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Journal of Hepatology Jul 2023Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis.
METHODS
In this IPD meta-analysis, we selected studies comparing anticoagulation vs. no treatment in patients with cirrhosis and portal vein thrombosis from PubMed, Embase, and Cochrane databases (until June 2020) (PROSPERO no.: CRD42020140026). IPD were subsequently requested from authors. The primary outcome - the effect of anticoagulation on all-cause mortality - was assessed by a one-step meta-analysis based on a competing-risk model with liver transplantation as the competing event. The model was adjusted for clinically relevant confounders. A multilevel mixed-effects logistic regression model was used to determine the effect of anticoagulation on recanalization.
RESULTS
Individual data on 500 patients from five studies were included; 205 (41%) received anticoagulation and 295 did not. Anticoagulation reduced all-cause mortality (adjusted subdistribution hazard ratio 0.59; 95% CI 0.49-0.70), independently of thrombosis severity and recanalization. The effect of anticoagulation on all-cause mortality was consistent with a reduction in liver-related mortality. The recanalization rate was higher in the anticoagulation arm (adjusted odds ratio 3.45; 95% CI 2.22-5.36). The non-portal-hypertension-related bleeding rate was significantly greater in the anticoagulation group.
CONCLUSIONS
Anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization, but at the expense of increasing non-portal hypertension-related bleeding.
PROSPERO REGISTRATION NUMBER
CRD42020140026.
IMPACT AND IMPLICATIONS
Anticoagulation is effective in promoting recanalization of portal vein thrombosis in patients with cirrhosis, but whether this benefit translates into improved survival is controversial. Our individual patient data meta-analysis based on a competing-risk model with liver transplantation as the competing event shows that anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization. According to our findings, portal vein thrombosis may identify a group of patients with cirrhosis that benefit from long-term anticoagulation.
Topics: Humans; Anticoagulants; Portal Vein; Treatment Outcome; Venous Thrombosis; Liver Cirrhosis; Thrombosis; Hemorrhage; Hypertension
PubMed: 36858157
DOI: 10.1016/j.jhep.2023.02.023 -
Nature May 2024The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal...
The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco macrophages. Functional ablation of Marco macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.
Topics: Animals; Female; Humans; Male; Mice; Bacteroidetes; Cholangitis, Sclerosing; Gastrointestinal Microbiome; Gene Expression Profiling; Inflammation; Interleukin-10; Liver; Macrophages; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Portal Vein; Receptors, Immunologic; Single-Cell Analysis; Symbiosis
PubMed: 38658756
DOI: 10.1038/s41586-024-07372-6 -
Radiographics : a Review Publication of... Nov 2023Radiologists are familiar with the appearances of a normal portal vein; variations in its anatomy are commonplace and require careful consideration due to the... (Review)
Review
Radiologists are familiar with the appearances of a normal portal vein; variations in its anatomy are commonplace and require careful consideration due to the implications for surgery. These alterations in portal vein anatomy have characteristic appearances that are clearly depicted on CT, MR, and US images. Similarly, there are numerous congenital and acquired disorders of the portal vein that are deleterious to its function and can be diagnosed by using imaging alone. Some of these conditions have subtle imaging features, and some are conspicuous at imaging but poorly understood or underrecognized. The authors examine imaging appearances of the portal vein, first by outlining the classic and variant anatomy and then by describing each of the disorders that impact portal vein function. The imaging appearances of portal vein abnormalities discussed in this review include occlusion from and differentiation between bland thrombus and tumor in vein and the changes associated with resultant hepatic artery buffer response changes, cavernous transformation of the portal vein, and portal biliopathy; ascending thrombophlebitis of the portal vein (pylephlebitis); portal hypertension and its causes and sequelae; the newly described disease entity portosinusoidal vascular disorder; and intra- and extrahepatic shunts of the portal system, both congenital and acquired (including Abernethy malformations), and the associated risks. Current understanding of the pathophysiologic processes of each of these disorders is considered to aid the approach to reporting. RSNA, 2023 Quiz questions for this article are available in the supplemental material.
