Porto-sinusoidal vascular disorder in chronic HBV: A significant coexistence not to be overlooked.

Background & Aims: Porto-sinusoidal vascular disorder (PSVD) encompasses a group of liver diseases with vascular abnormalities that can cause portal hypertension in the absence of cirrhosis. The new diagnostic criteria allow for coexistence with other liver diseases, however its relationship with chronic hepatitis B (CHB) remains unclear. This study aimed to assess HBV prevalence in a PSVD cohort and evaluate its clinical impact. Methods: This retrospective study was conducted on patients with PSVD at Hospital Clínic Barcelona. HBV serology was evaluated, and patients were categorized into HBV chronic infection, past infection, or no HBV exposure. Clinical characteristics and outcomes were compared. Results: We included 155 patients with PSVD. Prevalence of CHB and past HBV infection in patients with PSVD was higher than in the general population (5.8% vs. 0.5%, p <0.0001 and 20% vs. 9.1%, p <0.0001, respectively). Patients with CHB had a significant delay in PSVD diagnosis compared to those without CHB (11 [5-25] vs. 1 [0-3] years, p = 0.002) and had a more advanced disease (MELD score 12 [9-17] vs. 9 [7-11], p = 0.012) at the time of PSVD diagnosis. The clinical evolution of PSVD in patients with CHB was marked by a significantly higher transplantation rate at the last follow-up (33% vs. 4.1%, p = 0.001). Conclusions: Recognizing the coexistence of PSVD and CHB is important for timely diagnosis and optimal management, highlighting the potential benefits of specialized care for potentially improved outcomes. Impact and implications: The new diagnostic criteria for porto-sinusoidal vascular disorder (PSVD) allow for coexistence with other liver diseases. The results of the present study highlight, for the first time, a non-negligible prevalence of chronic hepatitis B in the PSVD population that was previously unknown. Coexistence may challenge and delay the PSVD diagnosis and is associated with a more unfavorable clinical course. Our findings will increase awareness of this coexistence and improve PSVD diagnosis and management. Furthermore, the data will encourage new studies to determine the prevalence and clinical behavior of other chronic liver diseases that coexist with PSVD.

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.

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.

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.

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

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

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

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

The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study.

BACKGROUND: A hypercoagulable state is not associated with development of portal vein thrombosis in cirrhosis, as we previously demonstrated. However, some groups demonstrated elevated levels of inflammatory markers and activation of hemostasis in the portal vein (PV) compared to posthepatic veins, but because the liver is involved in clearance of these markers, we hypothesize that interpretation of these data is not straightforward. AIM: To determine whether the PV has particular proinflammatory/hypercoagulable characteristics by comparing plasma sampled in the PV, hepatic vein (HV), and the systemic circulation. METHODS: Plasma samples from 51 cirrhotic patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt placement, were taken from the PV, HV, and jugular vein (JV). Markers of inflammation (lipopolysaccharide, tumor necrosis factor-α, interleukin-6, thiobarbituric acid-reactive substances), neutrophil-extracellular-traps (cfDNA, MPO-DNA), endothelial damage (von Willebrand factor [VWF]), and hemostasis were determined and compared among the three vascular beds. RESULTS: Markers of inflammation were slightly, but significantly higher in the PV than in the HV and systemic circulation. VWF and markers of hemostasis were modestly elevated in the PV. Levels of multiple markers were lower in the HV compared with the PV and systemic circulation. Higher model for end-stage liver disease score was associated with a more prothrombotic state in all three sample sites. CONCLUSION: In contrast to published studies, we did not detect a clear proinflammatory or prothrombotic environment in the PV of cirrhotic patients. Many markers are lowest in the HV, indicating that the low levels of these markers in the HV, at least in part, reflect clearance of those markers in the liver.

Impact of SARS-CoV-2 Pandemic on Vascular Liver Diseases.

BACKGROUND & AIMS: Vascular liver diseases (VLDs) are represented mainly by portosinusoidal vascular disease (PSVD), noncirrhotic splanchnic vein thrombosis (SVT), and Budd Chiari syndrome (BCS). It is unknown whether patients with VLDs constitute a high-risk population for complications and greater coronavirus disease 2019 (COVID-19)-related mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLDs, as well as to assess its impact on hepatic decompensation and survival. METHODS: This is an observational international study analyzing the prevalence and severity of SARS-CoV-2 infection in VLDs between March 2020 and March 2021, compared with the general population (GP). Patients from Spain (5 centers; n = 493) and France (1 center; n = 475) were included. RESULTS: Nine hundred sixty-eight patients were included: 274 with PSVD, 539 with SVT, and 155 with BCS. Among them, 138 (14%) were infected with SARS-CoV-2: 53 with PSVD, 77 with SVT, and 8 with BCS. The prevalence of SARS-CoV-2 infection in patients with PSVD (19%) and SVT (14%) was significantly higher than in the GP (6.5%; P < .05), whereas it was very similar in patients with BCS (5%). In terms of infection severity, patients with VLDs also presented a higher need of hospital admission (14% vs 7.3%; P < .01), intensive care unit admission (2% vs 0.7%; P < .01), and mortality (4% vs 1.5%; P < .05) than the GP. Previous history of ascites (50% vs 8%; P < .05) and post-COVID-19 hepatic decompensation (50% vs 4%; P < .05) were associated with COVID-19 mortality. CONCLUSIONS: Patients with PSVD and SVT could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease.

Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) is a relatively frequent event in patients with cirrhosis. While different risk factors for PVT have been reported, such as decreased portal blood flow velocity (PBFV) and parameters related with severity of portal hypertension, these are based on retrospective studies assessing only a discrete number of parameters. The aim of the current study was to evaluate the incidence and risks factors for non-tumoral PVT development in a large prospective cohort of patients with cirrhosis. METHODS: We performed an exhaustive evaluation of clinical, biochemical, inflammatory and acquired/hereditary hemostatic profiles in 369 patients with cirrhosis without PVT who were prospectively followed-up. Doppler ultrasound was performed at baseline and every 6 months or whenever clinically indicated. PVT development was always confirmed by computed tomography. RESULTS: Twenty-nine patients developed non-tumoral PVT, with an incidence of 1.6%, 6% and 8.4% at 1, 3 and 5 years, respectively. Low platelet count, PBFV <15 cm/sec and history of variceal bleeding were factors independently associated with a high PVT risk. No relationship between PVT development and any other clinical biochemical, inflammatory and acquired or hereditary hemostatic parameter was found. CONCLUSIONS: In patients with cirrhosis, the factors predictive of PVT development were mainly those related to the severity of portal hypertension. Our results do not support the role of hemostatic alterations (inherited or acquired) and inflammatory markers in the prediction of PVT in patients with cirrhosis. LAY SUMMARY: Patients with cirrhosis and more severe portal hypertension are at higher risk of non-tumoral portal vein thrombosis development. Acquired or inherited hemostatic disorders, as well as inflammatory status, do not seem to predict the development of portal vein thrombosis in patients with cirrhosis.

Risk of non-tumoural portal vein thrombosis in patients with HCV-induced cirrhosis after sustained virological response.

BACKGROUND & AIMS: Sustained virological response (SVR) to direct-acting antivirals ameliorates portal hypertension, improves hepatic function and may reverse the procoagulant state observed in patients with cirrhosis. However, an unexpected incidence of portal vein thrombosis (PVT) immediately after antiviral therapy has recently been reported. Therefore, we analysed the long-term impact of SVR on the development of non-tumoural PVT. METHODS: Our study comprised of two well-characterized prospective cohorts (hepatitis C virus '(HCV)-Cured': n = 354/'HCV-Active': n = 179) of patients with HCV cirrhosis who underwent standardized ultrasound surveillance. In the main analysis, the event of interest was de novo non-tumoural PVT and events known to modify its natural history (orthotopic liver transplantation, transjugular intrahepatic portosystemic shunt, death, tumoural PVT and anticoagulation) were considered as competing risk. Adjusted models were built using propensity scores for baseline covariates. Moreover, predictive factors were investigated by conventional multivariate analysis. RESULTS: Ten (2.8%) patients in the 'HCV-Cured' cohort developed a non-tumoural PVT during a median follow-up of 37.1 months, while 8 (4.5%) patients in the 'HCV-Active' cohort were diagnosed with non-tumoural PVT during a median follow-up of 42.2 months. High Child-Pugh score was the only independent risk factor for non-tumoural PVT development and stage A patients were at low risk. Importantly, HCV cure did not decrease the risk of non-tumoural PVT in inverse probability of treatment-weighted (IPTW) analysis (subdistribution hazard ratio: 1.31 (95% confidence interval [95% CI]: 0.43-3.97); P = .635). In contrast, SVR was associated with a substantial reduction in mortality (IPTW-adjusted sHR: 0.453 [95% CI: 0.287-0.715]; P < .001). CONCLUSIONS: The risk of non-tumoural PVT persists after HCV cure in patients with cirrhosis, despite improving survival. Even after aetiological cure, severity of liver disease remains the main determinant of non-tumoural PVT development.

Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension.

