Genetics in Family Medicine:
       The Australian Handbook for General Practitioners




Hereditary haemochromatosis
GP’s role                                                                                                        3

    Cl...
Hereditary haemochromatosis


    GP’s role
    •   Order iron studies (fasting transferrin saturation and serum ferritin)...
Genetics
•   The gene involved in HH is called the HFE gene.
•   Mutations in the HFE gene can lead to impaired regulation...
Iron studies
•   The transferrin saturation (ratio of serum iron and iron binding capacity) reflects increased absorption
...
Management
•   Follow up all patients with iron overload regardless of the HFE gene test result.
•   If HFE gene test show...
Implications for other family members
•    The family members of individuals with HH, unaffected C282Y homozygotes, compou...
Referral information
•   Patients or families requiring more detailed genetic counselling can be referred to Genetics Serv...
Patient and family fact sheet



                    Hereditary haemochromatosis


Hereditary haemochromatosis is a common...
Contacts and further information
    • Your local genetic service, which you can contact through your nearest community he...
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Hereditary haemochromatosis

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Transcript of "Hereditary haemochromatosis"

  1. 1. Genetics in Family Medicine: The Australian Handbook for General Practitioners Hereditary haemochromatosis
  2. 2. GP’s role 3 Clinical features 3 Genetics 4 Prevalence 4 Investigations 4 Iron studies 5 HFE gene test 5 Interpreting the results of the gene test 5 Management 6 Implications for other family members 7 Referral information 8 Bibliography 8 Patient and family fact sheet: Hereditary haemochromatosis Hereditary haemochromatosis Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007
  3. 3. Hereditary haemochromatosis GP’s role • Order iron studies (fasting transferrin saturation and serum ferritin). • Consider HFE gene testing or referral to gastroenterologist if: transferrin 45%, ferritin 250µg (pre-menopausal female) or 300µg (post-menopausal female/male). • Organise regular monitoring of iron indices in people being treated for iron overload. • Discuss the importance of cascade testing (see Contacts, support and testing) for 1° and 2° relatives when an individual has been diagnosed with HH or has been found to be heterozygous. • Refer to Genetics Services if appropriate for genetic counselling and discussion regarding issues such as testing (see Contacts, support and testing). • Refer family to a relevant support group (see Contacts, support and testing). • The MBS covers HFE gene testing for patients with: Raised ferritin or transferrin levels on more than one occasion, or A 1° relative diagnosed with HH Clinical features • Hereditary haemochromatosis (HH) is a common condition in which excessive iron absorption leads to greatly increased body iron stores. The deposition of iron occurs in parenchymal cells of the liver, heart, pancreas and other organs. • In the majority of patients with overt HH, the first symptoms develop between the ages of 30 and 60 years. • Clinical expression in children with HH is extremely uncommon before the late teens. • Antenatal diagnosis is not necessary as HH is an adult onset condition. • Menstruation and pregnancy account for the delayed presentation of the condition in women. • Common clinical features include one or more of the following: Lethargy and weakness Arthralgia Loss of libido Upper abdominal discomfort Hepatomegaly Grey/bronze skin pigmentation Testicular atrophy Joint swelling/tenderness • Liver function tests (LFTs) are frequently normal in asymptomatic patients, but may be abnormal in symptomatic patients. • Early diagnosis and treatment of HH is associated with a normal life expectancy. • Untreated HH can lead to serious complications and death. The complications include: Liver condition with fibrosis or cirrhosis Arthritis/osteophytosis at the metacarpal heads, particularly in the second and third MCP joints Impotence Diabetes mellitus – usually seen in the advanced stages of the condition Cardiomyopathy and arrhythmias Hepatocellular carcinoma in about 30% of patients with cirrhosis Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Hereditary haemochromatosis
  4. 4. Genetics • The gene involved in HH is called the HFE gene. • Mutations in the HFE gene can lead to impaired regulation of iron storage and are believed to be the most common cause of HH. • Frequencies of HFE genotypes in the Australian population are shown in Table 1. • About 90% of people of Northern European ancestry with symptoms of HH have the C282Y mutation in both copies of their HFE gene - homozygotes (see Contacts, support and testing for an explanation of terminology). • About 2% of people with HH have a C282Y gene mutation in one of their copies of the HFE gene, and the H63D gene mutation in their other copy (compound heterozygotes). • Compound heterozygotes have inherited one copy of the C282Y gene mutation from one parent and one copy of the H63D gene mutation from the other parent. • HH follows an autosomal recessive pattern of inheritance. • Therefore there is