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.

Comment in

The following popper user interface control may not be accessible. Tab to the next button to revert

the control to an accessible version.

Destroy user interface controlConsensus classifications of postoperative complications--are they really

useful? [Surgery. 2Liver failure following partial hepatectomy

Thomas S. Hellingcorresponding author

Author information Copyright and License information

This article has been cited by other articles in PMC.

Go to:

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

Go to:

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.

Go to:

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.

Go to:

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.

Go to:

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

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.

Go to:

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.

Go to:

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.

Go to:

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.

Go to:

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.

Go to:

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.

Go to:

References

1. Keen WW. Report of a case of resection of the liver for the removal of a neoplasm, with a table of

seventy-six cases of resection of the liver for hepatic tumors. Ann Surg. 1899;30:26783.

2. Couinaud C. Lobes et segments hepatiques: notes sur architecture anatomique et chirurgicale du foie.

Presse Med. 1954;62:70912. [PubMed]

3. Lortat-Jacob JL, Robert HG, Henry C. Un cas d'hepatectomie droite reglee. Memoires del'Acadamie de

Chirurgie. 1952;78:24451.

4. Quatttlebaum JK, Quattlebaum JK., Jr Technique of hepatic resection. Surgery. 1965;58:107580.

[PubMed]

5. Foster JH, Berman MM. Solid liver tumors. Major Problems in Clinical Surgery. 1977;22:2559.

6. Iwatsuki S, Starzl TE. Personal experience with 411 hepatic resections. Ann Surg. 1988;208:42134.

[PMC free article] [PubMed]

7. Savage AP, Malt RA. Elective and emergency hepatic resections: determinants of operative morbidity.

Ann Surg. 1991;214:68995. [PMC free article] [PubMed]

8. Scheel J, Stangl R. Blumgart LH. Churchill Livingstone; New York: 1994. Segment oriented anatomic

liver resection, Surgery of the liver and biliary tract.

9. Melendez J, Ferri E, Zwillman M, Fischer M, DeMatteo R, Leung D, et al. Extended hepatic resection: a

6-year retrospective study of risk factors for perioperative mortality. J Am Coll Surg. 2001;192:4753.

[PubMed]

10. Brancatisano R, Isla A, Habib N. Is radical hepatic surgery safe? Am J Surg. 1998;175:1613.

[PubMed]

11. Hoofnagle JH. Fulminant hepatic failure. Hepatology. 1995;21:240. [PubMed]

12. Bernuau J, Benhamou JP. Classifying acute liver failure. Lancet. 1993;342:2523. [PubMed]

13. Koniaris LG, McKillop IA, Schwartz SI. Liver regeneration. J Am Coll Surg. 2003;197:63459. [PubMed]

14. Takeda K, Togo S, Kunihiro O, Fujii Y, Kurosawa H, Tanaka K, et al. Clinicohistological features of liver

failure after excessive hepatectomy. Hepatogastroenterology. 2002;49:3548. [PubMed]

15. Quan D, Wall WJ. The safety of continuous hepatic inflow occlusion during major liver resection.

Liver Transplant Surg. 1996;2:99104.

16. Huguet B, Nordlinger B, Bloch P, Conard J. Tolerance of the human liver to prolonged normothermic

ischemia. Arch Surg. 1978;113:144851. [PubMed]

17. Bismuth H, Castaing D, Garden OJ. Major hepatic resection under total vascular exclusion. Ann Surg.

1990;210:139. [PMC free article] [PubMed]

18. Huguet C, Gavelli A, Chieco A, Bona S, Harb J, Joseph JM, et al. Liver ischemia for hepatic resection:

where is the limit? Surgery. 1992;111:2519. [PubMed]

19. Moussa ME, Uemoto SS, Habib NA. Effect of total hepatic vascular exclusion during liver resection on

hepatic ultra-structure. Liver Transplant Surg. 1996;2:4617.

20. Champion HR, Jones RT, Trump BF, Decker R, Wilson S, Miginski M, et al. A clinicopathologic study of

hepatic dysfunction following shock. Surg Gynecol Obstet. 1976;142:65762. [PubMed]

21. Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic

resection. Ann Surg. 1987;206:309. [PMC free article] [PubMed]

22. Yamanaka N, Okamoto E, Kawamura E, Kato T, Oriyama T, Fujimoto J, et al. Dynamics of normal and

injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography

and liver function. Hepatology. 1993;18:7985. [PubMed]

23. Huguet C, Gavelli A, Chieco A, Bona S, Harb J, Joseph JM, et al. Liver ischemia for hepatic resection:

where is the limit? Surgery. 1992;111:2519. [PubMed]

24. Heymsfield SB, Fulenwider T, Nordlinger B, Barlow R, Sones P, Kutner M. Accurate measurement of

liver, kidney, and spleen volume and mass by computerized axial tomography. Ann Intern Med.

1979;90:1857. [PubMed]

25. Higashiyama H, Yamaguchi T, Mori K, Nakano Y, Yokoyama T, Takeuchi T, et al. Graft size assessment

by preoperative computed tomography in living related partial liver transplantation. Br J Surg.

1993;80:48992. [PubMed]

26. Kubota K, Makuuchi M, Kusaka K, Kobayashi T, Miki K, Hasegawa K, et al. Measurement of liver

volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic

tumors. Hepatology. 1997;26:117681. [PubMed]

27. Shirabe K, Shimada M, Gion T, Hasegawa H, Takenaka K, Utunomiya T, et al. Postoperative liver

failure after major hepatic resection for hepatocellular carcinoma in the modern era with special

reference to remnant liver volume. J Am Coll Surg. 1999;188:3047. [PubMed]

28. Vauthey J-N, Chaoui A, Do K-A, Bilimoria MM, Fenstermacher MJ, Charnsangavej C, et al.

Standardized measurement of the future liver remnant prior to extended liver resection: methodology

and clinical associations. Surgery. 2000;127:51219. [PubMed]

29. Urata K, Kawasaki S, Matsunami H, Hashikura Y, Ikegami T, Ishizone S, et al. Calculation of child and

adult standard liver volume for liver transplantation. Hepatology. 1995;21:131721. [PubMed]

30. Kin Y, Nimura Y, Hayakawa N, Kamiya J, Kondo S, Nagino M, et al. Doppler analysis of hepatic blood

flow predicts liver dysfunction after major hepatectomy. World J Surg. 1994;18:1439. [PubMed]

31. Fukauchi T, Hirose H, Onitsuka A, Hayashi M, Senga S, Imai N, et al. Effects of portal-systemic shunt

following 90% partial hepatectomy in rats. J Surg Res. 2000;89:12631. [PubMed]

32. Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K, et al. Impact of graft size

mismatching on graft prognosis in liver transplantation from living donors. Transplantation.

1999;67:3217. [PubMed]

33. Kishikawa YK, Suehiro T, Nishizaki T, Shimada M, Itasaka H, Nomoto K, et al. Partial hepatic grafting:

porcine study on critical volume reduction. Surgery. 1995;118:48692. [PubMed]

34. Man K, Lo CM, Ng IO, Wong YC, Qin LF, Fan ST, et al. Liver transplantation in rats using small-for-size

grafts: a study of hemodynamic and morphological changes. Arch Surg. 2001;136:2805. [PubMed]

35. Troisi R, Cammu G, Giuseppe M, De Baerdemaeker L, Decruyenaere J, Hoste E, et al. Modulation of

portal graft inflow: a necessity in adult living-donor liver transplantation. Ann Surg. 2003;237:42936.

[PMC free article] [PubMed]

36. Boillot O, Delafosse B, Mechet I, Boucard C, Pouyet M. Small-for-size partial liver graft in an adult

recipient; a new transplant technique. Lancet. 2002;359:4067. [PubMed]

37. Kooby DA, Zakian KL, Challa SN, Matei C, Petrowsky H, Yoo HH, et al. Use of phosphorus-31 nuclear

magnetic resonance spectroscopy to determine safe timing of chemotherapy after hepatic resection.

Cancer Res. 2000;60:38006. [PubMed]

38. Corbin IR, Buist R, Volotovskyy V, Peeling J, Zhang M, Minuk GY. Regenerative activity and liver

function following partial hepatectomy in the rat using 31P-MR spectroscopy. Hepatology. 2002;36:345

53. [PubMed]

39. Bilimoria MM, Chaoui AS, Vauthey JN. Postoperative liver failure. J Am Coll Surg. 1999;189:3367.

[PubMed]

40. Eguchi S, Kamlot A, Ljubimova J, Hewitt WR, Lebow LT, Demetriou AA, et al. Fulminant hepatic failure

in rats: survival and effect on blood chemistry and liver regeneration. Hepatology. 1996;24:14529.

[PubMed]

41. Gaub X, Iversen J. Rat liver regeneration after 90% partial hepatectomy. Hepatology. 1984;4:9024.

[PubMed]

42. Chang CG, Van Way CW III, Dhar A, Helling TS, Jr, Hahn Y. The use of insulin and glucose during

resuscitation from hemorrhagic shock increases hepatic ATP. J Surg Res. 2000;92:1716. [PubMed]

43. Makuuchi M, Thai BL, Takayasu K, Takayama T, Kosuge T, Gunven P, et al. Preoperative portal vein

embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary

report. Surgery. 1990;107:5217. [PubMed]

44. Nagino M, Nimura Y, Kamiya J, Kondo S, Uesaka K, Kin Y, et al. Changes in hepatic lobe volume in

biliary tract cancer patients after right portal vein embolization. Hepatology. 1995;21:4349. [PubMed]

45. Hemming AW, Reed AI, Howard RJ, Fujita S, Hochwald SN, Caridi JG, et al. Preoperative portal vein

embolization for extended hepatectomy. Ann Surg. 2003;237:68691. [PMC free article] [PubMed]

46. Farges O, Belghiti J, Kianmanesh R, Regimbeau JM, Santoro R, Vilgrain V, et al. Portal vein

embolization before right hepatectomy: prospective clinical trial. Ann Surg. 2003;237:20817. [PMC free

article] [PubMed]

47. Azoulay D, Castaing D, Krissat J, Smail A, Hargreaves GM, Lemoine A, et al. Percutaneous portal vein

embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in

the injured liver. Ann Surg. 2000;232:66572. [PMC free article] [PubMed]

48. Fortner JG, Lincer RM. Hepatic resection in the elderly. Ann Surg. 1990;211:1415. [PMC free article]

[PubMed]

49. Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J Surg. 1998;22:40612.

