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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_815_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 1
Box1.1 • Definition of postoperative hepatic dysfunction
based on results from blood tests and clinical
observation
Total bilirubin (micromol/L)
<20 (0 points)
21–60 (1 point)
>60 (2 points)
Prothrombin time (seconds above normal)
<4 (0 points)
4–6 (1 point)
>6 (2 points)
Serum lactate (mmol/L)
≤1.5 (0 points)
1.6–3.5 (1 point)
>3.5 (2 points)
Encephalopathy grade (West haven Criteria)
None (0 points)
1 and 2 (1 point)
3 and 4 (2 points)
Severity of hepatic dysfunction
None = 0 points; mild = 1–2 points; moderate = 3–4 points;
severe >4 points
Adapted from Schindl MJ, Redhead DN, Fearon KC, etal. The
value of residual liver volume as a predictor of hepatic dysfunction
and infection after major liver resection. Gut 2005;54:289–96.
With permission from the BMJ Publishing Group Ltd.
Common causes of acute liver
failure: hepatic insufficiency
following liver resection
Liver resection is the only treatment with the
potential to cure patients with cancers that
have originated in the liver itself (primary liver
cancer) or that have originated elsewhere and
have subsequently spread to the liver (metastatic
liver cancer). Equally, it is a preferred therapy in
patients with benign liver tumours that have the
potential of malignant transformation (uncertain
benign primary liver tumours). Resection of up
to 70% of the liver is feasible, because the liver
has a remarkable capacity to regenerate. Within
6–8 weeks following 60–70% hepatectomy, the
liver has regained nearly its original size and
weight.
The most common cause of liver metastases is
from primary colorectal cancer, and it is estimated
that in the West there is a yearly incidence of 300
new cases of colorectal liver metastases per million
population. The current estimate is that this should
lead to approximately 100–150 patients per million
eligible for liver resection for this indication. To this
should be added the patients with primary benign
and malignant liver tumours, and hence about 150–
200 liver resections should probably be performed
per million population each year.
Ever since the first liver resection by Langenbuch
in 1887, this procedure has remained a major
undertaking and even in the recent past, liver
resection was still a dangerous surgical procedure
with a high mortality of 20–30% in the 1970s.
This was mainly due to excessive intraoperative
bleeding but, over the subsequent decades, the
procedure has become increasingly safe due
to improvements in surgical and anaesthetic
techniques. At present, mortality rates are reported
to be well below 5%. Currently, the single most
important cause of lethal outcome following
hepatic resection is liver failure. For this reason,
many researchers and clinicians have attempted
to design methods to identify patients at risk of
liver failure (and hence mortality) following liver
surgery. However, the development of such a
method has been hampered by several factors, as
outlined below.
The critical point determining lethal outcome
following liver resection has been a failure of the
residual liver to function properly. Focus in this
research area has been to determine a single liver
function test that identifies patients with impaired
liver function. This has proven exceedingly difficult,
and such a test is not available for a number of
reasons.
First, as outlined above, the liver has a remarkable
capacity to regenerate very rapidly, which emphasises
that there is tremendous overcapacity of several
liver functions. In this context, it is known that it is
entirely safe to resect 50% of an otherwise healthy
liver, because the residual half liver will simply
take over all vital liver functions such as clearing
bacteria, urea synthesis and synthesis of crucial
proteins. It has been estimated that a crucial liver
function, such as urea synthesis, has an overcapacity
of 300%, which implies that a static preoperative
liver function test will be unable to assess this
particular function. An alternative and innovative
strategy would be to give a challenge to the liver
and measure the ability of the liver to respond or
cope – a dynamic test.
The critical minimum residual liver volume for
healthy liver parenchyma has been estimated to be
approximately 25% after resection.
2
The second crucial problem has been that there
is only a poor correlation between volume and
function. However, it is still unclear why some
patients with smaller hepatic remnants do not
develop liver failure whilst some with greater residual
volumes do. These observations suggest, however,
2
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Liver function and failure
that peri- and intraoperative events superimposed on
the innate hepatic capacity to withstand injury play
a role. Hepatic insufficiency in this situation may
arise either if not enough liver volume is left after
partial hepatectomy or if the residual volume does
not function properly. A functional limitation may
arise, for example, in patients who have received
chemotherapy in order to reduce the number and
size of metastases prior to surgical treatment by liver
resection. One of the factors contributing to defective
defence may be preoperative fasting,
3
but equally,
prior chemotherapy and pre-existent steatosis may
play a role.
A third important aspect is that during liver
surgery, deliberate hypotension and temporary
hepatic blood inflow occlusion (the so-called
Pringle manoeuvre) are used by many surgeons
to reduce blood loss during hepatic surgery
(15 minutes ischaemia, 5 minutes reperfusion
[15/5 Pringle]). Other surgeons do not use this
manoeuvre, assuming that it causes oxidative
stress and ischaemia/reperfusion (I/R) injury.
