Budd–Chiari syndrome: a review by an expert panel

1. IntroductionBudd–Chiari syndrome is a rare disease with a potentially dismal outcome if not treated optimally. So far, diagnostic and intervention studies on Budd–Chiari syndrome have been small and difficult to interpret. Various definitions have been proposed for Budd–Chiari syndrome [1Dilawari 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: 21-36PubMed Google Scholar, 2Ludwig J. Hashimoto E. McGill D.B. van Heerden J.A. Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd–Chiari syndrome.Mayo Clin Proc. 1990; 65: 51-55Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 3Okuda K. Kage M. Shrestha S.M. Proposal of a new nomenclature for Budd–Chiari syndrome: hepatic vein thrombosis versus thrombosis of the inferior vena cava at its hepatic portion.Hepatology. 1998; 28: 1191-1198Crossref PubMed Scopus (157) Google Scholar], but agreement on a uniform nomenclature is lacking and will constitute an essential requirement for future collaborative studies. Moreover, events that represent failure of management, and hence should become end-points for therapeutic studies, need to be defined.In order to review the current status of the diagnosis and treatment of Budd–Chiari syndrome, a group of European investigators with special interest in vascular liver disease recently formed the European Group for the Study of Hepatic Vascular Diseases. The objectives of this group for the study of Budd–Chiari syndrome are threefold: (1) to establish a uniform definition and classification of the disease; (2) to contribute to the management of Budd–Chiari syndrome by identifying areas of consensus and areas where further research is needed and (3) to stimulate research through collaborative studies.On the occasion of the 36th meeting of the European Association for the Study of the Liver in Prague, an open workshop was held to discuss disease terminology, diagnostic work-up, therapeutic interventions and future collaborative studies. This workshop was organized by the European Group for the Study of Hepatic Vascular Diseases. During the workshop, it became apparent that in the absence of reliable data on prognostic factors and management of the disease, it is not yet possible to reach a consensus on strict diagnostic and therapeutic algorithms. The nomenclature and guidelines presented in this paper is based on available scientific data and a joint effort by experts in the field who organized existing criteria for clinical use and future studies. The nomenclature is based on the following assumptions: (a) in order to be widely accepted, it must be close to that in current use; (b) it must encompass entities that, although heterogeneous in some respects, have common pathogenesis and manifestations; (c) it must provide clear boundaries; and (d) it must be easy to adhere to, irrespective of institutional differences in available techniques.2. DefinitionSeveral authors who have challenged the term Budd–Chiari syndrome as being ambiguous, have attempted to introduce other nomenclatures, such as hepatic venous outflow obstruction and obliterative hepatocavopathy [2Ludwig J. Hashimoto E. McGill D.B. van Heerden J.A. Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd–Chiari syndrome.Mayo Clin Proc. 1990; 65: 51-55Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 3Okuda K. Kage M. Shrestha S.M. Proposal of a new nomenclature for Budd–Chiari syndrome: hepatic vein thrombosis versus thrombosis of the inferior vena cava at its hepatic portion.Hepatology. 1998; 28: 1191-1198Crossref PubMed Scopus (157) Google Scholar]. Although important for our understanding of Budd–Chiari syndrome, most of these nomenclatures have not been used in clinical practice. Although the cause, the mechanism and the nature of the vascular obstruction are not given, the term Budd–Chiari syndrome should be retained for two reasons: (a) it has stood the passage of time; and (b) it is more concise than any other terminology proposed to designate the whole spectrum of disorders encompassed by the present definition. Budd–Chiari syndrome is defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the junction of the inferior vena cava and the right atrium, regardless of the cause of obstruction. Outflow obstruction caused by hepatic veno-occlusive disease and cardiac disorders is excluded from this definition.Veno-occlusive disease, also referred to as sinusoidal obstruction syndrome, is defined as a non-thrombotic obstruction of sinusoids or central hepatic veins due to injury of the sinusoidal wall [[4]Deleve L. Shulman H. McDonald G. