Anemia of Chronic Disease (Basic and Clinical Oncology)

Front Cover......Page 1
Contents......Page 10
Contributors......Page 20
Introduction: Anemia of Chronic Disease: The Enigma and the Challenge......Page 24
BIOLOGY OF IRON......Page 30
IRON’S TOXICITY......Page 32
BIOMEDICAL ASPECTS OF IRON METABOLISM......Page 34
MECHANISMS FOR DIETARY IRON ABSORPTION AND ERYTHROID IRON UTILIZATION......Page 37
REGULATION OF DIETARY IRON ABSORPTION AND ERYTHROID IRON UTILIZATION The Role of HFE......Page 42
The Role of Hepcidin......Page 44
CELLULAR IRON UPTAKE......Page 46
INTRACELLULAR IRON STORAGE......Page 51
POSTTRANSCRIPTIONAL REGULATION OF CELLULAR IRON METABOLISM BY THE IRE=IRP SYSTEM......Page 53
IRON REGULATORY PROTEINS, IRP1 AND IRP2......Page 57
Mechanisms for Regulation of IRP1......Page 58
Mechanisms for Regulation of IRP2......Page 60
Targeted Disruption of IRP1 or IRP2......Page 61
OTHER REGULATORY MECHANISMS......Page 62
CONCLUSIONS......Page 63
ACKNOWLEDGMENTS......Page 64
INTRODUCTION......Page 90
CHEMICAL STRUCTURE OF Epo......Page 91
SITES AND CONTROL OF Epo PRODUCTION......Page 93
ASSAY OF CIRCULATING Epo AND INTERPRETATION OF RESULTS......Page 97
ACTION OF Epo ON HEMOPOIETIC CELLS......Page 98
PATHOPHYSIOLOGICAL ASPECTS......Page 101
INTRODUCTION......Page 116
Systemic Inflammatory Response Syndrome (SIRS)......Page 117
PATHOGENESIS......Page 118
Proinflammatory Cytokines......Page 120
Apoptosis......Page 121
Bacterial Factors......Page 122
Anti-inflammatory Responses......Page 123
From Excessive Proinflammatory Response to Immunosuppression: A Disorder Due to Uncontrolled Inflammation?......Page 124
Mechanisms of Immune Suppression in Sepsis......Page 125
EPIDEMIOLOGY......Page 126
CATEGORICAL DEFINITIONS AND PATIENT RISK......Page 127
Other Therapies......Page 128
CONCLUSIONS......Page 129
NORMAL IRON METABOLISM Molecular Mechanisms of Iron Absorption......Page 134
Molecular Regulation of Iron Metabolism......Page 137
A Pivotal Role for Macrophages in Iron Metabolism......Page 138
THE IMBALANCE OF IRON HOMEOSTASIS DURING INFLAMMATION Action of Cytokines......Page 140
The Role of ROS......Page 141
The Role of Reactive Nitrogen Species (RNS)......Page 142
DISTURBANCE OF IRON TRAFFICKING IN MACROPHAGES INFECTED WITH INTRACELLULAR PATHOGENS......Page 145
INTRODUCTION Inhibition of Erythroid Progenitors in the Pathogenesis of the Anemia of Chronic Disease......Page 156
Inflammatory Cytokines in the Anemia of Chronic Disease......Page 157
INHIBITION OF ERYTHROID PROGENITORS BY SPECIFIC CYTOKINES......Page 159
Tumor Necrosis Factor......Page 160
Interferons......Page 161
Effects of Other Cytokines on Erythroid Progenitors......Page 163
EFFECTS OF ERYTHROPOIETIN AND OTHER COLONY STIMULATING FACTORS ON CYTOKINE INHIBITION OF ERYTHROPOIESIS......Page 164
IMPLICATIONS FOR THERAPY......Page 165
ACKNOWLEDGMENTS......Page 166
INTRODUCTION......Page 174
EFFECTS OF CYTOKINES ON ERYTHROPOIETIN PRODUCTION (Table 1)......Page 177
INTERPRETATION OF SERUM Epo LEVELS What Is a Normal Epo Value?......Page 179
Serum Epo Levels and Erythropoietic Activity......Page 181
SERUM ERYTHROPOIETIN IN ANEMIA OF CHRONIC DISORDERS......Page 185
Serum Epo in HIV Infection......Page 186
Serum Epo in Rheumatoid Arthritis......Page 187
SERUM ERYTHROPOIETIN IN CANCER Initial Studies......Page 190
Studies in Patients Scheduled for rHuEpo Therapy......Page 191
Solid Tumors......Page 192
Chronic Myeloid Disorders......Page 193
