Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery

(ISGLS).
Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, Koch M, Makuuchi M,
Dematteo RP, Christophi C, Banting S, Usatoff V, Nagino M, Maddern G, Hugh TJ, Vauthey JN, Greig P,
Rees M, Yokoyama Y, Fan ST, Nimura Y, Figueras J, Capussotti L, Bchler MW, Weitz J.
Source

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany.
Abstract
BACKGROUND:

Posthepatectomy liver failure is a feared complication after hepatic resection and a major cause of
perioperative mortality. There is currently no standardized definition of posthepatectomy liver failure
that allows valid comparison of results from different studies and institutions. The aim of the current
article was to propose a definition and grading of severity of posthepatectomy liver failure.
METHODS:

A literature search on posthepatectomy liver failure after hepatic resection was conducted. Based on
the normal course of biochemical liver function tests after hepatic resection, a simple and easily
applicable definition of posthepatectomy liver failure was developed by the International Study Group
of Liver Surgery. Furthermore, a grading of severity is proposed based on the impact on patients' clinical
management.
RESULTS:

No uniform definition of posthepatectomy liver failure has been established in the literature addressing
hepatic surgery. Considering the normal postoperative course of serum bilirubin concentration and
International Normalized Ratio, we propose defining posthepatectomy liver failure as the impaired
ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized
by an increased international normalized ratio and concomitant hyperbilirubinemia (according to the
normal limits of the local laboratory) on or after postoperative day 5. The severity of posthepatectomy
liver failure should be graded based on its impact on clinical management. Grade A posthepatectomy
liver failure requires no change of the patient's clinical management. The clinical management of
patients with grade B posthepatectomy liver failure deviates from the regular course but does not
require invasive therapy. The need for invasive treatment defines grade C posthepatectomy liver failure.
CONCLUSION:

The current definition of posthepatectomy liver failure is simple and easily applicable in clinical routine.
This definition can be used in future studies to allow objective and accurate comparisons of operative
interventions in the field of hepatic surgery.

Crown Copyright 2011. Published by Mosby, Inc. All rights reserved.
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Destroy user interface controlConsensus classifications of postoperative complications--are they really
useful? [Surgery. 2Liver failure following partial hepatectomy
Thomas S. Hellingcorresponding author
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Abstract

While major liver resections have become increasingly safe due to better understanding of anatomy and
refinement of operative techniques, liver failure following partial hepatectomy still occurs from time to
time and remains incompletely understood. Observationally, certain high-risk circumstances exist,
namely, massive resection with small liver remnants, preexisting liver disease, and advancing age, where
liver failure is more likely to happen. Upon review of available clinical and experimental studies, an
interplay of factors such as impaired regeneration, oxidative stress, preferential triggering of apoptotic
pathways, decreased oxygen availability, heightened energy-dependent metabolic demands, and
energy-consuming inflammatory stimuli work to produce failing hepatocellular functions.
Keywords: Liver, hepatectomy, liver failure, liver resection
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Background

Among all organs, the liver is unique in its ability to repair itself after suffering loss of tissue mass from
toxins, infectious agents or surgical resection. This regenerative capacity has made it possible for
surgeons to remove large portions of liver without permanent impairment of function. From the first
descriptions by Keen in 1899 1 of major hepatic resections for tumors, the postoperative course of these
patients was largely uneventful, provided that they survived the operation. Mortality was high (almost
15% in 74 patients), usually from bleeding, and few, if any, of the deaths seemed to be due to liver
failure. With a clearer understanding of hepatic anatomy 2, and refinements in operative technique 3,4,
liver resection became more commonplace. Foster and Berman 5, in their 1974 liver tumor survey,
examined 621 patients who had undergone liver resection in 98 different hospitals. The overall mortality
rate was 13%. Upon reviewing the deaths, the authors found that 29 patients succumbed to liver
failure, most within 30 days of operation. Fourteen of these deaths were thought to be due to technical
causes, usually removal of too much liver or vascular compromise to remnant liver, and 12 deaths
were in patients with cirrhosis. Three cases of liver failure could not be explained. More recent clinical
series cast a similar light. In a series of over 400 partial hepatectomies, Iwatsuki and Starzl 6 detailed 19
in-hospital deaths. Eleven of these deaths were due to liver failure, nine after the first postoperative
week and six after 1 month. In this group of 11 patients, 8 had undergone extended right hepatectomy
(trisegmentectomy) and 7 were over 60 years of age. Savage and Malt 7 published a large series of
hepatectomies, 75% of which were major, in which 12 patients died of liver failure (and five from
septicemia) and 14 developed reversible liver insufficiency. Scheel and Stangl 8 observed a greater
chance of liver failure in non-cirrhotics (11.5%) if more than 50% of functioning liver was removed
resulting in 5 (of 18) deathsthan if less were resected (1.3%). The dangers of extended hepatic
resections, during which well over half of the liver was removed, were illustrated by Melendez and co-
authors 9. They encountered 14 postoperative deaths in these patients, 6 from sepsis and 3 from liver
failure. Others 10 noted similar findings, observing that sepsis and liver failure accounted for five of
seven postoperative deaths.

The interplay of clinical factors that predispose to liver failure following partial hepatectomy is the
subject of this review. We will examine a number of clinical situations, which might shed light on causes
of liver failure following resection and delve into experimental data that could help to explain some of
the clinical observations.
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Definition

There is no clear definition of liver failure following partial hepatectomy. In clinical series there is even
some confusion regarding cause of death, whether liver failure, sepsis, or multi-organ failure, all of
which may have in common progressive liver dysfunction. Of course, liver failure may be said to occur if,
following partial hepatectomy, a patient dies with deepening jaundice, worsening coagulopathy, and
encephalopathy. One may refer to the definition of acute or fulminant liver failure as suggested by
Hoofnagle 11 and Bernuau & Benhamou 12 consisting of a progressive hyperbilirubinemia,
derangements of synthetic function manifested by a decrease in hepatic dependent clotting factors, and
appearance of encephalopathy, which lead to death or eventual recovery. Clinicians often recognize a
normalization of the serum bilirubin for the first few days following partial hepatectomy, but then a
steady increase in bilirubin accompanied by other signs of liver insufficiency. This may correspond to a
failure of the regenerative process, as peak DNA synthesis occurs at about 7 days in humans 13. While
there may be an early and transient increase in total serum bilirubin for the first few days after partial
hepatectomy normally, a sustained and progressive rise may signal significant dysfunction, especially
when coupled with encephalopathic behavior. Histopathologically, some have classified liver failure
following hepatectomy as two types: cholestatic, characterized by bile plugging, hepatocyte
regeneration, and fibrosis in Disse's space; and nonregenerative, characterized by apoptosis of
hepatocytes 14. While liver failure may be fulminant, with death occurring within days, often the onset
is insidious, and deterioration of hepatic function extends over weeks before either proving fatal or
improving.
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The liver and ischemia

In the usual course of limited inflow occlusion during partial hepatectomy, it is unlikely that ischemia
alone is sufficient to produce enough hepatocellular injury to cause dysfunction. The liver is remarkably
resistant to normothermic ischemia. In-flow occlusion, the so-called Pringle maneuver, has been used to
control parenchymal bleeding for periods of up to 1 hour with little detectable penalty 15. In fact, the
maneuver is commonly done for hepatic resections to reduce bleeding. That some degree of cellular
damage occurs is manifested by modest and transient rises in serum transaminases but without clinical
evidence of dysfunction. A less common maneuver to control blood loss is total vascular exclusion (TVE).
The first report of TVE, clamping of in-flow and out-flow (inferior vena cava or individual hepatic veins),
for up to 38 minutes, was described by Huguet and associates 16 in nine patients undergoing partial
hepatectomy without a death. Henri Bismuth and colleagues 17 employed TVE and demonstrated the
resiliency of the liver to normothermic ischemia in 51 patients with occlusive periods averaging 50
minutes. There was only one postoperative death in a patient with fatty liver, and no clinically significant
liver dysfunction was reported in any of the survivors. Huguet and his co-workers 18 published a follow-
up study to their initial work compiling a series of 59 patients, this time with ischemic periods exceeding
1 hour with only one death in a patient who developed portal vein thrombosis and liver failure. Intra-
operative and postoperative biopsies showed no immediate or long-term derangement of hepatic
architecture by light microscopy. By electron microscopy, warm ischemic times of approximately 30
minutes produced collapse of sinusoids, focal chromatin condensation at the nuclear margin of
hepatocytes, and mitochondrial and endoplasmic reticulum swelling, but these changes were reversible
on reperfusion 19. Nevertheless, the liver is not immune to ischemia. Champion and co-authors 20
studied 19 patients after prolonged periods of hemorrhagic shock. Hyperbilirubinemia was seen 810
days afterwards associated with intracellular lipid deposition, periportal cell necrosis, acute and chronic
cellular infiltrate, and bile plugging. The additional insult of infection caused maximum hepatic
dysfunction, which often led to multi-system organ failure. Why, in this setting, histopathologic injury
was so obvious is not clear unless the splanchnic response to hypovolemia, with its intense
vasoconstriction, extends beyond the observable period of shock and produces periods of ischemia well
in excess of the hour ischemic times used in more controlled surgical situations.
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Remnant liver volume

Clinical investigations found that, following removal of up to 50% of functioning liver, there was usually
only a mild and short-lived increase in serum bilirubin and depression of serum proteinsboth visceral
and acute phaseindicating sustained conservation of hepatocellular function 6,7,8,21,22,23. In fact,
removal of up to 75% of the liver was tolerated in most patients. However, it would be advantageous to
estimate the size of the liver remnant after partial hepatectomy to reduce chances of liver insufficiency.
Heymsfield and colleagues 24 first described volumetric measurements of liver in 1979 using
computerized tomography (CT). In this method serial abdominal transverse cuts taken at 0.51.0-cm
intervals were utilized, the liver being traced with a cursor, and the segments and sectors of the liver
defined by right, middle, and left hepatic veins and portal vein bifurcations. The total liver volume and
segmental volumes could then be calculated in milliliters. This technique was initially applied to living
donor hepatic transplantation 25, but Kubota and co-workers 26 investigated its usefulness in resections
of hepatic tumors. The amount of functioning liver remaining after resection was expressed as a ratio of
remnant to total liver volume. In a series of 50 patients, resection of up to 5060% of functional liver
was well tolerated in those who had normal liver function pre-operatively. In further trials, Shirabe and
associates 27 reported a series of 80 patients who had volumetric studies prior to resection. Liver
volume was expressed as ml/m2 body surface area. There were seven patients who developed liver
failure post-operatively. The mean liver volume in these seven patients was significantly less (16363 vs
335112 ml/m2, p=0.0002), and in those with liver failure the liver volume was never more than 250
ml/m2. Others 28 have found major hepatectomies to be safe with remnant liver volumes at least 25%
of pre-operative values or measured size of approximately 318 cm3,29. With the presence of steatosis,
30% or more of the remnant liver should remain (D. Azoulay, personal communication).

Reduction in liver size apparently alters hepatic microcirculation. Kin and colleagues 30 observed a
decrease in portal flow velocity and increase in hepatic artery resistive index in patients developing liver
dysfunction following partial hepatectomy. Experimentally, creation of a surgical model of acute liver
failure, a 90% hepatectomy in the rat model, produced an immediate decrease in hepatic
microcirculatory flow and caused a remarkable increase in hepatic vascular resistance leading to liver
dysfunction and failure, mirroring clinical findings. This could be partially reversed by a portal-systemic
shunt 31. From these observations, it appears that a critical reduction in liver mass leads to sudden
portal hypertension, microcirculatory ischemia, reduced oxygen delivery, and hepatocellular
dysfunction.

Observations in small-for-size liver transplantation may also shed some light on mechanisms of liver
failure. Clinical experience has shown that the use of allografts with a graft-to-recipient weight ratio
(GRWR) of <1% leads to lower graft survival 32. Experimentally, the use of small allografts has produced
poor outcomes in the swine model 33, with severe ischemic changes and hyperemia seen histologically.
In the rat model 34, using allografts <30% of recipient weight, there was a transient increase in portal
pressure and an increase in hepatic microcirculatory blood flow. Again, histologically, there was
sinusoidal congestion and swelling of mitochondria. Modulation of portal inflow by ligation of the
splenic artery has resulted in lowering of portal and hepatic arterial flow with good graft survival 35.
Similarly, creation of a mesocaval type shunt and ligation of the superior mesenteric artery have
improved survival in swine and resulted in a favorable outcome in one patient with a GRWR < 1% 36. It
appears, then, that high portal and hepatic artery flows to small liver remnants are inherently
detrimental and contribute to alteration of microcirculatory flow, congestion, and hepatocellular
dysfunction.

Other factors may also be at work. Despite an increase in requirements brought on by surgical stress,
there appears to be a fall in hepatic energy levels over the first 48 hours following partial hepatectomy
37,38. In addition, Bilimoria and others 39 felt that liver failure after hepatectomy represented a failure
to regenerate at a critical mass of liver tissue. Eguchi and others 40 showed that expression of
hepatocyte growth factor (HGF) and c-met mRNA in remnant liver was delayed in a rat model of
fulminant hepatic failure after partial hepatectomy. There was only a modest increase in weight of the
remnant liver but no signs of regeneration by either BrdU uptake, proliferating cell nuclear antigen
(PCNA), or presence of mitotic figures. Survivability in a 90% hepatectomy model has been thought by
others 41 to hinge on the availability of glucose and normalization of blood insulin and glucagon. This
may in part, be due to reconstitution of intracellular adenine nucleotides and preservation of energy-
dependent functions involved in normal metabolism and new demands for cellular replication 42.

It is evident that some crucial amount of liver must remain; yet the precise mechanism for
hepatocellular failure below this critical mass cannot be completely explained. Very likely, energy supply
and demand are of the essence. Failure of usual metabolic tasks probably reflects an overwhelmed
hepatocyte mass, which must also deal with the added burden of regeneration.

Ipsilateral atrophy and compensatory hypertrophy are recognized occurrences after portal vein ligation.
Therapeutic use of this phenomenon was initially reported by Makuuchi and co-authors in 1990 43 in 14
patients with hilar bile duct carcinoma in order to reduce postoperative morbidity and mortality after
extensive liver resection. Pre-operative portal vein embolization (PVE) has been shown to increase the
remnant liver size by almost one-third 44. More recent clinical studies have shown a benefit from
preoperative PVE in reducing postoperative liver failure 45, particularly in diseased livers 46.
Additionally, the number of resectable patients has increased with the use of PVE due to increases in
remnant liver volume 47. This has proven to be a useful strategy in reducing the risk of postoperative
liver failure and increasing operability for liver tumors and, once again, demonstrates the importance of
remnant liver size in postoperative recovery.
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Aging

Age likely plays a role in survivability following partial hepatectomy. Fortner and Lincer 48 noticed a
significant increase in mortality after age 65 (11.1%) and found a further increase in mortality in this age
group with extended hepatic resection (30.7%). In the 10 deaths in older patients, 6 were due to liver
failure, and all had normal preoperative liver function. Similarly, Koperna and colleagues 49 described a
15% death rate in 97 patients over age 65, increasing to 25% for those over 80 years. In patients
developing postoperative liver failure (n=47) the mortality was 21%. Infectious complications were listed
as a frequent postoperative problem. On the other hand, two Asian studies showed equivalent hospital
mortality and morbidity in aged patients (even over 80 years) compared to their younger counterparts
when resections were done for hepatocellular carcinoma 50,51, although in both these reports a
minority (31% and 14%) of patients received a major liver resection.

