Expert Opinion

Towards a new definition of decompensated cirrhosis

Gennaro D’Amico1, Mauro Bernardi2, Paolo Angeli3,*

Keywords: ascites; jaundice;
gastrointestinal bleeding;
hepatic encephalopathy;
bacterial infection; acute
decompensation; non acute
decompensation; re-
compensation; acute-on-
chronic liver failure.
Received 6 April 2021; received
in revised form 9 June 2021;
accepted 14 June 2021; available
online 23 June 2021
Summary
There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic
encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the
decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient
prognosis and is therefore considered the most important stratification variable for the risk of death.
However, this classification is an oversimplification, as it does not discriminate between the prognostic
subgroups that characterise the course of decompensation, which depends on the type and number of
decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided
by observational studies characterising acute decompensation (AD), which occurs mostly in patients who
have already experienced decompensating events. Decompensation presents as AD in a portion of pa-
tients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic
encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of
cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic
liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the
first decompensation, AD mostly represents further decompensation.
© 2021 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

1
Gastroenterology Unit, Ospedale
V. Cervello, Clinica La Maddalena,
Palermo, Italy; 2Department of
Medical and Surgical Sciences,
University of Bologna, Bologna,
Italy; 3Department of Medicine,
Unit of Internal Medicine and
Hepatology (UIMH), University of
Padova, Italy
* Corresponding author. Address:
Dept. of Internal Medicine and
Hepatology, University of Padova
Italy. Tel.: 0039-0498212291; fax:
0039-0498218292.
E-mail address: pangeli@unipd.
it (P. Angeli).
https://doi.org/
10.1016/j.jhep.2021.06.018
Introduction
Defining the evolutionary stages and their prog-
nosis in chronic diseases is of paramount clinical
importance, as it constitutes the foundation guid-
ing management strategies. For decades it has been
understood that the natural history of cirrhosis is
marked by a prognostic watershed, represented by
the development of complications related to portal
hypertension and impaired liver function, such as
gastrointestinal bleeding, hepatic encephalopathy,
jaundice and ascites formation.1,2 This led to the
concept that the course of the disease can be
divided into 2 distinct clinical states: the usually
asymptomatic compensated stage, characterised by
preserved quality of life and a median survival
exceeding 12 years, and the decompensated stage,
marked by the occurrence of complications, with
median survival dropping to 2–4 years.3,4 Accord-
ingly, decompensation is universally considered
the most important stratification variable for the
risk of death either in clinical practice or in clinical
research.5 However, although there is an almost
unanimous consensus on the prognostic weight of
decompensation, a corresponding consensus on its
definition is still lacking. In a systematic review of
predictors of decompensation including 91 studies,
the definition of decompensation was based on 6
different combinations of development of ascites,
gastrointestinal bleeding, hepatic encephalopathy,
jaundice, hepatocellular carcinoma, increase in
Child-Pugh score, prolongation of prothrombin
time, development of oesophago-gastric varices,
and need for diuretics.6 However, the combination
of ascites, bleeding, hepatic encephalopathy and
jaundice, associated or not with other signs, was
included in the definition in 80% of studies. These
findings clearly indicate the need for a consensus
definition of decompensation. Therefore, herein,
we refer to decompensated cirrhosis as the pres-
ence or history of any one of ascites, bleeding, he-
patic encephalopathy, or jaundice.
Although classifying cirrhosis as compensated
and decompensated is clinically sound, it over-
simplifies the clinical course of the disease, which
encompasses many different prognostic subgroups.
In fact, it has been shown that the outcome of
decompensation depends on the type and number
of decompensating events. Ascites is by far the
most frequent first decompensating event, pre-
senting alone in 36% of patients and in combina-
tion with other complications in 37%.7 Therefore, it
marks transition to decompensation in 73% of pa-
tients and is widely considered the hallmark of
decompensation. Moreover, ascites is associated
with worse outcomes than variceal bleeding alone,
while the combination of both bleeding and ascites
is associated with the worst outcomes.8,9 In
accordance with these findings, an inception
cohort study showed that the 5-year mortality risk
is 20% for patients decompensating with bleeding
alone, 30% with any non-bleeding event, mostly
ascites, and 88% with any combination of > −2
events.10 In a comprehensive risk stratification of
the whole course of cirrhosis, these conditions
have been designated as states 3, 4 and 5, with

