Pre-emptive TIPS in high-risk acute variceal bleeding. An updated and revised individual patient data meta-analysis.

BACKGROUND AND AIMS: A previous individual patient data meta-analysis (IPD-MA) showed that compared with drugs+endoscopy, the placement of transjugular portosystemic shunt within 72 hours of admission (pre-emptive transjugular intrahepatic portosystemic shunt: p-TIPS) increases the survival of high-risk patients (Child-Pugh B+ active bleeding and Child-Pugh C<14 points) with cirrhosis and acute variceal bleeding. However, the previous IPD-MA was not a two-stage meta-analysis, did not consider the potential risk of selection bias of observational studies, and did not include the most recent randomized clinical trial. We performed an updated and revised IPD-MA to reassess the efficacy of p-TIPS, addressing all previous issues. APPROACH AND RESULTS: We included all studies from the previous IPD-MA and searched for other possible eligible publications until September 2022. We performed a two-stage IPD-MA of data from 8 studies (4 randomized clinical trials and 4 observational). In addition, we performed a sensitivity analysis excluding those patients dying up to the first 72 hours after admission in the Drugs+Endoscopy arms of the 4 observational studies. The primary end point was the effects of p-TIPS versus Drugs+Endoscopy on 1-year survival.We identified 1389 patients (342 p-TIPS and 1047 Drugs+Endoscopy). The two-stage IPD-MA showed that p-TIPS significantly reduced the mortality in the overall population (HR=0·43, 95% CI: 0.32-0.60, p <0.001. This effect was observed in both subgroups of patients with Child-Pugh. The sensitivity analysis confirmed the survival benefit of p-TIPS. CONCLUSIONS: The updated two-stage IPD-MA confirms the significant survival advantage of p-TIPS in high-risk patients with cirrhosis and acute variceal bleeding. As a result, we recommend p-TIPS as the preferred first-choice treatment for these patients.

Extensive splanchnic vein thrombosis after SARS-CoV-2 vaccination: A Vascular Liver Disease Group (VALDIG) initiative.

BACKGROUND AND AIMS: Since the introduction of SARS-CoV-2 vaccines, several cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) have been described, especially cerebral vein thrombosis. We aimed to retrospectively collect all new cases of acute onset first or recurrent splanchnic vein thrombosis (SVT) following a recent SARS-CoV-2 vaccination within the Vascular Liver Disease Group network. APPROACH AND RESULTS: New cases of SVT were identified from April 2021 to April 2022; follow-up was completed on December 31, 2022. Criteria to define VITT were derived from previous studies. Data from a pre-COVID cohort of patients with SVT (N=436) were used for comparison of clinical presentation, etiology, and outcome. Twenty-nine patients were identified with SVT occurring with a median of 11 days (range 2-76) after the first (48%), second (41%), or third (10%) vaccination (ChAdOx1 nCov-19 (n=12) or BNT162b2 (n=14), other (n=3) Only 2 patients(7%) fulfilled criteria for definite VITT. Twenty (69%) had SVT at multiple sites, including 4 (14%) with concomitant extra-abdominal thrombosis. Only 28% had an underlying prothrombotic condition, compared to 52% in the pre-COVID SVT cohort ( p =0.01). Five patients (17%) underwent bowel resection for mesenteric ischemia, compared with 3% in pre-COVID SVT ( p <0.001). Two patients died shortly after diagnosis (7%). CONCLUSIONS: Although definite VITT was rare, in 72% of cases, no other cause for SVT could be identified following SARS-CoV-2 vaccination. These cases were different from patients with nonvaccine-related SVT, with lower incidence of prothrombotic conditions, higher rates of bowel ischemia, and poorer outcome. Although SVT after SARS-CoV-2 vaccination is rare in absolute terms, these data remain relevant considering ongoing revaccination programs.

Recurrent splanchnic and extrasplanchnic thrombotic events in patients with non-cirrhotic portal vein thrombosis associated with local factors.

