Austrian consensus on the definition and treatment of portal

Transcription

consensus report
Wien Klin Wochenschr
DOI 10.1007/s00508-013-0337-z
Wiener klinische Wochenschrift
The Central European Journal of Medicine
Austrian consensus on the definition and treatment of
portal hypertension and its complications (Billroth II)
Markus Peck-Radosavljevic, Bernhard Angermayr, Christian Datz, Arnulf Ferlitsch, Monika Ferlitsch,
Valentin Fuhrmann, Michael Häfner, Ludwig Kramer, Andreas Maieron, Berit Payer, Thomas Reiberger,
Rudolf Stauber, Rudolf Steininger, Michael Trauner, Siegfried Thurnher, Gregor Ulbrich, Wolfgang Vogel,
Heinz Zoller, Ivo Graziadei
Received: 10 September 2012 / Accepted: 15 February 2013
© Springer-Verlag Wien 2013
Österreichischer Konsensus zur Definition und
Therapie der Portalen Hypertension und ihrer
Komplikationen (Billroth II)
Zusammenfassung Im November 2004 hielt die Österreichische Gesellschaft für Gastroenterologie und Hepatologie (ÖGGH) den ersten Konsensus über die Definitionen und die Therapie der Portalen Hypertension
und ihrer Komplikationen im Billroth-Haus in Wien,
Österreich ab (Billroth I Meeting). Diesem Treffen ging
ein internationales Expertenmeeting über die Portale
Hypertension mit einigen wichtigen Proponenten der
Baveno Konsensus-Konferenzen vorraus (http://www.
oeggh.at/videos.asp). Der Konsensus selber basiert auf
dem Baveno III Konsensus im Hinblick auf die portalhypertensive Blutung und den Vorschlägen des International Ascites Club in Hinblick auf die Therapie des As-
zites. Deren Aussagen wurden mit neuen Erkenntnissen
aus der rezenten Literatur und auch entsprechend der
praktischen Erfahrung der Teilnehmer des KonsensusTreffens modifiziert. Im Oktober 2001 organisierte die
ÖGGH das zweite Konsensus Treffen über die portale Hypertension und ihrer Komplikationen (Billroth II
Meeting). Die Billroth II Leitlinien über die Definitionen
und die Therapie der Portalen Hypertension und ihrer
Komplikationen lassen die Entwicklungen der letzten
7 Jahre inklusive des Baveno V Updates und etlicher
Schlüsselpublikationen mit einfließen und stellen den
neuen Standard im Management der Portalen Hypertension in Österreich dar.
Schlüsselwörter: Aszites, Varizenblutung, TIPS, Hepatorenales Syndrom, Hepatopulmonales Syndrom,
Portopulmonale Hypertension, Budd-Chiari Syndrom,
Somatostatin, Terlipressin, Carvedilol
For the Austrian Society of Gastroenterology and Hepatology
(ÖGGH)
M. Peck-Radosavljevic, MD () · A. Ferlitsch, MD ·
M. Ferlitsch, MD · V. Fuhrmann, MD · B. Payer, MD ·
T. Reiberger, MD · M. Trauner, MD
Klinische Abteilung für Gastroenterologie und Hepatologie,
Universitätsklinik für Innere Medizin III, Medizinische Universität
Wien, Währinger Gürtel 18–20, 1090 Vienna, Austria
e-mail: markus.peck@meduniwien.ac.at
B. Angermayr, MD
2. Medizinische Abteilung, Landesklinikum St. Pölten, St. Pölten,
Austria
C. Datz, MD
Abteilung Innere Medizin, Krankenhaus Oberndorf, Oberndorf bei
Salzburg, Austria
M. Häfner, MD
Krankenhaus St. Elisabeth, Vienna, Austria
A. Maieron, MD
4. Interne Abteilung, Krankenhaus St. Elisabeth, Linz, Austria
R. Stauber, MD
Klinische Abteilung für Gastroenterologie und Hepatologie,
Medizinische Universität Graz, Graz, Austria
R. Steininger, MD
Universitätsklinik für Chirurgie, Medizinische Universität Wien,
Vienna, Austria
S. Thurnher, MD
Klinische Abteilung für Radiologie und Nuklearmedizin,
Krankenhaus Barmherzige Brüder Wien, Vienna, Austria
W. Vogel, MD · H. Zoller, MD · I. Graziadei, MD
Universitätsklinik für Innere Medizin (Gastroenterologie
und Hepatologie), Medizinische Universität Innsbruck,
Innsbruck, Austria
L. Kramer, MD · G. Ulbrich, MD
1. Medizinische Abteilung mit Gastroenterologie, Krankenhaus
Hietzing, Vienna, Austria
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Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II) 1
consensus report
Summary In November 2004, the Austrian Society of
Gastroenterology and Hepatology (ÖGGH) held for
the first time a consensus meeting on the definitions
and treatment of portal hypertension and its complications in the Billroth-Haus in Vienna, Austria (Billroth
I-Meeting). This meeting was preceded by a meeting of
international experts on portal hypertension with some
of the proponents of the Baveno consensus conferences
(http://www.oeggh.at/videos.asp). The consensus itself is based on the Baveno III consensus with regard
to portal hypertensive bleeding and the suggestions of
the International Ascites Club regarding the treatment
of ascites. Those statements were modified by new
knowledge derived from the recent literature and also
by the current practice of medicine as agreed upon by
the participants of the consensus meeting. In October
2011, the ÖGGH organized the second consensus meeting on portal hypertension and its complications in Vienna (Billroth II-Meeting). The Billroth II-Guidelines on
the definitions and treatment of portal hypertension and
its complications take into account the developments of
the last 7 years, including the Baveno-V update and several key publications.
Keywords: Ascites, Variceal bleeding, TIPS, Hepatorenal
syndrome, Hepatopulmonary syndrome, Portopulmonary hypertension, Budd-Chiari Syndrome, Somatostatin, Terlipressin, Carvedilol
Abbreviations
AVBAcute variceal bleeding
BCSBudd-Chiari syndrome
CSPHClinically significant portal hypertension
FCBFailure to control bleeding
FFPFresh frozen plasma
GAVEGastric antral vascular ectasia
GOVGastro oesophageal varices
HCCHepatocellular carcinoma
HEHepatic encephalopathy
HPSHepatopulmonary syndrome
HRSHepatorenal syndrome
HVPGHepatovenous pressure gradient
IGVIsolated gastric varices
ISMNIsosorbidmononitrate
NSBBNonselective beta-blockers
PPHTNPortopulmonary hypertension
PTFEPolytetrafluoroethylene
PHGPortal hypertensive gastropathy
TIPSTransjugular intrahepatic portosystemic stent
SBPSpontaneous bacterial peritonitis
Introduction/background
In November 2004, the Austrian Society of Gastroenterology and Hepatology (ÖGGH) held for the first time a
consensus meeting on the definitions and treatment of
portal hypertension and its complications in the BillrothHaus in Vienna, Austria (Billroth I-Meeting). This meet-
ing was preceded by a meeting of international experts on
portal hypertension with some of the proponents of the
Baveno consensus conferences (http://www.oeggh.at/
videos.asp). The consensus itself is based on the Baveno
III consensus with regard to portal hypertensive bleeding [1] and the suggestions of the International Ascites
Club regarding the treatment of ascites [2]. Those statements were modified by new knowledge derived from the
recent literature and also by the current practice of medicine as agreed upon by the participants of the consensus
meeting. The section on TIPS-placement was based on
the consensus statement of the Vienna TIPS Study Group
(VTSG) [3].
In October 2011, the ÖGGH organized the second
consensus meeting on portal hypertension and its complications in Vienna (Billroth II-Meeting). The Billroth
II-Guidelines on the definitions and treatment of portal
hypertension and its complications take into account the
developments of the last 7 years, including the Baveno-V
update [4] and several key publications.
An effort was made to develop a practical guideline to
everyday medical practice. In order to reduce the areas
without specific recommendations for treatment to an
absolute minimum, we included treatment recommendations even in case of insufficient or contradictory data
through consensus of the participating physicians. The
evidence was graded according to a modified established
grading system [5]:
Grade definition
IRandomized controlled trials
II-1Controlled trials without randomization
II-2Cohort or case-control analytic studies
II-3Multiple time series, dramatic uncontrolled
experiments
IIIOpinions of respected authorities, descriptive
epidemiology
Criteria and definition of portal hypertension
1. Clinically significant portal hypertension (CSPH) is
defined as an increase of the hepatovenous pressure
gradient (HVPG) to a threshold above 10 mmHg [6] (I).
