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Do you know which disease fits this month’s case? Then test your knowledge in the quiz below!

Can you explain this microcytic anaemia? Beta-thalassaemia minor
Functional iron deficiency due to a gastric ulcer (Ulcus pepticum)
Diet-induced iron deficiency anaemia
Myelodysplastic syndrome: refractory anaemia with ring sideroblasts (RARS)


Online Version of this month´s case:

The correct answer to July´s Quiz is:

Diet-induced iron deficiency anaemia

Scattergrams and microscopy

Patient history: a microcytic anaemia was detected in a 66-year old man complaining about fatigue.

 

Table

Interpretation and Differential Diagnosis

The answer can be inferred from…

  • Microcytosis: low MCV and high MicroR
  • Hypochromic anaemia: low HGB, low MCH and high HYPO-He
  • Chronic ineffective erythropoiesis: low RET-He and normal Delta-He
  • High RBC size distribution: high RDW-CV
  • No abnormalities in WBC lineages

 

Case history

A 66-year old man turned to the general practitioner doctor complaining about fatigue. A blood sample was sent to the laboratory for analysis.

Case results

Blood analysis revealed microcytic (low MCV and high MicroR) hypochromic (low MCH and high HYPO-He) anaemia. Both RBC-He and RET-He were low, resulting in a normal value for Delta-He. This is a sign of chronic ineffective erythropoiesis. WBC lineages and PLT showed normal counts; no signs of dysplasia were observed (normal NEUT-GI, no NRBC or abnormal IPF): this makes a bone marrow failure unlikely for an ineffective erythropoiesis.
Microcytic hypochromic anaemia may be present in a number of pathological conditions: iron deficiency anaemia (IDA), thalassaemia, anaemia of chronic disease and myelodysplastic syndrome. The latter two conditions can be excluded in this case due to normal bone marrow function in this patient and absence of activation of immune system due to possible infection (no IG, no lymphocytosis or  neutrophilia, and no activation of lymphocytes or neutrophils where observed (normal values for RE-LYMPH and NEUT-RI).
Iron deficiency anaemia and beta-thalassaemia minor can be differentiated based on a combination of RBC parameters. In IDA and thalassemia the RBC are increased, but in B-thalassaemia minor, the size are uniformly small which results in a decreased red cell distribution width, which is not the case in IDA (in this case RDW-CV is high). Furthermore, the amount of % hypochromic cells in relation to % microcytes is much higher in IDA than in Thalassemia. These three parameters are used in a formula to calculate the Urrechaga index in order to differentiate IDA and beta-thalassaemia minor:

Urrechaga Index (MicroR - HYPO-He - RDW-CV)
> -5.1 ->  β-thalassaemia minor
< -5.1 ->  iron deficiency

In this case, the Urrechaga index is MicroR - HYPO-He - RDW-CV = - 12.6 which strongly supports the iron deficiency condition (< - 5.1). Based on these indices, iron deficiency anaemia was confirmed.


The following answers are incorrect for the described reasons

 

Beta-thalassaemia minor

Thalassaemia is an autosomal heritable disease caused by defective globin chain synthesis. The severity of the clinical symptoms is used to classify thalassaemias into major, intermedia and minor. β-Thalassaemia minor can be either generally asymptomatic or exhibit anaemia-related symptoms such as tiredness, weakness, numbness in the extremities, a weak immune system and depression.
Haematologically, it presents as a microcytic anaemia and should be differentiated from iron deficiency. Several different formulas, taking into account red blood cell parameters, have been proposed to differentiate thalassaemia from other microcytic anaemia conditions. Recently, it was demonstrated by Urrechaga et al. that an index using the Sysmex parameters MicroR, HYPO-He, RDW-CV shows the best sensitivity and specificity (1):

Urrechaga Index (MicroR - HYPO-He - RDW-CV)
> -5.1 ->  β-thalassaemia minor
< -5.1 ->  iron deficiency

In this case, MicroR - HYPO-He - RDW-CV = - 12.6, which strongly supports an iron deficiency condition and excludes thalassaemia.

