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

What Causes Low MCHC?

Low Mean Corpuscular Hemoglobin Concentration (MCHC) is most commonly caused by iron deficiency anemia, representing the final and most severe stage of iron depletion where hemoglobin synthesis is profoundly impaired. 1, 2

Primary Cause: Iron Deficiency Anemia

Low MCHC occurs when iron deficiency has progressed to its most advanced stage, characterized by:

• Hemoglobin concentration typically below 9 g/dL 2
• Transferrin saturation usually less than 16% 2
• This represents the third and final stage of iron deficiency, following earlier stages where only anisocytosis and microcytosis are present 2

Iron deficiency causes low MCHC because insufficient iron is available for hemoglobin synthesis in developing red blood cells, resulting in hypochromic (pale) cells with reduced hemoglobin concentration. 1

Other Important Causes

Thalassemia

• Alpha and beta thalassemia trait cause microcytosis and hypochromia with low MCH and MCHC 1
• In thalassemia, the MCV is typically reduced out of proportion to the level of anemia, helping distinguish it from iron deficiency 1
• Critical distinction: Thalassemia presents with low MCV and normal RDW (≤14.0%), while iron deficiency shows elevated RDW (>14.0%) 1

Chronic Inflammatory Conditions

• Can cause reduced MCHC, though this is less common than iron deficiency 1
• Anemia of chronic disease can present with microcytosis, particularly when prolonged 3

Sideroblastic Anemia

• Can present with microcytosis and hypochromia, resulting in low MCHC 1

Diagnostic Algorithm

Step 1: Confirm Iron Status

• Measure serum ferritin as the single most useful marker 1
  • Ferritin <15 μg/L indicates absent iron stores 1
  • Ferritin <30 μg/L indicates low body iron stores 1
• Measure transferrin saturation to assess circulating iron available for erythropoiesis 1
  • Transferrin saturation <16-20% indicates insufficient iron for red blood cell production 1

Step 2: Evaluate RDW to Differentiate Causes

• Low MCHC + High RDW (>14.0%) strongly suggests iron deficiency anemia 1
• Low MCHC + Normal RDW (≤14.0%) suggests thalassemia minor 1

Step 3: Account for Inflammation

• Ferritin is an acute phase reactant and can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency 1
• In inflammatory conditions, ferritin up to 100 μg/L may still indicate iron deficiency 1
• Ferritin >150 μg/L essentially excludes absolute iron deficiency even with concurrent inflammation 1

Critical Pitfalls to Avoid

• Do not assume all low MCHC is iron deficiency—normal RDW with low MCHC strongly suggests thalassemia minor, and inappropriate iron therapy can cause dangerous iron overload 1, 4
• Do not miss combined deficiency states: In patients with both iron and B12/folate deficiency, MCV may appear normal while MCHC remains low 1
• Do not overlook hemoglobin electrophoresis: Normal iron studies with low MCHC warrant hemoglobin electrophoresis, particularly in patients with appropriate ethnic background for thalassemia 1

Mandatory Investigation for Confirmed Iron Deficiency

In adult men and post-menopausal women with confirmed iron deficiency causing low MCHC:

• Gastrointestinal blood loss is the most common cause and requires investigation 1
• Perform upper gastrointestinal endoscopy with small bowel biopsies, as 2-3% of patients with iron deficiency anemia have celiac disease 1
• Perform colonoscopy or barium enema to exclude gastrointestinal malignancy 4