Iron Deficiency and Overload (eBook)

Series Editor Introduction 6
Preface 11
Contents 13
Contributors 15
Part 1: Iron Biochemistry and Metabolism 17
The Cellular Physiology of Iron 18
1. Introduction 18
2. What is Iron Used for in the Cell? 22
3. Cellular Iron Uptake 24
3.1. Transferrin-Bound Iron Delivery to Cells 25
3.2. Iron Movement Across the Endosomal and Plasma Membranes - Divalent Metal-Ion Transporter 1 27
3.3. Non-transferrin-Bound Iron Uptake 27
3.4. The Uptake of Other Forms of Iron 28
4. Intracellular Iron Utilization 29
5. Intracellular Iron Storage 31
6. Cellular Iron Release 32
7. Regulation of Cellular Iron Metabolism 33
8. Systemic Iron Metabolism 35
8.1. Systemic Iron Transport 35
8.2. Regulation of Systemic Iron Homeostasis 35
9. Conclusion 36
References 37
Regulation of Iron Absorption and Distribution 45
1. Introduction and Scope of Review 45
2. Iron Uptake and Release by Cells 46
3. Mechanisms of Iron Absorption and Loss by Mammals 47
4. Iron Transport Round the Body and Tissue Uptake 49
5. Regulation at the Cellular Level 52
6. Regulation of Whole Body Iron Status 53
7. Hepcidin in the Regulation of Iron Absorption and Distribution 55
8. Concluding Overview and Unknowns 56
References 57
The Role of Hepcidin in Iron Homeostasis 64
1. Introduction 64
2. The Interaction of The Hormone Hepcidin and Its Receptor Ferroportin Regulates Systemic Iron Metabolism 65
2.1. Hepcidin 65
2.2. Ferroportin 65
2.3. Regulation of Ferroportin by Hepcidin 65
2.4. Structure-Function Analysis of Hepcidin 66
2.5. Hepcidin Catabolism 66
2.6. Cellular Regulation of Ferroportin 66
3. Regulation of Hepcidin Synthesis by Iron 67
3.1. Hereditary Hemochromatosis Proteins Are Hepcidin Regulators 67
3.2. Hemojuvelin 67
3.3. The Bone Morphogenetic Protein (BMP) Pathway in Hepcidin Regulation 68
3.4. Transferrin and Transferrin Receptors 1 and 2 68
3.4.1. TfR1 68
3.4.2. TfR2 69
3.4.3. Holotransferrin 69
3.4.4. Iron Sensing 69
3.5. HFE 69
3.6. A Model of Hepcidin Regulation 70
4. Regulation of Systemic Iron Metabolism and Hepcidin Synthesis by Hypoxia-Inducible Transcription Factors 70
4.1. Gene Regulation by Hypoxia 70
4.2. Iron and Hepcidin Regulation by Hypoxia 70
4.3. HIF Involvement in Hepcidin Suppression During Iron Deficiency 71
5. Regulation of Plasma Iron and Of Hepcidin Synthesis by Inflammation 71
5.1. Hepcidin and the Acute Hypoferremia of Inflammation 71
5.2. Hepcidin and Anemia of Inflammation 71
5.3. Regulation of Hepcidin During Infection and Inflammation 72
5.4. Regulation of Hemojuvelin by Inflammation 72
6. Regulation of Hepcidin Synthesis by Erythropoietic Activity 72
6.1. Erythropoiesis Suppresses Hepcidin Synthesis 72
6.2. Hepcidin Suppression in Expanded but Ineffective Erythropoiesis 72
7. Summary 73
References 73
Iron as Nutrient: Strategies for Iron Acquisition and Usage by Pathogenic Microorganisms 78
1. Iron as Nutrient 78
1.1. The Importance of Fe Metabolism 78
1.2. Fe and Pathogenic Bacteria 79
2. Post-Synthetic Modification of Siderophores In Pathogenic Bacteria 79
2.1. Enterobactin Biosynthesis and Secretion 79
2.2. Glucosylated Enterobactin Is a Virulence Factor in Pathogenic Bacteria 80
3. Intracellular Iron Homeostasis In Bacteria 82
3.1. Small Regulatory RNAs and Environmental Stresses 82
3.2. Role and Mechanism of the sRNA RyhB During Fe Starvation 83
