Study protocol for a Randomised controlled trial of EArly transjugular intrahepatiC porTosystemic stent-shunt in Acute Variceal Bleeding (REACT-AVB trial).

INTRODUCTION: In liver cirrhosis, acute variceal bleeding (AVB) is associated with a 1-year mortality rate of up to 40%. Data on early or pre-emptive transjugular intrahepatic portosystemic stent-shunt (TIPSS) in AVB is inconclusive and may not reflect current management strategies. Randomised controlled trial of EArly transjugular intrahepatiC porTosystemic stent-shunt in AVB (REACT-AVB) aims to investigate the clinical and cost-effectiveness of early TIPSS in patients with cirrhosis and AVB after initial bleeding control. METHODS AND ANALYSIS: REACT-AVB is a multicentre, randomised controlled, open-label, superiority, two-arm, parallel-group trial with an internal pilot. The two interventions allocated randomly 1:1 are early TIPSS within 4 days of diagnostic endoscopy or secondary prophylaxis with endoscopic therapy in combination with non-selective beta blockers. Patients aged ≥18 years with cirrhosis and Child-Pugh Score 7-13 presenting with AVB with endoscopic haemostasis are eligible for inclusion. The primary outcome is transplant-free survival at 1 year post randomisation. Secondary endpoints include transplant-free survival at 6 weeks, rebleeding, serious adverse events, other complications of cirrhosis, Child-Pugh and Model For End-Stage Liver Disease (MELD) scores at 6 and 12 months, health-related quality of life, use of healthcare resources, cost-effectiveness and use of cross-over therapies. The sample size is 294 patients over a 4-year recruitment period, across 30 hospitals in the UK. ETHICS AND DISSEMINATION: Research ethics committee of National Health Service has approved REACT-AVB (reference number: 23/WM/0085). The results will be submitted for publication in a peer-reviewed journal. A lay summary will also be emailed or posted to participants before publication. TRIAL REGISTRATION NUMBER: ISRCTN85274829; protocol version 3.0, 1 July 2023.

The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study.

Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.

Portal decompression with transjugular intrahepatic portosystemic shunt prior to nonhepatic surgery: a single-center case series.

BACKGROUND AND AIMS: Cirrhosis increases perioperative and postoperative mortality in nonhepatic surgery. Transjugular intrahepatic portosystemic shunt (TIPSS), by reducing portal pressure, may reduce intraoperative bleeding and postoperative decompensation. We report our experience of prophylactic TIPSS in nonhepatic surgery. METHODS: Patients who underwent prophylactic TIPSS before nonhepatic surgery were identified from database with retrospective data collection via an e-patient record system. Primary outcome was discharged without hepatic decompensation after a planned surgery. RESULTS: Twenty-one patients [age (median, range): 55, 33-76 years, Child's score: 6, 5-9] who underwent prophylactic TIPSS before nonhepatic surgery over a period of 9 years were included. All patients underwent successful TIPSS with a reduction in portal pressure gradient from 21.5 (11-35) to 16 (7-25) mmHg (P < 0.001). Immediate post-TIPSS complications were seen in 7 (33%) patients including hepatic encephalopathy in four. Eighteen patients (86%) underwent planned surgical intervention. Significant postoperative complications included hepatic encephalopathy (3), sepsis (2) and bleed (1). Two patients died postoperatively with multi-organ failure. The primary outcome was achieved in 12 (57%) patients. Post-TIPSS portal pressure gradient was significantly higher in patients with the adverse primary outcome. Over a follow-up period of 11 (1-78) months; 1-, 6- and 12-months' survival was 90, 80 and 76%, respectively. CONCLUSION: Prophylactic TIPSS is associated with complications in up to one-third of patients, with 57% achieving the primary outcome. Careful patient selection in a multidisciplinary team setting is essential. Multicentre studies are necessary before the universal recommendation of prophylactic TIPSS.

Transjugular intrahepatic portosystemic stent-shunt in the management of portal hypertension.

These guidelines on transjugular intrahepatic portosystemic stent-shunt (TIPSS) in the management of portal hypertension have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the Liver Section of the BSG. The guidelines are new and have been produced in collaboration with the British Society of Interventional Radiology (BSIR) and British Association of the Study of the Liver (BASL). The guidelines development group comprises elected members of the BSG Liver Section, representation from BASL, a nursing representative and two patient representatives. The quality of evidence and grading of recommendations was appraised using the GRADE system. These guidelines are aimed at healthcare professionals considering referring a patient for a TIPSS. They comprise the following subheadings: indications; patient selection; procedural details; complications; and research agenda. They are not designed to address: the management of the underlying liver disease; the role of TIPSS in children; or complex technical and procedural aspects of TIPSS.

Small Intrahepatic Vein Budd-Chiari Syndrome Complicated by Fusobacterium nucleatum Peritonitis.

