URGENT CARE Special Section Ferrous Sulfate Urgent Care Section Urgent Care 100 Tablets Recognizing and Managing Iron Toxicity Christian Balmadrid, MD Since urgent care physicians will encounter patients Senior Emergency Medicine Resident suffering from excess iron intake only occasionally, iron toxicity can be challenging when it does present. The Michael Bono, MD Professor of Emergency Medicine authors review the basic science and the signs, symptoms and course of illness and provide an update on the clinical Eastern Virginia Medical School Norfolk, Virginia management of these patients. © 2009 Punchstock 36 EMERGENCY MEDICINE | MAY 2009 www.emedmag.com IRON TOXICITY cute care settings form the first line of defense against the relatively un- TABLE 1. Common Iron Preparations common problem of toxicity from heavy metals and specifically from Compound Elemental iron Airon. If this illness presents to an urgent care ferrous sulfate 20% physician who has not maintained familiarity ferrous fumarate 33% with its effects and treatment, the potential for ferrous gluconate 12% morbidity and mortality due to misdiagnosis or inappropriate treatment is significant. ferric pyrophosphate 30% This article will review the basic science, the ferrocholinate 14% identifying signs and symptoms, and the prin- ferroglycine sulfate 16% ciples of clinical management applicable to pa- ferrous sulfate, dried 33% tients suffering from iron toxicity. We hope our ferrous carbonate, anhydrous 38% discussion will help you to be optimally prepared to provide their care, but the relatively low in- carbonyl iron 100% cidence of the diagnosis tends to make these Data extracted from: Velez LI and Delaney KA.4 cases challenging by nature. It is strongly recom- mended that a toxicologist or the regional poison control center always be consulted for suspected poisoning from iron or any other metal. an essential cofactor in the normal function of he- Section Urgent Care moglobin, myoglobin, cytochromes, and numer- CAUSES AND PATTERNS ous other catalytic enzymes. It is absorbed through OF IRON TOXICITY the digestive tract, then bound to transferrin in the Reports of iron exposure collected by the bloodstream. Normally, 15% to 35% of transfer- American Association of Poison Control Centers rin’s iron binding capacity is utilized.4 Overdoses (AAPCC) totaled approximately 35,000 in 2004.1 of iron, however, can quickly lead to transferrin More than 100 iron-containing preparations are saturation, resulting in free iron circulating in the listed in the Physicians’ Desk Reference, but the serum, which is directly toxic to organs. vast majority of cases in 2004 were, as usual, a The toxicity of iron depends on the amount of result of iron-containing multivitamin ingestions.1 elemental iron the ingested formulation contains. Unintentional ingestions by children younger than Some common iron preparations are listed in 6 years accounted for 83% of those reported cases, Table 14 and the elemental iron content of some while intentional overdoses (suicide attempts) popular multivitamin and were much more common in adults.1 Although prenatal vitamin formu- >>FAST TRACK<< intentional overdose accounted for only a small lations on the market is In children, poisonings fraction of the cases, it accounted for the majority shown in Table 2.2 While are usually the result of the admissions (58%), and resulted in a much the minimum toxic dose of ingestion of adult higher mortality rate (10% vs 1%).2 In children, and the lethal dose of iron formulations, especially pediatric multivitamin formulations are usually are not firmly established, prenatal vitamins. minimally toxic, and life-threatening poisonings it can be expected that in- are usually the result of ingestion of more potent gestion of less than 20 mg/kg of elemental iron will adult formulations, especially prenatal vitamins, usually cause no symptoms, 20 to 40 mg/kg will which have the highest iron content. In one case produce mild toxicity, 40 to 60 mg/kg will provoke control study, the birth of a sibling within 6 months moderate symptoms, and levels greater than 60 was identified as a risk factor for iron ingestion in mg/kg can lead to severe toxicity.4 children less than 3 years old.3 Iron is an essential metal, meaning it is an ele- COURSE OF ILLNESS ment that the body needs but does not produce Iron has two distinct toxic effects. First, it is di- and must extract from dietary sources. It acts as rectly caustic to the GI mucosa, leading to vom- www.emedmag.com MAY 2009 | EMERGENCY MEDICINE 37 IRON TOXICITY iting, diarrhea, and abdominal pain. In severe cases, it can re- TABLE 2. Elemental Iron Content of Select sult in hemorrhagic necrosis with Multivitamin Formulations bleeding, perforation, and peritoni- tis. Second, it impairs intracellular Preparation Elemental iron metabolism, primarily through PRENATAL VITAMINS lipid peroxidation and free radical formation. One of its most impor- NataChew Prenatal Vitamins 29 mg tant consequences is