Cachexia

“ ... the shoulders, clavicles, chest and thighs melt away .... This illness is fatal"

- Hippocrates, 460-370 BC

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The term "cachexia" is derived from the Greek kakos and hexis, meaning ‘bad condition’. It is a syndrome characterised by a loss of body weight and muscle tissue, which occurs in absence of starvation and is not associated with an adaptive decrease in catabolism. Question 2 from the second paper of 2011 asked about the definitions, causes and consequences of cachexia for the critically ill patient. There has never been a widely agreed-upon definition of cachexia (this article told me so). There was a Cachexia Consensus Conference in 2008 during which a new definition was proposed. This definition included only “cachexia proper”, excluding causes such as malnutrition (starvation), malabsorption, and hyperthyroidism. The experts were keen to make the distinction between this weird metabolic syndrome which occurs often in the presence of optimal nutrition, and all other forms of weight loss.

Definition of cachexia

"Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass "

- Evans et al, 2008

  • A specific definition is proposed:
    • Loss of body weight (or failure to gain weight in children).
    • Loss of muscle tissue with or without  the loss of fat tissue.
    • May or may not be associated with decreased nutrient intake (may occur in the presence of nutritional plenty)
    • When associated with decreased nutrient intake, it is not associated with an adaptive decrease in protein catabolism.
  • Exclusions and caveats to this definition:
    • Weight loss is to be corrected for fluid gain in critically ill adults.
    • Endocrine disorders must be excluded in children failing to gain weight.
  • Characteristic features
    • Weight loss
    • Anorexia
    • Inflammation
    • Insulin resistance
    • Increased muscle protein breakdown

In the abovelinked article, Evans et al confess that the definition is not well tested in epidemiological studies; rather the definition is offered as a means of driving such studies.

Classical cachexia syndromes

This disease entity is encountered in several clinical settings. These are listed below alongside a link to a recent article discussing them in greater detail. In general, these syndromes tend to exhibit the cardinal features of cachexia: they are all cytokine-driven wasting diseases which cannot be cured by increasing the dietary intake.

Cachexia-like wasting diseases

These are "fake" cachexia syndromes, which resemble cachexia only insofar as they produce extreme muscle wasting or weight loss, and result in the appearance of severe malnutrition. Clinically, these may be indistinguishable from the "proper" cachexia and their effect on survival in intensive care is likely to be similar. The main distinction is that most of the below-listed disease entities have a convenient cure, which can reverse all of their adverse features. Cachexia "proper" is associated with a greater morbidity partly because there is no readily available solution to it.

The list:

  • Starvation
  • Malabsorption, eg. coeliac disease
  • Hyperthyroidism
  • Age-related loss of muscle mass
  • Primary depression
  • Anorexia nervosa
  • Drug-induced anorexia (eg. amphetamines)
  • Chronic immobility, eg. of stroke or paralysis

Causes and mechanisms of cachexia

The only sane thing that can be said here is "unclear mechanism; possible combination of multiple factors". A lucid article from 2006 (Morley et al)  is the main source for the summarised information below.

Pathologically decreased muscle protein synthesis

The influence of inflammatory cytokines is probably central.

  • Proinflammatory cytokines are responsible for this
  • Specific cytokines implicated include TNF-α, IFN-γ, IL-1 and IL-2.
  • These cytokines activate nuclear transcription factor kappa-B (NF-κB)
  • NF-κB is a major regulator of protein synthesis (among other things); under the influence of proinflammatory cytokines it acts to decrease the rate of muscle protein synthesis
  • TNF-α and IFN-γ act synergistically to inhibit myosin heavy chain synthesis
  • Why would the human organism have such counterproductive mechanisms? The evolutionary advantage of decreased protein synthesis during infective illness is theoretically the diversion of nutritional resources to immune cell function. IFN-γ also acts to decrease protein synthesis globally, thereby decreasing the replication of viruses.

Testosterone deficiency (and thus leptin excess) contributes significantly.

  • Testosterone stimulates myoblasts and increases satellite cells, promoting the repair of damaged muscle.
  • It also dampens the synthesis of cytokines by macrophages
  • Low testosterone concentrations are associated with elevated circulating leptin levels
  • Leptin is an anorectic and lipolytic hormone produced by adipocytes
  • A decrease in testosterone levels (and increase in leptin) is observed in cachectic patients (Engineer et al, 2012)
  • Leptin increase is probably responsible for the anorexia and weight loss in hypogonadal men.
  • Leptin excess may be responsible for the observation that in cachexia there is a failure of normal regulatory mechanisms which compensate for decreased nutrient intake (i.e. there is a failure to slow protein catabolism, decrease energy expenditure and increase appetite).

