Position Paper
`
`Revising consensus in portal hypertension: Report of the Baveno V
`consensus workshop on methodology of diagnosis and therapy
`in portal hypertension
`
`Roberto de Franchis*, On behalf of the Baveno V Faculty 1
`
`Department of Medical Sciences, University of Milan, Head, Gastroenterology 3 Unit, IRCCS Ca’ Granda Ospedale Maggiore Policlinico Foundation,
`Milan, Italy
`
`Introduction
`
`Portal hypertension is associated with the most severe complica-
`tions of cirrhosis, including ascites, hepatic encephalopathy, and
`bleeding from gastro-esophageal varices. Despite the progress
`achieved over the last decades, the 6-week mortality associated
`with variceal bleeding is still in the order of 10–20%. Awareness
`of the difficulty inherent to the evaluation of diagnostic tools and
`the design and conduct of good clinical trials for the treatment of
`portal hypertension has led to the organization, since 1986, of a ser-
`ies of consensus meetings. The first one was organized by Andrew
`Burroughs in Groningen, The Netherlands [1]. After Groningen,
`other meetings followed, in Baveno in 1990 (Baveno I) [2] and in
`1995 (Baveno II) [3,4], in Milan in 1992 [5], in Reston, USA, in
`1996 [6], in Stresa in 2000 (Baveno III) [7,8], again in Baveno in
`2005 (Baveno IV) [9,10], and in Atlanta in 2007 [11].
`The aims of these meetings were to develop definitions of key
`events in portal hypertension and variceal bleeding, to review the
`existing evidence on the natural history, the diagnosis and the
`therapeutic modalities of portal hypertension, and to issue evi-
`dence-based recommendations for the conduct of clinical trials
`and the management of patients. All these meetings were suc-
`cessful and produced consensus statements on some important
`points, although some issues remained unsettled.
`To continue the work of the previous meetings, a Baveno V
`workshop was held on May 21–22, 2010. The workshop was
`attended by many of the experts responsible for most of the
`major achievements of the last years in this field. Many of them
`had attended the previous meetings as well.
`The main fields of discussion of the Baveno V workshop were
`the same as in Baveno I–IV, i.e. the definitions of key events con-
`cerning the bleeding episode and the therapeutic options in
`patients with portal hypertension. For each of these topics, a ser-
`ies of consensus statements were discussed and agreed upon. As
`in Baveno IV, whenever applicable, the level of existing evidence
`was evaluated and the recommendations were ranked according
`to the Oxford System [12] (i.e.: level of evidence from 1 = highest
`
`Received 9 June 2010; received in revised form 12 June 2010; accepted 14 June 2010
`* Address: Gastroenterology 3 Unit,
`IRCCS Ca’ Granda Ospedale Maggiore
`Policlinico Foundation, Milan, Padiglione Beretta Est, Via F Sforza 35, 20122
`Milan, Italy. Tel.: +39 02 5503 5331/2; fax: +39 02 5503 5271.
`E-mail address: roberto.defranchis@unimi.it.
`1 The members of Baveno V Faculty given before references.
`
`to 5 = lowest; grade of recommendation from A = strongest, to
`D = weakest).
`The presentations given during the workshop are reported ‘in
`extenso’ in the Baveno V proceedings [13]. A summary of the most
`important conclusions is reported here.
`
`Definition of key events regarding the bleeding episode
`
`Definitions and criteria to evaluate failure to control bleeding and
`failure to prevent re-bleeding were introduced at Baveno II [3,4]
`and reviewed at Baveno III [7,8]. Since it was found that some of
`them were rather difficult to apply and did not adequately reflect
`the situation in clinical practice, new definitions and criteria were
`proposed at Baveno IV [9,10].
`The Baveno IV criteria are reported below:
`
`Baveno IV definitions and criteria for failure to control bleeding
`
`(1) The time frame for the acute bleeding episode should be
`120 h (5 days).
`(2) Failure signifies the need to change therapy: one criterion
`defines failure, whichever occurs first:
`a. Fresh hematemesis P2 h after the start of a specific
`drug treatment or therapeutic endoscopy. In the
`minority of patients who have a naso-gastric tube
`in place, aspiration of greater than 100 ml of fresh
`blood represents failure.
