Hereditary Haemochromatosis

Haemochromatosis is a disorder of iron metabolism characterised by excessive absorption of ingested iron. It can, if not controlled lead to saturation of iron binding protein, and deposition of haemosidrin in tissues causing a risk of damage to liver,pancreas and skin, joints, cardiac and endocrine problems. There are many other causes of iron overload but the most common of these is HFE-related (type 1) Hereditary Haemochromatosis (HH) which this website page will focus on.

Reflex testingfor HFE-related HH in the Molecular Laboratory Service, what does it mean

Interpretingthe genetic test results for FHE-related hereditary haemochromatosis

  • Homozygousfor p.C282Y
  • Compound heterozygous for p.C282Y and p.H63D
  • Homozygous for p.H63D
  • Heterozygous for p.C282Y
  • Heterozygous for p.H63D
  • p.C282Y and p.H63D variants are not present
  • p.C282Y variantis notpresent

Hereditary Haemochromatosis

Other possible causes of iron overload

Causes of iron overload include

  • infection or inflammation,
  • alcoholic liver disease,
  • cirrhosis,
  • haemolytic anaemia
  • transfusional / parenteral iron overload.
  • In addition, some people have a genetic predisposition to developing iron overload. The most common of these is HFE-Related (or Type 1) Hereditary Haemochromatosis which this website page will focus on.

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Hereditary Haemochromatosis

Reflex testing in the Molecular Laboratory Service, what does this mean?

A in line with the clinical guidelinespublished by the European Society for the Study of the Live and after consultation with other NHS services The molecular department in Glasgow has decided to test for one gene variant first. In practice this means:

  • When a test for haemochromatosis is requested, the service will only test for the p.C282Y gene variant. When this is found the second p.H63D gene variant will be looked for.
  • When a “family history of haemochromatosis” is mentioned on the request form, both p.C282Y and p.H63D variant are examined

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Hereditary Haemochromatosis

Homozygous for p.C282Y

Implications for patient

  • Iron overloadmayarise when someone inherits two copies of the C282Y variant (homozygous).
  • The majority (80-93%) of those who are clinically affected have this genotype with1 in 160 (0.6%) people in the European population are C282Y homozygotes.
  • Thechance of developing signs and symptoms is less than 100% (that is, the penetrance is incomplete):
  • The chance of a C282Y homozygote developing iron overload blood results in adulthood is around 38-50%. Fewer (10-33%) report the development of clinical symptoms,this being a little more likely in males and those with symptomatic relatives, and a little less likely in females and those who don’t have relatives with symptoms.
  • In the presence of iron overload, assuming all other reasons for iron overload have been excluded, the C282Y homozygote result would be consistent with a clinical diagnosis of HFE-related Hereditary Haemochromatosis.
  • Women who have regular menses are less likely to develop iron overload, when menses stops through contraceptive use or early menopause a gradual rise in Iron may be observed.

Actions

In the presence of:

  • Significant or slightly raised iron overload indices a referral to gastroenterology or haematology is advised.
  • Normal iron indices, patients can be recommended to request annual iron monitoring tests (Transferrin saturation and Ferritin) at their GP practice.
  • The genetic test does not need to be repeated when iron studies are requested in the future. Put on request form “genotype known”
  • This information with the explanation about Haemochromatosis can be given to the patient

Implications for relatives

  • Brothers and sisters of the patient have a 1 in 4 chance of being affected and should be offered counselling and testing
  • Partner testing: Offer testing to the father/mother of this patient’s children ( spouse or partner) and mention relationship on request form.
  • All children will be carriers but are only at risk if their other parent is affected or a carrier.
  • There are no immediate implications for younger children and babies, and testing can be postponed until they can give informed consent in early adulthood. .(Genetic Testing of Children)
  • The patient can be supplied with letters to give to their first degree relatives about testing

More information

If you would like to more information about Genetic Haemochromatosis and testing, please do not hesitate to contact:

