Hemochromatosis type 1is a disease in which too much iron builds up in the body. This is also called iron overload. Accumulation of iron in the organs is toxic and can cause organ damage. While many organs can be affected, iron overload is especially likely to affect the liver, heart, and pancreas. Early symptoms of hemochromatosis type 1 can include fatigue, weakness, and joint pain. Other symptoms may include abdominal pain, loss of sex drive, liver disease, diabetes, heart problems, and skin discoloration. Symptoms of hemochromatosis type 1 typically begin between the ages of 40-60 years-old. Hemochromatosis type 1 is the most common type of hemochromatosis, and it affects more men than women.

Hemochromatosis type 1 is caused by genetic changes (mutations or pathogenic variants) to theHFEgene. The disease is inherited in an autosomal recessive manner. A diagnosis of hemochromatosis type 1is suspected when a doctor observes signs and symptoms of the disease. A doctor may decide to order laboratory tests including a liver biopsy, MRI, or blood test. The diagnosis can be confirmed with genetic testing. Treatment of hemochromatosis type 1 usually involves reducing iron levels by removing blood (phlebotomy) or iron chelation. These treatments can prevent additional organ damage but typically do not reverse existing damage.

Hemochromatosis type 1 is caused by genetic changes (mutations or pathogenic variants) in the HFEgene. The HFE gene provides the body with instructions to make a protein that is located on the surface of cells. This protein helps detect the amount of iron in the body to determine how much iron should be absorbed from the diet. Pathogenic variants in the HFE gene cause these proteins to not be able to correctly tell the body how much iron to absorb. This causes iron to accumulate in tissues and organs, which can result in organ damage.

Normal Function

The HFE gene provides instructions for producing a protein that is located on the surface of cells, primarily liver and intestinal cells. The HFE protein is also found on some immune system cells.

The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. When the HFE protein is attached (bound) to a protein called transferrin receptor 1, the receptor cannot bind to a protein called transferrin. When transferrin receptor 1 is bound to transferrin, iron enters liver cells. So, it is likely that the HFE protein regulates iron levels in liver cells by preventing transferrin from binding to transferrin receptor 1.

The HFE protein regulates the production of a protein called hepcidin. Hepcidin is produced by the liver, and it determines how much iron is absorbed from the diet and released from storage sites in the body. When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. The formation of this protein complex triggers the production of hepcidin. So when the HFE protein is bound to transferrin receptor 1, hepcidin production is turned off and when the HFE protein is not bound to transferrin receptor 1, hepcidin production is turned on.

When the proteins involved in iron sensing and absorption are functioning properly, iron absorption is tightly regulated. On average, the body absorbs about 10 percent of the iron obtained from the diet.

Health Conditions Related to Genetic Changes

Porphyria

Mutations in the HFE gene can increase the risk of developing a condition called porphyria. Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is a vital molecule for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). HFE gene mutations are found more frequently in people with the most common form of porphyria, known as porphyria cutanea tarda, than in unaffected people.

Researchers suspect that HFE gene mutations may trigger this type of porphyria by increasing the absorption of iron. A buildup of excess iron, in combination with other genetic and nongenetic factors, interferes with the production of a molecule called heme. Heme is a component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). A blockage in heme production allows other compounds called porphyrins to build up to toxic levels in the liver and other organs. These compounds are formed during the normal process of heme production, but excess iron and other factors allow them to accumulate to toxic levels. The abnormal buildup of porphyrins leads to the characteristic features of porphyria cutanea tarda.

Hereditary hemochromatosis

Researchers have identified more than 100 mutations in the HFE gene that cause type 1 hemochromatosis, a form of hereditary hemochromatosis that begins during adulthood. Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron accumulates in, and eventually damages, the body's tissues and organs.

Two particular mutations are responsible for most cases of type 1 hemochromatosis. Each of these mutations changes one of the protein building blocks (amino acids) in the HFE protein. One mutation replaces the amino acid cysteine with the amino acid tyrosine at position 282 in the protein's chain of amino acids (written as Cys282Tyr or C282Y). The other mutation replaces the amino acid histidine with the amino acid aspartic acid at position 63 (written as His63Asp or H63D).

The Cys282Tyr mutation prevents the altered HFE protein from reaching the cell surface. The His63Asp mutation likely alters the three-dimensional shape of the protein. These mutations prevent the HFE protein from interacting with transferrin receptor 1 and other proteins. As a result, iron regulation is disrupted, and too much iron is absorbed from the diet. This increase in the absorption of dietary iron leads to the iron overload characteristic of type 1 hemochromatosis.

X-linked sideroblastic anemia

The Cys282Tyr mutation, which is a common cause of type 1 hereditary hemochromatosis (described above), may also increase the severity of the iron overload in X-linked sideroblastic anemia when it is inherited along with a mutation in the ALAS2 gene. The combination of HFE and ALAS2 gene mutations leads to more severe signs and symptoms of X-linked sideroblastic anemia by further increasing the absorption of dietary iron, leading to an even greater iron overload.

Other Names for This Gene

• hemochromatosis
• hemochromatosis, genetic; GH
• Hemochromatosis, Hereditary; HH
• Hereditary hemochromatosis protein
• HFE_HUMAN
• HLA-H antigen

Genomic Location

Hemochromatosis type 1 is inherited in an autosomal recessive manner. This means that people with hemochromatosis type 1 have a genetic change (mutation or pathogenic variant) in both copies of the HFEgene in each cell of the body. We inherit one copy of every gene from our mother and the other from our father. The parents of a person with hemochromatosis type 1 are each expected to have one changed copy of the HFE gene. People with one changed copy of a gene are known as carriers. Carriers typically do not have signs or symptoms of hemochromatosis type 1.

