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PubMed1995

Plasma neopterin/C-reactive protein ratio as an adjunct to the assessment of infection and cancer cachexia.

Neopterin (NPT), a pteridine intermediate metabolite in the biopterine synthetic pathway, is synthesized and secreted by monocytes/macrophages upon stimulation, mainly by gamma-interferon produced by activated T cells. C-reactive protein (CRP) is one of the major acute-phase reactants and its release is thought to be mediated by interleukin-6. Plasma concentrations of NPT and CRP were synchronously analyzed in 25 determinations of 5 patients with severe infectious complications and 50 determinations of 10 cancer-burden patients representing cachexia. The mean value of NPT (pmol/ml) was 201.6 in the infection group and 16.5 in the cancer cachexia group. The mean value of CRP (mg/dl) was 12.5 in the infection group and 3.4 in the cancer cachexia group. The number of samples in which NPT alone exceeded the cut-off level were 0/25 (0%) in the infection group and 38/50 (76.0%) in the cancer cachexia group. The number of samples in which both NPT and CRP exceeded the cut-off level was 25/25 (100%) in the infection group and 12/50 (24.0%) in the cancer cachexia group. The mean ratio of NPT to CRP was 11.3 in the infection group and 30.7 in the cancer cachexia group, respectively. These results suggest that gamma-interferon could play the principal role in the pathogenesis of cancer cachexia and that interleukin-6 modified the disease status. Interleukin-6 would be the critical mediator of host responses in infectious complications.

Aged↗
PubMed1993

Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions.

Cancer cachexia is a complex syndrome characterized primarily by diminished nutrient intake and progressive tissue depletion that is manifest clinically as anorexia and host weight loss. The gradual loss of host protein stores is central to this process. This review outlines the techniques that have been used to evaluate human amino acid metabolism, their application in patients with cancer cachexia, and possible therapeutic interventions designed to overcome alterations in host protein and amino acid metabolism associated with malignant cachexia. The techniques of nitrogen balance and 3-methylhistidine excretion provide indirect estimates of overall nitrogen metabolism and skeletal muscle myofibrillar protein breakdown. Measurement of circulating amino acid concentrations, particularly when combined with assessment of arterial-venous differences and regional amino acid balance allows for investigation of interorgan amino acid metabolism. One of the most significant advances in in vivo amino acid metabolic research has been the development of labeled amino acid tracer studies to evaluate whole body and regional amino acid kinetics. The use of stable and unstable amino acid isotopes in these techniques is reviewed in detail. Virtually all of these techniques have now been employed in the evaluation of human cancer cachexia. The results of studies evaluating amino acid concentrations, regional amino acid balance, and 3-methylhistidine excretion are summarized. The use of regional and whole body kinetic studies in cancer cachexia are reviewed extensively. Most investigators have observed increased rates of whole body protein turnover, synthesis, and catabolism in both weight-stable and weight-losing cancer patients. Some studies have suggested a relationship between the extent of disease and the degree of aberration in amino acid kinetic parameters. Investigators have attempted to reverse some of these alterations by provision of substrate (nutritional support) or administration of specific pharmacologic or anabolic agents such as hydrazine sulfate, insulin, growth hormone, and beta-2 agonists. The role of total parenteral nutrition (TPN) in cancer and its effects on protein and amino acid kinetics and tumor growth are addressed. The possible benefits of specific amino acid nutritional formulations with increased branched chain amino acids, arginine, and glutamine are reviewed. Although many of these approaches appear promising, significant impact on clinically definable parameters remains to be demonstrated. A better understanding of the underlying protein catabolic mechanisms of cancer cachexia will likely lead to more effective therapies to reverse the protein calorie malnutrition associated with cancer cachexia.

Amino Acids↗
PubMedDate not supplied

Cachexia induction by EL-4 lymphoma in mice and possible involvement of impaired lipoprotein lipase activity.

