What is Hemochromatosis?

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  • Slide 1:
    Title
  • Slide 2:
    Acknowledgements
    Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.
  • Slide 3:
    Outline
  • Slide 4:
    What is Hemochromatosis?
    Hereditary Hemochromatosis:
    Genetic defect in iron metabolism.
    Acquired: Liver diseases such as alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasms, porphyria cutanea tarda, and inflammatory disorders, such as rheumatoid arthritis. 1
    This group also includes iron overload resulting from ingested iron in foods, cookware, and medicines, as well as parenteral iron from iron injections or transfusions for chronic anaemia such as beta-thalassemia or sideroblastic anaemia. 1
    The treatment of hereditary hemochromatosis is different than acquired hemochromatosis. For acquired hemochromatosis the treatment depends on the cause of iron overload. 2
  • Slide 5:
    Symptoms: Traditional Concept
    There is a misconception that most hemochromatosis patients present with this classic triad when in fact fewer than 15% of patients do.3
    Diagnosis at this point means it is too late to prevent organ damage.
    Goal is to identify and treat patients before they reach this stage.
    Organ damage may only be partially reversible at this point.
  • Slide 6:
    Non-Specific Symptoms and Signs 4
    These symptoms are generally not evident in men until 40-60 years of age and generally have a later onset in women – post-menopausal.3 Women are also less likely to be symptomatic. However some patients do have symptoms before middle age.
    Liver:
    History of liver trouble
    Hepatomegaly
    Abdominal ache with hepatic tenderness
    Cirrhosis
    Primary hepatocellular carcinoma
    Cardiac:
    EKG abnormalities
    Palpitations
    Musculoskeletal:
    Arthraglia typically starting in the fingers, wrists and hips
    Iron fist - tender enlargement of the 1st and 2nd digits
    Generalized weakness
    Endocrine:
    Diabetes mellitus, type 2
    Loss of libido, impotence, testicular atrophy
    Menstrual irregularities, amenorrhea
    Hypothyroidism
  • Slide: 7
    The Genetics of Hemochromatosis
    There are different genetic causes of HH.4,5
    The most common is the classical adult onset form HFE – associated Hemochromatosis (type 1), accounting for >90% of cases6. HFE is the name of the gene causing the common adult onset hereditary hemochromatosis.
    Other forms of HH are rare: juvenile onset hemochromatosis (type 2), TfR2-related hereditary hemochromatosis (type 3), and ferroportin – related iron overload (type 4).
    There are patients with iron overload that cannot be explained by mutations in either of these genes or environmental factors; thus there are undiscovered genes.
    The classical adult onset form, HFE-associated Hemochromatosis will be the focus of this talk.
    1 in 7 to 1 in 10 people in the North European population are carriers of the C282Y mutation in the HFE gene. 7,8,9,10
    The disease incidence ranges from 1 in 200 to 1 in 400 in this population
    In one Canadian study before the discovery of the HFE gene, a population survey found 3 cases of hemochromatosis in a population of 1105. From this study the approximate incidence is 1 in 370; however this number may be higher with genotyping (testing for mutations in the HFE gene).9
    Another Canadian study before genotyping suggests that the incidence of hemochromatosis is 0.3% or 1 in 300 and the carrier rate is 11% or 1 in 9.11
    Penetrance is defined as the proportion of individuals with a genotype known to cause a specific disease who expressed the clinical symptoms of that disease. The penetrance of HH is currently under study and is thought to be low. This will be addressed later on in the lecture.
  • <number>
    Slide 8:
    Autosomal Recessive Inheritance
    The capital “B” in this diagram is the normal HFE gene. The mutated copy of the gene is represented by the lower case “b”. T “bb”
    Both parents are carriers of one HFE mutation but are unaffected
    Each child (of either sex) has a 1 in 4 or 25% chance to inherit both normal/non-mutated copies of the HFE gene (two capital B’s - BB).
    There are 2 chances in 4 or 50% chance for a child of either sex to inherit one HFE gene mutation and one normal/non-mutated HFE gene and thus they would be unaffected carriers like their parents (one capital B and one lower case b - Bb).
    Each child (of either sex) has a 1 in 4 or 25% chance to inherit both mutations in the HFE gene. This child is at risk to develop HFE-associated hemochromatosis in adult life (two lower case b’s - bb).