often no family history of the condition, or affected family members may appear to be scattered amongst or within generations. • Where both parents are heterozygous (carriers for a mutation in the HFE gene), there is a 25% chance that each of their children will inherit a gene mutation in both copies of their HFE gene, and be genetically predisposed to HH. • If only one parent is a carrier for a mutation in the HFE gene, there is a 50% chance that each of their children will be an HFE mutation carrier. Table 1. Frequencies of HFE genotypes in the Australian population HFE genotype Frequency No gene mutation found 2/3 Homozygous C282Y 1/200 Compound heterozygote (C282Y/ 1/50 H63D) Heterozygous C282Y 1/10 Heterozygous H63D 1/6 Homozygous H63D 1/100 Prevalence • More common in people of Northern European backgrounds: Affects about 1 in 250 people of Northern European background Approximately 1 in 8 people with this same ancestry are carriers for a mutation for haemochromatosis (heterozygotes) • Uncommon in Asian and African populations. Investigations • Assess risk by taking a family history (see Genetics in practice). • Note ancestry. • If there is a family history of HH, perform iron studies and an HFE gene test for 1° and 2° relatives of an index case if they are your patients and of an appropriate age. • If there is no family history but HH is suspected, the most useful tests are fasting transferrin saturation and serum ferritin. Hereditary haemochromatosis Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007
  5. 5. Iron studies • The transferrin saturation (ratio of serum iron and iron binding capacity) reflects increased absorption of iron, which is the underlying biological defect in HH. • A fasting transferrin saturation 45% is the most sensitive test for detecting early iron overload but a raised fasting transferrin saturation or ferritin is not diagnostic of HH. • HH is also unlikely if the ferritin is very high and the transferrin saturation is normal. • An elevated serum ferritin reflects an increase in body iron stores: Serum ferritin is also an acute phase reactant and can be elevated non-specifically in the presence of alcohol consumption, inflammation and other liver conditions Serum ferritin is abnormal when it is 250 µg/L in pre-menopausal women and 300 µg/L in men and post-menopausal women • If the fasting transferrin saturation or serum ferritin is increased on more than one occasion, HH should be suspected, even if there are no clinical symptoms or abnormal LFTs. In this situation, the HFE gene test should be ordered. • Some C282Y heterozygotes will have minor abnormalities in iron studies, but this has not been proven to be associated with the development of HH. • Iron studies may be normal in individuals with a genetic predisposition to HH who have not developed iron overload. Up to 40% of homozygotes have normal iron studies, which may be due to overt (blood donation) or covert (gynaecological or gastrointestinal) blood loss. HFE gene test • The MBS covers HFE gene testing for patients with: Raised ferritin or transferrin levels on more than one occasion, or A 1° relative diagnosed with HH • Most laboratories test for the HFE gene mutations C282Y and H63D (see Contacts, support and testing). Interpreting the results of the gene test • All patients with iron overload require follow-up regardless of the HFE gene test result, because in a small percentage of cases of HH a different, rarer gene mutation may be responsible. • Where no mutation is found in the HFE gene, and iron studies are normal, HH is exceedingly unlikely to develop. C282Y homozygote: 90% of Australians with HH have this genetic test result However, not all individuals with this genotype will develop HH It is estimated that 60 to 70% of C282Y homozygotes will develop iron overload during their lifetime Compound heterozygote: Only about 1% of people with this genotype develop HH Iron status should be monitored every 2 to 5 years C282Y and H63D heterozygote or H63D homozygote: The risk of developing HH is extremely small Some patients may have minor abnormalities in iron studies There is no need to monitor iron status unless levels are abnormal or symptoms are present Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Hereditary haemochromatosis
  6. 6. Management • Follow up all patients with iron overload regardless of the HFE gene test result. • If HFE gene test shows a patient to be C282Y homozygote and iron overload is absent, perform iron studies every 2 to 5 years. • If HFE gene test shows a patient to be C282Y homozygote and iron overload is present or the patient has other complications of HH: Lifelong venesection is required An initial course of 1 or 2 venesections per week is performed until the excess iron stores are removed The response to venesection treatment depends on the presenting symptoms and the stage of the condition at the time of diagnosis (see Table 2) Therapeutic venesection can still be arranged even if a patient is not eligible to donate blood for other reasons Once iron levels are at low normal levels, patients usually require one venesection every 3 to 4 months to keep levels low without rendering the patient iron-deficient A high red meat intake may increase the frequency of venesections required to