The effect of aging on liver function is unclear. Usual laboratory values such as hepatic enzyme profiles,
serum albumin, and cholesterol values seem to be well maintained over a wide age spectrum 52.
However, both basal and taurocholate-stimulated bile flow and bile acid secretion are decreased in
older experimental animals compared to younger animals 53, and bile acid synthesis has been shown to
decline in geriatric subjects 54. There also seems to be a reduced capacity for acute phase protein
synthesis in older patients after liver resection 55. Furthermore, it has been shown that aged livers do
not regenerate as well. Beyer and co-workers 56 established that 1-year-old rats had retarded
restoration of hepatic mass (6070%) after partial hepatectomy at 1 week compared with juvenile rats.
The induction of thymidylate synthetase and thymidine kinase, rate-determining enzymes of DNA
synthesis in liver regeneration, are delayed and maximum activity reduced in 60-week-old rats after
two-thirds hepatectomy 57. In humans, smaller allograft liver volumes are found at 1 week following
living donor liver transplantation in donors over 50 years of age compared with younger patients 58.
While it is speculative to attribute subtle alterations of liver function and slowing of regeneration to
higher rates of post-hepatectomy liver failure, diminished hepatic reserve in the elderly may prove
critical after major liver resection. These livers may be more susceptible to the additive effects of small
remnant liver mass, operative ischemia, or postoperative infection.
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Chronic liver disease

The presence of cirrhosis has been associated with a higher mortality rate after major resection, at times
exceeding 20% 59,60. This was thought to be due to compromised liver function from chronic disease
reducing functional liver mass. Indeed, liver failure is a common cause of death in cirrhotics, often linked
to septic events. Takenaka and colleagues 59 observed that half of the patients developing post-
hepatectomy liver failure had a preceding infection. Attempts to quantify preoperative hepatic reserve
using the clinical classification system of ChildPugh 61 have met with varying success 59,60, and some
have advocated a histologic grading scale, finding that fibrosis was an independent risk factor for death
62. Nevertheless, in the face of cirrhosis, the ChildPugh system of estimating hepatic reserve continues
to be a useful clinical tool to assess operative risk.

Chronic liver disease has been associated with higher risk of liver failure following partial hepatectomy.
Cirrhosis and ongoing inflammatory activity have been cited as contributing factors 59,62,63. Both serve
to impede healing. An increasingly common form of liver disease, nonalcoholic fatty liver disease and
the accompanying steatohepatitis, has been found to affect the risk of major liver resections 64
including postoperative liver failure. Little and co-authors 65 found a significantly greater operative
mortality in patients suffering from type I or II diabetes mellitus, the majority of whom died from
postoperative liver failure and were found to have steatotic changes. It is not clear why steatotic livers
are more susceptible to injury. Certainly, the presence of steatosis can be detrimental to graft function
both in cadaveric 66 and living donor 67 liver transplantation. The steatotic liver is more susceptible to
ischemia/reperfusion injury, perhaps due to an altered sinusoidal microcirculation 68. There also
appears to be some impairment of hepatic regeneration, as demonstrated experimentally in the rat
partial hepatectomy model with a delay seen in the appearance of regenerative markers such as
bromodeoxyuridine 69,70.

In an attempt to identify perturbations of liver function that might lead to postoperative failure,
indocyanine green elimination 71,72, elimination of hyaluronic acid 73,74, clearance of hepatic 99mTc-
diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (99mTc-DPTA-GSA) 75, and
measurement of hepatic mitochondrial redox state 76 have been proposed. Das and colleagues 77
found that the combination of these risk factors predicted morbidity in 100% of their patients. In the
setting of chronic liver disease, whether cirrhosis and/or chronic inflammation, damage to the
hepatocyte probably results from regional ischemia (cirrhosis) or liberation of inflammatory mediators.
That regeneration is slowed by the presence of cirrhosis has been shown in clinical studies using
volumetric determinations of remnant size 21,22. Slowed regeneration can, in part, be explained by
lower levels of HGF, possibly due to failure to convert HGF precursor to the biologically active form 78.
Down-regulation of cell cycle regulators and impairment of transcription factors may also play a role 79.
This may be caused by cirrhosis-induced hypoxia affecting hepatocytes and associated mesenchymal
support cells 80.
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Sepsis

Clinically, there appears to be a strong link between sepsis and post-hepatectomy liver failure. In one
series of 19 patients developing intraperitoneal septic complications after hepatectomy, 13 died of liver
failure 81. Experimentally, alteration of gut contents by antibiotic treatment reduced endotoxemia and
mortality after two-thirds hepatectomy in rats 82. Administration of endotoxin following hepatectomy
produced massive hepatic necrosis and 50% mortality, but not in sham-operated control animals 83, and
restricted liver cell proliferation, perhaps mediated by the cytokine interleukin-1 (IL-1) 84. Neutralization
of endotoxin and blocking of IL-1 reduced hepatic inflammation and reduced serum levels of
transaminases in hepatectomized rats 85. The lethality of endotoxin in such situations might be
explained, in part, by Kupffer cell dysfunction. Impairment of Kupffer cell activity has been detected by a
reduction in production of the hepatotrophic cytokine, tumor necrosis factor- (TNF-), which led to
retardation of regeneration 86,87. Panis and co-authors 88 have suggested that a critical mass of
remaining liver is dependent not only on the amount of functional hepatocytes but also on the number
of Kupffer cells available to assist in regeneration through elaboration of initiator cytokines and
clearance of portal vein endotoxin. The work of Shiratori and others 89 lent support to this theory by
observing that suppression of Kupffer cells by gadolinium chloride in hepatectomized rats reduced
concentrations of TNF- and IL-6, reduced PCNA labeling of hepatocytes, and disturbed liver
regeneration. Impaired clearance of endotoxin in hepatectomized rats led to multi-organ failure but
could be reversed by the endotoxin-neutralizing N-terminal bactericidal/permeability-increasing protein
90. Furthermore, translocation of enteric bacteria has been demonstrated in blood, mesenteric lymph
nodes and other organs as early as 2 hours following 90% hepatectomy in rats, reflecting an inability of
surviving Kupffer cells to provide adequate clearance 91. In fact, the rate of translocation of intestinal
microflora in portal and arterial blood after 70% hepatectomy was reported to be 100% at 24 hours 92.
This translocation was detected in the liver as well as other intra-abdominal organs. Return of Kupffer
cell function may not normalize for over 2 weeks 93. However, recovery of Kupffer cell activity has an
impact on outcome in patients in fulminant hepatic failure, regaining steadily their ability to clear 124I-
labeled microaggregated albumin in those that survived 94. Reduced Kupffer cell mass and impaired
function coupled with the enhanced permeability and availability of enteric microorganisms provides a
dangerous milieu for the production and liberation of endotoxin.

Endotoxin also has a specific effect on the hepatocyte. Administration of endotoxin to pigs resulted in
reduced clearance of hepatoiminodiacetic acid (HIDA) even before increases in cardiac index or
decreases in systemic vascular resistance 95. Direct contact of endotoxin with hepatocytes, perhaps
through membrane receptors, caused derangements of hepatocyte function identified as lysosomal
damage, decreased mitochondrial function, and impaired bile salt-independent bile flow and
sulfobromophthalein excretion 96,97,98. In perfused livers of endotoxemic rats, reduced clearance of
bilirubin and taurocholate were found, reflecting an impairment of intracellular transport rather than
altered conjugation 99. These changes could be explained by relocation of ATP-diphosphohydrolases as
a result of exposure to endotoxin 100. Others 101 have found a decrease in synthesis of canalicular
multispecific organic anion transporter protein, perhaps contributing to hyperbilirubinemia and
cholestasis. This effect was mediated by Kupffer cell activation by endotoxin and elaboration of IL-1 and
TNF-. In addition, bile plugging, described microscopically in cholestatic liver failure 14, might be
explained by alteration of the tight junction between hepatocyte couplets, increasing permeability and
producing bile regurgitation 102. Endotoxin has been found to impair regeneration by reducing
hepatocyte growth related mRNA and depressing PCNA 76,103.

Endotoxin, then, can play a dual role in post-hepatectomy liver failure. By action on the Kupffer cell
there is impairment of initiator cytokines necessary for regeneration. This effect is magnified with
reduction in Kupffer cell mass that accompanies extensive liver resections. At the same time endotoxin
alters the internal milieu of hepatocytes by its effect on transport mechanisms, initiation of
regeneration, and membrane function. The end result could be a small liver remnant with defective
reticuloendothelial activity, disrupted hepatocellular metabolism, and impaired regenerative pathways.
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Regeneration

Liver failure can be viewed as a net loss of functioning hepatocytes to the point that surviving
hepatocytes cannot maintain adequate metabolic functions. This represents either a failure to
regenerate after partial hepatectomy or accelerated destruction of hepatocytes from necrosis or
apoptosis. Post-hepatectomy liver regeneration is a complex, but well orchestrated, series of events
initiated by a number of autocrine, paracrine, and endocrine hepatotrophic factors 104. Regeneration
has most easily been studied in the rat or mouse partial hepatectomy model or in cell culture. These
may not be translatable to human liver regeneration as events occur much earlier in the rodent models
and cell culture methodology may not take into account the role of supporting cells, cytokines, and
hepatotrophic factors found in vivo.

Proliferation of all cellular components and matrix occurs with hepatocytes, the first to begin mitotic
activity. In humans with normal livers, regeneration occurs in the first 2 weeks after hepatectomy and is
completed by 3 months 21,105,106. The protooncogenes c-fos, c-jun, and c-myc are usually considered
the markers for the initial phase of regeneration 107. These genes are expressed even after massive
hepatectomy in experimental animals 108. Simultaneously, a number of genes are expressed in the early
phases of regeneration involved in control of growth 109. In response to these molecular events,
normally quiescent and highly differentiated hepatocytes enter and progress through the various stages
of cell replication. Gene expression is thought to occur after activation by a number of identifiable
hepatotrophic factors. Prominent among these are TNF-, HGF, epidermal growth factor (EGF),
transforming growth factor- (TGF)-, and IL-6. It appears that the cytokines TNF- and IL-6 are early
initiators of DNA synthesis in regenerating hepatocytes, although it is not clear whether their roles are
facultative or triggering 110,111. Cell cycle progression requires, in addition to these hepatotrophic
factors, activation of cyclin-dependent kinases (Cdks) that are regulated by cyclins and Cdks inhibitors
112. The Cdks inhibitor p21 has been identified as an important protein in halting liver regeneration and
may be induced by the presence of the hepatocyte proliferative inhibitor transforming growth factor-
(TGF- 113,114. Regeneration may also be halted by inhibition of nuclear factor kappa B (NFB) 115,116.
NFB probably prevents apoptosis by terminating activation of c-Jun NH2-terminal kinase (JNK) 117.

Part of the initial response of the remnant liver to partial hepatectomy is induction of members of the
signal transducers and activators of transcription (Stat). This family of factors participates in the
regulation of growth response genes and is induced early following partial hepatectomy 118.
Experimentally, in fatty livers, induction of Cdks after partial hepatectomy is abolished, alteration of
Stat-3 occurs, and adenosine triphosphate levels are reduced, which arrests hepatocyte proliferation
and impairs regeneration 119. In fact, others 120 have found hyperinduction of Stat-3 after liver injury in
obese mice, which impairs regeneration by up-regulating mechanisms that impede progression of the
cell cycle. Interference in the regenerative pathways, either by suppression of hepatotrophic factors or
by up-regulation of cell cycle inhibitors (or both), may help explain failure of the remnant liver to sustain
metabolic functions.

It is now apparent that nitric oxide (NO) plays an important role in liver regeneration. Generation of NO
is dependent on cytokine inducible nitric oxide synthase (iNOS). Levels of iNOS are elevated after partial
hepatectomy in the rat model 121. In transgenic mice with targeted disruption of the iNOS gene, partial
hepatectomy results in heightened caspase-3 activity, hepatocyte apoptosis, and liver failure 122. One
mechanism for the regenerative contribution of NO may lie in its ability to down-regulate S-
adenosylmethionine synthesis, which is involved in inhibition of HGF-induced cyclin D1 and D2
expression 123. Therefore, any disruption of NO synthesis would seem to have a deleterious effect on
regeneration and may, in fact, uncover apoptotic pathways.
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Apoptosis

Liver cell loss can occur via two mechanisms: necrosis and apoptosis. Histopathologic studies of failing
livers do not mention necrosis as a prominent finding and, in fact, observe apoptotic changes in some
specimens 14. Apoptosis of cells occurs from external or internal signaling. External signaling involves
the cell membrane receptors, TNF-receptor 1 (TNFR1) and the Fas/Apo receptor. Binding by TNF- or
Fas ligand activates the caspase cascade, eventually resulting in cell death. While hepatocytes are rich in
these cell surface receptors, activation usually results in initiation of regenerative rather than apoptotic
pathways 110,124. Despite the ability of TNF- to trigger apoptotic events by combination with its 55-
kDa TNFR1 and up-regulation of Fas/Apo 1 receptors 125,126, regenerative pathways seem to prevail
even to the degree of suppressing Fas-signaling apoptotic cascades 127. Whether apoptosis plays a
significant role in loss of hepatocytes after partial hepatectomy is unclear. Lee and co-workers 128
described a threefold rise in apoptotic cells at 1 hour following 70% hepatectomy in rats, and Sakamoto
and colleagues 129 reported a wave of apoptosis occurring between 60 and 96 hours after 70%
hepatectomies in mice. On the other hand experiments in our laboratory 130 have failed to disclose a
meaningful increase in apoptotic activity following partial hepatectomy in rats even with endotoxin
stimulation and high levels of TNF-. It appears difficult, in otherwise intact experimental animals, to
induce apoptosis over regeneration using commonly recognized external stimulators for death domain
activation in survivable models of partial hepatectomy.

Internal signaling of the caspase cascade can occur from oxidative stress focused on the mitochondria.
Formation of reactive oxygen species has been shown to promote apoptosis through creation of
voltage-dependent anion channels in the outer mitochondrial membrane 131. Leakage of cytochrome C
through these channels then induces the entire caspase cascade, resulting in apoptosis 132.
Additionally, oxidative stress can cause perturbations of Ca2 + homeostasis and influx of the cation into
the cytoplasm from outside the cell or the endoplasmic reticulum, the main intra-cellular store of Ca2 + .
Influx of Ca2 + can cause disruption of mitochondrial metabolism and alteration of gene transcription
leading to apoptosis 133. The focus of the anti-apoptotic proten Bcl-2 and the pro-apoptotic proteins
Bax and Bak may be regulation of Ca2 + flux from the endoplasmic reticulum 134.

Aging can increase susceptibility to oxidative stress. Ikeyama and associates 135 have shown that
hepatocytes from aged rats (2426 months old) exhibited reduced proliferative capacity when exposed
to hydrogen peroxide or epidermal growth factor. These same investigators subsequently discovered
that the proapoptotic gene gadd153 is up-regulated in aging rats and is particularly sensitive to oxidative
injury 136. Aberrant induction can also occur with stimulation by epidermal growth factor in aging rats.
Others 137 have determined that the calcium-binding protein senescence marker protein-30 (SMP-30)
decreases with aging. In mutant mice lacking SMP-30, hepatocytes were more susceptible to apoptosis
induced by TNF-. SMP-30 could be considered an anti-apoptotic protein that, with age and decreasing
levels, is less able to prevent progression of apoptotic events initiated by external signals.
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131. Madesh M, Hajnoczky G. VDAC-dependent permeabilization of the outer mitochondrial membrane
by superoxide induces rapid and massive cytochrome c release. J Cell Biol. 2001;155:100316. [PMC free
article] [PubMed]
132. Slee ET, Harte MT, Kluck RM, Wolf BB, Cassiano CA, Newmeyer DD, et al. Ordering the cytochrome
C-initiated caspase cascade: hierarchial activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-
dependent manner. J Cell Biol. 1999;144:28192. [PMC free article] [PubMed]
133. Ermak G, Davies KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol.
2002;38:71321. [PubMed]
134. Oakes SA, Opferman JT, Pozzan T, Korsmeyer SJ, Scorrano L. Regulation of endoplasmic reticulum
Ca2 + dynamics by proapoptotic BCL-2 family members. Biochem Pharmacol. 2003;66:133540.
[PubMed]
135. Ikeyama S, Kokkonen G, Martindale JL, Wang XT, Gorospe M, Holbrook N. Effects of aging and
caloric restriction of Fischer 344 rats on hepatocellular response to proliferative signals. Exp Gerontol.
2003;38:4319. [PubMed]
136. Ikeyama S, Wang X-T, Li J, Podlusky A, Martindale JL, Kokkonen G, et al. Expression of the pro-
apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury. J Biol
Chem. 2003;278:1672631. [PubMed]
137. Ishigami A, Fujita T, Handa S, Shirasawa T, Koseki H, Kitamura T, et al. Senescence marker protein-
30 knockout mouse liver is highly susceptible to tumor necrosis factor-alpha- and Fas-mediated
apoptosis. Am J Pathol. 2002;161:127381. [PMC free article] [PubMed]
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Endotoxin and interleukin-1 related hepatic inflammatory response promotes liver failure after partial
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Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic
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Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver
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2002]
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Partial hepatectomy with or without endotoxin does not promote apoptosis in the rat liver. [J Surg
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VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid
and massive cytochrome c release. [J Cell Biol. 2001]
Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -
8, and -10 in a caspase-9-dependent manner. [J Cell Biol. 1999]
Review Calcium and oxidative stress: from cell signaling to cell death. [Mol Immunol. 2002]
Review Regulation of endoplasmic reticulum Ca2+ dynamics by proapoptotic BCL-2 family members.
[Biochem Pharmacol. 2003]

Effects of aging and calorie restriction of Fischer 344 rats on hepatocellular response to proliferative
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Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells
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National Center for Biotechnology Information, U.S. National Library of Medicine 8600 Rockville Pike,
Bethesda MD, 20894 USANew Paradigms in Post-hepatectomy Liver Failure.
Golse N, Bucur PO, Adam R, Castaing D, Sa Cunha A, Vibert E.
Source

Centre Hpatobiliaire, Hpital Paul Brousse, Assistance Publique-Hpitaux de Paris, Universit Paris XI,
Paris, France, nicolas.golse@wanadoo.fr.
Abstract
INTRODUCTION:

Liver failure after hepatectomy remains the most feared postoperative complication. Many risk factors
are already known, related to patient's comorbidities, underlying liver disease, received treatments and
type of resection. Preoperative assessment of functional liver reserve must be a priority for the surgeon.
METHODS:

Physiopathology of post-hepatectomy liver failure is not comparable to fulminant liver failure. Liver
regeneration is an early phenomenon whose cellular mechanisms are beginning to be elucidated and
allowing most of the time to quickly recover a functional organ. In some cases, microscopic and
macroscopic disorganization appears. The hepatocyte hyperproliferation and the asynchronism between
hepatocytes and non-hepatocyte cells mitosis probably play a major role in this pathogenesis.
RESULTS:

Many peri- or intra-operative techniques try to prevent the occurrence of this potentially lethal
complication, but a better understanding of involved mechanisms might help to completely avoid it, or
even to extend the possibilities of resection.
CONCLUSION:

Future prevention and management may include pharmacological slowing of proliferation, drug or
physical modulation of portal flow to reduce shear-stress, stem cells or immortalized hepatocytes
injection, and liver bioreactors. Everything must be done to avoid the need for transplantation, which
remains today the most efficient treatment of liver failure.