2. The presence of varices, variceal hemorrhage, and/or
ascites (in the absence of significant cardiac, peritoneal, or renal comorbidities) is indicative of the presence of CSPH (I).
3. Measurement of the HVPG or endoscopic assessment
of esophageal varices is sufficient for diagnosis of
CSPH (I).
4. The accuracy of noninvasive tests for diagnosis of
CSPH (e.g., transient elastography, Doppler ultrasound, various indices containing dynamics in platelets or other parameters) should be further evaluated.
They are currently of limited use in daily clinical practice (III).
2 Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II)
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consensus report
Approach to the diagnosis of portal hypertension
1. All cirrhotic patients should be screened by endoscopy for the presence of varices at the time of the initial
diagnosis of cirrhosis (I).
2. Varices should be graded as absent, small (< 5 mm of
diameter), or large (≥ 5 mm) (II-1).
3. In compensated patients without varices, endoscopy
should be repeated at 2–3-year intervals to evaluate
the development of varices (I).
4. In compensated patients with varices but not receiving beta-blocker therapy, endoscopy should be repeated at 1–2-year intervals to evaluate progression of
varices. For compensated patients with varices receiving therapy with beta-blockers, there is no indication
for endoscopic monitoring of the varices, especially if
they are hemodynamic responders to beta-blockers as
measured by HVPG (I).
5. If HVPG is measured as ≥ 10 mmHg, endoscopy should
be repeated every year to screen for the presence of
varices, since CSPH is predictive of the formation of
esophagogastric varices [7, 8] (III).
6. There is no indication for subsequent endoscopic surveillance once large varices (≥ 5 mm) are detected, (I)
unless endoscopic band ligation is carried out.
7. HVPG is currently the only validated and reliable parameter suitable to monitor effects of pharmacological treatment on portal pressure [6] (I).
Preprimary prophylaxis of variceal bleeding
Background
1. The pathogenetic sequence “portal hypertension—
collateral vessels—varices” is commonly accepted (I).
2. Collateral vessels can be diagnosed before varices develop (I).
3. Portal pressure is predictive for development of varices (I).
4. “Low risk varices” are small-sized varices (diamater
< 5 mm) without red color signs (I).
5. The risk of bleeding within 2 years of low risk varices
is < 10 % [9] (I).
6. Spontaneous regression of varices is a rare event (I).
7. Treatment with nonselective beta-blockers (NSBB)
does not generally prevent the occurrence of varices
[7] (I).
8. A subgroup of cirrhotic patients without varices at endoscopy but with HVPG ≥ 10 mmHg may benefit from
beta-blocker treatment to prevent the occurrence of
varices [7] (II-1).
Recommendation
2. Measurement of HVPG may be performed in centers
with adequate expertise to obtain important prognostic information (decompensation, HCC development)
and to assess the risk of variceal bleeding and other
complications of cirrhosis and portal hypertension
(II-2).
3. Treatment with beta-blockers is not generally recommended in cirrhotic patients without varices at endoscopy (I).
Primary prophylaxis
Medical prophylaxis with nonselective beta-blockers
(NSBB) is recommended in patients with portal hypertension and varices of all grades. Thereby the progression
of the varices as well as the incidence of variceal bleeding
can be reduced.
Indications for medical treatment and follow-up
endoscopy
1. All patients with large varices (≥ 5 mm) should be
treated either with beta-blockers or with variceal
band ligation [10, 11] (I).
2. Even patients with small varices (< 5 mm) should receive beta-blocker prophylaxis, since this can reduce
the incidence of variceal bleeding [12] (II-3).
3. Additional endoscopic signs such as red color signs
are of no prognostic relevance and should not influence the indication for therapy (III).
4. There is no need for follow-up endoscopy in patients
on pharmacologic therapy (I).
Monitoring of beta-blockade
1. Increasing the dose of NSBB to achieve a 25 % reduction in resting heart rate (but not < 50 bpm) or development of symptoms can be used to adjust the dose of
beta-blockers in cirrhotic patients (I).
2. Some, but not all, patients treated with NSBB achieving these targets will be protected from variceal bleeding (I).
3. There is no relationship between reduction in portal
pressure or protection from variceal bleeding and the
degree of beta-blockade, as assessed by the reduction
in resting heart rate (I).
4. A reduction in HVPG below 12 mmHg—or more than
20 % from baseline—is the only tested parameter to
identify those patients treated with NSBB, who are
protected from variceal bleeding. The average dose of
propranolol to reach this target is 80 mg/day [13]. The
average dose of carvedilol to achieve these reductions
is 12.5 mg/day [14, 15] (II-1).
1. All patients should be screened endoscopically for
varices after diagnosis of cirrhosis (II-1).
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consensus report
5. Since hemodynamic response to NSBB defines an excellent long-term prognosis, centers with adequate
expertise in HVPG measurement should evaluate
the hemodynamic response to NSBB therapy [16, 17]
(II-2).
6. However, since about 60 % of patients treated with
NSBB who do not achieve these targets will not bleed
within 2 years, in primary prophylaxis it is not mandatory to check the HVPG response (II-2).
Choice of primary prophylaxis for patients with
large varices
1. Propranolol or Carvedilol [10, 11] should be used for
prophylactic pharmacologic treatment of patients
with varices [10, 18]. Carvedilol may be more effective
than propranolol in primary prophylaxis of variceal
bleeding [19, 20] (II-1).
2. In patients who have contraindications to beta-blocker therapy or are intolerant or not adherent to betablockers or do not respond to beta-blockers, endoscopic band ligation should be used. In particular, if
patients have a low bleeding tolerance (decompensated cirrhosis) (II-2).
3. If hemodynamic monitoring of HVPG is available,
treatment with beta-blockers should be preferred and
hemodynamic response should be evaluated (II-1).
4. Therapy with isosorbide-5-mononitrate (ISMN) is not
a good alternative [21].
5. There is no consensus if NSBB treatment should be
continued in patients without hemodynamic response to NSBB treatment, although patients with a
reduction of HVPG ≤ 20 % may also benefit from NSBB
treatment (III).
Combination of treatments for primary prophylaxis
1. For primary prophylaxis, the combination of NSBB
and ISMN cannot be recommended, because this
does not increase the effectiveness but the side effects
of therapy (I).
2. The combination of endoscopic treatment and pharmacologic therapy cannot be recommended at present because there are no data to support its use (III).
Acute variceal bleeding and rebleeding:
definition and prognostic value
Definition of acute variceal bleeding
1. Active bleeding at endoscopy.
2. When active bleeding cannot be detected: signs of an
upper GI bleeding (hematemesis, blood or coagulated
blood, melena) in patients with varices in the absence
of another source of bleeding.
3. Active variceal bleeding at endoscopy is characterized
by eminating blood from a varix (oozing or sprouting).
4. Active bleeding at endoscopy is a poor prognostic sign
regarding successful control of bleeding for the shortterm period after variceal bleeding [22].
Failure to control acute bleeding (based on
international consensus)
1. FCB (failure to control bleeding) is defined as death
or need to change therapy due to one of the following
occurrences within 120 h (5 days) of the initial bleeding episode.
2. Occurrence of fresh hematemesis within ≥ 2 h of starting specific drug therapy of therapeutic endoscopy.
3. Development of hypovolemic shock.
4. Drop in Hb by ≥ 3 g/dL (9 % in hematocrit) within
any 24-h period as long as no blood transfusions are
administered.
Failure of secondary prophylaxis (every variceal
bleeding after initiation of secondary prophylaxis)
1. Any clinically significant rebleeding caused by portal
hypertension from day 5 on.
2. Clinically significant rebleeding is defined as recurrent melena or hematemesis resulting in: hospital
admission, blood transfusions, drop in Hb ≥ 3 g/dL,
death within 6 week interval.
Treatment of acute variceal bleeding (AVB)
Treatment of patients with acute variceal bleeding
should be carried out in an institution where the therapeutic interventions are performed routinely and where
the staff is experienced in taking care of such patients.
