- Email: [email protected]
Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World
Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World Daniel J. Raiten, PhD
N
utritional iron deficiency is the leading nutrient deficiency worldwide affecting more than 1 billion people, predominantly women, infants, and young children.1 The consequences of iron deficiency are significant for short- and longterm health, economic growth, and development.2 The question of how to best identify those at risk, as well as how to monitor the success of interventions in patients and populations, is complicated by a number of factors that include a complex biology and homeostatic controls that can compromise the safety and efficacy of interventions to address this global scourge. The complexity of this situation is exemplified by the reciprocal relationships between iron and the inflammatory response under a variety of developmental and health conditions.3-6 Not only does iron play an integral role in the function of the immune system and key elements of the inflammatory response, the converse is also true. This complex interrelationship is graphically manifested in the area of iron assessment as the performance and interpretation of the most common biomarkers used for iron assessment are affected by the presence of inflammation.7 Inflammation can be acute (because of infection) or chronic (because of obesity or a myriad of noncommunicable diseases). In effect, the inflammatory response causes the body to mobilize iron out of the peripheral circulation and reduces its ability to absorb iron from the diet.8 This physiological response then causes changes in the concentrations of biomarkers that reflect changes in iron physiology rather than changes in nutrition. Thus, one might interpret such results as reflecting a nutritional “deficiency” that is in fact a response to an infection and inflammation rather than a decrease in iron consumption. The dilemma this presents is that if someone actually is not nutritionally deficient and receives iron, it may not be safe. The details of this challenge, clinically and programmatically, are the focus of a series of activities that will be summarized.
The Problem Despite years of concerted effort to address it, anemia still accounts for 8.8% of the global burden of disease, measured as disability adjusted life year.9 In the hardest hit regions of Africa and Asia, the prevalence of anemia is 70% among children and about 50% among pregnant and nonpregnant women.10 Although iron deficiency contributes to about 50% of anemia,11 iron deficiency and iron-deficiency anemia (IDA) have and continue to be used interchangeably with anemia.12 Iron supplementation for pregnant women, women of reproductive age, infants, and children has been the predominate mode of delivery recommended by the World Health Organization (WHO).13,14 Recent observations have raised concerns about the safety and effectiveness of not only iron supplements but also all available approaches to prevent and treat iron deficiency/IDA, particularly in the context of pandemic infections such as malaria. These questions have left the global health community in a quandary about not only how to address this problem, but also how to assess and monitor iron status of patients and populations. Although the concerns about the safety of iron in the context of infection are not new,15 the results of a large randomized clinical trial of iron/folic acid supplements for children in Tanzania highlighted the importance of this issue and exacerbated concerns about current approaches to address iron deficiency/IDA programmatically. The results of the study included an increase in morbidity and mortality among infants and children aged 1-35 months who received iron supplements (6 mg/d for infants, 1-11 months and 12.5 mg/d for children, 12-35 months), compared with the US recommended dietary allowance for similar age groups (11 mg/d for infants, 7-12 months and 7 mg/d for children, 1-3 years).16 When the data were subjected to further analysis, it turned out that not all children who received the supplements were adversely affected; adverse outcomes were more predominate in children who did not have any iron deficiency at the time of supplementation.17 These results led to an assessment of existing guidelines and ultimately the release of a joint WHO/ The United Nations Children’s Fund stateBMGF Bill and Melinda Gates Foundation ment revising iron and folic acid BOND CDC IDA INSPIRE NICHD sTfr TWG WHO
Biomarkers of Nutrition for Development Centers for Disease Control and Prevention Iron-deficiency anemia Inflammation and nutrition science for programs/policies and interpretation of research evidence Eunice Kennedy Shriver National Institute of Child Health and Human Development Soluble transferrin receptor Iron and Malaria Technical Working Group World Health Organization
From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD Please see the Author Disclosures at the end of this article. 0022-3476//$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpeds.2015.07.013
S3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
recommendations in malaria endemic regions. The revised guidance recommended the provision of supplements only to “those who are anemic, or at risk of becoming iron deficiency,”18 and, by implication, suggested the need to assess iron status in such settings. Newer evidence suggests that, although concerns still exist about iron safety (from supplements or as a component of multimicronutrient powders),19 with specific regard to morbidity and mortality from malaria, supplementation appears to be appropriate in settings with adequate malaria surveillance and treatment programs. The global iron intervention enterprise was thereby presented with an unsustainable set of challenges: (1) Should we screen for iron deficiency/IDA?; (2) How should we screen?; and (3) What do we do with the results?
The Complexity of Iron Our understanding of iron nutrition, biology, and homeostasis continues to evolve.20,21 This understanding has uncovered potential solutions and as well as new challenges. With regard to the latter, Table I includes a list of some of the priority concerns and questions confronting clinicians and those who develop and implement interventions at population levels. To summarize, at this point we know that iron deficiency and IDA are significant public health concerns. We have learned that the body has an exquisite set of homeostatic controls to both conserve and remove iron from the circulation. A number of potential solutions exist that apply what we know about iron content in food and bioavailability from the diet and account for this complicated system of homeostasis. At this point, however, none of the available solutions are without some concern, particularly in the context of infection such as malaria. Finally, the ability to determine the nature of an iron problem in patients or populations is problematic. Fundamentally, an immediate need exists to answer 3 core questions affecting our approach to iron nutrition in resource-constrained settings with high prevalence of infections such as malaria: (1) In environments where malaria and other infectious diseases are endemic, is the innate immune iron-withholding defense impaired or enhanced by nutritional iron deficiency?; (2) Is a lack of iron in the host detrimental by weakening host immune response, beneficial by further limiting the availability of this essential nutrient to infectious organisms, or both?; and (3) Does providing iron to the host via any of the currently available intervention vehicles have a harmful effect on the host?
