Budd-Chiari syndrome and veno-occlusive disease

Hematologic disorders

Hematologic diseases that cause vascular thrombosis are the most common conditions that predispose to BCS in North America and Western Europe. Of disorders with thrombotic tendencies, myeloproliferative diseases (MPDs) are most often associated with BCS. A review of reported cases indicates myelodysplasia as an underlying etiology in approximately half of affected patients. A recent meta-analysis of BCS studies implicates MPD in 40.9% of 1062 reported cases of BCS. Historically, polycythemia vera has been the most frequently occurring of the MPDs in BCS patients, constituting 8.5% of the cases of BCS in the collected series of Parker and 10.4% of the cases in the collected series of Mitchell et al.. However, in contemporary series the prevalence is considerably higher. In the series of 77 cases reported by Orloff et al., 31% had polycythemia vera, and its association with BCS was noted to diverge from the classic description of BCS in several ways. First, it was found more often in young adults, rather than in middle-aged and elderly patients. Second, polycythemia vera has been shown to be responsive to treatment with hydroxyurea, which should be started as soon as the disease is discovered and continued for life. Other treatments for polycythemia vera include serial phlebotomy, anagrelide, interferon alfa-2b, and ruxolitinib, recently approved by the US Food and Drug Administration (FDA). Whatever treatment regimen is used, the disease runs a benign course if treated early.

Paroxysmal nocturnal hemoglobinuria (PNH) is another hematologic disorder associated with BCS. It was responsible for 6.7% of the cases in the collected series of Mitchell et al. and 12% of the cases in the series of Valla et al.. In all the hematologic disorders associated with hepatic vein thrombosis, but particularly in PNH, thrombosis of other splanchnic vessels and even extraabdominal vessels has been observed. When diagnosed early, PNH should be treated with eculizumab to prevent long-term sequelae.

While hematologic diagnosis has become progressively more sophisticated, many other thrombogenic conditions have been identified in BCS, including other myeloproliferative states (e.g., essential thrombocythemia, primary erythrocytosis, myelofibrosis) and thrombophilic states, such as protein C deficiency, protein S deficiency, antithrombin III deficiency, and antiphospholipid syndrome with lupus anticoagulant or anticardiolipin antibodies or both. ^{, ,} Patients with the factor V Leiden mutation, which leads to activated protein C resistance, have a 5-fold to 10-fold increase in the risk of thrombosis if they are heterozygotic and a 50-fold to 100-fold increase if they are homozygotic. ^{, ,} More recent evidence indicates that multiple prothrombotic factors acting concurrently are involved in a substantial percentage of patients with BCS. ^, Rarely, hematologic malignancies, such as acute leukemia and lymphoma, have been associated with BCS.

In 2005 identification of the underlying cause of BCS was enhanced by the discovery of a very reliable and noninvasive marker for chronic MPDs. The marker is the gain-of-function mutation V617F of the JAK2 gene. By combining identification of this marker with results of bone marrow histology and clonality assay, more than 50% of BCS cases have been found to be caused by an underlying chronic MPD.

It cannot be overemphasized that every patient found to have BCS should undergo a thorough hematologic evaluation. The assessment is an expansion of the workup proposed by Mahmoud and Elias and others ^, ( Box 86.2 ). With these studies, it should be possible to diagnose all the known predisposing thrombogenic hematologic disorders associated with BCS. If this evaluation is uniformly performed, the incidence of idiopathic BCS will likely continue to decline.

Oral contraceptives

An increased incidence of thromboembolic phenomena involving various blood vessels and organs in women taking OCs has been well established. The first case of BCS associated with OC use was reported by Ecker and McKittrick, 5 years after these drugs became available commercially. Since then, more than 200 cases of BCS in patients taking OCs have been described, ^{, , , ,} and the increasing overall incidence of BCS in recent years has been attributed partly to the widespread use of these agents. In the collective review reported by Mitchell et al., use of OCs was believed to be responsible for 9.4% of BCS cases from 1960 to 1980. Valla et al. reported a relative risk of 2.37 for hepatic vein thrombosis among OC users, similar to that of cerebrovascular accident (stroke), myocardial infarction, and venous thromboembolism. Recent literature, however, has questioned the strength of the association between OCs and venous thrombotic disease. It has been proposed that OCs are not a primary cause of BCS but contribute to thrombosis only if there is an underlying hematologic disorder. In addition to causing BCS, OCs have been linked to other liver disorders, including veno-occlusive disease, portal vein thrombosis, cholestasis, hepatocellular adenoma, and possibly hepatocellular carcinoma and angiosarcoma. ^,