PMID:
23161285
[PubMed - in process] Prediction, prevention and management of postresection liver failure.
Hammond JS, Guha IN, Beckingham IJ, Lobo DN.
Source

Division of Gastrointestinal Surgery, Nottingham Digestive Diseases Centre National Institute of Health
Research Biomedical Research Unit, Nottingham University Hospitals, Queen's Medical Centre,
Nottingham, UK.
Abstract
BACKGROUND:

Postresection liver failure (PLF) is the major cause of death following liver resection. However, there is
no unified definition, the pathophysiology is understood poorly and there are few controlled trials to
optimize its management. The aim of this review article is to present strategies to predict, prevent and
manage PLF.
METHODS:

The Web of Science, MEDLINE, PubMed, Google Scholar and Cochrane Library databases were searched
for studies using the terms 'liver resection', 'partial hepatectomy', 'liver dysfunction' and 'liver failure' for
relevant studies from the 15 years preceding May 2011. Key papers published more than 15 years ago
were included if more recent data were not available. Papers published in languages other than English
were excluded.
RESULTS:

The incidence of PLF ranges from 0 to 13 per cent. The absence of a unified definition prevents direct
comparison between studies. The major risk factors are the extent of resection and the presence of
underlying parenchymal disease. Small-for-size syndrome, sepsis and ischaemia-reperfusion injury are
key mechanisms in the pathophysiology of PLF. Jaundice is the most sensitive predictor of outcome. An
evidence-based approach to the prevention and management of PLF is presented.
CONCLUSION:

PLF is the major cause of morbidity and mortality after liver resection. There is a need for a unified
definition and improved strategies to treat it.

Copyright 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

PMID:
21725970
[PubMed - indexed for MEDLINE] Review Article
Postoperative management after hepatic resection
Lindsay J. Wrighton, Karen R. OBosky, Jukes P. Namm, Maheswari Senthil
Department of Surgery, Loma Linda University, Loma Linda, California, USA
Corresponding to: Maheswari Senthil, MD. Department of Surgery, Division of Surgical Oncology, Loma
Linda University, Coleman Pavilion, Room # 21112, 11175 Campus Street, Loma Linda, California, USA.
Tel: 909-558-8390; Fax: 909-558-0236. Email: msenthil@llu.edu.
Abstract
Hepatic resection has become the mainstay of treatment for both primary and certain secondary
malignancies. Outcomes after hepatic resection have significantly improved with advances in surgical
and anesthetic techniques and perioperative care. Metabolic and functional changes after hepatic
resection are unique and cause significant challenges in management. In-depth understanding of
hepatic physiology is essential to properly address the postoperative issues. Strategies implemented in
the postoperative period to improve outcomes include adequate nutritional support, proper glycemic
control, and interventions to reduce postoperative infectious complications among several others. This
review article focuses on the major postoperative issues after hepatic resection and presents the
current management.
Key words
Management; postoperative; hepatic resection; liver resection
J Gastrointest Oncol 2012;3:41-47. DOI: 10.3978/j.issn.2078-6891.2012.003
Introduction
Outcomes after hepatic resection have signif icantly improved over the last few decades (1-4). Although,
no single factor is solely responsible, overall advances in surgical and anesthetic techniques, better
understanding of hepatic physiology and improvement in perioperative management have all been
contributory. Majority of postoperative management issues after liver resection are unique and require
a thorough understanding of liver metabolism and the pathophysiology of liver disease. The purpose of
this review is to elaborate on specific early postoperative management issues after liver resection,
examine current evidence and present the management options.
Fluid and Electrolyte management
The immediate postoperative period after hepatic resection is characterized by fluid and electrolyte
imbalances that are further accentuated by derangements of liver function. Maintenance of adequate f
luid balance and normal renal function is critical. Cirrhotics are prone to f luid shifts, vasodilation and
resultant hypotension. In this setting, colloids rather than crystalloids should be administered to restore
intravascular volume. New onset postoperative ascites frequently occurs in cirrhotic patients.
Management with sodium restriction and judicious use of diuretic therapy is recommended.
Paracentesis may be necessary to prevent tense ascites.
Hyperlactemia and hypophosphatemia are common derangements in patients undergoing liver
resection. Gluconeogenesis carried out by the liver normally consumes 40-60% of lactate. When the
liver is damaged or stressed, it produces lactate rather than metabolizing it. Watanabe, et al., examined
the relationship between lactate and base excess with clinical outcomes in 151 hepatic resection
patients. The initial arterial plasma lactate concentration was significantly higher in non-survivors than in
survivors, and correlated with bilirubin levels and was an excellent independent predictor of morbidity
and mortality. Due to the additive effects of lactate-containing intravenous solution, non-lactate
containing solutions are recommended for postoperative use (5).
Hypophosphatemia
Hypophosphatemia is encountered in nearly all patients after major hepatic resection. The pathogenesis
of hypophosphatemia after hepatic resection is poorly understood and is generally believed to be due to
increased phosphate uptake by regenerating hepatocytes. However, recent work by several
investigators has suggested that excessive urinary losses mediated by phosphaturic mediators termed
phosphatonins might be responsible for post-hepatic resection hypophosphatemia (6,7). Whether this
reflects an increased production of phosphaturic mediators by the injured liver versus decreased
clearance of a circulating mediator by the remnant liver is unclear.
Hypophosphatemia results in impaired energy metabolism, leading to cellular dysfunction in many
organ systems including respiratory failure, cardiac arrhythmias, hematologic dysfunction, insulin
resistance, and neuromuscular dysfunction (8,9). Standard liver resection management includes
adequate replacement of phosphate with supplementation of maintenance fluids with potassium
phosphate and oral/parenteral replacement. Currently, management of hypophosphatemia relies on
serum phosphate measurements, which may not be an accurate measure of actual intracellular
phosphate levels due to intraextracellular shifts. Acidosis can cause a shift of intracellular phosphate to
extracellular space resulting in normalization of extracellular phosphate levels. A lternatively,
measurements of serum 2,3- diphosphoglycerol (DPG) and nucleotide breakdown products in the urine
have been reported to be more sensitive physiologic markers of hypophosphatemia-related cellular
stress. Persistently low serum 2,3-DPG levels and high nucleotide breakdown products in the urine
would potentially indicate inadequate intracel lular phosphate replenishment (7). Fur ther validation
studies are needed to assess the clinical utility of these measures in the management of
hypophosphatemia. In summary, hypophosphatemia after hepatic resection can lead to deleterious
consequences and should be properly addressed. Universally accepted method for investigation,
optimal replacement and target serum levels are lacking. Future studies that further elucidate the
pathophysiology of hypophosphatemia after hepatic resection might lead to better management.
Nutrition
The post-hepatic resection period is characterized by a catabolic state, often with glucose and electroly
te imbalances as the body attempts to supply the high demand of the regenerating liver (10). Nutritional
support during this critical period is of paramount importance to ensure adequate hepatic regeneration
and postoperative-recovery. A perioperative nutritional plan should be devised for each individual
patient based on the nutritional status and hepatic function. Non-cirrhotic patients with adequate
preoperative nutritional status may not require any special intervention and should be started on early
oral/enteral diet. On the other hand, patients who are either malnourished, with or without
compromised liver function (cirrhosis or steatosis) and who undergo major hepatic resection will benefit
from perioperative nutritional support preferably through enteral route. The benefit of early enteral
nutrition has now been firmly established in a wide variety of surgical patients. Richter, et al. (11)
evaluated five randomized controlled studies that compared enteral versus parenteral nutrition in the
post-hepatic resection patients (12-16). Based on the results, the authors concluded that enteral
nutrition resulted in significantly lower rate of wound infections and catheter related complications than
parenteral nutrition. While there was no difference in mortality, patients receiving enteral nutrition
showed better post-operative immune competence as evidenced by decreased post-operative
infectious complications. Hotta, et al. found that supplementation with TPN had no effect on the post-
operative outcomes (17). Current evidence strongly supports the use of enteral route for nutritional
support unless otherwise contraindicated.
In addition to early enteral nutrition, branched chain amino acids and other immune-enhancing agents
have received recent attention and deserve special mention. Liver disease results in altered amino acid
metabolism characterized by low circulating levels of branched chain amino acids (leucine, isoleucine
and valine), elevated circulating levels of methionine and aromatic amino acids. Results from two large
randomized controlled trials have shown that branched chain amino acids (BCAA) supplementation in
patients with advanced cirrhosis was associated with improved nutritional status and decreased
frequency of complications of cirrhosis (18,19). Okabayashi et al. evaluated the impact of oral
supplementation of branched chain amino acids and carbohydrates on quality of life (QOL) measures in
patients undergoing hepatic resection (20). In this study QOL measures was assessed by subjective
perception of functioning and physical, mental, and social well-being and were evaluated before and
after surgery, up to 12 months post-operatively. The BCAA group showed steadily improving QOL
measures from pre-operative measurements - this trend continued 12 months post-operatively even
after supplements had been discontinued, while the control group showed no change. The authors
concluded that nutritional supplementation with BCAA restored nutritional status and whole-body
kinetics in patients following hepatic resection, with subjective improvement in post-operative quality
of life. In animal studies, BCAA supplementation has been shown to promote liver regeneration after
major hepatic resection (21). Ishikawa et al. demonstrated that short-term supplementation with BCAA
was associated with higher serum er y thropoietin levels in non-hepatitis patients undergoing curative
hepatic resection (22). It is hypothesized that higher erythropoietin levels might be beneficial in
protecting liver cells from ischemic injury. Recent randomized study in patients undergoing radiotherapy
for hepatocellular carcinoma reported that BCAA supplementation might be beneficial (23). Currently
there is reasonable evidence to support the use of BCAA supplementation in patients undergoing liver
resection particularly in patients with chronic liver disease.
Carefully devised nutritional plan based on patients overall clinical condition and degree of malnutrition
is essential. Adequate perioperative nutritional support and institution of early enteral nutrition are
crucial. Specialized nutrients such as BCAA might be beneficial in select subset of patients.
Glycemic control
Hyperglycemia induced by surgical stress causes dysregulation of liver metabolism and immune
function, resulting in adverse postoperative outcomes (24,25). Strict control of blood glucose by
intensive insulin therapy in surgical patients admitted to intensive care unit has been shown to reduce
morbidity and mortality (26). Insulin resistance after liver resection can make adequate blood glucose
control challenging. Interventions to achieve tight blood glucose control without increasing the
incidence of severe hypoglycemia are being evaluated by several investigators. Okabayashi et al.
examined the use of continuous blood glucose monitoring with closed loop insulin administration
system, a type of artificial pancreas (STG-22, Nikkiso, Tokyo, Japan) in patients undergoing hepatic
resection. Although the closed looped insulin administration system was reported to be safe and
effective, the mean blood glucose level remained above the target range of 90-110 mg/dl (27). Fisette et
al. evaluated the use hyperinsulinemic-normoglycemic clamp technique with 24-h preoperative
carbohydrate load (intervention) or standard glucose control through insulin sliding scale treatment
(control) in patients undergoing hepatic resection. The hyperinsulinemic-normoglycemic clamp
technique reduced post-operative liver dysfunction, infections, and complications when compared to
insulin sliding scale (28). Many different strategies have been proposed to achieve tight glucose control
in hepatic resection patients. Adoption of a particular glycemic control technique requires an institution
wide, standardized, multi-team approach to achieve optimal results.
Coagulopathy
Derangements in conventional markers of coagulation such as PT/INR, PTT and platelet count are
common post hepatectomy and correlates with the extent of resection. Multiple studies have noted a
postoperative increase in INR between postoperative day one and five and a corresponding decrease in
platelet count and fibrinogen (29-32). This is thought to be due to decreased synthetic function of the
remnant liver as well as hemodilution and consumption of clotting factors. Postoperative coagulopathy
peaks 2-5 days post surgery.
Prolongation of PT/INR is often self-limited and usually resolves without the need for transfusion of
fresh frozen plasma (FFP) in non-cirrhotics. Prophylactic administration of fresh frozen plasma to avoid
postoperative bleeding has been reported by several centers. Martin et al. from Memorial Sloan
Kettering cancer center reported their experience with prophylactic FFP transfusions for prothrombin
time >16 seconds in patients undergoing major liver resection for colorectal liver metastases. In this
study of 260 patients, 83 patients (32%) received FFP. One patient (0.4%) needed reoperation for
postoperative bleeding. There were no major transfusion related complications (33). Although the
incidence of postoperative bleeding is extremely low in this study, it is unclear if this is due to the
aggressive prophylactic use of FFP or better surgical technique. Other centers have reported
prophylactic use of FFP for INR above 2.0. Currently, there is no consensus regarding the criteria for
prophylactic FFP transfusion after hepatic resection. Cirrhotics are at increased risk of bleeding after
resection. A combination of FFP transfusions, vitamin K, octreotide and human r FVIIa may be utilized to
correct coagulopathy and prevent bleeding.
Pain management
Optimal postoperative pain control is necessary for early mobilization and improved respiratory
function. Postoperative pain management begins with preoperative planning and formulating a pain
management plan that is tailored to an individual patients liver function, respiratory and coagulation
status, comorbidities, and extent of resection. Opioids are the mainstay of postoperative pain control.
The most common opioids used are morphine, hydromorphone, and fentanyl. Side effects of opioid
administration include sedation, respiratory depression, nausea, vomiting, constipation, hypotension
and exacerbation of hepatic encephalopathy. Cirrhotic patients have increased bioavailability of opioids
and benzodiazepines due to decreased drug metabolism in the liver resulting in drug accumulation. The
size of liver resection has been correlated to the impairment of opioid metabolism, larger volume
resections result in greater impairment of opioid metabolism (34). Morphine is poorly excreted in the
setting of renal failure. Hydromorphone and fentanyl elimination is less affected by renal impairment
(35) and serve as better alternatives in cirrhotic patients with renal dysfunction. Although opioids are
frequently used in patients undergoing hepatic resection, the importance of close monitoring for drug
overdose and side effects cannot be overstressed.
Epidural anesthesia is an effective pain management option and adjunct to intravenous opioids for large
abdominal operations. It helps to reduce the pulmonary complications, duration of ileus and provides
better pain control than opioids alone (36,37). Risks associated with epidural catheter placement include
epidural hematoma, epidural abscess, and spinal cord injury. These risks are increased post
hepatectomy due to alterations in coagulation profile. Postoperative coagulopathy is at its peak 2-5 days
post surgery. This time frame coincides with the recommended time of removal for epidural catheters
and may necessitate transfusion of fresh frozen plasma and/ or platelets (32,38-40). Due to these risks,
the role of single dose epidural shots has been examined. Ko et al. reported that the combination of
single intrathecal injection of morphine combined with postoperative patient controlled analgesia (PCA)
resulted in improved pain control in the early postoperative period than PCA alone (41). Epidural
catheter use in hepatic resection has also been associated with greater transfusion requirement (see
Page and Kooby, this issue).
There are other drugs that may be useful as adjuncts to opioid administration. Intravenous
acetaminophen has recently become available in the United States. The recommended maximal dose is
2g/day in patients with hepatic impairment (35). NSAID use is generally not recommended post
hepatectomy, in cirrhotic patients, or in patients with renal insufficiency due to the risks of bleeding and
hepatorenal syndrome (35,42). Other non-opioid analgesics such as nefopam is widely used in European
countries but is not currently FDA (Food and Drug Administration) approved for routine use in United
States.
The use of local anesthetic infusions via the On-Q Pain Buster system placed in the musculofascial layer
of the subcostal wound combined with PCA decreased total morphine consumption and improved pain
at rest and after spirometry when compared to PCA alone in patients who underwent open hepatic
resection (43). An infusion of no more than 0.25% ropivacaine or duration of infusion of less than 2 days
is recommended due to increased plasma levels post hepatectomy. There are also case reports of the
use of paravertebral infusion of local anesthetic with PCA. However comparative studies are needed
prior to routine use of this technique (44).
There are many options available for post hepatectomy pain control. A multimodal approach specifically
chosen for an individual patient is recommended and may consist of intravenous opioids, non-opioid
injectables, continuous or single dose epidural anesthesia, and local anesthetic infusions with the
transition to oral opioids as tolerated.
Postoperative infection
Infection after hepatic resection is a major contributor of postoperative morbidity and mortality and
might be predictive of long-term outcomes (45). Risk factors predictive of postoperative infectious
complications are obesity, preoperative biliary drainage, extent of hepatic resection, operative blood
loss, comorbid conditions and postoperative bile leak (46-49). Shorter operating times and meticulous
surgical technique to decrease operative blood loss and postoperative bile leak may help reduce the
incidence of both the infectious and non-infectious complication after liver resection. Standard
measures to reduce the incidence of postoperative infectious complications such as early mobilization,
proper care and removal of central venous catheters and aggressive pulmonary toilet should be routine
in the postoperative period. Early recognition of postoperative infection, prompt institution of broad-
spectrum antibiotics and aggressive source control is of utmost importance. A recent study by Garwood
et al found that delay in antibiotic therapy was associated with increased infectious mortality (49).
Among the interventions investigated to reduce the postoperative infections, synbiotic treatment has
recently emerged as a promising approach. The concept of gutmediated SIRS and end organ injury after
major traumatic insult is now well established. Studies in patients undergoing liver resection have shown
that disruption of gut barrier function and intestinal microbial balance can result in systemic
inflammation and lead to infectious complications (50,51). Strategies such as early enteral nutrition are
aimed to protect the gut-barrier function and reduce infectious complication. Synbiotic treatment helps
improve intestinal microbial balance and reduce postoperative infectious complications. Pro-biotics are
viable bacteria that benefit the host by improving the intestinal microbial balance and are studied for
their effects on gut flora and impact on the immune system. Prebiotics are a group of non-digestive food
constituents that selectively alter the growth and activity of colonic flora. Combination of pro- and
prebiotics is termed the synbiotic therapy. Usami et al. examined the role of perioperative synbiotic
treatment in patients undergoing hepatic resection. In this study, patients were randomized to receive
either oral synbiotics or no synbiotics during the perioperative period. Perioperative synbiotic treatment
attenuated the decrease in intestinal integrity as evidenced by decreased serum diamine oxidase levels
(DAO) and reduced the rate of infectious complications (0% vs. 17.2% in the control group) (52).
Sugawara et al reported similar results from a study comparing perioperative synbiotics therapy with
postoperative synbiotic therapy. Overall infectious complication rate was 12.1% in the perioperative
synbiotic group vs. 30% in the control group (53). Administration of synbiotics is simple and safe and can
be utilized in patients undergoing major hepatic resection.
Thromboprophylaxis
The prevalence of postoperative venous thromboembolism (VTE), including deep venous thrombosis
(DVT) and pulmonary embolus (PE), in general surgery patients is 15-40% and is associated with
significant morbidity, mortality, and increased length of hospital stay (54). Early mobilization,
intermittent pneumatic compression devices and pharmacologic agents are used to prevent VTE. While
pharmacologic thromboprophylaxis is widely accepted for most general surgery procedures, the fear of
bleeding after major hepatectomy has limited its use (55). On the contrary, it is now evident that partial
hepatectomy patients are in fact hypercoagulable. This hypercoagulability is a result of many factors
including tissue trauma, decreased synthesis of factors involved in the clotting cascade by the remnant
liver, blood loss, hemodilution, increased acute phase response, malignant diagnosis, prior
chemotherapy, increased age, long anesthetic times, and limited postoperative mobility (26,54,55).
The reduced volume of liver not only results in reduced synthesis of procoagulants but the levels of
anticoagulants: protein C, S and antithrombin decrease by more than 50%. Von Willebrand factor and
factor VIII levels are increased especially in larger resections likely due to surgical trauma. Prothombotic
markers sP-Selectin and thrombin-antithrombin complexes are also significantly increased post
hepatectomy. Decreased anticoagulant levels combined with increased von Willebrand factor and factor
VIII produce a prothrombotic milieu that persists on postoperative day 5 when most INR values have
normalized (30). Thromboelastogram monitoring also demonstrates a state of postoperative
hypercoagulability after living donor hepatectomy (31). VTE may occur in the presence of elevated
standard measures of anticoagulation such as INR and PTT (56,57). A higher incidence of VTE has been
noted in patients not receiving thromboprophylaxis the night of surgery (29). In a retrospective review
of 415 patients undergoing major hepatectomy administration of pharmacologic thromboprophylaxis
lowered the rate of VTE but did not increase the rate of red blood cell transfusion post hepatectomy
(55). Pharmacologic thromboprophylaxis should be administered starting the day of surgery unless high
risk of bleeding exists.
Conclusion
Postoperative management after hepatic resection is challenging. Complex resections are being
increasingly performed in high risk and older patient population. A well-devised, customized
management approach based on patients overall condition, liver function, and nutritional status is vital
to reduce postoperative complications and to achieve optimal outcomes.
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Cite this article as: Wrighton LJ, O'Bosky KR, Namm JP, Senthil M. Postoperative management after
hepatic resection. J Gastrointest Oncol 2012;3:41-47. DOI: 10.3978/j.issn.2078-

