Neoplastic progression in short-segment Barrett's oesophagus is associated with impairment of chemical clearance, but not inadequate acid suppression by proton pump inhibitor therapy.

BACKGROUND: Pathophysiological mechanisms associated with neoplastic progression in patients with short-segment Barrett's oesophagus (SSBO), who represent the vast majority of the Barrett population, have not been defined. AIM: To evaluate pathophysiological characteristics of patients with SSBO and dysplasia detected at 3-year surveillance endoscopy (incident dysplasia). METHODS: Patients with SSBO underwent impedance-pH monitoring during heartburn-suppressing PPI therapy. Fifteen patients (12 males, median age 62 years) with incident dysplasia and 50 patients (43 males, median age 59 years) without dysplasia were compared. Impedance-pH parameters, including chemical clearance assessed by the post-reflux swallow-induced peristaltic wave (PSPW) index, were evaluated. RESULTS: All patients declared persisting heartburn suppression on maintenance PPI therapy at 3-year follow-up, 58/65 (89%) with standard dosages. The median gastric and oesophageal acid exposure time (GAET and OAET) did not differ between patients with and without incident dysplasia at the time of surveillance (36% and 0.6% vs. 33% and 0.5%) or index endoscopy (33% and 0.3% vs. 41% and 0.5%) (P > 0.05). Contrastingly, the median PSPW index was significantly lower in patients with than in patients without incident dysplasia at the time of surveillance (15%, vs. 32%) and index endoscopy (12% vs. 30%) (P = 0.001). The PSPW index, the GAET and the OAET did not vary over time (P > 0.05). A PSPW index <26% was predictive of incident dysplasia with a 75% accuracy. CONCLUSIONS: Neoplastic progression in SSBO is associated with impairment of chemical clearance, but not inadequate acid suppression by PPI therapy. Neoplastic progression in SSBO can be predicted by a low PSPW index.

Esophageal chemical clearance is impaired in gastro-esophageal reflux disease--a 24-h impedance-pH monitoring assessment.

BACKGROUND: Impedance-pH monitoring allows assessment of retrograde and antegrade intra-esophageal movement of fluids and gas. Reflux is followed by volume clearance and chemical clearance, elicited by secondary and swallow-induced peristalsis, respectively. We aimed to assess whether chemical clearance is impaired in gastro-esophageal reflux disease (GERD). METHODS: Blinded retrospective review of impedance-pH tracings from patients with erosive reflux disease (ERD) and non-erosive reflux disease (NERD), and from proton pump inhibitor (PPI)-refractory patients before and after laparoscopic fundoplication. The number of refluxes followed within 30 s by swallow-induced peristaltic waves was divided by the number of total refluxes to obtain a parameter representing chemical clearance namely the postreflux swallow-induced peristaltic wave (PSPW) index. KEY RESULTS: The PSPW index was significantly lower in 31 ERD (15%) and in 44 NERD (33%) off-PPI patients than in 30 controls (75%), as well as in 18 ERD (16%) and in 48 NERD (31%) on-PPI patients than in 26 on-PPI functional heartburn (FH) cases (67%) (P < 0.05 for all comparisons). In 29 PPI-refractory patients, the median PSPW index was unaltered by otherwise effective antireflux surgery (20% postoperatively, 21% preoperatively). The overall sensitivity, specificity, positive, and negative predictive values of the PSPW index in identifying GERD patients were 97%, 89%, 96%, and 93%. CONCLUSIONS & INFERENCES: Impairment of chemical clearance is a primary pathophysiological mechanism specific to GERD: it is unaffected by medical/surgical therapy, is not found in FH, and is more pronounced in ERD than in NERD. Using the PSPW index could improve the diagnostic efficacy of impedance-pH monitoring.

Reflux parameters as modified by EsophyX or laparoscopic fundoplication in refractory GERD.