The Response The global research community has engaged in a concerted effort to address these issues.22,23 Historically, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health has supported research that addresses various aspects of iron biology including seminal work on the impact of iron S4
Vol. 167, No. 4, Suppl. 1
Table I. Some of the questions, gaps, and challenges involving iron Biology Evolving appreciation of the factors controlling iron homeostasis (eg, the role of hepcidin, particularly from a developmental perspective) Exposure scenarios: oral supplements vs food-based and the role of nontransferrin bound iron Effects of acute vs chronic infection and inflammation on iron homeostasis Role of the microbiome in iron metabolism and vice versa Challenges with the use of anemia prevalence (as reflected by hemoglobin) as proxy for nutritional iron deficiency Biology and potential risks associated with the transition from iron deficiency to adequacy particularly in the context of risk and safety of iron interventions and malaria? Assessment Should anemia/hemoglobin serve an index of iron status or trigger for iron intervention programs? How to assess and address the other determinants of anemia so as to avoid potential of providing iron to those who do not need it. Clarity with regard to the impact of inflammation on selection, use and interpretation of iron biomarkers Markers that reflect iron nutrition as opposed to iron physiology and response to other conditions on iron status (eg, malaria, HIV, NCDs). Interventions What are the appropriate uses for supplements (pills or liquids) for prevention and treatment of iron deficiency? Safe approaches to prevent iron deficiency, including safety and efficacy of food-based interventions, including improved appreciation of contextual and biological factors that might modify safety and efficacy Implementation How to determine risk/benefit to support best practices for addressing iron and health? How to develop evidence-informed guidance that includes an appreciation of all of the above? How to synthesize such guidance at clinical, regional, and country level in a manner that is not confusing and still implementable within the health context of specific countries and health delivery systems? NCD, noncommunicable disease.
on neurological development24,25 and research describing the mechanisms by which iron affects neurodevelopment.26 In specific response to the issues outlined above, the NICHD in collaboration with the Bill and Melinda Gates Foundation (BMGF) have been engaged in a concerted effort to address 3 areas: (1) mechanisms to explain how and why iron might not be safe; (2) biomarkers that can be deployed that will accurately and reliably measure nutritional iron deficiency; and (3) safe and effective interventions to prevent and treat iron deficiency (eg, supplements, food-based solutions). In addition to these core efforts, another critical issue has emerged (ie, the prevalent use of “anemia” as a trigger for programs to address iron deficiency/IDA). There are two problems with this approach: (1) only about 50% of anemia is actually caused by nutritional iron deficiency; and (2) the primary marker of anemia is hemoglobin. The problem with hemoglobin in this context is that changes in hemoglobin concentrations are not specific to nutritional iron deficiency and, like many other biomarkers of iron, hemoglobin concentrations are susceptible to the influence of inflammation.8 Therefore, if we are using hemoglobin to assess nutritional iron, we are potentially over diagnosing the problem, and, if hemoglobin is used as the “trigger” for Raiten
SUPPLEMENT
October 2015 supplementation programs, we are potentially putting people at risk because we are giving iron to people who do not need it. Under the collaboration with the BMGF, this agenda has been organized into two tracks: (1) research; and (2) translation of evidence to help inform programs/policies. The following is a brief summary of these activities. Translation The Iron and Malaria Technical Report, developed under the leadership of the Iron and Malaria Technical Working Group (TWG) in 2009,27 is currently being updated with relevant data generated since 2009. The report was intended to inform technical agencies including the Centers for Disease Control and Prevention (CDC) and WHO about the current state of understanding of mechanisms, biomarkers, and interventions to address iron deficiency/IDA in areas of endemic malaria. Consultation involved working with global stakeholders through entities such as the Micronutrient Forum to consult with the food and nutrition community about the implications of the current science and guidance to regional and country health systems’ efforts to address iron deficiency/ IDA. Also, working with the International Union of Nutrition Science Task Force on Iron to conduct a risk:benefit analysis will allow a better process for making decisions about how best to address iron deficiency in programs to address both survival and long-term development. Inflammation and nutrition science for programs/policies and interpretation of research evidence (INSPIRE) project, based on the extant literature and the feedback from the stakeholder community, made it clear that a concerted effort was needed to summarize our current understanding and move toward solutions to address the interrelationships among nutrition, and immune and inflammatory response. The INSPIRE project had the following objectives: (1) review what we know about the interaction and impact of inflammation (from infection or other causes) on selection, use and interpretation of biomarkers specifically and nutrition more broadly to discuss basic biology to explain the role of nutrients in inflammation from a biological systems perspective and explore the bi-directional nature of the nutrition/ inflammation interaction (ie, the impact of nutrition on inflammation and the impact of inflammation on nutrition); (2) explore strategies to account for the nutrition/inflammation interaction; (3) explore new tools and technologies that might be used for biomarker development, monitoring, and evaluation of interventions; (4) develop a targeted research agenda via the TWG deliberations; and (5) develop a project summary for broad dissemination. A full report of the INSPIRE project has been published in the Journal of Nutrition.8 Table II provides a brief summary of key findings with regard to biomarker interpretation in the context of inflammation. Again in collaboration with BMGF and other partners, NICHD created the Biomarkers of Nutrition for Development (BOND) project as a vehicle to determine what bio-
Table II. Inflammation and biomarkers: key findings from the INSPIRE project Routine assessment of inflammatory status is advised to appropriately interpret the micronutrient status of both patients and populations. Prior to deciding on approaches to account for inflammation, issues related to biomarker assessment must be addressed, such as the need for high quality methods used to collect, store, transport, and analyze the specimens. The quality of key markers of inflammation (eg, CRP and AGP) measurements was emphasized. Some surveys measure either CRP or AGP, and some collect both. Consequently, strategies are needed for how to deal with each of the three scenarios for interpreting data from existing surveys. If resources are available, measuring both CRP and AGP is preferred. The relative merits of different approaches to account for inflammation were explored in the context of different scenarios. Possible options included: B Ignore inflammation B Exclusion of the sample with elevated biomarkers of inflammation B Change cut-off values B Standardization (to calculate the prevalence of micronutrient deficiency in those with and without inflammation, then calculate a weighted prevalence estimate using a “standard” prevalence estimate of inflammation) B Correction factor approach B Statistical options/regression modeling AGP, alpha-1-acid glycoprotein; CRP, C-reactive protein.
