Liver International ISSN 1478-3223

REVIEW ARTICLE

Liver failure after partial hepatic resection: denition,

pathophysiology, risk factors and treatment
Maartje A. J. van den Broek1, Steven W. M. Olde Damink1,2, Cornelis H. C. Dejong1, Hauke Lang3,4,
Massimo Malago2,3, Rajiv Jalan5 and Fuat H. Saner3
1 Department of Surgery, University Hospital Maastricht, Maastricht, the Netherlands
2 Department of Surgery, University College London Hospital, University College London, London, UK
3 Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
4 Department of General and Abdominal Surgery, Johannes Gutenberg University Mainz, Mainz, Germany
5 Liver Failure Group, Institute of Hepatology, University College London, London, UK

Keywords
goal-directed treatment hepatectomy
hepatic dysfunction post-resectional liver
failure risk analysis
Abbreviations
CT, computed tomography; HCC,
hepatocellular carcinoma; HE, hepatic
encephalopathy; ICGR15, indocyanine green
retention in 15 min; MEGX, lidocaine-
monoethylglycinexylidide test; MELD, model
for end-stage liver disease; PLF, post-
resectional liver failure; PTD, percutaneous
transhepatic drainage; RLV, remnant liver
volume.
Correspondence
Steven W.M. Olde Damink, MD, MSc, PhD,
Department of Surgery, University Hospital
Maastricht, PO Box 5800, 6202 AZ, Maastricht,
the Netherlands
Tel: 131 43 387 7489
Fax: 131 43 387 5473
e-mail: steven.oldedamink@ah.unimaas.nl
Abstract
Liver failure is a dreaded and often fatal complication that sometimes follows a
partial hepatic resection. This article reviews the definition, incidence, pathoge-
nesis, risk factors, risk assessment, prevention, clinical features and treatment of
post-resectional liver failure (PLF). A systematic, computerized search was
performed using key words related to partial hepatic resection and liver failure
to review most relevant literature about PLF published in the last 20 years.
The reported incidence of PLF ranges between 0.7 and 9.1%. An inadequate
quantity or quality of residual liver mass are key events in its pathogenesis. Major
risk factors are the presence of comorbid conditions, pre-existent liver disease and
small remnant liver volume (RLV). It is essential to identify these risk factors
during the pre-operative assessment that includes evaluation of liver volume,
anatomy and function. Preventive measures should be applied whenever possible
as curative treatment options for PLF are limited. These preventive measures
intend to increase RLV and protect remnant liver function. Management principles
focus on support of end-organ and liver function. Further research is needed to
elucidate the exact pathogenesis of PLF and to develop and validate adequate
treatment options.

Received 11 October 2007

Accepted 17 March 2008

DOI:10.1111/j.1478-3231.2008.01777.x

Partial hepatic resection is a feasible and relatively Methods

safe procedure and is even used in living donor
liver transplantation as an accepted alternative for
cadaveric donor liver transplantation (1). How-
ever, hepatobiliary surgeons are still concerned about
the risk of post-resectional liver failure (PLF).
This review aims to discuss the definition, incidence,
pathogenesis, risk factors and assessment, preven-
tion, clinical features and treatment of PLF in a
stepwise manner. The main focus of this article will
be directed towards risk analysis for and prevention
of PLF.
A systematic, computerized search of English litera-
ture (PubMed, Medline and Cochrane Database of
Systematic Reviews) was performed using key words
related to partial hepatic resection, hepatectomy,
liver failure and liver dysfunction to review the most
relevant literature of the last 20 years.
Definition
There is no uniformity concerning the definition of
PLF. In general, PLF is characterized as failure of one

Liver International (2008)

c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard 767
Liver failure after hepatic resection
or more of the hepatic synthetic and excretory func-
tions that include hyperbilirubinaemia, hypoalbumi-
naemia, prolonged prothrombin time, elevated serum
lactate and/or different grades of hepatic encephalo-
pathy (HE) (26).
PLF is quantitatively reasonably well defined by the
so-called 5050 criteria, which describe PLF as pro-
thrombin index o 50% (equal to an international
standardized ratio 4 1.7) and serum bilirubin
4 50 mmol/L (2.9 mg/dL) on post-operative day 5 (4).
When these 5050 criteria were fulfilled, patients had a
59% risk of mortality compared with 1.2% when they
were not met (sensitivity 69.6% and specificity
98.5%). These 5050 criteria have been validated
recently in a large retrospective study (7), which
showed a sensitivity of 50% and a specificity of 96.6%
for the prediction of PLF-related death in a cohort of
patients without underlying liver disease who had
undergone major hepatic resection. In this study, a
peak bilirubin of 7.0 mg/dL (120 mmol/L) was identi-
fied as a sensitive and specific cut-off value for predic-
tion of PLF-related death (7). However, both
definitions of PLF are open to discussion and need
prospective validation. Their shortcoming could be
overcome by the development of a new definition
comprising functional biomarkers. At the moment,
definitions comprising functional biomarkers like
indocyanine green elimination rate (8) or asymmetric
dimethylarginine (9) do not exist.
Incidence
The incidence of PLF ranges anywhere between 0 and
32% (see Table 1) (25, 1026), with the highest
incidences being reported in subgroups of patients
(27, 28). Owing to the lack of a uniform definition
of PLF, a considerable number of clinical conditions
may unintentionally be described as PLF, making it
difficult compare and extrapolate results from clinical
trials. Leaving the extremes out of consideration [e.g.
(3, 5, 17, 26)], the incidence of PLF varies between 0.7
and 9.1%.
In the past decade, mortality after partial hepatic
resection ranged from 0 to 5% and although the cause
of death after partial hepatic resection is multifacto-
rial, PLF seems to be the main cause (1875%)
(2931).
Pathogenesis
After the resection of various amounts of functional
liver mass, both death and regeneration of the remai-
ning hepatocytes occur. Physiologically, regeneration
768
van den Broek et al.
outweighs hepatocyte death and both liver mass and
function are restored rapidly (32, 33). For example,
during the first 10 days after right hepatectomy for
living donor liver transplantation, restoration of liver
mass up to 74% of the initial volume has been
reported (32). This regeneration is triggered by an
increased metabolic demand placed upon remnant
hepatocytes [see (34) for a review].
The ability of the liver remnant to surmount the
effect of surgical resection depends on its capacity to
limit hepatocyte death, to resist metabolic stress, to
preserve or recover an adequate synthetic function and
to enhance its regenerative power (3436). These
factors rely on both the quality and the quantity of
remaining liver parenchyma (37). A variety of intra-
operative as well as post-operative hits can be identi-
fied that may attribute to the development of PLF.
These include hepatic parenchymal congestion,
ischaemiareperfusion injury and reduced phagocyto-
sis capacity (3840).
Hepatic parenchymal congestion
Partial hepatic resection leads to a relatively augmen-
ted sinusoidal perfusion (39), leading to shearstress
and congestion of hepatic parenchyma and resulting in
vascular and parenchymal damage similar to the
small-for-size syndrome after liver transplantation,
although less severe (41). Moreover, inadequate ve-
nous drainage of the liver remnant induces hepatic
venous congestion and functional hepatic volume loss
(42). Hepatic parencymal congestion may be less
severe in patients with cirrhosis of the liver with pre-
existing portacaval collaterals.
Hepatic ischaemiareperfusion injury
Hepatic ischaemiareperfusion injury follows massive
bleeding or hepatic in- or outflow occlusion during
liver surgery. Although the resistance of the liver to
warm ischaemia is relatively high, hepatic ischaemia
and reperfusion activate a complex cascade [see (38)
for a review] that triggers the innate immune response
by recruitment and activation of Kupffer cells, en-
dothelial cells and the complement system. These
express pro-inflammatory proteins [nuclear factor-
kB, tumour necrosis factor-a, interleukin-6], reactive
oxygen species, chemokines, complement factors and
vascular cell adhesion molecules. Subsequently, poly-
morphonuclear neutrophils are activated, which
aggravate hepatic injury. Although these processes
are primarily intended to maintain homoeostasis,
unrestrained activation may become destructive.
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
 c


Table 1. List of articles concerning the incidence of post-operative morbidity, post-resectional liver failure and mortality for all patient groups after partial hepatic resection
(overview of descriptive case series with large patient numbers published between 1996 and 2007)
van den Broek et al.