4,5
There is little doubt that this procedure does
cause oxidative stress and I/R injury; however, the
consequence of this is variable. In a situation where
defence mechanisms against oxidative stress are
deficient, it may adversely affect liver function. In
this situation, hepatic steatosis may constitute an
additional predisposing factor to damage by I/R.
Ischaemia/reperfusion is the basis of
ischaemic preconditioning, a process in which
temporary clamping and release of the liver blood
flow has been shown to be beneficial in terms of
increasing resistance to subsequent injury.
6
In this situation it is assumed that defence
mechanisms against oxidative stress are adequate
and are indeed enhanced by short-term I/R injury.
7
The above three factors explain why it has been
exceedingly difficult to design a proper liver function
test that reliably singles out those patients at risk of
liver failure following liver resection. The term ‘liver
function’ is a rather crude denominator for a range
of functions that includes ammonia detoxification,
urea synthesis, protein synthesis and breakdown,
bile synthesis and secretion, gluconeogenesis and
detoxification of drugs, bacteria and bacterial toxins.
Chronic liver failure
The clinical signs of chronic liver failure are often
insidious and can also be related to the type of
disease. Cirrhosis is associated with a failure
of hepatic function and the consequences of
increased hepatic vascular resistance. Metabolic
impairment is manifest by jaundice, coagulopathy,
impaired ammonia clearance and encephalopathy,
hypoalbuminaemia and oedema. The presence of
increased vascular resistance is associated with the
development of splenomegaly, ascites and gastrooesophageal or abdominal wall varices. The slow
progression of many chronic liver diseases, over
years, implies a gradual, almost incremental, loss
of liver cell mass or function. There are many
causes of liver failure, including hepatitis B and
C virus, autoimmune diseases such as primary
biliary cirrhosis, primary sclerosing cholangitis
and autoimmune hepatitis, alcoholic liver disease,
Wilson's disease, α
others. All are associated with chronic or repeated
cell injury and attempts at repair. The fibrosis and
scarring associated with this regeneration and repair
lead to the clinical condition termed cirrhosis, with
a typically small shrunken irregular liver and an
increased risk of cancer.
The Child–Pugh score for chronic liver disease
has served as a useful means of categorising
patients based on the severity of their liver disease.
It employs five clinical measures of liver disease
and each measure is scored 1–3, with 3 indicating
the most severe derangement (Table 1.1). In the
setting of liver transplantation, the Model for Endstage Liver Disease (MELD) or MELD-Na (MELD
including sodium) score or in the United Kingdom
UKELD score has replaced Child–Pugh scoring in
the assessment of severity of liver disease.
-antitrypsin deficiency and
1
8
Table1.1 • Child–Pugh score for chronic liver disease
Measure 1 point 2 points 3 points Units
Bilirubin (total) <34 (<2) 34–50 (2,3) >50 (>3) μmol/L (mg/dL)
Serum albumin >35 28–35 <28 g/L
INR <1.7 1.71–2.20 >2.20 No unit
Ascites None Suppressed with
Refractory No unit
medication
Hepatic encephalopathy None Grade I–II (or suppressed
with medication)
Child-Pugh A = 5–6 points; Child-Pugh B = 7–9 points; Child-Pugh C =10–15 points. 1 year survival: A = 100%; B = 80%; C = 45%.
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Grade III–IV (or
refractory)
No unit
3
Chapter 1
Metabolic liver function
The liver plays a central role in fat, carbohydrate
and protein metabolism, as well as in acid–
base homeostasis. In the context of liver failure,
disturbances of fat metabolism are probably not
crucially important. With respect to carbohydrate
metabolism, it is well known that the liver plays a
central role in the conversion of lactate to glucose.
Part of this lactate is formed due to anaerobic
metabolism of, amongst others, glucose in skeletal
muscle. This metabolic route of glucose to lactate
(muscle) and then back to glucose (liver) is very
important for glycaemic homeostasis and is called
the Cori cycle. Liver failure will be manifested by
lactic acidosis and hypoglycaemia.
Next to its role in carbohydrate metabolism, the
liver plays a central function in nitrogen homeostasis.
Hepatic synthesis and breakdown of proteins and
amino acids, and detoxification and clearance of the
nitrogenous waste products from other organs are
of central importance. For example, the gut uses the
amino acid glutamine as a fuel for enterocytes, which
results in the production of waste end-products
of intestinal metabolism, such as ammonia. This
ammonia is then transported via the portal vein to the
liver, where it is detoxified with the formation of urea.
effects on brain function, affecting neurotransmission
as well as impairing mitochondrial function and
key cellular transport systems. There is a direct
correlation between arterial ammonia concentration
and the presence of brain herniation.
