Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options.
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Cachexia↗
Biomedical subjects
K C Fearon
Publications and source records attributed to K C Fearon.
Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis.
Glutamine, a conditionally essential amino acid, is important for immune function. It is now being formulated for incorporation into total parenteral nutrition (TPN). The aims of this study were to examine the effect of glutamine administration on lymphocyte proliferation and proinflammatory cytokine release in patients with severe acute pancreatitis. Fourteen patients were randomized (in a double-blind fashion) to receive either conventional or isocaloric, isonitrogenous glutamine-supplemented (0.22 g glutamine x kg(-1) x d(-1) as glycyl-glutamine) TPN for 7 d. DNA synthesis (index of lymphocyte proliferation) and the 24-h release of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 from peripheral blood mononuclear cells were measured in vitro on days 0, 4, and 7. Thirteen patients completed the study protocol (6 glutamine TPN, 7 conventional TPN). Glutamine supplementation increased median DNA synthesis by 3099 cpm over the study period against 219 cpm in the conventional group (increase not significantly different between the two groups) . Glutamine supplementation did not significantly influence TNF or IL-6 release, but, in contrast, median IL-8 release was reduced by day 7 in the glutamine group while it was increased in the conventional group (-17.7 ng/mL (median change over study period) versus +43.3 ng/mL, respectively; P=0.045). Small patient numbers and substantial interindividual variation limit the conclusions, but there is a trend for the glutamine group to have improved lymphocyte proliferation, and in the case of IL-8, reduced proinflammatory cytokine release.
Adult↗
Albumin synthesis rates are not decreased in hypoalbuminemic cachectic cancer patients with an ongoing acute-phase protein response.
OBJECTIVE: To determine whether suppression of albumin synthesis contributes to the hypoalbuminemia observed in weight-losing cancer patients with evidence of an ongoing acute-phase protein response (APPR). BACKGROUND DATA: Proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) are known to downregulate albumin synthesis and increase acute-phase protein production in isolated hepatocytes. However, whether albumin synthesis is suppressed in hypoalbuminemic cancer patients with evidence of an ongoing acute-phase response is unknown. METHODS: Albumin synthesis rates were determined in six healthy controls and in six weight-losing pancreatic cancer patients with an ongoing APPR using a flooding dose technique with [2H5]-phenylalanine. The presence of an APPR was defined as a serum C-reactive protein concentration >10 mg/L. Serum cytokines (TNF, IL-6) and soluble TNF receptors (sTNF-R 55 and 75), along with serum cortisol and insulin, were also measured in both groups. RESULTS: Cancer patients had reduced serum albumin (median 32 [range, 23-36] vs. 42 g/L [40-45]; p < 0.01) and increased serum C-reactive protein concentrations (72 [23-126] vs. <5 mg/L; p < 0.01) when compared with controls. TNF was not detected in either group. sTNF-R 55 levels were significantly elevated in the cancer patients (3.8 [1.9-8.1] vs. 1.2 pg/mL [0.9-2.2]; p < 0.01). Circulating IL-6, insulin, and cortisol concentrations were not significantly different between the groups. The intravascular albumin mass was lower (88 [56-93] vs. 133 g [105-177]; p < 0.01), but the intravascular albumin fractional synthetic rate was higher (13.9 [13.5-18.5] vs. 10.3%/d [71-11.3]; p < 0.01) in the cancer patients compared with the controls. The total intravascular albumin synthetic rate was, however, similar between the two groups (12.7 [7.7-15.7] vs. 11.7 g/d [8.5-18.7]; p NS). CONCLUSIONS: In weight-losing pancreatic cancer patients with evidence of an ongoing APPR, hypoalbuminemia is not caused by a decreased rate of albumin synthesis.
Acute-Phase Proteins↗
Changes in nutritional status associated with unresectable pancreatic cancer.