    While hemochromatosis is an autosomal recessive condition, it can look pseudo-dominant with parent to child transmission, because of the high carrier frequency. It is very common in the Northern European population.
  • Slide 9:
    The HFE Gene
    HFE gene on chromosome 6p21.3
    Two common mutations in HFE gene
    C282Y allele (one version of a gene, in this case a mutation): Over 95% of Canadian hemochromatosis patients are homozygous, that is they have two copies of the C282Y allele.12
    This ranges between 69 to 100% depending on the population studied.13
    H63D allele: Approximately 1 in 4 to 1 in 6 persons of Northern European background is a carrier (they have one normal allele and the second allele has a change or a mutation) of the H63D allele. This allele is not as strongly associated with iron overload as the C282Y allele.7,13,14
    Approximately 1-2% of people who are compound heterozygotes (they have two different mutant alleles of the gene), C282Y/H63D, develop clinical hemochromatosis.4
    Of those homozygous for the H63D/H63D allele, <1% develop clinical hemochromatosis.13
  • Slide 10:
    Case (1)
    Initial consultation: history and exam
  • Slide 11:
    Case (2)
    Second consultation: results of routine blood
    Third consultation: more blood work
  • Slide 12:
    Case (3)
    Fourth consultation: working towards a diagnosis
  • Slide 13:
    Consider Hemochromatosis! (1)2
    Symptomatic patients
    Abnormal serum iron markers on routine blood work:
    Liver function tests: Bilirubin Transamninases Alkaline phosphatase Gamma - Glutamyl transpeptidase Albumin Prothrombin time (INR)
  • Slide 14:
    Consider Hemochromatosis! (2)2
    Asymptomatic patients
  • Slide 15:
    Diagnostic Testing for HH
    Fasting transferrin saturation (TS): 2
    > 45% indicates significant Fe accumulation (sensitivity and specificity 94%)3
    TS = Serum iron x 100%
    Total Iron Binding Capacity (TIBC)
    The easiest way to get TS levels is to order serum iron and TIBC then do the TS calculation if the lab does not do the calculation for you
    Patient must be fasting as TS can be increased after a meal in which there is large iron content.
    Serum ferritin: at these levels indicates significant iron accumulation3
    Liver biopsy if ferritin >1000 in HH to assess damage2
    Genetic testing – DNA testing for common mutations (C282Y, H63D)2
  • Slide 16:
    Genetic Testing for HH should be offered to those patients with:
    Must be offered to an affected family member FIRST
    A known mutation should be identified before offering DNA testing to other family members.
    If the affected family member is unavailable, then refer relatives to genetics clinic for counseling and evaluation.
    First-degree relatives or spouse (if there are adult children at risk since if spouse is negative, no need to test children) of a diagnosed case of HH. Some genetics centres offers testing to first-degree relatives of a carrier because HH is so common.
  • Slide 17:
    What is the value of Genetic Testing?
    Think of the whole family as your patient. Genetic testing allows you to identify family members at risk of developing hemochromatosis.
    Predictive value: Once at-risk family members are identified, a screening or treatment plan can be developed to prevent organ damage and reduce morbidity and morality.
    Screening plan to monitor for iron overload:
    Serum Ferritin
    Fasting Transferrin Saturation
    Treatment plan to reduce further organ damage.
    Phlebotomy (500mL) weekly or biweekly until serum ferritin falls below 50ng/mL2
    Diet: Avoid iron supplements, vitamin C and raw fish.
  • Slide 18:
    Discussing Genetic Testing
    Informed Choice:
    Genetic testing is different than other medical tests/procedures because it does not change over time. Genetic testing may also reveal information about family members who do not want this information. Likewise it can reveal unexpected findings such as non-paternity.
    Walk patient through various decisions (testing, no testing) and outcomes (positive, negative) to help aid in the decision whether or not to have genetic testing.
    Risks, benefits and limitations:
    Risks: The patient may face insurance or employment discrimination.
    The patient’s family members may not want to know this information.
    Benefits:
    The cause of iron overload can be identified.
    The disease can be prevented if detected early enough.
    The patient can be assessed for iron overload and treated for hemochromatosis if testing positive, before major organ damage.
    The patient’s family can now be screened to find those at increased risk for hemochromatosis.
