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Malaise and fatigue
Synopsis
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
Pitfalls
- 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
Terminology
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
Classification
- 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
Diagnosis
Clinical Presentation
History
- 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
Causes
- 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
- Respiratory
- 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%)
- 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:
Risk factors and/or associations
Age
- Fatigue as a complaint to clinicians peaks between 20 and 40 years, then declines and increases again after age 75 years
Sex
- 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
- Determine duration 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
- Assess the following characteristics of the reported fatigue: severity, temporal features (onset, course, duration), exacerbating and relieving factors, and any associated physical concerns
- 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
- Results of laboratory tests affect management in about 5% of patients; if initial results are within reference ranges, repeated testing is generally not indicated
- 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
- Chronic fatigue syndrome (myalgic encephalomyelitis)
- 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
- Sleepiness is the impairment of the normal arousal mechanism and is characterized by a tendency to fall asleep
- 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
- Fatigue as a syndrome
Treatment
Goals
- Ameliorate or eliminate fatigue, thereby improving quality of life
Disposition
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
- Treat any underlying cause(s) discovered through the initial history, physical examination, or laboratory evaluation
- 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
Monitoring
- 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
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
Prevention
- Strategies that address stress reduction, proper sleep hygiene, and regular physical activity are important lifestyle measures for maintaining healthy energy levels
Sources
Cornuz J et al: Fatigue: a practical approach to diagnosis in primary care. CMAJ. 174(6):765-7, 2006 Reference