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Division of General Internal Medicine, Department of Internal Medicine, General Internal Medicine Centre, University of Washington, Box 354760, 4245 Roosevelt Way Northeast, Seattle, WA 98105, USA
Division of General Internal Medicine, Department of Internal Medicine, General Internal Medicine Centre, University of Washington, Box 354760, 4245 Roosevelt Way Northeast, Seattle, WA 98105, USA
Further defining a patient’s complaint of “fatigue” as either sleepiness, dyspnea on exertion, weakness, generalized lack of energy, or feeling down or depressed can aid in evaluation and management.
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Laboratory evaluation rarely reveals a cause for fatigue but reasonable initial studies include complete blood count, basic metabolic panel, hepatic function testing, erythrocyte sedimentation rate, thyroid-stimulating hormone, ferritin, and screening for HIV and hepatitis C in at-risk populations.
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Even in the absence of anemia, in women of child-bearing age with a ferritin less than 50 ng/mL, iron replacement is associated with improvement of subjective fatigue.
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In situations where there is a low level of clinical concern for illness, additional diagnostic testing does not improve patient reassurance.
Introduction
Fatigue is a common symptom and the presenting concern for 5% to 10% of visits in primary care.
Time lost at work, medical visits, and evaluation result in significant costs to patients and society. Often the underlying cause of a patient’s fatigue is not found, but rarely fatigue can be the initial symptom of a life-threatening disease, such as a yet undiagnosed malignancy or heart failure. For these reasons a guide to a rational, systematic approach to evaluation of fatigue is important.
History
History is the most important part of the evaluation of a patient presenting with fatigue and acts as a guide regarding the patient’s subsequent work-up. The first key aspect is to define what the patient is describing; fatigue can be used by patients to describe sleepiness, dyspnea on exertion, weakness, generalized lack of energy, or feeling down or depressed. However, to a medical professional the term fatigue is typically defined as a generalized lack of energy that does not improve with sleep and gets worse with activity.
A 56-year-old man with obesity, hypertension, and osteoarthritis presents to clinic with fatigue. He reports that he feels “run down.” He continues to take part in moderate daily exercise without chest pain or increased shortness of breath but he reports that when he sits at his desk he finds himself nodding off, “too fatigued to make it through the day” without a nap.
“Fatigue” can describe sleepiness; ask the patient if the sensation improves with naps and activity, if they are describing a frequent desire to fall asleep primarily when at rest. If so these symptoms are consistent with sleepiness, typically caused by an underlying sleep disorder, such as obstructive sleep apnea. The patient in this case has risk factors and symptoms suggestive of obstructive sleep apnea. Work has been done regarding components of the patient history that may help tease out if the symptom they are describing is sleepiness or fatigue (Table 1).
Table 1Questions to assist is differentiating fatigue from sleepiness
Adapted from Bailes S, Libman E, Baltzan M, et al. Brief and distinct empiric sleepiness and fatigue scales. J Psychosom Res 2006;60:605–13.
Sleepiness
Fatigue
How likely are you to doze off or fall asleep in the following situations, in contrast to just feeling tired?
Sitting and reading
Watching television
Sitting inactive in a public place (eg, theater, meeting)
As a passenger in a car for an hour when circumstances permit
Sitting and talking to someone
Sitting quietly after lunch without alcohol
How strongly do you agree with the following statements?
Exercise brings on my fatigue
I start things without difficulty but get weak as I go on
A 36-year-old woman with history of migraines presents with fatigue. She reports the fatigue is “ruining my life,” she is sleeping poorly, feels too fatigued to get out of bed in the morning, too fatigued to eat, too fatigued to play with her kids. She becomes tearful as she discusses her symptoms.
Fatigue can be a symptom of depression, can be caused by a medical condition that coexists with a patient’s depression, or can be a way that a patient describes a depressed mood. The fatigue this patient describes is suggestive of fatigue associated with depression. Further questioning may be helpful. Consider using the Patient Health Questionnaire-9 (Fig. 1), a well-validated tool that asks patients to describe the frequency of many symptoms of depression, including lack of energy. If the patient also reports many other symptoms of depression (anhedonia; feeling down, depressed, or hopeless; sleep and appetite changes, a feeling of guilt or failure) it is reasonable to focus your initial management on depression. After treatment of the depression reassess their fatigue and evaluate further if this symptom persists.