Topics: Humans; Portal Vein; Hypertension, Portal; Portal System; Hepatic Artery; Thrombosis; Vascular Diseases
PubMed: 37856316
DOI: 10.1148/rg.230058 -
Journal of Hepatology Feb 2024Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However,...
BACKGROUND & AIMS
Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However, the regulators of hepatic vascular reconstitution remain unclear. In this study, we aimed to investigate the regulatory mechanisms of hepatic vascular reconstitution and identify biomarkers predicting PHLF in patients undergoing hepatectomy.
METHODS
Candidate genes that were associated with hepatic vascular reconstitution were screened using adeno-associated virus vectors in Alb-Cre-CRISPR/Cas9 mice subjected to partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursor transfusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) models. The level of candidates was detected in biopsies from patients undergoing ALPPS. Risk factors for PHLF were also screened using retrospective data.
RESULTS
Downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic organoids, which was abrogated by a Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by a PEDF-neutralizing antibody. The expression of Gata3/RAMP and PEDF/VEGFA tended to have a negative correlation in patients undergoing ALPPS. A nomogram incorporating multiple factors, such as serum PEDF/VEGF index, was constructed and could efficiently predict the risk of PHLF.
CONCLUSIONS
The balance of Gata3 and Ramp2 in hepatocytes regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization via changes in the expression of PEDF and VEGFA, revealing potential targets for the prevention and treatment of PHLF.
IMPACT AND IMPLICATIONS
In this study, we show that the balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution by promoting a shift from pigment epithelium-derived factor (PEDF) to vascular endothelial growth factor A (VEGFA) expression during hepatectomy- or ALLPS (associating liver partition and portal vein ligation for staged hepatectomy)-induced liver regeneration. We also identified serum PEDF/VEGFA index as a potential predictor of post-hepatectomy liver failure in patients who underwent hepatectomy. This study improves our understanding of how hepatocytes contribute to liver regeneration and provides new targets for the prevention and treatment of post-hepatectomy liver failure.
Topics: Humans; Mice; Animals; Liver Regeneration; Vascular Endothelial Growth Factor A; Retrospective Studies; Endothelial Cells; Liver; Hepatectomy; Hepatocytes; Portal Vein; Liver Neoplasms; Liver Failure; Ligation; GATA3 Transcription Factor; Receptor Activity-Modifying Protein 2
PubMed: 37918568
DOI: 10.1016/j.jhep.2023.10.016 -
Journal of Clinical Medicine Mar 2024Portal vein thrombosis (PVT) is a rare disease with an estimated incidence of 2 to 4 cases per 100,000 inhabitants. The most common predisposing conditions for PVT are... (Review)
Review
Portal vein thrombosis (PVT) is a rare disease with an estimated incidence of 2 to 4 cases per 100,000 inhabitants. The most common predisposing conditions for PVT are chronic liver diseases (cirrhosis), primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease, or myeloproliferative disorders. PVT can be classified on the basis of the anatomical site, the degree of venous occlusion, and the timing and type of presentation. The main differential diagnosis of PVT, both acute and chronic, is malignant portal vein invasion, most frequently by hepatocarcinoma, or constriction (typically by pancreatic cancer or cholangiocarcinoma). The management of PVT is based on anticoagulation and the treatment of predisposing conditions. The aim of anticoagulation in acute thrombosis is to prevent the extension of the clot and enable the recanalization of the vein to avoid the development of complications, such as intestinal infarction and portal hypertension. The treatment with anticoagulant therapy favors the reduction of portal hypertension, and this allows for a decrease in the risk of bleeding, especially in patients with esophageal varices. The anticoagulant treatment is generally recommended for at least three to six months. Prosecution of anticoagulation is advised until recanalization or lifelong if the patient has an underlying permanent pro-coagulant condition that cannot be corrected or if there is thrombosis extending to the mesenteric veins.
