Professional Documents
Culture Documents
Decompensated Cirrhosis: Clinical Practice Guidelines
Decompensated Cirrhosis: Clinical Practice Guidelines
Decompensated cirrhosis
About these slides
• These slides give a comprehensive overview of the EASL clinical practice guidelines on the
management of decompensated cirrhosis
• The guidelines were first presented at the International Liver Congress 2018 and are published
in the Journal of Hepatology
– A full copy of the publication can be downloaded from the Clinical Practice Guidelines section of the
EASL website
• Please feel free to use, adapt, and share these slides for your own personal use; however,
please acknowledge EASL as the source
About these slides
• Definitions of all abbreviations shown in these slides are provided within the slide notes
• When you see a home symbol like this one: , you can click on this to return to the outline or
topics pages, depending on which section you are in
• Chair
– Paolo Angeli
• Panel
– Càndid Villanueva, Claire Francoz,
Rajeshwar P Mookerjee, Jonel Trebicka,
Aleksander Krag, Wim Laleman,
Pere Gines, Mauro Bernardi (EASL
Governing Board Representative)
• Reviewers
– Alexander Gerbes, Thierry Gustot,
Guadalupe Garcia-Tsao
Grade of evidence
I Randomized, controlled trials
II-1 Controlled trials without randomization
II-2 Cohort or case-control analytical studies
II-3 Multiple time series, dramatic uncontrolled experiments
III Opinions of respected authorities, descriptive epidemiology
Grade of recommendation
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
Compensated Decompensated
Stage 0: no varices, mild PH Stage 3: Bleeding
LSM >15 and <20 or HVPG >5 and <10 mmHg
Stage 4:
Stage 1: no varices, CSPH First non-bleeding decompensation
LSM ≥20 or HVPG ≥10 mmHg
Stage 5:
Stage 2: varices (=CSPH) Second decompensating event
End stage
Stage 6: late decompensation:
Refractory ascites, persistent PSE or
jaundice, infections, renal and other organ
dysfunction
ACLF
Death
Compensated Decompensated
Stage 0: no varices, mild PH Stage 3: Bleeding
Asymptomatic
LSM >15 and <20 or HVPG >5 and <10 mmHg
Stage 4: Symptomatic
Stage 1: no varices, CSPH First non-bleeding decompensation
LSM ≥20 or HVPGsurvival:
Median ≥10 mmHg12 years Median survival: 2 years
Stage 5:
Stage 2: varices (=CSPH) Second decompensating event
End stage
Stage 6: late decompensation:
Refractory ascites, persistent PSE or
jaundice, infections, renal and other organ
dysfunction
ACLF
Death
Cirrhosis
Adrenal Kidney
HE HPS
dysfunction dysfunction
• Impact is variable
• Probably depends on the status of liver disease at the time
• Several strategies have been evaluated to prevent disease progression in patients with DC
– Targeting microbiome abnormalities and bacterial translocation to improve the gut–liver axis
(i.e. rifaximin)
– Improving the disturbed circulatory function (i.e. long-term albumin)
– Treating the inflammatory state (i.e. statins)
– Targeting portal hypertension (i.e. β-blockers)
Grading of ascites*
Grade 1 Mild ascites: only detectable by ultrasound examination
Grade 2 Moderate ascites: manifest by moderate symmetrical distension of abdomen
Grade 3 Large or gross ascites: provokes marked abdominal distension
*Ascites recurring on ≥3 occasions within a 12-month period despite dietary sodium restriction and adequate diuretic dosage are considered recurrent
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Uncomplicated ascites: evaluation and diagnosis
Neutrophil count and culture of ascitic fluid culture† should be performed to exclude bacterial
peritonitis II-2 1
• Neutrophil count >250 cells/µl denotes SBP
Ascitic total protein concentration should be performed to identify patients at higher risk of
II-2 1
developing SBP‡
The SAAG should be calculated when the cause of ascites is not immediately evident, and/or
II-2 1
when conditions other than cirrhosis are suspected §
Cytology should be performed to differentiate malignancy-related from non-malignant ascites II-2 1
*Grade of evidence II-2, grade of recommendation 1; †Bedside inoculation blood culture bottles with 10 ml fluid each;
‡
A total protein concentration <1.5 g/dl is generally considered a risk factor for SBP;
§
SAAG ≥1.1 g/dl indicates that portal hypertension is involved in ascites formation with an accuracy of about 97%
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Uncomplicated ascites: prognosis
Since the development of grade 2 or 3 ascites in patients with cirrhosis is associated with
