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Genetic Screening for Relatives of Hemochromatosis Patients. Resident Grand Rounds Dawn Graziano December 9, 2003. Case Presentation. PS is a 49 y/o female with DM dx’ed 1997 presents to clinic for f/u PMHx: DM, OA Meds: Glucophage, Tylenol

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genetic screening for relatives of hemochromatosis patients

Genetic Screening for Relatives of Hemochromatosis Patients

Resident Grand Rounds

Dawn Graziano

December 9, 2003

case presentation
Case Presentation
  • PS is a 49 y/o female with DM dx’ed 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.
case presentation3
Case Presentation
  • Family hx:

Father ↓ hemochromatosis, cirrhosis

Mother ↑ COPD, Crohn’s

Daugher ↑ DM

Brother ↑ A&W

Sister ↑ A&W

slide4
Given this patient’s history of hemochromatosis

in a first degree relative,

what testing, if any, is indicated?

overview
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
review of iron overload
Review of Iron Overload
  • Normal iron content of body = 3-4 g
      • Hgb in circulating rbc’s = 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
review of iron overload7
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
review of iron overload8
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

review of iron overload9
Review of Iron Overload
  • Clinical Presentation
    • Early sx’s: fatigue, impotence, arthralgia, arthritis, ↑LFT’s, abdominal pain, hepatomegaly
    • Late sx’s: skin bronzing, arthropathy, cardiomyopathy, DM, cirrhosis
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

Causes of Iron Overload
diagnosis of iron overload
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

diagnosis of iron overload12
Diagnosis of Iron Overload
  • Traditionally, ↑ transferrin sat → repeat fasting trans sat + ferritin
  • Fasting trans sat > 45% identifies 98% of affected patients
diagnosis of iron overload13
Diagnosis of Iron Overload
  • Liver biopsy:
    • histologic eval,
    • hepatic iron concentration (HIC)
      • nl <36 µmol/g
      • >71 suggestive of hemochromatosis
    • hepatic iron index (HII) = HIC/age in years
      • If >1.9 virtually diagnostic of HH.
hereditary hemochromatosis
Hereditary Hemochromatosis
  • Autosomal recessive
  • ↑ intestinal iron absorption
  • Mutation(s) in HFE gene
hfe genotype
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
hfe genotype17
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
prevalence of c282y and h63d mutations in hfe in the us steinberg et al jama may 2001
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 (>12 y/o, not pregnant, trans sat avail, did not list “other” as race/ethnicity)

prevalence of c282y and h63d mutations in hfe in the us steinberg et al jama may 200121
Prevalence of C282Y and H63D Mutations in HFE in the US, Steinberg, et al, JAMA, May 2001.

Results

HFE GenotypePrev. 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)

prevalence of c282y and h63d mutations in hfe in the us steinberg et al jama may 200122
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.

prevalence of c282y and h63d mutations in hfe in the us steinberg et al jama may 200123
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
prevalence of c282y and h63d mutations in hfe in the us steinberg et al jama may 200124
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.
slide26
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
slide27
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 LFT’s
    • Hemochromatic arthropathy
slide28
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
slide29
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

slide30
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

slide31
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
why screen for hemochromatosis
Why Screen for Hemochromatosis?
  • Prevalent disease
  • Long asymptomatic phase
  • Low risk, accessible treatment that prevents long-term sequelae of disease
slide33
Is there a cost-effective screening strategy for relatives of hemochromatosis patients?

What is the role of genetic testing?

slide34
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
slide35
Screening for Hereditary Hemochromatosis in Siblings and Children of Affected Patients, El-Serag, et al, Annals of Int Med, February 2000.
slide36
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
slide37
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

slide38
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.

slide39
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.

slide40
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.

slide41
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.

slide42
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 >1 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

slide43
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

>1 sibling: gene testing proband 1st lower cost

slide44
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.

slide45
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.

slide46
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.

slide47
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
return to case presentation
Return to Case Presentation

49 year old female with family history significant for hemochromatosis in father.

Told in the past, “my iron was high.”

return to case presentation49
Return to Case Presentation

Labs

iron 169 (40-160)

transferrin sat 45% (15-45%)

ferritin 305 (20-200)

LFT’s wnl

return to case presentation50
Return to Case Presentation

Genetic Testing

C282Y: heterozygous

H63D: not present

return to case presentation51
Return to Case Presentation

Patient was referred to GI

Plan: follow serial iron studies, LFT’s.

Liver biopsy not indicated.

Siblings to be screened

with genetic testing.

conclusions
Conclusions

Hemochromatosis is present in approximately 5 per 1000 white Americans

Taking a thorough family history may identify patients at risk for disease

conclusions53
Conclusions

Evidence supports genetic testing for relatives of hemochromatosis patients

More studies are needed on the penetrance of disease and other possible genotypes

thanks to

Thanks to:

Dr. Joel Bruggen

Dr. David Miller

Christine Brandon