Rage signalling promotes intestinal tumourigenesis.

Development of colon cancer is a multistep process that is regulated by intrinsic and extrinsic cellular signals. Extrinsic factors include molecular patterns that are derived from either pathogens (PAMPs) or cellular damage (DAMPs). These molecules can promote tumourigenesis by activation of the innate immune system, but the individual contribution of ligands and their receptors remains elusive. The receptor for advanced glycation end products (Rage) is a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment such as Hmgb1 and S100 protein. Here we show that Rage signalling has a critical role in sporadic development of intestinal adenomas, as Apc(Min/+) Rage(-/-) mice are protected against tumourigenesis.

An overview of the current diagnosis and recent developments in neuroendocrine tumours of the gastroenteropancreatic tract: the diagnostic approach.

Neuroendocrine tumours of the gastroenteropancreatic tract (GEP-NETs) comprise a group of very heterogeneous neoplasms, which are considered 'rare diseases'. Epidemiological studies on the incidence of GEP-NETs worldwide have reported a remarkable increase in the detection of these tumours. In a recent study, based on pathology reports (PALGA) to investigate the incidence of pancreatic and duodenal neuroendocrine tumours in the Netherlands from 1991 until 2009, we also noticed a significant increase in the incidence of these tumours. In particular, the incidence of non-functioning neuroendocrine tumours had significantly increased over this period. Remarkably, a substantial discrepancy was observed between the numbers of neuroendocrine tumours diagnosed in the clinical as opposed to the pathological setting, emphasising that these tumours provide a real diagnostic challenge. To improve the diagnosis of GEP -NET s, we advocate that these complex neoplasms should receive more specialised attention. In this mini-review we provide an overview of the current diagnostic approach to GEP-NETs, and add the recent developments in establishing the diagnosis of these tumours, in order to increase knowledge and awareness of GEP-NETs among clinicians and pathologists. Early detection in order to prevent morbidity from GEP-NETs is advocated.

Expression and ligand binding of bombesin receptors in pulmonary and intestinal carcinoids.

INTRODUCTION: Carcinoids are mainly found in the gastrointestinal (65%) and bronchopulmonary tract (25%). These neuroendocrine tumors secrete a wide range of bioactive peptides, including gastrin releasing peptide and neuromedin B, the mammalian analogs of bombesin. The purpose of this study was to investigate the quantity and localization of bombesin receptors in gastrointestinal and pulmonary carcinoids, and to reveal whether bombesin-like peptides (BLP) and their receptors are of any value in distinguishing pulmonary carcinoids from carcinoids of intestinal origin. METHODS: Carcinoid tumors with pulmonary (no.=9) or intestinal (no.=15) localizations were analyzed by immunohistochemistry, autoradiography, and radioimmunoassay, to examine the presence of bombesin receptor subtypes and determine BLP levels in these tumors. RESULTS: All 3 bombesin receptor subtypes (GRPR, NMBR, and BRS-3) were present on pulmonary and intestinal carcinoids by immunohistochemistry. In pulmonary carcinoids, low receptor ligand binding densities together with high and low BLP levels were found. Intestinal carcinoids showed predominantly high receptor ligand binding densities in combination with low BLP levels. CONCLUSIONS: The expression of bombesin receptor subtypes is independent from the carcinoid tumor origin, and is therefore not recommended as a distinction marker, although carcinoids of pulmonary and intestinal origin possess different receptor binding affinities for bombesin and dissimilar BLP levels. The combined presence of bombesin and its receptors might suggest the presence of a paracrine or autocrine growth loop in carcinoids.