    Limitations:
    The test can not identify all causes of iron overload.
    Testing positive will not tell the patient when or if they will develop symptoms of iron overload.
    Testing will identify common mutations but will not identify rare mutations in the hemochromatosis gene. Patients who have symptoms strongly suggestive of HH, and DNA results show them to be carriers of C282Y, may be referred to genetics for further testing for rare mutations.
    Psychological Issues:
    Generally research has shown that there are few if any adverse psychological consequences from genetic testing for HH.
    Patients with a history of psychological problems might be at increased risk.
    Positive health behaviour can be reinforced
    Mutation carriers may develop a fatalistic attitude toward to health.
    Family issues: Family members may not want to be aware of information from genetic testing.
    May feel guilty for passing this mutation on to their children.
    May reveal non-paternity
    Discrimination: Patient may face higher life insurance premiums as a result of a positive test or employment discrimination.
  • Slide 19:
    Case (3)
    Seamus’ genetic testing results: C282Y homozygote. This means he carries two copies of the C282Y mutation.
    Who else should be offered testing?
  • Slide 20:
    Seamus’ Family History
    Seamus is the 60 year old man indicated by the arrow; his father died of liver cancer; 55 year old brother has type 2 diabetes and 64 year old sister has arthritis. His other sister and 3 other brothers are reported to be in good health.
    Who should be offered genetic testing?
    All of Seamus’ siblings should be offered genetic testing for hemochromatosis as they are at a minimum risk of 25% of inheriting the susceptible genotype.
    Seamus’ sister with arthritis and brother with diabetes may already be showing signs of disease.
    It is possible that Seamus’ father may also have been affected with hemochromatosis. Further information about his cancer diagnosis and history of liver problems may be helpful.
  • Slide 21:
    Genetic testing of minor children
    Seamus and his wife request HH testing for their 13 year old daughter.
    Would you offer their daughter testing?
    Consider potential benefits and harms: 15, 16
    Medical issues:
    Timely medical benefits to the child should be the primary justification for genetic testing of children and adolescents. Seamus’ daughter is 13 y.o. If she does have hereditary hemochromatosis, then she would not be expected to develop symptoms until she is well into adulthood. Thus testing for HH at 13 is not a timely medical benefit. She can wait and make her own medical decision once she reaches adulthood.
    Possible harms include increased surveillance.
    Psychosocial issues:
    Potential harms: anxiety, self-image, career, insurance, lifestyle and distortion of parents’ perception of the child, altered expectations of the child.
    If the medical or psychological benefits of a genetic test will not accrue until adulthood, as in adult onset diseases, testing should generally be deferred.
    Reproductive issues:
    Benefits: informed planning decisions.
    Harms: Coerced decisions.
    Sexually active teenagers may be counseled on their own. Testing may be appropriate in this situation.
    For adult onset conditions, it is generally accepted that the child make a decision after they reach adulthood or capacity to give consent.
    Another alternative would be to offer Seamus’ wife testing if she is not a carrier then there is significantly reduced risk of their daughter becoming affected assuming the paternity is correct.
  • Slide 22:
    Consequences of having a mutation
    Research shows very few negative emotional consequences to having a HH mutation. 17
    Potential consequences:
    Emotional
    Discrimination
    Family issues
    Unanticipated outcome
  • Slide 23:
    “So if I have the gene…I’ll get the disease”
    Penetrance is defined as the proportion of individuals with a mutation (or genotype) known to cause a specific disease who exhibit clinical symptoms of that disorder.
    So, for hemochromatosis, that would be the proportion of individuals with a C282Y/C282Y or C282Y/H63D or H63D/H63D genotype who exhibit clinical symptoms of hemochromatosis.
    Note that the penetrance depends on the specific genotype involved: C282Y/C282Y (majority of cases) > C282Y/H63D > H63D/H63D (very few people have symptoms).
  • Slide 24:
    Mutated HFE Genes = Hemochromatosis?
    Incomplete penetrance:
    Incomplete penetrance refers to the phenomenon that not every person with a mutant genotype will exhibit clinical symptoms of the disorder.
    Some factors contributing to incomplete penetrance (in HH) are environment, diet, alcohol, lifestyle (donating blood) and age at menarche & menopause, heaviness of periods, number of pregnancies, use of iron supplements and other genetic factors (modifier genes).