12
Brain
glutamine concentration is elevated in acute liver
failure, which may influence the development of
hepatic encephalopathy through toxic metabolites,
modulation of hepatic blood flow or by amplifying
the toxic effects of ammonia.
in significant swelling of astrocytes in culture
13
Lactate can result
14
and
raised brain lactate concentration is seen in a wide
range of experimental models of acute liver failure.
Therapeutic approaches in hepatic encephalopathy
aim to address these areas with strategies to lower
ammonia levels, protect systems by inducing
mild hypothermia, reduce blood–brain ammonia
transfer, decrease brain lactate synthesis and reduce
inflammation. However, in the face of overwhelming
liver failure, attempts to modulate these mechanisms
of hepatic encephalopathy have been shown at best
to prolong life by hours to a few days. In some
selected patients, this may provide a ‘bridge to liver
transplantation’; however, patients undergoing
surgery for metastatic disease are ineligible for
transplantation and therefore their only hope lies in
the intrinsic ability of the liver to regenerate.
Why do patients die from liver
failure?
The failing liver can trigger a range of events
resulting in multi-organ failure, sepsis and death.
When three or more organs are involved, the chance
of death approaches 80%.
hepatic encephalopathy are the leading causes of
death in this group who experience progressive
systemic failure.
Risk of bacterial infection is increased considerably
following partial hepatectomy.
compromised as the liver’s phagocytic and synthetic
capacity is impaired by its reduced size. The shear
force generated by increased portal venous blood
flow per unit area, as well as ischaemic injury at
the time of surgery, can further impair immune
capacity.
10
Management of sepsis in these patients
necessitates intensive care multi-organ support and
broad-spectrum antibiotics subsequently guided by
culture results.
Hepatic encephalopathy is a reversible neuropsychiatric syndrome, with multifactorial cause. It is
characterised by cerebral oedema, raised intracranial
pressure, with risk of brain herniation and death.
range of factors may contribute to this phenomenon,
including rising concentration of ammonia,
glutamine and lactate. Ammonia has a range of
9
Bacterial infection and
2
Immune function is
11
A
Assessment of the liver
Measuring liver volume
Advances in imaging techniques have permitted the
development of invivo imaging of the liver. Threedimensional models of the liver can be constructed
from computed tomography (CT) or other crosssectional imaging modalities, such as magnetic
resonance imaging (MRI). The volume of the liver
can then be calculated based on known separation
of image slices combined with planar mapping
of cross-sectional areas. In addition, such threedimensional computer models can be simulated to
map the effects of surgery by performing virtual
hepatic resection, and studies have demonstrated
that there is a good correlation between computer
modelling and actual resection weight of surgical
liver specimens (
Figs 1.1–1.3).
3D printers to create a replica of the patient’s liver.
This enables the relationship between the tumour
and the vascular/biliary anatomy of the liver to be
better understood, aiding complex liver resections.
Blood tests of liver function
As part of many blood chemistry analyses, it is
possible to request liver function tests. These tests
2,15
Some centres use
16
4
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Liver function and failure
Volume (imageJ) (mL)
2500
0
Weight (PA) (g)
Figure1.1 • Three-dimensional reconstruction of the liver preoperatively (red) showing tumours. Computer prediction
of residual liver volume based on virtual hepatectomy of 3-D model (yellow) and actual photograph of resection showing
residual liver segments.
Reproduced from Schindl MJ, Redhead DN, Fearon KC, etal. The value of residual liver volume as a predictor of hepatic
dysfunction and infection after major liver resection. Gut 2005;54:289–96. With permission from the BMJ Publishing
Group Ltd.
r2=0.976
2000
1500
P>0.0001
Figure1.2 • Correlation between volume of resection
calculated with ImageJ and actual measured weights of
the resection specimens (n = 15, Pearson's test).
Reproduced with permission from Dello SA, van Dam
RM, Slangen JJ, etal. Liver volumetry plug and play: do it
yourself with ImageJ. World J Surg 2007;31(11):2215–21.
refer to the transaminases, alkaline phosphatase,
γ-glutamyl transferase and bilirubin. They are not
truly measures of function but do give an indication
of processes going on within the liver. Aspartate
aminotransferase and alanine aminotransferase are
hepatocyte enzymes that are released in conditions
in which hepatocytes are damaged or killed,
such as ischaemic injury, hepatitis, severe sepsis
and in response to cancer. Liver-specific alkaline
phosphatase is expressed predominantly in the
biliary epithelium and is elevated in conditions such
as cholangitis or biliary obstruction. γ-Glutamyl
transferase is expressed by both hepatocytes and
biliary epithelium, and can also be induced by high
alcohol consumption.
Biochemical markers of true liver function vary
depending on whether acute or chronic liver failure
or injury is being considered (Table1.2).
