French guidelines on TIPS: Indications and modalities.

Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension-related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre-therapeutic assessment, in the procedure itself and in the follow-up have led the board of the French Association for the Study of the Liver to establish recommendations.

TIPS prevents further decompensation and improves survival in patients with cirrhosis and portal hypertension in an individual patient data meta-analysis.

BACKGROUND & AIMS: Further decompensation represents a prognostic stage of cirrhosis associated with higher mortality compared with first decompensation. A transjugular intrahepatic portosystemic shunt (TIPS) is indicated to prevent variceal rebleeding and for refractory ascites, but its overall efficacy to prevent further decompensations is unknown. This study assessed the incidence of further decompensation and mortality after TIPS vs. standard of care (SOC). METHODS: Controlled studies assessing covered TIPS compared with SOC for the indication of refractory ascites and prevention of variceal rebleeding published from 2004 to 2020 were considered. We collected individual patient data (IPD) to perform an IPD meta-analysis and to compare the treatment effect in a propensity score (PS)-matched population. Primary outcome was the incidence of further decompensation and the secondary outcome was overall survival. RESULTS: In total, 3,949 individual patient data sets were extracted from 12 controlled studies and, after PS matching, 2,338 patients with similar characteristics (SOC = 1,749; TIPS = 589) were analysed. The 2-year cumulative incidence function of further decompensation in the PS-matched population was 0.48 (95% CI 0.43-0.52) in the TIPS group vs. 0.63 (95% CI 0.61-0.65) in the SOC group (stratified Gray's test, p <0.0001), considering mortality and liver transplantation as competing events. The lower further decompensation rate with TIPS was confirmed by adjusted IPD meta-analysis (hazard ratio 0.44; 95% CI 0.37-0.54) and was consistent across TIPS indication subgroups. The 2-year cumulative survival probability was higher with TIPS than with SOC (0.71 vs. 0.63; p = 0.0001). CONCLUSIONS: The use of TIPS for refractory ascites and for prevention of variceal rebleeding reduces the incidence of a further decompensation event compared with SOC and increases survival in highly selected patients. IMPACT AND IMPLICATIONS: A further decompensation (new or worsening ascites, variceal bleeding or rebleeding, hepatic encephalopathy, jaundice, hepatorenal syndrome-acute kidney injury and spontaneous bacterial peritonitis) in patients with cirrhosis is associated with a poor prognosis. Besides the known role of TIPS in portal hypertension-related complications, this study shows that TIPS is also able to decrease the overall risk of a further decompensation and increase survival compared with standard of care. These results further support the role of TIPS in the management of patients with cirrhosis and portal hypertension-related complications.

The pressing need for a global HEV vaccine.

Based on the worldwide distribution of hepatitis E virus (HEV) and its ability to cause major epidemics in low-income countries, the global availability of a HEV vaccine is a pressing clinical need. Populations at risk of severe forms of the infection are well characterised: patients with chronic liver disease - at risk of liver failure; pregnant women - at risk of fulminant hepatitis or obstetrical complications; and immunosuppressed patients, particularly those with solid organ transplants - at risk of chronic hepatitis and rapid progression to cirrhosis. Only one hepatitis E vaccine is presently being manufactured. It has been proven to be effective and safe. However, its accessibility, as well as data on its long-term efficacy and the duration of protection it confers, are limited. While individuals considered to be at risk of severe infection appear to be ideal targets for the vaccine, its effectiveness and tolerability have not yet been studied in populations with chronic liver disease and immunosuppressed patients. Hepatitis E vaccination could also play an important role in controlling outbreaks in large waterborne epidemics. Clinical trials on these populations are needed.

Hepatic encephalopathy is not a contraindication to pre-emptive TIPS in high-risk patients with cirrhosis with variceal bleeding.

BACKGROUND: A pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown. We aimed to (1) assess the prevalence of HE in patients with AVB; (2) evaluate the outcome of patients presenting HE at admission after pTIPS; and (3) determine if HE at admission is a risk factor for death and post-TIPS HE. PATIENTS AND METHODS: This is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation. RESULTS: 671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p<0.001). In high-risk patients with HE at admission, pTIPS was associated with a lower 1-year mortality than endoscopic+drug (HR 0.374, 95% CI 0.166 to 0.845, p=0.0181). The incidence of HE was not different between patients treated with pTIPS and endoscopic+drug (38.2% vs 38.7%, p=0.9721), even in patients with HE at admission (56.4% vs 58.7%, p=0.4594). Age >56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients. CONCLUSION: pTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission.

Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Long-term Outcome.

BACKGROUND: Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS: Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS: Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS: LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

Incidence and factors predictive of recurrent thrombosis in people with non-cirrhotic portal vein thrombosis.

BACKGROUND & AIMS: Clinical guidelines do not recommend long-term anticoagulation in non-cirrhotic splanchnic vein thrombosis (NC-SVT) without underlying thrombophilia because it is assumed that there is a very low risk of recurrent thrombosis (RT). Our first aim was to describe the incidence of RT in people with NC-SVT without an indication for long-term anticoagulation. The second aim was to identify RT risk factors and afterwards verify them in a validation cohort. METHODS: This is a multicentre, retrospective observational study evaluating risk factors for RT in 64 people with NC-SVT of idiopathic/local factor aetiology. In a subgroup of 48 individuals, the potential value of additional thrombophilic parameters to predict RT was analysed. Findings were validated in 70 individuals with idiopathic/local factor NC-SVT. RESULTS: Of the 64 participants in the training cohort, 17 (26%) presented splanchnic and/or extrasplanchnic RT (overall-RT) during follow-up (cumulative incidence: 2, 10, 19, and 34% at 1, 2, 5, and 10 years, respectively). In addition, 53% of people with splanchnic RT were asymptomatic. No clinical or biochemical parameters predicted overall-RT. However, in the 48 people with an additional comprehensive thrombophilic study, factor VIII ≥150% was the only independent factor predicting overall-RT (hazard ratio 7.10, 95% CI 2.17-23.17, p <0.01). In the validation cohort, 19 individuals (27%) presented overall-RT, and it was also independently predicted by factor VIII >150% (hazard ratio 3.71, 95% CI 1.31-10.5, p <0.01). The predictive value of factor VIII was confirmed in both people with idiopathic/local factor aetiology associated NC-SVT. CONCLUSIONS: People with idiopathic/local factor NC-SVT are at risk of overall-RT. Splanchnic RT can be asymptomatic and requires screening for its detection. Values of factor VIII ≥150% may help identify individuals at high risk of overall-RT who could benefit from long-term anticoagulation. IMPACT AND IMPLICATIONS: People with idiopathic/isolated local factor non-cirrhotic portal vein thrombosis were previously thought to be at minimal risk of re-thrombosis and therefore did not receive scheduled follow-up. The results of this study are of special interest for hepatologists treating people with non-cirrhotic splanchnic thrombosis, as they show a 25% incidence of re-thrombosis and support the close follow-up of people with factor VIII >150% to ensure the early identification of new thrombotic events.

Decompensation in Advanced Nonalcoholic Fatty Liver Disease May Occur at Lower Hepatic Venous Pressure Gradient Levels Than in Patients With Viral Disease.

BACKGROUND & AIMS: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension-related decompensation in patients with advanced NAFLD (aNAFLD). METHODS: Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels. RESULTS: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P = .019) than in the aHCV group. For any of the HVPG cutoff analyzed (<10, 10-12, or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD group than in the aHCV group. CONCLUSIONS: Patients with aNAFLD have higher prevalence of portal hypertension-related decompensation at any value of HVPG as compared with aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed.

Hepatitis E, what is the real issue?

Hepatitis E virus (HEV) infection is a worldwide disease and the primary cause of acute viral hepatitis with an estimated 3.3 million symptomatic cases every year and 44,000 related deaths. It is a waterborne infection in the developing countries. In these countries, HEV genotypes 1 and 2 cause large outbreaks and affect young subjects resulting in significant mortality in pregnant women and patients with cirrhosis. In developed countries, HEV genotypes 3 and 4 are responsible for autochthonous, sporadic hepatitis and transmission is zoonotic. Parenteral transmission by the transfusion of blood products has been identified as a potential new mode of transmission. HEV can also cause neurological disorders and chronic infections in immunocompromised patients. The progression of acute hepatitis E is usually asymptomatic and resolves spontaneously. Diagnosis is based on both anti-HEV IgM antibodies in serum and viral RNA detection in blood or stools by PCR in immunocompetent patients, while only PCR is validated in immunocompromised individuals. Ribavirin is the only validated treatment in chronic infection. A vaccine has been developed in China.

