Cirrosis Hepatica Descompensada

Clinical Practice Guidelines JOURNAL
OF HEPATOLOGY
EASL Clinical Practice Guidelines for the management of patients with

decompensated cirrhosisq
European Association for the Study of the Liver ⇑
Summary signs, the most frequent of which are ascites, bleeding,

The natural history of cirrhosis is characterised by an asymp- encephalopathy, and jaundice. Following the first appearance
tomatic compensated phase followed by a decompensated of any of these, the disease usually progresses more rapidly
phase, marked by the development of overt clinical signs, the towards death or liver transplantation (LT). This phase of the
most frequent of which are ascites, bleeding, encephalopathy, disease has been designated ‘‘decompensated cirrhosis”.2
and jaundice. The following Clinical Practice Guidelines (CPGs) Progression of the decompensated disease may be further accel-
represent the first CPGs on the management of decompensated erated by the development of other complications such as
cirrhosis. In this context, the panel of experts, having empha- rebleeding, acute kidney injury (AKI), with or without the
sised the importance of initiating aetiologic treatment for any features of HRS, hepato-pulmonary syndrome (HPS), portopul-
degree of hepatic disease at the earliest possible stage, extended monary hypertension (PPHT), cirrhotic cardiomyopathy (CCM),
its work to all the complications of cirrhosis, which had not and bacterial infections. Indeed, the development of bacterial
been covered by the European Association for the Study of the infections as well as hepatocellular carcinoma may accelerate
Liver guidelines, namely: ascites, refractory ascites, hypona- the course of the disease at any stage, but especially in decom-
tremia, gastrointestinal bleeding, bacterial infections, acute kid- pensated cirrhosis.3 Having defined the potential field of action,
ney injury, hepatorenal syndrome, acute-on-chronic liver and having emphasised the importance of initiating aetiologic
failure, relative adrenal failure, cirrhotic cardiomyopathy, hep- treatment for any degree of hepatic disease at the earliest pos-
atopulmonary syndrome, and porto-pulmonary hypertension. sible stage, the panel decided to extend the work to all those
The panel of experts, produced these GPGs using evidence from complications of cirrhosis which have not yet been covered by
PubMed and Cochrane database searches providing up to date EASL guidelines, namely: gastrointestinal (GI) bleeding, bacte-
guidance on the management of decompensated cirrhosis with rial infections other than SBP, acute-on-chronic liver failure
the only purpose of improving clinical practice. (ACLF), adrenal failure, HPS, PPHT and CCM. In doing so, we have
Ó 2018 European Association for the Study of the Liver. Published by had to deal with the recommendations regularly proposed by
Elsevier B.V. All rights reserved. very well recognised international expert groups who have
worked in the field of GI bleeding or ascites and ascites-related
complications for many years. Given their extreme importance
Introduction in clinical practice, only specific aspects of their recommenda-
When the panel of experts nominated by the European Associ- tions were further developed in an attempt to give a more inte-
ation for the Study of the Liver (EASL) governing board began grated view of the pathophysiology and management of patients
work to update the Clinical Practice Guidelines (CPGs) on with decompensated cirrhosis. Thus, this document can no longer
ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal be considered an update of earlier guidelines, but rather the first
syndrome (HRS),1 it became obvious that all other complica- CPG on the management of decompensated cirrhosis with the
tions of decompensated cirrhosis had to be covered. Within this sole purpose of improving clinical practice.
framework, a formal definition of decompensated cirrhosis was
sought. The natural history of cirrhosis is characterised by a
silent, asymptomatic course until increasing portal pressure Guidelines development process
and worsening liver function produce a clinical phenotype. In A panel of hepatologists with a great interest in decompen-
the asymptomatic phase of the disease, usually referred to as sated cirrhosis, approved by the EASL Governing Board, wrote
compensated cirrhosis, patients may have a good quality of life, and discussed this CPG between March 2017 and February
and the disease may progress undetected for several years. 2018. The guidelines were independently peer reviewed, and
Decompensation is marked by the development of overt clinical all contributors to the CPG disclosed their conflicts of interest
by means of a disclosure form provided by the EASL Office
prior to work commencing. The EASL Ethics Committee
q
Clinical Practice Guideline Panel: Paolo Angeli (Chair), Mauro Bernardi
reviewed the composition of the panel to eliminate the
(Governing Board representative), CÁndid Villanueva, Claire Francoz, Rajeshwar
P. Mookerjee, Jonel Trebicka, Aleksander Krag, Wim Laleman, Pere Gines potential for real or perceived bias. The CPG panel conflict of
⇑ Corresponding author. Address: European Association for the Study of the Liver interests are declared in this submission. These guidelines have
(EASL), The EASL Building – Home of Hepatology, 7 rue Daubin, CH 1203 Geneva, been produced using evidence from PubMed and Cochrane
Switzerland. Tel.: +41 (0) 22 807 03 60; fax: +41 (0) 22 328 07 24.
E-mail address: easloffice@easloffice.eu.
database searches before 27 March 2018. Tables describing
Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J
Hepatol (2018), https://doi.org/10.1016/j.jhep.2018.03.024
Clinical Practice Guidelines
Table 1. Level of Evidence and Grade of Recommendations.

Level of evidence
I Randomised, controlled trials
II-1 Controlled trials without randomisation
II-2 Cohort and case-control analytical studies
II-3 Multiple time series, dramatic uncontrolled experiments
III Opinions of respected authorities, descriptive epidemiology
Grade of recommendations
1 Strong recommendation: Factors influencing the strength of the recommendation included the quality of the evidence, presumed
patient-important outcomes, and cost
2 Weaker recommendation: Variability in preferences and values, or more uncertainty: more likely a weak recommendation is
warranted. Recommendation is made with less certainty: higher cost or resource consumption
the rationale behind the levels of evidence and of recommen- result of an abnormal bacterial translocation (BT). Changes in
dations are provided (Table 1). the microbiome and increased intestinal permeability account
for this phenomenon. A similar role is likely played by other
molecules, called danger associated molecular patterns
Pathophysiology of decompensated cirrhosis (DAMPs), released by the diseased liver because of local inflam-
The transition from compensated asymptomatic cirrhosis to mation and cell apoptosis and necrosis. Both PAMPs and DAMPs
decompensated cirrhosis occurs at a rate of about 5% to 7% per bind with innate recognition receptors of immune cells that,
year.4 Once decompensation has occurred, cirrhosis becomes a once activated, produce and release pro-inflammatory mole-
systemic disease, with multi-organ/system dysfunction.5 At this cules, along with reactive oxygen and nitrogen species. This cas-
stage, patients become highly susceptible to bacterial infections cade of events contributes to the development of circulatory
because of complex cirrhosis-associated immune dysfunction, dysfunction and, along with it, directly favours the development
which involves both innate and acquired immunity.6 In turn, of multi-organ dysfunction and failure (Fig. 1).5 Current strate-
patients with bacterial infections are burdened by severe mor- gies for prophylaxis and treatment of decompensation and organ
bidity, up to ACLF, and high mortality.6,7 Because of these events, failure in cirrhosis rely on measures aimed to prevent or improve
decompensation represents a prognostic watershed, as the med- the outcome of each complication, that is renal sodium retention
ian survival drops from more than 12 years for compensated cir- leading to ascites formation, ammonia production in hepatic
rhosis to about two years for decompensated cirrhosis.4 For encephalopathy, effective hypovolaemia after large-volume
decades the clinical manifestations of decompensated cirrhosis paracentesis (LVP) or during HRS, renal dysfunction induced by
have been seen as the consequence of a haemodynamic distur- SBP, and intestinal dysbiosis or bacterial overgrowth in patients
bance, the hyperdynamic circulatory syndrome, ascribable to predisposed to develop infections. All these strategies will be
peripheral arterial vasodilation that mainly occurs in the discussed in these CPGs. However, the improved knowledge of
splanchnic circulatory area. The extent of such vasodilation is the pathophysiological background of decompensated cirrhosis
to endanger effective volaemia, ultimately leading to peripheral now offers the opportunity for more comprehensive therapeutic
organ hypoperfusion, the kidney being most affected.8 Indeed, and prophylactic approaches to disease management. Indeed,
reduced effective volaemia brings about the activation of vaso- besides treating the underlying aetiologic factor(s), whenever
constrictor and water and sodium retaining mechanisms, such possible, mechanistic approaches to counteract key pathophysi-
as the renin-angiotensin-aldosterone (RAAS), sympathetic ner- ologic mechanisms may prevent or delay disease progression
vous system and arginine-vasopressin secretion. This explains and the incidence of complications and multi-organ dysfunction,
some of the cardinal features of decompensated cirrhosis, such thus improving patient survival and quality of life, as well as
as renal retention of sodium and water leading to ascites forma- reducing the economic burden of the disease.
tion and HRS. Other manifestations attributable to haemody-
namic abnormalities include HPS, increased susceptibility to
shock, and a reduced cardiovascular responsiveness to physio- Management of decompensated cirrhosis
logical and pharmacological vasoconstrictor stimuli. Subsequent Ideally, the strategy of management of patients with decompen-
studies have highlighted that a cardiac dysfunction, due to CCM,9 sated cirrhosis should be based on preventing cirrhosis progres-
is also involved in the pathogenesis of effective hypovolaemia.10 sion (i.e. further decompensation) rather than treating
This occurs particularly in the most advanced stages of decom- complications as they occur. The ultimate treatment for decom-
pensation, when such an abnormality prevents cardiac output pensated cirrhosis would be one that targets primarily the
from increasing enough to comply with the needs of systemic pathological alterations within the liver with the aim of restor-
circulation. Although the molecular mechanisms responsible ing the integrity of liver architecture by suppressing inflamma-
for arterial vasodilation, consisting of an enhanced endothelial tion, causing fibrosis regression, regularising the portal and
production of vasodilating substances, such as nitric oxide, car- arterial circulation, and normalising cell number and function.
bon monoxide, prostacyclin and endocannabinoids have been Unfortunately, such a treatment does not exist at present. Sev-
convincingly demonstrated,11 the primary causes of such abnor- eral antifibrotic or anti-inflammatory drugs have shown pro-
malities remained somewhat obscure until it became clear that mise in experimental models of chronic liver diseases, but no
patients with advanced cirrhosis present a state of chronic treatment has yet been translated into clinical practice.13 Mean-
inflammation, as witnessed by increased circulating levels of while, the overall management of decompensated cirrhosis can
pro-inflammatory cytokines and chemokines.12 This is likely be addressed using two approaches. The first approach is the
caused by the systemic spread of bacteria and bacterial products, suppression of the aetiological factor(s) that has caused liver
called pathogen associated molecular patterns (PAMPs), as a inflammation and cirrhosis development, whereas the second
2 Journal of Hepatology 2018 vol. xxx j xxx–xxx

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OF HEPATOLOGY
approach is based on targeting key factors of pathogenesis of with cirrhosis and a Child-Pugh scores of 7–10. In addition,
cirrhosis decompensation and progression. enoxaparin appeared to delay the occurrence of hepatic decom-
pensation and to improve survival suggesting that both PVT and
decompensation may be related to a worsening of portal hyper-
Effects of suppression of aetiological factor on tension and the consequent progressive damage of the intestinal
outcome of decompensated cirrhosis mucosal barrier.26 From the same perspective, two other strate-
Removal of the aetiological factor(s) causing liver injury is an gies should be considered. In 2010, it was shown that pentoxi-
important cornerstone in the management of cirrhosis. This fylline treatment significantly reduced the risk of liver-related
approach is clearly effective in preventing decompensation complications compared to placebo in an RCT of patients with
and improving outcome in patients with compensated cirrhosis. advanced cirrhosis. The prevention of these complications,
However, results in patients with decompensated cirrhosis are which included bacterial infections, renal failure, and hepatic
less efficacious and probably depend, among other factors, on encephalopathy was probably related to the fact that pentoxi-
the actual status of liver disease at the time of removing the fylline prevents intestinal BT and the consequent development
aetiological factor of liver injury. For example, although in some of systemic inflammation.27 Finally, some investigations have
patients with decompensated alcoholic cirrhosis suppression of shown that treatment with propranolol is not only effective in
alcohol consumption is associated with progressive ‘‘re-com- reducing portal hypertension and the consequent the risk of var-
pensation” of cirrhosis and excellent long-term outcome, in iceal bleeding but also in decreasing the risk of other complica-
other patients alcoholic cirrhosis progresses despite stopping tions of cirrhosis related to portal hypertension, such as ascites,
alcohol intake.14,15 Likewise, in patients with cirrhosis due to HRS, SBP, and hepatic encephalopathy.28 These effects occur
hepatitis B virus (HBV) infection, treatment with antiviral specifically in patients who respond to propranolol treatment
agents is associated with improved outcome in some, but not by markedly decreasing portal pressure, emphasising the strong
all patients.16 Moreover, treatment of patients with decompen- relationship between pressure and complications of cirrhosis.
sated cirrhosis due to hepatitis C virus infection with direct Nevertheless, in these studies most of patients had compensated
antiviral agents is associated with beneficial effects in liver cirrhosis. Therefore, studies should be performed in the group of
function and portal hypertension and likely improves outcome, patients with decompensated cirrhosis with the objective of
but these effects are unfortunately not generalisable to all assessing these beneficial effects in cirrhosis progression.
patients treated.17,18 The beneficial effects of removing respon-
sible factors in other aetiologies of decompensated cirrhosis are Recommendations
less clear, perhaps with the exception of autoimmune hepatitis.
In patients with decompensated cirrhosis, the aetiologi-

cal factor, should be removed, particularly alcohol con-
Effects of targeting key pathogenic events in sumption and hepatitis B or C virus infection as this
prevention of cirrhosis progression strategy is associated with decreased risk of decompen-
Several strategies have been evaluated to prevent disease pro- sation and increased survival (II-2,1).
gression in patients with decompensated cirrhosis, including i)
targeting microbiome abnormalities and BT, to improve gut-liver Strategies based on targeting abnormalities in gut-liver
axis; ii) improving the disturbed circulatory function; iii) treating axis by antibiotic administration (i.e. rifaximin), improv-
the inflammatory state; and iv) targeting portal hypertension. ing the disturbed systemic circulatory function (i.e. long-
Administration of rifaximin has been shown to reduce the term albumin administration), decreasing the inflamma-
risk of development of several complications of cirrhosis besides tory state (i.e. statins), and reducing portal hypertension
hepatic encephalopathy in retrospective studies and small case (i.e. beta-blockers) have shown potential benefit to
series.19 Nonetheless, data from prospective randomised dou- decrease cirrhosis progression in patients with decom-
ble-blind studies are lacking. In patients with decompensated pensated cirrhosis. However, further clinical research is
cirrhosis, treatment with norfloxacin reduces the risk of SBP needed with these strategies to confirm their safety
and HRS,20,21 but its use is hampered by the possibility of and potential benefits as therapeutic approaches with
increased risk of infection by resistant bacteria. The potential the aim of preventing cirrhosis progression in decom-
effectiveness of improving circulatory and kidney function by pensated patients.
long-term administration of albumin to patients with decom-
pensated cirrhosis has been explored in two recent randomised
controlled trials (RCTs), both published in abstract form, with Management of specific complications of
contradictory findings.22,23 The discrepant findings may be decompensated cirrhosis
related to different doses of albumin used and/or heterogeneity Ascites
in the study population. Further studies are needed to find out Ascites is the most common cause of decompensation in cirrhosis,
whether long-term albumin administration is efficacious in as 5% to 10% of patients with compensated cirrhosis per year
decompensated cirrhosis. Interestingly, treatment with statins, develop this complication.29 The mainstay of ascites formation
through their pleotropic effects, has been shown to reduce portal is renal sodium retention due to the activation of sodium retain-
hypertension and improve survival in patients with advanced ing systems, such as the renin-angiotensin-aldosterone system
cirrhosis.24,25 These remarkable effects require validation in (RAAS) and sympathetic nervous system. The resulting positive
future studies. Another potential terapeutical strategy in the fluid balance ultimately leads to extracellular fluid volume
prevention of decompensation may be anticoagulation. Indeed, expansion. Reduced effective volaemia secondary to splanchnic
in a small RCT, a 12-month course of enoxaparin was safe and arterial vasodilation is a main determinant of these alterations,8
effective in preventing portal vein thrombosis (PVT) in patients but renal function abnormalities induced by systemic inflammation
Journal of Hepatology 2018 vol. xxx j xxx–xxx 3

Cirrhosis
Portal hypertension Liver injury
Bacterial translocation Damaged cells

PAMPs DAMPs
Other potential Activation if innate pattern

recognition receptors
mechanisms
Release of pro-inflamamtory molecules

(ROS/RNS)
Splanchnic arteriolar vasodilation

and cardiovascular dysfunction
++
Adrenal HE Kidney HPS

dysfunction dysfunction
Fig. 1. The new theory on the development of complications and organ failure/s in patients with cirrhosis (adapted from Ref. 5). DAMP, damage-
associated molecular pattern; HE, hepatic encephalopathy; HPS, hepatopulmonary syndrome; PAMP, pathogen-associated molecular pattern; RNS, reactive
nitrogen species; ROS, reactive oxygen species.
also play a role, especially in the most advanced stages of cirrho- bedside inoculation of at least 10 ml into blood culture bottles
sis.5 Portal hypertension also contributes30 by acting as a com- to enhance its sensitivity.35 The calculation of serum-ascites
partmentalising factor of the expanded extracellular fluid albumin gradient (SAAG) may be useful when the cause of
volume. ascites is not immediately evident, as SAAG ≥1.1 g/dl indicates
The occurrence of ascites impairs patient working and social that portal hypertension is involved in ascites formation with
life, often leads to hospitalisation, requires chronic treatment an accuracy of about 97%.36 Other tests, such as amylase, cytol-
and is a direct cause of further complications, such as SBP, ogy, or culture for mycobacteria should be guided by clinical
restrictive ventilatory dysfunction, or abdominal hernias. The presentation. Ascitic cholesterol determination followed by
appearance of ascites heralds a poor prognosis, as the five-year cytology and carcinoembryonic antigen (CEA) determination
survival drops from about 80% in compensated patients to about in samples where cholesterol concentration exceeds 45 mg/dl
30% in patients with decompensated cirrhosis and ascites.4 appears to be a cost-effective method for the differential diag-
nosis between malignancy-related and non-malignant ascites.37
Uncomplicated ascites
Evaluation of patients with ascites
Cirrhosis is the main cause of ascites in the Western world, being Recommendations
responsible for about 80% of cases. Malignancy, heart failure,
tuberculosis, pancreatic disease, or other rarer diseases account
A diagnostic paracentesis is recommended in all patients
for the remaining cases. Initial patient evaluation should include
with new onset grade 2 or 3 ascites, or in those hospi-
history, physical examination, abdominal ultrasound, and labo-
talised for worsening of ascites or any complication of
ratory assessment of liver and renal functions, serum and urine
cirrhosis (II-2;1).
electrolytes, as well as an analysis of the ascitic fluid.
Neutrophil count and culture of ascitic fluid culture
Diagnosis of ascites (bedside inoculation blood culture bottles with 10 ml
Ascites can be graded from 1 to 3 according to the amount of fluid each) should be performed to exclude bacterial
fluid in the abdominal cavity31 (Table 2). The ascites that recurs peritonitis. A neutrophil count above 250 cells/ll is
at least on three occasions within a 12-month period despite required to diagnose SBP (II-2;1).
dietary sodium restriction and adequate diuretic dosage is Ascitic total protein concentration should be performed
defined as recidivant.32 to identify patients at higher risk of developing SBP
Diagnostic paracentesis is indicated in all patients with new (II-2;1).
onset of grade 2 or 3 ascites and in those admitted to the hospi-
tal for any complication of cirrhosis.31,32 Manual or automated The SAAG should be calculated when the cause of ascites
neutrophil count, total protein and albumin concentration, is not immediately evident, and/or when conditions
and culture should be always assessed. A neutrophil count other than cirrhosis are suspected (II-2;1).
above 250 cells/ll denotes SBP.33 A total protein concentration Cytology should be performed to differentiate malig-
<1.5 g/dl is generally considered a risk factor for SBP, although nancy-related from non-malignant ascites (II-2;1).
there are conflicting data.33,34 Ascitic fluid culture requires the

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OF HEPATOLOGY
Prognosis of patients with ascites
The development of ascites in patients with cirrhosis is associ- Recommendations
ated with a poor prognosis, as their one and two-year mortality
is about 40 and 50%, respectively.1 Thus, patients with ascites
A moderate restriction of sodium intake (80–120 mmol/
should generally be considered for referral for LT. Hypona-
day, corresponding to 4.6–6.9 g of salt) is recommended
traemia, low arterial pressure, glomerular filtration rate (GFR)
in patients with moderate, uncomplicated ascites (I;1).
and low renal sodium excretion are independent predictors of
This is generally equivalent to a no added salt diet with
mortality in cirrhosis with ascites.38 As these parameters are
avoidance of pre-prepared meals. Adequate nutritional
not included in the Child-Pugh score, and only serum creatinine
education of patients on how to manage dietary sodium
(SCr), which overestimates GFR in cirrhosis,39 is included in the
is also recommended (II-2;1).
model for end-stage liver disease (MELD) score, the most com-
monly used prognostic scores can underestimate the mortality Diets with a very low sodium content (<40 mmol/day)
risk in patients with ascites. Modifications of the MELD score, should be avoided, as they favour diuretic-induced com-
such as the MELD-Na and MELD-Ascites scores have only par- plications and can endanger a patient’s nutritional status
tially overcome this limitation.40 Thus, patients with ascites (II-2;1).
may not receive adequate priority in transplant lists, and Prolonged bed rest cannot be recommended because
improved methods to assess prognosis in these patients are there is insufficient evidence that it is beneficial in the
needed. A prognostic score able to identify patients with low treatment of ascites (III;1).
MELD score (<18) at high risk of 12-month adverse outcome
has recently been proposed, but it still has limited application.41
Diuretics. Neither diuretics nor LVP are associated with a survival
benefit because they act downstream of the pathophysiological
Recommendation cascade, being symptomatic therapies. The negative fluid balance
induced by diuretics should not lead to a body weight loss exceed-
ing 0.5 kg/day in patients without peripheral oedema and
Since the development of grade 2 or 3 ascites in patients 1 kg/day in the presence of peripheral oedema to avoid plasma
with cirrhosis is associated with reduced survival, LT volume contraction, ultimately leading to renal failure and
should be considered as a potential treatment option hyponatraemia.48 Since secondary hyperaldosteronism plays a
(II-2;1). pivotal role in the renal sodium retention in patients with cirrho-
sis,49,50 anti-mineralocorticoid drugs (spironolactone, canrenone
or K-canrenoate) represent a mainstay in the medical treatment
Management of uncomplicated ascites of ascites.50 Four hundred mg/day represents the maximal dosage
Ascites is uncomplicated when it is not infected, refractory or usually recommended.31,32 The mechanism of action of anti-min-
associated with HRS.31,32 eralocorticoids explains their slow effect. In fact, the activated
aldosterone pathway, which involves interaction with a cytosolic
receptor and, then, a nuclear receptor, needs to be exhausted
Grade 1 or mild ascites. No data on the evolution of grade 1
before their natriuretic effect arises. Therefore, the dosage of
ascites are available, nor it is known whether its treatment
these drugs should not be increased earlier than 72 h. Amiloride,
modifies its natural history.
a diuretic acting in the collecting duct, is less effective than anti-
mineralocorticoids, and should only be used in patients who
Grade 2 or moderate ascites. Patients who develop grade 2 ascites develop severe side effects with aldosterone antagonists.51
do not require hospitalisation, unless other complications are Proximal tubular sodium reabsorption promotes renal sodium
present. They have a positive sodium balance, which can be cor- retention through various mechanisms, such as increased angio-
rected by reducing the dietary sodium intake and increasing tensin II production, sympatho-adrenergic hyperactivity and
renal sodium excretion with diuretics. Although upright posture reduced renal perfusion.49 As proximal tubular sodium reabsorp-
favours renal sodium reabsorption42 and attenuates the tion can become relatively prevalent in patients with long-stand-
response to diuretics,43 there is no evidence that a prolonged ing ascites,52,53 loop diuretics are indicated in this setting.
maintenance of the supine position eases the treatment of However, they should be combined with but not substituted for
ascites. anti-mineralocorticoids. Indeed, despite their potent activity,
Sodium restriction. The prophylactic use of salt restriction in the natriuretic effect of loop diuretics can be completely blunted
patients who never had ascites is not supported by evidence. by unopposed hyperaldosteronism.54 Whether diuretic treat-
Dietary sodium restriction can lead to the resolution of ascites ment should be initiated with anti-mineralocorticoids alone or
in about 10% of patients,44 especially in those with the first epi- should also include a loop diuretic has long been debated. Two
sode of ascites. A clear advantage from the use of low-sodium studies have addressed this matter providing apparently conflict-
diets associated with diuretics has not emerged from clinical tri- ing results because of differences in patient populations.55,56 In
als comparing different dietary regimens.44,45 Extreme sodium both studies, the effects of a diuretic regimen initially consisting
restriction favours the development of diuretic-induced of spironolactone or K-canrenoate alone at stepwise increasing
hyponatraemia and renal failure.46 Moreover, even moderate
sodium restriction, when not prescribed with an adequate edu- Table 2. Grading of ascites.
cational programme, is often associated with reduced calorie Grade 1. Mild ascites: it is only detectable by ultrasound examination
intake,47 and may impair nutritional status. The current opinion Grade 2. Moderate ascites: it is manifest by moderate symmetrical
is that dietary sodium should only be moderately restricted distension of abdomen
Grade 3. Large or gross ascites: it provokes marked abdominal distension
(80–120 mmol/day), mainly to avoid excess salt intake.

dosages (from 100/200 to 400 mg/day), with furosemide added in

non-responder patients, were compared with those of the combi- Recommendations
nation of anti-mineralocorticoids with furosemide (from 40 to
160 mg/day) from the beginning of treatment. In one study,56
Patients with the first episode of grade 2 (moderate)
the response rate, the rapidity of ascites mobilisation and the
ascites should receive an anti-mineralocorticoid drug
incidence of diuretic-induced complications were similar in
alone, starting at 100 mg/day with stepwise increases
both regimens. However, as the sequential treatment required less
every 72 h (in 100 mg steps) to a maximum of 400
dose adjustments, it appeared to be more suitable for treating
mg/day if there is no response to lower doses (I;1).
ascites on an outpatient basis. In the other study,55 the combined
regimen achieved the resolution of ascites in a shorter time, with In patients who do not respond to anti-mineralocorti-
a lower incidence of side effects, mainly hyperkalemia. Such coids, as defined by a body weight reduction of less than
divergent results likely arose from differences in the patient 2 kg/week, or in patients who develop hyperkalemia,
populations. In one study,56 patients with ascites at the first furosemide should be added at an increasing stepwise
appearance and well preserved renal function prevailed, while, in dose from 40 mg/day to a maximum of 160 mg/day (in
the other,55 most patients had recurrent ascites and many showed 40 mg steps) (I;1).
a substantial reduction of GFR. Thus, patients with ascites Patients with long-standing or recurrent ascites should
at the first appearance can confidently be treated with anti- be treated with a combination of an anti-mineralocorti-
mineralocorticoids alone, as they will likely develop a satisfactory coid drug and furosemide, the dose of which should be
response with few side effects. Patients with long-standing, increased sequentially according to the response, as
recurrent ascites should receive the combination therapy, which explained (I;1).
likely shortens the time to achieve natriuresis and lowers the
Torasemide can be given in patients exhibiting a weak
incidence of hyperkalemia.1 In a randomised double-blind cross-
response to furosemide (I;2).
over trial torasemide induced greater cumulative 24 h diuresis than
furosemide, suggesting that torasemide might be more advanta- During diuretic therapy a maximum weight loss of 0.5
geous in patients exhibiting a weak response to furosemide.57 kg/day in patients without oedema and 1 kg/day in
Following mobilisation of ascites, diuretics should be tapered patients with oedema is recommended (II-2;1).
to the lowest dosages able to maintain patients with minimal or Once ascites has largely resolved, the dose of diuretics
no ascites, to minimise side effects. Whenever possible, an aeti- should be reduced to the lowest effective dose (III;1).
ologic treatment of the underlying cirrhosis should be insti-
During the first weeks of treatment patients should
tuted, as this eases the control of ascites in many cases.
undergo frequent clinical and biochemical monitoring
Complications of diuretic therapy. The haemodynamic status of
particularly on first presentation (I;1).
patients with cirrhosis and ascites8 makes them highly suscep-
tible to rapid reductions in extracellular fluid volume, which In patients presenting with GI haemorrhage, renal
mostly occur with loop diuretics. Thus, renal failure is frequent impairment, hepatic encephalopathy, hyponatraemia,
in this setting,48 as is hepatic encephalopathy, also favoured by or alterations in serum potassium concentration, these
increased renal ammonia production. Loop diuretics can also abnormalities should be corrected before starting diure-
lead to potassium and magnesium depletion. Hyponatraemia tic therapy (III;1). In these patients, cautious initiation of
is another common diuretic-induced side effect in cirrhosis. It diuretic therapy and frequent clinical and biochemical
mostly, but not exclusively, occurs with loop diuretics, as they assessments should be performed (III;1). Diuretic ther-
inhibit Na-K-Cl transporter and, therefore, solute-free water apy is generally not recommended in patients with per-
generation. Plasma volume contraction can also enhance argi- sistent overt hepatic encephalopathy (III;1).
nine-vasopressin release. Thus, hyponatraemia can also ensue Diuretics should be discontinued if severe hypona-
with anti-mineralocorticoid administration, albeit infrequently. traemia (serum sodium concentration <125 mmol/L),
Most experts agree on at least temporarily withdrawing diuret- AKI, worsening hepatic encephalopathy, or incapacitat-
ics when serum sodium concentration decreases below 120– ing muscle cramps develop (III;1).
125 mmol/L. Hyperkalemia, especially in patients with reduced
renal perfusion, and painful gynecomastia are the most com- Furosemide should be stopped if severe hypokalemia
mon side effects induced by anti-mineralocorticoids. occurs (<3 mmol/L). Anti-mineralocorticoids should be
stopped if severe hyperkalemia occurs (>6 mmol/L) (III;1).
Muscle cramps can impair quality of life in patients receiving
diuretics. Albumin infusion can relieve cramps,58 as well as Albumin infusion or baclofen administration (10
baclofen (10 mg/day, with a weekly increase of 10 mg/day up mg/day, with a weekly increase of 10 mg/day up to 30
to 30 mg/day), which was safely used in a recent RCT.59 One mg/day) are recommended in patients with muscle
RCT investigated the use of quinidine at the dose of 400 mg/day cramps (I;1).
for four weeks in patients with cirrhosis with painful muscle
cramps. Although more effective than placebo, quinidine was
associated with diarrhoea in about one-third of cases requiring Grade 3 or large ascites. The treatment of choice for the manage-
treatment withdrawal.60 Because of the frequency of diuretic- ment of patients with grade 3 ascites is represented by LVP.
induced side effects, especially during the first month of treat- Paracentesis should be performed under strict sterile conditions
ment,55 serial measurements of SCr, sodium, and potassium using disposable sterile materials. The procedure is associated
are warranted. The assessment of urine sodium excretion can with a very low risk of local complications, particularly bleed-
be limited to non-responders, to unveil excessive sodium intake. ing61,62 even in patients with international normalized ratio

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(INR)>1.5 and platelet count <50,000/ll, minor bleeding from Table 3. Contraindications to paracentesis.
puncture site occurred in two out of 142 paracentesis.61 Thus, Uncooperative patient
there are no data supporting the prophylactic use of fresh frozen Abdominal skin infection at the proposed puncture sites
plasma of pooled platelets, even though these are employed in Pregnancy
Severe coagulopathy (accelerated fibrinolysis or disseminated
many centres when prothrombin activity is below 40% and pla-
intravascular coagulation)
telet count <40,000/ll. LVP should be avoided in the presence of Severe bowel distension
disseminated intravascular coagulation. Other contraindications
to LVP are reported (Table 3).
The removal of large volumes of ascitic fluid is potentially Drugs contraindicated in patients with ascites
associated with a further reduction of effective blood volume, a As non-steroidal anti-inflammatory drugs inhibit renal prosta-
condition known as post-paracentesis circulatory dysfunction glandin synthesis, they should not be used in patients with cir-
(PPCD).63 The clinical manifestations of PPCD are renal failure, rhosis and ascites, where an increased vasodilating
dilutional hyponatraemia, hepatic encephalopathy and prostaglandin synthesis counteracts the renal vasoconstrictor
decreased survival.63 Plasma volume expansion should be per- effects of angiotensin II. Indeed, their administration can lead
formed at the completion of LVP to prevent this complication. to acute renal failure, hyponatraemia, and diuretic resistance.71
Artificial plasma expanders, such as dextran-70 (8 g/L of ascites It would appear that selective inhibitors of cyclooxygenase-2 do
removed)64 or polygeline (150 ml/L),64 saline solution (170 ml/ not impair renal function and response to diuretics in patients
L),65 only show a similar efficacy to 20% albumin (8 g/L)64 when with ascites.72 However, it is not known whether these drugs
less than 5 L of ascites are removed. However, polygeline is no can be safely used in clinical practice when analgesia is needed.
longer used in many countries because of the potential risk of Patients with ascites are also particularly sensitive to the renal
transmission of prions and dextran carries the risk of severe aller- vasoconstrictor effect of endogenous adenosine, and dipyri-
gic reaction and renal failure. A meta-analysis of randomised tri- damole can induce a marked reduction in renal perfusion.73
als showed that albumin is superior to any other plasma expander The maintenance of an adequate arterial pressure in cirrhosis
or vasoconstrictor not only in preventing PPCD, but also its clini- with ascites is assured by the activation of endogenous vasocon-
cal consequences, such as hyponatraemia and mortality.66 More- strictor systems. Thus, angiotensin-converting enzyme
over, albumin infusion after LVP appears to be more cost-effective inhibitors,74 angiotensin II receptor antagonists, and a1-adren-
than a cheaper plasma volume expander, such as polygeline, ergic blockers75 should be avoided, as they can induce arterial
because of the lower number of liver-related complications and hypotension and renal function impairment. Aminoglycosides
hospital costs for a 30-day period.67 LVP combined with infusion should be avoided in the treatment of bacterial infections,
of albumin in patients with grade 3 ascites is more effective and except in specific cases (discussed later), because they are asso-
safer than diuretics.68,69 However, LVP does not modify the ciated with high incidence of nephrotoxicity.76 Although cirrho-
underlying pathophysiological abnormalities leading to ascites sis with ascites and preserved renal function does not appear to
formation. Thus, patients treated with LVP require diuretic ther- be a risk factor for renal failure induced by contrast media,77
apy to prevent the re-accumulation of ascites.70 this cannot be excluded in patients with impaired renal func-
tion. In these cases, preventive measures such as plasma volume
expansion with saline may be employed.78
Recommendations
Recommendations
LVP is the first-line therapy in patients with large ascites
(grade 3 ascites), which should be completely removed
in a single session (I;1). Non-steroidal anti-inflammatory drugs should not be
used in patients with ascites because of the high risk of
LVP should be followed with plasma volume expansion developing further sodium retention, hyponatraemia,
to prevent PPCD (I;1). and AKI (II-2;1).
In patients undergoing LVP of greater than 5 L of ascites, Angiotensin-converting-enyzme inhibitors, angiotensin
plasma volume expansion should be performed by infus- II antagonists, or a1-adrenergic receptor blockers should
ing albumin (8 g/L of ascites removed), as it is more not generally be used in patients with ascites because of
effective than other plasma expanders, which are not increased risk of renal impairment (II-2;1).
recommended for this setting (I;1).
The use of aminoglycosides is discouraged, as they are
In patients undergoing LVP of less than 5 L of ascites, the associated with an increased risk of AKI. Their use should
risk of developing PPCD is low. However, it is generally be reserved for patients with severe bacterial infections
agreed that these patients should still be treated with that cannot be treated with other antibiotics (II-2;1).
albumin because of concerns about use of alternative
plasma expanders (III;1). In patients with ascites and preserved renal function, the
use of contrast media does not appear to be associated
After LVP, patients should receive the minimum dose of with an increased risk of renal impairment (II-2). There
diuretics necessary to prevent re-accumulation of ascites are insufficient data in patients with renal failure. Never-
(I;1). theless, a cautious use of contrast media and the use of
When needed, LVP should also be performed in patients preventive measures for renal impairment are recom-
with AKI or SBP (III;1). mended (III;1).

Refractory ascites refractory ascites will be developed in the section dedicated to

Evaluation of patients with refractory ascites GI bleeding.
According to the criteria of the International Ascites Club, refrac-
tory ascites is defined as ‘‘ascites that cannot be mobilised or the Transjugular intrahepatic portosystemic shunts. Transjugular
early recurrence of which (i.e., after LVP) cannot be satisfactorily intrahepatic portosystemic shunts (TIPS) decompresses the portal
prevented by medical therapy”.31,32 The diagnostic criteria of system by shunting an intrahepatic portal branch into a hepatic
refractory ascites are shown in Table 4. Refractoriness of ascites vein. Its insertion accentuates perpheral arterial vasodilation in
is associated with a poor prognosis, with a median survival of the short term. However, within 4–6 weeks its result is an
about six months.79 Therefore, if a patient with refractory ascites improvement in effective volaemia and renal function, ultimately
has not yet been considered for LT, he/she should be immediately leading to an increase in renal sodium excretion.81–85 TIPS-
referred to a liver transplant center. The potential underestimation induced natriuresis can be delayed by advanced age and reduced
of the mortality risk by commonly used prognostic scores, as dis- pre-TIPS GFR,84 and prevented by intrinsic kidney disease.86 TIPS
cussed earlier also applies to patients with refractory ascites.80 may also exert beneficial effects on nitrogen balance and nutri-
tion87 and quality of life.88 A major complication after TIPS inser-
tion using bare stent grafts is the development of hepatic
Recommendations encephalopathy, which can occur in up to 50% of patients.89,90
The incidence of this complication can be significantly reduced
The diagnosis of refractory ascites relies on the assess- to about 18% with the use of polytetrafluoroethylene (PTFE)-cov-
ment of the response of ascites to diuretic therapy and ered stent grafts of 8 mm,91 a result confirmed by a recent ran-
salt restriction. Such an evaluation should be done in domised trial comparing 8 mm and 10 mm stent grafts.92
stable patients without associated complications, such Notably, this favourable effect is better than with larger stent
as bleeding or infection, after ascertaining patient com- grafts underdilated to 8 mm. Indeed, it has been shown that
pliance to treatment (III;1). underdilated 10 mm stent grafts passively expand to almost the
full diameter within 1–6 weeks.93 It must be underlined that the
Patients with refractory ascites should be evaluated for
indication for TIPS insertion in these studies was the prevention
LT (III;1).
or treatment of recurrent bleeding, which may restrict the rele-
vance of these results in patients with refractory ascites. Dysfunc-
tion of TIPS with bare stent grafts because of stent thrombosis and
Management of refractory ascites stenosis can develop in up to 80% of cases.89 This complication has
Large-volume paracentesis. There is general agreement that LVP been significantly reduced with the use of PTFE-covered stents.94
is an effective and safe treatment of refractory ascites,31,35
which should be associated with albumin administration to pre- Controlled studies and meta-analysis. The clinical effects of TIPS
vent PPCD. with bare stents in patients with refractory or recurrent ascites
have been assessed in six prospective RCTs,95–100 whose main
Diuretics in patients with refractory ascites. Once refractoriness of features are reported (Table 5). Based on these RCTs, seven
ascites has been ascertained, diuretics should be discontinued. meta-analyses were performed.101–107 The final messages can
Only when renal sodium excretion on diuretics exceeds 30 be summarised as follow: i) TIPS controlled ascites better than
mmol/day, maintenance of diuretic therapy can be considered, LVP, and ii) TIPS is followed by a greater incidence of hepatic
when tolerated.31 encephalopathy. However, discrepant results were obtained
with respect to survival. A better survival with LVP, mainly
Non-selective beta-blockers in patients with refractory ascites. The because of a detrimental effect of TIPS in Child-Pugh class C
controversial issue on the use of non-selective beta-blockers patients, was reported by one study,96 while no difference was
(NSBBs) in patients with ascites and, particularly, in those with reported by two.95,100 A better survival with TIPS was reported
Table 4. Definition and diagnostic criteria for refractory ascites in cirrhosis.

