Decompensated Cirrhosis: Clinical Practice Guidelines

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
These slides are intended for use as an educational resource and

should not be used in isolation to make patient management
decisions. All information included should be verified before treating
patients or using any therapies described in these materials
• Please send any feedback to: slidedeck_feedback@easloffice.eu

Guideline panel
• 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
EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Outline
Methods • Grading evidence and recommendations
• Definition and pathophysiology of

Background decompensated cirrhosis
Guidelines • Key recommendations

Methods
Grading evidence and recommendations
Grading evidence and recommendations
• Grading is adapted from the GRADE system1
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
1. Guyatt GH, et al. BMJ. 2008:336:924–6;

Background
Definition and pathophysiology of decompensated cirrhosis
Multi-stage model for the clinical course of cirrhosis
• Transition from compensated cirrhosis to DC occurs at a rate of ~5–7% per year

• DC is a systemic disease, with multi-organ/system dysfunction
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
D’Amico G, et al. J Hepatol 2018;68:56376;

Multi-stage model for the clinical course of cirrhosis
• Transition from compensated cirrhosis to DC occurs at a rate of ~5–7% per year

• DC is a systemic disease, with multi-organ/system dysfunction
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
D’Amico G, et al. J Hepatol 2018;68:56376;

Pathophysiology of DC
Cirrhosis
Portal hypertension Liver injury

Bacterial translocation/PAMPs Damaged cells/DAMPs
Other Activation of innate pattern recognition receptors
potential
mechanisms Release of pro-inflammatory molecules (ROS/RNS)
Splanchnic arteriolar vasodilation and

cardiovascular dysfunction
++
Adrenal Kidney
HE HPS
dysfunction dysfunction
Bernardi M, et al. J. Hepatol 2015;63:1272–84;

Management strategies for DC
• Management of DC aims to improve outcomes of complications
Uncomplicated Ascites Hepatic Renal impairment

hydrothorax
Refractory AKI CKD
Hyponatremia Complications of DC Bacterial infections
ACLF RAI GI bleeding Cardiopulmonary
CCM HPS PPHT
Increased understanding of DC pathophysiology permits the development

of more comprehensive therapeutic and prophylactic approaches
to prevent or delay disease progression

Key recommendations
Topics
1. Overall management of DC Click on a topic to skip

to that section
– Suppression of aetiological factor(s)
– Treatment of key pathogenic factors
2. Management of specific complications of DC
– Ascites
– Refractory ascites
– Hepatic hydrothorax
– Hyponatremia
– Gastrointestinal bleeding
– Bacterial infections
– Renal impairment
– Acute-on-chronic liver failure
– Relative adrenal insufficiency
– Cardiopulmonary complications

Overall management of DC
• Management should aim to prevent progression, not treat complications

• No treatment exists that can act on cirrhosis progression directly
• Two alternative approaches can be taken:
– Suppress aetiological factor(s) that cause liver inflammation and cirrhosis development
– Target key factors in the pathogenesis of cirrhosis decompensation and progression

Suppression of aetiological factor(s)
• Impact is variable
• Probably depends on the status of liver disease at the time
Recommendation Grade of evidence Grade of recommendation
In patients with DC the aetiological factor should be removed, particularly alcohol

consumption and hepatitis B or C virus infection, as this strategy is associated with II-2 1
decreased risk of decompensation and increased survival

Treatment of key pathogenic factors
• 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)
Further clinical research is needed to confirm the safety and

potential benefits of these therapeutic approaches to
prevent cirrhosis progression in patients with DC

Ascites
• Most common complication of decompensation in cirrhosis

– Develops in 5–10% of patients with compensated cirrhosis per year
• Significant impact on patients
– Impairs patient working and social life
– Frequently leads to hospitalization
– Requires chronic treatment
– Direct cause of further complications
– Poor prognosis (5-year survival, ~30%)
• Ascites can be uncomplicated or refractory
– Ascites is uncomplicated when not infected, refractory or associated with impairment of renal function

Uncomplicated ascites: evaluation and diagnosis
• Cirrhosis is responsible for 80% of cases of ascites

• Initial patient evaluation:
– History
– Physical examination
– Abdominal ultrasound
– Laboratory assessment
• Liver and renal function, serum and urine electrolytes, analysis of ascitic fluid
• Ascites is graded based on amount of fluid in the abdominal cavity
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
Uncomplicated ascites: evaluation and diagnosis
• Diagnostic paracentesis is indicated in:*

