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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. [ABSTRACT FROM AUTHOR]

Background & Aims: Alcohol‐related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol‐related liver disease (ALD) phenotypes and viral cirrhosis. Methods: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d‐ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a‐ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD. Results: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty‐two days transplant‐free survival was worse among AH, but statistical differences were only observed between AH and d‐ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one‐year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a‐ALD (0.48; 0.29–0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH. Conclusions: Contrary to expected, AH patients with AVB present no worse one‐year survival than other patients with different alcohol‐related phenotypes or viral cirrhosis. Abstinence influences long‐term survival and could explain these counterintuitive results. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes. However, it is a poorly understood complication, with no consensus for diagnosis. Therefore, HE is often underdiagnosed. Differential diagnosis may be cumbersome because of non‐specific symptoms, such as confusion, cognitive disorders, the aetiological factors of cirrhosis and comorbidities, which are often observed in cirrhotic patients. Therefore, an overt or covert form of HE should be systematically investigated. Advice is provided to drive patient work‐up. Effective treatments are available to prevent or treat HE bouts, but the issue of single or combination therapy has not been resolved. Transjugular intrahepatic portosystemic shunt (TIPS) placement largely improved the prognosis of cirrhotic patients, but HE occurrence of HE is often a fear, even when post‐TIPS HE can be avoided by a careful selection of patients and preventive treatment. HE is an indication of liver transplantation. However, its reversibility post‐transplantation and the consequences of transplantation in patients with other causes of neurological disorders remain controversial, which supports the performance of an extensive work‐up in expert centres for this subset of patients. The present guidelines assist clinicians in the diagnosis of the overt or covert form of HE to implement curative and preventive treatments and clarify which patients require referral to expert centres for consideration for liver transplantation. These guidelines are very clinically oriented and address different frequent clinical issues to help physicians make bedside decisions. [ABSTRACT FROM AUTHOR]

Portal hypertension (PHT) and hepatocellular carcinoma (HCC) often coexist, and their association impairs the prognosis of patients with cirrhosis. The interplay between these two conditions is of major therapeutic significance, both from the perspective of offering adequate treatment for HCC and for preventing or managing the complications of PHT. Recommendations on the management of PHT were heavily revised at the last Baveno VII conference, redefining screening and extending the indications for prophylaxis. PHT can preclude locoregional therapies, and TIPS placement can be discussed in patients with HCC. New systemic therapies for HCC can influence the level of PHT and favour bleeding. Complications of PHT should be prevented and treated adequately in all patients, especially those presenting with advanced HCC. Specific aspects of the management of both conditions will be discussed in the present expert opinion, which considers very recent data in the HCC field. [ABSTRACT FROM AUTHOR]

Ascites is the most common complication of cirrhosis, which develops in 5%‐10% of patients per year. Its management is based on symptomatic measures including restriction of sodium intake, diuretics and paracentesis. Underlying liver disease must always be treated and may improve ascites. In some patients, ascites is not controlled by medical therapies and has a major impact on quality of life and survival. TIPS placement and liver transplantation must therefore be discussed. More recently, repeated albumin infusions and Alfapump® have emerged as new therapies in ascites. In this review, the current data on these different options are analysed and an algorithm to help the physician make clinical decisions is suggested. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is common in patients with chronic diseases. It is evaluated using the International Index of Erectile Function (IIEF5) questionnaire. The relationship between ED and cirrhosis is complex. The aims of our study were (1) to assess the prevalence of ED in cirrhosis and (2) to evaluate factors associated with ED, with a special focus on minimal hepatic encephalopathy (MHE). We performed a prospective, observational study. Patients with cirrhosis were invited to complete the IIEF5 questionnaire. The exclusion criteria were clinical hepatic encephalopathy (HE) and dementia. MHE was evaluated by the psychometric hepatic encephalopathy test score (PHES) and the critical flicker frequency (CFF). Between April 2016 and April 2017, 87 patients were included (age: 55 [51–57] years, Child–Pugh score: 8 [7–9], MELD score: 13 [11–16]. Minimal HE was diagnosed in 33% of the patients according to the PHES and in 44% of the patients according to the CFF. ED was diagnosed in 74/87 patients (85%) when compared to 12.5% in healthy controls (p < 0.001). In a multivariate analysis, the independent factors associated with ED were age, Child–Pugh and MELD scores. Significant correlations were identified between the IIEF5 and each component of the PHES. ED should be systematically screened in cirrhotics, especially in patients with MHE. [ABSTRACT FROM AUTHOR]