Several lines of evidence have postulated that reduction in the activity of lipoprotein lipase (LPL) is involved in cachexia induction in cancer patients. Recently we have demonstrated that murine melanoma B16 has the ability to reduce the LPL activity and thereby induce cachexia symptoms in mice following intraperitoneal inoculation. In order to further investigate the relationship between LPL activity and cachectic syndrome, cachexia models other than melanoma B16 are required. However, there are few animal cachexia models in which LPL activity is involved in the induction of cachectic symptoms. In this study, cachectic symptoms and plasma LPL activity were investigated in mice bearing EL-4 mouse lymphoma. In EL-4 bearing mice the body weight including tumor weight in the abdominal cavity was rather higher than that of normal mice without tumor, whereas weights of carcass wet and gastrocnemius muscle were significantly decreased in EL-4 bearing mice. Elevated blood levels of triglyceride and non-esterified fatty acid were observed in mice bearing EL-4, associated with the impaired plasma LPL activity. Overall, this study indicated that EL-4 lymphoma in mice results in a severe cachexia which is possibly related to impaired LPL activity and also provided a useful cachexia model for understanding the role of LPL in the development of cancer cachexia.

Animals↗
PubMed2001

[Decreased growth hormone secreting cells of the hypophysis in senile cachexia].

Basic morphometry of the pituitary gland in aged patients with cachexia was performed. In 10 control specimens, growth hormone(GH) cells accounted for 42.9 +/- 3.4% of the total, compared with 33.8 +/- 7.0%(p < or = 0.01) in patients with severe cachexia senilis. ACTH cells accounted for 16.0 +/- 7.4% in the control group and 14.1 +/- 9.0% in the senile cachexia group(p > or = 0.1). The mean pituitary weight was 0.60 g in control cases and 0.46 g in cases of extreme cachexia(p < or = 0.01). In the hypophyses of patients with senile cachexia, atrophy of GH cells and increase of the fibrous stroma were also prominent. The ratio of the summarized value for total GH cells in cachexia senilis patients and controls was 1:2.2. The difference was regarded as sufficiently large to be a causative factor in the establishment of cachexia senilis.

Adrenocorticotropic Hormone↗
PubMed2004

[Role of NF-kappa B in cancer cachexia].

OBJECTIVE: To assess the putative involvement of NF-kappaB and pro-inflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethacin (IND) on cachexia. METHODS: Thirty young male BALB/c mice were divided randomly into five groups: A, control; B, tumor-bearing plus saline; C, tumor-bearing plus IND (0.25 mg/kg); D, tumor-bearing plus IND (0.5 mg/kg); and E, tumor-bearing plus IND (2.0 mg/kg). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum TNF-alpha and IL-6 levels and activity of NF-kappaB in spleen were investigated in all animals. RESULTS: Cachexia was observed in all tumor-bearing mice. No difference was found between groups in food intake (P > 0.05). By day 16, body weights of non-tumor mice were about 82.0% of healthy controls (P < 0.01), and the weight of gastrocnemius was decreased by 28.7% (P < 0.01). Gastrocnemius weight was increased markedly (P < 0.01) after treatment of IND (0.5 mg/kg). Tumor-bearing caused a significant increase in serum TNF-alpha and IL-6 levels (P < 0.01). The concentration of TNF-alpha (P < 0.05) and IL-6 (P < 0.01) in tumor-bearing mice was reduced after administration of 0.5 mg/kg IND for 7 days. NF-kappaB activation in the spleen was increased in tumor-bearing mice in comparison with controls. NF-kappaB activity was reduced in mice treated with IND. The maximal inhibition was observed at an dosage of 0.5 mg/kg (P < 0.01). Liner positive correlation was found between NF-kappaB activity and cytokine levels (r(TNF-alpha) = 0.918, P(TNF-alpha) = 0.028; r(IL-6) = 0.884, P(IL-6) = 0.046). CONCLUSIONS: Cachexia induced by colon 26 adenocarcinoma cells may be partially attributed to the enhanced TNF-alpha and IL-6 levels which is controlled by NF-kappaB. IND may inhibit the activation of NF-kappaB, decrease serum TNF-alpha and IL-6 levels and thus alleviate the cachexia.

Adenocarcinoma↗
PubMed2004

CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice.