Substance P receptor expression in patients with inflammatory bowel disease. Determination by three different techniques, i.e., storage phosphor autoradiography, RT-PCR and immunohistochemistry.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation accompanied by changes in motility. It is known that regulatory peptides like substance P (SP) are important pro-inflammatory peptides which are also involved in neuronal conduction. To get clues for new diagnostic and therapeutic approaches we describe the SP receptor (NK-1) distribution in IBD compared to control intestinal tissue, on mRNA and protein level by three complementary techniques. Autoradiography showed differences within the intestinal wall of control patients; mucosal binding was 17 fmol/g and muscular binding was significantly (p=0.01) higher (98 fmol/g). In inflamed specimens of patients with IBD mucosal SP binding was increased compared to controls (55+/-10 vs 18+/-4 fmol/g mucosa, p=0.002). However RT-PCR showed that the mRNA content of the NK-1 receptor in these samples was not increased. In non-inflamed samples of patients with Crohn's disease (CD) and ulcerative colitis (UC) SP binding was similar as in controls, while mRNA was significantly decreased in CD patients (0.7+/-0.02 vs 4.4+/-0.7, p=0.01) but not in UC patients (4.4+/-0.7 vs 4.1+/-1.4). Immunohistochemistry identified a broad spectrum of NK-1 receptor locations in control intestine. No aberrant expression in IBD was found. This study showed that although there was no difference in location of the SP receptors in IBD patients versus controls, the quantity of SP binding was significantly increased in the inflamed mucosa of IBD patients, while the mRNA level was not increased. Further a difference in mRNA level between non-inflamed tissue of CD and UC patients was shown, with mRNA in CD being lower. These changes in SP receptor expression during chronic inflammation suggest that SP receptors are a potential target for therapeutic regulation of the inflammatory response.

The 13carbon urea breath test for the diagnosis of Helicobacter pylori infection in subjects with atrophic gastritis: evaluation in a primary care setting.

BACKGROUND: (13)Carbon urea breath testing is reliable to detect current infection with Helicobacter pylori but has been reported to be of limited value in selected patients with atrophic body gastritis or acid-lowering medication. AIM: To evaluate the accuracy of (13)carbon urea breath testing for H. pylori detection in 20 asymptomatic patients with histologically confirmed atrophic body gastritis in a primary care setting. METHODS: (13)Carbon urea breath testing and serology were compared with H. pylori culture of a corpus biopsy as reference test. RESULTS: All tests were in agreement in 12 patients, being all positive in six and all negative in six. One patient was positive for serology and culture but negative for (13)carbon urea breath testing, five patients had only positive serology and two patients had only positive (13)carbon urea breath testing. (13)Carbon urea breath testing showed an accuracy with culture of 85% and anti-H. pylori serology with culture of 75%. (13)Carbon urea breath testing carried out in patients with positive serology showed an accuracy of 92%. Receiver operating characteristic curve analysis of (13)carbon urea breath testing shows optimal discrimination at the prescribed cut-off value. CONCLUSIONS: (13)Carbon urea breath testing can be used as diagnostic H. pylori test in asymptomatic patients with atrophic body gastritis, preferably in addition to serology, to select subjects for anti-H. pylori therapy.

Faecal elastase-I: helpful in analysing steatorrhoea?

BACKGROUND: The faecal elastase-1 test (FE-1) is considered easy to perform and sensitive to detect severe and moderate exocrine pancreatic insufficiency. However, little information is available on the specificity of this test in the analysis of steatorrhoea. Our aim was to evaluate the clinical value of FE-1 in the analysis of patients sent in for faecal fat determination. METHODS: Stool samples were collected over 24 hours in 40 healthy controls and 119 patients: 58 patients with chronic pancreatitis and 61 nonpancreatic disease patients with chronic diarrhoea. Faecal fat excretion was determined and FE-1 was measured using a commercially available ELISA kit, which employs two monoclonal antibodies to bind to two distinct epitopes of human pancreatic elastase-1. RESULTS: Faecal elastase-1 test shows good reproducibility. The test lacks sensitivity in detecting exocrine pancreatic insufficiency and chronic pancreatitis (68 and 59%, respectively). However, it is specific with respect to differentiating pancreatic from nonpancreatic causes in patients with steatorrhoea. CONCLUSION: FE-1 lacks sensitivity to detect chronic pancreatitis. It can serve as a simple, noninvasive method to determine the aetiology of steatorrhoea.

Gastrin releasing peptide receptor expression is decreased in patients with Crohn's disease but not in ulcerative colitis.

