Baveno VII – Renewing consensus in portal hypertension

Description of HVPG measurement

• 1.1.

  The use of an end-hole, compliant balloon occlusion catheter reduces the random error of wedged hepatic vein pressure (WHVP) measurements and is preferred over the use of a conventional straight catheter. (A.1) (New)

• 1.2.

  A small volume of contrast medium should be injected when the occlusion balloon is inflated to confirm a satisfactory occluded position and to exclude the presence of hepatic venous-to-venous communications. (A.1) (New)

• 1.3.

  Hepatic venous-to-venous communications may result in underestimation of the WHVP and must be reported. (A.1) (New)

• 1.4.

  Deep sedation during liver haemodynamic measurement may cause inaccurate HVPG values.(B.1) If light sedation is required, low dose midazolam (0.02 mg/kg) does not modify the HVPG and is acceptable. (B.1) (New)

• 1.5.

  Slow speed (up to 7.5 mm/s) permanent tracings of pressures, recorded either on paper or electronically, are recommended. Digital, on-screen, readings are much less accurate and should not be used. (A.1) (New)

• 1.6.

  To properly reflect portal venous pressure, WHVP requires a stabilisation time. Recording of WHVP requires a minimum of 1 minute, with particular attention to stability during the last 20–30 seconds. WHVP should be recorded in triplicate. (D.1) (New)

• 1.7.

  The wedged to free hepatic vein pressure gradient has superior clinical prognostic value than wedged to right atrial pressure gradient and should be used as the standard reference.(B.1) Right atrial pressure can be measured to rule out a post-hepatic component of portal hypertension. (B.1) (New)

• 1.8.

  Free hepatic vein pressure must be measured in the hepatic vein within 2–3 cm of its confluence with the inferior vena cava (IVC). IVC pressure should be measured as an internal control, at the level of the hepatic vein ostium. If the free hepatic vein pressure is more than 2 mmHg above IVC pressures, the presence of a hepatic vein outflow obstruction should be ruled out by injecting a small amount of contrast medium. (A.1) (New)

Diagnosis of CSPH in patients with cirrhosis

• 1.9.

  HVPG values >5 mmHg indicate sinusoidal portal hypertension. (A.1) (Unchanged)

• 1.10.

  In patients with viral- and alcohol-related cirrhosis, HVPG measurement is the gold-standard method to determine the presence of “clinically significant portal hypertension” (CSPH), which is defined as an HVPG ≥10 mmHg. (A.1) (Changed)

• 1.11.

  In patients with primary biliary cholangitis, there may be an additional pre-sinusoidal component of portal hypertension that cannot be assessed by HVPG.(B.1) As such, in these patients, HVPG may underestimate the prevalence and severity of PH. (B.1) (New)

• 1.12.

  In patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis, although an HVPG ≥10 mmHg remains strongly associated with the presence of clinical signs of portal hypertension, these signs can also be present in a small proportion of patients with HVPG values <10 mmHg. (C.2) (New)

• 1.13.

  In patients with chronic liver disease and clinical signs of portal hypertension (gastro-oesophageal varices, ascites, portosystemic collateral vessels) but with HVPG <10 mmHg, porto-sinusoidal vascular disorder (PSVD) must be ruled out. (B.1) (New)

• 1.14.

  In alcohol-related or viral cirrhosis, a decrease in HVPG in response to non-selective beta-blockers (NSBBs) is associated with a significant reduction in the risk of variceal bleeding or of other decompensating events. (A.1) (Changed)

Inclusion of HVPG assessment in trial design

• 1.15.

  HVPG measurements should be encouraged in clinical trials investigating novel therapies but are not essential if portal hypertension-associated endpoints are well defined. (B.1) (Unchanged)

• 1.16.

  In viral, alcohol-related, and reasonably in NASH-related cirrhosis, HVPG response assessment is recommended as a surrogate endpoint in phase II clinical trials where a low rate of events is expected. (D.2) (Changed)

• 1.17.

  Test-retest reliability of HVPG measurement is excellent but influenced by the stage of liver disease (lower in decompensated patients) and its aetiology (higher in patients with alcohol-related disease). This should be taken into consideration when designing clinical trials based on HVPG assessment. (C.1) (New)

Assessment of surgical risks

• 1.18.

  The presence of CSPH, determined either by HVPG ≥10 mmHg or by clinical manifestations of portal hypertension, is associated with a higher risk of decompensation and mortality in patients with cirrhosis undergoing liver resection for hepatocellular carcinoma (HCC). (A.1) (New)

• 1.19.

  In candidates for non-hepatic abdominal surgery, a HVPG ≥16 mmHg is associated with an increased risk of short-term mortality after surgery. (C.1) (New)

PPG in the setting of TIPS

• 1.20.

  Portal pressure gradient (PPG) should be measured before and after transjugular intrahepatic portosystemic shunt (TIPS) insertion. (A.1) (New)

• 1.21.

  Anatomic locations for post-TIPS PPG measurement should include the main portal vein and the IVC (at the shunt outflow). (B.1) (New)

• 1.22.

  The immediate post-TIPS PPG may be influenced by various factors, such as general anaesthesia, use of vasoactive agents or haemodynamic instability and therefore immediate post-TIPS PPG may not represent long-term PPG.(B.1) PPG measurements in haemodynamically stable, non-sedated patients better reflect post-TIPS PPG values and are recommended.(B.1) (New)

• 1.23.

