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Catabolic Wasting
Updated: 05/23/2003
Catabolic wasting or cachexia is a clinical wasting syndrome that is characterized by unintended and progressive weight loss, weakness, and low body fat and muscle. At least 5% of body weight is lost. Cachexia is not caused by poor appetite and nutritional intake, but rather by a metabolic state in which a "breaking down" rather than a "building up" occurs in bodily tissues no matter how much nutritional intake occurs. Additionally, whether a patient receives nutrition orally or intravenously makes no difference. The patient simply cannot gain weight, so eating more is not an answer.
It is estimated that half of all cancer patients experience catabolic wasting, with a higher occurrence seen in cases of malignancies of the lung, pancreas, and gastrointestinal tract. The syndrome is equally common in AIDS patients and can also be present in bacterial and parasitic diseases, rheumatoid arthritis, and chronic diseases of the bowel, liver, lungs, and heart. It is usually associated with anorexia and can manifest as a condition in aging or as a result of physical trauma. Catabolic wasting is a symptom that diminishes the quality of life, worsens the underlying condition, and is a major cause of death.
Cachexia and Cancer
Researchers previously believed that cancer increased metabolic demand (stolen protein), produced toxins, and suppressed appetite, resulting in malnutrition. New research, however, shows that although cancer may raise resting metabolic rate, improved nutrition does not alleviate the symptoms of anorexia, chronic nausea, early satiety, and changes in taste that make even favorite foods unpalatable to some cancer patients. The view of clinicians is that bodily wasting is the result of a combined action of tumor products and host immune factors--in particular, cytokines--that lead to poor appetite, muscle wasting, and an altered metabolism. The cytokines interleukin-1 (IL-1), IL-6, interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and brain-derived neurotrophic factor appear to increase and play a role in the progression of cachexia in cancer, as well as in other diseases associated with bodily wasting.
Other metabolic alterations associated with the syndrome are hyperglyceridemia, lipolysis, and accelerated protein turnover, all leading to a loss of fat mass and body protein. The dysregulation of metabolic processes produces a negative energy balance.
Clinicians are currently treating cancer-related catabolic wasting with a variety of interventions, including nutritional supplementation, administration of cytokine inhibitors, steroids, hormones, cannabinoids, and thalidomide. Gemcitabine, a chemotherapeutic drug, has shown clinical benefits in treating cachexia. Newer nutritional intervention with megestrol acetate derivatives, gamma-receptor agonists, amino acid manipulations, myostatin inhibitors, and uncoupling protein modifiers is currently being explored. Further research must be done to investigate gender differences in relation to pathophysiology and therapy.
There is some evidence that the drug hydrazine sulfate may help cancer patients gain weight and improve the cachectic state. The drug is by prescription and should be given by a complementary physician familiar with its use, as it can be toxic. The dose is usually 60 mg a day. Narcotic painkillers or benzodiazepine anxiety-reducing agents cannot be given concomitantly.
Cachexia and HIV
Bodily wasting is a common manifestation of HIV, occurring at any state of infection and indicative of disease progression. Malnutrition, a result of appetite loss, is commonly due to nausea and vomiting. Weakness and diarrhea are often present as well. Persons with HIV may also experience malabsorption of nutrients due to enteric infections associated with the disease, even if they consume sufficient calories.
The effects of malnutrition are thought to contribute to increased immune suppression including a reduction in T-lymphocyte helper and suppressor cells, altered phagocytic functions, and decreased killer-cell activity, leading to opportunistic infections and cancers. Proinflammatory cytokines IL-1, IL-6, and TNF have been cited in many studies as potential causes of wasting. Most people with advanced HIV and AIDS have some degree of wasting.
To reverse weight loss, appetite stimulants, anabolic agents (such as growth hormone or testosterone), cytokine inhibitors, and hormones are often prescribed. Megestrol acetate and dronabinol (which contains the active ingredient in marijuana) are approved for the treatment of wasting. Thalidomide, which aids in the healing of aphthous ulcers of the mouth and esophagus, is now available.
Diagnosis
Unfortunately, the cachectic state is all too apparent to any observer. In severe chronic disease with the development of multiple organ failure, some degree of malabsorption of nutrients probably contributes to the cachectic state. The entire picture is reflected in a continuing decline of the serum albumin as the illness progresses. Conversely, an increase in serum albumin suggests an improvement in the nutritional state. As long as a patient is maintained on nutrition by the normal route (by mouth), optimizing the state of digestive secretions is probably advisable, although there may not be clinical studies demonstrating this. The Heidelburg test reflects this environment and can be used to ascertain the need for either hydrochloric acid or pancreatic enzyme supplementation.
