Cachexia

What is cachexia?

Cachexia is not starvation; starvation may be part of cachexia and cachexia may result from starvation but they are different. It is associated with the advanced stages of various serious illnesses including² :

• Many types of cancer (particularly pancreatic cancer, stomach cancer, oesophageal cancer, colorectal cancer).

• HIV/AIDS.

• Congestive heart failure.

• Rheumatoid arthritis.

• Tuberculosis.

• Chronic obstructive pulmonary disease (COPD).

• Cystic fibrosis.

• Crohn's disease.

• Chronic kidney disease (CKD).

Cachexia is also seen in the elderly, without any apparent associated disease.

The prevalence of cachexia varies depending on the diagnostic criteria used: 5-15% in cardiac disease, 5-15% in COPD, 15-32% in rheumatoid arthritis, 50-75% in CKD, and between 60% and 80% in cancer patients. The prevalence exceeds 80% in the last 1-2 weeks of life² .

Cancer cachexia^{3 4}

Cancer cachexia is characterised by the loss of lean body mass with or without the loss of fat and is associated with reduced effectiveness of anti-cancer treatments, increased susceptibility to treatment-related toxicities, decreased quality of life, functional impairment, and increased cancer-related mortality.

Uncontrolled symptoms which impair nutritional intake, and metabolic derangements (including elevated energy expenditure and increased catabolism), and chronic inflammation, contribute to the development of cancer cachexia. Weight loss in cancer patients is not readily reversible by conventional nutritional support.

Cardiac cachexia

This is a common complication of chronic heart failure (CHF) which is associated with a poorer prognosis. Cardiac cachexia 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 role⁵ .

Adipose tissue cells (adipocytes) have been shown to release enzymes in CHF, which induce skeletal muscle wasting and reduce fat and bone mass⁶ .

Pathogenesis

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)⁷ . 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 degradation⁸ .

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 tissue⁹ .

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.

Differential diagnosis

There are many causes of abnormal weight loss apart from cancer and cardiac failure. See the separate Abnormal Weight Loss article for a full list.

Cachexia treatment and management

Apart from maintaining optimal management of the underlying condition, there are currently no standardised treatments for cachexia or severe wasting. However there is a growing consensus advocating multimodal interventions to alleviate and/or stabilise cachexia and severe wasting. The different treatment modalities include pharmacological and non-pharmacological interventions, such as exercise and nutrition² .

General measures

Hypercaloric feeding has repeatedly been shown as ineffective in increasing lean mass. It may cause weight gain but this is due to deposition of fat¹⁰ . 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 obstruction¹¹ .

The National Institute for Health and Care Excellence (NICE) recommends oral, enteral or parenteral support (according to need and swallowing ability) for adults when¹² :

• 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.

See also the separate Enteral Feeding and Enteral Nutrition and Nutritional Support in Primary Care articles.

Pharmacological measures¹³

• Insulin: insulin resistance is observed in cachexia. The possibility of utilising the insulin signalling system is currently being explored¹⁴ .

• 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 explored¹⁵ .

• Enobosarm (a selected androgen receptor modulator) and anamorelin (a ghrelin agonist) have completed phase III trials¹⁶ . However, in 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion regarding anamorelin, recommending the refusal of the marketing authorisation for the intended use of treatment of anorexia, cachexia or unintended weight loss in patients with non-small cell lung cancer¹⁷ .

• 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.

Prognosis

Overall, the prognosis for the cachexia depends upon the severity of the underlying disease. However cachexia is often a complication with a very poor prognosis, and often represents the last step of several chronic diseases¹⁸ .

Prevention

Exercise is a possible preventative measure against cancer cachexia¹⁹ . Nutritional counselling is also likely to be of benefit.