BACKGROUND: EsophyX is a novel transoral incisionless fundoplication device developed to mimic surgical fundoplication. EsophyX fundoplication improves acid reflux parameters in proton pump inhibitor (PPI)-responsive GERD patients but its efficacy in refractory GERD has been scarcely studied. AIM: To assess reflux parameters before and after EsophyX or laparoscopic fundoplication and their relationship with symptoms in refractory GERD. METHODS: In an open-label study, we enrolled prospectively patients with heartburn/regurgitation persisting despite high-dose PPI therapy. Impedance-pH monitoring was performed on PPI therapy before intervention and off PPI therapy 3 months after intervention. RESULTS: Ten patients chose to undergo EsophyX (EndoGastric Solutions, Redmond, WA, USA) fundoplication while ten chose laparoscopic fundoplication, and the baseline characteristics were comparable. Distal and proximal refluxes were significantly reduced post-operatively in the surgical but not in the endoscopic group and the median values were significantly lower in the former than in the latter. The oesophageal acid exposure time was normal in 50% of cases after EsophyX and in 100% of cases after surgery (P=0.033); the number of distal refluxes was normal in 20% and 90% of cases (P=0.005) and the number of proximal refluxes was normal in 40% and 100% of cases (P=0.011), respectively. A positive persisting symptom-reflux association was found post-operatively in 6/10 patients in the EsophyX group and in 0/10 patients in the surgical group (P=0.011). CONCLUSIONS: In patients with refractory GERD, EsophyX fundoplication is significantly less effective than laparoscopic fundoplication in improving reflux parameters and accordingly, in inducing symptom remission.

Characteristics of gastro-esophageal reflux episodes in Barrett's esophagus, erosive esophagitis and healthy volunteers.

BACKGROUND: Gastro-esophageal reflux is considered a major culprit in the pathogenesis of Barrett's esophagus (BE). Still, there is controversy on the role of weakly acidic and weakly alkaline reflux in BE. To compare characteristics of reflux episodes patients with BE, erosive esophagitis (EE), and healthy volunteers (HV). METHODS: One hundred consecutive patients with BE (75 short-segment BE, 25 long-segment BE), 50 with EE and 48 HV underwent multichannel intraluminal impedance-pH off-therapy. We quantified esophageal acid exposure, characteristics, and proximal extension of reflux episodes. KEY RESULTS: Total and acid reflux episodes gradually increased from HV [28 (17.5-43) and 18 (8-31)] to EE [73.5 (54-96) and 52 (39-68)], short-segment BE (SSBE) [83 (73.2-131) and 65 (43.3-95)] and long-segment BE (LSBE) [105 (102-187) and 77 (75-107)]. Weakly acidic reflux episodes were significantly higher (P < 0.05) in LSBE [36 (27.5-50.5)] and SSBE [34 (18.5-41)] compared to EE [21.5 (15-37)] and HV [19 (14-25)]. No differences in terms of proportion of acid, weakly acidic and weakly alkaline reflux were found [HV (49%-49%-2%) vs EE (68%-32%-1%) vs SSBE (65%-34%-1%) vs LSBE (69%-30%-1%); P = ns]. In LSBE, a higher percentage of reflux episodes (P < 0.05) reached the proximal esophagus (59%) compared with SSBE (43%). CONCLUSIONS & INFERENCES: Barrett esophagus patients have more severe reflux as shown by the number of acid and weakly acidic reflux episodes, re-reflux episodes and proximal migration. Given that PPI change only the pH of the refluxate, the role of weakly acidic reflux in Barrett's patients on acid suppressive therapy warrants further investigation.

Reflux patterns in patients with short-segment Barrett's oesophagus: a study using impedance-pH monitoring off and on proton pump inhibitor therapy.

BACKGROUND: In short-segment Barrett's oesophagus (SSBO) heartburn may be absent and oesophageal acid exposure time (OAET) assessed with pH-only monitoring may be normal. By detecting reflux episodes independently of their acidity, multichannel intraluminal impedance-pH (MII-pH) monitoring allows a comprehensive characterization of reflux events, either off or on proton pump inhibitor (PPI) therapy. AIM: To assess reflux parameters by MII-pH monitoring in newly diagnosed SSBO, at baseline and as modified with PPI therapy. METHODS: Short-segment Barrett's oesophagus was defined by oesophageal intestinal metaplasia up to 3 cm in length. 24-h MII-pH monitoring was performed before and during PPI therapy. RESULTS: Fifty patients were studied prospectively. Normal OAET was found at baseline in 15 patients (30%), 8 and 2 of whom with a higher than normal number of acid and weakly acidic refluxes, respectively. Overall, abnormal reflux parameters were detected by MII-pH monitoring in 90% of patients. Reflux events were prevalent in the upright period. On PPI therapy, acid refluxes decreased and a correspondent increase in weakly acidic refluxes was observed (median from 48.5 to 9 and from 16 to 57.5, respectively) (P < 0.001). CONCLUSIONS: Acid refluxes, mainly in the upright period, characterize SSBO. PPI therapy transforms acid refluxes into weakly acidic refluxes.

