Sei sulla pagina 1di 13

Review

Acute-on chronic liver failure


Rajiv Jalan1,⇑, Pere Gines2, Jody C Olson3, Rajeshwar P Mookerjee1, Richard Moreau4,
Guadalupe Garcia-Tsao5, Vicente Arroyo2, Patrick S Kamath3
1
Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London,
United Kingdom; 2Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalunya, Spain, Institut d’Investigacions Biomèdiques
August-Pi-Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas yDigestivas (CIBEREHED), Spain; 3Division of
Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States; 4INSERM, U773, Centre de Recherche
Biomédicale Bichat-Beaujon CRB3, Paris and Clichy, France; 5Section of Digestive Diseases, Yale University School of Medicine,
New Haven, CT, United States

Summary manifesting as jaundice and coagulopathy, complicated within


4 weeks by ascites and/or encephalopathy in a patient with previously
Acute-on-chronic liver failure (ACLF) is an increasingly recogni- diagnosed or undiagnosed chronic liver disease’; and a second at a
sed entity encompassing an acute deterioration of liver function EASL-AASLD single topic symposium [3]; ‘Acute deterioration of
in patients with cirrhosis, which is usually associated with a pre-existing, chronic liver disease, usually related to a precipitating
precipitating event and results in the failure of one or more event and associated with increased mortality at 3 months due to
organs and high short term mortality. Prospective data to define multi-system organ failure’. These definitions are too imprecise to
this is lacking but there is a large body of circumstantial evidence allow homogeneous diagnostic criteria and clinical studies are cur-
suggesting that this condition is a distinct clinical entity. From rently underway to reach an evidence-based definition. The latter
the pathophysiologic perspective, altered host response to injury definition implies that organ failure is a central component of this
and infection play important roles in its development. This syndrome and leads to the hypothesis that the organs may behave
review focuses upon the current understanding of this syndrome differently to chronic decompensated liver disease. This review
from the clinical, prognostic and pathophysiologic perspectives focuses upon the current understanding of this syndrome from
and indicates potential biomarkers and therapeutic targets for the clinical, prognostic and pathophysiologic perspectives and
intervention. indicates potential biomarkers and therapeutic targets for inter-
Ó 2012 European Association for the Study of the Liver. Published vention. It is the second definition that will be used in the descrip-
by Elsevier B.V. All rights reserved. tion that follows unless otherwise stated.

Introduction Epidemiology

Acute-on-chronic liver failure (ACLF) is an increasingly recognised Data regarding the epidemiology of ACLF is rare. At the recently
entity encompassing an acute deterioration of liver function in held EASL-AASLD Single Topic Symposium on the management
patients with cirrhosis, either secondary to superimposed liver of critically ill cirrhotic patients in the ICU (Atlanta, 2010), data
injury or due to extrahepatic precipitating factors such as infection were presented from the nationwide in-patient sample in the
culminating in the end-organ dysfunction (Fig. 1). Occasionally, no US for the year 2006. Using the parameters of the need for
specific precipitating event can be found. Although the exact path- mechanical ventilation and/or invasive cardiovascular monitor-
ophysiology of the development of ACLF remains to be elucidated, ing, 26,300 patients were identified. In-hospital mortality was
unregulated inflammation is thought to be a major contributing found to be 53% and the mean length of hospitalization was about
factor. A characteristic feature of ACLF is its rapid progression, 14 days. The total charges associated with the ICU admissions
the requirement for multiple organ supports and a high incidence alone were 3 billion US dollars with a suggestion that the ICU
of short and medium term mortality of 50–90% [1]. The condition mortality in cirrhotic patients has remained unchanged [3]. It is
remains undefined but two consensus working definitions for this likely that a significant proportion of these patients had ACLF
syndrome exist. The first was put forward by the Asia–Pacific but is difficult to confirm until evidence-based definition of ACLF
association for the study of liver disease [2]; ‘Acute hepatic insult is derived.

Keywords: Acute-on chronic liver failure; Hepatorenal syndrome; Hepatic ence-


phalopathy; Immune failure; Liver support; Liver transplantation. Clinical and prognostic factors (P)
Received 3 April 2012; received in revised form 19 June 2012; accepted 19 June 2012
⇑ Corresponding author. Address: Liver Failure Group, UCL Institute for Liver and
Data on the natural history of patients with cirrhosis progressing
Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street,
London NW3 2PF, United Kingdom. Tel.: +44 2074332795. to multiorgan failure and its outcome are limited. In a study
E-mail address: r.jalan@ucl.ac.uk (R. Jalan). reported in a preliminary form, the group at UCL hypothesized

Journal of Hepatology 2012 vol. 57 j 1336–1348


JOURNAL OF HEPATOLOGY
Acute insult Table 1. SOFA scoring system.
100
Organ Measurement Score
PaO2 to FIO2 ratio ≥400 mmHg 0
Liver function (%)

300 to 399 mmHg 1


Threshold for organ failure 200 to 299 mmHg 2
100 to 199 mmHg 3
?Too late!
<100 mmHg 4
Chronic decompensation
of cirrhosis Platelet count ≥150,000 per µl 0
0
Months 100,000 to 149,999 per µl 1
50,000 to 99,999 per µl 2
Fig. 1. Acute-on chronic liver failure: diagrammatic representation of the 20,000 to 49,999 per µl 3
clinical concept. This figure describes the clinical concept of ACLF to distinguish
it from chronic decompensated cirrhosis. The red line describes the course of a <20,000 per µl 4
patient with chronic decompensation of cirrhosis that during evolution of their Serum bilirubin <1.2 mg/dl 0
liver disease will at some point develop organ dysfunction. This is usually in
association with advanced liver disease where the only option for treatment is 1.2 to 1.9 mg/dl 1
liver transplantation and the chances of reversibility of liver disease are very 2.0 to 5.9 mg/dl 2
limited. This is in contradistinction to the patient with acute-on chronic liver
failure (depicted by the blue line) who may often have a good liver reserve and 6.0 to 11.9 mg/dl 3
can deteriorate acutely over a short period, usually in association with a ≥12.0 mg/dl 4
precipitating illness that results in organ failure and high risk of death. The
patient may also have advanced liver disease but be stable and deteriorate Hypotension MAP ≥70 mmHg 0
acutely following a precipitating event, and progress to organ failure. By contrast, MAP <70 mmHg, 1
this patient has a potential for reversibility and recovery to the state the patient no pressor agents used
was in, prior to the acute event.
Dobutamine, any dose 2
Dopamine 5 µg/kg/min 2
that in patients with cirrhosis who present with acute deteriora- Dopamine >5 to 15 µg/kg/min 3
tion of cirrhosis due to a precipitating factor and progress to Dopamine >15 µg/kg/min 4
develop a single organ dysfunction have significantly different Epinephrine ≤0.1 µg/kg/min 3
outcome to those that do not develop a single organ dysfunction
Epinephrine >0.1 µg/kg/min 4
[4]. In a prospective study to explore this hypothesis, a group of
patients with liver cirrhosis that were admitted to a single unit Norepinephrine ≤0.1 µg/kg/min 3
over a 5.5-year period and managed according pre-defined man- Norepinephrine >0.1 µg/kg/min 4
agement guidelines were analyzed. Organ failure was defined as Glasgow coma score 15 0
the need for support of any organ. The patients were followed-up 13-14 1
clinically and biochemically until death or transplantation.
10-12 2
Among the approximately 500 patients studied, about one third
developed a single organ failure, of which 53% died during the 6-9 3
first hospital admission, also indicating that the occurrence of a 3-5 4
single organ dysfunction was reversible in nearly 50% of cases. Serum creatinine or Serum creatinine <1.2 mg/dl 0
The study also showed that both the severity of inflammation urine output Serum creatinine 1.2 to 1.9 mg/dl 1
and the occurrence of new infection were associated with a
Serum creatinine 2.0 to 3.4 mg/dl 2
higher risk of death [5].
The prognostic factors determining the outcome of patients Serum creatinine 3.5 to 4.9 mg/dl 3
with cirrhosis and multiorgan failure are currently under evalua- Urine output 200 to 499 ml/day 3
tion, but it seems that the scoring systems addressing the sever- Serum creatinine >5.0 mg/dl 4
ity of liver disease, such as Child-Pugh score [6] or Model of End
Urine output <200 ml/day 4
Stage Liver Disease (MELD) [7] perform less well than the scoring
MAP, mean arterial pressure.
systems addressing organ dysfunction such as the Sequential
Organ Failure Assessment (SOFA) (Table 1) [8] or the Acute Phys-
iology, Age and Chronic Health Evaluation (APACHE) [9] scores.
The available data describing the outcome of patients with cir-
rhosis who develop organ failure and are admitted to the ICU
are summarized in Table 2 and 3 [10–44]. Critical examination liver disease measured using conventional clinical and biochem-
of the data indicates two fundamentally important conclusions. ical testing (Child-Pugh score) that is important, but the degree of
First, the data suggest that the occurrence of an organ failure in end-organ failure that determines outcome. In these complex
patients with cirrhosis with a defined severity of liver disease patients, a concept similar to the PIRO concept in sepsis (predis-
indicates a poor prognosis with very wide survival figures, which position, infection/inflammation, response, organ failure) [45] might
is possibly related to criteria for ICU admission. This notion is be useful in describing pathophysiology and clinical categories
supported by the second conclusion that it is not the severity of (Fig. 2).

