garcea 2009 liver failure after resection
TRANSCRIPT
-
7/29/2019 Garcea 2009 Liver Failure After Resection
1/11
R E V I E W A R T I C L E
Liver failure after major hepatic resection
Giuseppe Garcea
G. J. Maddern
Received: 17 August 2008 / Accepted: 19 September 2008 / Published online: 26 December 2008
Springer 2008
Abstract
Introduction The consequence of excessive liver resec-tion is the inexorable development of progressive liver
failure characterised by the typical stigmata associated with
this condition, including worsening coagulopathy, hyper-
bilirubinaemia and encephalopathy. The focus of this
review will be to investigate factors contributing to hepa-
tocyte loss and impaired regeneration.
Methods A literature search was undertaken of Pubmed
and related search engines, examining for articles relating
to hepatic failure following major hepatectomy.
Results In spite of improvements in adjuvant chemo-
therapy and increasing surgical confidence and expertise,
the parameters determining how much liver can be resected
have remained largely unchanged. A number of preopera-
tive, intraoperative and post-operative factors all contribute
to the likelihood of liver failure after surgery.
Conclusions Given the magnitude of the surgery, mortal-
ity and morbidity rates are extremely good. Careful patient
selection and preservation of an obligate volume of remnant
liver is essential. Modifiable causes of hepatic failure
include avoidance of sepsis, drainage of cholestasis with
restoration of enteric bile salts and judicious use of portal
triad inflow occlusion intra-operatively. Avoidance of post-
operative sepsis is most likely to be achieved by patient
selection, meticulous intra-operative technique and post-
operative care. Modulation of portal vein pressures post-
operatively may further help reduce the risk of liver failure.
Keywords Liver failure Liver resection
Introduction
Liver resection is the accepted gold standard of treatment for
liver tumours. Unfortunately, only 1020% of patients with
colorectal liver metastases are candidates for hepatic resec-
tion [1]. The resectability rate for hepatocellular carcinoma is
about 2030% in normal livers, but reduced in patients with
cirrhotic liver [2, 3]. Hence, in any cohort of patients with
primary or secondary tumours, most will be unsuitable for
curative resection due to the presence of extrahepatic disease,
anatomical distribution of their lesions or tumour burden.
The aim of liver resection is to remove all macroscopic
disease (with negative resection margins) and leave sufficient
functioning liver [4] with preservation of vascular inflow and
outflow. The acceptable residual functioning volume should
be approximately 20% of the standard liver volume or the
equivalent of a minimum of two segments [4]. In patients
without normal liver parenchyma, this obligate functional
volume has been estimated to range from 30 to 60% in
patients with chemotherapy steatosis or hepatitis, and from
40 to 70% in cases of cirrhosis [5]. In spite of improvements
in adjuvant chemotherapy and increasing surgical confidence
and expertise, the parameters determining how much liver
can be resected have remained largely unchanged.
Liver failure
The consequence of excessive liver resection is the inexora-
ble development of progressive liver failure characterised by
the typical stigmata associated with this condition, including
worsening coagulopathy, hyperbilirubinaemia and encepha-
lopathy. This rarely occurs in isolation and is often coupled
with failure of multiple organs and/or features of sepsis.
G. Garcea (&) G. J. Maddern
Department of Hepatobiliary and Upper Gastrointestinal
Surgery, The Queen Elizabeth Hospital, 28 Woodville Road,
Adelaide, SA 5011, Australia
e-mail: [email protected]
123
J Hepatobiliary Pancreat Surg (2009) 16:145155
DOI 10.1007/s00534-008-0017-y
-
7/29/2019 Garcea 2009 Liver Failure After Resection
2/11
Whilst fulminant liver failure is probably easily diagnosed,
the true contribution of milder forms of liver dysfunction to
mortality post-operatively may be harder to assess and
accurately quantify. Clinically, a mild derangement in liver
function is very common after extended liver resection and
generally resolves within 6 or 7 days postoperatively. Lack of
resolution of this mild dysfunction may herald the insidious
onset of liver failure. Attempts to classify histological chan-ges following surgery-induced hepatic failure have revealed
interesting results, albeit from a small number of patients
(n = 7) [6]. From these clinical findings, liver failure could
be defined as either cholestatic (characterised by regener-
ation of hepatocytes and fibrosis) or nonregenerative
(characterised by pronounced apoptosis of hepatocytes) [6].
The incidence of liver failure after major hepatic resection
ranges from 0 to 30%; however, the lack of a standardised
definition of liver failure makes comparison of reported
incidence between centres difficult [7]. Liver failure would
appear to be a major contributor to post-operative mortality,
being implicated in 1875% of cases [810].
Liver regeneration and liver failure
Normal mechanism of liver regeneration
The liver is unique amongst all other body organs in its
ability to regenerate fully after extensive liver damage,
either due to resection or secondary to drug-induced/viral-
induced damage. Following partial hepatectomy, 95% of thenormally quiescent liver cells re-enter the cell cycle, with an
increase in DNA synthesis that peaks at 24 h following
injury [11]. Induction of DNA synthesis in other liver cells
occurs later, at 48 h for Kupffer and stellate cells and 96 h
for endothelial cells [11]. Clinical studies suggest that
regeneration is evident within 2 weeks following resection
and is complete at 3 months following resection [12, 13].
Hepatocyte activation requires their priming by
inflammatory cytokines, such as interleukin 6 (IL-6) and
tumour necrosis factor alpha (TNF-a) (Fig. 1). These
cytokines are released by Kupffer cells in response to portal-
system-carried factors such as lipopolysaccharide (LPS).
Fig. 1 Overview of the mechanism of liver regeneration following hepatectomy
146 J Hepatobiliary Pancreat Surg (2009) 16:145155
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
3/11
Once primed, hepatocytes respond to a number of growth
factors including hepatocyte growth factor (HGF) released
by stellate cells. HGF release by stellate cells occurs by
cleavage of pro-HGF by proteases such as urokinase-type
plasminogen activator (uPA). In addition, other trophic
factors from different sources (Fig. 1) also act on the primed
hepatocytes, moving them from G0 to S-phases of the cell
cycle. IL-6, if administered in adequate concentrations, candirectly stimulate hepatocyte proliferation, even in the
absence of other growth factors [14]. The synthesis of
transforming growth factor beta (TGF-b) (which acts in an
inhibitory fashion on hepatocyte proliferation) is blocked in
the early stages of hepatocyte proliferation, but is eventually
restored, bringing an end to hepatocyte regeneration [14].