Fig. 1Patient Health Questionnaire (PHQ-9)—Depression Scale.
As can be seen this initial clarification regarding what the patient is describing with the word fatigue can quickly focus the differential diagnosis. An additional example is patients using the term fatigue to describe shortness of breath limiting their ability to be active, what a medical professional would describe as dyspnea on exertion, concerning for cardiac or pulmonary causes of a patient’s symptoms. See Table 2 for differential diagnoses based on character of a patient’s fatigue.
Table 2Differential diagnosis based on further characterization of fatigue symptoms
In patients who have fatigue manifesting in a lack of energy, without improvement with rest, additional questions are aimed at teasing out potential life-threatening and common diagnosis. Red flag symptoms include weight loss and/or night sweats concerning for occult malignancy; a history of transient focal neurologic symptoms, such as focal weakness, vision loss, or urinary incontinence concerning of multiple sclerosis; and a history of melena concerning for gastrointestinal bleeding. Examples of symptoms that could lead one to make a diagnosis of a common cause of fatigue are constipation, weight gain, and menorrhagia associated with hypothyroidism; depressed mood and early morning awakenings associated with depression; or diffuse pain associated with fibromyalgia.
There are many other aspects of the history that are also important to consider. The chronicity can be telling; sudden onset of symptoms after a febrile illness with prominent pharyngitis is concerning of Epstein-Barr virus (EBV) or cytomegalovirus. In patients with a lifelong history of fatigue it is less likely that an underlying malignancy is the cause.
Medications are a common cause of secondary fatigue. Medications commonly associated with fatigue include β-blockers; antihistamines including the nonsedating second-generation agents; narcotics; muscle relaxants; sleep aids, such as zolpidem; benzodiazepines; and some antidepressants. Of the serotonin reuptake inhibitors, paroxetine is likely the most sedating. The serotonin-norepinephrine reuptake inhibitor venlafaxine is also more commonly associated with fatigue.
Substance use, including alcohol, can lead to fatigue and therefore needs to be explored. In addition, injection drug use greatly broadens the differential diagnosis. This is an important component of the history to obtain.
Physical examination
As one collects the patient history considerable time is spent asking about concerning symptoms, typically ruling out possible causes of secondary fatigue. The physical examination has a similar focus. Does the patient have scleral icterus concerning for undiagnosed liver disease? Do they have a goiter concerning of undiagnosed thyroid dysfunction? Does the patient have crackles on pulmonary examination concerning for a cardiac or pulmonary cause of their fatigue?
It is estimated that physical examination aids in making clear diagnosis of the cause of a patient’s fatigue only 2% of the time,
although it is still an important component of the initial evaluation. An additional value of a complete physical examination at the initial visit for the evaluation of fatigue is that it may help build trust in your patient that you are fully evaluating their concern.
Laboratory evaluation
A 52-year-old woman with a history of menorrhagia, status post hysterectomy 1 year ago, depression, and generalized anxiety currently on duloxetine and clonazepam presents with fatigue of insidious onset, bothersome over the past 3 months. She brings in a list of laboratory work she would like performed, which includes urine testing for heavy metals, Lyme disease testing, and celiac disease testing.
Often one of the most challenging aspects of evaluating a patient with nonspecific fatigue characterized by a generalized lack of energy is deciding on the appropriate scope of laboratory evaluation. Although in general the data are sparse, it seems that laboratory studies only rarely reveal the cause of a patient’s fatigue; diagnosis is made after laboratory evaluation in approximately 5% of cases.
