Cachexia: More Than Weight Loss

A person suffering from a severe sickness may often be depicted as someone frail, weak, and malnourished. People may lack appetite, have gastrointestinal symptoms (like vomiting and diarrhoea), and disengage from physical activity when they are sick, leading to weight loss and muscle weakness. Hence, body composition is greatly affected by disease mechanisms and may be completely altered throughout the illness. Although poor nutritional intake is highlighted as a cause of why a person living with a disease may be experiencing dramatic weight loss, modifications of a person’s metabolism and systemic inflammation can be just as, or even more, important contributors (Baker Rogers et al., 2023).

Cachexia is a complex condition with a multimodal pathophysiology. It is a syndrome characterised by potent weight loss, fatigue, and malaise. The body of a person who suffers from cachexia changes, with the result being a decrease in muscle mass and a rapid breakdown of fat tissue (Ohnuma, 2003). Once believed to be products of inadequate nutrition, the symptoms of cachexia are now attributed to a general inflammatory state in the body, the upregulation of mediators that promote the breakdown of compounds (catabolism), and the reduction of mediators that allow growth (anabolism).

Figure 1: Cachexia-induced weight loss (Pepersack, 2011).

Cachexia is most closely associated with cancer but can also emerge in those who have developed acquired immunodeficiency syndrome (AIDS) and those living with chronic, non-communicable conditions, like kidney and heart failure. There are three stages of cachexia: pre-cachexia, cachexia, and refractory cachexia. Clinicians aim to recognise the syndrome in its earliest stage to improve a patient’s prognosis (McGovern et al., 2022). Yet, the condition may often be missed as the diagnostic criteria conventionally only focus on a person’s weight loss (with a 5% decrease in body weight being indicative of cachexia), and not the metabolic and inflammatory signs and symptoms (Baker Rogers et al., 2023).

Therefore, this article will explore cancer cachexia by delving into its intricate pathophysiology and describing the inflammatory and metabolic changes that occur. It will then discuss the common misconceptions and challenges associated with cachexia diagnosis and treatment and give insight into future developments.

Figure 2: Symptoms of cachexia (Eldridge, 2023).

Cachexia and Cancer

Cachexia is estimated to afflict 30% of people who have cancer, making it a prevalent secondary complication of the disease (Law, 2022). In a study conducted in France, involving 1030 elderly cancer patients, the majority had co-existing cachexia (Poisson et al., 2021). This syndrome can have a detrimental impact on individuals who are already battling cancer. Organ health can decline in response to skeletal muscle wasting, as the muscles needed for breathing and cardiac muscles become too weak to sustain vital functions. Cachexia can also weaken a cancer patient to the point where they can no longer engage with their cancer treatment, allowing the cancer to progress more freely. Strikingly, in 20% of cancer patients, cachexia is reported to be the direct cause of death (Porporato, 2016). ‌

Immune System

One of the hallmarks of cancer is systemic inflammation that aids the growth of the tumour. Cancer patients may present with high levels of cytokines (which are chemicals that mediate inflammation) and C reactive protein (CRP) on a blood test (Hanahan, 2022). Cancer is a disease that can take time to become noticeable, therefore inflammation can become chronic. The release of inflammatory mediators by tumour cells may cause alterations to a person’s immune system and metabolism. As a result, their body can become self-destructive, favouring the lysis of fat and muscle tissue, and ignorant to signals that promote hunger (Setiawan et al., 2023).

Figure 3: Pathophysiology of cachexia (Setiawan et al., 2023).

Tumour necrosis factor alpha (TNFa) is a key regulator of inflammation. It acts as a pro-inflammatory cytokine by activating immune cells called macrophages and by inducing cell death. TNFa has also been associated with cachexia-specific pathways. For example, TNFa can alter hormonal signalling in the brain by causing the increased secretion of corticotrophin-releasing hormone (CRH). CRH is secreted from the hypothalamus in the brain and has an anorexigenic effect. In other words, when present in high concentrations, the hormone has been linked with suppressed appetite (Patel & Patel, 2017; Yoo et al., 2021). Additionally, TNFa can promote the nuclear factor kappa B (NF-kB) pathway. NF-kB can initiate catabolism in various cells, especially in skeletal muscle cells (Patel & Patel, 2017). In turn, this can lead to the degradation of skeletal muscle fibres, which manifests as muscle wasting in patients affected by cachexia. The levels of several interleukins, like IL-1 and IL-6, are also found to be high in cancer patients. These cytokines drive the inflammatory response but have also been connected to the progression of cachexia (Porporato, 2016).

