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Professional and Patient Perspective
Tsat% and mortality
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Herbert L. Bonkovsky, M.D., Farmington, CT, USA Professor, University of Connecticut Health Center, Richard G. Stevens, Ph.D.
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The two companion papers of Dr. Mainous and colleagues in the March/April 2004 issue of Annals of Family Medicine [1,2] provide additional evidence that an elevation of serum transferrin saturation is associated with a significant increase in all-cause mortality. They also show that persons self reporting a high dietary intake of iron, particularly with high red meat consumption, had a significant increased risk of death from all causes. Of course, it would be useful to know more details about the subjects, particularly those with elevated serum transferrin saturations. In particular, in the NHANES surveys, serum transferrin saturations were measured only once, and they were not necessarily measured in a fasting state or at the same time of day. Both of these are important, because there is a diurnal variation in serum iron concentrations, and recent ingestion of iron-containing foods can increase serum iron concentrations substantially. Indeed, we sometimes measure serum iron levels before and after administration of iron supplements in order to assess whether patients are able to respond normally to such supplements with increased iron absorption from the gastrointestinal tract. Then, too, we have no data about total body iron stores or about HFE gene status in the subjects studied. It is highly likely, however, that patients with one or more mutations in HFE, associated with classical hereditary hemochromatosis, were over represented in the subjects with serum transferrin saturations greater than 55%. As Mainous, et al., point out, heavy iron overload, such as occurs in classical hereditary hemochromatosis (usually due to homozygosity for the C282Y HFE mutation) clearly leads to increased mortality, especially due to hepatic cirrhosis, diabetes mellitus, cardiac disease, and development of hepatocellular carcinoma. An important question is whether increased mortality is restricted to those with only the very highest body iron levels as reflected in transferrin saturations of 80 to 90%. It appears that this is not the case. After excluding from analysis those subjects who died or were diagnosed with cancer within 4 years of blood draw, we reported that cancer risk in the NHANES I cohort was elevated in subjects with baseline transferrin saturation of between 50 and 60% compared to <30% (RR=1.4), as well as in those with transferrin saturation >60% compared to <30% (RR=1.8) [3]. Similarly, Mainous et al. [1] reported that, for all cause mortality in the same cohort, the relative risk for those with baseline transferrin saturation between 55 and 60% was 1.5, and for those with transferrin saturation >60% it was 1.67. Another finding in our original analysis of NHANES I [4], was an inverse association of baseline serum albumin level and cancer risk, which we speculated might be related to the relationship of body iron stores and risk. Others reported an inverse association of serum albumin with all- cause mortality in Britain that rivaled that of smoking and overall mortality (after excluding deaths within 5 years of blood draw). It would be interesting to know whether serum albumin is related to overall mortality in the NHANES cohorts as well. In the second paper by Mainous et al. [2], an interesting interaction of high transferrin saturation with high iron intake is reported; mortality is increased only in those with both. If elevated transferrin saturation is a marker for HFE mutations, these results suggest that the mutations by themselves are not necessarily deleterious, and only become so when high amounts of iron are consumed. An extension of this idea is that HFE mutation carriers may be at increased sensitivity to prooxidant xenobiotic exposures, such as ionizing radiation [5]. The main take home message for family medicine physicians is that measurement of serum iron and iron binding capacity, with calculation of the serum transferrin saturation, might reasonably be added to screening lab tests for all adults. Such testing is best done in the morning after at least an 8-hour fast, to avoid possibly spurious increases. Those found to have increases, if confirmed, should undergo additional evaluation, including measurement of serum ferritin, assessment of liver status, more extensive dietary histories, and HFE mutational analyses. Long term interventional trials of dietary restriction and/or iron reduction by therapeutic phlebotomy would be logical and important extensions of the elegant work of Mainous and colleagues [1,2]. References 1. Mainous, III, AG, Gill, JM, Carek, PJ: Elevated serum transferrin saturation and mortality. Ann Fam Med 2004; 2: 133-138. 2. Mainous, III, AG, Wells, B, Carek, PJ, Gill, JM, Geesey, ME: The mortality risk of elevated serum transferrin saturation and consumption of dietary iron. Ann Fam Med 2004; 2: 139-144 3. Stevens, RG, Graubard, BI, Micozzi, MS, Neriishi, K, Blumberg, BS: Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer. 1994; 56:364-9. 4. Stevens, RG, Jones, DY, Micozzi, MS, Taylor, PR: Body iron stores and the risk of cancer. New Engl J Med. 1998; 319:1047-52. 5. Stevens, RG, Morris, JE, Anderson, LE: Hemochromatosis heterozygotes may constitute a radiation-sensitive subpopulation. Radiat Res. 2000; 153:844-7. Competing interests: None declared |