reduced survival, LT should be considered as a potential treatment option II-2 1
• Patients with cirrhosis and ascites are highly susceptible to rapid reductions in extracellular
fluid volume
– Can lead to renal failure and hepatic encephalopathy
• Loop diuretics can lead to potassium and magnesium depletion and hyponatraemia
• Muscle cramps can impair quality of life in patients receiving diuretics
Frequent clinical and biochemical monitoring during the first weeks of treatment (particularly on
I 1
first presentation)
Recommended maximum weight loss: 0.5 kg/day in patients without oedema, 1 kg/day in
II-2 1
patients with oedema
Once ascites have largely resolved, the dose of diuretics should be reduced to the lowest
III 1
effective dose
Discontinue diuretics in case of severe hyponatraemia,* AKI, worsening hepatic encephalopathy,
III 1
or incapacitating muscle cramps
Discontinue furosemide for severe hypokalaemia (<3 mmol/L )
III 1
Discontinue anti-mineralocorticoids for hyperkalaemia (>6 mmol/L)
Albumin infusion or baclofen administration † are recommended in patients with muscle cramps I 1
*Serum sodium <125 mmol/L; †10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Uncomplicated ascites: management of Grade 3 ascites
• Patients with DC and ascites are at increased risk of renal impairment from several types
of drug
NSAIDs should not be used (high risk of developing further sodium retention, hyponatraemia,
II-2 1
and AKI)
Angiotensin-converting enyzme inhibitors, angiotensin II antagonists, or 1-adrenergic
II-2 1
receptor blockers should not generally be used (increased risk of renal impairment)
Aminoglycosides are discouraged (increased risk of AKI)
• Reserved for patients with severe bacterial infections that cannot be treated with II-2 1
other antibiotics
Contrast media
• In patients with preserved renal function: does not appear to be associated with increased II 2
risk of renal impairment
• In patients with renal failure: insufficient data, cautious use and preventative measures III 1
recommended
Refractory ascites
Diagnostic criteria
Patients must be on intensive diuretic therapy* for at least 1 week and on a salt-restricted diet of
Treatment duration
less than 90 mmol/day
Lack of response Mean weight loss of <0.8 kg over 4 days and urinary sodium output less than the sodium intake
Early ascites recurrence Reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization
• HE: development of encephalopathy in the absence of any other precipitating factor
• Renal impairment: increase of serum creatinine by >100% to a value >2 mg/dl (177 µmol/L) in
patients with ascites responding to treatment
Diuretic-induced
• Hyponatraemia: a decrease of serum sodium by >10 mmol/L to a serum sodium of <125 mmol/L
complications
• Hypo- or hyperkalaemia: a change in serum potassium to
<3 mmol/L or >6 mmol/L despite appropriate measures
• Incapacitating muscle cramps
The diagnosis of refractory ascites relies on the assessment of the response of ascites to
diuretic therapy and salt restriction
• Evaluation should be done in stable patients without associated complications, such as III 1
bleeding or infection, after ascertaining patient compliance to treatment
Patients with refractory ascites should be evaluated for LT III 1
Repeated LVP plus albumin (8 g/L of ascites removed) are recommended as first-line
I 1
treatment for refractory ascites
Diuretics should be discontinued in patients with refractory ascites who do not excrete >30
III 1
mmol/day of sodium under diuretic treatment
Although controversial data exist on the use of NSBBs in refractory ascites, caution should be
exercised in severe cases*
• High doses of NSBB should be avoided (i.e. propranolol >80 mg/day) II-2 1
• Carvedilol can not be recommended at present I 2
• Definition
– Accumulation of transudate in the pleural space
• In the absence of cardiac, pulmonary or pleural disease
– Ascites moves through small diaphragmatic defects
• Negative intrathoracic pressure induced by inspiration
– Can lead to respiratory failure
– Can be complicated by spontaneous bacterial infections (empyema)
– Associated with poor prognosis
• Median survival: 812 months
• Diagnosis
– Once pleural effusion has been ascertained, cardiopulmonary and primary pleural diseases should
be excluded*
– Diagnostic thoracentesis is required to rule out bacterial infection*
Patients with cirrhosis who develop hyponatraemia should be evaluated for LT II-2 1
