Splanchnic vein thrombosis associated with SARS-CoV-2 infection: A VALDIG case-control study.

Background & Aims: Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a risk factor for splanchnic vein thrombosis (SVT) is unknown. This study aims to assess the impact of SARS-CoV-2 infection on the presentation and prognosis of recent SVT and to identify specific characteristics of SARS-CoV-2-associated SVT. Methods: This is a retrospective study collecting health-related data of 27 patients presenting with recent SVT in the context of SARS-CoV-2 infection in 12 Vascular Liver Disease Group (VALDIG) centres and in comparison with 494 patients with recent SVT before the SARS-CoV-2 pandemic. Results: Twenty-one patients with SARS-CoV-2 had portal vein thrombosis with or without thrombosis of another splanchnic vein, two had superior mesenteric vein thrombosis, one had splenic vein thrombosis, and three had hepatic vein thrombosis. Diagnosis of SVT was made 10 days (95% CI 0-24 days) after the diagnosis of SARS-CoV-2 infection. Fever (52 vs. 15%; p <0.001) and respiratory symptoms (44 vs. 0%; p <0.001) were more frequent, and median lymphocyte count was lower (1.1 × 103/mm3vs. 1.6 × 103/mm3; p = 0.043) in patients with infection than in those without SARS-CoV-2 infection. A prothrombotic condition was identified in 44 and 52% of patients with and without SARS-CoV-2 infection, respectively (p = 0.5). All patients with SARS-CoV-2 received anticoagulation therapy. During a median follow-up of 250 days, three SARS-CoV-2-infected patients (11%) required intestinal resection for infarction 1 to 3 months after diagnosis of SVT compared with 13 (2.6%) controls (p = 0.044). Partial or complete recanalisation of the thrombosed splanchnic vein was performed in 33% of patients with SARS-CoV-2. Conclusions: SARS-CoV-2 infection can be associated with recent SVT. Intestinal infarction leading to intestinal resection might be more frequent in patients with SARS-CoV-2. Impact and implications: SARS-CoV-2 infection can be associated with recent SVT. SVT occurring during SARS-CoV-2 infection is characterised by a higher frequency of respiratory symptoms and a lower lymphocyte count. Intestinal infarction leading to intestinal resection appears to occur more frequently in patients with SARS-CoV-2.

Left gastric vein embolization during TIPS placement for acute variceal bleeding has no effect on bleeding recurrence: Results of a multicenter study.

PURPOSE: The purpose of this study was to evaluate whether concomitant left gastric vein embolization (LGVE) during transjugular intrahepatic portosystemic shunt (TIPS) for acute variceal hemorrhage could reduce the risk of bleeding recurrence. MATERIAL AND METHOD: A national multicenter observational study was conducted in 14 centers between January 2019 and December 2020. All cirrhotic patients who underwent TIPS placement for acute variceal bleeding were included. During TIPS procedure, size of left gastric vein (LGV), performance of LGVE, material used for LGVE and portosystemic pressure gradient (PPG) before and after TIPS placement were collected. A propensity score for the occurrence of LGVE was calculated to assess effect of LGVE on rebleeding recurrence at six weeks and one year. RESULTS: A total of 356 patients were included (mean age 57.3 ± 10.8 [standard deviation] years; 283/356 [79%] men). Median follow-up was 11.2 months [interquartile range: 1.2, 13.3]. The main indication for TIPS was pre-emptive TIPS (162/356; 46%), rebleeding despite secondary prophylaxis (105/356; 29%), and salvage TIPS (89/356; 25%). Overall, 128/356 (36%) patients underwent LGVE during TIPS procedure. At six weeks and one year, rebleeding-free survival did not differ significantly between patients who underwent LGVE and those who did not (6/128 [5%] vs. 15/228 [7%] at six weeks, and 11/128 [5%] vs. 22/228 [7%] at one year, P = 0.622 and P = 0.889 respectively). A total of 55 pairs of patients were retained after propensity score matching. In patients without LGVE, the rebleeding rate was not different from those with LGVE (3/55 [5%] vs. 4/55 [7%], P > 0.99, and 5/55 [9%] vs. 6/55[11%], P > 0.99, at six weeks and one year respectively). Multivariable analysis identified PPG after TIPS placement as the only predictor of bleeding recurrence (hazard ratio = 1.09; 95% confidence interval: 1.02-1.18; P = 0.012). CONCLUSION: In this multicenter national real-life study, we did not observe any benefit of concomitant LGVE during TIPS placement for acute variceal bleeding on bleeding recurrence rate.

