Etiology of the Budd-Chiari syndrome

INTRODUCTION — The Budd-Chiari syndrome can be defined as any pathophysiologic process that results in an interruption or diminution of the normal flow of blood out of the liver [1,2]. However, as commonly used, the Budd-Chiari syndrome implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. An alternative nomenclature that recognizes an obliterative process involving principally the inferior vena cava ("obliterative hepatocavopathy") has also been proposed [3]. The term is usually distinguished from two other conditions that interfere with hepatic venous flow: sinusoidal obstruction syndrome (hepatic veno-occlusive disease) and right heart failure.

●Disorders that involve the microscopic centrilobular veins and small sublobular veins within the liver are usually due to nonthrombotic fibrous occlusion and obliteration of these small veins. The distinct anatomic location, pathology, and conditions (eg, ingestion of toxic pyrrolizidine alkaloids or exposure to high doses of radiation or chemotherapeutic agents) with which sinusoidal obstruction syndrome is associated allow it to be placed in its own category [4,5]. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

●Although disorders of the heart may present clinically as the Budd-Chiari syndrome (eg, constrictive pericarditis, chronic right-sided heart failure with severe tricuspid insufficiency), the pathogenesis and treatment of these disorders are quite different from those usually considered typical of the Budd-Chiari syndrome. (See "Congestive hepatopathy".)

Thus, the Budd-Chiari syndrome is due to occlusion or partial occlusion of one, two, or all three of the major hepatic veins (right, middle, and left) and/or occlusion or partial occlusion of the inferior vein cava (figure 1) [6]. In addition, several small veins that enter the inferior vena cava directly from the posterior surface of the caudate lobe and occasionally from the right and left hepatic lobes may or may not be involved by the occlusive process.

This topic review will discuss the major causes of the Budd-Chiari syndrome. The symptoms, diagnosis, and treatment of this disorder are discussed separately. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis".)

ETIOLOGY — An underlying disorder can be identified in over 80 percent of patients with the Budd-Chiari syndrome [7-14]. More than one thrombotic risk factor is present in many patients; 46 percent had more than one risk factor in one series [14]. Many of these disorders are characterized by a hypercoagulable state, which is important to consider when treating Budd-Chiari syndrome (eg, the importance of anticoagulation after endovascular intervention) (table 1). An evaluation for acquired and inherited thrombotic conditions is generally performed for patients with Budd-Chiari syndrome, and this is discussed separately. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Myeloproliferative disorders — As many as 50 percent of all cases of the Budd-Chiari syndrome may be due to an underlying chronic myeloproliferative disorder (eg, polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia) and an accompanying hypercoagulable state. Peripheral blood evidence for myeloproliferation may not be present if portal hypertension, splenomegaly, and a hypersplenic state accompany the Budd-Chiari syndrome.

The combination of a myeloproliferative disorder (occult or overt) associated with a hypercoagulable state (or states) is common [14-17]. In one of the largest published series (involving 237 patients evaluated at four centers between 1984 and 2001), 23 percent had an overt myeloproliferative disorder (polycythemia vera in 45 patients and essential thrombocytosis in 9 patients) [18]. In another large series, 49 percent of 103 patients who underwent testing had a myeloproliferative disorder, the most common of which was polycythemia vera [14]. (See "Overview of the myeloproliferative neoplasms".)

Spontaneous erythroid colony formation in the presence of low serum erythropoietin levels, increased megakaryocyte colony growth, and clonal karyotypic abnormalities have all been reported in patients with Budd-Chiari syndrome due to myeloproliferative disorders [19] and in some so-called "idiopathic" cases of Budd-Chiari syndrome, suggesting the presence of an occult myeloproliferative syndrome in these persons [15,16,20-23]. In one study, for example, spontaneous endogenous erythroid colony formation in vitro and/or bone marrow biopsies suggested that a primary myeloproliferative disorder was present in 78 percent of such patients [22].

JAK2 tyrosine kinase (V617F) mutations have been described in 26 to 59 percent of patients with Budd-Chiari syndrome, many of whom had negative results from standard testing for myeloproliferative disorders [14,17,23-25]. A JAK2 mutation is present in almost all patients with polycythemia vera and approximately 50 percent of patients with essential thrombocythemia or chronic idiopathic myelofibrosis. One report described Budd-Chiari syndrome associated with hypereosinophilic syndrome and a JAK2 mutation [26]. We suggest that patients diagnosed with Budd-Chiari syndrome in whom no underlying disorder can be identified be tested for a JAK2 mutation. (See "Overview of the myeloproliferative neoplasms", section on 'Mutations in PV, ET, and PMF'.)