Standard recommendations regarding the initial, rational laboratory evaluation include complete blood count, a basic metabolic panel, hepatic function testing, an erythrocyte sedimentation rate, thyroid dysfunction screening with a thyroid-stimulating hormone, and pregnancy testing in women of childbearing age. HIV disease and hepatitis C screening should also be considered in those not screened previously or with ongoing risk factors. Hepatitis C screening is recommended in the “baby boomer” generation (those born between 1945 and 1965) and in patients with risk factors, such as a history of injection drug use. Fatigue is the most common symptom of hepatitis C. Routine HIV screening in all adult patients is also recommended by many organizations including the US Preventative Services Task Force, although the correlation of fatigue with otherwise undiagnosed HIV infection is unclear. Ferritin testing should be considered. In randomized controlled trials treatment of menstruating females with ferritin levels of less than 50 ng/mL, even in the absence of anemia, resulted in symptomatic improvement of fatigue (Table 3).
There are many additional tests that are frequently ordered by providers, often at the request of their patients. Unless there are specific symptoms, risk factors, or abnormalities in the initial screening laboratory evaluation these are unlikely to be useful. As more tests are ordered the risk of false-positive results also increases (Table 4).
Table 4Tests of low utility in evaluation of isolated fatigue
Test
Data to Support
Vitamin D
No evidence to support association of vitamin D deficiency and fatigue
Vitamin B12
Consider if patient has other signs/symptoms of vitamin B12 deficiency (eg, macrocytic anemia, lower extremity paresthesias)
Heavy metal toxicity
Indicated if have history of exposure, obtain an occupational history
Lyme disease
Consider in patients with history consistent with potential exposure and symptoms consistent with Lyme disease, not isolated fatigue
EBV/cytomegalovirus
Consider in younger patients in the setting of viral symptoms before fatigue onset
Celiac disease
Recommended by the National Institute for Health and Clinical Excellence, United Kingdom; consider if other signs/symptoms of disease (diarrhea, iron deficiency)
There are times when testing a vitamin D level is appropriate, but evidence that hypovitaminosis D causes isolated fatigue is lacking. For example, in patients presenting with low bone density and in those presenting with diffuse bony pain one should consider osteomalacia and check vitamin D levels.
It is common for patients to inquire regarding testing of their vitamin D level based on having read about associations between low vitamin D levels and a myriad of concerning conditions, such as cardiovascular disease and cancer. Reassure patients that although there is some controversy regarding when to test and when to supplement vitamin D, in the setting of fatigue there is little controversy: it is not recommended. A large Institute of Medicine review in 2011 did not identify good evidence that vitamin D was important in prevention of nonbone health conditions, such as cancer, heart disease, or fatigue.
The Endocrine Society recommends screening at-risk individuals, but the indication for treatment in these patients is limited to bone health and fall prevention, not improvement in pain, fatigue, or other health outcomes.
Studies support that vitamin D in combination with calcium supplementation can reduce the risk of fracture in community-dwelling adults, although there is controversy regarding what dose should be recommended and in which populations of patients.
Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
In addition, the US Preventative Services Task force recommends vitamin D supplementation to prevent falls in community-dwelling adults 65 years of age and older.
Regardless, none of the recommendations for screening or testing are for evaluation or management of fatigue.
There are several potential presentations of vitamin B12 deficiency including macrocytic anemia, symmetric distal polyneuropathy, and cognitive deficits. However, to present with fatigue unaccompanied with these other findings is atypical. Fatigue in isolation is not an indication for vitamin B12 testing.
Heavy metal toxicity can present in a variety of ways, although it is very rare that heavy metal toxicity is the cause of a patient’s fatigue. The following information may be of use in discussing a patient’s concerns about potential heavy metal toxicity leading to their symptoms.
Chronic lead toxicity may present with vague symptoms including fatigue, but overall this is a very rare condition. Obtaining an occupational history may be helpful. Exposure in adults is typically related to a job, such as the manufacturing of batteries, lead smeltering, or steel welding or cutting.
Consuming home-distilled alcohol and Aryvedic medications have also been associated with cases of lead toxicity. However, without history of a potential exposure testing lead levels is not recommended for evaluation of fatigue. Should testing be perused, it should be serum (blood) testing.
Current exposures to mercury in the general population are from consumption of fish, amalgam dental fillings, and thimerosal-containing vaccines, none of which commonly result in toxicity.
