Reperfusion-induced self-antigen excretion (RISE) following major liver resection

Major liver surgery often requires the surgeon to temporarily halt the afferent
blood flow in order to prevent excessive blood loss. Vascular inflow occlusion
(VIO) however predisposes the liver to a detrimental inflammatory response once
the circulation is restored. Altogether, the ramifications that result from
this temporary withdrawal of oxygen supply are known as ischemia and
reperfusion (I/R) injury, and the extent to which this occurs determines the
functional outcome of the liver after surgery. Recently, it has become clear
that (over)activation of the immune system forms the mainstay of hepatic I/R
injury. More importantly, it has been shown in animal models that endogenous
self-antigens, known as damage-associated molecular patterns (DAMPs), are
released from stressed liver cells in the earliest stages of reperfusion and,
as such, form the most proximal triggers of hepatic I/R injury. Clinical data
on DAMP release following hepatic I/R are however scarce to date. Therefore,
the aim of this study is to investigate DAMP release in patients that undergo a
major liver resection with or without VIO and to correlate the results to the
expression of acute-phase inflammatory response genes and routine clinical
parameters for hepatocellular damage.

To investigate the release of damage-associated molecular patterns (DAMPs)
following major hepatic resection with or without VIO and to correlate the
outcomes to the acute inflammatory response and clinical parameters for
hepatocellular damage.

The study is designed as an observational study. Because the decision to apply
VIO is often made during surgery, patients will be allocated to a group
postoperatively. Therefore, the inclusion of subjects in this study will
continue until the calculated sample size of n=30 patients has been reached for
the VIO group and n=15 patients for the control group. As approximately 65% of
all major liver resections are performed under VIO, this distribution of
subjects is in accordance with the clinical practice. However, since about 40%
of patients are diagnosed with irresectable disease at the time of surgery we
estimate that a maximum of 75 patients will need to be included in this study.

Blood will be drawn preoperatively as well as at 1 and 6 hours of
reperfusion/post resection. At all time points, samples will be derived from
the central venous line that is in place in all patients undergoing a liver
resection. Also, two biopsies will be taken from the future remnant liver
during the operation (i.e. one biopsy before resection and one biopsy at 30 min
of reperfusion/post resection). A third biopsy from the part of the liver that
is to be resected is taken as part of the side-study.
Furthermore, clinical parameters for hepatocellular damage (i.e., AST and ALT)
and liver function (i.e., total bilirubin and INR) that are determined as part
of the standard perioperative care will be used for this study.

Considering that all blood samples are derived from the central venous line
that is in place in all patients undergoing a liver resection, this will carry
no additional risk. Moreover, the first two samples will be taken in the
operating room when patients are under general anesthesia. The biopsies,
however, carry a risk of bleeding, albeit this procedure is carried out under
direct vision of the surgeon, which means that any bleeding site can be
immediately controlled.
Notably, the potential benefits of this study are substantial. Currently, DAMP
release is considered to be a cardinal early event in I/R injury as well as a
possible target for future interventions. However, systemic concentrations of
DAMPs as well as their correlation to clinical outcomes have not yet been
determined in a clinical setting of warm hepatic I/R.
In addition, the side study will supply novel information regarding gene
expression profiles in cholestatic versus non-cholestatic liver tissue. The
outcomes thereof could shed new light on the pathophysiology of cholestasis,
which is expected to be of relevance for the surgical as well as hepatological
field of practice.
Lastly, both studies aims to do obtain data in a minimally invasive setting
that will impose no significant burden on patients participating in this study.