Cachexia

Cachexia

ICD-10	R64
ICD-9	799.4
MeSH	D002100

Cachexia (pron.: /kəˈkɛksiə/; 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 seen in patients with cancer, AIDS, chronic obstructive lung 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.

Disease settings

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, particularly emphysema.

In each of these settings, full-body wasting occurs, which affects especially the skeletal muscle, resulting in muscle atrophy. However, when presenting comorbidly with malabsorption syndrome, (as seen, for example, in Crohn's disease or celiac disease), simply consuming more food is not sufficient to reverse wasting and the malabsorption must be treated before the patient will be able to stabilize body mass.

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 malnutrition syndromes are kwashiorkor and marasmus, although these do not always have an underlying causative illness; they 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.

Treatment

Currently, no widely accepted drugs to treat cachexia and no FDA-approved drugs to treat cancer cachexia are available.

Cachexia may be treated by steroids, such as corticosteroids, or drugs that mimic progesterone, which increase appetite, may reverse weight loss, but have no evidence of reversing muscle loss. Medical marijuana has been allowed for the treatment of cachexia in some US states, such as Delaware, Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, Arizona, Vermont, New Jersey, Rhode Island and Connecticut.

Omega-3 fatty acids

A 2007 [systematic review] of n-3 fatty acids and cachexia found 17 studies, eight of which were high-quality. It concluded there was evidence of oral n-3 fatty acid supplements benefiting cancer patients, improving appetite, weight and quality of life. A 2009 trial found a supplement of eicosapentaenoic acid helped cancer patients retain muscle mass.

Drugs in development

Three phase-2 clinical presentations occurred at ASCO 2010, with these results: ALD518 is a humanized anti-IL-6 antibody. In testing, 124 patients with advanced non-small cell lung cancer (NSCLC) were randomized to one of four treatment groups (about 30 per group). Researchers concluded the ALD518 given to patients with NSCLC was safe and well tolerated. ALD518 improved the lung symptom score, reversed fatigue, and less loss of lean body mass occurred (−0.19 kg on ALD518 vs. −1.50 kg on placebo).

GTx-024 is a selective androgen receptor modulator (SARM). In testing, 159 patients with either NSCLC, colorectal cancer, non-Hodgkin's lymphoma, chronic lymphocytic leukemia or breast cancer were randomized to oral GTx-024 (3 mg or 1 mg) or placebo daily for 16 weeks. As a result, a statistically significant increase in lean body mass (LBM) was observed in both treatment groups compared to baseline (1 mg, p =0.001; 3 mg, p =0.045).

VT-122 is a coadministration of propranolol and etodolac. In testing, 37 patients with advanced NSCLC were randomized to one of three treatment groups (about 12 per group). Researchers observed a statistically significant difference in the proportion of subjects who responded with an improvement of ≥ 5% in LBM at week 12 (group A, control, n = 0/12; group B, low dose VT-122, n = 7/12 p = 0.0191; group C, high dose VT-122, n = 5/12, p = 0.0174). No patient in group A gained any lean body mass. An increasing trend in improvement was seen at weeks 6 and 9 for groups B and C.

At the fifth annual meeting of the Society on Cachexia and Wasting Disorders in Barcelona December 5–8, 2009, data were presented on various molecules in development. Novel therapeutic approaches shown here include type 4 melanocortin receptor antagonist SNT 207979, an IL-6 antagonist ALD518, the appetite-promoting synthetic ghrelin SUN11031, the soluble myostatin decoy receptor ActRIIB-Fc, the fast skeletal muscle troponin-activating substance CK-2017357, the anticatabolic/anabolic transforming agent MT-102, the anti-inflammatory agent celecoxib, testosterone supplementation and vitamin D. Two of the presenting companies were Cytokinetics and Ohr Pharmaceutical. Cytokinetics' molecule acts as a skeletal muscle activator by making certain proteins more sensitive to calcium, as a potential treatment for diseases and conditions associated with aging, muscle wasting or neuromuscular dysfunction. Ohr Pharmaceutical's drug, OHR/AVR118, modulates proinflammatory chemokine and cytokine synthesis, including TNF-alpha.

Other preclinical work

In a study published in 2010, researchers demonstrated a link between cachexia and activin and myostatin activity, and successfully reversed the effects in mice, by inhibiting that activity through treatment with a soluble version of the ActRIIB receptor (sActRIIB).

Prevalence

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 listed diagnosis codes, based on a sample of 26,325 unweighted encounters. The CDC National Ambulatory Medical Care Survey, a sample of US outpatient visits listed no visits where cachexia was listed as one of up to three recorded diagnoses treated during the visit, out of a sample of 32,778 unweighted visits.

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. 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.

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.

Pathogenesis

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 (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 .

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.

Treatments

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.

Recent 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.

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 recent randomized, placebo-controlled trial in patients with cancer cachexia showed the drug was well tolerated and effective at attenuating loss of weight and 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, recent 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.

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. Recent 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.

A recent phase-2 study involving the administration of antioxidants, pharmaconutritional support, progestogen (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.

See also

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

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)