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Cachexia is a prominent feature in many chronic diseases, but its pathogenesis is still not fully understood. This article reviews recent research into the role of the gut barrier in the pathogenesis of inflammation and cachexia with special emphasis on two potentially catabolic diseases: liver cirrhosis and chronic heart failure.There is increasing evidence that catabolic diseases such as liver cirrhosis and chronic heart failure are associated with increased gut permeability, endotoxemia and enhanced expression of proinflammatory cytokines. In liver cirrhosis normalization of portal hypertension by insertion of a transjugular intrahepatic portosystemic stent shunt obviously causes improvement not only of gut barrier function, but also of nutritional status.Although its pathogenesis is not yet completely understood, proinflammatory cytokines have been implicated in the onset and progression of cachexia. Recent data support the hypothesis that impaired gut barrier function and increased permeability further translocation of endotoxins. Increased endotoxemia might be a potent trigger of systemic inflammatory response which is involved in the pathogenesis of the cachexia syndrome. Thus, it is tempting to speculate that therapeutic strategies for the improvement of gut barrier function will concomitantly improve nutritional status.

OBJECTIVES: Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD). METHODS: Six DLG5 variants (p.R30Q, P.P1371Q, P.G1066G, rs2289308, DLG-e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test. RESULTS: Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability. CONCLUSIONS: We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

Normothermic, nonpulsatile cardiopulmonary bypass (CPB) impairs systemic and splanchnic oxygen transport and increases gastrointestinal permeability. It is an important therapeutic goal to avoid splanchnic dysoxia during CPB. Small-dose prostacyclin therapy improves splanchnic oxygen transport and microcirculation in septic patients. In this study, we sought to determine if during cardiac surgery, the prostacyclin analog epoprostenol improves the balance of systemic and splanchnic oxygen transport. Eighteen patients undergoing cardiac valve replacement were randomized to receive either epoprostenol (3 ng x kg(-1) x min(-1)) or placebo during, and for 1 hour after, surgery. Systemic and splanchnic oxygen delivery, consumption, and extraction and arterial, mixed venous, and hepato-venous lactate concentrations were measured before, during, and after CPB. Gastrointestinal permeability was measured 1 day before and 1 day after surgery using the triple sugar permeability test. During CPB, the epoprostenol group had decreased systemic oxygen consumption and splanchnic oxygen extraction (P = 0.024). These effects were not present 1 hour after the end of epoprostenol infusion. The study was not adequately powered to determine whether epoprostenol altered the trend towards increased lactate metabolism and increased postoperative gastrointestinal permeability, nor could we demonstrate any differences between groups in clinically relevant end-points. In conclusion, these findings suggest that during normothermic CPB, small-dose epoprostenol therapy may reduce systemic oxygen consumption and splanchnic oxygen extraction.

Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD.Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation.Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group.Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment.

Objectives Treatment results of advanced hepatocellular carcinoma have remained unsatisfactory; the response rates to intravenous doxorubicin are no better than 20%. Oral tamoxifen has been proposed on the basis of beneficial results in some trials. The aim of this study was to evaluate whether the addition of doxorubicin to oral tamoxifen improves survival compared to oral tamoxifen alone. Methods Thirty-two consecutive patients with a priori defined contra-indications against surgery (transplantation, resection) or chemo-embolization were evaluated to receive chemotherapy. All patients received oral tamoxifen 30 mg bid; 16 also received intravenous doxorubicin 50 mg/m 2 every 4 weeks. The control group consisted of the remaining 16 patients who either were considered unfit for doxorubicin because of a Karnofsky index < 50% (n = 5), cardiac disease (n = 6) or who refused to have cytotoxic drug therapy (n = 5). Results Median survival time was 148 days (95% Cl 89.2-206.8) in the doxorubicin group and 96 days (95% Cl 49.0-143.0) in the control group, and this was not significantly different (P= 0.408), regardless of the presence or absence of cirrhosis. Conclusions In conclusion, the results of our study indicate that combination therapy using doxorubicin and tamoxifen is unlikely to considerably improve survival compared to tamoxifen alone in patients with advanced hepatocellular carcinoma.