Liver International (2008)

Post-operative Thirty-day Operative In-hospital
morbidity PLF mortality mortality mortality
Author (reference) Year Startstop No. Hx n % n % n % n % n %
Virani (10) 2007 20012004 783 177 23 NA NA 20 2.6 NA NA NA NA

2008 The Authors. Journal compilation

Benzoni (12) 2006 19892005 287 137 48 26 9.1 NA NA NA NA 13 4.5
Schroeder (3) 2006 1991NA 587 188 32 145 32.1a 50 8.5 NA NA NA NA
Balzan (4) 2005 19982002 775 NA NA 27 3.5b NA NA 26 3.4 NA NA
Sun (24) 2005 20012004 146 37 25 1 0.7c NA NA 1 1.4 NA NA
Poon (13) 2004 19891996 402 150w 37 20 5.0 17 4.2 NA NA 30w 7.5
19962003 820 246 30 27 3.3 22 2.7 NA NA 30 3.7
Dimick (14) 2004 19882000 16 582 NA NA NA NA NA NA NA NA 1227 7.4

c 2008 Blackwell Munksgaard

Coelho (15) 2004 19942003 83 37 45 6 7.2 7 8.4 NA NA 8 9.6
Imamura (5) 2003 19942002 1056 400 38 1 0.1d 0 0 0 0 0 0
Jarnagin (2) 2002 19912001 1803 817 45 99 5.5e NA NA 55 3.1 NA NA
McCall (11) 2001 19982001 123 68 55 9 7.3f 3 2.4 NA NA NA NA
Alfieri (16) 2001 19841999 254 65 26 6 2.4g 8 3.1 10 3.9 NA NA
Das (19) 2001 19941998 100 14 14 4 4.0h 1 1.0 NA NA 3 3.0
Buell (25) 2000 19901999 160 43 27 2 1.3 NA NA 3 1.8 NA NA
Akashi (17) 2000 19851988 96 37w 39 11 11.5 NA NA 5 5.2 10 10
19951998 109 17 16 4 3.7 NA NA 1 0.9 4 3.7
Belghiti (18) 1999 19901997 747 164 22 6z 1.2 33 4.4 NA NA NA NA
Midorikawa (26) 1999 19941998 277 179 65 0 0 NA NA NA NA 0 0
Brancatisano (20) 1998 19891995 200 74 37 14 7.0 5 2.5 NA NA 10 5.0
Finch (21) 1998 19881996 133 58 45 7 5.3k NA NA 6 4.5 NA NA
Taniguchi (22) 1997 19881995 210 114 54 4 1.9l 5 2.4 NA NA 9 4.3
Rees (23) 1996 19861995 150 35 23 1 0.7 1 0.7 NA NA NA NA

PLF defined as a 4 100% increase in serum bilirubin; b5050 criteria on post-operative day 5; cserum bilirubin Z170 mmol/L; dbilirubin 4 5 mg/dL and/or prothrombin index o 50% during three
consecutive days; eprolonged hyperbilirubinaemia, clinically apparent ascites, prolonged coagulopathy and/or HE; fHE, coagulopathy and cholestasis; gbilirubin 4 5 mg/dL; hHE, ascites, prothrombin
index o 40% and serum bilirubin 4 10 mg/dL; khepatorenal failure; and lhepatic coma.
Data only available from a subset of 452 patients.
wSignificant decrease in group II vs group I (P o 0.05).
zData only reported in the healthy group.
HE, hepatic encephalopathy; Hx, partial hepatic resection; NA not available; PLF, post-resectional liver failure.