IL-6 is a multifunctional cytokine implicated in several cancers. IL-6 is a growth factor for certain tumors and contributes to drug resistance, cachexia and bone resorption. Cachexia is characterized by progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. We have developed CNTO 328 (cCLB8), a human-mouse chimeric MAb to IL-6 (K(d) approx. 10(-12) M) that inhibits IL-6 function. A phase I study with CNTO 328 in multiple myeloma patients demonstrated that the antibody was safe and had a circulating half-life of approximately 17 days. Since IL-6 is implicated in cachexia, we hypothesized that CNTO 328 could inhibit tumor-induced cachexia. We used 2 human tumor-induced cachexia models in nude mice. In the first model, human melanoma cells were inoculated in female nude mice. Control treated animals lost 19% (+/-7.7%) body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)-treated animals lost only 1.5% (+/-1.3%) body weight from day 0 to day 31 (p = 0.023). In the second cachexia model, human prostate tumor cells were injected into male nude mice. By day 29, control treated animals lost 6% (+/-3.5%) body weight, whereas CNTO 328 (10 mg/kg)-treated animals gained 7% (+/-4%) body weight (p = 0.01). Since CNTO 328 blocks human IL-6 but not mouse IL-6, the data indicate that tumor cell-secreted IL-6 directly contributes to body weight loss, highlighting the potential role for CNTO 328 as an anticachectic agent.

Animals↗
PubMed1991

Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells.

Nude mice were inoculated with CHO/IFN-gamma cells, a line of Chinese hamster ovary tumor cells, that had been genetically engineered to produce murine IFN-gamma. Severe cachexia, as evident from body weight loss and reduced food intake, occurred in these mice, but not in those injected with CHO/control cells, i.e. the original, non-IFN-gamma-producing line. The essential role of IFN-gamma in the pathogenesis of cachexia was confirmed by the demonstration that monoclonal antibodies (MAbs) against IFN-gamma, given prior to injection of the tumor cells, prevented cachexia. In addition to IFN-gamma, the presence of the tumor cells was also required for cachexia to develop. As evident from pair-feeding experiments, reduced food intake could only partially account for the rapid and extensive body-weight loss. Cachexia was characterized by a marked reduction in the amount of interscapular fat tissue. Injected tumor cells exclusively invaded intraperitoneal adipose tissue and elicited an inflammatory cell infiltrate, indicating that interscapular fat loss was due to humoral factors. Our data suggest that, among the humoral factors responsible for cancer-associated cachexia, IFN-gamma plays a prominent role.

Adipose Tissue↗
PubMed1995

Establishment and characterization of cachexia-inducing and -non-inducing clones of murine colon 26 carcinoma.

To investigate the mechanism causing cachexia and its association with shorter patient survival, we cloned weight-loss-inducing and -non-inducing sublines of murine colon 26 carcinoma (colon 26). One clone, clone 20, induced substantial weight loss, wasting of adipose tissue and muscle, and hypoglycemia in mice with a minimum tumor burden of 0.3 g (2 g per 100 g body weight). Clone-20-bearing mice had a median survival of 24.5 days with average tumor weight of 0.4 g. In contrast, clone 5 induced neither severe weight loss, wasting of adipose tissue and muscle, nor hypoglycemia; clone-5-bearing mice survived for a median of 70 days with average tumor weight of 12 g. These results clearly indicate that shorter survival is associated with the degree of cachexia and is independent of tumor size. Using this pair of colon 26 clones, we examined mediators of cachexia. Neither TNF alpha, IL-1 alpha nor IFN gamma was detected in the serum of mice bearing either clone, while IL-6 was detected in mice bearing both clones by ELISA and a bioassay. Administration of anti-IL-6 monoclonal antibody (MAb) partially but significantly suppressed cachexia induction in clone-20-bearing mice. These results point to the involvement of IL-6 in experimental cachexia. However, our finding of the presence of IL-6 in the serum of mice bearing clone 5, which does not induce weight loss, clearly indicates that IL-6 is not solely responsible for the induction of cachexia.

Animals↗
PubMed2001

Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen.

