What laboratory tests do you order when a patient complains of fatigue?

Laboratory Evaluation for Patients Complaining of Fatigue

For patients complaining of fatigue, the initial laboratory workup should include complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), iron studies, inflammatory markers (ESR, CRP), and urinalysis. 1

Initial Laboratory Evaluation

When a patient presents with fatigue, the following tests should be ordered:

• First-line laboratory tests:
  • Complete blood count (CBC) with differential
  • Comprehensive metabolic panel (CMP) including:
    • Electrolytes
    • Blood urea nitrogen
    • Serum creatinine
    • Liver function tests
    • Fasting blood glucose/glycohemoglobin
  • Thyroid-stimulating hormone (TSH)
  • Iron studies (plasma iron, transferrin, transferrin saturation, ferritin)
  • Inflammatory markers (ESR, CRP)
  • Urinalysis 1

Fatigue Severity Assessment

Fatigue should be quantified using a severity scale:

• Ask patients: "How would you rate your fatigue on a scale of 0 to 10 over the past 7 days?"
• Alternatively, ask patients to rate their fatigue as none, mild, moderate, or severe
• Scores of 0-3 or none to mild fatigue require no further assessment beyond initial workup
• Scores of 4-10 or moderate to severe fatigue warrant more focused evaluation 2, 1
• Scores ≥7 are associated with marked decrease in physical functioning 2

Additional Testing Based on Severity and Clinical Suspicion

For moderate to severe fatigue (score ≥4) or when initial tests are normal but symptoms persist:

• Endocrine evaluation:

  • Free T4 (if TSH is abnormal)
  • Morning cortisol and ACTH
  • Gonadal hormones 1

• Nutritional assessment:

  • Vitamin D levels
  • Magnesium levels 1

• Specialized testing based on clinical suspicion:

  • Cardiac evaluation: BNP or NT-proBNP levels
  • Autoimmune markers for suspected rheumatologic disease
  • Full iron status investigation including hepcidin level for persistent major fatigue 1

Important Clinical Considerations

• Normal laboratory values do not exclude fatigue-causing conditions; expanded testing should be considered when symptoms persist despite normal initial workup 1

• Always assess for contributing factors:

  • Medication side effects
  • Sleep disturbances
  • Emotional distress (depression and anxiety)
  • Pain 2, 1
  • Physical activity levels 3

• The timing of fatigue onset in relation to completion of any active therapy (if applicable) affects the recommended workup 2

• Laboratory studies affect management in only 5% of patients, and if initial results are normal, repeat testing is generally not indicated 3

Common Pitfalls to Avoid

• Failing to quantify fatigue severity, which determines the extent of workup needed
• Overlooking medication side effects as a common cause of fatigue
• Excessive laboratory testing when initial results are normal
• Not considering chronic conditions that may cause fatigue (e.g., multiple sclerosis, Parkinson's disease) 4
• Neglecting to assess for depression, which commonly presents with fatigue 3

Remember that fatigue can be classified as secondary to other medical conditions, physiologic, or chronic, and treatment approaches will differ based on the underlying cause 3.