared, and surgical correction is required for the late gastric or duodenal stenosis.

Mechanism Target:

INHIBITS Fibrotic Healing of Corrosive Injury and Gastric Outlet Obstruction — Operative correction relieves the mechanical obstruction produced by the healed corrosive injury.

Show evidence (1 reference)

PMID:2231830 SUPPORT Human Clinical

"They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation."

Establishes the obstructing stricture that surgery addresses; the cited cases were managed surgically, but this abstract does not itself report operative outcomes.

Show evidence (1 reference)

PMID:2870463 SUPPORT Human Clinical

"Under rare circumstances in which large numbers of iron tablets are present in the gastrointestinal tract, surgical removal may be indicated."

States the indication for surgical removal of retained iron tablets.

Liver Transplantation

Action: Liver Transplantation NCIT:C15271

Considered earlier in iron poisoning than in many other hepatotoxic exposures, because the hepatic injury is periportal — striking the zone on which regeneration depends — and carries a relatively high mortality.

Mechanism Target:

INHIBITS Periportal Hepatocellular Necrosis — Transplantation replaces the liver whose regenerative zone the poisoning has destroyed.

Show evidence (1 reference)

PMID:11778670 SUPPORT Human Clinical

"From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation."

Links transplantation directly to the hepatotoxicity of iron poisoning.

Show evidence (3 references)

PMID:38060750 SUPPORT Human Clinical

"We report a case of a severe iron tablet overdose with suicidal intent that progressed to fulminant hepatic failure despite medical treatment, ultimately treated with liver transplantation."

Documents transplantation actually performed for iron-induced fulminant hepatic failure after medical treatment failed.

PMID:38060750 SUPPORT Human Clinical

"Severe acute hepatotoxicity treated with liver transplantation is rare in adults, with very limited published literature."

Records how thin the evidence base is: transplantation for this indication is reported, but rarely, so this treatment rests on case-level evidence.

PMID:11778670 SUPPORT Other

"From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation."

States the indication for earlier transplant consideration in iron-induced hepatotoxicity.

Oral Deferiprone (investigational for acute poisoning)

Action: Pharmacotherapy NCIT:C15986

Agent: deferiprone CHEBI:68554

An orally active iron chelator established for chronic transfusional iron overload and proposed for acute poisoning where parenteral deferoxamine is unaffordable or unavailable. The supporting efficacy data in the acute setting are from a rat model, not from humans; this is not established therapy for acute iron poisoning and should not be curated as such.

Mechanism Target:

INHIBITS Ingestion of Iron in Excess of Absorptive and Binding Capacity — Oral chelation of the ingested iron burden, with a dose-dependent reduction of gastrointestinal iron accumulation demonstrated histologically in rats. The edge is drawn to the ingested burden rather than to plasma non-transferrin-bound iron because the supporting measurement is gastrointestinal tissue iron, not a plasma iron species.

Show evidence (1 reference)

PMID:10674529 SUPPORT Model Organism

"Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract."

Demonstrates dose-dependent removal of iron by oral deferiprone in the rat acute-overdose model.

Show evidence (2 references)

PMID:10674529 SUPPORT Model Organism

"Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007)."

Reports the mortality reduction in the rat model that motivates interest in oral deferiprone for acute poisoning.

PMID:10674529 SUPPORT Model Organism

"Its efficacy, by oral administration, in acute iron poisoning has not been tested."

The authors' own statement that human efficacy in acute poisoning was untested, which is why this treatment is curated as investigational.

🌍

Environmental Factors

2

Unintentional ingestion of iron supplements by young children

The packaging story is more equivocal than it is usually told. Deaths in children under six fell from 29 to 1 across the 1997 unit-dose packaging regulation (PMID:15939855), but that mandate was vacated in 2003 after Nutritional Health Alliance v. FDA, and a 2000-2017 National Poison Data System cohort found severe exposures continued to decline anyway (DOI:10.1177/0009922819901010). A third strand cuts the same way from the other end of the timeline: PMID:10798501, published before the mandate could have had an effect, reports paediatric iron fatalities already falling from a peak of 10 in 1991 to 2 by 1995. All three results are curated here; none is a controlled comparison, and the entry does not assert that packaging alone caused the fall. The same source undercuts a simpler reading of the exposure itself. Child-resistant containers were already in use, and children were getting the iron out of them anyway, or out of ones an adult had left open. That is why the regulatory move was to unit-dose blistering rather than to more child resistance, and it is part of why this exposure is described above as set by product form rather than by any host factor.

The classic exposure: a child under five swallows adult-strength iron tablets or prenatal vitamins from a household supply. Acute iron poisoning is most common in this age group, and the exposure is determined by product availability and packaging rather than by any host factor.

Show evidence (6 references)

PMID:21975503 SUPPORT Other

"Multiple factors-including legal and manufacturing practices-have changed the landscape of iron poisoning over the decades."

Supports the framing of this exposure as one whose incidence is set by legal and manufacturing practice rather than by host biology, which is what the packaging notes below record.

PMID:10798501 SUPPORT Human Clinical

"The children often obtained the iron from a child-resistant container opened by themselves or another child or left open or improperly closed by an adult."

The exposure route in detail, and the finding that makes the packaging story one about product form rather than about container closures: child-resistant containers were already in use and were being defeated, either by a child or by an adult who left one open. National Consumer Product Safety Commission and poison-centre data, 1980 to 1996.

PMID:10798501 SUPPORT Human Clinical

"Pediatric iron-related fatalities increased in 1986, peaked at 10 in 1991, and declined to 2 by 1995."

Independent support for the equivocation recorded in the notes, arriving from the pre-mandate side of it: paediatric iron fatalities were already falling before the 1997 unit-dose regulation, having peaked in 1991. This is a different data source and a different case definition from the 29-to-1 figure of PMID:15939855, so the two are curated separately rather than merged into one series.

+ 3 more references

Mechanism Target:

TRIGGERS Ingestion of Iron in Excess of Absorptive and Binding Capacity — Swallowing the tablets is the route by which the toxic iron burden is established. That an intervention acting only on access to the tablets, with no change to host biology, was followed by fewer ingestions and fewer deaths is consistent with the exposure being what initiates the disease — though the study is a before-and-after comparison, so secular trend is not excluded (see this exposure's notes).

Show evidence (2 references)

PMID:15939855 SUPPORT Human Clinical

"The average number of iron ingestion calls per 1000 of all calls to poison control centers regarding children younger than 6 years decreased from 2.99 per 1000 to 1.91 per 1000 (odds ratio, 1.29 [95% confidence interval, 1.27-1.32]; P<.001). The number of deaths decreased from 29 to 1 (odds..."

Both ingestions and deaths fell after an intervention that changed only access to the tablets. This is an uncontrolled before-and-after comparison, not a dose-response design, so it is consistent with — rather than proof of — ingestion being what triggers the disease.

DOI:10.1177/0009922819901010 SUPPORT Human Clinical

"Despite removal of iron packaging regulations in the United States, there continues to be a decrease in the incidence of severe iron exposures in children."

Complicates the attribution rather than the edge: severity kept falling after the packaging mandate was withdrawn in 2003, so the earlier before-and-after result is confounded by a secular trend. The exposure route itself is unaffected.

Deliberate self-poisoning with iron tablets

Intentional ingestion of iron, typically by adolescents and adults, accounts for the larger ingested doses and is the route behind most severe and fatal adult cases.

Show evidence (5 references)

PMID:33729557 SUPPORT Human Clinical

"Acute iron toxicity in adults is rare, usually occurring due to intentional ingestion in suicide attempts."

Establishes intentional ingestion as the usual route of acute iron toxicity in adults.

PMID:33729557 SUPPORT Human Clinical

"Ingestion of large amounts of iron salts can lead to hemorrhagic shock, multi-system organ failure, coagulopathy, and death."

Gives the severe outcomes associated with the large ingested doses typical of this exposure route.

PMID:30598567 SUPPORT Human Clinical

"Acute iron toxicity is usually seen in children with accidental ingestion of iron-containing syrups."

The clinical-epidemiologic half of this entry's scope problem: the disease as usually encountered is paediatric and accidental, which is the population nearly every cohort cited here describes. HUMAN_CLINICAL because this is a generalization about patients rather than about the literature; the companion item below makes the separate claim about the literature and is tagged OTHER accordingly. PARTIAL rather than SUPPORT, because the relationship is indirect. This sentence describes paediatric accidental poisoning, the opposite of the adult deliberate exposure it sits under, and it bears on that exposure only by establishing the contrast that makes this route the uncommon one. In the source it is the first half of a contrastive pair, so the "However" of the companion item below is what carries the claim that bears on this entry directly.

+ 2 more references

Mechanism Target:

TRIGGERS Ingestion of Iron in Excess of Absorptive and Binding Capacity — Deliberate ingestion establishes the iron burden, generally at higher doses than unintentional paediatric exposure.

Show evidence (1 reference)

PMID:33729557 SUPPORT Human Clinical

"Acute iron toxicity in adults is rare, usually occurring due to intentional ingestion in suicide attempts."

Names intentional ingestion as the route by which the adult iron burden is established, which is what this edge asserts.

🔬

Biochemical Markers

1

Serum iron concentration

Reference Ranges

50.0–150.0 microg/dL (general reference interval cited for acute-poisoning comparison)

Reference interval (50.0–150.0 microg/dL) At or above the conventional toxic threshold when symptomatic (350.0–500.0 microg/dL) At or above the conventional toxic threshold regardless of symptoms (500.0–1700.0 microg/dL) At or above the lowest concentration reported with hepatotoxicity (1700.0– microg/dL) → Hepatic necrosis

At or above the conventional toxic threshold when symptomatic: By long-standing convention a concentration of 350 microg/dL is considered toxic in a patient who has symptoms, and likely to need treatment to prevent decompensation. Below 500 microg/dL the convention is conditional on the presence of symptoms, which is why this band is separated from the one below it. Curated as the tradition its source describes it as, not as a validated decision threshold; the serum_iron_versus_ingested_dose discussion is the context to read it in.

At or above the conventional toxic threshold regardless of symptoms: At or above 500 microg/dL the conventional threshold no longer depends on whether the patient has symptoms. The upper bound of this band is not a second threshold: it is simply where the band reporting the lowest concentration ever observed with hepatotoxicity begins.

At or above the lowest concentration reported with hepatotoxicity: 1700 microg/dL is the lowest acute serum iron concentration reported in association with hepatotoxicity, not a validated decision threshold. Hepatotoxicity has not been shown to be excluded below it.

Quoted as the reference range against which acute poisoning concentrations are judged in a review of iron-poisoning hepatotoxicity, not derived from a laboratory reference-interval study. Equivalent to 9-27 micromol/L in the same source.

Show evidence (1 reference)

PMID:11778670 SUPPORT Other

"Since this greatly exceeds the reference range of 50-150 microg/dL (9-27 micromol/L), it supports a dose-related etiology."

States the reference interval used, in both unit systems.

Show evidence (3 references)

PMID:11778670 SUPPORT Other

"The lowest acute serum iron concentration associated with hepatotoxicity was 1700 microg/dL (304 micromol/L)."

Gives the lowest serum iron concentration reported in association with hepatotoxicity, the basis for the upper interpretation band.

PMID:2870463 SUPPORT Human Clinical

"By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine."

Establishes the serum iron concentration as an input to the chelation decision.

PMID:39509998 SUPPORT Other

"Traditionally, a concentration of 350 μg/dL with symptoms, or 500 μg/dL without symptoms, is considered toxic and will likely need treatment to prevent decompensation."

Source for the two conventional-threshold interpretation bands above. Quoted from the study's background, where it states established practice rather than a result, so it attests that the convention exists and takes this conditional form and not that either figure has been validated.

🔬

Diagnosis

3

Serum iron concentration

How much weight the serum iron concentration should carry is contested, and this entry does not settle it. On one account it is one of three inputs to the chelation decision, alongside an estimate of the ingested body iron burden and the clinical features, and the ingested dose is unusable as a severity measure because it is rarely known accurately and absorption is unpredictable once vomiting and diarrhoea have removed some of it. A paediatric cohort reports the reverse on both counts: the dose and the clinical signs guided management and the serum iron did not. A third series reports the strongest quantitative result on this question in either direction, and reports it within a severity stratum rather than pooled: among patients whose symptoms stayed minor, an early concentration at or below 300 microg/dL was followed by no later toxic concentration at all. All three positions are curated below, together with the conventional toxicity thresholds and the reason a concentration drawn too soon can under-read the exposure rather than measure it. The one use not in dispute is discriminating this disease from the chronic iron-overload states that share a MONDO synonym with it.

The value of the serum iron concentration is genuinely contested in the cited literature and this entry does not resolve it; see the serum_iron_versus_ingested_dose CONTROVERSY discussion, which states the disagreement and what would settle it. Both positions are curated here with their evidence rather than one being chosen. A curator adding a numeric decision threshold should treat that disagreement as the context for the threshold, not curate the threshold as settled. The conventional thresholds are now curated on the biochemical entry on exactly that footing.

Show evidence (10 references)

PMID:2870463 SUPPORT Human Clinical

"By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine."

Establishes the serum iron concentration as one of the three inputs to the chelation decision.

PMID:33729557 SUPPORT Human Clinical

"Peak serum iron levels may be helpful in differentiating acute toxicity from chronic iron overload states."

Supports the use of peak serum iron to distinguish acute poisoning from chronic iron overload.

PMID:3784842 SUPPORT Human Clinical

"The amount of elemental iron ingested is unacceptable since it is seldom known with accuracy and absorption is unpredictable because of vomiting and diarrhoea."

Refutes the ingested dose as a severity measure, which is why a measured serum concentration is relied on; it does not itself validate the serum measurement.

+ 7 more references

Abdominal radiography for retained iron tablets

Iron tablets are visible on abdominal radiography, so a film both supports the diagnosis and shows how much unabsorbed tablet burden remains. That is what gates whole bowel irrigation and tells the clinician when to stop it — the rectal effluent can run clear while radiography still shows iron in the gut, so the effluent alone is not a reliable endpoint.

A single case report, so it establishes that radiography shows retained iron and that effluent clearing is an unreliable endpoint, not the test's sensitivity or specificity. A negative film does not exclude a significant ingestion; that limitation was not sourced to a cached reference and is deliberately not asserted here.

Show evidence (2 references)

PMID:8629765 SUPPORT Human Clinical

"The rectal effluent cleared within 2 days of the start of PEG-ELS therapy despite the persistence of iron in the gastrointestinal tract as shown on radiography."

Shows radiography visualising retained gastrointestinal iron, and that it disagreed with — and outlasted — the effluent endpoint.

PMID:8629765 SUPPORT Human Clinical

"We present a case of a 33-month-old boy who ingested at least 160 mg/kg elemental iron and received 44.3 L of PEG-ELS (2,953 ml/kg) over 5 days because of the persistence of iron tablets in teh gastrointestinal tract."

The radiographic tablet burden is what drove the duration of decontamination in this case. Quoted verbatim, including the source's "teh" typo.

Gastric iron encrustation at autopsy

Gross iron encrustation over the gastric rugae is reported as specific for acute ingestion when it is present, making it a post-mortem discriminator between acute poisoning and chronic iron overload.

Reported from a single autopsy case with literature review, so the specificity claim rests on a narrow base. The same source cautions that the clinical course and laboratory testing of severe acute iron overdose is fairly non-specific.

Show evidence (2 references)

PMID:33729557 SUPPORT Human Clinical

"Gross findings of gastric iron encrustation are specific for acute ingestion when present."

States the specificity of gastric iron encrustation for acute ingestion.

PMID:33729557 SUPPORT Human Clinical

"At autopsy, iron encrustations were present over the gastric rugae."

The autopsy observation on which the specificity claim is grounded.

🪜

Stages

4

Phase 1 - Acute gastrointestinal irritation (up to 6 hours)

Features of acute gastrointestinal irritation dominate the first six hours, and most patients do not progress beyond this stage. Severe poisoning declares itself here through impaired consciousness, convulsions and metabolic acidosis.

Show evidence (2 references)

PMID:3784842 SUPPORT Human Clinical

"Features of acute gastrointestinal irritation dominate the period up to 6 hours after ingestion and most patients do not develop other features or progress beyond this stage."

Defines the timing and dominant features of the first phase and notes that most patients stop here.

PMID:3784842 SUPPORT Human Clinical

"Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis."

Gives the features that mark severe poisoning within the first phase.

Phase 2 - Remission (6 to 12 hours)

A period of apparent improvement in which the gastrointestinal features remit while cellular toxicity continues. It is the deceptive interval of iron poisoning and the reason apparent recovery does not license discharge.

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"The second phase, 6 to 12 hours after ingestion, is one of remission of features."

Defines the timing and nature of the remission phase.

Phase 3 - Shock, acidosis and organ failure (12 to 48 hours)

Reached by only a small minority of patients. Shock and metabolic acidosis recur or develop, and renal failure and extensive hepatocellular necrosis may appear.

The mortality association above comes from a single-centre retrospective series with four deaths. It describes which features accompanied the fatal cases; it is not a validated prognostic rule.

Show evidence (3 references)

PMID:3784842 SUPPORT Human Clinical

"Phase 3 comprises the period 12 to 48 hours from ingestion and is reached only by a small minority of patients."

Defines the timing of the third phase and that few patients reach it.

PMID:3784842 SUPPORT Human Clinical

"Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop."

Gives the organ failures that characterise the third phase.

PMID:14722368 SUPPORT Human Clinical

"Presence of shock or acute liver failure with coagulopathy and/or severe acidosis predicted all the four deaths."

The feature combination defining this phase is what preceded every death in a 21-patient paediatric cohort, which is why this is the phase in which most deaths occur.

Phase 4 - Gastric or duodenal stenosis (2 to 6 weeks)

A late phase seen mainly in young children, in which vomiting recurs because the healed iron-induced ulcers have narrowed the gastric outlet or duodenum.

Emergency-medicine sources commonly teach a five-stage scheme that splits the hepatotoxicity of days 2-5 into a stage of its own between shock and late stenosis. The four-phase scheme curated here is the one stated in the cited source; the two describe the same course at different granularity, and the hepatic injury is carried in this entry by the Periportal Hepatocellular Necrosis pathophysiology node.

Show evidence (1 reference)

PMID:3784842 SUPPORT Human Clinical

"The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers."

Defines the timing, population and mechanism of the fourth phase.

📊

Prevalence

3

Children presenting with accidental poisoning to a paediatric emergency service, India, 1998-2003

Unknown Unknown

Reported as iron's share of paediatric accidental-poisoning presentations (21 of 337) at one teaching hospital, not as a population rate, so no normalized rate per 100,000 is given. It measures what fraction of poisoned children were poisoned by iron, not how common iron poisoning is.

Show evidence (1 reference)

PMID:14722368 SUPPORT Human Clinical

"Of these 21(7%) patients had iron poisoning; 18 were transferred to PICU."

Gives iron's share of paediatric accidental poisonings at this centre, and the proportion needing intensive care.

Children younger than 6 years in the United States, before the 1997 unit-dose packaging regulation

Unknown Unknown

Reported as iron-ingestion calls per 1000 of all poison-control-centre calls concerning children under 6, averaged over the ten years before the regulation, rather than as a population rate; not convertible to cases per 100,000 population, so no normalized rate is given.

Show evidence (1 reference)

PMID:15939855 SUPPORT Human Clinical

"The average number of iron ingestion calls per 1000 of all calls to poison control centers regarding children younger than 6 years decreased from 2.99 per 1000 to 1.91 per 1000 (odds ratio, 1.29 [95% confidence interval, 1.27-1.32]; P<.001)."

Gives the pre- and post-regulation call frequencies among young children.