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome.Sem Liv Dis. 2002; 22: 27-41Crossref Scopus (532) Google Scholar]. Veno-occlusive disease occurs following administration of toxic agents and is, at present, encountered almost exclusively in association with bone marrow transplantation [[5]Shulman H.M. Fisher L.B. Schoch H.G. Henne K.W. McDonald G.B. Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms.Hepatology. 1994; 19: 1171-1181Crossref Scopus (255) Google Scholar]. The epidemiology, pathophysiology, treatment and prognosis of veno-occlusive disease are so distinct from other forms of hepatic venous outflow obstruction that its inclusion in future clinical studies on Budd–Chiari syndrome would introduce an unacceptable source of heterogeneity [[6]Stuart K. Bras G. Veno-occlusive disease of the liver.Q J Med. 1957; 26: 291-314PubMed Google Scholar]. Obstruction of the small hepatic veins without involvement of the large veins is included in the definition of Budd–Chiari syndrome, while the specific entity of veno-occlusive disease is excluded. The rationale for this distinction has been much debated but is justified by several arguments. Except for veno-occlusive disease as defined above, the obstruction limited to the small veins are generally due to thrombosis, allergic phlebitis or granulomatous involvement, all reported causes of large hepatic vein obstruction [[7]Valla D. Benhamou J. Obstruction of the hepatic venous system.in: Bircher J. Benhamou J. McIntyre N. Rizzetto M. Rodes J. Oxford textbook of clinical hepatology. 2nd ed. Oxford Medical Publication, Oxford1999: 1469-1478Google Scholar]. Although the manifestations are sometimes difficult to distinguish from those of veno-occlusive disease, the context is usually outside the setting of bone marrow transplantation. A differentiation between isolated small vein thrombosis and veno-occlusive disease can be achieved by means of liver biopsy.3. ClassificationBudd–Chiari syndrome can be classified according to etiology, site of obstruction, manifestations and duration of the disease.3.1 EtiologyBudd–Chiari syndrome is considered primary when obstruction of the hepatic venous outflow tract is the result of an endoluminal venous lesion (thrombosis or web) (Table 1). It is considered secondary when the obstruction results from the presence in the lumen of material not originating from the venous system (malignant tumor or a parasitic mass invading the lumen) or from extrinsic compression by a neighboring tumor (abscesses, cysts, benign or malignant solid tumors) [[3]Okuda K. Kage M. Shrestha S.M. Proposal of a new nomenclature for Budd–Chiari syndrome: hepatic vein thrombosis versus thrombosis of the inferior vena cava at its hepatic portion.Hepatology. 1998; 28: 1191-1198Crossref PubMed Scopus (157) Google Scholar]. In practice, Budd–Chiari syndrome is regarded as primary when no causes of secondary obstruction are found. Modern imaging techniques allow easy recognition of these associated lesions. Venous compression can be complicated by thrombosis, particularly when prothrombotic factors are present by chance (inherited thrombophilia) or by association (inflammatory response secondary to an adjacent abscess).Table 1Classification of Budd–Chiari syndrome according to etiologyDesignationDefinitionPrimaryHepatic venous outflow obstruction originating from endoluminal venous lesion (thrombosis, webs, endophlebitis)SecondaryHepatic venous outflow obstruction originating from a lesion outside the venous system (tumor, abscess, cysts). The lesion can obstruct outflow by invading the lumen or by extrinsic compression. Open table in a new tab 3.2 Site of obstructionObstruction of the hepatic venous outflow tract is classified according to its location: small hepatic veins, large hepatic veins, inferior vena cava and combined obstruction of large hepatic veins and inferior vena cava (Table 2) [[2]Ludwig J. Hashimoto E. McGill D.B. van Heerden J.A. Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd–Chiari syndrome.Mayo Clin Proc. 1990; 65: 51-55Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]. The term thrombosis should be used only when there is pathological evidence for this lesion. This classification can be used in the absence of pathological examination of the venous outflow tract, which should be preferred in future clinical investigations [[8]Tang T. Batts K. de Groen P. van Hoek B. Haagsma E. Hop W. et al.The prognostic value of histology in the assessment of patients with Budd–Chiari syndrome.J Hepatol. 2001; 35: 338-343Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. The site of obstruction is in general easily determined through non-invasive imaging (Doppler-ultrasound, magnetic resonance (MRI), computed tomography) or conventional venography.Table 2Classification of Budd–Chiari syndrome according to site of obstruction [2]Ludwig J. Hashimoto E. McGill D.B. van Heerden J.A. Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd–Chiari syndrome.Mayo Clin Proc. 1990; 65: 51-55Abstract Full Text Full Text PDF PubMed Scopus (180) Google ScholarDesignationDefinitionSmall hepatic veinsVeins that cannot be shown clearly on hepatic venograms or by ultrasound studies; they include terminal hepatic veins (central veins), intercalated veins and interlobular veins.Large hepatic veinsVeins that are regularly demonstrable on hepatic venograms and ultrasound studies; segmental branches of hepatic veins are generally includedInferior vena cava (IVC)A segment of the IVC which extends from the entry level of the right, middle and left hepatic veins to the junction between the IVC and the right atriumCombined obstructionCombination of obstruction in the large hepatic veins and IVC Open table in a new tab 3.3 Manifestations and duration of diseaseIt is important to recognize that Budd–Chiari syndrome is not always a severe disease requiring aggressive treatment. Lack of long-term prognostic studies of unselected patients has limited our knowledge about the real prevalence of the different clinical forms of the syndrome. Budd–Chiari syndrome is considered asymptomatic when there are no signs of abdominal pain, ascites, hepatomegaly, edema, encephalopathy and gastrointestinal bleeding, or a history of any of them [[9]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: 1042-1047Google Scholar]. The diagnosis of asymptomatic Budd–Chiari syndrome in these patients is often made in the course of a routine examination, e.g. in patients with myeloproliferative syndrome.There is currently no consensus on the classification of disease severity (fulminant vs. non-fulminant) and disease duration (acute, subacute and chronic). To be clinically useful, such a classification should be based on factors influencing prognosis and factors, which guide physicians in their management of the disease. These factors should be extracted from future studies based on large retrospective or prospective data sets. A purely descriptive stratification for disease severity should be used in clinical studies until such a prognostic classification is validated. In previous classifications, duration of symptoms, rate of disease progression, severity of manifestations and the age of venous or hepatic lesions have been variously used to differentiate among fulminant, acute, subacute or chronic disease [1Dilawari 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: 21-36PubMed Google Scholar, 7Valla D. Benhamou J. Obstruction of the hepatic venous system.in: Bircher J. Benhamou J. McIntyre N. Rizzetto M. Rodes J. Oxford textbook of clinical hepatology. 2nd ed. Oxford Medical Publication, Oxford1999: 1469-1478Google Scholar, 10Reynolds T. Peters R. Budd–Chiari syndrome.in: Schiff L. Diseases of the liver. 4th ed. JB Lippincott, Philadelphia, PA1975: 1502-1510Google Scholar, 11Bismuth H. Sherlock D.J. Portasystemic shunting versus liver transplantation for the Budd–Chiari syndrome.Ann Surg. 1991; 214: 581-589Crossref Scopus (104) Google Scholar, 12Mahmoud A.E. Mendoza A. Meshikhes A.N. Olliff S. West R. Neuberger J. et al.Clinical spectrum, investigations and treatment of Budd–Chiari syndrome [see comments].Q J Med. 1996; 89: 37-43Crossref Scopus (95) Google Scholar, 13Klein A.S. Cameron J.L. Diagnostis and management of the Budd–Chiari syndrome [see comments].Am J Surg. 1990; 160: 128-133Abstract Full Text PDF Scopus (62) Google Scholar, 14Orloff M.J. Daily P.O. Orloff S.L. Girard B. Orloff M.S. A 27-year experience with surgical treatment of Budd–Chiari syndrome.Ann Surg. 2000; 232: 340-352Crossref Scopus (148) Google Scholar]. The prognostic value of these categories has not been assessed. It is well known that the disease can have a long insidious course or a rapid downhill course. Furthermore, the apparent age of the macroscopic and microscopic damage to the liver may differ from the apparent duration of symptoms. Several cases with a recent clinical onset have been associated with marked liver fibrosis, suggesting a long preclinical course [[15]Parker P. Occlusion of hepatic veins in man.Medicine. 1959; 38: 369-402PubMed Google Scholar]. Recent thrombosis superimposed on older lesions probably explains the acute clinical onset in these patients.4. Diagnostic investigationsThe aims of diagnostic work-up in Budd–Chiari syndrome are threefold: assessment of the diagnosis, liver injury and etiology.4.1 Assessment of diagnosisSince the disease can deteriorate rapidly, the need to obtain the correct diagnosis is usually urgent. The diagnosis of Budd–Chiari syndrome should be suspected under the following circumstances: (a) whenever ascites, liver enlargement and upper abdominal pain are present simultaneously; (b) for patients with signs of chronic liver disease, whenever intractable ascites contrasts with mildly altered liver function tests; (c) whenever liver disease is documented in a patient known to have a prothrombotic disorder; (d) whenever fulminant hepatic failure is associated with liver enlargement and ascites; (e) whenever chronic liver disease remains unexplained after alcoholism, chronic viral hepatitis B or C, autoimmunity, iron overload, Wilson's disease and alpha-1 antitrypsin deficiency have been excluded. These circumstances, although suggestive, are not sufficient to make a diagnosis of Budd–Chiari syndrome. This is established only upon demonstration of an obstructed hepatic venous outflow tract. Obviously, histopathological assessment of an explanted liver or of a necropsy specimen is the ultimate method to firmly establish the diagnosis [15Parker P. Occlusion of hepatic veins in man.Medicine. 1959; 38: 369-402PubMed Google Scholar, 16Miller W.J. Federle M.P. Straub W.H. Davis P.L. Budd–Chiari syndrome: imaging with pathologic correlation.Abdom Imaging. 1993; 18: 329-335Crossref Scopus (89) Google Scholar]. However, in the clinical setting, various imaging modalities are available for investigating the gross hepatic vascular anatomy: ultrasound, MRI, computed tomography and X-ray venography (Fig. 1A). Ultrasound combined with Doppler imaging has a diagnostic sensitivity of more than 75% and should be the first line of investigation [17Bolondi L. Gaiani S. Li Bassi S. Zironi G. Bonino F. Brunetto M. et al.Diagnosis of Budd–Chiari syndrome by pulsed Doppler ultrasound.Gastroenterology. 1991; 100: 1324-1331Google Scholar, 18Chawla Y. Kumar S. Dhiman R.K. Suri S. Dilawari J.B. Duplex Doppler sonography in patients with Budd–Chiari syndrome.J Gastroenterol Hepatol. 1999; 14: 904-907Crossref PubMed Scopus (55) Google Scholar]. Hepatic veins devoid of flow signal, collateral hepatic venous circulation, a spider-web appearance usually located in the vicinity of the hepatic vein ostia and stagnant, reversed or turbulent flow can all be indicative of Budd–Chiari syndrome [19Kane R. Eustace S. Diagnosis of Budd–Chiari syndrome: comparison between sonography and MR angiography.Radiology. 1995; 195: 117-121PubMed Google Scholar, 20Millener P. Grant E.G. Rose S. Duerinckx A. Schiller V.L. Tessler F.N. et al.Color Doppler imaging findings in patients with Budd–Chiari syndrome: correlation with venographic findings.AJR Am J Roentgenol. 1993; 161: 307-312Crossref Scopus (94) Google Scholar]. Lack of visualization or tortuosity of the hepatic veins at real-time ultrasonography is common but not specific for Budd–Chiari syndrome because such features can be seen in advanced cirrhosis. A distinctive feature of Budd–Chiari syndrome, however, is the association with intrahepatic or subcapsular hepatic venous collaterals. When it is technically difficult to obtain an adequate sonographic evaluation or when the diagnostic features cannot be demonstrated, computed tomography or, preferably, MRI should be performed as a second line of investigation [19Kane R. Eustace S. Diagnosis of Budd–Chiari syndrome: comparison between sonography and MR angiography.Radiology. 1995; 195: 117-121PubMed Google Scholar, 21Gupta S. Barter S. Phillips G.W. Gibson R.N. Hodgson H.J. Comparison of ultrasonography, computed tomography and 99mTc liver scan in diagnosis of Budd–Chiari syndrome.Gut. 1987; 28: 242-247Crossref Scopus (54) Google Scholar]. With the combination of these imaging procedures, the diagnosis will remain uncertain only in a small minority of cases. Uncertainty is likely to occur mainly in patients with cirrhosis. The third line of investigation should be retrograde cannulation of the hepatic veins for venography and liver biopsy [[22]Kreel L. Freston J. Clain D. Vascular radiology in the Budd–Chiari syndrome.Br J Radiol. 1967; 40: 755-759Crossref PubMed Scopus (45) Google Scholar]. Venography is useful in the assessment of the extent of outflow obstruction and also allows for pressure measurements, while the concurrent liver biopsy yields data that is useful not only for confirming the diagnosis of Budd–Chiari syndrome but also for ruling out other processes such as veno-occlusive disease and cirrhosis of other etiologies [[23]Tanaka M. Wanless I.R. Pathology of the liver in Budd–Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules.Hepatology. 1998; 27: 488-496Crossref Scopus (192) Google Scholar]. The disadvantage of venography is that it is often impossible to cannulate the hepatic veins and that the procedure usually requires the use of considerable amounts of iodine-containing contrast medium.4.2 Assessment of disease severityLiver injury and the extent of venous obstruction should be assessed to clarify prognosis and treatment of the disease. Although a liver biopsy can help in the diagnosis of Budd–Chiari syndrome, its value in the assessment of disease severity and prognosis has been shown to be of limited value [8Tang T. Batts K. de Groen P. van Hoek B. Haagsma E. Hop W. et al.The prognostic value of histology in the assessment of patients with Budd–Chiari syndrome.J Hepatol. 2001; 35: 338-343Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 24Zeitoun 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.Hepatology. 1999; 30: 84-89Crossref Scopus (200) Google Scholar]. This is probably due to sample variation, which is caused by the inhomogeneous distribution of disease in the liver. Liver histology, therefore, should not be considered essential to assess liver injury in patients with an established diagnosis of Budd–Chiari syndrome. Laboratory and radiological investigations, in addition to being safer, are probably better in providing prognostic information and in guiding therapy. Child–Pugh score and renal function are important determinants of prognosis [8Tang T. Batts K. de Groen P. van Hoek B. Haagsma E. Hop W. et al.The prognostic value of histology in the assessment of patients with Budd–Chiari syndrome.J Hepatol. 2001; 35: 338-343Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 24Zeitoun 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.Hepatology. 1999; 30: 84-89Crossref Scopus (200) Google Scholar]. The combination of Doppler-ultrasound and MRI allow optimal delineation of venous obstruction for therapeutic decisions. Venography with pressure measurements, in particular, should be performed when percutaneous or surgical shunting is considered. A major, as yet, unanswered issue is how to take the degree of liver dysfunction into account when choosing the type of medical or surgical therapy. The uncontrolled non-randomized studies performed thus far do not allow this issue to be addressed [14Orloff M.J. Daily P.O. Orloff S.L. Girard B. Orloff M.S. A 27-year experience with surgical treatment of Budd–Chiari syndrome.Ann Surg. 2000; 232: 340-352Crossref Scopus (148) Google Scholar, 25Ringe B. Lang H. Oldhafer K.J. Gebel M. Flemming P. Georgii A. et al.Which is the best surgery for Budd–Chiari syndrome: venous decompression or liver transplantation? A single-center experience with 50 patients.Hepatology. 1995; 21: 1337-1344Crossref Google Scholar, 26Henderson J. Warren D. Millikan W. Surgical options, hematologic evaluation and pathological changes in Budd–Chiari syndrome.Am J Surg. 1990; 159: 41-50Abstract Full Text PDF PubMed Scopus (110) Google Scholar].4.3 Assessment of etiologyThe cause of Budd–Chiari syndrome should be investigated systematically. Liver imaging allows recognition of the lesions causing secondary Budd–Chiari syndrome. In primary Budd–Chiari syndrome, the search for an underlying thrombogenic condition can be carried out using the following investigations: hemogram, determination of plasma levels of coagulation factors and inhibitors, determination of genetic defects in the factor V and prothrombin gene, determination of antiphospholipid antibodies and lupus anticoagulant, and flow cytometry testing for paroxysmal nocturnal hemoglobinuria [27Mohanty S. Saxena R. Acharya S.K. Activated protein C resistance in Budd–Chiari syndrome.Int J Hematol. 2000; 72: 255Google Scholar, 28Janssen 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: 2364-2368PubMed Google Scholar, 29Deltenre 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: 264-268Crossref PubMed Scopus (142) Google Scholar, 30Bucciarelli P. Franchi F. Alatri A. Bettini P. Moia M. Budd–Chiari syndrome in a patient heterozygous for the G20210A mutation of the prothrombin gene.Thromb Haemost. 