Efficacy in intra-oesophageal acid suppression may decrease after 2-year continuous treatment with proton pump inhibitors.

BACKGROUND: Long-term intra-oesophageal acid suppression with proton pump inhibitors represents a management option for Barrett's oesophagus and severe reflux oesophagitis, but its stability over time has not been adequately assessed. AIM: Our aim was to evaluate prospectively the efficacy of proton pump inhibitors in suppressing intra-oesophageal acidity after 2-year continuous treatment. METHODS: Forty-five patients with Barrett's oesophagus or severe reflux oesophagitis on a proton pump inhibitor regimen (once or twice daily) that normalised the total percentage acid exposure time were re-evaluated by means of 24-h oesophageal pH-monitoring after 2-year of continuous unmodified treatment. RESULTS: A significant rise in the total percentage acid exposure time was observed at 2-year follow-up (P=0.029), owing to an increased value in 27 (60%) cases (9 on a twice daily regimen), higher than normal in 10 of them (22% of the whole group) (3 on a twice daily regimen). In 18 patients (40%) the total percentage acid exposure time was stable or decreased. Heartburn remained efficiently suppressed in all patients. CONCLUSIONS: The efficacy of proton pump inhibitors in suppressing intra-oesophageal acidity during continuous treatment may decrease over time, up to abnormal levels of oesophageal acid exposure in a minority of cases. This may occur without heartburn recurrence and with both once and twice daily regimens.

Pathophysiological characteristics of the various forms of gastro-oesophageal reflux disease. Spectrum disease or distinct phenotypic presentations?

BACKGROUND: The traditional approach to gastro-oesophageal reflux disease as a spectrum disease has recently been criticised and the distinct phenotypic presentations model has been proposed. AIM: To evaluate the main pathophysiological characteristics of various gastro-oesophageal reflux disease presentations. METHODS: Oesophageal manometry and 24-h pH-monitoring were performed in a gastro-oesophageal reflux disease series collected in a 7-year period. RESULTS: Four hundred and twenty-one subjects were studied. Mean total percentage acid reflux time was significantly higher in long-segment Barrett's oesophagus and in ulcerative oesophagitis than in all the other gastro-oesophageal reflux disease groups, whilst in short-segment Barrett's oesophagus results were quite similar to those found in non-erosive reflux disease and in erosive reflux disease. Patients with ulcerative oesophagitis and long-segment Barrett's oesophagus were older than all the other gastro-oesophageal reflux disease groups. The mean lower oesophageal sphincter pressure was significantly reduced in non-erosive reflux disease, erosive reflux disease, ulcerative oesophagitis, short-segment Barrett's oesophagus and long-segment Barrett's oesophagus as compared with functional heartburn and hypersensitive oesophagus and with controls. CONCLUSIONS: In keeping with the spectrum model of gastro-oesophageal reflux disease, severity of acid reflux increases from non-erosive reflux disease through erosive reflux disease up to ulcerative oesophagitis and long-segment Barrett's oesophagus. Ulcerative oesophagitis and long-segment Barrett's oesophagus could represent an advanced step in the natural history of gastro-oesophageal reflux disease. Our results do not confirm the distinct phenotypic presentations hypothesis.

Intra-oesophageal acid suppression in complicated gastro-oesophageal reflux disease: esomeprazole versus lansoprazole.