Prerequisites for therapy (III)
1. Facilities for tight hemodynamic monitoring
2. Continuous monitoring of O2 saturation
3. A sufficient intravenous line for hemodynamic stabilisation and treatment
4. Intubation for endoscopy is desirable under the following conditions:
– Massive and uncontrollable variceal bleeding
– Hepatic encephalopathy (HE grade III and IV)
– Impossibility to maintain blood oxygenation at 90 %
or above
– Evidence of aspiration (or rarely aspiration
pneumonia)
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consensus report
Time management of endoscopic treatment
Assessment of prognosis
1. Endoscopic treatment should be performed as soon
as possible after hemodynamic stabilization (at the
latest 12 h after admission, ideally during the first 6 h),
especially in patients with clinically significant bleeding or in patients with suspected cirrhosis (III).
2. In patients with mild bleeding not causing hemodynamic changes and not requiring transfusions, endoscopy can be performed electively (III).
HVPG of > 20 mmHg, active bleeding at endoscopy, and
Child-Pugh Class C are associated with an increased failure to control bleeding and early mortality [24] (II-2).
Blood volume restitution
1. Blood volume restitution should be done cautiously
and conservatively, using packed red cells to maintain
the hemoglobin between 7–8 g/dL (unless comorbidities/active bleeding mandate more aggressive substitution) (I), and substitution of fluids sufficient to
maintain hemodynamic stability. Targets for systolic
blood pressure are 90–100 mmHg, and for heart rate
100 bpm or less.
2. Further data from prospective studies are required
to determine the need for treating coagulopathy
and thrombocytopenia. In patients with severe coagulation disorders (PT < 30 %) or thrombocytopenia
(< 30,000/µL), substitution therapy using fresh frozen
plasma (FFP) or platelets should be considered (III).
3. Therapy with prothrombin-complex containing clotting-factor concentrates should be omitted (III).
Antibiotic prophylaxis to prevent bacterial
infections/spontaneous bacterial peritonitis
Antibiotic prophylaxis is an integral part of the therapy
of variceal bleeding, which should be started before
endoscopic therapy. Broad-spectrum antibiotics should
be administered either orally or intravenously [23]. All
patients should be screened for the presence of a bacterial infection (I).
Prevention/therapy of hepatic encephalopathy
1. Lactulose can be administered either orally or by a
nasogastric tube or by enema to prevent hepatic encephalopathy, even though its therapeutic efficacy is
unproven for acute variceal bleeding (III).
2. In case of overt hepatic encephalopathy, L-ornithinL-aspartat should be given intravenously in combination with sufficient volume substitution for the first
24–48 h. Later it should be given orally on demand.
Alternatively, rifaximin might be used for long-term
prophylaxis (I).
3. For none of these above interventions, controlled data
on their efficacy are available.
13
Use of balloon tamponade
1. Balloon tamponade should only be used in patients
with bleeding as a temporary “bridge” until definitive
treatment can be instituted, if other options such as
the bleeding stent are not available (I).
2. A better contemporary alternative to stop uncontrolled bleeding is the bleeding stent [25], which
should be preferred to ballon tamponade for esophegeal variceal bleeding if possible, even though controlled data are still not available (II-2).
Pharmacological treatment
1. In suspected variceal bleeding, vasoactive drugs
should be started as soon as possible, before diagnostic endoscopy (I).
2. For vasoactive therapy, somatostatin (for continuous
intravenous application) and the vasopression-analogon terlipressin (application as a bolus) have proven
efficacy to control bleeding (I). They have similar efficacy and can be substituted one for the other. Terlipressin should not be used in patients with clinically
significant coronary heart disease, pAVK, higher grade
cardiac rhythm abnormalities, and severe grades of
asthma and COPD.
3. Drug therapy may be maintained for up to 5 days to
prevent early rebleeding (I). After this period, medical
therapy for secondary prophylaxis should be started
immediately (I).
Recommended drug doses
1. Somatostatin: initially a bolus of 500 µg, afterwards
500 µg/h (7 µg/kg/h) by continuous infusion. If the
patient does not bleed for 24 h, treatment with a dose
of 250 µg/h (3.5 µg/kg/h) should be continued for the
next 24 h up to 5 days.
2. Terlipressin: initially a bolus of 2 mg every 4 h. If the
patient does not bleed for 24 h under this regimen,
bolus administration of 1 mg every 4 h should be continued for the next 24 h up to 5 days.
Endoscopic therapy of esophageal variceal
bleeding
1. In acute bleeding, endoscopic ligation is the preferred
endoscopic method over endoscopic sclerotherapy(I).
consensus report
2. Endoscopic treatments are best used in association
with pharmacological therapy (vasoactive drugs + antibiotics), which preferably should be started before
endoscopy (I).
3. Even when no active bleeding can be detected at endoscopy, endoscopic therapy of varices is highly recommended (I).
4. Cyanoacrylate is not a standard treatment for esophageal varices but might be used as a rescue therapy of
refractory bleeding (II-3).
5. Erythromycin may improve visibility during endoscopy while the impact on bleeding control is unclear
(III).
Early TIPS-placement
1. Recent data show that early TIPS-placement (within
72 h, even better within 24 h) can not only improve
FCB but also mortality in patients with high risk of
FCB [26, 27] (I).
2. Early TIPS-placement should be performed in patients with acute variceal bleeding and either
– An HVPG ≥ 20 mmHg at the time of acute variceal
bleeding [26] or
– Child-Pugh C status at admission (but Child-Pugh
score < 14) or
– Child-Pugh B status with active bleeding at endoscopy [27] despite treatment with vasoactive drugs
and antibiotics.
3. The decision for TIPS-implantation should consider
the standard exclusion criteria for TIPS-implantation
such as cardiac insufficiency (in particular right heart
failure) and technical contraindications (lack of vascular connectability) (II-3).
4. Acute hepatic encephalopathy is not a contraindication for an early TIPS (III).
5. For Child-Pugh C patients with a score of ≥ 14, no evidence for an improved outcome with an early TIPS is
available, since these patients were excluded from the
trials.
Prevention of variceal rebleeding (secondary
prophylaxis)
Standard therapy
1. Secondary prophylaxis should be started as soon as
possible, ideally at day 5 after the acute variceal episode (or whenever vasoactive therapy is discontinued) (III).
2. Combination of nonselective beta-blocker (NSBB)
(propranolol) therapy and endoscopic rubber band
ligation are the therapies of choice (I). Data from primary prophylaxis suggest that carvedilol might be at
least as effective as propranolol for lowering portal
pressure in cirrhosis [20] but no data for secondary
prophylaxis of acute variceal bleeding are available:
they should be generated (III).
3. Medical therapy with (II-2) NSBB alone is a valid
choice if their effectiveness can be documented by
HVPG. NSBB nonresponders can be treated with a
combination of NSBB with ISMN under hemodynamic monitoring (III). Nonresponders to combination medical therapy require endoscopy band ligation
(III).
4. Propranolol should be titrated to a daily dosage of
minimum 80 mg in 2–3 fractions, carvedilol should
be administered once or twice daily with a minimum
daily dosage of 12.5 mg (starting with 6.25 mg/day for
1 week) (III).
5. Endoscopic band ligation to prevent rebleeding is
continued at 2–3 week intervals until ideally complete
eradication of varices (small residual varices can be
accepted) (III).
6. Patients with advanced stage liver disease should be
evaluated for liver transplantation. In these patients,
endoscopic and/or medical therapy should be continued until transplantation (II-2).
Treatment of patients with contraindications to
beta-blockers or combination drug therapy
1. Band ligation is the preferred treatment to prevent
recurrent variceal hemorrhage in patients who have
a contraindication to beta-blocker or combination
therapy (III).
2. ISMN monotherapy is not considered an alternative
to beta-blocker therapy (II-2).
Treatment of low-risk patients (early stage liver
disease, sufficient tolerance of bleeding) with
failure of secondary prophylaxis
1. Variceal band ligation is the therapy of choice in variceal rebleeding (or insufficient decrease in HVPG) despite medical therapy, although band ligation could
have moderate beneficial effects especially in these
patients [28] (II-2). It might also be warranted in situations with combination prophylaxis (NSSB), if band
ligation was incomplete or finished some time (> 12
months) ago (III).
2. TIPS implantation with PTFE (polytetrafluoroethylene) -covered stent grafts (very rarely also shunt surgery) is a good treatment option for low-risk patients
in whom medical and endoscopic treatment have repeatedly failed (at least twice) (II-2).