In addition to promoting cell growth, the cytokine
pathway (specifically the production of IL-6) also inhibits
liver apoptosis (Fig. 1), thus further protecting the post-
operative liver. Inducible nitric oxide is released by hepa-
tocytes in response to cytokine release from Kupffer cells
and may act in suppressing the inhibition of HGF-inducedcyclin D1 and D2 expression [15]. In iNOS gene knockout
murine models, hepatectomy has been found to result in
hepatic failure characterised by marked apoptosis of
hepatocytes [16]. Re-establishment of normal liver archi-
tecture is achieved by stellate cells, in conjunction with
proteins such as connexin-32 and keratin-8, which are
involved in the production of an extra-cellular matrix
approximately 4 days following liver damage [11].
Correlation between liver regeneration and the failing
liver
If enough viable liver remains to support bodily functions
post-operatively, then regeneration (or the lack of it) should
not have an impact on subsequent function of the organ.
However, this would not be the case in the present under-
standing of liver failure following hepatectomy, where a
lack of liver regeneration is frequently linked with the
development of liver failure. This finding could be explained
by postulating that the 20% rule, defining the obligate
mass of liver tissue remaining post-hepatectomy, is depen-
dent on liver regeneration in order to preserve long-term
homeostatic function. Alternatively, the lack of regeneration
found in failing livers may be an index of excessive resection
rather than a contributory cause of failure.
On-going loss of hepatocytes as a consequence of surgery
may mean liver regeneration is essential in order to continue
metabolic activity, in spite of the initial volume of liver
remnant being adequate. As will be discussed subsequently in
this review, physiological and blood-flow-related changes
contribute to post-hepatectomy hepatocyte loss, which may
be exacerbated by other factors such as sepsis. Marked
apoptosis has been described following hepatectomy in
animal models, further contributing to hepatocyte loss [17].
The disturbance of this balance between immediate/on-going
hepatocyte loss and replacement explains the insidious nature
of evolving liver failure following major hepatectomy.
Hence, once the initial liver injury (i.e. resection) has been
sustained, the subsequent recovery of liver function is
dependent on a number of patient-related operative and post-
operative factors (Fig. 2). The focus of this review will be toinvestigate factors contributing to hepatocyte loss and
impaired regeneration in patients undergoing hepatectomy
and how a better understanding of this interplay can be used
to optimise outcome after extended liver resection.
Energy charge following hepatic resection
Failure to regenerate occurs once the remnant volume of liver
falls below a certain threshold. The rate of hepatic metabo-
lism, or the so-called energy charge, has been shown to
decrease following partial hepatectomy [18]. The energycharge also relates to the volume of remaining liver, and once
a certain threshold of volume is reached, regeneration ceases
as the energy demands of other metabolic process (such as
gluconeogenesis) take precedence [19]. Arterial ketone body
ratio offers an index of the mitochondrial adenylate charge of
the liver, and this has been used to predict the prognosis of
patients undergoing hepatic resection [20, 21]. Preservation
of energy metabolism has been shown to increase survival
probability in small-for-size liver grafts and following
hepatectomy in animal models [2224].
Preserving liver remnant may be achieved by selective
portal vein embolisation to the segments of liver planned
for resection, resulting in hypertrophy of the future remnant
liver volume. Portal vein embolisation may be achieved
preoperatively using radiological means or as part of a
staged liver resection. Portal vein embolisation has been
shown to increase liver volume by 816%, although this
increase is dependent on underlying liver function [2528].
Two-stage liver resection involves removing disease from
one lobe, allowing the liver to regenerate, and then
undertaking a second resection to clear any remaining
disease. In this manner, the critical threshold for obligate
remaining liver is never reached. Unfortunately, disease
progression between intervening resections is a significant
risk and has been reported to be as high 46.7% [28].
Haemodynamics following hepatectomy
Normal liver flow
The liver receives a dual blood supply from both the
hepatic artery and the portal vein, with the contribution of
J Hepatobiliary Pancreat Surg (2009) 16:145155 147
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
4/11
blood flow being widely accepted as 20 and 80% respec-
tively. Following portal vein embolisation, a phenomenon
known as the hepatic arterial buffer response results in
an increased arterial flow to the embolised and non-em-
bolised lobe (due to an adenosine-mediated response
system) [29]. Since the return from the distal portal cir-
culation is unchanged and more blood flow is now
channeled down the remaining portal vein branch, flow tothe non-embolised lobe also increases [30] (Fig. 3).
Portal flow following hepatectomy
Following hepatectomy, the reduction in liver size, and as a
consequence, vascular capacity, result in a marked
decrease in portal vein flow, an increase in hepatic artery
resistance and an increase in portal vein pressure [31]. The
subsequent increase in shear stress in liver sinusoids is an
important initiating factor in liver regeneration and like-
wise a reduction in shear stress may contribute to liver
atrophy [32, 33]. Hepatocytes are surrounded by a three-
dimensional network of vessels which are fenestrated (the
liver sieve) and thus are directly exposed to portal pressure
via these sieve plates. The lack of hepatocyte regeneration
in patients with portal hypertension would seem at odds
with this model of shear stress. This could be explained by
the loss of sieve plates in cirrhotic patients blocking
the stimulus of raised portal pressure on hepatocytes [32]
or by excessive fibrosis limiting the regeneration of hepa-
tocytes [32].
Shear stress and liver damage
Whilst shear stress is an important component of liver
regeneration, excessive pressures may result in microcir-
culatory collapse and subsequent hepatocyte necrosis.
These changes are frequently found with hepatectomies
involving resection of up to 90% of liver [34]. The
reduction in portal vein flow accompanying the dramaticrise in portal pressure further contributes to reduced
regeneration. These observations have been reported in
small-for-size liver transplants where severe ischaemic
changes with sinusoidal congestion have been found in
association with increased portal vein pressure [3537].