Removal of the cause and administration of normal saline are recommended in the management
III 1
of hypovolaemic hyponatraemia
Fluid restriction* to 1,000 ml/day is recommended in the management of hypervolaemic
III 1
hyponatraemia since it may prevent a further reduction in serum sodium levels
*Beyond fluid restriction, hypertonic saline should be limited to rare patients with life-threatening complications. It can be considered in patients with severe hyponatraemia
who are expected to undergo LT within days. Correction of serum sodium concentration after attenuation of symptoms should be slow (≤8 mmol/L per day) to avoid
irreversible neurological sequelae (II-3;1). Albumin can be administered but data are very limited (II-3;2). Use of vaptans should be limited to clinical trials (III;1)
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Variceal haemorrhage: pathophysiology and natural history
Patients with DC are at high risk and should have an OGD to screen for varices, unless
II-2 1
previously diagnosed and treated
If OGD is performed, the presence, size and presence of red wale marks should be reported II-2 1
In patients without varices in whom aetiological factor persists and/or remain decompensated,
screening OGD should be repeated yearly
III 2
• In other patients the screening interval could be prolonged, but the exact interval is unclear
and more data are required
*High-risk = small varices with red signs, medium or large varices irrespective of Child–Pugh classification or small varices in Child–Pugh C patients
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Variceal haemorrhage: prophylaxis with NSBBs and EBL
• NSBBs and EBL are equally effective in preventing first bleeding in patients with high-risk
varices
– Choice between options depends on factors such as patient preference, contraindications or
adverse events
Recommendation Grade of evidence Grade of recommendation
Ascites is not a contraindication for NSBBs. However, caution should be exercised in cases of I 1
severe or refractory ascites
• High doses of NSBBs should be avoided II-2 1
• The use of carvedilol can not be recommended at present I 2
NSBBs should be discontinued in patients with progressive hypotension or those who III 1
develop an acute intercurrent condition*
After recovery, reinstatement of NSBBs can be attempted III 2
• When NSBB intolerance or contraindications persist, patient’s bleeding risk should be III 1
managed by expeditious EBL
• NSBBs and EBL in combination reduces the risk of re-bleeding compared with monotherapy
ENDOSCOPY
ENDOSCOPY
*History, physical and blood exam, cultures; †Somatostatin/terlipressin; ‡Ceftriaxone (1 g/24 hours) is the first choice in patients with DC, those already on quinolone prophylaxis,
and in hospital settings with high prevalence of quinolone-resistant bacterial infections. Oral quinolones (norfloxacin 400 mg BID) should be used in the remaining patients (I;1)
Figure adapted from de Franchis R, et al. J Hepatol 2015;63:74352;
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Acute variceal haemorrhage: treatment
• Vasoactive drugs and ligation are the primary options for acute VH
– There may be a role for TIPS in selected high-risk patients
The combination of vasoactive drugs and ligation is recommended as the first therapeutic
I 1
option in acute variceal bleeding
Early pre-emptive covered TIPS (placed within 24–72 hours) can be suggested in selected
high-risk patients, such as those with Child–Pugh class C with score <14
I 2
• However, the criteria for high-risk patients, particularly Child–Pugh B with active bleeding,
remains debatable and needs further study
TIPS should be used as the rescue therapy of choice in cases of persistent bleeding or early
I 1
re-bleeding
With the pre-requisite of expertise, balloon tamponade should be used in case of uncontrolled III 1
bleeding as a temporary ‘‘bridge” (max 24 hours) until definitive treatment can be instituted
• Removable, covered and self-expanding oesophageal stents can be used as an alternative I 2
to balloon tamponade
In the context of bleeding, where encephalopathy is commonly encountered, prophylactic
I 2
lactulose may be used to prevent encephalopathy, but further studies are needed
β-blockers and vasodilators should be avoided during the acute bleeding episode III 1
*Culture should be performed to guide antibiotic therapy (Grade of evidence II-2, grade of recommendation 1)
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Management of SBP: empirical antibiotics
