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

Current knowledge in pathophysiology and management of Budd-Chiari syndrome and non-cirrhotic non-tumoral splanchnic vein thrombosis

Budd-Chiari Syndrome (BCS) and non-cirrhotic non-tumoral portal vein thrombosis (NCPVT) are two rare disorders, with several similarities that are categorized under the term splanchnic vein thrombosis. Both disorders are frequently associated with an underlying pro-thrombotic disorder. They can cause severe portal hypertension and usually affect oung patients, negatively influencing life expectancy when the diagnosis and treatment is not done at an early stage. Yet, they have specific features that require individual considerations. The current review will focus on the available knowledge on pathophysiology, diagnosis and management of both entities. BCS is defined as the obstruction of hepatic venous outflow regardless of its causative mechanism or level of obstruction. This obstruction can be traced to the small hepatic venules up to the entrance of the inferior vein cava (IVC) into the right atrium. Hepatic outflow obstruction related to cardiac disease, pericardial disease or sinusoidal obstruction syndrome have different pathophysiological and clinical implications and are excluded from this definition. BCS is classified as primary when the obstruction originates in the vein and thrombosis is the main cause, or secondary when the vein is externally compressed (abscess, tumor). The focus of this review is on primary BCS. NCPVT refers to the presence of a thrombus in the main portal vein trunk and/or the left or right intrahepatic portal vein branches that may extend to the splenic vein and/or the superior or inferior mesenteric veins. Isolated splenic or mesenteric vein thrombosis are out of the scope of this review.Copyright © 2019. Published by Elsevier B.V

Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: 'a note of caution'

BACKGROUND: New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection. METHODS: This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications. RESULTS: Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005). CONCLUSIONS: OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels

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

Changes in Hepatic Venous Pressure Gradient Predict Hepatic Decompensation in Patients Who Achieved Sustained Virologic Response to Interferon-Free Therapy

BaCKgRoUND aND aIMS: Sustained virologic response (SVR) to interferon (IFN)-free therapies ameliorates portal hypertension (PH); however, it remains unclear whether a decrease in hepatic venous pressure gradient (HVPG) after cure of hepatitis C translates into a clinical benefit. We as- sessed the impact of pretreatment HVPG, changes in HVPG, and posttreatment HVPG on the development of hepatic decompensation in patients with PH who achieved SVR to IFN-free therapy. Moreover, we evaluated transient elastogra- phy (TE) and von Willebrand factor to platelet count ratio (VITRO) as noninvasive methods for monitoring the evolu- tion of PH. appRoaCH aND ReSUltS: The study comprised 90 patients with HVPG ≥ 6 mm Hg who underwent paired HVPG, TE, and VITRO assessments before (baseline [BL]) and after (follow-up [FU]) IFN-free therapy. FU HVPG but not BL HVPG predicted hepatic decompensation (per mm Hg, hazard ratio, 1.18; 95% confidence interval, 1.08- 1.28; P < 0.001). Patients with BL HVPG ≤ 9 mm Hg or patients who resolved clinically significant PH (CSPH) were protected from hepatic decompensation. In patients with CSPH, an HVPG decrease ≥ 10% was similarly protective (36 months, 2.5% vs. 40.5%; P < 0.001) but was observed in a substantially higher proportion of patients (60% vs. 24%; P < 0.001). Importantly, the performance of noninva- sive methods such as TE/VITRO for diagnosing an HVPG reduction ≥ 10% was inadequate for clinical use (area under the receiver operating characteristic curve [AUROC], < 0.8), emphasizing the need for HVPG measurements. However, TE/VITRO were able to rule in or rule out FU CSPH (AUROC, 0.86-0.92) in most patients, especially if assessed in a sequential manner. CoNClUSIoNS: Reassessment of HVPG after SVR im- proved prognostication in patients with pretreatment CSPH. An “immediate” HVPG decrease ≥ 10% was observed in the majority of these patients and was associated with a clinical benefit, as it prevented hepatic decompensation. These results support the use of HVPG as a surrogate endpoint for inter- ventions that lower portal pressure by decreasing intrahepatic resistance

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 &lt; 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 &lt; 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

DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma

Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine-phosphate-guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C-related HCC) and validation sets (n = 83; 47% alcohol-related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF-6] domain family member 1, insulin-like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2). Conclusions: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA-based signatures indicating tumors with progenitor cell features

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

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

Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. METHODS: We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. RESULTS: Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)μg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001). CONCLUSIONS: NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. LAY SUMMARY: Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF