Advertisement

Primary Budd-Chiari syndrome

  • Dominique-Charles Valla
    Correspondence
    Tel.: +33 1 40 87 55 94; fax: +33 1 40 87 44 26.
    Affiliations
    Centre de Référence des Maladies Vasculaires du Foie, AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy 92118, France

    Université Paris-Diderot-Paris7, UFR de Médecine, Paris 75018, France

    INSERM, U773, Hôpital Beaujon, Clichy 92118, France
    Search for articles by this author
Open AccessPublished:October 27, 2008DOI:https://doi.org/10.1016/j.jhep.2008.10.007
      Primary Budd-Chiari syndrome is characterized by a blocked hepatic venous outflow tract at various levels from small hepatic veins to inferior vena cava, resulting from thrombosis or its fibrous sequellae. This rare disease affects mainly young adults. Multiple risk factors have been identified and are often combined in the same patient. Myeloproliferative diseases of atypical presentation account for nearly 50% of patients; their diagnosis can be made by showing the V617F mutation in Janus tyrosine kinase-2 gene of peripheral blood granulocytes and, should this mutation be absent, by showing clusters of dystrophic megacaryocytes at bone marrow biopsy. Presentation and manifestations are extremely varied, so that the diagnosis must be considered in any patient with acute or chronic liver disease. Doppler-ultrasound, computed tomography or magnetic resonance imaging of hepatic veins and inferior vena cava are usually successful in demonstrating non-invasively the obstacle or its consequences, the collaterals to hepatic veins or inferior vena cava. The disease is considered to be spontaneously lethal within 3 years of first symptoms. A therapeutic strategy has been proposed where anticoagulation, correction of risk factors, diuretics and prophylaxis for portal hypertension are used first; then angioplasty for short-length venous stenoses; then TIPS; and ultimately liver transplantation. Treatment progression is dictated by the response to previous therapy. This strategy has achieved 5-year survival rates approaching 90%. Medium-term prognosis depends on the severity of liver disease. Long-term outcome might be jeopardized by transformation of underlying conditions and hepatocellular carcinoma.

      Keywords

      1. Introduction

      Budd-Chiari syndrome is characterized by an obstruction of the hepatic venous outflow tract in the absence of right heart failure or constrictive pericarditis [
      • 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.
      ]. By convention, hepatic veno-occlusive disease (recently renamed sinusoidal obstruction syndrome) occurring in the setting of an exposure to toxic plants or therapeutic agents is also excluded. The obstacle causing BCS can thus be located at the level of the small or large hepatic veins, or on the suprahepatic portion of inferior vena cava (IVC). When the blockage is caused by invasion or compression by a tumour, BCS is considered secondary, an entity which will not be discussed here. Otherwise, it is related to thrombosis and considered primary.
      Recent years have witnessed significant advances in several areas. The purpose of this article is to provide an update oriented towards the practical management of this disease.

      2. Epidemiology

      Primary BCS is a rare disease. In the late 1980s, in Japan and in France, incidence estimates derived from questionnaire surveys were about 0.2 per million inhabitants per year, while the prevalence estimate were about 2 per million inhabitants [
      • Okuda H.
      • Yamagata H.
      • Obata H.
      • Iwata H.
      • Sasaki R.
      • Imai F.
      • et al.
      Epidemiological and clinical features of Budd-Chiari syndrome in Japan.
      ,
      • Valla D.
      Hepatic venous outflow tract obstruction etipathogenesis: Asia versus the West.
      ]. However, in Nepal, the disease appeared to be at least 10 times more common, and represented the leading cause for hospital admission in a liver unit [
      • Shrestha S.M.
      • Okuda K.
      • Uchida T.
      • Maharjan K.G.
      • Shrestha S.
      • Joshi B.L.
      • et al.
      Endemicity and clinical picture of liver disease due to obstruction of the hepatic portion of the inferior vena cava in Nepal.
      ,
      • Valla D.
      Hepatic venous outflow tract obstruction etipathogenesis: Asia versus the West.
      ]. Current estimates are lacking. There were differences between Asian and Western individuals with BCS: terminal IVC was frequently obstructed in Asians, and usually patent in Western patients. However, this pattern has changed over time in India, where obstruction of terminal IVC now accounts for a lesser proportion of cases [
      • Amarapurkar D.N.
      • Punamiya S.J.
      • Patel N.D.
      Changing spectrum of Budd-Chiari syndrome in India with special reference to non-surgical treatment.
      ,
      • Dilawari J.B.
      • Bambery P.
      • Chawla Y.
      • Kaur U.
      • Bhusnurmath S.R.
      • Malhotra H.S.
      • et al.
      Hepatic outflow obstruction (Budd-Chiari syndrome). Experience with 177 patients and a review of the literature.
      ]. Most affected Western patients have been young females whereas in Asia, middle-aged patients of either sex were predominantly affected. Recent data from a European cohort however indicate a change in demographics as the male to female ratio is closer to 1 and mean age is about 45 years [
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Primignani M.
      • Elias E.
      • Bahr M.
      • et al.
      A prospective follow-up study on 163 patients with Budd-Chiari syndrome: results from the european network for vascular disorders of the Liver (EN-Vie).
      ].

      3. Pathogenesis of venous lesions

      At the time of presentation, venous involvement may take the aspect of a fresh thrombus, superimposed on a previous stenosis, or of a mere stenosis. The latter may involve the entire length of a hepatic vein or of IVC; or be localized to a short portion of it, even taking the aspect of a membrane or ‘web’. In all instances, the primary lesion is a thrombus, later evolving toward a fibrous sequellae [
      • Okuda K.
      Inferior vena cava thrombosis at its hepatic portion (obliterative hepatocavopathy).
      ]. Short length stenoses are particularly visible in the cephalad segment of inferior vena cava or major hepatic veins [
      • 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.
      ].
      Rarely, venous involvement occurs simultaneously in all hepatic veins. Usually, there is an asynchronous and progressive involvement which progresses at a variable speed. The obstruction is followed by the development of a collateral circulation by-passing the obstacle by connecting blocked territories to contiguous territories that have remained well-drained. The collaterals can run an intra- or extra-hepatic course.

      4. Etiology

      This is an important aspect of Budd-Chiari syndrome, a disease best understood as the hepatic expression of underlying prothrombotic conditions, particularly blood diseases. As improved outcome of BCS as a liver disease has resulted from advances in management, the importance of underlying conditions for therapy and long-term outcome has been revealed.

