Malaise and fatigue

Malaise and fatigue


Key Points

  • Fatigue comprises the subjective, self-reported symptoms of tiredness, exhaustion, lack of energy, and weariness; malaise is a subjective sense of being unwell
  • Many underlying causes exist, falling into broad categories that include chronic medical disease, psychiatric disease, lifestyle factors, medications, and treatment effects
  • Focus of evaluation for fatigue is to identify common underlying causes and any life-threatening diseases, such as cancer
    • In up to a third of cases, a medical cause cannot be determined 
  • Basic set of laboratory studies is appropriate in the initial evaluation, with more specific testing chosen according to specific findings as elicited through the history and physical examination
  • Treatment focuses on treating the underlying cause, if found, or instituting measures to alleviate fatigue as a symptom
  • Patients with unexplained fatigue should be followed up with scheduled visits to assess progress/improvement or worsening
  • High levels of fatigue are associated with excess mortality among the general population


  • Earlier medical history is a key element in identifying possible causes of fatigue and should be incorporated in the diagnostic approach
  • Differentiating fatigue caused by organic disease from that caused by the stresses of modern-day life, which is highly prevalent and often chronic, is a challenge for clinicians
  • Extensive laboratory testing to identify an occult cause of fatigue is often unrevealing and is discouraged


Clinical Clarification

  • Fatigue comprises the subjective, self-reported symptoms of tiredness, exhaustion, lack of energy, and weariness
  • Malaise is a subjective sense of being unwell
  • Fatigue includes 3 major components: 
    • Generalized weakness, resulting in inability to initiate certain activities
    • Easy fatigability and reduced capacity to maintain performance
    • Mental fatigue resulting in impaired concentration, loss of memory, and emotional lability
  • Fatigue is a common symptom with many potential underlying causes
    • Broad categories include chronic medical disease, psychiatric disease, lifestyle factors, medications, and treatment effects
  • Fatigue is rarely an isolated symptom and most commonly occurs with other symptoms, conditions, and situations, such as pain, emotional distress, anemia, and sleep disturbances 
  • Physiologic fatigue is that which results from imbalances in the routines of exercise, sleep, diet, or other activity; it is not caused by an underlying medical condition and is relieved with rest 


  • By duration:
    • Acute fatigue: lasting less than 1 month; generally attributable to physical exertion or an acute illness 
    • Prolonged fatigue: lasting 1 month or more 
    • Chronic fatigue: lasting 6 months or more 


Clinical Presentation


  • History and physical examination should focus on identifying common underlying causes and life-threatening problems, such as cancer 
  • Specific description of symptoms
    • One of several terms may be used or offered, including exhaustion, tiredness, lethargy, languidness, lassitude, listlessness, and lack of energy 
  • Accompanying symptoms
    • Fatigue very often occurs with other concerns, especially pain, psychological distress, and sleep loss
    • Additionally elicited or offered symptoms can assist with identifying underlying causes; examples include:
      • Involuntary weight loss may suggest one of several neoplasias, infections, or endocrine disorders
      • Fever may suggest an infection or a hematologic malignancy
      • Dyspnea on exertion may suggest heart failure, coronary artery disease, or primary pulmonary disease
      • Nausea with vomiting may suggest an unusual cause such as adrenal insufficiency, viral hepatitis, or gastrointestinal neoplasia
      • Myalgias may suggest a rheumatologic condition such as fibromyalgia (diffuse muscle pain) or polymyalgia rheumatica (shoulders and hips)
      • Morning stiffness or arthralgias may suggest rheumatoid arthritis
      • Sad mood, poor memory, or lack of concentration may suggest depression
      • Involuntary weight loss could imply an occult onset of, or recurrence of, malignancy or hyperthyroidism
      • Weight gain could imply atypical depressive episode or hypothyroidism
      • Blurry or double vision, as well as paresis or numbness of extremities, could be consistent with multiple sclerosis
      • Snoring with daytime somnolence may suggest sleep apnea
      • Menometrorrhagia may suggest anemia or iron deficiency
  • Socioeconomic factors
    • Life events such as death of a loved one, job loss, or retirement may precipitate fatigue
  • Lifestyle factors
    • Inadequate sleep duration or poor quality of sleep may suggest a primary sleep disorder or depression
    • Unusual dietary patterns (including fad diets) may suggest nutritional deficiency
    • Vigorous exercise schedule in athletes may suggest overtraining
    • Injection drug use poses a risk for HIV or hepatitis B infection
  • OTC and prescription drug use
    • Common drug class culprits are β-blockers, antihistamines, muscle relaxants, and benzodiazepines
  • Illicit drugs and alcohol
    • Recreational drugs such as marijuana and cocaine may lead to fatigue
    • Excessive alcohol consumption may disrupt sleep
  • Earlier medical history is a key element in identifying possible causes of fatigue and should be incorporated in the diagnostic approach

