What are the causes of fatigue?

Causes of Fatigue

Fatigue is multifactorial, with the most common causes being sleep disorders (affecting 30-75% of patients), depression (18.5%), medication side effects, and thyroid dysfunction, while serious organic causes like cancer or anemia are rare (0.6% and 2.8% respectively). 1, 2, 3

Primary Medical Causes

Endocrine Dysfunction

• Hypothyroidism is one of the first and most important causes to investigate, as it frequently presents with fatigue and nonspecific symptoms 1
• Thyroid dysfunction should be assessed early, particularly in patients who received radiation to the neck or thorax 4
• Hypogonadism occurs in patients with advanced disease and may contribute to fatigue 4
• Adrenal insufficiency and hot flashes can cause fatigue 4

Hematologic Causes

• Anemia occurs in approximately 2.8% of patients presenting with tiredness and is a treatable cause 1, 3
• Anemia is considered the cardinal symptom associated with fatigue, though the relationship is multifactorial 5
• Iron deficiency, even without anemia, can contribute to fatigue 6

Cardiovascular Disease

• Cardiac dysfunction should be assessed, particularly in patients with cardiovascular risk factors or those who received cardiotoxic treatments 1
• Congestive heart failure and related cardiac conditions contribute substantially to fatigue symptoms 4
• Certain cardiac medications (such as β-blockers) may elicit bradycardia and subsequent fatigue 4

Other Organ System Dysfunction

• Pulmonary, renal, hepatic, and neurologic dysfunction all contribute to fatigue 4
• Infection should be evaluated as a contributing factor 4

Psychological and Behavioral Factors

Mental Health Disorders

• Depression affects 18.5% of patients with tiredness and is more frequent among those complaining of fatigue compared to those without this symptom 1, 3
• Anxiety frequently accompanies fatigue and requires specific assessment 1, 2
• Emotional distress can both cause and exacerbate fatigue symptoms 2

Sleep Disturbances

• Sleep disorders affect 30-75% of patients with fatigue, ranging from hypersomnia to insomnia 1, 2
• Poor sleep hygiene, including irregular sleep schedules, daytime napping, and caffeine/alcohol consumption before bed, contributes to fatigue 2
• Sleep-related disorders of breathing are among the most common causes of persistent fatigue 3

Medication and Substance-Related Causes

Pharmacologic Contributors

• Medication side effects, including sedation, are common contributors to fatigue 1, 2
• Prescription and over-the-counter medications or supplements should be systematically reviewed 1, 2
• Combinations of different medication classes (e.g., narcotics, antidepressants, antiemetics, antihistamines) may contribute to excessive drowsiness and increasing fatigue 4
• Deleting or adjusting the dose of medications may be appropriate to treat fatigue 4

Substance Use

• Alcohol or substance abuse can lead to or aggravate other health problems such as sleep disturbance and contribute significantly to fatigue 4

Nutritional and Metabolic Factors

Nutritional Deficiencies

• Specific deficiencies linked to fatigue include vitamin B6, B12, folate, ferritin, zinc, vitamin D, magnesium, copper, phosphate, and calcium 1, 2
• Imbalances in sodium, potassium, calcium, and magnesium serum levels are often reversible and, with appropriate supplementation, may improve fatigue 4
• Weight changes and caloric intake alterations can contribute to fatigue 2
• Nutritional intake may be affected by nausea, vomiting, loss of appetite, food disinterest, mucositis, odynophagia, bowel obstruction, diarrhea, and constipation 4

Activity-Related Factors

Physical Deconditioning

• Decreased physical activity worsens fatigue symptoms 1, 2
• Deconditioning should be assessed, including changes in exercise or activity patterns 4
• Patients should be queried about their ability to accomplish normal daily activities and participate in formal or informal exercise programs 4

Pain and Symptom Clusters

Pain as a Contributing Factor

• Pain often clusters with fatigue and requires effective treatment 2
• Pain and fatigue together may have a synergistic effect that worsens the overall symptom experience 4
• Fatigue rarely occurs in isolation and often clusters with other symptoms 2

Rare but Serious Causes

Malignancy

• Previously undiagnosed cancer is a rare cause, accounting for only 0.6% of cases (95% CI [0.3; 1.3]) 3
• Despite being rare, cancer should be considered when fatigue is accompanied by other symptoms such as unintentional weight loss or pulmonary complaints 4

Inflammatory and Immune System Activation

Chronic Inflammatory Processes

• Persistent fatigue may be caused by chronic inflammatory processes involving the T-cell compartment 4
• Elevated serum markers (interleukin-1 receptor antagonist, soluble tumor necrosis factor type II, and neopterin) and lower cortisol levels correlate with fatigue 4
• Raised inflammatory markers in the absence of obvious symptoms represent reversible causes of fatigue 6

Clinical Pearls and Common Pitfalls

Diagnostic Considerations

• Laboratory results affect management in only about 5% of fatigue cases, but core testing remains essential to rule out treatable causes 1, 2, 7
• Overlooking psychological causes, such as depression and anxiety, leads to inadequate treatment 1, 2
• Ignoring medication side effects can perpetuate fatigue 1, 2
• Missing sleep disorders results in incomplete management 1, 2
• Excessive psychosocial stress is among the most common causes of persistent fatigue 3