Causes of Anemia
Anemia can be classified based on morphology and underlying mechanisms, with the most common causes being iron deficiency, chronic disease, and blood loss. 1, 2
Classification by Red Blood Cell Morphology
Microcytic Anemia (MCV < 80 fL)
Iron deficiency anemia: Most common cause globally 3
- Due to blood loss (GI bleeding, menstruation)
- Reduced dietary iron intake
- Malabsorption (celiac disease, post-bariatric surgery) 1
- Increased requirements (pregnancy, infancy)
Anemia of chronic disease/inflammation: Cytokine-mediated iron sequestration 1, 4
Thalassemia: Genetic disorders affecting hemoglobin synthesis 1
Sideroblastic anemia: Defects in heme synthesis 1
- Genetic (SLC25A38, STEAP3)
- Acquired (alcohol, lead poisoning, medications)
Normocytic Anemia (MCV 80-100 fL)
Acute blood loss: Initially normocytic before becoming microcytic 1
Chronic kidney disease: Decreased erythropoietin production 1
- Functional iron deficiency
- Reduced erythropoietin production
- Uremic toxins affecting erythropoiesis
Hemolytic anemia: Increased destruction of RBCs 1
- Immune-mediated
- Mechanical (heart valves, microangiopathies)
- Hereditary (sickle cell disease, G6PD deficiency)
Bone marrow failure: Decreased production of all cell lines 1
- Aplastic anemia
- Myelodysplastic syndrome
- Leukemia/lymphoma infiltration
Macrocytic Anemia (MCV > 100 fL)
Vitamin B12 deficiency: 1
- Pernicious anemia (autoimmune)
- Malabsorption (Crohn's disease, celiac disease)
- Dietary deficiency (strict vegans)
- H. pylori gastritis, antacid use
Folate deficiency: 1
- Dietary deficiency
- Increased requirements (pregnancy, hemolysis)
- Medications (methotrexate, anticonvulsants)
Alcoholism: Direct toxic effect on bone marrow 1
Medications: Chemotherapy, antiretrovirals, anticonvulsants 1
Myelodysplastic syndrome: Ineffective erythropoiesis 1
Hypothyroidism: Reduced metabolic rate affecting erythropoiesis 1
Classification by Pathophysiologic Mechanism
Decreased Production
- Nutritional deficiencies (iron, B12, folate)
- Bone marrow disorders
- Chronic inflammation
- Renal insufficiency
- Endocrine disorders (hypothyroidism)
Increased Destruction/Loss
- Hemolysis (intravascular or extravascular)
- Acute or chronic blood loss
- Hypersplenism
Special Populations
Elderly
- Multiple contributing causes are common 1, 6
- One-third have nutritional deficiency
- One-third have anemia of chronic disease
- One-third have unexplained anemia (possibly due to erythropoietin resistance and subclinical inflammation) 6
Inflammatory Bowel Disease
- Iron deficiency due to chronic blood loss and malabsorption
- Anemia of chronic inflammation
- Vitamin B12/folate deficiency
- Medication-induced (sulfasalazine, azathioprine) 1, 5
Chronic Kidney Disease
- Decreased erythropoietin production
- Functional iron deficiency
- Uremic toxins affecting erythropoiesis
- Blood loss from dialysis and frequent phlebotomy 1
Diagnostic Approach
Complete blood count with indices:
- Hemoglobin/hematocrit
- MCV (microcytic, normocytic, macrocytic)
- RDW (elevated in iron deficiency)
Reticulocyte count:
- Low: decreased production
- High: blood loss or hemolysis
Iron studies:
Additional tests as indicated:
- Vitamin B12 and folate levels
- Hemolysis markers (LDH, haptoglobin, bilirubin)
- Kidney function tests
- Inflammatory markers (CRP, ESR)
- Bone marrow examination in selected cases
Common Pitfalls in Diagnosis
- Relying solely on hemoglobin/hematocrit without investigating the cause 2
- Overlooking multiple concurrent causes, especially in elderly patients 1
- Failing to consider inflammation's effect on ferritin interpretation 1, 2
- Not investigating GI blood loss in non-menstruating patients with iron deficiency 1, 2
- Attributing anemia solely to a known condition without complete evaluation 7
Understanding the morphologic classification and underlying pathophysiologic mechanisms of anemia is essential for appropriate diagnosis and management of this common clinical condition.