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EASL Clinical Practice Guidelines: Vascular diseases of the liver

  • European Association for the Study of the Liver
Published:October 27, 2015DOI:https://doi.org/10.1016/j.jhep.2015.07.040

      Introduction

      Vascular disorders of the liver, although affecting less than 5/10,000 patients, collectively account for a number of rare conditions that represent an important health problem worldwide in the field of liver diseases. A common characteristic of most of these disorders is that they can cause non-cirrhotic portal hypertension with an ensuing high morbidity and mortality. In addition, special relevance addresses the fact that patients are usually young with an otherwise normal life expectancy that may be markedly shortened if they are not adequately managed.
      Advances in the knowledge of vascular liver disorders are hampered by the small number of cases and a limited number of studies assessing natural history, pathophysiology or therapy. However, in recent years, interest for these disorders has increased as reflected in the rise in the number of publications on this topic. In addition, EASL has encouraged this increased interest by sponsoring a monothematic conference in June 2012 in Tallinn on vascular disorders of the liver, and by proposing an EASL clinical practice guidelines on the issue. These guidelines will not cover all possible vascular disorders of the liver but are mainly based on the subjects discussed during the monothematic conference; Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia and portal vein thrombosis in cirrhosis.
      Guidelines have been written according to published studies retrieved from Pubmed. The evidence and recommendations have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. The strength of evidence has been classified into three levels: high (A), moderate (B) or low quality (C), while the grade of recommendation in two levels: strong (1) or weak (2) (Table 1). The higher the quality of the evidence, the more likely a strong recommendation is warranted. Where no clear evidence existed, recommendations were based on agreed opinions of the writing committee members.
      Table 1Evidence and recommendation grading (adapted from the GRADE system).

      Aetiological factors in splanchnic vein thrombosis in patients without underlying liver disease

      In the last decades several aetiological factors for splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), have been identified. These can be divided into local and systemic factors. Local risk factors for the development of BCS include solid malignancies or cysts that compress the venous tract [
      • Janssen H.L.
      • Garcia-Pagan J.C.
      • Elias E.
      • Mentha G.
      • Hadengue A.
      • Valla D.C.
      Budd-Chiari syndrome: a review by an expert panel.
      ]. PVT is most often seen as a complication of liver cirrhosis or hepatobiliary malignancies. Other local risk factors are intra-abdominal surgery and infections or inflammation in the abdomen. Systemic risk factors can be identified in most patients with SVT. In a large multicentre European En-Vie study on patients with BCS (n = 163) and PVT (n = 105), prothrombotic factors were present in up to 84% and 42%, respectively [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ] (Table 2). These data are consistent with earlier retrospective studies using similar diagnostic tools [
      • Denninger M.H.
      • Chait Y.
      • Casadevall N.
      • Hillaire S.
      • Guillin M.C.
      • Bezeaud A.
      • et al.
      Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
      ,
      • Valla D.
      • Casadevall N.
      • Huisse M.G.
      • Tulliez M.
      • Grange J.D.
      • Muller O.
      • et al.
      Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders.
      ]. In other parts of the world, especially in Asia other aetiological factors are observed, including Behçet disease, webs (also known as membranous obstruction) of the inferior vena cava (IVC) and hydatid cysts [
      • Mohanty D.
      • Shetty S.
      • Ghosh K.
      • Pawar A.
      • Abraham P.
      Hereditary thrombophilia as a cause of Budd-Chiari syndrome: a study from Western India.
      ,
      • Uskudar O.
      • Akdogan M.
      • Sasmaz N.
      • Yilmaz S.
      • Tola M.
      • Sahin B.
      Etiology and portal vein thrombosis in Budd-Chiari syndrome.
      ]. Most studies have been performed in adults with SVT. In children with SVT prothrombotic factors seem to play an important aetiological role, however SVT may also be caused by age-specific factors, such as neonatal sepsis and umbilical catheterisation [
      • El-Karaksy H.
      • El-Raziky M.
      Splanchnic vein thrombosis in the mediterranean area in children.
      ]. The aetiology of BCS and PVT is often multifactorial. In the En-Vie study a combination of two or more genetic or acquired prothrombotic factors occurred in 46% of BCS and 10% of PVT patients [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. In PVT a prothrombotic factor was found in 36% of patients with a local risk factor [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. In BCS patients, 18% of the patients even had three risk factors. In over 60% of SVT patients diagnosed with inherited thrombophilia an additional risk factor was found.
      Table 2Aetiological factors in Budd-Chiari syndrome and portal vein thrombosis
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Valla D.C.
      Budd-Chiari syndrome.
      ,
      • Murad S.D.
      • Valla D.C.
      • de Groen P.C.
      • Zeitoun G.
      • Hopmans J.A.
      • Haagsma E.B.
      • et al.
      Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome.
      .
      BCS, Budd-Chiari syndrome; PVT, portal vein thrombosis; PNH, paroxysmal nocturnal haemoglobinuria; n.d, no date.

      Inherited and acquired thrombophilia

      The term “thrombophilia” defines both inherited and acquired conditions that are associated with an increased risk of venous thrombosis, and is characterized by a hypercoagulable state [
      • Middeldorp S.
      • van Hylckama Vlieg A.
      Does thrombophilia testing help in the clinical management of patients?.
      ]. Both inherited deficiencies of natural inhibitors of the coagulation system, increased levels of coagulation factors and genetic mutations of coagulant factors are associated with an increased risk of SVT. The prevalence of inherited deficiencies of antithrombin, protein C and protein S are difficult to assess in SVT patients, a result of decreased liver synthesis which is often encountered in these patients. Also treatment with vitamin K antagonists (VKA) hampers the diagnosis of protein C and protein S deficiency. The prevalence of antithrombin deficiency ranges between 0–5% in both BCS and PVT, of protein C deficiency between 4–20% in BCS and 0–7% in PVT, and of protein S deficiency between 0–7% in BCS and 0–30% in PVT [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Denninger M.H.
      • Chait Y.
      • Casadevall N.
      • Hillaire S.
      • Guillin M.C.
      • Bezeaud A.
      • et al.
      Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
      ,
      • Janssen H.L.
      • Meinardi J.R.
      • Vleggaar F.P.
      • van Uum S.H.
      • Haagsma E.B.
      • Der Meer F.J.
      • et al.
      Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
      ,
      • Smalberg J.H.
      • Darwish M.S.
      • Braakman E.
      • Valk P.J.
      • Janssen H.L.
      • Leebeek F.W.
      Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome.
      ,
      • Primignani M.
      • Martinelli I.
      • Bucciarelli P.
      • Battaglioli T.
      • Reati R.
      • Fabris F.
      • et al.
      Risk factors for thrombophilia in extrahepatic portal vein obstruction.
      ]. Because this is strikingly higher than in the general population, deficiencies of these coagulation inhibitors are considered an aetiological factor in the pathogenesis of BCS and PVT, and should be included in the diagnostic work-up.
      In BCS patients the prevalence of Factor V Leiden mutation (FVL) ranges between 7% and 32%. Most of these BCS patients are heterozygous carriers, although homozygous patients have been described occasionally [
      • Leebeek F.W.
      • Lameris J.S.
      • van Buuren H.R.
      • Gomez E.
      • Madretsma S.
      • Sonneveld P.
      Budd-Chiari syndrome, portal vein and mesenteric vein thrombosis in a patient homozygous for factor V Leiden mutation treated by TIPS and thrombolysis.
      ]. It is well known that homozygote carriers have a significantly higher risk of deep vein thrombosis compared to heterozygotes, however this has not been demonstrated for SVT. The prevalence of the FVL mutation in patients with PVT is lower, ranging between 3% and 9% [
      • Smalberg J.H.
      • Kruip M.J.
      • Janssen H.L.
      • Rijken D.C.
      • Leebeek F.W.
      • de Maat M.P.
      Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: similarities and differences.
      ]. FVL carriers have a 4- to 11-fold increased risk of BCS, and a 2-fold risk of PVT [
      • Dentali F.
      • Galli M.
      • Gianni M.
      • Ageno W.
      Inherited thrombophilic abnormalities and risk of portal vein thrombosis. a meta-analysis.
      ]. Prothrombin G20210A gene variant is more common in PVT than in BCS [
      • Smalberg J.H.
      • Kruip M.J.
      • Janssen H.L.
      • Rijken D.C.
      • Leebeek F.W.
      • de Maat M.P.
      Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: similarities and differences.
      ]. A meta-analysis reported a 4- to 5-fold increase in the risk of PVT in carriers of the prothrombin G20210A gene variant [
      • Dentali F.
      • Galli M.
      • Gianni M.
      • Ageno W.
      Inherited thrombophilic abnormalities and risk of portal vein thrombosis. a meta-analysis.
      ], whereas the risk of BCS is approximately 2-fold increased [
      • Janssen H.L.
      • Meinardi J.R.
      • Vleggaar F.P.
      • van Uum S.H.
      • Haagsma E.B.
      • Der Meer F.J.
      • et al.
      Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
      ]. The mechanism for the difference in prevalence of FVL and the prothrombin G20210A gene variant in BCS and PVT remains unresolved. The prevalence of antiphospholipid antibodies (APA) in BCS and PVT has been estimated to be around 5–15% [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Denninger M.H.
      • Chait Y.
      • Casadevall N.
      • Hillaire S.
      • Guillin M.C.
      • Bezeaud A.
      • et al.
      Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
      ]. However, in most studies only one measurement of APA was carried out, whereas according to the current guidelines this measurement should be repeated after 12 weeks in order to confirm presence of APA [
      • Miyakis S.
      • Lockshin M.D.
      • Atsumi T.
      • Branch D.W.
      • Brey R.L.
      • Cervera R.
      • et al.
      International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
      ].
      In addition to the above mentioned risk factors for SVT, more recent studies have investigated whether increased levels of procoagulant factors or disorders of fibrinolysis are associated with an increased risk of SVT. Elevated factor VIII levels are found in patients with PVT [
      • Martinelli I.
      • Primignani M.
      • Aghemo A.
      • Reati R.
      • Bucciarelli P.
      • Fabris F.
      • et al.
      High levels of factor VIII and risk of extra-hepatic portal vein obstruction.
      ,
      • Raffa S.
      • Reverter J.C.
      • Seijo S.
      • Tassies D.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Hypercoagulability in patients with chronic noncirrhotic portal vein thrombosis.
      ]. A significant increase of endogenous thrombin irrespective of the underlying prothrombotic or thrombophilic disorder was also observed in PVT [
      • Raffa S.
      • Reverter J.C.
      • Seijo S.
      • Tassies D.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Hypercoagulability in patients with chronic noncirrhotic portal vein thrombosis.
      ]. Hypofibrinolysis, defined by an increase of clot lysis time, was also associated with an increased risk of BCS. This was mainly determined by increased plasminogen activator inhibitor-1 levels. So far the importance of these findings for prognosis and treatment of SVT has not been studied [
      • Marchetti M.
      • Castoldi E.
      • Spronk H.M.
      • van Oerle R.
      • Balducci D.
      • Barbui T.
      • et al.
      Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera.
      ].