Definition
Diuretic-resistant ascites Ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium
restriction and diuretic treatment
Diuretic-intractable Ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-
ascites induced complications that preclude the use of an effective diuretic dosage
Diagnostic criteria
Treatment duration Patients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least one week and
on a salt-restricted diet of less than 90 mmol/day
Lack of response Mean weight loss of <0.8 kg over four days and urinary sodium output less than the sodium intake
Early ascites recurrence Reappearance of grade 2 or 3 ascites within four weeks of initial mobilisation
Diuretic-induced Diuretic-induced hepatic encephalopathy is the development of encephalopathy in the absence of any other precipitating factor
complications Diuretic-induced renal impairment is an increase of serum creatinine by >100% to a value >2 mg/dl (177 lmol/L) in patients with
ascites responding to treatment
Diuretic-induced hyponatremia is defined as a decrease of serum sodium by >10 mmol/L to a serum sodium of <125 mmol/L
Diuretic-induced hypo- or hyperkalemia is defined as a change in serum potassium to <3 mmol/L or >6 mmol/L despite
appropriate measures
Invalidating muscle cramps

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OF HEPATOLOGY
Table 5. Characteristics and results of six randomised controlled trials comparing bared TIPS and LVP in patients with cirrhosis and refractory or
recidivant ascites.
Refs. Refractory/ Exclusion criteria Enrolled Ascites Encephalopathy Survival
recidivant patients improved (%) (%)
ascites (%) (N) (%)
TIPS LVP TIPS LVP TIPS LVP TIPS LVP
Lebrec et al. 100/0 Age >70 yr; severe extra-hepatic diseases; HCC; pulmonary 13 12 38 0* 15 6 29 60
1995 hypertension; HE, bacterial infection; severe alcoholic hepatitis; portal
or hepatic vein obstruction or thrombosis; obstruction of biliary tract;
obstruction of hepatic artery; serum creatinine >1.7 mg/dl
Rössle et al. 55/45 HE ≥grade 2; serum bilirubin >5 mg/dl, serum creatinine >3 mg/dl; 29 31 84 43* 23 13 58 32
2000 portal-vein thrombosis, hepatic hydrothorax; advanced cancer; failure
of LVP (ascites persisting after LVP or need for LVP >once per week)
Ginés et al. 100/0 Age >18 or >75 yr; serum bilirubin >10 mg/dl; prothrombin time <40% 35 35 51 17* 60 34 26 30
200290 (INR 2.5); platelet count <than 40,000/mm3; serum creatinine >3 mg/
dl, HCC, complete portal vein thrombosis; cardiac or respiratory
failure; organic renal failure; bacterial infection; chronic HE
Sanyal et al. 100/0 Causes of ascites other than cirrhosis; advanced liver failure (serum 52 57 58 16* 38 21 35 33
2003100 bilirubin bilirubin >5 mg/dl, PT INR >2); incurable cancers or
nonhepatic diseases that were likely to limit life expectancy to 1 yr;
congestive heart failure; acute renal failure; parenchymal renal
disease; portal vein thrombosis; bacterial infections; HE ≥grade II;
florid alcoholic hepatitis, HCC; gastrointestinal hemorrhage within 6 w
of randomisation.
Salerno 68/32 Age > 72 yr; recurrent HE ≥grade 2; serum bilirubin >6 mg/dl; serum 33 33 79 42* 61 39 59 29*
et al. 200499 creatinine >3 mg/dl; Child-Pugh score >11; complete portal vein
thrombosis; HCC; gastrointestinal bleeding within 15 d of
randomisation; serious cardiac or pulmonary dysfunctions;bacterial
infection; SAAG gradient <11 g/L.
Narahara 100/0 Age >70 yr, chronic HE, HCC and other malignancies, complete portal 30 30 87 30* 20 5 20 5*
et al. 201197 vein thrombosis with cavernomatous transformation, bacterial
infection, severe cardiac or pulmonary disease, organic renal disease.
HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; INR, international normalized ratio; LVP, large volume paracentesis; PT, prothrombin time; SAAG, serum-
ascites albumin gradient; TIPS, transjugular intrahepatic portosystemic shunt.
*
Significantly lower than TIPS.
in another two studies,97,99 while, in the remaining one,98 those belonging to Child-Pugh class C.96 The main exclusion cri-
although a survival advantage was not found, TIPS was indepen- teria for TIPS insertion in the seven RCTs are reported in Table 5.
dently associated with transplant-free survival at multivariate A score system based on SCr, INR, serum bilirubin and aetiology
analysis. In four meta-analyses including the five studies avail- of cirrhosis has been proposed to predict survival after TIPS
able at that time no survival advantantage with TIPS emerged. insertion for refractory ascites.112 Another simple predictor of
However, a trend towards reduced mortality with TIPS was survival suggested for patients receiving TIPS for refractory
seen104 after the exclusion of an outlier trial.96 The latter was ascites consists of the combination of serum bilirubin
also excluded in the only meta-analysis on individual patient concentration and platelet count.113 Another factor that seems
data, and an increased transplant-free survival was found.107 to influence mortality is the number of TIPS procedures per-
Finally, the two meta-analyses that included all six trials102,103 formed in a centre, as the risk of inpatient mortality is lower
provided contrasting results, as an improved transplant-free sur- in hospitals performing ≥20 TIPS per year.114
vival was found in one,107 while a survival advantage with TIPS
was limited to patients with recurrent ascites in the other.102 Other treatments. Based on the exclusion criteria reported
Fewer studies assessing the effects of TIPS with PTFE-covered (Table 5), a substantial portion of patients with refractory
stent grafts are available. Two retrospective studies108,109 ascites are not candidates for TIPS insertion. Thus, the search
reported better control of ascites and one-year108 or two- for alternative treatments is warranted.
year109 survival with covered stent grafts than bare stent grafts
in patients with refractory ascites. A survival benefit of TIPS vs. Medical treatments. Therapies aimed at improving circulatory
serial paracentesis in patients with refractory ascites has been and renal function have been proposed. The a1-adrenergic
reported in a single-centre case-control propensity score analy- agonist midodrine has been shown to improve systemic and
sis.110 In a recent RCT comparing covered TIPS vs. LVP in renal haemodynamics in patients with cirrhosis and uncom-
patients with recurrent ascites, a better one-year transplant- plicated ascites.115 In a small RCT comparing the addition of
free survival was seen in patients treated with covered stents, midodrine (7.5 mg t.i.d) to diuretic treatment with diuretic
without any significant increase in occurrence of hepatic treatment alone in patients with refractory or recurrent
encephalopathy.111 Thus, currently available data suggest that ascites for six months, only a transient beneficial effect on
TIPS improves survival compared to LVP in patients with recur- the control of ascites was seen at the third month.116 The
rent ascites, but it does not in those with refractory ascites. use of terlipressin, an analogue of vasopressin with a predom-
A careful selection of patients is also crucial to maximise the inant vasoconstrictor effect in the splanchnic circulatory area
beneficial effects of TIPS, as TIPS can even be detrimental in in patients with refractory ascites has only been assessed in
patients with the most advanced stages of cirrhosis, such as acute studies. In one,117 terlipressin administration (1 to

2 mg intravenous [i.v.], according to body weight) only carrying AlfapumpÒ has shown a significant GFR decline within
increased renal sodium excretion when associated with six months, which was associated with a marked increase in
exogenous atrial natriuretic factor. In another,118 2 mg of ter- plasma renin activity and norepinephrine concentration.127 This
lipressin led to an increase in GFR, renal plasma flow and likely represented the pathophysiological background of 18
renal sodium excretion. However, in this study only eight episodes of AKI experienced by seven patients.
patients with refractory ascites were included. Whether a
prolonged treatment with terlipressin may lead to a clinically
relevant improvement of renal function and sodium excretion
in refractory ascites is not known. Recommendations
The a2-adrenoceptor agonist clonidine, a sympatholytic
drug, which suppresses RAAS activity and improves the
response to diuretics in patients with cirrhosis and ascites Repeated LVP plus albumin (8 g/L of ascites removed)
was tested in a large prospective RCT. It was shown that cloni- are recommended as first line treatment for refractory
dine administration on top of diuretics for three months led to ascites (I;1).
an overall response to diuretics in 60% of cases, while no Diuretics should be discontinued in patients with refrac-
response was seen with diuretics alone. This effect was asso- tory ascites who do not excrete >30 mmol/day of sodium
ciated with significant reductions of RAAS and sympathetic under diuretic treatment (III;1).
nervous system activity. Interestingly, the favourable effects Although controversial data exist on the use of NSBBs in
of clonidine were predicted by the variant genotype of G pro- refractory ascites, caution should be exercised in cases of
tein (GNB3 C825T) and adrenergic receptor (ADRA2C Del 322–
severe or refractory ascites. High doses of NSBB should
325) polymorphisms, and the baseline norepinephrine level.119 be avoided (i.e. propranolol >80 mg/day) (II-2;1). The
Small scale or pilot studies evaluated the effects of various use of carvedilol can not be recommended at present
combinations of midodrine with either clonidine,120 the antag- (I;2).
onist of vasopressin V2-receptors tolvaptan,121 or octreotide
and albumin122 in patients with refractory and recurrent Patients with refractory or recurrent ascites (I;1), or
ascites. Some promising results were obtained, but they need those for whom paracentesis is ineffective (e.g. due to
to be confirmed by sufficiently powered RCTs. A recent RCT123 the presence of loculated ascites) should be evaluated
compared the effects of the combined administration of mido- for TIPS insertion (III;1).
drine (5 mg t.i.d) and rifaximin (550 mg b.i.d) on top of diuret- TIPS insertion is recommended in patients with recur-
ics for 12 weeks with diuretics alone. After 12 weeks, 80% of rent ascites (I;1) as it improves survival (I;1) and in
patients in the active arm were complete responders with a patients with refractory ascites as it improve the control
significant improvement in survival in the midodrine/rifaximin of ascites (I;1).
arm. Due to weakness in the study design, these results are
The use of small-diameter PTFE-covered stents in
not definitive, but they certainly warrant further investigation.
patients is recommended to reduce the risk of TIPS dys-
function and hepatic encephalopathy with a high risk of
AlfapumpÒ. The automated low-flow ascites pump (AlfapumpÒ)
hepatic encephalopathy is recommended (I;1).
system consists of a subcutaneously implanted battery-powered
programmable pump. It is connected to catheters that transfer Diuretics and salt restriction should be continued after
ascites from the peritoneal cavity to the bladder, from which it TIPS insertion up to the resolution of ascites (II-2;1), as
is eliminated with urine. The device has internal sensors that well as close clinical follow-up (III,1).
monitor pump function. In two multicentre safety and efficacy Careful selection of patients for elective TIPS insertion is
studies,124,125 AlfapumpÒ ensured a significant reduction of the crucial, as is the experience of the centre performing this
number and volume of paracentesis in patients with advanced procedure. TIPS is not recommended in patients with
cirrhosis and refractory ascites. However, adverse effects serum bilirubin > 3 mg/dl and a platelet count lower
directly related to the device occurred in about one-third124 to than 75 x 109/L, current hepatic encephalopathy grade
half125 of cases. In a multicentre RCT in patients with refractory ≥2 or chronic hepatic encephalopathy, concomitant
ascites, AlfapumpÒ reduced the median number of paracentesis active infection, progressive renal failure, severe systolic
per month by 85% with respect to LVP, and significantly or diastolic dysfunction, or pulmonary hypertension
improved quality of life and nutritional parameters, as assessed (III;1).
by hand-grip strength and body mass index. AlfapumpÒ had no
effect on survival and was associated with a significantly higher At present the addition of clonidine or midodrine to
incidence of serious adverse events (85.2 vs. 45.2%), mainly rep- diuretic treatment cannot be recommended (III;1).
resented by AKI.126 Thus, even though AlfapumpÒ is effective in AlfapumpÒ implantation in patients with refractory
reducing the need for paracentesis in patients with refractory ascites not amenable to TIPS insertion is suggested in
ascites, its frequent side effects require close monitoring of experienced centres. However, close patient monitoring
patients. Indeed, in addition to device-related adverse event, it is warranted because of the high risk of adverse events
should be noted that the evaluation of kidney and circulatory including renal dysfunction and technical difficulties (I;2).
function in 10 patients with cirrhosis and refractory ascites

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Hepatic hydrotorax
Hepatic hydrotorax describes the accumulation of transudate in Recommendations
the pleural space of patients with decompensated cirrhosis in
the absence of cardiac, pulmonary or pleural disease. Its forma-
Patients with hydrothorax should be evaluated for LT
tion is secondary to small diaphragmatic defects, more often
(III;1).
located in the right side, through which ascites moves into the
pleural space because of the negative intrathoracic pressure Cardiopulmonary and primary pleural disease should be
induced by inspiration. Hepatic hydrothorax can lead to respira- ruled out before diagnosing hepatic hydrothorax (III;1).
tory failure and can be complicated by spontaneous bacterial Diagnostic thoracentesis should be performed especially
infections (empyema). Its appearance is associated with poor when infection of the pleural effusion is suspected
prognosis, as the median survival of patients with hepatic (III;1).
hydrothorax ranges from 8–12 months.128,129 Notably, the most Diuretics and thoracentesis are recommended as the
common prognostic scores, such as Child-Pugh and MELD, seem first-line management of hepatic hydrothorax (III;1).
to underestimate such an adverse outcome.128
Therapeutic thoracentesis is indicated in patients with
dyspnoea (III;1). Chronic pleural should not be per-
Diagnosis of hepatic hydrothorax
formed because of the frequent occurrence of complica-
Once pleural effusion has been ascertained, cardiopulmonary
tions (II-2;1).
and primary pleural diseases should be excluded by standard
clinical approaches. Diagnostic thoracentesis is required to rule In selected patients, TIPS insertion for recurrent symp-
out bacterial infection, whose diagnosis relies on the same crite- tomatic hepatic hydrothorax is recommended (II-2;1).
ria described for ascites. The protein content of pleural effusion Pleurodesis can be suggested to patients with refractory
in uncomplicated hepatic hydrothorax is low and the serum to hepatic hydrothorax not amenable to LT or TIPS inser-
pleural fluid albumin gradient is greater than 1.1 g/dl.128 tion. However, the frequent occurrence of side effects
The presence and extent of diaphragmatic defects can be related to this technique restricts its use to selected
assessed indirectly, by radioisotope techniques, or directly by patients (I;2).
magnetic resonance imaging or colour-Doppler
ultrasonography.130,131 Mesh repair of diaphragmatic defects is suggested for
the management of hepatic hydrothorax in very selected
Treatment of hepatic hydrothorax patients. The best results can be achieved in patients
The first-line management relies on the treatment of ascites with non-advanced cirrhosis without renal dysfunction
with diuretics and/or LVP as discussed earlier. However, it is (II-2;2).
not rare for pleural effusion to persist despite successful treat-
ment of ascites (refractory hydrothorax). Therapeutic thoracen-
tesis is required to relieve dyspnoea. Its efficacy in refractory Hyponatremia
hepatic hydrothorax is transient and repeated thoracentesis Definition and pathophysiology
are required, which increase the risk of complications such as Hyponatremia is common in patients with advanced cirrhosis,
pneumothorax, pleural or soft tissue infection, and bleeding.132 and has been arbitrarily defined as serum sodium concentra-
The frequent occurrence of these complications discourages the tion lower than 130 mmol/L.141,142 However, according to
use of chronic pleural drainage, which can also be followed by guidelines on hyponatremia in the general patient popula-
renal dysfunction from fluid loss.133 tion,143 reductions below 135 mmol/L should also be consid-
Whenever indicated and possible, LT represents the best ered. Patients with hyponatremia have a poor prognosis, as it
option for patients with refractory hepatic hydrothorax, which is associated with increased mortality144,145 and morbidity,
does not seem to adversely affect the outcome of transplanta- particularly neurological complications,146,147 and reduced sur-
tion.134,135 TIPS has been effectively employed as definitive vival after LT.148 Incorporating serum sodium concentration
treatment or bridge to transplantation in patients with refrac- into the MELD score, a new score (MELD-Na) was generated
tory hepatic hydrotorax, whose general outcome seems to be that provides more accurate survival predictions than MELD
related to the severity of the underlying cirrhosis.136,137 These alone,149 especially in patients with ascites and hyponatremia
results have been confirmed by a more recent meta-analysis.138 with intermediate MELD score values.150 Both hypovolaemic
Pleurodesis induced by various agents, such as talc, tetracy- and hypervolaemic hyponatremia can occur in patients with
cline, doxycycline, bleomycin and povidone-iodine, can be cirrhosis. The second, most common, is characterised by an
offered to patients who are not candidates for TIPS or LT. A expansion of the extracellular fluid volume, with ascites and
recent meta-analysis showed that the pooled rate of complete oedema. It may occur spontaneously, or because of excessive
response after pleurodesis was 72%. However, the pooled rate hypotonic fluids (i.e., 5% dextrose), or secondary to complica-
of complications related to this procedure was as high as tions of cirrhosis leading to an abrupt worsening of effective
82%.139 Finally, thoracoscopic repair with mersilene mesh volaemia. The main drivers are non-osmotic hypersecretion
appears to be effective in patients with well-defined diaphrag- of vasopressin and enhanced proximal nephron sodium reab-
matic defects.140 Advanced liver disease, as assessed by MELD sorption, which impair free water generation and are both
score, and preoperative renal dysfunction appear to adversely caused by effective hypovolaemia. As opposed to hyper-
affect three-month survival. Unfortunately, clear cut-off values volaemic hyponatremia, hypovolaemic hyponatremia is
cannot be retrieved from that study. characterised by the frequent absence of ascites and oedema.

It is caused by a prolonged negative sodium balance with by the EMA for management of severe hypervolemic hypona-
marked loss of extracellular fluid often due to excessive diure- tremia (<125 mmol/L). The unique indication given for tolvap-
tic therapy. tan by the EMA is SIADH, while the FDA also included heart
failure and liver cirrhosis. However, the occurrence of serious
Management of hyponatremia hepatic injury in three patients with autosomal dominant poly-
It is generally considered that hyponatremia should be treated cystic kidney disease treated with tolvaptan in a double-blind
when serum sodium is lower than 130 mmol/L, although there placebo-controlled trial160 led the FDA to conclude that this
is no good evidence regarding the level of serum sodium at drug should not be used in patients with underlying liver
which treatment should be initiated. Hypovolaemic hypona- disease.
tremia requires plasma volume expansion with saline solution
and the correction of the causative factor. The management of
hypervolemic hyponatremia requires attainment of a negative Recommendations
water balance. Non-osmotic fluid restriction is helpful in pre-
venting a further decrease in serum sodium levels, but it is sel- The development of hyponatremia (serum sodium con-
dom effective in improving natremia. Hypertonic sodium centration <130 mmol/L) in patients with cirrhosis car-
chloride administration to patients with decompensated cirrho- ries an ominous prognosis, as it is associated with
sis may improve natremia but enhances volume overload and increased mortality and morbidity. These patients
worsens the amount of ascites and oedema. Therefore, it should should be evaluated for LT (II-2,1).
be limited to severely symptomatic hyponatremia, as defined by
The removal of the cause and administration of normal
life-threatening manifestations, cardio-respiratory distress,
saline are recommended in the management of hypov-
abnormal and deep somnolence, seizures and coma, which do
olemic hyponatremia (III;1).
not frequently occur in patients with cirrhosis. Furthermore,
hypertonic sodium chloride administration can be considered Fluid restriction to 1,000 ml/day is recommended in the
in patients with severe hyponatremia who are expected to get management of hypervolemic hyponatremia since it
a liver transplant within a few days. In these cases, hypona- may prevent a further reduction in serum sodium levels
tremia must not be corrected completely and rapidly to avoid (III;1).
the risk of central pontine myelinolysis that is increased in The use of hypertonic saline in the management of
advanced cirrhosis.143 In practice, after an initial rapid correc- hypervolemic hyponatremia should be limited to the
tion aimed at attenuating clinical symptoms (5 mmol/L in the rare cases presenting with life threatening complica-
first hour), serum sodium concentration should not increase tions. It could also be considered in patients with severe
more than 8 mmol/L per day.143 Albumin infusion appears to hyponatremia who are expected to get LT within a few
improve serum sodium concentration, but more information is days. The correction of serum sodium concentration,
needed.151 once an attenuation of symptoms has been obtained,
should be slow (≤8 mmol/L per day) to avoid irreversible
Vaptans neurological sequelae, such as osmotic demyelination
Vaptans are selective antagonists of the V2-receptors of argi- (II-3;1).
nine-vasopressin in the principal cells of the collecting ducts
Albumin administration can be suggested in hyperv-
that enhance solute-free water excretion.152 Indeed, these
olemic hyponatremia, but data are very limited to sup-
drugs are effective in improving serum sodium concentration
port its use (II-3;2).
in conditions associated with high vasopressin levels, such as
the syndrome of inappropriate antidiuretic hormone secretion At present, the use of vaptans should be limited to con-
(SIADH) and heart failure.152 The effects of the administration trolled clinical studies (III;1).
of vaptans to hyponatremic patients with cirrhosis and ascites
have been assessed in several studies. Namely, tolvaptan,
satavaptan and lixivaptan lead to an increased urine volume, Gastrointestinal bleeding
a solute-free water excretion, and an improvement of hypona- Pathophysiology
tremia in 45–82% of cases.153–155 In another study, a short- Variceal haemorrhage (VH) occurs because of the rupture of
term intravenous infusion of conivaptan for one to four days the variceal wall due to excessive wall tension. Variceal wall
in patients with end stage liver disease awaiting OLT was also tension is an intrinsic property of the vessel wall that opposes
effective in increasing serum sodium concentration.156 How- the expansive force determined by variceal transmural pres-
ever, the safety of vaptans has only been established for sure, which depends on portal pressure and vessel size. Tissue
short-term treatments lasting from one week to one month. support surrounding the varix may counteract the increase in
When satavaptan was used long term, in addition to diuretics, variceal pressure and size, protecting the wall from rupture.161
despite improving both serum sodium concentration and con- Once variceal wall rupture occurs, the amount of bleeding is
trol of ascites, a higher all-cause mortality rate, mostly associ- related to transmural pressure (which mainly depends on por-
ated with known complications of cirrhosis, was reported tal pressure), to the area of rupture in the vessel wall and to
compared to standard medical treatment.157,158 Moreover, a blood viscosity and/or alterations of haemostasis.161 All these
recent study cast doubt on the efficacy of tolvaptan in patients factors can be influenced by therapy. Drug therapy and por-
with cirrhosis and severe hypervolemic hyponatremia (serum tal-systemic derivative procedures, reduce portal (and variceal)
sodium ≤125 mEq/L) in a real-life setting.159 At present, both pressure. Endoscopic therapies and other physical methods,
conivaptan and tolvaptan have been approved in the US by such as balloon tamponade or expandable prosthesis, act
the FDA, while only tolvaptan in Europe has been approved merely by both interrupting the blood flow into the varix

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OF HEPATOLOGY
and sealing the vascular wall. Portal pressure is a key factor
determining both variceal rupture and the severity of the Recommendations
bleeding episode.161 During acute bleeding, portal pressure
may increase because of different factors such as over-transfu-
Because they are deemed high risk, patients in whom
sion or absorption of blood from the gut, which may have a
decompensation develops should have EGD performed
role in failure to control bleeding and/or precipitating rebleed-
to screen for gastro-oesophageal varices, unless previ-
ing. Portal pressure is usually assessed by the hepatic venous
ously diagnosed and treated (II-2;1).
pressure gradient (HVPG).
If EGD is performed, the presence, size and presence of
Natural history of gastro-oesophageal varices and variceal red wale marks should be reported (II-2;1).
haemorrhage In patients without varices on screening EGD in whom
Variceal haemorrhage, causative of 70% of all upper GI bleed- the aetiological factor persists and/or the state of decom-
ing events in patients with portal hypertension, remains one pensation continues, screening EGD should be repeated
of the most severe and immediate life-threatening complica- every year. In the remaining patients the screening could
tions in patients with cirrhosis and constitutes the second be prolonged, but the exact interval is unclear and more
most frequent decompensating event after ascites.162,163 data is required (III;2).
Decompensated patients have ‘clinically significant portal
hypertension’ (CSPH) per definition and, consequently, a high
risk of having gastro-oesophageal varices. In fact, while only
Prevention and treatment of variceal haemorrhage
42% of Child A patients have gastro-oesophageal varices,
Considering the high-risk of death when VH occurs in patients
72% of Child B/C patients do.164 When decompensation devel-
with decompensated cirrhosis, implementation of strategies to
ops, patients without varices on a previous endoscopy should
adequately treat VH and to prevent (re)bleeding and death
have a repeat endoscopy performed given the risk of develop-
should be actively pursued in patients with decompensated cir-
ing varices due to worsening of portal hypertension and liver
rhosis. It should be noted that the current recommendations
dysfunction. In those without varices at screening, ‘‘de novo”
will concentrate on decompensated patients given the focus of
varices develop at a rate of 7–8%/year,165,166 which could be
these CPGs.
higher in patients decompensated due to worsening of portal
hypertension and liver dysfunction. The progression rate from
Primary and secondary prophylaxis of VH in decompensated
small to large varices runs up to 22% at one year and 51% at
patients
three years in patients with Child B/C cirrhosis, especially
The Baveno VI168 and American Association for the Study of
when alcoholic in origin and/or when red wale marks are pre-
Liver Diseases (AASLD)169 guidelines primarily recommend
sent at first endoscopy, compared to 2% and 16%, respectively,
NSBBs for primary prophylaxis of VH in patients with cirrhosis
in compensated patients without those risk factors.165,166
who have high-risk varices and also, combined with endoscopic
Prospective studies have consistently demonstrated that the
band ligation (EBL), for secondary prophylaxis of VH. Both
risk of VH, estimated overall at 5–15% per year, is related
NSBBs and EBL have shown to be equally effective in preventing
to variceal size.166–170 This risk is further amplified by the
first bleeding in patients with high-risk varices. The choice
severity of liver dysfunction (Child B/C) and/or the presence
between options depends on factors such as patient preference,
of red wale marks on varices. Thus, not only medium/large
contraindications or adverse events. Although numerically EBL
varices (i.e. varices that do not collapse with insufflation at
induces less side effects, it has been associated with more sev-
endoscopy), but also small varices with red signs or in Child
ere and potentially life-threatening complications, resulting
C should be considered ‘high-risk’ varices. Despite improve-
from bleeding EBL-ulcers. Moreover, EBL does not impact on
ment in therapy, overall mortality with each episode of VH
portal hypertension. Thus, it does not reduce/prevent other
remains around 15% to 25% at six weeks. Such risk is much
complications and surveillance endoscopies are required to
higher in patients who develop VH in addition to other
detect variceal recurrence, supporting overall primary prefer-
decompensation (over 80% at five-years) than in those pre-
ence for NSBBs.174,175 For prevention of rebleeding (secondary
senting with VH as an isolated decompensating event (20%
prophylaxis), combined therapy with NSBBs plus EBL is recom-
at five-years).170,171 Mortality risk is particularly high when
mended because combination therapy significantly decreases
VH is associated with AKI and/or concomitant bacterial infec-
the probability of rebleeding compared to monotherapy using
tions.172 Without secondary prophylaxis, rebleeding occurs in
either EBL or drug therapy. NSBBs are the cornerstone of com-
approximately 60% to 70% of patients, usually within one to
bined therapy because a meta-analysis shows an improvement
two years of the index haemorrhagic event.173 Although
in survival with the addition of NSBBs (± nitrates) to EBL, while
increasing efforts are performed to test non-invasively for
the addition of EBL to NSBBs (± nitrates) has no effect on mor-
the presence of gastro-oesophageal varices, these efforts lar-
tality.176 Recent RCTs indicate that guiding therapy according
gely remain restricted to compensated cirrhosis.167 Given
to the HVPG response to NSBBs can be valuable in this high-risk
the high prevalence of ‘high-risk varices’ in decompensated
setting.91,177 HVPG-guided therapy may improve the outcomes
cirrhosis, oesophago-gastroduodenoscopy (EGD) should be
achieved with current first-line therapy combining NSBBs and
performed to detect the presence, size of varices and presence
EBL,91 and may achieve a similar survival as covered TIPS, which
of red wale marks.168,169
is the most effective therapy in terms of preventing bleeding.177

Accordingly, HVPG-guided therapy can be used when available. haemodynamic depressive effect and may be best avoided or
However, this approach has relevant drawbacks such as inva- very closely monitored.185 Thirdly, the concept of titration of
siveness and limited availability and, therefore, cannot be NSBBs to a target heart rate of 50–55 bpm might be challenged
widely recommended. NSBBs, such as propranolol and nadolol, in decompensated patients given that, in parallel to the progres-
act on portal hypertension because non-selective beta-blockade sion of liver disease, the hyperdynamic state evolves similarly,
reduces cardiac output and splanchnic blood flow while the which may lead to treatment of the most vulnerable patients
unopposed effect of alpha-1 adrenergic receptors leads to paradoxically with higher, and potentially hazardous, doses.
splanchnic vasoconstriction, thus reducing portal pressure and Therefore, the use of NSBBs should be based on a critical risk/ben-
its consequential complications. Nonetheless, haemodynamic efit evaluation in patients with refractory ascites and signs of sys-
response rates to NSBBs are modest: approximately 46% of cases temic circulatory dysfunction.168,191 Parameters such as severe
according to meta-analyses,178,179 endorsing the overall search hyponatraemia,191 low mean arterial pressure38 or cardiac out-
for novel therapeutic options. Carvedilol, an NSBB with intrinsic put,192 and increasing SCr193 identify more vulnerable patients
anti-alpha-1 receptor activity, has been associated with a among those with decompensated cirrhosis, in whom a dose
greater reduction in portal pressure than the traditional NSBBs reduction or temporal discontinuation of NSBB treatment should
and has therefore become a valuable alternative.180 Its benefi- be considered. The recent BAVENO VI consensus168 proposed that
cial action on alpha-1 receptors reduces both porto-collateral in patients with refractory ascites and (i) systolic blood pressure
and intrahepatic resistance, however, this is at the cost of more <90 mmHg, or (ii) SCr >1.5 mg/dl, or (iii) hyponatraemia <130
profound effects on systemic arterial pressure, particularly in mmol/L, the NSBB dose should be reduced or even temporarily
decompensated patients. The problem with all the recommen- discontinued. Abrupt interruption of beta-blockers for a mean
dations mentioned so far is that they are based on high quality of three to six days was recently found to be associated with nei-
RCTs that usually excluded patients with more advanced cirrho- ther an apparent increase in the risk of variceal bleeding nor with
sis, while major controversy has arisen in recent years regarding a haemodynamic rebound.194 If upon rechallenge, NSBB intoler-
the use and safety of NSBBs in patients with advanced disease, ance occurs, EBL should be considered as an alternative in primary
particularly in those with refractory ascites and/or SBP. The dis- prophylaxis.168 In the setting of refractory ascites and secondary
cussion was initiated by the Clichy group,181 who reported poor prophylaxis, covered TIPS placement may be considered if the
survival and increased risk of PPCD among patients with refrac- patient is an appropriate candidate.111,168
tory ascites on NSBB therapy. The mechanism underlying these
findings was thought to relate to further induction of systemic
arterial hypotension and exhaustion of cardiac reserve, in light Recommendations
of the progressive hyperdynamic circulation typically associated
with end-stage disease. As a result, end-organ perfusion Primary prophylaxis must be initiated upon detection of
becomes critical and sets off a multitude of complications, like ‘‘high-risk varices” (i.e. small varices with red signs,
HRS. Therefore, ‘‘the window hypothesis” was proposed which medium or large varices irrespective of Child-Pugh clas-
suggested refractory ascites as a critical juncture where the pro- sification or small varices in Child-Pugh C patients)
tective effects of NSBBs may cease and a detrimental impact because of increased risk of VH (I;1).
may begin.182 However, this hypothesis was challenged by
Patients with small varices with red wale marks or
opposing reports suggesting protective effects with NSBBs even
Child-Pugh C should be treated with NSBBs (III;1).
in decompensated patients.183–186 Illustratively, a recent post
hoc analysis of three RCTs where vaptans and NSBBs were co- Patients with medium-large varices should be treated
administered to patients with ascites showed that NSBBs did with either NSBBs or EBL (I;1). The choice of treatment
not increase mortality.183 On the contrary, during follow-up, can be based on local resources and expertise, patient
29% of initial NSBB users stopped taking NSBBs, inducing a preference, contraindications and adverse events (III;2).
marked rise in mortality and coinciding with variceal bleeding, NSBBs could be preferred because in addition to lower-
bacterial infection and/or development of HRS.183 Non-haemo- ing portal pressure, they also exert other potential bene-
dynamic effects of NSBBs, like reduction of intestinal permeabil- ficial effects (II-2;2).
ity, inflammation and BT, are considered to contribute to the Although ascites is not a contraindication for NSBBs, cau-
beneficial effect, particularly in this advanced stage.187–189 tion should be exercised in cases of severe or refractory
Whether NSBBs are detrimental in some patients with advanced ascites (I;1). High doses of NSBB should be avoided
cirrhosis should be clarified by future studies (ideally RCTs), as (II-2;1). The use of carvedilol can not be recommended
well as the optimal drug-schedule in such stages. Meanwhile at present (I;2).
some considerations could be made regarding dosing, type of
NSBB and titration.168,184,185,190 Firstly, dosing of NSBBs was In patients with progressive hypotension (systolic BP
suggested as a potential determinant according to a Danish <90 mmHg), or in patients who develop an acute inter-
study in which low propranolol doses (<160 mg/day) were asso- current conditions such as bleeding, sepsis, SBP or AKI,
ciated with reduced mortality after experiencing an SBP NSBBs should be discontinued (III,1). After recovery,
compared to higher doses.184,190 Secondly, not all NSBBs proved reinstatement of NSBBs can be attempted (III,2). When
equal. Carvedilol, which exhibits additional vasodilatory NSBB intolerance or contraindications persist, patients
anti-alfa-1-adrenergic activity, might be deleterious in decom- bleeding risk should be managed by expeditious EBL
pensated patients as it is more likely to cause a systemic (III,1).

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OF HEPATOLOGY
which is considered the main treatment outcome by consen-
Recommendations sus.168,199 Blood volume restitution should be initiated
promptly to restore and maintain haemodynamic stability to
ensure tissue perfusion and oxygen delivery. To facilitate resus-
Combination therapy of NSBBs + EBL is recommended
citation at least two catheters should be placed, large enough to
since it reduces the risk of rebleeding compared with
allow rapid volume expansion, which can usually be done with
monotherapy (I,1).
crystalloids.196 No benefit has been demonstrated with the use
Similar recommendations as for primary prophylaxis can of colloids compared to crystalloids.200 Red blood cells are used
be made with respect to NSBB usage in patients with to improve oxygen delivery to tissues in case of severe anaemia.
ascites or developing an acute inter-current condition A restrictive transfusion strategy is adequate in most patients
(III,2). with acute GI bleeding, with a haemoglobin threshold for
If the patient continues to be intolerant to NSBB, covered transfusion of 7 g/dl and a target range after transfusion of
TIPS placement is recommended provided that there are 7 to 9 g/dl.201 The threshold for transfusion may be higher in
no absolute contraindication (cf. criteria in ascites sec- patients with massive haemorrhage or in those with underlying
tion) (III,1). conditions that preclude an adequate physiological response to
acute anaemia. Recommendations regarding management of
coagulopathy and thrombocytopenia cannot be made based on
currently available data.168,169,199
Variceal haemorrhage
As mentioned above vasoactive drug therapy should be initi-
Acute GI bleeding in cirrhosis, either because of gastro-oesopha-
ated as soon as AVH is suspected. Starting vasoactive drugs
geal varices or non-variceal lesions, is a medical emergency
before endoscopy decreases the incidence of active bleeding dur-
with a high incidence of complications and high mortality and
ing endoscopy and facilitates endoscopic therapy, improving the
therefore requires intensive care (Fig. 2). Acute variceal haemor-
control of bleeding, and potentially survival.197,198 Either terli-
rhage (AVH) must be suspected in any cirrhotic patient present-
pressin, somatostatin or octreotide are accepted drugs with pro-
ing with upper acute GI bleeding and treatment should be
ven efficacy.202 All these drugs require i.v administration. The
started as soon as bleeding is clinically confirmed, regardless
recommended dose of terlipressin is 2 mg/4 h during the first
the lack of confirmation by upper endoscopy.195 Initial therapy
48 h, followed by 1 mg/4 h thereafter. The recommended dose
should be directed at restoring volaemia.196 Vasoactive drug
of somatostatin is a continuous infusion of 250 lg/h (that can
therapy197,198 and antibiotic prophylaxis195,196 should be initi-
be increased up to 500 lg/h) with an initial bolus of 250 lg.
ated as soon as AVH is suspected. Goals of therapy in AVH
The recommended dose of octreotide is a continuous infusion
include the control of bleeding, as well as the prevention of
of 50 lg/h with an initial bolus of 50 lg. A bolus of somatostatin
early recurrence and the prevention of six-week mortality,
Acute gastrointestinal bleeding + portal hypertension

Airway
Initial assesment (history, physical & blood exam, cultures) Breathing
& resuscitation Circulation
- Volume replacement with crystalloids
(or colloids)
Balloon tamponade or esophageal stenting
Immediate start of drug therapy

- Restrictive transfusion
(somatostatin/terlipressin) Hb threshold of 7 g/dl & target of 7- 9 g/dl
Antibiotic prophylaxis
(ceftriaxone or norfloxacine)
if masive bleeding
Early diagnostic endoscopy (<12 h)

ENDOSCOPY
ENDOSCOPY
Confirm variceal bleeding
Endoscopic therapy ( band ligation )
+
+ maintain vasoactive drug therapy 3-5 days
and antibiotic prophylaxis (ceftriaxone or norfloxacine )
Control Further bleeding

(~85% of cases) (~15% of cases)
Consider early TIPS Rescue with TIPS

in high-risk
Fig. 2. Algorithm for the management of acute gastrointestinal bleeding in patients with cirrhosis (adapted from Ref. 168). TIPS, transjugular
portosystemic shunts.

or octreotide can be given again if bleeding is ongoing. Once AVH prophylactic antibiotics, up to 10–15% of patients with AVH have
is confirmed, vasoactive drug therapy should be administered persistent bleeding or early rebleeding.195,199 In such cases, TIPS
for five days to avoid early rebleeding.168,169 Shorter administra- should be considered as the rescue therapy of choice.168,169
tion of vasoactive drugs (48–72 h) can be considered in less sev- When TIPS is not feasible or in case of modest rebleeding, a sec-
ere episodes although more data are required.203 Once blood ond endoscopic therapy may be attempted while vasoactive
volume restitution has been initiated and haemodynamic stabil- drugs can also be optimised, by doubling the dose of somato-
ity has been achieved, upper endoscopy should be performed, as statin and/or changing to terlipressin if not used previously. Bal-
soon as possible within the first 12 h after admission, to ascer- loon tamponade should be used in case of massive bleeding, as a
tain the cause of haemorrhage (up to 30% of cirrhotic patients temporary ‘‘bridge” until definitive treatment can be instituted
bleed from non-variceal causes) and to provide endoscopic ther- and for a maximum of 24 h, preferably under intensive care facil-
apy if indicated.168,169 Erythromycin should be considered ities.168,169 Because of the high risk of aspiration pneumonia,
before emergency endoscopy (250 mg i.v., 30–120 min before) tamponade should be preceded by prophylactic orotracheal
to facilitate the procedure by improving visibility, in the absence intubation in comatose or encephalopathic patients. Removable,
of contraindications (QT prolongation).204 When AVH is con- covered and self-expanding oesophageal stents are an alterna-
firmed by endoscopy, EBL should be performed within the same tive to balloon tamponade, and may have lower rates of serious
procedure. EBL is more effective than sclerotherapy to control adverse events.213 RCTs suggest that in high-risk patients, early
bleeding, with fewer adverse effects, and may even improve sur- (preemptive) PTFE-coated TIPS placed within 72 h (ideally in less
vival.196 Sclerotherapy can be used when ligation is not feasible. than 24 h) may result in better permanent control of bleeding
The combination of endoscopic therapy and vasoactive drugs is and may improve survival.214,215 However, these studies had rel-
more effective than the isolated use of either of these options evant drawbacks such as the inclusion of a highly selected pop-
alone,205,206 because it combines the local haemostatic effect ulation because of strict exclusion criteria, while observational
on the varices induced by endoscopic treatment and the portal studies have not confirmed the effect on survival.216,217 The
hypotensive effect achieved with drugs. This combination is cur- use of Child-Pugh class B plus active bleeding at endoscopy as
rently considered the standard of care in AVH.168,169 Cyanoacry- a criterion to select high-risk patients has also been criticised.218
late injection and EBL are accepted options for endoscopic It has also been suggested that a recalibrated MELD score may
therapy in patients bleeding from gastric (cardiofundal) varices better identify patients at high risk than other scores.219 At pre-
as both therapies are equally effective.207 However, EBL should sent, early TIPS should be considered in patients with Child-Pugh
only be performed on small gastric varices in which the com- class C, with a score <14. However, future studies should clarify
plete vessel can be suctioned into the ligation device. Other which criteria may be preferred to select high-risk patients
endoscopic therapies, such as the endoscopic ultrasound–guided before a wide implementation of early TIPS. Future studies
insertion of coils and/or cyanoacrylate, are available for fundal should also clarify whether an adequate stratification of risk in
varices. Prevention of complications should run simultaneously patients with AVH can optimise therapy.
to haemostatic therapies from admission of patients with cirrho-
sis and acute GI bleeding. The main complications, whatever the
cause of bleeding, include bacterial infections (such as aspiration Recommendations
pneumonia or SBP), hepatic encephalopathy and deterioration of
renal function. Bacterial infections are observed in more than Acute GI bleeding, both due to gastro-oesophageal
50% of patients and may already be present at the time of bleed- varices or to non-variceal lesions, carries a high inci-
ing (20%) acting as a precipitating event.196 Moreover, the pres- dence of complications and mortality in decompensated
ence of bacterial infection is an independent predictor of failure cirrhosis and therefore requires close monitoring
to control bleeding and death.208 Antibiotic prophylaxis is rec- (II-2;1).
ommended because it reduces the incidence of infections and
improves control of bleeding and survival.199,208 Ceftriaxone (1 Volume replacement should be initiated promptly to
g/24 h) for up to seven days, is the first choice in patients with restore and maintain haemodynamic stability (III;1).
advanced cirrhosis, in those on quinolone prophylaxis and in Either colloids and/or crystalloids should be used
hospital settings with high prevalence of quinolone-resistant (III;1). Starch should not be used for volume replace-
bacterial infections.209,210 Oral quinolones (norfloxacin 400 mg ment (I;1).
b.i.d) can be used in the remaining patients. These recommenda- A restrictive transfusion strategy is recommended in
tions are however best evaluated and cross-checked from the most patients with a haemoglobin threshold for transfu-
perspective of local resistance patterns. Renal function should sion of 7 g/dl and a target range of 7–9 g/dl (I;1).
be preserved by the adequate replacement of fluids and elec-
Antibiotic prophylaxis is recommended in cirrhotic
trolytes.211 Nephrotoxic drugs (such as aminoglycosides and
patients with acute GI bleeding because it reduces the
non-steroidal anti-inflammatory drugs [NSAIDs]) as well as
incidence of infections and improves control of bleeding
LVP, beta-blockers, vasodilators and other hypotensive drugs
and survival. Treatment should be initiated on presenta-
should be avoided during the course of AVH. Oral non-absorb-
tion of bleeding and continued for up to seven days (I;1).
able disaccharides may be used to prevent the development of
Ceftriaxone (1 g/24 h) is the first choice in patients with
hepatic encephalopathy,169 although more studies are needed.
decompensated cirrhosis, those already on quinolone
When encephalopathy develops, lactulose or lactitol should be
prophylaxis, and in hospital settings with high preva-
used.168,169 Proton pump inhibitors (PPIs) have not shown effi-
lence of quinolone-resistant bacterial infections. Oral
cacy for the management of AVH. However, a short course ther-
quinolones (norfloxacin 400 mg b.i.d) should be used in
apy with PPI after EBL may reduce the size of post-banding
the remaining patients (I;1).
ulcers.212 Despite therapy with vasoactive drugs plus EBL and

JOURNAL
OF HEPATOLOGY
B or C at enrollment were found to predict the incidence of PHG,
Recommendations which might range between 30 and 45%.220,221 The incidence
and severity of PHG may increase following endoscopic treat-
ment for oesophageal varices.222 Portal hypertension should
Vasoactive drug therapy should be initiated as soon as be distinguished from gastric antral vascular ectasia (GAVE or
acute variceal bleeding is suspected, and before endo- watermelon stomach), which have different underlying
scopy. Terlipressin, somatostatin or octreotide are pathophysiologies and different therapeutic implications. The
accepted options. In patients with acute variceal bleed- diagnosis of PHG is made by endoscopy and typically shows a
ing drug therapy should be administered for three to five snake-skin mosaic pattern (mild subtype), which may have
days (I;1). superimposed red signs (severe PHG) and is most commonly
Gastroscopy should be performed within the first 12 h located in the proximal stomach (fundus and body) whereas
after admission once haemodynamic stability has been GAVE is characterised by the presence of red spots without a
achieved, to ascertain the cause of haemorrhage and to background mosaic pattern, typically located in the gastric
provide endoscopic therapy (II-2;1). antrum.170 Similar endoscopical lesions, as documented in
PHG, may be observed in other areas of the GI tract where they
When acute variceal bleeding is confirmed by endo-
have been termed portal hypertensive duodenopathy, portal
scopy, variceal ligation should be performed within the
hypertensive enteropathy or portal hypertensive colopathy
same procedure (I;1).
depending on the location of the lesions.223 PHG and every form
In the absence of contraindications (QT prolongation) of enteropathy might be clinically important because they are
pre-endoscopy erythromycin (250 mg i.v., 30–120 min sometimes responsible for insidious blood loss (chronic iron
before) can be used to facilitate the procedure (I;2). deficient anaemia) and in exceptional cases even overt acute
The combination of vasoactive drugs and ligation is rec- bleeding. When PHG is found as an incidental asymptomatic
ommended as the first therapeutic option in acute vari- finding without concomitant oesophageal or gastric varices, its
ceal bleeding (I;1). relevance is unclear and endoscopic follow-up or prophylactic
treatment is not recommended.168 First-line therapy for chronic
Early pre-emptive covered TIPS (placed within 24–72 h)
haemorrhage from PHG is an NSBB.168,224,225 The same consid-
can be suggested in selected high-risk patients, such as
erations regarding the use of NSBBs in decompensated patients
those with Child class C with score <14 (I;2). However,
should be made as for gastro-oesophageal varices, except that
the criteria for high-risk patients, particularly Child B
there is no alternative, endoscopic, standard intervention avail-
with active bleeding, remains debatable and needs fur-
able for PHG. In addition, iron supplementation should be pro-
ther study.
vided.168,226 In patients with medically refractory PHG and
compensated cirrhosis, TIPS has shown to improve the endo-
scopic appearance and decrease the transfusion requirement.227
Recommendations In case of acute PHG bleeding, albeit rare, small and uncon-
trolled studies have suggested pharmacological intervention
with somatostatin-analogues or terlipressin because of their
Up to 10–15% of patients have persistent bleeding or
portal hypotensive effects and reduction in gastric blood
early rebleeding despite treatment with vasoactive
flow.226,228 In addition, similar measures are to be taken as for
drugs plus variceal ligation, and prophylactic antibiotics.
AVH (antibiotic prophylaxis, restrictive transfusion policy). For
TIPS should be used as the rescue therapy of choice in
portal hypertension intestinopathy, there is no established stan-
such cases (I;1).
dard of treatment and an approach analogous to that for PHG is
Balloon tamponade should be used in case of uncon- suggested. As for any given complication, LT should be consid-
trolled bleeding, but with pre-requisite of expertise ered as part of the management of decompensated patients.
and as a temporary ‘‘bridge” until definitive treatment
can be instituted and for a maximum of 24 h (III;1).
Removable, covered and self-expanding oesophageal Recommendations
stents can be used as alternative to balloon tamponade
(I;2). NSBB and iron supplementation and/or blood transfu-
In the context of bleeding, where encephalopathy is sion, when indicated, are recommended as first-line
commonly encountered, prophylactic lactulose may be therapy for chronic haemorrhage from PHG is an (I;1).
used to prevent encephalopathy, but further studies In patients with transfusion-dependent PHG in whom
are needed (I;2). NSBBs fail or are not tolerated, covered TIPS placement
Beta-blockers and vasodilators should be avoided during may be used provided the patient has no contraindica-
the acute bleeding episode (III,1). tion for TIPS (II-3;2).
Acute PHG bleeding may be treated with somatostatin-
analogues or terlipressin but substantiating data are lim-
Portal hypertension gastropathy and intestinopathy ited (I;2).
Portal hypertension gastropathy (PHG) often presents in decom-
pensated patients given that its natural history is significantly Gastric varices
influenced by the severity of liver disease and portal hyperten- The Sarin classification is most commonly used for risk stratifi-
sion. The presence of oesophageal varices and a Child-Pugh class cation and management of gastric varices (Table 6).229 Gastric