3.3. Roles of RyhB in Biofilms, Chemotaxis, and Acid Resistance 84
3.4. Similar Regulatory Mechanism in Other Species 85
3.5. Siderophore Biosynthesis and RyhB 85
3.6. Concluding Remarks 86
References 86
Iron as a Drug and Drug-Drug Interactions 90
1. Pharmacology 90
2. Oral Iron Preparations 91
2.1. Bioavailability 91
2.2. Adverse Drug Events with Oral Iron Preparations 91
2.3. Drug Interactions 92
3. Parenteral Iron Preparations 92
3.1. Iron Dextran 92
3.2. Iron Sucrose (Iron Saccharate) 94
3.3. Ferric Gluconate 94
3.4. Adverse Drug Events with Parenteral Iron Preparations 94
4. Toxicity 95
4.1. Acute Toxicity 95
4.2. Clinical Effects 95
4.3. Range of Toxicity 96
4.4. Treatment 96
4.5. Chronic Toxicity 97
4.6. Clinical Effects 97
4.7. Range of Toxicity 98
4.8. Treatment 99
5. Conclusion 100
References 100
Part 2: Iron Overload and Deficiency Pathologies 105
Iron Deficiency and Excess in the Brain: Implications for Cognitive Impairment and Neurodegeneration 106
1. Nutritional Iron Deficiency and its Neurochemical Aspect 107
2. The Impact of Nutritional Iron Deficiency on Brain Iron 108
3. Early Iron Deficiency and its Consequence on Brain Function and Behavior 111
4. Brain Iron Deficiency and Dopamine-Endogenous Opiate Interaction and Function 112
5. Iron and Zinc Interaction in the Hippocampus 113
5.1. The Normal Development of Ferritin Distribution in the Hippocampus 113
5.2. Effects of Iron Deficiency on Distribution of Ferritin in the Hippocampus 113
5.3. Effects of Zinc Alone and Zinc Added to Iron Therapy 114
6. Brain Iron and Parkinson’S Disease 116
6.1. Transition Metals in Parkinson’s Disease 116
7. Iron in Parkinsonian Brain 117
8. Sources of Iron and its Interaction with Neuromelanin 119
9. Consequences of Iron Overload in the Parkinsonian Substantia Nigra 122
10. Conclusion 124
References 125
Brain Iron Deposition in Aging and Disease: Role of HO-1 135
7.1. Introduction 135
7.2. Iron Deposition in the Aging And Degenerating CNS 136
7.2.1. Aging 136
7.2.2. Alzheimer’s Disease 137
7.2.3. Parkinson’s Disease 137
7.2.4. Other Neurological Disorders 137
7.2.5. Glial Senescence and Iron Sequestration 138
7.2.5.1. The Cysteamine Model 138
7.2.5.2. Mitochondrial Precursors of Senescent Glial Granules 138
7.2.5.3. Non-Transferrin Iron Sequestration in ‘‘Stressed’’ Astroglial Mitochondria 139
7.3. Heme Oxygenase-1 and Brain Iron Homeostasis 139
7.3.1. Heme Oxygenase 139
7.3.2. HO-1 and Astroglial Iron 140
7.3.3. HO-1 and Human Brain Aging 142
7.3.4. HO-1 and Alzheimer’s Disease 142
7.3.5. HO-1 and Parkinson’s Disease 143
7.3.6. HO-1 and Other Human CNS Disorders 145
7.4. Conclusions 145
References 146
Iron Deficiency and Neuropharmacology 150
1. Introduction 150
2. Monoamines 151
2.1. Dopamine 151
2.1.1. Dopaminergic Brain Regions and Consequences of ID 151
2.1.2. Synthesis 151
2.1.3. Catabolism 153
2.1.4. Dopamine Receptors 153
2.1.5. DA Transport 154
2.1.6. D2R-DAT Link 155
2.1.7. Iron Deficiency During Development 155
2.2. Norepinephrine 156
2.2.1. Synthesis 156
2.2.2. Degradation and Transport 157
2.3. Serotonin 158
2.3.1. Synthesis 158
2.3.2. Transport 158
2.3.3. Receptors 159
2.3.4. Catabolism 159
2.4. GABA/Glutamate 159
2.4.1. Synthesis 160
2.4.2. Receptors 161
2.4.3. Iron Deficiency and Drugs of Abuse 161
2.4.4. Adhd 161
2.5. Endorphins 162
