Jan Hastka

Anemia is defined as a decrease in the hemoglobin concentration below the age- and sex-specific lower limit, established by WHO as 130 g/L in men and 120 g/L in women. In principle, there are many differential diagnoses which must be considered. The diagnostic evaluation furthermore is complicated by the fact that anemias are often multicausal. A rational evaluation of anemia should always take into account the epidemiological data and also the individual patient’s history. The classification according to the size and the hemoglobin content of the red blood cells based on the erythrocyte indices still plays a central diagnostic role. The worldwide most important cause of a hypochromic-microcytic anemia is iron deficiency. Anemia of chronic disease (ACD) and thalassemia are to be considered as differential diagnoses. Disorders of vitamin B12 and folic acid metabolism are clinically the most important causes of hyperchromic-macrocytic anemia. The normochromic-normocytic group includes most forms of anemias. In these cases one should not try to cover all possible causes by a fully comprehensive laboratory panel within the first blood sample already. It is more appropriate to proceed step-by-step to evaluate the most frequent and clinically most important reasons first. This especially applies to geriatric and multimorbid patients where the diagnostic effort must be adjusted to the individual needs and prognosis of the patient, not only from economical but also from ethical reasons. In unexplained anemias, consultation of a hematologist should be considered. In case of doubt, bone marrow biopsy is required to precisely evaluate the hematopoiesis and to exclude a hematological disorder.

Article Erratum zu: Rationale Anämieabklärung was published on December 1, 2015 in the journal Journal of Laboratory Medicine (volume 39, issue 6).

Zusammenfassung: Eine Anämie ist definiert als eine Verminderung der Hämoglobinkonzentration unter die alters- und geschlechtsspezifische Norm. Diese beträgt nach der WHO 120 g/L für Frauen und 130 g/L für Männer. Prinzipiell gibt es viele Differentialdiagnosen, die bei der Abklärung einer Anämie ursächlich berücksichtigt werden müssen. Die Diagnose wird zusätzlich dadurch erschwert, dass Anämien häufig nicht nur eine Ursache haben, sondern multifaktoriell bedingt sind. Eine rationale Anämieabklärung sollte immer die epidemiologischen Daten und die individuelle Anamnese berücksichtigen. Eine zentrale diagnostische Rolle spielt nach wie vor die Einteilung der Anämien nach der Größe und dem Hämoglobingehalt der Erythrozyten anhand der Erythrozytenindizes. Die weltweit wichtigste Ursache einer hypochrom-mikrozytären Anämie ist der Eisenmangel, differentialdiagnostisch sind die Anämie der chronischen Erkrankungen (anemia of chronic disorders, ACD) und Thalassämien zu berücksichtigen. Die klinisch wichtigste Ursache einer hyperchrom-makrozytären Anämie sind Störungen des Vitamin-B12- und Folsäurestoffwechsels, bzw. der DNA-Synthese. Die normochrom-normozytäre Gruppe beinhaltet die meisten Anämieformen. Bei deren Abklärung sollte man nicht versuchen alle möglichen Ursachen durch ein allesumfassendes Laborpanel bereits mit der ersten Blutentnahme zu erfassen. Es ist sinnvoller schrittweise vorzugehen und zunächst nur die wichtigsten Ursachen diagnostisch abzudecken. Dies gilt insbesondere für geriatrische und multimorbide Patienten, bei denen der diagnostischen Aufwand nicht nur aus wirtschaftlichen, sondern auch aus ethischen Gründen der individuellen Prognose und den Bedürfnissen des Patienten angepasst werden sollte. Bei ungeklärten Anämien sollte eine Vorstellung bei einem Hämatologen erwogen werden, weil im Zweifelsfall auch eine Knochenmarkpunktion erfolgen muss, um die Hämatopoese genau zu beurteilen und eine hämatologische Grunderkrankung auszuschließen.

