Koak, Yashwant; (2001) The pathophysiology and management of columnar-lined lower oesophagus: An in vivo study. Masters thesis (M.S), UCL (University College London).

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Abstract

Aim: The aetiology of the lower oesophageal columnar metaplasia (Columnar-lined Lower Oesophagus - CLO) is not clearly understood. The aim of this study was to determine the nature and constituents of the gastrointestinal refluxate that induce CLO. In addition, influence of medical acid suppression and surgical control of reflux in CLO is not completely established. A further aim was to assess the therapeutic role of proton pump inhibition (PPI) and anti-reflux surgery in preventing CLO. Method: Ten in vivo CLO models were established by surgical gastro and oesophago intestinal anastomosis in Sprague-Dawley rats to achieve physiological refluxate of gastric, bile, duodenal secretions and mixed gastric + bile, gastric + duodenal, gastric + pancreatic, duodenogastropancreatic, duodenopancreatic biliary, jejunogastric and jejunoesophageal reflux. PPI elixir was administered to half of each group during 4 months of post-operative period. In another study 1 model of CLO were established by surgical anastomosis to achieve jejunoesophageal reflux. Half of the group underwent a second operation at 12 weeks to reverse the reflux. After 4 months the lower oesophagus was examined with H&E stains for length and intensity of columnar change and severity of inflammation by three experienced pathologist blinded to the experiment. Sections were further stained with diastase PAS, immunostaining (p53, Ki67, TFF2, LHK) and mRNA in situ hybridisation for trefoil peptide phenotype (TFF1, TFF2, TFF3) distribution. Results: Inflammation and columnar metaplasia of the lower oesophagus was seen in all groups. Length of columnar change in gastric reflux (GR) and duodenal reflux (DR) was significantly longer than all other groups [GR (length in cm ± SEM) (1.3 ± 0.2) (all p < 0.05), DR (1.17 ± 0.1) (p < 0.001)]. The severity of inflammation and metaplastic change was higher in the gastric and biliary dominant groups as compared to the other groups. Although, PPI treatment with omeprazole (OMP) did not cause significant change in CLO there was a trend towards longer CLO length in duodenal dominant reflux (DDR) group and shorter CLO length in gastric dominant reflux group (GDR) and biliary dominant reflux group (BDR) compared to untreated group [Columnar mucosa (length in cm ± SEM) No OMP GDR (1.17 ± 0.08), DDR (1.05 ± 0.05) BDR (1.07 ± 0.17), OMP GDR (1 ± 0.13), DDR (1.08 ± 0.15), BDR (0.83 ± 0.11 ) (all p > 0.05) (Mann-Whitney U test)]. There was significant weight gain, normalisation of oesophageal pH and decrease in serum & oesophageal bile acid concentration after antireflux procedure [Weight in grams (mean ± SEM) Group 1 (Non-reversed) (244.58 ± 9.76) Group 2 (Reversed) (384.86 ± 6.35), postop pH Group 1 (7.37 ± 0.08) Group 2 (8.19 ± 0.05), serum bile acid (μmol/l) Group 1 (120.33 ± 20.35) Group 2 (38.8 ± 7.72), oesophageal bile acid (μmol/1) Group 1 (46 ± 9.49) Group 2 (25.53 ± 5.10) (all p < 0.03)]. The length of columnar mucosa, degree of acute inflammation and degree of metaplasia were signiilcantly reduced by anti-reflux surgery (all p < 0.05). The morphology of specialized columnar epithelium and ulcer associated cell lineage tended to revert to native mature epithelium after anti-reflux surgery. The histological changes in these in vivo models were similar to human CLO before and after successful anti-reflux surgery. Conclusion: 1. Reflux of pure gastric, pure duodenal, pure biliary secretions, mixed refluxates or neutral pH reflux can all produce columnar metaplasia in oesophagus. 2. Reflux of gastric or duodenal contents produced metaplasia of much greater intensity and extent compared to other groups. 3. Proton pump inhibition showed a trend towards increased columnar metaplasia in duodenal dominant reflux group, and decrease in gastric reflux group. 4. Duodenal reflux may be the cause of ineffectiveness of proton pump inhibition in a significant number of patients with CLO. 5. Morphology of experimental CLO and its reversal is similar to human 6. Anti-reflux procedure successfully reverts the mitogenic changes of columnar metaplasia induced by chronic gastroesophageal and gastroduodenoesophageal reflux in an in vivo model. 7. Morphology of CLO after successful anti-reflux surgery resembles mature gastric and intestinal columnar epithelium.

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