Background & Aim: Human beta‐defensin‐1 (hBD‐1) is a natural antimicrobial peptide expressed in the epithelia of multiple tissues including the digestive tract. In the current study, hBD‐1 levels were determined in different subsets of patients with decompensated cirrhosis including acute‐on‐chronic liver failure (ACLF). In addition, the association with mortality of hBD‐1, C‐reactive protein (CRP) and procalcitonin (PCT) was assessed. Methods: A total of 125 patients were divided into three groups: 39 with ACLF (derivation cohort), 46 with acute decompensation without ACLF (AD) and 40 with decompensated cirrhosis without an acute event (DC). The data from 24 different ACLF patients were used for validation and 15 healthy individuals as control group. Results: Serum hBD‐1, CRP and PCT levels were higher in ACLF compared to both AD and DC groups (P < 0.001). Healthy controls demonstrated similar hBD‐1 and PCT values compared to DC group. In ROC curve, the performance of hBD‐1 to predict 60‐day mortality in ACLF group was similar in derivation and validation cohorts (c‐statistic 0.834 and 0.879, respectively). CRP was a poor predictor of mortality. In ACLF group, patients with high hBD‐1 (>36.625 ng/mL) had a poor prognosis at 60 days compared to those with lower values (log‐rank P = 0.001). In Cox multivariate regression analysis, only hBD‐1 (HR 1.020, 95%CI 1.006‐1.035, P = 0.006) emerged as an independent predictor of death in ACLF group. In AD group, neither hBD‐1 nor PCT or CRP variables were associated with mortality. Conclusions: High hBD‐1 was detected at presentation in patients with ACLF who died during follow‐up period. hBD‐1 is an accurate predictor of short‐term mortality in patients with ACLF. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Early TIPS placement must be considered in patients with Child‐Pugh B and active bleeding at endoscopy or in patients with Child‐Pugh C 10‐13 and variceal bleeding. However, active bleeding at endoscopy is a subjective criterion. Moreover, a previous study has shown that a MELD‐based score accurately predicted 6‐week mortality and helped to stratify patients. Using a prospective series of patients included in a multicentre study before the era of early TIPS, we aimed (i) to identify factors associated with 6‐week mortality, focusing on the prognostic value of active bleeding; and (ii) to assess whether a recalibrated MELD‐based score accurately predicted 6‐week mortality. Methods: Ancillary study of the prospective multicentre Baveno IV study, including patients with acute variceal bleeding. Results: Two hundred and nineteen patients were analysed (Child‐Pugh A/B/C = 18/45/37%). The overall actuarial likelihood of survival on day 42 was 84%. The variability for the diagnosis of active bleeding at endoscopy was high (range, 41.4% to 84.6% among the centres). Active bleeding at endoscopy was not associated with 6‐week mortality in the entire population or in Child‐Pugh B patients. In a multivariate analysis, independent factors associated with mortality were liver function, infection, HE and HCC. The recalibrated MELD‐based score was accurate in predicting 6‐week mortality (AUROC = 0.787). The recalibrated MELD‐based score demonstrated better performance compared to the MELD score. Conclusion: The recalibrated MELD‐based score accurately predicted mortality in our prospective cohort. Active bleeding at endoscopy had no prognostic value in cirrhotic patients presenting with acute variceal bleeding. Standardizing active bleeding assessment at endoscopy is warranted. [ABSTRACT FROM AUTHOR]

Background & Aims The Baveno VI consensus meeting concluded that an early transjugular intra-hepatic porto-systemic shunt (TIPS) must be considered in high-risk patients with cirrhosis, presenting with variceal bleeding (VB) (Child B + active bleeding at endoscopy or Child C10-13 patients). Whether this therapeutic approach is feasible in a real-life setting remains unclear. The aim of this study was to determine (i) the proportion of patients eligible for early-TIPS among patients with cirrhosis and VB, (ii) the proportion of these patients who underwent early-TIPS placement and the main reasons for discarding TIPS, and (iii) the outcomes of patients who experienced early-TIPS placement. Methods A large, national, prospective, multicentre audit of academic and non-academic centres, in which all French centres recruiting patients with gastrointestinal bleeding were invited to participate. All consecutive patients with cirrhosis and portal hypertension-related bleeding were included. Results A total of 964 patients were included (58 centres: 26 academic, 32 non-academic; patient characteristics: male sex 77%; age 59.6 ± 12.1 years; aetiologies of cirrhosis (alcoholic 67%, viral 15%, other 18%); source of bleeding (oesophageal varices 80%, gastric varices 11%, other 9%); active bleeding at endoscopy 34%; Child A 21%, B 44%, C 35%. Overall, 35% of the patients were eligible for early-TIPS, but only 6.8%, displaying less severe cirrhosis underwent early-TIPS placement. The main reason for discarding TIPS was a lack of availability. The actuarial probability of survival at one year was significantly increased in early-TIPS patients (85.7 ± 0.07% vs. 58.9 ± 0.03%, p  = 0.04). The severity of liver disease was the only parameter independently associated with improved one-year survival. Conclusion In this real-life study, one-third of the patients with cirrhosis, admitted for VB fulfilled the criteria for early-TIPS placement, whereas only 7% had access to TIPS. TIPS was restricted to patients displaying less severe cirrhosis. The severity of liver disease was the only parameter that influenced survival. Lay summary Bleeding from oesophageal or gastric varices is a severe complication of cirrhosis, related to an increased pressure in the portal vein perfusing the liver. Some patients are described as “severe”, either because their liver disease is already severe, or because the bleeding is very important. Those patients could benefit from a prothesis, placed inside the liver by an interventional radiologist, aiming to decrease the pressure in the portal vein, just after the control of bleeding by medications and endoscopic treatment. New studies are warranted to demonstrate a real beneficial effect of this therapeutic attitude, which is not adopted in real-life practice, as shown by this national French audit of practice. [ABSTRACT FROM AUTHOR]