Weight loss is common in patients with pancreatic cancer; however, the nature and progress of their nutritional depletion are not well documented. In this study, pre-illness weight and duration of weight loss were recorded in 20 patients with histologically confirmed unresectable cancer of the pancreas. Patients then underwent nutritional analysis at monthly intervals until death. The median period of assessment was 27 weeks (interquartile range 22.5-38.0 weeks). At the time of diagnosis, all patients had lost weight [median 14.2% (10.0-20.0%) of pre-illness stable weight], and this weight loss was progressive, increasing to a median of 24.5% by the time of the last assessment (P =0.0004). Body mass index was significantly reduced from a pre-illness median value of 24.9 kg m-2 (22.4-27.4 kg m-2) to 20.7 kg m-2 (19.5-23.6 kg m-2) at the time of diagnosis and further to 17.7 kg m-2 (16.6-23.1 kg m-2) just before death (P =0.0003). Further evidence of tissue depletion was evident from the significant reductions in lean body mass [43.4 kg (36.9-53.0 kg) to 40.1 kg (33.5-50.7 kg) P =0.008] and fat mass [12.5 kg (8.9-17.8 kg) to 9.6 kg (6.3-15.1 kg) P =0.03). This study confirms that the majority of patients with unresectable pancreatic cancer have already undergone significant weight loss by the time of diagnosis and that the natural history of this process is one of inexorable progression. These results highlight the need for selective non-toxic therapeutic intervention to attenuate cachexia and indicate that such interventions should be instituted early in the course of the disease.
Anthropometry↗
A pilot study of megestrol acetate and ibuprofen in the treatment of cachexia in gastrointestinal cancer patients.
Advanced gastrointestinal cancer patients with weight loss and an acute-phase response (n = 15) were given megestrol acetate (480 mg day(-1)) and ibuprofen (1200 mg day(-1)) for 6 weeks. Overall, there was an increase in body weight (P = 0.01) and a reduction in C-reactive protein concentrations (P = 0.02), with no change in total body water (P = 0.24) over this period. This regimen may be an effective non-toxic treatment for cancer cachexia and is worthy of further study.
Adult↗
Down-regulation of the acute-phase response in patients with pancreatic cancer cachexia receiving oral eicosapentaenoic acid is mediated via suppression of interleukin-6.
1. Weight loss in pancreatic cancer is associated with persistent elevation of the acute-phase protein response. The effect of oral administration of eicosapentaenoic acid on the regulation of the acute-phase response in weight-losing patients with pancreatic cancer was investigated in vitro and in vivo. 2. Oral supplementation with eicosapentaenoic acid, in patients with cancer cachexia, resulted in a significant reduction in the serum concentration of the acute-phase protein C-reactive protein (11.0 +/- 4.8 mg/l before eicosapentaenoic acid compared with 0.8 +/- 0.8 mg/l after 4 weeks of eicosapentaenoic acid, P < 0.05), but no significant reduction in the serum concentration of the hepatocyte-stimulating cytokine interleukin-6. Production of interleukin-6 by peripheral blood mononuclear cells isolated from patients was significantly reduced after supplementation with eicosapentaenoic acid (interleukin-6 production by peripheral blood mononuclear cells exposed to 10 micrograms of lipopolysaccharide/ml: 10.2 +/- 2.1 ng/ml before supplementation with eicosapentaenoic acid compared with 3.5 +/- 1.7 ng/ml after supplementation, P < 0.05) and supernatants from these cells had reduced potential to stimulate C-reactive protein production by isolated human hepatocytes (hepatocyte C-reactive protein production in response to supernatants from peripheral blood mononuclear cell cultures exposed to 10 micrograms of lipopolysaccharide/ml: 150.4 +/- 18.6 ng/ml before eicosapentaenoic acid versus 118 +/- 14.9 ng/ml after 4 weeks of eicosapentaenoic acid, P < 0.05). The potential of lipopolysaccharide-stimulated peripheral blood mononuclear cell supernatants to stimulate C-reactive protein production by hepatocytes could be attenuated by neutralizing anti-interleukin-6 antibody in control subjects and in patients before, but not after, treatment with eicosapentaenoic acid. 3. In conclusion, eicosapentaenoic acid can down-regulate the acute-phase response in patients with pancreatic cancer cachexia and this process is likely to involve suppression of interleukin-6 production.