      Myeloproliferative neoplasms

      Myeloproliferative neoplasms (MPNs) are a common underlying cause of abdominal vein thrombosis. MPNs are chronic clonal haematopoietic stem cell disorders characterized by an overproduction of mature and functional granulocytes, red blood cells and/or platelets. One of the main complications of MPNs is the development of arterial and venous thrombotic complications caused by increased platelet aggregation and thrombin generation [
      • Marchetti M.
      • Castoldi E.
      • Spronk H.M.
      • van Oerle R.
      • Balducci D.
      • Barbui T.
      • et al.
      Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera.
      ,
      • Tripodi A.
      • Primignani M.
      • Lemma L.
      • Chantarangkul V.
      • Mannucci P.M.
      Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis.
      ]. It has previously been estimated that MPNs are observed in 30–40% of patients with BCS or PVT, whereas this is the cause in only a minority of other types of venous thromboembolism [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Smalberg J.H.
      • Darwish M.S.
      • Braakman E.
      • Valk P.J.
      • Janssen H.L.
      • Leebeek F.W.
      Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome.
      ,
      • Kiladjian J.J.
      • Cervantes F.
      • Leebeek F.W.
      • Marzac C.
      • Cassinat B.
      • Chevret S.
      • et al.
      The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases.
      ,
      • Colaizzo D.
      • Amitrano L.
      • Tiscia G.L.
      • Grandone E.
      • Guardascione M.A.
      • Margaglione M.
      A new JAK2 gene mutation in patients with polycythemia vera and splanchnic vein thrombosis.
      ]. MPN is diagnosed based on several criteria including the characteristic peripheral blood cell changes (increased haemoglobin levels and thrombocytosis) and bone marrow findings. In SVT patients however the relevance of these commonly used criteria for the diagnosis of MPN is debated. Due to portal hypertension (PH) leading to hypersplenism and haemodilution the characteristic thrombocytosis and erythrocytosis may be masked [
      • Chait Y.
      • Condat B.
      • Cazals-Hatem D.
      • Rufat P.
      • Atmani S.
      • Chaoui D.
      • et al.
      Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis.
      ]. Previously, diagnosis of MPNs in these patients relied on bone marrow (BM) biopsy findings and growth of erythroid colonies in the absence of exogenous erythropoietin, referred to as spontaneous endogenous erythroid colonies or EEC. This could also be used to identify patients at risk of aggravation of MPN [
      • Chait Y.
      • Condat B.
      • Cazals-Hatem D.
      • Rufat P.
      • Atmani S.
      • Chaoui D.
      • et al.
      Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis.
      ]. Nowadays the JAK2V617F mutation, a common gain-of-function mutation leading to the development of MPN, is of major importance in the diagnostic strategy of MPN. This mutation is present in nearly all patients with polycythemia vera and in about 50% of patients with essential thrombocythemia and primary myelofibrosis. The JAK2V617F mutation has been detected in a large number of unselected BCS and PVT patients. In a recent meta-analysis the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders were reported [
      • Smalberg J.H.
      • Arends L.R.
      • Valla D.C.
      • Kiladjian J.J.
      • Janssen H.L.
      • Leebeek F.W.
      Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.
      ]. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% and 41.1%, respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% and 27.7%, respectively. MPN and JAK2V617F were more frequent in BCS compared to PVT. Polycythemia vera was more prevalent in BCS than in PVT. JAK2V617F screening in SVT patients without typical haematological MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively [
      • Smalberg J.H.
      • Arends L.R.
      • Valla D.C.
      • Kiladjian J.J.
      • Janssen H.L.
      • Leebeek F.W.
      Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.
      ]. It can be concluded that in all patients with SVT BM histology and screening for JAK2V617F should be performed as part of the standard diagnostic work-up [
      • Janssen H.L.
      • Leebeek F.W.
      JAK2 mutation: The best diagnostic tool for myeloproliferative disease in splanchnic vein thrombosis?.
      ]. In some cases, MPN is difficult to diagnose and additional tests, such as peripheral blood smear, erythropoietin levels or endogenous erythroid colony formation in vitro may be added to the diagnostic algorithm, as suggested by the WHO [
      • Campo E.
      • Swerdlow S.H.
      • Harris N.L.
      • Pileri S.
      • Stein H.
      • Jaffe E.S.
      The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
      ]. Recently two research groups simultaneously reported the presence of somatic mutations in the gene encoding calreticulin (CALR), a protein present in the endoplasmic reticulum and involved in the regulation of STAT-signalling pathway [
      • Klampfl T.
      • Gisslinger H.
      • Harutyunyan A.S.
      • Nivarthi H.
      • Rumi E.
      • Milosevic J.D.
      • et al.
      Somatic mutations of calreticulin in myeloproliferative neoplasms.
      ,
      • Nangalia J.
      • Massie C.E.
      • Baxter E.J.
      • Nice F.L.
      • Gundem G.
      • Wedge D.C.
      • et al.
      Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.
      ]. These mutations were detected using whole exome sequencing in the majority of patients with MPN with non-mutated JAK2. CALR mutations were absent in polycythemia vera patients, and occurred in up to 80% of patients with JAK2 negative essential thrombocythemia and primary myelofibrosis. In two recent studies [
      • Turon F.
      • Cervantes F.
      • Colomer D.
      • Baiges A.
      • Hernandez-Gea V.
      • Garcia-Pagan J.C.
      Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.
      ,
      • Plompen E.P.
      • Valk P.J.
      • Chu I.
      • Darwish M.S.
      • Plessier A.
      • Turon F.
      • et al.
      Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis.
      ], CALR mutations were evaluated in patients with SVT being positive in 0.7 and 1.9% of patients respectively. The rate increased when only patients with MPN were considered (2.3 and 5.4% respectively). Indeed, CALR was found positive in respectively 9.1% (1 out of 11 patients) and 30% (4 out of 13 patients) of JAK2 negative MPN.
      The exact pathogenetic mechanism of SVT in MPNs still remains to be resolved, but besides characteristic erythrocytosis and thrombocytosis, platelet and leukocyte functional abnormalities seem to have a pathogenetic role [
      • Landolfi R.
      • Di G.L.
      • Falanga A.
      Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation.
      ].

      Other aetiological factors

      Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematological disorder of haematopoietic stem cells and is most strongly associated with BCS [
      • Ziakas P.D.
      • Poulou L.S.
      • Rokas G.I.
      • Bartzoudis D.
      • Voulgarelis M.
      Thrombosis in paroxysmal nocturnal hemoglobinuria: sites, risks, outcome. An overview.
      ]. PNH has been reported in 9–19% of tested BCS patients [
      • Smalberg J.H.
      • Darwish M.S.
      • Braakman E.
      • Valk P.J.
      • Janssen H.L.
      • Leebeek F.W.
      Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome.
      ,
      • Hoekstra J.
      • Leebeek F.W.
      • Plessier A.
      • Raffa S.
      • Murad S.D.
      • Heller J.
      • et al.
      Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study.
      ], whereas a prevalence of 0–2% has been reported in PVT [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. The exact mechanism for the development of SVT is yet unknown [
      • Hoekstra J.
      • Leebeek F.W.
      • Plessier A.
      • Raffa S.
      • Murad S.D.
      • Heller J.
      • et al.
      Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study.
      ]. Patients with a PNH cell population above 60% of the granulocytes appear to be at a greater risk for thrombosis [
      • Brodsky R.A.
      Narrative review: paroxysmal nocturnal hemoglobinuria: the physiology of complement-related hemolytic anemia.
      ]. Testing for PNH should routinely be performed in all BCS and considered in PVT patients [
      • van Bijnen S.T.
      • van Rijn R.S.
      • Koljenovic S.
      • te Boekhorst P.
      • de Witte T.
      • Muus P.
      Possible high risk of thrombotic events in patients with paroxysmal nocturnal haemoglobinuria after discontinuation of eculizumab.
      ]. Autoimmune-mediated diseases, inflammatory bowel disease, vasculitis, sarcoidosis and connective tissue disease may also be associated with SVT, although these disorders were hardly observed in the En-Vie study, Behçet’s disease is especially observed in the Mediterranean area [
      • Bayraktar Y.
      • Balkanci F.
      • Bayraktar M.
      • Calguneri M.
      Budd-Chiari syndrome: a common complication of Behcet’s disease.
      ]. Other rare causes of SVT include cytomegalovirus infections and celiac disease [
      • Justo D.
      • Finn T.
      • Atzmony L.
      • Guy N.
      • Steinvil A.
      Thrombosis associated with acute cytomegalovirus infection: a meta-analysis.
      ,
      • Kochhar R.
      • Masoodi I.
      • Dutta U.
      • Singhal M.
      • Miglani A.
      • Singh P.
      • et al.
      Celiac disease and Budd Chiari syndrome: report of a case with review of literature.
      ].
      Hormonal factors, including oral contraceptive use and pregnancy are considered risk factors for SVT. Oral contraceptives have been shown to be associated with at least a 2-fold risk for BCS [
      • Janssen H.L.
      • Meinardi J.R.
      • Vleggaar F.P.
      • van Uum S.H.
      • Haagsma E.B.
      • Der Meer F.J.
      • et al.
      Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
      ,
      • Valla D.
      • Le M.G.
      • Poynard T.
      • Zucman N.
      • Rueff B.
      • Benhamou J.P.
      Risk of hepatic vein thrombosis in relation to recent use of oral contraceptives. A case-control study.
      ]. For PVT the risk may be slightly increased, but this has not yet been well-established [
      • Janssen H.L.
      • Meinardi J.R.
      • Vleggaar F.P.
      • van Uum S.H.
      • Haagsma E.B.
      • Der Meer F.J.
      • et al.
      Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
      ]. It should be noted that in many patients other concomitant aetiological factors were identified.

      Aetiological factors and their importance for treatment

      Diagnosing the underlying aetiological factor for developing SVT is important, since it may have therapeutic or prognostic implications. For instance, the presence of a prothrombotic disorder may influence the duration of anticoagulant treatment in PVT patients. For patients with BCS, lifelong anticoagulant treatment is warranted considering the severity of the disorder. In individuals with acute PVT, anticoagulant therapy is given for 6 months. However, long-term treatment is sometimes given, depending upon the underlying disorder. In general, the duration of anticoagulant therapy is strongly dependent upon the risk of recurrent thrombosis. Although only a few retrospective studies have focused on the risk of recurrence in PVT, these studies revealed that an underlying prothrombotic state was an independent predictor of recurrent thrombosis [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Spaander M.C.
      • Hoekstra J.
      • Hansen B.E.
      • van Buuren H.R.
      • Leebeek F.W.
      • Janssen H.L.
      Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ]. On the other hand, the risk of bleeding in these patients, who frequently present with variceal bleeding, should be taken into account. Therefore recent guidelines have suggested long-term anticoagulant therapy only to those individuals with major underlying thrombophilic risk factors, such as homozygous FVL mutation and prothrombin gene variant [
      • Plessier A.
      • Rautou P.E.
      • Valla D.C.
      Management of hepatic vascular diseases.
      ]. However, other guidelines state that thrombophilic defects have an uncertain predictive value for recurrence and decisions regarding duration of anticoagulant treatment if the result of testing is not evidence-based [
      • Tait C.
      • Baglin T.
      • Watson H.
      • Laffan M.
      • Makris M.
      • Perry D.
      • et al.
      Guidelines on the investigation and management of venous thrombosis at unusual sites.
      ]. Follow-up studies are needed to establish the duration of anticoagulant treatment especially those with no or mild thrombophilic disorders. Current guidelines do not support the testing of other family members in case a thrombophilia defect is identified [
      • Baglin T.
      • Gray E.
      • Greaves M.
      • Hunt B.J.
      • Keeling D.
      • Machin S.
      • et al.
      Clinical guidelines for testing for heritable thrombophilia.
      ].
      In case of an underlying MPN, anticoagulant treatment with VKA should be given indefinitely for SVT. Nearly all MPN patients nowadays are treated with aspirin. However it is still unknown whether aspirin should be added to the treatment of SVT patients with MPN using VKA. Although a potential benefit of aspirin in patients with PVT and MPN was observed in a retrospective study, this should be confirmed in prospective studies [
      • Tait C.
      • Baglin T.
      • Watson H.
      • Laffan M.
      • Makris M.
      • Perry D.
      • et al.
      Guidelines on the investigation and management of venous thrombosis at unusual sites.
      ,
      • Hoekstra J.
      • Bresser E.L.
      • Smalberg J.H.
      • Spaander M.C.
      • Leebeek F.W.
      • Janssen H.L.
      Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms.
      ]. MPN patients should be treated with anti-proliferative therapy, such as alpha interferon or hydroxyurea, in order to normalise peripheral blood cell counts. In patients with polycythemia vera a haematocrit <45% should be aimed for [
      • Marchioli R.
      • Finazzi G.
      • Specchia G.
      • Cacciola R.
      • Cavazzina R.
      • Cilloni D.
      • et al.
      Cardiovascular events and intensity of treatment in polycythemia vera.
      ]. The diagnosis of underlying PNH in patients with SVT may have important implications for treatment. Long-term treatment with eculizumab may be indicated in these individuals [
      • van Bijnen S.T.
      • van Rijn R.S.
      • Koljenovic S.
      • te Boekhorst P.
      • de Witte T.
      • Muus P.
      Possible high risk of thrombotic events in patients with paroxysmal nocturnal haemoglobinuria after discontinuation of eculizumab.
      ].
      Figure thumbnail fx7

