Lukas Degen

The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans

BACKGROUND AND AIMS The mechanism of intraduodenal fat induced inhibition of food intake is still unclear. Therefore, we tested the ability of duodenal fatty acids to suppress food intake at a lunchtime meal; in addition, we were interested to test if these effects were mediated by cholecystokinin (CCK) A receptors. SUBJECTS AND METHODS Three sequential double blind, three period crossover studies were performed in 12 healthy males each: (1) subjects received intraduodenal fat with or without 120 mg of tetrahydrolipstatin, an inhibitor of gastrointestinal lipases, or saline; (2) volunteers received intraduodenal long chain fatty acids, medium chain fatty acids, or saline; (3) subjects received long chain fatty acids or saline together with concomitant intravenous infusions of saline or loxiglumide, a specific CCK-A receptor antagonist. The effect of these treatments on food intake and feelings of hunger was quantified. RESULTS Intraduodenal fat perfusion significantly (p<0.05) reduced calorie intake. Inhibition of fat hydrolysis abolished this effect. Only long chain fatty acids significantly (p<0.05) decreased calorie intake, whereas medium chain fatty acids were ineffective. Infusion of loxiglumide abolished the effect of long chain fatty acids. CONCLUSIONS Generation of long chain fatty acids through hydrolysis of fat is a critical step for fat induced inhibition of food intake; the signal is mediated via CCK-A receptors.

P‐Glycoprotein and Surfactants: Effect on Intestinal Talinolol Absorption

Surfactants used in pharmaceutical formulations can modulate drug absorption by multiple mechanisms including inhibition of intestinal P‐glycoprotein (P‐gp). Our objective was to analyze the effect of 2 surfactants with different affinity for P‐gp in vitro on the intestinal absorption and bioavailability of the P‐gp substrate talinolol in humans.

Gastrointestinal satiety signals in humans — Physiologic roles for GLP-1 and PYY ?

The present review summarizes the appetite suppressing effects of PYY and GLP-1 in the regulation of food intake in humans. Current evidence supports a role for gastrointestinal peptides as regulators of satiety. The regulation of satiety is, however, complex and it is not surprising that multiple control systems exist. It is interesting to note that nutrients in the small intestine such as hydrolysis products of fat stimulate the release of satiety peptides such as GLP-1 or PYY that serve as satiety signals. Both peptides, released from L-cells from the gastrointestinal tract by the local action of digested food, exert various regulatory functions: stimulation of insulin secretion and inhibition of glucagon secretion as typical actions of GLP-1, inhibition of gastric emptying, and inhibition of appetite for both GLP-1 and PYY. The review focuses on the question, whether the two peptides are true endocrine factors that act as physiologic, hormonal regulators of appetite.

Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis

Background/aims: The apical sodium dependent bile acid transporter ASBT (SLC10A2) contributes substantially to the enterohepatic circulation of bile acids by their reabsorption from the intestine. In the rat, its adaptive regulation was observed in the kidneys, cholangiocytes, and terminal ileum after bile duct ligation. Whether adaptive regulation of the human intestinal ASBT exists during obstructive cholestasis is not known. Methods: Human ASBT mRNA expression along the intestinal tract was analysed by real time polymerase chain reaction in biopsies of 14 control subjects undergoing both gastroscopy and colonoscopy. Their duodenal ASBT mRNA expression was compared with 20 patients with obstructive cholestasis. Additionally, in four patients with obstructive cholestasis, duodenal ASBT mRNA expression was measured after reconstitution of bile flow. Results: Normalised ASBT expression in control subjects was highest (mean arbitrary units (SEM)) in the terminal ileum (1010 (330)). Low ASBT expression was found in colonic segments (8.3 (5), 4.9 (0.9), 4.8 (1.7), and 1.1 (0.2) in the ascending, transverse, descending, and sigmoid colon, respectively). Duodenal ASBT expression in control subjects (171.8 (20.3)) was found to be approximately fourfold higher compared with patients with obstructive cholestasis (37.9 (6.5); p<0.0001). Individual ASBT mRNA expression was inversely correlated with bile acid and bilirubin plasma concentrations. In four cholestatic patients, average ASBT mRNA increased from 76 (18) before to 113 (18) after relief of cholestasis (NS). Immunohistochemical assessment indicated that ASBT protein was expressed on the apical surface of duodenal epithelial cells. Conclusion: Obstructive cholestasis in humans leads to downregulation of ASBT mRNA expression in the distal part of the human duodenum.

Colon Capsule Endoscopy compared to Conventional Colonoscopy under routine screening conditions

BackgroundColonoscopy (CSPY) for colorectal cancer screening has several limitations. Colon Capsule Endoscopy (PillCam Colon, CCE) was compared to CSPY under routine screening conditions.MethodsWe performed a prospective, single-center pilot study at a University Hospital. Data were obtained from November 2007 until May 2008. Patients underwent CCE on Day 1 and CSPY on Day 2. Outcomes were evaluated regarding sensitivity and specificity of polyp detection rate, with a significance level set at >5 mm.Results59 individuals were included in this study, the results were evaluable in 56 patients (males 34, females 22; median age 59). CCE was complete in 36 subjects. Polyp detection rate for significant polyps was 11% on CSPY and 27% on CCE.6/56 (11%) patients had polyps on CSPY not detected on CCE (miss rate).Overall sensitivity was 79% (95% confidence interval [CI], 61 to 90), specificity was 54% (95% CI, 35 to 70), positive predictive value (PPV) was 63% and negative predictive value (NPV) was 71%. Adjusted to significance of findings, sensitivity was 50% (95% CI, 19 to 81), specificity was 76% (95% CI, 63 to 86), PPV was 20% and NPV was 93%.ConclusionIn comparison to the gold standard, the sensitivity of CCE for detection of relevant polyps is low, however, the high NPV supports its role as a possible screening tool.Trial RegistrationNCT00991003.