Attempts at reducing portal vein pressure have included
portal-systemic shunts and splenectomy [38]. Control of
portal pressure has been shown to improve the survival of
small-for-size grafts in a number of studies [3941]. In
animal models of partial hepatectomy, porto-caval shunting
has resulted in a reduced rate of hepatic necrosis and
reduced apoptotic index in the shunted animals [42, 43]. Inspite of these encouraging results, a marked delay in liver
regeneration has also been reported to be associated with
porto-caval shunts [42, 44]. This could be explained by an
over-reduction of portal shear stress or by diversion of
hepatotrophic factors into the systemic circulation as a
consequence systemic shunting. As discussed previously,
important trophic factors are carried in the portal circula-
tion, which are also required for liver regeneration
following hepatectomy. Liver atrophy is a well-recognised
Fig. 2 Interplay of patient-
related intraoperative and post-
operative factors in the
development of liver failure
post-hepatectomy
148 J Hepatobiliary Pancreat Surg (2009) 16:145155
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
5/11
complication of porto-systemic shunting, in cirrhotic livers
at least, and may limit the use of such shunts outside of an
experimental setting. There is, however, animal model
evidence of non-portal growth factors influencing liver
regeneration [45] and of complete liver regeneration being
possible, even with porto-caval shunting [46]. In addition,
the use of mesocaval shunts may be a satisfactory com-
promise by reducing excessive shear stress, whilst
maintaining gastroduodenosplenopancreatic venous return
to the liver and thus preserving hepatotrophic inflow [47].
Alternatively, pharmacological control of portal pressure
may provide short-term post-operative control of portal
pressure in major hepatectomies, which can be ceased
when necessary to allow normal regeneration subsequently.
Intraoperative and post-operative ischaemia
A variety of techniques have been adopted during liver
resection to help reduce the degree of blood loss intraop-
eratively. The Pringle manoeuvre has been widely adopted
and involves clamping the hepatic inflow usually inter-
mittently or up to 1 h continuously. Although blood loss
has been shown to be reduced by this method [48],
bleeding may still occur from the hepatic veins, and for this
reason, some centers have advocated total vascular exclu-
sion of the liver (clamping of the supra and infra hepatic
inferior vena cava coupled with Pringle occlusion) during
resection to create a completely bloodless field. The liver
appears remarkably tolerant to even prolonged periods of
ischaemia, and for the most part, neither the Pringle nor
total vascular exclusion (TVE) appears to cause any per-
manent damage to hepatic tissue, with any histological
changes observed rapidly reversing on re-perfusion [49].
Ischaemic reperfusion has been advocated as a means of
reducing the deleterious effect of ischaemia reperfusion on
the liver. This involves a short period of ischaemia (usually
about 5 min) followed by up to 30 min of reperfusion.
Following this, Pringle clamping can be employed either
continuously or in intermittent cycles. Ischaemic precon-
ditioning (IP) has been shown to decrease the severity of
liver necrosis [50], exhibit an anti-apoptotic effect [51],
Fig. 3 Normal hepatic inflow, demonstrating the hepatic arterial buffer response (figure adapted from Ref. [103])
J Hepatobiliary Pancreat Surg (2009) 16:145155 149
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
6/11
preserve liver microcirculation [52], and improve survival
rates following hepatectomy [53]. More recently IP has
been described as promoting liver regeneration via the up-
regulation of cytokines such as TNF-a and IL-6, and the
down-regulation of TGF-b [54].
For liver resections of the magnitude where liver failure
post-operatively is a significant risk, the impact of IP may
not be as beneficial. There is evidence that in animalsundergoing 90% hepatectomy, IP may serve to impair liver
regeneration [55]. In addition, a number of deleterious
effects have been associated with hepatic inflow occlusion
including bacterial translocation of gut organisms and
elevated endotoxins in the portal system [56]. As will be
discussed in the following section, bacteraemia together
with associated sepsis is a frequent association with post-
operative liver failure and prolonged inflow occlusion may
exacerbate this. Finally, prolonged hypotension can
adversely affect liver function, as evidenced by necrosis,
bile plugging and inflammatory cell infiltrates in conjunc-
tion with hyperbilirubinaemia [57]. Post-operative hypo-tension (whether due to bleeding, sepsis or increased
inotropic requirements) may significantly prolong hepatic
ischaemia, especially when prolonged Pringle clamping has
been applied, and result in post-operative liver failure. Thus,
although TVE and Pringle clamping are relatively safe to
employ, their use may combine with other factors also
contributing to liver hypoperfusion, resulting in significant
liver dysfunction. This may only be partially ameliorated by
IP in the context of extended hepatectomies (Fig. 4).
Sepsis
Sepsis affects post-operative liver function and regenera-
tion in a number of different ways. Sepsis is an important
cause of post-operative hypotension and in this manner
may prolong hepatic ischaemia following surgery (see
above). In addition, sepsis adversely affects Kupffer cellfunction, may increase the concentration of liver-toxic
cytokines, and endotoxins released by bacteria have a
direct inhibitory action on hepatocyte proliferation (Fig. 5).
This complex interplay between sepsis and liver regener-
ation explains the frequent association of sepsis with liver
failure in post-hepatectomy patients.
Sepsis and Kupffer cell function
Kupffer cell activation is an important component in the
early initiation of liver regeneration. Leukocyte-Kupffer
cell interaction is thought to trigger a local inflammatoryresponse leading to release of TNF-a and IL-6 which then
act on hepatocytes leading to proliferation [58]. This
interaction is thought to be mediated by an intracellular
adhesion molecule known as ICAM-1, and ICAM-1-defi-
cient mice exhibit impaired liver regeneration with a
concomitant decrease in TNF-a and IL-6 concentrations,
following 70% hepatectomy [58]. The complement cascade
is pivotal to this regeneration pathway [59]. Administration
of endotoxin to hepatectomised rats results in massive
necrosis and up to 50% mortality [60], possibly by interfering
with Kupffer cell activation, either via the complement
pathway or Kupffer cell-leukocyte interaction.
Following large volume hepatectomy, Kupffer cell
numbers are reduced and hence the rapid clearance of
bacteria from blood (one of the predominant roles of
Kupffer cells) is diminished. Dysfunction of Kupffer cell
activity may persist for up 2 weeks following hepatec-
tomy [61]. As a result, impaired clearance of blood-borne
enteric bacteria and their associated endotoxins make
hepatectomised animal models prone to the rapid devel-
opment of multi-organ failure in the presence of sepsisFig. 4 Shear stress and hepatocyte regeneration
Fig. 5 Effect of sepsis on liver function and regeneration after
hepatectomy
150 J Hepatobiliary Pancreat Surg (2009) 16:145155
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
7/11
[62]. Translocation of enteric organisms following hepa-
tectomy is well documented and the application of Pringle
clamping may be, in part, responsible [56]. As a result,
hepatectomy results in a proclivity for rapid, over-
whelming sepsis leading to multi-organ failure, whilst in
turn, sepsis acts to diminish the regenerative ability of the
liver.