Children in the United States, 1980-1996 (national surveillance)

Unknown Unknown

Reported as a national annual count of iron-ingestion injuries, not as a population rate: the source gives no denominator, so no rate per 100,000 is derived here. The step change is the informative part rather than the level. Injuries roughly doubled at a single point in 1986 and then held, with no comparable trend before or after, while fatalities moved on a different trajectory, peaking in 1991 and falling to 2 by 1995. Age was spread evenly across under-2s, 2-year-olds and 3-to-4-year-olds.

Show evidence (1 reference)

PMID:10798501 SUPPORT Human Clinical

"Pediatric iron-related injuries increased 150% in 1986, from an annual average of 1,200 from 1980 through 1985 to 3,000 from 1986 through 1996."

Gives the national annual injury counts and the 1986 step change. Quoted as counts because the source reports counts; converting them to a rate would require a denominator it does not supply.

🐁

Animal Models

1

Rat oral iron LD50 model of acute iron overdose Chemically induced

Wistar rats given 612 mg/kg elemental iron orally, a dose corresponding to the LD50 in that species, used to test whether an orally administered chelator can reduce mortality after acute iron ingestion.

Species

Rat

Genotype

wild type

Background

Wistar

Publication

PMID:10674529

Pathograph links

Ingestion of Iron in Excess of Absorptive and Binding Capacity recapitulates fidelity: moderate Reproduces the defining exposure of human iron poisoning — a single acute oral iron load large enough to kill — and the gastrointestinal iron accumulation that follows it.

Limitations: The dose is set at the rodent LD50 rather than scaled from human ingestions, and rodent gastrointestinal anatomy and dosing pharmacokinetics differ from the human paediatric case; LD50 estimates for iron salts vary widely between studies and strains, so this model supports relative comparisons (chelated versus unchelated) far better than absolute human dose extrapolation.

Readouts

Mortality after acute oral iron load

Direction: DECREASED

Interpretation: Direction is stated relative to the unchelated model arm: the model itself is lethal at this iron dose, and mortality fell when oral chelation was added, showing the lethality is iron-dependent and chelation-modifiable.

Show evidence (1 reference)

PMID:10674529 SUPPORT Model Organism

"Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007)."

Quantifies the mortality readout and its response to chelation.

Gastrointestinal tissue iron accumulation

Direction: DECREASED

Interpretation: Direction is stated relative to the unchelated model arm: the model accumulates gastrointestinal tissue iron, and that accumulation fell dose-dependently with chelation, tying the readout to the iron burden.

Show evidence (1 reference)

PMID:10674529 SUPPORT Model Organism

"Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract."

Reports the histological iron-accumulation readout and its dose response.

Show evidence (1 reference)

PMID:10674529 SUPPORT Model Organism

"Our objective was to determine whether orally administered deferiprone can reduce the mortality of rats following acute, toxic, oral doses of iron."

States the model's design — acute toxic oral iron dosing in rats — and its use as a testbed for acute-poisoning therapy.

Show evidence (1 reference)

PMID:10674529 SUPPORT Model Organism

"Rats were administered 612 mg/kg elemental iron orally, corresponding to LD50 in the species tested."

Defines the model: the species, route, and the dose at which it was calibrated.

{ }

Source YAML

click to show

name: Iron Poisoning
creation_date: "2026-08-23T00:00:00Z"
category: Environmental
parents:
- heavy metal poisoning
categories:
- Toxic Exposure Disorder
- Heavy Metal Poisoning
- Environmental Health Disorder
synonyms:
- acute iron poisoning
- acute iron toxicity
- acute iron overdose
- ferrous sulfate poisoning
description: >-
  Iron poisoning is an acute toxic syndrome caused by ingestion of iron salts in
  quantities that overwhelm regulated intestinal absorption and the iron-binding
  capacity of plasma transferrin. It is classically a poisoning of young children
  who swallow adult-strength ferrous sulfate tablets or prenatal vitamins, and of
  adolescents and adults who take iron in deliberate self-harm. Toxicity has two
  arms. A corrosive arm, in which iron salts injure the gastrointestinal mucosa
  directly, produces vomiting, diarrhoea, abdominal pain and blood loss within
  hours, and — weeks later, as those ulcers heal by scarring — gastric or duodenal
  stenosis. A cellular arm, in which iron absorbed beyond transferrin's binding
  capacity circulates as non-transferrin-bound iron, disturbs intermediary
  metabolism and mitochondrial function, producing metabolic acidosis, shock,
  periportal hepatocellular necrosis, and a distinctive coagulopathy attributed
  to reversible iron inhibition of the coagulation serine proteases rather than
  to hepatic synthetic failure. The clinical course is conventionally divided into
  phases separated by a deceptive period of apparent remission. Deferoxamine
  chelation is the specific antidote; the introduction of unit-dose packaging of
  iron supplements was followed by a sharp fall in paediatric deaths, though
  severity continued to fall after that packaging mandate was withdrawn.
disease_term:
  preferred_term: iron poisoning
  term:
    id: MONDO:0800385
    label: iron poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800385
      label: iron poisoning
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for iron poisoning.
  icd10cm_mappings:
  - term:
      id: ICD10CM:T45.4
      label: Poisoning by, adverse effect of and underdosing of iron and its compounds
    mapping_predicate: skos:broadMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      A broadMatch, not an exact one. The ICD-10-CM rubric bundles poisoning with
      adverse effect and underdosing of iron, so it is wider than this entry,
      which covers acute poisoning only.
  - term:
      id: ICD10CM:T45.4X1A
      label: Poisoning by iron and its compounds, accidental (unintentional), initial encounter
    mapping_predicate: skos:narrowMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      Narrower than this entry because it fixes both intent (accidental) and
      encounter type (initial). It is the code for the paediatric unintentional
      ingestion that dominates this disease.
  - term:
      id: ICD10CM:T45.4X2A
      label: Poisoning by iron and its compounds, intentional self-harm, initial encounter
    mapping_predicate: skos:narrowMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      The intent-specific counterpart code, covering the deliberate ingestion
      route curated in this entry's environmental section.

notes: >-
  MONDO:0800385 carries "iron overload" as an EXACT synonym. That synonym is a
  hazard rather than a guide for this entry: the chronic iron-overload disorders
  (hereditary haemochromatosis, transfusional haemosiderosis) are separate
  diseases with a different route to tissue iron, a different tempo, and a
  different therapeutic logic, and this entry deliberately curates only the acute
  ingestion syndrome that the MONDO textual definition describes ("Ingested iron
  can cause direct caustic injury to the gastrointestinal mucosa"). Literature
  retrieved under the phrase "iron overload" is very often about the chronic
  disorders and should not be curated here without checking which entity it
  concerns. The two are separable clinically as well as conceptually: peak serum
  iron is reported as helpful in telling acute toxicity from chronic overload,
  and gastric iron encrustation at autopsy is specific for acute ingestion.

references:
- reference: PMID:3784842
  title: "Management of acute iron poisoning."
- reference: PMID:11778670
  title: "Hepatotoxicity in acute iron poisoning."
- reference: PMID:6421970
  title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."

pathophysiology:
- name: Ingestion of Iron in Excess of Absorptive and Binding Capacity
  biological_scale: ORGANISM
  description: >-
    Ingestion of a supratherapeutic dose of an iron salt delivers elemental iron
    to the gastrointestinal lumen in amounts that exceed the tightly regulated
    physiological control of iron entry. Under normal conditions systemic iron is
    held within narrow limits by the hepcidin-ferroportin axis acting on
    absorptive enterocytes; an overdose bypasses that control both by sheer mass
    and by corroding the mucosal barrier that enforces it.
  triggers:
  - preferred_term: exposure to iron via ingestion
    term:
      id: ECTO:0900035
      label: exposure to iron via ingestion
  chemical_entities:
  - preferred_term: iron(2+)
    term:
      id: CHEBI:29033
      label: iron(2+)
  evidence:
  - reference: PMID:31949017
    reference_title: "Iron metabolism and iron disorders revisited in the hepcidin era."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload.
    explanation: >-
      Establishes that iron's safety depends on tight homeostatic control, which
      is the control an overdose defeats.
  - reference: PMID:31949017
    reference_title: "Iron metabolism and iron disorders revisited in the hepcidin era."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive enterocytes and iron-recycling macrophages.
    explanation: >-
      Identifies the enterocyte hepcidin-ferroportin checkpoint that normally sets
      systemic iron entry.
  downstream:
  - target: Direct Corrosive Injury to Gastrointestinal Mucosa
    causal_link_type: DIRECT
    description: >-
      Iron salts in the lumen are directly toxic to the gastrointestinal mucosa
      they contact.
    evidence:
    - reference: PMID:3784842
      reference_title: "Management of acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss.
      explanation: >-
        States the direct mucosal toxicity of ingested iron salts and the
        symptoms it produces.
  - target: Non-Transferrin-Bound Iron in Plasma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - absorption of iron across the injured mucosa into portal blood
    description: >-
      Iron absorbed in excess of what transferrin can bind circulates in an
      unbound, redox-active form.
    evidence:
    - reference: PMID:6421970
      reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Although nontransferrin-bound Fe3+ is thought to initiate the disorder, little is known about how it interferes with blood coagulation.
      explanation: >-
        Identifies non-transferrin-bound iron as the circulating species held
        responsible for systemic toxicity in acute iron poisoning.

- name: Direct Corrosive Injury to Gastrointestinal Mucosa
  biological_scale: TISSUE
  description: >-
    Iron salts in contact with gastric and small-intestinal mucosa produce
    erosion, ulceration, haemorrhage and, at the severe end, mucosal necrosis and
    infarction. Injury is typically greatest in the stomach and proximal small
    bowel, but enteric-coated preparations can carry the injury distally and
    spare the proximal gut entirely — evidence that the lesion tracks where the
    preparation dissolves rather than following a fixed anatomical distribution.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: gastric mucosal epithelial cell
    term:
      id: CL:0002178
      label: epithelial cell of stomach
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:2231830
    reference_title: "Gastrointestinal pathology in adult iron overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation.
    explanation: >-
      Describes the severity range of the acute corrosive lesion and its delayed
      stricturing sequel.
  - reference: PMID:2231830
    reference_title: "Gastrointestinal pathology in adult iron overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Damage to distal areas of the bowel can occur with complete sparing of proximal portions particularly if the iron is an enteric-coated preparation.
    explanation: >-
      Shows the injury follows where the iron preparation dissolves, supporting a
      direct contact-corrosive mechanism rather than a fixed anatomical
      susceptibility.
  downstream:
  - target: Hypovolaemia and Circulatory Shock
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - gastrointestinal fluid and blood loss into the lumen
    description: >-
      Blood and fluid lost through the corroded mucosa can by itself depress the
      circulation.
    evidence:
    - reference: PMID:3784842
      reference_title: "Management of acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Rarely, blood loss may be sufficient to cause hypotension.
      explanation: >-
        Attributes hypotension in the early phase to gastrointestinal blood loss,
        establishing this corrosive route to circulatory compromise.
  - target: Fibrotic Healing of Corrosive Injury and Gastric Outlet Obstruction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - healing of iron-induced mucosal ulcers by fibrous scarring
    description: >-
      The acute ulcers heal by scarring, and the scar contracts the lumen weeks
      after the poisoning has otherwise resolved.
    evidence:
    - reference: PMID:3784842
      reference_title: "Management of acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers.
      explanation: >-
        States explicitly that the late stenosis is produced by the healing of the
        earlier iron-induced ulceration.

- name: Non-Transferrin-Bound Iron in Plasma
  biological_scale: MOLECULAR
  description: >-
    Once absorbed iron exceeds the binding capacity of transferrin, iron
    circulates unbound to its physiological carrier. This non-transferrin-bound
    fraction is redox-active and enters cells outside transferrin-receptor
    control, so the cellular iron-handling machinery that would normally throttle
    uptake is bypassed. It is the species to which the systemic, as opposed to
    corrosive, manifestations of iron poisoning are attributed.
  chemical_entities:
  - preferred_term: iron(3+)
    term:
      id: CHEBI:29034
      label: iron(3+)
  biological_processes:
  - preferred_term: iron ion transport
    term:
      id: GO:0006826
      label: iron ion transport
    modifier: INCREASED
  evidence:
  - reference: PMID:6421970
    reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although nontransferrin-bound Fe3+ is thought to initiate the disorder, little is known about how it interferes with blood coagulation.
    explanation: >-
      Names non-transferrin-bound Fe3+ as the initiating circulating species in
      acute iron toxicity.
  - reference: PMID:40650208
    reference_title: "The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiological significance of NTBI and LPI lies in their ability to enter cells via alternative transport pathways that are not regulated by the transferrin receptor system or by cellular iron levels.
    explanation: >-
      States the transferrin-receptor bypass that this node's description
      asserts, and why it matters pathophysiologically.
  - reference: PMID:40650208
    reference_title: "The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The redox-active and chelatable fraction of NTBI is referred to as labile plasma iron (LPI).
    explanation: >-
      Identifies the redox-active fraction, and — being by definition chelatable —
      the fraction the antidote acts on.
  downstream:
  - target: Iron-Catalysed Oxidative Organelle Injury
    causal_link_type: DIRECT
    description: >-
      Redox-active unbound iron catalyses free-radical chemistry inside the cells
      it enters.
    evidence:
    - reference: PMID:40650208
      reference_title: "The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Both NTBI and LPI contribute to oxidative stress by participating in free-radical-generating reactions.
      explanation: >-
        States the step this edge asserts: the unbound plasma iron of the source
        node drives free-radical generation and oxidative stress.
    - reference: PMID:40650208
      reference_title: "The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        NTBI and LPI bypassing normal cellular control mechanisms can rapidly exceed the cell's capacity to safely store excess iron, leading to toxicity.
      explanation: >-
        Gives the reason the unbound fraction becomes injurious once inside the
        cell, completing this edge.
  - target: Reversible Iron Inhibition of Coagulation Serine Proteases
    causal_link_type: DIRECT
    description: >-
      Non-transferrin-bound iron acts directly on the serine proteases of the
      coagulation cascade.
    evidence:
    - reference: PMID:6421970
      reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Instead, thrombin was markedly inhibited by iron in its clotting effect on fibrinogen and, specifically, in its fibrinopeptide A-generating capacity, the inhibitory effect being reversible upon iron removal by EDTA chelation and gel filtration.
      explanation: >-
        Demonstrates direct, chelation-reversible inhibition of thrombin by iron,
        establishing this as a direct edge.

- name: Iron-Catalysed Oxidative Organelle Injury
  biological_scale: CELLULAR
  description: >-
    Redox-active iron entering cells catalyses Fenton-type generation of reactive
    oxygen species, peroxidising membrane lipids and damaging intracellular
    organelles. The affected cells are those exposed to the highest iron flux —
    the mucosa in contact with the ingested salt and, through the portal
    circulation, the hepatocyte. Two organelles are proposed as the proximate
    targets: mitochondria, which may make cells with high mitochondrial activity
    preferentially vulnerable, and lysosomes, whose iron-catalysed oxidative
    destabilisation releases digestive enzymes into the cytoplasm. Both routes
    are described in the cellular iron-toxicity literature rather than
    demonstrated in acute poisoning — see this node's notes.
  biological_processes:
  - preferred_term: iron-catalysed reactive oxygen species generation
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: INCREASED
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They also cause metabolic acidosis by interfering with intermediary metabolism and producing shock and reduced tissue perfusion.
    explanation: >-
      Attributes the metabolic derangement of iron poisoning to interference with
      intermediary metabolism, the clinical expression of this node.
  - reference: PMID:37629109
    reference_title: "Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Based on its role as the major biological catalyst of free radical reactions and the Fenton reaction, iron has also been implicated in all diseases associated with free radical pathology and tissue damage.
    explanation: >-
      Identifies iron as the catalyst of Fenton free-radical chemistry, which is
      the molecular event this node asserts.
  - reference: PMID:40650208
    reference_title: "The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This unregulated uptake can lead to iron accumulation in vulnerable tissues such as the liver and the heart.
    explanation: >-
      Names the liver as a tissue in which unregulated iron uptake accumulates,
      supporting the organ selectivity this node describes.
  - reference: PMID:11978485
    reference_title: "Molecular bases of cellular iron toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These latter likely involve toxic effects of iron on intracellular organelles, in particular, mitochondria and lysosomes.
    explanation: >-
      Names mitochondria and lysosomes as the intracellular targets of iron
      toxicity. PARTIAL because this review is framed on chronic iron overload,
      not acute ingestion; see this node's notes on the extrapolation.
  - reference: PMID:11978485
    reference_title: "Molecular bases of cellular iron toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This suggests the general concept that iron may be preferentially toxic to cells with high mitochondrial activity.
    explanation: >-
      Offers a selectivity principle — mitochondrial activity predicts
      vulnerability — that would predict hepatocyte susceptibility here. Stated
      by the authors as a general concept, and derived from chronic-overload
      tissue tropism, so it is curated as PARTIAL rather than as established for
      acute poisoning.
  - reference: PMID:11978485
    reference_title: "Molecular bases of cellular iron toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      An alternative-and not mutually exclusive-mechanism for cellular iron toxicity involves iron-catalyzed oxidative destabilization of lysosomes, leading to leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death.
    explanation: >-
      Supplies a second, lysosomal route from iron to cell death, explicitly
      offered as non-exclusive with the mitochondrial route. PARTIAL for the same
      chronic-overload provenance.
  notes: >-
    The organelle-level detail on this node comes from PMID:11978485, a review
    whose clinical frame is hereditary and secondary haemochromatosis, not acute
    ingestion. It is used here because the mitochondrial and lysosomal routes it
    describes are cell-level mechanisms that do not depend on how the iron
    arrived, and because acute iron poisoning has no comparable mechanistic
    literature of its own. That extrapolation is the reason all three items are
    PARTIAL. One arm of the same review is deliberately NOT curated: its
    proposal that iron-mediated damage to the mitochondrial genome accumulates
    mutational events is explicitly about long-term toxicity, and cannot apply
    to a poisoning that kills within about 48 hours. This is the trap the
    entry's top-level notes warn about — literature reached through the "iron
    overload" synonym is usually about the chronic disorders — and it is
    recorded here rather than resolved silently.
  downstream:
  - target: Metabolic Acidosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired aerobic ATP generation with a shift to anaerobic metabolism
    description: >-
      Interference with intermediary metabolism, compounded by reduced tissue
      perfusion, generates an acidosis.
    evidence:
    - reference: PMID:3784842
      reference_title: "Management of acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        They also cause metabolic acidosis by interfering with intermediary metabolism and producing shock and reduced tissue perfusion.
      explanation: >-
        States both routes to the acidosis — metabolic interference and
        perfusion failure.
  - target: Periportal Hepatocellular Necrosis
    causal_link_type: DIRECT
    description: >-
      The hepatocyte, receiving absorbed iron first through the portal vein,
      sustains the oxidative injury at the highest local concentration.
    evidence:
    - reference: PMID:11778670
      reference_title: "Hepatotoxicity in acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Unlike most other hepatotoxins, the periportal areas of the hepatic lobule are the primary sites of injury.
      explanation: >-
        The periportal localisation is the anatomical signature of injury by an
        agent arriving in portal blood, supporting this edge.