1000
500
0
0 500 1000 1500 2000 250
Figure1.3 • Mapping the territory of the right hepatic
lobe drained by the middle hepatic vein. The numbers
represent the volumes of the territories at risk if segment
5 and 8 tributaries of the middle hepatic vein were not
reconstructed in a potential right lobe living-donor liver
transplant.
Reproduced with permission of MeVis imaging technologies,
Bremen, Germany. Kindly provided by H. Lang and A.
Radtke, Plainz, Germany.
Table1.2 • Blood tests useful to assess function in
acute and chronic liver injury
Acute Chronic
Albumin − +++
Prothrombin time +++ +++
Bilirubin + +++
Lactate ++ −
Glucose
++ −
requirement
Ammonia + +
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5
Chapter 1
ICG retention (%)
Time
Tests of liver function measuring
substance clearance
The ability to accurately predict postoperative
outcome based on preoperative liver function would
be a valuable addition to preoperative assessment.
The tests currently in common use include the
indocyanine green (ICG) clearance test, hepatobiliary
scintigraphy with radioisotope clearance, lidocaine
clearance test, the aminopyrine breath test and the
galactose elimination test. These tests aim to provide
an indicator of dynamic liver function, in that they
can provide real-time assessment of liver function in
response to a challenge. However, none of these tests
challenge the liver to demonstrate its full functional
capacity. Serum bilirubin and clotting factors provide
a static indirect estimation of liver metabolism and
synthetic function, but are influenced by a range
of other factors that limit their relevance and
suitability to predict postoperative outcome. The
most commonly used test for liver function prior to
liver resections is the ICG clearance test.
Indocyanine green (ICG)
ICG is a compound that is used widely to measure liver
function. It is rapidly cleared from blood, specifically
by hepatocytes, and is excreted into bile without
enterohepatic circulation. Hepatocytes are highly
effective at clearing ICG such that hepatic blood flow
is the limiting factor in patients with otherwise normal
liver parenchyma. In more severe liver disease both
hepatic blood flow and hepatocyte function may be
compromised, so impairing the clearance of ICG. ICG
clearance can be measured as ‘disappearance’ from
the blood or can also be measured as accumulation in
bile. Liver dysfunction is suggested by a slower rate of
clearance from the blood and is usually expressed as
percentage retention at 5 or 15 minutes after injection.
Continuous measurement of ICG clearance can also
be performed, offering potentially improved accuracy,
by measurement of the area under the clearance curve
Fig.1.4). In some centres ICG clearance is routinely
(
performed during preoperative work-up, with cut-off
values set for which patients are ‘safe’ to proceed to
resection. However, there is no evidence to suggest
that outcomes are improved in centres that use this
test compared to centres that do not. In chronic liver
disease, the discriminative ability of ICG clearance
is greatest in those with intermediate to severe liver
failure. Addition of this test to the MELD score
can improve prognostic accuracy for patients with
intermediate to severe liver dysfunction.
17
However,
given the relationship with hepatic blood flow, caution
should be exercised when interpreting ICG clearance
in the context of abnormally high cardiac output.
Hepatobiliary scintigraphy and SPECT
Using a radiolabelled tracer that is eliminated
exclusively by the liver, such as [
(technetium is a gamma-emitting radioisotope),
blood clearance and hepatic uptake can be measured
using a gamma camera to provide an indication of
hepatic function (
Fig.1.5). Hepatobiliary scintigraphy
may improve predictive value compared to future
liver remnant volume, especially in patients with
uncertain quality of liver parenchyma.
nuclear medicine techniques with CT (SPECT: singlephoton emission computed tomography) enables the
generation of a 3D image of liver function which
can be related to liver volume. Using this technique,
segmental liver function and liver functional volume
can be calculated.
De Graaf et al. demonstrated in 2010 that by
combining CT with [
99m
the function of the proposed future liver remnant
can be accurately obtained.
at the Amsterdam Medical Centre, subsequently
demonstrated that routine implementation of
this technique for patients requiring major liver
resection significantly reduced postoperative liver
failure and failure-related mortality.
reported that a better understanding of preoperative
liver function improved patient selection and led
to an increased use of portal vein embolisation to
optimise the future liver remnant.
99m
Tc]mebrofenin
18
Combining
Tc]mebrofenin SPECT,
19
This group, based
20
The authors
Combining CT with nuclear medicine
techniques enables regional liver function to be
calculated and can be used to assess preoperative
function.
19,20
Lidocaine (MEG-X)
Lidocaine, also known as monoethylglycinexylidide
(MEG-X), is a local anaesthetic that is taken up
by the liver and undergoes biotransformation by
a cytochrome P450 enzyme, CYP1A2. The rate of
disappearance of lidocaine from plasma correlates
Figure1.4 • Typical ICG clearance curve for a subject
with healthy liver function.