– All patients with new-onset grade 2 or 3 ascites
– Patients hospitalized for worsening ascites or any complication of cirrhosis
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%
Uncomplicated ascites: prognosis
• Development of ascites in patients with cirrhosis is associated with a poor prognosis

– 1-year mortality: 40%
– 2-year mortality: 50%
• Patients with ascites should be considered for referral for LT
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 may not receive adequate priority in transplant lists

– Most commonly used prognostic scores can underestimate mortality risk
• Improved methods to assess prognosis in these patients are needed

Uncomplicated ascites: management
• Grade 1 or mild ascites

– No data on evolution and not known if treatment modifies natural history
• Grade 2 or moderate ascites
– Hospitalization not required
– Correct sodium imbalance:
• Dietary restriction and increased renal excretion with diuretics
Moderate restriction of sodium intake (80–120 mmol/day, corresponding to 4.6–6.9 g of salt)

I 1
is recommended
Generally equivalent to a no added salt diet with avoidance of pre-prepared meals. Adequate
II-2 1
nutritional education of patients on how to manage dietary sodium is also recommended
Very low sodium diets (<40 mmol/day) should be avoided II-2 1
Prolonged bed rest cannot be recommended III 1

Uncomplicated ascites: recommended diuretics
• Mainstay of medical treatment are anti-mineralocorticoid drugs*

• Loop diuretics may be added in patients with long-standing ascites
First episode of grade 2 ascites

• Anti-mineralocorticoid drug alone (from 100 mg/day with 100 mg stepwise increased every I 1
72 hours to a maximum of 400 mg/day if no response to lower doses)
In patients who do not respond to anti-mineralocorticoids † or who develop hyperkalaemia,
furosemide should be added (from 40 mg/day with 40 mg stepwise increases to a maximum of I 1
160 mg/day)
Long-standing or recurrent ascites
• Combination of an anti-mineralocorticoid drug and furosemide (dose increased sequentially I 1
according to response)
Torasemide can be given in patients exhibiting a weak response to furosemide I 2
*Spironolactone, canrenone or K-canrenoate; †Body weight reduction <2 kg/week

Uncomplicated ascites: considerations prior to initiating diuretics
• Patients with cirrhosis and ascites are highly susceptible to rapid reductions in extracellular
fluid volume
– Can lead to renal failure and hepatic encephalopathy
GI haemorrhage, renal impairment, hepatic encephalopathy, hyponatraemia, or alterations in

serum potassium concentration, should be corrected before starting diuretic therapy
III 1
• In these patients, cautious initiation of diuretic therapy and frequent clinical and biochemical
assessments should be performed
Diuretic therapy is generally not recommended in patients with persistent overt hepatic
III 1
encephalopathy

Uncomplicated ascites: monitoring of patients receiving diuretics
• 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
Uncomplicated ascites: management of Grade 3 ascites
• Grade 3 or large ascites

– LVP, under strict sterile conditions, is the treatment of choice
• Ascites should be completely removed in a single session*
– Contraindications to LVP include:
• Uncooperative patient, abdominal skin infection at puncture sites, pregnancy, severe coagulopathy, severe
bowel distention
LVP should be followed with plasma volume expansion I 1

Plasma volume expansion should be performed by albumin infusion (8 g/L ascites)
• For >5 L of ascites: more effective than other plasma expanders I 1
• For <5 L of ascites (low risk of PPCD): treat with albumin due to concerns about use of III 1
alternative plasma expanders
After LVP, patients should receive the minimum dose of diuretics necessary to prevent
I 1
re-accumulation of ascites
When needed, LVP should be performed in patients with AKI or SBP III 1
*Grade of evidence I, grade of recommendation 1

Uncomplicated ascites: contraindicated drugs
• 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: definition
• International Ascites Club:

– “Ascites that cannot be mobilized or the early recurrence of which (after LVP) cannot be
satisfactorily prevented by medical therapy”
Refractory ascites
Diuretic resistant Diuretic intractable
Ascites that cannot be mobilized Ascites that cannot be mobilized

or the early recurrence of which or the early recurrence of which
cannot be prevented because of a cannot be prevented because of the
lack of response to sodium development of diuretic-induced
restriction and diuretic treatment complications that preclude the
use of an effective diuretic dosage

Refractory ascites: diagnostic criteria
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
*Spironolactone 400 mg/day and furosemide 160 mg/day

Refractory ascites: diagnosis
• Refractory ascites is associated with a poor prognosis

– Median survival around 6 months
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

