Ferrotoxic disease: the next great public health challenge.
Readers maybe challenged by the interpretation of ferritin concentrations reported from this study. Ferritin values in the range of 200 [micro]g/L, which were found to be disadvantageous, are common in practice. Reluctance to assign cause-and-effect relationships, or to test the relationship between ferritin concentrations and outcomes at all, may be based on the assumption that high ferritin values might in some sense be "nonspecific" (perhaps "acute phase") in this context. It might also be thought that high ferritin concentrations occur too commonly and in too many different diseases to be useful in terms of determining diagnosis or prognosis or designing treatment strategies. The seemingly discontinuous association between increased ferritin concentrations and clinical outcomes for commonly observed increases in ferritin vs the larger increases seen with hereditary iron overload may lead to the presumption that iron is the culprit in the hereditary variety but may not be in the common variety.
Ferritin can be produced in apparently unlimited amounts by virtually all cells in response to excess intracellular iron (2) and augmented by inflammatory cytokines primed in a positive feedback manner by iron excess (3). Concentrations of the inflammatory markers interleukin-6 (IL-6)  and high-sensitivity C-reactive protein (hsCRP) are positively associated with ferritin values (4), and reduction of body iron concentrations by phlebotomy results in reduction of both ferritin and IL-6 values (3). Ferritin concentrations are used to diagnose both iron deficiency and excess and to monitor therapeutic iron unloading. Ferritin sequesters and detoxifies excess iron, functions that appear to be optimal up to ferritin concentrations of about 80-100 [micro]g/L (5, 6) but become less efficient as ferritin values rise (7).
Measurement of the percentage of transferrin molecules carrying iron, the % transferrin saturation (%TS), is also used to assess iron status (2). In contrast to ferritin, the amount oftransferrin available for binding iron is limited. Like ferritin, low %TS values reflect depleted iron stores. However, %TS values are a less reliable guide than ferritin for evaluation of increased body iron concentrations (8) or the adequacy of iron unloading (9). Transferrin carries essential iron to cells and also binds and detoxifies noxious redox-active iron (10). Concentrations reflect to a variable extent both transport and redox-active iron. In contrast to ferritin, concentrations of IL-6 and hsCRP are negatively associated with %TS values, indicating an important protective (antioxidant) function of transferrin (3,4). Marked increases of %TS are associated with adverse disease outcome, as as cited by Ellervik et al. (1) However, Stack and colleagues (11) observed that both high %TS values (reflecting increased iron plus redox-active iron) and low %TS values, likely a result of high hepcidin concentrations rather than reduced iron concentrations per se (12), are associated with increased total and cardiovascular mortality. Outcome associations followed a J-shaped pattern, with intermediate levels between about 24%TS and 40%TS associated with lowest mortality (11). Such intermediate %TS levels, representing the "limits of normal," occur commonly in practice (2), likely indicating successful compensation of potentially noxious redox activity.
Iron is essential for virtually all life forms because of its role in biological oxidation and energy production (13, 14). This abundant element is brought into the food chain cautiously, atom by atom, by plant and microbial siderophores and then handed off repeatedly en route to cells. Complex checks and balances, exemplified by ferritin and transferrin, supply essential iron while blocking noxious iron excess. The innate reactivity of iron supports life but only so long as stray atoms are ligand bound to prevent freewheeling oxidative stress. Humans are exposed chronically to nutritional iron excess (15) and no "ferrostat" exists to sense and excrete excesses. Thus, in cells and tissues iron may reach supraphysiologic concentrations that overwhelm protective mechanisms. Basic studies have shown direct links between iron-catalyzed oxidative stress and biochemical and cell biological changes leading to abnormalities characteristic of disease (13, 14). Ferritin may indeed have pathophysiologic roles apart from iron sequestration and transport, but its concentrations remain the most reliable measure of overall body iron burden (2) and damage from iron-catalyzed oxygen free-radical-mediated oxidative stress that leads to diseases of aging (4, 5). Several studies have identified a steep dose effect for outcomes with ferritin concentrations as low as about 70 [micro]g/L to 150 [micro]g/L in neoplastic, metabolic, cardiovascular, and other diseases (5,6,16,17). Correspondingly, the "normal" reference interval for ferritin may be defined as that value associated with minimal disease risk and maximal longevity, with concentrations of about 70 [micro]g/L to 100 [micro]g/L representing the ideal upper limit from this perspective (5, 6, 16).
The findings of Ellervik et al. (1) may indeed reflect cause-and-effect relationships between iron excess represented by ferritin concentrations and disease. Among diseases of concern mentioned in this report are vascular (6), neoplastic (16), and metabolic (17) diseases, for which prospective randomized clinical trials of iron reduction have shown significantly improved outcomes indicating cause-and-effect relationships to iron-catalyzed oxidative stress. Other examples exist, including numerous well-designed cohort studies showing improvement of laboratory measures of disease activity with iron unloading in nonalcoholic fatty liver disease and observational studies showing a mean ferritin concentration of about 220 [micro]g/L in fresh myocardial infarction. Obviously, knowledge of the relationship between concentrations of body iron and disease is far from complete. The term "ferrotoxic disease" has been proposed to describe the range of conditions for which body iron burden is a contributing factor (5, 16). Hereditary hemochromatosis should be considered a subtype of ferrotoxic disease.
Data reported so far suggest that increased ferritin concentrations, representing increased body iron burden, are common and not benign. Concentrations rise imperceptibly with aging, as influenced by hereditary and acquired (especially dietary) factors (15). Alteration of ferritin concentrations, as with blood transfusion or blood loss or ingestion of variable amounts of readily absorbable iron, modify disease risk (6, 15). Thus, iron concentrations can be modified readily and inexpensively by dietary iron restriction (15, 18) or by phlebotomy (6, 16, 17) to alter intermediate measures of disease and improve clinical outcomes. Laboratory testing for iron status, appreciation of the relationship between iron status and disease risk, and availability of inexpensive and nontoxic strategies for reducing risk by iron reduction herald the potential for fruitful clinical research and the prospect of unprecedented improvement in population health.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
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Leo R. Zacharski [1,2] *
 Research Service, Veterans Affairs Medical Center, White River Junction, VT;  Department of Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH.
* Address correspondence to the author at: Research Service (151), Veterans Affairs New England Health Care System, VA Medical Center, White River Jct., VT 05009. Fax 802-296-6308; e-mail firstname.lastname@example.org.
Received August 15, 2014; accepted August 20, 2014.
Previously published online at DOI: 10.1373/clinchem.2014.231266
 Nonstandard abbreviations: IL-6, interleukin-6; hsCRP, high-sensitivity C-reactive protein; %TS, % transferrin saturation.
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|Author:||Zacharski, Leo R.|
|Date:||Nov 1, 2014|
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