BACKGROUND: Gastrin releasing peptide (GRP) and neuromedin B are bombesin (BN)-like peptides involved in regulating motility and inflammation in the gastrointestinal tract, which may be useful in treating inflammatory bowel disease (IBD). Three bombesin-like peptide receptors have been reported, but no studies have investigated their localisation in normal and inflamed human intestine. AIM: To localise and characterise BN receptors in normal intestine and to see whether this is modified in IBD. METHODS: Full thickness intestinal tissue samples were collected from 13 patients with Crohn's disease (CD), 11 with ulcerative colitis (UC), and 19 controls. BN receptor expression was characterised and quantified with storage phosphor autoradiography using BN, GRP, neuromedin B, and the synthetic analogue BN(6-14) as ligands. RESULTS: Only BN receptor type 2 (high affinity for GRP) was present in intestinal tissue. Minimal BN binding was detected in the mucosa. In normal colonic smooth muscle, mean BN binding was 336 fmol/g tissue in longitudinal muscle, including the myenteric plexus, and 71 fmol/g in circular muscle. In CD, colonic smooth muscle BN binding was significantly decreased (longitudinal muscle, 106; circular muscle, 19 fmol/g), in contrast to UC (377 and 62 fmol/g, respectively). In CD, a small (not significant) decrease was seen in ileal muscle compared with controls (111 v 169 and 18 v 32 fmol/g tissue for longitudinal and circular muscle, respectively). CONCLUSIONS: Only the GRP receptor is expressed in human intestine; expression is highest in longitudinal muscle and myenteric plexus of the colon. Expression is decreased in inflamed and non-inflamed colon of CD, but not in UC.

The effect of motilin on the rectum in healthy volunteers.

AIMS: The role of motilin in the regulation of upper gastrointestinal (GI) motility is well defined. However, little is known about the effects on the distal GI tract. To investigate the effect of exogenous motilin on rectal function, barostat measurements in the rectum were performed and lower abdominal symptoms were scored. METHODS: Eight fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min in a double-blind, randomized, cross-over design. Rectum volume was measured with a barostat device during constant pressure and during isobaric distensions. Lower abdominal symptoms were scored by visual analogue scales. Plasma motilin concentrations were measured by radioimmunoassay. RESULTS: Baseline rectum volumes were similar between treatments: 185 +/- 62 mL (motilin) and 136 +/- 41 mL (placebo). During the constant pressure procedure, motilin increased rectum volume [area under the effect curve (AUEC)] by 6%[95% confidence interval (CI) -3, 16] of baseline, compared with placebo. During isobaric distensions motilin increased rectum volume (AUEC) by 43 mL (95% CI 0.4, 85; P < 0.05) and compliance by 10 mL mmHg-1 (95% CI 0.3, 20; P < 0.05) relative to placebo. Motilin did not induce changes in the sensation of rectal feelings. CONCLUSION: Exogenous motilin increased rectal compliance in healthy volunteers, without affecting rectal sensations.

Ratio between serum IL-8 and pepsinogen A/C: a marker for atrophic body gastritis.

BACKGROUND AND AIMS: Elevated serum gastrin and a low pepsinogen A/C ratio are well-recognized markers for atrophic body gastritis (ABG). We have shown that the presence of body atrophy is also associated with elevated serum pro-inflammatory cytokines. This study tested the hypothesis that serum cytokines provide additional information to gastrin and pepsinogens in screening for ABG. METHODS: Two hundred and twenty-six consecutive patients were investigated on referral for upper gastrointestinal endoscopy: 150 were patients with gastro-oesophageal reflux disease, receiving acid inhibitory medication either with proton pump inhibitors (n = 113) or with histamine2-receptor antagonists (n = 37), and 76 were nontreated controls, who had normal endoscopic findings. Gastric mucosal biopsies were sampled for histological examination (Sydney classification). Serum samples were analyzed for gastrin, chromogranin A (CgA), and pepsinogens A and C by RIA, and for the interleukins (IL)-1beta, IL-6, and IL-8 by ELISA. RESULTS: Subjects with ABG had significantly higher serum gastrin (P < 0.01) and serum CgA (P < 0.01) levels and significantly lower pepsinogen A/C ratios (P < 0.001) than those without ABG. Additionally, serum IL-1beta, IL-6 and, especially, IL-8 levels were significantly higher in the subjects with than in those without ABG (P < 0.0001, for all cytokines). To optimize the detection of body atrophy we defined the ABG index: the ratio between the simultaneously measured IL-8 and pepsinogen A/C. The area under the ROC curve for the ABG index was significantly greater than that for serum gastrin and for serum pepsinogen A/C alone (0.91 +/- 0.029 vs. 0.72 +/- 0.042, and vs. 0.83 +/- 0.031, P = 0.018 and P = 0.049). Using the ABG index at a cut-off value of 1.8 pg mL-1, 91% of the cases were classified correctly. CONCLUSIONS: The ratio between serum IL-8 and pepsinogen A/C accurately predicts the presence of ABG. We therefore propose the ABG index as a noninvasive screening test for ABG in population-based studies.