Refractory ascites: management
• LVP is a safe and effective treatment

– Should be associated with albumin administration to prevent PPCD
• Drug treatments are controversial or inadequately studied
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
*See also section on gastrointestinal bleeding

Refractory ascites: indications for TIPS
• TIPS decompresses the portal system*

– Short term: accentuates peripheral arterial vasodilation
– Within 4–6 weeks: improves effective volaemia and renal function to increase renal sodium excretion
Patients should be evaluated for TIPS insertion when:

• There is refractory or recurrent ascites I 1
• Paracentesis is ineffective III 1
TIPS insertion is recommended in patients:
• With recurrent ascites as it improves survival I 1
• With refractory ascites as it improves the control of ascites I 1
The use of small-diameter PTFE-covered stents is recommended to reduce the risk of TIPS
I 1
dysfunction and hepatic encephalopathy
After TIPS insertion, continue the following until ascites resolution:
• Diuretics and salt restriction II-2 1
• Close clinical follow-up III 1
*By shunting an intrahepatic portal branch into a hepatic vein

Hepatic hydrothorax: definition and diagnosis
• 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: 812 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*
*Grade of evidence III, grade of recommendation 1

Hepatic hydrothorax: treatment
• First-line management relies on treatment of ascites with diuretics and/or LVP

– Not rare for pleural effusion to persist (refractory hepatic hydrothorax)
• Therapeutic thoracentesis is required to relieve dyspnoea
Patients with hydrothorax should be evaluated for LT III 1

Diuretics and thoracentesis are recommended as the first-line management of hepatic
III 1
hydrothorax
Therapeutic thoracentesis is indicated in patients with dyspnoea III 1
• Chronic pleural drainage should not be performed because of the frequent occurrence II-2 1
of complications

Hepatic hydrothorax: beyond diuretics and thoracentesis
• Other treatments are appropriate in selected patients
In selected patients, TIPS insertion for recurrent symptomatic hepatic hydrothorax is

II-2 1
recommended
Pleurodesis can be suggested to patients with refractory hepatic hydrothorax not amenable to LT
or TIPS insertion I 2
• The frequent occurrence of side effects restricts its use to selected patients
Mesh repair of diaphragmatic defects is suggested for the management of hepatic hydrothorax
in very selected patients
II-2 2
• The best results are achieved in patients with non-advanced cirrhosis without renal
dysfunction

Hyponatraemia
• Common in patients with advanced cirrhosis

– Arbitrarily defined as serum sodium concentration <130 mmol/L
• Hypo- and hypervolaemic hyponatraemia can occur
• Associated with:
– Increased mortality and morbidity, particularly neurological complications
– Reduced survival after LT
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)
Variceal haemorrhage: pathophysiology and natural history
• Occurs when variceal wall ruptures due to excessive wall tension

– Portal pressure is a key factor in both rupture and severity of bleeding
• 70% of GI bleeding events result from VH in patients with portal hypertension
– Second most common decompensating event
– Most severe and immediate life threatening complication
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

Variceal haemorrhage: prevention and treatment
• High risk of death when VH occurs in patients with DC

– Strategies to adequately treat VH and prevent (re)bleeding and death should be actively pursued
Primary prophylaxis must be initiated upon detection of high-risk varices* because of

I 1
increased risk of VH
Patients with small varices with red wale marks or Child–Pugh C should be treated
III 1
with NSBBs
Patients with medium–large varices should be treated with either NSBBs or EBL I 1
• Choice of treatment can be based on local resources and expertise, patient preference, III 2
contraindications and AEs
• NSBBs could be preferred because in addition to lowering portal pressure, they also exert II-2 2
other potential beneficial effects
*High-risk = small varices with red signs, medium or large varices irrespective of Child–Pugh classification or small varices in Child–Pugh C patients
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
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
*Such as bleeding, sepsis, SBP or AKI

Variceal haemorrhage: prevention of variceal rebleeding
• NSBBs and EBL in combination reduces the risk of re-bleeding compared with monotherapy
Combination therapy of NSBBs + EBL is recommended I 1

Covered TIPS placement is recommended in patients who continue to be intolerant
III 1
to NSBBs*
*Provided that there are no absolute contraindications

Variceal haemorrhage: management of acute GI bleeding
• Medical emergency: high rate of complications and mortality in DC

– Requires immediate treatment and close monitoring
Acute GI bleed + portal hypertension Airway
Balloon tamponade or oesophageal stenting
Breathing
Initial assessment* and resuscitation Circulation
• Volume replacement with colloids
and/or crystalloids should be initiated
Immediate start of vasoactive drug therapy †
promptly (III;1)
Antibiotic prophylaxis (I;1)‡
(if massive bleeding)
Starch should not be used (I;1)

