Table Of ContentIron Metabolism
Diagnosis and Therapy
of Anemias
Third edition
M. Wick
W. Pinggera
P. Lehmann
Springer-Verlag Wien GmbH
Dr. Manfred Wick
Institute of Clinical Chemistry, Klinikum Grosshadern, University of Munich, Germany
Prim. Univ.-Prof. Dr. Wulf Pinggera
Medical Department, General Hospital, Amstetten, Austria
Dr. Paul Lehmann
Boehringer Mannheim GmbH, Mannheim, Germany
Translation of
Eisenstoffwechsel. Diagnostik und Therapie der Anamien.
Dritte, erweiterte Auflage
Wien-New York: Springer-Verlag 1996
© 1996 Springer-Verlag Wien
Originally published by Springer-VerlagfWien in 1996
This work is subject to copyright.
All rights are reserved, whether the whole or part of the material is concerned,
specifically those of translation, reprinting, re-use of illustrations, broadcasting,
reproduction by photocopying machines or similar means, and storage in data banks.
© 1991, 1995, 1996 Springer-Verlag Wien
Originally published by Springer-VerlagfWien in 1996
Product Liability: The publisher can give no guarantee for information about drug
dosage and application thereof contained in this book. In every individual case the
respective user must check its accuracy by consulting other pharmaceutical literature.
The use of registered names, trademarks, etc. in this publication does not imply,
even in the absence of a specific statement, that such names are exempt from the
relevant protective laws and regulations and therefore free for general use.
Typesetting and Printing: Adolf Holzhausens Nachfolger, A-1070 Wien
Printed on acid-free and chlorine free bleached paper
With 33 Figures
ISBN 978-3-211-82884-7 ISBN 978-3-7091-3688-1 (eBook)
DOI 10.1007/978-3-7091-3688-1
Foreword
This book is a joint work by three authors. It seemed appropriate
to divide the work, in view of the rapid development of clinical
chemistry, together with the knowledge that medicine as a sci
ence is constantly in a state of flux and that it influences clinical
practice.
We have endeavored to describe clearly the relevance of the
principal analytes of iron metabolism to early recognition, dia
gnosis, and the monitoring of therapy, as well as to provide use
ful bedside support for the doctor.
Diagnostics, and in particular the methods of clinical chem
istry, have advanced so much in recent years that it seems worth
while also extending the range of routine diagnostics. The
authors have decided to update the book.
Based on papers for the "Consensus Conferences Frankfurt
in J annuary 1996 [171] and Oxford in March 1996" [188] a new
chapter "therapeutic approaches in anemias" was established.
The authors are grateful to Cheryl Byers and Doris Raab of
Boehringer Mannheim and to Michael Katzenberger of Springer
Verlag for their committed cooperation and their expert support
in the publication of this book.
M. Wick
W. Pinggera
July 1996 P. Lehmann
Table of Contents
Introduction .................................................................................... .
