Haemochomatosis
Jennifer Newstead
Thirty years ago haemochromatosis was considered a rare condition. Medical students were taught that it presented in middle aged males with cirrhosis, diabetes and bronzing of the skin. A few years ago I – an otherwise healthy female in my thirties - was diagnosed with haemochromatosis. There is no greater stimulus for finding out about a condition than having it yourself. I discovered that haemochromatosis was far more common than I had realised and the HFE gene test has revolutionised the approach to diagnosis, making it much easier to diagnose before irreversible complications have occurred. These developments have also generated discussion about population screening for the disorder.
What is haemochromatosis?
Haemochromatosis is an inherited disorder of iron metabolism in which the body accumulates iron. If untreated the excess iron can lead to cirrhosis of liver, cardiomyopathy, diabetes and primary liver cancer. The patient is usually asymptomatic in the early stages of iron overload but as iron stores increase (s)he may report chronic unexplained tiredness, joint pains, abdominal pain, impotence and increasing skin pigmentation. Because the symptoms tend to be insidious and nonspecific, haemochromatosis can be difficult to diagnose and there are many reports of patients being unwell for a number of years and seeing multiple practitioners before the diagnosis is finally made. The treatment of haemochromatosis involves regular venesection to remove the excess iron. Initially this may be performed weekly. When the excess iron stores have been removed, venesections are usually carried out every 3 months for the rest of the patient’s life to prevent reaccumulation. Many patients now choose to have their venesection performed through the Red Cross Blood Bank so that their blood can be used for blood products. Patients who are diagnosed early and comply with treatment have a normal life expectancy.
Epidemiology and Genetics
Haemochromatosis is more common in people of Celtic or northern European background. It is thought that having a condition causing iron accumulation offered a survival advantage for those with a low dietary iron intake or for women who had many pregnancies. This may explain why the incidence in Ireland may be as high as 1 in a 100. In Australia, studies in blood donors show that 1 in 300 have iron overload associated with haemochromatosis.
| “It is thought that having a condition causing iron accumulation offered a survival advantage for those with a low dietary iron intake or for women who had many pregnancies.” |
Feder discovered the HFE gene in 1996. There is now a commercially available blood test for the gene and it was the first gene test in Australia to attract the medicare rebate. Ninety percent of cases of haemochromatosis are associated with the C282Y/C282Y mutation of this gene. In Australia the frequency of this genotype is approximately 1 in 200. The frequency of the C282Y/C282Y mutation is the same in men and women, although women usually develop symptoms later than men and are more likely to develop joint pains. However, not all individuals with the C282Y/C282Y genotype develop iron overload - studies of penetrance estimate it to fall between 40 and 70 percent.
Haemochromatosis is an autosomal recessive condition. Individuals who are homozygous for the C282Y mutation have inherited one copy of the abnormal gene from each of their parents. Approximately 1 in 10 Australians are C282Y carriers. Carriers have a single mutation and are almost always asymptomatic.
Investigations
Patients with symptoms suggestive of haemochromatosis should have their fasting transferrin saturation and ferritin levels measured. If the fasting transferrin saturation is greater than 45%, the measurement should be repeated and if it remains elevated the HFE gene test should be performed. The ferritin level may also be elevated in patients with haemochromatosis but there are many other causes of elevated ferritin. Liver function tests are usually normal in the early stages of the disease but as iron stores rise, aminotransferinase becomes elevated.
In the past all patients suspected of having haemochromatosis needed to undergo a liver biopsy. Since the discovery of the HFE gene, most cases of haemochromatosis can be diagnosed via blood test and a liver biopsy is only performed if liver damage is suspected. In patients with iron overload, the diagnosis of haemochromatosis can be confirmed if the HFE genotype is C282Y/C282Y. Occasionally haemochromatosis occurs with other HFE genotypes such as C282Y/H63D.
The gene test has also made it easier to screen family members for the disorder. It is recommended that all first-degree family members be tested for haemochromatosis.
Population screening
The realization that haemochromatosis is more common than previously thought, together with the possibility of using blood tests to detect asymptomatic cases, has stimulated vigorous debate about widespread screening for the condition. Haemochromatosis meets several of the World Health Organisation’s key public health criteria for population based screening:
it is common,
it can be identified at an early stage by measuring transferrin saturation (phenotypic screening) or genetic susceptibility (genotypic screening),
the burden of disease may be high, and
there is an effective treatment, which if commenced early can prevent serious complications.
There have been many debates regarding the merits of genotypic versus phenotypic screening but at this stage there is no support for widespread screening because of significant gaps in our knowledge of haemochromatosis. Further research is needed regarding:
the penetrance of the disorder in those with susceptible genotype,
the effect of disease modifiers such as dietary iron intake,
the natural history of early stages of iron overload,
the evidence of benefit for treating those with early disease,
the effectiveness of screening, and
optimal screening strategies.
In addition genetic screening
raises concerns
about the potential for discrimination and the
consequences for family members.
The discovery of the HFE gene has greatly simplified the diagnosis of haemochromatosis and furthered our understanding of the condition. Population screening may occur in the future. At this stage doctors should consider the possibility of haemochromatosis in patients who present with chronic tiredness, joint pains or abnormal liver function tests, and offer screening to all first-degree family members.
Jennifer Newstead (MBBS, Grad Dip Epi and Biostats) is a general practitioner who practises in Melbourne. She is co-author of a resource about genetic conditions for general practitioners, which is to be released later this year.