Pregnancy and postpartum

Budd-Chiari syndrome has been observed in women during pregnancy and, more often, during the postpartum period. The first case of BCS reported by Chiari occurred in a woman who developed the disorder after childbirth. In the collective review by Mitchell et al., 9.9% of BCS cases occurred during pregnancy or postpartum, and in a series of 105 patients with BCS observed from 1963 through 1978, Khuroo and Datta reported 16 patients (15.2%) with BCS after pregnancy; 8 patients died, and 7 were lost to follow-up after discharge. The hypercoagulable state that is known to occur during pregnancy is presumed to be responsible for the association with BCS, although only 1 of 77 cases of BCS occurred peripartum in a recently reported large series. As with OCs, it is increasingly clear that many patients in whom BCS develops in association with pregnancy may also have an underlying thrombophilia, either inherited or acquired.

Malignant neoplasms

Occlusion of the suprahepatic IVC by invasive tumors has been the cause of BCS in numerous case reports. This etiology represents prototypical secondary BCS. The most common cancers associated with BCS are hepatocellular carcinoma (see Chapter 89 ), renal cell carcinoma, adrenal carcinoma, and leiomyosarcoma of the IVC. An example of a cholangiocarcinoma occluding the intrahepatic portion of the IVC is shown in Fig. 86.1 A. Other malignancies that have been infrequently associated with BCS include carcinomas of the lung, pancreas, and stomach; melanoma; reticulum cell sarcoma; adrenal sarcoma; and sarcoma of the right atrium.

Infections

Infections involving the liver were believed to be responsible for 3% of BCS cases reviewed by Parker, 9.9% of the cases reported by Mitchell et al., and none of the cases in sizable series reported in more recent years. The most common infections associated with BCS are those caused by parasites, particularly amebic liver abscesses, hydatid disease, and schistosomiasis (see Chapters 73 and 74 ). Syphilitic gumma of the liver accounted for 1.8% of BCS cases in Parker’s review but has not been reported as a cause of BCS in recent years. Aspergillosis involving the hepatic veins and IVC has been a rare cause of BCS. In India, Victor et al. provided evidence that filariasis can cause BCS. These cases represent rare entities that are infrequently reported in BCS literature, but may be more prevalent than reported in developing countries where health reporting is limited.

Trauma

Abdominal trauma may in particular circumstances predispose patients to the development of BCS (see Chapter 113 ). Trauma was responsible for 1.2% of BCS cases reported by Parker and 2.4% of the cases reviewed by Mitchell et al.. Blunt and penetrating trauma have been implicated occasionally in BCS patients, in whom severe liver injury leads to deep laceration at the level of the hepatic veins. Endothelial injury at this location can lead to thrombosis, scar, and ultimately the development of BCS.

Connective tissue disorders

Occasional cases of BCS have been reported in association with various connective tissue and autoimmune diseases, most of which are known to have thrombotic tendencies, including Behçet’s disease, Sjögren’s syndrome, mixed connective tissue disease, sarcoidosis, and rheumatoid arthritis. Numerous cases of BCS in patients with Behçet’s disease have been described. ^, A recent large series examining vascular complications in 5970 patients with Behçet’s disease reported BCS in 2.4% of the 882 affected patients. Median time from diagnosis to development of BCS was 2.3 years.

Membranous obstruction of the vena cava (MOVC)

More than 600 cases of BCS resulting from MOVC have been reported from Japan, China and other parts of Asia, India, and South Africa. In the United States and Europe, MOVC is rare. A congenital cause of this condition has been proposed, but evidence strongly suggests it represents the end result of acquired thrombosis. ^{, ,}

MOVC usually runs a chronic course during many years, and extensive hepatic fibrosis or cirrhosis and portal hypertension will have developed in most patients by the time they come to medical attention. An increased incidence of hepatocellular carcinoma has been observed in association with MOVC. ^, The therapeutic implications of this condition and other forms of IVC occlusion are distinctly different from those of occlusion confined to the major hepatic veins.

Miscellaneous rare conditions

Other conditions that have been rarely associated with BCS include inflammatory bowel disease, hepatic torsion after partial resection of the liver, live-donor liver transplantation of the left lateral section, lipoid nephrosis, and protein-losing enteropathy. The latter two conditions are associated with a prothrombotic condition that may predispose patients to BCS.