The clarification of enlarged lymph nodes is a common issue in clinical routine. By now, open surgery with complete lymph node extirpation, followed by histopathology, is considered as standard. We investigated the value of fine needle aspiration (FNA) and core needle biopsy (CNB) when supporting the conventional morphology by immunotyping. In total, 101 lymph nodes (reactive, n = 19; lymphoma, n = 46; metastatic, n = 36) were examined. CNB specimens were sufficient for unequivocal diagnosis by histopathology in 95 %. The FNA cytology allowed a correct diagnosis in 49 %. When supported by immunocytology, the success rate improved to 72 %. By accepting “suspicious of” as correct diagnosis, the ratio increased to 91 %. Additional use of flow cytometry in 46 samples minimized the “suspicious of” diagnoses and increased the proportion of unequivocal diagnoses in FNA specimens to 87 %. Flow cytometry allowed a correct subtyping in 20 of 21 B cell lymphoma but recognised only one of five Hodgkin lymphoma. All eight reactive samples were correctly diagnosed by flow cytometry. In summary, CNB allows a reliable clarification of an unclear lymphadenopathy. FNA is a powerful first diagnostic approach, especially if cytology is supported by immunocytology. The most substantial contribution of flow cytometry in FNA is the discrimination between reactive lymphadenopathy and B cell lymphoma.

The differentiation between primary myelofibrosis (PMF) and essential thrombocythaemia (ET) may be difficult especially in early-stage disease. In PMF, increased levels of inflammatory cytokines induce impaired iron utilisation and disturbed erythropoiesis. In conditions with impaired iron support to erythropoiesis, zinc protoporphyrin (ZPP) is produced instead of heme. Here, we investigate whether ZPP concentration can be useful in the differentiation between PMF and ET. Seventy newly diagnosed patients (PMF, n = 24; ET, n = 46) were analysed. Intraerythrocytic ZPP concentration (normal ≤ 40 μmol/mol heme) was measured by an Aviv front-face haematofluorometer. In PMF, ZPP concentrations were significantly increased when compared to ET (99 ± 37 μmol/mol heme vs. 36 ± 13 μmol/mol heme, p < 0.0001). There was also a significant difference between early-stage PMF and advanced disease (77 ± 30 μmol/mol heme vs. 122 ± 31 μmol/mol heme, p = 0.003). ZPP >76 μmol/mol heme as observed in 71% of PMF patients were not seen in ET. In PMF patients responding to immunosuppressive treatment (n = 4), the increase in haemoglobin was accompanied by declining ZPP. In summary, by detecting the disturbed iron metabolism common in PMF, ZPP may assist in the differentiation between PMF and ET. Concentrations >60 μmol/mol heme are unlikely in ET if iron deficiency is excluded. ZPP determination is also useful for monitoring the effect of therapy in PMF.

The soluble transferrin receptor (sTfR) is established as a test for iron deficiency (ID). In chronic lymphocytic leukemia (CLL), sTfR is not reliable for screening for ID as the latter is strongly dependent on tumor burden. We investigated whether the influence of the tumor load can be excluded or minimized using the sTfR/log ferritin ratio (TfR-F-Index) and the C-reactive protein (CRP)-adjusted TfR-F-Index in 87 patients with CLL. sTfR was measured nephelometrically (normal: 0.81-1.75 mg/L). A cut-off value of 1.5 for the TfR-F-Index and 0.8 for the CRP-adjusted TfR-F-Index, in patients with a CRP >5 mg/L, was used. All Binet A patients had normal sTfR values (1.34+/-0.2 mg/L), TfR-F-Index (0.67+/-0.2) and a CRP-adjusted TfR-F-Index. In Binet B and C, sTfR and the TfR-F-Index were significantly increased compared to Binet A patients (p<0.0001). The differences between Binet B and C were not significant. sTfR was increased in 85%, TfR-F-Index in 46% and the CRP-adjusted TfR-F-Index in 54% of the Binet B patients, in Binet C patients, 80%, 50% and 60% showed increases, respectively. sTfR and the TfR-F-Index decreased or even normalized following successful treatment. Similar to sTfR, the TfR-F-Index is strongly associated with tumor burden in patients with CLL. Thus, these parameters do not allow for a reliable diagnosis of ID in this patient group.