Liver transplantation for Budd-Chiari syndrome: When is it really necessary?^†

The Budd-Chiari syndrome (BCS) results from obstruction to the hepatic venous outflow tract from the level of the hepatic venules to the entrance of the inferior vena cava into the right atrium.1 This obstruction causes venous stasis, centrilobular congestion, and hepatocyte necrosis, which leads to centrilobular fibrosis, nodular regenerative hyperplasia, and ultimately cirrhosis of the liver.2 The principal manifestations of BCS are abdominal pain, ascites, and hepatomegaly with some alteration in the liver biochemical tests. Clinical presentations, however, may range from completely asymptomatic patients, in whom only 1 hepatic vein is obstructed,3 to patients with liver failure, including, rarely, fulminant failure. The most common cause of hepatic venous outflow obstruction in the West is venous thrombosis due to prothrombotic states, whereas in the Eastern world, membranous obstruction of the inferior vena cava is more prevalent.4, 5 The prothrombotic states may be inherited, such as the factor V Leiden mutation, or acquired, such as myeloproliferative disorders.6-9 The inherited conditions associated with most severe thrombophilia, such as antithrombin deficiency and paroxysmal nocturnal hemoglobinuria, are not common causes of BCS. The diagnosis of BCS is usually made by cross-sectional abdominal imaging, either computerized tomography or magnetic resonance imaging being more accurate than ultrasonography. Neither hepatic venography nor liver biopsies are mandatory for diagnosis if the diagnosis is clear on cross-sectional imaging.

Abbreviations

BCS, Budd-Chiari syndrome; OLT, orthotopic liver transplantation; TIPS, transjugular intrahepatic portosystemic shunt.

Treatment for BCS is usually approached in a stepwise manner.10 Because thrombophilia is present, anticoagulation, usually life-long, is recommended in all patients even following successful liver transplantation.11, 12 Sodium restriction, diuretics and paracentesis for control of ascites, and beta blockers and endoscopic therapy for varices are supportive management only; they do not correct the underlying pathophysiology, which is hepatic venous outflow tract obstruction. If, despite optimal anticoagulation and supportive therapy, patients have treatment failure, then an attempt can be made at thrombolytic therapy or angioplasty. Treatment failure is defined as worsening liver function, refractory ascites, hepatorenal syndrome, or hepatic encephalopathy despite optimal therapy.10 Thrombolytic therapy and angioplasty are likely to be most successful when there is localized involvement of the hepatic veins. When efforts at thrombolytic therapy or angioplasty are either not feasible or unsuccessful, a functional side-to-side portosystemic shunt is considered, either radiological, such as a transjugular intrahepatic portosystemic shunt (TIPS), or surgical. The side-to-side portocaval shunt serves as an outflow for the hepatic sinusoid, resulting in hepatic decongestion and reversal of the hepatic necrosis. TIPS is preferable to a surgical shunt in most instances, especially if patients have caudate lobe compression of the inferior vena cava or are candidates for liver transplantation. Results with TIPS for BCS are excellent, particularly since the introduction of polytetrafluoroethylene-covered stents.13 The majority of patients can be managed with this stepped-up approach. In support of this, Plessier et al.10 showed that a conservative step-up approach leads to a complete response at 1 year in 84% of patients. For the minority of patients who continue to deteriorate despite TIPS, liver transplantation may be considered. Liver transplantation, which is associated with the requirement of considerable resources and life-long immunosuppressive therapy, is most beneficial in those patients in whom survival is significantly prolonged by the procedure.

The article by Ulrich et al.14 in this issue of Liver Transplantation addresses the outcome of patients with BCS who underwent orthotopic liver transplantation (OLT) between 1988 and 2006. They performed 42 liver transplants on 39 patients with excellent outcomes; 5-year and 10-year survival rates were 90% and 84%, respectively. These results compare favorably with those from other centers, including the report by Mentha et al.,15 who reported 69% survival at 10 years in 248 patients from the European Liver Transplant Registry. Ulrich et al. state that the posttransplant survival appears to be higher in patients with BCS than in patients transplanted for other indications (10-year survival of 71% in their other patient groups) because of local expertise, timely OLT, and standardized postoperative anticoagulation.

Although the results are impressive, there are several issues that need to be addressed. First, it appears that the indication for OLT was not strictly defined. For example, indications for liver transplantation in patients with other causes of cirrhosis are advanced disease, as defined by high Child-Pugh or Model for End-Stage Liver Disease scores, and complications. In this cohort, however, 69% of the patients with BCS were of Child-Pugh class A or B (Model for End-Stage Liver Disease scores were not reported). This suggests that the majority of the patients did not have advanced liver disease and were, in fact, in better health than the usual patients who receive a liver transplant. In addition, disease severity was assessed only according to histology,16 a classification that lacks validation. Because of the high likelihood of sampling errors related to inhomogeneous distribution of lesions, histology has not been shown to have any impact on the prognosis of patients with BCS.17

Putting all this together, one might hypothesize that the patients in the current study could have had similar survival even if hepatic transplantation had not been performed. In 2004, a large multicenter study was conducted in which a prognostic model, assessing long-term transplantation-free survival, was developed.18 This model, later referred to as the Rotterdam BCS index, was able to distinguish 3 classes of patients. The patients who fell in the poorest class had a 5-year survival rate of 42% without transplant. These patients, with severe ascites, hepatic encephalopathy, and high bilirubin levels and prothrombin times, were the most appropriate candidates for OLT, as all other therapies were less likely to be successful. In contrast, patients without these features or with less severe liver disease fell into class I, and 5-year survival in them was excellent (89%); intermediate-risk patients had 5-year survival rates of 74% without liver transplant. Unfortunately, in the article by Ulrich et al.,14 clinical parameters are not reported, and hence the prognostic score of the patients included cannot be estimated. Assuming a linear association between the Child-Pugh and Rotterdam BCS classes, the estimates for 5-year survival of two-thirds of the patients in the Ulrich series would have been between 74% and 89% without liver transplantation, comparable to the observed survival. In other words, the survival benefit of transplanting many of these seemingly minimally affected patients may be limited. The percentage of patients with BCS (2.1%) among the entire cohort of patients who received liver transplants in the Ulrich study also is higher than the 0.5% reported from the United Network for Organ Sharing database,19 and this suggests that the indications for OLT in the Ulrich study may have been more liberal than those in the United States. It is important to emphasize that liver transplantation for BCS is associated with an increased risk of vascular complications and that patients require life-long anticoagulation.20 Therefore, the indications for liver transplantation in this group should be very clear.

In our view, most patients with BCS can be managed successfully with a “step-up” algorithm, with the initial approach being minimally invasive. Anticoagulation is the mainstay of initial therapy, along with supportive therapy. TIPS should be used in patients who fail conservative therapy, that is, in those patients who have worsening of hepatic and/or renal function. Liver transplantation, which is associated with excellent long-term survival, should probably be reserved for the select group of patients who, despite adequate conservative therapy, continue to deteriorate.