Metabolism

Cachexia can also be referred to as a metabolic syndrome. Metabolic syndrome is used to categorise multiple disorders that impact a person’s metabolism and predispose them to an increased risk of cardiovascular disease. High blood pressure, obesity, abnormal lipid levels and resistance to the blood sugar-lowering hormone, insulin, are the characteristic signs of metabolic syndrome (Rochlani et al., 2017). Yet, cachexia is a condition that modifies metabolism. It is acknowledged that cancer patients with cachexia have a higher energy expenditure compared to their energy intake. This means that catabolism becomes dominant compared to anabolism. The increased energy expenditure is associated with a tumour’s ability to redirect resources to sustain itself. One mechanism that the tumour is dependent on is the production of the waste product lactate, which starts up an energetically inefficient cycle that produces new glucose molecules for the tumour to use as fuel (Law, 2022).

Figure 4: Disrupted energy balance in cachexia patients (Law, 2022).

The overproduction of glucose, driven by the tumour, causes the upregulation of insulin. Insulin is a hormone that lowers blood glucose levels by diverting glucose to be stored in fat and muscle tissue or to form glycogen. Patients with type II diabetes experience a similar disruption in metabolism as they also overproduce insulin to address their hyperglycaemia (high blood sugar) (Fonseca et al., 2020). However, a chronically high level of insulin can disrupt the adequacy of certain signalling pathways, making insulin ineffective as a signalling hormone. Consequently, the production of new glucose molecules is not terminated efficiently, which leads to the continuous breakdown of fat and proteins in muscle. In part due to this alteration in glucose metabolism, cancer patients may develop cachexia (Masi & Patel, 2020).

Furthermore, cachexia affects the fat composition in a person’s body. Inflammatory mediators, like IL-6 and NF-kB, seem to cause a shift from white adipose tissue to brown adipose tissue, which is fat that is known to produce high amounts of heat energy (Fonseca et al., 2020). As a higher percentage of brown fat tissue in the body stimulates weight loss and the lowering of white fat content, the browning of fat is a potentially significant mechanism in the cause of cachexia. Naturally, brown adipose tissue is most abundant in infants but is also re-established as people age (Saito, 2013). This may be one of the factors that makes the elderly population, who also have cancer, more vulnerable to cachexia (Ali & Garcia, 2014).

Figure 5: Adipose tissue browning (Petruzzelli et al., 2014).

Common Misconceptions

"Cachexia is the same as anorexia"

Anorexia nervosa is a psychiatric disorder where an individual limits their energy intake, mostly due to reasons associated with how they perceive themselves and their weight (Frank et al., 2019). Cachexia is a metabolic disorder that primarily modifies energy expenditure. Although anorexia is a common symptom of cachexia in cancer patients, severe weight loss occurs due to the combined action of poor food intake and high energy expenditure (Baker Rogers et al., 2023). Aversion to eating in cancer patients can be a product of other symptoms, like gastrointestinal symptoms and changes in taste perception. Cancer treatment, such as chemotherapy, may also induce a lack of appetite. As mentioned previously, systemic inflammation can stimulate the release of different hormones from the brain. The tumour releases high amounts of inflammatory cytokines that inhibit orexigenic neurones (appetite-stimulating) in the hypothalamus and activate anorexigenic neurones (appetite-suppressing) (Yeom & Yu, 2022).

Ghrelin is an important hormone released in the stomach that acts to improve appetite and cause a person to feel hungry. It is thought that in patients with cachexia, ghrelin is over-produced to compensate for the muscle and fat wasting and the reduced nutritional intake. Over time, similarly to what happens in people with hyperinsulinemia, ghrelin becomes ineffective as the body becomes desensitised to its actions. Although there isn’t enough research to support this pathway, resistance to ghrelin may be a molecular mechanism for inducing anorexia in cachexia patients (Setiawan et al., 2023).

