Cachexia

Cachexia diseases
Classification and external resources
Specialty Oncology, psychiatry
ICD-10 R64
ICD-9-CM 799.4
DiseasesDB 28890
Patient UK Cachexia
MeSH D002100

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 decrease of body mass, less fatty tissue accumulation 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,[1] coeliac disease,[2] chronic obstructive pulmonary disease, multiple sclerosis, Rheumatoid arthritis, 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 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.[3][4] 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.[5] 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.[6]

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.[7] 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.[8]

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.[9]

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.[10]

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:

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.[9]

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.[12] 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 hypercatabolic disease states such as cachexia;[13][14][15] 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.[13][14] Progestins such as megestrol acetate are a treatment option in refractory cachexia with anorexia as a major symptom.[16][17]

Cachexia occurs less frequently now in HIV/AIDS than in the past due to the advent of highly active antiretroviral therapy (HAART).[18] 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.[16] Non-drug therapies which have been shown to be effective in cancer induced cachexia include nutritional counselling, psychotherapeutic interventions, and physical training.[16] Anabolic-androgenic steroids like oxandrolone[19][20] 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.[16]

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:

Medical marijuana has been allowed for the treatment of cachexia in some US states, such as Illinois, Maryland, Delaware, Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, Arizona, Vermont, New Jersey, Rhode Island, Maine, and New York [22][23] Hawaii[24] and Connecticut.[17][25]

There is insufficient evidence to support the use of oral fish oil for the management of cachexia associated with advanced cancer.[26][27]

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.[9]

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.[28]

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.[28]

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.[28]

New studies indicate NSAIDS, like Sulindac, were found to significantly decrease cachexia.[29]

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[30] or HIV/AIDS.[31]

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.[32] 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.[33]

