Nutritional Anemia

The 2007 first edition text concluded that despite a great deal of programmaticexperience, scientific data and new information on iron metabolism andthe role of other nutrients in the etiology of nutritional anemia, there hasunfortunately been little documented success in addressing the problem at apublic health level. Now, 15 years later, the release of this second edition text,which has been comprehensively expanded to 27 chapters, further highlightsthe complexity of the topic and the phenomenal advances we have observedin science during this timeframe. Unfortunately, despite this, these phenomenaladvances have not yet been translated into anemia reduction. This secondedition text addresses some of the potential reasons why these advancesin discovery and implementation have not resulted in acceptable progress inanemia reduction. Anemia prevalence among women and children remainsunacceptably high in most regions of the world, despite the global andnational attention and the plethora of policies, interventions,and programs designed to treat, prevent, and reduce anemia.This landmark publication aims to inform government, NGO, and international agencies on how to effectively measure, treat, prevent, and reduce anemia globally. We hope this second edition text will be a currentand comprehensive resource on anemia for all those involved inglobal health and nutrition policy, strategy, programming, or research,and, ultimately, helps to facilitate meaningful progress in anemia reduction globally. Preface Contents Part I: Prevalence, Biology, Lab Methods and Interpretation of Biomarkers 1: Anaemia: Worldwide Prevalence and Progress in Reduction Introduction Defining Anaemia Definitions of Anaemia Causes of Anaemia The Global Prevalence of Anaemia World Health Organization Other Groups Global Burden of Disease Global Determinants of Anaemia Global Burden of Disease Attributable to Anaemia Anaemia Reduction Targets Progress in Anaemia Reduction Progress in 2020 and Beyond COVID-19 Pandemic References 2: Iron Biology: Metabolism and Homeostasis Introduction Biological Roles of Iron The Iron Economy Iron Homeostasis: Tissues and Cellular Transporters Tissues, Cells, and Fluxes Cellular Iron Homeostasis Iron Import Heme Import Ferritin and Cytoplasmic Storage Iron Exporters Heme Exporters Extracellular Iron Carriers Hormonal Control of Iron Homeostasis by Hepcidin and Its Receptor Ferroportin Hepcidin Mechanism of Action of Hepcidin Hepcidin-Independent Homeostatic Mechanisms Regulation of Hepcidin by Iron Dual Regulation of Hepcidin by Extracellular Iron and Iron Stores Tissues Involved in Hepcidin Regulation Sensors and Pathways that Regulate Hepcidin Regulation of Hepcidin by Erythropoiesis Hepcidin in Inflammation, Liver Injury, and Host Defense Hepcidin Is Induced by Infections and Inflammation The Role of Hepcidin in Host Defense Genetic Disorders of the Hepcidin-Ferroportin System Conclusion References 3: Measurement Methods for Anemia and Iron Status Surveillance Introduction Anemia Assessment Hemoglobinometers Automated Hematology Analyzer WHO Haemoglobin Colour Scale Clinical Pallor Biochemical Iron Indicators Blood Specimen Collection Blood Specimen Processing and Storage Biomarkers of Iron Status Standard Reference Materials Laboratory Capacity Strengthening Future Directions Variations in Hb Concentrations and the Impact on Anemia Estimates in Field Settings Innovations in Blood Processing Point of Care Multiplex Assays Improvements in Assay Harmonization Conclusion References 4: Interpretation of Biomarkers and Diagnosis of Nutritional Anaemias Introduction Red Cell Indices and Red Blood Cell Morphology Reticulocyte Count and Reticulocyte Haemoglobin Content Mean Cell Volume Mean Cell Haemoglobin Red Cell Distribution Width Percentage of Hypochromic Cells Blood Film Biomarkers of Iron Status and the Diagnosis of Iron Deficiency Anaemia Serum Ferritin Serum Iron and Transferrin Saturation Soluble Transferrin Receptor Zinc Protoporphyrin Hepcidin Biomarkers for the Diagnosis of Iron Deficiency Anaemia: A Summary Biomarkers of Vitamin B12 and Folate Status and the Diagnosis of Associated Anaemias Vitamin B12 Folate Biomarkers for the Diagnosis of Nutritional Megaloblastic Anaemias: A Summary Conclusion References 5: Effects of Inflammation on Micronutrient Biomarkers Associated with Anemia Introduction Effects of Inflammation on Micronutrient Biomarkers Iron Vitamin A Zinc Folate and Vitamin B-12 Riboflavin Implications for Clinical Medicine and Public Health Approaches to Adjust for the Effects of Inflammation on Micronutrient Biomarkers