Renato Caviglia

Dilated Intercellular Spaces of Esophageal Epithelium in Nonerosive Reflux Disease Patients with Physiological Esophageal Acid Exposure

OBJECTIVES:It has been demonstrated that dilation of intercellular spaces of esophageal epithelium is a marker of tissue injury in GERD patients with a pathological esophageal acid exposure time. To evaluate the relationship among ultrastructural changes, acid esophageal exposure, and GERD symptoms, intercellular space diameters have been assessed in nonerosive reflux disease (NERD) patients with/without abnormal acid exposure time.METHODS:Following a pharmacological wash-out, 20 NERD patients underwent upper endoscopy, esophageal manometry, and 24-h pH monitoring. Biopsies were taken at 5 cm above the lower esophageal sphincter and intercellular space diameters were measured on transmission electron microscopy photomicrographs. Seven asymptomatic controls underwent the same protocol.RESULTS:Acid exposure time was in the normal range in all controls and in 11 patients (NERD pH-negative); it was abnormal in 9 patients (NERD pH-positive). Mean intercellular space diameter in NERD pH-negative and in NERD pH-positive patients was three times greater than in controls (1.45 and 1.49 μm vs 0.45, p < 0.001). Mean values of maximum intercellular spaces in all NERD patients were greater, two-fold or more, than those in controls (p < 0.001). No difference in mean and maximal space diameters was observed between NERD pH-positive and pH-negative patients.CONCLUSIONS:Dilation of intercellular spaces is a feature of NERD patients, irrespective of esophageal acid exposure, and can be considered an objective, structural marker of GERD symptoms. Impaired esophageal mucosal resistance, even to small amounts of acid refluxate, plays a key role in the pathophysiology of NERD.

Presence of gas in the refluxate enhances reflux perception in non-erosive patients with physiological acid exposure of the oesophagus

Objective: The mechanisms underlying symptoms in gastro-oesophageal reflux disease, particularly in non-erosive reflux disease (NERD), remain to be fully elucidated. Weakly acidic reflux and the presence of gas in the refluxate could be relevant in the pathogenesis of symptoms. Methods: To assess the relationship between symptoms and weakly acidic, acid and mixed (liquid–gas) reflux, 24 h oesophageal pH–impedance monitoring was performed in 32 NERD and in 20 oesophagitis patients. In 12 NERD patients the study was repeated following 4 weeks treatment with a proton pump inhibitor (PPI). Impedance–pH data were compared with those of 10 asymptomatic controls. Heartburn and acid regurgitation were considered in the analysis of symptoms. Results: 15 NERD patients showed a physiological acid exposure time (pH-negative). Weakly acidic reflux was significantly less frequent in patients (25% (2%), mean (SE)) than in controls (54% (4%), p<0.01). Gas was present in 45–55% of reflux events in patient groups and controls, and decreased following PPI treatment. In NERD pH-negative patients, weakly acidic reflux accounted for 32% (10%) (vs 22% (6%) in NERD pH-positive and 12% (8%) in oesophagitis patients) and mixed reflux for more than two-thirds of all symptom-related refluxes. Multivariate logistic analysis showed that in NERD pH-negative patients, the risk of reflux perception was significantly higher when gas was present in the refluxate (odds ratio, 3.2; 95% CI, 1.2 to 10; p<0.01). Conclusions: The large majority of symptoms, in all patients, are related to acid reflux. In NERD patients, the presence of gas in the refluxate significantly enhances the probability of reflux perception. These patients are also more sensitive to less acidic reflux than oesophagitis patients.

Effect of endoscopic augmentation of the lower oesophageal sphincter (Gatekeeper reflux repair system) on intraoesophageal dynamic characteristics of acid reflux