      Budd-Chiari syndrome

      BCS is defined as the obstruction of hepatic venous outflow that can be located from the small hepatic venules up to the entrance of the IVC into the right atrium [
      • Janssen H.L.
      • Garcia-Pagan J.C.
      • Elias E.
      • Mentha G.
      • Hadengue A.
      • Valla D.C.
      Budd-Chiari syndrome: a review by an expert panel.
      ]. Hepatic outflow obstruction related to cardiac disease, pericardial disease or sinusoidal obstruction syndrome (SOS) are excluded from this definition. BCS can be classified into: i) primary, caused by thrombosis in the absence of compression by space occupying lesions, or invasion by malignancy or parasites; and ii) secondary otherwise. Given the different therapeutic and prognostic implications, we will only discuss primary BCS. In Western countries pure hepatic vein thrombosis is most common [
      • Plessier A.
      • Valla D.C.
      Budd-Chiari syndrome.
      ], while in Asia a pure IVC or combined IVC/hepatic vein block predominates. The pathophysiological consequences include obstruction, which leads to sinusoidal congestion, ischemia, and finally hepatocellular necrosis. They can result in centrilobular fibrosis, nodular regenerative hyperplasia and/or cirrhosis.

      Clinical manifestations

      Clinical presentation is heterogeneous and ranges from absence of symptoms to fulminant hepatic failure [
      • Janssen H.L.
      • Garcia-Pagan J.C.
      • Elias E.
      • Mentha G.
      • Hadengue A.
      • Valla D.C.
      Budd-Chiari syndrome: a review by an expert panel.
      ,
      • Hernandez-Guerra M.
      • Turnes J.
      • Rubinstein P.
      • Olliff S.
      • Elias E.
      • Bosch J.
      • et al.
      PTFE-covered stents improve TIPS patency in Budd-Chiari syndrome.
      ]. An asymptomatic presentation is often associated with the presence of large hepatic venous collaterals. In a multicentre prospective study of a large cohort of patients with BCS at diagnosis, ascites were present in 83% of patients, hepatomegaly in 67%, abdominal pain in 61%, esophageal varices in 58% and gastrointestinal bleeding in 5% [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ]. In approximately 15% of cases, BCS and PVT occur simultaneously [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Darwish M.S.
      • Valla D.C.
      • de Groen P.C.
      • Zeitoun G.
      • Haagsma E.B.
      • Kuipers E.J.
      • et al.
      Pathogenesis and treatment of Budd-Chiari syndrome combined with portal vein thrombosis.
      ]. Therapeutic options and prognosis tend to be worse in BCS-PVT patients [
      • Darwish M.S.
      • Valla D.C.
      • de Groen P.C.
      • Zeitoun G.
      • Haagsma E.B.
      • Kuipers E.J.
      • et al.
      Pathogenesis and treatment of Budd-Chiari syndrome combined with portal vein thrombosis.
      ].
      Imaging studies display hepatic nodules in 60–80% of patients with BCS. They are usually benign and are the result of perfusion disturbances. Although, these nodules are characteristically small, in most cases under 4 cm in diameter, multiple (frequently more than 10 lesions), hypervascularized, and disseminated throughout the liver. A pathognomonic pattern is not detected on computed tomography (CT) or magnetic resonance (MR) imaging. Cumulative incidence of hepatocellular carcinoma (HCC) in BCS has been shown to be 4% (after a median follow-up of 5 years) [
      • Moucari R.
      • Rautou P.E.
      • Cazals-Hatem D.
      • Geara A.
      • Bureau C.
      • Consigny Y.
      • et al.
      Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.
      ], therefore differential diagnosis is essential. Biopsy has been suggested in patients with less than or equal to three nodules, nodules with a diameter more than or equal to 3 cm, heterogeneity or washout on the venous phase, changes in two consecutive imaging techniques, or increase in alpha-fetoprotein levels [
      • Moucari R.
      • Rautou P.E.
      • Cazals-Hatem D.
      • Geara A.
      • Bureau C.
      • Consigny Y.
      • et al.
      Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.
      ]. However, radiological and histological characterization of hepatic nodules in BCS cannot rely on the well-established criteria of HCC in cirrhosis and the only formal recommendation is close and careful multidisciplinary surveillance.

      Diagnosis

      Diagnosis is established with unequivocal radiological confirmation of hepatic venous outflow obstruction. Doppler ultrasound has a diagnostic sensitivity of more than 75% and is the first line investigation [
      • Janssen H.L.
      • Garcia-Pagan J.C.
      • Elias E.
      • Mentha G.
      • Hadengue A.
      • Valla D.C.
      Budd-Chiari syndrome: a review by an expert panel.
      ]. If an experienced sonographer is not available, MR imaging and CT evaluation are used for diagnostic confirmation [
      • Janssen H.L.
      • Garcia-Pagan J.C.
      • Elias E.
      • Mentha G.
      • Hadengue A.
      • Valla D.C.
      Budd-Chiari syndrome: a review by an expert panel.
      ,
      • Plessier A.
      • Valla D.C.
      Budd-Chiari syndrome.
      ]. Venography is recommended if the diagnosis remains uncertain or for the characterization of anatomy prior to treatment. If imaging has failed to demonstrate obstruction of large veins then a liver biopsy can be used in order to assess small hepatic vein thrombosis.

      Treatment

      The recommended stepwise therapeutic algorithm of BCS based on retrospective cohorts and prospective series of patients [
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      ,
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ] is summarized in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Recommended stepwise therapeutic algorithm of Budd-Chiari syndrome.
      Patients with BCS have often required therapy for ascites and varices. These treatments should be administered following the same treatment recommendations as for ascites and portal hypertension in cirrhosis.
      Patients with BCS should receive anticoagulant therapy as soon as possible for an indefinite period of time in an attempt to reduce the risk of clot extension and new thrombotic episodes [
      • Janssen H.L.
      • Garcia-Pagan J.C.
      • Elias E.
      • Mentha G.
      • Hadengue A.
      • Valla D.C.
      Budd-Chiari syndrome: a review by an expert panel.
      ,
      • Darwish M.S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Fabris F.
      • Eapen C.E.
      • Bahr M.J.
      • et al.
      Etiology, management, and outcome of the Budd-Chiari syndrome.
      ,
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      ,
      • DeLeve L.D.
      • Valla D.C.
      • Garcia-Tsao G.
      Vascular disorders of the liver.
      ]. According to the recommendation for deep vein thrombosis, the patient should be treated with low molecular weight heparin (LMWH) for at least 5 to 7 days, and also with oral anticoagulant treatment with VKA, aiming at an international normalised ratio (INR) between 2 and 3. LMWH can be stopped when INR is within the target range for two consecutive measurements.
      A high rate of bleeding complications while on anticoagulation (up to 50% of patients) has been reported in a cohort of BCS patients diagnosed between 1995 and 2005 [
      • Rautou P.E.
      • Douarin L.
      • Denninger M.H.
      • Escolano S.
      • Lebrec D.
      • Moreau R.
      • et al.
      Bleeding in patients with Budd-Chiari syndrome.
      ]. In a more recent prospective cohort of patients diagnosed between 2005 and 2007, bleeding complications were less frequently observed (17% of patients), likely due to a better management of anticoagulation during invasive procedures or adequate prophylaxis for PH-related bleeding [
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ].
      Treatment of the underlying prothrombotic cause (for instance MPNs) should be logically initiated concomitantly. Indeed, the benefits from early treatment for an underlying myeloproliferative disorder has been suggested in a retrospective cohort analysis [

      Chagneau-Derrode C, Roy L, guilhot J, gloria O, Ollivier-Hourmand I, Bureau C, et al. Impact of cytoreductive therapy on the outcome of patients with myeloproliferative neoplasms and hepatosplanchnic vein thrombosis., 58 ed 2013. p. 857A.

