Etiology
Sleep disorders
Insomnia: this is the most common sleep disorder, with a prevalence of approximately 19% in the general population.[24] The DSM-5-TR defines insomnia disorder as dissatisfaction with sleep quantity and/or quality that causes significant distress or impairment, and which is associated with difficulty in initiating, maintaining, and/or returning to sleep (i.e., with early morning awakening) on at least 3 nights per week, for at least 3 months, and despite adequate opportunity to sleep.[25] Most patients with insomnia do not necessarily report disordered sleep but rather accompanying symptoms such as fatigue. Insomnia disorder may be associated with an underlying cause, such as:
Use of stimulants such as caffeine, nicotine, alcohol, quinine, and tobacco
Sleep-breathing disorders
Periodic limb disorder/restless legs syndrome
Panic attacks or recurrent nightmares during sleep
Posttraumatic stress disorder
Psychiatric disorders
Sleep phase disorders: shift work, jet lag
Concurrent medical conditions or their treatment, including any form of pain, and drug intoxication or withdrawal
Prescription drugs: beta blockers, theophylline, stimulants, decongestants, thyroid hormone, corticosteroids, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, ticagrelor, and phenytoin.
Obstructive sleep apnea/hypopnea syndrome (OSAHS): patients with OSAHS have a nonrestorative sleep, which leads to physical and mental fatigue.[26]
Obesity hypoventilation syndrome (OHS): patients with OHS have a BMI ≥class 1 (≥30 kg/m²) and features of OSAHS (including fatigue) or features of nocturnal hypoventilation such as waking headaches, peripheral edema, hypoxemia (arterial oxygen saturation less than 94% on air) and unexplained polycythemia.[26]
Restless legs syndrome (RLS): associated with symptoms of fatigue. Impairment of subjective sleep quality depends on the severity of RLS.[27] Among older people, the severity of RLS symptoms affects both quality of sleep and quality of life, including daily functioning, social functioning, general wellbeing, and emotional experience.[28]
Psychiatric and psychosocial disorders
Depression: studies done in the community and in primary care settings have shown a strong association of unexplained chronic fatigue with general psychiatric disorders, mainly depression.[4][9][12][29] However, this relationship is unclear, as fatigue may be a cause or a result of depression. In an attempt to clarify this, one study examined psychosocial variables and unexplained chronic fatigue through a community survey in the UK.[5] A greater prevalence of unexplained chronic fatigue in people with psychiatric morbidity was found. This prevalence seemed to increase with increasing severity of psychiatric disease.
In addition to depression, anxiety and somatization disorders, as well as psychosocial stressors may be associated with fatigue.
Hematologic disorders
Fatigue is a cardinal symptom of anemia regardless of cause. It has been found that even in the absence of anemia, checking ferritin levels in menstruating women is relevant to identify patients likely to respond to iron supplementation. Women without anemia but with a ferritin level <50 nanograms/mL report a reduction of fatigue when given iron supplements.[16][17][30][31]
Chronic myeloid leukemia, myelodysplastic syndrome, and lymphoma all present with fatigue in addition to other symptoms.
Cardiovascular disease
The cardinal symptoms limiting exercise in patients with heart failure are fatigue and/or dyspnea. Fatigue has been shown to be the major presenting symptom in 10% to 20% of new cases of heart failure.[32][33]
Studies have shown that in women diagnosed with acute myocardial infarction, 71% experienced unusual fatigue as a prodromal symptom, and 43% experienced fatigue as an acute symptom, whereas only 57% had chest pain.[34][35]
In general, women are more likely than men to have a delayed presentation and to present more frequently with unstable angina and non-ST-segment elevation and without chest pain.[36][37]
In addition to heart failure and acute myocardial ischemia, atrial fibrillation may also present with fatigue along with other symptoms.
