Iron is an essential element but can be toxic in high amounts. Iron poisoning most often occurs when children accidentally ingest iron supplements. Symptoms of iron toxicity can be severe and include vomiting, abdominal pain, shock, liver damage, and gastrointestinal bleeding and necrosis. Diagnosis involves measuring serum iron levels and a chelation challenge test. Treatment focuses on gastric lavage, administering charcoal or antacids, correcting dehydration and acidosis, and chelation therapy with desferrioxamine or deferiprone to remove excess iron from the body.

1. IRON TOXICITY
By: CHANDAKA JYOTHI
18GT1T0004,
PHARM.D,4TH YEAR
SRI VENKATESWARA COLLEGE OF PHARMACY

2. CONTENTS:
• Introduction
• Epidemiology
• Physical appearance
• Uses/ source
• Fatal dose
• Clinical features
• Diagnosis
• Pathophysiolosy
• Toxicokinetics
• Treatment
• Reference

3. Introduction
• Iron is the fourth most abundant atomic element in the earth's crust and is found in the minerals hematite, magnetite, and siderite.
Biologically, iron is an essential element for most living organisms because it is a component or cofactor of many critical proteins such as
hemoglobin, myoglobin and enzymes such as catalase, xanthine oxidase, aconitase, reduced nicotinamide adenine dinucleotide,
ribonucleotide reductase, peroxidases, cytochrome oxidase etc.

4. 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
• The AAPCC reported 1.5 million poisoning exposures for children and adolescents younger than 20 years.
•Children younger than 6 years accounted for 77% of the pediatric exposures and 50% of all reported exposures.
•Several reviews of poisoning hospitalizations suggest that iron poisoning is an infrequent cause of hospitalization;
the hospitalization rate for iron poisoning among children aged 0 to 4 years has been estimated at 8.7 per 100,000 children.

5. Physical Appearance of iron:
•Metallic iron is silvery white in colour, occurring naturally as haematite, magnetite, etc. and usually causes no problems.
• It is an essential element and deficiency results in anaemia.
• It is more than the required intake daily, the excess is excreted. But in some individuals with inborn errors, even normal dietary iron can cause toxic effects
due to accumulation, e.g. haemochromatosis (bronze diabetes).
• Iron salts are administered therapeutically in individuals with iron deficiency anaemia.
•Iron poisoning is related in most instances to overdose of iron salts.
•For instance ferrous sulfate (green vitriol) which occurs as bluish green crystals whereas ferric oxide, i.e. rust does not cause iron poisoning.

6. Uses/Sources:
Dietary Sources: The required daily amount of iron of 10–20 mg for adults is supplied through average diet.
• The required intake increases to 25–30 mg in pregnancy.
•The average daily intake for adults is 15 mg.
Environmental Sources: Iron is found in 5.1% of the earth’s crust.
• It is the second most abundant heavy metal, and the fourth most abundant element.
Industrial uses: Iron is used mainly in powder metallurgy and serves as a catalyst in chemical reactions.
• Iron is a component of carbon steels, cast iron, high-speed steels, high-strength low-alloy steels, manganese alloy steels, and stainless steels.
• Steel is the most important alloy of iron. It contains 0.25–2% of carbon. Alloyed with carbon (C), manganese (Mn), chromium (Cr), nickel (Ni) and other elements, iron is
used to form steel.
• Wrought iron is almost pure iron.
Other uses:
Iron uses include magnets, dyes, pigments, and abrasives.

