Iron supplements are widely available, particularly in homes with small children and young women. The attractiveness of the bright color and sugar coating of the tablets and their initial distribution in non–child-resistant vials made children susceptible to ingestion. The 1997 Federal requirement that all iron-containing pharmaceuticals containing more than 30 milligrams of elemental iron be distributed only in blister packs reduced the reported incidence of iron ingestion and deaths in young children.^1,2 This requirement was removed in 2003, but blister packs remain in common use along with child-resistant bottles, and serious iron poisonings in young children have remained low.² Women of childbearing age are at risk for intentional iron overdose due to the availability of iron and increased stress during pregnancy and the postnatal period.³ Children with inadvertent overdoses^4,5 and adults with intentional overdose⁶ are at risk of serious toxicity or death.

Total-body iron store averages about 4 grams in adults; the range is between 2 and 6 grams, with less iron in women than in men. About two thirds of the body’s iron is incorporated into hemoglobin, and the remainder is found in other iron-containing proteins such as myoglobin, cytochromes, and other enzymes and cofactors, or is stored as ferritin. The recommended daily intake of iron is about 8 milligrams for boys, adult men, and nonmenstruating women; 18 milligrams for menstruating women; and 27 milligrams for pregnant females.⁷ Because excess iron is toxic, the body uses several mechanisms to maintain iron homeostasis: serum protein binding, intracellular storage, and, most importantly, regulation of GI tract absorption.⁸

The oral bioavailability of iron depends on the formulation ingested. Inorganic iron has <10% bioavailability, with ferrous iron (Fe²⁺) better absorbed than ferric iron (Fe³⁺). Common ionic formulations include ferrous chloride, ferrous fumarate, ferrous gluconate, ferrous lactate, and ferrous sulfate (Table 198-1). Nonionic formulations include carbonyl iron and iron polysaccharide (iron dextran). Most dietary iron is in the ferric form and chelated to the heme moiety. Following ingestion, the ferric ion is separated from heme and reduced to ferrous iron by a brush border ferrireductase. Chelated iron, such as that found in meat, is more readily absorbed than the iron in ionic preparations. Commercially available formulations of iron chelated with amino acids (e.g., glycinate) mimic the benefits of dietary meat for iron absorption (Table 198-1).

Ferrous iron is transported into enterocytes by a membrane proton-coupled metal transporter.⁷ Within the enterocyte, ferrous iron is oxidized to ferric iron. Transferrin, a serum protein, serves as a carrier and moves ferric iron from the enterocytes into the circulation and transports iron through the body. The serum total iron-binding capacity assay primarily measures the amount of serum transferrin and is generally two to three times the normal serum iron concentration (50 to 170 micrograms/dL or 9 to 30 micromol/L). Iron is stored within the body in the form of ferritin, a large intracellular storage protein that can reversibly bind as many as 4500 molecules of iron. Ferritin can also be incorporated by phagolysosomes to form hemosiderin granules. In adults, about 0.5 to 1 gram of elemental iron is stored as ferritin and hemosiderin, primarily in the bone marrow, spleen, and liver. In iron deficiency, iron is mobilized from ferritin and transported via transferrin to the hematopoietic cells in the spleen and bone marrow, where it is incorporated into appropriate molecules.⁸ Under normal conditions, unbound iron, or free iron, does not exist within the body, and essentially all circulating plasma iron is normally bound to transferrin.

There is no physiologic mechanism for removal of iron once it has entered the body.⁷ Regulation of GI iron uptake and limitation of absorption by sloughing of mucosal cell containing surplus iron are the principal mechanisms for maintaining physiologic iron concentrations.⁷

PATHOPHYSIOLOGY

Iron is a potent catalyst for the production of oxidants such as free radicals.⁹ Through this mechanism, iron is a direct GI tract irritant and causes vomiting, diarrhea, abdominal pain, mucosal ulceration, and bleeding soon after a significant ingestion. As the mucosal surface is injured, the regulatory enterocyte barrier is compromised, and free iron passes unimpeded into the blood, becoming systemically available.

Free iron disrupts critical cellular processes and induces acidosis and widespread organ toxicity. It enters the mitochondria, where it inhibits oxidative phosphorylation by disrupting the electron transport chain, which results in metabolic acidosis with an elevated lactate. Production of toxic hydroxyl radicals, induction of membrane lipid peroxidation, liberation of hydrogen ions from reduction of ferrous iron, and hypotension all contribute to the metabolic acidosis seen with acute iron toxicity. Hepatotoxicity occurs as the portal blood supply delivers a large amount of iron to the liver. In addition, coagulopathy unrelated to hepatotoxicity may occur through inhibition of thrombin formation and the effect of thrombin on fibrinogen. Myocardial and vascular dysfunction result from vasodilation, negative ionotropic effect, and direct myocardial iron deposition.

TOXICITY

The amount of ingested elemental iron correlates with the potential for toxicity (Table 198-2). Toxic effects are reported after oral doses as low as 10 or 20 milligrams/kg of elemental iron. In general, moderate toxicity occurs at doses of 20 to 60 milligrams/kg of elemental iron, and severe toxicity can be expected following ingestion of >60 milligrams/kg of elemental iron.⁶ The most commonly prescribed formulation, a ferrous sulfate 325-milligram tablet, contains 65 milligrams of elemental iron, and approximately 20 to 35 tablets would be expected to produce moderate toxicity after an acute ingestion in an adult. Pediatric multivitamins typically contain 10 to 18 milligrams of elemental iron per tablet, and this reduced amount is associated with a near absence of fatalities after ingestion of iron-containing pediatric multivitamins in children compared with adult iron supplements.¹⁰ Ferric chloride poisoning can occur with occupational inhalation, accidental ingestion through mislabeling, and suicidal ingestion.¹¹ Ingestion of commercially available chemical hand warmers, containing 95 to 120 grams of reduced elemental iron (not an iron salt), may cause corrosive injury of the esophagus and stomach¹² and result in significant iron absorption with potential toxicity.¹³

Exceptions to the correlation of ingested dose and toxicity include chelated iron and carbonyl iron. Despite their increased iron content, chelated sources of supplemental iron are less toxic than nonchelated iron in overdose, because the ligand sterically limits the iron from participating in redox reactions.¹⁴ Similarly, carbonyl iron is a nonionic iron molecule that does not participate in redox reactions, and the limited experience with overdose of carbonyl iron suggests a lower incidence of toxicity compared with ingestion of an equivalent amount of ionic iron.¹⁵

Five stages of clinical toxicity are traditionally described, although in more practical terms, acute iron toxicity can be considered to manifest in two clinical stages: local GI tract toxicity and systemic toxicity.

Stage 1 of iron poisoning is characterized by abdominal pain, vomiting, and diarrhea.¹⁶

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