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Cachexia is a complex syndrome associated with underlying illness causing ongoing muscle loss that is not entirely reversed with nutritional therapy. A range of diseases can cause cachexia, most commonly cancer, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease and AIDS. The pathophysiology is incompletely understood but is considered a inflammatory state that causes detrimental metabolic changes and alterations in body composition. In contrast to weight loss from inadequate caloric intake, cachexia causes predominantly muscle loss instead of fat loss and it is not as responsive to nutritional intervention. Diagnosis of cachexia can be difficult due to a lack of well-established diagnostic criteria. Cachexia can improve with treatment of the underlying illness but other current treatment approaches have limited results. Cachexia is associated with increased mortality and poor quality of life.

Cachexia
Other namesWasting syndrome
SpecialtyOncology, Internal Medicine, Physical Medicine and Rehabilitation

The term is from Greek κακός kakos, "bad", and ἕξις hexis, "condition".

DefinitionEdit

Identification, treatment and research of cachexia has historically been limited by a lack of a widely accepted definition of cachexia. Multiple definitions have been proposed and in 2011 an international consensus group adopted the definition of cachexia as “a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that can be partially but not entirely reversed by conventional nutritional support.”[1]

Cachexia differs from weight loss due to malnutrition from malabsorption, anorexia nervosa or anorexia due to primary depression. Weight loss from inadequate caloric intake generally causes more fat loss than muscle loss, whereas cachexia causes predominantly muscle wasting. Cachexia is also distinct from sarcopenia, age-related muscle loss, although they often co-exist.[2]

Although these definitions have not been used in clinical trials, they provide a framework for researchers and clinicians to better identify and research the condition.

CausesEdit

Cachexia can be caused by a wide range of medical conditions but is most often associated with end-stage cancer, known as cancer cachexia. About 50% of all cancer patients suffer from cachexia. Those with upper gastrointestinal and pancreatic cancers have the highest frequency of developing a cachexic symptom. This figure rises to 80% in terminal cancer patients.[3] In addition to increasing morbidity and mortality, aggravating the side effects of chemotherapy, and reducing quality of life, cachexia is considered the immediate cause of death of a large proportion of cancer patients, ranging from 22% to 40% of the patients.[4]

Congestive heart failure, AIDS, chronic obstructive pulmonary disease, and chronic kidney disease are also conditions that often cause cachexia.[5] Cachexia can also be the result of advanced stages of cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, tuberculosis, multiple system atrophy, mercury poisoning, Crohn's disease, rheumatoid arthritis, celiac disease,[6] type 1 diabetes mellitus, as well as other systemic diseases.[7]

MechanismEdit

The exact mechanism in which these diseases cause cachexia is poorly understood and likely is multifactorial with multiple biologic pathways involved. Inflammatory cytokines appear to play a central role including TNF-alpha (which is also nicknamed 'cachexin' or 'cachectin'), interferon gamma and interleukin 6. Cytokines by themselves are capable of inducing weight loss and TNF-alpha has been shown to have direct catabolic effect on skeletal muscle and adipose tissue and produces muscle atrophy through the ubiquitin proteasome pathway. The mechanism involves the formation of reactive oxygen species leading to upregulation of the transcription factor NF-κB. NF-κB is a known regulator of the genes that encode cytokines and cytokine receptors. The increased production of cytokines induces proteolysis and breakdown of myofibrillar proteins.[8] Systemic inflammation also causes reduced protein synthesis through inhibition of the Akt/mTOR pathway.[9]

Although many different tissues and cell types may be responsible for the increase in circulating cytokines, evidence indicates tumors themselves are an important source of factors that may promote cachexia in cancer. Tumor-derived molecules such as lipid mobilizing factor, proteolysis-inducing factor, and mitochondrial uncoupling proteins may induce protein degradation and contribute to the cachectic syndrome.[10]

Uncontrolled inflammation in cachexia can lead to an elevated resting metabolic rate, further increasing the demands for protein and energy sources.[9]

