Anemia of chronic disease differential diagnosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Differential Diagnosis
Concomitant iron deficiency — For those patients who qualify for the diagnosis of ACD, as described immediately above, the major differential is whether the patient has ACD alone or ACD with concomitant iron deficiency anemia (ACD/IDA).
●Measurement of soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index appears to be the most effective way to distinguish between ACD and ACD/IDA; sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also present [89]. (See 'Soluble transferrin receptor' above.)
●Evaluation of the percentage of hypochromic red cells and reticulocyte hemoglobin content may help in the identification of true iron deficient erythropoiesis in patients with ACD [90,91]. As an example, in two studies, a reticulocyte hemoglobin content (ret-He) <26 pg/cell was a stronger predictor of iron deficiency and IDA than routine iron studies (eg, serum iron, transferrin, transferrin saturation, ferritin, sTfR. In guidelines for functional iron deficiency [92], a ret-He cutoff >25 pg/cell may help in distinguishing between iron deficiency and ACD, although there is some overlap when iron deficiency is mild. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Findings on CBC'.)
●While bone marrow examination is not required for most patients in whom ACD is suspected, in difficult cases the diagnosis can often be established by bone marrow examination. Findings in the most common disorders include:
•ACD – Bone marrow macrophages contain normal to increased iron, while erythroid precursors show decreased to absent amounts of iron (ie, decreased to absent sideroblasts) (picture 1).
•Iron deficiency – Stainable iron is absent from both macrophages and erythroid precursors. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Differential diagnosis'.)
•Myelodysplastic syndromes – Single or multi-lineage dysplastic changes with or without increased number of sideroblasts, including ring forms, are commonly seen in patients with myelodysplasia (picture 2). (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on 'Pathologic features' and "Sideroblastic anemias: Diagnosis and management", section on 'Diagnostic approach'.)
•Sideroblastic anemias – The diagnostic hallmark of congenital or acquired sideroblastic anemia is the presence of ring sideroblasts on bone marrow examination (picture 3). The amount of iron in bone marrow macrophages is strikingly increased due to ineffective erythropoiesis. Single or multi-lineage dysplastic changes are not seen. Evaluation of sideroblastic anemias, including genetic testing, is presented separately. (See "Sideroblastic anemias: Diagnosis and management" and "Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on 'MDS with ring sideroblasts'.)
●Serum erythropoietin (EPO) levels are lower in ACD than in patients with IDA and comparable degrees of anemia [7]. However, serum EPO levels in anemic subjects scatter too broadly to be of diagnostic use in distinguishing IDA from ACD [93]. This is illustrated in the figure, which shows that the correlation between EPO levels and hematocrit is semi-logarithmic, with wide scatter of EPO levels for any particular level of hematocrit (figure 1).
●If the distinction between ACD and ACD/IDA cannot be made by laboratory tests alone, one may monitor the response to a short trial (eg, four to six weeks) of oral iron supplementation.
Other candidate disorders — As mentioned above, the anemia in ACD is commonly normocytic and normochromic, and hypoproliferative and other blood cell lines are not affected.
●The most common disorders with a similar presentation are chronic kidney disease (CKD) and anemia in the older adult, although some of these patients may also have an underlying component of inflammation. (See "Inflammation in renal insufficiency" and "Anemia in the older adult", section on 'Inflammation'.)
●Several endocrine disorders, including hyperthyroidism, hypothyroidism, panhypopituitarism, and primary and secondary hyperparathyroidism may also present with a normocytic, normochromic hypoproliferative anemia. They are diagnosed via the accompanying endocrine signs, symptoms, and hormone assays.
For patients with more severe anemia (eg, hemoglobin concentration <8 g/dL) along with hypochromic and microcytic red cells, the differential diagnosis is wider (table 3). The most common conditions, which need to be excluded, include IDA, the thalassemic disorders, sideroblastic anemias, and the sideroblastic variants of the myelodysplastic syndrome [94]. A further discussion for distinguishing among the various causes of a microcytic anemia is presented separately; although, of these conditions, only IDA is associated with low serum iron levels. (See "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis'.)