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Purpose: Status epilepticus (SE) in patients with cirrhosis is a rare but serious situation. Diagnosis may be difficult in emergency presentation, especially when patients present with hepatic encephalopathy (HE). Misdiagnosis must be avoided since some anti-epileptic drugs aggravate HE. In this retrospective study, we therefore assessed the frequency of SE in patients with cirrhosis, evaluated the accuracy of diagnosis and determined rates of mortality.Method: We reviewed data from all patients hospitalized from 2005 to 2013 in the Hepatology ICU for complications of cirrhosis with an initial diagnosis of SE. We attempted to reach a consensus decision on a possible diagnosis of SE in reviews of EEG traces and medical records by an expert electrophysiologist, a hepatologist and a neurologist.Results: An initial diagnosis of SE was made for 20 patients with cirrhosis. Critical review suggested that 15 of these patients were correctly diagnosed with true SE. However, initial diagnoses may have been mistaken for at least 3 patients, who presented clinical and electrical signs of HE without evidence for SE. Overall, we estimated a prevalence of 0.7% for SE in patients with cirrhosis (15 of 2010 patients admitted to our ICU) in our series. In-hospital mortality was of 73%. In the 12 months after the SE episode, mortality was 87%.Conclusion: As SE may be misdiagnosed in patients with cirrhosis, a joint review of the patients by neurologists and hepatologists could reduce errors in diagnosis. [ABSTRACT FROM AUTHOR]

Portal hypertension accounts for the majority of morbidity and mortality that is encountered in patients with cirrhosis. Portal hypertension is initiated in large part through increases in intrahepatic vascular resistance. Fibrosis, regenerative nodule formation, and intrahepatic vasoconstriction are classical mechanisms that account for increased intrahepatic vascular resistance in cirrhosis. Recent data suggest that intrahepatic angiogenesis and sinusoidal remodeling could also be involved in sinusoidal resistance, fibrosis, and portal hypertension. While angiogenesis is defined as the formation of new vessels deriving from existing ones, sinusoidal remodeling in its pathological form associated with cirrhosis is characterized by increased mural coverage of vessels by contractile HSC. Most attention on the mechanisms of these processes has focused on the liver sinusoidal endothelial cell (SEC), the hepatic stellate cell (HSC), and the paracrine signaling pathways between these two cell types. Interventions that target these vascular structural changes have beneficial effects on portal hypertension and fibrosis in some animal studies which has stimulated interest for pursuing parallel studies in humans with portal hypertension. [ABSTRACT FROM AUTHOR]

Background/Aim: In cirrhosis, systemic nitric oxide (NO) overproduction and hepatic NO hypoproduction lead to arterial vasodilatation and portal hypertension. The mechanisms involved in these alterations in endothelial NO synthase (eNOS)-derived NO production in hepatic and systemic vasculature remain unknown. The aim of this study was to evaluate the regulation of eNOS and its major modulators in the liver and aorta during the development of cirrhosis in rats. Methods: Activated eNOS and Akt and expressions, and caveolin-1 (Cav-1) and scavenger receptor class B type I (SR-BI) expressions were measured before and 1, 2, 3 and 4 weeks after bile duct ligation. Plasma high-density lipoprotein (HDL) levels were measured. Results: Activated aortic eNOS increased at week 1, whereas it began to decrease at week 3 in the liver. Aortic expression of Cav-1 decreased at week 3 while hepatic expression increased by four-fold. Activated aortic Akt increased progressively while in the liver it gradually decreased during the development of cirrhosis. HDL levels decreased during the first week and decreased thereafter. The hepatic expression of SR-BI decreased. Conclusion: This study shows that the modulation of Akt and Cav-1 is inverted in the liver and the aorta during the development of cirrhosis. In addition, decreased HDL levels may play a role in reduced hepatic eNOS activity. [ABSTRACT FROM AUTHOR]