markers are best suited for the range of uses represented by the global health community from bench scientists, to clinicians, program and policy.28 With the use of expert panels to develop evidence-informed advice about what are the most suitable biomarkers of exposure, status, function, and effect (impact of a given status or intervention), the BOND project has created a web-based resource to provide this advice to the global community. The initial phase of BOND involved 6 nutrients: iodine, zinc, vitamin A, folate, vitamin B12, and iron. The reviews generated are being published as a series of papers in the Journal of Nutrition beginning with iodine.29 The material from the reviews is also being used to create an interactive web-based service to provide advice to users.30 Research Ten studies have been funded under the aegis of the TWG collaboration with BMGF that range from basic laboratory projects to investigate various possible mechanisms that explain potential adverse effects of iron in the context of malaria to clinical trials that address the safety of iron interventions in children and pregnant women in low resource malaria endemic settings.31-40 Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia Project resulted in collaborations with the CDC and the Global Alliance for Improved Nutrition to use national data from 18 countries to address the influence of inflammation on iron biomarkers and other determinants of anemia. In light of the current view of the potential value of specific biomarkers of iron status, particularly in the context of inflammation including the recommendations of the TWG with regard to the utility of the ratio of soluble transferrin receptor (sTfr) standards to serum ferritin,27 the NICHD
Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World
S5
THE JOURNAL OF PEDIATRICS
www.jpeds.com
has collaborated with the CDC to improve the comparability of sTfr assays. The utility of sTfr demands a comparability of the various assays, which necessitates the development of standard materials. This collaboration is addressing that need.
Conclusions Our ability to make decisions about the safe and efficacious use of iron across a range of potential uses from infant formulas to programs to address national needs to prevent iron deficiency, demands: (1) a full appreciation of iron biology; (2) an appreciation of the current health context, including the collision of infection and noncommunicable disease, all mediated in some manner by the inflammatory response, and all superimposed on conditions of over- and undernutrition; and (3) a clear understanding of the relative benefits of nutritional iron adequacy for human health and development balanced against the potential risks of providing iron under circumscribed circumstances. Many questions remain that impact our ability to define the research agenda, clinical management, and programmatic response to iron deficiency/IDA. These complex relationships should not be viewed in isolation, as they are in many respects not unique to iron. Instead, they can be applied to improve our understanding of the role of nutrition in all aspects of health promotion and disease prevention. Our ability to more fully integrate nutrition as a biological construct into all levels of the health system will demand a similar approach. n
Author Disclosures D.R. received support for the projects described in this article by Bill and Melinda Gates Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Division of Nutrition Research Coordination, and the Office of Dietary Supplements. We would like to acknowledge the partnership of the US Centers for Disease Control and Prevention, Department of Nutrition for Health and Development at the WHO, the Global Alliance for Improved Nutrition, and the numerous scientists and collaborators who have helped with these projects. We also wish to acknowledge the assistance of Alexandra Porter in the preparation of this manuscript. Alexandra Porter declares no conflicts of interest or industry relationships. Reprint requests: Daniel J. Raiten, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd-Rm 4B-11, Bethesda, MD 20892. E-mail: [email protected].
References 1. World Health Organization. Nutrition: iron deficiency anemia 2014. http://www.who.int/nutrition/topics/ida/en/. Accessed June 10, 2015. 2. Prado EL, Dewey KG. Nutrition and brain development in early life. Nutr Rev 2014;72:267-84. S6
Vol. 167, No. 4, Suppl. 1 3. Burke RM, Leon JS, Suchdev PS. Identification, prevention and treatment of iron deficiency during the first 1000 days. Nutrients 2014;6: 4093-114. 4. Rawat R, Stoltzfus RJ, Ntozini R, Mutasa K, Iliff PJ, Humphrey JH. Influence of inflammation as measured by alpha-1-acid glycoprotein on iron status indicators among HIV-positive postpartum Zimbabwean women. Eur J Clin Nutr 2009;63:787-93. 5. Shanmugam NK, Trebicka E, Fu LL, Shi HN, Cherayil BJ. Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota. J Immunol 2014;193:1398-407. 6. Gartner A, Berger J, Bour A, El Ati J, Traissac P, Landais E, et al. Assessment of iron deficiency in the context of the obesity epidemic: importance of correcting serum ferritin concentrations for inflammation. Am J Clin Nutr 2013;98:821-6. 7. Ayoya MA, Spiekermann-Brouwer GM, Stoltzfus RJ, Nemeth E, Habicht JP, Ganz T, et al. Alpha 1-acid glycoprotein, hepcidin, C-reactive protein, and serum ferritin are correlated in anemic schoolchildren with Schistosoma haematobium. Am J Clin Nutr 2010;91:1784-90. 