Peter D. Fairclough

Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002)

The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) commissioned this update of the 2002 guidance. The aim, as before, is to provide guidance on the appropriateness, method and frequency of screening for people at moderate and high risk from colorectal cancer. This guidance provides some new recommendations for those with inflammatory bowel disease and for those at moderate risk resulting from a family history of colorectal cancer. In other areas guidance is relatively unchanged, but the recent literature was reviewed and is included where appropriate.

Acromegaly, colonic polyps and carcinoma

It has been suggested that patients with acromegaly may be at risk of developing colorectal carcinoma. In order to clarify this issue, we have evaluated the prevalence of carcinoma, premalignant tubulovillous adenomas and hyperplastic colonic polyps in a large cohort of patients with acromegaly.

Are we meeting the standards set for endoscopy? Results of a large-scale prospective survey of endoscopic retrograde cholangio-pancreatograph practice

Objective: To examine endoscopic retrograde cholangio-pancreatography (ERCP) services and training in the UK. Design: Prospective multicentre survey. Setting: Five regions of England. Participants: Hospitals with an ERCP unit. Outcome measures: Adherence to published guidelines, technical success rates, complications and mortality. Results: Organisation questionnaires were returned by 76 of 81 (94%) units. Personal questionnaires were returned by 190 of 213 (89%) ERCP endoscopists and 74 of 91 (81%) ERCP trainees, of whom 45 (61%) reported participation in <50 ERCPs per annum. In all, 66 of 81 (81%) units collected prospective data on 5264 ERCPs, over a mean period of 195 days. Oximetry was used by all units, blood pressure monitoring by 47 of 66 (71%) and ECG monitoring by 37 of 66 (56%) units; 1484 of 4521 (33%) patients were given >5 mg of midalozam. Prothrombin time was recorded in 4539 of 5264 (86%) procedures. Antibiotics were given in 1021 of 1412 (72%) cases, where indicated. Patients’ American Society of Anesthesiology (ASA) scores were 3–5 in 670 of 5264 (12.7%) ERCPs, and 4932 of 5264 (94%) ERCPs were scheduled with therapeutic intent. In total, 140 of 182 (77%) trained endoscopists demonstrated a cannulation rate ⩾80%. The recorded cannulation rate among senior trainees (with an experience of >200 ERCPs) was 222/338 (66%). Completion of intended treatment was done in 3707 of 5264 (70.4%) ERCPs; 268 of 5264 (5.1%) procedures resulted in a complication. Procedure-related mortality was 21/5264 (0.4%). Mortality correlated with ASA score. Conclusion: Most ERCPs in the UK are performed on low-risk patients with therapeutic intent. Complication rates compare favourably with those reported internationally. However, quality suffers because there are too many trainees in too many low-volume ERCP centres.

Human Peyer’s Patch T Cells Are Sensitized to Dietary Antigen and Display a Th Cell Type 1 Cytokine Profile

Animal studies have demonstrated that feeding Ags induces regulatory (Th2, Th3) cells in Peyer’s patches (PP), which migrate to the periphery and produce immunomodulatory cytokines such as IL-4, IL-10, or TGF-β. In this work we have attempted to extend this paradigm to man by analyzing the response of human PP T cells to in vitro challenge with the common dietary Ag β-lactoglobulin (βlg) of cow’s milk. PP T cells stimulated with βlg showed enhanced proliferation compared with blood T cells from the same patient. Increased expression of CD25 and the Th1-associated chemokine receptor CCR5 was also seen on CD4+ and CD8+ PP T cells, but not blood T cells, stimulated with βlg. By enzyme-linked immunospot assay and RT-PCR, the PP T cell recall response to βlg and casein was dominated by IFN-γ, with negligible IL-4, IL-5, IL-10, or TGF-β. To help explain the PP T cell response to βlg, we examined IL-12 expression. Both IL-12p40 and -p35 transcripts were abundantly expressed in PP, but not in adjacent normal ileal mucosa. Immunoreactive IL-12p40-containing cells were present below the PP dome epithelium. Furthermore, in culture, PP, but not paired PBMC, spontaneously released IL-12p70. These results suggest that the human response to oral Ags in the gut may be different from that in rodents.

Inhibition of NF-κB Signaling in Human Dendritic Cells by the Enteropathogenic Escherichia coli Effector Protein NleE

Intestinal dendritic cells (DCs) send processes between epithelial cells into the gut lumen to sample pathogens. Noninvasive enteropathogenic Escherichia coli (EPEC) colonize the gut using a type three secretion system (T3SS) to inject effector proteins into epithelial cells. We hypothesized that EPEC might also inject proteins into DC processes to dampen immune recognition. Using a T3SS-linked fluorescence resonance energy transfer-based system we show that EPEC injects effectors into in vitro grown human myeloid DCs. Injected cells emit a blue signal due to cleavage of the green fluorescence resonance energy transfer-based substrate CCF2/AM by β-lactamase. When cultured with a mutant EPEC unable to translocate effector proteins, myeloid DCs show rapid activation of NF-κB, secrete large amounts of proinflammatory cytokines and increase expression of CD80, CD83, and CD86, whereas wild-type EPEC barely elicits cytokine production and shuts off nuclear translocation of NF-κB p65. By deleting effector protein genes, we identified NleE as being critical for this effect. Expression of NleE in HeLa cells completely prevented nuclear p65 accumulation in response to IL1-β, and luciferase production in an NF-κB reporter cell line. DCs cocultured with wild-type EPEC or NleE-complemented strains were less potent at inducing MLR. EPEC was also able to inject effectors into DCs sending processes through model gut epithelium in a transwell system and into Peyer’s patch myeloid DCs. Thus, EPEC translocate effectors into human DCs to dampen the inflammatory response elicited by its own pathogen-associated molecular patterns.

