What is the differential diagnosis for an adult patient with fatigue and no pre-existing medical conditions?

Differential Diagnosis of Fatigue in Adults Without Pre-existing Medical Conditions

For an adult presenting with fatigue and no known medical conditions, systematically evaluate nine key contributing factors: depression (present in 18.5% of fatigue cases), sleep disorders (affecting 30-75% of fatigued patients), anemia, thyroid dysfunction, medication side effects, nutritional deficiencies, pain, anxiety, and decreased physical activity. 1, 2

Initial Assessment Framework

Severity Quantification

• Use a 0-10 numeric rating scale where 1-3 indicates mild fatigue, 4-6 moderate, and 7-10 severe fatigue 3, 2
• Scores ≥4 warrant comprehensive evaluation with focused history, physical examination, and targeted laboratory testing 3, 2

Primary Medical Causes (Rule Out First)

Thyroid Dysfunction

• Hypothyroidism is one of the most important initial causes to investigate, as it frequently presents with fatigue and nonspecific symptoms 1
• Check thyroid-stimulating hormone (TSH) in all patients with moderate-to-severe fatigue 2

Anemia

• Occurs in approximately 2.8% of patients presenting with tiredness 1
• Obtain complete blood count and iron studies (ferritin, iron, total iron-binding capacity) 2

Cardiac Dysfunction

• Assess for cardiovascular disease, particularly in patients with risk factors 1
• Consider echocardiography if clinically indicated

Psychological and Behavioral Contributors

Depression (Most Common Cause)

• Present in 18.5% of patients with fatigue—significantly higher than in non-fatigued patients 1, 4
• Use the two-question screen: "In the last month, have you often felt dejected, sad, depressed or hopeless?" and "In the last month, did you experience significantly less pleasure than usual with things you normally like to do?" 3
• Depression and fatigue are independent conditions that frequently co-occur; 25-33% of fatigued patients also have depression 3, 2

Sleep Disorders

• Affect 30-75% of patients with fatigue, ranging from insomnia to hypersomnia 3, 1, 2
• Evaluate for obstructive sleep apnea, restless leg syndrome, and periodic limb movement disorder 3
• Assess sleep hygiene: irregular sleep schedules, daytime napping, caffeine/alcohol consumption before bed 2
• Critical pitfall: When sleep disturbances are present, always assess for depression as this is a common manifestation 3

Anxiety

• Frequently accompanies fatigue and requires specific assessment 1, 2
• Often clusters with depression and sleep disturbance 3

Medication and Substance-Related Causes

• Systematically review all prescription medications, over-the-counter drugs, and supplements for sedating effects 1, 2
• Medication side effects are common contributors but frequently overlooked 2
• Assess alcohol and substance use patterns 3

Nutritional and Metabolic Factors

Specific Deficiencies to Evaluate:

• Vitamin B6, B12, folate 1
• Ferritin (even without anemia) 1
• Vitamin D, magnesium, zinc 1
• Copper, phosphate, calcium 1

Nutritional Assessment:

• Document weight changes and caloric intake patterns 3, 2
• Evaluate electrolyte imbalances (sodium, potassium, calcium, magnesium) which are often reversible and may improve fatigue with supplementation 3, 2

Activity Level Assessment

• Decreased physical activity worsens fatigue symptoms 1, 2
• Paradoxically, regular physical activity reduces fatigue in individuals with no clear organic cause 1
• Document changes in exercise or activity patterns 3

Essential Laboratory Testing

Core Tests for Moderate-to-Severe Fatigue (Score ≥4):

• Complete blood count 2
• Thyroid-stimulating hormone 2
• Basic metabolic panel 2
• Liver function tests 2
• Inflammatory markers (C-reactive protein) 2

Important caveat: Laboratory results affect management in only approximately 5% of fatigue cases, but testing remains essential to rule out treatable causes 1, 5

Pain Assessment

• Pain often clusters with fatigue, sleep disturbance, and emotional distress 3, 2
• Effective pain treatment is essential when present 2

Critical Pitfalls to Avoid

1. Overlooking psychological causes (depression, anxiety) leads to inadequate treatment—these are the most common causes 1, 2
2. Ignoring medication side effects perpetuates fatigue 1, 2
3. Missing sleep disorders results in incomplete management 2
4. Excessive laboratory testing when initial workup is normal; repeat testing is generally not indicated if initial results are unrevealing 5
5. Focusing exclusively on somatic causes leads to overdiagnosis, as previously undiagnosed cancer accounts for only 0.6% of fatigue cases 4

Structured Follow-Up

• Schedule regular follow-up visits rather than sporadic urgent appointments for effective long-term management 5
• Continue monitoring even if initial evaluation is unrevealing, as fatigue patterns may evolve 3