Gut dysbiosis contributes to the development of Budd-Chiari syndrome through immune imbalance.

Budd-Chiari syndrome (B-CS) is a rare and lethal condition characterized by hepatic venous outflow tract blockage. Gut microbiota has been linked to numerous hepatic disorders, but its significance in B-CS pathogenesis is uncertain. First, we performed a case-control study (Ncase = 140, Ncontrol = 63) to compare the fecal microbiota of B-CS and healthy individuals by metagenomics sequencing. B-CS patients' gut microbial composition and activity changed significantly, with a different metagenomic makeup, increased potentially pathogenic bacteria, including Prevotella, and disease-linked microbial function. Imbalanced cytokines in patients were demonstrated to be associated with gut dysbiosis, which led us to suspect that B-CS is associated with gut microbiota and immune dysregulation. Next, 16S ribosomal DNA sequencing on fecal microbiota transplantation (FMT) mice models examined the link between gut dysbiosis and B-CS. FMT models showed damaged liver tissues, posterior inferior vena cava, and increased Prevotella in the disturbed gut microbiota of FMT mice. Notably, B-CS-FMT impaired the morphological structure of colonic tissues and increased intestinal permeability. Furthermore, a significant increase of the same cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, IL-17F, and IL-13) and endotoxin levels in B-CS-FMT mice were observed. Our study suggested that gut microbial dysbiosis may cause B-CS through immunological dysregulation. IMPORTANCE: This study revealed that gut microbial dysbiosis may cause Budd-Chiari syndrome (B-CS). Gut dysbiosis enhanced intestinal permeability, and toxic metabolites and imbalanced cytokines activated the immune system. Consequently, the escalation of causative factors led to their concentration in the portal vein, thereby compromising both the liver parenchyma and outflow tract. Therefore, we proposed that gut microbial dysbiosis induced immune imbalance by chronic systemic inflammation, which contributed to the B-CS development. Furthermore, Prevotella may mediate inflammation development and immune imbalance, showing potential in B-CS pathogenesis.

Successful Blood Transfusion Management of a Living Donor Liver Transplant Recipient in the Presence of Anti-Jra: A Case Report.

A 48-year-old Japanese woman was diagnosed with Budd-Chiari syndrome and transferred for possible living donor liver transplantation (LDLT). Examinations before LDLT revealed that the recipient had anti-Jra and preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA). Rituximab was administrated at 16 days prior to the patient's scheduled LDLT for the prophylaxis of antibody-mediated rejection by DSA. The clinical significance of anti-Jra has not been clearly established because of the rarity of this antibody, so we discussed blood transfusion strategy with the Department of Blood Transfusion Service and prepared for Jra-negative packed red blood cells (RBCs). Intraoperative blood salvage was used during LDLT procedures to reduce the use of packed RBCs. Although post-transplantation graft function was excellent, a total of 44 U of Jra-negative RBCs were transfused during the entire perioperative period. Because sufficient amounts of Jra-negative packed RBCs were supplied, Jra mismatched blood transfusion was avoided. The patient was discharged from our hospital on postoperative day 102 without clinical evidence of any blood transfusion-related adverse events. Although there are some controversies of blood transfusion related to anti-Jra antibodies, the current strategies of blood transfusion for liver transplantation with anti-Jra are as follows: (1) sufficient supply and transfusion of Jra-negative matched packed RBCs and (2) application of intraoperative blood salvage to reduce the total amount of rare blood type RBCs. These strategies may be changed when the mechanism of anti-Jra alloimmunization is fully understood in the future.

Associations of antiphospholipid antibodies with splanchnic vein thrombosis: a systematic review with meta-analysis.

Splanchnic vein thrombosis (SVT) refers to Budd-Chiari syndrome (BCS) and portal vein system thrombosis (PVST). Current practice guidelines have recommended the routine screening for antiphospholipid antibodies (APAs) in patients with SVT. A systematic review and meta-analysis of observational studies was performed to explore the association between APAs and SVT. The PubMed, EMBASE, and ScienceDirect databases were searched for all relevant papers, in which the prevalence of positive APAs or levels of APAs should be compared between BCS or noncirrhotic PVST patients versus healthy controls, or between cirrhotic patients with portal vein thrombosis (PVT) versus those without PVT. Fourteen studies were eligible. Only 1 study evaluated the role of APAs in BCS patients and found that positive immunoglobulin (Ig) G anticardiolipin antibody (aCL) was more frequently observed in BCS patients than in healthy controls; however, the associations of other APAs with BCS were not evaluated. Positive IgG aCL was more frequently observed in noncirrhotic patients with PVST than in healthy controls; however, other APAs, such as IgM aCL, lupus anticoagulants (LAs), anti-ß2-glycoprotein-I antibody (aß2GPI), and aß2GPI-oxidized low-density lipoprotein antibody (ox-LDL) were not associated with noncirrhotic PVST. Positive unclassified aCL was more frequently observed in cirrhotic patients with PVT than in those without PVT; however, the association of IgG aCL and IgM aCL with the development of PVT in liver cirrhosis remained inconsistent among studies. The risk of BCS and noncirrhotic PVST might be increased by positive IgG aCL but not IgM aCL, LA, aß2GPI, or aß2GPI ox-LDL. However, the evidence regarding APAs in BCS originated from only 1 study. The association between APAs and PVT in liver cirrhosis was unclear.

