Iron Toxicity

Done by:Mohammed AL Zahrani

Outline• Chemical properties• Epidemiology of iron poisoning• Sources of iron • Iron absorption• Toxicity of iron• Pathophysiology of iron poisoning • Diagnosis• Management• Case of iron toxicity • Hemochromatosis

CHEMICAL PROPERTIES

• Iron is a lustrous, ductile, malleable, silver-gray metal (group VIII of the periodic table).

• It is known to exist in four distinct crystalline forms.

• It dissolves readily in dilute acids. • Chemically active and forms two major series of

chemical compounds, the bivalent iron (II), or ferrous, compounds and the trivalent iron (III), or ferric, compounds.

• One of the most abundant metals on Earth, as well as an essential nutrient.

• Component of several metalloproteins and plays a vital function (e.g. oxygen sensing and transport, electron transfer, and catalysis)

• Has unique ability to serve as an electron donor and acceptor renders this metal irreplaceable and indispensable for life

Iron distribution within the body

Epidemiology of Iron Poisoning

• The American Association of Poison Control Centers (AAPCC) is a consortium of 66 regional poison control and information centers located throughout the United States.

http://www.aapcc.org/

In 1997, there were 26,544 AAPCC-reported exposures for all types of iron-containing compounds by children and adolescents accounting for 1.7% of all reported pediatric poisoning exposures

87% were in children younger than 6 years.

• Sixty-two percent of these childhood exposures were to pediatric multivitamin tablets, which rarely lead to serious toxicity after ingestion.

• Thirty percent of these exposures were to adult preparations such as iron pills or prenatal vitamins with iron, which are responsible for almost all of the serious toxicity related to iron poisoning.

• Early series reported mortality rates of 50% from iron poisoning

• For the past 10 years, there has been an average of only 3 to 4 deaths per year reported by the AAPCC

• The AAPCC did a special review of morbidity and mortality in children younger than 6 years for the period 1985-1990.

• Eight of 111 deaths during this period were related to iron poisoning

Reasons Of Why Children Ingest Drugs?• Developmental level• Inadequate parental knowledge about the

toxic potential of individual agents• Easy access to medications• Imitative behavior• Lack of supervision• Intra-familial conflict

Sources Of Iron

• Iron preparations are available most commonly in the form of iron salts. The amount of elemental iron in each preparation varies depending upon the salt form

IRON ABSORPTION

• The absorption of iron is dependent on the body iron stores, hypoxia, and rate of erythropoiesis

• Dietary iron absorption occurs mostly at the duodenum and the upper portions of the jejunum

• The body has no effective means of excreting iron and thus the regulation of absorption of dietary iron plays a critical role in iron homeostasis

• Iron absorption, including the reduction of iron to a ferrous state, apical uptake, intracellular storage or transcellular trafficking, and basolateral release

• Dietary iron is found in heme (10%) and non-heme (90%) forms and their absorption occurs under different mechanisms

Absorption of dietary non-heme iron

1. Release of elemental iron from digested food and its maintenance in a soluble form(GASTRIC ACID)

The low pH of the gastric effluent dissolves ingested inorganic iron and facilitates its

enzymatic reduction (Fe3+ is reduced to Fe2+) Which enzyme?

2. Iron is transported across the intestinal epithelium by divalent metal transporter 1 (DMT-1)

ferric reductases present on the apical surface of duodenal enterocytes

Absorption of dietary Heme iron

1. Absorbed into the enterocytes by Heme carrier protein 1, a membrane protein found in the proximal intestine, where heme absorption is greater

2. Metabolized by heme oxygenase to release Fe2+

3. some intact heme iron crosses the cell, leaving the enterocyte through the action of the heme exporters

• Once inside the intestinal epithelial cell, iron is exported across the basolateral membrane of the enterocyte into the circulation where it binds to transferrin

• Transferrin-bound iron enters target cells through a process of receptor-mediated endocytosis

• In RES Heme iron is metabolized by heme-oxygenase, and iron is stored as ferritin

• Basolateral iron transport is mediated by ferroportin 1 and then iron is oxidized by Hephaestin before being bound by plasma transferrin

Iron Absorption in Overdose

• Iron absorption is a highly regulated process• How these processes are affected in overdose

is unknown.• Supratherapeutic doses of iron are well

absorbed after ingestion• Peak serum iron level is achieved within

several hours of ingestion

• It is unclear whether very high doses lead to delayed absorption and peak level; however in many reported cases, children became toxic soon after ingestion.

