Hereditary Causes of Iron Overload
By far, the most common cause of pathological iron overload is a genetic disorder called hereditary hemochromatosis. This condition causes the body to absorb and store an abnormally high amount of iron from the diet. The most common type, Type 1, is caused by a mutation in the HFE gene, particularly the C282Y variant. A person must inherit two copies of the mutated gene, one from each parent, to be at risk for developing the condition. However, not everyone with two copies of the gene will develop iron overload, indicating that other factors, such as diet and lifestyle, also play a role.
Other, rarer forms of hereditary hemochromatosis exist, caused by mutations in different genes, including HJV, HAMP, TFR2, and SLC40A1. These variants can cause iron to accumulate more quickly and at an earlier age, with conditions like juvenile hemochromatosis appearing in adolescents and young adults.
Acquired Causes of Iron Overload
Aside from genetic predispositions, several acquired conditions can lead to excess iron accumulation. This is known as secondary hemochromatosis. A primary driver is a medical need for repeated blood transfusions, which are required for conditions like thalassemia, sickle cell anemia, and myelodysplastic syndromes. Each unit of transfused blood contains a significant amount of iron, which the body cannot excrete, leading to a dangerous buildup over time.
List of Secondary Causes of Iron Overload
- Repeated blood transfusions: Patients with chronic anemia who receive frequent transfusions accumulate iron from the donor blood.
- Chronic liver disease: Conditions such as alcoholic liver disease or chronic viral hepatitis can impair the liver's ability to process and store iron correctly.
- Excessive oral iron intake: While rare in healthy individuals, taking high doses of iron supplements over a prolonged period can cause iron overload, especially in children.
- Excessive breakdown of red blood cells: Certain congenital hemolytic anemias cause a high turnover of red blood cells, which can release excess iron into the body.
- African iron overload: A form of iron overload prevalent in sub-Saharan Africa, often associated with a genetic component and the consumption of iron-rich fermented beverages.
How Iron Overload Damages the Body
Regardless of the cause, the mechanism of tissue damage is similar. Normally, iron is transported in the blood bound to a protein called transferrin. When this capacity is overwhelmed by excess iron, "free" iron is created, which is toxic. This free iron, or non-transferrin bound iron (NTBI), is a pro-oxidant that can generate harmful free radicals. These free radicals damage cells in organs where iron accumulates, such as the liver, heart, and pancreas, leading to inflammation and scarring.
Iron Overload Risks by Organ Affected
| Organ | Effect of Iron Overload | Potential Outcome | Early Signs |
|---|---|---|---|
| Liver | Iron accumulation in hepatocytes. | Cirrhosis, liver cancer. | Fatigue, upper abdominal pain. |
| Heart | Iron deposits in heart muscle cells. | Irregular heart rhythms, heart failure. | Shortness of breath, fatigue. |
| Pancreas | Iron buildup in the pancreas. | Diabetes, sometimes called "bronze diabetes". | Increased thirst and urination. |
| Joints | Calcium pyrophosphate crystal deposits. | Arthritis, joint pain and stiffness. | Pain in knuckles and finger joints. |
| Pituitary Gland | Iron accumulation in the pituitary. | Hypogonadism, leading to low libido. | Erectile dysfunction, amenorrhea. |
Conclusion
Understanding what leads to iron overload is the first step toward managing this potentially life-threatening condition. The causes range from hereditary genetic mutations to acquired factors like frequent blood transfusions or excessive supplementation. While the symptoms, such as fatigue and joint pain, can be non-specific, early diagnosis through blood tests and potentially genetic testing is key to preventing irreversible organ damage. Fortunately, treatments like therapeutic phlebotomy and chelation therapy are highly effective when initiated promptly. If you have a family history of hemochromatosis or symptoms of iron overload, it is crucial to consult a healthcare professional. To learn more about the genetic aspects of hereditary hemochromatosis, you can read more from a reputable source like the National Human Genome Research Institute.
Treatment and Prevention
After diagnosing the cause of iron overload, medical professionals will outline a treatment plan. For hereditary hemochromatosis and some other conditions, the primary treatment is therapeutic phlebotomy, which involves removing blood, similar to a donation, to reduce iron levels. For patients who cannot undergo phlebotomy, such as those with anemia, iron chelation therapy with medication may be used instead. Preventative measures include avoiding iron supplements and multivitamins containing iron, as well as limiting alcohol, which increases the risk of liver damage. Individuals should also avoid raw seafood due to a heightened risk of infection.
Hereditary vs. Acquired Iron Overload
Regardless of whether the iron overload is hereditary or acquired, early intervention is critical for preventing complications. Hereditary forms typically develop slowly over decades, often manifesting in adulthood. In contrast, acquired iron overload from multiple transfusions can build up more quickly, and careful monitoring of iron levels is required. Regular screening for organ damage, especially in the liver and heart, is vital for managing the condition and adjusting treatment as needed.
Iron and its Regulation
Iron metabolism is a tightly regulated process in the body, primarily controlled by the hormone hepcidin. In hereditary hemochromatosis, mutations disrupt the signaling pathway that controls hepcidin, causing lower levels of the hormone and leading to increased iron absorption. In acquired iron overload from conditions like myelodysplasia, erythroid precursors produce erythroferrone (ERFE), which also suppresses hepcidin and leads to excessive iron absorption. This shows that various pathways can lead to the same result: a breakdown in the body's natural defense against excess iron.
