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Diagnostic Work-Up of Iron Deficiency Diagnostisches Vorgehen Bei Eisenmangel

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Diagnostic Work-Up of Iron Deficiency Diagnostisches Vorgehen Bei Eisenmangel J Lab Med 2004;28(5):391–399 ᮊ 2004 by Walter de Gruyter • Berlin • New York. DOI 10.1515/LabMed.2004.054 Ha¨ matologie Redaktion: T. Nebe Diagnostic work-up of iron deficiency Diagnostisches Vorgehen bei Eisenmangel Georgia Metzgeroth and Jan Hastka unterschiedliche Stadien erfassen. Durch Bestimmung von mehreren Parametern ist es mo¨ glich, den Eisensta- III. Medizinische Universita¨ tsklinik, Klinikum Mannheim, tus einer Person pra¨ zis zu charakterisieren und den Universita¨ t Heidelberg, Germany Schweregrad des Eisenmangels genau einzustufen. Von besonderem klinischem Interesse sind neuere Parameter Abstract der eisendefizita¨ ren Erythropoese: das Zinkprotoporphy- rin (ZPP), die lo¨ slichen Transferrinrezeptoren (sTfR), die Iron deficiency (ID) is defined as a diminished total body hypochromen Erythrozyten (Hypo) und das Retikulozy- iron content. Three degrees of severity have been tenha¨ moglobin (CHr). ZPP kann als ein zuverla¨ ssiger und defined: storage iron depletion (stage I), iron-deficient preiswerter Screeningparameter des gesamten Eisen- erythropoiesis (stage II), and iron deficiency anemia stoffwechsels verwendet werden, indem es das Endsta- (stage III). When assessing the patient’s iron status, it is dium der Ha¨ msynthese u¨ berwacht. Die Bestimmung der important to bear in mind that each of the various iron sTfR-Konzentration erlaubt die Differenzierung zwischen tests indicate something different in terms of ID. As they einem echten Eisenmangel und Eisenverwertungssto¨ run- detect different stages of ID, the parameters efficiently gen bei Ana¨ mien der chronischen Erkrankung (ACD). complement each other to characterize the iron status in Hypo und CHr scheinen die besten Parameter zu sein, the individual patient. Of particular clinical interest are um Eisenmangel bei Ha¨ modialysepatienten unter Eryth- newer iron tests of the iron-deficient erythropoiesis: zinc ropoietintherapie zu diagnostizieren. protoporphyrin (ZPP), soluble transferrin receptor (sTfR), hypochrome erythrocytes (Hypo) and reticulocyte hemo- Schlu¨ sselwo¨ rter: Eisenmangel; Ferritin; hypochrome globin (CHr). Supervising the final step of the heme pro- Erythrozyten; lo¨ slicher Transferrin-Rezeptor; Retikulozy- duction, ZPP can be used as a reliable and inexpensive ten-Ha¨ moglobin; Zinkprotoporphyrin. screening test of the whole iron metabolism. sTfR meas- urement is a useful tool to distinguish between real iron deficiency and functional iron deficiency in anemia of Iron deficiency (ID) probably represents the most com- chronic disorders. Hypo and CHr seem to be the best mon deficiency disease in humans. It is estimated that parameters to diagnose ID in hemodialysis patients treat- about 500 million people worldwide suffer from ID, and ed with recombinant human erythropoietin. it is by no means a problem confined to the so-called third world. In industrial countries, the estimated preva- Keywords: ferritin; hypochrome erythrocytes; iron defi- lence of ID in women of child-bearing age is 20% w1x. ciency; reticulocyte hemoglobin; soluble transferrin This widespread occurrence results from different socio- receptor; zinc protoporphyrin. economic and physiological factors. But it is mainly pro- moted by the fact that ID is mostly regarded as a minor Zusammenfassung clinical problem, as the disease is not immediately life- Eisenmangel ist definiert als Verminderung des Ganzko¨r- threatening. Consequently, the assessment of the iron pereisens. Abha¨ ngig von dessen Schweregrad werden status is frequently performed with minimal effort, and drei Stadien unterschieden: Speichereisenmangel (Sta- unsuitable screening tests like the serum iron concentra- dium I), eisendefizita¨ re Erythropoese (Stadium II) und tion or the red cell indices are used. Eisenmangelana¨ mie (Stadium III). Wenn man den Eisen- It is of course true that ID per se is not immediately status einer Person beurteilt, muß man immer beru¨ ck- endangering life. Nevertheless, it is clinically important to sichtigen, daß die verschiedenen ‘‘Eisen-Parameter’’ diagnose ID as soon as possible. This is in particular true for pregnant women and small children, as neonates and Correspondence: Prof. Dr. Jan Hastka, III. Medizinische infants are at greatest risk of long-term or permanent Universita¨ tsklinik, Wiesbadenerstraße 7-11, 68305 Mannheim, damage. Even at the preanemic stage, insufficient iron Germany support causes developmental delays with cognitive, Tel.: q49-621-383-4110 Fax: q49-621-383-4201 neurodevelopmental and behavioral deficits in infants E-mail: [email protected] w2–6x. The early diagnosis of ID is also of vital interest in 392 G. Metzgeroth and