Research Gaps and Opportunities References Part II: Special Populations 6: Nutritional Anemia in Infants and Children Nutritional Anemia in Children Anemia Caused by B12 Deficiency Other Nutritional Anemias ID in Children of Different Ages The Newborn and the First 6 Months of Life The Older Infant and Toddler The Preschool and School Child The Adolescent Biomarkers of Iron Status in Children Iron Status and Inflammation Health Consequences of ID and Effects of Iron Supplements IDA ID and Brain Development The Prenatal Situation Infants and Preschool Children Low Birth Weight Infants School-Age Children Health Economic Aspects Adverse Effects of Iron Supplements in Children Iron and Infections Iron and the Microbiome Iron and Poor Neurodevelopment Interventions to Decrease the Prevalence of IDA in Children Delayed Cord Clamping Breastfeeding Iron Supplemented Infant Formulas and Follow-On Formulas Iron Supplements Iron-Rich Foods Avoiding Cow’s Milk Conclusions References 7: Nutritional Anemia in Pregnancy and Lactation Background Epidemiology Biology Anemia Nutrient Deficiencies Iron Vitamin A B Vitamins Vitamins C, D, and E Copper Overweight and Obesity Genetic Factors Interventions Supplementation with Iron and Other Micronutrients Other Nutrition-Related Interventions Conclusions References 8: Nutritional Anemia in the Elderly Definition of Elderly Diagnosis of Anemia Prevalence and Pathogenesis of Anemia in the Elderly Iron Deficiency Folate Deficiency Vitamin B12 (Cobalamin) Deficiency The Impact of Anemia on Health Management Public Health Nutrition Conclusion References 9: Iron Deficiency and Anaemia in Athletes Introduction What Constitutes an Iron Deficiency in Athlete Populations? Impact of Iron Deficiency on Physical Capacity and Performance Mechanisms of Iron Deficiency in Athlete Populations Treatment of Iron Deficiency in Athletes Increasing Dietary Iron Intake Oral Iron Supplementation Parenteral Iron Administration Conclusion References Part III: Sources of Iron and Bioavailability 10: Sources of Iron: Diet, Supplemental, and Environmental Introduction Iron Sources Common Dietary Iron Sources Iron in Animal-Based Foods Iron in Plant-Based Foods Iron Intake in Specific Cases: Dietary Restrictions and Increased Requirements General Considerations on Dietary Sources of Iron Intentionally Increased Iron Intake (Dietary and Non-dietary) Indirect Methods to Increase Dietary Iron Intake: Food Processing and Preparation Non-intentionally Increased Iron Intake (Dietary and Non-dietary) Environmental Contaminants Iron in the Environment References 11: Iron Bioavailability: Enhancers and Inhibitors Introduction Muscle Tissue (MFP) Ascorbic Acid Phytic Acid Polyphenols Calcium Conclusion References Part IV: The Role of Nutrition in Anemia 12: Vitamin A in Nutritional Anemia Introduction Vitamin A Vitamin A Deficiency Disorders (VADD) Anemia as a VADD Evidence of Association: Vitamin A Deficiency and Anemia Effects of Vitamin A Supplementation on Hematologic Status Children Women of Reproductive Age Mechanisms and Pathways of Interaction Mobilization of Tissue Iron Stores Erythropoiesis Anemia of Infection Iron Absorption Conclusions References 13: The Role of B-Vitamins in Nutritional Anemia Introduction Folate Deficiency Metabolic Role of Folate Causes of Folate Deficiency Detection of Deficient Folate Status Consequences of Deficient Folate Status Severe Deficiency: Anemia Other Manifestations of Insufficient Folate Status Vitamin B12 Deficiency Metabolic Role of Vitamin B12 Causes of B12 Deficiency Detection of Deficient B12 Status Consequences of Deficient B12 Status Severe Deficiency: Anemia and Neuropathy Other Manifestations of Insufficient B12 Status Other B-Vitamins Implicated in Anemia Interaction of Riboflavin with Iron Interaction of Riboflavin with Folate Interaction of Riboflavin with Vitamin B6 Public Health Measures to Address B-Vitamin Insufficiency and Related Policy Addressing Folate Insufficiency Food Fortification Summary and Recommendations References 14: The Role of Zinc in the Etiology of Anemia Coexistence of Anemia and Zinc Deficiency Associations Between Zinc Deficiency and Anemia How Could Zinc Deficiency Contribute to Anemia? Direct Mechanisms Heme Synthesis Superoxide Dismutase Erythropoietin Hepcidin Indirect Mechanisms Iron Absorption Oxidative Stress and Membrane Fragility Inflammation Zinc Supplementation Animals and Cell Culture Humans Conclusion References 15: The Role of Vitamin D in Anemia Introduction Vitamin D Vitamin D and Anemia Mechanisms Iron and Inflammation Indices Observational Studies Observational Studies in