See also

References

  1. ↑ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1169. ISBN 1-4160-2999-0.
  2. ↑ Meresse, B; Ripoche, J; Heyman, M; Cerf-Bensussan, N (October 2008). "Celiac disease: from oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis". Mucosal Immunology. 2: 8–23. doi:10.1038/mi.2008.75. PMID 19079330. Retrieved 2016-03-30.
  3. ↑ Lainscak M, Podbregar M, Anker SD (December 2007). "How does cachexia influence survival in cancer, heart failure and other chronic diseases?". Current Opinion in Supportive and Palliative Care. 1 (4): 299–305. doi:10.1097/SPC.0b013e3282f31667. PMID 18685379.
  4. ↑ Bossola M, Pacelli F, Doglietto GB (August 2007). "Novel treatments for cancer cachexia". Expert Opin Investig Drugs. 16 (8): 1241–53. doi:10.1517/13543784.16.8.1241. PMID 17685872.
  5. 1 2 3 4 Ebner, Nicole; Springer, Jochen; Kalantar-Zadeh, Kamyar; Lainscak, Mitja; Doehner, Wolfram; Anker, Stefan D.; von Haehling, Stephan (July 2013). "Mechanism and novel therapeutic approaches to wasting in chronic disease". Maturitas. 75 (3): 199–206. doi:10.1016/j.maturitas.2013.03.014.
  6. ↑ Payne, C; Wiffen, PJ; Martin, S (Jan 18, 2012). "Interventions for fatigue and weight loss in adults with advanced progressive illness.". The Cochrane database of systematic reviews. 1: CD008427. doi:10.1002/14651858.cd008427.pub2. PMID 22258985.
  7. ↑ K.C.H. Fearon; et al. (Sep 2002). "Cancer cachexia". Int J Cardiol. 85 (1): 73–81. doi:10.1016/S0167-5273(02)00235-8. PMID 12163211.
  8. ↑ O. Alhamarneh; et al. (July 2010). "Serum IL10 and circulating CD4+CD25high regulatory T cell numbers as predictors of clinical outcome and survival in patients with head and neck squamous cell carcinoma". Head Neck. 33 (3): n/a. doi:10.1002/hed.21464.
  9. 1 2 3 N.B. Kumar; et al. (December 2010). "Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment". Curr Treat Options Oncol. 11 (3): 107–117. doi:10.1007/s11864-010-0127-z.
  10. ↑ Garcia J.M.; Garcia-Touza M.; Hijazi R.A.; Taffet G.; Epner D.; Mann D.; Smith R.G.; Cunningham G.R.; Marcelli M. (May 2005). "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia". J. Clin. Endocrinol. Metab. 90 (5): 2920–6. doi:10.1210/jc.2004-1788. PMID 15713718.
  11. ↑ M.E. Martignoni; et al. (Nov 2003). "Cancer Cachexia". Mol Cancer. 2 (1): 36. doi:10.1186/1476-4598-2-36.
  12. ↑ DHHS, 2009. "Care Management Guidelines Fatigue, Anorexia and Cachexia" (PDF). Retrieved 23 February 2014.
  13. 1 2 Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Mol. Aspects Med. doi:10.1016/j.mam.2016.04.006. PMID 27106402. 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).
  14. 1 2 Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (June 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". J. Am. Med. Dir. Assoc. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. 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.
  15. ↑ Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutr. Clin. Pract. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486. 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.
  16. 1 2 3 4 5 6 7 8 9 European Palliative Care Research Collaborative. "New European Guidelines: CLINICAL PRACTICE GUIDELINES ON CANCER CACHEXIA IN ADVANCED CANCER PATIENTS". Retrieved 23 February 2014.
  17. 1 2 Gagnon B, Bruera E (May 1998). "A review of the drug treatment of cachexia associated with cancer". Drugs. 55 (5): 675–88. doi:10.2165/00003495-199855050-00005. PMID 9585863.
  18. ↑ "AIDS Wasting Syndrome".
  19. ↑ Marcia Nelms; Kathryn P. Sucher; Karen Lacey; Sara Long Roth (16 June 2010). Nutrition Therapy and Pathophysiology. Cengage Learning. pp. 766–. ISBN 1-133-00809-7.
  20. ↑ Giovanni Mantovani (6 October 2007). Cachexia and Wasting: A Modern Approach. Springer Science & Business Media. pp. 673–. ISBN 978-88-470-0552-5.
  21. 1 2 Suzuki, H; Asakawa, A; Amitani, H; Nakamura, N; Inui, A (May 2013). "Cancer cachexia--pathophysiology and management.". Journal of gastroenterology. 48 (5): 574–94. doi:10.1007/s00535-013-0787-0. PMC 3698426Freely accessible. PMID 23512346.
  22. ↑ "About the Medical Marijuana Program".
  23. ↑ Rules Governing the Maine Medical Use of Marijuana Program - 10-144 CMR Chapter 122 - Section 3.1.3
  24. ↑ "Medical Marijuana Registry Program | Eligible Debilitating Medical Conditions". health.hawaii.gov. Retrieved 2016-04-27.
  25. ↑ Yavuzsen T.; Davis M.P.; Walsh D.; LeGrand S.; Lagman R. (November 2005). "Systematic review of the treatment of cancer-associated anorexia and weight loss". J. Clin. Oncol. 23 (33): 8500–11. doi:10.1200/JCO.2005.01.8010. PMID 16293879.
  26. ↑ Dewey, A; Baughan, C; Dean, T; Higgins, B; Johnson, I (Jan 24, 2007). "Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia.". The Cochrane database of systematic reviews (1): CD004597. doi:10.1002/14651858.CD004597.pub2. PMID 17253515.
  27. ↑ Ries, A; Trottenberg, P; Elsner, F; Stiel, S; Haugen, D; Kaasa, S; Radbruch, L (Jun 2012). "A systematic review on the role of fish oil for the treatment of cachexia in advanced cancer: an EPCRC cachexia guidelines project.". Palliative medicine. 26 (4): 294–304. doi:10.1177/0269216311418709. PMID 21865295.
  28. 1 2 3 J.M. Argilés; et al. (Sep 2011). "Anti-inflammatory therapies in cancer cachexia". Eur J Pharmacol. 668: S81–6. doi:10.1016/j.ejphar.2011.07.007. PMID 21835173.
  29. ↑ "Brown fat found to be at the root of cancer-related wasting syndrome".
  30. ↑ May, PE; Barber, A; D'Olimpio, JT; Hourihane, A; Abumrad, NN (April 2002). "Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine.". American journal of surgery. 183 (4): 471–9. doi:10.1016/s0002-9610(02)00823-1. PMID 11975938.
  31. ↑ "Glutamine". WebMD. WebMD, LLC. Retrieved 2015-03-15.
  32. ↑ "HCUP-US NIS Overview".
  33. ↑ "Redirect - NAMCS/NHAMCS - Homepage".

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