  In patients with variceal bleeding undergoing TIPS, reduction of absolute PPG to <12 mmHg is associated with near complete protection from portal hypertensive bleeding and is the preferred target for haemodynamic success. (A.1) A relative reduction of PPG, by at least 50% from pre-TIPS baseline, may also be useful. (B.2) (New)

• 1.24.

  PPG re-measurement is indicated to evaluate the need for TIPS revision if there is clinical or Doppler-ultrasonographic suspicion of TIPS dysfunction. (B.1) (New)

Research agenda

• Further evaluate the usefulness, safety, and accuracy of direct portal pressure measurement by endoscopic ultrasound.

• Further investigate the prognostic role of HVPG and define specific cut-offs in patients with NASH-cirrhosis.

• Confirm the utility of HVPG-guided therapy in randomised clinical trials.

• Further investigate the prognostic role of HVPG in patients undergoing extrahepatic surgery in prospective cohorts that should compare HVPG with non-invasive tests.

• Evaluate test-retest HVPG reliability at an individual level and examine factors that determine variability.

• Evaluate portocaval- vs. porto-atrial-measured PPG and clinical outcomes after TIPS (e.g., rebleeding).

• Determine the optimal PPG decrease required to medically control recurrent/refractory ascites. Further investigate the correlation between the haemodynamic outcomes of TIPS and the clinical response of ascites.

• Investigate the optimal PPG increase (in the context of TIPS reduction) needed to ameliorate adverse events related to over-shunting.

Definition of cACLD

• 2.1

  The use of elastography in clinical practice has enabled the early identification of patients with untreated/active chronic liver disease at risk of having CSPH and consequently, at risk of decompensation and liver-related death. (A.1) (Changed)

• 2.2

  The term “compensated advanced chronic liver disease (cACLD)” had been proposed to reflect the continuum of severe fibrosis and cirrhosis in patients with ongoing chronic liver disease. A pragmatic definition of cACLD based on liver stiffness measurement (LSM) is aimed at stratifying the risk of CSPH and decompensation at point of care, irrespective of histological stage or the ability of LSM to identify these stages. (B.1) (Changed)

• 2.3

  Currently, both terms “cACLD” and “compensated cirrhosis” are acceptable, but not interchangeable. (B.1) (Changed)

Criteria to identify cACLD

• 2.4

  LSM values by transient elastography (TE) <10 kPa in the absence of other known clinical/imaging signs rule out cACLD; values between 10 and 15 kPa are suggestive of cACLD; values >15 kPa are highly suggestive of cACLD. (B.1) (Changed)

• 2.5

  Patients with chronic liver disease and an LSM <10 kPa by TE have a negligible 3-year risk (≤1%) of decompensation and liver-related death. (A.1) (New)

• 2.6

  Patients with cACLD should be referred to a liver disease specialist for further work-up. (B.1) (Changed)

• 2.7

  Invasive methods (liver biopsy, HVPG) can be used for further work-up in an individualised manner at referral centres. (B.1) (Changed)

Outcome and prognosis

• 2.8

  LSM (irrespective of the technique used for its measurement) holds prognostic information in cACLD, both at index investigation and during follow-up. (A.1) (New)

• 2.9

  A rule of 5 for LSM by TE (10-15-20-25 kPa) should be used to denote progressively higher relative risks of decompensation and liver-related death independently of the aetiology of chronic liver disease. (B.1) (New)

How to monitor

• 2.10

  Patients with LSM values 7–10 kPa and ongoing liver injury should be monitored on a case-by-case basis for changes indicating progression to cACLD. (C.2) (New)

• 2.11

  TE can lead to false positive results, therefore an index LSM ≥10 kPa should be repeated in fasting conditions as soon as feasible or complemented with an established serum marker of fibrosis (fibrosis-4 ≥2.67, enhance liver fibrosis test ≥9.8, FibroTest ≥0.58 for alcohol-related/viral liver disease, FibroTest ≥0.48 for non-alcoholic fatty liver disease). (B.2) (New)

• 2.12

  In patients with cACLD, LSM could be repeated every 12 months to monitor changes. (B.2) (New)

• 2.13

  A clinically significant decrease in LSM, which is associated with substantially reduced risk of decompensation and liver-related death, can be defined as a decrease in LSM of ≥20% associated with LSM <20 kPa or any decrease to a LSM <10 kPa. (C.2) (New)

Diagnosis of CSPH in patients with cACLD

• 2.14

  Although the concept of CSPH is HVPG-driven, non-invasive tests are sufficiently accurate to identify CSPH in clinical practice. (A.1) (New)

• 2.15

  LSM by TE ≤15 kPa plus platelet count ≥150×10⁹/L rules out CSPH (sensitivity and negative predictive value >90%) in patients with cACLD. (B.2) (New)

• 2.16

  In patients with virus- and/or alcohol-related cACLD and non-obese (BMI <30 kg/m²) NASH-related cACLD, a LSM value by TE of ≥25 kPa is sufficient to rule in CSPH (specificity and positive predictive value >90%), defining the group of patients at risk of endoscopic signs of portal hypertension and at higher risk of decompensation. (B.1) (Changed)

• 2.17

  In patients with virus- and/or alcohol-related and non-obese NASH-related cACLD with LSM values <25 kPa, the ANTICIPATE model can be used to predict the risk of CSPH. Based on this model, patients with LSM values between 20–25 kPa and platelet count <150×10⁹/L or LSM values between 15–20 kPa and platelet count <110×10⁹/L have a CSPH risk of at least 60%. (B.2) (New)

• 2.18

  In patients with NASH-related cACLD, the ANTICIPATE-NASH model (including LSM, platelet count and BMI) may be used to predict the risk of CSPH, but further validation is needed. (C.2) (New)