      ].
      The experience of correcting hepatic venous outflow obstruction with thrombolysis is limited. Good results have been reported in patients with recent and incomplete thrombosis treated with local and early infusion of a thrombolytic agent combined with angioplasty or stenting [
      • Sharma S.
      • Texeira A.
      • Texeira P.
      • Elias E.
      • Wilde J.
      • Olliff S.P.
      Pharmacological thrombolysis in Budd Chiari syndrome: a single centre experience and review of the literature.
      ]. Complications however, can be fatal [
      • Smalberg J.H.
      • Spaander M.V.
      • Jie K.S.
      • Pattynama P.M.
      • van Buuren H.R.
      • van den B.B.
      • et al.
      Risks and benefits of transcatheter thrombolytic therapy in patients with splanchnic venous thrombosis.
      ].
      Partial or segmental stenoses are present in 60% of patients with IVC obstruction, and 25–30% of those with hepatic vein obstruction [
      • Valla D.
      • Hadengue A.
      • El Younsi M.
      • Azar N.
      • Zeitoun G.
      • Boudet M.J.
      • et al.
      Hepatic venous outflow block caused by short-length hepatic vein stenoses.
      ]. Angioplasty or stenting of these stenosis could re-establish the physiological drainage of portal and sinusoidal blood. Post-angioplasty re-stenosis is frequent but can be reduced when done in combination with a stent. Misplacement of a stent may compromise the subsequent performance of a transjugular intrahepatic portosystemic shunt (TIPS) or orthotopic liver transplantation (OLT). Overall angioplasty/stenting is the definitive treatment for less than 10% of Western BCS patients [
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ]. The efficacy may be greater in other regions of the world where there is a higher prevalence of this specific form of BCS [
      • Han G.
      • Qi X.
      • Zhang W.
      • He C.
      • Yin Z.
      • Wang J.
      • et al.
      Percutaneous recanalization for Budd-Chiari syndrome: an 11-year retrospective study on patency and survival in 177 Chinese patients from a single center.
      ].
      Patients with BCS non-responsive to medical treatment or that are not candidates for angioplasty/stenting must be treated with derivative techniques. There is no clear explanation as to why some patients do not respond to medical treatment, therefore the characteristics of BCS patients’ receiving TIPS differ from centre to centre. Some criteria have been proposed: clinical failure to therapy (treatment failure) was considered when criteria for complete or ongoing response were lacking [
      • Plessier A.
      • Sibert A.
      • Consigny Y.
      • Hakime A.
      • Zappa M.
      • Denninger M.H.
      • et al.
      Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome.
      ]. Complete response was considered when all of the following six criteria were met and stable: (1) absence of clinically detectable ascites, with normal serum sodium and creatinine levels, in the absence of diuretic therapy, or on low dose diuretics (spironolactone 75 mg/d or furosemide 40 mg/d) and moderate NaCl intake; (2) increase in coagulation factor V to a level above 40% of normal value; (3) decrease in conjugated serum bilirubin to a level below 15 μmol/L; (4) absence of first or recurrent PH-related bleeding while on primary or secondary prophylaxis with non-selective beta blockers or with endoscopic therapy; (5) no occurrence of spontaneous bacterial infection; and (6) BMI >20 kg/m2 after substraction of ascites and edema. Ongoing response was considered when all of the following three criteria were met on a 2-weekly evaluation basis: (1) in the presence of ascites, a negative sodium and water balance was achieved using low dose diuretics and moderate sodium intake, together with normal serum sodium and creatinine levels, or with increasing serum sodium if initially low and decreasing serum creatinine levels if initially high; (2) factor V level was increasing if initially low; and (3) serum conjugated bilirubin level was decreasing if initially high. These response criteria must be validated in future studies.
      Derivative techniques, either surgical shunts or TIPS, are aimed to transform the portal system into an outflow tract [
      • Tilanus H.W.
      Budd-Chiari syndrome.
      ]. The most frequent surgical shunt performed is the mesocaval shunt with a polytetrafluoroethylene (PTFE) stent or autologous jugular vein interposition. It is easier to do than the porto-caval side-to-side shunt when hypertrophy of the caudate lobe is present. Surgical shunts are ineffective if there is associated IVC thrombosis or severe compression of the IVC by an enlarged liver. In this situation some groups have performed a meso-atrial shunt or a cavo-atrial shunt plus a porto-caval shunt. Surgical shunts have not demonstrated to be an independent survival advantage in cohorts of patients with BCS [
      • Zeitoun G.
      • Escolano S.
      • Hadengue A.
      • Azar N.
      • El Younsi M.
      • Mallet A.
      • et al.
      Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting.
      ,
      • Langlet P.
      • Valla D.
      Is surgical portosystemic shunt the treatment of choice in Budd-Chiari syndrome?.
      ]. This is likely related to the high inherent mortality rate of the patient population with severe BCS, as well as to the high rate of dysfunction/thrombosis of the shunts [
      • Panis Y.
      • Belghiti J.
      • Valla D.
      • Benhamou J.P.
      • Fekete F.
      Portosystemic shunt in Budd-Chiari syndrome: long-term survival and factors affecting shunt patency in 25 patients in Western countries.
      ,
      • Bachet J.B.
      • Condat B.
      • Hagege H.
      • Plessier A.
      • Consigny Y.
      • Belghiti J.
      • et al.
      Long-term portosystemic shunt patency as a determinant of outcome in Budd-Chiari syndrome.
      ,
      • Hemming A.W.
      • Langer B.
      • Greig P.
      • Taylor B.R.
      • Adams R.
      • Heathcote E.J.
      Treatment of Budd-Chiari syndrome with portosystemic shunt or liver transplantation.
      ]. On the other hand, TIPS has a lower morbidity and mortality rate than surgery and is feasible in most patients with IVC obstruction and in those with severe IVC stenosis. A recent multicentre retrospective European study including 124 BCS patients treated with TIPS showed excellent 1- and 5-year OLT-free survival (88% and 78%, respectively) [
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ]. These results have been confirmed by a recent prospective study [
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ]. PTFE-covered stents reduce the recurrence of post-procedure TIPS obstruction or dysfunction [
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ,
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ]. TIPS placement in patients with BCS requires special training. Indeed, in more than 45% of cases, a transcaval approach (direct puncture from the intrahepatic IVC) may be required due to complete thrombosis of the hepatic veins [
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ].
      OLT in patients with BCS is associated with a survival [
      • Mentha G.
      • Giostra E.
      • Majno P.E.
      • Bechstein W.O.
      • Neuhaus P.
      • O’Grady J.
      • et al.
      Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 centres.
      ] similar to that obtained in patients initially treated with TIPS [
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ]. It has been suggested that the placement of previous TIPS can make a posterior OLT more difficult if it is needed. However, this has not been confirmed in more recent studies [
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ,
      • Segev D.L.
      • Nguyen G.C.
      • Locke J.E.
      • Simpkins C.E.
      • Montgomery R.A.
      • Maley W.R.
      • et al.
      Twenty years of liver transplantation for Budd-Chiari syndrome: a national registry analysis.
      ]. BCS recurrence may occur after OLT. The incidence of this complication has markedly dropped since the initiation of early anticoagulation treatment after OLT and its lifelong maintenance. An exception for the need for anticoagulation could be in those patients whom the prothrombotic disorder is corrected by OLT (e.g. most inherited thrombophilia). The natural history of MPN must also be considered in the post-transplant course.
      There are patients with severe BCS who may benefit from being treated directly with OLT, without previous use of TIPS. However, up until now there is no reliable method to identify such patients [
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ,
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ].

      Budd-Chiari and pregnancy

      Pregnancy in patients with BCS has an excellent maternal outcome provided patients have a well controlled disease. Fetal outcome is less favourable but it has been reported that pregnancies reaching week 20 of gestation are associated with an acceptable fetal prognosis even when 76% had preterm delivery [
      • Rautou P.E.
      • Angermayr B.
      • Garcia-Pagan J.C.
      • Moucari R.
      • Peck-Radosavljevic M.
      • Raffa S.
      • et al.
      Pregnancy in women with known and treated Budd-Chiari syndrome: maternal and fetal outcomes.
      ]. VKA are associated with a high risk of miscarriage and congenital malformations [
      • Perarnau J.M.
      • Bacq Y.
      Hepatic vascular involvement related to pregnancy, oral contraceptives, and estrogen replacement therapy.
      ]. Therefore, a pregnancy test must be done as early as possible, if positive mothers should switch to LMWH [
      • Bates S.M.
      • Greer I.A.
      • Pabinger I.
      • Sofaer S.
      • Hirsh J.
      Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      ] with periodic monitoring of anti-Xa activity.

      Prognosis

      There have been various attempts to determine parameters or combinations of parameters that may predict prognosis in BCS patients [
      • Seijo S.
      • Plessier A.
      • Hoekstra J.
      • Dell’Era A.
      • Mandair D.
      • Rifai K.
      • et al.
      Good long-term outcome of Budd-Chiari syndrome with a step-wise management.
      ,
      • Zeitoun G.
      • Escolano S.
      • Hadengue A.
      • Azar N.
      • El Younsi M.
      • Mallet A.
      • et al.
      Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting.
      ,
      • Garcia-Pagan J.C.
      • Heydtmann M.
      • Raffa S.
      • Plessier A.
      • Murad S.
      • Fabris F.
      • et al.
      TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.
      ,
      • Murad S.D.
      • Valla D.C.
      • de Groen P.C.
      • Zeitoun G.
      • Hopmans J.A.
      • Haagsma E.B.
      • et al.
      Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome.
      ]. Although all of these prognostic indices are valid for the assessment of transplant-free survival and invasive therapy-free survival, their predictive accuracy is suboptimal for use in individual patients in day to day clinical practice [
      • Rautou P.E.
      • Moucari R.
      • Escolano S.
      • Cazals-Hatem D.
      • Denie C.
      • Chagneau-Derrode C.
      • et al.
      Prognostic indices for Budd-Chiari syndrome: valid for clinical studies but insufficient for individual management.
      ]. Development of HCC or progression of the haematological disease may modify prognosis of BCS.
      Figure thumbnail fx8

      Acute portal vein thrombosis (non-cirrhotic, non-malignant)

      Definition and scope

      Acute PVT is defined as a recent formation of a thrombus within the portal vein and/or right or left branches. The thrombus may extend into the mesenteric or splenic veins; occlusion may be complete or partial. We will limit the discussion to acute PVT occurring in the absence of malignancy and cirrhosis [
      • DeLeve L.D.
      • Valla D.C.
      • Garcia-Tsao G.
      Vascular disorders of the liver.
      ,
      • de Franchis R.
      Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ]. Acute PVT may also occur in patients with long-standing obstruction of portions of the portal venous system [
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ].

      Manifestations

      According to prospective [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ] and retrospective studies [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Turnes J.
      • Garcia-Pagan J.C.
      • Gonzalez M.
      • Aracil C.
      • Calleja J.L.
      • Ripoll C.
      • et al.
      Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation.
      ,
      • Condat B.
      • Pessione F.
      • Helene D.M.
      • Hillaire S.
      • Valla D.
      Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.
      ], acute abdominal pain is present in 90% of acute PVT patients. A systemic inflammatory response syndrome is present in 85% of patients diagnosed with acute PVT which contrasts with local or systemic infection being present in only 20% of these patients. A significant number of patients only have mild non-specific symptoms so that the diagnosis is overlooked and PVT is recognised only at the stage of cavernomatous transformation. Liver tests generally show no, or only mildly and transient abnormalities. Ascites is present in 50% of patients; in most patients only visible on imaging [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. Due to improved awareness and availability of sensitive non-invasive imaging, diagnosis of portal venous obstruction is now made in 50 to 70% of cases at the stage of acute PVT [
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Condat B.
      • Pessione F.
      • Helene D.M.
      • Hillaire S.
      • Valla D.
      Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.
      ].

      Course and outcome

      Intestinal infarction is the most concerning immediate complication of acute porto-mesenteric vein thrombosis, with a related mortality of up to 60%. Extensive bowel resection may be necessary with a risk of short bowel syndrome [
      • Acosta S.
      • Alhadad A.
      • Svensson P.
      • Ekberg O.
      Epidemiology, risk and prognostic factors in mesenteric venous thrombosis.
      ,
      • Clavien P.A.
      • Durig M.
      • Harder F.
      Venous mesenteric infarction: a particular entity.
      ,
      • Clavien P.A.
      • Harder F.
      Mesenteric venous thrombosis. An 18-year retrospective study.
      ,
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      ]. The incidence of intestinal infarction has currently declined to 2–20% in patients treated with anticoagulation [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. In patients not receiving anticoagulation therapy, spontaneous recanalisation of symptomatic PVT appears to be exceptional [
      • Hall T.C.
      • Garcea G.
      • Metcalfe M.
      • Bilku D.
      • Dennison A.R.
      Management of acute non-cirrhotic and non-malignant portal vein thrombosis: a systematic review.
      ].
      Recognising venous mesenteric infarction is difficult as clinical, biological and radiological manifestations are non-specific. Persisting severe abdominal pain despite adequate anticoagulation, organ failure (shock, renal failure, metabolic acidosis, elevated arterial lactates), massive ascites and rectal bleeding all appear to be suggestive of infarction [
      • Acosta S.
      • Alhadad A.
      • Svensson P.
      • Ekberg O.
      Epidemiology, risk and prognostic factors in mesenteric venous thrombosis.
      ,
      • Clavien P.A.
      • Durig M.
      • Harder F.
      Venous mesenteric infarction: a particular entity.
      ,
      • Clavien P.A.
      • Harder F.
      Mesenteric venous thrombosis. An 18-year retrospective study.
      ,
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      ]. In a recent study, diabetes was the only factor independently associated with intestinal resection [
      • Elkrief L.
      • Corcos O.
      • Bruno O.
      • Larroque B.
      • Rautou P.E.
      • Zekrini K.
      • et al.
      Type 2 diabetes mellitus as a risk factor for intestinal resection in patients with superior mesenteric vein thrombosis.
      ].

