Iron and Heavy Metals

Foundations

Iron poisoning used to be the leading cause of poisoning death in children. In 1997 the U.S. Food and Drug Administration (FDA) required warning labels and implemented changes in the packaging of iron supplements after which there was an abrupt decrease in the number of poisonings and deaths. Although the FDA rescinded its strict packaging restrictions on iron supplements in 2003, iron poisoning currently remains relatively uncommon. In 2017, there were 6033 calls to poison centers concerning iron exposures and there were two deaths. Calls regarding multivitamins containing iron were much more common, resulting in 11,157 calls but no deaths.

Iron is an important metal that is essential to the function of hemoglobin, myoglobin, and many cytochromes and enzymes. Certain disease states result from too much or too little iron, such as hemochromatosis and anemia, respectively. Iron is absorbed mostly in the small intestine. Depending on total body stores, as little as 10% or as much as 95% of the ingested iron is taken into cells. In the cell, iron has three pathway options: storage bound to ferritin, transfer to the serum where it is bound to transferrin, or loss when the intestinal cell is sloughed off. Under normal conditions only 15% to 35% of the iron-binding capacity of transferrin is used. The total iron-binding capacity (TIBC), a crude measure of the ability of serum proteins (including transferrin) to bind iron, ranges from 300 to 400 μg/dL. Normal serum iron concentrations range from 50 to 150 μg/dL. When iron concentrations rise after a significant overdose, transferrin becomes saturated. Excess iron circulates free and unbound in the serum. Unbound iron is directly toxic to target organs.

Iron has two distinct toxic effects: (1) direct caustic injury to the gastrointestinal mucosa, and (2) impaired cellular metabolism, primarily of the heart, liver, and central nervous system (CNS). The caustic effects of iron on the gut cause the initial symptoms of vomiting, diarrhea, and abdominal pain. Hemorrhagic necrosis of gastric or intestinal mucosa can lead to bleeding, perforation, and peritonitis. Metabolic acidosis occurs when unbound iron moves into cells and localizes near the mitochondrial cristae, resulting in uncoupling of oxidative phosphorylation and impairment of adenosine triphosphate synthesis. Hydration of the iron molecule creates an excess of unbuffered protons, worsening metabolic acidosis. Cell membranes are injured by free radical–mediated lipid peroxidation. Hypotension occurs as iron increases capillary permeability and leads to both arteriolar and venodilation. Direct myocardial toxicity decreases cardiac output. These effects, combined with severe gastrointestinal fluid losses, can lead to shock, cardiovascular collapse, and death.

In an iron overdose, determining the amount of elemental iron ingested is most important, because cellular toxicity depends on the effects of elemental iron. Different formulations of iron salts contain different percentages of elemental iron ( Table 146.1 ). The total amount of elemental iron ingested can be approximated by multiplying the estimated number of tablets by the fraction of elemental iron contained in the tablet. Ingestions of less than 20 mg/kg of elemental iron usually causes no symptoms. Ingestion of 20 to 60 mg/kg results in mild to moderate symptoms, and ingestion of more than 60 mg/kg may lead to severe morbidity and mortality. Newer forms of iron are carbonyl iron and iron polysaccharide: both are non-ionic and associated with lower toxicity. Neither form is directly corrosive. The conversion to the iron ion, which is responsible for toxicity, is very slow in these newer preparations. There are no reported cases of serious toxicity or death from the ingestion of the non-ionic compounds.

Clinical Features

The clinical effects of acute iron poisoning have traditionally been divided into five stages ( Table 146.2 ). The timing of each stage varies for individual patients. The severity of phase 4 is primarily dose-related, and it is usually during this phase that fatality occurs.

Differential Diagnoses

Many toxins are irritating to the gastrointestinal tract and can cause nausea, vomiting, and diarrhea. Hemorrhagic gastroenteritis in the setting of an ingestion history should raise suspicion for caustic ingestions, ethanol, toxic alcohols, salicylates, ibuprofen, colchicine, and other heavy metals, such as arsenic, inorganic mercury, and iron.

Diagnostic Testing

The presence of early gastrointestinal symptoms suggests a potentially serious ingestion, whereas absence of gastrointestinal symptoms is usually reassuring. A serum iron concentration measured at 3 to 5 hours after ingestion is the most useful laboratory test to evaluate the potential severity of an iron overdose. Sustained-release or enteric-coated preparations may have erratic absorption, so the serum concentration should be repeated at 6 to 8 hours after ingestion. Peak serum iron below 350 μg/dL is generally associated with minimal toxicity; 350 to 500 μg/dL with moderate toxicity; and above 500 μg/dL with severe toxicity. Because iron is rapidly cleared from the serum and deposited in the liver, the concentration of iron after a substantial ingestion may be deceptively low if it is measured several hours after its peak absorption. TIBC is an inaccurate test and is not useful to gauge the severity of iron poisoning.

A screening abdominal radiograph may also be helpful to confirm a recent large ingestion and should be interpreted in the context of serum levels, as described later. Most tablets that contain a significant amount of elemental iron are radiopaque ( Fig. 146.1 ). False-negative radiographs may occur with chewable, liquid, and completely dissolved iron compounds, so negative radiography should not be used to exclude iron ingestion in cases of suspected or witnessed ingestion. Repeated radiographs can also demonstrate the efficacy of gastrointestinal decontamination efforts.