Alfapump® implantable device in management of refractory ascites: An update.

Refractory ascites (RA) is a frequent and life-threatening complication of cirrhosis. In selected patients with RA, transjugular intrahepatic portosystemic shunt (TIPS) placement and liver transplantation (LT) are currently considered the best therapeutic alternatives to repeated large volume paracentesis. In patients with a contraindication to TIPS or LT, the alfapump® system (Sequana Medical, Ghent, Belgium) has been developed to reduce the need for iterative paracentesis, and consequently to improve the quality of life and nutritional status. We report here recent data on technical progress made since the first implantation, the efficacy and tolerance of the device, the position of the pump in the therapeutic arsenal for refractory ascites, and the grey areas that remain to be clarified regarding the optimal selection of patients who are potential candidates for this treatment.

Systematic screening for advanced liver fibrosis in patients with coronary artery disease: The CORONASH study.

Although coronary artery disease (CAD) and advanced liver fibrosis (AdLF) are commonly associated in patients with non-alcoholic fatty liver disease (NAFLD), the prevalence of AdLF and the diagnostic performance of non-invasive fibrosis tests (NITs) in CAD patients remains unknown. We aimed to prospectively screen for AdLF in patients with documented CAD using NITs and Fibroscan. High and intermediate zones of NITs were combined to define AdLF. AdLF was suspected whenever APRI ≥ 0.5, Forns index ≥ 4.2, NAFLD fibrosis score (NFS) ≥ -1.455/0.12 for age

Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.

A total of 2%-10% of patients with vascular liver disease (VLD) have paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab reduces complement-mediated haemolytic activity in PNH. This study was aimed at assessing the impact of eculizumab on VLD outcome. Retrospective cohort of PNH patients, in Valdig registry, who had VLD diagnosed between 1997 and 2019 is considered. Eculizumab was the exposure of interest. Studied outcomes were death, venous thrombosis, bleeding, arterial ischemic event, infection, and liver-related complications. We compared survival and new thrombotic events from PNH/VLD cohort to Envie2 non-PNH cohort. Sixty-two patients (33 women), median age 35 years (28-48) and median follow-up VLD diagnosis 4.7 years (1.2-9.5), were included. Clone size was 80% (70-90), median hemoglobin concentration was 10.0 g/dl (8-11), and lactate dehydrogenase (LDH) was 736 IU (482-1744). Forty-two patients (68%) had eculizumab; median exposure time was 40.1 [9.3-72.6] months. Mortality was significantly lower in exposed versus nonexposed period: 2.6 versus 8.7 per 100 (PY), incidence rate ratio (IRR) was 0.29, 95% CI (0.1-0.9), p = .035. Thrombosis recurrence occurred less frequently during the exposure to eculizumab: 0.5 versus 2.8 per 100 PY, IRR 0.22 (0.07-0.64). Other secondary end points (i.e., bleeding, arterial ischemic lesions, infection, and liver complications) were less common during the exposure to eculizumab, although not reaching statistical significance. Six-year thrombosis-free survival was 70%, 95% CI [0.60-0.83] for PNH cohort and 83%, 95% CI [0.70-1.00] for non-PNH Envie 2 patients, (p < .001). In conclusion, patients with PNH and VLD are at higher risk of recurrent thrombosis than non-PNH patients. Eculizumab is significantly associated with a lower mortality and less thrombotic recurrence in patients with PNH and VLD.

