EASL Clinical Practice Guidelines

Budd-Chiari syndrome

BCS is defined as the obstruction of hepatic venous outflow that can be located from the small hepatic venules up to the entrance of the IVC into the right atrium [1]. Hepatic outflow obstruction related to cardiac disease, pericardial disease or sinusoidal obstruction syndrome (SOS) are excluded from this definition. BCS can be classified into: i) primary, caused by thrombosis in the absence of compression by space occupying lesions, or invasion by malignancy or parasites; and ii) secondary otherwise. Given the different therapeutic and prognostic implications, we will only discuss primary BCS. In Western countries pure hepatic vein thrombosis is most common [48], while in Asia a pure IVC or combined IVC/hepatic vein block predominates. The pathophysiological consequences include obstruction, which leads to sinusoidal congestion, ischemia, and finally hepatocellular necrosis. They can result in centrilobular fibrosis, nodular regenerative hyperplasia and/or cirrhosis.

Clinical manifestations

Clinical presentation is heterogeneous and ranges from absence of symptoms to fulminant hepatic failure [[1], [49]]. An asymptomatic presentation is often associated with the presence of large hepatic venous collaterals. In a multicentre prospective study of a large cohort of patients with BCS at diagnosis, ascites were present in 83% of patients, hepatomegaly in 67%, abdominal pain in 61%, esophageal varices in 58% and gastrointestinal bleeding in 5% [2]. In approximately 15% of cases, BCS and PVT occur simultaneously [[2], [50]]. Therapeutic options and prognosis tend to be worse in BCS-PVT patients [50].

Imaging studies display hepatic nodules in 60–80% of patients with BCS. They are usually benign and are the result of perfusion disturbances. Although, these nodules are characteristically small, in most cases under 4 cm in diameter, multiple (frequently more than 10 lesions), hypervascularized, and disseminated throughout the liver. A pathognomonic pattern is not detected on computed tomography (CT) or magnetic resonance (MR) imaging. Cumulative incidence of hepatocellular carcinoma (HCC) in BCS has been shown to be 4% (after a median follow-up of 5 years) [51], therefore differential diagnosis is essential. Biopsy has been suggested in patients with less than or equal to three nodules, nodules with a diameter more than or equal to 3 cm, heterogeneity or washout on the venous phase, changes in two consecutive imaging techniques, or increase in alpha-fetoprotein levels [51]. However, radiological and histological characterization of hepatic nodules in BCS cannot rely on the well-established criteria of HCC in cirrhosis and the only formal recommendation is close and careful multidisciplinary surveillance.

 

Diagnosis

Diagnosis is established with unequivocal radiological confirmation of hepatic venous outflow obstruction. Doppler ultrasound has a diagnostic sensitivity of more than 75% and is the first line investigation [1]. If an experienced sonographer is not available, MR imaging and CT evaluation are used for diagnostic confirmation [[1], [48]]. Venography is recommended if the diagnosis remains uncertain or for the characterization of anatomy prior to treatment. If imaging has failed to demonstrate obstruction of large veins then a liver biopsy can be used in order to assess small hepatic vein thrombosis.

Treatment

The recommended stepwise therapeutic algorithm of BCS based on retrospective cohorts and prospective series of patients [[2], [52], [53]] is summarized in Fig. 1.


Fig. 1
Recommended stepwise therapeutic algorithm of Budd-Chiari syndrome.

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Patients with BCS have often required therapy for ascites and varices. These treatments should be administered following the same treatment recommendations as for ascites and portal hypertension in cirrhosis.

Patients with BCS should receive anticoagulant therapy as soon as possible for an indefinite period of time in an attempt to reduce the risk of clot extension and new thrombotic episodes [[1], [2], [52], [54]]. According to the recommendation for deep vein thrombosis, the patient should be treated with low molecular weight heparin (LMWH) for at least 5 to 7 days, and also with oral anticoagulant treatment with VKA, aiming at an international normalised ratio (INR) between 2 and 3. LMWH can be stopped when INR is within the target range for two consecutive measurements.