2.6. Estrogen 162
3. Conclusions 162
References 163
Peripheral Effects of Iron Deficiency 168
1. Historical Account of Iron Deficiency and its Clinical Manifestations 168
2. Prevalence of Iron Deficiency and its Causes 170
3. Pathogenesis of the Manifestations of Iron Deficiency 172
3.1. Proteins and Enzymes 172
3.2. Epithelial Cells and Skeleton 173
4. Laboratory Evaluation of Iron Deficiency 173
5. Clinical Manifestations of Iron Deficiency and Iron Deficiency Anemia 175
5.1. Clinical Manifestations of Anemia 175
5.2. Effects on the Hematopoietic System 175
5.3. Effects on Non-hematopoietic Systems 177
5.4. Tongue and Mouth 177
5.5. Hypopharynx and Esophagus 178
5.6. Stomach 179
5.7. Nails 180
5.8. Hair 181
5.9. Other Manifestations 181
References 182
Iron-Metabolism in Neurons of the Motor System of the Central Nervous System: Lessons from Iron Deficiency and Overloading Pathologies 190
1. Introduction 190
2. Neuronal Iron Metabolism in the Normal Brain 191
3. Iron Homeostasis in Myelin-Forming Cells 195
4. Cerebral Iron Homeostasis in Iron Deficiency 196
5. Management of Iron in the Brain in Conditions with Raised Cerebral Iron 197
6. Conclusions and Outlook 199
References 199
The Effects of Brain Iron Deficiency on Cognitive and Behavioral Aspects 203
1. Introduction 203
2. Iron in the Brain 204
3. The Role of Iron in Myelination 205
4. Brain Iron and Brain Dopamine 205
5. Iron and Schizophrenia 206
6. Iron Deficiency, Learning, and Hippocampus Integrity 206
6.1. Animal Studies 206
6.2. Human Studies 208
7. Iron Deficiency and Pretems 208
8. Long-Term Effects of Transient Iron Deficiency Period 209
9. The Auditory System and Iron Deficiency 210
10. Iron Deficiency and the Endocrine System 210
11. Iron Deficiency and the Immune System 211
12. Conclusion 211
References 212
Stress, Immunology, and Cytokines 215
1. Characteristics of Stress 215
2. Stress, the CNS, and the Immune System 216
3. Cytokines as Mediators of Neuroimmune Communication 216
4. The Interaction Between Cytokines and the HPA Axis 218
5. Cytokines in the CNS 219
6. Inflammatory Cytokines, Glucocorticoids, and Human Disease 220
7. Stress and TH1/TH2 Subsets 220
8. Stress, Glucocorticoids, and TH1/TH2 Balance 222
9. Stress, Inflammation, and Autoimmune Diseases 222
10. T-helper Cell Commitment Toward Specific Lineages: the Role of the TH17 Subset in Inflammation 223
11. Summary 224
References 224
Part 3: Diagnostic and Clinical Aspects in CNS Disorders 229
MRI of Brain Iron and Neurodegenerative Diseases: A Potential Biomarker 230
1. Introduction 230
2. Other Forms of Iron in the Brain 234
3. Biology of Brain Iron and Copper 234
4. Inborn Errors of Brain Iron Metabolism 238
5. Mri Techniques for Imaging Brain Iron 239
6. Brain Iron Imaging at Seven Tesla 241
7. Conclusion 242
References 243
Alzheimer’s Dementia 248
1. Clinical and Pathological Features of Alzheimer’s Disease 248
2. Iron and the Pathogenesis of Alzheimer’s Disease 249
3. Evidence for Dysregulation of Brain Iron Homeostasis in Ad Patients 250
4. Experimental Evidence for a Pathogenic Role for Iron in AD 250
5. Therapeutic Implications of Iron in Ad Pathogenesis 252
References 253
Inherited Disorders of Brain Iron Homeostasis 257
15.1. Human Iron Physiology: an Overview 257
15.2. Genetic Disorders of CNS Iron Homeostasis 260
