Exhausting
Definition: Fatigue in a medical context is used to cover experiences of low energy that are not caused by normal life.
A 2021 review proposed a definition for fatigue as a starting point for discussion: "A multi-dimensional phenomenon in which the biophysiological, cognitive, motivational and emotional state of the body is affected resulting in significant impairment of the individual's ability to function in their normal capacity".
Another definition is that fatigue is "a significant subjective sensation of weariness, increasing sense of effort, mismatch between effort expended and actual performance, or exhaustion independent from medications, chronic pain, physical deconditioning, anaemia, respiratory dysfunction, depression, and sleep disorders".

Terminology: The use of the term "fatigue" in medical contexts may carry inaccurate connotations from the more general usage of the same word. More accurate terminology may also be needed for variants within the umbrella term of fatigue.

Comparison with other terms: 

Tiredness: Tiredness which is a normal result of work, mental stress, anxiety, overstimulation and understimulation, jet lag, active recreation, boredom, or lack of sleep is not considered medical fatigue. This is the tiredness described in MeSH Descriptor Data.

Sleepiness: Sleepiness refers to a tendency to fall asleep, whereas fatigue refers to an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion. Sleepiness and fatigue often coexist as a consequence of sleep deprivation. However sleepiness and fatigue may not correlate. Fatigue is generally considered a longer-term condition than sleepiness (somnolence).

Presentation: 

Common features: Distinguishing features of medical fatigue include

unpredictability,
not linking fatigue to an obvious cause, such as a physical exertion,
variability in severity,
fatigue being relatively profound/overwhelming, and having extensive impact on daily living,
lack of improvement with rest,
where an underlying disease is present, the quantum of fatigue often does not correlate with the severity of the underlying disease.

Differentiating features: Differentiating characteristics of fatigue that may help identify the possible cause of fatigue include

Post-exertional malaise; a common feature of ME/CFS, and experienced by a significant proportion of people with Long Covid, but not a feature of other fatigues.

Increased by heat or cold; MS fatigue is in many cases affected in this way.
Remission; MS fatigue may reduce during periods of other MS symptom remission. ME/CFS may also have lower periods of activity.
Cognitive declines; sleep deprivation causes cognitive and neurobehavioral effects including unstable attention and slowing of response times. ME/CFS and MS may cause brain fog over longer timescales.
Intermittency; Fatigues often vary in how and when they occur. Some fatigues (RA, cancer fatigue) seem to often be continual (24/7) whilst others (MS, Sjögren's, lupus, brain injury) are often intermittent. A 2010 study found that Sjögren's patients reported fatigue after rising, an improvement in mid-morning, and worsening later in the day, whereas lupus (SLE) patients reported lower fatigue after rising followed by increasing fatigue through the day. ME/CFS symptoms can be continual, or can fluctuate during the day, from day to day, and over longer periods.
The pace of onset may be a related differentiating factor; MS fatigue can have abrupt onset.
Feeling of weight; some fatigues, including that caused by MS, create a sense of weight or gravity; "I feel like I have lead weights attached to my limbs ... or I am being pulled down by gravity."
Some people may have multiple causes of fatigue.

Causes: 

Drug use: A 2021 study in a Korean city found that alcohol consumption was the variable with the most correlation with overall fatigue. A 2020 Norway study found that 69% of substance use disorder patients had severe fatigue symptoms, and particularly those with extensive use of benzodiazepines. Causality, as opposed to correlation, were not proven in these studies.

Unknown: In up to a third of fatigue primary care cases, no medical or psychiatric diagnosis is found.
Tiredness is a common medically unexplained symptom.

Sleep disturbance: Fatigue can often be traced to poor sleep habits. Sleep deprivation and disruption is associated with subsequent fatigue. Sleep disturbances due to disease may impact fatigue. Caffeine and alcohol can disrupt sleep, causing fatigue.

Medications: Fatigue may be a side effect of certain medications (e.g., lithium salts, ciprofloxacin); beta blockers, which can induce exercise intolerance, medicines used to treat allergies or coughs) and many cancer treatments, particularly chemotherapy and radiotherapy. Use of benzodiazepines has been found to correlate with higher fatigue.