Table 6. Classification, prevalence and risk of bleeding of gastric varices. randomised trials are available comparing BRTO with other
Type Definition Relative Overall bleeding therapies. Several variations of this technique are available,
frequency risk without such as balloon-occluded antegrade transvenous obliteration
treatment (BATO).236
GOV 1 OV extending below cardia 70% 28%
into lesser curvature
GOV 2 OV extending below cardia 21% 55% Recommendations
into fundus
IGV 1 Isolated varices in the 7% 78%
fundus NSBBs are suggested for primary prevention of VH from
IGV 2 Isolated varices else in the 2% 9% gastro-oesophageal varices type 2 or isolated gastric
stomach
varices type 1 (III;2).
GOV, gastro-oesophageal varices; IGV, isolated gastric varices; OV, oesophageal
varices. Primary prevention for gastro-oesophageal varices type
1 follow the recommendations of oesophageal varices
varices are present in about 20% of patients with cirrhosis. Gas- (III;2).
tro-oesophageal varices type 1, which are the most common
Acute gastric VH should be treated medically, like oeso-
(75% of gastric varices), are oesophageal varices extending
phageal VH (I;1). Cyanoacrylate is the recommended
below the cardia into the lesser curvature and, in the absence
endoscopic haemostatic treatment for cardiofundal
of specific studies, are commonly managed following guidelines
varices (gastro-oesophageal varices type 2 or isolated
for oesophageal varices.168 Cardiofundal varices (gastro-oeso-
gastric varices type 1) (I;2).
phageal varices type 2 & isolated gastric varices type 1) bleed
less frequently. However, haemorrhage from cardiofundal TIPS with potential embolisation efficiently controls
varices is often more severe, more difficult to control and shows bleeding and prevents rebleeding in fundal VH (gastro-
a higher risk of recurrent bleeding and mortality (up to 45%) oesophageal varices type 2 or isolated gastric varices
compared to oesophageal varices.229 Cardiofundal varices are type 1) and should be considered in appropriate candi-
more frequent in patients with splanchnic venous thrombosis, dates (II-2;1).
which should be investigated by imaging. The evidence to sup- Selective embolisation (BRTO/BATO) may also be used to
port recommendations for management of gastric VH is much treat bleeding from fundal varices associated with large
less robust than that for oesophageal varices. Regarding primary gastro/splenorenal collaterals, although more data is
prophylaxis of bleeding from gastric varices, a single ran- required (III;2).
domised trial suggested that cyanoacrylate injection may be
more effective than NSBBs in preventing first bleeding in
patients with large cardiofundal varices, although survival was
Bacterial infections
similar.230 Therefore, the last BAVENO consensus concluded
The risk of bacterial infection in cirrhosis is caused by multiple
that further studies are needed to evaluate the risk/benefit ratio
factors that include liver dysfunction, portosystemic shunting,
of using cyanoacrylate in this setting before a formal recom-
gut dysbiosis, increased BT, cirrhosis-associated immune dys-
mendation can be made and meanwhile propose NSBBs as the
function,237,238 and genetic factors This immune defect facili-
primary approach.168 Acute gastric VH is medically treated like
tates BT, induced by increased intestinal permeability and gut
bleeding oesophageal varices. However, injection therapy with
bacterial overgrowth observed in cirrhosis.239 Genetic immune
cyanoacrylate (‘glue’) may be the preferable option for endo-
defects can contribute to the high risk of bacterial infections
scopic haemostasis.231 Although equally effective as EBL in ini-
in cirrhosis, particularly SBP. Cirrhotic patients carrying NOD2
tial haemostasis, the rebleeding rate is significantly lower.232
variants associated with impaired recognition of the bacterial
TIPS, with or without additional embolisation of collaterals, is
product muramyl dipeptide have a higher risk of SBP and a
equally effective in gastric and oesophageal VH for control of
reduced survival time.240
acute bleeding events and prevention of rebleeding.233 In case
of massive bleeding, balloon tamponade with the Linton-Nach-
las tube may serve as a bridge to other treatments. Regarding Spontaneous bacterial peritonitis
secondary prophylaxis, in one RCT repeated cyanoacrylate Definition
injection was superior to NSBBs to prevent rebleeding from car- Spontaneous bacterial peritonitis has been defined as a bacterial
diofundal varices,232 while the addition of NSBBs to cyanoacry- infection of ascitic fluid without any intra-abdominal surgically
late did not improve the outcomes achieved with glue alone in treatable source of infection. SBP is very common in patients
another RCT.234 Another trial comparing TIPS to glue injection with cirrhosis and ascites.241,242 When first described, its mor-
showed that TIPS proved more effective in preventing rebleed- tality exceeded 90% but it has been reduced to approximately
ing from gastric varices, with similar survival and frequency of 20% with early diagnosis and treatment.243
complications.235 The option of early TIPS should be strongly
considered, particularly in cardiofundal varices given the high Diagnosis
rebleeding rate, provided that patient is an appropriate The diagnosis of SBP is based on diagnostic paracentesis.33,244
candidate for such a procedure. Alternatively, balloon-occluded All patients with cirrhosis and ascites are at risk of SBP and
retrograde transvenous obliteration (BRTO) can be considered. the prevalence of SBP in outpatients is 1.5–3.5% and 10% in
This interventional radiological procedure enables treatment hospitalised patients.245 Half the episodes of SBP are present
of fundal varices associated with a large gastro/splenorenal at the time of hospital admission while the rest are acquired
collaterals, which has the theoretical advantage over TIPS of during hospitalisation.33 Patients with SBP may have one of
not diverting portal blood inflow from the liver. However, no the following:33 i) local symptoms and/or signs of peritonitis:

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OF HEPATOLOGY
abdominal pain, abdominal tenderness, vomiting, diarrhoea, positive in 75% of cases.255 Spontaneous bacterial pleural
ileus; ii) signs of systemic inflammation: hyper or hypothermia, empyema was associated with SBP in 50% of cases.255
chills, altered white blood cell count, tachycardia, and/or
tachypnoea; iii) worsening of liver function; iv) hepatic
Secondary bacterial peritonitis
encephalopathy; v) shock; vi) renal failure; and, vii) GI bleeding.
A small proportion (5%) of patients with cirrhosis may develop
However, it is important to point out that SBP may be asymp-
peritonitis due to perforation or inflammation of an intra-
tomatic, particularly in outpatients.245 In an observational study
abdominal organ, a condition known as secondary bacterial
in 239 patients with SBP, delayed diagnostic paracenteseis (>12
peritonitis.256 The differentiation of this condition from SBP is
h after admission) was associated with a 2.7-fold increase in
important. Secondary bacterial peritonitis should be suspected
mortality.246 Peritoneal infection causes an inflammatory reac-
in patients who have localised abdominal symptoms or signs,
tion resulting in an increased number of neutrophils in ascitic
presence of multiple organisms on ascitic culture, very high
fluid. Despite the use of sensitive methods, ascites culture is
ascitic neutrophil count and/or high ascitic protein concentra-
negative in as many as 60% of patients with clinical manifesta-
tion, or in those patients with an inadequate response to ther-
tions suggestive of SBP and increased ascites neutrophil count.33
apy.256 Patients with suspected secondary bacterial peritonitis
The gold standard for ascitic neutrophil count is manual micro-
should undergo prompt computed tomography (CT) scanning
scopy, but it is labour intensive and associated with interob-
and early consideration for surgery.
server variability, time and costs. In most places this has been
substituted with automated counts based on flow cytometry
for counting and differentiating cells. This technique has been Recommendations
documented to have high linearity with manual microscopy
and thus sensitivity and specificity close to 100%.247,248 The
greatest sensitivity for the diagnosis of SBP is reached with a A diagnostic paracentesis should be carried out in all
cut-off neutrophil count of 250/mm3, although the greatest patients with cirrhosis and ascites without delay at hos-
specificity is reached with a cut-off of 500 neutrophils/mm3.33 pital admission to rule out SBP. A diagnostic paracentesis
The use of reagent strips cannot be recommended for the rapid should also be performed in patients with GI bleeding,
diagnosis of SBP.249 Although the presence of bacterial DNA in shock, fever or other signs of systemic inflammation, GI
plasma and/or ascites is associated with an impairment of circu- symptoms, as well as in patients with worsening liver
latory function,250 there are not enough data to support its use and/or renal function, and hepatic encephalopathy
in clinical practice.251 Ascites culture is essential to guide antibi- (II-2;1).
otic therapy. Patients with an ascitic fluid neutrophil count ≥250 The diagnosis of SBP is based on neutrophil count in asci-
cells/mm3 and negative culture have culture-negative SBP.252 tic fluid of >250/mm3 (II-2;1). Neutrophil count is deter-
Their clinical presentation is like that of patients with culture- mined by microscopy, but can be substituted with a flow
positive SBP and should be treated in a similar manner. Some cytometry based automated count. The use of reagent
patients have ‘bacterascites’ in which cultures are positive but strips has no clear evidence to support it in routine prac-
there is normal ascitic neutrophil count (<250/mm3).33 In some tice (II-2;1).
patients bacterascites is the result of secondary bacterial coloni-
Although ascitic fluid culture positivity is not a pre-
sation of ascites from an extraperitoneal infection. These
requisite for the diagnosis of SBP, culture should be
patients usually have general symptoms and signs of infection.
performed in order to guide antibiotic therapy (II-2;1).
In other patients, bacterascites is due to the spontaneous coloni-
sation of ascites, and can either be clinically asymptomatic or Blood cultures should be performed in all patients with
lead to abdominal pain or fever. While in some patients, partic- suspected SBP before starting antibiotic treatment (II-2;1).
ularly in those who are asymptomatic, bacterascites represents Patients with bacterascites (neutrophil count less than
a transient and spontaneously reversible colonisation of ascites, 250/mm3 but positive bacterial culture) exhibiting signs
in other patients, mainly those who are symptomatic, bac- of systemic inflammation or infection should be treated
terascites may represent the first step in the development of with antibiotics (II-2;1). Otherwise, the patient should
SBP.33 Spontaneous fungal peritonitis is a rare, less recognised undergo a second paracentesis. If the culture results
and studied complication, occurring in <5% of cases, but obser- come back positive again, regardless of the neutrophil
vational data suggest a worse prognosis.253 count, the patient should be treated (III;1).
The diagnosis of spontaneous bacterial pleural empyema
Spontaneous bacterial pleural empyema
should be based on positive pleural fluid culture and
Infection of a pre-existing hydrothorax, known as spontaneous
increased neutrophil count of >250/mm3 or negative
bacterial pleural empyema, is uncommon. One study followed
pleural fluid culture and a neutrophil count of >500/
3,390 patients with cirrhosis for four years and observed it in
mm3 in the absence of pneumonia (II-2;1).
2.4% of the overall population and 16% of patients with pre-
existing hydrothorax, with associated mortality of 38%.254 The Secondary bacterial peritonitis should be suspected in
diagnosis is based on pleural fluid analysis obtained by diagnos- case of multiple organisms on ascitic culture, very high
tic thoracocentesis. In the largest observational study reported ascitic neutrophil count and/or high ascitic protein con-
so far, the diagnosis of spontaneous bacterial empyema was centration, or in those patients with an inadequate
established when the pleural fluid analysis showed a positive response to therapy. Patients with suspected secondary
culture and more than 250 neutrophils/mm3 or a negative cul- bacterial peritonitis should undergo prompt CT scanning
ture and more than 500 neutrophils/mm3, in the absence of lung and early considerations for surgery (III,1).
infection.255 Pleural fluid culture in blood culture bottles was

Management of spontaneous bacterial peritonitis nity-acquired SBP from health care-associated and nosocomial
Empirical antibiotic therapy. Empirical antibiotic therapy must SBP6,266–268 and to consider both the severity of infection and
be initiated immediately after the diagnosis of SBP.33 Potentially the local resistance profile in order to decide the empirical
nephrotoxic antibiotics (i.e., aminoglycosides) should not be antibiotic treatment of SBP. Piperacillin/tazobactam has been
used as empirical therapy.76 In the 1990 s, cefotaxime, a third- recommended as the primary approach for health care and
generation cephalosporin, was extensively investigated in nosocomial SBP in areas with low prevalence of infections sus-
patients with SBP because at that time it covered most causative tained by MDROs. On the contrary meropenem alone or/and
organisms and because of its high ascitic fluid concentrations combined with glycopeptides or with daptomycin has been sug-
during therapy.1,33 Infection resolution was obtained in 77 to gested as the primary approach for health care-associated SBP
98% of patients. A dose of 4 g/day is as effective as a dose of 8 when severe, or in areas with high prevalence of MDROs, and
g/day.257 A five-day therapy is as effective as a 10-day treat- for nosocomial SBP in general.6,266,268,269 Regarding the severity
ment.258 Alternatively, amoxicillin/clavulanic acid, first given i. of infection, it should be highlighted that, recently, the new cri-
v. then orally, has similar results with respect to SBP resolution teria for the definition of sepsis, namely qSOFA and Sepsis-3270
and mortality as cefotaxime259 and at a much lower cost. How- have been validated in patients with cirrhosis and bacterial
ever, there is only one comparative study with a small sample infections, proving that they are more accurate than those
size and results should be confirmed in larger trials. In addition, related to the systemic inflammatory response syndrome in
some concern exists regarding amoxicillin/clavulanic acid as its predicting hospital mortality.271 Accordingly, a new algorithm
use is associated with a high rate of drug induced liver injury has been proposed for the application of qSOFA and Sepsis-3
(DILI).260 Administration of i.v. ciprofloxacin for seven days in the management of cirrhotic patients (Fig. 3). Some more
results in a similar SBP resolution rate and hospital survival as detailed recommendations on the empirical antibiotic treat-
cefotaxime, but at a significantly higher cost.261 However, ment of SBP based on the severity and the environment of the
switch therapy (i.e., use of i.v. antibiotic initially, followed by infection as well as on local resistance profiles are provided
oral step-down administration) with ciprofloxacin is more (Fig. 4). A randomised trial with 32 nosocomial episodes of
cost-effective than i.v. ceftazidime.262 Oral ofloxacin has shown SBP, found meropenem plus daptomycin more effective
similar results as i.v. cefotaxime in uncomplicated SBP, without (86.7%) than ceftazidime (25%) to manage SBP, defined as
renal failure, hepatic encephalopathy, GI bleeding, ileus, or >25% decrease of neutrophil count at 48 h and to <250/mm3
shock.263 However, the spread of resistant bacteria in the at day seven.243 If ascitic fluid neutrophil count fails to decrease
healthcare environment during the last two decades has led to to less than 25% of the pretreatment value after two days of
an alarming increase in the number of infections caused by
multi-drug resistant organisms (MDROs)264 that are defined SBP or SBE
by an acquired non-susceptibility to at least one agent in three
or more antimicrobial categories.265 Patients with advanced cir-
Community-acquired Healthcare-associated Nosocomial
rhosis are highly susceptible to the development of infections SBP or SBE SBP or SBE SBP or SBE
caused by MDROs, because they require repeated hospitalisa-
tions, are often submitted toinvasive procedures and are fre- 3rd generation AREA DEPENDENT: Carbapenem alone or
quently exposed to antibiotics, either as prophylaxis or as cephalosporin or Like nosocomial + daptomycin,
treatment. All these factors are well kown risk factors for the piperacillin-tazobactam infections if high vancomycin or
prevalence of MDRO§ linezold# if high
development of infections sustained by MDROs.266 Bacterial or sepsis prevalence of MDR
resistance increases four fold the risk of mortality of SBP.267 In Gram+ bacteria or
particular, nosocomial SBP has been associated with multi-drug sepsis
resistance and poor outcomes.266 The landscape of bacterial
Fig. 4. Recommended empirical antibiotic treatment of SBP or SBE
resistance is continuously changing and challenging recommen- (adapted from Ref. 6). SBE, spontaneous bacterial empyema; SBP, sponta-
dations for antibiotics. Thus, it is crucial to separate commu- neous bacterial peritonitis; MDRO, multidrug resistant organism.
If baseline SOFA score available?

No Yes
Apply sepsis-3 criteria and qSOFA Apply sepsis-3 criteria
Sepsis-3 and Sepsis-3 and

Positive Negative
qSOFA negative qSOFA positive
Sepsis -3 positive Poor outcome

Good outcome Good outcome
and qSOFA negative Patient con need transfer to ICU
Grey zone
Monitoring SOFA
score is required
Fig. 3. Algorithm for the application of qSOFA and Sepsis-3 criteria in patients with cirrhosis and bacterial infections (adapted form Ref. 271). ICU,
intensive care unit.

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OF HEPATOLOGY
antibiotic treatment, there is a high likelihood of failure to
respond to therapy.33 This should raise the suspicion of an infec- Third-generation cephalosporins are recommended as
tion caused by bacteria resistant to antibiotic therapy, indicat- first-line antibiotic treatment for community-acquired
ing the need for modification of antibiotic treatment according SBP in countries with low rates of bacterial resistance
to in vitro sensitivity or on an empirical basis, or the presence (I;1). In countries with high rates of bacterial resistance
of ‘secondary peritonitis’. In this context, it should be high- piperacillin/tazobactam or carbapenem should be con-
lighted that the progressive increase of the use of carbapenems sidered (II-2;1).
because of the worldwide pandemic of extended spectrum beta-
Healthcare associated and nosocomial SBP is more likely
lactamases (ESBLs) producing Enterobacteriaceae has promoted
to harbour resistance to antibiotics. Piperacillin/tazobac-
the emergence of carbapenem-resistant Enterobacteriaceae. This
tam should be given in areas with low prevalence of
implies a potential shift from MDR bacteria to extensively drug
multi-drug resistance while carbapenem should be used
resistance (XDR) bacteria defined by a non-susceptibility to at
in areas with high prevalence of ESBL producing Enter-
least one agent in all but two or fewer antimicrobial categories
obacteriaceae. Caarbapenem should be combined with
or to pandrug resistance (PDR) bacteria defined by a non-sus-
glycopeptides or daptomycin or linezolid in areas with
ceptibility to all agents in all antimicrobial categories.265 The
high prevalence of gram positive MDR bacteria (I;1).
shift requires an active surveillance in patients at risk, in order
to identify patients who are colonised or infected by these Severe infections sustained by XDR bacteria may require
clones and prevent their dissemination. The shift may also seri- the use of antibiotics known to be highly nephrotoxic in
ously affect the effectiveness of the broadest spectrum empiri- patients with cirrhosis, such as vancomycin or aminogly-
cal antibiotic treatment among those previously cosides. In these cases, patients’ plasma level should be
recommended for SBP and infections other than SBP. Carbapen- monitored in accordance with local policy thresholds
emase-producing and carbapenem-resistant non-carbapene- (III;1).
mase-producing Enterobacteriaceae can be treated with De-escalation according to bacterial susceptibility based
tigecycline or with the combination of tigecycline at high doses on positive cultures is recommended to minimise resis-
and a carbapenem in continuous infusion. Addition of i.v. col- tance selection pressure (II-2;1).
istin could be necessary in severe infections. Severe infections
caused by Pseudomonas aeuruginosa resistant to carbapenems The efficacy of antibiotic therapy should be checked with
and quinolones usually require the combination of i.v. a second paracentesis at 48 h from starting treatment.
amikacin/tobramycin or colistin plus a carbapenem/ceftazidime Failure of first-line antibiotic therapy should be sus-
(needed as synergic antibiotics despite antibiotic resistance). pected if there is worsening of clinical signs and symp-
Vancomycin resistant Enterococci should be treated with line- toms and/or increase or no marked reduction in
zolid, daptomycin or tigecycline. All this means reintroducing leucocyte count (at least 25%) in 48 h (II-2;1).
into clinical practice antibiotics known to be highly nephrotoxic The duration of treatment should be at least 5–7 days
in patients with cirrhosis. It follows that serum levels of amino- (III;1).
glycosides and vancomycin must be monitored closely in these
Spontaneous bacterial empyema should be managed
patients, to decrease the risk of renal failure. The shift from MDR
similarly to SBP (II-2;2).
to XDR bacteria re-emphasises the interest of the pharmaceuti-
cal industry for the development of new antibiotics. Several new
glycopeptides such as oritavancin, new oxazolidinones such as
tedizolid phosphate, new cephalosporins, such as ceftaroline and Intravenous albumin in patients with spontaneous bacterial peri-
ceftobiprole and razupenem, a new carbapemen, display extended tonitis. SBP without septic shock may precipitate deterioration
activity against gram-positive bacteria including vancomycin- of circulatory function with severe liver failure, hepatic
resistant Enterococci. In contrast, few newly developed encephalopathy, and type 1 HRS and has approximately 20%
antibiotics are active against gram-negative MDROs. Temocillin, hospital mortality despite infection resolution.272 A ran-
a derivative of ticarcillin, is effective against organisms domised, controlled study in patients with SBP treated with
producing ESBLs. Among cephalosporin-betalactamase inhibitor cefotaxime showed that albumin (1.5 g/kg body weight at diag-
combinations, ceftazidime/avibactam and ceftolozane/tazobac- nosis, followed by 1 g/kg on day three) significantly decreased
tam represent further new alternatives to carbapenems for the the incidence of type 1 HRS (from 30% to 10%) and reduced mor-
treatment of patients with infections sustained by ESBL tality from 29% to 10% compared with cefotaxime alone. Treat-
producing, carbapenem-resistant Enterobacteriaceae and Pseu- ment with albumin was particularly effective in patients with
domonas aeruginosa. However, there are currently no data baseline serum bilirubin ≥68 lmol/L (4 mg/dl) or SCr ≥88
regarding the clinical use of these drugs in cirrhosis.266 lmol/L (1 mg/dl). It is unclear whether i.v. albumin is useful
in patients with baseline bilirubin <68 lmol/L and creatinine
<88 lmol/L, as the incidence of type 1 HRS in patients meeting
Recommendations these criteria was very low in the two treatment groups (7%
without albumin and 0% with albumin).272 The application of
Empirical i.v. antibiotics should be started immediately the schedule of this therapeutic option should be implemented
following the diagnosis of SBP (II-2;1). in clinical practice.273 Non-randomised studies in patients with
SBP also show that the incidence of renal failure and death are
Environment (nosocomial vs. community acquired), local
very low in patients with moderate liver failure and without
bacterial resistance profiles and severity of infection
renal dysfunction at diagnosis of SBP, so albumin is probably
should guide empirical antibiotic treatment (I;1).
not necessary.274

Patients with prior SBP

Recommendation In patients who survive an episode of SBP, the cumulative recur-
rence rate at one year is approximately 70%.33 Probability of
The administration of albumin (1.5 g/kg at diagnosis and survival at one year after an episode of SBP is 30–50% and falls
1 g/kg on day 3) is recommended in patients with SBP (I;1). to 25–30% at two years. Therefore, patients recovering from an
episode of SBP should be considered for LT. There is only one
randomised, double-blind, placebo-controlled trial of nor-
floxacin (400 mg/day orally) in patients who had a previous epi-
Prophylaxis of SBP
sode of SBP.281 Treatment with norfloxacin reduced the
Since most episodes of SBP are thought to result from the translo-
probability of recurrence of SBP from 68% to 20%. In an open-
cation of enteric gram-negative bacteria, the ideal prophylactic
label, randomised study comparing norfloxacin 400 mg/day to
agent should be safe, affordable and effective at decreasing the
rufloxacin 400 mg/week in the prevention of SBP recurrence,
amounts of these organisms from the gut while preserving the
the one-year probability of SBP recurrence was 26% and 36%,
protective anaerobic flora (selective intestinal decontamina-
respectively (p = 0.16).282 Norfloxacin was more effective in
tion).267 Given the high cost and inevitable risk of developing
the prevention of SBP recurrence due to Enterobacteriaceae (0%
resistant organisms, the use of prophylactic antibiotics must be
vs. 22%, p = 0.01). The use of intermittent ciprofloxacin has been
strictly restricted to patients at high risk of SBP.267 Three high-risk
associated with a higher rate of quinolone-resistant organisms
patient populations have been identified: i) patients with acute GI
and should be avoided.282,283 It is uncertain whether prophy-
haemorrhage; ii) patients with low total protein content in ascitic
laxis should be continued without interruption until LT or death
fluid and no prior history of SBP (primary prophylaxis), and iii)
in all patients with prior SBP, or if treatment could be discontin-
patients with a previous history of SBP (secondary prophylaxis).275
ued in patients showing an improvement of liver disease. Many
patients receive rifaximin to prevent recurrent episodes of
Primary prophylaxis in patients with low total protein content in
HE.284 However, rifaximin may also be effective against
ascitic fluid without prior history of SBP. Cirrhotic patients with
recurrent SBP.285 There are no data to guide new indications
low ascitic fluid protein concentration (<10 g/l) and/or high
for primary or secondary prophylaxis of SBP among patients
serum bilirubin levels are at high risk of developing a first epi-
already on rifaximin. More in detail, it is not known whether
sode of SBP.267 Several studies have evaluated prophylaxis with
norfloxacin prophylaxis should be started in patients being trea-
norfloxacin in patients without prior history of SBP.267 Fernandez
ted with rifaximin for prevention of recurrent HE. Likewise, it is
et al. randomised 68 patients with cirrhosis and low ascites pro-
not known whether norfloxacin prophylaxis should be stopped
tein levels (<15 g/l) with advanced liver failure (Child-Pugh score
in patients who would require rifaximin to prevent HE. Prospec-
≥9 points with serum bilirubin level ≥3 mg/dl) or impaired renal
tive studies are required to investigate the potential benefits
function (SCr level ≥1.2 mg/dl, blood urea nitrogen level ≥25 mg/dl,
and side effects of combined therapy with norfloxacin and
or serum sodium level ≤130 mEq/L) to receive norfloxacin
rifaximin.
(400 mg/day for 12 months) or placebo.276 Norfloxacin signifi-
cantly improved the three-month probability of survival (94%
vs. 62%; p = 0.03) but at one year the difference in survival
Recommendations
was not significant (60% vs. 48%; p = 0.05). Norfloxacin adminis-
tration significantly reduced the one-year probability of developing The administration of prophylactic Norfloxacin (400
SBP (7% vs. 61%) and HRS (28% vs. 41%). In a double-blind pla- mg/day, orally) is recommended in patients who recover
cebo-controlled trial, 100 patients with ascitic fluid total protein from an episode of SBP (I;1).
level <15 g/l were randomised to ciprofloxacin (500 mg/day for
Despite some promising evidence, at present, rifaximin
12 months) or placebo.277 The probability of survival at one year
cannot be recommended as an alternative to norfloxacin
was higher in patients receiving ciprofloxacin (86% vs. 66%;
for secondary prophylaxis of SBP (I;2). Thus, at present,
p <0.04). Meta-analyses of all the trials together or including only
no recommendation can be given to guide primary or
pure primary prophylaxis support a significant preventive effect
secondary prophylaxis of SBP among patients already
against SBP (RR 0.2; 95% CI 0.07–0.52; p = 0.001).278,279 The
on rifaximin for the prevention of recurrent HE.
survival benefit is most pronounced at three months (94% vs.
62%, p = 0.003) and seems to decrease over time and may be lost Patients who recover from SBP have a poor long-term
after 12 months follow-up (RR 0.65; 95% CI; 0.41–1.02).280 survival and should be considered for LT (II-2,1).
Since it has been suggested that PPI may increase the
risk for the development of SBP, its use should be
Recommendations restricted to those with a clear indication (II-2,1).
Primary prophylaxsis with norfloxacin (400 mg/day) in

patients with Child-Pugh score ≥9 and serum bilirubin Concomitant medications
level ≥3 mg/dl, with either impaired renal function or Very frequently PPIs are used in patients with cirrhosis, which
hyponatraemia, and ascitic fluid protein lower than 15 may increase the risk of SBP. Indications for long-term use
g/L is recommended (I;1). should be carefully assessed and PPIs discontinued when possi-
Norfloxacin prophylaxis should be stopped in patients ble.286,287 NSBBs may be detrimental in end-stage liver disease
with long-lasting improvement of their clinical condi- with haemodynamic derangement, patients should be moni-
tion and disappearance of ascites (III;1). tored closely and doses adjusted or drug discontinued if con-
traindications occur.168,190,288 Probiotics have been assessed as

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OF HEPATOLOGY
combination therapy with norfloxacin in one randomised trial Cellulitis
in a mixed group of patients on primary and secondary preven-
tion of SBP. No additional benefits were demonstrated.289
Community-acquired Healthcare- Nosocomial
Infections other than SBP cellulitis associated cellulitis cellulitis
Prevalence, diagnosis and impact on prognosis
Non-SBP infections are frequent in patients with cirrhosis and Piperacillin- AREA DEPENDENT: 3rd generation
tazobactam Like nosocomial cephalosporin or
present or develop during hospitalisation in 25–30% of patients.
or 3rd generation infections if high meropemen + oxacillin
The most frequent infections other than SBP are: urinary tract, cephalosporin + prevalence of MDROs or glycopeptides or
pneumonia, skin and soft tissue infections, and bacter- oxacillin or if sepsis daptomycin or
aemia.242,290 They constitute a heterogeneous group regarding linezolid*
clinical course and prognosis. Non-SBP infections increase the

Fig. 5. Recommended empirical antibiotic treatment of soft tissue infec-
odds ratio for death by 3.75 and are associated with a 30% tions (adapted from Ref. 6). MDRO, multidrug resistant organism.
one-month and 63% 12-month mortality.291 Endocarditis, sec-
ondary peritonitis, pneumonia and bacteraemia have worse
prognoses. The combination of data on liver and renal dysfunc- Pneumonia
tion and the type of infection enables the identification of
patients with poor prognosis.290 In particular, non-SBP infec- Community-acquired Healthcare-associated Nosocomial
tions, as well as SBP, are known as common precipitating factors pneumonia pneumonia pneumonia
for ACLF.3 An early diagnosis of all these infections and of SBP is
a crucial step in the management of patients with cirrhosis. Piperacillin-tazobactam AREA DEPENDENT: Ceftazidime or
Since the presentation and the initial course of any bacterial or ceftriaxone + Like nosocomial meropemen§ +
macrolide or infections if high levofloxacin ±
infection may be subtle and not very specific, clinical suspicion levofloxacin or prevalence of MDROs§ glycopeptides or
is important. Indeed, all inpatients with cirrhosis should be con- moxifloxacin or if sepsis linezolid#
sidered as potentially infected until proven otherwise. There-
fore, a complete work-up should be carried out at admission Fig. 6. Recommended empirical antibiotic treatment of pneumonia
(adapted from Ref. 6). MDRO, multidrug resistant organism.
and at any time during the hospital stay when clinical deterio-
ration occurs.6 In addition, close microbiological surveillance is
needed in patients who are at risk of developing infections UTI
caused by methicillin resistant organisms. C reactive protein
and procalcitonin can be used for detecting infection and to
Community-acquired Healthcare- Nosocomial
define the severity of the infection,6 while their use in the UTI associated UTI UTI
stewardship of antibiotic treatment deserves further
investigation.292 To optimise the empirical antibiotic treatment, UNCOMPLICATED: AREA DEPENDENT: UNCOMPLICATED:
it is quite important to distinguish among community acquired, ciprofloxacin or Like nosocomial fosfomycin or
health care associated and nosocomial infections. Mortality for cotrimoxazole infections if high nitrofurantoin
IF SEPSIS: 3rd prevalence of MDR§ IF SEPSIS:
nosocomial infections is higher (25–48%) than for community- generation cephalospo- or if sepsis meropemen +
acquired infection (7–21%) since they are more commonly rin or piperacillin- teicoplanin or
sustained by MDR bacteria.6,266,268 Like in SBP, there is an tazobactam vancomycin§ #
increasing challenge of resistant bacteria among non-SBP infec-
Fig. 7. Recommended empirical antibiotic treatment of UTI (adapted from
tions. Among 312 patients with cirrhosis and blood stream Ref. 6). MDR, multidrug resistant; UTI, urinary tract infection.
infections gram-negative bacteria, gram-positive bacteria and
Candida were the cause of blood stream infections episodes in
53%, 47% and 7% of the cases, and 31% of the infections were it cannot be recommended. The issue of the management of infec-
caused by MDR bacteria.293 tions sustained by XDR bacteria has been previously developed.
Management of infections other than SBP

In a randomised trial 94 patients with cirrhosis and infections Recommendations
(most prevalent were urinary tract infections [46%], SBP [22%],
and pneumonia [19%]) were randomised to a broad-spectrum Infections other than SBP are frequent and associated
antibiotic regimen or a standard regimen. In–hospital mortality with increased mortality. Hospitalised patients with cir-
was significantly higher in the standard than in the broad-spec- rhosis should be assessed and monitored closely for the
trum group (25% vs. 6%; p = 0.01).294 Some more specific sugges- presence of infections to enable early diagnosis and
tions on the empirical antibiotic treatment of infections other appropriate treatment (II-1;1).
than SBP based on the type, the severity and the environment
of the infection as well as on local resistance profiles are given Empirical antibiotic therapy should be commenced
(Figs. 5–7). In patients who fail to respond to a broad-spectrum promptly at suspicion of infection (II-1;1).
antibiotic treatment a fungal infection, including fungal SBP295 The choice of empirical antibiotic therapy should be
should be suspected and investigated.296 based on several factors including: environment (noso-
Finally, in two randomised trials, concomitant albumin may comial vs. health care associated or community
protect against deterioration in renal and circulatory func- acquired), local resistance profiles, severity and type of
tion.297,298 However, albumin did not improve survival and thus infection (I;1).

glomerulopathy),305 however the prevalence of CKD in this pop-

In the context of high bacterial resistance to antibiotics, ulation is still unknown. ARF is a common complication in
carbapenem alone or in combination with other antibi- patients with decompensated cirrhosis.306 Historically, the diag-
otics proved to be superior to third-generation cephalos- nosis was based on an increase in SCr of 50% from baseline to a
porins in healthcare associated infections other than SBP, final value >1.5 mg/dl (133 lmol/L).1,32,307 Recently, the term
and therefore, should be preferred (I;1). ARF was replaced by AKI,308–310 irrespectively of its different
types. AKI is now defined, as proposed by the Kidney Disease
Severe infections sustained by XDR bacteria can require
Improving Global Outcomes (KDIGO) group,310 as either an
the use of antibiotics known to be highly nephrotoxic
absolute increase in SCr of more than or equal to 0.3 mg/dl
in patients with cirrhosis such as vancomycin or amino-
(≥26.4 lmol/L) in less than 48 h, or by a percentage increase
glycosides. In these cases, patients’ plasma level should
in SCr of more or equal to 50% (1.5-fold from baseline) in less
be monitored in accordance with local policy thresholds
than seven days. A new staging system was also introduced,
(III;1).
mainly based on the percentage increase of SCr from baseline
Routine use of albumin is not recommended in infec- (Table 7), either at the time of the first fulfillment of the KDIGO
tions other than SBP (I;1). criteria (initial stage) or at the peak value of SCr during hospital-
isation in case of progressive AKI (peak stage).310 Based on the
Prophylaxis of infections other than SBP staging system and according to the results of several prospec-
There is preliminary evidence that in patients with Child-Pugh tive studies,311–317 a new algorithm for the management of AKI
class C, norfloxacin administration can reduce the risk of infec- in patients with cirrhosis has been proposed318 (Fig. 8). Recent
tions and can decrease six-month mortality. However, more studies have suggested that in patients with cirrhosis, in AKI
data are needed before a recommendation can be made.21 stage 1, SCr <1.5 mg/dl is associated with a worse outcome than
an SCr ≥1.5 mg/dl.313,314,317 Thus, in contrast with the KDIGO
staging system, it has been proposed to distinguish between a
Renal impairment stage 1A (SCr <1.5 mg/dl) and a stage 1B (SCr ≥1.5 mg/dl) within
Definition and diagnosis AKI stage 1.313,314,317 It should be highlighted that the KDIGO
Renal impairment in patients with cirrhosis was defined more criteria also include criteria based on urinary output in the diag-
than 30 years ago by an SCr value ≥1.5 mg/dl because this value nosis of AKI (Fig. 9).310 These criteria were not considered by the
was considered an index of GFR ≤40 ml/min.32 The use of SCr in recent International Club of Ascites (ICA) consensus because (a)
the evaluation of renal function in patients with cirrhosis, has these patients are frequently oliguric with avid sodium reten-
several well-known limitations. However, the diagnosis of renal tion, despite a relatively normal GFR, (b) they may have an
dysfunction in liver disease is still based on it.32,299 The diagno- increased urine output because of diuretics, and (c) on a regular
sis should be based on different diagnostic categories including ward, urine collection is often inaccurate and always
chronic kidney disease (CKD) and acute renal failure (ARF). untimely.318 However, these criteria may also be applied when-
When only based on reduction of GFR, the diagnosis of CKD in ever a patient with cirrhosis requires a bladder catheter. The
patients with cirrhosis is still challenging, because all the SCr- definition of baseline SCr used in the KDIGO criteria is crucial
based equations that have been proposed overestimate GFR in since it has been observed that about 25–30% of episodes of
patients with cirrhosis.300–304 It can be reasonably assumed that AKI occur before hospitalisation, representing the so-called
patients with decompensated cirrhosis frequently have CKD ‘‘community-acquired AKI”. Ideally, ‘‘community-acquired AKI”
caused by certain comorbidities (i.e. diabetes, arterial hyperten- should be diagnosed at the time of hospital admission, requir-
sion) and/or specific causes (i.e. IgA nephropathy, virus-induced ing, according to the KDIGO criteria, an SCr value dated within
Table 7. International Club of Ascites (ICA-AKI) new definitions for the diagnosis and management of acute kidney injury in patients with cirrhosis.
Subject Definition
Baseline sCr A value of sCr obtained in the previous three months, when available, can be used as baseline sCr. In patients with more than one value within
the previous three months, the value closest to the admission time to the hospital should be used
In patients without a previous sCr value, the sCr on admission should be used as baseline.
Definition of - Increase in sCr ≥0.3 mg/dl (≥26.5 lmol/L) within 48 h; or,
AKI - A percentage increase sCr ≥50% which is known, or presumed, to have occurred within the prior seven days
Staging of - Stage 1: increase in sCr ≥0.3 mg/dl (≥26.5 lmol/L) or an increase in sCr ≥1.5-fold to 2-fold from baseline;
AKI - Stage 2: increase in sCr >2-fold to 3-fold from baseline;
- Stage 3: increase of sCr >3-fold from baseline or sCr ≥4.0 mg/dl (353.6 lmol/L) with an acute increase ≥0.3 mg/dl (≥26.5 lmol/L) or initiation
of renal replacement therapy
Progression Progression Regression
of AKI
Progression of AKI to a higher Regression of AKI to a lower stage
stage and/or need for RRT
Response to No response Partial response Full response
treatment
No regression of AKI Regression of AKI stage with a reduction of sCr to ≥0.3 Return of sCr to a value within 0.3 mg/dl
mg/dl (≥26.5 lmol/L) above the baseline value (≥26.5 lmol/L) of the baseline value
AKI, acute kidney injury; sCr, serum creatinine; RRT, renal replacement therapy.

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Initial AKI# stage 1a° Initial AKI# stage >1a°
Close monitoring Withdrawal of diuretics (if not yet applied) and volume
Remove risk factors (withdrawal of nephrotoxic drugs, vasodilators and expansion with albumin (1 g/kg) for 2 days
NSAIDs, taper/withdraw diuretics and β-blockers, expand plasma
volume, treat infections* when diagnosed)
Response ?
Resolution Persistance Progression YES NO
Close follow up Does AKI meet criteria of HRS ?
Further treatment of
AKI decided on a NO YES
case-by-case basis
Specific
treatment for Vasoconstrictors
#
AKI at the first fulfilling of KDIGO criteria other AKI and albumin
phenotypes
Fig. 8. Algorithm for the management of AKI in patients with cirrhosis (adapted from Ref. 318). AKI, acute kidney injury; HRS, hepatorenal syndrome;
NSAID, non-steroidal anti-inflammatory.
KDIGO urine output criteria = an urinary output <0.5 ml/kg B.W./h/x 6-12 h Table 8. Definitions of kidney disease.
Stage Serum creatinine criteria Definition Functional criteria Structural
1° An urinary output <0.5 ml/kg B.W./h x 6-12 h criteria
AKI Increase in sCr ≥50% within seven days, No criteria
2° An urinary output <0.5 ml/kg B.W./h x 12 h
or
3° An urinary output <0.5 ml/kg B.W./h x 24 h or anuria per 12 h increase in sCr ≥0.3 mg/dl within two days
AKD GFR <60 ml/min per 1.73 m2 for <3 months, Kidney damage
Fig. 9. Criteria based on urinary output for the diagnosis of AKI (adapted or for <3 months
from Ref. 310). AKI, acute kidney injury; B.W., body weight. decrease in GFR ≥35% for < 3 months,
or
increase in sCr ≥50 % for < 3 months
the last week before admission. This point is so crucial for the CKD GFR <60 ml/min per 1.73 m2 for ≥3 months Kidney damage
application of the KDIGO criteria that it has been suggested that for ≥3 months
an SCr value be calculated when not available the seven days AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease;
prior to admission. The baseline SCr can be calculated by inver- GFR, glomerular filtration rate; sCr, serum creatinine.
sely applying the formulas that are used to calculate the esti-
mated GFR, considering normal values of GFR of 75 ml/min.319
Whilst an imputed SCr is accepted in the general population,
it can not be used in patients with cirrhosis.320 Indeed, all
SCr-based formulas overestimate the true GFR in these patients Recommendations
leading to an overestimation of the baseline SCr and thus under-
estimating the prevalence of AKI on admission.320 Therefore, it In patients with liver diseases, even a mild increase in
has been proposed that not only the value obtained in the last SCr should be considered since it may underlie a marked
seven days, but also that within the last three months be con- decrease of GFR (II-2;1).
sidered as a baseline value of SCr in patients with cirrhosis
The first step to be addressed in the diagnostic process is
(Table 7). In addition, an SCr value obtained within the last three
to establish if the patient has a CKD, AKD or AKI as well
months is the reference to define acute kidney disease (AKD), a
as an overlap between these diagnostic categories
third category of renal impairment, along with AKI and CKD,
(II-2;1).
which has been recently proposed in KDIGO recommendations.
AKD is clearly a distinct category with different outcome, The diagnosis of CKD should be based on a GFR <60 ml/
whether or not it is associated with AKI. AKD is defined by a min/1.73 m2 estimated by SCr-based formulas, with or
GFR <60 ml/min/1.73 m2 for less than three months, or a without, signs of renal parenchymal damage (protein-
decrease in GFR ≥35% for less than three months, or an increase uria/haeamturia/ultrasongraphy abnormalities) for at
in SCr <50% within the last three months (Table 8). However, no least three months (II-2;1).
data exist about the prognostic impact of AKD, with or without The diagnostic process should be completed by staging
AKI, in patients with cirrhosis. Thus, waiting for these data, it CKD, which relies on GFR levels, and by investigating
seems even more justified to make the diagnosis of AKI in its cause. It should be highlighted that any SCr based
patients with cirrhosis on an increase in SCr ≥50% during the formula overestimates GFR in patients with cirrhosis
last three months. This assumption may also facilitate the diag- (II-2, 1).
nosis of AKI overlapping CKD.

