Acute iron poisoning

INTRODUCTION — The epidemiology, pharmacology, clinical manifestations, evaluation, and management of poisoning after acute iron ingestion and iatrogenic intravenous (IV) iron overdose are reviewed here. Iron deficiency, iron requirements, and iron balance are discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents" and "Regulation of iron balance".)

EPIDEMIOLOGY — Almost 11,000 iron exposures in children younger than six years of age are reported annually in the United States [1]. The overall number of exposures in this age group is decreasing. In addition, the number of major effects and death in children are improved when compared with the period from 1990 to 2000. However, mortality due to both unintentional and intentional iron ingestions still occurs, pointing to the potential significant toxicity of iron supplements [1].

The epidemiology varies significantly by the type of ingestion:

●Unintentional ingestion – The vast majority of childhood iron poisonings are unintentional and result in no or minimal toxicity. The most serious exposures involve prenatal vitamins and pure iron preparations that contain ferrous sulfate tablets, which typically have significantly more elemental iron per tablet (60 to 65 mg) than other iron preparations. These tablets appeal to children because they are often brightly colored, are sugar coated, and have the appearance of candy [2-5]. In one population-based case-control study, the birth of a sibling within six months was identified as a risk factor for iron poisoning in children younger than three years of age (adjusted odds ratio [aOR] 1.9, 95% CI 0.9-3.9); the risk was greatest within the first postpartum month (aOR 3.6, 95% CI 0.8-16.5) [5].

Children's chewable vitamins with iron are less likely than adult preparations to cause serious toxicity. There were no fatalities among 195,780 exposures to chewable children's vitamins with iron reported by the American Association of Poison Control Centers between 1983 and 1998 [6]. During the same time period, there were 60 deaths among 147,079 ingestions of adult preparations containing iron. (See 'Ingestion of chewable vitamins' below.)

Although the majority of patients treated for iron ingestion in health care facilities experience some toxicity, there has been a reduction in the number of fatalities from unintentional exposures [7,8]. This reduced fatality rate has been attributed to the implementation of preventive measures, particularly unit dose packaging, which followed several highly publicized deaths [2,8,9]. These regulations were unfortunately withdrawn in 2003 [10]. (See "Prevention of poisoning in children", section on 'Primary prevention'.)

As with most unintentional ingestions, the best therapy is prevention. Child-resistant closures are required on vitamin bottles that contain more than 250 mg of elemental iron. Nevertheless, some intoxications involve packages or containers that are left open, improperly closed, or opened by a child [2,3]. All medications should be kept in a safe place and stored in their original packaging or in child-resistant containers. Caregivers of children should be instructed to call their regional poison control center (1-800-222-1222) in the event of ingestion.

●Intentional ingestion – The epidemiology of intentional iron overdose differs from that of unintentional ingestion. In one institutional review of 113 cases of iron overdose requiring hospital admission, 58 percent were determined to be intentional (based upon information provided by the patient, family/caregivers, or friends) [11]. Among the intentional ingestions, 80 percent occurred among females, with a mean age of 19.8 years. The mortality rate is increased among patients with intentional ingestion (10 percent in this series versus less than 1 percent for unintentional iron ingestions).

●Intravenous (IV) iron overdose – IV iron overdoses are rare and reflect dosing errors during routine administration [12-15].

PHARMACOLOGY

Iron preparations

Oral — Oral iron preparations are available most commonly in the form of iron salts. The amount of elemental iron in each preparation varies depending upon the salt form (table 1) [16]:

●Ferrous gluconate (12 percent elemental iron)

●Ferrous sulfate (20 percent elemental iron)

●Ferrous fumarate (33 percent elemental iron)

Time-release formulations or enteric-coated iron preparations are available and may have delayed absorption. This is an important consideration when interpreting serum iron levels (SILs). (See 'Serum iron level interpretation' below.)

Iron is an ingredient in many multiple-vitamin preparations. Prenatal vitamins typically contain 60 to 65 mg of elemental iron, whereas most multivitamin preparations contain 15 to 18 mg (table 2). The "placebo" row of some 28-day oral contraceptive pill packages may contain iron and is another potential source for accidental ingestion (eg, the placebo row of Loestrin Fe and Estrostep Fe each contain 75 mg of ferrous fumarate [25 mg elemental iron]).

Nonionic forms of iron include carbonyl iron and iron polysaccharide complex. Carbonyl iron is produced by vaporizing submicroscopic spheres of uncharged, highly purified metallic iron (Feº). Feº must be converted to ferrous iron (Fe2+) by gastric acid before it can be absorbed. As a result, carbonyl iron is absorbed more slowly and has a higher bioavailability than ferrous sulfate. In addition, it has a greater safety margin than ferrous sulfate. There have been no published reports of serious or fatal poisoning from ingestion of carbonyl iron [17].

Iron polysaccharide complex is produced by the neutralization of ferric chloride-carbohydrate solution. It contains 46 percent elemental iron by weight and appears to be less toxic than ferrous salts. In one large retrospective series of iron polysaccharide complex overdose, there were no major effects or deaths reported [18].

Intravenous — High-molecular-weight (HMW) iron dextran was the first available formulation for intramuscular and intravenous (IV) administration, but its use was limited by a high incidence of serious adverse effects, specifically anaphylactic reactions. Several other IV iron compounds have subsequently been developed as safer alternatives to HMW iron dextran (table 3):

●Ferric carboxymaltose

●Ferric gluconate

●Ferumoxytol

●Iron sucrose

●Low-molecular-weight iron dextran

These IV iron preparations are formulated to release iron slowly over many hours to many days. With all of these IV formulations, the iron is tightly bound to carbohydrate carriers, which is important when interpreting SILs because the iron level obtained does not reflect free, circulating iron. (See 'IV iron overdose' below.)

The use of these preparations for the treatment of iron deficiency are discussed in greater detail separately. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron' and "Iron deficiency in infants and children <12 years: Treatment", section on 'Intravenous iron therapy'.)