BACKGROUND: Acid suppression is the mainstay of therapy in gastro-oesophageal reflux disease. Esomeprazole 40 mg is more effective than lansoprazole 30 mg in healing mucosal lesions in severe erosive reflux oesophagitis. However, data comparing esomeprazole with lansoprazole in patients with complications of gastro-oesophageal reflux disease, such as ulcerative reflux oesophagitis and Barrett's oesophagus, are lacking. AIM: To compare the efficacy of esomeprazole and lansoprazole at their standard dosages in suppressing oesophageal acid exposure in complicated gastro-oesophageal reflux disease. METHODS: Thirty patients with complicated gastro-oesophageal reflux disease (7 with ulcerative reflux oesophagitis and 23 with Barrett's oesophagus), randomly assigned to receive 40 mg esomeprazole (n=16) or 30 mg lansoprazole (n=14) once daily, underwent oesophageal 24-h pH monitoring while on therapy. Total, upright diurnal and supine nocturnal percentage acid reflux time were assessed. RESULTS: Esomeprazole was significantly more effective than lansoprazole in decreasing oesophageal acid exposure. Normalisation of both total and supine nocturnal percentage acid reflux time was obtained in 12 of 16 (75%) patients treated with esomeprazole but only in 4 of 14 (28%) cases treated with lansoprazole (p=0.026). CONCLUSIONS: Normalisation of oesophageal acid exposure can be achieved in the majority of complicated gastro-oesophageal reflux disease cases with esomeprazole 40 mg once daily.

Pathophysiological characteristics of patients with non-erosive reflux disease differ from those of patients with functional heartburn.

BACKGROUND: Patients with endoscopy-negative heartburn can be subdivided into non-erosive reflux disease and functional heartburn on the basis of abnormal and normal, respectively, oesophageal acid exposure. Different pathophysiological characteristics could explain the reportedly low efficacy of proton pump inhibitors in functional heartburn. AIM: To assess if non-erosive reflux disease and functional heartburn are pathophysiologically distinguishable. METHODS: Oesophageal manometry and pH-monitoring were performed in 145 patients with endoscopy-negative heartburn, in 72 patients with erosive reflux disease, in 58 patients with complicated reflux disease, and in 60 controls. RESULTS: Patients with non-erosive reflux disease (84 cases) and functional heartburn (61 cases) differed with regard to the prevalence of hiatal hernia (49% vs. 31%, P = 0.008), the mean lower oesophageal sphincter tone (18.5 vs. 28.4 mmHg, P < 0.05), and the number of upright diurnal acid refluxes lasting more than 5 min (3.6 vs. 0.37, P < 0.05). The results were very close in thenon-erosive reflux disease, erosive reflux disease and complicated reflux disease groups, whilst patients with functional heartburn were indistinguishable from controls. CONCLUSIONS: Pathophysiological characteristics typical of gastro-oesophageal reflux disease are found in patients with non-erosive reflux disease but not in patients with functional heartburn. This could explain the reportedly low efficacy of proton pump inhibitors in functional heartburn and suggests considering different management strategies.

Laparoscopic fundoplication versus lansoprazole for gastro-oesophageal reflux disease. A pH-metric comparison.

BACKGROUND: Treatment strategies that abolish abnormal reflux could prevent long-term complications of gastro-oesophageal reflux disease. AIMS: To compare the efficacy of laparoscopic fundoplication and lansoprazole in abolishing abnormal reflux in patients with gastro-oesophageal reflux disease. PATIENTS: Study population comprised 130 patients referred for possible antireflux surgery and with heartburn as the dominant symptom. METHODS: After oesophageal manometric and pH-metric evaluation and detailed information 55 patients asked to undergo laparoscopic antireflux surgery while 75 chose a medical treatment regimen based on lansoprazole. Treatment efficacy was assessed by ambulatory oesophageal pH-monitoring. RESULTS: All 55 patients who underwent fundoplication became free of heartburn: oesophageal pH-monitoring gave normal results in 85%. In patients treated with lansoprazole, at individualized daily dosages titrated to abolish both heartburn and abnormal acid reflux, normal pH-metric results were obtained in 96% of cases (p<0.05 vs surgically treated patients). CONCLUSIONS: Lansoprazole at individualized dosages was significantly more effective than laparoscopic fundoplication, in the short-term, in abolishing abnormal reflux in gastro-oesophageal reflux disease patients.

Combined endoscopic and surgical management of Dieulafoy vascular malformation.