Journal of Hepatology 2022 vol. 76 j 202–207

states 1 and 2 pertaining to compensated cirrhosis:
absence of varices defining state 1 and presence of
varices state 2, with a 5-year risk of death of 1.5%
and 10%, respectively.10
One proposal to increase granularity in the risk
stratification of decompensated cirrhosis is to
include patients with very advanced disease in a
further decompensation state. This was first sug-
gested after 2 meta-analyses showed that in-
fections and renal failure occurring in
decompensated cirrhosis are associated with 1-
year mortality of 63%.11,12 It is now clear that bac-
terial infections and systemic inflammation play a
key role throughout the course of cirrhosis by
precipitating or aggravating decompensation and
organ dysfunction beyond the liver, with circula-
tory and renal dysfunction being a major mani-
festation.13 The American Association for the Study
of Liver Disease guidance for portal hypertension
proposed that this disease state should include
recurrent variceal haemorrhage, refractory ascites,
hyponatremia, hepatorenal syndrome, recurrent
hepatic encephalopathy and jaundice.14 Such dis-
ease progression is characterised by severe clinical
deterioration, very high levels of inflammatory
markers,15 and very high mortality in the order of
60% to 80% at 1 year.11,12
The CANONIC and PREDICT studies
Deeper insights into the clinical course of decom-
pensated cirrhosis have been provided by 2 recent
large observational studies looking at acute
decompensation (AD). The first, the CANONIC
study,16 aimed to establish diagnostic criteria for
acute-on-chronic liver failure (ACLF), introduced the
concept of AD as a distinct clinical presentation of
decompensation of cirrhosis defined by the acute
development of > −1 major complication(s): first or
recurrent grade 2 or 3 ascites within less than 2
weeks, first or recurrent acute hepatic encepha-
lopathy in patients with previously normal con-
sciousness, acute gastrointestinal bleeding, and any
type of acute bacterial infection. Therefore, the
concept of AD is essentially based on the rapidity of
onset of the complications on which the definition
of decompensation is based. This rapidity of pre-
sentation has been observed in hospitalised pa-
tients, with 73% having experienced previous
decompensating events (CANONIC). Additionally,
the CANONIC study introduced bacterial infection as
a defining event of AD. Although bacterial infections
were not traditionally considered as a marker of
decompensation, they were considered as such and
included in the definition of AD because of their
high prevalence and association to bacterial trans-
location and impaired leukocyte functions in
cirrhosis.17,18 Moreover, the prognosis of patients
with cirrhosis worsens once a bacterial infection has
occurred irrespective of its resolution.11,19
Even though the need for hospitalisation was
not included among the diagnostic criteria of AD,
Journal of Hepatology 2022 vol. 76 j 202–207
only patients admitted to hospital were included in
the CANONIC study. This may represent a source of
selection bias, as the criteria used to decide
whether to admit a patient are subjective and can
vary among different centres. Moreover, the pro-
portion and outcome of patients presenting fea-
tures of AD who are not admitted to hospital
remain undefined.
A further important step forward in the risk
stratification of decompensation proposed by the
CANONIC study was the definition of ACLF based
on the development of organ failures: liver, kidney,
brain, circulation, coagulation, and lung. The
number of organ failures subclassifies ACLF into
grades 1, 2 or 3 according to whether it is associ-
ated with 1, 2 or > −3 organ failures. Patients with
ACLF had a worse short-term outcome than those
with AD: 28-day mortality ranged from 5% in pa-
tients with AD without ACLF to 22–77% in those
with ACLF at admission, depending on the grade of
ACLF. This range was further expanded from 6% in
AD without ACLF to 92% in ACLF grade 3, consid-
ering the final diagnosis made a week after hos-
pital admission.20
Several investigations confirmed AD as a
distinct entity with respect to either compensated,
or stable decompensated cirrhosis, or ACLF in
terms of extent of systemic inflammation, assessed
by determining either indirect parameters such as
white blood cell count and C reactive protein or
circulating levels of pro-inflammatory cytokines,
post-transcriptional abnormalities of serum albu-
min, severity of cirrhosis assessed by commonly
used prognostic scores such as Child-Pugh and
model for end-stage liver disease (MELD)
scores,21,22 and presence of extrahepatic organ
dysfunction and failure.13,23,24 Indeed, AD clearly
stands in between compensated or stable decom-
pensated cirrhosis and ACLF. Furthermore, the 3-
month mortality of patients with AD without
ACLF can be more accurately predicted by a specific
prognostic score, the CLIF Consortium acute
decompensation score (CLIF-C ADs)25 based on age,
serum sodium, white-cell count, creatinine, and
international normalised ratio, and differs from the
traditional Child-Pugh, MELD and MELD-Na26
scores, which were developed in the setting of
compensated and stable decompensated cirrhosis,
long before the definition of AD.
The second study, PREDICT, looked at the clin-
ical events occurring over a 3-month period from
AD and 3- and 12-month mortality risk.27 Like the
CANONIC study, it included hospitalised patients
with 80% having had a previous decompensating
event. Three different courses were identified,
irrespective of the aetiology of cirrhosis: i) pre-
ACLF, developing ACLF during follow-up; ii) un-
stable decompensated cirrhosis, followed by at
least a re-hospitalisation without developing ACLF;
iii) stable decompensated cirrhosis, neither devel-
oping ACLF nor requiring hospital re-admission.
203
Expert Opinion