    From the European Consensus Conference on Haemochromatosis in 2000, the proportion of C282Y homozygotes that will have iron overload assessed by serum ferritin is 19-58%.5
    The exact penetrance of hemochromatosis is still under study but ranges from 1% to 55% to 100% in the literature.17 More recent data suggests the penetrance is lower than previous reports. One of the reasons for the range in penetrance is that the various studies have different definitions of hemochromatosis and different methods of ascertainment (study of blood donors’ verses a study of patients followed in a hemochromatosis clinic).
    This brings us to a philosophical question: What constitutes disease?
    Genotype: People with two HFE mutations (C282Y/C282Y or H63D/H63D homozygotes, C282Y/H63D compound heterozygotes)? – But they may never develop clinical symptoms of iron overload.
    Biochemistry: People with the abnormal biochemistry, elevated TS (‘biochemical penetrance’) but no symptoms of iron overload? One study in Wales found that 85% of men and 44% of women with the C282Y/C282Y genotype had elevated TS – again these people may not develop clinical symptoms. 1
    Clinical presentation: People with symptoms of iron overload – cirrhosis, cardiomyopathy, type 2 diabetes etc?
    Thus the definition of disease can vary depending on what is being referred to; genotype or serum iron measures or symptoms of iron overload.
    One of the problems in determining the penetrance of HH is that the various studies have different definitions of the clinical signs leading to the wide range of the reported percentage of penetrance.
  • Slide 25:
    Medical Management 3, 6, 2
    The goal of treatment is to detect patients before they manifest symptoms of iron overload.
    Early treatment can prevent organ damage and improve survival
    Some symptoms may be reversible with phlebotomy
    Phlebotomy:
    Removal of 400-500mL of blood weekly or biweekly
    Check hematocrit prior to each phlebotomy; allow hematocrit to fall by no more than 20% of normal
    Check ferritin every ~10 phlebotomies
    Stop frequent phlebotomy when ferritin 20-50mcg/L or transferring saturation is <30%
    Continue phlebotomy at intervals (every 3-4 months) to keep serum ferritin between 20-50mcg/L
    Dietary recommendations: Patients should avoid:
    Vitamin C (increases the absorption of iron) and iron supplements
    Excessive consumption of alcohol
    Eating raw shellfish – A marine bacteria, Vibrio vulnificus causes septicemia and high mortality especially in people with chronic liver disease or other dysfunction that increases serum iron levels i.e. HH.18
    Consider hematology or GI consult for confirmed cases to guide treatment and monitoring.
    Management of C282Y heterozygotes (carriers)6
    In C282Y heterozygotes who have indirect markers of iron overload, especially if they have abnormal liver enzymes or clinical evidence of liver disease - a liver biopsy is recommended to diagnose HH.
    C282Y heterozygotes that have iron overload may carry a second undetected, RARE mutation in the HFE gene.
    Generally C282Y and H63D heterozygous carriers are not at risk for iron overload.
  • Slide 26:
    Summary
    Think genetically!
    Think of the family history as a whole. For example in Seamus family, there were members with liver cancer, cardiomyopathy and IDDM. When you put all of these together, you see the symptoms of hemochromatosis.
    Three generation family history
    Drawing out the family history allows you to assess relationships and track conditions through the family
    Risks, benefits & limitations of genetic testing
    Early treatment, diagnosis, discrimination, psychological consequences….
  • Slide 27:
    Resources
  • <number>
    Slide 28:
    The Genetics Education Project Committee
    Committee Members
  • Slide 29:
    References 1
  • Slide 30:
    References 2
  • Slide 31:
    References 3
  • Slide 32:
    References 4
  • Slide 33:
    References 5
  • Slide 34:
    The Genetics Education Project
    Logo
  • What is Hemochromatosis?

    1. 1. The Genetics Education Project Hereditary Hemochromatosis Prepared by: Sean Blaine BSc, MD, CCFP Family Physician - Stratford, Ontario Assistant Professor, University of Toronto June C Carroll MD, CCFP, FCFP Sydney G. Frankfort Chair in Family Medicine Mount Sinai Hospital, University of Toronto Andrea L Rideout, MS, CGC, CCGC Certified Genetic Counsellor Project Manager – The Genetics Education Project Funded by: Ontario Women’s Health Council Version: February 2006
    2. 2. The Genetics Education Project Acknowledgments  Reviewers: Members of The Genetics Education Project  Funded by: Ontario Women’s Health Council as part of its funding to The Genetics Education Project * Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.
