Acute Iron Toxicity 

Acute Iron Toxicity – Urgent Action

• Obtain peak serum iron concentration; do not delay clinical management while results are pending
• Initiate prompt deferoxamine therapy when large-dose ingestion is suspected based on history, clinical manifestations, or laboratory analysis

8 Interesting Facts of Acute Iron Toxicity

1. Acute iron toxicity is caused by accidental or intentional overdose of iron-containing vitamins or pure iron preparations; severity of poisoning is determined by amount of elemental iron in the ingested substance and by symptoms
2. It is important to correctly estimate the amount of elemental iron ingested, based on the formulation
3. Diagnosis is clinical, based on symptoms of toxicity (eg, nausea, vomiting, diarrhea) and known ingestion of iron-containing products
4. Abdominal radiography can be used to detect ingested iron-containing pills, which are radiopaque, and suggest need for gastrointestinal decontamination
5. Serum iron concentration aids in confirmation of diagnosis and predicts severity of toxicity; concentration more than 500 mcg/dL is associated with potentially severe toxicity ¹
6. Treatment for severe iron toxicity includes supportive care, gastrointestinal decontamination via whole bowel irrigation, and chelation therapy with deferoxamine
7. Promptly initiate deferoxamine chelation in presence of serum iron concentration over 500 mcg/dL, severe symptoms, metabolic acidosis, or iron-containing pills on radiograph, despite gastrointestinal decontamination
8. Late complications of acute iron poisoning include gastrointestinal tract injury (eg, scarring, strictures) and hepatic failure

Pitfalls

• Errors in calculating amount of elemental iron ingested (can affect toxicity predictions; iron is available in different formulations)
• Failure to recognize quiescent phase (stage 2) of poisoning; patients appear to have symptom resolution but may subsequently develop systemic toxicity with clinical deterioration
• Inadequate fluid replacement to maintain euvolemia

Terminology

Clinical Clarification

• Acute iron toxicity is caused by accidental or intentional overdose of iron or iron-containing vitamins or preparations; severity of poisoning is determined by amount of elemental iron ingested and by symptoms ²
• Minimum toxic dose has not been defined but ingestion of less than 20 mg/kg of elemental iron is nontoxic; incremental symptoms are noted as the amount of elemental iron ingested increases, with severe symptoms noted among those who have ingested more than 60 mg/kg of elemental iron ³
  • Clinical guidelines recommend medical evaluation for both pediatric and adult patients who have moderate, severe, or persistent symptoms or have ingested more than 40 mg/kg of elemental iron

Classification

• Iron toxicity is classified into 5 clinical stages, ⁴ which often overlap; patients do not necessarily experience all stages
  • Stage 1: Local gastrointestinal effects ³
    • Occurs within 6 hours of iron overdose owing to direct local effects of iron on gastric and intestinal mucosa ^1 3
    • Presents with abdominal pain, vomiting, diarrhea, hematemesis, or hematochezia ³
  • Stage 2: Quiescent phase (may not be observed in severe cases)
    • Coincides with progressive absorption into circulation and distribution of iron into tissue intracellular compartments
    • Resolution of gastrointestinal symptoms and apparent clinical recovery occur 6 to 24 hours after iron overdose
    • Some reports suggest that stage 2 does not exist and that metabolic effects continue during this time
  • Stage 3: Systemic toxicity
    • Manifests with recurrence of gastrointestinal symptoms ⁵ and multiorgan failure with shock due to hypovolemia, metabolic acidosis, seizures, coagulopathy, and hepatic and kidney failure ³
    • Normally occurs 48 to 96 hours after ingestion ³
  • Stage 4: Hepatic failure
    • Fulminant hepatic failure; rare and usually fatal
    • Occurs 2 to 5 days after ingestion ⁴
  • Stage 5: Gastrointestinal obstruction
    • Late onset of gastric or duodenal strictures 2 to 8 weeks after iron overdose ^1 6

Diagnosis

Clinical Presentation ³

History

• Establish whether ingestion was intentional or accidental
• Determine type of iron ingested, amount of elemental iron contained, quantity ingested, and time since ingestion
  • Ferrous fumarate has 33% elemental iron (one 200-mg tablet contains 65 mg elemental iron)
  • Ferrous sulfate has 20% elemental iron (one 300-mg tablet contains 60 mg elemental iron)
  • Ferrous gluconate has 12% elemental iron (one 300-mg tablet contains 36 mg elemental iron)
  • Ferrous elixir contains 44 mg elemental iron in 5 mL
  • Adult multivitamins with iron contain 10 to 110 mg elemental iron per tablet
  • Children’s multivitamins with iron contain 10 to 18 mg elemental iron per tablet

Table

Amount of elemental iron in various formulations.