- name: Reversible Iron Inhibition of Coagulation Serine Proteases
  biological_scale: MOLECULAR
  description: >-
    Non-transferrin-bound iron reversibly inactivates the serine proteases of the
    coagulation cascade — thrombin, factor Xa and kallikrein — without damaging
    the zymogens or fibrinogen itself. This produces a coagulopathy that is
    mechanistically distinct from the coagulopathy of hepatic synthetic failure,
    an attribution the authors state as likely rather than established; the two
    may coexist in severe poisoning. Because the
    inhibition is relieved by removing the iron, it is in principle correctable
    by chelation rather than only by factor replacement.
  molecular_functions:
  - preferred_term: serine-type endopeptidase activity of the coagulation cascade
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:6421970
    reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Studies of the mechanism by which iron prevents a normal plasma coagulation revealed that the proenzymes of the coagulation cascade and fibrinogen were not damaged by iron.
    explanation: >-
      Excludes zymogen and fibrinogen damage, localising the defect to the active
      proteases.
  - reference: PMID:6421970
    reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Because the amidolytic activity of human thrombin as well as factor Xa, kallikrein, and bovine trypsin was also reversibly suppressed by ferrous sulfate as well as ferric citrate, we consider it likely that the coagulopathy occurring in iron poisoning is the consequence of a general, physiologically important phenomenon: the susceptibility of serine proteases to nontransferrin-bound Fe3+.
    explanation: >-
      Identifies the general susceptibility of coagulation serine proteases to
      non-transferrin-bound iron as the mechanism of the coagulopathy.
  - reference: PMID:6421970
    reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      At iron concentrations comparable to those of previous animal investigations, we reproduced the coagulopathy, in other words, the dose-related prolongation of the prothrombin, thrombin, and partial thromboplastin time, in human plasma in vitro.
    explanation: >-
      Shows the clotting-time prolongation is reproduced in human plasma by iron
      alone, without any hepatic contribution.

- name: Metabolic Acidosis
  biological_scale: ORGANISM
  description: >-
    A metabolic acidosis develops from impaired intermediary metabolism together
    with the reduced tissue perfusion of evolving shock. With coma and shock it
    is one of the three features conventionally accepted as marking severe
    poisoning.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning.
    explanation: >-
      Establishes metabolic acidosis as one of the accepted markers of severe
      iron poisoning.
  downstream:
  - target: Hypovolaemia and Circulatory Shock
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - acidaemia-associated depression of myocardial and vascular function
    description: >-
      Acidosis and circulatory failure reinforce each other in the decompensated
      phase.
    evidence:
    - reference: PMID:3784842
      reference_title: "Management of acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
      explanation: >-
        Describes shock and acidosis as the paired features of the decompensated
        phase.

- name: Periportal Hepatocellular Necrosis
  biological_scale: TISSUE
  description: >-
    Extensive hepatocellular necrosis develops early in severe poisoning and
    carries a high mortality. Its periportal distribution is unusual among
    hepatotoxins and matters prognostically: the periportal zone is the principal
    site of hepatic regeneration, so injury concentrated there removes the liver's
    own capacity to recover. Hepatotoxicity appears to be dose-related, the lowest
    associated acute serum iron concentration reported greatly exceeding the
    reference range.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Review of this literature and of experimental animal studies demonstrates that it occurs early in the clinical course and has a relatively high mortality.
    explanation: >-
      Establishes the early onset and high mortality of the hepatic injury.
  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As this is the principle sitefor hepatic regeneration, this accountsfor the relatively high mortality rate.
    explanation: >-
      Gives the mechanistic reason the periportal localisation is prognostically
      important. Quoted verbatim, including the source's spacing errors.
  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lowest acute serum iron concentration associated with hepatotoxicity was 1700 microg/dL (304 micromol/L). Since this greatly exceeds the reference range of 50-150 microg/dL (9-27 micromol/L), it supports a dose-related etiology.
    explanation: >-
      Supports a dose-related aetiology for the hepatotoxicity and gives the
      lowest reported associated serum iron concentration.

- name: Hypovolaemia and Circulatory Shock
  biological_scale: ORGANISM
  description: >-
    Circulatory failure in iron poisoning is multifactorial: gastrointestinal
    fluid and blood loss through the corroded mucosa, acidosis, and reduced
    tissue perfusion reinforce one another. Shock recurring or developing in the
    later phase, together with acidosis, marks the decompensation in which most
    deaths occur, and maintaining the intravascular volume is correspondingly
    central to management.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
    explanation: >-
      States directly that shock recurs or develops in the decompensated phase,
      which is what this node asserts.
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume.
    explanation: >-
      Indirect: a management statement about maintaining intravascular volume,
      from which the hypovolaemia is inferred rather than reported.
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron poisoning continues to be a major toxicologic problem, with major impact on the gastrointestinal and circulatory systems.
    explanation: >-
      Identifies the circulatory system, alongside the gastrointestinal tract, as
      a principal target of iron poisoning.
  downstream:
  - target: Acute Kidney Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - renal hypoperfusion during the shock phase
    description: >-
      Renal failure appears in the decompensated phase alongside shock and
      hepatocellular necrosis.
    evidence:
    - reference: PMID:3784842
      reference_title: "Management of acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
      explanation: >-
        Places renal failure in the same decompensated phase as shock, supporting
        a hypoperfusion route.

- name: Acute Kidney Injury
  biological_scale: ORGANISM
  description: >-
    Renal failure develops in the decompensated phase of severe poisoning,
    alongside recurrent shock, acidosis and hepatocellular necrosis.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
    explanation: >-
      Reports renal failure as a feature of the third phase of severe iron
      poisoning.

- name: Fibrotic Healing of Corrosive Injury and Gastric Outlet Obstruction
  biological_scale: TISSUE
  description: >-
    Weeks after the acute event, the iron-induced mucosal ulcers heal by fibrous
    scarring that narrows the lumen, most often at the gastric outlet or duodenum,
    and the patient returns with recurrent vomiting. This delayed structural
    complication is unusual among acute poisonings and is the reason iron
    ingestion requires follow-up well beyond the acute admission. In adults, and
    particularly after enteric-coated preparations, the stricture may instead form
    in the distal small bowel.
  locations:
  - preferred_term: pyloric antrum
    term:
      id: UBERON:0001165
      label: pyloric antrum
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers.
    explanation: >-
      Establishes the timing, mechanism and presentation of the late stenosis.
  - reference: PMID:2231830
    reference_title: "Gastrointestinal pathology in adult iron overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe an adult example of both, each occurring in the distal portion of the small intestine.
    explanation: >-
      Documents that the acute injury and the late stricture can both occur
      distally in adults, extending the lesion beyond the classical gastric and
      proximal small-bowel sites.

stages:
- name: Phase 1 - Acute gastrointestinal irritation (up to 6 hours)
  description: >-
    Features of acute gastrointestinal irritation dominate the first six hours,
    and most patients do not progress beyond this stage. Severe poisoning declares
    itself here through impaired consciousness, convulsions and metabolic acidosis.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features of acute gastrointestinal irritation dominate the period up to 6 hours after ingestion and most patients do not develop other features or progress beyond this stage.
    explanation: >-
      Defines the timing and dominant features of the first phase and notes that
      most patients stop here.
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis.
    explanation: >-
      Gives the features that mark severe poisoning within the first phase.
- name: Phase 2 - Remission (6 to 12 hours)
  description: >-
    A period of apparent improvement in which the gastrointestinal features remit
    while cellular toxicity continues. It is the deceptive interval of iron
    poisoning and the reason apparent recovery does not license discharge.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phase, 6 to 12 hours after ingestion, is one of remission of features.
    explanation: >-
      Defines the timing and nature of the remission phase.
- name: Phase 3 - Shock, acidosis and organ failure (12 to 48 hours)
  description: >-
    Reached by only a small minority of patients. Shock and metabolic acidosis
    recur or develop, and renal failure and extensive hepatocellular necrosis may
    appear.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phase 3 comprises the period 12 to 48 hours from ingestion and is reached only by a small minority of patients.
    explanation: >-
      Defines the timing of the third phase and that few patients reach it.
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
    explanation: >-
      Gives the organ failures that characterise the third phase.
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presence of shock or acute liver failure with coagulopathy and/or severe acidosis predicted all the four deaths.
    explanation: >-
      The feature combination defining this phase is what preceded every death in
      a 21-patient paediatric cohort, which is why this is the phase in which
      most deaths occur.
  notes: >-
    The mortality association above comes from a single-centre retrospective
    series with four deaths. It describes which features accompanied the fatal
    cases; it is not a validated prognostic rule.
- name: Phase 4 - Gastric or duodenal stenosis (2 to 6 weeks)
  description: >-
    A late phase seen mainly in young children, in which vomiting recurs because
    the healed iron-induced ulcers have narrowed the gastric outlet or duodenum.
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers.
    explanation: >-
      Defines the timing, population and mechanism of the fourth phase.
  notes: >-
    Emergency-medicine sources commonly teach a five-stage scheme that splits the
    hepatotoxicity of days 2-5 into a stage of its own between shock and late
    stenosis. The four-phase scheme curated here is the one stated in the cited
    source; the two describe the same course at different granularity, and the
    hepatic injury is carried in this entry by the Periportal Hepatocellular
    Necrosis pathophysiology node.

phenotypes:
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Vomiting is the earliest and most consistent feature, arising from direct
    corrosive injury to the gastric mucosa. Its recurrence weeks later signals the
    late stenosis rather than fresh poisoning.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  frequency: FREQUENT
  evidence:
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were asymptomatic, others had vomiting (n =15, 83%), diarrhoea (n =13, 72%), malena (n = 8, 44%), and hemetemesis (n=6, 33%) generally within 6 hours of ingestion.
    explanation: >-
      Vomiting in 15 of 21 poisoned children (71%), which is the FREQUENT band.
      A single-centre retrospective paediatric cohort of 21 iron poisonings; the
      band is derived against all 21 patients, since three were asymptomatic and
      the paper's own percentages use the 18 symptomatic patients as denominator.

  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss.
    explanation: >-
      Lists vomiting as a direct consequence of the gastrointestinal toxicity of
      iron salts.
- category: Gastrointestinal
  name: Diarrhoea
  description: Diarrhoea accompanies the early corrosive gastrointestinal phase.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  frequency: FREQUENT
  evidence:
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were asymptomatic, others had vomiting (n =15, 83%), diarrhoea (n =13, 72%), malena (n = 8, 44%), and hemetemesis (n=6, 33%) generally within 6 hours of ingestion.
    explanation: >-
      Diarrhoea in 13 of 21 poisoned children (62%), which is the FREQUENT band.
      A single-centre retrospective paediatric cohort of 21 iron poisonings; the
      band is derived against all 21 patients, since three were asymptomatic and
      the paper's own percentages use the 18 symptomatic patients as denominator.

  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss.
    explanation: >-
      Lists diarrhoea among the direct gastrointestinal effects of iron salts.
- category: Gastrointestinal
  name: Abdominal pain
  description: >-
    Abdominal pain is part of the early corrosive syndrome. Significant protracted
    abdominal pain is specifically a warning of severe gastrointestinal
    complications.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss.
    explanation: >-
      Lists abdominal pain among the direct gastrointestinal effects of iron salts.
  - reference: PMID:2231830
    reference_title: "Gastrointestinal pathology in adult iron overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant protracted abdominal pain should alert the clinician of its possibility.
    explanation: >-
      Gives protracted abdominal pain diagnostic weight as a marker of severe
      gastrointestinal complications.
  diagnostic: true
- category: Gastrointestinal
  name: Gastrointestinal haemorrhage
  description: >-
    Blood loss from the corroded mucosa can be significant and, at the severe end,
    sufficient to cause hypotension.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  frequency: FREQUENT
  evidence:
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were asymptomatic, others had vomiting (n =15, 83%), diarrhoea (n =13, 72%), malena (n = 8, 44%), and hemetemesis (n=6, 33%) generally within 6 hours of ingestion.
    explanation: >-
      Overt gastrointestinal bleeding was common: melaena in 8 of 21 poisoned
      children (38%) and haematemesis in 6 of 21 (29%). The band is derived from
      melaena alone because the paper does not report how far the two overlap;
      that does not matter here, since the true union is bounded between 38%
      (complete overlap) and 67% (disjoint) and both ends fall inside FREQUENT.
      A single-centre retrospective paediatric cohort of 21 iron poisonings; the
      band is derived against all 21 patients, since three were asymptomatic and
      the paper's own percentages use the 18 symptomatic patients as denominator.

  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron salts are directly toxic to the gastrointestinal tract causing vomiting, diarrhoea, abdominal pain and occasionally significant blood loss.
    explanation: >-
      Reports significant blood loss as a direct gastrointestinal effect of iron
      salts.
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage.
    explanation: >-
      Gastrointestinal haemorrhage is severe enough in iron poisoning to warrant
      blood component replacement.
- category: Metabolic
  name: Metabolic acidosis
  description: >-
    A metabolic acidosis arising from interference with intermediary metabolism
    and from reduced tissue perfusion. It is one of the three accepted indicators
    of severe poisoning.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning.
    explanation: >-
      Establishes metabolic acidosis as an accepted marker of severe iron
      poisoning.
  diagnostic: true
- category: Neurological
  name: Impaired consciousness and coma
  description: >-
    Impairment of consciousness characterises severe poisoning; coma is one of the
    three accepted markers of severity.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis.
    explanation: >-
      Reports impaired consciousness as a feature of severe iron poisoning.
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning.
    explanation: >-
      Names coma specifically, which is what the HP term on this phenotype
      asserts; the preceding snippet covers the milder impairment of
      consciousness on the same continuum.
- category: Neurological
  name: Convulsions
  description: Convulsions occur in severe poisoning.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe poisoning is characterised by impairment of consciousness, convulsions and metabolic acidosis.
    explanation: >-
      Reports convulsions as a feature of severe iron poisoning.
- category: Cardiovascular
  name: Hypotension
  description: >-
    Hypotension may follow gastrointestinal blood loss early, and recurrent or
    developing shock characterises the decompensated phase.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely, blood loss may be sufficient to cause hypotension.
    explanation: >-
      Reports hypotension as a consequence of gastrointestinal blood loss in iron
      poisoning.
- category: Cardiovascular
  name: Shock
  description: >-
    Shock is one of the three accepted markers of severe poisoning and, with
    acidosis, defines the decompensated phase in which most deaths occur.
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The commonly encountered clinical features are also unreliable although it is generally accepted that coma, shock and metabolic acidosis indicate severe poisoning.
    explanation: >-
      Establishes shock as an accepted marker of severe iron poisoning.
  diagnostic: true
- category: Hematologic
  name: Coagulopathy
  description: >-
    A dose-related prolongation of the prothrombin, thrombin and partial
    thromboplastin times, caused by reversible iron inhibition of the coagulation
    serine proteases and, in later severe poisoning, compounded by hepatic
    synthetic failure.
  phenotype_term:
    preferred_term: Abnormality of coagulation
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  evidence:
  - reference: PMID:6421970
    reference_title: "Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Coagulopathy is a hallmark of severe ferrous sulfate poisoning in humans and laboratory animals.
    explanation: >-
      Establishes coagulopathy as a hallmark feature of severe iron poisoning.
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage.
    explanation: >-
      Disorders of coagulation are a management target in iron poisoning,
      supporting them as a clinical feature.
- category: Hepatic
  name: Hepatocellular necrosis
  description: >-
    Extensive hepatocellular necrosis, characteristically periportal, appearing
    early in the course of severe poisoning.
  phenotype_term:
    preferred_term: Hepatic necrosis
    term:
      id: HP:0002605
      label: Hepatic necrosis
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
    explanation: >-
      Reports extensive hepatocellular necrosis in the decompensated phase.
  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike most other hepatotoxins, the periportal areas of the hepatic lobule are the primary sites of injury.
    explanation: >-
      Specifies the periportal distribution of the hepatic necrosis.
- category: Hepatic
  name: Acute hepatic failure
  description: >-
    Hepatotoxicity in acute iron poisoning occurs early and carries a relatively
    high mortality, prompting earlier consideration of liver transplantation than
    in many other poisonings.
  phenotype_term:
    preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine progressed to shock and/or impaired consciousness; two had acute liver failure.
    explanation: >-
      Acute liver failure in 2 of 21 poisoned children (10%), the OCCASIONAL
      band. Note the shock figure in the same sentence is deliberately NOT used
      as a frequency for the Shock phenotype, because it counts shock and
      impaired consciousness together and cannot be split.

  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation.
    explanation: >-
      Frames the hepatotoxicity as severe enough to warrant transplant
      consideration, i.e. as hepatic failure.
- category: Renal
  name: Acute kidney injury
  description: Renal failure appears in the decompensated phase of severe poisoning.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrence or development of shock, and metabolic acidosis are usual and renal failure and features of extensive hepatocellular necrosis may develop.
    explanation: >-
      Reports renal failure as a feature of the third phase.
- category: Gastrointestinal
  name: Gastric outlet obstruction from stricture
  description: >-
    Gastric or duodenal stenosis presenting weeks after ingestion with recurrent
    vomiting, produced by fibrous healing of the earlier corrosive ulceration. In
    adults the stricture may instead form distally in the small bowel.
  phenotype_term:
    preferred_term: Gastrointestinal obstruction
    term:
      id: HP:0004796
      label: Gastrointestinal obstruction
  evidence:
  - reference: PMID:2231830
    reference_title: "Gastrointestinal pathology in adult iron overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation.
    explanation: >-
      Reports delayed obstruction from stricture formation as a gastrointestinal
      consequence of iron overdose.
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The last (fourth) phase, 2 to 6 weeks after ingestion, is only likely to develop in young children and is characterised by recurrence of vomiting due to gastric or duodenal stenosis caused by healing of iron-induced mucosal ulcers.
    explanation: >-
      Gives the timing and presentation of the delayed gastric or duodenal
      stenosis.