Functional iron deficiency due to a gastric ulcer (Ulcus pepticum)


A peptic ulcer is a defect in the gastric or duodenal wall that extends through the mucosa into the deeper layers of the wall. More than 50% of cases are caused by Helicobacter pylori. Frequent use of nonsteroidal anti-inflammatory drugs (NSAIDs) is another common cause.
Besides the chronic inflammation, these patients frequently have iron deficiency anaemia due to gastrointestinal blood loss, which occurs in the majority of cases. The bleeding is usually weak and often occurs asymptomatically for the patient. A chronic bleeding and inflammation result in iron deficiency when the intake of iron is not enough (which is also decreased by chronic inflammation) to compensate for iron loss caused by the bleeding. However, the body also responds to a chronic bleeding by increasing erythropoiesis, which leads to a very pronounced reticulocytosis, and by directing extra fluid into the vascular space to keep the blood volume constant, which leads to decreased RBC values. No effective reticulocytosis and no decreased RBC were observed in this case. Furthermore the Delta-He would be mostly decreased in case of inflammation which is not observed in this case.

Myelodysplastic syndrome: refractory anaemia with ring sideroblasts (RARS)


The myelodysplastic syndromes comprise a heterogeneous group of malignant haematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production. Refractory anaemia with ring sideroblasts (RARS) is characterized by anaemia, erythroid dysplasia and ring sideroblasts. Anaemia is usually macrocytic or normocytic, and the number of reticulocytes is very low. Patients may also have thrombocytopenia or neutropenia. In the observed case, the patient had an extremely microcytic anaemia with a normal reticulocyte count and no abnormalities like NRBC, which is not typical for RARS. White blood cells lineages were not affected, (no neutropenia or abnormal NEUT-GI were observed); RARS could therefore be excluded.

Underlying Disease

Anaemia is a common condition, particularly in young women and in the geriatric population, and it is a significant public health problem in developing countries. Anaemia is defined by the World Health Organisation as a haemoglobin concentration below 120 g/L in women and below 130 g/L in men. Iron deficiency is the most frequent cause of anaemia (29% of all causes) and remains the most common cause of microcytosis, followed by thalassaemia. Iron deficiency states are characterized by hypochromic, microcytic anaemia. Patients suffer from fatigue, paleness, tachycardia and shortness of breath.

Iron metabolism is finely tuned to regulate intestinal absorption and serum iron levels. Iron deficiency is defined as a low serum iron concentration, elevated transferrin iron binding capacity (as a response to deficiency) and a low serum ferritin concentration (reflecting low iron stores). Iron deficiency anaemia (IDA) requires a differential diagnosis from anaemia of chronic disease (ACD), β-thalassaemia and myelodysplastic syndromes (MDS), which can all present with microcytic and hypochromic red blood cells (RBC) (2). The biggest challenge is to differentiate IDA and beta-thalassaemia minor. Iron deficiency anaemia and beta-thalassaemia can be differentiated based on a combination of RBC parameters.
Already the first CBC results can be useful for differentiating thalassaemia minor and iron deficiency. For example, in IDA, the RBC is usually normal to slightly increased, while it is elevated in mild thalassaemia. Another informative parameter is the red cell distribution width (RDW). As IDA progresses, each successive wave of new red blood cells gets smaller and smaller, which results in a high RDW. In contrast, in thalassaemia all red blood cells are uniformly small, and the RDW is low. MircoR and HYPO-He are other useful parameters to differentiate between thalassaemia and IDA: in IDA, the number of microcytes and the fraction of hypochromic RBC (HYPO-He) are equally increased resulting in a MicroR to HYPO-He ratio of lower then 2, whereas in thalassaemia the ratio MicroR to HYPO-He is mostly increased (>2)  (9). Several different formulas have been proposed that take into account red blood cell parameters from the blood count (3-4):

Green and King index (MCV2 * RDW-CV / HGB)
< 73 → β-thalassaemia minor
> 73 → iron deficiency

Urrechaga index (MicroR - HYPO-He - RDW-CV)
> -5.1 → β-thalassaemia minor
< -5.1 → iron deficiency

Recently it has been demonstrated by Urrechaga et al. that the index using the Sysmex parameters MicroR, HYPO-He, RDW-CV shows a very good sensitivity and specificity (1).
In this case, the values of the Green and King index (=80,3) and Urrechaga index (= -12,6) all indicate iron deficiency and not thalassaemia.

Literature

  1. Urrechaga E et al. (2011): Erythrocyte parameters in iron deficiency and thalassemia. J Clin Lab Anal. 25:223-228
  2. Harrington AM et al. (2008): Iron deficiency anemia, β-thalassemia minor, and anemia of chronic disease. Am J Clin Pathol, 129:466-471
  3. Green R and King R (1989): A new red cell discriminant incorporating volume dispersion for differentiating iron deficiency anemia from thalassemia minor. Blood Cells, 15:481-495
  4. Urrechaga E et al. (2011): The role of automated measurement of RBC subpopulations in differential diagnosis of microcytic anemia and β-thalassemia screening. Am J Clin Pathol. 135:374-379

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