6
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with liver function; however, measurement of
lidocaine is more complex than that of ICG.
a b
c d
e f
Figure1.5 • Hepatobiliary scintigraphy before major liver
surgery in a patient with a large hepatocellular carcinoma
of the right liver (a, b) and a patient with a Klatskin
type IIIa tumour before (c, d) and 3weeks after portal
vein embolisation (e, f). Panels a and b show a large
afunctional right-sided hepatic mass with sufficient future
liver remnant function in segments 2–3. Panels c and d
show relatively small liver segments 2–3 with insufficient
future liver remnant function (1%/min/m
function of segments 2–3 increased significantly after
PVE (panels e and f) with sufficient future liver remnant
function (2.7%/min/m
hemihepatectomy).
Images courtesy of R. Bennink, Amsterdam Medical
Centre, Netherlands.
2
) for safe resection (extended right
2
). Volume and
Aminopyrine breath test
The aminopyrine breath test was the first breath
test proposed for the assessment of liver function
in patients with liver disease. The test uses
aminopyrine, which is a stable, non-radioactive,
isotopically labelled compound eliminated almost
exclusively by the liver. Following oral intake,
the compound is taken up by the gut and then
transported to the liver, where it is metabolised
by microsomal cytochrome P450 function. This
metabolism liberates 13CO
, which can be
2
measured non-invasively in exhaled air. This test
is not readily available at the bedside and requires
fairly sophisticated apparatus to measure stable
isotopic enrichment in the exhaled air. Induction
of microsomal metabolism by various drugs may
constitute a problem.
13
C2-
Liver function and failure
Urea synthesis
Recently, the feasibility of measuring urea synthesis
using stable isotopes and relating this to liver volume
in patients undergoing liver resection was explored.
21
As liver failure is almost always accompanied by
hyperammonaemia, it was hypothesised that this
is related to a presumed failure of hepatic urea
synthesis. Using stable isotopically
13
C-labelled urea,
urea synthesis was measured before and after major
hepatic resection, and liver volumes before and after
resection were determined using CT.
Major hepatic resection did not affect total
body ureagenesis, because the synthesis of urea per
gram of residual liver increased 2.6-fold.21 Therefore,
it is unlikely that urea synthesis is a limiting factor in
the initial aetiology of liver failure and this test is not
likely to contribute to predicting liver failure following
liver resection.
Glutathione synthesis
Unfortunately, most of the above tests focus on
very specific functions or pathways. None of them
assesses the main hepatic protection system against
many diverse forms of stress and intoxications: the
intracellular content and synthesis of glutathione
(GSH). It is generally accepted that GSH plays a key
role in the protection of the liver against many forms
of stress, ischaemia and toxic compounds such as
paracetamol. Unfortunately, there is currently no
adequate test to assess hepatic GSH synthesis and
metabolism invivo in humans, even though such a
test would be of great clinical importance. We have
previously explored the feasibility of measuring
GSH synthesis in vivo during liver surgery in
humans using stable isotopically labelled
2
H2glycine, a component of GSH (γ-glutamyl-cysteinyl-
glycine), but this approach was not suitable,
because part of the deuterium label of glycine was
lost (unpublished data). Future research will have to
focus on designing a test that is both dynamic and
focuses on the GSH system, making it possible to
determine liver function correlated to liver volume,
and assess an individual's risk of developing liver
failure following hepatic resection.
Measuring liver blood flow
Blood flow in the splanchnic area, particularly the gut
and liver, can be measured in a number of ways. These
can basically be either invasive (i.e. intraoperative)
or non-invasive. During open abdominal surgery,
blood flow can be measured in the portal vein and
hepatic artery. Portal vein blood flow measurements
provide predominantly information on the flow
across the intestines. By summing up the blood flow
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7
Chapter 1
in the hepatic artery and portal vein, total hepatic
blood flow can be calculated. Theoretically, this
could also be achieved by measuring hepatic venous
outflow, but this is impractical in humans because of
the short common outflow tract of the three hepatic
veins. Non-invasive MRI-based techniques are
being developed that may offer improved accuracy
of measurement of liver blood flow and provide
the potential for repeat measurements.
22
The ratio
of portal vein to hepatic artery blood flow changes
with increasing resistance of the liver and may
indicate the development of fibrosis or cirrhosis.
Methodology for assessing the importance of blood
flow as a predictor of liver parenchymal condition
has not been fully evaluated, but may provide a
means of determining regenerative capacity and
safety of surgery in some patients.
Such measurements of hepatic and portal arterial
blood flow can be obtained using 6–8 mm and
12–14 mm handle ultrasonic flow probes (Transonic
Systems, Kimal PLC, Uxbridge, UK). Essentially,
the vessels have to be dissected free for this flow
measurement and the three-quarters circular probe
is applied to the vessel. These probes are believed to
provide the most accurate technique for assessing
flow in relatively small vessels. However, there is
considerable variability in measurement related to
Doppler ultrasound signal strength and coupling with
the vessel wall. Also, there are likely to be changes
in diameter of the artery, in particular related to its
handling during surgery. However, the advantage
is that repeated measurements can be obtained and
the surgeon can operate this application without
help from a radiologist. Furthermore, post-resection
blood flow measurements can be taken before closure
of the abdomen, typically 1–2 hours after the first
measurement. This gives an impression of blood flow
across the residual liver following major resection.