Fish Oil Studies
Depletion of muscle and adipose tissue in cancer cachexia appears to arise not only from decreased food intake, but also from the production of catabolic factors secreted by certain tumors such as tumor necrosis factor and other autoimmune cytokines. Experiments with a cachexia-inducing tumor in mice showed that when part of the carbohydrate calories in their diet was replaced by fish oil, host body weight loss was inhibited. The catabolic-inhibiting effect occurred without an alteration of either the total calorie consumption or nitrogen intake (Tisdale et al. 1990).
Fish oil concentrate was found to inhibit tumor-induced lipolysis directly (Beck et al. 1991). The catabolic fat loss-preventing effect of fish oil arose from an inhibition of the elevation of cyclic AMP (adenosine monophosphate, a nucleotide involved in energy metabolism) in fat cells. The increased protein degradation in the skeletal muscle of catabolic animals was also inhibited by fish oil; this effect was due to the inhibition by fish oil of muscle prostaglandin E2 production in response to a tumor-produced proteolytic factor. Thus, reversal of cachexia by fish oil in this mouse model results from its capacity to interfere with tumor-produced catabolic factors (Tisdale 1996). Similar factors have been detected in human cancer cachexia.
Studies show that the DHA fraction of fish oil is the best documented supplement to suppress the inflammatory cytokines involved in the catabolic process such as TNF-a, IL-6, IL-1(b), and prostaglandin E2(Khalfoun et al. 1997; De Caterina et al. 1998, 1999; Jeyarajah et al. 1999; Kelley et al. 1999; James et al. 2000; Kremer 2000; Watanabe et al. 2000; Yano et al. 2000; Das 2001; Tepaske et al. 2001). Catabolic wasting patients should consider taking 8 capsules a day of Super GLA/DHA, a combination of gamma-linolenic acid and primarily the DHA fraction of fish oil. Both GLA and DHA significantly suppress inflammatory cytokines (Purasiri et al. 1994; Mancuso et al. 1997; Dirks et al. 1998; DeLuca et al. 1999; James et al. 2000).
Beneficial Effects of Glutamine
Glutamine has been one of the most intensively studied nutrients in the field of nutrition support in recent years. Animal studies show that glutamine is effective against catabolic stress (Millward et al. 1989; Castell et al. 1994; Ziegler et al. 1996). Glutamine supplementation was shown to improve organ function, survival, or both in most published studies. These studies also have supported the concept that glutamine is a critical nutrient for the gut mucosa and immune cells (Furst et al. 1989; Castell et al. 1994; Campos et al. 1996; Ziegler et al. 1996).
Molecular and protein chemistry studies define the basic mechanism involved in glutamine action in the gut, liver, and other cells and organs (Ziegler et al. 1996). Double-blind prospective clinical investigations suggest that glutamine-enriched diets are generally safe and effective in catabolic patients (Griffiths 1997). Intravenous glutamine has been shown to increase plasma glutamine levels; exert protein anabolic effects; improve gut structure and function; and reduce important indices of disease, including infection rates and length of hospital stay in selected patient subgroups (Sacks 1999).
Glutamine is the most abundant free amino acid in the human body. In catabolic stress situations, such as after surgical operations or trauma and during sepsis, glutamine is rapidly transported to organs and to blood cells. This results in an intracellular depletion of glutamine in the muscles and the ensuing catabolic wasting effect (Balzola et al. 1996). Increasing evidence suggests that glutamine is a crucial substrate for immunocompetent cells. Glutamine depletion decreases the proliferation of lymphocytes, possibly by arresting a critical phase of the growth cycle of the cells (Roth et al. 1996).
Glutamine is a precursor for the synthesis of glutathione and stimulates the formation of heat-shock proteins (Zhou et al. 1997). Moreover, there are suggestions that glutamine plays a crucial role in the stimulation of intracellular protein synthesis (Hankard et al. 1996). Experimental studies revealed that glutamine deficiency causes a necrotizing enterocolitis--an inflammation of the small intestine and colon, leading to cell death--and increases the mortality of animals subjected to bacterial stress (Becker et al. 2000).
A clinical human study involving bone-marrow transplant patients demonstrated, after supplementation with glutamine, a decrease in the incidence of infections and a shortening of hospital stay. In critically ill patients, parenteral glutamine reduced nitrogen loss and caused a reduction of the mortality rate (Roth et al. 1996). In surgical patients, glutamine invoked an improvement of several immunological parameters (Slotwinski et al. 2000). Moreover, glutamine exerted a nutritional (tropic) effect on the intestinal mucosa, decreased the intestinal permeability, and thus may prevent the translocation of bacteria.
In conclusion, glutamine is an important metabolic substrate of rapidly proliferating cells. It influences the cellular hydration (molecular water content) state and has multiple effects on the immune system, intestinal function, and protein metabolism (Sacks 1999). In several disease states, glutamine may become an indispensable nutrient supplement. Catabolic wasting patients should consider supplementing with 2000 mg of glutamine a day. |