Formulation	Percentage of elemental iron	Amount of elemental iron per dose
Ferrous fumarate	33	65 mg in 200-mg tablet
Ferrous sulfate	20	60 mg in 300-mg tablet
Ferrous gluconate	12	36 mg in 300-mg tablet
Ferrous elixir		44 mg in 5 mL of solution
Adult multivitamin with iron		10-110 mg/tablet
Children’s multivitamin with iron		10-18 mg/tablet

Citation: Data from Iron. In: ToxED [database online]. Elsevier; 2016. Updated March 5, 2018. Accessed March 25, 2019. http://www.toxed-ip.com/ToxEdView.aspx?id=130148

• If no symptoms have developed by 6 hours after ingestion, the patient typically will not develop toxicity ³
  • An exception is ingestion of enteric-coated iron tablets, which can mask initial gastrointestinal symptoms
• Clinical manifestations are dose dependent
  • Ingestion of less than 20 mg/kg usually does not cause symptoms ⁵
  • Ingestion of 20 to 60 mg/kg results in mild to moderate symptoms ⁵
  • Ingestion of more than 60 mg/kg may lead to severe symptoms or death ⁵

Table

Expected symptoms and management based on iron dose ingested.

Ingested dose of elemental iron	Expected manifestations	Typical evaluation and management required
Less than 20 mg/kg	Asymptomatic	None
20-40 mg/kg	Mild gastrointestinal irritation with vomiting and abdominal pain lasting less than 6 hours	None; minimally symptomatic patients can often be managed at home
40-60 mg/kg	Moderate gastrointestinal irritation with vomiting and abdominal pain lasting up to about 8 hours; systemic toxicity is not expected	Serum iron concentration is indicated and abdominal radiograph may be indicated; general supportive measures (eg, IV fluids) and period of monitoring is required
More than 60 mg/kg	Severe gastrointestinal symptoms and systemic toxicity may occur	Full evaluation is indicated (eg, iron concentrations, abdominal radiograph for pill ingestion); obtain ancillary studies in patient with significant symptoms; general supportive measures are often required; whole-bowel irrigation and/or chelation may be required
More than 100 mg/kg	Severe gastrointestinal symptoms and potentially lethal systemic toxicity may occur	Full evaluation is indicated (eg, iron concentrations, abdominal radiograph for pill ingestion, ancillary studies); early aggressive treatment with fluid resuscitation, whole-bowel irrigation, and chelation will be required

Citation: Data from Perth Children’s Hospital. Emergency Department Guidelines: Poisoning–Iron. PCH website. Published May 2018. Accessed March 25, 2019. https://pch.health.wa.gov.au/For-health-professionals/Emergency-Department-Guidelines/Poisoning-Iron; and Royal Children’s Hospital Melbourne: Clinical Practice Guidelines: Iron Poisoning. RCH website. Updated December 2017. Accessed March 25, 2019. https://www.rch.org.au/clinicalguide/guideline_index/Iron_poisoning/

• Early symptoms, within 6 hours of ingestion (stage 1)
  • Nausea and vomiting
    • Vomiting is the most sensitive indicator of serious ingestion
  • Diarrhea (may be bloody)
  • Abdominal pain
  • Vomitus or stool may be dark green or black owing to iron tablets
  • Hematemesis or melena may be present in some patients
• Initial gastrointestinal symptoms may transiently resolve (stage 2) before further deterioration
• Subsequent symptoms developing after 48 hours (stages 3 and 4) may include:
  • Recurrence of gastrointestinal symptoms ⁵
  • Lethargy
  • Dyspnea
  • Anorexia
  • Abdominal bloating
  • Bleeding, bruising
  • Jaundice
  • Altered level of consciousness or coma
  • Seizures