There is also evidence of alteration in feeding control loops in cachexia. High levels of leptin, a hormone secreted by adipocytes, block the release of Neuropeptide Y(NPY), which is the most potent feeding-stimulatory peptide in the hypothalamic orexigenic network, leading to decreased energy intake despite the high metabolic demand for nutrients.[10]

DiagnosisEdit

Diagnostic guidelines and criteria have only recently been proposed despite the prevalence of cachexia. Diagnostic criteria and they have shifted over time as understanding of cachexia as a complex syndrome evolved resulting in multiple different criteria proposed. Despite the varying and changing criteria, the primary features of cachexia include progressive depletion of muscle and fat mass; reduced oral intake; abnormal metabolism of carbohydrate, protein, and fat; and reduced quality of life or increased physical impairment.[11]

Historically, body weight and weight changes were used as the primary metrics of cachexia including low body mass index, involuntary weight loss of >10%, or >5% in 12 months in the setting of concurrent illness. However, using weight alone may not identify many patients as it is affected by edema, tumor mass and the high prevalence of obesity in the general population.[12] It also does not take into account changes in body composition, especially loss of lean body mass.

In the attempt to include a broader evaluation of the burden of cachexia, diagnostic criteria using assessments of laboratory metrics and symptoms in addition to weight have been proposed. This criteria included weight loss of at least 5% in 12 months or low BMI (<22 kg/m2) with 3 of 5 of the following features: decreased muscle strength, fatigue, anorexia, low fat‐free mass index, or abnormal biochemistry (increased inflammatory markers, anemia, low serum albumin).[2]

Laboratory markers are often used in evaluation of patients with cachexia including albumin, prealbumin, CRP, or hemoglobin. However, laboratory metrics used and cut-off values are not standardized across different guidelines and diagnostic criteria. Acute phase reactants (IL-6, IL-1b, tumor necrosis factor-a, IL-8, interferon-g) are sometimes measured but correlate poorly with outcomes. Currently, there are no biomarkers to identify precachectic patients with cancer who may progress to further stages.[11][12]

In the effort to better classify cachexia severity, several scoring systems have been proposed including the Cachexia Staging Score (CSS) and CASCO. The CSS takes into account weight loss, subjective reporting of muscle function, performance status, appetite loss, and laboratory changes to categorize patients into non-cachexia, pre-cachexia, cachexia and refractory cachexia. The Cachexia SCOre (CASCO) is another validated score that includes evaluation of body weight loss and composition, inflammation/metabolic disturbances/immunosuppression, physical performance, anorexia, and quality of life.[12]

Evaluation of changes in body composition is limited by the difficulty in measuring muscle mass and health in a non-invasive and cost-effective way. Imaging with quantification of muscle mass has been investigated including bioelectrical impedance, computed tomography, dual-energy X-ray absorptiometry, and MRI but are not widely used.[12]

TreatmentEdit

The management of cachexia depends on the underlying cause, the general prognosis, and patient goals and wishes.[13] The most effective approach to cachexia is treating the underlying disease process, as evidenced by the reduction in cachexia from AIDS since the advent of highly active antiretroviral therapy (HAART).[14] However this is often not possible or may be inadequate to reverse the cachexia syndrome in other diseases. Approaches to mitigate the muscle loss include exercise, nutritional therapies, and medications. There are many therapies previously studied or currently investigated for cachexia that are not widely used in clinical practice.

ExerciseEdit

Therapy that includes regular physical exercise is recommended for the treatment of cancer cachexia due to the positive effects of exercise on skeletal muscle.[15][16] Individuals with cancer cachexia generally report low levels of physical activity and few engage in an exercise routine, owing to low motivation to exercise and a belief that exercising may worsen their symptoms or cause harm.[17][18] As of 2018, the efficacy of resistance and aerobic exercise in cancer cachexia has not been definitively established due to a lack of published evidence;[19] however, trials of the effectiveness of exercise therapy – in combination with nutrition and medication – are underway.[19]

MedicationsEdit

Appetite stimulant medications are often used for cachectic patients to increase oral intake but are not effective in stopping the underlying catabolic process and may have detrimental side effects. These medications include steroids, cannabinoids, or progestins such as megestrol acetate.[11][20][21] Anti-emetics such as 5-HT3 antagonists are also commonly used in cancer cachexia if nausea is a prominent symptom.[8]

