What is the differential diagnosis and treatment approach for a patient presenting with anemia, considering various underlying causes such as iron deficiency, vitamin B12 or folate deficiency, chronic diseases, and blood loss?

Anemia Differential Diagnosis and Treatment Approach

Initial Diagnostic Framework

Begin by classifying anemia using mean corpuscular volume (MCV) and reticulocyte count, while simultaneously excluding correctable causes including iron deficiency, vitamin B12/folate deficiency, blood loss, renal insufficiency, and medication effects. 1

Essential Initial Laboratory Tests

• Complete blood count with MCV and red cell distribution width (RDW) to classify anemia type 1
• Reticulocyte count to distinguish between decreased production (low reticulocyte index <1.0-2.0) versus increased destruction or blood loss (high reticulocyte index) 1
• Serum ferritin with interpretation based on inflammatory status 1
• C-reactive protein (CRP) to assess for inflammation affecting ferritin interpretation 1
• Vitamin B12 and folate levels especially if macrocytosis present 1
• Transferrin saturation as additional iron marker 1

Classification by MCV

Microcytic Anemia (MCV <80 fL)

Iron deficiency anemia is the most common cause and requires evaluation for blood loss sources. 1, 2

Diagnostic Criteria for Iron Deficiency

• Without inflammation: Ferritin <30 μg/L confirms iron deficiency 1, 3
• With inflammation: Ferritin up to 100 μg/L may still indicate iron deficiency 1, 3
• Ferritin <15 μg/L is highly specific for iron deficiency regardless of inflammation 1, 3
• Transferrin saturation <20% supports diagnosis 1

Critical Evaluation Steps

• Investigate and exclude sources of blood loss in all patients with iron deficiency anemia 1
• Endoscopy is warranted in older patients with iron deficiency anemia to evaluate for gastrointestinal malignancy, with 60-70% having identifiable GI bleeding sources 2, 4
• Consider occult blood testing and thorough drug exposure history 1

Normocytic Anemia (MCV 80-100 fL)

Evaluate reticulocyte index to distinguish between production defects and blood loss/hemolysis. 1

Low Reticulocyte Index (<1.0-2.0)

• Anemia of chronic disease characterized by ferritin >100 μg/L and transferrin saturation <20% 1
• Chronic kidney disease with glomerular filtration rate <60 mL/min/1.73 m² 1
• Bone marrow dysfunction from malignancy or myelosuppressive chemotherapy 1
• Early iron deficiency before MCV drops 1, 3

High Reticulocyte Index (>2.0)

• Acute blood loss requiring stool guaiac testing and endoscopy 1
• Hemolysis requiring Coombs test, haptoglobin, indirect bilirubin, and lactate dehydrogenase 1

Macrocytic Anemia (MCV >100 fL)

Vitamin B12 and folate deficiency are the most common causes of megaloblastic macrocytic anemia. 1

Diagnostic Approach

• Measure serum B12 and folate levels in all patients with macrocytosis 1
• Consider homocysteine or methylmalonic acid if B12 deficiency suspected but serum levels equivocal 1
• Evaluate for myelodysplastic syndrome if nutritional deficiencies excluded 1, 2
• Review medications including hydroxyurea, antiretrovirals, anticonvulsants, sulfasalazine, and methotrexate 1, 2

Critical Diagnostic Pitfalls

Mixed Deficiency States

In combined iron and B12 deficiency, macrocytosis from B12 deficiency can be masked by microcytosis from iron deficiency, resulting in normal MCV despite both deficiencies. 5, 3

• High RDW indicates coexisting deficiencies even when MCV appears normal 3
• Never assume normal MCV excludes B12 deficiency when iron deficiency coexists 3
• Check both iron studies and B12/folate levels regardless of MCV in patients with gastrointestinal disease 5

Inflammation Effects on Ferritin

Acute and chronic inflammatory conditions, liver disease, and malignancy elevate ferritin independent of iron status. 1

• Use ferritin threshold of 100 μg/L in inflammatory states rather than 30 μg/L 1, 3
• Measure CRP or other inflammatory markers when ferritin interpretation is uncertain 1
• Consider total iron binding capacity if inflammation affects ferritin levels 1

