What is the HFE gene and how is it related to hemochromatosis?

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The HFE gene is a gene located on chromosome 6 that plays a key role in regulating the body’s absorption of iron from the diet. It provides instructions for making a protein (also called HFE) that interacts with other proteins involved in iron homeostasis, helping to maintain normal iron levels in the body. Mutations in the HFE gene can impair this regulatory process, leading to hereditary hemochromatosis, a condition characterized by excessive iron absorption and iron overload.

Key Aspects of the HFE Gene and Its Role in Hemochromatosis:

1. Function of the HFE Gene:

The HFE gene encodes the HFE protein, which is involved in regulating iron absorption by interacting with the transferrin receptor on the surface of cells.
The HFE protein helps control the body’s response to iron levels by influencing the production of hepcidin, a hormone produced by the liver that regulates iron absorption in the intestines. When the body has sufficient iron, hepcidin levels rise to reduce iron absorption. Conversely, low iron levels suppress hepcidin, allowing for more iron to be absorbed.
In a normally functioning system, this regulation prevents excessive iron buildup in the body.

2. Mutations in the HFE Gene:

Two main mutations in the HFE gene are most commonly associated with hereditary hemochromatosis:

C282Y Mutation: This is the most common and significant mutation linked to hereditary hemochromatosis. It involves a substitution of the amino acid cysteine with tyrosine at position 282 in the HFE protein. This mutation disrupts the protein’s ability to regulate iron absorption, leading to unregulated iron uptake by the intestines.
H63D Mutation: This mutation involves a substitution of histidine with aspartic acid at position 63 in the HFE protein. While less severe than the C282Y mutation, the H63D mutation can still contribute to iron overload, particularly in people who inherit one copy of the H63D mutation and one copy of the C282Y mutation (compound heterozygous).

3. How HFE Mutations Lead to Hemochromatosis:

When both copies of the HFE gene (one from each parent) carry the C282Y mutation (homozygous C282Y), the body absorbs more iron than it needs from the diet. This excess iron cannot be excreted, so it is stored in various organs, including the liver, heart, pancreas, and joints. Over time, this leads to iron overload, or hemochromatosis, and the excessive iron causes tissue damage and organ dysfunction.

Homozygous C282Y: People with two copies of the C282Y mutation (homozygous C282Y) are at the highest risk of developing iron overload and hemochromatosis.
Compound Heterozygous (C282Y/H63D): Individuals who inherit one copy of the C282Y mutation and one copy of the H63D mutation (compound heterozygous) may also develop hemochromatosis, but the condition is often less severe than in homozygous C282Y individuals.

4. Inheritance of HFE Mutations:

Autosomal Recessive Inheritance: Hereditary hemochromatosis caused by HFE gene mutations is inherited in an autosomal recessive pattern. This means a person must inherit two copies of the mutated gene (one from each parent) to develop the condition. People who inherit one mutated gene and one normal gene are carriers but usually do not develop iron overload, although they may have mildly elevated iron levels.
If both parents are carriers of an HFE mutation, their children have:
- A 25% chance of inheriting two mutated genes (and developing hemochromatosis),
- A 50% chance of inheriting one mutated gene and being a carrier, and
- A 25% chance of inheriting no mutations and being unaffected.

5. Types of Hereditary Hemochromatosis Linked to HFE:

Type 1 Hereditary Hemochromatosis: This is the most common form of hereditary hemochromatosis and is primarily caused by mutations in the HFE gene. It typically presents in adulthood, with symptoms often becoming noticeable in people between 40 and 60 years of age.
The condition can progress over decades, and if untreated, it can lead to complications such as liver disease (cirrhosis), heart disease, diabetes, arthritis, and hormonal imbalances due to iron deposits in various organs.

6. Symptoms and Complications:

The symptoms of hemochromatosis usually appear later in life because it takes time for excess iron to accumulate to dangerous levels. Common symptoms include:

Fatigue
Joint pain
Abdominal pain
Skin pigmentation changes (bronze or gray tint)
Liver enlargement or cirrhosis
Diabetes (due to damage to the pancreas)
Heart problems (e.g., heart failure, arrhythmias)
Hormonal imbalances, such as loss of libido or menstrual irregularities

Without treatment, iron overload can cause serious damage to organs such as the liver (leading to cirrhosis or liver cancer), the heart, and the pancreas.

7. Diagnosis:

Blood Tests: Elevated levels of ferritin (a protein that stores iron) and transferrin saturation (a measure of iron bound to transferrin, the protein that transports iron) are common indicators of iron overload. These tests are typically used as an initial screening for hemochromatosis.
Genetic Testing: Genetic testing confirms the presence of mutations in the HFE gene, particularly the C282Y and H63D mutations. This test is used to confirm the diagnosis of hereditary hemochromatosis.
Liver Function Tests and Imaging: These may be used to assess liver damage caused by iron overload.

8. Treatment:

The primary treatment for hereditary hemochromatosis is therapeutic phlebotomy (regular blood removal), which helps reduce iron levels by forcing the body to use stored iron to make new red blood cells.
Dietary Changes: Patients are often advised to avoid iron supplements and limit alcohol and vitamin C, which can increase iron absorption.
Monitoring: Regular monitoring of iron levels and organ function is necessary to prevent complications and ensure effective management.

Conclusion:

The HFE gene plays a crucial role in regulating iron absorption. Mutations in this gene, particularly the C282Y and H63D mutations, are the primary cause of hereditary hemochromatosis. These mutations impair the body’s ability to regulate iron absorption, leading to iron overload and, if untreated, serious complications like liver disease, heart failure, and diabetes. Early diagnosis and treatment, usually through blood removal (phlebotomy), can prevent or minimize these complications and help individuals maintain normal iron levels.

Ironbound™ A Strategy For The Management Of Hemochromatosis