Varices and screening endoscopy in patients that cannot be treated with NSSBs

• 2.19

  Patients with compensated cirrhosis who are not candidates for initiating NSBBs (contraindication/intolerance) for the prevention of decompensation should undergo an endoscopy for variceal screening if LSM by TE is ≥20 kPa or platelet count is ≤150×10⁹L. (A.1) (New)

• 2.20

  Patients avoiding screening endoscopy can be followed up by yearly repetition of TE and platelet count. If LSM increases (≥20 kPa) or platelet count declines (≤150×10⁹L), these patients should undergo screening endoscopy (Fig. 1). (D.1) (Unchanged)

Spleen stiffness

• 2.21

  Spleen stiffness measurement (SSM) by TE can be used in cACLD due to viral hepatitis (untreated HCV; untreated and treated HBV) to rule out and rule in CSPH (SSM <21 kPa and SSM >50 kPa, respectively). Validation of the best cut-off using a 100 Hz specific TE-probe, as well as using point-shear wave elastography and 2D-shear wave elastography is needed. (B.2) (New)

• 2.22

  In patients who are not candidates for NSBBs (contraindication/intolerance) and in whom endoscopy would be required according to the Baveno VI criteria (LSM by TE ≥20 kPa or platelet count ≤150×10⁹L), SSM ≤40 kPa by TE can be used to identify those at low probability of high-risk varices, in whom endoscopy can be avoided. (C.2) (New)

Research agenda

• Define risk of decompensation associated with different LSM cut-offs in different aetiologies of cACLD.

• Validate and refine non-invasive tools for CSPH in patients with NASH.

• Evaluate the diagnostic value of LSM for CSPH in aetiologies other than viral/alcohol/NASH.

• Establish whether sex and age require specific calibration of NITs for CSPH.

• Validate circulating biomarkers for prediction of decompensation in all aetiologies.

• Validate LSM thresholds for CSPH, high-risk varices and decompensation obtained from devices other than TE.

• Validate what constitutes a clinically significant improvement or worsening of LSM in all aetiologies.

• Validate SSM in non-viral aetiologies.

• Evaluate emerging methods to diagnose CSPH and determine response to NSBBs, such as contrast-enhanced ultrasound-based methods (SHAPE), MRI methods, and the combination of elastography, novel imaging methods and tests addressing liver function.

Research agenda

• Define the impact of the removal/suppression of primary aetiological factors (particularly non-alcoholic fatty liver disease) other than HCV/HBV infection and alcohol-related liver disease in cACLD.

• Identify factors responsible for liver disease progression despite removal/suppression of the primary aetiological factor.

• Establish the optimal percent/absolute decrease in HVPG associated with a reduction in hepatic decompensation following the removal/suppression of the primary aetiological factor in patients with cACLD and CSPH.

• Evaluate the diagnostic ability of NITs for monitoring disease regression and determining the presence of CSPH after removal/suppression of a non-viral primary aetiological factor.

• Evaluate and validate other non-invasive risk stratification algorithms (e.g., LSM/VITRO [von Willebrand factor antigen to platelet ratio] and SSM) in patients in whom the primary aetiological factor has been removed/suppressed.

• Establish estimates for the regression of varices after removal/suppression of the primary aetiological factor and collect long-term data on the risk of hepatic decompensation (and more specifically, variceal bleeding) and its evolution over time in patients with cACLD.

Research agenda

• The gut microbiome can be targeted by several means including pre-, pro-, syn- and post-biotics, diet, faecal microbiota transplantation, phage therapy, drugs, bioengineered bacteria, and antibiotics. Interventional trials are needed to assess the functional mechanisms and clinical outcomes associated with such therapies.

• The composition of the gut microbiome (e.g., high relative abundance of Enterobacteriaceae) in various body fluids (stool, saliva, blood, bile, intestinal mucosa, skin) is associated with severity of cirrhosis, complications, and presence of organ failures and acute-on-chronic liver failure (ACLF). Components of the gut microbiome should be explored for biomarkers to inform stage of disease (diagnostic), and to predict the risk of progression (prognostic), the likelihood of benefitting from an intervention (predictive) and the efficacy of an intervention.

• Faecal microbiota transplant (by enema or by the oral route) seems to be safe in patients with cirrhosis and hepatic encephalopathy but efficacy studies are pending.

• Antifibrotic strategies including targeting the farnesoid X receptor pathway, the renin-angiotensin system, and angiogenesis should be further explored in cirrhosis and portal hypertension.

Research agenda

• Competing risks from comorbidities should be considered in future studies in compensated cirrhosis.

• Determine the impact of early detection and treatment of comorbidities.

• Determine the impact of sarcopenia and frailty (and of its treatment) on prognosis and mortality of patients with compensated cirrhosis.

• Determine the prognostic significance of the sole presence of minimal ascites only detected in imaging procedures, minimal hepatic encephalopathy, and chronic bleeding from PHG.

• Determine the prognostic significance of the sole presence of jaundice in compensated cirrhosis, and its definition.

• Evaluate the role of statins in preventing decompensation.

• Determine the impact of sole bacterial infection and non-bacterial infections on the natural history of compensated cirrhosis.

• Determine the impact of vaccination (pneumococcal, haemophilus, influenza, coronavirus) on the natural history of compensated cirrhosis.

• Evaluate the prevention of bacterial infections in patients with CSPH and its impact on the incidence of decompensation.

• Identify factors predicting which infections will give rise to decompensation and/or worsen prognosis.

Research agenda

• Determine the role of vasoactive drugs and antibiotics in Child-Pugh A patients.