Sepsis and circulating TNF-a
One of the earliest TNF-a mediated event within hepato-
cytes is activation of NF-kappaB (the main gateway to pro-
inflammatory cytokine pathways). In addition to exerting a
proliferative effect on hepatocytes, NF-kappaB may also
induce apoptosis [63]. In the context of liver resection, the
proliferative pathway appears to predominate [63].
Excessive circulating levels of TNF-a after massive hepa-
tectomy may contribute to liver failure and death, and
suppression of TNF-a has been shown to improve survival
[64]. Sepsis is a further stimulus for elevation of TNF-a,and whilst not yet proven, this may serve as a further
mechanism contributing to on-going liver damage and
inhibition of liver regeneration.
Endotoxins and hepatocytes
Endotoxin release from blood-borne bacteria appears to
have a direct action on hepatocytes resulting in decreased
mitochondrial function and impaired bile salt excretion
[6567]. These effects appear to be mediated indepen-
dently of changes in cardiovascular status. Endotoxin
treatment has been found to inhibit liver regeneration by
suppression of proliferative inhibitory pathways via up-
regulation of TGF-b [67], leading to hepatocyte apoptosis
and perisinusoidal fibrosis [68].
Cholestasis
Obstructive jaundice is a ubiquitous presenting sign in
patients with hilar cholangiocarcinomas. Preoperative bil-
iary drainage of the future liver remnant has been
advocated by some centres in order to optimise patients
prior to surgery [69]. However, major hepatectomy in the
absence of preoperative drainage has been described with
acceptable mortality rates [70]. Drainage may comprise
internal stenting using a plastic endoprosthesis (with sub-
sequent inflammatory changes making hilar dissection and
delineation between normal and malignant tissue prob-
lematic) or external biliary drainage, with diversion of bile
flow extra-hepatically. Cholestasis and diversion of biliary
flow present particular problems and risks in patients fac-
ing major hepatectomies (Fig. 6).
Cholestasis and restricted portal venous flow
The portal vein, hepatic artery and bile duct are enclosed ina sheath of tissue known as the Glissonian capsule, with a
limited amount of space within called the space of Mall
(Fig. 3). Dilatation of the biliary tract reduces the volume
within this space leading to reduction in portal venous flow,
accompanied by an increase in hepatic arterial flow
(hepatic buffer response) [71]. The reduction in portal
venous flow is further exacerbated by hepatectomy, which
may contribute to impaired regeneration post-surgery. In
addition, portal-systemic shunting accompanying obstruc-
tive jaundice may further reduce portal venous flow [72].
Impaired liver regeneration and induction of apoptosis
Hepatectomy in the presence of cholestasis has been found
to significantly inhibit liver regeneration and the expression
of c-myc, which normally precedes the first wave of
mitosis [73, 74], and to decrease the expression of tran-
scription factors involved in hepatocyte proliferation such
as cyclin E [74]. Other liver-regeneration cytokines, such
as epidermal growth factor and IL-6, are also depressed
following hepatectomy in animal models with obstructive
jaundice [72, 75, 76]. High levels of bile salts are associ-
ated with increased hepatocyte apoptosis [77], possibly via
a FAS-dependent mechanism [78].
Interruption of enterohepatic circulation
Bile salts within the small bowel lumen have an important
function in maintaining bowel integrity and prevention of
bacterial translocation [79]. In the presence of obstructive
jaundice, the normal enterohepatic circulation is interrupted
and so portal bacteraemia may be present, increasing
the risk of septic complications following hepatectomy.
Fig. 6 Effect of cholestasis on liver function and regeneration
J Hepatobiliary Pancreat Surg (2009) 16:145155 151
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
8/11
Supplementation with bile salts has been show to improve
intestinal barrier function [80]. External biliary drainage
(whilst reducing blood levels of bilirubin) still results in
diversion of bile salts outside of the gut lumen and this may
account for reduced liver regeneration in rats undergoing
hepatectomy with external drains [81]. Liver regeneration
has been found to be preserved with internal drainage [82]
which therefore may be preferable to external drainage.However, in the context of hilar malignancies (where
multiple biliary drainages may be required) endoscopic
internal drainage can be difficult and carries with it a risk of
cholangitis [83]. In addition, internal endoprostheses serve
to increase the technical difficulty of resection. For this
reason, external biliary drainage is often preferred, but the
addition of bile replacement agents may help restore gut
immunity [83].
Cirrhosis, steatosis and the post-chemotherapy liver
Patients with liver cirrhosis have an increased risk of
mortality following resection, with some series reporting
the risk to be as high as 20% [84]. In addition to an overall
operative risk, cirrhosis results in a higher probability of
liver failure and is associated with reduced regeneration
following hepatectomy. Cirrhotic livers demonstrate lower
levels of hepatocyte growth factor (due to a failure of
conversion of the precursor to the active form) [85] and
impaired transcription factors [86] leading to a reduction of
DNA synthesis and lower volumes of regenerated liver
[87]. Cirrhotic livers show an increased risk of ischaemia-
reperfusion injury, and hyperbaric oxygen administration
following hepatectomy has demonstrated some value in
augmenting liver function and regeneration post-hepatec-
tomy [88]. Fibrosis leading to regional ischaemia is also
thought to contribute to impaired growth and regeneration
[89]. Exogenous administration of IL-6 and hepatocyte
growth factor have been shown in animal models to inde-
pendently improve survival and regeneration after surgery
[87, 90]. Attempts to predict which cirrhotic patients are at
greater risk of fulminant liver failure after hepatectomy
have included the Child-Pugh classification system and
functional assessment of liver-related clearance of quanti-
fiable materials such as indocyanine green, hayaluronic
acid or hepatic 99 mTc-diethylenetriamine pentaacetic
acid-galactosyl-human serum albumin [9193].
Steatosis of the liver is an increasingly common finding
either due to life-style related factors or as a common
sequel to chemotherapy for colorectal liver metastases.
Steatosis is associated with a delay in regeneration,
increased susceptibility to ischaemia/reperfusion injury and
increased risk of trauma and bleeding following hepatec-
tomy [9496]. Chemotherapy agents, such as oxaliplatin,
have been found to lead to severe sinusoidal dilatation and
fibrosis in livers of some patients, which may further
increase the risk of hepatic failure in these individuals
undergoing resection surgery [97].
