Digestion

Moss, Steven F.; Armstrong, David; Arnold, Rudi; Ferenci, Peter; Fock, Kwong M.; Holtmann, Gerald; McCarthy, Denis M.; Moraes-Filho, Joaquim P.; Mutschler, Ernst; Playford, Raymond; Spechler, Stuart J.; Stanghellini, Vincenzo; Modlin, Irvin M.

doi: 10.1159/000071290pmid: 12853722

Gastroesophageal reflux disease (GERD) has in recent times become an important public health issue owing to the considerable health care resources utilized in its management, its deleterious effect on quality of life and the increasing prevalence of a relatively rare complication of reflux disease – esophageal adenocarcinoma. We review here the major current challenges in the field of reflux disease and its complications, and provide some approaches that may be useful in management. The issues to be faced include the very limited comprehension of the reasons behind the increasing prevalence of the disease, difficulties in correlating symptoms with objective data of pathological gastroesophageal reflux and the relatively unsophisticated tools we are employing to investigate the underlying pathophysiology. It is certain that the lack of well-defined and characterized methodologies to compare the effects of therapy require the development of more effective questionnaire-type analytic tools. In regard to treatment, there is little doubt that the widely prescribed proton pump inhibitors have dose-equivalent efficacy and are the most highly effective agents capable of suppressing acid, controlling many of the symptoms of GERD and healing erosions. Nevertheless, many patients continue to experience symptoms on withdrawal or at night. Pharmacological agents that can effectively increase lower esophageal sphincter pressure or promote motility are as yet unavailable. Although the introduction of laparoscopic techniques has resulted in a modest revival in surgical intervention using a variety of ‘wrap-type’ operations, the indications are few and the procedure is associated with a significant morbidity and even mortality especially if the expertise of the surgeon is an issue. Endoscopic techniques of regulating reflux are at this time experimental and not applicable to the general population. Intestinal metaplasia in the lower esophagus is probably very common. Whether and how to, first, screen for, and then, perform surveillance in Barrett’s esophagus remains highly problematic and contentious.

Netzer, Peter; Halter, Fred; Ma, Thomas Y.; Hoa, Neil; Nguyen, Nathan; Nakamura, Toshikazu; Tarnawski, Andrzej S.

doi: 10.1159/000071291pmid: 12853723

Background/Aims: Expression of the hepatocyte growth factor (HGF) and cyclooxygenase-2 (COX-2) is upregulated at the margins of healing gastric ulcers. We investigated in vitrothe interference of HGF, the selective COX-2 inhibitor NS-398 and the nonselective COX inhibitor indomethacin with gastric epithelial wound healing and actin microfilament (actin-MF) formation. Methods: Standardized gastric epithelial wounds, created in confluent RGM1 rat cell monolayers were treated with: HGF (10 ng/ml), NS-398 (1–100 µM) or indomethacin (0.01– 0.5 mM). The areas of re-epithelialization and cell proliferation were measured 24 h after wounding. Actin-MFs were labeled with fluorescein-conjugated phalloidin and their distribution was examined using a Nikon epifluorescence microscope. Results: HGF caused a significant increase in gastric monolayer wound re-epithelialization and this was not affected by mitomycin C. Both indomethacin and NS-398 inhibited HGF-stimulated re-epithelialization, but the basal wound re-epithelialization rate and cell proliferation was only significantly inhibited by indomethacin. HGF triggered actin stress fiber formation which was inhibited by both indomethacin and NS-398, but only indomethacin interfered with actin-MF formation at the baseline condition. Conclusions: HGF significantly increased gastric wound re-epithelialization by activating cell migration which may be mediated by the COX-2 pathway.

doi: 10.1159/000072282pmid: N/A

Strid, Hans; Simrén, Magnus; Stotzer, Per-Ove; Ringström, Gisela; Abrahamsson, Hasse; Björnsson, Einar S.

