Metabolic interactions between alcohol, the liver, and the gastrointestinal tract

Campbell, Stewart (2002) Metabolic interactions between alcohol, the liver, and the gastrointestinal tract. MD thesis, University of Glasgow.

Abstract

This thesis examines the metabolic interactions between alcohol and the liver and gastrointestinal tract. The metabolism of alcohol by the liver and gastrointestinal tract may determine susceptibility to alcohol- related disease, but is also likely to be responsible for alcohol related damage to these organs. The three introductory chapters review the current understanding of alcohol related gastrointestinal and liver disease and alcohol metabolism. Chapter 1 reviews the epidemiology of alcohol consumption and alcohol related disease, and then discusses in detail the hepatic and gastrointestinal lesions associated with alcohol. Differing patterns of genetic and environmental susceptibility are then discussed, followed by a detailed review of the processes involved in alcohol metabolism, focussing on pathogenic mechanisms related to metabolism (i.e. redox shift, hepatic hypermetabolism, acetaldehyde induced damage, free- radical generation, cytochrome induction, antioxidant, phospholipid and vitamin depletion, endotoxin-mediated damage and mechanisms of hepatic fibrogenesis). Chapter 2 concentrates on alcohol dehydrogenase, which is quantitatively the most important enzjone involved in alcohol metabolism. The complex pharmacokinetics of alcohol are reviewed in detail in Chapter 3. The validity of common assumptions made by researchers examining alcohol metabolism is discussed, and illustrated by using specific examples. Chapter 4 states the aims of this thesis. The first major aim is to determine if a rise in gastric alcohol dehydrogenase activity following Helicobacter pylori eradication is associated with any change in the pre-systemic metabolism of alcohol, and to determine to what extent this is influenced by changes in gastric emptying. A secondary aim of this thesis is to develop an improved assay for gastric alcohol dehydrogenase activity. The second major aim of this thesis is to determine if there is any evidence from conventional biochemical liver function tests or plasma markers of hepatic fibrogenesis for hepatic damage following abrupt alcohol withdrawal. The fifth chapter describes in detail the development of a rapid, colorimetric, semiautomated assay for gastric alcohol dehydrogenase. In chapter 6, the effect of Helicobacter pylori eradication on alcohol metabolism and gastric alcohol dehydrogenase activity is assessed. Evidence for hepatic damage following abrupt alcohol withdrawal in subjects who are alcoholics, but have, at worst, well- compensated liver disease is sought in the experiments described in Chapter 7. Although there is no worsening of hepatic transaminases following alcohol withdrawal when considering the group of subjects as a whole, 32% of subjects did meet pre- defined criteria for worsening of transaminases. Concomitant intake of a small dose of paracetamol during the withdrawal period was associated with a marked transaminase rise. High basal levels, of, and changes following alcohol withdrawal, of plasma levels of aminoterminal procollagen HI peptide suggest that alcoholics may have reduced degradation of collagen whilst still drinking, and may have increased deposition of collagen, or a reduction in hepatic clearance, following alcohol withdrawal. High levels of tissue inhibitor of metalloproteinases-1 in alcoholics, which did not change following alcohol withdrawal, suggest that there may be inhibition of collagen degradation even in alcoholics who have, at worst, clinically compensated liver disease. This thesis has three major conclusions. Firstly, it concludes that the colorimetric technique described for assaying gastric alcohol dehydrogenase activity can offer significant advantages over conventional methods. Secondly, although Helicobacter eradication increases gastric alcohol dehydrogenase activity, there is no change in alcohol bioavailability, suggesting that this enzyme plays at most a minor role in determining alcohol bioavailability. Thirdly, the minor changes in hepatic transaminases and markers of fibrosis following alcohol withdrawal may reflect mild liver injury; with perhaps a minor tendency to increased fibrosis or decreased hepatic clearance. The cumulative effect of repeated episodes of abrupt alcohol withdrawal may therefore be clinically significant, although this would require clarification by further studies.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Mike Lean
• Keywords: Medicine, Physiology
• Date of Award: 2002
• Depositing User: Enlighten Team
• Unique ID: glathesis:2002-73413
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jun 2019 08:56
• Last Modified: 14 Jun 2019 08:56
• URI: https://theses.gla.ac.uk/id/eprint/73413