Serum Protein Electrophoresis: An Underused but Very Useful Test

Serum protein electrophoresis is used in clinical practice to identify patients with multiple myeloma and other serum protein disorders. It is an inexpensive and easy-to-perform screening procedure. Electrophoresis separates serum proteins based on their physical properties and identifies morphologic patterns in response to acute and chronic inflammation, various malignancies, liver or renal failure, and hereditary protein disorders. For gastroenterologists, the use of serum protein electrophoresis may be helpful in the diagnosis of both common diseases with unusual presentations and rare disorders with typical presentations. Therefore, it represents an ideal screening tool.

Role of Free Fatty Acids in Regulating Gastric Emptying and Gallbladder Contraction

The limited effectiveness of orlistat, an inhibitor of gastrointestinal lipases, in inhibiting fat digestion is not completely understood. Therefore we studied the effect of orally and duodenally administered orlistat on gastric emptying, cholecystokinin (CCK) secretion, and gallbladder contraction. In healthy males, gastric emptying of solids and fat were quantified scintigraphically, gallbladder contraction by ultrasound and CCK release by radioimmunoassay. Three studies were performed: (1) oral and (2) duodenal orlistat with a fat-containing meal, and (3) duodenal orlistat with a fat-free meal. Gastric emptying rates of solids and fat (T50% accelerated by 16 and by 22%, p< 0.05, respectively) were significantly faster after duodenal perfusion of orlistat; gallbladder contraction and CCK release were reduced under these conditions (p < 0.005, respectively). With oral orlistat no significant effect was documented on these parameters. We conclude that fat hydrolysis is essential in the regulation of fat-induced gastric emptying and gallbladder contraction.

Cystic and solid lesions of the pancreas.

More than 95% of malignant tumours of the pancreas are exocrine carcinomas. The exocrine carcinomas have to be distinguished from benign serous cystadenomas and tumours, the latter including mucinous cystic neoplasms, serous cysts, and solid pseudopapillary neoplasms. Cystic lesions have to be separated from pseudocysts, which are the most common cysts. Pseudocysts are due to extensive confluent autodigestive tissue necrosis caused by alcoholic, biliary, or traumatic acute pancreatitis. This review focuses on the classification of the different types of solid and cystic lesions based on histological criteria. The various imaging procedures are also discussed, along with their strengths and limitations.

Contents Vol. 79, 2009

C. Beglinger, Basel (Switzerland) B. Göke, Munich (Germany) International Journal of Gastroenterology Founded as ‘Archiv für Verdauungskrankheiten’ 1895 by I. Boas Continued as ‘Gastroenterologia’ 1939–1967 Former Editors: P. Morawitz (1934–1936), R. Staehelin (1937–1943), A. Hurst (1940–1945), W. Löffl er (1943–1961), T.C. Hunt (1947–1967), N. Henning (1953–1962), B. Ihre (1953–1967), H. Bartelheimer (1963–1967), M. Demole (1963–1971), H. Kapp (1968–1970), R. Lambert (1972–1978), W. Creutzfeldt (1979–1992), R. Arnold (1993–2003)

S2040 Tumor Infiltrating Lymphocytes and RHAMM Expression Predict Prognosis in Patients with Rectal Cancer

Background: Pre-therapeutic molecular-based tumor expression profiling represents an opportunity for the development of more efficient treatment regimens. The identification of rectal cancer patients with poor clinical outcome at diagnosis would have a significant impact on the selection of pre-operative treatment modalities. Aim: The aim of this study was to evaluate the independent prognostic effect of 8 immunohistochemical protein markers on a large cohort of untreated rectal tumors leading to the identification of patients with adverse prognosis. Methods: Immunohistochemistry on 482 pre-operatively untreated rectal cancer resections was performed using a tissue microarray for 7 tumor markers involved in colorectal tumor progression (MST1, RKIP, APAF-1, RHAMM, EphB2, p53 and Ki67) and for CD8+ tumor infiltrating lymphocytes (TILs). Complete clinico-pathological data was available for all cases. Tumors were randomized into matched test and validation sets (Group 1, Group 2, N = 241 each). Univariate survival analysis was performed. Significant markers common to both groups were combined into multi-marker phenotype combinations and KaplanMeier plots on both groups were evaluated. The independent prognostic factors were entered into multivariable analysis with T stage, N stage, gender, tumor diameter and age. Results: In Group 1, absence of TILs (p=0.012), loss of RKIP (p=0.014) and RHAMM positivity (p<0.001) demonstrated significant adverse prognosis. In Group 2, absence of TILs (p<0.001), negative Ki67 (p=0.012) and RHAMM positivity (p< 0.001) were associated with worse survival time. TILs and RHAMM expression were common to both groups. Multi-marker combinations of TILs and RHAMM were analyzed. Significantly worse survival time was demonstrated in patients with TIL-/ RHAMM + tumors in both Groups 1 and 2 (p< 0.001, each). In multivariable analysis, absence of TILs (p = 0.003; HR = 1.8 (1.2-2.6)) and RHAMM positivity (p< 0.001; HR = 2.0 (1.4-2.7)) both demonstrated strong independent adverse prognostic value. Conclusion: Our results highlight a significantly poorer clinical outcome in patients with absence of CD8+TILs and simultaneous RHAMM positivity. The combined immunohistochemical analysis of these markers on pre-operative tumor biopsies may serve as an additional tool in the selection of patients for pre-operative treatment regimens.