Toxicity Associated with Iron

At a Glance

Acute iron poisoning from accidental ingestion of iron supplementation is one of the leading causes of pediatric overdose mortality; therefore, iron toxicity should be considered in any case of pediatric overdose.

The clinical presentation of iron toxicity manifests in four distinct stages:

  • Stage I (30 min to 6 hours) includes predominantly gastrointestinal effects, such as vomiting, diarrhea, and acute gastrointestinal hemorrhage. Central nervous system and cardiovascular effects (i.e., lethargy, hypotension, and shock) may also be present. Most patients with mild to moderate toxicity do not progress past this stage, and symptoms resolve within 4-6 hours.

  • Stage II (6-24 hours) is described as “quiescent” with modest improvement in gastrointestinal, central nervous system, and cardiovascular symptoms. This stage may not occur in severe cases.

  • In Stage III (12-48 hours), there is a recurrence of the severe systemic effects with gastrointestinal symptoms, shock, metabolic acidosis, coagulopathy, and rarely acute respiratory distress syndrome. Hepatotoxicity may develop within 12-96 hours.

  • A late Stage IV (4-6 weeks after recovery) is described with evolution of gastric or intestinal strictures in which patients present with signs of gastric outlet or proximal intestinal obstruction.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The diagnosis of iron overdose can be made by documenting excessive amounts of iron in serum 4-6 hours after ingestion (8 hours for slow-release iron).

  • Less than 350 mcg/dL is associated with minimal toxicity.

  • 350-500 mcg/dL with mild to moderate toxicity

  • greater than 500 mcg/dL with serious systemic toxicity

Most serum iron assays are easily performed on automated chemistry analyzers and include three steps: iron is first released from transferrin by decreasing the pH of the serum; the iron is then reduced from Fe3+ to Fe2+; finally, iron is complexed with a chromogen, such as bathophenanthroline or ferrozine. Such iron-chromogen complexes have an extremely high absorbance at the appropriate wavelength, which is proportional to iron concentration.

Other laboratory testing in seriously ill patients should include electrolytes, blood urea nitrogen, liver enzymes (e.g., alanine aminotransferase, aspartate aminotransferase, bilirubin), arterial blood gas, complete blood count (CBC) with differential, prothrombin time, partial thromboplastin time, and type and crossmatch.

Metabolic acidosis with an elevated anion gap is typically present in patients with severe iron toxicity. In absence of serum iron concentrations the presence of anion gap metabolic acidosis may be the best predictor of toxicity.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Since photometric methods are used to measure serum iron concentrations, testing specimens containing common spectral interferences, such as hemolysis, hyperbilirubinemia, and hyperlipidemia, should be avoided. In addition to the spectal interference from hemoglobin, iron in hemoglobin can also be measured in hemolyzed specimens, introducing another level of interference. Plastic or gel-containing tubes that form a physical separation between erythrocytes and plasma during centrifugations minimize the hemoglobin interference.

Because ferric ion has a higher affinity for desferoxamine (DFO), an iron chelator, than transferring, photometric iron assays are unreliable after administration of DFO. DFO has a serum half-life of 50 minutes, so specimens should be collected at least 4 hours after last administration of DFO to minimized interference.

Because of the large quantities of iron in the environment, laboratories need to ensure that glassware, water, and reagents are not contaminated with iron.

What Lab Results Are Absolutely Confirmatory?

A serum iron concentration 4-6 hours after ingestion is most predictive of the clinical course. Concentrations greater than 500 mcg/dL are usually considered toxic, whereas concentrations between 350 and 500 mcg/dL in asymptomatic patients are usually predictive of a benign outcome.

In patients taking desferoxamine (DFO), atomic absorption spectrometry (AAS) can be used to accurately measure iron concentrations.

Additional Issues of Clinical Importance

Body iron content is 3-5 grams in adults with 70% in ferrous form (Fe2+) in hemoglobin and myoglobin and 25% in the ferric state (Fe3+) in transferrin, ferrition, and hemosiderin. Iron is absorbed in the duodenum and jejunum in the ferrous state. Plasma iron is then bound in the ferric state to transferring (30-40% saturation). The normal physiologic regulation of iron contributes to the likelihood and severity of toxicity for several reasons:

  • There is limited physiologic regulation of the amount of iron absorbed in the gastrointestinal tract with significantly higher absorbance rates in children.

  • Normally transferrin (iron binding protein in plasma) and ferritin (iron storage protein that sequesters iron intracellularly) protect cells by binding iron; however, the protective mechanisms are overwhelmed with acute intoxication.

  • There is no specific mechanism for iron elimination, except for sloughing of intestinal cells and menstrual bleeding.

Iron toxicity is manifested by several predictable multiorgan system disturbances. GI toxicity includes vomiting, diarrhea, crampy abdominal pain, hematemesis, and melena due to direct mucosal corrosion. The cardiovascular system is affected by free iron damage to small vessels with consequential post-arteriolar dilation, venous pooling, capillary leak, decreased venous return, and shock. Processes that contribute to metabolic acidosis include mitochondrial dysfunction (lipid peroxidation of mitochondrial membranes); in situ conversion of iron from ferrous to ferric state, which releases protons; and interference with Kreb cycle enzymes and lactic acidosis (from noted cardiovascular disturbances).

Hepatotoxicity occurs as free iron accumulates in the liver with resultant cloudy swelling, followed by periportal disturbances, including inhibition of thrombin synthesis. The toxicity to the central nervous system is usually related to volume depletion and poor perfusion.

Chelation therapy is the mainstay of modern treatment for systemic effects of severe iron poisoning. The specific iron chelator DFO binds iron and hastens its excretion in urine.

Errors in Test Selection and Interpretation

Several additional nonspecific studies may correlate with toxic clinical course, including elevated serum glucose (>150 mcg/dL) and leukocytosis (>15,000/mm3), but these tests are not sensitive or specific enough to have clinical utility.

In iron toxicity, iron exceeds total iron binding capacity (TIBC); however, measurement of TIBC and the ratio of iron to TIBC are not recommended because of limitations in the methodology. In the TIBC assay, excess iron is added to serum to bind all available iron-binding sites. Then excess unbound iron is removed by an absorbent material prior to measurement of bound iron. In the presence of excess endogenous iron, this material may be insufficient to remove all iron, leading to a false increase in TIBC.

DFO binds free iron, creating ferrioxamine, which is excreted in urine. Urine containing ferrioxamine may be brick orange or “vin rose” color. DFO challenge tests consist of administering an intramuscular dose of DFO and using the appearance of a “vin rose” colored urine to predict iron toxicity and the effectiveness of chelation therapy. These tests are no longer valid, as some patients with toxic iron concentrations (>500 mcg/dL) were found to have urine that did not change color after administration of DFO.

Serum iron concentrations obtained at less than 4 hours or more than 24 hours post ingestion are not accurate indicators or predictors of toxicity, because results may be falsely low. In some cases of iron overdose, because of the distribution of iron to tissues, iron concentrations may become undetectable by 24 hours and mislead clinicians interpreting the results.

Serum iron is useful to confirm the diagnosis of iron toxicity if drawn at the appropriate time. However, serum iron concentrations cannot always be correlated with the severity or clinical phase of iron intoxication, because iron assays measure the free iron circulating in the blood and it is the intracellular iron that causes systemic toxicity.