• Identify an optimal shorter time frame limit for vasoactive drug therapy?

• Define active bleeding at endoscopy, and assess its subjectivity and prognostic value.

• Identify the clinical role of non-invasive markers of portal pressure.

• Determine the role of haemostatic powder in acute and refractory variceal bleeding.

• Determine the role of thrombin in gastric variceal bleeding.

• Assess pre-emptive TIPS in patients with gastric varices.

• Define the optimal management of patients not fulfilling the high-risk criteria used for pre-emptive TIPS.

• Determine the cost-effectiveness of SEMS.

• Develop alternatives to Blakemore/Linton as they are in short supply.

• Determine the role of global haemostasis tests, such as viscoelastic tests and thrombin generation assays, to assess and correct haemostasis abnormalities in decompensated cirrhosis and AVB (using clinical endpoints).

• Determine the potential role of prothrombin complex concentrates, fibrinogen, or cryoprecipitate in bleeding patients with cirrhosis.

• Evaluate whether there is any relation between low platelet count (up to which level?) or fibrinogen and the risk of variceal bleeding, failure to control bleeding, or bleeding after endoscopic band ligation.

• Identify patients that will benefit from variceal embolisation during TIPS.

• Determine the role of endoscopic ultrasound-guided therapy with tissue adhesive with or without coils.

• Determine the impact of PVT on the prognosis of cirrhotic patients with AVB.

• Identify the optimal duration of vasoactive therapy in cirrhotic patients with PVT and AVB.

• Determine the role of pre-emptive TIPS in cirrhotic patients with PVT presenting with AVB.

• Establish the optimal management of AVB in patients with cirrhosis and PVT, including management of anticoagulation and timing of endoscopic/invasive procedures.

Definition of “further decompensation”

• 7.1
  Further decompensation in cirrhosis represents a prognostic stage associated with an even higher mortality than that associated with first decompensation. Specific events that define further decompensation are any of the following: (B.1) (New)

  1. Development of a second portal hypertension-driven decompensating event (ascites, variceal haemorrhage or hepatic encephalopathy) and/or jaundice;
  2. Development of recurrent variceal bleeding, recurrent ascites (requirement of ≥3 large-volume paracenteses within 1 year), recurrent encephalopathy, development of SBP and/or HRS-AKI;
  3. In patients presenting with bleeding alone, development of ascites, encephalopathy, or jaundice after recovery from bleeding but not if these events occur around the time of bleeding.

Preventing further decompensation in patients with ascites

• 7.2

  Patients with decompensated cirrhosis should be considered for liver transplantation. (A.1) (New)

• 7.3

  Patients with ascites who are not on traditional NSBBs (i.e., propranolol or nadolol) or carvedilol should undergo screening endoscopy. (B.1) (New)

• 7.4

  TIPS should be considered in patients with recurrent ascites (requirement of ≥3 large-volume paracenteses within 1 year) irrespective of the presence or absence of varices or history of variceal haemorrhage. (A.1) (New)

• 7.5

  In patients with ascites and low-risk varices (small [<5 mm], no red signs, not Child-Pugh C), traditional NSBBs or carvedilol may be used to prevent first variceal haemorrhage. (B.2) (Changed)

• 7.6

  In patients with ascites and high-risk varices (large varices [≥5 mm]), or red spot signs, or Child-Pugh C), prevention of first variceal haemorrhage is indicated, with traditional NSBBs or carvedilol being preferred over EVL. (B.1) (Changed)

• 7.7

  In patients with ascites, traditional NSBBs or carvedilol should be dose-reduced or discontinued in case of persistently low blood pressure (systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg) and/or HRS-AKI.(B.1) Once blood pressure returns to baseline and/or HRS-AKI resolves, NSBBs can be re-initiated or re-titrated.(B.1) If a patient remains intolerant to NSBBs, EVL is then recommended to prevent variceal haemorrhage. (B.1) (Changed)

Preventing recurrent variceal haemorrhage (secondary prophylaxis)

• 7.8

  First-line therapy for the prevention of recurrent variceal haemorrhage is the combination of traditional NSBBs or carvedilol and EVL. (A.1) (Changed)

• 7.9

  TIPS is the treatment of choice in patients who rebleed despite traditional NSBBs or carvedilol and EVL. (B.1) (Unchanged)

• 7.10

  In patients who cannot get/tolerate EVL or carvedilol or traditional NSBBs, any of these therapies can be maintained alone (A1) and TIPS should be considered in patients with recurrent ascites. (B.1) (Changed)

• 7.11

  In patients who bleed despite adherence to traditional NSBBs or carvedilol as primary prophylaxis, the combination of traditional NSBBs or carvedilol and EVL is recommended, and TIPS should be considered in those with recurrent ascites. (B.1) (New)

Preventing recurrent bleeding from PHG

• 7.12

  PHG and portal hypertension-associated gastric or small intestinal polypoid lesions have to be distinguished from gastric antral vascular ectasia because treatments are different. (B.1) (Changed)

• 7.13

  NSBBs are the first-line therapy for preventing recurrent bleeding from PHG. (A.1) (Unchanged)

• 7.14

  Endoscopic therapy (e.g., argon plasma coagulation or hemospray) may be used to treat recurrent bleeding from PHG. (D.1) (New)

• 7.15

  TIPS should be considered for transfusion-dependent PHG despite traditional NSBBs or carvedilol and endoscopic therapy. (C.1) (Changed)

Role of infections in decompensated cirrhosis

• 7.16

  Bacterial infections are common in patients with decompensated cirrhosis and may cause further decompensation. (A.1) (New)

