EASL Guidelones On Management Decompensated Liver Cirrhosis

JOURNAL
OF HEPATOLOGY
Clinical Practice Guidelines
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, encephalopathy,
The natural history of cirrhosis is characterised by an asymptomatic and jaundice. Following the first appearance of any of these, the disease
compensated phase followed by a decompensated phase, marked by the usually progresses more rapidly towards death or liver transplantation
development of overt clinical signs, the most frequent of which are (LT). This phase of the disease has been designated ‘‘decompensated
ascites, bleeding, encephalopathy, and jaundice. The following Clinical cirrhosis”.2 Progression of the decompensated disease may be further
Practice Guidelines (CPGs) represent the first CPGs on the management accelerated by the development of other complications such as
of decompensated cirrhosis. In this context, the panel of experts, having rebleeding, acute kidney injury (AKI), with or without the features of
emphasised the importance of initiating aetiologic treatment for any HRS, hepato-pulmonary syndrome (HPS), portopulmonary hypertension
degree of hepatic disease at the earliest possible stage, extended its work (PPHT), cirrhotic cardiomyopathy (CCM), and bacterial infections.
to all the complications of cirrhosis, which had not been covered by the Indeed, the development of bacterial infections as well as hepatocellular
European Association for the Study of the Liver guidelines, namely: carcinoma may accelerate the course of the disease at any stage, but
ascites, refractory ascites, hyponatremia, gastrointestinal bleeding, especially in decompensated cirrhosis. 3 Having defined the potential
bacterial infections, acute kidney injury, hepatorenal syndrome, acute- field of action, and having emphasised the importance of initiating
on-chronic liver failure, relative adrenal failure, cirrhotic aetiologic treatment for any degree of hepatic disease at the earliest
cardiomyopathy, hepatopulmonary syndrome, and porto-pulmonary possible stage, the panel decided to extend the work to all those
hypertension. The panel of experts, produced these GPGs using evidence complications of cirrhosis which have not yet been covered by EASL
from PubMed and Cochrane database searches providing up to date guidelines, namely: gastrointestinal (GI) bleeding, bacterial infections
guidance on the management of decompensated cirrhosis with the only other than SBP, acute-on-chronic liver failure (ACLF), adrenal failure,
purpose of improving clinical practice. 2018 European Association for the HPS, PPHT and CCM. In doing so, we have had to deal with the
Study of the Liver. Published by Elsevier B.V. All rights reserved. recommendations regularly proposed by 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
Introduction extreme importance in clinical practice, only specific aspects of their
When the panel of experts nominated by the European Association for recommendations were further developed in an attempt to give a more
the Study of the Liver (EASL) governing board began work to update integrated view of the pathophysiology and management of patients with
the Clinical Practice Guidelines (CPGs) on ascites, spontaneous bacterial decompensated cirrhosis. Thus, this document can no longer be
peritonitis (SBP), and hepatorenal syndrome (HRS), 1 it became obvious considered an update of earlier guidelines, but rather the first CPG on the
that all other complications of decompensated cirrhosis had to be management of decompensated cirrhosis with the sole purpose of
covered. Within this framework, a formal definition of decompensated improving clinical practice.
cirrhosis was sought. The natural history of cirrhosis is characterised by
a silent, asymptomatic course until increasing portal pressure and
worsening liver function produce a clinical phenotype. In the Guidelines development process
asymptomatic phase of the disease, usually referred to as compensated A panel of hepatologists with a great interest in decompensated cirrhosis,
cirrhosis, patients may have a good quality of life, and the disease may approved by the EASL Governing Board, wrote and discussed this CPG
progress undetected for several years. Decompensation is marked by the between March 2017 and February 2018. The guidelines were
development of overt clinical independently peer reviewed, and 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 (Governing Board reviewed the composition of the panel to eliminate the potential for real
representative), CÁndid Villanueva, Claire Francoz, Rajeshwar P. Mookerjee, Jonel Trebicka,
Aleksander Krag, Wim Laleman, Pere Gines or perceived bias. The CPG panel conflict of interests are declared in this
⇑ Corresponding author. Address: European Association for the Study of the Liver (EASL), submission. These guidelines have been produced using evidence from
The EASL Building – Home of Hepatology, 7 rue Daubin, CH 1203 Geneva, Switzerland. Tel.: PubMed and Cochrane database searches before 27 March 2018. Tables
+41 (0) 22 807 03 60; fax: +41 (0) 22 328 07 24. describing
E-mail address: [email protected].
Journal of Hepatology 2018 vol. xxx 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
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 recommendations are nitrogen species. This cascade of events contributes to the development
provided (Table 1). of circulatory dysfunction and, along with it, directly favours the
development of multi-organ dysfunction and failure (Fig. 1).5 Current
strategies for prophylaxis and treatment of decompensation and organ
Pathophysiology of decompensated cirrhosis failure in cirrhosis rely on measures aimed to prevent or improve the
The transition from compensated asymptomatic cirrhosis to outcome of each complication, that is renal sodium retention leading to
decompensated cirrhosis occurs at a rate of about 5% to 7% per year. 4 ascites formation, ammonia production in hepatic encephalopathy,
Once decompensation has occurred, cirrhosis becomes a systemic effective hypovolaemia after large-volume paracentesis (LVP) or during
disease, with multi-organ/system dysfunction.5 At this stage, patients HRS, renal dysfunction induced by SBP, and intestinal dysbiosis or
become highly susceptible to bacterial infections because of complex bacterial overgrowth in patients predisposed to develop infections. All
cirrhosis-associated immune dysfunction, which involves both innate these strategies will be discussed in these CPGs. However, the improved
and acquired immunity.6 In turn, patients with bacterial infections are knowledge of the pathophysiological background of decompensated
burdened by severe morbidity, up to ACLF, and high mortality. 6,7 cirrhosis now offers the opportunity for more comprehensive therapeutic
Because of these events, decompensation represents a prognostic and prophylactic approaches to disease management. Indeed, besides
watershed, as the median survival drops from more than 12 years for treating the underlying aetiologic factor(s), whenever possible,
compensated cirrhosis to about two years for decompensated cirrhosis. 4 mechanistic approaches to counteract key pathophysiologic mechanisms
For decades the clinical manifestations of decompensated cirrhosis have may prevent or delay disease progression and the incidence of
been seen as the consequence of a haemodynamic disturbance, the complications and multi-organ dysfunction, thus improving patient
hyperdynamic circulatory syndrome, ascribable to peripheral arterial survival and quality of life, as well as reducing the economic burden of
vasodilation that mainly occurs in the splanchnic circulatory area. The the disease.
extent of such vasodilation is to endanger effective volaemia, ultimately
leading to peripheral organ hypoperfusion, the kidney being most
affected.8 Indeed, reduced effective volaemia brings about the activation Management of decompensated cirrhosis
of vasoconstrictor and water and sodium retaining mechanisms, such as Ideally, the strategy of management of patients with decompensated
the renin-angiotensin-aldosterone (RAAS), sympathetic nervous system cirrhosis should be based on preventing cirrhosis progression (i.e. further
and arginine-vasopressin secretion. This explains some of the cardinal decompensation) rather than treating complications as they occur. The
features of decompensated cirrhosis, such as renal retention of sodium ultimate treatment for decompensated cirrhosis would be one that targets
and water leading to ascites formation and HRS. Other manifestations primarily the pathological alterations within the liver with the aim of
attributable to hemodynamic abnormalities include HPS, increased restoring the integrity of liver architecture by suppressing inflammation,
susceptibility to shock, and a reduced cardiovascular responsiveness to causing fibrosis regression, regularizing the portal and arterial
physiological and pharmacological vasoconstrictor stimuli. Subsequent circulation, and normalizing cell number and function . Unfortunately,
studies have highlighted that a cardiac dysfunction, due to CCM, 9 is also such a treatment does not exist at present. Several antifibrotic or anti-
involved in the pathogenesis of effective hypovolaemia. 10 This occurs inflammatory drugs have shown promise in experimental models of
particularly in the most advanced stages of decompensation, when such chronic liver diseases, but no treatment has yet been translated into
an abnormality prevents cardiac output from increasing enough to clinical practice.13 Meanwhile, the overall management of
comply with the needs of systemic circulation. Although the molecular decompensated cirrhosis can be addressed using two approaches. The
mechanisms responsible for arterial vasodilation, consisting of an first approach is the suppression of the etiological factor(s) that has
enhanced endothelial production of vasodilating substances, such as caused liver inflammation and cirrhosis development, whereas the
nitric oxide, carbon monoxide, prostacyclin and endocannabinoids have second approach is based on targeting key factors of pathogenesis of
been convincingly demonstrated,11 the primary causes of such cirrhosis decompensation and progression.
abnormalities remained somewhat obscure until it became clear that
patients with advanced cirrhosis present a state of chronic inflammation,
as witnessed by increased circulating levels of pro-inflammatory
Effects of suppression of aetiological factor on outcome of
cytokines and chemokines.12 This is likely caused by the systemic spread
decompensated cirrhosis
of bacteria and bacterial products, called pathogen associated molecular
Removal of the aetiological factor(s) causing liver injury is an important
patterns (PAMPs), as a result of an abnormal bacterial translocation
cornerstone in the management of cirrhosis. This approach is clearly
(BT). Changes in the microbiome and increased intestinal permeability
effective in preventing decompensation and improving outcome in
account for this phenomenon. A similar role is likely played by other
patients with compensated cirrhosis. However, results in patients with
molecules, called danger associated molecular patterns (DAMPs),
decompensated cirrhosis are less efficacious and probably depend,
released by the diseased liver because of local inflammation and cell
among other factors, on the actual status of liver disease at the time of
apoptosis and necrosis. Both PAMPs and DAMPs bind with innate
removing the aetiological factor of liver injury. For example, although in
recognition receptors of immune cells that, once activated, produce and
some patients with decompensated alcoholic cirrhosis suppression of
release pro-inflammatory molecules, along with reactive oxygen and
alcohol consumption is associated with progressive ‘‘re-compensation”
2 Journal of Hepatology 2018 vol. xxx j xxx–xxx
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OF HEPATOLOGY
of cirrhosis and excellent long-term outcome, in other patients alcoholic Recommendations
cirrhosis progresses despite stopping alcohol intake. 14,15 Likewise, in
patients with cirrhosis due to hepatitis B virus (HBV) infection,
In patients with decompensated cirrhosis, the aetiological factor,
treatment with antiviral agents is associated with improved outcome in
some, but not all patients. 16 Moreover, treatment of patients with should be removed, particularly alcohol consumption and
decompensated cirrhosis due to hepatitis C virus infection with direct hepatitis B or C virus infection as this strategy is associated with
antiviral agents is associated with beneficial effects in liver function and decreased risk of decompensation and increased survival (II-
portal hypertension and likely improves outcome, but these effects are 2,1).
unfortunately not generalisable to all patients treated. 17,18 The beneficial
Strategies based on targeting abnormalities in gut-liver axis by
effects of removing responsible factors in other aetiologies of
antibiotic administration (i.e. rifaximin), improving the disturbed
decompensated cirrhosis are less clear, perhaps with the exception of
autoimmune hepatitis. systemic circulatory function (i.e. longterm albumin
administration), decreasing the inflammatory state (i.e. statins),
and reducing portal hypertension (i.e. beta-blockers) have shown
Effects of targeting key pathogenic events in prevention of potential benefit to decrease cirrhosis progression in patients
cirrhosis progression with decompensated cirrhosis. However, further clinical research
Several strategies have been evaluated to prevent disease progression in is needed with these strategies to confirm their safety and
patients with decompensated cirrhosis, including i) targeting microbiome potential benefits as therapeutic approaches with the aim of
abnormalities and BT, to improve gut-liver axis; ii) improving the
preventing cirrhosis progression in decompensated patients.
disturbed circulatory function; iii) treating the inflammatory state; and
iv) targeting portal hypertension.
Administration of rifaximin has been shown to reduce the risk of
development of several complications of cirrhosis besides hepatic Management of specific complications of decompensated
encephalopathy in retrospective studies and small case series. 19 cirrhosis
Nonetheless, data from prospective randomised double-blind studies are Ascites
lacking. In patients with decompensated cirrhosis, treatment with Ascites isthemostcommoncauseofdecompensationincirrhosis, as 5% to
norfloxacin reduces the risk of SBP and HRS, 20,21 but its use is hampered 10% of patients with compensated cirrhosis per year develop this
by the possibility of increased risk of infection by resistant bacteria. The complication.29 The mainstay of ascites formation is renal sodium
potential effectiveness of improving circulatory and kidney function by retention due to the activation of sodium retaining systems, such as the
long-term administration of albumin to patients with decompensated renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous
cirrhosis has been explored in two recent randomised controlled trials system. The resulting positive fluid balance ultimately leads to
(RCTs), both published in abstract form, with contradictory findings. 22,23 extracellular fluid volume expansion. Reduced effective volaemia
The discrepant findings may be related to different doses of albumin secondary to splanchnic arterial vasodilation is a main determinant of
used and/or heterogeneity in the study population. Further studies are these alterations,8
needed to find out whether long-term albumin administration is butrenalfunctionabnormalitiesinducedbysystemicinflammation
efficacious in decompensated cirrhosis. Interestingly, treatment with
statins, through their pleotropic effects, has been shown to reduce portal
hypertension and improve survival in patients with advanced
cirrhosis.24,25 These remarkable effects require validation in future
studies. Another potential terapeutical strategy in the prevention of
decompensation may be anticoagulation. Indeed, in a small RCT, a 12-
month course of enoxaparin was safe and effective in preventing portal
vein thrombosis (PVT) in patients with cirrhosis and a Child-Pugh
scores of 7–10. In addition, enoxaparin appeared to delay the occurrence
of hepatic decompensation and to improve survival suggesting that both
PVT and decompensation may be related to a worsening of portal
hypertension and the consequent progressive damage of the intestinal
mucosal barrier.26 From the same perspective, two other strategies should
be considered. In 2010, it was shown that pentoxifylline treatment
significantly reduced the risk of liver-related complications compared to
placebo in an RCT of patients with advanced cirrhosis. The prevention
of these complications, which included bacterial infections, renal failure,
and hepatic encephalopathy was probably related to the fact that
pentoxifylline prevents intestinal BT and the consequent development of
systemic inflammation.27 Finally, some investigations have shown that
treatment with propranolol is not only effective in reducing portal
hypertension and the consequent the risk of variceal bleeding but also in
decreasing the risk of other complications of cirrhosis related to portal
hypertension, such as ascites, HRS, SBP, and hepatic encephalopathy. 28
These effects occur specifically in patients who respond to propranolol
treatment by markedly decreasing portal pressure, emphasising the
strong relationship between pressure and complications of cirrhosis.
Nevertheless, in these studies most of patients had compensated
cirrhosis. Therefore, studies should be performed in the group of patients
with decompensated cirrhosis with the objective of assessing these
beneficial effects in cirrhosis progression.
Journal of Hepatology 2018 vol. xxx j xxx–xxx 3
Cirrhosis
Portal hypertension Liver injury
Bacterial translocation Damaged cells

PAMPs DAMPs
Otherpotential Activationifinnate pattern

recognition receptors
mechanisms
Release of pro-inflamamtory molecules

(ROS/RNS)
Splanchnic arteriolarvasodilation
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, damageassociated molecular pattern; HE,
hepatic encephalopathy; HPS, hepatopulmonary syndrome; PAMP, pathogen-associated molecular pattern; RNS, reactive
nitrogen species; ROS, reactive oxygen species. 97%.36 Other tests, such as amylase, cytology, or culture for
mycobacteria should be guided by clinical presentation. Ascitic
also play a role, especially in the most advanced stages of cirrhosis. 5
cholesterol determination followed by cytology and carcinoembryonic
Portal hypertension also contributes30 by acting as a compartmentalising
antigen (CEA) determination in samples where cholesterol concentration
factor of the expanded extracellular fluid volume.
exceeds 45 mg/dl appears to be a cost-effective method for the
The occurrence of ascites impairs patient working and social life,
differential diagnosis between malignancy-related and non-malignant
often leads to hospitalisation, requires chronic treatment and is a direct
ascites.37
cause of further complications, such as SBP, restrictive ventilatory
dysfunction, or abdominal hernias. The appearance of ascites heralds a Recommendations
poor prognosis, as the five-year survival drops from about 80% in
compensated patients to about 30% in patients with decompensated A diagnostic paracentesis is recommended in all patients with new
cirrhosis and ascites.4
onset grade 2 or 3 ascites, or in those hospitalised for worsening
Uncomplicated ascites of ascites or any complication of cirrhosis (II-2;1).
Evaluation of patients with ascites Neutrophil count and culture of ascitic fluid culture (bedside
Cirrhosis is the main cause of ascites in the Western world, being inoculation blood culture bottles with 10 ml fluid each) should
responsible for about 80% of cases. Malignancy, heart failure,
be performed to exclude bacterial peritonitis. A neutrophil count
tuberculosis, pancreatic disease, or other rarer diseases account for the
remaining cases. Initial patient evaluation should include history, above 250 cells/ll is required to diagnose SBP (II-2;1).
physical examination, abdominal ultrasound, and laboratory assessment Ascitic total protein concentration should be performed to identify
of liver and renal functions, serum and urine electrolytes, as well as an
analysis of the ascitic fluid. patients at higher risk of developing SBP
(II-2;1).
Diagnosis of ascites
Ascites can be graded from 1 to 3 according to the amount of fluid in the The SAAG should be calculated when the cause of ascites is not
abdominal cavity31 (Table 2). The ascites that recurs at least on three immediately evident, and/or when conditions other than
occasions within a 12-month period despite dietary sodium restriction
cirrhosis are suspected (II-2;1).
and adequate diuretic dosage is
defined as recidivant.32 Cytology should be performed to differentiate malignancy-related
Diagnostic paracentesis is indicated in all patients with new onset of from non-malignant ascites (II-2;1).
grade 2 or 3 ascites and in those admitted to the hospital for any Prognosis of patients with ascites
complication of cirrhosis.31,32 Manual or automated neutrophil count, The development of ascites in patients with cirrhosis is associated with a
total protein and albumin concentration, and culture should be always poor prognosis, as their one and two-year mortality is about 40 and 50%,
assessed. A neutrophil count above 250 cells/ ll denotes SBP.33 A total respectively.1 Thus, patients with ascites should generally be considered
protein concentration <1.5 g/dl is generally considered a risk factor for for referral for LT. Hyponatraemia, low arterial pressure, glomerular
SBP, although there are conflicting data. 33,34 Ascitic fluid culture requires filtration rate (GFR) and low renal sodium excretion are independent
the bedside inoculation of at least 10 ml into blood culture bottles to predictors of mortality in cirrhosis with ascites. 38 As these parameters are
enhance its sensitivity.35 The calculation of serum-ascites albumin not included in the Child-Pugh score, and only serum creatinine (SCr),
gradient (SAAG) may be useful when the cause of ascites is not which overestimates GFR in cirrhosis, 39 is included in the model for end-
immediately evident, as SAAG ≥1.1 g/dl indicates that portal stage liver disease (MELD) score, the most commonly used prognostic
hypertension is involved in ascites formation with an accuracy of about scores can underestimate the mortality risk in patients with ascites.
Modifications of the MELD score, such as the MELD-Na and MELD-
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OF HEPATOLOGY
Ascites scores have only partially overcome this limitation. 40 Thus, inducedbydiureticsshould notleadtoabodyweightlossexceeding 0.5
patients with ascites may not receive adequate priority in transplant lists, kg/day in patients without peripheral oedema and 1 kg/day in the
and improved methods to assess prognosis in these patients are needed. presence of peripheral oedema to avoid plasma volume contraction,
A prognostic score able to identify patients with low MELD score (<18) ultimately leading to renal failure and hyponatraemia. 48 Since secondary
at high risk of 12-month adverse outcome has recently been proposed, hyperaldosteronism plays a pivotal role in the renal sodium retention in
but it still has limited application. 41 patients with cirrhosis,49,50 anti-mineralocorticoid drugs (spironolactone,
canrenone or K-canrenoate) represent a mainstay in the medical
Recommendation
treatment of ascites.50 Four hundredmg/day represents the maximal
dosage usually recommended.31,32 The mechanism of action of anti-
Since the development of grade 2 or 3 ascites in patients with mineralocorticoids explains their slow effect. In fact, the activated
cirrhosis is associated with reduced survival, LT should be aldosterone pathway, which involves interaction with a cytosolic
receptor and, then, a nuclear receptor, needs to be exhausted before their
considered as a potential treatment option
natriuretic effect arises. Therefore, the dosage of these drugs should not
(II-2;1). be increased earlier than 72 h. Amiloride, a diuretic acting in the
Management of uncomplicated ascites collecting duct, is less effective than antimineralocorticoids, and should
Ascites is uncomplicated when it is not infected, refractory or associated only be used in patients who develop severe side effects with aldosterone
with HRS.31,32 antagonists.51
Proximal tubular sodium reabsorption promotes renal sodium
retention through various mechanisms, such as increased angiotensin II
Grade 1 or mild ascites. No data on the evolution of grade 1 ascites are production, sympatho-adrenergic hyperactivity and reduced renal
available, nor it is known whether its treatment modifies its natural perfusion.49 As proximal tubular sodium reabsorption can become
history. relatively prevalent in patients with long-standing ascites, 52,53 loop
diuretics are indicated in this setting. However, they should be combined
Grade 2 or moderate ascites. Patients who develop grade 2 ascites do not with but not substituted for anti-mineralocorticoids. Indeed, despite their
require hospitalisation, unless other complications are present. They potent activity, the natriuretic effect of loop diuretics can be completely
have a positive sodium balance, which can be corrected by reducing the blunted by unopposed hyperaldosteronism. 54 Whether diuretic treatment
dietary sodium intake and increasing renal sodium excretion with should be initiated with anti-mineralocorticoids alone or should also
diuretics. Although upright posture favours renal sodium reabsorption 42 include a loop diuretic has long been debated. Two studies have
and attenuates the response to diuretics, 43 there is no evidence that a addressed this matter providing apparently conflicting results because of
prolonged maintenance of the supine position eases the treatment of differences in patient populations. 55,56 In both studies, the effects of a
ascites. diuretic regimen initially consisting of spironolactone or K-canrenoate
Sodium restriction. The prophylactic use of salt restriction in patients alone at stepwise increasing
who never had ascites is not supported by evidence. Dietary sodium
Table 2. Grading of ascites.
restriction can lead to the resolution of ascites in about 10% of patients, 44
Grade 1. Mild ascites: it is only detectable by ultrasound examination
especially in those with the first episode of ascites. A clear advantage
Grade 2. Moderate ascites: it is manifest by moderate symmetrical distension of
from the use of low-sodium diets associated with diuretics has not abdomen
emerged from clinical trials comparing different dietary regimens. 44,45 Grade 3. Large or gross ascites: it provokes marked abdominal distension
Extreme sodium restriction favours the development of diuretic-induced dosages (from 100/200 to 400 mg/day), with furosemide added in non-
hyponatraemia and renal failure.46 Moreover, even moderate sodium responder patients, were compared with those of the combination of anti-
restriction, when not prescribed with an adequate educational mineralocorticoids with furosemide (from 40 to 160 mg/day) from the
programme, is often associated with reduced calorie intake, 47 and may beginning of treatment. In one study,56 the response rate, the rapidity of
impair nutritional status. The current opinion is that dietary sodium ascites mobilisation and the incidence of diuretic-induced complications
should only be moderately restricted (80–120 mmol/day), mainly to were similar in
avoid excess salt intake. bothregimens.However,asthesequentialtreatmentrequiredless dose
adjustments, it appeared to be more suitable for treating ascites on an
Recommendations outpatient basis. In the other study,55 the combined regimen achieved the
resolution of ascites in a shorter time, with a lower incidence of side
A moderate restriction of sodium intake (80–120 mmol/ day, effects, mainly hyperkalemia. Such divergent results likely arose from
corresponding to 4.6–6.9 g of salt) is recommended in patients differences in the patient populations. In one study, 56 patients with ascites
with moderate, uncomplicated ascites (I;1). This is generally at the first appearance and well preserved renal function prevailed,
while, in theother,55 mostpatientshadrecurrentascitesandmanyshowed a
equivalent to a no added salt diet with avoidance of pre-prepared
substantial reduction of GFR. Thus, patients with ascites at the first
meals. Adequate nutritional education of patients on how to
appearance can confidently be treated with antimineralocorticoids alone,
manage dietary sodium is also recommended (II-2;1).
astheywill likely developa satisfactory response with few side effects.
Diets with a very low sodium content (<40 mmol/day) should be Patients with long-standing, recurrent ascites should receive the
avoided, as they favour diuretic-induced complications and can combination therapy, which likely shortens the time to achieve
natriuresis and lowers the incidence of hyperkalemia. 1 In a randomised
endanger a patient’s nutritional status
double-blind crossovertrialtorasemideinducedgreatercumulative 24
(II-2;1). hdiuresisthan furosemide, suggesting that torasemide might be more
Prolonged bed rest cannot be recommended because there is advantageous in patients exhibiting a weak response to furosemide. 57
insufficient evidence that it is beneficial in the treatment of Following mobilisation of ascites, diuretics should be tapered to the
ascites (III;1). lowest dosages able to maintain patients with minimal or no ascites, to
Diuretics. Neither diuretics nor LVP are associated with a survival minimise side effects. Whenever possible, an aetiologic treatment of the
benefit because they act downstream of the pathophysiological cascade, underlying cirrhosis should be instituted, as this eases the control of
being symptomatic therapies. The negative fluid balance ascites in many cases. Complications of diuretic therapy. The
haemodynamic status of patients with cirrhosis and ascites 8 makes them initiation of diuretic therapy and frequent clinical and
highly susceptible to rapid reductions in extracellular fluid volume, biochemical assessments should be performed (III;1). Diuretic
which mostly occur with loop diuretics. Thus, renal failure is frequent in therapy is generally not recommended in patients with persistent
this setting,48 as is hepatic encephalopathy, also favoured by increased
overt hepatic encephalopathy (III;1).
renal ammonia production. Loop diuretics can also lead to potassium and
magnesium depletion. Hyponatraemia is another common diuretic- Diuretics should be discontinued if severe hyponatraemia (serum
induced side effect in cirrhosis. It mostly, but not exclusively, occurs sodium concentration <125 mmol/L), AKI, worsening hepatic
with loop diuretics, as they inhibit Na-K-Cl transporter and, therefore, encephalopathy, or incapacitating muscle cramps develop (III;1).
solute-free water generation. Plasma volume contraction can also
Furosemide should be stopped if severe hypokalemia occurs (<3
enhance arginine-vasopressin release. Thus, hyponatraemia can also
ensue with anti-mineralocorticoid administration, albeit infrequently. mmol/L). Anti-mineralocorticoids should be stopped if severe
Most experts agree on at least temporarily withdrawing diuretics when hyperkalemia occurs (>6 mmol/L) (III;1).
serum sodium concentration decreases below 120– 125 mmol/L. Albumin infusion or baclofen administration (10 mg/day, with a
Hyperkalemia, especially in patients with reduced renal perfusion, and weekly increase of 10 mg/day up to 30 mg/day) are
painful gynecomastia are the most common side effects induced by anti-
recommended in patients with muscle cramps (I;1).
mineralocorticoids.
Muscle cramps can impair quality of life in patients receiving
diuretics. Albumin infusion can relieve cramps, 58 as well as baclofen (10
Grade 3 or large ascites. The treatment of choice for the management of
mg/day, with a weekly increase of 10 mg/day up to 30 mg/day), which
patients with grade 3 ascites is represented by LVP. Paracentesis should
was safely used in a recent RCT. 59 One RCT investigated the use of
be performed under strict sterile conditions using disposable sterile
quinidine at the dose of 400 mg/day for four weeks in patients with
materials. The procedure is associated with a very low risk of local
cirrhosis with painful muscle cramps. Although more effective than
complications, particularly bleeding61,62 even in patients with
placebo, quinidine was associated with diarrhoea in about one-third of
international normalized ratio (INR)>1.5 and platelet count <50,000/ ll,
cases requiring treatment withdrawal. 60 Because of the frequency of
diureticinduced side effects, especially during the first month of minor bleeding from puncture site occurred in two out of 142
treatment,55 serial measurements of SCr, sodium, and potassium are paracentesis.61 Thus, there are no data supporting the prophylactic use of
warranted. The assessment of urine sodium excretion can be limited to fresh frozen plasma of pooled platelets, even though these are employed
non-responders, to unveil excessive sodium intake. in many centres when prothrombin activity is below 40% and platelet
count <40,000/ll. LVP should be avoided in the presence of
Recommendations
disseminated intravascular coagulation. Other contraindications to LVP
are reported (Table 3).
Patients with the first episode of grade 2 (moderate) ascites should The removal of large volumes of ascitic fluid is potentially associated
receive an anti-mineralocorticoid drug alone, starting at 100 with a further reduction of effective blood volume, a condition known as
mg/day with stepwise increases every 72 h (in 100 mg steps) to a post-paracentesis circulatory dysfunction (PPCD). 63 The clinical
maximum of 400 mg/day if there is no response to lower doses manifestations of PPCD are renal failure, dilutional hyponatraemia,
hepatic encephalopathy and decreased survival. 63 Plasma volume
(I;1).
expansion should be performed at the completion of LVP to prevent this
In patients who do not respond to anti-mineralocorticoids, as complication. Artificial plasma expanders, such as dextran-70 (8 g/L of
defined by a body weight reduction of less than 2 kg/week, or in ascites removed)64 or polygeline (150 ml/L),64 saline solution (170 ml/
patients who develop hyperkalemia, furosemide should be added L),65 only show a similar efficacy to 20% albumin (8 g/L) 64 when less
at an increasing stepwise dose from 40 mg/day to a maximum of than 5 L of ascites are removed. However, polygeline is no longer used
160 mg/day (in 40 mg steps) (I;1). in many countries because of the potential risk of transmission of prions
and dextran carries the risk of severe allergic reaction and renal failure.
Patients with long-standing or recurrent ascites should be treated A meta-analysis of randomised trialsshowed that albumin issuperior to
with a combination of an anti-mineralocorticoid drug and anyotherplasma expander or vasoconstrictor not only in preventing
furosemide, the dose of which should be increased sequentially PPCD, but also its clinical consequences, such as hyponatraemia and
according to the response, as explained (I;1). mortality.66 Moreover, albumin infusion after LVPappears to be more
cost-effective than a cheaper plasma volume expander, such as
Torasemide can be given in patients exhibiting a weak response to
polygeline, because of the lower number of liver-related complications
furosemide (I;2). and hospital costs for a 30-day period. 67 LVP combined with infusion of
albumin in patients with grade 3 ascites is more effective and safer than
During diuretic therapy a maximum weight loss of 0.5 kg/day in diuretics.68,69 However, LVP does not modify the underlying
patients without oedema and 1 kg/day in patients with oedema is pathophysiological abnormalities leading to ascites formation. Thus,
recommended (II-2;1). patients treated with LVP require diuretic therapy to prevent the re-
accumulation of ascites.70
Once ascites has largely resolved, the dose of diuretics should be
reduced to the lowest effective dose (III;1). Recommendations

