As just noted, fatigue is an important somatic symptom of depression, often coexisting with early-morning awakening, appetite and sexual disturbances, and multiple bodily complaints. Abnormalities of central nervous system neurotransmitter metabolism and function are believed to play a major role in the pathogenesis of depression (see Chapter 227). Chronic anxiety may result in generalized fatigue, in part because it interferes with obtaining adequate physical and psychological rest. Patients report trouble falling asleep and a host of associated bodily complaints. Many maintain their neck muscles in a constantly tensed state, which gives rise to occipital-nuchal headaches. Seemingly unprovoked episodes of palpitations, difficulty breathing, and chest tightness may occur, especially in those whose anxiety is accompanied by a panic disorder (see Chapter 226).

Patients in whom somatization represents an underlying personality disorder may complain of chronic fatigue, often accompanied by a host of other refractory symptoms. Such individuals have a lifelong history of bodily complaints that elude diagnosis and treatment. Their symptoms are a cross they bear in a crude attempt to achieve a modicum of self-esteem (see Chapter 230).

Many of the medications used to treat anxiety, depression, and insomnia can cause fatigue by virtue of their sedating side effects. When used in excess, they may actually worsen the patient’s symptoms and sense of fatigue rather than alleviate them. Of the antidepressants, the tricyclics and trazodone are among the most sedating, which makes them useful when agitation or insomnia is a problem, but they can also lead to a feeling of being “knocked out” (see Chapter 227). Inappropriate use of hypnotics or anxiolytics (e.g., antihistamines, such as diphenhydramine and chlorpheniramine, and benzodiazepines) may produce excessive sedation or, paradoxically, exacerbate difficulty in falling or staying asleep (see Chapters 226 and 232). Centrally acting antihypertensive agents (e.g., reserpine, methyldopa, clonidine) may precipitate fatigue, and reserpine in doses greater than 0.5 mg/d can cause depression in patients with a prior history of the condition. On the other hand, beta-blockers do not significantly increase the risk of depression and result in only a small increase in the risk of fatigue—on the order of 18 cases per 1,000 patient-years—regardless of lipid solubility and central nervous system penetration.

Endocrine disturbances are important, treatable precipitants. Dysfunction of the thyroid, adrenal, pituitary, parathyroid, or endocrine pancreas can be subtle in onset, starting out inconspicuously as fatigue, perhaps accompanied by more specific symptoms. For example, hypothyroidism may present as fatigue, perhaps in association with weight gain, dry skin, mild hoarseness, or cold intolerance (see Chapter 104). In the elderly, hyperthyroidism may take an atypical form (apathetic hyperthyroidism) characterized by fatigue, marked weight loss, apathy, and otherwise unexplained atrial fibrillation (see Chapter 103). Patients with Addison disease manifest an insidious onset of fatigue in conjunction with weight loss, vague gastrointestinal upset, postural hypotension, and eventually hyperpigmentation. Panhypopituitarism from postpartum hemorrhage or a tumor of the sellar region can cause fatigue. The postpartum patient fails to lactate or resume menstruation; lassitude, decreased libido, and loss of axillary and pubic hair ensue. Later, symptoms of hypothyroidism may develop. The patient with a pituitary tumor may note galactorrhea and amenorrhea (see Chapter 100). Poorly controlled diabetes mellitus may present as fatigue accompanied by polyuria when glycosuria is severe enough to produce caloric wasting and volume depletion (see Chapter 102). The condition is easy to overlook when fatigue dominates the clinical presentation and obscures the more characteristic features of hyperglycemia (see Chapter 102). Similarly, fatigue may be the initial symptom of hyperparathyroidism and other causes of hypercalcemia.

Chronic renal failure may present inconspicuously with fatigue and few localizing symptoms or signs aside from laboratory findings of azotemia, mild anemia, impaired renal concentrating ability, and abnormal urinary sediment (see Chapter 142). Hepatocellular failure is an important source of lassitude. Jaundice, ascites, petechiae, asterixis, spider angiomata, and other signs of hepatic insufficiency usually contribute to the clinical picture. However, in anicteric hepatitis and mild forms of chronic hepatitis, jaundice may be minimal or absent while fatigue is prominent; the same holds for the prodromal phase of acute viral hepatitis (see Chapter 70 and 71).

Iron deficiency is often blamed for fatigue, although the correlation between iron deficiency anemia and fatigue is poor, especially when the anemia is mild (see Chapter 79). In a double-blind study of menstruating women with mild anemia resulting from iron deficiency, no significant difference was noted between the effects of iron and of placebo on fatigue. The relation between severe anemia (hematocrit <20) and fatigue is more direct. Lassitude prevails, at times in association with exertional dyspnea or with postural hypotension when blood loss is acute.

Occult malignancy is a much-feared etiology. Although fatigue and lassitude accompany most cancers, pancreatic carcinoma is the archetypal example of a tumor that may present initially as marked fatigue with few localizing symptoms. Severe weight loss, depression, and apathy may also dominate the clinical picture before other manifestations of the malignancy become evident. Malignancies causing hypercalcemia (e.g., breast cancer, myeloma) may present with fatigue, although usually the hypercalcemia is a late development.

The hallmark of fatigue associated with cardiopulmonary disease is a history of exertional dyspnea. Fatigue sometimes dominates the clinical presentation of patients with chronic congestive heart failure or chronic lung disease, especially when patients with heart failure are treated aggressively for symptoms of pulmonary congestion (see Chapters 32 and 47). Sleep apnea is an often overlooked pulmonary cause of chronic fatigue. Daytime sleepiness, excessive snoring, irregular breathing, disturbed sleep, and hemoglobin desaturation are characteristic. If untreated, sleep apnea may progress to pulmonary hypertension (see Chapter 46).

Profound fatigue, low-grade fever, and lymphadenopathy are the hallmarks of a number of much-feared infectious etiologies, including mononucleosis, viral hepatitis, and HIV infection. Other viral illnesses, such as cytomegalovirus infection and the possibly postviral chronic fatigue syndrome (CFS) (as discussed later), may also present in this way. Tuberculosis and subacute bacterial endocarditis are important infectious etiologies of fatigue in which few localizing symptoms may be present. A history of cough, night sweats, HIV infection, or exposure is sometimes elicited from the patient with tuberculosis (see Chapter 49). Recent dental work, a heart murmur, and intravenous drug abuse are risk factors for subacute bacterial endocarditis. Lyme disease is noteworthy for fatigue accompanied by joint complaints, headache, and low-grade fever (see Chapter 160). Other tick-borne diseases such as babesiosis and anaplasmosis may present in similar fashion with fatigue, other nonspecific complaints, low-grade fever, and sometimes in conjunction with Lyme disease, giving the appearance of a more severe, seemingly resistant form of Lyme disease (see Chapter 160).

Marked fatigue may dominate the initial clinical presentation of most rheumatoid diseases, before characteristic inflammatory connective tissue manifestations become evident (see Chapter 156).

CFS is an idiopathic condition characterized by new onset of persistent or relapsing fatigue in persons with no evident underlying illness or prior history of such symptoms. CFS accounts for about 5% to 10% of all cases of chronic fatigue. Prevalence in community populations is low (0.07% in Olmsted County study), with peak prevalence in women ages 20 to 50 years; mean age is 38 years. Women outnumber men by 3 to 1 and account for about 85% of cases; most are white and well educated, but the condition is not restricted to them.