Figure 6: Anorexia (Marks, 2023).

"Cachexia is cured by increasing nutritional intake"

Patients with cachexia often present with poor appetite, which limits their food intake drastically. Despite nutritional support being a common management strategy for cachexia, supplementing nutrients is not sufficient to completely treat it. Cachexia increases energy expenditure and reduces energy intake in an affected person, so both components need to be tackled to treat the condition effectively (Gaafer & Zimmers, 2021).

Yet, certain nutrient supplementation can be particularly effective in reversing muscle wasting in patients suffering from cancer cachexia. Experimental studies conducted on murine and rat models have found that the building blocks of proteins known as amino acids, in particular leucine, glutamine, and glycine, have shown anti-inflammatory and regenerative effects when supplemented. Amino acids are required for protein synthesis, a step that is imperative for the formation of skeletal muscle. Hence, it may prove to be effective for dieticians to monitor the levels of amino acids in cancer patients who are at risk of developing cachexia to begin nutritional interventions early in the disease pathogenesis (van de Worp et al., 2020). However, more research is still needed to ascertain the true efficacy of supplementing specific nutrients in the treatment of cancer cachexia in humans. Nevertheless, nutrition experts play a vital role in creating management plans for patients who suffer from anorexia along with cachexia. Therefore, energy intake should be part of the multidisciplinary approach taken to treat cachexia (Gaafer & Zimmers, 2021).

Figure 7: Nutritional support for cachexia (Vollmering, 2021).

"Cachexia only affects skeletal muscles"

Muscle wasting is a debilitating consequence of cachexia. Not only does the patient undergo significant weight loss, but they also face extreme fatigue and dangerous complications when muscles that are needed for vital functions, such as breathing, become too weak. Skeletal muscles are voluntary muscles, meaning the contractions and relaxations are consciously controlled by the person. Cachexia primarily causes the deterioration of skeletal muscles, but it can also have destructive effects on other muscles. Cardiac muscles are structurally similar to skeletal muscles but can function without a voluntary stimulus. The effects of inflammatory cytokines and the upregulation of catabolic mechanisms can also cause cardiac muscle wasting (Rausch et al., 2021). The loss of cardiac mass is detrimental as the heart starts to pump blood less effectively, often leading to heart failure (which can be fatal) (Saha et al., 2022).

In addition, it is suggested that smooth muscles can also be affected by cachexia. Unlike skeletal muscles, smooth muscles function without a person needing to think about it. This musculature makes up a large proportion of the gastrointestinal tract. In a study involving 57 patients with pancreatic cancer, it was found that those who also had co-existing cachexia showed to have abnormal smooth muscles in their small intestines. Cachectic cancer patients had smooth muscles that were thicker, due to increased collagen deposition, and showed abnormal protein expression when compared to non-cachectic patients with pancreatic cancer. The findings of researchers Vaes and colleagues imply that systemic inflammation that is implicit in the pathogenesis of cachexia may cause aberrations in the smooth musculature of patients. These alterations in the smooth muscles, caused by cachexia, can be potential causes for gastrointestinal symptoms that many cancer patients present with. Therefore, cachexia is still a largely unexplored condition, and more research is required to understand how it can be effectively managed in cancer patients (Vaes et al., 2021).

Figure 8: Muscular changes in cachexia (Rausch et al., 2021).

Conclusion

Cachexia is a complicated condition that is characterised by changes in the immune system and a person’s metabolism that cause significant weight loss. It is a common manifestation in cancer patients who are already in a vulnerable health state, often being a sign of poor prognosis. Cachexia should not be confused with anorexia as increased energy expenditure is a significant aspect of why an affected person suffers from weight loss. Due to this, cachexia requires a multifactorial treatment plan, as solely increasing food intake will not manage the condition. Finally, a considerable amount of research is still needed to understand the pathophysiology of cachexia because apart from affecting skeletal muscles and adipose tissue, it may also be involved in causing cardiac and smooth muscle abnormalities.

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