Approach
Diagnosis is made primarily by a pattern of laboratory findings and supported by the clinical setting.
Symptoms and signs
Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise are non-specific symptoms of anaemia.
There may be a history of an underlying autoimmune, malignant, or infectious disorder; recent major surgery, major trauma, or a critical illness; or of chronic kidney disease, congestive heart failure, or chronic pulmonary disease.
Common presenting features of such underlying disorders include fever; anorexia; night sweats; arthralgia; myalgia; weight loss; the presence of a mass; adenopathy; hepatomegaly; splenomegaly; decreased breath sounds with rales; stiff neck; rash; abdominal tenderness; and tenderness of joints, shoulder girdle, or bones.
History of bleeding is unusual and, if present, an alternative or additional workup is required.
Initial investigations
Full blood count, peripheral blood smear, reticulocyte count, serum iron and ferritin, total iron-binding capacity (TIBC), transferrin saturation, and creatinine are part of the initial workup.
The anaemia of chronic disease (ACD) syndrome is defined by the following constellation of laboratory test results:
Mild to moderate anaemia that is either normocytic normochromic or microcytic hypochromic
Otherwise normal red blood cell (RBC) morphology
Normal or elevated serum ferritin
Transferrin saturation <15%
RBC indices that are normocytic and normochromic suggest ACD of fairly recent onset. RBC indices and blood smear that are microcytic and hypochromic suggest ACD that has been present for some weeks or months.[31][32] The diagnostic approach can most easily be based on mean corpuscular volume (MCV) measurement.[31]
Subsequent investigations
Further testing to rule out other causes of anaemia is often warranted (when results of initial testing are not classic or when the clinical setting is unexpected or complex). C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in the presence of inflammation, and support the diagnosis of ACD if the cause of anaemia is uncertain.
People with low MCV
Serum iron, TIBC, transferrin saturation, and ferritin are initial tests to rule out iron deficiency anaemia.
Low ferritin (<67 picomol/L [<30 nanograms/mL]) is generally diagnostic of iron deficiency, whereas ferritin is normal or elevated in ACD.[5][33] Prominent anisocytosis and poikilocytosis, including pencil-shaped RBC forms, on the peripheral smear, tend to favour iron deficiency over ACD. Increased CRP and significantly elevated ESR support ACD.
Transferrin saturation in ACD is typically >5% but <15%, and reduced TIBC is also suggestive of ACD. By contrast, very low transferrin saturation (<5%) and elevated TIBC suggest iron deficiency.
It is important to note that ACD and iron deficiency can co-exist. For example, in inflammatory bowel disease, iron deficiency is common, due to dietary factors, malabsorption, and blood loss, alongside ACD, due to inflammation.[34] Where there is a combination of iron deficiency and ACD, the ferritin level is less helpful in diagnosis. However, ferritin is elevated approximately threefold over baseline when inflammation is present. Thus, a ferritin level of 100 picomol/L (45 nanograms/mL) in a patient with a known recent ferritin value of 33 picomol/L (15 nanograms/mL) and no interim iron therapy would suggest co-existent ACD and iron deficiency.
If iron deficiency is not conclusively ruled out, further approaches, informed by clinical suspicion and test availability, include:[17][35][36][37][38]
A systematic search for bleeding
Soluble transferrin receptor (sTfR) assay (elevated in iron deficiency, and normal in ACD)
Ratio of sTfR to log ferritin (>2 in iron deficiency or co-existing iron deficiency and ACD but <1 in ACD alone)
Bone marrow examination for evaluation of iron stores
If iron studies are normal and there is no evidence of an underlying condition that might lead to ACD, one of the thalassemias is a possibility, particularly if the anaemia and low MCV are known to be longstanding or there is a positive family history. This entity is more common in people of Mediterranean, south Asian, or east Asian ancestry.[39] In this case, quantitative haemoglobin (Hb) analysis is recommended.
People with normal MCV
Common causes include ACD, mild iron deficiency, renal insufficiency, thyroid disease, significant malnutrition, and primary bone marrow disorders (e.g., myelodysplasia).
Iron studies are indicated (as for patients with low MCV), as is checking the serum creatinine level (elevated in renal disease). Thyroid function tests are indicated as hypo- and hyperthyroidism are occasional causes of anaemia.
Erythropoietin testing may show a level lower than expected for the degree of anaemia.
Specific questioning about drugs, alcohol, radiation, and chemical exposure is required to rule out a normocytic anaemia due to these agents.
People with elevated MCV
People with elevated MCV are not initially considered to have ACD. Specific questions concerning alcohol consumption and nutrition are important because malnourished individuals or those with a history of chronic alcohol misuse may have folate or B12 deficiency leading to macrocytic anaemia (excluded by measuring serum B12 and folate).
Liver function tests are indicated in people with suspected liver disease as liver disease may result in macrocytic anaemia.
Haemolytic anaemia is suspected when the absolute reticulocyte count is higher than expected for the degree of anaemia or if lactate dehydrogenase (LDH) and indirect bilirubin levels are elevated.
Patients with an isolated elevated MCV should also undergo testing for myelodysplastic syndrome.
Bone marrow examination, if not previously performed to evaluate iron store
As a final step, bone marrow examination, to assess for underlying bone marrow abnormalities, may be considered if:
Abnormalities on the blood smear are not consistent with the underlying disorder causing ACD (e.g., low granulocytes, low platelets, markedly increased platelets, nucleated RBC, other circulating precursor cells)
LDH is elevated without other adequate explanation
No other explanation for the anaemia is apparent (a situation more often encountered in people aged >50 years, given the rising incidence of myelodysplasia and the various haematological malignancies with age).
Haematology consultation is commonly obtained prior to this step.
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