`b. 3 g drop in Hb (9% drop in Ht) if no transfusion is
`administered.
`c. Death
`d. Adjusted blood transfusion requirement index (ABRI,
`see below) P0.75 at any time point. (The threshold of
`ABRI defining failure requires validation).
`
`Adjusted blood requirement index (ABRI)
`
`ABRI ¼ Blood Units transfused
`½final Ht initial HtÞ þ 0:1Š
`- Ht (or Hb) is measured at least every:
`6 h for the first 2 days
`12 h for days 3–5
`- The transfusion target should be an haematocrit of 24% or a
`haemoglobin of 8 g/dl.
`
`Journal of Hepatology 2010 vol. 53 j 762–768
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`Baveno IV definitions and criteria for failure of secondary prophylaxis
`
`Failure to prevent re-bleeding is defined as a single episode of
`clinically significant
`re-bleeding from portal hypertensive
`sources.
`Clinically significant re-bleeding:
`(a) Hematemesis/melaena. In the minority of patients who
`have a naso-gastric tube in place, aspiration of greater than
`100 ml of fresh blood represents failure, plus
`(b) Adjusted Blood Requirement Index (ABRI) P0.5 (The
`threshold of ABRI defining failure requires validation), or
`(c) Decrease 3 g of Hb if no transfusion is given.
`After Baveno IV, the diagnostic performance of the Baveno
`II–III and Baveno IV criteria was evaluated by analysing the
`population of a study of the use of recombinant factor VII in
`acute variceal bleeding [14]. The conclusions of the study were
`as follows: Baveno IV criteria have a rather high accuracy; ABRI
`in its current definition does not add to the accuracy of the
`other Baveno IV criteria; the best timing for measurement of
`hematocrit and the ideal cut off value of ABRI score should
`be further investigated.
`As a consequence, at Baveno V the Baveno IV consensus state-
`ments were modified as follows:
`
`Baveno V definitions and criteria for failure to control bleeding
`
`- The time frame for the acute bleeding episode should be
`120 h (5 days).
`- Failure is defined as death or need to change therapy
`defined by one of the following criteria: (2b;B)
`- Fresh hematemesis or NG aspiration of P100 ml of fresh
`blood P2 h after the start of a specific drug treatment or
`therapeutic endoscopy.
`- Development of hypovolaemic shock.
`- 3 g drop in Hb (9% drop of Ht) within any 24 h period if no
`transfusion is administered. This time frame needs to be
`further validated.
`- The potential value of an index of blood transfusion
`requires prospective validation (5;D).
`
`Baveno V definitions and criteria for failure of secondary prophylaxis
`
`- Failure to prevent re-bleeding is defined as a single episode
`of clinically significant re-bleeding from portal hyperten-
`sive sources after day 5 (5;D).
`- Clinically significant re-bleeding: recurrent melena or
`hematemesis resulting in any of the following:
`
`1. hospital admission,
`2. blood transfusion,
`3. 3 g drop in Hb,
`4. death within 6 weeks.
`
`Areas requiring further study (5;D)
`
`JOURNAL OF HEPATOLOGY
`Expected response to transfusions/within determined
`policy of transfusion.
`
`Therapeutic options in patients with portal hypertension
`
`Pre-primary prophylaxis (prevention of the formation of varices)
`
`Background
`
`- Prevention of the development of complications of portal
`hypertension is an important area of research (5;D).
`- Hepatic venous pressure gradient (HVPG) P10 mm Hg is pre-
`dictive of varices formation and decompensation (1b;A).
`
`Recommendations for management
`
`- All cirrhotic patients should be screened for varices at diagno-
`sis (5;D).
`- Pre-primary prophylaxis should only include patients without
`gastro-esophageal varices (5;D).
`- Treatment of underlying liver disease may reduce portal
`hypertension and prevent its clinical complications (1b;A).
`- There is no indication, at this time, to use beta-blockers to pre-
`vent the formation of varices (1b;A).
`- HVPG measurement in pre-primary prophylaxis may be rec-
`ommended only in the context of clinical trials (5;D).
