Liver Ischaemia Reperfusion Injury (IRI) leads to production of reactive oxygen
species and cytokines, which affects hepatocellular function following liver resection
and transplantation.
This thesis examines 2 hypotheses:
1) The role of intravenous glycine in amelioration of liver IRI in a in vivo animal
model of partial lobar liver IRI.
2) Does prophylactically administered N-acetylcysteine prevent liver IRI in
patients undergoing elective liver resection.
Materials and Methods
1) A rabbit model of hepatic lobar IRI was used to evaluate glycine. 3 groups
(n=6) Sham group (laparotomy alone), ischaemia reperfusion (I/R) group (1
hour ischaemia and 6 hours of reperfusion), and glycine I/R group (IV glycine
5 mg/kg prior to the I/R protocol) were used. Portal blood flow, bile flow and
bile was analysed by H1NMR spectroscopy. Hepatic microcirculation,
intracellular tissue oxygenation, serum TNFα, IL-8, ALT, AST were measured
at 1, 2, 4 and 6 hours following reperfusion.
2) A randomised double blind clinical trial was conducted to assess the effect of
NAC on liver IRI following liver resections. The main outcomes were:
morbidity and mortality, ICAM-1 expression in liver tissue, liver function tests.
Patients were randomised to receive NAC as IV infusion (NACG) or a placebo
group (PG) which received 5% dextrose only. Immunohistochemistry for
ICAM-1 was carried out on perioperative liver biopsies. Results
1) Glycine normalised the bile flow, reduced phosphatidylcholine shedding,
lactate surge, and stimulated bile acid, pyruvate, glucose and acetoacetate
release. Glycine improved portal blood flow, hepatic microcirculation by the
2nd hour, and hepatic intracellular tissue oxygenation by the 4th hour of
reperfusion. Glycine ameliorated serum TNFα at 1, 2 and 4 hours and serum Il-
8, AST and ALT up to 6 hours post reperfusion as compared to the I/R alone
group.
2) Of the 43 patients, 15 received NAC, 16 were randomised to the PG, 12 were
excluded due to inoperable tumours. Serum ALT was reduced in NACG
(p=0.001), while serum ALP was higher in the NACG (p=0.003). ICAM-1
expression was up-regulated in 6/16 patients in the PG and in 3/15 patients in
NACG. ICAM-1 was down-regulated in 1/15 patients in the NACG and none
in the PG, the difference was not significant.
Conclusions
1) Glycine ameliorated liver IRI, improved bile flow and composition.
2) NAC ameliorated parenchymal liver injury and enhanced liver regeneration in
patients undergoing elective liver resection