• 7.17

  In all patients hospitalised with decompensation, bacterial infections should be ruled out. The minimal work-up for infections should include diagnostic paracentesis, chest X-ray, cultures of blood, ascites and urine, and skin examination. (A.1) (New)

• 7.18

  Patients with bacterial infections should be promptly treated with antibiotics. The empirical antibiotic treatment should be tailored to local epidemiology, risk factors for multidrug-resistant bacteria and severity of infection.(A.1) If no response to antibiotics is observed, consider viral and fungal infections. (C.1) (Changed)

The role of sarcopenia and frailty in further decompensation

• 7.19

  Frailty, malnutrition, and sarcopenia have an impact on survival in patients with decompensated cirrhosis. They should be evaluated with available standardised tools. (B.1) (New)

• 7.20

  All patients with decompensated cirrhosis should receive nutrition consultation and be advised regarding the benefits of regular exercise. (B.1) (New)

• 7.21

  While sarcopenia improves in some patients after TIPS, pre-procedural sarcopenia has also been associated with poor outcomes (e.g., encephalopathy, slower resolution of ascites) and a higher mortality. Therefore, sarcopenia by itself should not be an indication for TIPS. (C.2) (New)

Definition of cirrhosis recompensation

• 7.22

  The concept of recompensation implies that there is at least partial regression of the structural and functional changes of cirrhosis after removal of the aetiology of cirrhosis. (A.1) (New)

• 7.23
  Clinically, the definition of “recompensation” is based on expert consensus and requires fulfilment of all the following criteria: (C.2) (New)

  1. Removal/suppression/cure of the primary aetiology of cirrhosis (viral elimination for hepatitis C, sustained viral suppression for hepatitis B, sustained alcohol abstinence for alcohol-induced cirrhosis);
  2. Resolution of ascites (off diuretics), encephalopathy (off lactulose/rifaximin) and absence of recurrent variceal haemorrhage (for at least 12 months);
  3. Stable improvement of liver function tests (albumin, INR, bilirubin).
• 7.24

  Because CSPH may persist despite recompensation, NSBBs should not be discontinued unless CSPH resolves. (B.1) (New)

• 7.25

  Resolution of ascites (while on diuretics or after TIPS) and/or lack of recurrent variceal haemorrhage (while on traditional NSBBs + EVL or carvedilol + EVL or after TIPS) without removal/suppression/cure of the primary aetiologic factor and without improvement in liver synthetic function, is not evidence of recompensation. (B.1) (New)

Research agenda

Aetiological work-up in primary thrombosis of the portal venous system or hepatic venous outflow tract

• 8.1

  For patients with primary thrombosis of the splanchnic veins in the absence of cirrhosis, close collaboration with subspecialists is recommended for a complete work-up that considers prothrombotic factors and systemic diseases. (A.1) (Changed)

• 8.2

  Various combinations of risk factors for thrombosis can be present, so that identification of 1 risk factor does not deter from a complete work-up. (A.1) (New)

• 8.3

  In all adult patients, myeloproliferative neoplasia (MPN) should be searched for by testing for the V617F JAK2 mutation in peripheral blood. (A.1) (Unchanged)

• 8.4

  In patients with no detectable JAK2 V617F mutation, consider additional investigations for MPN, including somatic calreticulin and JAK2-exon12 mutations, and next-generation sequencing. (A.1) (Changed)

• 8.5

  In all adult patients with primary thrombosis of the splanchnic veins without an MPN driver mutation, bone marrow biopsy should be discussed in collaboration with haematologists to rule out MPN, irrespective of blood cell counts. Bone marrow biopsy should be considered particularly in patients without major risk factors for thrombosis. (B.2) (Changed)

Budd-Chiari syndrome – definition

• 8.6

  Budd-Chiari syndrome (BCS) is the consequence of an obstruction to the hepatic venous outflow. Obstruction can be located from the level of the small hepatic veins to the level of the entrance of the IVC into the right atrium. (A.1) (Unchanged)

• 8.7

  BCS is the preferred designation for any primary hepatic venous outflow tract obstruction. (D.1) (New)

• 8.8

  BCS is considered secondary when the mechanism for venous obstruction is an extrinsic compression, for example by a benign or malignant tumour. BCS is considered primary otherwise. (A.1) (Changed)

Budd-Chiari syndrome – diagnosis

• 8.9

  BCS presentation and manifestations are extremely diverse, so that the diagnosis must be considered in any patient with acute, acute-on-chronic, or chronic liver disease. (A.1) (Changed)

• 8.10

  BCS is diagnosed by the demonstration of an obstruction of the venous lumen, or by the presence of hepatic vein collaterals together with the absence of patent hepatic veins. (A.1) (Unchanged)

• 8.11

  Liver biopsy should not be performed to diagnose BCS when vascular imaging demonstrates obstruction of the hepatic venous outflow tract. (B.1) (Unchanged)

• 8.12

  Liver biopsy is necessary to diagnose BCS if obstruction of the small hepatic veins is not seen on imaging. (B.1) (Changed)

• 8.13

  In patients with BCS, hepatic nodules are frequent and most often benign. However, HCC may occur and therefore patients should be monitored with periodic imaging and alpha-fetoprotein measurements. (B.1) (Changed)

• 8.14

  A 6-month interval can be proposed for periodic imaging. (C.1) (New)

• 8.15

  It is still unclear which of ultrasound or MRI should be used for periodical screening. (C.1) (New)

• 8.16

  Patients developing nodules should be referred to centres experienced in managing BCS. (D.1) (Unchanged)

