What does a low mean corpuscular hemoglobin concentration indicate and how should it be evaluated and managed?

Low MCHC: Diagnostic Evaluation and Management

A low mean corpuscular hemoglobin concentration (MCHC) indicates hypochromic red blood cells—most commonly caused by iron deficiency—and requires immediate iron studies (serum ferritin, transferrin saturation, and C-reactive protein) to confirm the diagnosis and guide treatment. 1

What Low MCHC Means

Low MCHC reflects reduced hemoglobin content within red blood cells, creating hypochromia on peripheral smear. 1 This finding strongly suggests iron deficiency anemia as the primary etiology, though other causes must be systematically excluded. 2, 3

Mean corpuscular hemoglobin (MCH) is actually a more reliable marker than MCHC for detecting iron deficiency because it is less dependent on storage conditions and laboratory equipment, and it decreases in both absolute and functional iron deficiency. 2, 3, 1 When you see low MCHC, check the MCH as well—it will often be even more informative. 2

Immediate Diagnostic Workup

First-Line Laboratory Tests

Order the following panel immediately when low MCHC is detected:

• Serum ferritin – the single most specific test for iron deficiency 3, 1

  • < 15 μg/L confirms absent iron stores 3, 1
  • < 30 μg/L indicates low body iron stores in patients without inflammation 2, 3, 1
  • < 100 μg/L may still indicate iron deficiency when inflammation is present 2, 3, 1
  • > 150 μg/L essentially excludes absolute iron deficiency even with concurrent inflammation 3, 1

• Transferrin saturation (TSAT) – less affected by inflammation than ferritin 2, 3, 1

  • < 15–20% indicates insufficient circulating iron for erythropoiesis 2, 3, 1

• C-reactive protein (CRP) – essential for interpreting ferritin values 2, 1

  • Ferritin is an acute-phase reactant and can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency 3, 1

• Complete blood count with MCV and RDW 2, 1

  • Low MCV with elevated RDW (> 14%) suggests iron deficiency 3
  • Low MCV with normal RDW (≤ 14%) suggests thalassemia trait 3

• Absolute reticulocyte count – assesses bone marrow response 2, 1

  • Low or inappropriately normal count indicates impaired red cell production 2, 1

Diagnostic Algorithm

Step 1: Confirm Iron Deficiency

If ferritin < 30 μg/L (without inflammation): Iron deficiency is confirmed. 2, 3, 1

If ferritin 30–100 μg/L with elevated CRP: Suspect combined iron deficiency and anemia of chronic disease. 3, 1 Consider a therapeutic trial of iron while managing the underlying inflammatory condition. 3

If ferritin > 100 μg/L and TSAT < 20%: Diagnose anemia of chronic disease rather than iron deficiency. 3 Focus treatment on the underlying inflammatory condition. 3

Step 2: If Iron Studies Are Normal Despite Low MCHC

When iron parameters are normal but MCHC remains low, consider alternative diagnoses:

• Thalassemia trait (especially alpha or beta thalassemia) 3, 1, 4

  • Order hemoglobin electrophoresis, particularly in patients of Mediterranean, African, or Southeast Asian descent 3, 1
  • In thalassemia trait, MCV is typically reduced disproportionately to the degree of anemia 3, 1
  • Beta-thalassemia trait shows elevated HbA2 levels (> 3.5%) 4
  • Do not give iron supplementation to patients with thalassemia trait; instead offer genetic counseling if planning pregnancy 2

• Anemia of chronic disease 3, 1

  • Typically presents with normocytic anemia, low serum iron, ferritin > 100 μg/L, and TSAT < 20% 3

• Sideroblastic anemia 3, 1

  • Consider if other causes are excluded

Step 3: Investigate the Underlying Cause of Iron Deficiency

In adult men and postmenopausal women with confirmed iron deficiency, gastrointestinal blood loss is the most common cause and requires endoscopic evaluation to exclude malignancy. 5, 2, 3

• Upper gastrointestinal endoscopy with small bowel biopsy to exclude gastric cancer and celiac disease (present in 2–3% of iron deficiency cases) 5, 1
• Colonoscopy or barium enema to exclude colonic cancer and polyps 5

In premenopausal women, menstrual blood loss is the most common cause, but gastrointestinal evaluation is still warranted if iron deficiency is severe or refractory to treatment. 5

Additional causes to assess:

• Malabsorption (celiac disease, inflammatory bowel disease, prior gastric surgery) 5, 2
• NSAID use (common cause of occult GI bleeding) 5
• Dietary insufficiency 5

Treatment Approach for Confirmed Iron Deficiency

Oral Iron Supplementation (First-Line)

• Ferrous sulfate 325 mg (65 mg elemental iron) 1–3 times daily between meals 1
• Expect hemoglobin increase of approximately 1–2 g/dL every 2–4 weeks 1
• Continue iron supplementation for 3–6 months after hemoglobin normalizes to replenish iron stores 1
• Check hemoglobin, reticulocytes, and iron studies after 4–8 weeks of therapy 1

Therapeutic confirmation: A rise in hemoglobin of ≥ 1 g/dL within 2 weeks of iron therapy strongly confirms iron deficiency, even if initial iron studies were equivocal. 1

Intravenous Iron (Second-Line)

Consider parenteral iron if: 1

• Patient is intolerant to oral iron
• Poor response to oral iron (malabsorption)
• Severe anemia requiring rapid correction
• Chronic kidney disease with TSAT ≤ 30% and ferritin ≤ 500 ng/mL 2

Critical Pitfalls to Avoid

Do not rely on MCV alone. Iron deficiency can present with normal MCV in early stages, and MCH may be more sensitive than MCV for detecting iron deficiency. 3, 1

Do not dismiss "normal" ferritin in inflammatory states. In patients with infection, malignancy, chronic inflammatory disease, or liver disease, use higher ferritin thresholds (45–100 μg/L) to diagnose iron deficiency. 3, 1 Ferritin can be falsely elevated as an acute-phase reactant. 3, 1

Do not forget to investigate the cause of iron deficiency. Iron deficiency in adults often indicates ongoing blood loss requiring evaluation, particularly for gastrointestinal malignancy in men and postmenopausal women. 5, 2, 1

Watch for mixed deficiencies. In elderly individuals or patients with inflammatory bowel disease, simultaneous iron and vitamin B12 deficiencies can neutralize the MCV (making it appear normal) while MCHC remains low and RDW is elevated. 2 This mixed-deficiency pattern mandates assessment of both iron and B12 status. 2

Do not give iron to patients with thalassemia trait. If hemoglobin electrophoresis confirms thalassemia, iron supplementation is contraindicated and genetic counseling should be offered. 2

Special Considerations

Reactive thrombocytosis frequently accompanies iron deficiency anemia and represents a secondary, non-clonal response to iron shortage. 1 This elevated platelet count will normalize with iron repletion.

In chronic kidney disease patients not on dialysis with TSAT ≤ 30% and ferritin ≤ 500 ng/mL, consider a 1–3 month trial of oral or intravenous iron. 2

Low MCHC (< 32 g/dL) in dialysis patients independently predicts nonatherosclerotic cardiovascular disease and may reflect left atrial overload and left ventricular hypertrophy. 6