What are the possible causes of chronic anemia?

Causes of Chronic Anemia

Chronic anemia results from three primary mechanisms: decreased red blood cell production, increased destruction, or blood loss, with iron deficiency and anemia of chronic disease being the most common causes in clinical practice. 1

Initial Diagnostic Framework

The evaluation begins with a complete blood count (CBC) with indices and peripheral blood smear to characterize red blood cell size, shape, and color 1. The morphologic approach classifies anemia by mean corpuscular volume (MCV), while the kinetic approach uses reticulocyte index to distinguish production versus destruction/loss mechanisms 1.

Major Categories by MCV

Microcytic Anemia (MCV <80 fL)

Iron deficiency is the most common cause of microcytic anemia 1:

• Chronic blood loss (gastrointestinal tract most common in men and postmenopausal women) 2
• Reduced iron intake or absorption 3
• Functional iron deficiency in inflammatory states 4

Other microcytic causes include 1:

• Thalassemia (alpha and beta variants) 5, 6
• Anemia of chronic disease 1, 4
• Sideroblastic anemia 1, 6

Normocytic Anemia (MCV 80-100 fL)

The reticulocyte count is the key follow-up test to distinguish causes 1:

Low reticulocyte index indicates decreased production 1:

• Anemia of chronic inflammation/disease (infections, autoimmune disorders, malignancy) 7, 8, 9
• Chronic kidney disease with erythropoietin deficiency 5, 10
• Bone marrow failure or infiltration 1, 4
• Early iron deficiency 1

High reticulocyte index indicates increased production in response to 1:

• Acute or chronic hemorrhage 4
• Hemolysis 1, 4

Macrocytic Anemia (MCV >100 fL)

Megaloblastic causes (most common) 1:

• Vitamin B12 deficiency (pernicious anemia, malabsorption, lack of intrinsic factor) 5, 4
• Folate deficiency 5, 3

Non-megaloblastic causes 1, 4:

• Myelodysplastic syndrome 1, 4
• Medications (hydroxyurea, methotrexate, azathioprine) 4, 3
• Alcoholism 1, 4
• Hypothyroidism 4

Specific Chronic Disease States

Anemia of Chronic Disease/Inflammation

This is the second most common anemia worldwide after iron deficiency 7, 8. The pathophysiology involves 7, 8, 9:

• Hepcidin upregulation by inflammatory cytokines, causing iron sequestration in macrophages and hepatocytes 7, 8
• Suppressed erythropoietin response to anemia 7, 8
• Shortened red blood cell survival 7, 8
• Direct inhibition of erythroid cell differentiation 7

Common underlying conditions include 7, 8:

• Infections (acute and chronic) 5, 7
• Autoimmune disorders 7, 8
• Malignancy 1, 7
• Chronic kidney disease 10, 7
• Congestive heart failure 10, 11, 7
• Inflammatory bowel disease 3

Chronic Kidney Disease

Anemia prevalence increases as glomerular filtration rate declines, especially below 30 mL/min/1.73m² 10. Multiple mechanisms contribute 10, 12, 13:

• Erythropoietin deficiency (primary cause) 5, 10
• Absolute and functional iron deficiency 10, 12
• Shortened red blood cell survival 5
• Uremic toxins inhibiting erythropoiesis 5

Diagnostic Pitfalls and Key Laboratory Interpretations

Iron Studies in Inflammatory States

A critical caveat: ferritin is an acute-phase reactant and can be falsely elevated in inflammation 3, 4, 2:

• Without inflammation: ferritin <30 μg/L indicates iron deficiency 3, 4, 3
• With inflammation: ferritin up to 100 μg/L may still represent iron deficiency 3, 4, 3
• Ferritin >100 μg/L with transferrin saturation <16-20% suggests anemia of chronic disease 3, 4, 3
• Ferritin 30-100 μg/L indicates likely combined iron deficiency and anemia of chronic disease 3, 4, 3

Absolute vs. Functional Iron Deficiency

Absolute iron deficiency 1:

• Transferrin saturation <15-16% 1, 3
• Ferritin <30 ng/mL (without inflammation) 1

Functional iron deficiency 4, 10:

• Adequate total body iron stores but unavailable for erythropoiesis 4, 10
• Occurs in chronic kidney disease and inflammatory states 10, 12
• Ferritin may be normal or elevated with low transferrin saturation 4, 10

Less Common but Important Causes

Hemoglobinopathies 5, 6:

• Sickle cell disease (responds poorly to erythropoietin) 5
• Alpha thalassemia (more common in Asian populations) 5, 6

Bone marrow disorders 1, 4:

• Myelodysplastic syndrome 1, 4
• Aplastic anemia 1, 4
• Bone marrow infiltration by malignancy 4

Medication-induced 3:

• Sulfasalazine, thiopurines, methotrexate, calcineurin inhibitors 3

Hyperparathyroidism with osteitis fibrosa 5:

• Marrow fibrosis replaces erythroid elements 5

Aluminum toxicity 5:

• Prolongs treatment time or necessitates higher erythropoietin doses 5