Causes of Haemochromatosis
The causes of Haemochromatosis are primarily genetic, with the condition most often resulting from mutations in the HFE gene. These mutations disrupt the body’s normal regulation of iron absorption, leading to excessive iron being absorbed from the diet. The exact causes of Haemochromatosis can vary depending on the type, but the underlying problem remains the same: the body stores too much iron, and this iron builds up over time to toxic levels.
In normal physiology, iron absorption is tightly controlled. The body only takes in as much iron as it needs, and unused iron is stored safely in ferritin proteins. However, in Haemochromatosis, this control mechanism fails. Instead of moderating absorption, the intestines continue to draw in iron even when the body already has an excess.
1. Genetic Mutations – The Root Cause
The majority of hereditary Haemochromatosis cases are linked to mutations in the HFE gene, which regulates how much iron is absorbed in the gut.
a. C282Y Mutation
The most common and clinically significant
Individuals with two copies (homozygous) are most likely to develop symptoms
Alters a protein involved in sensing body iron levels
b. H63D Mutation
Milder than C282Y
Often present in compound heterozygotes (one copy of each mutation)
May cause iron overload when combined with other risk factors
c. S65C Mutation
Less common
Usually does not cause disease unless combined with another HFE mutation
The faulty gene prevents the liver from producing hepcidin, a hormone that controls iron absorption. Without enough hepcidin, the gut continues to absorb iron unchecked.
2. Inherited Types of Haemochromatosis
Different types are classified based on the gene affected:
| Type | Gene Involved | Typical Onset | Severity |
| Type 1 | HFE | Adulthood | Mild to moderate |
| Type 2 | HJV, HAMP | Childhood/adolescence | Severe |
| Type 3 | TFR2 | Young adulthood | Moderate |
| Type 4 | SLC40A1 (ferroportin) | Variable | Mild, dominant inheritance |
These types are inherited in an autosomal recessive or dominant pattern. Family history plays a key role in determining risk.
3. Secondary (Non-Hereditary) Iron Overload
Although genetic forms account for most cases, iron overload can also result from non-genetic causes:
Repeated blood transfusions, especially in conditions like thalassaemia or sickle cell anaemia
Excessive iron supplementation, particularly over long periods
Chronic liver disease, which affects iron metabolism
Alcohol abuse, which enhances iron absorption
Certain rare anemias, such as sideroblastic anaemia
These causes require different management approaches and are not classified as true Haemochromatosis.
4. Role of Hepcidin
Hepcidin is a hormone produced by the liver that regulates iron absorption by signalling the gut to reduce intake when iron levels are high.
In people with Haemochromatosis:
Hepcidin levels are abnormally low
Iron transport proteins in the intestine remain active
This leads to continuous absorption, even when the body is overloaded
Understanding this hormonal mechanism has paved the way for future treatments targeting hepcidin regulation.
5. Environmental and Lifestyle Factors
While genetic mutations are the primary cause, certain lifestyle choices can influence the severity or onset of symptoms:
High dietary iron intake, especially from red meat or iron-fortified foods
Excessive alcohol consumption, which damages the liver and increases iron absorption
Vitamin C supplementation, which enhances iron uptake
Viral infections, such as hepatitis, may worsen liver damage
These factors don’t cause Haemochromatosis, but they can aggravate iron overload in genetically predisposed individuals.
6. Gender Differences in Presentation
Men are more likely to show symptoms earlier due to:
Lack of natural iron loss through menstruation
Higher baseline iron levels
Less frequent medical evaluations related to hormonal health
Women may remain asymptomatic until after menopause, when menstrual blood loss ceases.
Conclusion | Causes of Haemochromatosis
The causes of Haemochromatosis are predominantly genetic, with mutations in the HFE gene leading to the body’s inability to regulate iron absorption. Without intervention, iron accumulates over time and can damage multiple organs. While inherited forms are most common, secondary causes such as chronic liver disease and transfusion overload also contribute to iron excess in some patients. Understanding the causes of Haemochromatosis is vital for early detection, appropriate testing, and prevention of long-term complications.