Physical examination

• Signs may depend on stage of presentation and may include: ³
  • Stage 1: gastrointestinal manifestations
    • Abdominal tenderness
    • Dehydration, if significant vomiting or diarrhea
  • Stage 3: shock and multiorgan failure
    • Tachycardia
    • Pallor
    • Tachypnea
    • Hypotension
    • Cool skin and delayed capillary refill
    • Oliguria
    • Altered level of consciousness
    • Coma
  • Stage 4: hepatic failure
    • Jaundice
    • Abdominal tenderness
    • Ascites
    • Purpura
    • Altered level of consciousness or coma

Causes and Risk Factors

Causes

• Accidental or unintentional ingestion of iron-containing products (usually adult formulations of ferrous sulfate, ferrous gluconate, or ferrous fumarate) ³ in pediatric populations
• In rare occurrences, iron may be ingested by adolescents or adults to induce self-harm
• Toxic dose ⁴
  • Severe systemic toxicity may occur with doses more than 60 mg/kg
• Effects of an acute toxic ingestion include:
  • Direct mucosal cell necrosis and corrosion of gastrointestinal tract mucosa
  • Unbound circulating iron results in potent vasodilation, increased capillary permeability, and other increased vascular permeability
  • Unbound iron is a mitochondrial poison; disruption of oxidative phosphorylation results in increased anaerobic metabolism and lactic acidosis

Risk factors and/or associations

Age

• Children younger than 6 years account for two-thirds of all cases ⁷

Other risk factors/associations

• Increased incidence of accidental overdose in children during mother’s subsequent pregnancies owing to presence of prenatal vitamins in the household ⁸

Diagnostic Procedures

• Abdominal radiograph of a 20-month-old-child with a history of ingesting prenatal iron tablets. – Many tablets are visible.From Liebelt EL: Iron. In: Shannon MW et al, eds: Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. 4th ed. Saunders; 2007:1119-28, Figure 72-1.

Primary diagnostic tools

• Acute iron poisoning is a clinical diagnosis, supported by laboratory testing
• Laboratory testing confirms diagnosis and monitors for clinical effects of poisoning (eg, metabolic acidosis, coagulopathy, liver damage, anemia) ⁷
• Obtain serum iron concentration 4 to 6 hours after ingestion if ingested material was a non–sustained-release product; enteric-coated preparation may have erratic absorption and, thus, another serum iron level should be obtained 6 to 8 hours postingestion ^4 7 9 10
• Obtain abdominal radiograph in patients with potentially toxic ingestion to assess for presence of radiopaque pills in gastrointestinal tract ¹
• Obtain ancillary studies (CBC, blood gas levels, coagulation studies, electrolyte levels, and hepatic function panel) in significantly symptomatic patients to monitor for systemic toxicity ⁷

Laboratory

• Serum iron concentration ¹
  • May aid confirmation of diagnosis or predict severe toxicity (depending on timing)
  • Check levels in the following patients: ⁹
    • If unknown amount ingested
    • Those who ingested more than 40 mg/kg of elemental iron
    • All symptomatic patients
    • All whose ingestion was intentional
  • Peak concentration usually occurs about 4 to 6 hours after ingestion; may occur later with sustained-release or enteric-coated formulations ¹
    • Measure serum iron concentration at 3 to 5 hours ⁵ after ingestion; repeat at 6 to 8 hours ⁵ if sustained-release or enteric-coated preparation was ingested
    • Serial concentrations may be used to confirm that peak absorption has occurred and to evaluate effectiveness of decontamination when performed
    • Maintain awareness that concentrations obtained after 4 to 6 hours may underestimate toxicity because iron is distributed into tissue intracellular compartments and bound to ferritin ⁹
  • Peak serum iron concentration may correlate with toxicity; clinically interpret concentrations in conjunction with signs and symptoms of toxicity ⁵
    • Concentration below 300 mcg/dL is associated with minimal toxicity
    • Concentration between 300 and 500 mcg/dL is associated with moderate toxicity ¹
    • Concentration above 500 mcg/dL is associated with potentially severe toxicity ^1 5
    • Concentration above 1000 mcg/dL is associated with significant morbidity and mortality ^1 5
• Hematocrit or hemoglobin level ¹
  • Elevated hematocrit may indicate significant fluid loss and may warrant fluid replacement ¹
• Arterial or venous blood gas test
  • Aids detection of metabolic acidosis (pH less than 7.35) ¹¹
• Serum electrolyte, BUN, and glucose measurements, with calculation of anion gap ¹
  • Hyperglycemia is characteristic of significant ingestion; ⁹ hypoglycemia may occur ⁵
  • A positive anion gap metabolic acidosis is seen with significant iron poisoning ¹
  • Diminishing bicarbonate levels are often associated with increasing degrees of severity of toxicity ⁴
• CBC with differential
  • Leukocytosis may be observed ⁵
• Hemoccult stool test ¹
  • Positive test results for blood in the stool is indicative of gastrointestinal bleeding
• Coagulation studies
  • Coagulation defects may occur early owing to direct effect of iron on clotting factors or later in association with hepatic failure ⁵
• Hepatic function panel
  • Elevated bilirubin, aspartate, and ALT levels are indicators of hepatic toxicity ⁵