Background and aims: Improvements in symptoms following endoscopic procedures for gastro-oesophageal reflux disease (GORD) are seldom supported by normalisation of acid exposure time at the distal oesophagus. However, the distribution of gastric acid within the proximal oesophagus is a main determinant of symptom generation in GORD patients. In this study, our aim was to assess the effect of endoscopic insertion of hydrogel expandable prostheses into the oesophageal submucosa on spatiotemporal characteristics of gastro-oesophageal reflux. Methods: Oesophageal manometry and multichannel ambulatory 24 hour pH monitoring were carried out in nine patients before and six months after the endoscopic procedure. Dynamic characteristics of gastro-oesophageal reflux in patients were also compared with those in 13 asymptomatic controls. Results: Acid exposure time (AET) at the distal oesophagus decreased from 11.7% (95% confidence interval 6.1–21.8) at baseline to 7.7% (3.7–11.6) at follow up (NS). Of the nine patients, distal AET normalised in three. AET at the middle (7.6% (2.9–12.3)) and proximal (2.4% (0.1–4.8)) oesophagus decreased significantly in all patients (2.4% (0.3–4.5), p <0.01; 1.2% (0.2–2.2), p<0.05 respectively). Proximal extent of acid events significantly decreased in all patients at follow up (37.3% v 9.5%), reaching values observed in asymptomatic controls. Median GORD health related quality of life scores significantly improved from 35.5 at baseline to 9.4. Conclusions: Despite the lack of a significant improvement in traditional pH variables, endoscopic implant of hydrogel prostheses above the lower oesophageal sphincter significantly decreases proximal spread of acid reflux into oesophageal body. This effect would explain the improvement in symptoms in patients six months after therapy.

Long-term treatment with infliximab in inflammatory bowel disease: safety and tolerability issues.

Crohns disease and ulcerative colitis represent the most common forms of inflammatory bowel disease (IBD), clinical conditions affecting the small and/or large bowel. It is well known that IBD is an immune-mediated condition and that TNF-α plays a pivotal role in the pathogenesis of the disease. TNF-α has been scrupulously studied as a target for therapeutic intervention in this setting. A number of biologic compounds have been developed, including the European Medicine Agency (EMEA)-approved agents, infliximab and adalimumab. Although their efficacy in induction and maintenance of remission has been established by several clinical trials, many issues regarding safety remain to be elucidated. In fact, anti-TNF treatment may be associated with a number of rare, but serious, adverse events, including infusion reactions, infections, lymphomas and other malignancies. A black-box warning has to be taken into consideration when looking at potential serious infections such as tuberculosis. Active infections, demyelinating disorders and severe heart failure are contraindications for anti-TNF treatment. This review focuses on drug toxicity and adverse events related to infliximab treatment in IBD.

Intercellular space diameters of the oesophageal epithelium in NERD patients: Head to head comparison between light and electron microscopy analysis

BACKGROUND Dilation of intercellular space diameters of oesophageal epithelium detected at transmission electron microscopy morphometry is a marker of tissue injury in non-erosive reflux disease patients. Semi-quantitative evaluation of intercellular space diameters using light microscopy seems to provide promising results. AIM/METHODS To comparatively evaluate intercellular space diameters in the same patients, by means of morphometry and semi-quantitative analysis, both on light microscopy and transmission electron microscopy microphotographs, biopsies were taken in 29 non-erosive reflux disease patients at distal and proximal oesophagus. Twelve asymptomatic controls underwent the same protocol. RESULTS Morphometric analysis on transmission electron microscopy microphotographs showed mean intercellular space diameter values of patients, at distal and proximal oesophagus, 3- and 2-fold, respectively, higher than those in controls (p<0.001). On light microscopy microphotographs, mean intercellular space diameter values of patients at distal oesophagus were higher than those in controls, an overlap between patients and controls being observed. The semi-quantitative score was positive in 79% of patients and in 25% of controls at distal esophagus. CONCLUSIONS Intercellular space diameter morphometric analysis at light microscopy is widely available, allows intercellular space diameter to be quantitatively measured with good sensitivity and specificity and could represent a useful tool in non-erosive reflux disease diagnosis. Despite satisfactory sensitivity, the semi-quantitative score at light microscopy is hampered by much lower specificity than transmission electron microscopy- and light microscopy-morphometry.