Journal of Hepatology 2012 vol. 57 j 1336–1348 1337


Review
Table 2. Comparison of the current literature on mortality rates of patients with cirrhosis and organ failure.

Reference Number of patients Patient selection ICU mortality (%) Hospital mortality (%)
Goldfarb et al., 1983 100 Cirrhosis on ICU, MV 89 -
Shellman et al., 1988 100 Cirrhosis on ICU - 64
Zauner et al., 1996 198 Cirrhosis on ICU
Zimmerman et al., 1996 117 Cirrhosis on ICU, MV 63
Lee et al., 1997 47 Cirrhosis on ICU, MV 83 -
Singh et al., 1998 54 Cirrhosis on ICU 43
Kress et al., 2000 138 Cirrhosis on ICU 56
Aggarwal et al., 2001 582 Cirrhosis on ICU 37 49
Wehler et al., 2001 143 Cirrhosis on ICU 36 46
Tsai et al., 2003 111 Cirrhosis on ICU 65
Chen et al., 2003 76 Cirrhosis on ICU, bleeding 68
Chen et al., 2004 67 Cirrhosis on ICU, renal failure 87
Ho et al., 2003 135 Cirrhosis on ICU 67
Tsai et al., 2004 160 Cirrhosis on ICU
Gildea et al., 2004 420 Cirrhosis on ICU 69 (1-yr mortality)
Arabi et al., 2004 129 Cirrhosis on ICU 74 -
Rabe et al., 2004 76 Cirrhosis on ICU, MV 59
du Cheyron et al., 2005 73 Cirrhosis on ICU, renal failure 65, no renal failure 35
Cholongitas et al., 2006 312 Cirrhosis on ICU 65
Mackle et al., 2006 107 Alcoholic liver disease on ICU 58 88
Chen et al., 2006 102 Cirrhosis on ICU 68
Jenq et al., 2007 134 Cirrhosis on ICU 68
Cholongitas et al., 2008 128 Cirrhosis on ICU after 48 h 55
Fang et al., 2008 111 Cirrhosis on ICU, renal failure 82
Juneja et al., 2009 104 Cirrhosis on ICU 42 56
Cholongitas et al., 2009 412 Cirrhosis on ICU 61
Thomson et al., 2010 137 Cirrhosis on ICU 38 47
Filloux et al., 2010 86 Cirrhosis on ICU 37 48
Juneja et al., 2011 73 Cirrhosis on ICU, MV 75 88
Levesque et al., 2012 377 Cirrhosis on ICU 35 43
Cavallazzi et al., 2012 441 Cirrhosis on ICU
Shawcross et al., 2012 660 Cirrhosis on ICU 51
ICU, intensive care unit; MV, mechanical ventilation.

Pathophysiological basis determined by the MELD score, age, and the American Society
of Anesthesiologists (ASA) score [46]. Patients with a low MELD
Precipitating event (I) score who die immediately following surgery often had cerebral
edema [47].
ACLF usually results following a precipitating event on the back- When HAV infection occurs in the setting of cirrhosis, there is
ground of established cirrhosis. The ‘event’ may directly exagger- a substantial risk of ACLF and death [48]. Hepatitis E virus (HEV)
ate liver injury such as alcoholic hepatitis, drug-induced liver is an important cause of ACLF in Southern and Central Asia, China,
injury, superimposed viral hepatitis, portal vein thrombosis and Africa, and the Indian subcontinent and leads to rapid hepatic
ischemic hepatitis or liver decompensation may be consequent decompensation and death. In a prospective study of 107 patients
upon extra-hepatic insults such as trauma, surgery, variceal with cirrhosis of varying severity, mortality was much higher in
bleeding or infection. In a proportion of patients, there may be patients with superimposed HEV infection vs. non-infected cir-
no identifiable precipitating event. The best studied precipitating rhotics. Mortality rate between HEV infected vs. non-infected cir-
events are surgery and superimposed viral hepatitis in relation to rhotics at 4 weeks was 43% vs. 22% (p = 0.001) respectively and
the development of ACLF. The most important predictors of 70% vs. 30% (p = 0.001) at one year [49]. Patients who acquire
post-operative mortality were severity of liver disease as acute HBV infection in the setting of chronic liver disease are

1338 Journal of Hepatology 2012 vol. 57 j 1336–1348


JOURNAL OF HEPATOLOGY
Table 3. Comparison of data on prognostic accuracy of organ failure scores and liver disease scores in patients with liver cirrhosis and organ failure.

Reference Number of Patient APACHE II APACHE III SOFA OFS Child-Pugh


patients selection (AUROC) (AUROC) (AUROC) (AUROC) score (AUROC)
Zauner et al., 1996 198 Cirrhosis on ICU 0.75 0.8 - - -
Zimmerman et al., 1996 117 Cirrhosis on ICU, Accurate for
MV risk stratification
Singh et al., 1998 54 Cirrhosis on ICU Predicts Does not
mortality predict mortality
Kress et al., 2000 138 Cirrhosis on ICU Predicts
mortality
Afessa et al., 2000 111 Cirrhosis on ICU, 0.78 0.76
bleeding
Wehler et al., 2001 143 Cirrhosis on ICU 0.79 0.94 0.74
Ho et al., 2003 135 Cirrhosis on ICU 0.833 0.75
Tsai et al., 2003 111 Cirrhosis on ICU 0.901 0.748
Chen et al., 2003 76 Cirrhosis on ICU, 0.887 0.900 0.706
bleeding
Tsai et al., 2004 160 Cirrhosis on ICU 0.892 0.906 0.712
Chen et al., 2004 67 Cirrhosis on ICU, 0.878 0.873
renal failure
Rabe et al., 2004 76 Cirrhosis on ICU, 0.66 0.87
MV
Gildea et al., 2004 420 Cirrhosis on ICU Predicts
mortality
Cholongitas et al., 2006 312 Cirrhosis on ICU 0.78 0.83 0.72
Chen et al., 2006 102 Cirrhosis on ICU 0.91 0.91
Jenq et al., 2007 134 Cirrhosis and 0.92
renal failure on ICU
Cholangitas et al., 2008 128 Cirrhosis on ICU 0.78 0.88 0.85 0.78
after 48 h
Fang et al., 2008 111 Cirrhosis on ICU
with renal failure
Juneja et al., 2009 104 Cirrhosis on ICU 0.90 0.93
Cholangitas et al., 2009 412 Cirrhosis on ICU 0.84
Thomson et al., 2010 137 Cirrhosis on ICU
Filloux et al., 2010 86 Cirrhosis on ICU
Juneja et al., 2011 73 Cirrhosis on ICU 0.77 0.94 0.83
requiring mechanical
ventilation
Levesque et al., 2012 377 Cirrhosis on ICU 0.92 0.79
Cavallazzi et al., 441 Cirrhosis on ICU
2012
ICU, intensive care unit; MV, mechanical ventilation.

more likely to suffer decompensation, which is common in carri- bleeding saves lives [54,55]. It is likely that the common end
ers who receive immunosuppressive therapy [50,51]. In a study point that leads from the precipitating event to the development
from India, patients with reactivation of HBV and ACLF were of ACLF is an altered host response to injury, resulting in an
shown to have improved survival if they were treated with ten- inappropriate inflammatory response and immune dysfunction
ofovir compared with no therapy [52]. Although the ethics of this increasing the susceptibility to infection [56].
study can be questioned, it illustrates that early intervention may
prevent occurrence of multiorgan failure by aggressively target- Inflammation and infection (R)
ing the precipitating event. This principle is also illustrated by
the demonstration that survival of patients with variceal bleeding The role of a systemic inflammatory response (SIRS), which is a
can be improved by the prompt use of antibiotics, which reduces collection of simple and relatively crude clinical and hematolog-
the risk of infection [53]. Rapid control of the bleeding episode ical measure using heart and respiratory rate, white cell count,
with the insertion of a transjugular intrahepatic stent shunt in and temperature, in determining the outcome of patients with
patients with advanced liver disease or those with active liver failure was first fully described in the acute liver failure,

Journal of Hepatology 2012 vol. 57 j 1336–1348 1339


Review
The PIRO concept of acute-on chronic liver failure Assessment Intervention

Predisposition Severity of cirrhosis • Aetiology Early identification


• Pugh score Risk stratification
• MELD Preventative strategies
• [Biomarkers] [Novel interventions]

Injury Precipitating event • Hepatic Rapid intervention to treat event


• Extra-hepatic Bundles of care
• [Therapies] [Novel interventions]

• Inflammation Vigilance, monitoring


Response Inflammation • Immune failure Goal directed approaches
• [Biomarkers] [Biomarkers and novel interventions]

Organ Organ failure • SOFA Intensive care, organ support


• APACHE Liver transplantation
• [Biomarkers] [Liver support, stem cell therapies]

Fig. 2. The PIRO concept of acute-on chronic liver failure. In patients with ACLF, it is useful to think about the PIRO concept in determining pathogenesis and prognosis.
Predisposition is indicated by the severity of the underlying illness. Injury by the nature and severity of the precipitating event. Response by host response to injury, which
determines the severity of inflammation and risk of infection. Organs by the extent of organ failure. Categorisation of patients into these entities allows definition of
interventions and helps define prognosis at different levels.