Children and Adolescents Observational Studies in Adults Randomized Control Trials Anemia Iron Status and Inflammation Indices Conclusions References 16: Oxidative Stress and Vitamin E in Anemia Introduction Oxidative Distress and Anemia Oxidative Distress Definition, Free Radicals, and Reactive Oxygen Species Oxidative Distress and Destruction of Erythrocytes Vitamin E Antioxidant Activity Vitamin E Definitions Antioxidant Functions Vitamin E Deficiency Symptoms in Humans Vitamin E Deficiency Syndromes Vitamin E Deficiency Caused by Defects in Lipoprotein Synthesis Vitamin E Malnourishment Protein Energy Malnutrition (PEM) Iron Deficiency Anemia Oxidative Distress in Anemia Caused by Inherited and Transmitted Diseases Thalassemia and Sickle Cell Anemia Glucose-6-Phosphate Dehydrogenase Deficiency Superoxide Dismutase-2 Deficiency Malaria HIV and AIDS Concluding Remarks References Part V: Physiological Consequences and Significance of Iron Deficiency and Anemia 17: Iron Deficiency and Anemia Associated with Infectious and Inflammatory Diseases Introduction Alterations of Iron Homeostasis in Inflammation and Infection Regulating Iron Metabolism During Infection Differences in Infections with Intra- and Extracellular Pathogens Modifications of Iron Metabolism Against Extracellular Pathogens Modifications of Iron Metabolism Against Intracellular Pathogens Anemia of Inflammation with or without Combined Iron Deficiency Definition, Etiology, and Epidemiology Diagnosis Current and Emerging Treatment Strategies Outlook and Perspectives References 18: Iron Deficiency, Anemia, and the Immune System Introduction Iron Is Essential But Potentially Toxic Iron Deficiency Can Cause Anemia Absolute and Functional Iron Deficiency Differs from Each Other Basic Principles of Iron Deficiency and Iron Deficiency Anemia Causes and Consequences of Iron Deficiency and Iron Deficiency Anemia Pathophysiology of Iron Deficiency and Iron Deficiency Anemia Functional Iron Deficiency Due to Inflammatory Processes Iron and the Immune System Iron and the Innate Immune System Iron and the Adaptive Immune System The Effect of the Hosts Iron Status on Vaccination Success Iron in Viral Infections Iron and Allergy as Immune-Mediated Disease Summary and Outlook References 19: Genetic Hemoglobin Disorders and Their Association with Hemoglobin Concentration and Biomarkers of Nutritional Anemia Hemoglobin and its Structure, Function and Synthesis Genetic Hemoglobin Disorders Laboratory Methodologies for Diagnosis Global Distribution of Genetic Hemoglobin Disorders Genetic Hemoglobin Disorders and their Association with Hemoglobin Concentration Genetic Hemoglobin Disorders and their Association with Biomarkers of Nutritional Anemia Ferritin Concentrations Soluble Transferrin Receptor Concentrations Zinc Concentrations Folate Concentrations Vitamin B12 and B6 and Riboflavin Concentrations Newborn Genetic Screening Programs Other Inherited Blood Disorders Conclusions References 20: Iron and the Human Gut Microbiota Introduction Iron Acquisition Is a Determinant of Bacterial Growth and Virulence The Gut Microbiota May Modulate Host Iron Absorption and Metabolism The Effect of Increasing Iron Intake and the Human Gut Microbiota Controlled Studies of Iron Fortification and Supplementation in Infants Controlled Studies of Iron Fortification and Supplementation in Children Controlled Studies of Iron Fortification and Supplementation in Adults Increasing Iron Intakes and Risk of Diarrhea Strategies to Balance the Need for Iron and the Risk of Adverse Effects Conclusions and Perspectives References 21: Safety of Interventions to Reduce Nutritional Anemia Introduction Mechanisms by Which Iron May Promote Infections Iron and Risk of Malaria Infection Iron and Other Infections Iron Interventions and the Gut Microbiome Iron Interventions and Diarrhea Iron Interventions and the Vaginal Microbiome Administration of Iron with Prebiotics and Probiotics Conclusions References 22: Novel Approaches to Oral Iron Supplementation Iron Deficiency Balancing Iron Absorption and Tolerability Bioavailability from Oral Iron Supplements Side Effects from Oral Iron Intermittent Iron Supplementation Advances in Understanding of Iron Biology and Iron Supplementation Studies in Young Women with and without Anemia Studies in Infants and Young Children Studies Investigating Side Effects from Intermittent and Daily Iron Supplementation Recommendations for Iron Supplementation Conclusion and Future Directions References 23: Cognitive and Behavioral Consequences of Iron Deficiency Introduction Effects of Iron Deficiency on Cognition and Behavior