• Iron pills can become conglomerated into a mass in the stomach

• The patients are often reported to be relatively asymptomatic :Iron bezoars reduce the rate of absorption

Toxicity of Iron

• Iron has the ability to produce oxygen free radicals under aerobic conditions, which turns it into a potential harmful component

• Free radicals are generated within the cell as part of normal cellular mechanisms

• However, the overproduction of reactive oxygen species (ROS), such as superoxide (•O2−) and hydroxyl (•OH) radicals may lead to cellular damage

The main sources of OH radicals

• The resulting effects are impaired synthesis of proteins, membrane lipids, and carbohydrates; induction of proteases; and altered cell proliferation

• In diseases of iron overload (e.g., HH), the generation of free radicals leads to tissue damage and organ failure.

• excess of free iron has been considered carcinogenic, once the generation of free radicals by this metal can promote DNA strand breaks, oncogenes activation, and tumor suppressor genes inhibition

• The role of iron in neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases suggested to be that iron overload increases brain oxidative stress status

• Since no mechanism exists for excreting iron, toxicity depends on the amount of iron already in the body.

• Intravenously > Intramuscular > orally

• No clinical signs of toxicosis are expected in dogs ingesting less than 20 mg/kg of elemental iron

• Dogs ingesting between 20 and 60 mg/kg of elemental iron can develop mild clinical signs

• Dogs greater than 60 mg/kg, serious clinical signs can develop.

• Death from iron toxicity has been reported from a wide range of doses (from 60 to 300 mg/kg).

Clinical signs

Pathophysiology of Iron

Poisoning

Stages Of Acute Iron Toxicity

• Stage I: local gastrointestinal effects• Stage II: quiescent phase• Stage III: systemic toxicity• Stage IV: recovery• Stage V: gastrointestinal obstruction

Stage I: Gastrointestinal Toxicity

• Nausea, vomiting, and diarrhea (5 mg Fe+2/kg)

• Gastrointestinal bleeding may lead to hematemesis or bloody diarrhea

• Attributed to the direct local corrosive effects of iron

• Occur early, usually within several hours

Stage I: Gastrointestinal Toxicity

• Pathologic effects are concentrated in the stomach and duodenum, areas of small bowel infarction can be observed distally; the colon is rarely affected

• These initial local corrosive changes sometimes lead to the formation of gastric antral and pyloric strictures, which are observed in some patients between 2 and 8 weeks after the initial episode of poisoning

Endoscopic image of : gastric antral vascular ectasia

Stage II: quiescent phase

• There is resolution of gastrointestinal symptoms with apparent clinical improvement

• Some studies show that patients had resolution of gastrointestinal symptoms, and became critically ill after 24 hours and died.

• This stage would rarely be seen today. Why?because children with significant early gastrointestinal symptoms would receive fluid resuscitation and chelation therapy soon after presentation.

Stage III: Systemic Toxicity

• Clinically manifest as shock with associated signs of hypoperfusion (pallor), cold extremities, tachycardia, tachypnea, hypotension(late finding).

• Hypovolemic shock and acidosis are the primary determinants of this shock state, but diminished cardiac function contributes.

Stage III: Systemic Toxicity

• Hypovolemic shock results from the gastrointestinal fluid losses as well as increased capillary permeability and possible loss of venous tone.

• Myocardial dysfunction may be seen in severe iron poisoning.

• Heart failure is frequently seen in chronic iron overload due to free radical-induced damage

Stage III: Systemic ToxicityPossible explanations for the acidosis have been proposed:

1. Conversion of free plasma iron to ferric hydroxide is accompanied by a rise in hydrogen ion concentration

2. Free radical damage to mitochondrial membranes prevents normal cellular respiration and electron transport with the subsequent development of lactic acidosis

3. Hypovolemia and attendant hypoperfusion contribute to (but are not the primary causes of) acidosis

4. Cardiogenic shock contributes to hypoperfusion.

Stage III: Systemic Toxicity• Hepatic injury: Portal blood delivers high

concentrations of iron to the liver(Ferritin) .• Range from cloudy swelling to peri-portal hepatic

necrosis, and elevated transaminases are observed

• Iron is concentrated within hepatic mitochondria where it destroys mitochondrial membranes hepatic necrosis and metabolic acidosis.

• Abnormalities in coagulation & inhibitory effect on clotting factors

Stage IV: Clinical Recovery

• Begin soon after the initiation of fluid and antidotal therapy.

• For severely poisoned patients recovery will be marked by resolution of acidosis and other signs of shock, usually within 3 to 4 days of the acute poisoning

• Full recovery may take longer.