where the presence of SIRS was associated with more severe in-dwelling cannulas and very early treatment remain the cor-
encephalopathy, associated infection, renal failure, and poor nerstones of therapy. The relationship between the SIRS response
outcome [57–59]. Elevated levels of multiple pro- and anti- and infection leads one to hypothesise that an inflammatory
inflammatory cytokines have been described in ACLF including response may lead to immune dysregulation, which may predis-
TNF-a, sTNF-aR1, sTNF-aR2, IL-2, IL-2R, IL-6, IL-8, IL-10, and pose to infection that would then further aggravate a pro-inflam-
IFN-! [60,61]. More recently, the mortality of patients presenting matory response resulting in a vicious cycle [56]. This
with renal dysfunction of cirrhosis has been shown to be signifi- immunopathology of ACLF is reminiscent of the multimodal
cantly higher in the group with SIRS [62,63]. It is not surprising immunological response observed in patients with severe sepsis,
that SIRS should be associated with increased inflammatory cyto- which is characterised by an initial SIRS response followed by a
kine response but the use of anti-TNF alpha strategies in patients mixed (MARS) and subsequently compensated anti-inflammatory
with alcoholic hepatitis who demonstrate an inflammatory response (CARS) (Fig. 3 and 4).
response is associated with an increased risk of infection and The associated mechanisms of this phenomenon are not clear
mortality [64,65]. but immune paresis has been suggested as a possible mechanism
Infection is a common feature of ACLF, which complicates the [71–73]. A recent study in cirrhotic patients suggested that a
natural history and is associated with significant morbidity and genetic predisposition may underlie the risk of infection. The
mortality [66]. About 40–50% of hospital admissions of cirrhotic investigators focussed on Toll-like receptor (TLR) 2 and nucleo-
patients are with sepsis and a further 20–40% will develop noso- tide-binding oligomerisation domain (NOD) 2 which recognize
comial infections. Overall in-hospital mortality rates of cirrhotic pathogen-associated molecular patterns (PAMS). In a multivari-
patients with infection are about 15%, which is about twice those ate analysis, they confirmed that TLR2 GT microsatellite polymor-
without infection. The mortality rate of cirrhotic patients with phism and NOD2 variants were independent predictors of
severe bacterial infection with septic shock is about 60–100% spontaneous bacterial peritonitis (SBP) when both risk factors
[66–70]. In cirrhotic patients, sepsis is a common precipitating were present, the risk of SBP was dramatically increased (odds
event resulting in hepatic encephalopathy, renal dysfunction ratio: 11.3; p = 0.00002) [74]. In alcoholic hepatitis patients,
and rebleeding, and mortality associated with variceal bleeding. neutrophil activation indicated by increased resting burst and
Vigilance, repeated cultures from various sites, cautious use of reduced phagocytic function was predictive of subsequent

1340 Journal of Hepatology 2012 vol. 57 j 1336–1348


JOURNAL OF HEPATOLOGY
Liver failure/bacterial translocation SIRS: Systemic inflammatory response

• Endotoxemia
• Reduced protein/complement synthesis
• Reduced immune surveillance Normal

Immune response
• Reduced albumin function ACLF: survivor
ACLF: non-survivor

Immune paralysis

Innate immunity Adaptive immunity


• Neutrophils: phagocytic defect • T-cell exhaustion
• Monocytes: DR loss • Inability to profilerate CARS: Compensatory anti-inflammatory response
• NK cells • Increased apoptosis

Fig. 3. Immune dysfunction of acute-on chronic liver failure. This figure describes the level of immune dysfunction that may be operative in patients with acute-on
chronic liver failure and proposes the hypothesis that the immune status of patients during the illness may not be constant. Patients may move from a pro-inflammatory to
an anti-inflammatory state, making them susceptible to infection. It is likely that the patients that do not resolve the compensated anti-inflammatory response are the ones
that will become infected and have the highest mortality rates.

Bacterial translocation
Bacterial infection

SIRS

Worsening systemic and


hepatic hemodynamics/
liver function

Compensated
cirrhosis

Increasing portal
pressure, fibrosis Multiorgan failure Death
and vasodilatation • Hypotension
• Renal failure
Decompensated • Jaundice
cirrhosis • Coagulopathy
• Encephalopathy
• VH
• Ascites
• HE

Fig. 4. Role of bacterial translocation in acute-on chronic liver failure. In the transition from compensated to decompensated cirrhosis (marked by the development of
variceal hemorrhage, ascites and/or hepatic encephalopathy) increasing portal pressure and liver fibrosis play a predominant role, while vasodilatation (and the resultant
hyperdynamic circulatory state) is not as prominent. Conversely, the development of multiorgan failure is characterized by significant alterations in systemic and hepatic
hemodynamics and worsening of liver function. Bacterial translocation plays an important role in the transition of patients from compensated to decompensated cirrhosis,
and together with bacterial infection is the most frequent precipitant of such deterioration via the systemic inflammatory response. VH, variceal hemorrhage; HE, hepatic
encephalopathy.

Journal of Hepatology 2012 vol. 57 j 1336–1348 1341


Review
infection, organ failure and mortality [72]. Importantly, data from neutralisation with high density lipoprotein administration has
ex vivo studies showed that this neutrophil dysfunction was been associated with a reduction in portal pressure [85]. An
reversible and possibly due to a circulating humoral factor that increase in reactive oxidant species, in particular superoxide, is
was hypothesised to be endotoxin [72]. In another study, also observed in ACLF, contributing to an increase in intrahepatic
monocyte HLA-DR expression was significantly reduced in ACLF resistance by reducing nitric oxide bioavailability [86]. In patients
who also showed an inability to produce TNF-a, the severity of with ACLF, defined according to APASL criteria, no differences in
which correlated with survival [71–73]. These observations the portal hemodynamics between decompensated cirrhosis and
provide potential biomarkers to predict infection risk and allow ACLF were observed [87], but using the EASL-AASLD definition,
individualisation of therapy. Modulation of enteric microflora the portal pressure was markedly higher [88] in those with ACLF
with probiotic therapy has been shown to restore neutro- pointing to the need to carefully define the population under
phil phagocytic capacity [75]. In a randomised clinical trial, study.
administration of the granulocyte-colony stimulating factor was Hepatic eNOS activity has been shown to be reduced in the
associated with improved survival of patients with ACLF [76]. context of cirrhosis with superadded inflammation [89,90]. NOS
The study included 47 patients with ACLF using the APASL defini- activity is subject to regulation by a number of inhibitors such
tion and the investigators showed a very high 2-month mortality as asymmetric dimethylarginine (ADMA), which is increased dur-
of 71% in the untreated group compared with about 30% in the ing inflammation resulting in high ADMA levels [91]. This has
treated group. Clearly, this study will need to be repeated with been suggested as both a prognostic marker and a possible target
larger numbers of patients but provides the proof of concept of therapy. Evidence suggests that in addition to decreased nitric
that modulation of immune paresis may prevent the progression oxide generation, there is also a reduced response to nitric oxide
of ACLF. in cirrhotic livers likely caused by dysfunction of the cyclic GMP
system. Phosphodiesterase-5 inhibitors such as sildenafil, which
increase cGMP, have been shown to have a beneficial effect on
The organs in ACLF (O) intrahepatic resistance [92]. Further studies are therefore needed
in ACLF in whom both liver blood flow and intrahepatic resis-
Liver and hepatic hemodynamics tance are altered.

The hallmark of the liver manifestation of ACLF is hyperbilirubi- Kidney dysfunction


nemia and coagulopathy but the pathophysiological basis is
unclear. It is likely that the histopathological characteristics of HRS is thought to be a functional disorder secondary to circula-
the liver during ACLF will be determined by the underlying cause tory dysfunction in which there is splanchnic vasodilatation, a
of cirrhosis and the nature of the precipitating event. The occur- lowering of arterial blood pressure, intense renal vasoconstric-
rence of ACLF due to a non-specific insults such as infection or a tion, impaired cardiac function and marked activation of the sym-
variceal bleeding is likely to be different from the effect of direct pathetic and neurohormonal systems [93–95]. However, in
hepatotoxins such as drugs or superimposed viral hepatitis. patients with ACLF who present with renal dysfunction, the char-
Recent studies in patients with acute deterioration of alcoholic acteristics may be widely variable. Thus, in some patients the cir-
cirrhosis and resultant ACLF showed presence of SIRS and biliru- culatory changes may predominate, and in other patients there
binostatis as early markers to identify these high-risk patients may be increased synthesis of pro-inflammatory mediators or
[77,78]. The investigators made the important observation that both. Administration of terlipressin and albumin remains the cur-
the presence of bilirubinostasis was associated with an increased rent gold standard for treatment of patients with HRS, but is
risk of subsequent infection. In another study, in a similar popu- unsuccessful in 54% of patients [96]. It is likely that in these latter
lation, the role of bilirubinostasis was confirmed and the investi- patients different factors predominate in the development of
gators also observed that K8/18 immunostaining was reduced renal dysfunction. In about 30–40% of patients with cirrhosis
suggesting loss of cellular actin and microtubular structure, who develop renal dysfunction, a bacterial infection is the precip-
which was associated with important prognostic information itating cause (SBP) [94]. Indeed, the presence of SIRS in patients
[79]. At present, there is no clarity on the mechanism of cell- with renal dysfunction was associated with infection in 56% of
death or capacity for regeneration of ACLF livers. Early biopsy the subjects, which was a major independent prognostic factor
may help in both the management of patients and providing an for mortality in these patients [63]. Traditionally, renal dysfunc-
understanding of the mechanisms involved, as new drugs, such tion has been suggested to be reversible with transplantation.
as pan-caspase inhibitors or stimulators of hepatic regeneration, However, recent data suggests that patients that are transplanted
may be useful [80]. with evidence of renal tubular injury on the background of cir-
Liver inflammation is an important determinant of portal rhosis are more likely to require renal replacement therapy after
pressure and prognosis in cirrhosis. Patients with ACLF that transplantation than patients undergoing transplantation with
occurs on the background of alcoholic hepatitis have increased HRS, suggesting that the basis of renal dysfunction in ACLF is
plasma TNF-a level and also the highest portal pressures [81]. not the same as HRS [97]. The important pathophysiological role
Indeed anti-TNF-a therapy has been shown to reduce portal of inflammation in modulating renal dysfunction associated with
pressure in patients with severe alcoholic hepatitis and cirrhosis ACLF is highlighted by the benefit of anti-inflammatory agents
[81]. Several lines of evidence exist implicating gut-derived such as albumin, pentoxifylline and N-acetylcysteine, which
endotoxemia in the pathogenesis of portal hypertension [82]. decreased the risk of renal dysfunction in patients with alcoholic
Modulation of the portal bacterial load using antibiotics such hepatitis [98,99]. Albumin in this situation probably acts as an
as quinolones and rifaxamin has been associated with a anti-inflammatory agent and has been shown to protect the kid-
reduction in inflammation and portal pressure [83,84]. Endotoxin ney during spontaneous bacterial peritonitis and is associated

