Hereditary Hemochromatosis

The Genetics Education Project

Hereditary HemochromatosisPrepared by: Sean Blaine BSc, MD, CCFP

Family Physician - Stratford, OntarioAssistant 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


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.


Outline

Hereditary hemochromatosis Clinical picture Symptom/pattern recognition When to offer testing Benefits, risks & limitations of genetic testing Management recommendations


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


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


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 ageSome patients may present earlier


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


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


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


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


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?


Case

Further blood work:– Ferritin 640 mcg/L(reference range <300mcg/L)– Transferrin saturation 60% (reference range <45%)

What is the diagnosis?


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


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


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)


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


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


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


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…


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 - 55Seamus -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


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.


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


“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


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


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


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


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

http://www.cdnhemochromatosis.ca/main.htm

http://www.cdnhemochromatosis.ca/main.htm

http://www.genetests.org/

http://www.irondisorders.org/

http://www.cagc-accg.ca/centre1.html


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


References1. 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.


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.


References9. 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.


References12. 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.


References16. 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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Hereditary Hemochromatosis