Budd-Chiari Syndrome

A number sign (#) is used with this entry because susceptibility to Budd-Chiari syndrome can result from mutation in the F5 gene (612309) on chromosome 1q24 or somatic mutation in the JAK2 gene (147796) on chromosome 9p24.

Clinical Features

Budd-Chiari syndrome is a spectrum of disease states, including anatomic abnormalities and hypercoagulable disorders, resulting in hepatic venous outflow occlusion. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain, and abdominal ascites (Zimmerman et al., 2006).

One of the causes of the Budd-Chiari syndrome is a membranous obstruction of the inferior vena cava (MOVC). Primary thrombosis due to a thrombophilia such as that resulting from defects in the natural coagulation inhibitors such as protein C (612283), protein S (176880), and antithrombin III (107300) are also causes. Riemens et al. (1995) reported a family in which 3 of 11 sibs (2 sisters and 1 brother) showed symptoms of MOVC developing in early adult life. All had signs of more longstanding disease, as judged by the presence of collaterals, cirrhosis, and, in one case, hepatocellular carcinoma. The brother died with lung metastasis from the hepatocellular carcinoma, while the 2 sisters had surgical removal of the membrane and were well 20 and 21 years after surgery. On family screening, no further cases of membranous obstruction of the inferior vena cava were found. There was no evidence of an inherited defect in a coagulation inhibitor or plasminogen deficiency (173350); however, Riemens et al. (1995) could not totally exclude a thrombotic etiology.

Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera (PV; 263300). Cario et al. (2003) described a third pediatric case of Budd-Chiari syndrome as the initial symptom of familial polycythemia vera in an 11-year-old girl; the patient's grandmother also had polycythemia vera. The patient's mother was unaffected. The patient underwent orthotopic liver transplantation and the polycythemia vera was treated with hydroxyurea. In agreement with the clinical diagnosis, the polycythemia rubra vera-1 gene (PRV1; 162860) showed increased mRNA expression in peripheral granulocytes.

Menon et al. (2004) reviewed all aspects of Budd-Chiari syndrome, including the inherited hypercoagulable states that had been found to be associated with the disorder. They noted that the relative risk of hepatic vein thrombosis among women who use oral contraceptives is 2.37, which is similar to their relative risk of stroke, myocardial infarction, and venous thromboembolism (Valla et al., 1986). Many patients in whom Budd-Chiari syndrome develops in association with the use of oral contraceptives or pregnancy also have an underlying thrombophilia, either inherited or acquired.

Molecular Genetics

Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation (R506Q; 612309.0001) in Budd-Chiari syndrome and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis.

Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. Budd-Chiari syndrome is rare in children.

Janssen et al. (2000) compared 43 patients with Budd-Chiari syndrome and 92 patients with portal vein thrombosis with 474 population-based controls. The relative risk of Budd-Chiari syndrome was 11.3 for individuals with the factor V Leiden mutation, 2.1 for those with a prothrombin (176930) gene mutation, and 6.8 for those with protein C deficiency. In patients with portal vein thrombosis, the corresponding figures were 2.7, 1.4, and 4.6, respectively. The relative risk of Budd-Chiari syndrome or portal vein thrombosis was not increased in the presence of inherited protein S or antithrombin deficiency.

Patel (2005) identified a V617F mutation in the JAK2 gene (147796.0001) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Chung et al. (2006) described Budd-Chiari syndrome in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the JAK2 V617F mutation and the factor V Leiden mutation.

Pathogenesis

Sozer et al. (2009) identified somatic homozygous JAK2 V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated patients with polycythemia vera who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients.