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.

Clinical Outcomes of Ablation Compared with Resection for Single Hepatocellular Carcinoma Lesions, as a Primary Treatment or Bridging to Liver Transplantation: A Retrospective Comparative Study.

BACKGROUND Ablative therapies (AT) are widely utilized as bridging treatment for liver transplantation (LT) candidates with hepatocellular carcinoma (HCC) who are on the transplant waiting list to minimize dropout rate. We aimed to investigate whether AT could be considered a primary treatment modality for LT candidates with single, small HCC lesions. MATERIAL AND METHODS We retrospectively investigated the outcomes of patients with AT for single HCC lesions as primary treatment or bridging to LT between 2010 and 2017, compared with surgical resection (SR) during the same time period as control. Univariate and multivariate survival analyses were performed. Matched analysis, after propensity score matching (PSM), was performed to minimize the selection bias confounding effect on outcomes. RESULTS Of 162 patients identified, 92 received AT and 70 had SR. PSM identified 38 paired matches in each group. Overall survival (OS) and disease-free survival (DFS) before matching showed comparable outcomes for each treatment after 1, 3, and 5 years. Multivariate analysis using Cox regression models adjusting the study confounders showed lesion size (>30 mm), not treatment received, was associated with worse DFS (hazard ratio, 2.21 [95% confidence interval, 1.14-4.28]). In the matched groups, OS and DFS were equivalent and consistent with the whole-cohort survival outcomes. Explant histopathology of patients having AT as a bridge to LT showed complete pathological response in 85.7% of patients. CONCLUSIONS This study supports the use of AT with curative intent for single ≤3-cm HCCs, particularly in LT candidates, with salvage transplantation kept as a backup in case of recurrence.

Diaphragmatic hernia: a rare complication of hepatic ablation.

INTRODUCTION: Ablation has become an effective treatment for small hepatocellular carcinomas (HCC). Whilst ablation is a safe and effective technique, diaphragmatic injury is a rarely associated but significant complication.Case presentation: We present a case of a 67 year old patient who developed a diaphragmatic defect following microwave ablation (MWA) for HCC. The diaphragmatic defect progressed to herniation which was complicated by perforation of intrahernial large bowel. The patient was treated by emergency laparotomy and an extended right hemi-colectomy was performed. CONCLUSION: Our report adds to the current available knowledge on diaphragmatic injury following hepatic ablation and demonstrates the potential for life threatening consequences associated with this complication.

Randomised clinical trial: standard of care versus early-transjugular intrahepatic porto-systemic shunt (TIPSS) in patients with cirrhosis and oesophageal variceal bleeding.

BACKGROUND: Early-transjugular intrahepatic porto-systemic shunt (TIPSS) has been recommended in international guidelines for high-risk patients with oesophageal variceal bleeding. AIM: To validate the results of a previous randomised control trial which supports use of early-TIPSS. METHODS: In a two-centre open-label parallel-group randomised control trial, patients with cirrhosis and acute variceal bleeding were recruited following haemostasis with vaso-active drugs and endoscopic band ligation. Participants were randomised to standard of care or early-TIPSS. The primary outcome was 1-year survival, secondary outcomes included early and late rebleeding, and complications of portal hypertension. RESULTS: Fifty-eight patients (58 ± 11.12 years; 32.7% female) were randomised. After one year, seven patients died in the standard of care group and six in the early-TIPSS group, a 1-year survival of 75.9% vs 79.3% respectively (P = 0.79). Variceal rebleeding occurred in eight patients in the standard of care group compared with three patients in the early-TIPSS group (P = 0.09). Not all participants randomised to early-TIPSS received the intervention in time. For those receiving TIPSS per-protocol, variceal rebleeding rates were reduced (0% vs 27.6%, P = 0.04) but this had no effect on survival (76.9% vs 75.9%, P = 0.91). Serious adverse events were similar in both treatment groups, except that rates of hepatic encephalopathy were higher in patients receiving TIPSS (46.1% vs 20.7%, P < 0.05). CONCLUSIONS: Early-TIPSS reduced variceal rebleeding, increased encephalopathy but had no effect on survival in high-risk patients with oesophageal variceal bleeding. Early-TIPSS may not be feasible in many centres however, larger studies are needed. ClinicalTrials.gov reference: NCT02377141.

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.

A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP).

BACKGROUND: In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure. METHODS: In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 µg/kg/day for 60 min followed by 30 µg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed. RESULTS: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3 (range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI -2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events. CONCLUSION: In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.

Impact of concomitant arterial injury on the outcome of laparoscopic bile duct injury.

BACKGROUND: Concomitant injury to the bile duct and hepatic artery is an increasingly recognized complication of laparoscopic cholecystectomy (LC). The impact of a concomitant arterial injury in patients with a bile duct injury (BDI) remains debatable. Early reports described a high incidence of septic complications, difficulty of biliary repair, and increased the risk of recurrent stricture. DATA SOURCES: A literature search on the clinical significance and management of a concomitant hepatic artery injury (HAI) to the outcome of biliary-enteric reconstruction following BDI was reviewed. Relevant articles were extracted through MEDLINE, with secondary references obtained from key articles. CONCLUSIONS: The association between failure of biliary repair and concomitant arterial injuries is not confirmed by the largest studies, which showed no difference in anastomotic stricture rate between patients who had an isolated BDI and those who had a combined HAI and BDI. However, right arterial injury associated with liver necrosis or damage to the right hepatic duct may require right hepatectomy.