Toxic dose — The toxic dose of iron is determined by the route of exposure and the iron formulation:

●Oral – The toxicity of oral iron depends upon the amount of elemental iron ingested. Various salt forms contain different percentages of elemental iron (table 1 and table 2) (see 'Iron preparations' above). As an example, a 15-kg child who ingests 10 tablets, each containing 325 mg of ferrous sulfate, has taken about 43 mg/kg of elemental iron.

The minimum toxic dose and the lethal doses of oral and IV iron are not firmly established. The following symptoms and toxicities have been reported at various doses:

•Patients who ingest less than 20 mg/kg of elemental iron are usually asymptomatic.

•Ingestions of 20 to 60 mg/kg of elemental iron have a low potential for serious toxicity.

•A small number of patients who have taken 40 to 60 mg/kg of elemental iron are symptomatic. In one retrospective review of 199 acute iron exposures, none of the patients who ingested between 40 and 60 mg/kg of iron developed serious toxicity [19].

•Ingestions ≥60 mg/kg of elemental iron are associated with serious toxicity and death [2,16,20,21].

●IV – Because of their unique structure, which reduces the potential for unbound iron in the circulation, IV iron preparations appear to have a lower likelihood of toxicity than oral preparations [22,23]. For example, in mice, the median lethal dose (LD₅₀) ranges from 155 to >1000 mg/kg elemental iron, depending upon the specific compound [23].

Iron toxicity — Ferric iron (Fe3+) is toxic to many cellular processes. The primary mechanism for iron-induced tissue damage is free radical production and lipid peroxidation [24]. Toxic effects on cells include the following [16,20,25,26]:

●Mucosal cell necrosis

●Impairment of capillary permeability

●Alteration of the lipid membrane of mitochondria

●Inhibition of enzymatic processes in the Krebs cycle

●Uncoupling of oxidative phosphorylation

●Direct vasodilation

●Inhibition of serum proteases (eg, thrombin)

Normally, transferrin (the chief iron-binding protein in plasma) and ferritin (an iron-storage protein that sequesters iron intracellularly) protect cells by binding iron, limiting the amount that is circulating in the ferric state. However, these protective mechanisms become quickly overwhelmed with an acute intoxication [27].

After iron ingestion, local toxicity (manifested as abdominal pain, vomiting, diarrhea, and gastrointestinal [GI] bleeding) develops from iron-induced damage to the GI mucosa. Systemic toxicity occurs as the result of injury to the cardiovascular system and liver. The cause of death from iron poisoning is usually shock or liver failure [24]. (See 'Clinical manifestations' below.)

Kinetics — Iron kinetics vary according to the route of administration:

●Oral – Iron is absorbed primarily in the duodenum and upper jejunum. It crosses cell membranes only in the ferrous state (Fe2+). Once absorbed by the mucosal cells, iron is oxidized to the ferric (Fe3+) form. From the enterocyte, iron is released into the plasma and bound to transferrin.

After therapeutic dosing, 10 to 35 percent of iron is absorbed. As much as 80 to 95 percent may be absorbed in iron-deficient patients [24,27]. The absorption of enteric-coated preparations is less than that of non-enteric-coated preparations.

The amount of iron that is absorbed in an overdose situation is unknown [25]. Physiologic regulation of iron absorption is lost in the setting of excessive iron ingestions. In addition, normal protective mechanisms (transport and storage proteins) become saturated, resulting in more free-circulating iron (which is responsible for cellular toxicity).

Peak SILs occur two to three hours after therapeutic dosing and four to six hours after ingestion of an overdose [24].

Absorbed iron is rapidly cleared from the circulation and taken up by the cells of various tissues, where high concentrations of iron disrupt mitochondrial function [26,28]. For the most part, entry of iron into the tissues is an active, saturable process; the liver is unique in that it also can passively absorb iron [29,30]. Because of the liver's capacity to absorb considerable quantities of iron, the half-life of iron after therapeutic and toxic dosing is similar (approximately six hours) [24].

There are no physiologic mechanisms for iron excretion. Iron may be lost via the constant sloughing of intestinal cells, as well as menstrual bleeding in menarchal women.

●Parenteral – IV formulations are made up of complexes of iron and carbohydrate nanoparticles that keep the iron compound stable until it is delivered to macrophages in the reticuloendothelial system that are primarily located in the liver, spleen, and bone marrow. There, the iron is released over time according to the specific iron compound and then either stored in the cytoplasm or transported by transferrin for incorporation into hemoglobin [23]. The iron-carbohydrate complex is kinetically robust for all formulations except for ferric gluconate. Kinetically robust compounds are less likely to rapidly release ferric iron (Fe3+) and exceed transferrin-binding capacity. These compounds also permit large doses (eg, up to 2 g for iron isomaltoside) and infusion times as short as 15 to 20 minutes [22,23].

CLINICAL MANIFESTATIONS — The manifestations of iron toxicity after ingestion are typically described in five (often overlapping) phases (table 4) [16,19-21]:

●Early gastrointestinal (GI) symptoms: 30 minutes to 6 hours after ingestion

●Latent (or relative stability): 6 to 24 hours after ingestion

●Shock and persistent elevated anion gap metabolic acidosis: 6 to 72 hours after ingestion

●Delayed hepatotoxicity/hepatic necrosis: 12 to 96 hours after ingestion

●Remote bowel obstruction (usually gastric outlet obstruction): 2 to 8 weeks after ingestion

The progression of these phases may occur rapidly after large oral overdoses. Therefore, the clinical phase should be determined by the patient's clinical and laboratory manifestations, not by the time since the ingestion:

●Gastrointestinal phase – The GI phase occurs between 30 minutes and 6 hours after ingestion. The clinical manifestations of this phase are the result of direct injury to the GI mucosa. Signs and symptoms may include abdominal pain, vomiting, diarrhea, hematemesis, melena, lethargy, shock (from capillary leak and third spacing), and metabolic acidosis. Vomitus and stools may be dark gray, green, or black due to the presence of disintegrating iron tablets. Vomiting is the most sensitive indicator of serious ingestions. Death in this phase is usually caused by hypovolemic shock [31].

Most patients with mild to moderate iron toxicity do not progress beyond this phase, and their symptoms may resolve within four to six hours. If no GI symptoms develop within six hours of a presumed iron ingestion, it is unlikely that iron toxicity will occur. Ingestion of enteric-coated iron tablets is an exception to the "six-hour rule."

