Iron is a vital mineral essential for producing red blood cells and for many other bodily functions. However, the body has no natural mechanism for excreting excess iron. When more iron is absorbed than the body needs, it is stored in organs, primarily the liver. Over time, this buildup can become toxic, damaging tissues and leading to a condition known as iron overload or hemochromatosis. The causes of this condition can be broadly divided into hereditary and secondary, or acquired, factors.
Hereditary Hemochromatosis: The Genetic Cause
Hereditary hemochromatosis (HH) is the most common cause of iron overload and is a genetic disorder passed down through families. It is primarily caused by mutations in the HFE gene, which regulates the body's iron absorption from food. A mutation in this gene leads to a faulty instruction, causing the body to absorb more iron than it needs, even when iron stores are full.
HFE Gene Mutations
The most common genetic alteration is the C282Y mutation. Individuals who inherit two copies of this mutated gene—one from each parent—are at the highest risk for developing HH and significant iron overload. A less common mutation, H63D, typically results in milder iron overload, even when two copies are inherited. Some individuals are 'compound heterozygotes,' having one copy of C282Y and one of H63D, which can also result in clinical iron overload.
Less Common Genetic Forms
Besides the HFE gene, other rare genetic mutations can cause different types of hereditary hemochromatosis with varying onsets and severity:
- Juvenile Hemochromatosis (Type 2): Caused by mutations in the HJV or HAMP genes, this form leads to rapid iron accumulation in adolescence, with symptoms often appearing between ages 15 and 30.
- Type 3 Hemochromatosis: Results from mutations in the TFR2 gene, causing symptoms that begin before age 30 and resemble Type 1.
- Type 4 Hemochromatosis (Ferroportin Disease): Caused by mutations in the SLC40A1 gene, affecting the iron-transport protein ferroportin. This can have an autosomal dominant inheritance pattern.
Secondary Iron Overload: Acquired Causes
Not all high iron levels are due to genetics. Secondary iron overload occurs when other medical conditions or treatments disrupt the body's iron regulation, leading to a harmful buildup over time.
Frequent Blood Transfusions
Each unit of blood contains a significant amount of iron (about 250 mg). Patients with blood disorders that require repeated transfusions, such as thalassemia and sickle cell disease, can develop severe iron overload because the body cannot excrete this excess iron.
Other Hematologic Disorders
Conditions characterized by ineffective erythropoiesis (impaired red blood cell production) can increase iron absorption and lead to iron overload, especially when combined with transfusions. This includes myelodysplastic syndromes and certain congenital hemolytic anemias.
Chronic Liver Disease
Underlying liver conditions, including chronic hepatitis C and alcoholic liver disease, can impair the liver's ability to properly regulate iron, contributing to or worsening iron overload. Excess iron then accelerates liver damage.
Other Factors and Risk Factors
- Excessive Iron Intake: While rare, consuming excessive iron through long-term use of iron supplements or dietary fortification can cause iron overload.
- Alcohol Misuse: Heavy alcohol consumption increases iron absorption and places additional strain on the liver, raising the risk of iron-related liver damage in genetically susceptible individuals.
- Dialysis: Long-term dialysis can sometimes lead to iron accumulation.
Understanding High Iron: A Comparison of Causes
| Feature | Hereditary Hemochromatosis (Primary) | Secondary Iron Overload |
|---|---|---|
| Underlying Cause | Inherited genetic mutation (e.g., HFE gene). | Acquired medical conditions or treatments. |
| Mechanism | Impaired regulation of intestinal iron absorption, leading to excessive uptake. | Excessive exogenous iron input (transfusions) or dysregulation due to other diseases. |
| Common Examples | HFE-related hemochromatosis, Juvenile hemochromatosis. | Thalassemia, Sickle cell disease, Chronic liver disease. |
| Onset | Typically mid-adulthood (men after 40, women after menopause). Juvenile types occur earlier. | Varies widely based on underlying condition and treatment history. |
| Treatment | Phlebotomy (regular blood removal). | Iron chelation therapy, sometimes phlebotomy. |
How High Iron is Diagnosed
Diagnosis typically involves a combination of blood tests and, if necessary, further evaluation.
- Blood Tests: Fasting serum iron, transferrin saturation (TSAT), and serum ferritin levels are the key initial tests. A high TSAT (>45%) and elevated ferritin (>250 ng/mL for men, >200 ng/mL for women) are suggestive of iron overload.
- Genetic Testing: If blood tests indicate iron overload, genetic testing for HFE gene mutations can confirm hereditary hemochromatosis.
- Liver Function Tests and Imaging: Liver function tests check for damage, and an MRI (Multi-Echo R2* MRI) can measure iron concentration in the liver non-invasively.
- Liver Biopsy: A biopsy may be performed to assess the degree of liver damage and measure the iron content.
Conclusion: Early Detection Is Key
High iron levels can be caused by genetic predispositions like hereditary hemochromatosis, or by secondary factors such as repetitive blood transfusions and chronic liver diseases. The body's inability to eliminate excess iron makes it a silent threat that can damage vital organs over time. Early diagnosis through blood testing and genetic analysis is crucial for preventing severe complications like liver disease, diabetes, and heart failure. With appropriate treatment, most people can manage their iron levels and avoid long-term damage. If you have a family history of hemochromatosis or experience unexplained symptoms like fatigue or joint pain, it is important to speak with a healthcare provider about getting tested. For further information on hemochromatosis and treatment, you can visit the Centers for Disease Control and Prevention website.