Imaging

• Abdominal radiograph ¹
  • Particularly important in patients with known or suspected abdominal obstruction (noted in late stage of toxicity)
  • Tablets containing significant amounts of elemental iron are radiopaque and can be seen on radiographs
    • Liquid preparations and chewable vitamins are not visible
  • Serial examinations may be helpful to assess effectiveness of whole-bowel irrigation ⁹

Differential Diagnosis

Most common

• Gastroenteritis ^d1 (Related: Gastroenteritis in Children)
  • Inflammation of gastrointestinal tract caused by viral, bacterial, or parasitic infection
  • As with iron poisoning, symptoms include diarrhea, nausea, and vomiting
    • Early symptoms of acute iron poisoning may be attributed to gastroenteritis in children if parents are unaware of iron ingestion
  • Unlike with iron poisoning, fever and myalgia may also be present, and condition does not typically progress to shock and multiorgan failure
  • Differentiated by history and clinical and laboratory findings
    • May occur in setting of local outbreak, history of eating contaminated food, or close contact with another infected person
    • No history of iron ingestion; normal serum iron concentrations
• Salicylate poisoning ^d2 (Related: Salicylate Toxicity) ¹²
  • Intentional or unintentional ingestion of toxic amounts of preparations containing salicylates
    • Aspirin and bismuth subsalicylate are common sources
  • As with iron poisoning, early symptoms include nausea, vomiting, and diarrhea
  • Tinnitus is a defining symptom of salicylate poisoning that does not occur in iron poisoning; deafness, hyperventilation, and electrolyte abnormalities may also occur ¹³
  • Differentiated by history of ingestion and results of laboratory tests for plasma salicylate levels
• Mercury poisoning ¹⁴
  • Ingestion of or exposure to inorganic mercury salts
  • As with iron poisoning, early symptoms include severe vomiting, diarrhea, and abdominal pain; shock and renal failure occur with severe poisoning
  • Patients may present with acrodynia, which is a hallmark of mercury poisoning that is not seen with iron poisoning ¹⁵
  • Differentiated by history of exposure or ingestion and by measurement of urinary mercury concentration
• Arsenic poisoning ¹⁶
  • Acute exposure to or ingestion of arsenic
  • As with iron poisoning, early symptoms include nausea, vomiting, abdominal pain, and diarrhea
  • Patients may also have prolonged QT interval on ECG ¹⁷
  • Differentiated by history of exposure or ingestion, results of urinalysis for arsenic metabolites, and total arsenic concentration
• Acetaminophen poisoning ^d3 (Related: Acetaminophen Toxicity)
  • Overdose of agents containing acetaminophen
  • As with iron poisoning, early signs and symptoms include nausea, vomiting, pallor, and lethargy
  • Patients can also present with signs or symptoms of liver failure, which is a late manifestation of severe iron poisoning ¹⁸
  • Differentiated by history of ingestion and measurement of serum acetaminophen concentration

