What is the recommended initial evaluation and laboratory workup for a patient presenting with fatigue?

Workup for Fatigue

Begin by quantifying fatigue severity using a 0-10 numeric rating scale, then pursue laboratory evaluation only for patients with moderate-to-severe fatigue (scores 4-10), as this stratified approach prevents unnecessary testing while identifying treatable causes that impact morbidity and mortality. 1

Initial Severity Assessment

• Use a 0-10 numeric rating scale where 0 = no fatigue and 10 = worst fatigue imaginable 2, 1
• Mild fatigue (scores 1-3) requires only education and periodic rescreening without diagnostic workup 1, 3
• Moderate-to-severe fatigue (scores 4-10) mandates comprehensive evaluation for treatable contributors 1, 3

Focused History for Moderate-to-Severe Fatigue

Document specific fatigue characteristics:

• Onset, pattern, duration, and temporal changes over time 2, 3
• Associated or alleviating factors and interference with daily functioning 2, 3
• Impact on work performance, family life, and social relationships 4

Screen for red flag symptoms requiring urgent evaluation:

• Fever, drenching night sweats, or unexplained weight loss (suggest malignancy or infection) 1, 3
• New or worsening pain, pulmonary complaints, or unintentional weight loss 1, 3
• Lymphadenopathy, hepatosplenomegaly, or concerning skin manifestations 1, 3

Assess treatable contributing factors:

• Medication review: Document all prescription drugs, over-the-counter medications, herbal supplements, and vitamins; identify β-blockers, SSRIs, narcotics, antidepressants, antiemetics, antihistamines, and sleep aids as common fatigue-inducing agents 1, 3
• Sleep disturbances: Screen for sleep apnea (especially with weight gain), insomnia, and poor sleep hygiene, as sleep problems affect 30-75% of fatigued patients 1, 3
• Mental health: Screen for depression (present in 25-33% of fatigued patients) and anxiety using validated tools like PHQ-9 or GAD-7 1, 3
• Nutritional issues: Document weight changes, calculate BMI, evaluate caloric intake changes, and assess for impediments to nutritional intake 1, 3
• Alcohol/substance abuse: Query about use patterns, as these aggravate sleep disturbance and fatigue 1, 3
• Physical deconditioning: Assess functional status, exercise patterns, and ability to accomplish normal daily activities 1, 3

Laboratory Workup for Moderate-to-Severe Fatigue (Scores 4-10)

Initial screening tests:

• Complete blood count with differential to assess for anemia and evaluate all cell lines (WBC, platelets) 2, 1, 3
• Comprehensive metabolic panel to assess electrolytes, hepatic function, and renal function 2, 1, 3
• Thyroid-stimulating hormone (TSH) to detect hypothyroidism, which is highly treatable 2, 1, 3
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to detect inflammatory processes 1

Context-specific additional testing:

• Electrocardiogram and echocardiogram for patients with cardiac risk factors or prior cardiotoxic therapy exposure 1, 3
• Vitamin B12, folate, and vitamin D levels when nutritional deficiencies are suspected 3
• Extended endocrine evaluation or specialist referral if other endocrine symptoms are present 2, 3

Critical Pitfalls to Avoid

• Do not order extensive laboratory testing for mild fatigue (scores 0-3), as results affect management in only 5% of patients and repeat testing is generally not indicated if initial results are normal 4, 5
• Do not attribute all symptoms to "fatigue" without evaluating for treatable medical conditions, especially hypothyroidism (occurs in ~50% after thoracic radiation), cardiac dysfunction, and anemia 3
• Recognize that fatigue rarely occurs in isolation; it frequently clusters with pain, sleep disturbance, and emotional distress requiring simultaneous management 3
• Always consider medication side effects as potential contributors before pursuing extensive workup 1, 3
• Focus on psychological causes when fatigue persists beyond one year with normal laboratory results, as psychiatric conditions are common in this population 5

Management Approach

For all patients with fatigue:

• Initiate structured physical activity program consisting of stretching plus aerobic exercise (e.g., 150 minutes of moderate walking per week), as this is a Category 1 recommendation that improves strength and energy 1, 3, 4
• Implement good sleep hygiene practices including consistent bedtime, limiting stimulants, and creating a restful environment 1, 3
• Provide education about fatigue patterns, energy conservation strategies, and self-monitoring of fatigue levels 2, 1, 3

Address identified contributing factors:

• Treat depression/anxiety with SSRIs (fluoxetine, paroxetine, or sertraline) when appropriate 3, 4
• Implement cognitive-behavioral therapy for insomnia and treat sleep apnea when present 1, 3
• Optimize pain management strategies 3
• Correct nutritional deficiencies and ensure adequate caloric intake 3
• Taper or discontinue fatigue-inducing medications when possible 1, 3
• Treat identified medical conditions (hypothyroidism, anemia, cardiac dysfunction) 3

Specialist referral when:

• Organ-specific dysfunction is identified (cardiology, endocrinology) 2, 3
• Fatigue persists despite addressing modifiable factors 1, 3
• Mental health intervention is needed for refractory depression or anxiety 1, 3

Follow-Up Strategy

• Schedule regular follow-up visits (at least annually) rather than sporadic urgent appointments for effective long-term management 1, 3, 4
• Rescreen fatigue severity using the numeric rating scale at each visit 1, 3
• Monitor symptom trajectory and response to interventions over time 3