During the first weeks of treatment patients should undergo
frequent clinical and biochemical monitoring particularly on first LVP is the first-line therapy in patients with large ascites (grade 3
presentation (I;1). ascites), which should be completely removed in a single session
In patients presenting with GI haemorrhage, renal impairment, (I;1). LVP should be followed with plasma volume expansion to
hepatic encephalopathy, hyponatraemia, or alterations in serum prevent PPCD (I;1).
potassium concentration, these abnormalities should be corrected
In patients undergoing LVP of greater than 5 L of ascites, plasma
before starting diuretic therapy (III;1). In these patients, cautious
volume expansion should be performed by infusing albumin (8
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OF HEPATOLOGY
The use of aminoglycosides is discouraged, as they are associated
g/L of ascites removed), as it is more effective than other plasma
with an increased risk of AKI. Their use should be reserved for
expanders, which are not recommended for this setting (I;1).
patients with severe bacterial infections that cannot be treated
In patients undergoing LVP of less than 5 L of ascites, the risk of
with other antibiotics (II-2;1).
developing PPCD is low. However, it is generally agreed that
In patients with ascites and preserved renal function, the use of
these patients should still be treated with albumin because of
contrast media does not appear to be associated with an
concerns about use of alternative plasma expanders (III;1).
increased risk of renal impairment (II-2). There are insufficient
After LVP, patients should receive the minimum dose of diuretics
data in patients with renal failure. Nevertheless, a cautious use of
necessary to prevent re-accumulation of ascites contrast media and the use of preventive measures for renal
impairment are recommended (III;1).
(I;1).
When needed, LVP should also be performed in patients with AKI
or SBP (III;1).
Table 3. Contraindications to paracentesis.
Uncooperative patient
Abdominal skin infection at the proposed puncture sites
Pregnancy
Severe coagulopathy (accelerated fibrinolysis or disseminated intravascular
coagulation)
Severe bowel distension
Drugs contraindicated in patients with ascites

As non-steroidal anti-inflammatory drugs inhibit renal prostaglandin
synthesis, they should not be used in patients with cirrhosis and ascites,
where an increased vasodilating prostaglandin synthesis counteracts the
renal vasoconstrictor effects of angiotensin II. Indeed, their
administration can lead to acute renal failure, hyponatraemia, and
diuretic resistance.71 It would appear that selective inhibitors of
cyclooxygenase-2 do not impair renal function and response to diuretics
in patients with ascites.72 However, it is not known whether these drugs
can be safely used in clinical practice when analgesia is needed. Patients
with ascites are also particularly sensitive to the renal vasoconstrictor
effect of endogenous adenosine, and dipyridamole can induce a marked
reduction in renal perfusion.73
The maintenance of an adequate arterial pressure in cirrhosis with
ascites is assured by the activation of endogenous vasoconstrictor
systems. Thus, angiotensin-converting enzyme inhibitors, 74 angiotensin
II receptor antagonists, and a1-adrenergic blockers75 should be avoided,
as they can induce arterial hypotension and renal function impairment.
Aminoglycosides should be avoided in the treatment of bacterial
infections, except in specific cases (discussed later), because they are
associated with high incidence of nephrotoxicity. 76 Although cirrhosis
with ascites and preserved renal function does not appear to be a risk
factor for renal failure induced by contrast media, 77 this cannot be
excluded in patients with impaired renal function. In these cases,
preventive measures such as plasma volume expansion with saline may
be employed.78
Recommendations
Non-steroidal anti-inflammatory drugs should not be used in

patients with ascites because of the high risk of developing
further sodium retention, hyponatraemia, and AKI (II-2;1).
Angiotensin-converting-enyzme inhibitors, angiotensin II
antagonists, or a1-adrenergic receptor blockers should not
generally be used in patients with ascites because of increased
risk of renal impairment (II-2;1).

Refractory ascites TIPS insertion in these studies was the prevention or treatment of
Evaluation of patients with refractory ascites recurrent bleeding, which may restrict the relevance of these results in
According to the criteria of the International Ascites Club, refractory patients with refractory ascites. Dysfunction of TIPS with bare stent
ascites is defined as ‘‘ascites that cannot be mobilised or the early grafts because of stent thrombosis and stenosis can develop in up to 80%
recurrence of which (i.e., after LVP) cannot be satisfactorily prevented of cases.89 This complication has been significantly reduced with the use
by medical therapy”.31,32 The diagnostic criteria of refractory ascites are of PTFE-covered stents.94
shown in Table 4. Refractoriness of ascites is associated with a poor
prognosis, with a median survival of about six months. 79 Therefore, if a Controlled studies and meta-analysis. The clinical effects of TIPS with
patient with refractory ascites has not yet been considered for LT, he/she bare stents in patients with refractory or recurrent ascites have been
should be immediately assessed in six prospective RCTs, 95–100 whose main features are reported
referredtoalivertransplantcenter.Thepotentialunderestimation of the (Table 5). Based on these RCTs, seven meta-analyses were
mortality risk by commonly used prognostic scores, as discussed earlier performed.101–107 The final messages can be summarised as follow: i)
also applies to patients with refractory ascites.80 TIPS controlled ascites better than LVP, and ii) TIPS is followed by a
greater incidence of hepatic encephalopathy. However, discrepant results
Recommendations were obtained with respect to survival. A better survival with LVP,
mainly because of a detrimental effect of TIPS in Child-Pugh class C
The diagnosis of refractory ascites relies on the assessment of the patients, was reported by one study, 96 while no difference was reported
response of ascites to diuretic therapy and salt restriction. Such by two.95,100 A better survival with TIPS was reported
an evaluation should be done in stable patients without Table 4. Definition and diagnostic criteria for refractory ascites in cirrhosis.
Definition
associated complications, such as bleeding or infection, after
ascertaining patient compliance to treatment (III;1).
Diuretic-resistant ascites Ascites that cannot be mobilized or the early recurrence of which cannot b
Patients with refractory ascites should be evaluated for diuretic treatment
Diuretic-intractable ascites Ascites that cannot be mobilized or the early recurrence of which cannot b
LT (III;1). that preclude the use of an effective diuretic dosage
Diagnostic criteria
Management of refractory ascites
Large-volume paracentesis. There is general agreement that LVP is an
Treatment duration Patients must be on intensive diuretic therapy (spironolactone 400 mg/day
effective and safe treatment of refractory ascites, 31,35 which should be diet of less than 90 mmol/day
associated with albumin administration to prevent PPCD. Lack of response Mean weight loss of <0.8 kg over four days and urinary sodium output les
Early ascites recurrence Reappearance of grade 2 or 3 ascites within four weeks of initial mobilisa
Diuretics in patients with refractory ascites. Once refractoriness of Diuretic-induced complications Diuretic-induced hepatic encephalopathy is the development of encepha
ascites has been ascertained, diuretics should be discontinued. Only renal impairment is an increase of serum creatinine by >100% to a value >
when renal sodium excretion on diuretics exceeds 30 mmol/day, Diuretic-induced hyponatremia is defined as a decrease of serum sodium b
hypo- or hyperkalemia is defined as a change in serum potassium to <3 m
maintenance of diuretic therapy can be considered, when tolerated. 31 cramps
Non-selective beta-blockers in patients with refractory ascites. The

controversial issue on the use of non-selective beta-blockers (NSBBs) in
patients with ascites and, particularly, in those with refractory ascites
8 Journal of Hepatology 2018 vol. xxx j xxx
will be developed in the section dedicated to GI bleeding.
Please cite this article in press as: The European Association for the Study of the Liver. EASL Clinical Practice Guidelines fo
Hepatol (2018), https://doi.org/10.1016/j.jhep.2018.03.024
Transjugular intrahepatic portosystemic shunts. Transjugular intrahepatic Table 5. Characteristics and results of six randomised controlled trials comparing bared
portosystemic shunts (TIPS) decompresses the portal system by shunting TIPS and LVP in patients with cirrhosis and refractory or recidivant ascites.
an intrahepatic portal branch into a hepatic vein. Its insertion accentuates
perpheral arterial vasodilation in the short term. However, within 4–6 Refs. Refractory/ Exclusion criteria Enrolled Ascites
weeks its result is an improvement in effective volaemia and renal Encephalopathy Survival recidivant patients
improved (%) (%)
function, ultimately leading to an increase in renal sodium excretion. 81–85 ascites (%)
TIPSinduced natriuresis can be delayed by advanced age and reduced (%)
pre-TIPS GFR,84 and prevented by intrinsic kidney disease. 86 TIPS may
also exert beneficial effects on nitrogen balance and nutrition 87 and
quality of life.88 A major complication after TIPS insertion using bare LVP
stent grafts is the development of hepatic encephalopathy, which can LVP
LVP
occur in up to 50% of patients. 89,90 The incidence of this complication can
LVP
be significantly reduced to about 18% with the use of Lebrec et al. 100/0 Age >70 yr; severe extra-hepatic diseases; HCC; pulmonary hyperten
polytetrafluoroethylene (PTFE)-covered stent grafts of 8 mm, 91 a result 1995 bacterial infection; severe alcoholic hepatitis; portal or hepatic vein o
confirmed by a recent randomised trial comparing 8 mm and 10 mm or thrombosis; obstruction of biliary tract; obstruction of hepatic arte
stent grafts.92 Notably, this favourable effect is better than with larger creatinine >1.7 mg/dl
Rössle et al. 55/45 HE ≥grade 2; serum bilirubin >5 mg/dl, serum creatinine >3 mg/dl;
stent grafts underdilated to 8 mm. Indeed, it has been shown that
29 31 84 43* 23 13 58 32 2000 portal-vein thrombosis, hepatic hydrothorax; advanced
underdilated 10 mm stent grafts passively expand to almost the full cancer; failure of LVP (ascites persisting after LVP or need for LVP >once per week)
diameter within 1–6 weeks.93 It must be underlined that the indication for Ginés et al. 100/0 Age >18 or >75 yr; serum bilirubin >10 mg/dl; prothrombin time <4
200290 2.5); platelet count <than 40,000/mm 3; serum creatinine >3 mg/
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OF HEPATOLOGY
complete portal vein thrombosis; cardiac or respiratory failure; organic renal

failure; bacterial infection; chronic HE y
Sanyal et al. 100/0 Causes of ascites other than cirrhosis; advanced liver failure r
(serum 52 57 58 16* 38 21 ;
35 33 2003100 bilirubin bilirubin >5 mg/dl, PT INR >2); incurable cancers or
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Salerno et al. 68/32 diuretics

Age > 72 yr; recurrent HE ≥grade 2; serum bilirubin >6 mg/dl; in creatinine
serum 60% of cases, while no RCT in patients with refractory
200499 >3 mg/dl; Child-Pugh score >11; complete portal vein thrombosis;
response HCC;
was seen with diuretics ascites, Alfapump reduced the
gastrointestinal bleeding within 15 d of randomisation; serious cardiac or
alone. This effect was associated
pulmonary dysfunctions;bacterial infection; SAAG gradient <11 g/L.
median number of paracentesis
with significant reductions of per month by 85% with respect to
Narahara 100/0 Age >70 yr, chronic HE, HCC and other malignancies, RAAS and sympathetic nervous LVP, and significantly improved
complete portal 30 30 87 30* 20 system activity. Interestingly, the quality of life and nutritional
* 97
5 20 5 et al. 2011 vein thrombosis with
favourable effects of clonidine parameters, as assessed by hand-
cavernomatous transformation, bacterial infection, severe cardiac or pulmonary disease,
organic renal disease. were predicted by the variant grip strength and body mass
HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; INR, international normalized ratio; LVP, genotype of paracentesis;
large volume G proteinPT,(GNB3prothrombin index. Alfapump
time; SAAG, serumasciteshadalbumin
no effect on
gradient;
TIPS, transjugular intrahepatic portosystemic shunt. * Significantly lower than TIPS. C825T) and adrenergic receptor survival and was associated with a
(ADRA2C Del 322– 325) significantly higher incidence of
polymorphisms, and the baseline serious adverse events (85.2 vs.
in another two studies,97,99 while, in the remaining one,98 although a norepinephrine level.119 Small 45.2%), mainly represented by
survival advantage was not found, TIPS was independently associated scale or pilot studies evaluated the AKI.126 Thus, even though
with transplant-free survival at multivariate analysis. In four meta- effects of various combinations of Alfapump is effective in reducing
analyses including the five studies available at that time no survival midodrine with either clonidine,120 the need for paracentesis in
advantantage with TIPS emerged. However, a trend towards reduced the antagonist of vasopressin V2- patients with refractory ascites, its
121
mortality with TIPS was seen104 after the exclusion of an outlier trial. 96 receptors tolvaptan, or octreotide frequent side effects require close
122
The latter was also excluded in the only meta-analysis on individual and albumin in patients with monitoring of patients. Indeed, in
patient data, and an increased transplant-free survival was found. 107 refractory and recurrent ascites. addition to device-related adverse
Finally, the two meta-analyses that included all six trials 102,103 provided Some promising results were event, it should be noted that the
obtained, but they need to be evaluation of kidney and
contrasting results, as an improved transplant-free survival was found in
107 confirmed by sufficiently powered circulatory function in 10 patients
one, while a survival advantage with TIPS was limited to patients with
RCTs. A recent RCT123 compared with cirrhosis and refractory
recurrent ascites in the other.102
the effects of the combined ascites carrying Alfapump has
Fewer studies assessing the effects of TIPS with PTFE-covered stent administration of midodrine (5 mg shown a significant GFR decline
grafts are available. Two retrospective studies108,109 reported better control t.i.d) and rifaximin (550 mg b.i.d) within six months, which was
of ascites and one-year108 or twoyear109 survival with covered stent grafts on top of diuretics for 12 weeks associated with a marked increase
than bare stent grafts in patients with refractory ascites. A survival with diuretics alone. After 12 in plasma renin activity and
benefit of TIPS vs. serial paracentesis in patients with refractory ascites weeks, 80% of patients in the norepinephrine concentration.127
has been reported in a single-centre case-control propensity score active arm were complete This likely represented the
analysis.110 In a recent RCT comparing covered TIPS vs. LVP in patients responders with a significant pathophysiological background of
with recurrent ascites, a better one-year transplantfree survival was seen improvement in survival in the 18 episodes of AKI experienced
in patients treated with covered stents, without any significant increase midodrine/rifaximin arm. Due to by seven patients.
in occurrence of hepatic encephalopathy. 111 Thus, currently available data weakness in the study design,
suggest that TIPS improves survival compared to LVP in patients with these results are not definitive, but
they certainly warrant further
recurrent ascites, but it does not in those with refractory ascites.
investigation.
A careful selection of patients is also crucial to maximise the
beneficial effects of TIPS, as TIPS can even be detrimental in patients
with the most advanced stages of cirrhosis, such as Alfapump. The automated low-
flow ascites pump (Alfapump)
system consists of a
Journal of Hepatology
subcutaneously implanted battery-
powered programmable pump. It
is connected to catheters that
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
transfer ascites from the peritoneal
2 mg intravenous [i.v.], according renal function and sodium cavity to the bladder, from which
to body weight) only increased excretion in refractory ascites is it is eliminated with urine. The
renal sodium excretion when not known. device has internal sensors that
associated with exogenous atrial monitor pump function. In two
The a2-adrenoceptor agonist
natriuretic factor. In another, 118 2 clonidine, a sympatholytic drug, multicentre 124,125
safety and efficacy
mg of terlipressin led to an which suppresses RAAS activity studies, Alfapump ensured a
increase in GFR, renal plasma and improves the response to significant reduction of the
flow and renal sodium excretion. diuretics in patients with cirrhosis number and volume of
However, in this study only eight and ascites was tested in a large paracentesis in patients with
patients with refractory ascites prospective RCT. It was shown advanced cirrhosis and refractory
were included. Whether a that clonidine administration on ascites. However, adverse effects
prolonged treatment with top of diuretics for three months directly related to the device
terlipressin may lead to a led to an overall response to occurred in about one-third124 to
125
clinically relevant improvement of half of cases. In a multicentre

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OF HEPATOLOGY
Recommendations
Repeated LVP plus albumin (8 g/L of ascites removed) are

recommended as first line treatment for refractory ascites (I;1).
Diuretics should be discontinued in patients with refractory ascites
who do not excrete >30 mmol/day of sodium under diuretic
treatment (III;1).
Although controversial data exist on the use of NSBBs in
refractory ascites, caution should be exercised in cases of severe
or refractory ascites. High doses of NSBB should be avoided
(i.e. propranolol >80 mg/day) (II-2;1). The use of carvedilol can
not be recommended at present
(I;2).
Patients with refractory or recurrent ascites (I;1), or those for
whom paracentesis is ineffective (e.g. due to the presence of
loculated ascites) should be evaluated for TIPS insertion (III;1).
TIPS insertion is recommended in patients with recurrent ascites
(I;1) as it improves survival (I;1) and in patients with refractory
ascites as it improve the control of ascites (I;1).
The use of small-diameter PTFE-covered stents in patients is
recommended to reduce the risk of TIPS dysfunction and
hepatic encephalopathy with a high risk of hepatic
encephalopathy is recommended (I;1).
Diuretics and salt restriction should be continued after TIPS
insertion up to the resolution of ascites (II-2;1), as well as close
clinical follow-up (III,1).
Careful selection of patients for elective TIPS insertion is crucial,
as is the experience of the centre performing this procedure.
TIPS is not recommended in patients with serum bilirubin > 3
mg/dl and a platelet count lower than 75 x 10 9/L, current hepatic
encephalopathy grade ≥2 or chronic hepatic encephalopathy,
concomitant active infection, progressive renal failure, severe
systolic or diastolic dysfunction, or pulmonary hypertension
(III;1).
At present the addition of clonidine or midodrine to diuretic
treatment cannot be recommended (III;1).
Alfapump implantation in patients with refractory ascites not

amenable to TIPS insertion is suggested in experienced centres.
However, close patient monitoring is warranted because of the
high risk of adverse events including renal dysfunction and
technical difficulties (I;2).
Hepatic hydrotorax Cardiopulmonary and primary pleural disease should be ruled out
Hepatic hydrotorax describes the accumulation of transudate in the before diagnosing hepatic hydrothorax (III;1). Diagnostic
pleural space of patients with decompensated cirrhosis in the absence of
thoracentesis should be performed especially when infection of
cardiac, pulmonary or pleural disease. Its formation is secondary to
small diaphragmatic defects, more often located in the right side, the pleural effusion is suspected
through which ascites moves into the pleural space because of the (III;1).
negative intrathoracic pressure induced by inspiration. Hepatic Diuretics and thoracentesis are recommended as the first-line
hydrothorax can lead to respiratory failure and can be complicated by
management of hepatic hydrothorax (III;1). Therapeutic
spontaneous bacterial infections (empyema). Its appearance is associated
with poor prognosis, as the median survival of patients with hepatic thoracentesis is indicated in patients with dyspnoea (III;1). Chronic
hydrothorax ranges from 8–12 months. 128,129 Notably, the most common pleural should not be performed because of the frequent occurrence
prognostic scores, such as Child-Pugh and MELD, seem to
of complications (II-2;1).
underestimate such an adverse outcome. 128
In selected patients, TIPS insertion for recurrent symptomatic
Diagnosis of hepatic hydrothorax hepatic hydrothorax is recommended (II-2;1). Pleurodesis can be
Once pleural effusion has been ascertained, cardiopulmonary and suggested to patients with refractory hepatic hydrothorax not
primary pleural diseases should be excluded by standard clinical amenable to LT or TIPS insertion. However, the frequent
approaches. Diagnostic thoracentesis is required to rule out bacterial
occurrence of side effects related to this technique restricts its use
infection, whose diagnosis relies on the same criteria described for
ascites. The protein content of pleural effusion in uncomplicated hepatic to selected patients (I;2).
hydrothorax is low and the serum to pleural fluid albumin gradient is Mesh repair of diaphragmatic defects is suggested for the
greater than 1.1 g/dl.128
management of hepatic hydrothorax in very selected patients.
The presence and extent of diaphragmatic defects can be assessed The best results can be achieved in patients with non-advanced
indirectly, by radioisotope techniques, or directly by magnetic resonance
cirrhosis without renal dysfunction
imaging or colour-Doppler
ultrasonography.130,131 (II-2;2).
Hyponatremia
Definition and pathophysiology
Treatment of hepatic hydrothorax Hyponatremia is common in patients with advanced cirrhosis, and has
The first-line management relies on the treatment of ascites with
been arbitrarily defined as serum sodium concentration lower than 130
diuretics and/or LVP as discussed earlier. However, it is not rare for
mmol/L.141,142 However, according to guidelines on hyponatremia in the
pleural effusion to persist despite successful treatment of ascites
general patient population,143 reductions below 135 mmol/L should also
(refractory hydrothorax). Therapeutic thoracentesis is required to relieve
be considered. Patients with hyponatremia have a poor prognosis, as it is
dyspnoea. Its efficacy in refractory hepatic hydrothorax is transient and
associated with increased mortality144,145 and morbidity, particularly
repeated thoracentesis are required, which increase the risk of
neurological complications,146,147 and reduced survival after LT.148
complications such as pneumothorax, pleural or soft tissue infection, and
Incorporating serum sodium concentration into the MELD score, a new
bleeding.132 The frequent occurrence of these complications discourages
score (MELD-Na) was generated that provides more accurate survival
the use of chronic pleural drainage, which can also be followed by
predictions than MELD alone,149 especially in patients with ascites and
renal dysfunction from fluid loss.133 hyponatremia with intermediate MELD score values.150 Both
Whenever indicated and possible, LT represents the best option for hypovolaemic and hypervolaemic hyponatremia can occur in patients
patients with refractory hepatic hydrothorax, which does not seem to with cirrhosis. The second, most common, is characterised by an
adversely affect the outcome of transplantation.134,135 TIPS has been expansion of the extracellular fluid volume, with ascites and oedema. It
effectively employed as definitive treatment or bridge to transplantation may occur spontaneously, or because of excessive hypotonic fluids (i.e.,
in patients with refractory hepatic hydrotorax, whose general outcome 5% dextrose), or secondary to complications of cirrhosis leading to an
seems to be related to the severity of the underlying cirrhosis. 136,137 These abrupt worsening of effective volaemia. The main drivers are non-
results have been confirmed by a more recent meta-analysis. 138 osmotic hypersecretion of vasopressin and enhanced proximal nephron
Pleurodesis induced by various agents, such as talc, tetracycline, sodium reabsorption, which impair free water generation and are both
doxycycline, bleomycin and povidone-iodine, can be offered to patients caused by effective hypovolaemia. As opposed to hypervolaemic
who are not candidates for TIPS or LT. A recent meta-analysis showed hyponatremia, hypovolaemic hyponatremia is characterised by the
that the pooled rate of complete response after pleurodesis was 72%. frequent absence of ascites and oedema.
However, the pooled rate of complications related to this procedure was It is caused by a prolonged negative sodium balance with marked loss of
as high as 82%.139 Finally, thoracoscopic repair with mersilene mesh extracellular fluid often due to excessive diuretic therapy.
appears to be effective in patients with well-defined diaphragmatic
defects.140 Advanced liver disease, as assessed by MELD score, and Management of hyponatremia
preoperative renal dysfunction appear to adversely affect three-month It is generally considered that hyponatremia should be treated when
survival. Unfortunately, clear cut-off values cannot be retrieved from serum sodium is lower than 130 mmol/L, although there is no good
that study. evidence regarding the level of serum sodium at which treatment should
Recommendations be initiated. Hypovolaemic hyponatremia requires plasma volume
expansion with saline solution and the correction of the causative factor.
The management of hypervolemic hyponatremia requires attainment of a
Patients with hydrothorax should be evaluated for LT
negative water balance. Non-osmotic fluid restriction is helpful in
(III;1). preventing a further decrease in serum sodium levels, but it is seldom