In patients with cirrhosis the diagnosis of AKI should be Volume replacement should be used in accordance with
based on adapted KDIGO criteria, thus, either on an the cause and severity of fluid losses (II-2,1).
increase in SCr of >0.3 mg/dl from baseline within 48 h, In case of no obvious cause of AKI, AKI stage >1A or infec-
or an increase of ≥50% from baseline within three tion-induced AKI, 20% albumin solution should be used at
months (II-2,1). the dose of 1 g of albumin/kg of body weight (with a max-
The staging of AKI should be based on an adapted KDIGO imum of 100 g of albumin) for two consecutive days (III,1).
staging system, thus distinguishing within AKI stage 1, In patients with AKI and tense ascites, therapeutic para-
between AKI stage 1A and AKI stage 1B according to a centesis should be associated with albumin infusion even
value of SCr <1.5 or ≥1.5 mg/dl, respectively (II-2,1). when a low volume of ascetic fluid is removed (III,1).
Precipitating factors
Infections, diuretic-induced excessive diuresis, GI bleeding, Types of AKI
therapeutic paracentesis without adequate volume expansion, All types of AKI can occur in patients with cirrhosis, namely pre-
nephrotoxic drugs, and NSAIDs are the other common precipi- renal AKI, HRS-AKI, intrarenal or intrinsic AKI, and post-renal
tating factors of AKI in patients with cirrhosis.20,242,306 The AKI. The most common cause of AKI in hospitalised patients
nephrotoxicity of contrast agents is still debated in patients with decompensated cirrhosis is pre-renal, accounting for
with cirrhosis321 but contrast imaging should be performed cau- approximately 68% of the cases.306,327,328 Intrarenal-AKI is
tiously, particularly in decompensated cirrhosis or in patients mainly represented by acute tubular necrosis (ATN).306 Finally,
with known CKD. Finally, the increase in intra-abdominal pres- post-renal AKI is uncommon in decompensated cirrhosis.328
sure associated with tense ascites may lead to AKI, by increasing Considering that most cases of pre-renal AKI are resolved by
renal venous pressure.322–324 volume expansion and that post-renal AKI is uncommon, the
key point is to differentiate HRS-AKI from ATN. As described
Management in the section ‘‘Hepatorenal syndrome”, the concept that HRS
The cause of AKI should be investigated as soon as possible, to is only a functional injury has been challenged during the last
prevent AKI progression. However, even in the absence of a defini- decade and, thus, the definition of HRS probably has to be
tive recognised cause of AKI, the management should be immedi- revised. In addition, as kidney biopsy is rarely performed in
ately started according to the initial stage (Fig. 2). Irrespective of the setting of AKI in clinical practice, the distinction between
the stage, diuretics should be discontinued. Similarly, even if HRS-AKI and ATN is difficult. Recently, novel biomarkers have
there are controversial data, beta-blockers should be stopped.168 emerged in this setting and urinary neutrophil gelatinase-
Other precipitating factors of AKI should be identified and treated, associated lipocalin (NGAL) is the most promising. Indeed, sev-
including screening and treatment of infection, volume expan- eral studies have shown that urinary NGAL, a marker of tubular
sion when appropriate, and discontinuation of all nephrotoxic damage, could help to determine the type of AKI.329–335
drugs, such as vasodilators or NSAIDs.318 Volume replacement However, cut-off values differ greatly according to series, there
should be used in accordance with the cause and the severity of are overlaps between the different types of AKI and it should be
fluid loss. Patients with diarrhoea or excessive diuresis should highlighted that no study has confirmed the diagnosis by
be treated with crystalloids, whilst patients with acute GI bleed- reference kidney biopsy. Diagnosis based on a combination of
ing should be given packed red blood cells to maintain haemoglo- multiple biomarkers may be interesting but needs further
bin level between 7–9 g/dl.325 In patients with AKI and tense evaluation.329,330,332–334
ascites, therapeutic paracentesis should be associated with albu-
min infusion since it improves renal function.326 In case of no
obvious cause and AKI stage >1A, 20% albumin solution at the Recommendations
dose of 1 g of albumin/kg of body weight (with a maximum of
100 g of albumin) for two consecutive days should be given.307 All types of AKI can occur in patients with cirrhosis,
All other therapeutic options, especially renal replacement ther- namely pre-renal, HRS, intrinsic, particularly ATN, and
apy (RRT) and kidney transplantation will be discussed in the sec- post-renal. Therefore, it is important to differentiate
tion dedicated to the management of HRS-AKI. among them (II-2,1).
The diagnosis of HRS-AKI is based on revised ICA criteria.
As kidney biopsy is rarely performed in the setting of
Recommendations
AKI, biomarkers should be implemented In clinical prac-
tice among the different biomarkers to date, urinary
When a diagnosis of AKI is made, its cause should be NGAL can be used to distinguish between ATN and HRS
investigated as soon as possible to prevent AKI progres- (II-2;2).
sion. Even in absence of an obvious cause, the manage-
ment should be immediately started. Maximal
attention in the screening and treatment of infections Prognosis
should be carried out (II-2,1). In patients with decompensated cirrhosis, AKI has a negative
Diuretics and/or beta-blockers as well as other drugs impact on hospital survival according to either the initial stage,314
that could be associated with the occurrence of AKI such or the peak stage.313,317 Even transient episodes of AKI are
as vasodilators, NSAIDs and nephrotoxic drugs should be associated with a negative impact on mid-term survival.315
immediately stopped (II-2,1). Nevertheless, a more comprehensive prognostic classification

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also considering extra-renal organ failures is much more accurate promoting bile salt-related direct tubular damage.350,351 All
than the KDIGO criteria for the prognosis in these patients. these findings suggest that the pathophysiology of AKI, and par-
Finally, looking to the data in the general population, it should ticular of HRS-AKI, in patients with decompensated cirrhosis
be highlighted that the risk for developing CKD is higher in seems more complex than previously hypothesised, supporting
patients with severe or repeated episodes of AKI.336 Since patients the concept that AKI-HRS is not purely functional in nature.
with decompensated cirrhosis are prone to develop frequent
episodes of AKI, it can be speculated that they are at higher risk Management
of developing CKD. The non-specific management of AKI as been previously
described. Thus, in this section, drug therapy, TIPS, RRT, LT
Hepatorenal syndrome
and simultaneous liver and kidney transplantation (SLK) will
Definition, diagnosis and classification
be considered.
For a long time, HRS has been defined as ‘‘a functional renal fail-
ure caused by intrarenal vasoconstriction which occurs in
patients with end-stage liver disease as well as in patients with Drug therapy. Once the diagnosis of HRS-AKI has been made,
acute liver failure or alcoholic hepatitis”.32,307 Several data chal- patients should promptly receive vasoconstrictive drugs, in
lenge this definition of HRS as well as the classification in type 1 association with albumin. The rational for using vasoconstric-
and type 2. Firstly, as described below, pathogenesis of HRS tors is to counteract the splanchnic arterial vasodilation,
includes both haemodynamic and inflammatory changes. Sec- improving renal perfusion.352 Terlipressin, a vasopressin ana-
ondly, the absence of renal parenchymal damage, defining the logue, is the most commonly used. The efficacy of terlipressin
functional nature, has never been proven by renal biop- plus albumin in the treatment of HRS has been proven in many
sies.337,338 The absence of significant proteinuria and/or haema- studies.353–360 In the most recent studies, rates of response
turia do not rule out renal lesions, particularly tubular and (complete or partial response) to this treatment range from 64
interstitial lesions.307 In addition, studies assessing novel kidney to 76%, with a complete response, from 46 to 56%.358–360 These
biomarkers have shown that tubular damage can occur in response rates must now be evaluated according to the new def-
patients with HRS-AKI when HRS is diagnosed according to initions of responses in HRS-AKI recently proposed by the ICA
the traditional criteria.328–330,332 Finally, it should be noted that (Table 7). In two meta-analyses terlipressin plus albumin was
HRS-AKI can occur in patients with underlying CKD. Type 1 and proven to improve not only renal function but also short-term
type 2 were historically defined based on time frame SCr survival in patients with HRS.361,362 Terlipressin was initially
increase.32,307 In the recent revised classification, type 1 HRS proposed to be administered by i.v. boluses at a starting dose
now corresponds to HRS-AKI.318 Consequently, type 2 HRS of 0.5–1 mg every 4–6 h, progressively increased to a maximum
should now include renal impairment which fulfills the criteria of 2 mg every 4–6 h in case of a reduction of baseline SCr <
of HRS but not of AKI, namely non-AKI-HRS (NAKI), and only 25%.353–358 Adding albumin to terlipressin is more effective
HRS-CKD as previously proposed.339 than terlipressin alone.354 One possible explanation is that albu-
min, by increasing volaemia, may counteract the decrease in
cardiac output associated with HRS192 but also by terli-
Pathophysiology pressin.363 In addition, antioxidant and anti-inflammatory prop-
According to the new theory that has been developed on the erties of albumin may have a beneficial effect.364 The dose of
pathophysiology of decompensated cirrhosis,5 the view on albumin in HRS treatment has not been well established. Stud-
HRS has been changed in recent years, moving from the idea ies have suggested adapting the dose according to the level of
that it was only related to renal hypoperfusion due to macrocir- central venous pressure (CVP), but there is evidence that CVP
culatory dysfunction (i.e. splanchnic arterial vasodilation and is inaccurate to manage volume expansion and to assess cardiac
reduction of cardiac output).192,338 The new theory is that the output in patients with cirrhosis. In contrast, CVP may be help-
increased circulating levels of pro-inflammatory cytokines and ful to prevent circulatory overload. Albumin has been used
chemokines340,341 may exercise a direct relevant role in the intravenously at the mean dose of 20–40 g/day. Treatment
development of HRS. Such cytokines have been associated with should be maintained until a complete response (SCr below
renal impairment in patients and in animal models of cirrhosis 1.5 mg/dl) or for a maximum of 14 days either in case of partial
with infection.342–345 Moving from the concept that AKI and response (decrease of SCr ≥50 with a final value still higher than
HRS-AKI are often precipitated by bacterial infection, the new 1.5 mg/dl) or in case of non-response. More recently, continuous
hypothesis on the pathogenesis of sepsis-induced AKI should i.v. infusion of terlipressin at an initial dose of 2 mg/day was
also be considered.346–348 This theory proposes that a synergic proposed,359,365 demonstrating a similar rate of response but
interplay of inflammation and microvascular dysfunction is lower adverse effects than the administration of the drug by
responsible for the amplification of the signal that PAMPs and i.v. boluses.360 Indeed, terlipressin, when administered by con-
DAMPs exert on proximal epithelial tubular cells. The recogni- tinuous i.v. infusion, has a more stable lowering effect on portal
tion of this signal and its subsequent spread to all the other pressure, even when used at lower doses than those provided by
proximal tubular epithelial cells cause a mitochondria-medi- i.v. boluses.360 The most common side effects of terlipressin are
ated metabolic downregulation and reprioritisation of cell func- diarrhoea, abdominal pain, circulatory overload and cardiovas-
tions to favour survival processes above all else.349 The cular ischaemic complications which have been reported in up
sacrificed functions include the absorption on the lumen side to 45–46% of patients when the drug was delivered by i.v.
of sodium and chloride. The consequent increases of sodium boluses.360 The rate of discontinuation because of side effects,
chloride delivery to the macula densa triggers further intrarenal mainly cardiovascular, is around 20%.360 Accordingly, a careful
activation of the RAAS and thus lowers GFR. Finally, severe clinical screening including electrocardiogram is recommended
cholestasis may further impair renal function by worsening in all patients before starting treatment. Patients can be treated
inflammation and/or macrocirculatory dysfunction, or by on a regular ward but the decision to transfer to a higher level of

care should be case based. Recurrent HRS in responders, after

the end of the treatment, has been reported in up to 20% of Albumin solution (20%) should be used at the dose
cases. Re-treatment is usually effective, however, in some cases, 20–40 g/day. Ideally, apart from routinely monitoring
continuous recurrence occurs, thus a long-term treatment with patients with HRS-AKI, the serial measurement of CVP
terlipressin plus albumin and a long-term hospitalisation are or other measures of assessing central blood volume,
required.366 The possibility of treating some of these patients can help to prevent circulatory overload by optimising
outside the hospital has recently been proposed367 but even if the fluid balance and helping to titrate the dose of albu-
promising, further studies are needed. Other vasoconstrictive min (II-2;1).
drugs include i.v. noradrenaline and oral midodrine plus subcu-
Noradrenaline can be an alternative to terlipressin. How-
taneous or i.v. octretide, both in combination with albumin.
ever, limited information is available (I;2).
Noradrenaline, given by continuous i.v. infusion at the dose of
0.5–3 mg/h, has been proven to be as effective as terlipressin In contrast to terlipressin, the use of noradrenaline
regarding the increase in mean arterial pressure, the reversal always requires a central venous line and, in several
of renal impairment and one-month survival.368–371 However, countries, the transfer of the patient to an ICU. Mido-
the number of patients treated with noradrenaline remains drine plus octreotide can be an option only when terli-
too small to definitively confirm its efficacy. In addition, in con- pressin or noradrenaline are unavailable, but its
trast to terlipressin, the use of noradrenaline always requires a efficacy is much lower than that of terlipressin (I;1).
central venous line and, in most countries, the transfer of the According to the new definition of HRS-AKI, complete
patient to an intensive care unit (ICU). The combination mido- response to the treatment should be defined by a final
drine plus octreotide, used in countries where terlipressin is SCr within 0.3 mg/dl (26.5 lmol/L) from the baseline
not yet available,372 has been shown to be much less effective value, while partial response should be defined by the
than terlipressin in the treatment of type 1 HRS in a recent regression of AKI stage to a final SCr ≥0.3 mg/dl (26.5
RCT.359 Vasoconstrictors, in particular terlipressin, in associa- lmol/L) from the baseline value (III;1).
tion with albumin, have also been proposed in the treatment
of type 2 HRS. The treatment has been proven to be effective Adverse events related to terlipressin or noradrenaline
in most cases but, unfortunately, recurrence after the with- include ischaemic and cardiovascular events. Thus, a care-
drawal of treatment is the norm. In addition, there are contro- ful clinical screening including electrocardiogram is rec-
versial data about the impact of this treatment on outcomes, ommended before starting the treatment. Patients can be
especially in candidates for LT.373,374 This may be, at least in treated on a regular ward, but the decision to transfer to
part, due to the suboptimal definition of type 2 HRS, as previ- higher dependency care should be case based. For the dura-
ously discussed. The most relevant factors that may impair tion of treatment, it is important to closely monitor the
the response to vasoconstrictors are: a) the baseline value of patients. According to the type and severity of side effects,
SCr, b) the degree of inflammation and c) the degree of cholesta- treatment should be modified or discontinued (I;1).
sis.375–377 The finding that the higher baseline values of SCr, the In cases of recurrence of HRS-AKI upon treatment cessa-
lower rate of response to terlipressin plus albumin,375 probably tion, a repeat course of therapy should be given (I;1).
reflects the presence of renal parenchymal damage337 and rep-
Terlipressin plus albumin is also effective in the treat-
resents one of the main reasons behind the adoption of the
ment of HRS outside the criteria of AKI (HRS-NAKI), for-
KDIGO criteria for the definition of AKI in patients with cirrho-
merly known as HRS type II. Unfortunately, recurrence
sis, and the introduction of the new algorithm for its manage-
after the withdrawal of the treatment is the norm, and
ment. Regarding inflammation, it has been recently shown
controversial data exists on the impact of the treatment
that, for the same value of baseline SCr, the rate of response is
on long-term clinical outcome, particularly from the per-
related to the number of extra-renal organ failures.376
spective of LT. As such, vasoconstrictors and albumin are
not recommended in this clinical scenario (I;1).
Recommendations
Transjugular intrahepatic portosystemic shunts. The use of TIPS
Vasoconstrictors and albumin are recommended in all may improve renal function in patients with type 1 HRS.378,379
patients meeting the current definition of AKI-HRS stage However, the applicability of TIPS in this clinical setting is usu-
>1A, should be expeditiously treated with vasoconstric- ally very limited because, in most patients, TIPS is contraindi-
tors and albumin (III;1). cated because of severe degree of liver failure. TIPS has been
studied in patients with type 2 HRS380 and in the management
Terlipressin plus albumin should be considered as the of refractory ascites, frequently associated with type 2 HRS. In
first-line therapeutic option for the treatment of HRS- these patients, TIPS has been shown to improve renal function.95,379
AKI. Telipressin can be used by i.v. boluses at the initial
dose of 1 mg every 4–6 h. However, giving terlipressin
Renal replacement therapy. Renal replacement therapy should be
by continuous i.v. infusion at initial dose of 2 mg/day
considered in the management of AKI, whatever the type. As far
makes it possible to reduce the global daily dose of the
as HRS-AKI, it should be considered in non-responders to vaso-
drug and, thus, the rate of its adverse effects. In case of
constrictors. RRT should also be considered in patients with
non-response (decrease in SCr <25% from the peak value),
end-stage kidney disease. The indications for RRT are the same
after two days, the dose of terlipressin should be increased
in patients with cirrhosis as in the general population including:
in a stepwise manner to a maximum of 12 mg/day (I;1).
severe and/or refractory electrolyte or acid-base imbalance,

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OF HEPATOLOGY
severe or refractory volume overload, and/or symptomatic is almost 50%, a specific policy of priority allocation is needed
azotaemia. However, published data on RRT in patients with for these patients. This can be made either by continuing to con-
cirrhosis are scant, with controversial effects on survival.381,382 sider the baseline MELD and/or MELD-Na score394 rather than
It has been stated that indications for RRT depend on the per- those during or after the end of the treatment, or by providing
spective of LT. It has been stated that RRT may be considered an exception to the MELD score.395
in patients who are candidates for LT, while, in contrast, the
decision to initiate RRT in non-candidates should be individu-
alised to avoid futility.20 However, it has recently been observed Recommendations
that critically ill liver cirrhotic patients requiring RRT have very
high mortality independent of LT options. Thus, RRT and treat- There is insufficient data to advocate TIPS in HRS-AKI but
ment at the ICU should not be limited to LT candidates but it could be suggested in selected patients with HRS-NAKI
should be based on the individual severity of illness.383 There- (II-2;2).
fore, repeated risk stratification is necessary during the course
LT is the best therapeutic option for patients with HRS
of treatment, assisted by prognostic scores in addition to clinical
regardless of the response to drug therapy (I;1).
judgment and patients0 wishes.383 The ideal timing for RRT ini-
tiation has not been defined in patients with cirrhosis. However, The decision to initiate RRT should be based on the indi-
data on AKI in patients with acute liver failure as well as in crit- vidual severity of illness (I;2).
ically ill patients without liver disease suggest that early RRT The indication for liver-kidney transplantation remains
improves survival.384–386 Both haemodialysis or continuous controversial. This procedure should be considered in
renal replacement therapy (CRRT), have been used in patients patients with significant CKD or with sustained AKI
with cirrhosis. Despite the available evidence,387 CRRT is prob- including HRS-AKI with no response to drug therapy
ably better tolerated, providing greater cardiovascular stability (II-2;1).
and allowing a slower correction of severe or refractory hypona-
traemia than haemodialysis.
Prevention of hepatorenal symdrome

Liver support systems. In two controlled studies, both the so-
The prevention of HRS-AKI, as for other causes of AKI, is based
called artificial liver support systems, either the molecular
on the use of albumin in patients who develop SBP272 and the
adsorbents recirculating system (MARSÒ) or PrometheusÒ,
prevention of SBP using norfloxacin,276 as discussed before. In
showed promising beneficial effects in patients with type 1
addition, the use of pentoxyfilline may decrease the incidence
HRS, but should be further investigated.388,389
of renal failure in patients with cirrhosis27 and of type 1 HRS
as well as mortality in patients with severe alcoholic hepati-
Liver transplantation and simultaneous liver-kidney transplanta- tis.396 However, recent papers do not confirm these
tion. The best therapeutic option in patients with HRS is LT.390 results397,398 and further studies are needed.
However, several studies have shown that SCr after LT is higher
in patients transplanted with HRS, compared to those without
HRS at the time of LT. In addition, the presence of HRS at the Recommendations
time of LT has a negative impact on survival after LT.391 The
treatment of type 2 HRS before LT has given conflicting results
Albumin (1.5 g/kg at diagnosis and 1 g/kg on day three)
on the clinical outcome after LT373,374 and thus, requires further
should be given in patients with SBP to prevent AKI (I;1).
investigation. SLK can be indicated in patients with cirrhosis
and CKD in the following conditions: a) estimated GFR (using Norfloxacin (400mg/day) should be given as prophylaxis
MDRD6 equation) ≤40 ml/min or measured GFR using iothala- of SBP to prevent HRS-AKI (I;1).
mate clearance ≤30 ml/min, b) proteinuria ≥2 g a day, c) kidney
biopsy showing >30% global glomerulosclerosis or >30% intersti-
tial fibrosis, or d) inherited metabolic disease. SLK is also indi- Acute-on-chronic liver failure
cated in patients with cirrhosis and sustained AKI irrespective Definitions and pathophysiology
of its type, including HRS-AKI when refractory to drug therapy, Since the CANONIC study, the first major international observa-
in the following conditions: a) AKI on RRT for ≥4 weeks or b) tional study characterising the syndrome of ACLF,3 a large num-
estimated GFR ≤ 35 ml/min or measured GFR ≤25 ml/min ≥4 ber of publications have described the association of this
weeks.392 Beyond these two conditions, in a candidate with high syndrome with different clinical, diagnostic and therapeutic
priority for LT due to a high MELD score, the option of SLK may approaches. ACLF occurs in 30% of admitted patients3,399 and
be considered in the presence of risk factors for underlying in 25% of outpatients,400 and is a major cause of death in cirrho-
undiagnosed CKD (diabetes, hypertension, abnormal renal sis, with an approximately 50% mortality rate.400 Even though
imaging and proteinuria >2 g/day).392 The development of there is an ongoing debate regarding the definition of
new biomarkers of kidney fibrosis, a common and irreversible ACLF,401–405 the concept of the development of ACLF is similar
feature of CKD, is also promising in this context.393 across different continents and health systems. There is agree-
Regarding the priority allocation of patients with HRS-AKI to ment that ACLF is not just decompensation of liver cirrhosis,
the waiting list, some rules should be applied in case of but a distinct syndrome.406 The reason is that ACLF is defined
response to drug therapy. In fact, by lowering SCr and increasing by a multi-organ failure and has a higher short-term mortality
serum sodium concentration, the treatment can significantly than a ‘‘simple decompensation” of cirrhosis.3,401,406 The risk
lower the MELD and MELD-Na score, potentially delaying LT. of developing ACLF is higher in outpatients with advanced liver
Considering that the survival rate in responders at three months disease according to the presence of ascites, low mean arterial

Box 1. CLIF-C Acute Decompensation Score (Ref. 407). ing to the definition of Asian Pacific Association for the Study of
CLIF-C Acute Decompensation score
the Liver (APASL).402 However, nowadays there is evidence that
bacterial infections are mainly involved in the development of
10 x [0.03 x Age + 0.66 x Ln(Creatinine) + 1.71 x Ln(INR) + organ failures and thereby of ACLF in Asia as well.415,416 In Wes-
0.88 x Ln(WBC) 0.05 x Sodium + 8] tern countries bacterial infections are the precipitating events in
one-third of patients admitted with ACLF and in two-thirds of
Age in years; creatinine in mg/dl; WBC (white blood count) in 109 cells/L; sodium in mmol/L
patients developing ACLF during follow-up.3,409,412,413 Based
on these data, preventive and early therapeutic interventions
for the treatment of infections are of major importance to pre-
pressure or anaemia and with a high MELD score.400 ACLF devel- vent the development of ACLF. The role of bacterial infections
ops on the background of acute decompensation (AD) of cirrho- as triggers of AD and development of organ failures has already
sis, but a remarkable number of patients (40%) admitted to been discussed.
hospital developed ACLF on the first episode of AD of their liver
disease.3 Thus, the presence of AD is an important clinical fea-
Active alcohol intake or binge
ture for the diagnosis of ACLF.3,401,406 The EASL-CLIF Consortium
Alcoholic liver disease was the most prevalent in patients with
has proposed and validated a prognostic score (CLIF-C AD score)
AD and ACLF in the CANONIC study, as well as in recent reports
for patients with AD who do not develop ACLF407 The CLIF-C AD
from India.415–417 Interestingly, active alcoholism and alcohol
score (Box 1) was proved to be more accurate for predicting out-
binge were not only a major trigger in these patients, but led
come in these patients than the MELD or MELD-Na score.407
to a more severe syndrome than other triggers in alcoholic cir-
Once developed, ACLF is characterised by hepatic and extrahep-
rhosis patients without heavy active alcoholism.3 The role and
atic organ dysfunction and/or failure, highly activated systemic
mechanisms of active alcoholism need further investigation,
inflammation, and a high 28-day mortality.3,12 The overwhelm-
especially regarding prevention and treatment.
ing and devasting inflammatory response is a key pathogenic
mechanism in the development of ACLF, probably explaining
Reactivation and superimposed viral hepatitis
why ACLF frequently happens in younger patients.3,401,406,408
Reactivation of HBV in patients with cirrhosis is the main pre-
The trigger of ACLF and this inflammatory response could not
cipitating event in the non-Caucasian Asian population,413,415
be identified in 40–50% of the patients in CANONIC study,3
occurring mostly in genotypes B and D, and hepatitis B e antigen
which might be associated with genetic predisposition, severe
positive patients. Interestingly, superimposed HAV and HEV can
portal hypertension or other factors predisposing the patients
also trigger ACLF in 14–18%.414,416 According to the Western
to development of AD and ACLF.409 However, identification of
experience, these are unusual causes.3,413 However, the role of
the precipitating events of AD are of great importance to pre-
HEV might have been overlooked, and might gain more impor-
vent and manage ACLF.410,411
tance now because of advances in diagnostics and increases in
awareness.3,418 A timely recognition and treatment of the pre-
Precipitating events
cipitating event might prevent ACLF and improve outcome in
The precipitating events vary between different populations,
these patients.
geographic areas and aetiologies. While in Western countries
(Europe, North and Latin America) bacterial infection, followed
Clinical and diagnostic features of ACLF
by active alcohol intake or binge are major precipitating
As discussed previously, organ failures in the presence of AD of
events,3,412,413 in Eastern countries (Asia, Pacific region) the
cirrhosis are the basis for the diagnosis of ACLF. However, in the
exacerbation of hepatitis B, followed by alcohol or bacterial
CANONIC study the presence and grading of ACLF was based on
infections are the major causes of AD and ACLF develop-
mortality and the independent association of organ dysfunc-
ment.414–416 But there are a number of other insults, which
tion/failure with mortality, which was chosen to be ≥15% at
might induce ACLF, such as superimposed infection with hepa-
28 days.3 Organ failures were defined based on a sequential
totropic viruses (especially HAV, HEV), DILI, GI bleeding, circula-
organ failure assessment (SOFA) score, which was adapted to
tory dysfunction upon different situation (e.g. surgery, LVP
patients with cirrhosis, the CLIF SOFA score (Table 9). However,
without albumin). Therefore, in general the precipitating factors
two organs received special attention, the kidney and the brain.3
might be differentiated into three major categories, hepatotoxic
In fact, it has been observed that even mild renal or brain dys-
injury (active alcohol intake or binge, DILI), immunological
function in the presence of another organ failure, is associated
insults (flairs of viral or autoimmune hepatitis, bacterial, fungal
with a significant short-term mortality and therefore defines
and viral infections, common cold, subclinical infections, etc.)
the presence of ACLF. Thus, patients with renal failure, defined
and haemodynamic derangement following procedures (haem-
as creatinine ≥2 mg/dl, were classified as ACLF grade Ia while
orrhage, surgery, LVP).
patients with a non-renal and non-cerebral organ failure
combined either with mild renal dysfunction (creatinine
Bacterial infections between 1.5 and 1.9 mg/dl) and/or grade I and II hepatic
Overall, the major precipitating factor for ACLF is bacterial encephalopathy, as well as those with cerebral failure combined
infections accounting for 30–57% of cases.409,410 The importance with mild renal dysfunction were classified as ACLF grade Ib
of bacterial infections for the development of organ failures and (Table 10).3 Thereafter, patients with two organ failures are
ACLF was also underlined by the studies of North American Con- classified as grade II ACLF, and have a 28-day mortality rate of
sortium for End-stage Liver Disease (NACSELD), who have 32%. Patients with three or more organ failures are classified
defined ACLF by the development of two organ failures in pres- as grade III ACLF and have an average 28-day mortality of 78%
ence of bacterial infections.412 By contrast, bacterial infections (Table 9). According to this EASL-CLIF definition of ACLF,
were not considered to be precipitating events for ACLF accord- approximately one-quarter of patients admitted to the hospital

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OF HEPATOLOGY
Table 9. CLIF-Sequential Organ Failure Assessment (SOFA) score (adapted from Ref. n° 3).
The CLIF-Sequential Organ Failure Assessment (SOFA) score
Organ/system 0 1 2 3 4
Liver (bilirubin mg/dl) <1.2 ≥1.2–<2.0 ≥2.0–<6.0 ≥6.0–<12.0 ≥12.0
Kidney (creatinine, mg/dl) <1.2 ≥1.2–<2.0 ≥2.0–<3.5 ≥3.5–<5.0 ≥5.0
Cerebral (HE grade) No HE Grade I Grade II Grade III Grade IV
Coagulation (INR and PLT count) <1.1 ≥1.1–<1.25 ≥1.25–<1.5 ≥1.5–<2.5 ≥2.5 or PLT ≤ 20.000/mm3
Circulation (MAP, mmHg and vasopressors) ≥70 <70 Dopamine ≤5* or Dopamine >5* or Dopamine >15*
dobutamine or E ≤0.1* or NE or E >0.1* or NE
terlipressin ≤0.1* >0.1*
Lungs
PaO2/FiO2, or >400 >300–≤400 >200–≤300 >100–≤200 ≤100
SpO2/FiO2 >512 >357–≤512 >214–≤357 >89- ≤214 ≤89
E, epinephrine; FiO2, fraction of inspired oxygen; HE, hepatic encephalopathy; NE, norepinephrine; PaO2, partial pressure of arterial oxygen; SpO2, pulse oximetric
saturation. The bold text indicates the diagnostic criteria for organ failures.
*
lg/kg/min.
Table 10. Classification and grades of ACLF (adapted from Ref. 3).
Grades of Clinical characteristics Recommendations
ACLF
No ACLF No organ failure, or single non-kidney organ failure, creatinine
<1.5 mg/dl, no HE The diagnosis of ACLF should be made in a patient with
ACLF Ia Single renal failure cirrhosis and AD (defined as the acute development or
ACLF Ib Single non-kidney organ failure, creatinine 1.5–1.9 mg/dl and/ worsening of ascites, overt encephalopathy, GI-haemor-
or HE grade 1–2 rhage, non-obstructive jaundice and/or bacterial infec-
ACLF II Two organ failures tions), when organ failure(s) involving high short-term
ACLF III Three or more organ failures
mortality develop (II-2;1).
ACLF, acute-on-chronic liver failure; HE, hepatic encephalopathy.
The diagnosis and the grading of ACLF should be based
on the assessment of organ function as defined by the
for AD of cirrhosis had ACLF at admission or develop it during
CLIF-C Organ Failure score (II-2,1).
the hospitalisation. After having simplified the CLIF SOFA score
into the CLIF Organ Failure score (Table 11), the EASL-CLIF Con- Potential precipitating factor(s), either hepatic (i.e. heavy
sortium formulated a new score, the CLIF-C ACLF score, which alcohol intake, viral hepatitis, DILI, autoimmune hepati-
enables the prediction of mortality in patients with ACLF.419 tis) and/or extrahepatic (i.e. infections haemodynamic
The CLIF-C ACLF score (Box 2) has been validated by different derangements following haemorrhage, surgery) should
independent series of patients.417,420,421 Other scores were be investigated. However, in a significant proportion of
recently proposed by the APASL ACLF Research Consortium patients, a precipitant factor may not be identified
and by the NACSELD, but they were not compared specifically (II-2,1).
with the CLIF-C-ACLF score.422,423
Management of ACLF
Box 2. CLIF-C Acute Liver Failure (ACLF) score (Ref. 419).
General management
CLIF-C ACLF score Unfortunately, there is no specific effective treatment for
ACLF.424 Therefore, treatment is currently based on organ sup-
10 x [0.033 x Clif OFs + 0.04 x Age + 0.63 x Ln(WBC) 2] port and management of associated complications. The cause
Age in years; CLIF OF score as in Table 10; sodium in mmol/L of liver injury can be specifically treated only in certain situa-
tions such as in ACLF secondary to HBV infection, as described
Table 11. Chronic Liver Failure – Organ Failure score system (adapted from Ref. 419).
Organ/system 1 point 2 points 3 points
Liver Bilirubin <6 mg/dl 6 ≤Bilirubin <12 mg/dl Bilirubin ≥12 mg/dl
Kidney Creatinine <2 mg/dl 2 Creatinine <3.5 mg/dl Creatinine ≥3.5 mg/dl or renal replacement
Brain/HE (West Haven criteria) Grade 0 Grades 1–2 Grades 3-4a
Coagulation INR <2.0 2.0 ≤INR <2.5 INR ≥2.5
Circulation MAP ≥70 mmHg MAP <70 mmHg Use of vasopressors
Lungs PaO2/FiO2 >300, PaO2/FiO2 ≤300–>200, PaO2/FiO2 ≤200b
or or or
SpO2/FiO2 >357 SpO2/FiO2 >214–≤357 SpO2/FiO2 ≤214b
Note: The bold text denotes criteria for diagnosing organ failures.
FIO2, fraction of inspired oxygen; HE, hepatic encephalopathy; INR, international normalized ratio; MAP, mean arterial pressure; PaO2, partial pressure of arterial oxygen;
SpO2, pulse oximetric saturation.
a
Patients submitted to mechanical ventilation due to HE and not to a respiratory failure were considered as presenting a cerebral failure (cerebral score = 3).
b
Other patients enrolled in the study with mechanical ventilation were considered as presenting a respiratory failure (respiratory score = 3).

later. Patients with ACLF should ideally be admitted to intensive and 13 treated with placebo, and showed significant differences
care or intermediate care units, yet this decision should be indi- in three-month survival (57% vs. 15%, respectively).426 There-
vidualised based on certain factors, particularly patients’ age fore, it seems evident that the presence of HBV infection should
and associated comorbidities. Moreover, patients suitable for be investigated in all patients with ACLF and antiviral therapy
LT should be referred to a transplant centre early in the course should be started as soon as possible.
of ACLF. Late referral may make transplantation impossible due
to the rapid evolution of ACLF in most patients.425 In patients in
Other therapies. A number of therapies have been assessed in
whom ACLF is associated with precipitating factors, such as bac-
patients with ACLF, including dexamethasone, plasma
terial infections, GI bleeding, or drug toxicity, early identifica-
exchange, chinese herbs, caspase inhibitors, mesenchymal stem
tion and management of these conditions is crucial to patient
cells transplantation, and administration of granulocyte-colony
survival. Nonetheless, it should be emphasised that this early
stimulating factor (G-CSF).430–432 In most cases, the information
treatment of triggering factors may not prevent the progression
is still very preliminary and no recommendations can be made
of ACLF in all patients. Meanwhile, as already stated, in approx-
regarding their potential use in clinical practice. However, a
imately half of patients with ACLF a precipitating factor cannot
note on G-CSF seems pertinent because this approach has been
be identified.3 Organ support is very important in the manage-
assessed in an RCT.432 The rationale behind this treatment
ment of patients with ACLF.424 Haemodynamic function should
seems to be the mobilisation of stem cells from the bone mar-
be monitored and vasopressor therapy administered in case of
row and their engraftment within the liver, although other ben-
marked arterial hypotension. Hepatic encephalopathy should
eficial effects may also occur. The only RCT evaluating this
be treated early with standard therapy. Special care should be
therapy included 47 patients with ACLF, as defined by the APASL
taken to preserve airway patency to prevent aspiration pneu-
criteria, 23 treated with G-CSF (12 doses of 5 lg/kg subcuta-
monia. In patients with coagulation failure, either because of
neously) and 24 treated with placebo in a double-blind manner.
impairment of coagulation factors or low platelet count, substi-
The main findings were an improvement in 60-day survival in
tutive therapy should be given only if there is clinically signifi-
the G-CSF group vs. the placebo group (66% vs. 26%, respec-
cant bleeding. If there is respiratory failure, patients should be
tively; p = 0.001) along with a reduction in Child-Pugh, SOFA,
given oxygen therapy and ventilation, if required. Finally, if
and MELD scores and a decrease in the occurrence of HRS, hep-
there is kidney failure its cause should be identified and man-
atic encephalopathy and sepsis in G-CSF treated patients.
aged accordingly. Volume expansion should be given to patients
Although these results are promising, additional studies in a lar-
with fluid loss or in the setting of SBP. Excessive volume expan-
ger number of patients are needed.
sion should be avoided. Patients meeting the criteria of AKI-HRS
should be treated with terlipressin and albumin or nore-
pinephrine, if terlipressin is not available. Patients with sus- Liver transplantation. Liver transplantation is theoretically the
pected ATN should be treated with RRT if they meet criteria definitive treatment for ACLF because it allows the cure of ACLF
for this treatment.392 syndrome as well as the underlying liver disease.425 However,
some important issues regarding LT for ACLF deserve a com-
Specific therapies ment, particularly the accessibility of patients to LT, evaluation
Liver support systems. Extracorporeal liver support systems, par- of candidate subjects, the outcomes of LT on survival, and futility.
ticularly albumin dialysis (MARS system) and fractionated The accessibility of patients with ALCF to LT is probably
plasma separation and adsorption (Prometheus system) have decreased compared to that of patients with other indications
been evaluated as therapies for ACLF. These systems remove for LT, because patients with ACLF have a high mortality rate
albumin-bound substances and other substances that accumu- after diagnosis of the condition. Early referral to transplant cen-
late in the context of ACLF and may have deleterious effects tres is therefore crucial. Then, because ACLF is a rapidly evolving
on the function of different organs. Both methods have been syndrome, candidate patients need to be submitted to a ‘‘fast-
evaluated in large RCTs in patients with ACLF and no significant track” clinical evaluation of organ function and potential comor-
effects on survival could be demonstrated.388,389 It should be bidities that could contraindicate LT. Data on outcome of
emphasised however, that the definition of ACLF in both trials patients with ACLF treated with liver LT are scarce but nonethe-
was different than the current definition of ACLF based on the less, patient survival at three-months after LT is about 80%,
CANONIC study.3 Moreover, a sub-analysis of the Prometheus much higher than what would be anticipated if patients were
study showed a beneficial effect on survival in patients with not transplanted.425,433,434 Almost all patients with ACLF-3
MELD score higher than 30.389 This finding deserves further developed complications after LT, especially pulmonary, renal
investigation. Nonetheless, based on the results of available and infectious, compared to patients with no ACLF, or ACLF-1
RCTs, extracorporeal liver support systems do not improve sur- and -2. This emphasises the need for special management when
vival of patients with ACLF and should not be recommended in transplanting patients with ACLF-3, with repeated systematic
this indication. screening for infection and careful monitoring of renal and res-
piratory parameters.434 Another point is that some patients
Antiviral therapy for chronic hepatitis B. Reactivation of hepatitis with ACLF are potentially too sick for LT. In the context of scar-
B is a very common cause of ACLF in certain areas of the world, city of donor livers, the potential benefit of LT for patients with
particularly in southwest Asia.414 A number of non-randomised ACLF must be balanced with the rationing. Thus, more data is
studies and an RCT have shown that treatment with lamivudine, needed to determine medical futility in patients with
tenofovir or entecavir is associated with inhibition of HBV repli- ALCF.425,434 However, if LT is contraindicated or not available
cation, improvement of liver function, and higher survival in for patients with organ failures ≥4 or CLIF-C ACLFs >64 at days
patients with ACLF secondary to hepatitis B infection.426–429 3–7 after diagnosis of ACLF-3, the intensive organ support
The only RCT included 24 patients, 14 treated with tenofovir should be discontinued owing to futility.425

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after stimulation by the standard dose- or low dose-short Syn-
Recommendations acthen tests can be utilised.447 The consensus statements from
the American College of Critical Care Medicine recommend
referring to a delta total serum cortisol <250 nmol/L (9 lg/dl)
At present, there is no specific therapy for ACLF aside
after adrenocorticotrophic hormone administration or a random
from antiviral therapy in patients with ACLF due to reac-
total cortisol <276 nmol/L (10 lg/dl) in critically ill patients.436
tivation of HBV infection. Treatment of ACLF should be
There is no reason for not employing these indications in
based on organ support and management of precipitants
patients with cirrhosis. However, the diagnosis of RAI based
(see point below) and associated complications. Patients
on serum total cortisol concentration, which is measured by
should be treated in intermediate care or intensive care
standard assays, may be flawed by the reduced serum levels
settings. Organ function, particularly, liver, kidney, brain,
of cortisol binding globulin (CBG) and albumin frequently seen
lung, coagulation, and circulation should be monitored
in patients with cirrhosis. This may lead to an overestimation
frequently and carefully throughout hospitalisation, as
of RAI, as more than 90% of circulating cortisol is bound to these
ACLF is a dynamic condition. However, monitoring and
proteins.448 The assessment of serum-free cortisol concentra-
management should be individualised according to
tion would overcome this limitation. Serum-free cortisol levels
specific circumstances, mainly patients’ age and comor-
<50 nmol/L at baseline, or <86 nmol/L (9 lg/dl) after adrenocor-
bidities (III, 1).
ticotrophic hormone suggest the presence of RAI in critically ill
Early identification and treatment of precipitating fac- patients.449 By comparing RAI diagnosis in clinically stable
tors of ACLF, particularly bacterial infections, are recom- patients with cirrhosis based on either total or free plasma cor-
mended. However, in some patients ACLF progresses tisol, a clear discrepancy emerged, as the prevalence of RAI was
despite treatment of precipitating factors (III;1). 58% using total cortisol criteria and 12% using free cortisol with
Administration of nucleoside analogues (tenofovir, ente- a peak plasma level <33 nmol/ after stimulation.450 Unfortu-
cavir) should be instituted as early as possible in patients nately, the methods for determining free cortisol are complex
with ACLF due to HBV infection (I;1). and expensive, so they are not used in routine clinical practice.
The surrogate methods that have been proposed for the calcula-
Early referral of patients with ACLF to liver transplant
tion of plasma free cortisol451,452 do not seem to be fully reliable
centres for immediate evaluation is recommended (II-3;1).
in patients with cirrhosis.450 For these reasons, salivary cortisol
Withdrawal of ongoing intensive care support can be has received attention, as it correlates with free cortisol levels
suggested in patients, who are not candidates for LT, irrespective of the concentration of binding proteins.453,454
with four or more organ failures after one week of ade- Baseline salivary cortisol <1.8 ng/ml (<0.18 lg/dl) or an incre-
quate intensive treatment (II-2, 2). ment <3 ng/ml (0.3 lg/dl)453 following a standard-dose short
Despite promising results, the administration of G-CSF Synacthen test are suggestive of RAI. However, even the evalu-
can not be recommended at present (1;2). ation of salivary cortisol is not without shortcomings.454
Relative adrenal insufficiency Recommendation