3. Surgical devasculariziation is a rescue therapy in case
of failure of medical and endoscopic treatment to prevent rebleeding in patients in whom neither a TIPS
can be implanted nor shunt surgery can be performed
(III).
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consensus report
Treatment for high-risk patients with failure of
medical/endoscopic therapy in the prophylaxis
of rebleeding
Gastro-oesophageal varices (GOV)
IGV 1
1. TIPS implantation is recommended for selected highrisk patients, in whom medical and endoscopic treatment fails to prevent rebleeding (at least twice) (II-2).
2. These patients should be considered for liver transplantation (III).
GOV 1
GOV 2
Portal hypertensive gastropathy (PHG), gastric
antral vascular ectasia (GAVE)
IGV 2
Definitions
1. PHG is defined as a macroscopically visible mosaic
like pattern of the gastric mucosa. The prevalence of
PHG in portal hypertension varies between 20 % and
80 %. PHG should be differentiated into PHG with and
without signs of bleeding [29]. Severe PHG is characterized by red marks and associated with a higher risk
of bleeding [30].
2. GAVE is a distinct clinical, endoscopic, and histopathologic entity endoscopically characterized by
aggregates of red spots arranged in linear pattern or
diffuse lesions (in this case they have to be confirmed
by biopsy of the antrum). GAVE can be seen with other
conditions than cirrhosis of the liver. The prevalence
of GAVE in cirrhosis is low (about 2 %) [31].
3. The incidence of acute PHG bleeding is low (less than
3 % at 3 years).
4. The incidence of chronic PHG bleeding is around 10–
15 % at 3 years.
5. The lesions may change over time (fluctuate, worsen,
or improve).
Treatment of acute PHG bleeding
1. Vasoactive drugs are used with a high success rate
(70–100 %) in uncontrolled studies. Controlled studies
are lacking but patients are managed in a similar way
as acute variceal bleedings in many centers (III).
2. Emergency transjugular intrahepatic porto-systemic
shunt (TIPS; or shunt surgery in rare cases) should be
regarded as rescue treatments in cases of failure of vasoactive drugs (III).
Treatment of chronic PHG bleeding
1. Nonselective beta-blockers (II-1), and if needed iron,
are the first-choice treatment.
2. Beta-blockers and isosorbide-5-mononitrate, as well
as other medical treatments (i.e., carvedilol, longacting somatostatin analogues), should be evaluated.
3. Treatment should be continued indefinitely (III).
13
Fig. 1 Gastroesophageal varices
4. TIPS is a rescue therapy in PHG-associated bleedings,
which could respond to a decrease in HVPG (II-3).
APC might be an additional therapeutic option for patients with refractory bleeding from PHG (III).
Treatment of GAVE bleeding
1. Argon plasma coagulation is an effective therapy in
patients with mild to moderate bleedings (II-3).
2. Multiple sessions are usually needed to control acute
bleeding or to stop chronic blood loss, but no controlled studies are available (III).
Gastric varices
Definitions
1. The classification of Sarin et al. should be used [32];
it distinguishes gastroesophageal varices type 1 and 2
(GOV 1 and 2) and isolated gastric varices 1 and 2 (IGV
1 and 2), which occur in 5–33 % of patients with portal
hypertension.
2. GOV2 and IGV1: the presence of red signs, large size,
and Child Class B or C should be considered as risk
factors for bleeding (Fig. 1). 3. GOV2, GOV1, and IGV1 are at the highest risk of bleeding (bleeding risk 55–78 %), which has a high mortality
rate [32, 33].
For therapy of bleeding gastric varices, the
following approaches can be used
1. Cyanoacrylate glue injection is the most effective
therapy for acute fundal variceal bleeding [34–37] (I).
consensus report
2. One single injection should consist of 0.5 ml cyanoacrylate and 0.5 ml lipiodol. Not more than 1.0 ml of
the cyanoacrylate/lipodol mixture should be injected
at each time to minimize the risk of embolization [38]
(II-2).
3. Endoscopic variceal sclerotherapy is no alternative
(bleeding control of 60–100 % but rebleeding rate of
up to 90 %) [39] (II-3).
4. Vasoactive drugs could be used in combination with
other treatments (III).
5. Balloon tamponade can be used as a bridge in case of
failure to control bleeding (III).
6. Endoscopic band ligation is not an established therapy for bleeding varices GOV2, IGV 1 + 2 due to a lower
rate of hemostasis and a higher rebleedings rate compared to cyanoacrylate [34, 36] (I); GOV1 are considered extensions of esophageal varices and should be
treated accordingly [33] (III).
7. Balloon-occluded retrograde transvenous obliteration (B-RTO) is a treatment option for gastric varices
mostly used in Japan [40–42]. It shows promising results there but the efficacy in Caucasians populations
has not adequately been documented.
8. TIPS (rarely surgery) is indicated as rescue therapy
(“emergency TIPS”: bleeding control rate up to 90 %)
[43] for patients not responding to medical and endoscopic therapy [44] (II-3). TIPS might be a good
first-line treatment option also for high-risk patients
with gastric variceal bleeding (GOV2, IGV1 + 2; “early
TIPS”) but has not been studied specifically in this
patient population. Surgical devascularization is a
rescue therapy in case of failure of medical and endoscopical treatment to prevent rebleeding in patients
in whom neither a TIPS can be implanted nor shunt
surgery can be performed.
For long-term therapy of fundal varices, there are
no established and prospectively evaluated therapies. Potential candidate therapies include
1. Long-term cyanoacrylate glue application
2. TIPS (rarely shunt surgery in patients with very good
liver function)
3. Medical therapy with NSBB (propranolol, carvedilol)
and/or ISMN
Management of ascites
Diagnostic approach in patients with ascites
1. Ascites should be graded according to the International
Ascites Club guidelines into uncomplicated (grade 1:
only visible on ultrasound; grade 2: moderate ascites;
grade 3: massive ascites), and refractory ascites (not
responsive or intolerant to diuretic therapy even after
paracentesis) [2].
2. All patients presenting with ascites for the first time,
with recurrence of ascites or deterioration of ascites,
need investigation of their ascites. Substitution of coagulation factors or platelets is not indicated even in
patients with severe coagulopathy, because paracentesis rarely leads to serious bleeding complications
[1, 45] (I).
3. Investigation of ascites should include at least the determination of the ascitic neutrophil count, protein
concentration, and serum-ascites albumin gradient
(I).
4. Additionally, aerobic and anaerobic blood culture
bottles should be inoculated with ascitic fluid for bacteriologic diagnosis of SBP (I).
Therapy of uncomplicated ascites
1. For initial therapy of patients with mild ascites (grade
1), sodium restriction (90 mmol NaCl/day, corresponding to 5.2 g NaCl/day) is recommended(III).
2. In patients with moderate ascites (grade 2), the initial
therapy consists of sodium restriction and diuretic
therapy (I).
3. Diuretic therapy should be started with spironolactone (100–200 mg). In case of insufficient ascites control or lack of effectiveness (< 1–2 kg weight reduction
within 7 days), furosemide should be added. The daily
dose of 400 mg spironolactone and 160 mg furosemide should not be exceeded. Alternatively, butizide
in combination with spironolactone can be used instead of or in combination with furosemide (I).
4. In patients with tense ascites (grade 3), paracentesis
is the treatment of choice and should be followed by
diuretic therapy. Total paracentesis should be carried
out as a single procedure, even when a large volume of
ascites is present (I).
5. Plasma volume expansion using albumin is recommended in all patients undergoing paracentesis,
especially if more than 5 L of ascites have been removed; for prevention of hypovolemia and circulatory
dysfunction. Albumin at a dose of 8 g/L of ascites removed should be administered (I).
6. Patients responsive to diuretics should primarily be
treated with sodium restriction and diuretics and
should not undergo serial paracentesis.
7. In patients with hyponatremia< 120 mmol/L (or mM),
diuretic therapy should be halted, since at these levels
diuretics are ineffective and worsen hyponatremia.
Substitution of concentrated NaCl solutions is not indicated (II-1).
8. Patients with moderate to severe ascites should be
considered for liver transplantation.
9. The administration of nonsteroidal antiinflammatory drugs (NSAID) in patients with decompensated
cirrhosis and ascites can lead to renal failure and
therefore should be avoided [46]. The same is true for
angiotensin-converting enzyme inhibitors [47, 48] (I).
