In anemia of inflammation, high concentrations of hepcidin triggered by IL-6, TNF-α and other cytokines cause reticuloendothelial cells to sequester iron, via hepcidin. This leads to iron-restricted erythropoiesis, even though bodily supplies of iron are adequate. Inflammatory mediators also trigger shortened red blood cell survival and blunted production of erythropoietin.5
Workup/Diagnosis of Anemia
Anemia is diagnosed on the basis of reduced hemoglobin concentrations (<12 g/dL for women and <13 g/dL for men). Standard analyses include mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), reticulocyte count, peripheral smear and iron markers, such as serum iron, ferritin, transferrin and transferrin saturation. A standard workup should also include renal function tests, haptoglobin and lactate dehydrogenase (to screen for hemolysis), as well as folic acid, B12 and vitamin D to rule out vitamin deficiencies. Other tests may be needed if clinically suspected or if further investigation is required.1
Dr. Weiss notes that the proper diagnosis of anemia in these patients can be challenging. “Apart from the underlying rheumatic disease, other pathophysiological mechanisms or disorders may contribute to anemia which need to be identified and treated. One major problem in treating such patients is the lack of good surrogate markers, which can correctly identify true iron deficiency in the setting of inflammation.”
For rheumatologists, one of the most common problems is distinguishing anemia of inflammation, true iron-deficiency anemia and anemia with both components. In both iron-deficiency anemia and anemia of inflammation, both serum iron and transferrin saturation are reduced. In anemia of inflammation, the concentration of ferritin is normal or increased and circulating transferrin is low. This contrasts with iron-deficiency anemia, in which ferritin is low and transferrin is normal to increased.1,5
Traditionally, marrow iron staining has been used to distinguish the two entities in cases of diagnostic uncertainty. Anemia with inflammation reveals stainable iron in bone marrow macrophages, whereas iron-deficiency anemia does not. However, this test has been criticized due to its invasive and qualitative nature, and because iron therapy sometimes causes marrow iron deposition that may be poorly bioavailable. Measures of serum ferritin have largely replaced this measure, but ferritin may be influenced by iron loading and inflammation, making it difficult to diagnose true iron deficiency if inflammation is also present.1,5 As a rule of thumb, a ferritin concentration greater than 150 ng/mL is rare in anemia of inflammation concomitant with absolute iron deficiency.
Researchers have developed newer clinical markers, including soluble transferrin receptor (sTfR) in serum, an indicator of the needs of iron for erythropoiesis. However, the test has some limits in clinical utility because of a lack of standardization, and because age, ethnicity and inflammation influence its normal range.1