BACKGROUND & AIMS: One-third of non-cirrhotic portal vein thrombosis (NCPVT) cases are associated with local factors. The risk of rethrombosis after anticoagulation withdrawal is unknown. We aimed to determine factors associated with new splanchnic or extrasplanchnic thrombotic events in this setting. METHODS: We performed a retrospective study including cases of recent NCPVT associated with local factors. High- and low-risk prothrombotic factors, prespecified according to RIPORT study criteria, were assessed. Univariate and multivariate Cox models assessed the influence of different variables on the occurrence of new thrombotic events. RESULTS: At baseline, 83/154 (53.9%) patients had at least one prothrombotic factor including 50 (32.5%) with a high-risk and 33 (21.4%) with a low-risk prothrombotic factor. Oestrogen-containing contraception was discontinued in all patients. During follow-up, 63/140 (45%) patients had at least one prothrombotic factor, including 47 (33.6%) with a high-risk and 16 (11.4%) with a low-risk prothrombotic factor. Seventeen new thrombotic events occurred after a median follow-up of 52 (IQR 14-62) (min-max 3.0-69.0) months. New thromboses were associated with high-risk factors (hazard ratio [HR] 3.817, 95% CI 1.303-11.180, p = 0.015), but were inversely related to recanalization (HR 0.222, 95% CI 0.078-0.635, p = 0.005) and anticoagulation (HR 0.976, 95% CI 0.956-0.995, p = 0.016). When a high-risk factor was present a new thrombotic event occurred in 7.4%, 14.6%, 14.6% and 28.8% of patients at 1, 3, 5 and 7 years under anticoagulants, respectively, compared to 21.2%, 21.2%, 58% and 58% without anticoagulants, respectively. CONCLUSIONS: In cases of recent NCPVT associated with local factors, high-risk factors for thrombosis are associated with new thrombotic events. Permanent anticoagulation appears beneficial in this high-risk situation. IMPACT AND IMPLICATIONS: In non-cirrhotic portal vein thrombosis (NCPVT) associated with local factors, systematic screening for prothrombotic factors is recommended, but the prevalence of the latter is not clearly established, and the risk of recurrent intra or extrasplanchnic thromboembolism is poorly described. Thus, interest in permanent anticoagulation remains. NCPVT associated with local factors is a matter of concern for hepatologists, gastroenterologists and digestive surgeons. Due to a lack of knowledge, practices are heterogeneous. Our findings highlight that systematic screening for prothrombotic factors in NCPVT is needed even when associated with local factors, as it may justify long-term anticoagulation for the prevention of new intra or extrasplanchnic thrombotic events in at least one-third of cases. The interest in long-term anticoagulation should be investigated prospectively in the absence of high-risk prothrombotic factors. CLINICAL TRIAL NUMBER: NCT0536064.

Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients.

BACKGROUND & AIMS: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. METHODS: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). RESULTS: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p <0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. CONCLUSION: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease. IMPACT AND IMPLICATIONS: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease.

Predicting survival in patients with 'non-high-risk' acute variceal bleeding receiving ß-blockers+ligation to prevent re-bleeding.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. IMPACT AND IMPLICATIONS: 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.

Hepatic venous pressure gradient predicts risk of hepatic decompensation and liver-related mortality in patients with MASLD.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here we investigate the prognostic value of HVPG in compensated (cACLD) MASLD. METHODS: This European multicentre study included MASLD-cACLD patients characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. RESULTS: 340 MASLD-cACLD patients [56.2% men; age: 62 (55-68) years; MELD: 8 (7-9); 71.2% diabetes] were included. Clinically significant portal hypertension (CSPH; i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio, SHR:5.13; p<0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (aSHR per mmHg:1.12; p<0.001). Liver-related mortality occurred in 37 patients with a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (aSHR per mmHg:1.20; p<0.001). CONCLUSION: HVPG measurement is of high prognostic value in MASLD-cACLD. While MASLD-cACLD patients without CSPH show a very low short-term risk of decompensation and liver-related mortality is rare, the presence of CSPH substantially increases both risks. IMPACT AND IMPLICATIONS: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in MASLD-cACLD patients without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk-stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.

Metabolomics as a tool to predict the risk of decompensation or liver-related death in patients with compensated cirrhosis.

BACKGROUND AND AIMS: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG > 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients. APPROACH AND RESULTS: This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664-0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model's performance [C-index of 0.808 (CI95% 0.735-0.882); p =0.032]. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710-0.860), not significantly different from the HVPG-based models including or not metabolites. CONCLUSIONS: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.

Genomic classification and outcomes of young patients with polycythemia vera and essential thrombocythemia according to the presence of splanchnic vein thrombosis and its chronology.

To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9-4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4-24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.

Interspecies transcriptomic comparison identifies a potential porto-sinusoidal vascular disorder rat model suitable for in vivo drug testing.