ACLF
or
Acute onset pre-ACLF

Bleeding
Ascites grade 2-3 AD*¶
Encephalopathy
Sepsis
OLT
First
Compensated Decompensating
cirrhosis event
Death
Progressive onset
Ascites
Encephalopathy NAD#
Jaundice

Fig. 1. New definition of decompensation. We propose that decompensation of cirrhosis may be characterised by an acute onset (AD) or by a progressive, non-
acute onset (NAD). AD is defined as any first or recurrent grade 2 or 3 ascites within less than 2 weeks, first or recurrent acute hepatic encephalopathy in patients
with previous normal consciousness, acute gastrointestinal bleeding, and any type of acute bacterial infection. NAD is defined as slow ascites formation, hepatic
encephalopathy grade 1–2 or higher if manageable in an out-patient setting, or progressive jaundice in non-cholestatic cirrhosis. AD presents as: ACLF in
approximately 16% of cases; pre-ACLF in 17%; UDC in 22%, characterised by persistent albeit unstable inflammatory status resulting in further AD events within 1
year; SDC, 48% with stable decrease of systemic inflammation and no further AD for at least 1 year. NAD presents with the progressive development of any single
event (58–72%) or any combination (28–42%) of ascites, encephalopathy or jaundice (in non-cholestatic cirrhosis). Over time, SDC might become undis-
tinguishable from NAD if inflammation subsides. AD progresses to death or OLT either directly (ACLF or UDC phenotypes), or through further AD events. NAD
progresses either to AD through further decompensation or directly to death or OLT through progressive liver function deterioration without the occurrence of AD
with or without further decompensation. *ACLF: 16%, pre-ACLF: 17%, UDC: 22%, SDC: 48%; {overall 80% with previous decompensating events; #patients free of
previous decompensating events: 1 decompensating event 58-72%, − >2 decompensating events 28-42%. ACLF, acute-on-chronic liver failure; AD, acute decom-
pensation; NAD, non-acute decompensation; OLT, orthotopic liver transplantation; SDC, stable decompensated cirrhosis; UDC, unstable decompensated cirrhosis.