      4.1 Multifactorial etiology

      Recent data from several centres have consistently shown that primary BCS must be regarded as a multifactorial disease where several prothrombotic disorders must concur for the development of thrombosis at this uncommon location. A combination of several prothrombotic conditions has been observed in at least 35% of patients, which is several times higher than expected in the general population [
      • 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.
      • van 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.
      ,
      • Primignani M.
      • Barosi G.
      • Bergamaschi G.
      • Gianelli U.
      • Fabris F.
      • Reati R.
      • et al.
      Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
      ]. It is of note, however, that a local (non-tumorous) factor is seldom identified, which contrasts with thrombosis in other venous territories. This multifactorial paradigm explains first the rarity of the disease by the uncommon concurrence of factors which, individually, might not be very uncommon. Second, the differing features among various areas or populations mentioned above can be explained by different combinations of various causes, depending on their background prevalence in the specific area or population (e.g. oral contraceptives in the West, extreme poverty in Asia and South Africa, as outlined below). The impact of this multifactorial paradigm for clinical practice is that identification of one causal factor should not halt the search for other factors. Table 1 summarizes the prevalence of the major causal factors reported in patients with primary BCS. Table 2 presents a summary of the diagnostic work-up for etiology of Budd-Chiari syndrome. Individual risk factors are discussed below.
      Table 1Approximate prevalence of major risk factors in patients with primary BCS
      Prevalence (%)
      Inherited conditions
      Antithrombin deficiency5
      Protein C deficiency
      May be over-diagnosed due to liver dysfunction.
      20
      Protein S deficiency
      May be over-diagnosed due to liver dysfunction.
      7
      Heterozygous Factor V Leiden20
      Heterozygous G20210A prothrombin7
      Acquired conditions
      V617F JAK2 positive MPD40
      V617F JAK2 negative MPD10
      Antiphospholipid syndrome10
      Behcet’s disease5
      PNH2
      Other general condition5
      External factors
      Oral contraceptives in women50
      Multiple factors including local factors35
      No factor5
      Data are averages from reports reviewed elsewhere
      • Valla D.C.
      The diagnosis and management of the Budd-Chiari syndrome: consensus and controversies.
      and from more recent reports
      • Primignani M.
      • Barosi G.
      • Bergamaschi G.
      • Gianelli U.
      • Fabris F.
      • Reati R.
      • et al.
      Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
      ,
      • Kiladjian J.J.
      • Cervantes F.
      • Leebeek F.W.G.
      • Chevret S.
      • Cazals-Hatem D.
      • Plessier A.
      • et al.
      Role of JAK2 mutation detection in Budd-Chiari syndrome and portal vein thrombosis associated to MPD.
      ,
      • Patel R.K.
      • Lea N.C.
      • Heneghan M.A.
      • Westwood N.B.
      • Milojkovic D.
      • Thanigaikumar M.
      • et al.
      Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the 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.
      ,
      • Colaizzo D.
      • Amitrano L.
      • Tiscia G.L.
      • Scenna G.
      • Grandone E.
      • Guardascione M.A.
      • et al.
      The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis.
      .
      a May be over-diagnosed due to liver dysfunction.
      Table 2Proposed work-up for investing underlying risk factors of Budd-Chiari syndrome
      A. In all patients
      • -
        Personal and familial history of recurrent spontaneous deep vein thrombosis
      • -
        Oral contraceptive use in female patients
      • -
        V617F JAK 2 mutation in peripheral blood granulocytes. When the mutation is undetected, bone marrow biopsy looking for clusters of dystrophic megacaryocytes (myeloproliferative diseases)
      • -
        Flow cytometry for CD55 and CD59 deficient blood cells (paroxysmal nocturnal hemoglobinuria)
      • -
        Activated protein C resistance. When present molecular test for Factor V Leiden mutation
      • -
        Molecular test for G20210A prothrombin gene mutation
      • -
        Lupus anticoagulant, anti beta2 glycoprotein-1 antibodies, anticardiolipin antibodies (antiphospholpid syndrome)
      B. In patients with no marked liver dysfunction (normal prothrombin level)
      • -
        Protein C, protein S and antithrombin plasma levels
      • -
        Plasma homocystein levels
      C- In patients with familial or personal history of recurrent spontaneous deep vein thrombosis: refer to blood coagulation specialist for a detailed study

      4.2 Myeloproliferative diseases (MPDs)

      MPDs account for about 50% of BCS patients, an enormous proportion compared to the background prevalence which might be in the order of 0.2% [
      • Mercier E.
      • Lissalde-Lavigne G.
      • Gris J.C.
      JAK2 V617F mutation in unexplained loss of first pregnancy.
      ]. A recent, crucial, advance in the field of chronic MPD has been the identification of a particular somatic mutation (V617F) in the Janus tyrosine kinase-2 (JAK2) gene in myeloid cells [
      • James C.
      • Ugo V.
      • Le Couedic J.P.
      • Staerk J.
      • Delhommeau F.
      • Lacout C.
      • et al.
      A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.
      ]. JAK2 is coupled to the growth factor receptor on the cells of the myeloid lineage. Activation by the ligand (erythropoietin, thrombopoietin or other growth factors) elicits the signal for proliferation and differentiation of the myeloid precursors into mature cells through JAK2 phosphorylation. V617F JAK2 mutation produces constitutive activation of signal transduction resulting in independence from, or hypersensitivity to, growth factors. This single somatic mutation can be detected in granulocytes or other blood cells of the myeloid lineage. V617F JAK2 has been found in about 80% and 50% of patients with polycythemia vera, and essential thrombocythemia or idiopathic myelofibrosis, respectively [
      • Hussein K.
      • Bock O.
      • Kreipe H.
      Histological and molecular classification of chronic myeloproliferative disorders in the Age of JAK2: persistence of old questions despite new answers.
      ]. In patients with primary BCS, the mutation has been detected in 37–45% of patients [
      • Primignani M.
      • Barosi G.
      • Bergamaschi G.
      • Gianelli U.
      • Fabris F.
      • Reati R.
      • et al.
      Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
      ,
      • De Stefano V.
      • Fiorini A.
      • Rossi E.
      • Za T.
      • Farina G.
      • Chiusolo P.
      • et al.
      Prevalence of the JAK2(V617F) mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders.
      ,
      • Kiladjian J.J.
      • Cervantes F.
      • Leebeek F.W.G.
      • Chevret S.
      • Cazals-Hatem D.
      • Plessier A.
      • et al.
      Role of JAK2 mutation detection in Budd-Chiari syndrome and portal vein thrombosis associated to MPD.
      ,
      • Regina S.
      • Herault O.
      • D’Alteroche L.
      • Binet C.
      • Gruel Y.
      JAK2 V617F is specifically associated with idiopathic splanchnic vein thrombosis.
      ,
      • Colaizzo D.
      • Amitrano L.
      • Iannaccone L.
      • Vergura P.
      • Cappucci F.
      • Grandone E.
      • et al.
      Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings.
      ,
      • Patel R.K.
      • Lea N.C.
      • Heneghan M.A.
      • Westwood N.B.
      • Milojkovic D.
      • Thanigaikumar M.
      • et al.
      Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome.
      ]. Other somatic mutations of the JAK2 gene or other genes have been identified in MPD, but they appear to account for only a minor proportion of the cases [
      • Kiladjian J.J.
      • Cervantes F.
      • Leebeek F.W.G.
      • Chevret S.
      • Cazals-Hatem D.
      • Plessier A.
      • et al.
      Role of JAK2 mutation detection in Budd-Chiari syndrome and portal vein thrombosis associated to MPD.
      ]. Also clusters of dystrophic megacaryocytes at bone marrow biopsy proved recently to be a specific feature for MPD [
      • 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.
      ]. About 80% of BCS patients with a MPD harbour V617F JAK2 mutation [
      • Primignani M.
      • Barosi G.
      • Bergamaschi G.
      • Gianelli U.
      • Fabris F.
      • Reati R.
      • et al.
      Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
      ,
      • Kiladjian J.J.
      • Cervantes F.
      • Leebeek F.W.G.
      • Chevret S.
      • Cazals-Hatem D.
      • Plessier A.
      • et al.
      Role of JAK2 mutation detection in Budd-Chiari syndrome and portal vein thrombosis associated to MPD.
      ]. In the remaining patients, evidence for the underlying MPD is derived from bone marrow biopsy findings. Testing for JAK2 mutation and bone marrow biopsy have replaced formerly used tests using cultures of erythroid progenitors to demonstrate endogenous colonies.
      Peripheral blood cell counts remain within normal values in most patients with MPD when BCS is present, due to hypersplenism, hemodilution and iron deficiency. In the past, this lack of typical changes in peripheral blood has represented a major limitation to the recognition of MPD. In practical terms, this means that all BCS patients, whatever the results of their blood cell counts, should be tested for V617F JAK2 in peripheral granulocytes, followed by bone marrow biopsy in those patients that test negative for the mutation. At present, uncertainties remain as to which of these patients with an essentially normal blood cell count should receive cytoreductive therapies. Advances are expected from the possibility to quantify the mutated cells.