Multicenter study on recent portal venous system thrombosis associated with cytomegalovirus disease.

BACKGROUND & AIMS: Recent non-malignant non-cirrhotic portal venous system thrombosis (PVT) is a rare condition. Among risk factors for PVT, cytomegalovirus (CMV) disease is usually listed based on a small number of reported cases. The aim of this study was to determine the characteristics and outcomes of PVT associated with CMV disease. METHODS: We conducted a French multicenter retrospective study comparing patients with recent PVT and CMV disease ("CMV positive"; n = 23) to patients with recent PVT for whom CMV testing was negative ("CMV negative"; n = 53) or unavailable ("CMV unknown"; n = 297). RESULTS: Compared to patients from the "CMV negative" and "CMV unknown" groups, patients from the "CMV positive" group were younger, more frequently had fever, and had higher heart rate, lymphocyte count and serum ALT levels (p ≤0.01 for all). The prevalence of immunosuppression did not differ between the 3 groups (4%, 4% and 6%, respectively). Extension of PVT was similar between the 3 groups. Thirteen out of 23 "CMV positive" patients had another risk factor for thrombosis. Besides CMV disease, the number of risk factors for thrombosis was similar between the 3 groups. Heterozygosity for the prothrombin G20210A gene variant was more frequent in "CMV positive" patients (22%) than in the "CMV negative" (4%, p = 0.01) and "CMV unknown" (8%, p = 0.03) groups. Recanalization rate was not influenced by CMV status. CONCLUSIONS: In patients with recent PVT, features of mononucleosis syndrome should raise suspicion of CMV disease. CMV disease does not influence thrombosis extension nor recanalization. More than half of "CMV positive" patients have another risk factor for thrombosis, with a particular link to the prothrombin G20210A gene variant. LAY SUMMARY: Patients with cytomegalovirus (CMV)-associated portal venous system thrombosis have similar thrombosis extension and evolution as patients without CMV disease. However, patients with CMV-associated portal venous system thrombosis more frequently have the prothrombin G20210A gene variant, suggesting that these entities act synergistically to promote thrombosis.

Rivaroxaban Prophylaxis in Noncirrhotic Portal Vein Thrombosis.

BACKGROUND: In patients with noncirrhotic chronic portal vein thrombosis (PVT), the benefit of long-term anticoagulation is unknown. We assessed the effects of rivaroxaban on the risk of venous thromboembolism and portal hypertension-related bleeding in such patients. METHODS: In this multicenter, controlled trial, we randomly assigned patients with noncirrhotic chronic PVT without major risk factors for thrombosis to receive either rivaroxaban 15 mg/day or no anticoagulation. The primary end point was 2-year thrombosis-free survival. Secondary end points included the occurrence of site-specific thromboses and major bleeding events. RESULTS: A total of 111 participants were enrolled in the trial, with a mean age of 50.4±13.2 years; 58% of participants were men. An unplanned interim analysis was requested by the independent data safety monitoring board (DSMB) after 10 thrombotic events occurred. The thrombosis incidence rate was 0 per 100 person-years in the rivaroxaban group and 19.71 per 100 person-years (95% confidence interval, 7.49 to 31.92) in the no anticoagulation group (log-rank P=0.0008) after a median follow-up of 11.8 months. Based on the interim analysis, the DSMB recommended switching patients from the no anticoagulation group to anticoagulation. After a median follow-up of 30.3 months (intraquartile range, 24.3 to 47.8), major bleeding occurred in two patients receiving rivaroxaban and in one patient not receiving anticoagulation. No deaths occurred. CONCLUSIONS: After a median follow-up of 11.8 months, among patients with noncirrhotic chronic PVT without major risk factors for thrombosis, daily rivaroxaban reduced the incidence of venous thromboembolism and did not increase major bleeding events. (Funded by grants from the French Ministry of Health and the Association de Malades des Vaisseaux du foie; ClinicalTrials.gov number, NCT02555111.)

Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis.

BACKGROUND: Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA). AIM: To know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult-to-treat PBC. METHODS: PBC patients treated for ≥3 months with UDCA, OCA and fibrates (bezafibrate or fenofibrate) due to failure of either second-line therapy were included in a multicentre, uncontrolled retrospective cohort study. Changes in biochemical liver tests and pruritus were analysed using a generalised linear mixed-effect model. RESULTS: Among 58 patients included, half received OCA as second-line and fibrates as third-line therapy (Group OCA-Fibrate), while the other half had the inverse therapeutic sequence (Group Fibrate-OCA). The mean duration of triple therapy was 11 months (range 3-26). Compared to dual therapy, triple therapy was associated with a significant gain in alkaline phosphatase (ALP) reduction: 22% per first year (95% CI 12%-31%), an effect that was stronger in OCA-Fibrate than in Fibrate-OCA group. Triple therapy was associated with a 3.4 (95% CI 1.4-8.2) odds ratio (OR) of reaching normal ALP and with a significant decrease in gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. The ORs of achieving the Paris-2 and Toronto criteria of adequate biochemical response were 6.8 (95% CI 2.8-16.7) and 9.2 (95% CI 3.4-25.1) respectively. Finally, triple therapy significantly improved pruritus in OCA-Fibrate but not in Fibrate-OCA group. CONCLUSIONS: Triple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult-to-treat PBC.

Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report.

A 64-year-old cirrhotic woman was admitted for alcoholic hepatitis associated with renal failure. Subsequently, she displayed symptoms of alcohol withdrawal progressing to delirium tremens. During hospitalization, she developed acute respiratory distress. The electrocardiogram showed diffuse anteroseptal ST elevation. Transthoracic echocardiography revealed systolic left ventricular apical balloon-like dilation, hypokinesis of the left ventricular mid- and apical segments, and a left ventricular ejection fraction of 30%. Coronary angiography was normal and led to the diagnosis of Takotsubo cardiomyopathy. This report describes a singular case of Takotsubo cardiomyopathy precipitated by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure.

A pragmatic non-invasive assessment of liver fibrosis in patients with psoriasis, rheumatoid arthritis or Crohn's disease receiving methotrexate therapy.

BACKGROUND AND AIMS: The reported hepatotoxicity of methotrexate underlines the need for a repeated non-invasive and reliable evaluation of liver fibrosis. We estimated, using a non-invasive strategy, the prevalence of significant liver fibrosis in patients treated by methotrexate and the predictors of significant fibrosis (fibrosis≥F2). METHODS: Fibrosis was prospectively evaluated using 9 non-invasive tests in consecutive patients with psoriasis, rheumatoid arthritis, or Crohn's disease. Significant fibrosis was assessed without liver biopsy by defining a "specific method" (result given by the majority of the tests) and a "sensitive method" (at least one test indicating a stage≥F2). RESULTS: One hundred and thirty-one patients (66 Psoriasis, 40 rheumatoid arthritis, and 25 Crohn's disease) were enrolled, including 83 receiving methotrexate. Seven tests were performed on average per patient, with a complete concordance in 75% of cases. Fibroscan® was interpretable in only 61% of patients. The best performances (AUROC>0.9) for predicting significant fibrosis were obtained by tests dedicated to steatohepatitis (FibroMeter NAFLD, NFS and FPI). The prevalence of fibrosis≥F2 according to the "specific" or the "sensitive" assessment of fibrosis was 10% and 28%, respectively. Methotrexate exposure did not influence the fibrosis stage. Factors independently associated with significant fibrosis according our "sensitive method" were age, male gender, and metabolic syndrome. CONCLUSION: We provided a non-invasive approach for identifying liver fibrosis≥F2 by using 8 biochemical tests and Fibroscan®. In this population, the risk of significant fibrosis was related to age, male gender, and presence of metabolic syndrome, but was not influenced by methotrexate.