These patient groups were clearly stratified in (38%), and the number of precipitants, rather than
terms of 3- and 12-month mortality (0% to 9.5% in their nature, was significantly associated with the
the stable decompensated cirrhosis group vs. 21% risk of 3-month mortality, although alcoholic
to 35.6% in the unstable decompensated cirrhosis hepatitis, bacterial infections or both were the
group vs. 53.7% to 67.4% in the pre-ACLF group, most frequently identified precipitating factors.
respectively). Indirect markers of systemic inflam-Still, more refinements are needed. It would be
mation, such as white blood cell count and, mainly,
desirable for the definition of AD to be based on
serum C reactive protein levels, increased pro- objective clinical criteria, including the severity of
gressively from the stable decompensated cirrhosisliver and other organ dysfunctions. A second rele-
to the pre-ACLF group. Furthermore, while these vant issue relates to the real impact of AD in the
markers tended to fade over time in unstable and clinical course of cirrhosis. Although we know from
stable decompensated cirrhosis, they kept the CANONIC and PREDICT studies that about a
increasing during the index hospitalisation in thequarter of patients presenting with AD have no
pre-ACLF group. Based on these and previous history of previous decompensation, its incidence
findings, it has recently been proposed that sys- in compensated and decompensated patients is
temic inflammation plays a major role in the still unsettled. The incidence of ACLF in this clinical
development of AD, its recurrence, and evolution context has only been assessed in 1 study including
to ACLF, which is the extreme manifestation of this
466 outpatients with or without previous decom-
pathophysiological mechanism.28 pensation:30 118 developed ACLF after a mean of 45
± 41 months of follow-up. One-year incidence was
Future directions: acute vs. non- 57/305 (18.7%) among decompensated and 4/161
acute decompensation (2.5%) among compensated patients. Unfortu-
The picture of AD emerging from the CANONIC and nately, this study did not assess the incidence of
PREDICT studies led to major advances in our un- AD. Finally, the concept (and current definition) of
derstanding of the clinical course of decom- AD does not apply to patients who develop
pensated cirrhosis. Moreover, an analysis of the decompensation in a progressive way, as in the
PREDICT study database revealed how precipi- case of the many patients who present with slow
tating factors influence AD phenotypes and their and progressive ascites formation or mild grade 1
31
outcome.29 Indeed, precipitating events were more or 2 hepatic encephalopathy or jaundice. Un-
often identifiable in the AD-ACLF cohort (71% of published data from a multicentre European data-
patients) than in the AD without ACLF cohort base including 1,858 consecutive patients with