13
consensus report
Refractory ascites
1. Refractory ascites is defined as ascites that cannot
be mobilized by intensive diuretic therapy (< 0.8 kg
weight loss within 4 days) or that is uncontrollable by
total paracentesis, substitution of albumin, and adequate diuretic therapy up to a maximum of 400 mg
spironolactone and 160 mg furosemide per day (ascites resistant to diuretic therapy).
2. Early recurrence (within 4 weeks) of grade 2 or grade 3
ascites after paracentesis is also defined as refractory
ascites [2].
3. Ascites is also defined as refractory, when the maximal
dose of diuretics cannot be administered due to side
effects such as electrolyte imbalance, renal failure,
and encephalopathy (ascites intolerant to diuretics).
4. For diagnosis of refractory ascites, analysis of 24 h
urine specimens for protein levels, creatinine clearance, and sodium excretion should be performed.
5. A characteristic feature of refractory ascites is an impaired urinary sodium excretion (< 90 mmol/24 h)
[49]. Diuretic treatment should be administered only
when urinary sodium excretion under diuretic therapy is greater than 30 mmol/day [2].
6. Due to the poor prognosis of patients with refractory
ascites, liver transplantation should be considered.
In patients awaiting liver transplantation or with contraindications to transplantation, therapy of ascites
should consist of repeated total paracentesis with albumin substitution, sodium restriction and diuretic
therapy (II-2).
7. In selected patients (see Chap. 14: “TIPS for therapy
of portal hypertension”), TIPS is a good and effective therapeutic alternative to repeated paracenteses. Especially in patients with contraindications to
liver transplantation or in patients with expected long
waiting times for transplantation, TIPS implantation
should be considered (II-1).
Spontaneous bacterial peritonitis (SBP)
Definition and management of SBP
1. All patients presenting with ascites for the first time,
with recurrence of ascites, and deterioration of ascites
need investigation of ascites. Paracentesis should also
be performed in patients suspected to have systemic
infection (either clinically or by laboratory tests),
worsening liver or renal function, and hepatic encephalopathy [50] ascitic fluid culture should be performed in blood culture bottles at bedside. Together
with paracentesis, blood should be investigated for
infection (blood culture). Even in the absence of signs
of infection in the ascitic fluid, positive blood cultures
hint at the responsible organism [51].
2. In case of an ascitic fluid neutrophil count > 250/µL
and/or a positive ascitic fluid culture, antibiotic therapy using a broad-spectrum antibiotic with good gram-
13
negative efficacy should be started immediately (e.g.,
3rd generation cephalosporine, quinolone, aminopenicillin/penicillinase inhibitor) (I). The use of reagent
strips cannot be recommended at present [52] (II-1).
3. In case of an ascitic fluid neutrophil count < 250/µL
and the presence of clinical signs of infection, broadspectrum antibiotic therapy should be started and
continued until the microbiological results from the
ascitic fluid are available (III). Other causes of abdominal bacterial infections or peritoneal carcinosis have
to be excluded in patients with high neutrophil count
and multimicrobial cultures.
4. Repeat paracentesis should be performed 48 h after
initiation of the antibiotic therapy to demonstrate a
drop of the ascites neutrophil count to 25 % of the initial value (III). A smaller drop is highly suggestive of
failure of the antibiotic regimen [50].
5. Patients with an ascitic fluid neutrophil count > 250/µL
and clinical suspicion of SBP should implicitly receive
albumin intravenously in addition to broad spectrum
antibiotics to prevent hepatorenal syndrome (I): 1.5 g/
kg body weight within 6 hours of diagnosis plus 1 g/kg
on day 3 [52].
Long-term prophylaxis of SBP
1. In patients with severe liver disease and ascites, but
without a previous episode of SPB, long-term prophylaxis using antibiotics can be indicated when the ascitic total protein concentration is below 1.5 g/dL [50]
(I). Given the inevitable risk of developing resistant
organisms, the use of prophylactic antibiotics should
be restricted to patients at high risk for SBP.
2. All patients who experienced one episode of SPB
should be treated continuously using oral quinolones
(norfloxacin, ciprofloxacin) (I). The use of rifaximin in
this indication should be explored.
3. Due to the poor prognosis of patients who recovered
from SBP, liver transplantation should be considered
in these patients (II-2).
Transjugular intrahepatic portosystemic shunt
(TIPS) for therapy of portal hypertension [3]
General suppositions for TIPS placement
1. Radiologic examination for evaluation of the patency of anatomical structures (veins of the liver, portal
vein) as the prerequisite for the technical success.
2. Echocardiography to detect contraindications for TIPS
(cardiac insufficiency, pulmonary hypertension).
3. Sufficient liver function, i.e., Child-Pugh score ≤ 11
and MELD ≤ 17.
4. In patients with Child-Pugh score > 11 and MELD
> 18, TIPS implantation should be considered very
carefully.
consensus report
TIPS for variceal bleeding
TIPS in acute variceal bleeding
1. TIPS is the standard first line treatment for high-risk patients with acute bleeding from esophageal varices after
initial combined medical/endoscopic control of bleeding (see “Early TIPS-implantation”, Chap. 7.10) (I).
2. TIPS is a therapeutic option in acute esophageal or
gastric variceal bleeding refractory to medical and endoscopic therapy [44] (II-2).
3. TIPS might be a good first-line treatment option also
for high-risk patients with gastric variceal bleeding
(GOV2, IGV1 + 2; “early TIPS”) but has not been studied specifically in this patient population (III).
TIPS for prophylaxis of variceal bleeding
1. TIPS is not indicated for primary prophylaxis (III).
2. TIPS can be the therapy of choice in secondary prophylaxis in patients who rebled at least twice despite
adequate secondary prophylaxis with a combination
of NSBB and endoscopic therapy (see 8.3 and 8.5);
documentation of nonresponse to drug therapy by
HVPG-measurement can help in the decision making
process (I).
TIPS for refractory ascites (III)
1. In patients with refractory ascites, SBP has to be excluded by investigation of ascitic fluid. The ascitic
fluid neutrophil count has to be < 250/µL, and bacterial cultures of ascitic fluid must be negative.
2. After total paracentesis with albumin substitution (8 g
albumin/L ascitic fluid), recurrence of ascites using a
maximal dose of 400 mg spironolactone and 160 mg
furosemide cannot be prevented despite dietary sodium restriction to 5.2 g/day.
3. After total paracentesis with albumin substitution (8 g
albumin/L ascitic fluid), recurrence of ascites cannot
be prevented because the maximal dose of 400 mg
spironolactone and 160 mg fursoemide cannot be
administered due to side effects of diuretic treatment
(hyponatremia, impairment of renal function, etc.).
4. If total paracentesis is required more often than once
within 4 weeks, TIPS placement should be considered.
5. In patients with previous episodes of spontaneous
encephalopathy (in the absence of triggers like bleeding, infection, electrolyte disturbances, or overdose of
diuretics), TIPS implantation should be restricted to
very selected cases only.
TIPS for other indications
1. TIPS should be considered in patients with liver cirrhosis and nonmalignant portal vein thrombosis [54] (II-2).
2. TIPS is a very good therapeutic option in patients with
Budd-Chiari-Syndrome, who do not improve from anticoagulation alone [44, 55, 56]. (see Chap. 15) (II-2).
3. TIPS is a therapeutic option in hepatic hydrothorax
[44] (II-2).
4. TIPS is also a therapeutic option for hepatorenal syndrome (II-2).
Hepatorenal syndrome (HRS)
Diagnosis of HRS
1. HRS describes the emergence of renal dysfunction in
decompensated cirrhosis with portal hypertension
and circulatory dysfunction [57]. HRS may also complicate other liver diseases including alcoholic hepatitis, acute liver failure, or Budd-Chiari-syndrome in
combination with portal hypertension [58].
2. HRS is usually triggered by events leading to circulatory compromise including SBP, diuretics overdose,
large-volume paracentesis without albumin replacement, variceal bleeding, infection, and sepsis.
3. The pathophysiological basis of HRS is a progressive systemic vasodilatation and renal vasoconstriction that emerges in response to splanchnic hyperemia, circulatory dysfunction, and neurohormonal
activation.
4. It has been demonstrated that low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites [59].
5. If HRS persists for a longer period, acute renal failure
with acute tubular necrosis may develop. ATN may be
difficult to differentiate from HRS clinically, but fractional excretion of urea (FeU) may be helpful in the
differential diagnosis. An FeU of < 35 % is indicative of
HRS.