Effect of oesophagitis on proximal extent of gastro‐oesophageal reflux

Abstract  Proximal oesophageal acid reflux is increased in gastro‐oesophageal reflux disease (GORD) patients with oesophageal and extra‐oesophageal symptoms, the latter particularly in presence of oesophagitis. This study was aimed to assess the proximal extent of reflux, both acid and weakly acidic, in GORD patients with and without oesophagitis and to characterize, using an animal model of GORD, the relationship between acute oesophagitis and proximal extent of reflux. Proximal extent of reflux was evaluated during 24‐h pH‐impedance monitoring in 17 oesophagitis, 27 non‐erosive reflux disease (NERD) patients and 10 asymptomatic controls. In five adult cats, reflux events were simulated by intra‐oesophageal retrograde injection of a radiopaque solution. Proximal extent of simulated reflux was fluoroscopically assessed before and after inducing acute oesophagitis. The percentage of proximal reflux was 11% in controls, 22% in NERD and 38% in oesophagitis patients (P < 0.05 vs NERD). Weakly acidic reflux showed higher proximal extent in oesophagitis than in NERD patients but it was less proximally propagated than acid reflux. In cats, proximal reflux was significantly increased during acute oesophagitis. Oesophagitis patients show higher proximal extent of reflux, acid and weakly acidic, when compared with NERD patients and controls. In the experimental model, acute oesophagitis favours proximal migration of simulated reflux.

Decreased number of activated macrophages in gallbladder muscle layer of cholesterol gallstone patients following ursodeoxycholic acid

We recently reported that, in symptomatic cholesterol gallstone patients, ursodeoxycholic acid (UDCA) improves gallbladder (GB) muscle contractility and decreases the biochemical parameters of oxidative stress and inflammation.1 UDCA also antagonises the hydrophobic bile acid damage to the liver by preventing hydrophobic bile acid-induced stimulation of macrophage oxidative processes.2 3 Macrophages also play a dominant role in the inflammatory and oxidative response in other conditions associated with impairment of intestinal motility, such as post-operative ileus.4–6 Following these findings, we carried out additional studies aimed at examining: the presence of macrophage infiltration and cyclooxygenase-2 (COX-2) expression in the GB muscle layer and the effect of short-term UDCA administration. From February 2004 to August 2007, …

Maintenance treatment with infliximab for the management of Crohn's disease in adults.

Crohn’s disease (CD) is a chronic, relapsing disease, the continuous cycle of which deeply affects the long-term course which, eventually, leads to fibrosis and development of transmural complications. It is well known that CD is an immune-mediated clinical condition and that tumor necrosis factor-α (TNF-α) plays a fundamental role in the pathogenesis of the disease. Current clinical guidelines recommend that patients with mild to moderate active CD should be treated initially with corticosteroids. Although this approach is effective in inducing remission, some patients may become dependent on, or refractory to, these drugs in the long term, thus increasing the risk of developing steroid-related adverse effects. A recent Cochrane systematic review established that infliximab (IFX) is effective in inducing remission in patients with CD. Although only a few published studies have assessed IFX for the maintenance of remission in the long term, there is evidence that IFX is superior to placebo in sustaining clinical remission and fistula healing; moreover, corticosteroid-sparing effects have been demonstrated. IFX is associated with the formation of antibodies to IFX which can lead to infusion reactions and shorter duration of response, but when comparing episodic vs scheduled maintenance treatment, the latter appears to sensibly reduce immunogenicity, thus offering improved efficacy and tolerance. The final point to consider is the best time to introduce IFX in the therapeutic algorithm of CD. Early use of IFX has been suggested to be more effective than late, and may potentially change the natural history of the disease. Effective induction and maintenance therapy with IFX is the only means with which to maintain long-lasting clinical and mucosal remission which, in turn, may modify the long-term course of the disease. Furthermore, when treating inflammatory bowel disease patients with IFX, an appropriate risk-benefit balance has to be taken into consideration, because the precise risk of serious adverse events associated with anti-TNF treatment in CD remains to be fully elucidated.

Presence of gas in the refluxate enhances reflux perception in patients with non-erosive reflux disease

