Cachexia is weight loss and deterioration in physical condition.
Cachexia is not starvation; starvation may be part of cachexia and cachexia may result from starvation but they are different. It is associated with various serious illnesses including:
- Many types of cancer (particularly of the pancreas, stomach, oesophagus, colon and rectum).
- Congestive heart failure.
- Rheumatoid arthritis.
- Tuberculosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis.
- Crohn's disease.
It is also seen in the elderly, without any apparent associated disease.
An international collaborative has defined cancer-related cachexia thus:
A multi-factorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be reversed by conventional nutritional support and leads to progressive functional impairment. The pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism.
Suggestions have been made to modify the definition to include factors such as C-reactive protein (CRP) level and appetite loss. A four category model has also been proposed - ie non-cachexic, ore-cachexic, cachexic and refractory.Ongoing research is helping to refine the definition further.
Cancer cachexia impairs quality of life and response to therapy, which increases morbidity and mortality of cancer patients.It is seen in 50% of cancer patients and accounts for at least 20% of deaths.
This is a common complication of chronic heart failure (CHF) which is associated with a poorer prognosis. It is defined as involuntary loss of 5% of body mass in twelve months or less. Myofibrillar proteins are degraded and there is also reduced protein synthesis. Endocrine factors are thought to play a regulatory role.
Adipose tissue cells (adipocytes) have been shown to release enzymes in CHF, which induce skeletal muscle wasting and reduce fat and bone mass.
Cancer cachexia represents the clinical consequence of an interaction between the tumour, the host metabolism and the involvement of pro-inflammatory cytokines (protein molecules which signal cells to produce an inflammatory reaction). The changes seen in cachexia may be characterised by an accelerated loss of skeletal muscle, often accompanied by loss of appetite and altered taste.
Skeletal muscle wasting is the principal cause of function impairment, fatigue and respiratory complications, The mechanisms involved have not been entirely elucidated but it is known that there is an increase in an enzyme, protein kinase R, which leads to muscle atrophy by a process of protein synthesis depression and an increase in degradation.
Adipose tissue loss is due to lipolysis. This is driven by a number of chemical triggers including lipid mobilising factor (LMF). Loss of adipose tissue and skeletal muscle mass is characteristic of cancer cachexia. Starvation on the other hand causes only loss of adipose tissue.
There is also an increase in the synthesis of proteins involved in the response to tissue injury - the so-called 'acute-phase response'.
Pathological changes occur in response to the body's acute-phase response to tissue damage, including synthesis by the liver of large amounts of proteins - eg, CRP, complement factors, fibrinogen and many others.
There are many causes of abnormal weight loss apart from cancer and cardiac failure. See separate Abnormal Weight Loss article for a full list.
Treatment of the underlying condition is important. Treatment of the cachexia per se needs a multi-targeted approach.
Hypercaloric feeding has repeatedly been shown as ineffective in increasing lean mass. It may cause weight gain but this is due to deposition of fat.The metabolic adaptations, notably the increase in the rate of protein catabolism, limit the ability of hypercaloric feeding to reverse the depletion of lean mass.
Parenteral nutritional support improves the way cancer patients withstand treatment and has a place in the palliative care of certain patients - eg, those with intestinal obstruction.
The National Institute for Health and Care Excellence (NICE) recommends oral, enteral or parenteral support (according to need and swallowing ability) for adults when:
- BMI is <18.5 kg/m3.
- There has been >10% of total body weight lost in the preceding 3-6 months.
- BMI is <20 and there has been 5% weight loss in the preceding 3-6 months.
The European Palliative Care Research Collaborative guidelines recommend that the enteral route should be used in certain patient groups (eg, to reverse weight loss). However, in refractory cachexia (patients with advanced cancer in whom a reversal of weight loss seems unlikely), normal eating should be encouraged in order to avoid stress-related eating disorders.
- Insulin: insulin resistance is observed in cachexia. The possibility of utilising the insulin signalling system is currently being explored.
- Growth hormone, testosterone, oxandrolone and megestrol acetate have all been used with beneficial effect and the use of the orexigenic (= appetite-stimulating) peptide ghrelin is being explored.
- Enobosarm (a selected androgen receptor modulator) and anamorelin (a ghrelin agonist) have completed phase III trials.
- Anti-inflammatory agents such as indometacin may be beneficial in patients with high CRP levels. The benefits of anti-inflammatory agents may be more apparent in non-malignant conditions and convey little benefit in patients with refractory cachexia.
- Steroids - eg, methylprednisolone - may be used in refractory cachexia for short periods (eg, two weeks).
- There may be a role for antioxidants in combating oxidative stress.
