What laboratory tests are recommended for a fatigue workup in patients with potential underlying metabolic, autoimmune, or sleep disorders?

Laboratory Workup for Fatigue

For a comprehensive fatigue workup, order the following core laboratory panel: complete blood count with differential, comprehensive metabolic panel (including electrolytes, glucose, renal and liver function), thyroid-stimulating hormone, C-reactive protein, urinalysis, and iron studies (ferritin and transferrin saturation). 1

Initial Severity Assessment

Before ordering labs, quantify fatigue severity using a 0-10 numeric rating scale, where mild fatigue scores 1-3, moderate 4-6, and severe 7-10. 2, 1 Patients scoring ≥4 warrant comprehensive laboratory evaluation and further diagnostic assessment. 2, 1

Core Laboratory Panel (All Patients)

Hematologic Assessment

• Complete blood count with differential to identify anemia, infection, or hematologic disorders 2, 1
• Red cell indices (MCV, RDW) to characterize anemia type 1
• Reticulocyte count to assess bone marrow response 1
• Serum ferritin and transferrin saturation to evaluate iron status, as iron deficiency (even without anemia) commonly contributes to fatigue 2, 1

Metabolic and Organ Function

• Comprehensive metabolic panel including:
  • Blood urea nitrogen and creatinine for renal function 2, 1
  • Liver function tests to detect hepatic disorders 2, 1
  • Electrolytes (sodium, potassium, calcium, magnesium) as imbalances cause fatigue 2, 1
  • Fasting glucose or HbA1c for diabetes screening 2, 1

Inflammatory and Endocrine Markers

• C-reactive protein to assess systemic inflammation 2, 1
• Erythrocyte sedimentation rate as an additional inflammatory marker 2
• Thyroid-stimulating hormone (TSH) to screen for hypothyroidism, a highly treatable cause of fatigue 2, 1

Additional Screening

• Urinalysis for protein, blood, and glucose to detect renal disease or infection 2, 1

Extended Laboratory Evaluation for Moderate-to-Severe Fatigue (Score ≥4)

When initial screening reveals moderate-to-severe fatigue, expand testing to include:

• Vitamin B12 and folate levels to identify nutritional deficiencies common in chronic disease 2, 1
• 25-hydroxyvitamin D as deficiency correlates with muscle fatigue and self-reported fatigue 2
• Hemolysis markers (haptoglobin, LDH, bilirubin) if anemia is present 1
• Soluble transferrin receptor for accurate iron deficiency assessment in inflammatory states 1
• Percentage of hypochromic red cells and reticulocyte hemoglobin for detailed iron status evaluation 1

Context-Specific Considerations

Autoimmune or Inflammatory Disease

For patients with known or suspected inflammatory bowel disease, rheumatologic conditions, or other autoimmune disorders, prioritize assessment of disease activity markers (CRP, ESR) and nutritional deficiencies (iron, B12, folate, vitamin D, zinc, magnesium). 2 These patients frequently harbor deficiencies even when appearing well-nourished. 2

Cancer or Post-Cancer Patients

Evaluate disease status comprehensively and assess for endocrine dysfunction, particularly hypothyroidism in patients who received neck or mediastinal radiation. 2, 3 Consider NT-proBNP if cardiac dysfunction from cardiotoxic chemotherapy or radiation is suspected. 2, 3

Suspected Adrenal Insufficiency

If clinical features suggest adrenal insufficiency (orthostatic hypotension, salt craving, hyperpigmentation), measure morning cortisol and consider ACTH stimulation testing. 4 Always check TSH, as hypothyroidism commonly coexists and requires careful treatment sequencing. 4

Critical Pitfalls to Avoid

• Do not assume fatigue is "functional" without excluding organic causes. While laboratory abnormalities explain only ~5% of fatigue cases, missing treatable conditions like hypothyroidism, anemia, or diabetes significantly impacts patient outcomes. 1, 5

• Isolated iron deficiency without anemia is not clinically significant for fatigue in most patients, though established anemia of any cause warrants thorough investigation and treatment. 2

• Screen for depression concurrently, as fatigue and depression overlap substantially and require different management approaches. 2 Use a simple two-question screen: "In the last month, have you felt dejected, sad, or hopeless?" and "Have you experienced less pleasure in activities you normally enjoy?" 2

• Assess sleep quality systematically using validated tools like the Pittsburgh Sleep Quality Index, as sleep disturbance strongly correlates with fatigue and represents a modifiable factor. 2

• Consider substance use (alcohol, drugs) as these associate with emotional distress, poor sleep, and anxiety. 2

Follow-Up Strategy

After identifying and treating reversible causes (anemia, hypothyroidism, electrolyte disturbances, vitamin deficiencies), reassess fatigue severity using the same numeric scale. 2, 1 If fatigue persists despite correction of laboratory abnormalities, consider referral for evaluation of sleep disorders, psychological factors, or specialized fatigue management programs. 2, 1 For persistent unexplained anemia, consult hematology. 1