When two carriers of hemochromatosis type 1 have children, each child has a:

• 25% chance to have hemochromatosis type 1
• 50% chance to be a carrier like each parent
• 25% chance to have two working copies of the HFE gene, meaning the child is unaffected and is not a carrier of hemochromatosis type 1

Hemochromatosis type 1 is a disease that shows reduced penetrance. This means that some people with pathogenic variants in the HFE gene never show symptoms of the disease. However, children or other family members who have pathogenic variants causing hemochromatosis may show symptoms of the disease.

Your doctor will diagnose hemochromatosis based on your medical and family histories, a physical exam, and the results from tests and procedures.

The disease sometimes is detected while checking for other diseases or conditions, such as arthritis, liver disease, diabetes, heart disease, or erectile dysfunction (impotence).

Specialists Involved

Family doctors and internal medicine specialists may diagnose and treat hemochromatosis. Other doctors also may be involved in diagnosing and treating the disease, including:

• Hematologists (blood disease specialists)
• Cardiologists (heart specialists)
• Endocrinologists (gland system specialists)
• Hepatologists (liver specialists)
• Gastroenterologists (digestive tract specialists)
• Rheumatologists (specialists in diseases of the joints and tissues)

Medical and Family Histories

To learn about your medical and family histories, your doctor may ask:

• About your signs and symptoms, including when they started and their severity.
• Whether you take iron (pills or injections) with or without vitamin C supplements (vitamin C helps your body absorb iron from food). If so, your doctor may ask how much iron you take. This information can help him or her diagnose secondary hemochromatosis.
• Whether other members of your family have hemochromatosis.
• Whether other members of your family have a history of medical problems or diseases related to hemochromatosis.

Physical Exam

Your doctor will do a physical exam to check for signs and symptoms of hemochromatosis. He or she will listen to your heart for irregular heartbeats and check for arthritis, abnormal skin color, and an enlarged liver.

Diagnostic Tests and Procedures

Your doctor may recommend one or more tests or procedures to diagnose hemochromatosis.

Blood Tests

In hemochromatosis, the amount of iron in your body may be too high, even though the level of iron in your blood is normal. Certain blood tests can help your doctor find out how much iron is in your body.

During these tests, a sample of blood is taken from your body. It's usually drawn from a vein in your arm using a needle. The procedure usually is quick and easy, although it may cause some short-term discomfort.

The blood tests you have may include transferrin saturation (TS), serum ferritin level, and liver function tests.

Transferrin is a protein that carries iron in the blood. The TS test shows how much iron the transferrin is carrying. This helps your doctor find out how much iron is in your body.

Your doctor may test your serum ferritin level if your TS level is high. A serum ferritin level test shows how much iron is stored in your body's organs. A buildup of iron may suggest hemochromatosis.

You may have liver function tests to check for damage to your liver. Liver damage may be a sign of hemochromatosis. If you have hemochromatosis, liver function tests may show the severity of the disease.

Blood tests alone can't diagnose hemochromatosis. Thus, your doctor may recommend other tests as well.

Liver Biopsy

During a liver biopsy, your doctor numbs an area near your liver and then removes a small sample of liver tissue using a needle. The tissue is then looked at under a microscope.

A liver biopsy can show how much iron is in your liver. This procedure also can help your doctor diagnose liver damage (for example, scarring and cancer). Liver biopsies are less common now than in the past.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is a safe test that uses radio waves, magnets, and a computer to create pictures of your organs. An MRI may be done to show the amount of iron in your liver.

Superconducting Quantum Interference Device

A superconducting quantum interference device (SQuID) is a machine that uses very sensitive magnets to measure the amount of iron in your liver. This machine is available at only a few medical centers.

Genetic Testing

Genetic testing can show whether you have a faulty HFE gene or genes. However, even if you do have two faulty HFE genes, the genetic test can't predict whether you'll develop signs and symptoms of hemochromatosis.

Also, genetic testing may not detect other, less common faulty genes that also can cause hemochromatosis.

There are two ways to do genetic testing. Cells can be collected from inside your mouth using a cotton swab, or a sample of blood can be drawn from a vein in your arm.

People who have hemochromatosis (or a family history of it) and are planning to have children may want to consider genetic testing and counseling. Testing will help show whether one or both parents have faulty HFE genes. A genetic counselor also can help figure out the likelihood of the parents passing the faulty genes on to their children.

Treatment for hemochromatosis type 1 may include reducing iron levels by removing blood (phlebotomy), iron chelation therapy, dietary changes, and treatment for complications of the disease. The goal of treatment is to reduce the amount of iron in the body to normal levels, prevent or delay organ damage from excess iron, and maintain normal amounts of iron throughout the lifetime.

Phlebotomy helps to remove excess iron from the body. Most people begin treatment with weekly therapeutic phlebotomy, although sometimes treatment is initially twice a week if iron levels are very elevated. Maintenance phlebotomy usually involves treatment every 2-4 months. Iron chelation therapy may be recommended for some people with hemochromatosis type 1 if they have other health issues. This involves removing excess iron using medications.

Dietary recommendations for people with hemochromatosis may include avoiding alcohol and red meat. People with hemochromatosis are not recommended to take iron or vitamin C supplements.