Because the causes of generalized fatigue are numerous, a thorough history, review of systems (ROS), and physical examination are paramount to narrow the focus to likely causes. The history and ROS should focus on the temporal onset of fatigue and its progression. Has it lasted days, weeks, or months? Activities of daily living, exercise, eating habits/appetite, sexual practices, and sleep habits should be reviewed. Features of depression or dementia should be sought. Travel history and possible exposures to infectious agents should be reviewed, along with the medication list. The ROS may elicit important clues as to organ system involvement. The past medical history may elucidate potential precursors to the current presentation, such as previous malignancy or cardiac problems. The physical examination should specifically assess weight and nutritional status, lymphadenopathy, hepatosplenomegaly, abdominal masses, pallor, rash, heart failure, new murmurs, painful joints or trigger points, and evidence of weakness or neurologic abnormalities. A finding of true weakness or paralysis should prompt consideration of neurologic disorders (Chap. 55: Weakness and Paralysis).

Determining the cause of fatigue can be one of the most challenging diagnostic problems in medicine because the differential diagnosis is very broad, including infection, malignancy, cardiac disease, endocrine disorders, neurologic disease, depression, or serious abnormalities of virtually any organ system, as well as side effects of many medications (Table 31-1). Symptoms of fever and weight loss will focus attention on infectious causes, whereas symptoms of progressive dyspnea might point toward cardiac, pulmonary, or renal causes. A presentation that includes arthralgia suggests the possibility of a rheumatologic disorder. Fatigue is a common presenting symptom of cancer. A previous malignancy, thought to be cured or in remission, may have recurred or metastasized widely. A previous history of valvular heart disease or cardiomyopathy may identify a condition that has decompensated. Treatment for Graves’ disease may have resulted in hypothyroidism. Sleep apnea is under-recognized and is a common cause of unexplained fatigue. Changes in medication should always be pursued, whether discontinued or recently started. Almost any new medication has the potential to cause fatigue. However, a temporal association with a new medication should not eliminate other causes, because many pts may have received new medications in an effort to address their complaints. Medications and their dosages should be carefully assessed, especially in elderly pts, in whom polypharmacy and inappropriate or misunderstood dosing is a frequent cause of fatigue. The time course for presentation is also valuable. Indolent presentations over months to years are more likely to be associated with slowly progressive organ failure or endocrinopathies, whereas a more rapid course over weeks to months suggests infection or malignancy.

Laboratory testing and imaging should be guided by the history and physical examination. However, a CBC with differential, electrolytes, BUN, creatinine, glucose, calcium, TFTs, and LFTs are useful in most pts with undifferentiated fatigue, because these tests will rule out many causes and may provide clues to unsuspected disorders. Similarly, a CXR is useful to evaluate many possible disorders rapidly, including heart failure, pulmonary disease, or occult malignancy that may be detected in the lungs or bony structures. Subsequent testing should be based on the initial results and clinical assessment of the likely differential diagnoses. For example, a finding of anemia would dictate the need to assess whether it has features of iron deficiency or hemolysis, thereby narrowing potential causes. Hyponatremia might be caused by syndrome of inappropriate antidiuretic hormone (SIADH), hypothyroidism, adrenal insufficiency, or medications or by underlying cardiac, pulmonary, liver, or renal dysfunction. An elevated WBC count would raise the possibility of infection or malignancy. Thus, the approach is generally one of gathering information in a serial but cost-effective manner to narrow the differential diagnosis progressively.

Treatment should be based on the diagnosis, if known. Many conditions, such as metabolic, nutritional, or endocrine disorders, can be corrected quickly by appropriate treatment of the underlying causes. Specific treatment can also be initiated for many infections, such as TB, sinusitis, or endocarditis. Pts with chronic conditions such as chronic obstructive pulmonary disorder (COPD), heart failure, renal failure, or liver disease may benefit from interventions that enhance organ function or correct associated metabolic problems, and it may be possible to gradually improve physical conditioning. In pts with cancer, fatigue may be caused by chemotherapy or radiation and may resolve with time; treatment of associated anemia, nutritional deficiency, hyponatremia, or hypercalcemia may increase energy levels. Replacement therapy in endocrine deficiencies typically results in improvement. Treatment of depression or sleep disorders, whether a primary cause of fatigue or secondary to a medical disorder, may be beneficial. A variety of treatments are now available for sleep apnea, including continuous positive airway pressure (CPAP). Withdrawal of medications that potentially contribute to fatigue should be considered, recognizing that other medications may need to be substituted for the underlying condition. In elderly pts, appropriate medication dose adjustments (typically lowering the dose) and restricting the regimen to only essential drugs may improve fatigue.