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The Genetics Education ProjectThe Genetics Education Project
Hereditary Hemochromatosis
Prepared by: Sean Blaine BSc, MD, CCFPFamily Physician - Stratford, Ontario
Assistant Professor, University of Toronto
June C Carroll MD, CCFP, FCFPSydney G. Frankfort Chair in Family Medicine
Mount Sinai Hospital, University of Toronto
Andrea L Rideout, MS, CGC, CCGCCertified Genetic Counsellor
Project Manager – The Genetics Education Project
Funded by: Ontario Women’s Health Council
Version: February 2006
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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.
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Outline
Hereditary hemochromatosis Clinical picture Symptom/pattern recognition When to offer testing Benefits, risks & limitations of genetic testing Management recommendations
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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
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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
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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
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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
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Bb
Bb
BB Bb Bb bb
Unaffected carrier
Unaffected
Autosomal Recessive Inheritance
Unaffectedcarrier
Susceptible genotype for Hemochromatosis
Unaffectedcarrier
Unaffected Carrier
Legend
B: Normal HFE gene
b: HFE gene with mutation
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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
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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
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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?
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Case
Further blood work:– Ferritin 640 mcg/L(reference range <300mcg/L)– Transferrin saturation 60% (reference range <45%)
What is the diagnosis?
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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
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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
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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)
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Genetic Testing for HHShould 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
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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
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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
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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…
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Seamus’ Family History
CA- Liver - 69 ‘old age’ - 80
Arthritis - 64A&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
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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.
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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
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“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
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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
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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
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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
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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
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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
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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.
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References5. 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.
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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.
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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.
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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.
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