Mercury toxicity symptoms may include fatigue, but the primary symptoms caused by ingestion of mercury, which would be the manifestation if the exposure were based on excessive fish consumption, are hand and feet paresthesias, ataxia, and visual field constriction. Inhalation of mercury vapor is characterized by tremor, changes in the gums, excessive salivation, and neuropsychiatric changes in severe cases, but more typically cases are mild and characterized by mild memory difficulties and kidney injury. Working with amalgam fillings in a dental office may be the setting for these inhalation exposures. The use of thimerosal, a preservative used in multidose vials of some vaccines, such as the seasonal flu vaccine, has been extensively studied and found to be safe.
In a study of patients with metal-on-metal hip implants, report of fatigue was common, as were elevated levels of cobalt and chromium presumed to be caused by the metal-on-metal hip implant.
But the fatigue did not correlate with the degree of elevation, arguing against a direct relationship between the elevated metal level and fatigue.
Lyme disease is another common concern in patients with nonspecific fatigue. Clearly fatigue is a common manifestation of infection in general, but there would be other characteristic symptoms of Lyme disease should this be the cause. In the case of early, localized disease 80% of patients have erythema migrans, a red rash at the site of the tick bite that slowly expands and may develop central clearing giving it a classic bull’s-eye appearance.
In early disseminated disease more common symptoms include meningitis, cranial nerve palsies, and less commonly AV block. In late disease monoarthritis or oligoarthritis are the most common symptoms. Fatigue alone, without these other symptoms, is not an indication for Lyme disease testing.
A controversial condition termed chronic Lyme disease is also believed to exist by some practioners. This includes post–Lyme disease syndrome, a rare and poorly understood condition that involves fatigue, widespread musculoskeletal pain, and subjective cognitive difficulties after treatment of Lyme disease.
It is not an indication of persistent Borrelia burgdorferi infection and is not an indication for prolonged antibiotic therapy. Another group of patients who may be identified as having chronic Lyme disease includes patients without a clear or documented history of B burgdorferi infection but with nonspecific signs and symptoms, such as fatigue and arthralgias. In these cases, patients should not be treated with antibiotics either.
Testing for Lyme disease is in the form of serologic testing for antibodies. Not surprisingly in early, localized disease the antibodies are often not yet present leading to a low sensitivity of the test. Another difficulty in interpretation of the results of Lyme disease serology is that even after effective treatment the antibodies may remain positive for years. This would not be an indication of persistent infection or an indication for prolonged therapy.
Fatigue is a common symptom in patients with infections, and there are many viral infections that can persist in the human body for prolonged to indefinite periods of time. Therefore, there has been significant interest in viral etiologies of fatigue, chronic fatigue syndrome (CFS) in particular. Associations between many viral infections and fatigue have been investigated with particular interest in EBV, cytomegalovirus, and human herpesvirus-6. Readers may recall a study released in 2009 that found an association between xenotropic murine leukemia virus–related virus and CFS, a study that was later retracted, the finding found to likely be caused by specimen contamination.
Chronic viral infection leading to fatigue remains an area of investigation, although at this point there is not sufficient evidence of a relationship to justify testing all patients with fatigue. EBV testing should primarily be reserved for patients younger than 40 years who present with fatigue that began after an episode of pharyngitis.
Celiac disease, when undiagnosed and thus untreated, can result in many health problems, some of these associated with fatigue, such as iron deficiency. However, in the absence of symptoms and signs of celiac disease, such as diarrhea, unexplained iron deficiency, or profound vitamin D deficiency, testing for celiac disease as a standard screening test in patients with fatigue is not generally recommended. That said, there are some organizations that do recommend testing for this, such as the National Institute for Health and Clinical Excellence, out of the United Kingdom.
Classically, celiac disease has been thought to be a disease of people of Northern European descent; therefore, it is possible that the threshold for testing is lower in European nations. However, recent research has indicated that celiac disease is not isolated to patients of Northern European descent; it is a more globally distributed disease, and there is concern for increasing prevalence of the disease.
Screening recommendations could change in the future.
