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 there is a fundamental pathology in place. Cachexia is seen in patients with cancer, AIDS, chronic obstructive lung disease, 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.

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

It was also prevalent in HIV patients before the advent of highly active anti-retroviral therapy (HAART) for that condition; now it is seen less frequently in those countries where such treatment is available. It is this characteristic that prompted a common African name for AIDS, "slim disease".

In those patients who have 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).

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. In most cases cachexia can be reversed with just eating. 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.

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.

Treatment
Currently, there are 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. Medical marijuana has been allowed for the treatment of cachexia in some states such as Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, and Arizona.

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. A 2009 trial found that a supplement of eicosapentaenoic acid helped cancer patients retain muscle mass.

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).

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).

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.

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. 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 [?] 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.

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).

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. 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.