Cachexia

Cachexia
ICD-10	R 64
ICD-9	799.4
MeSH	D002100

Cachexia ( /kəˈkɛksiə/; from Greek κακός kakos "bad" and ἕξις hexis "condition")^[1] 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 there is a fundamental pathology in place.

Cachexia is seen in patients with cancer, AIDS,^[2]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 that 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 amphetamines. 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.^[3]^[4]

Disease settings

Cachexia is often seen in end-stage cancer, and in that context is called "cancer cachexia."

In patients with congestive heart failure, there is also a cachectic syndrome. Also, a cachexia co-morbidity is seen in patients that have any of the range of illnesses classified as "COPD" (chronic obstructive pulmonary disease), particularly emphysema. Some severe cases of schizophrenia can present this condition where it is named vesanic cachexia (from vesania, a Latin term for insanity).^{[citation needed]}

It also can be observed in such parasitic diseases as african trypanosomiasis (Sleeping sickness).^{[citation needed]}

In each of these settings there is full-body wasting, which hits the skeletal muscle especially hard, resulting in muscle atrophy and great muscle loss. However, when presenting comorbidly with malabsorbtion syndrome, (as seen, for example, in Crohn's Disease or Celiac Disease) simply consuming more food is not sufficient to reverse wasting and the malabsorbtion must be treated before the patient will be able to stabilize body mass.^[5]

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 (TNF-α), which is also nicknamed cachexin (also spelled cachectin) for this reason, Interferon gamma (IFNγ), and Interleukin 6 (IL-6), as well as the tumor-secreted proteolysis inducing factor (PIF).

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.^[6]

Treatment

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

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.^[7]Medical marijuana has been allowed for the treatment of cachexia in some US states such as Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, and Arizona.^[7]^[8]

Omega-3 fatty acids

A 2007 systematic review of n-3 fatty acids and cachexia found seventeen studies, eight of which were high-quality. It concluded that there was evidence that oral n-3 fatty acid supplements benefit cancer patients, improving appetite, weight and quality of life.^[9] A 2009 trial found that a supplement of eicosapentaenoic acid helped cancer patients retain muscle mass.^[10]

Drugs in development

Three Phase 2 clinical presentations occurred at ASCO 2010 with the following results: ALD518 is a humanized anti-IL-6 antibody. In testing, 124 patients with advanced NSCLC were randomized to one of four treatment groups (~30/group). Researchers concluded that ALD518 given to patients with NSCLC was safe and well tolerated. ALD518 improved the lung symptom score, reversed fatigue, and there was less loss of LBM (-0.19 kg on ALD518 vs. -1.50 kg on placebo).^[11]

GTx-024 is a Selective Adrenergic Receptor Modulator (SARM). In testing, 159 patients with either non-small cell lung cancer, 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).^[12]

VT-122 is a co-administration of propranolol and etodolac. In testing, 37 patients with advanced NSCLC were randomized to one of three treatment groups (~12/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 Group B and C.^[13]

The world's leading scientists gathered at the 5th annual meeting of the Society on Cachexia and Wasting Disorders in Barcelona December 5–8, 2009 to present data on various molecules in development. Kung et al. report highlights from the 5th Cachexia Conference held in December 2009 in Barcelona, Spain.^[14] Novel therapeutic approaches shown here include type 4 melanocortin receptor antagonist SNT 207979, an IL-6 antagonism ALD518, the appetite promoting synthetic ghrelin SUN11031, the soluble myostatin decoy receptor ActRIIB-Fc, the fast skeletal muscle troponin activating substance CK-2017357, the anti-catabolic/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^{[clarification needed]} acts as a skeletal muscle activator by making certain proteins more sensitive to calcium. Potential treatment for diseases and conditions associated with aging, muscle wasting or neuromuscular dysfunction. Ohr Pharmaceutical's drug, OHR/AVR118, modulates pro-inflammatory chemokine and cytokine synthesis, including TNF-alpha.^{[citation needed]}

Other preclinical work

In a study published 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).^[15]

Prevalence

According to the 2007 AHRQ National Inpatient sample, there were a projected 129,164 hospital encounters in the United States where cachexia was listed as at least one of up to 14 listed diagnosis codes, based on a sample of 26,325 unweighted encounters.^[16] The CDC National Ambulatory Medical Care Survey (NAMCS), a sample of U.S. outpatient visits listed 0 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.^[17]

Cancer cachexia

Approximately 50% of all cancer patients suffer from cachexia. Patients with upper gastrointestinal and pancreatic cancers have the highest frequency of developing a cachexic symptom. This ﬁgure rises up to 80% in terminal cancer patients.^[18] 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.^[19]

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 five percent 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 all have failed to demonstrate success in reversing the metabolic abnormalities seen in cancer cachexia.^[20] It is crucial now to develope and refine current strategies to counteract the symptoms of cancer cachexia to improve function and quality of life of cancer patients.

Pathogenesis

Much research is currently focused on determining the mechanism of the development of cachexia. There are two main theories of the development of cancer cachexia. The first theory is the 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. The second theory is that the cachectic syndrome is maintained by tumor-derived factors. Factors such as lipid mobilizing factor which was 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, it is still uncertain how they interact and whether they come into play at the beginning or at the end stage of the disease.^[21]

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

The inﬂammatory cytokines that have been involved in wasting diseases are interleukin 6, TNF-alpha, IL1B, and Interferon-gamma. Although there may be many different tissues and cell types that are responsible for the increase in circulating cytokines during some types of cancer, there is evidence that 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-kB. NF-kB 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.^[20]

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 utilized to treat cancer cachexia but showed limited effect.

Recent studies using a more calorie dense (1.5 kcals/mL) and higher protein supplementation have suggested that at least weight stabilization can be achieved, although improvements in lean body mass has not been observed in these studies.^[20]

There have been therapeutic strategies based on either blocking cytokine 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 randomised placebo control trial in patients with cancer cachexia showed that the drug was well tolerated and effective at attenuating loss of weight and lean body mass in patients with advanced pancreatic cancer. An improvement in the lean body mass and improved quality of life was also observed in a randomised doubled blind trial using a protein and energy dense Omega-3 fatty acids-enriched oral supplement, provided that its consumption was equal or superior to 2.2 g eicosapentaenoic acid (EPA)/day. It is also through decreasing TNF-alpha production. However, recent data arising from a large multicenter double-blind placebo-controlled trial indicate that EPA administration alone is not successful in the treatment of weight losing patients with advanced gastrointestinal or lung cancer.^[22]

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 that 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 modiﬁyng NF-κB expression.^[22]

A recent phase II study, involving the administration of antioxidants, pharmaconutritional support, progestagen, and anti-cyclooxygenase-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 multitarged therapies (nutritional supplementation, appetite stimulants, and physical activity regimen) in the treatment of cancer cachexia.^[22]