Fatigue is one of the top 10 reasons for a visit to primary care and is reported by 5% to 10% of patients in the primary care setting.^1,2 Fatigue is the most common symptom reported by those with chronic illness.³ A cross-sectional survey found up to 38% of U.S. workers reported fatigue during the previous two weeks.⁴ Fatigue is strongly associated with absenteeism, decreased work productivity, and serious accidents.^5,6 Fatigue is estimated to cost employers more than $100 billion per year.⁴ Risk factors for fatigue in the general population include being female, unmarried, younger, and of lower educational attainment.⁷ Fatigue is an important component of frailty syndrome, which is commonly found in older patients with limited physiologic reserves and vulnerability to minor illness or injury, and independently predicts falls and functional decline in older people.^8–10 Decreased cognition, some forms of cancer, metabolic and reproductive health effects, and increased mortality have been associated with fatigue.^9,11

Fatigue encompasses a range of potential causes and related comorbidities and is a feeling of weariness or exhaustion.¹² This can be a physiologic, self-limited, normal response in healthy individuals. It may also be chronic or secondary to another condition. Fatigue may or may not respond to rest. In comparison, sleepiness is the tendency to doze off and responds to rest.¹³ Patients, physicians, and medical journals use the words fatigue, sleepiness, and weakness interchangeably; the three are often related and not mutually exclusive. There are widely used objective and subjective tools to assess and monitor sleepiness.¹³ In contrast, assessment tools for fatigue are not consistently validated and tend to be condition specific.¹⁴

Evaluation

The differential diagnosis list for fatigue is extensive (Table 1).^15,16 Table 2 provides a list of questions to ask when eliciting a history from a patient with fatigue.¹⁶ Physicians should use validated screening tools to rule out comorbid sleep, mood, and substance use disorders. Figure 1 suggests an approach to evaluating patients with fatigue. Medications should be reviewed to ensure the fatigue is not iatrogenic. A physical including cardiopulmonary, neurologic, and skin examinations should be performed. The initial laboratory workup should be guided by history, physical examination, and common causes of fatigue. Laboratory testing without specific indications is not high-yield and may only change treatment in 5% of patients.¹⁷

Despite a comprehensive workup, a definitive diagnosis is often not made. In one study investigating first-time reports of fatigue in young adults without known comorbid conditions presenting to primary care, most received a workup; however, only 27% were diagnosed with a condition that could explain the fatigue, the most common of which included anemia, vitamin B₁₂ deficiency, infection, pregnancy, and psychiatric diagnoses.¹⁷ In another study, only 8% of patients received a clear condition-based diagnosis one year after their presentation to primary care with fatigue. Nearly 17% received a psychological diagnosis.¹⁸

Physiologic Fatigue

Physiologic fatigue, caused by an imbalance between activities that burn energy and those that restore energy, is a normal response relieved by appropriate rest. Physiologic causes of fatigue should be assessed before investigating secondary or chronic fatigue.^15,16,19 Physicians should inquire about the patient's daily habits, including the amount and quality of sleep, activity level throughout the day, and nutritional status. Inadequate sleep is a widespread problem, with nearly 30% of U.S. adults reporting fewer than seven hours of sleep per night.²⁰ Patients at high risk of obstructive sleep apnea should be screened using a validated tool such as the STOP-Bang (snoring, tiredness, observed apnea, blood pressure, body mass index, age, neck circumference, gender) questionnaire.²¹ Good sleep hygiene can contribute to more restorative sleep. Patients should be reminded to adhere to consistent sleep schedules, limit screen time, and avoid caffeine and alcohol near bedtime.²² Excessive exercise of prolonged intensity and duration that depletes energy stores and does not allow for adequate recovery can leave patients feeling fatigued.²³ A prerequisite to having the energy to perform daily tasks is consuming the nutritional components to create this energy. Physicians should ask patients about their dietary habits and counsel them to avoid fad diets or excessively restrictive meal regimens. Ginseng may be helpful with nonspecific physiologic fatigue.²⁴