What is the process for diagnosing anemias?

Diagnostic Process for Anemia

Begin with a complete blood count (CBC) with red cell indices—hemoglobin <13 g/dL in men and <12 g/dL in non-pregnant women defines anemia—then immediately classify by mean corpuscular volume (MCV) to guide your differential diagnosis and subsequent testing. 1, 2

Step 1: Initial Laboratory Assessment

• Order a CBC with indices as your first test, using hemoglobin rather than hematocrit for better reproducibility across laboratories 2
• Obtain a peripheral blood smear to confirm RBC size, shape, and color—this provides critical diagnostic clues and identifies abnormalities in multiple cell lines that warrant hematology consultation 2
• Calculate the reticulocyte index (RI) to assess bone marrow production capacity (normal RI: 1.0-2.0); low RI indicates decreased production while high RI suggests ongoing blood loss or hemolysis 2

Step 2: Morphologic Classification by MCV

Microcytic Anemia (MCV <80 fL)

• Order iron studies immediately: serum ferritin, transferrin saturation (TSAT), total iron-binding capacity (TIBC), and serum iron 1, 2
• Absolute iron deficiency is defined as TSAT <15% and ferritin <30 ng/mL (or <30 μg/L without inflammation) 1, 2
• In inflammatory states, ferritin up to 100 μg/L may still indicate iron deficiency; measure C-reactive protein (CRP) to assess inflammation 3, 1
• If ferritin >100 μg/L with TSAT <20%, suspect anemia of chronic disease/inflammation and measure CRP 1
• If iron studies are normal, order hemoglobin electrophoresis to evaluate for thalassemia 1
• Consider genetic disorders (sideroblastic anemia, IRIDA, hemochromatosis) when ferritin is elevated with elevated TSAT, or when anemia is refractory to iron supplementation with family history 1

Normocytic Anemia (MCV 80-100 fL)

• Check reticulocyte index to distinguish between production defects (low RI) and blood loss/hemolysis (high RI) 1, 2
• Low reticulocyte index suggests iron deficiency, vitamin B12/folate deficiency, aplastic anemia, or bone marrow dysfunction 2
• High reticulocyte index indicates ongoing blood loss or hemolysis; proceed with hemolysis workup (lactate dehydrogenase, haptoglobin, bilirubin) 2, 4
• Measure inflammatory markers (CRP) to identify anemia of chronic disease 1

Macrocytic Anemia (MCV >100 fL)

• Check vitamin B12 and folate levels as first-line tests 1, 4
• Assess for medication causes (methotrexate, hydroxyurea, antiretrovirals), alcohol use, liver disease, and hypothyroidism 1
• If unexplained, consider myelodysplastic syndrome and refer to hematology 1

Step 3: Targeted History and Physical Examination

Critical History Elements

• Duration and onset of symptoms (fatigue, weakness, dyspnea, palpitations) 2
• Blood loss sources: menstrual history, gastrointestinal bleeding (melena, hematochezia), nosebleeds, blood donation 3
• Dietary intake: inadequate iron intake, vegetarian/vegan diet, pica (pagophagia—ice craving) 3
• Medications: chronic NSAID use, proton pump inhibitors (impair iron absorption), medications causing hemolysis or bone marrow suppression 3, 2
• Comorbidities: chronic kidney disease, inflammatory bowel disease, malignancy, chronic infections 1, 2
• Family history of hematologic disorders, especially for microcytic anemia refractory to treatment 1

Physical Examination Findings

• Look for specific iron deficiency signs: angular stomatitis, glossitis, koilonychia (spoon nails), blue sclerae 3
• Examine for bleeding sources: rectal examination, signs of gastrointestinal pathology 3
• Assess for hereditary hemorrhagic telangiectasia (visible telangiectasias) 3
• Check for signs of underlying chronic disease: lymphadenopathy, hepatosplenomegaly, jaundice 2

Step 4: Cause-Specific Investigation

Iron Deficiency Anemia Workup

• All adults with confirmed IDA require urinalysis/urine microscopy, celiac disease screening (serology or small bowel biopsy), and in appropriate cases, upper and lower GI endoscopy 3
• Celiac disease is found in 3-5% of IDA cases and should be routinely screened serologically 3
• In men and postmenopausal women with newly diagnosed IDA, gastroscopy and colonoscopy should be first-line GI investigations; CT colonography is reasonable if colonoscopy is not suitable 3
• Age, sex, hemoglobin concentration, and MCV are independent predictors of GI cancer risk and must be considered in holistic risk assessment 3

Anemia of Chronic Disease/Inflammation

• Diagnostic criteria: serum ferritin >100 μg/L and TSAT <20% in the presence of inflammation 3
• If ferritin is between 30-100 μg/L, a combination of true iron deficiency and anemia of chronic disease is likely 3
• Primary treatment involves addressing the underlying condition 1

Special Population Considerations

Chronic Kidney Disease

• Monitor hemoglobin every 3 months when GFR <30 mL/min 1
• Complete workup required if hemoglobin <12 g/dL in women or <13 g/dL in men 1
• Treat iron deficiency first; consider erythropoietin therapy if anemia persists despite iron therapy 1

Inflammatory Bowel Disease

• Anemia is typically multifactorial (iron deficiency from blood loss plus anemia of chronic disease) 1
• Minimum screening includes CBC, CRP, and serum ferritin at regular intervals based on disease activity 1
• Use disease-specific ferritin thresholds: <30 μg/L without inflammation, up to 100 μg/L with inflammation 3

Critical Pitfalls to Avoid

• Do not rely solely on ferritin in inflammatory conditions—it is an acute phase reactant and can be falsely elevated; always measure CRP to assess inflammation 2
• Do not assume anemia in elderly patients is a normal physiological response to aging; comprehensive evaluation is necessary 1
• Do not overlook combined deficiencies (e.g., iron and B12 deficiency occurring together), especially in elderly patients 1
• Do not miss occult GI bleeding in patients with iron deficiency who lack obvious blood loss sources 2
• In CKD patients, do not assume anemia is solely from erythropoietin deficiency—evaluate for other causes 2
• Refer to hematology when abnormalities are present in two or more cell lines (suggests bone marrow dysfunction), when anemia is refractory to treatment, or when genetic disorders are suspected 1, 2