• Restrictive transfusion is recommended
ENDOSCOPY
ENDOSCOPY
in most patients (Hb threshold, 7 g/dl;

Early diagnostic endoscopy (<12 hours) target range 7–9 g/dl) (I;1)
Confirm variceal bleeding

Endoscopic band ligation
+
Maintain drug therapy for 3–5 days and antibiotics ‡
Control Further bleeding

(~85% of cases) (~15% of cases)
Consider early TIPS in high risk patients Rescue with TIPS
*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;63:74352;
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

Management of persistent bleeding
• Up to 10–15% of patients have persistent bleeding or early re-bleeding

– Despite treatment with vasoactive drugs and EBL, and prophylactic antibiotics
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

Bacterial infections
• Risk of bacterial infection in patients with cirrhosis is caused by multiple factors

– Liver dysfunction
– Portosystemic shunting
– Gut dysbiosis
– Increased BT
– Cirrhosis-associated immune dysfunction
– Genetic factors
• Spontaneous bacterial peritonitis

– Definition: bacterial infection of ascitic fluid without any intra-abdominal surgically treatable source
of infection
– Prevalence: all patients with cirrhosis and ascites are at risk
• 1.5–3.5% in outpatients; 10% in hospitalized patients
– Prognosis: mortality exceeded 90% when first described
• Reduced to ~20% with early diagnosis and treatment

Spontaneous bacterial peritonitis: diagnosis
• Diagnosis is based on diagnostic paracentesis

• 50% of SBP episodes are present at hospital admission
– Signs/symptoms of peritonitis: abdominal pain, tenderness, vomiting or diarrhoea, ileus
– Signs of systemic inflammation: hyper- or hypothermia, chills, altered WBC count
– Worsening liver function, HE, shock, renal impairment, GI bleeding
However: SPB may be asymptomatic,

particularly in outpatients

Spontaneous bacterial peritonitis: diagnosis
• Diagnosis is based on diagnostic paracentesis

• 50% of SBP episodes are present at hospital admission
– Signs/symptoms of peritonitis: abdominal pain, tenderness, vomiting or diarrhoea, ileus
– Signs of systemic inflammation: hyper- or hypothermia, chills, altered WBC count
– Worsening liver function, HE, shock, renal failure, GI bleeding
Diagnostic paracentesis should be carried out in:

• Patients with cirrhosis and ascites, at admission, to rule out SBP
II-2 1
• Patients with GI bleeding, shock, fever or other signs of systemic inflammation, worsening
liver and/or renal function, and HE
SBP diagnosed by a neutrophil count in ascitic fluid >250/mm 3
• Neutrophil count is determined by microscopy or flow cytometry II-2 1
• No clear evidence to support routine use of reagent strips
Ascitic fluid culture positivity is not a prerequisite for SBP diagnosis* II-2 1
*Culture should be performed to guide antibiotic therapy (Grade of evidence II-2, grade of recommendation 1)
Management of SBP: empirical antibiotics
• Empirical IV antibiotics should be started immediately following diagnosis*

• Several factors should guide empirical antibiotic use†
– Environment (community acquired vs. nosocomial)
– Local bacterial resistance profiles
– Severity of infection
Third-generation cephalosporins are recommended as first-line antibiotic treatment for I 1

community-acquired SBP in countries with low rates of antibiotic resistance
• In countries with high rates of antibiotic resistance piperacillin/tazobactam or carbapenem II-2 1
should be considered
Antibiotic resistance is more likely in healthcare-associated and nosocomial SBP
• Piperacillin/tazobactam: in areas with low prevalence of MDR bacteria
• Carbapenem: in areas with high prevalence of ESBL-producing Enterobacteriaceae I 1
• Carbapenem + glycopeptides, daptomycin linezolid in areas with high prevalence of
gram-positive MDR bacteria
*Grade of evidence II-2, grade of recommendation 1; †Grade of evidence I, grade of recommendation 1

Management of SBP: empirical antibiotics
• Antibiotic therapy should be carefully controlled and monitored
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

Management of SBP: use of albumin
• 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
The administration of albumin is recommended in patients with SBP

• 1.5 g/kg at diagnosis and I 1
• 1 g/kg on Day 3
1. Sort P, et al. N Engl J Med 1999;341:403–9;

Management of SBP: primary prophylaxis
• 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
Primary prophylaxsis with norfloxacin (400 mg/day) is recommended in patients with:

