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

Laboratory Evaluation for Profound Fatigue

For a patient presenting with profound fatigue, order a comprehensive initial panel including: complete blood count, urinalysis, serum electrolytes (including calcium and magnesium), blood urea nitrogen, serum creatinine, fasting blood glucose (glycohemoglobin), lipid profile, liver function tests, and thyroid-stimulating hormone (TSH). 1

Core Laboratory Panel

The following tests form the essential workup and should be ordered together as the initial evaluation:

Hematologic Assessment

• Complete blood count (CBC) to evaluate for anemia, infection, or hematologic malignancies that commonly present with fatigue 1

Metabolic and Renal Function

• Serum electrolytes including calcium and magnesium, as electrolyte disturbances frequently cause fatigue 1
• Blood urea nitrogen (BUN) and serum creatinine to assess renal function, which when impaired causes significant fatigue 1
• Fasting blood glucose and glycohemoglobin to screen for diabetes and assess glycemic control 1

Hepatic Function

• Liver function tests to identify hepatic dysfunction as a contributor to fatigue 1

Endocrine Evaluation

• Thyroid-stimulating hormone (TSH) is essential, as both hyperthyroidism and hypothyroidism are primary or contributory causes of profound fatigue 1, 2

Additional Basic Tests

• Urinalysis to screen for protein, blood, glucose, and signs of renal or systemic disease 1
• Lipid profile as part of comprehensive metabolic assessment 1

Context-Dependent Additional Testing

When Clinical History Suggests Specific Etiologies

Iron studies (fasting transferrin saturation) should be ordered if hemochromatosis is suspected, particularly in patients of Northern European descent, as iron overload can cause fatigue and cardiac dysfunction 1

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are indicated when inflammatory or rheumatologic conditions are suspected 1

HIV screening is reasonable in high-risk patients, though cardiac symptoms typically occur late in HIV-related cardiomyopathy 1

Cancer-Related Fatigue Considerations

In patients with known or suspected malignancy, the cancer fatigue guidelines recommend the same core panel but emphasize that any treatable contributing factors identified (anemia, electrolyte disturbances, thyroid dysfunction) must be managed before attributing fatigue solely to cancer 1

Common Pitfalls to Avoid

Do not order free T4 reflexively with TSH unless TSH is abnormal (typically <0.2-0.3 or >5.0-6.0 mU/L), as this increases costs without improving diagnostic yield 3, 4

Avoid ordering extensive autoimmune panels, viral titers, or specialized hormone testing unless specific clinical features suggest these diagnoses, as the yield is low and therapeutic implications are often uncertain 1

Do not skip the basic metabolic panel even if a specific cause seems obvious, as multiple contributing factors commonly coexist in patients with profound fatigue 1

Clinical Integration

These laboratory tests should be interpreted alongside a thorough history focusing on:

• Onset, duration, and severity of fatigue (use 0-10 numerical rating scale) 1
• Impact on activities of daily living 1
• Associated symptoms (dyspnea, weight changes, sleep disturbances, pain) 1
• Medication history including alcohol, illicit drugs, chemotherapy, and alternative therapies 1
• Family history of cardiomyopathy or sudden death 1

Physical examination should document orthostatic vital signs, volume status, body mass index, and signs of cardiac, thyroid, or hepatic disease 1