diagnosis:
- name: Serum iron concentration
  description: >-
    How much weight the serum iron concentration should carry is contested, and
    this entry does not settle it. On one account it is one of three inputs to
    the chelation decision, alongside an estimate of the ingested body iron
    burden and the clinical features, and the ingested dose is unusable as a
    severity measure because it is rarely known accurately and absorption is
    unpredictable once vomiting and diarrhoea have removed some of it. A
    paediatric cohort reports the reverse on both counts: the dose and the
    clinical signs guided management and the serum iron did not. A third series
    reports the strongest quantitative result on this question in either
    direction, and reports it within a severity stratum rather than pooled: among
    patients whose symptoms stayed minor, an early concentration at or below 300
    microg/dL was followed by no later toxic concentration at all. All three
    positions are curated below, together with the conventional toxicity
    thresholds and the reason a concentration drawn too soon can under-read the
    exposure rather than measure it. The one use not in dispute is discriminating
    this disease
    from the chronic iron-overload states that share a MONDO synonym with it.
  evidence:
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine.
    explanation: >-
      Establishes the serum iron concentration as one of the three inputs to the
      chelation decision.
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peak serum iron levels may be helpful in differentiating acute toxicity from chronic iron overload states.
    explanation: >-
      Supports the use of peak serum iron to distinguish acute poisoning from
      chronic iron overload.
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amount of elemental iron ingested is unacceptable since it is seldom known with accuracy and absorption is unpredictable because of vomiting and diarrhoea.
    explanation: >-
      Refutes the ingested dose as a severity measure, which is why a measured
      serum concentration is relied on; it does not itself validate the serum
      measurement.
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dose of ingested iron and clinical signs were most useful guide to iron toxicity and management decisions; serum iron did not help.
    explanation: >-
      Directly contradicts the framing of the two items above. In this
      21-patient paediatric cohort the ingested dose and the clinical signs
      guided management and the serum iron did not, the reverse of the
      dose-is-unreliable / serum-is-relied-on ordering asserted by PMID:3784842
      and PMID:2870463. Curated as REFUTE rather than reconciled away.
  - reference: PMID:34121325
    reference_title: "Unintentional paediatric iron poisoning: A retrospective case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptomatic children had a significantly higher median peak serum iron concentration of 66 μmol/L (IQR 54-68 μmol/L) compared to 12 μmol/L (IQR 9-15 μmol/L) in asymptomatic children (P < 0.001).
    explanation: >-
      The other side of that disagreement, and the only quantitative evidence in
      this entry bearing on it. In 54 unintentional paediatric exposures the peak
      serum iron separated symptomatic from asymptomatic children with a large
      margin and P < 0.001, which is a discriminating measurement rather than an
      unhelpful one. Approximate conversions to the units used in this entry's
      reference range, derived rather than quoted: 66 micromol/L is about 369
      microg/dL and 12 micromol/L about 67 microg/dL, using the same factor
      implied by PMID:11778670 giving its reference interval as both 50-150
      microg/dL and 9-27 micromol/L.
  - reference: PMID:34121325
    reference_title: "Unintentional paediatric iron poisoning: A retrospective case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children symptomatic with gastrointestinal toxicity had a median suspected dose ingested of 60 mg/kg (IQR 38-150 mg/kg) that was similar to asymptomatic children
    explanation: >-
      Refutes the ingested dose as the alternative to serum iron: symptomatic and
      asymptomatic children had similar suspected doses, so in this cohort the
      quantity PMID:14722368 found most useful is the one that did not
      discriminate. PARTIAL rather than REFUTE, on the same reasoning the
      PMID:3784842 item above applies to the same kind of claim: knocking down
      the rival predictor does not contradict this entry's thesis that the serum
      iron is informative, and it does not validate the serum measurement
      either. A finding that corroborates by elimination is not one that
      opposes. The quote stops before the asymptomatic group's interquartile
      range because that span is square-bracketed in the source and the reference
      validator strips square-bracketed spans before matching; the source reports
      that comparison as P = 0.809, i.e. not significant.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Traditionally, a concentration of 350 μg/dL with symptoms, or 500 μg/dL without symptoms, is considered toxic and will likely need treatment to prevent decompensation.
    explanation: >-
      The first quotable statement in this entry of the conventional serum-iron
      toxicity thresholds. Note what the sentence is and is not: background,
      offered as the premise of the study rather than as a finding of it, and
      phrased as what is traditionally considered toxic. It is curated as
      evidence that the convention exists and takes this conditional form, not
      as evidence that either figure has been validated. Tagged OTHER for that
      reason, while this paper's own retrospective results below are tagged
      HUMAN_CLINICAL.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is generally recommended that an iron concentration is obtained at least 4 h after exposure to provide adequate absorption time and avoid falsely low iron concentrations.
    explanation: >-
      Adds the timing dimension the other sources cited here leave implicit, and
      gives it an absorption-kinetics reason: a sample drawn before absorption is
      complete can be falsely low, so an early concentration may under-read the
      exposure rather than measure it. That is what makes the 2-to-4-hour
      question this study asks a real one. Tagged OTHER because the sentence
      states a general recommendation rather than a result of this study.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No patients who developed at most minor symptoms (abdominal discomfort, nausea, vomiting, or diarrhea without evidence of systemic toxicity) and had a 2-4 h concentration ≤ 300 μg/dL symptoms had a subsequent concentration ≥ 350 μg/dL (negative predictive value [NPV] 100 %).
    explanation: >-
      The strongest quantitative support in this entry for the serum iron
      concentration being informative, and it is stratum-specific: within the
      minor-symptom group an early concentration at or below 300 microg/dL was
      followed by no subsequent toxic concentration. Read as a rule-out inside a
      defined stratum, not as a general predictor. Limits worth carrying: 75
      patients, single centre, retrospective, and the abstract does not report
      the age distribution, so this is not a third paediatric cohort alongside
      PMID:14722368 and PMID:34121325. The sentence carries a stray repeated
      word in the source and is quoted as printed.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this case series, a concentration of 300 μg/dL or less between 2 and 4 h was the ideal cutoff to predicting subsequent potentially toxic concentrations, with a sensitivity of 100 % and a specificity of 54 %.
    explanation: >-
      Gives the operating characteristics behind that rule-out, and the
      specificity is the half a curator should not drop: 54% means roughly half
      the patients the cutoff flags do not go on to a toxic concentration. A
      sensitive rule-out with poor specificity is useful for deciding whom to
      stop watching and close to useless for deciding whom to chelate, which is
      the distinction the contested-threshold discussion in this entry turns on.
  notes: >-
    The value of the serum iron concentration is genuinely contested in the cited
    literature and this entry does not resolve it; see the
    serum_iron_versus_ingested_dose CONTROVERSY discussion, which states the
    disagreement and what would settle it. Both positions are curated here with
    their evidence rather than one being chosen. A curator adding a numeric
    decision threshold should treat that disagreement as the context for the
    threshold, not curate the threshold as settled. The conventional thresholds
    are now curated on the biochemical entry on exactly that footing.
- name: Abdominal radiography for retained iron tablets
  description: >-
    Iron tablets are visible on abdominal radiography, so a film both supports
    the diagnosis and shows how much unabsorbed tablet burden remains. That is
    what gates whole bowel irrigation and tells the clinician when to stop it —
    the rectal effluent can run clear while radiography still shows iron in the
    gut, so the effluent alone is not a reliable endpoint.
  evidence:
  - reference: PMID:8629765
    reference_title: "Five days of whole-bowel irrigation in a case of pediatric iron ingestion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rectal effluent cleared within 2 days of the start of PEG-ELS therapy despite the persistence of iron in the gastrointestinal tract as shown on radiography.
    explanation: >-
      Shows radiography visualising retained gastrointestinal iron, and that it
      disagreed with — and outlasted — the effluent endpoint.
  - reference: PMID:8629765
    reference_title: "Five days of whole-bowel irrigation in a case of pediatric iron ingestion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case of a 33-month-old boy who ingested at least 160 mg/kg elemental iron and received 44.3 L of PEG-ELS (2,953 ml/kg) over 5 days because of the persistence of iron tablets in teh gastrointestinal tract.
    explanation: >-
      The radiographic tablet burden is what drove the duration of decontamination
      in this case. Quoted verbatim, including the source's "teh" typo.
  notes: >-
    A single case report, so it establishes that radiography shows retained iron
    and that effluent clearing is an unreliable endpoint, not the test's
    sensitivity or specificity. A negative film does not exclude a significant
    ingestion; that limitation was not sourced to a cached reference and is
    deliberately not asserted here.
- name: Gastric iron encrustation at autopsy
  description: >-
    Gross iron encrustation over the gastric rugae is reported as specific for
    acute ingestion when it is present, making it a post-mortem discriminator
    between acute poisoning and chronic iron overload.
  evidence:
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gross findings of gastric iron encrustation are specific for acute ingestion when present.
    explanation: >-
      States the specificity of gastric iron encrustation for acute ingestion.
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At autopsy, iron encrustations were present over the gastric rugae.
    explanation: >-
      The autopsy observation on which the specificity claim is grounded.
  notes: >-
    Reported from a single autopsy case with literature review, so the
    specificity claim rests on a narrow base. The same source cautions that the
    clinical course and laboratory testing of severe acute iron overdose is
    fairly non-specific.

biochemical:
- name: Serum iron concentration
  reference_ranges:
  - lower_bound: 50.0
    upper_bound: 150.0
    unit: microg/dL
    population: general reference interval cited for acute-poisoning comparison
    notes: >-
      Quoted as the reference range against which acute poisoning concentrations
      are judged in a review of iron-poisoning hepatotoxicity, not derived from a
      laboratory reference-interval study. Equivalent to 9-27 micromol/L in the
      same source.
    evidence:
    - reference: PMID:11778670
      reference_title: "Hepatotoxicity in acute iron poisoning."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Since this greatly exceeds the reference range of 50-150 microg/dL (9-27 micromol/L), it supports a dose-related etiology.
      explanation: >-
        States the reference interval used, in both unit systems.
    interpretation_bands:
    - name: Reference interval
      lower_bound: 50.0
      upper_bound: 150.0
      unit: microg/dL
      abnormal_flag: NORMAL
    - name: At or above the conventional toxic threshold when symptomatic
      lower_bound: 350.0
      upper_bound: 500.0
      unit: microg/dL
      abnormal_flag: HIGH
      interpretation: >-
        By long-standing convention a concentration of 350 microg/dL is
        considered toxic in a patient who has symptoms, and likely to need
        treatment to prevent decompensation. Below 500 microg/dL the convention
        is conditional on the presence of symptoms, which is why this band is
        separated from the one below it. Curated as the tradition its source
        describes it as, not as a validated decision threshold; the
        serum_iron_versus_ingested_dose discussion is the context to read it in.
    - name: At or above the conventional toxic threshold regardless of symptoms
      lower_bound: 500.0
      upper_bound: 1700.0
      unit: microg/dL
      abnormal_flag: HIGH
      interpretation: >-
        At or above 500 microg/dL the conventional threshold no longer depends on
        whether the patient has symptoms. The upper bound of this band is not a
        second threshold: it is simply where the band reporting the lowest
        concentration ever observed with hepatotoxicity begins.
    - name: At or above the lowest concentration reported with hepatotoxicity
      lower_bound: 1700.0
      unit: microg/dL
      abnormal_flag: CRITICAL_HIGH
      severity: SEVERE
      interpretation: >-
        1700 microg/dL is the lowest acute serum iron concentration reported in
        association with hepatotoxicity, not a validated decision threshold.
        Hepatotoxicity has not been shown to be excluded below it.
      phenotype_term:
        preferred_term: Hepatic necrosis
        term:
          id: HP:0002605
          label: Hepatic necrosis
  evidence:
  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The lowest acute serum iron concentration associated with hepatotoxicity was 1700 microg/dL (304 micromol/L).
    explanation: >-
      Gives the lowest serum iron concentration reported in association with
      hepatotoxicity, the basis for the upper interpretation band.
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine.
    explanation: >-
      Establishes the serum iron concentration as an input to the chelation
      decision.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Traditionally, a concentration of 350 μg/dL with symptoms, or 500 μg/dL without symptoms, is considered toxic and will likely need treatment to prevent decompensation.
    explanation: >-
      Source for the two conventional-threshold interpretation bands above.
      Quoted from the study's background, where it states established practice
      rather than a result, so it attests that the convention exists and takes
      this conditional form and not that either figure has been validated.
  notes: >-
    The measured serum iron concentration is the central laboratory quantity in
    iron poisoning: it feeds the chelation decision, separates acute poisoning
    from chronic overload, and in severe poisoning runs an order of magnitude
    above the normal interval. That said, its clinical usefulness is contested:
    PMID:14722368 reports that in a 21-patient paediatric cohort the ingested
    dose and clinical signs guided management while the serum iron did not, and
    that vin-rose urine was absent in 31% of chelated patients even with a high
    serum iron. The reference interval and the hepatotoxicity-associated
    concentration below are curated as measurements, not as decision rules. The
    conventional toxicity thresholds are curated in the interpretation bands
    above, as a tradition rather than as validated cutoffs. They were previously
    left out of this entry for want of a quotable source, the consensus guideline
    that states them having cached with an empty body; PMID:39509998 states them
    in its own background and so supplies the quotation. What that fixes is
    attribution, not validation, and the serum_iron_versus_ingested_dose
    discussion is the context a curator should read them in.

    The 150 to 350 microg/dL range is deliberately unbanded. It sits above the
    reference interval and below the lower conventional toxicity threshold, and
    no source this entry can quote says what a concentration there means. That
    gap is the honest state of the evidence rather than an oversight to patch; a
    band invented to fill it would assert an interpretation nobody has published.

histopathology:
- name: Gastric mucosal necrosis with superficial stainable iron
  description: >-
    At autopsy after fatal acute ingestion, stainable iron lies superficially
    over areas of mucosal necrosis, with fibrin thrombi in the submucosa beneath
    — the histological form of the corrosive injury, with the iron sitting where
    it was in contact rather than distributed through the tissue.
  evidence:
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Superficial deposits of stainable iron were present overlying areas of mucosal necrosis with underlying submucosal fibrin thrombi.
    explanation: >-
      Describes the histology of the corrosive gastric lesion and the
      superficial, contact distribution of the iron.
- name: Absent significant hepatic stainable iron despite fatal poisoning
  description: >-
    In the same fatal case, no significant stainable iron was found in the liver,
    even though the clinical course showed hepatic compromise with markedly
    elevated serum iron. Stainable hepatic iron is therefore not a reliable
    post-mortem marker of acute iron poisoning, and its absence does not exclude
    the diagnosis.
  evidence:
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No significant stainable iron was present in the liver.
    explanation: >-
      Reports the negative hepatic iron stain in a fatal acute iron poisoning.
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His clinical course and laboratory findings demonstrated hepatic and renal compromise with markedly elevated serum iron levels.
    explanation: >-
      Establishes that hepatic compromise and high serum iron were present in the
      same patient whose liver showed no significant stainable iron.
  notes: >-
    This sits in tension with the entry's Periportal Hepatocellular Necrosis
    node, which argues the hepatocyte takes the highest iron flux by way of the
    portal circulation. The tension is real but not necessarily a contradiction:
    the patient died 65.5 hours after ingestion and had been treated, so
    redistribution, chelation and clearance all intervene between the toxic
    exposure and the section. It is recorded here rather than omitted because a
    single autopsy is the whole of the cited histological evidence, and the
    negative is part of it.

environmental:
- name: Unintentional ingestion of iron supplements by young children
  description: >-
    The classic exposure: a child under five swallows adult-strength iron tablets
    or prenatal vitamins from a household supply. Acute iron poisoning is most
    common in this age group, and the exposure is determined by product
    availability and packaging rather than by any host factor.
  exposure_term:
    preferred_term: exposure to iron via ingestion
    term:
      id: ECTO:0900035
      label: exposure to iron via ingestion
  effect: Establishes the ingested iron burden that initiates poisoning.
  notes: >-
    The packaging story is more equivocal than it is usually told. Deaths in
    children under six fell from 29 to 1 across the 1997 unit-dose packaging
    regulation (PMID:15939855), but that mandate was vacated in 2003 after
    Nutritional Health Alliance v. FDA, and a 2000-2017 National Poison Data
    System cohort found severe exposures continued to decline anyway
    (DOI:10.1177/0009922819901010). A third strand cuts the same way from the
    other end of the timeline: PMID:10798501, published before the mandate could
    have had an effect, reports paediatric iron fatalities already falling from a
    peak of 10 in 1991 to 2 by 1995. All three results are curated here; none is
    a controlled comparison, and the entry does not assert that packaging alone
    caused the fall.

    The same source undercuts a simpler reading of the exposure itself.
    Child-resistant containers were already in use, and children were getting
    the iron out of them anyway, or out of ones an adult had left open. That is
    why the regulatory move was to unit-dose blistering rather than to more child
    resistance, and it is part of why this exposure is described above as set by
    product form rather than by any host factor.
  evidence:
  - reference: PMID:21975503
    reference_title: "Iron poisoning: a literature-based review of epidemiology, diagnosis, and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Multiple factors-including legal and manufacturing practices-have changed the landscape of iron poisoning over the decades.
    explanation: >-
      Supports the framing of this exposure as one whose incidence is set by
      legal and manufacturing practice rather than by host biology, which is
      what the packaging notes below record.
  - reference: PMID:10798501
    reference_title: "Pediatric iron poisonings in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The children often obtained the iron from a child-resistant container opened by themselves or another child or left open or improperly closed by an adult.
    explanation: >-
      The exposure route in detail, and the finding that makes the packaging
      story one about product form rather than about container closures:
      child-resistant containers were already in use and were being defeated,
      either by a child or by an adult who left one open. National Consumer
      Product Safety Commission and poison-centre data, 1980 to 1996.
  - reference: PMID:10798501
    reference_title: "Pediatric iron poisonings in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pediatric iron-related fatalities increased in 1986, peaked at 10 in 1991, and declined to 2 by 1995.
    explanation: >-
      Independent support for the equivocation recorded in the notes, arriving
      from the pre-mandate side of it: paediatric iron fatalities were already
      falling before the 1997 unit-dose regulation, having peaked in 1991. This
      is a different data source and a different case definition from the
      29-to-1 figure of PMID:15939855, so the two are curated separately rather
      than merged into one series.
  - reference: PMID:10798501
    reference_title: "Pediatric iron poisonings in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unit-dose packaging of potent iron supplements is expected to reduce the frequency of severe pediatric iron overdose incidents.
    explanation: >-
      The prediction, published in 2000, that unit-dose packaging would reduce
      severe paediatric poisoning. Curated as PARTIAL because it is an
      expectation rather than a result. It is worth having on the record
      precisely because this entry also curates what happened next: the mandate
      was vacated in 2003 and severe exposures fell either way.
  - reference: PMID:3784842
    reference_title: "Management of acute iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute iron poisoning is most common in children below the age of 5 years.
    explanation: >-
      Establishes young children as the population in which this exposure
      predominantly occurs.
  - reference: PMID:15939855
    reference_title: "Unit-dose packaging of iron supplements and reduction of iron poisoning in young children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron poisoning is a major cause of unintentional poisoning death in young children.
    explanation: >-
      Establishes the public-health weight of this unintentional exposure route.
  influences_mechanisms:
  - target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Swallowing the tablets is the route by which the toxic iron burden is
      established. That an intervention acting only on access to the tablets,
      with no change to host biology, was followed by fewer ingestions and fewer
      deaths is consistent with the exposure being what initiates the disease —
      though the study is a before-and-after comparison, so secular trend is not
      excluded (see this exposure's notes).
    evidence:
    - reference: PMID:15939855
      reference_title: "Unit-dose packaging of iron supplements and reduction of iron poisoning in young children."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The average number of iron ingestion calls per 1000 of all calls to poison control centers regarding children younger than 6 years decreased from 2.99 per 1000 to 1.91 per 1000 (odds ratio, 1.29 [95% confidence interval, 1.27-1.32]; P<.001). The number of deaths decreased from 29 to 1 (odds ratio, 13.56 [95% confidence interval, 1.85-99.52]; P = .03).
      explanation: >-
        Both ingestions and deaths fell after an intervention that changed only
        access to the tablets. This is an uncontrolled before-and-after
        comparison, not a dose-response design, so it is consistent with — rather
        than proof of — ingestion being what triggers the disease.
    - reference: DOI:10.1177/0009922819901010
      reference_title: "Iron Packaging Regulations in the United States and Pediatric Morbidity: A Retrospective Cohort Study"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Despite removal of iron packaging regulations in the United States, there continues to be a decrease in the incidence of severe iron exposures in children.
      explanation: >-
        Complicates the attribution rather than the edge: severity kept falling
        after the packaging mandate was withdrawn in 2003, so the earlier
        before-and-after result is confounded by a secular trend. The exposure
        route itself is unaffected.

- name: Deliberate self-poisoning with iron tablets
  description: >-
    Intentional ingestion of iron, typically by adolescents and adults, accounts
    for the larger ingested doses and is the route behind most severe and fatal
    adult cases.
  exposure_term:
    preferred_term: exposure to iron via ingestion
    term:
      id: ECTO:0900035
      label: exposure to iron via ingestion
  effect: Establishes a high ingested iron burden associated with severe poisoning.
  evidence:
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute iron toxicity in adults is rare, usually occurring due to intentional ingestion in suicide attempts.
    explanation: >-
      Establishes intentional ingestion as the usual route of acute iron toxicity
      in adults.
  - reference: PMID:33729557
    reference_title: "Suicidal iron overdose: A case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ingestion of large amounts of iron salts can lead to hemorrhagic shock, multi-system organ failure, coagulopathy, and death.
    explanation: >-
      Gives the severe outcomes associated with the large ingested doses typical
      of this exposure route.
  - reference: PMID:30598567
    reference_title: "Fatal Iron Toxicity in an Adult: Clinical Profile and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute iron toxicity is usually seen in children with accidental ingestion of iron-containing syrups.
    explanation: >-
      The clinical-epidemiologic half of this entry's scope problem: the disease
      as usually encountered is paediatric and accidental, which is the
      population nearly every cohort cited here describes. HUMAN_CLINICAL
      because this is a generalization about patients rather than about the
      literature; the companion item below makes the separate claim about the
      literature and is tagged OTHER accordingly.

