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ACID-INDUCED OESOPHAGEAL CONTRACTIONS; ROLE OF MAST CELLS AND SUBSTANCE P
Acid reflux into the oesophagus causes both pain and longitudinal muscle contraction; however, the precise pathways involved are uncertain. This study used isolated segments of a opossum oesophagus perfused with acid to investigate the pharmacological pathways. Thirty μm capsaicin and 100 μm substance P were used to desensitise the TRPV1 and substance P receptors and determine their role. The authors showed (figure) that acid perfusion causes oesophageal shortening, which was largely prevented by capsaicin and substance P desensitisation as well as by MEN1037, a specific neurokinin 2 receptor antagonist. They similarly showed that isolated longitudinal smooth muscle strip contractions were inhibited by the same procedures, although not by tetrodotoxin. The authors suggest that protons diffusing through the epithelium activate mast cells which produce mediators activating an axonal reflex which involves substance P release and subsequent longitudinal muscle contraction. These acid-induced sustained oesophageal contractions correlate with chest pain and these studies suggest novel ways in which these patients might be treated.
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Effect of neurokinin 2 receptor antagonist (MEN10376), substance P and capsaicin desensitisation on acid-induced oesophageal shortening. Grey bars represent control, white bars drug or treatment effect.
THE SEQUENTIAL TREATMENT REGIMEN FOR HELICOBACTER PYLORI ERADICATION
H pylori eradication treatments are becoming less effective with at least 25% of patients failing standard 7–10 day triple regimens. New approaches to eradicating H pylori have been developed, including the so-called sequential therapy, based on a proton pump inhibitor (PPI), amoxicillin, clarithromycin and tinidazole (see figure). Zullo et al, who previously published several key trials using this regimen, carried out a review of the published studies on the sequential regimen and performed a pooled-data analysis of the available results. They show that this 10 day course is 15–20% more effective than standard 7–10 day triple therapy and is effective in adults, children, elderly patients and in patients with and without ulcers. The cost of such therapy also compares favourably with available standard therapy. Even in the presence of clarithromycin resistance, sequential therapy seems to do better than standard triple therapy. The authors conclude that this treatment, which has a proven track record in Italy, should be assessed in the wider global community.
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The sequential treatment regimen.
PREDICTING PROGNOSIS IN REFRACTORY COELIAC DISEASE
While most people with coeliac disease respond well to a gluten-free diet, 2–5 % do not and such patients are often difficult to manage. This valuable report describes 93 such patients divided according to whether the intra-epithelial T lymphocytes showed normal surface markers (refractory coeliac disease (RCD) type I) or whether T cell markers were aberrant (RCD type II). Follow-up in the two groups averaged 72 and 44 months, respectively. During this time there were no cases of RCD type I that progressed to type 2. Despite strict adherence to a gluten-free diet in all, there was a striking difference in progression to secondary enteropathy-associated T cell lymphoma (EATL), which developed in 26 patients in the RCD type II group, who, as the figure shows, had a markedly worse prognosis. Thirty nine per cent of the treated patients died from their EATL and the authors speculate that autologous stem cell transplantation, which was tried in seven of the patients with encouraging results, might be a better treatment than the azathioprine and prednisolone most received.
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Kaplan-Meyer survival curve in RCD type 1 and type 2.
APPENDECTOMY AND RISKS OF DEVELOPING CROHN’S DISEASE
Although it is accepted that individuals who have undergone an appendectomy have a reduced risk of developing ulcerative colitis, no such benefit has been shown for Crohn’s disease and some studies have concluded that it might increase the risk. Uncertainty about risk estimates usually reflects inadequate study size so this study from Scandinavia, which examined over 700 000 appendectomy patients is welcomed. The study included 1655 patients with Crohn’s disease and, as the figure shows, the standardised incidence ratio (SIR) of developing Crohn’s disease was markedly increased after appendectomy. Appendectomy before the age of 10 years, however, did not increase the risk. The highest risk of developing Crohn’s disease occurred within the first 6 months and the risk fell 60% in the next 6 month period (see figure). Five years after appendectomy the risk had returned to normal for all those with an inflamed appendix. The authors conclude that the elevated early risk of developing Crohn’s ileitis and the lack of an increased risk of Crohn’s colitis beyond 5 years after appendectomy suggests that Crohn’s ileitis is often misdiagnosed in its early stages as appendicitis and that appendicectomy itself does not predispose to developing Crohn’s disease.
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Standardised incidence ratio of developing Crohn’s disease by time since appendectomy stratified by cause of appendicitis.
NODULAR REGENERATIVE HYPERPLASIA IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE TREATED WITH AZATHIOPRINE
Nodular regenerative hyperplasia (NRH) is a rare hepatic lesion whose aetiology and natural history are poorly understood. However, some cases have been described in patients taking purine analogues such as azathioprine. The symptoms, when present, are mainly associated with the complication of portal hypertension. Vernier-Massouille et al assessed the characteristics and clinical course of NRH in patients with inflammatory bowel disease (IBD) treated with azathioprine. Between 1994 and 2005, 37 patients (30 males, 7 females) were identified from 11 French centres. The median dose of azathioprine was 2 mg/kg/day and the median time between the start of azathioprine and the diagnosis of NRH was 48 months. In all, 31 of the 37 patients had portal hypertension at endoscopy or liver imaging, and only 6 had isolated biological abnormalities (see figure). Using multivariate analysis, male sex and stricturing were the two risk factors associated with NRH in patients treated with azathioprine. This study highlights the importance of regular monitoring of liver function and platelet count in patients with IBD treated with azathioprine.
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Cumulative survival without complications of portal hypertension from time of diagnosis of nodular regenerative hyperplasia in 37 patients.
THE ANGIOGENIC SWITCH OCCURS AT THE ADENOMA STAGE OF THE ADENOMA–CARCINOMA SEQUENCE IN COLORECTAL CANCER
Most colorectal cancers (CRC) develop along the adenoma–carcinoma sequence (ACS). Microvascular density (MVD), which is a surrogate marker of an angiogenic response, is significantly increased in both CRC and adenoma specimens compared with normal colonic mucosa. It is not clear however whether this angiogenic switch occurs at the time of invasion or much earlier. Staton et al examined the relationship between tissue factor (TF), vascular endothelial growth factor (VEGF) and the onset of angiogenesis in the adenoma–carcinoma sequence. Using 210 surgical specimens spanning the ACS, they stained for endothelial cells (CD31), VEGF and TF. Angiogenesis was quantified using Chalkley grid analysis for MVD and VEGF/TF expression were semi-quantitatively graded and correlated with standard prognostic indicators including 5 year follow-up. There was a significant increase in MVD across the ACS (p<0.0005; see figure) with significant correlations with Dukes’ stage (p = 0.01) and lymph node involvement (p = 0.02). The greatest increase in MVD was related to the onset of dysplasia, with an associated significant increase in VEGF expression (p<0.0005). The findings suggest that the angiogenic switch occurs at the onset of dysplasia in the ACS.
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Box and whisker plots with Chalkley score (CCS; horizontal line) representing MVD across the adenoma–carcinoma sequence.
Linked Articles
- Oesophagus
- Stomach
- Coeliac disease
- Inflammatory bowel disease
- Inflammatory bowel disease
- Colorectal cancer