BACKGROUND: Dieulafoy's disease (exulceratio simplex) is an uncommon cause of gastric hemorrhage as a result of an abnormally large, submucosal, eroded gastric artery, often located in the upper part of the stomach. It represents a clinical challenge because of the intermittent nature of massive bleeding accounting for a constantly fatal course in conservatively (nonsurgically or nonendoscopically) treated patients. Published therapeutic options include techniques of endoscopic hemostasis or operative procedures. STUDY DESIGN: Herein we report two patients in whom a combined endoscopic and operative approach was performed to obtain a definitive prevention of rebleeding and an undoubted anatomopathologic diagnosis. RESULTS: Our innovative combined endoscopic and operative approach has offered three significant advantages: endoscopic preoperative diagnosis and control of the bleeding; valid aid in the intraoperative localization of hemorrhagic lesions, which is erratic intraoperatively, requires gastrotomy, and prolongs the duration of operation; and endoscopy-guided limited wedge resection as opposed to standard techniques involving gastrotomy for simple ligation or oversewing of the involved vessel, local excision, or wide wedge resections that used to be recommended until the recent past. CONCLUSIONS: We confirm that seemingly obscure origins of massive recurring hemorrhage of the upper part of the gastrointestinal tract should increase the suspicion of Dieulafoy's disease, prompting careful examination of the gastric fundic area and greater curvature. Endoscopic hemostasis is the first choice; whenever operative treatment is indicated (because of the endoscopic or clinical situation), it should be as conservative as possible because of intraoperative endoscopic localization of the bleeding source.

Are routine duodenal and antral biopsies useful in the management of "functional" dyspepsia? A diagnostic and therapeutic study.

Fifty-three patients with previously uninvestigated chronic dyspepsia symptoms in the absence of gastrointestinal or extra-gastrointestinal disease (functional dyspepsia) underwent antral and duodenal mucosal biopsies to detect the role of such samplings in the presence of normal endoscopic findings. Patients were enrolled in a randomized, placebo-controlled, double-blind trial, receiving either eradicating treatment (colloidal bismuth subcitrate plus metronidazole) or placebo if they had Helicobacter pylori-associated gastritis (20 patients), or cisapride or placebo if they had normal antral mucosa (28 cases). Unsuspected celiac sprue was found in one patient. Eradicating treatment ameliorated histological gastritis (p = 0.01). However, owing to great placebo efficacy, symptom remission rates following a 1-month wash-out period in both treatment groups were no higher than that in controls. Independent of the initial randomization, an extremely low symptom recurrence rate was observed during a drug-free follow-up study equivalent to the mean duration of symptoms before enrollment. We conclude that in functional dyspepsia, bulbar and antral biopsies are not useful in clinical management, equivalent symptom relief can be achieved in patients randomly assigned to both drugs and placebos, and such improvement can be long lasting in the absence of any maintenance treatment. We believe the prevalence of unsuspected villous atrophy and the therapeutic role of investigation-based reassurance deserve further assessment.

Hemoductal pancreatitis secondary to gastroduodenal artery-ruptured pseudoaneurysm: a rare cause of hematemesis.

A 65-yr-old alcoholic man with a history of calcific pancreatitis presented with massive hematemesis complicated by lipothymia. Physical examination disclosed stigmata of chronic liver disease. The laboratory picture was predominantly of cholestatic type with impaired liver protein synthetic activity. Emergency esophagogastroduodenoscopy was unable to provide definitive diagnosis, but reendoscopy with a side-viewing duodenoscope revealed active bleeding through the ampulla of Vater. An ultrasound examination showed a large, complex pancreatic lesion that computed tomography showed to be a pancreatic pseudocyst with an inside pseudoaneurysm. A visceral angiography revealed an anomalous arising of the common hepatic artery from the superior mesenteric artery and a pseudoaneurysm of the gastroduodenal artery at its origin. A second massive hemorrhage required an emergency operation, and surgical liver biopsy revealed focal steatosis. In conclusion, bleeding of a pancreatic pseudoaneurysm may be massive but intermittent, and side-viewing duodenoscopy, even prolonged, is essential in the diagnosis.

Ageing and small-bowel mucosa: a morphometric study.

