Nutritional Anemia

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