6891.2012.003
Posthepatectomy liver failure: A definition and grading by the International Study Group of Liver Surgery
(ISGLS) Original Research Article

Surgery, Volume 149, Issue 5, May 2011, Pages 713-724
Nuh N. Rahbari, O. James Garden, Robert Padbury, Mark Brooke-Smith, Michael Crawford, Rene Adam,
Moritz Koch, Masatoshi Makuuchi, Ronald P. Dematteo, Christopher Christophi, Simon Banting, Val
Usatoff, Masato Nagino, Guy Maddern, Thomas J. Hugh, Jean-Nicolas Vauthey, Paul Greig, Myrddin
Rees, Yukihiro Yokoyama, Sheung Tat Fan, Yuji Nimura, Joan Figueras, Lorenzo Capussotti, Markus W.
Bchler, Jrgen Weitz View Abstract
Background

Posthepatectomy liver failure is a feared complication after hepatic resection and a major cause of
perioperative mortality. There is currently no standardized definition of posthepatectomy liver failure
that allows valid comparison of results from different studies and institutions. The aim of the current
article was to propose a definition and grading of severity of posthepatectomy liver failure.
Methods

A literature search on posthepatectomy liver failure after hepatic resection was conducted. Based on
the normal course of biochemical liver function tests after hepatic resection, a simple and easily
applicable definition of posthepatectomy liver failure was developed by the International Study Group
of Liver Surgery. Furthermore, a grading of severity is proposed based on the impact on patients' clinical
management.
Results

No uniform definition of posthepatectomy liver failure has been established in the literature addressing
hepatic surgery. Considering the normal postoperative course of serum bilirubin concentration and
International Normalized Ratio, we propose defining posthepatectomy liver failure as the impaired
ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized
by an increased international normalized ratio and concomitant hyperbilirubinemia (according to the
normal limits of the local laboratory) on or after postoperative day 5. The severity of posthepatectomy
liver failure should be graded based on its impact on clinical management. Grade A posthepatectomy
liver failure requires no change of the patient's clinical management. The clinical management of
patients with grade B posthepatectomy liver failure deviates from the regular course but does not
require invasive therapy. The need for invasive treatment defines grade C posthepatectomy liver failure.
Conclusion

The current definition of posthepatectomy liver failure is simple and easily applicable in clinical routine.
This definition can be used in future studies to allow objective and accurate comparisons of operative
interventions in the field of hepatic surgery.

Figures and tables from this article:

Table I. Applied definitions of posthepatectomy liver failure in studies on hepatic resection
View Within Article

Table II. Consensus definition and severity grading of posthepatectomy liver failure (PHLF) by the
International Study Group of Liver Surgery (ISGLS)
View Within Article

Table III. Criteria for grading of PHLF

BUN, Blood urea nitrogen; ICP, intracranial pressure.
View Within ArticlePostoperative course and clinical significance of biochemical blood tests following
hepatic resection

C. Reissfelder,
N. N. Rahbari,
M. Koch,
B. Kofler,
N. Sutedja,
H. Elbers,
M. W. Bchler,
J. Weitz*

Article first published online: 1 APR 2011

DOI: 10.1002/bjs.7459

Copyright 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Issue
British Journal of Surgery
British Journal of Surgery

Volume 98, Issue 6, pages 836844, June 2011

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Abstract
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References
Supporting Information
Cited By

View Full Article with Supporting Information (HTML) Get PDF (149K)
Abstract

Background:

Hepatic resection continues to be associated with substantial morbidity. Although biochemical tests are
important for the early diagnosis of complications, there is limited information on their postoperative
changes in relation to outcome in patients with surgery-related morbidity.
Methods:

A total of 835 consecutive patients underwent hepatic resection between January 2002 and January
2008. Biochemical blood tests were assessed before, and 1, 3, 5 and 7 days after surgery. Analyses were
stratified according to the extent of resection (3 or fewer versus more than 3 segments).
Results:

A total of 451 patients (540 per cent) underwent resection of three or fewer anatomical segments;
resection of more than three segments was performed in 384 (460 per cent). Surgery-related morbidity
was documented in 258 patients (309 per cent) and occurred more frequently in patients who had a
major resection (P = 0001). Serum bilirubin and international normalized ratio as measures of serial
hepatic function differed significantly depending on the extent of resection. Furthermore, they were
significantly affected in patients with complications, irrespective of the extent of resection. The extent of
resection had, however, little impact on renal function and haemoglobin levels. Surgery-related
morbidity caused an increase in C-reactive protein levels only after a minor resection.
Conclusion:

Biochemical data may help to recognize surgery-related complications early during the postoperative
course, and serve as the basis for the definition of complications after hepatic resection. Copyright
2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
View Full Article with Supporting Information (HTML) Get PDF (149K)


Estimation of remnant liver function before hepatectomy by means of technetium-99m-
diethylenetriamine-pentaacetic acid galactosyl human albumin.
Yumoto Y, Umeda M, Ohshima K, Ogawa H, Kurokawa T, Kajitani M, Yumoto E, Hanafusa T, Tsuboi H,
Higashi T, et al.
Source

Radioisotope Center, Okayama University, Japan.
Abstract

To improve the results of hepatectomy in cirrhotic patients, the likely reserve function of the liver was
evaluated before surgery. Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific
for galactose-terminated glycoproteins. Technetium-99m-diethylene triamine pentaacetic acid-
galactosyl human serum albumin (99mTc-GSA) is a newly developed analog ligand to ASPG-R. The
probable functional reserve of the remnant liver after hepatectomy was estimated preoperatively as the
hepatic binding protein (HBP) concentration specific for ASGP-R on the hepatocellular membrane of the
remnant liver. This estimate was based on the effective liver volume rate, obtained by the uptake of
99mTc-GSA. In all, 3 normal volunteers, 3 patients with chronic hepatitis (CH), 9 patients with liver
cirrhosis (LC), 2 patients with hepatic cystadenoma, 3 patients with hepatocellular carcinoma (HCC)
associated with CH, and 21 HCC patients with LC were studied. The mean value +/- SD obtained for HBP
in normal volunteers (three cases) and in patients with mild (four cases), moderate (two cases), and
severe liver damage (five cases) were 0.74 +/- 0.03 microM, 0.43 +/- 0.042 microM, 0.31 +/- 0.05
microM, and 0.20 +/- 0.05 microM, respectively. Most of the cases in which the preoperative HBP of the
remnant liver was above 0.22 microM had a good postoperative course irrespective of the type of
hepatectomy. On the other hand, in subjects with a remnant liver HBP of between 0.22 and 0.11
microM, postoperative severe liver dysfunction occurred in about 50% of cases. In all cases with a
remnant liver HBP below 0.1 microM, the prognosis was very poor, indicating that hepatectomy should
be avoided. The HBP concentration detected by the 99mTc-GSA study is a very sensitive indicator of
changes in the hepatic functional reserve, and the HBP value for the functional reserve of the remnant
liver is extremely useful for estimating the liver function before and after hepatectomy.

PMID:
8137465
[PubMed - indexed for MEDLINE]




Virtual Liver Resection and Volumetric Analysis of the Future Liver Remnant using Open Source Image
Processing Software
Joost R. van der Vorst,1 Ronald M. van Dam,corresponding author1 Rogier S. A. van Stiphout,2 Maartje
A. van den Broek,1 Ilona H. Hollander,1 Alfons G. H. Kessels,3 and Cornelis H. C. Dejong1,4
Author information Copyright and License information
This article has been cited by other articles in PMC.
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Abstract
Background

After extended liver resection, a remnant liver that is too small can lead to postresection liver failure. To
reduce this risk, preoperative evaluation of the future liver remnant volume (FLRV) is critical. The open-
source OsiriX PAC software system can be downloaded for free and used by nonradiologists to
calculate liver volume using a stand-alone Apple computer. The purpose of this study was to assess the
accuracy of OsiriX CT volumetry for predicting liver resection volume and FLVR in patients undergoing
partial hepatectomy.
Methods

Preoperative contrast-enhanced liver CT scans of patients who underwent partial hepatectomy were
analyzed by three observers. Two surgical trainees measured the total liver volume, resection volume,
and tumor volume using OsiriX, and a radiologist measured these volumes using CT scanner-linked
Aquarius iNtuition software. Resection volume was correlated with prospectively determined resection
weight, and differences in the measured liver volumes were analyzed. Interobserver variability was
assessed using BlandAltman plots.
Results

25 patients (M/F ratio: 13/12) with a median age of 61 (range, 3477) years were included. There were
significant correlations between the weight and volume of the resected specimens (Pearsons
correlation coefficient: R2 = 0.95). There were no major differences in total liver volumes, resection
volumes, or tumor volumes for observers 1, 2, and 3. BlandAltman plots showed a small interobserver
variability. The mean time to complete liver volumetry for one patient using OsiriX was 19 3 min.
Conclusions

OsiriX liver volumetry performed by surgeons is an accurate and time-efficient method for predicting
resection volume and FLRV.

Currently the focus of liver resection criteria is principally the limited functional reserve of liver tissue
that remains after resection. Extended resection, staged resection, preoperative portal vein
embolization to increase future remnant liver volume, and resection combined with tumor ablation is
becoming standard in specialized liver units worldwide. More preoperative chemotherapy is being used
in parallel with these aggressive strategies; as a consequence, more complicated and extended
resections are being performed with reduced residual parenchymal function and smaller remnant livers
[1].

