Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and AIDS. Systemic inflammation from these conditions can cause detrimental changes to metabolism and body composition. In contrast to weight loss from inadequate caloric intake, cachexia causes mostly muscle loss instead of fat loss. Diagnosis of cachexia can be difficult due to the lack of well-established diagnostic criteria. Cachexia can improve with treatment of the underlying illness but other treatment approaches have limited benefit. Cachexia is associated with increased mortality and poor quality of life.
The term is from Greek κακός kakos 'bad' and ἕξις hexis 'condition'.
Causes
Cachexia can be caused by diverse medical conditions, but is most often associated with end-stage cancer, known as cancer cachexia. About 50% of all cancer patients develop cachexia. Those with upper gastrointestinal and pancreatic cancers have the highest frequency of developing a cachexic symptom. Prevalence of cachexia rises in more advanced stages and is estimated to affect 80% of terminal cancer patients.
Congestive heart failure, AIDS, chronic obstructive pulmonary disease, and chronic kidney disease are other conditions that often cause cachexia. 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, trypanosomiasis, rheumatoid arthritis, and celiac disease as well as other systemic diseases.
Mechanism
The exact mechanism in which these diseases cause cachexia is poorly understood, and likely is multifactorial with multiple disease pathways involved. Inflammatory cytokines appear to play a central role including tumor necrosis factor (TNF) (which is also nicknamed 'cachexin' or 'cachectin'), interferon gamma and interleukin 6. TNF has been shown to have a direct catabolic effect on skeletal muscle and adipose tissue through the ubiquitin proteasome pathway. This 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. Systemic inflammation also causes reduced protein synthesis through inhibition of the Akt/mTOR pathway.
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 cachexia. Uncontrolled inflammation in cachexia can lead to an elevated resting metabolic rate, further increasing the demands for protein and energy sources.
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, 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.
Diagnosis
Diagnostic guidelines and criteria have only recently been proposed despite the prevalence of cachexia and varying criteria, the primary features of cachexia include progressive depletion of muscle and fat mass, reduced food intake, abnormal metabolism of carbohydrate, protein, and fat, reduced quality of life, and increased physical impairment.
Historically, body weight changes were used as the primary metrics of cachexia, including low body mass index and involuntary weight loss of more than 10%. Using weight alone is limited by the presence of edema, tumor mass and the high prevalence of obesity in the general population. Weight-based criteria do not take into account changes in body composition, especially loss of lean body mass.