Iron toxicity

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Background

  • Iron is the 4th most abundant atomic element in the earth's crust
  • Biologically a component of hemoglobin, myoglobin, catalase, xanthine oxidase, etc
  • Uptake highly regulated
  • Amount of elemental iron ingested determines the risk, not the amount of iron salt[1]

Elemental Iron Percentages

Iron Preparation % of Elemental Iron
Ferrous Fumarate 33%
Ferrous Sulfate 20%
Ferrous Gluconate 12%
Ferric pyrophosphate 30%
Ferroglycine sulfate 16%
Ferrous carbonate (anhydrous) 38%

Toxicity

Toxicity determined by mg/kg of elemental iron ingested[2]

Severity Elemental Iron Dose (mg/kg)^
Mild 10-20
Moderate 20-60
Severe >60

^Total amount of elemental iron ingested calculated by multiplying estimated number of tablets by the percentages of iron in the tablet preparation (see above)

Pathophysiology

  • Direct caustic injury to gastric mucosa[3]
  • Occurs early, usually within several hours
    • Causing vomiting, diarrhea, abdominal pain, and GI bleeding
    • Usually affects, the stomach, duodenum, colon rarely affected
    • Can lead to formation of gastric strictures 2-8 weeks post-ingestion
  • Impaired cellular metabolism
    • Inhibiting the electron transport chain causes lactic acidosis
    • Direct hepatic, CNS, and cardiac toxicity (decreased CO and myocardial contractility)
    • Cell membrane injury from lipid peroxidation[4]
  • Increased capillary permeability
    • Hypotension
    • Venodilation
    • Hypovolemic shock
  • Portal vein iron delivery to liver
    • Overwhelm storage capacity of Ferritin
    • Hepatotoxicity (cloudy swelling, periportal hepatic necrosis, elevated transaminases)
    • Destroys hepatic mitochondria, disrupts oxidative phosphorylation → worsening metabolic acidosis
  • Thrombin formation inhibition
    • Coagulopathy - direct effect on vitamin K clotting factors

Clinical Features

  • Absence of GI symptoms within 6hr of ingestion excludes significant iron ingestion (exception: enteric coated tablets)
  • Significant iron toxicity can result in a severe lactic acidosis from hypoperfusion due to volume loss, vasodilation and negative inotropin effects.
Iron Toxicity Stages
Staging Clinical Effect Time Frame
Stage 1 GI irritation: Nausea, vomiting, diarrhea, abdominal pain, hematemesis, hematochezia 30 mins-6 hours
Stage 2: Latent GI symptoms may improve or resolve 6-24 hours
Stage 3: Shock and metabolic acidosis Metabolic acidosis, lactic acidosis, dehydration 6-72 hours
Stage 4: Hepatotoxicity/Hepatic necrosis Hepatic failure with jaundice 12-96 hours
Stage 5: Bowel obstruction GI mucosa healing leads to scarring 2-8 weeks
  • Stage I: GI toxicity: nausea, vomiting, diarrhea, GI bleeding from local corrosive effects of iron on the gastric and intestinal mucosa
  • Stage II: Quiescent phase with resolution of GI symptoms and apparent clinical improvement
    • controversy between toxicologists whether this stage exists in significant poisonings
  • Stage III: Systemic toxicity: shock and hypoperfusion
    • Primarily hypovolemic shock and acidosis, myocardial dysfunction also contributes
    • GI fluid losses, increase capillary permeability, decreased venous tone
    • Severe anion gap acidosis
    • Free radical damage to mitochondria disrupt oxidative phosphorylation which leads to lactic acidosis
    • Hepatotoxicity from iron delivery via portal blood flow
  • Stage IV: Clinical recovery, resolution of shock and acidosis usually by days 3-4
  • Stage V: Late onset of gastric and pyloric strictures (2-8 week later) [5]

Differential Diagnosis


CAT MUDPILERS

Hyperglycemia

Diabetic Emergencies

Diabetes Mellitus (New or Known)