[PubMed]

50. Nagasue N, Chang Y-C, Takemoto Y, Taniura H, Kohno H, Nakamura T. Liver resection in the aged

(seventy years or older) with hepatocellular carcinoma. Surgery. 1993;13:14854. [PubMed]

51. Wu C-C, Chen J-T, Ho W-L, Yeh D-C, Tang J-S, Liu T-J, et al. Liver resection for hepatocellular

carcinoma in octogenarians. Surgery. 1999;125:3328. [PubMed]

52. Tietz NW, Shuey DF, Wekstein DR. Laboratory values in fit aging individuals sexagenarians through

centenarians. Clin Chem. 1992;38:116785. [PubMed]

53. Schmucker DL, Gilbert R, Jones AL, Hradek GT, Bazin H. Effect of aging on the hepatobiliary transport

of dimeric immunoglobulin A in the male Fischer rat. Gastroenterology. 1985;88:43643. [PubMed]

54. Einarsson K, Nilsell K, Leijd B. Influence of age on secretion of cholesterol and synthesis of bile acids

by the liver. N Engl J Med. 1985;313:27782. [PubMed]

55. Kimura F, Miyaaki M, Suwa T, Kakizaki S. Reduction of hepatic acute phase response after partial

hepatectomy in older patients. Res Exp Med. 1996;196:28190.

56. Beyer HS, Sherman R, Zieve L. Aging is associated with reduced liver regeneration and diminished

thymidine kinase mRNA content and enzyme activity in the rat. J Lab Clin Med. 1990;117:1018.

[PubMed]

57. Tsukamoto I, Nakata R, Kojo S. Effect of aging on rat liver regeneration after partial hepatectomy.

Biochem Mol Biol Int. 1993;30:7738. [PubMed]

58. Ikegami T, Nishizaki T, Yanaga K, Shimada M, Kishikawa K, Nomoto K, et al. The impact of donor age

on living donor liver transplantation. Transplantation. 2000;70:17037. [PubMed]

59. Takenaka K, Kanematsu T, Fukuzawa K, Sugimachi K. Can hepatic failure after surgery for

hepatocellular carcinoma in cirrhotic patients be prevented? World J Surg. 1990;14:1237. [PubMed]

60. Franco D, Capussotti L, Smadja C, Bouzari H, Meakins J, Kemeny F, et al. Resection of hepatocellular

carcinomas. Results in 72 European patients with cirrhosis. Gastroenterology. 1990;98:7338. [PubMed]

61. Pugh RNH, Murray-Lyon IM, Dawson JI, Pietroni MC, William R. Transection of the esophagus for

bleeding esophageal varices. Br J Surg. 1973;60:6469. [PubMed]

62. Farges O, Malassagne B, Flejou JF, Balzan S, Sauvanet A, Belghiti J. Risk of major liver resection in

patients with underlying chronic liver disease: a reappraisal. Ann Surg. 1999;229:21021. [PMC free

article] [PubMed]

63. Eguchi H, Umeshita K, Sakon M, Nagano H, Ito Y, Kishi-moto SI, et al. Presence of active hepatitis

associated with liver cirrhosis is a risk factor for mortality caused by post-hepatectomy liver failure. Dig

Dis Sci. 2000;45:13838. [PubMed]

64. Behrns KE, Tsiotos GG, DeSouza NF, Krishna MK, Ludwig J, Nagorney DM. Hepatic steatosis as a

potential risk factor for major hepatic resection. J Gastrointest Surg. 1998;2:2928. [PubMed]

65. Little SA, Jarnagin WR, DeMatteo RP, Blumgart LH, Fong Y. Diabetes is associated with increased

perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer. J

Gastrointest Surg. 2002;6:8894. [PubMed]

66. Selzner M, Clavien PA. Fatty liver in liver transplantation and surgery. Semin Liver Dis. 2001;21:105

13. [PubMed]

67. Soejima Y, Shimada M, Suehiro T, Kishikawa K, Yoshizumi T, Hashimoto K, et al. Use of steatotic graft

in living-donor liver transplantation. Transplantation. 2003;76:3448. [PubMed]

68. Sun CK, Zhang XY, Zimmerman A, Davis G, Wheatley AM. Effect of ischemia-reperfusion injury on the

microcirculation of the steatotic liver of the Zucker rat. Transplantation. 2001;72:162531. [PubMed]

69. Selzner M, Clavien PA. Failure of regeneration of the steatotic rat liver: disruption at two levels in the

regeneration pathway. Hepatology. 2000;31:3542. [PubMed]

70. Rao MS, Papreddy K, Abecassis M, Hashimoto T. Regeneration of liver with marked fatty changes

following partial hepatectomy in rats. Dig Dis Sci. 2001;46:18216. [PubMed]

71. Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S. The use of indocyanine green in the

measurement of hepatic blood flow and as a test of hepatic function. Clin Sci. 1961;21:4357. [PubMed]

72. Nonami T, Nakao A, Kurokawa T, Inagaki H, Matsushita Y, Sakamoto J, et al. Blood loss and ICG

clearance as best prognostic markers of post-hepatectomy liver failure. Hepato-gastroenterology.

1999;46:166972. [PubMed]

73. Yachida S, Wakabayashi H, Kokudo Y, Goda F, Okada S, Maeba T, et al. Measurement of serum

hyaluronate as a predictor of human liver failure after major hepatectomy. World J Surg. 2000;24:359

64. [PubMed]

74. Nanashima A, Yamaguchi H, Shibasaki S, Sawai T, Yama-guchi E, Yasutake T, et al. Measurement of

serum hyaluronic acid level during the perioperative period of liver resection for evaluation of functional

liver reserve. J Gastroenterol Hepatol. 2001;16:115863. [PubMed]

75. Hwang EH, Taki J, Shuke N, Nakajima K, Kinuya S, Konishi S, et al. Preoperative assessment of

residual hepatic functional reserve using 99mTc-DTPA-galactosyl-human serum albumin dynamic SPECT.

