Low MCHC: Differential Diagnosis and Management
Direct Answer
Low mean corpuscular hemoglobin concentration (MCHC < 27 g/dL) indicates hypochromic anemia and most commonly signals iron deficiency; immediately order serum ferritin, transferrin saturation, and C-reactive protein to confirm the diagnosis and initiate oral iron supplementation while investigating the underlying cause. 1
Initial Laboratory Work-Up
When MCHC is low, obtain the following tests simultaneously to establish the diagnosis and guide treatment:
- Complete blood count with red-cell indices (MCV, MCH, RDW) to characterize the anemia pattern 1, 2
- Serum ferritin – the single most specific test for iron deficiency 1, 2
- Transferrin saturation (TSAT) calculated as (serum iron × 100) ÷ TIBC 1, 3
- C-reactive protein (CRP) to detect inflammation that may falsely elevate ferritin 1, 2
- Absolute reticulocyte count to assess bone marrow response 1, 2
Interpreting Ferritin Results
Without Inflammation (Normal CRP)
- Ferritin < 30 µg/L confirms iron deficiency and requires no further testing 1, 3
- Ferritin < 15 µg/L provides 99% specificity for absolute iron deficiency 1, 3
- Ferritin > 100 µg/L essentially rules out iron deficiency when inflammation is absent 3
With Inflammation (Elevated CRP/ESR)
Because ferritin is an acute-phase reactant, higher thresholds are required:
- Ferritin 30–100 µg/L with TSAT < 20% indicates true iron deficiency coexisting with anemia of chronic disease 1, 3
- Ferritin > 100 µg/L with TSAT < 20% defines anemia of chronic disease with functional iron deficiency, not true iron deficiency 3
- In inflammatory states, ferritin up to 100 µg/L may still represent iron deficiency 1, 3
- Ferritin > 150 µg/L makes absolute iron deficiency unlikely even with inflammation 1, 3
Transferrin Saturation as the Decisive Marker
TSAT < 20% is the primary confirmatory test for iron deficiency, especially when ferritin is equivocal (30–100 µg/L) or potentially elevated by inflammation. 1, 3
- TSAT < 16% together with microcytosis (MCV < 80 fL) and hypochromia (MCHC < 27 g/dL) strongly supports iron-deficiency anemia 4, 1
- TSAT is less affected by inflammation than ferritin and provides more reliable assessment of iron availability for erythropoiesis 1, 2
Differential Diagnosis When Iron Studies Are Normal
If ferritin is normal or elevated and TSAT ≥ 20% despite low MCHC, consider:
Thalassemia Trait
- Order hemoglobin electrophoresis, particularly in patients of Mediterranean, African, or Southeast Asian descent 1, 2
- Thalassemia trait typically shows MCV disproportionately reduced relative to the degree of anemia, with normal iron parameters 1, 2
- Do not supplement iron in thalassemia trait; offer genetic counseling if planning pregnancy 2
Anemia of Chronic Disease
- Characterized by ferritin > 100 µg/L, TSAT < 20%, and elevated inflammatory markers 2, 3
- Treatment focuses on managing the underlying inflammatory condition rather than iron supplementation 2, 3
Sideroblastic Anemia
- Rare genetic disorders presenting with microcytic hypochromic anemia but elevated TSAT and increased ferritin 3
- Requires bone-marrow examination showing ring sideroblasts for confirmation 3
Investigation for Underlying Cause
Once iron deficiency is confirmed, identify the source of blood loss:
- In adult men and postmenopausal women, gastrointestinal bleeding is the presumptive source until proven otherwise 3
- Order bidirectional endoscopy (upper endoscopy + colonoscopy) promptly to exclude colorectal or gastric malignancy 3
- Do not delay endoscopic evaluation even if hemoglobin is above fast-track thresholds; investigation is indicated at any anemia level when iron deficiency is present 3
- In premenopausal women, assess menstrual blood loss, but do not attribute severe iron deficiency solely to menstruation—gastrointestinal pathology must still be investigated 3
- Evaluate for malabsorption (celiac disease, inflammatory bowel disease, prior gastric surgery) when iron deficiency is refractory to oral therapy 2, 3
Treatment of Confirmed Iron Deficiency
Oral Iron Therapy (First-Line)
- Initiate ferrous sulfate 325 mg (65 mg elemental iron) once to three times daily between meals 1, 3
- 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 (target ferritin > 50 µg/L) 1, 3
- Check hemoglobin, reticulocytes, and iron studies after 4–8 weeks of therapy 1
- A therapeutic rise in hemoglobin of ≥10 g/L (≈1 g/dL) within two weeks strongly confirms absolute iron deficiency, even when baseline iron studies are equivocal 1
Intravenous Iron (Second-Line)
Consider parenteral iron when:
- The patient is intolerant to oral iron 1
- Poor response to oral iron despite adherence 1
- Malabsorption is documented 3
- Severe anemia requires rapid correction 1
Common Pitfalls and How to Avoid Them
- Do not rely on MCV alone—iron deficiency can present with normal MCV in early stages; MCH and MCHC are more sensitive markers 1, 5
- Do not interpret ferritin without concurrent CRP measurement in patients with chronic disease, inflammation, or malignancy; ferritin can be falsely elevated up to 100 µg/L despite true iron deficiency 1, 3
- Do not discontinue iron supplementation once hemoglobin normalizes—iron stores must be restored (target ferritin > 50 µg/L) to prevent rapid recurrence 3
- Do not overlook combined deficiencies—iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by an elevated RDW despite normal or near-normal MCV 2, 3
- Do not assume mild anemia is less clinically significant—even mild preoperative anemia (hemoglobin 10–12 g/dL) is an independent risk factor for postoperative morbidity and mortality 4
- Do not postpone endoscopic investigation while awaiting response to iron therapy—malignancy work-up should proceed in parallel with iron supplementation 3
Special Populations
Inflammatory Bowel Disease
- In IBD patients in remission, ferritin < 30 µg/L reliably indicates iron deficiency 3
- During active IBD inflammation, use ferritin < 100 µg/L as a screening threshold and confirm iron deficiency with TSAT < 20% 3
Chronic Kidney Disease
- Absolute iron deficiency is defined as ferritin < 100 ng/mL and TSAT < 20% 3
- For non-dialysis CKD patients with TSAT ≤ 30% and ferritin ≤ 500 ng/mL, consider a 1–3 month trial of oral or intravenous iron 2, 3