`
`Areas requiring further study (5;D)
`
`- Basic mechanisms in the development and progression of por-
`tal hypertension.
`- Non-invasive techniques to identify patients with clinically
`significant portal hypertension.
`- The impact of treating the underlying chronic liver disease in
`the development of varices and other portal hypertensive
`related complications.
`- Treatments to prevent the development of varices and other
`portal hypertensive related complications in different risk
`groups (e.g. patients with HVPG between 6 and 10 mm Hg
`and those with HVPG P10 mm Hg).
`
`Prevention of the first bleeding episode
`
`Patients with small varices
`
`- Patients with small varices with red wale marks or Child C
`class have an increased risk of bleeding (1b;A) and should be
`treated with nonselective beta-blockers (NSBB) (5;D).
`- Patients with small varices without signs of increased risk may
`be treated with NSBB to prevent progression of varices and
`bleeding (1b;A). Further studies are required to confirm their
`benefit.
`
`Patients with medium-large varices
`
`- Prospective validation of Baveno IV and V criteria and compar-
`ison with Baveno II and III definitions.
`- Interactions of time events with prognostic factors.
`- Definition and usefulness of a transfusion index for failure
`criteria:
`Clinical applicability.
`Appropriate for randomised trials.
`
`- Either NSBB or endoscopic band ligation (EBL) is recom-
`mended for the prevention of the first variceal bleeding of
`medium or large varices (1a; A).
`- The choice of treatment should be based on local resources
`and expertise, patient preference and characteristics, side
`effects, and contra-indications (5;D).
`
`Journal of Hepatology 2010 vol. 53 j 762–768
`
`763
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`

`Position Paper
`- Carvedilol is a promising alternative (1b;A) which needs to be
`further explored.
`- Shunt
`therapy, endoscopic sclerotherapy, and isosorbide
`mononitrate alone should not be used in the prophylaxis of
`first variceal bleeding (1a;A).
`- There is insufficient data to recommend the use of NSBB in
`combination with Isosorbide-5-Mononitrate (ISMN), spirono-
`lactone, or EBL for primary prophylaxis (1b;A).
`
`Patients with gastric varices
`
`- Despite the absence of specific data on prophylactic studies,
`patients with gastric varices may be treated with NSBB (5;D).
`
`Role of HVPG measurement
`
`- In centers where adequate resources and expertise are avail-
`able, HVPG measurements should be routinely used for prog-
`nostic and therapeutic indications (5;D).
`- Controlled trials using pharmacological therapy in primary
`prophylaxis should include HVPG measurements (5;D).
`- A decrease in HVPG of at least 20% from baseline or to
`612 mm Hg after chronic treatment with NSBB is clinically
`relevant in the setting of primary prophylaxis (1a;A).
`- Acute HVPG response to intravenous propranolol may be used
`to identify responders to beta-blockers, specifically a decrease
`in HVPG of 10% or to 612 mm Hg may be relevant in this set-
`ting (1b;A).
`
`Prevention of hepatic encephalopathy
`
`- Recommendations regarding management and prevention of
`encephalopathy in patients with cirrhosis and upper GI bleeding
`cannot be made on the basis of currently available data (5;D).
`
`Assessment of prognosis
`
`- HVPG P20 mm Hg, Child-Pugh class C, and active bleeding at
`endoscopy are the variables most consistently found to predict
`5-day treatment failure (2b;B).
`- Child-Pugh class C, MELD score P 18, and failure to control
`bleeding or early re-bleeding are the variables most consis-
`tently found to predict 6-week mortality (2b;B).
`
`Timing of endoscopy
`
`- Patients with GI bleeding and features suggesting cirrhosis
`should have upper endoscopy as soon as possible after admis-
`sion (within 12 h) (5;D).
`
`Pharmacological treatment
`
`- In suspected variceal bleeding, vasoactive drugs should be
`started as soon as possible, before endoscopy (1b;A).
`- Vasoactive drugs
`(terlipressin,
`somatostatin, octreotide,
`vapreotide) should be used in combination with endoscopic
`therapy and continued for up to 5 days (1a;A).
`
`Areas requiring further study
`
`Endoscopic treatment
`
`- Studies evaluating the use of carvedilol.