204 Journal of Hepatology 2022 vol. 76 j 202–207

cirrhosis showed that first decompensation occurs is now clear that the degree of portal hypertension
with only 1 decompensating event in 58% of pa- as indicated by the presence of oesophageal varices,
tients and with any combination of > −2 events in is the most important indicator of the risk of
42% of patients.7 Corresponding findings from an decompensation and increasing severity of
inception cohort study of the clinical course of cirrhosis.10 Yet, even in patients without oesopha-
cirrhosis were 73% and 27%, respectively, confirm- geal varices, clinically significant portal hyperten-
ing that the first decompensation occurs with only sion indicated by a hepatic vein pressure gradient
1 decompensating event in approximately two- (HVPG) − >10 mmHg is significantly associated with
thirds of patients,10 while AD was characterised the risk of decompensation and disease progres-
by >−2 decompensating events in most patients, sion38 which is reduced by portal pressure reducing
both in the CANONIC and PREDICT studies. Incep- interventions.39 However, since both HVPG and
tion cohort studies where the inception point is the oesophageal varices may be present independently
first diagnosis of cirrhosis will clarify the real of overt clinical decompensation they should be
impact of AD relative to non-acute decompensa- considered as predictors of disease progression
tion (NAD) and the different outcomes of first or rather than indicators of decompensation per se.
subsequent episodes of AD. Thus, summing up the Although death or liver transplantation were the
presently available knowledge on the clinical only 2 recognised final outcomes of decompensated
course of cirrhosis, 2 distinct modalities of transi- cirrhosis, re-compensation has recently appeared
tion to decompensation may be recognised (Fig. 1): on the scene. This is based on the not infrequent
 AD: first or recurrent grade 2 or 3 ascites within disappearance of any decompensation sign
less than 2 weeks, first or recurrent acute he- following effective aetiological treatments. Re-
patic encephalopathy in patients with previous compensation is conceivably associated with
normal consciousness, acute gastrointestinal reduction of fibrosis and portal hypertension, as
bleeding, and any type of acute bacte- shown after successful aetiological treatment in
rial infection.16 compensated cirrhosis.39–41 However, the stability
 NAD: slow ascites formation, mild grade 1 or 2 of re-compensation is far from certain. Indeed, the
hepatic encephalopathy, or progressive jaundice risk of de novo/additional clinical decompensation
in non-cholestatic cirrhosis. in patients with HCV-related cirrhosis is still about
7% 2 years after sustained virological response, be-
It is therefore clear that AD and NAD have ing associated with baseline HVPG > −16 mmHg and a
different places in the clinical course of cirrhosis history of ascites.42 However, to assess the real
with AD representing mostly further decompen- impact of re-compensation and its stability, a
sation and NAD mostly the first decompensating consensus definition is needed. In our opinion, this
event (Box 1). would likely require a symptom-free time-period
Although jaundice has frequently been included from previous decompensation and the ability to
in the definition of NAD,6 this is not straightfor- maintain this state without any standard of care
ward because of its relevance in cholestatic vs. non- treatment other than the aetiological one. Criteria to
cholestatic chronic liver disease. In fact, while solid withdraw standard of care other than aetiological
data exist on the development of NAD marked by treatment is a crucial issue in defining re-
ascites or grade 1 or 2 hepatic encephalopathy, compensation because it may harm patients not
scarce data are available on the relevance of jaun-
dice as a marker of decompensation.10 Of note,
jaundice was either not even considered in the
Box 1. NAD and AD along the clinical course of cirrhosis.
definition of clinical decompensation5,32 or, when
it was, different criteria were used such as clinical
evaluation or bilirubin >3 mg/dl.3,6,32 Nevertheless, • NAD is mostly represented by the first decompensation. This occurs mostly with a single
the role of jaundice as a marker of first NAD should decompensating event in 58% to 72% of patients and usually does not require
be defined as it is still widely included in the hospitalisation. Even when presenting with 2 or more decompensating events, a sizable
proportion of these patients may be managed as outpatients or in the day-hospital setting.
definition of decompensation in the majority of
6,32–34 This also applies to the many patients with further decompensation represented by
published studies.
refractory ascites and mild to moderate recurrent encephalopathy free of other
Other well-known clinical complications of
complications.
cirrhosis such as hepatocellular carcinoma, malnu-
trition, sarcopenia and frailty have relevant negative • AD and ACLF occur mostly in patients with a history of previous decompensation and
prognostic implications in patients with therefore represents further decompensation. Moreover, most of these patients have a
cirrhosis.35–37 In spite of this, these complications, critical condition indicated by the association of 2 or more decompensating events among
with few exceptions,37 have never been considered bleeding, ascites, hepatic encephalopathy and jaundice. The most severe presentation of
as markers of decompensation. In our opinion this is AD is ACLF which is mostly triggered by alcoholic hepatitis or infections. Whether
justified because these complications may occur at associated with ACLF or not, AD is frequently associated with other organ dysfunctions.
any time along the course of the liver disease
without a well-known relationship with the main ACLF, acute-on-chronic liver failure; AD, acute decompensation; NAD, non-acute
pathways of decompensation, AD and NAD. Also, it decompensation.