• Child–Pugh score ≥9 and serum bilirubin level ≥3 mg/dl, and
I 1
• Either impaired renal function or hyponatraemia, and
• Ascitic fluid protein lower than 15 g/L
Norfloxacin prophylaxis should be stopped in patients with long-lasting improvement of their
III 1
clinical condition and disappearance of ascites
1. Wiest R, et al. Gut 2012;61:297–310;

Management of SBP: secondary prophylaxis
• 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
1. Rimola A, et al. J Hepatol 2000;32:142–53;

Management of other infections
• Non-SBP infections are frequent in patients with cirrhosis

– Associated with increased mortality
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
Assessing severity of infection
• qSOFA and Sepsis-3 criteria have been validated in patients with cirrhosis1
– Can be used to assess severity of infection
Is baseline SOFA score available?

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

Positive Negative
qSOFA negative qSOFA positive
Sepsis-3 positive
Poor outcome
Good outcome 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
Community-acquired Healthcare-associated Nosocomial
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
Community-acquired Healthcare-associated Nosocomial Community-acquired Healthcare-associated Nosocomial
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
Adapted from Jalan R, et al. J Hepatol 2013;60:1310–24;

Other infections: recommended empirical antibiotic treatment
Cellulitis
Community-acquired Healthcare-associated Nosocomial
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
Community-acquired Healthcare-associated Nosocomial Community-acquired Healthcare-associated Nosocomial
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

Renal impairment: definitions
• Definitions of renal impairment and staging of AKI have been updated
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
*Proteinuria/haeamaturia/ultrasonography abnormalities. †Stage 1A (sCr <1.5mg/dl), Stage 1B (sCr ≥1.5mg/dl)

Renal impairment: definitions
• Definitions of renal impairment and staging of AKI have been updated
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
*Proteinuria/haeamaturia/ultrasonography abnormalities. †Stage 1A (sCr <1.5mg/dl), Stage 1B (sCr ≥1.5mg/dl)

Renal impairment: definitions of kidney disease
• KDIGO group definitions
Definition Functional criteria Structural criteria

Increase in sCr ≥50% within 7 days,
AKI OR No criteria
increase in sCr ≥0.3 mg/dl within 2 days
GFR <60 ml/min per 1.73m2 for <3 months,
OR
AKD decrease in GFR ≥35% for <3 months, Kidney damage for <3 months
OR
increase in sCr ≥50 % for <3 months
CKD GFR <60 ml/min per 1.73 m2 for ≥3 months Kidney damage for ≥3 months

Renal impairment: definitions of kidney disease
• KDIGO group definitions
Definition Functional criteria Structural criteria

Increase in sCr ≥50% within 7 days,
AKI OR Increase in sCr ≥50% within 3 months* No criteria
increase in sCr ≥0.3 mg/dl within 2 days
GFR <60 ml/min per 1.73m2 for <3 months,
OR
AKD decrease in GFR ≥35% for <3 months, Kidney damage for <3 months
OR
increase in sCr ≥50 % for <3 months
CKD GFR <60 ml/min per 1.73 m2 for ≥3 months Kidney damage for ≥3 months
*International Club of Ascites-recommended adaptation of KDIGO group criteria

AKI in patients with cirrhosis: ICA definitions
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
Angeli P, et al. J. Hepatol 2015;62:96874;

AKI in patients with cirrhosis: ICA definitions
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
*ICA recommended adaptations of KDIGO group criteria

Angeli P, et al. J. Hepatol 2015;62:96874;
ICA management algorithm for AKI in cirrhosis
• Investigation and management should begin immediately

Initial AKI* stage 1A Initial AKI* stage >1A
Close monitoring Withdrawal of diuretics (if not yet

Remove risk factors (withdrawal of nephrotoxic applied) and volume expansion with
drugs, vasodilators and NSAIDs, taper/withdraw albumin (1 g/kg) for 2 days
diuretics and β-blockers, expand plasma volume,
treat infections† when diagnosed) Response
Resolution Persistance Progression YES NO
Close follow-up
Does AKI meet
criteria of HRS?
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;
Differentiating types of AKI
• All types of AKI can occur in patients with cirrhosis

– Pre-renal, HRS, intrinsic, particularly ATN, and post-renal
• Key point is to differentiate HRS-AKI from ATN
• Classification of HRS was recently revised by the ICA1
– Type 1 HRS now corresponds to HRS-AKI
– Type 2 HRS includes renal impairment that fulfills the criteria of HRS but not of AKI (non-AKI-HRS or NAKI)
It is important to differentiate among types of AKI in patients with cirrhosis II-2 1

