Common gene disorder causes serious “stealth” disease, but could be easily treated

Two major studies have revealed that the iron overload condition haemochromatosis, previously thought to be a low-level health risk, actually quadruples the risk of liver disease and doubles the risk of arthritis, and frailty in older age groups. It also causes higher risk of diabetes and chronic pain. The studies in UK Biobank data found that the number of deaths from liver cancer in men with the faulty genes was significantly higher than expected, although the number of deaths was small.

The research, led by a group from the University of Exeter in the U.K. with the U.S. National Institute on Aging and the University of Connecticut, is published in The BMJ and The Journals of Gerontology: Medical Sciences.

The research, funded by the UK Medical Research Council, suggests that routine screening may be needed for people at risk of haemochromatosis. Blood tests for iron and genetic testing are simple and cost-effective. The condition is easily treated by removing blood.

Haemochromatosis causes people to absorb too much iron from their diet. It accumulates around the body over time, damaging many organs and eventually causing disease. It is the most common genetic disorder in the UK. An estimated 250,000 people of European ancestry in the UK have the disease, which is caused when people have two particular faulty genes. One in eight people in some areas of the UK are carriers, meaning they have one of the two faulty genes that cause the disease. If both parents are carriers then two faulty genes can be passed on to their children.

Symptoms can include feeling tired all the time, muscle weakness and joint pains, meaning it is often misdiagnosed as the signs of ageing. The researchers found that in men, 1.6% of all the hip replacements and 5.8% of all liver cancers occurred in those with the two haemochromatosis gene mutations.

Professor David Melzer, from the Universities of Exeter in the UK and Connecticut in the USA, who led the research, said: “The haemochromatosis mutations were thought to only rarely cause health problems. We’ve shown that hereditary haemochromatosis is actually a much more common and stealth disease, including in older people. We now need to test ways of screening and diagnosing haemochromatosis earlier. It’s exciting to think that better care might prevent so much unnecessary disease.”

The team analysed data from 2,890 people with the two genetic mutations (called HFE C282Y homozygous), nearly ten times more than in the previous largest study. Having two copies defines most diagnoses of haemochromatosis. Of that group, one in five men and one in 10 women with the mutations developed additional diseases, compared to those without mutations. The average age of those studied was 63, and the data suggested that even more disease developed at older ages. The team found that both the men and women with the mutations aged 65 to 70 were much more likely to suffer from frailty and chronic pain, and had lower muscle strength. Fourteen of those with the faulty genes studied died of liver cancer.

Genetic haemochromatosis is thought to have evolved when past populations moved to places where meat was scarce. The ability to absorb more iron from a low-meat diet may have helped women have more babies. In Ireland, it is known as the “Celtic curse”, although it is common throughout Northern Europe and also occurs at a lower level in southern Europe.

The condition is twice as likely to be serious in men. Women have partial protection from the onset of genetic haemochromatosis until later in life because they lose iron through menstruation and having children, although some younger women do develop the disease.

Treatment initially involves the regular removal of blood, known as a venesection. This is usually carried out once every few weeks. When the iron levels are lowered, this reduces to around four times per year. This is known as maintenance therapy. Blood can be donated once the patient's iron levels reach maintenance.

Dr Luke Pilling, of the University of Exeter Medical School, first author of the BMJ paper, said: “We found that diagnosis of haemochromatosis is often delayed or missed. That’s not surprising as symptoms such as joint pains and tiredness are frequently mistaken as signs of ageing. Yet it is likely that these potentially deadly health risks could be treated and avoided, transforming lives, especially at older ages.”
Professor Debra Lapthorne, Director for the South West at the government agency Public Health England, which supports Professor Melzer’s research, said: “'We really welcome this study and think the work will be clinically very important as the results could have implications for clinical practice and help us find people much earlier, before significant damage is done. This work shows the real benefit to the population of linking academic research to policy and clinical practice.”

David Head, Chief Executive at Haemochromatosis UK, said: "Recently Haemochromatosis UK made calls to action for more research into the impact of chronic pain on the lives of people with haemochromatosis, so as a patient organisation we were delighted to learn of this work by Professor Melzer and his colleagues. The paper adds to growing evidence that the impact of haemochromatosis on individuals and healthcare services has been enormously underestimated and poorly understood. The problem can no longer be dismissed.”

The NHS advises that it is important to talk to your GP if you have a parent or sibling with haemochromatosis, even if you don't have symptoms yourself – tests can be done to check if you're at risk of developing problems. People are also advised to talk to their GPs about haemochromatosis if they have the following persistent or worrying symptoms – particularly if you have a northern European family background. Typical symptoms include feeling very tired all the time (fatigue); weight loss; weakness and joint pain. Also, some men with haemochromatosis develop an inability to get or maintain an erection (erectile dysfunction), and some women have irregular periods or absent periods. These symptoms usually come on between ages 30 and 60.

Case Study: Jenny Lees

In her 60s, Jenny Lees began suffering from severe tiredness and joint pains. She put these symptoms down to her busy lifestyle and ageing. It was only when her son Jason Cloke became diabetic and was then also diagnosed with the iron overload disease hereditary haemochromatosis that she was tested and found to have the disease too. For her son, the diagnosis came too late and he died of liver damage at the age of 42. Now, Jenny and her partner Ian are dedicated to raising awareness of the condition.

“Jason’s death devastated our family. As a mother, you’re always able to apply a sticking plaster and make it better. You can’t ever prepare for the death of your child.”

After her diagnosis, Jenny started her own treatment, initially giving around a pint of blood every two weeks, now reduced to four times each year. “I felt like I’d been born again,” said Jenny. “The tests now show my liver function is much better and initially I was able to get around far more easily. I take my treatment seriously – it’s no big deal and I want to live to see my grandchildren grow up.” Although the tiredness improved dramatically on treatment, the joint damage had probably already started and she later needed a hip replacement.

Both Jenny and Ian have now committed to raising awareness and funding for haemochromatosis charities. She supported friends of Jason’s in a 678 mile cycle ride from La Havre in France to Kirchheim in Germany, raising more than £12,500 for three charities including Haemochromatosis UK.

The two new papers are:

Common conditions associated with Hereditary Haemochromatosis genetic variants: cohort study in UK Biobank. Luke C Pilling, Jone Tamosauskaite, Garan Jones, Andrew R Wood, Lindsay Jones, Chia-Ling Kuo, George A Kuchel, Luigi Ferrucci, David Melzer. The BMJ.

Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: Evidence from 200,975 Older UK Biobank Participants. Jone Tamosauskaite, Janice L Atkins, Luke C Pilling, Chia-Ling Kuo, George A Kuchel, Luigi Ferrucci, David Melzer. Journal of Gerontology: Medical Sciences.