Interestingly, some data suggest that the liver may produce erythropoietin during the acute phase of Budd-Chiari syndrome [27]. Such a change could contribute to the apparent spontaneous erythroid colony formation in cultured bone marrow or peripheral blood mononuclear cells demonstrated in these patients.

Malignancy — Malignancies account for approximately 10 percent of cases of the Budd-Chiari syndrome. Direct compression or invasion of vascular structures and the hypercoagulable state associated with malignancy can result in venous thrombosis and/or obstruction (see "Risk and prevention of venous thromboembolism in adults with cancer"). Hepatocellular carcinomas are found most often, followed by cancer of the adrenal gland or kidney, sarcomas of the right atrium, inferior vena cava or hepatic veins, and cancers of the lung, pancreas, and stomach [9]. Hepatocellular carcinoma has also been associated with membranous obstruction of the inferior vena cava, another cause of Budd-Chiari syndrome. (See 'Membranous webs' below and "Clinical features and diagnosis of hepatocellular carcinoma".)

Infections and benign lesions of the liver — Infections or benign space-occupying lesions of the liver can, like tumors, compress and/or thrombose vascular structures, accounting for nearly 10 percent of cases of Budd-Chiari syndrome. Some of these disorders also may be accompanied by a hypercoagulable state. These lesions include hepatic cysts and abscesses, hepatic adenoma, hepatic mucinous cystic neoplasm (cystadenoma), syphilitic gumma, invasive aspergillosis, zygomycosis (mucormycosis), and aortic aneurysm [9].

Oral contraceptives and pregnancy — Nearly 20 percent of cases of the Budd-Chiari syndrome occur in women who have been on oral contraceptives (for as little as two weeks), are pregnant, or have delivered a child within the previous two months [28-32]. It is presumed that the hypercoagulable state in these women is responsible for this association. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)

Other hypercoagulable states — A number of other hypercoagulable states have been associated with the Budd-Chiari syndrome. These include [33,34]:

●G1691A factor V (Leiden) gene mutation, which produces activated protein C resistance [35-39] (see "Factor V Leiden and activated protein C resistance")

●G20210A factor II gene mutation [40] (see "Prothrombin G20210A")

●Antiphospholipid syndrome [41-45] (see "Clinical manifestations of antiphospholipid syndrome")

●Antithrombin deficiency [46,47] (see "Antithrombin deficiency")

●Protein C deficiency [48-50] (see "Protein C deficiency")

●Protein S deficiency (see "Protein S deficiency")

●Paroxysmal nocturnal hemoglobinuria [51,52] (see "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria")

The factor V Leiden mutation, the most frequent cause of hereditary thrombophilia, may be particularly important. This mutation was present in approximately 25 percent of patients in three series that included a total of 126 patients [37,53,54]. A systematic review and meta-analysis of observational studies in Budd-Chiari syndrome found that inherited deficiencies of antithrombin, protein C, and protein S were rare (2.3, 3.8, and 3 percent, respectively) [55].

The likelihood of thrombosis may be greatest when the factor V Leiden mutation occurs in combination with another predisposing disorder or condition such as pregnancy, the administration of oral contraceptives, or a myeloproliferative syndrome [35,56]. (See "Factor V Leiden and activated protein C resistance".)

That the interaction of one or more predisposing conditions may coexist was also supported in a study that included 32 patients with Budd-Chiari syndrome in whom the presence of most of the known prothrombotic conditions was investigated [57]. A myeloproliferative disorder was detected in 17 patients of whom 7 (41 percent) also had one or more prothrombotic coagulation disorders. Of 11 other patients without a myeloproliferative disorder, 9 had a single prothrombotic coagulation disorder (82 percent). The G20210A factor II gene mutation was observed in 2 of 32 patients (6 percent) with Budd-Chiari syndrome and in 5 of 36 patients (14 percent) with protal vein thrombosis. Among healthy controls, the mutation is seen in 1 to 5 percent of patients [58-61]. The prevalence of homozygous C677TMTHFR (methylene-tetrahydrofolate-reductase) gene mutation was 12.5 percent, which was similar to the healthy controls (approximately 10 percent).

In one of the studies described above [53], the presence of combined (acquired and inherited) risk factors was 25, 49, 19, and 7 percent of the group having zero, one, two, or three risk factors, respectively [53].

