Cachexia

Cachexia (from Greek κακός kakos "bad" and ἕξις hexis "condition") or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight. The formal definition of cachexia is the loss of body mass that cannot be reversed nutritionally: Even if the affected patient eats more calories, lean body mass will be lost, indicating a primary pathology is in place.

Cachexia is also known as seen in patients with cancer, AIDS,^[1] chronic obstructive pulmonary disease, multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia) and hormonal deficiency.

It is a positive risk factor for death, meaning if the patient has cachexia, the chance of death from the underlying condition is increased dramatically. It can be a sign of various underlying disorders; when a patient presents with cachexia, a doctor will generally consider the possibility of cancer, metabolic acidosis (from decreased protein synthesis and increased protein catabolism), certain infectious diseases (e.g., tuberculosis, AIDS), chronic pancreatitis, and some autoimmune disorders, or addiction to amphetamine. Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor.^[2][3] Cachexia includes sarcopenia as a part of its pathology.

Causes

Cachexia is often seen in end-stage cancer, and in that context is called cancer cachexia. Patients with congestive heart failure can have a cachectic syndrome. Also, a cachexia comorbidity is seen in patients who have any of the range of illnesses classified as chronic obstructive pulmonary disease.^[4] Cachexia is also associated with advanced stages of chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, HIV/AIDS and other progressive illnesses.^[5]

Cancer

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.^[6] 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.^[7]

Symptoms of cancer cachexia include progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. Cachexia should be suspected if involuntary weight loss of greater than 5% of premorbid weight occurs within a six-month period. Traditional treatment approaches, such as appetite stimulants, 5-HT₃ antagonists, nutrient supplementation, and COX-2 inhibitor, have failed to demonstrate success in reversing the metabolic abnormalities seen in cancer cachexia.^[8]

Mechanism

The exact mechanism in which these diseases cause cachexia is poorly understood, but there is probably a role for inflammatory cytokines, such as tumor necrosis factor-alpha (which is also nicknamed 'cachexin' or 'cachectin'), interferon gamma and interleukin 6, as well as the tumor-secreted proteolysis-inducing factor.

Related syndromes include kwashiorkor and marasmus, although these do not always have an underlying causative illness and are most often symptomatic of severe malnutrition.

Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin. Ghrelin levels are also high in patients who have cancer-induced cachexia.^[9]

Cancer

Much research is currently focused on determining the mechanism of the development of cachexia. The two main theories of the development of cancer cachexia are:

• Alteration of control loop: 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, but high metabolic demand for nutrients.
• Cachectic syndrome maintained by tumor-derived factors: Factors, such as lipid mobilizing factor extracted from the urine of cachectic patients, were suspected to induce protein degradation in skeletal muscle by upregulation of the ubiquitin-proteasome pathway and lipolysis in adipocytes. However, how they interact and whether they come into play at the beginning or at the end stage of the disease is uncertain.^[10]

Although the pathogenesis of cancer cachexia is poorly understood, multiple biologic pathways are known to be involved, including proinflammatory cytokines such as TNF-alpha, neuroendocrine hormones, IGF-1, and tumor-specific factors such as proteolysis-inducing factor.

The inflammatory cytokines involved in wasting diseases are interleukin 6, TNF-alpha, IL1B, and interferon-gamma. Although many different tissues and cell types may be responsible for the increase in circulating cytokines during some types of cancer, evidence indicates the tumors are an important source. Cytokines by themselves are capable of inducing weight loss. TNF-alpha has been shown to have direct catabolic effect on skeletal muscle and adipose tissue and produces muscle atrophy through the ubiquitin–proteasome proteolytic 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]

Management

The treatment or management of cachexia depends on the underlying causes, the general prognosis and other person related factors. Reversible causes, underlying diseases and contributing factors are treated if possible and acceptable.^[11] Non-drug therapies which have been shown to be effective in cancer induced cachexia include nutritional counselling, psychotherapeutic interventions, and physical training.^[12]

It is less frequent than in the past, thanks to HIV (human immunodeficiency virus) medications, called HAART.^[13] Treatment involving different combinations for cancer cachexia is recommended in Europe, as a combination of nutrition, medication and non-drug-treatment may be more effective than monotherapy.^[12] Steroids 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.^[12] Progestins such as megestrol acetate are an option in refractory cachexia with anorexia as a major symptom.^[12][14] Other drugs that have been used or are being investigated in cachexia therapy, but which lack conclusive evidence of efficacy or safety, and are not generally recommended include:

