
Am Fam Physician. 2023;108(1):58-69
Patient information: See related handout on myalgic encephalomyelitis/chronic fatigue syndrome.
Published online June 6, 2023.
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.8–10 Decreased cognition, some forms of cancer, metabolic and reproductive health effects, and increased mortality have been associated with fatigue.9,11
Clinical recommendation | Evidence rating | Comments |
---|---|---|
Evaluate for physiologic causes of fatigue before investigating secondary or chronic fatigue.15,16,19 | C | Expert opinion and consensus guidelines |
Use exercise therapy and psychological interventions (particularly cognitive behavior therapy) to treat fatigue related to cancer, inflammatory conditions, neurologic conditions, and fibromyalgia, but not ME/CFS.15,16,19,26–33,36,51,52 | B | Limited-quality patient-oriented evidence |
Use the National Academy of Medicine criteria to diagnose ME/CFS.19,38 | C | Consensus guideline informed by systematic review |
When treating ME/CFS, target the most severe symptoms and comorbidities.15,16,19,51,52 | C | Expert opinion and consensus guidelines |
Educate patients with ME/CFS about pacing, which may prevent postexertional malaise.15,16,19 | C | Expert opinion and consensus guidelines |

Recommendation | Sponsoring 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
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

Category | Disease/conditions | Evaluation options |
---|---|---|
Cardiovascular and pulmonary | Arrhythmias Cardiomyopathy Chronic obstructive pulmonary disease Coronary artery disease Heart failure Pulmonary hypertension Sarcoidosis Valvular heart disease | Chest computed tomography Chest radiography Echocardiography Electrocardiography Holter monitor Pulmonary function testing |
Endocrine and metabolic | Chronic kidney disease Diabetes mellitus Hypercalcemia Hypercortisolism Hyperthyroidism Hypothyroidism Primary adrenal insufficiency Severe obesity | A1C level Adrenocorticotropic hormone level Basic metabolic panel Cortisol level Renal ultrasonography Thyroid-stimulating hormone level Thyroid ultrasonography Urinalysis |
Environmental and exposure-related | Adverse medication effect Gulf War syndrome Heavy metals Mold/mycotoxins Substance use disorder | Alcohol screening (e.g., SBIRT [screening, brief intervention, and referral to treatment]) Chest radiography Lead level Medication levels Urine drug screening |
Gastrointestinal | Celiac disease Cirrhosis 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 |
Gynecologic | Endometriosis Pregnancy Premenstrual syndrome | Pelvic ultrasonography Urine pregnancy test |
Hematologic | Anemia Iron overload | Complete blood count Ferritin level Folate level Iron panel Vitamin B12 level |
Infectious diseases | Coccidioidomycosis COVID-19 Epstein-Barr virus* Giardiasis Hepatitis B Hepatitis C HIV Parvovirus B19 Q fever Syphilis Tick-borne diseases Tuberculosis West Nile virus | Epstein-Barr virus antibody Hepatitis B antigen Hepatitis C antibody HIV testing Lyme titer Monospot Purified protein derivative or quantiferon Rapid plasma reagin Serum treponemal antibody Stool ova and parasites |
Neurologic | Cerebrospinal fluid leak Cerebrovascular accident Chiari malformation Craniocervical instability Multiple sclerosis Myasthenia gravis Parkinson disease Seizures Spinal stenosis Traumatic brain injury Vitamin B12 deficiency | Acetylcholine receptor antibody Brain or spine magnetic resonance imaging Electroencephalography Methylmalonic acid level Vitamin B12 level |
Oncologic | Primary cancers Secondary cancers | Bone scan Complete blood count with differential Positron emission tomography/computed tomography |
Primary psychiatric | Anxiety* Bipolar disorder Depression* | Generalized Anxiety Disorder 7-item screening tool Medication levels Mood Disorder Questionnaire Patient Health Questionnaire-9 Thyroid-stimulating hormone level |
Rheumatologic | Fibromyalgia* Polymyalgia rheumatica Polymyositis 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 |
Sleep | Narcolepsy Periodic limb movement disorder* Sleep apnea* | Epworth Sleepiness Scale Polysomnography STOP-Bang (snoring, tired, observed, pressure, body mass index, age, neck size, gender) questionnaire |

History Typical reaction to activity that was previously tolerated? Any preceding triggers to the start of fatigue? Duration of symptoms? Pattern of symptoms? Function 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? | Sleep-related 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? Cognition-related Do you have problems performing the following activities? Driving Watching a movie Reading 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. Orthostasis 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
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