      Diagnosis

      Doppler ultrasound is usually the first imaging procedure performed in the context of abdominal pain. It may detect an absence of flow within the portal vein. The presence of a hyperechoic thrombus in the portal lumen may be lacking [
      • Plessier A.
      • Rautou P.E.
      • Valla D.C.
      Management of hepatic vascular diseases.
      ,
      • Senzolo M.
      • Riggio O.
      • Primignani M.
      Vascular disorders of the liver: recommendations from the Italian Association for the Study of the Liver (AISF) ad hoc committee.
      ]. Doppler ultrasound, and MR have a lower sensitivity than CT imaging. Doppler ultrasound is dependent on the expertise and awareness of the operator [
      • Plessier A.
      • Rautou P.E.
      • Valla D.C.
      Management of hepatic vascular diseases.
      ,
      • Senzolo M.
      • Riggio O.
      • Primignani M.
      Vascular disorders of the liver: recommendations from the Italian Association for the Study of the Liver (AISF) ad hoc committee.
      ]. Diagnosis and extension of acute portal venous obstruction should be confirmed by contrast enhanced CT and/or MR imaging. Acquiring images at the correct time (portal phase) is mandatory in order to prevent pitfalls. Images acquired during the late arterial phase are not optimal for the diagnosis of PVT. Furthermore, in cases of low portal vein flow, a delayed arrival of contrast to the portal vein could be seen on CT, giving the appearance of a filling defect resulting in a false positive diagnosis of thrombosis [
      • Berzigotti A.
      • Garcia-Criado A.
      • Darnell A.
      • Garcia-Pagan J.C.
      Imaging in clinical decision-making for portal vein thrombosis.
      ].
      Portal phase CT scan shows the absence of visible lumen corresponding to the portal vein clot; CT scan provides additional information regarding the extent of the thrombus to the mesenteric veins and arches, the presence of a local factor, or of congestion and ischemia of the bowel. Distal thrombosis (occlusion of second order radicals of superior mesenteric vein), anomalies of the bowel (homogeneous or heterogeneous hypoattenuating or hyperattenuating wall thickening, dilatation, abnormal or absent wall enhancement) or of the mesentery, mesenteric stranding, large ascites, pneumatosis, and portal venous gas are more frequently observed in patients who will need intestinal resection [
      • Elkrief L.
      • Corcos O.
      • Bruno O.
      • Larroque B.
      • Rautou P.E.
      • Zekrini K.
      • et al.
      Type 2 diabetes mellitus as a risk factor for intestinal resection in patients with superior mesenteric vein thrombosis.
      ].
      Studies addressing the duration of PVT are scarce. A recent thrombus can be defined as a thrombus occurring in the setting of abdominal pain and or systemic inflammatory response syndrome. A spontaneous hyperdense clot in the portal vein lumen on a non-enhanced CT scan may suggest that the thrombus dates back to less than 30 days after onset of symptoms [
      • Plessier A.
      • Rautou P.E.
      • Valla D.C.
      Management of hepatic vascular diseases.
      ]. Absence of portal cavernoma is also of help, although cavernoma may not develop in unilateral portal branch obstruction. A cavernoma may be identified as early as 15 to 30 days after the apparent onset of abdominal pain [
      • Plessier A.
      • Rautou P.E.
      • Valla D.C.
      Management of hepatic vascular diseases.
      ]. Furthermore, acute thrombosis may superimpose on a long-standing cavernoma.
      Underlying prothrombotic disorders and local factors are common in adults. These disorders constitute major determinants of outcome, and may require specific therapy (see section 1). In children, aetiological investigations have been negative or only show common weak prothrombotic conditions [
      • Ferri P.M.
      • Rodrigues F.A.
      • Fagundes E.D.
      • Xavier S.G.
      • Dias R.D.
      • Fernandes A.P.
      • et al.
      Evaluation of the presence of hereditary and acquired thrombophilias in Brazilian children and adolescents with diagnoses of portal vein thrombosis.
      ].

      Therapy

      The aim of therapy for acute PVT is; i) to prevent the extension of thrombosis to mesenteric veins and thereby, mesenteric venous infarction; and ii) to achieve portal vein recanalisation (Fig. 2) [
      • Plessier A.
      • Rautou P.E.
      • Valla D.C.
      Management of hepatic vascular diseases.
      ,
      • Senzolo M.
      • Riggio O.
      • Primignani M.
      Vascular disorders of the liver: recommendations from the Italian Association for the Study of the Liver (AISF) ad hoc committee.
      ].
      Figure thumbnail gr2
      Fig. 2Proposed algorithm for the management of acute portal vein thrombosis.

      Anticoagulation

      In a recent prospective study, thrombus extension was prevented in all patients who had early initiation of anticoagulation therapy [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. Only 2/95 cases of limited intestinal infarction were observed, although 60% of patients had initial involvement of the superior mesenteric vein. Furthermore, recanalisation of the portal, splenic and superior mesenteric veins was obtained in 39%, 80%, and 73% of anticoagulated patients, respectively. Recanalisation of the portal vein did not occur in any of the patients beyond the sixth month of anticoagulation treatment. These findings independently validated retrospective single centre studies [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Turnes J.
      • Garcia-Pagan J.C.
      • Gonzalez M.
      • Aracil C.
      • Calleja J.L.
      • Ripoll C.
      • et al.
      Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation.
      ,
      • Condat B.
      • Pessione F.
      • Helene D.M.
      • Hillaire S.
      • Valla D.
      Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.
      ]. Bleeding while on anticoagulation occurred in 9% of patients. Mortality rate was 2% and was not related to bleeding or PVT [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. Among baseline factors, splenic vein obstruction and ascites [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ] and delay in initiating anticoagulation [
      • Turnes J.
      • Garcia-Pagan J.C.
      • Gonzalez M.
      • Aracil C.
      • Calleja J.L.
      • Ripoll C.
      • et al.
      Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation.
      ] have been associated with the absence of recanalisation of the portal vein. These findings need further confirmation in other cohorts.
      In most previous studies, anticoagulation therapy was mainly based on unfractionated heparin or LMWH or derivatives at high so-called therapeutic doses. In the most recent prospective European study, unfractionated heparin and LMWHs have been used in 25% and 65% of patients, respectively [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. In most studies LMWH has been substituted for VKA targeting an INR between 2 and 3.
      Heparin-induced thrombocytopenia (HIT) has been found to occur in up to 20% of PVT patients treated with unfractionated heparin, a much higher rate compared to HIT in patients without PVT [
      • Randi M.L.
      • Tezza F.
      • Scapin M.
      • Duner E.
      • Scarparo P.
      • Scandellari R.
      • et al.
      Heparin-induced thrombocytopenia in patients with Philadelphia-negative myeloproliferative disorders and unusual splanchnic or cerebral vein thrombosis.
      ]. The incidence is probably lower in patients treated with LMWH.

      Thrombolysis

      The experience of local thrombolysis, either venous or arterial, has been reported in no more than 100 patients, mainly as case reports. The transhepatic route or transjugular routes have been used. The reported recanalisation rates have been similar to those achieved with anticoagulation alone. However, 50% of treated patients developed major procedure-related bleeding, with a fatal outcome in some [
      • Smalberg J.H.
      • Spaander M.V.
      • Jie K.S.
      • Pattynama P.M.
      • van Buuren H.R.
      • van den B.B.
      • et al.
      Risks and benefits of transcatheter thrombolytic therapy in patients with splanchnic venous thrombosis.
      ,
      • Ferro C.
      • Rossi U.G.
      • Bovio G.
      • Dahamane M.
      • Centanaro M.
      Transjugular intrahepatic portosystemic shunt, mechanical aspiration thrombectomy, and direct thrombolysis in the treatment of acute portal and superior mesenteric vein thrombosis.
      ,
      • Hollingshead M.
      • Burke C.T.
      • Mauro M.A.
      • Weeks S.M.
      • Dixon R.G.
      • Jaques P.F.
      Transcatheter thrombolytic therapy for acute mesenteric and portal vein thrombosis.
      ]. The transjugular approach for thrombolysis appears to be associated with reduced complications but the data remains limited to less than 30 treated patients [
      • Liu F.Y.
      • Wang M.Q.
      • Duan F.
      • Wang Z.J.
      • Song P.
      Interventional therapy for symptomatic-benign portal vein occlusion.
      ,
      • Wang M.Q.
      • Liu F.Y.
      • Duan F.
      • Wang Z.J.
      • Song P.
      • Fan Q.S.
      Acute symptomatic mesenteric venous thrombosis: treatment by catheter-directed thrombolysis with transjugular intrahepatic route.
      ]. With surgical thrombectomy, recanalisation is achieved in only 30% of the patients. It is associated with a high recurrence rate, when performed >30 days from apparent onset [
      • Malkowski P.
      • Pawlak J.
      • Michalowicz B.
      • Szczerban J.
      • Wroblewski T.
      • Leowska E.
      • et al.
      Thrombolytic treatment of portal thrombosis.
      ]. Recently it has been shown that balloon angioplasty and/or stent placement without thrombolysis or thrombectomy may be a safe and effective treatment modality for post-operative main portal vein and superior mesenteric vein thrombosis [
      • Cao G.
      • Ko G.Y.
      • Sung K.B.
      • Yoon H.K.
      • Gwon D.
      • Kim J.H.
      Treatment of postoperative main portal vein and superior mesenteric vein thrombosis with balloon angioplasty and/or stent placement.
      ]. As the long-term outcome of patients with chronic PVT is generally good (five-year survival rate above 70%) and mostly related to the associated conditions, the risk/benefit balance of such invasive procedures have to be considered [
      • Condat B.
      • Valla D.
      Non malignant portal vein thrombosis.
      ].

      Antibiotics

      When septic pylephlebitis is diagnosed, prolonged treatment with antibiotics adapted to isolated bacteria or to anaerobic digestive flora is necessary [
      • Chirinos J.A.
      • Garcia J.
      • Alcaide M.L.
      • Toledo G.
      • Baracco G.J.
      • Lichtstein D.M.
      Septic thrombophlebitis: diagnosis and management.
      ].

      Prognosis

      Recanalisation of the portal vein must be expected to occur up to 6 months whereas recanalisation of mesenteric and splenic veins steadily increase until 12 months follow-up [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ]. Over half of the patients (55%) not achieving recanalisation will develop gastroesophageal varices during their follow-up, with a two-year actual probability of variceal bleeding of 12% and 16% for ascites [
      • Turnes J.
      • Garcia-Pagan J.C.
      • Gonzalez M.
      • Aracil C.
      • Calleja J.L.
      • Ripoll C.
      • et al.
      Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation.
      ]. Severe portal biliopathy, detected during imaging studies, developed in 30% of patients with acute PVT within 1 year [
      • Llop E.
      • de Juan C.
      • Seijo S.
      • Garcia-Criado A.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Portal cholangiopathy: radiological classification and natural history.
      ].
      Figure thumbnail fx9

      Extrahepatic portal vein obstruction (non-cirrhotic, non-malignant)

      Extrahepatic portal vein obstruction (EHPVO) occurs due to the three following mechanisms: malignant invasion (frequently but improperly referred to as malignant thrombosis), portal vein narrowing within a malignant tumor, and thrombosis. Malignant invasion and portal vein narrowing will not be discussed further in this section. Following acute thrombosis, in the absence of recanalisation, the portal venous lumen obliterates and porto-portal collaterals develop. This process is called cavernomatous transformation of the portal vein, the result of which is the portal cavernoma, which fully develops in a couple of months after acute thrombosis. Chronic PVT has been used to designate the latter condition although these terms are not as factual as cavernoma or cavernomatous transformation. There is a debate as to whether portal cavernoma may result from other mechanisms than thrombosis. In children, aetiological investigation has been negative or has shown only weak common prothrombotic conditions [
      • Abd El-Hamid N.
      • Taylor R.M.
      • Marinello D.
      • Mufti G.J.
      • Patel R.
      • Mieli-Vergani G.
      • et al.
      ]. When a cavernoma is found in infancy or childhood in the absence of local or general factors for thrombosis, the hypothesis of a congenital malformation cannot be ruled out although evidence for this hypothesis is still poor [
      • Abd El-Hamid N.
      • Taylor R.M.
      • Marinello D.
      • Mufti G.J.
      • Patel R.
      • Mieli-Vergani G.
      • et al.
      ].