Management in the setting of a nondiagnostic evaluation
In a follow-up study of patients presenting to their primary care provider with fatigue, half were without a diagnosis to explain their symptoms in the year after their presentation.
There were a variety of diagnosis made in the other half of the patients that were possibly the cause of their fatigue. Of these, musculoskeletal problems were most common (19.4% of patients), most being lower extremity joint problems and back problems. Psychological problems were the second most common diagnosis category (16.5%), common diagnoses in this group being “strain,” “burnout,” depression, and anxiety. Only 8.2% of patients were given a diagnosis that the authors qualified as “clear somatic pathology” in the year after their presentation with fatigue, including anemia, thyroid dysfunction, diabetes, malignancy, rheumatoid arthritis, and heart failure.
In the 50% of patients without a diagnosis, what is to be done? Frequently the instinct is to order more tests. Even when providers suspect that a diagnosis may not be found, more tests are frequently ordered with the belief that this will offer the patient reassurance. In a systematic review assessing for evidence of patient reassurance after diagnostic testing in situations where there was a low level of clinician concern for serious illness (symptoms including dyspepsia, low back pain, and palpitations) there was no evidence of patient reassurance.
In this study 14 trials were identified comparing testing with nontesting for symptoms believed to be benign, meaning that based on clinical evaluation, the pretest probability of serious disease was low. There was no pattern of patient reassurance found, and patients did not have less concern about their illness, less health anxiety, or less symptoms based on having testing performed. The only possible benefit was a reduction in subsequent clinic visits, but the number of patients needed to test to avoid one clinic visit was on the order of 16 to 26 patients.
In the situation when the initial evaluation for fatigue is nondiagnostic there should be frank discussion with the patient regarding how to proceed. There are several key components: acknowledgment of the patient’s symptoms, patient reassurance that there will be active on-going management in the form of symptom-focused treatments, and a plan for follow-up regarding their on-going symptoms and to assess for development of any new symptoms.
Acknowledgment of the patient’s symptoms and in turn working to develop a collaborative, supportive relationship with the patient is recommended. It is often difficult for patients and providers to accept that there may not be a medical explanation for symptoms, but a shift of focus of your visits from diagnosis to symptom management is very important. This also needs to be something that the patient accepts in order for it to be successful. In a study regarding effective management of patients with medically unexplained symptoms, strategies to motivate patient involvement in their care and formulation of patient-centered treatment plans was successful in reducing symptom scores.
The provider should work with the patient to identify the most bothersome symptom they are experiencing, develop a treatment plan that is acceptable to the patient, and also develop a self-management plan. Schedule patients for frequent follow-up, slowly spacing out follow-up appointments over time. This too may foster a sense of support and encourage patient engagement in treatment recommendations.
Treatment of idiopathic fatigue is not highly evidence based, but there are several treatments that can be considered based on their benefit in similar conditions. A discussion of sleep quantity and quality should be part of treatment in all patients with fatigue. In the general population, high-quality sleep is associated with better overall sense of well-being and less fatigue.
The principles of good sleep hygiene should be reviewed with all patients with idiopathic fatigue (Table 5).
Table 5Sleep hygiene measures
Adapted from Hauri PJ. Sleep/wake lifestyle modifications: sleep hygiene. In: Barkoukis TJ, Matheson JK, Ferber R, et al, editors. Therapy in sleep medicine. Philadelphia: Elsevier; 2012. p. 151–60.
Generally Agreed on Sleep Hygiene Measures
Description
Eliminate bedroom noise
Can use sound “screening,” such as a white noise machine
Minimize napping
If napping necessary, limit to less than 20 min
Exercise
Exercise regularly but avoid exercising in the evening because this may result in difficulty initiating sleep
Avoid/limit caffeine
If drinking caffeinated beverage (eg, coffee) limit to one beverage in the morning
Avoid alcohol
Can result in awakenings after initially falling asleep
Eat light evening snack
Exception to this recommendation: patients with gastroesophageal reflux should not eat evening snack because this will likely cause reflux and in turn disturb sleep
Physical activity is also something that should be recommended to all patients with idiopathic fatigue. Studies indicate that among patients with fatigue in the setting of otherwise good health, regular exercise decreases symptoms of fatigue.