Schindl et al. reported that partial liver resection can only be performed safely if the remnant liver
volume is more than 26.6% of the total functional liver volume in patients with normal liver parenchyma
[2]. The safe margin increases to 40% in patients with high-grade steatosis and after oxaliplatin- or
irinotecan-based neoadjuvant chemotherapy, and the safe margins are >50% of the total liver volume
for cirrhotic livers [2, 3].

Both a small postoperative remnant liver size and an inappropriately functioning liver parenchyma
increase the risk of postresectional liver failure (PLF) [2, 4, 5]. Preoperative assessment of future
remnant liver volume and liver function is imperative to reduce this risk. Although accurate prediction of
postresectional liver function remains difficult, there are a variety of tests used to asses this [610]. For
example, the 15-minute indocyanine green retention test (ICG R15) measures the clearance capacity of
the liver and is probably the most commonly used test in patients who undergo liver resection. To
determine the maximum possible extent for safe liver resection, Makuuchi et al. and Clavien et al.
proposed the use of decision trees that incorporate the ICG R15 [11, 12]. More recently, the 13C-
methacetin LiMAx breath test has been proposed for assessing hepatic functional capacity [13].

A number of studies have validated tools to determine liver volume, with a particular focus on the
volume of the future remnant liver. Computed tomography (CT) or magnetic resonance imaging (MRI)
volumetry can be used to accurately predict total liver volume and future remnant liver volume [1416].
Usually specialized hepatic radiologists perform the volumetric assessments using commercial software
linked to radiological hardware. However, hepatic volumetry also can be performed accurately by a
nonradiologist on a personal computer using open source ImageJ provided by the National Institutes of
Health [15]. Recently, a more user-friendly, freely downloadable open source image analysis software
package, OsiriX, has become available. This software for Apple Mac OS has not yet been validated for
liver CT volumetry. The purpose of this study was to assess the accuracy of OsiriX in performing liver CT
volumetry by surgeons using personal computers and to compare the results to liver CT volumetry
performed by a radiologist using classical radiological software (iNtuition) linked to a CT-scanner
system.
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Patients and methods

A database of patients undergoing liver resection in Maastricht University Medical Centre (Maastricht,
The Netherlands) was created in 2000. Data of all patients were collected prospectively from 2000
onwards. From this database, all patients who underwent resection of two or more liver segments for
primary or secondary liver tumors were selected if the resection specimen weight had been obtained in
the operating room directly after resection (n = 110). From this group, the 25 most recently treated
patients were selected and included for volumetric analysis. All resection specimens were
postoperatively assessed by an experienced pathologist.
CT volumetry

Portal venous phase series of images from the preoperative contrast-enhanced CT scans were used for
CT volumetry. Two observers (JV and IH, both house officers; observers 1 and 2, respectively) performed
liver volumetry for all 25 patients on an iMac using OsiriX. Both observers were medical students in
their final year of medical school who were trained in liver anatomy and the use of OsiriX by one of the
liver surgeons (RD). A specialized liver radiologist (RS: observer 3) performed liver volumetry on exactly
the same scans using iNtuition (TeraRecon, Houston, TX). iNtuition is the standard commercially
available image analysis software package used in our liver unit. Total liver volume, resection volume,
and tumor volume were determined using OsiriX (observers 1 and 2) or iNtuition (observer 3).
Observers were blinded to the prospectively collected resection weights and to each others results. On
all slices, the gall bladder and the inferior caval vein were excluded in the regions of interest, and the
intrahepatic vascular and biliary structures were included. For patients who underwent a
hemihepatectomy, the transection line of the virtual liver resection followed Cantlies line from the top
of the gallbladder, paralleling the middle hepatic vein straight to the suprahepatic inferior caval vein.
The middle hepatic vein was excluded from the virtual resection. Extended or extra-anatomic resections
were guided by the operation notes. The total time required to perform liver volumetry was measured
for all three observers.
Calculation of liver volume with OsiriX

Downloading OsiriX

The 32-bit OsiriX version 3.3 was downloaded from: http://www.osirix-viewer.com under the
dropdown menu downloads. A 2.8-Ghz Intel Core 2 Duo 24 iMac (Apple Inc., Cupertino, CA, USA) was
used.

Loading a series of images into OsiriX

After inserting a CD-ROM or DVD containing CT scan data (including a commercial viewer), the Digital
Imaging and Communications in Medicine (DICOM) data were automatically extracted from the disc by
OsiriX and imported into the OsiriX viewer (Fig. 1a).
Fig. 1
Fig. 1
a Picture archiving and communication system integrated in Osirix Software package. b Outlining liver
tissue. c 3D liver image

Storing DICOM data in the OsiriX picture archiving and communication system (PACS)

DICOM data were stored in the OsiriX PACS using the Copy linked files to Database folder under file
in the OsiriX dropdown menu.

Contouring the liver and generating regions of interest

Volumetry was performed on sets of axial images in the portal venous phase using a slice thickness of 3
5 mm. As a consequence of using CD-ROM containing DICOM CT scan data of referring centers, the slice
thickness varied. Three kinds of volumetric assessments were performed prospectively in this study:
total liver volume, resection volume, and tumor volume. The outline of the future resection specimen
was traced manually on each slice with the closed polygon selection tool under the ROI tool button
using a pen tablet system (Intuos 3, Wacom Co ltd., Saitama, Japan). The Grow Region (2D/3D
Segmentation) tool in the ROI dropdown menu made it possible to automatically outline the total
liver and the metastases. This modality of OsiriX is based on the differences in Hounsfield units
between the liver parenchyma, bony structures, and body fat. The automatic outlines are hand-adjusted
with the closed polygon selection tool and repulsor tool to optimize the ROI (Fig. 1b).

Calculating actual liver volumes

After selecting all of the regions of interest within one series, OsiriX automatically calculated the
volume by multiplying surface and slice thickness and then adding up individual slice volumes. OsiriX
also provided 3D images using the ROI volume tool (Fig. 1c).
Statistical analysis

Actual resection weights obtained in the operating room were taken as the reference standard for CT
volumetric resection measurements for both modalities. The volumes measured by the specialized
radiologist using iNtuition were assumed to be the reference standard to validate OsiriX. Total liver
volume, resection volume, and tumor volume were reported. The percentage of functional remnant
liver volume (compared with the total functional volume) was calculated (FRLV%). Unless otherwise
stated, data are presented as the mean volume standard deviation. Pearsons correlation coefficient
R2 was used to test correlations between resection specimen weight and measured CT volumes using
OsiriX. The mean differences between observers 1, 2, and 3 were tested with one-way ANOVA and
paired t tests corrected using the Bonferroni correction. Interobserver agreement was assessed with
BlandAltman plots. For total volume, resection volume, tumor volume, and FRLV%, the average was
plotted against the difference and 95% limits of agreement were provided. P values <0.05 were
considered significant. Statistical analysis was performed using GraphPad Prism software (version 5.01;
California, USA).

BlandAltman plots were used to assess intraobserver variability between OsiriX and iNtuition
(observers 1 and 3) and between two observers using OsiriX (observers 1 and 2). For total volume,
resection volume, tumor volume, and functional remnant liver volume percentages, the average was
plotted against the difference and 95% limits of agreement were provided.
Go to:
Results
Patients

Twenty-five patients who underwent liver resection for colorectal cancer liver metastases were included
in this study (Table 1). Five of 25 patients (20%) were treated preoperatively with chemotherapy.
Microscopic examination of the resection specimens revealed minor steatohepatitis in one of the
patients. The liver parenchyma was normal in all others.
Table 1
Table 1
Patient characteristics
Specimen volume and resection specimen weight

For observers 1, 2, and 3, resection volumes assessed by OsiriX or iNtuition volumetry correlated
strongly with actual resection weights obtained in the operating room immediately after resection (R2 =
0.95, 0.94, and 0.95, respectively; Fig. 2). The resection weight-to-volume ratio measured by OsiriX was
0.85, 0.86, and 0.91 g/ml for observers 1, 2, and 3, respectively.
Fig. 2
Fig. 2
Actual resection weight measured in the operating room directly after resection is plotted against the
estimated resection volume by observers 1, 2, and 3
CT liver volumes

The FRLV% was calculated, and all volumes were plotted for each observer (Fig. 3). For the mean total
liver volume, no significant differences were found between observer 1 (1740 ml 471.6), observer 2
(1722 ml 466.3), and observer 3 (1683 ml 460.8). For the mean resection volume, no significant
differences were found between observer 1 (956 ml 462.7), observer 2 (965 ml 474.2), and observer
3 (918 ml 461.9). There also were no significant differences found for the mean tumor volume
measured by observer 1 (84.58 ml 208.5), observer 2 (79.03 ml 182.7), and observer 3 (86.31 ml
215.3). Finally, no significant differences were found in the mean FRLV% for observer 1 (46.27% 17.86),
observer 2 (45.4% 18.5), and observer 3 (46.78% 18.35).
Fig. 3
Fig. 3
a Mean total liver volume is plotted for observers 1, 2, and 3. Horizontal lines represent mean SD. No
significant differences were found. b Mean resection volume is plotted for observers 1, 2, and 3.
Horizontal lines represent ...
Intraobserver variability

Liver volumetry measurements were compared using BlandAltman plots, and the 95% limits of
agreement were calculated (Figs. 4 and and55).
Fig. 4
Fig. 4
a Mean total volume of observers 1 and 2 is plotted against the difference in total volume between
observers 1 and 2. b Mean resection volume of observers 1 and 2 is plotted against the difference in
resection volume between observers 1 and 2. c Mean ...
Fig. 5
Fig. 5
a Mean total volume of observers 1 and 3 is plotted against the difference in total volume between
observers 1 and 3. b Mean resection volume of observers 1 and 3 is plotted against the difference in
resection volume between observers 1 and 3. c Mean ...
Efficiency

The mean time needed to perform complete volumetry in a patient (total liver volume, resection
volume, and tumor volume) was 19 3 min when a 5-mm scan slice thickness was used.
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Discussion

Accurate preoperative risk assessment to determine whether a patient can undergo major or extended
liver resection remains the Holy Grail of liver surgery. In so far as volume equates to function,
assessment of liver volume, and particularly the volume of the liver remnant, is critical. Unfortunately,
liver volumetry is not always available, because it is usually linked to the CT scanner system and requires
an experienced radiologist. User-friendly and easily accessible instruments are needed to predict
remnant liver volume and parenchyma quality. OsiriX is an open source image analysis package and
PAC system that can be downloaded free of charge. The goal of this study was to validate OsiriX for liver
volumetry. The accuracy and efficiency of OsiriX for measuring liver volumes in patients undergoing
partial liver resection was analyzed and compared with actual resection weights and CT liver volumetry
using iNtuition software linked to the CT scanner system; the latter is currently the clinical standard at
the Maastricht University Medical Centre.

In this study, we found a strong and highly significant correlation between resection weight and
resection volume measured with OsiriX and iNtuition (Fig. 2). The mean resection weight-to-volume
ratio calculated with OsiriX was 0.85 0.11 for observer 1, 0.86 0.11 g/ml for observer 2, and 0.91
0.13 g/ml for observer 3. These ratios and the systematic overestimation of the liver volume were in
accordance with previous studies [14, 15]. A volumetric assessment of fully perfused livers compared
with the weight of a resection specimen in a nonperfused state in the operating room could explain the
systematic overestimation of liver volume. This, however, will not affect the functional remnant liver
volume as a percentage of the total functional liver volume, which Schindl et al. reported to be an
important determinant of the risk for developing postoperative liver failure [2].

To validate the OsiriX software package, volumetric assessments performed with OsiriX were
compared with those performed with iNtuition. In addition, we compared the volumes measured by
the two observers using OsiriX. One-way ANOVA and pairedt tests showed that there were no
significant differences in the mean volumes calculated with OsiriX and iNtuition or between the two
observers using OsiriX. This means that trained surgical trainees using OsiriX for liver CT volumetry
perform equally well as specialized radiologists using iNtuition.

Although there were no significant differences in the mean volumes, the results of the two software
packages at the individual patient level revealed some differences that must be noted. The differences
in measured volumes at the individual patient level can be clarified using BlandAltman plots (Figs. 4
and and5)5) and become particularly important in extended resections. In cases in which the
preoperative liver volume assessment shows that the reported functional remnant liver volume
percentage approaches 26.6%, extra care is recommended.

The measured volumes were consistently overestimated using iNtuition. In this study, we discovered
that volumes calculated by iNtuition are inexplicably altered when the window level is changed, e.g.,
from abdominal to liver. This may have resulted in differences in volumetric results between the two
packages as well as between subjects. Moreover, this casts some doubt as to whether iNtuition should
be considered the gold standard for clinical use. Terra Recon (the company that makes iNtuition) is
currently working on a solution to address this undesired phenomenon and is developing a dedicated
liver tissue template. Future research will be needed to determine whether the new template is more
accurate in assessing liver volume.

The mean time needed to analyze the total liver volume, tumor volume, and resection volume was 19
3 min at a slice thickness of 5 mm. This is slightly faster than the time reported for ImageJ, which is
another freely downloadable open source image analysis software package [15]. This can be explained
by the semiautomatic selection of the resection specimen that is possible with OsiriX. Especially in the
more caudal slices where there was a distinct difference in the Hounsfield units between liver
parenchyma and the surrounding tissues, the semiautomatic contouring appeared to be very useful,
fast, and precise. Additionally, it is possible to outline the liver on alternate individual slices. After
outlining only half of the slices, the missing regions of interest can be generated using the generate
missing ROIs tool in the ROI volume under the ROI dropdown menu. This method saves time because
only small adjustments need to be made in the automatically generated regions of interest.

With OsiriX, surgeons can perform a virtual resection to predict the future functional remnant liver
volume on their own computer. This enables optimization of preoperative planning and possibly reduces
the risk of postresection liver failure, especially in extended resections. Furthermore, OsiriX has a big
advantage in that it can be downloaded free of charge and it has an integrated PAC system in which the
data of all examined patients are automatically stored. Nowadays, volumetric assessment of the liver is
performed mainly by radiologists. At our center, the commercial image analysis software package
iNtuition is used for liver CT volumetry. This package is not readily accessible to liver surgeons and
hepatologists, which sometimes makes it difficult to use when considering different scenarios in the
planning of extended resections. OsiriX combines an image archiving system and a user-friendly image
analysis package. It allows one to store DICOM files of the CT scans of patients in a liver resection
registry and is plug-and-play after downloading the software. However, the OsiriX system has not yet
been validated for liver volumetry.

In the past we validated ImageJ, a software package developed by the National Institutes of Health,
and found a high correlation between resection volume and actual resection weight. There are some
drawbacks to ImageJ: patient DICOM files cannot be stored in a PAC system, it is not possible to
semiautomatically outline the liver, and missing regions of interest cannot be generated. Although the
ImageJ system is accurate, it is our impression that it is less sophisticated than OsiriX. A potential
obstacle for liver surgeons who want to use OsiriX is that it is only compatible with the Mac operating
system.

Although OsiriX can be used to perform liver volumetry, it does not accurately determine preoperative
liver function because volume does not always equate to function. To predict the risk of developing
postresection liver failure or infection, both function and volume are important. For patients treated
with preoperative chemotherapy or suffering from liver cirrhosis, a larger remnant liver volume is
needed to perform a safe resection. Because an accurate liver function test is not yet available, the
safety of extended resections and resections in patients pretreated with chemotherapy remains
uncertain. Nevertheless, CT volumetry of extended resections will offer additional information and
reduce the risk of developing postresection liver failure.
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Conclusions

The high correlation between resection weight and virtual resection volume, the weight-to-volume
ratios, and the acceptable low interobserver variability demonstrate that OsiriX can be used for CT
volumetry of the liver. OsiriX accurately measures total liver volume, metastases volume, and virtual
resection specimens. Using these measurements, clinicians are able to make an accurate prediction of
the functional remnant liver volume. In addition, we found OsiriX to be a very well organized and
efficient CT liver volumetry software package.
Go to:
Acknowledgments

The authors thank Johanne G. Bloemen and Simon A. W. G. Dello for acquisition of data and
administrative assistance and Marc H. A. Bemelmans and Steven W. M. Olde Damink for contributions to
conception and design of the study and technical assistance.

