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Ideas and Opinions |

Hereditary Hemochromatosis: Time for Targeted Screening

Pradyumna D. Phatak, MD; Herbert L. Bonkovsky, MD; and Kris V. Kowdley, MD
[+] Article and Author Information

From Rochester General Hospital, Rochester, New York; Carolinas Health Care System, Charlotte, North Carolina; and Virginia Mason Medical Center and the University of Washington School of Medicine, Seattle, Washington.


Grant Support: In part by the National Institutes of Health (grants K02957 and RO1-DK-38825).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Kris V. Kowdley, MD, Virginia Mason Medical Center, 1201 9th Avenue, Seattle, WA 98101.

Current Author Addresses: Dr. Phatak: Rochester General Hospital, 1425 Portland Avenue, Rochester, NY 14621.

Dr. Bonkovsky: Carolinas Health Care System, 1000 Blythe Boulevard, Charlotte, NC 28232.

Dr. Kowdley: Virginia Mason Medical Center, 1201 9th Avenue, Seattle, WA 98101.


Ann Intern Med. 2008;149(4):270-272. doi:10.7326/0003-4819-149-4-200808190-00009
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The discovery of the HFE gene in 1996 heralded a decade of major advances in the understanding of the mechanisms that control iron absorption and body iron stores. A genetic definition of the common form of hereditary hemochromatosis became possible, and testing for the common causative HFE mutations is now widely available in clinical laboratories. Several population screening studies have confirmed that disease penetrance in HFE-related hereditary hemochromatosis is lower than previously believed, making universal population-based screening for this disorder unattractive. However, hereditary hemochromatosis may still cause morbidity and mortality because of iron overload. Early detection and use of appropriate therapy can prevent these manifestations and can only be achieved by targeted case finding. In this article, the authors draw attention again to hereditary hemochromatosis as a cause of preventable organ dysfunction and propose targeted case finding for Caucasian men of Northern European ancestry.

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Phenotypic testing before genotype analysis in screening for hemochromatosis
Posted on August 21, 2008
Jecko Thachil
University of Liverpool
Conflict of Interest: None Declared
The perspective article by Phatak et al is timely and should encourage physicians to follow a logical approach in the screening and diagnosis of hemochromatosis [1]. The authors stress on swinging the pendulum towards screening for a condition with significant morbidity and mortality rather than no screening due to the fears of psychological harm and discrimination arising from genotype analysis. However, despite accepting a screening strategy, HFE mutation studies may continue to be the chosen initial test rather than the pragmatic way of phenotypic screening first as suggested in the article. The authors recommend measurement of fasting transferrin saturation and unsaturated iron-binding capacity as the initial test in phenotype screening, but there are merits for checking serum ferritin in these individuals at the same time. This is especially so because of the significant biological variability of transferrin saturation and unsaturated iron-binding capacity demonstrated in a recent study [2]. Including serum ferritin in the screening would help in avoiding genetic testing in individuals with normal ferritin and transferrin saturation, but at the same time identifying those who may have normal transferrin saturation and high serum ferritin, where HFE mutation tests may be appropriate. On the contrary, transferrin saturation should be done in situations where a high serum ferritin is an incidental finding during initiation of blood test for other reasons (an increasingly common hospital practice), which would help in making a decision for proceeding to genotype analysis. In summary, phenotype analysis should be the first step in screening for hemochromatosis but should also include serum ferritin measurements along with transferrin saturation before genetic testing. References 1.Phatak PD, Bonkovsky HL, Kowdley KV.Hereditary hemochromatosis: time for targeted screening.Ann Intern Med. 2008; 149: 270-2 2. Adams PC, Reboussin DM, Press RD, et al.Biological variability of transferring saturation and unsaturated iron-binding capacity. Am J Med. 2007; 120: 999.e1"“.e7. Conflict of Interest:

None declared

Screening Strategies for Hemochromatosis
Posted on September 29, 2008
Kris V. Kowdley
Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA
Conflict of Interest: None Declared

We appreciate the comments regarding the value of serum ferritin as an adjunctive test to serum transferrin-iron saturation in the diagnostic algorithm for hereditary hemochromatosis. We agree that serum ferritin level is the most useful noninvasive measure of body iron stores in patients with hemochromatosis and can help determine the need for therapeutic intervention. A ferritin-only screening approach has been recommended by Waalen et al, using a relatively high serum ferritin threshold value of 1000 µG/L(1). Twenty of 59 patients identified in a primary care clinic using a serum ferritin threshold value of 1000 µg/L during the course of a population screening study were C282Y homozygotes. However, we believe that a threshold serum ferritin level of 1000 µG/L will miss many cases with phenotypic expression and a lower threshold level will increase the likelihood of finding non-specific elevations. The multitude of causes other than iron overload for high serum ferritin levels make this test less valuable when used as part of a targeted screening strategy. Although serum transferrin saturation levels may also demonstrate variability (2) a persistently elevated serum transferrin saturation level as defined in our article remains the best predictive phenotypic test for the homozygous C282Y mutation (3,4). Thus, although serum ferritin may be a useful adjunctive test in screeing strategies and is certainly important to degreeof iron overload and risk of hepatic fibrosis once the diagnosis of HFE-hemochromatosis is confirmed, we remain convinced that serum ferritin is sufficiently nonspecific to be a useful initial screening test for the diagnosis of hemochromatosis.

Reference List

1. Waalen J, Felitti VJ, Gelbart T, et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach.[see comment]. Blood 2008; 111: 3373-76.

2. Adams PC, Reboussin DM, Press RD, et al. Biological variability of transferrin saturation and unsaturated iron-binding capacity. American Journal of Medicine 2007; 120: 999-7.

3. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis.[see comment]. N Engl J Med 2008; 358: 221-30.

4. Asberg A, Hveem K, Thorstensen K, et al. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons.[see comment]. Scandinavian Journal of Gastroenterology 2001; 36: 1108-15.

Conflict of Interest:

None declared

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