Association with diseases and illnesses: Fatigue is often associated with diseases and conditions. Some major categories of conditions that often list fatigue as a symptom include physical diseases, substance use illness, mental illnesses, and other diseases and conditions.

Physical diseases: autoimmune diseases, such as celiac disease, lupus, multiple sclerosis, myasthenia gravis, NMOSD, Sjögren's syndrome, rheumatoid arthritis, spondyloarthropathy and UCTD; this population's primary concern is fatigue;
blood disorders, such as anemia and hemochromatosis;
brain injury;
cancer, in which case it is called cancer fatigue;
Covid-19 and long Covid;
developmental disorders such as autism spectrum disorder;
endocrine diseases or metabolic disorders: diabetes mellitus, hypothyroidism and Addison's disease;
fibromyalgia;
heart failure and heart attack;
HIV
inborn errors of metabolism such as fructose malabsorption;
infectious diseases such as infectious mononucleosis or tuberculosis;
irritable bowel syndrome;
kidney diseases, e.g., acute renal failure, chronic renal failure;
leukemia or lymphoma;
liver failure or liver diseases, e.g., hepatitis;
Lyme disease;
neurological disorders such as narcolepsy, Parkinson's disease, postural orthostatic tachycardia syndrome (POTS) and post-concussion syndrome;
physical trauma and other pain-causing conditions, such as arthritis;
sleep deprivation or sleep disorders, e.g. sleep apnea;
stroke
thyroid disease such as hypothyroidism;

Mental illnesses: anxiety disorders, such as generalized anxiety disorder;
depression;
eating disorders, which can produce fatigue due to inadequate nutrition;

Other: myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
idiopathic chronic fatigue, a term used to describe chronic fatigue which does not have symptoms of ME/CFS. However ICF does not have a dedicated diagnostic code in the World Health Organization's ICD-11 classification.
Gulf War syndrome;

Primary vs. secondary: In some areas, it has been proposed that fatigue be separated into primary fatigue, caused directly by a disease process, and ordinary or secondary fatigue, caused by a range of causes including exertion and also secondary impacts on a person of having a disease (such as disrupted sleep). The ICD-11 MG22 definition of fatigue captures both types of fatigue; it includes fatigue that "occur[s] in the absence of... exertion... as a symptom of health conditions."

Obesity: Obesity correlates with higher fatigue levels and incidence.

Somatic symptom disorder: In somatic symptom disorder the patient is overfocused on a physical symptom, such as fatigue, that may or may not be explained by a medical condition.

Adverse life events: Adverse life events have been associated with fatigue.

Scientifically unsupported causes: The concept of adrenal fatigue is often raised in media but no scientific basis has been found for it.

Mechanisms: The mechanisms that cause fatigue are not well understood. Several mechanisms may be in operation within a patient, with the relative contribution of each mechanism differing over time.
Proposed fatigue explanations due to permanent changes in the brain may have difficulty in explaining the "unpredictability" and "variability" (i.e. appearing intermittently during the day, and not on all days) of the fatigue associated with inflammatory rheumatic diseases and autoimmune diseases (such as multiple sclerosis).

Inflammation: Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks, and has been linked to many types of fatigue. Findings implicate neuroinflammation in the etiology of fatigue in autoimmune and related disorders. Low-grade inflammation may cause an imbalance between energy availability and expenditure.
Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue. However a 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.

Reduced brain connectivity: Fatigue has been correlated with reductions in structural and functional connectivity in the brain. This has included in post-stroke, MS, NMOSD and MOG, and ME/CFS. This was also found for fatigue after brain injury, including a significant linear correlation between self-reported fatigue and brain functional connectivity.
Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex, fronto-parietal and cingulo-opercular,  and default mode network, salience network, and thalamocortical loop areas.
A 2024 review found that structural connectivity changes may underlie fatigue in pwRRMS but that the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies.