Cachexia, 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. Cachexia is also the body’s way of shutting down in order to prepare for death.
Cachexia is seen in particular with people who have advanced cancer, but patients who suffer from AIDS, coeliac disease, chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning(acrodynia), Crohn’s disease, untreated/severe type 1 diabetes mellitus, anorexia nervosa, hyperthyroidism and hormonal deficiency can also suffer from cachexia.
It is a positive risk factor for death, meaning if the person 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 adverse drug reactions, cancer, metabolic acidosis, certain infectious diseases (e.g., tuberculosis, AIDS), chronic pancreatitis and some autoimmune disorders.
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.
Cachexia includes sarcopenia as a part of its pathology. The term is from Greek kakos, “bad”, and hexis, “condition”.
Cancer and 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. Cachexia has been reported in patients with early-stage cancer and its presence is associated with mortality risk.
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-HT3antagonists, nutrient supplementation, and COX-2 inhibitor, have failed to demonstrate success in reversing the metabolic abnormalities seen in 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. 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.
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.
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.
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.
Treatment Plans in Conventional Oncology
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.
Therapy that includes regular physical exercise is recommended for the treatment of cancer cachexia due to the effects of exercise on skeletal muscle. Individuals with cancer cachexia generally report low levels of physical activity and few engage in an exercise routine, owing to low motivation to exercise and a belief that exercising may worsen their symptoms or cause harm. As of 2018, the efficacy of resistance and aerobic exercise in cancer cachexia has not been established due to a lack of published evidence; however, trials of the effectiveness of exercise therapy – in combination with nutrition and medication – are underway.
A growing body of evidence supports the efficacy of β-hydroxy β-methylbutyrate (HMB) as a treatment for reducing, or even reversing, the loss of muscle mass, muscle function, and muscle strength that occurs in cachexia; consequently, as of June 2016 it is recommended that both the prevention and treatment of muscle wasting conditions include supplementation with HMB, regular resistance exercise and consumption of a high-protein diet. Progestins such as megestrol acetate are a treatment option in refractory cachexia with anorexia as a major symptom.
Cachexia occurs less frequently in HIV/AIDS than in the past due to the advent of highly active antiretroviral therapy (HAART). 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. Non-drug therapies which have been shown to be effective in cancer induced cachexia include nutritional counselling, psychotherapeutic interventions and physical training. Anabolic-androgenic steroids like oxandrolone 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.
Other drugs that have been used or are being investigated in cachexia therapy, but which lack conclusive evidence of efficacy or safety, include: Thalidomide and cytokine antagonists Omega-3 fatty acids, including eicosapentaenoic acid (EPA) Non-steroidal anti-inflammatory drugs Prokinetics Ghrelin and ghrelin receptor agonist Anabolic catabolic transforming agents such as MT-102 Selective androgen receptor modulators Cyproheptadine Hydrazine
There is insufficient evidence to support the use of oral fish oil for the management of cachexia associated with advanced 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.
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.
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.
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. New studies indicate NSAIDS, like Sulindac, were found to significantly decrease cachexia in mice.
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. 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.
Discussion & tentative Conclusion
Cachexia is often seen in end-stage cancer, and in that context is called cancer cachexia. It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival.
Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state.
Cancer cachexia has been regarded as a non-curable disease, and has been estimated to be responsible for the death of over 20% of cancer patients. The management of cancer cachexia has improved in the past decade, as the mechanisms involved in the development and progression of the condition continue to be elucidated. Currently all conventional treatments for cancer cachexia are considered palliative, but new agents have improved patient survival as well as their quality of life.
Regular anti-neoplastic agents have ability to treat cancer, but in many cases worsen cachexia. Future progress in the field will be realized through development of treatment agents with ability to affect cancer progression as well as improve patient quality of life. This is the strength of the Institute’s HIP protocol.
To learn how Holistic Oncology can be helpful with cachexia, consider scheduling a coaching session
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In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. … 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013).
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Studies suggest dietary protein and leucine or its metabolite b-hydroxy b-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. … These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia.65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84 A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength.44, 65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84 However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB.85 Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion.71, 80 Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease.65, 72, 83, 86, 87 The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation.68 …
Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB.
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There are a number of nutrition products on the market that are touted to improve sports performance. HMB appears to be the most promising and to have clinical applications to improve muscle mass and function. Continued research using this nutraceutical to prevent and/or improve malnutrition in the setting of muscle wasting is warranted.
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