Acute-Phase Reaction↗
Modulation of human hepatocyte acute phase protein production in vitro by n-3 and n-6 polyunsaturated fatty acids.
OBJECTIVE: The authors investigate the role of a variety of essential polyunsaturated fatty acids on the spontaneous and interleukin-6 stimulated production of acute phase proteins by isolated human hepatocytes. SUMMARY BACKGROUND DATA: The altered production of acute phase proteins by the liver is one of the principal effects of the systemic inflammatory response in human disease. It has been shown that polyunsaturated fatty acids have certain anti-inflammatory properties that potentially are mediated through altered prostaglandin or proinflammatory cytokine production. However, the effect of polyunsaturated fatty acids on the responsiveness of the human hepatocyte to proinflammatory cytokines has not been studied in detail. METHODS: Hepatocytes isolated from human livers were maintained in primary culture in the presence of a variety of bovine serum albumin-complexed fatty acids. The influence of these fatty acids on hepatocyte acute phase protein production was assessed, in the presence and absence of recombinant interleukin-6, by measurement of acute phase proteins by enzyme-linked immunosorbent assay. RESULTS: Eicosapentaenoic and gammalinolenic acid increased spontaneous production of alpha 1-antichymotrypsin and prealbumin but decreased spontaneous production of transferrin and haptoglobin from isolated human hepatocytes. Eicosapentaenoic and gammalinolenic significantly increased interleukin-6-stimulated production of C-reactive protein and alpha 1-antichymotrypsin but reversed the stimulatory effect of interleukin-6 on haptoglobin production. These fatty acids also reversed the inhibitory effect of interleukin-6 on prealbumin production. CONCLUSIONS: These results show that certain fatty acids have the potential to modulate spontaneous and cytokine-induced alterations in human hepatic acute phase protein metabolism. These data indicate the presence of complex mechanisms of regulation of human hepatic protein metabolism by fatty acids, and further study will be required to establish the nature of their influence in vivo.
Acute-Phase Proteins↗
Abdominal pain associated with cranial nerve palsy and peripheral neuropathy.
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Abdominal Pain↗
Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes.
During the course of studies designed to identify the role of cytokines in the reprioritization of hepatic protein synthesis associated with cachexia we detected a hepatocyte-stimulating moiety in the supernatants of pancreatic cancer cells that was unrelated to interleukin (IL)-6. This study identifies that moiety as IL-8 and investigates the role of IL-8 in the induction of acute-phase protein production. The human pancreatic cancer cell line MIA PaCa-2 produced >1 ng/ml of IL-8 per 24 h, and supernatants from this cell line induced C-reactive protein (CRP) production from isolated human hepatocytes. Addition of neutralizing anti-human IL-8 antibody to such supernatants produced almost complete inhibition of CRP production. The addition of recombinant human IL-8 to hepatocytes resulted in a dose-dependent increase in CRP, alpha1-acid glycoprotein, and alpha1-antichymotrypsin production and a decrease in the production of transferrin and prealbumin. This study demonstrates that recombinant or tumor-derived IL-8 can modulate acute-phase protein production from isolated human hepatocytes and from human hepatoma cells.
Acute-Phase Proteins↗
Contribution of anorexia and hypermetabolism to weight loss in anicteric patients with pancreatic cancer.
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Adenocarcinoma↗
Serum concentrations of inflammatory mediators related to organ failure in patients with acute pancreatitis.