Leukemia and Lymphoma......Page 194
SERUM ERYTHROPOIETIN AND CHEMOTHERAPY Experimental Data......Page 196
Nonplatinum Chemotherapy in Patients......Page 199
Cisplatin Chemotherapy in Patients......Page 201
SERUM ERYTHROPOIETIN AS PREDICTOR OF RESPONSE TO rHuEpo......Page 202
ACKNOWLEDGMENTS......Page 204
INTRODUCTION......Page 230
THE PHYSIOLOGY OF ERYTHROCYTE AGING......Page 231
METHODS FOR ESTIMATION OF ERYTHROCYTE LIFE SPAN......Page 233
CAUSES OF DECREASED ERYTHROCYTE SURVIVAL AND LIFE SPAN......Page 234
EFFECT OF INFLAMMATION ON ERYTHROCYTE SURVIVAL......Page 235
UPTAKE OF EFFETE ERYTHROCYTES BY THE MACROPHAGE SYSTEM......Page 236
ERYTHROCYTE DESTRUCTION AND RELEASE OF IRON FROM HEMOGLOBIN AND MACROPHAGES......Page 238
MAJOR PROTEINS INVOLVED IN IRON RELEASE FROM HEMOGLOBIN AND MACROPHAGES......Page 242
IRON RELEASE FROM MACROPHAGES IN INFLAMMATION......Page 248
INTRODUCTION......Page 258
HEPCIDIN: A KEY MOLECULE IN IRON METABOLISM......Page 259
HEPCIDIN: A KEY MOLECULE IN ANEMIA OF CHRONIC DISEASES......Page 262
HEPCIDIN EXPRESSION REGULATORS IL-6: The Main Cytokine Involved in Hepcidin Over Expression......Page 263
Erythropoietin and Cytokines: A Duo in Hepcidin Regulation During Chronic Diseases......Page 265
Iron Status as a Regulator of Hepcidin Expression......Page 267
HFE Molecule as a Regulator of Hepcidin Expression......Page 268
Does Hepcidin Bind Iron?......Page 269
Hepcidin and Proteins of Iron Metabolism......Page 270
CONCLUSIONS......Page 273
INTRODUCTION......Page 284
HISTORICAL DEVELOPMENT OF THE CONCEPT OF IRON WITHHOLDING DEFENSE Defense Components......Page 285
Invader Contravention......Page 287
COMPONENTS OF IRON WITHHOLDING DEFENSE Constitutive Components......Page 289
Components Induced During Disease Episodes......Page 291
INVADER FACTORS ASSOCIATED WITH IRON WITHHOLDING DEFENSE Counteraction of Iron Withholding......Page 294
Suppression of Iron Withholding......Page 296
Success Only in Absence of Iron Withholding......Page 297
HOST FACTORS ASSOCIATED WITH IMPAIRED IRON WITHHOLDING DEFENSE Behavioral and Nutritional Factors......Page 299
Genetic Factors......Page 300
Physiological Factors......Page 302
ECOLOGICAL ASPECTS OF IRON WITHHOLDING DEFENSE......Page 303
INTRODUCTION......Page 310
IRON HOMEOSTASIS: A BRIEF SUMMARY......Page 311
Regulation of Iron at Systemic Level (Fig. 1)......Page 314
The Immunological System in Systemic Iron Metabolism......Page 317
HFE: The HFE gene encodes for a 343 amino acid pro-tein,......Page 323
Hepcidin (Table 3 and Refs. 17–19, 109, 115–120): Hepci-din......Page 326
DMT-1 (also called DCT1 or Nramp2): Two independent......Page 328
Immune Regulation of Iron Homeostasis: Lessons from Gene Knockout Mouse Models......Page 329
INTERPLAY BETWEEN IRON METABOLISM AND CYTOKINE ACTIVITIES......Page 336
Regulation of Iron Homeostasis by Cytokines......Page 337
Regulation of Cell Mediated Immune Effector Function by Iron......Page 340
CONCLUSION Iron as an Impelling Force Between Two Kinds of Immunity?......Page 341
Iron and Adaptive Immunity......Page 342
Caveat......Page 343
ACKNOWLEDGEMENTS......Page 344
INTRODUCTION......Page 364
CHRONIC INFLAMMATORY PROCESS......Page 365
HYPOPROLIFERATIVE ANEMIA OF NORMOCYTIC OR MICROCYTIC MORPHOLOGY......Page 367
ABSENCE OF OTHER CAUSES OF A HYPOPROLIFERATIVE ANEMIA......Page 368
CHANGES IN IRON METABOLISM......Page 369
DIAGNOSIS OF IRON DEFICIENCY IN THE SETTING OF INFLAMMATION......Page 370