in Children Effects of Iron Treatment on Child Cognitive Outcomes Long-Term Effects of Iron Treatment in Early Life on Child Behavioral and Affective Outcomes Effects of Iron Deficiency on Cognition and Behavior in Women of Reproductive Age Effects of Iron Treatment on Cognitive and Neurophysiological Outcomes in Women of Reproductive Age Effects of Iron Treatment on Behavioral and Affective Outcomes in Women of Reproductive Age Conclusion References Part VI: Program and Policy 24: Strengthening Fortification Markets to Reduce Iron Deficiency Anemia Introduction Why Have Fortification Markets Largely Failed Us? How Do we Make Fortification Markets more Functional? Strengthening Market Forces for Industry Engagement in Fortification Private–Private Partnerships to Broaden Business Opportunities Leveling the Playing Field through Process Data, Transparency, and New Business Innovations Leveling the Playing Field through Process Data Captured within Industry Settings Leveling the Playing Field Through Transparency and Self-Policing Leveling the Playing Field Through New Business Innovations Government as an Enabler of Fortification Programs Conclusion References 25: Food-Based Approaches for Combating Iron Deficiency Introduction Review of Evidence Food Fortification Introduction Efficacy of Mass Iron Fortification Effectiveness of Mass Iron Fortification Programs Summary Home Fortification Introduction Micronutrient Powders Efficacy of MNP in Infants and Young Children Efficacy of MNP in Preschool and School-Aged Children Efficacy of MNP in Pregnant and Lactating Women Small-Quantity Lipid-Based Nutrient Supplements Efficacy of SQ-LNS Summary Nutrition-Sensitive Agricultural Interventions Introduction Biofortification Efficacy of Biofortification in Children, Adolescents, and Women Other Agricultural Interventions to Combat Iron Deficiency Summary Program Considerations for Controlling ID Suggestions to Improve Food-Based ID Control Program Effectiveness Conclusions References 26: Food Fortification with Iron: Policy Considerations Overview of Food Fortification with Iron History and Status of Food Fortification with Iron Impact to Date Through Food Fortification with Iron Effective Policy for Food Fortification with Iron Policy Considerations to Design National Iron Fortification Programs Setting Mandatory Fortification Legislation and Standards Policy Considerations to Implement and Improve Iron Fortification Programs Policies to Aid in Coordinating National Efforts Policies Related to Regulatory Monitoring Policy Considerations to Support Monitoring of Iron Fortification Programming Conclusion References 27: Designing Effective Programs for Anemia Reduction Background Historical Perspective Consequences of Anemia and Target Populations Interventions to Reduce Nutritional Anemia Nutrition-Specific Strategies to Reduce Anemia Micronutrient Supplementation Fortification Improving Dietary Diversity and Quality Social and Behavior-Change Communication Nutrition-Sensitive Strategies to Reduce Anemia Water, Sanitation, and Hygiene (WASH) Reproductive Health Practices Intersectoral Actions Strategies for the Treatment of Iron Deficiency Anemia Development of Programs for Anemia Reduction Role of Policy in Anemia Reduction Conclusion References Index Understanding the causes of anemia is critical to inform appropriate strategies to prevent and treat anemia, particularly to reduce the risk of anemia and the burden of disease. The strength of this book lies in its cross-disciplinary nature. This publication summarizes the current state of evidence on the multifactorial causes of anemia, with a specific focus on nutritional anemia. The chapter authors are leading experts in nutrition and global health. The introductory chapters provide an overview of the global burden of anemia prevalence, the economic implications and functional consequences of anemia, and the significance of these factors to guide policy and programs. Subsequent chapters provide current evidence on iron and other micronutrient metabolism and homeostasis in regards to anemia, the multifactorial contributors to anemia (e.g. infection and genetics), and the interactions between nutrients that may contribute to anemia. The summarizing chapters detail program and policy approaches to treat, prevent and reduce anemia in the global context. Nutritional Anemia is a comprehensive resource for those involved in global health and nutrition policy, strategy, programming, or research, and serves as a guide for how government, NGO, and international agencies can effectively treat, prevent and reduce anemia globally.