Medication/Drug-Induced

Physiologic Stress Response

  • Sepsis / critical illness (stress hyperglycemia — very common in the ED)
  • Trauma / major surgery / burns
  • Acute coronary syndrome / myocardial infarction
  • Stroke (especially hemorrhagic)
  • Pancreatitis (both a cause and consequence)
  • Shock (any etiology)
  • Pain (catecholamine surge)
  • Seizure (postictal)
  • Physiologic stress alone rarely causes glucose >200 mg/dL in non-diabetics; glucose >200 in a "stress response" should prompt evaluation for undiagnosed diabetes or prediabetes

Endocrine

Pancreatic

  • Pancreatitis (acute or chronic — destruction of islet cells)
  • Pancreatic malignancy (adenocarcinoma, neuroendocrine tumors)
  • Post-pancreatectomy
  • Cystic fibrosis-related diabetes
  • Hemochromatosis (iron deposition in pancreas — "bronze diabetes")

Toxic/Overdose

Other

  • Renal failure (chronic kidney disease, acute kidney injury — impaired insulin clearance AND insulin resistance)
  • Cirrhosis / hepatic failure (impaired glycogenolysis regulation)
  • Pregnancy (gestational diabetes, steroid administration for fetal lung maturity)
  • Parenteral nutrition (TPN, dextrose-containing fluids)
  • Post-transplant diabetes (immunosuppressants)

Complications of Diabetes (Not Causes of Hyperglycemia)

These are associated conditions that may be present alongside hyperglycemia but do not themselves cause elevated glucose:

Evaluation

Work-Up

Urine changes from rusty colored vin rose to clear.
  • Two large-bore peripheral IVs
  • CBC
  • Chemistry - notice that this can appear like DKA
    • Anion gap metabolic acidosis
    • Hyperglycemia
  • Coags
  • LFTs
  • Iron levels
  • Urinalysis
    • Used to follow efficacy of Fe chelation
    • Urine changes from rusty colored vin rose to clear
  • Urine pregnancy test
  • Type and Screen
  • XR KUB
    • In ambiguous cases consider abdominal xray as most Fe tabletss are radioopaque[6]
    • However, a normal XR KUB does not rule out significant ingestion, particularly if liquid iron or chewable vitamins with iron were ingested [7]
  • EKG
  • A serum glucose > 150mg/dL and leukocyte count above 15,000 is 100% Sp and 50% Sn in predicting Fe levels > 300mcg/mL, but the absence cannot exclude iron toxicity [8]

Diagnosis

Serum iron concentration can guide treatment, but is not absolute in predicting or excluding toxicity.

Peak Serum Iron Level (mcg/dL)^ Category
<300 Nontoxic or mild
300-500 Significant GI symptoms and potential for systemic toxicity
>500 Moderate to severe systemic toxicity
>1000 Severe systemic toxicity and increased morbidity

^usually around 4hrs post ingestion although very high doses may lead to delayed peak

Management

Observation

  • Patients with asymptomatic ingestion of < 20mg/kg of elemental iron may only require observation for 6 hours
  • Volume resuscitation

Orogastric Lavage

  • Unclear benefit. Risk of aspiration, perforation, laryngospasm
  • Intubate prior to procedure if patient not protecting airway
  • Indication: Normal saline via large orogastric tube for moderate to severe iron poisoning if there are still many iron tablets (20-30) in abdominal radiograph may be beneficial

Whole bowel irrigation

  • Indicated for large ingestion
  • Administer polyethylene glycol solution at 2 L/hr in adults and 250-500 mL/hr in children
  • Do not base only on radioopaque evidence of iron pills as not all formulations are readily visible on XR
  • Orogastric lavage only is not likely to be successful after iron tablets have moved past the pylorus
  • Supported by case reports and uncontrolled case series, but rationale behind it makes it largely supported by toxicologists[9]
  • Promotes increased gastric emptying and avoids large bezoar formation[10]