`- Studies evaluating novel therapeutic options.
`
`Treatment of acute bleeding from varices
`
`Blood volume restitution
`
`- The goal of resuscitation is to preserve tissue perfusion. Vol-
`ume restitution should be initiated to restore and maintain
`hemodynamic stability.
`- PRBC transfusion should be done conservatively at a target
`hemoglobin level between 7 and 8 g/dl., although transfusion
`policy in individual patients should also consider other factors
`such as co-morbidities, age, hemodynamic status and ongoing
`bleeding (1b;A).
`- Recommendations regarding management of coagulopathy
`and thrombocytopenia cannot be made on the basis of cur-
`rently available data (5;D).
`- PT/INR is not a reliable indicator of the coagulation status in
`patients with cirrhosis (1b;A).
`
`Antibiotic prophylaxis
`
`- Antibiotic prophylaxis is an integral part of therapy for
`patients with cirrhosis presenting with upper gastrointestinal
`bleeding and should be instituted from admission (1a;A).
`- Oral quinolones are recommended for most patients (1b;A).
`- Intravenous ceftriaxone should be considered in patients with
`advanced cirrhosis (1b;A), in hospital settings with high prev-
`alence of quinolone-resistant bacterial
`infections and in
`patients on previous quinolone prophylaxis (5;D).
`
`- Endoscopic therapy is recommended in any patient who pre-
`sents with documented upper GI bleeding and in whom
`esophageal varices are the cause of bleeding (1a;A).
`- Ligation (EVL) is the recommended form of endoscopic ther-
`apy for acute esophageal variceal bleeding, although sclero-
`therapy may be used in the acute setting if
`ligation is
`technically difficult (1b;A).
`- Endoscopic therapy with tissue adhesive (e.g. N-butyl-cyano-
`acrylate) is recommended for acute bleeding from isolated
`gastric varices (IGV) (1b;A) and those gastro-esophageal vari-
`ces type 2 (GOV2) that extend beyond the cardia (5;D).
`- EVL or tissue adhesive can be used in bleeding from gastro-
`esophageal varices type 1 (GOV1) (5;D).
`
`Early TIPS placement
`
`- An early TIPS within 72 h (ideally 624 h) should be considered
`in patients at high-risk of treatment failure (e.g. Child-Pugh
`class C <14 points or Child class B with active bleeding) after
`initial pharmacological and endoscopic therapy (1b;A).
`
`Use of balloon tamponade
`
`- Balloon tamponade should only be used in massive bleeding
`as a temporary ‘‘bridge” until definitive treatment can be insti-
`tuted (for a maximum of 24 h, preferably in an intensive care
`facility) (5;D).
`
`Use of self-expandable metal stents
`
`self-expanding covered
`that
`- Uncontrolled data suggest
`esophageal metal stents may be an option in refractory
`
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`

`esophageal variceal bleeding, although further evaluation is
`needed (4;C).
`
`Management of treatment failures
`
`- Persistent bleeding despite combined pharmacological and
`endoscopic therapy is best managed by TIPS with PTFE-cov-
`ered stents (2b;B).
`- Re-bleeding during the first 5 days may be managed by a sec-
`ond attempt at endoscopic therapy. If re-bleeding is severe,
`PTFE-covered TIPS is likely the best option (2b;B).
`
`Areas requiring further study
`
`- The need for correction of coagulation disorders. Influence of
`coagulopathy and thrombocytopenia on outcome.
`- Improve prognostic models: Better stratification of risk to
`determine timing of the initial endoscopy, duration of drug
`therapy and type of treatment.
`- Treatment and prevention of HE.
`- Best antibiotic.
`- Role of self-expandable esophageal stents.
`- Treatment of gastric varices.
`- Treatment of paediatric patients: no studies define the best
`approach.
`- Treatment of bleeding ectopic varices like duodenal varices.
`- Role of erythromycin before endoscopy.
`
`Prevention of re-bleeding
`
`Time to start secondary prophylaxis
`- Secondary prophylaxis should start as soon as possible from
`day 6 of the index variceal episode (5;D).
`- The
`start
`time of
`secondary prophylaxis
`documented.