J Nucl Med. 1999;40:164451. [PubMed]

76. Mori K, Ozawa K, Yamamoto Y, Maki A, Shimahara Y, Kobayashi N, et al. Response of hepatic

mitochondrial redox state to oral glucose load. Redox tolerance test as a new predictor of surgical risk in

hepatectomy. Ann Surg. 1990;211:43846. [PMC free article] [PubMed]

77. Das BC, Isaji S, Kawarada Y. Analysis of 100 consecutive hepatectomies: risk factors in patients with

liver cirrhosis or obstructive jaundice. World J Surg. 2001;25:26672. [PubMed]

78. Kaibori M, Inoue T, Sakakura Y, Oda M, Nagahama T, Kwon AH, et al. Impairment of activation of

hepatocyte growth factor precursor into its mature form in rats with liver cirrhosis. J Surg Res.

2002;106:10814. [PubMed]

79. Zhao G, Nakano K, Chijiwa K, Ueda J, Tanaka M. Inhibited activities in CCAAT/enhancer-binding

protein, activating protein-1 and cyclins after hepatectomy in rats with thio-acetamide-induced liver

cirrhosis. Biochem Biophys Res Commun. 2002;292:47481. [PubMed]

80. Corpechot C, Barbu V, Wendum D, Chignard N, Housset C, Poupon R, et al. Hepatocyte growth factor

and c-Met inhibition by hepatic cell hypoxia: potential mechanism for liver regeneration failure in

experimental cirrhosis. Am J Pathol. 2002;160:61320. [PMC free article] [PubMed]

81. Yanaga K, Kanematsu T, Sugimachi K, Takenaka K. Intra-peritoneal septic complications after

hepatectomy. Ann Surg. 1986;203:14852. [PMC free article] [PubMed]

82. Leeuwen PAM, Hong RW, Rounds JD, Rodrick ML, Wilmore D. Hepatic failure and coma after liver

resection is reversed by manipulation of gut contents: the role of endotoxin. Surgery. 1991;110:16975.

[PubMed]

83. Mochita S, Ogata I, Hirata K, Ohta Y, Yamada S, Fugiwara K. Provocation of massive hepatic necrosis

by endotoxin after partial hepatectomy in rats. Gastroenterology. 1990;99:7717. [PubMed]

84. Straatsburg IH, Boermeester MA, Houdijk APJ, Frederiks WM, Wesdorp RIC, Van Leeuwen PAM, et al.

Endotoxin-and cytokine-mediated effects on liver cell proliferation and lipid metabolism after partial

hepatectomy: a study with recombinant N-terminal bactericidal/permeability-increasing protein and

interleukin-1 receptor antagonist. J Pathol. 1996;179:1005. [PubMed]

85. Boermeester MA, Straatsburg IH, Houdijk APJ, Frederiks WM, Wesdorp RIC, Vanoorden CJF, et al.

Endotoxin and interleukin-1 related hepatic inflammatory response promotes liver failure after partial

hepatectomy. Hepatology. 1995;22:1499506. [PubMed]

86. Callery MP, Kamei T, Flye MW. Kupffer cell tumor necrosis factor- production is suppressed during

liver regeneration. J Surg Res. 1991;50:51519. [PubMed]

87. Kimura T, Sakaida I, Terai S, Matsumura Y, Uchida K, Okita K. Inhibition of tumor necrosis factor-

alpha production retards liver regeneration after partial hepatectomy in rats. Biochem Biophys Res Com.

1997;231:55760. [PubMed]

88. Panis Y, McMullan DM, Emond JC. Progressive necrosis after hepatectomy and the pathophysiology

of liver failure after massive resection. Surgery. 1997;121:1429. [PubMed]

89. Shiratori Y, Hongo S, Hikiba Y, Ohmura K, Nagura T, Okano K, et al. Role of macrophages in

regeneration of liver. Dig Dis Sci. 1996;41:193946. [PubMed]

90. Boermeester MA, Houdijk APJ, Meyer S, Cuesta MA, Appelmelk BJ, Wesdorp RIC, et al. Liver failure

induces a systemic inflammatory response: prevention by recombinant N-terminal

bactericidal/permeability-increasing protein. Am J Pathol. 1995;147:142840. [PMC free article]

[PubMed]

91. Wang XD, Soltesz V, Andersson R, Bengmark S. Bacterial translocation in acute liver failure induced

by 90 per cent hepatectomy in the rat. Br J Surg. 1993;80:6671. [PubMed]

92. Kasravi FB, Wang L, Wang XD, Molin G, Bengmark S, Jeppson B. Bacterial translocation in acute liver

injury induced by D-galactosamine. Hepatology. 1996;23:97103. [PubMed]

93. Gross K, Katz S, Dunn SP, Cikrit D, Rosenthal R, Grosfeld JL. Bacterial clearance in the intact and

regenerating liver. J Pediatr Surg. 1985;20:3203. [PubMed]

94. Canalese J, Gove CD, Gimson AE, Wilkinson SP, Wardle EN, Williams R. Reticuloendothelial system

and hepatocytic function in fulminant hepatic failure. Gut. 1982;23:2659. [PMC free article] [PubMed]

95. McGinty MP, Stewart RM, Fabian TC, Proctor KG. Gamma-scintigraphy and early hepatocellular

dysfunction during posttraumatic sepsis. Surgery. 1994;116:53543. [PubMed]

96. Nolan JP. Endotoxin, reticuloendothelial function, and liver injury. Hepatology. 1981;1:45865.

[PubMed]

97. Mela L, Miller LD, Bacalzo LV. Role of intracellular variations of lysosomal enzyme activity and oxygen

tension in mitochondrial impairment in endotoxemia and hemorrhage. Ann Surg. 1973;178:72735.