INTRODUCTION: Macrophages are involved in development and progression of chronic liver disease and portal hypertension. The macrophage activation markers soluble (s)CD163 and soluble mannose receptor (sMR), are associated with portal hypertension in patient with liver cirrhosis but never investigated in patients with non-cirrhotic portal hypertension. We hypothesized higher levels in cirrhotic patients with portal hypertension than patients with non-cirrhotic portal hypertension. We investigated sCD163 and sMR levels in patients with portal hypertension due to idiopathic portal hypertension (IPH) and portal vein thrombosis (PVT) in patients with and without cirrhosis. METHODS: We studied plasma sCD163 and sMR levels in patients with IPH (n = 26), non-cirrhotic PVT (n = 20), patients with cirrhosis without PVT (n = 31) and with PVT (n = 17), and healthy controls (n = 15). RESULTS: Median sCD163 concentration was 1.51 (95% CI: 1.24-1.83) mg/L in healthy controls, 1.96 (95% CI: 1.49-2.56) in patients with non-cirrhotic PVT and 2.16 (95% CI: 1.75-2.66) in patients with IPH. There was no difference between non-cirrhotic PVT patients and healthy controls, whereas IPH patients had significantly higher levels than controls (P < 0.05). The median sCD163 was significantly higher in the cirrhotic groups compared to the other groups, with a median sCD163 of 6.31 (95% CI: 5.16-7.73) in cirrhotics without PVT and 5.19 (95% CI: 4.18-6.46) with PVT (P < 0.01, all). Similar differences were observed for sMR. CONCLUSION: Soluble CD163 and sMR levels are elevated in patients with IPH and patients with cirrhosis, but normal in patients with non-cirrhotic PVT. This suggests that hepatic macrophage activation is more driven by the underlying liver disease with cirrhosis than portal hypertension.

Autoimmune biomarkers in porto-sinusoidal vascular disease: Potential role in its diagnosis and pathophysiology.

BACKGROUND AND AIMS: Porto-sinusoidal vascular disease (PSVD) is a rare disease that requires excluding cirrhosis and other causes of portal hypertension for its diagnosis because it lacks a specific diagnostical test. Although it has been occasionally associated with autoimmune diseases, the pathophysiology of PSVD remains unknown. The aim of this study was to evaluate the potential role of autoimmunity in the pathophysiology and diagnosis of PSVD. METHODS: Thirty-seven consecutive patients with PSVD and 39 with cirrhosis matched by gender, signs of portal hypertension and liver function were included (training set). By using Indirect Immunofluorescence, ELISA and slot-blot methods data 22 autoantibodies were identified in patients with PSVD and cirrhosis. Presence of anti-endothelial cells antibodies (AECA) was assayed by a cell-based ELISA. Thirty-one PSVD, 40 cirrhosis patients, 15 patients with splenomegaly associated with haematological disease and 14 healthy donors were included in a validation set. FINDINGS: The proportion of patients with at least one positive antibody was statistically significantly higher in patients with PSVD compared with cirrhosis (92% vs 56%; P < .01). Specifically, AECA were significantly more frequent in PSVD than in cirrhosis (38% vs 15%; P = .013). Results were confirmed in the validation set. In the overall population, presence of AECA had a 63% positive predictive value for diagnosing PSVD and a 71% negative predictive value, with a specificity of 94% when the 1/16 level is used as cut-off. AECA positive serum samples react with a 68-72 kDa protein of human liver endothelial sinusoidal cells.

Co-expression gene network analysis reveals novel regulatory pathways involved in porto-sinusoidal vascular disease.

BACKGROUND & AIMS: Porto-sinusoidal vascular disease (PSVD) is a rare vascular liver disease of unknown etiology that causes portal hypertension. It usually affects young individuals and shortens live expectancy. The deregulated pathways involved in PSVD development are unknown and therefore we lack curative treatments. The purpose of this study was to integrate transcriptomic and clinical data by comprehensive network-based modeling in order to uncover altered biological processes in patients with PSVD. METHODS: We obtained liver tissue samples from 20 consecutive patients with PSVD and 21 sex- and age-matched patients with cirrhosis and 13 histologically normal livers (HNL) (initial cohort) and performed transcriptomic analysis. Microarray data were analyzed using weighted gene correlation network analysis to identify clusters of highly correlated genes differently expressed in patients with PSVD. We next evaluated the molecular pathways enriched in patients with PSVD and the core-related genes from the most significantly enriched pathways in patients with PSVD. Our main findings were validated using RNA sequencing in a different cohort of PSVD, cirrhosis and HNL (n = 8 for each group). RESULTS: Patients with PSVD have a distinctive genetic profile enriched mainly in canonical pathways involving hemostasis and coagulation but also lipid metabolism and oxidative phosphorylation. Serpin family (SERPINC1), the apolipoproteins (APOA, APOB, APOC), ATP synthases (ATP5G1, ATP5B), fibrinogen genes (FGB, FGA) and alpha-2-macroglobulin were identified as highly connective genes that may have an important role in PSVD pathogenesis. CONCLUSION: PSVD has a unique transcriptomic profile and we have identified deregulation of pathways involved in vascular homeostasis as the main pathogenic event of disease development. LAY SUMMARY: Porto-sinusoidal vascular disease is a rare but life-shortening disease that affects mainly young people. Knowledge of the disrupted pathways involved in its development will help to identify novel therapeutic targets and new treatments. Using a systems biology approach, we identify that pathways regulating endothelial function and tone may act as drivers of porto-sinusoidal vascular disease.