769
Liver failure after hepatic resection
Liver failure after hepatic resection
Reduced phagocytosis capacity
Infection complicates the course of PLF either as a
precipitant or during later stages (6). Partial hepatec-
tomy reduced the phagocytosis capacity of the hepatic
reticuloendothelial system with an S-shaped correla-
tion to the extent of the hepatic resection (40). Never-
theless, the liver remnant has to clear bacteria and
their products following bacterial translocation or
intra-abdominal infection (43). Diminished hepatic
clearance of bacteria might enhance the susceptibility
for the development of infections and PLF.
Risk factors
Independent predictors for the development of PLF
(see Table 2) are small remnant liver volume (RLV),
excessive intra-operative blood loss and need for blood
transfusion, pre-operative hypoalbuminaemia, pro-
longed operating time, male gender and advanced age
(2, 5, 6, 13, 44). At present, it is unclear whether extra-
hepatic procedures, like concomitant biliary or vascu-
lar reconstructions, influence the incidence of PLF
individually or by increasing operating time and/or
blood loss.
Comorbid conditions like diabetes mellitus as well
as pre-existent liver diseases like steatosis, cirrhosis,
cholestasis or chemotherapy-associated hepatotoxicity
predispose for the development of PLF (28, 4548).
Small remnant liver volume
The number of hepatic segments resected significantly
correlated with the post-operative complication rate
[odds ratio (OR) 1.2; 95% confidence interval (CI)
1.121.29] (2). RLV, defined as percentage remaining
Table 2. Risk factors for post-resectional liver failure
Surgery related
Small remnant liver volume
Excessive intra-operative blood loss
Prolonged operating time
Patient related
Pre-existent liver disease
Cirrhosis
Steatosis
Cholestasis
Chemotherapy-associated hepatotoxicity
Male gender
Advanced age (Z65 years)
Comorbid conditions
Malnutrition
Miscellaneous
Hepatic parenchymal congestion
Ischaemiareperfusion injury
Infection
770
van den Broek et al.
functional liver volume compared with pre-operative
functional liver volume, is regarded as a reliable
parameter to predict PLF and death, even more than
the anatomic extent of the resection (6, 27, 49).
However, the exact amount of residual liver mass
required to preserve sufficient liver function is un-
known. In general, an RLVZ2530% in otherwise
healthy livers is consistent with a good post-resectional
outcome (6, 44). RLV below 25% in normal livers
predicted PLF with a positive predictive value of 90%
(95% CI 6899%) and a specificity of 98% (95% CI
92100%) (44). When liver function is restricted, RLV
should be as high as 40% to guarantee adequate
remnant liver function (5, 50).
Excessive intra-operative blood loss and need for
blood transfusion
Intra-operative blood loss and need for blood transfu-
sion predispose patients to PLF (OR 4.17; 95% CI
1.0417.5) (2, 5, 51). The cut-off point for an adverse
outcome is suggested to be above 10001250 mL blood
loss. Excessive blood loss leads to massive fluid shifts,
which might induce bacterial translocation and sys-
temic inflammation (52). Massive bleeding also results
in severe coagulopathy, which predisposes for intra-
abdominal haematoma and infection (53). Further-
more, post-operative blood transfusions exert an
immunosuppressive effect (54).
Male sex
Male sex doubles the propensity for developing PLF
and post-resectional morbidity (OR 1.98; 95% CI not
available) (7, 44), consistent with earlier observations
that males are more susceptible to develop complica-
tions after surgery. Circulating sex hormones play a
pivotal role whereby testosterone is thought to exert an
immunodepressive effect while oestrogens exert an
immunoprotective effect (55).
Advanced age
Although data in the literature are conflicting, ad-
vanced age (Z65 years) seems to predispose for PLF
and post-resectional mortality (OR 1.8; 95% CI
0.784.19) (4), especially after extended hepatic resec-
tions (16, 56). Elderly patients suffer frequently from
comorbid conditions and have reduced regenerative
capacity of hepatocytes (57, 58).
Nutritional status
Approximately 6590% of patients with advanced
liver disease and 2055% of patients with colorectal
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
van den Broek et al.
cancer suffer from proteincalorie malnutrition (59,
60). Malnutrition seems to predispose subjects to a
higher post-resectional complication rate because of
malnutrition-related immune deficiency, reduced he-
patic protein synthesis and reduced regenerative capa-
city (6163). However, a clear-cut relation between
malnutrition and PLF has not yet been established.
Steatosis
Subjects suffering from different grades of steatosis
experience more post-operative complications than
controls (52 vs 35%, P o 0.01) (64). Patients with
biopsy-proven moderate hepatic steatosis had a higher
incidence of PLF (14%) than patients with healthy livers
(4%) (28). The presence of steatosis is hypothesized to
be associated with impaired hepatic microcirculation
(65), decreased resistance to ischaemiareperfusion
injury, increased intrahepatic oxidative stress and dys-
function in mitochondrial adenosine triphosphate
synthesis (66). Animal studies report an impaired
regeneration of steatotic livers, but this finding is not
supported by sparse clinical data from living donors
suffering from mild hepatic steatosis (67, 68).
Cholestasis
Patients with jaundice, because of either bile duct
obstruction or parenchymal liver disease, have signifi-
cantly increased morbidity rates after partial hepatic
resection (19, 69). Cherqui et al. (69) demonstrated a
morbidity rate of 50% in patients with obstructive
jaundice vs 15% in patients with normal serum
bilirubin (P o 0.01), but the incidence of PLF and
mortality did not differ from matched controls. Ex-
perimental animal models show that liver regeneration
is impaired in bile duct-ligated rats as the upregulation
of hepatic growth factors is reduced (70).
Cirrhosis
The incidence of PLF after partial hepatic resection in
patients with cirrhosis ranges between 5 and 10%
taking into account a higher number of restrictive
surgical procedures in this subgroup (27, 45, 47). The
high risk of developing PLF in patients with cirrhosis
can be explained by the wide range of comorbid
conditions like portal hypertension (71), diabetes
mellitus, jaundice (72), malnutrition, hypersplenism
and coagulopathy as well as frequent impaired pre-
operative liver function and hepatic functional reserve
(73). Furthermore, patients with cirrhosis have an
impaired hepatic regenerative capacity (37).
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
Liver failure after hepatic resection
Neoadjuvant chemotherapy treatment
Several clinical studies report that partial hepatic resec-
tion after systemic neoadjuvant chemotherapy treat-
ment is accompanied by increased post-resectional
morbidity and PLF-related death caused by chemothe-
rapy-associated hepatotoxicity (74, 75). Hepatic paren-
chymal injury occurring in 78% of patients receiving
oxaliplatin is addressed as the sinusoidal obstruction
syndrome (76, 77). Systemic treatment with irinothecan
is associated with an increased risk of steatohepatitis
[chemotherapy-associated steatohepatitis (78)], which
negatively affects 90-day mortality rate (74).
Risk assessment
Pre-operative risk assessment should ideally consist of
four features including clinical, biochemical, volu-
metric and functional data [see (79, 80) for a review].
An assessment focusing on only one of these aspects is
not considered to be useful. A thorough evaluation of
risk factors is generally believed to enable the selection
of candidates suitable for a safe partial hepatic resec-
tion with a low risk of PLF; however, its onset will
remain unpredictable in a subset of patients.
Assessment of clinical condition
The identification of comorbid conditions like obesity,
diabetes mellitus, cardiovascular, pulmonary, hepatic
or renal disease is pivotal as they increase the suscep-
tibility for major complications even if hepatic func-
tional reserve is adequate (3, 48). Additionally, the
existence of portal hypertension must be objectified,
as this elevates the risk of extensive bleeding and
PLF (71).
Nutritional status should be assessed using anthro-
pometry, subjective global assessment, measurement
of hand-grip strength or estimation of body cell mass
(81). Weight and (pre)albumin levels are unreliable
parameters for nutritional status as they are influenced
by ascites and diminished liver function or inflamma-
tion rather than malnutrition per se (82).
Assessment of biochemical parameters
Tests analyzing hepatic synthetic (serum albumin and
clotting factors) or excretory function (serum biliru-
bin) are non-specific for the assessment of hepatic
function and do not correlate to post-resectional out-
come; however, they may indicate hepatic dysfunction
(73, 79, 83). Furthermore, serum activity of transami-
nases as well as alkaline phosphatase and g-glutamyl-
transferase is non-specific for the evaluation of hepatic
771
Liver failure after hepatic resection
function but can signal hepatocyte necrosis, increased
hepatitic activity or the presence of cholestasis.
Assessment of liver anatomy and volumetry
Standard liver resection planning is based on two-
dimensional (2D) computed tomography (CT) or
