The HFE protein is found in the human body, primarily on the surface of cells in the liver, intestines, and some immune cells. It plays a role in sensing and regulating the body’s iron levels.
Normal Function of HFE Protein
The HFE protein regulates iron levels within the body, a process known as iron homeostasis. It interacts with other proteins to control iron. One interaction is with transferrin receptor 1 (TfR1); HFE binds to TfR1, preventing transferrin from binding. This action helps control iron entry into liver cells.
The HFE protein also regulates hepcidin, a liver hormone that determines iron absorption from the diet and release from storage sites throughout the body. When the HFE protein is not bound to TfR1, it can interact with other proteins, triggering hepcidin production. Conversely, hepcidin production is reduced when HFE is bound to TfR1. This system ensures iron absorption is carefully managed.
HFE Protein and Hereditary Hemochromatosis
Dysfunction of the HFE protein is linked to hereditary hemochromatosis, a genetic disorder characterized by excessive iron absorption and accumulation. This condition arises from specific mutations within the HFE gene, primarily C282Y and H63D. If an individual inherits two copies of the altered HFE gene, such as two C282Y mutations or one C282Y and one H63D, they are at a higher risk of developing hereditary hemochromatosis.
However, not everyone with these genetic changes will experience significant iron overload or symptoms. The disorder is inherited in an autosomal recessive pattern, meaning both parents must contribute a mutated gene copy for the condition to manifest.
How HFE Dysfunction Leads to Iron Overload
When the HFE protein is faulty due to genetic mutations, its ability to regulate iron is impaired, leading to iron overload. The mutated HFE protein does not properly interact with transferrin receptor 1 or adequately control hepcidin production. This disruption means that the body’s iron sensing mechanism is compromised.
In individuals with mutated HFE, hepcidin levels are inappropriately low. Hepcidin normally reduces iron absorption from the gut and iron release from cellular storage by binding to ferroportin. With insufficient hepcidin, ferroportin activity is not adequately suppressed, leading to increased iron absorption from the diet and elevated release of iron from storage sites.
This unchecked iron accumulation results in excess iron depositing in various organs and tissues. The liver is a primary site for this iron buildup, but other organs like the heart, pancreas, and joints can also be affected. Over time, this iron overload can damage these organs, leading to the clinical manifestations of hereditary hemochromatosis.
Recognizing and Managing Conditions Linked to HFE
Recognizing HFE dysfunction often begins with observing symptoms of iron overload. These can include persistent fatigue, joint pain, and abdominal discomfort. As iron accumulates, more severe signs like liver issues, such as elevated liver enzymes or cirrhosis, and skin changes causing a bronze or gray appearance, may develop.
Diagnosis of hereditary hemochromatosis involves a combination of blood tests and genetic testing. Initial blood tests measure serum ferritin levels, which reflect the body’s iron stores, and transferrin saturation, indicating how much iron is circulating in the blood. Ferritin levels above 300 ng/mL for men and 200 ng/mL for women, or transferrin saturation exceeding 45%, suggest iron overload.
If these iron markers are elevated, genetic testing for the HFE gene mutations (C282Y and H63D) is performed to confirm the diagnosis. Early diagnosis is beneficial as it allows for timely management before significant organ damage occurs.
The primary treatment for hereditary hemochromatosis is therapeutic phlebotomy, which involves regularly removing blood from the body to reduce iron levels. Phlebotomy sessions typically remove about 500 mL of blood, equating to approximately 200-250 mg of iron. The goal of this treatment is to reduce serum ferritin levels to a range of 50 to 100 ng/mL without causing anemia. Once iron levels are normalized, the frequency of phlebotomy can be reduced, often to three to four times per year, with some individuals able to donate blood regularly as a maintenance strategy.