Severe infections by XDR bacteria may require antibiotics known to be highly nephrotoxic in
patients with cirrhosis (e.g. vancomycin or aminoglycosides)
III 1
• In these cases, patients’ plasma levels should be monitored in accordance with local policy
thresholds
De-escalation according to bacterial susceptibility based on positive cultures is recommended
II-2 1
to minimize resistance selection pressure
Antibiotic efficacy should be checked with a second paracentesis at 48 hours from starting
treatment
• Suspect failure of first-line antibiotic if worsening clinical signs and symptoms and/or II-2 1
increase, or no marked reduction in leucocyte count (at least 25%) in 48 hours
The duration of treatment should be at least 5–7 days III 1
Spontaneous bacterial empyema should be managed similarly to SBP II-2 2
• In patients with SBP treated with a third generation intravenous cephalosporin antibiotic,
albumin significantly decreased the incidence of type-1 hepatorenal syndrome and
reduced mortality1
Recommendation Grade of evidence Grade of recommendation
• Patients with cirrhosis and low ascitic fluid protein concentration (<10 g/L) and/or high serum
bilirubin levels are at high risk of developing a first episode of SBP1
• In patients who survive an episode of SBP, the cumulative recurrence rate at 1 year is
approximately 70%1
Prophylactic norfloxacin (400 mg/day, orally) is recommended in patients who recover from
I 1
an episode of SBP
At present, rifaximin cannot be recommended as an alternative to norfloxacin for secondary
prophylaxis of SBP
I 2
• At present, no recommendation can be given to guide prophylaxis of SBP among patients
already on rifaximin for the prevention of recurrent HE
Patients who recover from SBP have a poor long-term survival and should be considered for
II-2 1
LT
PPIs may increase the risk for the development of SBP, their use should be restricted to those
II-2 1
with a clear indication
Hospitalized patients with cirrhosis should be monitored closely for the presence of
II-1 1
infections to enable early diagnosis and treatment
Empirical antibiotic therapy should be commenced promptly II-1 1
Empirical antibiotic therapy should be based on: environment, local resistance profiles,
I 1
severity and type of infection
In the context of high bacterial resistance to antibiotics, carbapenem alone or in combination
I 1
with other antibiotics should be preferred*
Severe infections by XDR bacteria may require antibiotics known to be highly nephrotoxic in
patients with cirrhosis (e.g. vancomycin or aminoglycosides)
III 1
• In these cases, patients’ plasma level should be monitored in accordance with local
policy thresholds
Routine use of albumin not recommended in infections other than SBP I 1
*Carbapenem alone or in combination with other antibiotics proved to be superior to third-generation cephalosporins in healthcare-associated infections other than SBP
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Assessing severity of infection
• qSOFA and Sepsis-3 criteria have been validated in patients with cirrhosis1
– Can be used to assess severity of infection
Sepsis-3 positive
Poor outcome
Good outcome and qSOFA Good outcome
Patient with need for transfer to ICU
negative
Grey zone
Monitoring SOFA
score is required
1. Singer M, et al. JAMA 2016;315:801–10; Figure adapted from Piano S, et al. Gut 2017; doi: 10.1136/gutjnl-2017-314324.
[Epub ahead of print]; EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Other infections: recommended empirical antibiotic treatment
Cellulitis
3rd-gen
AREA DEPENDENT:
Piperacillin-tazobactam cephalosporin or
Like nosocomial
or 3rd-gen meropemen + oxacillin or
infections if high
cephalosporin + glycopeptides or
prevalence of MDROs
oxacillin daptomycin or
or if sepsis
linezolid
Pneumonia UTI
UNCOMPLICATED:
UNCOMPLICATED:
Piperacillin-tazobactam AREA DEPENDENT: Ceftazidime or AREA DEPENDENT: fosfomycin or
ciprofloxacin or
or ceftriaxone + Like nosocomial meropemen + Like nosocomial nitrofurantoin
cotrimoxazole
macrolide or infections if high levofloxacin ± infections if high IF SEPSIS:
IF SEPSIS: 3rd-gen
levofloxacin or prevalence of MDROs glycopeptides or prevalence of MDROs meropemen +
cephalosporin
moxifloxacin or if sepsis linezolid or if sepsis teicoplanin or
or piperacillin-tazobactam
vancomycin
3rd-gen
AREA DEPENDENT:
Piperacillin-tazobactam cephalosporin or
Like nosocomial
or 3rd-gen meropemen + oxacillin or
infections if high
cephalosporin + glycopeptides or