doi: 10.1159/000071292pmid: 12853724

Background/Aims: Gastrointestinal (GI) symptoms are common among patients with chronic renal failure (CRF). The pathogenesis of these symptoms is probably multifactorial. Our aims were to assess gastric and small intestinal motility and the prevalence of small intestinal bacterial overgrowth (SIBO) in order to clarify possible pathophysiological mechanisms behind these symptoms in CRF patients. Methods: Twenty-two patients with CRF, 12 with GI symptoms and 10 without GI symptoms underwent antroduodenojejunal manometry. All patients with GI symptoms had diarrhea and half of them had abdominal pain, nausea and/or early satiety. Symptoms were unexplained by conventional investigations. Interdigestive motility was recorded for 5 h and postprandially for 1 h. Samples for culture from the small intestine were obtained through the manometry catheter. Results were compared with 34 healthy controls. Results: On manometry, 11 CRF patients demonstrated neuropathic-like abnormalities, with no significant difference between the patients with (7/12) and without (4/10) GI symptoms. SIBO was seen in 8 CRF patients (36%), 3 with and 5 without GI symptoms (p = 0.15). Six of eleven (55%) of the CRF patients with neuropathic-like abnormalities had SIBO, compared to 2/11 (18%) in those without abnormalities on conventional analysis (p = 0.07). The propagation velocity of phase III was significantly faster in CRF patients with GI symptoms compared to CRF patients without symptoms and healthy controls (21.4 (16.4–54.7) vs. 8.1 (4.6–9.6) and 10.8 (7.2–21.6) cm/min, p = 0.007 and p = 0.019, respectively). We found a higher proportion of retrograde pressure waves in late phase II in the proximal duodenum in patients with and without GI symptoms, than in healthy controls (29 (17–38) and 16 (14–42) vs. 8 (0–24)%, p < 0.0001 and p = 0.0005, respectively). The number of long clusters during the fasting recording was higher in both patient groups than in controls (9 (5–21) and 11 (7–15) vs. 4 (2–9)/5, p = 0.046 and p = 0.002, respectively). Conclusion: In the small intestine, abnormal motility and bacterial overgrowth are common in patients with chronic renal failure. These alterations correlate poorly with GI symptoms, but disturbed intestinal motility might explain diarrhea in some of these patients.

Terjung, Birgit; Lemnitzer, Isabelle; Dumoulin, Franz Ludwig; Effenberger, Wolfgang; Brackmann, Hans Hermann; Sauerbruch, Tilman; Spengler, Ulrich

doi: 10.1159/000071293pmid: 12853725

Background and Aims: To assess the risk of bleeding after percutaneous liver biopsy, we retrospectively analyzed 629 procedures with particular respect to patients with an increased a priori bleeding risk. Methods: Factors possibly related to the risk of bleeding were analyzed by univariate analysis. Those variables which were significant in the univariate analysis were then entered into a forward conditional logistic regression model. Results: Biopsy-related bleeding events defined as clinically overt complication (n = 10; 1.6%), an otherwise unexplained drop in serum hemogloblin concentration of greater than 2 g/dl (n = 45; 7.1%) or intra- or extrahepatic hematoma assessed by ultrasound (n = 17; 2.7%) were identified in 72 patients. 58% of the bleeding events occurred in patients with particular risk factors for bleeding. Biopsy-related mortality in the study cohort was 0.48%. Logistic regression analysis indicated mycobacterial infection [odds ratio (OR) 24.0], pre-biopsy prophylactic platelet substitution (OR 9.9), acute liver failure (OR 9.1), heparin administration on the day of biopsy (OR 8.7), advanced liver cirrhosis (OR 5.1), therapy with corticosteroids (OR 3.5) or metamizole (OR 2.8) and leukemia or lymphoma (OR 2.8) as significant (p ≤ 0.05) independent risk factors. Delayed bleeding (>24 h after biopsy) was identified in 70% of the bleeding events. Conclusions: In our study cohort which comprised a high proportion of patients with particular risk factors for bleeding, biopsy-related bleeding occurred more frequently and later than commonly observed and was associated with only a few prognostic factors. Considering these predictors before liver biopsy will aid to reduce the rate of bleeding complications.

Schepke, Michael; Roth, Felix; Koch, Lydia; Heller, Jörg; Rabe, Christian; Brensing, Karl-August; Schiedermaier, Peter; Schild, Hans H.; Sauerbruch, Tilman

doi: 10.1159/000071294pmid: 12853726

Background/Aim: Kidney function and portal pressure have prognostic relevance in nonshunted patients with cirrhosis. Since insertion of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal pressure and may improve the renal function, the aim of the present study was to investigate the prognostic role of renal impairment and portal hemodynamics in patients with compensated cirrhosis electively shunted due to recurrent variceal hemorrhages. Methods: Data of 101 consecutive and prospectively followed patients with compensated cirrhosis (bilirubin <5 mg/dl) undergoing elective TIPS due to recurrent variceal bleeding (45 died, and 8 were transplanted during the follow-up period) were evaluated in a multivariate Cox model. Results: Creatinine and sodium were identified as the only independent predictors of survival in this model. The 90th percentile of creatinine (>1.7 mg/dl) defined a subgroup with a similar poor prognosis as the 90th percentile of the model for end-stage liver disease (MELD) score. Neither baseline nor post-TIPS portal pressure correlated with the long-term outcome. Conclusions: In compensated patients undergoing TIPS due to variceal bleeding, renal impairment indicates a poor prognosis. Portal hemodynamic parameters are not predictive of survival in TIPS patients.