`
`should be
`
`Patients with cirrhosis
`
`- Combination of beta-blockers and band ligation is the pre-
`ferred therapy as it results in lower re-bleeding compared to
`either therapy alone (1a;A).
`- Hemodynamic response to drug therapy provides information
`about re-bleeding risk and survival (1a;A).
`- The addition of ISMN to beta-blockers may improve the effi-
`cacy of treatment in hemodynamic non-responders (5;D).
`
`Patients with cirrhosis who are unable or unwilling to be treated
`with EVL
`- Beta-blockers with Isosorbide Mononitrate is the preferred
`option (1a;A).
`
`Patients with cirrhosis who have contra-indications or intolerance to
`beta-blockers
`- Band ligation is the preferred treatment (5;D).
`
`Patients who fail endoscopic and pharmacological treatment for the
`prevention of re-bleeding
`
`- Transjugular Intra-hepatic Porto-systemic Shunt (TIPS) with
`Polytetrafluoroethylene (PTFE)-covered stents is effective and
`is the preferred option. Surgical shunt in Child-Pugh A and B
`patients is an alternative if TIPS is unavailable (2b;B).
`
`JOURNAL OF HEPATOLOGY
`- Transplantation provides good long-term outcomes in appro-
`priate candidates and should be considered (2b;B). TIPS may
`be used as a bridge to transplantation (4;C).
`
`Patients who have bled from isolated gastric varices type I (IGV1) or
`gastro-oesophageal varices type 2 (GOV2)
`- N-butyl-cyanoacrylate (1b;A) or TIPS (2b;B) are recommended.
`
`Patients who have bled from gastro-oesophageal varices type 1 with
`(GOV1)
`- May be treated with N-butyl-cyanoacrylate, band ligation of
`oesophageal varices or beta-blockers (2b;B).
`
`Patients who have bled from portal hypertensive gastropathy
`- Beta-blockers (1b;A) should be used for prevention of recur-
`rent bleeding.
`
`Patients in whom beta-blockers are contraindicated or fail and who
`cannot be managed by non-shunt therapy
`- TIPS (4;C) or surgical shunts (4;C) should be considered.
`
`Non-cirrhotic portal hypertension
`
`Similar to Baveno IV, a session in Baveno V was devoted to non-
`cirrhotic portal hypertension, focusing on the Budd-Chiari syn-
`drome and extra-hepatic portal vein obstruction.
`
`Budd-Chiari syndrome [BCS – hepatic venous outflow tract
`obstruction (HVOTO)]
`
`Definition
`- Budd-Chiari syndrome can be located from the level of the
`small hepatic veins to the level of the termination of inferior
`vena cava into the right atrium.
`- BCS is a heterogeneous condition with regard to causes and
`pathogenesis.
`- BCS is considered secondary when the mechanism for HVOTO
`is compression/invasion by a benign or malignant tumour,
`abscess or cyst.
`- BCS is considered primary otherwise.
`
`Aetiology
`- Myeloproliferative diseases should be investigated in all
`patients with primary BCS, first by testing for V617F JAK2
`mutation in peripheral blood. When V617F JAK2 is undetect-
`able, further tests for myeloproliferative diseases should be
`performed (e.g. molecular testing and bone marrow biopsy)
`(2b;B).
`- When liver synthetic function is impaired, low plasma levels
`of antithrombin, protein C, and protein S should not be con-
`sidered as specific for an inherited defect unless it is already
`known in family members. Similarly, anticardiolipin anti-
`bodies at low titres and increased serum homocysteine lev-
`els may not reflect underlying prothrombotic conditions
`(3b;B).
`
`Diagnosis
`
`- BCS is diagnosed by the demonstration of an obstruction of the
`venous lumen, or by the presence of hepatic vein collaterals
`(4;C).
`
`Journal of Hepatology 2010 vol. 53 j 762–768
`
`765
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`

`Position Paper
`- Liver biopsy is not necessary to make a diagnosis of BCS when
`vascular imaging has demonstrated obstruction of the hepatic
`venous outflow tract (4;C).
`- Liver biopsy is the only means to make a diagnosis of BCS of
`the small intra-hepatic veins (4;C).