      Manifestations

      Available data in patients with non-cirrhotic non-malignant EHPVO come from short-term prospective studies following acute thrombosis [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ], or from retrospective cohort studies where patients have received various forms of treatment [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ]. Due to the improved sensitivity of non-invasive imaging, diagnosis of EHPVO is increasingly being made at an early stage of acute PVT [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ]. Among features of PH, gastrointestinal bleeding has become a rare mode of presentation, by contrast with frequent fortuitous findings of an enlarged spleen, reduced blood cell counts, gastroesophageal varices or portal hypertensive gastropathy, or portosystemic collaterals at abdominal imaging [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ]. The severity of portal hypertension typically contrasts with a mild or absent liver dysfunction and with normal levels of transaminases, alkaline phosphatase, and gamma-glutamyl transferase. Some patients may experience post-prandial abdominal pain, or features of incomplete bowel obstruction related to ischemic stenosis. Less frequently, initial manifestations are with biliary symptoms (biliary pain, pancreatitis, cholecystitis) related to portal cholangiopathy, a condition characterized by compression and deformation of intra- and extrahepatic bile ducts by the collateral veins constituting the cavernoma. Progressive cholestatic disease or recurrent bacterial cholangitis are rare in patients with portal cholangiopathy [
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ].

      Outcome

      The most frequent complication is gastrointestinal bleeding related to PH [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ], followed by recurrent thrombosis (mostly in the splanchnic area) [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ] and more rarely, biliary complications [
      • Dhiman R.K.
      • Behera A.
      • Chawla Y.K.
      • Dilawari J.B.
      • Suri S.
      Portal hypertensive biliopathy.
      ]. Asymptomatic recurrent thrombosis in the splanchnic area is underestimated and its actual clinical significance requires further evaluation. Ascites, bacterial infections and overt encephalopathy are uncommon except following an episode of gastrointestinal bleeding [
      • Rangari M.
      • Gupta R.
      • Jain M.
      • Malhotra V.
      • Sarin S.K.
      Hepatic dysfunction in patients with extrahepatic portal venous obstruction.
      ]. Subclinical encephalopathy appears to be much more common than previously suspected [
      • Minguez B.
      • Garcia-Pagan J.C.
      • Bosch J.
      • Turnes J.
      • Alonso J.
      • Rovira A.
      • et al.
      Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy.
      ]. In children, a specific additional consequence appears to be growth failure [
      • Lautz T.B.
      • Sundaram S.S.
      • Whitington P.F.
      • Keys L.
      • Superina R.A.
      Growth impairment in children with extrahepatic portal vein obstruction is improved by mesenterico-left portal vein bypass.
      ]. Regenerative macronodules may develop but HCC has not been reported yet [
      • Marin D.
      • Galluzzo A.
      • Plessier A.
      • Brancatelli G.
      • Valla D.
      • Vilgrain V.
      Focal nodular hyperplasia-like lesions in patients with cavernous transformation of the portal vein: prevalence, MR findings and natural history.
      ]. Previous gastrointestinal bleeding and size of esophageal varices have been identified as independent predictors for gastrointestinal bleeding [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ]; the presence of an underlying prothrombotic condition as a predictor for recurrent thrombosis [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ]; dilated segments of the bile ducts, for clinical biliary complications [
      • Llop E.
      • de Juan C.
      • Seijo S.
      • Garcia-Criado A.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Portal cholangiopathy: radiological classification and natural history.
      ]; and age, ascites, extension to the superior mesenteric vein and severity of underlying conditions as predictors for death [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ].

      Diagnosis

      The diagnosis of EHPVO should be considered in patients with features of PH or hypersplenism; in patients affected with a condition associated with a risk for PVT (general: MPN antiphospholipid syndrome, inherited thrombophilic factors, or local: pancreatitis, diverticulitis, inflammatory bowel disease); in patients with abdominal pain; and in patients with biliary disease. Rarely, the diagnosis has to be considered in a context resembling decompensated cirrhosis (encephalopathy, and/or ascites, and/or bacterial infection).
      A diagnosis of EHPVO is based on the findings of Doppler ultrasound, and axial CT or MR imaging using vascular contrast agents. The experience and awareness of the radiologist is crucial. Essential features are; (a) the absence of visible lumen corresponding to the portal vein; and (b) the presence of numerous, serpiginous vascular channels in porta hepatis [
      • Bradbury M.S.
      • Kavanagh P.V.
      • Chen M.Y.
      • Weber T.M.
      • Bechtold R.E.
      Noninvasive assessment of portomesenteric venous thrombosis: current concepts and imaging strategies.
      ,
      • Ueno N.
      • Sasaki A.
      • Tomiyama T.
      • Tano S.
      • Kimura K.
      Color Doppler ultrasonography in the diagnosis of cavernous transformation of the portal vein.
      ]. Other less specific features may provide indirect clues for an obstructed portal vein: a dysmorphic liver where segment 1 and segment 4 are enlarged but surface is smooth; a mosaic pattern of parenchymal enhancement in the arterial phase, with homogeneous enhancement at a later phase; an increased enhancement of the peripheral parts of the liver at the arterial phase; a dilated hepatic artery; and a mild irregular dilatation of the bile ducts [
      • Vilgrain V.
      • Condat B.
      • Bureau C.
      • Hakime A.
      • Plessier A.
      • Cazals-Hatem D.
      • et al.
      Atrophy-hypertrophy complex in patients with cavernous transformation of the portal vein: CT evaluation.
      ]. A thickened gallbladder wall due to collateral veins should be differentiated from cholecystitis. A thickened heterogenous pancreas due to collateral veins should be differentiated from pancreatic cancer and chronic pancreatitis. In cases of pure portal vein obstruction, liver biopsy shows an essentially normal liver. However, a cavernomatous transformation of the portal vein can be superimposed on cirrhosis or obliterative portal venopathy where diagnosis requires a liver biopsy [
      • Plessier A.
      • Darwish M.S.
      • Hernandez-Guerra M.
      • Consigny Y.
      • Fabris F.
      • Trebicka J.
      • et al.
      Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ]. Liver biopsy in EHPVO is indicated in patients with persistently abnormal liver tests or a dysmorphic liver whose aspect is not typical for extrahepatic venous obstruction as described above. Non-invasive tests like elastometry would be most useful in recognising underlying liver disease [
      • Seijo S.
      • Reverter E.
      • Miquel R.
      • Berzigotti A.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension.
      ].
      Underlying prothrombotic disorders and local factors are common in adults. These disorders constitute major determinants of outcome, and may require specific therapy (Fig. 3).
      Figure thumbnail gr3
      Fig. 3Proposed algorithm for making a decision of permanent anticoagulation in patients with chronic extrahepatic portal vein obstruction. *Assessment based on personal and familial history of unprovoked deep vein thrombosis, and on findings of isolated or combined prothrombotic conditions.

      Therapy

      Prevention of thrombotic extension or recurrence

      The effect of specific treatments for underlying conditions has not been evaluated. Evidence for a favourable benefit/risk ratio of anticoagulation is low as no prospective study has ever been performed. In three retrospective cohort studies on non-cirrhotic PVT patients, long-term anticoagulation has been associated with a reduced risk of recurrent thrombosis. In a multivariate analysis it was found to be an independent factor in one study (risk ratio 0.39, p = 0.02) [
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ] and borderline in the other (hazard ratio 0.2, p = 0.1) [
      • Spaander M.C.
      • Hoekstra J.
      • Hansen B.E.
      • van Buuren H.R.
      • Leebeek F.W.
      • Janssen H.L.
      Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.
      ]. Prevention of rethrombosis was also observed at univariate analysis in a large cohort of patients whose initial presentation was with abdominal pain or intestinal ischemia [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ]. When evaluated in patients with EHPVO receiving anticoagulation, the risk of recurrent bleeding has not been shown to be increased in the context where prophylaxis for bleeding has been routinely performed [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ]. In another study where the strategy for bleeding prophylaxis has not been evaluated, anticoagulation therapy was significantly associated with an increased risk of bleeding [
      • Spaander M.C.
      • Hoekstra J.
      • Hansen B.E.
      • van Buuren H.R.
      • Leebeek F.W.
      • Janssen H.L.
      Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.
      ]. The severity of bleeding on anticoagulation has been found to be similar in patients with and without anticoagulation at the time of bleeding [
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ]. Multivariate analysis indicated a favourable impact of anticoagulation therapy on survival with a statistically significant decrease in mortality in one study [
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ], and a non-significant decrease in the other [
      • Spaander M.C.
      • Hoekstra J.
      • Hansen B.E.
      • van Buuren H.R.
      • Leebeek F.W.
      • Janssen H.L.
      Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.
      ]. Extrapolation of these data collected between 1983–1998 [
      • Hall T.C.
      • Garcea G.
      • Metcalfe M.
      • Bilku D.
      • Dennison A.R.
      Management of acute non-cirrhotic and non-malignant portal vein thrombosis: a systematic review.
      ], 1973–2005 [
      • Elkrief L.
      • Corcos O.
      • Bruno O.
      • Larroque B.
      • Rautou P.E.
      • Zekrini K.
      • et al.
      Type 2 diabetes mellitus as a risk factor for intestinal resection in patients with superior mesenteric vein thrombosis.
      ] and 1985–2009 [
      • Spaander M.C.
      • Hoekstra J.
      • Hansen B.E.
      • van Buuren H.R.
      • Leebeek F.W.
      • Janssen H.L.
      Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.
      ] requires caution.