Definition and pathophysiology
Relative adrenal insufficiency (RAI) is a condition of inadequate
cortisol response to stress in the setting of critical illness,435 also Diagnosis of RAI should be based on a delta serum total
named as ‘‘Critical Illness Related Corticosteroid Insufficiency” cortisol after 250 lg corticotropin injection of <248
(CIRCI).436 RAI has also been described in patients with cirrhosis nmol/L (9 lg/dl) or a random total cortisol of <276
and, although it is mainly present in critically ill patients with nmol/L (<10 lg/dl) (II-2,1). As serum free cortisol con-
sepsis or septic shock (68.9%), it also affects non-critically ill cir- centration can be influenced by the reduced serum levels
rhotic patients (41.8%), including those with compensated cir- of CBG and albumin frequently seen in patients with cir-
rhosis.437–442 The pathophysiology of RAI in cirrhosis is not rhosis, salivary cortisol determination can be preferred
well defined. Suppression of the hypothalamic-pituitaryadrenal (II-2;2).
axis activity, reduced effective volemia, which may impair adre-
nal perfusion, and both impaired cholesterol synthesis and
enhanced pro-inflammatory cytokine production likely con- Treatment of relative adrenal insufficiency
tribute to impair adrenal steroidogenesis.443,444 Adrenal dys- It is not known whether cortisol supplementation in clinically
function blunts the vascular effect of angiotensin II, stable cirrhosis with RAI is of any value. Two studies have eval-
norepinephrine and vasopressin, leading to further sympathetic uated the effects of treating RAI in critically ill patients with cir-
nervous system activity.445 These effects would worsen the car- rhosis. In one study 17 patients with cirrhosis and sepsis, in
dio-circulatory dysfunction of advanced cirrhosis, and favour whom RAI was diagnosed, received i.v. hydrocortisone (50 mg/
gut bacterial overgrowth, and hence BT, by impairing intestinal 6h), and were compared with 50 consecutive patients with cir-
motility.445 This explains why RAI in decompensated cirrhosis is rhosis and septic shock who had previously been admitted to
associated with a higher probability of severe sepsis and type-1 the same ICU but did not receive steroids. A higher rate of shock
HRS, and higher short-term mortality.437,446 resolution, survival in the ICU and hospital survival were seen in
the patients treated with hydrocortisone.455 In the second
study, 57 patients with cirrhosis, septic shock and RAI were ran-
Diagnosis domised to receive either i.v. 50 mg of hydrocortisone or normal
The diagnosis of RAI is influenced by the method employed, as saline every 6 h until haemodynamic stability was achieved, fol-
the measurement of serum total cortisol, either at baseline or lowed by steroid tapering over eight days. Lower vasopressor

doses and higher rates of shock reversal were seen in patients ular systolic function and facilitates the assessment of systolic
who received hydrocortisone. However, 28-day mortality did dysfunction at rest,468,469 as well as having prognostic impor-
not differ between the two groups. Moreover, shock relapse tance in heart failure.470 Studies of strain imaging in cirrhosis
and GI bleeding occurred more often in the hydrocortisone have demonstrated variable results; some showing impaired
group.456 systolic strain in patients compared with healthy controls, albeit
with no correlation to Child-Pugh score.471,472 Others demon-
strate systolic strain within normal range and not influenced
by the presence of ascites.473,474 However, interestingly, when
Recommendation patients undergo LT, the systolic strain improves.471
At present, hydrocortisone treatment (at a dose of 50 Characterisation of diastolic dysfunction in cirrhotic

mg/6h) of RAI cannot be recommended (I-2). cardiomyopathy
Numerous echocardiographic criteria along with transmitral
Doppler evaluation have been used to characterise diastolic dys-
function including, early diastolic/atrial filling ratio (E/A), early
Cardiopulmonary complications
diastolic filling/mitral annular velocity (E/e’) and tricuspid sys-
Cirrhotic cardiomyopathy
tolic jet velocity. Such measurements are influenced by the
Definition and pathophysiology
pre- and afterload changes of portal hypertension. The latest
Cirrhotic cardiomyopathy (CCM) refers to chronic cardiac dys-
American Society of Echocardiography (ASE) and European
function in a patient with established cirrhosis, characterised
Association of Cardiovascular Imaging guidelines for the evalu-
by a blunted contractile response to stress (pharmacologi-
ation of diastolic dysfunction recommend the following criteria
cal/surgical or inflammatory) and an altered diastolic relaxation,
based on a normal LVEF (often the case in cirrhosis):475
often associated with electrophysiological abnormalities such as
prolongation of the QTc interval. These phenomena occur in the
i. Average E/e’>14
absence of any other cardiac disease.457 Systemic inflammation
ii. Septal e’ velocity <7 cm/s OR Lateral e’ velocity <10 cm/s
is thought to be key in inducing myocardial dysfunction associ-
iii. Tricuspid velocity >2.8 m/s
ated with impaired diastolic relaxation and decreased left ven-
iv. Left atrial volume index (LAVI) >34 ml/m2
tricular ejection fraction, however, there are few controlled
studies.193,458,459 Shear stress generated by portal hypertension
exhibiting mechanical forces on myocardial fibres, may also Diastolic dysfunction translates to impaired relaxation of the
play a part.460 CCM is largely subclinical but its presence does left ventricle, abnormal filling of the left atrium, and a higher
influence prognosis in advanced disease,461 and it certainly left atrial volume. Indeed, increased LAVI has been associated
impacts on the course of interventions such as TIPS and LT.462 with greater risk of heart failure in ischaemic cardiac disease.476
Based on these guidelines, diastolic dysfunction is classified as:
Diagnosis grade I if one of the three principle criteria (1,3 and 4 above) are
Characterisation of systolic dysfunction in cirrhotic met; and grade II if two or more of the criteria are met.
cardiomyopathy However, there is heterogeneity in descriptions of the preva-
Systolic dysfunction refers to impaired left ventricle contractile lence of diastolic dysfunction in cirrhosis, in part reflecting the
responses to stress on echo, translating to a resting left ventric- different echo techniques and/or diagnostic criteria applied,
ular ejection fraction (LVEF) <55%. For most patients with cirrho- and the influence of vasoactive agents such as beta-blockers
sis, the resting systolic function is normal or even increased, due and terlipressin.
to the hyperdynamic circulation and reduced afterload to main- Several studies using an E/A ratio of ≤1 criteria have demon-
tain cardiac output. To investigate systolic dysfunction in cirrho- strated left atrial enlargement in patients with ascites and
sis, it is necessary to induce circulatory stress either advanced disease.464,477 Therapeutic paracentesis improves E/A
pharmacologically or through exercise. Systolic dysfunction then ratio and importantly, in all studies, there is no relation to aetiol-
manifests as a lack of an appropriate left ventricular contractile ogy.478 In patients treated with TIPS there was no relation to aeti-
response to the applied stress. As disease advances, the progres- ology, but diastolic dysfunction does show a positive correlation
sive reduction in peripheral vascular resistance unmasks systolic with higher MELD scores.462,479 A further study using E/e’ ratio to
dysfunction. Early studies used exercise stress testing to demon- define diastolic dysfunction in patients with ascites and elevated
strate a lack of increment in cardiac output or LVEF463,464 and plasma renin, demonstrated that an increased E/e’ was an inde-
this was even shown when noradrenaline levels were increased, pendent predictor of development of HRS type 1 and one-year
suggesting loss of sympathetic responsiveness.465 More recent mortality.480 By contrast, other studies fail to show a clear rela-
studies used pharmacological stress echo to show a blunted tionship with disease severity or survival,460,472,481 albeit in two
response.466 However, other studies using cardiac MRI, have studies echo criteria are not specified.460,472 Studies using the
shown normal chronotropic and inotropic responses suggesting LAVI criteria suggest a closer association between left atrial
the techniques used may give rise to variability.467 enlargement and Child-Pugh C disease.482
Newer techniques such as cardiac MRI with ‘T1 mapping’ and
Myocardial strain imaging for assessing systolic dysfunction Late Gadolinium enhancement are being deployed to assess
Myocardial strain imaging is a more recent echocardiographic whether fibrosis or oedema modulates myocardial function in
technique evaluating the degree of shortening of myocardial conditions such as amyloid and Fabry disease.483 Literature on
muscle fibres (‘strain’) influencing cardiac wall motion. The using such techniques in liver disease are very limited. A recent
measurement of left ventricular global longitudinal systolic study in patients with chronic hepatitis C showed no significant
strain (GLS) is believed to be a sensitive marker of left ventric- differences in echo parameters to controls, but demonstrated

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OF HEPATOLOGY
lower post-contrast myocardial T1 time and higher partition the physiological stress of LT on patients with pre-existing car-
coefficients, indicative of diffuse myocardial fibrosis.484 diac dysfunction is heterogenous, largely because of the differ-
ent echo criteria and thresholds applied.
Natural history One study in 173 transplant recipients assessed systolic
Impact of disease related physiological stress: sepsis, (resting ejection fraction <55%) and diastolic (E/A ratio <1 or a
decompensation and/or GI bleeding deceleration time >200 ms) dysfunction and reported it occur-
There are limited studies of cardiac assessment during acute cir- ring in 2% and 43% of patients, respectively. Whilst patients with
rhosis decompensation and associated haemodynamic instabil- diastolic dysfunction were older, interestingly, outcomes were
ity. In a seminal study of acute cirrhosis decompensation with not influenced by the presence of diastolic dysfunction.494 By
SBP, a subgroup with HRS were shown to have lower cardiac contrast, another study used echo and brain natriuretic peptide
outputs at diagnosis and this correlated inversely with high (BNP) levels to grade severity of cardiac dysfunction. Those
inflammatory indices.193 A follow-on study by the same group patients with higher BNP levels (>391) on day one tended to
identified that patients with HRS had cardiac outputs that were have higher mortality and longer dialysis requirements post
further reduced at follow-up, compared to patients who do not transplantation. Of these, a subset with BNP levels >567 had
develop HRS after SBP, and these patients had higher plasma ejection fractions <50%, and some of these died of cardiogenic
noradrenaline and renin.485 Other studies recapitulate this with shock within 72 h post-transplant. Autopsy in these patients
a demonstration of reduced kidney blood flow and importantly, showed diffuse myocardial fibrosis. In the main, BNP levels
suggest those with low cardiac index, also have increased tended to decrease towards normal values over a week.495
mortality.192,485 A further study performed a detailed echo assessment,
In relation to systemic inflammation and sepsis, one study including myocardial strain assessment with speckle tracking,
showed lipopolysaccharide binding protein (LBP) levels (a sur- in patients undergoing LT compared to non-transplanted
rogate for BT and lipopolysaccharide) in patients with ascites patients over a median follow-up of 18 months. Whilst patients
to be associated with significant diastolic dysfunction and left pre-transplant had increased left ventricular mass and diastolic
atrial enlargement. The E/e’ ratio in these patients correlated dysfunction, following transplantation, there was a significant
with LBP levels. This data supports findings from experimental improvement in systolic strain and reduced left ventricular
studies, which have shown a role for inflammation, signalling mass. Conversely, cirrhosis patients who were not transplanted
through the inflammasome and macrophage activation, as key had an increase in left ventricular mass, albeit systolic strain did
pathological processes related to myocardial dysfunction.486–488 not change significantly.471 This implies that some of the patho-
Acute GI bleeding in cirrhosis is understandably associated physiological changes in CCM, such as increased left ventricular
with significant haemodynamic disturbances and has not been mass and size, are reversible with resolution of the disease.
studied systematically in relation to cardiac function. Data However, studies with comprehensive characterisation of car-
assessing chronotropic function suggest the QTc interval is diac function post transplantation are limited.
increased in cirrhotic patients during an acute bleeding episode
compared to non-cirrhotic patients, and that this is associated Prognosis for cirrhotic cardiomyopathy
with higher MELD scores and independently predicts sur- Data relating cardiac dysfunction (especially diastolic dysfunc-
vival.489 This contrasts with a more recent study that fails to tion) with survival is variable. Some prospective studies, despite
demonstrate a clear link between QTc prolongation and mortal- detailed evaluation of patients, including those with ascites and
ity.490 Possible reasons for this heterogeneity in outcomes are using speckle tracking, show no relation between cardiac dys-
the variable nature of vasoactive agents and their respective function and survival, even among more decompensated
doses required for the control of bleeding in these studies. For patients.473,496 Many of the patients in these studies have evi-
example, one study showed terlirpessin decreased cardiac out- dence of diastolic dysfunction and some with even advanced
put by 17% and the reduction in wall motion after terlipressin grade II diastolic dysfunction albeit the GLS values in these
correlated with the Child-Pugh score.491 studies are within the normal range.
Conversely, other studies suggest an association between
Impact of interventions on cirrhotic cardiomyopathy presence of diastolic dysfunction and higher two-year mortality,
TIPS. Cardiac reserve is a major clinical consideration for elective with diastolic dysfunction ranging from 38–67%, especially in
TIPS placement and a 2D echo to assess LVEF is standard prac- patients with severe ascites.461,497 Indeed, in one such study, a
tice. Despite this, some patients do have cardiac decompensa- multivariate analysis showed left ventricular diastolic dysfunc-
tion post TIPS insertion. Several studies show an association tion was an independent predictor of mortality.461 Another
between presence of diastolic dysfunction at the time of TIPS study followed 80 patients to assess one-year mortality, finding
and poor survival.462,479 By contrast, others have not shown 46% had diastolic dysfunction on echo criteria and about half of
any difference in survival between patients with and without these had grade II dysfunction, in whom mean arterial blood
diastolic dysfunction at the time of TIPS.492 However, uniformly, pressure was lower and MELD score higher than grade I
studies suggest an increase in left ventricular and atrial volume patients. The presence of diastolic dysfunction was associated
over time, implying that such patients may be at greater risk of with a higher degree of ascites and plasma renin levels and
future heart failure, based on literature for ischaemic heart dis- 38% of these patients developed criteria for HRS type I. Survival
ease and dilated cardiomyopathy.476,493 was 95% in those without diastolic dysfunction, compared to
79% in those with grade I dysfunction and 39% with grade II
Liver transplantation. Just as data on the effects of cirrhosis com- diastolic dysfunction. E/e’ ratio was an independent predictor
plications on cardiac function are variable, data on the impact of of survival.480

complications may occur in patients with chronic liver disease:

Recommendations pneumonia, hepatic hydrotorax, HPS and PPHT. HPS is defined
as a disorder in pulmonary oxygenation, caused by intrapul-
monary vasodilatation and, less commonly, by pleural and pul-
Evaluation of cirrhosis patients with echocardiography
monary arteriovenous communications occurring in the clinical
should be performed with dynamic stress testing either
setting of portal hypertension.498,499 It is most commonly
pharmacologically, or through exercise, given that sys-
diagnosed in patients with cirrhosis498,499 and portal hyperten-
tolic dysfunction may be masked by the hyperdynamic
sion500 but, it has also been described in patients with pre-hepatic
circulation and reduced afterload. Failure to increment
portal hypertension,501 with venous obstruction but without
cardiac output after physiological/pharmacological
cirrhosis, and even in patients with acute or chronic hepatitis500
stress (and in the absence of influence of beta-blockade)
(Table 12). A severe impairment of liver function and a specific
indicates systolic dysfunction (II-1;1).
aetiology of liver disease are not needed for the development of
Myocardial strain imaging and assessment of GLS may HPS,498 based on the profiles of the patients studied. In terms of
serve as a sensitive marker of left ventricular systolic prevalence, HPS has been reported in 10% of patients with
function and facilitate its assessment at rest and in chronic viral hepatitis in 15–23% of those with cirrhosis and
decompensated patients (II-2;2). Cardiac MRI may also in 28% of those with Budd-Chiari syndrome.502–504 However,
identify structural changes. However, with all these the prevalence of HPS reported in patients with cirrhosis
techniques, there is the need for more controlled studies undergoing LT evaluation ranges from 5–32%,504–508 while
and correlation with clinical endpoints (III;2). intrapulmonary vascular dilatation (IPVD) can be detected by
Diastolic dysfunction may occur as an early sign of car- echocardiography in 50–60% of cirrhosis patients undergoing
diomyopathy in the setting of normal systolic function, LT evaluation. No relationship seems to exist between HPS
and should be diagnosed using the recent ASE guideli- and CCM.504 The clinical manifestations of HPS in patients
nes, namely: Average E/e’>14; Tricuspid velocity >2.8 with chronic liver disease primarily involve dyspnoea and
m/s and LAVI >34 ml/m2 (II-1;1). platypnoea.498,502,506 Dyspnoea is the most common respiratory
complaint in patients with HPS, but it is non-specific. Its onset is
In patients with AD of cirrhosis, reduced cardiac output
insidious, usually occurring on exertion. Platypnoea, which is a
(as a manifestation of CCM) is of prognostic significance
shortness of breath exacerbated by sitting up and improved by
as it is associated with the development of AKI (specifi-
lying supine, is a less sensitive but a more specific finding in
cally hepatorenal dysfunction) after infections such as
these patients. Hypoxemia with exertion or at rest is common
SBP (II-1;1).
and it is exacerbated in the upright position (orthodeoxia).
Prolongation of the QTc interval is common in cirrhosis There are no signs or hallmarks of HPS on physical examination.
and can be evaluated since it may indicate a poor out- However, tachypnoea and polypnoea, digital clubbing and/or
come. Agents that can prolong the QT interval should cyanosis in patients with the hallmarks of chronic liver disease
be used cautiously (II-2;2). suggest the presence of HPS.498,502,506
Detailed functional cardiac characterisation should be
Pathophysiology
part of the assessment for TIPS insertion (II-2;2) or LT
The pathophysiology of HPS is characterised by an IPVD occur-
(II-1;1).
ring within the pulmonary arterial circulation. This vascular
Standardized criteria and protocols for the assessment of abnormality consists of diffuse or localised abnormal dilated
systolic and diastolic function in cirrhosis are needed pulmonary capillaries and, less commonly, pleural and pul-
(II-2;2). monary arteriovenous communications,509 which result in
impaired oxygenation of venous blood as it passes through
the pulmonary circulation. IPVD impairs ventilatory/perfusion
(V/Q) ratio and may result in anatomic and functional shunt
Hepato-pulmonary syndrome leading to hypoxaemia (Fig. 10). In patients with advanced liver
Definitions and clinical manifestations cirrhosis this leads to a subtle increase in intrapulmonary blood
The association of chronic liver disease with respiratory symp- shunting, which is more pronounced in patients with HPS. The
toms and hypoxia is well recognised. Four main pulmonary consequent increase of shunting and V/Q mismatch in the
Table 12. Diagnostic criteria of hepatopulmonary syndrome.

Hypoxia with partial pressure of oxygen <80 mmHg or alveolar–arterial oxygen gradient ≥15 mmHg in ambient air (≥20 mmHg in patients older than
65 years).
Pulmonary vascular defect with positive findings on contrast-enhanced echocardiography or abnormal uptake in the brain (>6%) with radioactive
lung-perfusion scanning
Commonly in presence of portal hypertension, and in particular:
- hepatic portal hypertension with underlying cirrhosis
- pre-hepatic or hepatic portal hypertension in patients without underlying cirrhosis
Less commonly in presence of:
- acute liver failure, chronic hepatitis
All criteria were determined by means of positive contrast-enhanced echocardiography (i.e., microbubble opacification of the left heart chambers three to six cycles after
right atrial passage). The abbreviated formula for the alveolar–arterial gradient is as follows: PaO2 PaO2 = (FIO2 [Patm–PH2O] [PaCO2/0.8]) PaO2, where PaO2 denotes
partial pressure of alveolar oxygen, PaO2 partial pressure of arterial oxygen, FIO2 fraction of inspired oxygen, Patm atmospheric pressure, PH2O partial pressure of water
vapor at body temperature, and PaCO2 partial pressure of arterial carbon dioxide (0.8 corresponds to the standard gas-exchange respiratory ratio at rest); the normal range
is 4 to 8 mmHg.

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OF HEPATOLOGY
CX3CL1 and vascular endothelial growth factor (VEGF) A, pro-
Normal HPS
duced by circulating monocytes, also contribute to angiogene-
sis, recently recognised as a further pathogenetic factor of
pulmonary IPVD in experimental HPS.520–522 A downregulation
of miRNA-199 a-5p has recently been described as a contribu-
O2 Alveol O2 tory mechanism of pulmonary microvascular endothelial cell
proliferation and thus pathogenesis of HPS.523 Polymorphisms
in genes involved in the regulation of angiogenesis have also
been associated with the risk of HPS in patients with cirrho-
Capillary sis524 (Fig. 11). Finally, it has recently been observed that rosu-
8µ
vastatin, by down-regulating protein expression of nuclear
factor kappa B and VEGF-1,2 and Rho-associated A kinase,
500 µ may improve the intrapulmonary angiogenesis and the
alveolar-arterial oxygen pressure gradient in common bile duct
Fig. 10. The pathophysiology of hepatopulmonary syndrome (adapted
from Ref. 498). HPS, hepatopulmonary syndrome.
ligation rats.525
Diagnosis
upright position is the cause of the orthodeoxia.510 The patho-
In patients with portal hypertension and the clinical suspicion
genesis of IPVD is probably multifactorial (Fig. 11). The release
of HPS partial pressure of oxygen (PaO2) in arterial blood gas
of nitric oxide, which is a potent vasodilator, plays a critical role
(ABG) should be assessed. A PaO2 lower than 80 mmHg and or
in the development of HPS. The increased release of nitric oxide
an alveolar-arterial oxygen gradient (P[A-a]O2) ≥15 mmHg
in the pulmonary circulation is related to an increased expres-
while breathing ambient air at sea level should lead to further
sion and activity of two isoforms of nitric oxide synthase
investigations (Table 12). For adults ≥65 years a P[A-a]O2 ≥20
(NOS), the endothelial NOS (eNOS) and the inducible NOS
mmHg cut-off is used.526 However, it should be highlighted that
(iNOS).511–516 Meanwhile, BT and the BT-related endotoxaemia
although these criteria are well established, enabling one to
and pro-inflammatory response also contribute to the accumu-
unify the diagnostic methods and thus to better understand
lation of macrophages in the pulmonary microvasculature.517
the disease, they are based on a consensus of experts. Pulse
Endothelial activation of fractalkine (CX3CL1), a chemokine, in
oximetry indirectly measures oxygen saturation (SpO2), it is
the lung may favour the adherence of monocytes in the pul-
non-invasive and may be useful in the diagnosis of HPS in adults
monary microcirculation.518 Monocytes express iNOS and pro-
since a SpO2 <96% was found to be highly sensitive (100%) and
duce heme oxygenase-1, leading to increased carbon
specific (88%) for detecting HPS in patients with a PaO2 <70
monoxide production, further enhancing vasodilatation.519
• Portosystemic shunt
• Hepatic injury/failure • Hyperdynamic circulation
• Portal hypertension • Bacterial translocation
Increased release of Systemic

ET - 1 inflammation
Pulmonary capillary
ETB
receptor
Endothelial activation of CX3CL1 Recruitment of
CX3CL1 macrophages
Endothelial cell Endothelial cell in the lungs
Increased adherence of
macrophages/monocytes to Macrophage
Increased expression and endothelial cells
activity of eNOS
Genetic factors VFG-A release
Endothelial cell
Increased release of Endothelial cell Increased expression and

NO proliferation activity of iNOS and HO
ANGIOGENESIS Increased release of

NO and CO
VASODILATION HEPATOPULMONARY VASODILATION

SYNDROME
Fig. 11. The pathogenesis of hepatopulmonary syndrome. ET, endothelin; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; NO,
nitric oxide; HO, Heme oxygenase-1; CO, carbon monoxide; CX3CL1, fractalkine; VGF-A, vascular endothelial growth factor A.

mmHg, limiting ABG testing to only 14% of patients.527 The cardiography nor MAA scan can differentiate discrete arteriove-
validity of this non-invasive approach was not confirmed, nous communications from diffuse precapillary and capillary
recently, in paediatric patients with HPS.528 Serial SpO2 mea- dilatations or intracardiac shunt. The former distinction can be
surements may be useful to monitor impaired oxygenation over made by means of pulmonary angiography. The latter distinc-
time in patients with HPS. The ABG is essential for the staging of tion can be made by means of transoesophageal contrast-
the severity of HPS. HPS can be categorised as mild (PaO2 ≥80 enhanced echocardiography that directly reveals the intra-atrial
mmHg), moderate (PaO2 60–79 mmHg), severe (PaO2 50–59 septum. Pulmonary angiography should not be performed in all
mmHg), and very severe (PaO2 <50 mmHg).498,500,501,503 patients with suspected HPS, but only in: a) patients with the
Recently, it has been observed that HPS is associated with ele- severe hypoxaemia (PaO2 <60 mmHg) poorly responsive to
vated von Willenbrand factor antigen (vWF-Ag) levels. Thus, administration of 100% oxygen, and b) patients strongly sus-
vWF-Ag has been proposed as a potentially useful screening tool pected (by means of a CT chest scan) of having arteriovenous
for early detection of HPS, but further studies are needed to val- communications that would be amenable to embolisation.
idate it.529 The chest X ray is usually non-specific, nevertheless,
it can be used to effectively rule out other concomitant pul-
Recommendations
monary diseases since only a mild interstitial pattern in the
lower part of the lungs may be found, because of pulmonary
vasodilatation.498,500,501,503 A decrease in the single-breath dif- In presence of tachypnoea and polypnoea, digital club-
fusing capacity for carbon monoxide is the only alteration of bing and/or cyanosis in a patient with the hallmarks of
the routine pulmonary function test that is frequently and con- chronic liver disease, HPS should be suspected and
sistently abnormal in patients with HPS. However, it is not investigated (II-2,1).
specific and it may not normalise after LT.498,500,501,503 All the Pulse oximetry is the screening tool for HPS in adult
other respiratory function tests are non-specific, showing nor- patients, but not in paediatric patients. For patients with
mal or reduced forced vital capacity or maximum forced expira- SpO2 <96%, ABG analysis should be performed. A PaO2
tory volume during the first second (FEV1). Thus, they can only lower than 80 mmHg and or an alveolar-arterial oxygen
be used to rule out other concomitant pulmonary diseases. Tho- gradient (P[A-a]O2) ≥15 mmHg while breathing ambient
racic CT scans have also been proposed as a complementary air, should lead to further investigations. For adults ≥65
technique to rule out another underlying pulmonary pathol- years a P[A-a]O2 ≥20 mmHg cut-off should be used (II-2,1).
ogy,498,499 although there is little information regarding their
The use of contrast (microbubble) echocardiography to
specific role in the diagnosis of HPS. It has been suggested that
characterise HPS is recommended (II-2;1).
thoracic CT scans can be useful to measure the calibre of the
peripheral arteries and the bronchial/arterial relationship.530,531 Trans-oesophageal contrast-enhanced echocardiography
Furthermore, CT scanning makes it possible to define the vascu- can be performed to exclude definitively intra-cardiac
lar pattern of HPS in a similar manner to arteriography by shunts, albeit this technique is not devoid of risks
detecting pleural and pulmonary arteriovenous communica- (II-2;2).
tions. Contrast-enhanced transthoracic echocardiography with An MAA scan should be performed as a complementary
saline (shaken to produce microbubbles >10 lm in diameter) tool to quantify the degree of shunting in patients with
is the most useful method to detect pulmonary vascular dilata- severe hypoxaemia and coexistent intrinsic lung disease,
tion. After the administration of agitated saline in a peripheral or to assess the prognosis in patients with HPS and very
vein, microbubble opacification of the left atrium within three severe hypoxaemia (PaO2 <50 mmHg) (II-2;1).
to six cardiac cycles after right-atrial opacification indicates
microbubble passage through an abnormally dilated vascular Neither contrast echocardiography nor MAA scan can
bed, since microbubbles do not pass through normal capillar- definitively differentiate discrete arteriovenous commu-
ies.532 The injection of technetium-99 m–labeled macro-aggre- nications from diffuse precapillary and capillary dilata-
gated albumin (MAA) in the peripheral vein for lung scanning tions or cardiac shunts. Pulmonary angiography should
(MAA scan) is a potential alternative diagnostic procedure be performed only in patients with the severe hypox-
although it is more invasive and less sensitive. Particles, with aemia (PaO2 <60 mmHg), poorly responsive to adminis-
a 20–50 lm size, escape through the abnormal pulmonary cap- tration of 100% oxygen, and in whom there is a strong
illaries and stay in downstream capillary beds supplied by sys- suspicion of arteriovenous communications that are
temic arteries, such as the brain, kidneys, and spleen. amenable to embolisation (II-2;1).
Quantitative imaging of the MAA scan in the brain and lung
enables calculation of the degree of shunting.533,534 The mea- Natural history
surement of shunting with MAA scans may be useful as a com- The natural history of IPVD as well as of HPS is still unclear.
plementary diagnostic tool in patients with HPS in two clinical Most patients with IPVD maintain a normal gas exchange over
situations. Firstly, in patients with a severe hypoxaemia and a time, and it is not clear the reason why a subset of patients with
coexistent HPS and intrinsic lung disease since a shunting >6% IPVD develops HPS.537 A diagnosis of HPS is associated with a
at MAA scan proves the major contribution of HPS to hypox- poor outcome in terms of both survival and quality of
aemia. Secondly, in patients with HPS and very severe hypox- life.505,507,508 Regarding survival, it should be highlighted that
aemia (PaO2 <50 mmHg), since the presence of shunting >20% in patients undergoing evaluation for LT, the mortality rate
is associated with a poor outcome after LT.535 Despite the was almost double in patients with HPS compared to patients
potential role of lung perfusion scintigraphy for prognostic use with cirrhosis without HPS, independent of other potential pre-
in patients with cirrhosis and IPVD, its diagnostic accuracy for dictors of mortality such as age, MELD score and comorbidi-
HPS remains to be established.536 Finally, neither constrast eco- ties.505 In patients with cirrhosis and HPS, who were not

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OF HEPATOLOGY
evaluated for LT, the five-year survival rate was 23% while it was was associated with a large shunting at MAA scan, was found
63% in patients with cirrhosis without HPS who were matched to be a very strong predictor of mortality after LT.535 In 2007,
for the aetiology and severity of cirrhosis according to the five years after the introduction of MELD in US, the United Net-
Child-Pugh classification, age, and MELD score.503 Survival was work for Organ Sharing (UNOS) recommended assigning an
significantly worse among patients with HPS and a PaO2 of less MELD score of 22 for the initial application of patients with sev-
than 50 mmHg at the time of diagnosis.506,507 ere HPS (PaO2 <60 mmHg), with further increases every three
months, to balance pre- and post-LT outcomes between HPS
Management and non-HPS candidates.545 In the largest retrospective study
Medical treatment comparing the results of LT between the pre-MELD era and
Spontaneous resolution of HPS is uncommon. There is no estab- the MELD era in patients with HPS, the five-year survival rate
lished medical therapy currently available for HPS. Several drugs after LT was found to improve from 67% during the pre-MELD
have been applied for the treatment of HPS with conflicting results. era to 88% in the MELD era.546 Other data showed that in
However, no large randomised trial has been conducted, probably post-MELD era, there was no association between pre-LT oxy-
because of the low number of patients. Data from several uncon- genation and waitlist survival in patients with HPS. These find-
trolled clinical studies and anecdotal evidence indicate that treat- ings reflect not only the results of the introduction of HPS as a
ment with beta-blockers, cyclooxygenase inhibitors, systemic MELD exception, but also of an improved perioperative manage-
glucocorticoids and cyclophosphamide, almitrine bismesylate, ment in patients with HPS. The regular assessment of the sever-
inhaled nitric oxide, nitric oxide inhibitors, and antimicrobial ity of hypoxaemia may facilitate LT prior to the occurrence of
agents has been uniformly unsuccessful.505 Pentoxifylline has also very severe hypoxaemia. In fact, hypoxaemia can worsen in
been tried in the treatment of HPS in adults and children in two patients with HPS who are on the active transplantation list,
small pilot studies with contradictory results in terms of improve- with a median decrease in pO2 of 5.2 mmHg per year,508 and
ments in oxygenation and frequent GI side effects.538,539 Adminis- it has been recently confirmed that a pre-LT room-air PaO2
tration of garlic was found to be associated with an improvement ≤44.0 mmHg is still associated with increased post-LT mortal-
in the PaO2 in a small randomised study.540 However, a case of ity.547 Thus, it has been suggested that an ABG analysis should
moderate hepatotoxicity associated with short-term, high-dose be carried out every six months, but no study has clarified
garlicin therapy in an LT recipient with persistent HPS was which is the best method for conducting this (ABG analysis vs.
recently reported.541 The use of TIPS has been proposed to reduce pulse oximetry) nor how frequently it should be performed.
portal pressure in patients with HPS. However, data are insuffi- Despite the increased survival rate in patients with HPS after
cient even when a systemic analysis review is considered.542 In LT in the MELD era, it has recently been observed that HPS
addition, there is some concern that TIPS can enhance pulmonary MELD exception patients had lower overall mortality compared
vasodilation by exacerbating the hyperkinetic circulation. Thus, no to others awaiting LT, suggesting that the appropriateness of the
recommendation for the use TIPS to treat HPS can be given.498,505 HPS MELD exception policy should be reassessed.548 There are
Finally, coil embolisation (embolotherapy) has been shown to very few and small studies on the impact of HPS on anaesthetic
improve arterial oxygenation temporarily in the context of angio- procedures, as well as in the post-LT management in the ICU.
graphic arteriovenous communications.531,543 Endothelin-1 Nevertheless, it seems that inhaled nitric oxide, methylene blue,
receptor antagonists or angiogenesis inhibitors have not been extracorporeal membrane oxygenation and non-invasive venti-
tested up to now in patients with HPS. Thus, long-term oxygen lation may improve oxygenation immediately post-LT.549–551
therapy remains the most frequently recommended therapy for
symptoms in patients with severe hypoxaemia. However, some
aspects of this treatment such as efficacy, costs, and compliance, Recommendations
remain to be evaluated.
Patients with HPS and PaO2 <60 mmHg should be evalu-
ated for LT since it is the only treatment for HPS that has
Recommendations
been proven to be effective to date (II-2;1).
Since a severe hypoxaemia (PaO2 <45–50 mmHg) is
Long-term oxygen therapy is recommended in patients associated with increased post-LT mortality, an ABG
with HPS and severe hypoxaemia. Nevertheless, there analysis should be carried out every six months in order
is no available data concerning effectiveness, tolerance, to facilitate prioritisation to LT (II-2;1).
cost-effectiveness, compliance and effects on survival
rates of this therapy (II-2;1).
No recommendation can be proposed regarding the use Portopulmonary hypertension
of drugs or the placement of TIPS for the treatment of Definition and diagnosis
HPS (I;1). A diagnosis of PPHT should be considered in a patient with
established portal hypertension in the absence of other causes
of pulmonary artery or venous hypertension. namely: chronic
Liver transplantation thromboembolism, chronic lung disease/hypoxia; chronic left
The most common and the only successful treatment for HPS is heart disease.
LT. LT results in a complete reversal or in a significant improve- Patients may be asymptomatic but often present with exer-
ment of HPS in more than 85% of patients with severe hypox- tional dyspnoea and they may have clinical signs of right heart
aemia.544 In a prospective clinical study performed in the pre- failure when moderate to severe disease develops.552 Classifica-
MELD era, a pre-LT severe hypoxaemia, in particular when it tion of severity is based on mean pulmonary arterial pressure

(mPAP) and assumes there is high pulmonary vascular resis- portal hypertension may be on treatment with beta-blockers,
tance (PVR). PPHT is graded as mild (mPAP ≥25 and <35 withdrawing beta-blocker therapy may help to increase cardiac
mmHg); moderate (mPAP ≥35 and <45 mmHg), and severe output and thereby help exertional dyspnoea, in patients with
(mPAP ≥45 mmHg).498 The diagnosis also requires there to be advanced PPHT.568
normal pulmonary occlusion pressures, to exclude elevation of
pulmonary pressure resulting from elevated left ventricular fill- Endothelin receptor antagonists. Bosentan has been shown to
ing pressure. Transthoracic Doppler echocardiography (TDE) is improve pulmonary artery haemodynamics and exercise toler-
the main screening tool for evaluating the presence of PPHT ance in patients with PPHT, independently of liver disease
when screening high-risk patients, such as those being consid- severity.569–572 One retrospective study reports survival rates
ered for TIPS or LT.553–555 As a screening test, some studies sug- of up to 89% at three years.573 Others have shown improve-
gest a pulmonary artery systolic pressure of >30 mmHg on TDE ments in cardiac index up to 39%, albeit in a small number of
has a negative predictive value of 100%, but a positive predictive patients, but an increase in aminotransferases, which responded
value of only 59%.554 However, when assessing patients for LT, to dose reduction or discontinuation.571 The FDA places a cau-
the threshold for right heart catheterisation is less clear, with tion on this class of drug in patients with advanced liver dys-
a right ventricular systolic pressure >50 mmHg and/or signifi- function. There is limited data on the use of other members in
cant right ventricular hypertrophy seen as the trigger for this this family of agent, including ambrisentan and macitentan,
investigation to rule out significant PPHT.555 for PPHT.574,575
Phosphodiesterase subtype-5 inhibitors. Blockade of phosphodi-

Pathophysiology
In patients with portal hypertension, PPHT is thought to arise esterase-5 inhibitors facilitate the vasodilatory effects of nitric
from limited blood flow in the pulmonary arterial circulation oxide, through reduced metabolism of cGMP. Small case series
because of vasoconstriction. Numerous factors are thought to suggest that sildenafil improves functional capacity and
be responsible for this including: Changes in endogenous vaso- increases cardiac output.576–578 It should be noted that silde-
regulators; increased endothelin 1 and reduced prostacyclin syn- nafil can precipitate variceal bleeding and as such, caution
thase from pulmonary endothelial cells; proliferation of smooth should be exercised.579
muscle cells/endothelial activation and platelet aggregation.
Prostacyclin analogues. Prostacyclin analogues have many poten-
Natural history and prognosis tial benefits including vasodilatory, reduced vascular smooth
From studies in patients evaluated for LT, the incidence is muscle proliferation and anti-thrombotic. Case series suggest
thought to be between 3–10% based on haemodynamic criteria. improved pulmonary haemodynamics with i.v. epoprostenol
Furthermore, female sex and pre-existing autoimmune liver dis- and the potential for improved five-year survival compared to
ease are thought to be independent risk factors.556 Genetic vari- registry data in pulmonary artery hypertension (70 vs.
ation in oestradiol levels may increase the predisposition to 40%).580–583 However, lower doses than those used in idiopathic
pulmonary artery vasoconstriction. Indeed, women are at three pulmonary hypertension are suggested to reduce the develop-
times greater risk than men.557 There is also an association ment of thrombocytopenia and splenomegaly. Other studies
between patients who have moderate to severe PPHT and the have also looked at use of inhaled iloprost and reported short-
presence of large portosystemic shunts.558 However, there is term haemodynamic benefit.584
no clear association between the severity of liver disease or por-
Impact of the management of other complications of cirrhosis
tal hypertension and the development of severe PPHT.556,559
Caution should be exercised when considering TIPS placement
Studies quote survival rates at one year of between 35–46%
for the treatment of other complications of cirrhosis in patients
without specific treatment.560,561 Mortality is often associated
with proven PPHT. The anticipated increase in right ventricular
with other complications of liver disease such as hepatocellular
filling pressures and cardiac output may precipitate marked
cancer, sepsis and GI bleeding and right ventricular failure.
increases in PVR and right-sided pressure overload.585,586
Increased rates of mortality are related to higher right atrial
Moderate PPHT (mPAP >35 and <45 mmHg) is a relative con-
pressure and lower cardiac index.559,562 In a multicentre reg-
traindication for TIPS placement, and severe PPHT is an absolute
istry study, patients with PPHT were shown to have worse out-
contraindication.586
comes than patients with idiopathic pulmonary hypertension,
with a five-year survival of 40% vs. 64%.563 However, a retro-
spective French study challenges this, whilst reporting Recommendations
increased mortality in those with a lower cardiac index, likely
reflecting failed compensation to increased right ventricular
dysfunction, and patients with more advanced liver disease.564 Screening for PPHT should be via TDE in patients deemed
potential recipients for TIPS or LT; in those with a posi-
Medical treatment tive screening test, right heart catheterisation should
The evidence base for pharmacological therapies in PPHT is lim- be performed (II-1;1).
ited with most data extrapolated from studies in pulmonary In patients with PPHT who are listed for transplantation,
arterial hypertension not related to liver disease.565,566 Drugs echocardiography should be repeated on the waitlist,
to promote acute vasodilatation during right heart catheterisa- albeit, the specific interval is unclear (III;1).
tion assessment, theoretically may be deleterious as they run
the risk of further reducing cardiac index. There is a lack of data Beta-blockers should be stopped and varices managed
to clarify this.567 Conversely, whilst patients with advanced by endoscopic therapy in cases of proven PPHT (II-3;1).

JOURNAL
OF HEPATOLOGY
Therapies that have been approved for primary pul- Recommendations

monary arterial hypertension may have benefit in PPHT
to improve exercise tolerance and haemodynamics. How- If mPAP <35 mmHg and right ventricular function is pre-
ever, endothelin antagonists should be used with caution served, LT should be considered (II-2,1). A mPAP of ≥45
because of concerns over hepatic impairment (II-2;1). mmHg should be considered an absolute contraindica-
TIPS should not be used in patients with PPHT (II-3;1). tion to LT irrespective of therapy applied (III,1).
Therapy to lower mPAP and improve right ventricular
function should be commenced in patients with mPAP
Liver transplantation
≥35 mmHg. Right ventricular function should be period-
Historically, severe PPHT has been a relative contraindication
ically evaluated (II-2,1).
for LT because of very poor outcomes. However, with the advent
of improved haemodynamic control with agents such as i.v. MELD exception can be considered in patients with proven
prostacyclin, there are case series showing normal pulmonary PPHT in whom targeted therapy fails to decrease mPAP
haemodynamics almost two years post LT.587,588 <35 mmHg but does facilitate normalisation of PVR to
<240 dynes/s cm5 and right ventricular function (II-3;2).
Stratifying risk for LT. In patients with an mPAP ≥45–50 mmHg, MELD exception should be advocated in patients with
most centres would deem this an absolute contraindication to proven PPHT of moderate severity (assessment mPAP
transplantation irrespective of therapy applied.562,587,589 ≥35 mmHg) in whom targeted treatment lowers mPAP
Patients with an mPAP >35 have increased risk post LT, associ- <35 mmHg and PVR <400 dynes/s cm5 (II-2;1).
ated with increased hospital stay and longer ventilator require-
ments.562,590,591 If LT is considered in such patients, it is Conclusions
suggested that their PPHT is treated aggressively to lower mPAP These guidelines on the management of patients with decom-
and improve right ventricular function.588,592,593 pensated cirrhosis were developed based on a new pathophys-
To facilitate access to LT before there is further progression iological background that offers the opportunity for more
of PPHT to a point where transplantation risks are deemed too comprehensive therapeutic or prophylactic approaches to man-
high, MELD exception (MELD 22 points) has been granted to age the disease. The knowledge of the key pathophysiologic
patients with PPHT (mPAP >25 mmHg and PVR >240 dynes/s mechanisms makes it possible nowadays to counteract the pro-
per cm5) with at least moderate disease severity (baseline gression of cirrhosis and so to prevent its complications. This
mPAP >35 mmHg).594 Patients are considered surgical candi- represents a step forward, shifting our approach from treating
dates if, after targeted therapy to lower PAP, they have the complications of decompensated cirrhosis to preventing
improved mPAP (<35 mmHg) and PVR (<400 dyne/s per cm5) their occurrence. However, to make this possible it is crucial
and/or normalise their PVR. Applying this exception has been to think about new models of specialist care for patients with
noted to reduce waitlist mortality.595 cirrhosis. A care coordination programme, has been proven to
improve survival and to reduce emergent readmission to the
Per-operative considerations. All patients should be monitored hospital in these patients.604 Care coordinators can facilitate
with a pulmonary artery catheter. Therapy to lower mPAP the development of educational programmes for patients and
should be continued throughout the operative period, given that caregivers optimising their adherence to guideline recommen-
there is often a rise in cardiac output post re-perfusion and this dations. In addition, they can plan invasive procedures in a
may add more stress on any pre-existing impaired right ventri- day hospital, allowing transfer of real-time information to pri-
cle function.595–597 Indeed, in some cases, a severe acute rise in mary care physicians to improve quality and coordination of
PAP may lead to graft failure because of hepatic congestion care. In so doing, it is possible to prevent unnecessary visits to
through a failing right ventricle. The management of such the emergency department and/or emergent readmission to
adverse haemodynamics, in addition to i.v. prostacyclin or the hospital. These measures will progressively reduce the bur-
inhaled nitric oxide includes the use of extracorporeal mem- den of cirrhosis.
brane oxygen therapy (ECMO).598,599
Conflict of interest
Postoperative considerations. Monitoring PAP response to ther- Paolo Angeli: Consultancy fee from Sequana Medical AG, Gilead
apy is via serial transthoracic echo with tissue Doppler at 4– Italy and Biovie; Patent inventor from Biovie; Research grant
6-month intervals and consideration of tapering pulmonary from Gilead; Speaker’s fee from Bhering, Kedrion 2016. Mauro
artery targeted therapy, though no controlled data exists to Bernardi: Consultancy fee from CLS Behring GmbH, Baxter
provide guidance on this.581,600,601 Case reports and series Healthcare SA, Grifols SA; Speaker’s fee from CLS Behring GmbH,
suggest that 29–64% of patients with moderate to severe Baxter Healthcare SA, PPTA Europe, Octapharma AG, Gilead
PPHT under long-term follow-up post-transplant have been Sciences, AbbVie Italia. Wim Laleman: Speaker’s fee for Gore,
able to discontinue therapy over time.599–602 Indeed, some Norgine, 4C, Abbvie, Sirtex; Consultancy fee for AbbVie, Gilead,
suggest a return to normal right ventricle function following MSD, Intercept; Research grant from Gilead. Jonel Trebicka:
therapy for PPHT in the pre-transplant period and then after Speaker’s fee or Consultancy fee from Gore & associates (TIPS),
transplant surgery.581,601 PPHT MELD exception patients have Sequana medical (alpha-pump), Alexion (PNH), Versantis (lipo-
worse one-year mortality or graft failure than patients with- somes). Aleksander Krag: None. Claire Francoz: None. Pere
out PPHT.603 Gines: Advisory/Consultancy fee for Sequana Grifols, Mallinck-

rodt, Ferring Pharmaceuticals; Research Funding from Sequana, hepatitis C virus-associated cirrhosis. Gastroenterology 2017;153:
Grifols, Ferring Pharmaceuticals. 1273–1283.
[19] Kang SH, Lee YB, Lee JH, Nam JY, Chang Y, Cho H, et al. Rifaximin
Please refer to the accompanying ICMJE disclosure forms for treatment is associated with reduced risk of cirrhotic complications and
further details. prolonged overall survival in patients experiencing hepatic
encephalopathy. Aliment Pharmacol Ther 2017;46:845–855.
Acknowledgments [20] Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med
2009;361:1279–1290.
We would like to thank Alessandra Brocca Dr, Marta Tonon MD, [21] Moreau R, Elkrief L, Bureau C, Pararnau JM, Thavenot T, Saliba F, et al. A
Husain-Syed Faeq MD for the great editorial work. We acknowledge randomized trial of 6-month norfloxacin therapy in patients with
ICREA for the ACADEMIA AWARD given to Pere Ginès. We would like Child-Pugh class C cirrhosis. J Hepatol 2017;66:S1.
to thank the reviewers of this Clinical Practice Guideline for their [22] Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al.
time and critical reviewing: EASL Governing Board, Alexander Long-term albumin administration in decompensated cirrhosis: an
open label randomized trial. Lancet 2018, [In press].
Gerbes, Thierry Gustot, Guadalupe Garcia-Tsao.
[23] Sola E, Sola C, Simon-Talero M, Martin-Llahi M, Castellote J, Garcia-
Martinez R, et al. Midodrine and albumin for prevention of complica-
References tions of cirrhosis in patients in the waiting list for liver transplantation.
[1] EASL clinical practice guidelines on the management of ascites, A randomized, multicenter, double-blind, placebo-controlled trial. J
spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrho- Hepatol 2017;66:S11.
sis. J Hepatol 2010;53:397–417. [24] Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC,
[2] D’Amico G. The clinical course of cirrhosis. Population based studies and et al. Simvastatin lowers portal pressure in patients with cirrhosis and
the need of personalized medicine. J Hepatol 2014;60:241–242. portal hypertension: a randomized controlled trial. Gastroenterology
[3] Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on- 2009;136:1651–1658.
chronic liver failure is a distinct syndrome that develops in patients [25] Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M,
with AD of cirrhosis. Gastroenterology 2013;144:1426–1437. Genesca J, et al. Addition of simvastatin to standard therapy for the
[4] D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic prevention of variceal rebleeding does not reduce rebleeding but
indicators of survival in cirrhosis: a systematic review of 118 studies. J increases survival in patients with cirrhosis. Gastroenterology
Hepatol 2006;44:217–231. 2016;150:1160–1170.
[5] Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of [26] Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, et al.
decompensation and organ failure in cirrhosis: From peripheral arterial Enoxaparin prevents portal vein thrombosis and liver decompensation
vasodilation to systemic inflammation hypothesis. J Hepatol in patients with advanced cirrhosis. Gastroenterology 2012;143:
2015;63:1272–1284. 1253–12609.
[6] Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. [27] Lebrec D, Thabut D, Oberti F, Perarnau JM, Condat B, Barraud H, et al.
Bacterial infections in cirrhosis: a position statement based on the EASL Pentoxifylline does not decrease short-term mortality but does reduce
Special Conference. J Hepatol 2013;60:1310–1324. complications in patients with advanced cirrhosis. Gastroenterology
[7] Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo 2010;138:1755–1762.
M, et al. Infections in patients with cirrhosis increase mortality four- [28] Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J.
fold and should be used in determining prognosis. Gastroenterology Hemodynamic response to pharmacological treatment of portal hyper-
2010;139:1246–1256. tension and long-term prognosis of cirrhosis. Hepatology 2003;37:
[8] Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. 902–908.
Peripheral arterial vasodilation hypothesis: a proposal for the initiation [29] Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, et al.
of renal sodium and water retention in cirrhosis. Hepatology Compensated cirrhosis: natural history and prognostic factors. Hepa-
1988;8:1151–1157. tology 1987;7:122–128.
[9] Wiese S, Hove JD, Bendtsen F, Moller S. Cirrhotic cardiomyopathy: [30] Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R,
pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol et al. Hepatic venous pressure gradient predicts clinical decompensa-
2014;11:177–186. tion in patients with compensated cirrhosis. Gastroenterology
[10] Arroyo V, Terra C, Gines P. Advances in the pathogenesis and treatment 2007;133:481–488.
of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007;46: [31] Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The
935–946. management of ascites in cirrhosis: report on the consensus conference
[11] Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver of the International Ascites Club. Hepatology 2003;38:258–266.
diseases: from the patient to the molecule. Hepatology 2006;43: [32] Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, et al.
S121–S131. Definition and diagnostic criteria of refractory ascites and hepatorenal
[12] Claria J, Stauber RE, Coenraad MJ, Moreau R, Jalan R, Pavesi M, et al. syndrome in cirrhosis. International Ascites Club. Hepatology
Systemic inflammation in decompensated cirrhosis: Characterization 1996;23:164–176.
and role in acute-on-chronic liver failure. Hepatology 2016;64: [33] Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B,
1249–1264. et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial
[13] Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic fibrosis: peritonitis: a consensus document. International Ascites Club. J Hepatol
Concept to treatment. J Hepatol 2015;62:S15–S24. 2000;32:142–153.
[14] Alvarez MA, Cirera I, Sola R, Bargallo A, Morillas RM, Planas R. [34] Bruns T, Lutz P, Stallmach A. Nischalke HD Low ascitic fluid protein does
Long-term clinical course of decompensated alcoholic cirrhosis: a not indicate an increased risk for spontaneous bacterial peritonitis in
prospective study of 165 patients. J Clin Gastroenterol 2011;45: current cohorts. J Hepatol 2015;63:527–528.
906–911. [35] Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic fluid
[15] Powell Jr WJ, Klatskin G. Duration of survival in patients with Laennec’s culture technique. Gastroenterology 1988;95:1351–1355.
cirrhosis. Influence of alcohol withdrawal, and possible effects of recent [36] Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA,
changes in general management of the disease. Am J Med McHutchison JG. The serum-ascites albumin gradient is superior to
1968;44:406–420. the exudate-transudate concept in the differential diagnosis of ascites.
[16] Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of Ann Intern Med 1992;117:215–220.
entecavir in treatment-naive patients with hepatitis B virus-related [37] Gerbes AL, Jüngst D, Xie YN, Permanetter W, Paumgartner G. Ascitic
decompensated cirrhosis. J Hepatol 2010;52:176–182. fluid analysis for the differentiation of malignancy-related and nonma-
[17] Cheung MC, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, lignant ascites. Proposal of a diagnostic sequence. Cancer 1991;68:
et al. Outcomes after successful direct-acting antiviral therapy for 1808–1814.
patients with chronic hepatitis C and decompensated cirrhosis. J [38] Llach J, Gines P, Arroyo V, Rimola A, Tito L, Badalamenti S, et al.
Hepatol 2016;65:741–747. Prognostic value of arterial pressure, endogenous vasoactive systems,
[18] Lens S, Alvarado E, Mariño Z, et al. Effects of all-oral antiviral and renal function in cirrhotic patients admitted to the hospital for the
therapy on HVPG and systemic hemodynamics in patients with treatment of ascites. Gastroenterology 1988;94:482–487.