prevalence of MDROs
oxacillin daptomycin or
or if sepsis
Most clinically relevant linezolid
Pneumonia UTI
UNCOMPLICATED:
UNCOMPLICATED:
Piperacillin-tazobactam AREA DEPENDENT: Ceftazidime or AREA DEPENDENT: fosfomycin or
ciprofloxacin or
or ceftriaxone + Like nosocomial meropemen + Like nosocomial nitrofurantoin
cotrimoxazole
macrolide or infections if high levofloxacin ± infections if high IF SEPSIS:
IF SEPSIS: 3rd-gen
levofloxacin or prevalence of MDROs glycopeptides or prevalence of MDROs meropemen +
cephalosporin
moxifloxacin or if sepsis linezolid or if sepsis teicoplanin or
or piperacillin-tazobactam
vancomycin
In patients with liver diseases, even a mild increase in SCr should be considered since it may
II-2 1
underlie a marked decrease of GFR
First step is to establish CKD, AKD, AKI or overlap II-2 1
Diagnosis of CKD should be based on a GFR <60 ml/min/1.73 m2 estimated by SCr-based
II-2 1
formulas, with or without signs of renal parenchymal damage* for at least 3 months
The diagnostic process should be completed by staging CKD, which relies on GFR levels, and
by investigating its cause II-2 1
• Note that SCr-based formulae overestimate GFR in cirrhosis
Diagnosis of AKI should be based on adapted KDIGO criteria
• Either an increase in SCr of >0.3 mg/dl from baseline within 48 hours, or an increase of ≥50% II-2 1
from baseline within 3 months
Staging of AKI should be based on an adapted KDIGO system† II-2 1
In patients with liver diseases, even a mild increase in SCr should be considered since it may
II-2 1
underlie a marked decrease of GFR
First step is to establish CKD, AKD, AKI or overlap II-2 1
Diagnosis of CKD should be based on a GFR <60 ml/min/1.73 m2 estimated by SCr-based
II-2 1
formulas, with or without signs of renal parenchymal damage* for at least 3 months
The diagnostic process should be completed by staging CKD, which relies on GFR levels, and
by investigating its cause II-2 1
• Note that SCr-based formulae overestimate GFR in cirrhosis
Diagnosis of AKI should be based on adapted KDIGO criteria
• Either an increase in SCr of >0.3 mg/dl from baseline within 48 hours, or an increase of II-2 1
≥50% from baseline within 3 months
Staging of AKI should be based on an adapted KDIGO system† II-2 1
Subject Definition
• sCr obtained within 3 months prior to admission
Baseline sCr • If >1 value within the previous 3 months, the value closest to the admission
• If no previous sCr, the sCr on admission should be used
Definition of • Increase in sCr ≥0.3 mg/dl (≥26.5 µmol/L) within 48 hours or
AKI • Increase sCr ≥50% within the prior 7 days
• Stage 1: increase in sCr ≥0.3 mg/dl (≥26.5 µmol/L) or an increase in sCr ≥1.5-fold to 2-fold
from baseline
Staging
• Stage 2: increase in sCr >2-fold to 3-fold from baseline
of AKI
• Stage 3: increase of sCr >3-fold from baseline or sCr ≥4.0 mg/dl (353.6 µmol/L) with acute increase
≥0.3 mg/dl (≥26.5 µmol/L) or initiation of renal replacement therapy
Progression of Progression Regression
AKI Progression of AKI to a higher stage and/or need for RRT Regression of AKI to a lower stage
No response Partial response Full response
Response to
No regression of Regression of AKI stage with a reduction of sCr Return of sCr to a value within
treatment
AKI to ≥0.3 mg/dl (≥26.5 µmol/L) above baseline 0.3 mg/dl (≥26.5 µmol/L) of baseline
Subject Definition
• sCr obtained within 3 months prior to admission
Baseline sCr • If >1 value within the previous 3 months, the value closest to the admission
• If no previous sCr, the sCr on admission should be used
Definition of • Increase in sCr ≥0.3 mg/dl (≥26.5 µmol/L) within 48 hours or
AKI • Increase sCr ≥50% within the prior 7 days
• Stage 1: increase in sCr ≥0.3 mg/dl (≥26.5 µmol/L) or an increase in sCr ≥1.5-fold to 2-fold
Stage 1A (sCr <1.5mg/dl)*
from baseline Stage 1B (sCr ≥1.5mg/dl)*
Staging
• Stage 2: increase in sCr >2-fold to 3-fold from baseline
of AKI
• Stage 3: increase of sCr >3-fold from baseline or sCr ≥4.0 mg/dl (353.6 µmol/L) with acute increase
≥0.3 mg/dl (≥26.5 µmol/L) or initiation of renal replacement therapy
Progression of Progression Regression
AKI Progression of AKI to a higher stage and/or need for RRT Regression of AKI to a lower stage
No response Partial response Full response
Response to
No regression of Regression of AKI stage with a reduction of sCr Return of sCr to a value within
treatment
AKI to ≥0.3 mg/dl (≥26.5 µmol/L) above baseline 0.3 mg/dl (≥26.5 µmol/L) of baseline
Close follow-up
Does AKI meet
criteria of HRS?
