Causes of Low RBC Indices
Low RBC indices (specifically low MCV and MCH) are most commonly caused by iron deficiency anemia, followed by thalassemia, anemia of chronic disease, and sideroblastic anemia. 1, 2
Primary Causes by Index Type
Low Mean Corpuscular Volume (MCV <80 fL) - Microcytic Anemia
The morphologic classification identifies four main causes of microcytic anemia 1:
- Iron deficiency anemia - the most common cause of microcytosis, resulting from inadequate iron for hemoglobin synthesis 1, 2
- Thalassemia (both alpha and beta variants) - hereditary defects in red blood cell production causing impaired hemoglobin chain synthesis 1
- Anemia of chronic disease/chronic inflammation - inflammatory conditions that interfere with iron utilization 1
- Sideroblastic anemia - defective heme synthesis despite adequate iron stores 1
Low Mean Corpuscular Hemoglobin (MCH) - Hypochromic Anemia
Low MCH indicates decreased hemoglobin content per red blood cell, creating pale (hypochromic) cells 2. This occurs in the same conditions that cause microcytosis, as both reflect impaired hemoglobin synthesis 2, 3.
Additional Causes of Anemia Beyond Microcytic Patterns
Nutritional Deficiencies
- Folate deficiency - causes macrocytic anemia (MCV >100 fL), not low indices 1
- Vitamin B12 deficiency - also causes macrocytosis, not microcytosis 1
Blood Loss and Destruction
- Acute or chronic hemorrhage - initially normocytic, but becomes microcytic once iron stores are depleted 1
- Hemolysis - typically normocytic with elevated reticulocyte count 1
Bone Marrow and Systemic Conditions
- Bone marrow failure or suppression - from cancer, chemotherapy, or radiation 1
- Renal insufficiency - causes normocytic anemia due to decreased erythropoietin production 1
- Lead poisoning - can cause microcytosis with elevated erythrocyte protoporphyrin 1
Distinguishing Between the Main Microcytic Causes
Iron Deficiency vs. Thalassemia
Use RDW to differentiate: A low MCV with RDW >14.0% indicates iron deficiency anemia, whereas low MCV with RDW ≤14.0% suggests thalassemia minor 1. Iron deficiency causes greater variation in red blood cell size than thalassemia 1.
Confirmatory testing for iron deficiency 1, 2:
- Transferrin saturation <15%
- Ferritin <30 ng/mL (most specific test in absence of inflammation)
- Elevated TIBC
Confirmatory testing for thalassemia 2:
- Hemoglobin electrophoresis
- Family history of hereditary anemia 1
- Elevated RBC count despite low hemoglobin 4
Anemia of Chronic Disease
This presents with microcytosis but differs from iron deficiency by having 1:
- Normal or elevated ferritin (inflammation elevates ferritin)
- Low serum iron with low TIBC
- Recent or current infection, chronic inflammation 1
Clinical Pitfalls to Avoid
Do not rely on MCV alone - the kinetic approach using reticulocyte index provides critical information about bone marrow response and helps distinguish production defects from blood loss or hemolysis 1.
Beware of mixed deficiencies - patients can have both iron deficiency and thalassemia trait, or iron deficiency masked by concurrent B12/folate deficiency 1.
Consider lead poisoning in at-risk populations, as it elevates erythrocyte protoporphyrin and causes microcytosis similar to iron deficiency 1.
Inflammation confounds iron studies - ferritin can be falsely elevated in cancer or chronic inflammatory conditions despite true iron deficiency 1, 2.