brand logo

Am Fam Physician. 2023;108(1):58-69

Patient information: See related handout on myalgic encephalomyelitis/chronic fatigue syndrome.

Published online June 6, 2023.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Fatigue is among the top 10 reasons patients visit primary care offices, and it significantly affects patients' well-being and occupational safety. A comprehensive history and cardiopulmonary, neurologic, and skin examinations help guide the workup and diagnosis. Fatigue can be classified as physiologic, secondary, or chronic. Physiologic fatigue can be addressed by proper sleep hygiene, a healthy diet, and balancing energy expenditure. Secondary fatigue is improved by treating the underlying condition. Cognitive behavior therapy, exercise therapy, and acupuncture may help with some of the fatigue associated with chronic conditions. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, severe, and potentially debilitating disorder with demonstrated inflammatory, neurologic, immunologic, and metabolic abnormalities. ME/CFS has a poor prognosis, with no proven treatment or cure. It may become more common after the COVID-19 pandemic because many patients with long COVID (post–COVID-19 condition) have symptoms similar to ME/CFS. The most important symptom of ME/CFS is postexertional malaise. The 2015 National Academy of Medicine diagnostic criteria diagnose ME/CFS. Exercise can be harmful to patients with ME/CFS because it can trigger postexertional malaise. Patients should be educated about pacing their activity not to exceed their limited energy capacity. Treatment should prioritize comorbidities and symptoms based on severity.

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.810 Decreased cognition, some forms of cancer, metabolic and reproductive health effects, and increased mortality have been associated with fatigue.9,11

RecommendationSponsoring organization
Do not routinely order sleep studies (polysomnography) to screen for or diagnose sleep disorders in workers having chronic fatigue or insomnia.American College of Occupational and Environmental Medicine

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


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

CategoryDisease/conditionsEvaluation options
Cardiovascular and pulmonaryArrhythmias
Chronic obstructive pulmonary disease
Coronary artery disease
Heart failure
Pulmonary hypertension
Valvular heart disease
Chest computed tomography
Chest radiography
Holter monitor
Pulmonary function testing
Endocrine and metabolicChronic kidney disease
Diabetes mellitus
Primary adrenal insufficiency
Severe obesity
A1C level
Adrenocorticotropic hormone level
Basic metabolic panel
Cortisol level
Renal ultrasonography
Thyroid-stimulating hormone level
Thyroid ultrasonography
Environmental and exposure-relatedAdverse medication effect
Gulf War syndrome
Heavy metals
Substance use disorder
Alcohol screening (e.g., SBIRT [screening, brief intervention, and referral to treatment])
Chest radiography
Lead level
Medication levels
Urine drug screening
GastrointestinalCeliac disease
Food allergy or intolerances*
Inflammatory bowel diseases
Small intestinal bacterial overgrowth*
Abdominal computed tomography
Comprehensive metabolic panel
C-reactive protein
Endomysial antibody
Erythrocyte sedimentation rate
Liver ultrasonography
Tissue transglutaminase
Premenstrual syndrome
Pelvic ultrasonography
Urine pregnancy test
Iron overload
Complete blood count
Ferritin level
Folate level
Iron panel
Vitamin B12 level
Infectious diseasesCoccidioidomycosis
Epstein-Barr virus*
Hepatitis B
Hepatitis C
Parvovirus B19
Q fever
Tick-borne diseases
West Nile virus
Epstein-Barr virus antibody
Hepatitis B antigen
Hepatitis C antibody
HIV testing
Lyme titer
Purified protein derivative or quantiferon
Rapid plasma reagin
Serum treponemal antibody
Stool ova and parasites
NeurologicCerebrospinal fluid leak
Cerebrovascular accident
Chiari malformation
Craniocervical instability
Multiple sclerosis
Myasthenia gravis
Parkinson disease
Spinal stenosis
Traumatic brain injury
Vitamin B12 deficiency
Acetylcholine receptor antibody
Brain or spine magnetic resonance imaging
Methylmalonic acid level
Vitamin B12 level
OncologicPrimary cancers
Secondary cancers
Bone scan
Complete blood count with differential
Positron emission tomography/computed tomography
Primary psychiatricAnxiety*
Bipolar disorder
Generalized Anxiety Disorder 7-item screening tool
Medication levels
Mood Disorder Questionnaire
Patient Health Questionnaire-9
Thyroid-stimulating hormone level
Polymyalgia rheumatica
Rheumatoid arthritis
Systemic lupus erythematosus
Anti-cyclic citrullinated peptides antibody
Antinuclear antibodies
C-reactive protein
Creatine phosphokinase
Erythrocyte sedimentation rate
Radiography of affected joints
Rheumatoid factor
Periodic limb movement disorder*
Sleep apnea*
Epworth Sleepiness Scale
STOP-Bang (snoring, tired, observed, pressure, body mass index, age, neck size, gender) questionnaire
Typical reaction to activity that was previously tolerated?
Any preceding triggers to the start of fatigue?
Duration of symptoms?
Pattern of symptoms?
How would you rate your level of fatigue?
What helps relieve your fatigue?
What exacerbates your fatigue?
In what level of function can you participate? How does it compare with before you became sick?
How does your illness affect your ability to work and manage household responsibilities?
How do you feel when you try to “push through” the fatigue?
Postexertional malaise
How do you feel after normal physical or emotional activity?
How much activity does it take you to feel ill?
What symptoms do you experience when standing or exerting yourself?
How much time is required for recovery from physical or mental exertion?
What activity avoidance or modification do you have to make due to your illness?
Do you have any trouble falling asleep or staying asleep?
After sleeping, do you feel rested?
How would you describe your sleep quality?
Do you require more naps than other people?
Do you have problems performing the following activities?
Watching a movie
Completing timed complex tasks
Following/participating in conversation
Doing more than one thing at a time
Compare your work/school success before and after becoming ill.
Describe how you feel when you have been standing still for more than a few minutes.
What happens when you quickly change position from lying down or sitting to standing?
How long can you tolerate standing before feeling sick?
How does hot weather affect you?
Do you study or work in a reclined position? Why?

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

Already a member/subscriber?  Log In


From $145
  • Immediate, unlimited access to all AFP content
  • More than 130 CME credits/year
  • AAFP app access
  • Print delivery available

Issue Access

  • Immediate, unlimited access to this issue's content
  • CME credits
  • AAFP app access
  • Print delivery available

Article Only

  • Immediate, unlimited access to just this article
  • CME credits
  • AAFP app access
  • Print delivery available
Purchase Access:  Learn More

Continue Reading

More in AFP

More in Pubmed

Copyright © 2023 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See permissions for copyright questions and/or permission requests.