Other hormonal contributors to poor muscle protein synthesis

  • Myostatin: a paracrine hormone produced in muscle which regulates its growth. Myostatin gene-deletion models in mice produce grotesquely over-muscled mice (Morrisette et al, 2009)
  • Insulin-like growth factor 1 (IGF-1) increases protein synthesis, and is seen to be deficient in cachectic individuals.
  • Glucocorticoids inhibit protein synthesis by inhibiting cellular amino acid transporters

Pathologically increased protein breakdown

  • Decreased circulating anabolic hormones (eg. androgens, insulin)
  • Increased circulating catabolic cytokines and hormones (eg. cortisol and catecholamines)
  • Thus, there is not only decreased protein synthesis but also increased protein catabolism
  • Passive mobilisation of stored nutrients due to decreased insulin activity
  • Increased ubiquitin ligase activity in muscle, specifically resulting in accelerated muscle loss.
  • One specific stimulus for ubiquitin-proteasome system activation is cortisol, which is generated in excess during critical illness, and which is supplemented liberally by intensivists.

Disorganised management of nutrient resources

  • Apart from their influence on the synthesis of proteins, cytokines also influence fat reserves by increasing the rate of lipolysis and β-oxidation.
  • Decreased lipoprotein lipase activity leads to decreased hepatic fat storage and hyperlipidaemia.
  • Cytokines also influence the central nervous system, producing anorexia, malaise and anhedonia. The upshot of this is decreased nutrient intake.

Pathologically increased nutrient demand by tissues:

  • Aggressively multiplying malignant tissue
  • Increased workload in pathological states, eg. respiratory effort in COPD
  • Paraneoplastic endocrine-mediated change of fatty tissue from white to brown, which is associated with increased thermogenesis (Kir et al, 2014)

Pathologically decreased nutrient supply to tissues:

  • Chronically decreased cardiac output in cardiac cachexia
  • Chronic hypoxia in respiratory failure

Factors which exacerbate cachexia

  • Malnutrition
  • Malabsorption
  • Hyperthyroidism
  • Immobility
  • Corticosteroid use
  • Catecholamine excess

Consequences of cachexia in the critically ill

These are very similar to the consequences of malnutrition in the critically ill patient, which are discussed in greater detail in a dedicated chapter. In brief:

  • Poor wound healing
  • Impaired immune function and increased risk of sepsis
  • Muscle wasting due to protein catabolism:
    • Decreased ventilatory drive
    • Weakness complicating separation from the ventilator
    • Weakness complicating physiotherapy and mobilisation
      • Exposure to the complications of immobility, eg. DVT
  • Cardiomyopathy as a consequence of atrophy
  • Mucosal atropthy and diminished barrier function of the gut
  • Apathy and depression
  • Increased duration of ICU stay
  • Increased in-hospital mortality

References

Anker SD, Coats AJ. Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation. Chest. 1999 Mar;115(3):836-47.

Steinborn W, Anker S.D., Cardiac Cachexia: Pathophysiology and Clinical Implications. Basic Appl Myol 13 (4): 191-201, 2003

The experts report that at least in cardiac failure cachexia is a strong independent risk factor for mortality.

Fearon, Kenneth. "Cachexia: Treat wasting illness on multiple fronts." Nature 529.7585 (2016): 156-156.

Kir, Serkan, et al. "Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia." Nature 513.7516 (2014): 100-104.

Laviano, Alessandro, Angela Koverech, and Alessia Mari. "Cachexia: clinical features when inflammation drives malnutrition." Proceedings of the Nutrition Society 74.04 (2015): 348-354.

Loncar, Goran, et al. "Cardiac cachexia: hic et nunc:“hic et nunc”—here and now." International journal of cardiology 201 (2015): e1-e12.

Wagner, P. D. "Possible mechanisms underlying the development of cachexia in COPD." European Respiratory Journal 31.3 (2008): 492-501.

Morley, John E., David R. Thomas, and Margaret-Mary G. Wilson. "Cachexia: pathophysiology and clinical relevance." The American journal of clinical nutrition 83.4 (2006): 735-743.

Engineer, Diana R., and Jose M. Garcia. "Leptin in anorexia and cachexia syndrome." International journal of peptides 2012 (2012).

Morissette, Michael R., et al. "Effects of myostatin deletion in aging mice." Aging cell 8.5 (2009): 573-583.

Baronzio, G., et al. "Proinflammatory and regulatory cytokine levels in AIDS cachexia." In vivo (Athens, Greece) 13.6 (1998): 499-502.

Fouque, D., et al. "A proposed nomenclature and diagnostic criteria for protein–energy wasting in acute and chronic kidney disease." Kidney international 73.4 (2008): 391-398.

Roubenoff, Ronenn, et al. "Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation." Journal of Clinical Investigation 93.6 (1994): 2379.

Coletti, Dario, Laura Belli, and Sergio Adamo. "Cachexia: novel perspectives for an old syndrome." Basic Appl Myol 16.5&6 (2006): 131-139.