Iron overload, or hemochromatosis, occurs when the body accumulates an excessive amount of iron, which it has no natural mechanism to excrete. This surplus iron is stored in tissues and organs, eventually leading to organ damage and other health problems. The causes can be broadly divided into two major types: hereditary and secondary factors.
Hereditary Hemochromatosis: The Genetic Cause
The most prevalent form of iron overload is hereditary hemochromatosis, an inherited disorder caused by genetic mutations that disrupt the body's control over iron absorption. In a healthy body, iron absorption from food is carefully regulated, but with these mutations, the body continues to absorb high amounts of iron regardless of its internal stores.
HFE Gene Mutations
The vast majority of hereditary hemochromatosis cases are linked to mutations in the HFE gene, which is most common in people of Northern European ancestry.
- C282Y Mutation: The most significant mutation is homozygosity for C282Y (inheriting a mutated gene from both parents). This is responsible for the majority of cases of clinically severe iron overload.
- C282Y/H63D Compound Heterozygosity: A less common pattern involves inheriting one copy of the C282Y mutation and one copy of the H63D mutation. This can lead to milder iron overload, though not all individuals with this genotype develop the condition.
Non-HFE Hemochromatosis
Other, rarer genetic mutations can cause different types of hereditary hemochromatosis, with varying ages of onset and severity.
- Juvenile Hemochromatosis (Type 2): Caused by mutations in the HJV or HAMP genes, iron buildup occurs much earlier, with symptoms often appearing between ages 15 and 30.
- Type 3 and 4 Hemochromatosis: Mutations in the TFR2 and SLC40A1 genes, respectively, also result in iron metabolism disruption.
Secondary Causes of Iron Overload
Secondary iron overload occurs when an underlying medical condition or treatment leads to excessive iron accumulation. Unlike the hereditary form, it is not primarily due to a genetic defect in iron absorption.
Common Secondary Causes
- Repeated Blood Transfusions: Each unit of transfused blood contains a significant amount of iron (around 200–250 mg). For patients with conditions requiring frequent transfusions, such as thalassemia or sickle cell disease, this is a major cause of iron buildup over time.
- Anemias with Ineffective Red Blood Cell Production: Certain types of anemia, including sideroblastic anemias and myelodysplastic syndromes, result in the body producing red blood cells inefficiently. This triggers an increased rate of iron absorption from the gut, leading to iron overload.
- Chronic Liver Disease: Conditions like chronic hepatitis C, alcoholic liver disease, or metabolic dysfunction-associated steatotic liver disease can impair the liver's ability to process iron, causing it to build up. Excessive alcohol intake, especially, exacerbates this process.
- Excessive Iron Intake: While rare, consuming excessive iron supplements, particularly for an extended period, or drinking alcohol brewed in iron pots can lead to iron overload.
- Atransferrinemia: A rare, inherited disorder in which the body lacks or has very low levels of transferrin, the protein that transports iron in the blood. This leads to a misdistribution and buildup of iron in organs.
Hereditary vs. Secondary Iron Overload: A Comparison
| Feature | Hereditary Hemochromatosis (Primary) | Secondary Iron Overload |
|---|---|---|
| Underlying Cause | Genetic mutations (most commonly HFE) affecting iron regulation. | Underlying medical conditions or treatments causing excess iron accumulation. |
| Mechanism | The body absorbs an abnormally high amount of iron from the diet. | Iron is introduced into the body through external sources like transfusions or is mishandled due to other diseases. |
| Common Triggers | Family history of hemochromatosis, Northern European ancestry. | Repeated blood transfusions, chronic liver disease, certain types of anemia. |
| Treatment Method | Regular blood removal (phlebotomy) to deplete iron stores. | Often involves iron chelation therapy (medications that bind and remove iron), especially for those who cannot undergo phlebotomy. |
| Primary Organs Affected | Liver, heart, pancreas, joints, and pituitary gland. | Similar organs, but patterns of iron deposition can vary depending on the cause. |
The Role of Hepcidin
At the molecular level, many forms of iron overload involve a deficiency or dysfunction of hepcidin, a hormone produced in the liver that acts as the "master regulator" of iron homeostasis. Hepcidin works by controlling the release of iron from certain cells into the bloodstream. In most hereditary hemochromatosis cases, faulty genes lead to inappropriately low hepcidin levels, causing the body to continuously absorb more iron than it needs. In secondary iron overload from conditions like anemia with ineffective erythropoiesis, the body also suppresses hepcidin to increase iron absorption, despite already having excess iron.
Conclusion
What causes iron overload in the body can be complex, ranging from common genetic mutations to complications arising from other medical conditions and treatments. The most significant factor is hereditary hemochromatosis, primarily involving mutations in the HFE gene, but secondary causes like frequent blood transfusions or chronic liver disease are also major contributors. Early diagnosis is critical, as timely treatment can prevent or delay significant organ damage. For individuals with a family history or symptoms of chronic fatigue, joint pain, or liver issues, discussing a potential iron overload with a healthcare provider is essential for effective management.
