The discovery of the HFE gene about 30 years ago explained the most common inherited form of the condition. We now know that rarer forms can result from changes in several other genes. Most of these genetic defects disrupt the hepcidin–ferroportin system, which normally controls how much iron is absorbed from food and released into the bloodstream. When hepcidin production or activity is insufficient, too much iron enters the blood and gradually accumulates in tissues and organs.

These discoveries identified the hepcidin pathway as a potential therapeutic target. Drugs that mimic hepcidin or increase its activity are being developed. In a small proof-of-concept study involving people with HFE-related hemochromatosis, the hepcidin mimetic rusfertide substantially reduced the need for phlebotomy while treatment continued. These results are encouraging, but such drugs remain experimental and require further evaluation before they can become routine treatment. For now, regular phlebotomy remains the standard and highly effective therapy.