Hemochromatosis type 2 is 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.

Symptoms of hemochromatosis type 2 typically begin during childhood. Early symptoms of hemochromatosis type 2 typically include liver disease, heart disease, and low levels of sex hormones. Having low levels of sex hormones can cause women to stop having their monthly periods and men to have delayed puberty. People with hemochromatosis type 2 may have heart disease by age 30. Other symptoms may include abdominal pain, diabetes, and skin discoloration.

Hemochromatosis type 2 is caused by genetic changes (mutations or pathogenic variants) to the HFE2 (HJV) or HAMPgenes. The disease is inherited in an autosomal recessive manner. A diagnosis of hemochromatosis type 2 is 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 2 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 2 is caused by genetic changes (mutations or pathogenic variants) in the HFE2(also known as HJV) or HAMP genes. The HAMP gene provides instructions to the body to make a protein called hepcidin. Hepcidin controls iron absorption in the small intestine. Pathogenic variants in the HAMP gene cause hepcidin to not be able to limit iron absorption when there is already too much iron in the body. The HFE2 (HJV) gene is thought to provide instructions to the body to help regulate hepcidin. Pathogenic variants in the HFE2 (HJV) gene, cause this protein to not be able to regulate hepcidin. Therefore, pathogenic variants in either of these genes cause iron to accumulate in tissues and organs, which can result in organ damage.

Normal Function

The HJV gene provides instructions for making a protein called hemojuvelin. This protein is made in the liver, heart, and muscles used for movement (skeletal muscles). Hemojuvelin plays a role maintaining proper iron levels in the body by controlling the levels of another protein called hepcidin. Hepcidin is necessary for maintaining an appropriate balance of iron (iron homeostasis) in the body.

Health Conditions Related to Genetic Changes

Hereditary hemochromatosis

More than 30 HJV gene mutations have been found to cause type 2 hemochromatosis, a form of hereditary hemochromatosis that begins during childhood or adolescence. 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.

Most HJV gene mutations change one of the protein building blocks (amino acids) used to make hemojuvelin. Most frequently, the amino acid glycine is replaced by the amino acid valine at protein position 320 (written as Gly320Val or G320V). Other mutations create a premature stop signal in the instructions for making the hemojuvelin protein resulting in an abnormally small protein.

Mutations in the HJV gene lead to an altered hemojuvelin protein that cannot function properly. Without adequate hemojuvelin, hepcidin levels are reduced and iron homeostasis is disturbed. As a result, too much iron is absorbed during digestion, which leads to iron overload and damage to tissues and organs in the body that is found in hereditary hemochromatosis.

Other Names for This Gene

• hemochromatosis type 2 (juvenile)
• HFE2
• HFE2A
• JH
• RGM domain family, member C
• RGMC
• RGMC_HUMAN

Genomic Location

Normal Function

The HAMP gene provides instructions for the production of a protein called hepcidin. Hepcidin, which is produced primarily in the liver, plays a major role in maintaining iron balance in the body. When blood iron levels are high, iron enters liver cells and triggers them to increase production of hepcidin. Hepcidin then circulates in the blood and stops iron absorption in the small intestine when the body's supply of iron is too high.

Hepcidin interacts primarily with other proteins in the small intestine, liver, and certain white blood cells to adjust iron absorption and storage. In this way, an appropriate balance of iron (iron homeostasis) is maintained and iron absorption is adjusted to reflect the body's needs.

Health Conditions Related to Genetic Changes

Hereditary hemochromatosis

At least 14 mutations in the HAMP gene can cause type 2 hemochromatosis, a form of hereditary hemochromatosis that begins during childhood or adolescence. 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.

Mutations in the HAMP gene result in the production of abnormal hepcidin with decreased function. This altered hepcidin cannot stop iron absorption, even when the body has sufficient supplies of iron. As a result, tissues and organs become overloaded with iron, especially the liver and the heart, leading to organ damage in hereditary hemochromatosis.

Other Names for This Gene

• HEPC
• HEPC_HUMAN
• Hepcidin
• HFE2B
• LEAP-1
• LEAP1
• Liver-expressed antimicrobial peptide
• PLTR
• Putative liver tumor regressor

Genomic Location

• 25% chance to have hemochromatosis type 2
• 50% chance to be a carrier like each parent
• 25% chance to have two working copies of the HFE2 (HJV) and HAMP genes, meaning the child is unaffected and is not a carrier of hemochromatosis type 2

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.