What is the differential diagnosis and management for fatigue?

Differential Diagnosis for Fatigue

Begin systematic screening with a 0-10 numeric rating scale at every clinical encounter, and immediately pursue comprehensive diagnostic evaluation for any patient scoring ≥4, as this threshold indicates moderate-to-severe fatigue requiring investigation of treatable underlying causes. 1

Initial Screening Approach

• Use a 0-10 numeric rating scale where 1-3 indicates mild fatigue, 4-6 moderate, and 7-10 severe fatigue 1
• Screen at initial visit, at regular intervals during treatment, and as clinically indicated 1
• Any score ≥4 mandates immediate comprehensive evaluation using tools like the Brief Fatigue Inventory to assess both severity and functional impact 1
• Assess impact on daily activities and functional capacity, as identical fatigue scores can produce vastly different disability levels 2

Comprehensive Differential Diagnosis

Hematologic Causes

• Anemia - compare current hemoglobin/hematocrit with baseline values; assess all cell lines including WBC and platelets 1
• Bone marrow suppression from medications or underlying disease 1

Endocrine and Metabolic Disorders

• Hypothyroidism - measure TSH and free T4; consider comprehensive endocrine evaluation if other symptoms present 1, 2
• Hypogonadism, adrenal insufficiency, hypopituitarism - particularly in patients on immunotherapy 2
• Diabetes mellitus (unstable) - assess glucose control and complications 1
• Vitamin D deficiency, low IGF-1, magnesium deficiency - correlate with muscle fatigue 2

Cardiovascular and Pulmonary Causes

• Cardiac dysfunction - assess for heart failure, arrhythmias, coronary disease 1
• Pulmonary dysfunction - evaluate for COPD, restrictive lung disease, pulmonary hypertension 1
• Postural hypotension - check orthostatic vital signs 3

Renal and Hepatic Causes

• Renal dysfunction - assess creatinine, BUN, electrolytes 1
• Hepatic dysfunction - evaluate liver enzymes, synthetic function 1

Rheumatologic and Inflammatory Conditions

• Polymyalgia rheumatica-like syndrome - severe proximal myalgia in upper/lower extremities with highly elevated inflammatory markers but normal creatine kinase 2
• Inflammatory arthritis - oligoarthritis of large joints or symmetrical polyarthritis; check rheumatoid factor and anti-CCP antibodies 2
• Systemic lupus erythematosus, other autoimmune disorders 2

Infectious Causes

• Active infection - assess for fever, elevated WBC, specific infectious symptoms 1
• Chronic infections (HIV, hepatitis, tuberculosis, Lyme disease) 4

Neurological Causes

• Multiple sclerosis, Parkinson's disease, stroke, traumatic brain injury 5, 6
• Neuromuscular disorders (myasthenia gravis, post-polio syndrome, muscular dystrophies) 6
• Sleep disorders including sleep apnea, restless leg syndrome, periodic limb movement 1, 4

Psychiatric Causes

• Depression - use two-question screen: "In the last month, have you felt dejected, sad, depressed or hopeless?" and "Did you experience significantly less pleasure with things you normally enjoy?" 1
• Anxiety disorders 1
• Depression accounts for 18.5% of persistent fatigue cases 4

Medication-Related Causes

• Statin-induced myopathy - presents with myalgia and normal-to-mildly elevated CK 2
• Persistent use of sleep aids, pain medications, antiemetics 1
• Review all current medications and supplements for fatigue-inducing side effects 1, 2

Malignancy

• Previously undiagnosed cancer accounts for only 0.6% of fatigue cases 4
• Evaluate risk of recurrence in cancer survivors based on stage, pathologic factors, treatment history 1

Nutritional Causes

• Malnutrition, weight loss, inadequate caloric intake 1
• Specific vitamin deficiencies (B12, folate, vitamin D) 2

Other Contributing Factors

• Pain - uncontrolled or undertreated 1
• Deconditioning and decreased activity level 1
• Alcohol/substance abuse 1
• Excessive psychosocial stress 4

Mandatory Laboratory Evaluation for Fatigue Score ≥4

Order the following tests for all patients with moderate-to-severe fatigue:

• Complete blood count with differential - assess hemoglobin, WBC, platelets 1, 2
• Comprehensive metabolic panel - evaluate electrolytes, hepatic and renal function 1, 2
• Thyroid function tests (TSH, free T4) - screen for hypothyroidism 1, 2
• Inflammatory markers (ESR, CRP) - assess for inflammatory conditions 2
• Creatine kinase - evaluate for myopathy 2

Additional targeted testing based on clinical findings:

• Iron studies, vitamin B12, folate if anemia present 7
• Cortisol, testosterone if endocrine dysfunction suspected 2
• Rheumatoid factor, anti-CCP antibodies if inflammatory arthritis suspected 2

Focused History Components

Obtain the following specific details:

• Onset, pattern, duration - when did fatigue start, does it vary throughout the day, how long has it persisted 1, 8
• Change over time - is it worsening, improving, or stable 1
• Associated or alleviating factors - what makes it better or worse 1
• Timing relative to medications - particularly new medications or dose changes 8
• Sleep quality - difficulty falling asleep, staying asleep, early morning awakening, snoring, witnessed apneas 1, 8
• Mood symptoms - sadness, anhedonia, hopelessness, anxiety 1, 8
• Pain location and severity - assess for undertreated pain 1
• Nutritional intake - recent weight changes, appetite, dietary restrictions 1
• Activity level - baseline exercise capacity, recent deconditioning 1
• Social and environmental contributors - psychosocial stressors, caregiver burden 1

Physical Examination Focus

• Vital signs including orthostatic blood pressure 3
• Thyroid examination for goiter or nodules 1
• Cardiac examination for murmurs, gallops, irregular rhythm 1
• Pulmonary examination for crackles, wheezes, decreased breath sounds 1
• Abdominal examination for hepatosplenomegaly, masses 1
• Musculoskeletal examination for joint swelling, tenderness, muscle weakness 2
• Neurological examination for focal deficits, tremor, gait abnormalities 6
• Mental status examination for depression, cognitive impairment 1

Common Pitfalls to Avoid

• Do not assume fatigue will resolve spontaneously - it requires active management even when underlying disease is controlled 8
• Do not pursue extensive imaging or invasive testing without specific clinical indicators - previously undiagnosed cancer is rare (0.6%) and should not drive initial workup 4
• Do not overlook depression - it is the most common treatable cause at 18.5% prevalence 4
• Do not ignore medication review - many commonly prescribed drugs cause fatigue 1, 2
• Do not skip assessment of sleep quality - sleep disorders are among the most common causes of persistent fatigue 4