6. The diagnosis of HRS mandates [58]
−presence of ascites.
−no improvement in creatinine to < 1.5 mg/dL after
at least 2 days without diuretics and volume expansion with albumin (at 1 g/kg body weight, maximum 100 g/day).
−absence of shock.
−no recurrent or recent administration of nephrotoxic drugs.
−absence of parenchymal kidney disease (proteinuria < 500 mg/day, no hematuria, normal renal
ultrasound). HRS can be subdivided into type I and
type II HRS.
a. Type I HRS: progressive renal failure with serum
creatinine > 2.5 mg/dL or a doubling of serum
creatinine within 2 weeks and
b. Type II HRS: refractory ascites with serum creatinine concentration between 1.5 mg/dL and
2.5 mg/dL. In type II HRS, the risk of progression
to type I HRS has substantially increased.
13
consensus report
7. Due to muscular atrophy and tubular creatinine secretion in cirrhosis, serum creatinine and creatinine clearance significantly overestimate renal function in HRS.
Management, general measures
HRS type 1 occurs in patients with severe liver dysfunction and is associated with a high short term mortality
rate. Patients with HRS 1 should receive intensive care
treatment and be immediately listed for liver transplantation if they are appropriate candidates. The ideal treatment for HRS should aim to improve renal function,
prolong survival, and increase the likelihood of receiving a liver transplant in suitable candidates. In order to
prevent further impairment of renal function (I), therapy
should be initiated as soon as the diagnosis is made.
−The first therapeutic goal is targeted at the precipitating
event and includes adequate hydration to ensure euvolemia, discontinuation of diuretics and nephrotoxic
medication, and withholding vasodilative agents (I).
−
Bacterial infection should be diagnosed early and
treated aggressively with antibiotics (I).
−Gastrointestinal bleeding should be managed appropriately (I).
Specific treatment for HRS
The role of vasoconstrictors
The most extensively investigated and thus widely used
vasoconstrictors are vasopressin analogues, in particular
terlipressin [60–62]. Terlipressin is able to improve circulatory dysfunction via vasoconstriction of the dilated
splanchnic vascular bed by increasing arterial pressure
in type I HRS [50] (I). Treatment should be initiated at
a dose of 1 mg/4–6 h (i.v. bolus) and may be increased
to a maximum of 2 mg/4–6 h, if an appropriate therapeutic response cannot be achieved within 3 days [63].
Response to treatment is defined as:
−reversal of HRS or complete response, when serum
creatinine decreases below 1.5 mg/dL;
−partial response, indicated by a decrease of serum creatinine of > 50 %, but not below 1.5 mg/dL;
−no response, when serum creatinine levels do not decrease more than 50 % of pretreatment values.
Response to therapy with vasoconstrictors can be
achieved in approximately 50 % of patients within several
days up to 2 weeks [64–66]. There is no evidence that in
case of nonresponse, the treatment with vasocontrictors
beyond 2 weeks is beneficial.
Recurrence of HRS after withdrawal of therapy is rare
and retreatment with vasoconstrictors is generally effective. In selected patients with recurrent HRS type 1, treatment may be extended for more than 2 weeks and used
13
as a bridging therapy to liver transplantation [67] (II-3).
Predictive factors of response are pretreatment serum
creatinine levels, bilirubin levels, increase in mean arterial pressure through therapy, and age [68, 69].
Although not investigated prospectively in randomized controlled trials, continuous infusion of terlipressin
may achieve response rates comparable with those of i.v.
bolus administration, but possibly with less severe complications [70] (II-2).
Terlipressin is associated with a significant risk of systemic ischemic complications.
Noradrenaline (0.5–3 mg/h starting dose) is an equally
effective and much cheaper alternative to terlipressin. It
is administered as a continuous infusion to achieve a rise
in arterial pressure. It is less well studied than terlipressin, but this regime may be even preferred over terlipressin for less side effects [71] (I).
Another vasoconstrictor reported in the literature but
not in general use in Austria is the alpha adrenergic agonist midodrine. Midodrine is given orally at doses starting from 2.5 to 75 mg/8 h in combination with octreotide
subcutaneously at doses from 100 µg to 200 µg/8 h, but
even higher doses may be necessary to achieve a therapeutic response [72, 73] (II-2).
It is generally accepted that terlipressin and norepinephrine are given in combination with albumin (1 g/
kg on day 1 followed by 40 g/day) in order to improve the
effect of treatment on hemodynamics [74] and should
preferably be administered via a central venous line (II-1).
TIPS in HRS
Basically, insertion of a transjugular intrahepatic portosystemic shunt (TIPS) should be considered in all
patients with HRS. TIPS has been shown to improve renal
function in type 1 and 2 HRS [72, 75, 76]. Although TIPS
may be effective in reversing HRS in some patients, its
use is often limited due to advanced liver disease with
serum bilirubin exceeding 5 mg/dL or hepatic encephalopathy [76, 77]. TIPS is indicated in selected patients,
mostly with HRS type II and often serves as a bridge to
liver transplantation (III).
Role of renal replacement therapy and artificial
liver support systems
Currently, there are no larger randomized controlled trials
showing a survival benefit for any extracorporeal treatment
modality (neither renal replacement therapy nor liver
support system) for patients with hepatorenal syndrome
[78, 79]. Extracorporeal treatments (both renal replacement therapy and additive liver support systems) can only
provide a bridge to liver transplant, but evidence from
randomized controlled trials is lacking as well. No randomized controlled trials comparing renal replacement
therapy vs. extracorporeal liver support systems looking
at survival benefit have been performed so far. Both treat-
consensus report
ment modalities are comparatively safe methods. The risk
of arterial hypotension is higher with intermittent extracorporeal treatment employing large volume depletion
and should be avoided in hemodynamically impaired
patients. Up to date anticoagulation such as citrate anticoagulation is also safe in patients with advanced stage liver
disease and should preferably be used.
Liver transplantation
Liver transplantation is the treatment of choice for suitable candidates with HRS. Patients should be given high
priority on the waiting list. This relates to type-1 as well
as type-2 HRS (I).
Simultaneous liver kidney transplantation is not
routinely recommended and may only be indicated in
patients with prolonged HRS undergoing renal replacement therapy since recovery of renal function is unusual
in these patients [80].
Prevention of HRS
Long term treatment with norfloxacin (400 mg/day) in
patients with end stage liver disease has been demonstrated to reduce the recurrence of HRS and improved
survival [81] (I).
Short term and long term administration of Pentoxifylline was shown to have beneficial effects on renal
function in patients with severe alcoholic hepatitis and
advanced cirrhosis [82, 83].
Management of vascular liver disease
Noncirrhotic portal hypertension can be caused by vascular disorders of the liver, which encompass a heterogeneous group of diseases with portal hypertension
but without liver cirrhosis. Vascular liver disorders can
sometimes occur in liver cirrhosis—especially BuddChiari syndrome.
The three main vascular liver disorders associated
with portal hypertension are portal vein thrombosis
(PVT), sinusoidal obstruction syndrome (SOS), and
Budd-Chiari syndrome (BCS), where the affected vascular compartments are the portal- and splanchnic veins,
the sinusoids and the hepatic outflow tract, respectively.
Congenital vascular malformations and hereditary
hemorrhagic telangiectasia are rare vascular liver diseases
that can also be associated with portal hypertension.
Epidemiology
1. The lifetime risk of PVT is estimated to be 1 % [84, 85].
Chronic portal vein thrombosis is found in 10–25 % of
patients with nonmalignant liver cirrhosis. Although
data on the epidemiology of acute portal vein thrombo-
Table 1. Risk factors for PVT and BCS
Risk factor
PVT (%)
BCS (%)
Myeloproliferative disease
30–40
40–50
Atypical
14
25–35
Classic
17
10–25
Antiphospholipid syndrome
6–19
4–25
PNH
0–2
0–4
Beçet disease
0–31
0–33
Faktor V Leiden
6–32
6–32
14–40
5–7
10–30
Prothormbin gene-mutation
Protein C deficiency
0–26
Protein S deficiency
2–30
7–20
AT III deficiency
0–26
0–23
Plasminogen deficiency
0–6
0–4
Recent pregnancy
6–40
6–12
Hormonal contraception
12
6–60
Hyperhomocysteinemia
12–22
37
MTHFR genotype 677TT
11–50
12–22
sis are lacking, acute extrahepatic portal vein thrombosis accounts for up to 30 % of variceal bleeds [86] (IIb).