• 8.17

  Characterisation of the nodule may first include MRI using hepatobiliary contrast agents.(C.1) Biopsy of the lesion is indicated for a definitive diagnosis of HCC. (C.1) (New)

Budd-Chiari syndrome – management

• 8.18

  Management of BCS should be undertaken using a stepwise approach including anticoagulation, angioplasty/stent/thrombectomy/thrombolysis, TIPS and orthotopic liver transplantation, at experienced centres. (B.1) (Unchanged)

• 8.19

  Long-term anticoagulation should be given to all patients with primary BCS. (B.1) (Changed)

• 8.20

  Because of the increased risk of heparin-induced thrombocytopenia, the use of unfractionated heparin is generally not recommended and may only be reserved for special situations (e.g., glomerular filtration rate <30 ml/min, pending invasive procedures). (D.2) (New)

• 8.21

  Stenoses that are amenable to percutaneous angioplasty/stenting (short length stenoses) should be actively looked for and treated accordingly. (B.1) (Unchanged)

• 8.22

  TIPS insertion should be attempted by operators with specific experience in BCS when angioplasty/stenting/thrombectomy/thrombolysis is not feasible, and when the patient does not improve on medical therapy including anticoagulants. (B.1) (Unchanged)

• 8.23

  Consider improvement as a combination of several of the following outcomes: decreasing rate of ascites formation, decreasing serum bilirubin, serum creatinine and INR when elevated (or increasing factor V in patients receiving vitamin K antagonists). (D.1) (New)

• 8.24

  The BCS-TIPS prognostic index score can be used to predict outcome in patients in whom TIPS insertion is being considered. (B.1) (Changed)

• 8.25

  Liver transplantation should be considered in patients with uncontrolled clinical manifestation despite a stepwise approach, or in patients with a high BCS-TIPS prognostic index score (>7) before TIPS placement. (C.1) (Changed)

• 8.26

  In patients with BCS presenting as acute liver failure, urgent liver transplantation should be considered. Emergency TIPS should be performed, if possible, independently of listing for liver transplantation. (C.1) (New)

PVT and portal cavernoma in the absence of cirrhosis – definition

• 8.27

  PVT is characterised by the presence of a thrombus in the portal vein trunk or its branches. Portal cavernoma is a network of porto-portal collaterals which develops as a consequence of prior portal vein obstruction. (D.1) Obstruction leading to cavernoma is mostly related to thrombosis in adults, but less likely so in children and young adults. (B.1) (Changed)

• 8.28

  Imaging tools should be used to distinguish PVT from the extravascular compression of the venous lumen by a neighbouring space-occupying formation. (D.1) (New)

• 8.29

  Cirrhosis and/or malignancy should be ruled out and other underlying liver diseases (e.g., PSVD or other chronic liver disease) should be investigated. (D.1) (Changed)

PVT and portal cavernoma in the absence of cirrhosis – diagnosis

• 8.30

  For diagnosis of PVT or cavernoma, Doppler ultrasound, CT or MR angiography should demonstrate solid intraluminal material not showing enhancement after injection of vascular contrast agents (for PVT) or a network of porto-portal collaterals (for cavernoma). (B.1) If diagnosed by Doppler ultrasound, confirmation with contrast-enhanced CT or MR angiography is needed. (D.1) (Changed)

• 8.31

  A standardised documentation (as proposed in Table 1) of initial site, extent/degree of luminal obstruction, and chronicity of clot formation is required to enable subsequent evaluation of the spontaneous course and/or response to treatment. (D.1) (New)

• 8.32

  PVT and portal cavernoma in adults are frequently associated with ≥1 risk factor(s) for thrombosis, which may be occult at presentation and should be investigated. (B.1) (Unchanged)

• 8.33

  In patients with PVT following abdominal surgery or pancreatitis, invasive procedures (e.g., bone marrow biopsy and liver biopsy) should be discussed on an individual basis considering the expected low diagnostic yield in such populations and the risk of morbidity associated with these procedures. (C.2) (New)

• 8.34

  If the liver is dysmorphic on imaging or liver tests are persistently abnormal, liver biopsy and HVPG measurement are recommended to rule out cirrhosis or PSVD.(B.1) Liver stiffness by TE may be useful to exclude cirrhosis although precise cut-offs cannot be proposed yet. (C.2) (Changed)

PVT and portal cavernoma in the absence of cirrhosis - management

• 8.35

  In the absence of cirrhosis, recent PVT rarely resolves spontaneously. Therefore, at diagnosis, anticoagulation should be started immediately at a therapeutic dosage. (B.1) (Changed)

• 8.36

  Because of the increased risk of heparin-induced thrombocytopenia, the use of unfractionated heparin is not generally recommended and may only be reserved for special situations (e.g. glomerular filtration rate <30 ml/min, pending invasive procedures). (D.2) (New)

• 8.37

  As a primary treatment option for recent PVT in the absence of cirrhosis, start with low-molecular-weight heparin (LMWH) and switch to vitamin K antagonists when possible. (B.1) (Changed) DOACs can be considered the primary option in selected cases in the absence of so-called “triple positive” anti-phospholipid syndrome, although data are limited. (C.2) (New)

Recent PVT in the absence of cirrhosis – management

• 8.38

  Anticoagulation should be given for at least 6 months in all patients with recent PVT in the absence of cirrhosis. (B.1) (Unchanged)

• 8.39

  After 6 months, long-term anticoagulation is recommended in patients with a permanent underlying prothrombotic state (B.1) and should also be considered in patients without an underlying prothrombotic state. (B.2) (New)