`- Hepatic nodules are frequent and most often are benign. HCC
`may occur and therefore the patient should be referred to cen-
`ters experienced in managing BCS (5;D).
`
`Management
`- Controlled clinical trials for BCS have not been performed,
`hence the current recommendations for therapy are based
`on cohort studies and expert opinion (5;D).
`- Management of BCS should be undertaken at centers with
`experience in this condition.
`- Anticoagulation should be recommended to all patients, in the
`absence of major contra-indications (5;D).
`- Previous bleeding related to portal hypertension is not consid-
`ered a major contra-indication for anticoagulation, provided
`appropriate prophylaxis for recurrent bleeding is initiated
`(5;D).
`- Complications of portal hypertension may be treated as rec-
`ommended for the other types of liver diseases (5;D).
`- Stenoses that are amenable to percutaneous angioplasty/
`stenting should be actively looked for, and treated accordingly
`(5;D).
`- TIPS insertion should be attempted by experts when angio-
`plasty/stenting is not feasible, and when the patient does
`not improve on medical therapy (5;D).
`- Liver transplantation should be considered in patients with
`manifestations refractory to the above procedures (5;D).
`- More data are needed to provide a definition of treatment fail-
`ure (5;D).
`- The response to treatment should be closely monitored by
`assessing sodium and water balance, serum ALT levels, serum
`bilirubin level and the occurrence of complications of treat-
`ment (5;D).
`- A satisfactory long term control of the disease is indicated by
`the absence of clinically detectable ascites, jaundice, encepha-
`lopathy, gastrointestinal bleeding, and bacterial
`infection
`together with a good performance status, regardless of liver
`tests (4;C).
`
`Extra-hepatic portal vein obstruction (EHPVO)
`
`Definition
`
`- EHPVO is defined by obstruction of the extra-hepatic portal
`vein with or without involvement of the intra-hepatic portal
`veins and does not include isolated thrombosis of splenic vein
`or superior mesenteric vein (SMV).
`- EHPVO is characterized by features of recent thrombosis or of
`portal hypertension with portal cavernoma as a sequel of por-
`tal vein obstruction.
`- Presence of cirrhosis and/or malignancy should be stated.
`
`Aetiology
`
`- EHPVO is a heterogeneous entity with regards to causes and
`pathogenesis.
`
`- EHPVO is frequently associated with one or several risk factors
`for thrombosis which may be occult at presentation.
`- Presence of cirrhosis, malignancy and other intra-abdominal
`causes such as inflammation, trauma, etc. do not exclude the
`presence of systemic risk factors.
`
`Clinical presentation
`
`- Recent EHPVO: can be assumed when patients present with
`symptoms such as abdominal pain, ascites, or fever in the
`absence of portal cavernoma and porto-systemic collaterals.
`Patients also can be asymptomatic (5;D).
`- Chronic EHPVO: is associated with portal cavernoma.
`
`Diagnosis
`
`- EHPVO is diagnosed by Doppler US, CT, or MRI, which demon-
`strate portal vein obstruction, presence of intraluminal mate-
`rial or portal vein cavernoma.
`
`Natural history
`- The natural course of EHPVO is mainly determined by the
`presence or absence of associated diseases such as cirrhosis
`or malignancy.
`- Most patients with EHPVO in the absence of cirrhosis and
`malignancy have a relatively benign course.
`- Morbidity is mainly related to variceal bleeding, recurrent
`thrombosis, symptomatic portal biliopathy, and hypersplen-
`ism.
`
`Classification
`In classifying EHPVO, the following characteristics should be
`specified (5;D):
`
`
`Site of PVT
` Presentation
` Type of underlying liver disease
` Degree of portal vein occlusion (incomplete or total)
` Extent of
`involvement of extra-hepatic portal venous
`system
`
`Treatment: recent EHPVO: anticoagulation
`- Recent EHPVO rarely resolves spontaneously.
`- In non-cirrhotic patients with symptomatic recent EHPVO,
`low molecular weight heparin should be started immediately
`followed by oral anticoagulant therapy (2b;B). In asymptom-
`atic patients, anticoagulation should be considered.
`- Anticoagulation should be given for at least three months,
`unless an underlying persistent prothrombotic state has been
`documented, in which case life-long anticoagulation is recom-
`mended (5;D).