8. Raiten DJ, Ashour FA, Ross AC, Meydani SN, Dawson HD, Stephensen CB, et al. Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE). J Nutr 2015;145:1039S-108S. 9. Kasssebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615-24. 10. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. Lancet Glob Health 2013;1: e16-25. 11. World Health Organization. Worldwide prevalence of anaemia 19932005: WHO global database on anaemia. Geneva: World Health Organization; 2008, http://www.who.int/vmnis/publications/anaemia_ prevalence/en/. Accessed June 10, 2015. 12. World Health Organization. Iron deficiency anaemia: Assessment, prevention and control. A guide for programme managers. Geneva, Switzerland: World Health Organization; 2001. WHO/NHD/01.3, http://whqlibdoc.who.int/hq/2001/WHO_NHD_01.3.pdf. Accessed June 10, 2015. 13. World Health Organization. Guideline: Intermittent iron supplementation in preschool and school-age children. Geneva: World Health Organization; 2011, http://www.who.int/nutrition/publications/micro nutrients/guidelines/guideline_iron_supplementation_children/en/. Accessed June 10, 2015. 14. World Health Organization. Guideline: Daily iron and folic acid supplementation in pregnant women. Geneva: World Health Organization; 2012, http://www.who.int/nutrition/publications/micronutrients/ guidelines/daily_ifa_supp_pregnant_women/en/. Accessed June 10, 2015. 15. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr 2001;131:616S-33S. 16. Institute of Medicine Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001. 17. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006;367:133-43. 18. World Health Organization. Iron supplementation of young children in regions where malaria transmission is intense and infectious disease highly prevalent 2006. http://www.who.int/malaria/publications/atoz/ who_statement_iron/en/. Accessed June 10, 2015. 19. Soofi S, Cousens S, Iqbal SP, Akhund T, Khan J, Ahmed I, et al. Effect of provision of daily zinc and iron with several micronutrients on growth
Raiten
SUPPLEMENT
October 2015
20.
21.
22.
23.
24. 25. 26. 27.
28.
29.
30.
and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet 2013;382:29-40. Buratti P, Gammella E, Rybinska I, Cairo G, Recalcati S. Recent advances in iron metabolism: relevance for health, exercise, and performance. Med Sci Sports Exerc 2015;47:1596-604. Gulec S, Anderson GJ, Collins JF. Mechanistic and regulatory aspects of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 2014; 307:G397-409. Pasricha SR, Drakesmith H, Black J, Hipgrave D, Biggs BA. Control of iron deficiency anemia in low- and middle-income countries. Blood 2013;121:2607-17. Schumann K, Solomons NW. Can iron supplementation be reconciled with benefits and risks in areas hyperendemic for malaria? Food Nutr Bull 2013;34:349-56. Lozoff B. Iron deficiency and child development. Food Nutr Bull 2007; 28:S560-71. Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr 2011;141:740S-6S. Georgieff MK. Long-term brain and behavioral consequences of early iron deficiency. Nutr Rev 2011;69(Suppl 1):S43-8. Raiten DJ, Namaste S, Brabin B. Considerations for the safe and effective use of iron interventions in areas of malaria burden—executive summary. Int J Vitam Nutr Res 2011;81:57-71. Raiten DJ, Namaste S, Brabin B, Combs G Jr, L’Abbe MR, Wasantwisut E, et al. Executive summary—biomarkers of nutrition for development: building a consensus. Am J Clin Nutr 2011;94: 633S-50S. Rohner F, Zimmermann M, Jooste P, Pandav C, Caldwell K, Raghavan R, et al. Biomarkers of nutrition for development—iodine review. J Nutr 2014;144:1322S-42S. Biomarkers of Nutrition for Development (BOND) Program. http:// www.nichd.nih.gov/global_nutrition/programs/bond/Pages/index.aspx. Accessed June 10, 2015.
31. Frosch AE, Ondigo BN, Ayodo GA, Vulule JM, John CC, Cusick SE. Decline in childhood iron deficiency after interruption of malaria transmission in highland Kenya. Am J Clin Nutr 2014;100:968-73. 32. Brittenham GM, Andersson M, Egli I, Foman JT, Zeder C, Westerman ME, et al. Circulating non-transferrin-bound iron after oral administration of supplemental and fortification doses of iron to healthy women: a randomized study. Am J Clin Nutr 2014;100:813-20. 33. Dostal A, Chassard C, Hilty FM, Zimmermann MB, Jaeggi T, Rossi S, et al. Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J Nutr 2012;142:271-7. 34. Jaeggi T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 2015;64:731-42. 35. Hurrell R. Iron and malaria: absorption, efficacy and safety. Int J Vitam Nutr Res 2010;80:279-92. 36. Zlotkin S, Newton S, Aimone AM, Azindow I, Amenga-Etego S, Tchum K, et al. Effect of iron fortification on malaria incidence in infants and young children in Ghana: a randomized trial. JAMA 2013;310:938-47. 37. Hubbard AC, Bandyopadhyay S, Wojczyk BS, Spitalnik SL, Hod EA, Prestia KA. Effect of dietary iron on fetal growth in pregnant mice. Comp Med 2013;63:127-35. 38. Ferrer P, Tripathi AK, Clark MA, Hand CC, Rienhoff HY Jr, Sullivan DJ Jr. Antimalarial iron chelator, FBS0701, shows asexual and gametocyte Plasmodium falciparum activity and single oral dose cure in a murine malaria model. PLoS One 2012;7:e37171. 39. van Santen S, de Mast Q, Swinkels DW, van der Ven AJ. Hepcidin in malaria superinfection: can findings be translated to humans? Nat Med 2011;17:1341. 40. Portugal S, Carret C, Recker M, Armitage AE, Gonc¸alves LA, Epiphanio S, et al. Host-mediated regulation of superinfection in malaria. Nat Med 2011;17:732-7.
Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World
S7
N
utritional iron deficiency is the leading nutrient deficiency worldwide affecting more than 1 billion people, predominantly women, infants, and young children.1 The consequences of iron deficiency are significant for short- and longterm health, economic growth, and development.2 The question of how to best identify those at risk, as well as how to monitor the success of interventions in patients and populations, is complicated by a number of factors that include a complex biology and homeostatic controls that can compromise the safety and efficacy of interventions to address this global scourge. The complexity of this situation is exemplified by the reciprocal relationships between iron and the inflammatory response under a variety of developmental and health conditions.3-6 Not only does iron play an integral role in the function of the immune system and key elements of the inflammatory response, the converse is also true. This complex interrelationship is graphically manifested in the area of iron assessment as the performance and interpretation of the most common biomarkers used for iron assessment are affected by the presence of inflammation.7 Inflammation can be acute (because of infection) or chronic (because of obesity or a myriad of noncommunicable diseases). In effect, the inflammatory response causes the body to mobilize iron out of the peripheral circulation and reduces its ability to absorb iron from the diet.8 This physiological response then causes changes in the concentrations of biomarkers that reflect changes in iron physiology rather than changes in nutrition. Thus, one might interpret such results as reflecting a nutritional “deficiency” that is in fact a response to an infection and inflammation rather than a decrease in iron consumption. The dilemma this presents is that if someone actually is not nutritionally deficient and receives iron, it may not be safe. The details of this challenge, clinically and programmatically, are the focus of a series of activities that will be summarized.
The Problem Despite years of concerted effort to address it, anemia still accounts for 8.8% of the global burden of disease, measured as disability adjusted life year.9 In the hardest hit regions of Africa and Asia, the prevalence of anemia is 70% among children and about 50% among pregnant and nonpregnant women.10 Although iron deficiency contributes to about 50% of anemia,11 iron deficiency and iron-deficiency anemia (IDA) have and continue to be used interchangeably with anemia.12 Iron supplementation for pregnant women, women of reproductive age, infants, and children has been the predominate mode of delivery recommended by the World Health Organization (WHO).13,14 Recent observations have raised concerns about the safety and effectiveness of not only iron supplements but also all available approaches to prevent and treat iron deficiency/IDA, particularly in the context of pandemic infections such as malaria. These questions have left the global health community in a quandary about not only how to address this problem, but also how to assess and monitor iron status of patients and populations. Although the concerns about the safety of iron in the context of infection are not new,15 the results of a large randomized clinical trial of iron/folic acid supplements for children in Tanzania highlighted the importance of this issue and exacerbated concerns about current approaches to address iron deficiency/IDA programmatically. The results of the study included an increase in morbidity and mortality among infants and children aged 1-35 months who received iron supplements (6 mg/d for infants, 1-11 months and 12.5 mg/d for children, 12-35 months), compared with the US recommended dietary allowance for similar age groups (11 mg/d for infants, 7-12 months and 7 mg/d for children, 1-3 years).16 When the data were subjected to further analysis, it turned out that not all children who received the supplements were adversely affected; adverse outcomes were more predominate in children who did not have any iron deficiency at the time of supplementation.17 These results led to an assessment of existing guidelines and ultimately the release of a joint WHO/ The United Nations Children’s Fund stateBMGF Bill and Melinda Gates Foundation ment revising iron and folic acid BOND CDC IDA INSPIRE NICHD sTfr TWG WHO
Biomarkers of Nutrition for Development Centers for Disease Control and Prevention Iron-deficiency anemia Inflammation and nutrition science for programs/policies and interpretation of research evidence Eunice Kennedy Shriver National Institute of Child Health and Human Development Soluble transferrin receptor Iron and Malaria Technical Working Group World Health Organization
From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD Please see the Author Disclosures at the end of this article. 0022-3476//$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpeds.2015.07.013
S3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
recommendations in malaria endemic regions. The revised guidance recommended the provision of supplements only to “those who are anemic, or at risk of becoming iron deficiency,”18 and, by implication, suggested the need to assess iron status in such settings. Newer evidence suggests that, although concerns still exist about iron safety (from supplements or as a component of multimicronutrient powders),19 with specific regard to morbidity and mortality from malaria, supplementation appears to be appropriate in settings with adequate malaria surveillance and treatment programs. The global iron intervention enterprise was thereby presented with an unsustainable set of challenges: (1) Should we screen for iron deficiency/IDA?; (2) How should we screen?; and (3) What do we do with the results?
The Complexity of Iron Our understanding of iron nutrition, biology, and homeostasis continues to evolve.20,21 This understanding has uncovered potential solutions and as well as new challenges. With regard to the latter, Table I includes a list of some of the priority concerns and questions confronting clinicians and those who develop and implement interventions at population levels. To summarize, at this point we know that iron deficiency and IDA are significant public health concerns. We have learned that the body has an exquisite set of homeostatic controls to both conserve and remove iron from the circulation. A number of potential solutions exist that apply what we know about iron content in food and bioavailability from the diet and account for this complicated system of homeostasis. At this point, however, none of the available solutions are without some concern, particularly in the context of infection such as malaria. Finally, the ability to determine the nature of an iron problem in patients or populations is problematic. Fundamentally, an immediate need exists to answer 3 core questions affecting our approach to iron nutrition in resource-constrained settings with high prevalence of infections such as malaria: (1) In environments where malaria and other infectious diseases are endemic, is the innate immune iron-withholding defense impaired or enhanced by nutritional iron deficiency?; (2) Is a lack of iron in the host detrimental by weakening host immune response, beneficial by further limiting the availability of this essential nutrient to infectious organisms, or both?; and (3) Does providing iron to the host via any of the currently available intervention vehicles have a harmful effect on the host?