Anabolic-androgenic steroids like oxandrolone may be beneficial in cancer cachexia but their use is recommended for maximal 2 weeks since a longer duration of treatment increases the burden from side effects.[21][22]

NutritionEdit

The increased metabolic rate in cachexia and appetite suppression common in cachexia contribute to malnutrition which compounds muscle loss.[9] Studies using a calorie-dense (1.5 kcals/ml) and higher protein supplementation have suggested at least weight stabilization can be achieved, although improvements in lean body mass have not been observed in these studies.[8]

SupplementsEdit

Administration of exogenous amino acids have been investigated to serve as a protein-sparing metabolic fuel by providing substrates for both muscle metabolism and gluconeogenesis. Specifically the branched-chain amino acids leucine and valine may have potential in inhibiting overexpression of proteolytic pathways.[23] The conditionally essential amino acid glutamine has been used as a component of oral supplementation to reverse cachexia in patients with advanced cancer[24] or HIV/AIDS.[25]

β-hydroxy β-methylbutyrate (HMB) is a metabolite of leucine that acts as a signalling molecule to stimulate protein synthesis. It is reported to have multiple targets, including stimulating MTOR and decreasing proteasome expression. HMB has shown to be effective in multiple muscle wasting disorders in animal models, however the data in humans is mixed. Studies showed positive results for chronic pulmonary disease, hip fracture, and in AIDS‐related and cancer‐related cachexia but not in rheumatoid cachexia, renal failure, and gastric bypass. However, many of these clinical studies used HMB as a component of combination treatment with glutamine, arginine, leucine, higher dietary protein and/or vitamins, which limits the assessment of the efficacy of HMB alone.[26][27]

Treatments under investigationEdit

Several medications are under investigation or have been previously trialed for use in cachexia. These are currently not in widespread clinical use:

Medical marijuana has been allowed for the treatment of cachexia in some US states, such as Illinois, Maryland, Delaware, Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, Arizona, Vermont, New Jersey, Rhode Island, Maine, and New York [31][32] Hawaii[33] and Connecticut.[20][34]

Role of multimodal therapyEdit

Despite the extensive investigation into single therapeutic targets for cachexia, the most effective treatments utilize multi-targeted therapies. In Europe, a combination of non-drug approaches including physical training, nutritional counselling and psychotherapeutic intervention are utilized based on evidence that this approach may be more effective than monotherapy.[21] Administration of antioxidants, pharmaconutritional support, progestin (megestrol acetate and medroxyprogesterone acetate), and anticyclooxygenase-2 drugs showed efficacy and safety in the treatment of patients with advanced cancer of different sites suffering cachexia.[28] Combination treatments with branched-chain amino acids and β-hydroxy β-methylbutyrate.[27]

EpidemiologyEdit

Accurate epidemiological data on the prevalence of cachexia is lacking due to changing diagnostic criteria and under-identification of patients in clinical practice.[35] It is estimated that cachexia from any disease is estimated to affect >5 million people in the United States.[11] In the United States and other industrialized countries in North America and Europe, the prevalence of cachexia is growing and estimated at about 1% of the population. The prevalence is less in Asia but due to the larger population, represents a similar burden. Cachexia is also a significant problem in South America and Africa but epidemiological data is limited.[35]

The most frequent causes of cachexia in the United States by population prevalence are: 1) COPD, 2) heart failure, 3) cancer cachexia, 4) chronic kidney disease. The prevalence of cachexia ranges from 15%–60% among patients with cancer. This wide range is attributed to differences in cachexia definition, cancer populations, and timing of diagnosis.[11] Although the prevalence of cachexia among patients with COPD or CHF is lower (estimated 5% to 20%), the large number of patients with these conditions dramatically increase the total cachexia burden.[7][35]

Cachexia contributes to significant loss of function and healthcare utilization. Estimates using the National Inpatient Sample in the United States suggest that cachexia was the reason for 177,640 inpatient stays in 2016.[36]

See alsoEdit

ReferencesEdit

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External linksEdit