    3. 3. The Genetics Education Project Outline  Hereditary hemochromatosis  Clinical picture  Symptom/pattern recognition  When to offer testing  Benefits, risks & limitations of genetic testing  Management recommendations
    4. 4. The Genetics Education Project What Is Hemochromatosis ?  Disorder of iron overload – Hereditary hemochromatosis (HH) – Acquired hemochromatosis  HH: genetic defect in iron metabolism – Excess iron absorbed from the gut – Symptoms due to pathologic deposition of iron in body tissue = iron overload
    5. 5. The Genetics Education Project Symptoms – Traditional Concept  Classic Triad: – Cirrhosis (hepatic damage) – Diabetes (type II) (pancreatic damage) – Bronzing of skin (hyperpigmentation)  Traditional triad means diagnosed too late!  Damage may be only partially reversible  Goal is to detect the disease BEFORE organ damage occurs
    6. 6. The Genetics Education Project Non-Specific Symptoms and Signs  Liver: hepatomegaly, elevated liver enzymes  Cardiac: myocardial infarction, cardiomyopathy  Endocrine: impotence/amenorrhea, diabetes  Musculoskeletal: arthritis/arthralgia  Fatigue: unexplained, severe and chronic Generally not evident until 40-60 years of age Some patients may present earlier
    7. 7. The Genetics Education Project The Genetics of Hemochromatosis  HFE– associated Hemochromatosis accounts for > 90% of cases and is the most common adult onset form:  Autosomal recessive inheritance  C282Y mutation – Carrier rate 1 in 7 - 10 Caucasians – Incidence 1 in 200 - 400  Penetrance is low
    8. 8. The Genetics Education Project Bb Bb BB Bb Bb bb Unaffected carrier Unaffected Autosomal Recessive Inheritance Unaffected carrier Susceptible genotype for Hemochromatosis Unaffected carrier Unaffected Carrier Legend B: Normal HFE gene b: HFE gene with mutation
    9. 9. The Genetics Education Project The HFE Gene  HFE gene on chromosome 6 – Involved in iron homeostasis – HFE protein normally limits amount of iron uptake by gut and regulates amount of iron stored in the tissues  Two common mutations in HFE – C283Y allele – H63D allele  HFE gene mutations produce altered HFE protein unable to properly regulate iron metabolism - results in an excess of iron storage in tissues
    10. 10. The Genetics Education Project Case  Seamus, 60 y.o. male: – 3 month history of fatigue & joint pain – drinks 2 beers/day – brother with type 2 diabetes  Physical exam: – hepatomegaly – enlarged and tender knuckles – several tattoos
    11. 11. The Genetics Education Project Case  Seamus’ routine blood work: – Fasting glucose - normal – Bilirubin - normal – ALT 67 U/L (reference range 0-40) – AST 73 U/L (reference range 0-37) – GGT 92 U/L (reference range 5-35)  Seamus stops drinking, 6 weeks later: – ALT & AST levels are unchanged – GGT - normal – Hepatitis A & B serology negative What next?
    12. 12. The Genetics Education Project Case  Further blood work: – Ferritin 640 mcg/L(reference range <300mcg/L) – Transferrin saturation 60% (reference range <45%)  What is the diagnosis?
