What is the differential diagnosis (Dx) and workup for generalized fatigue?

Differential Diagnosis and Workup for Generalized Fatigue

Begin by screening fatigue severity using a 0-10 numeric scale, then pursue focused evaluation only for moderate-to-severe fatigue (scores 4-10), as this approach prevents overdiagnosis while identifying the most common culprits: sleep disorders, depression (18.5% of cases), and psychosocial stress. 1

Initial Severity Screening

• Screen all patients using a numeric rating scale (0-10) or categorize as none, mild, moderate, or severe 2
• Patients scoring 0-3 (mild fatigue) require only rescreening at regular intervals without further workup 2, 3
• Patients scoring 4-10 (moderate to severe) warrant focused evaluation 4, 2
• Scores ≥7 typically correlate with marked decrease in physical functioning 4, 2

Differential Diagnosis by Frequency

Most Common Causes

• Depression accounts for 18.5% of persistent fatigue cases 1
• Sleep disorders and sleep-related breathing disorders are among the most common causes 1
• Excessive psychosocial stress is a leading contributor 1
• Medication side effects, particularly sedating medications 4, 3

Less Common Causes

• Anemia and other organic causes account for only 4.3% of cases 1
• Previously undiagnosed cancer is rare, representing only 0.6% of cases 1
• Thyroid dysfunction 3
• Chronic infections (HIV, tuberculosis if risk factors present) 3

Focused History Components

Fatigue Characteristics

• Document onset, pattern, duration, and changes over time 4, 2, 3
• Identify associated or alleviating factors 4, 2
• Assess interference with normal functioning and daily activities 4, 2
• Obtain patient's self-assessment of potential causes 4, 2

Review of Systems

• Complete review to identify affected organ systems and direct physical evaluation 4, 2
• Specifically assess for respiratory symptoms that might warrant chest imaging 3

Nine Treatable Contributing Factors to Assess

1. Pain - commonly clusters with fatigue 4, 2
2. Emotional distress - screen for depression and anxiety which frequently co-occur 4, 2, 3
3. Sleep disturbance - evaluate quality, quantity, hygiene, and screen for sleep apnea 4, 2, 3
4. Anemia 4
5. Nutrition - assess weight changes, caloric intake, appetite, fluid/electrolyte balance 4, 3
6. Activity level - evaluate exercise patterns and ability to accomplish daily activities 4, 3
7. Alcohol/substance abuse 4, 3
8. Medication side effects - review ALL medications including over-the-counter, herbals, vitamins 4, 3
9. Comorbidities - review existing conditions and optimize management 4, 3

Medication-Specific Review

• Note recent medication changes 3
• Evaluate for drug interactions causing excessive drowsiness 3
• Consider cardiac medications (β-blockers) that may cause bradycardia and fatigue 3

Laboratory Studies (Judicious Use)

Laboratory results affect management in only 5% of patients, and if initial results are normal, repeat testing is generally not indicated 5

Initial Laboratory Panel

• Complete blood count with differential (anemia, infection, malignancy) 3
• Comprehensive metabolic panel (liver/kidney function) 3
• Thyroid-stimulating hormone (TSH) 3
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammation 3

Conditional Testing

• HIV testing and tuberculosis screening only if risk factors present 3
• Further investigations beyond history, physical examination, and simple laboratory tests are needed only in the presence of additional symptoms or findings 1

Physical Examination Focus

• Identify common secondary causes including pregnancy 5
• Screen for life-threatening problems such as cancer 5
• Check for lymphadenopathy, organomegaly, or masses 3

Imaging Studies

• Chest X-ray only as initial screening if respiratory symptoms present 3
• CT scan only if lymphadenopathy, organomegaly, or masses suspected 3
• Further imaging based solely on specific clinical findings 3

Watchful Waiting Strategy

Consider a period of watchful waiting in the absence of red flags, as this prevents excessive focus on somatic causes and reduces overdiagnosis 6, 1

• Schedule regular follow-up visits rather than sporadic urgent appointments 5
• If diagnosis remains unclear after initial evaluation, watchful waiting with regularly scheduled follow-up helps prevent overdiagnosis 1
• Medical causes usually declare themselves over the next several visits if present 7

Common Pitfalls to Avoid

• Don't pursue a "fishing expedition" with extensive testing if medical cause is not evident on initial presentation 7
• Avoid overlooking medication side effects as potential contributors 2, 3
• Don't assume psychiatric illness is a diagnosis of exclusion - it should be suspected based on history 7
• Recognize that fatigue rarely occurs in isolation and often clusters with pain, sleep disturbance, or emotional distress 4, 2, 3
• Avoid an exclusively somatic focus to prevent overdiagnosis, since dangerous disorders are rare 1

Management Principles (Regardless of Cause)

• Implement structured physical activity plan with gradual increase in intensity - this applies to all types of fatigue 3, 5
• Implement good sleep hygiene practices 3
• Address nutritional deficiencies 3
• Consider psychoeducative and psychotherapeutic approaches 1
• Treat any identified underlying causes 3
• Reassess fatigue severity at each visit 3