The Response The global research community has engaged in a concerted effort to address these issues.22,23 Historically, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health has supported research that addresses various aspects of iron biology including seminal work on the impact of iron S4
Vol. 167, No. 4, Suppl. 1
Table I. Some of the questions, gaps, and challenges involving iron Biology Evolving appreciation of the factors controlling iron homeostasis (eg, the role of hepcidin, particularly from a developmental perspective) Exposure scenarios: oral supplements vs food-based and the role of nontransferrin bound iron Effects of acute vs chronic infection and inflammation on iron homeostasis Role of the microbiome in iron metabolism and vice versa Challenges with the use of anemia prevalence (as reflected by hemoglobin) as proxy for nutritional iron deficiency Biology and potential risks associated with the transition from iron deficiency to adequacy particularly in the context of risk and safety of iron interventions and malaria? Assessment Should anemia/hemoglobin serve an index of iron status or trigger for iron intervention programs? How to assess and address the other determinants of anemia so as to avoid potential of providing iron to those who do not need it. Clarity with regard to the impact of inflammation on selection, use and interpretation of iron biomarkers Markers that reflect iron nutrition as opposed to iron physiology and response to other conditions on iron status (eg, malaria, HIV, NCDs). Interventions What are the appropriate uses for supplements (pills or liquids) for prevention and treatment of iron deficiency? Safe approaches to prevent iron deficiency, including safety and efficacy of food-based interventions, including improved appreciation of contextual and biological factors that might modify safety and efficacy Implementation How to determine risk/benefit to support best practices for addressing iron and health? How to develop evidence-informed guidance that includes an appreciation of all of the above? How to synthesize such guidance at clinical, regional, and country level in a manner that is not confusing and still implementable within the health context of specific countries and health delivery systems? NCD, noncommunicable disease.
on neurological development24,25 and research describing the mechanisms by which iron affects neurodevelopment.26 In specific response to the issues outlined above, the NICHD in collaboration with the Bill and Melinda Gates Foundation (BMGF) have been engaged in a concerted effort to address 3 areas: (1) mechanisms to explain how and why iron might not be safe; (2) biomarkers that can be deployed that will accurately and reliably measure nutritional iron deficiency; and (3) safe and effective interventions to prevent and treat iron deficiency (eg, supplements, food-based solutions). In addition to these core efforts, another critical issue has emerged (ie, the prevalent use of “anemia” as a trigger for programs to address iron deficiency/IDA). There are two problems with this approach: (1) only about 50% of anemia is actually caused by nutritional iron deficiency; and (2) the primary marker of anemia is hemoglobin. The problem with hemoglobin in this context is that changes in hemoglobin concentrations are not specific to nutritional iron deficiency and, like many other biomarkers of iron, hemoglobin concentrations are susceptible to the influence of inflammation.8 Therefore, if we are using hemoglobin to assess nutritional iron, we are potentially over diagnosing the problem, and, if hemoglobin is used as the “trigger” for Raiten
SUPPLEMENT
October 2015 supplementation programs, we are potentially putting people at risk because we are giving iron to people who do not need it. Under the collaboration with the BMGF, this agenda has been organized into two tracks: (1) research; and (2) translation of evidence to help inform programs/policies. The following is a brief summary of these activities. Translation The Iron and Malaria Technical Report, developed under the leadership of the Iron and Malaria Technical Working Group (TWG) in 2009,27 is currently being updated with relevant data generated since 2009. The report was intended to inform technical agencies including the Centers for Disease Control and Prevention (CDC) and WHO about the current state of understanding of mechanisms, biomarkers, and interventions to address iron deficiency/IDA in areas of endemic malaria. Consultation involved working with global stakeholders through entities such as the Micronutrient Forum to consult with the food and nutrition community about the implications of the current science and guidance to regional and country health systems’ efforts to address iron deficiency/ IDA. Also, working with the International Union of Nutrition Science Task Force on Iron to conduct a risk:benefit analysis will allow a better process for making decisions about how best to address iron deficiency in programs to address both survival and long-term development. Inflammation and nutrition science for programs/policies and interpretation of research evidence (INSPIRE) project, based on the extant literature and the feedback from the stakeholder community, made it clear that a concerted effort was needed to summarize our current understanding and move toward solutions to address the interrelationships among nutrition, and immune and inflammatory response. The INSPIRE project had the following objectives: (1) review what we know about the interaction and impact of inflammation (from infection or other causes) on selection, use and interpretation of biomarkers specifically and nutrition more broadly to discuss basic biology to explain the role of nutrients in inflammation from a biological systems perspective and explore the bi-directional nature of the nutrition/ inflammation interaction (ie, the impact of nutrition on inflammation and the impact of inflammation on nutrition); (2) explore strategies to account for the nutrition/inflammation interaction; (3) explore new tools and technologies that might be used for biomarker development, monitoring, and evaluation of interventions; (4) develop a targeted research agenda via the TWG deliberations; and (5) develop a project summary for broad dissemination. A full report of the INSPIRE project has been published in the Journal of Nutrition.8 Table II provides a brief summary of key findings with regard to biomarker interpretation in the context of inflammation. Again in collaboration with BMGF and other partners, NICHD created the Biomarkers of Nutrition for Development (BOND) project as a vehicle to determine what bio-
Table II. Inflammation and biomarkers: key findings from the INSPIRE project Routine assessment of inflammatory status is advised to appropriately interpret the micronutrient status of both patients and populations. Prior to deciding on approaches to account for inflammation, issues related to biomarker assessment must be addressed, such as the need for high quality methods used to collect, store, transport, and analyze the specimens. The quality of key markers of inflammation (eg, CRP and AGP) measurements was emphasized. Some surveys measure either CRP or AGP, and some collect both. Consequently, strategies are needed for how to deal with each of the three scenarios for interpreting data from existing surveys. If resources are available, measuring both CRP and AGP is preferred. The relative merits of different approaches to account for inflammation were explored in the context of different scenarios. Possible options included: B Ignore inflammation B Exclusion of the sample with elevated biomarkers of inflammation B Change cut-off values B Standardization (to calculate the prevalence of micronutrient deficiency in those with and without inflammation, then calculate a weighted prevalence estimate using a “standard” prevalence estimate of inflammation) B Correction factor approach B Statistical options/regression modeling AGP, alpha-1-acid glycoprotein; CRP, C-reactive protein.
