What is the current approach to diagnosing and classifying anemia?

Current Approach to Diagnosing and Classifying Anemia

The diagnosis and classification of anemia begins with measuring hemoglobin concentration to confirm anemia, followed by a systematic algorithmic approach using mean corpuscular volume (MCV) and reticulocyte count to categorize the anemia type and guide targeted diagnostic testing. 1, 2

Initial Diagnosis of Anemia

Hemoglobin thresholds for diagnosing anemia:

• Men ≥18 years: Hemoglobin <13.5 g/dL (135 g/L) 1, 3
• Women ≥18 years: Hemoglobin <12.0 g/dL (120 g/L) 1, 3
• Children 6 months-5 years: <11.0 g/dL 3
• Children 5-11 years: <11.5 g/dL 3
• Children 12-13 years: <12.0 g/dL 3

Important caveats: These standard definitions may not apply to pregnant or menstruating women, individuals living at high altitude, smokers, elderly patients ≥70 years, non-Caucasian populations, patients with chronic lung disease, or those with hemoglobinopathies. 1, 3

Primary Classification Algorithm

Step 1: Obtain Complete Blood Count with Red Cell Indices

Essential initial laboratory tests include: 2, 3

• Complete blood count (CBC) with hemoglobin, hematocrit, and red cell indices
• Mean corpuscular volume (MCV) - the primary classification parameter
• Red cell distribution width (RDW)
• Reticulocyte count (absolute and percentage)
• Peripheral blood smear examination

Step 2: Classify by MCV (Mean Corpuscular Volume)

The MCV is the cornerstone of anemia classification, dividing anemias into three major categories: 1, 2

Microcytic Anemia (MCV <80 fL)

Most common causes: 1, 2

• Iron deficiency anemia (most common)
• Thalassemia
• Anemia of chronic disease
• Sideroblastic anemia
• Lead poisoning (rare)

Key diagnostic tests for microcytic anemia: 1, 2

• Serum ferritin: <30 μg/L indicates iron deficiency in the absence of inflammation 1, 2
• In the presence of inflammation: Ferritin up to 100 μg/L may still indicate iron deficiency 1
• Transferrin saturation (TSAT): <15-16% suggests iron deficiency 2, 3
• RDW >14% with low MCV suggests iron deficiency anemia 2
• RDW ≤14% with low MCV suggests thalassemia minor 2
• Total iron binding capacity (TIBC): Elevated in iron deficiency 2

Critical distinction: Ferritin is an acute-phase reactant and becomes elevated during inflammation, potentially masking iron deficiency. In inflammatory states, use the higher ferritin threshold of 100 μg/L to diagnose iron deficiency. 1, 3

Normocytic Anemia (MCV 80-100 fL)

Most common causes: 1, 3

• Acute blood loss
• Hemolysis
• Anemia of chronic disease/inflammation
• Renal insufficiency
• Bone marrow failure (aplastic anemia, pure red cell aplasia)
• Primary bone marrow diseases (leukemias, myelodysplastic syndrome)
• Bone marrow infiltration by malignancy

Macrocytic Anemia (MCV >100 fL)

Most common causes: 1, 2

• Vitamin B12 deficiency (pernicious anemia, H. pylori gastritis, antacid use, veganism)
• Folate deficiency (increased requirement in pregnancy, hemolysis, chronic disease)
• Myelodysplastic syndrome
• Alcoholism
• Certain medications (e.g., azathioprine)

Key diagnostic tests for macrocytic anemia: 2, 3

• Vitamin B12 level
• Folate level
• Methylmalonic acid and homocysteine (elevated in B12 deficiency) 3

Step 3: Assess Reticulocyte Count

The reticulocyte count determines whether the bone marrow is responding appropriately to anemia and provides critical information about the direction of investigation: 1

Low or Normal Reticulocyte Count (Decreased Production)

Indicates decreased red blood cell production due to: 1, 2

• Nutritional deficiencies (iron, B12, folate)
• Bone marrow dysfunction
• Anemia of chronic disease
• Aplastic anemia or bone marrow infiltration

All deficiency states are excluded by increased reticulocytes. 1

Elevated Reticulocyte Count (Increased Production)

Indicates appropriate bone marrow response, suggesting: 1, 2

• Acute or chronic blood loss
• Hemolytic anemia
• Response to treatment of nutritional deficiency

For hemolytic anemia, additional tests include: 3

• Decreased haptoglobin
• Elevated lactate dehydrogenase (LDH)
• Elevated indirect bilirubin
• Direct Coombs test (positive in immune-mediated hemolysis)

Specific Diagnostic Pathways

Microcytic Anemia with Low/Normal Reticulocytes

Diagnostic sequence: 1, 2

1. Check serum ferritin and transferrin saturation
2. If ferritin <30 μg/L (or <100 μg/L with inflammation): Iron deficiency anemia
3. If normal iron studies with persistent microcytosis: Consider thalassemia trait - obtain hemoglobin electrophoresis 2
4. If elevated ferritin with low transferrin saturation: Anemia of chronic disease 2

Microcytic Anemia with Elevated Reticulocytes

Primary consideration: 1

• Hemoglobinopathies (thalassemia syndromes)
• Obtain hemoglobin electrophoresis

Normocytic Anemia with Low/Normal Reticulocytes

Diagnostic considerations: 1

• Check renal function (creatinine, estimated GFR) for renal anemia
• Assess for chronic disease (inflammatory markers: CRP, ESR)
• Consider bone marrow evaluation if other causes excluded

Normocytic Anemia with Elevated Reticulocytes

Primary diagnosis: 1

• Hemolytic anemia - proceed with hemolysis workup (LDH, haptoglobin, indirect bilirubin, Coombs test)

Macrocytic Anemia with Low/Normal Reticulocytes

Diagnostic sequence: 1, 2

1. Check vitamin B12 and folate levels
2. Review medication history
3. Assess alcohol intake
4. Check liver and thyroid function tests
5. If unexplained, consider myelodysplastic syndrome - bone marrow evaluation may be needed

Critical Pitfalls to Avoid

Mixed anemias can present with normal MCV when microcytosis and macrocytosis coexist (e.g., combined iron deficiency and B12/folate deficiency), leading to missed diagnoses. 1, 2 Always review the RDW, which will be elevated in mixed anemias, and examine the peripheral smear for dual populations of red cells.

Functional iron deficiency occurs in inflammatory states where iron is sequestered in macrophages despite adequate total body iron stores. This is mediated by hepcidin upregulation, which reduces ferroportin expression and blocks iron export from macrophages. 1 These patients may have normal or elevated ferritin but low transferrin saturation, creating iron-deficient erythropoiesis.

Anemia of chronic disease can be microcytic or normocytic. 1 Inflammatory cytokines upregulate hepcidin production, reduce erythropoietin production, and directly inhibit erythropoiesis. 1

For genetic disorders of iron metabolism or heme synthesis (rare microcytic anemias), consider these when: 1

• Anemia is refractory or incompletely responsive to iron supplementation
• Elevated ferritin and/or transferrin saturation with microcytic anemia
• Low transferrin saturation with low-normal ferritin (>20 μg/L)
• Family history of anemia
• Associated features such as neurologic disease or skin photosensitivity

In these genetic anemias, iron overload may be of greater consequence than the anemia itself, making accurate diagnosis essential to prevent severe morbidity and mortality from unrecognized tissue iron loading. 1

Frequency of Monitoring

Screen chronic kidney disease patients at minimum yearly for anemia, given the high prevalence and association with increased mortality and progression to end-stage renal disease. 1 More frequent monitoring may be indicated in patients with diabetes or progressive kidney disease. 1