Disclosure All authors state no conflict of interest.

Open Access This article is distributed under the terms of the Creative Commons Attribution
Noncommercial License which permits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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Footnotes

Joost R. van der Vorst and Ronald M. van Dam contributed equally to the study and the manuscript.
These authors share first authorship.

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Contributor Information

Joost R. van der Vorst, Email: j.r.van_der_vorst@lumc.nl.

Ronald M. van Dam, Email: r.vandam@mumc.nl.
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Articles from Springer Open Choice are provided here courtesy of SpringerPreoperative






Assessment of Postoperative Remnant Liver Function Using Hepatobiliary Scintigraphy

Roelof J. Bennink, MD1,
Sander Dinant, MD2,
Deha Erdogan2,
Bob H. Heijnen, MD, PhD2,
Irene H. Straatsburg, PhD2,
Arlene K. van Vliet, PhD2 and
Thomas M. van Gulik, MD, PhD2

+ Author Affiliations

1Department of Nuclear Medicine, Academic Medical Centre Amsterdam, Amsterdam, The
Netherlands
2Department of Surgery, Academic Medical Centre Amsterdam, Amsterdam, The Netherlands


Next Section
Abstract

Hepatic resection is the therapy of choice for malignant and symptomatic benign hepatobiliary tumors.
The concept of remnant liver volume (RLV) has been introduced and can be assessed with CT. However,
inhomogeneous liver function distribution and a lack of correlation between morphologic hypertrophy
and functional recovery fuelled the enthusiasm for functional imaging. The aim of the present study was
to assess liver function reserve (LFR) and remnant liver function (RLF) before and after major liver
surgery with hepatobiliary scintigraphy (HBS) and to compare scintigraphic results with volumetric CT
data and indocyanine-green (ICG) clearance test results. Furthermore, HBS was used to assess functional
recovery of liver function, and results were compared with volumetric data. Methods: Fifteen patients
with a partial liver resection were included. HBS was performed before, 1 d after, and 3 mo after
surgery. ICG clearance and CT were performed before and 3 mo after surgery. Liver function determined
with HBS was compared with ICG and volumetric data. Results: Liver function determination using HBS
was highly reproducible. A strong positive association (r = 0.84) was found between LFR determined
with HBS and ICG clearance. Little or no association (r = 0.27) was found between CT volumetric analysis
and corresponding ICG clearance. A strong positive association (r = 0.95) was found between the RLF
determined preoperatively on HBS and the actually measured value postoperatively. A weak positive
association (r = 0.61) was found between functional liver regeneration and liver volume regeneration in
the 3 mo after partial liver resection. Conclusion: HBS offers a unique combination of functional liver
uptake and excretion with the ability to assess the preoperative LFR and to estimate the RLF
preoperatively. Determination of the RLF instead of the RLV might clarify some of the discrepancies
observed in the literature between RLV and clinical outcome in patients with an inhomogeneous liver
function. Finally, liver function regeneration can be monitored using HBS.
Keywords

hepatobiliary scintigraphy
liver function test
remnant liver function

Hepatic resection is the therapy of choice for malignant and symptomatic benign hepatobiliary tumors.
Recent improvement in the safety of liver surgery has resulted in more extended hepatic resections
(1,2). The improvement of results is largely due to better techniques and selection of patients (3).

The maximum extent of resection compatible with a safe postoperative outcome remains unknown, but
the risk for perioperative complications is generally believed to increase when the remnant liver volume
(RLV) is too small (4). Therefore, preoperative assessment of hepatic function and RLV is advocated (3).
Preoperative liver volume and RLV can accurately be estimated by CT (5,6). However, most strategies
evaluating preoperative hepatic function reserve and estimating the RLV rely on a homogeneous liver
function (7). Unlike patients undergoing liver resection for metastatic cancer or benign liver conditions,
patients with hepatocellular carcinoma or obstructing tumors such as cholangiocarcinoma may have
underlying chronic liver disease or cholestasis with primary or secondary impaired total or segmental
liver function (810).

Hepatobiliary scintigraphy (HBS) using 99mTc-labeled iminodiacetic acid (IDA) analogues has been
proposed as a liver function test (11). Liver uptake function can be measured by first-pass hepatocyte
extraction fraction or the IDA liver uptake rate (12,13). The rate of preoperative 99mTc-mebrofenin liver
uptake correlates well with the indocyanine-green (ICG) clearance test in patients scheduled for major
liver surgery (14). Because IDA scintigraphy is commonly used for the evaluation of hepatobiliary
function (15), HBS might be interesting for evaluation of both total and regional hepatocyte uptake
function as well as excretory kinetics for risk assessment before major liver surgery.

Therefore, the aim of this study was to validate total and regional HBS as a tool to measure total and
regional liver function before and after major liver surgery and to compare scintigraphic results with
volumetric data and ICG clearance test results. Furthermore, the correlation between the immediate
postoperative remnant liver function (RLF) predicted on preoperative scintigraphy and the RLF
scintigraphically measured 24 h after surgery was assessed. Finally, the relationship between liver
function regeneration determined with HBS and volumetric analysis was assessed.
Previous SectionNext Section
MATERIALS AND METHODS
Patients

During a period of 2 y, 55 patients for whom partial liver resection for hepatobiliary tumors was being
considered presented at our medical center and were asked to participate in a trial assessing the
metabolic effects of major liver resection. Eight patients refused to participate. In 6 patients, concurrent
volumetric data were not available. Sixteen patients had an unresectable tumor. Three patients had a
severe peroperative complication (blood loss > 2 L), excluding them from further participation in the
primary trial. Seven patients had severe perioperative complications (sepsis, n = 4; abdominal bleeding,
n = 1; or lethal hepatic insufficiency, n = 2). We included 15 consecutive patients (7 men, 8 women;
mean age, 60.8 y; range, 3777 y) with a perioperative uncomplicated partial liver resection. No patients
had biliary obstruction at the time of inclusion. Six patients were treated for cholangiocarcinoma, 7
patients had a solitary metastasis of a colon carcinoma, and 2 patients had a hepatocellular carcinoma
without liver cirrhosis. Five patients had a right hemihepatectomy, 4 patients had an extended right
hemihepatectomy, 3 patients had a left hemihepatectomy, and 3 patients had only 1 or 2 liver segments
removed. All patients underwent an ICG clearance test 1 d before and 3 mo after surgery. Immediate
postoperative ICG clearance was not measured. All patients underwent hepatic CT volumetric analysis
and HBS performed a maximum of 2 wk before and 3 mo after surgery. All patients underwent HBS 24 h
after surgery. The volume of the resected liver was measured by immersing the specimen in water. The
postoperative liver volume was calculated by subtracting the volume of the resected specimen from the
preoperatively measured CT liver volume. The study was approved by the Medical Ethics Committee of
the Academic Medical Center of the University of Amsterdam. Each patient gave written informed
consent before participating in the study.
ICG Clearance Test

On every occasion, bilateral intravenous lines were placed in the antecubital veins. After the patient had
fasted overnight, 25 mg of ICG (Infracyanine; Laboratoires Pharmaceutiques) were dissolved in 10 mL of
5% dextrose solution and injected rapidly into the antecubital vein. The clearance tests were performed
after overnight fasting because food consumption stimulates hepatic function and bile flow. Blood
samples were drawn contralateral to the side of injection before administration of ICG (blank) and at 5,
10, 15, and 20 min after ICG injection. Plasma samples were read against the plasma blank at 805 nm by
photospectrometry to determine the concentration of ICG. The theoretic maximum concentration at
zero minutes was estimated using the least-squares method (16). Results were expressed as the
percentage ICG cleared at 15 min.
CT Volumetric Analysis

CT volumetric analysis was performed as described by Vauthey et al. (6). Patients underwent diagnostic
CT of the abdomen with and without intravenous contrast medium before and 3 mo after surgery. All CT
examinations were performed with a helical scanner (Philips). CT of the abdomen was performed to
include the whole liver in a single breath-hold, using 5-mm collimation. Liver volumes were calculated by
integrated software techniques that use density threshold seeding. With this technique, the level of
density desired for inclusion in the dataset was selected. Regions that were of the selected density but
should not be included in the datasetsuch as inferior vena cava, gallbladder, and abdominal and chest
wall muscleswere excluded. Liver volumes were calculated before and 3 mo after surgery. Liver
volume recovery was calculated by subtraction of the liver volume measured immediately after surgery
from the liver volume measured after 3 mo. CT volumetric analysis was compared with ICG clearance, as
the gold standard, before and 3 mo after surgery. Finally, the relationship between liver function
regeneration determined with HBS and volumetric analysis was assessed.
Scintigraphic Test

Patients underwent HBS using the radiopharmaceutical agent 99mTc-labeled mebrofenin. After
intravenous administration of 85 MBq of 99mTc-mebrofenin, a dynamic image acquisition was
performed with a -camera (Diacam; Siemens) with the liver and heart in the field of view, using a 128
128 matrix. Dynamic acquisition was performed in 1 h at 10 s per frame for 60 frames (liver uptake
sequence), followed by 50 frames of 1 min each (bile excretion sequence). The liver uptake rate was
calculated as described by Ekman et al. (13). Regions of interest (ROIs) were drawn around the liver,
heart, and large vessels within the mediastinum (serving as blood pool) and around the total
hepatocellular carcinoma (indicative of total activity). The liver ROI was drawn automatically on a
threshold-based algorithm using 20% of the maximum liver value on a summed image of the first 10 min
of the acquisition as the cutoff. Three different timeactivity curves based on the liver, blood pool, and
total hepatocellular carcinoma were generated. Liver uptake based on these 3 parameters was
calculated in %/min. Furthermore, an ROI could be drawn around parts of the liver to calculate regional
differences in 99mTc-mebrofenin uptake. Hepatic 99mTc-mebrofenin uptake was calculated using
scanned radioactivity values acquired between 150 and 350 s after injection, to ensure that the
calculations were made during a phase of homogeneous distribution of the agent in the blood pool and
before the rapid phase of hepatic excretion (13).

All studies were processed twice by the same operator to assess the reproducibility of the hepatic
uptake calculations. Scintigraphic liver uptake was correlated with ICG clearance, as the gold standard,
before and 3 mo after surgery.

Regional liver function was calculated in retrospect, after completion of the trial. The regional uptake of
the future remnant liver on the preoperative HBS was calculated by manual division of the global liver
ROI into 2 parts. The surgeon who performed the hemihepatectomy guided the drawing of the remnant
liver ROI. In this remnant liver ROI, the estimated RLF was calculated. Furthermore, the remnant liver
ROI of the immediate postoperative HBS was copied on the preoperative HBS dataset to recalculate the
RLF. Subsequently, the preoperative estimated RLF was compared with the actually measured
immediate postoperative RLF. Functional hepatic recovery was calculated by subtraction of the
scintigraphic liver function measured immediately after surgery from the liver function measured after 3
mo. Three months after surgery, functional scintigraphic liver regeneration was compared with CT
volumetric regeneration.
Statistical Analysis

A commercial computer package (SPSS Inc.) was used to analyze the data. The relationship between ICG
clearance, liver uptake of 99mTc-mebrofenin, and CT volumetric analysis was tested using the standard
Pearson correlation coefficient. All results are expressed as mean SEM. All statistical tests were 2-
tailed, and differences were evaluated at the 5% level of significance.
Previous SectionNext Section
RESULTS

Patient volumetric and functional data are summarized in Table 1. A total of 45 HBS examinations were
performed on 15 patients (Fig. 1). For every scintigraphic examination, the hepatic uptake rate of
99mTc-mebrofenin was calculated twice, once on the day the scintigraphy was performed and once in a
batch after completion of the trial by the same operator. An excellent correlation (r = 0.99; R2 = 0.98; P
< 0.001) was found between the 2 calculations (Fig. 2A). BlandAltman statistics are shown in Figure 3A.
For 27 HBS examinations (preoperative and 3 mo after surgery), a corresponding ICG clearance test was
performed. A strong positive association (r = 0.84; R2 = 0.71; P < 0.001) was found between the liver
function reserve (LFR) determined with HBS and ICG clearance (Fig. 2B).
FIGURE 1.
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FIGURE 1.

Preoperative HBS in patient 13, with a proximal cholangiocarcinoma. (A) Reframed images of the
dynamic acquisition. Homogeneous liver uptake with moderate cholestasis is seen in the left side,
without functional repercussion. (B) A summed image from 150 to 350 s after intravenous injection of
80 MBq of 99mTc-mebrofenin, with an ROI drawn semiautomatically (threshold, 20%) around the entire
liver and a second ROI drawn in the mediastinum (blood pool). (C) A blood-poolcorrected liver-uptake
timeactivity curve. Liver uptake (d) is calculated as the increase in specific (corrected for blood pool)
99mTc-mebrofenin uptake (y-axis) per minute over a period of 200 s (x-axis).
FIGURE 2.
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FIGURE 2.

Scatter plots with linear regression line of HBS liver function calculation reproducibility (A), HBS and ICG
clearance LFR assessment (B), HBS preoperative and postoperative (postop.) RLF measurement (C), and
liver volume and function recovery (D).
FIGURE 3.
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FIGURE 3.

BlandAltman plots of hepatic 99mTc-mebrofenin uptake, expressed as percentage uptake per minute.
(A) A plot of the mean of the repeated liver uptake function calculation on HBS in 45 studies (horizontal
axis) vs. the differences in the repeated calculations (vertical axis). (B) A plot of the mean of FLR
determination on HBS before and after surgery in 15 studies (horizontal axis) vs. the differences in the
repeated measurements (vertical axis). The horizontal solid lines indicate the mean difference between
the 2 calculations. The horizontal dashed lines indicate the 95% limits of agreement (mean 1.96 SD).
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TABLE 1

Patient Volumetric and Functional Data

Upon guidance of the surgeon, an ROI encompassing the future remnant liver was drawn on the
preoperative HBS image (Figs. 4A and 5A). The scintigraphic RLF within this ROI was assessed and
compared with the scintigraphic liver uptake 1 d after surgery (Figs. 4B and 5B). A strong positive
association (n = 15; r = 0.95; R2 = 0.90; P < 0.001) was found between these measurements (Fig. 2C).
BlandAltman statistics are shown in Figure 3B. When the ROI of the remnant liver on the immediate
postoperative HBS image was copied onto the baseline preoperative scintigram to calculate the RLF, the
correlation (n = 15; r = 0.97; R2 = 0.94; P < 0.001) was slightly better.
FIGURE 4.
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FIGURE 4.

Summed images of patient 3 from 150 to 350 s after intravenous injection of 80 MBq of 99mTc-
mebrofenin preoperatively (A), 1 d postoperatively after right-sided hemihepatectomy (B), and 3 mo
postoperatively (C). Images are normalized to the preoperative HBS. In A, an ROI is drawn over the
entire liver (black), the future remnant liver (white), and the mediastinal blood pool (bl). The ROIs were
copied on the HBS performed 1 d and 3 mo postoperatively. The total liver function was 16.05%/min,
and the RLF was estimated at 5.88%/min on preoperative HBS. The measured RLF 1 d postoperatively
was 5.15%/min. After 3 mo, liver function recovered to 12.80%/min, with hypertrophy visible on HBS.

Liver volumes were assessed with CT preoperatively and 3 mo after surgery. In 27 CT volumetric analysis
assessments (preoperative and 3 mo after surgery), a corresponding ICG clearance test was performed.
Little or no association (r = 0.27) was found between the measured liver volume and function,
determined with CT and ICG clearance, respectively.

Finally, functional liver regeneration was assessed with HBS and compared with volume regeneration
assessed with CT volumetric analysis (Table 2). A strong positive association (n = 10; r = 0.81; R2 = 0.66; P
< 0.01) was found between liver function assessed with HBS and ICG clearance 3 mo after surgery. A
weak association (n = 15; r = 0.61; R2 = 0.37; P = 0.16) was found between functional liver regeneration
and liver volume regeneration in the 3 mo after partial liver resection (Fig. 2D). An example of HBS in a
patient with a right-sided hemihepatectomy is shown in Figure 4. An example of HBS in a patient with a
left-sided hemihepatectomy is shown in Figure 5.
FIGURE 5.
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FIGURE 5.