Stage V: Gastrointestinal Obstruction

• late onset of gastric and pyloric strictures, which may occur 2 to 8 weeks after the initial injury.

• These strictures occur in mucosa in which there was previous damage, and they frequently require surgical therapy

Diagnosis

Diagnosis

• Testing serum iron concentration is the best method to confirm iron poisoning.

Repeat the serum iron test four to six hours after initial measurement. WHY?• Total iron-binding capacity• An abdominal radiographic examination can

be useful to identify metallic objects.

Laboratory testing should include:• Serum electrolytes, blood urea nitrogen

(BUN), and glucose• Alanine and aspartate aminotransferases and

bilirubin• Venous or arterial blood gases in moderately

and severely poisoned patients• Complete blood count with differential• Prothrombin and partial thromboplastin time

Peak serum iron concentrations typically correlate with the following levels of toxicity:

• Less than 350 mcg/dL – Minimal toxicity.• Between 350 and 500 mcg/dL – Mild to

moderate GI symptoms (rarely develop serious complications).

• Greater than 500 mcg/dL – Serious systemic toxicity.

• Greater than 1000 mcg/dL – Significant morbidity and mortality

• Toxicity may not be related to dose.• The ideal serum iron level is a peak level

drawn between 2 and 6 hours after ingestion

DIFFERENTIAL DIAGNOSIS • Other agents that can cause vomiting with

toxic ingestion include salicylates, caustic agents, theophylline, isopropanol, arsenic and mercurial salts, nonsteroidal antiinflammatory drugs (NSAIDs), organophosphorus compounds, nicotine carbamates, mushrooms, and colchicine

Clinical Management of Iron Poisoning

• Clinical evaluation. • Fluid resuscitation: establish intravenous

access and administer normal (0.9%) saline at an initial dose of 20 mL/kg followed by a continuous infusion

• Laboratory evaluation.• Abdominal radiograph

Chelation Therapy• Criteria for initiation of therapy include a history of iron

ingestion with:1. Any clinical sign of shock2. Lethargy, coma, or altered mental status3. Persistent vomiting, diarrhea, hematemesis,

hematochezia, or other gastrointestinal symptoms4. Positive anion-gap metabolic acidosis 5. Large number of pills on abdominal radiograph6. Serum iron level greater than 500 μg/dL7. Estimated dose greater than 60 mg Fe+2/kg.

• Deferoxamine is 15 mg/kg per hour as a continuous intravenous infusion.

• Can be given at a dose of 90 mg/kg intramuscularly (If IV access is not feasible)

• Chelation therapy should continue until there is significant resolution of systemic toxicity, specifically acidosis and shock.

• Deferoxamine SE: Hypotension, acute respiratory distress syndrome (ARDS).

Gastrointestinal decontamination

• Any patient with probable or confirmed significant exposure should have whole bowel irrigation.

• polyethylene glycol-electrolyte solution at a rate of 0.5 L/h for children or 2 L/h for adolescents.

• SE: nausea, bloating, vomiting, and diarrhea• Whole bowel irrigation is continued until the

effluent is clear.Magnesium hydroxide might be used to reduce absorption but no supporting data

• Patient with no history of abdominal pain, nausea, vomiting, or diarrhea & with a normal physical examination and remains asymptomatic for 6 hours, the patient may be safely discharged.

• Patients with minimal gastrointestinal symptoms only but an otherwise normal physical examination should have abdominal radiographs, an arterial blood gas, and electrolytes. If there are no pills visible on an abdominal radiograph and there is no evidence of metabolic acidosis after several hours, the patient is unlikely to develop systemic toxicity.

• A serum iron level less than 500 μg/dL would support identifying this as a low-risk patient. This patient may be admitted to the hospital for observation or discharged home with close follow-up.

• Any patient with more than mild gastrointestinal symptoms or with evidence of altered mental status, shock, or acidosis should receive chelation therapy and be admitted to the hospital.

• Patients with severe toxicity may require intensive care therapy.

• If a hospital has limited pediatric critical care facilities or does not have access to toxicology consultation, plans to transfer a patient to a tertiary care hospital should be made early, before the patient becomes unstable for transfer.

• Toxicological consultation should be requested for patients who have significant toxicity or who are receiving deferoxamine.

Management in the Pregnant Patient

• Deferoxamine is reported to be teratogenic ( pregnancy Class C ).

• deferoxamine should be administered to pregnant women with signs and symptoms of significant iron poisoning.