15.2.1. Friedreich’s Ataxia 260
15.2.2. Pantothenate Kinase-2-Associated Neurodegeneration 263
15.2.3. Aceruloplasminemia 265
15.2.4. Neuroferritinopathy 268
15.2.5. X-Linked Sideroblastic Anemia with Ataxia 270
15.2.6. IRP2 Deficiency 271
15.2.7. Differential Diagnosis 272
15.3. Hemochromatosis and the CNS 272
15.3.1. General Considerations 272
15.3.2. Mutant HFE and Alzheimer’s Disease 273
15.3.3. Mutant HFE and Parkinson’s Disease 274
15.3.4. Mutant HFE and Amyotrophic Lateral Sclerosis 275
15.3.5. Mutant HFE and Ischemic Stroke 275
15.4. Concluding Remarks 275
References 276
Part 4: Public Health Issues 283
Iron and Heart Disease: A Review of the Epidemiologic Data 284
1. Introduction 284
2. Serum Measures of Body Iron Stores 285
3. Body Iron Stores And Risk of Heart Disease: The Epidemiologic Data 287
3.1. Cohort Studies Based on Serum Ferritin 287
3.2. Cohort Studies Based on TS 291
3.3. Case-Control or Cross-Sectional Studies 293
3.4. Dietary Iron and CHD Risk 294
3.5. Blood Donor Studies and Iron and Oxidized LDL Cholesterol 294
4. Clinical Trials: Reducation of Iron Stores and Cvd Risk 296
5. Iron Overload and Chd Risk 297
6. Summary 297
7. Recommendations 298
References 298
Global Concept of Iron Deficiency 304
1. Pregnancy and The Newborn 306
2. Malaria 307
3. Latent Iron Deficiency 307
4. Management Strategies 309
5. Burden of Disease in A Population 310
6. Effect on Blood Transfusion Services 312
7. Tests in Under-Resourced Countries 313
8. Haemoglobinometry 314
References* 315
Nutritional Iron Deficiency in Early Childhood 318
1. Introduction 318
2. Defining the Prevalence of Iron Deficiency 319
3. Risk Factors for Iron Deficiency in Early Childhood 320
4. Iron Deficiency and Deficits in Psychomotor Development 322
5. Iron Deficiency and Susceptibility to Infection 324
6. Prevention of Iron Deficiency in Childhood 325
6.1. Dietary Education 325
6.2. Iron Supplementation 325
6.3. Iron Fortification of Food 326
6.4. Screening for Anaemia 327
7. Conclusions 327
References 328
Iron and Women’s Health 332
1. Introduction 332
2. Basic Biochemical Functions 334
2.1. Major Heme Proteins 334
3. Metabolism 334
3.1. Chemical Forms and Absorption of Iron 335
3.2. Transport 336
3.3. Storage 336
3.4. Excretion 336
4. Clinical Values of Iron Status 337
4.1. Iron Deficiency 337
4.2. Iron Deficiency Anemia 338
4.3. Iron Supplementation and Fortification 338
4.4. Iron and Ovulation 339
4.5. Iron Overload 339
4.6. Lifestyle Factors That Can Affect Women’s Iron Status 339
5. Pregnancy and Lactation 340
5.1. Iron Requirements 340
5.2. Iron Deficiency Anemia 341
5.3. Iron Supplementation 341
5.4. Maternal Iron Supplementation, Pregnancy Outcomes, and Infant Iron Status 343
5.5. Maternal Post-pregnancy Iron Status 343
5.6. Lactation 345
6. Menopause 345
6.1. Intake 345
6.2. Iron Deficiency and Iron Overload in Older Women 346
6.3. Iron Supplement Use in Postmenopausal Women 347
7. Diseases Related to Iron Status 347
7.1. Metabolic Syndrome and Type 2 Diabetes 347
7.2. Osteoporosis 349
8. Conclusions 350
References 353
Appendix A: Reference Ranges for Common Laboratory Assays of Iron Metabolism 356
Introductory Comments 356
References 359
Appendix B: Nutritional Sources of Iron 360
Introductory Comments 360
References 359
Subject Index 363
About the Editors 376
About the Series Editor 377