What are the causes and treatments of fatigue?

Causes of Fatigue

Fatigue stems from a constellation of treatable medical, psychological, and lifestyle factors that must be systematically evaluated, with thyroid dysfunction, anemia, cardiac disease, depression, sleep disorders, and medications being the most critical causes to identify. 1, 2

Primary Medical Causes

The following medical conditions must be evaluated as they represent reversible causes of fatigue:

• Thyroid dysfunction is one of the first and most important causes to investigate, as hypothyroidism frequently presents with fatigue and nonspecific symptoms 1
• Anemia is a common treatable cause, occurring in approximately 2.8% of patients presenting with tiredness 1
• Cardiac dysfunction should be assessed, particularly in patients with cardiovascular risk factors or those who received cardiotoxic treatments 1, 3
• Endocrine disorders including hypogonadism, adrenal insufficiency, and hot flashes contribute to fatigue 3
• Infection and other comorbidities such as pulmonary, renal, hepatic, and neurologic dysfunction require evaluation 3

Psychological and Behavioral Factors

Mental health conditions are among the most common causes of persistent fatigue:

• Depression is a significant contributor, affecting 18.5% of patients with tiredness and occurring in 25-33% of patients with fatigue 1, 2
• Anxiety frequently accompanies fatigue and requires specific assessment 1, 2
• Emotional distress can both cause and exacerbate fatigue symptoms 2
• Excessive psychosocial stress is one of the most common causes of persistent fatigue 4

Sleep-Related Causes

Sleep disturbances are extremely prevalent in fatigued patients:

• Sleep disorders affect 30-75% of patients with fatigue, ranging from hypersomnia to insomnia 2
• Poor sleep hygiene including irregular sleep schedules, daytime napping, and caffeine/alcohol consumption before bed contributes to fatigue 2

Medication and Substance-Related Causes

Pharmacologic factors frequently contribute to or worsen fatigue:

• Medication side effects including sedation are common contributors, particularly with combinations of narcotics, antidepressants, antiemetics, and antihistamines 3, 2
• Cardiac medications such as β-blockers may elicit bradycardia and subsequent fatigue 3
• Prescription and over-the-counter medications or supplements should be systematically reviewed 3, 2
• Alcohol or substance abuse can lead to or aggravate other health problems such as sleep disturbance 3

Nutritional and Metabolic Factors

Nutritional deficiencies and metabolic imbalances are reversible causes:

• Specific deficiencies linked to fatigue include vitamin B6, B12, folate, ferritin, zinc, vitamin D, magnesium, copper, phosphate, and calcium 1
• Electrolyte imbalances in sodium, potassium, calcium, and magnesium are often reversible and may improve fatigue with appropriate supplementation 3
• Weight changes and caloric intake alterations can contribute to fatigue 2
• Low serum levels of vitamin D, IGF-1, and magnesium have been linked to muscle fatigue 5

Activity-Related Factors

Physical deconditioning perpetuates fatigue:

• Decreased physical activity worsens fatigue symptoms 1, 2
• Deconditioning results in an inability to continue exercise at the same intensity with resultant deterioration in performance 6

Pain

• Pain often clusters with fatigue and requires effective treatment 2

Critical Clinical Pearls

When evaluating fatigue, avoid these common pitfalls:

• Laboratory results affect management in only about 5% of fatigue cases, but core testing remains essential to rule out treatable causes 1, 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
• Previously undiagnosed cancer is a rare cause, accounting for only 0.6% of cases, so an exclusively somatic focus should be avoided to prevent overdiagnosis 4