What is the best approach to diagnose anemia in a patient?

How to Diagnose Anemia

Begin by obtaining a complete blood count (CBC) with hemoglobin measurement, red blood cell indices (MCV, RDW), reticulocyte count, and iron studies (serum ferritin and transferrin saturation) as the minimum diagnostic workup. 1

Define Anemia Using Standard Thresholds

Apply the WHO definition of anemia, which remains valid across clinical contexts 2, 1:

• Adult men: Hemoglobin <13.0 g/dL 2, 1
• Non-pregnant adult women: Hemoglobin <12.0 g/dL 2, 1
• Pregnant women: Hemoglobin <11.0 g/dL 2
• Children 6 months-5 years: Hemoglobin <11.0 g/dL 1
• Children 5-11 years: Hemoglobin <11.5 g/dL 1
• Children 12-13 years: Hemoglobin <12.0 g/dL 1

Critical caveat: These standard definitions may not apply to elderly individuals, smokers, those living at high altitudes, or patients with certain chronic conditions—adjust thresholds accordingly in these populations. 1, 3

Minimum Initial Laboratory Workup

Once anemia is confirmed, obtain these tests immediately 2, 1:

• Complete blood count with white blood cells, hemoglobin, and platelets to assess bone marrow function 2
• Red blood cell indices: MCV (mean corpuscular volume) and RDW (red cell distribution width) 2, 1
• Reticulocyte count to evaluate bone marrow response 2, 1
• Serum ferritin as a surrogate marker for tissue iron stores 2, 1
• Transferrin saturation (TfS) to assess iron available for erythropoiesis 2, 1
• C-reactive protein (CRP) to detect inflammation 2

Use hemoglobin rather than hematocrit because hemoglobin testing is more reproducible across laboratories and is not affected by storage time or patient variables like serum glucose. 2, 1

Classify Anemia by Mean Corpuscular Volume (MCV)

The MCV is your primary classification tool and directs subsequent diagnostic steps 1, 3:

Microcytic Anemia (MCV <80 fL)

Most commonly caused by iron deficiency, thalassemia, chronic disease anemia, or sideroblastic anemia. 1

Key diagnostic findings for iron deficiency 1:

• Serum ferritin <30 μg/L (without inflammation)
• Transferrin saturation <15%
• Increased total iron binding capacity (TIBC)

Important pitfall: Ferritin is an acute phase reactant and may be falsely elevated in inflammatory states despite true iron deficiency—consider additional markers like percent hypochromic red cells or reticulocyte hemoglobin content in these cases. 2, 3

Normocytic Anemia (MCV 80-100 fL)

Caused by acute bleeding, hemolysis, bone marrow failure, chronic inflammatory anemia, or renal insufficiency. 1

Use the reticulocyte count to differentiate 1:

• Low or normal reticulocyte count: Indicates decreased red blood cell production (bone marrow failure, chronic disease, renal insufficiency, or deficiencies)
• High reticulocyte count: Suggests adequate bone marrow response to bleeding or hemolysis

The anemia of chronic kidney disease is normochromic and normocytic, indistinguishable from other chronic conditions—do not assume CKD is the sole cause without excluding other etiologies. 1

Macrocytic Anemia (MCV >100 fL)

Most commonly megaloblastic, indicating vitamin B12 or folate deficiency. 1

Obtain 1:

• Vitamin B12 level
• Folate level
• Consider methylmalonic acid and homocysteine levels to confirm B12 deficiency

Critical warning: Never give folic acid before checking B12 levels, as this can mask B12 deficiency while allowing irreversible neurological complications to progress. 3

Macrocytosis may also result from thiopurine treatment (azathioprine, 6-mercaptopurine), alcohol abuse, hypothyroidism, or reticulocytosis. 2

Extended Workup When Cause Remains Unclear

If the minimum workup does not establish a diagnosis, proceed with 2, 1:

• Vitamin B12 and folic acid levels (if not already obtained)
• Haptoglobin, lactate dehydrogenase, and bilirubin to evaluate for hemolysis
• Differential white blood cell count
• Percent hypochromic red cells or reticulocyte hemoglobin content for functional iron deficiency
• Renal function tests (creatinine, urea) to evaluate kidney disease 2, 1
• Peripheral blood smear for morphologic abnormalities 1

Abnormalities in two or more cell lines (white blood cells, hemoglobin, platelets) warrant hematology consultation. 2

Special Population Considerations

Chronic Kidney Disease Patients

Screen annually at minimum for anemia (hemoglobin <13.5 g/dL in men, <12.0 g/dL in women), with more frequent monitoring in diabetic patients who develop anemia at earlier stages of CKD. 2, 1

Inflammatory Bowel Disease Patients

Assess for anemia at every clinical visit, with complete blood count, CRP, and serum ferritin as minimum requirements to detect anemia, inflammatory flares, or iron deficiency at early stages. 2

Iron Deficiency Anemia in Adults

For confirmed iron deficiency anemia, test non-invasively for H. pylori and celiac disease before endoscopy, and perform bidirectional endoscopy in men and postmenopausal women (strong recommendation). 1 In premenopausal women, bidirectional endoscopy is conditionally recommended, particularly in younger patients. 1

Common Diagnostic Pitfalls to Avoid

• Mixed anemia can present with normal MCV when microcytosis and macrocytosis coexist—examine the RDW and peripheral smear. 1
• Low or "normal" reticulocytes in the setting of anemia indicate inability to respond properly, either from deficiencies causing inappropriate erythropoiesis or primary bone marrow disease. 2
• Increased reticulocytes exclude deficiencies and should prompt evaluation for hemolysis. 2
• In patients with extensive small bowel resection, extensive ileal Crohn's disease, or ileal-anal pouch, assess vitamin B12 and folic acid more frequently than once yearly. 2