Gastrointestinal bleeding is a frequent and severe complication of portal hypertension. The most frequent cause of the bleeding is variceal rupture. Despite improvements in prognosis after variceal bleeding over the past two decades, the 6-week mortality rate remains high, ranging from 15 to 30%. Patients die from uncontrolled bleeding, early rebleeding, infection, or renal failure within the first weeks of a bleeding episode. Poor hepatic function, severe portal hypertension with a hepatic venous pressure gradient (HVPG) >20mmHg, and active bleeding at endoscopy are independently associated with poor prognosis. First-line treatment includes resuscitation, prophylactic antibiotic therapy, the combined use of vasoactive drugs (started as soon as possible), and an endoscopic procedure. Reconstitution of blood volume should be done cautiously to maintain the haematocrit between 25 and 30%. Terlipressin, somatostatin, or octreotide can be used, and drug therapy is maintained from 48h to 5days. Ligation is the endoscopic treatment of choice in bleeding oesophageal varices; in gastric varices, obturation with cyanoacrylate is preferable. Uncontrolled bleeding should be an indication for a salvage transjugular portosystemic shunt (TIPS). In patients with Child–Pugh score A, shunt surgery might be an alternative to TIPS. Trials are currently ongoing into the precise indications of early TIPS in selected patients with an HVPG >20mmHg, and into the usefulness of administration of recombinant activated factor VII when there is an active bleeding at endoscopy. [Copyright &y& Elsevier]

Primary prevention of variceal bleeding with β-blockers improves survival in patients with large oesophageal varices (LOV). Therefore, cirrhotic patients frequently undergo screening endoscopy. As portal hypertension is related to liver fibrosis, this study aimed to assess the predictive value of FibroTest, a non-invasive marker of liver fibrosis, for the diagnosis of LOV in cirrhotic patients. Methods: Ninety-nine cirrhotic patients had clinical examination, blood sample (liver function tests, platelet count, FibroTest) and upper endoscopy. Measurements of endoscopic and biochemical parameters were made blindly. Sensitivity, specificity, predictive values and area under the receiver operating characteristic curves were assessed for FibroTest, platelet count and Child–Pugh score. The main endpoint was the presence of LOV. Results: Platelet count, prothrombin time, ascites, FibroTest and Child–Pugh class were significantly different among patients with or without LOV. FibroTest had the highest discriminative power with an area under receiver operating characteristics curves of 0.77 (SE=0.06), compared with 0.64 (0.08) and 0.68 (0.08) for platelet count and Child–Pugh score, respectively ( P=0.08). A cut-off at 0.80 had a 86% negative predictive value for the diagnosis of LOV (Se=92%, Sp=21%). Conclusion: FibroTest could aid in the diagnosis of LOV and may therefore reduce the indication of endoscopic screening in cirrhotic patients. [ABSTRACT FROM AUTHOR]

COMMENTARY ON: : Safety of Recombinant Activated Factor VII in Randomized Clinical Trials. Levi M, Levy JH, Andersen HF, Truloff D. N Engl J Med 2010;363:179. Copyright (2010) by the Massachusetts medical Society (MMS). Abstract reprinted with permission from the MMS . http://www.ncbi.nlm.nih.gov/pubmed/21047223 Abstract: Background: The use of recombinant activated factor VII (rFVIIa) on an off-label basis to treat life-threatening bleeding has been associated with a perceived increased risk of thromboembolic complications. However, data from placebo-controlled trials are needed to properly assess the thromboembolic risk. To address this issue, we evaluated the rate of thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label basis. Methods: We analysed data from 35 randomized clinical trials (26 studies involving patients and nine studies involving healthy volunteers) to determine the frequency of thromboembolic events. The data were pooled with the use of random-effects models to calculate the odds ratios and 95% confidence intervals. Results: Among 4468 subjects (4119 patients and 349 healthy volunteers), 498 had thromboembolic events (11.1%). Rates of arterial thromboembolic events among all 4468 subjects were higher among those who received rFVIIa than among those who received placebo (5.5% vs. 3.2%, P =0.003). Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who received placebo (5.3% vs. 5.7%). Among subjects who received rFVIIa, 2.9% had coronary arterial thromboembolic events, as compared with 1.1% of those who received placebo (P =0.002). Rates of arterial thromboembolic events were higher among subjects who received rFVIIa than among subjects who received placebo, particularly among those who were 65years of age or older (9.0% vs. 3.8%, P =0.003); the rates were especially high among subjects 75years of age or older (10.8% vs. 4.1%, P =0.02). Conclusions: In a large and comprehensive cohort of persons in placebo-controlled trials of rFVIIa, treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial but not venous thromboembolic events, especially among the elderly. (Funded by Novo Nordisk.). [Copyright &y& Elsevier]

Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e. , Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation for secondary prophylaxis. We investigated prognostic factors for re-bleeding and mortality in 'non-high-risk' AVB to identify subgroups who may benefit from more potent treatments (i.e. , TIPS) to prevent further decompensation and mortality. A total of 2,225 adults with cirrhosis and variceal bleeding were prospectively recruited at 34 centres between 2011-2015; for the purpose of this study, case definitions and information on prognostic indicators at index AVB and on day 5 were further refined in low-risk patients, of whom 581 (without failure to control bleeding or contraindications to TIPS) who were managed by non-selective beta-blockers/endoscopic variceal ligation, were finally included. Patients were followed for 1 year. Overall, 90 patients (15%) re-bled and 70 (12%) patients died during follow-up. Using clinical routine data, no meaningful predictors of re-bleeding were identified. However, re-bleeding (included as a time-dependent co-variable) increased mortality, even after accounting for differences in patient characteristics (adjusted cause-specific hazard ratio: 2.57; 95% CI 1.43-4.62; p = 0.002). A nomogram including CTP, creatinine, and sodium measured at baseline accurately (concordance: 0.752) stratified the risk of death. The majority of 'non-high-risk' patients with AVB have an excellent prognosis, if treated according to current recommendations. However, about one-fifth of patients, i.e. those with CTP ≥8 and/or high creatinine levels or hyponatremia, have a considerable risk of death within 1 year of the index bleed. Future clinical trials should investigate whether elective TIPS placement reduces mortality in these patients. Pre-emptive transjugular intrahepatic portosystemic shunt placement improves outcomes in high-risk acute variceal bleeding; nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation. This is the first large-scale study investigating prognostic factors for re-bleeding and mortality in 'non-high-risk' acute variceal bleeding. While no clinically meaningful predictors were identified for re-bleeding, we developed a nomogram integrating baseline Child-Turcotte-Pugh score, creatinine, and sodium to stratify mortality risk. Our study paves the way for future clinical trials evaluating whether elective transjugular intrahepatic portosystemic shunt placement improves outcomes in presumably 'non-high-risk' patients who are identified as being at increased risk of death. [Display omitted] • International study to determine prognostic factors in patients with 'non-high-risk' acute variceal bleeding. • No clinically meaningful predictors of re-bleeding were observed. • Child-Turcotte-Pugh score, creatinine, and sodium stratified mortality risk. • Future clinical trials should investigate whether elective TIPS placement reduces mortality in a subset of patients. [ABSTRACT FROM AUTHOR]

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). 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. 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). 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. 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. [Display omitted] • Compared with SOC, TIPS reduces the incidence of further decompensation. • The number of patients needed to treat with TIPS to save one life is 13. • Overall, TIPS improves survival in highly selected patients [ABSTRACT FROM AUTHOR]

There are uncertainties regarding the burden of liver disease in patients with type 2 diabetes (T2D). Thus, we aimed to quantify the burden of liver disease, identify risk factors, and estimate attributable risks in patients with T2D. We measured adjusted hazard ratios of liver disease progression to hepatocellular carcinoma and/or decompensated cirrhosis in a 2010-2020 retrospective, bicentric, longitudinal, cohort of 52,066 hospitalized patients with T2D. Mean age was 64±14 years and 58% were men. Alcohol use disorders accounted for 57% of liver-related complications and were associated with all liver-related risk factors. Non-metabolic liver-related risk factors accounted for 37% of the liver burden. T2D control was not associated with liver disease progression. The incidence (95% CI) of liver-related complications and of competing mortality were 3.9 (3.5–4.3) and 27.8 (26.7–28.9) per 1,000 person-years at risk, respectively. The cumulative incidence of liver disease progression exceeded the cumulative incidence of competing mortality only in the presence of well-identified risk factors of liver disease progression, including alcohol use. The incidence of hepatocellular carcinoma was 0.3 (95% CI 0.1-0.5) per 1,000 person-years in patients with obesity and it increased with age. The adjusted hazard ratios of liver disease progression were 55.7 (40.5-76.6), 3.5 (2.3-5.2), 8.9 (6.9-11.5), and 1.5 (1.1-2.1), for alcohol-related liver disease, alcohol use disorders without alcohol-related liver disease, non-metabolic liver-related risk factors, and obesity, respectively. The attributable fractions of alcohol use disorders, non-metabolic liver-related risk factors, and obesity to the liver burden were 55%, 14%, and 7%, respectively. In this analysis of data from 2 hospital-based cohorts of patients with T2D, alcohol use disorders, rather than obesity, contributed to most of the liver burden. These results suggest that patients with T2D should be advised to drink minimal amounts of alcohol. There is uncertainty on the burden of liver-related complications in patients with type 2 diabetes. We studied the risks of liver cancer and complications of liver disease in over 50,000 patients with type 2 diabetes. We found that alcohol was the main factor associated with complications of liver disease. This finding has major implications on the alcohol advice given to patients with type 2 diabetes. [Display omitted] • We report on liver disease progression in 52,066 hospitalized patients with T2D. • The incidence of liver-related complications was 3.9/1,000 persons years at risk. • Alcohol use disorders accounted for 57% of liver-related complications. • Non-metabolic liver-related risk factors accounted for 37% of liver-related complications. • Obesity and the metabolic syndrome in the absence of alcohol accounted for <10% of the liver disease burden. [ABSTRACT FROM AUTHOR]

Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis. A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization. A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9). Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade. Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade. [Display omitted] • Bacterial infections still occur in around one-fifth of patients with cirrhosis and acute variceal bleeding despite antibiotic prophylaxis. • Respiratory bacterial infections are the most frequent, occurring early after admission. • Respiratory infections are related to the severity of cirrhosis, presence of severe hepatic encephalopathy and airway manipulation. • Over 50% of the bacteria isolated in this series were resistant to third-generation cephalosporines. [ABSTRACT FROM AUTHOR]

The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p < 0.001) and mortality (47% vs. 10%; p < 0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt. • Variceal bleeding is frequently associated with ACLF in cirrhosis. • ACLF is independently associated with rebleeding and mortality. • Patients with variceal bleeding and ACLF can benefit from a pre-emptive (early) TIPS. [ABSTRACT FROM AUTHOR]

Keywords: Magnetic resonance spectroscopy; MRI; MRS; Cirrhosis; Hepatic encephalopathy Whereas glutamine/creatine and glutamate/creatine levels were increased in patients with MHE, myoinositol/creatine levels were decreased. Magnetic resonance spectroscopy, MRI, MRS, Cirrhosis, Hepatic encephalopathy. [Extracted from the article]

Background & Aims We report the first real-life results of the sofosbuvir + daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients. Methods The France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER “Therapeutic options for hepatitis B and C: A French cohort” is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n = 768) with a HCV genotype 1 who initiated sofosbuvir (400 mg/day) and daclatasvir (60 mg/day) before October 1st 2014, with or without ribavirin (1–1.2 g/day) for a duration of 12 weeks or 24 weeks. The main endpoint criterion was sustained virological response at 12 weeks (SVR12), defined by the absence of detectable HCV-RNA 12 weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n = 45), otherwise considered as virological failure (n = 18). Results A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir + daclatasvir) to 99% (24-week sofosbuvir + daclatasvir + ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p = 0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p = 0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p = 0.0054). Conclusion The sofosbuvir + daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12 weeks in non-cirrhotic and 24 weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact. Lay summary The sofosbuvir + daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir + daclatasvir combination seems to be 12 weeks in non-cirrhotic patients and 24 weeks for those with cirrhosis. Clinical trial number: NCT01953458. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatic encephalopathy (HE) is a neurological complication observed in patients with liver disease and/or porto-systemic shunt. The proportion of cirrhotic patients developing overt HE is about 20%, and 60–80% of cirrhotic patients exhibit mild cognitive impairment potentially related to minimal HE. However, the pathophysiological mechanisms of HE remain poorly understood. In this context, metabolomics was used to highlight dysfunction of metabolic pathways in cerebrospinal fluid (CSF) samples of patients suffering from HE. Methods CSF samples were collected in 27 control patients without any proven neurological disease and 14 patients with symptoms of HE. Plasma samples were obtained from control patients, and from cirrhotic patients with and without HE. Metabolomic analysis was performed using liquid chromatography coupled to high-resolution mass spectrometry. Results Concentrations of 73 CSF metabolites, including amino acids, acylcarnitines, bile acids and nucleosides, were altered in HE patients. Accumulation of acetylated compounds, which could be due to a defect of the Krebs cycle in HE patients, is reported for the first time. Furthermore, analysis of plasma samples showed that concentrations of metabolites involved in ammonia, amino-acid and energy metabolism are specifically and significantly increased in CSF samples of HE patients. Lastly, several drugs were detected in CSF samples and could partially explain worsening of neurological symptoms for some patients. Conclusion By enabling the simultaneous monitoring of a large set of metabolites in HE patients, CSF metabolomics highlighted alterations of metabolic pathways linked to energy metabolism that were not observed in plasma samples. Lay summary CSF metabolomics provides a global picture of altered metabolic pathways in CSF samples of HE patients and highlights alterations of metabolic pathways linked to energy metabolism that are not observed in plasma samples. [ABSTRACT FROM AUTHOR]