Gall bladder dysmotility: a risk factor for gall stone formation in hypertriglyceridaemia and reversal on triglyceride lowering therapy by bezafibrate and fish oil.

BACKGROUND AND AIM: The aim of this study was to unravel the mechanisms responsible for the increased risk of gall stone disease in hypertriglyceridaemia (HTG) and to compare the effects of triglyceride lowering therapy by bezafibrate and fish oil on determinants of cholelithiasis (biliary lipid composition and gall bladder motility) in HTG patients. PATIENTS AND METHODS: Gall bladder motility (ultrasonography) was studied postprandially and during infusion of cholecystokinin (CCK). Determinants of cholelithiasis and serum lipids were compared between nine HTG patients and 10 age, sex, and body mass index matched normolipidaemic controls. The effects of bezafibrate and fish oil in HTG patients were studied in a randomised cross over trial. RESULTS: HTG patients showed 14-fold higher serum triglyceride (TG) levels than controls. Biliary lipid composition, fasting gall bladder volumes, and CCK levels did not differ between HTG patients and controls. Gall bladder emptying was reduced in HTG patients compared with controls during CCK infusion (-22%) as well as in response to a meal (-37%; both p<0.001). Postprandial CCK levels were significantly higher in HTG patients. Both bezafibrate and fish oil reduced serum TG levels (-68% and -51% v baseline, respectively; both p<0.01). Fasting CCK levels were not affected whereas CCK induced gall bladder emptying increased during bezafibrate (+29%; p<0.001) and tended to increase on fish oil therapy (+13%; p=0.07). Postprandial gall bladder motility improved on bezafibrate and fish oil (+47 and +25% v baseline, respectively; both p<0.02) at least partly due to increased gall bladder sensitivity to CCK (both p<0.05 v baseline). Bezafibrate but not fish oil increased the molar ratio of cholesterol to bile acids (+40%; p

The effect of equicaloric medium-chain and long-chain triglycerides on pancreas enzyme secretion.

It has been shown previously that medium chain triglycerides (MCT) do not affect gallbladder emptying and cholecystokinin (CCK) release. The effect of MCT on exocrine pancreas secretion in humans is unknown. We have compared the effect of enteral administration of MCT versus long chain triglycerides (LCT) on exocrine pancreatic secretion. Eight healthy subjects (three female, five male; mean age 22 +/- 1.9 years) participated in two experiments, performed in random order. Duodenal contents, obtained by aspiration, were used to calculated the output of pancreatic enzymes and bilirubin. An equicaloric amount of either MCT or LCT (2 kcal min-1) oil was continuously administered in the proximal jejunum for 2 h. Gallbladder volume was measured by ultrasonography and blood samples were drawn for determination of CCK. The experiments consisted of 1 h basal secretion, 2 h of continuous oil administration and 1 h poststimulation. During the LCT feeding the pancreatic enzyme secretion, bilirubin output, gallbladder emptying and CCK release increased significantly (P < 0.05) over basal levels. MCT had no effect on pancreatic enzyme secretion nor gallbladder emptying or CCK release. We conclude that enteral administration of MCT in the proximal jejunum does not stimulate exocrine pancreatic secretion nor gallbladder contraction or CCK release, in contrast to an equicaloric amount of LCT.

The serological gastric biopsy: a non-endoscopical diagnostic approach in management of the dyspeptic patient: significance for primary care based on a survey of the literature.

BACKGROUND: Measurement of the serum concentration of the secretory products of the gastric mucosa, pepsinogen A (PgA), pepsinogen C (PgC) and gastrin is called the serological gastric biopsy. Additional measurement of Helicobacter pylori antibodies and antibodies to parietal cells and intrinsic factor supports the non-invasive diagnostic value of the serum markers. In many clinical studies, the diagnostic potential of the serum markers in predicting the topography and severity of gastric mucosal disorders has been established. The aim was to assess the diagnostic value of the serological gastric biopsy for primary care. METHOD: Survey of the literature. RESULTS: The cell-physiological background of the serological gastric biopsy, the interpretation of the outcome of serum markers and the relation of these parameters to various gastric mucosal disorders are described. Measurement of PgA is a reliable way to discriminate between mucosal gastritis and functional dyspepsia. PgA is raised in duodenal, gastric and pyloric ulcer even though gastrin is normal. Both PgA and gastrin are raised in renal insufficiency and the Zollinger-Ellison syndrome. A low PgA is indicative of mucosal atrophy and a good indicator for gastric hypoacidity. An additional low PgA:C ratio is indicative of atrophic gastritis or extensive intestinal metaplasia of the stomach. A hypopepsinogenaemia can also be an alarm symptom for gastric cancer. A low PgA and a high gastrin is indicative of corpus atrophy. CONCLUSION: In primary care, the serological gastric biopsy might be a feasible and appropriate diagnostic method for management of the dyspeptic patient. Further research in general practice has to be done to validate the predictive value of the serological gastric biopsy and to define a diagnostic strategy.

Exogenous motilin affects postprandial proximal gastric motor function and visceral sensation.

Our aim was to investigate the effect of motilin on postprandial proximal gastric motor and sensory function in healthy volunteers. Ten fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min. A liquid meal (200 ml) was ingested within 2 min at the start of the infusion. Proximal gastric volume was measured with a barostat device. Abdominal symptoms were scored by visual analog scales. Plasma motilin concentrations were measured using RIA. Endogenous motilin levels were not affected by meal ingestion. After meal intake, gastric relaxation was similar for motilin and placebo. After postprandial relaxation, motilin resulted in a faster return of gastric volume to baseline (P = 0.007). Motilin significantly increased postprandial feelings of nausea (P = 0.03) and tended to increase abdominal pain and abdominal tension. In conclusion, after normal postprandial gastric relaxation, motilin accelerated the return of gastric volume to baseline. In addition, motilin increased postprandial feelings of nausea.

Dose-related effects of motilin on proximal gastrointestinal motility.

AIM: To assess non-invasively the dose-response relations for the effects of exogenous motilin on antrum contraction frequency, gall-bladder volume and gastric myoelectrical activity. METHODS: In a double-blind, randomized, placebo-controlled, five-way crossover study, 10 fasted healthy volunteers were infused intravenously with synthetic human motilin (0.5, 1, 2 and 4 pmol x min/kg) or placebo for 60 min. Gall-bladder volume and antrum contractions were assessed by ultrasonography and gastric myoelectrical activity by electrogastrography. Motilin concentrations were measured using a radioimmunoassay. RESULTS: Baseline plasma motilin levels (60 pmol/L) were similar for all treatments. Motilin levels increased upon the start of infusion and rapidly returned to baseline after cessation of the infusion. At motilin doses of 2 and 4 pmol.min/kg, the antrum contraction frequency was significantly augmented, with maximum differences of two contractions per 2-min interval compared to placebo, while no changes in gastric myoelectrical activity were observed. Changes in gall-bladder volume were not significantly different for any of the motilin doses compared to placebo. CONCLUSIONS: Motilin increased antrum contraction frequency, whereas no effect on gastric myoelectrical activity was observed. Antrum contraction frequency appears to be a useful biomarker for motilin efficacy, and motilin doses of 2 and 4 pmol x min/kg were equally effective.

Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy.