●Latent phase – The latent phase (sometimes also referred to as the "relative stability" or "quiescent" phase) occurs from 6 to 24 hours after ingestion and is a period of apparent recovery. The resolution of GI symptoms is presumed to occur as circulating free iron is redistributed into the reticuloendothelial systems.

This phase may be transient or may not appear at all in patients with severe iron poisoning. Patients appear stable, but they may not be asymptomatic. Careful evaluation may reveal poor perfusion, hyperventilation (secondary to metabolic acidosis), and oliguria (secondary to hypovolemia) [24].

It is critical to differentiate patients who are in this phase from those with low-toxicity ingestions who have exhibited only mild GI symptoms and for whom toxicity has now resolved. Patients whose GI symptoms have improved should be observed and re-evaluated to determine whether they have truly recovered or are progressing to further clinical deterioration.

●Shock and metabolic acidosis – Cardiovascular toxicity (manifested as shock, pallor, tachycardia, and/or hypotension) may develop. Coagulopathy (preceding liver dysfunction) can occur because of iron's effect (as a protease inhibitor) on prothrombin [32,33].

The etiology of the shock state may be hypovolemic, distributive, or cardiogenic, depending on the time of onset [24]:

•Hypovolemic shock, due to fluid and blood losses, occurs within the first few hours.

•Distributive shock develops a few hours later. The etiology is poorly understood. Decreased vascular tone and increased vascular permeability may be caused primarily by iron or possibly ferritin.

•Cardiogenic shock develops within 24 to 48 hours after the ingestion due to the depressant effect of iron on myocardial cells.

Metabolic acidosis is often profound and is an indicator of iron-induced toxicity. It is caused, at least in part, by hydration of absorbed ferric ions, which releases three protons (Fe3⁺ + 3H2O —> Fe(OH)³ + 3H⁺) [24]. Lactic acidosis may also occur as the result of hypovolemia/poor tissue perfusion and iron-induced mitochondrial dysfunction.

The following clinical features, leading to multisystem organ failure, can be seen in the shock and metabolic acidosis phase:

•GI hemorrhage, with hematemesis and melena, may recur. Bowel perforation may develop.

•Progressive pulmonary dysfunction (acute lung injury or the acute respiratory distress syndrome) is a distinguishing characteristic of this phase. The etiology likely includes free radical production, causing capillary leak, along with hypotension and metabolic acidosis.

•An iron-induced coagulopathy may worsen bleeding and hypovolemia.

•Renal and neurologic dysfunction can develop during this phase.

Patients may develop jaundice, coma, and worsening coagulopathy from hepatic dysfunction. Death in this third phase is caused by widespread cellular dysfunction, which results from mitochondrial disruption [31]. Once a critical amount of iron has reached the mitochondria, therapy has little effect and outcome is poor.

●Hepatotoxicity/hepatic necrosis – The onset of hepatotoxicity is usually within two days of ingestion. Although hepatic necrosis does not occur in all iron-poisoned patients, it may develop within 12 to 96 hours after ingestion. The liver is particularly vulnerable to iron toxicity for several reasons: it is exposed to high concentrations of iron through the portal circulation, it absorbs iron passively, and hepatocytes have high metabolic activity. Liver failure is the second most common cause of death from iron poisoning.

●Bowel obstruction – Bowel obstruction occurs as the result of GI scarring. Symptoms typically develop two to eight weeks after the ingestion. The classic location for GI obstruction is the gastric outlet, since this is where iron tablets aggregate and damage tissue, with subsequent scar tissue formation [24,34]. Vomiting is the presenting symptom of this late sequela.

Serious iron toxicity from iatrogenic overdose of intravenous (IV) iron preparations, while theoretically possible, has not occurred despite overdoses of up to 10 times normal dosing. (See 'IV iron overdose' below.)

EVALUATION

Approach — Evaluation and management of acute iron ingestion is provided in the algorithms for symptomatic and asymptomatic patients (algorithm 1A-B) and the rapid overview table (table 4).

Although iatrogenic overdoses involving intravenous (IV) iron preparations have occurred, serious poisoning has not been described. (See 'IV iron overdose' below.)

Stabilization — Patients who require resuscitation must be rapidly identified, and receive appropriate treatment including airway protection, respiratory support, and volume resuscitation. (See "Approach to the child with occult toxic exposure", section on 'Initial evaluation and stabilization'.)

Patients with moderate to severe iron poisoning often require fluid resuscitation with isotonic crystalloid (eg, normal saline) for hypovolemic shock during the early phases of treatment. (See "Hypovolemic shock in children in resource-abundant settings: Initial evaluation and management" and "Treatment of severe hypovolemia or hypovolemic shock in adults".)

History — The following historical information is essential for determining the significance of an iron ingestion and directing further management:

●What type of iron was taken, and how much? One determinant of the severity of an overdose is the mg/kg of elemental iron that was ingested and the formulation of iron. What was the specific IV iron preparation? (See 'Iron preparations' above and 'Toxic dose' above.)

●When did the ingestion occur? Symptoms of iron intoxication generally develop soon after the ingestion. Patients who have not developed symptoms within six hours are unlikely to have ingested a significant amount of iron unless they have ingested an enteric-coated preparation.

●Was the ingestion unintentional or intentional? An intentional ingestion, whether as a suicide attempt/gesture or as a form of child abuse, is more likely to be significant [35]. (See 'Epidemiology' above.)

●Did the patient have access to other toxic substances? For children, are there other children at home who could have also ingested iron [20]?

Physical examination — Initial physical findings of iron poisoning include:

●Tachycardia with poor peripheral perfusion (prolonged capillary refill time and/or diminished pulses); hypotension reflects uncompensated hypovolemic shock

●Tachypnea due to metabolic acidosis with lungs clear to auscultation

●Epigastric abdominal tenderness with vomiting and diarrhea; hematemesis and/or melena may also be present

●Lethargy or coma

Subtle findings, including signs of poor perfusion (such as lethargy and tachycardia), metabolic acidosis (tachypnea), or gastrointestinal (GI) symptoms (abdominal tenderness, persistent vomiting, or diarrhea) may identify a patient with a significant ingestion who has progressed to the latent phase. (See 'Clinical manifestations' above.)