7. Fatal dose:
The usual fatal dose corresponds to about 200 to 250 mg of elemental iron per kg of body weight. This can be calculated from the percentage of
elemental iron in a particular preparation, e.g. a single 150 mg tablet of anhydrous ferrous sulfate which contains 37% of elemental iron will
contain a total of 55 mg of elemental iron. But such calculations can be misleading since serious hepatotoxicity can result at much lower
concentrations of iron in the body which can lead to death

8. Clinical Features :
Most cases occur in children. There are 5 stages:
■ Stage I (0.5 to 2 hours) includes vomiting, haematemesis, abdominal pain, diarrhoea, haematochezia, lethargy, shock, acidosis, and coagulopathy. Necrosis
to the GI tract occurs from the direct effect of iron on GI mucosa. Severe gastrointestinal haemorrhagic necrosis with large losses of fluid and blood contribute
to shock. Free iron and ferritin produce vasodilatation that may also contribute to shock.
■ Stage II (after Stage I) includes apparent recovery and may contribute to a false sense of security. Observe closely.
■ Stage III (2 to 12 hours after Stage I) includes profound shock, severe acidosis, cyanosis and fever. Increased total peripheral resistance, decreased plasma
volume, haemoconcentration, decrease in total blood volume, hypotension, CNS depression, and metabolic acidosis have been reported.

9. ■ Stage IV (2 to 4 days) includes possible hepatotoxicity, convulsions, and coma. Thought to be a direct action of iron on mitochondria. Monitor
liver function tests and bilirubin. Acute lung injury may also occur. The primary site of hepatic injury is the periportal areas of the hepatic lobule
(the principal site for hepatic regeneration), which may explain the increase in mortality and poorer prognosis. Iron induced hepatotoxicity is a
presumed result of free radical generation and lipid peroxidation. Iron catalyses hydroxyl radical formation (the most potent-free radical), which
initiates lipid peroxidation. Based on limited data, antioxidants may have a hepatoprotective role in iron poisoning.
■ Stage V (days to weeks) includes GI scarring and strictures. GI obstruction secondary to gastric or pyloric scarring may occur due to
corrosive effects of iron. Evaluate with barium contrast studies. Sustained-release preparations have resulted in small intestinal necrosis with
resultant scarring and obstruction.

10. Causes:
• There are several causes of iron poisoning, including overdose, iron overload, and genetic predisposition.
• Overdose
• Acute iron toxicity is usually the result of an accidental overdose.
• Most cases occur in children younger than 5 years old who accidentally eat iron supplements or adult multivitamins.
• Iron overload
• Iron overload is also known as chronic iron toxicity. Causes include:
• repeated blood transfusions to treat anemia.
• excessive iron therapy, either intravenously for anemia, or with supplements
• liver diseases, such as chronic hepatitis C or alcoholism
• Genetic causes
• Iron overload can occur naturally due to certain diseases. One example is hereditary hemochromatosis, which is a genetic condition that leads to
abnormally increased absorption of iron in the body from food.

11. Diagnosis:
1. x-ray: Like all other heavy metals, iron and its compounds are radiopaque. However, chewable iron tablets and liquid iron formulations
are usually not visualised on x-ray. Completely dissolved iron tablets/capsules may also not be radiopaque.
2. Serum iron level: Poisoning is indicated if this exceeds 150 mcg/100 ml, and serious toxicity is usually associated with levels beyond 500
to 600 mcg/100 ml. Peak levels are seen around 4 hours after ingestion. Measuring the total iron binding capacity and relating it to the
serum iron level is often misleading and unreliable.
3. Total leucocyte count (TLC), electrolytes, glucose, blood gas, clotting studies, liver function and renal function tests are useful estimates.

12. 4. Chelation challenge test: Desferrioxamine in a dose of 25 mg/kg (maximum 1 gm) is given IM. If the serum iron has exceeded iron binding
capacity, the excess iron is chelated to desferrioxamine and the complex is excreted as a pinkish (vin rosé) colour in the urine (Fig 9.20). But a
negative result does not rule out iron poisoning.
5. Qualitative desferrioxamine colour test (QDCT): 2 ml of gastric fluid and 2 drops of 30% hydrogen peroxide are placed in 2 plastic tubes. 0.5
ml of solution of desferrioxamine (500 mg in 4 ml distilled water) is added into one tube and the resulting colour change is compared with the
other tube (control). If the test is positive, an orange to red colour will develop in the tube in which desferrioxamine was added. The test must be
done within 2 hours of ingestion of iron.

