The HFE gene plays a central role in regulating the body’s iron levels. Mutations within this gene are the most common cause of hereditary hemochromatosis, a condition characterized by excessive iron absorption and accumulation. This genetic change disrupts the balance of iron metabolism, leading to a progressive buildup of the mineral in various organs and tissues. Understanding the function of the HFE gene and how its mutations interfere with normal physiology helps explain the mechanism behind this inherited disorder.
The HFE Gene’s Role in Iron Regulation
The HFE gene provides instructions for creating a protein that acts as a sensor for iron stores, primarily in liver cells. This HFE protein works with other molecules to control the production of hepcidin, a hormone secreted by the liver that regulates iron. Hepcidin limits the amount of iron absorbed from the diet and released from storage sites.
When the HFE protein functions correctly, it gauges the iron saturation of the blood, signaling the liver to adjust hepcidin output. If iron levels are high, hepcidin increases, blocking the iron-exporting protein ferroportin on intestinal cells and reducing absorption. Conversely, low iron levels decrease hepcidin production, allowing more dietary iron to enter the bloodstream. A faulty HFE protein prevents this sensing mechanism from working efficiently.
Understanding Hemochromatosis
Hereditary hemochromatosis occurs when the mutated HFE gene leads to inadequate hepcidin production, regardless of the body’s actual iron stores. The liver mistakenly perceives that iron levels are too low, resulting in inappropriate over-absorption of iron from the gastrointestinal tract. Instead of absorbing the typical 10% of dietary iron, individuals with hemochromatosis absorb a much higher percentage.
This excessive iron, which the body has no efficient way to excrete, gradually accumulates in parenchymal cells throughout the body. The accumulation of iron can damage organs such as the liver, leading to scarring known as cirrhosis and an elevated risk of liver cancer. Iron deposition also frequently affects the heart, causing issues like arrhythmias or heart failure, and the pancreas, resulting in the development of diabetes mellitus.
Symptoms often develop subtly and are non-specific, which can delay diagnosis. Many people initially report fatigue, weakness, and joint pain, particularly in the knuckles of the index and middle fingers. As the condition progresses, excess iron can cause the skin to take on a bronze or grayish hue. Early detection and intervention are crucial because, while symptoms like fatigue may be reversible, severe organ damage such as cirrhosis and joint destruction are typically permanent.
Inheritance Patterns and Specific Mutations
Hereditary hemochromatosis is classified as an autosomal recessive disorder. This means an individual must inherit two altered copies of the HFE gene, one from each parent, to develop the condition. Individuals who inherit only one mutated copy are considered heterozygous carriers and rarely develop significant iron overload. The condition is most prevalent in populations of Northern European descent.
Two specific mutations account for the majority of hemochromatosis cases: C282Y and H63D. The C282Y mutation is the most common and severe. It prevents the HFE protein from properly folding and reaching the cell surface, impairing its function. A person with two copies of the C282Y mutation (C282Y homozygote) has the highest risk of iron overload and clinical disease.
The H63D mutation is less impactful on protein function. Individuals who are homozygous for H63D (two copies) have a low risk of developing hemochromatosis. A third genotype, known as compound heterozygous, occurs when a person inherits one copy of C282Y and one copy of H63D. This combination carries a moderate risk of iron overload, which is higher than the H63D homozygote but lower than the C282Y homozygote.
Diagnosis and Management Options
Diagnosis of hereditary hemochromatosis begins with blood tests to measure iron status. The first-line tests include serum ferritin and transferrin saturation. Transferrin saturation measures the percentage of iron-carrying protein in the blood that is bound to iron; a value consistently above 45% is highly suggestive of hemochromatosis. Serum ferritin measures the amount of iron stored in the body, and elevated ferritin levels indicate iron overload, although ferritin can also be elevated in other conditions like inflammation or liver disease.
If iron studies are suggestive of iron overload, genetic testing is used to confirm the diagnosis by looking for the C282Y and H63D mutations in the HFE gene. This non-invasive test definitively identifies the genetic cause of the iron excess. In cases where advanced organ damage is suspected, imaging techniques like MRI can be used to quantify iron concentration in organs such as the liver.
The most effective management strategy for hemochromatosis is therapeutic phlebotomy, a procedure that involves regularly removing blood from the body, similar to blood donation. Since most of the body’s iron is contained within red blood cells, this process forces the body to use stored iron to make new blood cells, effectively reducing overall iron stores. The initial phase of treatment requires frequent phlebotomies, often weekly, until ferritin levels are brought down to a target range, typically less than 50 ng/mL.
Once iron levels are normalized, patients enter a maintenance phase, requiring less frequent blood removal, usually every two to four months, for the rest of their lives. In addition to phlebotomy, patients are advised to avoid iron supplements and multivitamins containing iron, as well as supplemental Vitamin C, which can increase iron absorption. Limiting alcohol consumption is also recommended to reduce the risk of further liver damage.