JOURNAL
OF HEPATOLOGY
[39] Caregaro L, Menon F, Angeli P, Amodio P, Merkel C, Bortoluzzi A, et al. [61] Lin CH, Shih FY, Ma MH, Chiang WC, Yang CW, Ko PC. Should bleeding
Limitations of serum creatinine level and creatinine clearance as tendency deter abdominal paracentesis? Dig Liver Dis 2005;37:
filtration markers in cirrhosis. Arch Intern Med 1994;154:201–205. 946–951.
[40] Bernardi M, Gitto S, Biselli M. The MELD score in patients awaiting liver [62] Pache I, Bilodeau M. Severe haemorrhage following abdominal para-
transplant: strengths and weaknesses. J Hepatol 2011;54:1297–1306. centesis for ascites in patients with liver disease. Aliment Pharmacol
[41] Biselli M, Dall’Agata M, Gramenzi A, Gitto S, Liberati C, Brodosi L, et al. A Ther 2005;21:525–529.
new prognostic model to predict dropout from the waiting list in [63] Gines P, Tito L, Arroyo V, Planas R, Panes J, Viver J, et al. Randomized
cirrhotic candidates for liver transplantation with MELD score <18. comparative study of therapeutic paracentesis with and without
Liver Int 2015;35:184–191. intravenous albumin in cirrhosis. Gastroenterology 1988;94:
[42] Bernardi M, Santini C, Trevisani F, Baraldini M, Ligabue A, Gasbarrini G. 1493–1502.
Renal function impairment induced by change in posture in patients [64] Gines A, Fernandez-Esparrach G, Monescillo A, Vila C, Domenech E,
with cirrhosis and ascites. Gut 1985;26:629–635. Abecasis R, et al. Randomized trial comparing albumin, dextran 70, and
[43] Ring-Larsen H, Henriksen JH, Wilken C, Clausen J, Pals H, Christensen NJ. polygeline in cirrhotic patients with ascites treated by paracentesis.
Diuretic treatment in decompensated cirrhosis and congestive heart Gastroenterology 1996;111:1002–1010.
failure: effect of posture. Br Med J 1986;292:1351–1353. [65] Sola-Vera J, Minana J, Ricart E, Planella M, Gonzalez B, Torras X, et al.
[44] Bernardi M, Laffi G, Salvagnini M, Azzena G, Bonato S, Marra F, et al. Randomized trial comparing albumin and saline in the prevention of
Efficacy and safety of the stepped care medical treatment of ascites in paracentesis-induced circulatory dysfunction in cirrhotic patients with
liver cirrhosis: a randomized controlled clinical trial comparing two ascites. Hepatology 2003;37:1147–1153.
diets with different sodium content. Liver 1993;13:156–162. [66] Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin infusion in
[45] Gauthier A, Levy VG, Quinton A, Michel H, Rueff B, Descos L, et al. Salt or patients undergoing large-volume paracentesis: a meta-analysis of
no salt in the treatment of cirrhotic ascites: a randomised study. Gut randomized trials. Hepatology 2012;55:1172–1181.
1986;27:705–709. [67] Moreau R, Valla DC, Durand-Zaleski I, Bronowicki JP, Durand F, Chaput
[46] Reynolds TB, Lieberman FL, Goodman AR. Advantages of treatment of JC, et al. Comparison of outcome in patients with cirrhosis and ascites
ascites without sodium restriction and without complete removal of following treatment with albumin or a synthetic colloid: a randomised
excess fluid. Gut 1978;19:549–553. controlled pilot trail. Liver Int 2006;26:46–54.
[47] Morando F, Rosi S, Gola E, Nardi M, Piano S, Fasolato S, et al. Adherence [68] Gines P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, et al.
to a moderate sodium restriction diet in outpatients with cirrhosis and Comparison of paracentesis and diuretics in the treatment of cirrhotics
ascites: a real-life cross-sectional study. Liver Int 2015;35:1508–1515. with tense ascites. Results of a randomized study. Gastroenterology
[48] Pockros PJ, Reynolds TB. Rapid diuresis in patients with ascites from 1987;93:234–241.
chronic liver disease: the importance of peripheral edema. Gastroen- [69] Salerno F, Badalamenti S, Incerti P, Tempini S, Restelli B, Bruno S, et al.
terology 1986;90:1827–1833. Repeated paracentesis and i.v. albumin infusion to treat ’tense’ ascites
[49] Bernardi M, Trevisani F, Gasbarrini A, Gasbarrini G. Hepatorenal in cirrhotic patients. A safe alternative therapy. J Hepatol
disorders: role of the renin-angiotensin-aldosterone system. Semin 1987;5:102–108.
Liver Dis 1994;14:23–34. [70] Fernandez-Esparrach G, Guevara M, Sort P, Pardo A, Jimenez W, Gines P,
[50] Bernardi M, Servadei D, Trevisani F, Rusticali AG, Gasbarrini G. et al. Diuretic requirements after therapeutic paracentesis in non-
Importance of plasma aldosterone concentration on the natriuretic azotemic patients with cirrhosis. A randomized double-blind trial of
effect of spironolactone in patients with liver cirrhosis and ascites. spironolactone vs. placebo. J Hepatol 1997;26:614–620.
Digestion 1985;31:189–193. [71] Elia C, Graupera I, Barreto R, Solà E, Moreira R, Huelin P, et al. Severe
[51] Angeli P, Dalla Pria M, De Bei E, Albino G, Caregaro L, Merkel C, et al. acute kidney injury associated with non-steroidal antiinflammatory
Randomized clinical study of the efficacy of amiloride and potassium drugs in cirrhosis: a case-control study. J Hepatol 2015;63:593–600.
canrenoate in nonazotemic cirrhotic patients with ascites. Hepatology [72] Claria J, Kent JD, Lopez-Parra M, Escolar G, Ruiz-Del-Arbol L, Gines P,
1994;19:72–79. et al. Effects of celecoxib and naproxen on renal function in nona-
[52] Angeli P, Gatta A, Caregaro L, Menon F, Sacerdoti D, Merkel C, et al. zotemic patients with cirrhosis and ascites. Hepatology
Tubular site of renal sodium retention in ascitic liver cirrhosis evalu- 2005;41:579–587.
ated by lithium clearance. Eur J Clin Invest 1990;20:111–117. [73] Llach J, Gines P, Arroyo V, Salmeron JM, Gines A, Jimenez W, et al. Effect
[53] Gatta A, Angeli P, Caregaro L, Menon F, Sacerdoti D, Merkel C. A of dipyridamole on kidney function in cirrhosis. Hepatology
pathophysiological interpretation of unresponsiveness to spironolac- 1993;17:59–64.
tone in a stepped-care approach to the diuretic treatment of ascites in [74] Pariente EA, Bataille C, Bercoff E, Lebrec D. Acute effects of captopril on
nonazotemic cirrhotic patients. Hepatology 1991;14:231–236. systemic and renal hemodynamics and on renal function in cirrhotic
[54] Perez-Ayuso RM, Arroyo V, Planas R, Gaya J, Bory F, Rimola A, et al. patients with ascites. Gastroenterology 1985;88:1255–1259.
Randomized comparative study of efficacy of furosemide vs. spirono- [75] Albillos A, Lledo JL, Rossi I, Perez-Paramo M, Tabuenca MJ, Banares R,
lactone in nonazotemic cirrhosis with ascites. Relationship between the et al. Continuous prazosin administration in cirrhotic patients: effects
diuretic response and the activity of the renin-aldosterone system. on portal hemodynamics and on liver and renal function. Gastroen-
Gastroenterology 1983;84:961–968. terology 1995;109:1257–1265.
[55] Angeli P, Fasolato S, Mazza E, Okolicsanyi L, Maresio G, Velo E, et al. [76] Cabrera J, Arroyo V, Ballesta AM, Rimola A, Gual J, Elena M, et al.
Combined vs. sequential diuretic treatment of ascites in non-azotaemic Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-
patients with cirrhosis: results of an open randomised clinical trial. Gut microglobulin to discriminate functional renal failure from acute
2010;59:98–104. tubular damage. Gastroenterology 1982;82:97–105.
[56] Santos J, Planas R, Pardo A, Durandez R, Cabre E, Morillas RM, et al. [77] Guevara M, Fernández-Esparrach G, Alessandria C, Torre A, Terra C,
Spironolactone alone or in combination with furosemide in the Montañà X, et al. Effects of contrast media on renal function in patients
treatment of moderate ascites in nonazotemic cirrhosis. A randomized with cirrhosis: a prospective study. Hepatology 2004;40:646–651.
comparative study of efficacy and safety. J Hepatol 2003;39:187–192. [78] Solomon R, Werner C, Mann D, D’Elia J, Silva P. Comparison of saline,
[57] Gerbes AL, Bertheau-Reitha U, Falkner C, Jüngst D, Paumgartner G. mannitol, and furosemide to prevent acute decreases in renal
Advantages of the new loop diuretic torasemide over furosemide in function induced by radiocontrast agents. N Engl J Med 1994;331:
patients with cirrhosis and ascites. A randomized, double blind cross- 1416–1420.
over trial. J Hepatol 1993;17:353–358. [79] Salerno F, Borroni G, Moser P, Badalamenti S, Cassara L, Maggi A, et al.
[58] Angeli P, Albino G, Carraro P, Dalla Pria M, Merkel C, Caregaro L, et al. Survival and prognostic factors of cirrhotic patients with ascites: a
Cirrhosis and muscle cramps: evidence of a causal relationship. study of 134 outpatients. Am J Gastroenterol 1993;88:514–519.
Hepatology 1996;23:264–273. [80] Guardiola J, Baliellas C, Xiol X, Fernandez Esparrach G, Gines P, Ventura
[59] Elfert AA, Abo Ali L, Soliman S, Zakaria S, Shehab El-Din I, Elkhalawany P, et al. External validation of a prognostic model for predicting survival
W, et al. Randomized placebo-controlled study of baclofen in the of cirrhotic patients with refractory ascites. Am J Gastroenterol
treatment of muscle cramps in patients with liver cirrhosis. Eur J 2002;97:2374–2378.
Gastroenterol Hepatol 2016;28:1280–1284. [81] Huonker M, Schumacher YO, Ochs A, Sorichter S, Keul J, Rossle M.
[60] Lee FY, Lee SD, Tsai YT, et al. A randomized controlled trial of quinidine Cardiac function and haemodynamics in alcoholic cirrhosis and effects
in the treatment of cirrhotic patients with muscle cramps. J Hepatol of the transjugular intrahepatic portosystemic stent shunt. Gut
1991;12:236–240. 1999;44:743–748.

[82] Sanyal AJ, Freedman AM, Luketic VA, Purdum 3rd PP, Shiffman ML, [101] Albillos A, Banares R, Gonzalez M, Catalina MV, Molinero LM. A meta-
DeMeo J, et al. The natural history of portal hypertension after analysis of transjugular intrahepatic portosystemic shunt vs. paracen-
transjugular intrahepatic portosystemic shunts. Gastroenterology tesis for refractory ascites. J Hepatol 2005;43:990–996.
1997;112:889–898. [102] Bai M, Qi XS, Yang ZP, Yang M, Fan DM, Han GH. TIPS improves liver
[83] Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L. transplantation-free survival in cirrhotic patients with refractory
Transjugular intrahepatic portosystemic stent shunt: effects on hemo- ascites: an updated meta-analysis. World J Gastroenterol
dynamics and sodium homeostasis in cirrhosis and refractory ascites. 2014;20:2704–2714.
Ann Intern Med 1995;122:816–822. [103] Chen RP, Zhu Ge XJ, Huang ZM, Ye XH, Hu CY, Lu GR, et al. Prophylactic
[84] Wong F, Sniderman K, Liu P, Blendis L. The mechanism of the initial use of transjugular intrahepatic portosystemic shunt aids in the
natriuresis after transjugular intrahepatic portosystemic shunt. Gas- treatment of refractory ascites: metaregression and trial sequential
troenterology 1997;112:899–907. meta-analysis. J Clin Gastroenterol 2014;48:290–299.
[85] Gerbes AL, Gülberg V, Waggershauser T, Holl J, Reiser M. Renal effects of [104] D’Amico G, Luca A, Morabito A, Miraglia R, D’Amico M. Uncovered
transjugular intrahepatic portosystemic shunt in cirrhosis: comparison transjugular intrahepatic portosystemic shunt for refractory ascites: a
of patients with ascites, with refractory ascites, or without ascites. meta-analysis. Gastroenterology 2005;129:1282–1293.
Hepatology 1998;28:683–688. [105] Deltenre P, Mathurin P, Dharancy S, Moreau R, Bulois P, Henrion J, et al.
[86] Ochs A, Rossle M, Haag K, Hauenstein KH, Deibert P, Siegerstetter V, Transjugular intrahepatic portosystemic shunt in refractory ascites: a
et al. The transjugular intrahepatic portosystemic stent-shunt proce- meta-analysis. Liver Int 2005;25:349–356.
dure for refractory ascites. N Engl J Med 1995;332:1192–1197. [106] Saab S, Nieto JM, Lewis SK, Runyon BA. TIPS vs. paracentesis for
[87] Plauth M, Schutz T, Buckendahl DP, Kreymann G, Pirlich M, Grungreiff S, cirrhotic patients with refractory ascites. Cochrane Database Syst Rev
et al. Weight gain after transjugular intrahepatic portosystemic shunt is 2006:CD004889.
associated with improvement in body composition in malnourished [107] Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular
patients with cirrhosis and hypermetabolism. J Hepatol 2004;40: intrahepatic portosystemic shunt for refractory ascites: a meta-analysis
228–233. of individual patient data. Gastroenterology 2007;133:825–834.
[88] Gülberg V, Liss I, Bilzer M, Waggershauser T, Reiser M, Gerbes AL. [108] Maleux G, Perez-Gutierrez NA, Evrard S, Mroue A, Le Moine O, Laleman
Improved quality of life in patients with refractory or recidivant ascites W, et al. Covered stents are better than uncovered stents for
after insertion of transjugular intrahepatic portosystemic shunts. transjugular intrahepatic portosystemic shunts in cirrhotic patients
Digestion 2002;66:127–130. with refractory ascites: a retrospective cohort study. Acta Gastroenterol
[89] Casado M, Bosch J, Garcia-Pagan JC, Bru C, Banares R, Bandi JC, et al. Belg 2010;73:336–341.
Clinical events after transjugular intrahepatic portosystemic shunt: [109] Tan HK, James PD, Sniderman KW, Wong F. Long-term clinical outcome
correlation with hemodynamic findings. Gastroenterology of patients with cirrhosis and refractory ascites treated with tran-
1998;114:1296–1303. sjugular intrahepatic portosystemic shunt insertion. J Gastroenterol
[90] Riggio O, Angeloni S, Salvatori FM, De Santis A, Cerini F, Farcomeni A, Hepatol 2015;30:389–395.
et al. Incidence, natural history, and risk factors of hepatic encephalopa- [110] Gaba RC, Parvinian A, Casadaban LC, Couture PM, Zivin SP, Lakhoo J,
thy after transjugular intrahepatic portosystemic shunt with polyte- et al. Survival benefit of TIPS vs. serial paracentesis in patients with
trafluoroethylene-covered stent grafts. Am J Gastroenterol refractory ascites: a single institution case-control propensity score
2008;103:2738–2746. analysis. Clin Radiol 2015;70:e51–e57.
[91] Sauerbruch T, Mengel M, Dollinger M, Zipprich A, Rossle M, Panther E, [111] Bureau C, Thabut D, Oberti F, Dharancy S, Carbonell N, Bouvier A, et al.
et al. Prevention of rebleeding from esophageal varices in patients with Transjugular intrahepatic portosystemic shunts with covered stents
cirrhosis receiving small-diameter stents vs. hemodynamically con- increase transplant-free survival of patients with cirrhosis and recur-
trolled medical therapy. Gastroenterology 2015;149:660–668. rent ascites. Gastroenterology 2017;152:157–163.
[92] Wang Q, Lv Y, Bai M, Wang Z, Liu H, He C, et al. Eight millimetre covered [112] Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A
TIPS does not compromise shunt function but reduces hepatic model to predict poor survival in patients undergoing transjugular
encephalopathy in preventing variceal rebleeding. J Hepatol 2017;67: intrahepatic portosystemic shunts. Hepatology 2000;31:864–871.
508–516. [113] Bureau C, Metivier S, D’Amico M, Peron JM, Otal P, Pagan JC, et al. Serum
[93] Pieper CC, Jansen C, Meyer C, Nadal J, Lehmann J, Schild HH, et al. bilirubin and platelet count: a simple predictive model for survival in
Prospective evaluation of passive expansion of partially dilated tran- patients with refractory ascites treated by TIPS. J Hepatol
sjugular intrahepatic portosystemic shunt stent grafts-a three-dimen- 2011;54:901–907.
sional sonography study. J Vasc Interv Radiol 2017;28:117–125. [114] Sarwar A, Zhou L, Novack V, Tapper EB, Curry M, Malik R, et al. Hospital
[94] Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, volume and mortality after trans-jugular intrahepatic portosystemic
Cortez C, et al. Improved clinical outcome using polytetrafluo- shunt creation in the United States. Hepatology 2017.
roethylene-coated stents for TIPS: results of a randomized study. [115] Angeli P, Volpin R, Piovan D, Bortoluzzi A, Craighero R, Bottaro S, et al.
Gastroenterology 2004;126:469–475. Acute effects of the oral administration of midodrine, an alpha-
[95] Gines P, Uriz J, Calahorra B, Garcia-Tsao G, Kamath PS, Del Arbol LR, adrenergic agonist, on renal hemodynamics and renal function in
et al. Transjugular intrahepatic portosystemic shunting vs. paracentesis cirrhotic patients with ascites. Hepatology 1998;28:937–943.
plus albumin for refractory ascites in cirrhosis. Gastroenterology [116] Singh V, Dhungana SP, Singh B, Vijayverghia R, Nain CK, Sharma N, et al.
2002;123:1839–1847. Midodrine in patients with cirrhosis and refractory or recurrent ascites:
[96] Lebrec D, Giuily N, Hadengue A, Vilgrain V, Moreau R, Poynard T, et al. a randomized pilot study. J Hepatol 2012;56:348–354.
Transjugular intrahepatic portosystemic shunts: comparison with [117] Gadano A, Moreau R, Vachiery F, Soupison T, Yang S, Cailmail S, et al.
paracentesis in patients with cirrhosis and refractory ascites: a Natriuretic response to the combination of atrial natriuretic peptide
randomized trial. French Group of Clinicians and a Group of Biologists. and terlipressin in patients with cirrhosis and refractory ascites. J
J Hepatol 1996;25:135–144. Hepatol 1997;26:1229–1234.
[97] Narahara Y, Kanazawa H, Fukuda T, Matsushita Y, Harimoto H, Kidokoro [118] Krag A, Moller S, Henriksen JH, Holstein-Rathlou NH, Larsen FS,
H, et al. Transjugular intrahepatic portosystemic shunt vs. paracentesis Bendtsen F. Terlipressin improves renal function in patients with
plus albumin in patients with refractory ascites who have good hepatic cirrhosis and ascites without hepatorenal syndrome. Hepatology
and renal function: a prospective randomized trial. J Gastroenterol 2007;46:1863–1871.
2011;46:78–85. [119] Lenaerts A, Codden T, Meunier JC, Henry JP, Ligny G. Effects of clonidine
[98] Rossle M, Ochs A, Gulberg V, Siegerstetter V, Holl J, Deibert P, et al. A on diuretic response in ascitic patients with cirrhosis and activation of
comparison of paracentesis and transjugular intrahepatic portosys- sympathetic nervous system. Hepatology 2006;44:844–849.
temic shunting in patients with ascites. N Engl J Med 2000;342: [120] Singh V, Singh A, Singh B, Vijayvergiya R, Sharma N, Ghai A, et al.
1701–1707. Midodrine and clonidine in patients with cirrhosis and refractory or
[99] Salerno F, Merli M, Riggio O, Cazzaniga M, Valeriano V, Pozzi M, et al. recurrent ascites: a randomized pilot study. Am J Gastroenterol
Randomized controlled study of TIPS vs. paracentesis plus albumin in 2013;108:560–567.
cirrhosis with severe ascites. Hepatology 2004;40:629–635. [121] Rai N, Singh B, Singh A, Vijayvergiya R, Sharma N, Bhalla A, et al.
[100] Sanyal AJ, Genning C, Reddy KR, Wong F, Kowdley KV, Benner K, et al. Midodrine and tolvaptan in patients with cirrhosis and refractory
The North American study for the treatment of refractory ascites. or recurrent ascites: a randomised pilot study. Liver Int 2017;37:
Gastroenterology 2003;124:634–641. 406–414.

JOURNAL
OF HEPATOLOGY
[122] Tandon P, Tsuyuki RT, Mitchell L, Hoskinson M, Ma MM, Wong WW, Intern Med 2002;162:323–328;
et al. The effect of 1 month of therapy with midodrine, octreotide-LAR Cordoba J, Garcia-Martinez R, Simon-Talero M. Hyponatremic and
and albumin in refractory ascites: a pilot study. Liver Int 2009;29: hepatic encephalopathies: similarities, differences and coexistence.
169–174. Metab Brain Dis 2010;25:73–80.
[123] Hanafy AS, Hassaneen AM. Rifaximin and midodrine improve clinical [146] Cordoba J, Garcia-Martinez R, Simon-Talero M. Hyponatremic and
outcome in refractory ascites including renal function, weight loss, and hepatic encephalopathies: similarities, differences and coexistence.
short-term survival. Eur J Gastroenterol Hepatol 2016;28:1455–1461. Metab Brain Dis 2010;25:73–80.
[124] Bellot P, Welker MW, Soriano G, von Schaewen M, Appenrodt B, Wiest [147] Amodio P, Del Piccolo F, Petteno E, Mapelli D, Angeli P, Iemmolo R, et al.
R, et al. Automated low flow pump system for the treatment of Prevalence and prognostic value of quantified electroencephalogram
refractory ascites: a multi-center safety and efficacy study. J Hepatol (EEG) alterations in cirrhotic patients. J Hepatol 2001;35:37–45.
2013;58:922–927. [148] Londono MC, Guevara M, Rimola A, Navasa M, Taura P, Mas A, et al.
[125] Stirnimann G, Berg T, Spahr L, Zeuzem S, McPherson S, Lammert F, et al. Hyponatremia impairs early posttransplantation outcome in patients
Treatment of refractory ascites with an automated low-flow ascites with cirrhosis undergoing liver transplantation. Gastroenterology
pump in patients with cirrhosis. Aliment Pharmacol Ther 2006;130:1135–1143.
2017;46:981–991. [149] Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T, et al.
[126] Bureau C, Adebayo D, Chalret de Rieu M, Elkrief L, Valla D, et al. Evidence-based incorporation of serum sodium concentration into
AlfapumpÒ system vs. large volume paracentesis for refractory ascites: MELD. Gastroenterology 2006;130:1652–1660.
A multicenter randomized controlled study. J Hepatol [150] Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT,
2017;67:940–949. et al. Hyponatremia and mortality among patients on the liver-
[127] Sola E, Sanchez-Cabus S, Rodriguez E, Elia C, Cela R, Moreira R, et al. transplant waiting list. N Engl J Med 2008;359:1018–1026.
Effects of alfapump system on kidney and circulatory function in [151] McCormick PA, Mistry P, Kaye G, Burroughs AK, McIntyre N. Intra-
patients with cirrhosis and refractory ascites. Liver Transpl venous albumin infusion is an effective therapy for hyponatraemia in
2017;23:583–593. cirrhotic patients with ascites. Gut 1990;31:204–207.
[128] Badillo R, Rockey DC. Hepatic hydrothorax. Clinical features, manage- [152] Quittnat F, Gross P. Vaptans and the treatment of water-retaining
ment, and outcomes in 77 patients and review of the literature. disorders. Semin Nephrol 2006;26:234–243.
Medicine 2014;93:135–142. [153] Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, et al.
[129] Garbuzenko DV, Arefyev NO. Hepatic hydrothorax: An update and Tolvaptan, an oral vasopressin antagonist, in the treatment of hypona-
review of the literature. World J Hepatol 2017:1197–1204. tremia in cirrhosis. J Hepatol 2012;56:571–578.
[130] Zenda T, Miyamoto S, Murata S, Mabuchi H. Detection of diaphragmatic [154] Gerbes AL, Gulberg V, Gines P, Decaux G, Gross P, Gandjini H, et al.
defect as the cause of severe hepatic hydrothorax with magnetic Therapy of hyponatremia in cirrhosis with a vasopressin receptor
resonance imaging. Am J Gastroenterol 1998;9:2288–2289. antagonist: a randomized double-blind multicenter trial. Gastroen-
[131] Hewett LJ, Bradshaw ML, Gordon LL, Rockey DC. Diagnosis of isolated terology 2003;124:933–939.
hepatic hydrothorax using peritoneal scintigraphy. Hepatology [155] Gines P, Wong F, Watson H, Milutinovic S, del Arbol LR, Olteanu D.
2016;64:1364–1366. Effects of satavaptan, a selective vasopressin V(2) receptor antagonist,
[132] Alonso JC. Pleural effusion in liver disease. Semin Respir Crit Care Med on ascites and serum sodium in cirrhosis with hyponatremia: a
2010;31:698–705. randomized trial. Hepatology 2008;48:204–213.
[133] Orman ES, Lok AS. Outcomes of patients with chest tube insertion for [156] O’Leary JG, Davis GL. Conivaptan increases serum sodium in hypona-
hepatic hydrothorax. Hepatol Int 2009;3:582–586. tremic patients with end-stage liver disease. Liver Transpl
[134] Xiol X, Tremosa G, Castellote J, Gornals J, Lama C, et al. Liver 2009;15:1325–1329.
transplantation in patients with hepatic hydrothorax. Transpl Int [157] Wong F, Gines P, Watson H, Horsmans Y, Angeli P, Gow P, et al. Effects
2005;18:672–675. of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites
[135] Sersté T, Moreno C, Francoz C, Razek WA, Paugham C, et al. The impact recurrence after paracentesis in patients with cirrhosis. J Hepatol
of preoperative hepatic hydrothorax on the outcome of adult liver 2010;53:283–290.
transplantation. Eur J Gastroenterol Hepatol 2010;22:207–212. [158] Wong F, Watson H, Gerbes A, Vilstrup H, Badalamenti S, Bernardi M,
[136] Gordon FD, Anastopoulos HT, Crenshaw W, Gilchrist B, McEniff N, et al. Satavaptan for the management of ascites in cirrhosis: efficacy
Falchuk KR, et al. The successful treatment of symptomatic, refractory and safety across the spectrum of ascites severity. Gut
hepatic hydrothorax with transjugular intrahepatic portosystemic 2012;61:108–116.
shunt. Hepatology 1997;25:1366–1369. [159] Pose E, Sola E, Piano S, Gola E, Graupera I, Guevara M, et al. Limited
[137] Siegerstetter V, Deibert P, Ochs A, Olschewski M, Blum HE, Rossle M. efficacy of tolvaptan in patients with cirrhosis and severe hypona-
Treatment of refractory hepatic hydrothorax with transjugular intra- tremia: real-life experience. Am J Med 2017;130:372–375.
hepatic portosystemic shunt: long-term results in 40 patients. Eur J [160] Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ,
Gastroenterol Hepatol 2001;13:529–534. Higashihara E, et al. Tolvaptan in patients with autosomal dominant
[138] Ditah IC, Al Bawardy BF, Saberi B, Ditah C, Kamath PS. Transjugular polycystic kidney disease. N Engl J Med 2012;367:2407–2418.
intrahepatic portosystemic stent shunt for medically refractory hepatic [161] Bosch J, Groszmann RJ, Shah VH. Evolution in the understanding of the
hydrothorax: A systematic review and cumulative meta-analysis. pathophysiological basis of portal hypertension: How changes in
World J Hepatol 2015;7:1797–1806. paradigm are leading to successful new treatments. J Hepatol
[139] Hou F, Qi X, Guo X. Effectiveness and safety of pleurodesis for hepatic 2015;62:S121–S130.
hydrothorax: A systematic review and meta-analysis. Dig Dis Sci [162] D’Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Post-
2016;61:3321–3334. therapeutic outcome and prognostic indicators. Hepatology
[140] Huang PM, Kuo SW, Chen JS, Lee JM. Thoracoscopic mesh repair of 2003;38:599–612.
diaphragmatic defects in hepatic hydrothorax: A 10-year experience. [163] Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical course of
Ann Thorac Surg 2016;101:1921–1927. alcoholic liver cirrhosis: a Danish population-based cohort study.
[141] Angeli P, Wong F, Watson H. Gines P, and the participants to CAPPS. Hepatology 2010;51:1675–1682.
Hyponatremia in cirrhosis: results of a survey. Hepatology [164] Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A.
2006;44:1535–1542. Endoscopic screening for varices in cirrhotic patients: data from a
[142] Gines P, Berl T, Bernardi M, Bichet DG, Hamon G, Jimenez W, et al. national endoscopic database. Gastrointest Endosc 2007;65:82–88.
Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatol- [165] Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, et al.
ogy 1998;28:851–864. Incidence and natural history of small esophageal varices in cirrhotic
[143] Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. patients. J Hepatol 2003;38:266–272.
Clinical practice guideline on diagnosis and treatment of hypona- [166] Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas
traemia. Intensive Care Med 2014;40:320–331. R, et al. Beta-blockers to prevent gastroesophageal varices in patients
[144] Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. with cirrhosis. N Engl J Med 2005;353:2254–2261.
Serum sodium predicts mortality in patients listed for liver transplan- [167] Abraldes JG, Bureau C, Stefanescu H, Augustin S, Ney M, Blasco H, et al.
tation. Hepatology 2005;41:32–39. Non invasive tools and risk of clinically significant portal hypertension
[145] Porcel A, Diaz F, Rendon P, Macias M, Martin-Herrera L, Giron-Gonzalez and varices in compensated cirrhosis : the ‘‘ANTICIPATE” study.
JA. Dilutional hyponatremia in patients with cirrhosis and ascites. Arch Hepatology 2016;64:2173–2184.

[168] De Franchis RBaveno VI faculty. Expanding consensus in portal [189] Mookerjee RP, Pavesi M, Thomsen KL, Mehta G, Macnaughtan J,
hypertension: report of the BAVENO VI Consensus Workshop: Strati- Bendtsen F, et al. Treatment with non-selective beta blockers is
fying risk and individualizing care for portal hypertension. J Hepatol associated with reduced severity of systemic inflammation and
2015;63:743–752. improved survival of patients with acute-on-chronic liver failure. J
[169] Garcia-Tsao G, Sanyal AJ, Grace ND, Carey WPractice Guidelines Hepatol 2016;64:574–582.
Committee of the American Association for the Study of Liver [190] Madsen BS, Nielsen KF, Fialla AD, Krag A. Keep the sick from harm in
DiseasesPractice Parameters Committee of the American College of spontaneous bacterial peritonitis: Dose of beta blockers matters. J
Gastroenterology. Prevention and management of gastroesophageal Hepatol 2016;64:1455–1456.
varices and variceal hemorrhage in cirrhosis. Hepatology [191] Serste T, Gustot T, Rautou PE, Francoz C, Njimi H, Durand F, et al. Severe
2007;46:922–938. hyponatremia is a better predictor of mortality than MELDNa in
[170] North Italian Endoscopic Club for the Study and Treatment of patients with cirrhosis and refractory ascites. J Hepatol 2012;57:
Esophageal Varices. Prediction of the first variceal hemorrhage in 274–280.
patients with cirrhosis of the liver and esophageal varices. A prospec- [192] Krag A, Bendtsen F, Henriksen JH, Moller S. Low cardiac output predicts
tive multicenter study. N Engl J Med 1988;319:983–989. development of hepatorenal syndrome and survival in patients with
[171] D’Amico G, Pasta L, Morabito A, et al. Competing risks and prognostic cirrhosis and ascites. Gut 2010;59:105–110.
stages of cirrhosis: a 25-year inception cohort study of 494 patients. [193] Ruiz-del-Arbol L, Urman J, Fernandez J, Gonzalez M, Navasa M,
Aliment Pharmacol Ther 2014;39:1180–1193. Monescillo A, et al. Systemic, renal, and hepatic hemodynamic
[172] Augustin S, Muntaner L, Altamirano JT, Gonzalez A, Saperas E, Dot J, derangement in cirrhotic patients with spontaneous bacterial peritoni-
et al. Predicting early mortality after acute variceal hemorrhage based tis. Hepatology 2003;38:1210–1218.
on classification and regression tree analysis. Clin Gastroenterol [194] Payance A, Bissonnette J, Roux O, Elkrief L, Gault N, Francoz C, et al. Lack
Hepatol 2009;7:1347–1354. of clinical or haemodynamic rebound after abrupt interruption of beta-
[173] Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet blockers in patients with cirrhosis. Aliment Pharmacol Ther
2003;361:952–954. 2016;43:966–973.
[174] Garcia-Pagan JC, De Gottardi A, Bosch J. Review article: the modern [195] Garcia-Tsao G, Bosch J. Management of varices and variceal hemor-
management of portal hypertension–primary and secondary prophy- rhage in cirrhosis. N Engl J Med 2010;362:823–832.
laxis of variceal bleeding in cirrhotic patients. Aliment Pharmacol Ther [196] Villanueva C, Escorsell A. Optimizing general management of acute
2008;28:178–186. variceal bleeding in cirrhosis. Curr Hepatol Rep 2014;13:198–207.
[175] Hernandez-Gea V, Aracil C, Colomo A, Garupera I, Poca M, Torras X, [197] Avgerinos A, Nevens F, Raptis S, Fevery J. Early administration of
et al. Development of ascites in compensated cirrhosis with severe somatostatin and efficacy of sclerotherapy in acute oesophageal
portal hypertension treated with beta-blockers. Am J Gastroenterol variceal bleeds: the European Acute Bleeding Oesophageal
2012;107:418–427. Variceal Episodes (ABOVE) randomised trial. Lancet 1997;350:
[176] Puente A, Hernandez-Gea V, Graupera I, Roque M, Colomo A, Poca M, 1495–1499.
et al. Drugs plus ligation to prevent rebleeding in cirrhosis: an updated [198] Levacher S, Letoumelin P, Pateron D, Blaise M, Lapandry C, Pourriat JL.
systematic review. Liver Int 2014;34:823–833. Early administration of terlipressin plus glyceryl trinitrate to control
[177] Villanueva C, Graupera I, Aracil C, Alvarado E, Minana J, Puente A, et al. active upper gastrointestinal bleeding in cirrhotic patients. Lancet
A randomized trial to assess whether portal pressure guided therapy to 1995;346:865–868.
prevent variceal rebleeding improves survival in cirrhosis. Hepatology [199] Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive
2017;65:1693–1707. bleeding in cirrhosis: Risk stratification, diagnosis, and management:
[178] D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal 2016 practice guidance by the American Association for the study of
hypertension: an evidence-based approach. Semin Liver Dis liver diseases. Hepatology 2017;65:310–335.
1999;19:475–505. [200] Myburgh JA. Fluid resuscitation in acute illness–time to reappraise the
[179] Albillos A, Banares R, Gonzalez M, Ripoll C, Gonzalez R, Catalina MV, basics. N Engl J Med 2011;364:2543–2544.
et al. Value of the hepatic venous pressure gradient to monitor drug [201] Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V,
therapy for portal hypertension: a meta-analysis. Am J Gastroenterol Aracil C, et al. Transfusion strategies for acute upper gastrointestinal
2007;102:1116–1126. bleeding. N Engl J Med 2013;368:11–21.
[180] Li T, Ke W, Sun P, Chen X, Belgaumkar A, Huang Y, et al. Carvedilol for [202] Seo YS, Park SY, Kim MY, Kim JH, Park JY, Yim HJ, et al. Lack of difference
portal hypertension in cirrhosis: systematic review with meta-analysis. among terlipressin, somatostatin, and octreotide in the control of
BMJ Open 2016;6:e010902. acute gastroesophageal variceal hemorrhage. Hepatology 2014;60:
[181] Serste T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. 954–963.
Deleterious effects of beta-blockers on survival in patients with [203] Azam Z, Hamid S, Jafri W, Salih M, Abbas Z, Abid S, et al. Short course
cirrhosis and refractory ascites. Hepatology 2010;52:1017–1022. adjuvant terlipressin in acute variceal bleeding: a randomized double
[182] Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic blind dummy controlled trial. J Hepatol 2012;56:819–824.
and non-haemodynamic effects of beta-blockers improve survival of [204] Altraif I, Handoo FA, Aljumah A, Alalwan A, Dafalla M, Saeed AM, et al.
patients with cirrhosis during a window in the disease. Gut Effect of erythromycin before endoscopy in patients presenting with
2012;61:967–969. variceal bleeding: a prospective, randomized, double-blind, placebo-
[183] Bossen L, Krag A, Vilstrup H, Watson H, Jepsen P. Non-selective beta- controlled trial. Gastrointest Endosc 2011;73:245–250.
blockers do not affect mortality in cirrhosis patients with ascites: Post [205] Banares R, Albillos A, Rincon D, Alonso S, Gonzalez M, Ruiz-del-Arbol L,
hoc analysis of three RCTs with 1198 patients. Hepatology et al. Endoscopic treatment vs. endoscopic plus pharmacologic treat-
2016;63:1968–1976. ment for acute variceal bleeding: a meta-analysis. Hepatology
[184] Bang UC, Benfield T, Hyldstrup L, Jensen JE, Bendtsen F. Effect of 2002;35:609–615.
propranolol on survival in patients with decompensated cirrhosis: a [206] Villanueva C, Piqueras M, Aracil C, Gomez C, Lopez-Balaguer JM,
nationwide study based Danish patient registers. Liver Int Gonzalez B, et al. A randomized controlled trial comparing ligation and
2016;36:1304–1312. sclerotherapy as emergency endoscopic treatment added to somato-
[185] Reiberger T, Mandorfer M. Beta adrenergic blockade and decompen- statin in acute variceal bleeding. J Hepatol 2006;45:560–567.
sated cirrhosis. J Hepatol 2017;66:849–859. [207] Rios Castellanos E, Seron P, Gisbert JP, Bonfill Cosp X. Endoscopic
[186] Leithead JA, Rajoriya N, Tehami N, Hodson J, Gunson BK, Tripathi D, injection of cyanoacrylate glue vs. other endoscopic procedures for
et al. Non-selective b-blockers are associated with improved survival in acute bleeding gastric varices in people with portal hypertension.
patients with ascites listed for liver transplantation. Gut 2015;64: Cochrane Database Syst Rev 2015;5:CD010180.
1111–1119. [208] Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic
[187] Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer U, Patch D, prophylaxis for the prevention of bacterial infections in cirrhotic
et al. Beta-blockers protect against spontaneous bacterial peritonitis in patients with gastrointestinal bleeding: a meta-analysis. Hepatology
cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189–1193. 1999;29:1655–1661.
[188] Reiberger T, Ferlitsch A, Payer BA, Mandorfer M, Heinisch BB, Hayden H, [209] Fernandez J, Ruiz del Arbol L, Gomez C, Durandez R, Serradilla R,
et al. Non-selective beta-blocker therapy decreases intestinal perme- Guarner C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of
ability and serum levels of LBP and IL-6 in patients with cirrhosis. J infections in patients with advanced cirrhosis and hemorrhage.
Hepatol 2013;58:911–921. Gastroenterology 2006;131:1049–1056.