`- Antibiotic therapy should be given if there is any evidence of
`SIRS/infection (5;D).
`
`Treatment: chronic EHPVO: anticoagulation
`- In patients with chronic EHPVO, there is no consensus on the
`indication for anticoagulant therapy.
`- However, in those patients with a persistent documented pro-
`thrombotic state, anticoagulant therapy can be considered
`(5;D).
`
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`- There is insufficient evidence in favour of interventional ther-
`apy such as TIPS and local thrombolysis.
`
`Treatment: bleeding
`- For primary prophylaxis of variceal bleeding there is insuffi-
`cient data on whether beta-blockers or endoscopic therapy
`should be preferred.
`- For control of acute variceal bleeding, endoscopic therapy is
`effective (2b;B).
`- For secondary prophylaxis endoscopic therapy is effective
`(2a;B). There is preliminary evidence to suggest that beta-
`blockers are as effective as endoscopic ligation therapy.
`- Decompressive surgery or interventional radiological proce-
`dures should be considered for patients with failure of endo-
`scopic therapy (5;D).
`- Mesenteric-left portal vein bypass (Rex bypass) is preferred in
`managing bleeding from paediatric patients with chronic
`EHPVO, if feasible (2b;B).
`
`Portal biliopathy-diagnosis
`- Portal biliopathy is present in nearly all patients with EHPVO.
`In the majority, it is asymptomatic.
`- MRCP is the first line of investigation.
`- ERCP is only recommended if a therapeutic intervention is
`contemplated.
`
`Portal biliopathy-treatment
`Asymptomatic: No treatment (5;D).
`Symptomatic:
`- Bile duct stones: Endoscopic therapy.
` Common bile duct stricture: Endoscopic stenting; (3b;B) and
`porto-systemic shunt surgery should be considered, whenever
`possible, (3b;B). If not relieved by the above, hepatico-jejunos-
`tomy may be considered (3b;B).
`
`Chronic EHPVO in children: treatment
`- Mesenteric-left portal vein bypass (Rex bypass) should be con-
`sidered in all children with complications of chronic EHPVO,
`who should be referred to centers with experience in treating
`this condition (5;D).
`
`Unresolved issues and future studies
`- Prospective data on the frequency and clinical profile of recent
`and chronic EHPVO.
`- Natural history of EHPVO in children vs. adults; hepatic
`dysfunction.
`- Primary prophylaxis of variceal bleeding.
`- Case–control studies on frequency of prothrombotic states in
`EHPVO (particularly in the East), identification of high-risk
`population.
`- Usefulness of long-term anticoagulants, emergency TIPS, Rex
`shunt surgery.
`- Assessment of factors associated with treatment failure, dis-
`ease progression and thrombosis recurrence.
`- Experimental models of recent and chronic EHPVO.
`- Management of ectopic varices.
`
`Other issues
`
`In Baveno IV, a session was devoted to predictive models in por-
`tal hypertension, during which classification stages of cirrhosis
`
`JOURNAL OF HEPATOLOGY
`were proposed. Prospective validation of this classification is
`under way.
`
`Conclusions
`
`The purpose of the consensus definitions about the variceal
`bleeding episode is to use them in trials and other studies on por-
`tal hypertension, as well as in clinical practice. This does not
`mean that authors cannot use their own definitions, but they
`are encouraged to use and evaluate in parallel these Baveno V
`consensus definitions. This should result in some measure of
`standardisation and increased ease of interpretation among dif-
`ferent studies. Equally important, if there are uniformly defined
`end-points, meta-analyses will be based on more homogeneous
`studies, which is an essential pre-requisite of this methodology.
`It is desirable that future studies be reported using these defini-
`tions as part of the evaluation. Change or refinement can then
`take place, as they have at Baveno V with respect to the previous
`consensus meetings, to ensure that the consensus definitions do
`have clinical relevance and are easily applied in practice.
`Several definitions agreed upon in the previous Baveno work-
`shops were taken for granted and not discussed in Baveno V. Inter-
`ested readers can refer to the Baveno I–IV reports [2–4,7–10].