markers are best suited for the range of uses represented by the global health community from bench scientists, to clinicians, program and policy.28 With the use of expert panels to develop evidence-informed advice about what are the most suitable biomarkers of exposure, status, function, and effect (impact of a given status or intervention), the BOND project has created a web-based resource to provide this advice to the global community. The initial phase of BOND involved 6 nutrients: iodine, zinc, vitamin A, folate, vitamin B12, and iron. The reviews generated are being published as a series of papers in the Journal of Nutrition beginning with iodine.29 The material from the reviews is also being used to create an interactive web-based service to provide advice to users.30 Research Ten studies have been funded under the aegis of the TWG collaboration with BMGF that range from basic laboratory projects to investigate various possible mechanisms that explain potential adverse effects of iron in the context of malaria to clinical trials that address the safety of iron interventions in children and pregnant women in low resource malaria endemic settings.31-40 Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia Project resulted in collaborations with the CDC and the Global Alliance for Improved Nutrition to use national data from 18 countries to address the influence of inflammation on iron biomarkers and other determinants of anemia. In light of the current view of the potential value of specific biomarkers of iron status, particularly in the context of inflammation including the recommendations of the TWG with regard to the utility of the ratio of soluble transferrin receptor (sTfr) standards to serum ferritin,27 the NICHD
Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World
S5
THE JOURNAL OF PEDIATRICS
www.jpeds.com
has collaborated with the CDC to improve the comparability of sTfr assays. The utility of sTfr demands a comparability of the various assays, which necessitates the development of standard materials. This collaboration is addressing that need.
Conclusions Our ability to make decisions about the safe and efficacious use of iron across a range of potential uses from infant formulas to programs to address national needs to prevent iron deficiency, demands: (1) a full appreciation of iron biology; (2) an appreciation of the current health context, including the collision of infection and noncommunicable disease, all mediated in some manner by the inflammatory response, and all superimposed on conditions of over- and undernutrition; and (3) a clear understanding of the relative benefits of nutritional iron adequacy for human health and development balanced against the potential risks of providing iron under circumscribed circumstances. Many questions remain that impact our ability to define the research agenda, clinical management, and programmatic response to iron deficiency/IDA. These complex relationships should not be viewed in isolation, as they are in many respects not unique to iron. Instead, they can be applied to improve our understanding of the role of nutrition in all aspects of health promotion and disease prevention. Our ability to more fully integrate nutrition as a biological construct into all levels of the health system will demand a similar approach. n
Author Disclosures D.R. received support for the projects described in this article by Bill and Melinda Gates Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Division of Nutrition Research Coordination, and the Office of Dietary Supplements. We would like to acknowledge the partnership of the US Centers for Disease Control and Prevention, Department of Nutrition for Health and Development at the WHO, the Global Alliance for Improved Nutrition, and the numerous scientists and collaborators who have helped with these projects. We also wish to acknowledge the assistance of Alexandra Porter in the preparation of this manuscript. Alexandra Porter declares no conflicts of interest or industry relationships. Reprint requests: Daniel J. Raiten, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd-Rm 4B-11, Bethesda, MD 20892. E-mail: [email protected].
References 1. World Health Organization. Nutrition: iron deficiency anemia 2014. http://www.who.int/nutrition/topics/ida/en/. Accessed June 10, 2015. 2. Prado EL, Dewey KG. Nutrition and brain development in early life. Nutr Rev 2014;72:267-84. S6
Vol. 167, No. 4, Suppl. 1 3. Burke RM, Leon JS, Suchdev PS. Identification, prevention and treatment of iron deficiency during the first 1000 days. Nutrients 2014;6: 4093-114. 4. Rawat R, Stoltzfus RJ, Ntozini R, Mutasa K, Iliff PJ, Humphrey JH. Influence of inflammation as measured by alpha-1-acid glycoprotein on iron status indicators among HIV-positive postpartum Zimbabwean women. Eur J Clin Nutr 2009;63:787-93. 5. Shanmugam NK, Trebicka E, Fu LL, Shi HN, Cherayil BJ. Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota. J Immunol 2014;193:1398-407. 6. Gartner A, Berger J, Bour A, El Ati J, Traissac P, Landais E, et al. Assessment of iron deficiency in the context of the obesity epidemic: importance of correcting serum ferritin concentrations for inflammation. Am J Clin Nutr 2013;98:821-6. 7. Ayoya MA, Spiekermann-Brouwer GM, Stoltzfus RJ, Nemeth E, Habicht JP, Ganz T, et al. Alpha 1-acid glycoprotein, hepcidin, C-reactive protein, and serum ferritin are correlated in anemic schoolchildren with Schistosoma haematobium. Am J Clin Nutr 2010;91:1784-90. 