Deferoxamine

  • Indications
    • Pregnancy
    • Systemic toxicity and iron level > 350 mcg/dL
    • Iron level >500mcg/dL
    • Metabolic acidosis
    • Altered Mental Status
    • Progressive symptoms, including shock, coma, seizures, refractory GI symptoms
    • Large number of pills on KUB
    • Estimated dose > 60mg/kg Fe2+
  • Administered IV due to poor oral absorption
    • One mole of Deferoxamine (100mg) binds one mole of iron (9mg) to form ferrioxamine
    • Results in vin-rose urine (ferrioxamine is a reddish compound)
  • Dose
    • 5-15 mg/kg/hr, max of 35 mg/kg/hr or 6g total per day
    • Start slower at 5-8 mg/kg/hr if hypotensive and uptitrate as tolerated
    • Titrate up for worsening metabolic acidosis, progressive organ failure, persistent vin rosé urine (ongoing choleation)
    • Can give 90 mg/kg IM if unable to obtain IV, but must establish IV ASAP given patient will need fluid resuscitation
  • Adverse reactions
    • Hypotension
    • May cause flushing (anaphylactoid reaction)
    • Rarely causes ARDS - associated with prolonged use
    • Safe in pregnancy (give if obvious signs of shock/toxicity)

Hemodialysis

  • Not effective in removing iron due to large volumes of distribution
  • Dialysis can removes deferoxamine-iron complex in renal failure patients

Exchange transfusion

  • Minimal evidence but has been described in larger overdoses[11]

Not Indicated

Activated charcoal

  • Does not absorb significant amounts if iron and is not recommended

Poison Control

  • 1-800-222-1222 (United States)

Disposition

  • Discharge after 6hr observation for asymptomatic (or only vomited 1-2x) AND ingestion <20mg/kg
  • Admit to ICU if deferoxamine required
  • Psychiatric evaluation if intentional ingestion


Medication Dosing

  • Deferoxamine 5-15 mg/kg/hr IV infusion IV drip (max 6 g/day) — Start 5-8 mg/kg/hr if hypotensive; titrate up for worsening acidosis
  • Deferoxamine 5-15 mg/kg/hr IV infusion IV drip (max 6 g/day)

See Also

External Links

References

  1. ↑ The Royal Children's Hospital Melbourne Clinical Practice Guidelines. 2020. https://www.rch.org.au/clinicalguide/guideline_index/Iron_poisoning/
  2. ↑ Robotham JL, Lietman PS: Acute iron poisoning. A review. Am J Dis Child 1980; 134:875-879.
  3. ↑ Robotham JL, Lietman PS. Acute iron poisoning. A review. Am J Dis Child 1980; 134:875-879.
  4. ↑ Aisen P et al. Iron toxicosis. Int Rev Exp Pathol 1990. 31:1-46.
  5. ↑ Fine, J. Iron Poisoning. Curr Probl Pediatr, Vol 30, Iss 3, p 71-90, March 2000
  6. ↑ The Royal Children's Hospital Melbourne Clinical Practice Guidelines. 2020. https://www.rch.org.au/clinicalguide/guideline_index/Iron_poisoning/
  7. ↑ Everson GW, Oudjhane K, Young LW, Krenzelok EP. Effectiveness of abdominal radiographs in visualizing chewable iron supplements following overdose. Am J Emerg Med. 1989 Sep;7(5):459-63. doi: 10.1016/0735-6757(89)90245-3. PMID: 2757710.
  8. ↑ Lacouture PG et al. Emergency assessment of severity in iron overdose by clinical and laboratory methods. J Pediatr 1981; 99:89-91.
  9. ↑ Hoffman RS et al. Goldfrank's Toxicologic Emergencies. 10th Ed. Pg 618-219. McGraw Hill, 2015.
  10. ↑ Position paper: Whole bowel irrigation. J Toxicol Clin Toxicol 2004; 42:843-854.
  11. ↑ Movassaghi N. et al. Comparison of exchange transfusion and deferoxamine in the treatment of acute iron poisoning. J Pediatr 1969; 75:604-608.
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