ACKNOWLEDGMENTS......Page 373
APPENDIX......Page 374
DISTINGUISHING THE ANEMIA OF CHRONIC DISEASE FROM OTHER FORMS OF ANEMIA......Page 378
RED BLOOD CELL MORPHOLOGY AND TRADITIONAL CLASSIFICATION OF ANEMIAS ON THE BASIS OF MEAN CORPUSCULAR VOLUME......Page 380
THE TRADITIONAL MARKERS OF IRON STATUS INCLUDING FERRITIN, TRANSFERRIN, AND SERUM IRON IN DIAGNOSIS OF ACD......Page 381
SOLUBLE TRANSFERRIN RECEPTOR AND TfR-F INDEX IN THE DIFFERENTIAL DIAGNOSIS OF IDA AND ACD......Page 384
ANALYSIS OF HEMOGLOBIN SYNTHESIS AND RED BLOOD CELLS......Page 387
NOVEL MARKERS OF IRON TURNOVER......Page 388
SUMMARY......Page 389
Treatment of ACD: An Introduction......Page 394
INTRODUCTION......Page 396
MECHANISM OF ACTION......Page 397
SERUM ERYTHROPOIETIN LEVELS AS GUIDELINES FOR THERAPY......Page 398
Maintenance Therapy......Page 399
ERYTHROPOIETIN THERAPY OF ANEMIA IN PATIENTS WITH RHEUMATOID ARTHRITIS......Page 401
ERYTHROPOIETIN IN PATIENTS WITH MALIGNANCY OR CHEMOTHERAPY......Page 402
SIDE EFFECTS......Page 403
SUMMARY......Page 405
INTRODUCTION......Page 410
INEFFECTIVENESS AND POTENTIAL HARM OF ROUTINE IRON THERAPY IN THE ANEMIA OF CHRONIC DISEASE......Page 411
Causes of Iron Deficiency......Page 412
Clinical Features of Iron Deficiency......Page 414
Management of Iron Deficiency Anemia......Page 416
IRON THERAPY FOR PATIENTS WITH COMBINED IRON DEFICIENCY AND THE ANEMIA OF CHRONIC DISEASE......Page 417
Oral Iron Therapy......Page 418
Parenteral Iron Therapy......Page 419
IRON THERAPY IN ANEMIA OF CHRONIC DISEASE PATIENTS RECEIVING ERYTHROPOIETIN......Page 422
ACKNOWLEDGMENTS......Page 423
Blood Transfusions......Page 426
RBC TRANSFUSION THERAPY IN CHRONIC ANEMIA......Page 428
Guidelines for RBC Transfusion Therapy......Page 429
Nonimmune Complications of ABT......Page 431
Immune Complications of ABT......Page 433
INFECTIOUS RISKS OF ABT......Page 436
Traditional Transfusion-Transmitted Viruses......Page 438
Bacterial Contamination of Blood Components......Page 440
Theoretical Infectious Risks of ABT......Page 443
PURPORTED NONINFECTIOUS RISKS OF ABT......Page 446
Immunologically Active Allogeneic WBCs as Mediators of TRIM......Page 447
WBC-Derived Soluble Mediators as Mediators of TRIM......Page 449
RCTs Comparing Recipients of Non-WBC-Reduced vs. WBC-Reduced Allogeneic RBCs......Page 450
TRIM and Increased Mortality......Page 454
SUMMARY......Page 455
INTRODUCTION......Page 466
ANEMIA AND ADVERSE OUTCOMES Mortality......Page 467
Morbidity......Page 469
Quality of Life......Page 471
ERYTHROPOIETIN, IRON, AND ERYTHROPOIESIS......Page 472
ERYTHROPOIETIN RESPONSE TO ANEMIA......Page 474
IRON-RESTRICTED ERYTHROPOIESIS......Page 476
LABORATORY EVALUATION OF IRON METABOLISM Biochemical Parameters......Page 483
Hematologic Parameters......Page 486
Erythropoietin Assay......Page 487
IRON THERAPY STRATEGIES......Page 489
CURRENT ISSUES IN ERYTHROPOIETIN THERAPY Safety......Page 490
Central Nervous System Effects......Page 493
Darbopoietin Alfa......Page 494
CONCLUSION......Page 495
INTRODUCTION Definition of Anemia......Page 518
Mechanisms of Anemia in Cancer Patients......Page 519
Signs and Symptoms of Anemia in Cancer Patients......Page 520
Incidence and Prevalence of Cancer-Related Anemia......Page 525
INDICATIONS FOR ANEMIA TREATMENT......Page 527
Red Blood Cell Transfusions......Page 528
Recombinant Human Erythropoietin......Page 533
Erythropoietin Treatment—Practical Considerations......Page 535
Tolerance of Erythropoietin......Page 537
