What laboratory investigations are recommended for a patient presenting with persistent fatigue?

Laboratory Investigations for Persistent Fatigue

Initial laboratory evaluation for a patient presenting with persistent fatigue should include complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, inflammatory markers, urinalysis, and iron studies. 1

First-Line Laboratory Tests

The following laboratory tests should be ordered for all patients with persistent fatigue:

• Complete Blood Count (CBC) with differential - To evaluate for anemia, infection, and other hematologic abnormalities 1
• Comprehensive Metabolic Panel (CMP) - Including electrolytes, blood urea nitrogen, serum creatinine, liver function tests, and fasting blood glucose/glycohemoglobin 1
• Thyroid-Stimulating Hormone (TSH) - Primary screening test for thyroid dysfunction 1
• Iron Studies - Including plasma iron, transferrin, transferrin saturation, and ferritin 2, 1
• Inflammatory Markers - Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) 2, 1
• Urinalysis - To screen for infection, kidney disease, and diabetes 1
• Lipid Profile - To assess for dyslipidemia 1

Additional Testing Based on Clinical Suspicion

• Vitamin D Level - Particularly in patients with inflammatory bowel disease or other malabsorption conditions 1
• Free T4 - If TSH is abnormal 1
• Hepcidin Level - For more accurate assessment of iron deficiency, especially in inflammatory conditions 2
• Natriuretic Peptides (BNP or NT-proBNP) - When heart failure is suspected, particularly in patients with dyspnea or exercise intolerance 1
• Autoimmune Markers - If rheumatologic disease is suspected 1

Interpretation and Follow-up

• When evaluating iron deficiency, it's important to assess multiple parameters together (iron, transferrin, transferrin saturation, ferritin, CRP, hepcidin) rather than relying on a single test 2
• For patients with anemia, iron studies should be repeated 8-10 weeks after treatment initiation, not earlier (especially after iron infusion, as ferritin levels may be falsely elevated) 2
• Normal laboratory values do not exclude fatigue-causing conditions; expanded testing should be considered when symptoms persist despite normal initial workup 1

Special Considerations

Iron Deficiency Assessment

Iron deficiency is a common cause of fatigue even without anemia. A full investigation of iron status should be performed in cases of persistent major fatigue, not just anemia 2. The combination of tests provides a more accurate picture than any single test.

Chronic Fatigue Evaluation

For patients with chronic fatigue, consider:

• Medication side effects review 1
• Sleep disturbance assessment 1
• Evaluation for emotional distress, including depression and anxiety 1
• Nutritional assessment for deficiencies in vitamin D, magnesium, and other nutrients 1

Common Pitfalls to Avoid

1. Relying solely on hemoglobin levels - Iron deficiency without anemia can still cause significant fatigue 1
2. Premature repeat testing - If initial results are normal, repeat testing is generally not indicated unless symptoms change or worsen 3
3. Overlooking medication effects - Many medications can contribute to fatigue and should be reviewed thoroughly 1
4. Missing subclinical thyroid disease - Even subtle thyroid abnormalities can cause fatigue 1
5. Ignoring sleep disorders - Sleep disturbances are common contributors to fatigue and should be assessed 1

Remember that laboratory studies affect management in only about 5% of patients with fatigue 3, but they are essential to rule out serious underlying conditions and guide appropriate treatment.