magnetic resonance imaging, supplemented with in-
tra-operative ultrasonography. These imaging techni-
ques provide good-quality data about total, functional
(i.e. total liver volume minus tumour volume) and
remnant liver volume. Furthermore, information
about the condition of hepatic parenchyma and the
anatomy of liver segments, biliary structures, hepatic
vasculature and tumour localization can be extracted.
However, 2D CT supplies marginal information about
the distribution pattern of hepatic venous in- and
outflow related to hepatic segments and precise tu-
mour localization (84). In this context, 3D reconstruc-
tions have proven to deliver useful additional
information in selected cases like extended hepatic
resections (85, 86).
Appropriate formulas combining body surface area
and weight are available for different populations for
the calculation of total liver volume (87) and these
formulas are hypothesized to reflect the metabolic
demands more exactly than CT volumetry alone.
Assessment of liver function
Assessment of liver function is critical to determine
hepatic functional reserve and to predict the risk of
PLF. Several dynamic tests can quantitatively evaluate
liver function, among which indocyanine green reten-
tion in 15 min (ICGR15), the galactose elimination
test, the lidocainemonoethylglycinexylidide test
(MEGX) and the 14C aminopyrine breath test are most
frequently used and assess hepatic clearance or con-
version of xenobiotics (79).
Indocyanine green retention in 15 min depends on
hepatic perfusion rate, and subjects with an ICGR15
above 1520% are generally believed to have an
impaired hepatic functional reserve. In this particular
group, adequate remnant liver function needs to be
preserved (19, 45, 88). The hepatic cytosolic capacity
is reflected by the galactose elimination test and
the critical value is considered to be elimination
of o 6 mg/min/kg in patients without and o 4 mg/
min/kg in patients with hepatocellular carcinoma
(HCC) (89).
The MEGX test and the 14C aminopyrine breath test
are based on the rate of metabolite formation of drugs.
MEGX test reflects the conversion rate of lidocaine
by hepatic cytochrome P450, and a value  25 mg/L
772
van den Broek et al.
is related to PLF in patients with cirrhosis (90). Finally,
the aminopyrine breath test evaluates the hepatic
oxidative function by measurement of 14CO2 exhala-
tion. The normal value is an exhalation of 7% 14CO2
and the critical value seems to be below 2.3% (91, 92).
There is no consensus regarding the validity of a sole
test for assessment of liver function and hepatic
functional reserve in operative planning.
Scoring systems reflecting liver function in patients
with cirrhosis
Scoring systems used to assess the feasibility of a
partial hepatic resection in patients with cirrhosis are
the ChildPugh score and the model for end-stage
liver disease (MELD) score (3, 93, 94). As they are both
designed for other purposes, their validity to predict
post-resectional liver function has only recently been
established and results are inconsistent. In general,
ChildPugh class C is considered to be an absolute
contra-indication for surgery and class B permits only
minor liver resections (95).
Schroeder et al. (3) reported the superiority of the
ChildPugh score to the MELD score in predicting
short-term morbidity and mortality after partial he-
patic resection. However, other authors state that the
pre-operative MELD score is a highly reliable predic-
tor in certain subgroups. A MELD score above 11 in
patients with cirrhosis could predict PLF accurately
[area under receiver operating characteristic curve
0.92 (95% CI 0.870.96)] (96).
Prevention
For patients with limited hepatic functional reserve or
small RLV, preventive measures are obligatory.
Small remnant liver volume
Small RLV can be prevented by pre-operative portal
vein embolization, two-stage hepatectomy, local
tumour destruction and/or tumour downsizing by
neoadjuvant chemotherapy.
Portal vein embolization is advised in patients with
normal liver function if RLV is estimated to be below
2530% or in patients with impaired liver function
(reflected by an IGCR15 between 15 and 20%) and
estimated RLV below 4045% (9799). Its effective-
ness depends on the severity of pre-existent liver
disease and comorbid conditions, ranging from a 28
to 46% volume increase after 24 weeks (98, 99).
Portal vein embolization increased the feasibility of
hepatectomy by 19% (98), but had a complication rate
between 9 and 13% [see (97) for a review]. Portal vein
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
van den Broek et al.
embolization is hypothesized to facilitate intrahepatic
tumour growth, but this does not seem to affect long-
term outcome after partial hepatic resection for colo-
rectal liver metastases (100).
Two-stage hepatectomy utilizes the regenerative
capacity of the liver, aiming to perform a safe, curative
hepatic resection for initially irresectable tumours.
Studies focusing on the feasibility of two-stage hepa-
tectomy, combined with other techniques like che-
motherapy and/or portal vein embolization, reported
a success rate of 7081%, together with an increase in
median survival time when compared with palliative
chemotherapy alone in case of colorectal metastases
(101, 102) [see (103) for a review]. Tanaka et al. (104)
reported that two-stage hepatectomy combined with
portal vein embolization induced a significantly great-
er hypertrophy ratio when compared with portal vein
embolization alone.
Excessive intra-operative blood loss
Lowering central venous pressure during dissection to
 5 mmHg limits intra-operative blood loss without
deterioration of renal function (105, 106). A combina-
tion of the former with continuous as well as inter-
mittent portal triad clamping or application of total
vascular exclusion is most advantageous for the pre-
vention of excessive intra-operative blood loss (107).
The latter procedures are equally effective but total
vascular exclusion induces more important haemody-
namic changes and higher complication rates (108).
Ischaemic preconditioning
An improvement of post-operative liver function is
reported after ischaemic preconditioning by tempora-
rily clamping the portal triad before a prolonged
episode of hepatic ischaemia when compared with no
preconditioning. This procedure reduced hepatocyte
damage in a murine (109, 110) as well as a human
model (66, 111, 112). Recently, Petrowsky et al. (113)
reported that ischaemic preconditioning combined
with continuous portal triad clamping is as effective
as intermittent clamping in non-cirrhotic livers,
although intermittent clamping was accompanied
by significantly increased intra-operative blood loss,
transfusion requirement and operating time.
Advanced age
The protective effect of ischaemic preconditioning
seems to diminish in patients aged above 6570 years
(112, 113). Consequently, intermittent clamping is
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
Liver failure after hepatic resection
suggested to be superior to continuous clamping in
elderly (113).
Nutritional status
It has been hypothesized that the nutritional status of
depleted patients should be corrected via oral, enteral
or parenteral methods before surgery. A meta-analysis
on the effect of total parenteral nutrition compared
with enteral nutrition on morbidity and mortality
after liver resection revealed no superiority of either
form of nutrition (114). However, a beneficial effect of
additional parenteral nutrition has been demonstrated
in a subgroup of patients who had cirrhosis and
underwent major hepatectomy (63).
Steatosis
Data from living liver donors suffering from biopsy-
proven moderate steatosis revealed that a body weight
reduction of 5% or intervention with a low-fat, high-
protein diet and exercise significantly improved hepa-
tic steatosis (115, 116). The effect of voluntary weight
loss before hepatectomy for malignancy has never
been studied. However, weight reduction before sur-
gery may not be feasible because of time deficit and the
often pre-existent malnutrition.
Cholestasis
Various studies failed to show an advantage of pre-
operative percutaneous transhepatic drainage (PTD)
in patients suffering from obstructive jaundice; more-
over, PTD-associated complication rate was high and
total hospital stay significantly increased (117, 118). A
recent meta-analysis confirmed these results and con-
cluded that pre-operative PTD should not be routinely
used in patients with jaundice (119). Selective PTD
significantly reduced morbidity rate only when intra-
hepatic segmental cholangitis accompanied biliary
carcinoma (120).
Cirrhosis
Patients with cirrhosis of the liver are more susceptible
to the development of PLF in case of resection of
comparable tumour volumes. However, cirrhosis of
the liver cannot be prevented and, therefore, preven-
tion of PLF in these patients can only be achieved by
careful patient selection, adequate nutritional support
and the use of an appropriate surgical technique [see
(45) for a detailed discussion]. In general, patients
with cirrhosis and ChildPugh C are considered not
eligible for surgery and patients with class B should
undergo only minor liver resections (95).
773
Liver failure after hepatic resection
Manifestation
Post-resectional liver failure reflects a deregulation of
the synthetic, excretory and detoxifying capacity of the