The development of cancer cachexia has been linked to cytokines related to interleukin6 (IL-6). We examined the kinetics of IL-6, IL-11, oncostatinM (OSM) and leukaemia inhibitory factor (LIF) induction in the splenocytes of tumour-bearing mice. Using a lung carcinoma line, which grows in C57BL/6J mice, we observed that when the tumour grew and cachexia was observed, the splenocytes produced IL-6, IL-11, and OSM, but not LIF. Cytokine expression was observed within 1 week (day 3 for IL-6 and IL-11, and day 1 for OSM) of administration of tumour cells, and was observed in splenocytes without tumour metastases to the spleen. Cytokine expression preceded cachexia (determined by changes in serum triglyceride levels and decrease in epididymal fat-pad weights) development by over 1 week. Exogenous administration of IL-11 resulted in the accelerated onset of cachexia, compared to control protein treatment, but without an effect on the tumour burden. In vivo treatment with a neutralizing dose of anti-OSM antibody inhibited the triglyceride dysregulation only until the synthesis of IL-6 and IL-11 began in the spleen (day 3). Afterward, IL-6 and IL-11 induced lipid catabolism in the absence of functional OSM. We conclude from the data described above that cachexia developed due to a systemic cytokine response induced by a tumour burden, and that IL-6-like cytokines contributed independently to lipid hypercatabolism in the aetiology of cancer cachexia.

Animals↗
PubMed1993

Pathophysiology of cancer cachexia.

Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure in the presence of diminished food intake due to anorexia and to gastrointestinal disturbances. Rates of glucose production by the liver, gluconeogenesis and glycolysis to lactate (Cori cycle) are increased, fat mobilisation and oxidation are accelerated. There is a redistribution of body proteins away from muscle towards visceral proteins, resulting in marked muscle protein loss. Cancer cachexia differs from simple starvation and demonstrates metabolic similarities to sepsis or polytrauma. The metabolic response in the patient with cancer is largely due to mediators released by the tumour or by the host; recently the role of cytokines such as tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1) and -6 (IL-6) and interferon gamma (INF gamma) has been emphasized. Catabolic hormones such as glucocorticoids and adrenaline have also been implicated. Cytokines have the potential to reproduce experimentally the clinical syndrome of cancer cachexia. There is evidence of increased production of several of them in certain types of cancer. There are overlapping activities of the cytokines TNF alpha, IL-1, IFN gamma and IL-6. The contribution of each of them to cancer cachexia remains unclear. Inhibition of cytokine activity using specific antibodies in cancer-bearing experimental animals demonstrated partial prevention of cachexia. A positive feedback between macrophage-derived IL-1 and tumour-derived IL-6 has been demonstrated recently in experimental cancer cachexia. Cytokines may support tumour growth by acting as growth factors.

Cachexia↗
PubMed2007

Central infusion of the melanocortin receptor antagonist agouti-related peptide (AgRP(83-132)) prevents cachexia-related symptoms induced by radiation and colon-26 tumors in mice.

Cachexia is a clinical wasting syndrome that occurs in multiple disease states, and is associated with anorexia and a progressive loss of body fat and lean mass. The development of new therapeutics for this disorder is needed due to poor efficacy and multiple side effects of current therapies. The pivotal role played by the central melanocortin system in regulating body weight has made this an attractive target for novel cachexia therapies. The mixed melanocortin receptor antagonist AgRP is an endogenous peptide that induces hyperphagia. Here, we used AgRP(83-132) to investigate the ability of melanocortin antagonism to protect against clinical features of cachexia in two distinct animal models. In an acute model, food intake and body weight gain were reduced in mice exposed to radiation (300 RAD), and delivery of AgRP(83-132) into the lateral cerebral ventricle prevented these effects. In a chronic tumor cachexia model, adult mice were injected subcutaneously with a cell line derived from murine colon-26 adenocarcinoma. Typical of cachexia, tumor-bearing mice progressively reduced body weight and food intake, and gained significantly less muscle mass than controls. Administration of AgRP(83-132) into the lateral ventricles significantly increased body weight and food intake, and changes in muscle mass were similar to the tumor-free control mice. These findings support the idea that antagonism of the central melanocortin system can reduce the negative impact of cachexia and radiation therapy.

Adenocarcinoma↗
PubMed2002

Cachexia: a therapeutic approach beyond cytokine antagonism.