JOURNAL
OF HEPATOLOGY
[210] Tandon P, Abraldes JG, Keough A, Bastiampillai R, Jayakumar S, gastric variceal bleed: a randomised controlled trial. Gut
Carbonneau M, et al. Risk of bacterial infection in patients with 2010;59:729–735.
cirrhosis and acute variceal hemorrhage, based on child-pugh class, and [233] Chau TN, Patch D, Chan YW, Nagral A, Dick R, Burroughs AK. ‘‘Salvage”
effects of antibiotics. Clin Gastroenterol Hepatol 2015;13:1189–1196. transjugular intrahepatic portosystemic shunts: gastric fundal com-
[211] Cardenas A, Gines P, Uriz J, Bessa X, Salmeron JM, Mas A, et al. Renal pared with esophageal variceal bleeding. Gastroenterology
failure after upper gastrointestinal bleeding in cirrhosis: incidence, 1998;114:981–998.
clinical course, predictive factors, and short-term prognosis. Hepatol- [234] Hung HH, Chang CJ, Hou MC, Liao WC, Chan CC, Huang HC, et al.
ogy 2001;34:671–676. Efficacy of non-selective beta-blockers as adjunct to endoscopic
[212] Shaheen NJ, Stuart E, Schmitz SM, Mitchell KL, Fried MW, Zacks S, et al. prophylactic treatment for gastric variceal bleeding: a randomized
Pantoprazole reduces the size of postbanding ulcers after variceal band controlled trial. J Hepatol 2012;56:1025–1032.
ligation: a randomized, controlled trial. Hepatology 2005;41:588–594. [235] Lo GH, Liang HL, Chen WC, Chen MH, Lai KH, Hsu PI, et al. A prospective,
[213] Escorsell A, Pavel O, Cardenas A, Morillas R, Llop E, Villanueva C, et al. randomized controlled trial of transjugular intrahepatic portosystemic
Esophageal balloon tamponade vs. esophageal stent in controlling acute shunt vs. cyanoacrylate injection in the prevention of gastric variceal
refractory variceal bleeding: A multicenter randomized, controlled rebleeding. Endoscopy 2007;39:679–685.
trial. Hepatology 2016;63:1957–1996. [236] Saad WE. Endovascular management of gastric varices. Clin Liver Dis
[214] Monescillo A, Martínez-Lagares F, Ruiz-del-Arbol L, et al. Influence of 2014;18:829–885.
portal hypertension and its early decompression by TIPS placement on [237] Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA,
the outcome of variceal bleeding. Hepatology 2004;40:793–801. et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on
[215] García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in patients cirrhosis is reversible and predicts the outcome. Hepatology
with cirrhosis and variceal bleeding. N Engl J Med 2010;362: 2007;46:831–840.
2370–2379. [238] Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghoner A, Vidacek D,
[216] Garcia-Pagan JC, Di Pascoli M, Caca K, Laleman W, Bureau C, Appenrodt Siewert E, et al. Patients with acute on chronic liver failure display
B, et al. Use of early-TIPS for high-risk variceal bleeding: results of a ‘‘sepsis-like” immune paralysis. J Hepatol 2005;42:195–201.
post-RCT surveillance study. J Hepatol 2013;58:45–50. [239] Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis.
[217] Rudler M, Cluzel P, Corvec TL, Benosman H, Rousseau G, Poynard T, Hepatology 2005;41:422–433.
et al. Early-TIPSS placement prevents rebleeding inhigh-risk patients [240] Appenrodt B, Grunhage F, Gentemann MG, Thyssen L, Sauerbruch T,
with variceal bleeding, without improving survival. Aliment Pharmacol Lammert F. Nucleotide-binding oligomerization domain containing 2
Ther 2014;40:1074–1080. (NOD2) variants are genetic risk factors for death and spontaneous
[218] Augustin S, Altamirano J, Gonzalez A, Dot J, Abu-Suboh M, Armengol JR, bacterial peritonitis in liver cirrhosis. Hepatology 2010;51:
et al. Effectiveness of combined pharmacologic and ligation therapy in 1327–1333.
high-risk patients with acute esophageal variceal bleeding. Am J [241] Fernandez J, Navasa M, Gomez J, et al. Bacterial infections in cirrhosis:
Gastroenterol 2011;106:1787–1795. epidemiological changes with invasive procedures and norfloxacin
[219] Reverter E, Tandon P, Augustin S, Turon F, Casu S, Bastiampillai R, et al. prophylaxis. Hepatology 2002;35:140–148.
A MELD-based model to determine risk of mortality among patients [242] Fasolato S, Angeli P, Dallagnese L, et al. Renal failure and bacterial
with acute variceal bleeding. Gastroenterology 2014;146:412–419. infections in patients with cirrhosis: epidemiology and clinical features.
[220] Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural Hepatology 2007;45:223–229.
history of portal hypertensive gastropathy in patients with liver [243] Piano S, Fasolato S, Salinas F, Romano A, Tonon M, Morando F, et al. The
cirrhosis and mild portal hypertension. Am J Gastroenterol empirical antibiotic treatment of nosocomial spontaneous bacterial
2004;99:1959–1965. peritonitis: Results of a randomized, controlled clinical trial. Hepatol-
[221] Thuluvath PJ, Yoo HY. Portal Hypertensive gastropathy. Am J Gastroen- ogy 2016;63:1299–1309.
terol 2002;97:2973–2978. [244] Runyon BA. The evolution of ascitic fluid analysis in the diagnosis of
[222] Yoshikawa I, Murata I, Nakano S, Otsuki M. Effects of endoscopic spontaneous bacterial peritonitis. Runyon BA. Am J Gastroenterol
variceal ligation on portal hypertensive gastropathy and gastric 2003;98:1675–1677.
mucosal blood flow. Am J Gastroenterol 1998;93:71–74. [245] Evans LT, Kim WR, Poterucha JJ, Kamath PS. Spontaneous bacterial
[223] Urrunaga NH, Rockey DC. Portal hypertensive gastropathy and colopa- peritonitis in asymptomatic outpatients with cirrhotic ascites. Hepa-
thy. Clin Liver Dis 2014;18:389–406. tology 2003;37:897–901.
[224] Hosking SW, Kennedy HJ, Seddon I, Triger DR. The role of propranolol in [246] Kim JJ, Tsukamoto MM, Mathur AK, Ghomri YM, Hou LA, Sheibani S,
congestive gastropathy of portal hypertension. Hepatology et al. Delayed paracentesis is associated with increased in-hospital
1987;7:437–441. mortality in patients with spontaneous bacterial peritonitis. Am J
[225] Perez-Ayuso RM, Pique JM, Bosch J, Panes J, Gonzalez A, Perez R, et al. Gastroenterol 2014;109:1436–1442.
Propranolol in prevention of recurrent bleeding from severe portal [247] Van de Geijn GM, van Gent M, van Pul-Bom N, Beunis MH, van Tilburg
hypertensive gastropathy in cirrhosis. Lancet 1991;337:1431–1434. AJ, Njo TL. A new flow cytometric method for differential cell counting
[226] Ripoll C, Garcia-Tsao G. Treatment of gastropathy and gastric antral in ascitic fluid. Cytometry B Clin Cytom 2016;90:506–511.
vascular ectasia in patients with portal hypertension. Curr Treat [248] Fleming C, Brouwer R, van Alphen A, Lindemans J, de Jonge R. UF-1000i:
Options Gastroenterol 2007;10:483–494. validation of the body fluid mode for counting cells in body fluids. Clin
[227] Kamath P, Lacerda M, Ahlquist D, McKusick MA, Andrews JC, Nagorney Chem Lab Med 2014;52:1781–1790.
DA. Gastric Mucosal Responses to intrahepatic portosystemic shunting [249] Gülberg V, Gerbes AL, Sauerbruch T, Appenrodt B. Insufficient sensi-
in patients with cirrhosis. Gastroenterology 2000;118:905–911. tivity of reagent strips for spontaneous bacterial peritonitis. Hepatology
[228] Zhou Y, Qiao L, Wu J, Hu H, Xu C. Comparison of the efficacy of 2007;46:1669.
octreotide, vasopressin, and omeprazole in the control of acute [250] Bellot P, García-Pagán JC, Francés R, Abraldes JG, Navasa M, Pérez-
bleeding in patients with portal hypertensive gastropathy: a controlled Mateo M, et al. Bacterial DNA translocation is associated with systemic
study. J Gastroenterol Hepatol 2002;17:973–979. circulatory abnormalities and intrahepatic endothelial dysfunction in
[229] Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, patients with cirrhosis. Hepatology 2010;52:2044–2052.
classification and natural history of gastric varices: a long-term follow- [251] Bruns T, Reuken PA, Stengel S, Gerber L, Appenrodt B, Schade JH, et al.
up study in 568 portal hypertension patients. Hepatology The prognostic significance of bacterial DNA in patients with decom-
1992;16:1343–1349. pensated cirrhosis and suspected infection. Liver Int 2016;36:
[230] Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of 1133–1142.
gastric variceal bleeding comparing cyanoacrylate injection and beta- [252] Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: a variant of
blockers: a randomized controlled trial. J Hepatol 2011;54:1161–1167. spontaneous bacterial peritonitis. Hepatology 1984;4:1209–1211.
[231] Rios CE, Seron P, Gisbert JP, Bonfill CX. Endoscopic injection of [253] Gravito-Soares M, Gravito-Soares E, Lopes S, Ribeiro G, Figueiredo P.
cyanoacrylate glue vs. other endoscopic procedures for acute bleeding Spontaneous fungal peritonitis: a rare but severe complication of liver
gastric varices in people with portal hypertension. Cochrane Database cirrhosis. Eur J Gastroenterol Hepatol 2017;29:1010–1016.
Syst Rev 2015;5:CD010180. [254] Chen CH, Shih CM, Chou JW, Liu YH, Hang LW, Hsia TC, et al. Outcome
[232] Mishra SR, Chander Sharma B, Kumar A, Sarin SK. Endoscopic predictors of cirrhotic patients with spontaneous bacterial empyema.
cyanoacrylate injection vs. beta-blocker for secondary prophylaxis of Liver Int 2011;31:417–424.

[255] Xiol X, Castellvi JM, Guardiola J, Sese E, Castellote J, Perello A, et al. torenal syndrome and improves survival in cirrhosis. Gastroenterology
Spontaneous bacterial empyema in cirrhotic patients: a prospective 2007;133:818–824.
study. Hepatology 1996;23:719–723. [277] Terg R, Fassio E, Guevara M, Cartier M, Longo C, Lucero R, et al.
[256] Soriano G, Castellote J, Alvarez C, Girbau A, Gordillo J, Baliellas C, et al. Ciprofloxacin in primary prophylaxis of spontaneous bacterial peri-
Secondary bacterial peritonitis in cirrhosis: a retrospective study of tonitis: A randomized, placebo-controlled study. J Hepatol
clinical and analytical characteristics, diagnosis and management. J 2008;48:774–779.
Hepatol 2010;52:39–44. [278] Loomba R, Wesley R, Bain A, et al. Role of fluoroquinolones in the
[257] Rimola A, Salmeron JM, Clemente G, Rodrigo L, Obrador A, Miranda ML, primary prophylaxis of spontaneous bacterial peritonitis: meta-analy-
et al. Two different dosages of cefotaxime in the treatment of sis. Clin Gastroenterol Hepatol 2009;7:487–493.
spontaneous bacterial peritonitis in cirrhosis: results of a prospective, [279] Saab S, Hernandez JC, Chi AC, et al. Oral antibiotic prophylaxis reduces
randomized, multicenter study. Hepatology 1995;21:674–679. spontaneous bacterial peritonitis occurrence and improves short-term
[258] Runyon Runyon BA, McHutchison JG, Antillon MR, Akriviadis EA, survival in cirrhosis: a meta-analysis. Am J Gastroenterol 2009;104:
Montano AA. Short-course vs. long-course antibiotic treatment of 993–1001.
spontaneous bacterial peritonitis. A randomized controlled study of [280] Krag A, Wiest R, Gluud LL. Fluoroquinolones in the primary prophylaxis
100 patients. Gastroenterology 1991;100:1737–1742. of spontaneous bacterial peritonitis. Am J Gastroenterol
[259] Ricart E, Soriano G, Novella MT, Ortiz J, Sabat M, Kolle L, et al. 2010;105:1444–1445.
Amoxicillin-clavulanic acid vs. cefotaxime in the therapy of bacterial [281] Gines P, Rimola A, Planas R, Vargas V, Marco F, Almela M, et al.
infections in cirrhotic patients. J Hepatol 2000;32:596–602. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in
[260] deLemos AS, Ghabril M, Rockey DC, Gu J, Barnhart HX, Fontana RJ, et al. cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology
Drug-induced liver injury network (DILIN). Amoxicillin-clavulanate- 1990;12:716–724.
induced liver injury. Dig Dis Sci 2016;61:2406–2416. [282] Bauer TM, Follo A, Navasa M, Vila J, Planas R, Clemente G, et al. Daily
[261] Terg R, Cobas S, Fassio E, Landeira G, Rios B, Vasen W, et al. Oral norfloxacin is more effective than weekly rufloxacin in prevention of
ciprofloxacin after a short course of intravenous ciprofloxacin in the spontaneous bacterial peritonitis recurrence. Dig Dis Sci
treatment of spontaneous bacterial peritonitis: results of a multicenter, 2002;47:1356–1361.
randomized study. J Hepatol 2000;33:564–569. [283] Terg R, Llano K, Cobas SM, Brotto C, Barrios A, Levi D, et al. Effects of oral
[262] Angeli P, Guarda S, Fasolato S, Miola E, Craighero R, Piccolo F, et al. ciprofloxacin on aerobic gram-negative fecal flora in patients with
Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the cirrhosis: results of short- and long-term administration, with daily and
treatment of spontaneous bacterial peritonitis in patients with cirrho- weekly dosages. J Hepatol 1998;29:437–442.
sis: similar efficacy at lower cost. Aliment Pharmacol Ther 2006;23:75–84. [284] Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al.
[263] Navasa M, Follo A, Llovet JM, Clemente G, Vargas V, Rimola A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med
Randomized, comparative study of oral ofloxacin vs. intravenous 2010;362:071–1081.
cefotaxime in spontaneous bacterial peritonitis. Gastroenterology [285] Elfert A, Abo Ali L, Soliman S, Ibrahim S, Abd-Elsalam S. Randomized-
1996;111:1011–1017. controlled trial of rifaximin vs. norfloxacin for secondary prophylaxis of
[264] Fernandez J, Bert F, Nicolas-Chanoine MH. The challenges of multi- spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol
drug-resistance in hepatology. J Hepatol 2016;65:1043–1054. 2016;28:1450–1454.
[265] Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, [286] Min YW, Lim KS, Min BH, Gwak GY, Paik YH, Choi MS, et al. Proton
et al. Multidrug-resistant, extensively drug-resistant and pandrug- pump inhibitor use significantly increases the risk of spontaneous
resistant bacteria: an international expert proposal for interim stan- bacterial peritonitis in 1965 patients with cirrhosis and ascites: a
dard definitions for acquired resistance. Clin Microbiol Infect propensity score matched cohort study. Aliment Pharmacol Ther
2012;18:268–281. 2014;40:695–704.
[266] Fernandez J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, et al. [287] Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk
Prevalence and risk factors of infections by multiresistant bacteria in factor for hepatic encephalopathy and spontaneous bacterial peritonitis
cirrhosis: a prospective study. Hepatology 2012;55:1551–1561. in patients with cirrhosis with ascites. Hepatology 2016;64:
[267] Wiest R, Krag A, Gerbes A. Spontaneous bacterial peritonitis: recent 1265–1272.
guidelines and beyond. Gut 2012;61:297–310. [288] Mandorfer M, Bota S, Schwabl P, Bucsics T, Pfisterer N, Kruzik M, et al.
[268] Piano S, Brocca A, Mareso S, Angeli P. Infections complicating cirrhosis. Nonselective beta blockers increase risk for hepatorenal syndrome and
Liver Int 2018;38:126–133. death in patients with cirrhosis and spontaneous bacterial peritonitis.
[269] Lutz P, Nischalke HD, Kramer B, Goeser F, Kaczmarek DJ, Schlabe S, et al. Gastroenterology 2014;146:1680–1690.
Antibiotic resistance in healthcare-related and nosocomial sponta- [289] Pande C, Kumar A, Sarin SK. Addition of probiotics to norfloxacin does
neous bacterial peritonitis. Eur J Clin Invest 2017;47:44–52. not improve efficacy in the prevention of spontaneous bacterial
[270] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, peritonitis: a double-blind placebo-controlled randomized-controlled
Bauer M, et al. The third international consensus definitions for sepsis trial. Eur J Gastroenterol Hepatol 2012;24:831–839.
and septic shock (Sepsis-3). JAMA 2016;315:801–810. [290] Fernandez J, Acevedo J, Arroyo V. Response to the clinical course and
[271] Piano S, Bartoletti M, Tonon M, Baldassarre M, Chies G, Romano A, et al. short-term mortality of cirrhotic patients with non-spontaneous bac-
Assessment of Sepsis-3 criteria and quick SOFA in patients with terial peritonitis infections. Liver Int 2017;37:623.
cirrhosis and bacterial infections. Gut 2017. [291] Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo
[272] Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. M, et al. Infections in patients with cirrhosis increase mortality four-
Effect of intravenous albumin on renal impairment and mortality in fold and should be used in determining prognosis. Gastroenterology
patients with cirrhosis and spontaneous bacterial peritonitis. N EnglJ 2010;139:1256.
Med 1999;341:403–409. [292] Piano S, Morando F, Carretta G, Tonon M, Vettore E, Rosi S, et al.
[273] Garioud A, Cadranel JF, Pauwels A, Nousbaum JB, Thévenot T, Dao T, Predictors of early readmission in patients with cirrhosis after the
et al. Association Nationale des Hépato-gastroentérologues des Hôpi- resolution of bacterial infections. Am J Gastroenterol 2017;112:
taux Généraux de France, Association Française pour l’Etude du Foie, 1575–1583.
Club de Réflexion des Cabinets et Groupes d’Hépato-Gastroentérologie. [293] Bartoletti M, Giannella M, Lewis R, Caraceni P, Tedeschi S, Paul M, et al.
Albumin Use in Patients With Cirrhosis in France: Results of the ‘‘ALBU- A prospective multicentre study of the epidemiology and outcomes of
LIVE” Survey: A Case for Better EASL Guidelines Diffusion and/or bloodstream infection in cirrhotic patients. Clin Microbiol Infect 2017.
Revision. J Clin Gastroenterol 2017;51:831–838. [294] Merli M, Lucidi C, Di Gregorio V, Lattanzi B, Giannelli V, Giusto M, et al.
[274] Poca M, Concepcion M, Casas M, Alvarez-Urturi C, Gordillo J, Hernan- An empirical broad spectrum antibiotic therapy in health-care-associ-
dez-Gea V, et al. Role of albumin treatment in patients with sponta- ated infections improves survival in patients with cirrhosis: A ran-
neous bacterial peritonitis. Clin Gastroenterol Hepatol 2012;10: domized trial. Hepatology 2016;63:1632–1639.
309–315. [295] Fiore M, Chiodini P, Pota V, Sansone P, Passavanti MB, Leone S, et al.
[275] Fernandez J, Tandon P, Mensa J, Garcia-Tsao G. Antibiotic prophylaxis in Risk of spontaneous fungal peritonitis in hospitalized cirrhotic patients
cirrhosis: Good and bad. Hepatology 2016;63:2019–2031. with ascites: a systematic review of observational studies and meta-
[276] Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. analysis. Minerva Anestesiol 2017;83:1309–1316.
Primary prophylaxis of spontaneous bacterial peritonitis delays hepa- [296] Piano S, Angeli P. Reply letter. Hepatology 2016;64:998–999.

JOURNAL
OF HEPATOLOGY
[297] Guevara M, Terra C, Nazar A, Sola E, Fernandez J, Pavesi M, et al. [320] Rosi S, Piano S, Frigo AC, Morando F, Fasolato S, Cavallin M, et al. New
Albumin for bacterial infections other than spontaneous bacterial ICA criteria for the diagnosis of acute kidney injury in cirrhotic patients:
peritonitis in cirrhosis. A randomized, controlled study. J Hepatol can we use an imputed value of serum creatinine? Liver Int
2012;57:759–765. 2015;35:2108–2114.
[298] Thevenot T, Bureau C, Oberti F, Anty R, Louvet A, Plessier A, et al. Effect [321] Guevara M, Fernandez-Esparrach G, Alessandria C, Torre A, Terra C,
of albumin in cirrhotic patients with infection other than spontaneous Montana X, et al. Effects of contrast media on renal function in patients
bacterial peritonitis. A randomized trial. J Hepatol 2015;62:822–830. with cirrhosis: a prospective study. Hepatology 2004;40:646–651.
[299] Piano S, Romano A, Di Pascoli M, Angeli P. Why and how to measure [322] Umgelter A, Reindl W, Franzen M, Lenhardt C, Huber W, Schmid RM.
renal function in patients with liver disease. Liver Int 2017;37: Renal resistive index and renal function before and after paracentesis in
116–122. patients with hepatorenal syndrome and tense ascites. Intensive Care
[300] Gonwa TA, Jennings L, Mai ML, Stark PC, Levey AS, Klintmalm GB. Med 2009;35:152–156.
Estimation of glomerular filtration rates before and after orthotopic [323] Cabrera J, Falcón L, Gorriz E, Pardo MD, Granados R, Quinones A,
liver transplantation: evaluation of current equations. Liver Transpl Maynar M. Abdominal decompression plays a major role in early
2004;10:301–309. postparacentesis haemodynamic changes in cirrhotic patients with
[301] Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, tense ascites. Gut 2001;48:384–389.
plasma creatinine and the Cockcroft and Gault formula for the [324] de Cleva R, Silva FP, Zilberstein B, Machado DJ. Acute renal failure due
estimation of glomerular filtration rate. Nephrol Dial Transplant to abdominal compartment syndrome: report on four cases and
2003;18:2024–2031. literature review. Rev Hospital das Clin 2001;56:123–130.
[302] Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, [325] Nadim MK, Durand F, Kellum JA, Levitsky J, O’Leary JG, Karvellas CJ,
et al. Estimating glomerular filtration rate from serum creatinine and et al. Management of the critically ill patient with cirrhosis: A
cystatin C. N Engl J Med 2012;367:20–29. multidisciplinary perspective. J Hepatol 2016;64:717–735.
[303] Roy L, Legault L, Pomier-Layrargues G. Glomerular filtration rate [326] Umgelter A, Reindl W, Wagner KS, Franzen M, Stock K, Schmid RM,
measurement in cirrhotic patients with renal failure. Clin Nephrol et al. Effects of plasma expansion with albumin and paracentesis on
1998;50:342–346. haemodynamics and kidney function in critically ill cirrhotic patients
[304] Francoz C, Nadim MK, Baron A, Prie D, Antoine C, Belghiti J, et al. with tense ascites and hepatorenal syndrome: a prospective uncon-
Glomerular filtration rate equations for liver-kidney transplantation in trolled trial. Critical care 2008;12:R4.
patients with cirrhosis: validation of current recommendations. Hepa- [327] Moreau R, Lebrec D. Diagnosis and treatment of acute renal failure in
tology 2014;59:1514–1521. patients with cirrhosis. Best Pract Res Clin Gastroenterol
[305] Francoz C, Glotz D, Moreau R, Durand F. The evaluation of renal 2007;21:111–123.
function and disease in patients with cirrhosis. J Hepatol [328] Moreau R, Lebrec D. Acute renal failure in patients with cirrhosis:
2010;52:605–613. perspectives in the age of MELD. Hepatology 2003;37:233–243.
[306] Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. [329] Fagundes C, Pepin MN, Guevara M, Barreto R, Casals G, Sola E, et al.
Hepatology 2008;48:2064–2077. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the
[307] Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention differential diagnosis of impairment of kidney function in cirrhosis. J
and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56: Hepatol 2012;57:267–273.
310–1318. [330] Belcher JM, Sanyal AJ, Peixoto AJ, Perazella MA, Lim J, Thiessen-
[308] Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Philbrook H, et al. Kidney biomarkers and differential diagnosis of
Acute Kidney Injury Network: report of an initiative to improve patients with cirrhosis and acute kidney injury. Hepatology
outcomes in acute kidney injury. Crit Care 2007;11:R31. 2014;60:622–632.
[309] Nadim MK, Kellum JA, Davenport A, Wong F, Davis C, Pannu N, et al. [331] Qasem AA, Farag SE, Hamed E, Emara M, Bihery A, Pasha H. Urinary
Hepatorenal syndrome: the 8th International Consensus Conference of biomarkers of acute kidney injury in patients with liver cirrhosis. ISRN
the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2012;16: Nephrol 2014;2014:376795.
R23. [332] Barreto R, Elia C, Sola E, Moreira R, Ariza X, Rodriguez E, et al. Urinary
[310] Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. neutrophil gelatinase-associated lipocalin predicts kidney outcome and
Nephron Clin Pract 2012;120:c179–c184. death in patients with cirrhosis and bacterial infections. J Hepatol
[311] Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al. 2014;61:35–42.
Association of AKI with mortality and complications in hospitalized [333] Ariza X, Sola E, Elia C, Barreto R, Moreira R, Morales-Ruiz M, et al.
patients with cirrhosis. Hepatology 2013;57:753–762. Analysis of a urinary biomarker panel for clinical outcomes assessment
[312] de Carvalho JR, Villela-Nogueira CA, Luiz RR, Guzzo PL, da Silva Rosa JM, in cirrhosis. PLoS One 2015;10:e0128145.
Rocha E, et al. Acute kidney injury network criteria as a predictor of [334] Puthumana J, Ariza X, Belcher JM, Graupera I, Ginès P, Parikh CR. Urine
hospital mortality in cirrhotic patients with ascites. J Clin Gastroenterol interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis
2012;46:21–26. in patients with cirrhosis: a systematic review and meta-analysis. Clin
[313] Fagundes C, Barreto R, Guevara M, Garcia E, Solà E, Rodríguez E, et al. A Gastroenterol Hepatol 2017;15:1003–1013.
modified acute kidney injury classification for diagnosis and risk [335] Huelin P, Elia C, Solà E, Solé C, Moreira R, Carol M. New diagnostic
stratification of impairment of kidney function in cirrhosis. J Hepatol algorithm of acute kidney injury in cirrhosis that includes categoriza-
2013;59:474–481. tion of stage 1 and assessment of urine NGAL. Relevance for the
[314] Piano S, Rosi S, Maresio G, Fasolato S, Cavallin M, Romano A, et al. differential diagnosis and clinical outcomes. J Hepatol 2017;66:S11.
Evaluation of the Acute Kidney Injury Network criteria in hospi- [336] Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and
talized patients with cirrhosis and ascites. J Hepatol 2013;59:482–489. chronic kidney disease as interconnected syndromes. N Engl J Med
[315] Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated 2014;371:58–66.
cirrhosis. Gut 2013;62:131–137. [337] Trawale JM, Paradis V, Rautou PE, Francoz C, Escolano S, Sallee M, et al.
[316] Wong F, O’Leary JG, Reddy KR, Patton H, Kamath PS, Fallon MB, et al. The spectrum of renal lesions in patients with cirrhosis: a clinico-
New consensus definition of acute kidney injury accurately predicts 30- pathological study. Liver Int 2010;30:725–732.
day mortality in patients with cirrhosis and infection. Gastroenterology [338] Wadei HM, Geiger XJ, Cortese C, Mai ML, Kramer DJ, Rosser BG, et al.
2013;145:1280–1288. Kidney allocation to liver transplant candidates with renal failure of
[317] Huelin P, Piano S, Solà E, Stanco M, Solé C, Moreira R, et al. Validation of undetermined etiology: role of percutaneous renal biopsy. Am J
a staging system for acute kidney injury in patients with cirrhosis and Transplant 2008;8:2618–2626.
association with acute-on-chronic liver failure. Clin Gastroenterol [339] Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, et al.
Hepatol 2017;15:438–445. Working Party proposal for a revised classification system of renal
[318] Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. dysfunction in patients with cirrhosis. Gut 2011;60:702–709.
Diagnosis and management of acute kidney injury in patients with [340] Stadlbauer V, Wright GA, Banaji M, Mukhopadhya A, Mookerjee RP,
cirrhosis: revised consensus recommendations of the International Moore K, et al. Relationship between activation of the sympathetic
Club of Ascites. J Hepatol 2015;62:968–974. nervous system and renal blood flow autoregulation in cirrhosis.
[319] Kidney Disease: Inproving Global Outcomes (KDIGO) CKD Work Group. Gastroenterology 2008;134:111–119.
KDIGO. Clinical practice guideline for the evaluation and management [341] Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in
of chronic kidney disease. Kidny Int 2012;2013:1–150. liver cirrhosis. J Hepatol 2014;60:197–209.

[342] Albillos A, de la Hera A, Gonzalez M, Moya JL, Calleja JL, Monserrat J, namics in patients with cirrhosis. J Gastroenterol Hepatol 2009;24:
et al. Increased lipopolysaccharide binding protein in cirrhotic patients 1791–1797.
with marked immune and hemodynamic derangement. Hepatology [364] Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R.
2003;37:208–217. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis
[343] Navasa M, Follo A, Filella X, Jimenez W, Francitorra A, Planas R, et al. and its complications. Hepatology 2013;58:1836–1846.
Tumor necrosis factor and interleukin-6 in spontaneous bacterial [365] Gerbes AL, Huber E, Gulberg V. Terlipressin for hepatorenal syndrome:
peritonitis in cirrhosis: relationship with the development of renal continuous infusion as an alternative to i.v. bolus administration.
impairment and mortality. Hepatology 1998;27:1227–1232. Gastroenterology 2009;137:1179–1181.
[344] Shah N, Dhar D, El Zahraa Mohammed F, Habtesion A, Davies NA, [366] Piano S, Morando F, Fasolato S, Cavallin M, Boscato N, Boccagni P, et al.
Jover-Cobos M, et al. Prevention of acute kidney injury in a rodent Continuous recurrence of type 1 hepatorenal syndrome and long-term
model of cirrhosis following selective gut decontamination is asso- treatment with terlipressin and albumin: a new exception to MELD
ciated with reduced renal TLR4 expression. J Hepatol 2012;56: score in the allocation system to liver transplantation? J Hepatol
1047–1053. 2011;55:491–496.
[345] Shah N, Mohamed FE, Jover-Cobos M, Macnaughtan J, Davies N, Moreau [367] Gow PJ, Ardalan ZS, Vasudevan A, Testro AG, Ye B, Angus PW.
R, et al. Increased renal expression and urinary excretion of TLR4 in Outpatient terlipressin infusion for the treatment of refractory ascites.
acute kidney injury associated with cirrhosis. Liver Int 2013;33: Am J Gastroenterol 2016;111:1041–1042.
398–409. [368] Alessandria C, Ottobrelli A, Debernardi-Venon W, Todros L, Cerenzia
[346] Alobaidi R, Basu RK, Goldstein SL, Bagshaw SM. Sepsis-associated acute MT, Martini S, et al. Noradrenalin vs terlipressin in patients with
kidney injury. Semin Nephrol 2015;35:2–11. hepatorenal syndrome: a prospective, randomized, unblinded, pilot
[347] Emlet DR, Shaw AD, Kellum JA. Sepsis-associated AKI: epithelial cell study. J Hepatol 2007;47:499–505.
dysfunction. Semin Nephrol 2015;35:85–95. [369] Duvoux C, Zanditenas D, Hezode C, Chauvat A, Monin JL, Roudot-
[348] Prowle JR, Bellomo R. Sepsis-associated acute kidney injury: macrohe- Thoraval F, et al. Effects of noradrenalin and albumin in patients with
modynamic and microhemodynamic alterations in the renal circula- type I hepatorenal syndrome: a pilot study. Hepatology 2002;36:374–380.
tion. Semin Nephrol 2015;35:64–74. [370] Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al.
[349] de Seigneux S, Martin PY. Preventing the progression of AKI to CKD: the Noradrenaline vs. terlipressin in the treatment of hepatorenal syn-
role of mitochondria. J Am Soc Nephrol 2017;28:1327–1329. drome: a randomized study. J Hepatol 2012;56:1293–1298.
[350] Bairaktari E, Liamis G, Tsolas O, Elisaf M. Partially reversible renal [371] Sharma P, Kumar A, Shrama BC, Sarin SK. An open label, pilot,
tubular damage in patients with obstructive jaundice. Hepatology randomized controlled trial of noradrenaline vs. terlipressin in the
2001;33:1365–1369. treatment of type 1 hepatorenal syndrome and predictors of response.
[351] van Slambrouck CM, Salem F, Meehan SM, Chang A. Bile cast Am J Gastroenterol 2008;103:1689–1697.
nephropathy is a common pathologic finding fo kidney injury associ- [372] Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA. Octreotide/
ated with severe liver dysfunction. Kidney Int 2013;84:192–197. Midodrine therapy significantly improves renal function and 30-day
[352] Durand F, Graupera I, Gines P, Olson JC, Nadim MK. Pathogenesis of survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci
hepatorenal syndrome: implications for therapy. Am J Kidney Dis 2007;52:742–748.
2016;67:318–328. [373] Restuccia T, Ortega R, Guevara M, Gines P, Alessandria C, Ozdogan O,
[353] Moreau R, Durand F, Poynard T, Duhamel C, Cervoni JP, Ichai P, et al. et al. Effects of treatment of hepatorenal syndrome before transplan-
Terlipressin in patients with cirrhosis and type 1 hepatorenal syn- tation on posttransplantation outcome. A case-control study. J Hepatol
drome: a retrospective multicenter study. Gastroenterology 2002;122: 2004;40:140–146.
923–930. [374] Rodriguez E, Henrique Pereira G, Sola E, Elia C, Barreto R, Pose E, et al.
[354] Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with and without Treatment of type 2 hepatorenal syndrome in patients awaiting
albumin for patients with hepatorenal syndrome: results of a prospec- transplantation: Effects on kidney function and transplantation out-
tive, nonrandomized study. Hepatology 2002;36:941–948. comes. Liver Transpl 2015;21:1347–1354.
[355] Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, [375] Boyer TD, Sanyal AJ, Garcia-Tsao G, Blei A, Carl D, Bexon AS, et al.
et al. A randomized prospective double blind, placebo controlled study Predictors of response to terliupressin plus albumin in hepatorenal
of terlipressin for type 1 hepatorenal syndrome. Gastroenterology syndrome (HRS) type 1: relationship of serum creatinine to hemody-
2008;134:1360–1368. namics. J Hepatol 2011;55:315–321.
[356] Martin-Llahi M, Pepin MN, Guevara M, Diaz F, Torre A, Monescillo A, [376] Piano S, Schmidt HH, Ariza X, Amoros A, Romano A, Solà E, et al. Impact
et al. Terlipressin and albumin vs albumin in patients with cirrhosis of Acute-on-Chronic Liver Failure on response to treatment with
and hepatorenal syndrome: a randomized study. Gastroenterology terlipressin and albumin in patients with type 1 hepatorenal syndrome.
2008;134:1352–1359. J Hepatol 2017;66:S572.
[357] Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O’Leary JG, et al. [377] Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN, Marinelli
REVERSE study investigators terlipressin plus albumin is more effective M, et al. Predictors of response to therapy with terlipressin and
than albumin alone in improving renal function in patients with albumin in patients with cirrhosis and type 1 hepatorenal syndrome.
cirrhosis and hepatorenal syndrome type 1. Gastroenterology Hepatology 2010;51:219–226.
2016;150:1579–1589. [378] Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, et al.
[358] Rodriguez E, Elia C, Sola E, Barreto R, Graupera I, Andrealli A, et al. Long term outcome after transjugular intrahepatic portosystemic stent-
Terlipressin and albumin for type-1 hepatorenal syndrome associated shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase
with sepsis. J Hepatol 2014;60:955–961. II study. Gut 2000;47:288–295.
[359] Cavallin M, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, et al. [379] Guevara M, Gines P, Bandi JC, Gilabert R, Sort P, Jimenez W, et al.
Terlipressin plus albumin vs. midodrine and octreotide plus albumin in Transjugular intrahepatic portosystemic shunt in hepatorenal syn-
the treatment of hepatorenal syndrome: A randomized trial. Hepatol- drome: effects on renal function and vasoactive systems. Hepatology
ogy 2015;62:567–574. 1998;28:416–422.
[360] Cavallin M, Piano S, Romano A, Fasolato S, Frigo AC, Benetti G, et al. [380] Testino G, Ferro C, Sumberaz A, Messa P, Morelli N, Guadagni B, et al.
Terlipressin given by continuous intravenous infusion vs. intravenous Type-2 hepatorenal syndrome and refractory ascites: role of transjugu-
boluses in the treatment of hepatorenal syndrome: A randomized lar intrahepatic portosystemic stent-shunt in eighteen patients with
controlled study. Hepatology 2016;63:983–992. advanced cirrhosis awaiting orthotopic liver transplantation. Hepato-
[361] Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for gastroenterology 2003;50:1753–1755.
hepatorenal syndrome. Cochrane Database Syst Rev 2012:CD005162. [381] Keller F, Heinze H, Jochimsen F, Passfall J, Schuppan D, Buttner P. Risk
[362] Facciorusso A, Chandar AK, Murad MH, Prokop LJ, Muscatiello N, factors and outcome of 107 patients with decompensated liver disease
Kamath PS. Singh SComparative efficacy of pharmacological strategies and acute renal failure (including 26 patients with hepatorenal
for management of type 1 hepatorenal syndrome: a systematic review syndrome): the role of hemodialysis. Ren Fail 1995;17:135–146.
and network meta-analysis. Lancet Gastroenterol Hepatol [382] Sourianarayanane A, Raina R, Garg G, McCullough AJ, O’Shea RS.
2017;2:94–102. Management and outcome in hepatorenal syndrome: need for renal
[363] Narahara Y, Kanazawa H, Taki Y, Kimura Y, Atsukawa M, Katakura T, replacement therapy in non-transplanted patients. Int Urol Nephrol
et al. Effects of terlipressin on systemic, hepatic and renal hemody- 2014;46:793–800.

JOURNAL
OF HEPATOLOGY
[383] Staufer K, Roedl K, Kivaranovic D, Drolz A, Horvatits T, Rasoul- [406] Arroyo V, Moreau R, Jalan R, Gines P. Acute-on-chronic liver failure: A
Rockenschaub S, et al. Renal replacement therapy in critically ill liver new syndrome that will re-classify cirrhosis. J Hepatol 2015;62:
cirrhotic patients-outcome and clinical implications. Liver Int S131–S143.
2017;37:843–850. [407] Jalan R, Pavesi M, Saliba F, Amoros A, Fernandez J, Holland-Fischer P,
[384] Wu VC, Ko WJ, Chang HW, Chen YS, Chen YW, Chen YM, et al. Early et al. The CLIF Consortium Acute Decompensation score (CLIF-C ADs)
renal replacement therapy in patients with postoperative acute liver for prognosis of hospitalised cirrhotic patients without acute-on-
failure associated with acute renal failure: effect on postoperative chronic liver failure. J Hepatol 2015;62:831–840.
outcomes. J Am Coll Surg 2007;205:266–276. [408] Arroyo V, Moreau R, Kamath PS, Jalan R, Gines P, Nevens F, et al. Acute-
[385] Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, on-chronic liver failure in cirrhosis. Nat Rev Dis Primers 2016;2:16041.
et al. Initiation strategies for renal-replacement therapy in the inten- [409] Trebicka J. Predisposing factors in acute-on-chronic liver failure. Semin
sive care unit. N Engl J Med 2016;375:122–133. Liver Dis 2016;36:167–173.
[386] Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstadt [410] Sarin SK, Choudhury A. Acute-on-chronic liver failure. Curr Gastroen-
H, et al. Effect of early vs delayed initiation of renal replacement terol Rep 2016;18:61.
therapy on mortality in critically ill patients with acute kidney [411] Bajaj JS, O’Leary JG, Reddy KR, Wong F, Biggins SW, Patton H, et al.
injury: the elain randomized clinical trial. JAMA 2016;315: Survival in infection-related acute-on-chronic liver failure is defined by
2190–2199. extrahepatic organ failures. Hepatology 2014;60:250–256.
[387] Wong LP, Blackley MP, Andreoni KA, Chin H, Falk RJ, Klemmer PJ. [412] Silva PE, Fayad L, Lazzarotto C, Ronsoni MF, Bazzo ML, Colombo BS,
Survival of liver transplant candidates with acute renal failure receiving et al. Single-centre validation of the EASL-CLIF consortium definition of
renal replacement therapy. Kidney Int 2005;68:362–370. acute-on-chronic liver failure and CLIF-SOFA for prediction of mortality
[388] Banares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, et al. in cirrhosis. Liver Int 2015;35:1516–1523.
Extracorporeal albumin dialysis with the molecular adsorbent recircu- [413] Li H, Chen LY, Zhang NN, Li ST, Zeng B, Pavesi M, et al. Characteristics,
lating system in acute-on-chronic liver failure: the RELIEF trial. diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis
Hepatology 2013;57:1153–1162. associated to hepatitis B. Sci Rep 2016;6:25487.
[389] Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U, Betz C, [414] Shalimar, Saraswat V, Singh SP, Duseja A, Shukla A, Eapen CE, et al.
et al. Effects of fractionated plasma separation and adsorption on Acute-on-chronic liver failure in India: The Indian National Association
survival in patients with acute-on-chronic liver failure. Gastroenterol- for Study of the Liver consortium experience. J Gastroenterol Hepatol
ogy 2012;142:782–789. 2016;31:1742–1749.
[390] Boyer TD, Sanyal AJ, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt [415] Shi Y, Yang Y, Hu Y, Wu W, Yang Q, Zheng M, et al. Acute-on-chronic
B, et al. Impact of liver transplantation on the survival of patients liver failure precipitated by hepatic injury is distinct from that
treated for hepatorenal syndrome type 1. Liver Transpl 2011;17: precipitated by extrahepatic insults. Hepatology 2015;62:232–242.
1328–1332. [416] Shalimar, Kumar D, Vadiraja PK, Nayak B, Thakur B, Das P, et al. Acute
[391] Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg on chronic liver failure because of acute hepatic insults: Etiologies,
BS. Impact of pretransplant renal function on survival after liver course, extrahepatic organ failure and predictors of mortality. J
transplantation. Transplantation 1995;59:361–365. Gastroenterol Hepatol 2016;31:856–864.
[392] Nadim MK, Sung RS, Davis CL, Andreoni KA, Biggins SW, Danovitch GM, [417] Dhiman RK, Agrawal S, Gupta T, Duseja A, Chawla Y. Chronic liver
et al. Simultaneous liver-kidney transplantation summit: current state failure-sequential organ failure assessment is better than the asia-
and future directions. Am J Transplant 2012;12:2901–2908. pacific association for the study of Liver criteria for defining acute-on-
[393] Francoz C, Nadim MK, Durand F. Kidney biomarkers in cirrhosis. J chronic liver failure and predicting outcome. World J Gastroenterol
Hepatol 2016;65:809–824. 2014;20:14934–14941.
[394] Angeli P, Gines P. Hepatorenal syndrome, MELD score and liver [418] Pischke S, Suneetha PV, Baechlein C, Barg-Hock H, Heim A, Kamar N,
transplantation: an evolving issue with relevant implications for et al. Hepatitis E virus infection as a cause of graft hepatitis in liver
clinical practice. J Hepatol 2012;57:1135–1140. transplant recipients. Liver Transpl 2010;16:74–82.
[395] Cillo U, Burra P, Mazzaferro V, Belli L, Pinna AD, Spada M, et al. A [419] Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Gines P, et al.
multistep, consensus-based approach to organ allocation in liver Development and validation of a prognostic score to predict mortality
transplantation: toward a ‘‘blended principle model”. Am J Transplant in patients with acute-on-chronic liver failure. J Hepatol 2014;61:
2015;1:2552–2561. 1038–1047.
[396] Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentox- [420] McPhail MJ, Shawcross DL, Abeles RD, Chang A, Patel V, Lee GH, et al.
ifylline improves short-term survival in severe acute alcoholic hepati- Increased survival for patients with cirrhosis and organ failure in liver
tis: a double-blind, placebo-controlled trial. Gastroenterology intensive care and validation of the chronic liver failure-sequential
2000;119:1637–1648. organ failure scoring system. Clin Gastroenterol Hepatol 2015;13:
[397] Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, 1353–1360.
et al. Prednisolone with vs without pentoxifylline and survival of [421] Lee M, Lee JH, Oh S, Jang Y, Lee W, Lee HJ, et al. CLIF-SOFA scoring
patients with severe alcoholic hepatitis: a randomized clinical trial. system accurately predicts short-term mortality in acutely decompen-
JAMA 2013;310:1033–1041. sated patients with alcoholic cirrhosis: a retrospective analysis. Liver
[398] Parker R, Armstrong MJ, Corbett C, Rowe IA, Houlihan DD. Systematic Int 2015;35:46–57.
review: pentoxifylline for the treatment of severe alcoholic hepatitis. [422] O’Leary JG, Reddy KR, Garcia-Tsao G, Biggins SW, Wong F, Fallon MB,
Aliment Pharmacol Ther 2013;37:845–854. et al. NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score
[399] Allen AM, Kim WR. Epidemiology and healthcare burden of acute-on- predicts 30-day survival in hospitalized patients with cirrhosis. Hepa-
chronic liver failure. Semin Liver Dis 2016;36:123–126. tology 2018.
[400] Piano S, Tonon M, Vettore E, Stanco M, Pilutti C, Romano A, et al. [423] Choudhury A, Jindal A, Maiwall R, Sharma MK, Sharma BC, Pamecha V,
Incidence, predictors and outcomes of acute-on-chronic liver failure in et al. APASL ACLF Working PartyLiver failure determines the outcome
outpatients with cirrhosis. J Hepatol 2017;67:1177–1184. in patients of acute-on-chronic liver failure (ACLF): comparison of
[401] Arroyo V, Jalan R. Acute-on-chronic liver failure: definition, diagnosis, APASL ACLF research consortium (AARC) and CLIF-SOFA models.
and clinical characteristics. Semin Liver Dis 2016;36:109–116. Hepatol Int 2017;11:461–471.
[402] Sarin SK, Kedarisetty CK, Abbas Z, Amarapurkar D, Bihari C, Chan AC, [424] Hernaez R, Sola E, Moreau R, Gines P. Acute-on-chronic liver failure: an
et al. Acute-on-chronic liver failure: consensus recommendations of the update. Gut 2017;66:541–553.
Asian Pacific Association for the Study of the Liver (APASL) 2014. [425] Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C,
Hepatol Int 2014;8:453–471. et al. Clinical Course of acute-on-chronic liver failure syndrome and
[403] Jalan R, Yurdaydin C, Bajaj JS, Acharya SK, Arroyo V, Lin HC, et al. effects on prognosis. Hepatology 2015;62:243–252.
Toward an improved definition of acute on chronic liver failure. [426] Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir
Gastroenterology 2014;147:4–10. improves the outcome in patients with spontaneous reactivation of
[404] Bajaj JS. Defining acute-on-chronic liver failure: will East and West ever hepatitis B presenting as acute-on-chronic liver failure. Hepatology
meet? Gastroenterology 2013;144:1337–1339. 2011;53:774–780.
[405] Kim TY, Song DS, Kim HY, Sinn DH, Yoon EL, Kim CW, et al. [427] Lin B, Pan CQ, Xie D, Xie J, Xie S, Zhang X, et al. Entecavir improves the
Characteristics and discrepancies in acute-on-chronic liver failure: outcome of acute-on-chronic liver failure due to the acute exacerbation
need for a unified definition. PLoS One 2016;11:e0146745. of chronic hepatitis B. Hepatol Int 2013;7:460–467.