Journal of Hepatology 2022 vol. 76 j 202–207 205

Expert Opinion

yet fully re-compensated. Identification of such
criteria will require expert consensus and prospec-
tive validation studies. It is conceivable that non-
invasive markers of portal hypertension and liver
fibrosis, as well as liver function measures, would be
part of such criteria. While re-compensation might
be expected after aetiologic cure resulting in a
progressive reduction of fibrosis and portal hyper-
tension, and even reversion of cirrhosis,43–45 this is
not expected to happen with ongoing exposure to
the aetiological agent, even with disease-modifying
treatments such as long-term use of human albu-
min, beta-blockers, and/or statins.46,47 The sole or
main target of these agents is to reduce the risk of
further decompensation, thereby prolonging sur-
vival and increasing quality of life. Therefore, accu-
rate predictors of the risk of further
decompensation are needed to define re-
compensation. For now, patients recovering from
decompensation should still be carefully monitored
because of the risk of new/further decompensation.
Abbreviations
ACLF, acute-on-chronic liver failure; AD, acute
decompensation; HVPG, hepatic vein pressure
gradient; MELD, model for end-stage liver disease;
NAD, non-acute decompensation.
Financial support
The authors received no financial support to pro-
duce this manuscript.
Conflict of interest
P.A.: 2016-2020 Biovie Advisory Board; 2018-2020
CSL Behring Speaker Invitation and Advisory
Board; 2018-2020 Grifols Speaker invitation and
Advisory Board; 2018-2020 Ferring Advisory Board.
The other authors report no conflicts of interest.
Please refer to the accompanying ICMJE disclo-
sure forms for further details.
Authors’ contributions
All 3 authors contributed equally to the production
of this manuscript.
Supplementary data
Supplementary data to this article can be
found online at https://doi.org/10.1016/j.jhep.2021.
06.018.

