Iron Deficiency with Normocytic Indices: Investigation Approach
Despite a Mentzer index of 25 (suggesting iron deficiency over thalassemia) and confirmed low ferritin, the normocytic MCV does not eliminate the need for investigation—you should still proceed with full evaluation for iron deficiency anemia causes, as microcytosis is not always present in iron deficiency and its absence does not reduce the risk of serious underlying pathology. 1
Understanding the Discordance
The presence of a normocytic MCV in confirmed iron deficiency (low ferritin) is not uncommon and occurs in several scenarios:
- Mean cell hemoglobin (MCH) is more sensitive than MCV for detecting iron deficiency, as MCH decreases earlier in the iron depletion process and is less dependent on storage conditions 1
- Microcytosis loses sensitivity in the presence of chronic disease, concurrent vitamin B12/folate deficiency, or early iron deficiency 1
- Combined deficiencies (e.g., iron plus folate/B12) can mask microcytosis, though this may be recognized by an elevated red cell distribution width (RDW) 1
- Normal CBC parameters do not exclude iron deficiency—individuals can have normal RBC count, hemoglobin, hematocrit, MCV, and MCHC while having reduced serum iron and ferritin 2
Investigation Remains Mandatory
The British Society of Gastroenterology guidelines are explicit: investigation should be considered at any level of anaemia in the presence of iron deficiency, regardless of MCV. 1
Key principles:
- There is no a priori reason why mild anaemia or normocytic anaemia should be less indicative of important disease than severe or microcytic anaemia 1
- The case for investigation is stronger with more severe degrees of anaemia, as these patients are more likely to have serious underlying GI pathology, but this does not exclude investigation in milder or normocytic cases 1
- Colorectal cancer and gastric cancer can present with iron deficiency anemia at any hemoglobin level and with any MCV 1
Required Testing
Proceed with the standard iron deficiency anemia workup:
- Urinalysis or urine microscopy to exclude urinary blood loss 1
- Coeliac disease screening (tissue transglutaminase antibodies or small bowel biopsy at gastroscopy)—found in 3-5% of IDA cases 1
- Hemoglobin electrophoresis if there is appropriate ethnic background, to exclude thalassemia trait despite the normal MCV 1
- Upper and lower GI endoscopy in men, postmenopausal women, or those with GI symptoms/family history 1
Clinical Pitfalls to Avoid
Do not assume normocytic indices mean "less serious" iron deficiency:
- Measuring only CBC without iron studies misses many cases of iron depletion that will progress to iron deficiency anemia 2
- The Mentzer index (MCV/RBC) of 25 suggests iron deficiency over thalassemia (cutoff typically <13 for thalassemia, >13 for iron deficiency), but this does not change investigation requirements 3, 4
- Ferritin <15 μg/L is highly specific for iron deficiency (specificity 0.99), and values <45 μg/L warrant consideration of GI investigation even with normal MCV 1
Risk Stratification
While the absolute cancer risk may be lower in normocytic iron deficiency compared to severe microcytic anemia, age, sex, hemoglobin concentration, and MCV are all independent predictors that need holistic assessment 1. The normocytic picture does not provide sufficient reassurance to defer investigation in the presence of confirmed iron deficiency.
Bottom line: Proceed with full investigation as you would for microcytic iron deficiency anemia—the normocytic MCV is a red herring that should not delay appropriate workup. 1