[PMC free article] [PubMed]

98. Utili R, Abernathy CO, Zimmerman HJ. Studies on the effects of E. coli endotoxin on canalicular bile

formation in the isolated perfused rat liver. J Lab Clin Med. 1977;89:47182. [PubMed]

99. Roelofsen H, van der Veere CN, Ottenhoff R, Schoemaker B, Jansen PL, Oude Elferink RP. Decreased

bilirubin transport in the perfused liver of endotoxemic rats. Gastroenterology. 1994;107:107584.

[PubMed]

100. Zinchuk VS, Okada T, Seguchi H. Lipopolysaccharide alters ecto-ATP-diphosphohydrolase and

causes relocation of its reaction product in experimental intrahepatic cholestasis. Cell Tissue Res.

2001;304:1039. [PubMed]

101. Nakamura J, Nishida T, Hayashi K, Kawada N, Ueshima S, Sugiyama Y, et al. Kupffer cell-mediated

down regulation of rat hepatic CMOAT/MRP-2 gene expression. Biochem Biophys Res Commun.

1999;255:1439. [PubMed]

102. Kawaguchi T, Sakisaka S, Harada M, Hanada S, Taniguchi E, Koga H, et al. Endotoxin increases

paracellular permeability of isolated rat hepatocyte couplets. Hepatol Res. 2001;20:14454. [PubMed]

103. Jensen SA. Liver gene regulation in rats following both 70 or 90% hepatectomy and endotoxin

treatment. J Gastroenterol Hepatol. 2001;16:52530. [PubMed]

104. Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;76:606. [PubMed]

105. Marcos A, Fisher RA, Ham JM, Shiffman ML, Sanyal AJ, Luketic VAC, et al. Liver regeneration and

function in donor and recipient after right lobe adult to adult living donor liver transplantation.

Transplantation. 2000;69:13759. [PubMed]

106. Yamanaka N, Okamoto E, Kawamura E, Kato T, Oriyama T, Fujimoto J, et al. Dynamics of normal and

injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography

and liver function. Hepatology. 1993;18:7985. [PubMed]

107. Fausto N. Protooncogenes and growth factors associated with normal and abnormal liver growth.

Dig Dis Sci. 1991;36:6538. [PubMed]

108. Panis Y, Lomri N, Emond JC. Early gene expression associated with regeneration is intact after

massive hepatectomy in rats. J Surg Res. 1998;79:1038. [PubMed]

109. Haber BA, Mohn KL, Diamond RH, Taub R. Induction patterns of 70 genes during nine days after

hepatectomy define the temporal course of liver regeneration. J Clin Invest. 1993;91:131926. [PMC

free article] [PubMed]

110. Bruccoleri A, Gallucci R, Germolec DR, Blackshear P, Simeonova P, Thurman RG, et al. Induction of

early-immediate genes by tumor necrosis factor contribute to liver repair following chemical-induced

hepatotoxicity. Hepatology. 1997;25:13341. [PubMed]

111. Sakamoto T, Liu Z, Murase N, Ezure T, Yokomuro S, Poli V, et al. Mitosis and apoptosis in the liver of

interleukin-6-deficient mice after partial hepatectomy. Hepatology. 1999;29:40311. [PubMed]

112. Ehrenfried JA, Ko TC, Thompson EA, Evers BM. Cell cycle-mediated regulation of hepatic

regeneration. Surgery. 1997;122:92735. [PubMed]

113. Wu H, Wade M, Krall L, Grisham J, Xiong Y, Van Dyke T. Targeted in vivo expression of the cyclin-

dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development,

and regeneration. Genes Dev. 1996;10:24560. [PubMed]

114. Datto MB, Li Y, Pannus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor- induces the

cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA.

1995;92:554554. [PMC free article] [PubMed]

115. Xu Y, Bialik S, Jones BE, Iimuro Y, Kitsis RN, Srinivasan A, et al. NF-B inactivation converts a

hepatocyte cell line TNF- response from proliferation to apoptosis. Am J Physiol Cell Physiol.

1998;275:C105866.

116. Liu H, Ma Y, Pagliari LJ, Perlman H, Yu C, Lin A, et al. TNF-alpha-induced apoptosis of macrophages

following inhibition of NF-B: a central role for disruption of mitochondria. J Immunol. 2004;172:1907

15. [PubMed]

117. Liu H, Lo CR, Czaja MJ. NF-B inhibition sensitizes hepatocytes to TNF-induced apoptosis through a

sustained activation of JNK and c-Jun. Hepatology. 2000;35:7728. [PubMed]

118. Cressman DE, Diamond RH, Taub R. Rapid activation of the Stat3 transcription complex in liver

regeneration. Hepatology. 1995;21:14439. [PubMed]

119. Yang SQ, Lin HZ, Mandal AK, Huang J, Diehl AM. Disrupted signaling and inhibited regeneration in

obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology.

Hepatology. 2001;34:694706. [PubMed]

120. Torbenson M, Yang SQ, Liu HZ, Huang J, Gage W, Diehl AM. STAT-3 overexpression and p21 up-

regulation accompany impaired regeneration of fatty livers. Am J Pathol. 2002;161:15561. [PMC free

article] [PubMed]

121. Ronco MT, Alvarez Mde L, Monti JA, Carrillo MC, Pisani GB, Lugano MCC, et al. Role of nitric oxide

increase on induced programmed cell death during early stages of rat liver regeneration. Biochim

Biophys Acta. 2004;1690:706. [PubMed]

122. Rai RM, Lee FY, Rosen A, Yang SQ, Lin HZ, Koteish A, et al. Impaired liver regeneration in inducible

nitric oxide synthasedeficient mice. Proc Natl Acad Sci USA. 1998;95:1382934. [PMC free article]

[PubMed]

123. Garcia-Trevijano ER, Martinez-Chantarv ML, Latasa MU, Mato JM, Avila MA. NO sensitizes rat

hepatocytes to proliferation by modifying S-adenosylmethionine levels. Gastroenterology.