      4.3 Other acquired conditions

      Behcet’s disease usually causes BCS through its well-known involvement of the IVC. However, cases of pure hepatic vein involvement have also been reported [
      • Bismuth E.
      • Hadengue A.
      • Hammel P.
      • Benhamou J.P.
      Hepatic vein thrombosis in Behcet’s disease.
      ,
      • Bayraktar Y.
      • Balkanci F.
      • Bayraktar M.
      • Calguneri M.
      Budd-Chiari syndrome: a common complication of Behcet’s disease.
      ]. In areas where Behcet’s disease is prevalent, it represents the leading cause for BCS.
      Paroxysmal nocturnal hemoglobinuria is an extremely rare disease with a frequently devastating course. The cumulative incidence of hepatic vein thrombosis is extraordinarily high in this disease (about 35%). Features of blood disease are varied so that tests for paroxysmal nocturnal hemoglobinuria should be obtained routinely in all BCS patients. Flow-cytometry on peripheral blood for detection of the CD55 and CD59 deficient clone is the current standard for diagnosis. Recently, a specific treatment with eculizumab has been shown to reduce the incidence of haemolytic as well as thrombotic episodes [
      • Hillmen P.
      • Muus P.
      • Duhrsen U.
      • Risitano A.M.
      • Schubert J.
      • Luzzatto L.
      • et al.
      Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria.
      ,
      • Hillmen P.
      • Young N.S.
      • Schubert J.
      • Brodsky R.A.
      • Socie G.
      • Muus P.
      • et al.
      The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.
      ]. Bone marrow transplantation has been successfully performed in some patients with BCS.
      The prevalence of antiphospholipid syndrome cannot be clearly ascertained as anticardiolipin antibodies are commonly found in patients with a chronic liver disease, whatever its origin [
      • Mangia A.
      • Margaglione M.
      • Cascavilla I.
      • Gentile R.
      • Cappucci G.
      • Facciorusso D.
      • et al.
      Anticardiolipin antibodies in patients with liver disease.
      ]. Using stringent criteria, the prevalence of antiphospholipid syndrome has been estimated to be about 15% among BCS patients. Finding lupus anticoagulant is stronger evidence for antiphospholipid syndrome than anti beta2 glycoprotein-1 antibodies. Anticardiolipin antibodies appear to be the least specific features unless they are repeatedly detected at high titers. There is no specific therapy yet available for this condition.
      As plasma homocysteine levels are increased in patients with liver disease [
      • Bosy-Westphal A.
      • Ruschmeyer M.
      • Czech N.
      • Oehler G.
      • Hinrichsen H.
      • Plauth M.
      • et al.
      Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation.
      ], the role of hyperhomocysteinemia as a cause for BCS is similarly difficult to evaluate. However, the assessment of vitamin deficiencies is certainly worth while in patients with thrombosis.
      Oral contraceptive use has long been known as a risk factor for BCS, particularly the form with pure hepatic vein involvement. Pregnancy also appears to be a triggering factor for hepatic vein thrombosis. However, in both instances, an underlying condition is usually present [
      • Janssen H.L.
      • Meinardi J.R.
      • Vleggaar F.P.
      • van Uum S.H.
      • Haagsma E.B.
      • van 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.
      ].
      Last, pure IVC obstruction has been associated to a very poor standard of living in a case control study, although the mechanism by which this occurs has not been clarified yet [
      • Shrestha S.M.
      • Okuda K.
      • Uchida T.
      • Maharjan K.G.
      • Shrestha S.
      • Joshi B.L.
      • et al.
      Endemicity and clinical picture of liver disease due to obstruction of the hepatic portion of the inferior vena cava in Nepal.
      ]. This association conveniently explains the predominance of IVC obstruction among BCS patients from some areas of the world [
      • Dilawari J.B.
      • Bambery P.
      • Chawla Y.
      • Kaur U.
      • Bhusnurmath S.R.
      • Malhotra H.S.
      • et al.
      Hepatic outflow obstruction (Budd-Chiari syndrome). Experience with 177 patients and a review of the literature.
      ,
      • Kew M.C.
      • McKnight A.
      • Hodkinson J.
      • Bukofzer S.
      • Esser J.D.
      The role of membranous obstruction of the inferior vena cava in the etiology of hepatocellular carcinoma in Southern African blacks.
      ].