To investigate the clinical relevance of interleukin-6 (IL-6) serum levels in patients with Crohn's disease (CD), single point IL-6 measurements in sera from consecutive CD patients and healthy donors (HD), as well as longitudinal measurements during the course of steroid therapy for active CD were performed. Patients with steroid-induced remission were followed until clinical relapse.One hundred thirty-six CD patients without steroid or other immunosuppressive treatment within 2 months and surgical procedures within 3 months before study entry were investigated; 63 patients with active CD were enrolled into the follow-up program. Clinical activity was evaluated by the Crohn's disease activity index (CDAI) and serum IL-6 levels measured by enzyme-linked immunosorbent assay.IL-6 serum levels were significantly elevated in CD patients compared to HD (p0.001). In individual patients serum IL-6 levels correlated with corresponding CDAI scores in a subgroup referred to as primarily inflammatory patients presenting without bowel stenosis, previous intestinal resection, or concomitant inflammatory disorders (r = 0.72, p0.001). Primarily inflammatory patients displayed higher serum IL-6 levels (median: 6.0 pg/ml; range: 1.3-25) than CD patients with bowel stenosis (median: 2.0; range: 1.3-4.9; p0.01) or extensive intestinal resection (median: 1.5; range: 1.3-13.7; p0.001). Longitudinally measured serum IL-6 levels reflected the clinical response during steroid therapy and predicted clinical relapse after steroid-induced remission at week 9 of the treatment protocol.Serum IL-6 is a clinically relevant parameter for CD that correlates with inflammatory activity and implies a prognostic value after steroid-induced remission.

Evaluation of nutritional status is a major problem in patients with liver cirrhosis this is due to water retention and the effect of liver function on protein synthesis. Despite problems evaluating the patient, malnutrition has been found to be a common complication in liver cirrhosis and is associated with poorer outcome. Nutritional restrictions, like protein restriction, are no longer recommended in most patients with liver cirrhosis but are considered harmful. An intake of 1 to 1.5 g/kg protein and 25 to 40 kcal/kg body weight a day is recommended (depending on the situation of the patient). If adequate intake cannot be achieved by oral nutrition, stepwise nutritional support with the introduction of an additional late evening meal, sip feeding or tube feeding is recommended. Parenteral nutrition should be used as a second line treatment for acutely ill patients. Data indicate that improvement of nutritional status prior to liver transplantation might reduce complications.

The effect of normothermic (36.2 degrees C +/- 0.6 degree C) nonpulsatile cardiopulmonary bypass (CPB) on splanchnic (hepatic) blood flow (SBF), splanchnic oxygen transport (DO2spl) and oxygen consumption (VO2spl), splanchnic lactate uptake and gastric mucosal pH (pHi, gastric tonometry) was studied in 12 adults (New York Heart Association class II, ejection fractionor = 0.4) undergoing coronary artery surgery. SBF was estimated with the constant-infusion indocyanine green (ICG) technique using a hepatic venous catheter. DO2spl, VO2spl, and splanchnic lactate uptake were calculated using the Fick principle after the induction of anesthesia, during aortic cross-clamping, after CPB, and 2 and 7 h after admission to the intensive care unit (ICU). SBF, DO2spl, and VO2spl did not decrease during CPB but increased after ICU admission, whereas pHi decreased 7 h after ICU admission. Initial ICG extraction was 0.78, which decreased to 0.54 during aortic clamping and remained low thereafter. The increased arterial blood lactate concentrations were not associated with a decreased splanchnic lactate uptake. We conclude that normothermic CPB is not associated with deterioration in the global intestinal oxygen supply. The increase of blood lactate levels and the decrease in ICG extraction, as well as in pHi, are consistent with a systemic inflammatory response to CPB.This study demonstrated that normothermic cardiopulmonary bypass (at flows2.4 L.min-1.m-2) was not associated with deterioration in global intestinal oxygen delivery, which suggests that increased blood lactate concentrations and decreased gastric mucosal pH and indocyanine green extraction are manifestations of a systemic inflammatory response to cardiopulmonary bypass.

