What laboratory tests should be ordered to evaluate a patient presenting with fatigue?

Laboratory Evaluation for Fatigue

Order a core panel of laboratory tests for all patients presenting with fatigue, including: complete blood count with differential, comprehensive metabolic panel (electrolytes, BUN, creatinine, liver function tests), thyroid-stimulating hormone (TSH), urinalysis, fasting glucose or HbA1c, and inflammatory markers (ESR/CRP). 1, 2

Initial Screening and Quantification

• Use a 0-10 numeric rating scale to quantify fatigue severity before ordering labs: mild (1-3), moderate (4-6), severe (7-10) 3, 2
• Patients scoring ≥4 require comprehensive laboratory evaluation and focused assessment 3
• Screen for concurrent symptoms (pain, sleep disturbance, emotional distress) as fatigue rarely occurs in isolation 3, 2

Core Laboratory Panel (Order for All Patients)

Hematologic Assessment

• Complete blood count (CBC) with differential to detect anemia, infection, or hematologic malignancy 3, 1, 2
• Include red cell indices (MCV, RDW) and reticulocyte count to characterize anemia type 2
• Compare current hemoglobin/hematocrit to baseline values if available 3

Metabolic and Renal Function

• Comprehensive metabolic panel including electrolytes (sodium, potassium, chloride, bicarbonate), calcium, and magnesium 3, 1, 2
• Blood urea nitrogen (BUN) and serum creatinine to assess kidney function 3, 1, 2
• Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) to evaluate hepatic disorders 3, 1, 2

Endocrine Screening

• Thyroid-stimulating hormone (TSH) is essential as hypothyroidism is a highly treatable cause of fatigue 3, 1, 2
• Consider more comprehensive endocrine evaluation if other symptoms suggest dysfunction (diabetes screening with fasting glucose or HbA1c) 3, 1, 2

Additional Core Tests

• Urinalysis for protein, blood, and glucose to screen for renal disease or infection 3, 1, 2
• Inflammatory markers (ESR and/or CRP) to identify underlying inflammatory conditions 3, 2
• Fasting lipid profile to assess cardiovascular risk 1

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

Iron Studies and Nutritional Assessment

• Serum ferritin and transferrin saturation to assess iron stores, particularly important as low iron can cause fatigue even without anemia 3, 2
• Vitamin B12 and folate levels to identify deficiencies 2
• 25-OH vitamin D level, especially in patients with chronic disease or limited sun exposure 3

Hemolysis Evaluation (If Anemia Present)

• Haptoglobin, lactate dehydrogenase (LDH), and indirect bilirubin if hemolytic anemia suspected 2
• Percentage of hypochromic red cells and reticulocyte hemoglobin for detailed iron assessment 2
• Soluble transferrin receptor for accurate iron deficiency assessment in inflammatory states 2

Context-Specific Laboratory Testing

Cancer Patients or Survivors

• Evaluate disease status and risk of recurrence based on treatment history 3
• Consider more extensive workup if fatigue begins or worsens >6-12 months post-treatment, or if accompanied by weight loss, pain, or other concerning symptoms 3
• Screen for treatment-related complications: TSH if neck/thoracic radiation received, cardiac biomarkers if cardiotoxic therapy given 3

Cardiac Disease Suspicion

• B-type natriuretic peptide (BNP) or NT-proBNP if heart failure suspected 1, 2
• Consider echocardiogram for patients with history of cardiotoxic treatments 3

Inflammatory Conditions

• Elevated inflammatory markers warrant investigation for underlying inflammatory or autoimmune disease 3, 2
• Consider disease-specific testing based on clinical presentation 3

Critical Interpretation Points

Laboratory results directly affect management in only ~5% of fatigue cases, but testing remains essential to identify treatable causes. 4 The primary value is ruling out serious underlying conditions rather than confirming a specific diagnosis.

Key Findings That Require Action

• Anemia: Persistently low hemoglobin or iron stores are reversible causes requiring treatment even in absence of bowel symptoms 3
• Thyroid dysfunction: Hypothyroidism is highly prevalent and completely treatable 3
• Electrolyte disturbances: Abnormalities in calcium, magnesium, or other electrolytes require correction 3, 1
• Renal or hepatic dysfunction: Abnormal kidney or liver function may explain fatigue and guide further evaluation 3, 1
• Elevated inflammatory markers without clear source: May indicate occult malignancy, infection, or autoimmune disease requiring investigation 3

Common Pitfalls to Avoid

• Do not repeat normal laboratory tests without clinical indication—if initial comprehensive workup is unrevealing, repeat testing rarely provides new information 4
• Do not attribute all fatigue to "stress" or "depression" without completing objective laboratory evaluation to exclude medical causes 3
• Do not overlook iron deficiency in the absence of anemia—low ferritin alone can cause significant fatigue 3, 2
• Do not fail to assess disease recurrence in cancer survivors—new or worsening fatigue may herald recurrent malignancy 3
• Do not order excessive specialized testing initially—focus on the core panel first, then expand based on clinical findings 4

Follow-Up Strategy

• Re-screen fatigue severity after treating any identified abnormalities (correct anemia, optimize thyroid function, address electrolyte imbalances) 3, 2
• If comprehensive laboratory evaluation is normal but moderate-to-severe fatigue persists, shift focus to non-laboratory causes: sleep disorders, depression/anxiety, deconditioning, medications, or primary fatigue syndromes 3
• Schedule regular follow-up visits rather than sporadic appointments for effective long-term management 4