Budd-Chiari syndrome is a rare disorder with significant liver-related complications. We present a 28-year-old woman with a 1-month history of weight loss and ascites. Hepatic venogram showed patent hepatic veins and inferior vena cava; however, there was an increased hepatic venous pressure gradient, which is clinically significant for portal hypertension. Hereditary and acquired thrombophilia workup was unrevealing. During admission, she developed peritonitis with Fusobacterium nucleatum and was treated with piperacillin-tazobactam. Liver biopsy showed vascular changes with features of venous outflow obstruction, and she was diagnosed with "small hepatic vein" Budd-Chiari syndrome. She was treated with transjugular intrahepatic portosystemic stent-shunt and tinzaparin, with significant clinical improvement.

Review article: a multidisciplinary approach to the diagnosis and management of Budd-Chiari syndrome.

BACKGROUND: Budd-Chiari syndrome (BCS) is a rare but fatal disease caused by obstruction in the hepatic venous outflow tract. AIM: To provide an update of the pathophysiology, aetiology, diagnosis, management and follow-up of BCS. METHODS: Analysis of recent literature by using Medline, PubMed and EMBASE databases. RESULTS: Primary BCS is usually caused by thrombosis and is further classified into "classical BCS" type where obstruction occurs within the hepatic vein and "hepatic vena cava BCS" which involves thrombosis of the intra/suprahepatic portion of the inferior vena cava (IVC). BCS patients often have a combination of prothrombotic risk factors. Aetiology and presentation differ between Western and certain Asian countries. Myeloproliferative neoplasms are present in 35%-50% of European patients and are usually associated with the JAK2-V617F mutation. Clinical presentation is diverse and BCS should be excluded in any patient with acute or chronic liver disease. Non-invasive imaging (Doppler ultrasound, computed tomography, or magnetic resonance imaging) usually provides the diagnosis. Liver biopsy should be obtained if small vessel BCS is suspected. Stepwise management strategy includes anticoagulation, treatment of identified prothrombotic risk factors, percutaneous revascularisation and transjugular intrahepatic portosystemic stent shunt to re-establish hepatic venous drainage, and liver transplantation in unresponsive patients. This strategy provides a 5-year survival rate of nearly 90%. Long-term outcome is influenced by any underlying haematological condition and development of hepatocellular carcinoma. CONCLUSIONS: With the advent of newer treatment strategies and improved understanding of BCS, outcomes in this rare disease have improved over the last three decades. An underlying haematological disorder can be the major determinant of outcome.

Diastolic dysfunction on echocardiography does not predict survival after transjugular intrahepatic portosystemic stent-shunt in patients with cirrhosis.

BACKGROUND: Cardiac dysfunction is frequently observed in patients with cirrhosis. There remains a paucity of data from routine clinical practice regarding the role of echocardiography in the pre-assessment of transjugular intrahepatic portosystemic stent-shunt. AIM: Our study aimed to investigate if echocardiography parameters predict outcomes after transjugular intrahepatic portosystemic stent-shunt insertion in cirrhosis. METHODS: Patients who underwent echocardiography and transjugular intrahepatic portosystemic stent-shunt insertion at the liver unit (Birmingham, UK) between 1999 and 2016 were included. All echocardiography measures (including left ventricle ejection fraction; early maximal ventricular filling/late filling velocity ratio, diastolic dysfunction as per British Society of Echocardiography guidelines) were independently reviewed by a cardiologist. Predictors of 30-day and overall transplant free-survival were assessed. RESULTS: One Hundred and Seventeen patients with cirrhosis (median age 56 years; 54% alcohol; Child-Pugh B/C 71/14.5%; Model For End-Stage Liver Disease 12) underwent transjugular intrahepatic portosystemic stent-shunt for ascites (n = 78) and variceal haemorrhage (n = 39). Thirty-day and overall transplant-free survival was 90% (n = 105) and 31% (n = 36), respectively, over a median 663 (IQR 385-2368) days follow-up. Model for End-Stage Liver Disease (P < 0.001) and Child-Pugh Score (P = 0.002) significantly predicted 30-day and overall transplant-free survival. Model for End-Stage Liver Disease ≥15 implied three-fold risk of death. Six per cent (n = 7) of patients pre-transjugular intrahepatic portosystemic stent-shunt had a history of ischaemic heart disease and 34% (n = 40) had 1 or more cardiovascular disease risk factors. Fifty per cent (n = 59) had an abnormal echocardiogram and 33% (n = 39) had grade 1-3 diastolic dysfunction. On univariate analysis none of the echocardiography measures pre-intervention were related to 30-day or overall transplant-free survival post-transjugular intrahepatic portosystemic stent-shunt. CONCLUSIONS: Ventricular, in particular diastolic dysfunction in patients with cirrhosis does not predict survival after transjugular intrahepatic portosystemic stent-shunt insertion. Model for End-Stage Liver Disease and Child-Pugh scores remain the best predictors of survival. Further prospective study is required to clarify the role of routine echocardiography prior to transjugular intrahepatic portosystemic stent-shunt insertion.

Timing of Transjugular Intrahepatic Portosystemic Stent-shunt in Budd-Chiari Syndrome: A UK Hepatologist's Perspective.

