Chapter 198: Iron

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 Iron is directly irritating and corrosive to the GI tract and typically induces vomiting within the first few hours following ingestion. Vomiting is the clinical sign most consistently associated with acute iron toxicity. Patients with symptoms of gastric irritation may either recover over several hours or progress to systemic toxicity. The absence of GI symptoms within 6 hours of ingestion essentially excludes a significant iron ingestion.

Stage 2, or the "latent" stage, does not always occur. If present, this stage is a 6- to 24-hour interval following ingestion during which GI symptoms may resolve and falsely reassure the patient and physician. However, this is not a truly quiescent phase. Patients with significant toxicity have ongoing clinical illness and progressive systemic deterioration because of volume loss and worsening metabolic acidosis, despite the absence of GI symptoms. Alternatively, the resolution of GI findings may signal the end of mild poisoning, and in such a circumstance, the results of the patient's laboratory studies should be normal.

Stage 3 is characterized by systemic toxicity from iron-induced disruption of cellular metabolism with resultant shock and lactic acidosis. Iron-induced coagulopathy may worsen bleeding and hypovolemia. The coagulopathy may be biphasic, with prolonged prothrombin time and partial thromboplastin time within the first 24 hours. This initial coagulopathy appears to be reversible with chelation therapy, because it is free iron that initially interferes with the activity of factors in the coagulation cascade. Subsequent coagulopathy is from iron-induced hepatic injury that reduced coagulation factor production. During stage 3, renal failure, cardiomyopathy, and failure of other critical organ systems may also occur.

Stage 4, the hepatic stage, develops 2 to 5 days following ingestion.^6,17 It results from iron uptake by the reticuloendothelial system with local lipid peroxidation; it manifests as elevation of aminotransferase levels and may progress to hepatic failure.

Stage 5 refers to delayed sequelae, including gastric outlet obstruction secondary to the corrosive effects of iron on the pyloric mucosa. Delayed sequelae are rare and occur 4 to 6 weeks after ingestion.¹⁶

LABORATORY TESTING

Laboratory tests should include CBC, determination of serum electrolyte levels, renal and liver function studies, coagulation function tests, serum glucose, and serum iron levels, with the understanding that these results are to assess the overall condition of the patient, because iron toxicity is largely a clinical diagnosis.

Arterial blood gas analysis and serum lactate determination are usually unnecessary in mild cases, because determination of serum electrolyte levels (anion gap evaluation) usually yields all the important information. However, in patients with moderate to severe toxicity or in those with respiratory compromise, arterial blood gas results yield useful information regarding the patient's acid-base status. With moderate to severe ingestions, the blood bank should perform blood typing and screening in anticipation of potential need.

Interpret serum iron levels to assess toxicity and direct management with caution. In general, serum iron levels measured within 4 to 6 hours after an acute ingestion correlate with the severity of toxicity (Table 198-2), but low serum iron levels do not necessarily mean absence of toxicity. Serum iron levels may be low because of variable times to peak level following ingestions of different iron preparations, and treatment with deferoxamine can artificially lower serum iron levels. Serum total iron-binding capacity has little value in the assessment of iron-poisoned patients. It becomes falsely elevated in the presence of elevated serum iron levels or deferoxamine, and significant organ damage occurs despite exceeding the serum iron level.

IMAGING

Standard ferrous sulfate tablets and reduced iron are radiopaque and frequently visible on routine radiographs,^12,13 and this may help guide GI decontamination when present. However, many iron preparations are not routinely detected, including pediatric chewable and liquid preparations, and absence of radiopaque material on radiographs does not exclude iron ingestion.²

Iron poisoning is a clinical diagnosis. Signs and symptoms consistent with iron poisoning should guide treatment, rather than serum iron concentrations alone (Figure 198-1). Patients who are asymptomatic on ED arrival, have not ingested a potentially toxic amount, and have normal findings on physical examination can be observed and do not require specific medical treatment. Patients who vomit once or twice from the gastric irritant effects of iron but who are otherwise asymptomatic can also be observed and may require no specific treatment.

Patients with clinical toxicity should first be stabilized with attention to airway, breathing, and circulation, after which GI decontamination and chelation therapy with deferoxamine may proceed.^2,18 Antiemetics such as metoclopramide or ondansetron should be used for repetitive vomiting. Patients with persistent vomiting and abnormal vital sign values or other signs of poor perfusion or shock should undergo aggressive fluid resuscitation and treatment with deferoxamine. Coagulopathy should be treated with parenteral vitamin K₁ and/or fresh frozen plasma, as indicated. Significant blood loss may require transfusion.