During liver surgery, organ blood flow can also be
measured by means of colour Doppler ultrasound
scanning (e.g. Aloka Prosound SSD 5000; Aloka Co.
Ltd, Tokyo, Japan). A 5-MHz probe is used to trace the
vessels and calculate the cross-sectional area. Then,
time-averaged mean velocities of the bloodstream
are measured at the point where the cross-sectional
area of the portal vein and hepatic artery have been
measured. For accurate velocity measurements, care
must be taken to keep the angle between the ultrasonic
beam direction and blood flow direction below 60°.
If an accessory hepatic artery is present, flow in
both arteries should obviously be measured.
23,24
In
our experience, this method gives roughly the same
values as the ultrasonic flow measurement described
above. Theoretically, it is possible to perform such
flow measurements preoperatively or postoperatively
using a percutaneous approach, although the
measurement in the hepatic artery requires a skilled
ultrasonographer.
In recent years, technical improvements in hardware
and software applications for MRI have made it
possible to measure blood flow in the portal vein and
hepatic artery non-invasively. By linking this method
of flow measurement to hepatic volumetry, blood
flow per volume unit of liver can be calculated.
25,26
It has been suggested that MRI may provide a more
accurate and reliable assessment of portal vein and
hepatic artery blood flow than ultrasonography,
particularly given the wide interobserver variability
seen with the latter technique.
22
Although limited
to the preoperative period, MRI flow studies
may provide complementary information to
intraoperative ultrasonography.
A further technique that is emerging is the use of
near-infrared spectroscopy. This technique measures
absorption of near-infrared wavelength light and
from this can be calculated tissue oxygenation, since
haemoglobin oxygenation status alters absorption of
this wavelength light. This technique is more useful
for estimating tissue oxygenation and perfusion at a
sinusoidal level, but could potentially be combined
with other measures to estimate liver blood flow.
27
Effect of major liver resection on hepatic
blood flow
Direct measurement of hepatic artery and portal vein
blood flow before and after liver resection reveals
interesting results. When expressed as absolute values,
portal blood flow does not change significantly
whereas hepatic artery blood flow generally falls.
Typically, portal vein flow is approximately 840 mL/
min and post-resection805 mL/min, whereas hepatic
artery flow pre-resection is approximately 450 mL/
min and post-resection 270 mL/min. When these
flows are expressed in relation to the preoperative
and residual postoperative liver volume, it can be
seen that the portal blood flow increases from a
mean of 0.55 ml/min per gram of liver to 1.09 ml/
min per gram of liver, and the hepatic artery flow
remains relatively constant (
Fig.1.6).
In experimental research, pressure measurements
can also be obtained using radial artery invasive
monitoring to estimate hepatic artery pressure and
direct portal vein pressure measurement, using a
small needle coupled to a pressure transducer similar
to that used for measuring central venous pressure.
The combination of flow and pressure measurement
then allows calculation of hepatic sinusoidal
resistance (
Fig.1.6).
Assessment of innate immunity
The liver forms an important part of the innate
immune system by producing acute-phase proteins
and other opsonins, proteins that bind to bacteria
facilitating their phagocytosis. In addition, 85% of
8
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Liver blood flow (mL/min/g liver tissue)
1.50
postoperative
preoperative
P<0.028
postoperative
preoperative
1.00
0.50
0.00
Portal vein
Figure1.6 • Directly measured blood flow
intraoperatively in six patients during major hepatic
resection. Measurements were taken from the main portal
vein and the main hepatic artery simultaneously using
multichannel Transonics ultrasound flow probes. During
the liver resection one branch of each of the portal vein
and hepatic artery is ligated. The post-resection blood flow
measurement has been taken just before closure of the
abdomen, typically 1–2 hours after the first measurement.
Results are expressed per gram of liver tissue.
the reticuloendothelial system is located in the liver
(Kupffer cells) and clearly surgical resection will
involve a reduction of this cell mass.
It is not unreasonable to expect that major liver
resection might result in some impairment of innate
immunity. Our group has previously demonstrated
that major liver resection is associated with increased
frequency of infection as well as increased likelihood
of objective evidence of liver function impairment.
In a separate study, our group has also shown that
major liver resection is associated with a temporary
defect in the ability of the reticuloendothelial system
to clear albumin microspheres that were used as a
surrogate for bacteria.
Loss of approximately 50% of liver volume, such
as might occur during a right hepatectomy, is
associated with impairment of reticuloendothelial cell
clearance equivalent to that of non-surgical patients
with Child C chronic liver disease.