BACKGROUND: Porto-sinusoidal vascular disorder (PSVD) involves a group of rare vascular liver diseases of unknown aetiology that may lead to the development of portal hypertension and its life-threatening complications. Its pathophysiology is not well understood, and animal models described to date do not fully recapitulate human disease. METHODS: We developed three different PSVD rat models by either immunosensitization (repetitive intraportal LPS or intramuscular spleen extract injections) or toxic (Selfox: combination of FOLFOX and a selenium-enriched diet) treatment and characterized them at haemodynamic, histological, biochemical and transcriptional levels. We compared these results to human data. RESULTS: All three models developed significant portal hypertension, while only the LPS and the Selfox models displayed PSVD-specific and nonspecific histological alterations in the absence of cirrhosis. Transcriptional comparison between rat models and human data showed that both LPS and Selfox models recapitulate the main transcriptional alterations observed in humans, especially regarding haemostasis, oxidative phosphorylation and cell cycle regulation. Reproducibility and feasibility was higher for the Selfox model. CONCLUSIONS: The Selfox rat model faithfully reproduces the main alterations described in PSVD. Its use as a preclinical model for drug testing in progressing PSVD can be a significant step forward towards the development of new therapeutic targets for this rare condition.

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

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

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

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

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

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

Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis.

BACKGROUND & AIMS: In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. METHODS: A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS: Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). CONCLUSIONS: Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. IMPACT AND IMPLICATIONS: We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.

Adding Inflammatory Markers and Refining National Institute on Alcohol Abuse and Alcoholism Criteria Improve Diagnostic Accuracy for Alcohol-associated Hepatitis.

BACKGROUND & AIMS: Although histology is considered the gold standard for diagnosis of alcohol-associated hepatitis (AH), it is not required for entry into therapeutic studies if patients meet National Institute on Alcohol Abuse and Alcoholism (NIAAA) consensus criteria for probable AH. Our aim was to assess the diagnostic accuracy of NIAAA criteria against liver biopsy and to explore new criteria to enhance diagnostic accuracy for AH. METHODS: A total of 268 consecutive patients with alcohol-related liver disease with liver biopsy were prospectively included: 210 and 58 in the derivation and validation cohorts, respectively. NIAAA criteria and histological diagnosis of alcoholic steatohepatitis (ASH) were independently reviewed by clinical investigators and pathologists from Hospital Clínic and Mayo Clinic. Using biopsy-proven ASH as gold standard we determined diagnostic capability of NIAAA criteria and proposed the new improved criteria. RESULTS: In the derivation cohort, diagnostic accuracy of NIAAA for AH was modest (72%) due to low sensitivity (63%). Subjects who did not meet NIAAA with ASH at liver biopsy had lower 1-year survival compared with subjects without ASH (70% vs 90%; P < .001). NIAAAm-CRP criteria, created by adding C-reactive protein and modifying the variables of the original NIAAA, had higher sensitivity (70%), accuracy (78%), and specificity (83%). Accuracy was also higher in a sensitivity analysis in severe AH (74% vs 65%). In the validation cohort, NIAAAm-CRP and NIAAA criteria had a sensitivity of 56% vs 52% and an accuracy of 76% vs 69%, respectively. CONCLUSION: NIAAA criteria are suboptimal for the diagnosis of AH. The proposed NIAAAm-CRP criteria may improve accuracy for noninvasive diagnosis of AH in patients with alcohol-related liver disease.

The genetics of portal hypertension: Recent developments and the road ahead.

Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome-wide association studies or whole-exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non-cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.

Lack of endothelial autophagy does not impair liver regeneration after partial hepatectomy in mice.

Liver sinusoidal endothelial cells (LSEC) are key elements in regulating the liver response to injury and regeneration. While endothelial autophagy is essential to protect endothelial cells from injury-induced oxidative stress and fibrosis, its role in liver regeneration has not been elucidated. This study was intended to investigate the role of endothelial autophagy in liver regeneration in the context of partial hepatectomy (PHx). Analysis of autophagy levels in rat LSEC after PHx indicated a tendency to decrease activity the first 2 days after surgery. PHx performed in mice with impaired endothelial autophagy (Atg7flox/flox ;VE-Cadherin-Cre+ ) and their littermate controls showed no differences neither in liver-to-body weight ratio, histological analysis, hepatocyte proliferation nor vascular integrity during the first 7 days after PH and liver regeneration was completely achieved. Our results indicate that endothelial autophagy does not play an essential role in the coordination of the liver regeneration process after PHx.

Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.

BACKGROUND AND AIMS: A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR). METHODS: The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package). RESULTS: Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%. CONCLUSIONS: A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR.

Alcohol-related liver disease phenotype impacts survival after an acute variceal bleeding episode.

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.

Non-invasive tests for clinically significant portal hypertension after HCV cure.

BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting. METHODS: A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort). RESULTS: HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843-0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%). CONCLUSIONS: NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment. LAY SUMMARY: Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden.

Effects of Early Placement of Transjugular Portosystemic Shunts in Patients With High-Risk Acute Variceal Bleeding: a Meta-analysis of Individual Patient Data.

BACKGROUND & AIMS: Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS. METHODS: We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients. RESULTS: Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323-0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307-0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253-0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy. CONCLUSIONS: In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy.