Genetic Screening for Relatives of Hemochromatosis Patients

1
Genetic Screening for Relatives of
Hemochromatosis Patients

• Resident Grand Rounds
• Dawn Graziano
• December 9, 2003

2
Case Presentation

• PS is a 49 y/o female with DM dxed 1997 presents
  to clinic for f/u
• PMHx DM, OA
• Meds Glucophage, Tylenol
• Social hx 1 ½ ppd x 30 years. Denies EtOH,
  drugs. Lives with husband, daughter in W-S.

3
Case Presentation

• Family hx
• Father ? hemochromatosis, cirrhosis
• Mother ? COPD, Crohns
• Daugher ? DM
• Brother ? AW
• Sister ? AW

4

• Given this patients history of hemochromatosis
• in a first degree relative,
• what testing, if any, is indicated?

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Overview

• Background
• Study 1 Prevalence of Mutations
• Study 2 Phenotypic Expression of Disease
• Study 3 Cost Effectiveness Analysis of
  Screening for Hemochromatosis in Relatives
• Return to Case Presentation
• Conclusion

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Review of Iron Overload

• Normal iron content of body 3-4 g
• Hgb in circulating rbcs 2.5 g
• Iron containing proteins 400 mg
• Iron bound to transferrin in plasma 3-7 mg
• Storage iron (ferritin or hemosiderin)
• Adult men 1 g
• Adult women less storage, but depends on
  menses/pregnancies/lactation/iron intake

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Review of Iron Overload

• No regulated mechanism of iron loss
• Iron is lost in sweat/shed skin cells/GI losses
  (1 mg/d)
• Premenopausal women lose 0.5 1 mg/d 2? menses

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Review of Iron Overload

• As iron increases, iron saturation of transferrin
  increases and iron is offloaded to cells with
  high levels of transferrin receptors
• heart
• liver
• thyroid
• gonads
• pancreas

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Review of Iron Overload

• Clinical Presentation
• Early sxs fatigue, impotence, arthralgia,
  arthritis, ?LFTs, abdominal pain, hepatomegaly
• Late sxs skin bronzing, arthropathy,
  cardiomyopathy, DM, cirrhosis

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Causes of Iron Overload

• Hereditary Hemochromatosis
• 2? Iron Overload
• Anemias
• Thalassemia major
• Sideroblastic Anemia
• Chronic hemolytic anemias
• Dietary iron overload
• Chronic Liver Disease
• Hep C, B
• EtOH induced liver dz
• Porphyria cutanea tarda
• Fatty liver dz

• Miscellaneous
• African iron overload
• Neonatal iron overload
• Aceruloplasminemia
• Congenital atransferrinemia

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Diagnosis of Iron Overload

• ? plasma iron conc (nl 60-150 µg/dL)
• ? calculated transferrin sat (nl 20-45)
  represents transport of excess iron from
  intestine
• ? plasma ferritin (nl 40-200)
• represents iron accumulation in tissues

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Diagnosis of Iron Overload

• Traditionally, ? transferrin sat ? repeat fasting
  trans sat ferritin
• Fasting trans sat gt 45 identifies 98 of
  affected patients

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Diagnosis of Iron Overload

• Liver biopsy
• histologic eval,
• hepatic iron concentration (HIC)
• nl lt36 µmol/g
• gt71 suggestive of hemochromatosis
• hepatic iron index (HII) HIC/age in years
• If gt1.9 virtually diagnostic of HH.

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Hereditary Hemochromatosis

• Autosomal recessive
• ? intestinal iron absorption
• Mutation(s) in HFE gene

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Model of HFE Protein
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HFE Genotype

• C282Y missense mutation leads to cytosine to
  tyrosine substitution at amino acid 282
• H63D missense mutation leads to histidine to
  aspartate substitution at amino acid 63

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HFE Genotype

• 80 C282Y/C282Y
• 4-7 compound heterozygotes (C282Y/H63D)
• 3-10 C282Y/WT or H63D/WT (heterozygotes)
• 1 H63D/H63D
• 5-7 WT/WT

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HFE Genotype
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What is the prevalence of these genetic
mutations in the U.S. population?
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Prevalence of C282Y and H63D Mutations in HFE in
the US, Steinberg, et al, JAMA, May 2001.