      PARTIAL rather than SUPPORT, because the relationship is indirect. This
      sentence describes paediatric accidental poisoning, the opposite of the
      adult deliberate exposure it sits under, and it bears on that exposure
      only by establishing the contrast that makes this route the uncommon one.
      In the source it is the first half of a contrastive pair, so the
      "However" of the companion item below is what carries the claim that
      bears on this entry directly.
  - reference: PMID:30598567
    reference_title: "Fatal Iron Toxicity in an Adult: Clinical Profile and Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, the literature on acute iron toxicity with suicidal intent in adults is scant.
    explanation: >-
      The bibliographic half, and the reason the adult intentional exposure
      curated here rests on case reports rather than on cohorts. OTHER because
      the sentence describes the state of the literature and presents no patient
      data, which is the convention this entry applies to the PMID:21975503 item
      in the preceding exposure entry. It is kept as its own item, separate from
      the clinical generalization it follows in the source, so that each of the
      two claims carries the classification that fits it.
  - reference: PMID:30598567
    reference_title: "Fatal Iron Toxicity in an Adult: Clinical Profile and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delay in treatment was there due to misdiagnosis of the intoxicating agent. She developed fulminant hepatic failure with rapid clinical deterioration.
    explanation: >-
      A fatal adult case, and the only cited source in which the diagnosis itself
      was the delay: the ingested agent was misidentified before iron was
      recognised. That is the practical cost of the adult route being
      under-described, and it is a different failure from any the diagnosis
      section models, which assume iron is already suspected. Single case
      report.
  influences_mechanisms:
  - target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Deliberate ingestion establishes the iron burden, generally at higher doses
      than unintentional paediatric exposure.
    evidence:
    - reference: PMID:33729557
      reference_title: "Suicidal iron overdose: A case report and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Acute iron toxicity in adults is rare, usually occurring due to intentional ingestion in suicide attempts.
      explanation: >-
        Names intentional ingestion as the route by which the adult iron burden is
        established, which is what this edge asserts.

treatments:
- name: Deferoxamine Chelation
  description: >-
    Intravenous deferoxamine is the specific antidote, indicated in severe
    intoxication on the basis of estimated body iron burden, clinical features and
    serum iron concentration. It binds circulating iron so that it can be
    excreted, and is given alongside supportive care with particular attention to
    intravascular volume.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deferoxamine
      term:
        id: CHEBI:4356
        label: desferrioxamine B
  target_mechanisms:
  - target: Non-Transferrin-Bound Iron in Plasma
    treatment_effect: INHIBITS
    description: >-
      Chelation removes the unbound circulating iron that drives the systemic arm
      of the poisoning.
    evidence:
    - reference: PMID:2870463
      reference_title: "Iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine.
      explanation: >-
        Establishes that chelation is directed at the body iron burden, i.e. at
        the circulating iron this node represents.
  evidence:
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume.
    explanation: >-
      States the indication and route for deferoxamine in severe iron poisoning.
  - reference: PMID:12503657
    reference_title: "Acute iron ingestion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole bowel irrigation in addition to gastric lavage with an iron dose of over 50 mg/kg as well as deferoxamine treatment for patients in whom clinical and laboratory indications are present.
    explanation: >-
      Reports deferoxamine given on clinical and laboratory indications in a
      paediatric case series.
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Desferrioxamine infusion and supportive care of shock was the mainstay.
    explanation: >-
      Confirms deferoxamine infusion, with shock support, as the mainstay of
      management in a real paediatric cohort.
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On desferrioxamine infusion Vin-rose colour urine was not seen in 31% even in presence of high serum iron.
    explanation: >-
      A caution rather than support for the treatment: the classically taught
      vin-rose urine was absent in nearly a third of chelated patients despite a
      high serum iron, so its absence must not be read as evidence that
      chelation is unnecessary or ineffective.

- name: Whole Bowel Irrigation
  description: >-
    Whole bowel irrigation with polyethylene glycol solution is used to clear
    unabsorbed iron tablets from the gut. It is specifically endorsed for
    substantial iron ingestions because the morbidity is high and other
    decontamination options are lacking — activated charcoal does not absorb iron
    and gastric lavage is a questionable intervention.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: gastrointestinal decontamination by whole bowel irrigation
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
    treatment_effect: INHIBITS
    description: >-
      Removing unabsorbed tablets from the lumen limits the iron burden still
      available for absorption and for continued mucosal corrosion.
    evidence:
    - reference: PMID:15533024
      reference_title: "Position paper: whole bowel irrigation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WBI should be considered for patients who have ingested substantial amounts of iron as the morbidity is high and there is a lack of other options for gastrointestinal decontamination.
      explanation: >-
        Endorses whole bowel irrigation specifically for iron ingestion, acting on
        the unabsorbed luminal burden.
  evidence:
  - reference: PMID:15533024
    reference_title: "Position paper: whole bowel irrigation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although some volunteer studies have shown substantial decreases in the bioavailability of ingested drugs, no controlled clinical trials have been performed and there is no conclusive evidence that WBI improves the outcome of the poisoned patient.
    explanation: >-
      Records the honest limit of the evidence base: whole bowel irrigation is
      recommended for iron on grounds of high morbidity and absent alternatives,
      not on demonstrated outcome benefit.
  - reference: PMID:1754488
    reference_title: "Gastrotomy and whole bowel irrigation in iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ipecac and gastric lavage are questionable interventions for the overdose patient, and activated charcoal does not absorb iron.
    explanation: >-
      Sources the claim that the usual decontamination alternatives do not work
      for iron, which is why whole bowel irrigation is reached for.
  - reference: PMID:1754488
    reference_title: "Gastrotomy and whole bowel irrigation in iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because less than half of the iron was removed during surgery, and because the chelation requirement was modest, it is likely that whole bowel irrigation removed a significant amount of iron.
    explanation: >-
      A single-case inference that irrigation removed substantial iron; suggestive
      of the mechanism, not a demonstration of outcome benefit.
  notes: >-
    Contraindicated in bowel obstruction, perforation, ileus, haemodynamic
    instability, or a compromised unprotected airway — relevant in iron poisoning,
    where shock and late obstruction both occur.

- name: Fluid Resuscitation and Supportive Care
  description: >-
    Maintenance of intravascular volume, correction of acidosis and of coagulation
    disorders, and replacement of blood components when there is gastrointestinal
    haemorrhage. Prompt recognition and initiation of management is the single
    most critical element in reducing morbidity and mortality.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: fluid therapy
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  target_mechanisms:
  - target: Hypovolaemia and Circulatory Shock
    treatment_effect: INHIBITS
    description: >-
      Volume replacement counters the hypovolaemia produced by gastrointestinal
      fluid and blood loss.
    evidence:
    - reference: PMID:2870463
      reference_title: "Iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume.
      explanation: >-
        Identifies maintenance of intravascular volume as a specific supportive
        care target in severe iron poisoning.
  evidence:
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage.
    explanation: >-
      Lists the supportive measures beyond chelation in iron poisoning.
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prompt recognition and initiation of management of children with acute iron poisoning is the single most critical element in decreasing the morbidity and mortality associated with these products.
    explanation: >-
      Establishes timeliness of management as the dominant determinant of outcome.
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shock responded to normal saline (33 +/- 15 mL/kg) and dopamine (10 +/- 4 microg/kg/min) within 4-24 hours in 7 of 9 patients.
    explanation: >-
      Shock in iron poisoning responded to volume replacement plus an inotrope in
      7 of 9 affected children, direct support for fluid resuscitation acting on
      the hypovolaemia node.

- name: Surgical Removal of Retained Iron and Correction of Stricture
  description: >-
    Surgical removal of iron may be indicated when large numbers of tablets remain
    in the gastrointestinal tract and cannot be cleared, and surgical correction is
    required for the late gastric or duodenal stenosis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Fibrotic Healing of Corrosive Injury and Gastric Outlet Obstruction
    treatment_effect: INHIBITS
    description: >-
      Operative correction relieves the mechanical obstruction produced by the
      healed corrosive injury.
    evidence:
    - reference: PMID:2231830
      reference_title: "Gastrointestinal pathology in adult iron overdose."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        They may occur acutely, ranging in severity from mucosal injury to complete infarction, or several weeks later, as obstruction due to stricture formation.
      explanation: >-
        Establishes the obstructing stricture that surgery addresses; the cited
        cases were managed surgically, but this abstract does not itself report
        operative outcomes.
  evidence:
  - reference: PMID:2870463
    reference_title: "Iron poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Under rare circumstances in which large numbers of iron tablets are present in the gastrointestinal tract, surgical removal may be indicated.
    explanation: >-
      States the indication for surgical removal of retained iron tablets.

- name: Liver Transplantation
  description: >-
    Considered earlier in iron poisoning than in many other hepatotoxic
    exposures, because the hepatic injury is periportal — striking the zone on
    which regeneration depends — and carries a relatively high mortality.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Periportal Hepatocellular Necrosis
    treatment_effect: INHIBITS
    description: >-
      Transplantation replaces the liver whose regenerative zone the poisoning has
      destroyed.
    evidence:
    - reference: PMID:11778670
      reference_title: "Hepatotoxicity in acute iron poisoning."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation.
      explanation: >-
        Links transplantation directly to the hepatotoxicity of iron poisoning.
  evidence:
  - reference: PMID:38060750
    reference_title: "Liver Transplantation for Acute Hepatic Failure Following Intentional Iron Overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a case of a severe iron tablet overdose with suicidal intent that progressed to fulminant hepatic failure despite medical treatment, ultimately treated with liver transplantation.
    explanation: >-
      Documents transplantation actually performed for iron-induced fulminant
      hepatic failure after medical treatment failed.
  - reference: PMID:38060750
    reference_title: "Liver Transplantation for Acute Hepatic Failure Following Intentional Iron Overdose."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe acute hepatotoxicity treated with liver transplantation is rare in adults, with very limited published literature.
    explanation: >-
      Records how thin the evidence base is: transplantation for this indication
      is reported, but rarely, so this treatment rests on case-level evidence.
  - reference: PMID:11778670
    reference_title: "Hepatotoxicity in acute iron poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation.
    explanation: >-
      States the indication for earlier transplant consideration in iron-induced
      hepatotoxicity.

- name: Oral Deferiprone (investigational for acute poisoning)
  description: >-
    An orally active iron chelator established for chronic transfusional iron
    overload and proposed for acute poisoning where parenteral deferoxamine is
    unaffordable or unavailable. The supporting efficacy data in the acute setting
    are from a rat model, not from humans; this is not established therapy for
    acute iron poisoning and should not be curated as such.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deferiprone
      term:
        id: CHEBI:68554
        label: deferiprone
  target_mechanisms:
  - target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
    treatment_effect: INHIBITS
    description: >-
      Oral chelation of the ingested iron burden, with a dose-dependent reduction
      of gastrointestinal iron accumulation demonstrated histologically in rats.
      The edge is drawn to the ingested burden rather than to plasma
      non-transferrin-bound iron because the supporting measurement is
      gastrointestinal tissue iron, not a plasma iron species.
    evidence:
    - reference: PMID:10674529
      reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract.
      explanation: >-
        Demonstrates dose-dependent removal of iron by oral deferiprone in the rat
        acute-overdose model.
  evidence:
  - reference: PMID:10674529
    reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007).
    explanation: >-
      Reports the mortality reduction in the rat model that motivates interest in
      oral deferiprone for acute poisoning.
  - reference: PMID:10674529
    reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Its efficacy, by oral administration, in acute iron poisoning has not been tested.
    explanation: >-
      The authors' own statement that human efficacy in acute poisoning was
      untested, which is why this treatment is curated as investigational.
  notes: >-
    The motivation is access rather than superiority: deferoxamine's cost and
    parenteral route limit its use worldwide.

animal_models:
- name: Rat oral iron LD50 model of acute iron overdose
  species: Rat
  genotype: wild type
  background: Wistar
  category: Chemically induced
  description: >-
    Wistar rats given 612 mg/kg elemental iron orally, a dose corresponding to the
    LD50 in that species, used to test whether an orally administered chelator can
    reduce mortality after acute iron ingestion.
  publication: PMID:10674529
  evidence:
  - reference: PMID:10674529
    reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rats were administered 612 mg/kg elemental iron orally, corresponding to LD50 in the species tested.
    explanation: >-
      Defines the model: the species, route, and the dose at which it was
      calibrated.
  modeled_mechanisms:
  - target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the defining exposure of human iron poisoning — a single acute
      oral iron load large enough to kill — and the gastrointestinal iron
      accumulation that follows it.
    limitations: >-
      The dose is set at the rodent LD50 rather than scaled from human ingestions,
      and rodent gastrointestinal anatomy and dosing pharmacokinetics differ from
      the human paediatric case; LD50 estimates for iron salts vary widely between
      studies and strains, so this model supports relative comparisons (chelated
      versus unchelated) far better than absolute human dose extrapolation.
    readouts:
    - name: Mortality after acute oral iron load
      target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
      direction: DECREASED
      interpretation: >-
        Direction is stated relative to the unchelated model arm: the model itself
        is lethal at this iron dose, and mortality fell when oral chelation was
        added, showing the lethality is iron-dependent and chelation-modifiable.
      evidence:
      - reference: PMID:10674529
        reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007).
        explanation: >-
          Quantifies the mortality readout and its response to chelation.
    - name: Gastrointestinal tissue iron accumulation
      target: Ingestion of Iron in Excess of Absorptive and Binding Capacity
      direction: DECREASED
      interpretation: >-
        Direction is stated relative to the unchelated model arm: the model
        accumulates gastrointestinal tissue iron, and that accumulation fell
        dose-dependently with chelation, tying the readout to the iron burden.
      evidence:
      - reference: PMID:10674529
        reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract.
        explanation: >-
          Reports the histological iron-accumulation readout and its dose response.
    evidence:
    - reference: PMID:10674529
      reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our objective was to determine whether orally administered deferiprone can reduce the mortality of rats following acute, toxic, oral doses of iron.
      explanation: >-
        States the model's design — acute toxic oral iron dosing in rats — and its
        use as a testbed for acute-poisoning therapy.

prevalence:
- population: Children presenting with accidental poisoning to a paediatric emergency service, India, 1998-2003
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Reported as iron's share of paediatric accidental-poisoning presentations
    (21 of 337) at one teaching hospital, not as a population rate, so no
    normalized rate per 100,000 is given. It measures what fraction of poisoned
    children were poisoned by iron, not how common iron poisoning is.
  evidence:
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these 21(7%) patients had iron poisoning; 18 were transferred to PICU.
    explanation: >-
      Gives iron's share of paediatric accidental poisonings at this centre, and
      the proportion needing intensive care.
- population: Children younger than 6 years in the United States, before the 1997 unit-dose packaging regulation
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Reported as iron-ingestion calls per 1000 of all poison-control-centre calls
    concerning children under 6, averaged over the ten years before the
    regulation, rather than as a population rate; not convertible to cases per
    100,000 population, so no normalized rate is given.
  evidence:
  - reference: PMID:15939855
    reference_title: "Unit-dose packaging of iron supplements and reduction of iron poisoning in young children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The average number of iron ingestion calls per 1000 of all calls to poison control centers regarding children younger than 6 years decreased from 2.99 per 1000 to 1.91 per 1000 (odds ratio, 1.29 [95% confidence interval, 1.27-1.32]; P<.001).
    explanation: >-
      Gives the pre- and post-regulation call frequencies among young children.
- population: Children in the United States, 1980-1996 (national surveillance)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Reported as a national annual count of iron-ingestion injuries, not as a
    population rate: the source gives no denominator, so no rate per 100,000 is
    derived here. The step change is the informative part rather than the level.
    Injuries roughly doubled at a single point in 1986 and then held, with no
    comparable trend before or after, while fatalities moved on a different
    trajectory, peaking in 1991 and falling to 2 by 1995. Age was spread evenly
    across under-2s, 2-year-olds and 3-to-4-year-olds.
  evidence:
  - reference: PMID:10798501
    reference_title: "Pediatric iron poisonings in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pediatric iron-related injuries increased 150% in 1986, from an annual average of 1,200 from 1980 through 1985 to 3,000 from 1986 through 1996.
    explanation: >-
      Gives the national annual injury counts and the 1986 step change. Quoted as
      counts because the source reports counts; converting them to a rate would
      require a denominator it does not supply.

discussions:
- discussion_id: serum_iron_versus_ingested_dose
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    In acute iron poisoning, which better identifies the patient who will develop
    toxicity — the serum iron concentration, or the suspected ingested dose of
    elemental iron? The cited literature does not agree. Two paediatric cohorts
    answer in opposite directions, and a third series finds a timed serum-iron
    cutoff with complete negative predictive value inside the mild-symptom
    stratum.
  attaches_to:
  - diagnosis#Serum iron concentration
  - biochemical#Serum iron concentration
  - pathophysiology#Ingestion of Iron in Excess of Absorptive and Binding Capacity
  rationale: >-
    How to read the enums here, first, because they are counter-intuitive. Every
    evidence item on this discussion is marked SUPPORT, including items on
    opposite sides of the question, because what each supports is the claim that
    the literature disagrees, and that is this discussion's only claim. There is
    no schema slot for which side a source is on; the explanations carry it. The
    polarity that takes a side lives on the serum-iron diagnosis entry instead,
    where the claim being supported or refuted is that the serum iron is
    informative.

    This is a live disagreement between published positions rather than a gap,
    and both positions are curated on the serum-iron diagnosis entry with their
    own evidence. PMID:14722368, a 21-patient Indian cohort with four deaths,
    found the ingested dose and clinical signs guided management while the serum
    iron did not help. PMID:34121325, a 54-patient Australian cohort of
    unintentional exposures with no severe toxicity, found the reverse on both
    counts: peak serum iron separated symptomatic from asymptomatic children at
    P < 0.001, while suspected dose did not differ between them.

    The cohorts are not interchangeable and the difference may be the answer
    rather than a contradiction. One is a referral series containing deaths; the
    other is a poisons-information-service series of unintentional exposures in
    which nobody became severely toxic. A measurement can discriminate mild
    toxicity from none and still fail to guide management once a child is
    already shocked, and an ingested dose reported by a parent may be estimated
    very differently in the two settings. Nothing cited here resolves which
    explanation holds.

    A third series, PMID:39509998, narrows the disagreement without settling it,
    and narrows it along the axis the proposed experiment below names. It
    analysed the serum iron inside a severity stratum rather than pooled and
    found it discriminating in the mild one: among patients whose symptoms
    stayed minor, a concentration at or below 300 microg/dL drawn 2 to 4 hours
    after ingestion was followed by no subsequent toxic concentration, giving
    complete negative predictive value. That is the mild-range half of the
    stratified prediction below, arriving from a study that was run without
    reference to it. It is not the whole of that prediction: no severe stratum
    was analysed, the ingested dose was not compared against the concentration,
    and the abstract does not report the age distribution of its 75 patients, so
    it does not stand as a third paediatric cohort. Its specificity of 54% also
    bounds what it licenses, since a rule for whom to stop watching is not a rule
    for whom to chelate.