Background and Aims: The mechanisms underlying symptoms in GERD, particularly in endoscopy negative reflux disease (NERD), are not fully understood. Weakly acidic reflux and presence of gas in the refluxate could be relevant in the pathogenesis of NERD. It has been reported that balloon distension of the oesophagus induces heartburn and chest pain. Aim and Methods: To assess the symptom association of weakly acidic, acid and mixed (liquid+gas) reflux, 24-h ambulatory esophageal pH-impedance monitoring, following a 3-week PPI or H2 antagonists washout, was performed in 26 NERD patients, without history of erosive disease, in 20 ERD patients (grade I n=12, grade II n=8) and in 10 asymptomatic controls. Endoscopy was performed 1-2 weeks before the pH-impedance study. Reflux was classified as acid (pH drop below 4), weakly acidic (nadir pH between 4 and 7) and weakly alkaline (impedance drop without pH change below 7). Pure liquid reflux and mixed reflux were defined according to published criteria. Acid exposure time was defined as pathological if percent time at pH <4 exceeded 5% of total recording time at 5 cm above LES. Heartburn and acid regurgitation were considered in the analysis of symptoms. Results: 11 out of 26 NERD patients showed a physiological acid exposure time (pH-negative). Weakly acidic refluxes were 55% in controls, 27% in NERD pH negative, 23% in NERD pH positive and 26% in ERD patients. Gas was present in 45-55% of reflux in all study groups. Out of the 26 NERD patients, 23 reported 247 symptoms during the study [mean 9 (range 1-25)], 13 ERD patients reported 72 symptoms [4 (1-16)]. In NERD pH-negative patients, of all symptomatic refluxes (n=47), 30% were weakly acidic, compared to 11% (out of 119 symptom-related refluxes) in NERD pH-positive and 7% (out of 63 symptom-related refluxes) in ERD patients. Multivariate logistic analysis showed that only in NERD pH-negative patients the risk of reflux perception was very high when gas was present in the refluxate (odds ratio: 5.0; 95% confidence intervals: 1.3–18; P<0.02). Conclusions: In all patients, the great majority of symptoms are related to acid reflux. In NERD patients with physiological acid exposure of the esophagus, presence of gas in the refluxate significantly enhances probability of reflux perception. NERD patients, particularly those with a physiological acid esposure, are more sensitive to less acidic reflux than ERD patients. These findings could play a role in the reduced response to PPI treatment, frequently observed in these patients.

Expression of GH/IGF-1 Axis Compounds in Moderate-Severe Crohn's Disease: Role of Mucosal Inflammation and Anti TNF-α Treatment

AIM: Growth failure in children and adolescents, weight loss and catabolism in adults, are well known features of active Crohns disease (CD). Increasing evidence shows that these features may be due to growth hormone (GH) resistance caused by persistent chronic inflammation. Aim of this study was to evaluate, in CD patients, a possible peripheral GHresistance (intestinal mucosa), and eventual modifications following anti TNF-α treatment. MATERIALS AND METHODS: 9 patients (5 F, median age 42.2 years, range 19-67) with moderate-severe active CD (CDAI>220), consecutively scheduled to receive three infliximab infusions at a dose of 5 mg/kg for induction of remission, were studied. Biopsy specimens from normal appearing duodenal mucosa were collected, in the 2 weeks prior to the first and after the third infusion. Confocal and real time PCR analysis of insulin-like growth factor 1 (IGF-1), activated signal transducer and activator of transcription protein 5 (phosphoSTAT5) and suppressor of cytokine signalling protein 3 (SOCS-3) were carried out and normalised to GAP, 18S and H3 referring genes. Four dyspeptic patients (2 F, median age 39 years, range 24-57), who underwent upper endoscopy with duodenal biopsy sampling, represented our control group. Differences between CD patients and controls were analysed by one-way ANOVA and REST-coupled ANOVA analysis. RESULTS: In CD patients, a significant inverse correlation was found when comparing phospho-STAT5 levels with CDAI (r=-0.71; p=0.003). Confocal analysis showed a significant decrease in phospho-STAT5 immunoreactivity in sections from CD patients, compared to controls (p<0.001). After treatment, phospho-STAT5 levels significantly increased (p<0.001). Molecular data for phospho-STAT5 were in keeping with biochemical findings. At baseline, compared with controls, in CD patients, the PCR analysis of IGF-1, showed a trend towards a decrease, while SOCS3 showed a trend towards an increase. Following treatment, SOCS-3 and IGF-1 target genes showed a trend toward a decrease and an increase, respectively. Nevertheless, following infliximab induction treatment, IGF-1, phospho-STAT5 and SOCS-3 levels did not reach those of the control group. CONCLUSION: The present study underline the effect of inflammation on the growth hormone axis not only at the level of hepatic metabolism, but also in the intestinal mucosa, since biologic agents able to inhibit pro-inflammatory cytokines, in particular TNF-α, the main inflammatory mediator, reverse growth hormone resistance. These therapeutic approaches could prevent the onset of those clinical conditions with a negative impact on child growth and quality of life of adults.