Physical examination

  • Examination is individualized according to known prior medical problems and any acute symptoms or concerns
  • Findings on physical examination may also be minimal or absent
  • Some physical findings may suggest the underlying cause (but are not necessarily sensitive, specific, or diagnostic)
    • Fever may suggest infection or hematologic malignancy
    • Pale mucous membranes may suggest anemia
    • Lymphadenopathy may suggest an infectious or neoplastic process
    • Bradycardia may suggest hypothyroidism; tachycardia may suggest hyperthyroidism
    • Wheezing may suggest chronic obstructive pulmonary disease
    • Peripheral edema may suggest congestive heart failure or chronic kidney or liver disease
    • Tender, warm, swollen joints may suggest rheumatoid arthritis
    • Hyperactive deep tendon reflexes may be found in any of several neurologic conditions associated with fatigue (eg, upper motor neuron diseases, multiple sclerosis)
    • Harsh systolic murmur at right upper sternal border that radiates to carotids may suggest aortic stenosis
    • Malar rash may suggest systemic lupus erythematosus
    • Unkempt appearance or obvious lack of grooming may suggest psychological causes (eg, depression)
    • Jaundice, hepatomegaly, and ascites may suggest chronic liver disease
    • Restricted range of motion about the shoulder and hips and inability to actively abduct the shoulders past 90° may suggest polymyalgia rheumatica in a patient aged 50 years or older

Causes and Risk Factors


  • Fatigue is a common symptom with many potential underlying causes; there can be multiple contributing causes in a single person
  • Physiologic, psychological, and situational factors can cause or contribute to fatigue
  • Acute and chronic illnesses that cause fatigue include:
    • Respiratory
      • Chronic obstructive pulmonary disease
      • Sleep apnea
      • Pulmonary fibrosis
    • Cardiovascular
      • Congestive heart failure
      • Aortic stenosis and aortic insufficiency
      • Coronary artery disease
    • Endocrine
      • Hypothyroidism
      • Hyperthyroidism
      • Adrenal insufficiency
      • Diabetes mellitus
    • Gastrointestinal and hepatic
      • Chronic liver disease/cirrhosis
      • Viral or autoimmune hepatitis
      • Celiac disease
      • Primary biliary cholangitis (primary biliary cirrhosis)
    • Hematologic
      • Anemia
      • Hemochromatosis
    • Oncologic
      • Lymphoma
      • Acute or chronic leukemia
      • Pancreatic cancer
      • Others, in association with chemotherapy and radiation therapy
      • Others, occult
      • Any advanced-stage cancer 
    • Infectious
      • SARS-CoV-2, the coronavirus that causes COVID-19 
      • HIV infection or AIDS
      • Epstein-Barr virus mononucleosis
      • Hepatitis A, B, C, D, or E
      • Endocarditis
      • Tuberculosis
    • Rheumatologic/musculoskeletal
      • Fibromyalgia
      • Systemic lupus erythematosus
      • Rheumatoid arthritis
      • Polymyalgia rheumatica
      • Sarcoidosis
    • Metabolic or nutritional
      • Chronic kidney disease
      • Iron deficiency
      • Protein-energy malnutrition
      • Hyponatremia
      • Hypercalcemia
      • Hypocalcemia
    • Neurologic
      • Multiple sclerosis
      • Amyotrophic lateral sclerosis and other motor neuron diseases
      • Myasthenia gravis 
    • Other
      • Chronic fatigue syndrome
  • Psychological factors that can cause or contribute to fatigue include:
    • Major depression
    • Seasonal affective disorder
    • Anxiety disorders
    • Somatic symptom disorder
  • Situational factors that can cause or contribute to fatigue include:
    • Sleep disorders (eg, insomnia, frequent awakening) 
    • Financial stress
    • Grief
    • Divorce
    • Overwork 
    • Physical or emotional abuse (eg, domestic abuse)
    • Social isolation
    • Cancer treatment using chemotherapy or radiation therapy
    • Occupational exposures to toxins (heavy metal or pesticides)
  • Prescription drugs may have adverse effects that cause fatigue
    • β-blockers
    • Muscle relaxants
    • First-generation antihistamines
    • Benzodiazepines
    • Withdrawal from glucocorticoids (causing adrenal insufficiency)
  • Alcohol or recreational drug use may contribute to or cause fatigue
    • Excessive alcohol
    • Marijuana
    • Opioids
    • Cocaine
  • Frequency of causes
    • A systematic review and meta-analysis of studies reporting on the final diagnosis in patients who presented with a main complaint of fatigue in primary care settings found the following prevalences: 
      • Anemia: 2.8% (confidence interval, 1.6%-4.8%) 
      • Malignancy: 0.6% (confidence interval, 0.3%-1.3%)
      • Serious somatic disease: 4.3% (confidence interval, 2.7%-6.7%)
      • Depression: 18.5% (confidence interval, 16.2%-21%)