The diagnosis of HRS-AKI is based on revised ICA criteria (see next slide)
• As kidney biopsy is rarely performed in the setting of AKI, biomarkers should be implemented
II-2 2
• In clinical practice among the different biomarkers to date, urinary NGAL can be used to
distinguish between ATN and HRS
1. Angeli et al. J. Hepatol 2015;62:968–74;

ICA diagnostic criteria for HRS-AKI
• Cirrhosis and ascites

• Diagnosis of AKI according to ICA-AKI criteria
• No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin
1 g per kg of body weight
• Absence of shock
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media, etc.)
• No macroscopic signs of structural kidney injury,* defined as:
– Absence of proteinuria (>500 mg/day)
– Absence of microhaematuria (>50 RBCs per high power field)
– Normal findings on renal ultrasonography
*Patients who fulfil these criteria may still have structural damage such as tubular damage
Angeli et al. J. Hepatol 2015;62:96874;
Management of HRS-AKI: treatment
• First-line therapy is terlipressin plus albumin*
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)
*Grade of evidence I, grade of recommendation 1;

†
Continuous IV infusion allows for dose reduction to reduced adverse effects; ‡ Limited data are available
Management of HRS-AKI: screening and monitoring
• 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
*Continuous IV infusion allows for dose reduction to reduced adverse effects

Management of HRS: TIPS and LT
• In most patients with HRS-AKI TIPS is contraindicated because of severe degree of liver failure
There is insufficient data to advocate TIPS in HRS-AKI

II-2 2
• It could be suggested in selected patients with HRS-NAKI
LT is the best therapeutic option for patients with HRS regardless of the response to
I 1
drug therapy
The decision to initiate RRT should be based on the individual severity of illness I 2
The indication for liver-kidney transplantation remains controversial
• Should be considered in patients with significant CKD or sustained AKI including HRS-AKI II-2 1
with no response to drug therapy

Prevention of HRS
• 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

Acute-on-chronic liver failure
• Frequent occurrence in cirrhotic patients

– 30% of admitted patients and 25% of outpatients
• Major cause of death in patients with cirrhosis (50% mortality rate)
• Develops on a background of acute decompensation
• Characterized by hepatic and extrahepatic organ failure, highly activated systemic inflammation
and a high 28-day mortality
• Precipitating events vary between populations and may include:
– Bacterial infections (3057% of cases)
– Active alcohol intake or alcohol binge
– Reactivation of HBV
– Superimposed HAV and HEV infection

EASL-CLIF prognostic and diagnostic scores for ACLF
CLIF-C ACLF score for mortality prediction1*

10 x [0.033 x Clif OFs + 0.04 x Age + 0.63 x Ln(WBC) – 2]
Chronic liver failure – organ failure score system 1

Organ/system† 1 point 2 points 3 points
Liver (bilirubin, mg/dl) <6 ≥6–<12 ≥12.0
Kidney (creatinine, mg/dl) <2.0 ≥2.0–<3.5 ≥3.5 or renal replacement
Brain/HE (West Haven Criteria) Grade 0 Grades 1–2 Grades 3–4‡
Coagulation (INR, PLT count) <2.0 ≥2.0–<2.5 ≥2.5
Circulation (MAP, mmHg and
≥70 <70 Use of vasopressors
vasopressors)
Lungs PaO2/FiO2, or >300 ≤300–>200 ≤200§
SpO2/FiO2 >357 >214–≤357 ≤214§
*Age in years, creatinine in mg/dL, WBC in 106 cells/L, sodium in mmol/L;

†
Bold text indicates the diagnostic criteria for organ failures; ‡Patients submitted to mechanical ventilation due to HE and not to a respiratory failure were considered as presenting
a cerebral failure (cerebral score = 3); §Other patients enrolled in the study with mechanical ventilation were considered as presenting a respiratory failure (respiratory score = 3)
1. Jalan R, et al. J Hepatol 2014;61:1038–47;
Classification and grades of ACLF
• 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
Grades of ACLF Clinical characteristics

NO ACLF No organ failure, or single non-kidney organ failure, creatinine <1.5 mg/dl, no HE
ACLF 1a Single renal failure
ACLF 1b Single non-kidney organ failure, creatinine 1.5–1.9 mg/dl and/or HE grade 1–2
ACLF II Two organ failures
ACLF III Three or more organ failures
Moreau R, et al. Gastroenterology 2013;144:1426–37;