    The practical consequence has changed in one respect and not in the other.
    This entry now curates the conventional serum-iron thresholds, on the
    biochemical entry, because PMID:39509998 states them quotably and they are
    curated as what its own sentence calls them, a tradition, rather than as
    validated cutoffs. The elemental-iron dose bands remain curated nowhere: no
    source this entry can quote states them, and unlike the serum concentration
    the ingested dose has now failed to discriminate outright in one cohort.
  proposed_experiments:
  - experiment_id: serum_iron_versus_dose_discrimination_by_severity_stratum
    name: Test both predictors against outcome, stratified by severity stratum
    description: >-
      In a cohort spanning both settings - unintentional exposures and referred
      severe poisonings - record suspected ingested dose and timed serum iron
      against a hard outcome, and analyse within severity strata rather than
      pooled. The specific question is whether serum iron discriminates in the
      mild range while dose discriminates in the severe range, which would make
      both cited findings correct in their own populations and would explain the
      disagreement without either being wrong. Report how the ingested dose was
      ascertained, since parental estimate and pharmacy reconciliation are not
      the same measurement. PMID:39509998 is a partial instance of this design
      and is the reason it is worth running in full: it stratified by symptom
      severity and found the serum iron discriminating in the mild stratum, but
      analysed no severe stratum and did not put the ingested dose alongside the
      concentration in the same comparison.
  evidence:
  - reference: PMID:34121325
    reference_title: "Unintentional paediatric iron poisoning: A retrospective case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Suspected dose ingested is a poor predictor of toxicity.
    explanation: >-
      The Australian cohort's own conclusion, and one half of the disagreement
      this discussion records.
  - reference: PMID:34121325
    reference_title: "Unintentional paediatric iron poisoning: A retrospective case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median suspected dose of elemental iron ingested was 72 mg/kg (IQR 41-140 mg/kg). Seventeen (31%) children were symptomatic. There were no cases of severe toxicity.
    explanation: >-
      Characterises that cohort as unintentional exposures without severe
      toxicity, which is the population difference that may explain why its
      finding diverges from the referral series with four deaths.
  - reference: PMID:14722368
    reference_title: "Acute iron poisoning: clinical picture, intensive care needs and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dose of ingested iron and clinical signs were most useful guide to iron toxicity and management decisions; serum iron did not help.
    explanation: >-
      The opposing position, from the referral cohort, and the reason there is a
      controversy to record at all. Marked SUPPORT like every other item on this
      discussion, because what it supports is the disagreement itself rather
      than either side of it; marking one side of a two-sided question REFUTE
      would make the other read as this discussion's thesis. Curated alongside
      the other cohorts rather than beneath them.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with only minor GI symptoms and an iron concentration of ≤ 300 μg/dL between 2 and 4 h post-ingestion are unlikely to develop further toxicity.
    explanation: >-
      The third position, and the closest thing cited anywhere in this entry to a
      test of this discussion's own proposed experiment: it asks what the serum
      iron is worth inside a severity stratum rather than pooled, and finds it
      discriminating in the mild one. That is the direction the stratified
      analysis predicts, but only one arm of it, so it narrows the disagreement
      rather than resolving it.
  - reference: PMID:39509998
    reference_title: "Utility of iron concentration two to four hours post ingestion in predicting toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No patients who developed at most minor symptoms (abdominal discomfort, nausea, vomiting, or diarrhea without evidence of systemic toxicity) and had a 2-4 h concentration ≤ 300 μg/dL symptoms had a subsequent concentration ≥ 350 μg/dL (negative predictive value [NPV] 100 %).
    explanation: >-
      The quantitative form of that finding, and the basis for calling the
      discrimination complete within its stratum rather than merely significant.
      Its limits are curated with it on the serum-iron diagnosis entry: 75
      patients, single centre, retrospective, specificity 54%, and an age
      distribution the abstract does not report.
- discussion_id: iron_effects_on_fibrinogen_versus_proteases
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    This entry models the coagulopathy of acute iron poisoning as reversible iron
    inhibition of the coagulation serine proteases, leaving fibrinogen itself
    undamaged. A separate literature reports the opposite kind of effect, in
    which ferric iron generates hydroxyl radicals that convert fibrinogen into
    fibrinolysis-resistant fibrin. Do both happen in acute iron poisoning, and if
    the second does, is the coagulopathy still correctable by removing the iron?
  attaches_to:
  - pathophysiology#Reversible Iron Inhibition of Coagulation Serine Proteases
  rationale: >-
    The two reported effects are not variants of one another. PMID:6421970, the
    source this entry's coagulation node is built on, found iron inactivating
    thrombin, factor Xa and kallikrein reversibly while leaving the zymogens and
    fibrinogen intact, which is an anticoagulant effect and matches the bleeding
    seen clinically. PMID:23170793 reports ferric ions generating hydroxyl
    radicals that convert fibrinogen into dense matted deposits with permanent
    resistance to enzymatic degradation, which is a prothrombotic effect on the
    substrate the first paper found undamaged.

    Three things keep this a gap rather than a contradiction to resolve. The
    second finding comes from a chronic degenerative disease frame, atherosclerosis
    and diabetes, where the iron burden and its time course are nothing like an
    overdose. The two describe different iron species and different targets, so
    they can both be true without meeting. And no cited source looks for
    fibrinogen structural change in acute iron poisoning at all.

    What makes it worth recording is that the entry's node carries a therapeutic
    implication which the second mechanism would not share. Protease inhibition is
    reversible, so the node states the coagulopathy is in principle correctable by
    chelation rather than only by factor replacement. A structural conversion of
    fibrinogen described as permanently resistant to degradation would not be
    undone by removing the iron. If both operate, chelation would correct one arm
    of the coagulopathy and not the other, and the node's framing is incomplete
    rather than wrong.
  proposed_experiments:
  - experiment_id: fibrinogen_structure_in_acute_iron_poisoning_plasma
    name: Look for fibrinogen structural change in acute iron poisoning plasma
    description: >-
      In plasma from patients with acute iron poisoning, sampled before and after
      chelation, assay both arms in the same specimens: protease activity for the
      reversible inhibition arm, and clot ultrastructure with fibrinolytic
      susceptibility for the fibrinogen arm. The discriminating result is what
      chelation does to each. Recovery of protease activity without recovery of
      clot architecture would show the two arms coming apart and would qualify the
      claim that this coagulopathy is correctable by removing the iron. Benchmark
      against plasma from a non-iron coagulopathy so that any change is
      attributable to iron rather than to critical illness.
  evidence:
  - reference: PMID:23170793
    reference_title: "Oxidation inhibits iron-induced blood coagulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We have recently shown that trivalent iron (ferric ions) generates hydroxyl radicals, which subsequently convert FBG into abnormal fibrin clots in the form of DMDs.
    explanation: >-
      The competing effect, on the molecule PMID:6421970 reported as undamaged.
      PARTIAL because the work is framed on chronic degenerative disease rather
      than acute poisoning, so it establishes that ferric iron can do this to
      fibrinogen and not that it does so in this disease.
  - reference: PMID:23170793
    reference_title: "Oxidation inhibits iron-induced blood coagulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A characteristic feature of DMDs is their remarkable and permanent resistance to the enzymatic degradation.
    explanation: >-
      The property that gives this gap its therapeutic edge. The node's claim that
      the coagulopathy is correctable by removing the iron rests on the inhibition
      being reversible; a fibrin deposit described as permanently resistant to
      enzymatic degradation would not be reversed by chelation. PARTIAL on the
      same disease-frame grounds.
- discussion_id: evidence_base_quality_for_diagnosis_and_management
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    The diagnostic and management claims in this entry rest on case series,
    expert consensus, animal studies and adult volunteer studies rather than on
    controlled human trials in acute iron poisoning. Which of them would survive
    a trial-grade evidence base, and which are conventions that have persisted
    for want of better data?
  attaches_to:
  - diagnosis#Serum iron concentration
  - diagnosis#Abdominal radiography for retained iron tablets
  - treatments#Whole Bowel Irrigation
  - treatments#Oral Deferiprone (investigational for acute poisoning)
  rationale: >-
    This is a standing limitation on the entry rather than a gap in one
    mechanism, and it is stated by a review of the field rather than inferred
    here: diagnosis and management of iron poisoning have minimally evolved, and
    the evidence for them remains principally case series, expert consensus,
    animal studies and adult volunteer studies. That is visible throughout this
    entry, and recording it once in sourced form is more honest than repeating
    the caveat at every node. It is why the serum iron concentration is curated
    with a REFUTE beside its SUPPORT items rather than resolved; why oral
    deferiprone is investigational on rat data with its own
    HUMAN_MODEL_MISMATCH; why abdominal radiography rests on a single case
    report; why the Phase 3 mortality association is noted as a four-death
    series and not a prognostic rule; and why the commonly taught serum-iron
    chelation threshold and elemental-iron dose bands are curated nowhere in
    this entry at all. A curator who finds any of those thin should read this
    first: the thinness is the field's, not an artefact of what was reachable
    here.
  proposed_experiments:
  - experiment_id: prospective_registry_of_acute_iron_ingestion
    name: Prospective multicentre registry of acute iron ingestion
    description: >-
      Enrol consecutive acute iron ingestions across multiple poison centres
      with a common dataset — ingested preparation and estimated elemental dose,
      timed serum iron, abdominal radiograph findings, decontamination given,
      chelation timing and dose, and outcome. That is the design that would let
      the conventions in this entry be tested rather than inherited: whether
      serum iron predicts outcome once dose and clinical signs are accounted for
      (the disagreement between PMID:2870463 and PMID:14722368), whether
      radiographic tablet burden changes management, and what elemental-iron
      dose actually separates benign from severe. A registry rather than a trial
      because withholding chelation from a severely poisoned child is not
      randomisable.
  evidence:
  - reference: PMID:21975503
    reference_title: "Iron poisoning: a literature-based review of epidemiology, diagnosis, and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Despite these changes, diagnosis and management of iron poisoning have minimally evolved, and the current evidence for iron poisoning is yet based principally on case series, expert consensus, animal studies, and adult volunteer studies.
    explanation: >-
      States the evidence base of the field directly, which is what makes this a
      sourced limitation rather than a curator's impression of one.
  - reference: PMID:21975503
    reference_title: "Iron poisoning: a literature-based review of epidemiology, diagnosis, and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although seen less frequently than acetaminophen or salicylate poisoning, acute iron poisoning remains a dangerous threat, particularly to pediatric patients.
    explanation: >-
      Establishes that the thin evidence base attaches to a disease that is
      still dangerous, which is why the gap matters rather than being merely
      academic.
- discussion_id: ferroptosis_in_acute_iron_poisoning
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which route carries the hepatocellular and mucosal cell death of acute iron
    poisoning: ferroptosis (iron-dependent, GPX4-restrained lethal lipid
    peroxidation), lysosomal destabilisation ending in apoptotic or necrotic
    death, or unregulated oxidative organelle damage requiring no death
    programme at all? The three are not mutually exclusive, and none has been
    demonstrated in this disease.
  attaches_to:
  - pathophysiology#Iron-Catalysed Oxidative Organelle Injury
  - pathophysiology#Periportal Hepatocellular Necrosis
  rationale: >-
    Ferroptosis is a well-characterised, iron-dependent regulated cell-death
    pathway, and acute iron poisoning is the most extreme iron load a human
    tissue encounters — so the pathway is an obvious candidate for the cell death
    in this disease. But that inference runs from the general mechanism to this
    disease, not from evidence in it: the acute-iron-poisoning literature is a
    clinical toxicology literature of case series and poison-centre surveillance,
    and it predates the description of ferroptosis. No ferroptosis marker has been
    demonstrated in human acute iron poisoning tissue. The distinction is not
    academic, because a regulated pathway is druggable in ways that
    Fenton-chemistry damage is not: if ferroptosis carries a meaningful share of
    the hepatocyte death, a ferroptosis inhibitor becomes a candidate adjunct to
    chelation. This entry therefore curates the oxidative organelle injury it has
    evidence for, and records ferroptosis as an untested possibility rather than
    annotating GO:0097707 on the pathograph.

    The gap is wider than ferroptosis alone. PMID:11978485 proposes a separate,
    explicitly non-exclusive route in which iron-catalysed oxidative
    destabilisation of lysosomes spills digestive enzymes into the cytoplasm and
    ends in apoptotic or necrotic death. So there are at least two mechanistically
    distinct candidate death routes on offer — lipid-peroxidative ferroptosis and
    lysosomal rupture — and the acute iron poisoning literature demonstrates
    neither. Both are drawn from chronic iron-overload and general
    iron-toxicity biology. Establishing which, if either, carries the hepatocyte
    death in acute poisoning is the question; the experiments below should
    discriminate between them rather than test ferroptosis in isolation.

    A third literature bears on this without being about it, and it argues for
    restraint rather than for ferroptosis. Acetaminophen hepatotoxicity is the
    best-studied iron-dependent drug-induced liver injury, and a critical review
    of it warns in general terms against applying death mechanisms across cell
    types and disease states without validation, then concludes from the
    published data that hepatic antioxidant defences normally hold lipid
    peroxidation below pathophysiological relevance, so that ferroptosis becomes
    a significant mode of drug-induced cell death only where those defences are
    severely compromised. Acute iron poisoning is a plausible candidate for
    exactly that compromised state, which is the argument for testing it, not a
    demonstration that it holds. The same literature also supplies a specific
    route that would connect the two organelles this entry annotates on one node:
    lysosomal damage releasing iron that the mitochondrial calcium uniporter then
    takes up, making the lysosome the source and the mitochondrion the site.
    Whether that relay operates in iron poisoning, where the iron arrives from
    outside the cell rather than from a damaged lysosome, is untested and is
    worth distinguishing in the experiments below.
  proposed_experiments:
  - experiment_id: death_route_discrimination_in_poisoning_liver
    name: Discriminate the ferroptotic and lysosomal death routes in poisoned liver
    description: >-
      In explanted or post-mortem liver from acute iron poisoning, benchmarked
      against liver injured by a non-iron hepatotoxin, assay both candidate
      routes in the same tissue: lipid-peroxidation products and
      ferroptosis-associated transcriptional signatures for the ferroptotic
      route, and lysosomal membrane permeabilisation — cathepsin release into
      the cytosol, LAMP staining — for the lysosomal route. The point is to
      discriminate between them, so a design that assays only one cannot answer
      the question. The non-iron comparator is what separates an
      iron-specific death signature from generic oxidative necrosis.
  - experiment_id: gpx4_readout_validation_against_selenium_status
    name: Validate GPX4 abundance as a ferroptosis readout against selenium status
    description: >-
      Before GPX4 abundance is used as an index of ferroptotic pressure in
      poisoned tissue, establish what it is measuring. GPX4 is a selenoprotein
      whose expression tracks intracellular selenium utilisation and
      selenoprotein-synthesis capacity, so a low GPX4 in poisoned liver may
      reflect selenium status rather than iron-driven consumption. Measure
      selenium status and selenoprotein-synthesis capacity alongside GPX4 in the
      same specimens and test whether GPX4 varies with iron exposure once
      selenium status is accounted for. If it does not, the lipid hydroperoxide
      products should be the primary ferroptosis readout in the discrimination
      experiment above.
  - experiment_id: ferroptosis_inhibition_rat_acute_iron_model
    name: Ferroptosis inhibition in the rat acute oral iron model
    description: >-
      Add a ferroptosis inhibitor to the established rat acute oral iron LD50
      model, alone and with chelation, and measure mortality, transaminases and
      hepatic histology. A survival benefit beyond chelation alone would establish
      a regulated-death contribution and a therapeutic target.
  evidence:
  - reference: PMID:32165281
    reference_title: "Lipid peroxidation and ferroptosis: The role of GSH and GPx4."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ferroptosis (FPT) is a form of cell death due to missed control of membrane lipid peroxidation (LPO).
    explanation: >-
      Defines the candidate pathway and situates it as a failure of control over
      lipid peroxidation — the process iron catalyses — which is why it is a
      plausible but as yet untested contributor here.
  - reference: PMID:11978485
    reference_title: "Molecular bases of cellular iron toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      An alternative-and not mutually exclusive-mechanism for cellular iron toxicity involves iron-catalyzed oxidative destabilization of lysosomes, leading to leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death.
    explanation: >-
      Supplies the competing lysosomal death route that widens this gap. PARTIAL
      because, like the ferroptosis proposal, it is drawn from chronic
      iron-overload biology and has not been shown in acute iron poisoning.
  - reference: PMID:39649034
    reference_title: "Ferroptosis and Intrinsic Drug-induced Liver Injury by Acetaminophen and Other Drugs: A Critical Evaluation and Historical Perspective."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, concerns arise when such mechanisms are applied across different cell types and disease states without sufficient validation.
    explanation: >-
      Makes this discussion's central caution a sourced one rather than a
      curator's assertion. The gap recorded here is precisely that ferroptosis is
      being carried into acute iron poisoning from other cell types and disease
      states, and a critical review of the ferroptosis literature in
      drug-induced liver injury names that move as the thing to be wary of.
  - reference: PMID:39649034
    reference_title: "Ferroptosis and Intrinsic Drug-induced Liver Injury by Acetaminophen and Other Drugs: A Critical Evaluation and Historical Perspective."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Overall, the published data support the idea that multi-layered endogenous antioxidant defense mechanisms in the liver limit the occurrence of pathophysiologically relevant LPO under normal conditions. Only when these defense mechanisms are severely compromised does ferroptosis become a significant mode of drug-induced cell death.
    explanation: >-
      Sets the condition under which ferroptosis would be expected to matter,
      which is what makes it testable here rather than merely plausible: hepatic
      antioxidant defences ordinarily keep lipid peroxidation below
      pathophysiological relevance, and ferroptosis becomes significant only when
      they are severely compromised. PARTIAL because the finding is about
      drug-induced liver injury, chiefly acetaminophen, and not about iron
      poisoning; whether an acute iron load compromises those defences to that
      degree is the open question, not something this establishes.
  - reference: PMID:39554796
    reference_title: "Role of Mitochondrial Iron Uptake in Acetaminophen Hepatotoxicity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      After APAP overdose, the toxic metabolite, NAPQI, damages lysosomes, causing excess iron release and the mitochondrial uptake of Fe2+ by the mitochondrial calcium uniporter (MCU).
    explanation: >-
      Supplies a specific lysosome-to-mitochondrion iron relay, which is
      mechanistically interesting here because this entry annotates both
      organelles on one node without asserting a route between them. INDIRECT, and
      with an important disanalogy stated rather than glossed: in acetaminophen
      injury the lysosome is the iron source because a reactive metabolite damages
      it, whereas in iron poisoning the iron arrives from plasma. The relay is
      a hypothesis to discriminate, not a mechanism to import.
  - reference: PMID:38867112
    reference_title: "PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: >-
      Loss of PRDX6 decreases the expression of selenoproteins and induces ferroptosis via a reduction in GPX4.
    explanation: >-
      Cited ONLY as a caveat on how this gap should be tested, not as evidence
      about acute iron poisoning. It is cell-line selenium biology with no
      ingestion, no human subject and no poisoning, and the "iron toxicity" of
      its title means ferroptotic death in culture rather than the clinical
      syndrome. What it contributes is that GPX4 abundance is set by
      selenoprotein-synthesis capacity, which makes a low GPX4 an ambiguous
      readout in the proposed post-mortem experiment above. It does nothing to
      close this gap; if anything it shows how far the ferroptosis literature
      sits from the disease.
  - reference: PMID:37629109
    reference_title: "Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, the recent discovery of ferroptosis, which is a cell death program based on free radical generation by iron and cell membrane lipid oxidation, sparked thousands of investigations and the association of iron with cardiac, kidney, liver, and many other diseases, including cancer and infections.
    explanation: >-
      Shows ferroptosis being associated with iron and with liver disease in the
      general iron-toxicity literature. It is PARTIAL precisely because that is
      the inference this gap questions: the association is drawn across iron
      diseases at large, not demonstrated in acute iron poisoning.