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OF HEPATOLOGY
effective in improving natremia. Hypertonic sodium chloride Fluid restriction to 1,000 ml/day is recommended in the
administration to patients with decompensated cirrhosis may improve management of hypervolemic hyponatremia since it may
natremia but enhances volume overload and worsens the amount of
prevent a further reduction in serum sodium levels
ascites and oedema. Therefore, it should be limited to severely
symptomatic hyponatremia, as defined by life-threatening (III;1).
manifestations, cardio-respiratory distress, abnormal and deep The use of hypertonic saline in the management of hypervolemic
somnolence, seizures and coma, which do not frequently occur in hyponatremia should be limited to the rare cases presenting with
patients with cirrhosis. Furthermore, hypertonic sodium chloride life threatening complications. It could also be considered in
administration can be considered in patients with severe hyponatremia patients with severe hyponatremia who are expected to get LT
who are expected to get a liver transplant within a few days. In these
within a few days. The correction of serum sodium
cases, hyponatremia must not be corrected completely and rapidly to
concentration, once an attenuation of symptoms has been
avoid the risk of central pontine myelinolysis that is increased in
obtained, should be slow (≤8 mmol/L per day) to avoid
advanced cirrhosis.143 In practice, after an initial rapid correction aimed
irreversible neurological sequelae, such as osmotic
at attenuating clinical symptoms (5 mmol/L in the first hour), serum
demyelination
sodium concentration should not increase more than 8 mmol/L per
day.143 Albumin infusion appears to improve serum sodium (II-3;1).
concentration, but more information is needed. 151 Albumin administration can be suggested in hypervolemic
hyponatremia, but data are very limited to support its use (II-
Vaptans 3;2).
Vaptans are selective antagonists of the V2-receptors of arginine-
At present, the use of vaptans should be limited to controlled
vasopressin in the principal cells of the collecting ducts that enhance
clinical studies (III;1).
solute-free water excretion.152 Indeed, these drugs are effective in Gastrointestinal bleeding
improving serum sodium concentration in conditions associated with Pathophysiology
high vasopressin levels, such as the syndrome of inappropriate Variceal haemorrhage (VH) occurs because of the rupture of the variceal
antidiuretic hormone secretion (SIADH) and heart failure. 152 The effects wall due to excessive wall tension. Variceal wall tension is an intrinsic
of the administration of vaptans to hyponatremic patients with cirrhosis property of the vessel wall that opposes the expansive force determined
and ascites have been assessed in several studies. Namely, tolvaptan, by variceal transmural pressure, which depends on portal pressure and
satavaptan and lixivaptan lead to an increased urine volume, a solute- vessel size. Tissue support surrounding the varix may counteract the
free water excretion, and an improvement of hyponatremia in 45–82% of increase in variceal pressure and size, protecting the wall from rupture. 161
cases.153–155 In another study, a shortterm intravenous infusion of Once variceal wall rupture occurs, the amount of bleeding is related to
conivaptan for one to four days in patients with end stage liver disease transmural pressure (which mainly depends on portal pressure), to the
awaiting OLT was also effective in increasing serum sodium area of rupture in the vessel wall and to blood viscosity and/or
concentration.156 However, the safety of vaptans has only been alterations of haemostasis.161 All these factors can be influenced by
established for short-term treatments lasting from one week to one therapy. Drug therapy and portal-systemic derivative procedures, reduce
month. When satavaptan was used long term, in addition to diuretics, portal (and variceal) pressure. Endoscopic therapies and other physical
despite improving both serum sodium concentration and control of methods, such as balloon tamponade or expandable prosthesis, act
ascites, a higher all-cause mortality rate, mostly associated with known merely by both interrupting the blood flow into the varix and sealing the
complications of cirrhosis, was reported compared to standard medical vascular wall. Portal pressure is a key factor determining both variceal
treatment.157,158 Moreover, a recent study cast doubt on the efficacy of rupture and the severity of the bleeding episode. 161 During acute
tolvaptan in patients with cirrhosis and severe hypervolemic bleeding, portal pressure may increase because of different factors such
hyponatremia (serum sodium ≤125 mEq/L) in a real-life setting. 159 At as over-transfusion or absorption of blood from the gut, which may have
present, both conivaptan and tolvaptan have been approved in the US by a role in failure to control bleeding and/or precipitating rebleeding.
the FDA, while only tolvaptan in Europe has been approved by the EMA Portal pressure is usually assessed by the hepatic venous pressure
for management of severe hypervolemic hyponatremia (<125 mmol/L). gradient (HVPG).
The unique indication given for tolvaptan by the EMA is SIADH, while
the FDA also included heart failure and liver cirrhosis. However, the Natural history of gastro-oesophageal varices and variceal haemorrhage
occurrence of serious hepatic injury in three patients with autosomal Variceal haemorrhage, causative of 70% of all upper GI bleeding events
dominant polycystic kidney disease treated with tolvaptan in a double- in patients with portal hypertension, remains one of the most severe and
blind placebo-controlled trial160 led the FDA to conclude that this drug immediate life-threatening complications in patients with cirrhosis and
should not be used in patients with underlying liver disease. constitutes the second most frequent decompensating event after
Recommendations ascites.162,163 Decompensated patients have ‘clinically significant portal
hypertension’ (CSPH) per definition and, consequently, a high risk of
The development of hyponatremia (serum sodium concentration having gastro-oesophageal varices. In fact, while only 42% of Child A
patients have gastro-oesophageal varices, 72% of Child B/C patients
<130 mmol/L) in patients with cirrhosis carries an ominous
do.164 When decompensation develops, patients without varices on a
prognosis, as it is associated with increased mortality and
previous endoscopy should have a repeat endoscopy performed given the
morbidity. These patients should be evaluated for LT (II-2,1). risk of developing varices due to worsening of portal hypertension and
The removal of the cause and administration of normal saline are liver dysfunction. In those without varices at screening, ‘‘de novo”
varices develop at a rate of 7–8%/year, 165,166 which could be higher in
recommended in the management of hypovolemic hyponatremia
patients decompensated due to worsening of portal hypertension and
(III;1). liver dysfunction. The progression rate from small to large varices runs

up to 22% at one year and 51% at three years in patients with Child B/C and potentially life-threatening complications, resulting from bleeding
cirrhosis, especially when alcoholic in origin and/or when red wale EBL-ulcers. Moreover, EBL does not impact on portal hypertension.
marks are present at first endoscopy, compared to 2% and 16%, Thus, it does not reduce/prevent other complications and surveillance
respectively, in compensated patients without those risk factors. 165,166 endoscopies are required to detect variceal recurrence, supporting overall
Prospective studies have consistently demonstrated that the risk of VH, primary preference for NSBBs.174,175 For prevention of rebleeding
estimated overall at 5–15% per year, is related to variceal size. 166–170 This (secondary prophylaxis), combined therapy with NSBBs plus EBL is
risk is further amplified by the severity of liver dysfunction (Child B/C) recommended because combination therapy significantly decreases the
and/or the presence of red wale marks on varices. Thus, not only probability of rebleeding compared to monotherapy using either EBL or
medium/large varices (i.e. varices that do not collapse with insufflation drug therapy. NSBBs are the cornerstone of combined therapy because a
at endoscopy), but also small varices with red signs or in Child C should meta-analysis shows an improvement in survival with the addition of
be considered ‘high-risk’ varices. Despite improvement in therapy, NSBBs (± nitrates) to EBL, while the addition of EBL to NSBBs (±
overall mortality with each episode of VH remains around 15% to 25% nitrates) has no effect on mortality. 176 Recent RCTs indicate that guiding
at six weeks. Such risk is much higher in patients who develop VH in therapy according to the HVPG response to NSBBs can be valuable in
addition to other decompensation (over 80% at five-years) than in those this high-risk setting.91,177 HVPG-guided therapy may improve the
presenting with VH as an isolated decompensating event (20% at five- outcomes achieved with current first-line therapy combining NSBBs and
years).170,171 Mortality risk is particularly high when VH is associated EBL,91 and may achieve a similar survival as covered TIPS, which is the
with AKI and/or concomitant bacterial infections. 172 Without secondary most effective therapy in terms of preventing bleeding. 177 Accordingly,
prophylaxis, rebleeding occurs in approximately 60% to 70% of patients, HVPG-guided therapy can be used when available. However, this
usually within one to two years of the index haemorrhagic event. 173 approach has relevant drawbacks such as invasiveness and limited
Although increasing efforts are performed to test non-invasively for the availability and, therefore, cannot be widely recommended. NSBBs,
presence of gastro-oesophageal varices, these efforts largely remain such as propranolol and nadolol, act on portal hypertension because non-
restricted to compensated cirrhosis.167 Given the high prevalence of selective beta-blockade reduces cardiac output and splanchnic blood
‘high-risk varices’ in decompensated cirrhosis, oesophago- flow while the unopposed effect of alpha-1 adrenergic receptors leads to
gastroduodenoscopy (EGD) should be performed to detect the presence, splanchnic vasoconstriction, thus reducing portal pressure and its
size of varices and presence of red wale marks.168,169 consequential complications. Nonetheless, haemodynamic response rates
Recommendations to NSBBs are modest: approximately 46% of cases according to meta-
analyses,178,179 endorsing the overall search for novel therapeutic options.
Carvedilol, an NSBB with intrinsic anti-alpha-1 receptor activity, has
Because they are deemed high risk, patients in whom been associated with a greater reduction in portal pressure than the
decompensation develops should have EGD performed to screen traditional NSBBs and has therefore become a valuable alternative. 180 Its
for gastro-oesophageal varices, unless previously diagnosed and beneficial action on alpha-1 receptors reduces both porto-collateral and
treated (II-2;1). intrahepatic resistance, however, this is at the cost of more profound
effects on systemic arterial pressure, particularly in decompensated
If EGD is performed, the presence, size and presence of red wale
patients. The problem with all the recommendations mentioned so far is
marks should be reported (II-2;1). that they are based on high quality RCTs that usually excluded patients
with more advanced cirrhosis, while major controversy has arisen in
In patients without varices on screening EGD in whom the recent years regarding the use and safety of NSBBs in patients with
aetiological factor persists and/or the state of decompensation advanced disease, particularly in those with refractory ascites and/or
continues, screening EGD should be repeated every year. In the SBP. The discussion was initiated by the Clichy group, 181 who reported
remaining patients the screening could be prolonged, but the poor survival and increased risk of PPCD among patients with refractory
exact interval is unclear and more data is required (III;2). 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 of the progressive
hyperdynamic circulation typically associated with end-stage disease. As
Prevention and treatment of variceal haemorrhage Considering the high-
a result, end-organ perfusion becomes critical and sets off a multitude of
risk of death when VH occurs in patients with decompensated cirrhosis,
complications, like HRS. Therefore, ‘‘the window hypothesis” was
implementation of strategies to adequately treat VH and to prevent
proposed which suggested refractory ascites as a critical juncture where
(re)bleeding and death should be actively pursued in patients with
the protective effects of NSBBs may cease and a detrimental impact may
decompensated cirrhosis. It should be noted that the current
begin.182 However, this hypothesis was challenged by opposing reports
recommendations will concentrate on decompensated patients given the
suggesting protective effects with NSBBs even in decompensated
focus of these CPGs.
patients.183–186 Illustratively, a recent post hoc analysis of three RCTs
where vaptans and NSBBs were coadministered to patients with ascites
Primary and secondary prophylaxis of VH in decompensated patients
showed that NSBBs did not increase mortality.183 On the contrary, during
The Baveno VI168 and American Association for the Study of Liver
follow-up, 29% of initial NSBB users stopped taking NSBBs, inducing a
Diseases (AASLD)169 guidelines primarily recommend NSBBs for
marked rise in mortality and coinciding with variceal bleeding, bacterial
primary prophylaxis of VH in patients with cirrhosis who have high-risk
infection and/or development of HRS.183 Non-haemodynamic effects of
varices and also, combined with endoscopic band ligation (EBL), for
NSBBs, like reduction of intestinal permeability, inflammation and BT,
secondary prophylaxis of VH. Both NSBBs and EBL have shown to be
are considered to contribute to the beneficial effect, particularly in this
equally effective in preventing first bleeding in patients with high-risk
advanced stage.187–189 Whether NSBBs are detrimental in some patients
varices. The choice between options depends on factors such as patient
with advanced cirrhosis should be clarified by future studies (ideally
preference, contraindications or adverse events. Although numerically
RCTs), as well as the optimal drug-schedule in such stages. Meanwhile
EBL induces less side effects, it has been associated with more severe
some considerations could be made regarding dosing, type of NSBB and

JOURNAL
OF HEPATOLOGY
titration.168,184,185,190 Firstly, dosing of NSBBs was suggested as a potential

determinant according to a Danish study in which low propranolol doses
Recommendations
(<160 mg/day) were associated with reduced mortality after
experiencing an SBP compared to higher doses. 184,190 Secondly, not all
NSBBs proved equal. Carvedilol, which exhibits additional vasodilatory Primary prophylaxis must be initiated upon detection of ‘‘high-risk
anti-alfa-1-adrenergic activity, might be deleterious in decompensated varices” (i.e. small varices with red signs, medium or large
patients as it is more likely to cause a systemic haemodynamic varices irrespective of Child-Pugh classification or small varices
depressive effect and may be best avoided or very closely monitored. 185 in Child-Pugh C patients) because of increased risk of VH (I;1).
Thirdly, the concept of titration of NSBBs to a target heart rate of 50–55
bpm might be challenged in decompensated patients given that, in Patients with small varices with red wale marks or Child-Pugh C
parallel to the progression of liver disease, the hyperdynamic state should be treated with NSBBs (III;1). Patients with medium-large
evolves similarly, which may lead to treatment of the most vulnerable varices should be treated with either NSBBs or EBL (I;1). The
patients paradoxically with higher, and potentially hazardous, doses. choice of treatment can be based on local resources and expertise,
Therefore, the use of NSBBs should be based on a critical risk/benefit
patient preference, contraindications and adverse events (III;2).
evaluation in patients with refractory ascites and signs of systemic
circulatory dysfunction.168,191 Parameters such as severe hyponatraemia, 191 NSBBs could be preferred because in addition to lowering portal
low mean arterial pressure38 or cardiac output,192 and increasing SCr193 pressure, they also exert other potential beneficial effects (II-2;2).
identify more vulnerable patients among those with decompensated Although ascites is not a contraindication for NSBBs, caution
cirrhosis, in whom a dose reduction or temporal discontinuation of
should be exercised in cases of severe or refractory ascites (I;1).
NSBB treatment should be considered. The recent BAVENO VI
High doses of NSBB should be avoided (II-2;1). The use of
consensus168 proposed that in patients with refractory ascites and (i)
systolic blood pressure <90 mmHg, or (ii) SCr >1.5 mg/dl, or (iii) carvedilol can not be recommended at present (I;2).
hyponatraemia <130 mmol/L, the NSBB dose should be reduced or even In patients with progressive hypotension (systolic BP <90 mmHg),
temporarily discontinued. Abrupt interruption of beta-blockers for a or in patients who develop an acute intercurrent conditions such
mean of three to six days was recently found to be associated with as bleeding, sepsis, SBP or AKI, NSBBs should be discontinued
neither an apparent increase in the risk of variceal bleeding nor with a
(III,1). After recovery, reinstatement of NSBBs can be
haemodynamic rebound.194 If upon rechallenge, NSBB
attempted (III,2). When NSBB intolerance or contraindications
intoleranceoccurs,EBLshouldbeconsidered asanalternativeinprimary
prophylaxis.168 In the setting of refractory ascites and secondary persist, patients bleeding risk should be managed by expeditious
prophylaxis, covered TIPS placement may be considered if the patient is EBL
an appropriate candidate.111,168 (III,1).
Recommendations
Combination therapy of NSBBs + EBL is recommended since it

reduces the risk of rebleeding compared with monotherapy (I,1).
Similar recommendations as for primary prophylaxis can be made
with respect to NSBB usage in patients with ascites or
developing an acute inter-current condition
(III,2).
If the patient continues to be intolerant to NSBB, covered TIPS
placement is recommended provided that there are no absolute
contraindication (cf. criteria in ascites section) (III,1).
Variceal haemorrhage
Acute GI bleeding in cirrhosis, either because of gastro-oesophageal
varices or non-variceal lesions, is a medical emergency with a high
incidence of complications and high mortality and therefore requires
intensive care (Fig. 2). Acute variceal haemorrhage (AVH) must be
suspected in any cirrhotic patient presenting with upper acute GI
bleeding and treatment should be started as soon as bleeding is clinically
confirmed, regardless the lack of confirmation by upper endoscopy. 195
Initial therapy should be directed at restoring volaemia. 196 Vasoactive
drug therapy197,198 and antibiotic prophylaxis195,196 should be initiated as
soon as AVH is suspected. Goals of therapy in AVH include the control
of bleeding, as well as the prevention of early recurrence and the
prevention of six-week mortality, which is considered the main
treatment outcome by consensus. 168,199 Blood volume restitution should

be initiated promptly to restore and maintain haemodynamic stability to AVH is confirmed by endoscopy, EBL should be performed within the
ensure tissue perfusion and oxygen delivery. To facilitate resuscitation at same procedure. EBL is more effective than sclerotherapy to control
least two catheters should be placed, large enough to allow rapid volume bleeding, with fewer adverse effects, and may even improve survival. 196
expansion, which can usually be done with crystalloids. 196 No benefit has Sclerotherapy can be used when ligation is not feasible. The combination
been demonstrated with the use of colloids compared to crystalloids. 200 of endoscopic therapy and vasoactive drugs is more effective than the
Red blood cells are used to improve oxygen delivery to tissues in case of isolated use of either of these options alone, 205,206 because it combines the
severe anaemia. A restrictive transfusion strategy is adequate in most local haemostatic effect on the varices induced by endoscopic treatment
patients with acute GI bleeding, with a haemoglobin threshold for and the portal hypotensive effect achieved with drugs. This combination
transfusion of 7 g/dl and a target range after transfusion of 7 to 9 g/dl. 201 is currently considered the standard of care in AVH. 168,169 Cyanoacrylate
The threshold for transfusion may be higher in patients with massive injection and EBL are accepted options for endoscopic therapy in
haemorrhage or in those with underlying conditions that preclude an patients bleeding from gastric (cardiofundal) varices as both therapies
adequate physiological response to acute anaemia. Recommendations are equally effective.207 However, EBL should only be performed on
regarding management of coagulopathy and thrombocytopenia cannot be small gastric varices in which the complete vessel can be suctioned into
made based on the ligation device. Other endoscopic therapies, such as the endoscopic
currently available data.168,169,199 ultrasound–guided insertion of coils and/or cyanoacrylate, are available
As mentioned above vasoactive drug therapy should be initiated as for fundal varices. Prevention of complications should run
soon as AVH is suspected. Starting vasoactive drugs before endoscopy simultaneously to haemostatic therapies from admission of patients with
decreases the incidence of active bleeding during endoscopy and cirrhosis and acute GI bleeding. The main complications, whatever the
facilitates endoscopic therapy, improving the control of bleeding, and cause of bleeding, include bacterial infections (such as aspiration
potentially survival.197,198 Either terlipressin, somatostatin or octreotide pneumonia or SBP), hepatic encephalopathy and deterioration of renal
are accepted drugs with proven efficacy. 202 All these drugs require i.v function. Bacterial infections are observed in more than 50% of patients
administration. The recommended dose of terlipressin is 2 mg/4 h during and may already be present at the time of bleeding (20%) acting as a
the first 48 h, followed by 1 mg/4 h thereafter. The recommended dose precipitating event.196 Moreover, the presence of bacterial infection is an
of somatostatin is a continuous infusion of 250 lg/h (that can be independent predictor of failure to control bleeding and death. 208
Antibiotic prophylaxis is recommended because it reduces the incidence
increased up to 500 lg/h) with an initial bolus of 250 lg. The
of infections and improves control of bleeding and survival. 199,208
recommended dose of octreotide is a continuous infusion of 50 lg/h with Ceftriaxone (1 g/24 h) for up to seven days, is the first choice in patients
an initial bolus of 50 lg. A bolus of somatostatin or octreotide can be with advanced cirrhosis, in those on quinolone prophylaxis and in
given again if bleeding is ongoing. Once AVH is confirmed, vasoactive hospital settings with high prevalence of quinolone-resistant bacterial
drug therapy should be administered for five days to avoid early infections.209,210 Oral quinolones (norfloxacin 400 mg b.i.d) can be used
rebleeding.168,169 Shorter administration of vasoactive drugs (48–72 h) can in the remaining patients. These recommendations are however best
be considered in less severe episodes although more data are required. 203 evaluated and cross-checked from the perspective of local resistance
Once blood volume restitution has been initiated and haemodynamic patterns. Renal function should be preserved by the adequate
stability has been achieved, upper endoscopy should be performed, as replacement of fluids and electrolytes. 211 Nephrotoxic drugs (such as
soon as possible within the first 12 h after admission, to ascertain the aminoglycosides and non-steroidal anti-inflammatory drugs [NSAIDs])
cause of haemorrhage (up to 30% of cirrhotic patients bleed from non- as well as LVP, beta-blockers, vasodilators and other hypotensive drugs
variceal causes) and to provide endoscopic therapy if indicated. 168,169 should be avoided during the course of AVH. Oral non-absorbable
Erythromycin should be considered before emergency endoscopy (250 disaccharides may be used to prevent the development of hepatic
mg i.v., 30–120 min before) to facilitate the procedure by improving encephalopathy,169 although more studies are needed. When
visibility, in the absence of contraindications (QT prolongation). 204 When encephalopathy develops, lactulose or lactitol should be used. 168,169
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
(ceftriaxoneor norfloxacine)
if masive bleeding
Early diagnostic endoscopy (<12 h)

ENDOSCOPY
ENDOSCOPY
Confirm variceal bleeding
Endoscopic therapy(band ligation)
+
+ maintain vasoactivedrug therapy 3-5 days
and antibiotic prophylaxis ceftriaxoneor
( 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.
JOURNAL
OF HEPATOLOGY
Proton pump inhibitors (PPIs) have not shown efficacy for the Recommendations
management of AVH. However, a short course therapy with PPI after
EBL may reduce the size of post-banding ulcers. 212 Despite therapy with
Vasoactive drug therapy should be initiated as soon as acute
vasoactive drugs plus EBL and prophylactic antibiotics, up to 10–15% of
patients with AVH have persistent bleeding or early rebleeding. 195,199 In variceal bleeding is suspected, and before endoscopy.
such cases, TIPS should be considered as the rescue therapy of Terlipressin, somatostatin or octreotide are accepted options. In
choice.168,169 When TIPS is not feasible or in case of modest rebleeding, a patients with acute variceal bleeding drug therapy should be
second endoscopic therapy may be attempted while vasoactive drugs can administered for three to five days (I;1).
also be optimised, by doubling the dose of somatostatin and/or changing
Gastroscopy should be performed within the first 12 h after
to terlipressin if not used previously. Balloon tamponade should be used
admission once haemodynamic stability has been achieved, to
in case of massive bleeding, as a temporary ‘‘bridge” until definitive
treatment can be instituted and for a maximum of 24 h, preferably under ascertain the cause of haemorrhage and to provide endoscopic
intensive care facilities.168,169 Because of the high risk of aspiration therapy (II-2;1).
pneumonia, tamponade should be preceded by prophylactic orotracheal When acute variceal bleeding is confirmed by endoscopy, variceal
intubation in comatose or encephalopathic patients. Removable, covered
ligation should be performed within the same procedure (I;1).
and self-expanding oesophageal stents are an alternative to balloon
tamponade, and may have lower rates of serious adverse events. 213 RCTs In the absence of contraindications (QT prolongation) pre-
suggest that in high-risk patients, early (preemptive) PTFE-coated TIPS endoscopy erythromycin (250 mg i.v., 30–120 min before) can
placed within 72 h (ideally in less than 24 h) may result in better be used to facilitate the procedure (I;2).
permanent control of bleeding and may improve survival. 214,215 However,
The combination of vasoactive drugs and ligation is recommended
these studies had relevant drawbacks such as the inclusion of a highly
selected population because of strict exclusion criteria, while as the first therapeutic option in acute variceal bleeding (I;1).
observational studies have not confirmed the effect on survival. 216,217 The Early pre-emptive covered TIPS (placed within 24–72 h) can be
use of Child-Pugh class B plus active bleeding at endoscopy as a suggested in selected high-risk patients, such as those with Child
criterion to select high-risk patients has also been criticised. 218 It has also class C with score <14 (I;2). However, the criteria for high-risk
been suggested that a recalibrated MELD score may better identify patients, particularly Child B with active bleeding, remains
patients at high risk than other scores. 219 At present, early TIPS should be debatable and needs further study.
considered in patients with Child-Pugh class C, with a score <14.
However, future studies should clarify which criteria may be preferred to
select high-risk patients before a wide implementation of early TIPS. Recommendations
Future studies should also clarify whether an adequate stratification of
risk in patients with AVH can optimise therapy. Up to 10–15% of patients have persistent bleeding or early
rebleeding despite treatment with vasoactive drugs plus variceal
Recommendations ligation, and prophylactic antibiotics. TIPS should be used as the
rescue therapy of choice in such cases (I;1).
Acute GI bleeding, both due to gastro-oesophageal varices or to Balloon tamponade should be used in case of uncontrolled
non-variceal lesions, carries a high incidence of complications bleeding, but with pre-requisite of expertise and as a temporary
and mortality in decompensated cirrhosis and therefore requires ‘‘bridge” until definitive treatment can be instituted and for a
close monitoring maximum of 24 h (III;1). Removable, covered and self-
(II-2;1). expanding oesophageal stents can be used as alternative to
Volume replacement should be initiated promptly to restore and balloon tamponade
maintain haemodynamic stability (III;1). Either colloids and/or (I;2).
crystalloids should be used (III;1). Starch should not be used for In the context of bleeding, where encephalopathy is commonly
volume replacement (I;1). encountered, prophylactic lactulose may be used to prevent
A restrictive transfusion strategy is recommended in most patients encephalopathy, but further studies are needed (I;2).
with a haemoglobin threshold for transfusion of 7 g/dl and a Beta-blockers and vasodilators should be avoided during the acute
bleeding episode (III,1).
target range of 7–9 g/dl (I;1).
Antibiotic prophylaxis is recommended in cirrhotic patients with Portal hypertension gastropathy and intestinopathy Portal hypertension
acute GI bleeding because it reduces the incidence of infections gastropathy (PHG) often presents in decompensated patients given that
and improves control of bleeding and survival. Treatment should its natural history is significantly influenced by the severity of liver
be initiated on presentation of bleeding and continued for up to disease and portal hypertension. The presence of oesophageal varices
seven days (I;1). Ceftriaxone (1 g/24 h) is the first choice in and a Child-Pugh class B or C at enrollment were found to predict the
patients with decompensated cirrhosis, those already on incidence of PHG, which might range between 30 and 45%. 220,221 The
quinolone prophylaxis, and in hospital settings with high incidence and severity of PHG may increase following endoscopic
prevalence of quinolone-resistant bacterial infections. Oral treatment for oesophageal varices.222 Portal hypertension should be
quinolones (norfloxacin 400 mg b.i.d) should be used in the distinguished from gastric antral vascular ectasia (GAVE or watermelon
remaining patients (I;1). stomach), which have different underlying pathophysiologies and
different therapeutic implications. The diagnosis of PHG is made by