8. Raiten DJ, Ashour FA, Ross AC, Meydani SN, Dawson HD, Stephensen CB, et al. Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE). J Nutr 2015;145:1039S-108S. 9. Kasssebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615-24. 10. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. Lancet Glob Health 2013;1: e16-25. 11. World Health Organization. Worldwide prevalence of anaemia 19932005: WHO global database on anaemia. Geneva: World Health Organization; 2008, http://www.who.int/vmnis/publications/anaemia_ prevalence/en/. Accessed June 10, 2015. 12. World Health Organization. Iron deficiency anaemia: Assessment, prevention and control. A guide for programme managers. Geneva, Switzerland: World Health Organization; 2001. WHO/NHD/01.3, http://whqlibdoc.who.int/hq/2001/WHO_NHD_01.3.pdf. Accessed June 10, 2015. 13. World Health Organization. Guideline: Intermittent iron supplementation in preschool and school-age children. Geneva: World Health Organization; 2011, http://www.who.int/nutrition/publications/micro nutrients/guidelines/guideline_iron_supplementation_children/en/. Accessed June 10, 2015. 14. World Health Organization. Guideline: Daily iron and folic acid supplementation in pregnant women. Geneva: World Health Organization; 2012, http://www.who.int/nutrition/publications/micronutrients/ guidelines/daily_ifa_supp_pregnant_women/en/. Accessed June 10, 2015. 15. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr 2001;131:616S-33S. 16. Institute of Medicine Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001. 17. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006;367:133-43. 18. World Health Organization. Iron supplementation of young children in regions where malaria transmission is intense and infectious disease highly prevalent 2006. http://www.who.int/malaria/publications/atoz/ who_statement_iron/en/. Accessed June 10, 2015. 19. Soofi S, Cousens S, Iqbal SP, Akhund T, Khan J, Ahmed I, et al. Effect of provision of daily zinc and iron with several micronutrients on growth
Raiten
SUPPLEMENT
October 2015
20.
21.
22.
23.
24. 25. 26. 27.
28.
29.
30.
and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet 2013;382:29-40. Buratti P, Gammella E, Rybinska I, Cairo G, Recalcati S. Recent advances in iron metabolism: relevance for health, exercise, and performance. Med Sci Sports Exerc 2015;47:1596-604. Gulec S, Anderson GJ, Collins JF. Mechanistic and regulatory aspects of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 2014; 307:G397-409. Pasricha SR, Drakesmith H, Black J, Hipgrave D, Biggs BA. Control of iron deficiency anemia in low- and middle-income countries. Blood 2013;121:2607-17. Schumann K, Solomons NW. Can iron supplementation be reconciled with benefits and risks in areas hyperendemic for malaria? Food Nutr Bull 2013;34:349-56. Lozoff B. Iron deficiency and child development. Food Nutr Bull 2007; 28:S560-71. Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr 2011;141:740S-6S. Georgieff MK. Long-term brain and behavioral consequences of early iron deficiency. Nutr Rev 2011;69(Suppl 1):S43-8. Raiten DJ, Namaste S, Brabin B. Considerations for the safe and effective use of iron interventions in areas of malaria burden—executive summary. Int J Vitam Nutr Res 2011;81:57-71. Raiten DJ, Namaste S, Brabin B, Combs G Jr, L’Abbe MR, Wasantwisut E, et al. Executive summary—biomarkers of nutrition for development: building a consensus. Am J Clin Nutr 2011;94: 633S-50S. Rohner F, Zimmermann M, Jooste P, Pandav C, Caldwell K, Raghavan R, et al. Biomarkers of nutrition for development—iodine review. J Nutr 2014;144:1322S-42S. Biomarkers of Nutrition for Development (BOND) Program. http:// www.nichd.nih.gov/global_nutrition/programs/bond/Pages/index.aspx. Accessed June 10, 2015.
31. Frosch AE, Ondigo BN, Ayodo GA, Vulule JM, John CC, Cusick SE. Decline in childhood iron deficiency after interruption of malaria transmission in highland Kenya. Am J Clin Nutr 2014;100:968-73. 32. Brittenham GM, Andersson M, Egli I, Foman JT, Zeder C, Westerman ME, et al. Circulating non-transferrin-bound iron after oral administration of supplemental and fortification doses of iron to healthy women: a randomized study. Am J Clin Nutr 2014;100:813-20. 33. Dostal A, Chassard C, Hilty FM, Zimmermann MB, Jaeggi T, Rossi S, et al. Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J Nutr 2012;142:271-7. 34. Jaeggi T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 2015;64:731-42. 35. Hurrell R. Iron and malaria: absorption, efficacy and safety. Int J Vitam Nutr Res 2010;80:279-92. 36. Zlotkin S, Newton S, Aimone AM, Azindow I, Amenga-Etego S, Tchum K, et al. Effect of iron fortification on malaria incidence in infants and young children in Ghana: a randomized trial. JAMA 2013;310:938-47. 37. Hubbard AC, Bandyopadhyay S, Wojczyk BS, Spitalnik SL, Hod EA, Prestia KA. Effect of dietary iron on fetal growth in pregnant mice. Comp Med 2013;63:127-35. 38. Ferrer P, Tripathi AK, Clark MA, Hand CC, Rienhoff HY Jr, Sullivan DJ Jr. Antimalarial iron chelator, FBS0701, shows asexual and gametocyte Plasmodium falciparum activity and single oral dose cure in a murine malaria model. PLoS One 2012;7:e37171. 39. van Santen S, de Mast Q, Swinkels DW, van der Ven AJ. Hepcidin in malaria superinfection: can findings be translated to humans? Nat Med 2011;17:1341. 40. Portugal S, Carret C, Recker M, Armitage AE, Gonc¸alves LA, Epiphanio S, et al. Host-mediated regulation of superinfection in malaria. Nat Med 2011;17:732-7.
Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World
S7