Iron toxicity

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

Elemental Iron Percentages
Iron Preparation % of Elemental Iron
Ferrous Fumarate33%
Ferrous Sulfate20%
Ferrous Gluconate12%
Ferric pyrophosphate30%
Ferroglycine sulfate16%
Ferrous carbonate (anhydrous)38%

Toxicity

Toxicity determined by mg/kg of elemental iron ingested[1]

Severity Elemental Iron Dose (mg/kg)^
Mild10-20
Moderate20-60
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[2]
  • 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[3]
  • 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 1GI irritation: nausea and vomiting, abdominal pain, diarrhea30 mins-6 hours
Stage 2: LatentReduced GI symptoms6-24 hours
Stage 3: Shock and metabolic acidosisMetabolic acidosis, lactic acidosis, dehydration6-72 hours
Stage 4: Hepatotoxicity/ Hepatic necrosisHepatic failure12-96 hours
Stage 5: Bowel obstructionGI mucosa healing leads to scarring2-8 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) [4]

Differential Diagnosis

Heavy metal toxicity

CAT MUDPILERS

Hyperglycemia

Evaluation

Work-Up

A serum glucose > 150mg/dL and leukocyte count above 15000 is 100% specific and 50% sensitive in predicting Fe levels > 300mcg/mL[5]

  • 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
  • Type and Screen
  • Xr KUB
    • In ambiguous cases consider abdominal xray as most Fe tabs are radioopaque


Serum Iron Concentration

Serum iron concentration can guide treatment but are not absolute in predicting or excluding toxicity

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

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

Management

Observation x 6 hrs
  • Patients with asymptomatic ingestion of <20mg/kg only require observation x 6hr
  • Volume resuscitation

Whole bowel irrigation
  • Initiate for large overdoses of iron
  • 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[6]
  • Promotes increased gastric emptying and avoids large bezoar formation[7]

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)
  • May increase to 15 mg/kg/hr (determined empirically and never clinically tested), max 35 mg/kg/hr or 6 g total per day
    • Can start slower at 5-8 mg/kg/hr if concern for hypotension and uptitrate
    • Can give 90 mg/kg IM if unable to obtain IV
    • However IVF resuscitation is critical so IV access should be established ASAP
  • Adverse reactions
    • Hypotension
    • May cause flushing (anaphylactoid reaction)
    • Rarely causes ARDS - associated with prolonged use
    • Probably safe to use 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[8]

Not Indicated

Orogastric lavage
  • Does not remove large numbers of pills and may have serious adverse events

Activated charcoal
  • Does not bind iron

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

See Also

Toxidromes

References
  1. Robotham JL, Lietman PS: Acute iron poisoning. A review. Am J Dis Child 1980; 134:875-879.
  2. Robotham JL, Lietman PS. Acute iron poisoning. A review. Am J Dis Child 1980; 134:875-879.
  3. Aisen P et al. Iron toxicosis. Int Rev Exp Pathol 1990. 31:1-46.
  4. Fine, J. Iron Poisoning. Curr Probl Pediatr, Vol 30, Iss 3, p 71-90, March 2000
  5. Lacouture PG et al. Emergency assessment of severity in iron overdose by clinical and laboratory methods. J Pediatr 1981; 99:89-91.
  6. Hoffman RS et al. Goldfrank's Toxicologic Emergencies. 10th Ed. Pg 618-219. McGraw Hill, 2015.
  7. Position paper: Whole bowel irrigation. J Toxicol Clin Toxicol 2004; 42:843-854.
  8. 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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