Concordance in a World without a Gold Standard: A New Non-Invasive Methodology for Improving Accuracy of Fibrosis Markers

BACKGROUND: Assessing liver fibrosis is traditionally performed by biopsy, an imperfect gold standard. Non-invasive techniques, liver stiffness measurements (LSM) and biomarkers [FibroTest(R) (FT)], are widely used in countries where they are available. The aim was to identify factors associated with LSM accuracy using FT as a non-invasive endpoint and vice versa. METHODS: The proof of concept was taken using the manufacturers recommendations for excluding patients at high risk of false negative/positive. The hypothesis was that the concordance between LSM and FT, would be improved by excluding high-risk patients. Thereafter, the impact of potential variability factors was assessed by the same methods. Liver biopsy and independent endpoints were used to validate the results. RESULTS: Applying manufacturers' recommendations in 2,004 patients increased the strength of concordance between LSM and FT (P<0.00001). Among the 1,338 patients satisfying recommendations, the methodology identified a significant LSM operator effect (P = 0.001) and the following variability factors (all P<0.01), related to LSM: male gender, older age, and NAFLD as a cause of liver disease. Biopsy confirmed in 391 patients these results. CONCLUSION: This study has validated the concept of using the strength of concordance between non-invasive estimates of liver fibrosis for the identification of factors associated with variability and precautions of use

2D shear wave liver elastography by aixplorer to detect portal hypertension in cirrhosis: an individual patient data meta-analysis

Background & Aims: Liver stiffness measured with 2-dimensional shear wave elas- tography by Supersonic Imagine (2DSWE-SSI) is well-established for fibrosis diagnos- tics, but non-conclusive for portal hypertension. Methods: We performed an individual patient data meta-analysis of 2DSWE-SSI to identify clinically significant portal hypertension (CSPH), severe portal hyperten- sion and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta-analytical integration of diagnos- tic accuracies with optimized rule-out (sensitivity-90%) and rule-in (specificity-90%) cut-offs. Results: Five studies from seven centres shared data on 519 patients. After exclu- sion, we included 328 patients. Eighty-nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE-SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of pa- tients, with minimal between-study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE-SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut-off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral 2 aetiology or BMI < 25 kg/m . 2DSWE-SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in. Conclusion: Liver stiffness using 2-dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE-SSI cannot predict varices needing treatment

Abdominal Surgery in Patients With Idiopathic Noncirrhotic Portal Hypertension: A Multicenter Retrospective Study

In patients with idiopathic noncirrhotic portal hypertension (INCPH), data on morbidity and mortality of abdominal surgery are scarce. We retrospectively analyzed the charts of patients with INCPH undergoing abdominal surgery within the Vascular Liver Disease Interest Group network. Forty‐four patients with biopsy‐proven INCPH were included. Twenty‐five (57%) patients had one or more extrahepatic conditions related to INCPH, and 16 (36%) had a history of ascites. Forty‐five procedures were performed, including 30 that were minor and 15 major. Nine (20%) patients had one or more Dindo‐Clavien grade ≥ 3 complication within 1 month after surgery. Sixteen (33%) patients had one or more portal hypertension–related complication within 3 months after surgery. Extrahepatic conditions related to INCPH (P = 0.03) and history of ascites (P = 0.02) were associated with portal hypertension–related complications within 3 months after surgery. Splenectomy was associated with development of portal vein thrombosis after surgery (P = 0.01). Four (9%) patients died within 6 months after surgery. Six‐month cumulative risk of death was higher in patients with serum creatinine ≥ 100 μmol/L at surgery (33% versus 0%, P < 0.001). An unfavorable outcome (i.e., either liver or surgical complication or death) occurred in 22 (50%) patients and was associated with the presence of extrahepatic conditions related to INCPH, history of ascites, and serum creatinine ≥ 100 μmol/L: 5% of the patients with none of these features had an unfavorable outcome versus 32% and 64% when one or two or more features were present, respectively. Portal decompression procedures prior to surgery (n = 10) were not associated with postoperative outcome. Conclusion: Patients with INCPH are at high risk of major surgical and portal hypertension–related complications when they harbor extrahepatic conditions related to INCPH, history of ascites, or increased serum creatinine

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation

Background It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders. Methods We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort. Results PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects. Conclusions These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability

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

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

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. ClinicalTrials.gov number: NCT03056612. Lay summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk

Rôles des biomarqueurs pour le diagnostic et le suivi des maladies du foie

Les maladies du foie sont un problème majeur de santé public. L'incidence de stéatopathie non alcoolique est en constante augmentation, et touche 25% de la population. La cirrhose, stade ultime de toutes les maladies du foie, est responsable de plus de 2% des décès dans le monde. A l'inverse, la maladie vasculaire porto-sinusoïdale (MVPS) est une maladie rare du foie, responsable d'une hypertension portale sans cirrhose, touchant les sujets jeunes, qui est encore sous-diagnostiquée. Les biomarqueurs sont utilisés au cours des maladies du foie depuis plus de 20 ans. Les biomarqueurs ont initialement été développés pour l'estimation non invasive de la fibrose hépatique au cours des hépatites virales. On distingue 2 catégories de biomarqueurs : les tests sanguins, et les méthodes d'imagerie. Les vésicules extra-cellulaires (EV), sont des nanoparticules pouvant être relarguées dans l'espace extra-cellulaire par toute cellule. Leur composition reflète le type de cellule dont elles dérivent mais également du stimulus responsable de leur formation. Ainsi, l'intérêt des EV comme biomarqueurs suscite un intérêt croissant. 1ère partie : Intérêt des EV hépatocytaires pour prédire la décompensation chez les malades atteints de cirrhose alcoolique compensée. Nous avons dosé les taux plasmatiques d'EV hépatocytaires par une méthode d'ELISA et filtration chez 500 malades atteints de cirrhose alcoolique compensée, inclus dans la cohorte française multicentrique prospective CIRRAL. 419 malades étaient sevrés, alors que 81 malades avaient une consommation d'alcool >6 unités par semaine. Le critère de jugement principale était la décompensation à 2 ans. Les taux plasmatique d'EV > 50 UI/L prédisaient la décompensation à 2 ans, indépendamment du score MELD et du FibroTest, chez les malades ayant une consommation d'alcool active ; en revanche, ils n'étaient pas associés à la décompensation chez les malades sevrés. 2ème partie : Intérêt de la mesure de l'élasticité hépatique par Fibroscan pour discriminer la maladie vasculaire porto-sinusoidale de la cirrhose chez les malades atteints d'hypertension portale. Nous avons mené une étude rétrospective multicentrique. Nous avons comparé la dureté du foie mesurée par Fibroscan entre des malades atteints de MVPS (n=77) et des malades atteints de cirrhose alcoolique (n=117), virale C (n=110) ou métabolique (n=46) histologiquement prouvée compensée. Tous les malades présentaient des signes d'hypertension portale. La dureté du foie 20 kPa avait une sensibilité de 94% et une valeur prédictive négative de 97% pour écarter le diagnostic de MVPS. Ces résultats ont été validés dans une cohorte de validation. 3ème partie : intérêt de la composition protéique des EV hépatocytaires pour le diagnostic de stéato-hépatite non alcoolique chez les malades atteints de diabète de type 2. Il s'agit d'une étude effectuée dans le cadre du RHU Quid-Nash. Une analyse exploratoire de la composition protéiques des EV a été effectuée par analyse protéomique chez 9 témoins sains, 23 malades diabétiques (stéatose simple n=8, NASH n=15). Ces analyses nous ont permis d'identifier 9 protéines significativement surexprimées chez les malades atteints de NASH par rapport aux malades ayant une stéatose isolée.Liver diseases are a major public health problem. The incidence of non-alcoholic fatty liver diseases is increasing, affecting 25% of the population. Cirrhosis, the ultimate stage of all chronic liver diseases, is responsible for more than 2% of deaths worldwide. Conversely, porto-sinusoidal vascular disease (PSVD) is a rare liver disease, responsible for portal hypertension without cirrhosis, affecting young subjects, which is still under-diagnosed. Biomarkers have been used in patients with liver diseases for more than 20 years. Biomarkers were initially developed for the non-invasive estimation of liver fibrosis in patients with viral hepatitis. There are 2 categories of biomarkers: blood-based tests, and imaging methods. Extracellular vesicles (EV) are nanoparticles that can be released into the extracellular space by any cell. Their composition reflects the type of cell from which they derive but also the stimulus responsible for their formation. Thus, EVs are promising biomarkers. Part 1: Usefulness of hepatocyte EVs to predict decompensation in patients with compensated alcoholic cirrhosis. We measured plasma hepatocyte EV levels by a method combining ELISA and filtration in 500 patients with compensated alcohol-related cirrhosis included in the French multicenter prospective CIRRAL cohort. 419 patients had past alcohol consumption, while 81 patients had an active alcohol consumption >6 units per week. The primary endpoint was decompensation at 2 years. Plasma EV levels > 50 IU/L predicted decompensation at 2 years, independently of MELD score and FibroTest, in patients with active alcohol consumption; however, they were not associated with decompensation in patients with past alcohol consumption. Part 2: Usefulness of liver stiffness measurement using Fibroscan to distinguish porto-sinusoidal vascular disease from cirrhosis in patients with portal hypertension. We conducted a retrospective multicenter study. We compared liver stiffness measurement by Fibroscan between patients with PSVD (n=77) and patients with histologically proven compensated alcohol- (n=117), hepatitis C- (n=110) or NAFLD-related (n=46) cirrhosis. All patients had clinical signs of portal hypertension. Liver stiffness measurement 20 kPa had a sensitivity of 94% and a negative predictive value of 97% to rule out the diagnosis of PSVD. These results were validated in a validation cohort. Part 3: Study of the protein composition of EVs for the diagnosis of non alcoholic steatohepatitis in patients with diabetes. This study is part of the RHU Quid-Nash project. An exploratory analysis of the protein composition of EVs was performed by proteomic analysis in 9 healthy controls, 23 diabetic patients (simple steatosis n=8, NASH n=15). These analyses allowed us to identify 9 proteins significantly overexpressed in patients with NASH compared to patients with isolated steatosis