      4.4 Inherited conditions

      Identification of Factor V Leiden as a risk factor for venous thrombosis has been another major advance for the understanding of BCS pathogenesis. Factor V Leiden accounts for 7–25% of patients with primary BCS, a proportion similar to that found in patients with deep venous thrombosis of the lower limbs [
      • Amarapurkar D.N.
      • Punamiya S.J.
      • Patel N.D.
      Changing spectrum of Budd-Chiari syndrome in India with special reference to non-surgical treatment.
      ,
      • 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.
      • van 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.
      ,
      • Deltenre P.
      • Denninger M.H.
      • Hillaire S.
      • Guillin M.C.
      • Casadevall N.
      • Briere J.
      • et al.
      Factor V Leiden related Budd-Chiari syndrome.
      ]. In most BCS patients, factor V Leiden is associated with other risk factors for thrombosis, as expected from its relatively weak thrombotic potential [
      • Deltenre P.
      • Denninger M.H.
      • Hillaire S.
      • Guillin M.C.
      • Casadevall N.
      • Briere J.
      • et al.
      Factor V Leiden related Budd-Chiari syndrome.
      ].
      By contrast, G20210A prothrombin gene mutation, another recently discovered inherited prothrombotic disorder, appears to be less over-represented among BCS patients than the former prothrombotic conditions [
      • 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.
      • van 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.
      ,
      • Primignani M.
      • Barosi G.
      • Bergamaschi G.
      • Gianelli U.
      • Fabris F.
      • Reati R.
      • et al.
      Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
      ].
      The prevalence of primary deficiencies in protein C, protein S or antithrombin among BCS patients is difficult to estimate for the following reasons: (a) these coagulation inhibitors are synthesized by the liver; (b) the diagnosis of primary deficiencies is based on the determination of the plasma level (most mutations are private which makes a diagnosis by molecular biology alone difficult); (c) liver dysfunction related to BCS induces a non-specific decrease in plasma levels of these inhibitors; and (d) complete family screening is usually impossible. In most cases, the issue of a possible primary deficiency will thus remain unanswered [
      • Valla D.C.
      Thrombosis and anticoagulation in liver disease.
      ].
      A number of systemic diseases have been incriminated (sarcoidosis, cryptogenic bowel disease, hypereosinophilic syndrome, etc.). Collectively, these diseases account for only a minority of the cases.
      Other recently identified inherited risk factors [
      • Rosendaal F.R.
      Venous thrombosis: the role of genes, environment, and behavior.
      ] have not been extensively studied in BCS patients. In any case, it is obvious that not all inherited risk factors for thrombosis have been identified yet [
      • Bezemer I.D.
      • Bare L.A.
      • Doggen C.J.
      • Arellano A.R.
      • Tong C.
      • Rowland C.M.
      • et al.
      Gene variants associated with deep vein thrombosis.
      ].
      In practical terms, in a patient with decreased coagulation factor levels or marked liver dysfunction, and without a family history of idiopathic thrombosis, it would seem futile to test for diagnostic purpose, plasminogen, protein C, protein S, or antithrombin deficiency, serum homocysteine and plasma factor VIII levels.

      4.5 Site-specificity for thrombosis

      The increasing amount of available data lends support to the concept of site-specificity for thrombosis according to the underlying prothrombotic disorder [
      • 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.
      ,
      • De Stefano V.
      • Fiorini A.
      • Rossi E.
      • Za T.
      • Farina G.
      • Chiusolo P.
      • et al.
      Prevalence of the JAK2(V617F) mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders.
      ,
      • Colaizzo D.
      • Amitrano L.
      • Iannaccone L.
      • Vergura P.
      • Cappucci F.
      • Grandone E.
      • et al.
      Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings.
      ]. MPD is clearly more common among BCS patients than among patients with portal vein thrombosis, and even more so than among patients with venous thrombosis at other sites. Factor V Leiden is more strongly associated with BCS than with portal vein thrombosis, whereas the converse appears to apply to G20210A prothrombin. Further site-specificity might be present also within the hepatic venous outflow tract itself. Indeed, factor V Leiden appears to be particularly common in patients with IVC obstruction [
      • Deltenre P.
      • Denninger M.H.
      • Hillaire S.
      • Guillin M.C.
      • Casadevall N.
      • Briere J.
      • et al.
      Factor V Leiden related Budd-Chiari syndrome.
      ]. Furthermore, oral contraceptives and pregnancy have been specifically associated with hepatic vein involvement [
      • Valla D.
      Hepatic venous outflow tract obstruction etipathogenesis: Asia versus the West.
      ].
      Although these considerations are of little practical significance at present, in the future they may help in the understanding of an important observation: the usual lack of a local – mechanical or inflammatory – factor explaining why thrombosis develops at such an unusual site in the context of a general prothrombotic condition [
      • 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.
      ].

      5. Clinical and laboratory features

      Various forms of presentation and course have been described, ranging from fulminant to chronic, the latter being the most frequent one. Asymptomatic forms appear to account for about 15% of patients [
      • Hadengue A.
      • Poliquin M.
      • Vilgrain V.
      • Belghiti J.
      • Degott C.
      • Erlinger S.
      • et al.
      The changing scene of hepatic vein thrombosis: recognition of asymptomatic cases.
      ]. These asymptomatic forms are characteristically associated preservation of some hepatic veins and IVC, or with large intrahepatic or extrahepatic collaterals.
      The clinical manifestations of BCS have been well characterized [
      • Dilawari J.B.
      • Bambery P.
      • Chawla Y.
      • Kaur U.
      • Bhusnurmath S.R.
      • Malhotra H.S.
      • et al.
      Hepatic outflow obstruction (Budd-Chiari syndrome). Experience with 177 patients and a review of the literature.
      ,
      • Hadengue A.
      • Poliquin M.
      • Vilgrain V.
      • Belghiti J.
      • Degott C.
      • Erlinger S.
      • et al.
      The changing scene of hepatic vein thrombosis: recognition of asymptomatic cases.
      ,
      • Griffith J.F.
      • Mahmoud A.E.
      • Cooper S.
      • Elias E.
      • West R.J.
      • Olliff S.P.
      Radiological intervention in Budd-Chiari syndrome: techniques and outcome in 18 patients.
      ]. Abdominal pain, ascites, liver and spleen enlargement, and portal hypertension are important features, as well as a prominent dilation of subcutaneous veins of the trunk in those patients with long standing IVC obstruction. Each or all of these features may, however, be lacking. Liver function tests are altered to a various extent according to patients.
      Presentation bears little relationship with the actual duration of the disease. Most patients presenting with acute manifestations have extensive fibrosis or cirrhosis. Less than 10% of patients presenting with an acute illness actually have a recent disease [
      • Dilawari J.B.
      • Bambery P.
      • Chawla Y.
      • Kaur U.
      • Bhusnurmath S.R.
      • Malhotra H.S.
      • et al.
      Hepatic outflow obstruction (Budd-Chiari syndrome). Experience with 177 patients and a review of the literature.
      ,
      • Langlet P.
      • Escolano S.
      • Valla D.
      • Coste-Zeitoun D.
      • Denie C.
      • Mallet A.
      • et al.
      Clinicopathological forms and prognostic index in Budd-Chiari syndrome.
      ].
      In BCS patients, HCC appears to be as significant as a long-term complication as it is in other chronic liver diseases. HCC developed in 11 of 97 patients of a recent cohort followed-up for a mean 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.
      ]. Serum α foetoprotein appeared to be more specific for a diagnosis of HCC in patients with BCS than with other liver diseases. Patients with long-standing IVC obstruction carried a risk of developing HCC that was 70-fold higher than those with pure hepatic vein involvement. Multivariate analyses in larger cohorts, as well as molecular studies are further needed to clarify HCC pathophysiology in this non-inflammatory disease of the liver.