1342 Journal of Hepatology 2012 vol. 57 j 1336–1348


JOURNAL OF HEPATOLOGY
with improved survival in patients with renal failure [100,101].
Administration of prophylactic norfloxacin, a selective gut decon- Acute on Chronic Liver Failure
taminant reduced the incidence of renal failure and improved
survival [102]. The mechanism of the protective effect of norflox-
acin was explored in animal models of cirrhosis and AKI and
shown to result from modulation of renal NFkB and cytokines Inflammation Hyperammonemia
possibly mediated through a TLR4-based mechanism. In a preli-
minary observation, increased TLR4 has been shown in renal
tubules in ACLF patients, which was not observed in HRS [103]. Astrocytic swelling
These data provide potential novel insights into pathophysiology
and the potential for the development of novel biomarkers and
therapeutic approaches. Thus, the use of urinary biomarkers that
reflect renal injury may allow early diagnosis of renal dysfunction Activation of transcription factors
of cirrhosis and allow the functional causes of renal dysfunction
to be better distinguished from the inflammatory causes. The bio-
markers of interest are markers of tubular injury such as kidney
Activation of NFkB Cytokines
injury molecule-1, pi and alpha glutathione S-transferase; mark-
ers of inflammation such as NAG, NGAL, FABP, and IL-18 [104]. It
is possible that novel therapeutic approaches may be developed if
this hypothesis can be confirmed. Oxidative stress
iNOS; nitrotyrosine
Brain dysfunction

Hepatic encephalopathy (HE) is a common manifestation of ACLF Hepatic Encephalopathy


[1,105–107]. Local and systemic changes have been implicated in
the pathophysiology of the development of this neurological syn- Fig. 5. Pathophysiological mechanisms of brain dysfunction in acute-on
drome. From the pathophysiological perspective, like the situa- chronic liver failure. This figure describes the possible mechanisms underlying
the pathogenesis of hepatic encephalopathy in acute-on chronic liver failure. It is
tion in acute liver failure, brain swelling is an important feature likely that similar mechanisms are operative in other organs, where susceptibility
of ACLF also [105–108]. As the syndrome occurs on the back- to an inflammatory insult is provided by organ characteristics that are a feature of
ground of existing cirrhosis and chronic portacaval shunting, a that particular organ in cirrhosis.
degree of brain atrophy protects from this brain swelling, result-
ing in an increase in intracranial pressure. There are, however,
several reports of significant increases in intracranial pressure
in patients with ACLF [105–107]. Studies using MRI have shown recent study, the acute effect of insertion of a transjugular intra-
that this increase in brain swelling can be reversed with liver hepatic shunt, which is known to induce endotoxemia, was stud-
transplantation supporting the notion that, like acute liver fail- ied in patients with cirrhosis. The study demonstrated that TIPSS-
ure, the brain manifestation of ACLF is a reversible disorder induced endotoxemia led to an increase in the rate of production
[109]. Ammonia is thought to play a key role in the development of nitric oxide, which was associated with endothelial dysfunc-
of HE but no direct relationship between the severity of hyperam- tion and increased cerebral blood flow supporting the hypothesis
monemia and HE could be demonstrated [110]. On the back- that multiple hits and brain swelling is a feature of ACLF [115]
ground of this hyperammonemia, an added hepatic insult and/ (Fig. 5). However, the insertion of TIPSS in relatively well cirrho-
or superimposed inflammation leads to the development of brain tics without hepatic encephalopathy undergoing TIPSS was not
edema suggesting a synergy between ammonia and inflamma- associated with a change in cerebral blood flow, stressing the
tion. The synergy between ammonia and inflammation has been pathophysiologically distinct nature of ACLF from otherwise sta-
demonstrated in animal models of cirrhosis where acute brain ble cirrhosis [116].
swelling was observed following administration of endotoxin
mimicking the clinical situation seen in ACLF [108]. The mecha- Cardiac and systemic hemodynamics
nism is likely to be related to generation of cytokines in the brain,
increased iNOS expression, oxidative stress and formation of In patients with decompensated cirrhosis, a hyperdynamic cir-
nitrated protein adducts [108,111]. Studies in animal models culation is the key hemodynamic feature. The increased cardiac
have suggested that ammonia may prime the brain to the delete- output observed in this situation is mainly due to a vasodilated
rious effects of superimposed inflammation by induction of splanchnic bed but paradoxically, the blood flow in other
microglial cells, which have a huge repertoire for cytokine pro- organ, such as kidneys, brain and peripheral organs, is
duction; and a reduction in ammonia in cirrhotic models pre- decreased [117]. Additionally, patients with cirrhosis may have
vents the effect of superimposed inflammation [108,111–113]. an underlying cirrhotic cardiomyopathy, which may make
Conversely, reduction in bacterial translocation using a non- them susceptible to cardiovascular collapse during an acute
absorbable antibiotic, rifaximin was shown to prevent the occur- inflammatory insult, but data supporting that hypothesis does
rence of HE, suggesting that reducing inflammation may be pro- not exist [118]. The hallmark of ACLF is cardiovascular collapse
tective as well [114]. Cerebral blood flow is known to be akin to the patients with acute liver failure and severe sepsis,
progressively reduced in cirrhosis but in ACLF may be paradoxi- often requiring large doses of inotropes. Unlike decompensated
cally increased as seen in patients with acute liver failure. In a cirrhosis, where the cardiac output remains elevated, in ACLF,

