24,000 men hold key to iron disorder
Australian researchers have answered important questions about the genetic blood disorder haemochromatosis. Adam Cresswell reports
WITH a German surname and a mother who can trace her roots all the way back to Irish convicts two centuries ago, paediatrician Honey Heussler ticks both boxes when it comes to her risk for the iron-overload disorder haemochromatosis.
The condition, affecting one in about 200 Australians, has been known for nearly 30 years as the Celtic disease’’ because of its high prevalence in people of Irish and North European ancestry. While treatable, undiagnosed it can lead to liver cancer and arthritis.
Heussler’s own mother has it, and so do several members of her mother’s family. Genetic detective work over the past few years has suggested an intriguing theory to explain why it has remained much more common than other disease-causing genetic mutations.
Heussler, who works at Brisbane’s Mater Children’s Hospital, found out she had the condition when she checked her own blood as a 21-year-old medical student — and found her iron reading was six times the normal level.
Although her mother’s condition meant that Heussler knew she had to look out for signs she, too, was getting it, the discovery still came as a shock. It took a year of giving blood, as frequently as once a week, to return her iron levels to normal. Giving blood is still the only treatment for the condition, which causes the body to absorb too much iron from food.
Heussler, who has now had haemochromatosis for 25 years, still gives blood four to six times a year. When I lived in the UK meat was really expensive and I hardly ate any meat at all — and I only had to give blood twice a year,’’ she said.
Even though she gives blood, she nevertheless experiences some symptoms, including fatigue and arthritis, particularly in her thumbs and big toes.
Australian experts from Melbourne, Perth and Brisbane last week published findings in the New England Journal of Medicine (2008;358:221-30) that showed men with the condition are nearly 30 times more likely than women to develop serious complications such as liver cancer and arthritis.
The findings were held up by the study’s authors as indicating a need for more men to be checked for signs they were carrying the two copies of the genetic mutation that are necessary for the full condition to develop.
Such people are called homozygotes, and according to some estimates there are thought to be about 100,000 people in Australia with this double mutation.
Men are considered more prone to complications because menstruation allows affected women to purge their excess iron, giving them a level of protection before menopause sets in and menstruation stops. By contrast, iron levels in affected men can start building up from a much younger age.
One of the new study’s co-authors, Greg Anderson from the Queensland Institute of Medical Research, says one theory to explain the Irish link is that the ability to absorb more iron might have conferred a survival advantage at times when nutritious food was hard to find, such as during the Irish potato famine of the mid-19th century. The Irish diaspora that followed then took the trait around the world.
The fact that it’s quite common still is an indication that there might be some benefit in having the mutation,’’ Professor Anderson said. If there were no benefit, generally it would be bred out of the population. If a mutation is going to help a woman reproduce — and pregnancy is a time when there are high iron requirements — that would be something that led to the perpetuation of the mutation in the population.’’
He says some theories hold that the link is with Viking rather than Celtic genes.
Research published 10 years ago suggests that the C282Y gene mutation responsible first appeared about 60 to 70 generations ago — putting the first emergence of the condition at about 600 to 800AD, assuming an average generation time of 20 years.
A paper published in 2000 in the journal Genetic Testing (2000;4(2):163-9) detected the frequency of the mutation responsible in 40 European racial groups. It concluded the
most elevated values (for the mutation) are observed in residual Celtic populations in Ireland, the United Kingdom, and France, in accordance with the hypothesis . . . concerning a Celtic origin of the hereditary haemochromatosis mutation’’.
Heussler says the Irish theory is plausible’’ but doubts it could be proved. The notion that people with haemochromatosis enjoyed a survival advantage during the Irish potato famine could equally be applied to any time of famine, as potatoes themselves have no iron, she says.
A book published last year by US researcher Sharon Moalem, called SurvivaloftheSickest , also suggests the haemochromatosis mutation is unusually common because it offers protection. But Moalem points to a different threat — the Black Death, which wiped out one-third of Europe’s population in the 14th century.
The death toll in northern countries was higher, possibly because the colder winters forced people indoors where the infection could travel more easily. This higher death toll could have concentrated the numbers of mutation-carrying survivors in northern countries, Moalem suggests.
Meanwhile, the Australian research published last week has led to calls for Caucasian men aged 30 to 50 to think about being tested for haemochromatosis.
Previous research published in 2002 had suggested that less than 1 per cent of those with the mutation would develop serious symptoms. But the new research has overturned this figure, and shows a huge difference between men and women.
The researchers tracked 32,000 Victorian people for 12 years, and found while about 1 per cent of women with the mutation risked serious health problems from iron overload, in men the proportion was 28 per cent.
Katie Allen, lead author of theNEJM study, says the result reopens the debate on whether population-based genetic screening for hereditary haemochromatosis should be considered’’.
This opens up the possibility that there could be a significant number of men who will either get the disease or already have it, and don’t realise it.’’
A blood test that can detect the genetic mutation is already available, but is typically only used when a diagnosis of haemochromatosis is suspected.
Associate Professor Allen, a paediatric gastroenterologist at the Murdoch Childrens Research Institute in Melbourne, says fatigue, arthritis and sometimes abdominal pain are among the first symptoms of haemochromatosis. However, problems can be avoided by donating blood regularly.
She says a further study analysing the costeffectiveness of population screening for haemochromatosis is awaiting publication.
While previous long-term studies of the condition only included 10 and 23 people with the genetic mutation, 203 of the 31,192 in the latest study were affected.
Another co-author of the study, gastroenterologist John Olynyk, of the Western Australian Institute for Medical Research, says he suspects the true number of Australians with the mutation is about 160,000, half of them men.
Of the 24,000 men in that group that the new study suggests risk serious complications,
at least half will not be diagnosed’’ with haemochromatosis, Professor Olynyk said.
It’s important to work out who these 24,000 men are. If you are of north European descent, between 30 and 50, male, and going to your doctor anyway, you should be encouraged to have some iron tests done to be screened for haemochromatosis.’’
Family affliction: Doctor Honey Heussler gives blood as a way of battling a disease that also affects several other family members