    13. 13. The Genetics Education Project Consider Hemochromatosis! In symptomatic patients with:  Unexplained liver disease, with abnormal serum iron markers  Type II diabetes particularly with: – Hepatomegaly, elevated liver enzymes, atypical cardiac disease, early onset sexual dysfunction  Early onset arthropathy, cardiac disease, male sexual dysfunction
    14. 14. The Genetics Education Project Consider Hemochromatosis! In asymptomatic patients with:  Unexplained elevation of liver enzymes or asymptomatic hepatomegaly  Abnormal serum iron markers on routine blood work  Lethargy/fatigue  First degree relatives of a confirmed HH case
    15. 15. The Genetics Education Project Diagnostic testing for HH  Transferrin saturation: – > 45% indicates significant Fe accumulation  Serum ferritin - levels indicating significant iron accumulation: – >200 mcg/L pre-menopausal women – >300 mcg/L post-menopausal women – >300 mcg/L for men  Liver biopsy if ferritin >1000 to assess damage Consider genetic testing – DNA testing for common mutations (C282Y, H63D)
    16. 16. The Genetics Education Project Genetic Testing for HH Should be offered to those patients with:  Appropriate clinical presentation  Elevated transferrin saturation and ferritin  Liver biopsy suggestive of iron overload  First degree relative of a known case * Must be offered to an affected family member or index case FIRST – A known mutation should be identified before offering DNA testing to other family members
    17. 17. The Genetics Education Project What is the value of genetic testing?  To confirm diagnosis  Sequential screening of family members – Family members with identified mutations can be offered: • Screening plan to monitor for iron overload. – Normal life expectancy if diagnosed before DM or cirrhosis • Treatment plan to prevent further organ damage, morbidity & mortality. – Prolonged survival with serial phlebotomy – Goal of ferritin <50 may take > 1 year • Environmental modification – Diet, alcohol, viral hepatitis A/B immunization
    18. 18. The Genetics Education Project Discussing Genetic Testing  Informed choice  Risks, benefits & limitations of testing  Walk patient through various scenarios – Positive test result – Negative test results  Psychosocial issues: self-concept, insurance discrimination, family issues, non-paternity OR Refer to your local Genetics Clinic
    19. 19. The Genetics Education Project Case (cont.)  Seamus decides to have genetic testing  Genetic testing for Seamus shows – HFE: C282Y/C282Y (homozygote) – This is the susceptible genotype and Seamus has hemochromatosis – After 6 months of weekly phlebotomy his liver function parameters normalize  Let’s look at his family history…
    20. 20. The Genetics Education Project Seamus’ Family History CA- Liver - 69 ‘old age’ - 80 Arthritis - 64 A&W - 62 All A&W All A&W All A&W All A&W Diabetes - 55 Seamus -60 Ireland/Ireland Angela – 13 A&W Heidi -55 A&W Accident -21 Both A&W A&W -65 Diabetes -69 A&W WW II Germany/England Alzheimer disease - 95 Legend CA liver Arthritis IDDM 3 3 3 N
    21. 21. The Genetics Education Project Genetic testing of minor children  Seamus and his wife request HH testing for their 13 year old daughter.  Would you offer their daughter testing?  Consider potential benefits and harms: – Medical issues – Psychosocial issues – Reproductive issues  For adult onset conditions it is generally accepted that the child make a decision after they reach the age of understanding and the capacity to give consent - generally adulthood.
    22. 22. The Genetics Education Project More consequences of having a mutation  Research shows very few negative emotional consequences to having a HH mutation  Potential consequences: – anxiety, depression or relief – positive health behaviour may be reinforced – may develop fatalistic attitude toward to health – insurance discrimination  Unanticipated outcomes – i.e. nonpaternity
    23. 23. The Genetics Education Project “So if I have the gene…I’ll get the disease”  Not necessarily!  This statement refers to an important concept in genetics  Penetrance – The proportion of individuals with a mutation causing a particular disorder who exhibit clinical symptoms of that disorder
    24. 24. The Genetics Education Project Mutated HFE Genes = Hemochromatosis? No, because of  Incomplete penetrance: – Even though some individuals have the susceptible genotype they may never manifest symptoms of the disease due to: • Environmental factors: blood donation • Genetic factors: other modifying genes  Low penetrance for C282Y homozygotes