Impact of post-transplant flow cytometric panel-reactive antibodies on late-onset hepatic venous outflow obstruction following pediatric living donor liver transplantation.

The development of late-onset hepatic venous outflow obstruction (LOHVOO) following pediatric living donor liver transplantation (LDLT) can lead to uncontrollable fibrotic damage in liver grafts, even long-term patency of the graft outflow is achieved with appropriate therapeutic modalities. The aim of this study was to verify our hypothesis that some immunological responses, particularly cellular and/or antibody-mediated rejection (AMR), are associated with LOHVOO, which occurs following damage to liver sinusoidal endothelial cells in zone 3 of liver grafts. One hundred and eighty-nine patients underwent LDLT between May 2001 and December 2010 at our institute. Nine patients (4.8%) were identified as having LOHVOO. The preoperative factors, operative factors, and mortality, morbidity, and survival rates were examined and compared between the groups with and without LOHVOO. No statistical differences were observed between the groups with regard to preoperative factors, technical factors, or postoperative complications. However, FlowPRA reactivity was found to be a statistically significant risk factor for LOHVOO (P=0.006). The patients with both class I- and class II-reactive antibodies also had a significant risk of developing LOHVOO (P=0.03) and exhibited significantly higher retransplant rates. In conclusion, although further studies are needed to clarify this phenomenon, the pathophysiological mechanism underlying the development of LOHVOO after LDLT may be explained by immune-mediated responses that facilitate damage in zone 3 of liver grafts.

Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature.

In Western countries, thrombotic risk factors for Budd-Chiari syndrome (BCS) are very common, including factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, etc. However, the data regarding thrombotic risk factors in Chinese BCS patients are extremely limited. An observational study was conducted to examine this issue. A total of 246 BCS patients who were consecutively admitted to our department between July 1999 and December 2011 were invited to be examined for thrombotic risk factors. Of these, 169 patients were enrolled. Neither factor V Leiden mutation nor prothrombin G20210A mutation was found in any of 136 patients tested. JAK2 V617F mutation was positive in four of 169 patients tested. Neither MPL W515L/K mutation nor JAK2 exon 12 mutation was found in any of 135 patients tested. Overt myeloproliferative neoplasms were diagnosed in five patients (polycythemia vera, n=3; essential thrombocythemia, n=1; idiopathic myelofibrosis, n=1). Two of them had positive JAK2 V617F mutation. Both CD55 and CD59 deficiencies were found in one of 166 patients tested. This patient had a previous history of paroxysmal nocturnal haemo-globinuria before BCS. Anticardiolipin IgG antibodies were positive or weakly positive in six of 166 patients tested. Hyperhomocysteinaemia was found in 64 of 128 patients tested. 5,10-methylenetetrahydrofolate reductase C677T mutation was found in 96 of 135 patients tested. In conclusion, factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, and paroxysmal nocturnal haemoglobinuria are very rare in Chinese BCS patients, suggesting that the etiological distribution of BCS might be different between Western countries and China.

Large clones with PNH-type phenotype are not common in patients presenting with intra-abdominal thrombosis--a prospective study.

Intra-abdominal thrombosis is a complication of paroxysmal nocturnal hemoglobinuria (PNH). There is scarcity of data on cases presenting with thrombosis in whom PNH is the predisposing factor. We assessed the role of PNH defect in 81 patients with intra-abdominal thrombosis, 44 patients of Budd Chiari syndrome and 37 patients of extra hepatic venous obstruction. Flowcytometry with glycosylphosphatidyl inositol-anchored proteins (GPI-AP)-CD55, -CD59, and -CD16 was performed on all patients and controls to assess the prevalence of deficiencies and PNH-type phenotype clone size. Deficiencies of individual GPI-AP were seen in 17.3% cases versus 3.4% controls. This was due to CD55 deficiency on red blood cells and CD16 deficiency on the granulocytes. Deficiency of multiple GPI-APs was less frequent (3.7% cases). Data of this study indicate that the PNH defect as detected with CD55, CD59, and CD16 is not an important cause of intra-abdominal thrombosis in northwestern India.