• Purpose to estimate prevalence of HFE mutations
  in U.S.
• Design cross-sectional population-based study of
  samples in DNA bank from phase 2 of NHANES III
• Genotypes 5171 specimens (gt12 y/o, not pregnant,
  trans sat avail, did not list other as
  race/ethnicity)

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Prevalence of C282Y and H63D Mutations in HFE in
the US, Steinberg, et al, JAMA, May 2001.

• Results
• HFE Genotype Prev. Est. (95 CI)
• C282Y/C282Y 0.26 (0.12-0.49)
• H63D/H63D 1.89 (1.48-2.43)
• C282Y/H63D 1.97 (1.54-2.49)
• C282Y/WT 8.33 (7.45-9.33)
• H63D/WT 21.36 (20.02-67.76)
• WT/WT 66.20 (64.57-67.76)

22
Prevalence of C282Y and H63D Mutations in HFE in
the US, Steinberg, et al, JAMA, May 2001.

• Results
• C282Y 1 in 385 are homozygotes
• within previously published estimates of 1
  in 200 to 1 in 500
• No significant differences between men and women.

23
Prevalence of C282Y and H63D Mutations in HFE in
the US, Steinberg, et al, JAMA, May 2001.

• C282Y mutation estimated to be present in 5.4 of
  the total U.S. population
• H63D mutation estimated to be present in 13.5 of
  the total U.S. population

24
Prevalence of C282Y and H63D Mutations in HFE in
the US, Steinberg, et al, JAMA, May 2001.

• Limits of Study
• Powered only to estimate prevalence of
  homozygosity within total population (5171)
• Randomly eliminated 20 of available subjects.

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What proportion of homozygotes actually express
the disease?
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Disease-Related Conditions in Relatives of
Patients with Hemochromatosis, Bulaj, et al,
NEJM, November 2000.

• Purpose determine proportion of homozygotes with
  conditions related to hemochromatosis
• 291 probands identified (184 presented with
  signs/symptoms of HH, 107 found because of ?
  transferrin sat at hemochromatosis screen or
  health maintenance)
• 214 homozygous 1st degree relatives identified

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Disease-Related Conditions in Relatives of
Patients with Hemochromatosis, Bulaj, et al,
NEJM, November 2000.

• Homozygous relatives had iron profiles checked
  and were assessed for disease related conditions
• Cirrhosis
• Hepatic fibrosis
• Elevated LFTs
• Hemochromatic arthropathy

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Disease-Related Conditions in Relatives of
Patients with Hemochromatosis, Bulaj, et al,
NEJM, November 2000.

• Divided into 3 groups
• Iron overload with disease-related conditions
• Iron overload without disease-related conditions
• No iron overload

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Disease-Related Conditions in Relatives of
Patients with Hemochromatosis, Bulaj, et al,
NEJM, November 2000.

• Results
• All ages
• 38 of homozygous male relatives with at least 1
  disease-related condition
• 10 of homozygous female relatives with at least
  1 disease-related condition

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Disease-Related Conditions in Relatives of
Patients with Hemochromatosis, Bulaj, et al,
NEJM, November 2000.

• Results
• Age-related
• 52 of men with at least 1 disease-related
  condition by age 40
• 16 of women with at least 1 disease-related
  condition by age 50

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Disease-Related Conditions in Relatives of
Patients with Hemochromatosis, Bulaj, et al,
NEJM, November 2000.

• Limits of study
• Not all patients received gold standard of
  diagnosis (liver bx). Few female relatives
  (40/101) agreed to bx.
• Only evaluated the C282Y/C282Y genotype

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Why Screen for Hemochromatosis?