Cachexia is seen in a number of chronic diseases, and it is always associated with a poor prognosis. Irrespective of etiology, the development of cachexia appears to share a common pathophysiological pathway. This includes induction of proteasome-dependent myofibril-degradation, which is thought to be secondary to stimulation by enhanced levels of pro-inflammatory cytokines. Elevation of tumor necrosis factor-alpha (TNFalpha) and other plasma cytokines has been demonstrated in many conditions associated with cachexia. Despite improved pathophysiological understanding, a specific treatment for cachexia has not yet been established. Whilst direct TNFalpha antagonism has therapeutic appeal, this review will focus on manipulation of downstream pathways and the potential benefits. For example, nuclear factor-kappaB (NF-kappaB) is one of the most important signal transducers of TNFalpha, and drugs targeting this signalling cascade might be useful in the treatment of cachexia. Although the use of some of these substances, for example glucocorticoids, remains controversial, others may prove beneficial in the treatment of this syndrome. The role of other approaches such as proteasome-inhibitors remains to be elucidated. Alternatively, interleukin-10 and other immunosuppressive cytokines may also be able to counterbalance certain features of cachexia.

Cachexia↗
PubMed2006

Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia.

Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30-60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome--more accurately described as 'cachexia'--manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-alpha, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia.

Adipose Tissue↗
PubMed1999

The impact of cachexia on cardiorespiratory reflex control in chronic heart failure.

BACKGROUND: The mechanism of persistent neurohormonal and cardiorespiratory reflex abnormalities in chronic heart failure remain unclear. Also, why chronic heart failure patients who develop cachexia demonstrate a particularly abnormal neurohormonal profile and have a high risk of death is not known. Impaired reflex control within the cardiac and respiratory systems, and abnormal heart rate variability have both been linked to a poor outcome. Muscle reflexes may contribute to persistent neurohormonal overactivity in wasted patients. Thus, we hypothesized that patients with cardiac cachexia might exhibit particularly profound abnormalities in cardiorespiratory reflexes and heart ratevariability. METHODS AND RESULTS: We investigated 39 chronic heart failure patients: 13 with cardiac cachexia (non-intentional, non-oedematous, documented weight loss of >7.5% of previous normal weight over more than 6 months), and 26 non-cachectic chronic heart failure patients matched according to the severity of chronic heart failure (all men, mean age: 59 vs 60 years, NYHA functional class: 2.6 vs 2.5, peak O(2)consumption: 16.2 vs 16.8 ml. kg(-1). min(-1), left ventricular ejection fraction: 23 vs 24%, all P>0.2 for cachectic vs non-cachectic). In the assessment of the cardiorespiratory reflex control we investigated: cardiac sympathovagal balance (using spectral analysis of heart rate variability to derive low (LF, 0. 04-0.15Hz) and high frequency (HF, 0.15-0.4Hz) components), baroreflex sensitivity (using the phenylephrine method), and peripheral chemosensitivity (using the transient hypoxic method). There was a severely abnormal pattern of cardiorespiratory reflex control in patients with cachexia compared with non-cachectic patients. The former group exhibited severely impaired autonomic reflex control, characterized by an abnormal profile of heart rate variability (reduced LF component), and depressed baroreflex sensitivity (P=0.0001 and P=0.02, respectively, vs non-cachectics). Patients with cachexia also demonstrated an increased peripheral chemosensitivity (0.91 vs0.46 l. min(-1). %SaO(2)(-1), P<0.001, cachectic vs non-cachectic, respectively). In the correlation analyses the degree of impairment in the reflex control was more closely related to wasting, and to the level of neurohormonal activation (as measured by the levels of epinephrine and norepinephrine) than to conventional markers of the severity of heart failure. CONCLUSIONS: Chronic heart failure patients who developed cardiac cachexia demonstrate an abnormal reflex control within the cardiovascular and respiratory systems. The nature of the link between this phenomenon and hormonal changes and the poor prognosis of cachectic chronic heart failure patients warrants further investigation.

Cachexia↗
PubMed2003

Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti-parathyroid hormone-related protein antibody.

