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PubMed2005

Body composition and mortality in chronic obstructive pulmonary disease.

BACKGROUND: Survival studies have consistently shown significantly greater mortality rates in underweight and normal-weight patients with chronic obstructive pulmonary disease (COPD) than in overweight and obese COPD patients. OBJECTIVE: To compare the contributions of low fat-free mass and low fat mass to mortality, we assessed the association between body composition and mortality in COPD. DESIGN: We studied 412 patients with moderate-to-severe COPD [Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stages II-IV, forced expiratory volume in 1 s of 36 +/- 14% of predicted (range: 19-70%). Body composition was assessed by using single-frequency bioelectrical impedance. Body mass index, fat-free mass index, fat mass index, and skeletal muscle index were calculated and related to recently developed reference values. COPD patients were stratified into defined categories of tissue-depletion pattern. Overall mortality was assessed at the end of follow-up. RESULTS: Semistarvation and muscle atrophy were equally distributed among disease stages, but the highest prevalence of cachexia was seen in GOLD stage IV. Forty-six percent of the patients (n = 189) died during a maximum follow-up of 5 y. Cox regression models, with and without adjustment for disease severity, showed that fat-free mass index (relative risk: 0.90; 95% CI: 0.84, 0.96; P = 0.003) was an independent predictor of survival, but fat mass index was not. Kaplan-Meier and Cox regression plots for cachexia and muscle atrophy did not differ significantly. CONCLUSIONS: Fat-free mass is an independent predictor of mortality irrespective of fat mass. This study supports the inclusion of body-composition assessment as a systemic marker of disease severity in COPD staging.

Body Composition↗
PubMed1991

Resting energy expenditure in patients with newly detected gastric and colorectal cancers.

Resting energy expenditure (REE) was measured in 104 patients with newly detected gastric or colorectal (GCR) cancer and was compared with two groups of control subjects without cancer: healthy subjects (H control subjects) and patients with nonmalignant diseases of the gastrointestinal tract (GI patients). REE in GCR-cancer patients was not significantly different from REE in GI patients or H control subjects. Comparison of measured REE with predicted REE obtained from prediction equations may erroneously suggest that increased REE is a contributing factor in the development of cancer cachexia. No significant differences in REE were found when patients with liver metastases were compared with patients without metastases. There were no differences in REE between gastric and colorectal cancer patients. The decrease in energy expenditure, which normally occurs during starvation and weight loss in healthy men and women, could not be demonstrated in weight-losing, GCR-cancer patients. In conclusion, elevation of REE contributes little to the pathogenesis of cancer cachexia in GCR-cancer patients.

Age Factors↗
PubMed2006

Greater whole-body myofibrillar protein breakdown in cachectic patients with chronic obstructive pulmonary disease.

BACKGROUND: Experimental studies indicate that greater skeletal muscle protein breakdown is a trigger for the cachexia that often is prevalent in chronic obstructive pulmonary disease (COPD). OBJECTIVE: We compared myofibrillar protein breakdown (MPB) with whole-body (WB) protein breakdown (PB) in 9 cachectic COPD patients [x +/- SEM forced expiratory volume in 1 s (FEV(1)): 48 +/- 4% of predicted], 7 noncachectic COPD patients (FEV(1): 53 +/- 5% of predicted), and 7 age-matched healthy control subjects, who were matched by body mass index with the noncachectic patients. DESIGN: After the subjects fasted overnight (10 h) and discontinued the maintenance medication, a primed constant and continuous infusion protocol was used to infuse L-[ring-(2)H(5)]-phenylalanine and L-[ring-(2)H(2)]-tyrosine to measure WB protein turnover and L-[(2)H(3)]-3-methylhistidine to measure WB MPB. Three arterialized venous blood samples were taken between 80 and 90 min of infusion to measure amino acid concentrations and tracer enrichments. RESULTS: Body composition, WB protein turnover, and WB MPB did not differ significantly between the noncachectic COPD and control subjects. Cachectic COPD patients had lower fat mass and fat-free mass values (both: P < 0.01) than did the noncachectic COPD patients. WB MPB was significantly (P < 0.05) higher in the cachectic COPD group (18 +/- 3 nmol . kg(-1) . min(-1)) than in the combined control and noncachectic COPD groups (10 +/- 1 nmol . kg(-1) . min(-1)), but WB protein turnover did not differ significantly between the groups. Correlations with fat-free mass were significant (P < 0.05) for plasma glutamate and branched-chain amino acids, and that for WB MPB trended toward significance (P = 0.07). CONCLUSION: Cachexia in clinically stable patients with moderate COPD is characterized by increased WB MPB, which indicates that myofibrillar protein wasting is an important target for nutritional and pharmacologic modulation.

