Summary

Inherited haemochromatosis is a disorder that causes your body to absorb too much iron from your diet. It is due to having genetic alterations inherited from your father and mother. The human body tightly controls iron levels by taking in only what is needed. It does not have a way of getting rid of excess iron. In haemochromatosis, the genes that control iron absorption are not working properly and the body absorbs too much iron. It stores it in organs and tissues in a condition known as iron overload. If left untreated iron can progressively build up and cause severe organ damage. 

If you have symptoms that suggest you have haemochromatosis your doctor will usually request a Full Blood Count (FBC) and an iron studies panel of tests. If these results indicate haemochromatosis, your doctor may next order an HFE gene test which is the only definitive way to make a diagnosis.

Why get tested?

Haemochromatosis is a relatively common genetic disease in people whose ancestors came from northern Europe. It occurs because of inherited gene mutations.  A number of genes contain the DNA code involved in the regulation of iron uptake by cells in the liver and intestines.

If you have haemochromatosis, your body absorbs more iron that it needs. It is important that you are diagnosed because, if left untreated, the progressive build-up of iron can cause permanent damage to organs and tissues, such as the heart, liver, pancreas, skin and the joints.

How the body regulates iron levels

Our bodies cannot make iron.  Iron must be absorbed from our diet or from supplements. The amount of iron absorbed is determined by our body's needs.  We normally use just a little bit of iron each day. We do not have a way to get rid of excess iron. Instead, the body closely controls iron levels by regulating how much iron from our diet is absorbed.

What happens in haemochromatosis?

In haemochromatosis there is a breakdown in the process that controls iron levels and the body behaves as if there is an iron shortage. It responds by absorbing more iron from food. There is no mechanism to get rid of the excess iron and it accumulates in organs and tissues where it can cause damage. Clinical features of iron overload may include extreme tiredness, sore joints, abdominal pain, weight loss, and loss of sex drive. With time it is possible to develop arthritis, liver disease or liver cancer, diabetes, heart problems (cardiomyopathy), infertility and changes in skin colour. 

The genetic alterations that cause haemochromatosis 

There are a number of gene mutations that can cause iron overload by altering proteins that help the body regulate the amount of iron absorbed. There are four types of hereditary haemochromatosis depending on which genes carry a mutation. Type 1 haemochromatosis is the most common with mutations in the HFE gene.   We inherit two copies of the HFE gene, one from each parent. This is called an autosomal recessive pattern of inheritances – see diagram 1. 

In type 1 haemochromatosis, both copies of the HFE gene are faulty and the body makes an HFE protein that does not function correctly with the result that more iron than the body requires is absorbed.

Very rare forms of haemochromatosis are types 2 and 3. These too have autosomal recessive patterns of inheritances. Another form, type 4 has an autosomal dominant inheritance pattern where only one copy of the altered gene in each cell is sufficient to cause the disorder.

Testing for haemochromatosis

If iron overload is suspected, your doctor will request a full blood count (FBC), which gives information on the amount of haemoglobin in your blood, as well as the size and shape of the red blood cells.  They will also request iron studies, a group of tests that looks at the overall iron status in your body. This panel of tests consists of blood iron, transferrin and ferritin levels. A transferrin saturation level is calculated from these results. If your results suggest haemochromatosis, an HFE genetic test may be ordered to make a definitive diagnosis. The HFE test shows whether there is a mutation in the HFE gene.

An inherited genetic mutation can increase the risk of developing iron overload. However, many people have these mutations but do not develop symptoms of iron overload. This means the HFE test cannot be used in isolation and your doctor needs to consider the results of the HFE test together with your blood and liver test results and symptoms.

If iron studies test results show that you have high transferrin saturation (>45%) and a high ferritin level (>300 ug/L), you may have haemochromatosis.  However, these are not specific for haemochromatosis and could be due to other causes.  This is why genetic testing is required to confirm the diagnosis.

