Hemochromatosis

Hemochromatosis is an inherited rare disorder of iron metabolism, leading to iron overload. It is characterised by excess iron deposits throughout the body, leading to cirrhosis of the liver and damage to other organs.

Cause of Hemochromatosis

Proof that the disease is hereditary came with the discovery of a strong association with histocompatibility (HLA) antigens in the mid-1970s, and with the more recent cloning of the hemochromatosis (HFE) gene. HFE is a protein which is probably involved in the regulation of iron transport, although its precise role is not yet known.

Hemochromatosis is due to a single mutation, known as the C282Y mutation in HFE. Patients with hemochromatosis usually carry two mutations (they are known as homozygotes). People with one mutation (heterozygotes or carriers) may have abnormal serum iron and ferritin tests, and occasionally develop the disease. Close family members (parents, siblings and children) should be screened for the disease by measurement of the transferrin saturation and serum ferritin, and in some cases by genetic testing.

There are other causes of iron overload, e.g. secondary to thalassaemia and other haemolytic diseases, that may require frequent blood transfusions.

Symptoms

The earliest sign of the disease is usually lethargy followed by more specific symptoms due to diabetes, sexual dysfunction, joint involvement and heart problems. Usually there is a characteristic metallic grey skin pigmentation and enlargement of the liver. Since the symptoms are often mild and non-specific in the early stages, a high index of suspicion is required even if a patient's symptoms appear trivial or seem to be easily explained by another cause, such as alcohol excess. Pre-menopausal women can develop hemochromatosis, contrary to popular belief.

Diagnosis

A raised transferrin saturation (ratio of serum iron and iron-binding capacity) and / or serum ferritin concentration suggests the possibility of hemochromatosis. Liver biopsy, with assessment of the degree and distribution of excess iron, together with quantification of the hepatic (liver) iron is the "gold standard" in diagnosing hemochromatosis.

The hepatic iron index (hepatic iron concentration divided by the age of the patient) shows the distinction between homozygous hemochromatosis and other conditions associated with a minor increase in hepatic iron stores. An hepatic iron index of greater than 2 has been shown to be reliable in differentiating homozygous hemochromatosis from heterozygous hemochromatosis, alcoholic liver disease and chronic liver disease in general.

HLA (histocompatibility) typing is also useful in family studies. The majority (90%) of Australian patients with hemochromatosis are homozygous for the mutation C282Y. A second mutation, H63D, in conjunction with one copy of the C282Y mutation (compound heterozygotes) is also associated with iron overload.

Liver biopsy has an important role in diagnosis. Not only does it allow the diagnosis to be made with great confidence, it also detects associated conditions such as alcoholic liver disease, and it provides the most reliable prediction of the future for the patient. The finding of established cirrhosis in a patient with hemochromatosis indicates a risk of complications, in particular liver cancer. Such patients should be advised of the risks and offered periodic screening for liver cancer. The absence of cirrhosis makes it unnecessary to do this, provided the patient complies fully with venesection (releasing blood) treatment.

Some patients, knowing that a genetic test is available, will decline liver biopsy. Provided that the C282Y mutation has been shown to be associated with hemochromatosis in that particular family, it is reasonable to rely on this test in certain family members. However, patients should be aware that the test is not 100% reliable, and that avoidance of liver biopsy will reduce the prognostic information available to the patient and clinician, and will make it more difficult, or even impossible, to obtain life insurance.

Medical Treatment

Treatment involves removal of excess iron by venesection (releasing blood). About 450ml of blood is removed once a week until the iron stores are in the low normal range, as determined by the serum ferritin concentration. This may take 6-12 months. Thereafter, venesections are done approximately every 3 months to maintain the serum ferritin between 50 and 100ug/L. The treatment, which should be lifelong, is usually well tolerated.