What are the causes of a low Mean Corpuscular Hemoglobin Concentration (MCHC)?

Causes of Low MCHC (Mean Corpuscular Hemoglobin Concentration)

The primary causes of low MCHC include iron deficiency anemia, thalassemias, sideroblastic anemias, and certain genetic disorders affecting iron metabolism or heme synthesis. 1, 2, 3

Main Causes of Low MCHC

Iron Deficiency Anemia

• Most common cause of low MCHC
• Characterized by:
  • Reduced iron stores (serum ferritin <30 μg/L) 2
  • Low transferrin saturation (<20%) 2
  • Progressive decrease in hemoglobin parameters:
    1. First stage: Anisocytosis and microcytosis with normal hemoglobin
    2. Second stage: Declining MCV and MCH with mild anemia
    3. Final stage: Low MCHC with hemoglobin <9 g/dL 4
• Etiologies include:
  • Nutritional deficiency
  • Blood loss (especially gastrointestinal)
  • Malabsorption
  • Increased iron requirements (pregnancy, growth)

Thalassemias

• Genetic disorders affecting globin chain synthesis
• Beta thalassemia trait is the most common hemoglobinopathy causing low MCHC 5
• Characterized by:
  • Microcytosis out of proportion to anemia
  • Normal or elevated red cell count
  • Normal or elevated iron studies
  • Hemoglobin electrophoresis showing abnormal patterns

Sideroblastic Anemias

• Disorders of heme synthesis
• Can be inherited or acquired
• Characterized by:
  • Ring sideroblasts in bone marrow
  • Microcytosis with hypochromia
  • Paradoxical iron overload despite anemia 1, 3

Genetic Disorders of Iron Metabolism

• Iron-refractory iron deficiency anemia (IRIDA) due to TMPRSS6 gene mutations
• Atransferrinemia (defects in TF gene)
• DMT1 deficiency
• Ferroportin disease 3
• These disorders present with:
  • Microcytic, hypochromic anemia
  • Variable iron studies
  • Poor response to oral iron therapy 1

Diagnostic Approach to Low MCHC

Initial Laboratory Evaluation

• Complete blood count (CBC) with red cell indices
• Peripheral blood smear examination
• Reticulocyte count
• Iron studies:
  • Serum ferritin
  • Serum iron
  • Total iron-binding capacity (TIBC)
  • Transferrin saturation 2

Additional Testing Based on Initial Results

• If iron deficiency suspected:
  • Evaluate for sources of blood loss
  • Consider GI evaluation in men and postmenopausal women 2
• If thalassemia suspected:
  • Hemoglobin electrophoresis
  • Genetic testing
• If sideroblastic anemia suspected:
  • Bone marrow examination
  • Genetic testing for inherited forms 1

Clinical Pearls and Pitfalls

• Low MCHC with normal MCV is uncommon and warrants further investigation
• Iron deficiency is the most common cause but should be a diagnosis of exclusion
• Patients with microcytic anemia refractory to iron therapy should be evaluated for hemoglobinopathies or genetic disorders of iron metabolism 5
• In some genetic anemias (particularly sideroblastic anemias), iron overload may be more clinically significant than the anemia itself 1
• Relative hypochromia (low MCHC) can have prognostic implications in certain conditions like heart failure, even in the absence of anemia 6
• The combination of iron deficiency with thalassemia results in more severe reductions in hemoglobin parameters than either condition alone 7

By systematically evaluating patients with low MCHC using appropriate laboratory tests and clinical context, the underlying cause can be identified and appropriate management initiated to address both the anemia and any potential complications.