Physiological Principles .................................................................. 3
Absorption of Iron . .... ... ................................. ............................ ... 3
Iron Transport ....................... ... .................... ....... .......................... 5
Transferrin and Iron-Binding Capacity..................................... 5
Transferrin Saturation (nS) ...................................................... 7
Transferrin Receptor (TfR) ....................................................... 7
Iron Storage......... ............................. ....... .... .............................. 9
Ferritin and Isoferritins .......... .............. ....... ...... ......... ........... 10
Iron Distribution. ....... ......................... .... .... ... ............................ 12
Iron Requirement ...................................................................... 12
Iron Losses ................................................................................ 15
Erythropoiesis ........................................................................... 15
Physiological Cell Maturation ... ............................................ 15
Hemoglobin Synthesis .......................................................... 17
Erythropoietin (EPO) ............................................................. 17
Erythrocyte Degradation ............. ....... ............. ............ ... ....... 19
Hemoglobin Degradation ...................................................... 20
Disturbances of Iron Metabolism /
Disturbances of Erythropoiesis ............... .......... ......................... 22
Iron Deficiency.................... ........................... .............................. 22
Iron Overload ....................... ............. .............. .............................. 24
Disturbances of Iron Distribution ................................................. 25
Disturbances of Iron Utilization .................................................... 26
Disturbances of Iron Utilization in Dialysis Patients .................... 27
Non-Iron-Induced Disturbances of Erythropoiesis ....................... 28
Disturbances of Stem Cell Proliferation.... ................................ 28
Vitamin Bl2 and Folic Acid Deficiency.................................... 29
Hemoglobinopathies ................ .... ....... ................................... ... 30
Disturbances of Porphyrin Synthesis ........................................ 32
VIII Table of Contents
Pathologically Increased Hemolysis ............... ............. ................. 35
General Features of Hemolysis ................................................. 35
Haptoglobin.. ......................................... ...... ... .............. ... .......... 35
Features of Severe Hemolysis ................................................... 36
Corpuscular Hemolysis ................................................................. 37
Extracorpuscular, Intravascular Hemolysis .................................. 37
Methods ........................................................................................... 38
Determination of Iron .... ... ... ... ... ................................. ....... .... ....... 39
Methods .................................................................................... 40
Sample Material ...................... ..................... ... ...... ... ....... ....... ... 41
Determination of the Iron Saturation "" Total Iron-Binding
Capacity (TIBC) and of the Latent Iron-Binding Capacity
(LIB C) ................................................................................... 43
Determination of the Iron-Binding Proteins: Ferritin and
Transferrin . ... .............................. ....................... ....... ....... ......... 44
Immunoassay Methods .... ............. ... ...... ................. .... .... ...... .... 44
Ferritin .. .......... ... ...... ........................ ... ........................... .... ... ........ 47
Methods .................................................................................... 48
Reference Range ............... ................................. ....... ... .... ... ... ... 51
Transferrin in Serum ..................................................................... 52
Transferrin Saturation (TfS)....................................................... 53
Methods .................................................................................... 54
Transferrin Receptor (TfR) ........................................................... 55
Methods .................................................................................... 55
Haptoglobin .................................................................................. 55
Methods .................................................................................... 56
Determination of Vitamin Bl2 and Folate ..................................... 67
Vitamin Bl2 ................................................................................... 58
Methods .................................................................................... 58
Folic Acid . ... .... ......................... ..... ........... ... ........... .... ... ... ... ... ...... 60
Methods .................................................................................... 60
Erythropoietin (EPO) .................................................................... 62
Diagnostic Strategies: Ferritin in Iron Metabolism ... .......... ........ 63
The Body's Iron Balance .............................................................. 63
Iron Absorption Test ................................................................. 64
Clinical Significance of the Determination of Ferritin . ................ 67
Clinical Interpretation: Decreased Ferritin Concentration .. .......... 69