BACKGROUND: Serum chromogranin A (CgA), a marker of neuroendocrine neoplasia, increases during profound gastric acid inhibition, possibly reflecting the trophic effect of gastrin on the enterochromaffin-like (ECL) cells. AIMS: This study investigated the clinical value of serum CgA as a screening test for gastric fundic enterochromaffin-like (ECL) cell hyperplasia during acid-suppressive therapy. METHOD: A consecutive series of 230 dyspeptic patients referred for upper gastrointestinal endoscopy was investigated in a cross-sectional design. They were 154 patients on continuous medium-term (6 weeks to one year) or long-term (longer than one year) acid inhibition with either proton pump inhibitors (PPIs, n = 117) or histamine2-receptor antagonists (H2RAs, n = 37) for gastro-oesophageal reflux disease, and 76 nontreated subjects, with normal endoscopic findings (control group). Fasting blood samples were analysed for gastrin and CgA. Gastric biopsy specimens (oxyntic mucosa) were examined for histological evaluation of gastritis (Sydney classification) and of ECL cell hyperplasia (Solcia classification). RESULTS: Serum CgA levels correlated positively with serum gastrin, following a quadratic function (r = 0.78, P < 0.0001). Elevated serum CgA values during long-term acid inhibition correlated with the presence and severity of fundic ECL cell hyperplasia. Multivariate analysis identified hypergastrinaemia (P < 0.0001), duration of acid inhibition (P < 0.0001), H. pylori infection (P = 0.008), ECL cell hyperplasia (P = 0.012), and body gland atrophy (P = 0.043) as independent predictors of elevated serum CgA. In subjects on long-term acid inhibition (n = 123), serum CgA was equally sensitive but more specific than serum gastrin for the detection of ECL cell hyperplasia (sensitivity, 91.3% for both; specificity, 73% vs. 43%, P < 0.0001). CONCLUSIONS: During long-term gastric acid inhibition, serum CgA levels reflect the presence and severity of fundic ECL cell hyperplasia. Serum CgA is therefore a useful screening test for gastric ECL cell proliferative changes within this context.

Effect of intraduodenal and intravenous amino acids on proximal gastric motor function in man.

The present study was performed to investigate the effect of amino acids during the intestinal and postabsorptive phase of digestion on proximal gastric motor function measured with an electronic barostat. Eight healthy volunteers participated in three experiments performed during continuous infusion of: (1) intravenous and intraduodenal saline, (2) intraduodenal amino acids, and (3) intravenous amino acids. Both intraduodenal and intravenous amino acids induced gastric relaxation and increased gastric compliance. Only during intraduodenal amino acids did plasma CCK levels increase significantly. Correlation between intragastric volume measurements (with pressure set at MDP + 2 mm Hg) and plasma CCK levels was 0.90 (P < 0.001) during the early intestinal phase. Relaxation of the proximal stomach is related to plasma CCK in the early intestinal phase, whereas in the postabsorptive phase of amino acids other mechanisms play a role in proximal gastric relaxation.

Effect of somatostatin on postprandial gallbladder relaxation.

Although the inhibitory effect of somatostatin (SST) on gallbladder contraction is well known, the influence of SST on gallbladder motility during the late postprandial or relaxation phase has not been studied. We therefore investigated the effect of SST on gallbladder relaxation and gut hormone release during the late postprandial phase. Eight healthy volunteers participated in two experiments performed in random order during continuous infusion of either SST or saline (placebo) starting 2 h after meal ingestion. At regular intervals, gallbladder volumes were measured (ultrasonography) and blood samples were taken for determination of plasma cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and neurotensin levels (radioimmunoassay). Postprandial gallbladder contraction was similar in both experiments: 68 +/- 4% vs. 66 +/- 4%. During SST infusion, postprandial gallbladder contraction was significantly (P<0.01) reduced (2874 +/- 813% *240 min) compared with saline (9391 +/- 1595% *240 min). Plasma CCK, PP, PYY and neurotensin levels were in the same range in the early postprandial phase but were significantly reduced during SST infusion compared with placebo (late postprandial phase). Plasma levels of CCK correlated with gallbladder volumes during both the contraction and relaxation phase (r=0.68, P=0.01 and r=0.61, P=0.008, respectively). SST enhances gallbladder relaxation and reduces hormone secretion in the late postprandial phase. The results point to an association between CCK and gallbladder volume not only during the postprandial contraction phase but also during the relaxation phase.

Pancreatic polypeptide secretion in patients with chronic pancreatitis and after pancreatic surgery.