Age and other co-morbidities
A number of patient-related factors contribute to an
increased probability of hepatic failure following hepa-
tectomy. Determining their liver-specific contribution to
mortality and liver dysfunction is problematic. Liver
function appears to be well maintained even at extremes of
age [98], however, some evidence exists that age influences
restoration of liver volume after hepatectomy in rats [99,
100], and in humans, an age of above 50 was found to
negatively influence transplanted liver volumes [101].
Likewise, diabetes has been associated with a greater risk
of mortality from liver failure following liver surgery, and
this could be secondary to the presence of steatotic liver in
these individuals [102]. Given the complex interaction
between factors contributing to liver failure after hepatec-
tomy, it is likely that careful attention to co-morbidities
with subsequent optimisation of patients is an important
component in planning and undertaking major liver
resections.
Conclusion
Major liver resections have now become the accepted goldstandard of treatment for a wide range of primary and
secondary liver malignancies. Given the magnitude of the
surgery, mortality and morbidity rates are extremely good;
however, a small but significant number of individuals will
succumb to liver failure in the immediate post-operative
period. Careful patient selection and preservation of an
obligate volume of remnant liver is essential. Modifiable
causes of hepatic failure include avoidance of sepsis,
drainage of cholestasis with restoration of enteric bile salts
and judicious use of portal triad inflow occlusion intraop-
eratively. Avoidance of post-operative sepsis is most likely
to be achieved by patient selection, meticulous intra-operative technique and post-operative care. Modulation of
portal vein pressures post-operatively may further help
reduce the risk of liver failure.
References
1. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of
colorectal liver metastases. World J Surg. 1995;19(1):5971.
152 J Hepatobiliary Pancreat Surg (2009) 16:145155
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
9/11
2. Farmer DG, Rosove MH, Shaked A, Busuttil RW. Current
treatment modalities for hepatocellular carcinoma. Ann Surg.
1994;219:23647.
3. Tranberg KG. Percutaneous ablation of liver tumours. Best Prac
Res Clin Gastroenterol. 2004;18:12545.
4. Garden OJ, Rees M, Poston GJ, Mirza D, Saunders M, Leder-
mann J, et al. Guidelines for resection of colorectal cancer liver
metastases. Gut. 2008;55:iii18.
5. Pawlik TM, Schulick RD, Choti MA. Expanding criteria for
resectability of colorectal liver metastases. Oncologist. 2008;13:
5164.
6. Takeda K, Togo S, Kunhiro O, Fujii Y, Kuroswa H, Tanaka K,
et al. Clinicohistological features of liver failure after excessive
hepatectomy. Hepatogastroenterology. 2002;49:3548.
7. van den Broek MA, Damink SW, Dejong CH, Lang H, Malago
M, Jalan R, et al. Liver failure after partial hepatic resection:
definition, pathophysiology, risk factors and treatment. Liver Int.
2008;28:76780.
8. Detroz B, Sugarbaker PH, Knol JA, Petrelli N, Hughes KS.
Causes of death in patients undergoing liver surgery. Cancer
Treat Res. 1994;69:24157.
9. Bolder U, Brune A, Schmidt S, Tacke J, Jauch KW, Lohein D.
Preoperative assessment of mortality risk in hepatic resection by
clinical variables: a multivariate analysis. Liver Transpl Surg.
1999;5:22737.
10. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ,
Rees M. Surgical resection of hepatic metastases from colorectal
cancer: a systematic review of published studies. Br J Cancer.
2006;94:98299.
11. Taub R. Liver regeneration: from myth to mechanism. Nature.
2004;5:83647.
12. Yamanaka N, Okamoto E, Kawamura E, Kato T, Oriyama T,
Fujimoto J. Dynamics of normal and injured human liver regen-
eration after hepatectomy as assessed on the basis of computed
tomography and liver function. Hepatology. 1993;18:7985.
13. Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T.
Human liver regeneration after major hepatic resection. Ann
Surg. 1987;206:309.
14. Zimmers TA, McKillop IH, Pierce RH, Yoo J, Koniaris LG.
Massive liver growth in mice induced by systemic interleukin-6
administration. Hepatology. 2003;38:32634.
15. Garcia-Trevijano ER, Martinez-Chantarv ML, Latasa MU, Mato
JM, Avila MA. NO sensitises rat hepatocytes to proliferation by
modifying S-adenosylmethionine levels. Gastroenterology.
2002;122:135563.
16. Rai RM, Lee FY, Rosen A, Yang SQ, Lin HZ, Koteish A.
Impaired liver regeneration in inducible nitric oxide synthases
deficient mice. Proc Natl Acad Sci USA. 1998;95:1382934.
17. Sakamoto T, Liu Z, Murase N, Ezure T, Yokomuro S, Poli V.
Mitosis and apoptosis in the liver of interleukin-6-deficient mice
after partial hepatectomy. Hepatology. 1999;29:40311.
18. Kooby DA, Zakian KL, Challa SN, Matei C, Petrowsky H, Yoo
HH. Use of phosphorus-31 nuclear magnetic resonance spec-
troscopy to determine safe timing of chemotherapy after hepaticresection. Cancer Res. 2000;60:38006.
19. Ozawa K, Yamada T, Ukikusa M. Mitochondrial phosphoryla-
tive activity and DNA synthesis in regenerating liver of diabetic
rats. J Surg Res. 1981;31:3845.
20. Saibara T, Onishi S, Maeda T, Yamamoto Y. Arterial blood
ketone body ratio as a possible indicator for predicting fulminant
hepatitis in patients with acute hepatitis. Liver. 1992;12:3926.
21. Asano M, Ozawa K, Tobe T. Postoperative prognosis as related
to blood ketone body ratios in hepatectomized patients. Eur J
Surg Res. 1983;15:30211.
22. Kerem M, Berdirli A, Orfluoglu E, Deniz K, Turkozkahn N,
Pasaglu H, et al. Ischemic preconditioning improves liver
regeneration by sustaining energy metabolism after partial
hepatectomy in rats. Liver Int. 2006;26:9949.
23. Ma Y, Wu LW, Wu JL, Liang YJ, Zhu ZY, Hu RD, et al. Energy
metabolism and survival of liver grafts from non-heart beating
donor rats with warm ischaemia injury. Hepatobiliary Pancreat
Dis Int. 2006;5:5215.
