24,000 men hold key to iron dis­or­der

Aus­tralian re­searchers have an­swered im­por­tant ques­tions about the ge­netic blood dis­or­der hae­mochro­mato­sis. Adam Cress­well re­ports

The Weekend Australian - Travel - - Health -

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.’’

Pic­ture: David Sproule

Fam­ily af­flic­tion: Doc­tor Honey Heus­sler gives blood as a way of bat­tling a dis­ease that also af­fects sev­eral other fam­ily mem­bers

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