Journal of Hepatology 2012 vol. 57 j 1336–1348 1343


Review
despite splanchnic vasodilation, the cardiac output can be Hepato-adrenal axis
reduced and both systolic and diastolic functions are affected.
This cardiovascular abnormality is associated with increased Adrenal insufficiency is reported in 51–68% of patients with
risk of death, particularly in those patients who present with cirrhosis and severe sepsis, particularly in patients with high
renal dysfunction [119]. In another study, where the definition Child-Pugh and MELD scores and hemodynamic instability.
of ACLF was based upon the APASL criteria, no differences in Adrenal insufficiency is associated with increased mortality
cardiac output were observed, highlighting the fact that the compared to patients without adrenal insufficiency [131].
designation is crucial in defining which patients are being Administration of hydrocortisone to patients with septic shock
described. The mechanisms underlying the cardiac dysfunction and adrenal insufficiency was shown to improve the circulatory
in ACLF are likely similar to those in severe sepsis, such as car- function but routine use of hydrocortisone during sepsis has
diovascular-active factors like TNF and nitric oxide which are not been confirmed to improve the outcome [132]. Interpreta-
increased, and cortisol which is decreased [120]. The former tion of response to synacthen test in cirrhosis and ACLF is dif-
can further dilate the vasculature and the latter decreases the ficult due to methodological constraints, so no conclusions can
sensitivity to vasoconstrictors. However, no study has yet dem- be made.
onstrated the benefit of vasodilators/vasoconstrictors in the
management of ACLF. It is important to monitor the cardiac
situation using appropriate methods to guide fluid replacement Intensive care management, organ support and
and inotrope support. The choice of inotropes is also unclear transplantation
but vasopressin analogue in this situation should be used cau-
tiously as it may further reduce cardiac perfusion and an Intensive care management of patients with ACLF has been
already compromised hepatic blood flow [121]. recently reviewed and a full description is beyond the scope
of this review. The essential principles are those of multiple
Coagulation organ support to allow the treatment of the precipitating
event and the recovery of the liver. The two specific aspects
Routine diagnostic tests of coagulation are usually abnormal of treatment relevant to this group of patients are discussed
in patients with cirrhosis due to multiple defects. An below [3].
increased bleeding tendency has been attributed to the degree Liver support devices are intended to provide detoxification
of abnormalities in these tests, but this has not been formally functions to patients with ACLF until liver transplantation, recov-
proven [122]. Thrombin generation is normal in stable cirrho- ery or futility. The overall efficacy of liver support devices have
tics with a rebalancing of pro- and anti-coagulant factors (pro- failed to reach a level sufficient to gain approval for widespread
viding there are sufficient platelets >50,000  109/L). Since use [133]. Liver support devices are of two main types; artificial
hypercoagulation may exist [123], bleeding abnormalities are livers-acellular devices such as albumin dialysis and plasma-
far less frequent than it would be expected [124]. In cirrhosis exchange/diafiltration, and bio-artificial livers, which incorporate
with sepsis, endogenous low-molecular weight heparinoids are cells from human, animal, or transformed sources. An unpub-
detected, and disappear with resolution of infection [68]. Anti- lished study using the ELAD device which incorporates liver can-
biotics are known to reduce early variceal rebleeding rates cer cells, C3A cells, into the device, was shown in a preliminary
[125]. The use of prophylactic blood products to correct study to be useful in patients with ACLF, mainly induced by
abnormalities to prevent bleeding is empirical and often HBV reactivation in a small randomised controlled study [134].
guided by local protocols; virtually none of these are evi- A pivotal clinical trial in USA and Europe has been stopped. None
dence-based [126]. Moreover, normalization of abnormal coag- of the bioartificial liver devices as far as we know, are in clinical
ulation parameters is difficult to achieve, and creates volume trials for ACLF patients at present.
excess, increasing the risk of transfusion-related acute lung The best studied artificial liver support devices are the
injury and other transfusion reactions. Even recombinant fac- molecular adsorbents recirculating system (MARS) and Prome-
tor VIIa, which corrects prothrombin time, does not reduce theus devices, which are based upon the principles of albumin
blood loss during variceal bleeding [127]. Conversely, antifibri- dialysis [135]. These devices are based on the concept that albu-
nolytic agents do reduce blood loss during liver transplanta- min is a complex molecule with a plethora of physiological
tion, but have not been evaluated prophylactically during functions besides providing oncotic properties [136]. Studies
other procedures or for bleeding. Apart from increased fibrino- have demonstrated that during hepatic failure, the circulating
lysis, which is seen in ACLF, defective platelet function is the albumin undergoes structural and functional modifications that
other major abnormality [128]. The thrombopoietin analog negatively affect its biological activity [136]. These devices are
eltrombopag may be thrombogenic at least in stable cirrhosis designed to provide additional detoxification functions. Several
(there has been a suspended trial in this area), probably studies have confirmed that the use of these devices can remove
because of the interaction with the very high levels of vWF inflammatory molecules, reduce NO and improve systemic and
in cirrhosis. The use of fresh frozen plasma is limited by the hepatic hemodynamics, severe hepatic encephalopathy leading
volume of transfusions; safer prothrombin complex concen- to large clinical trials [61]. The randomised controlled trial of
trates which have 20 times the concentration of factors than the Prometheus device in patients with ACLF has been recently
FFP are now available [129]. Currently, prophylactic transfu- published [137]. The data show that the approach is safe and
sions of any coagulation products are difficult to justify and well tolerated, although there is no overall significant survival
it is likely that more comprehensive, global tests of coagula- benefit at 28 days. Subgroup analysis suggested that patients
tion are needed to guide the correction of coagulation on an with a MELD score of >30 and those with hepatorenal syndrome
individual basis [130]. may have some benefit. MARS was tested in a similar cohort,

1344 Journal of Hepatology 2012 vol. 57 j 1336–1348


JOURNAL OF HEPATOLOGY
the RELIEF trial, which has been reported in a preliminary com-
munication and again failed to show any survival benefit [138]. Key Points
A better definition of ACLF would allow the study of a more
homogenous cohort, but it is likely that modifications to the • Acute-on chronic liver failure is a syndrome that defines
a subgroup of cirrhotic patients who develop organ
current devices will be necessary to improve their efficacy and
failure following hospital admission with or without an
capacity.
identifiable precipitating event and have increased
Liver transplantation in patients with ACLF has not been sys- mortality rates
tematically analysed but a recent retrospective study was per-
formed in 332 patients of whom 157 patients had ACLF and • Altered host response to injury such as deranged
175 patients had no ACLF pre-transplant [139]. Thirty-four systemic inflammatory response plays an important
patients received a liver-kidney transplant, of whom 10 pathophysiological role
(29.4%) had ACLF. The definition was based on a rapid increase
in MELD by >5 points. The results showed that the group with • Bacterial infection that occurs on the background of
ACLF had a 26% mortality compared with a mortality of 17% in varying degrees of immune paralysis plays an important
the non-ACLF group. The difference was statistically different in role in determining the outcome of this syndrome
univariate analysis, but when only single organ transplants
were analysed, the results were not statistically different. On
• Systemic, cardiac and hepatic hemodynamics are
important determinants of outcome
multivariate analysis, ACLF was not an independent predictor
of post-transplant mortality, arguing strongly that this is a • The end-organs such as the kidney and the brain show
good indication for transplantation [139]. The timing of trans- evidence of inflammation
plantation is crucial as patients with ACLF may provide a win-
dow of opportunity. Therefore, living-donor transplantation is • Survival of patients is dependent upon the severity of
an attractive option, the experience of which has been reported organ failure
extensively from South-East Asia, mainly in patients with ACLF
resulting from re-activation of hepatitis B virus infection. The • Treatment strategies are limited to organ support but
data from Hong Kong suggests that although the patients with better understanding of the pathophysiology is likely to
lead to discovery of novel biomarkers and therapeutic
ACLF and HRS had stormier post-operative course, living donor
strategies
transplantation could be performed safely and overall there
were no significant differences in survival with 5-year survivals
of about 80% [140]. Similar observations have been made
regarding the safety and feasibility of living donor transplanta-
tion from the Chinese groups [141]. Currently, in most coun- Conflict of interest
tries there is no priority for ACLF patients who have
significantly higher short-term mortality. A better understand- The authors declared that they do not have anything to disclose
ing of the natural history and prognostic criteria will allow regarding funding or conflict of interest with respect to this
ACLF to be incorporated as a possible new indication for high manuscript.
urgency allocation.
Acknowledgements

Conclusions and future perspectives A lot of the manuscript is based around the discussions during a
meeting that took place at Atlanta, 2010; ‘Intensive Care of the
In conclusion, ACLF is a devastating syndrome with inordinately Patient with Acute-on Chronic Liver Failure: Summary of an
high mortality, which is clinically, pathophysiologically and American Association for the Study of Liver Diseases and
prognostically a distinct clinical entity, but the condition has European Association for the Study of the Liver Single Topic
not yet been defined. In order to fill this knowledge gap, groups Conference.’
in Europe, US and Asia have started to study this entity as part
of large consortia. One such consortium in Europe, the EASL References
CLIF-Consortium, has just finished the recruitment of 1400
[1] Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis
patients prospectively; the results of the study are eagerly of therapeutic options. Blood Purif 2002;20:252–261.
awaited [142]. It is likely that a better definition will require [2] Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, et al. Acute-on-
new biomarkers, which will allow the development of new chronic liver failure: consensus recommendations of the Asian Pacific
drugs and devices and, therefore, engagement with the industry Association for the Study of the Liver (APASL). Hepatol Int 2009;3:269–282.
[3] Olson JC, Wendon JA, Kramer DJ, Vicente A, Jalan R, Garcia-Tsao G, et al.
will be crucial to bring these emerging treatments to patients.
Intensive care of the patient with cirrhosis. Hepatology 2011;54:
The liver transplant community will need to be engaged to 1864–1872.
define which patients with ACLF should be transplanted and [4] Jalan R, Stadlbauer V, Sen S, Mookerjee R, Davies N, Hodges S, et al. Natural
define new allocation policy. Finally, it is likely that there will history of acute decompensation of cirrhosis: the basis of the definition,
be a resurgence of research activity in cirrhosis to allow the prognosis, and pathophysiology of acute-on-chronic liver failure. Hepatol-
ogy 2006;44 (Suppl. 1):371A–372A.
determination of modifiable factors that predispose to ACLF, [5] Jalan R, Sen S, Williams R. Prospects for extracorporeal liver support. Gut
and likely to personalise their management based on clinical 2004;53:890–898.
and genetic factors.

