What is the appropriate workup for unexplained fatigue in a 36-year-old female?

Workup for Unexplained Fatigue in a 36-Year-Old Female

The appropriate workup for unexplained fatigue in a 36-year-old female should begin with quantifying fatigue severity using a 0-10 scale, followed by a focused history, physical examination, and targeted laboratory studies including complete blood count, comprehensive metabolic panel, and thyroid function tests. 1

Initial Assessment

Fatigue Severity Assessment

• Use a 0-10 numeric rating scale to quantify fatigue:
  • 0: No fatigue
  • 1-3: Mild fatigue (requires education only)
  • 4-6: Moderate fatigue (requires evaluation)
  • 7-10: Severe fatigue (requires prompt evaluation) 1, 2

Focused History

• Document specific characteristics:
  • Onset, pattern, duration of fatigue
  • Change over time
  • Associated or alleviating factors
  • Interference with daily function 2
• Assess for common contributing factors:
  • Medications (prescription and over-the-counter)
  • Alcohol/substance use
  • Sleep disturbances
  • Pain
  • Emotional distress (depression, anxiety)
  • Activity level and exercise patterns 2, 1

Physical Examination

• Complete physical exam with emphasis on:
  • Vital signs (including orthostatic measurements)
  • Cardiopulmonary assessment
  • Lymph node examination
  • Abdominal exam for organomegaly
  • Skin examination for pallor
  • Neurological examination 1, 3

Laboratory Evaluation

First-Line Testing

• Complete blood count (CBC) with differential
• Comprehensive metabolic panel (CMP)
• Thyroid-stimulating hormone (TSH)
• Urinalysis 2, 1

Additional Testing Based on History and Physical Findings

• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP)
• Iron studies (ferritin, iron, TIBC)
• Vitamin B12 and folate levels
• Vitamin D level
• HbA1c or fasting glucose 2, 1

Management Based on Findings

If Secondary Cause Identified

• Treat the underlying condition:
  • Anemia: Iron supplementation or B12 as indicated
  • Hypothyroidism: Thyroid replacement
  • Depression: Consider SSRIs (fluoxetine, paroxetine, sertraline) 4
  • Sleep disorders: Sleep hygiene education and appropriate referral

If No Clear Secondary Cause (Physiologic Fatigue)

• Structured exercise program:
  • Start with stretching and light aerobic exercise (e.g., walking)
  • Gradually increase intensity based on tolerance 1, 4
• Energy conservation strategies:
  • Schedule activities during peak energy times
  • Delegate non-essential tasks
  • Use labor-saving devices 1
• Sleep hygiene optimization:
  • Regular sleep schedule
  • Limit screen time before bed
  • Short naps (20-30 minutes) during the day if needed 4

Special Considerations

Evaluate for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• Consider if fatigue persists >6 months with:
  • Post-exertional malaise (worsening of symptoms after physical or mental exertion)
  • Unrefreshing sleep
  • Cognitive impairment
• Note: Exercise can worsen symptoms in ME/CFS patients 3

Mental Health Assessment

• Screen for depression and anxiety:
  • "In the last month, have you often felt dejected, sad, depressed or hopeless?"
  • "In the last month, did you experience significantly less pleasure than usual with the things you normally like to do?" 2

Follow-up

• Schedule regular follow-up visits rather than sporadic urgent appointments 4
• Reassess fatigue levels at each visit
• If initial laboratory studies are normal and fatigue persists without new symptoms, repeat testing is generally not indicated 4
• Consider referral to specialist if:
  • Fatigue persists despite interventions
  • New symptoms develop
  • Severe functional impairment occurs

Common Pitfalls to Avoid

• Failing to quantify fatigue severity
• Overlooking psychological factors (depression, anxiety)
• Relying solely on pharmacologic interventions
• Recommending increased exercise for all patients (may worsen ME/CFS)
• Missing medication side effects as a cause of fatigue
• Failing to schedule regular follow-up visits 1

Remember that laboratory studies affect management in only about 5% of patients with fatigue, and if initial results are normal, repeat testing is generally not indicated unless new symptoms develop 4.