Title: Enabling timely diagnosis of hereditary haemochromatosis
Funder: Department of Health and Social Care

Abstract: Research question: How to enable timely diagnosis of hereditary haemochromatosis? Background: Hereditary Haemochromatosis (HH) involves iron overload, and is the most common genetic disease of northern Europeans, predominantly caused by the HFE p.C282Y genetic variant67. The UK has the second highest prevalence of this mutation worldwide, with >350,000 people being p.C282Y homozygotes (two copies of the mutation)2 8 9. HH is easily identifiable with simple clinical tests and preventative treatment with venesection is safe and effective. Estimates of mutation penetrance vary in the literature, and it is unclear how many heterozygotes (carriers) actually develop disease10. In UK Biobank, male homozygotes have 10.7% excess disease (haemochromatosis itself, liver disease, diabetes, or osteoarthritis) and a two-fold sarcopenia and frailty risk, compared to those without the mutation. P.C282Y homozygous men also have a 7% risk of liver cancer by age 75. Although the disease burden is thought to be less in women, who have partial protection from menstrual blood losses, this is unclear and risks after menopause need clarifying. Another key issue is how to identify patients earlier to prevent progression to severe disease. My work in UK Biobank shows that many UK patients are progressing to serious disease before diagnosis of HH; in p.C282Y homozygous men only 12.1% were diagnosed with haemochromatosis at baseline (mean age 56.9 years). Worryingly, half of the homozygous men with incident liver cancer were not diagnosed with haemochromatosis2. Identifying haemochromatosis patients earlier may prevent substantial excess disease. Treatment for HH with venesection even produces donated blood that can be used for transfusion, providing a potential win-win for improving HH care in the UK. Aims: My aims are to answer some key remaining questions about the effect of the haemochromatosis genotypes in key groups; to understand the nature of current service problems leading to late diagnosis in both men and women; and to provide quantitative modelling data on options for improving care. This will ultimately support intervention trials to improve HH care. Specific objectives are to: Quantify any excess disease in p.C282Y homozygous women, specifically postmenopausal, and in p.C282Y heterozygotes. Identify barriers to early diagnosis, quantifying excess morbidity already present at diagnosis and testing potential lifestyle factors modifying risk of excess morbidity after diagnosis. Model scenarios for reducing avoidable morbidity, including economic evaluation of possible options to improve earlier diagnosis and screening strategies. Methods: Secondary data analysis of >450,000 UK Biobank participants of European ancestries, with baseline (2006-2010) genotyping data (including 2,890 p.C282Y homozygotes) and follow-up until 2020 in primary care records, hospital admissions, cancer registry and death records. This is the largest HH dataset in the world, with 10 times more p.C282Y homozygotes than the previous largest study. Timelines for delivery: 3.5 years (85% FTE).Anticipated impact and dissemination: The findings will improve the diagnosis, prevention and treatment of haemochromatosis, and provide foundations for re-examining options for earlier diagnosis, including screening scenarios. Results will be disseminated through scientific publications, and presented at academic conferences, the Haemochromatosis UK patient conference and to the UK parliamentary group on haemochromatosis.

Lay abstract: Background: The most common inherited disease in northern Europeans is known as hereditary haemochromatosis (HH). HH is caused by a mutation to the HFE gene (having two copies of a faulty gene known as HFE p.C282Y) that causes the body to absorb too much iron from the diet. My analyses suggests there are approximately 350,000 people in the UK with the causal mutations for this condition, with the UK having the second highest prevalence of this condition in the world. Sufferers of this iron-overload disease can build up iron in their organs, which results in serious diseases such as liver disease, diabetes and osteoarthritis later in life. This is especially a problem in men; 7% of all men with the haemochromatosis mutations likely to develop liver cancer by the age of 75 years. Though the risks are thought to be less in women due to protection of iron-overload by menstrual blood loss, this is not clear and risks after menopause need clarifying. Hereditary haemochromatosis is easy to diagnose with a simple blood test to check iron levels, which if high can be confirmed with a genetic test. It can be safely treated by the removal of blood to lower iron levels. Common early symptoms include extreme tiredness and joint pain, which may be misdiagnosed as the usual signs of ageing. My work has shown that many UK patients are progressing to serious disease, including liver cancer, before being diagnosed with haemochromatosis. In the UK Biobank study, only 12.1% of men with HH mutations were diagnosed with haemochromatosis. Worryingly, only half of the males with the HH mutations who went on to develop liver cancer were diagnosed with haemochromatosis before the emergence of the cancer2. These and similar statistics, plus extensive patient testimony, point to a major lost opportunity to prevent the complications of iron overload, despite the ease of testing and treatment. In fact, maintenance treatment for HH even produces donated blood that can be used for transfusion, providing a potential win-win for improving HH care in the UK. Aims and Methods: My overall aims in this fellowship are to answer some key remaining questions about the effect of the haemochromatosis faulty genes in key groups, including women; to understand the nature of current service problems leading to late diagnosis in both men and women; and to estimate how much excess disease and costs to the NHS could be avoided by different scenarios for earlier diagnosis or screening for haemochromatosis. These aims will ultimately support field trials for improving care in HH.To achieve these aims, I will analyse data from the UK Biobank - a large volunteer study including more than 450,000 participants of European ancestries. The UK Biobank is a unique dataset with lots of information about patients' genetics and environmental factors, including lifestyle and medical history, and contains by far the largest sample of people with haemochromatosis mutations in the world. Participants in the UK Biobank are also followed-up via linked electronic medical records from general practices, hospital admissions, cancer records and death records. UK Biobank is the largest study on hereditary haemochromatosis in the world. Patient and Public Involvement: I have taken advice from members of the Haemochromatosis UK (HUK) patient charity in developing this project. I will continue to work with HUK patient members at a number of key points throughout the fellowship via small group workshops, and also through an online questionnaire to all HUK patient members on their experience of HH diagnosis. Dissemination: Results will be presented at scientific conferences, the Haemochromatosis UK patient conference and to the UK parliamentary group on haemochromatosis.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: DISPUTED AETIOLOGY AND OTHER