Case of Iron toxicity

©2005 Children’s Hospital of Michigan Regional Poison Control Center

Case History

A 2-year-old female child presents to the emergency department after a reported ingestion of One-A-Day Kids Scooby-Doo! Complete Multivitamin with Iron tablets. The amount of tablets taken is unknown but mom thinks that “half the bottle” may be missing (50 tablets in a full bottle).

Case History

• The ingestion took place approximately 15-30 minutes ago. The child has no symptoms but there is tablet residue in the mouth. There are no other reported ingestions or exposures.

• PMHx: None, healthy child • SurgHx: None• Allergies: None • Meds: Scooby-Doo Vitamin with Iron• Soc. Lives with mother and father, no tobacco

in the house

Physical Examination

• Wt 16.4 kg , HR-112, Resp-26, Temp-37• General: Playing/appears without distress. No

vomiting noted.• Pupils equal, round, reactive, 4 mm bilaterally.

No pallor• Ears, nose, mouth and throat: External inspection

of ears and nose are normal. Tympanic membranes are normal. Oral mucosa normal, some pill residue seen, tonsils normal.

Physical Examination

• Neck: Supple. No lymphadenopathy.• Chest: Clear to auscultation bilaterally with good air

entry.• Cardiac: Normal S1, S2, rhythm and rate. No murmurs,

gallops or rubs.• Abdomen: Soft, No TTP, No guarding, rebound or rigidity.• Skin: Cool and dry. No acute rashes or lesions.• Musculoskeletal: No edema. Normal pulses. No acute

trauma.• Neurologic: Playful, active, normal strength, gait/station

appropriate for age.

Labs

• Na 136, K 4.0, Cl 104, bicarb 22, glucose 85• WBC 6.9, Hb 11.5, Plt 345• Serum iron 246 mcg/dl (1 hour level) Range

50-180 mcg/dl

How common are pediatric iron overdoses?

• Iron ingestions in children have been known to cause serious illness since at least the 1950s.

How much iron is in One-A-Day Kids Scooby-Doo! Complete Multivitamin with iron?

How much iron is in One-A-Day Kids Scooby-Doo! Complete Multivitamin with iron?

How much iron is in One-A-Day Kids Scooby-Doo! Complete Multivitamin with iron?

• One-A-Day Kids Scooby-Doo! Complete Multivitamin contains 18 mg of elemental iron.

Is this a potentially toxic ingestion of iron?

• Labeling on iron containing tablets may inform you of the exact amount of elemental iron but it may also give only a list of the contents.

• In order to develop a reasonable idea of the toxic dose, you need to know how much elemental iron has been ingested with respect to the child’s weight.

Formulation Elemental Iron %

Ferrous fumarate 33%

Ferrous chloride 28%

Ferrous sulfate 20%

Ferrous lactate 19%

Ferrous gluconate 12%

Listed below are the common forms of iron in different iron formulations:

How do you determine toxicity in these cases?

• Ingestions of 10-20 mg/kg elemental iron may produce toxic effects.

• Children ingesting more than 20 mg/kg should be referred to the hospital.

• In this child’s worse case scenario, 25 tablets (half-bottle) of 18 mg elemental iron suggest an ingestion of about 27 mg/kg.

This child would be expected to develop some signs of toxicity, and should be referred to the hospital if at home.

What is the pathophysiology of iron toxicity?

• Corrosive effect on the GI mucosa (nausea, vomiting, abdominal pain, hematemesis, and diarrhea)

• Cellular toxicity due to impaired oxidative phosphorylation and mitochondrial dysfunction.

• The end result is significant metabolic acidosis.

Hypovolemia

What manifestations are typically seen in acute iron overdose?

• Stage I: local gastrointestinal effects• Stage II: quiescent phase• Stage III: systemic toxicity• Stage IV: recovery• Stage V: gastrointestinal obstruction

How does the serum iron level correlate with clinical symptoms?

• Iron levels of 50-150 mcg/dl are considered normal. • Serious toxicity can develop with

iron levels of 350-500 mcg/dl.• Levels greater than 500 mcg/dl are consistently

associated with significant toxicity.

Describe how you would help limit the absorption of iron in these cases. Should you give activated charcoal?

• Gastric lavage probably has limited value in these cases.

• To limit the amount of iron absorbed we can use deferoxamine, sodium bicarbonate, phosphosoda, magnesium hydroxide, and sodium polystyrene sulfonate.

• Whole bowel irrigation is recommended.

Should you give activated charcoal?

• Activated charcoal does not bind elemental iron well; therefore its role in overdose is limited.