maintain normal iron stores and therefore patients may choose to reduce their red meat intake Diet modification may help if patients cannot undergo venesection, but it is not nearly as effective Vitamin C (ascorbic acid) supplements should be avoided, since vitamin C increases iron absorption Patients should abstain from alcohol consumption until iron levels are normalised through venesection Fibrosis does not reverse following venesection therapy It is rare for patients not to tolerate venesection therapy Non-cirrhotic patients diagnosed and treated early have a normal life expectancy provided they continue treatment Cirrhosis is unlikely — If the ferritin level is 1000 µg/L, the AST level is normal and there is no hepatomegaly — If the patient is non-cirrhotic at diagnosis and is adequately treated Cirrhosis rarely develops, but if cirrhosis does develop, it does not regress to normal despite treatment Patients with cirrhosis have a risk of primary liver cancer even when complete iron depletion is achieved. These patients should be screened every six months with hepatic ultrasound and serum a-fetoprotein levels Liver biopsy may be performed to either confirm or exclude the presence of cirrhosis if blood tests are suggestive of cirrhosis Table 2. Response to venesection Symptom Good Variable Poor Fatigue • Skin pigmentation • Abdominal pain • Cardiomyopathy • Diabetes • Hypogonadism • Hepatic fibrosis • Arthropathy • Cirrhosis • Hereditary haemochromatosis Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007
  7. 7. Implications for other family members • The family members of individuals with HH, unaffected C282Y homozygotes, compound heterozygotes and C282Y heterozygotes may be at increased risk of also having HH (see Table 3). • Individuals known to carry these gene mutations should be encouraged to: Inform family members that they may be at increased risk of HH Give family members written information about HH Advise family members to discuss their risk of HH with their GP or Genetics Services • Since all individuals inherit one copy of the HFE gene from each of their parents, an individual’s risk of inheriting a predisposition for HH depends on the genotype of their parents. • It is recommended that 1° and 2° relatives of individuals who have HH or are homozygous for the C282Y gene mutation are tested with iron studies and the HFE gene test. • Siblings of individuals with HH, or siblings of unaffected C282Y homozygotes, have at least a 25% chance of having the same genotype, and 50% chance of being a carrier for the HFE mutation. Where possible, parents should also be tested. • Genetic screening of adult children of a patient with HH is not required if the other parent is tested and does not have an HFE gene mutation. • The most appropriate age for screening at-risk children should be decided on a case-by-case basis by the treating specialist. • Predictive genetic testing of asymptomatic children should generally be delayed at least until the age of 18 years. • The Human Genetics Society of Australasia recommends that predictive genetic testing of children should be carried out only when a specific treatment intervention is available and delay is inappropriate. • If parents are worried, explain that the partner of the homozygote can be tested and if they test negative for an HFE gene mutation, then the children can only be carriers. • Pre-test genetic counselling should occur if parents insist on testing their children. Table 3. Parents’ HFE genotype and probability of HFE genotypes for offspring Parent 1 HFE Parent 2 HFE Probability offspring Probability offspring genotype genotype C282Y homozygote C282Y heterozygote C282Y heterozygote 25% 50% C282Y heterozygote Compound heterozygote 25% 25% No gene mutation 0% 50% C282Y heterozygote 50% 50% C282Y homozygote Compound heterozygote 50% 50% No gene mutation 0% 50% Compound heterozygote 25% 0% Compound heterozygote No gene mutation 0% 50% Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Hereditary haemochromatosis
  8. 8. Referral information • Patients or families requiring more detailed genetic counselling can be referred to Genetics Services. • Venesection can be performed in a number of settings, including: The Australian Red Cross Blood Service which offers a therapeutic venesection service for patients with HH, provided that they do not suffer from a transfusion transmissible condition. The referring doctor is required to review the ongoing need for venesection at least every 12 months In association with a hepatology clinic Some private pathology services Some medical practitioners (a Medicare item number applies) Bibliography Barlow-Stewart K, 2004. Haemochromatosis. In The Australasian Genetics Resource Book (Ed Barlow-Stewart K), Centre for Genetics Education, Royal North Shore Hospital, Sydney NSW ISBN 0-9580797-2-2. Accessible at http://www.genetics.com.au Delatycki MB, Allen KJ, Nisselle AE, et al, 2005. Use of community genetic screening to prevent HFE- associated hereditary haemochromatosis. Lancet, 266: 314-316. Digestive Health Foundation (formerly Australian Gastroenterology Institute), 2000. Haemochromatosis – a guide for clinical practice in the era of genetic testing. http://www.medeserv.com.au/gesa/members_booklets/haemochromatosis/haemochromatosis_2nd