J. Hastka: Diagnostic work-up of iron deficiency individuals whose negative iron balance is caused by a Table 1 Reference ranges of the different iron parameters w9x. malignancy of the gastrointestinal tract. Finally, there is no reason whatsoever for a considerable number of Parameter Reference values women, many children and elderly to suffer from a dis- BM – hemosiderin* 2 ease which can be diagnosed and treated without any BM – sideroblasts 15–50% problems. Hemoglobin Women: 123–153 g/l Men: 140–175 g/l MCV 80–96 fl MCH 28–33 pg Stages of iron deficiency Hypochrome erythrocytes -2.5% Reticulocyte hemoglobin G26 pg Before speaking about the assessment of the iron status, Serum iron Women: 6.6–26 mmol/l it must be clarified what the term ‘‘ID’’ means. ID is Men: 11–28 mmol/l defined as a state in which the total body iron content is Serum ferritin Women: 15–150 mg/l less than normal. But ‘‘iron deficiency’’ in itself does not Men: 30–400 mg/l mean very much, unless we take into account its severity, Transferrin 200–400 mg/dl Transferrin saturation 16–45% which is very important from the clinical point of view. sTfR** Women: 1.9–4.4 mg/l Depending on the severity, three stages of ID are distin- Men: 2.2–5.0 mg/l guished: storage iron depletion, iron-deficient erythro- TfR-F index** Women: 0.9–3.7 poiesis, and iron deficiency anemia w7x. The formerly Men: 0.9–3.4 used terms ‘‘prelatent-latent-manifest’’ are misleading Zinc protoporphyrin F40 mmol/mol heme and should be avoided. sTfR: soluble transferrin receptor; BM: bone marrow; MCH: The negative iron balance first leads to storage iron mean corpuscular hemoglobin; MCV: mean red cell volume. depletion (stage I), where the total body iron is *Scale 0–4. **The reference range is test-dependent, here Tina- quantᮋ/Roche Diagnostics. decreased, without the synthesis of hemoglobin being affected. In this stage, there is no immediate clinical dys- individual parameters do not measure a single entity function. In stage II, the iron-deficient erythropoiesis,ID called ‘‘iron deficiency’’, but they are related to different becomes a disease, as the amount of iron is no longer stages of ID. Consequently, the ‘‘best parameter’’ of ID sufficient to meet the requirement of the erythropoietic does not exist. By detecting different stages, the various precursors in the bone marrow. The hemoglobin concen- tests, however, efficiently complement one another in tration, however, is still within the reference range. Finally, order to characterize the severity of ID in the individual when the iron supply is insufficient to maintain a normal patient w10x. hemoglobin concentration, stage III of ID, the iron defi- Prussian blue staining of the bone marrow and the ciency anemia, is reached. determination of ferritin reflect the iron stores. Parame- Iron tests There are numerous parameters of iron metabolism which can be used for the assessment of the patient’s iron status (Table 1) w8x. The gold standard is still Prussian blue staining of the bone marrow. As bone marrow exam- ination is not routinely practicable, other tests are required for the evaluation of the iron status in clinical practice. Numerous laboratory tests are used, such as the serum concentration of iron, ferritin and transferrin, the determination of hemoglobin and the red cell indices mean red cell volume (MCV) and mean corpuscular hemoglobin (MCH), and the measurement of the trans- ferrin saturation. In addition to these standard markers, Figure 1 Diagnostic sensitivity of various iron tests of iron defi- new iron tests have been established in the last years, ciency (ID). Bone marrow (BM) hemosiderin and serum ferritin e.g. the measurement of soluble transferrin receptor in assess the iron stores and allow the diagnosis of iron depletion the serum (sTfR), the percentage of hypochromic eryth- (ID, stage I). Pathological values of sideroblast count, transferrin rocytes (Hypo), the reticulocyte hemoglobin (CHr), and saturation, soluble transferrin receptor, hypochrome erythro- the concentration of erythrocytic zinc protoporphyrin cytes, reticulocyte hemoglobin, and zinc protoporphyrin indicate that an iron-deficient erythropoiesis (ID, stage II) has already (ZPP). developed. Finally, hemoglobin below reference range defines When assessing the iron status, it is important to iron deficiency anemia (ID, stage III), which in severe cases is always bear in mind that each of the various tests indi- accompanied by low red cell indices. cate something different in terms of ID (Figure 1). The I, II, III: iron deficiency, stage I, II and III, respectively. G. Metzgeroth and J. Hastka: Diagnostic work-up of iron deficiency 393 ters of the iron-deficient erythropoiesis indicate whether the ZPP concentrations are mostly )100 mmol/mol the ID in a given patient is clinically relevant or not. The heme w10, 11x. presence of iron-deficient
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