Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium

Clinical trials; Liver transplant; Quality of lifeEnsayos clínicos; Trasplante de hígado; Calidad de vidaAssaigs clínics; Trasplantament de fetge; Qualitat de vidaManagement of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis

Spontaneous portosystemic shunt embolization in liver transplant recipients with recurrent hepatic encephalopathy

Angiogenesis; Portal hypertension; Collateral vesselsAngiogénesis; Hipertensión portal; Vasos colateralesAngiogènesi; Hipertensió portal; Vasos col·lateralsIntroduction and objectives Spontaneous portosystemic shunts (SPSS) are a common cause of recurrent hepatic encephalopathy (HE). Shunt occlusion is an effective and safe procedure when performed in patients with cirrhosis and preserved liver function. We aimed to describe our experience with SPSS embolization after liver transplantation (LT). Patients We identified five patients who underwent SPSS embolization after LT. Clinical, biochemical and technical procedure data were collected. Results At presentation, all patients had developed graft cirrhosis and HE after LT. Median Model for End-stage Liver Disease (MELD) at embolization was 9 (range 7-12), median Child-Pugh was 8 (range 7-9). Splenorenal and mesocaval shunt were the most frequent types of SPSS found. Three patients have been completely free of HE. Of the two patients who had HE recurrence after embolization, one patient had two episodes of HE which was controlled well with medications. The other patient required three embolizations because of recurrent HE. Median follow-up was 4.4 years (range 1.0-5.0) and MELD score at last follow up was 13 (range 10-18) and median Child-Pugh score B, 7 points (range 5-12). Conclusions SPSS can be considered as a cause of HE after LT. SPSS embolization is feasible and safe in LT recipients.Isabel Campos-Varela's research activity is funded by grant PI19/00330, funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF) - A way to build Europe. Macarena Simón-Talero is a recipient of the Juan Rodés grant JR17/00029 from Instituto de Salud Carlos III, Spain. CIBERehd is supported by Instituto de Salud Carlos III. The work was independent of all funding

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (ADNo ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. Lay summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Spontaneous portosystemic shunts in liver cirrhosis : new approaches to an old problem

Portal hypertension is the main consequence of liver cirrhosis, leading to severe complications such as variceal hemorrhage, ascites or hepatic encephalopathy. As an attempt to decompress the portal venous system, portal flow is derived into the systemic venous system through spontaneous portosystemic shunts (SPSSs), bypassing the liver. In this review, we aim to provide an overview of the published reports in relation to the prevalence and physiopathology behind the appearance of SPSS in liver cirrhosis, as well as the complications derived from its formation and its management. The role of SPSS embolization is specifically discussed, as SPSSs have been assessed as a therapeutic target, mainly for patients with recurrent/persistent hepatic encephalopathy and preserved liver function. Furthermore, different aspects of the role of SPSS in liver transplantation, as well as in candidates for transjugular intrahepatic portosystemic shunt are reviewed. In these settings, SPSS occlusion has been proposed to minimize possible deleterious effects, but results are so far inconclusiv

Reply to: “Definition of SPSS: we need to speak the same language”: Computer-assisted image processing for better quantification

In response to Nicoara-Farcau and colleagues, we agree that gastrorenal shunts, seem important, since they are found in many patients with gastric varices and herefore possibly associate with bleeding. In total, 990 SPSS in patients with available follow up data were found. The distribution of the types of SPSS is shown. In conclusion, we acknowledge that we need a unified definition of SPSS.Peer ReviewedPostprint (author's final draft

Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis

Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis : A pilot study (RIFA-AH)

Background & Aims: Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort. Methods: This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days. Results: Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p =.049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p =.01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p =.15) without significant differences. No serious adverse events were associated with rifaximin treatment. Conclusions: Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis

BACKGROUND & AIMS: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. METHODS: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. RESULTS: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p 83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. LAY SUMMARY: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.status: publishe

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.status: publishe