Aged↗
PubMed2002

TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways.

Cachexia is associated with poor prognosis in patients with chronic disease. Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in mediating cachexia and has been demonstrated to inhibit skeletal muscle differentiation in vitro. It has been proposed that TNFalpha-mediated activation of NFkappaB leads to down regulation of MyoD, however the mechanisms underlying TNFalpha effects on skeletal muscle remain poorly understood. We report here a novel pathway by which TNFalpha inhibits muscle differentiation through activation of caspases in the absence of apoptosis. TNFalpha-mediated caspase activation and block of differentiation are dependent upon the expression of PW1, but occur independently of NFkappaB activation. PW1 has been implicated previously in p53-mediated cell death and can induce bax translocation to the mitochondria. We show that bax-deficient myoblasts do not activate caspases and differentiate in the presence of TNFalpha, highlighting a role for bax-dependent caspase activation in mediating TNFalpha effects. Taken together, our data reveal that TNFalpha inhibits myogenesis by recruiting components of apoptotic pathways through PW1.

Animals↗
PubMed1998

Elevated serum interleukin-6 levels in patients with pancreatic cancer.

The vast majority of pancreatic cancer patients have advanced disease at the time of diagnosis and they eventually become so emaciated that death primarily occurs from cancer cachexia. Cancer cachexia may be mediated by certain cytokines such as interleukin-6. In this study, we measured serum interleukin-6 levels in 55 patients with histologically proven pancreatic cancer and investigated their relationships to the clinical status of pancreatic cancer. A control population of 20 normal healthy adults and 25 chronic pancreatitis patients with comparable gender and age distribution characteristics was also studied. Serum interleukin-6 levels were measured using a quantitative sandwich enzyme-linked immunosorbent assay. Thirty pancreatic cancer patients (54.5%) had detectable levels, although interleukin-6 levels were detectable in only one healthy control and in two chronic pancreatitis patients. The specificity of serum interleukin-6 in this population was 93.3%, resulting in high diagnostic accuracy (72.0%). Among the pancreatic cancer patients, the detection rates of serum interleukin-6 levels increased significantly with the disease extent (p < 0.01). Moreover, a significant difference was also found in the detection rates between the 30 pancreatic cancer patients with body weight loss (76.7%) and the remaining 25 patients without weight loss (28.0%, p < 0.01). These results may provide new insight into both diagnosis and treatment of pancreatic cancer, because the diagnostic accuracy of serum interleukin-6 was high and because anti-interleukin-6 therapeutics could improve symptoms in pancreatic cancer patients with high interleukin-6 levels.

Adult↗
PubMed1993

Effects of tumor necrosis factor-alpha on muscle-protein turnover in female Wistar rats.