impairment of Natalins Rx 60 mg adenosine triphosphate synthesis, Natalins 45 mg which results from alteration of the CHILDREN’S MULTIVITAMINS lipid membrane of mitochondria, inhibition of enzymatic processes Bugs Bunny With Iron 18 mg in the Krebs cycle, and uncoupling Centrum Jr. Plus Iron 18 mg of oxidative phosphorylation.2,4 Centrum Kids Complete Rugrats® 18 mg In addition to its effects at the Flintstones® With Iron 18 mg cellular level, iron also acts as a di- Poly-Vi-Sol With Iron rect vasodilator, can increase cap- illary permeability, and is directly Tablet 12 mg toxic to the myocardium.2 These Drops 10 mg/mL effects, in addition to the severe Shamu and His Crew® Plus Iron 18 mg GI fluid losses that occur from the Sunkist® Complete 18 mg vomiting and diarrhea, can lead to shock in severe cases.4 ADULT MULTIVITAMINS Depending on the source, acute Centrum® 18 mg iron toxicity is typically described Centrum® Silver 4 mg in four or five stages. Signs and Complete for Men 5 mg symptoms may overlap, however. Complete for Women 10 mg As noted for each below, there is a Urgent Care Section Urgent Care classical timeline for these symp- Natural MD toms, but it may be quite acceler- Men/Basic Life Prescription 5 mg ated with larger ingestions. Women/Basic Life Prescription 5 mg Stage 1: Gastrointestinal ef- Women/Standard Life Prescription 10 mg fects, 30 minutes to 6 hours. One-A-Day® Maximum 18 mg Stage 1 is characterized primarily ® by GI effects, and is the result of One-A-Day Women’s 27 mg iron’s direct toxic effects on the GI Stresstabs® Plus Iron 18 mg mucosa. Vomiting will usually oc- cur within the first 1 to 1.5 hours Data extracted from: Liebelt LL and Kronfol R.2 following the ingestion in severe toxicity, but may be delayed up to 6 hours with enteric-coated iron tablets. Vomiting and if a patient remains asymptomatic for 6 hours is the most sensitive indicator of severe toxicity. after a presumed iron ingestion, it is unlikely that Other symptoms can include abdominal pain, di- any serious side effects will occur (again, unless arrhea, hematemesis, melena, and lethargy. Lab enteric coated iron tablets were ingested, which results will show a metabolic acidosis. If death may have delayed effects).2,4 occurs in this stage, it is usually secondary to hy- Stage 2: Latent phase, 6 to 24 hours. This is a povolemic shock. Patients with mild to moderate period of apparent recovery in which the patient’s toxicity usually will not progress beyond Stage 1, GI symptoms have resolved because the circulat- 38 EMERGENCY MEDICINE | MAY 2009 www.emedmag.com IRON TOXICITY ing free iron has redistributed into the reticuloen- dothelial system, where it no longer produces its TABLE 3. Peak Serum Iron in toxic GI effects. In severe toxicity, this stage may Correlation with Toxicity not occur at all. The challenge, clinically, is to dis- tinguish between the patient in a true latent phase Peak serum iron (μg/dL) Toxicity that may progress to more serious stages and the 50-150 none patient who only had mild GI toxicity that has now 150-300 mild resolved. Careful examination and assessment may produce clues. Although patients in the latent 300-500 moderate (rarely develop serious complications) phase may appear stable, they are not necessarily asymptomatic. There may still be poor perfusion, >500 severe (serious systemic toxicity) hyperventilation (secondary to metabolic acidosis), or oliguria (secondary to hypovolemia).2,4 >1000 significant morbidity and mortality Stage 3: Shock and metabolic acidosis, 6 to 72 hours. Patients will have severe metabolic aci- Data extacted from: Liebelt LL and Kronfol R2; Velez LI and dosis in this stage, partly as a result of hydration Delaney KA.4 of absorbed ferric ions, which releases hydrogen ions as a by-product of the reaction.2 Additionally, lactic acidosis results secondary to hypovolemia from Stage 1 may recur within the first few hours, and poor tissue perfusion as well as iron-induced resulting in further hypovolemia and hypovole- Section Urgent Care mitochondrial dysfunction.2 mic shock. A few hours later, distributive shock Different types of shock may occur in this may occur secondary to iron’s effect as a vasodi- stage, including hypovolemic, distributive, and lator and its tendency to increase vascular perme- cardiogenic shock. Gastrointestinal symptoms ability. Also of concern is iron’s direct toxicity to www.emedmag.com MAY 2009 | EMERGENCY MEDICINE 39 IRON TOXICITY the myocardium, which may lead to cardiogenic The most useful laboratory value to follow in shock within 1 to 2 days.2 acute iron toxicity is the serum iron level. Peak Other symptoms at this stage may include GI serum iron levels usually correlate with toxicity as hemorrhage, bowel perforation, iron-induced co- shown in Table 3.2,4 It is important to note, how- agulopathy (iron causes thrombin dysfunction), ever, that measurements of serum iron level reflect renal and hepatic dysfunction (leading to jaun- free iron circulating in the blood.