- discussion_id: deferiprone_human_translation_acute_poisoning
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the mortality benefit of oral deferiprone seen in the rat acute
    oral-iron model translate to human acute iron poisoning, where the chelator
    must be given after ingestion rather than coadministered with the iron?
  attaches_to:
  - treatments#Oral Deferiprone (investigational for acute poisoning)
  - pathophysiology#Ingestion of Iron in Excess of Absorptive and Binding Capacity
  rationale: >-
    The rat result is a real, dose-responsive survival benefit, but its design
    limits what it can say about the clinical problem: deferiprone was
    coadministered with the iron or given two hours later, whereas a poisoned
    child presents hours after an ingestion of unknown size, often already
    vomiting — which is both the reason an oral agent is attractive and the reason
    it may not be retained. The authors state plainly that oral efficacy in acute
    poisoning had not been tested in humans. The stakes are access rather than
    superiority: deferoxamine's cost and parenteral route put it out of reach in
    much of the world, so an oral alternative would change who can be treated at
    all. Until human data exist, deferiprone is curated here as investigational
    and deferoxamine remains the antidote.

    This discussion attaches to the ingested-burden node rather than to plasma
    non-transferrin-bound iron, matching where this treatment's
    target_mechanisms edge points and for the same reason: the only measurement
    supporting oral deferiprone in the acute setting is gastrointestinal tissue
    iron, not a plasma iron species. A systemically absorbed chelator plausibly
    also acts on plasma NTBI, but nothing in the cited evidence measures that,
    so both links are drawn where the evidence is rather than where the
    pharmacology is assumed to reach.
  proposed_experiments:
  - experiment_id: delayed_oral_chelation_rat_model
    name: Delayed-administration oral chelation in the rat model
    description: >-
      Repeat the rat acute oral iron model with deferiprone given at intervals
      matching realistic human presentation delays, and in animals made to vomit
      or with delayed gastric emptying, to test whether the benefit survives the
      timing and retention conditions of a real poisoning.
  - experiment_id: deferiprone_registry_human_cohort
    name: Registry-based human comparative cohort
    description: >-
      In settings where parenteral deferoxamine is unavailable and oral
      deferiprone is used, assemble a poison-centre registry cohort comparing
      chelated and unchelated acute iron poisonings on mortality, peak serum iron
      and hepatic injury, with severity adjustment.
  evidence:
  - reference: PMID:10674529
    reference_title: "The efficacy of oral deferiprone in acute iron poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Its efficacy, by oral administration, in acute iron poisoning has not been tested.
    explanation: >-
      The authors state that human oral efficacy in acute poisoning is untested,
      which is precisely the translational gap recorded here.

📚

References & Deep Research

References

3

PMID:3784842

Management of acute iron poisoning.

No top-level findings curated for this source.

PMID:11778670

Hepatotoxicity in acute iron poisoning.

No top-level findings curated for this source.

PMID:6421970

Blood coagulation and acute iron toxicity. Reversible iron-induced inactivation of serine proteases in vitro.

No top-level findings curated for this source.

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Iron Poisoning (Acute Iron Toxicity) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 45 citations 2026-08-23T13:37:42.119348

Iron Poisoning (Acute Iron Toxicity) — Comprehensive Research Report

1. Disease Information

Overview. Iron poisoning (acute iron toxicity) is a potentially lethal toxidrome resulting from ingestion of excessive elemental iron, most commonly from iron-containing dietary supplements, prenatal vitamins, or ferrous salt medications (ferrous sulfate, ferrous gluconate, ferrous fumarate). It is distinct from chronic iron overload disorders (hereditary hemochromatosis, transfusional hemosiderosis) — iron poisoning is an acute, dose-dependent, environmentally/behaviorally mediated toxic exposure rather than a genetic disorder of iron regulation, although both converge on overlapping downstream cellular iron-toxicity mechanisms (oxidative stress, ferroptosis). It remains "one of the leading causes of fatal poisoning in children under 6 years of age" historically, and continues to be an important cause of both unintentional pediatric poisoning and intentional (self-harm) poisoning in adolescents/adults (StatPearls: Iron Toxicity; Wikipedia: Iron poisoning).

Key identifiers: - ICD-10-CM: T45.4X1A (Poisoning by iron and its compounds, accidental, initial encounter); related codes T45.4X2A (intentional self-harm), T45.4X3A (assault), T45.4X4A (undetermined intent) (icd10data.com) - ICD-10 (WHO): T45.4 — Poisoning by iron and its compounds - MeSH: Overlaps with "Iron Overload" (D019190) and "Poisoning" (D011041); no dedicated acute-toxicity MeSH heading distinct from the general iron/poisoning headings - MONDO: No MONDO term dedicated specifically to "acute iron poisoning" was identified in this search (MONDO's iron-related terms center on hereditary iron-overload disorders, e.g., hemochromatosis, FTH1-related iron overload — Orphanet: FTH1-related iron overload); acute iron poisoning is more naturally represented as a toxic/environmental exposure entity than a MONDO disease class - UMLS/SNOMED CT: "Iron poisoning" / "Iron toxicity" concepts exist in clinical toxicology terminologies (WikEM, Medscape "Iron Toxicity" and "Pediatric Iron Toxicity")

Synonyms: Acute iron toxicity, acute iron overdose, ferrous sulfate poisoning, iron ingestion (toxic), iron salt poisoning.

Data provenance: Knowledge derives predominantly from aggregated poison-control-center surveillance (American Association of Poison Control Centers, AAPCC National Poison Data System), case reports/series (often intentional adult overdoses), retrospective cohort studies, and animal (mouse/rat) toxicology data — rather than large prospective clinical trials, given the acute/emergent nature and rarity of severe cases.

Sources: PubMed: Acute iron poisoning (PMID:8187690) · StatPearls: Iron Overload and Toxicity · Merck Manual: Iron Poisoning · Medscape: Iron Toxicity

2. Etiology

Disease causal factor: Ingestion of a supratherapeutic dose of elemental iron, overwhelming normal intestinal mucosal regulation of iron absorption and saturating plasma iron-binding capacity (transferrin), producing free/non-transferrin-bound iron that is directly cytotoxic. This is a purely environmental/exposure-mediated disease process — there is no genetic causal variant required, though genetic background (e.g., HFE hemochromatosis carrier status) may theoretically modulate baseline iron handling (not well studied for acute poisoning specifically).

Toxic dose thresholds (elemental iron, oral): - <20 mg/kg: generally non-toxic/asymptomatic - 20–40(–60) mg/kg: mild-to-moderate toxicity — self-limited GI symptoms (vomiting, abdominal pain, diarrhea) - >40–60 mg/kg: potentially serious/severe systemic toxicity - >60 mg/kg: potentially lethal - Animal-model acute lethal dose: ~150–200 mg/kg elemental iron - Lowest reported lethal dose in a human: a 21-month-old child who ingested 325–650 mg elemental iron as ferrous sulfate

A standard 325 mg ferrous sulfate tablet contains ~65 mg elemental iron (ferrous sulfate is ~20% elemental iron by weight); prenatal vitamins and adult-strength ferrous sulfate tablets are the highest-risk products because of their high elemental-iron density relative to pediatric multivitamins.

Sources: California Poison Control: Iron Ingestion · Iron Ingestion: Evidence-Based Consensus Guideline · StatPearls (Archived): Iron Toxicity

Risk factors (environmental/behavioral, not genetic): - Age <5 years — accounts for the overwhelming majority of unintentional serious morbidity/mortality (young children accidentally ingesting adult-formulation iron tablets, mistaking them for candy due to bright coloring) - Household presence of prenatal vitamins or high-dose ferrous sulfate (highest elemental-iron-per-tablet products) - Adolescent/young adult female sex for intentional ingestion (self-harm/suicide attempts) — the dominant mechanism of severe iron poisoning in adults - Lack of child-resistant/unit-dose packaging (historically) - Careless storage — parents/caregivers may perceive iron/vitamin supplements as "safe," reducing vigilance

Protective factors: - Unit-dose (blister) packaging and child-resistant containers for products with ≥30 mg elemental iron/dosage unit (US FDA 1997 rule, effective July 1997) — associated with a marked reduction in pediatric iron-poisoning deaths - Label warning statements mandated by FDA guidance - Early recognition/early chelation therapy — greatly reduces mortality

Gene-environment interaction: Not a defined feature of this condition in the literature reviewed; acute iron poisoning is an environmentally/behaviorally driven exposure rather than a gene-environment interaction disease. (Contrast with hereditary hemochromatosis, where HFE variants confer chronically increased iron absorption — a distinct disease entity.)

Sources: FDA: Small Entity Compliance Guide, Iron-Containing Supplements Label Warning · Federal Register: Iron-Containing Supplements and Drugs · PubMed: Unit-dose packaging of iron supplements and reduction of iron poisoning in young children · AAP: Accidental Iron Poisoning in Children

3. Phenotypes

Iron toxicity classically progresses through five overlapping clinical stages (not all patients pass through every stage sequentially):

Stage	Timing	Phenotype
I — Gastrointestinal/corrosive	0–6 h	Direct mucosal corrosive injury: vomiting (HP:0002013), abdominal pain (HP:0002027), diarrhea (HP:0002014), often hematemesis/hematochezia (bloody vomiting/stool) from massive GI fluid/blood loss; can cause hemodynamic instability/hypovolemic shock even at this early stage
II — Latent	6–24 h	Apparent GI improvement, but ongoing cellular toxicity: persistent tachycardia (HP:0001649), lethargy (HP:0001257), evolving metabolic acidosis (HP:0011900) — a deceptively "quiet" period that can mislead clinicians into premature discharge
III — Shock/metabolic decompensation (most deaths occur here)	24–48+ h	Recurrent GI symptoms, worsening metabolic (lactic) acidosis, circulatory (hypovolemic/distributive) shock (HP:0001744-adjacent concepts), coagulopathy (HP:0001928), multi-organ dysfunction
IV — Hepatotoxicity	2–5 days	Fulminant hepatic failure (HP:0006554) from direct mitochondrial/hepatocellular iron toxicity — can progress to require liver transplantation
V — Late GI scarring/obstruction	2–8 weeks	Gastric outlet obstruction and small-bowel/pyloric strictures from mucosal scar formation — presents with recurrent vomiting, abdominal pain, and obstipation weeks after the acute event; historically treated surgically (Mikulicz procedure, gastrojejunostomy, Billroth I resection)

Additional/organ-specific phenotypes: - Cardiovascular: hypotension, cardiovascular collapse, cardiogenic and distributive shock - Hematologic: coagulopathy — iron (Fe³⁺/non-transferrin-bound iron) reversibly inhibits serine proteases of the coagulation cascade (thrombin, factor Xa, kallikrein), causing bleeding diathesis distinct from hepatic-synthetic coagulopathy - Renal: acute kidney injury from hypoperfusion/direct toxicity - CNS: lethargy progressing to coma in severe cases - Metabolic: anion-gap metabolic acidosis (from uncoupled oxidative phosphorylation, lactic acid accumulation, and hydrolysis of ferric iron to iron hydroxide releasing free H⁺)

Severity/frequency: Symptom severity is dose-dependent (see thresholds above); most pediatric exposures are asymptomatic or mild (small unintentional ingestions), while intentional adult overdoses (tens of tablets) are far more likely to reach severe/fatal stages.

Suggested HPO terms: HP:0002013 (Vomiting), HP:0002014 (Diarrhea), HP:0002027 (Abdominal pain), HP:0001649 (Tachycardia), HP:0001257 (Lethargy), HP:0011900 (Metabolic acidosis), HP:0001928 (Abnormal coagulation), HP:0006554 (Acute hepatic failure), HP:0100626 (Chronic hepatic failure — for late sequelae), HP:0002583 (Gastrointestinal obstruction), HP:0002014-adjacent for hematochezia/melena, HP:0001744-adjacent for shock.

Quality of life: Acute survivors of severe poisoning may face long-term morbidity from hepatic injury or GI stricture requiring reconstructive surgery; specific validated QoL instrument data for iron-poisoning survivors was not identified in this search.

Sources: WikEM: Iron toxicity · Medscape: Pediatric Iron Toxicity · Radiology: Fibrous Stricture of the Stomach Due to Iron (Feosol) Poisoning · PubMed: Gastrointestinal pathology in adult iron overdose (PMID:2231830) · PMC: Liver Transplantation for Acute Hepatic Failure Following Intentional Iron Overdose · Tennessee Poison Center: Delayed manifestations of iron poisoning

4. Genetic/Molecular Information

Iron poisoning is not a Mendelian genetic disease; it has no causal gene in the OMIM/ClinVar sense. There are no pathogenic variants, no inheritance pattern, and no chromosomal abnormalities associated with the exposure itself.

Relevant molecular target/pathway genes (not causal, but mechanistically involved in toxicity/handling): - TF (transferrin) — plasma iron-binding protein; saturation of TF binding capacity (normally 20–35% saturated) is the threshold event producing non-transferrin-bound iron (NTBI) toxicity - SLC40A1 (ferroportin) — cellular iron export - FTH1/FTL (ferritin heavy/light chain) — intracellular iron storage/sequestration; ferritin destruction is implicated as a source of catalytic free iron in iron-mediated hepatocyte injury (paralleling acetaminophen hepatotoxicity mechanisms) - HFE — theoretically could modulate baseline transferrin saturation/absorption but is not established as a modifier of acute poisoning severity in the literature surveyed

Epigenetics/somatic considerations: Not applicable — this is an acute exogenous toxic exposure, not a heritable or somatic-mutation disease.

Sources: PMC: Iron Load Toxicity in Medicine — Molecular and Cellular Aspects · PMC: Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity · ScienceDirect: Iron mediated toxicity and programmed cell death

5. Environmental Information

Primary environmental/exposure factors: - Iron-containing oral dietary supplements: ferrous sulfate, ferrous gluconate, ferrous fumarate, carbonyl iron, prenatal multivitamins - Product form and elemental-iron density (adult-strength tablets vs. pediatric chewables) — a major determinant of exposure severity - Household storage practices and accessibility to young children - Packaging regulation status (unit-dose blister packaging vs. bulk bottles)

Behavioral/lifestyle factors: - Deliberate self-poisoning (intentional overdose), disproportionately among adolescent and young adult females — the dominant severe-poisoning mechanism in the adult population - Caregiver perception of supplements as "safe," reducing protective vigilance

Infectious agents: Not applicable — iron poisoning is a chemical/toxicologic, not infectious, process.

Suggested exposure-ontology grounding (ECTO-style): "exposure to iron salts via ingestion" / "ferrous sulfate ingestion."

Sources: AAP: Accidental Iron Poisoning in Children · SAGE: Iron Packaging Regulations in the United States and Pediatric Morbidity

6. Mechanism / Pathophysiology

Causal chain (initial trigger → clinical manifestation):

Ingestion of excess elemental iron → normal intestinal mucosal regulatory mechanisms (which limit absorption under physiologic conditions) are overwhelmed by supratherapeutic dose.
Direct corrosive mucosal injury — iron salts act as a direct GI irritant/corrosive, producing hemorrhagic gastritis/enteritis, mucosal necrosis, and erosion (Stage I phenotype). "Iron promotes direct mucosa irritation and at the intracellular level favors free radical production, oxidative damage, hinders oxidative phosphorylation, and ultimately causes cell death" (ScienceDirect: Iron Poisoning overview).
Systemic absorption and saturation of plasma protein binding — once transferrin's iron-binding capacity is exceeded (pathologically detectable when transferrin saturation exceeds ~75%), non-transferrin-bound iron (NTBI) appears in plasma; its redox-active, chelatable fraction is termed labile plasma iron (LPI). NTBI/LPI enter cells via transporters outside normal transferrin-receptor-mediated regulation, bypassing cellular iron homeostasis controls.
Cellular/mitochondrial toxicity — free iron concentrates in mitochondria and catalyzes Fenton-type reactions, generating reactive oxygen species (ROS) that cause lipid peroxidation of mitochondrial membranes, uncoupling oxidative phosphorylation, and disrupting the electron transport chain. This is mechanistically convergent with ferroptosis — an iron-dependent regulated cell-death pathway involving glutathione/GPX4 depletion and lipid-peroxide accumulation, a mechanism well-characterized in iron-catalyzed acetaminophen hepatotoxicity and increasingly recognized as relevant to iron-overdose hepatocyte injury.
Metabolic acidosis — arises from two convergent mechanisms: (a) impaired oxidative phosphorylation → anaerobic metabolism → lactic acidosis; (b) when plasma protein-binding capacity is saturated, ferric iron hydrolyzes with water to form iron hydroxide and free H⁺ ions, directly compounding acidosis.
Coagulopathy — non-transferrin-bound Fe³⁺ (and its hydrolytic species) reversibly inhibits serine proteases of the coagulation cascade: thrombin's fibrinogen-clotting and fibrinopeptide-A-generating activity is markedly suppressed, as is factor Xa and kallikrein activity. This effect is reversible with iron chelation (EDTA in vitro), and is distinct from the coagulopathy of established hepatic synthetic failure — both mechanisms can coexist in severe poisoning.
Hepatotoxicity — the liver, as the first-pass site of portal-venous iron delivery and major iron-storage organ, sustains direct mitochondrial/oxidative injury, potentially progressing to fulminant hepatic failure (Stage IV) requiring transplantation in severe/intentional overdoses.
Cardiovascular collapse/shock — from combined hypovolemia (GI fluid/blood loss), direct iron-mediated myocardial and vascular endothelial toxicity, and acidosis-driven cardiac dysfunction; this is the dominant cause of death in Stage III.
Delayed structural sequelae — the initial corrosive mucosal injury heals by fibrotic scarring, which can mechanically obstruct the gastric outlet or proximal small bowel weeks later (Stage V).

Cell types/tissues implicated: gastrointestinal mucosal epithelial cells (enterocytes, gastric mucosa), hepatocytes, cardiomyocytes/vascular endothelium, and — at the molecular level — mitochondria across affected cell types.

Suggested GO terms: GO:0006879 (cellular iron ion homeostasis), GO:0055072 (iron ion homeostasis), GO:0034614 (cellular response to reactive oxygen species), GO:0006749 (glutathione metabolic process), GO:0034599 (cellular response to oxidative stress), GO:0006119 (oxidative phosphorylation), GO:0097267 (omega-hydroxylase P450 pathway — n/a), GO:1990448 (ferroptosis-related term where available, e.g., GO:0097707 "ferroptosis").

Suggested CHEBI terms: CHEBI:18248 (iron atom/ion), CHEBI:29033 (Fe(II) ion), CHEBI:29034 (Fe(III) ion), CHEBI:75771 (ferrous sulfate), CHEBI:75832 (ferrous gluconate).

Sources: PMID:8187690 — Acute iron poisoning · PMC: Iron Load Toxicity in Medicine · PMC: Role of Mitochondrial Iron Uptake in Acetaminophen Hepatotoxicity · PubMed: Ferroptosis and Intrinsic Drug-induced Liver Injury (PMID:39649034) · PubMed: Blood coagulation and acute iron toxicity — reversible iron-induced inactivation of serine proteases (PMID:6421970) · PMC: Oxidation Inhibits Iron-Induced Blood Coagulation · PMC: Non-Transferrin-Bound Iron, Labile Plasma Iron, and Iron Toxicity

7. Anatomical Structures Affected

Organ level: - Primary: stomach and small intestine (direct corrosive injury); liver (systemic iron trapping and hepatotoxicity) - Secondary/complication-related: cardiovascular system (shock), kidneys (acute kidney injury secondary to hypoperfusion), coagulation system (functional coagulopathy) - Body systems: digestive, hepatobiliary, cardiovascular, hematologic

Tissue/cell level: - Gastric and intestinal mucosal epithelium (erosion, hemorrhagic necrosis) - Hepatocytes (oxidative/mitochondrial injury, necrosis, fulminant failure) - Vascular endothelium (increased permeability contributing to shock) - Cardiomyocytes (direct toxic and hypoperfusion-related injury)

Subcellular level: mitochondria (site of iron concentration, ROS generation, oxidative-phosphorylation uncoupling); cell membranes (lipid peroxidation target)

Suggested UBERON terms: UBERON:0000945 (stomach), UBERON:0002108 (small intestine), UBERON:0002107 (liver), UBERON:0000948 (heart), UBERON:0002113 (kidney), UBERON:0001969 (blood plasma).