Treatment of Acute Variceal Bleeding in 2021-When to Use Transjugular Intrahepatic Portosystemic Shunts?

Variceal bleeding in patients with cirrhosis is associated with high mortality if not adequately managed. Treatment of acute variceal bleeding with adequate resuscitation maneuvers, restrictive transfusion policy, antibiotic prophylaxis, pharmacologic therapy, and endoscopic therapy is highly effective at controlling bleeding and preventing death. There is a subgroup of high-risk cirrhotic patients in whom this strategy fails, however, and who have a high-mortality rate. Placing a preemptive transjugular intrahepatic portosystemic shunt in these high-risk patients, as soon as possible after admission, to achieve early control of bleeding has proved not only to control bleeding but also to improve survival.

Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.

BACKGROUND & AIMS: Myeloproliferative neoplasms (MPNs) are the most frequent cause of non-tumoural non-cirrhotic splanchnic vein thrombosis (NC-SVT). Diagnosis of MPN is based on blood cell count alterations, bone marrow histology, and detection of specific gene mutations. Next-generation sequencing (NGS) allows the simultaneous evaluation of multiple genes implicated in myeloid clonal pathology. The aim of this study was to evaluate the potential role of NGS in elucidating the aetiology of NC-SVT. METHODS: DNA samples from 80 patients (75 with idiopathic or exclusively local factor [Idiop/loc-NC-SVT] and 5 with MPN and NC-SVT [SVT-MPN] negative for Janus kinase 2 gene [JAK2] [V617F and exon 12], calreticulin gene [CALR], and thrombopoietin gene [MPL] mutations by classic techniques) were analysed by NGS. Mutations involved in myeloid disorders different from JAK2, CALR, and MPL genes were categorised as high-molecular-risk (HMR) variants or variants of unknown significance. RESULTS: In 2/5 triple-negative SVT-MPN cases (40%), a mutation in exon 12 of JAK2 was identified. JAK2-exon 12 mutation was also identified in 1/75 patients with Idiop/loc-NC-SVT. Moreover, 28/74 (37.8%) of the remaining Idiop/loc-NC-SVT had at least 1 HMR variant. Sixty-two patients with Idiop/loc-NC-SVT were not receiving long-term anticoagulation and 5 of them (8.1%) had recurrent NC-SVT. This cumulative incidence was significantly higher in patients with HMR variants than in those without. CONCLUSIONS: NGS identified JAK2-exon12 mutations not previously detected by conventional techniques. In addition, NGS detected HMR variants in approximately one-third of patients with Idiop/loc-NC-SVT. These patients seem to have a higher risk of splanchnic rethrombosis. NGS might be a useful diagnostic tool in NC-SVT. LAY SUMMARY: Next-generation sequencing (NGS) performs massive sequencing of DNA allowing the simultaneous evaluation of multiple genes even at very low mutational levels. Application of this technique in a cohort of patients with non-cirrhotic non-tumoral portal vein thrombosis (NC-SVT) and a negative study for thrombophilic disorders was able to identify patients with a mutation in exon 12 not previously detected by conventional techniques. Moreover, NGS detected High Molecular Risk (HMR)-variants (Mutations involved in myeloid disorders different from JAK2, CALR and MPL genes) in approximately one third of patients. These patients appear to be at increased risk of rethrombosis. All these findings supports NGS as a potential useful tool in the management of NC-SVT.

New Insights into the Pathogenesis, Risk Factors, and Treatment of Portal Vein Thrombosis in Patients with Cirrhosis.

Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis regardless of etiology. Notwithstanding the commonality of the problem, the pathophysiology and risk factors for PVT in cirrhosis are largely unknown. The clinical impact of PVT in the natural history of cirrhosis is unclear, indications for PVT treatment are not well defined, and treatment recommendations are based on experts' opinion and consensus only. Therefore, this review aims to summarize current knowledge of mechanisms and risk factors for PVT development and assess the current evidence of PVT management, with a special focus on strategies of anticoagulation and transjugular intrahepatic portosystemic shunt placement.

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study.

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.