Laboratory studies — The purpose of the laboratory evaluation is to confirm the diagnosis of iron poisoning and to monitor for clinical effects (such as metabolic acidosis, liver injury, coagulopathy, and anemia).

Symptomatic patients — Symptomatic patients require the following laboratory studies according to the degree of poisoning (algorithm 1A) [3,16,28]:

●Mild poisoning (nausea, self-limited vomiting, and/or mild abdominal pain):

•Plasma glucose

•Serum electrolytes

•Blood urea nitrogen (BUN) and creatinine

•Venous or arterial blood gas

•Peak serum iron level (SIL) (see 'Serum iron level interpretation' below):

-Four to six hours after ingestion of regular iron

-Eight hours after ingestion of extended-release iron  

●Moderate to severe poisoning (persistent vomiting, hypovolemic shock, and/or altered mental status [lethargy or coma]):

•All studies as above for mild poisoning and

•Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin

•Complete blood count (CBC) with differential

•Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR)

•Type and screen if clinical evidence of bleeding

All symptomatic patients should also undergo an emergency plain radiograph of the abdomen. (See 'Plain radiograph of the abdomen' below.)

An elevated anion gap metabolic acidosis is an important but nonspecific predictor of iron toxicity and is an indication for treatment with deferoxamine. (See 'Deferoxamine' below.)

Although leukocytosis (white blood cell count >15,000 cells/microL) and hyperglycemia (>150 mg/dL) are associated with SILs greater than 300 mcg/dL, they are nonspecific [36,37]. More importantly, the absence of leukocytosis or hyperglycemia cannot be used to exclude iron toxicity.

Of note, total serum iron binding capacity (TIBC) should not be used to manage patients with iron overdose [9]. TIBC measures the amount of iron in the blood that can be bound to transferrin. In theory, there should be no free iron when TIBC is greater than the SIL. However, laboratory methods used to measure TIBC are inaccurate in patients with iron overdose. In addition, deferoxamine interferes with the measurement of TIBC. Finally, multiple case reports have described iron toxicity in cases where the TIBC was greater than SIL [38-40].

Asymptomatic patients — All asymptomatic patients who present to the emergency department and have ingested more than a trivial amount of iron require observation for the development of symptoms and measurement of a peak SIL (algorithm 1B) (see 'Serum iron level interpretation' below):

●Regular iron: Four to six hours after ingestion

●Extended-release iron: Eight hours after ingestion

In addition to a SIL, asymptomatic patients at risk for toxicity (ingestion of an unknown amount of iron, an estimated dose ≥40 mg/kg elemental iron, or an intentional ingestion) also require prompt measurement of the following laboratory studies at the time of presentation [3,16,28]:

●Plasma glucose

●Serum electrolytes

●BUN and creatinine

●Venous or arterial blood gas

These patients should also undergo an emergency plain radiograph of the abdomen. (See 'Plain radiograph of the abdomen' below.)

Asymptomatic patients with a peak SIL ≥500 mcg/dL (90 micromol/L) or the presence of a high anion gap metabolic acidosis require treatment with deferoxamine (see 'Deferoxamine' below) and measurement of the following:

●ALT, AST, and total bilirubin

●CBC with differential

●PT, PTT, and INR

Serum iron level interpretation — Measurement of a peak SIL is useful for confirming the diagnosis of iron ingestion. It may also be helpful in predicting serious toxicity but only if blood samples are drawn at the appropriate time: four to six hours after ingestion of regular iron formulations and eight hours after ingestion of extended-release iron [21,24]. Because iron is rapidly cleared from the serum, levels obtained after eight hours may be deceivingly low. Interpretation of iron levels after iatrogenic IV iron overdose is discussed separately. (See 'IV iron overdose' below.)

Peak SILs typically correlate with the following levels of toxicity after oral iron overdose:

●Less than 350 mcg/dL (63 micromol/L) – Minimal toxicity

●Between 350 and 500 mcg/dL (63 and 90 micromol/L) – Mild to moderate GI symptoms (rarely develop serious complications) [3]

●Greater than 500 mcg/dL (90 micromol/L) – Serious systemic toxicity

●Greater than 1000 mcg/dL (179 micromol/L) – Significant morbidity and mortality [16,20,21,38,41]

However, the correlation of SIL with the severity or the clinical phase of iron intoxication is not exact because it measures free iron circulating in the blood. It is intracellular iron that causes systemic toxicity. Several retrospective series have reported patients with SILs greater than 500 mcg/dL (90 micromol/L) who were asymptomatic, as well as patients with cardiovascular instability with SILs less than 500 mcg/dL (90 micromol/L) [19,38,41]. These lower levels may not have represented peak SILs. Although iron is rapidly absorbed, absorption from the ingestion of sustained-release tablets, enteric-coated tablets, or ongoing release of iron from concretions of pills may be delayed. These reports illustrate the fact that there is no test (including SIL) that is superior to the clinical status of the patient for determining the severity of an iron ingestion.

Previously, the deferoxamine challenge test was proposed as an alternative method of identifying the presence of circulating ferric iron. It consisted of administering an intramuscular dose of deferoxamine and waiting to see if the patient developed "vin rosé" or brick iron urine indicating the presence of ferrioxamine that is created by binding of deferoxamine to free iron. However, multiple reports have identified patients with an SIL greater than 500 mcg/dL whose urine did not change color with deferoxamine [42]. Thus, the deferoxamine challenge test is no longer recommended to confirm the ingestion of a toxic dose of iron or to guide management.

Plain radiograph of the abdomen — In addition to laboratory studies (see 'Laboratory studies' above), the following patients require a plain anterior-posterior (AP) radiograph of the abdomen:

●Any symptoms of poisoning

●Ingestion of an unknown amount of iron or estimated ingestion of more than 40 mg/kg of elemental iron

●Intentional ingestion of iron

The presence of radiopaque pills in the stomach confirms the ingestion of iron (image 1) and is used to determine further management (algorithm 1B and algorithm 1A). (See 'Gastrointestinal decontamination' below.)

The radiopacity of iron tablets depends on the type of formulation and content of elemental iron. Many liquid iron preparations and chewable vitamins with iron (which have low concentrations of iron) are not visible. Consequently, the presence of few or no pills does not necessarily mean that the ingestion was insignificant. This was demonstrated in a retrospective review describing 93 children with iron ingestions (55 percent chewable tablets, 40 percent non-chewable tablets). Abdominal radiographs were obtained in 54 patients [43]. Radiopaque densities were visualized in only one case.

Patients with a significant iron overdose who have no radiopaque pills seen on plain radiograph are unlikely to benefit from GI decontamination [44-46]. (See 'Gastrointestinal decontamination' below.)

DIAGNOSIS — The diagnosis of iron poisoning is suspected based upon a history of iron ingestion and clinical manifestations of poisoning such as persistent vomiting and diarrhea, hypovolemic shock, altered mental status, and/or unexplained metabolic acidosis. It is confirmed by the presence of visible iron pills on plain abdominal radiograph or a peak serum iron level (SIL) ≥500 mcg/dL (90 micromol/L). A peak SIL also helps to identify the level of expected toxicity after an oral overdose and guides management decisions. (See 'Serum iron level interpretation' above.)

DIFFERENTIAL DIAGNOSIS — Other agents that can cause vomiting with toxic ingestion include salicylates, theophylline, caustic agents, isopropanol, arsenic and mercurial salts, organophosphate and carbamate compounds, nicotine, nonsteroidal antiinflammatory drugs (NSAIDs), mushrooms, and colchicine [16]. In many instances, the history helps to distinguish iron from these toxins. When history is lacking, an elevated peak serum iron level (SIL; ≥500 mcg/dL [90 micromol/L]) identifies iron as the cause of serious toxicity. In addition, characteristic signs other than vomiting and, with selected agents, laboratory findings, help to distinguish these poisons from iron:

●Salicylates – Elevated plasma salicylate concentration, especially when associated with hyperthermia and hyperventilation (see "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation")

●Theophylline – Elevated theophylline level, especially when associated with seizures and tachyarrhythmias (see "Theophylline poisoning")

●Organophosphates or carbamates – Muscarinic signs in addition to vomiting and diarrhea (ie, bronchorrhea, bronchospasm, bradycardia, miosis, or excessive tearing and oral sections), cardiac arrhythmias, muscle fasciculations with weakness, and seizures in association with decreased red blood cell acetylcholinesterase (see "Organophosphate and carbamate poisoning")

●Nicotine – Muscarinic signs in addition to vomiting and diarrhea (ie, bronchorrhea, bronchospasm, bradycardia, miosis, or excessive tearing and oral sections), seizures, muscle weakness, and rhabdomyolysis (see "Nicotine poisoning (e-cigarettes, tobacco products, plants, and pesticides)", section on 'Clinical features of poisoning')

●NSAIDS – Serious toxicity occurring only after very large ingestions and consisting of anion gap metabolic acidosis, depressed mental status, and cardiac arrhythmia (see "Nonsteroidal antiinflammatory drug (NSAID) poisoning")

●Mushrooms – History of mushroom ingestion with vomiting followed by characteristic mushroom syndrome (table 5) (see "Clinical manifestations and evaluation of mushroom poisoning")

●Colchicine – History of colchicine ingestion (medication or plant) associated with onset of multisystem organ failure (see "Potentially toxic plant ingestions in children: Clinical manifestations and evaluation", section on 'Gastroenteritis with systemic toxicity')

Iron poisoning should also be considered for patients who present with vomiting, abdominal pain, and an elevated anion gap metabolic acidosis without an obvious medical cause, even in the absence of a history of ingestion. The approach to metabolic acidosis, including causes of elevated anion gap metabolic acidosis, are discussed separately. (See "Approach to the child with metabolic acidosis" and "Approach to the adult with metabolic acidosis".)

MANAGEMENT — The management of iron poisoning after acute ingestion is determined by the presence of and degree of symptoms on initial presentation and is provided in the algorithms for symptomatic and asymptomatic patients (algorithm 1A and algorithm 1B)and the rapid overview (table 4).

Moderate to severe poisoning — Patients at risk for serious systemic toxicity should receive treatment to limit further absorption of iron. Indications of potential serious toxicity include the following:

●Ingestion of ≥60 mg/kg of elemental iron by history or based upon pills visible on plain radiograph of the abdomen

●Peak serum iron level (SIL) ≥500 mcg/dL (90 micromol/L)

●Persistent serious symptoms such as vomiting, diarrhea, and/or altered mental status

●Systemic symptoms, including subtle symptoms that can be seen in the latent phase, such as tachycardia, poor perfusion, tachypnea, and/or hypotension (see 'Clinical manifestations' above)

SIL may not be rapidly available at some institutions. In this situation, the decision to proceed with aggressive gastrointestinal (GI) decontamination and/or initiate deferoxamine therapy must be made based on the amount of elemental iron ingested, presence of systemic symptoms, and findings on abdominal radiograph. (See 'Gastrointestinal decontamination' below and 'Deferoxamine' below.)

Systemic symptoms must be distinguished from local GI symptoms. Many patients with SILs <500 mcg/dL (90 micromol/L) may have some abdominal pain, vomiting, and/or diarrhea as the result of GI irritation. In contrast to systemic symptoms, GI symptoms generally do not require fluid resuscitation, although smaller children may develop significant, protracted vomiting and diarrhea. (See 'Mild poisoning' below.)

Supportive care — Airway protection and respiratory support should be provided as needed. (See "Approach to the child with occult toxic exposure", section on 'Initial evaluation and stabilization'.)

Volume resuscitation to maintain euvolemia is essential. Hypovolemic shock is the major cause of mortality during the first phase of iron intoxication. Patients who present with severe GI-phase symptoms require urgent intensive management to maintain effective circulating blood volume [3,31] (see 'Clinical manifestations' above). Intravenous (IV) access should be obtained. Normal saline should be administered in boluses of 20 mL/kg as necessary to improve perfusion and tachycardia, and to maintain blood pressure. (See "Hypovolemic shock in children in resource-abundant settings: Initial evaluation and management".)