2002;122:135563. [PubMed]

124. Desbarats J, Newell MK. Fas engagement accelerates liver regeneration after partial hepatectomy.

Nature Med. 2000;6:9203. [PubMed]

125. Leist M, Ganter F, Kunstle G, Bohlinger I, Tiegs G, Bluethmann H, et al. The 55kD tumor necrosis

factor receptor and CD95 independently signal murine hepatocyte apoptosis and subsequent liver

failure. Mol Med. 1996;2:10924. [PMC free article] [PubMed]

126. Itch N, Yonehara S, Ishii A, Goeddel D. The polypeptide encoded by the cDNA for human cell surface

antigen Fas can mediate apoptosis. Cell. 1991;66:23343. [PubMed]

127. Fujita J, Marino NW, Wada H, Jungbluth AA, Mackrell PJ, Rivadeneira DE, et al. Effect of TNF gene

depletion on liver regeneration after partial hepatectomy in mice. Surgery. 2001;129:4854. [PubMed]

128. Lee FYJ, Li Z, Yang S, Lin HZ, Trush M, Diehl AM. Tumor necrosis factor increases mitochondrial

oxidant production and induces expression of uncoupling protein-2 in the regenerating rat liver.

Hepatology. 1999;29:67787. [PubMed]

129. Sakamoto T, Liu Z, Murase N, Ezure T, Yokomuro S, Poli V, et al. Mitosis and apoptosis in the liver of

interleukin-6-deficient mice after partial hepatectomy. Hepatology. 1999;29:40311. [PubMed]

130. Helling TS, Dhar A, Helling TS, Jr, Moore BT, Vanway C. Partial hepatectomy with or without

endotoxin does not promote apoptosis in the rat liver. J Surg Res. 2004;116:110. [PubMed]

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]

Articles from HPB : The Official Journal of the International Hepato Pancreato Biliary Association are

provided here courtesy of Blackwell Publishing

Formats:

Abstract

|

Article

|

PubReader

|

ePub (beta)

|

PDF (109K)

Related citations in PubMed

Hepatic surgery for metastases from neuroendocrine tumors. [Surg Oncol Clin N Am. 2003]

Mitochondrial respiratory function and antioxidant capacity in normal and cirrhotic livers following

partial hepatectomy. [Cell Mol Life Sci. 2004]

[Hepatic surgery. What progress? What future?]. [Gastroenterol Clin Biol. 2009]

Rodent models of partial hepatectomies. [Liver Int. 2008]

Hepatic expression of regeneration marker genes following partial hepatectomy in the rat. Influence

of 1,25-dihydroxyvitamin D3 in hypocalcemia. [J Hepatol. 1997]

See reviews... See all...

Cited by other articles in PMC

NIM811 Prevents Mitochondrial Dysfunction, Attenuates Liver Injury and Stimulates Liver

Regeneration after Massive Hepatectomy,, [Transplantation. 2011]

Activation of farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse

livers [Hepatology (Baltimore, Md.). 2010]

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver

regeneration in mice [The Journal of Clinical Investigation. 2009...]

See all...

Links

PubMed

Recent activity

Clear Turn Off

Liver failure following partial hepatectomy

PMC

Posthepatectomy liver failure: a definition and grading by the International Stu...

PubMed

Intraperitoneal septic complications after hepatectomy.

PMC

See more...

Review Fulminant hepatic failure: summary of a workshop. [Hepatology. 1995]

Classifying acute liver failure. [Lancet. 1993]

Review Liver regeneration. [J Am Coll Surg. 2003]

Clinicohistological features of liver failure after excessive hepatectomy. [Hepatogastroenterology.

2002]

Tolerance of the human liver to prolonged normothermic ischemia. A biological study of 20 patients

submitted to extensive hepatectomy. [Arch Surg. 1978]

Major hepatic resection under total vascular exclusion. [Ann Surg. 1989]

Liver ischemia for hepatic resection: where is the limit? [Surgery. 1992]

A clinicopathologic study of hepatic dysfunction following shock. [Surg Gynecol Obstet. 1976]

Personal experience with 411 hepatic resections. [Ann Surg. 1988]

Elective and emergency hepatic resection. Determinants of operative mortality and morbidity. [Ann

Surg. 1991]

Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic

hepatitis and cirrhosis. [Ann Surg. 1987]

Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis

of computed tomography and liver function. [Hepatology. 1993]

Liver ischemia for hepatic resection: where is the limit? [Surgery. 1992]

Accurate measurement of liver, kidney, and spleen volume and mass by computerized axial

tomography. [Ann Intern Med. 1979]

Graft size assessment by preoperative computed tomography in living related partial liver

transplantation. [Br J Surg. 1993]

Measurement of liver volume and hepatic functional reserve as a guide to decision-making in

resectional surgery for hepatic tumors. [Hepatology. 1997]

Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern

era with special reference to remnant liver volume. [J Am Coll Surg. 1999]

Standardized measurement of the future liver remnant prior to extended liver resection: methodology

and clinical associations. [Surgery. 2000]

Calculation of child and adult standard liver volume for liver transplantation. [Hepatology. 1995]

Doppler analysis of hepatic blood flow predicts liver dysfunction after major hepatectomy. [World J

Surg. 1994]

Effects of portal-systemic shunt following 90% partial hepatectomy in rats. [J Surg Res. 2000]

Impact of graft size mismatching on graft prognosis in liver transplantation from living donors.