Association of Budd-Chiari syndrome and celiac disease.

BACKGROUND AND AIMS: An association between Budd-Chiari syndrome (BCS) and celiac disease (CD) is uncommon. The aims of our study were to investigate the etiology of BCS and to search for a particular HLA Ag pattern among patients. PATIENTS AND METHODS: BCS diagnosis was based on Doppler ultrasound and CD diagnosis on duodenal biopsy, transglutaminase (TGAb) and gliadin antibodies (GAb). Patients were screened for prothrombotic disorders and seven had a PCR-SSO test for HLA genotypes. Patients were treated with anticoagulants and gluten-free diet. RESULTS: Nine patients were included; mean age 27 years (20-42); sex ratio (F/M) 2; mean follow-up duration 31 months (6-54). All patients had endoscopic and histological features of CD. GAb/TGAb were found in 78 % (n=7). Ag HLA found were HLA DQß1(*)02 (n=6) and DQß1(*)03 (n=3). Prothrombotic conditions identified were latent myeloproliferative disorder (n=1), protein C deficiency (n=1), probable factor V Leiden (n=1) and oral contraceptive use (n=1). No prothrombotic state could be identified in the five other patients. CONCLUSION: The BCS-CD association is relatively frequent in our country. Underlying prothrombotic conditions were absent in more than 50 % of cases, suggesting CD plays a role in the occurrence of thrombosis. HLA alleles found are strongly associated with CD, without any particular pattern for the BCS-CD association.

[Association Budd Chiari syndrome, antiphospholipid syndrome and Grave's disease]. / Association syndrome de Budd Chiari, syndrome des antiphospholipides et maladie de Basedow.

BACKGROUND: Antiphospholipid syndrome is revealed by Budd Chiari syndrome in 5% of the cases. Antiphospholipid syndrome is characterized by venous or arterial thrombosis, foetal loss and positivity of antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies and anti-beta2-glycoprotein I. Anticardiolipin antibodies was reported in auto-immune thyroid disorders, particularly in Grave's disease. Antiphospholipid syndrome associated to Grave's disease was reported in only three cases. AIM: To describe a case report of association of Grave's disease and antiphospholipid syndrome. OBSERVATION: We report the first case of Grave's disease associated with antiphospholipid syndrome, revealed by Budd Chiari syndrome. CONCLUSION: Our observation is particular by the fact that it is about a patient presenting a Grave's disease associated with antiphospholipid syndrome revealed by Budd Chiari syndrome. This triple association has never been reported in literature. Although association between antiphospholipid syndrome and Grave's disease was previously described, further studies evaluating the coexistence of these two affections in the same patient would be useful.

Successful liver transplantation for Budd-Chiari syndrome in a patient with paroxysmal nocturnal hemoglobinuria treated with the anti-complement antibody eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by somatic mutations in the phosphatidylinositol glycan-complementation class A gene and the resulting absence of a key complement regulatory protein, CD59. Affected red blood cells in patients with PNH undergo intravascular complement-mediated lysis with resulting anemia, hemoglobinuria, and venous thromboses. Hepatic venous outflow thrombosis [Budd-Chiari syndrome (BCS)] is especially common in PNH patients and often fatal. The few case reports of outcomes in patients undergoing liver transplant for BCS secondary to PNH detail instances of recurrent BCS as well as early thrombotic portal vein occlusion and hepatic artery thrombosis requiring retransplantation. PNH is therefore generally considered a contraindication to liver transplantation. Here we present the first report of a patient with PNH and BCS undergoing successful liver transplantation while receiving eculizumab, a humanized monoclonal antibody that blocks the activation of the terminal complement at C5.

[Extensive portocava thrombosis revealing a primary antiphospholipid syndrome: a case report]. / Thrombose portocave extensive révélant un syndrome primaire des anticorps antiphospholipides: à propos d'un cas.

We report a 20-year-old woman who presented with a massive portal thrombosis that rapidly extended to the superior and inferior vein cava system causing an acute Budd-Chiari syndrome. The investigations concluded to a primary antiphospholipid syndrome without any other prothrombotic factors. The outcome was fatal, 18 months later, despite anticoagulation, with hepatorenal syndrome and severe liver failure.