- Because of metabolic derangements seen in cancer cachexia, effective nutritional treatment regimens will probably require manipulation of host intermediary metabolism in addition to feeding: omega-3 fatty acids (eg, eicosapentaenoic acid) have been studied for their ability to reduce cytokine release but their benefits are not clearly established.
- Vitamin and mineral supplementation may be required in some cases.
Overall, the prognosis for the cachexia depends upon the severity of the underlying disease.
Exercise is being explored as a possible preventative measure against cancer cachexia. Nutritional counselling is also likely to be of benefit.
Further reading and references
Mueller TC, Bachmann J, Prokopchuk O, et al; Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia - can findings from animal models be translated to humans? BMC Cancer. 2016 Feb 816(1):75. doi: 10.1186/s12885-016-2121-8.
Khamoui AV, Kim JS; Candidate mechanisms underlying effects of contractile activity on muscle morphology and energetics in cancer cachexia. Eur J Cancer Care (Engl). 2012 Mar21(2):143-57. doi: 10.1111/j.1365-2354.2011.01287.x. Epub 2011 Aug 31.
Fearon K, Strasser F, Anker SD, et al; Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011 May12(5):489-95. doi: 10.1016/S1470-2045(10)70218-7. Epub 2011 Feb 4.
Blum D, Stene GB, Solheim TS, et al; Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model--a study based on data from an international multicentre project (EPCRC-CSA). Ann Oncol. 2014 Aug25(8):1635-42. doi: 10.1093/annonc/mdu086. Epub 2014 Feb 20.
Martin L; Diagnostic criteria for cancer cachexia: data versus dogma. Curr Opin Clin Nutr Metab Care. 2016 Mar 4.
Penet MF, Winnard PT Jr, Jacobs MA, et al; Understanding cancer-induced cachexia: imaging the flame and its fuel. Curr Opin Support Palliat Care. 2011 Dec5(4):327-33.
Shum AM, Polly P; Cancer cachexia: molecular targets and pathways for diagnosis and drug intervention. Endocr Metab Immune Disord Drug Targets. 2012 Sep 112(3):247-59.
Mangner N, Matsuo Y, Schuler G, et al; Cachexia in chronic heart failure: endocrine determinants and treatment perspectives. Endocrine. 2012 Aug 19.
Loncar G, Fulster S, von Haehling S, et al; Metabolism and the heart: An overview of muscle, fat, and bone metabolism in heart failure. Int J Cardiol. 2011 Oct 6.
Lucia S, Esposito M, Rossi Fanelli F, et al; Cancer Cachexia: From Molecular Mechanisms to Patient's Care. Crit Rev Oncog. 201217(3):315-21.
Tisdale MJ; Cancer cachexia. Curr Opin Gastroenterol. 2010 Mar26(2):146-51.
Donohoe CL, Ryan AM, Reynolds JV; Cancer cachexia: mechanisms and clinical implications. Gastroenterol Res Pract. 20112011:601434. Epub 2011 Jun 13.
Madeddu C, Maccio A, Mantovani G; Multitargeted treatment of cancer cachexia. Crit Rev Oncog. 201217(3):305-14.
Suzuki H, Asakawa A, Amitani H, et al; Cancer cachexia--pathophysiology and management. J Gastroenterol. 2013 May48(5):574-94. doi: 10.1007/s00535-013-0787-0. Epub 2013 Mar 20.
Akbulut G; New perspective for nutritional support of cancer patients: Enteral/parenteral nutrition. Exp Ther Med. 2011 Jul2(4):675-684. Epub 2011 Apr 1.
Nutrition support in adults: oral nutrition support, enteral tube feeding and parenteral nutrition; NICE Clinical Guideline (2006)
Clinical practice guidelines on cancer cachexia in advanced cancer patients; European Palliative Care Research Collaborative, 2011 (Link to downloadable pdf file)
Aoyagi T, Terracina KP, Raza A, et al; Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol. 2015 Apr 157(4):17-29. doi: 10.4251/wjgo.v7.i4.17.
Honors MA, Kinzig KP; The role of insulin resistance in the development of muscle wasting during cancer cachexia. J Cachexia Sarcopenia Muscle. 2012 Mar3(1):5-11. Epub 2011 Dec 1.
Gullett NP, Hebbar G, Ziegler TR; Update on clinical trials of growth factors and anabolic steroids in cachexia and wasting. Am J Clin Nutr. 2010 Apr91(4):1143S-1147S. Epub 2010 Feb 17.
Crawford J; Clinical results in cachexia therapeutics. Curr Opin Clin Nutr Metab Care. 2016 Mar 11.
Argiles JM, Busquets S, Lopez-Soriano FJ, et al; Are there any benefits of exercise training in cancer cachexia? J Cachexia Sarcopenia Muscle. 2012 Jun3(2):73-6. Epub 2012 May 8.
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