Summed images of patient 15 from 150 to 350 s after intravenous injection of 80 MBq of 99mTc-
mebrofenin preoperatively (A), 1 d postoperatively after left-sided hemihepatectomy (B), and 3 mo
postoperatively (C). Images are normalized to the preoperative HBS. In A, an ROI is drawn over the
entire liver (black), the future remnant liver (white), and the mediastinal blood pool (bl). The ROIs were
copied on the HBS performed 1 d and 3 mo postoperatively. The total liver function was 10.30%/min,
and the RLF was estimated at 8.99%/min on preoperative HBS. The measured RLF 1 d postoperatively
was 9.30%/min. After 3 mo, liver function recovered to 11.79%/min, with hypertrophy visible on HBS.
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TABLE 2

Liver Recovery Data
Previous SectionNext Section
DISCUSSION

Improvements in the safety of liver surgery have resulted in more extended hepatic resections (1,2). The
improvement of results is largely due to better techniques, resulting in reduction of blood loss (3).
However, better selection of patients and exclusion of high-risk patients seems to be another important
contributor (3). Furthermore, preoperative (selective) portal vein embolization is used in patients with
and without underlying liver disease to increase the safety of and tolerance to major hepatectomy with
a small liver remnant (4).

Important parameters in risk assessment for major hepatectomy are the preoperative LFR and the RLV
(3,4). Several methods of liver function assessment have been used, including liver biochemistry, Child
classification, and quantitative liver function tests (3). The ICG clearance test is regarded as the most
accurate test for the evaluation of preoperative hepatic function reserve and for predicting
postoperative mortality (17,18). However, test results reflect total liver function but cannot provide
information on the distribution of liver function among liver segments.

Preoperative liver volume and RLV can accurately be assessed with CT (6). The combination of functional
data with morphology is able to predict hepatic dysfunction in patients with normal liver parenchyma
undergoing major liver resection (19). However, many patients undergoing partial hepatectomy for
hepatocellular carcinoma have associated liver cirrhosis (8). Furthermore, patients with obstructing
biliary tumors such as cholangiocarcinoma may have cholestasis with secondary impaired total or
segmental liver function (9). Therefore, 99mDTPA-galactosyl human serum albumin (99mTc-GSA)
scintigraphy was previously tested (20) and refined for hepatic function testing and risk assessment for
safe partial hepatectomy (21,22). Major limitations are the availability of 99mTc-GSA and the fact that
99mTc-GSA is not excreted into the bile, making it impossible to study liver uptake and excretory
function within a single testa capability that can be useful in tumors or pathology with the possibility
of obstruction (23).

HBS has been performed on liver transplant patients to assess the functional and morphologic status of
the graft, including structural complications such as bile leakage or bile duct obstruction (24,25). The
uptake mechanism of IDA analogues by the hepatocyte is similar to the uptake mechanisms of other
anorganic anions (15). Both ICG and IDA analogues are excreted in the bile by hepatocytes by the ATP-
dependent export pump multidrug-resistanceassociated protein 2, without undergoing
biotransformation during transit through the hepatocyte (2628). Measurement of liver uptake function
by iodide clearance rate was described by Ekman et al. (13). We adopted this technique but used
99mTc-mebrofenin as the radiopharmaceutical. 99mTc-Mebrofenin shows a high liver uptake and
minimal urinary excretion and strongly resists displacement by a high bilirubin level (15).

In our study, a strong positive association was found between the LFR measured with ICG and HBS,
confirming earlier observations (14). Furthermore, the reproducibility of the liver function calculation
based on HBS was high. However, reproducibility depends largely on the level of automatic and
systematic ROI drawing, which is subject to a learning curve. Therefore, only 1 operator performed
calculations in this phase of the trial program.

One can argue that diseased regions are difficult to localize on planar registration and that differences in
volumes of liver ROIs might influence the findings (23). Therefore, SPECT techniques offer potential
advantages in localization (23,29,30). However, quantitative or semiquantitative analysis in SPECT has
limitations of its own, and implementation of attenuation and scatter correction should be considered
(31,32). Furthermore, the LFR determined with planar dynamic HBS correlated well with ICG clearance,
and the RLF assessed preoperatively correlated well with the value measured postoperatively.
Therefore, we feel confident about using planar HBS for the assessment of LFR and RLF. The asymmetric
liver shape can produce over- or underestimation of uptake on planar anterior dynamic scintigraphy.
Although such estimation errors did not significantly affect data in this study, dual-head dynamic
acquisition with geometric mean value calculation could improve the reliability of RLF and will be
evaluated in the future.

CT has been shown to assess liver volumes accurately (6). However, the question remains whether
volume and function can be related in any given situation. When a small tumor has to be resected from
a homogeneous and normally functioning liver, volume and function can be related (19). For these
patients, restricted surgery is needed and the significance of RLF determination is questionable (4). For
multiple resectable or large tumors, liver function distribution is not homogeneous. Furthermore,
patients with hepatocellular carcinoma frequently present with an associated underlying disease such as
cirrhosis or cholestasis, induced by obstructing biliary tumors, that affects total or segmental liver
function. In these patients, morphologic volumetric analysis may not reflect functional volumetric
analysis, possibly explaining the reported lack of association between the volume of the remaining liver
and the postoperative course (4,19).

In assessments of functional recovery of the liver after hemihepatectomy, our results showed only a
weak association between functional liver regeneration and liver volume regeneration in the 3 mo after
partial liver resection. This finding emphasizes the importance of functional imaging and might play an
important role in patients subject to preoperative techniques, such as portal embolization, to enhance
liver function (33).

Finally, HBS offers the ability to assess both liver uptake and excretory function. Besides preoperative
assessment of the functional consequences of possible cholestasis, postoperative assessment of RLF can
be combined with biliary function and bile leak assessment. This combination of investigations is not
possible with laboratory (ICG), morphologic (CT), or other scintigraphic techniques (23,29,30).
Previous SectionNext Section
CONCLUSION

HBS offers the unique combination of functional liver uptake and excretion evaluations with the ability
to assess LFR preoperatively and to estimate RLF preoperatively. Determination of the RLF instead of the
RLV might clarify some of the discrepancies observed in the literature between RLV and clinical outcome
in patients with inhomogeneous liver function.
Previous SectionNext Section
Footnotes

Received Nov. 7, 2003; revision accepted Dec. 29, 2003.

For correspondence or reprints contact: Roelof J. Bennink, MD, Department of Nuclear Medicine,
Academic Medical Centre, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.

E-mail: r.bennink@amc.uva.nl

Previous Section

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Fan ST. Methods and related drawbacks in the estimation of surgical risks in cirrhotic patients
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Abstract/FREE Full Text

Heyman S. Hepatobiliary scintigraphy as a liver fhe








"50-50 criteria" on postoperative day 5: an accurate predictor of liver failure and death after
hepatectomy.
Balzan S, Belghiti J, Farges O, Ogata S, Sauvanet A, Delefosse D, Durand F.
Source

Department of Hepatopancreatobiliary Surgery and Liver Transplantation, Beaujon Hospital, University
Paris 7, Paris, France.
Abstract
OBJECTIVE:

To standardize the definition of postoperative liver failure (PLF) for prediction of early mortality after
hepatectomy.
SUMMARY BACKGROUND DATA:

The definition of PLF is not standardized, making the comparison of innovations in surgical techniques
and the timely use of specific therapeutic interventions complex.
METHODS:

Between 1998 and 2002, 775 elective liver resections, including 69% for malignancies and 60% major
resections, were included in a prospective database. The nontumorous liver was abnormal in 43% with
steatosis >30% in 14%, noncirrhotic fibrosis in 43%, and cirrhosis in 12%. The impact of prothrombin
time (PT) <50% and serum bilirubin (SB) >50 micromol/L on postoperative days (POD) 1, 3, 5, and 7 was
analyzed.
RESULTS:

The lowest PT level was observed on postoperative day (POD) 1, while the peak of SB was observed on
POD 3. These 2 variables tended to return to preoperative values by POD 5. The median interval
between hepatectomy and postoperative death was 15 days (range, 5-39 days). Postoperative mortality
significantly increased in patients with PT <50% and SB >50 microml/L. The conjunction of PT <50% and
SB >50 micromol/L on POD 5 was a strong predictive factor of mortality. In patients with significant
morbidity, this "50-50 criteria" was met 3 to 8 days before clinical evidence of complications.
CONCLUSIONS:

The association of PT <50% and SB >50 microml/L on POD 5 (the 50-50 criteria) was a simple, early, and
accurate predictor of more than 50% mortality rate after hepatectomy. This criteria could be identified
early enough, before clinical evidence of complications, for specific interventions to be applied in due
time. he 50-50 Criteria on Postoperative Day 5
An Accurate Predictor of Liver Failure and Death After Hepatectomy
Silvio Balzan, MD,* Jacques Belghiti, MD,* Olivier Farges, MD, PhD,* Satoshi Ogata, MD, PhD,* Alain
Sauvanet, MD,* Didier Delefosse, MD, and Franois Durand, MD*
Author information Copyright and License information
This article has been cited by other articles in PMC.
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Abstract
Objective:

To standardize the definition of postoperative liver failure (PLF) for prediction of early mortality after
hepatectomy.
Summary Background Data:

The definition of PLF is not standardized, making the comparison of innovations in surgical techniques
and the timely use of specific therapeutic interventions complex.
Methods:

Between 1998 and 2002, 775 elective liver resections, including 69% for malignancies and 60% major
resections, were included in a prospective database. The nontumorous liver was abnormal in 43% with
steatosis >30% in 14%, noncirrhotic fibrosis in 43%, and cirrhosis in 12%. The impact of prothrombin
time (PT) <50% and serum bilirubin (SB) >50 mol/L on postoperative days (POD) 1, 3, 5, and 7 was
analyzed.
Results:

The lowest PT level was observed on postoperative day (POD) 1, while the peak of SB was observed on
POD 3. These 2 variables tended to return to preoperative values by POD 5. The median interval
between hepatectomy and postoperative death was 15 days (range, 539 days). Postoperative mortality
significantly increased in patients with PT <50% and SB >50 ml/L. The conjunction of PT <50% and SB
>50 mol/L on POD 5 was a strong predictive factor of mortality. In patients with significant morbidity,
this 50-50 criteria was met 3 to 8 days before clinical evidence of complications.
Conclusions:

The association of PT <50% and SB >50 ml/L on POD 5 (the 50-50 criteria) was a simple, early, and
accurate predictor of more than 50% mortality rate after hepatectomy. This criteria could be identified
early enough, before clinical evidence of complications, for specific interventions to be applied in due
time.

Technical improvements in liver surgery during the last decade have resulted in an expansion of the
indications for major hepatectomies, especially in high-risk patients with various underlying liver
conditions (fibrosis, steatosis, or chemotherapy-induced injury).16 However, the risk of postoperative
liver failure (PLF) and fatal outcome have remained important concerns.1,2,7 Although several clinical
and biologic variables such as ascites, encephalopathy, jaundice, prolonged prothrombin time (PT),
hyperbilirubinemia, and hypoalbuminemia are usual markers of impaired liver function, there is neither
a standardized definition of PLF based on these markers nor precise data on their correlation with
postoperative mortality. The need for a standardized definition of PLF is important for the evaluation of
technical improvements in different fields of liver surgery like preoperative portal vein deprivation and
the result of different methods of vascular clamping. The recent advent of liver assist devices makes it
even more important to predict a poor outcome at an early stage so as to determine when they should
be used.8,9 The Child-Pugh score, which accurately evaluates preoperative liver function, is
inappropriate postoperatively.10 After surgery, encephalopathy, ascites, and hypoalbuminemia may be
related to factors other than liver dysfunction itself such as the consequence of anesthesia, portal
hypertension, lymphatic dissection, or hemodilution. Both bilirubin and prothrombin index (2 of the 3
components of MELD score) are frequently affected in the early postoperative days after major
resection, but to which extent and at which time points have not been clearly established.11,12

Based on a large series of liver resections performed over a short period of time, the aim of the present
study was to evaluate the reliability and usefulness of an arbitrarily defined score combining
prothrombin index and bilirubin, with threshold values based upon those of Child-Pugh score (ie, 50% of
normal for prothrombin index and 50 mol/L for bilirubin) for defining PLF and assessing postoperative
mortality in a population of patients undergoing hepatectomy.
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METHODS
Patient Demographics

Between October 1998 and December 2002, 803 elective hepatic resections were performed at our
institution and were included in a prospective database. After exclusion of patients with malignant
obstructive jaundice and abnormal preoperative serum bilirubin (SB) >50 ml/L at the time of liver
resection, 775 hepatectomies, performed in 704 patients were analyzed in this study. There were 383
males and 321 females with a mean age of 54 10 years. Indications for resection are listed in Table 1.
Malignant disease was present in 531 cases (69%), including 314 primary tumors and 217 metastases. In
the remaining 244 cases without malignant disease, we included 68 patients who underwent hepatic
resections for living-related transplantation (Table 1). There were 464 (60%) major hepatic resections
(namely, removal of 3 segments or more) and 311 minor hepatic resections. Detailed pathologic
examination of the nontumorous liver parenchyma showed that underlying changes were present in 307
cases (40%), including steatosis >30% in 107 (14%), noncirrhotic fibrosis in 237 (31%), and cirrhosis in 94
(12%).
Table thumbnail
TABLE 1. Indications for Hepatectomy and Operative Data in 775 Cases of Liver Resection
Surgical Procedures

Selection criteria for hepatic resection included adequate medical condition of the patient and
preservation of sufficient functional liver parenchyma. In addition to biologic liver function tests,
preoperative imaging investigations included abdominal ultrasound and dynamic computed tomography
in all patients. Additional investigations were performed when needed, according to individual
situations. Portal vein embolization or ligation was performed 3 to 8 weeks before hepatectomy in 62
(8%) patients according to our protocol for preoperative portal vein occlusion: anticipated right or
extended right hepatectomy in patients with chronic underlying liver disease or estimated remnant liver
volume less than 30% of the total functional liver volume.13 Liver resection was performed
laparoscopically in 23 cases (3%). Conventional liver resection was performed through an exclusive
abdominal incision in 729 (94%) cases, an exclusive right thoracic approach was used in 10 (1%) cases,
and a thoracoabdominal approach in 13 (2%). The latter was used for bulky right-sided tumors that
bulged into the pleural cavity. For major liver resection, extraparenchymal control of ipsilateral inflow
and outflow was attempted before resection whenever possible. Liver transection was performed using
the clamp crushing method or an ultrasonic dissector, according to the surgeon's preference. Total
vascular exclusion of the liver (namely, clamping of the portal triad and the infrahepatic and
suprahepatic inferior vena cava) was used in 34 cases (4.4%). Other resections were performed under
intermittent portal triad clamping in 507 (65%) cases for a mean duration of 48 23 minutes. In 234
(30%) cases, liver resection was performed without hepatic inflow occlusion.
Postoperative Course

Admission in Intensive Care Unit (ICU) was routine in patients with cirrhosis or associated cardiovascular
comorbidities, in those who were submitted to extensive hepatectomies, or in case of intraoperative
adverse event (such as hypothermia or massive bleeding). Our policy was to avoid the use of
postoperative fresh frozen plasma. As a result, no patient included in this series received fresh frozen
plasma or any other substitutive to coagulation factors during the first postoperative week. The aim of
this study was to investigate if the early kinetics of liver function tests correlated with the postoperative
outcome. For this purpose, liver function tests were sampled routinely on postoperative days (POD) 1, 3,
5, and 7 and complications were recorded prospectively. Based on the Child-Pugh score, threshold
values of 50% for PT and of 50 mol/L for SB were chosen to evaluate the impact of these tests on
postoperative mortality. The arbitrary choice of these threshold values was justified by the fact that they
correspond to the widely used limits of Child score.