ed.pdf Gaff C, Newstead J and Metcalfe S, 2003. Haemochromatosis. In The Genetics File. Victorian Department of Human Services, Melbourne ISBN 0 7311 61777 http://www.mcri.edu.au/GF/pages/GeneticsFile.asp Gertig D, et al, 2003. Population genetic screening for hereditary haemochromatosis. Medical Journal of Australia, 179: 517-518. Human Genetics Society of Australasia Policy Statement on Predictive testing in children and adolescents under Policies and Statements section at http://www.hgsa.com.au NSW Health, 2000. Haemochromatosis – Information for health care providers on diagnosis and management. http://www.health.nsw.gov.au/genetichealth Newstead J, Delatycki M, Aitken M, 2002. Haemochromatosis and family testing – what should a GP do? Australian Family Physician, 31: 533-537. Olynyk JK, Cullen DJ, Aquilla S, Rossi E, Summerville L, Powell L, 1999. A population-based study of the clinical expression of the haemochromatosis gene. New England Journal of Medicine, 341: 718-724. Online Mendelian Inheritance in Man, OMIM, McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). Accessed March 2007. http://www.ncbi.nlm.nih.gov/omim/ Powell LW, Dixon JL, Ramm GA, Purdie DM, et al, 2006. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Archives of Internal Medicine, 166: 294-301. Royal Australian College of General Practitioners, 2005. Guidelines for Preventive Activities in General Practice (The Red Book) 6th Edition. http://www.racgp.org.au/downloads/pdf/2005Redbook_6th_ed_appen3.pdf Hereditary haemochromatosis Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007
  9. 9. Patient and family fact sheet Hereditary haemochromatosis Hereditary haemochromatosis is a common condition in which too much iron is absorbed from food and stored in the body. It is usually picked up between the ages of 30 and 60 – earlier in men than in women. The condition can cause tiredness, sore joints, loss of sex drive, impotence, abdominal pain, heart disease, diabetes, an enlarged liver and even, occasionally, cirrhosis of the liver and liver cancer. If it is not detected for many years, hereditary haemochromatosis can be a severe condition. But if picked up early and treated, the condition can be mild. People with treated hereditary haemochromatosis usually have a normal lifespan. Haemochromatosis arises from an alteration to a particular gene known as the HFE gene. It follows an autosomal recessive pattern of inheritance (see fact sheet on 'How do genetic conditions occur? '). This means that someone with the condition has an alteration in both copies of their HFE gene. The parents of an affected person will be carriers and there are likely to be other family members who are carriers. There may also be relatives with alterations in both copies of the gene who are healthy at present, but will develop the disorder in the future. It is worth noting that having alterations in both HFE genes does not give you haemochromatosis – it only indicates that you have a high likelihood of getting the condition. At least a third of people with alterations in both their HFE genes will have no problems from it. If someone in the family has hereditary haemochromatosis, then all members of the immediate family should have blood tests known as iron studies, which measure the amount of iron in the body. They should also have tests to see if they have two, one or no alterations in HFE. Those who have abnormal iron studies will usually be referred to a specialist for follow up and treatment. Those with alterations in both HFE genes but normal iron studies need follow up by their doctor. Depending on these results, your doctor may recommend that other adult family members also be tested. Because the condition does not generally affect children, it is usually best to wait to test until they are adults. A word of caution about the gene test. The test picks up both HFE gene alterations in most people with hereditary haemochromatosis. But it does not always do so and it is possible to have hereditary haemochromatosis, but not have it show up on a genetic test. Anybody with hereditary haemochromatosis, and their close relatives, should have genetic counselling, which may involve referral to a genetics service. Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Hereditary haemochromatosis 1
  10. 10. Contacts and further information • Your local genetic service, which you can contact through your nearest community health centre, public hospital or health department. • Australasian Genetic Alliance at http://www.australasiangeneticalliance.org.au • Haemochromatosis Society Australia at http://www.haemochromatosis.org.au • Better Health Channel at http://www.betterhealth.vic.gov.au • MyDr at http://www.mydr.com.au • The Centre for Genetics Education at http://www.genetics.edu.au • HealthInsite at http://www.healthinsite.com • MedicineNet at http://www.medicinenet.com • For other related fact sheets, you can contact the Gene Technology Information Service on free call Australia-wide 1800 631 276 or email gtis-australia@unimelb.edu.au or visit Biotechnology Australia's website at http://www.biotechnology.gov.au Hereditary haemochromatosis Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007

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