The liver also synthesises and exports many acute-
phase proteins involved in innate immunity or
homeostasis. C-reactive protein, for example, binds to
phosphoryl choline moieties of encapsulated bacteria
and acts as an opsonin, promoting phagocytosis.
Mannan-binding lectin, complement fragments and
-acid glycoprotein (orosomucoid) can also act
α
1
as opsonins. Transferrin and caeruloplasmin are
important in the binding and carriage of free metal
ions and α
1
NS
4
*
1
*
Portal vein
Hepatic artery
28
Hepatic artery
2
-antitrypsin and α1-antichymotrypsin act
Liver function and failure
as antiproteases. Liver failure or liver surgery may be
associated with a reduction in synthesis of some of
these acute-phase proteins (mannan-binding lectin,
haptoglobin, α-fetuin and fibronectin), whereas the
concentrations of others may be increased despite
a reduction in functional liver tissue (C-reactive
protein, liver fatty acid-binding protein; unpublished
data). The exact significance of these changes is
unclear but may contribute to a global impairment
in innate immunity in the injured liver.
Liver regeneration
The liver is unique in that it is the only organ in the
adult that is capable of regenerating or renewing itself
to restore the ratio between pre-injury liver volume
and body weight. Knowledge of the capacity for the
liver to regenerate is presumed to be ancient and
is the basis for the punishment meted out by Zeus
to Prometheus, who according to Greek mythology
was chained to a rock and had his liver eaten daily
by an eagle, only for it to regenerate overnight. This
continued for several years until the eagle was finally
killed by Hercules, who also released Prometheus.
While the speed of liver regeneration is exaggerated
in this myth, it is true that it is an extremely rapid
process. In the context of surgery, liver regeneration
happens very rapidly, with most of the cell division
required for regeneration occurring within 72 hours
of injury in mice. Full liver function and volume are
usually restored within 6–12weeks in humans. In
chronic injury or in the presence of fibrosis, liver
regeneration can be chaotic with repeated insults
causing scarring, and nodular regeneration with
disordered architecture leading to cirrhosis.
Molecular signals for hepatic regeneration
At a cellular level, liver regeneration depends on
the coexistence of three key factors: changes in
the microenvironment of the liver cell supporting
growth, the ability of differentiated hepatocytes
to proliferate and inhibition of processes, linking
injury to programmed cell death.
Stimuli for liver regeneration stimulate transcription factors that turn on a variety of genes
expressing growth factors. Although not direct
growth factors, the hormones insulin and adrenaline
potentiate the effects of growth factors on hepatocyte
regeneration. All elements of the liver are required
to regenerate; however, the coordination of these
processes is complex. Removal of the stimulus for
regeneration by growth to pre-injury capacity and
transforming growth factor-β act as brakes that slow
regeneration of liver elements (
hepatic regeneration include cirrhosis and fibrosis
and ongoing liver injury such as might occur with
biliary obstruction or sepsis.
Fig.1.7). Barriers to
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9
Chapter 1
1. Initiation
cell
Increased portal flow
Lipopolysaccharides
Soluble factors
Hepatic
sinusoid
Serotonin
Platelets
Sinusoidal
endothelial
Figure1.7 • Schematic of some of the factors known to regulate liver regeneration.
Kupffer cell
TNF alpha
Interleukin-6
Hepatocyte
Stellate cell
Epidermal
growth factor
Hepatocyte
growth factor
Extracellular
matrix
2. Hepatocyte
priming
TGF-b
3. Hepatocyte
proliferation
Insulin
adrenaline
–
+
Cell populations involved in liver
regeneration
Histology of normal liver regeneration following
resection or acute injury shows the presence of
high mitotic rates in mature hepatocytes. Normally,
these cells are mitotically quiescent but can move
into S phase extremely rapidly. For example,
following 70% hepatectomy in rat, approximately
30–40% of hepatocytes are seen to be undergoing
mitosis within 48 hours of surgery and the liver
will regain its normal size within 10 days. The
situation is more complex in chronically injured
liver (e.g. cirrhotic liver); here, the hepatocytes are
less able to undergo mitosis and are frequently in
cell cycle arrest. Furthermore, the accumulation of
excess scar tissue deposited in cirrhosis contributes
to the inability of the liver to respond to injury
and regenerate effectively. In this setting a second
population of cells becomes activated and may
contribute to parenchymal regeneration. These
intrahepatic cells are located in the canal of
Hering (the most distal branch of the biliary tree);
termed hepatic progenitor cells (HPCs), they are
bipotential and are capable of giving rise to both
biliary and hepatocyte populations under the
influence of macrophage-derived factors.
response is seen in chronic or severe injury and
sometimes appears as a ductular reaction. It is also
worth noting that there is an increasing recognition
that intrahepatic stem cells are a likely source of a
29
This
significant proportion of liver cancers. The role of
circulating extrahepatic cells in liver regeneration
has received interest recently and the potential bone
marrow origin of hepatocytes has been suggested.
