What is the recommended lab workup for a patient presenting with fatigue?

Fatigue Lab Workup

For patients presenting with fatigue, initial laboratory testing should be limited to a complete blood count with differential, comprehensive metabolic panel, thyroid-stimulating hormone (TSH), and inflammatory markers (ESR/CRP), with further testing only pursued if red flags are present or initial screening suggests specific abnormalities. 1

Initial Severity Assessment

Before ordering any labs, quantify fatigue severity using a 0-10 numeric rating scale:

• Scores 0-3 (mild fatigue): No laboratory workup needed; rescreen at regular intervals 1, 2
• Scores 4-6 (moderate fatigue): Proceed with focused evaluation and basic laboratory testing 3
• Scores ≥7 (severe fatigue): Immediate comprehensive assessment warranted, as this typically indicates marked functional impairment 3, 1

Focused History Before Lab Testing

The history should guide which labs to order, not the reverse. Specifically assess:

• Onset, pattern, and duration of fatigue and whether it changed over time 3
• Medication review: Sleep aids, pain medications, antiemetics, and over-the-counter supplements are commonly overlooked contributors 3, 1
• Alcohol and substance use 3, 2
• Sleep quality and quantity, including symptoms of sleep apnea 2, 4
• Depression and anxiety symptoms, as these account for 18.5% of persistent fatigue cases 5
• Pain assessment, as pain commonly clusters with fatigue 2
• Nutritional issues including weight changes and caloric intake 3

Core Laboratory Panel

The following tests should be ordered for moderate to severe fatigue (scores ≥4):

• Complete blood count with differential: Assess hemoglobin/hematocrit for anemia and evaluate other cell lines (WBC, platelets) 3, 1
• Comprehensive metabolic panel: Evaluate electrolytes, hepatic function, and renal function 3, 1
• Thyroid-stimulating hormone (TSH): Screen for thyroid dysfunction 3, 1, 6
• Inflammatory markers (ESR and CRP): Assess for underlying inflammation 1

Important Caveats

Laboratory studies affect management in only 5% of patients with fatigue, and if initial results are normal, repeat testing is generally not indicated. 7 This underscores the importance of avoiding extensive workups in the absence of specific clinical indicators.

Common pitfalls to avoid:

• Do not order extensive testing reflexively: The differential diagnosis is broad, but most causes are identified through history and physical examination, not laboratory testing 7, 5
• Previously undiagnosed cancer accounts for only 0.6% of fatigue cases, making it a rare cause despite being a common concern 5
• Anemia and other organic causes are rare, accounting for only 4.3% of cases 5

When to Pursue Additional Testing

Additional laboratory evaluation or imaging should only be pursued when:

• Red flags are present on history or physical examination (unintentional weight loss, lymphadenopathy, hepatosplenomegaly, pulmonary complaints) 3, 1
• Other symptoms substantiate suspicion for specific conditions 3
• Moderate to severe fatigue begins after or worsens during the 6-12 month period following cancer treatment 3
• Initial screening tests reveal abnormalities requiring further investigation 3

Imaging studies (chest X-ray, CT chest/abdomen/pelvis, PET/CT) should only be ordered if red flags are identified, not as routine screening. 1

Additional Testing Based on Specific Clinical Scenarios

Consider more comprehensive endocrinologic evaluation or specialist referral if:

• Other endocrine symptoms are present beyond isolated fatigue 3
• TSH is abnormal 3
• Patient has risk factors for specific endocrinopathies 6

For cancer survivors specifically:

• Compare current hemoglobin/hematocrit with end-of-treatment values 3
• Consider echocardiogram if patient received cardiotoxic treatments 3
• Screen thyroid function if patient received radiation to neck or thorax 3

Physical Examination Priorities

The physical examination should include:

• Lymph node assessment 1
• Hepatosplenomegaly evaluation 1
• Cardiopulmonary and neurologic examination 4
• Skin examination 4

Management Regardless of Lab Results

Irrespective of laboratory findings, all patients with fatigue should be offered:

• Structured physical activity program: Stretching and aerobic exercise (such as walking) 2-3 times weekly for 30-60 minutes 1, 7, 4
• Psychoeducation about fatigue causes and self-monitoring strategies 3
• Regular scheduled follow-up visits rather than sporadic urgent appointments for effective long-term management 7

Note: Psychostimulants and dietary supplements are not recommended due to lack of efficacy. 1