    25. 25. The Genetics Education Project Medical Management  The goal - detect patients before symptoms of iron overload.  Phlebotomy weekly or biweekly  Check ferritin every ~10 phlebotomies  Stop frequent phlebotomy when ferritin 25-50mcg/L  Maintenance phlebotomy every 3-4 months  Dietary recommendations  Consider hematology or GI consult for confirmed cases to guide treatment and monitoring
    26. 26. The Genetics Education Project Summary  Think genetically!  Three generation family history  Risks, benefits & limitations of genetic testing  HH Pattern recognition – Multiple signs, symptoms, and disease manifestations may be a clue to early diagnosis  HH Goal: detect and treat affected individuals before signs of organ damage
    27. 27. The Genetics Education Project Resources  The Canadian Hemochromatosis Society: – http://www.cdnhemochromatosis.ca/main.htm  Gene Reviews: http://www.genetests.org/ – See HFE-associated Hemochromatosis  Iron Disorders Institute website: – http://www.irondisorders.org/  Review article from the American College of Gastroenterology: – Adams P et al. EASL international consensus conference on haemochromatosis. J Hepat. 2000; 33:485-504. – Tavill AS et. al Diagnosis and management of hemochromatosis. Hepatology. 2001;33:1321-1328.  Contact your local genetics centre – http://www.cagc-accg.ca/centre1.html
    28. 28. The Genetics Education Project The Genetics Education Project Committee  June Carroll MD CCFP  Judith Allanson MD FRCP FRCP(C) FCCMG FABMG  Sean Blaine MD CCFP  Mary Jane Esplen PhD RN  Sandra Farrell MD FRCPC FCCMG  Judy Fiddes  Gail Graham MD FRCPC FCCMG  Jennifer MacKenzie MD FRCPC FAAP FCCMG  Wendy Meschino MD FRCPC FCCMG  Joanne Miyazaki  Andrea Rideout MS CGC CCGC  Cheryl Shuman MS CGC  Anne Summers MD FCCMG FRCPC  Sherry Taylor PhD FCCMG  Brenda Wilson BSc MB ChB MSc MRCP(UK) FFPH
    29. 29. The Genetics Education Project References 1. Dooley J. Diagnosis and management of genetic haemochromatosis. Best Pract Res Clin Haematol. 2002; 15:277-293. 2. Borgaonkar MR Hemochromatosis more common than you think. Can Fam Physician 2003; 49:36-43. 3. Pietrangelo A. Hereditary Hemochromatosis- a new look at an old disease NEJM 2004; 350:2383-2397. 4. Cazzola M. Genetic disorders of iron overload and the novel “ferroportin disease.” Haematologica 2003; 88: 721-724.
    30. 30. The Genetics Education Project References 5. Adams P et al. EASL international consensus conference on haematchromatosis. J Hepat. 2000; 33:485-504. 6. Olynyk JK, Cullen DJ Aquilia A et al. A population study of the clinical expression of the hemochromatosis gene. NEJM 1999; 341:718-724. 7. Worwood M. Genetics of Haemochromatosis. Bailleres Clin Haemtol. 1994; 7:903-18. 8. Milman N, Pedersen P, Steig T, Melsen GV. Frequencies of the hereditary hemochromatosis allele in different populations. Comparison of previous phenotypic methods and novel genotypic methods. Int J Hematol. 2003; 77: 48-54.
    31. 31. The Genetics Education Project References 9. Feder JN, Gnirke A Thomas W et al. A novel MHC class I- like gene is mutated in patients with hereditary hemochromatosis. Nat Genet. 1996; 13:399-408. 10. Borwein S Ghent CN Valberg LS. Diagnostic efficacy of screening for hereditary hemochromatosis. Can Med Assoc J 1984; 131:89901. Adams PC Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology. 1998; 114:319-323. 11. Ramrakhiani S, Bacon BR. Hemochromatosis: Advances in Molecular genetics and clinical diagnosis. J Clin Gastroenterol 1998; 27:41-46.
    32. 32. The Genetics Education Project References 12. Jackson HA, Carter K, Darke C et al. HFE mutations, iron deficiency and overload in 10 500 blood donors. Br J Haematol 2001; 114:474-484. 13. Tavill AS Diagnosis and management of hemochromatosis. Hepatology 2001; 33: 1323-1328. 14. Canadian College of Medical Genetics. Position statement – genetic testing of children November 26, 2000. 15. American College of Medical Genetics. Genetic testing in children and adolescents, points to consider: ethical, legal and psychological implications of (ACMG/ASHG). Am J Hum Genet 57:1233-1241.
    33. 33. The Genetics Education Project References 16. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359:211- 218. 17. Patch C, Roderick P, Rosenberg W. Comparison of genotypic and phenotypic strategies for population screening in hemochromatosis: Assessment of anxiety, depression, and perception of health. Genet Med 2005; 7:550-556. 18. Gordon RS, McManus. From the NIH Highly invasive new bacterium isolated from US east coast waters. JAMA. 1984; 251: 323-325.
    34. 34. The Genetics Education Project

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