2. SOS is the most frequent cause of portal hypertension in patients receiving high dose chemotherapy
especially during “conditioning” of patients for bone
marrow transplantation. The incidence of SOS is up to
10 % in a large cohort study of European bone marrow
transplant recipients. SOS has also been associated
with drugs listed in Table 1 and plant alkaloids (IIb). 3. All forms of hepatic venous outflow tract obstruction
are referred to as Budd-Chiari syndrome, independent of the level or cause of obstruction [87, 88]. The
mean age-standardized incidence and prevalence
of BCS in a Swedish cohort was estimated to be 0.8
per million per year and 1.4 per million, respectively
[89]. The main causes of primary BCS are prothrombotic conditions, which have been identified in 77 %
of patients with BCS. Myeloproliferative disorders are
single most important prothrombotic condition identified in 39 % of patients with BCS [90]. Additional prothrombotic risk factors associated with BCS and PVT
are listed in Table 1 (IIb).
Pathophysiology
1. JAK2 positive myeloproliferative disorders have been
reported in 20 to 35 % of patients with acute PVT
[91–93]. Other causes of thrombophilia frequently
identified in patients with portal vein thrombosis include protein S and protein C deficiency, antithrombin
III deficiency, paroxysmal nocturnal hemoglobinuria.
2. Accepted risk factors for SOS are toxic conditioning
regimens for bone marrow transplantation especially
regimens including cyclophosphamide in combination with either busulfan (especially when given orally) or total body irradiation or regimens that include
13
consensus report
Table 2. Drugs associated with SOS
6-mercaptopurine
6-thiogunanine
Actinomycin D
Azathioprine
Busulfan
Cytosine arabinoside
Cyclophosphamide
Dacarbazine
systemic thrombophilic conditions listed in Table 1.
The absence of elevated platelet counts or elevated
hematocrit or negative testing for the JAK2 mutation
p.Val617Phe are insufficient to exclude myeloproliferative disease (IIc).
5. Sinusoidal obstruction syndrome should be considered in patients who received total body irradiation or
drugs listed in Table 2 (typically patients being conditioned for marrow transplantation), who present with
portal hypertension and hyperbilirubinemia (IIc).
Gemzutumab-ozogamicin
Melphalan
Management of noncirrhotic portal hypertension
Oxaliplatn
Urethane
N, N-bis(2-chloroethyl)-N-nitrosourea (BCNU) or
multiple alkylating agents [94] (Table 2). As no established causal treatment exists, management should
include prophylactic management strategies avoiding
the precipitating factors. 3. BCS and portal vein thrombosis have similar pathophysiology where, in addition to local factors such
as liver abscess and abdominal trauma, the acquired
causes such as Behçet’s disease, hypereosinophilic
syndrome, and granulomatous venulitis are risk factors. Weak risk factors for BCS include factor V Leiden
and prothrombin gene mutations and oral contraceptive use (at least with earlier generation contraceptives until 1985) [95].
4. Investigations for vascular liver diseases as underlying
cause or precipitating factor should be carried out in
all patients with clinical manifestation of decompensated portal hypertension.
Comprehensive guidelines [95], a systematic meta analysis [96] and authoritative reviews [97–99] have been published on vascular disorders of the liver, which allow us to
give the following recommendations:
Diagnosis
1. In all patients with first presentation or worsening of
portal hypertension, duplex sonography of the portal vein and hepatic veins should be carried out to
exclude portal vein thrombosis or Budd-Chiari syndrome (III).
2. In patients with high clinical suspicion, contrast enhanced CT, MRI, or angiography should be carried
out despite normal ultrasound to exclude or confirm
portal vein thrombosis or Budd-Chiari syndrome (III).
3. Acute portal vein thrombosis (with or without concomitant intestinal infarction) should be considered
in all patients with abdominal pain for more than 24 h
(III).
4. Portal vein thrombosis and Budd-Chiari syndrome
should prompt investigations for local prothrombotic
conditions (infection, abscess, tumor, cysts, etc.) and
13
1. Whenever possible, correct the underlying risk factor
for venous thrombosis (III).
2. The possibility for correcting venous outflow in BCS
by angioplasty or the possibility to increase portal
flow in BCS or PVT by insertion of a TIPS should be
evaluated by an experienced interventionist. TIPS improves transplant-free survival in BCS but not in SOS
[95] (IIc).
3. Patients with PVT or BCS should receive anticoagulation therapy for at least 3 months unless liver transplantation is imminent. For patients with a permanent
prothrombotic condition, lifelong anticoagulation is
advisable. Low molecular weight heparins are initiated and shifted to oral anticoagulation after stabilization of the patient. In patients with high bleeding
risk, therapeutic drug monitoring of LMW heparin is
recommended (anti F Xa level 0.5–0.8 IU/ml). The target INR for oral anticoagulation is 2–3 (IIb).
4. Patients with PVT or BCS should be screened for
esophageal or gastric varices. Large varices should be
managed endoscopically before long term anticoagulation is initiated (III).
5. Long term anticoagulation is recommended in patients with an unknown cause or thrombus extension
into the mesenteric vein (III).
6. Liver transplantation should be considered in all
patients with noncirrhotic portal hypertension and
significant liver failure. This includes patients with
recently diagnosed BCS and patients with SOS and a
favorable hematological prognosis (III).
Hepato-pulmonary vascular disorders
Portopulmonary hypertension
Definition
Portopulmonary hypertension (PPHTN) is kind of pulmonary hypertension that is associated with portal
hypertension.
PPHTN is defined as [100, 101]:
1. Underlying disease with portal hypertension
2. Mean pulmonary artery pressure (PAPm) > 25 mmHg
consensus report
3. Mean pulmonary artery occlusion pressure < 15 mmHg
Pulmonary vascular resistance > 240 dyn×sec×cm−5 is
recommended additionally by the ERS Task Force Pulmonary-Hepatic Vascular Disorders [101].
Staging of severity [2]
Mild PAPm > 25 mmHg–< 35 mmHg
Moderate PAPm ≥ 35 mmHg–45 mmHg
Severe PAPm ≥ 45 mmHg
PPHTN is a frequent cause of pulmonary hypertension
[102]. Its prevalence in patients with cirrhosis that are
listed for liver transplantation ranges between 2–16 %
(II-2). PPHTN is the second most common cause of pulmonary-hepato-pulmonary vascular disorder in patients
with cirrhosis [103–109] (II-2).
Diagnosis
Symptoms of portal hypertension usually occur prior to
symptoms of pulmonary hypertension (dyspnea, syncope, chest pain) [110, 111] (II-2). Patients with portal
hypertension and dyspnea at rest and during exercise
should be tested for presence of PPHTN. They should
undergo transthoracic echocardiographic evaluation
including contrast-enhanced echocardiography to rule
out hepatopulmonary syndrome (III).
Patients with estimated systolic pulmonary artery
pressure > 40–50 mmHg or signs of abnormal right
ventricular function via transthoracic echocardiography should undergo pulmonary artery catheterization,
which is the gold standard for assessment of pulmonary
hemodynamics.
Preferably, this testing should be performed in addition to hepatic hemodynamic assessment in the hepatic
catheter laboratory. Also, pulmonary function testing
including arterial blood gas analysis, thoracic CT scan,
pulmonary angiography and/or ventilation–perfusion
scan, assessment of autoantibodies (ANA, ANCA,…), and
HIV status are recommended [100, 101].
Therapy
Several case series reported effects of medical therapy
of PPHTN. Currently, there is a lack of randomized controlled studies. Patients that suffer from NYHA II dyspnea
or higher despite optimized therapy of portal hypertension, should receive medical therapy [101] (II-2). This
could include:
• P
rostaglandin-derivates (Epoprostenol, Iloprost,…)
improved pulmonary hemodynamics and exercise capacity [112–116] (II-2).
• C
ase series using endothelin receptor antagonists
(Bosentan, Ambrisentan) reported improved pulmonary hemodynamics without adverse events on the
hepatic function [117–120] (II-2).
• Sildenafil improved pulmonary hemodynamics in a
small uncontrolled cohort [118] (II-2).
• Long term oxygen therapy (LTOT) is recommended in
patients with PaO2 < 60 mmHg [101] (III).
