Budd-Chiari syndrome with short-length stenosis: still room for the angioplasty and wait-and-see strategy

We read with interest the study in The Lancet Gastroenterology & Hepatology by Qiuhe Wang and colleagues. 1 This randomised controlled trial aimed to elucidate whether routine stenting plus angioplasty was superior to angioplasty alone for preventing restenosis in patients with Budd-Chiari syndrome with short-length stenosis. The authors found that patients treated with angioplasty plus routine stenting had a lower incidence of restenosis than did patients treated with angioplasty alone, with no differences in survival. Based on these findings, the authors suggested that stenting combined with angioplasty should be used as a first-line invasive treatment in patients with Budd-Chiari syndrome with short-length stenosis

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-alpha, 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

Congenital antithrombin deficiency in patients with splanchnic vein thrombosis

Splanchnic vein thromboses (SVT) are a rare condition that can be life-threatening. The most severe thrombophilia associated to SVT is antithrombin (AT) deficiency, usually caused by SERPINC1 mutations. Although transitory AT deficiencies and congenital disorders of the N-glycosylation pathways (CDG) have been recently reported as causes of AT deficiency, the current AT clinical screening still only includes anti-FXa activity. This study aims to 1) improve the detection of antithrombin deficiency in SVT and 2) characterize the features of antithrombin deficiency associated with SVT.The study was performed in 2 cohorts: 1) 89 SVT patients with different underlying etiologies but in whom AT deficiency had been ruled out by classical diagnostic methods; and 2) 271 unrelated patients with confirmed AT deficiency and venous thrombosis. Antithrombin was evaluated by functional (anti-FXa and anti-FIIa) and immunological methods (ELISA, crossed immunoelectrophoresis, western blot), and SERPINC1 sequencing was performed.In 4/89 patients (4.5%) additional alterations in AT were found (two had SERPINC1 mutations, one had a specific variant causing transient AT deficiency and one patient had CDG). In 11 of the 271 patients (4.1%) with AT deficiency and thrombosis, thrombosis was located at the splanchnic venous territory.AT deficiency may be underdiagnosed by current clinical screening techniques. Therefore, a comprehensive AT evaluation should be considered in cases of rethrombosis or doubtful interpretation of anti-FXa activity levels. SVT is a relatively common localization of the thrombotic event in patients with congenital AT deficiency.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis

Short-chain fatty acids (SCFAs) are gut microbiota-derived products that participate in maintaining the gut barrier integrity and host's immune response. We hypothesize that reduced SCFA levels are associated with systemic inflammation, endotoxemia, and more severe hemodynamic alterations in cirrhosis. Patients with cirrhosis referred for a hepatic venous pressure gradient (HVPG) measurement (n = 62) or a transjugular intrahepatic portosystemic shunt placement (n = 12) were included. SCFAs were measured in portal (when available), hepatic, and peripheral blood samples by GC-MS. Serum endotoxins, proinflammatory cytokines, and NO levels were quantified. SCFA levels were significantly higher in portal vs. hepatic and peripheral blood. There were inverse relationships between SCFAs and the severity of disease. SCFAs (mainly butyric acid) inversely correlated with the model for end-stage liver disease score and were further reduced in patients with history of ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis. There was an inverse relationship between butyric acid and HVPG values. SCFAs were directly related with systemic vascular resistance and inversely with cardiac index. Butyric acid inversely correlated with inflammatory markers and serum endotoxin. A global reduction in the blood levels of SCFA in patients with cirrhosis is associated with a more advanced liver disease, suggesting its contribution to disease progression.-Juanola, O., Ferrusquía-Acosta, J., García-Villalba, R., Zapater, P., Magaz, M., Marín, A., Olivas, P., Baiges, A., Bellot, P., Turon, F., Hernández-Gea, V., González-Navajas, J. M., Tomás-Barberán, F. A., García-Pagán, J. C., Francés, R. Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis

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.This study was supported by the Instituto de Salud Carlos III FIS PI17/00398, the Ministry of Education and Science, Spain (SAF-2016-75767-R); Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR-SGR2017-517) a grant from Generalitat de Catalunya, Fondo Europeo de Desarrollo Regional (FEDER) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), funded by Instituto de Salud Carlos III. Marta Magaz is a recipient of a Río Hortega grant from Instituto de Salud Carlos III. Pol Olivas has been funded by Contractes Clínic de Recerca ”Emili Letang-Josep Font’’ 2020, granted by Hospital Clínic de Barcelona.Peer reviewe

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

IntroductionMacrophages 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.MethodsWe 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).ResultsMedian 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.ConclusionSoluble 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

Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis

Carta a l'editorWe studied the role of the recently identified CALR mutations in 141 patients with Budd-Chiari Syndrome (BCS) or portal vein thrombosis (PVT) in a large multinational cohort. A CALR mutation was present in one of the 141 patients (0.7%). This patient was previously diagnosed with primary myelofibrosis. This results in CALR positivity in one out of 44 (2.3%) patients with myeloproliferative neoplasm (MPN), and in one of 11 (9.1%) JAK2V617F negative patients diagnosed with MPN. We suggest that analysis of CALR mutations should be performed in JAK2V617F negative BCS and PVT patients..