AIM: We investigated polypeptide (PP) secretion under basal conditions, in response to bombesin infusion and to meal ingestion in patients with chronic pancreatitis (CP) and patients after different types of pancreatic surgery. METHODS: Included were patients with CP without (n = 20) and with (n = 30) exocrine pancreatic insufficiency, patients after duodenum preserving resection of the head of the pancreas (DPRHP; n = 20), after Whipple's procedure (n = 19), following distal pancreatectomy (DP; n = 12), and healthy controls (n = 36). RESULTS: In CP patients basal and bombesin stimulated PP levels were significantly (p<0.01) reduced compared to controls only when exocrine insufficiency was present. Meal-stimulated PP secretion was significantly (p<0.01-0.05) reduced in CP patients both with and without exocrine insufficiency. Plasma PP peak increments after bombesin and meal ingestion correlated significantly with exocrine function. Basal PP, meal, and bombesin-stimulated PP secretion had low sensitivities of 22%, 42%, and 60% respectively, in detecting chronic pancreatitis. In patients after pancreatic surgery that included pancreatic head resection (DPRHP or Whipple operation) basal and stimulated PP secretion were significantly (p<0.01-0.05) reduced. CONCLUSION: Basal and meal or bombesin-stimulated PP levels are significantly reduced in patients with CP only when exocrine insufficiency is present. Determination of plasma PP levels has low sensitivity and is not useful in detecting chronic pancreatitis without exocrine insufficiency. In patients after pancreatic surgery, PP secretion is dependent on the type of operation (head vs tail resection).

Proximal and distal gut hormone secretion in slow transit constipation.

BACKGROUND: It has been suggested that slow transit constipation might be part of a panenteric disorder. Gastrointestinal peptides are involved in regulation of motility. DESIGN: In the present study we have evaluated whether plasma levels of proximal and distal gut hormones in the fasting state, and for 120 min after a solid meal in 29 patients with slow transit constipation are different from those obtained from 29 healthy controls. Plasma levels of the gut hormones cholecystokinin, gastrin, pancreatic polypeptide, motilin, neurotensin and peptide YY were determined using sensitive radioimmunoassays. In the patient group, oro-caecal transit time was determined by means of the hydrogen breath test on a separate test day. The results of transit were related with postprandial hormone secretion. RESULTS: Fasting plasma levels of cholecystokinin and pancreatic polypeptide were significantly (P < 0.05) increased in constipated patients. Postprandially, secretion of pancreatic polypeptide and cholecystokinin was significantly (P < 0.05) increased in the patients, while secretion of peptide YY was significantly (P < 0.05) reduced. Plasma motilin levels were not different between patients and controls. Altered postprandial hormone secretion was mainly observed in constipated patients with prolonged oro-caecal transit time. CONCLUSIONS: In patients with slow transit constipation, fasting and postprandial secretion of proximal gut hormones apart from motilin is increased and of distal gut hormones decreased, especially in those with severely delayed intestinal transit.

Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment.

Parietal cell protrusion (PCP), swelling and bulging of parietal cells, has been observed in the oxyntic mucosa of patients receiving omeprazole. The frequency of this event and the underlying mechanisms remain to be clarified. As such, it is unknown whether there is a relation with either serum gastrin or Helicobacter pylori infection, and whether PCP predisposes to the development of fundic gland cysts (FGC). We therefore investigated the development of PCP and FGC in gastroesophageal reflux disease (GERD) patients treated with omeprazole and correlated findings to duration of therapy, gastrin, and H pylori infection. In a randomized, double-blinded study, GERD patients were evaluated by endoscopy with biopsy sampling for histology and culture at baseline, and after 3 and 12 months' therapy with omeprazole 40 mg daily. H pylori-positive patients were randomized to additional eradication therapy or placebo antibiotics at baseline. All histological slides were scored blinded for time and outcome of culture for the presence of PCP and FGC. Fasting serum samples from all visits were used for gastrin measurements. The prevalence of PCP increased during omeprazole therapy from 18% at baseline to 79% and 86% at 3 and 12 months (P < .001, baseline v both 3 and 12 months). The prevalence of FGC increased from 8% to 17% and 35% (P < .05, baseline v 12 months). The prevalence of PCP and FGC did not differ among the H pylori-positive and H pylori-negative patients at baseline (PCP 16% v 20% and FGC 7% v 8%, respectively). Whereas H pylori eradication did not significantly affect development of PCP (P = .7), FGC developed significantly more often in the H pylori-eradicated patients when compared with persistent H pylori-positive patients (P < .05). PCP development was related to serum gastrin rise during therapy. In conclusion, PCP occurs in most patients within the first months of omeprazole treatment and is related to increased gastrin levels. FGC develops more gradually and is enhanced by H pylori eradication.