Journal of Hepatology 2012 vol. 57 j 1336–1348 1345


Review
[6] Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection [29] Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG,
of the oesophagus for bleeding oesophageal varices. Br J Surg et al. The APACHE III prognostic system. Risk prediction of hospital
1973;60:646–649. mortality for critically ill hospitalized adults. Chest 1991;100:1619–1636.
[7] Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg [30] Arabi Y, Ahmed QA, Haddad S, Aljumah A, Al-Shimemeri A. Outcome
CL, et al. A model to predict survival in patients with end-stage liver predictors of cirrhosis patients admitted to the intensive care unit. Eur J
disease. Hepatology 2001;33:464–470. Gastroenterol Hepatol 2004;16:333–339.
[8] Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. [31] Mackle IJ, Swann DG, Cook B. One year outcome of intensive care patients
The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ with decompensated alcoholic liver disease. Br J Anaesth 2006;97:
dysfunction/failure. On behalf of the Working Group on Sepsis-Related 496–498.
Problems of the European Society of Intensive Care Medicine. Intensive [32] Chen YC, Tian YC, Liu NJ, Ho YP, Yang C, Chu YY, et al. Prospective cohort
Care Med 1996;22:707–710. study comparing sequential organ failure assessment and acute physiology,
[9] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of age, chronic health evaluation III scoring systems for hospital mortality
disease classification system. Crit Care Med 1985;13:818–829. prediction in critically ill cirrhotic patients. Int J Clin Pract
[10] Goldfarb G, Nouel O, Poynard T, Rueff B. Efficiency of respiratory assistance 2006;60:160–166.
in cirrhotic patients with liver failure. Intensive Care Med 1983;9:271–273. [33] Jenq CC, Tsai MH, Tian YC, Lin CY, Yang C, Liu NJ, et al. RIFLE classification
[11] Shellman RG, Fulkerson WJ, DeLong E, Piantadosi CA. Prognosis of patients can predict short-term prognosis in critically ill cirrhotic patients. Intensive
with cirrhosis and chronic liver disease admitted to the medical intensive Care Med 2007;33:1921–1930.
care unit. Crit Care Med 1988;16:671–678. [34] Cholongitas E, Betrosian A, Senzolo M, Shaw S, Patch D, Manousou P, et al.
[12] Zauner CA, Apsner RC, Kranz A, Kramer L, Madl C, Schneider B, et al. Prognostic models in cirrhotics admitted to intensive care units better
Outcome prediction for patients with cirrhosis of the liver in a medical ICU: predict outcome when assessed at 48 h after admission. Gastroenterol
a comparison of the APACHE scores and liver-specific scoringsystems. Hepatol 2008;23:1223–1227.
Intensive Care Med 1996;22:559–563. [35] Fang JT, Tsai MH, Tian YC, Jenq CC, Lin CY, Chen YC, et al. Outcome
[13] Zimmerman JE, Wagner DP, Seneff MG, Becker RB, Sun X, Knaus WA. predictors and new score of critically ill cirrhotic patients with acute renal
Intensive care unit admissions with cirrhosis: risk-stratifying patient failure. Nephrol Dial Transplant 2008;23:1961–1969.
groups and predicting individual survival. Hepatology 1996;23:1393–1401. [36] Juneja D, Gopal PB, Kapoor D, Raya R, Sathyanarayanan M, Malhotra P.
[14] Lee KC, Chiang AA. The outcome of terminal liver cirrhosis patients Outcome of patients with liver cirrhosis admitted to a specialty liver
requiring mechanical ventilation. Zhonghua Yi Xue Za Zhi (Taipei) intensive care unit in India. J Crit Care 2009;24:387–393.
1997;59:88–94. [37] Cholongitas E, Calvaruso V, Senzolo M, Patch D, Shaw S, O’Beirne J, et al.
[15] Singh N, Gayowski T, Wagener MM, Marino IR. Outcome of patients with RIFLE classification as predictive factor of mortality in patients with
cirrhosis requiring intensive care unit support: prospective assessment of cirrhosis admitted to intensive care unit. J Gastroenterol Hepatol
predictors of mortality. J Gastroenterol 1998;33:73–79. 2009;24:1639–1647.
[16] Kress JP, Rubin A, Pohlman AS, Hall JB. Outcomes of critically ill patients [38] Thomson SJ, Moran C, Cowan ML, Musa S, Beale R, Treacher D, et al.
denied consideration for liver transplantation. Am J Respir Crit Care Med Outcomes of critically ill patients with cirrhosis admitted to intensive care:
2000;162:418–423. an important perspective from the non-transplant setting. Aliment Phar-
[17] Aggarwal A, Ong JP, Younossi ZM, Nelson DR, Hoffman-Hogg L, Arroliga AC. macol Ther 2010;32:233–243.
Predictors of mortality and resource utilization in cirrhotic patients [39] Filloux B, Chagneau-Derrode C, Ragot S, Voultoury J, Beauchant M, Silvain C,
admitted to the medical ICU. Chest 2001;119:1489–1497. et al. Short-term and long-term vital outcomes of cirrhotic patients
[18] Wehler M, Kokoska J, Reulbach U, Hahn EG, Strauss R. Short-term prognosis admitted to an intensive care unit. Eur J Gastroenterol Hepatol
in critically ill patients with cirrhosis assessed by prognostic scoring 2010;22:1474–1480.
systems. Hepatology 2001;34:255–261. [40] Juneja D, Gopal PB, Kapoor D, Raya R, Sathyanarayanan M. Profiles and
[19] Tsai MH, Chen YC, Ho YP, Fang JT, Lien JM, Chiu CT, et al. Organ system outcome of patients with liver cirrhosis requiring mechanical ventilation. J
failure scoring system can predict hospital mortality in critically ill cirrhotic Intensive Care Med (in press).
patients. J Clin Gastroenterol 2003;37:251–257. [41] Feltracco P, Brezzi M, Barbieri S, Milevoj M, Galligioni H, Cillo U, et al.
[20] Tsai MH, Peng YS, Lien JM, Weng HH, Ho YP, Yang C, et al. Multiple organ Intensive care unit admission of decompensated cirrhotic patients: prog-
system failure in critically ill cirrhotic patients. A comparison of two nostic scoring systems. Transplant Proc 2011;43:1079–1084.
multiple organ dysfunction/failure scoring systems. Digestion 2004;69: [42] Levesque E, Hoti E, Azoulay D, Ichaï P, Habouchi H, Castaing D, et al.
190–200. Prospective evaluation of the prognostic scores for cirrhotic patients
[21] Chen YC, Tsai MH, Ho YP, Hsu CW, Lin HH, Fang JT, et al. Comparison of the admitted to an intensive care unit. J Hepatol 2012;56:95–102.
severity of illness scoring systems for critically ill cirrhotic patients with [43] Cavallazzi R, Awe OO, Vasu TS, Hirani A, Vaid U, Leiby BE, et al. Model for
renal failure. Clin Nephrol 2004;61:111–118. End-stage liver disease score for predicting outcome in critically ill medical
[22] Chen YC, Tsai MH, Hsu CW, Ho YP, Lien JM, Chang MY, et al. Role of serum patients with liver cirrhosis. J Crit Care 2012;27:424.e1–424.e6.
creatinine and prognostic scoring systems in assessing hospital mortality in [44] Shawcross DL, Austin MJ, Abeles RD, McPhail MJ, Yeoman AD, Taylor NJ,
critically ill cirrhotic patients with upper gastrointestinal bleeding. J et al. The impact of organ dysfunction in cirrhosis: survival at a cost? J
Nephrol 2003;16:558–565. Hepatol 2012;56:1054–1062.
[23] Ho YP, Chen YC, Yang C, Lien JM, Chu YY, Fang JT, et al. Outcome prediction [45] Moreno RP, Metnitz B, Adler L, Hoechtl A, Bauer P, Metnitz PG. SAPS 3
for critically ill cirrhotic patients: a comparison of APACHE II and Child- Investigators. Sepsis mortality prediction based on predisposition, infection
Pugh scoring systems. J Intensive Care Med 2004;19:105–110. and response. Intensive Care Med 2008;34:496–504.
[24] Gildea TR, Cook WC, Nelson DR, Aggarwal A, Carey W, Younossi ZM, et al. [46] Plataki M, Hubmayr RD. The physical basis of ventilator-induced lung
Predictors of long-term mortality in patients with cirrhosis of the liver injury. Expert Rev Respir Med 2010;4:373–385.
admitted to a medical ICU. Chest 2004;126:1598–1603. [47] Teh SH, Nagorney DM, Stevens SR, Offord KP, Therneau TM, Plevak DJ, et al.
[25] Cholongitas E, Senzolo M, Patch D, Kwong K, Nikolopoulou V, Leandro G, Risk factors for mortality after surgery in patients with cirrhosis. Gastro-
et al. Risk factors, sequential organ failure assessment and model for end- enterology 2007;132:1261–1269.
stage liver disease scores for predicting short term mortality in cirrhotic [48] Keeffe EB. Is hepatitis A more severe in patients with chronic hepatitis
patients admitted to intensive care unit. Aliment Pharmacol Ther B and other chronic liver diseases? Am J Gastroenterol 1995;90:
2006;23:883–893. 201–205.
[26] Afessa B, Kubilis PS. Upper gastrointestinal bleeding in patients with [49] Kumar Acharya S, Kumar Sharma P, Singh R, Kumar Mohanty S, Madan K,
hepatic cirrhosis: clinical course and mortality prediction. Am J Gastroen- Kumar Jha J, et al. Hepatitis E virus (HEV) infection in patients with
terol 2000;95:484–489. cirrhosis is associated with rapid decompensation and death. J Hepatol
[27] Rabe C, Schmitz V, Paashaus M, Musch A, Zickermann H, Dumoulin FL, et al. 2007;46:387–394.
Does intubation really equal death in cirrhotic patients? Factors influencing [50] Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al.
outcome in patients with liver cirrhosis requiring mechanical ventilation. Systematic review: the effect of preventive lamivudine on hepatitis B
Intensive Care Med 2004;30:1564–1571. reactivation during chemotherapy. Ann Intern Med 2008;148:519–528.
[28] du Cheyron D, Bouchet B, Parienti JJ, Ramakers M, Charbonneau P. The [51] Carman WF, Korula J, Wallace L, MacPhee R, Mimms L, Decker R. Fulminant
attributable mortality of acute renal failure in critically ill patients with reactivation of hepatitis B due to envelope protein mutant that escaped
liver cirrhosis. Intensive Care Med 2005;31:1693–1699. detection by monoclonal HBsAg ELISA. Lancet 1995;345:1406–1407.