      6. Pathophysiology

      The marked clinical and pathological heterogeneity among BCS patients partly stems from the diversity of location of the obstruction (IVC or major hepatic veins), but also from the variable number of obstructed hepatic veins [
      • Parker R.G.F.
      Occlusion of the hepatic veins in man.
      ], and likely from the various speed of the obstructive process. In addition, a deleterious role of a loss of intrahepatic portal perfusion has been demonstrated in patients undergoing liver transplantation [
      • Cazals-Hatem D.
      • Vilgrain V.
      • Genin P.
      • Denninger M.H.
      • Durand F.
      • Belghiti J.
      • et al.
      Arterial and portal circulation and parenchymal changes in Budd-Chiari syndrome: a study in 17 explanted livers.
      ]. In these patients with end-stage liver disease, there was a close relationship between deprivation of portal blood supply, and liver cell loss in the corresponding areas. Portal venous deprivation can result either from intrahepatic portal vein thrombosis, or from focally retrograde portal blood flow. Thus, maintenance of portal blood supply might be crucial for preventing progression of liver disease. Regenerative macronodules, occasionally mimicking focal nodular hyperplasia, are found in arterialized liver, in those areas that are deprived of portal perfusion but apparently well-drained by hepatic venous collaterals [
      • Cazals-Hatem D.
      • Vilgrain V.
      • Genin P.
      • Denninger M.H.
      • Durand F.
      • Belghiti J.
      • et al.
      Arterial and portal circulation and parenchymal changes in Budd-Chiari syndrome: a study in 17 explanted livers.
      ]. Nodular regenerative hyperplasia is commonplace in these arterialised livers [
      • Cazals-Hatem D.
      • Vilgrain V.
      • Genin P.
      • Denninger M.H.
      • Durand F.
      • Belghiti J.
      • et al.
      Arterial and portal circulation and parenchymal changes in Budd-Chiari syndrome: a study in 17 explanted livers.
      ].
      Extrahepatic portal vein thrombosis is superimposed on BCS in about 15% of patients [
      • Murad S.D.
      • 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.
      ]. As compared with patients having a patent portal vein, manifestations at diagnosis were not more severe and, although survival tended to be decreased, the difference was not statistically significant [
      • Murad S.D.
      • 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.
      ]. Therefore, it might be that superimposed extrahepatic portal vein thrombosis is mainly a consequence of portal vein blood stasis, in a context of multiple prothrombotic factors. According to this view, superimposed extrahepatic portal vein thrombosis might be a reflection of severe liver disease rather than a factor for its aggravation.
      The asynchronous involvement of the hepatic veins, and the mechanisms of atrophy-hypertrophy which result, explain that a markedly dysmorphic liver is common. The hypertrophy of the central parts of the liver (mainly the caudate lobe) is related in part to the maintenance of an adequate venous drainage through the numerous small caudate lobe veins that reach the IVC directly; and for another part, to a better preservation of portal perfusion than in the peripheral areas.
      BCS-related hepatic fibrosis differs from that related to alcoholic or viral liver disease, by its predominant, although not exclusive, centrilobular distribution. In addition, the RNA expression of fibrogenic and angiogenic factors differs from that of chronic liver disease related to alcohol or viral hepatitis [
      • Paradis V.
      • Bieche I.
      • Dargere D.
      • Cazals-Hatem D.
      • Laurendeau I.
      • Saada V.
      • et al.
      Quantitative gene expression in Budd-Chiari syndrome: a molecular approach to the pathogenesis of the disease.
      ].

      7. Diagnosis

      A diagnosis of BCS should be considered in any patient with acute or chronic liver disease. Obviously, the diagnosis is more likely when there is no other, more common, cause of liver disease; or when there is a known underlying prothrombotic condition.
      Diagnosis is based on the demonstration of an obstructed hepatic venous outflow tract [
      • Miller W.J.
      • Federle M.P.
      • Straub W.H.
      • Davis P.L.
      Budd-Chiari syndrome: imaging with pathologic correlation.
      ]. For that purpose, modern, non-invasive imaging means are most efficient, provided two conditions are fulfilled. The examiner should (a) be experienced and (b), be aware of the clinical diagnostic suspicion. The arguments for an obstruction comprise a dilatation of the vein upstream to an obstacle; the presence of a solid endoluminal material; the transformation of the veins into a cord devoid of flow signal; and venous collaterals, seen as abnormal circulating structures branching to or from the hepatic veins or IVC. Doppler-ultrasound, triphasic CT scan or MRI is usually sufficient to show these diagnostic features. Patchy enhancement of hepatic parenchyma is only suggestive of a perfusion defect, which can be seen in many other vascular disorders of the liver. At present, there is almost no place for direct or retrograde venography, for the sole purpose of making a diagnosis of BCS [
      • 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.
      ].
      Liver biopsy is of diagnostic interest only in the rare forms of the disease where thrombosis is limited to the small intrahepatic veins, i.e. with a normal appearance of the large veins at non-invasive imaging [
      • 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.
      ]. Biospy usually brings non-specific evidence for an impaired blood outflow, including congestion, coagulative necrosis or simple loss of hepatocytes without inflammatory infiltrates, and/or fibrosis, all features predominating in the centrilobular area. Such features of outflow obstruction are encountered in patients with BCS, veno-occlusive disease, or cardiac or pericardial disease. Thrombosis of the hepatic veins is an uncommon finding in needle biopsy specimens. In clinical practice, the most challenging differential diagnosis is constrictive pericarditis.

      8. Natural course and prognosis

      Fortuitously recognized, asymptomatic forms carry a good prognosis [
      • Hadengue A.
      • Poliquin M.
      • Vilgrain V.
      • Belghiti J.
      • Degott C.
      • Erlinger S.
      • et al.
      The changing scene of hepatic vein thrombosis: recognition of asymptomatic cases.
      ]. Symptomatic forms have a poor spontaneous course as it has been estimated that 90% of untreated patients will die within 3 years [
      • Tavill A.S.
      • Wood E.J.
      • Kreel L.
      • Jones E.A.
      • Gregory M.
      • Sherlock S.
      The Budd-Chiari syndrome: correlation between hepatic scintigraphy and the clinical, radiological, and pathological findings in nineteen cases of hepatic venous outflow obstruction.
      ]. Death can be related to refractory ascites leading to emaciation, hepatic failure, gastrointestinal bleeding, or a combination thereof.
      Contrasting with a high degree of heterogeneity in causes, presentation, and level of hepatic venous outflow block, it is remarkable that all the prognostic information appears to be accounted for by the components of the Child-Pugh score or the MELD score [
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Primignani M.
      • Elias E.
      • Bahr M.
      • et al.
      A prospective follow-up study on 163 patients with Budd-Chiari syndrome: results from the european network for vascular disorders of the Liver (EN-Vie).
      ]. However, it should be kept in mind that these markers are poor predictors of the outcome in an individual patient. Therefore, they are of no help in the practical management. The major interest of the disease-specific prognostic scores is for clinical studies adjusting the outcome of patient groups on their baseline characteristics.

      9. Treatment

      Randomized clinical trials of treatment options are still lacking. International expert panel conferences have permitted a consensual elaboration of recommendations based on comprehensive reviews of evidence, and on the confrontation of experience in referral centres [
      • 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.
      ,
      • de Franchis R.
      Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension..
      ]. Recent studies have generally supported these recommendations.

