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Haemochromatosis

  • Haemochromatosis is an inherited disorder in which there is excessive iron absorption from the gut, leading to excessive iron deposition within tissues.
  • Inheritance is autosomal recessive and most commonly due to mutations in the HFE gene.
  • Many affected individuals will have evidence of iron accumulation, but only a small percentage will develop end-organ damage.
  • Untreated iron overload results in tissue damage affecting liver, pancreas, joints, pituitary gland and heart.
  • Iron overload can be detected by blood tests to measure serum ferritin and fasting transferrin saturation.
  • Venesection is a very effective treatment and, if initiated early in the course of the disease, can reduce complications and restore normal life expectancy.

Clinical features

  • Symptoms are often non-specific and are found in other conditions.
  • They include unexplained fatigue or joint pain.
  • Liver disease may be the presenting feature.
  • Other complications include endocrine disorders (for example, diabetes and hypogonadotrophic hypogonadism) arthritis and cardiac disease (heart failure and arrhythmias).
  • Men are 10 times as likely to develop symptoms as women, since women lose iron through menstruation and are less likely to develop iron overload.

Diagnosis

A diagnosis of haemochromatosis should be considered in patients with:

  • abnormal liver markers;
  • unexplained liver disease;
  • type 2 diabetes mellitus with raised liver enzymes;
  • atypical late onset diabetes;
  • early onset atypical arthropathy; and
  • patients with a first-degree relative with confirmed haemochromatosis.

Genetic basis

  • Haemochromatosis is an autosomal recessive condition: the affected individual carries two altered copies of the HFE gene. In most cases the parents are healthy because although they have one altered copy of the gene, this has no adverse effect when the second copy of the gene is normal. They are said to be carriers of haemochromatosis. Each child of two carriers has a 25%, or 1 in 4, chance of inheriting both gene alterations and is then at risk of developing complications of the disorder.
  • Haemochromatosis is common, and it is estimated that 1 in 10 people in the UK are carriers. Therefore, people who have two copies of the altered gene have a 1 in 10 chance that their partner will be a carrier. A child could then inherit an altered gene from both parents and develop haemochromatosis. Usually people with an autosomal recessive condition do not have children with the same condition, but haemochromatosis can appear to be an exception because of the high carrier frequency in the general population. This highlights the importance of family screening once the diagnosis is made.
  • The gene HFE is the gene most commonly altered in haemochromatosis, the most common mutations being C282Y and H63D. C282Y homozygotes (patients who have the C282Y alteration in both of their HFE genes) have an increased chance of developing symptoms of haemochromatosis. Patients who have one C282Y mutation and one H63D mutation have a 1% chance of developing symptoms of haemochromatosis.
  • There are some rare forms of both adult and juvenile onset haemochromatosis caused by mutations in different genes.

Clinical management

  • In cases of iron overload where the diagnosis of haemochromatosis is suspected, referral to a specialist is recommended. Definitive diagnosis and management will be undertaken in hospital by a gastroenterologist or hepatologist.
  • Venesection should be commenced in all patients with a confirmed diagnosis of haemochromatosis once the serum ferritin is elevated. If patients are diagnosed in the pre-cirrhotic, pre-diabetic stage and treated by venesection to remove excess iron, then the life expectancy is normal. Once cirrhosis is present, there is a high risk of liver cancer even when iron depletion has been achieved.
  • Assessment for extra-hepatic complications may include ECG, blood glucose, joint X-rays, hormone assessment and echocardiography.
  • Patients and their first-degree relatives should be offered HFE genotyping and may wish to be seen by a clinical geneticist.

Genetic testing

Genetic testing can be used to:

  • confirm the diagnosis in someone with possible haemochromatosis (diagnostic testing); and
  • provide information about the genetic status of relatives of someone with haemochromatosis through carrier testing.

Testing for the two common alterations in the HFE gene is now routinely available. C282Y homozygotes and C282Y/H63D heterozygotes should be offered surveillance in the form of a monitoring blood test for blood iron levels at 1-3 yearly intervals (EASL and British Society of Haematology Guidelines) and referred to a specialist if these become elevated. C282Y/H63D heterozygotes have a lower risk of developing symptomatic haemochromatosis than C282Y homozygotes.

Genetic testing is widely available across the UK and usually provided through specialist clinics or regional genetic centres.

 

This information is intended for educational use and was current in August 2013. For clinical management, it is recommended that local guidelines and protocols are used.