liver remnant. In addition, the majority of patients
suffering from PLF will also meet the criteria of the
systemic inflammatory response syndrome and ex-
perience multiple organ failure (121). Unfortunately,
a substantial number of patients suffering from PLF
deteriorate, leading to a fatal outcome in approxi-
mately 80% (44). However, PLF is a potentially
reversible disorder because of the regenerative capacity
of the liver remnant.
At present, there is no validated organ failure score
for the prediction of PLF and PLF-related death.
Recently, the sequential organ failure assessment score
has been shown to be superior to acute physiology
and chronic health evaluation, MELD and Child
Pugh for the prediction of mortality in patients with
acute-on-chronic liver failure (122). Future research
should explore the value of these organ failure
scores in patients who have undergone partial hepatic
resection.
Liver
The clinical consequences of PLF are jaundice, coagu-
lopathy, ascites, oedema and/or HE (123). Data from
Suc et al. (33) and Balzan et al. (4) concerning liver
function on different days after uncomplicated hepatic
resection showed an initial increase of serum bilirubin
and a decrease of prothrombin time before norma-
lization of these values on the seventh post-operative
day. However, when the prothrombin index dropped
below 50% and serum bilirubin exceeded 50 mmol/L
on post-operative day 5, the risk of early mortality
increased significantly (4).
Circulation
Circulatory failure occurring during PLF resembles the
circulatory failure of patients with sepsis (121). The
pathophysiological changes usually observed are en-
hanced vascular permeability, diffuse intravascular
coagulation and peripheral vasodilatation that are
clinically represented by reduced peripheral resistance
and haemodynamic instability (124).
Kidneys
Post-resectional renal dysfunction can either result
from perioperative disturbances in renal circulation
inducing acute tubular necrosis (105) or accompany
PLF. It is characterized by azotaemia or oliguria and
may cause ascites formation, pleural effusion and fluid
774
van den Broek et al.
overload requiring diuretics or haemofiltration (125).
There is a distinct chance of reversibility of renal failure
when there is recovery of PLF. Furthermore, it can be
hypothesized that the pivotal role of the kidney in
ammonia excretion is impaired, leading to hyperammo-
naemia and HE in patients suffering from PLF (126).
Lung
Although moderate pulmonary oedema seems to be a
normal finding after partial hepatic resection owing to
general haemodynamic alterations, this usually does
not impair oxygen exchange (127). Severe remote lung
injury, pulmonary oedema and acute respiratory dis-
tress syndrome can develop as part of the multiple
organ dysfunction syndrome that accompanies PLF.
Hepatic encephalopathy
Hepatic encephalopathy is a potentially reversible
neuropsychiatric disorder, characterized by varying
degrees of confusion and disorientation (128). Hyper-
ammonaemia plays a central role in its development
(129) and has a direct toxic effect on neurotransmis-
sion and astrocyte function. It has become clear that
inflammation makes the brain more vulnerable to
ammonia (130) and may play an additional role in
the development of HE during PLF. However, data
concerning HE after partial hepatic resection are
sparse.
Treatment
Large, randomized trials concerning the treatment of
PLF are lacking, and therefore, recommendations for
treatment modalities are difficult to make. Manage-
ment principles resemble those applied to patients
with acute liver failure, acute-on-chronic liver failure
or sepsis and focus on support of liver and end-organ
function (124, 131).
Goal-directed therapy should be provided for circu-
latory disturbances, renal and ventilatory dysfunction,
coagulopathy, malnutrition and HE (see Table 3). As
there seems to be a strong link between infection and
PLF, frequent cultures for bacteria and fungi are
essential. The use of prophylactic antibiotics after
hepatectomy for the prevention of infectious compli-
cations is not supported by evidence from the litera-
ture (132). However, the administration of antibiotics
in patients suffering from acute liver failure is asso-
ciated with a significant decrease in infectious compli-
cations and this may also be advantageous in patients
suffering from PLF (133).
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
van den Broek et al.
Table 3. Goal-directed therapy in patients suffering from post-
resectional liver failure
Circulatory CVP 812 mmHg
disturbances MAP 6590 mmHg
Haematocrit Z30%
Pulmonary capillary wedge pressure
 1215 mmHg
Renal dysfunction Urine output Z0.5 mL/kg/h
Ventilatory Arterial oxygen saturation Z93%
dysfunction Central venous oxygen saturation Z70%
Hepatic Improvement to grade  2
encephalopathy
Coagulopathy In case of bleeding
Platelet count Z50  109/L
International standardized ratio  1.5
Malnutrition Enteral energy supply of 2000 kcal/day
CVP, central venous pressure; MAP, mean arterial pressure.
Support of liver function
Plasma exchange
Plasma exchange is an extracorporeal supportive pro-
cedure in which plasma is separated from blood cells
and treated or substituted with fresh-frozen plasma.
This technique supplies defective plasma components
(e.g. albumin and clotting factors) and removes water-
soluble toxins related to hepatic coma (e.g. ammo-
nium), thereby improving the clinical condition of
patients suffering from PLF but not survival (134, 135).
Molecular absorbent recirculating system
The molecular absorbent recirculating system (MARSs,
Gambro, Lund, Sweden) removes water-soluble along
with albumin-bound toxins from the plasma by means
of dialysing blood against an albumin-containing
dialysate across an albumin-impregnated membrane
(136, 137). Promising results have been shown when
applied during acute liver failure or acute-on-chronic
liver failure (138), but the use of MARSs for treat-
ment of PLF has only been validated in small, uncon-
trolled and non-randomized trials. Unfortunately,
MARSs treatment for PLF and progressive septic
multi-organ failure did not positively affect patient
survival (139141).
Prometheuss
Prometheuss (Fresenius Medical Care, St. Wendel,
Germany) uses the principle of fractionated plasma
separation and adsorption for removal of water-soluble
along with albumin-bound toxins. Albumin-bound
toxins pass an albumin-permeable membrane and
native albumin is subsequently detoxified by adsorp-
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
Liver failure after hepatic resection
tion, after which the cleansed albumin is returned to
the patient (136, 137). The detoxifying capacity of
Prometheuss appears to be superior to that of
MARSs when applied during acute-on-chronic liver
failure, but no clinical survival benefit has been proven
yet (142). Studies on the application of Prometheuss
for PLF are lacking.
Bioartificial liver and the extracorporeal liver
assist device
Bioartificial liver-supporting systems using cryopre-
served xenogenic or human hepatocytes have been
validated in one large, prospective controlled trial for
acute liver failure and primary non-function after liver
transplantation. Results are promising as the applica-
tion is safe, but survival only significantly improved
for acute liver failure patients (143). Again, data on the
application of these bioartificial liver-supporting sys-
tems for the treatment of PLF are lacking. Moreover,
bioartificial liver-supporting systems are not routinely
available in a substantial number of hospitals.
Rescue hepatectomy and liver transplantation
The use of a rescue hepatectomy and subsequent liver
transplantation in patients suffering from PLF may be
of value in desperate situations where conventional
measures fail. It is based on the concept that the
necrotic liver is the source of unknown humoral
substances that contribute to the systemic inflamma-
tory response syndrome (144). The efficacy of ortho-
topic liver transplantation for PLF has only recently
been reported (145). Although orthotopic liver trans-
plantation for patients suffering from PLF was asso-
ciated with considerable morbidity, the mean survival
time was prolonged from 1.4 to 42.2 months. All
patients (n = 4) who suffered from PLF but were not
appropriate candidates for liver transplantation died,
while those undergoing orthotopic liver transplanta-
tion all survived (n = 7). However, no criteria are
available for the selection of patients who will benefit
from emergency liver transplantation for PLF and
these need to be defined by the appropriate commit-
tees. We propose to consider patients eligible for
emergency transplantation who have favourable tu-
mour characteristics (i.e. R0 resection, low T and
negative N status, HCC within Milan criteria and
absence of extra-hepatic disease), without comorbid
conditions and without a limited life expectancy
because of other medical conditions. Kings College
Criteria may be applied when those patient criteria
are met.
775
Liver failure after hepatic resection
Conclusion
The incidence of PLF after partial hepatic resection
ranges between 0.7 and 9.1%. An inadequate quantity
or quality of residual liver mass are key events in the
pathogenesis of PLF. Additional hits include hepatic
parenchymal congestion, intra-operative ischaemia