[Transplantation. 1999]

Partial hepatic grafting: porcine study on critical volume reduction. [Surgery. 1995]

Liver transplantation in rats using small-for-size grafts: a study of hemodynamic and morphological

changes. [Arch Surg. 2001]

Modulation of portal graft inflow: a necessity in adult living-donor liver transplantation? [Ann Surg.

2003]

Small-for-size partial liver graft in an adult recipient; a new transplant technique. [Lancet. 2002]

Use of phosphorous-31 nuclear magnetic resonance spectroscopy to determine safe timing of

chemotherapy after hepatic resection. [Cancer Res. 2000]

Regenerative activity and liver function following partial hepatectomy in the rat using (31)P-MR

spectroscopy. [Hepatology. 2002]

Postoperative liver failure. [J Am Coll Surg. 1999]

Fulminant hepatic failure in rats: survival and effect on blood chemistry and liver regeneration.

[Hepatology. 1996]

Rat liver regeneration after 90% partial hepatectomy. [Hepatology. 1984]

The use of insulin and glucose during resuscitation from hemorrhagic shock increases hepatic ATP. [J

Surg Res. 2000]

Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct

carcinoma: a preliminary report. [Surgery. 1990]

Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization.

[Hepatology. 1995]

Preoperative portal vein embolization for extended hepatectomy. [Ann Surg. 2003]

Portal vein embolization before right hepatectomy: prospective clinical trial. [Ann Surg. 2003]

Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for

hepatocellular carcinoma in injured liver. [Ann Surg. 2000]

Hepatic resection in the elderly. [Ann Surg. 1990]

Hepatic resection in the elderly. [World J Surg. 1998]

Liver resection in the aged (seventy years or older) with hepatocellular carcinoma. [Surgery. 1993]

Liver resection for hepatocellular carcinoma in octogenarians. [Surgery. 1999]

Laboratory values in fit aging individuals--sexagenarians through centenarians. [Clin Chem. 1992]

Effect of aging on the hepatobiliary transport of dimeric immunoglobulin A in the male Fischer rat.

[Gastroenterology. 1985]

Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. [N Engl J Med.

1985]

Aging is associated with reduced liver regeneration and diminished thymidine kinase mRNA content

and enzyme activity in the rat. [J Lab Clin Med. 1991]

Effect of ageing on rat liver regeneration after partial hepatectomy. [Biochem Mol Biol Int. 1993]

The impact of donor age on living donor liver transplantation. [Transplantation. 2000]

Can hepatic failure after surgery for hepatocellular carcinoma in cirrhotic patients be prevented?

[World J Surg. 1990]

Resection of hepatocellular carcinomas. Results in 72 European patients with cirrhosis.

[Gastroenterology. 1990]

Transection of the oesophagus for bleeding oesophageal varices. [Br J Surg. 1973]

Risk of major liver resection in patients with underlying chronic liver disease: a reappraisal. [Ann Surg.

1999]

Can hepatic failure after surgery for hepatocellular carcinoma in cirrhotic patients be prevented?

[World J Surg. 1990]

Risk of major liver resection in patients with underlying chronic liver disease: a reappraisal. [Ann Surg.

1999]

Presence of active hepatitis associated with liver cirrhosis is a risk factor for mortality caused by

posthepatectomy liver failure. [Dig Dis Sci. 2000]

Hepatic steatosis as a potential risk factor for major hepatic resection. [J Gastrointest Surg. 1998]

Diabetes is associated with increased perioperative mortality but equivalent long-term outcome after

hepatic resection for colorectal cancer. [J Gastrointest Surg. 2002]

Review Fatty liver in liver transplantation and surgery. [Semin Liver Dis. 2001]

See more ...

The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic

function. [Clin Sci. 1961]

Blood loss and ICG clearance as best prognostic markers of post-hepatectomy liver failure.

[Hepatogastroenterology. 1999]

Measurement of serum hyaluronate as a predictor of human liver failure after major hepatectomy.

[World J Surg. 2000]

Measurement of serum hyaluronic acid level during the perioperative period of liver resection for

evaluation of functional liver reserve. [J Gastroenterol Hepatol. 2001]

Preoperative assessment of residual hepatic functional reserve using 99mTc-DTPA-galactosyl-human

serum albumin dynamic SPECT. [J Nucl Med. 1999]

Response of hepatic mitochondrial redox state to oral glucose load. Redox tolerance test as a new

predictor of surgical risk in hepatectomy. [Ann Surg. 1990]

See more ...

Intraperitoneal septic complications after hepatectomy. [Ann Surg. 1986]

Hepatic failure and coma after liver resection is reversed by manipulation of gut contents: the role of

endotoxin. [Surgery. 1991]

Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats.

[Gastroenterology. 1990]

Endotoxin- and cytokine-mediated effects on liver cell proliferation and lipid metabolism after partial

hepatectomy: a study with recombinant N-terminal bactericidal/permeability-increasing protein and

interleukin-1 receptor antagonist. [J Pathol. 1996]

Endotoxin and interleukin-1 related hepatic inflammatory response promotes liver failure after partial

hepatectomy. [Hepatology. 1995]

Kupffer cell tumor necrosis factor-alpha production is suppressed during liver regeneration. [J Surg

Res. 1991]

Inhibition of tumor necrosis factor-alpha production retards liver regeneration after partial

hepatectomy in rats. [Biochem Biophys Res Commun. 1997]

Progressive necrosis after hepatectomy and the pathophysiology of liver failure after massive

resection. [Surgery. 1997]

Role of macrophages in regeneration of liver. [Dig Dis Sci. 1996]

Liver failure induces a systemic inflammatory response. Prevention by recombinant N-terminal

bactericidal/permeability-increasing protein. [Am J Pathol. 1995]

Bacterial translocation in acute liver failure induced by 90 per cent hepatectomy in the rat. [Br J Surg.

