Fatigue¶
Chapter 25 | Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 25
Key Clinical Points¶
- Fatigue is the subjective experience of physical and mental weariness, sluggishness, low energy, and exhaustion.
- Clinical definition: Difficulty initiating or maintaining voluntary mental or physical activity.
- Must be distinguished from muscle weakness (reduction of neuromuscular power), somnolence (sleepiness), and dyspnea (shortness of breath).
- Laboratory testing identifies the cause of unexplained chronic fatigue in only about 5% of cases; extensive testing often leads to incidental findings.
- Standard screening includes CBC, electrolytes (Na, K, Ca), glucose, renal/liver/thyroid function, HIV, and adrenal function.
- Psychiatric disorders (depression, anxiety, somatoform) are common causes; symptoms are present in >75% of patients with unexplained chronic fatigue.
- Obstructive sleep apnea (OSA) is a major cause of excessive daytime sleepiness and should be investigated via polysomnography.
- Endocrine issues (hypo/hyperthyroidism, adrenal insufficiency, hypercalcemia, diabetes, Vitamin D deficiency) are common causes.
- Post-infectious fatigue occurs after SARS-CoV-1, SARS-CoV-2, Dengue, and Ebola; ~1/3 of COVID-19 patients report fatigue 3+ months post-diagnosis.
- Cancer-related fatigue affects 40% of patients at diagnosis and >80% during the disease course.
1. DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): Fatigue refers to the subjective experience of physical and mental weariness, sluggishness, low energy, and exhaustion. • Clinical Definition: Difficulty initiating or maintaining voluntary mental or physical activity. • Key Distinctions: Must be differentiated from: ◦ Muscle weakness: Reduction of neuromuscular power. ◦ Somnolence: Sleepiness. ◦ Dyspnea: Shortness of breath.
2. EPIDEMIOLOGY¶
• Prevalence: ◦ Point prevalence: 6.7% ◦ Lifetime prevalence: 25% (based on a large NIH survey of the U.S. general population).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Psychiatric Disease: ◦ Common in depression, anxiety, and somatoform disorders. ◦ Psychiatric symptoms are reported in more than three-quarters (75%) of patients with unexplained chronic fatigue. • Neurologic Disease: ◦ Patients often report 'weakness,' but objective muscle weakness is rarely discernible. ◦ If present, must be localized to the central nervous system, peripheral nervous system, neuromuscular junction, or muscle. • Sleep Disorders: ◦ Obstructive sleep apnea (OSA) is a major cause of excessive daytime sleepiness. ◦ Investigation: Overnight polysomnography (especially in patients with snoring, obesity, or other predictors of OSA). • Endocrine Disorders: ◦ Hypothyroidism: Associated with hair loss, dry skin, cold intolerance, constipation, and weight gain. ◦ Hyperthyroidism: Associated with heat intolerance, sweating, and palpitations. ◦ Adrenal Insufficiency: May present with anorexia, weight loss, nausea, myalgias, and arthralgias; may include hyponatremia, hyperkalemia, and hyperpigmentation. ◦ Hypercalcemia: Mild → vague fatigue; Severe → lethargy, stupor, and coma. ◦ Glucose Disorders: Both hypoglycemia and hyperglycemia cause lethargy/confusion; Type 1 diabetes is associated with fatigue independent of glucose levels. ◦ Other: Cushing's disease, hypoaldosteronism, hypogonadism, and low vitamin D status. • Liver and Kidney Disease: ◦ Chronic liver failure and chronic kidney disease (CKD) cause fatigue. ◦ CKD: Over 80% of hemodialysis patients report fatigue. • Obesity: ◦ Associated with fatigue and sleepiness independent of OSA. ◦ Bariatric surgery leads to improved daytime sleepiness sooner than expected from weight loss alone. • Malnutrition: ◦ Present in malnutrition or as a comorbidity in chronic illnesses (e.g., cancer-associated fatigue). • Infection: ◦ Acute and chronic infections cause fatigue as part of the broader infectious syndrome. ◦ Specific risks: Tuberculosis, HIV, chronic hepatitis, endocarditis. ◦ Infectious mononucleosis: Can cause prolonged fatigue for weeks to months (rarely the cause of unexplained chronic fatigue). ◦ Post-infectious: SARS-CoV-1, SARS-CoV-2, Dengue, and Ebola. ◦ COVID-19: Approximately one-third of patients report fatigue 3 or more months post-diagnosis. • Drugs: ◦ Causes: Medications, drug withdrawal, and chronic alcohol use. ◦ Specific agents: Antidepressants, antipsychotics, anxiolytics, opiates, antispasticity agents, antiseizure agents, and beta blockers. • Cardiovascular and Pulmonary Disorders: ◦ Common in congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). ◦ Associated with increased risk of all-cause mortality, especially cardiovascular deaths. • Malignancy: ◦ Sign of occult malignancy if accompanied by weight loss. ◦ Cancer-related fatigue: 40% at diagnosis; >80% during the disease course. • Hematologic Disorders: ◦ Chronic/progressive anemia → fatigue, exertional tachycardia, and breathlessness. ◦ Low serum ferritin (without anemia) → reversible with iron replacement. • Immune-Mediated Disorders: ◦ Common in SLE, polymyalgia rheumatica, rheumatoid arthritis, IBD, ANCA-associated vasculitis, sarcoidosis, and Sjögren's syndrome. ◦ Associated with primary immunodeficiency diseases. • Pregnancy: ◦ Commonly reported during all stages of pregnancy and postpartum. • Disorders of Unclear Cause: ◦ Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). ◦ Fibromyalgia. ◦ Gulf-War syndrome (Chronic multisymptom illness). ◦ Idiopathic chronic fatigue: No sufficient features for ME/CFS diagnosis.