Ammonia is one of the main players in the pathogenesis of hepatic encephalopathy (HE) in patients with chronic liver diseases. The usefulness of measuring ammonemia has been debated since many years. New data reveal that besides helping in the differential diagnosis of HE, ammonemia could be a prognostic marker not only in patients with HE, but also in patients without any neurological symptoms, suggesting a potential toxic role of ammonia beyond the brain. Finally, targeting ammonemia while monitoring therapeutic response could be a way to improve outcomes in patients with HE. [Display omitted] • Venous ammonemia can easily be performed in routine practice. • Ammonemia is useful to characterize neurological disorders in patients with chronic liver diseases. • A normal ammonemia rules out hepatic encephalopathy, and prompts to seek for other causes of acute encephalopathy. • Hyperammonemia is associated with a higher risk of grade III-IV encephalopathy, organ failure and mortality in decompensated patients. • Monitoring ammonemia could guide therapeutic interventions especially when symptoms persist under a first line of treatment. [ABSTRACT FROM AUTHOR]

Background & Aims All trials on severe alcoholic hepatitis (AH) have included patients with “pure” AH, i.e., without concomitant gastrointestinal bleeding (GIB). Severe AH is often suspected in cirrhotic patients with GIB. We aimed at (1) assessing the prevalence of AH in patients with GIB and Maddrey discriminant function (DF) ⩾32; (2) comparing the outcome in AH patients with or without GIB (AH-GIB+, AH-GIB−); and (3) assessing the performance of the Lille model for survival in AH-GIB+ patients. Methods We retrospectively included all patients with alcoholic cirrhosis admitted between January 2005 and March 2011 with the following: (1) jaundice <3 months; (2) DF ⩾32 at admission; (3) bilirubin level >50 μmol/L; and (4) active drinking. Exclusion criteria were advanced hepatocellular carcinoma, other etiology of cirrhosis, severe comorbidities and DF <32 after stabilization. In our centre, we systematically plan a liver biopsy for these patients. Patients with severe AH received prednisolone. Results We screened 161 patients (86 GIB+, 75 GIB−), and analyzed data for 58 and 47 patients in each group, respectively. The 2 groups did not differ in prevalence of AH (77.3% vs. 81%), demographic data, MELD/Child-Pugh score, or DF. The 2 groups were similar in 6-month probability of survival (73.9 ± 6.0% vs. 69.9 ± 7%, p = 0.49). The probability of developing infection was lower for AH-GIB+ patients (24.1% vs. 44.7%, p = 0.04). The AUC for the Lille model in predicting 6-month survival was 0.71 ± 0.06 for all patients and 0.74 ± 0.06 for AH-GIB+ patients ( p >0.05). Conclusions Prevalence of AH is 80% for patients with cirrhosis and GIB, recent jaundice and DF ⩾32. Infection was lower for AH-GIB+ patients, which suggests a beneficial role of antibiotic prophylaxis treatment. Survival among subjects with GIB was the same as among subjects without GIB. [ABSTRACT FROM AUTHOR]

Background & Aims: Chronic hepatitis C is both a virologic and fibrotic disease and complications can occur in patients with sustained virologic response (SVR) with residual fibrosis. Due to the limitations of repeated biopsies, no studies have assessed the dynamic of fibrosis before and after treatment. Using biopsy as reference, FibroTest™ has been validated as a biomarker of fibrosis progression and regression, with similar prognostic values. The aim was to estimate the impact of SVR on the dynamic of fibrosis presumed by FibroTest™. Methods: In a prospective cohort, the main end point was the 10-year regression rate of fibrosis, defined as a minimum 0.20 decrease in FibroTest™, equivalent to one METAVIR stage. Results: A total of 933 patients with both repeated FibroTest™ and transient elastography were included. At 10years, among the 415 patients with baseline advanced fibrosis, 49% (95% CI 33–64%) of the 108 SVR had a regression, which was greater than in the 219 non-responders [23% (14–33%; p <0.001 vs. SVR)] and not lower than in the 88 non-treated [45% (10–80%; p =0.39 vs. SVR)] patients. In all 171 SVR, cirrhosis regressed in 24/43 patients, but 15 new cirrhosis cases occurred out of 128 patients, that is only a net reduction of 5.3% [(24–15)=9/171); (2.4–9.8%)]. Four cases of primary liver cancer occurred in SVR [4.6% (0–9.8)], and 13 in non-responders [5.6% (1.5–9.8); p =0.07]. Conclusions: In patients with chronic hepatitis C, and as presumed by FibroTest™, virological cure was associated with slow regression of fibrosis 10years later, a disappointing 5% decrease in cirrhosis cases, and a remaining 5% risk of primary liver cancer. [Copyright &y& Elsevier]