[428] Zhang Y, Hu XY, Zhong S, Yang F, Zhou TY, Chen G, et al. Entecavir vs [449] Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum-free
lamivudine therapy for naive patients with spontaneous reactivation of cortisol in critically ill patients. N Engl J Med 2004;350:1629–1638.
hepatitis B presenting as acute-on-chronic liver failure. World J [450] Tan T, Chang L, Woodward A, McWhinney B, Galligan J, Macdonald GA,
Gastroenterol. 2014;20:4745–4752. et al. Characterising adrenal function using directly measured plasma
[429] Xiang-Hui Y, Lang X, Yan Z, Li Z, Xiao-Feng S, Hong R. Prediction of free cortisol in stable severe liver disease. J Hepatol 2010;53:841–848.
prognosis to lamivudine in patients with spontaneous reactivation of [451] Coolens JL, Van Baelen H, Heyns W. Clinical use of unbound plasma
hepatitis B virus-related acute-on-chronic liver failure: using virologic cortisol as calculated from total cortisol and corticosteroid-binding
response at week 4. Eur J Intern Med 2014;25:860–864. globulin. J Steroid Biochem 1987;26:197–202.
[430] Chen JF, Wang KW, Zhang SQ, Lei ZY, Xie JQ, Zhu JY, et al. Dexametha- [452] le Roux CW, Sivakumaran S, Alaghband-Zadeh J, Dhillo W, Kong WM,
sone in outcome of patients with hepatitis B virus-related acute-on- Wheeler MJ. Free cortisol index as a surrogate marker for serum free
chronic liver failure. J Gastroenterol Hepatol 2014;29:800–806. cortisol. Ann Clin Biochem 2002;39:406–408.
[431] Guo YM, Li FY, Gong M, Zhang L, Wang JB, Xiao XH, et al. Short-term [453] Arafah BM, Nishiyama FJ, Tlaygeh H, Hejal R. Measurement of salivary
efficacy of treating hepatitis B virus-related acute-on-chronic liver cortisol concentration in the assessment of adrenal function in critically
failure based on cold pattern differentiation with hot herbs: A ill subjects: a surrogate marker of the circulating free cortisol. J Clin
randomized controlled trial. Chin J Integr Med 2016;22:573–580. Endocrinol Metab 2007;92:2965–2971.
[432] Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, et al. [454] Thevenot T, Borot S, Remy-Martin A, Sapin R, Cervoni JP, Richou C, et al.
Granulocyte colony-stimulating factor mobilizes CD34(+) cells and Assessment of adrenal function in cirrhotic patients using concentra-
improves survival of patients with acute-on-chronic liver failure. tion of serum-free and salivary cortisol. Liver Int 2011;31:425–433.
Gastroenterology 2012;142:505–512. [455] Fernandez J, Escorsell A, Zabalza M, Felipe V, Navasa M, Mas A, et al.
[433] Finkenstedt A, Nachbaur K, Zoller H, Joannidis M, Pratschke J, Graziadei Adrenal insufficiency in patients with cirrhosis and septic shock: Effect
IW, et al. Acute-on-chronic liver failure: excellent outcomes after liver of treatment with hydrocortisone on survival. Hepatology 2006;44:
transplantation but high mortality on the wait list. Liver Transpl 1288–1295.
2013;19:879–886. [456] Arabi YM, Aljumah A, Dabbagh O, Tamim HM, Rishu AH, Al-Abdulka-
[434] Artru F, Louvet A, Ruiz I, Levesque E, Labreuche J, Ursic-Bedoya J, et al. reem A, et al. Low-dose hydrocortisone in patients with cirrhosis and
Liver transplantation in the most severely ill cirrhotic patients: A septic shock: a randomized controlled trial. CMAJ 2010;182:
multicenter study in acute-on-chronic liver failure grade 3. J Hepatol 1971–1977.
2017;67:708–715. [457] Moller S, Henriksen JH. Cirrhotic cardiomyopathy: a pathophysiological
[435] Bouachour G, Tirot P, Gouello JP, Mathieu E, Vincent JF, Alquier P. review of circulatory dysfunction in liver disease. Heart 2002;87:9–15.
Adrenocortical function during septic shock. Intensive Care Med [458] Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth 2010;104:3–11.
1995;21:57–62. [459] Mehta G, Gustot T, Mookerjee RP, Garcia-Pagan JC, Fallon MB, Shah VH,
[436] Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. et al. Inflammation and portal hypertension - the undiscovered
Recommendations for the diagnosis and management of corticosteroid country. J Hepatol 2014;61:155–163.
insufficiency in critically ill adult patients: consensus statements from [460] De BK, Majumdar D, Das D, Biswas PK, Mandal SK, Ray S, et al. Cardiac
an international task force by the American College of Critical Care dysfunction in portal hypertension among patients with cirrhosis and
Medicine. Crit Care Med 2008;36:1937–1949. non-cirrhotic portal fibrosis. J Hepatol 2003;39:315–319.
[437] Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, Fang JT, et al. Adrenal [461] Karagiannakis DS, Vlachogiannakos J, Anastasiadis G, Vafiadis-Zoubou-
insufficiency in patients with cirrhosis, severe sepsis and septic shock. lis I, Ladas SD. Diastolic cardiac dysfunction is a predictor of dismal
Hepatology 2006;43:673–681. prognosis in patients with liver cirrhosis. Hepatol Int 2014;8:588–594.
[438] Acevedo J, Fernandez J, Prado V, Silva A, Castro M, Pavesi M, et al. [462] Rabie RN, Cazzaniga M, Salerno F, Wong F. The use of E/A ratio as a
Relative adrenal insufficiency in decompensated cirrhosis: Relationship predictor of outcome in cirrhotic patients treated with transjugular
to short-term risk of severe sepsis, hepatorenal syndrome, and death. intrahepatic portosystemic shunt. Am J Gastroenterol 2009;104:
Hepatology 2013;58:1757–1765. 2458–2466.
[439] Jang JY, Kim TY, Sohn JH, Lee TH, Jeong SW, Park EJ, et al. Relative [463] Grose RD, Nolan J, Dillon JF, Errington M, Hannan WJ, Bouchier IA, et al.
adrenal insufficiency in chronic liver disease: its prevalence and effects Exercise-induced left ventricular dysfunction in alcoholic and non-
on long-term mortality. Aliment Pharmacol Ther 2014;40:819–826. alcoholic cirrhosis. J Hepatol 1995;22:326–332.
[440] Tsai MH, Huang HC, Peng YS, Chen YC, Tian YC, Yang CW, et al. Critical [464] Wong F, Girgrah N, Graba J, Allidina Y, Liu P, Blendis L. The cardiac
illness-related corticosteroid insufficiency in cirrhotic patients with response to exercise in cirrhosis. Gut 2001;49:268–275.
acute gastroesophageal variceal bleeding: risk factors and association [465] Bernardi M, Rubboli A, Trevisani F, Cancellieri C, Ligabue A, Baraldini M,
with outcome. Crit Care Med 2014;42:2546–2555. et al. Reduced cardiovascular responsiveness to exercise-induced
[441] Fede G, Spadaro L, Tomaselli T, Privitera G, Scicali R, Vasianopoulou P, sympathoadrenergic stimulation in patients with cirrhosis. J Hepatol
et al. Comparison of total cortisol, free cortisol, and surrogate markers 1991;12:207–216.
of free cortisol in diagnosis of adrenal insufficiency in patients with [466] Kim MY, Baik SK, Won CS, Park HJ, Jeon HK, Hong HI, et al. Dobutamine
stable cirrhosis. Clin Gastroenterol Hepatol 2014;12:504–512. stress echocardiography for evaluating cirrhotic cardiomyopathy in
[442] Kim G, Huh JH, Lee KJ, Kim MY, Shim KY, Baik SK. Relative adrenal liver cirrhosis. Korean J Hepatol 2010;16:376–382.
insufficiency in patients with cirrhosis: a systematic review and meta- [467] Krag A, Bendtsen F, Dahl EK, Kjaer A, Petersen CL, Moller S. Cardiac
analysis. Dig Dis Sci 2017;62:1067–1079. function in patients with early cirrhosis during maximal beta-adren-
[443] Fede G, Spadaro L, Tomaselli T, Privitera G, Germani G, Tsochatzis E, ergic drive: a dobutamine stress study. PLoS One 2014;9:e109179.
et al. Adrenocortical dysfunction in liver disease: a systematic review. [468] Stanton T, Leano R, Marwick TH. Prediction of all-cause mortality from
Hepatology 2012;55:1282–1291. global longitudinal speckle strain: comparison with ejection fraction
[444] McNeilly AD, Macfarlane DP, O’Flaherty E, Livingstone DE, Mitic T, and wall motion scoring. Circ Cardiovasc Imaging 2009;2:356–364.
McConnell KM, et al. Bile acids modulate glucocorticoid metabolism [469] Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,
and the hypothalamic–pituitary–adrenal axis in obstructive jaundice. J et al. Recommendations for chamber quantification: a report from the
Hepatol 2010;52:705–711. American Society of Echocardiography’s Guidelines and Standards
[445] Worlicek M, Knebel K, Linde HJ, Moleda L, Scholmerich J, Straub RH, Committee and the Chamber Quantification Writing Group, developed
et al. Splanchnic sympathectomy prevents translocation and in conjunction with the European Association of Echocardiography, a
spreading of E coli but not S aureus in liver cirrhosis. Gut 2010;59: branch of the European Society of Cardiology. J Am Soc Echocardiogr
1127–1134. 2005;18:1440–1463.
[446] Cholongitas E, Goulis I, Pagkalidou E, Haidich AB, Karagiannis AKA, [470] Stampehl MR, Mann DL, Nguyen JS, Cota F, Colmenares C, Dokainish H.
Nakouti T, et al. Relative adrenal insufficiency is associated with the Speckle strain echocardiography predicts outcome in patients with
clinical outcome in patients with stable decompensated cirrhosis. Ann heart failure with both depressed and preserved left ventricular
Hepatol 2017;16:584–590. ejection fraction. Echocardiography 2015;32:71–78.
[447] Trifan A, Chiriac S, Stanciu C. Update on adrenal insufficiency in [471] Chen Y, Chan AC, Chan SC, Chok SH, Sharr W, Fung J, et al. A detailed
patients with liver cirrhosis. World J Gastroenterol 2013;19:445–456. evaluation of cardiac function in cirrhotic patients and its alteration
[448] Galbois A, Rudler M, Massard J, Fulla Y, Bennani A, Bonnefont-Rousselot with or without liver transplantation. J Cardiol 2016;67:140–146.
D, et al. Assessment of adrenal function in cirrhotic patients: salivary [472] Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP,
cortisol should be preferred. J Hepatol 2010;52:839–845. Valente J, et al. Systolic and diastolic dysfunction in cirrhosis: a tissue-

JOURNAL
OF HEPATOLOGY
Doppler and speckle tracking echocardiography study. Liver Int [494] Raevens S, De Pauw M, Geerts A, Berrevoet F, Rogiers X, Troisi RI, et al.
2013;33:1158–1165. Prevalence and outcome of diastolic dysfunction in liver transplanta-
[473] Nazar A, Guevara M, Sitges M, Terra C, Sola E, Guigou C, et al. LEFT tion recipients. Acta Cardiol 2014;69:273–280.
ventricular function assessed by echocardiography in cirrhosis: rela- [495] Saner FH, Neumann T, Canbay A, Treckmann JW, Hartmann M,
tionship to systemic hemodynamics and renal dysfunction. J Hepatol Goerlinger K, et al. High brain-natriuretic peptide level predicts
2013;58:51–57. cirrhotic cardiomyopathy in liver transplant patients. Transpl Int
[474] Cesari M, Fasolato S, Rosi S, Angeli P. Cardiac dysfunction in patients 2011;24:425–432.
with cirrhosis: is the systolic component its main feature? Eur J [496] Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP,
Gastroenterol Hepatol 2015;27:660–666. Valente J, et al. Systolic dysfunction and diastolic dysfunction do not
[475] Nagueh SF, Smiseth OA, Appleton CP, Byrd 3rd BF, Dokainish H, influence medium-term prognosis in patients with cirrhosis. Eur J
Edvardsen T, et al. Recommendations for the evaluation of left Intern Med 2014;25:241–246.
ventricular diastolic function by echocardiography: an update from [497] Alexopoulou A, Papatheodoridis G, Pouriki S, Chrysohoou C, Raftopou-
the American society of echocardiography and the european associa- los L, Stefanadis C, et al. Diastolic myocardial dysfunction does not
tion of cardiovascular imaging. Eur Heart J Cardiovasc Imaging affect survival in patients with cirrhosis. Transpl Int 2012;25:
2016;17:1321–1360. 1174–1181.
[476] Takemoto Y, Barnes ME, Seward JB, Lester SJ, Appleton CA, Gersh BJ, [498] Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. ERS task force
et al. Usefulness of left atrial volume in predicting first congestive heart pulmonary-hepatic vascular disorders (PHD) scientific committee.
failure in patients > or = 65 years of age with well-preserved left Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004;24:
ventricular systolic function. Am J Cardiol 2005;96:832–836. 861–880.
[477] Valeriano V, Funaro S, Lionetti R, Riggio O, Pulcinelli G, Fiore P, et al. [499] Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in
Modification of cardiac function in cirrhotic patients with and without chronic liver disease. Hepatology 2014;59:1627–1637.
ascites. Am J Gastroenterol 2000;95:3200–3205. [500] Kaymakoglu S, Kahraman T, Kudat H, Demir K, Cakaloglu Y, Adalet I,
[478] Pozzi M, Carugo S, Boari G, Pecci V, de Ceglia S, Maggiolini S, et al. et al. Hepatopulmonary syndrome in noncirrhotic portal hypertensive
Evidence of functional and structural cardiac abnormalities in patients. Dig Dis Sci 2003;48:556–560.
cirrhotic patients with and without ascites. Hepatology 1997;26: [501] Fuhrmann V, Madl C, Mueller C, Holzinger U, Kitzberger R, Funk GC,
1131–1137. et al. Hepatopulmonary syndrome in patients with hypoxic hepatitis.
[479] Cazzaniga M, Salerno F, Pagnozzi G, Dionigi E, Visentin S, Cirello I, et al. Gastroenterology 2006;131:69–75.
Diastolic dysfunction is associated with poor survival in patients with [502] Rodríguez-Roisin R, Agustí AG, Roca J. The hepatopulmonary syndrome:
cirrhosis with transjugular intrahepatic portosystemic shunt. Gut new name, old complexities. Thorax 1992;47:897–902.
2007;56:869–875. [503] Fallon MB, Abrams GA. Pulmonary dysfunction in chronic liver disease.
[480] Ruiz-del-Arbol L, Achecar L, Serradilla R, Rodriguez-Gandia MA, Rivero Hepatology 2000;32:859–865.
M, Garrido E, et al. Diastolic dysfunction is a predictor of poor outcomes [504] Voiosu AM, Daha IC, Voiosu TA, Mateescu BR, Dan GA, Băicusß CR, et al.
in patients with cirrhosis, portal hypertension, and a normal creatinine. Prevalence and impact on survival of hepatopulmonary syndrome and
Hepatology 2013;58:1732–1741. cirrhotic cardiomyopathy in a cohort of cirrhotic patients. Liver Int
[481] Cesari M, Frigo AC, Tonon M, Angeli P. Cardiovascular predictors of 2015;35:2547–2555.
death in patients with cirrhosis. Hepatology 2017. [505] Rodríguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome; a liver-
[482] Merli M, Torromeo C, Giusto M, Iacovone G, Riggio O, Puddu PE. induced lung vascular disorder. N Engl J Med 2008;358:2378–2387.
Survival at 2 years among liver cirrhotic patients is influenced by left [506] Schenk P, Schoniger-Hekele M, Fuhrmann V, Madl C, Silberhumer G,
atrial volume and left ventricular mass. Liver Int 2017;37:700–706. Muller C. Prognostic significance of the hepatopulmonary syndrome in
[483] Kozor R, Nordin S, Treibel TA, Rosmini S, Castelletti S, Fontana M, et al. patients with cirrhosis. Gastroenterology 2003;125:1042–1052.
Insight into hypertrophied hearts: a cardiovascular magnetic resonance [507] Swanson KL, Wiesner RH, Krowka MJ. Natural history of hepatopul-
study of papillary muscle mass and T1 mapping. Eur Heart J Cardiovasc monary syndrome: impact of liver transplantation. Hepatology
Imaging 2016;18:1034–1040. 2005;41:1122–1129.
[484] Ngu PJ, Butler M, Pham A, Roberts SK, Taylor AJ. Cardiac remodelling [508] Fallon MB, Krowka MJ, Brown RS, Trotter JF, Zacks S, Roberts KE, et al.
identified by cardiovascular magnetic resonance in patients with Impact of hepatopulmonary syndrome on quality of life and survival in
hepatitis C infection and liver disease. Int J Cardiovasc Imaging liver transplant candidates. Gastroenterology 2008;135:1168–1175.
2016;32:629–636. [509] Schraufnagel DE, Kay JM. Structural and pathologic changes in the lung
[485] Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, vasculature in chronic liver disease. Clin Chest Med 2006;17:1–15.
et al. Circulatory function and hepatorenal syndrome in cirrhosis. [510] Boryczka G, Hartleb M, Rudzki K, Janik MA. Influence of an upright body
Hepatology 2005;42:439–447. position on the size of intrapulmonary blood shunts in patients with
[486] Zhang W, Xu X, Kao R, Mele T, Kvietys P, Martin CM, et al. Cardiac advanced liver cirrhosis. J Physiol Pharmacol 2015;66:855–861.
fibroblasts contribute to myocardial dysfunction in mice with sepsis: [511] Fallon MB, Abrams GA, Luo B, Hou Z, Dai J, Ku DD. The role of
the role of NLRP3 inflammasome activation. PLoS One 2014;9:e107639. endothelial nitric oxide synthase in the pathogenesis of a rat model of
[487] Gaskari SA, Liu H, D’Mello C, Kunos G, Lee SS. Blunted cardiac response hepatopulmonary syndrome. Gastroenterology 1997;113:606–614.
to hemorrhage in cirrhotic rats is mediated by local macrophage- [512] Luo B, Liu L, Tang L, Zhang J, Ling Y, Fallon MB. ET-1 and TNF- alpha in
released endocannabinoids. J Hepatol 2015;62:1272–1277. HPS: analysis in prehepatic portal hypertension and biliary and
[488] Liu H, Lee SS. Nuclear factor-kappaB inhibition improves myocardial nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol
contractility in rats with cirrhotic cardiomyopathy. Liver Int 2008;28: 2004;286:G294–G303.
640–648. [513] Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and
[489] Trevisani F, Di Micoli A, Zambruni A, Biselli M, Santi V, Erroi V, et al. QT portal hypertension: too much, not enough. Hepatology 2002;35:
interval prolongation by acute gastrointestinal bleeding in patients 478–491.
with cirrhosis. Liver Int 2012;32:1510–1515. [514] Ling Y, Zhang J, Luo B, Song D, Liu L, Tang L, et al. The role of endothelin-
[490] Zhao J, Qi X, Hou F, Ning Z, Zhang X, Deng H, et al. Prevalence, risk 1 and the endothelin B receptor in the pathogenesis of hepatopul-
factors and in-hospital outcomes of QTc interval prolongation in liver monary syndrome in the rat. Hepatology 2004;39:1593–1602.
cirrhosis. Am J Med Sci 2016;352:285–295. [515] Tang L, Luo B, Patel RP, Ling Y, Zhang J, Fallon MB. Modulation of
[491] Krag A, Bendtsen F, Mortensen C, Henriksen JH, Moller S. Effects of a pulmonary endothelial endothelin B receptor expression and signaling:
single terlipressin administration on cardiac function and perfusion in implications for experimental hepatopulmonary syndrome. Am J
cirrhosis. Eur J Gastroenterol Hepatol 2010;22:1085–1092. Physiol Lung Cell Mol Physiol 2007;292:L1467–L1472.
[492] Wannhoff A, Hippchen T, Weiss CS, Friedrich K, Rupp C, Neumann- [516] Frossard JL, Schiffer E, Cikirikcioglu B, Bourquin BJ, Morel DR, Pastor
Haefelin C, et al. Cardiac volume overload and pulmonary hypertension MC. Opposite regulation of endothelial NO synthase by HSP90 and
in long-term follow-up of patients with a transjugular intrahepatic caveolin in liver and lungs of rats with hepatopulmonary syndrome.
portosystemic shunt. Aliment Pharmacol Ther 2016;43:955–965. Am J Physiol Gastrointest Liver Physiol 2007;293:G864–G870.
[493] Busk TM, Bendtsen F, Henriksen JH, Fuglsang S, Clemmesen JO, Larsen [517] Rabiller A, Nunes H, Lebrec D, Tazi KA, Wartski M, Dulmet E, et al.
FS, et al. Effects of transjugular intrahepatic portosystemic shunt (TIPS) Prevention of gram-negative translocation reduces the severity of
on blood volume distribution in patients with cirrhosis. Dig Liver Dis hepatopulmonary syndrome. Am J Respir Crit Care Med 2002;166:
2017;49:1353–1359. 514–517.

[518] Thenappan T, Goel A, Marsboom G, Fang YH, Toth PT, Zhang HJ, et al. A [540] De BK, Dutta D, Pal SK, Gangopadhyay S, Das Baksi S, Pani A. The role of
central role for CD68(1) macrophages in hepatopulmonary syndrome: garlic in hepatopulmonary syndrome: a randomized controlled trial.
reversal by macrophage depletion. Am J Respir Crit Care Med Can J Gastroenterol 2010;24:183–188.
2011;183:1080–1091. [541] Shaikh SA, Tischer S, Choi EK, Fontana RJ. Good for the lung but bad for
[519] Zhang J, Yang W, Luo B, Hu B, Maheshwari A, Fallon MB. The role of CX the liver? Garlic-induced hepatotoxicity following liver transplanta-
(3)CL1/CX(3)CR1 in pulmonary angiogenesis and intravascular mono- tion. J Clin Pharm Ther 2017;42:646–648.
cyte accumulation in rat experimental hepatopulmonary syndrome. J [542] Tsauo J, Weng N, Ma H, Jiang M, Zhao H, Li X. Role of transjugular
Hepatol 2012;57:752–758. intrahepatic portosystemic shunts in the management of hepatopul-
[520] Carter EP, Hartsfield CL, Miyazono M, Jakkula M, Morris Jr KG, monary syndrome: a systemic literature review. J Vasc Interv Radiol
McMurtry IF. Regulation of heme oxygenase-1 by nitric oxide during 2015;26:1266–1271.
hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol [543] Poterucha JJ, Krowka MJ, Dickson ER, Cortese DA, Stanson AW, Krom
2002;283:L346–L353. RA. Failure of hepatopulmonary syndrome to resolve after liver
[521] Zhang J, Luo B, Tang L, Wang Y, Stockard CR, Kadish I, et al. Pulmonary transplantation and successful treatment with embolotherapy. Hepa-
angiogenesis in a rat model of hepatopulmonary syndrome. Gastroen- tology 1995;21:96–100.
terology 2009;136:1070–1080. [544] Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, Man-
[522] Zhang J, Yang W, Hu B, Wu W, Fallon MB. Endothelin-1 activation of the zarbeitia C, et al. Hepatopulmonary syndrome and portopulmonary
endothelin B receptor modulates pulmonary endothelial CX3CL1 and hypertension: a report of the multicenter liver transplant database.
contributes to pulmonary angiogenesis in experimental hepatopul- Liver Transpl 2004;10:174–182.
monary syndrome. Am J Pathol 2014;184:1706–1714. [545] Gupta S, Castel H, Rao RV, Picard M, Lilly L, Faughnan ME, et al.
[523] Zeng J, Chen L, Chen B, Lu K, Belguise K, Wang X, et al. MicroRNA-199 a- Improved survival after liver transplantation in patients with hep-
5p Regulates the Proliferation of Pulmonary Microvascular Endothelial atopulmonary syndrome. Am J Transplant 2010;10:354–363.
Cells in Hepatopulmonary Syndrome. Cell Physiol Biochem [546] Fallon MB, Mulligan DC, Gish RG, Krowka MJ. Model for end-stage liver
2015;37:1289–1300. disease (MELD) exception for hepatopulmonary syndrome. Liver
[524] Roberts KE, Kawut SM, Krowka MJ, Brown Jr RS, Trotter JF, Shah V, et al. Transpl 2006;12:S105–S107.
Genetic risk factors for hepatopulmonary syndrome in patients with [547] Iyer VN, Swanson KL, Cartin-Ceba R, Dierkhising RA, Rosen CB,
advanced liver disease. Gastroenterology 2010;39:130–139. Heimbach JK, et al. Hepatopulmonary syndrome: favorable outcomes
[525] Chang CC, Wang SS, Hsieh HG, Lee WS, Chuang CL, Hc Lin, et al. in the MELD exception era. Hepatology 2013;57:427–2435.
Rosuvastatin improves hepatopulmonary syndrome through inhibition [548] Goldberg DS, Krok K, Batra S, Trotter JF, Kawut SM, Fallon MB. Impact of
of inflammatory angiogenesis of lung. Clin Sci 2015;129:449–460. the hepatopulmonary syndrome MELD exception policy on outcomes
[526] Rodriquez-Roisin R, Krowka MJ, Herve P, Fallon MB. ERS (European of patients after liver transplantation: an analysis of the UNOS
Respiratory Society) Task ForcePHD Scientific Committee. Highlights of database. Gastroenterology 2014;146:1256–1265.
the ERS task force on pulmonary-hepatic vascular disorders (PHD). J [549] Fleming GM, Cornell TT, Welling TH, Magee JC, Annich GM. Hepatopul-
Hepatol 2005;42:924–927. monary syndrome use of extracorporeal life support for life-threatening
[527] Arguedas MR, Singh H, Faulk DK, Fallon MB. Utility of pulse oximetry hypoxia following liver transplantation. Liver Transpl 2008;14:966–970.
screening for hepatopulmonary syndrome. Clin Gastroenterol Hepatol [550] Monsel A, Mal H, Brisson H, Luo R, Eyraud D, Vénizet C, et al.
2007;5:749–754. Extracorporeal membrane oxygenation as a brifge to liver trnsplanta-
[528] Hoerning A, Raub S, Neudorf U, Muntjes C, Kathemann S, Lainka E, et al. tion for acute respiratory distress syndrome-induced life-threatening
Pulse oximetry is insufficient for timely diagnosis of hepatopulmonary hypoxemia aggravated by hepatopulmonary syndrome. Crit Care
syndrome in children with liver cirrhosis. J Pediatr 2014;164:546–552. 2011;15:R234.
[529] Horvatits T, Drolz A, Roedl K, Herkner H, Ferlitsch A, Perkmann T, et al. [551] Chihara Y, Egawa H, Tsuboi T, Oga T, Handa T, Yamamoto K, et al.
Von Willebrand factor antigen for detection of hepatopulmonary Immediate nonivasive ventilation may improve mortality in patients
syndrome in patients with cirrhosis. J Hepatol 2014;61:544–549. with hepatopulmonary syndrome after liver transplantation. Liver
[530] Köksal D, Kaçar S, Köksal AS, Tüfekçioğlu O, Küçükay F, Okten S, et al. Transpl 2011;17:44–148.
Evaluation of intrapulmonary vascular dilatations with high-resolution [552] McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR,
computed thorax tomography in patients with hepatopulmonary et al. ACCF/AHA 2009 expert consensus document on pulmonary
syndrome. J Clin Gastroenterol 2006;40:77–83. hypertension a report of the American College of Cardiology Founda-
[531] Lee KN, Lee HJ, Shin WW, Webb WR. Hypoxemia and liver cirrhosis tion Task Force on Expert Consensus Documents and the American
(hepatopulmonary syndrome) in eight patients: comparison of the Heart Association developed in collaboration with the American
central and peripheral pulmonary vasculature. Radiology 1999;211:549–553. College of Chest Physicians; American Thoracic Society, Inc.; and the
[532] Abrams GA, Jaffe CC, Hoffer PB, Binder HJ, Fallon MB. Diagnostic utility Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:
of contrast echocardiography and lung perfusion scan in patients with 1573–1619.
hepatopulmonary syndrome. Gastroenterology 1995;109: [553] Torregrosa M, Genesca J, Gonzalez A, Evangelista A, Mora A, Margarit C,
1283–1288. et al. Role of Doppler echocardiography in the assessment of portopul-
[533] Wolfe JD, Tashkin DP, Holly FE, Brachman MB, Genovesi MG. Hypox- monary hypertension in liver transplantation candidates. Transplanta-
emia of cirrhosis: detection of abnormal small pulmonary vascular tion 2001;71:572–574.
channels by a quantitative radionuclide method. Am J Med [554] Raevens S, Colle I, Reyntjens K, Geerts A, Berrevoet F, Rogiers X, et al.
1977;63:746–754. Echocardiography for the detection of portopulmonary hypertension in
[534] Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of liver transplant candidates: an analysis of cutoff values. Liver Transpl
macroaggregated albumin lung perfusion scan to diagnose hepatopul- 2013;19:602–610.
monary syndrome: a new approach. Gastroenterology 1998;114: [555] Cotton CL, Gandhi S, Vaitkus PT, Massad MG, Benedetti E, Mrtek RG,
305–310. et al. Role of echocardiography in detecting portopulmonary hyper-
[535] Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evalu- tension in liver transplant candidates. Liver Transpl 2002;8:1051–1054.
ation of outcomes and predictors of mortality in patients with hepato- [556] Kawut SM, Krowka MJ, Trotter JF, Roberts KE, Benza RL, Badesch DB,
pulmonary syndrome undergoing liver transplantation. Hepatology et al. Clinical risk factors for portopulmonary hypertension. Hepatology
2003;37:192–197. 2008;48:196–203.
[536] Kalambokis G, Tsianos EV. Pitfalls in the assessment of intrapulmonary [557] Paulus JK, Roberts KE. Oestrogen and sexual Dimorphism of pulmonary
shunt using lung perfusion scintigraphy in patients with cirrhosis. Liver arterial hypertension; a transitional challenge. Eur Respir J 2013;41:
Int 2010;31:138–139. 1014–1016.
[537] Kochar R, Tanikella R, Fallon MB. Serial pulse oximetry in hepatopul- [558] Talwalkar JA, Swanson KL, Krowka MJ, Andrews JC, Kamath PS.
monary syndrome. Dig Dis Sci 2011;56:1862–1868. Prevalence of spontaneous portosystemic shunts in patients with
[538] Tanikella R, Philips GM, Faulk DK, Kawut SM, Fallon MB. Pilot study of portopulmonary hypertension and effect on treatment. Gastroenterol-
pentoxifylline in hepatopulmonary syndrome. Liver Transpl 2008;14: ogy 2011;141:1673–1679.
1199–1203. [559] Hadengue A, Benhayoun MK, Lebrec D, Benhamou JP. Pulmonary
[539] Gupta LB, Kumar A, Jaiswal AK, Yusuf J, Metha V, Tyagi S, et al. hypertension complicating portal hypertension: prevalence and rela-
Pentoxyfylline therapy for hepatopulmonary syndrome: a piloto study. tion to splanchnic hemodynamics. Gastroenterology 1991;100:
Arch Intern Med 2008;168:1820–1823. 520–528.

JOURNAL
OF HEPATOLOGY
[560] Robalino BD, Moodie DS. Association between primary pulmonary [584] Melgosa MT, Ricci GL, Garcia-Pagan JC, Blanco I, Escribano P, Abraldes
hypertension and portal hypertension: analysis of its pathophysiology JG, et al. Acute and long-term effects of inhaled iloprost in portopul-
and clinical, laboratory and hemodynamic manifestations. J Am Coll monary hypertension. Liver Transpl 2010;16:348–356.
Cardiol 1991;17:492–498. [585] Colombato LA, Spahr L, Martinet JP, Dufresne MP, Lafortune M, Fenyves
[561] Swanson KL, Wiesner RH, Nyberg SL, Rosen CB, Krowka MJ. Survival in D, et al. Haemodynamic adaptation two months after transjugular
portopulmonary hypertension: Mayo Clinic experience categorized by intrahepatic portosystemic shunt (TIPS) in cirrhotic patients. Gut
treatment subgroups. Am J Transplant 2008;8:2445–2453. 1996;39:600–604.
[562] Cartin-Ceba R, Krowka MJ. Portopulmonary hypertension. Clin Liver Dis [586] Boyer TD, Haskal ZJ. American Association for the Study of Liver D. The
2014;18:421–438. Role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in the
[563] Condino AA, Ivy DD, O’Connor JA, Narkewicz MR, Mengshol S, Management of Portal Hypertension: update 2009. Hepatology
Whitworth JR, et al. Portopulmonary hypertension in pediatric patients. 2010;51:306.
J Pediatr 2005;147:20–26. [587] Yoshida EM, Erb SR, Pflugfelder PW, Ostrow DN, Ricci DR, Ghent CN,
[564] Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, et al. et al. Single-lung vs. liver transplantation for the treatment of
Portopulmonary hypertension: survival and prognostic factors. Am J portopulmonary hypertension–a comparison of two patients. Trans-
Respir Crit Care Med 2008;178:637–643. plantation 1993;55:688–690.
[565] Krowka MJ, Cartin-Ceba R. Portopulmonary hypertension: formidable [588] Krowka MJ, Wiesner RH, Heimbach JK. Pulmonary contraindications,
dual threat vs. hopeful dual therapy. Liver Transpl 2014;20:635–636. indications and MELD exceptions for liver transplantation: a contem-
[566] Kawut SM, Horn EM, Berekashvili KK, Garofano RP, Goldsmith RL, porary view and look forward. J Hepatol 2013;59:367–374.
Widlitz AC, et al. New predictors of outcome in idiopathic pulmonary [589] Kuo PC, Plotkin JS, Gaine S, Schroeder RA, Rustgi VK, Rubin LJ, et al.
arterial hypertension. Am J Cardiol 2005;95:199–203. Portopulmonary hypertension and the liver transplant candidate.
[567] Ricci GL, Melgosa MT, Burgos F, Valera JL, Pizarro S, Roca J, et al. Transplantation 1999;67:1087–1093.
Assessment of acute pulmonary vascular reactivity in portopulmonary [590] Krowka MJ, Plevak DJ, Findlay JY, Rosen CB, Wiesner RH, Krom RA.
hypertension. Liver Transpl 2007;13:1506–1514. Pulmonary hemodynamics and perioperative cardiopulmonary-related
[568] Provencher S, Herve P, Jais X, Lebrec D, Humbert M, Simonneau G, et al. mortality in patients with portopulmonary hypertension undergoing
Deleterious effects of beta-blockers on exercise capacity and hemody- liver transplantation. Liver Transpl 2000;6:443–450.
namics in patients with portopulmonary hypertension. Gastroenterol- [591] Mangus RS, Kinsella SB, Marshall GR, Fridell JA, Wilkes KR, Tector AJ.
ogy 2006;130:120–126. Mild to moderate pulmonary hypertension in liver transplantation. J
[569] Halank M, Miehlke S, Hoeffken G, Schmeisser A, Schulze M, Strasser RH. Surg Res 2013;184:1150–1156.
Use of oral endothelin-receptor antagonist bosentan in the treatment of [592] Raevens S, De Pauw M, Reyntjens K, Geerts A, Verhelst X, Berrevoet F,
portopulmonary hypertension. Transplantation 2004;77:1775–1776. et al. Oral vasodilator therapy in patients with moderate to severe
[570] Hoeper MM, Halank M, Marx C, Hoeffken G, Seyfarth HJ, Schauer J, et al. portopulmonary hypertension as a bridge to liver transplantation. Eur J
Bosentan therapy for portopulmonary hypertension. Eur Respir J Gastroenterol Hepatol 2013;25:495–502.
2005;25:502–508. [593] Ramsay MA, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB.
[571] Savale L, Magnier R, Le Pavec J, Jais X, Montani D, O’Callaghan DS, et al. Severe pulmonary hypertension in liver transplant candidates. Liver
Efficacy, safety and pharmacokinetics of bosentan in portopulmonary Transpl Surg 1997;3:494–500.
hypertension. Eur Respir J 2013;41:96–103. [594] Krowka MJ, Fallon MB, Mulligan DC, Gish RG. Model for end-stage liver
[572] Barth F, Gerber PJ, Reichen J, Dufour JF, Nicod LP. Efficiency and disease (MELD) exception for portopulmonary hypertension. Liver
safety of bosentan in child C cirrhosis with portopulmonary Transpl 2006;12:S114–S116.
hypertension and renal insufficiency. Eur J Gastroenterol Hepatol [595] DuBrock HM, Goldberg DS, Sussman NL, Bartolome SD, Kadry Z, Salgia
2006;18:1117–1119. RJ, et al. Predictors of waitlist mortality in portopulmonary hyperten-
[573] Hoeper MM, Seyfarth HJ, Hoeffken G, Wirtz H, Spiekerkoetter E, Pletz sion. Transplantation 2017;101:1609–1615.
MW, et al. Experience with inhaled iloprost and bosentan in portopul- [596] Ramsay M. Portopulmonary hypertension and right heart failure in
monary hypertension. Eur Respir J 2007;30:1096–1102. patients with cirrhosis. Curr Opin Anaesthesiol 2010;23:145–150.
[574] Cartin-Ceba R, Swanson K, Iyer V, Wiesner RH, Krowka MJ. Safety and [597] Paulsen AW, Whitten CW, Ramsay MA, Klintmalm GB. Considerations
efficacy of ambrisentan for the treatment of portopulmonary hyper- for anesthetic management during veno-venous bypass in adult
tension. Chest 2011;139:109–114. hepatic transplantation. Anesth Analg 1989;68:489–496.
[575] DuBrock HM, Channick RN, Krowka MJ. What’s new in the treatment of [598] Ramsay MA, Spikes C, East CA, Lynch K, Hein HA, Ramsay KJ, et al. The
portopulmonary hypertension? Expert Rev Gastroenterol Hepatol perioperative management of portopulmonary hypertension with
2015;9:983–992. nitric oxide and epoprostenol. Anesthesiology 1999;90:299–301.
[576] Reichenberger F, Voswinckel R, Steveling E, Enke B, Kreckel A, [599] Stratta C, Lavezzo B, Ballaris MA, Panio A, Crucitti M, Andruetto P, et al.
Olschewski H, et al. Sildenafil treatment for portopulmonary hyper- Extracorporeal membrane oxygenation rescue therapy in a case of
tension. Eur Respir J 2006;28:563–567. portopulmonary hypertension during liver transplantation: a case
[577] Cadden IS, Greanya ED, Erb SR, Scudamore CH, Yoshida EM. The use of report. Transplant Proc 2013;45:2774–2775.
sildenafil to treat portopulmonary hypertension prior to liver trans- [600] Ashfaq M, Chinnakotla S, Rogers L, Ausloos K, Saadeh S, Klintmalm GB,
plantation. Ann Hepatol 2009;8:158–161. et al. The impact of treatment of portopulmonary hypertension on
[578] Fisher JH, Johnson SR, Chau C, Kron AT, Granton JT. Effectiveness of survival following liver transplantation. Am J Transplant
phosphodiesterase-5 inhibitor therapy for portopulmonary hyperten- 2007;7:1258–1264.
sion. Can Respir J 2015;22:42–46. [601] Hollatz TJ, Musat A, Westphal S, Decker C, D’Alessandro AM, Keevil J,
[579] Tzathas C, Christidou A, Ladas SD. Sildenafil (viagra) is a risk factor for et al. Treatment with sildenafil and treprostinil allows successful liver
acute variceal bleeding. Am J Gastroenterol 2002;97:1856. transplantation of patients with moderate to severe portopulmonary
[580] Kuo PC, Johnson LB, Plotkin JS, Howell CD, Bartlett ST, Rubin LJ. hypertension. Liver Transpl 2012;18:686–695.
Continuous intravenous infusion of epoprostenol for the treat- [602] Khaderi S, Khan R, Safdar Z, Stribling R, Vierling JM, Goss JA, et al. Long-
ment of portopulmonary hypertension. Transplantation 1997;63: term follow-up of portopulmonary hypertension patients after liver
604–606. transplantation. Liver Transpl 2014;20:724–727.
[581] Sussman N, Kaza V, Barshes N, Stribling R, Goss J, O’Mahony C, et al. [603] Goldberg DS, Batra S, Sahay S, Kawut SM, Fallon MB. MELD exceptions
Successful liver transplantation following medical management of for portopulmonary hypertension: current policy and future imple-
portopulmonary hypertension: a single-center series. Am J Transplant mentation. Am J Transplant 2014;14:2081–2087.
2006;6:2177–2182. [604] Morando F, Maresio G, Piano S, Fasolato S, Cavallin M, Romano A, et al.
[582] Fix OK, Bass NM, De Marco T, Merriman RB. Long-term follow-up of How to improve care in outpatients with cirrhosis and ascites: a new
portopulmonary hypertension: effect of treatment with epoprostenol. model of care coordination by consultant hepatologists. J Hepatol
Liver Transpl 2007;13:875–885. 2013;59:257–264.
[583] Awdish RL, Cajigas HR. Early initiation of prostacyclin in portopul-
monary hypertension: 10 years of a transplant center’s experience.
Lung 2013;191:593–600.


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Clinical Practice Guidelines JOURNAL

EASL Clinical Practice Guidelines for the management of patients with

European Association for the Study of the Liver ⇑

Summary signs, the most frequent of which are ascites, bleeding,

Journal of Hepatology 2018 vol. xxx j xxx–xxx

Table 1. Level of Evidence and Grade of Recommendations.

2 Journal of Hepatology 2018 vol. xxx j xxx–xxx

In patients with decompensated cirrhosis, the aetiologi-

Journal of Hepatology 2018 vol. xxx j xxx–xxx 3

Portal hypertension Liver injury

Bacterial translocation Damaged cells

Other potential Activation if innate pattern

Release of pro-inflamamtory molecules

Splanchnic arteriolar vasodilation

Adrenal HE Kidney HPS

4 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 5

dosages (from 100/200 to 400 mg/day), with furosemide added in

6 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 7

Refractory ascites refractory ascites will be developed in the section dedicated to

Table 4. Definition and diagnostic criteria for refractory ascites in cirrhosis.

8 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 9

10 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 11

12 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 13

14 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Acute gastrointestinal bleeding + portal hypertension

Immediate start of drug therapy

Early diagnostic endoscopy (<12 h)

Confirm variceal bleeding

Endoscopic therapy ( band ligation )

Control Further bleeding

Consider early TIPS Rescue with TIPS

Journal of Hepatology 2018 vol. xxx j xxx–xxx 15

16 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 17

18 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 19

If baseline SOFA score available?

Apply sepsis-3 criteria and qSOFA Apply sepsis-3 criteria

Sepsis-3 and Sepsis-3 and

Sepsis -3 positive Poor outcome

20 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Journal of Hepatology 2018 vol. xxx j xxx–xxx 21

Patients with prior SBP

Primary prophylaxsis with norﬂoxacin (400 mg/day) in

22 Journal of Hepatology 2018 vol. xxx j xxx–xxx

clinical course and prognosis. Non-SBP infections increase the

Management of infections other than SBP

Journal of Hepatology 2018 vol. xxx j xxx–xxx 23

glomerulopathy),305 however the prevalence of CKD in this pop-

24 Journal of Hepatology 2018 vol. xxx j xxx–xxx

Initial AKI# stage 1a° Initial AKI# stage >1a°

Resolution Persistance Progression YES NO

Close follow up Does AKI meet criteria of HRS ?

Journal of Hepatology 2018 vol. xxx j xxx–xxx 25