The role of gastrin in the development of gastric preneoplastic and neoplastic changes

Murugesan, Senthil The role of gastrin in the development of gastric preneoplastic and neoplastic changes. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

The hormone gastrin regulates gastric acid secretion and through its effects on cell proliferation, apoptosis and angiogenesis also regulates gastric epithelial and enterochromaffin-like (ECL) cell growth. The influence of various factors (host, bacterial and environmental) upon fasting serum gastrin concentrations and to what extent these factors interact to influence the progression of gastric preneoplastic pathology is not fully understood. Long standing hypergastrinaemia secondary to hypochlorhydria resulting from autoimmune gastritis can result in the development of ECL-cell hyperplasia. In some patients this progresses to type-1 gastric neuroendocrine tumour formation. The factors that influence this progression have not been fully characterised. The management of type-1 gastric neuroendocrine tumours is dependent on their size. However, there is still controversy regarding the optimal management of larger (> 1cm) tumours. Antrectomy is one option and the results of an octreotide suppression test (to determine gastrin dependency of type-1 gastric neuroendocrine tumours in order to predict response to antrectomy) have been reported in a single patient. This aims of this thesis were to assess: 1. The interaction between various factors (host, bacterial and environmental) that may influence fasting serum gastrin concentrations and the development of gastric preneoplastic pathology. 2. The roles of certain factors in the progression of ECL-cell hyperplasia to type-1 gastric neuroendocrine tumours. 3. The role of an octreotide suppression test in identifying patients with type-1 gastric neuroendocrine tumours who may benefit from antrectomy. In a large cohort of >1000 prospectively recruited patients, we demonstrated that in addition to H. pylori infection, the presence of a host factor (advancing age), a bacterial virulence factor (cagA) and elevated fasting serum gastrin concentrations (>100pM) were significantly associated with the presence of gastric preneoplastic pathology. Concurrent proton pump inhibitor therapy was however not associated with the presence of gastric preneoplastic pathology. The interactions between H. pylori infection, proton pump inhibitor use and the presence of gastric preneoplastic pathology in determining fasting serum gastrin concentrations were found to be complex. In addition, other host and environmental factors also influenced fasting serum gastrin concentrations. Although results from our study did not demonstrate any statistically significant associations, there did appear to be correlations between the presence of factors such as hypothyroidism, positive anti-gastric parietal and intrinsic factor antibodies and extent of gastric atrophy with the presence of more advanced degrees of gastric ECL-cell hyperplasia. Although a positive octreotide suppression test was associated with tumour regression following antrectomy in four patients with type-1 gastric neuroendocrine tumours, a fifth patient who had a positive test did not show tumour regression and needed additional surgery. In conclusion, gastrin appears to act as an important co-factor in the pathogenesis of epithelial and neuroendocrine neoplasia in the stomach, but interactions with other factors are complex.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2012 (completed)
Subjects:	?? RB ??
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	07 Feb 2014 12:42
Last Modified:	16 Dec 2022 04:39
DOI:	10.17638/00012373
Supervisors:	Pritchard, Mark Varro, Andrea
URI:	https://livrepository.liverpool.ac.uk/id/eprint/12373