Risk factors and/or associations

  • Fatigue as a complaint to clinicians peaks between 20 and 40 years, then declines and increases again after age 75 years 
  • Fatigue is more likely to be reported by women 
Other risk factors/associations
  • Extremes of highly sedentary behavior and very intense physical activity are both linked to fatigue 

Diagnostic Procedures

Primary diagnostic tools

  • Fatigue as a symptom is elicited through history, and further diagnostic assessment seeks any specific underlying cause(s); in some cases no cause can be determined 
    • A cause for fatigue is found in about two-thirds of cases 
  • Clinical evaluation begins with a comprehensive medical, medication, and psychosocial history
    • Assess the following characteristics of the reported fatigue: severity, temporal features (onset, course, duration), exacerbating and relieving factors, and any associated physical concerns 
      • Determine duration of fatigue
        • Sudden onset of fatigue is more likely to arise in the setting of acute medical illness, whereas chronic fatigue (lasting 6 months or more) often has a psychological component
      • Discern whether there may have been a precipitating acute illness (eg, recent viral illness) or major life event
      • Inquire about impact of fatigue on daily function and overall quality of life
        • Fatigue that is not relieved by rest and interferes with daily activity is often due to an underlying medical illness 
      • Inquire about nutrition and weight change, prescribed medications, or self-medication
      • Discern if there is a psychological component, with symptoms such as sad mood, anxiety, anhedonia, or insomnia
      • Assess sleep patterns or impact of sleep on malaise or fatigue
        • Sleep often does not improve when it is caused by psychological disorders (or sleep apnea) 
      • Careful trials of eliminating drugs (one by one) may identify a medication as a contributor or cause of fatigue 
    • Physical examination should focus on any areas that are suggested as a potential cause or contributor, as elicited by history
    • Several validated scales are available to assess fatigue severity in the initial assessment as well as to monitor symptoms over time; these can be used for clinical assessment although they are often used for research purposes
  • A limited basic laboratory evaluation may follow, with specific studies that may be directed by any enlightening aspects of the history or physical examination findings
    • A reasonable set of initial standard laboratory tests might include a CBC, electrolyte levels, glucose level, liver and kidney function tests, thyroid function tests, and urinalysis 
    • Additional clues from the history or examination may indicate the need for additional tests, but only as directed by the history and physical examination 
      • Examples of such tests include ferritin level, erythrocyte sedimentation rate, antinuclear antigen test, anti–cyclic citrullinated peptide antibodies test, C-reactive protein level, chest radiography, and chest CT
    • When history and examination findings do not point to an underlying condition, extensive evaluation with laboratory tests and imaging usually does not yield useful diagnostic information 
      • Results of laboratory tests affect management in about 5% of patients; if initial results are within reference ranges, repeated testing is generally not indicated 
        • However, if after initial management of an identified cause/contributor, the condition does not improve or worsens with treatment, further clinical evaluation is advisable to look into alternative explanations for the fatigue
    • One systematic review and meta-analysis of studies reporting on ultimate diagnoses among patients reporting fatigue in primary care settings found that serious somatic disease was uncommon 
      • Serious somatic disease was found in 4.3% (confidence interval, 2.7%-6.7%), whereas depression was found in 18.5% (confidence interval, 16.2%-21%) 
      • Prevalence of anemia was 2.8% (confidence interval, 1.6%-4.8%) and prevalence of any malignancy was 0.6% (confidence interval, 0.3%-1.3%) 
  • All patients should undergo age- and sex-appropriate cancer screening tests to identify any occult malignancy that could account for fatigue