      Prevention of the complications of EHPVO

      In most available surveys, patients have been treated for portal hypertension according to the recommendations for patients with cirrhosis. Hemodynamic data in animals with pre-hepatic PH [
      • Koshy A.
      • Girod C.
      • Lee S.S.
      • Hadengue A.
      • Cerini R.
      • Lebrec D.
      Discrepancy between portal pressure and systemic hemodynamic changes after incremental doses of propranolol in awake portal hypertensive rats.
      ] and in patients with non-cirrhotic portal hypertension [
      • Braillon A.
      • Moreau R.
      • Hadengue A.
      • Roulot D.
      • Sayegh R.
      • Lebrec D.
      Hyperkinetic circulatory syndrome in patients with presinusoidal portal hypertension. Effect of propranolol.
      ] indicate beneficial effects of non-selective beta adrenergic blockade on splanchnic haemodynamics. Theoretical deleterious effects of non-selective beta blockers on patients with extended thrombosis promoting abdominal pain or intestinal ischemia have never been proved.
      According to multivariate analysis, beta adrenergic blockade decreases the risk of bleeding in patients with large varices [
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ], and improves survival in patients with chronic portomesenteric venous obstruction [
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ]. Sclerotherapy reduces the incidence of bleeding in previously untreated patients. Endoscopic variceal band ligation is superior to sclerotherapy according to a short-term randomized controlled trial in children [
      • Zargar S.A.
      • Javid G.
      • Khan B.A.
      • Yattoo G.N.
      • Shah A.H.
      • Gulzar G.M.
      • et al.
      Endoscopic ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic portal venous obstruction.
      ]. In children, combination of ligation and sclerotherapy provides marginal advantage to either band ligation alone or sclerotherapy alone. In adults, by two years of follow-up, there was no difference in the rate of recurrent bleeding between treatment with propranolol or with band ligation for non-cirrhotic portal hypertension (including a majority of patients with EHPVO) [
      • Sarin S.K.
      • Gupta N.
      • Jha S.K.
      • Agrawal A.
      • Mishra S.R.
      • Sharma B.C.
      • et al.
      Equal efficacy of endoscopic variceal ligation and propranolol in preventing variceal bleeding in patients with noncirrhotic portal hypertension.
      ]. In the latter study, none of the patients were receiving anticoagulation. Rebleeding rate was about 20% at two years.
      In selected patients, low mortality and rebleeding rates have been observed with surgical portosystemic shunting using superior mesenteric or splenic veins [
      • Orloff M.J.
      • Orloff M.S.
      • Girard B.
      • Orloff S.L.
      Bleeding esophagogastric varices from extrahepatic portal hypertension: 40 years’ experience with portal-systemic shunt.
      ]. However, the proportion of patients where these shunts are feasible remains unclear. The data with TIPS are still extremely limited in patients without cirrhosis or malignancy. While covered TIPS insertion appears to be feasible when intrahepatic portal veins are visible, results are available only on a short-term follow-up (average 18 months) [
      • Fanelli F.
      • Angeloni S.
      • Salvatori F.M.
      • Marzano C.
      • Boatta E.
      • Merli M.
      • et al.
      Transjugular intrahepatic portosystemic shunt with expanded-polytetrafuoroethylene-covered stents in non-cirrhotic patients with portal cavernoma.
      ]. Encephalopathy appears to occur at a similar rate as in patients with cirrhosis.
      In children with patent superior mesenteric and left portal veins, a bypass can be constructed between these two veins (so-called mesenterico-Rex shunt). The feasibility and long-term patency appears to be high. Gastrointestinal bleeding is effectively prevented. An improvement in mental status and in coagulation factor levels as been observed [
      • Mack C.L.
      • Zelko F.A.
      • Lokar J.
      • Superina R.
      • Alonso E.M.
      • Blei A.T.
      • et al.
      Surgically restoring portal blood flow to the liver in children with primary extrahepatic portal vein thrombosis improves fluid neurocognitive ability.
      ,
      • Superina R.A.
      • Alonso E.M.
      Medical and surgical management of portal hypertension in children.
      ]. There is no report of adult patients treated with mesenterico-Rex shunt.
      Only patients with clinical manifestations of portal cholangiopathy should be considered for a specific treatment [
      • Dhiman R.K.
      • Behera A.
      • Chawla Y.K.
      • Dilawari J.B.
      • Suri S.
      Portal hypertensive biliopathy.
      ]. Bile stones should be treated endoscopically. Risk of endobiliary maneuvers is haemobilia from ruptured intrabiliary varices, which can be massive. Biliary stricture associated with jaundice or bile stones can also be treated endoscopically with repeated stenting. When superior mesenteric vein or splenic veins are evident a surgical shunt can be considered. Because of anecdotal reports of successful TIPS placement, such a procedure can also be considered although results beyond a few months of follow-up have not been reported [
      • Fanelli F.
      • Angeloni S.
      • Salvatori F.M.
      • Marzano C.
      • Boatta E.
      • Merli M.
      • et al.
      Transjugular intrahepatic portosystemic shunt with expanded-polytetrafuoroethylene-covered stents in non-cirrhotic patients with portal cavernoma.
      ,
      • Senzolo M.
      • Tibbals J.
      • Cholongitas E.
      • Triantos C.K.
      • Burroughs A.K.
      • Patch D.
      Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation.
      ].

      Overall outcome

      Overall outcome is relatively good in patients with extrahepatic PVT in the absence of cirrhosis or malignancy. Five-year survival rates above 70% have been reported in large cohorts spanning over the last 20 years [
      • Amitrano L.
      • Guardascione M.A.
      • Scaglione M.
      • Pezzullo L.
      • Sangiuliano N.
      • Armellino M.F.
      • et al.
      Prognostic factors in noncirrhotic patients with splanchnic vein thromboses.
      ,
      • Spaander M.C.
      • Hoekstra J.
      • Hansen B.E.
      • van Buuren H.R.
      • Leebeek F.W.
      • Janssen H.L.
      Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding.
      ,
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • Denninger M.H.
      • Guillin M.C.
      • Poliquin M.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      ,
      • Rajani R.
      • Bjornsson E.
      • Bergquist A.
      • Danielsson A.
      • Gustavsson A.
      • Grip O.
      • et al.
      The epidemiology and clinical features of portal vein thrombosis: a multicentre study.
      ,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • Karani J.B.
      • Kane P.A.
      • Heaton N.D.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      ]. No comparison with the general population is available.
      Figure thumbnail fx10

      Idiopathic non-cirrhotic portal hypertension

      Introduction

      Many disorders are associated with non-cirrhotic intrahepatic PH such as infiltrative diseases, vascular malignancies, schistosomiasis, congenital hepatic fibrosis and sarcoidosis [
      • Schouten J.N.
      • Garcia-Pagan J.C.
      • Valla D.C.
      • Janssen H.L.
      Idiopathic noncirrhotic portal hypertension.
      ]. The diagnosis of idiopathic non-cirrhotic portal hypertension (INCPH) can be made if all these disorders have been excluded and consequently no clear liver disease has been identified (Table 3). The nomenclature of this condition is ambiguous and it has been referred to as hepatoportal sclerosis, non-cirrhotic portal fibrosis, idiopathic PH, incomplete septal cirrhosis and nodular regenerative hyperplasia [
      • Nakanuma Y.
      • Hoso M.
      • Sasaki M.
      • Terada T.
      • Katayanagi K.
      • Nonomura A.
      • et al.
      Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology.
      ]. Agreement on a uniform nomenclature is an essential requirement. Since the focus of the current guideline is on vascular liver disease, we restrict our recommendations for INCPH which is thought to be caused largely by parenchymal vascular obstruction, while other forms of non-cirrhotic intrahepatic portal hypertension are associated with a large group of distinct liver diseases and presumably have less of a vascular etiology [
      • Schouten J.N.
      • Garcia-Pagan J.C.
      • Valla D.C.
      • Janssen H.L.
      Idiopathic noncirrhotic portal hypertension.
      ]. Thrombophilia, immunological disorders, specific medication (e.g. azathioprine and didanosine) and infections (e.g. HIV infection) have been identified as the major potential causes for portal venous obliteration [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ]. In Western INCPH patients, a 40% prevalence of thrombophilic disorders has been reported [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ].
      Table 3Diagnostic criteria of idiopathic non-cirrhotic portal hypertension.
      *All criteria must be fulfilled in order to diagnose INCPH. **Splenomegaly must be accompanied by additional signs of portal hypertension in order to fulfil this criterion. Chronic liver disease must be excluded since severe fibrosis might be understaged on liver biopsy.

      Clinical presentation

      Clinical presentation is dependent on referral patterns and on the medical specialist who makes the diagnosis (e.g. hepatologist vs. haematologist). In large studies from India the majority of patients present with gastrointestinal haemorrhage related to PH. This is most commonly due to esophageal varices, although gastric varices and portal hypertensive gastropathy can occur in a minority. Commonly, and more often than in other causes of PH (e.g. liver cirrhosis and PVT), a large spleen is observed in patients with INCPH [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Dhiman R.K.
      • Chawla Y.
      • Vasishta R.K.
      • Kakkar N.
      • Dilawari J.B.
      • Trehan M.S.
      • et al.
      Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature.
      ]. At initial diagnosis, patients present mainly with normal liver function [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ,
      • Dhiman R.K.
      • Chawla Y.
      • Vasishta R.K.
      • Kakkar N.
      • Dilawari J.B.
      • Trehan M.S.
      • et al.
      Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature.
      ]. Only a minority demonstrate impaired liver function, mainly in the context of intercurrent conditions. The presence of ascites may be associated with poor survival [
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ]. Hepatic encephalopathy has been rarely reported but can be found due to massive portosystemic shunting [
      • Krasinskas A.M.
      • Eghtesad B.
      • Kamath P.S.
      • Demetris A.J.
      • Abraham S.C.
      Liver transplantation for severe intrahepatic noncirrhotic portal hypertension.
      ].

      Diagnosis

      Diagnosis of INCPH remains a challenge because there is no single test that can be regarded as a gold standard. Patients with INCPH are often radiologically misclassified as cirrhotic since abdominal ultrasonography in these patients demonstrates liver surface nodularity and thickening of portal vein walls in combination with signs of PH [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ]. A clue for the correct non-invasive diagnosis of INCPH might be low liver stiffness measurement by transient elastography (<12 kPa) [
      • Seijo S.
      • Reverter E.
      • Miquel R.
      • Berzigotti A.
      • Abraldes J.G.
      • Bosch J.
      • et al.
      Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension.
      ,
      • Chang P.E.
      • Miquel R.
      • Blanco J.L.
      • Laguno M.
      • Bruguera M.
      • Abraldes J.G.
      • et al.
      Idiopathic portal hypertension in patients with HIV infection treated with highly active antiretroviral therapy.
      ]. A recent study demonstrated metabolomic analysis as a potential tool for the diagnosis of INCPH [
      • Seijo S.
      • Lozano J.J.
      • Alonso C.
      • Reverter E.
      • Miquel R.
      • Abraldes J.G.
      • et al.
      Metabolomics discloses potential biomarkers for the noninvasive diagnosis of idiopathic portal hypertension.
      ].
      In order to exclude severe fibrosis or cirrhosis, liver histology remains essential in the diagnosis of INCPH. Macroscopical examination often reveals organised thrombi in the large portal vein branches, liver surface nodularity, and liver dysmorphism [
      • Ibarrola C.
      • Colina F.
      Clinicopathological features of nine cases of non-cirrhotic portal hypertension: current definitions and criteria are inadequate.
      ]. In the past, INCPH has been classified morphologically into four different categories: idiopathic PH (equivalent to hepatoportal sclerosis or non-cirrhotic portal fibrosis), nodular regenerative hyperplasia, partial nodular transformation and incomplete septal cirrhosis [
      • Nakanuma Y.
      • Hoso M.
      • Sasaki M.
      • Terada T.
      • Katayanagi K.
      • Nonomura A.
      • et al.
      Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology.
      ]. However, since all these entities share histopathological characteristics (obliterative vascular lesions), it has been suggested that INCPH can be viewed as a distinct single entity with various pathological aspects, rather than different clinicopathological entities [
      • Schouten J.N.
      • Garcia-Pagan J.C.
      • Valla D.C.
      • Janssen H.L.
      Idiopathic noncirrhotic portal hypertension.
      ]. The most prevalent histological features observed in INCPH patients are phlebosclerosis, nodular regeneration, sinusoidal dilatation, paraportal shunt vessels and perisinusoidal fibrosis [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ,
      • Verheij J.
      • Schouten J.N.
      • Komuta M.
      • Nevens F.
      • Hansen B.E.
      • Janssen H.L.
      • et al.
      Histological features in western patients with idiopathic non-cirrhotic portal hypertension.
      ]. Phlebosclerosis is generally regarded as the primary lesion in the development of the intrahepatic haemodynamic changes [
      • Wanless I.R.
      Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.
      ]. Potentially this obliteration of portal venules results in disturbed intrahepatic circulation and subsequently parenchymal remodeling (nodular regeneration). In order to demonstrate the presence of these lesions, large liver specimens containing a sufficient amount of portal tracts are needed (transjugular specimens often are too small). Nevertheless, a sufficient specimen size can show normal liver histology in liver biopsies from INCPH patients.