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

Factors de risc de trombosi portal no tumoral en la cirrosi hepàtica

[spa] La cirrosis hepática es el estadio final de diferentes enfermedades hepáticas y se asocia a una alta morbi-mortalidad. El desarrollo de hipertensión portal es un punto clave en la historia natural de la enfermedad ya que es el factor de riesgo más importante para la aparición de descompensaciones y complicaciones de la cirrosis. Una de las complicaciones que pueden aparecer conrelativa frecuencia durante la evolución es el desarrollo de una trombosis portal no tumoral (TP), sobretodo en estadios más avanzados de la enfermedad. Actualmente no existe forma de predecir que pacientes desarrollarán o no una TP. Estudios previos han evaluado los posibles factores de riesgo para el desarrollo de TP pero la mayoría son retrospectivos o transversales, incluyendo pocos pacientes, y no han tenido en cuenta todos los factores que pueden estar implicados. Por ello, los factores de riesgo para desarrollar TP no han sido determinados. Adicionalmente, en el caso concreto de la cirrosis por VHC, durante los últimos años han aparecido los antivirales de acción directa que han permitido la curación del VHC en pacientes con cirrosis que hasta hace pocos años no tenían la opción de eliminación del VHC. La curación del VHC se ha asociado a una mejoría de la función hepática, mejoría de la hipertensión portal y a un aumento de la supervivencia. No obstante se desconoce el impacto de la curación del VHC sobre el riesgo de desarrollar TP. Esta tesis está focalizada en el estudio de la TP no tumoral en la cirrosis hepática des de un punto de vista etiológico, estudiando los factores de riesgo más relevantes implicados en su desarrollo.En este contexto hemos diseñado el primer estudio de esta tesis (Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors) cuyo objetivo principal es determinar los factores predictivos de TP no tumoral en la cirrosis. Para ello se diseñó un estudio prospectivo en el que se incluyeron 369 pacientes con cirrosis hepática sin TP con una evaluación basal exhaustiva de parámetros clínicos, analíticos, inflamatorios y factores de coagulación adquiridos y hereditarios. 29 pacientes desarrollaron TP durante un seguimiento medio de 48±27 meses con una incidencia de 1.6, 6 y 8.4% a 1, 3 y 5 años. El recuento de plaquetas, la velocidad del flujo portal menor a 15 cm/seg y la historia previa de hemorragia por varices fueron predictores independientes asociados a un mayor riesgo de TP. Sin embargo, nuestros resultados no apoyan el papel de las alteraciones de coagulación (ni adquiridas ni hereditarias) ni de los marcadores inflamatorios en la predicción de TP en la cirrosis. El segundo estudio de esta tesis, titulado ¿Risk of non-tumoural portal vein thrombosis in patients with HCV-induced cirrhosis after sustained virological response¿ tiene como objetivo principal evaluar el impacto de la respuesta viral sostenida (RVS) en el desarrollo de TP no tumoral en pacientes con cirrosis hepática por VHC tratados con antivirales de acción directa. Se diseñó un estudioen el que se compararon dos cohortes de pacientes cirróticos por VHC, bien caracterizadas y con seguimiento prospectivo, una de pacientes con RVS post tratamiento (¿VHC-curado¿; n= 354) y la otra con VHC activo (¿VHC-activo¿; n= 179). Diez pacientes (2.8%) de la cohorte ¿VHC-curado¿ y 8 (4.5%) de la cohorte ¿VHC-activo¿ desarrollaron TP no tumoral durante un seguimiento medio de 42.2 meses. El Child-Pugh score elevado resultó el único factor de riesgo independiente para el desarrollo de TP, siendo los pacientes Child-Pugh A de bajo riesgo. En el análisis ajustado mediante IPTW (inverse probability of treatment-weighted analysis), la curación del VHC no se asoció a una disminución del riesgo de desarrollar TP (sHR: 1.31; 95%CI [0.43-3.97]; p=0.0635). Sin embargo, la RVS se asoció a una disminución significativa de la mortalidad (análisis IPTW: sHR: 0.453; (95%CI [0.287-0.715]; P<0.001). Con los resultados del estudio se puede concluir que el riesgo de TP no tumoral persiste después de la curación del VHC en pacientes con cirrosis hepática a pesar de mejorar la supervivencia. La severidad de la enfermedad hepática persiste como un factor determinante para su desarrollo