References [14] Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive

[1] Saunders JB, Walters JRF, Davies P, Paton A. A 20-year prospective study of
cirrhosis. Br Med J 1981;282:263–266.
[2] Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al.
Compensated cirrhosis: natural history and prognostic factors. Hepatol-
ogy 1987;7:122–128.
[3] D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic in-
dicators of survival in cirrhosis: a systematic review of 118 studies.
J Hepatol 2006;44:217–231.
[4] Planas R, Montoliu S, Ballestè B, Rivera M, Mireia M, Masnou H, et al.
Natural History of patients hospitalized for management of cirrhotic as-
cites. Clin Gastro Hepatol 2006;4:1385–1394.
[5] Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet
2014;383:1749–1761.
[6] D’Amico G, Perricone G. Prediction of decompensation in patients with
compensated cirrhosis: does etiology matter? Curr Hepatol Rep
2019;18:144–156.
[7] D’Amico G, Villanueva C, Burroughs AK, Dollinger MM, Planas R, Sola R,
et al. Clinical stages of cirrhosis a multicenter study of 1858 patients.
Hepatology 2010;52(S1):329A.
[8] Zipprich A, Garcia-Tsao G, Rogowsky S, Fleig WE, Seufferlein T,
Dollinger MM. Prognostic indicators of survival in patients with
compensated and decompensated cirrhosis. Liv Int 2012:1407–1414.
[9] Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. The clinical course
of alcoholic liver cirrhosis: a Danish population-based cohort study.
Hepatology 2010;51:1675–1682.
[10] D’Amico G, Pasta L, Morabito A, D’Amico M, Caltagirone M, Malizia G, et al.
Competing risks and prognostic stages in cirrhosis: a 25-year inception
cohort study of 494 patients. Aliment Pharmacol Ther 2014;39:1180–
1193.
[11] Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M,
et al. Infections in patients with cirrhosis increase mortality four-fold and
should be used in determining prognosis. Gastroenterology
2010;139:1246–1256.
[12] Fede G, D’Amico G, Arvaniti V, Tsochatzis E, Germani G, Georgiadis D, et al.
Renal Failure and cirrhosis: a systematic review of mortality and prog-
nosis. J Hepatol 2012;56:810–818.
[13] Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of
decompensation and organ failure in cirrhosis: from peripheral arterial
vasodilatation to systemic inflammation hypothesis. J Hepatol
2015;63:1272–1284.
bleeding in cirrhosis: risk stratification, diagnosis and management: 2016
guidance by the American Association for the Study of liver Diseases.
Hepatology 2016;65:310–335.
[15] Clària J, Stauber RE, Coenraad MJ, Moreau R, Jalan R, Pavesi M, et al.
Systemic inflammation in decompensated cirrhosis: characterization
and role in acute-on-chronic liver failure. Hepatology 2016;64:1249–
1264.
[16] Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-
chronic liver failure is a distinct syndrome that develops in patients with
acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–1437.
[17] Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial
infections in cirrhosis: a position statement based on the EASL Special
Conference 2013. J Hepatol 2014;60:1310–1324.
[18] Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in
decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev
Gastroenterol Hepatol 2021;18:167–180.
[19] Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Brujats A, Calleja JL,
et al. Bacterial infections adversely influence the risk of decompensation
and survival in compensated cirrhosis. J Hepatol 2021. https://doi.org/10.
1016/j.jhep.2021.04.022.
[20] Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C, et al.
Clinical Course of acute-on-chronic liver failure syndrome and effects on
prognosis. Hepatology 2015;62:243–252.
[21] Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transec-
tion of the oesophagus for bleeding oesophageal varices. Br J Surg
1973;60:646–649.
[22] Kamath PS, Kim WR. The model for end-stage liver disease (MELD).
Hepatology 2007;45:797–805.
[23] Domenicali M, Baldassarre M, Giannone FA, Naldi M, Mastroroberto M,
Biselli M, et al. Posttranscriptional changes of serum albumin: clinical and
prognostic significance in hospitalized patients with cirrhosis. Hepatology
2014;60:1851–1860.
[24] Trebicka J, Amoros A, Pitarch C, Titos E, Alcaraz-Quiles J, Schierwagen R,
et al. Addressing profiles of systemic inflammation across the different
clinical phenotypes of acutely decompensated cirrhosis. Front Immunol
2019;10:476.
[25] Jalan R, Pavesi M, Saliba F, Amorós A, Fernandez J, Holland-Fischer P, et al.
The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for
prognosis of hospitalised cirrhotic patients without acute-on-chronic liver
failure. J Hepatol 2015;62:831–840.