• 8.40

  If anticoagulation is discontinued, D-dimers <500 ng/ml 1 month after discontinuation may be used to predict a low risk of recurrence. (C.2) (New)

• 8.41

  In patients without cirrhosis who do not develop complications of recent PVT despite the absence of portal vein recanalisation, interventions other than anticoagulation are not required. (B.2) (Changed)

• 8.42

  A follow-up contrast-enhanced CT scan should be performed 6 months after recent PVT. (C.1) (New)

• 8.43

  Because of the risk of recurrence of splanchnic vein thrombosis, patients need to be followed up, irrespective of the discontinuation of anticoagulation. (C.1) (New)

• 8.44

  The risk of intestinal infarction and organ failure is increased in patients with recent PVT and (i) persistent severe abdominal pain despite anticoagulation therapy, (ii) bloody diarrhoea, (iii) lactic acidosis, (iv) bowel loop distention, or (v) occlusion of second order radicles of the superior mesenteric vein. Therefore, a multidisciplinary approach with early image-guided intervention, thrombolysis and surgical intervention should be considered in referral centres. (C.2) (New)

Past PVT or cavernoma in the absence of cirrhosis – management

• 8.45

  In patients with past PVT or cavernoma, including those with incomplete resolution of recent PVT at 6 months, long-term anticoagulation is recommended in patients with a permanent underlying prothrombotic state (B.1) and should also be considered in patients without an underlying prothrombotic state. (B.2) (New)

• 8.46

  No data are available to recommend or discourage anticoagulation in childhood-onset past PVT or cavernoma in the absence of an underlying prothrombotic state. (C.1) (New)

• 8.47

  In patients with past PVT or cavernoma not yet receiving anticoagulants, anticoagulation should be started after adequate prophylaxis for portal hypertensive bleeding has been initiated in patients with high-risk varices. (C.2) (Changed)

• 8.48

  Mesenteric-left portal vein bypass (Meso-Rex operation) should be considered in all children with complications of portal cavernoma, and these patients should be referred to centres with experience in treating this condition. (B.1) (Unchanged)

• 8.49

  Patients with refractory complications of PVT or cavernoma should be referred to expert centres to consider percutaneous recanalisation of the portal vein or other vascular interventional procedures. (C.1) (New)

Treatment of portal hypertension in extrahepatic portal vein obstruction

• 8.50

  There is insufficient data on whether beta-blockers or endoscopic therapy should be preferred for primary prophylaxis of portal hypertension-related bleeding in patients with past PVT or cavernoma. Guidelines for cirrhosis should be applied. (C.2) (Changed)

• 8.51

  Oesophageal variceal band ligation can be performed safely without withdrawing vitamin K antagonists. (C.2) (New)

• 8.52

  All patients in whom thrombosis has not been recanalised should be screened for gastroesophageal varices within 6 months of the acute episode. In the absence of varices, endoscopy should be repeated at 12 months and 2 years thereafter. (B.1) (Unchanged)

• 8.53

  In patients with acute portal hypertension-related bleeding, recommendations for patients with cirrhosis may be applied. (D.1) (Changed)

• 8.54

  Based on recommendations for cirrhosis, the combination of NSBBs and band ligation is recommended for secondary prophylaxis. (D.1) (New)

Research agenda

Use of anticoagulants in non-cirrhotic vascular liver diseases

• 9.1

  LMWH and vitamin K antagonists are widely accepted and used to treat primary thrombosis of the portal venous system or hepatic venous outflow tract. (A.1) (Unchanged)

• 9.2

  There are no major concerns regarding the safety of DOACs in patients with non-cirrhotic vascular liver diseases, as long as liver function is preserved. DOACs should be used with caution in patients with impaired liver function (equivalent to Child-Pugh class B), as well as in patients with creatinine clearance below 30 ml/min. The use of DOACs in patients with severe liver dysfunction (equivalent to Child-Pugh C) is not recommended outside study protocols. (C.2) (New)

Anticoagulation and PVT in cirrhosis

• 9.3

  Screening for PVT is recommended in all patients who are potential liver transplant candidates, at the time of screening for HCC. (D.2) (Changed)

• 9.4

  Occurrence of PVT in the presence of HCC does not directly imply vascular malignant invasion, but further imaging is recommended (CT scan and/or MRI and/or contrast-enhanced ultrasound). (D.2) (Changed)

• 9.5

  Anticoagulation is recommended in patients with cirrhosis and (i) recent (<6 months) completely or partially occlusive (>50%) thrombosis of the portal vein trunk with or without extension to the superior mesenteric vein, or (ii) symptomatic PVT, independently of the extension, or (iii) PVT in potential candidates for liver transplantation, independently of the degree of occlusion and extension. (C.2) (New)

• 9.6

  In potential liver transplant candidates, the goal of anticoagulation is to prevent re-thrombosis or progression of thrombosis to facilitate adequate portal anastomosis in liver transplantation and reduce post-transplant morbidity and mortality. (C.1) (Changed)

• 9.7

  Anticoagulation should be considered in patients with cirrhosis and minimally occlusive (<50%) thrombosis of the portal vein trunk that (i) progresses on short-term follow-up (1–3 months) or (ii) compromises the superior mesenteric vein. (C.2) (New)

• 9.8

  Anticoagulation should be (i) maintained until portal vein recanalisation or for a minimum of 6 months, (ii) continued after recanalisation in patients awaiting liver transplantation, and (iii) considered after recanalisation in all others, while balancing the benefits of preventing recurrence and increasing survival with the risk of bleeding. (C.1) (New)

