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

Toxicity

• Toxicity determined by mg/kg of elemental iron
• Total amount of elemental iron ingested can calculated by multiplying the estimated number of tablets by the percentages of iron in the tablet preparation
• Clinical severity is based approximated by elemental dose per kilograms:

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

• 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.

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%

Pathophysiology

• Direct caustic injury to gastric mucosa
• 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
• Increased capillary permeability
  • Hypotension
  • Venodilation
  • hypovolemic shock
• Portal vein iron delivery to liver
  • overwhelm storage capatcity 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

Iron Toxicity Stages

Staging	Clinical Effect	Time Frame
Stage 1	GI irritation: nausea and vomiting, abdominal pain, diarrhea	30-60 mins
Stage 2: latent	reduced GI symptoms	6-24 hours
Stage 3: shock and metabolic acidosis	metabolic acidosis, lactic acidosis, dehydration, coags, renal failure	6-72 hours
Stage 4: hepatotox	hepatic failure	12-96 hours
Stage 5: bowel obstruction	GI bowel scarring/healing	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)

Differential Diagnosis

Heavy metal toxicity

• Aluminum toxicity
• Antimony toxicity
• Arsenic toxicity
• Barium toxicity
• Bismuth toxicity
• Cadmium toxicity
• Chromium toxicity
• Cobalt toxicity
• Copper toxicity
• Gold toxicity
• Iron toxicity
• Lead toxicity
• Lithium toxicity
• Manganese toxicity
• Mercury toxicity
• Nickel toxicity
• Phosphorous toxicity
• Platinum toxicity
• Selenium toxicity
• Silver toxicity
• Thallium toxicity
• Tin toxicity
• Zinc toxicity

CAT MUDPILERS

• C-Cyanide
• A-ASA, Alcohol
• T-Toluene
• M-Methanol, Metformin
• U-Uremia
• D-DKA
• P-Paraldehyde, Post-ictal lactic acidosis (transient, 60-90 min), Phenformin (withdrawn in 1970s)
• I-Iron, INH, Inhalents, Inborn Errors
• L-Lactic Acidosis
• E-Ethylene glycol, Ethanol
• R-Rhabdomyolysis
• S-Salicylates, Solvents, Starvation

Evaluation

Work-Up

• 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 (usually around 4hrs post ingestion although very high doses may lead to delayed peak):

• <300 mcg/dL: nontoxic or mild
• 300-500 mcg/dL: Significant GI symptoms and potential for systemic toxicity
• >500 mcg/dL: Moderate to severe systemic toxicity
• >1000 mcg/dL: severe systemic toxicity and increased morbidity

If unable to obtain a serum iron level a glucose > 150mg/dL and leukocyte count above 15000 is 100% specific and 50% sensitive in predicint=g levels > 300mcg/mL

Management

Observation x 6 hrs

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

Whole bowel irrigation

• Consider only for large overdose with visible pills in the stomach on x-ray
• Promotes increased gastric emptying and avoids large bezoar formation

Deferoxamine

• Systemic toxicity and iron level > 350 mcg/dL
• Metabolic acidosis
• Progressive symptoms
• Serum iron level >500 mcg/dL
• large #of pills on KUB
• estimated dose > 60mg/kg Fe2+
• Administered IV or IM because of poor oral absorption
• one mole of Deferoxamine (100mg) bind one mole of iron (9mg) to form ferrioxamine
  • vin-rose urine (ferrioxamine is a reddish compound)
• 15mg/kg/hr (determined empirically and never clinically tested), max 35mg/kg/hr
  • can start slower at 8mg/kg/hr if concern for hypotension and uptitrate
• can give 90mg/kg IM if unable to obtain IV however IVF is critical so IV access should be established ASAP
• can cause 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

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

Authors

Daniel Ostermayer, Jordan Swartz, Ann Huang, Ross Donaldson, Marissa Camilon, Neil Young, Kevin Lu, Aaron Snyder, Lisa Yee, Claire, Michael Hwang, Kenn Ghaffarian, Michael Holtz