Community Genetic Counsellors on Tel: 0141 354 9200/0141 354 9229 (secretary)

email

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Hereditary Haemochromatosis

Compound heterozygous for p.C282Y and p.H63D

Implications for patients

  • Iron overloadmayarise in compound heterozygotes for the C282Y and the H63D gene variants. This genotype is present in 5% of clinically affected people.
  • 1 in 70 (1.3%) people in the European population have this genotype. This genotype appears to be associated with a small increased chance of developing (usually mild) iron overload. However this is often associated with co-morbid factors such as obesity, non-alcoholic fatty liver disease (NAFLD), chronic alcohol consumption and end-stage cirrhosis.
  • In the presence of iron overload, assuming all other reasons for iron overload have been excluded, this result would be consistent with a clinical diagnosis of HFE-related Hereditary Haemochromatosis.

Compound heterozygotes for the C282Y and the H63D (particularly where other reasons for iron overload have been excluded) may also be referred for genetic counselling to discuss cascade testing within the family.The patient can be supplied with letters to give to their first degree relatives

Actions

In the presence of:

  • Significantly raised iron indices, a referral to gastroenterology or haematology is advised
  • Slightly raised iron indices, patients can be recommended to request annual iron monitoring tests (transferrin saturation and ferritin) at their GP practice.
  • Normal iron indices, patients can be recommended to request three-yearly iron monitoring tests (transferrin saturation and ferritin) at their GP practice.
  • The genetic test does not need to be repeated when iron studies are requested in the future. Put on biochemistry request form “genotype known”
  • This information with the explanation about Haemochromatosis can be given to the patient

Implications for relatives

  • Brothers and sisters of the patient have a 1 in 4 chance of being affected and should be offered counselling and testing
  • Partner testing: Offer testing to the father/mother of this patient’s children ( spouse or partner) and mention relationship on request form

.

  • All children will be carriers but are only at risk if their other parent is affected or a carrier.
  • There are no immediate implications for younger children and babies, and testing can be postponed until they can give informed consent in early adulthood. (Genetic Testing of Children)
  • The patient can be supplied with letters to give to their first degree relatives about testing

More information

If you would like to more information about Genetic Haemochromatosis and testing, please do not hesitate to contact:

Community Genetic Counsellors on Tel: 0141 354 9200/0141 354 9229 (secretary)

email

.

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Hereditary Haemochromatosis

Homozygous for p.H63D

Implications for patient

  • Iron overload is unlikely in people homozygous for the H63D gene alteration.
  • 1 in 50 people in the UK general population have this genotype.
  • Homozygousity for H63D is an insufficient genetic explanation for iron overload.
  • When homozygousity of H63D is seen in association with raised iron or transferrin saturation, co-morbid factors are usually present.
  • This result neither confirms nor excludes HFE-related Haemochromatosis.
  • In the majority of homozygote for H63D, where iron indices in the patient have been normal (for example if the result were identified as a result of a family cascade test) regular iron monitoring would not be necessary.
  • Patients could be made aware to contact their GP should they develop any symptoms that they were concerned about.

Action

  • For H63D homozygotes, any diagnosis of Hereditary Haemochromatosis should be made on clinical grounds, in which cased iron monitoring in the patient may be appropriate.
  • The genetic test does not need to be repeated when iron studies are requested in the future. Put on the biochemistry request form “genotype known”
  • This information with the explanation about Haemochromatosis can be given to the patient

Implications for relatives.

  • Testing for haemochromatosis should only be offered on clinical grounds and only when patients present with relevant complaints.
  • Partner testing: Offer testing to the father/mother of this patient’s children (spouse or partner) and mention relationship on request form.
  • All children will be carriers (which is harmless) and only have a chance of compound heterozygousity if their other parent is a carrier of p.C282Y (see p.C282Y and p.H63D).
  • Children under 18 years and babies do not need to be offered testing.

More information

If you would like to more information about Genetic Haemochromatosis and testing, please do not hesitate to contact:

Community Genetic Counsellors on Tel: 0141 354 9200/0141 354 9229 (secretary)

email

.