BACKGROUND: Many cancer patients experience a wasting syndrome (cachexia) characterized by weight loss and abnormalities in carbohydrate, protein, and lipid metabolism. Recent experimental studies suggest that the development of cancer cachexia involves the host's production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). PURPOSE: Our goal was to evaluate in rats the effects of an 8-day TNF-alpha treatment on overall protein metabolism in the liver, diaphragm, heart, and hind-leg muscles. METHODS: Four experimental groups corresponding to specific tissues (liver, diaphragm, heart, and hind-leg muscles) in female Wistar rats (100-150 g) were studied. Each group consisted of 25 TNF-alpha-treated and 25 control female Wistar rats. The TNF-alpha-treated rats were given intraperitoneal injections of recombinant-derived human TNF-alpha (0.5 mL) that was administered in two daily injections of 50 micrograms/kg (total dose of 100 micrograms/kg per day) for 8 days. Control animals followed the same injection schedule as the treatment group and received 0.5 mL of physiological saline instead of TNF-alpha. All rats were radioactively labeled with NaH14CO3 24 hours prior to TNF-alpha treatment. At 0, 1, 2, 4, and 8 days during TNF-alpha treatment, five rats per group were killed to measure the radioactive decay of labeled protein in specific tissues in order to estimate fractional protein turnover. During necropsy, the liver, hind-leg muscles (soleus muscle analyzed separately on 8th day only), heart, and diaphragm were rapidly weighed, and each was homogenized. Total protein content and total DNA were also determined. Total protein radioactivity and specific protein radioactivity (per milligram of protein) were evaluated for liver, diaphragm, heart, and hind-leg muscles. Radioactivity was counted in a liquid scintillation counter. Fractional rates of protein synthesis, protein degradation, total protein, and protein accumulation or loss were calculated. RESULTS: The TNF-alpha treatment administered to female Wistar rats for 8 days resulted in a transient decrease in food intake and body weight 24 hours after the beginning of the TNF-alpha treatment. In all types of tissues studied, TNF-alpha treatment resulted in increases in both the protein synthesis and protein degradation, with a greater increase in the protein degradation that resulted in a reduced protein accumulation following TNF-alpha treatment. This reduction in protein accumulation was directly associated with a decreased soleus muscle mass on day 8 of the treatment. CONCLUSIONS: Data suggest that TNF-alpha enhances muscle degradation in experimental situations where body weight loss is not apparent.

Animals↗
PubMed1992

Paraneoplastic syndromes in lung cancer.

Paraneoplastic syndromes are caused by factors produced by cancer cells that often act at a site distant from both the primary site and its metastases. These syndromes are estimated to occur in only 7% to 15% of patients with cancer and are diagnoses of exclusion. If the definition of paraneoplastic syndrome is broadened to include indirect effects of the tumor such as cachexia or the anemia of chronic disease, the incidence is much higher. Lung cancer, particularly small cell lung cancer, is the most common malignancy causing paraneoplastic syndromes. This review focuses on recently published literature on paraneoplastic syndromes associated with lung cancer, including humoral hypercalcemia of malignancy, autoimmune paraneoplastic neurologic syndromes, neuromuscular disorders, and cancer cachexia. It includes advances in both molecular biology and immunology, and in clinical investigation.

Cachexia↗
PubMed1992

Tumor necrosis factor-alpha in pediatric HIV-1 infection.

OBJECTIVE: To evaluate the diagnostic and prognostic value of serum tumor necrosis factor-alpha (TNF-alpha) levels in HIV-1-infected children. DESIGN: Serum levels of TNF-alpha were evaluated in 57 HIV-1-infected symptomatic children aged between 7 months and 8 years. METHODS: TNF-alpha levels were determined by enzyme immunoassay. The sensitivity of the assay was 10 pg/ml. RESULTS: TNF-alpha levels (mean +/- s.d.) were significantly elevated in HIV-1-infected patients (285 +/- 390 pg/ml), compared with HIV-1-uninfected age-matched controls (22.7 +/- 4.9 pg/ml). Among HIV-1-infected children the highest levels of TNF-alpha were noted in those with Mycobacterium avium intracellulare (MAI) infection and those with interstitial lymphoid pneumonitis (LIP). In contrast, patients with Pneumocystis carinii pneumonia, progressive encephalopathy or cachexia did not have markedly elevated TNF-alpha levels. CONCLUSIONS: Serum TNF-alpha is increased in symptomatic HIV-1-infected children, with higher levels in children with LIP or MAI. Serum TNF-alpha levels are not diagnostic for cachexia or progressive encephalopathy.

AIDS Dementia Complex↗
PubMed1999

Metabolic sequelae of cancers (excluding bone marrow transplantation).

