Characterisation Of The Mechanisms Of Gastrointestinal And Hepatic Iron Transport In Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Hereditary haemochromatosis is a very common genetic disease that affects approximately 1:200 Australians. It alters the way the body uses iron. Iron is essential for health but too much iron is toxic to the body and causes harmful damage to organs. In hereditary haemochromatosis the body absorbs too much iron from the diet and most of the extra iron goes to the liver where it may cause liver cirrhosis and liver cancer. Some of the excess iron also goes to the heart, pancreas and joints where it ....Hereditary haemochromatosis is a very common genetic disease that affects approximately 1:200 Australians. It alters the way the body uses iron. Iron is essential for health but too much iron is toxic to the body and causes harmful damage to organs. In hereditary haemochromatosis the body absorbs too much iron from the diet and most of the extra iron goes to the liver where it may cause liver cirrhosis and liver cancer. Some of the excess iron also goes to the heart, pancreas and joints where it can lead to heart failure, diabetes and arthritis, respectively. There are several types of haemochromatosis that are caused by mutations in different genes that are important in the regulation of iron metabolism. In this study we will investigate two types of haemochromatosis caused by mutations in genes called HFE and transferrin receptor 2. How defects in these genes cause iron overload is not known. We will use laboratory models that have mutations in HFE and transferrin receptor 2 genes to identify for the first time how these proteins control the amount of iron the body absorbs from the diet and how much iron to delivered to the tissues such as the liver. From this study, we will gain a better understanding of the role of HFE and transferrin receptor 2 in both normal iron metabolism and haemochromatosis. This new knowledge will provide opportunities for the development of new more effective therapies for the prevention and treatment of iron overload.Read moreRead less
The Role Of The Liver In The Pathogenesis Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$592,023.00
Summary
Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations ....Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations in HFE lead to the development of Fe overload are unknown. Other types of HH have been identified that have similar clinical characteristics to HH type 1 which are due to mutations in hepcidin or haemojuvelin (type 2) and transferrin receptor 2 genes (type 3). It is thought that HFE acts together with these molecules in the same or closely related pathways to regulate iron metabolism. It is hypothesised that HFE and transferrin receptor 2 act as sensors of body iron levels which signal to the iron stores regulator, hepcidin to control the absorption of dietary iron and the deposition of iron in the liver. In this study, we will use mice with mutations in HFE and transferrin receptor 2 which have many of the characteristics of human HH type 1 and type 3 to identify 1) how HFE and transferrin receptor 2 sense body iron levels, 2) how they signal to hepcidin to regulate iron metabolism and 3) how mutations in HFE and transferrin receptor 2 lead to dysfunctional sensing of iron levels and impaired signalling to hepcidin causing increased iron absorption and liver iron overload in HH. This study will provide new knowledge about the role of HFE and other closely related molecules in the regulation of normal iron metabolism and the development of iron overload in HH and identify the potential of molecules such as hepcidin for therapeutical use for the prevention and treatment of iron overload.Read moreRead less
Regulation Of Liver Iron Loading In Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$663,188.00
Summary
Hereditary haemochromatosis is a common iron overload disorder. It affects 1 in 200 Australians causing liver iron overload, fibrosis, cirrhosis and cancer. The severity of liver iron overload in haemochromatosis is variable. In this study we will determine whether factors that are known to regulate iron metabolism such as iron levels, oxidative stress and inflammation modify liver iron transport systems and the degree of liver iron loading in animal models of haemochromatosis.
One of the current challenges in public health is to translate the progress from the Human Genome Project into reduced morbidity and mortality from disease. Once genetic defects are characterised, knowledge about the variability in severity of disease in mutation carriers, is important from a public health perspective. Hereditary Haemochromatosis (HH) is a common genetic disorder of iron overload that results in a wide spectrum of disease, varying from non-specific symptoms to severe damage to l ....One of the current challenges in public health is to translate the progress from the Human Genome Project into reduced morbidity and mortality from disease. Once genetic defects are characterised, knowledge about the variability in severity of disease in mutation carriers, is important from a public health perspective. Hereditary Haemochromatosis (HH) is a common genetic disorder of iron overload that results in a wide spectrum of disease, varying from non-specific symptoms to severe damage to liver, heart, pancreas and joints from iron deposition. It is easily treatable by regular blood donation, and population-based screening for HH has therefore been advocated. In this study we aim to address gaps in the existing data on HH regarding dietary and lifestyle factors that contribute to the variable clinical picture of HH. The study will be based on the Melbourne Collaborative Cohort Study, a cohort of 31,500 men and women who have been followed for approximately 10 years. Information on dietary and lifestyle factors was collected at initial enrollment, along with a blood specimen. We will test all non-Southern European participants (31,176) for the common HH mutations in the HFE gene and then select a subgroup of 1150 people, including all people with the main genetic defect as well as a comparison group, for further clinical followup. Participants will have genetic counselling and informed consent will be obtained. Participants will complete a short questionnaire and give a blood sample for measurement of iron overload, liver function, and other relevant blood tests, then undergo a brief clinical examination. Results of all tests will be given at a followup visit by genetic counsellor or physician. This study will provide important data on natural history of HH risk factors that influence variability in clinical presentation and the association of HFE mutations with chronic diseases and all cause mortality.Read moreRead less
Environmental Risk Factors For Iron Overload-related Disease In A Cohort Study Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$152,936.00
Summary
Results published last year from our Melbourne HealthIron study of hereditary haemochromatosis (iron overload disease) show that almost one third of the 50,000 men genetically at risk of iron overload in Australia will develop symptoms of disease including fatigue, arthritis and liver damage. We will use data from the recent follow-up of the Health2020 cohort, of which HealthIron is a sub-study, to determine environmental risk factors for progression to disease in people with iron overload.
Early Versus Delayed Therapeutic Venesection For The Prevention Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$196,012.00
Summary
This study will investigate treatment by blood removal for the inherited iron overload condition hereditary haemochromatosis: Is treatment more effective in reducing risk of disease if performed early as a preventive measure rather than later after diagnosis with symptoms? Details of the lifetime history of blood donation from the Australian Red Cross Blood Service will be combined with existing information from questionnaires and clinical examination of 1,439 study participants in Melbourne.
I am a hepatology scientist investigating the mechanisms associated with the development of hepatic fibrosis and cirrhosis in chronic liver diseases affecting children (cystic fibrosis liver disease and biliary atresia) and adults (haemochromatosis).