Budd-Chiari syndrome (BCS) is a rare but fatal disease caused by the obstruction in hepatic venous outflow tract (usually by thrombosis) and is further classified into two subtypes depending on the level of obstruction. Patients with BCS often have a combination of prothrombotic risk factors. Clinical presentation is diverse. Stepwise management strategy has been suggested with excellent 5-year survival rate. It includes anticoagulation, treatment of identified prothrombotic risk factor, percutaneous recanalization, and transjugular intrahepatic portosystemic shunt (TIPS) to reestablish hepatic venous outflow and liver transplantation in unresponsive patients. Owing to the rarity of BCS, there are no randomized controlled trials (RCTs) precisely identifying the timing for TIPS. TIPS should be considered in patients with refractory ascites, variceal bleed, and fulminant liver failure. Liver replacement is indicated in patients with progressive liver failure and in those in whom TIPS is not technically possible. The long-term outcome is usually influenced by the underlying hematologic condition and the development of hepatocellular carcinoma. This review focuses on the timing and the long-term efficacy of TIPS in patients with BCS.

Outcomes of pregnancy in patients with known Budd-Chiari syndrome.

AIM: To analyse the risk of pregnancy (a prothrombotic state) in patients with Budd-Chiari Syndrome (BCS). METHODS: Retrospective study of pregnancy in women with known BCS at single center from January 2001 to December 2015. RESULTS: Out of 53 females with BCS, 7 women had 16 pregnancies. Median age at diagnosis of BCS in these women was 25 years (range 21-34 years). At least one causal factor for BCS was identified in 6 women (86%). Six women had undergone radiological decompressive treatment. All patients had anticoagulation. Six fetuses were lost before 20 wk gestation in 2 women. There were 9 deliveries over 32 wk gestation and one delivery at 27 wk. All infants did well. Seven babies were born by emergency caesarean section. There were no cases of thrombosis. Two patients had notable vaginal (PV) bleeding in 3 pregnancies. None of the patients had variceal haemorrhage. Two patients were diagnosed with pulmonary hypertension, one during pregnancy and the other in the post-partum period. There was no maternal mortality. CONCLUSION: Maternal outcomes in patients with treated BCS are favourable and fetal outcomes beyond 20 wk gestation are good. There has been increased rate of caesarean section. Pulmonary hypertension is an important finding that needs further validation. These patients should be managed in centers experienced in treating high-risk pregnancies.

Long-term outcomes following percutaneous hepatic vein recanalization for Budd-Chiari syndrome.

BACKGROUND & AIMS: A proportion of patients with Budd-Chiari Syndrome (BCS) associated with stenosis or short occlusion of the hepatic vein (HV) or upper inferior vena cava (IVC) can be treated with recanalization by percutaneous venoplasty ± HV stent insertion. We studied the long-term outcomes of this approach. METHODS: Single-centre retrospective analysis of patients referred for radiological assessment ± intervention over a 27-year period. Of 155 BCS patients, 63 patients who underwent venoplasty were studied and compared to a previously reported series treated by TIPSS (n = 59). RESULTS: Patients treated with HV interventions (32 venoplasty alone, 31 endovascular stents): mean age, 34.9 ± 10.9; M:F ratio 27:36; median follow-up, 113.0 months; 62% of patients had ≥1 haematological risk factor. Technical success was 100%, with symptom resolution in 73%. Cumulative secondary patency at 1, 5, 10 years was 92%, 79%, 79% and 69%, 69%, 64% in the stenting and venoplasty groups respectively. Where long-term patency was not achieved, 10 patients required TIPSS, and 8 underwent surgery. Actuarial survival at 1, 5, 10 years was 97%, 89% and 85%. When compared to TIPSS, HV interventions resulted in similar patency and survival rates but significantly lower procedural complications (9.5% vs 27.1%) and hepatic encephalopathy (0% vs 18%). Patient age predicted survival following multivariate analysis. CONCLUSIONS: Our data support the stepwise approach to management of BCS, with very good outcomes from venoplasty combined with stenting when required. TIPSS should only be offered where HV interventions are not feasible or unsuccessful.

U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients.

These updated guidelines on the management of variceal haemorrhage have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines which this document supersedes were written in 2000 and have undergone extensive revision by 13 members of the Guidelines Development Group (GDG). The GDG comprises elected members of the BSG liver section, representation from British Association for the Study of the Liver (BASL) and Liver QuEST, a nursing representative and a patient representative. The quality of evidence and grading of recommendations was appraised using the AGREE II tool.The nature of variceal haemorrhage in cirrhotic patients with its complex range of complications makes rigid guidelines inappropriate. These guidelines deal specifically with the management of varices in patients with cirrhosis under the following subheadings: (1) primary prophylaxis; (2) acute variceal haemorrhage; (3) secondary prophylaxis of variceal haemorrhage; and (4) gastric varices. They are not designed to deal with (1) the management of the underlying liver disease; (2) the management of variceal haemorrhage in children; or (3) variceal haemorrhage from other aetiological conditions.