Management of transjugular intrahepatic portosystemic shunt (TIPS)-associated refractory hepatic encephalopathy by shunt reduction using the parallel technique: outcomes of a retrospective case series.

PURPOSE: To investigate the reproducibility and technical and clinical success of the parallel technique of transjugular intrahepatic portosystemic shunt (TIPS) reduction in the management of refractory hepatic encephalopathy (HE). MATERIALS AND METHODS: A 10-mm-diameter self-expanding stent graft and a 5-6-mm-diameter balloon-expandable stent were placed in parallel inside the existing TIPS in 8 patients via a dual unilateral transjugular approach. Changes in portosystemic pressure gradient and HE grade were used as primary end points. RESULTS: TIPS reduction was technically successful in all patients. Mean ± standard deviation portosystemic pressure gradient before and after shunt reduction was 4.9 ± 3.6 mmHg (range, 0-12 mmHg) and 10.5 ± 3.9 mmHg (range, 6-18 mmHg). Duration of follow-up was 137 ± 117.8 days (range, 18-326 days). Clinical improvement of HE occurred in 5 patients (62.5%) with resolution of HE in 4 patients (50%). Single episodes of recurrent gastrointestinal hemorrhage occurred in 3 patients (37.5%). These were self-limiting in 2 cases and successfully managed in 1 case by correction of coagulopathy and blood transfusion. Two of these patients (25%) died, one each of renal failure and hepatorenal failure. CONCLUSION: The parallel technique of TIPS reduction is reproducible and has a high technical success rate. A dual unilateral transjugular approach is advantageous when performing this procedure. The parallel technique allows repeat bidirectional TIPS adjustment and may be of significant clinical benefit in the management of refractory HE.

Tipsitis: incidence and outcome-a single centre experience.

INTRODUCTION: Infection of transjugular intrahepatic portosystemic stent shunt (TIPSS) called 'Tipsitis' has been reported but appears unusual. We report here our experience of patients who were diagnosed to have Tipsitis at our centre. METHODS: Retrospective single centre study. Patients identified from a dedicated data base. Patients with TIPSS with otherwise unexplained sustained bacteraemia were included. RESULTS: Over 14 years of age, of 785 patients with TIPSS, eight (1%) had Tipsitis. Indication for TIPSS: variceal bleed, seven; refractory ascites, one. Child-Pugh score: 8.3 (1.4). Seven patients had overlapping stents in situ. Duration to Tipsitis: 21.6 (7.1) months. At diagnosis, TIPSS was occluded in four and patent in three. Tipsitis developed within 2 weeks of shunt interventions in two patients and was owing to development of bilio-venous fistula in one. The organisms identified were: Lactobacillus rhamnosus, Escherichia coli, Enterobacter cloacae, Enterococcusfaecium and Staphylococcus aureus. Median duration of antibiotic therapy: 3 (0.3-3) months. Symptoms initially resolved in all but one. Symptoms recurred in three and this was related to premature cessation of antibiotics in two. Five patients died at a median 1.3 (0.3 to 33) months after Tipsitis with Tipsitis contributing to death in three. CONCLUSION: Tipsitis is a rare but serious problem. It should be suspected in patients with TIPSS and unexplained sustained bacteraemia. Shunt interventions, where TIPSS is inserted for variceal bleed, and use of overlapping shunts at TIPSS insertion may be risk factors for its development. Prolonged antibiotics are usually required but Tipsitis may recur despite apparently successful treatment.

Improved clinical outcome with transjugular intrahepatic portosystemic stent-shunt utilizing polytetrafluoroethylene-covered stents.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) with standard uncovered stents has a 50% one-year primary patency rate, and is complicated by hepatic encephalopathy in 35% of patients. Newer covered stents appear to have improved patency. This large study aimed to assess the shunt function and clinical efficacy of polytetrafluoroethylene-covered stents in a single centre. METHODS: A total of 316 patients with uncovered stents before the introduction of covered stents (group 1) and 157 patients with the Viatorr Gore polytetrafluoroethylene-covered stents at the time of TIPSS creation (group 2) were studied. RESULTS: The mean follow-up was 22.8+/-25.4 and 13.1+/-12.5 months, respectively (P<0.01). Shunt insufficiency was greater in group 1 [54 versus 8% at 12 months; relative hazard (RH) 8.6; 95% confidence interval (CI) 4.8-15.5; P<0.001]. The incidence of variceal rebleeding was greater in group 1 (11 versus 6% at 12 months; RH 2.4; 95% CI 1.1-5.1; P<0.05). The incidence of hepatic encephalopathy was greater in group 1 (32 versus 22% at 12 months; RH 1.5; 95% CI 1.1-2.3; P<0.05). Mortality was similar in the two groups. CONCLUSION: The Viatorr type of polytetrafluoroethylene-covered stent results in vastly improved patency compared with uncovered stents, with reduced rates of variceal rebleeding and hepatic encephalopathy. This type of covered stent has the potential for superior clinical efficacy compared with uncovered stents.