reperfusion injury and post-operative infection.
Risk factors for the development of PLF are small
RLV, excessive intra-operative blood loss, need for
blood transfusion, malnutrition, advanced age, male
gender and pre-existent liver disease. A prerequisite for
the avoidance of PLF is a thorough pre-operative
assessment that includes evaluation of liver volume,
anatomy and function. Preventive measures should
be applied whenever possible as curative treatment
options are limited. When an RLV below 2530% in
livers without and below 40% in livers with pre-
existing liver disease is expected, portal vein emboliza-
tion and/or two-stage hepatectomy are recommended.
Additional liver damage can be prevented by ischaemic
preconditioning. Management principles focus on
support of liver and end-organ function and resemble
those applied during acute liver failure and sepsis.
Till the establishment of a uniform definition of
PLF, the extrapolation of study results will remain
difficult. Further research is needed to elucidate the
exact pathogenesis of PLF and to develop a highly
reliable model to predict the development of PLF.
Treatment modalities for PLF have barely been studied
in randomized-controlled trials, leaving the treatment
of a patient suffering from PLF to the expert opinion.
Acknowledgements
Grants and financial support: Steven W. M. Olde Damink
was supported by the Hendrik Casimir Karl Ziegler Fellow-
ship of the Nordrheinwestfalische Akademie fur Wis-
senschaften and the Royal Dutch Academy of Science
(KNAW) and a Clinical Fellowship from the Netherlands
Organization for Health Research and Development (Grant
907-06-177). Cees H. C. Dejong was supported by a Clinical
Fellowship from the Netherlands Organization for Health
Research and Development (Grant 907-00-033).
References
1. Broelsch CE, Malago M, Testa G, Valentin Gamazo C.
Living donor liver transplantation in adults: outcome in
Europe. Liver Transpl 2000; 6: S6465.
2. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in
perioperative outcome after hepatic resection: analysis of
1,803 consecutive cases over the past decade. Ann Surg 2002;
236: 397406; discussion 397406.
776
van den Broek et al.
3. Schroeder RA, Marroquin CE, Bute BP, Khuri S, Henderson
WG, Kuo PC. Predictive indices of morbidity and mortality
after liver resection. Ann Surg 2006; 243: 373379.
4. Balzan S, Belghiti J, Farges O, et al. The 5050 criteria
on postoperative day 5: an accurate predictor of liver
failure and death after hepatectomy. Ann Surg 2005; 242:
8248.
5. Imamura H, Seyama Y, Kokudo N, et al. One thousand
fifty-six hepatectomies without mortality in 8 years. Arch
Surg 2003; 138: 11981206; discussion 1206.
6. Schindl MJ, Redhead DN, Fearon KC, Garden OJ, Wigmore
SJ. The value of residual liver volume as a predictor of
hepatic dysfunction and infection after major liver resec-
tion. Gut 2005; 54: 28996.
7. Mullen JT, Ribero D, Reddy SK, et al. Hepatic insufficiency
and mortality in 1,059 noncirrhotic patients undergoing
major hepatectomy. J Am Coll Surg 2007; 204: 85462.
8. Sugimoto H, Okochi O, Hirota M, et al. Early detection of
liver failure after hepatectomy by indocyanine green elimi-
nation rate measured by pulse dye-densitometry. J Hepato-
biliary Pancreat Surg 2006; 13: 5438.
9. Nijveldt RJ, Teerlink T, Siroen MP, et al. Elevation of
asymmetric dimethylarginine (ADMA) in patients develo-
ping hepatic failure after major hepatectomy. J Parenter
Enteral Nutr 2004; 28: 3827.
10. Virani S, Michaelson JS, Hutter MM, et al. Morbidity and
mortality after liver resection: results of the patient safety in
surgery study. J Am Coll Surg 2007; 204: 128492.
11. McCall J, Koea J, Gunn K, Rodgers M, Jarvis J. Liver
resections in Auckland 19982001: mortality, morbidity
and blood product use. NZ Med J 2001; 114: 5169.
12. Benzoni E, Lorenzin D, Baccarani U, et al. Resective surgery
for liver tumor: a multivariate analysis of causes and risk
factors linked to postoperative complications. Hepatobiliary
Pancreat Dis Int 2006; 5: 52633.
13. Poon RT, Fan ST, Lo CM, et al. Improving perioperative
outcome expands the role of hepatectomy in management
of benign and malignant hepatobiliary diseases: analysis of
1222 consecutive patients from a prospective database. Ann
Surg 2004; 240: 698708; discussion 610708.
14. Dimick JB, Wainess RM, Cowan JA, Upchurch GR Jr, Knol
JA, Colletti LM. National trends in the use and outcomes of
hepatic resection. J Am Coll Surg 2004; 199: 318.
15. Coelho JC, Claus CM, Machuca TN, Sobottka WH, Gon-
calves CG. Liver resection: 10-year experience from a single
institution. Arq Gastroenterol 2004; 41: 22933.
16. Alfieri S, Carriero C, Caprino P, et al. Avoiding early
postoperative complications in liver surgery. A multivariate
analysis of 254 patients consecutively observed. Dig Liver
Dis 2001; 33: 3416.
17. Akashi K, Mizuno S, Isaji S. Comparative study of peri-
operative management of hepatic resection. Dig Dis Sci
2000; 45: 198895.
18. Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred
forty-seven hepatectomies in the 1990s: an update to
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
van den Broek et al.
evaluate the actual risk of liver resection. J Am Coll Surg
2000; 191: 3846.
19. Das BC, Isaji S, Kawarada Y. Analysis of 100 consecutive
hepatectomies: risk factors in patients with liver cirrhosis or
obstructive jaundice. World J Surg 2001; 25: 26672; discus-
sion 26372.
20. Brancatisano R, Isla A, Habib N. Is radical hepatic surgery
safe? Am J Surg 1998; 175: 1613.
21. Finch MD, Crosbie JL, Currie E, Garden OJ. An 8 year
experience of hepatic resection: indications and outcome.
Br J Surg 1998; 85: 3159.
22. Taniguchi H, Takahashi T. Analysis of 210 elective hepatic
resections. Hepatogastroenterology 1997; 44: 162431.
23. Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty
hepatic resections: evolution of technique towards bloodless
surgery. Br J Surg 1996; 83: 15269.
24. Sun HC, Qin LX, Wang L, et al. Risk factors for post-
operative complications after liver resection. Hepatobiliary
Pancreat Dis Int 2005; 4: 3704.
25. Buell JF, Rosen S, Yoshida A, et al. Hepatic resection:
effective treatment for primary and secondary tumors.
Surgery 2000; 128: 68693.
26. Midorikawa Y, Kubota K, Takayama T, et al. A comparative
study of postoperative complications after hepatectomy in
patients with and without chronic liver disease. Surgery
1999; 126: 48491.
27. Shirabe K, Shimada M, Gion T, et al. Postoperative liver
failure after major hepatic resection for hepatocellular
carcinoma in the modern era with special reference to
remnant liver volume. J Am Coll Surg 1999; 188: 3049.
28. Behrns KE, Tsiotos GG, DeSouza NF, Krishna MK, Ludwig J,
Nagorney DM. Hepatic steatosis as a potential risk factor
for major hepatic resection. J Gastrointest Surg 1998; 2:
2928.
29. Detroz B, Sugarbaker PH, Knol JA, Petrelli N, Hughes KS.
Causes of death in patients undergoing liver surgery. Cancer
Treat Res 1994; 69: 24157.
30. Bolder U, Brune A, Schmidt S, Tacke J, Jauch KW, Lohlein
D. Preoperative assessment of mortality risk in hepatic
resection by clinical variables: a multivariate analysis. Liver
Transpl Surg 1999; 5: 22737.
31. 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.
32. Nadalin S, Testa G, Malago M, et al. Volumetric and
functional recovery of the liver after right hepatectomy for
living donation. Liver Transpl 2004; 10: 10249.
33. Suc B, Panis Y, Belghiti J, Fekete F. Natural history of
hepatectomy. Br J Surg 1992; 79: 3942.
34. Michalopoulos GK, DeFrances MC. Liver regeneration.
Science 1997; 276: 606.
35. Morita T, Togo S, Kubota T, et al. Mechanism of post-
operative liver failure after excessive hepatectomy investi-
gated using a cDNA microarray. J Hepatobiliary Pancreat
Surg 2002; 9: 3529.
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
Liver failure after hepatic resection
36. Jin X, Zhang Z, Beer-Stolz D, Zimmers TA, Koniaris LG.
Interleukin-6 inhibits oxidative injury and necrosis after
extreme liver resection. Hepatology 2007; 46: 80212.
37. Yamanaka N, Okamoto E, Kawamura E, et al. Dynamics of
normal and injured human liver regeneration after hepa-
tectomy as assessed on the basis of computed tomography
and liver function. Hepatology 1993; 18: 7985.
38. Jaeschke H. Molecular mechanisms of hepatic ischemia
reperfusion injury and preconditioning. Am J Physiol
Gastrointest Liver Physiol 2003; 284: G1526.
39. Kin Y, Nimura Y, Hayakawa N, et al. Doppler analysis of
hepatic blood flow predicts liver dysfunction after major
hepatectomy. World J Surg 1994; 18: 1439.
40. Schindl MJ, Millar AM, Redhead DN, et al. The adaptive
response of the reticuloendothelial system to major liver
resection in humans. Ann Surg 2006; 243: 50714.
41. Palmes D, Budny TB, Dietl KH, Herbst H, Stratmann U,
Spiegel HU. Detrimental effect of sinusoidal overperfusion
after liver resection and partial liver transplantation. Transpl
Int 2005; 17: 86271.
42. Hemming AW, Reed AI, Langham MR, Fujita S, van der
Werf WJ, Howard RJ. Hepatic vein reconstruction for
resection of hepatic tumors. Ann Surg 2002; 235: 8508.
43. van Leeuwen PA, Hong RW, Rounds JD, Rodrick ML,
Wilmore D. Hepatic failure and coma after liver resection
is reversed by manipulation of gut contents: the role of
endotoxin. Surgery 1991; 110: 16974; discussion 16574.
44. Shoup M, Gonen M, DAngelica M, et al. Volumetric
