What labs should be ordered for a patient, potentially of childbearing age or an older adult, presenting with complaints of fatigue, tiredness, and nocturnal awakenings?

Laboratory Workup for Fatigue, Tiredness, and Nocturnal Awakenings

Order a focused laboratory panel including complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), and consider additional testing for vitamin deficiencies based on clinical context. 1

Essential First-Line Laboratory Tests

Core Metabolic and Hematologic Evaluation

• Complete Blood Count (CBC): Anemia occurs in approximately 2.8% of patients presenting with tiredness and represents a common, highly treatable cause of fatigue 1
• Comprehensive Metabolic Panel (CMP): This evaluates electrolyte abnormalities (sodium, potassium, chloride, calcium), renal function (BUN, creatinine), liver function, and glucose levels—all of which can contribute to fatigue 1, 2
• Thyroid-Stimulating Hormone (TSH): Hypothyroidism is one of the first and most important causes to investigate, as it frequently presents with fatigue and nonspecific symptoms 1

Clinical Context: Why These Tests Matter

Laboratory results affect management in only about 5% of fatigue cases, but core testing remains essential to rule out treatable causes 1. The CMP is particularly important because metabolic derangements—including electrolyte imbalances, renal dysfunction, and hepatic abnormalities—can directly cause fatigue through multiple mechanisms 2, 3.

Additional Testing Based on Clinical Suspicion

Nutritional Deficiencies

If the initial workup is unrevealing and clinical suspicion remains high, consider testing for:

• Vitamin B12 and folate levels 1
• Ferritin (iron stores) 1
• Vitamin D, magnesium, zinc, copper, and phosphate 1

These specific deficiencies are linked to fatigue and are potentially correctable 1.

Specialized Testing for Specific Populations

• In patients with chronic kidney disease: Approximately 70% report fatigue, with metabolic acidosis, hyperphosphatemia, and anemia being key contributors 4
• In patients with liver disease: Liver function tests (AST, ALT, bilirubin, albumin) should be evaluated, as fatigue is the most common symptom in liver disease and may relate to changes in neurotransmission 5

Critical Assessment Beyond Laboratory Testing

Sleep Disorder Evaluation

The presence of true sleepiness (involuntary tendency to fall asleep) rather than fatigue (tiredness, low energy) suggests an alternative sleep disorder requiring urgent evaluation 6, 7. Key distinctions:

• Fatigue is the expected consequence of insomnia and sleep disturbance 6
• True sleepiness is uncommon in chronic insomnia and suggests obstructive sleep apnea, narcolepsy, or periodic limb movement disorder 6, 7
• Involuntary napping episodes during the day or while driving mandate urgent polysomnography 7

Sleep disturbances affect 30-75% of patients with fatigue 1, 8. Patients should be specifically queried about:

• Sleep-disordered breathing (snoring, gasping, observed apneas) 8
• Restless leg syndrome symptoms 8
• Sleep quality and nocturnal awakenings 8

Medication Review

Systematically review all medications, including over-the-counter drugs and supplements, as medication side effects are common contributors to fatigue 1, 8. Specific culprits include:

• Stimulants: Caffeine, methylphenidate, amphetamines can paradoxically worsen sleep and contribute to insomnia 6
• Antidepressants: SSRIs, SNRIs, MAO inhibitors can disrupt sleep 6
• Cardiovascular agents: β-blockers, α-receptor agents, diuretics 6
• Pulmonary medications: Theophylline, albuterol 6
• Narcotic analgesics: Oxycodone, codeine, propoxyphene 6
• Alcohol use or withdrawal 6

Psychological Evaluation

• Depression affects 18.5% of patients with tiredness—more frequent than in those without this symptom 1
• Anxiety frequently accompanies fatigue and requires specific assessment 1
• Psychiatric disorders and chronic pain are associated with insomnia rates of 50-75% 6

Common Pitfalls to Avoid

1. Overlooking psychological causes (depression, anxiety) leads to inadequate treatment 1
2. Ignoring medication side effects can perpetuate fatigue 1
3. Missing sleep disorders results in incomplete management 1
4. Failing to distinguish fatigue from pathological sleepiness, which requires urgent polysomnography 7
5. Over-relying on laboratory testing when the yield is only 5%, while missing behavioral and psychological contributors 1

Red Flags Requiring Immediate Attention

• Involuntary sleep episodes during activities or driving 7
• Severe cognitive impairment beyond typical insomnia complaints (memory problems, impaired attention, difficulty with complex tasks) 6
• Severe irritability, loss of interest, or depression disproportionate to sleep loss 6
• Quality of life deterioration leading to avoidance of social activities, exercise, or work 6