Treatment Algorithms

Iron Deficiency Anemia Treatment

Treat iron deficiency following identification and management of underlying blood loss sources. 1

Without Active Inflammation

• Oral iron supplementation with no more than 100 mg elemental iron daily 3
• Lower-dose formulations may be equally effective with fewer adverse effects 4
• Normalization of hemoglobin typically occurs by 8 weeks in most patients 4

With Active Inflammation or Malabsorption

• Parenteral iron is preferred because systemic inflammation inhibits oral iron absorption 3
• Multiple intravenous iron formulations available differing in dose and frequency 1, 6
• Oral iron has limited efficacy in chronic inflammatory conditions 7

Non-Response to Oral Iron

• Evaluate for non-adherence, malabsorption, ongoing blood loss, or systemic disease 2
• Consider parenteral iron infusion for patients who have not responded to or cannot tolerate oral therapy 4

Vitamin B12 Deficiency Treatment

CRITICAL: Treat vitamin B12 deficiency immediately before initiating folic acid, as folate supplementation may mask severe B12 depletion while allowing irreversible neurological damage to progress. 1, 3

With Neurological Involvement

• Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement 1, 3
• Then hydroxocobalamin 1 mg IM every 2 months for life 1
• Seek urgent specialist advice from neurologist and hematologist 1

Without Neurological Involvement

• Hydroxocobalamin 1 mg IM three times weekly for 2 weeks 1
• Followed by maintenance 1 mg IM every 2-3 months for life 1
• Oral vitamin B12 can be as effective as intramuscular in managing B12 deficiency anemia 2

Folate Deficiency Treatment

Only after excluding B12 deficiency: Oral folic acid 5 mg daily for minimum of 4 months 1

Anemia of Chronic Disease

Optimization of underlying disease treatment should precede any erythropoiesis-stimulating agent (ESA) therapy. 1

When to Consider ESA Therapy

• Insufficient response to intravenous iron despite optimized disease therapy 1
• Target hemoglobin level not above 12 g/dL 1
• Use lowest dose to avoid RBC transfusions 1, 8
• ESAs increase risk of death, myocardial infarction, stroke, and thromboembolism when targeting hemoglobin >11 g/dL 1, 8

ESA Contraindications

• Uncontrolled hypertension 8
• Cancer patients receiving curative-intent chemotherapy 1, 8
• Pure red cell aplasia history 8

Red Blood Cell Transfusion Indications

Blood transfusion may be considered when hemoglobin <7 g/dL, or above if symptoms or particular risk factors present. 1

• Hemoglobin <7.5 g/dL with symptoms or hemodynamic instability requires packed red cell transfusion 3
• Transfusions should be followed by subsequent intravenous iron supplementation 1
• Not appropriate for chronic anemia management as it does not address underlying disorder 7
• Not a substitute for immediate correction needs 1, 8

Special Populations

Inflammatory Bowel Disease

• Annual screening of B12 and folate levels recommended 1
• Closer surveillance needed for patients with extensive small bowel disease, ileal resection, or ileal-anal pouch 1, 5
• Terminal ileum is primary site for B12 absorption making ileal disease high-risk 5

Post-Bariatric Surgery

• Protein malabsorption and dietary insufficiency increase risk years after surgery 1
• Thiamine deficiency requires immediate treatment if suspected 1
• Regular monitoring essential for early detection 1

Cancer Patients on Chemotherapy

• ESAs only indicated for anemia from myelosuppressive chemotherapy with minimum 2 additional months planned 1, 8
• Not indicated for patients receiving hormonal agents, biologics, or radiotherapy alone 1, 8
• Discontinue following completion of chemotherapy course 1

Monitoring and Follow-Up

• Serial monitoring of hemoglobin, MCV, ferritin, and B12 levels assesses treatment response 3
• Relapse of anemia after therapy is frequent requiring close follow-up 6
• Blood pressure monitoring essential during ESA therapy as hypertension is common side effect 8