NO YES
Further treatment of
AKI decided on a Specific treatment for Vasoconstrictors
case-by-case basics other AKI phenotypes and albumin
*Initial AKI stage is defined as AKI stage at the time of first fulfilment of the AKI criteria;
†
Treatment of spontaneous bacterial peritonitis should include albumin infusion according to current guidelines
Adapted from Angeli P, et al. J Hepatol 2015;62:968–74;
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Differentiating types of AKI
*Patients who fulfil these criteria may still have structural damage such as tubular damage
Angeli et al. J. Hepatol 2015;62:96874;
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Management of HRS-AKI: treatment
All patients meeting the current definition of HRS-AKI stage >1A should be expeditiously treated
III 1
with vasoconstrictors and albumin
Terlipressin can be administered by IV boluses (1 mg every
4–6 hours) or by continuous IV infusion (2 mg/day) †
• In case of non-response (decrease in SCr <25% from the peak value) after 2 days, the dose I 1
of terlipressin should be increased in a stepwise manner to a maximum of 12 mg/day
Albumin solution (20%) should be used at 20–40 g/day
• Serial measures assessing central blood volume can help to titrate the dose of albumin to II-2 1
prevent circulatory overload
Noradrenaline can be an alternative to terlipressin ‡ I 2
• Requires a central venous line often in an ICU I 1
Midodrine + octreotide can be an option when terlipressin or noradrenaline are unavailable I 1
(but efficacy is much lower)
• Patients receiving treatment for HRS-AKI should be monitored for AEs and treatment response
– AEs related to terlipressin or noradrenaline include ischaemic and cardiovascular events
Careful clinical screening including ECG before starting the treatment is recommended
• The decision to treat on a regular ward or transfer to higher dependency care should be case
based
I 1
Close monitoring of patients for the duration of treatment is important
• Treatment should be modified or discontinued according to the type and severity of
side effects
Response to treatment:
• CR: final SCr within 0.3 mg/dl (26.5 µmol/L) from baseline III 1
• PR: regression of AKI stage to a final SCr ≥0.3 mg/dl (26.5 µmol/L) from baseline
In case of recurrence a repeat course of therapy should be given I 1
• In most patients with HRS-AKI TIPS is contraindicated because of severe degree of liver failure
• Based on the use of albumin in patients who develop SBP and the prevention of SBP
using norfloxacin
Albumin (1.5 g/kg at diagnosis and 1 g/kg on Day 3) should be given in patients with SBP to
I 1
prevent AKI
Norfloxacin (400 mg/day) should be given as prophylaxis of SBP to prevent HRS-AKI I 1
• Even mild renal or brain dysfunction in the presence of another organ failure, is associated with
a significant short-term mortality and therefore defines the presence of ACLF
• Diagnosis of ACLF is based on organ failure in the presence of AD in patients with cirrhosis
ACLF diagnosis: cirrhosis and AD* plus organ failure(s) involving high short-term mortality II-2 1
Diagnosis and grading should be based using the CLIF-C Organ Failure score II-2 1
Potential precipitating factor(s) should be investigated†
• Hepatic: heavy alcohol intake, viral hepatitis, DILI, autoimmune hepatitis II-2 1
• Extrahepatic: infections haemodynamic derangements following haemorrhage, surgery
*Defined as the acute development or worsening of ascites, overt encephalopathy, GI haemorrhage, non-obstructive jaundice and/or bacterial infections; †Note that in a
significant proportion of patients, a precipitant factor may not be identified
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Management of ACLF
• The cause of liver injury can be treated in certain situations, e.g. HBV
• Early action is crucial to patient survival
– Treatment of precipitating factors
– Referral for LT before evolution of ACLF makes LT impossible
Diagnosis of RAI
• <248 nmol/L (9 lg/dl) change in total serum cortisol after 250 lg corticotropin injection, or II-2 1
• Random total cortisol of <276 nmol/L (<10 lg/dl)
Salivary cortisol determination can be preferred
• Serum free cortisol concentration can be influenced by reduced serum levels of CBG and II-2 2
albumin, frequently seen in patients with cirrhosis
Hydrocortisone treatment (at a dose of 50 mg/6 hours) of RAI cannot be recommended I 2
• CCM is largely subclinical but its presence influences prognosis in advanced disease
• Numerous electrocardiographic criteria, along with transmitral Doppler assessment, are used
for the evaluation and diagnosis of diastolic dysfunction
– However, there is the need for more controlled studies and correlation with clinical endpoints
Recommendation Grade of evidence Grade of recommendation
ECG in patients with cirrhosis should be performed with dynamic stress testing*
(systolic dysfunction may be masked by hyperdynamic circulation and reduced afterload)
II-1 1
• Lack of increased CO after physiological/pharmacological stress † indicates systolic
dysfunction
Myocardial strain imaging and assessment of GLS may be useful in the assessment of left
II-2 2
ventricular systolic function in patients with DC