PubMed: 38592411
DOI: 10.3390/jcm13051517 -
La Revue de Medecine Interne Jan 2024Splanchnic vein thrombosis includes Budd-Chiari syndrome and portal vein thrombosis. These diseases share common features: (i) they are rare diseases and (ii) they can... (Review)
Review
Splanchnic vein thrombosis includes Budd-Chiari syndrome and portal vein thrombosis. These diseases share common features: (i) they are rare diseases and (ii) they can lead to portal hypertension and its complications. Budd-Chiari syndrome and portal vein thrombosis in the absence of underlying liver disease share many risk factors, the most common being myeloproliferative neoplasms. A rapid and comprehensive workup for thrombosis risk factors is necessary in these patients. Long-term anticoagulation is indicated in most patients. Portal vein thrombosis can also develop in patients with cirrhosis, and is associated with a worse course of cirrhosis. Indications for anticoagulation in patients with cirrhosis are increasing. Transjugular intrahepatic portosystemic shunt is a second-line procedure in this setting. Because of the rarity of these diseases, high-level evidence studies are rare. However, collaborative studies have provided a better understanding of their natural history and allowed to improve the management of these patients. This review focuses on the causes, diagnosis, and management of patients with Budd-Chiari syndrome, patients with portal vein thrombosis without underlying liver disease, and patients with cirrhosis and portal vein thrombosis.
Topics: Humans; Budd-Chiari Syndrome; Portal Vein; Venous Thrombosis; Thrombosis; Portasystemic Shunt, Transjugular Intrahepatic; Liver Cirrhosis; Anticoagulants
PubMed: 37838484
DOI: 10.1016/j.revmed.2023.07.005 -
Pediatric Transplantation Nov 2023Liver transplantation (LT) has been indicated for smaller and more clinically severe patients in recent years. Small biliary atresia (BA) patients often show portal... (Review)
Review
Liver transplantation (LT) has been indicated for smaller and more clinically severe patients in recent years. Small biliary atresia (BA) patients often show portal hypoplasia and sclerotic portal vein (PV), which may make PV reconstruction more difficult during the operation. Among PV complications, intraoperative PV thrombosis can be considered a disaster, and it is important to prevent this catastrophic event by the precise assessment of the PV structure and PVF using radiological imaging before and during LT. However, there are no objective parameters to indicate whether sufficient PVF can be obtained. PV pressure (PVP) and PV flow (PVF) have mainly been studied in adult living donor LT, for the purpose of preventing small-for-size syndrome, and PVP has been considered an objective parameter of graft inflow modulation (GIM). In the setting of pediatric LT, GIM is mainly performed to prevent hypoperfusion, and it must be performed before graft implantation. GIM to maximize the PVF of pediatric patients with potentially low PVF in LT consists of the interruption of collateral vessels, the assessment of the usability of the native PV, and technical modifications in PV reconstruction. Reliable objective parameters that represent sufficient PVF before graft implantation are desired. Our recent study proposed that a PVP of ≥25 mmHg before graft implantation can be considered an objective parameter to obtain sufficient PVF (cutoff value: 50 mL/min/100 g of graft weight). Further investigation is needed to determine the best strategy for successful PV reconstruction in pediatric LT.
PubMed: 37470148
DOI: 10.1111/petr.14563 -
Journal of Hepatology Dec 2023Historically, anticoagulants were contraindicated in patients with cirrhosis owing to concerns about bleeding risks. However, recent studies have shown that patients... (Review)
Review
Historically, anticoagulants were contraindicated in patients with cirrhosis owing to concerns about bleeding risks. However, recent studies have shown that patients with cirrhosis are not naturally anticoagulated and are at increased risk of prothrombotic events, such as portal venous thrombosis. In this article, we review preclinical and clinical data on the effects of anticoagulants in cirrhosis, including their potential benefits in reducing liver fibrosis, portal hypertension, and improving survival. Despite promising preclinical evidence, clinical translation has proven challenging. Nevertheless, we discuss the use of anticoagulation in specific clinical scenarios, such as patients with atrial fibrillation and portal vein thrombosis, and highlight the need for further research, including randomised-controlled trials, to determine the optimal role of anticoagulants in the management of patients with cirrhosis.
Topics: Humans; Anticoagulants; Portal Vein; Evidence Gaps; Liver Cirrhosis; Venous Thrombosis
PubMed: 37302580
DOI: 10.1016/j.jhep.2023.06.001