What is hereditary haemochromatosis?

Genetics

• Hereditary haemochromatosis is a single gene disorder classified by type depending on the age of onset, inheritance or genetic cause.
• Type 1 haemochromatosis is the most common type. It is caused by mutations in the High Iron Fe (HFE) gene on chromosome 6.
• Type 2 haemochromatosis is caused by mutations in either the HFE2 or HAMP genes.
• Type 3 haemochromatosis is caused by mutations in the TFR2 gene.
• Type 4 haemochromatosis is caused by mutations in the SLC40A1 gene.
• 93 per cent of hereditary haemochromatosis cases have been linked to two different mutations in the HFE gene called C282Y and H63D.
• 7 per cent of hereditary haemochromatosis cases are due to other mutations in the HFE gene or other genes.

Biology

• The HFE, HFE2, HAMP, SLC40A1 and TFR2 genes are all involved in regulating the absorption, transport and storage of iron in the body.
• For example, the HFE gene codes for a protein found in the membranes of cells of the duodenum. This is the first section of the small intestine, the part of the gut where iron is absorbed from food.
• A mutation in any of these genes impairs the body’s ability to control iron absorption during digestion and manage the distribution of iron to parts of the body where it is needed.
• The result is that excessive amounts of iron are absorbed and deposited in various organs, such as the liver, heart and pancreas.
• Humans cannot increase the removal of iron from the body so excess iron can overload tissues and organs, eventually causing considerable damage to them.

Symptoms

• The onset of symptoms depends on the type of haemochromatosis:
  • type 1 and 4 are adult-onset
  • type 2 is juvenile-onset
  • type 3 usually presents before the patient is 30 years old.
• Early symptoms of hereditary haemochromatosis include fatigue, weakness, impotence and pain in the abdomen and joints.
• Many people with haemochromatosis are unaware they have the disease until it has reached the advanced stages.
• Later symptoms of the disease can include:
  • liver cirrhosis
  • diabetes mellitus
  • heart disease
  • arthritis
  • increased pigmentation of the skin resulting in a permanent tan
  • shrinking of the gonads (testes and ovaries) and pituitary gland (small gland located at the base of the brain responsible for making several hormones).
• If left untreated, between one-third and one-half of affected individuals die of liver cancer.
• Symptoms differ between men and women.
  • Men are more likely to present with liver disease.
  • Women are more likely to present with fatigue and arthritis.
  • These less severe symptoms in women are likely to be because they generally lose more iron out of the body through menstruation, pregnancy and lactation.

Diagnosis

• Hereditary haemochromatosis can be detected even before the onset of symptoms using the transferrin saturation (TS) test:
  • This test measures the level of iron in the blood against the body’s capacity to store iron.
  • If transferrin saturation is over 55 per cent this may indicate iron overload and the test will be repeated after an overnight fast.
• A serum ferritin (SF) test may also be carried out:
  • This measures the level of ferritin, a protein which stores iron in the blood. The amount of ferritin increases if the levels of iron in the blood increase.
  • High levels of serum ferritin can indicate that a person has high levels of iron in the blood.
• A person’s DNA can also be tested for mutations in the HFE gene.

Treatment

• A simple treatment is to remove up to a pint (568 ml) of blood from the body at regular intervals (usually weekly) to reduce the number of red blood cells.
• Red blood cells are full of the protein haemoglobin, which contains iron.
• Removing some red blood cells stimulates the body to make new red blood cells.
• This draws on the body’s iron reserves to make more haemoglobin within the cells.
• Blood is removed until iron levels return to normal.
• It may be repeated every few months to maintain safe iron levels and manage the patient’s disease.