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1. Screening Strategies for Hemochromatosis

   • Kris V. Kowdley, MD
   • Pradyumna D. Phatak, Herbert L. Bonkovsky

   Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA

   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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   Published September 29, 2008
2. Phenotypic testing before genotype analysis in screening for hemochromatosis

   • Jecko Thachil, MRCP FRCPath

   University of Liverpool
   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

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   Published August 21, 2008