Suggested GO Cellular Component terms: GO:0005739 (mitochondrion), GO:0016020 (membrane).

Sources: PubMed: Gastrointestinal pathology in adult iron overdose (PMID:2231830) · Radiology: Fibrous Stricture of the Stomach Due to Iron Poisoning

8. Temporal Development

Onset: Acute — symptoms typically begin within 30 minutes to 6 hours of ingestion (Stage I); onset pattern is acute/toxic rather than insidious, dose-dependent in latency and severity.

Progression (staged, as above): - Stage I (0–6 h): corrosive GI phase - Stage II (6–24 h): latent/deceptive improvement - Stage III (24–48+ h): shock/metabolic decompensation — responsible for the majority of deaths - Stage IV (2–5 days): hepatotoxicity/hepatic failure - Stage V (2–8 weeks): GI stricture/obstruction

Not all patients progress through every stage; a patient with a small ingestion may resolve after Stage I, while patients with massive ingestion can rapidly develop multi-organ failure and death within the first 24–48 hours without ever exhibiting a clear "latent" phase.

Disease course pattern: Self-limited (in mild ingestions) to rapidly progressive/fulminant (in severe ingestions), with a distinct delayed structural complication window (weeks) that is atypical among acute poisonings and requires specific counseling/follow-up.

Critical period for intervention: Early recognition and chelation (ideally initiated in Stage I–II, before shock/organ failure) is the key modifiable window — "[Deferoxamine] greatly reduces mortality in children, provided it is given at an early stage" (ScienceDirect: Deferoxamine overview).

Sources: Medscape: Pediatric Iron Toxicity · EM Board Bombs: A Rusty Diagnosis — Acute Iron Poisoning · Tennessee Poison Center: Delayed manifestations of iron poisoning

9. Inheritance and Population

Epidemiology (US, AAPCC data): - 2022: 5,311 single exposures to iron/iron salts reported to US poison control centers — 2,154 in children <6 years, 209 in children 6–12 years, 762 in adolescents 13–19 years; 2 deaths reported. An additional 7,565 single exposures to iron-containing multivitamins were reported, 81% in children <6 years. - Historical incidence: ~11,000 iron exposures per year in US children <6 years old (2015 AAPCC data) - Mortality trend: From 1983–2000, at least 43 US children died from iron supplement ingestion; from 1983–1991, iron accounted for >30% of deaths from unintentional pediatric drug-product ingestion. Fatal pediatric iron ingestions have declined markedly since the 1990s, coincident with unit-dose packaging/labeling regulation (1997 FDA rule) — one pediatric iron-poisoning death reported 1998–2002 following the regulation.

Inheritance pattern: Not applicable — iron poisoning is an acquired toxic exposure, not an inherited disease. No penetrance, expressivity, anticipation, mosaicism, founder-effect, or carrier-frequency concepts apply.

Population demographics: - Unintentional poisoning: overwhelmingly children <5 years old ingesting adult-formulation iron products - Intentional/severe poisoning: predominantly adolescent and young adult females attempting self-harm — the dominant mechanism behind severe/fatal adult cases described in case series (e.g., five fatal cases of suicidal ingestion of 20–60 iron/iron-folic tablets in adolescent females, with autopsy findings of multi-organ petechial hemorrhage, GI mucosal necrosis/erosion) - Sex ratio: skewed toward young children of either sex for unintentional exposures; skewed toward females for intentional adult/adolescent poisoning - Geographic distribution: Reported globally; incidence and severity strongly modulated by product-packaging regulation, healthcare access, and cultural availability of iron supplements (notably relevant in regions with widespread maternal iron-supplementation programs)

Sources: UpToDate: Acute iron poisoning · Medscape: Pediatric Iron Toxicity · PubMed: Unit-dose packaging of iron supplements (PMID:15939855) · Journal of Population Therapeutics and Clinical Pharmacology: Suicidal Acute Iron Poisoning in Adolescent Females — A Case Series · PMC: Fatal Iron Toxicity in an Adult — Clinical Profile and Review

10. Diagnostics

Clinical/laboratory tests: - Serum iron level (peak, typically drawn 2–6 h post-ingestion): correlates with severity — - <300 µg/dL: mild/unlikely severe toxicity - 300–500 µg/dL: mild toxicological effects - 500–1000 µg/dL: moderate-to-severe toxicity (500 µg/dL is a classic threshold indication for deferoxamine) - >1000 µg/dL: death is common - Total iron-binding capacity (TIBC) — historically used but now considered unreliable in acute overdose (assay interference) - Serum glucose and WBC count — elevated values (glucose >150 mg/dL, WBC >15,000/µL) have been proposed as early surrogate markers correlating with significant ingestion, though sensitivity/specificity are limited - Arterial/venous blood gas — assesses metabolic (anion-gap) acidosis, a marker of systemic toxicity severity - Coagulation studies (PT/INR, PTT, fibrinogen) — assess iron-induced serine-protease inhibition and/or hepatic synthetic coagulopathy - Liver function tests — for Stage IV hepatotoxicity surveillance - Abdominal X-ray (KUB) — iron tablets are radiopaque; a positive film supports the diagnosis and guides need for whole bowel irrigation (WBI), though a negative film does not exclude significant ingestion (chewable/liquid formulations may not be radiopaque, and tablets may already have dissolved)

Diagnostic/clinical criteria: No formal DSM/ICD diagnostic-criteria instrument; diagnosis is clinical (history of ingestion + staged symptom pattern) supported by serum iron level and imaging.

Differential diagnosis: Other causes of anion-gap metabolic acidosis and toxic ingestion (salicylates, ethylene glycol, methanol), other causes of hematemesis/corrosive GI injury (caustic ingestion, NSAID gastropathy), sepsis/septic shock (can mimic Stage III), other causes of fulminant hepatic failure (acetaminophen, viral hepatitis).

Genetic testing: Not applicable/not indicated (no causal genetic variant).

Screening: No population screening program exists (this is an acute poisoning, not a chronic/heritable condition); the relevant "screening" analog is regulatory/product-based prevention (packaging, labeling) rather than clinical genetic or biochemical screening.

Suggested NCIT/LOINC anchors: serum iron (LOINC 2498-4), TIBC (LOINC 2500-7), abdominal X-ray (a radiologic procedure, NCIT-codable).

Sources: Medscape: Iron Toxicity — Workup · California Poison Control: Iron Ingestion · Iron Ingestion: Evidence-Based Consensus Guideline for Out-of-Hospital Management

11. Outcome / Prognosis

Mortality: With prompt recognition and treatment, outcomes for mild-to-moderate unintentional pediatric ingestions are generally good, and fatal pediatric ingestions have declined substantially since packaging/labeling regulation. However, severe (typically intentional, high-dose) ingestions carry substantial mortality: "A majority of acute iron toxicity cases [reaching severe multi-organ involvement] are fatal given the rapid progression to multi-organ failure" in reported case series, and reported US poison-control mortality remained at 2 deaths in 2022 among >5,300 reported iron exposures.

Morbidity: - Acute survivors of Stage III/IV disease may have prolonged ICU courses, need for liver transplantation in fulminant hepatic failure, and dialysis for acute kidney injury. - Delayed morbidity: gastric outlet obstruction/intestinal stricture (Stage V) can require reconstructive GI surgery (pyloroplasty, gastrojejunostomy, gastric resection) weeks to months after the acute event.

Prognostic factors: Elemental iron dose ingested, peak serum iron level, time-to-treatment (chelation), presence/severity of metabolic acidosis and shock at presentation, and development of hepatic failure.

Recovery potential: Generally favorable with early deferoxamine chelation in symptomatic-but-not-yet-shocked patients; poor once fulminant hepatic failure or refractory shock/coagulopathy develop.

Sources: PMC: Fatal Iron Toxicity in an Adult — Clinical Profile and Review · PMC: Liver Transplantation for Acute Hepatic Failure Following Intentional Iron Overdose · PubMed: Suicidal iron overdose — case report and review of literature

12. Treatment

Initial/supportive management: - Aggressive IV fluid resuscitation for hypovolemia/shock - Correction of metabolic acidosis and electrolyte abnormalities - Whole bowel irrigation (WBI) with polyethylene glycol solution (adults: 1–2 L/h; children: 25–40 mL/kg/h) when radiopaque tablets are visible on abdominal X-ray, continued until the film clears — though "existing data are still insufficient to support or exclude its efficacy" rigorously, it remains standard practice for radiographically confirmed significant ingestions. - Activated charcoal is NOT effective — it does not adsorb iron and should be given only if co-ingestants are suspected; concurrent WBI may further reduce charcoal's efficacy for those co-ingestants. - Endoscopic removal or, rarely, gastrotomy for large iron tablet bezoars/masses not clearable by WBI

Pharmacotherapy — chelation: - Deferoxamine (desferrioxamine) — the mainstay/first-line chelator for acute iron poisoning. Mechanism: high affinity for ferric (Fe³⁺) iron, forming the stable octahedral complex ferrioxamine, 1:1 molar binding, which is renally excreted (producing the classic "vin rosé"/rusty-red urine). Indications for IV infusion: significant clinical toxicity signs, metabolic acidosis, shock, serum iron >500 µg/dL, and/or radiographically visible tablet burden. Dosing: IV infusion starting at 15 mg/kg/h (not exceeding 1 g/h), typically over 6 hours with reassessment; hypotension is the main dose-limiting adverse effect, mitigated by ensuring adequate hydration first. - Oral chelators (deferiprone, deferasirox) — primarily used for chronic transfusional iron-overload states (e.g., thalassemia), not first-line for acute poisoning, though deferiprone has shown efficacy in animal models of acute iron overdose (decreased morbidity/mortality in rats) and limited human case reports (efficacy of oral deferiprone in acute iron poisoning) — these remain investigational/adjunctive for acute toxicology, with deferoxamine as standard of care given cost/access limitations of parenteral therapy being the main barrier globally.

Surgical/interventional: - Late complications (gastric outlet obstruction, pyloric/small-bowel stricture) may require surgical correction: Mikulicz (Heineke-Mikulicz) pyloroplasty, gastrojejunostomy, or gastric resection with Billroth I anastomosis. - Liver transplantation for fulminant hepatic failure refractory to medical management (reported in severe intentional overdoses).

Supportive/rehabilitative care: ICU-level monitoring, correction of coagulopathy (FFP/blood products as needed), dialysis for renal failure, nutritional support post-surgical GI reconstruction.

Experimental: Deferiprone as an oral alternative/adjunct for acute poisoning remains under investigation, particularly attractive in resource-limited settings lacking IV deferoxamine access.

Treatment outcomes/adverse events: Deferoxamine-induced hypotension (rate-related); rare deferoxamine-associated ARDS with prolonged high-dose infusion (a recognized but not detailed-in-this-search complication historically reported in the toxicology literature).

Suggested NCIT terms: NCIT:C15986 (Pharmacotherapy) with therapeutic_agent bound to CHEBI (deferoxamine — CHEBI:4058) or NCIT (deferoxamine, deferiprone, deferasirox); NCIT:C15329 (Surgical Procedure) for pyloroplasty/gastrojejunostomy/gastric resection; NCIT:C15289 (Organ Transplantation) for liver transplant; a WBI/decontamination procedure term (gastrointestinal decontamination) if a suitable NCIT concept exists.

Sources: ScienceDirect: Deferoxamine overview · Merck Manual: Iron Poisoning · Medscape: Pediatric Iron Toxicity Treatment & Management · PubMed: The efficacy of oral deferiprone in acute iron poisoning · PMC: Management of Acute Ferrous Sulfate Poisoning Using Activated Charcoal Monotherapy: A Case Report · PubMed: Gastrotomy and whole bowel irrigation in iron poisoning · PMC: A Review on Iron Chelators in Treatment of Iron Overload Syndromes

13. Prevention

Primary prevention: - Unit-dose (blister) packaging for iron-containing supplements/drugs with ≥30 mg elemental iron per dosage unit — mandated by 1997 FDA rule; associated with a marked drop in pediatric iron-poisoning deaths (reduced to essentially one reported US pediatric death 1998–2002). Note: the unit-dose packaging mandate was later withdrawn in 2003 following Nutritional Health Alliance v. FDA, which held the FDCA did not authorize FDA to regulate packaging specifically for poison prevention purposes — though label warning-statement requirements persisted. - Child-resistant containers (general Poison Prevention Packaging Act mechanisms) - Safe storage counseling for caregivers, particularly regarding prenatal vitamins and adult-strength ferrous sulfate

Secondary prevention: - Early recognition and prompt poison-control/ED evaluation after any known or suspected iron ingestion in a child, given the deceptive Stage II latent period - Abdominal radiography to assess ingestion burden and guide decontamination

Behavioral/public health interventions: - Poison control center public-awareness campaigns (e.g., 1-800 poison helpline) - Label warning statements on iron-containing products (bright-color tablet warnings, "keep out of reach of children") - For adolescent/adult intentional-ingestion risk: mental health screening and access-restriction counseling in at-risk populations (given the demographic skew toward young female self-harm)

Screening: No genetic/biochemical population screening applies; the closest analog is regulatory product-safety oversight rather than clinical screening.

Sources: FDA: Guidance for Industry — Iron-Containing Supplements and Drugs: Label Warning · Federal Register: Iron-Containing Supplements and Drugs; Removal of Unit-Dose Packaging Requirements · SAGE Journals: Iron Packaging Regulations in the United States and Pediatric Morbidity

14. Other Species / Natural Disease

Acute iron toxicity is well documented as an induced/experimental toxicology model rather than a naturally occurring veterinary disease entity in the OMIA sense. Relevant cross-species data:

Rats: LD50 estimates for ferrous sulfate vary widely by study — approximately 780–1,100 mg iron/kg body weight in one estimate, and up to 2.8 g/kg in another; ferrous sulfate heptahydrate showed no acute toxicity up to 2,000 mg/kg in some OECD-guideline studies. Comparator salts: ferrous chloride oral LD50 300–2,000 mg/kg (132–881 mg Fe/kg); ferric sulfate oral LD50 500–2,000 mg/kg (females). Repeated-dose/reproductive-developmental toxicity of ferrous sulfate heptahydrate has been assessed at 30–1,000 mg/kg/day in OECD combined study designs.
Mice: Used in classic iron-toxicity determination studies (e.g., "Determination of Iron Toxicity in Mice," ScienceDirect).
Young rats: Comparative acute toxicity of carbonyl iron and sodium iron EDTA vs. ferrous sulfate has been specifically studied, relevant to formulating safer pediatric iron products (carbonyl iron shows a substantially better safety margin than ferrous sulfate in this context).
Veterinary relevance: Accidental iron-supplement ingestion (e.g., companion animals ingesting human iron tablets/prenatal vitamins) is a recognized veterinary toxicology concern, paralleling the pediatric human scenario, though detailed OMIA/VetCompass-specific case data were not retrieved in this search.

Comparative biology: The core toxic mechanism — mucosal corrosion, NTBI-driven oxidative/mitochondrial injury, and coagulation-factor inhibition — is conserved across mammalian species, supporting rodent models as reasonably translatable for acute-toxicity dose-response and chelator-efficacy studies (e.g., deferiprone efficacy data derived from rat acute-overdose models).

Suggested NCBITaxon terms: NCBITaxon:9606 (Homo sapiens), NCBITaxon:10116 (Rattus norvegicus), NCBITaxon:10090 (Mus musculus).

Sources: OECD SIDS Initial Assessment Profile — Ferrous compounds · ResearchGate: Acute Toxicity of Carbonyl Iron and Sodium Iron EDTA Compared with Ferrous Sulfate in Young Rats · ScienceDirect: Determination of Iron Toxicity in Mice

15. Model Organisms

Rodent models (rat, mouse): The dominant experimental system for acute iron-toxicity research — used to establish LD50/dose-response relationships for various iron salts (ferrous sulfate, ferrous chloride, ferric sulfate, carbonyl iron, sodium iron EDTA), and to test chelator efficacy. Notably, oral deferiprone reduced morbidity and mortality in rat models of acute iron overdose, directly informing the human investigational use described above (§12).

Model characteristics: - Recapitulates key phenotypes: GI mucosal injury, systemic organ toxicity, mortality dose-dependence - Used to compare relative toxicity/safety margins of different iron formulations (informing safer pediatric supplement formulation design, e.g., carbonyl iron vs. ferrous sulfate) - Used for OECD-guideline repeated-dose and reproductive/developmental toxicity screening of iron salts

Limitations: Rodent GI anatomy/physiology and dosing-route pharmacokinetics differ from humans; LD50 estimates vary substantially between studies/rodent strains/iron salt forms, complicating direct extrapolation of a single "lethal dose" figure to humans (human thresholds are instead derived largely from case-series/poison-control data rather than allometric scaling from animal LD50s).

Applications: Dose-response characterization, chelator (deferoxamine, deferiprone) efficacy and pharmacokinetic testing, comparative formulation safety (carbonyl iron vs. ferrous salts) to inform pediatric product design and regulatory policy.

Resources: No dedicated genetically engineered (knockout/transgenic) mouse model is relevant here, since this is a toxic-exposure phenotype rather than a genetic disease — models are induced (dosing) rather than genetic.

Sources: PubMed: The efficacy of oral deferiprone in acute iron poisoning · ResearchGate: Acute Toxicity of Carbonyl Iron and Sodium Iron EDTA Compared with Ferrous Sulfate in Young Rats · OECD SIAM: Ferrous compounds SIDS assessment

Summary of Key Ontology Term Suggestions

Category	Terms
HPO	HP:0002013 Vomiting, HP:0002014 Diarrhea, HP:0002027 Abdominal pain, HP:0001649 Tachycardia, HP:0001257 Lethargy, HP:0011900 Metabolic acidosis, HP:0001928 Abnormal coagulation, HP:0006554 Acute hepatic failure, HP:0002583 GI obstruction
GO (BP)	GO:0055072 iron ion homeostasis, GO:0034614 cellular response to ROS, GO:0034599 cellular response to oxidative stress, GO:0006119 oxidative phosphorylation, GO:0097707 ferroptosis
GO (CC)	GO:0005739 mitochondrion
CL	Gastric/intestinal mucosal epithelial cell, hepatocyte, cardiomyocyte
UBERON	UBERON:0000945 stomach, UBERON:0002108 small intestine, UBERON:0002107 liver, UBERON:0000948 heart
CHEBI	CHEBI:29033 Fe(II), CHEBI:29034 Fe(III), CHEBI:75771 ferrous sulfate, CHEBI:4058 deferoxamine
NCIT	NCIT:C15986 Pharmacotherapy (deferoxamine), NCIT:C15329 Surgical Procedure, NCIT:C15289 Organ Transplantation
NCBITaxon	NCBITaxon:9606 (human), NCBITaxon:10116 (rat), NCBITaxon:10090 (mouse)

Notes on evidence gaps

This report identified no MONDO/OMIM identifier specifically dedicated to acute iron poisoning as distinct from chronic iron-overload disorders — a curator populating a dismech-style entry should likely model this as an environmental/toxic-exposure disease entity (paralleling entries like Arsenic_Poisoning) rather than force-fitting it to a hereditary-iron-overload MONDO branch. Quantitative QoL data, detailed genetic-modifier studies, and single-cell/omics profiling specific to acute iron poisoning were not found and are likely genuinely sparse in the literature (this is predominantly a clinical-toxicology/emergency-medicine literature base rather than a molecular-genetics one).

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	19
On topic	7
Off topic	0

All extracted references resolved successfully.

Iron Poisoning

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Iron Poisoning (Acute Iron Toxicity) — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

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 Key Ontology Term Suggestions

Notes on evidence gaps

Reference Validation