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Hereditary Haemochromatosis

Heterozyous for p.C282Y (also known as carriers)

Implications for the patient

  • There is no predictable risk of iron overload in people with one copy of the C282Y gene alteration, and without the H63D gene alteration. In Britain around 1 in 12 (8%) people are carriers of the C282Y mutation.
  • This genotype is unlikely to cause a clinical presentation of HFE-related Hereditary Haemochromatosis or iron overload.

Action

  • None
  • Significant raised iron indices; referral to a gastroenterologist or haematologist may be considered for the diagnosis of possible other causes.
  • When raised iron indices are found, the genetic test may need to be repeated if the patient was only tested for the p.C282Y variant. Request testing for the H63D variant.
  • This information with the explanation about Haemochromatosis can be given to the patient

Implications for relatives

  • One or both parents of the proband may be carriers or a parent may be homozygous
  • Brothers and sisters have a 1 in 4 chance of being affected only if both parents are carriers
  • Partner testing: Offer testing to the father/mother of this patient’s children ( spouse or partner) and mention relationship on request form.
  • Children have a 1 in 2 chance of being a carrier and can only be homozygous if both parents carry the gene variants .
  • Carrier testing for first degreeadult relatives can be considered.
  • There will be no immediate implication for children under the age of 18 years and babies thus testing is not recommended at this stage.

More information

If you would like to more information about Genetic Haemochromatosis and testing, please do not hesitate to contact:

Community Genetic Counsellors on Tel: 0141 354 9200/0141 354 9229 (secretary)

email

Back to Main Page

Hereditary Haemochromatosis

Heterozygous for p.H63D (also known as carriers)

Implication for patients

  • There is no predictable risk of iron overload in people with one copy of the H63D gene alteration, and without the C282Y gene alteration.
  • In Britain around 1 in 7 people are carriers of the H63D variant.
  • This genotype is very unlikely to cause a clinical presentation of HFE-related Hereditary Haemochromatosis or iron overload.

Action

  • In the presence of significant raised indices refer to a gastroenterologist or haematologist to eliminate other causes for iron overload
  • The genetic test does not need to be repeated when iron studies are requested in the future. Put on request form “genotype known”
  • This information with the explanation about Haemochromatosis can be given to the patient

Implications for relatives

  • Testing of closed relatives only recommended if relatives present with clinical problems
  • Partner testing: Offer testing to the father/mother of this patient’s children ( spouse or partner) and mention relationship on request form.
  • Testing of Babies and children not recommended.

More information

If you would like to more information about Genetic Haemochromatosis and testing, please do not hesitate to contact:

Community Genetic Counsellors on Tel: 0141 354 9200/0141 354 9229 (secretary)

email

.

Back to Main Page

Hereditary Haemochromatosis

Neither the C282Y nor H63D gene variant is present

Implications for the patient

  • This genotype indicates that a diagnosis of HFE-related Haemochromatosis is very unlikely. There is no predictable risk of iron overload.

Action

  • In the presence of significant raised indices, look for other causes and consider referral to a gastroenterologist of haematologist.

Implications for the relatives

  • No testing needed.

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Hereditary Haemochromatosis

p.C282Y variant is not present

Implications for the patient

  • This genotype indicates that a diagnosis of HFE-related Haemochromatosis is very unlikely. There is no predictable risk of iron overload.
  • This sample has only been tested for the p. C282Y mutation as mentioned in the reflex screening procedures

Action

  • In the presence of significant raised indices, look for other causes and consider referral to a gastroenterologist of haematologist.
  • If the sample was send because there was an indication of a family history or a partner who is affected or a carrier, please ask for the variant p.H63D to be looked at.

Implications for the relatives

  • No testing needed.

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Clinical Genetics

Southern GeneralHospital

Glasgow, G51 4TF

What is hereditary haemochromatosis?

Hereditary haemochromatosis (HH) is a treatable inherited condition where the body absorbs too much iron from the diet. When too much iron builds up in the body this is known as iron overload. The excess iron is stored in the liver and other organs of the body such as the pancreas, heart, endocrine (hormone producing) glands and joints.

