Hepatic Insufficiency Clinical Trial
Official title:
The Impact of Liver Transplantation on Reticuloendothelial Clearance Capacity
Study summary: "Liver transplantation and the reticuloendothelial clearance capacity."
The purpose of this study is to evaluate the effect of liver transplantation on the immune
system.
This study will involve the taking of a number of observations but does not involve any
treatment, which differs from normal care. Indications for transplantation are solely based
on the best clinical practice, which is usually performed at the department.
The study measures liver function based on the clearance of different "marker" substances by
the liver. These substances are given intravenously and their clearance will be measured
from bloodstream.
All substances used in this study are registered in the United Kingdom for clinical
applications and already used in clinical practice over years. They are safe and without any
risk to harm individuals under study. Furthermore no side effects or any symptoms caused by
the administration of these substances are expected.
Measurements of liver function are undertaken before transplantation, 1 and 7 days following
the transplant. There is no restriction from any of the patient's prescribed medication. All
blood samples will be removed from the cannula (drip) and will not require repeated
injections. It is hoped that this research will lead to a greater understanding of the
effects of liver transplantation on the immune system.
Introduction
Liver cells called hepatocytes undertake the most important metabolic functions of the
liver. The liver also contains a large number of immune cells called Kupffer cells. These
cells act as a filter removing bacteria and other dangerous substances from the blood
passing through the liver. Although we know and understand a great deal about how liver
cells behave and function after transplant we have no idea what happens to the immune cells
in the liver. These immune cells make up 85% of the total body reserves of these cells and
serve an important function by clearing bacteria and bacterial products from the blood. A
failure of these cells is associated with risk of infection. Infections, blood clotting
disorders and many other serious medical issues are typical for patients suffering from
chronic liver failure.
This study will use microscopic particles of a human protein called albumin in the form of
microspheres to simulate bacteria in the blood. We can detect these microspheres by
attaching a radioactive label to the spheres and measuring emission in a detector called a
gamma counter. The level of radiation is quite small and similar to a bone scan. We have
previously shown that healthy liver rapidly clears these albumin microspheres from the
blood. We have also shown previously that after major liver surgery there is a delay in
clearance of microspheres, which we believe equates to a poorly functioning innate immune
system.
Liver transplantation is the only successful life-extending treatment for patients with
chronic liver failure and cirrhosis. During liver transplantation it is known that a
proportion of hepatocytes damaged and recover following the transplant. We want to establish
the immediate particulate clearance capacity of the liver following transplantation and the
pattern of recovery one week later. This is used as a surrogate for liver clearance of
bacteria and bacterial products.
We also intend to measure the production of a set of proteins called acute phase proteins,
which are produced by the liver and may be important in helping immune cells recognize
bacteria. These proteins, also called opsonins, bind to the walls of bacteria and make it
easier for immune cells to attach to the bacteria and eat them.
We also want to find out if there is any difference between non-marginal and marginal liver
grafts and their reticuloendothelial clearance capacity. This study may provide important
information regarding the need for post-operative antibiotics and prevention of infection in
this patient group.
This research will be the first of its kind to address this issue in this vulnerable group
of patients and no study has ever looked at the effect of transplantation on the immune
cells of the liver. This study will investigate the ability of the liver to clear particles
(albumin microspheres) from the blood and will monitor the recover and improvement in
function of these cells over a period of time.
Results of any pilot studies
A study also from the eLISTER group (Edinburgh liver injury in surgery and transplantation
experimental research) about the effect of major liver resection on innate immunity to
bacterial endotoxin was approved by Lothian research Ethics Committee LREC/2002/1/31. This
trial was performed between May 2003 and 2005. This study looked at the adaptive response of
the reticuloendothelial system to major liver resection. We found a strong correlation
between clearance of albumin microspheres and ICG (indocyanine green clearance), supporting
the assertion that hepatocellular function and RES phagocytosis are related if only in terms
of liver volume. We also demonstrated marked defects in RES phagocytosis in patients with
chronic liver disease or normal liver function, who had undergone a major liver resection.
Validation of technique of measurement of phagocytic clearance of Tc-99m labelled
(Nanocoll®) microaggregated human albumin To determine reticuloendothelial system (RES)
phagocytosis activity and liver phagocytic function respectively we will measure plasma
clearance of 99mTc labelled micro-aggregated human albumin without any imaging studies. It
has been shown in several studies that this is a reliable method to estimate RES
phagocytosis activity. By measuring the plasma radioactivity disappearance rate instead of
doing imaging studies a radioactivity dose of less than 15 MBq is sufficient to determine
99mTc plasma clearance accurately. Disappearance of 99mTc blood activity will be measured
serially at 3-minutes intervals to 30 minutes, at 10-minutes intervals to 60 minutes and at
20-minutes intervals to 120 minutes. Three half-life times required for the 99mTc albumin
microspheres counting rate to fall from 100% to 50%, from 50% to 25% and from 25% to 12.5%
of the value obtained at three minutes after injection are noted and the mean half-life and
standard deviation, expressing the microspheres blood clearance, is calculated. To determine
the possibly non-linear nature of albumin microspheres clearance over time the area under
the curve will be calculated over the observation time using integral function. Mean
half-life of albumin microspheres in the blood and area under the curve at day 1 and day 7
after transplantation will be expressed as a percentage of preoperative values and compared
between individuals and patient groups. We hypothesize that the phagocytosis activity of
marginal compared to good liver grafts is significantly impaired after liver transplantation
due to the decreased number of phagocytes as well as due to the decreased synthesis of
substances which usually facilitates phagocytosis. If this hypothesis is true, the RES
phagocytosis activity in the marginal grafts should be significantly increased after liver
transplantation and should be comparable to the RES phagocytosis activity of non-marginal
grafts.
Aims
This project will test the hypothesis that liver transplantation of normal and marginal
grafts results in a significant impairment of innate immunity to bacterial endotoxin.
We intend to characterise the nature or reticuloendothelial clearance impairment following
liver transplantation and its recovery on marginal and non-marginal grafts. We also wish to
correlate clearance capacity with measures of hepatocyte injury (ALT/AST) and liver
dysfunction score to establish whether the two processes are independent or related.
In this regard we will compare marginal and non-marginal organs and the relationship between
reticuloendothelial cell dysfunction and cold ischemic time. Reticuloendothelial clearance
capacity will also be related to evidence of clinical infection in the postoperative course.
Research questions - Hypotheses
I. Liver transplantation results in a significant impairment of innate immunity to bacterial
endotoxin.
II. The degree of impairment in innate immunity to endotoxin is directly related to the
functional status of the liver graft. (Patients undergoing liver transplantation with
non-marginal and marginal grafts will be compared).
III. To establish whether there is any correlation between liver cell (hepatocyte) injury
and immune cell (Kupffer cell) injury after transplantation.
IV. To establish the effect of liver transplantation on serum expression of acute phase
protein opsonins.
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