What are the causes of target cells without hypochromia in patients, particularly those of African, Mediterranean, or Asian descent?

Causes of Target Cells Without Hypochromia

Target cells without hypochromia are most commonly caused by hemoglobinopathies—particularly sickle cell disease, hemoglobin C disease, hemoglobin E disease, and hemoglobin D Punjab—as well as liver disease and post-splenectomy states. 1, 2, 3

Hemoglobinopathies (Primary Causes)

Sickle Cell Disease

• Sickle cell disease produces target cells through a distinct mechanism unrelated to iron deficiency, involving abnormal hemoglobin S polymerization that alters red blood cell membrane properties without causing hypochromia 1, 4, 5
• Target cell formation in sickle cell disease occurs due to band 3-based membrane alterations and changes in the Donnan ratio, leading to decreased cell pH and volume through K+Cl- cotransport and Gardos channel activation 4
• These patients characteristically have normochromic or slightly hypochromic anemia with target cells visible on peripheral smear 1, 2

Hemoglobin C Disease

• Hemoglobin C produces target cells through crystallization of the abnormal hemoglobin within red blood cells, causing membrane deformation without reducing hemoglobin content 5
• This structural hemoglobin variant was identified in 0.32% of screened populations in endemic areas 3

Hemoglobin E Disease

• Hemoglobin E is one of the main structural hemoglobin variants that produces target cells with relatively preserved hemoglobin content 2
• The clinical manifestations range from mild hypochromic anemia to moderate hematological disease 2

Hemoglobin D Punjab

• Hemoglobin D Punjab produces target cells and was identified in 0.76% of screened populations in South Asian ethnic groups 3
• This variant causes hemolytic anemia with target cell formation through membrane alterations related to the abnormal hemoglobin structure 3

Distinguishing Features from Iron Deficiency

Key Morphologic Differences

• Target cells in iron deficiency anemia are accompanied by prekeratocytes (present in 78% of cases) and pencil cells, which are notably absent in hemoglobinopathies 6
• In beta-thalassemia minor, target cells are present in similar numbers to iron deficiency anemia, but prekeratocytes average only 0.21 per 1,000 RBCs compared to 0.78 in iron deficiency 6
• Basophilic stippling, often cited as a feature of thalassemia, was present in only 17% of beta-thalassemia cases and does not reliably distinguish these conditions 6

Laboratory Parameters

• Hemoglobinopathies typically show normal or near-normal MCH and MCHC (indicating absence of hypochromia), distinguishing them from iron deficiency which shows low MCH and MCHC 2, 6
• MCV may be low in thalassemia but is often normal or only mildly reduced in other hemoglobinopathies 2
• RDW is typically normal or only mildly elevated in hemoglobinopathies, whereas it is markedly elevated (>14.0%) in iron deficiency 6

Other Non-Hypochromic Causes

Liver Disease

• Chronic liver disease produces target cells through alterations in red blood cell membrane lipid composition without affecting hemoglobin synthesis 5
• The mechanism involves increased cholesterol-to-phospholipid ratio in the red cell membrane, creating excess membrane surface area relative to cell volume 5

Post-Splenectomy State

• Splenectomy results in target cell formation because the spleen normally removes cells with membrane abnormalities 5
• These target cells persist in circulation without hypochromia because hemoglobin content remains normal 5

Diagnostic Algorithm

Initial Evaluation

• Order hemoglobin electrophoresis or HPLC as the definitive test to identify structural hemoglobin variants when target cells are present without hypochromia 2, 3
• Check iron studies (ferritin, transferrin saturation) to exclude coexisting iron deficiency 6
• Review peripheral smear for prekeratocytes and pencil cells, which favor iron deficiency over hemoglobinopathy 6

Ethnic and Geographic Considerations

• Hemoglobinopathies should be strongly suspected in patients of African, Mediterranean, Middle Eastern, or Asian descent with target cells and normal hemoglobin indices 1, 2
• Population screening in endemic areas shows 5.1% prevalence of sickle cell disease and significant rates of other hemoglobin variants 3

Confirmatory Testing

• Genetic testing may be required for definitive diagnosis of specific hemoglobinopathy subtypes 2
• Family screening should be considered once a hemoglobinopathy is identified, as these are inherited conditions 1, 2

Common Pitfalls to Avoid

• Do not assume all target cells indicate iron deficiency or thalassemia—structural hemoglobin variants are equally common causes and require different management 2, 3, 6
• Avoid treating empirically with iron supplementation without confirming iron deficiency, as this provides no benefit in hemoglobinopathies and may delay appropriate diagnosis 2, 6
• Do not rely on basophilic stippling to distinguish thalassemia from other causes, as it is present in only a minority of cases 6
• Do not overlook liver disease or post-splenectomy state as causes of target cells in patients without anemia or with normochromic indices 5