The principal endpoint was postoperative mortality, defined as death occurring during postoperative in
hospital stay or within 60 days of surgery. Postoperative complications were divided into major and
minor. Minor complications were the adverse events with no or minimal impact on in-hospital stay. Life-
threatening complications were considered as major postoperative complications. Complications with a
clear link with liver failure included portal vein thrombosis, infected ascites, severe sepsis, renal failure,
and gastrointestinal hemorrhage.
Statistical Methods

Statistical analysis was performed using Epi Info version 2002 (Centers for Disease Control and
Prevention). Data are expressed as median values and ranges or absolute values and percentages. P
values <0.05 were considered significant. Survival was analyzed using the Kaplan-Meier estimates and
comparisons were performed using the log-rank test. Student t test, 2 test, and Fisher exact test were
used for univariate analysis where needed. Multivariate analysis was performed using logistic
regression. Odds ratio with 95% confidence intervals derived from logistic regression were calculated.
Sensitivity and specificity, as well as test accuracy, were computed for the proposed criteria of PLF.
Go to:
RESULTS
Kinetics of Postoperative Liver Function Tests

The kinetics of postoperative PT and SB are shown in Figure 1. Postoperative PT level was minimum on
POD 1 (65% 18%) and, thereafter increased progressively reaching a level similar to preoperative
values on POD 5 (83% 19% versus 95% 13%). Postoperative SB increased until POD 3 (36 29
mol/L) and thereafter slowly decreased to 26 11 mol/L on POD 7. The trend of these 2 biologic
markers to return to preoperative values was evident on POD 5.
figure 9FF1
FIGURE 1. Kinetics of postoperative biologic liver function tests. Means and SD of prothrombin time (PT)
and total serum bilirubin (SB) in overall group of hepatectomies. Kinetic of postoperative prothrombin
time (PT) and serum total bilirubin level (SB). ...
Operative Mortality and Impact of PT <50% and/or SB >50 mol/L

In-hospital death occurred in 26 patients (3.4%), including 21 (80%) with abnormal liver parenchyma (12
of them with cirrhosis) and 20 (77%) following major hepatectomies. Three patients died early after
major resection: 1 patient of myocardial infarction on POD 2 and 2 of peritonitis following bowel
necrosis on POD 3 and POD 5, respectively. Apart from these 3 patients who obviously died without liver
dysfunction, the 23 other patients died between POD 5 and 39 (median POD 15) from multiple
complications. These complications were first identified between POD 3 and 18 (median, 10). Except for
the 3 early deaths, the remaining 23 deaths were due to postoperative complications clearly related to
liver dysfunction, including portal vein thrombosis in 7, bacterial peritonitis in 6, severe sepsis in 16,
renal failure in 5, and gastrointestinal hemorrhage in 2.

The mortality rate increased from 16% to 40% in patients who had PT <50% on POD 3 and POD 7,
respectively. In parallel, the mortality rate increased from 11% to 17% in patients with SB >50 mol/L on
POD 3 and POD 7, respectively (Table 2).
Table thumbnail
TABLE 2. Operative Mortality According to Occurrence of Prothrombin Time <50% and/or Serum
Bilirubin <50 mol/L

Whatever the postoperative time point, patients with neither PT <50% nor SB >50 mol/L at any time
during the study period had a significantly lower risk of mortality, around 1%, compared with the
remaining patients with either PT <50% or SB >50 mol/L (P <0.001). As shown in Table 2, the prediction
of a fatal outcome was even more accurate when both variables were used in combination. Seven
percent and 2.5% had simultaneously PT <50% and SB >50 mol/L on POD 3 and POD 7, respectively.
Mortality was 19% in those with PT <50% and SB >50 mol/L on POD 3 compared with 63% on POD 7.
We empirically defined the 50-50 criteria as the concomitant presence of PT <50% and SB >50 mol/L.
On POD 5, patients who met this criterion had a 59% risk of early postoperative mortality, compared
with 1.2% risk of mortality if the criteria was not fulfilled (P <0.001). The relative risk of death was 66
(95% CI, 30147) if the 50-50 criteria was present on POD 5 and the accuracy of this test to predict in-
hospital mortality was 97.7% (95% CI, 96.6%98.7%; sensitivity, 69.6%; specificity, 98.5%).

A total of 172 (22%) patients stayed more than 48 hours in ICU, with a mean duration of 8.4 7.2 days,
ranging from 3 to 60 days. All of the 11 patients who survived, despite fulfilling the 50-50 criteria on POD
5, experienced severe complications with a mean stay in ICU of 22 11 days (range, 457 days) and a
mean hospital stay of 43 8 days (range, 1769 days). The 7 postoperative deaths without the 50-50
criteria on POD 5 occurred between POD 10 and POD 60 and were due to gastrointestinal hemorrhage
secondary to portal vein thrombosis in 3 and severe sepsis in 4. The 50-50 criteria was included in a
multivariate logistic regression model with other variables. As shown in Table 3, the 50-50 criteria on
POD 5, age over 65 years, and the presence of severe fibrosis on nontumorous liver parenchyma were
the only independent predictors of death on multivariate analysis, including variables otherwise
significant on univariate analysis (namely, extension of liver resection [major or minor hepatectomy],
malignant disease, presence of steatosis of more than 30% and the need for peroperative blood
transfusions).
Table thumbnail
TABLE 3. Predictive Factors of Operative Mortality After Liver Resection
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DISCUSSION

Technical improvements in the field of liver surgery have increased the possibility to extend the volume
of resected parenchyma, leaving a small remnant liver. It also made it possible to perform resections in
patients with underlying liver lesions such as fibrosis, cirrhosis, severe steatosis, and/or chemotherapy-
related liver lesions.16 All these factors potentially impair postoperative regeneration and favor the
occurrence of PLF.1,2,7 The presence of PLF, by turn, increases the patient's susceptibility to major
complications, especially severe infections, which often result in early postoperative death.14,15
Although this particular condition is of increasing frequency, a standardized definition of PLF is still
lacking. None of the previously proposed definitions of liver failure established outside the context of
surgery can be easily extrapolated to the early period following liver resection. Some of the variables
used to assess liver function, namely, alanine aminotransferase, gamma-glutamyl transferase, and
alkaline phosphatase, are influenced by the surgical insult to and/or regeneration of the remnant liver
rather than reflecting hepatic function.11,12 Child-Pugh score, which was designed to predict the
postoperative outcome of cirrhotic patients, is likely to be biased in the postoperative period.10,16
Neurologic status and ascites are not useful prognostic factors in the early postoperative course.
Neurologic status, indeed, can be affected by external factors such as anesthesia and the administration
of sedative drugs. Similarly, ascites, which can be related to the extent of resection and/or to lymph
nodes dissection, is not a reliable marker of hepatic dysfunction.17 Serum albumin, a protein with a long
half-life, can also be affected by nonspecific factors such as preoperative nutritional status,
postoperative ascites, and hemodilution.18

In contrast to the variables cited above, 2 components of Child-Pugh score, namely, PT and SB, are less
likely to be biased following liver resection and have indeed been used by others in the evaluation of
liver function in a similar clinical setting.13,8,19 However, the threshold values and the time point at
which these 2 biologic factors are accurate indicators of PLF have not been determined. Five large
studies evaluating the results of liver resections after the year 2000 have arbitrarily used different limits
for PT (range, 30%70%) and SB (range, 5085 mol/L) at different postoperative time points.1
3,8,19,20 Additionally, the fact that liver function tests follow a specific kinetic after liver resection,
characterized by early impairment and subsequent normalization, has not been taken into account.

The results of the present study clearly confirm that following the early physiologic changes in these 2
variables (from POD 1 to POD 3): there is a trend to a return to normal values on POD 5. Our approach
was therefore to analyze the accuracy of PT <50% and SB >50 mol/L at different time points for
predicting postresection outcome. The values of PT and SB indicating a significant impairment of liver
function were chosen according to the widely used Child score. The value of 50% of normal for PT
corresponds to an INR of 1.7, and a serum bilirubin of 50 mol/L corresponds to a value of 3 mg/dL.
Again, early alterations of liver function tests following hepatic resection do not always reflect clinically
relevant events. The results of this study showed that, during the first 3 postoperative days, both PT
<50% or a SB >50 mol/L did not accurately predict outcome. On the contrary, the persistence of either
PT <50% or SB >50 mol/L on POD 5 proved important for predicting mortality and might be considered
an indicator of PLF. The main result of this study was to demonstrate that the conjunction of these 2
values on POD 5, the 50-50 criteria, could predict nearly 100% morbidity rate and 50% mortality rate.

The main preoperative factors predicting postoperative liver dysfunction include the presence of
impaired preoperative liver function, the presence of chronic liver disease, extensive liver resection, and
the presence of a small remnant liver.2,5,2124 Although the aim of the present study was not to
identify preoperative predictive factors of PLF, the presence of a large proportion of patients at risk
allowed us to observe a substantial number of adverse events associated with or directly related to liver
failure. Consequently, the overall mortality rate of 3.4% in this population of patients, including a large
number of major resections with abnormal underlying liver parenchyma, is far from the zero mortality
achieved in highly selected groups.2,25

As shown in the present study, more than 50% of the postoperative deaths occurred after 2 weeks.
Indeed, unlike the rapid evolution of patients with fulminant hepatic failure, PLF occurring after liver
resection is associated with more insidious complications that are more difficult to diagnose. The early
recognition of PLF, which precedes clinical evidence of complications, was one of the key findings of this
study. Before POD 3, early impairment of liver function tests had a poor predictive value. The presence
of 50-50 criteria after POD 3, in contrast, should be considered as an alarm. The presence of 50-50
criteria on POD 5, in particular, requires aggressive investigations in search of specific complications.
These aggressive investigations may include multiple bacteriologic examinations to identify bacterial
peritonitis or pneumonia as well as Doppler-US and CT scans to rule out portal thrombosis. These 2
complications inevitably lead to death if not identified and treated promptly. The presence of 50-50
criteria on POD 5 may also help to decide the use of liver assist devices or even to consider rescue liver
transplantation in selective cases.

A number of studies have laid down preoperative criteria to select patients for hepatectomy, while
others have defined the preoperative and intraoperative interventions to increase the safety of
resections.15 The present study is the first to propose a tool that can be used in the postoperative
period to accurately predict outcome, leading to a comprehensive definition of PLF. We think that there
is a strong need for standardization of the definition of PLF to evaluate the results of innovations in the
different fields of liver surgery, including the effect of preoperative portal vein deprivation and the
impact of different techniques of vascular clamping. We have shown that the 50-50 criteria on POD 5 is
an accurate and early indicator of PLF, predicting 50% mortality after liver resection. Although the
results of this study require a prospective validation using our 50-50 criteria and the investigation of the
applicability of MELD score, we propose to define postoperative PLF as the presence of 50-50 criteria on
POD 5.
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Discussions

Dr. Slooff: It is a privilege for me to comment on this paper from such a distinguished Hepatobiliary Unit.

The paper concerns a proposal for a standardized definition for liver failure after hepatectomy. The
incentive, as the authors state, for such a definition is its need for comparison of different resection
techniques or for the initiation and evaluation of experimental or clinical extracorporeal liver support
systems.

The arguments for the choice of the 2 variables from the definition, prothrombin time and serum total
bilirubin is arbitrary and thus debatable. It is based on the fact that they are part of the Child-Pugh and
MELD scores originally not validated for post resection functional evaluations.

Also, the cutoff points for PT and serum bilirubin are taken arbitrarily, and this counts also for identifying
day 5 as the time point for the kinetics. Looking at Figure 1, the trend of normalization of the PT values is
already present from day 1 onwards and for serum total bilirubin on day 4. I question as well if these
kinetics depicted in this figure are really the same for patients with cirrhosis, fibrosis normal liver tissue
containing tumors, or healthy living donors.

It is conceivable, especially in this very heterogeneous patient material with the varying resection
techniques, that other variables related to the patients and the type and techniques of the operations
were also related to postoperative liver failure and mortality.

Why was not first a multivariate analysis performed taking mortality due to liver failure as the major
endpoint? If dynamic factors were predictive, the next step could have been the analysis of the kinetics.

I thank the authors for sending the paper beforehand and giving me the opportunity to study their
analysis.

Dr. Belghiti: Thank you for this very interesting comment and the point you made. As you said, we need
a uniform definition for postoperative liver failure. The inaccuracy of clinical assessment during the
postoperative period prompts the use of biologic factors. Why we selected prothrombin time less than
50% and serum bilirubin more than 50 mol/L (50-50 criteria) at day 5?

Prothrombin time and bilirubin were chosen as these factors are included in both Child and MELD scores
and are the most significant factors indicating liver function. Second, the level of PT <50% corresponding
to INR of 1.7 and bilirubin >50 mol/L corresponding to 3 mg/dL indicate significant impairment of liver
function in the Child-Pugh score. Third, the day 5 was considered because these 2 tests should return to
normal values by this time. Before POD 3, early impairment of liver function test has a poor predictive
value; the persistence of 50-50 criteria after POD 3 should be considered as a red signal with a risk of
20% mortality, which increases to 60% at day 5.

Although we analyzed a large group of patients in a short period of time, I agree that this group was
heterogeneous. Therefore, we add a multivariate analysis demonstrating that the most significant
predictive factor of mortality was the presence of 50-50 criteria at day 5.

Dr. Rikkers: Prof. Belghiti, this is a very nice contribution.

Both of the variables that you analyzed can be affected by blood transfusion. Were these 2 factors
predictive independent of whether patients were transfused or not during their operations?

Dr. Belghiti: I agree that you have an important point. Perioperative blood transfusion did not reach
significance level even on univariate analysis. Our policy is to avoid the use of postoperative fresh-frozen
plasma. In order not to interfere with the postoperative coagulation tests, no patient included in this
study received fresh frozen plasma during the first postoperative week.

Dr. Clavien: I would like to congratulate the authors for this important study including a large population
of patients, and very importantly, using a database covering a relatively short period of time. The
credibility and applicability of the data are also boosted by the selection of readily available and
objective criteria to the clinicians. Complicated formulas are typically unpopular and felt out of clinical
practice rapidly. I have 2 questions. First, why did you limit your data to postoperative day 5? Did you
perform any types of multivariate analyses, for example, with an attempt to identify earlier criteria
including intraoperative events? On the same token, a significant proportion of cirrhotic patients were
included? Is cirrhosis per se a risk factor, and should we not consider a specific formula for this high-risk
population? My second question relates to the validation of such prognostic score coming from a
database. Did you or do you plan to apply this score system in your next 100 or 200 patients to
prospectively test the actual value of your 50-50 criteria?

Dr. Belghiti: Thank you for this excellent question. Although I did not show this result in my slides, the
presence of chronic liver disease is an important impact factor on postoperative mortality and the
presence of 50-50 criteria at day 5 has a higher predictive value for risk of mortality than in patients with
normal liver. From the methodologic point of view, this criterion should be validated prospectively, and
we are currently doing so. However, since the result of this study, we have dramatically changed our
postoperative approach toward our patients with this 50-50 criterion. On day 5, the presence of this
criterion leads us to conduct a multidisciplinary meeting, aggressive investigations including multiple
bacteriological examinations to identify ascites and pneumonia as well as Doppler ultrasound and CT
scan to rule out portal thrombosis. These 2 complications inevitably lead to death if not treated
promptly. Therefore, it is probably unethical for a randomized study to be conducted on them.

Dr. Hckerstedt: This 50-50 criterion is a very nice expression, of course, but how useful is this
knowledge? Because on day 5, it is too late to do much for the individual patients. The ICU people can
keep them alive for a few days or weeks but, as you say yourself, 60% of them will die eventually. In that
respect, I am afraid that it is not of much use. Certainly, we need the preoperative tests, but now we are
talking about surprises happening to the patients during or after surgery. And on day 5, it is too late to
improve the situation, so I suggest we concentrate on day 1 or perhaps day 2.

Dr. Belghiti: I feel that you are too pessimistic. The presence of a low PT on day 1 is not a grave sign. The
postoperative bilirubin value, which is an important factor of liver impairment, is exceptionally elevated
on day 1. Therefore, before day 3, it is quite impossible to define biologic postoperative liver failure. It is
on day 5 that both PT and bilirubin should return to normal value; their levels around 50-50 is a sign of
liver failure and have a high predictive value of postoperative death. Although it is always too late, we
must keep in mind that the majority of postoperative deaths occur after 2 weeks, leaving some place for
searching and treating complications. Furthermore, it seems difficult to decide on the use of liver assist
devices or even to consider rescue liver transplantation in selective cases before POD 5.

Dr. Hckerstedt: We do not need slow reactors like bilirubin, but fast reactors that have a half time,
which is just a few hours.
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Footnotes

Reprints: Jacques Belghiti, MD, Department of Hepatobiliary Surgery and Liver Transplantation, Beaujon
Hospital, 100, Bd du Gnral Leclerc, 92118 Clichy, France. E-mail: jacques.belghiti@bjn.ap-hop-paris.fr.

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