The HFE gene, or Human Hemochromatosis gene, is a set of instructions within the body’s DNA that plays a fundamental role in maintaining iron balance. This gene provides the blueprint for the HFE protein, which is primarily located on the surface of liver cells, cells lining the small intestine, and some immune cells. The HFE protein acts as a key sensor, helping the body determine whether iron levels are adequate, low, or excessive. Proper function of this protein is necessary for systemic iron homeostasis, ensuring the body absorbs only the iron it needs and prevents toxic accumulation.
The HFE Protein’s Role in Iron Regulation
The HFE protein is an atypical major histocompatibility complex (MHC) class I-like molecule that works with other proteins to regulate the body’s iron supply. Its mechanism is linked to hepcidin, a peptide hormone produced in the liver that serves as the master regulator of iron metabolism. In conditions of sufficient iron, the HFE protein contributes to signaling pathways that promote hepcidin production.
A major part of the HFE protein’s job involves its interaction with transferrin receptor 1 (TfR1), a protein on the cell surface that binds to iron-carrying transferrin in the blood. When iron levels are low, HFE binds to TfR1, which prevents the production of hepcidin. When iron levels are high, increased amounts of iron-loaded transferrin are present in the blood, which outcompetes HFE for binding to TfR1, freeing the HFE protein.
This newly unbound HFE protein forms a complex with transferrin receptor 2 (TfR2) and other regulatory molecules in liver cells. This complex signals the liver to increase hepcidin production. Hepcidin then circulates, limiting the release of iron into the blood from intestinal cells, macrophages, and liver storage sites by promoting the degradation of the iron-export protein ferroportin.
HFE Gene Mutations and Hemochromatosis
Hereditary Hemochromatosis (HH) is an autosomal recessive genetic disorder that most commonly results from mutations in the HFE gene. The mutations cause the HFE protein to malfunction, which leads to the liver mistakenly sensing low iron levels. This failure in the iron-sensing mechanism results in inappropriately low production of hepcidin, regardless of the actual iron stores in the body.
With insufficient hepcidin, ferroportin remains active on cell surfaces, leading to unchecked iron absorption from the diet and excessive iron release from storage cells. This causes a gradual, progressive iron overload throughout the body. Since the condition is autosomal recessive, a person must inherit two copies of a mutated HFE gene, one from each parent, to be at high risk of developing the disorder.
Two specific mutations account for the vast majority of HFE-related HH cases. The most common mutation is C282Y, which prevents the HFE protein from reaching the cell surface. Homozygosity for C282Y (inheriting two copies) is present in 80–90% of individuals with iron overload. The second common mutation is H63D, which is associated with a milder form of the condition because the protein’s function is impaired, though it still reaches the cell surface. Individuals who inherit one copy of C282Y and one copy of H63D (compound heterozygotes) are also at increased risk for developing iron overload.
Symptoms and Diagnostic Testing
The chronic accumulation of excess iron from a faulty HFE protein can damage multiple organs over many years. Early symptoms are nonspecific, including fatigue, weakness, and joint pain, which can be mistaken for other conditions. Iron deposition in the liver can lead to an enlarged liver, eventually progressing to fibrosis and cirrhosis, which increases the risk of liver cancer.
Other major target organs include the heart, where iron accumulation can cause cardiomyopathy and irregular heart rhythms, and the pancreas, which can lead to the development of diabetes. Joint pain, or arthralgia, is a common symptom, often affecting the knuckles of the first and second fingers. Individuals may also experience:
- Skin darkening or “bronzing.”
- Abdominal pain.
- Loss of libido.
- Hypogonadism.
Diagnosis of HFE-related HH begins with blood tests to assess iron status. The two key tests are transferrin saturation (TSAT) and serum ferritin. TSAT measures the percentage of iron-carrying transferrin protein that is loaded with iron, and elevated levels are the earliest indicator of iron overload. Serum ferritin measures the amount of iron stored in the body; levels above 1,000 µg/L are associated with a higher risk of liver disease. If these tests are elevated, the diagnosis is confirmed with genetic testing for the HFE gene to identify the C282Y and H63D mutations.
Treatment and Long-Term Management
The standard treatment for HFE-related Hereditary Hemochromatosis is therapeutic phlebotomy, which is the removal of blood, similar to a regular blood donation. This procedure works because the body must use excess iron stores to create new red blood cells to replace those removed. The process is simple, safe, and inexpensive, directly reducing the total body iron burden.
Treatment is divided into two phases: induction and maintenance. During the induction phase, blood is removed frequently, often weekly, until iron levels return to a normal range (defined as a serum ferritin level below 50 ng/mL). Once iron-depletion is achieved, the patient moves to the maintenance phase, requiring less frequent phlebotomies, usually two to four times a year, to keep iron levels controlled.
Long-term management involves lifestyle adjustments to prevent further iron accumulation. Patients are advised to avoid taking iron supplements, including multivitamins that contain iron, and to limit excessive consumption of alcohol, as iron and alcohol are synergistic liver toxins. Regular monitoring of serum ferritin and TSAT is necessary to guide the frequency of phlebotomy and ensure iron levels remain within the therapeutic range.