Cardiac MRI may identify structural changes III 2
Diastolic dysfunction may occur as an early sign of CCM in the setting of normal systolic
function, and should be diagnosed using ASE criteria:
• Average E/e’>14 II-1 1
• Tricuspid velocity >2.8 m/s
• LAVI >34 ml/m2
• Cardiac evaluation in patients with cirrhosis is important since CCM can influence prognosis
In patients with AD, reduced CO (as a manifestation of CCM) is associated with the
II-1 1
development of AKI (specifically hepatorenal dysfunction) after infections such as SBP
QTc interval prolongation is common in cirrhosis and may indicate a poor outcome
II-2 2
• Agents that can prolong the QT interval should be used cautiously
Detailed functional cardiac characterization should be part of the assessment for
• TIPS insertion II-2 2
• LT II-1 1
Standardized criteria and protocols for the assessment of systolic and diastolic function in
II-2 2
cirrhosis are needed
• Four main pulmonary complications may occur in patients with chronic liver disease
– Pneumonia
– Hepatic hydrotorax
– HPS
– Portopulmonary hypertension
• HPS is defined as a disorder in pulmonary oxygenation, caused by intrapulmonary
vasodilatation and, less commonly, by pleural and pulmonary arteriovenous communications
occurring in the clinical setting of portal hypertension
• Clinical manifestations of HPS in patients with chronic liver disease primarily involve dyspnoea
and platypnoea
• Portosystemic shunt
• Hepatic injury/failure
• Hyperdynamic circulation
• Portal hypertension
• Bacterial translocation
ANGIOGENESIS Increased NO
and CO release
• Hypoxia with partial pressure of oxygen <80 mmHg or alveolar–arterial oxygen gradient
≥15 mmHg in ambient air (≥20 mmHg in patients older than 65 years)
• Pulmonary vascular defect with positive findings on contrast-enhanced echocardiography or
abnormal uptake in the brain (>6%) with radioactive lung-perfusion scanning
• Commonly in presence of portal hypertension, and in particular:
– Hepatic portal hypertension with underlying cirrhosis
– Pre-hepatic or hepatic portal hypertension in patients without underlying cirrhosis
• Less commonly in presence of:
– Acute liver failure, chronic hepatitis
• In patients with portal hypertension and the clinical suspicion of HPS partial pressure of oxygen
(PaO2) in ABG should be assessed
In patients with chronic liver disease, HPS should be suspected and investigated in presence of
II-2 1
tachypnoea and polypnoea, digital clubbing and/or cyanosis
Screening in adults:
• If pulse oximetry SpO2 <96% – ABG analysis should be performed
II-2 1
• If ABG PaO2 <80mmHg and/or P[A-a]O2 ≥15 mmHg* (in ambient air) – further
investigations should be performed
The use of contrast (microbubble) echocardiography to characterize HPS is recommended II-2 1
*For adults ≥65 years a P[A-a]O2 ≥20 mmHg cut-off should be used
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024
Diagnosis of HPS
• When PaO2 suggests HPS, further investigations are needed to determine the
underlying mechanism
Recommendation Grade of evidence Grade of recommendation
MAA scan should be performed to quantify the degree of shunting in patients with severe
hypoxaemia and coexistent intrinsic lung disease, or to assess the prognosis in patients with II-2 1
HPS and very severe hypoxaemia (PaO2 <50 mmHg)
Neither contrast echocardiography nor MAA scan can definitively differentiate discrete
arteriovenous communications from diffuse precapillary and capillary dilatations or cardiac
shunts
• Pulmonary angiography should be performed only in patients with the severe hypoxaemia II-2 1
(PaO2 <60 mmHg), poorly responsive to administration of 100% oxygen, and in whom there
is a strong suspicion of arteriovenous communications that are amenable to embolization
Trans-oesophageal contrast-enhanced echocardiography (although associated with risks) can
II-2 2
definitively exclude intra-cardiac shunts
• There is no established medical therapy currently available for HPS, the only successful
treatment for HPS is LT
Recommendations for medical treatment Grade of evidence Grade of recommendation
Long-term oxygen therapy is recommended in patients with HPS and severe hypoxaemia
despite the lack of available data concerning effectiveness, tolerance, cost effectiveness, II-2 1
compliance and effects on survival rates of this therapy
No recommendation can be proposed regarding the use of drugs or the placement of
I 1
TIPS for the treatment of HPS
Recommendations for liver transplantation
Patients with HPS and PaO2 <60 mmHg should be evaluated for LT since it is the only
II-2 1
treatment for HPS that has been proven to be effective to date
Severe hypoxaemia (PaO2 <45–50 mmHg) is associated with increased post-LT mortality
II-2 1
• ABG analysis should be carried out every 6 months to facilitate prioritization to LT
• PPHT occurs in patients with portal hypertension in the absence of other causes of arterial or
venous hypertension
• Classification is based on mean pulmonary arterial pressure (mPAP), and assumes high
pulmonary vascular resistance (PVR) and normal pulmonary occlusion pressures
– Mild: mPAP ≥25 and <35 mmHg
– Moderate: mPAP ≥35 and <45 mmHg
– Severe: mPAP ≥45 mmHg