1346 Journal of Hepatology 2012 vol. 57 j 1336–1348


JOURNAL OF HEPATOLOGY
[52] Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves [75] Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect
the outcome in patients with spontaneous reactivation of hepatitis B of probiotic treatment on deranged neutrophil function and cytokine
presenting as acute-on-chronic liver failure. Hepatology 2011;53:774–780. responses in patients with compensated alcoholic cirrhosis. J Hepatol
[53] Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic 2008;48:945–951.
prophylaxis for the prevention of bacterial infections in cirrhotic patients [76] Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, et al.
with gastrointestinal bleeding: a meta-analysis. Hepatology 1999;29: Granulocyte colony-stimulating factor mobilizes CD34(+) cells and
1655–1661. improves survival of patients with acute-on-chronic liver failure. Gastro-
[54] Monescillo A, Martínez-Lagares F, Ruiz-del-Arbol L, Sierra A, Guevara C, enterology 2012;142:505–512.
Jiménez E, et al. Influence of portal hypertension and its early decompres- [77] Katoonizadeh A, Laleman W, Verslype C, Wilmer A, Maleux G, Roskams T,
sion by TIPS placement on the outcome of variceal bleeding. Hepatology et al. Early features of acute-on-chronic alcoholic liver failure: a prospective
2004;40:793–801. cohort study. Gut 2010;59:1561–1569.
[55] García-Pagán JC, Caca K, Bureau C, Laleman W, Appenrodt B, Luca A, et al. [78] Jalan R, Mookerjee RP. Acute-on-chronic liver failure: an early biopsy is
Early TIPS (Transjugular Intrahepatic Portosystemic Shunt) Cooperative essential? Gut 2010;59:1455–1456.
Study Group. Early use of TIPS in patients with cirrhosis and variceal [79] Mookerjee RP, Lackner C, Stauber R, Stadlbauer V, Deheragoda M, Aigels-
bleeding. N Engl J Med 2010;362:2370–2379. reiter A, et al. The role of liver biopsy in the diagnosis and prognosis of
[56] Malik R, Mookerjee RP, Jalan R. Infection and inflammation in liver failure: patients with acute deterioration of alcoholic cirrhosis. J Hepatol
two sides of the same coin. J Hepatol 2009;51:426–429. 2011;55:1103–1111.
[57] Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. [80] Adebayo D, Mookerjee RP, Jalan R. Mechanistic biomarkers in acute liver
The systemic inflammatory response syndrome in acute liver failure. injury: are we there yet? J Hepatol 2012;56:1003–1005.
Hepatology 2000;32:734–739. [81] Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R, Jalan R. Tumour
[58] Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, et al. necrosis factor a is an important mediator of portal and systemic haemo-
Infection and the progression of hepatic encephalopathy in acute liver dynamic derangements in alcoholic hepatitis. Gut 2003;52:1182–1187.
failure. Gastroenterology 2003;125:755–764. [82] Benten D, Wiest R. Gut microbiome and intestinal barrier failure – The
[59] Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A, et al. Pathogenesis of ‘‘Achilles heel’’ in hepatology? J Hepatol 2012;56:1221–1223.
intracranial hypertension in acute liver failure: inflammation, ammonia [83] Vlachogiannakos J, Saveriadis AS, Viazis N, Theodoropoulos I, Foudoulis K,
and cerebral blood flow. J Hepatol 2004;41:613–620. Manolakopoulos S, et al. Intestinal decontamination improves liver
[60] Gustot T. Multiple organ failure in sepsis: prognosis and role of systemic haemodynamics in patients with alcohol-related decompensated cirrhosis.
inflammatory response. Curr Opin Crit Care 2011;17:153–159. Aliment Pharmacol Ther 2009;29:992–999.
[61] Sen S, Davies NA, Mookerjee RP, Cheshire LM, Hodges SJ, Williams R, et al. [84] Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting J. The effect of
Pathophysiological effects of albumin dialysis in acute-on-chronic liver selective intestinal decontamination on the hyperdynamic circulatory state
failure: a randomized controlled study. Liver Transpl 2004;10:1109–1119. in cirrhosis. A randomized trial. Ann Intern Med 2003;139:186–193.
[62] Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The [85] Thabut D, Tazi KA, Bonnefont-Rousselot D, Aller M, Farges O, Guimont MC,
systemic inflammatory response syndrome in cirrhotic patients: relation- et al. High-density lipoprotein administration attenuates liver proinflam-
ship with their in-hospital outcome. J Hepatol 2009;51:475–482. matory response, restores liver endothelial nitric oxide synthase activity, and
[63] Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, lowers portal pressure in cirrhotic rats. Hepatology 2007;46:1893–1906.
et al. Model for end-stage liver disease score and systemic inflammatory [86] Laviña B, Gracia-Sancho J, Rodríguez-Vilarrupla A, Chu Y, Heistad DD, Bosch
response are major prognostic factors in patients with cirrhosis and acute J, et al. Superoxide dismutase gene transfer reduces portal pressure in CCl4
functional renal failure. Hepatology 2007;46:1872–1882. cirrhotic rats with portal hypertension. Gut 2009;58:118–125.
[64] Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, [87] Kumar A, Das K, Sharma P, Mehta V, Sharma BC, Sarin SK. Hemodynamic
et al. Foie-alcool group of the association Française pour l’Etude du Foie. A studies in acute-on-chronic liver failure. Dig Dis Sci 2009;54:869–878.
double-blind randomized controlled trial of infliximab associated with [88] Jalan R, Mookerjee RP. Systemic hemodynamics, hepatic blood flow and
prednisolone in acute alcoholic hepatitis. Hepatology 2004;39:1390–1397. portal pressure in patients with cirrhosis and multiorgan failure: the role of
[65] Boetticher NC, Peine CJ, Kwo P, Abrams GA, Patel T, Aqel B, et al. A sympathetic activation. Hepatology 2008;48 (Suppl. 1):1077A.
randomized, double-blinded, placebo-controlled multicenter trial of eta- [89] Mookerjee RP, Wiesenthal A, Icking A, Hodges SJ, Davies NA, Schilling K,
nercept in the treatment of alcoholic hepatitis. Gastroenterology et al. Increased gene and protein expression of the novel eNOS regulatory
2008;135:1953–1960. protein NOSTRIN and a variant in alcoholic hepatitis. Gastroenterology
[66] Linderoth G, Jepsen P, Schonheyder HC, et al. Short-term prognosis of 2007;132:2533–2541.
community-acquired bacteremia in patients with liver cirrhosis or alco- [90] Shah V, Haddad FG, Garcia-Cardena G, Frangos JA, Mennone A, Groszmann
holism: a population-based cohort study. Alcohol Clin Exp Res 2006;30: RJ, et al. Liver sinusoidal endothelial cells are responsible for nitric oxide
636–641. modulation of resistance in the hepatic sinusoids. J Clin Invest
[67] Borzio M, Salerno F, Piantoni L, et al. Bacterial infection in patients with 1997;100:2923–2930.
advanced cirrhosis: a multicentre prospective study. Dig Liver Dis [91] Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, et al.
2001;33:41–48. Increasing dimethylarginine levels are associated with adverse clinical
[68] Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. outcome in severe alcoholic hepatitis. Hepatology 2007;45:62–71.
Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a [92] Lee KC, Yang YY, Wang YW, Hou MC, Lee FY, Lin HC, et al. Acute
prospective study. J Hepatol 2002;37:463–470. administration of sildenafil enhances hepatic cyclic guanosine monophos-
[69] Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, phate production and reduces hepatic sinusoid resistance in cirrhotic
et al. Infections in patients with cirrhosis increase mortality four-fold and patients. Hepatol Res 2008;38:1186–1193.
should be used in determining prognosis. Gastroenterology 2010;139: [93] Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med
1246–1256. 2009;361:1279–1290.
[70] Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in [94] Martín-Llahí M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R,
cirrhosis. Hepatology 2009;50:2022–2033. et al. Prognostic importance of the cause of renal failure in patients with
[71] Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute on chronic liver cirrhosis. Gastroenterology 2011;140:488–496.
failure display ‘‘sepsis-like’’ immune paralysis. J Hepatol 2005;42:195–201. [95] Stadlbauer V, Wright G, Banaji M, Mukhopadhyay A, Mookerjee R, Moore K,
[72] Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA, et al. Relationship between activation of the sympathetic nervous system
et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on and renal blood flow autoregulation in cirrhosis. Gastroenterology
cirrhosis is reversible and predicts outcome. Hepatology 2007;46:831–840. 2008;134:111–119.
[73] Berry PA, Antoniades CG, Carey I, McPhail MJ, Hussain MJ, Davies ET, et al. [96] Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN, Marinelli M,
Severity of the compensatory anti-inflammatory response determined by et al. Predictors of response to therapy with terlipressin and albumin in
monocyte HLA-DR expression may assist outcome prediction in cirrhosis. patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology
Intensive Care Med 2011;37:453–460. 2010;51:219–226.
[74] Nischalke HD, Berger C, Aldenhoff K, Thyssen L, Gentemann M, Grünhage F, [97] Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W, Ye W, et al.
et al. Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are Impact of etiology of acute kidney injury on outcomes following liver
associated with increased risk for spontaneous bacterial peritonitis in liver transplantation: acute tubular necrosis versus hepatorenal syndrome. Liver
cirrhosis. J Hepatol 2011;55:1010–1016. Transpl 2012;18:539–548.