GI DECONTAMINATION

Do not use ipecac syrup because it may obscure the initial signs of clinical toxicity and is not proven to be more effective at gastric emptying than is iron-induced vomiting.¹⁹ Do not give activated charcoal, cathartics, oral sodium bicarbonate, or phosphosoda. Activated charcoal does not adsorb significant amounts of iron in an overdose to prevent toxicity, and its use may complicate endoscopy if that becomes necessary.¹⁹ Cathartics should not be given. Orogastric lavage may not be effective if the ingested tablets are large or if several hours have elapsed since ingestion, but it may be useful in rare cases if performed shortly after large ingestion, prior to significant vomiting, or if a modified-release formulation was ingested.^2,20 There are no data to support the efficacy of oral sodium bicarbonate or phosphosoda in forming insoluble iron salts and preventing absorption.^2,19

Radiopaque tablets visible on radiography indicate potential for progressive toxicity and can guide decontamination measures (Figure 198-2). Whole-bowel irrigation with a polyethylene glycol solution is effective in children with large iron ingestions.^2,21 Administration of 250 to 500 mL/h in children or 2 L/h in adults by nasogastric tube may clear the GI tract of iron pills before absorption can occur.²¹ Endoscopy can remove large iron loads or an iron-containing gastric bezoar.^22,23 Laparoscopic gastrotomy may be a rare option for removal of an iron-containing gastric bezoar in profoundly ill patients when other measures are unsuccessful or impractical.²⁴

DEFEROXAMINE

Deferoxamine is chelating agent derived from Streptomyces pilosus used to treat iron toxicity. Deferoxamine binds free iron, iron from plasma, and iron from inside cells and mitochondria, but not iron bound to organic molecules. Upon binding, it forms the complex ferrioxamine, which is renally excreted. Deferoxamine can be safely administered to children and pregnant women.³ Although deferoxamine binds a small amount of iron (9 milligrams of elemental iron for each 100 milligrams of deferoxamine) and thus chelates only a small fraction of the total amount of iron ingested, removing this small but critical amount of iron often proves clinically effective in restoring cellular function. Deferoxamine may work by other mechanisms in addition to binding excess iron, and complete binding of ingested iron is not the goal of therapy.

Administration of deferoxamine is indicated in the iron-poisoned patient with systemic toxicity, persistent emesis, metabolic acidosis, progressive symptoms, or a serum iron level predictive of moderate to severe toxicity (Figure 198-1).^2,18 The manufacturer recommends IM administration for all patients not in shock,²⁵ but most toxicologists advise IV administration rather than IM administration because of the unreliability of IM absorption and enhanced iron excretion following IV administration.^2,18

The initial deferoxamine adult dose is 1000 milligrams (children 50 milligrams/kg) IV. Begin the infusion slowly, starting at 5 milligrams/kg per hour to avoid producing a rate-related drop in blood pressure. Aggressive volume resuscitation may be required in the volume-depleted, hypotensive, iron-toxic patient who is in need of deferoxamine. Hypotension is not a contraindication to IV deferoxamine administration.

The infusion rate of deferoxamine IV can be increased up to 15 milligrams/kg per hour as tolerated. The recommended amount of deferoxamine for an acute iron overdose is a total of 360 milligrams/kg or 6 grams in an adult during the first 24 hours, typically ordered as 500-milligram infusions over 4 to 8 hours after the initial 1000-milligram dose.^18,25 Amounts larger than this are associated with complications, including mucormycosis, renal insufficiency or failure,²⁶ pulmonary toxicity,²⁷ and sepsis from Yersinia enterocolitica, which may be related to duration of therapy.

As ferrioxamine is excreted, the urine color changes to what is classically called "vin rosé" but is more typically a brown or rusty hue.²⁸ Theoretically, the disappearance of the "vin rosé" color means that the patient no longer has significant toxicity because there is no more free iron available to be complexed with deferoxamine and excreted. False-negative results, color-change latency, and difficulty in visualizing a color change can limit the utility of this test.¹⁸

There is uncertainty regarding the duration of deferoxamine therapy.^2,18,25 Recommended endpoints include clinical recovery and normal iron levels, measurement of normal iron-to-creatinine ratios, and clinical recovery with normal iron level in conjunction with normal urine color. Clinical recovery of the patient is probably the most important factor guiding the decision to terminate therapy because measured iron levels are artificially depressed by the presence of deferoxamine and urine color change can be unreliable. Continue deferoxamine therapy in patients who continue to exhibit severe iron toxicity after 24 hours of treatment, using a decreased rate to avoid the associated risks mentioned earlier.

OTHER THERAPIES

Oral iron chelators—deferiprone and deferasirox—reduce iron absorption when administered simultaneously or within 1 hour of iron ingestion.²⁹ However, there is no evidence of benefit in human overdoses, and oral chelation therapy would theoretically be of use only when taken promptly after the iron ingestion; thus their use is limited by the time to presentation for treatment and the significant vomiting expected with clinical iron toxicity. Oral iron chelating agents should NOT replace intravenous deferoxamine when chelation is indicated in clinical iron toxicity.

Although hemodialysis and hemofiltration do not remove iron, such treatment may be necessary to remove the deferoxamine–iron complex in patients with renal failure who are unable to excrete the complex in their urine.^18,30,31 Severe iron poisoning can be treated with exchange transfusion in addition to deferoxamine therapy.³²

Patients who have not ingested a potentially toxic amount of iron, who remain asymptomatic (other than vomiting once or twice from the gastric irritant effects of iron), and who have normal findings on physical examination for a period of 6 hours can be safely discharged or transferred for appropriate mental health evaluation. Patients who receive deferoxamine therapy should be admitted to the intensive care unit. The regional poison control center should be contacted for both data collection purposes and assistance with management.