13. PATHOPHYSIOLOGY

24. Toxicokinetics:
Iron poisoning occurs when serum iron level exceeds the total iron-binding capacity (TIBC), resulting in free circulating iron in the bloodstream.
Mode of Action Free iron causes:
a. Massive postarteriolar dilatation which results in venous pooling.
b. b. Increased capillary permeability resulting in decreased plasma volume.
c. c. Oxidation of ferrous to ferric iron releasing hydrogen ions. Subsequent hydration of ferric iron results in metabolic acidosis.
d. d. Inhibits mitochondrial function leading to hepatic damage, hypoglycaemia, and hypoprothrombinaemia.
e. e. Inhibits thrombin-induced conversion of fibrinogen into fibrin.
f. f. Has a direct corrosive action on the GI mucosa.

25. Treatment:
1. Stomach wash with normal saline performed gently may be of benefit in massive ingestions. Desferrioxamine must not be used for lavage.
2. Activated charcoal is ineffective.
3. Magnesium hydroxide solution (1%) administered orally may help reduce absorption of iron by precipitating theformation of ferrous
hydroxide. Magnesium hydroxide and calcium carbonate containing antacids may safely be used in therapeutic doses to help reduce iron
absorption.
4. Obtain serum iron levels, creatinine, electrolytes, blood haemoglobin concentration, blood prothrombin time, baseline liver function tests, and
arterial blood gases in seriously poisoned patients.
5. Correction of hypovolaemia, and metabolic acidosis.

26. 6. Chelation therapy:
a. This is indicated in any of the following situations:
• More than one episode of vomiting or diarrhoea.
• Significant abdominal pain, hypovolaemia, or acidosis.
• Multiple radio opacities on abdominal radiograph.
• Serum iron level greater than 350 mcg/100 ml.
b. Chelation can be done either with desferrioxamine (parenteral) or deferiprone (oral).
• Dose (desferrioxamine):
- Intravenous Dose: Administer by continuous infusion at a rate of up to 15 mg/kg/hr. Faster rates or IV boluses may cause hypotension in some individuals.
Infusion rates up to 35 mg/ kg/hr have been used in children with severe overdoses without adverse effects.

27. - Intramuscular Dose: Administer 90 mg/kg, up to a maximum of 1 gm/dose, every 8 hours as needed. Pain and induration at the injection site
are often experienced.
- Total Daily Dose: The recommended total intravenous or intramuscular daily dose should not generally exceed 6 grams.
- Duration of Infusion: Duration of infusion is guided by the patient’s clinical condition. Patients with moderate toxicity are generally treated for
8 to 12 hours, those with severe toxicity may require desferrioxamine for 24 hours or longer. Patients should be re-evaluated for evidence of
recurrent toxicity (hypotension, metabolic acidosis) several hours after the infusion is discontinued. Infusion duration of greater than 24 hours
has been associated with the development of ARDS.

28. Adverse Effects:
Sepsis: desferrioxamine induces Yersinia enterocolitica septicaemia and mucormycosis in children.
Visual Toxicity: Continuous intravenous administration of desferrioxamine produce visual toxicity (decreased visual acuity, night blindness,
colour blindness, retinal pigmentary abnormalities).
Sometimes Visual toxicity can be associated in patients with rheumatoid arthritis and chronic renal failure.
Ototoxicity:is risk factor of desferrioxamine (dose, duration of therapy and the presence of a low serum ferritin).

29. Reference:
• https://www.ncbi.nlm.nih.gov/books/NBK459224/
• https://www.healthline.com/health/iron-poisoning
• https://www.slideshare.net/MohammedALZahrani29/iron-toxicity-61259331
• https://www.ncbi.nlm.nih.gov/books/NBK459224/
• Modern Medical Toxicology,4th Edition by VV.Pillay