Fatigue--What is it? Why is it?

Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, with almost 98 percent in one study reporting that they suffer from fatigue. Even in the general population, it is estimated that 7-45 percent exhibit persistent fatigue.

Fatigue is a multifaceted and broadly defined condition. This makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology, including autoimmune disease. Fatigue is defined by debilitating periods of exhaustion that interfere with normal activities, even such simple tasks as climbing stairs or crossing the room. The type of fatigue experienced in autoimmune disease is variable. These differences are likely related to the particular tissues/organs, cell types, brain areas, and molecular and physiological mechanisms affected by the condition.

While the exact mechanisms of fatigue are not well understood, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and daytime sleepiness--which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system, a region impacted either directly or indirectly in many autoimmune disorders.

Growing evidence indicates that neuroinflammation is a primary factor contributing to fatigue. Since inflammation plays a large part in inducing fatigue, it is plausible that inflammatory pathways and the subsequent physiological alterations are treatable targets for fatigue in patients with autoimmune disease. Evidence in autoimmune and related disease conditions such as neurosarcoidosis, which is associated with increased lung inflammation, sleep disturbances, and fatigue, exhibit reduced fatigue from anti-inflammatory treatment.

Several non-inflammatory factors are known to affect fatigue, including impairments in hydration status, pain, interactions from pharmaceuticals, muscle/exercise, hypothyroidism, radiation therapy, lung function, and cardiac characteristics such as blood pressure, heart rate, cardiac output, and stroke volume. Inflammatory mediators are reported to affect different aspects that contribute to fatigue, including motivation, sleepiness, cognition, anxiety, depression, and stress.

Cognitive (learning) fatigue involves declines in alertness, orientation, and mental performance on cognitive tasks. It is associated with feelings of exhaustion that follow sustained cognitive demands. Individuals with autoimmune diseases such as multiple sclerosis often experience cognitive deficits and increased perceived cognitive fatigue associated with impaired cortical brain activity.

Autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis, have a high coexistence with anxiety, depression and pain, which can serve to induce fatigue.

The perception of effort and motivation can modify fatigue and are affected in autoimmune disease. Animal studies indicate that effort expenditure is influenced by inflammation. In general, inflammation increases averseness toward negative stimuli and positive stimuli.

Metabolism, a physiological process known to play a role in fatigue, as previously mentioned, involves the conversion of fuel sources to energy-related molecules. Alterations in metabolism have been implicated in sleep regulation and fatigue. It also is tied to glycogen (animal starch) metabolism, glycogen synthesis, and energy enzymes and their derivatives, which could potentially alter fatigue. Alterations in metabolism also are implicated in the development of autoimmune disease.

Sleepiness, a factor in fatigue, occurs with chronic insomnia which also is associated with an increased incidence of developing an autoimmune disease. Findings in animal model of systemic lupus erythematosus suggest that sleep deprivation could be involved in the cause of the disease. Clinical diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis is also partially based upon non-restorative sleep, suggesting relationships between poor sleep and fatigue. It is reported that up to 50 percent of individuals with insomnia also indicate enhanced pain, which could contribute to fatigue.

What are the future directions for study? First, a detailed description of particular types of fatigue needs to be established in the clinic. Second, standardized questionnaires and diagnostic tests that can indicate more precisely the determinants observed from fatigue are needed. Also, understanding the neurocircuitry of fatigue and its relationship between inflammation and autoimmune diseases is needed.

More information on interactions between circadian timing and sleep/wake state or sleep loss, alterations in neuronal activity, and normal daily functioning that affect fatigue is required.

The relationship of gender to fatigue in autoimmune disease should be a topic for future research. Several autoimmune diseases are associated with disproportionately greater incidence and disease severity in particular genders, and little information is known regarding the relationship of fatigue with these gender differences.

Recent research reveals a relationship between types of fatigue and certain brain areas, cell types, and phenotypes that mediate the symptoms observed. Immunomodulatory agents and drugs targeting inflammatory pathways could serve to treat fatigue occurring in autoimmune and related diseases. Understanding the mechanisms behind fatigue not only will aid individuals with autoimmune diseases but also could benefit transplant recipients, cancer patients, and infectious disease patients who experience debilitating fatigue.

Used with Permission --Source: Excerpted and adapted from "Fatigue, Sleep and Autoimmune Related Disorders," report by Doctors Mark R. Zielinski, David M. Systrom, and Noel R. Rose, May 21, 2019, from an American Autoimmune Related Diseases Association (AARDA)-sponsored symposium; submitted to "Autoimmune and Autoinflammatory Disorders," a section of Frontiers in Immunology, published August 6, 2019

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