Although uncommon, patients with serious upper GI bleeding warrant consultation with a pediatric gastroenterologist and serial measurement of hemoglobin to determine the need for transfusion therapy. (See "Approach to upper gastrointestinal bleeding in children".)

Patients who require supportive care as the result of iron ingestion are likely experiencing significant toxicity. Further evaluation and treatment are necessary. (See 'Evaluation' above and 'Deferoxamine' below and 'Gastrointestinal decontamination' below.)

Gastrointestinal decontamination — Because iron does not bind to activated charcoal, GI decontamination for acute iron poisoning consists of whole-bowel irrigation (WBI) and, rarely, orogastric lavage or other means (eg, upper endoscopy or gastrotomy) to remove large numbers of iron pills from the stomach as determined by pills seen on plain abdominal radiograph (algorithm 1A and algorithm 1B) [9]:

●Orogastric lavage – In most patients, the risk of gastric lavage following iron overdose outweighs the limited benefit. However, orogastric lavage with normal saline via a large-bore orogastric tube may be indicated for patients with moderate to severe iron poisoning and large amounts of iron still unabsorbed in the stomach (eg, 20 to 30 pills visible on abdominal radiograph). Gastric lavage carries a significant risk of complications including aspiration, esophageal or gastric perforation, and laryngospasm. Patients who cannot protect their airway require rapid sequence intubation prior to the procedure. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)

A repeat radiograph should be obtained to evaluate the efficacy of gastric evacuation and to determine whether further decontamination measures are necessary.

●WBI – GI decontamination with WBI has the potential to remove iron from the intestine before absorption and tissue uptake can occur [44]. We suggest WBI rather than no GI decontamination for the following patients in whom the amount of unabsorbed iron based upon the number of pills seen on radiograph and the elemental iron content of the product ingested (table 1 and table 2) has the potential for worsening toxicity based upon patient weight (see 'Toxic dose' above):

•Symptoms of moderate to severe iron poisoning

•High anion gap metabolic acidosis

•Peak SIL ≥500 mcg/dL (90 micromol/L)

•Patients who have a continued rise in SILs despite administration of deferoxamine

•Asymptomatic or mildly symptomatic patients with an estimated ingested dose ≥60 mg/kg elemental iron based on the number of visible pills on radiograph.

The procedure for performing WBI, as well as the contraindications and complications, is described separately (see "Gastrointestinal decontamination of the poisoned patient", section on 'Whole bowel irrigation'). In patients with iron poisoning, effective WBI requires placement of a nasogastric tube, control of emesis, and concomitant management of shock. Serial abdominal radiographs (eg, every 12 hours) during WBI may be useful in determining the efficacy of WBI. The endpoints of treatment are improved clinical status, a clear rectal effluent, and the absence of iron tablets or significantly decreased number of tablets seen on repeat abdominal radiograph [44].

Case reports and case series have described improved outcomes for patients with iron poisoning who received WBI [9,47-50]. Most of the patients also received deferoxamine therapy. Consequently, the effect of WBI, independent of deferoxamine, is difficult to ascertain. On the other hand, there have been no reports of significant complications from WBI. Patients with vomiting and an unprotected airway are at risk of aspiration, but this has not been reported as a direct result of WBI.

●Upper GI endoscopy or surgical gastrotomy – Iron tablets may become embedded in the gastric wall, forming bezoars or pseudo-concretions that are resistant to lavage and/or WBI. In such cases, endoscopy or surgical gastrotomy may have benefit, especially when clinical toxicity persists. Case reports have described surgical removal of iron from the stomach (gastrotomy) for pill concretions that could not be removed with other methods of GI decontamination [51,52]. Endoscopic removal of a large number of pills or pill concretions may also be attempted, providing an alternative to a major surgical operative procedure. Chelation therapy along with supportive care should continue.

●Treatments to avoid – Other forms of GI decontamination that should not be performed after iron overdose include:

•Activated charcoal because it binds iron poorly and is ineffective

•Syrup of ipecac to induce vomiting because it is ineffective in general, and iron ingestion frequently causes spontaneous vomiting (see "Gastrointestinal decontamination of the poisoned patient", section on 'Outdated treatments')

•Gastric lavage with bicarbonate or phosphate solutions because of the large volume of bicarbonate necessary to achieve effect and reports of phosphate poisoning [20,53-56]

•Gastric lavage with deferoxamine because of the large volumes required in an overdose to have any appreciable effect

•Catharsis via the administration of magnesium-containing preparations (eg, milk of magnesia) because it is ineffective [21,57]

Deferoxamine — IV deferoxamine is the antidote of choice for serious iron overdose. It is a chelating agent that, in acute iron intoxication, binds with ferric iron (Fe3+) in the blood to form water-soluble ferrioxamine that is then excreted by the kidneys. Ferrioxamine gives urine the classically described "vin rosé" color, which appears as orange to reddish brown. Deferoxamine must be administered early in the treatment, preferably as soon as the potential for serious poisoning is recognized, because iron moves rapidly from the circulation into cells where, in acute intoxication, it is not readily accessible for chelation. (See 'Kinetics' above.)

We recommend IV deferoxamine for patients with an oral iron overdose and any one of the following signs of serious poisoning (algorithm 1A and algorithm 1B) [9]:

●Severe symptoms (hypovolemia/shock, lethargy/coma, persistent vomiting/diarrhea)

●Elevated anion gap metabolic acidosis

●Peak SIL greater than 500 mcg/dL (90 micromol/L) (see 'Serum iron level interpretation' above)

●Estimated ingested dose from visible pills on radiograph ≥60 mg/kg elemental iron (see 'Toxic dose' above)

Prior to administration of deferoxamine, consultation with a medical toxicologist and/or regional poison control center is recommended. Our approach is to administer deferoxamine initially as a continuous IV infusion at 15 mg/kg per hour and then incrementally increase by 5 to 10 mg/kg per hour every two to four hours, based upon the patient's clinical course, up to a maximum dose of 35 mg/kg per hour [58]. Criteria for increasing the dose include one or more of the following:

●Persistent presence of vin rosé urine (which demonstrates ongoing chelation of iron with deferoxamine)

●Persistent or worsening metabolic acidosis

●Presence or development of other organ failure (eg, liver)

This approach is based upon the potential for early onset of multisystem organ failure in patients with a large overdose. Because of the kinetics of iron absorption and the possibility of lung toxicity with prolonged administration of deferoxamine, we suggest administering these larger doses of deferoxamine during the first 24 hours of treatment [59]. Other experts start at a lower dose of 5 mg/kg per hour and increase up to a maximum of 15 mg/kg per hour because of concern for potential adverse effects [9].