endoscopy and typically shows a snake-skin mosaic pattern (mild varices are present in about 20% of patients with cirrhosis. Gastro-
subtype), which may have superimposed red signs (severe PHG) and is oesophageal varices type 1, which are the most common (75% of gastric
most commonly located in the proximal stomach (fundus and body) varices), are oesophageal varices extending below the cardia into the
whereas GAVE is characterised by the presence of red spots without a lesser curvature and, in the absence of specific studies, are commonly
background mosaic pattern, typically located in the gastric antrum. 170 managed following guidelines for oesophageal varices. 168 Cardiofundal
Similar endoscopical lesions, as documented in PHG, may be observed varices (gastro-oesophageal varices type 2 & isolated gastric varices type
in other areas of the GI tract where they have been termed portal 1) bleed less frequently. However, haemorrhage from cardiofundal
hypertensive duodenopathy, portal hypertensive enteropathy or portal varices is often more severe, more difficult to control and shows a higher
hypertensive colopathy depending on the location of the lesions. 223 PHG risk of recurrent bleeding and mortality (up to 45%) compared to
and every form of enteropathy might be clinically important because oesophageal varices.229 Cardiofundal varices are more frequent in
they are sometimes responsible for insidious blood loss (chronic iron patients with splanchnic venous thrombosis, which should be
deficient anaemia) and in exceptional cases even overt acute bleeding. investigated by imaging. The evidence to support recommendations for
When PHG is found as an incidental asymptomatic finding without management of gastric VH is much less robust than that for oesophageal
concomitant oesophageal or gastric varices, its relevance is unclear and varices. Regarding primary prophylaxis of bleeding from gastric varices,
endoscopic follow-up or prophylactic treatment is not recommended. 168 a single randomised trial suggested that cyanoacrylate injection may be
First-line therapy for chronic haemorrhage from PHG is an more effective than NSBBs in preventing first bleeding in patients with
NSBB.168,224,225 The same considerations regarding the use of NSBBs in large cardiofundal varices, although survival was similar. 230 Therefore,
decompensated patients should be made as for gastro-oesophageal the last BAVENO consensus concluded that further studies are needed to
varices, except that there is no alternative, endoscopic, standard evaluate the risk/benefit ratio of using cyanoacrylate in this setting
intervention available for PHG. In addition, iron supplementation should before a formal recommendation can be made and meanwhile propose
be provided.168,226 In patients with medically refractory PHG and NSBBs as the primary approach.168 Acute gastric VH is medically treated
compensated cirrhosis, TIPS has shown to improve the endoscopic like bleeding oesophageal varices. However, injection therapy with
appearance and decrease the transfusion requirement. 227 In case of acute cyanoacrylate (‘glue’) may be the preferable option for endoscopic
PHG bleeding, albeit rare, small and uncontrolled studies have suggested haemostasis.231 Although equally effective as EBL in initial haemostasis,
pharmacological intervention with somatostatin-analogues or terlipressin the rebleeding rate is significantly lower. 232 TIPS, with or without
because of their portal hypotensive effects and reduction in gastric blood additional embolisation of collaterals, is equally effective in gastric and
flow.226,228 In addition, similar measures are to be taken as for AVH oesophageal VH for control of acute bleeding events and prevention of
(antibiotic prophylaxis, restrictive transfusion policy). For portal rebleeding.233 In case of massive bleeding, balloon tamponade with the
hypertension intestinopathy, there is no established standard of treatment Linton-Nachlas tube may serve as a bridge to other treatments.
and an approach analogous to that for PHG is suggested. As for any Regarding secondary prophylaxis, in one RCT repeated cyanoacrylate
given complication, LT should be considered as part of the management injection was superior to NSBBs to prevent rebleeding from
of decompensated patients. cardiofundal varices,232 while the addition of NSBBs to cyanoacrylate did
not improve the outcomes achieved with glue alone in another RCT. 234
Another trial comparing TIPS to glue injection showed that TIPS proved
Recommendations more effective in preventing rebleeding from gastric varices, with
similar survival and frequency of complications.235 The option of early
NSBB and iron supplementation and/or blood transfusion, when TIPS should be strongly considered, particularly in cardiofundal varices
indicated, are recommended as first-line therapy for chronic given the high rebleeding rate, provided that patient is an appropriate
candidate for such a procedure. Alternatively, balloon-occluded
haemorrhage from PHG is an (I;1).
retrograde transvenous obliteration (BRTO) can be considered. This
In patients with transfusion-dependent PHG in whom NSBBs fail interventional radiological procedure enables treatment of fundal varices
or are not tolerated, covered TIPS placement may be used associated with a large gastro/splenorenal collaterals, which has the
provided the patient has no contraindication for TIPS (II-3;2). theoretical advantage over TIPS of not diverting portal blood inflow
from the liver. However, no randomised trials are available comparing
Acute PHG bleeding may be treated with somatostatinanalogues or
BRTO with other therapies. Several variations of this technique are
terlipressin but substantiating data are limited (I;2). available, such as balloon-occluded antegrade transvenous obliteration
(BATO).236
Gastric varices
The Sarin classification is most commonly used for risk stratification and Recommendations
management of gastric varices (Table 6).229 Gastric
Table 6. Classification, prevalence and risk of bleeding of gastric varices. NSBBs are suggested for primary prevention of VH from gastro-
Type Definition Relative Overall bleeding
frequency risk without oesophageal varices type 2 or isolated gastric varices type 1
treatment (III;2).
GOV 1 OV extending below cardia into 70% 28%
Primary prevention for gastro-oesophageal varices type 1 follow
lesser curvature
GOV 2 OV extending below cardia into 21% 55% the recommendations of oesophageal varices
fundus
IGV 1 Isolated varices in the fundus 7% 78% (III;2).
IGV 2 Isolated varices else in the stomach 2% 9% Acute gastric VH should be treated medically, like oesophageal
VH (I;1). Cyanoacrylate is the recommended endoscopic
GOV, gastro-oesophageal varices; IGV, isolated gastric varices; OV, oesophageal varices.
haemostatic treatment for cardiofundal varices (gastro-

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OF HEPATOLOGY
oesophageal varices type 2 or isolated gastric varices type 1) for the rapid diagnosis of SBP. 249 Although the presence of bacterial
(I;2). DNA in plasma and/or ascites is associated with an impairment of
circulatory function,250 there are not enough data to support its use in
TIPS with potential embolisation efficiently controls bleeding and
clinical practice.251 Ascites culture is essential to guide antibi-
prevents rebleeding in fundal VH (gastrooesophageal varices
type 2 or isolated gastric varices type 1) and should be
considered in appropriate candidates (II-2;1). cells/mm and negative culture have culture-negative SBP. Their clinical
presentation is like that of patients with culturepositive SBP and should
Selective embolisation (BRTO/BATO) may also be used to treat be treated in a similar manner. Some patients have ‘bacterascites’ in
bleeding from fundal varices associated with large which cultures are positive but there is normal ascitic neutrophil count
gastro/splenorenal collaterals, although more data is required (<250/mm3).33 In some patients bacterascites is the result of secondary
(III;2). bacterial colonisation of ascites from an extraperitoneal infection. These
Bacterial infections patients usually have general symptoms and signs of infection. In other
The risk of bacterial infection in cirrhosis is caused by multiple factors
patients, bacterascites is due to the spontaneous colonisation of ascites,
that include liver dysfunction, portosystemic shunting, gut dysbiosis,
and can either be clinically asymptomatic or lead to abdominal pain or
increased BT, cirrhosis-associated immune dysfunction, 237,238 and genetic
fever. While in some patients, particularly in those who are
factors This immune defect facilitates BT, induced by increased
asymptomatic, bacterascites represents a transient and spontaneously
intestinal permeability and gut bacterial overgrowth observed in
reversible colonisation of ascites, in other patients, mainly those who are
cirrhosis.239 Genetic immune defects can contribute to the high risk of
symptomatic, bacterascites may represent the first step in the
bacterial infections in cirrhosis, particularly SBP. Cirrhotic patients
development of SBP.33 Spontaneous fungal peritonitis is a rare, less
carrying NOD2 variants associated with impaired recognition of the
recognised and studied complication, occurring in <5% of cases, but
bacterial product muramyl dipeptide have a higher risk of SBP and a
observational data suggest a worse prognosis.253
reduced survival time.240
Spontaneous bacterial pleural empyema

Spontaneous bacterial peritonitis Infection of a pre-existing hydrothorax, known as spontaneous bacterial
Definition pleural empyema, is uncommon. One study followed 3,390 patients with
Spontaneous bacterial peritonitis has been defined as a bacterial cirrhosis for four years and observed it in 2.4% of the overall population
infection of ascitic fluid without any intra-abdominal surgically treatable and 16% of patients with preexisting hydrothorax, with associated
source of infection. SBP is very common in patients with cirrhosis and mortality of 38%.254 The diagnosis is based on pleural fluid analysis
ascites.241,242 When first described, its mortality exceeded 90% but it has obtained by diagnostic thoracocentesis. In the largest observational study
been reduced to approximately 20% with early diagnosis and reported so far, the diagnosis of spontaneous bacterial empyema was
treatment.243 established when the pleural fluid analysis showed a positive culture and
more than 250 neutrophils/mm3 or a negative culture and more than 500
Diagnosis neutrophils/mm3, in the absence of lung infection. 255 Pleural fluid culture
The diagnosis of SBP is based on diagnostic paracentesis. 33,244 All in blood culture bottles was positive in 75% of cases. 255 Spontaneous
patients with cirrhosis and ascites are at risk of SBP and the prevalence bacterial pleural empyema was associated with SBP in 50% of cases. 255
of SBP in outpatients is 1.5–3.5% and 10% in hospitalised patients. 245
Half the episodes of SBP are present at the time of hospital admission
while the rest are acquired during hospitalisation. 33 Patients with SBP Secondary bacterial peritonitis
may have one of the following:33 i) local symptoms and/or signs of A small proportion (5%) of patients with cirrhosis may develop
peritonitis: abdominal pain, abdominal tenderness, vomiting, diarrhoea, peritonitis due to perforation or inflammation of an intraabdominal
ileus; ii) signs of systemic inflammation: hyper or hypothermia, chills, organ, a condition known as secondary bacterial peritonitis. 256 The
altered white blood cell count, tachycardia, and/or tachypnoea; iii) differentiation of this condition from SBP is important. Secondary
worsening of liver function; iv) hepatic encephalopathy; v) shock; vi) bacterial peritonitis should be suspected in patients who have localised
renal failure; and, vii) GI bleeding. However, it is important to point out abdominal symptoms or signs, presence of multiple organisms on ascitic
that SBP may be asymptomatic, particularly in outpatients. 245 In an culture, very high ascitic neutrophil count and/or high ascitic protein
observational study in 239 patients with SBP, delayed diagnostic concentration, or in those patients with an inadequate response to
paracenteseis (>12 h after admission) was associated with a 2.7-fold therapy.256 Patients with suspected secondary bacterial peritonitis should
increase in mortality.246 Peritoneal infection causes an inflammatory undergo prompt computed tomography (CT) scanning and early
reaction resulting in an increased number of neutrophils in ascitic fluid. consideration for surgery.
Despite the use of sensitive methods, ascites culture is negative in as Recommendations
many as 60% of patients with clinical manifestations suggestive of SBP
and increased ascites neutrophil count. 33 The gold standard for ascitic A diagnostic paracentesis should be carried out in all patients with
neutrophil count is manual microscopy, but it is labour intensive and cirrhosis and ascites without delay at hospital admission to rule
associated with interobserver variability, time and costs. In most places
out SBP. A diagnostic paracentesis should also be performed in
this has been substituted with automated counts based on flow cytometry
patients with GI bleeding, shock, fever or other signs of
for counting and differentiating cells. This technique has been
systemic inflammation, GI symptoms, as well as in patients with
documented to have high linearity with manual microscopy and thus
sensitivity and specificity close to 100%.247,248 The greatest sensitivity for worsening liver and/or renal function, and hepatic
the diagnosis of SBP is reached with a cut-off neutrophil count of encephalopathy
250/mm3, although the greatest specificity is reached with a cut-off of (II-2;1).
500 neutrophils/mm3.33 The use of reagent strips cannot be recommended The diagnosis of SBP is based on neutrophil count in ascitic fluid

susceptible to the development of infections caused by MDROs, because

of >250/mm3 (II-2;1). Neutrophil count is determined by
they require repeated hospitalisations, are often submitted toinvasive
microscopy, but can be substituted with a flow cytometry based procedures and are frequently exposed to antibiotics, either as
automated count. The use of reagent strips has no clear evidence prophylaxis or as treatment. All these factors are well kown risk factors
to support it in routine practice (II-2;1). for the development of infections sustained by MDROs. 266 Bacterial
Although ascitic fluid culture positivity is not a prerequisite for the resistance increases four fold the risk of mortality of SBP. 267 In
particular, nosocomial SBP has been associated with multi-drug
diagnosis of SBP, culture should be performed in order to guide resistance and poor outcomes. 266 The landscape of bacterial resistance is
antibiotic therapy (II-2;1). continuously changing and challenging recommendations for antibiotics.
Blood cultures should be performed in all patients with suspected Thus, it is crucial to separate community-acquired SBP from health care-
associated and nosocomial SBP6,266–268 and to consider both the severity
SBP before starting antibiotic treatment (II-2;1). Patients with
of infection and the local resistance profile in order to decide the
bacterascites (neutrophil count less than 250/mm 3 but positive empirical antibiotic treatment of SBP. Piperacillin/tazobactam has been
bacterial culture) exhibiting signs of systemic inflammation or recommended as the primary approach for health care and nosocomial
infection should be treated with antibiotics (II-2;1). Otherwise, the SBP in areas with low prevalence of infections sustained by MDROs.
patient should undergo a second paracentesis. If the culture results On the contrary meropenem alone or/and combined with glycopeptides
or with daptomycin has been suggested as the primary approach for
come back positive again, regardless of the neutrophil count, the
health care-associated SBP when severe, or in areas with high
patient should be treated (III;1). prevalence of MDROs, and for nosocomial SBP in general. 6,266,268,269
The diagnosis of spontaneous bacterial pleural empyema should be Regarding the severity of infection, it should be highlighted that,
based on positive pleural fluid culture and increased neutrophil recently, the new criteria for the definition of sepsis, namely qSOFA and
Sepsis-3270 have been validated in patients with cirrhosis and bacterial
count of >250/mm3 or negative pleural fluid culture and a
infections, proving that they are more accurate than those related to the
neutrophil count of >500/ mm3 in the absence of pneumonia (II- systemic inflammatory response syndrome in predicting hospital
2;1). mortality.271 Accordingly, a new algorithm has been proposed for the
Secondary bacterial peritonitis should be suspected in case of application of qSOFA and Sepsis-3 in the management of cirrhotic
multiple organisms on ascitic culture, very high ascitic patients (Fig. 3). Some more detailed recommendations on the empirical
neutrophil count and/or high ascitic protein concentration, or in antibiotic treatment of SBP based on the severity and the environment of
those patients with an inadequate response to therapy. Patients the infection as well as on local resistance profiles are provided (Fig. 4).
with suspected secondary bacterial peritonitis should undergo A randomised trial with 32 nosocomial episodes of SBP, found
prompt CT scanning and early considerations for surgery (III,1). meropenem plus daptomycin more effective (86.7%) than ceftazidime
(25%) to manage SBP, defined as >25% decrease of neutrophil count at
Management of spontaneous bacterial peritonitis
48 h and to <250/mm3 at day seven.243 If ascitic fluid neutrophil count
Empirical antibiotic therapy. Empirical antibiotic therapy must be
fails to decrease to less than 25% of the pretreatment value after two
initiated immediately after the diagnosis of SBP. 33 Potentially
days of
nephrotoxic antibiotics (i.e., aminoglycosides) should not be used as
empirical therapy.76 In the 1990 s, cefotaxime, a thirdgeneration SBP or SBE
cephalosporin, was extensively investigated in patients with SBP
because at that time it covered most causative organisms and because of Community-acquired Healthcare-associated Nosocomial
its high ascitic fluid concentrations during therapy. 1,33 Infection SBP or SBE SBP or SBE SBP or SBE
resolution was obtained in 77 to 98% of patients. A dose of 4 g/day is as
effective as a dose of 8 g/day.257 A five-day therapy is as effective as a 3rd generation AREA DEPENDENT: Carbapenem alone or
10-day treatment.258 Alternatively, amoxicillin/clavulanic acid, first given cephalosporin or Like nosocomial + daptomycin,
piperacillin-tazobactam infections if high vancomycin or
i. prevalence of MDRO
§
linezold# if high
v. then orally, has similar results with respect to SBP resolution and or sepsis prevalence of MDR
Gram+ bacteria or
mortality as cefotaxime259 and at a much lower cost. However, there is sepsis
only one comparative study with a small sample size and results should
be confirmed in larger trials. In addition, some concern exists regarding
amoxicillin/clavulanic acid as its use is associated with a high rate of
drug induced liver injury (DILI). 260 Administration of i.v. ciprofloxacin
for seven days results in a similar SBP resolution rate and hospital
survival as cefotaxime, but at a significantly higher cost. 261 However,
switch therapy (i.e., use of i.v. antibiotic initially, followed by oral step-
down administration) with ciprofloxacin is more cost-effective than i.v.
ceftazidime.262 Oral ofloxacin has shown similar results as i.v.
cefotaxime in uncomplicated SBP, without renal failure, hepatic
encephalopathy, GI bleeding, ileus, or shock. 263 However, the spread of
resistant bacteria in the healthcare environment during the last two
decades has led to an alarming increase in the number of infections
caused by multi-drug resistant organisms (MDROs) 264 that are defined by
an acquired non-susceptibility to at least one agent in three or more
antimicrobial categories.265 Patients with advanced cirrhosis are highly

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OF HEPATOLOGY
Fig. 4. Recommended empirical antibiotic treatment of SBP or SBE (adapted from Ref. represent further new alternatives to carbapenems for the treatment of
6). SBE, spontaneous bacterial empyema; SBP, spontaneous bacterial peritonitis; patients with infections sustained by ESBL producing, carbapenem-
MDRO, multidrug resistant organism.
resistant Enterobacteriaceae and Pseudomonas aeruginosa. However,
antibiotic treatment, there is a high likelihood of failure to respond to
there are currently no data regarding the clinical use of these drugs in
therapy.33 This should raise the suspicion of an infection caused by
cirrhosis.266
bacteria resistant to antibiotic therapy, indicating the need for
modification of antibiotic treatment according to in vitro sensitivity or
on an empirical basis, or the presence of ‘secondary peritonitis’. In this
Recommendations
context, it should be highlighted that the progressive increase of the use
of carbapenems because of the worldwide pandemic of extended
spectrum betalactamases (ESBLs) producing Enterobacteriaceae has Empirical i.v. antibiotics should be started immediately following
promoted the emergence of carbapenem-resistant Enterobacteriaceae.
the diagnosis of SBP (II-2;1).
This implies a potential shift from MDR bacteria to extensively drug
resistance (XDR) bacteria defined by a non-susceptibility to at least one Environment (nosocomial vs. community acquired), local bacterial
agent in all but two or fewer antimicrobial categories or to pandrug resistance profiles and severity of infection should guide
resistance (PDR) bacteria defined by a non-susceptibility to all agents in empirical antibiotic treatment (I;1).
all antimicrobial categories.265 The shift requires an active surveillance in
patients at risk, in order to identify patients who are colonised or infected
by these clones and prevent their dissemination. The shift may also Third-generation cephalosporins are recommended as first-line
seriously affect the effectiveness of the broadest spectrum empirical antibiotic treatment for community-acquired SBP in countries
with low rates of bacterial resistance (I;1). In countries with high
rates of bacterial resistance piperacillin/tazobactam or
IfbaselineSOFAscoreavailable?
No carbapenem Yesshould be considered (II-2;1).
Healthcare associated and nosocomial SBP is more likely to

Applysepsis-3criteriaandqSOFA Applysepsis-3criteria
harbour resistance to antibiotics. Piperacillin/tazobactam should be
given in areas with low prevalence of multi-drug resistance while
Sepsis-3and Sepsis-3and
qSOFAnegative
carbapenem should be used in areas with high
Positive prevalence of ESBL
Negative
qSOFApositive
producing Enterobacteriaceae. Caarbapenem should be combined
with glycopeptides or daptomycin or linezolid in areas with high
Sepsis-3positive Pooroutcome
Goodoutcome
andqSOFAnegative prevalence of gram positive MDR bacteria
PatientconneedtransfertoICU (I;1). Severe infections
Goodoutcome
sustained by XDR bacteria may require the use of antibiotics
Greyzone known to be highly nephrotoxic in patients with cirrhosis, such as
MonitoringSOFA vancomycin or aminoglycosides. In these cases, patients’ plasma
scoreisrequired
level should be monitored in accordance with local policy
thresholds
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.
antibiotic treatment among those previously recommended for SBP and (III;1).
infections other than SBP. Carbapenemase-producing and carbapenem- De-escalation according to bacterial susceptibility based on
resistant non-carbapenemase-producing Enterobacteriaceae can be
positive cultures is recommended to minimise resistance
treated with tigecycline or with the combination of tigecycline at high
doses and a carbapenem in continuous infusion. Addition of i.v. colistin selection pressure (II-2;1).
could be necessary in severe infections. Severe infections caused by The efficacy of antibiotic therapy should be checked with a second
Pseudomonas aeuruginosa resistant to carbapenems and quinolones paracentesis at 48 h from starting treatment. Failure of first-line
usually require the combination of i.v. amikacin/tobramycin or colistin
antibiotic therapy should be suspected if there is worsening of
plus a carbapenem/ceftazidime (needed as synergic antibiotics despite
clinical signs and symptoms and/or increase or no marked
antibiotic resistance). Vancomycin resistant Enterococci should be
treated with linezolid, daptomycin or tigecycline. All this means reduction in leucocyte count (at least 25%) in 48 h (II-2;1).
reintroducing into clinical practice antibiotics known to be highly The duration of treatment should be at least 5–7 days
nephrotoxic in patients with cirrhosis. It follows that serum levels of
aminoglycosides and vancomycin must be monitored closely in these (III;1).
patients, to decrease the risk of renal failure. The shift from MDR to Spontaneous bacterial empyema should be managed similarly to
XDR bacteria re-emphasises the interest of the pharmaceutical industry SBP (II-2;2).
for the development of new antibiotics. Several new glycopeptides such
Intravenous albumin in patients with spontaneous bacterial peritonitis.
as oritavancin, new oxazolidinones such as tedizolid phosphate, new
SBP without septic shock may precipitate deterioration of circulatory
cephalosporins, such as ceftaroline and ceftobiprole and razupenem, a
function with severe liver failure, hepatic encephalopathy, and type 1
new carbapemen, display extended activity against gram-positive
HRS and has approximately 20% hospital mortality despite infection
bacteria including vancomycinresistant Enterococci. In contrast, few
resolution.272 A randomised, controlled study in patients with SBP treated
newly developed antibiotics are active against gram-negative MDROs.
with cefotaxime showed that albumin (1.5 g/kg body weight at
Temocillin, a derivative of ticarcillin, is effective against organisms
diagnosis, followed by 1 g/kg on day three) significantly decreased the
producing ESBLs. Among cephalosporin-betalactamase inhibitor
incidence of type 1 HRS (from 30% to 10%) and reduced mortality from
combinations, ceftazidime/avibactam and ceftolozane/tazobactam
29% to 10% compared with cefotaxime alone. Treatment with albumin

was particularly effective in patients with baseline serum bilirubin ≥68 Recommendations
lmol/L (4 mg/dl) or SCr ≥88 lmol/L (1 mg/dl). It is unclear whether i.v.
albumin is useful in patients with baseline bilirubin <68 lmol/L and Primary prophylaxsis with norfloxacin (400 mg/day) in patients
creatinine <88 lmol/L, as the incidence of type 1 HRS in patients with Child-Pugh score ≥9 and serum bilirubin level ≥3 mg/dl,
meeting these criteria was very low in the two treatment groups (7% with either impaired renal function or hyponatraemia, and ascitic
without albumin and 0% with albumin). 272 The application of the fluid protein lower than 15 g/L is recommended (I;1).
schedule of this therapeutic option should be implemented in clinical
practice.273 Non-randomised studies in patients with SBP also show that Norfloxacin prophylaxis should be stopped in patients with long-
the incidence of renal failure and death are very low in patients with lasting improvement of their clinical condition and
moderate liver failure and without renal dysfunction at diagnosis of SBP, disappearance of ascites (III;1).
so albumin is probably not necessary.274
Patients with prior SBP
Recommendation In patients who survive an episode of SBP, the cumulative recurrence
rate at one year is approximately 70%. 33 Probability of survival at one
The administration of albumin (1.5 g/kg at diagnosis and 1 g/kg on year after an episode of SBP is 30–50% and falls to 25–30% at two
years. Therefore, patients recovering from an episode of SBP should be
day 3) is recommended in patients with SBP (I;1). considered for LT. There is only one randomised, double-blind, placebo-
controlled trial of norfloxacin (400 mg/day orally) in patients who had a
previous episode of SBP.281 Treatment with norfloxacin reduced the
Prophylaxis of SBP probability of recurrence of SBP from 68% to 20%. In an openlabel,
Since most episodes of SBP are thought to result from the translocation randomised study comparing norfloxacin 400 mg/day to rufloxacin 400
of enteric gram-negative bacteria, the ideal prophylactic agent should be mg/week in the prevention of SBP recurrence, the one-year probability
safe, affordable and effective at decreasing the amounts of these of SBP recurrence was 26% and 36%, respectively (p = 0.16). 282
organisms from the gut while preserving the protective anaerobic flora Norfloxacin was more effective in the prevention of SBP recurrence due
(selective intestinal decontamination). 267 Given the high cost and to Enterobacteriaceae (0% vs. 22%, p = 0.01). The use of intermittent
inevitable risk of developing resistant organisms, the use of prophylactic ciprofloxacin has been associated with a higher rate of quinolone-
antibiotics must be strictly restricted to patients at high risk of SBP. 267 resistant organisms and should be avoided. 282,283 It is uncertain whether
Three high-risk patient populations have been identified: i) patients with prophylaxis should be continued without interruption until LT or death
acute GI haemorrhage; ii) patients with low total protein content in in all patients with prior SBP, or if treatment could be discontinued in
ascitic fluid and no prior history of SBP (primary prophylaxis), and iii) patients showing an improvement of liver disease. Many patients receive
patients with a previous history of SBP (secondary prophylaxis).275 rifaximin to prevent recurrent episodes of HE. 284 However, rifaximin
may also be effective against recurrent SBP. 285 There are no data to guide
Primary prophylaxis in patients with low total protein content in ascitic new indications for primary or secondary prophylaxis of SBP among
fluid without prior history of SBP. Cirrhotic patients with low ascitic patients already on rifaximin. More in detail, it is not known whether
fluid protein concentration (<10 g/l) and/or high serum bilirubin levels norfloxacin prophylaxis should be started in patients being treated with
are at high risk of developing a first episode of SBP. 267 Several studies rifaximin for prevention of recurrent HE. Likewise, it is not known
have evaluated prophylaxis with norfloxacin in patients without prior whether norfloxacin prophylaxis should be stopped in patients who
history of SBP.267 Fernandez et al. randomised 68 patients with cirrhosis would require rifaximin to prevent HE. Prospective studies are required
and low ascites protein levels (<15 g/l) with advanced liver failure to investigate the potential benefits and side effects of combined therapy
(Child-Pugh score ≥9 points with serum bilirubin level ≥3 mg/dl) or with norfloxacin and rifaximin.
impaired renal function (SCr level ≥1.2 mg/dl, blood urea nitrogen level
≥25 mg/dl, or serum sodium level ≤130 mEq/L) to receive norfloxacin Recommendations
(400 mg/day for 12 months) or placebo. 276 Norfloxacin significantly
improved the three-month probability of survival (94% vs. 62%; p = The administration of prophylactic Norfloxacin (400 mg/day,
0.03) but at one year the difference in survival was not significant (60%
orally) is recommended in patients who recover from an episode
vs. 48%; p = 0.05). Norfloxacin administration significantly reduced the
of SBP (I;1).
one-year probability of developing SBP (7% vs. 61%) and HRS (28%
vs. 41%). In a double-blind placebo-controlled trial, 100 patients with Despite some promising evidence, at present, rifaximin cannot be
ascitic fluid total protein level <15 g/l were randomised to ciprofloxacin recommended as an alternative to norfloxacin for secondary
(500 mg/day for 12 months) or placebo. 277 The probability of survival at prophylaxis of SBP (I;2). Thus, at present, no recommendation
one year was higher in patients receiving ciprofloxacin (86% vs. 66%; p
can be given to guide primary or secondary prophylaxis of SBP
<0.04). Meta-analyses of all the trials together or including only pure
among patients already on rifaximin for the prevention of
primary prophylaxis support a significant preventive effect against SBP
(RR 0.2; 95% CI 0.07–0.52; p = 0.001). 278,279 The survival benefit is most recurrent HE.
pronounced at three months (94% vs. 62%, p = 0.003) and seems to Patients who recover from SBP have a poor long-term survival and
decrease over time and may be lost after 12 months follow-up (RR 0.65;
95% CI; 0.41–1.02).280 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 restricted to those with a
clear indication (II-2,1).