• Incidence between 3–10% cirrhosis patients based on haemodynamic criteria; women are at 3x
greater risk and it is more common in autoimmune liver disease
• There is no clear association between the severity of liver disease or portal hypertension and
the development of severe PPHT
Screening for PPHT should be via TDE in patients deemed potential recipients for TIPS
or LT II-1 1
• In those with a positive screening test, right heart catheterization should be performed
In patients with PPHT who are listed for LT, echocardiography should be repeated on the
III 1
waitlist (the specific interval is unclear)
β-blockers should be stopped and varices managed by endoscopic therapy in cases of
II-3 1
proven PPHT
Therapies approved for primary pulmonary arterial hypertension may improve exercise
tolerance and haemodynamics in PPHT
II-2 1
• However, endothelin antagonists should be used with caution because of concerns over
hepatic impairment
TIPS should not be used in patients with PPHT II-3 1
• Although severe PPHT has, historically, been a contraindication for LT, the advent of improved
haemodynamic control (with agents such as IV prostacyclin) allows LT to be considered
If mPAP <35 mmHg and right ventricular function is preserved, LT should be considered II-2 1
• mPAP of ≥45 mmHg should be considered an absolute contraindication to LT irrespective of III 1
therapy applied
Therapy to lower mPAP and improve right ventricular function should be commenced in
patients with mPAP ≥35 mmHg II-2 1
• Right ventricular function should be periodically evaluated
MELD exception can be considered in patients with proven PPHT in whom targeted therapy
fails to decrease mPAP <35 mmHg but does facilitate normalization of PVR to <240 dyn.s/cm -5 II-3 2
and right ventricular function
MELD exception should be advocated in patients with proven PPHT of moderate severity
(mPAP ≥35 mmHg) in whom targeted treatment lowers mPAP <35 mmHg and PVR <400 II-2 1
dyn.s/cm-5
NSBB and iron supplementation and/or blood transfusion, when indicated, are
I 1
recommended as first-line therapy for chronic haemorrhage from PHG
In patients with transfusion-dependent PHG in whom NSBBs fail or are not tolerated, covered
II-3 2
TIPS placement may be used in the absence of contraindications
Acute PHG bleeding may be treated with somatostatin analogues or terlipressin but
I 2
substantiating data are limited
• The Sarin classification is most commonly used for risk stratification and management of
gastric varices
Relative Overall bleeding risk
Type Definition frequency without treatment
Gastro-oesophageal varices (GOV)
GOV type 1 OV extending below cardia into lesser curvature 70% 28%
GOV type 2 OV extending below cardia into fundus 21% 55%
Isolated gastric varices (IGV)
IGV type 1 Isolated varices in the fundus 7% 78%
IGV type 2 Isolated varices else in the stomach 2% 9%
NSBBs are suggested for primary prevention of VH from GOV type 2 or IGV type 1 III 2
Primary prevention for GOV type 1 follows the recommendations of oesophageal varices III 2
Acute gastric VH should be treated medically, like oesophageal VH I 1
• Cyanoacrylate is the recommended endoscopic haemostatic treatment for cardiofundal I 2
varices (GOV type 2 or IGV type 1)
TIPS with potential embolization efficiently controls bleeding and prevents re-bleeding in
II-2 1
fundal VH (GOV type 2 or IGV type 1) and should be considered in appropriate candidates
Selective embolization (BRTO/BATO) may also be used to treat bleeding from fundal varices
III 2
associated with large gastro/splenorenal collaterals, although more data is required
• Both neutrophil count and culture results should be taken into account
Patients with bacterascites (neutrophil count <250/mm3 but positive bacterial culture) II-2 1
exhibiting signs of systemic inflammation or infection should be treated with antibiotics
• Otherwise, the patient should undergo a second paracentesis
• If the culture results come back positive again, regardless of the neutrophil count, the III 1
patient should be treated
Spontaneous bacterial pleural empyema diagnosed by:
• Positive pleural fluid culture and neutrophil count >250/mm 3 or II-2 1
• Negative pleural fluid culture and neutrophil count >500/mm 3 in the absence of pneumonia
Secondary bacterial peritonitis should be suspected in case of multiple organisms on ascitic
culture, very high ascitic neutrophil count and/or high ascitic protein concentration, or in those
patients with an inadequate response to therapy III 1
• Patients with suspected secondary bacterial peritonitis should undergo prompt CT scanning
and early considerations for surgery
SBP or SBE
Vasoconstrictors and albumin are not recommended the treatment of HRS outside the criteria
of AKI (HRS-NAKI)*
I 1
• Terlipressin plus albumin is effective in the treatment of HRS-NAKI, but recurrence after
withdrawal of treatment is the norm, and controversial data exist on the impact of the
treatment on long-term clinical outcome, particularly from the perspective of LT
*Bold text indicates the diagnostic criteria for organ failures; †μg/kg/min
1. Jalan R, et al. J Hepatol 2015;62:831–40;
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024