      9.1 Underlying disease

      Logically, prompt recognition and treatment of underlying diseases has been recommended. However, data on these aspects are largely lacking. Specific therapy for the underlying causes, if any, should be applied early. This important aspect is beyond the scope of this article. There is hope that recent advances in the understanding of MPD and newly available agents for paroxysmal nocturnal haemoglobinuria will result in a clinical benefit for BCS patients affected with these diseases. For many conditions, particularly antiphospholipid syndrome and hereditary thrombophilias, anticoagulation therapy remains the only available therapeutic means. Recombinant antithrombin is available for deficient patients but only for use over a limited period of time [
      • 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.
      ].

      9.2 Anticoagualtion therapy

      Early initiation of anticoagulation therapy is recommended for all patients regardless of whether an underlying prothrombotic disorder has been identified or not [
      • 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.
      ,
      • de Franchis R.
      Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension..
      ]. Although anticoagulation has not been evaluated in randomized clinical trials, there is much circumstantial evidence for a favourable benefit/risk ratio in BCS patients [
      • 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.
      ]. Immediate anticoagulation is therefore recommended [
      • de Franchis R.
      Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension..
      ]. This treatment will be sufficient in controlling the liver disease in 10% of patients, mainly those with a mild disease [
      • 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.
      ]. A surprisingly high incidence of heparin induced thrombocytopenia has been reported with unfractionated heparin [
      • 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.
      ] and, more recently, with low-molecular weight heparins [
      • Primignani M.
      • Dell’ Era A.
      • Fabris F.M.
      • Reati R.
      • Artoni A.
      • Mannucci P.M.
      High incidence of heparin-induced thrombocythemia (HIT) in splanchnic vein thrombosis treated with low molecular weight heparin 5LMWH.
      ]. These findings have remained unexplained. However, it is safe to recommend that unfractionated heparin,be avoided as it can be replaced by low molecular weight heparin for initiation of anticoagulation. There is no evidence that the efficacy of vitamin K antagonists differs from that of heparin. At present, therefore, the choice for the type of anticoagulation should be dictated by pharmacokinetic considerations and by context, i.e. a need for rapid and short acting anticoagulation therapy, or long-term treatment.

      9.3 Percutaneous angioplasty

      About a third of patients harbour short length stenosis either of the hepatic veins or of the IVC. Such patients are candidates for percutaneous transluminal angioplasty. The efficacy and the inocuity of this procedure (with or without stenting) have been confirmed, at least when a retrograde, transjugular or transfemoral route is used [
      • 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.
      ,
      • Eapen C.E.
      • Velissaris D.
      • Heydtmann M.
      • Gunson B.
      • Olliff S.
      • Elias E.
      Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome.
      ]. Therefore, active search for such short-length stenoses, and when found, an appropriate percutaneous intervention, have been recommended in patients with symptomatic BCS. In asymptomatic patients, the benefit-risk ratio of this therapeutic option is still debated. Available data suggest significant procedure-related morbidity with the transhepatic approach to hepatic vein angioplasty, which is considered when a transvenous approach has failed.
      Taken together, anticoagulation and angioplasty appear to succeed in controlling BCS in only 20–30% of patients, at least in a Western series where pure hepatic vein involvement predominates [
      • 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.
      ].

      9.4 Transjugular intrahepatic portosystemic shunt

      Consistent data indicate that in patients where the disease is not fully controlled by the preceding options, the next step should be TIPS insertion. Indeed, in experienced hands, the transcaval approach is technically and clinically successful in most patients [
      • Eapen C.E.
      • Velissaris D.
      • Heydtmann M.
      • Gunson B.
      • Olliff S.
      • Elias E.
      Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome.
      ,
      • 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.
      ,
      • Perello A.
      • Garcia-Pagan J.C.
      • Gilabert R.
      • Suarez Y.
      • Moitinho E.
      • Cervantes F.
      • et al.
      TIPS is a useful long-term derivative therapy for patients with Budd-Chiari syndrome uncontrolled by medical therapy.
      ]. Furthermore, the advent of covered stents has allowed maintained patency for prolonged periods [
      • 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.
      ]. Increased difficulties and morbidity of the procedure in BCS patients as compared with the usual cirrhotic patients should not be underestimated. Improved survival in TIPS treated patients is most obvious among those with the most severe disease at baseline. In that subset of patients, 5-year survival rose from 45% in a reference cohort – where TIPS was only marginally used – [
      • 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.
      ], to 71% in a series of TIPS treated patients [
      • 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.
      ]. Overall, 60% of current Western patients may require, and be satisfactorily treated with, a covered-stent TIPS.

      9.5 Liver transplantation

      In the remaining 10–20% of patients, anticoagulation, percutaneous angioplasty and TIPS fail either due to technical failure or to poor clinical results of a technically successful procedure. In such patients, liver transplantation is the remaining option. Two recent retrospective analyses of the outcome in large series of transplanted patients have shown 5-year survival rates reaching 80% [
      • 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.
      ,
      • 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.
      ]. The true impact of liver transplantation is difficult to assess based on these two studies, as their data do not allow for a comparison with patients of similar severity given less demanding treatments. Most recent reports suggest that previous attempt at TIPS or percutaneous stenting of the outflow tract did not compromise the results of liver transplantation [
      • 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.
      ].
      Patients with blocked portal vein are poor candidates to TIPS or liver transplantation, although each of these procedures has been reported to be successful in a few patients [
      • Murad S.D.
      • 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.
      ]. Therefore, maintenance of a patent portal vein clearly stands as a major therapeutic target. However, it should be remembered that after adjustment for severity at diagnosis of BCS, prognosis was not influenced by the presence of portal vein obstruction [
      • Murad S.D.
      • 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.
      ,
      • 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.
      ]. This means that compensated patients with preserved liver function despite extensive blockade of the splanchnic veins usually have prolonged survival when treated only with anticoagulation, and percutaneous angioplasty of the outflow tract when possible.
      The implementation of these treatment procedures requires experienced operators. Furthermore, patients should be managed in close cooperation with a transplantation center, as an emergency transplantation may happen to be indicated. Indications for percutaneous manoeuvres are based on imaging and haemodynamic data obtained at IVC and hepatic vein catheterization. Thus, while venograpy has little place among diagnostic procedures, it occupies a central place in the elaboration of therapy.
      The above strategy is summarized in Table 3. This strategy aiming at minimal invasiveness is based on response to previous therapy rather than on the actual severity of the patient. It has allowed to achieve 5-year survival rates in the order of 90% [
      • Darwish Murad S.
      • Plessier A.
      • Hernandez-Guerra M.
      • Primignani M.
      • Elias E.
      • Bahr M.
      • et al.
      A prospective follow-up study on 163 patients with Budd-Chiari syndrome: results from the european network for vascular disorders of the Liver (EN-Vie).
      ,
      • 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.
      ,
      • Eapen C.E.
      • Velissaris D.
      • Heydtmann M.
      • Gunson B.
      • Olliff S.
      • Elias E.
      Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome.
      ]. This considerable improvement in survival expectancy has been obtained together with an excellent quality of life due to complete resolution of clinical signs and symptoms, and quasi-normalization of liver function tests [
      • 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.
      ].
      Table 3Proposed treatment strategy for Budd-Chiari syndrome
      A. In all patients
      • -
        Initiate anticoagulation immediately
        • Use low molecular weight heparin (in the absence of known allergy)
        • Monitor platelet counts every other day. Sustitute heparin for daparanoid sulphate when there is a drop in platelet counts. Perform tests for heparin-induced thrombocytopenia to establish or rule out diagnosis
        • Monitor antifactor X activity (heparinemia). Check antithrombin level if a target level of 0.5 IU/ML cannot be achieved using conventional doses. Administer recombinant antithrombin if level below 50% of normal
        • Shift to oral anticoagulation targeting an INR 2 to 3 as soon as possible
      • -
        Refer to the haematologist for paroxysmal nocturnal hemoglobinuria and myeloproliferative disease. Consider rapid cytoreductive therapy in patients with myeloproliferative disease and increased blood cell counts. Stop oral contraceptives and hormonal therapy Provide prophylactic therapy for portal hypertension and treat active bleeding according to guidelines for cirrhosis
      • -
        Treat ascites with diuretics and blood volume expansion if needed. Limit to minimum the number of paracentesis because of the risk of intraperitoneal bleeding on anticoagulation
      • -
        Monitor clinical improvement (encephalopathy, weight, fever, pain), decrease in serum transaminase level, decrease in serum bilirubin and creatinine if previously abnormal, increase in prothrombin level (or, on anticoagulation, factor V level) and response and tolerance to diuretics
      • -
        Consider risk, benefit and possible technical difficulties of angioplasty in patients with short length stenosis in hepatic vein or inferior vena cava
      B. In patients not improving or deteriorating with the above measures, proceed to angioplasty with or without stenting, if appropriate. Indication can be broad when the risk of the procedure is deemed minimal
      C. Proceed to insertion of a covered TIPS when the patient is not responding to the above treatments whether angioplasty has been technically successful or not. Revise TIPS as needed based on clinical, Doppler-ultrasound and hemodynamic assessment
      D. Consider liver transplantation when the patient is not responding to the above treatments unless TIPS dysfunction can be corrected