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Concomitant medications Finally, in two randomised trials, concomitant albumin may protect
Very frequently PPIs are used in patients with cirrhosis, which may against deterioration in renal and circulatory function. 297,298 However,
increase the risk of SBP. Indications for long-term use should be albumin did not improve survival and thus
carefully assessed and PPIs discontinued when possible. 286,287 NSBBs
Cellulitis
may be detrimental in end-stage liver disease with haemodynamic
derangement, patients should be monitored closely and doses adjusted or
drug discontinued if contraindications occur. 168,190,288 Probiotics have been Community-acquired Healthcare- Nosocomial
assessed as combination therapy with norfloxacin in one randomised cellulitis associated cellulitis cellulitis
trial in a mixed group of patients on primary and secondary prevention
of SBP. No additional benefits were demonstrated.289 Piperacillin- AREADEPENDENT: 3rd generation
tazobactam Likenosocomial cephalosporin or
or3 rd generation infections ifhigh meropemen +oxacillin
Infections other than SBP cephalosporin+ prevalenceofMDROs orglycopeptides or
Prevalence, diagnosis and impact on prognosis oxacillin orifsepsis daptomycinor
linezolid*
Non-SBP infections are frequent in patients with cirrhosis and present or
develop during hospitalisation in 25–30% of patients. The most frequent
Fig. 5. Recommended empirical antibiotic treatment of soft tissue infections (adapted
infections other than SBP are: urinary tract, pneumonia, skin and soft from Ref. 6). MDRO, multidrug resistant organism.
tissue infections, and bacteraemia. 242,290 They constitute a heterogeneous
group regarding clinical course and prognosis. Non-SBP infections Pneumonia
increase the odds ratio for death by 3.75 and are associated with a 30%
one-month and 63% 12-month mortality. 291 Endocarditis, secondary
Community-acquired Healthcare-associated Nosocomial
peritonitis, pneumonia and bacteraemia have worse prognoses. The
pneumonia pneumonia pneumonia
combination of data on liver and renal dysfunction and the type of
infection enables the identification of patients with poor prognosis. 290 In Piperacillin-tazobactam AREADEPENDENT: Ceftazidimeor
particular, non-SBP infections, as well as SBP, are known as common orceftriaxone+ Likenosocomial meropemen§ +
precipitating factors for ACLF.3 An early diagnosis of all these infections macrolideor infections ifhigh levofloxacin ±
levofloxacinor prevalenceofMDROs § glycopeptidesor
and of SBP is a crucial step in the management of patients with cirrhosis.
moxifloxacin orifsepsis linezolid#
Since the presentation and the initial course of any bacterial infection
may be subtle and not very specific, clinical suspicion is important. Fig. 6. Recommended empirical antibiotic treatment of pneumonia (adapted from Ref.
Indeed, all inpatients with cirrhosis should be considered as potentially 6). MDRO, multidrug resistant organism.
infected until proven otherwise. Therefore, a complete work-up should
be carried out at admission and at any time during the hospital stay when UTI
clinical deterioration occurs.6 In addition, close microbiological
surveillance is needed in patients who are at risk of developing Community-acquired Healthcare- Nosocomial
infections caused by methicillin resistant organisms. C reactive protein UTI associated UTI UTI
and procalcitonin can be used for detecting infection and to define the
severity of the infection,6 while their use in the stewardship of antibiotic UNCOMPLICATED: AREADEPENDENT: UNCOMPLICATED:
treatment deserves further investigation.292 To optimise the empirical ciprofloxacin or Likenosocomial fosfomycin or
cotrimoxazole infections ifhigh nitrofurantoin
antibiotic treatment, it is quite important to distinguish among IFSEPSIS: 3rd prevalenceofMDR§ IF SEPSIS:
community acquired, health care associated and nosocomial infections. generation cephalospo- orifsepsis meropemen +
Mortality for nosocomial infections is higher (25–48%) than for rin orpiperacillin- teicoplanin or
tazobactam vancomycin§ #
communityacquired infection (7–21%) since they are more commonly
sustained by MDR bacteria.6,266,268 Like in SBP, there is an increasing Fig. 7. Recommended empirical antibiotic treatment of UTI (adapted from Ref. 6).
challenge of resistant bacteria among non-SBP infections. Among 312 MDR, multidrug resistant; UTI, urinary tract infection.
patients with cirrhosis and blood stream 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 itcannot be recommended. The issue of the management of infections
the infections were caused by MDR bacteria.293 sustained by XDR bacteria has been previously developed.
Management of infections other than SBP

Recommendations
In a randomised trial 94 patients with cirrhosis and infections (most
prevalent were urinary tract infections [46%], SBP [22%], and
pneumonia [19%]) were randomised to a broad-spectrum antibiotic Infections other than SBP are frequent and associated with
regimen or a standard regimen. In–hospital mortality was significantly increased mortality. Hospitalised patients with cirrhosis should
higher in the standard than in the broad-spectrum group (25% vs. 6%; p be assessed and monitored closely for the presence of infections
= 0.01).294 Some more specific suggestions on the empirical antibiotic
to enable early diagnosis and appropriate treatment (II-1;1).
treatment of infections other than SBP based on the type, the severity
and the environment of the infection as well as on local resistance Empirical antibiotic therapy should be commenced promptly at
profiles are given (Figs. 5–7). In patients who fail to respond to a broad-
suspicion of infection (II-1;1).
spectrum antibiotic treatment a fungal infection, including fungal SBP 295
should be suspected and investigated.296 The choice of empirical antibiotic therapy should be based on
several factors including: environment (nosocomial vs. health

care associated or community acquired), local resistance

profiles, severity and type of infection (I;1).

In the context of high bacterial resistance to antibiotics, ≥1.5 mg/dl) within AKI stage 1. 313,314,317 It should be highlighted that the
carbapenem alone or in combination with other antibiotics KDIGO criteria also include criteria based on urinary output in the
proved to be superior to third-generation cephalosporins in diagnosis of AKI (Fig. 9).310 These criteria were not considered by the
recent International Club of Ascites (ICA) consensus because (a) these
healthcare associated infections other than SBP, and therefore,
patients are frequently oliguric with avid sodium retention, despite a
should be preferred (I;1).
relatively normal GFR, (b) they may have an increased urine output
Severe infections sustained by XDR bacteria can require the use of because of diuretics, and (c) on a regular ward, urine collection is often
antibiotics known to be highly nephrotoxic in patients with inaccurate and always untimely.318 However, these criteria may also be
cirrhosis such as vancomycin or aminoglycosides. In these applied whenever a patient with cirrhosis requires a bladder catheter.
cases, patients’ plasma level should be monitored in accordance The definition of baseline SCr used in the KDIGO criteria is crucial
since it has been observed that about 25–30% of episodes of AKI occur
with local policy thresholds
before hospitalisation, representing the so-called ‘‘community-acquired
(III;1).
AKI”. Ideally, ‘‘community-acquired AKI” should be diagnosed at the
Routine use of albumin is not recommended in infections other time of hospital admission, requiring, according to the KDIGO criteria,
than SBP (I;1). an SCr value dated within
Prophylaxis of infections other than SBP
There is preliminary evidence that in patients with Child-Pugh class C, Table 7. International Club of Ascites (ICA-AKI) new definitions for the diagnosis and
management of acute kidney injury in patients with cirrhosis.
norfloxacin administration can reduce the risk of infections and can
decrease six-month mortality. However, more data are needed before a Subject Definition
recommendation can be made.21 Baseline sCr A value of sCr obtained in the previous three months, when available, can be used as ba
months, the value closest to the admission time to the hospital should be used In patie
baseline.
Definition of - Increase in sCr ≥0.3 mg/dl (≥26.5 lmol/L) within 48 h; or,
Renal impairment AKI - A percentage increase sCr ≥50% which is known, or presumed,
Definition and diagnosis within the prior seven days
Renal impairment in patients with cirrhosis was defined more than 30 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
AKI - Stage 2: increase in sCr >2-fold to 3-fold from baseline;
years ago by an SCr value ≥1.5 mg/dl because this value was considered
an index of GFR ≤40 ml/min.32 The use of SCr in the evaluation of renal - Stage 3: increase of sCr >3-fold from baseline or sCr ≥4.0 mg/dl (353.6 lmol/L)
replacement therapy
function in patients with cirrhosis, has several well-known limitations. Progression Progression Regression
However, the diagnosis of renal dysfunction in liver disease is still based of AKI
on it.32,299 The diagnosis should be based on different diagnostic Progression of AKI to a higher Regression of AKI to a lower stage stage and/or need fo
categories including chronic kidney disease (CKD) and acute renal
failure (ARF). When only based on reduction of GFR, the diagnosis of Response to No response treatment Partial response
CKD in patients with cirrhosis is still challenging, because all the
No regression of AKI Regression of AKI stage with a reduction of
SCrbased equations that have been proposed overestimate GFR in
(≥26.5 lmol/L) above the baseline value
patients with cirrhosis.300–304 It can be reasonably assumed that patients
AKI, acute kidney injury; sCr, serum creatinine; RRT, renal replacement therapy.
with decompensated cirrhosis frequently have CKD caused by certain
comorbidities (i.e. diabetes, arterial hypertension) and/or specific causes
(i.e. IgA nephropathy, virus-induced glomerulopathy), 305 however the
prevalence of CKD in this population is still unknown. ARF is a
common complication in patients with decompensated cirrhosis. 306 24 Journal of Hepatology 2018 vol. xxx j
Historically, the diagnosis was based on an increase in SCr of 50% from Please cite this article in press as: The European Association for the Study of the Liver. EASL Clinical Practice Guidelines fo
baseline to a final value >1.5 mg/dl (133 lmol/L).1,32,307 Recently, the
term ARF was replaced by AKI, 308–310 irrespectively of its different types.
AKI is now defined, as proposed by the Kidney Disease Improving
Global Outcomes (KDIGO) group,310 as either an absolute increase in
SCr of more than or equal to 0.3 mg/dl (≥26.4 lmol/L) in less than 48 h,
or by a percentage increase in SCr of more or equal to 50% (1.5-fold
from baseline) in less than seven days. A new staging system was also
introduced, mainly based on the percentage increase of SCr from
baseline (Table 7), either at the time of the first fulfillment of the
KDIGO criteria (initial stage) or at the peak value of SCr during
hospitalisation in case of progressive AKI (peak stage). 310 Based on the
staging system and according to the results of several prospective
studies,311–317 a new algorithm for the management of AKI in patients
with cirrhosis has been proposed 318 (Fig. 8). Recent studies have
suggested that in patients with cirrhosis, in AKI 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 stage 1A (SCr <1.5 mg/dl) and a stage 1B (SCr
InitialAKI# stage 1a°

patients with cirrhosis on an patients with cirrhosis.20,242,306 The
InitialAKI# stage >1a°
increase in SCr ≥50% during the nephrotoxicity of contrast agents
last three months. This assumption is still debated in patients with
Close monitoring may also Withdrawal
facilitate theof diuretics
diagnosis(if of
not yetcirrhosis
applied) 321
andbut
volume
contrast imaging
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 AKI overlapping CKD. should be performed cautiously,
volume, treat infections* when diagnosed) Table 8. Definitions of kidney disease. particularly in decompensated
Definition Functional criteriaResponse? cirrhosis or in patients with known
CKD. Finally, the increase in
AKI Increase in sCr ≥50% within sevenintra-abdominal
days, or pressure
Resolution Persistance Progression increase YES NO days
associated
in sCr ≥0.3 mg/dl within two with tense ascites may
lead to AKI, by increasing renal
AKD GFR <60 ml/min per 1.73 m2 322–324
Closefollowup venous
DoesAKI meet pressure.
criteria of HRS ?
decrease in GFR ≥35% for < 3 months, or
Further treatment of increase in sCr ≥50 % for < 3 months
AKI decided on a NO Management YES
case-by-case basis The cause of AKI should be
CKD GFR <60 ml/min per 1.73 m2
Specific investigated as soon as possible, to
Vasoconstrictors
treatment forpreventAKIprogression.However,
AKD, acute kidney disease; AKI, acute
and albumin
#
AKI atthe first fulfillingof KDIGO criteria otherAKI
phenotypesevenintheabsenceofadefinitive
kidney injury; CKD, chronic kidney disease;
GFR, glomerular filtration rate; sCr, serum
recognised cause of AKI, the
creatinine.
Fig. 8. Algorithm for the management of AKI in patients with cirrhosis (adapted from management should be
Ref. 318). AKI, acute kidney injury; HRS, hepatorenal syndrome; immediately started according to
NSAID, non-steroidal anti-inflammatory. overestimation of the baseline SCr the initial stage (Fig. 2).
and thus underestimating the Recommendations Irrespective of the stage, diuretics
prevalence of AKI on should be discontinued. Similarly,
KDIGO urine output criteria = an
urinary output <0.5 ml/kg B.W./h/x admission.320 Therefore, it has even
In patients with liver diseases, even a mildif increase
there are controversial
in SCr should
been proposed that not only the data, beta-blockers
decrease of GFR be
should
6-12 h
be considered since it may underlie a marked
Stage value obtained
Serum creatinine criteria in the last seven stopped.168
days, but also that within the last (II-2;1). OtherprecipitatingfactorsofAKIsh
1° An urinaryoutput <0.5 ml/kg B.W./h x 6-12 h
three months be considered as a The first step to be addressed in ouldbeidentifiedandtreated,
the diagnostic process is to
2° An urinary output <0.5 ml/kgbaseline
B.W./h x 12 h of SCr in patients
value
establish if the patient has a CKD, AKD screening
including or AKI asand
welltreatment
as an
3° An urinary output <0.5 ml/kgwith
B.W./h cirrhosis (Table
x 24 h or anuria per 127).
h In of infection, volume expansion
Fig. 9. Criteria based on urinary output for addition, an SCr value obtained overlap between these diagnostic categories
when appropriate, and
the diagnosis of AKI (adapted from Ref. within the last three months is the (II-2;1). discontinuation of all nephrotoxic
310). AKI, acute kidney injury; B.W.,
reference to define acute kidney
body weight. The diagnosis of CKD should drugs, be based such
on as vasodilators
a GFR <60 ml/ or
disease (AKD), a third category of 2 NSAIDs.318 Volume replacement
renal impairment, along with AKI min/1.73 m estimated by SCr-based formulas, with or without,
should be used in accordance with
the last week before admission. and CKD, which has been recently signs of renal parenchymal damage
the cause and the severity of fluid
This point is so crucial for the proposed in KDIGO (proteinuria/haeamturia/ultrasongraphy abnormalities) for at or
loss. Patients with diarrhoea
application of the KDIGO criteria recommendations. AKD is clearly
least three months (II-2;1). excessive diuresis should be
that it has been suggested that an a distinct category with different
SCr value be calculated when not outcome, whether or not it is The diagnostic process should betreated with by
completed crystalloids,
staging CKD, whilst
patients with acute GI bleeding
available the seven days prior to associated with AKI. AKD is which relies on GFR levels, and by investigating its cause. It
should be given packed red blood
admission. The baseline SCr can defined should be highlighted that any SCr
by a GFR <60 cellsbased
to formula
maintainoverestimates
haemoglobin
be calculated by inversely ml/min/1.73 m2 for less than three
GFR in patients with cirrhosis level between 7–9 g/dl.325 In
applying the formulas that are months, or a decrease in GFR
(II-2, 1). patients with AKI and tense
used to calculate the estimated ≥35% for less than three months,
Precipitating factors ascites, therapeutic paracentesis
GFR, considering normal values or an increase in SCr <50% within
Infections, diuretic-induced should be associated with albumin
of GFR of 75 ml/min.319 Whilst an the last three months (Table 8).
excessive diuresis, GI bleeding, infusion since it improves renal
imputed SCr is accepted in the However, no data exist about the
therapeutic paracentesis without function.326 In case of no obvious
general population, it can not be prognostic impact of AKD, with
adequate volume expansion, cause and AKI stage >1A, 20%
used in patients with cirrhosis. 320 or without AKI, in patients with
nephrotoxic drugs, and NSAIDs albumin solution at the dose of 1 g
Indeed, all SCr-based formulas cirrhosis. Thus, waiting for these
are the other common of albumin/kg of body weight
overestimate the true GFR in these data, it seems even more justified
precipitating factors of AKI in (with a maximum of 100 g of
patients leading to an to make the diagnosis of AKI in
In patients with cirrhosis the diagnosis of AKI should be based on

adapted KDIGO criteria, thus, either on an increase in SCr of Volume replacement should be used in accordance with the cause
>0.3 mg/dl from baseline within 48 h, or an increase of ≥50% and severity of fluid losses (II-2,1).
from baseline within three months (II-2,1).
In case of no obvious cause of AKI, AKI stage >1A or infection-
The staging of AKI should be based on an adapted KDIGO
26 staging system, thus distinguishing within AKI Journal of Hepatology
stage 1, 2018 vol. xxxAKI,
induced 20% albumin solution should be used at the dose of
j xxx–xxx
1 g of albumin/kg of body weight (with a maximumof100 g of
between
Please cite this AKI stage
article in press 1A and
as: The AKI stage
European 1B for
Association according
the Study oftotheaLiver.
value EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018),
albumin) fortwoconsecutive days(III,1). In patients with AKI and
of SCr <1.5 or ≥1.5 mg/dl, respectively (II-2,1). tense ascites, therapeutic paracentesis should be associated with
albumin infusion even when a low volume of ascetic fluid is
removed (III,1).
JOURNAL
OF HEPATOLOGY
albumin) for two consecutive days the concept that HRS is only a for developing CKD is higher in on HRS has been changed in
should be given.307 All other functional injury has been patientswithsevereorrepeatedepiso recent years, moving from the idea
therapeutic options, especially challenged during the last decade desofAKI.336 Sincepatients with that it was only related to renal
renal replacement therapy (RRT) and, thus, the definition of HRS decompensated cirrhosis are prone hypoperfusion due to
and kidney transplantation will be probably has to be revised. In to develop frequent episodes of macrocirculatory dysfunction (i.e.
discussed in the section dedicated addition, as kidney biopsy is AKI, it can be speculated that they splanchnic arterial vasodilation
to the management of HRS-AKI. rarely performed in the setting of are at higher risk of developing and reduction of cardiac
AKI in clinical practice, the CKD. output).192,338 The new theory is
distinction between HRS-AKI and that the increased circulating
Recommendations ATN is difficult. Recently, novel Hepatorenal syndrome levels of pro-inflammatory
biomarkers have emerged in this Definition, diagnosis and cytokines and chemokines340,341
setting and urinary neutrophil classification may exercise a direct relevant role
When a diagnosis of AKI is For a long time, HRS has been
gelatinaseassociated lipocalin in the development of HRS. Such
made, its cause should be (NGAL) is the most promising. defined as ‘‘a functional renal cytokines have been associated
investigated as soon as Indeed, several studies have failure caused by intrarenal with renal impairment in patients
possible to prevent AKI shown that urinary NGAL, a vasoconstriction which occurs in and in animal models of cirrhosis
progression. Even in marker of tubular damage, could patients with end-stage liver with infection.342–345 Moving from
help to determine the type of disease as well as in patients with the concept that AKI and HRS-
absence of an obvious
AKI.329–335 However, cut-off values acute liver failure or alcoholic AKI are often precipitated by
cause, the management
differ greatly according to series, hepatitis”.32,307 Several data bacterial infection, the new
should be immediately challenge this definition of HRS
there are overlaps between the hypothesis on the pathogenesis of
started. Maximal attention different types of AKI and it as well as the classification in type sepsis-induced AKI should also be
in the screening and should be highlighted that no 1 and type 2. Firstly, as described considered.346–348 This theory
treatment of infections study has confirmed the diagnosis below, pathogenesis of HRS proposes that a synergic interplay
should be carried out (II- by reference kidney biopsy. includes both haemodynamic and of inflammation and
Diagnosis based on a combination inflammatory changes. Secondly, microvascular dysfunction is
2,1).
of multiple biomarkers may be the absence of renal parenchymal responsible for the amplification
Diuretics and/or beta- damage, defining the functional
interesting but needs further of the signal that PAMPs and
blockers as well as other evaluation.329,330,332–334 nature, has never been proven by DAMPs exert on proximal
drugs that could be renal biopsies.337,338 The absence of epithelial tubular cells. The
associated with the Recommendations significant proteinuria and/or recognition of this signal and its
haematuria do not rule out renal subsequent spread to all the other
occurrence of AKI such as
lesions, particularly tubular and proximal tubular epithelial cells
vasodilators, NSAIDs and All types of AKI can occur in patients with cirrhosis,307 namely pre-
interstitial lesions. In addition, cause a mitochondria-mediated
nephrotoxic drugs should renal, HRS, intrinsic, particularly ATN, and post-renal. Therefore,
studies assessing novel kidney metabolic downregulation and
be immediately stopped it is important to differentiate among them (II-2,1).
biomarkers have shown that reprioritisation of cell functions to
(II-2,1). of HRS-AKI is based on revised ICA criteria.
tubular As kidney
damage can biopsy
occuris in favour survival processes above
Types of AKI rarely performed in the setting of AKI, biomarkers should when
patients with HRS-AKI be all else.349 The sacrificed functions
All types of AKI can occur in HRS the
implemented In clinical practice among is diagnosed according totothe
different biomarkers include the absorption on the
patients with cirrhosis, namely traditional criteria.328–330,332 Finally, lumen side of sodium and
date, urinary NGAL can be used to distinguish between ATN and
prerenal AKI, HRS-AKI, it should be noted that HRS-AKI chloride. The consequent
HRS can occur in patients with
intrarenal or intrinsic AKI, and increases of sodium chloride
(II-2;2). underlying CKD. Type 1 and type
post-renal AKI. The most delivery to the macula densa
common cause of AKI in Prognosis 2 were historically defined based triggers further intrarenal
32,307
hospitalised patients with In patients with decompensated on time frame SCr increase. In activation of the RAAS and thus
decompensated cirrhosis is pre- cirrhosis, AKI has a negative the recent revised classification, lowers GFR. Finally, severe
renal, accounting for impactonhospitalsurvivalaccordin type 1 HRS now corresponds to cholestasis may further impair
318
approximately 68% of the gtoeithertheinitialstage, 314
or the HRS-AKI. Consequently, type 2 renal function by worsening
cases.306,327,328 Intrarenal-AKI is peak stage.313,317 Even transient HRS should now include renal inflammation and/or
mainly represented by acute episodes of AKI are associated impairment which fulfills the macrocirculatory dysfunction, or
tubular necrosis (ATN). 306 Finally, with a negative impact on mid- criteria of HRS but not of AKI, by promoting bile salt-related
post-renal AKI is uncommon in term survival.315 Nevertheless, a namely non-AKI-HRS (NAKI), direct tubular damage.350,351 All
decompensated cirrhosis.328 more comprehensive prognostic and only HRS-CKD 339
as previously these findings suggest that the
Considering that most cases of classification also considering proposed. pathophysiology of AKI, and
pre-renal AKI are resolved by extra-renal organ failures is much particular of HRS-AKI, in patients
volume expansion and that post- more accurate than the KDIGO with decompensated cirrhosis
Pathophysiology
renal AKI is uncommon, the key criteria for the prognosis in these seems more complex than
According to the new theory that
point is to differentiate HRS-AKI patients. Finally, looking to the previously hypothesised,
has been developed on the
from ATN. As described in the data in the general population, it supporting the concept that AKI-
pathophysiology of
section ‘‘Hepatorenal syndrome”, should be highlighted that the risk decompensated cirrhosis,5 the view