24. Miyagi S, Iwane T, Akamatsu Y, Nakamura A, Sato A, Satomi
S. The significance of preserving the energy status and micro-
circulation in liver grafts from non-heart beating donors. Cell
Transplant. 2008;17:1738.
25. Farges O, Belghiti J, Kianmanesh R. Portal vein embolisation
before right hepatectomy: prospective clinical trial. Ann Surg.
2003;237:20817.
26. Madoff DC, Hicks ME, Abdalla EK. Portal vein embolisation
with polyvinyl alcohol particles and coils in preparation for
major liver resection for hepatobiliary malignancy. Safety and
effectiveness: study in 26 patients. Radiology. 2003;227:25160.
27. Vauthey JN, Cahaui A, Do KA. Standardized measurement of the
future liver remnant prior to extended liver resection. Method-
ology and clinical associations. Surgery. 2000;127:5129.
28. Popescu I, David L, Brasoveanu V, Boros M, Hrehoret D. Two-
stage hepatectomy: an analysis of a single centers experience.
Magy Seb. 2006;59:1849.
29. Lautt WW. Mechanims and role of intrinsic regulation of
hepatic arterial blood flow: hepatic arterial buffer response. Am
J Physiol. 1985;249:G54956.
30. Nagino M, Kanai M, Morioka A. Portal and arterial embolisa-
tion before extensive liver resection in patients with markedly
poor functional reserve. J Vasc Interv Radiol. 2000;11:10638.
31. Kin Y, Nimura Y, Hayakawa N, Kamiqya J, Kondo S, Nagino M.
Doppler analysis of hepatic blood flow predicts liver dysfunction
after major hepatectomy. World J Surg. 1994;18:1439.
32. Sato A, Tsukada K, Hatakeyama K. Role of shear stress and
immune responses in liver regeneration after a partial hepatec-
tomy. Surg Today. 1999;29:19.
33. Niiya T, Murakami M, Aoki T, Murai N, Shimizu Y, Kusano M.
Immediate increase of portal pressure, reflecting sinusoidal
shear stress, induced liver regeneration after partial hepatec-
tomy. J Hepatobiliary Pancreat Surg. 1999;6:27580.
34. Fukauchi T, Hirosi H, Onitsuka A, Hayahsi M, Senga S, Imai N.
Effects of portal-systemic shunt following 90% partial hepa-
tectomy in rats. J Surg Res. 2000;89:12631.
35. Kishikawa YK, Suehrio T, Niahizaki T, Shamida M, Itasaka H,
Nomoto K. Partial hepatic grafting: porcine study on critical
volume reduction surgery. Surgery. 1995;118:48691.
36. Man K, Lo CM, Ng IO, Wong YC, Qin LF, Fan ST. Liver
transplantation in rats using small-for-size grafts: a study of
haemodynamic and morphological changes. Arch Surg.
2001;136:2805.
37. Kiuchi T, Kasahara M, Uryuhama K, Inomata Y, Uemoto S,
Asnouman K. Impact of graft mismatching on graft prognosis in
liver transplantation from living donors. Transplantation.
1999;67:3217.
38. Ito K, Ozasa H, Horkawa S. Effects of prior splenectomy onremnant liver after partial hepatectomy with Pringle maneuver
in rats. Liver Int. 2005;25:43844.
39. Asakura T, Ohkochi N, Orii T, Koyamada N, Tsukamoto S, Sato
M, et al. Portal vein pressure is the key for successful liver
transplantation of an extremely small graft in the pig model.
Transpl Int. 2003;16:37682.
40. Oya H, Sato S, Yamamot T, Takeishi H, Nakasuka T, KobayshiY,
et al. Surgical procedures for decompression of excessive shear
stress in small-for-size living donor liver transplantation: new
hepatic vein reconstruction. Transpl Proc. 2005;37:110811.
41. Troisi R, Riccardi S, Smeets P, Petrovic M, Van Maele G, Colle
I, et al. Effects of hemi-portocaval shunts for inflow modulation
J Hepatobiliary Pancreat Surg (2009) 16:145155 153
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
10/11
on the outcome of small-for-size grafts in living liver donor
transplantation. Am J Transplant. 2005;5:1397404.
42. Iida T, Yagi S, Taniguchi K, Hori T, Uemoto S. Improvement of
morphological changes after 70% hepatectomy with portocaval
shunt: preclinical study in the porcine model. J Surg Res.
2007;143:23846.
43. Wang H, Ohkohi N, Enomoto Y, Usuda M, Miyagi S, Masuoka H,
et al. Effectof portocaval shunt on residual extreme small liver after
extended hepatectomy in porcine. WorldJ Surg. 2006;30:201422.
44. Hata Y, Yoshiawa Y, Une Y, Saasaki F, Nakajima Y, Takahashi
H, et al. Liver regeneration following portacaval shunt in rats:
30, 50-cyclic AMP changes in plasma and liver tissue. Res Exp
Med (Berl). 1992;192:1316.
45. Griesler HP, Voohees AB, Price JB. The nonportal origin of the
factors initiating hepatic regeneration. Surgery. 1979;86:2107.
46. Guest J, Ryan CJ, Benjamin IS, Blumgart LH. Portacaval
transposition and subsequent partial hepatectomy in the rat:
effects on liver atrophy, hypertrophy and regenerative hyper-
plasia. Br J Exp Pathol. 1977;58:1406.
47. Pouyet M, Mechet I, Paquet C, Scoazec J. Liver regeneration
and haemodynamic in pigs with mesocaval shunt. J Surg Res.
2007;138:12834.
48. Man K, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Prospective
evaluation of Pringle maneuver in hepatectomy for liver
tumours by a randomized study. Ann Surg. 1997;226:70411.
49. Moussa ME, Uemoto SS, Habib NA. Effect of total vascular
exclusion during liver resection on hepatic ultrastructure. Liver
Transplantation. 1996;2:4617.
50. Peralta C, Hotter G, Closa D, Prats N, Xaus C, Gelpi E, et al. The
protective role of adenosine in inducing nitric oxide synthesis in
rat liver ischaemia preconditioning is mediated by activation of
adenosine A2 receptors. Hepatology. 1999;29:12632.
51. Yadav SS, Sindram D, Perry DK, Clavien PA. Ischaemic precon-
ditioningprotects the mouseliver by inhibition of apoptosis through
a caspase-dependent pathway. Hepatology. 1999;30:122331.