      References

        • 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.
        J Hepatol. 2003; 38: 364-371
        • Okuda H.
        • Yamagata H.
        • Obata H.
        • Iwata H.
        • Sasaki R.
        • Imai F.
        • et al.
        Epidemiological and clinical features of Budd-Chiari syndrome in Japan.
        J Hepatol. 1995; 22: 1-9
        • Valla D.
        Hepatic venous outflow tract obstruction etipathogenesis: Asia versus the West.
        J Gastroenterol Hepatol. 2004; 19: S204-S211
        • Shrestha S.M.
        • Okuda K.
        • Uchida T.
        • Maharjan K.G.
        • Shrestha S.
        • Joshi B.L.
        • et al.
        Endemicity and clinical picture of liver disease due to obstruction of the hepatic portion of the inferior vena cava in Nepal.
        J Gastroenterol Hepatol. 1996; 11: 170-179
        • Amarapurkar D.N.
        • Punamiya S.J.
        • Patel N.D.
        Changing spectrum of Budd-Chiari syndrome in India with special reference to non-surgical treatment.
        World J Gastroenterol. 2008; 14: 278-285
        • Dilawari J.B.
        • Bambery P.
        • Chawla Y.
        • Kaur U.
        • Bhusnurmath S.R.
        • Malhotra H.S.
        • et al.
        Hepatic outflow obstruction (Budd-Chiari syndrome). Experience with 177 patients and a review of the literature.
        Medicine (Baltimore). 1994; 73: 21-36
        • Darwish Murad S.
        • Plessier A.
        • Hernandez-Guerra M.
        • Primignani M.
        • Elias E.
        • Bahr M.
        • et al.
        A prospective follow-up study on 163 patients with Budd-Chiari syndrome: results from the european network for vascular disorders of the Liver (EN-Vie).
        J Hepatol. 2007; 46: S4
        • Okuda K.
        Inferior vena cava thrombosis at its hepatic portion (obliterative hepatocavopathy).
        Semin Liver Dis. 2002; 22: 15-26
        • 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.
        Hepatology. 1997; 25: 814-819
        • 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.
        Hepatology. 2000; 31: 587-591
        • Janssen H.L.
        • Meinardi J.R.
        • Vleggaar F.P.
        • van Uum S.H.
        • Haagsma E.B.
        • van 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.
        Blood. 2000; 96: 2364-2368
        • Primignani M.
        • Barosi G.
        • Bergamaschi G.
        • Gianelli U.
        • Fabris F.
        • Reati R.
        • et al.
        Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis.
        Hepatology. 2006; 44: 1528-1534
        • Mercier E.
        • Lissalde-Lavigne G.
        • Gris J.C.
        JAK2 V617F mutation in unexplained loss of first pregnancy.
        N Engl J Med. 2007; 357: 1984-1985
        • James C.
        • Ugo V.
        • Le Couedic J.P.
        • Staerk J.
        • Delhommeau F.
        • Lacout C.
        • et al.
        A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.
        Nature. 2005; 434: 1144-1148
        • Hussein K.
        • Bock O.
        • Kreipe H.
        Histological and molecular classification of chronic myeloproliferative disorders in the Age of JAK2: persistence of old questions despite new answers.
        Pathobiology. 2007; 74: 72-80
        • De Stefano V.
        • Fiorini A.
        • Rossi E.
        • Za T.
        • Farina G.
        • Chiusolo P.
        • et al.
        Prevalence of the JAK2(V617F) mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders.
        J Thromb Haemost. 2007; 5: 708-714
        • Kiladjian J.J.
        • Cervantes F.
        • Leebeek F.W.G.
        • Chevret S.
        • Cazals-Hatem D.
        • Plessier A.
        • et al.
        Role of JAK2 mutation detection in Budd-Chiari syndrome and portal vein thrombosis associated to MPD.
        Blood. 2006; 106: 377
        • Regina S.
        • Herault O.
        • D’Alteroche L.
        • Binet C.
        • Gruel Y.
        JAK2 V617F is specifically associated with idiopathic splanchnic vein thrombosis.
        J Thromb Haemost. 2007; 5: 859-861
        • Colaizzo D.
        • Amitrano L.
        • Iannaccone L.
        • Vergura P.
        • Cappucci F.
        • Grandone E.
        • et al.
        Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings.
        J Med Genet. 2007; 44: 412-416
        • Patel R.K.
        • Lea N.C.
        • Heneghan M.A.
        • Westwood N.B.
        • Milojkovic D.
        • Thanigaikumar M.
        • et al.
        Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome.
        Gastroenterology. 2006; 130: 2031-2038
        • 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.
        Br J Haematol. 2005; 129: 553-560
        • Bismuth E.
        • Hadengue A.
        • Hammel P.
        • Benhamou J.P.
        Hepatic vein thrombosis in Behcet’s disease.
        Hepatology. 1990; 11: 969-974
        • Bayraktar Y.
        • Balkanci F.
        • Bayraktar M.
        • Calguneri M.
        Budd-Chiari syndrome: a common complication of Behcet’s disease.
        Am J Gastroenterol. 1997; 92: 858-862
        • Hillmen P.
        • Muus P.
        • Duhrsen U.
        • Risitano A.M.
        • Schubert J.
        • Luzzatto L.
        • et al.
        Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria.
        Blood. 2007; 110: 4123-4128
        • Hillmen P.
        • Young N.S.
        • Schubert J.
        • Brodsky R.A.
        • Socie G.
        • Muus P.
        • et al.
        The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.
        N Engl J Med. 2006; 355: 1233-1243
        • Mangia A.
        • Margaglione M.
        • Cascavilla I.
        • Gentile R.
        • Cappucci G.
        • Facciorusso D.
        • et al.
        Anticardiolipin antibodies in patients with liver disease.
        Am J Gastroenterol. 1999; 94: 2983-2987
        • Bosy-Westphal A.
        • Ruschmeyer M.
        • Czech N.
        • Oehler G.
