Iron Toxicity

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The Basics (1)

Iron is an abundant element and is essential for living organisms. Synthesis of oxygen transport proteins and formation of heme enzymes involved in electron transfer and oxidation reductions require iron. The figure below is a diagram of the iron cycle in the body. Iron is absorbed in the GI tract, delivered to the tissues, and transported to the mitochondria for synthesis. Once in the body, there is no mechanism for the excretion of excess iron and can only be excreted through blood loss.

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Sources

Iron is found in most foods, may be added to some food products, and available as a dietary supplement. Iron poisoning usually occurs when too many iron pills/supplements are ingested; however, there are some disorders that can cause primary or secondary iron overload in the body. I will discuss this in the genetic susceptibility section. Below is a list of foods with their iron content and percent daily values listed.

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Biotransformation

Here is a great video that shows how iron is metabolized in the human body.

There are two iron oxides: ferric (Fe3+) and ferrous (Fe2+). Ferric iron cannot be directly absorbed and must be converted into an absorbable form. Dcytb enzyme converts ferric iron into ferrous iron in the intestinal lumen where it can now be transported into the enterocytes via DMT1 transporter along with protons. Inside the enterocyte ferrous iron is either stored in its nontoxic form or exported into the blood circulation via ferroportin. From here ferrous iron is converted to ferric iron via hephaestin. The ferric iron can now bind to apotransferrin and can be transported to other tissues and cells in the body.

Toxicokinetics (2)

Normal serum iron levels range from 50 to 150 ug/dL, but when iron levels are high, the transferrin can become saturated. Excess unbound iron can then circulate in the blood as free iron which is toxic to target organs. This free iron can also enter cells and disrupt oxidative phosphorylation, catalyze lipid peroxidation, and form free radicals, ultimately leading to cell death.

Carcinogenicity (3)

Iron overload, when the body stores too much iron, has been found to induce hepatocellular carcinoma. Below is a table listing conditions that have been associated with iron overload-induced cancers in humans.

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Target organs (4)

Click on the info icons below to learn what organs are impacted by iron overload.

Signs and symptoms of toxicity (5)

Below is a table of the stages of iron toxicity, the clinical effect, and the time frame after ingestion.

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• GI symptoms can include abdominal pain, diarrhea, hematemesis, nausea, and vomiting
• CNS symptoms can include coma and stupor

Genetic susceptibility or heritable traits (5)

Primary: often inherited

• • Hereditary Hemochromatosis
    • most common genetic iron overload disorder
    • increased intestinal iron absorption occurs from mutations in certain genes involved in iron metabolisms

Secondary: arises from disorders that cause excess iron absorption

• • Hemoglobinopathies
    • disorders that are inherited where there are mutations in the globin gene causing abnormal production or structure of the hemoglobin molecules
    • Eg. sickle cell anemia, thalassemia
  • Frequent blood transfusions and exogenous iron intake can also cause secondary iron overload

Treatments (6)

• Isotonic crystalloids (saline, lactated ringer solution)
  • Can be administered to attain hemodynamic stability
• Gastric lavage
  • Can remove iron from the stomach 1-2 hours post-ingestion
• Chelation therapy
  • Deferoxamine can be used to chelate iron

Biomarkers (2)

• Serum iron levels
  • measured at peak: 4-6 hours after ingestion
    • <350 ug/dL = minimal toxicity
    • 350-500 ug/dL = moderate toxicity
    • >500 ug/dL = severe systemic toxicity
  • measured again 6-8 hours after ingestion to account for iron being deposited in the liver
• Transferrin, transferrin saturation, ferritin, and soluble transferrin receptors are also markers of iron

Essentiality and deficiency (7)

Iron is essential for living organisms to transport oxygen, produce energy, and many other metabolic processes!

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Iron deficiency can impact normal functions and a person with it can be fatigued and weak and experience other health ailments.

References:

1. Abbaspour, Nazanin et al. “Review on iron and its importance for human health.” Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences vol. 19,2 (2014): 164-74.
2. Yuen HW, Becker W. Iron Toxicity. [Updated 2020 Jun 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459224/
3. Toyokuni, Shinya. “Role of Iron in Carcinogenesis: Cancer as a Ferrotoxic Disease.” Cancer Science, vol. 100, no. 1, 2009, pp. 9–16., doi:10.1111/j.1349-7006.2008.01001.x.
4. Anderson, Gregory J. “Mechanisms of Iron Loading and Toxicity.” American Journal of Hematology, vol. 82, no. S12, 2007, pp. 1128–1131., doi:10.1002/ajh.21075.
5. Palmer, William C., et al. “Diagnosis and Management of Genetic Iron Overload Disorders.” Journal of General Internal Medicine, vol. 33, no. 12, 2018, pp. 2230–2236., doi:10.1007/s11606-018-4669-2.
6. Clifford S Spanierman, MD. “Iron Toxicity.” Practice Essentials, Pathophysiology, Epidemiology, Medscape, 29 Apr. 2021, emedicine.medscape.com/article/815213.
7. Meenakshi Nagdevelast updated – January 29, et al. “17 Surprising Benefits of Iron.” Organic Facts, 29 Jan. 2020, www.organicfacts.net/health-benefits/minerals/health-benefits-of-iron.html.