Differential Diagnosis

Most common

  • Important to differentiate the following from fatigue as a symptom of a medical or psychological condition
    • Fatigue as a syndrome
      • Chronic fatigue syndrome (myalgic encephalomyelitis) 
        • A specific clinical diagnosis characterized by unexplained persistent or relapsing fatigue, not relieved by rest, that substantially limits daily activity and lasts at least 6 months
        • Disorder is heterogeneous; patients report varying combinations of overwhelming and disabling fatigue along with memory or concentration impairment, sore throat, muscle pain, arthralgias, and/or headaches
        • Accounts for only a small percentage of patients who present with chronic fatigue and generally represents a diagnosis of exclusion
        • National Academy of Medicine proposes that certain symptom constructs may help distinguish adults with chronic fatigue syndrome from those with other conditions; they include the following: 
          • Intense fatigue or tiredness that is worsened by exertion and not alleviated by rest
          • Neurocognitive difficulties characterized by slowness of thought or mental fog
          • Unrefreshing sleep
    • Sleepiness misidentified as fatigue
      • Sleepiness is the impairment of the normal arousal mechanism and is characterized by a tendency to fall asleep
        • With sleepiness, patients report daytime sleep tendency, and they are temporarily aroused by activity 
        • In contrast, fatigue is intensified by activity; patients with fatigue report a lack of energy, mental exhaustion, poor muscle endurance, and delayed recovery after physical exertion 
    • Physiologic fatigue
      • Physiologic fatigue is an imbalance in the routines of exercise, sleep, diet, or other activity that is not caused by an underlying medical condition and is relieved with rest 
      • Physiologic fatigue may be discerned and suspected through careful history
      • Differentiating fatigue caused by organic disease from that caused by the stresses of modern-day life, which is highly prevalent and often chronic, is a challenge for clinicians
      • A trial of deintensification of exercise regimens, greater attention to nutritional intake, and/or efforts to improve sleep duration or quality may identify 1 or more of these lifestyle factors as causative or contributory to a patient’s fatigue



  • Ameliorate or eliminate fatigue, thereby improving quality of life


Recommendations for specialist referral

  • Refer to psychologist for cognitive behavioral therapy in willing patients with persistent unexplained fatigue
  • Refer to psychiatrist when fatigue is caused by depression, particularly if patient reports suicidal ideation or displays psychotic features

Treatment Options

  • Treatment depends on underlying cause, if identified
    • Treat any underlying cause(s) discovered through the initial history, physical examination, or laboratory evaluation
      • Withdraw or taper medications that could cause or contribute to fatigue, if clinically viable
      • Optimize management of known comorbidities to reduce their contribution to symptoms
      • Inform and educate on improving lifestyle-related factors that likely contribute to fatigue, such as use of recreational drugs
    • Assess response to any treatment at an appropriate interval (which will vary) to ensure that there is improvement or resolution of fatigue
    • If response is insufficient, further evaluation may be warranted to search for potential alternative explanations
  • For fatigue that remains unexplained despite a proper evaluation, focus efforts on relief of symptoms and also emphasize the benefits of moderate exercise, regular sleep habits, and ways to reduce perceived stress
    • Adopt a supportive communication style and schedule follow-up visits to monitor symptom progression
  • Selected illnesses in which fatigue is a prominent component have treatments with demonstrated benefits for alleviation of fatigue
    • One example of such an intervention is physical exercise, which has been found to improve fatigue in multiple sclerosis, fibromyalgia, and chronic kidney disease 
    • Another example is cognitive behavioral therapy, which may improve fatigue in patients with rheumatoid arthritis, multiple sclerosis, or various advanced-stage cancers 


  • Patients who continue to experience fatigue that remains unexplained after initial evaluation should be monitored regularly for symptom improvement, progression, or development of new symptoms
    • A reasonable interval for follow-up is every 1 to 3 months
  • Persistent fatigue can be monitored through simple assessment using easy questions, such as the following:
    • How severe has it been, on average, during the past week? (mild, moderate, or severe)
    • How much does fatigue interfere with interpersonal relationships, ability to function at work, and/or activities of daily living?
  • Fatigue may also be more formally evaluated with serial scoring using 1 or more of the validated tools
    • (Brief Fatigue Inventory, Multidimensional Fatigue Inventory, Patient-Reported Outcome Measurement Information System, Edmonton Symptom Assessment Scale)

Complications and Prognosis


  • High levels of fatigue are associated with excess mortality among the general population
    • In a large population-based cohort study of adults aged 40 to 79 years who were followed up for 20 years, the presence of fatigue was associated with an increase in all-cause mortality among patients reporting highest levels (top quartile) compared with lowest quartile (hazard ratio, 1.26; confidence interval, 1.1-1.45) 
  • Fatigue among older adults (older than 70 years) is associated with poor health status, reduced daily function, and increased mortality 

Screening and Prevention


  • Strategies that address stress reduction, proper sleep hygiene, and regular physical activity are important lifestyle measures for maintaining healthy energy levels


Cornuz J et al: Fatigue: a practical approach to diagnosis in primary care. CMAJ. 174(6):765-7, 2006 Reference 


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