        • Hinrichsen H.
        • Plauth M.
        • et al.
        Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation.
        Am J Clin Nutr. 2003; 77: 1269-1277
        • 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.
        Gastroenterology. 1986; 90: 807-811
        • Kew M.C.
        • McKnight A.
        • Hodkinson J.
        • Bukofzer S.
        • Esser J.D.
        The role of membranous obstruction of the inferior vena cava in the etiology of hepatocellular carcinoma in Southern African blacks.
        Hepatology. 1989; 9: 121-125
        • Deltenre P.
        • Denninger M.H.
        • Hillaire S.
        • Guillin M.C.
        • Casadevall N.
        • Briere J.
        • et al.
        Factor V Leiden related Budd-Chiari syndrome.
        Gut. 2001; 48: 264-268
        • Valla D.C.
        Thrombosis and anticoagulation in liver disease.
        Hepatology. 2008; 47: 1384-1393
        • Rosendaal F.R.
        Venous thrombosis: the role of genes, environment, and behavior.
        Hematology Am Soc Hematol Educ Program. 2005; 1–12
        • Bezemer I.D.
        • Bare L.A.
        • Doggen C.J.
        • Arellano A.R.
        • Tong C.
        • Rowland C.M.
        • et al.
        Gene variants associated with deep vein thrombosis.
        Jama. 2008; 299: 1306-1314
        • Hadengue A.
        • Poliquin M.
        • Vilgrain V.
        • Belghiti J.
        • Degott C.
        • Erlinger S.
        • et al.
        The changing scene of hepatic vein thrombosis: recognition of asymptomatic cases.
        Gastroenterology. 1994; 106: 1042-1047
        • Griffith J.F.
        • Mahmoud A.E.
        • Cooper S.
        • Elias E.
        • West R.J.
        • Olliff S.P.
        Radiological intervention in Budd-Chiari syndrome: techniques and outcome in 18 patients.
        Clin Radiol. 1996; 51: 775-784
        • Langlet P.
        • Escolano S.
        • Valla D.
        • Coste-Zeitoun D.
        • Denie C.
        • Mallet A.
        • et al.
        Clinicopathological forms and prognostic index in Budd-Chiari syndrome.
        J Hepatol. 2003; 39: 496-501
        • 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.
        Gut. 2008; 57: 828-835
        • Parker R.G.F.
        Occlusion of the hepatic veins in man.
        Medicine (Baltimore). 1959; 38: 369-402
        • Cazals-Hatem D.
        • Vilgrain V.
        • Genin P.
        • Denninger M.H.
        • Durand F.
        • Belghiti J.
        • et al.
        Arterial and portal circulation and parenchymal changes in Budd-Chiari syndrome: a study in 17 explanted livers.
        Hepatology. 2003; 37: 510-519
        • Murad S.D.
        • 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.
        Am J Gastroenterol. 2006; 101: 83-90
        • Paradis V.
        • Bieche I.
        • Dargere D.
        • Cazals-Hatem D.
        • Laurendeau I.
        • Saada V.
        • et al.
        Quantitative gene expression in Budd-Chiari syndrome: a molecular approach to the pathogenesis of the disease.
        Gut. 2005; 54: 1776-1781
        • Miller W.J.
        • Federle M.P.
        • Straub W.H.
        • Davis P.L.
        Budd-Chiari syndrome: imaging with pathologic correlation.
        Abdom Imaging. 1993; 18: 329-335
        • Tavill A.S.
        • Wood E.J.
        • Kreel L.
        • Jones E.A.
        • Gregory M.
        • Sherlock S.
        The Budd-Chiari syndrome: correlation between hepatic scintigraphy and the clinical, radiological, and pathological findings in nineteen cases of hepatic venous outflow obstruction.
        Gastroenterology. 1975; 68: 509-518
        • de Franchis R.
        Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension..
        J Hepatol. 2005; 43: 167-176
        • 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.
        Hepatology. 2006; 44: 1308-1316
        • Primignani M.
        • Dell’ Era A.
        • Fabris F.M.
        • Reati R.
        • Artoni A.
        • Mannucci P.M.
        High incidence of heparin-induced thrombocythemia (HIT) in splanchnic vein thrombosis treated with low molecular weight heparin 5LMWH.
        J Hepatol. 2008; 48: S113
        • Eapen C.E.
        • Velissaris D.
        • Heydtmann M.
        • Gunson B.
        • Olliff S.
        • Elias E.
        Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome.
        Gut. 2006; 55: 878-884
        • 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.
        Hepatology. 2004; 40: 1197-1202
        • Perello A.
        • Garcia-Pagan J.C.
        • Gilabert R.
        • Suarez Y.
        • Moitinho E.
        • Cervantes F.
        • et al.
        TIPS is a useful long-term derivative therapy for patients with Budd-Chiari syndrome uncontrolled by medical therapy.
        Hepatology. 2002; 35: 132-139
        • 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.
        Hepatology. 2004; 39: 500-508
        • 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.
        Gastroenterology. 2008; 135: 808-815
        • 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.
        J Hepatol. 2006; 44: 520-528
        • 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.
        Liver Transpl. 2007; 13: 1285-1294
        • Valla D.C.
        The diagnosis and management of the Budd-Chiari syndrome: consensus and controversies.
        Hepatology. 2003; 38: 793-803
        • Primignani M.
        • Martinelli I.
        • Bucciarelli P.
        • Battaglioli T.
        • Reati R.
        • Fabris F.
        • et al.
        Risk factors for thrombophilia in extrahepatic portal vein obstruction.
        Hepatology. 2005; 41: 603-608
        • Colaizzo D.
        • Amitrano L.
        • Tiscia G.L.
        • Scenna G.
        • Grandone E.
        • Guardascione M.A.
        • et al.
        The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis.
        J Thromb Haemost. 2007; 5: 55-61