The pathogenesis of cancer anorexia/cachexia is still unclear, partly explaining why its treatment remains disappointing. Anorexia plays a central role but cancer cachexia is more complex than chronic starvation. One of the key differences is the preferential mobilization of fat and the sparing of skeletal muscle in simple starvation compared to an equal mobilization of fat and skeletal muscle in cancer patients. An increase in basal energy expenditure also appears to play a contributory role in many patients. Cytokines, essentially but not exclusively tumor necrosis factor-alpha, play an essential pathogenic role and the syndrome can be compared to a low grade chronic inflammatory state. Parenteral nutrition could facilitate the administration of complete doses of chemotherapy or radiotherapy but no significant survival benefit or decrease in treatment-induced toxicity have been demonstrated in prospective randomized trials. The gut should have the preference for nutritional support. Percutaneous endoscopic gastrostomy is used more and more often in patients with a functionally intact gastrointestinal tract, especially in patients with head and neck cancer. Progestational drugs can to some extent stimulate appetite, food intake, energy level, increase weight and decrease the severity of nausea and vomiting. However, pharmacological treatment of cancer cachexia remains disappointing and more trials with anticytokine drugs, anabolic agents or polyunsaturated fatty acids should be conducted.

Adrenal Cortex Hormones↗
PubMed1998

Anti-cachectic effect of FK317, a novel anti-cancer agent, in colon26 and LX-1 models in mice.

The effects of FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6- methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0(2, 7). 0(10, 2] tetradeca-2,4,6-trien-9-yl acetate), a novel anti-cancer agent, on murine adenocarcinoma colon26- and human lung carcinoma LX-1-induced cachexia were investigated in mice. Mice bearing colon26 or LX-1 s.c. lost weight and became cachectic, associated with tumor growth. FK317 and mitomycin C (MMC) inhibited the growth of both tumors. FK317 ameliorated the weight loss induced by the presence of colon26 or LX-1, while MMC enhanced it. An attenuation of the reduction in the weights of epididymal fat, gastrocnemius muscle and carcass was observed in FK317-treated tumor-bearing mice in both cachexia models, but not in MMC-treated mice. The decreases in the circulating levels of triglyceride, glucose and non-esterified fatty acid, which were induced by the presence of colon26, was partially inhibited by treatment with FK317. Overall, this study revealed that FK317 is a potent anti-cancer drug with anti-cachectic activity, suggesting that FK317 has potential utility for the treatment of cancer.

Adenocarcinoma↗
PubMed2004

Serum levels of leptin and proinflammatory cytokines in patients with gastrointestinal cancer.

The aim was to investigate the serum levels of leptin, TNF-alpha, IL-1 beta, IL-6, insulin, and growth hormone in patients with upper gastrointestinal cancer and cachexia. A total of 39 patients with various advanced stage (stage IV) gastrointestinal malignancies were enrolled. These cancer patients were divided into two groups according to the presence or absence of cachexia. Fifteen healthy adults were recruited as the control group. Body mass index (BMI; kg/m2) was calculated. Serum leptin, tumour necrosis factor (TNF)-alpha interleukin (IL)-1 beta, interleukin (IL)-6, growth hormone, insulin, glucose, triglyceride, total protein, albumin, erythrocyte sedimentation rate, and CRP were measured. In both cancer groups (cachectic and non-cachectic) body mass index and serum leptin levels were lower than controls (p < 0.001). Serum IL-1 beta, IL-6, and growth hormone levels were higher in both cachectic and non-cachectic groups than those of controls (p < 0.05). Serum TNF-alpha level in non-cachectic group was also significantly higher than in control group (p < 0.01). There is no significant difference between three groups in terms of insulin resistance as assessed by HOMA index. Our results showed that some proinflammatory cytokine levels were increased and leptin level was decreased due to upper gastrointestinal cancers. Increased cytokine levels may lead to decreased food intake and caused a weight loss.

Adult↗
PubMed1984

Tumor-bearing depresses distant mast-cell-mediated mitogenesis.

