Excess morbidity associated with the Hereditary Haemochromatosis mutations

Early community studies of people with two haemochromatosis C282Y mutations (termed ‘homozygous’) concluded that less than 1% developed clinical disease. We studied the mutations in UK Biobank, with a sample nearly ten times larger than the previous largest community study. We found that by an average age of 63, 20% of males and 10% of females with the double mutations had already developed excess disease. We also found that rates of frailty and chronic pain were much higher in the 65 to 70 year olds with the mutation, consistent with the continued accumulation of damage with advancing age.

The previously reported low penetrance led to a policy of not screening for the disease outside known affected families, which resulted in many sufferers developing serious disease before being diagnosed. Haemochromatosis is easily prevented with blood donations, which are rich in iron. Improving early detection and treatment could improve the health of a sizable group of people.

This work was supported by the Medical Research Council, who have provided further support for us to extend this work.


Press Release – January 2019
Common gene disorder causes serious “stealth” disease, but could be easily treated

The Western world’s most common genetic disorder causes far higher levels of serious disease and disability than previously thought, despite being easy to detect and treat.

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. Deaths from liver cancer in men with the faulty genes were significantly higher than expected, although numbers were small.

The research, led by a group from the University of Exeter in the UK with the US 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 ten 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. 

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Scientific papers:

Pilling LC, Tamosauskaite J, Jones G, Wood AR, Jones L, Kuo CL, Kuchel GA, Ferrucci L, Melzer D. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019. https://doi.org/10.1136/bmj.k5222

Tamosauskaite J, Atkins JL, Pilling LC, Kuo CL, Kuchel GA, Ferrucci L, Melzer D. Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain:  Evidence from 200,975 Older UK Biobank Participants. J Gerontol A Biol Sci Med Sci. 2019. https://doi.org/10.1093/gerona/gly270