Endocrine disorders
Hypothyroidism: in a large cross-sectional study, it was observed that the association between fatigue and hypothyroidism was only marginally significant. Furthermore, the fatigue symptom has a very low sensitivity (16%) for the diagnosis of hypothyroidism. Therefore, not reporting a specific symptom such as fatigue does not rule out thyroid disease.[38] Further randomized studies are required to assess the effect of thyroid replacement therapy on symptoms of fatigue in people with subclinical hypothyroidism (mildly elevated TSH with normal level of free thyroid hormones), which affects up to 10% of the adult population.[39]
Diabetes mellitus: fatigue is viewed as a common presentation of diabetes mellitus type 1, as well as type 2. However, data regarding the frequency of fatigue in people with diabetes are very sparse. In one of the few studies performed, fatigue in children with diabetes was assessed. Fatigue was noted in 52% of children under 15 years of age with type 1 diabetes and was the first symptom experienced in 7%.[40]
Fatigue may be a significant symptom (although not always a presenting symptom) of other, more rare endocrine disorders, such as Addison disease, vitamin D deficiency (osteomalacia), hypopituitarism, acromegaly, growth hormone deficiency, hyperthyroidism, Cushing syndrome, and diabetes insipidus.[41][42][43]
Infectious disease
Epstein-Barr virus (EBV): fatigue has typically been associated with EBV infectious mononucleosis. The diagnostic accuracy of symptoms was evaluated in a study of patients ≥16 years presenting with a sore throat. The presence of fatigue had a sensitivity of 93%, a specificity of 23%, and a 0.30 negative likelihood ratio, which led to the conclusion that, as a symptom of infectious mononucleosis, the absence of fatigue is helpful in ruling out the diagnosis.[44]
HIV infection: fatigue is the most frequent and debilitating complaint affecting those with HIV.[45] HIV-positive patients >35 years of age reported significantly higher levels of fatigue than younger HIV-positive patients.[45] The causes of fatigue in HIV are multiple. Anemia is the most common hematologic abnormality. In addition, hypothyroidism, deficiency of cortisol, and depression are frequent causes of fatigue that should be excluded.
Long COVID: describes the signs and symptoms that continue or develop after acute coronavirus 2 (SARS-CoV-2) infection. Fatigue is an important manifestation of long COVID.[46][47]
Lyme disease: a prospective study showed that fatigue was present in more than half of patients with confirmed early Lyme disease, and that the complaint of fatigue was more frequent than arthralgia, myalgia, or headache.[48] Lyme disease may also lead to post-treatment Lyme disease syndrome (fatigue, musculoskeletal pain, and neurocognitive difficulties) that may last for years despite antibiotic treatment.[49] Prolonged antibiotic therapy is not useful.[50]
Cytomegalovirus, toxoplasmosis, Q fever, brucellosis, and tuberculosis may all present with fatigue. Although coxsackie B virus, Chlamydia, and Mycoplasma infections can also cause fatigue, it is not usually the chief complaint.
Influenza virus, which affects the upper and lower respiratory tract. Fever, headache, myalgia, and fatigue are often associated with upper respiratory symptoms such as sore throat and lower respiratory symptoms of cough.[51]
Drugs and toxins
Drugs, both recreational and medicinal, are common causes of fatigue. Therefore, when a patient presents with a history of fatigue a careful evaluation of medication, both prescribed and over-the-counter, should be undertaken and recreational drug use explored.
Pharmacologic drugs most frequently associated with fatigue include antihistamines, antihypertensives, antiarrhythmics, antidepressants, antiemetics, antiepileptics, corticosteroids, diuretics, and neuroleptic agents. Ticagrelor, known to produce dyspnea, has also been associated with reports of central sleep apnea (causing fatigue).[52]
Chronic alcohol misuse may also result in fatigue and should not be overlooked.
Heavy metal toxicity can very rarely be the cause of fatigue. An occupational history is required. Risk factors for lead toxicity include battery production, glass artisans, use of very old household paints, or the use of Ayurvedic medicines. Risk factors for mercury toxicity include consumption of fish and amalgam dental fillings.[53] In one study, fatigue was one of the most common symptoms in patients with elevated levels of cobalt and chromium after a metal-on-metal hip implant.[54]
Pulmonary disease
COPD is often associated with symptoms of fatigue.[55] In addition to dyspnea, fatigue contributes to a reduced quality of life and decreased exercise tolerance.[56][57] Therefore, fatigue is a symptom to investigate and manage in all patients with COPD.[55]
Other pulmonary diseases that may be associated with fatigue include sarcoidosis, asthma, pulmonary hypertension, pleural disease, and pneumonitis.[58][59][60] However, the presence of more specific symptoms usually points to diagnosis.
Gastrointestinal disorders
Celiac disease: typically, celiac disease in childhood presents with steatorrhea, weight loss, and failure to thrive. However, only one third of adults with the disease report such complaints. The most frequent presenting symptom in adults with celiac disease is fatigue, emphasizing the fact that presentation in this group is often atypical.[61][62]
Chronic liver disease: fatigue has been well recognized as a complaint of patients with chronic liver disease including viral and cholestatic liver disease. One study showed that intensity of fatigue was higher in patients with primary biliary cirrhosis (PBC) compared with age- and sex-matched controls.[63] The fatigue impact score was significantly higher (worse) in the PBC patient group in contrast to the controls. No difference was seen between the fatigue scores in the PBC patients with Child-Pugh scores of 5 and those with Child-Pugh scores of >5.[63] In patients with chronic hepatitis C and hepatitis B virus infections, the Short Form 36 (SF-36) score, a questionnaire that allows assessment of patient quality of life, was substantially reduced in items concerning energy and fatigue, compared with the score of a control population.[64][65]
Inflammatory bowel disease (IBD): the pathogenesis of fatigue is only partially understood.[66] It may be caused by malnutrition, weight loss, and inflammation.