The impact of hepatic dysfunction on the elimination and hydrolysis of three potential tyrosine sources for total parenteral nutrition, the dipeptides L-alanyl-L-tyrosine (Ala-Tyr) and glycyl-L-tyrosine (Gly-Tyr), and N-acetyl-L-tyrosine (Nac-Tyr) were evaluated in six patients with hepatic failure (five chronic, one acute) and seven healthy subjects. In controls, whole-body clearance (Cltot) of Ala-Tyr was higher than of Gly-Tyr (3,169 +/- 214 vs. 1,780 +/- 199 mL/kg/min, P.01), and both exceeded clearance of Nac-Tyr (309 +/- 29 mL/kg/min, P.01). Both dipeptides were hydrolyzed and released tyrosine immediately. In hepatic failure, elimination and hydrolysis of Ala-Tyr and Gly-Tyr were comparable to controls, but Cltot of Nac-Tyr was reduced (236 +/- 26 mL/kg/min). Neither in controls nor in patients an increase in plasma tyrosine concentration was seen after Nac-Tyr, and the major part of Nac-Tyr infused was lost in urine. The Cltot of tyrosine as evaluated after Ala-Tyr infusion (with the immediate release of tyrosine) was severely reduced in hepatic failure (152.7 +/- 38.4 vs. 484.4 +/- 41.4 mL/kg/min, P.001) and half-life (kle) was retarded from 14.4 +/- 1.4 to 90.2 +/- 32.2 minutes (P.03). The authors conclude that acute and chronic hepatic dysfunction does not affect elimination and hydrolysis of the dipeptides Ala-Tyr and Gly-Tyr and the constituent amino acids are released immediately. Nac-Tyr elimination was not grossly affected by hepatic failure, but neither in healthy subjects nor in hepatic failure patients was an increase of tyrosine seen. Both dipeptides but not Nac-Tyr may serve as a tyrosine source in parenteral nutrition. Moreover, by its rapid hydrolysis, the use of Ala-Tyr, for the first time, enables a simple rapid nonisotope evaluation of tyrosine kinetics for assessment of liver function.

Objective: To assess the prevalence of and risk factors for clinical and subclinical vitamin D deficiency in Crohn's disease. Patients: Vitamin D status was determined, in winter, in 50 consecutive outpatients with Crohn's disease and in 50 healthy controls. Methods: Vitamin D status was determined by measurement of 25-hydroxyvitamin D (25-OH-D), 1,25-dihydroxyvitamin D (1,25-(OH) 2 -D), vitamin-D-binding protein and of the C-terminal fragment of parathormone in serum, and by calculation of the free 1,25-(OH) 2 -D index [as a ratio of the molar concentrations of free 1,25-(OH) 2 -D and vitamin-D-binding protein]. Precise and evaluable dietary records were obtained from 18 patients only

Background: Chronic heart failure (CHF) is a state of chronic inflammation. High serum levels of TNF alpha and the presence of cardiac cachexia are known to predict poor survival in CHF. Abnormal balance of pro- and anti-inflammatory circulating cytokine mRNA gene expression is thought to contribute to cachexia in humans, but has never been studied in CHF patients. Methods and Results: We studied 7 patients with cardiac cachexia (age 70±4 years, LVEF 28±2%, peak VO2 12.7±1.6 mL/kg/min, all >6% weight loss in previous 6–24 months), 19 noncachectic CHF patients (age 68±2 years, LVEF 31±2%, peak VO2 14.7±1.1 mL/kg/min) and 17 control subjects of similar age and gender (peak VO2 25.1±1.7 mL/kg/min, LVEF 71±2%). The mRNA gene expression of circulating mononuclear blood cells for pro-inflammatory mediators that have been implicated in the wasting process of ageing (TNF, STAT-1, STAT-3, SOCS-1 and SOCS-3) as well as anti-inflammatory cytokines (IL-10, tumor growth factor (TGF) beta were investigated by real time polymerase chain reaction. Values for the house keeping gene and genes of interest were calculated from double determinations within 40 cycles. We found higher TNF expression in cachectic compared to noncachectic CHF patients (log mean −0.5±0.17 vs. −1.2±0.12, p=0.002, ANOVA-p=0.0071) and control subjects (log mean −1.2±0.1, p=0.006). In contrast, there was no change in IL-10 gene expression in cachectic patients compared to noncachectic patients and controls (log mean −2.6±0.2 vs. −3.0±0.09 vs. −2.9±0.1, all p>0.13). Consequently TNF/IL-10 expression ratio was highest in cachectic patients (308±138 vs. 132±55 in noncachectic CHF patients vs. 101±37 in controls, p0.17). Similarly, no differences were found for gene expression of TGF beta (p>0.15). Conclusion: The balance between the pro-inflammatory cytokine TNF and the anti-inflammatory cytokine IL-10 on the level of mRNA expression of circulating mononuclear cells is significantly disturbed. Proinflammatory cytokine imbalance in cardiac cachexia may be important for the pathophysiology of body wasting and may represent the activated immune reflex.

Liver cirrhosis in erythropoietic protoporphyria: improvement of liver function with ursodeoxycholic acid