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Randy S. Alexander, Washington, DC Founder & Chairman, Iron Disorders Institute
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The two articles about transferrin-iron saturation percentage (Tsat%) are rich in data and contain findings that are significant to us at Iron Disorders Institute (IDI). The mortality graph showing a 22-year period is powerful! Penetrance of HFE, the gene for Type I hereditary hemochromatosis has been the subject of heated debate among experts for the past two years. This mortality paper provides us with good evidence that penetrance of HFE should be defined by abnormal clinical findings such as Tsat% rather than end-stage organ disease as it was by Beutler, et al. These findings amplify the importance of putting back the routine Tsat % taken out of lab panels in 1999 an issue that IDI advocates and is working to change. In the high iron participants but not in the normal persons, diabetes was one of the ten leading causes of death. The Iron Disorders Institute has initiated dialogue with the American Diabetes Association to have them consider excess iron as a risk factor for diabetes and to help us educate what is a known fact, that excess iron is an underlying cause for diabetes in many people. Physicians need to be sensitized to the importance of excess iron, noting that 2.3% of the study participants had an elevated Tsat %>55%. Tsat% is not an expensive test when you think of the benefit of early detection. When high iron is detected, it is most important to get the patient deironed promptly and properly, following a safe protocol to avoiding over bleeding. The second paper dealing with Tsat% offers a compelling argument for re-thinking the continued iron fortification of the U.S. food supply and for broad base education programs for physicians and the public about the importance of Iron-Out-of-Balance. Patients can assuredly reduce the frequency of phlebotomy by employing certain diet techniques but nothing removes iron except blood loss. Physicians should not be left with the impression that a patient can forgo phlebotomy by diet modification only.” Randy S. Alexander, Founder & Chairman Iron Disorders Institute and hereditary hemochromatosis C282Y/C282Y patient. Competing interests: None declared |
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Eugene Weinberg, Bloomington, IN Iron Disorders Institute, Scientific Advisory Board
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It has been postulated for several decades that persons with an elevated iron burden have a decreased risk of survival. In a set of 2000 adults in Denmark, carriers of the hemochromatosis gene mutation C282Y were observed to have premature mortality but actual iron values were not available (Bathum, et al) In contrast, in the two excellent studies reported in this journal, serum Tsat% values were obtained for a group of 10,000 US adults (NHANES I Epidemiologic Follow-up Study) The results presented are highly significant and hopefully will prompt modification in the practice of iron adulteration in foods. In the first study in a 22-year span, persons whose Tsat% value was over 55% (2.3% of group) had a 1.6 relative risk (with a narrow 95% CI) of dying as compared with less iron burdened controls. Thus at the end of 22 years, 74% of controls had survived versus 64% of those with elevated iron. In the second report over a 12-year period, intakes of dietary iron and red meat were examined. Persons who had elevated transferrin saturation plus high dietary iron (> 18 mg/day) had an increased all- cause mortality risk (RR 2.90 [95% CI 1.39-6.04]) compared with those with normal transferrin iron saturation and low iron intake. Similarly, elevated transferrin iron saturation plus high red meat consumption (7 times/ week) increased risk of death (RR 2.26 [95% CI 1.45-3.52]). These studies reemphasize the necessity of including transferrin saturation values in routine biochemical profiles of adults of all ages, and not least, of the critical need to lower elevated iron as early as possible. Just as persons are urged to use cholesterol-lowering drugs while their cardiovascular system remains intact, so must persons be urged to lower their iron burden while their overall health remains uncompromised. Eugene Weinberg, Ph.D, Indiana University Iron Disorders Institute Scientific Advisory Board Member, Chair Publications Bathum,. L, Christiansen, L., Nybo, H., Ranberg, K.A., Gaist, D., Jeune, B., Petersen, N.E., Vaupel, J., Christensen, K. “Association of Mutations in the Hemochromatosis Gene with Shorter Life Expectancy.” Archives of Internal Medicine 161 (2001):2441-4. Competing interests: None declared |
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