Water and solute absorption from hypotonic glucose-electrolyte solutions in human jejunum.

While oral rehydration therapy with glucose-electrolyte solutions is highly effective, the optimal formulation has not yet been defined. Recent clinical studies suggest that stool volume, and thus water losses, may be reduced if glucose is replaced by a polymeric substrate which reduces osmolality. It is possible that the efficacy of glucose monomer based oral rehydration solutions (ORS) will also improve if osmolality is decreased. Using jejunal triple lumen perfusion in healthy adult volunteers net water and solute absorption were studied from three hypotonic solutions with different sodium concentrations (46, 60, 75 mmol/l) but identical glucose concentrations (90 mmol/l), thus allowing osmolality to rise (210, 240, and 270 mOsm/kg, respectively). Results from these solutions (ORS 45:210, ORS 60:240, and ORS 75:270) were compared with the World Health Organisation oral rehydration solution (WHO-ORS). Greatest water absorption was seen with ORS 60:240 (p less than 0.01). Sodium absorption from ORS 60:240 and WHO-ORS was similar and greater than sodium absorption from ORS 45:210 (p less than 0.05). Potassium and glucose absorption were greater from ORS 60:240 than from any of the other hypotonic solutions (p less than 0.05) and were equal to absorption from WHO-ORS). These results in a short segment of healthy human jejunum suggest that hypotonic ORS containing monomeric glucose may increase water absorption.

Effect of octreotide on gall stone prevalence and gall bladder motility in acromegaly.

Octreotide therapy in acromegaly is associated with an increased prevalence of gall stones, which may be the result of an inhibition of gall bladder motility. Gall stone prevalence in untreated acromegalic patients relative to the general population is unknown, however, and the presence of gall stones and gall bladder motility in these patients and in acromegalic patients receiving octreotide was therefore examined. Thirty four percent of 39 patients who had taken octreotide for a mean of 20 months had gall stones compared with 16% of 38 patients who had not been treated with octreotide (p < 0.005). In a subgroup of 21 patients studied prospectively over 4 to 18 months, two patients developed stones. No patient had symptoms referrable to their gall stones. In 31 untreated acromegalic patients, the mean fasting gall bladder volume was similar to that in normal subjects. Maximal percentage emptying, however, was impaired (34 v 64%, p < 0.001) and the mean postprandial residual gall bladder volume increased (21.7 v 9.0 ml, p < 0.001). Treatment with octreotide increased the mean postprandial residual volume further to 36.8 ml (p < 0.001). Gall bladder emptying in untreated acromegalic subjects is impaired. Octreotide further increases postprandial residual gall bladder volume and this may be a factor in the increased gall stone prevalence seen in these patients.

Ranitidine in Reflux Oesophagitis

This study was designed to assess the effect of ranitidine on patients with symptomatic oesophageal reflux. In a double-blind comparative trial in 46 patients a twice daily dose of 150 mg ranitidine was compared with placebo. Relief of pain, endoscopic healing and histological improvement were significantly better in those treated with ranitidine. Thus, ranitidine is of value in the management of patients with reflux oesophagitis and may prevent the development of peptic stricture.

Increased levels of insulin-like growth factor binding protein-2 in sera and tumours from patients with colonic neoplasia with and without acromegaly.

OBJECTIVE Patients with acromegaly are at increased risk of developing colorectal carcinoma and premalignant tubulovillous adenoma. The pathogenesis of these neoplasms could involve a stimulatory effect of serum growth factors on colonic epithelial cell proliferation. The aim of this study was to evaluate changes in (1) serum IGF‐I, IGF‐II, IGFBP‐3 and IGFBP‐2 and (2) changes in local expression of IGFBPs and p53 in colonic epithelium in patients with colonic neoplasia with and without acromegaly.

RESPONSE OF CIRCULATING SOMATOSTATIN, INSULIN, GASTRIN AND GIP, TO INTRADUODENAL INFUSION OF NUTRIENTS IN NORMAL MAN

We have studied the effect of direct infusion of nutrients into the duodenum of normal subjects on circulating plasma somatostatin, insulin, gastrin and gastric inhibitory polypeptide (GIP) levels. Six normal subjects were given on four separate occasions 150 ml of isotonic solutions containing 100 calories of carbohydrate, protein, or fat, and a control solution of saline, by infusion into the second part of the duodenum. Plasma somatostatin rose slightly after carbohydrate, mean basal 30 ± 3 pg/ml, peak 46±16 pg/ml at 15 min; and more markedly after protein, peak 57 ± 9 pg/ml at 30 min. However, fat was the most potent intraduodenal stimulus to plasma somatostatin release into circulation, peak 101 ± 11 pg/ml at 30 min. The plasma insulin rise was greatest after carbohydrate, peak 68 ± 10 i.u., but there was a significant rise after protein also, peak 34 ±6 i.u. Plasma gastrin rose significantly after protein only, peak 70 ± 22 pg/ml. Plasma GIP rose markedly after carbohydrate, basal 506 ± 50 pg/ml, peak 1480 ± 120 pg/ml. Protein was also a potent stimulus of circulating plasma GIP release, peak 1200 ± 190 pg/ml, while fat was the least potent, peak 730±190 pg/ml. Thus, calorie for calorie, fat is the most potent intraduodenal nutrient stimulus of circulating somatostatin. We postulate therefore that somatostatin may be an enterogastrone–a circulating hormone released by intraduodenal fat which inhibits gastric acid secretion. Fat is the least potent intraduodenal nutrient stimulus of circulating GIP release. This is evidence against the hypothesis that circulating GIP acts as an enterogastrone.