Diagnosis 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
Management of ACLF
• There is no specific therapy for ACLF

• Treatment is based on organ support and management of complications
Treatment of ACLF should be based on organ support, management of precipitants and

III 1
associated complications
Patients should be treated in intermediate care or intensive care settings III 1
ACLF is a dynamic condition and organ function should be monitored frequently and
carefully throughout hospitalization
• Particularly, liver, kidney, brain, lung, coagulation, and circulation III 1
• Monitoring and management should be individualized, mainly according to patients’ age
and comorbidities

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
Early identification and treatment of precipitating factors of ACLF, particularly bacterial

infections, is recommended. III 1
However, in some patients ACLF progresses despite treatment of precipitating factors
Nucleoside analogues (tenofovir, entecavir) should be instituted as early as possible in
I 1
patients with HBV-related ACLF
Early referral of patients with ACLF to LT centres for immediate evaluation is recommended II-3 1
Withdrawal of intensive care support after 1 week can be suggested in patients who are not LT
II-2 2
candidates and have ≥4 organ failures
Administration of G-CSF cannot be recommended at present I 2

Relative adrenal insufficiency
• Inadequate cortisol response to stress in the setting of critical illness*

– Pathophysiology in cirrhosis is not well defined
• Diagnosis is influenced by the method used to measure cortisol
• It is not known whether cortisol supplementation in clinically stable cirrhosis with RAI is of any value
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
*Also known as critical illness-related corticosteroid insufficiency (CIRCI)

Cirrhotic cardiomyopathy
• CCM occurs in patients with established cirrhosis characterized by:

– Blunted contractile response to stress (pharmacological/surgery or inflammatory)
– Altered diastolic left ventricular relaxation or/and increased left atrial volume
– Electrophysiological abnormalities e.g. prolonged QTc
– Cardiac output tending to decrease with decompensation
– Systolic dysfunction: LVEF <55%
• 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
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
*Either pharmacologically, or through exercise; †And in the absence of influence of β-blockade

• 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

Hepatopulmonary syndrome
• 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

Pathogenesis of HPS
• Portosystemic shunt
• Hepatic injury/failure
• Hyperdynamic circulation
• Portal hypertension
• Bacterial translocation
Increased ET-1 release Systemic inflammation

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

proliferation expression and activity
ANGIOGENESIS Increased NO
and CO release
VASODILATION HEPATOPULMONARY VASODILATION

SYNDROME

Diagnostic criteria for HPS
• 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

Diagnosis of HPS
• 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
Diagnosis of HPS
• When PaO2 suggests HPS, further investigations are needed to determine the
underlying mechanism
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

Management of HPS
• 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

Portopulmonary hypertension
• 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

Monitoring and medical management of PPHT
• The evidence base for pharmacological therapies in PPHT is limited
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

Liver transplantation in PPHT
• 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

Additional recommendations
Portal hypertension gastropathy
• Often presents in patients with DC

– Natural history significantly influenced by the severity of liver disease and portal hypertension
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

Gastric varices: classification, prevalence and risk
• 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%

Management of gastric varices
• Gastric varices are present in about 20% of patients with cirrhosis
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

Diagnosis of SBP
• 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

Empirical antibiotic treatment of SBP or SBE
SBP or SBE
Community-acquired SBP Healthcare-associated Nosocomial

or SBE SBP or SBE SBP or SBE
3rd-gen AREA DEPENDENT: Carbapenem alone

cephalosporin or Like nosocomial or + daptomycin,
piperacillin-tazobactam infections if high vancomycin (or
prevalence of MDROs linezolid*) if high
or if sepsis prevalence of MDR
Gram+ bacteria or sepsis
*In areas with a high prevalence of vancomycin-resistant enterococci

AKI management
• Investigation and management should begin immediately
Investigate AKI cause as soon as possible to prevent AKI progression

• Management should begin immediately (even absent obvious cause) II-2 1
• Screening and treatment of infection are most important
Diuretics and/or β-blockers as well as other drugs that could be associated with the occurrence of
II-2 1
AKI such as vasodilators, NSAIDs and nephrotoxic drugs should be immediately stopped
Volume replacement should be used in accordance with the cause and severity of fluid losses II-2 1
In case of no obvious cause of AKI, AKI stage >1A or infection-induced AKI:
• 20% albumin solution should be used at a dose of 1 g /kg of body weight (maximum of 100 g of III 1
albumin) for 2 consecutive days
In patients with AKI and tense ascites, therapeutic paracentesis should be associated with albumin
III 1
infusion even when a low volume of ascitic fluid is removed