`The suggestions about the topics of future studies reflect the
`opinions of the experts about the areas where new information
`is most needed.
`As long as new diagnostic tools and new treatments appear,
`they will have to be assessed in comparison with present-day
`standards.
`
`Baveno V Faculty
`
`The following were members of the Baveno V scientific committee
`
`Jaime Bosch, Barcelona, Spain; Andrew K Burroughs, London, UK;
`Gennaro D’Amico, Palermo, Italy; Roberto de Franchis, Milan,
`Italy; Guadalupe Garcia-Tsao, West Haven CT, USA; Norman D
`Grace, Boston, MA, USA; Roberto J Groszmann, West Haven, CT,
`USA; Didier Lebrec, Clichy, France; Carlo Merkel, Padua, Italy;
`Massimo Primignani, Milan, Italy; Francesco Salerno, Milan, Italy;
`Shiv K Sarin, New Delhi, India; Thorkild IA Sørensen, Copenhagen,
`Denmark.
`
`The following chaired sessions or symposia
`
`Jaime Bosch, Barcelona, Spain; Andrew K Burroughs, London, UK;
`Juan Carlos Garcia-Pagàn, Barcelona, Spain; Guadalupe Garcia-
`Tsao, West Haven CT, USA; Roberto J Groszmann, West Haven,
`CT, USA; Loren Laine, Los Angeles, CA, USA; Didier Lebrec, Clichy,
`France; Carlo Merkel, Padua, Italy; Shiv K Sarin, New Delhi, India;
`Dominique Thabut, Paris, France; Dominique Valla, Clichy,
`France; Candid Villanueva, Barcelona, Spain.
`
`The following participated in the presentations and the discussion as
`Panelists in the consensus sessions
`
`Argentina: Julio Vorobioff, Rosario; Belgium: Frederik Nevens, Leu-
`ven; Denmark: Flemming Bendtsen, Copenhagen; France: Chris-
`tophe Bureau, Toulouse, Paul Calés, Angers, Jean Pierre Vinel,
`
`Journal of Hepatology 2010 vol. 53 j 762–768
`
`767
`
`Page 6 of 7
`
`BioVie Inc. - Exhibit 2037
`Mallinckrodt Pharmaceuticals Ireland Limited v. BioVie Inc.
`IPR No. 2018-00974
`
`

`

`Position Paper
`Toulouse; Germany: Tilman Sauerbruch, Bonn; India: Ashish
`Kumar, New Delhi, Yogesh Chawla, Chandigarh; Italy: Giovanni
`Barosi, Pavia, Gennaro D’Amico, Palermo, Alessandra Dell’Era,
`Milan, Manuela Merli, Rome, Massimo Primignani, Milan; Paki-
`stan: Shaha Abid, Karachi; Spain: Agustin Albillos, Alcalà de Hen-
`ares, Angels Escorsell, Barcelona, Cristina Ripoll, Madrid; Taiwan:
`Gin Ho Lo, Taipei; The Netherlands: Harry Janssen, Rotterdam;
`United Kingdom: Peter Hayes, Edinburgh; United States: Norman
`D Grace, Boston, MA, Patrick Kamath, Rochester, MN.
`
`The following gave review lectures
`
`Juan G Abraldes, Barcelona, Spain; Rafael Bañares, Madrid, Spain;
`Annalisa Berzigotti, Barcelona, Spain; Laurent Castéra, Bordeaux,
`France; Roberto de Franchis, Milan,
`Italy; Gennaro D’Amico,
`Palermo, Italy; Juan Carlos Garcia-Pagàn, Barcelona, Spain; Simon
`Ling, Toronto, Canada; Brian S Mittmann, Los Angeles, CA, USA;
`Richard Moreau, Clichy, France; Massimo Pinzani, Florence, Italy;
`Marco Senzolo, Padua, Italy; Benjamin Shneider, Pittsburgh, PA,
`USA; Thorkild IA Sørensen, Copenhagen, Denmark; Armando Tri-
`podi, Milan, Italy.
`
`Conflict of interest
`
`The authors who have taken part in this study declared that they
`do not have anything to disclose regarding funding or conflict of
`interest with respect to this manuscript.
`
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