However, if this phenomenon occurs at all, it is
extremely rare. The bone marrow does, however,
supply macrophages and myofibroblasts that are
involved in the liver's scarring response to injury.
The relationship between bone marrow-derived
cells and the response to injury is complex, with
different macrophage subtypes shown to either
promote fibrosis or repair. However, administration
of bone marrow-derived macrophages to the fibrotic
liver via the portal vein has been shown to reduce
fibrosis and improve markers of regeneration in
preclinical models.
30
The use of bone marrow
populations to stimulate liver regeneration in both
animal models and clinical studies is likely to be an
area of future development (see later).
Consequences of surgery
Unfortunately, at present it is unclear what the key
mechanisms of liver failure are, and why the liver
usually regenerates but sometimes progresses into
liver failure. It is believed that ischaemia/reperfusion
(I/R) injury plays an important role in the sequence of
events leading to liver failure. Hepatic resections are
major surgical procedures, often leading to significant
blood loss. In order to reduce blood loss, central
10
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Liver function and failure
<5%% fat 6–15% 16–30% 31–45% 46–60% 61–75% >76%
venous pressure is reduced during liver surgery and
hepatobiliary surgeons frequently occlude hepatic
blood inflow temporarily (Pringle manoeuvre).
Obviously, all these factors may contribute to
an I/R injury in the liver. A key component of I/R
injury is the generation of oxygen free radicals. The
latter can induce ischaemic necrosis and caspasedependent apoptosis, and may contribute to failure
of vital metabolic synthetic pathways. However, it
remains to be investigated which one of these plays
a key role during liver failure. In this context, it has
been proposed that the balance between hepatocyte
regeneration and apoptosis can be tipped towards
either side by hepatic defence mechanisms against
oxygen free radical damage. Also, oxygen free
radicals play a role in determining whether apoptosis
or ischaemic necrosis occurs in the liver. Apparently,
the equilibrium between oxygen free radicals and
their scavengers plays a pivotal role in determining
whether regeneration or decay occurs. Glutathione
(GSH) is the principal oxygen free radical scavenger
in the liver and the principal defence mechanism
against I/R damage. Hepatic GSH levels decrease
following I/R damage, inflammation and nutritional
deprivation. It seems conceivable that a reduction
in liver volume following surgery contributes to
insufficient hepatic free radical scavenging capacity
as a consequence of reduced GSH synthesis. I/R
injury may aggravate this situation.
Small-for-size syndrome
The original descriptions of small-for-size syndrome described a condition arising in split liver
transplantation characterised by the development
of ascites, portal hypertension and liver dysfunction
in an otherwise healthy transplanted portion of
liver. The underlying cause for this syndrome is
believed to relate to blood flow and the failure of
a small liver volume to cope with often very high
blood flows in patients with previous chronic
liver disease undergoing transplantation. The
validity of this hypothesis was supported by the
observation that partial diversion of portal blood
flow into the graft using a portocaval shunt could
limit or prevent the development of small-for-size
syndrome. Subsequently, other manoeuvres have
also been effected, such as ligation or embolisation
of the splenic artery, which works in the same way
by reducing portal vein flow.
In patients undergoing even very major liver
resection it is rare to develop small-for-size syndrome.
Some patients do, however, develop ascites, jaundice
and chronic liver dysfunction, and it is more likely
that this syndrome is more dependent on a failure to
regenerate than on excessive blood flow.
Hepatic steatosis
Fat infiltration of the liver is an increasing problem
with increased prevalence of obesity and the
metabolic syndrome (obesity and type 2 diabetes).
Macroscopically the liver may appear enlarged,
pale or yellow-coloured with rounded edges.
Microscopically the liver can have microsteatosis
(small fat droplets within every hepatocyte) or
macrosteatosis (regional infiltration of hepatocytes
with large fat droplets) (see
Assessment of steatosis
Assessment of hepatic steatosis is notoriously
difficult. Experienced surgeons can estimate liver
fat by judging the size, rounded or sharp edges of
the liver and its appearance. Even using colour as an
estimate is prone to error, as can be seen in
The gold standard for hepatic fat assessment is
histology. Trucut or wedge biopsies can be assessed
by a pathologist and a reliable estimate of the
percentage fat content produced. In addition, useful
information including the distribution – macrosteatosis
or microsteatosis – and the presence of fibrosis or
Figure1.8 • Macroscopic and microscopic images of
steatotic liver.
Fig.1.8).
Fig.1.9.
Figure1.9 • Physical appearance of livers with varying fat content confirmed by histology to demonstrate the poor
correlation between colour and objective measurement of fat content.
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11