analysis predicts hepatic dysfunction in patients undergoing
major liver resection. J Gastrointest Surg 2003; 7: 32530.
45. Poon RT, Fan ST. Hepatectomy for hepatocellular carcino-
ma: patient selection and postoperative outcome. Liver
Transpl 2004; 10: S3945.
46. Karoui M, Penna C, Amin-Hashem M, et al. Influence of
preoperative chemotherapy on the risk of major hepatect-
omy for colorectal liver metastases. Ann Surg 2006; 243: 17.
47. Farges O, Malassagne B, Flejou JF, Balzan S, Sauvanet A,
Belghiti J. Risk of major liver resection in patients with
underlying chronic liver disease: a reappraisal. Ann Surg
1999; 229: 2105.
48. Little SA, Jarnagin WR, DeMatteo RP, Blumgart LH, Fong Y.
Diabetes is associated with increased perioperative morta-
lity but equivalent long-term outcome after hepatic resec-
tion for colorectal cancer. J Gastrointest Surg 2002; 6: 8894.
49. Yigitler C, Farges O, Kianmanesh R, Regimbeau JM, Abdalla
EK, Belghiti J. The small remnant liver after major liver
resection: how common and how relevant? Liver Transpl
2003; 9: S1825.
50. Fan ST. Methods and related drawbacks in the estimation of
surgical risks in cirrhotic patients undergoing hepatectomy.
Hepatogastroenterology 2002; 49: 1720.
51. Kooby DA, Stockman J, Ben-Porat L, et al. Influence of
transfusions on perioperative and long-term outcome in
patients following hepatic resection for colorectal metas-
tases. Ann Surg 2003; 237: 8609; discussion 86970.
777
Liver failure after hepatic resection
52. Luyer MD, Buurman WA, Hadfoune M, et al. Pretreatment
with high-fat enteral nutrition reduces endotoxin and
tumor necrosis factor-alpha and preserves gut barrier func-
tion early after hemorrhagic shock. Shock 2004; 21: 6571.
53. Silva MA, Muralidharan V, Mirza DF. The management of
coagulopathy and blood loss in liver surgery. Semin Hematol
2004; 41: 1329.
54. Jensen LS, Andersen AJ, Christiansen PM, et al. Postopera-
tive infection and natural killer cell function following
blood transfusion in patients undergoing elective colorectal
surgery. Br J Surg 1992; 79: 5136.
55. Yokoyama Y, Schwacha MG, Samy TS, Bland KI, Chaudry
IH. Gender dimorphism in immune responses following
trauma and hemorrhage. Immunol Res 2002; 26: 6376.
56. Koperna T, Kisser M, Schulz F. Hepatic resection in the
elderly. World J Surg 1998; 22: 40612.
57. Suttner SW, Surder C, Lang K, Piper SN, Kumle B, Boldt J.
Does age affect liver function and the hepatic acute phase
response after major abdominal surgery? Intensive Care Med
2001; 27: 17629.
58. Iakova P, Awad SS, Timchenko NA. Aging reduces proli-
ferative capacities of liver by switching pathways of C/
EBPalpha growth arrest. Cell 2003; 113: 495506.
59. Lautz HU, Selberg O, Korber J, Burger M, Muller MJ.
Proteincalorie malnutrition in liver cirrhosis. Clin Investig
1992; 70: 47886.
60. Read JA, Choy ST, Beale PJ, Clarke SJ. Evaluation of
nutritional and inflammatory status of advanced colorectal
cancer patients and its correlation with survival. Nutr
Cancer 2006; 55: 7885.
61. Bozzetti F. Rationale and indications for preoperative fee-
ding of malnourished surgical cancer patients. Nutrition
2002; 18: 9539.
62. Windsor JA, Hill GL. Weight loss with physiologic impair-
ment. A basic indicator of surgical risk. Ann Surg 1988; 207:
2906.
63. Fan ST, Lo CM, Lai EC, Chu KM, Liu CL, Wong J.
Perioperative nutritional support in patients undergoing
hepatectomy for hepatocellular carcinoma. N Engl J Med
1994; 331: 154752.
64. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis
on perioperative outcome following hepatic resection. J
Gastrointest Surg 2003; 7: 103444.
65. Seifalian AM, Piasecki C, Agarwal A, Davidson BR. The
effect of graded steatosis on flow in the hepatic parenchymal
microcirculation. Transplantation 1999; 68: 7804.
66. Serafin A, Rosello-Catafau J, Prats N, Xaus C, Gelpi E,
Peralta C. Ischemic preconditioning increases the tolerance
of Fatty liver to hepatic ischemiareperfusion injury in the
rat. Am J Pathol 2002; 161: 587601.
67. Selzner M, Clavien PA. Failure of regeneration of the
steatotic rat liver: disruption at two different levels in the
regeneration pathway. Hepatology 2000; 31: 3542.
68. Marcos A, Fisher RA, Ham JM, et al. Liver regeneration and
function in donor and recipient after right lobe adult to
778
van den Broek et al.
adult living donor liver transplantation. Transplantation
2000; 69: 13759.
69. Cherqui D, Benoist S, Malassagne B, Humeres R, Rodriguez
V, Fagniez PL. Major liver resection for carcinoma in
jaundiced patients without preoperative biliary drainage.
Arch Surg 2000; 135: 3028.
70. Makino H, Shimizu H, Ito H, et al. Changes in growth
factor and cytokine expression in biliary obstructed rat liver
and their relationship with delayed liver regeneration
after partial hepatectomy. World J Gastroenterol 2006; 12:
20539.
71. Bruix J, Castells A, Bosch J, et al. Surgical resection of
hepatocellular carcinoma in cirrhotic patients: prognostic
value of preoperative portal pressure. Gastroenterology 1996;
111: 101822.
72. Lau W, Leung K, Leung TW, et al. A logical approach to
hepatocellular carcinoma presenting with jaundice. Ann
Surg 1997; 225: 2815.
73. Hemming AW, Scudamore CH, Shackleton CR, Pudek M,
Erb SR. Indocyanine green clearance as a predictor of
successful hepatic resection in cirrhotic patients. Am J Surg
1992; 163: 5158.
74. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy
regimen predicts steatohepatitis and an increase in 90-day
mortality after surgery for hepatic colorectal metastases.
J Clin Oncol 2006; 24: 206572.
75. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal
injury increases morbidity after major hepatectomy in
patients with colorectal liver metastases receiving preopera-
tive chemotherapy. Ann Surg 2008; 247: 11824.
76. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to
hepatic sinusoids: sinusoidal obstruction syndrome (veno-
occlusive disease). Semin Liver Dis 2002; 22: 2742.
77. Rubbia-Brandt L, Mentha G, Terris B. Sinusoidal obstruc-
tion syndrome is a major feature of hepatic lesions asso-
ciated with oxaliplatin neoadjuvant chemotherapy for liver
colorectal metastases. J Am Coll Surg 2006; 202: 199200.
78. Fong Y, Bentrem DJ. CASH (chemotherapy-associated
steatohepatitis) costs. Ann Surg 2006; 243: 89.
79. Gazzaniga GM, Cappato S, Belli FE, Bagarolo C, Filauro M.
Assessment of hepatic reserve for the indication of hepatic
resection: how I do it. J Hepatobiliary Pancreat Surg 2005;
12: 2730.
80. Mullin EJ, Metcalfe MS, Maddern GJ. How much liver
resection is too much? Am J Surg 2005; 190: 8797.
81. Henkel AS, Buchman AL. Nutritional support in patients
with chronic liver disease. Nat Clin Pract Gastroenterol
Hepatol 2006; 3: 2029.
82. Katsuramaki T, Mizuguchi T, Kawamoto M, et al. Assess-
ment of nutritional status and prediction of postoperative
liver function from serum apolioprotein a-1 levels with
hepatectomy. World J Surg 2006; 30: 188691.
83. Zimmermann H, Reichen J. Hepatectomy: preoperative
analysis of hepatic function and postoperative liver failure.
Dig Surg 1998; 15: 111.
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
van den Broek et al.
84. Lamade W, Glombitza G, Fischer L, et al. The impact of 3-
dimensional reconstructions on operation planning in liver
surgery. Arch Surg 2000; 135: 125661.
85. Lang H, Radtke A, Liu C, Fruhauf NR, Peitgen HO, Broelsch
CE. Extended left hepatectomy-modified operation plan-
ning based on three-dimensional visualization of liver
anatomy. Langenbecks Arch Surg 2004; 389: 30610.
86. Wigmore SJ, Redhead DN, Yan XJ, et al. Virtual hepatic
resection using three-dimensional reconstruction of helical
computed tomography angioportograms. Ann Surg 2001;
233: 2216.
87. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface
area and body weight predict total liver volume in Western
adults. Liver Transpl 2002; 8: 23340.
88. Lau H, Man K, Fan ST, Yu WC, Lo CM, Wong J. Evaluation
of preoperative hepatic function in patients with hepatocel-
lular carcinoma undergoing hepatectomy. Br J Surg 1997;
84: 12559.
89. Redaelli CA, Dufour JF, Wagner M, et al. Preoperative
galactose elimination capacity predicts complications and
survival after hepatic resection. Ann Surg 2002; 235: 7785.
90. Ercolani G, Grazi GL, Calliva R, et al. The lidocaine
(MEGX) test as an index of hepatic function: its clinical
usefulness in liver surgery. Surgery 2000; 127: 46471.
91. Hepner GW, Vesell ES. Quantitative assessment of hepatic
function by breath analysis after oral administration of
(14C) aminopyrine. Ann Intern Med 1975; 83: 6328.
92. Gill RA, Goodman MW, Golfus GR, Onstad GR, Bubrick
MP. Aminopyrine breath test predicts surgical risk for
patients with liver disease. Ann Surg 1983; 198: 7014.
93. Child CG, Turcotte JG. Surgery and portal hypertension.
Major Probl Clin Surg 1964; 1: 185.
94. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter
Borg PC. A model to predict poor survival in patients
undergoing transjugular intrahepatic portosystemic shunts.
Hepatology 2000; 31: 86471.
95. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular
carcinoma: the BCLC staging classification. Semin Liver Dis
1999; 19: 32938.
96. Cucchetti A, Ercolani G, Vivarelli M, et al. Impact of model
for end-stage liver disease (MELD) score on prognosis after
hepatectomy for hepatocellular carcinoma on cirrhosis.
Liver Transpl 2006; 12: 96671.
97. Madoff DC, Abdalla EK, Vauthey JN. Portal vein emboliza-
