Initial Laboratory Workup for Chronic Fatigue
Order a focused panel of basic laboratory tests to exclude common medical causes: complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). 1
Core Laboratory Tests
The initial workup should systematically exclude treatable medical conditions that commonly present with fatigue:
- CBC with differential to screen for anemia, infection, or hematologic malignancy 1
- Comprehensive metabolic panel to evaluate for electrolyte disturbances, renal dysfunction, hepatic disease, and glucose abnormalities 1
- TSH to exclude hypothyroidism or hyperthyroidism 1
- ESR or CRP as inflammatory markers to screen for systemic inflammatory conditions 1
Additional Targeted Testing Based on Clinical Context
Beyond the core panel, additional tests should be guided by specific clinical findings rather than ordered routinely:
- Creatine kinase (CK) if muscle pain is prominent or metabolic myopathy is suspected, particularly if fatigue worsens with physical exertion, cold, fasting, or infection 2
- Vitamin D, B12, and iron studies if nutritional deficiencies are suspected based on dietary history or risk factors 1
- Sleep study referral if unrefreshing sleep or sleep apnea symptoms are prominent, though primary sleep disorders must be distinguished from chronic fatigue syndrome 3
Important Diagnostic Considerations
Chronic fatigue syndrome (CFS) is a clinical diagnosis made by exclusion after ruling out other medical and psychiatric conditions through history, physical examination, and this restricted set of laboratory investigations 3. The diagnosis requires:
- Severe fatigue lasting longer than 6 months that is not relieved by rest 4
- At least 4 of the following: postexertional malaise, unrefreshing sleep, impaired memory/concentration, muscle pain, polyarthralgia, sore throat, tender lymph nodes, or new headaches 4
- Exclusion of other medical or psychiatric conditions that could explain symptoms 3
Critical Pitfalls to Avoid
Do not order extensive or exotic laboratory panels without specific clinical indications. There is no definitive laboratory test or validated biomarker for chronic fatigue syndrome 3. Extensive testing without clinical justification leads to false positives, unnecessary patient anxiety, and increased costs without improving diagnostic accuracy 1.
Recognize that normal laboratory results do not exclude CFS—the condition arises from functional (non-structural) changes in the brain rather than identifiable laboratory abnormalities 3. Studies have clearly shown CFS is not an ongoing infection, immunological disorder, endocrine disorder, or primary sleep disorder 3.
Metabolic Disease Red Flags
Consider inherited metabolic disorders if fatigue has a dynamic nature worsened by increased metabolism (physical exertion, cold, fasting, infection), particularly in younger patients 2. This warrants specialized biochemical and molecular testing for glycogen storage disease, fatty acid oxidation disorders, or mitochondrial diseases 2.
Assessment After Initial Workup
Once medical causes are excluded, evaluate for concurrent depression, pain disorders, and sleep disturbances as these commonly coexist with chronic fatigue and require specific management 4, 5.