A direct effect of ageing in reducing mucosal surface area of the small intestine is still disputed. The aim of this study was to morphometrically evaluate a panel of jejunal biopsy specimens obtained from 16 elderly patients and 22 younger controls, all complaining of abdominal symptoms but without evidence of malabsorption and/or malnutrition in either group. Quantitative histology was performed by calculating the surface area to volume ratio of jejunal mucosa and the mean enterocyte height. The mean of surface to volume ratios in geriatric patients (97.6 +/- 18), although slightly reduced, did not significantly differ from that of younger controls (107.6 +/- 26) and no significant correlation was found between surface to volume ratio and age in years. The mean enterocyte height in the elderly group (30.1 +/- 1.2 microns) did not significantly differ from that of younger controls (31.3 +/- 2.3 microns). In conclusion, the frequent finding of malnutrition due to malabsorption in the elderly should not be attributed to a reduction of jejunal surface area as a mere consequence of age.

Quantitative assessment of the mucosal architecture of jejunal biopsy specimens: a comparison between linear measurement, stereology, and computer aided microscopy.

Fifty jejunal biopsy specimens obtained from normal subjects and from untreated and treated patients with coeliac disease were assessed blindly by three independent observers, each of them using different morphometric techniques-namely, linear measurement, stereology, and computer aided microscopy. In two of 26 control biopsy specimens linear measurement was not possible because of distortion of villi. Highly significant (p less than 0.001) correlation coefficients were found between the different techniques. With all methods significant differences between controls and patients with coeliac disease and between treated and untreated coeliac patients were found. Only by stereology, however, was there no overlap between results for patients and those for controls. In view of the limitations of linear measurement and the high cost and complexity of computer aided microscopy, we propose that a simple stereological technique using an eyepiece graticule is the method of choice in the quantitative assessment of mucosal architecture in jejunal biopsy specimens.

Jejunal intraepithelial lymphocytes in coeliac disease: are they increased or decreased?

We have quantified intraepithelial lymphocytes in the same biopsy series (21 healthy controls, 14 untreated coeliacs, 15 treated coeliacs, five non-coeliac patients with an abnormal jejunal mucosa) both as counts/100 epithelial cells and using as reference value a fixed area of muscularis mucosae. As expected, the number of intraepithelial lymphocytes/100 epithelial cells was significantly higher in untreated and treated coeliacs than in healthy controls, as well as in untreated when compared with treated coeliac patients. Otherwise, the number of intraepithelial lymphocytes lying in the area of mucosal surface overlying a fixed area of muscularis mucosae was significantly lower in treated and untreated coeliacs, than in healthy controls, as well as in untreated when compared with treated coeliacs. A highly significant inverse correlation was found between the number of intraepithelial lymphocytes/100 epithelial cells and the mucosal surface area measured as surface to volume ratio. When the number of intraepithelial lymphocytes/100 epithelial cells was corrected for differences in surface to volume ratio, the results were very similar to those obtained by a muscularis mucosae related count. In five coeliacs both intraepithelial lymphocyte and enterocyte muscularis mucosae related counts rose after a period of gluten free diet but the mean per cent increase of enterocytes was significantly higher than that of lymphocytes. Our results are compatible with a decrease in the total number of intraepithelial lymphocytes in the entire small bowel in coeliac disease. In untreated coeliac mucosae, however, a derangement in the usual proportions of intraepithelial lymphocytes and enterocytes is evident and may be important in the pathogenesis of coeliac disease.

Observer variation in assessment of jejunal biopsy specimens. A comparison between subjective criteria and morphometric measurement.

in an observer variation study, the agreement rate reached by a pair of observers who measured 85 jejunal biopsy specimens using surface/volume ratio was compared with that reached by a pair of observers who subjectively assessed the same biopsy series. Both the agreement reached between the subjective observers and that reached between the objective observers proved significant by kappa statistics. However, both total and partial kappa values were greater for the pair of objective observers in every diagnostic category. Moreover, the percentage of agreement on the grading of all biopsy specimens, independent of the diagnostic categories, proved significantly higher for the objective observers. In the pair who made a qualitative assessment, interobserver variation was particularly evident in the grading of partial villous atrophy. Contrastingly, in the pair who made a quantitative assessment, agreement was present in all but one slide. The kappa values for the observers examining the same biopsy specimens on two separate occasions indicated closer agreement rates for the two objective observers. It is concluded that morphometric measurement is more reliable than subjective criteria in the assessment of jejunal biopsy specimens and that qualitative assessment of biopsy specimens should be coupled with quantitative histology.