Adverse effects of IV deferoxamine therapy include hypotension and the development of acute respiratory distress syndrome:

●Hypotension can occur during the initial administration of deferoxamine. This effect appears to be related to rapid infusion and may be caused by histamine release [59]. It can generally be avoided by providing vigorous fluid resuscitation. This is preferable to slowing down the rate of the deferoxamine infusion, which should be avoided whenever possible.

●Acute respiratory distress syndrome has been reported in patients who have received continuous infusions of deferoxamine for 32 to 72 hours or more [60,61]. The etiology of lung toxicity is unknown. Some investigators have proposed that once iron has been removed from blood, deferoxamine binds with intracellular iron, resulting in cellular damage [59]. Others have challenged this theory and suggest that acute respiratory distress syndrome is secondary to the iron toxicity itself and not the deferoxamine.

The typical duration of therapy is about 24 hours. Recommendations for duration of deferoxamine therapy have used resolution of clinical symptoms such as metabolic acidosis and shock as the endpoint for stopping therapy [9,44]. However, such nonspecific guidelines may result in prolonged treatment and increase the risk of lung toxicity from deferoxamine [60,61]. We suggest that the decision to stop deferoxamine therapy be made in consultation with a medical toxicologist and/or regional poison control center, taking into consideration the patient's clinical status and SIL. (See 'Additional resources' below.)

Although there are no randomized trials or case-control series in humans evaluating the efficacy of deferoxamine as an antidote for iron overdose, anecdotal reports and case series describe improved clinical outcomes when IV deferoxamine is administered [62,63]. Studies in dogs have reported dramatically improved survival following lethal iron overdose for animals who received deferoxamine [64,65].

Elimination enhancement — Deferoxamine remains the primary mode of therapy for patients with severe iron poisoning. (See 'Deferoxamine' above.)

Extracorporeal methods of iron removal are limited in effectiveness because they only remove free-circulating iron and must be started soon after ingestion before intracellular iron transport occurs. Extracorporeal removal with exchange transfusion or continuous veno-venous hemofiltration has been associated with good outcomes in cases of massive iron overdose and life-threatening toxicity where clinical deterioration persisted and SILs remained very high despite administration of deferoxamine [66,67]. However, these measures carry a significant risk of complications such as bleeding and hemodynamic instability and should be regarded as novel and unreliable therapies of last resort for iron poisoning that should only be performed in consultation with a medical toxicologist.

Liver transplantation — Liver transplant may be lifesaving for patients with massive iron poisoning. For example, liver transplant was successful in two adolescent patients with large intentional iron overdose who developed rapidly progressive fulminant hepatic failure despite deferoxamine therapy [68]. However, the specific timing and indications for liver transplant following severe iron poisoning are unclear. The decision to proceed with transplant requires a multidisciplinary approach that involves the medical toxicologist, gastroenterologist, intensivist, and transplant surgeon.

Mild poisoning — Patients with mild poisoning symptoms (eg, nausea, self-limited vomiting, and/or mild abdominal pain) should be managed according to the results of initial ancillary studies (algorithm 1A and algorithm 1B). Chelation with deferoxamine is indicated for those who initially appear to have mild poisoning but whose findings indicate a high risk for moderate to severe poisoning (see 'Deferoxamine' above):

●Estimated ingested dose from visible pills on abdominal radiograph ≥60 mg/kg elemental iron

●Elevated anion gap metabolic acidosis

●Peak SIL ≥500 mcg/dL (90 micromol/L)

In addition, GI decontamination is suggested for patients with toxic amounts of iron pills present on abdominal radiograph. (See 'Gastrointestinal decontamination' above.)

Patients with mild GI symptoms, normal baseline laboratory studies, few or no visible iron pills on abdominal radiograph, and SIL 350 to 500 mcg/dL may be observed. If symptoms improve or subside, they may be safely discharged home or, if an intentional ingestion, medically cleared for mental health evaluation [69].

Asymptomatic patients — The management of patients who are initially asymptomatic after an iron ingestion is provided in the algorithm (algorithm 1B). Patients who remain asymptomatic during observation and have a peak SIL <500 mcg/dL (90 micromol/L) may be discharged to home or, if the ingestion was intentional, medically cleared for a mental health evaluation.

Special circumstances

Pregnant patients — Indications for deferoxamine therapy in pregnant patients are the same as those for other patients. Withholding deferoxamine when it is clinically indicated, out of a misguided notion that it may be toxic to the fetus, is a serious error that may have severe consequences for mother and fetus. (See 'Deferoxamine' above.)

Iron overdose during pregnancy is common but unique among overdoses because the fetus is protected from the direct effects of iron. Transplacental iron absorption is a saturable process. Consequently, significant accumulation of fetal iron does not occur [70,71]. The fetus is at risk only when the mother experiences clinical decompensation, such as hypotension, liver failure, or pulmonary failure.

IV iron overdose — SILs following iatrogenic overdoses of IV iron preparations may be elevated well above 500 mcg/dL (90 micromol/L), but these levels have been associated with minimal or no subsequent toxicity in case reports as summarized below [12,13]. Furthermore, IV iron preparations are manufactured to avoid exceeding transferrin-binding capacity during IV administration and, when compared with oral iron preparations, appear to have a much higher toxic dose. (See 'Kinetics' above and 'Toxic dose' above.)

Thus, the decision to administer deferoxamine to patients with IV iron overdoses should be based primarily on the development of significant clinical toxicity (eg, severe metabolic acidosis with shock or signs of hepatotoxicity) and not solely on the SILs [12]. Consultation with a poison center or medical toxicologist is warranted.