• Beta-blocking agents have deleterious effects on hemodynamics and exercise capacity in patients with
PPHTN and should be strictly avoided [121] (II-2).
• Calcium channel blockers are not recommended as
they may increase HVPG [101] (III).
• Systemic anticoagulation cannot be recommended
for all patients because of the lack of data and because
it may increase the risk of bleeding. Administration
should be performed after individualized evaluation
of the risk-benefit ratio [101] (III).
• TIPS is not recommended in PPHTN as it may increase
the risk of right heart decompensation [101] (III).
• Liver transplantation is an effective treatment option
of PPHTN. However, patients must be stratified according to severity of PPHTN [101] (II-2):
1. Patients with mild PPHTN (PAPm < 35 mmHg,
good cardiac function) should proceed to liver
transplantation.
2. Patients with moderate PPHTN (PAPm ≥ 35 mmHg–
45 mmHg, good cardiac function) should receive
vasodilator therapy prior to liver transplantation.
3. Liver transplantation is contraindicated in patients
with severe PPHTN (PAPm ≥ 45 mmHg). These
patients should be considered for medical therapy
of PPHTN, only.
Hepatopulmonary syndrome
Definition
Hepatopulmonary syndrome (HPS) is the most common
hepatopulmonary vascular disorder in patients with liver
cirrhosis with a prevalence of 20–30 % [122, 123] (II-2). It
is defined as gas exchange abnormality as a consequence
of liver disease due to intrapulmonary vascular dilatation
and shunting [101].
Diagnostic criteria of HPS are:
1. Presence of liver disease.
2. Gas exchange abnormality (alveolar arterial oxygen
tension difference (AaDO2) ≥ 15 mmHg or AaDO2
≥ 20 mmHg in patients for patients aged > 64 years,
respectively.
3. Positive contrast-enhanced echocardiography (intrapulmonary shunting is defined as detection of microbubbles in the left atrium 4–6 heartbeats after the initial appearance in the right side of the heart).
13
consensus report
Staging of severity
Dr. Bernhard Angermayr
Landesklinikum St. Pölten,
2. Medizinische Abteilung
Severity of HPS will be staged according to criteria mentioned below [101] (III):
Dr. Eva Brownstone
KA Rudolfstiftung, 4. Medizinische
Abteilung
Theresa Bucsics
Univ.-Klinik für Innere Medizin III, AKH
Prim. Dr. Christian Datz
Krankenhaus Oberndorf, Abteilung Innere
Medizin
Dr. Arnulf Ferlitsch
PD Dr. Valentin Fuhrmann
Univ.-Prof. Dr. Ivo Graziadei
Klinische Abteilung für Gastroenterologie
und Hepatologie, Medizinische Universität
Innsbruck
Dr. Evelyn Grilnberger
Otto Wagner Spital
Prim. Dr. Michael Häfner
KH St. Elisabeth, Interne Abteilung
Dr. Birgit Heinisch
Dr. Sadia Hoppe
KH Hietzing, I. Medizinische Abteilung
Dr. Thomas Horvatits
Prim. Dr. Andreas Kirchgatterer
V. Interne Abteilung, Klinikum Wels
Prim. Dr. Peter Knoflach
Klinikum Wels-Grieskirchen, Abteilung für
Innere Medizin I
Dr. Andreas Kopecky
Thermenklinikum Baden, Interne
Abteilung
Dr. Peter Kotlan
Ordination Markt Priestling
Prof. Dr. Ludwig Kramer
Krankenhaus Hietzing, 1. Medizinische
Abteilung mit Gastroenterologie
Dr. Anna Kreil
Otto Wagner Spital
Waltraud Leiss
Dr. Simone Luszczak
Landesklinikum St. Pölten,
2. Medizinische Abteilung
Prim. Dr. Christian Madl
Abteilung
Dr. Andreas Maieron
Krankenhaus St. Elisabeth Linz, 4. Interne
Abteilung
Dr. Ilona Marszalek
Ordination Dr. Biowski-Frotz, Wien
Prof. Dr. Christian Müller
Dr. Roland Nömeyer
Klinikum Wels-Grieskirchen, Abteilung für
Innere Medizin I
Dr. Julia Palkovits
Dr. Berit Anna Payer
Prof. Dr. Markus PeckRadosavljevic
Prim. Dr. Johann Pidlich
Thermenklinikum Baden, Interne
Abteilung
Dr. Csilla Putz-Bankuti
Universitätsklinik für Innere Medizin,
LKH Graz
Dr. Thomas Reiberger
1. Mild HPS: AaDO2 ≥ 15 mmHg, PaO2 ≥ 80 mmHg
2. Moderate HPS: AaDO2 ≥ 15 mmHg, PaO2 < 80 mmHg– ≥ 60 mmHg
3. Severe HPS: AaDO2 ≥ 15 mmHg, PaO2 < 60 mmHg– ≥ 50 mmHg
4. Very severe HPS: AaDO2 ≥ 15 mmHg, PaO2 < 50 mmHg
(< 300 mmHg on 100 % oxygen)
Diagnosis
HPS positive patients should undergo lung perfusion scanning for intrapulmonary shunt quantification and should
have pulmonary function testing and pulmonary imaging (chest x-ray and thoracic computed tomography) for
exclusion of other structural pulmonary diseases. Pulmonary artery catheterization should be performed at least in
patients with severe and very severe HPS for assessment of
intrapulmonary shunting, cardiac index, and exclusion of
additional portopulmonary hypertension (III).
Therapy
Patients with mild and moderate HPS should have control blood gas analysis at regular intervals as HPS is a progressive disease [124] (II-2).
Long term oxygen therapy (LTOT) should be started
in patients with severe and very severe HPS (PaO2
< 60 mmHg). Oxygen supply should be adjusted to raise
PaO2 > 60 mmHg (III).
Patients with severe HPS should be listed for liver
transplantation only due to the severity of gas exchange
abnormality as transplantation is the only proven therapy of HPS. They should receive an exceptional position ranking comparable to patients with hepatocellular
carcinoma (III). Evaluation for liver transplantation in
patients with very severe HPS should be based on an
individualized risk–benefit assessment as the cardiopulmonary complication rate has significantly increased in
these patients following transplantation [101] (III).
Appendix
Participants “Billroth II”, 2. ÖGGH-Consensus Conference “Portal Hypertension”, Palais Clam Gallas, Vienna
011011
13
Dr. Birgit Reinhart
Dr. Karoline Reinhart
consensus report
Dr. Petra Salzl
Dr. Monika Schmid
Dr. Christiane Schrutka
Abteilung
Dr. Bernhard Stadler
Klinikum Wels-Grieskirchen
Prof. Dr. Rudolf Stauber
Medizinische Universität Graz, Abteilung
Gastroenterologie und Hepatologie
Dr. Philipp Steininger
Krankenhaus St. Elisabeth Wien, Interne
Abteilung
Prof. Dr. Rudolf Steininger
Universitätsklinik für Chirurgie,
Medizinische Uni Wien
Prim. Dr. Siegfried Thurnher
Krankenhaus Barmherzige Brüder Wien,
Radiologie und Nuklearmedizin
Prof. Dr. Michael Trauner
Prof. Dr. Barbara Tribl
Dr. Gregor Ulbrich
Prim. Prof. Dr. Wolfgang Vogel
Innsbruck
Dr. Martina Wichlas
KH Barmherzige Brüder, II. Medizinische
Abteilung
Dr. Afrodite Zendeli
KH Barmherzige Brüder, II. Medizinische
Abteilung
Prof. Dr. Heinz Zoller
Innsbruck
Acknowledgments
We would like to thank Ms. Alexandra Weisgram for the
coordination of the meeting and the editorial assistance
during the consensus meeting and Ms. Andrea Reichel
for her assistance during the consensus meeting.
Conflict of interest
A. Ferlitsch: Consultant for Pejcl Medizintechnik, Austria;
Boston Scientifc: Travel expenses; Boston Scientific, Cook
Medical, Ferring: Sponsoring of dedicated meetings.
V. Fuhrmann: Forschungsunterstützung von den Firmen Actelion, Air Liquide und Vivisol.
T. Reiberger: Roche (speaking/teaching, travel grant),
MSD (speaking/teaching, research grant), Phenex Pharma (research grant), Gilead Sciences (research grant,
travel grant), Janssen (research grant).
Rest of the authors declare that there are no actual or
potential conflicts of interest in relation to this article.
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