• Thalidomide and cytokine antagonists^[12]
• Cannabinoids^[12]
• Omega-3 fatty acids, including eicosapentaenoic acid (EPA)^[12]
• Non-steroidal anti-inflammatory drugs^[12]
• Prokinetics^[12]
• Ghrelin and ghrelin receptor agonist^[4]
• Anabolic catabolic transforming agents such as MT-102^[4]
• Selective androgen receptor modulators^[4]
• Cyproheptadine^[15]
• Hydrazine^[15]

Medical marijuana has been allowed for the treatment of cachexia in some US states, such as Illinois, Delaware, Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, Arizona, Vermont, New Jersey, Rhode Island, Maine^[16] and Connecticut.^[14][17]

There is insufficient evidence to support the use of oral fish oil for the management of cachexia associated with advanced cancer.^[18][19]

Cancer

Only limited treatment options exist for patients with clinical cancer cachexia. Current strategy is to improve appetite by using appetite stimulants to ensure adequate intake of nutrients. Pharmacological interventions with appetite stimulants, nutrient supplementation, 5-HT₃ antagonists and Cox-2 inhibitor have been used to treat cancer cachexia, but with limited effect.

Studies using a more 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]

Therapeutic strategies have been based on either blocking cytokines synthesis or their action. Thalidomide has been demonstrated to suppress TNF-alpha production in monocytes in vitro and to normalize elevated TNF-alpha levels in vivo. A randomized, placebo-controlled trial in patients with cancer cachexia showed the drug was well tolerated and effective at attenuating loss of weight and lean body mass (LBM) in patients with advanced pancreatic cancer. An improvement in the LBM and improved quality of life were also observed in a randomized, double-blind trial using a protein and energy-dense, omega-3 fatty acids-enriched oral supplement, provided its consumption was equal or superior to 2.2 g of eicosapentaenoic acid per day. It is also through decreasing TNF-alpha production. However, data arising from a large, multicenter, double-blind, placebo-controlled trial indicate EPA administration alone is not successful in the treatment of weight loss in patients with advanced gastrointestinal or lung cancer.^[20]

Peripheral muscle proteolysis, as it occurs in cancer cachexia, serves to mobilize amino acids required for the synthesis of liver and tumor protein. Therefore, the administration of exogenous amino acids may theoretically serve as a protein-sparing metabolic fuel by providing substrates for both muscle metabolism and gluconeogenesis. Studies have demonstrated dietary supplementation with a specific combination of high protein, leucine and fish oil improves muscle function and daily activity and the immune response in cachectic tumor-bearing mice. In addition, β-hydroxy-β-methyl butirate derived from leucine catabolism used as a supplement in tumor-bearing rats prevents cachexia by modifying NF-κB expression.^[20]

A phase-2 study involving the 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. These data reinforce the use of the multitargeted therapies (nutritional supplementation, appetite stimulants, and physical activity regimen) in the treatment of cancer cachexia.^[20]

New studies indicate NSAIDS, like Sulindac, were found to significantly decrease cachexia.^[21]

Also studies have shown branched-chain amino acids can return the metabolism of a cachectic patient from catabolic-losing weight- to anabolic- increasing muscle, in over 55% of patients. Branched-chain amino acids consist primarily of leucine and valine. In a research paper published by the Indian J of Palliat Care, the effects the findings concluded that bcaa's interfere with brain serotonergic activity and inhibit the overexpression of critical muscular proteolytic pathways. The potential role of branched-chain amino acids as antianorexia and anticachexia agents was proposed many years ago, but experimental studies and clinical trials have since tested their ability to stimulate food intake and counteract muscle wasting in anorectic, weight-losing patients. In experimental models of cancer cachexia, BCAAs were able to induce a significant suppression in the loss of body weight, producing a significant increase in skeletal muscle wet weight[30] as well as in muscle performance and total daily activity.

The conditionally essential amino acid glutamine has been used as a component of oral supplementation to reverse cachexia in patients with advanced cancer^[22] or HIV/AIDS.^[23]

Epidemiology

According to the 2007 AHRQ National Inpatient Sample, in a projected 129,164 hospital encounters in the United States, cachexia was listed as at least one of up to 14 recorded diagnosis codes based on a sample of 26,325 unweighted encounters.^[24] A sample of 32,778 unweighted US outpatient visits collected by the CDC's National Ambulatory Medical Care Survey did not list any visits where cachexia was one of up to three recorded diagnoses treated during the visit.^[25]

See also

• Progressive disease
• Terminal illness
• Journal of Cachexia, Sarcopenia and Muscle

References

External links

• Manifestations and treatment of cachexia, from Cancer Medicine
• Scientists find key to "wasting syndrome" seen in cancer, AIDS (U.S. Department of Veterans Affairs)