HRS is not purely functional in according to the level of central required.366 The possibility of damage337 and represents one of
nature. venous pressure (CVP), but there treating some of these patients the main reasons behind the
is evidence that CVP is inaccurate outside the hospital has recently adoption of the KDIGO criteria
Management to manage volume expansion and been proposed367 but even if for the definition of AKI in
The non-specific management of to assess cardiac output in patients promising, further studies are patients with cirrhosis, and the
AKI as been previously described. with cirrhosis. In contrast, CVP needed. Other vasoconstrictive introduction of the new algorithm
Thus, in this section, drug therapy, may be helpful to prevent drugs include i.v. noradrenaline for its management. Regarding
TIPS, RRT, LT and simultaneous circulatory overload. Albumin has and oral midodrine plus inflammation, it has been recently
liver and kidney transplantation been used intravenously at the subcutaneous or i.v. octretide, shown that, for the same value of
(SLK) will be considered. mean dose of 20–40 g/day. both in combination with albumin. baseline SCr, the rate of response
Treatment should be maintained Noradrenaline, given by is related to the number of extra-
Drug therapy. Once the diagnosis until a complete response (SCr continuous i.v. infusion at the dose renal organ failures.376
of HRS-AKI has been made, below 1.5 mg/dl) or for a of 0.5–3 mg/h, has been proven to
patients should promptly receive maximum of 14 days either in be as effective as terlipressin
vasoconstrictive drugs, in case of partial response (decrease regarding the increase in mean
association with albumin. The of SCr ≥50 with a final value still arterial pressure, the reversal of Recommendations
rational for using vasoconstrictors higher than renal impairment and one-month
is to counteract the splanchnic 1.5 mg/dl) or in case of non- survival.368–371 However, the
Vasoconstrictors and
arterial vasodilation, improving response. More recently, number of patients treated with
continuous i.v. infusion of noradrenaline remains too small to albumin are recommended
renal perfusion.352 Terlipressin, a
terlipressin at an initial dose of 2 definitively confirm its efficacy. in all patients meeting the
vasopressin analogue, is the most
mg/day was proposed,359,365 In addition, in contrast to current definition of AKI-
commonly used. The efficacy of
terlipressin plus albumin in the demonstrating a similar rate of terlipressin, the use of HRS stage >1A, should be
treatment of HRS has been proven response but lower adverse effects noradrenaline always requires a expeditiously treated with
in many studies.353–360 In the most than the administration of the drug central venous line and, in most vasoconstrictors and
recent studies, rates of response by i.v. boluses.360 Indeed, countries, the transfer of the
albumin (III;1).
(complete or partial response) to terlipressin, when administered by patient to an intensive care unit
continuous i.v. infusion, has a (ICU). The combination Terlipressin plus albumin
this treatment range from 64 to
76%, with a complete response, more stable lowering effect on midodrine plus octreotide, used in should be considered as
from 46 to 56%.358–360 These portal pressure, even when used at countries where terlipressin is not the first-line therapeutic
response rates must now be lower doses than those provided yet available,372 has been shown to option for the treatment of
evaluated according to the new by i.v. boluses.360 The most be much less effective than
HRSAKI. Telipressin can
definitions of responses in HRS- common side effects of terlipressin in the treatment of
be used by i.v. boluses at
AKI recently proposed by the ICA terlipressin are diarrhoea, type 1 HRS in a recent RCT.359
abdominal pain, circulatory Vasoconstrictors, in particular the initial dose of 1 mg
(Table 7). In two meta-analyses
overload and cardiovascular terlipressin, in association with every 4–6 h. However,
terlipressin plus albumin was
proven to improve not only renal ischaemic complications which albumin, have also been proposed giving terlipressin by
function but also short-term have been reported in up to 45– in the treatment of type 2 HRS. continuous i.v. infusion at
survival in patients with HRS.361,362 46% of patients when the drug The treatment has been proven to initial dose of 2 mg/day
Terlipressin was initially proposed was delivered by i.v. boluses.360 be effective in most cases but,
makes it possible to
to be administered by i.v. boluses The rate of discontinuation unfortunately, recurrence after the
reduce the global daily
at a starting dose of 0.5–1 mg because of side effects, mainly withdrawal of treatment is the
cardiovascular, is around 20%. 360 norm. In addition, there are dose of the drug and, thus,
every 4–6 h, progressively
Accordingly, a careful clinical controversial data about the the rate of its adverse
increased to a maximum of 2 mg
every 4–6 h in case of a reduction screening including impact of this treatment on effects. In case of non-
of baseline SCr < 25%.353–358 electrocardiogram is outcomes, especially in candidates response (decrease in SCr
Adding albumin to terlipressin is recommended in all patients for LT.373,374 This may be, at least <25% from the peak
more effective than terlipressin before starting treatment. Patients in part, due to the suboptimal
value), after two days, the
alone.354 One possible explanation can be treated on a regular ward definition of type 2 HRS, as
dose ofterlipressin should
is that albumin, by increasing but the decision to transfer to a previously discussed. The most
higher level of care should be case relevant factors that may impair be increased in a stepwise
volaemia, may counteract the
based. Recurrent HRS in the response to vasoconstrictors manner to a maximum of
decrease in cardiac output
associated with HRS192 but also by responders, after the end of the are: a) the baseline value of SCr, 12 mg/day (I;1).
terlipressin.363 In addition, treatment, has been reported in up b) the degree of inflammation and
Albumin solution (20%)
antioxidant and anti-inflammatory to 20% of cases. Re-treatment is c) the degree of cholestasis. 375–377
should be used at the dose
properties of albumin may have a usually effective, however, in The finding that the higher
some cases, continuous recurrence baseline values of SCr, the lower 20–40 g/day. Ideally, apart
beneficial effect.364 The dose of
occurs, thus a long-term treatment rate of response to terlipressin plus from routinely monitoring
albumin in HRS treatment has not
been well established. Studies with terlipressin plus albumin and albumin,375 probably reflects the patients with HRS-AKI,
have suggested adapting the dose a long-term hospitalisation are presence of renal parenchymal the serial measurement of

JOURNAL
OF HEPATOLOGY
CVP or other measures of starting the treatment. of refractory ascites, frequently cirrhosis. Despite the available
assessing central blood Patients can be treated on associated with type 2 HRS. In evidence,387 CRRT is probably
volume, can help to a regular ward, but the these patients, TIPS has been better tolerated, providing greater
shown to improve renal cardiovascular stability and
prevent circulatory decision to transfer to
function.95,379 allowing a slower correction of
overload by optimising the higherdependencycaresho
severe or refractory
fluid balance and helping uldbecasebased.Forthedur hyponatraemia than
Renal replacement therapy. Renal
to titrate the dose of ation of treatment, it is haemodialysis.
replacement therapy should be
albumin (II-2;1). important to closely considered in the management of
Noradrenaline can be an monitor the patients. AKI, whatever the type. As far as Liver support systems. In two
According to the type and HRS-AKI, it should be considered controlled studies, both the
alternative to terlipressin. in non-responders to socalled artificial liver support
severity of side effects,
vasoconstrictors. RRT should also systems, either the molecular
However, limited treatment should be
be considered in patients with end- adsorbents recirculating system
modified or discontinued (MARS) or Prometheus, showed
information is available stage kidney disease. The
(I;1). promising beneficial effects in
(I;2). indications for RRT are the same
In cases of recurrence of in patients with cirrhosis as in the patients with type 1 HRS, but
In contrast to terlipressin, the general population including: should be further
HRS-AKI upon treatment investigated.388,389
use of noradrenaline severe and/or refractory
always requires a central cessation, a repeat course electrolyte or acid-base imbalance,
venous line and, in several severe or refractory volume Liver transplantation and
of therapy should be given overload, and/or symptomatic simultaneous liver-kidney
countries, the transfer of
(I;1). azotaemia. However, published transplantation. The best
the patient to an ICU. data on RRT in patients with therapeutic option in patients with
Midodrine plus octreotide Terlipressin plus albumin is cirrhosis are scant, with HRS is LT.390 However, several
can be an option only also effective in the controversial effects on studies have shown that SCr after
when terlipressin or treatment of HRS outside survival.381,382 It has been stated LT is higher in patients
noradrenaline are the criteria of AKI (HRS- that indications for RRT depend transplanted with HRS, compared
unavailable, but its NAKI), formerly known on the perspective of LT. It has to those without HRS at the time
been stated that RRT may be of LT. In addition, the presence of
efficacy is much lower as HRS type II.
considered in patients who are HRS at the time of LT has a
than that of terlipressin Unfortunately, recurrence candidates for LT, while, in negative impact on survival after
(I;1). after the withdrawal of the contrast, the decision to initiate LT.391 The treatment of type 2
According to the new treatment is the norm, and RRT in non-candidates should be HRS before LT has given
definition of HRS-AKI, controversial data exists individualised to avoid futility.20 conflicting results on the clinical
on the impact of the However, it has recently been outcome after LT373,374 and thus,
complete response to the
treatment on long-term observed that critically ill liver requires further investigation.
treatment should be
cirrhotic patients requiring RRT SLK can be indicated in patients
defined by a final SCr clinical outcome,
have very high mortality with cirrhosis and CKD in the
within 0.3 mg/dl (26.5 particularly from the
independent of LT options. Thus, following conditions: a) estimated
perspective of LT. As RRT and treatment at the ICU GFR (using MDRD6 equation)
lmol/L) from the baseline
such, vasoconstrictors and should not be limited to LT ≤40 ml/min or measured GFR
value, while partial
albumin are not candidates but should be based on using iothalamate clearance ≤30
response should be
recommended in this the individual severity of illness. 383 ml/min, b) proteinuria ≥2 g a day,
defined by the regression Therefore, repeated risk
clinical scenario (I;1). c) kidney biopsy showing >30%
of AKI stage to a final stratification is necessary during global glomerulosclerosis or
SCr ≥0.3 mg/dl (26.5 the course of treatment, assisted >30% interstitial fibrosis, or d)
lmol/L) from the baseline by prognostic scores in addition to inherited metabolic disease. SLK
Transjugular intrahepatic clinical judgment and patients0 is also indicated in patients with
value (III;1).
portosystemic shunts. The use of wishes.383 The ideal timing for cirrhosis and sustained AKI
Adverse events related to TIPS may improve renal function RRT initiation has not been irrespective of its type, including
terlipressin or in patients with type 1 HRS. 378,379 defined in patients with cirrhosis. HRS-AKI when refractory to drug
noradrenaline include However, the applicability of However, data on AKI in patients therapy, in the following
ischaemic and TIPS in this clinical setting is with acute liver failure as well as conditions: a) AKI on RRT for ≥4
usually very limited because, in in critically ill patients without weeks or b) estimated GFR ≤ 35
cardiovascular events.
most patients, TIPS is liver disease suggest that early ml/min or measured GFR ≤25
Thus, a careful clinical
contraindicated because of severe RRT improves survival.384–386 Both ml/min ≥4 weeks.392 Beyond these
screening including degree of liver failure. TIPS has haemodialysis or continuous renal two conditions, in a candidate
electrocardiogram is been studied in patients with type replacement therapy (CRRT), with high priority for LT due to a
recommended before 2 HRS380 and in the management have been used in patients with high MELD score, the option of

SLK may be considered in the type 1 HRS as well as mortality in Box 1. CLIF-C Acute Decompensation geographic areas and aetiologies.
presence of risk factors for patients with severe alcoholic Score (Ref. 407). While in Western countries
underlying undiagnosed CKD hepatitis.396 However, recent (Europe, North and Latin
CLIF-C Acute Decompensation score
(diabetes, hypertension, abnormal papers do not confirm these America) bacterial infection,
renal imaging and proteinuria >2 results397,398 and further studies are 10 x [0.03 x Age + 0.66 x Ln(Creatinine) followed +by1.71 active alcohol+intake
x Ln(INR)
g/day).392 The development of new needed. 0.88x Ln(WBC) 0.05 x Sodium8]+ or binge are major precipitating
3,412,413
biomarkers of kidney fibrosis, a events,
9
in Eastern countries
Age in years; creatinine in mg/dl; WBC (white blood count)
cells/L;
in sodium
10 in mmol/L
common and irreversible feature (Asia, Pacific region) the
of CKD, is also promising in this Recommendations exacerbation of hepatitis B,
context.393 followed by alcohol or bacterial
Regarding the priority pressure or anaemia and with a infections are the major causes of
Albumin (1.5 g/kg at
allocation of patients with HRS- high MELD score.400 ACLF AD and ACLF development.414–416
AKI to the waiting list, some rules diagnosis and 1 g/kg on develops on the background of But there are a number of other
should be applied in case of acute decompensation (AD) of insults, which might induce
day three) should be given cirrhosis, but a remarkable number ACLF, such as superimposed
response to drug therapy. In fact,
by lowering SCr and increasing in patients with SBP to of patients (40%) admitted to infection with hepatotropic viruses
serum sodium concentration, the hospital developed ACLF on the (especially HAV, HEV), DILI, GI
prevent AKI (I;1). first episode of AD of their liver bleeding, circulatory dysfunction
treatment can significantly lower
the MELD and MELD-Na score, disease.3 Thus, the presence of AD upon different situation (e.g.
Norfloxacin (400mg/day)
potentially delaying LT. is an important clinical feature for surgery, LVP without albumin).
Considering that the survival rate should be given as the diagnosis of ACLF.3,401,406 The Therefore, in general the
in responders at three months is EASL-CLIF Consortium has precipitating factors might be
prophylaxis of SBP to
almost 50%, a specific policy of proposed and validated a differentiated into three major
priority allocation is needed for prevent HRS-AKI (I;1). prognostic score (CLIF-C AD categories, hepatotoxic injury
these patients. This can be made score) for patients with AD who (active alcohol intake or binge,
either by continuing to consider do not develop ACLF407 The DILI), immunological insults
the baseline MELD and/or CLIF-C AD score (Box 1) was (flairs of viral or autoimmune
Acute-on-chronic liver failure
MELD-Na score394 rather than proved to be more accurate for hepatitis, bacterial, fungal and
Definitions and pathophysiology
those during or after the end of the predicting outcome in these viral infections, common cold,
Since the CANONIC study, the
treatment, or by providing an patients than the MELD or subclinical infections, etc.) and
first major international
exception to the MELD score.395 MELD-Na score.407 Once haemodynamic derangement
observational study characterising
developed, ACLF is characterised following procedures
Recommendations the syndrome of ACLF,3 a large
by hepatic and extrahepatic organ (haemorrhage, surgery, LVP).
number of publications have
dysfunction and/or failure, highly
described the association of this
There is insufficient data to advocate TIPS in HRS-AKI but it activated systemic inflammation,
syndrome with different clinical, Bacterial infections
and a high 28-day mortality. 3,12
diagnostic
could be suggested in selected patients and
with HRS-NAKI therapeutic Overall, the major precipitating
The overwhelming and devasting
approaches. ACLF occurs in 30% factor for ACLF is bacterial
(II-2;2). inflammatory response is a key
of admitted patients3,399 and in 25% infections accounting for 30–57%
pathogenic mechanism in the
of patients
LT is the best therapeutic option for with400HRS
outpatients, andregardless
is a major of cases.409,410 The importance of
development of ACLF, probably
cause of death in cirrhosis, with an bacterial infections for the
of the response to drug therapy (I;1). explaining why ACLF frequently
approximately 50% mortality development of organ failures and
happens in younger
should be based on the individual severity
rate.400 of illness
Even (I;2). there is an
though ACLF was also underlined by the
patients.3,401,406,408 The trigger of
ongoing debate regarding the studies of North American
The indication for liver-kidney transplantation 401–405 remains ACLF and this inflammatory
definition of ACLF, the Consortium for End-stage Liver
controversial. This procedure should be considered in patients of response could not be identified in
concept of the development Disease (NACSELD), who have
with significant CKD or with sustained 40–50% of the patients in
ACLF is AKI including
similar HRS-
across different defined ACLF by the development
CANONIC study,3 which might be
AKI with no response to drug therapy
continents and health systems. of two organ failures in presence
associated with genetic
(II-2;1). There is agreement that ACLF is of bacterial infections.412 By
predisposition, severe portal
Prevention of hepatorenal not just decompensation of liver contrast, bacterial infections were
hypertension or other factors
symdrome cirrhosis, but a distinct not considered to be precipitating
The prevention of HRS-AKI, as syndrome.406 The reason is that predisposing the patients to
409
events for ACLF according to the
for other causes of AKI, is based ACLF is defined by a multi-organ development of AD and ACLF.
definition of Asian Pacific
on the use of albumin in patients failure and has a higher short-term However, identification of the
Association for the Study of the
who develop SBP272 and the mortality precipitating events of AD are of
than a ‘‘simple Liver (APASL).402 However,
prevention of SBP using decompensation” great importance to prevent and
of nowadays there is evidence that
norfloxacin,276 as discussed before. cirrhosis.3,401,406 The risk of manage ACLF.410,411
bacterial infections are mainly
In addition, the use of developing ACLF is higher in involved in the development of
pentoxyfilline may decrease the outpatients with advanced liver Precipitating events organ failures and thereby of
incidence of renal failure in disease according to the presence The precipitating events vary ACLF in Asia as well.415,416 In
patients with cirrhosis27 and of of ascites, low mean arterial between different populations, Western countries bacterial

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OF HEPATOLOGY
infections are the precipitating Clinical and diagnostic features of Table 9. CLIF-Sequential Organ Failure Assessment (SOFA) score (adapted from Ref. n
events in one-third of patients ACLF 3).
admitted with ACLF and in two- As discussed previously, organ The CLIF-Sequential Organ Failure Assessment (SO
thirds of patients developing failures in the presence of AD of

ACLF during follow-up.3,409,412,413 cirrhosis are the basis for the Organ/system 0 1
Based on these data, preventive diagnosis of ACLF. However, in Liver (bilirubin mg/dl) <1.2 ≥1.2–<2.0 ≥2.
the CANONIC study the presence Kidney (creatinine, mg/dl) <1.2 ≥1.2–<2.0 ≥2.
and early therapeutic interventions
for the treatment of infections are and grading of ACLF was based Cerebral (HE grade) No HE Grade I G
of major importance to prevent the on mortality and the independent Coagulation (INR and PLT count) <1.1 ≥1.1–<1.25 ≥1.2
Circulation (MAP, mmHg and vasopressors) ≥70 <70 Dopamine ≤
development of ACLF. The role association of organ dobutamin
of bacterial infections as triggers dysfunction/failure with mortality,
of AD and development of organ which was chosen to be ≥15% at
Lungs
failures has already been 28 days.3 Organ failures were
PaO2/FiO2, or >400 >300–≤400 >200
discussed. defined based on a sequential SpO /FiO >512 >357–≤512 >214
2 2
organ failure assessment (SOFA) E, epinephrine; FiO2, fraction of inspired oxygen; HE, hepatic encephalopathy; NE,
Active alcohol intake or binge score, which was adapted to norepinephrine; PaO2, partial pressure of arterial oxygen; SpO 2, pulse oximetric saturation. The
*
Alcoholic liver disease was the patients with cirrhosis, the CLIF bold text indicates the diagnostic criteria for organ failures.
lg/kg/min.
most prevalent in patients with SOFA score (Table 9). However,
AD and ACLF in the CANONIC two organs received special
study, as well as in recent reports attention, the kidney and the
Table 10.
from India.415–417 Interestingly, brain.3 In fact, it has been observed Recommendations
active alcoholism and alcohol that even mild renal or brain Grades of Clinical characteristics
ACLF
binge were not only a major dysfunction in the presence of
another organ failure, is associated No ACLF The failure,
No organ diagnosis of ACLF
or single should
non-kidney organbefailure,
madecreatinine
in a patient with cirrhosis
trigger in these patients, but led to <1.5 mg/dl, no HE
with a significant short-term ACLF Ia and AD (defined as the acute development or worsening of
a more severe syndrome than Single renal failure
other triggers in alcoholic mortality and therefore defines the ACLF Ib ascites, overt encephalopathy, GI-haemorrhage, non-obstructive
Single non-kidney organ failure, creatinine 1.5–1.9 mg/dl and/ or HE
cirrhosis patients without heavy presence of ACLF. Thus, patients jaundice and/or bacterial infections), when organ failure(s)
grade 1–2
active alcoholism.3 The role and with renal failure, defined as ACLF II Two organ failures high short-term mortality develop (II-2;1).
involving
mechanisms of active alcoholism creatinine ≥2 mg/dl, were ACLF III Three or more organ failures
The diagnosis and the grading of ACLF should be based on the
need further investigation, classified as ACLF grade Ia while
patients with a non-renal and non- assessment of organ function as defined by the CLIF-C Organ
especially regarding prevention
and treatment. cerebral organ failure combined Classification and Failure score (II-2,1).
either with mild renal dysfunction grades of ACLF
Potential precipitating factor(s), either hepatic (i.e. heavy alcohol
Reactivation and superimposed (creatinine between 1.5 and 1.9 (adapted from
mg/dl) and/or grade I and II
Ref. 3). intake, viral hepatitis, DILI, autoimmune hepatitis) and/or
viral hepatitis
hepatic encephalopathy, as well as ACLF, acute-on- extrahepatic (i.e. infections haemodynamic derangements
Reactivation of HBV in patients chronic liver
with cirrhosis is the main those with cerebral failure failure; following haemorrhage, surgery) should be investigated.
HE,
precipitating event in the non- combined with mild renal hepatic However, in a significant proportion of patients, a precipitant
Caucasian Asian population,413,415 dysfunction were classified as encephalopathy. factor may not be identified
occurring mostly in genotypes B ACLF grade Ib (Table 10).3 (II-2,1).
and D, and hepatitis B e antigen Thereafter, patientswith the CLIF-C-ACLF score.
positive patients. Interestingly, with two organ failures
superimposed HAV and HEV can are classified as grade
II ACLF, and have aBox 2. CLIF-C Acute Liver Failure (ACLF) score (Ref. 419). Management of ACLF
also trigger ACLF in 14–
18%.414,416 According to the 28-day mortality rate of 32%. CLIF-C ACLF score
Western experience, these are Patients with three or more organ
unusual causes.3,413 However, the failures are classified as grade III 10 x [0.033 x Clif OFs + 0.04 x Age + 0.63 x Ln(WBC) 2]
role of HEV might have been ACLF and have an average 28-day Age in years; CLIF OF score as in Table 10; sodium in mmol/L
overlooked, and might gain more mortality of 78% (Table 9).
importance now because of According to this EASL-CLIF
advances in diagnostics and definition of ACLF,
increases in awareness.3,418 A approximately one-quarter of
timely recognition and treatment patients admitted to the hospital for AD of cirrhosis had ACLF at admission or develop it during the
of the precipitating event might hospitalisation. After having simplified the CLIF SOFA score into the
prevent ACLF and improve CLIF Organ Failure score (Table 11), the EASL-CLIF Consortium
outcome in these patients. formulated a new score, the CLIF-C ACLF score, which enables the
prediction of mortality in patients with ACLF.419 The CLIF-C ACLF
score (Box 2) has been validated by different independent series of
patients.417,420,421 Other scores were recently proposed by the APASL

ACLF Research Consortium and by the NACSELD, but they were not should be treated with RRT if they respectively).426 Therefore, it
compared specifically meet criteria for this treatment.392 seems evident that the presence of
422,423
HBV infection should be
Specific therapies investigated in all patients with
Liver support systems. ACLF and antiviral therapy
General management Extracorporeal liver support should be started as soon as
Unfortunately, there is no specific effective treatment for ACLF. 424 systems, particularly albumin possible.
Therefore, treatment is currently based on organ support and dialysis (MARS system) and
management of associated complications. The cause of liver injury can fractionated plasma separation and Other therapies. A number of
be specifically treated only in certain situations such as in ACLF adsorption (Prometheus system) therapies have been assessed in
secondary to HBV infection, as described have been evaluated as therapies patients with ACLF, including
for ACLF. These systems remove dexamethasone, plasma exchange,
albumin-bound substances and chinese herbs, caspase inhibitors,
Table 11. Chronic Liver Failure – Organ Failure score system (adapted from Ref. 419). other substances that accumulate mesenchymal stem cells
Organ/system 1 point in the context of ACLF and may transplantation, and administration
Liver Bilirubin <6 mg/dl have deleterious
6 ≤Bilirubin <12 mg/dl effects on the of granulocyte-colony stimulating
Kidney Creatinine <2 mg/dl function
2 Creatinine <3.5of different organs. Both
mg/dl factor (G-CSF).430–432 In most
Brain/HE (West Haven criteria) Grade 0 methods have been evaluated in cases, the information is still very
Coagulation INR <2.0 large RCTs in patients with ACLF preliminary and no
Circulation MAP ≥70 mmHg and no significant effects on
Lungs PaO2/FiO2 >300, or PaO
recommendations can be made
survival could be regarding their potential use in
SpO2/FiO2 >357 SpO
demonstrated.388,389 It should be clinical practice. However, a note
Note: The bold text denotes criteria for diagnosing organ failures. emphasised however, that the on G-CSF seems pertinent
FIO2, fraction of inspired oxygen; HE, hepatic encephalopathy; INR, international normalized definition of ACLF in both trials because this approach has been
ratio; MAP, mean arterial pressure; PaO 2, partial pressure of arterial oxygen; SpO 2, pulse
was different than the current assessed in an RCT.432 The
oximetric saturation.
a definition of ACLF based on the rationale behind this treatment
Patients submitted to mechanical ventilation due to HE and not to a respiratory failure were
CANONIC study.3 Moreover, a seems to be the mobilisation of
considered as presenting a cerebral failure (cerebral score = 3).
b Other patients enrolled in the study with mechanical sub-analysis of the Prometheus stem cells from the bone marrow
ventilation were considered as presenting a respiratory failure study showed a beneficial effect and their engraftment within the
(respiratory score = 3).
424
on survival in patients with MELD liver, although other beneficial
later. Patients with ACLF should ACLF. Haemodynamic function score higher than 30.389 This
ideally be admitted to intensive should be monitored and finding effects may also occur. The only
deserves further RCT evaluating this therapy
care or intermediate care units, yet vasopressor therapy administered investigation. Nonetheless, based
this decision should be in case of marked arterial on the results of available RCTs, included 47 patients with ACLF,
individualised based on certain hypotension. Hepatic extracorporeal as defined by the APASL criteria,
liver support 23 treated with G-CSF (12 doses
factors, particularly patients’ age encephalopathy should be treated systems do not improve survival
and associated comorbidities. early with standard therapy. of patients with ACLF and should of 5 lg/kg subcutaneously) and 24
Moreover, patients suitable for LT Special care should be taken to not be recommended in this treated with placebo in a double-
should be referred to a transplant preserve airway patency to indication. blind manner. The main findings
centre early in the course of prevent aspiration pneumonia. In were an improvement in 60-day
ACLF. Late referral may make patients with coagulation failure, survival in the G-CSF group vs.
Antiviral therapy for chronic
transplantation impossible due to either because of impairment of the placebo group (66% vs. 26%,
hepatitis B. Reactivation of
the rapid evolution of ACLF in coagulation factors or low platelet respectively; p = 0.001) along
hepatitis B is a very common
most patients. 425
In patients in count, substitutive therapy should with a reduction in Child-Pugh,
cause of ACLF in certain areas of
whom ACLF is associated with be given only if there is clinically SOFA, and MELD scores and a
the world, particularly in
precipitating factors, such as significant bleeding. If there is decrease in the occurrence of
southwest Asia.414 A number of
bacterial infections, GI bleeding, respiratory failure, patients should HRS, hepatic encephalopathy and
non-randomised studies and an
or drug toxicity, early be given oxygen therapy and sepsis in G-CSF treated patients.
RCT have shown that treatment
identification and management of ventilation, if required. Finally, if Although these results are
with lamivudine, tenofovir or
these conditions is crucial to there is kidney failure its cause promising, additional studies in a
entecavir is associated with
patient survival. Nonetheless, it should be identified and managed larger number of patients are
inhibition of HBV replication,
should be emphasised that this accordingly. Volume expansion needed.
improvement of liver function,
early treatment of triggering should be given to patients with
and higher survival in patients
factors may not prevent the fluid loss or in the setting of SBP. Liver transplantation. Liver
with ACLF secondary to hepatitis
progression of ACLF in all Excessive volume expansion transplantation is theoretically the
B infection.426–429 The only RCT
patients. Meanwhile, as already should be avoided. Patients definitive treatment for ACLF
included 24 patients, 14 treated
stated, in approximately half of meeting the criteria of AKI-HRS because it allows the cure of
with tenofovir and 13 treated with
patients with ACLF a precipitating should be treated with terlipressin ACLF syndrome as well as the
3
placebo, and showed significant
factor cannot be identified. Organ and albumin or norepinephrine, if underlying liver disease.425
differences in three-month
support is very important in the terlipressin is not available. However, some important issues
survival (57% vs. 15%,
management of patients with Patients with suspected ATN
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OF HEPATOLOGY
regarding LT for ACLF deserve a Recommendations immediate evaluation is in decompensated cirrhosis is