Treatment

Goals

• Eliminate excess iron
• Prevent complications of toxicity

Disposition

Admission criteria

Admit pediatric and adult patients with any of the following: ³

• Symptomatic ingestion (eg, vomiting, diarrhea, altered level of consciousness, gastrointestinal bleeding) regardless of presumed amount ingested ⁴
• Ingestion requiring whole-bowel irrigation and/or IV fluid administration ^4 9
• Stated or suspected self-harm or malicious administration
• Ingestion of more than 40 mg/kg and ingestion of unknown quantity may require admission ⁹

Criteria for ICU admission

• IV chelation with deferoxamine is usually administered in the ICU setting ⁴
• Patients with significant toxicity require management in the ICU; ⁴ manifestations may include:
  • Severe gastrointestinal symptoms
  • Decreased level of consciousness
  • Hemodynamic instability
  • Metabolic acidosis
  • Serum iron concentrations higher than 500 mcg/dL

Recommendations for specialist referral

• Medical toxicology consultation is suggested in all cases for diagnostic and management recommendations ³

Treatment Options

Supportive care

• Initiate volume resuscitation with IV fluids if patient presents with persistent or severe diarrhea or vomiting ^1 19

Gastrointestinal decontamination

• Consider when radiographs show significant number of iron-containing tablets or capsules ^9 19
• Indications include:
  • Ingestion of more than 60 mg/kg ^4 9
  • Manifestations consistent with significant toxicity (eg, hematemesis, lethargy) ²⁰
  • Persistently rising iron concentrations
• Whole-bowel irrigation using polyethylene glycol–based electrolyte solution is the preferred method when not contraindicated; perform in consultation with a medical toxicologist or poison control center ^1 19
• Gastric lavage can be used for gastric emptying, but it is less effective; larger-bore tubes may be difficult to insert in children but even with successful insertion, they may not be large enough to allow passage of large pills or conglomerates of pills ¹
  • Consider only if patient has taken a toxic dose, has not vomited, and still has iron-containing pills in stomach on a radiograph
• Do not use activated charcoal, as it does not absorb iron well ³
• Endoscopic removal may be indicated in patients with potentially lethal ingestion where whole-bowel irrigation fails or is contraindicated ⁴

Chelation therapy with IV deferoxamine

• Decision to initiate is based on presence of toxicity or predicted severe toxicity based on serum iron concentration ¹⁴
  • Deferoxamine chelates iron to form ferrioxamine; the latter is then excreted unchanged by the kidneys; chelation may limit cellular uptake of iron
  • Indications include: ⁴¹⁹
    • Severe symptoms (eg, shock, altered mental status, persistent gastrointestinal symptoms ¹)
    • Peak serum iron concentration over 500 mcg/dL
    • Significant metabolic acidosis
    • Radiographs show significant number of iron-containing pills, despite gastrointestinal decontamination
  • In general, serum concentrations below 300 mcg/dL usually do not require chelation therapy ¹
• Treatment must begin early after ingestion, before iron shifts to intracellular compartments
• Optimal dose and duration have not been established
  • Continue infusion until there is significant clinical resolution (eg, absence of symptoms, resolution of anion gap acidosis) and decontamination is complete (usually 1-2 days) ^1 9
  • Repeated serum iron concentrations are not helpful to monitor therapy when deferoxamine is administered ¹
    • May be falsely low in the presence of deferoxamine because chelator interferes with standard methods of measurement ²¹
  • Maintain care to ensure adequate urine output during treatment
• Adverse effects include hypotension, acute respiratory distress syndrome, and yersinia sepsis ⁵⁷
  • Hypotension is caused by rapid initial infusion of deferoxamine and is prevented by ensuring adequate fluid replacement and not exceeding the recommended rate of infusion ⁷
  • Acute respiratory distress syndrome can occur with longer infusions of deferoxamine (32 hours or longer); closely monitor patients for respiratory distress ⁷

Exchange transfusion or hemodialysis: in rare situations involving massive ingestion, these options may be considered (eg, iron concentrations greater than 1000 mcg/dL, failure to respond to initial therapy) ⁵

• Treatment must begin early after ingestion, before iron shifts to intracellular compartments