Is there an antidote for iron ?• The antidote for iron poisoning is

deferoxamine (DFO).

When the child can safely be discharged from the emergency department?

If a child remains asymptomatic with no GI symptoms at 6 hours, they can be safely discharged with follow-up.

HemochromatosisIron overload

What is iron overload?• A serious chronic condition that develops

when the body absorbs too much iron over many years and excess iron builds up in organ tissues (for example, heart tissue and liver tissue).

What causes iron overload ?• Occurs as a result of a gene mutation that

causes the body to absorb more than a healthy amount of iron.

• Iron overload less often occurs as a complication of other blood disorders, chronic transfusion therapy, chronic hepatitis, or excessive iron ingestion.

Is iron overload dangerous?• Yes, Iron overload is dangerous because it can

lead to hemochromatosis, a disease characterized by fatigue, weakness, joint pain, abdominal pain, or organ damage.

• It can eventually become a serious health problem. The key to preventing hemochromatosis is early diagnosis and treatment.

Test for iron overload

• Simple blood tests can measure the iron levels within patient body.

• The tests are inexpensive and can be done at doctor’s office.

HEMOCHROMATOSIS

• Hemochromatosis is the disease that occurs as a result of significant iron overload.

• It can have genetic or nongenetic causes. • In the United States about one million people

have the disease, usually because of a gene mutation.

• When the disease is genetic, it is called hereditary hemochromatosis.

Early symptoms of hemochromatosis

• Fatigue, weakness, weight loss, joint pain, or abdominal pain.

• Usually symptoms begin during middle age• If hemochromatosis is not treated, it can lead

to these conditions:

Treatment for hemochromatosis• Hemochromatosis can be treated by a

phlebotomy.• It’s the same procedure that is used when you

donate blood.• It is safe, simple, and effective• Frequency depends on how much iron has

built up in patient’s body. • Most people have them once or twice a week

for a year or more

• Phlebotomies will be for the rest of patient’s life.

• SE: feel tired afterwards and like to rest for an hour or so.

• It’s a good idea to drink liquids (water, milk, or fruit juices) before and after a phlebotomy.

•

Without phlebotomies, hemochromatosis can cause death. Treatment is worth the effort.

/What can the patient do to stay healthy?

HistoryWhat form of iron was ingested?Ferrous gluconate (12 percent elemental iron)Ferrous sulfate (20 percent elemental iron)Ferrous fumarate (33 percent elemental iron)How many mg/kg of elemental iron was ingested?When did the ingestion occur?

Diagnostic evaluation: For all patients with systemic symptoms, those who have ingested >40 mg/kg of elemental iron, and those for whom the amount of elemental iron ingested is unknownSerum iron concentration: Measure serum iron concentration within 4 to 6 hours after ingestion (8 hours for extended release tablets)Arterial or venous pHAbdominal radiograph looking for radiopaque pillsOther initial labs: Electrolytes, BUN, creatinine, glucose, liver function tests, prothrombin, partial thromboplastin time, CBC with differential, type and cross match

Clinical features: Overlapping phases of clinical manifestationsGastrointestinal phase: (30 minutes to 6 hours) Abdominal pain, vomiting, diarrhea, hematemesis, melena, lethargy, shock (from capillary leak and third spacing), metabolic acidosisLatent: (6 to 24 hours) Improvement in GI symptoms; may have poor perfusion, tachypnea, tachycardiaShock and metabolic acidosis: (4 hours to 4 days) Hypovolemic, distributive, or cardiogenic shock with profound metabolic acidosis, coagulopathy, renal insufficiency/failure, pulmonary dysfunction/failure, central nervous system dysfunctionHepatotoxicity: (within 2 days) Coma, coagulopathy, jaundice. Severity is dose dependent.Bowel obstruction: (2 to 4 weeks) Vomiting, dehydration, abdominal pain, usually gastric outlet obstruction

ManagementSecure airway and breathingTreat volume depletion aggressively with isotonic infusionWhole bowel irrigation: For all patients with a significant number of pills in stomach and small intestine on radiographDeferoxamine: Continuous IV infusion (can cause hypotension). Begin at 15 mg/kg/hour. May increase to 35/mg/kg/hour during first 24 hours for severe ingestions. A toxicologist and/or regional poison control center should be consulted to determine the optimum dose of deferoxamine and duration of therapy. Treat in the following circumstances:Severe symptoms: Altered mental status, hemodynamic instability, persistent vomiting, diarrheaAnion gap metabolic acidosisSerum iron concentration >500 mcg/dLSignificant number of pills on x-ray

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