A randomized controlled trial of the effect of aerobic exercise training on feelings of energy and fatigue in sedentary young adults with persistent fatigue.
When low-intensity versus moderate-intensity activity was compared, although both resulted in improved “vigor” or energy level, the benefit on fatigue was more impressive in patients taking part in low-intensity activity. An example of low-intensity activity is using an exercise bike for 30 minutes three times a week, benefits seen by week 6. The concept that low-intensity exercise may have more benefit on symptoms of fatigue than higher-intensity activity is consistent with the exercise interventions found to be of benefit in patients with two other conditions associated with significant fatigue, fibromyalgia and CFS. In patients with CFS and fibromyalgia graded exercise therapy has been shown to be of benefit. This involves very slowly increasing a patient’s level of physical activity over the course of weeks to months.
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
Another therapy often recommended for treatment of fatigue in the setting of CFS and fibromyalgia is cognitive behavioral therapy. When available this therapy should also be extended to patients with idiopathic fatigue.
It is also critical to assess for comorbid conditions and treat those appropriately. Depression and anxiety can coexist with or be causative of fatigue. If an antidepressant medication is being considered take into account the patient’s significant fatigue symptoms when choosing the agents to be prescribed. Of the serotonin reuptake inhibitors, paroxetine may be more sedating and therefore should be avoided in patients with significant fatigue. Bupropion is an antidepressant medication that tends to be activating and therefore should more strongly be considered. If the patient also has pain symptoms a serotonin-norepinephrine reuptake inhibitor may be a good choice, potentially treating mood symptoms and pain symptoms with a single agent.
Sleep disorders can also be causative or coexist with fatigue. Pharmacologic treatment may be challenging because medications to treat insomnia are by definition sedating, but cautious treatment should be considered because good sleep can in turn improve fatigue.
Chronic fatigue syndrome
A subset of patients with long-standing idiopathic fatigue may meet diagnostic criteria of CFS. In addition to fatigue lasting more than 6 months and unrevealing laboratory evaluation (overall consistent with the laboratory studies recommended previously) patients with CFS often have additional symptoms, such as sore throat, tender lymph nodes, and polyarthralgias (Box 1). Management of CFS is essentially the same as that suggested for long-standing idiopathic fatigue including graded exercise therapy; cognitive behavioral therapy; and treatment of comorbid conditions, such as depression and insomnia.
Centers for Disease Control and Prevention diagnostic criteria for CFS
Consider a diagnosis of CFS if these three criteria are met:
1.
The individual has severe chronic fatigue for 6 or more consecutive months that is not caused by ongoing exertion or other medical conditions associated with fatigue (these other conditions need to be ruled out by a doctor after diagnostic tests have been conducted)
2.
The fatigue significantly interferes with daily activities and work
3.
The individual concurrently has four or more of the following eight symptoms:
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Postexertion malaise lasting more than 24 hours
•
Unrefreshing sleep
•
Significant impairment of short-term memory or concentration
•
Muscle pain
•
Multijoint pain without swelling or redness
•
Headaches of a new type, pattern, or severity
•
Tender cervical or axillary lymph nodes
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A sore throat that is frequent or recurring
In summary, although fatigue is a common symptom in primary care, frequently a clear biomedical cause is not identified and, in those cases, evaluation and management offers many challenges. On presentation, first work to discover what symptom the patient is describing with the word fatigue: perhaps sleepiness, depressed mood, or lack of energy. In the setting of fatigue that manifests as generalized lack of energy, made worse with activity and not improved with rest, then perform a thorough history followed by a limited initial laboratory screen. Should this be unrevealing, the management of patients’ subjective symptoms and comorbid medical conditions should become the focus.
References
Nijrolder I.
van der Windt D.A.
van der Horst H.E.
Prognosis of fatigue and functioning in primary care: a 1-year follow-up study.
Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force.
A randomized controlled trial of the effect of aerobic exercise training on feelings of energy and fatigue in sedentary young adults with persistent fatigue.
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
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