Distinguishing Pernicious Anemia, Thalassemia Trait, and Iron-Deficiency Anemia
These three conditions all cause microcytic anemia but differ fundamentally in their underlying mechanisms, laboratory patterns, and clinical implications—iron-deficiency anemia results from depleted iron stores, thalassemia trait is a genetic disorder producing structurally abnormal hemoglobin, and pernicious anemia is an autoimmune disease causing vitamin B12 deficiency that typically presents with macrocytic (not microcytic) anemia.
Core Pathophysiologic Differences
Iron-Deficiency Anemia
- Iron-deficiency anemia develops from depleted body iron stores due to chronic blood loss, inadequate dietary intake, or malabsorption, resulting in insufficient iron for hemoglobin synthesis 1.
- The condition produces microcytic, hypochromic red cells because each erythrocyte contains less hemoglobin than normal 1.
- Reticulocyte counts remain low or normal because the bone marrow cannot mount an appropriate response without adequate iron 1.
Thalassemia Trait
- Thalassemia trait is an inherited genetic disorder affecting globin chain synthesis, producing structurally abnormal hemoglobin molecules 1.
- Patients have lifelong microcytosis from birth with uniformly small red cells, not acquired iron deficiency 2.
- Iron stores remain normal or elevated in thalassemia trait, distinguishing it from iron deficiency 1.
Pernicious Anemia
- Pernicious anemia is an autoimmune disease characterized by chronic atrophic gastritis that destroys gastric parietal cells, eliminating intrinsic factor production and preventing vitamin B12 absorption 3, 4.
- This condition typically produces macrocytic anemia with hypersegmented neutrophils, not microcytic anemia 4, 5.
- Anti-intrinsic factor antibodies are found in 60% of patients and are highly specific for pernicious anemia, while anti-parietal cell antibodies appear in 90% but have lower specificity 4.
Laboratory Discrimination Algorithm
Step 1: Mean Corpuscular Volume (MCV) Classification
Iron-deficiency anemia:
- MCV markedly reduced (often <70 fL in severe cases) 1
- Red cell distribution width (RDW) elevated >14% reflecting a mixed population of older normal-sized cells and newer microcytic cells 1, 6
Thalassemia trait:
- MCV reduced but RDW typically ≤14% because red cells are uniformly small 1, 6
- MCV disproportionately low relative to the degree of anemia (e.g., MCV 60-65 fL with only mild anemia) 6
Pernicious anemia:
- MCV elevated >100 fL (macrocytic, not microcytic) 4, 5
- Peripheral smear shows megaloblastic changes with hypersegmented neutrophils 4
Step 2: Iron Studies Interpretation
Iron-deficiency anemia:
- Serum ferritin <30 µg/L confirms depleted iron stores 1, 6
- Transferrin saturation <16-20% indicates iron-deficient erythropoiesis 1, 6
- Serum iron low, total iron-binding capacity elevated 1
Thalassemia trait:
- Serum ferritin normal or elevated (>30 µg/L) 1, 6
- Transferrin saturation normal (>20%) 6
- Hemoglobin electrophoresis shows elevated HbA2 >3.5% in β-thalassemia trait 7, 2
Pernicious anemia:
- Iron studies typically normal unless concurrent iron deficiency exists 1
- Serum vitamin B12 markedly reduced 3, 5
- Methylmalonic acid and homocysteine elevated when B12 deficiency is present 5
Step 3: Confirmatory Testing
For suspected iron-deficiency anemia:
- A hemoglobin rise ≥10 g/L within 2 weeks of oral iron therapy confirms the diagnosis even when iron studies are equivocal 6
- Investigate the source of iron loss in adults, particularly gastrointestinal bleeding or heavy menstrual bleeding 1, 6
For suspected thalassemia trait:
- Order hemoglobin electrophoresis only after confirming normal iron studies (ferritin >30 µg/L and transferrin saturation >20%) 1, 6
- Molecular testing identifies α-thalassemia trait, which does not elevate HbA2 7, 2
For suspected pernicious anemia:
- Anti-intrinsic factor antibodies are 60% sensitive but highly specific for pernicious anemia 4
- Anti-parietal cell antibodies are 90% sensitive but less specific 4
- Upper endoscopy with gastric body biopsies demonstrates chronic atrophic gastritis 4, 5
Red Cell Count Patterns
- Thalassemia trait produces elevated red blood cell counts (often >5.5 million/µL) despite low hemoglobin, reflecting the body's compensatory response to ineffective hemoglobin synthesis 2.
- Iron-deficiency anemia shows normal or reduced red cell counts relative to the degree of anemia 1, 2.
- Pernicious anemia demonstrates reduced red cell counts with large, oval macrocytes 4, 5.
Clinical Presentation Differences
Iron-Deficiency Anemia
- Symptoms develop gradually as iron stores deplete: fatigue, pallor, exertional dyspnea 1
- Koilonychia (spoon nails), glossitis, and angular cheilitis may appear in severe chronic cases 1
- Pica (especially ice craving) is characteristic 1
Thalassemia Trait
- Most patients are asymptomatic with only mild anemia discovered incidentally 2
- Lifelong microcytosis present from childhood 2
- Family history of microcytic anemia in parents or siblings 2
Pernicious Anemia
- Neurologic symptoms are prominent: paresthesias, ataxia, loss of vibration and position sense, cognitive impairment 3, 5
- Glossitis with a smooth, beefy-red tongue is characteristic 3, 5
- Onset is insidious, and patients may become acclimatized to gradual symptom progression 3
- Neurologic sequelae may become irreversible if B12 deficiency is not promptly recognized and treated 3, 5
Critical Diagnostic Pitfalls
- Do not assume all microcytic anemia is iron deficiency—thalassemia trait requires no iron therapy and iron supplementation may cause harm through iron overload 1.
- Do not order hemoglobin electrophoresis as a first-line test; confirm abnormal iron studies first to avoid unnecessary expense 6.
- Recognize that ferritin can be falsely elevated by inflammation, infection, malignancy, or liver disease; in these contexts, transferrin saturation <20% confirms true iron deficiency 1, 6.
- Pernicious anemia presents with macrocytic, not microcytic, anemia—if MCV is low, the diagnosis is not pernicious anemia unless concurrent iron deficiency exists 4, 5.
- Combined deficiencies can coexist: iron deficiency may occur alongside B12 or folate deficiency, producing a mixed picture with elevated RDW 1, 6.
- In women of African, Mediterranean, or Southeast Asian ancestry, mild anemia unresponsive to iron therapy after 4 weeks warrants hemoglobin electrophoresis to evaluate for thalassemia trait 1.