POSITIVE EFFECTS OF CORRECTION OF ACD......Page 538
Initial Clinical Trials in Cancer Patients......Page 539
Clinical Trials in Patients with Hematological Malignancies......Page 540
Clinical Trials in Patients with Solid Tumors......Page 551
Prevention of Anemia with Erythropoietin Treatment......Page 556
Clinical Trials in Patients Undergoing Radiotherapy......Page 557
Clinical Trials in Surgical Cancer Patients......Page 558
Clinical Trials and the Impact of Anemia Treatment on QOL......Page 560
Clinical Trials and the Impact of Anemia Treatment and Outcome on Cancer Treatment......Page 562
CONCLUSION......Page 564
ACKNOWLEDGMENT......Page 565
INTRODUCTION: ACD AS A DEFENSE STRATEGY OF THE BODY!......Page 588
SEVERE ACD IS ASSOCIATED WITH A POOR PROGNOSIS: DOES THIS IMPLY THAT ANEMIA CORRECTION MAY BE BENEFICIAL?......Page 592
POTENTIAL HAZARDS OF SPECIFIC THERAPEUTIC REGIMEN Iron......Page 595
Transfusion......Page 598
Recombinant Human Erythropoietin......Page 600
GENERAL CONSIDERATION CONCERNING ANEMIA CORRECTION IN ACD......Page 605
ACKNOWLEDGMENT......Page 607
FREQUENCY OF ANEMIA OF CHRONIC DISEASE IN HEMATOLOGIC AND ONCOLOGIC DISORDERS......Page 622
Blunted Erythropoietin Production......Page 624
Non-ACD Factors Contributing to Anemia in Cancer Patients......Page 625
DIAGNOSIS OF ACD IN CANCER PATIENTS......Page 626
TREATMENT General Principles......Page 627
Darbepoetin......Page 628
ACKNOWLEDGMENTS......Page 629
INTRODUCTION......Page 636
RESULTS AND DISCUSSION......Page 637
Iron Status, Anemia of Chronic Disease, and Infection......Page 644
TUBERCULOSIS......Page 645
HIV INFECTION......Page 649
HIV=TUBERCULOSIS COINFECTION......Page 652
HEPCIDIN AS KEY MEDIATOR OF INFECTION-RELATED ANEMIA OF CHRONIC DISEASE......Page 653
INTRODUCTION AND PATHOGENESIS......Page 662
DIFFERENTIAL DIAGNOSIS OF ANEMIA......Page 665
LABORATORY DIAGNOSIS......Page 666
CLINICAL IMPACT OF ACD IN RHEUMATIC DISORDERS......Page 669
TREATMENT OF ACD......Page 670
SUMMARY AND POSSIBLE THERAPEUTIC FUTURE OPTIONS......Page 676
INTRODUCTION......Page 688
MECHANISMS Blood Loss......Page 689
Erythropoietin Response......Page 690
Inflammation......Page 691
Other Mechanisms......Page 692
THERAPY......Page 693
SUMMARY......Page 694
INTRODUCTION......Page 700
EPIDEMIOLOGY OF RENAL DISEASE IN THE UNITED STATES......Page 702
ANEMIA AND CHRONIC RENAL DISEASE......Page 703
ERYTHROPOIETIN AND THE KIDNEY......Page 704
ERYTHROPOIETIN PRODUCTION IN RENAL DISEASE......Page 706
ERYTHROPOIETIN PRODUCTION IN ACUTE RENAL FAILURE......Page 707
UREMIA AND ERYTHROPOIESIS......Page 708
ERYTHROPOIESIS IN UREMIA......Page 709
ERYTHROPOIESIS AND INFLAMMATION......Page 710
RENAL FAILURE AND MYELOFIBROSIS......Page 711
SHORTENED ERYTHROCYTE LIFE SPAN......Page 712
MEMBRANE ALTERATIONS IN UREMIC ERYTHROCYTES......Page 714
ABNORMAL HEMOSTASIS......Page 717
TRENDS IN rHuEPO THERAPY......Page 719
MANAGEMENT OF ANEMIA......Page 720
CLINICAL SEQUELAE OF ANEMIA IN CHRONIC RENAL DISEASE......Page 723
CLINICAL BENEFITS OF rHuEPO THERAPY......Page 724
CONCLUSION......Page 726
IMPORTANCE OF ACD IN IBD......Page 756
SPECIFIC PATHOGENESIS OF ANEMIA IN IBD Iron Deficiency Anemia......Page 757
Anemia of Chronic Disease......Page 758
Drug-Associated Anemia......Page 759
CURRENT THERAPY......Page 760
Iron Deficiency......Page 761
Anemia of Chronic Disease......Page 762
UNANSWERED ISSUES......Page 763
Index......Page 774
Back Cover......Page 782