Leucocyte activation and proinflammatory cytokine release (tumour necrosis factor (TNF) and interleukin 6 (IL-6)) are thought to contribute to the induction of a systemic inflammatory response, an acute-phase response and multiple organ failure in patients with acute pancreatitis. The serum concentration of TNF, soluble TNF receptors (sTNFR55 and sTNFR75), IL-6 and C-reative protein (CRP) in 58 patients with acute pancreatitis was assessed during the first 2 days of admission. Thirty patients had mild disease and 28 severe disease, of whom 18 developed local pancreatic complications alone (Atlanta classification) and ten developed organ failure (a Goris score of 1 or more). TNF was detected in only 17 patients on the first day of admission, while soluble TNF receptors were detected in all patients and IL-6 in 34. On the first and second days of admission there was a progressive and significant (P < 0.03) increase in the median concentration of sTNFR55, sTNFR75 and IL-6 in patients eventually classified into those with mild disease, a local pancreatic complication alone, or organ failure. This pattern was also evident in CRP levels from the second but not the first day of admission. These findings suggest that proinflammatory cytokines or their soluble receptors may be more accurate early predictors of outcome than CRP, Moreover, markers of inflammation in the sera of patients with acute pancreatitis are highest in those who subsequently develop organ failure.
Acute Disease↗
Laparotomy for abdominal sepsis in the critically ill.
Among 125 patients admitted to an intensive care unit (ICU) with severe abdominal sepsis over a 3-year period, further laparotomy was required in 60 (48 per cent). The median age of these 60 patients was 67 (range 22-88) years and their admission APACHE (Acute Physiology and Chronic Health Evaluation) II score was 24 (range 7-40); 25 patients (42 per cent) survived to leave the ICU but only 19 (32 per cent) survived to leave hospital. These patients underwent 95 (median 1; range 1-6) operations after admission to the ICU and survival fell with increasing number of operations in the ICU (P = 0.01). A total of 81 operations (85 per cent) were therapeutic in that pus was drained or dead tissue removed, and 41 operations (43 per cent) resulted in improvement in the patient's condition within 48 h of surgery. Only nine per cent of patients not improved by their first operation in the ICU survived (P < 0.0001). The source of sepsis was eradicated from the abdomen in 37 patients (62 per cent); this was a prerequisite for survival but was achieved less frequently with increasing number of operations (P < 0.002). When operations were delayed until the diagnosis was clear, the need for subsequent procedures was significantly increased (P < 0.05). Multiple operations for patients with abdominal sepsis in the ICU were associated with diminishing returns and alternative surgical strategies merit active consideration.
Abdomen↗
Proinflammatory cytokine release by peripheral blood mononuclear cells from patients with acute pancreatitis.
Proinflammatory cytokine release was measured from peripheral blood mononuclear cells (PBMCs) isolated from six volunteers and, on admission, from 16 patients with acute pancreatitis. Tumour necrosis factor (TNF) release in patients did not differ significantly from that of volunteers, whereas both interleukin (IL) 6 and IL-8 release in patients was raised when compared with that in the volunteer group (mean(s.e.m.) IL-6 20.7(4.6) versus 9.3(1.7) ng/ml, P = 0.03; IL-8 283(40) versus 128(22) ng/ml, P = 0.04). When variation in white cell count was accounted for, IL-6 and IL-8 release but not that of TNF was significantly greater in patients with severe disease than in those with mild disease. These results point to a complex upregulation of proinflammatory cytokine release from PBMCs in patients with acute pancreatitis, components of which relate to the clinical progress of the disease.
Acute Disease↗
The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer.
Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2-4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.
Acute-Phase Proteins↗
Simultaneous measurement of albumin and fibrinogen synthetic rates in normal fasted subjects.
Albumin and fibrinogen synthesis appear to account for the majority of protein exported by the liver and therefore make a substantial contribution to that of whole-body protein synthesis. However, data on the protein synthetic rates of albumin and fibrinogen in normal subjects are limited. Albumin and fibrinogen synthetic rates were measured simultaneously over a 120-min period in normal subjects (n = 6) by using a flooding dose of 2H5-phenylalanine. Tracer incorporation into proteins was measured by gas chromatography/mass spectrometry. Body mass index, circulating concentrations of insulin, albumin, fibrinogen, C-reactive protein, and plasma volumes of the subjects were all within the normal reference range. There was a small and transient rise in circulating insulin concentrations following the flooding dose of phenylalanine. The median fractional synthetic rate and absolute synthetic rate for albumin was 10.3%/d and 208 mg.kg-1.d-1, respectively. The median fractional synthetic rate and absolute synthetic rate for fibrinogen was 19.5%/d and 28 mg.kg-1.d-1. In the context of the current interest in manipulating the inflammatory response of patients with various disease states, we introduce the concept of an acute phase protein quotient (APPQ). The APPQ is defined as the absolute rate of fibrinogen synthesis divided by that of albumin. In this group of normal subjects, the median APPQ was 0.14.