206 Journal of Hepatology 2022 vol. 76 j 202–207

[26] Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT,
et al. Hyponatremia and mortality among patients on the liver-transplant
waiting list. N Engl J Med 2008;359:1018–1026.
[27] Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, et al.
The PREDICT study uncovers three clinical courses of acutely decom-
pensated cirrhosis that have distinct pathophysiology. J Hepatol
2020;73:842–854.
[28] Arroyo V, Angeli P, Moreau R, Jalan R, Clària J, Trebicka J, et al. The sys-
temic inflammation hypothesis: towards a new paradigm of acute
decompensation and multiorgan failure in cirrhosis. J Hepatol 2020.
https://doi.org/10.1016/j.jhep.2020.11.048.
[29] Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, et al.
PREDICT identifies precipitating events associated with the clinical course
of acutely decompensated cirrhosis. J Hepatol 2020. https://doi.org/10.
1016/j.jhep.2020.11.019.
[30] Piano S, Tonon M, Vettore E, Stanco M, Pilutti C, Romano A, et al. Inci-
dence, predictors and outcomes of acute-on-chronic liver failure in out-
patients with cirrhosis. J Hepatol 2017;67:1177–1184.
[31] Tonon M, Piano S, Gambino CG, Romano A, Pilutti C, Incicco S, et al.
Outcomes and mortality of grade 1 ascites and recurrent ascites
in patients with cirrhosis. Clin Gastroenterol Hepatol 2021;19:358–366.
[32] Planas R, Ballesté B, Alvarez MA, Rivera M, Montoliu S, Galeras JA, et al.
Natural history of decompensated hepatitis C virus-related cirrhosis. A
study of 200 patients. J Hepatol 2004;40:823–830.
[33] Wiegand J, Kühne M, Pradat P, Mössner J, Trepo C, Tillmann HL. Different
patterns of decompensation in patients with alcoholic vs. non-alcoholic
liver cirrhosis. Aliment Pharmacol Ther 2012;35:1443–1450.
[34] Lee HW, Cheuk-Fung Yip T, Tse YK, Lai-Hung Wong G, Kim BK, Kim SU,
et al. Hepatic decompensation in cirrhotic patients receiving antiviral
therapy for chronic hepatitis. Clin Gastroenterol Hepatol 2020;2. S1542-
3565(20)31223-4.
[35] Mendoza Y, Cocciolillo S, Murgia G, Chen T, Margini C, Sebastiani G, et al.
Noninvasive markers of portal hypertension detect decompensation in
overweight or obese patients with compensated advanced chronic liver
disease. Clin Gastroenterol Hepatol 2020;18:3017–3025.
[36] Caregaro L, Alberino F, Amodio P, Merkel C, Bolognesi M, Angeli P, et al.
Malnutrition in alcoholic and virus-related cirrhosis. Am J Clin Nutr
1996;63:602–609.
Journal of Hepatology 2022 vol. 76 j 202–207
[37] Bunchorntavakul C, Reddy KR. Review article: malnutrition/sarcopenia
and frailty in patients with cirrhosis. Aliment Pharmacol Ther
2020;51:64–77.
[38] Villanueva C, Albillos A, Genescà J, Abraldes J, Calleja JL, Aracil C, et al.
Development of hyperdinamic circulation and response to b-blockers in
compensated cirrhosis with portal hypertension. Hepatology
2016;63:197–206.
[39] Villanueva C, Albillos A, Genesca J, Garcia-Pagan JC, Calleja JL, Aracil C,
et al. B-blockers to prevent decompensation of cirrhosis in patients with
clinically significant portal hypertension (PREDESCI): a randomised,
double-blind, placebo-controlled, multicentre trial. Lancet
2019;393:1597–1608.
[40] Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al.
Regression of cirrhosis during treatment with tenofovir disoproxil
fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
Lancet 2013;381:468–475.
[41] Di Marco V, Calvaruso V, Ferraro D, Bavetta MG, Cabibbo G, Conte E, et al.
Effects of eradicating hepatitis C virus infection in patients with cirrhosis
differ with stage of portal hypertension. Gastroenterology
2016;151:130–139.
[42] Lens S, Baiges A, Alvarado E, LLop E, Martinez J, Fortea JI, et al. Clinical
outcome and hemodynamic changes following HCV eradication with oral
antiviral therapy in patients with clinically significant portal hyperten-
sion. J Hepatol 2020;73:1415–1424.
[43] Shim JH, Lee HC, Kang Kim KM, Lim YS, Chung YH, et al. Efficacy of
entecavir in treatment-naïve patients with hepatitis B virus-related
decompensated cirrhosis. J Hepatol 2010;52:176–182.
[44] Gentile I, Scotto R, Coppola C, Staiano L, Amoruso DC, De Simone T, et al.
Treatment with direct-acting antivirals improves the clinical outcome in
patients with HCV-related decompensated cirrhosis: results from an
Italian real-life cohort (Liver Network Activity-LINA cohort). Hepatol Int
2019;13:66–74.
[45] Capone RR, Buhac I, Kohberger RC, Balint JA. Resistant ascites in alcoholic
liver cirrhosis: course and prognosis. Am J Dig Dis 1978;23:867–871.
[46] Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG. Long-term
albumin administration in decompensated cirrhosis (ANSWER): an open-
label randomized trial. Lancet 2018;391:2417–2429.
[47] Bernardi M, Caraceni P. Novel perspectives in the management
of decompensated cirrhosis. Nat Rev Gastroenterol Hepatol
2018;15:753–764.
207