HRS outside AKI criteria
• HRS-NAKI has an impaired response to vasorestrictors
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
*Formerly known as HRS type II

Previous CLIF prognostic and diagnostic scores
CLIF-C Acute decompensation score1*

10 x [0.03 x Age + 0.66 x Ln(Creatinine) + 1.71 x Ln(INR) + 0.88 x
Ln(WBC) 0.05 x Sodium + 8]
Sequential Organ Failure Assessment (SOFA) score

Organ/system* 0 1 2 3 4
Liver (bilirubin mg/dl) <1.2 ≥1.2–<2.0 ≥2.0–<6.0 ≥6.0–<12.0 ≥12.0
Kidney (creatinine mg/dl) <1.2 ≥1.2–<2.0 ≥2.0–<3.5 ≥3.5–<5.0 ≥5.0
Cerebral (HE grade) NO HE Grade I Grade II Grade III Grade IV
≥2.5 or PLT
Coagulation (INR and PLT count) <1.1 ≥1.1–<1.25 ≥1.25–<1.5 ≥1.5–<2.5
≤20,000/mm3
Dopamine ≤5 Dopamine >5 Dopamine >15
Circulation
≥70 <70 or dobutamine or A ≤0.1 or A >0.1
(MAP mmHg and vasopressors†)
or terlipressin or NA ≤0.1 or NA >0.1
Lungs
PaO2/FiO2, or >400 >300–≤400 >200–≤300 >100–≤200 ≤100
SpO2/FiO2 >512 >357–≤512 >214–≤357 >89- ≤214 ≤89
*Bold text indicates the diagnostic criteria for organ failures; †μg/kg/min
1. Jalan R, et al. J Hepatol 2015;62:831–40;

Decompensated Cirrhosis: Clinical Practice Guidelines

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Clinical Practice Guidelines

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• Please send any feedback to: slidedeck_feedback@easloffice.eu

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Methods • Grading evidence and recommendations

• Definition and pathophysiology of

Guidelines • Key recommendations

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Grading is adapted from the GRADE system1

1. Guyatt GH, et al. BMJ. 2008:336:924–6;

• Transition from compensated cirrhosis to DC occurs at a rate of ~5–7% per year

D’Amico G, et al. J Hepatol 2018;68:56376;

• Transition from compensated cirrhosis to DC occurs at a rate of ~5–7% per year

D’Amico G, et al. J Hepatol 2018;68:56376;

Portal hypertension Liver injury

Splanchnic arteriolar vasodilation and

Bernardi M, et al. J. Hepatol 2015;63:1272–84;

• Management of DC aims to improve outcomes of complications

Uncomplicated Ascites Hepatic Renal impairment

Hyponatremia Complications of DC Bacterial infections

ACLF RAI GI bleeding Cardiopulmonary

CCM HPS PPHT

Increased understanding of DC pathophysiology permits the development

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

1. Overall management of DC Click on a topic to skip

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Management should aim to prevent progression, not treat complications

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Recommendation Grade of evidence Grade of recommendation

In patients with DC the aetiological factor should be removed, particularly alcohol

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Further clinical research is needed to confirm the safety and

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Most common complication of decompensation in cirrhosis

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Cirrhosis is responsible for 80% of cases of ascites

• Diagnostic paracentesis is indicated in:*

Recommendation Grade of evidence Grade of recommendation

• Development of ascites in patients with cirrhosis is associated with a poor prognosis

Recommendation Grade of evidence Grade of recommendation

• Patients may not receive adequate priority in transplant lists

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Grade 1 or mild ascites

Recommendation Grade of evidence Grade of recommendation

Moderate restriction of sodium intake (80–120 mmol/day, corresponding to 4.6–6.9 g of salt)

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Mainstay of medical treatment are anti-mineralocorticoid drugs*

Recommendation Grade of evidence Grade of recommendation

First episode of grade 2 ascites

*Spironolactone, canrenone or K-canrenoate; †Body weight reduction <2 kg/week

Recommendation Grade of evidence Grade of recommendation

GI haemorrhage, renal impairment, hepatic encephalopathy, hyponatraemia, or alterations in

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Recommendation Grade of evidence Grade of recommendation

• Grade 3 or large ascites

Recommendation Grade of evidence Grade of recommendation

LVP should be followed with plasma volume expansion I 1

*Grade of evidence I, grade of recommendation 1

Recommendation Grade of evidence Grade of recommendation

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• International Ascites Club:

Diuretic resistant Diuretic intractable