Metabolomics refers to the study of biological components below 1000 Daltons (Da) involved in metabolic pathways as substrates, products or effectors. According to the interconnected metabolic disturbances that have been described in the pathophysiology of hepatic encephalopathy (HE), this technique appears to be well adapted to study and better delineate the disease. This review will focus on recent advances in metabolomics in the field of HE. Thus, after a brief overview of the general principles of metabolomics, we will discuss metabolomics as a potentially efficient tool for unraveling new HE pathophysiological insights, biomarkers identification, or as a predicting tool for treatment response or outcome prognosis. Finally, we will give our vision on the prospects offered by metabolomics for improving care of HE patients. [Display omitted] • Metabolomics refers to the study of biological components below 1000 Daltons (Da). • Untargeted metabolomics provide potential associations of metabolites to metabolic pathways which can be further associated to a biochemical phenotype. • According to the pathophysiology of HE made from a close interaction between systemic inflammation and metabolic disturbances metabolomics appears as a promising technique. • Recent studies suggest that metabolomics could unravel new HE pathophysiological pathways, enable the identification of new biomarkers and help in the prognostication. • Some portable devices are in development and could lead to bring metabolomics to the bedside of HE patients. [ABSTRACT FROM AUTHOR]

Background & Aims: In decompensated cirrhosis, the early innate immune response to the Toll-like receptor 4 (TLR4) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine IL-10. In LPS-stimulated non-cirrhotic immune cells, the constitutively active glycogen synthase kinase (GSK) 3 favors pro- vs. anti-inflammatory cytokines, by acting on gene induction. However, in these cells, TLR4 dampens its own pro-inflammatory response by inducing early (within minutes) AKT-mediated phosphorylation of GSK3β (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3β (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases IL-10. Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from patients with advanced cirrhosis and normal subjects. Methods: Cells were pre-incubated with or without GSK3 inhibitor (SB216763 or lithium chloride) for 1h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1h and ELISA at 20h, respectively. GSK3β phosphorylation was assessed using Western blotting. Results: In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-α and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3β on Ser9 found in normal monocytes, was abolished in cirrhotic cells. Conclusions: GSK3 is involved in the early TLR4-mediated pro-inflammatory response in patients with decompensated cirrhosis. This was associated with a defect in AKT-mediated GSK3β phosphorylation resulting in unrestricted ‘pro-inflammatory’ activity of the enzyme. [Copyright &y& Elsevier]

Abstract: Cirrhosis is the end-stage consequence of fibrosis progression in patients with chronic hepatitis C. The median time from infection to cirrhosis is 30 years, with a high inter-individual variability, which is now better understood. Several factors have been clearly shown to be associated with fibrosis progression rate: duration of infection, age, male gender, alcohol consumption, HIV co-infection and low CD4 count. Metabolic conditions such as steatosis, being overweight and diabetes are emerging as independent co-factors of fibrogenesis. The recent validation of non-invasive biomarkers should facilitate the study of fibrosis progression in large populations. [Copyright &y& Elsevier]

Abstract: Background: Treatment of ascitic cirrhosis requires monitoring of blood biochemistry. A direct measure of ascites could simplify the medical procedure. We aimed to assess the correlation of sodium (Na), potassium (K), chloride (Cl), urea (U), and creatinine (Creat) in ascitic fluid and venous blood. Methods: Ascitic fluid and venous blood samples were collected simultaneously from 70 cirrhotic patients. Na, K, Cl, U, and Creat were measured in all samples using a biochemical auto-analyzer. Results: Results are expressed as the mean and SD of 200 concomitant samples of ascitic fluid and venous blood (mmol/L for Na, K, and Cl; g/L for U; mg/L for Creat). In ascites and blood the results were, respectively: 133.1±6.6 and 131.8±6.3 for Na (p <0.0001, r =0.95), 4.1±0.8 and 4.3±0.9 for K (p <0.0001, r =0.90), 107.2±7.6 and 101±7 for Cl (p <0.0001, r =0.93), 0.54±0.52 and 0.53±0.5 for U (p <0.0001, r =0.99), and 9.8±7.5 and 11±7 for Creat (p <0.0001, r =0.99). Analysis of ascites predicted blood results for different cut-offs (Na≤125, K≤3.2, K≥5.5 and Creat≥14) with a sensitivity of 1.00, 0.89, 0.71, and 0.92, and a specificity of 1.00, 0.95, 0.98, and 0.92, respectively. Conclusions: Correlations for Na, K, Cl, U, and Creat are strong between ascites and venous blood in cirrhotic patients. These parameters could, therefore, be assayed directly in ascitic fluid to monitor diuretic therapy in patients without venous access or when biochemical measurements, such as liver tests or coagulation tests, are not required, and in patients with poor venous access. [Copyright &y& Elsevier]