comment, particularly the associated with a higher
recommended (II-3;1).
accessibility of patients to LT, probability of severe sepsis and
At present, there is no
evaluation of candidate subjects, Withdrawal of ongoing type-1 HRS, and higher short-term
the outcomes of LT on survival, specific therapy for ACLF mortality.437,446
intensive care support can
and futility. The accessibility of aside from antiviral
be suggested in patients,
patients with ALCF to LT is therapy in patients with
who are not candidates for
probably decreased compared to ACLF due to reactivation Diagnosis
that of patients with other LT, with four or more
of HBV infection. The diagnosis of RAI is
indications for LT, because organ failures after one
Treatment of ACLF influenced by the method
patients with ACLF have a high week of adequate employed, as the measurement of
should be based on organ
mortality rate after diagnosis of intensive treatment (II-2, serum total cortisol, either at
support and management
the condition. Early referral to 2). baseline or after stimulation by the
transplant centres is therefore of precipitants (see point
standard dose- or low dose-short
crucial. Then, because ACLF is a below) and associated Despite promising results,
Synacthen tests can be utilised. 447
rapidly evolving syndrome, complications. Patients the administration of G- The consensus statements from
candidate patients need to be should be treated in the American College of Critical
submitted to a ‘‘fasttrack” clinical CSF can not be
intermediate care or Care Medicine recommend
evaluation of organ function and recommended at present referring to a delta total serum
intensive care settings.
potential comorbidities that could
Organ function, cortisol <250 nmol/L (9 lg/dl)
contraindicate LT. Data on (1;2).
particularly, liver, kidney, after adrenocorticotrophic
outcome of patients with ACLF
hormone administration or a
treated with liver LT are scarce brain, lung, coagulation, Relative adrenal insufficiency random total cortisol <276 nmol/L
but nonetheless, patient survival at and circulation should be Definition and pathophysiology (10 lg/dl) in critically ill
three-months after LT is about monitored frequently and Relative adrenal insufficiency
80%, much higher than what patients.436 There is no reason for
carefully throughout (RAI) is a condition of inadequate
would be anticipated if patients not employing these indications in
hospitalisation, as ACLF cortisol response to stress in the
were not transplanted.425,433,434 patients with cirrhosis. However,
setting of critical illness,435 also
is a dynamic condition. the diagnosis of RAI based on
Almost all patients with ACLF-3 named as ‘‘Critical Illness Related
developed complications after LT, However, monitoring and serum total cortisol concentration,
Corticosteroid Insufficiency”
especially pulmonary, renal and management should be which is measured by standard
(CIRCI).436 RAI has also been
infectious, compared to patients individualised according assays, may be flawed by the
described in patients with cirrhosis
with no ACLF, or ACLF-1 and -2. reduced serum levels of cortisol
to specific circumstances, and, although it is mainly present
This emphasises the need for binding globulin (CBG) and
mainly patients’ age and in critically ill patients with sepsis
special management when albumin frequently seen in
comorbidities (III, 1). or septic shock (68.9%), it also
transplanting patients with ACLF- patients with cirrhosis. This may
affects non-critically ill cirrhotic
3, with repeated systematic Early identification and lead to an overestimation of RAI,
patients (41.8%), including those
screening for infection and careful treatment of precipitating as more than 90% of circulating
with compensated cirrhosis.437–442
monitoring of renal and cortisol is bound to these
factors of ACLF, The pathophysiology of RAI in
respiratory parameters.434 Another proteins.448 The assessment of
particularly bacterial cirrhosis is not well defined.
point is that some patients with serum-free cortisol concentration
infections, are Suppression of the hypothalamic-
ACLF are potentially too sick for would overcome this limitation.
recommended. However, pituitaryadrenal axis activity,
LT. In the context of scarcity of Serum-free cortisol levels <50
reduced effective volemia, which
donor livers, the potential benefit in some patients ACLF nmol/L at baseline, or <86 nmol/L
may impair adrenal perfusion, and
of LT for patients with ACLF progresses despite (9 lg/dl) after adrenocorticotrophic
both impaired cholesterol
must be balanced with the treatment of precipitating synthesis and enhanced pro- hormone suggest the presence of
rationing. Thus, more data is factors (III;1). inflammatory cytokine production RAI in critically ill patients.449 By
needed to determine medical likely contribute to impair adrenal comparing RAI diagnosis in
Administration of nucleoside clinically stable patients with
futility in patients with steroidogenesis.443,444 Adrenal
ALCF.425,434 However, if LT is analogues (tenofovir, cirrhosis based on either total or
dysfunction blunts the vascular
contraindicated or not available entecavir) should be effect of angiotensin II, free plasma cortisol, a clear
for patients with organ failures ≥4 instituted as early as norepinephrine and vasopressin, discrepancy emerged, as the
or CLIF-C ACLFs >64 at days 3– possible in patients with leading to further sympathetic prevalence of RAI was 58% using
7 after diagnosis of ACLF-3, the nervous system activity.445 These total cortisol criteria and 12%
ACLF due to HBV
intensive organ support should be effects would worsen the cardio- using free cortisol with a peak
infection (I;1).
discontinued owing to futility.425 circulatory dysfunction of plasma level <33 nmol/ after
Early referral of patients stimulation.450 Unfortunately, the
advanced cirrhosis, and favour gut
bacterial overgrowth, and hence methods for determining free
with ACLF to liver
BT, by impairing intestinal cortisol are complex and
transplant centres for motility.445 This explains why RAI expensive, so they are not used in

routine clinical practice. The vasopressor doses and higher rates cardiomyopathy variable results; some showing
surrogate methods that have been of shock reversal were seen in Systolic dysfunction refers to impaired systolic strain in patients
proposed for the calculation of patients who received impaired left ventricle contractile compared with healthy controls,
plasma free cortisol451,452 do not hydrocortisone. However, 28-day responses to stress on echo, albeit with no correlation to Child-
seem to be fully reliable in mortality did not differ between translating to a resting left Pugh score.471,472 Others
patients with cirrhosis.450 For these the two groups. Moreover, shock ventricular ejection fraction demonstrate systolic strain within
reasons, salivary cortisol has relapse and GI bleeding occurred (LVEF) <55%. For most patients normal range and not influenced
received attention, as it correlates more often in the hydrocortisone with cirrhosis, the resting systolic by the presence of ascites.473,474
with free cortisol levels group.456 function is normal or even However, interestingly, when
irrespective of the concentration increased, due to the patients undergo LT, the systolic
of binding proteins.453,454 Baseline hyperdynamic circulation and strain improves.471
salivary cortisol <1.8 ng/ml (<0.18 reduced afterload to maintain
lg/dl) or an increment <3 ng/ml Recommendation cardiac output. To investigate Characterisation of diastolic
(0.3 lg/dl)453 following a standard- systolic dysfunction in cirrhosis, it dysfunction in cirrhotic
is necessary to induce circulatory cardiomyopathy
dose short Synacthen test are At present, hydrocortisone
stress either pharmacologically or Numerous echocardiographic
suggestive of RAI. However, even
treatment (at a dose of 50 through exercise. Systolic criteria along with transmitral
the evaluation of salivary cortisol
dysfunction then manifests as a Doppler evaluation have been
is not without shortcomings.454 mg/6h) of RAI cannot be lack of an appropriate left used to characterise diastolic
Recommendation ventricular contractile response to dysfunction including, early
recommended (I-2).
the applied stress. As disease diastolic/atrial filling ratio (E/A),
Diagnosis of RAI should be based on a delta serum total cortisol advances, the progressive early diastolic filling/mitral
reduction in peripheral vascular annular velocity (E/e’) and
after 250 lg corticotropin injection of <248 nmol/L (9
Cardiopulmonary resistance unmasks systolic tricuspid systolic jet velocity.
complications
random total cortisol of <276 nmol/L (<10 dysfunction. Early studies used Such measurements are influenced
Cirrhotic
serum free cortisol concentration can be cardiomyopathy
influenced by the exercise stress testing to by the pre- and afterload changes
Definition
reduced serum levels of CBG and albumin andfrequently
pathophysiology
seen in demonstrate a lack of increment in of portal hypertension. The latest
Cirrhotic cardiomyopathy (CCM) cardiac output or LVEF463,464 and
patients with cirrhosis, salivary cortisol determination can be American Society of
refers to chronic cardiac this was even shown when
preferred Echocardiography (ASE) and
dysfunction in a patient with noradrenaline levels were
(II-2;2). European Association of
established cirrhosis, characterised increased, suggesting loss of
Treatment of relative adrenal Cardiovascular Imaging
by a blunted contractile response sympathetic responsiveness.465
insufficiency guidelines for the evaluation of
to stress (pharmacological/surgical More recent studies used
It is not known whether cortisol or inflammatory) and an altered diastolic dysfunction recommend
supplementation in clinically diastolic pharmacological stress echo to the following criteria based on a
relaxation, often show a blunted response.466
stable cirrhosis with RAI is of any associated normal LVEF (often the case in
with However, other studies using
value. Two studies have evaluated electrophysiological abnormalities cirrhosis):475
the effects of treating RAI in such as prolongation of the QTc cardiac MRI, have shown normal
critically ill patients with cirrhosis. interval. These phenomena occur chronotropic and inotropic i. Average E/e’>14
In one study 17 patients with in the absence of any other cardiac responses suggesting the ii. Septal e’ velocity <7 cm/s
cirrhosis and sepsis, in whom RAI disease.457 Systemic inflammation techniques used may give rise to OR Lateral e’ velocity <10
was diagnosed, received i.v. is thought to be key in inducing variability.467 cm/s
hydrocortisone (50 mg/ 6h), and myocardial dysfunction associated iii. Tricuspid velocity >2.8
were compared with 50 with impaired diastolic relaxation Myocardial strain imaging for m/siv. Left atrial volume
consecutive patients with cirrhosis and decreased left ventricular assessing systolic dysfunction index (LAVI) >34 ml/m2
and septic shock who had ejection fraction, however, there Myocardial strain imaging is a
previously been admitted to the are few controlled studies.193,458,459 more recent echocardiographic Diastolic dysfunction
same ICU but did not receive Shear stress generated by portal technique evaluating the degree of translates to impaired relaxation of
steroids. A higher rate of shock hypertension exhibiting shortening of myocardial muscle the left ventricle, abnormal filling
resolution, survival in the ICU and mechanical forces on myocardial fibres (‘strain’) influencing of the left atrium, and a higher left
hospital survival were seen in the fibres, may also play a part. 460 cardiac wall motion. The atrial volume. Indeed, increased
patients treated with CCM is largely subclinical but its measurement of left ventricular LAVI has been associated with
hydrocortisone.455 In the second presence does influence prognosis global longitudinal systolic strain greater risk of heart failure in
study, 57 patients with cirrhosis, in advanced disease,461 and it (GLS) is believed to be a sensitive ischaemic cardiac disease.476 Based
septic shock and RAI were certainly impacts on the course of marker of left ventricular systolic on these guidelines, diastolic
randomised to receive either i.v. interventions such as TIPS and function and facilitates the dysfunction is classified as: grade
50 mg of hydrocortisone or LT.462 assessment of systolic dysfunction I if one of the three principle
normal saline every 6 h until at rest,468,469 as well as having criteria (1,3 and 4 above) are met;
haemodynamic stability was prognostic importance in heart and grade II if two or more of the
Diagnosis
achieved, followed by steroid failure.470 Studies of strain imaging criteria are met.
Characterisation of systolic
tapering over eight days. Lower in cirrhosis have demonstrated
dysfunction in cirrhotic
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OF HEPATOLOGY
However, there is Natural history is associated with higher MELD dysfunction and reported it
heterogeneity in descriptions of Impact of disease related scores and independently predicts occurring in 2% and 43% of
the prevalence of diastolic physiological stress: sepsis, survival.489 This contrasts with a patients, respectively. Whilst
dysfunction in cirrhosis, in part decompensation and/or GI more recent study that fails to patients with diastolic dysfunction
reflecting the different echo bleeding demonstrate a clear link between were older, interestingly,
techniques and/or diagnostic There are limited studies of QTc prolongation and mortality.490 outcomes were not influenced by
criteria applied, and the influence cardiac assessment during acute Possible reasons for this the presence of diastolic
of vasoactive agents such as beta- cirrhosis decompensation and heterogeneity in outcomes are the dysfunction.494 By contrast,
blockers and terlipressin. associated haemodynamic variable nature of vasoactive another study used echo and brain
Several studies using an E/A instability. In a seminal study of agents and their respective doses natriuretic peptide (BNP) levels to
ratio of ≤1 criteria have acute cirrhosis decompensation required for the control of grade severity of cardiac
demonstrated left atrial with SBP, a subgroup with HRS bleeding in these studies. For dysfunction. Those patients with
enlargement in patients with were shown to have lower cardiac example, one study showed higher BNP levels (>391) on day
ascites and advanced disease. 464,477 outputs at diagnosis and this terlirpessin decreased cardiac one tended to have higher
Therapeutic paracentesis improves correlated inversely with high output by 17% and the reduction mortality and longer dialysis
E/A ratio and importantly, in all inflammatory indices.193 A follow- in wall motion after terlipressin requirements post transplantation.
studies, there is no relation to on study by the same group correlated with the Child-Pugh Of these, a subset with BNP levels
aetiology.478 In patients treated identified that patients with HRS score.491 >567 had ejection fractions <50%,
with TIPS there was no relation to had cardiac outputs that were and some of these died of
aetiology, but diastolic further reduced at follow-up, cardiogenic shock within 72 h
Impact of interventions on
dysfunction does show a positive compared to patients who do not post-transplant. Autopsy in these
cirrhotic cardiomyopathy
correlation with higher MELD develop HRS after SBP, and these TIPS. Cardiac reserve is a major patients showed diffuse
scores.462,479 A further study using patients had higher plasma clinical consideration for elective myocardial fibrosis. In the main,
E/e’ ratio to define diastolic noradrenaline and renin.485 Other TIPS placement and a 2D echo to BNP levels tended to decrease
dysfunction in patients with studies recapitulate this with a assess LVEF is standard practice. towards normal values over a
ascites and elevated plasma renin, demonstration of reduced kidney Despite this, some patients do week.495
demonstrated that an increased blood flow and importantly, have cardiac decompensation post A further study performed a
E/e’ was an independent predictor suggest those with low cardiac TIPS insertion. Several studies detailed echo assessment,
of development of HRS type 1 and index, also have increased show an association between including myocardial strain
one-year mortality.480 By contrast, mortality.192,485 presence of diastolic dysfunction assessment with speckle tracking,
other studies fail to show a clear In relation to systemic at the time of TIPS and poor in patients undergoing LT
relationship with disease severity inflammation and sepsis, one survival.462,479 By contrast, others compared to non-transplanted
or survival,460,472,481 albeit in two study showed lipopolysaccharide have not shown any difference in patients over a median follow-up
studies echo criteria are not binding protein (LBP) levels (a survival between patients with and of 18 months. Whilst patients pre-
specified.460,472 Studies using the surrogate for BT and without diastolic dysfunction at transplant had increased left
LAVI criteria suggest a closer lipopolysaccharide) in patients the time of TIPS.492 However, ventricular mass and diastolic
association between left atrial with ascites to be associated with uniformly, studies suggest an dysfunction, following
enlargement and Child-Pugh C significant diastolic dysfunction increase in left ventricular and transplantation, there was a
disease.482 and left atrial enlargement. The atrial volume over time, implying significant improvement in
Newer techniques such as E/e’ ratio in these patients that such patients may be at systolic strain and reduced left
cardiac MRI with ‘T1 mapping’ correlated with LBP levels. This greater risk of future heart failure, ventricular mass. Conversely,
and Late Gadolinium data supports findings from based on literature for ischaemic cirrhosis patients who were not
enhancement are being deployed experimental studies, which have heart disease and dilated transplanted had an increase in left
to assess whether fibrosis or shown a role for inflammation, cardiomyopathy.476,493 ventricular mass, albeit systolic
oedema modulates myocardial signalling through the strain did not change
function in conditions such as inflammasome and macrophage Liver transplantation. Just as data significantly.471 This implies that
amyloid and Fabry disease.483 activation, as key pathological on the effects of cirrhosis some of the pathophysiological
Literature on using such processes related to myocardial complications on cardiac function changes in CCM, such as
techniques in liver disease are dysfunction.486–488 are variable, data on the impact of increased left ventricular mass and
very limited. A recent study in Acute GI bleeding in cirrhosis the physiological stress of LT on size, are reversible with resolution
patients with chronic hepatitis C is understandably associated with patients with pre-existing cardiac of the disease. However, studies
showed no significant differences significant haemodynamic dysfunction is heterogenous, with comprehensive
in echo parameters to controls, but disturbances and has not been largely because of the different characterisation of cardiac
demonstrated lower post-contrast studied systematically in relation echo criteria and thresholds function post transplantation are
myocardial T1 time and higher to cardiac function. Data assessing applied. limited.
partition coefficients, indicative of chronotropic function suggest the One study in 173 transplant
diffuse myocardial fibrosis.484 QTc interval is increased in recipients assessed systolic Prognosis for cirrhotic
cirrhotic patients during an acute (resting ejection fraction <55%) cardiomyopathy
bleeding episode compared to and diastolic (E/A ratio <1 or a Data relating cardiac dysfunction
non-cirrhotic patients, and that this deceleration time >200 ms) (especially diastolic dysfunction)

with survival is variable. Some facilitate its assessment at rest without

and in decompensated
cirrhosis, and patientseven in localised abnormal dilated
prospective studies, despite (II-2;2). Cardiac MRI may also patients
identify with acute or
structural chronic pulmonary capillaries and, less
changes.
500
detailed evaluation of patients, However, with all these techniques, hepatitis
there is(Table
the need12).forAmoresevere commonly, pleural and pulmonary
including those with ascites and controlled studies and correlationimpairment
with clinical ofendpoints
liver function and a arteriovenous communications,509
(III;2).
using speckle tracking, show no specific aetiology of liver disease which result in impaired
relation between cardiac Diastolic dysfunction may occur are as an needed
not early sign for ofthe oxygenation of venous blood as it
dysfunction and survival, even cardiomyopathy in the setting ofdevelopment
normal systolic function,
of HPS, 498 and on passes through the pulmonary
based
among more decompensated should be diagnosed using the recent ASE guidelines, namely:
the profiles of the patients studied. circulation. IPVD impairs
patients.473,496 Many of the patients Average E/e’>14; Tricuspid velocity In terms >2.8ofm/sprevalence,
and LAVI HPS>34has ventilatory/perfusion (V/Q) ratio
in these studies have evidence of ml/m2 (II-1;1). been reported in 10% of patients and may result in anatomic and
diastolic dysfunction and some with chronic viral hepatitis in 15– functional shunt leading to
with even advanced grade II In patients with AD of cirrhosis,23% reduced
of those cardiac output (as
with cirrhosis anda in hypoxaemia (Fig. 10). In patients
diastolic dysfunction albeit the manifestation of CCM) is of prognostic
28% of those significance as it is
with Budd-Chiari with advanced liver cirrhosis this
GLS values in these studies are associated with the development syndrome. of 502–504
AKI However,
(specificallythe leads to a subtle increase in
within the normal range. prevalence
hepatorenal dysfunction) after infections suchofas SBP
HPS (II-1;1).
reported in intrapulmonary blood shunting,
Conversely, other studies patients with cirrhosis undergoing which is more pronounced in
Prolongation of the QTc interval is common in cirrhosis and can
suggest an association between LT evaluation ranges from 5– patients with HPS. The
presence of diastolic dysfunction be evaluated since it may indicate 32%,a poor
504–508 outcome. Agents that
while intrapulmonary consequent increase of shunting
and higher two-year mortality, can prolong the QT interval should be useddilatation
vascular cautiously (II-2;2).
(IPVD) can be and V/Q mismatch in the
with diastolic dysfunction ranging detected by
Detailed functional cardiac characterisation echocardiography
should be part of the in
from 38–67%, especially in 50–60% of cirrhosis patients
patients with severe ascites.461,497 assessment for TIPS insertion (II-2;2) or LT LT evaluation. No
undergoing
Indeed, in one such study, a relationship seems to exist
(II-1;1).
multivariate analysis showed left between HPS and CCM.504 The
ventricular diastolic dysfunction Standardized criteria and protocolsclinical
for themanifestations
assessment of of systolic
HPS in
was an independent predictor of patients
and diastolic function in cirrhosis are needed with chronic liver disease
mortality.461 Another study primarily involve dyspnoea and
followed 80 patients to assess one- (II-2;2). platypnoea.498,502,506 Dyspnoea is
year mortality, finding 46% had Hepato-pulmonary syndrome the most common respiratory
diastolic dysfunction on echo Definitions and clinical complaint in patients with HPS,
criteria and about half of these had manifestations but it is non-specific. Its onset is
grade II dysfunction, in whom The association of chronic liver insidious, usually occurring on
mean arterial blood pressure was disease with respiratory symptoms exertion. Platypnoea, which is a Fig. 10. The pathophysiology of
lower and MELD score higher and hypoxia is well recognised. shortness of breath exacerbated by hepatopulmonary syndrome (adapted
than grade I patients. The presence Four main pulmonary sitting up and improved by lying from Ref. 498). HPS, hepatopulmonary
syndrome.
of diastolic dysfunction was supine, is a less sensitive but a
associated with a higher degree of Table 12. Diagnostic criteria of more specific finding in these
ascites and plasma renin levels hepatopulmonary syndrome.
patients. Hypoxemia with exertion upright position is the cause of the
complications may occur in 510
and 38% of these patients or at rest is common and it is orthodeoxia. The pathogenesis
patients with chronic liver disease: of IPVD is probably multifactorial
developed criteria for HRS type I. exacerbated in the upright position
pneumonia, hepatic hydrotorax,
Survival was 95% in those without (orthodeoxia). There are no signs (Fig. 11). The release of nitric
HPS and PPHT. HPS is defined as
diastolic dysfunction, compared to or hallmarks of HPS on physical oxide, which is a potent
a disorder in pulmonary
79% in those with grade I examination. However, vasodilator, plays a critical role in
oxygenation, caused by
dysfunction and 39% with grade II tachypnoea and polypnoea, digital the development of HPS. The
intrapulmonary vasodilatation and,
diastolic dysfunction. E/e’ ratio clubbing and/or cyanosis in increased release of nitric oxide in
less commonly, by pleural and
was an independent predictor of patients with the hallmarks of the pulmonary circulation is
pulmonary arteriovenous
survival.480 chronic liver disease suggest the related to an increased expression
communications occurring in the and activity of two isoforms of
Recommendations presence of HPS.498,502,506
clinical setting of portal nitric oxide synthase (NOS), the
hypertension.498,499 It is most endothelial NOS (eNOS) and the
Pathophysiology
commonly diagnosedshould in patients (iNOS). 511–516
Evaluation of cirrhosis patients with echocardiography
498,499
be The pathophysiology of HPS is inducible NOS
with either
cirrhosis and portal
performed with dynamic stress testing pharmacologically,
500
characterised by an IPVD Meanwhile, BT and the BT-
or through exercise, given thathypertension but, it may
systolic dysfunction has be
also
occurring within the pulmonary related endotoxaemia and pro-
been described in patients with
masked by the hyperdynamic circulation and reduced afterload. arterial circulation. This vascular inflammatory response also
pre-hepatic portal hypertension, 501 contribute to the accumulation of
Failure to increment cardiac output after abnormality consists of diffuse or
with venous obstruction but
physiological/pharmacological stress (and in the absence of
influence of beta-blockade) indicates systolic dysfunction (II-
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).
1;1).
Pulmonary vascular defect with positive findings on contrast-enhanced echocardiography or abnormal uptake in the brain (>6%) with radioactive lung-perfusion scanning
Myocardial
Commonly strain
in presence imaging
of portal and assessment
hypertension, of GLS may serve as a
and in particular:
- hepatic portal hypertension with underlying cirrhosis
sensitive marker of left ventricular systolic function and
- pre-hepatic or hepatic portal hypertension in patients without underlying cirrhosis
Less
36 commonly in presence of: Journal of Hepatology 2018 vol. xxx j xxx–xxx
- 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: PaO 2 PaO2 = (FIO2 [Patm–PH2O] [PaCO2/0.8]) PaO2, where PaO2 denotes partial pressure of alveolar oxygen, PaO 2 partial
pressure of arterial oxygen, FIO2 fraction of inspired oxygen, Patm atmospheric pressure, PH 2O partial pressure of water vapor at body temperature, and PaCO 2 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.
JOURNAL
OF HEPATOLOGY
macrophages in the pulmonary are based on a consensus of scans have also been proposed as with HPS and very severe
microvasculature.517 Endothelial experts. Pulse oximetry indirectly a complementary technique to rule hypoxaemia (PaO2 <50 mmHg),
activation of fractalkine measures oxygen saturation out another underlying pulmonary since the presence of shunting
(CX3CL1), a chemokine, in the (SpO2), it is non-invasive and may pathology,498,499 although there is >20% is associated with a poor
lung may favour the adherence of be useful in the diagnosis of HPS little information regarding their outcome after LT.535 Despite the
monocytes in the pulmonary in adults since a SpO2 <96% was specific role in the diagnosis of potential role of lung perfusion
microcirculation.518 Monocytes found to be highly sensitive HPS. It has been suggested that scintigraphy for prognostic use in
express iNOS and produce heme (100%) and specific (88%) for thoracic CT scans can be useful to patients with cirrhosis and IPVD,
oxygenase-1, leading to increased detecting HPS in patients with a measure the calibre of the its diagnostic accuracy for HPS
carbon monoxide production, PaO2 <70 mmHg, limiting ABG peripheral arteries and the remains to be established.536
further enhancing testing to only 14% of patients. 527 bronchial/arterial relationship.530,531 Finally, neither constrast
vasodilatation.519 CX3CL1 and The validity of this non-invasive Furthermore, CT scanning makes ecocardiography nor MAA scan
vascular endothelial growth factor approach was not confirmed, it possible to define the vascular can differentiate discrete
(VEGF) A, produced by recently, in paediatric patients pattern of HPS in a similar manner arteriovenous communications
circulating monocytes, also with HPS.528 Serial SpO2 to arteriography by detecting from diffuse precapillary and
contribute to angiogenesis, measurements may be useful to pleural and pulmonary capillary dilatations or intracardiac
recently recognised as a further monitor impaired oxygenation arteriovenous communications. shunt. The former distinction can
pathogenetic factor of pulmonary over time in patients with HPS. Contrast-enhanced transthoracic be made by means of pulmonary
IPVD in experimental HPS.520–522 The ABG is essential for the echocardiography with saline angiography. The latter distinction
A downregulation of miRNA-199 staging of the severity of HPS. (shaken to produce microbubbles can be made by means of
a-5p has recently been described HPS can be categorised as mild >10 lm in diameter) is the most transoesophageal
as a contributory mechanism of (PaO2 ≥80 mmHg), moderate useful method to detect pulmonary contrastenhanced
pulmonary microvascular (PaO2 60–79 mmHg), severe vascular dilatation. After the echocardiography that directly
endothelial cell proliferation and (PaO2 50–59 mmHg), and very administration of agitated saline in reveals the intra-atrial septum.
thus pathogenesis of HPS.523 severe (PaO2 <50 a peripheral vein, microbubble Pulmonary angiography should
Polymorphisms in genes involved mmHg).498,500,501,503 Recently, it has opacification of the left atrium not be performed in all patients
in the regulation of angiogenesis been observed that HPS is within three to six cardiac cycles with suspected HPS, but only in:
have also been associated with the associated with elevated von after right-atrial opacification a) patients with the severe
risk of HPS in patients with Willenbrand factor antigen (vWF- indicates microbubble passage hypoxaemia (PaO2 <60 mmHg)
cirrhosis524 (Fig. 11). Finally, it has Ag) levels. Thus, vWF-Ag has through an abnormally dilated poorly responsive to
recently been observed that been proposed as a potentially vascular bed, since microbubbles administration of 100% oxygen,
rosuvastatin, by down-regulating useful screening tool for early do not pass through normal and b) patients strongly suspected
protein expression of nuclear detection of HPS, but further capillaries.532 The injection of (by means of a CT chest scan) of
factor kappa B and VEGF-1,2 and studies are needed to validate it.529 technetium-99 m–labeled macro- having arteriovenous
Rho-associated A kinase, may The chest X ray is usually non- aggregated albumin (MAA) in the communications that would be
improve the intrapulmonary specific, nevertheless, it can be peripheral vein for lung scanning amenable to embolisation.
angiogenesis and the alveolar- used to effectively rule out other (MAA scan) is a potential Recommendations
arterial oxygen pressure gradient concomitant pulmonary diseases alternative diagnostic procedure
in common bile duct ligation since only a mild interstitial although it is more invasive and
rats.525 pattern in the lower part of the In presence of tachypnoea and polypnoea, dig
less sensitive. Particles, with a 20–
lungs may be found, because of cyanosis in a patient with the hallmarks of c
50 lm size, escape through the
Diagnosis pulmonary HPS should be suspected and investigated (I
abnormal pulmonary capillaries
In patients with portal vasodilatation.498,500,501,503 A and stay in downstream capillary Pulse oximetry is the screening tool for HPS i
hypertension and the clinical decrease in the single-breath beds supplied by systemic arteries, not in paediatric patients. For patients with
suspicion of HPS partial pressure diffusing capacity for carbon such as the brain, kidneys, and
monoxide is the only alteration of analysis should be performed. A PaO2 lower th
of oxygen (PaO2) in arterial blood spleen. Quantitative imaging of
gas (ABG) should be assessed. A the routine pulmonary function the MAA scan in the brain and an alveolar-arterial oxygen gradient (P[A-a]O2
PaO2 lower than 80 mmHg and or test that is frequently and lung enables calculation of the breathing ambient air, should lead to further
an alveolar-arterial oxygen consistently abnormal in patients degree of shunting.533,534 The adults ≥65 yearsaP[A-a]O2 ≥20 mmHg cut-o
gradient (P[A-a]O2) ≥15 mmHg with HPS. However, it is not measurement of shunting with 2,1). The use of contrast (microbubble) e
while breathing ambient air at sea specific and it may not normalise MAA scans may be useful as a
after LT.498,500,501,503 All the other characterise HPS is recommended (II-2;1).
level should lead to further complementary diagnostic tool in
investigations (Table 12). For respiratory function tests are non- patients with HPS in two clinical Trans-oesophageal contrast-enhanced echoca
adults ≥65 years a P[A-a]O2 ≥20 specific, showing normal or situations. Firstly, in patients with performed to exclude definitively intra-cardi
mmHg cut-off is used.526 However, reduced forced vital capacity or a severe hypoxaemia and a
maximum forced expiratory technique is not devoid of risks
it should be highlighted that coexistent HPS and intrinsic lung
although these criteria are well volume during the first second disease since a shunting >6% at (II-2;2).
established, enabling one to unify (FEV1). Thus, they can only be MAA scan proves the major An MAA scan should be performed as a com
the diagnostic methods and thus to used to rule out other concomitant contribution of HPS to quantify the degree of shunting in pa
better understand the disease, they pulmonary diseases. Thoracic CT hypoxaemia. Secondly, in patients hypoxaemia and coexistent intrinsic lung d
uncontrolled clinical studies and Recommendations oxygenation and waitlist survival