Combination of Model for End-Stage Liver Disease and Lactate Predicts Death in Patients Treated With Salvage Transjugular Intrahepatic Portosystemic Shunt for Refractory Variceal Bleeding.

BACKGROUND AND AIMS: Data about the prognosis of salvage transjugular intrahepatic portosystemic shunt (TIPS) using covered stents for refractory variceal bleeding caused by portal hypertension are scarce. We aimed to assess survival and to identify predictors of mortality in these patients. APPROACH AND RESULTS: One hundred sixty-four patients with cirrhosis from five centers treated with salvage TIPS between 2007 and 2017 were retrospectively divided into a derivation cohort (83 patients) and a validation cohort (81 patients). Comparisons were performed using the Mann-Whitney and Fischer's exact test. Six-week overall survival (OS) was correlated with variables on the day of the TIPS using Kaplan-Meier curves with log-rank test and univariate/multivariate analyses using the Cox model. Eighty-three patients were included in the derivation cohort (male, 78%; age, 55 years, alcohol-associated cirrhosis, 88%; Model for End-Stage Liver Disease [MELD], 19 [15-27]; arterial lactate, 3.7 mmol/L [2.0-8.3]). Six-week OS rate was 58%. At multivariate analysis, the MELD score (OR, 1.064; 95% CI, 1.005-1.126; P = 0.028) and arterial lactate (OR, 1.063; 95% CI, 1.013-1.114; P = 0.032) were associated with 6-week OS. Six-week OS rates were 100% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 5% in patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. The 81 patients of the validation cohort had similar MELD and arterial lactate level but lower creatinine level (94 vs 106 µmol/L, P = 0.008); 6-week OS was 67%. Six-week OS rates were 86% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 10% for patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. In the overall cohort, rebleeding rate was 15.8% at 6 weeks, and the acute-on-chronic liver failure grade (OR, 1.699; 95% CI, 1.056-1.663; P = 0.040) was independently associated with rebleeding. CONCLUSIONS: After salvage TIPS, 6-week mortality remains high and can be predicted by MELD score and lactate. Survival rate at 6 weeks was >85% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15, while mortality was >90% for lactate ≥12 mmol/L and/or MELD score ≥ 30.

Management of Severe and Refractory Ascites.

Considering the poor prognosis, severe and refractory ascites is a milestone in cirrhotic patients. Liver transplantation must be considered first. In the case of contraindication to liver transplantation or when the waiting period is estimated to be more than 6 months, transjugular intrahepatic portosystemic shunt should be discussed in eligible patients. Regardless of the type of treatment, a careful selection of patients is crucial to avoid further decompensation and specific complications of each treatment.

Hepatitis E, what's the real issue?

Hepatitis E Virus (HEV) infection is a worldwide disease and the primary cause of acute viral hepatitis in the world with an estimated 20 million cases every year and 70 000 deaths. Hepatitis E is a waterborne infection in the developing countries. In these countries, HEV genotypes 1 and 2 cause large outbreaks and affect young subjects, resulting in significant mortality in pregnant women and patients with cirrhosis. In the developed countries, HEV genotypes 3 and 4 are responsible for autochthonous, sporadic hepatitis and transmission is zoonotic. Parenteral transmission by the transfusion of blood products has been identified as a potential new mode of transmission. The prevalence of positive HEV viraemia in blood donors in Europe ranges from 1/600 to 1/2500 in highly endemic European countries. HEV can cause neurological disorders and chronic infections in immunocompromised patients. The progression of acute hepatitis E is usually asymptomatic and resolves spontaneously. Diagnostic tools include anti-HEV IgM antibodies in serum and/or viral RNA detection in the blood or the stools by PCR. Ribavirin is used to treat chronic infection. A vaccine has been developed in China.