1998; 79: 445-446Google Scholar, 31Pelletier S. Landi B. Piette J.C. Ekert P. Coutellier A. Desmoulins C. et al.Antiphospholipid syndrome as the second cause of non-tumorous Budd–Chiari syndrome.J Hepatol. 1994; 21: 76-80Abstract Full Text PDF Scopus (105) Google Scholar, 32Aggarwal R. Ravishankar B. Misra R. Aggarwal A. Dwivedi S. Naik S.R. Significance of elevated IgG anticardiolipin antibody levels in patients with Budd–Chiari syndrome.Am J Gastroenterol. 1998; 93: 954-957Crossref Scopus (24) Google Scholar, 33Valla D. Dhumeaux D. Babany G. Hillon P. Rueff B. Rochant H. et al.Hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria. A spectrum from asymptomatic occlusion of hepatic venules to fatal Budd–Chiari syndrome.Gastroenterology. 1987; 93: 569-575Google Scholar]. Primary Budd–Chiari syndrome is associated with one or more underlying thrombogenic conditions in at least 75% of the patients [28Janssen 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: 2364-2368PubMed Google Scholar, 34Mahmoud A.E. Elias E. Beauchamp N. Wilde J.T. Prevalence of the factor V Leiden mutation in hepatic and portal vein thrombosis [see comments].Gut. 1997; 40: 798-800Crossref Scopus (133) Google Scholar, 35Denninger 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: 587-591Crossref PubMed Scopus (572) Google Scholar, 36Minnema M.C. Janssen H.L. Niermeijer P. de Man R.A. Budd–Chiari syndrome: combination of genetic defects and the use of oral contraceptives leading to hypercoagulability.J Hepatol. 2000; 33: 509-512Abstract Full Text Full Text PDF Scopus (35) Google Scholar]. Several forms of hypercoagulability are inherited, a fact, which can be used to trace affected family members. Several systemic disorders, such as myeloproliferative disorders, may necessitate specific therapy, in addition to anticoagulation. Careful evaluation of the peripheral blood pattern for evidence of a primary myeloproliferative disorder may be followed by bone marrow biopsy, determination of total red cell mass and serum erythropoietin determination. Alternatively, culture of bone marrow or peripheral blood progenitors for assessment of spontaneous erythroid colony formation, when available, may support the diagnosis of a primary myeloproliferative disorder [37Valla D. Casadevall N. Lacombe C. Varet B. Goldwasser E. Franco D. et al.Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd–Chiari syndrome.Ann Intern Med. 1985; 103: 329-334Crossref Scopus (273) Google Scholar, 38Acharya J. Westwood N.B. Sawyer B.M. Messinezy M. Burroughs A.K. Mehta A.B. et al.Identification of latent myeloproliferative disease in patients with Budd–Chiari syndrome using X-chromosome inactivation patterns and in vitro erythroid colony formation.Eur J Haematol. 1995; 55: 315-321Crossref Scopus (22) Google Scholar, 39Dayal S. Pati H.P. Pande G.K. Sharma M.P. Saraya A.K. Multilineage hemopoietic stem cell defects in Budd Chiari syndrome.J Hepatol. 1997; 26: 293-297Abstract Full Text PDF Scopus (28) Google Scholar].The diagnosis of inherited deficiencies in protein C, protein S and antithrombin in patients with Budd–Chiari syndrome is difficult because acquired deficiencies can develop in the event of liver failure, acute thrombosis and anticoagulant therapy. Therefore, decreased levels of coagulation inhibitors are of significance only when associated with normal or slightly reduced levels of coagulation factors. Otherwise, correction for the effect of liver insufficiency must be performed using e.g. the factor II or X plasma levels [[28]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: 2364-2368PubMed Google Scholar]. Family studies can provide useful information. Testing for methylene tetrahydrofolate reductase gene is not yet considered an essential part of the etiological work-up. Investigation of other recently documented thrombogenic factors (homocystein, factor XI, factor VIII) may prove useful but the sensitivity and specificity of the findings in the presence of chronic liver disease have to be assessed.Since a combined etiology is found in at least 25% of the patients, identification of a single cause should not preclude investigation of other etiological factors [[35]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: 587-591Crossref PubMed Scopus (572) Google Scholar]. Hormonal supplementation, for oral contraception, may enhance pre-existing prothrombotic tendency and be implicated in the pathogenesis of Budd–Chiari syndrome [[28]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–Ch