Journal of Hepatology 2012 vol. 57 j 1336–1348 1347


Review
[98] Holt S, Goodier D, Marley R, Patch D, Burroughs A, Fernando B, et al. [120] Fernández J, Escorsell A, Zabalza M, Felipe V, Navasa M, Mas A, et al. Adrenal
Improvement in renal function in hepatorenal syndrome with N-acetyl- insufficiency in patients with cirrhosis and septic shock: effect of treatment
cysteine. Lancet 1999;353:294–295. with hydrocortisone on survival. Hepatology 2006;44:1288–1295.
[99] Akriviadis E, Bolta R, Briggs W, et al. Pentoxifylline improves short-term [121] Møller S, Hansen EF, Becker U, Brinch K, Henriksen JH, Bendtsen F. Central
survival in severe alcoholic hepatitis: a double-blind, placebo-controlled and systemic haemodynamic effects of terlipressin in portal hypertensive
trial. Gastroenterology 2000;119:1637–1648. patients. Liver 2000;20:51–59.
[100] Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. [122] Lisman T, Leebeek FW, de Groot PG. Haemostatic abnormalities in patients
Effect of intravenous albumin on renal impairment and mortality in with liver disease. J Hepatol 2002;37:280–287.
patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med [123] Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis
1999;5 (341):403–409. R, et al. An imbalance of pro- vs. anti-coagulation factors in plasma from
[101] Ortega R, Ginès P, Uriz J, Cárdenas A, Calahorra B, De Las Heras D, et al. patients with cirrhosis. Gastroenterology 2009;137:2105–2111.
Terlipressin therapy with and without albumin for patients with hepato- [124] Senzolo M, Coppell J, Cholongitas E, Riddell A, Triantos CK, Perry D, et al.
renal syndrome: results of a prospective, nonrandomized study. Hepatol- The effects of glycosaminoglycans on coagulation: a thromboelastographic
ogy 2002;36:941–948. study. Blood Coagul Fibrinolysis 2007;18:227–236.
[102] Fernàndez J, Navasa M, Planas R, et al. Primary prophylaxis of spontaneous [125] Jun CH, Park CH, Lee WS, Joo YE, Kim HS, Choi SK, et al. Antibiotic
bacterial peritonitis delays hepatorenal syndrome and improves survival in prophylaxis using third generation cephalosporins can reduce the risk
cirrhosis. Gastroenterology 2007;133:818–824. of early rebleeding in the first acute gastroesophageal variceal
[103] Shah N, Dhar D. El Zahraa Mohammed F, Habtesion A, Davies NA, Jover- hemorrhage: a prospective randomized study. J Korean Med Sci
Cobos M, et al. Prevention of acute kidney injury in a rodent model of 2006;21:883–890.
cirrhosis following selective gut decontamination is associated with [126] Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation
reduced renal TLR4 expression. J Hepatol 2012;56:1047–1053. test results predict bleeding in the setting of invasive procedures: an
[104] Cárdenas A, Ginès P. Acute-on-chronic liver failure: the kidneys. Curr Opin evidence-based review. Transfusion 2005;45:1413–1425.
Crit Care 2011;17:184–189. [127] Bosch J, Thabut D, Albillos A, Carbonell N, Spicak J, Massard J, et al.
[105] Crippin JS, Gross Jr JB, Lindor KD. Increased intracranial pressure and International Study Group on rFVIIa in UGI hemorrhage. recombinant
hepatic encephalopathy in chronic liver disease. Am J Gastroenterol factor VIIa for variceal bleeding in patients with advanced cirrhosis: a
1992;87:879–882. randomized, controlled trial. Hepatology 2008;47:1604–1614.
[106] Jalan R, Dabos K, Redhead DN, Lee A, Hayes PC. Elevation of intracranial [128] Lisman T, Porte RJ. Platelet function in patients with cirrhosis. J Hepatol
pressure following transjugular intrahepatic portosystemic stent-shunt for 2012;56:993–994.
variceal haemorrhage. J Hepatol 1997;27:928–933. [129] Mannucci PM, Franchi F, Dioguardi N. Correction of abnormal coagulation
[107] Donovan JP, Schafer DF, Shaw Jr BW, Sorrell MF. Cerebral edema and in chronic liver disease by combined use of fresh-frozen plasma and
increased intracranial pressure in chronic liver disease. Lancet prothrombin complex concentrates. Lancet 1976;2 (7985):542–545.
1998;351:719–721. [130] Stravitz RT, Lisman T, Luketic VA, Sterling RK, Puri P, Fuchs M, et al.
[108] Wright G, Davies NA, Shawcross DL, Hodges SJ, Zwingmann C, Brooks HF, Minimal effects of acute liver injury/acute liver failure on hemostasis as
et al. Endotoxemia produces coma and brain swelling in bile duct ligated assessed by thromboelastography. J Hepatol 2012;56:129–136.
rats. Hepatology 2007;45:1517–1526. [131] Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, Fang JT, et al. Adrenal
[109] García Martínez R, Rovira A, Alonso J, Aymerich FX, Huerga E, Jacas C, et al. insufficiency in patients with cirrhosis, severe sepsis and septic shock.
A long-term study of changes in the volume of brain ventricles and white Hepatology 2006;43:673–681.
matter lesions after successful liver transplantation. Transplantation [132] Fernandez J, Escorsell A, Zabalza M, Felipe V, Navasa M, Mas A, et al. Adrenal
2010;89:589–594. insufficiency in patients with cirrhosis and septic shock: effect of treatment
[110] Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, et al. with hydrocortisone on survival. Hepatology 2006;44:1288–1295.
Infection and systemic inflammation, not ammonia, are associated with [133] Stadlbauer V, Davies NA, Sen S, Jalan R. Artificial liver support systems in
grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol the management of complications of cirrhosis. Semin Liver Dis
2011;54:640–649. 2008;28:96–109.
[111] Pedersen HR, Ring-Larsen H, Olsen NV, Larsen FS. Hyperammonemia acts [134] Zhong-Ping Duan JZ, Xin S, Ju Chen M, He D, Brotherthon J, Maxwell K, et al.
synergistically with lipopolysaccharide in inducing changes in cerebral Interim results of randomized controlled trial of ELAD in acute on chronic
hemodynamics in rats anaesthetised with pentobarbital. J Hepatol liver disease. Hepatology 2007;46:274A.
2007;47:245–252. [135] Stange J, Mitzner S, Ramlow W, Gliesche T, Hickstein H, Schmidt R. A new
[112] Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia- procedure for the removal of protein bound drugs and toxins’’. ASAIO J
Verdugo JM, et al. Hyperammonemia induces neuroinflammation that 1993;39 (3):M621–M625.
contributes to cognitive impairment in rats with hepatic encephalopathy. [136] Jalan R, Schnurr K, Mookerjee RP, Sen S, Cheshire L, Hodges S, et al.
Gastroenterology 2010;139:675–684. Alterations in the functional capacity of albumin in patients with decom-
[113] Wright G, Vairappan B, Stadlbauer V, Mookerjee RP, Davies NA, Jalan R. pensated cirrhosis is associated with increased mortality. Hepatology
Reduction in hyperammonaemia by ornithine phenylacetate prevents 2009;50:555–564.
lipopolysaccharide-induced brain edema and coma in cirrhotic rats. Liver [137] Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U, Betz C, et al.
Int 2012;32:410–419. Effects of fractionated plasma separation and adsorption on survival
[114] Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin in patients with acute-on-chronic liver failure. Gastroenterology 2012
treatment in hepatic encephalopathy. N Engl J Med 2010;25 (in press).
(362):1071–1081. [138] Banares R, Nevens F, Larsen F, et al. Extracorporeal liver support with the
[115] Jalan R, Olde Damink SW, Ter Steege JC, Redhead DN, Lee A, Hayes PC, et al. molecular adsorbent recirculating system (MARS) in patients with acute-
Acute endotoxemia following transjugular intrahepatic stent-shunt inser- on-chronic liver failure (AOCLF) the RELIEF trial. J Hepatol 2010;52:S459.
tion is associated with systemic and cerebral vasodilatation with increased [139] Bahirwani R, Shaked O, Bewtra M, Forde K, Reddy KR. Acute-on-chronic
whole body nitric oxide production in critically ill cirrhotic patients. J liver failure before liver transplantation: impact on posttransplant out-
Hepatol 2011;54:265–271. comes. Transplantation 2011;92:952–957.
[116] Iversen P, Keiding S, Mouridsen K, Ott P, Vilstrup H. Transjugular [140] Chen Z, Wen T, Zeng Y, Wang L, Lu JJ, Gong S, et al. A single institution
intrahepatic portosystemic shunt does not alter cerebral blood flow. Clin experience with living donor liver transplantation for acute-on-chronic
Gastroenterol Hepatol 2011;9:1001–1003. hepatitis B liver failure. Hepatogastroenterology 2011;58:1267–1273.
[117] Helmy A, Jalan R, Newby DE, Hayes PC, Webb DJ. Role of angiotensin II in [141] Chok KS, Fung JY, Chan SC, Cheung TT, Sharr WW, Chan AC, et al. Outcomes
regulation of basal and sympathetically stimulated vascular tone in early of living-donor liver transplantation in patients with preoperative type-1
and advanced cirrhosis. Gastroenterology 2000;118:565–572. hepatorenal syndrome and acute hepatic decompensation. Liver Transpl
[118] Liu H, Lee SS. Acute-on-chronic liver failure: the heart and systemic 2012 (in press).
hemodynamics. Curr Opin Crit Care 2011;17:190–194. [142] Moreau R, Ginés P, Jalan R, Pavesi M, Durand F, Angeli P, et al. Diagnosis,
[119] Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, et al. Prevalence and prognosis of acute-on-chronic liver failure (ACLF): results of
Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology the EASL-chronic liver failure consortium CANONIC study. J Hepatol
2005;42:439–447. 2012;56 (Suppl. 2):S552–S553.

1348 Journal of Hepatology 2012 vol. 57 j 1336–1348