Aged↗
Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro.
Eicosapentaenoic acid (EPA) has been shown to have an inhibitory effect on the growth of several pancreatic cancer cell lines in vitro. This study investigates the mechanism of growth inhibition and cytotoxicity of EPA on the pancreatic cancer cell line MIA PaCa-2. Cells were analysed for cell count, viability, cell cycle distribution and ultrastructural changes. There was a time- and dose-dependent decrease in cell count and viability in cultures of pancreatic cancer cells supplemented with EPA. Flow cytometric DNA analysis of MIA PaCa-2 cells incubated with EPA demonstrated the presence of sub G1 populations corresponding to the presence of apoptotic cells and the blockade of cell cycle progression in S-phase and G2/M-phase. The presence of apoptosis in EPA-supplemented cultures was further confirmed by DNA fragmentation and ultrastructural changes associated with apoptosis. Therefore, we conclude that EPA mediates its effect on the pancreatic cancer cell line MIA PaCa-2, at least in part, via cell cycle arrest and the induction of apoptosis.
Antineoplastic Agents↗
Metabolic disturbance and sensitivity to endotoxin in patients with advanced cancer: relationship to lymphocyte reactivity, tumour necrosis factor (TNF) production and survival.
Increased TNF production and impaired lymphocyte function have been individually linked with metabolic disturbance, endotoxaemia and mortality in humans. The inter-relationship between these observations was investigated in humans with cancer. In 13 patients with metastatic colorectal cancer and seven healthy volunteers, observations (n = 23) included peripheral blood mononuclear cell (PBMC) TNF production, IL-2 production and phytohaemagglutinin (PHA) response; the acute-phase protein response (APPR) (serum C-reactive protein (CRP), albumin, CRP/albumin ratio), and survival. APPR correlated with survival (CRP, r = -0.689, P = 0.006; CRP/albumin, r = -0.758, P = 0.002; albumin, r = 0.655, P = 0.011), but not with TNF production. TNF production in response to in vitro endotoxin correlated with impaired lymphocyte function in patients (r = 0.567, P = 0.043) and in the whole group (r = 0.65, P = 0.001). The ratio (basal PBMC TNF production)/(lymphocyte function) correlated with CRP (r = 0.569, P = 0.042), CRP/albumin (r = 0.617, P = 0.025), endotoxin sensitivity (r = 0.567, P = 0.043) and survival (r = -0.545, P = 0.038) in patients, and the whole group (P < 0.002). Impaired lymphocyte function may influence TNF production, endotoxin sensitivity and metabolic disturbance in humans with cancer. (r = Spearman correlation coefficient.)
Adult↗
Circulating endotoxin, tumour necrosis factor-alpha, and their natural antagonists in the pathophysiology of acute pancreatitis.
Inflammatory mediators, such as endotoxin and tumour necrosis factor-alpha (TNF-alpha) have been implicated in the pathogenesis of acute pancreatitis. However, serum levels of these mediators in patients with acute pancreatitis are often not detectable on hospital admission. In contrast, their circulating antagonists (antiendotoxin antibodies and soluble TNF-alpha receptors) are detectable in all patients. With increasing severity of disease, patients are more likely to manifest a fall in antiendotoxin levels, suggesting exposure to endotoxin. Similarly, there is a stepwise increase in soluble TNF-alpha receptors with increasing severity of disease. This suggests that the degree of TNF-alpha-induced inflammation correlates with disease severity. The role of endotoxin, TNF-alpha and their relevant antagonists as markers or mediators of the systemic complications of acute pancreatitis remains under investigation.
Acute Disease↗