      Natural history

      Mortality by variceal haemorrhage in INCPH is significantly lower than that observed in cirrhotic patients, likely because of a preserved liver function [
      • Schouten J.N.
      • Garcia-Pagan J.C.
      • Valla D.C.
      • Janssen H.L.
      Idiopathic noncirrhotic portal hypertension.
      ]. In comparison to patients with cirrhosis a higher incidence of PVT has been reported in patients with INCPH [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ,
      • Siramolpiwat S.
      • Seijo S.
      • Miquel R.
      • Berzigotti A.
      • Garcia-Criado A.
      • Darnell A.
      • et al.
      Idiopathic portal hypertension: Natural history and long-term outcome.
      ]. Starting early anticoagulation therapy leads to recanalisation in 54% of patients [
      • Siramolpiwat S.
      • Seijo S.
      • Miquel R.
      • Berzigotti A.
      • Garcia-Criado A.
      • Darnell A.
      • et al.
      Idiopathic portal hypertension: Natural history and long-term outcome.
      ]. A minority of patients develop liver failure over time, which might even necessitate a liver transplantation [
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ,
      • Krasinskas A.M.
      • Eghtesad B.
      • Kamath P.S.
      • Demetris A.J.
      • Abraham S.C.
      Liver transplantation for severe intrahepatic noncirrhotic portal hypertension.
      ]. A poor outcome can be implicated by a precipitating factor or an additional cause for liver damage [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ]. Liver function impairment and ascites in these patients can possibly be explained by a reduction in portal flow and subsequently atrophy of the peripheral hepatic parenchyma. Despite low liver-related mortality, overall survival in INCPH patients is lower than generally considered as a result of high mortality related to INCPH associated disorders [
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ].

      Treatment

      Treatment and prophylaxis of variceal gastrointestinal bleeding

      Data on the management or prophylaxis of variceal bleeding and INCPH are lacking [
      • Schouten J.N.
      • Garcia-Pagan J.C.
      • Valla D.C.
      • Janssen H.L.
      Idiopathic noncirrhotic portal hypertension.
      ]. Endoscopic therapy has been found to be effective in controlling acute variceal bleeding in 95% of the INCPH patients [
      • Chawla Y.K.
      • Dilawari J.B.
      • Dhiman R.K.
      • Goenka M.K.
      • Bhasin D.K.
      • Kochhar R.
      • et al.
      Sclerotherapy in noncirrhotic portal fibrosis.
      ]. No data has yet been published regarding endoscopic band ligation in these patients. However, considering the superiority of ligation in patients with cirrhosis or EHPVO, applying this treatment in INCPH patients with varices is preferable. With uncontrolled bleeding, portal systemic shunting by insertion of TIPS should be considered. Although there is literature from India on emergency surgical shunting, this is currently not regarded to be superior to TIPS insertion, which is less invasive. Complications of portosystemic shunting such as hepatic encephalopathy are rare due to the preserved liver function in most of the patients [
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ]. Endoscopic therapy has been shown to reduce the risk of variceal rebleeding in patients with INCPH [
      • Bhargava D.K.
      • Dasarathy S.
      • Sundaram K.R.
      • Ahuja R.K.
      Efficacy of endoscopic sclerotherapy on long-term management of oesophageal varices: a comparative study of results in patients with cirrhosis of the liver, non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHO).
      ]. Data are lacking regarding the efficacy of non-selective beta blockers in the setting of INCPH, however in keeping with the good results of bleeding prophylaxis in the setting of cirrhosis we recommend to use the same approach in INCPH patients.

      Anticoagulation

      Anticoagulation therapy has been proposed by several investigators to prevent disease progression and to maintain portal vein patency [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schiano T.D.
      • Kotler D.P.
      • Ferran E.
      • Fiel M.I.
      Hepatoportal sclerosis as a cause of noncirrhotic portal hypertension in patients with HIV.
      ]. However, considering the fact that gastrointestinal bleeding is the main complication and the role of thrombophilia in the pathogenesis is uncertain, this treatment is still debated and cannot be generally recommended. Anticoagulation can only be considered in patients with INCPH with clear underlying prothrombotic conditions or in patients who develop PVT.

      Liver transplantation

      Several reports describe liver transplantation in the setting of INCPH [
      • Hillaire S.
      • Bonte E.
      • Denninger M.H.
      • Casadevall N.
      • Cadranel J.F.
      • Lebrec D.
      • et al.
      Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.
      ,
      • Schouten J.N.
      • Nevens F.
      • Hansen B.
      • Laleman W.
      • van den B.M.
      • Komuta M.
      • et al.
      Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.
      ,
      • Krasinskas A.M.
      • Eghtesad B.
      • Kamath P.S.
      • Demetris A.J.
      • Abraham S.C.
      Liver transplantation for severe intrahepatic noncirrhotic portal hypertension.
      ]. The indications for liver transplantation are unmanageable PH-related complications and progressive liver failure.
      Figure thumbnail fx11

      Hepatic vascular malformations in hereditary haemorrhagic telangiectasia

      Definition

      Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease, is a genetic disorder with autosomal dominant inheritance, characterized by widespread cutaneous, mucosal and visceral telangiectasias and is reported to affect 1–2/10,000 people in the general population [
      • Govani F.S.
      • Shovlin C.L.
      Hereditary haemorrhagic telangiectasia: a clinical and scientific review.
      ]. The clinical presentation of HHT varies widely based on the number, type and location of the telangiectasias or larger vascular malformations (VMs). The clinical criteria for HHT diagnosis, known as the Curaçao criteria, have been established by a panel of experts (Table 4): the diagnosis of HHT is certain with three criteria, likely with two, and unlikely with one or no criteria [
      • Shovlin C.L.
      • Guttmacher A.E.
      • Buscarini E.
      • Faughnan M.E.
      • Hyland R.H.
      • Westermann C.J.
      • et al.
      Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).
      ]. Most patients have mutations in one of the two known disease-related genes: endoglin (ENG, on chromosome 9, HHT1) and activin A receptor type II-like 1 (ACVRL1, on chromosome 12, HHT2), both of which are involved in the TGFβ pathway. Mutations in the SMAD4 gene can cause a rare syndrome combining juvenile polyposis and HHT; recently additional genes have been found on chromosome 5 and 7 [
      • Govani F.S.
      • Shovlin C.L.
      Hereditary haemorrhagic telangiectasia: a clinical and scientific review.
      ]. Genetic testing is available on a clinical basis.
      Table 4Diagnostic criteria of HHT – Doppler ultrasound grading of liver VMs.

      Hepatic VMs in HHT

      Hepatic VMs are found in 44–74% of HHT-affected subjects [
      • Buscarini E.
      • Leandro G.
      • Conte D.
      • Danesino C.
      • Daina E.
      • Manfredi G.
      • et al.
      Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia.
      ,
      • Memeo M.
      • Stabile Ianora A.A.
      • Scardapane A.
      • Suppressa P.
      • Cirulli A.
      • Sabba C.
      • et al.
      Hereditary haemorrhagic telangiectasia: study of hepatic vascular alterations with multi-detector row helical CT and reconstruction programs.
      ], implying a prevalence in the general (non-HHT) population varying between 1/7000 to 1/12,500. The prevalence of hepatic VMs depends substantially on HHT genotype, with greater frequency of hepatic VMs in HHT2 genotype than in HHT1 genotype [
      • Lesca G.
      • Olivieri C.
      • Burnichon N.
      • Pagella F.
      • Carette M.F.
      • Gilbert-Dussardier B.
      • et al.
      Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.
      ,
      • Letteboer T.G.
      • Mager H.J.
      • Snijder R.J.
      • Lindhout D.
      • Ploos van Amstel H.K.
      • Zanen P.
      • et al.
      Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia.
      ]. The penetrance of most of the clinical features of HHT depends on the patient’s age, with a mean age of patients with hepatic VMs of 52 years [
      • Buscarini E.
      • Danesino C.
      • Olivieri C.
      • Lupinacci G.
      • De G.F.
      • Reduzzi L.
      • et al.
      Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.
      ]. Previous data shows a strong and significant predominance of hepatic VMs in females who have HHT, both for asymptomatic and symptomatic lesions, with a male/female ratio varying from 1:2 to 1:4.5; therefore, the expression of HHT in the liver is likely dependent on the patient’s sex [
      • Buscarini E.
      • Leandro G.
      • Conte D.
      • Danesino C.
      • Daina E.
      • Manfredi G.
      • et al.
      Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia.
      ,
      • Lesca G.
      • Olivieri C.
      • Burnichon N.
      • Pagella F.
      • Carette M.F.
      • Gilbert-Dussardier B.
      • et al.
      Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.
      ].

      Pathogenesis

      Hepatic VMs unique to HHT involve the liver diffusely and evolve in a continuum from small telangiectases to large arteriovenous malformations, 21% of patients show an increased size of liver VMs and complexity over a median follow-up of 44 months [
      • Buscarini E.
      • Leandro G.
      • Conte D.
      • Danesino C.
      • Daina E.
      • Manfredi G.
      • et al.
      Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia.
      ].
      Three different and often concomitant types of intrahepatic shunting (hepatic artery to portal vein, hepatic artery to hepatic vein and/or portal vein to hepatic vein) can lead to different but possibly coexistent clinical features: high-output cardiac failure (HOCF), PH, encephalopathy, biliary ischemia, and mesenteric ischemia, the latter two being due to a blood flow steal through arteriovenous shunting. Perfusion abnormality can also entail hepatocellular regenerative activity, either diffuse or partial, leading to focal nodular hyperplasia (FNH), which has a 100-fold greater prevalence in HHT patients than in the general population, or to nodular regenerative hyperplasia [
      • Garcia-Tsao G.
      • Korzenik J.R.
      • Young L.
      • Henderson K.J.
      • Jain D.
      • Byrd B.
      • et al.
      Liver disease in patients with hereditary hemorrhagic telangiectasia.
      ,
      • Buscarini E.
      • Danesino C.
      • Plauchu H.
      • de Fazio C.
      • Olivieri C.
      • Brambilla G.
      • et al.
      High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.
      ,
      • Buscarini E.
      • Plauchu H.
      • Garcia T.G.
      • White Jr., R.I.
      • Sabba C.
      • Miller F.
      • et al.
      Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.
      ,
      • Faughnan M.E.
      • Palda V.A.
      • Garcia-Tsao G.
      • Geisthoff U.W.
      • McDonald J.
      • Proctor D.D.
      • et al.
      International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.
      ].

      Clinical presentations

      Only 8% of patients with liver VMs are symptomatic in cross-sectional surveys [
      • Memeo M.
      • Stabile Ianora A.A.
      • Scardapane A.
      • Suppressa P.
      • Cirulli A.
      • Sabba C.
      • et al.
      Hereditary haemorrhagic telangiectasia: study of hepatic vascular alterations with multi-detector row helical CT and reconstruction programs.
      ,
      • Buscarini E.
      • Danesino C.
      • Olivieri C.
      • Lupinacci G.
      • De G.F.
      • Reduzzi L.
      • et al.
      Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia – results of extensive screening.
      ]. A recent cohort study with a median follow-up of 44 months has shown that hepatic VM-related morbidity and mortality will occur in 25% and 5% of patients respectively, with incidence rates of complications and death 3.6 and 1.1 per 100 person-years, respectively. The clinical outcome of liver VMs correlates with their severity [
      • Buscarini E.
      • Leandro G.
      • Conte D.
      • Danesino C.
      • Daina E.
      • Manfredi G.
      • et al.
      Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia.
      ].
      HOCF represents the predominant complication associated with HHT [
      • Buscarini E.
      • Plauchu H.
      • Garcia T.G.
      • White Jr., R.I.
      • Sabba C.
      • Miller F.
      • et al.
      Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.
      ,
      • Faughnan M.E.
      • Palda V.A.
      • Garcia-Tsao G.
      • Geisthoff U.W.
      • McDonald J.
      • Proctor D.D.
      • et al.
      International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.
      ], but complicated PH occurs at a rate comparable to that of HOCF (1.4 and 1.2 respectively per 100 person-years); HOCF and complicated PH each accounts for about a half of hepatic VM–associated fatalities. In patients with chronic cardiac overload due to liver VMs atrial fibrillation occurred at a 1.6 rate per 100 person-years, suggesting that this arrhythmia in patients with liver VMs is not purely coincidental and should be approached with special caution [