Management

Disposition

The asymptomatic patient who is reliably known to have ingested less than 40 mg/kg of elemental iron does not need additional therapy and can be discharged home after appropriate poison prevention counseling with reliable care takers. In patients who ingest more than 40 mg/kg, an iron concentration should be obtained at 3 to 5 hours post-ingestion and also 6 to 8 hours post-ingestion. If peak iron remains less than 300 μg/dL, is not rising, and the patient is asymptomatic during 6 hours of observation, the patient can be discharged home. If the patient is exhibiting signs of severe toxicity, even if the ingested dose is unknown, or meets criteria for deferoxamine chelation therapy, admission to an intensive care unit with poison center or toxicologist consultation is advised. If indicated, a psychiatric consultation should be requested.

Foundations

Lead poisoning remains one of the most common and preventable environmentally mediated problems in the United States. The elimination of leaded gasoline and the ban on leaded paint in households in the 1970s exponentially reduced the number of lead poisonings in the United States. However, the Center for Disease Control and Prevention (CDC) estimates that approximately 535,000 children, aged 1 to 5 years old, still have elevated blood lead levels (BLLs) from various environmental exposures. Immigrant and refugee children are at much greater risk for lead poisoning than children born in the United States because of exposures prior to arrival in the United States. ^, Adult lead poisoning has been decreasing over time and the CDC reported that in 2013, 20.4 per 100,000 adult workers had BLLs of 10 mcg/dL or greater, down from 26.6 in 2010. Given the continued wide use of lead in industry, there are many potential sources of exposure. Retained bullet fragments are another important source to investigate ( Table 146.3 ).

Most lead exposures occur by ingestion in children and workplace inhalation in adults. Dermal absorption may also occur but is much less significant. Children and pregnant women absorb almost four times the amount of ingested lead than other adults. Once absorbed, lead is bound to red bloods cells and slowly distributes to the soft tissues where it is eventually stored, primarily in bone. The half-life of lead in the red blood cell is approximately 30 days, but once in the bone, the half-life can last decades. Lead easily crosses the placenta, and maternal blood levels correlate with umbilical cord blood levels. Neonatal lead exposure also occurs through breast milk. Most lead is ultimately excreted in the urine and bile.

There is no biologic role for lead in the human body. Lead complexes with sulfhydryl groups of proteins, which can alter enzyme and receptor function and distort structural proteins. Lead is also structurally similar to calcium and interferes with calcium-dependent cellular processes. Its toxic effects are most prominent in the hematopoietic and neurologic systems.

Clinical Features

The clinical features of lead poisoning are broad and often nonspecific ( Table 146.4 ). Symptoms depend on the BLL, whether the patient is an adult or child, and whether the exposure is acute or chronic. Although all organ systems are affected, the most sensitive are the hematologic, vascular, and nervous systems. Lead inhibits heme biosynthesis, and the classic manifestation of hematopoietic lead toxicity is anemia. Anemia may be either normochromic or hypochromic. Chronic kidney disease and hyperuricemic gout (“saturnine gout”) can also result from elevated BLLs. Chronic kidney disease consequently may worsen underlying anemia. Lead poisoning is associated with chronic hypertension. In the peripheral nervous system, segmental demyelination and degeneration of motor axons result in peripheral neuropathies. Wrist-drop and foot-drop are characteristic of adult lead poisoning but rarely seen today. Importantly, lead toxicity can cause neuropsychiatric disorders. Many are difficult to distinguish during an emergency department (ED) evaluation, so collaboration with a primary care physician is essential to identify new cognitive deficits. In children, elevated BLL is associated with decreased intelligence quotient (IQ) scores, hyperactivity, decreased attention span, overaggressive behavior, learning disabilities, and criminal behavior. Severely high BLLs may present with lead encephalopathy associated with increased capillary permeability and cerebral edema.

Differential Diagnoses

The differential diagnoses of lead poisoning are broad, and because the symptoms of early poisoning are nonspecific, lead poisoning today is often initially not considered or misdiagnosed. Lead poisoning could be confused for neuropathies (such as carpal tunnel or Landry-Guillain-Barré syndrome) or abdominal or urologic pathologies (such as gastroenteritis, nephrolithiasis, or appendicitis). ^, The subtle neuropsychiatric signs in children can also be misdiagnosed as attention deficit hyperactivity disorder or other behavioral disturbances. Therefore, it is necessary to consider lead poisoning in the appropriate circumstance, particularly where another diagnosis is not established as the primary cause of the presentation.

Diagnostic Testing

Lead toxicity rarely presents primarily to the ED. Most patients encountered in the ED have been referred for management of an elevated screening BLL measured in a clinic or workplace surveillance program. Some patients may seek ED care following an ingestion of a leaded foreign body or with worrisome symptoms following a possible environmental exposure. Diagnostic testing should consist of a venous BLL, including those cases referred in for an abnormal screening test. Capillary screens (such as finger or heel sticks) may be falsely elevated. If the patient is symptomatic, other tests include a complete blood cell count, basic metabolic panel, liver and renal function tests, and urinalysis. A peripheral smear classically shows basophilic stippling, but this finding is relatively rare. Because lead-containing objects and paint chips are radiopaque, abdominal radiographs can confirm acute ingestion and determine the need for bowel decontamination. In cases of altered mental status, seizures, or coma, a computed tomography (CT) scan of the head may show cerebral edema associated with acute lead encephalopathy and can assist in ruling out other causes of these neurologic signs. In children, plain radiographs of the wrist and knees classically demonstrate increased metaphyseal activity termed lead lines that are characteristic of chronic exposures. However, such x-rays are not routinely obtained in the ED.

Management