tion in preparation for major hepatic resection: evolution of a
new standard of care. J Vasc Interv Radiol 2005; 16: 77990.
98. Azoulay D, Castaing D, Smail A, et al. Resection of
nonresectable liver metastases from colorectal cancer after
percutaneous portal vein embolization. Ann Surg 2000; 231:
4806.
99. Imamura H, Shimada R, Kubota M, et al. Preoperative
portal vein embolization: an audit of 84 patients. Hepato-
logy 1999; 29: 1099105.
100. Kokudo N, Tada K, Seki M, et al. Proliferative activity of
intrahepatic colorectal metastases after preoperative hemi-
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard
Liver failure after hepatic resection
hepatic portal vein embolization. Hepatology 2001; 34:
26772.
101. Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H.
Two-stage hepatectomy: a planned strategy to treat irresecta-
ble liver tumors. Ann Surg 2000; 232: 77785.
102. Jaeck D, Oussoultzoglou E, Rosso E, Greget M, Weber JC,
Bachellier P. A two-stage hepatectomy procedure combined
with portal vein embolization to achieve curative resection
for initially unresectable multiple and bilobar colorectal
liver metastases. Ann Surg 2004; 240: 103749; discussion
104951.
103. Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies
for safer liver surgery and partial liver transplantation. N
Engl J Med 2007; 356: 154559.
104. Tanaka K, Shimada H, Matsuo K, Ueda M, Endo I, Togo S.
Remnant liver regeneration after two-stage hepatectomy for
multiple bilobar colorectal metastases. Eur J Surg Oncol
2007; 33: 32935.
105. Melendez JA, Arslan V, Fischer ME, et al. Perioperative
outcomes of major hepatic resections under low central
venous pressure anesthesia: blood loss, blood transfusion,
and the risk of postoperative renal dysfunction. J Am Coll
Surg 1998; 187: 6205.
106. Jones RM, Moulton CE, Hardy KJ. Central venous pressure
and its effect on blood loss during liver resection. Br J Surg
1998; 85: 105860.
107. Dixon E, Vollmer CM Jr, Bathe OF, Sutherland F. Vascular
occlusion to decrease blood loss during hepatic resection.
Am J Surg 2005; 190: 7586.
108. Belghiti J, Noun R, Zante E, Ballet T, Sauvanet A. Portal
triad clamping or hepatic vascular exclusion for major liver
resection. A controlled study. Ann Surg 1996; 224: 15561.
109. Kanoria S, Jalan R, Davies NA, Seifalian AM, Williams R,
Davidson BR. Remote ischaemic preconditioning of the
hind limb reduces experimental liver warm ischaemia
reperfusion injury. Br J Surg 2006; 93: 7628.
110. Koti RS, Yang W, Dashwood MR, Davidson BR, Seifalian
AM. Effect of ischemic preconditioning on hepatic micro-
circulation and function in a rat model of ischemia reperfu-
sion injury. Liver Transpl 2002; 8: 118291.
111. Fernandez L, Carrasco-Chaumel E, Serafin A, et al. Is
ischemic preconditioning a useful strategy in steatotic liver
transplantation? Am J Transplant 2004; 4: 88899.
112. Clavien PA, Selzner M, Rudiger HA, et al. A prospective
randomized study in 100 consecutive patients undergoing
major liver resection with versus without ischemic precon-
ditioning. Ann Surg 2003; 238: 843; discussion 84251.
113. Petrowsky H, McCormack L, Trujillo M, Selzner M, Jochum W,
Clavien PA. A prospective, randomized, controlled trial com-
paring intermittent portal triad clamping versus ischemic
preconditioning with continuous clamping for major liver
resection. Ann Surg 2006; 244: 9218; discussion 92830.
114. Richter B, Schmandra TC, Golling M, Bechstein WO.
Nutritional support after open liver resection: a systematic
review. Dig Surg 2006; 23: 13945.
779
Liver failure after hepatic resection
115. Hwang S, Lee SG, Jang SJ, et al. The effect of donor weight
reduction on hepatic steatosis for living donor liver trans-
plantation. Liver Transpl 2004; 10: 7215.
116. Nakamuta M, Morizono S, Soejima Y, et al. Short-term
intensive treatment for donors with hepatic steatosis in
living-donor liver transplantation. Transplantation 2005;
80: 60812.
117. Pitt HA, Gomes AS, Lois JF, Mann LL, Deutsch LS, Long-
mire WP Jr. Does preoperative percutaneous biliary drai-
nage reduce operative risk or increase hospital cost? Ann
Surg 1985; 201: 54553.
118. Hatfield AR, Tobias R, Terblanche J, et al. Preoperative
external biliary drainage in obstructive jaundice. A prospec-
tive controlled clinical trial. Lancet 1982; 2: 8969.
119. Sewnath ME, Karsten TM, Prins MH, Rauws EJ, Obertop H,
Gouma DJ. A meta-analysis on the efficacy of preoperative
biliary drainage for tumors causing obstructive jaundice.
Ann Surg 2002; 236: 1727.
120. Kanai M, Nimura Y, Kamiya J, et al. Preoperative intrahe-
patic segmental cholangitis in patients with advanced
carcinoma involving the hepatic hilus. Surgery 1996; 119:
498504.
121. Kimura F, Shimizu H, Yoshidome H, et al. Circulating
cytokines, chemokines, and stress hormones are increased
in patients with organ dysfunction following liver resection.
J Surg Res 2006; 133: 10212.
122. Sen S, Mohseni S, Cheshire LM, Williams R, Bjornsson E,
Jalan R. Baseline SOFA score and its lack of early improve-
ment accurately predicts mortality in patients with acute-
on-chronic liver failure. Hepatology 2004; 40: 498A.
123. Sass DA, Shakil AO. Fulminant hepatic failure. Liver Transpl
2005; 11: 594605.
124. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed
therapy in the treatment of severe sepsis and septic shock.
N Engl J Med 2001; 345: 136877.
125. Matsumata T, Taketomi A, Fujiwara Y, Shimada M, Takena-
ka K, Sugimachi K. Renal function after elective hepatic
resection. Hepatogastroenterology 1996; 43: 6027.
126. Olde Damink SW, Jalan R, Deutz NE, et al. The kidney plays
a major role in the hyperammonemia seen after simulated
or actual GI bleeding in patients with cirrhosis. Hepatology
2003; 37: 127785.
127. Thasler WE, Bein T, Jauch KW. Perioperative effects of
hepatic resection surgery on hemodynamics, pulmonary
fluid balance, and indocyanine green clearance. Langenbecks
Arch Surg 2002; 387: 2715.
128. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K,
Blei AT. Hepatic encephalopathy definition, nomencla-
ture, diagnosis, and quantification: final report of the
working party at the 11th World Congresses of Gastroentero-
logy, Vienna, 1998. Hepatology 2002; 35: 71621.
129. Shawcross D, Jalan R. The pathophysiologic basis of hepatic
encephalopathy: central role for ammonia and inflamma-
tion. Cell Mol Life Sci 2005; 62: 2295304.
780
van den Broek et al.
130. Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A.
Pathogenesis of intracranial hypertension in acute liver
failure: inflammation, ammonia and cerebral blood flow.
J Hepatol 2004; 41: 61320.
131. Jalan R. Acute liver failure: current management and future
prospects. J Hepatol 2005; 42(Suppl.): S11523.
132. Wu CC, Yeh DC, Lin MC, Liu TJ, PEng FK. Prospective
randomized trial of systemic antibiotics in patients under-
going liver resection. Br J Surg 1998; 85: 48993.
133. Rolando N, Gimson A, Wade J, Philpott-Howard J, Casewell
M, Williams R. Prospective controlled trial of selective
parenteral and enteral antimicrobial regimen in fulminant
liver failure. Hepatology 1993; 17: 196201.
134. Onodera K, Sakata H, Yonekawa M, Kawamura A. Artificial
liver support at present and in the future. J Artif Organs
2006; 9: 1728.
135. Liu J, Kjaergard LL, Als-Nielsen B, Gluud C. Artificial and
bioartificial support systems for liver failure: a cochrane
hepato-biliary group protocol. Liver 2002; 22: 4338.
136. Sen S, Williams R, Jalan R. Emerging indications for
albumin dialysis. Am J Gastroenterol 2005; 100: 46875.
137. Krisper P, Stauber RE. Technology insight: artificial extra-
corporeal liver support how does Prometheus compare
with MARS? Nat Clin Pract Nephrol 2007; 3: 26776.
138. Heemann U, Treichel U, Loock J, et al. Albumin dialysis in
cirrhosis with superimposed acute liver injury: a prospec-
tive, controlled study. Hepatology 2002; 36: 94958.
139. Rittler P, Ketscher C, Inthorn D, Jauch KW, Hartl WH. Use
of the molecular adsorbent recycling system in the treat-
ment of postoperative hepatic failure and septic multiple
organ dysfunction preliminary results. Liver Int 2004; 24:
13641.
140. van de Kerkhove MP, de Jong KP, Rijken AM, de Pont AC,
van Gulik TM. MARS treatment in posthepatectomy liver
failure. Liver Int 2003; 23(Suppl. 3): 4451.
141. Kellersmann R, Gassel HJ, Buhler C, Thiede A, Timmer-
mann W. Application of Molecular Adsorbent Recirculating
System in patients with severe liver failure after hepatic
resection or transplantation: initial single-centre expe-
riences. Liver 2002; 22(Suppl. 2): 568.
142. Krisper P, Haditsch B, Stauber R, et al. In vivo quantification
of liver dialysis: comparison of albumin dialysis and fractio-
nated plasma separation. J Hepatol 2005; 43: 4517.
143. Demetriou AA, Brown RS Jr, Busuttil RW, et al. Prospective,
randomized, multicenter, controlled trial of a bioartificial
liver in treating acute liver failure. Ann Surg 2004; 239:
6607; discussion 66770.
144. Jalan R, Pollok A, Shah SH, Madhavan K, Simpson KJ. Liver
derived pro-inflammatory cytokines may be important in
producing intracranial hypertension in acute liver failure.
J Hepatol 2002; 37: 5368.
145. Otsuka Y, Duffy JP, Saab S, et al. Postresection hepatic
failure: successful treatment with liver transplantation. Liver
Transpl 2007; 19: 32938.
Liver International (2008)


c 2008 The Authors. Journal compilation

c 2008 Blackwell Munksgaard