52. Szijarto A, Hahn O, Lotz G, Schaff Z, Madarasz E, Kupcsulik
PK. Effect of ischemic preconditioning on rat liver microcir-
culation monitored with laser Doppler flowmetry. J Surg Res.
2006;131:1507.
53. Yin DP, Sankary HN, Chong AS, Ma LL, Shen J, Foster P, et al.
Protective effect of ischemic preconditioning on liver preserva-
tion-reperfusion injury in rats. Transplantation. 1998;66:1527.
54. Gomez D, Homer-Vanniasinkam S, Graham AM, Prasad KR.
Role of ischaemic preconditioning in liver regeneration fol-
lowing major liver resection and transplantation. World J
Gastroenterol. 2007;13:65770.
55. Eipel C, Glanemann M, Nuessler AK, Menger MD, Neuhaus P,
Vollmar B. Ischemic preconditioning impairs liver regeneration
in extended reduced-size livers. Ann Surg. 2005;241:47784.
56. Filos KS, Kirkilesis I, Spilopoulou I, Scopa CD, Nikolopoulou
V, Kouraklis G, et al. Bacterial translocation, endotoxaemia and
apoptosis following Pringle maneuver in rats. Injury. 2004;35:
3543.
57. Champion HR, Jones RT, Trump BF, Decker R, Wilson S,Miginski M. A clinicopathologic study of hepatic dysfunction
following shock. Surg Gynecol Obstet. 1976;142:65762.
58. Selzner N, Selzner M, Odermatt B, Tian Y, Van Rooijen N,
Calvien PA. ICAM-1 triggers liver regeneration through leu-
kocyte recruitment and Kupffer cell-dependent release of TNF-
alpha/IL-6 in mice. Gastroenterology. 2003;124:692700.
59. Strey CW, Markiewski K, Mastellos D. The proinflammatory
mediators C3a and C5a are essential for liver regeneration. J Exp
Med. 2003;198:91323.
60. Mochita S, Ogata I, Hirata K, Ohta YSY, Fugiwara K. Provo-
cation of massive hepatic necrosis by endotoxin after partial
hepatectomy in rats. Gastroenterology. 1990;99:7717.
61. Gross K, Katz S, Dunn SP, Cikrit D, Rosentahl R, Grosfeld JL.
Bacterial clearance in the intact and regenerating liver. J Pediatr
Surg. 1985;20:3203.
62. Boermeester MA, Hodijik APJ, Meyer MS, Cuesta MA, Papp-
elmelk BJ, Wesdor RC. Liver failure induces a systemic
inflammatory response: prevention by recombinant N-terminal
bactericidal/permeability-increasing protein. Am J Physiol.
1995;147:142840.
63. Chaisson ML, Brooling JT, Ladiges W, Tsai S, Fausto N. Hepa-
tocyte-specific inhibition of NF-kappaB leads to apoptosis but not
after partial hepatectomy. J Clin Invest. 2002;110:193202.
64. Ogata I, Yamashitia K, Horiuchi H, Okuda K, Todo S. A novel
tumour necrosis factor-alpha suppressant, ONO-SM362 and
promotes liver regeneration after extensive hepatectomy. Sur-
gery. 2008;143:54555.
65. Nolan JP. Endotoxin, reticuloendothelial function and liver
injury. Hepatology. 1981;1:45865.
66. Roelofsen H, van der Veere CN, Ottenhoff R, Schoemaker B,
Jansen PL, Oude Elferenk RP. Decreased bilirubin transport in
the perfused liver of endotoxemic rats. Gastroenterology.
1994;107:107584.
67. Akita K, Okuno M, Enya M, Imai S, Moriwaki H, Kawada N,
et al. Impaired liver regeneration in mice by lipopolysaccharide
via TNF-alpha/kallikrein-mediated activation of latent TGF-
beta. Gastroenterology. 2002;123:35264.
68. Yoshimoto N, Togo S, Kuboto T, Kammiukai N, Saito S,
Nagano Y, et al. Role of transforming growth factor-beta (TGF-
beta1) in endotoxin-induced hepatic failure after extensive
hepatectomy in rats. J Endotoxin Res. 2005;11:339.
69. Belghiti J, Ogata S. Preoperative optimization of the liver for
resection in patients with hilar cholangiocarcinoma. HPB
(Oxford). 2005;7:2523.
70. Khuntikeo N, Pugkhem A, Bhudisawasdi V, Uttarvichien T.
Major hepatic resection for hilar cholangiocarcinoma without
preoperative biliary drainage. Asian Pac J Cancer Prev. 2008;9:
835.
71. Kanda H, Nimura Y, Yasui A, Uematsu T, Kamiaya S, Machiki
Y. Hepatic blood flow after acute biliary obstruction and
drainage in conscious dogs. Hepatogastroenterology. 1996;43:
23540.
72. Baer HU, Guastella T, Wheatley AM, Zimmermann A, Blum-
gart LH. Acute effects of partial hepatectomy on liver blood
flow in the jaundiced rat. J Hepatol. 1993;19:27782.
73. Tracy TF, Bailey PV, Goerke ME, Sotelo-Avila C, Weber TR.
Cholestasis without cirrhosis alters regulatory liver gene
expression and inhibits hepatic regeneration. Surgery. 1991;110:
17682.
74. Nakano K, Chiiiwa K, Tanaka K. Lower activity of CCAAT/
enhancer-binding protein and expression of cyclin E, but not
cyclin D1, activation protein-1 and p21 (WAF1) after partial
hepatectomy in obstructive jaundice. Bioch Biophys Res Com-
mun. 2001;280:6405.
75. Bissig KD, Marti U, Solioz M, Forestier M, Zimmermann H,
Luthi M, et al. Epidermal growth factor is decreased in liver ofrats with biliary cirrhosis but does not act as a paracrine growth
factor immediately after hepatectomy. J Hepatol. 2000;33:
27581.
76. Fujiwara Y, Shimada H, Yamashita Y, Adachi E, Shirabe K,
Takenaka K, et al. Cytokine characteristics of jaundice in mouse
liver. Cytokine. 2001;13:18891.
77. Wang DS, Dou KF, Li KZ, Gao ZQ, Song ZS, Liu ZC. Hepa-
tocellular apoptosis after hepatectomy in obstructive jaundice in
rats. World J Gastroenterol. 2003;9:273741.