• Prevalent disease
• Long asymptomatic phase
• Low risk, accessible treatment that prevents
  long-term sequelae of disease

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• Is there a cost-effective screening strategy for
  relatives of hemochromatosis patients?
• What is the role of genetic testing?

34
Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Purpose to compare the cost effectiveness of no
  screening with 4 different screening strategies,
  incorporating iron studies and genetic testing

35
Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.
36
Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• 5 Strategies
• No screening
• Iron Studies
• Gene test proband/spouse/children
• Gene test proband/relatives
• Gene test relatives

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• 1. No Screening
• Assumed 50 would develop organ damage
• cirrhosis
• DM
• cardiomyopathy

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• 2. Serum Iron Studies
• Measured serum transferrin and ferritin in
  children of proband starting at age 10, repeated
  for negative tests q5 yrs until age 40.
• Siblings were screened once.

39
Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• 3. Gene test proband/spouse/children
• Proband tested. If homozygous, spouse tested.
• If spouse heterozygous, children tested.
• Homozygous children followed with iron studies
  as above.

40
Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• 4. Gene test proband/relatives
• Proband tested. If homozygous, children and
  siblings tested.
• If relatives homozygous, iron studies.
• If proband not homozygous, children?periodic
  iron studies, siblings tested once with iron
  studies.

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• 5. Gene test relatives before proband
• Relatives gene tested.
• If homozygous ? serum iron studies.

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Screening Children
• If 1 child, gene testing proband, then child most
  cost effective (508 per life-yr saved)
• If gt1 child, gene testing proband, then spouse,
  then children most cost effective (3665 per
  life-yr saved for 2 children)
• Serum iron studies 7934
• Relatives tested first 12,277

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Screening Siblings
• No screening life expectancy 65 years
• All other strategies cost less yielded greater
  benefit than no screening.
• 1 sibling screening sibling 1st lower cost
• gt1 sibling gene testing proband 1st lower cost

44
Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Proportion of patients with phenotypic
  hemochromatosis in whom HFE test positive for
  C282Y/C282Y affects cost effectiveness.
• In this study, it was varied between 60-100,
  testing proband/spouse/children cost effective.
• As it approaches 100, gene testing relatives 1st
  becomes less expensive.

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Recommendations
• Gene Test Proband
• If homozygous ? gene test spouse
• ? gene test siblings
• If spouse heterozygous ? gene test children
• Iron studies in heterozygotes unnecessary.

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Without gene testing, all 1st degree relatives
  would need iron studies until age 40
• With gene testing 95 of children and 75 of
  siblings spared further testing.

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Screening for Hereditary Hemochromatosis in
Siblings and Children of Affected Patients,
El-Serag, et al, Annals of Int Med, February 2000.

• Limits of study
• Cost of genetic testing assumed to be less than
  what is available at NCBH (173 vs 245) and iron
  profile more (85 vs 58)
• Assumed higher percentage of patients with HH
  were homozygous for C282Y

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Return to Case Presentation

• 49 year old female with family history
  significant for hemochromatosis in father.
• Told in the past, my iron was high.

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Return to Case Presentation

• Labs
• iron 169 (40-160)
• transferrin sat 45 (15-45)
• ferritin 305 (20-200)
• LFTs wnl

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Return to Case Presentation

• Genetic Testing
• C282Y heterozygous
• H63D not present

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Return to Case Presentation

• Patient was referred to GI
• Plan follow serial iron studies, LFTs.
• Liver biopsy not indicated.
• Siblings to be screened
• with genetic testing.

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Conclusions

• Hemochromatosis is present in approximately 5 per
  1000 white Americans
• Taking a thorough family history may identify
  patients at risk for disease

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Conclusions

• Evidence supports genetic testing for relatives
  of hemochromatosis patients
• More studies are needed on the penetrance of
  disease and other possible genotypes

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Thanks to

• Dr. Joel Bruggen
• Dr. David Miller
• Christine Brandon

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