A methylcholanthrene-induced sarcoma grafted subcutaneously in rats was used in early transplantation generations. Tumor-bearing rats showed weight loss compatible with cachexia. Healthy rats of the same age served as controls. In tumor-bearing rats the basal mesenteric proliferation was unaffected whereas the strictly mast-cell-mediated hyperproliferative reaction in the mesentery was significantly reduced after intraperitoneal injection of the mast-cell-secretagogue compound 48/80, as judged from specific DNA activity and mitosis counting. However, in mesentery and peritoneal lavage the number of mast cells, their histamine-releasing capacity, and their content of histamine, 5-hydroxytryptamine and heparin were unaffected by tumor-burden. The findings suggest the presence of a tumor-associated systemic factor of unknown nature which interferes with the biochemical events leading to the mast-cell-dependent mitogenesis. Since this mitogenic reaction may normally compensate for injury at the cellular level it is questioned whether the decreased mast-cell-dependent proliferation in tumor-bearing is a component of cachexia.

Animals↗
PubMed1990

Metabolic responses to cachectin/TNF. A brief review.

Cachectin/tumor necrosis factor (TNF-alpha) is a macrophage-secreted cytokine initially found to be a lipoprotein lipase-suppressing serum factor in cachectic, parasite-infected animals. Cloning of the cDNA encoding the gene for cachectin enabled biosynthesis of recombinant human cachectin and proof that the protein is identical to TNF-alpha. Numerous biological activities have subsequently been attributed to this pluripotent cytokine. In addition to suppressing LPL, cachectin/TNF mediates decreased lipogenic enzyme synthesis in adipocytes, causing a state of "cellular cachexia" in vitro. Similarly, catabolic cellular energy responses are induced by cachectin/TNF in cultured skeletal muscle cells which exhibit accelerated glycogenolysis, enhanced lactate production, and increased expression of hexose transporters. Persistent cachectin/TNF production occurs in chronic infection and malignancy, and chronic exposure induces a cachexia syndrome characterized by anorexia, weight loss, and anemia. Acute systemic appearance of cachectin/TNF is capable of inducing a state of lethal shock, disseminated hemorrhagic necrosis, catabolic hormone release, and multiple organ injury. Inhibiting the toxic effects of cachectin/TNF with monoclonal anti-cachectin antibodies during overwhelming Gram-negative bacteremia confers protection against septic shock. In these studies, the unprotected controls succumbed within hours, but baboons immunized against cachectin/TNF did not develop the characteristic increases of IL-1, IL-6, or catabolic stress hormones and did not die, suggesting that cachectin/TNF is a pivotal, proximal factor in the humoral cascade mediating septic shock syndrome. Recent evidence indicates that when produced in lesser quantities, cachectin/TNF may participate in the degradative and reparative mechanisms of physiological tissue remodelling and homeostasis. Future studies of the immunological and metabolic effects of cachectin/TNF should lead to a better understanding of the pathogenesis of infection and inflammation.

Animals↗
PubMed2002

Lethal weight loss: the focus shifts to signal transduction.

A hallmark of life-threatening disease in vertebrates is cachexia, a syndrome of weight loss with progressive erosion of body protein. Tumor necrosis factor (TNF) and other endogenously derived factors are sufficient to mediate the pathophysiology of cachexia in vivo, but the downstream signaling pathways have remained a mystery until recently. Tracey describes the involvement of the stress-activated protein kinase p38 and the transcriptional regulators nuclear factor kappa B and peroxisome proliferator-activated receptor gamma coactivator-1 in causing alterations in myocytes and skeletal muscle physiology. Furthermore, soluble factors including TNF and proteolysis-inducing factor may enhance protein degradation through the ubiquitin-proteosome pathway.

Animals↗
PubMed1984

Protein synthesis in muscle measured in vivo in cachectic patients with cancer.

Rates of synthesis of protein were measured in vivo in skeletal muscle and in the whole body of cachectic patients with cancer and in normal healthy men, using a tracer infusion of leucine labelled with a stable isotope. Synthesis of protein in muscle was significantly reduced in the patients with cancer (0.030 v 0.198%/hour; p less than 0.01), whereas whole body rates of protein synthesis and degradation did not differ significantly between the two groups. Thus depression of synthesis of protein in muscle appeared to be the immediate cause of muscle wasting in cancerous cachexia. Any therapeutic intervention that aims at preventing the onset of cachexia should be designed to stimulate the synthesis of protein in muscle, and measurement of turnover of protein may be used to evaluate such treatment provided that rates of protein synthesis are measured directly in specific tissues.