Additional prothrombotic conditions that may contribute to venous thrombosis (such as high levels of factor XI) continue to be described [62]. Whether they are associated with the Budd-Chiari syndrome requires further investigation. A single case-control study suggests that impaired fibrinolysis, partially caused by elevated plasminogen activator inhibitor 1 levels, may play a role in the pathogenesis of Budd-Chiari syndrome [63].

Behçet syndrome — Vasculitis is an important feature of Behçet syndrome (see "Clinical manifestations and diagnosis of Behçet syndrome"). In one study of 493 cases, 53 had one or more large vessel thrombosis [64]. Fourteen of these 53 patients had hepatic vein thrombosis, eight also had inferior vena cava thrombosis, and two had both inferior vena cava and portal vein thrombosis. Only two patients had isolated hepatic vein thrombosis.

Membranous webs — Membranous obstruction (partial or complete) of the inferior vena cava (MOVC) and/or the hepatic veins is an unusual but potentially treatable cause of the Budd-Chiari syndrome in the United States [65], but it is much more common in South Africa, India, and Asia [66,67]. These web-like lesions, which usually are found just cephalad to the entrance of the right hepatic vein into the inferior vena cava, may be the result of a congenital anomaly. However, they are more often attributable to an acquired thrombotic process such as a myeloproliferative disease [68,69]. MOVC has also been associated with the subsequent development of hepatocellular carcinoma [70,71].

It is important to diagnose MOVC or so-called short-length hepatic vein stenoses [72] because of the availability of treatment options (eg, anticoagulation, angioplasty, or stenting) that are usually not germane to other causes of the Budd-Chiari syndrome.

Miscellaneous — Miscellaneous associations with the Budd-Chiari syndrome include systemic lupus erythematosus, mixed-connective tissue disease, Sjögren's disease, inflammatory bowel disease, hypereosinophilic syndrome, idiopathic granulomatous venulitis, sarcoidosis, protein-losing enteropathy, minimal change nephrotic syndrome, neurofibromatosis, alpha-1 antitrypsin deficiency, trauma (including laparoscopic cholecystectomy) or torsion of the liver, and rare familial cases [9,73].

Idiopathic — Approximately 20 percent of cases of the Budd-Chiari syndrome are listed as idiopathic [74]. As more and more conditions which predispose to Budd-Chiari syndrome, such as occult myeloproliferative disease and factor V Leiden mutation, are recognized, the percentage of cases described as idiopathic will continue to decrease [22].

HEMODYNAMIC CONSEQUENCES — Regardless of the cause, patients with Budd-Chiari syndrome develop postsinusoidal portal hypertension, which leads to complications similar to those observed in patients with cirrhosis. However, the systemic hemodynamic effects differ from those that are observed classically in patients with cirrhosis.

The most detailed study evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with Budd-Chiari syndrome who were admitted for complications of portal hypertension [75]. Systemic, cardiopulmonary pressures, and cardiac indices in patients with Budd-Chiari syndrome were within the normal range for most patients, but were significantly different compared with a matched group of cirrhotic patients. Despite normal systemic vascular resistance, there was activation of the neurohumoral vasoactive systems and plasma volume expansion. Normal pressures were not observed in all patients; in approximately one-third (mostly those with longer duration of illness) systemic vascular resistance was decreased.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatic, portal, and splenic vein thrombosis".)

SUMMARY AND RECOMMENDATIONS

●Background – The Budd-Chiari syndrome can be defined as any pathophysiologic process that results in an interruption or diminution of the normal flow of blood out of the liver.

●Etiology – An underlying disorder can be identified in over 80 percent of patients with the Budd-Chiari syndrome. Many of these disorders are characterized by a hypercoagulable state, which is important to consider when treating the Budd-Chiari syndrome (eg, the importance of anticoagulation after endovascular intervention (table 1). As a general rule, work-up should include hepatic imaging and evaluation for inflammatory, immunologic, and thrombotic disorders. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and 'Etiology' above.)

●Hemodynamic consequences – Regardless of the cause, patients with Budd-Chiari syndrome develop postsinusoidal portal hypertension, which leads to complications similar to those observed in patients with cirrhosis. However, the systemic hemodynamic effects differ from those that are observed classically in patients with cirrhosis. (See 'Hemodynamic consequences' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen C Hauser, MD, who contributed to an earlier version of this topic review.