Iron is readily available as ferrous salts, either alone or in combination with other minerals and vitamins. Its common salts are ferrous gluconate, sulfate, fumarate, and succinate, which are 12%, 20%, 33%, and 35% elemental iron, respectively. These fractions are important because toxicity is related to the amount of elemental iron ingested. Iron is marketed in both conventional and delayed-release formulations. Product labels may not specify the tablet formulation, an important determinant of the onset and duration of toxicity. Carbonyl iron is a highly purified form of metallic iron. It is uncharged and not a salt [4].

Iron absorption, transport, and storage are well reviewed elsewhere [5]. Because there is no endogenous mechanism for iron excretion, total body iron is a function of the absorptive process. Absorption occurs in the proximal small bowel, with approximately 10% of the ingested dose absorbed, but with tenfold variations depending on iron stores and the amount ingested. The actual mechanism of iron absorption is not well understood, but it is believed to be an active process. Iron can also be passively absorbed once the active process is saturated, such as after a massive overdose [6]. Even in such a situation, a relatively small amount (15%) is actually absorbed [6].

Peak serum iron concentrations occur within 4 to 6 hours after an overdose of conventional tablets. The time to peak serum concentration is not known for delayed-release products. The half-life after therapeutic dosing is approximately 6 hours [5], with rapid decline because of tissue distribution. In plasma, iron is bound to transferrin, a specific β₁-globulin responsible for iron transport throughout the body. In iron overdose, transferrin-binding capacity is exceeded, but free plasma iron does not truly exist. Iron complexes with other plasma proteins and organic ligands and is referred to as nontransferrin-bound plasma iron [7]. However, it is only loosely bound and is quite available to produce tissue damage and organ dysfunction.

There are two typical overdose scenarios: innocent overdose by young children and purposeful overdose by adolescents and adults. Serious iron overdose in young children frequently involves the ingestion of a product intended for adults, typically a prenatal iron supplement. Ingestion of pediatric preparations, such as multivitamin plus iron tablets, is more common [8]; such preparations are unlikely to result in significant toxicity because of their low elemental iron content (as little as 4 mg per tablet). Although liquid iron preparations are often found in homes with infants and toddlers, there are no published cases of clinically important iron poisoning because of these products. Iron overdose is less common among teenagers and adults, but when it occurs, it is typically more severe. Of particular note is the high incidence of deliberate iron overdose in pregnant women [9].

Iron exerts both local and systemic effects. The local irritant effect on the gastrointestinal tract results in nausea, vomiting,
abdominal cramps, and diarrhea. These symptoms are produced by relatively small doses (20 mg per kg of elemental iron). The degree of systemic toxicity is, however, dose related. Because most published data are anecdotal, specific values have not been established. In the pediatric literature, more than 60 mg per kg of elemental iron produces significant systemic toxicity [10], with a lethal dose being 200 to 250 mg per kg [10]. Both the figures are likely overestimates; more realistic figures are probably half as much. The lowest reported lethal dose for a toddler is approximately 75 mg per kg of elemental iron [11]. The author’s own experience and that of others [12] suggests that the range of toxicity in adults is similar to that in children. An ingestion of 1.5 g of elemental iron by an adult should be cause for concern. Adults have died after ingestion of as little as 2 [13] and 5 g [12] of elemental iron; the former patient had significant hepatic disease and the latter ingested 70 mg per kg. There have been no published reports of serious or fatal poisoning from the ingestion of carbonyl iron products [4]. Although its bioavailability after therapeutic dosing is similar to ferrous salts, its absorption is limited after an overdose. Single doses of 10 g (140 mg per kg) have been tolerated in humans.

Poor, unpredictable absorption of iron and its unknown capacity for binding by ferritin and as hemosiderin contribute to uncertainty regarding the toxic dose. As reflected by serum iron concentrations, which are measured in micrograms per deciliter, the size of the potentially toxic iron pool is likely to be small—on the order of milligrams—even after gram quantities of iron have been ingested. That the body burden of iron is relatively small after an overdose is not well appreciated, but it has important implications for the dose and duration of deferoxamine therapy.

Iron itself is neither caustic nor corrosive. It is a potent catalyst of free radical formation, which results in highly reactive species that attack many intracellular molecules [14]. Iron-generated free radical formation is thought to contribute to acute iron toxicity [15] and to be responsible for much of the damage and dysfunction of chronic iron overload [7].