Aged↗
PubMed1991

Increased concentrations of tumour necrosis factor in "cachectic" patients with severe chronic heart failure.

OBJECTIVE: To ascertain whether patients with cardiac failure and reduced body weight ("cardiac cachexia") have increased circulating concentrations of tumour necrosis factor (cachectin). DESIGN: Patients with cardiac failure were prospectively identified as "cachectic" (body fat less than 27% in men and less than 29% in women measured by skinfold thickness callipers) or "non-cachectic". Tumour necrosis factor was assayed blind to patient group. SETTING: Cardiology unit in a tertiary referral centre. PATIENTS: 26 consecutive patients (10 women) (mean age 61) admitted for investigation or treatment of chronic heart failure. All were in New York Heart Association class III or IV. RESULTS: In nine of the 16 cachectic patients the concentration of tumour necrosis factor was increased (mean (SEM) 74 (20) pg/ml) compared with one of the 10 "non-cachectic" patients (22 pg/ml, p less than 0.001). Patients with a raised circulating concentration of tumour necrosis factor weighed significantly less (55.6 (3.5) kg) than those in whom the concentration of tumour necrosis factor was normal (69.0 (4.1) kg) (p = 0.02). CONCLUSIONS: Circulating concentrations of tumour necrosis factor were increased in a significant proportion of patients with chronic heart failure and low body weight. Tumour necrosis factor stimulates catabolism experimentally and it may be a factor in the weight loss seen in patients with "cardiac cachexia".

Adult↗
PubMed1994

Tumor necrosis factor: a pleiotropic cytokine and therapeutic target.

Advances in the molecular biology of human diseases indicate that the most striking manifestations of illness may be caused not by exogenous pathogenic or tumor products, but rather by toxic peptides produced by the host itself. Tumor necrosis factor (TNF), a polypeptide cytokine produced during infection, injury, or invasion, has proved pivotal in triggering the lethal effects of septic shock syndrome, cachexia, and other systemic manifestations of disease. Because removing TNF from the diseased host may prevent development of the illness, this factor has recently been the focus of intensive research. This review discusses the biology of this cytokine, with particular emphasis on its potential therapeutic role in septic shock and cachexia.

Animals↗
PubMed1997

Sickness behavior in mice deficient in interleukin-6 during turpentine abscess and influenza pneumonitis.

Interleukin-6 (IL-6), among other cytokines, is thought to be involved in the regulation of sickness behavior (e.g., anorexia, cachexia, fever, and lethargy) induced by infections bacterial and viral origin) and sterile tissue necrosis (burns and surgical traumas). Mice deficient in IL-6 (IL-6 KO) were generated by gene targeting. Homozygous IL-6 KO male and female mice and their appropriate controls were implanted with biotelemeters to monitor body temperature (Tb) and motor activity (Act). Normal circadian rhythms in Tb and Act as well as rates of food intake and weight gain did not differ significantly between sex-matched IL-6 KO and control groups at 30 degrees C in a 12:12-h light-dark cycle. Sterile tissue damage was induced in mice by subcutaneous injection of turpentine (0.1 ml, left hindlimb). Influenza pneumonitis was induced by intranasal inoculation of mouse-adapted influenza A virus (17.5 plaque-forming units). Lack of IL-6 completely prevented fever, anorexia, and cachexia because of turpentine abscess in both sexes. It did not prevent lethargy, although IL-6 KO mice recovered to normal Act significantly sooner than wild-type mice. Symptoms of sickness were only slightly modified during influenza virus infection in IL-6 KO mice. Attenuation of sickness behavior was more pronounced in IL-6 KO female than in male mice. We conclude that, although IL-6 is induced during both turpentine abscess and influenza infection, this cytokine appears to be more critical in induction of the symptoms of sickness behavior during sterile tissue abscess than during influenza infection.

Abscess↗