Irritable bowel syndrome (IBS): fatigue is a frequent complaint in IBS and correlates with female sex and younger age.[67]
Renal disorders
Fatigue and lack of energy are the most important problems reducing the quality of life for patients undergoing hemodialysis.[68] Patients with renal failure are prone to anemia, malnutrition caused by uremia, and loss of appetite. In addition, they are usually subject to dietary restrictions. These factors all contribute to developing fatigue.[69]
Neurologic disorders
Parkinson disease: about 40% of patients with Parkinson disease report fatigue among their main symptoms, and it still remains even after adjusted for the presence of depression, dementia, and sleep disturbances.[70][71][72]
Stroke: investigations demonstrated that two-thirds of patients reported fatigue after stroke and 40% considered fatigue one of the worst sequelae, lasting for some patients for ≥3 years. A pilot study suggests that fatigue correlates with the location of brain lesions, with a higher frequency in brainstem lesions.[73] A meta-analysis of 24 studies (n=2102) has shown that factors associated with post-stroke fatigue include female sex, depressive symptoms, longer time since stroke and greater disability.[74]
Multiple sclerosis: fatigue has been found to be the most disabling symptom in patients with multiple sclerosis. One study found a correlation between the presence and the severity of fatigue and the localization of lesions in the brain. Fatigue severity was significantly higher in patients with parietal lobe, internal capsule, or periventricular trigone lesions.[70][75][76][77]
Fatigue is also regarded as a common and often debilitating feature of lateral amyotrophic sclerosis, myasthenia gravis, dystonias, and myopathies.[70] However, these conditions usually present with more specific symptoms than fatigue.
Rheumatologic disorders
Half of patients with systemic lupus erythematosus report fatigue as their most disabling symptom.[78] Psychosocial variables seem to be strongly related to fatigue in these patients.[79]
Other rheumatologic etiologies include fibromyalgia and rheumatoid arthritis (although rheumatoid arthritis does not usually present with fatigue).[80]
Cancer
Fatigue is the most common unrelieved symptom of cancer.[81][82] A specific diagnostic has been proposed, cancer-related fatigue, which is defined as diminished energy and mental capacity as well as increased need to rest that is disproportionate to any recent change in activity level and is evident nearly every day during any 2-week period in the past month.[83] Causes of cancer-related fatigue are multiple and include cachexia, weight loss, anemia, cytokine increase, and psychological factors, especially depression.[84]
Idiopathic causes
Chronic fatigue syndrome (also known as myalgic encephalomyelitis [ME]) has been defined by the 1994 Center for Disease Control criteria (the “Fukuda” criteria) as clinically evaluated, unexplained, persistent or relapsing fatigue lasting at least 6 months, plus 4 or more specifically defined associated symptoms including subjective memory impairment, myalgia, arthralgia, headache, unrefreshing sleep, and post-exertional malaise (lasting >24 hours).[18] More recently, the US Institute of Medicine has proposed the term "systemic exertion intolerance disease" (SEID) as an alternative to chronic fatigue syndrome.[23] SEID is classified as profound fatigue of new or definite onset that reduces or impairs ability to engage in pre-illness activities; lasts >6 months; is not a result of ongoing excessive exertion; is not alleviated by rest; is accompanied by both post-exertional malaise and unrefreshing sleep; and occurs with either cognitive impairment or orthostatic intolerance.[23] The UK National Institute of Health and Care Excellence state that there is no diagnostic test or universally accepted definition for ME/CFS.[85]
The etiology of chronic fatigue syndrome (myalgic encephalomyelitis) remains unknown. Neuroendocrine, neuroinflammation, genetic, immunologic, psychological, metabolomic, and infectious causes have been investigated as initial triggers.[86][87][88] No chronic active viral, prion, or other infection has been found in the vast majority of patients with ME/CFS.[89]
Idiopathic chronic fatigue is defined as clinically evaluated unexplained chronic fatigue with no obvious medical cause that fails to meet the criteria for chronic fatigue syndrome.[18]
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