Why is the amount of iron in the body important?

We all need iron from our diet to make new red blood cells. This iron is stored in the liver. However, when we have too much iron in the liver it can become enlarged and damaged. Excess iron may also be stored in the organs mentioned above and joints, causing damage.

What are the symptoms of hereditary haemochromatosis when there is considerable iron overload?

  • Constant tiredness, weakness, lethargy
  • Abdominal pain
  • Joint pain (arthritis); this can affect any joint but

commonly affects the knuckle and first joint of the

first two fingers

  • Late onset diabetes
  • Cirrhosis of the liver (scarring of liver tissue that

damages liver function)

  • Bronzing of the skin, like a permanent tan
  • Loss of libido
  • Late onset diabetes

People with HH can have no symptoms for many years and some will never experience problems

What age do people develop hereditary haemochromatosis?

The build up of iron takes many years so the onset of HH is normally between 30 and 60 years. Women tend to develop HH later in life than men. The reason for this is that before the menopause, having periods (menstruation) regularly removes blood, and therefore iron, from the body. So before the menopause woman do not accumulate so much iron in their bodies as men do, unless they use contraceptives that stop the periods or have early removal of the womb.

Is it possible to cure or prevent hereditary haemochromatosis?

An early diagnosis means that treatment can begin before an individual develops serious symptoms. For individuals diagnosed after symptoms present, it is not possible to undo tissue damage (such as cirrhosis of the liver) if that damage has already occurred. For this reason it is important that immediate family members of an individual with HH are offered genetic testing to find out if they are at risk.

Some symptoms may improve after treatment begins and individuals may feel more energetic and happier.

Some individuals who are at risk of iron overload but have iron levels within the normal range choose to donate blood. This can help by removing iron and makes sure their blood is put to good use.

What causes hereditary haemochromatosis?

HH is caused by changes in a gene known as HFE. These changes make the gene not work the way it is supposed to.

We all have about 25,000 pairs of genes inside every cell of our body. Genes are the instructions that tell our body how to grow and develop. We inherit one copy of each gene from our mother and the other copy from our father. When we have children we pass on one copy of each of our genes and our partner provides the other.

Someone that has one gene change and their other gene is working properly, is a carrier of HH. Carriers are healthy as they still have one copy working properly, and they are not at increased risk of developing iron overload.

When someone has a change in both copies of their HFE gene then they are at risk of developing iron overload. There are two common gene changes, known as C282Y and H63D.

These changes are common in the Northern European population, probably due to an evolutionary advantage in times when food was scarce. About 1 in 8 people in this population will carry a C282Y gene change, and about 1 in 5 people will carry an H63D gene change.

What is the difference between C282Y and H63D?

Having two copies of the C282Y gene change:

People with two copies of the C282Y gene change are at risk developing HH. However, many individuals with two of these changes will never develop iron overload. Yearly blood tests are recommended to monitor iron levels.

Having one copy of C282Y and one copy of H63D:

People with one copy of C282Y and one copy of H63D have a smaller risk of developing HH and the degree of iron overload tends to be less than for individuals with two copies of C282Y. It is recommended that iron levels are monitored every 3 years.

It is not clear if having two copies of H63D increases the risk of HH therefore occasional checking for iron overload is suggested.

How do you test for hereditary haemochromatosis?

There are two types of tests used to help determine if someone has Hereditary Haemochromatosis.

The first is a gene test. This is a blood test that checks if an individual has any gene changes and is at risk of developing iron overload.

The check if an individual has iron overload, two other blood tests (called serum ferritin and total iron binding capacity) check the amount of iron in the blood.

Should someone with haemochromatosis have a low iron diet?

It is advisable for people with HH to avoid taking in too much iron. They can do this by:

  • not taking multivitamins containing iron or iron tablets
  • avoiding or reducing foods which are rich in iron such as red meat and red wine
  • avoiding foods fortified with iron, such as some breakfast cereals

Who in the family is at risk of hereditary haemochromatosis?