1. health and fitness
2. disease

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
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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
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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
– Diabetes (type II)
– Bronzing of skin
(hepatic damage)
(pancreatic damage)
(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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Autosomal Recessive Inheritance
Legend
Unaffected Carrier
Unaffected carrier
Bb
Bb
BB
Bb
Unaffected
Unaffected
carrier
Bb
B: Normal HFE
gene
b: HFE gene with
mutation
bb
Susceptible genotype for
Unaffected
Hemochromatosis
carrier
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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 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
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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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Legend
Seamus’ Family History
CA liver
Arthritis
IDDM
Ireland/Ireland
Germany/England
‘old age’ - 80
CA- Liver - 69
WW II
Alzheimer disease - 95
3
Arthritis - 64
3
All A&W
Seamus -60
All A&W
Heidi Accident -21 A&W -65
A&W - 62
Diabetes - 55
-55 A&W
N
Diabetes -69
3
All A&W All A&W
Angela – 13
A&W
Both A&W
A&W
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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
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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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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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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.
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References
9.
Feder JN, Gnirke A Thomas W et al. A novel MHC class Ilike 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 359:211218.
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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