Persistent Fatigue: Differential Diagnosis and When to See a Doctor

Chronic fatigue (≥6 months) is a common but nonspecific symptom requiring systematic evaluation.

Major Etiologic Categories

Category	Key Conditions	Clues
Sleep Disorders	Obstructive sleep apnea, insomnia, restless legs, narcolepsy	Snoring, witnessed apneas, unrefreshing sleep, daytime sleepiness
Endocrine/Metabolic	Hypothyroidism, diabetes (DM1/2), adrenal insufficiency, hypercalcemia	Weight change, cold/heat intolerance, polyuria/polydipsia, hypotension
Hematologic	Anemia (iron, B12, folate, chronic disease), malignancy	Pallor, dyspnea on exertion, menorrhagia, GI bleeding
Cardiopulmonary	Heart failure, COPD, pulmonary hypertension	Orthopnea, PND, edema, exertional dyspnea
Infectious/Post-infectious	EBV, CMV, HIV, TB, Long COVID, chronic hepatitis	Fever, lymphadenopathy, risk factors, post-viral onset
Rheumatologic/Autoimmune	SLE, RA, vasculitis, fibromyalgia	Joint pain, rash, Raynaud's, morning stiffness
Psychiatric	Depression, anxiety, somatic symptom disorder	Anhedonia, worry, sleep disturbance, stress correlation
Medication/Substance	Beta-blockers, antihistamines, antidepressants, opioids, alcohol, sedatives	Temporal relationship to initiation/dose change
Neurologic	MS, Parkinson's, myasthenia gravis	Weakness, numbness, vision changes, fatigability
Malignancy	Occult solid tumors, lymphomas	Weight loss, night sweats, age >50, risk factors

Initial Workup

CBC, CMP, TSH, ferritin, B12/folate, HbA1c, ESR/CRP, UA, HIV (if risk), sleep study if suggested. Further testing guided by history/exam.

See a physician if fatigue is persistent, progressive, unexplained, or accompanied by red-flag symptoms.