What is the approach to a patient presenting with fatigue and pallor, potentially indicating anemia due to iron deficiency, vitamin deficiency, or chronic disease?

Approach to Fatigue with Pallor

Begin with a complete blood count (CBC) with indices and peripheral blood smear to characterize the anemia, followed by serum ferritin and transferrin saturation to determine if iron deficiency is present, adjusting ferritin thresholds based on inflammatory status. 1, 2

Initial Laboratory Assessment

Order the following tests immediately:

• CBC with differential and indices to assess hemoglobin, mean corpuscular volume (MCV), and identify other cytopenias 1
• Peripheral blood smear to confirm RBC size, shape, and color 1
• Serum ferritin as the most efficient test for iron deficiency 2, 3
• Transferrin saturation (TSAT) calculated as serum iron/TIBC × 100 2
• Inflammatory markers (CRP, ESR) to interpret ferritin accurately, as ferritin is an acute phase reactant 1, 2

Interpreting Iron Studies Based on Inflammatory Status

Without Inflammation Present

• Ferritin <30 mcg/L confirms iron deficiency 1, 2
• Transferrin saturation <16-20% indicates insufficient iron for erythropoiesis 1, 2

With Inflammation Present (elevated CRP/ESR)

• Ferritin threshold increases to 100 mcg/L as the lower limit of normal 1, 2
• Ferritin 30-100 mcg/L with TSAT <20% suggests combined iron deficiency and anemia of chronic disease 1
• Ferritin >100 mcg/L with TSAT <20% indicates anemia of chronic disease 1

Morphologic Classification by MCV

Microcytic Anemia (MCV <80 fL)

• Most commonly caused by iron deficiency 1
• Other causes include thalassemia, anemia of chronic disease, and sideroblastic anemia 1
• Check hemoglobin electrophoresis if microcytosis persists with normal iron studies to exclude thalassemia 2

Normocytic Anemia (MCV 80-100 fL)

• Obtain reticulocyte count (corrected for anemia) to distinguish production vs. destruction 1
• Low reticulocyte index (<1.0-2.0) suggests decreased RBC production from iron deficiency, vitamin B12/folate deficiency, or bone marrow dysfunction 1
• High reticulocyte index suggests blood loss or hemolysis 1

Macrocytic Anemia (MCV >100 fL)

• Check vitamin B12 and folate levels 1
• Most commonly indicates vitamin B12 or folate deficiency from insufficient uptake or inadequate absorption 1
• Consider medication effects (hydroxyurea, methotrexate, azathioprine, sulfasalazine) 1

Additional Essential Testing

Check the following to identify treatable causes:

• Vitamin B12 and folate levels for macrocytic anemia or suspected deficiency 1
• Serum creatinine and GFR to evaluate for chronic kidney disease 1
• Thyroid function (TSH) as hypothyroidism contributes to anemia 2
• Stool guaiac testing for occult gastrointestinal blood loss 2

Investigating the Underlying Cause

Critical: Exclude Gastrointestinal Malignancy

All adults with confirmed iron deficiency anemia require investigation for gastrointestinal blood loss, except premenopausal women with documented menorrhagia 2

• Bidirectional endoscopy (upper and lower) is mandatory to exclude gastrointestinal malignancy 2
• Do not assume menstruation is the cause in women >40 years or those with severe anemia without excluding GI pathology 2
• Do not stop investigation after negative initial endoscopy if anemia is severe, progressive, or unresponsive to iron therapy 2

History Must Include

• Duration and onset of symptoms (syncope, dyspnea, headache, vertigo, chest pain, fatigue disrupting daily activities) 1
• Menstrual history in women including volume and duration of bleeding 4, 5
• Gastrointestinal symptoms including blood in stool, change in bowel habits 1
• Dietary history for inadequate iron intake, vegetarian/vegan diet 5
• Medication review for NSAIDs, anticoagulants, proton pump inhibitors, H2-blockers 2, 5
• Comorbidities including inflammatory bowel disease, chronic kidney disease, heart failure, cancer 1, 5

Physical Examination Findings

• Pallor of mucous membranes and conjunctiva 1, 4
• Koilonychia (spoon nails) indicating chronic iron deficiency 4
• Systolic flow murmur from increased cardiac output 4
• Signs of underlying disease: jaundice, splenomegaly, neurologic symptoms, petechiae 1

Treatment Approach

Oral Iron Therapy (First-Line for Most Patients)

Initiate ferrous sulfate 325 mg daily or on alternate days 2, 5

• Alternate-day dosing may improve absorption as daily iron increases hepcidin levels that inhibit absorption 2
• Avoid taking with proton pump inhibitors, H2-blockers, or food that reduces absorption 2
• Common side effects include dyspepsia, constipation, heartburn contributing to non-compliance 2
• Target hemoglobin increase of at least 2 g/dL within 4 weeks 1
• Normalization typically occurs by 8 weeks in most patients 6

Intravenous Iron Therapy (Preferred in Specific Situations)

Use IV iron as first-line treatment in the following scenarios: 1, 2

• Clinically active inflammatory bowel disease 1
• Previous intolerance to oral iron 1
• Hemoglobin <10 g/dL 1
• Malabsorption conditions (celiac disease, post-bariatric surgery) 5
• Ongoing blood loss exceeding oral absorption capacity 2
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 5
• Second and third trimesters of pregnancy 5
• 65% of oral iron non-responders respond to IV iron compared to only 21% continuing oral therapy 2

Vitamin B12 Deficiency Treatment

For pernicious anemia or severe B12 deficiency: 7

• Administer 100 mcg intramuscularly or deep subcutaneous daily for 6-7 days 7
• Then alternate days for 7 doses, then every 3-4 days for 2-3 weeks 7
• Maintenance: 100 mcg monthly for life 7
• Oral B12 is not dependable for pernicious anemia 7

Treatment Goals and Monitoring

Target the following endpoints: 1, 2

• Ferritin >30 mcg/L to replenish iron stores 2
• Transferrin saturation >20% 2
• Hemoglobin normalization (>13 g/dL men, >12 g/dL women) 1

Common Pitfalls to Avoid

• Do not rely on ferritin alone in patients with inflammation as it is an acute phase reactant 1, 2
• Do not use hemoglobin alone for diagnosis as it has low sensitivity and specificity 8
• Do not transfuse blood unless absolutely necessary (typically hemoglobin <8 g/dL with symptoms) as oral or IV iron is safer and effective 2, 6
• Do not attribute iron deficiency solely to menstruation without excluding GI pathology in women >40 years 2

Special Considerations for Fatigue

Fatigue may persist despite correcting anemia and requires additional evaluation: 1

• Assess for subclinical disease activity in inflammatory conditions 1
• Evaluate sleep quality using validated tools like Pittsburgh Sleep Quality Index 1
• Screen for psychological symptoms including depression and anxiety 1
• Check vitamin D levels as deficiency is common and contributes to fatigue 1
• Review medications for side effects causing fatigue 1
• Isolated iron deficiency without anemia does not clinically contribute to fatigue 1