Increased CD11b neutrophil expression in Budd-Chiari syndrome or portal vein thrombosis secondary to polycythaemia vera.

Budd-Chiari syndrome and portal vein thrombosis (BCS/PVT) are frequently associated with polycythaemia vera (PV). In an attempt to elucidate the mechanisms of BCS/PVT secondary to PV (T-PV), CD11b neutrophil expression, neutrophil oxidative burst and platelet-neutrophil complexes (PNC) were assessed in 17 such patients. Three groups served as controls: BCS/PVT not secondary to PV (T-nPV; n = 20), PV without thrombosis (PV-nT; n = 16), and healthy controls (HC; n = 20). Baseline CD11b expression (in mean fluorescence intensity units) was 101 [95% confidence interval (CI): 79-128] in T-PV patients, versus 25 (95% CI: 18-35) in T-nPV, 59 (95% CI: 43-80) in PV-nT, and 34 (95% CI: 25-48) in HC (P < 0.001). After N-formyl-L-methionyl-L-leucyl-L-phenylalanine activation, T-PV patients also showed higher CD11b values: 190 (95% CI: 151-238), versus 55 (95% CI: 41-72) in T-nPV, 111 (95% CI: 81-153) in PV-nT, and 77 (95% CI: 63-95) in HC (P < 0.001). In BCS/PVT, CD11b neutrophil expression had 90% specificity and 100% sensitivity for the association with PV. Finally, PV patients had higher oxidative burst and PNC than T-nPV patients or HC (P < 0.05). These results support a role for neutrophils in BCS/PVT secondary to PV and indicate that neutrophil CD11b expression could be of use for PV screening in BCS/PVT patients.

Coexistence of homozygous factor V Leiden mutation and antiphospholipid antibodies in two patients presented with Budd-Chiari syndrome.

Two female patients are reported, who presented with Budd-Chiari syndrome (hepatic vein thrombosis), and were found to have both, antiphospholipid antibodies and homozygous factor V Leiden mutation. Both patients also had recurrent fetal losses, as well as splenic and portal vein thrombosis. The coexistence of homozygous factor V Leiden mutation and antiphospholipid antibodies in patients with Budd-Chiari syndrome is extremely rare. The interaction of antiphospholipid antibodies and factor V Leiden mutation in the pathogenesis of antiphospholipid syndrome and their contribution to Budd-Chiari syndrome are discussed.

[Antiphospholipid antibodies in digestive diseases]. / Les anticorps antiphospholipides en pathologie digestive.

DIAGNOSIS AND PROGNOSIS: Antiphospholipids comprise a very heterogeneous group of auto-antibodies including anticardiolipids demonstrated by immunological methods and lupus anticoagulants detected by coagulation tests. Antiphospholipids are encountered in various conditions other than dysimmune disease and are frequently involved in thrombotic manifestations. We discuss here the implications of these antibodies in digestive tract diseases and present an analysis of their diagnostic and prognostic value for optimal therapeutic and monitoring approaches. CLINICAL MANIFESTATIONS: The risk of thrombosis is high in patients with cryptogenetic inflammatory bowel disease. The prevalence of antiphospholipid antibodies (AcAPL) is abnormally high in these patients, but their contribution to the development of thrombosis remains controversial. Patients with liver disease generally exhibit coagulation disorders, with paradoxical thrombotic manifestations. AcAPL are strongly implicated in the development of thrombosis, particularly in patients with alcoholic liver disease, hepatitis C, regenerative nodular hyperplasia, and cirrhosis, independently of the presence of an associated hepatocellular carcinoma. Antiphospholipid syndrome is considered to be the second leading cause of non-tumor-related Budd-Chiari syndrome, after myeproliferative syndromes. Likewise for portal or mesenteric vein thrombosis where antiphospholipid antibodies would be involved in the causal mechanism. UNDERLYING MECHANISMS: Due to the diversity of these antibodies, it is unlikely that a unique mechanism could explain all the different thrombotic manifestations associated with their presence.

Budd-Chiari syndrome in a patient with ulcerative colitis: association with anticardiolipin antibodies.

This is the first reported case of a young patient with ulcerative colitis who developed acute Budd-Chiari syndrome and was found positive for anticardiolipin antibodies. Although an association between ulcerative colitis and Budd-Chiari syndrome, and between the latter and antiphospholipid antibodies, has been shown in the literature, the coexistence of these three conditions has never been reported. The patient we describe did poorly and was considered as a candidate for liver transplantation in spite of prompt heparin therapy, probably because of the presence of multiple risk factors.