Cachexia: Sparse Study Conditions

1. February 2016
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Once under way, there is barely any way back. In the case of cancer but also many other chronic diseases, the body breaks down muscle and fat. Our understanding of the molecular processes is just as limited as the treatment options available.

The iPhone, the iPad, and Macintosh – the genius behind Apple’s success was Steve Jobs. But anyone who remembers his last years as the head of his company, will recall his gaunt face and haggard body that seemed to be literally being eaten away by cancer.

The tumour defeated and the patient dead

For many tumours, however, the division of roles seems to be reversed. Cachexia often affects metabolism and appearance before the cancer has even been diagnosed. The progressive degradation of skeletal muscle – and in many cases also fatty deposits – is more to blame for the death of a patient than the tumour itself, a situation that occurs in at least one quarter of all cases.

It is now well known that the physical decay cannot be stopped in the late stages, although it may be reversible in the early stages. However, hospitals and nursing homes are rather bad at responding appropriately. Doctors and nurses use their entire repertory of pharmacological options to fight against the tumour or chronic disease in question, which is accompanied by increasing frailty. This is often successful – the cancer stops spreading, or the heart and lungs recover. However, cachexia often continues. Apart from high-calorie food and hormone supplements, the arsenal of treatment options is rather limited. This is partly because there is still relatively little known about the causes and processes at the molecular level.

A waning appetite but the same nutritional needs

Until recently, experts could not even agree on an accurate description of cachexia as a condition. According to a recent definition, cachexia manifests itself as a weight loss of over five percent within six months. Alternatively, a BMI of under 20 or sarcopenia with a weight loss of more than two percent are signs of a growing weakness and can no longer be compensated for by a normal diet.

Blood parameters and a series of standardised questionnaires also indicate that the body’s supply of necessary nutrients is insufficient. The most common of these is the NRS-2002 (Nutritional Risk Score). Higher creatinine levels are seen in the urine. Inflammatory parameters can also provide an indication of the muscle-wasting process; interleukin-1, -6, and -8 as well as TNF∝ and the transcription factor NFkB are markers for this. In addition to disease-related changes in metabolism, problems with swallowing, heartburn, dry mouth, or pain when eating also lead to malnutrition. Although energy demand decreases with increasing age, the nutritional requirements remain the same. The increasing loss of appetite leads to a cycle of malnutrition. Those who were previously overweight will not notice the consequences of a shortage of nutrients until later on.

Mortality increases dramatically

The consequences of such malnutrition are dramatic. Although physical capacity is reduced, mental capacity may remain unaffected. A 2010 publication compared the mortality rate in malnourished cancer patients with those of normal weight. After six months, the mortality of patients with cachexia was approx. 50% higher than that of the control group. In the case of patients with chronic cardiac insufficiency, the mortality rate was even higher. After two years, the mortality rate of cachectic subjects was twice that of those without muscle loss. Although a high body mass index is generally rather counter-productive for health, it delayed death in these cases.

Pancreatic cancer frequently accompanied by muscle breakdown and increasing frailty. Four out of ten patients from whom the primary tumour has been surgically removed are malnourished. Anyone undergoing surgery requires a long time to recover from the metabolic imbalance. It often takes up to 18 months [Paywall] until the weight has been regained. The same is true in the case of pancreatitis.

Unintentional weight loss in hospital

In internal medicine and surgical wards, 30–80 per cent of patients lose weight during their stay. A 2006 Study by Matthias Pirlich of German hospitals revealed that approx. 18 percent of those treated suffered from moderate malnutrition, while nearly ten percent suffered from severe malnutrition. Compared with other European countries, however, Germany is below the average. The situation in nursing homes does not look much different: A study over five years in 13 countries revealed that 18 percent of all residents had a BMI of under 20 and that 11.5 percent suffering from moderate or severe cachexia. In cases where the two criteria appeared together, the mortality risk increased fourfold.

In order to stop this process, early intervention is required. This involves extra calories initially but also anti-inflammatory agents such as antioxidants, omega-3 fatty acids, or L-carnitine. Glucocorticoids can also stimulate the appetite and enhance the mood, thereby motivating patients to compensate for nutritional deficits. A targeted exercise programme is also suitable for stimulating hunger. Preliminary data from the surgical department of a German hospital confirms that a customised, low-intensity exercise programme can help counteract cachexia. Such programmes are also worthwhile from an economic perspective. A meta-study noted an average hospital stay of 17 days for malnourished patients and 10 ten days for patients without weight problems.

Fat conversion: from white to brown

Despite the huge therapeutic potential, the pharmaceutical industry has been rather restrained with regard to cachexia. Talk of “key molecules” crops up time and again, although there has not been enough material in recent studies for any drug to be considered a great success. The events leading to unintentional weight-loss still appear to be a black box. Last year Bruce Spiegelman from Harvard and Erwin Wagner from Spain published the results of animal experiments demonstrating that white fat cells are converted to brown fat cells in cachectic mice. In the mitochondria of these cells, the metabolism switches from the synthesis of ATP and the storage of energy to the production of thermal energy.

Inflammatory processes involving IL-6 support these processes. Accordingly, anti-inflammatory agents can inhibit this conversion. However, they cannot completely prevent it. The Harvard group was able to show that the parathyroid-hormone-related protein (PTHrP) of tumorous cells plays a crucial role in these reactions. Using a PTHrP block, the scientists even managed to stop muscle degradation in the mice investigated. Similar results were also published in September 2015 [Paywall] by Australian scientists. They focussed on a receptor from the TNF family (FN14). Using matching antibodies, they were able to stop cachexia in the experimental mice. By contrast, when transformed into mice, human FN14 induced muscle breakdown. However, especially with regard to subjects with cancer, the extrapolation of these results from animals to humans is to be done with caution, even if the results give hope of further progress.

Cachexia markers present long before tumour diagnosis

This also applies to diagnostics. Last year, Brian Volpin from the Dana-Faber Institute in Boston published pancreatic cancer results. In a prospective study of 1,500 subjects, he found high concentrations of branched-chain amino acids in those who would later develop a tumour. Isoleucine, leucine and valine – probably from the breakdown of muscle tissue – appeared in the plasma several years before the outbreak of the disease. These results were confirmed in animal experiments but not for other types of tumours.

According to a worldwide estimate, approx. nine million people suffer from chronic and unwanted muscle breakdown. According to a 2009 study, in Europe alone, the direct financial burden due to malnutrition is more than 31 billion euros. If the indirect costs (e.g. such as loss of work and lost years of life) are accounted for, this values increases by tenfold. New treatments may indeed open up promising avenues in the fight against cancer but are of little use if patients are too weak to undergo them.

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