Minimal or no toxicity has occurred after iatrogenic IV iron overdose of 16 to 20 mg/kg of elemental iron despite very high SILs and no antidotal treatment:

●After receiving 1 g of iron sucrose (normal dose 200 mg), a patient developed transient dizziness and abdominal pain with normal vital signs. A rapid glucose was elevated (163 mg/dL), but white blood cell count and electrolytes were normal. SIL one hour after the infusion was 1301 mcg/dL (233 micromol/L). Because her symptoms had resolved, she was observed and remained asymptomatic and hemodynamically stable with normal liver function tests. The SIL returned to the normal range at approximately 24 hours [12].

●Three patients given iron dextran 7 mg/kg instead of 0.7 mg/kg (10-fold dosing error) and another patient who received IV iron sucrose 1000 mg instead of 200 mg had minimal GI symptoms initially but became asymptomatic despite SILs up to 1000 mcg/dL (179 micromol/L ) [13].

Ingestion of chewable vitamins — Any patient who may have ingested a toxic amount of iron must be referred to a hospital for evaluation and management. However, an evidence-based consensus guideline for the outpatient management of iron ingestion from the American Association of Poison Control Centers suggests that many children with unintentional ingestions of children's chewable vitamins with iron may be carefully observed at home with appropriate follow-up [72]. Children who develop persistent vomiting or diarrhea may need referral to the hospital for evaluation and treatment of dehydration.

PITFALLS IN MANAGEMENT — Several pitfalls in the management of acute iron poisoning have been identified and should be avoided. These include [16]:

●Inaccurate calculation of dose of elemental iron ingested (see 'Toxic dose' above)

●Inadequate fluid repletion (see 'Supportive care' above)

●Failure to recognize patients in the latent phase (see 'Clinical manifestations' above)

●Excessive reliance on the serum iron level (SIL) to make management decisions in symptomatic patients or decisions regarding administration of deferoxamine in asymptomatic patients (see 'Serum iron level interpretation' above and 'Moderate to severe poisoning' above)

●Reliance on the total iron binding capacity (TIBC), a negative abdominal radiograph, or associated laboratory tests to predict toxicity (see 'Evaluation' above and 'Laboratory studies' above and 'Plain radiograph of the abdomen' above)

●Withholding deferoxamine from pregnant patients (see 'Pregnant patients' above)

●Inadequate deferoxamine dose (see 'Deferoxamine' above)

●Discontinuation of deferoxamine on the basis of urine color alone (see 'Deferoxamine' above)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

SUMMARY AND RECOMMENDATIONS

●Toxic dose – The ingested dose (mg/kg of elemental iron) and the iron formulation (table 1 and table 2) determine the likely toxicity after an oral iron overdose. Ingestions ≥60 mg/kg of elemental iron are associated with serious toxicity and death. (See 'Toxic dose' above.)

●Clinical manifestations – The clinical features of acute iron poisoning after ingestion occur in five (often overlapping) phases (see 'Clinical manifestations' above) (table 4):

•Early gastrointestinal (GI) symptoms (persistent vomiting, hypovolemic shock, or altered mental status indicates moderate to severe poisoning)

•Latent (or relative stability)

•Shock and elevated anion gap metabolic acidosis

•Delayed hepatotoxicity/hepatic necrosis

•Remote gastric outlet obstruction

●Evaluation and management – The evaluation and management of acute iron ingestion depends upon the presenting symptoms and estimated iron dose and is provided in the algorithms (algorithm 1A and algorithm 1B) and the rapid overview table (table 4). (See 'Evaluation' above.)

●Diagnosis – The diagnosis of iron poisoning is suspected based upon a history of iron ingestion and clinical manifestations of poisoning. It is confirmed by the presence of a toxic amount of visible iron pills on plain abdominal radiograph or a peak serum iron level (SIL) ≥500 mcg/dL (90 micromol/L). A peak SIL also helps to identify the level of expected toxicity after an oral overdose, which adds in management decisions. (See 'Diagnosis' above and 'Serum iron level interpretation' above.)

●Moderate to severe poisoning – The management of moderate to severe iron poisoning after acute ingestion consists of (algorithm 1A and table 4) (see 'Management' above and 'Moderate to severe poisoning' above):

•Supportive care – Provide airway protection and respiratory support, as needed. Volume resuscitation to maintain euvolemia is essential. (See 'Supportive care' above.)

•Gastrointestinal decontamination – The need for GI decontamination is determined by the number and location of iron pills seen on plain radiograph of the abdomen. We suggest whole-bowel irrigation (WBI) rather than no GI decontamination for patients who have potential for worsening toxicity based on the number of iron pills visible on plain abdominal radiograph (Grade 2C). Except for rare cases of massive oral iron overdose, the risk of gastric lavage usually outweighs the limited benefit. (See 'Gastrointestinal decontamination' above.)

•Deferoxamine – We recommend that patients, including pregnant patients, with any of the following indications receive iron chelation with intravenous (IV) deferoxamine (Grade 1B) (see 'Deferoxamine' above and 'Pregnant patients' above):

-Severe symptoms (lethargy or coma, hypovolemic shock, or persistent vomiting and/or diarrhea)

-Elevated anion gap metabolic acidosis

-Estimated ingested dose from visible pills on radiograph ≥60 mg/kg elemental iron

-Peak SIL ≥500 mcg/dL (90 micromol/L)

Prior to administration of deferoxamine, we recommend consultation with a medical toxicologist and/or regional poison control center. Chelation of iron with deferoxamine should occur as soon as the potential for serious iron toxicity is apparent. Our approach to deferoxamine administration is provided above. (See 'Deferoxamine' above.)

●IV iron overdose – SILs following iatrogenic overdoses of IV iron preparations may be elevated well above 500 mcg/dL with minimal or no subsequent toxicity. Thus, chelation of patients with IV iron overdoses should be based on the development of significant clinical toxicity (eg, severe metabolic acidosis with shock or signs of hepatotoxicity). (See 'IV iron overdose' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Rana Kronfol, MD, who contributed to earlier versions of this topic review.