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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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Resident Grand Rounds
December 9, 2003
Father ↓ hemochromatosis, cirrhosis
Mother ↑ COPD, Crohn’s
Daugher ↑ DM
Brother ↑ A&W
Sister ↑ A&W
in a first degree relative,
what testing, if any, is indicated?
2 Iron Overload
Chronic hemolytic anemias
Dietary iron overload
Chronic Liver Disease
Hep C, B
EtOH induced liver dz
Porphyria cutanea tarda
Fatty liver dz
African iron overload
Neonatal iron overload
Congenital atransferrinemiaCauses of Iron Overload
represents iron accumulation in tissues
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)
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)
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.
38% of homozygous male relatives with at least 1 disease-related condition
10% of homozygous female relatives with at least 1 disease-related condition
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
What is the role of genetic testing?
1. No Screening
Assumed 50% would develop organ damage
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.
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.
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.
5. Gene test relatives before proband
Relatives gene tested.
If homozygous → serum iron studies.
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
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
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.
Gene Test Proband
If homozygous → gene test spouse
→ gene test siblings
If spouse heterozygous → gene test children
Iron studies in heterozygotes unnecessary.
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.
Limits of study
49 year old female with family history significant for hemochromatosis in father.
Told in the past, “my iron was high.”
iron 169 (40-160)
transferrin sat 45% (15-45%)
ferritin 305 (20-200)
H63D: not present
Patient was referred to GI
Plan: follow serial iron studies, LFT’s.
Liver biopsy not indicated.
Siblings to be screened
with genetic testing.
Hemochromatosis is present in approximately 5 per 1000 white Americans
Taking a thorough family history may identify patients at risk for disease
Evidence supports genetic testing for relatives of hemochromatosis patients
More studies are needed on the penetrance of disease and other possible genotypes
Dr. Joel Bruggen
Dr. David Miller