Drug therapy

• Chelating agent ²
  • Deferoxamine ¹
    • For dosing in children younger than 3 years, consult a medical toxicologist via regional poison control center or local medical toxicology service.
    • Deferoxamine Mesylate Solution for injection; Children and Adolescents 3 to 17 years: 15 mg/kg/hour continuous IV infusion until signs and symptoms of iron poisoning are resolved and serum iron concentration within normal range; higher doses (up to 35 mg/kg/hour) have been safely used and may be needed in severe ingestions. Max of 6 g/day IV recommended in FDA-approved labeling; however, higher doses (16 to 20 g/day) are often necessary.
    • Deferoxamine Mesylate Solution for injection; Adults: 15 mg/kg/hour continuous IV infusion until signs and symptoms of iron poisoning are resolved and serum iron concentration within normal range; higher doses (up to 35 mg/kg/hour) have been safely used and may be needed in severe ingestions. Max: 6 g/day IV recommended in FDA-approved labeling; however, higher doses (16 to 20 g/day) are often necessary.

Nondrug and supportive care

Initiate volume resuscitation with IV fluids if patient presents with persistent or severe diarrhea or vomiting. ^1 19

Procedures

Whole-bowel irrigation ¹

General explanation

• Administration of polyethylene glycol electrolyte solution to hasten passage of substances through gastrointestinal tract
• Solution is taken orally or via nasogastric tube
• Administered at rate of 500 mL/hour in children younger than 6 years, 1 L/hour in children aged 6 to 12 years, and 1.5 to 2 L/hour in adolescents and adults; continued until rectal effluent is clear ²²
• A follow-up abdominal radiograph may be used to confirm elimination of pills

Indication

• Pills visible on abdominal radiograph with ingestion of elemental iron more than 60 mg/kg
• Manifestations consistent with significant toxicity (eg, hematemesis, lethargy)
• Persistently rising iron concentration

Contraindications

• Compromised unprotected airway ²³
• Bowel obstruction, ileus, bowel perforation, or significant bowel hemorrhage ²³
• Hemodynamic instability ²³

Complications

• May cause nausea, vomiting, abdominal pain, and bloating ⁵

Comorbidities

• Renal disease ⁹
  • Patients with preexisting kidney disease must be closely monitored because chelated iron complex is excreted primarily through the kidneys
  • Peritoneal dialysis or hemodialysis may be necessary if oliguria or anuria develops

Special populations

• Pregnant patients
  • Management of suspected iron toxicity does not differ largely compared with management in nonpregnant patients ³
  • Base dosing of deferoxamine on prepregnancy weight ⁵

Monitoring

• General discharge criteria ⁹
  • Ingestion of less than 40 mg/kg
    • May discharge if asymptomatic 6 hours after ingestion and if abdominal radiograph findings are negative (when pills ingested)
  • Ingestion of more than 40 mg/kg or unknown amount of ingestion
    • Monitor for symptoms and measure serum iron concentration every 4 hours until it is decreasing
    • May discharge patient if asymptomatic and serum iron concentration is falling and is less than 500 mcg/dL on 2 measurements 4 hours apart
    • Maintain awareness that with severe poisoning, a period of apparent clinical improvement may represent latent period (usually 6-24 hours after ingestion) before overt systemic toxicity develops
• Monitoring during deferoxamine administration ⁴
  • Frequently monitor vital signs and monitor for potential adverse effects (e.g., acute respiratory distress syndrome)
  • Continuous cardiac monitoring is required during infusion
  • Monitor fluid balance closely; note that red discoloration of urine is not uncommon

Complications and Prognosis

Complications

• Gastrointestinal strictures (Related: Small-Bowel Obstruction)
• Hepatic failure (Related: Acute Kidney Injury)²⁴
• Gastrointestinal bleeding

Prognosis ¹

• Accidental ingestion is common; however, severe toxicity requiring chelation is rare
• Severe poisoning is usually managed successfully with supportive care and chelation therapy
• If condition goes untreated, death may occur as result of shock or liver failure

Screening and Prevention

Prevention ³

• Child-resistant packaging
• Advise parents as follows:
  • Store vitamins in original packaging, out of reach of children (as with medications)
    • Remember that although vitamin supplements may seem less dangerous than medications (to an adult), they are nonetheless dangerous to small children, who may choke on them or swallow an overdose

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