Kalia, Neena; Wood, Richard F.M.; Pockley, A. Graham; Brown, Nicola J.

doi: 10.1159/000071295pmid: 12853727

Background/Aims: Microcirculatory disturbances following small intestinal ischaemia-reperfusion (I/R) injury lead to tissue damage that may affect short- and long-term outcome after transplantation. The immunosuppressive drug Tacrolimus (FK506) attenuates I/R injury in a number of organs, raising the possibility that it might be able to control both I/R injury and rejection after small bowel transplantation. However, its effects on intestinal I/R injury have not been evaluated. Methods: PVG rats were subjected to 30 min intestinal ischaemia. Animals received Tacrolimus (1 mg/kg i.p.) 4 and 1 h prior to ischaemia. The mucosa was visualised in an exteriorised ileal segment using in vivo microscopy. FITC-BSA or Acridine orange was used to quantitate macromolecular leak (MML) and leucocyte adhesion respectively every 15 min for 2 h during reperfusion. Heart rate and mean blood pressure (mBP) were monitored throughout the experiment. Results: Ten of 12 untreated animals subjected to intestinal I/R injury failed to survive the 2-hour reperfusion period. MML and leucocyte adhesion were increased in untreated animals (p < 0.001) and blood flow stasis eventually ensued. Similar results were obtained for Tacrolimus pre-treated I/R animals, with 10 of 12 animals again failing to survive reperfusion. Conclusions: Despite previous evidence that Tacrolimus reduces I/R injury in other organs, it did not improve survival rates or prevent villus microcirculatory disturbances following intestinal I/R injury. The severity of microcirculatory damage suffered by the small intestine highlights the importance of alternative therapies to combat I/R in this organ.

Hernández, Gerardo A.; Appleyard, Caroline B.

doi: 10.1159/000071296pmid: 12853728

Background: The involvement of enteropathogenic microorganisms in the pathogenesis of inflammatory bowel disease (IBD) and their importance in the different phases of inflammation are still unknown. Aim: To quantify the aerobic bacterial load in models of acute and chronic ‘reactivated’ colitis, and correlate this with damage. Methods: Acute colitis was induced in rats by administration of trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS). Colitis was ‘reactivated’ 6 weeks later by intravenous administration of TNBS. The distal colon was removed and scored macroscopically before inoculating samples. Results: Bacterial load in rats with acute colitis (72 h) and chronic ‘reactivated’ colitis or their controls was significantly higher than untreated (p < 0.05); however, there were significantly more bacteria in acute colitis than in chronic ‘reactivated’ or their controls (p < 0.05). Both acute and chronic ‘reactivated’ colitis had significantly higher damage scores than untreated animals (p < 0.05). Bacterial load and damage score were significantly correlated only with acute colitis. Conclusions: The role of enteric microflora in the pathogenesis of IBD is greater during the acute phase of colitis. The correlation between bacterial load and tissue damage suggests that damage contributes to bacterial multiplication and exacerbation of colitis. Normal colonic flora may contribute to the relapse of the disease.

Kanetake, Kazuto; Iwata, Hisashi; Mori, Yoshio; Takagi, Hisato; Hirota, Toshio; Nitta, Toyoo; Hayashi, Masatomo; Onitsuka, Atsuyoshi; Hirose, Hajime

doi: 10.1159/000071297pmid: 12853729

The aim of this study was to analyze which types of T cells are at work and the specific nature of their response, using a mouse 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis model. The response of T cells to TNBS was analyzed by anti-TNBS mixed-lymphocyte reaction. T cell clones were established by limiting dilution. Phenotypes and T cell receptor (TCR) Vβ of T cells were analyzed by flow cytometry. Colitis was induced by administration of TNBS enemas, and lamina propria lymphocytes were isolated and analyzed. The proliferative responses to TNBS of spleen T cells were partially inhibited by the addition of antimouse CD4 or CD8 antibodies to the mixed-lymphocyte culture. Conversely, these were inhibited by the addition of both antibodies. Flow cytometric analysis showed that TCR Vβ14 T cells specifically increased in the CD8+ T cell population. We established CD8+ TCR Vβ14 T cell clones which were TNBS reactive and self-restricted. Investigation using lamina propria lymphocytes in TNBS-induced colitis revealed that the rate of CD8+ TCR Vβ14 T cells changed with histological inflammatory activity which also attained a peak on day 5 following enema administration. Both CD4+ and CD8+ T cell subsets responded to TNBS, and the rate of CD8+ TCR Vβ14 T cells changed with histological inflammatory activity in TNBS-induced colitis.

doi: 10.1159/000072283pmid: N/A