Free radicals produce damage at their site of origin. Because of local protective mechanisms, a significant concentration of free radicals is required to cause damage. Sites exposed to high iron concentrations are most susceptible to injury. One such area is the gastrointestinal tract. Gastrointestinal mucosal necrosis and bleeding [16] may occur without systemic toxicity. Notably, gut toxicity can occur distally with proximal sparing [16] and may be absent in the face of fatal systemic poisoning [6].

Systemic toxicity results when the absorbed iron is transported to target organs, such as the liver and heart. Nontransferrin-bound iron is rapidly cleared by the liver [17], putting this organ at risk for toxicity [18].

Traditionally, acute iron intoxication is divided into five clinical stages [19]: gastrointestinal toxicity, relative stability, circulatory shock, hepatic necrosis, and gastrointestinal scarring. An orderly progression through all these stages may not occur. Fatalities are possible without significant gastrointestinal involvement [6], and hepatotoxicity may be absent in otherwise severe poisoning. Presenting signs and symptoms depend on the time since ingestion.

The most common time of presentation is during the first stage (gastrointestinal toxicity), when abdominal pain, vomiting, diarrhea, hematemesis, and hematochezia are seen. Gastrointestinal toxicity usually occurs within the first few hours of overdose. If enteric-coated tablets have been ingested, gastrointestinal toxicity can be delayed as long as 12 hours. The severity of this stage is variable. Life-threatening hypovolemic shock may occur, especially if initial symptoms were severe or ignored. Occasionally, segmental intestinal infarction may occur, necessitating bowel resection [16]. Isolated hepatotoxicity or gastrointestinal obstruction would be an unlikely presentation of iron poisoning.

The second stage, a period of relative stability, follows initial gastrointestinal symptoms. Apparent improvement in the patient’s clinical status should not lead to complacency. Patients are not completely asymptomatic; careful assessment and repeated monitoring should document some degree of hypovolemia, circulatory shock, and acidosis.

The third stage, circulatory shock, can occur within several hours of iron overdose and may persist up to 48 to 72 hours. Its pathogenesis is complex and poorly understood and is based on the results of limited experimental animal data [20,21,22,23]. Circulatory shock may be hypovolemic, distributive, or cardiogenic. The time of onset can be somewhat helpful in elucidating its cause, but there is considerable overlap. Shock occurring within a few hours of the overdose suggests hypovolemia secondary to fluid and, rarely, blood loss from the gastrointestinal tract. Hyperferremia-associated coagulopathy may contribute to bleeding [24]. Distributive shock depends on iron absorption and begins within the first 24 hours. Suggested mechanisms include direct effects of iron or ferritin or an effect mediated by release of vasoactive substances, resulting in decreased vascular tone or increased vascular permeability [22]. Cardiogenic shock usually occurs 1 to 3 days after overdose [25].

The occurrence of metabolic acidosis in iron poisoning usually precedes circulatory shock. Acidosis is a direct toxic effect of iron that occurs after the plasma’s capacity to bind the absorbed ferric ion has been exceeded. When this occurs, the ferric ion becomes hydrated and protons are released [Fe³⁺ + 3H₂O → Fe(OH)₃ + 3H⁺]. Thus, each unbound ferric ion generates three protons. The acidosis can be quite profound, requiring large amounts of bicarbonate for treatment [23]. Other factors contributing to acidosis include the generation of organic acids resulting from iron’s interference with intracellular oxidative metabolism and lactate production secondary to shock.

The fourth stage, hepatotoxicity, is second only to shock as a cause of death [18]. It may occur any time during the first 48 hours after overdose. The pathogenesis of hepatic necrosis is believed to be iron-catalyzed free radical production and subsequent lipid peroxidation of hepatic mitochondrial membranes [15].

The fifth stage, gastrointestinal scarring, is the consequence of iron’s local action on the gut and usually occurs 2 to 4 weeks after overdose. Ongoing and protracted abdominal pain during the first week is associated with the later development of this complication [16]. Most cases involve the gastric outlet, but isolated strictures of distal intestine have been reported [16].

The consequences of iron poisoning in pregnant women are no different from those in other patients, but because transplacental iron passage is an energy-requiring saturable process, the fetus is relatively protected [26]. Although deferoxamine in animals is associated with potential harm to the fetus, its risk in humans is overemphasized [26]. The health of the fetus depends on its mother, and treatment should be no different from that given to a nonpregnant woman.