Parathyroid hormone-related protein (PTHrP) plays a central role in humoral hypercalcemia of malignancy (HHM), which is one of the most frequent paraneoplastic syndromes. PTHrP produced by the tumor acts through a common PTH/PTHrP receptor to promote bone resorption, inhibit calcium excretion from the kidney, and induce hypercalcemia. Patients with HHM often develop cachexia associated with typical symptoms such as anorexia, malaise, nausea, constipation, polyuria, polydipsia, and confusion. The etiology of the cachexia is not fully understood but is thought to be caused by hypercalcemia and various cytokines such as interleukin-6, tumor necrosis factor-alpha, leukemia inhibitory factor, and others. In this study, we investigated the role of PTHrP in hypercalcemia and cachexia in HHM by using humanized anti-PTHrP antibody. A mouse monoclonal antibody that binds to PTHrP amino acid sequence 1-34 and inhibits PTHrP function has been humanized to create a specific and potent agent for the treatment of patients with HHM. The mouse monoclonal antibody has been shown to have antihypercalcemic activity against nude mice bearing human tumors. Because a mouse antibody is highly immunogenic in human patients, the complementarity-determining regions from the mouse antibody were grafted into a human antibody. The resulting humanized antibody specifically recognizes PTHrP(1-34) and neutralizes PTHrP functions in vitro and in vivo. The humanized anti-PTHrP antibody was administered intravenously to HHM model animals bearing tumors such as LC-6 human lung carcinoma. These animals showed symptoms similar to those of patients with HHM (eg, hypercalcemia and cachexia). The humanized anti-PTHrP antibody-treated animals responded with normalization of blood ionized calcium level through an improvement of bone metabolism and calcium excretion. Moreover, the treated animals also showed an improvement in body weight, ultromotivity, metabolic alkalosis, food consumption, water intake, serum phosphorus, and renal function. Consequently, the humanized antibody-treated animals experienced complete resolution of hypercalcemia and cachexia. These results suggest that the humanized antibody would be an effective and beneficial agent for patients with HHM, and that PTHrP is a major pathogenetic factor of hypercalcemia and cachexia in patients with HHM.

Animals↗
PubMed2004

Cardiac cachexia.

Chronic heart failure (CHF) remains an important and increasing public health care problem. It is a complex syndrome affecting many body systems. Body wasting (i.e., cardiac cachexia) has long been recognised as a serious complication of CHF. Cardiac cachexia is associated with poor prognosis, independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Patients with cardiac cachexia suffer from a general loss of fat tissue, lean tissue, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but there is increasing evidence that metabolic, neurohormonal and immune abnormalities may play an important role. Cachectic CHF patients show raised plasma levels of epinephrine, norepinephrine, and cortisol, and they show high plasma renin activity and increased plasma aldosterone level. Several studies have also shown that cardiac cachexia is linked to raised plasma levels of tumour necrosis factor alpha and other inflammatory cytokines. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.

Cachexia↗
PubMed1997

Biology of cachexia.

About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle mass. Such patients have a decreased survival time, compared with the survival time among patients without weight loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. These changes cannot be fully explained by the accompanying anorexia, and nutritional supplementation alone is unable to reverse the wasting process. Despite a falling caloric intake, patients with cachexia frequently show an elevated resting energy expenditure as a result of increases in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity, glucose and triglyceride-fatty acid cycling, and gluconeogenesis. A number of cytokines, including tumor necrosis factor-apha, interleukins 1 and 6, interferon gamma, and leukemia-inhibitory factor, have been proposed as mediators of the cachectic process. However, the results of a number of clinical and laboratory studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer cachexia. In addition, cachexia has been observed in some xenograft models even without a cytokine involvement, suggesting that other factors may be involved. These probably include catabolic factors, which act directly on skeletal muscle and adipose tissue and the presence of which has been associated with the clinical development of cachexia. A polyunsaturated fatty acid, eicosapentaenoic acid, attenuates the action of such catabolic factors and has been shown to stabilize the process of wasting and resting energy expenditure in patients with pancreatic cancer. Such a pharmacologic approach may provide new insights into the treatment of cachexia.

Cachexia↗
PubMedDate not supplied

The biochemical basis of metabolism in cancer cachexia.

Cancer cachexia is a syndrome of progressive body wasting characterized by loss of adipose tissue and skeletal muscle mass. It is the most common side effect of malignancy occurring in approximately one-half of untreated cancer patients. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of carbohydrate, lipid, and protein metabolism. This leads to a shorter survival time and a decreased response to therapy. Cachexia is often found before any signs or symptoms of the cancer. An uncertainty with cachexia is whether nutritional support is feeding the patient or the tumor. Often, cachexia is not responsive to simple nutritional interventions. Furthermore, appetite stimulants, cytokine inhibitors, and Cori cycle inhibitors have been used to treat cancer cachexia.

Anorexia↗