4. CLINICAL FEATURES¶
• History Focus: ◦ Quality, pattern, time course, associated symptoms, and alleviating factors. ◦ Determine if symptom is acute or chronic (Chronic: >1 month or >6 months). ◦ Identify impairment type: mental, physical, or both. • Review of Systems: ◦ Distinguish fatigue from excessive sleepiness, dyspnea on exertion, exercise intolerance, and muscle weakness. • Red Flags: ◦ Fever, chills, night sweats, or weight loss → suspect occult infection or malignancy.
5. DIFFERENTIAL DIAGNOSIS¶
• Psychiatric: Depression, anxiety, somatoform disorders. • Neurologic: MS, Parkinson's, ALS, CNS dysautonomias, stroke, migraine, TBI, myasthenia gravis. • Sleep: Obstructive sleep apnea. • Endocrine: Hypo/hyperthyroidism, adrenal insufficiency, DM, Cushing's, hypoaldosteronism, hypogonadism, vitamin D deficiency. • Liver/Kidney: Chronic liver failure, chronic kidney disease. • Obesity: Obesity, physical inactivity, diabetes, depression. • Infection: TB, HIV, hepatitis, endocarditis, mononucleosis, SARS-CoV-1, SARS-CoV-2, Dengue, Ebola. • Drugs: Antidepressants, antipsychotics, anxiolytics, opiates, antispasticity agents, antiseizure agents, beta blockers, alcohol. • Cardiovascular/Pulmonary: CHF, COPD. • Malignancy: Occult malignancy. • Hematologic: Anemia, low serum ferritin. • Immune-Mediated: SLE, PMR, RA, IBD, ANCA-associated vasculitis, sarcoidosis, Sjögren's syndrome, primary immunodeficiency. • Pregnancy: All stages of pregnancy and postpartum. • Unclear Cause: ME/CFS, fibromyalgia, Gulf-War syndrome, idiopathic chronic fatigue.
6. INVESTIGATIONS & DIAGNOSIS¶
• Clinical Evaluation: ◦ Detailed history and physical examination are primary. ◦ Laboratory testing identifies the cause of chronic fatigue in only about 5% of cases. ◦ Extensive testing should be avoided to prevent irrelevant incidental findings. • Screening Tests: 1. Complete Blood Count (CBC): Screen for anemia, infection, malignancy. 2. Electrolytes: Sodium, potassium, calcium. 3. Glucose: Diabetes screening. 4. Renal Function: Kidney disease. 5. Liver Function: Liver disease. 6. Thyroid Function: Hypo/hyperthyroidism. 7. HIV Test. 8. Adrenal Function. 9. Erythrocyte Sedimentation Rate (ESR): Only if value is very high; used in ME/CFS guidelines. • Tests to Avoid: 1. Routine ANA: Not informative in isolation; often positive at low titers in healthy adults. 2. Unfocused studies: Whole-body imaging scans → avoid due to cost, risk, and irrelevant findings.
7. MANAGEMENT & TREATMENT¶
• Primary Goal: Address the underlying disorder (curative or palliative). ◦ If fatigue is refractory, evaluate for multiple contributing factors. • Antidepressants: 1. Use if symptoms of depression are present. 2. Note: Antidepressants can cause fatigue; discontinue if not clearly effective. • Cognitive-Behavioral Therapy (CBT): 1. Useful in ME/CFS. 2. Useful for cancer-associated fatigue. • Graded Exercise Therapy: 1. Method: Physical exercise (typically walking) gradually increased with attention to target heart rates. 2. Evidence: Shown to modestly improve fatigue in ME/CFS, cancer, MS, and diabetes. • Psychostimulants: 1. Agents: Amphetamines, modafinil, armodafinil. 2. Use: Increase alertness/concentration; reduce excessive daytime sleepiness. 3. Limitations: Generally unhelpful in randomized trials for TBI, Parkinson's, cancer, and MS. • Vitamin D: 1. Treatment: Vitamin D replacement. 2. Indication: Patients with low vitamin D status.
8. PROGNOSIS & COMPLICATIONS¶
• Refractory Nature: Fatigue may be refractory to traditional disease-modifying therapies in many chronic illnesses. • Multifactorial Causes: Importance of evaluating for multiple contributing factors. • Biologic Basis: Limited knowledge of how fatigue is detected/registered in the nervous system hampers development of more effective therapies.
9. SPECIAL CONSIDERATIONS¶
• Pregnancy: ◦ Fatigue is very commonly reported by women during all stages of pregnancy and postpartum.
10. KEY PEARLS & CLINICAL TRAPS¶
• Red Flags: Fever, chills, night sweats, or weight loss → suspect infection or malignancy. • Diagnostic Pitfalls: ◦ Routine ANA is not informative in isolation. ◦ Whole-body imaging scans are not indicated (risk of incidental findings). • Yield of Testing: Laboratory testing identifies the cause of chronic fatigue in only ~5% of cases. • Therapeutic Alliance: A complete physical examination demonstrates a systematic approach and builds trust/alliance.
Reference Tables¶
TABLE 24-2 Treatment of Vertigo AGENT a Antihistamines¶
Harrison's 22e, p.165
| AGENTa | DOSEb |
|---|---|
| Antihistamines | |
| Meclizine | 25–50 mg 3 times daily |
| Dimenhydrinate | 50 mg 1–2 times daily |
| Promethazine | 25 mg 2–3 times daily (also can be given rectally and IM) |
| Anticholinergic | |
| Scopolamine transdermalc | Patch |
| Other | |
| Diuretics and/or low-sodium (1000 mg/d) diete | |
| Antimigrainous drugsf | |
| Selective serotonin reuptake inhibitorsg |