78. Myoshi H, Rust C, Roberts PJ, Burgart LJ, Gores GJ. Hepato-
cyte apoptosis after bile duct ligation in the mouse involves Fas.
Gastroenterology. 1999;117:669777.
154 J Hepatobiliary Pancreat Surg (2009) 16:145155
123
-
7/29/2019 Garcea 2009 Liver Failure After Resection
11/11
79. Sano T, Ajiki T, Takeyama Y, Kuroda Y. Internal biliary
drainage improves decreased number of gut mucosal T lym-
phocytes and MAdCAM-1 expression in jaundiced rats. Surgery.
2004;136:6939.
80. Kamiya S, Nagino M, Kanazawa H, Komatsu S, Mayumi T,
Takagi K. The value of bile replacement during external biliary
drainage: an analysis of intestinal permeability, integrity and
microflora. Ann Surg. 2004;239:5107.
81. Lyomasa S, Teraski M, Kuriki H, Nimura Y, Shionoya S,
Kojima S. Decrease in regeneration capacity of rat liver after
external biliary drainage. Eur J Surg Res. 1992;24:26572.
82. Suzuki H, Lyomasa S, Nimura Y, Yoshida S. Internal biliary
drainage, unlike external drainage, does not suppress the
regeneration of cholestatic rat liver after partial hepatectomy.
Hepatology. 1994;20:131822.
83. Nagino M, Takada T, Miyazaki M, Miyakawa S, Tsukada K,
Kondo S, et al. Preoperative biliary drainage for biliary tract and
ampullary carcinomas. J Hepatobiliary Pancreat Surg. 2008;15:
2530.
84. Takenaka K, Kanematsu T, Fukuzawa K, Sugimachi K. Can
hepatic failure after surgery for hepatocellular carcinoma in
cirrhotic patients be prevented? World J Surg. 1990;14:1237.
85. Kaibori M, Inoue T, Sakakjura Y, Oda M, Nagahama T, Kwon
AH. Impairment of activation of hepatocyte growth factor pre-
cursor into its mature form in rats with liver cirrhosis. J Surg
Res. 2002;106:10814.
86. Zhao G, Nakano K, Chijiwa K, Ueda J, Tanaka M. Inhibited
activities in CCCAAT/enhancer-binding proteins and cyclins
after hepatectomy in rats with thioacetamide-induced liver cir-
rhosis. Biochem Biophys Res Commun. 2002;292:47481.
87. Tiberio GA, Tiberio L, Benetti A, Cervi E, Montani N, Dreano
M, et al. IL-6 promotes compensatory liver regeneration in
cirrhotic rat liver after partial hepatectomy. Cytokine. 2008;42:
372378.
88. Ozdogan M, Ersoy E, Dundar K, Albayrak L, Devay S, Gun-
dogdu H. Beneficial effect of hyperbaric oxygenation on liver
regeneration in cirrhosis. J Surg Res. 2005;129:2604.
89. Corpechot C, Barbu V, Wendum D, Chignard N, Housset C,
Poupon R. Hepatocyte growth factor and c-Met inhibition by
hepatic cell hypoxia: potential mechanism for liver regeneration
in experimental cirrhosis. Am J Pathol. 2002;160:61320.
90. Xue F, Takahara T, Yata Y, Kuwabara Y, Shinno E, Nonome K,
et al. Hepatocyte growth factor gene therapy accelerates
regeneration in cirrhotic mouse livers after hepatectomy. Gut.
2003;52:694700.
91. Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S. The
use of indocyanine green in the measurement of hepatic blood
flow and as a test of hepatic function. Clin Sci. 1961;21:4357.
92. Nanshima A, Yamaguchi H, Shibasaki S, Sawai T, Yamaguchi
E, Yasutake T. Measurement of serum hyaluronic acid level
during the perioperative period of liver resection for evaluation
of hepatic reserve. J Gastroenterol Hepatol. 2001;16:115863.
93. Hwang EH, Taki J, Shuke E, Nakajuma K, Kinuya S, Konishi S.
Preoperative assessment of residual hepatic functional reserve
using 99m-TC-DTPA-galatosyl-human-serum albumin dynamic
SPECT. J Nucl Med. 1999;40:164451.
94. Rao MS, Papreddy K, Abecassis M, Hashimoto T. Regeneration
of liver with marked fatty changes following partial hepatec-
tomy in rats. Dig Dis Sci. 2001;46:3542.
95. Sun CK, Zhang XY, Zimmerman A, Davis G, Wheatley AM.
Effect of ischaemia-reperfusion on the microcirculation of the
steatotic liver of the Zucker Rat. Transplantation. 2001;72:
162531.
96. Selzner M, Clavien PA. Failure of regeneration of the steatotic
liver: disruption at two levels in the regeneration pathway.
Hepatology. 2000;31:3542.
97. Arotcarena R, Cales V, Berthelemy P, Parent Y, Malet M,
Etcharry F, et al. Severe sinusoidal lesions: a serious and
overlooked complication of oxaliplatin-containing chemother-
apy? Gastroenterol Clin Biol. 2006;30:13136.
98. Tietz NW, Shuey DF, Wekstein DR. Laboratory values in fit
ageing individuals: sexagenarians through centenarians. Clin
Chem. 1992;38:116785.
99. Tsukamoto S, Nakata R, Kojo S. Effect of aging on rat liver
regeneration after partial hepatectomy. Biochem Mol Biol Int.
1993;30:7738.
100. Beyer HS, Sherman R, Zieve L. Aging is associated with
reduced liver regeneration and diminished thymidine kinase
mRNA content and enzyme activity in the rat. J Lab Clin Med.
1990;117:1018.
101. Ikegami T, Nishizaki T, Yanaga K, Shjimada M, Kishikawa YK.
The impact of donor age on living donor transplantation.
Transplantation. 2000;70:17037.
102. Little SA, Jarnagin WR, DeMattteo RP, Blumgart LH, Fong Y.
Diabetes is associated with increased preoperative mortality but
equivalent long-term outcome after hepatic resection for colo-
rectal cancer. J Gastrointest Surg. 2002;6:8894.
103. Yokoyama Y, Nagino M, Nimura Y. Mechanism of impaired
hepatic regeneration in cholestatic liver. Hepatobiliary Pancreat
Surg. 2007;14(2):15966.
J Hepatobiliary Pancreat Surg (2009) 16:145155 155
123