1993]

Bacterial translocation in acute liver injury induced by D-galactosamine. [Hepatology. 1996]

Bacterial clearance in the intact and regenerating liver. [J Pediatr Surg. 1985]

Reticuloendothelial system and hepatocytic function in fulminant hepatic failure. [Gut. 1982]

Gamma-scintigraphy and early hepatocellular dysfunction during posttraumatic sepsis. [Surgery.

1994]

Review Endotoxin, reticuloendothelial function, and liver injury. [Hepatology. 1981]

Role of intracellular variations of lysosomal enzyme activity and oxygen tension in mitochondrial

impairment in endotoxemia and hemorrhage in the rat. [Ann Surg. 1973]

Studies on the effects of C. coli endotoxin on canalicular bile formation in the isolated perfused rat

liver. [J Lab Clin Med. 1977]

Decreased bilirubin transport in the perfused liver of endotoxemic rats. [Gastroenterology. 1994]

Lipopolysaccharide alters ecto-ATP-diphosphohydrolase and causes relocation of its reaction product

in experimental intrahepatic cholestasis. [Cell Tissue Res. 2001]

Kupffer cell-mediated down regulation of rat hepatic CMOAT/MRP2 gene expression. [Biochem

Biophys Res Commun. 1999]

See more ...

Review Liver regeneration. [Science. 1997]

Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic

hepatitis and cirrhosis. [Ann Surg. 1987]

Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver

transplantation. [Transplantation. 2000]

Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis

of computed tomography and liver function. [Hepatology. 1993]

Review Protooncogenes and growth factors associated with normal and abnormal liver growth. [Dig

Dis Sci. 1991]

Early gene expression associated with regeneration is intact after massive hepatectomy in rats. [J Surg

Res. 1998]

Induction patterns of 70 genes during nine days after hepatectomy define the temporal course of liver

regeneration. [J Clin Invest. 1993]

Induction of early-immediate genes by tumor necrosis factor alpha contribute to liver repair following

chemical-induced hepatotoxicity. [Hepatology. 1997]

Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy.

[Hepatology. 1999]

Cell cycle-mediated regulation of hepatic regeneration. [Surgery. 1997]

See more ...

Rapid activation of the Stat3 transcription complex in liver regeneration. [Hepatology. 1995]

Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for

nonalcoholic fatty liver disease pathophysiology. [Hepatology. 2001]

STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers. [Am J

Pathol. 2002]

Role of nitric oxide increase on induced programmed cell death during early stages of rat liver

regeneration. [Biochim Biophys Acta. 2004]

Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. [Proc Natl Acad Sci U S A.

1998]

NO sensitizes rat hepatocytes to proliferation by modifying S-adenosylmethionine levels.

[Gastroenterology. 2002]

Clinicohistological features of liver failure after excessive hepatectomy. [Hepatogastroenterology.

2002]

Induction of early-immediate genes by tumor necrosis factor alpha contribute to liver repair following

chemical-induced hepatotoxicity. [Hepatology. 1997]

Fas engagement accelerates liver regeneration after partial hepatectomy. [Nat Med. 2000]

The 55-kD tumor necrosis factor receptor and CD95 independently signal murine hepatocyte

apoptosis and subsequent liver failure. [Mol Med. 1996]

The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.

[Cell. 1991]

Effect of TNF gene depletion on liver regeneration after partial hepatectomy in mice. [Surgery. 2001]

Tumor necrosis factor increases mitochondrial oxidant production and induces expression of

uncoupling protein-2 in the regenerating mice [correction of rat] liver. [Hepatology. 1999]

Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy.

[Hepatology. 1999]

Partial hepatectomy with or without endotoxin does not promote apoptosis in the rat liver. [J Surg

Res. 2004]

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

signals. [Exp Gerontol. 2003]

Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells

to oxidant injury. [J Biol Chem. 2003]

Senescence marker protein-30 knockout mouse liver is highly susceptible to tumor necrosis factor-

alpha- and Fas-mediated apoptosis. [Am J Pathol. 2002]

You are here: NCBI > Literature > PubMed Central (PMC)

Write to the Help Desk

Simple NCBI Directory

Getting Started

NCBI Education

NCBI Help Manual

NCBI Handbook

Training & Tutorials

Resources

Chemicals & Bioassays

Data & Software

DNA & RNA

Domains & Structures

Genes & Expression

Genetics & Medicine

Genomes & Maps

Homology

Literature

Proteins

Sequence Analysis

Taxonomy

Training & Tutorials

Variation

Popular

PubMed

Nucleotide

BLAST

PubMed Central

Gene

Bookshelf

Protein

OMIM

Genome

SNP

Structure

Featured

Genetic Testing Registry

PubMed Health

GenBank

Reference Sequences

Map Viewer

Human Genome

Mouse Genome

Influenza Virus

Primer-BLAST

Sequence Read Archive

NCBI Information

About NCBI

Research at NCBI

NCBI Newsletter

NCBI FTP Site

NCBI on Facebook

NCBI on Twitter

NCBI on YouTube

NLM

NIH

DHHS

USA.gov

Copyright | Disclaimer | Privacy | Browsers | Accessibility | Contact

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