• 9.9

  Patients with low platelet count (e.g., <50 ×10⁹/L) are at higher risk of PVT, but also of bleeding complications on anticoagulation, and should be assessed on a case-by-case basis. (C.2) (Changed)

• 9.10

  TIPS is recommended in patients with thrombosis of the portal vein trunk without recanalisation on anticoagulation, especially in patients listed for liver transplantation. (C.2) (New)

• 9.11

  Anticoagulation is preferably initiated with LMWH and maintained with either LMWH, vitamin K antagonists or DOACs. Advantages of LMWH are that its use is based on solid data. Vitamin K antagonists carry challenges with regard to INR monitoring in patients with cirrhosis. Advantages of DOACs are that they are easier to use but less data are available. (C.1) (Changed)

• 9.12

  Currently available data suggest that there are no major safety concerns regarding the use of DOACs in patients with Child-Pugh class A cirrhosis. Due to the possibility of accumulation, DOACs should be used with caution in patients with Child-Pugh class B cirrhosis, as well as in patients with creatinine clearance below 30 ml/min. The use of DOACs in those with Child-Pugh class C cirrhosis is not recommended outside study protocols. (B.2) (New)

• 9.13

  DOACs likely have different safety-efficacy profiles in patients with cirrhosis, although at the moment no recommendation can be made in favour of a specific DOAC in this setting. (D.2) (New)

Porto-sinusoidal vascular disorder

• 9.14

  PSVD is a broad clinico-pathological entity encompassing non-cirrhotic portal fibrosis, idiopathic portal hypertension or non-cirrhotic intrahepatic portal hypertension, and various overlapping histological patterns including nodular regenerative hyperplasia, obliterative portal venopathy, hepatoportal sclerosis, incomplete septal cirrhosis. (B.1) (New)

• 9.15

  The absence of portal hypertension does not rule out PSVD. The presence of common causes of liver disease (e.g., viral hepatitis, excessive alcohol consumption, metabolic syndrome, etc.) does not rule out PSVD, and both can coexist. The presence of PVT does not rule out PSVD, and both can coexist. (B.1) (New)

• 9.16

  PSVD should be considered in the following situations: (i) signs of portal hypertension contrasting with atypical features of cirrhosis (e.g., HVPG <10 mmHg; liver stiffness measurement <10 kPa; smooth liver surface and no atrophy of segment IV; hepatic vein-to-vein communications; although none of these features is considered pathognomonic for PSVD); or (ii) liver blood test abnormalities or portal hypertension in a patient with a condition known to be associated with PSVD (Table S1); or (iii) unexplained liver blood test abnormalities even without signs of portal hypertension. (B.1) (New)

Diagnosis of PSVD

• 9.17

  PSVD can be observed in the absence of clinical, laboratory or imaging features of portal hypertension. (B.1) (New)

• 9.18

  A liver biopsy specimen of adequate size (>20 mm) and of minimal fragmentation – or otherwise considered adequate for interpretation by an expert pathologist – is required for the diagnosis of PSVD. (C.1) (New).

• 9.19

  Diagnosis of PSVD requires the exclusion of cirrhosis and of other causes of portal hypertension (B.1), together with 1 of the following 3 criteria (C.2): (i) at least 1 feature specific for portal hypertension; or (ii) at least 1 histologic lesion specific for PSVD; or (iii) at least 1 feature not specific for portal hypertension together with at least 1 histologic lesion compatible although not specific for PSVD (Table 2). (New)

Management of PSVD

• 9.20

  Once the diagnosis of PSVD is made, patients should be screened for associated immunological diseases, prothrombotic or genetic disorders and exposure to drugs/toxins (Table S1). (D.2) (New)

• 9.21

  Endoscopic screening for gastro-oesophageal varices is required at diagnosis of PSVD. (C.1) (New)

• 9.22

  The non-invasive Baveno VII criteria for screening of oesophageal varices used in patients with cirrhosis cannot be applied to patients with PSVD. (B.1) (New)

• 9.23

  During follow-up, the frequency of endoscopic screening for varices has not yet been defined. Management according to cirrhosis guidelines is recommended, except for stopping rules. (D.2) (New)

• 9.24

  There is insufficient data on which therapy should be preferred for portal hypertension prophylaxis in PSVD. Management according to cirrhosis guidelines is recommended. (D.2) (New)

• 9.25

  A contrast-enhanced CT scan is suggested at diagnosis of PSVD in order to assess the anatomy/patency of the portal venous system and potential portosystemic collaterals. (D.2) (New)

• 9.26

  Screening for PVT in patients with PSVD: there is no data on the best screening method and interval.(D.2) (New) Doppler ultrasound every 6 months is suggested in patients with PSVD and features of portal hypertension.(C.1) (New) In case of abdominal pain, Doppler ultrasound or cross-sectional imaging should be performed to rule out splanchnic vein thrombosis. (B.1) (New)

• 9.27

  No recommendation can be made regarding anticoagulation therapy to prevent the development of PVT in PSVD. (D.2) (New)

• 9.28

  In those patients developing PVT, anticoagulant therapy should be started according to recommendations for non-cirrhotic PVT. (C.1) (New)

• 9.29

  TIPS can be considered to treat severe complications of portal hypertension. Underlying/associated conditions, which negatively impact post-TIPS outcome, must be taken into account in making individual decisions regarding TIPS insertion. (C.2) (New)

• 9.30

  Liver transplantation is an option in selected patients with PSVD and severe or refractory complications of portal hypertension or with advanced liver dysfunction. Indications should be discussed in expert centres. (D.2) (New)

Research agenda