Accuracy of calprotectin using the Quantum Blue Reader for the diagnosis of spontaneous bacterial peritonitis in liver cirrhosis.

AIM: We aimed to evaluate the accuracy of the dosage of calprotectin in ascitic fluid (AF) using the Quantum Blue assay, for the prompt diagnosis of spontaneous bacterial peritonitis (SBP). METHODS: We prospectively collected 236 AF samples from 119 cirrhotic patients hospitalized in two French centers between May 2016 and May 2017. Bloody and chylous/cloudy AF, and secondary peritonitis were excluded. SBP was diagnosed if neutrophils in AF were >250/mm3 using standard cytology. The Quantum Blue Reader selectively measured the calprotectin antigen (MRP8/14) in 12 min within the measurable range from 0.18 to 1.80 µg/mL; values outside this range were registered as 0.17 and 1.81 µg/mL. RESULTS: A total of 36 AF were considered as SBP (15.2%). SBP had higher median levels of calprotectin than non-SBP (1.81 vs. 0.25 µg/mL, P < 0.001). Calprotectin levels were positively correlated with neutrophils in AF (r = 0.57, P < 0.001) and C-reactive protein (r = 0.43, P < 0.001), but not with the Child-Pugh and Model for End-Stage Liver Disease scores. The optimal threshold of calprotectin to diagnose SBP was set at 1.51 µg/mL (80th percentile of calprotectin), yielding sensitivity, specificity, and positive and negative predictive values of 86.1%, 92.0%, 65.9%, and 97.3%, respectively. Only one asymptomatic patient with SBP had a low calprotectin level, but a high serum C-reactive protein level that strongly suggested an ongoing infection. We also showed that intraclass correlation coefficients for inter- and intra-observer agreement were excellent, with 0.95 and 0.89, respectively. CONCLUSIONS: The dosage of calprotectin in AF using the Quantum Blue assay is a rapid and reliable method of ruling out SBP in hospitalized cirrhotic patients.

The epidemiology of Budd-Chiari syndrome in France.

INTRODUCTION: Epidemiological data is lacking on primary Budd-Chiari syndrome (BCS) in France. METHODS: Two approaches were used: (1) A nationwide survey in specialized liver units for French adults. (2) A query of the French database of discharge diagnoses screening to identify incident cases in adults. BCS associated with cancer, alcoholic/viral cirrhosis, or occurring after liver transplantation were classified as secondary. RESULTS: Approach (1) 178 primary BCS were identified (prevalence 4.04 per million inhabitants (pmi)), of which 30 were incident (incidence 0.68 pmi). Mean age was 40 ±â€¯14 yrs. Risk factors included myeloproliferative neoplasms (MPN) (48%), oral contraceptives (35%) and factor V Leiden (16%). None were identified in 21% of patients, ≥2 risk factors in 25%. BMI was higher in the group without any risk factor (25.7 kg/m2 vs 23.7 kg/m2, p < 0.001). Approach (2) 110 incident primary BCS were admitted to French hospitals (incidence 2.17 pmi). MPN was less common (30%) and inflammatory local factors predominated (39%). CONCLUSION: The entity of primary BCS as recorded in French liver units is 3 times less common than the entity recorded as nonmalignant hepatic vein obstruction in the hospital discharge database. The former entity is mostly related to MPN whereas the latter with abdominal inflammatory diseases.

Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results.

BACKGROUND: The Baveno VI consensus meeting concluded that an early TIPS must be considered in high-risk cirrhotic patients 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. AIMS: To determine (1) the proportion of patients eligible for early-TIPS among cirrhotic patients with VB, (2) the proportion of these patients who underwent early-TIPS placement and the main reasons for discarding TIPS, and (3) the outcomes of patients who experienced early-TIPS placement in a large, national, prospective, multicentre audit including academic and non-academic centres. MATERIALS AND METHODS: All French centres recruiting gastrointestinal bleeding were invited to participate. All consecutive patients with cirrhosis and PHT-related bleeding were included. RESULTS: 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,viral/other, 67%/15%/18%); source of bleeding (EV/GV/other, 80/11/9%); 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 cirrhotic patients 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.

Predictive value of CT for first esophageal variceal bleeding in patients with cirrhosis: Value of para-umbilical vein patency.

PURPOSE: To evaluate if the presence/size of a para-umbilical vein (PUV) on computed tomography (CT) are associated with a first esophageal variceal hemorrhage (EVH) in patients with cirrhosis and whether imaging features can help identify patients at increased risk of EVH. MATERIALS AND METHODS: From January 2010 to June 2012 patients with cirrhosis who underwent CT and upper gastrointestinal endoscopy within six months were included. The presence/size of PUV was noted. PUV>5mm were considered large (LPUV). Association with a first EVH was searched for, and validated in a prospective cohort of 55 patients. RESULTS: 172 patients (113 men, mean 60±12 yo) were included. Forty-three patients (25%) experienced a first EVH. LPUV were more frequent in the group without EVH (27% vs. 7%, p=0.005). At multivariate analysis, factors associated with a first EVH were spleen size>135mm (Odd Ratio [OR]=1.32 [95% confident interval [CI] 1.16-1.51], p<0.001), ascites (OR=4.07 [95%CI-1.84-9.01], p=0.001) and small/absent PUV (OR=3.06 [95%CI-1.86-5.05], p<0.001). An imaging score combining these factors was significantly associated with first EVH in the study and the validation cohorts (EVH in 0%, 19%, and 33% when score 0-1, 2-3, and 4-5, respectively). CONCLUSIONS: A simple imaging score combining the PUV and spleen size, and the presence of ascites could help to identify cirrhotic patients at high-risk for EVH.

Prognosis of cirrhotic patients admitted to the general ICU.

BACKGROUND: The prognosis of cirrhotic patients admitted to the ICU is considered to be poor but has been mainly reported in liver ICU. We aimed to describe the prognosis of cirrhotic patients admitted to a general ICU, to assess the predictors of mortality in this population, and, finally, to identify a subgroup of patients in whom intensive care escalation might be discussed. RESULTS: We performed a retrospective monocentric study of all cirrhotic patients consecutively admitted between 2002 and 2014 in a general ICU in a regional university hospital. Two hundred and eighteen cirrhotic patients were admitted to the ICU. The 28-day and 6-month mortality rates were 53 and 74 %, respectively. Among the 115 patients who were discharged from ICU, only eight patients underwent liver transplantation, whereas 48 had no clear contraindication. Multivariable analyses on 28-day mortality identified three independent variables, incorporated into a new three-variable prognostic model as follows: SOFA ≥ 12 (OR 4.2 [2.2-8.0]; 2 points), INR ≥ 2.6 (OR 2.5 [1.3-4.8]; 1 point), and renal replacement therapy (OR 2.3 [1.1-5.1]; 1 point). For a value of the score at 4 (16 % of patients), 28-day and 3-month mortality rates were 91 and 100 %, respectively. An external validation of the score among 149 critically ill cirrhotic patients showed a good accuracy for predicting in-ICU mortality. CONCLUSIONS: Mortality of cirrhotic patients admitted to a general ICU was comparable to that of other studies. A pragmatic score integrating the SOFA score, INR, and the need for extrarenal epuration was strongly associated with mortality. Among the 16 % of patients presenting with score 4 at ICU admission, 100 % died in the 3-month follow-up period. The prognostic evaluation on day 3 remains essential for the majority of patients. However, this score calculable at ICU admission might identify patients in whom the benefit of intensive care escalation should be discussed, in particular when liver transplantation is contraindicated.