Prelatent Iron Deficiency... ... ... ... ... ... ... ... ... ... ...... .......... ... ......... 70
Latent Iron Deficiency . ...... ... ... ... ... ... ... ... ... ... ... ................... ...... 70
Manifest Iron Deficiency: Iron Deficiency Anemia .................. 70
Table of Contents IX
Differential Diagnosis of Iron Deficiency.. .......... ..................... 72
Clinical Pictures of Iron Deficiency .... ....... ....... ..................... ... 72
Clinical Interpretation: Elevated Ferritin Concentration ............... 76
Representative Ferritin Increase ....... ......................................... 77
Primary Hemochromatosis . ............. .......... ................................ 78
Secondary Hemochromatoses ................ ....... ......... ...... ... .......... 79
Non-representative Ferritin Increase ......................................... 80
Macrocytic Anemia ...... ........................... .......... ..................... ....... 80
Folic Acid Deficiency ............................................................... 83
Vitamin B12 Deficiency ............................................................. 84
Normocytic Anemia ...................................................................... 86
Extracorpuscular Hemolytic Anemias ...................................... 86
Corpuscular Anemias ................................................................ 88
Disturbances of Iron Utilization .................................................... 89
Uremic Anemia ......................................................................... 90
Erythropoietin ....................................................................... 90
Erythropoietin as Tumor Marker ...... .... ....... .................. ........ 91
Other Factors Influencing Uremic Anemia ........................... 92
Anemias in Chronic Inflammatory Processes and Malignant
Neoplasia ............................................................................... 93
Diagnosis of Anemias ... ............. ......... ... ........... ....... ......... ... ...... ... ... 94
Representative Ferritin Levels ...................................................... 94
Transferrin, Transferrin Saturation and Transferrin Receptor in
Disturbances of Iron Distribution .... ,. .... .......... ... .................. ..... 96
Deficiencies in the Cofactors of Erythropoiesis. ......... ......... ... ... ... 98
Therapeutic Approaches in Anemias ...... ...................................... 100
Remedying Iron Deficiency ............. ....... ....... ............................... 100
Oral Administration of Iron ......... ....... ........... ......... ... ......... ... ... 100
Parenteral Administration of Iron ............................................. 101
Erythropoietin Deficiency .. ............. .... ... ....... ................................ 102
Anemia in Renal Failure ........................................................... 102
Tumor-induced Anemias ........................................................... 104
Vitamin B12 Deficiency ................................................................ 104
Folic Acid Deficiency .. .... .... ... ... ....... ....... ....... ... ......... ......... ......... 105
Autologous Blood Donors ............. ... .... ................................ ........ 105
Other Indications. ... .... .... ....... .......... ... ........................ ......... ... ....... 106
References ........................................................................................ 113
Recommended Reading .................................................................. 125
Subject Index ................................................................................... 127
Introduction
Disturbances of iron metabolism, particularly iron deficiency,
are among the most commonly overlooked or misinterpreted dis
eases. This is due to the fact that the determination of transport
iron in serum or plasma, which used to be the test in convention
al diagnosis, does not allow a representative estimate of the
body's total iron reserves. A proper estimate was formerly possi
ble only by the costly and invasive determination of storage iron
in the bone marrow, however, sensitive, well-standardized
immuno-chemical methods for the precise determination of the
iron storage protein ferritin in plasma are now available. Since
the secretion of this protein correctly reflects the iron stores in
the majority of cases, these methods permit fast and reliable
diagnoses, particularly of iron deficiency conditions. The fact
that iron deficiency is so common and is usually simple to treat
ought to be well known in the medical world.
Even non-iron-determined causes of anemia can now be
identified rapidly by highly sensitive, well standardized immu
no-chemical methods. This book is intended to contribute to a
better understanding of the main pathophysiological foundations
and diagnostic principles (Fig. 1).
2 Introduction
Absorption Blood loss Hb synthesis
Dietary iron
Bone marrow
Erythroblasts
Ferritin
Hel
reduc
tion
Hemolysis
Ferritin
RE cells
Intestine
Heme
Hepatocytes
Bile F,e;r-ri-tin- -------...
Feces
Urine
Excretion Transport Storage
Fig. 1. Physiological Fundaments of Iron Metabolism
Physiological Principles
Iron, as a constituent of hemoglobin and cytochromes, is one of
the most important biocatalysts in the human body.
Absorption of Iron
The absorption of iron by the human body is limited by the phy
sico-chemical and physiological properties of iron ions, and is
possible only through protein binding of the Fe2+ ion (Fig. 2).
Cells of the intestinal mucosa
Lumen of the
intestine Blood
j
Apo·
e ------..t.ra nsfernn
Fe-chelate(s)
Ligand(s) Ape- Jt Ferritin Transferrin
A A A
ferritin ~===
~ ~eJ
Fig. 2. Intestinal Iron Absorption