Large population studies have shown that 38%-50% of people with two mutations in the HFE gene develop iron overload with elevated serum ferritin levels and 10%-33% eventually develop haemochromatosis symptoms such as fatigue and joint pain and/or organ damage resulting in liver and heart damage and diabetes.

First-degree relatives such as parents, siblings and children of people with known haemochromatosis are at high risk of developing the disease and should be offered an HFE gene test, even if they have not yet developed abnormalities in their iron related blood tests.  If the relative has a genetic makeup that suggests they are at risk of developing haemochromatosis, they can be closely monitored and started on treatment early in the disease process.

_{Diagram 1: Autosomal recessive pattern of inheritance}

The HFE genetic mutation

We inherit genes from our parents. They are packed inside chromosomes which are present in the nuclei of most of our cells.

Genes form the body's blueprint for producing proteins that control body functions. 

We have 46 chromosomes. They come in pairs – 23 inherited from our mother and 23 from our father. 

The HFE gene is on chromosome 6. 

You can pass the altered gene on to your children. If you have two copies of the altered gene, all your children will have at least one copy.

If you inherit one altered gene, you have a 50 per cent chance of passing the mutation on to your children. 

Having the test

Sample

The HFE gene test is done on a blood sample, usually taken from a vein in the arm

Any preparation?

There is no special preparation required before this test.

Your results

Mutations are named according to their location on the gene.  The most common mutation that causes haemochromatosis is C282Y.

If you inherit C282Y mutations in both copies of the HFE gene, you are at risk of developing haemochromatosis, although many people do not develop the disease.

Another mutation, H63D is associated with a more moderate risk of developing haemochromatosis.

A third mutation, S65C may lead to mild to moderate iron overload but not cause haemochromatosis. The HFE gene test may look for one or both mutations, in addition to the C282Y mutation.

Most cases of haemochromatosis are found in people who have two copies of the C282Y mutation, one on each of the pair of chromosomes.

People who have two copies of the H63D mutation may have a very slightly increased risk of developing haemochromatosis, while people who have only one copy of any of these mutations and one normal gene are not at increased risk.

Occasionally, haemochromatosis occurs in people who have one abnormal copy of C282Y and one of either H63D or S65Y. These people are known as compound heterozygotes. S65C is rarely tested for but when it occurs in combination with C282Y may cause iron overload in some people. The S65C mutation by itself will not cause a raised levels of transferrin saturation or serum ferritin.

Some people with a single mutation for C282Y or H63D have elevated transferrin saturation and serum ferritin levels but do not develop the complications related to iron overload.

_{Table 1: The range of results of the HFE genetic test and how they relate to the level of risk of developing haemochromatosis.}
 

Questions to ask your doctor

The choice of tests your doctor makes will be based on your medical history and symptoms.   It is important that you tell them everything you think might help. 

You play a central role in making sure your test results are accurate. Do everything you can to make sure the information you provide is correct and follow instructions closely. 

Talk to your doctor about any medications you are taking. Find out if you need to fast or stop any particular foods or supplements. These may affect your results. Ask:

• Why does this test need to be done?
• Do I need to prepare (such as fast or avoid medications) for the sample collection?
• Will an abnormal result mean I need further tests?
• How will the results from this test change the course of my care?
• What will happen next, after the test?

Any more to know?

About 100 mutations in the HFE gene have been recognised but most of these are very rare and the clinical significance of many of them is not yet known. Only C282Y and H63D mutations are commonly tested for.  In some circumstances, your doctor may request that the laboratory looks for rare mutations. 

Iron overload may also occur in people who receive regular blood transfusions.  This is sometimes referred to as secondary haemochromatosis and is different to the genetic condition described in this article. 

Treatment of haemochromatosis is usually straightforward.  One common treatment involves the regular removal of blood known as a venesection which is similar to a blood donation.  This removes excess iron from the body.

More information

Pathology and diagnostic imaging reports can be added to your My Health Record. You and your healthcare provider can now access your results whenever and wherever needed.

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