Etude des facteurs de discordance entre le FibroTest et le FibroScan en l' absence de Gold standard (une nouvelle méthodologie pour améliorer la fiabilité diagnostique des tests non invasifs de fibrose hépatique)

L évaluation de la fibrose hépatique est classiquement réalisée par une ponction biopsie hépatique, un gold standard imparfait. Les méthodes non invasives de mesure de la fibrose hépatique, comme l élastométrie impulsionnelle (FibroScan, FS) et les biomarqueurs (FibroTest, FT), sont largement utilisés dans les pays où ils sont disponibles. L objectif de ce travail était d identifier les facteurs de variabilité du FS en prenant le FT pour référence, et vice versa. Pour la preuve du concept, nous avons utilisé les recommandations des fabricants afin d exclure les patients à haut risque de faux positifs /faux négatifs. L hypothèse était que la concordance entre les résultats du FS et du FT serait améliorée en excluant les sujets à haut risque. Ensuite, l effet de facteurs de variabilité potentiels a été évalué par les mêmes méthodes. La biopsie et d autres facteurs indépendants ont été utilisés pour valider les résultats. Cette étude a été menée chez 2004 patients. L application des recommandations des fabricants augmentait la concordance entre les résultats du FT et du FS (p<0,00001). Parmi les 1338 patients qui remplissaient ces recommandations, nous avons identifié un effet opérateur (p=0,001), et les facteurs suivants augmentaient significativement la variabilité du FS (p<0,01) : sexe masculin, âge élevé, NAFLD comme cause de l hépatopathie. La biopsie hépatique, réalisée chez 391 patients, a confirmé ces résultats. Cette étude a validé le concept que le niveau de concordance entre deux estimateurs non invasifs de fibrose hépatique permet d identifier des facteurs de variabilité, et ainsi d'améliorer les précautions d utilisation des tests.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Combination treatment with letermovir and ganciclovir for maintenance therapy of multidrug-resistant CMV infection in a liver transplant recipient

We report the case of a liver transplant recipient, cytomegalovirus (CMV) donor-positive (D+), recipient-negative (R−), with primary multidrug-resistant CMV infection treated with a combination therapy of letermovir and (val)ganciclovir

Thromboses veineuses splanchniques

Splanchnic vein thromboses include thrombosis of the portal venous system (including the portal, mesenteric and splenic vein) and hepatic vein thrombosis (also called Budd-Chiari syndrome). They are rare manifestations of venous thromboembolism. These thromboses are frequently associated with local or systemic factors. The therapeutic approach is often complex due to heterogeneity of patients and limited available data in the literature. The cornerstone of treatment is anticoagulation. However, the bleeding risk, related to portal hypertension, should be accurately assessed to individualize the treatment. A multidisciplinary consultation team including several specialists is provided at the University Hospitals of Geneva for the optimal management of those patients