the prognosis in patients with HPS and veryevidence
anecdotal severe hypoxaemia
indicate that in patients with HPS. These
(PaO2 <50 mmHg) (II-2;1). treatment with beta-blockers, findings reflect not only the results
Long-term oxygen therapy is
cyclooxygenase inhibitors, of the introduction of HPS as a
Neither contrast echocardiography nor MAA scan can definitively recommended in patients
systemic glucocorticoids and MELD exception, but also of an
differentiate discrete arteriovenous communications from with HPS and severe
diffuse precapillary and capillarycyclophosphamide, almitrine
dilatations or cardiac shunts. improved perioperative
bismesylate, inhaled nitric oxide, hypoxaemia. management in patients with HPS.
Pulmonary angiography should be performed only in patients
with the severe hypoxaemia nitric (PaO oxide inhibitors, and Nevertheless, there is no The regular assessment of the
responsive to administration ofantimicrobial
100% oxygen,agents
and inhaswhom been available data concerning severity of hypoxaemia may
505
uniformly unsuccessful.
there is a strong suspicion of arteriovenous communications that effectiveness, tolerance, facilitate LT prior to the
Pentoxifylline has also been tried
are amenable to embolisation (II-2;1). occurrence of very severe
cost-effectiveness,
in the treatment of HPS in adults hypoxaemia. In fact, hypoxaemia
Natural history compliance and effects on
and children in two small pilot can worsen in patients with HPS
The natural history of IPVD as studies with contradictory results survival rates of this who are on the active
well as of HPS is still unclear. in terms of improvements in therapy (II-2;1). transplantation list, with a median
Most patients with IPVD maintain oxygenation and frequent GI side decrease in pO2 of 5.2 mmHg per
No recommendation can be
a normal gas exchange over time, effects.538,539 Administration of year,508 and it has been recently
proposed regarding the
and it is not clear the reason why a garlic was found to be associated confirmed that a pre-LT room-air
subset of patients with IPVD with an improvement in the PaO2 use of drugs or the
PaO2 ≤44.0 mmHg is still
develops HPS.537 A diagnosis of in a small randomised study.540 placement of TIPS for the associated with increased post-LT
HPS is associated with a poor However, a case of moderate treatment of HPS (I;1). mortality.547 Thus, it has been
outcome in terms of both survival hepatotoxicity associated with suggested that an ABG analysis
and quality of life.505,507,508 short-term, high-dose garlicin should be carried out every six
Regarding survival, it should be therapy in an LT recipient with Liver transplantation months, but no study has clarified
highlighted that in patients persistent HPS was recently The most common and the only which is the best method for
undergoing evaluation for LT, the reported.541 The use of TIPS has successful treatment for HPS is conducting this (ABG analysis vs.
mortality rate was almost double been proposed to reduce portal LT. LT results in a complete pulse oximetry) nor how
in patients with HPS compared to pressure in patients with HPS. reversal or in a significant frequently it should be performed.
patients with cirrhosis without However, data are insufficient improvement of HPS in more than Despite the increased survival rate
HPS, independent of other even when a systemic analysis 85% of patients with severe in patients with HPS after LT in
potential predictors of mortality review is considered.542 In hypoxaemia.544 In a prospective the MELD era, it has recently
such as age, MELD score and addition, there is some concern clinical study performed in the been observed that HPS MELD
comorbidities.505 In patients with that TIPS can enhance pulmonary preMELD era, a pre-LT severe exception patients had lower
cirrhosis and HPS, who were not vasodilationbyexacerbatingthehyp hypoxaemia, in particular when it overall mortality compared to
evaluated for LT, the five-year erkineticcirculation.Thus,no was associated with a large others awaiting LT, suggesting
survival rate was 23% while it was recommendation for the use TIPS shunting at MAA scan, was found that the appropriateness of the
63% in patients with cirrhosis to treat HPS can be given.498,505 to be a very strong predictor of HPS MELD exception policy
without HPS who were matched Finally, coil embolisation mortality after LT.535 In 2007, five should be reassessed.548 There are
for the aetiology and severity of (embolotherapy) has been shown years after the introduction of very few and small studies on the
cirrhosis according to the Child- to improve arterial oxygenation MELD in US, the United Network impact of HPS on anaesthetic
Pugh classification, age, and temporarily in the context of for Organ Sharing (UNOS) procedures, as well as in the post-
MELD score.503 Survival was angiographic arteriovenous recommended assigning an MELD LT management in the ICU.
significantly worse among patients communications.531,543 Endothelin- score of 22 for the initial Nevertheless, it seems that inhaled
with HPS and a PaO2 of less than 1 receptor antagonists or application of patients with severe nitric oxide, methylene blue,
50 mmHg at the time of angiogenesis inhibitors have not HPS (PaO2 <60 mmHg), with extracorporeal membrane
diagnosis.506,507 been tested up to now in patients further increases every three oxygenation and non-invasive
with HPS. Thus, long-term months, to balance pre- and post- ventilation may improve
Management oxygen therapy remains the most LT outcomes between HPS and oxygenation immediately post-
Medical treatment frequently recommended therapy non-HPS candidates.545 In the LT.549–551
Spontaneous resolution of HPS is for symptoms in patients with largest retrospective study
uncommon. There is no severe hypoxaemia. However, comparing the results of LT
established medical therapy some aspects of this treatment between the pre-MELD era and Recommendations
currently available for HPS. such as efficacy, costs, and the MELD era in patients with
Several drugs compliance, remain to be HPS, the five-year survival rate
Patients with HPS and PaO2
havebeenappliedforthetreatmentof evaluated. after LT was found to improve
<60 mmHg should be
HPSwithconflictingresults. from 67% during the pre-MELD
However, no large randomised era to 88% in the MELD era.546 evaluated for LT since it is
trial has been conducted, probably Other data showed that in post- the only treatment for
because of the low number of MELD era, there was no HPS that has been proven
patients. Data from several association between pre-LT

JOURNAL
OF HEPATOLOGY
to be effective to date (II- right heart catheterisation is less outcomes than patients with Phosphodiesterase subtype-5
2;1). clear, with a right ventricular idiopathic pulmonary inhibitors. Blockade of
systolic pressure >50 mmHg hypertension, with a five-year phosphodiesterase-5 inhibitors
Since a severe hypoxaemia
and/or significant right ventricular survival of 40% vs. 64%.563 facilitate the vasodilatory effects
(PaO2 <45–50 mmHg) is hypertrophy seen as the trigger for However, a retrospective French of nitric oxide, through reduced
associated with increased this investigation to rule out study challenges this, whilst metabolism of cGMP. Small case
post-LT mortality, an significant PPHT.555 reporting increased mortality in series suggest that sildenafil
ABG analysis should be those with a lower cardiac index, improves functional capacity and
carried out every six Pathophysiology likely reflecting failed increases cardiac output.576–578 It
In patients with portal compensation to increased right should be noted that sildenafil can
months in order to
hypertension, PPHT is thought to ventricular dysfunction, and precipitate variceal bleeding and
facilitate prioritisation to
arise from limited blood flow in patients with more advanced liver as such, caution should be
LT (II-2;1). disease.564 exercised.579
the pulmonary arterial circulation
because of vasoconstriction.
Numerous factors are thought to Medical treatment Prostacyclin analogues.
Portopulmonary hypertension be responsible for this including: The evidence base for Prostacyclin analogues have many
Definition and diagnosis pharmacological therapies in potential benefits including
Changes in endogenous
A diagnosis of PPHT should be PPHT is limited with most data vasodilatory, reduced vascular
vasoregulators; increased
considered in a patient with extrapolated from studies in smooth muscle proliferation and
endothelin 1 and reduced
established portal hypertension in pulmonary arterial hypertension anti-thrombotic. Case series
prostacyclin synthase from
the absence of other causes of not related to liver disease.565,566 suggest improved pulmonary
pulmonary endothelial cells;
pulmonary artery or venous Drugs to promote acute haemodynamics with i.v.
proliferation of smooth muscle
hypertension. namely: chronic vasodilatation during right heart epoprostenol and the potential for
cells/endothelial activation and
thromboembolism, chronic lung catheterisation assessment, improved five-year survival
platelet aggregation.
disease/hypoxia; chronic left heart theoretically may be deleterious as compared to registry data in
disease. Natural history and prognosis they run the risk of further pulmonary artery hypertension (70
Patients may be asymptomatic From studies in patients evaluated reducing cardiac index. There is a vs. 40%).580–583 However, lower
but often present with exertional for LT, the incidence is thought to lack of data to clarify this.567 doses than those used in idiopathic
dyspnoea and they may have be between 3–10% based on Conversely, whilst patients with pulmonary hypertension are
clinical signs of right heart failure haemodynamic criteria. advanced portal hypertension may suggested to reduce the
when moderate to severe disease Furthermore, female sex and pre- be on treatment with beta- development of thrombocytopenia
develops.552 Classification of existing autoimmune liver disease blockers, withdrawing beta- and splenomegaly. Other studies
severity is based on mean are thought to be independent risk blocker therapy may help to have also looked at use of inhaled
pulmonary arterial pressure factors.556 Genetic variation in increase cardiac output and iloprost and reported shortterm
(mPAP) and assumes there is high oestradiol levels may increase the thereby help exertional dyspnoea, haemodynamic benefit.584
pulmonary vascular resistance predisposition to pulmonary artery in patients with advanced
(PVR). PPHT is graded as mild vasoconstriction. Indeed, women PPHT.568 Impact of the management of
(mPAP ≥25 and <35 mmHg); are at three times greater risk than other complications of cirrhosis
moderate (mPAP ≥35 and <45 men.557 There is also an association Caution should be exercised when
Endothelin receptor antagonists.
mmHg), and severe (mPAP ≥45 between patients who have considering TIPS placement for
Bosentan has been shown to
mmHg).498 The diagnosis also moderate to severe PPHT and the the treatment of other
improve pulmonary artery
requires there to be normal presence of large portosystemic complications of cirrhosis in
haemodynamics and exercise
pulmonary occlusion pressures, to shunts.558 However, there is no patients with proven PPHT. The
tolerance in patients with PPHT,
exclude elevation of pulmonary clear association between the anticipated increase in right
independently of liver disease
pressure resulting from elevated severity of liver disease or portal ventricular filling pressures and
severity.569–572 One retrospective
left ventricular filling pressure. hypertension and the development cardiac output may precipitate
study reports survival rates of up
Transthoracic Doppler of severe PPHT.556,559 Studies marked increases in PVR and
to 89% at three years.573 Others
echocardiography (TDE) is the quote survival rates at one year of right-sided pressure overload.585,586
have shown improvements in
main screening tool for evaluating between 35–46% without specific Moderate PPHT (mPAP >35 and
cardiac index up to 39%, albeit in
the presence of PPHT when treatment.560,561 Mortality is often <45 mmHg) is a relative
a small number of patients, but an
screening high-risk patients, such associated with other contraindication for TIPS
increase in aminotransferases,
as those being considered for TIPS complications of liver disease placement, and severe PPHT is an
which responded to dose reduction
or LT.553–555 As a screening test, such as hepatocellular cancer, absolute contraindication.586
or discontinuation.571 The FDA
some studies suggest a pulmonary sepsis and GI bleeding and right places a caution on this class of
artery systolic pressure of >30 ventricular failure. Increased rates drug in patients with advanced
mmHg on TDE has a negative of mortality are related to higher Recommendations
liver dysfunction. There is limited
predictive value of 100%, but a right atrial pressure and lower data on the use of other members
positive predictive value of only cardiac index.559,562 In a multicentre in this family of agent, including Screening for PPHT should
59%.554 However, when assessing registry study, patients with PPHT ambrisentan and macitentan, for be via TDE in patients
patients for LT, the threshold for were shown to have worse PPHT.574,575

deemed potential transplantation irrespective of targeted therapy, though no possible it is crucial to think about
recipients for TIPS or LT; therapy applied.562,587,589 Patients controlled data exists to provide new models of specialist care for
in those with a positive with an mPAP >35 have increased guidance on this.581,600,601 Case patients with cirrhosis. A care
risk post LT, associated with reports and series suggest that 29– coordination programme, has been
screening test, right heart
increased hospital stay and longer 64% of patients with moderate to proven to improve survival and to
catheterisation should be
ventilator requirements.562,590,591 If severe PPHT under long-term reduce emergent readmission to
performed (II-1;1). LT is considered in such patients, follow-up post-transplant have the hospital in these patients. 604
In patients with PPHT who it is suggested that their PPHT is been able to discontinue therapy Care coordinators can facilitate
are listed for treated aggressively to lower over time.599–602 Indeed, some the development of educational
mPAP and improve right suggest a return to normal right programmes for patients and
transplantation,
ventricular function.588,592,593 ventricle function following caregivers optimising their
echocardiography should
To facilitate access to LT therapy for PPHT in the pre- adherence to guideline
be repeated on the waitlist, transplant period and then after recommendations. In addition,
before there is further progression
albeit, the specific interval of PPHT to a point where transplant surgery.581,601 PPHT they can plan invasive procedures
is unclear (III;1). transplantation risks are deemed MELD exception patients have in a day hospital, allowing transfer
Beta-blockers should be too high, MELD exception worse one-year mortality or graft of real-time information to
(MELD 22 points) has been failure than patients without primary care physicians to
stopped and varices granted to patients with PPHT PPHT.603 improve quality and coordination
(mPAP >25 mmHg and PVR >240 Recommendations of care. In so doing, it is possible
managed by endoscopic
dynes/s per cm5) with at least to prevent unnecessary visits to
therapy in cases of proven moderate disease severity the emergency department and/or
If mPAP <35 mmHg and right ventricular
emergent function is preserved,
readmission to the
(baseline mPAP >35 mmHg).594
PPHT (II-3;1). LT should be considered (II-2,1). A mPAP of ≥45 mmHg
hospital. These measures shouldwill
Patients are considered surgical
candidates if, after targeted progressively
be considered an absolute contraindication to LTreduce the burden
irrespective of of
Therapies that have been
approved for primary
therapy to lower PAP, they have therapy applied (III,1). Therapy to cirrhosis.
lower mPAP and improve right
improved mPAP (<35 mmHg) and ventricular function should be commenced in patients with mPAP
pulmonary arterial
PVR (<400 dyne/s per cm5) and/or
hypertension may have normalise their PVR. Applying
Conflictshould
≥35 mmHg. Right ventricular function of interest
be periodically
benefit in PPHT to evaluated (II-2,1). Paolo Angeli: Consultancy fee
this exception has been noted to
from Sequana Medical AG, Gilead
improve exercise reduce waitlist mortality.595 MELD exception can be considered in patients with proven PPHT
Italy and Biovie; Patent inventor
tolerance and in whom targeted therapy fails to decrease mPAP <35 mmHg
from Biovie; Research grantbut
from
haemodynamics. Per-operative considerations. All Gilead;
does facilitate normalisation of PVR to <240 Speaker’s
dynes/s cm fee from
However, endothelin patients should be monitored with Bhering, Kedrion 2016. Mauro
ventricular function (II-3;2).
antagonists should be used a pulmonary artery catheter. Bernardi: Consultancy fee from
with caution because of Therapy to lower mPAP should be advocated in patients with proven CLS PPHT of moderate
Behring GmbH,severity
Baxter
concerns over hepatic continued throughout the (assessment mPAP Healthcare SA, Grifols SA;
operative period, given that there Speaker’s fee from CLS Behring
impairment (II-2;1).
is often a rise in cardiac output GmbH, Baxter Healthcare SA,
TIPS should not be used in post re-perfusion and this may add PPTA Europe, Octapharma AG,
patients with PPHT (II-3;1). more stress on any pre-existing Conclusions Gilead Sciences, AbbVie Italia.
impaired right ventricle These guidelines on the Wim Laleman: Speaker’s fee for
function.595–597 Indeed, in some management of patients with Gore, Norgine, 4C, Abbvie,
cases, a severe acute rise in PAP decompensated cirrhosis were Sirtex; Consultancy fee for
Liver transplantation
may lead to graft failure because developed based on a new AbbVie, Gilead, MSD, Intercept;
Historically, severe PPHT has
of hepatic congestion through a pathophysiological background Research grant from Gilead. Jonel
been a relative contraindication
failing right ventricle. The that offers the opportunity for Trebicka: Speaker’s fee or
for LT because of very poor
management of such adverse more comprehensive therapeutic Consultancy fee from Gore &
outcomes. However, with the
haemodynamics, in addition to i.v. or prophylactic approaches to associates (TIPS), Sequana
advent of improved
prostacyclin or inhaled nitric manage the disease. The medical (alpha-pump), Alexion
haemodynamic control with
oxide includes the use of knowledge of the key (PNH), Versantis (liposomes).
agents such as i.v. prostacyclin,
extracorporeal membrane oxygen pathophysiologic mechanisms Aleksander Krag: None. Claire
there are case series showing
therapy (ECMO).598,599 makes it possible nowadays to Francoz: None. Pere Gines:
normal pulmonary
counteract the progression of Advisory/Consultancy fee for
haemodynamics almost two years
cirrhosis and so to prevent its Sequana Grifols, Mallinckrodt,
post LT.587,588 Postoperative considerations. complications. This represents a Ferring Pharmaceuticals; Research
Monitoring PAP response to step forward, shifting our Funding from Sequana, Grifols,
Stratifying risk for LT. In patients therapy is via serial transthoracic approach from treating the Ferring Pharmaceuticals.
with an mPAP ≥45–50 mmHg, echo with tissue Doppler at 4– 6- complications of decompensated Please refer to the
most centres would deem this an month intervals and consideration cirrhosis to preventing their accompanying ICMJE disclosure
absolute contraindication to of tapering pulmonary artery occurrence. However, to make this forms for further details.

JOURNAL
OF HEPATOLOGY
Acknowledgments clinical relevance. Nat Rev encephalopathy. Aliment al. Compensated cirrhosis: natural
Gastroenterol Hepatol Pharmacol Ther 2017;46:845–855. history and prognostic factors.
We would like to thank Alessandra
2014;11:177–186. [20] Ginès P, Hepatology 1987;7:122–128.
Brocca Dr, Marta Tonon MD,
[10] Arroyo V, Terra C, Gines P. Schrier RW. [30] Ripoll C, Groszmann R, Garcia-
Husain-Syed Faeq MD for the great Advances in the pathogenesis and Renal failure in Tsao G, Grace N, Burroughs A,
editorial work. We acknowledge treatment of type-1 and type-2 cirrhosis. N Planas R, et al. Hepatic venous
ICREA for the ACADEMIA hepatorenal syndrome. J Hepatol Engl J pressure gradient predicts clinical
AWARD given to Pere Ginès. We 2007;46: 935–946. Med 2009;361:1279–1290. decompensation in patients with
would like to thank the reviewers of [11] Iwakiri Y, Groszmann RJ. The [21] Moreau R, Elkrief L, Bureau C, compensated cirrhosis.
hyperdynamic circulation of Pararnau JM, Thavenot T, Saliba Gastroenterology 2007;133:481–
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their time and critical reviewing: patient to the molecule. month norfloxacin therapy in [31] Moore KP, Wong F, Gines P,
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EASL Guidelones On Management Decompensated Liver Cirrhosis

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JOURNAL

EASL Clinical Practice Guidelines for the management of patients with

European Association for the Study of the Liver⇑

Journal of Hepatology 2018 vol. xxx xxx–xxx

Portal hypertension Liver injury

Bacterial translocation Damaged cells

Otherpotential Activationifinnate pattern

Release of pro-inflamamtory molecules

Adrenal HE Kidney HPS

reduced to the lowest effective dose (III;1). Recommendations

Severe coagulopathy (accelerated fibrinolysis or disseminated intravascular

Severe bowel distension

Drugs contraindicated in patients with ascites

Non-steroidal anti-inflammatory drugs should not be used in

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

Non-selective beta-blockers in patients with refractory ascites. The

complete portal vein thrombosis; cardiac or respiratory failure; organic renal

Salerno et al. 68/32 diuretics

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

Repeated LVP plus albumin (8 g/L of ascites removed) are

treatment cannot be recommended (III;1).

Alfapump implantation in patients with refractory ascites not

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

titration.168,184,185,190 Firstly, dosing of NSBBs was suggested as a potential

Combination therapy of NSBBs + EBL is recommended since it

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

Immediate start of drug therapy

Early diagnostic endoscopy (<12 h)

Confirm variceal bleeding

Endoscopic therapy(band ligation)

Control Further bleeding

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

Spontaneous bacterial pleural empyema

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

susceptible to the development of infections caused by MDROs, because

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

Healthcare associated and nosocomial SBP is more likely to

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

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

Management of infections other than SBP

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

care associated or community acquired), local resistance

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

InitialAKI# stage 1a°

In patients with cirrhosis the diagnosis of AKI should be based on

Journal of Hepatology 2018 vol. xxx j xxx–xxx 27

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

Journal of Hepatology 2018 vol. xxx j xxx–xxx 29

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

thirds of patients developing failures in the presence of AD of

Journal of Hepatology 2018 vol. xxx j xxx–xxx 31

regarding LT for ACLF deserve a Recommendations immediate evaluation is in decompensated cirrhosis is

Journal of Hepatology 2018 vol. xxx j xxx–xxx 33

Journal of Hepatology 2018 vol. xxx j xxx–xxx 35