A high rate of bleeding complications while on anticoagulation (up to 50% of patients) has been reported in a cohort of BCS patients diagnosed between 1995 and 2005 [55]. In a more recent prospective cohort of patients diagnosed between 2005 and 2007, bleeding complications were less frequently observed (17% of patients), likely due to a better management of anticoagulation during invasive procedures or adequate prophylaxis for PH-related bleeding [53].

Treatment of the underlying prothrombotic cause (for instance MPNs) should be logically initiated concomitantly. Indeed, the benefits from early treatment for an underlying myeloproliferative disorder has been suggested in a retrospective cohort analysis [56].

The experience of correcting hepatic venous outflow obstruction with thrombolysis is limited. Good results have been reported in patients with recent and incomplete thrombosis treated with local and early infusion of a thrombolytic agent combined with angioplasty or stenting [57]. Complications however, can be fatal [58].

Partial or segmental stenoses are present in 60% of patients with IVC obstruction, and 25–30% of those with hepatic vein obstruction [59]. Angioplasty or stenting of these stenosis could re-establish the physiological drainage of portal and sinusoidal blood. Post-angioplasty re-stenosis is frequent but can be reduced when done in combination with a stent. Misplacement of a stent may compromise the subsequent performance of a transjugular intrahepatic portosystemic shunt (TIPS) or orthotopic liver transplantation (OLT). Overall angioplasty/stenting is the definitive treatment for less than 10% of Western BCS patients [53]. The efficacy may be greater in other regions of the world where there is a higher prevalence of this specific form of BCS [60].

Patients with BCS non-responsive to medical treatment or that are not candidates for angioplasty/stenting must be treated with derivative techniques. There is no clear explanation as to why some patients do not respond to medical treatment, therefore the characteristics of BCS patients’ receiving TIPS differ from centre to centre. Some criteria have been proposed: clinical failure to therapy (treatment failure) was considered when criteria for complete or ongoing response were lacking [52]. Complete response was considered when all of the following six criteria were met and stable: (1) absence of clinically detectable ascites, with normal serum sodium and creatinine levels, in the absence of diuretic therapy, or on low dose diuretics (spironolactone 75 mg/d or furosemide 40 mg/d) and moderate NaCl intake; (2) increase in coagulation factor V to a level above 40% of normal value; (3) decrease in conjugated serum bilirubin to a level below 15 μmol/L; (4) absence of first or recurrent PH-related bleeding while on primary or secondary prophylaxis with non-selective beta blockers or with endoscopic therapy; (5) no occurrence of spontaneous bacterial infection; and (6) BMI >20 kg/m2 after substraction of ascites and edema. Ongoing response was considered when all of the following three criteria were met on a 2-weekly evaluation basis: (1) in the presence of ascites, a negative sodium and water balance was achieved using low dose diuretics and moderate sodium intake, together with normal serum sodium and creatinine levels, or with increasing serum sodium if initially low and decreasing serum creatinine levels if initially high; (2) factor V level was increasing if initially low; and (3) serum conjugated bilirubin level was decreasing if initially high. These response criteria must be validated in future studies.

Derivative techniques, either surgical shunts or TIPS, are aimed to transform the portal system into an outflow tract [61]. The most frequent surgical shunt performed is the mesocaval shunt with a polytetrafluoroethylene (PTFE) stent or autologous jugular vein interposition. It is easier to do than the porto-caval side-to-side shunt when hypertrophy of the caudate lobe is present. Surgical shunts are ineffective if there is associated IVC thrombosis or severe compression of the IVC by an enlarged liver. In this situation some groups have performed a meso-atrial shunt or a cavo-atrial shunt plus a porto-caval shunt. Surgical shunts have not demonstrated to be an independent survival advantage in cohorts of patients with BCS [[62], [63]]. This is likely related to the high inherent mortality rate of the patient population with severe BCS, as well as to the high rate of dysfunction/thrombosis of the shunts [[64], [65], [66]]. On the other hand, TIPS has a lower morbidity and mortality rate than surgery and is feasible in most patients with IVC obstruction and in those with severe IVC stenosis. A recent multicentre retrospective European study including 124 BCS patients treated with TIPS showed excellent 1- and 5-year OLT-free survival (88% and 78%, respectively) [67]. These results have been confirmed by a recent prospective study [53]. PTFE-covered stents reduce the recurrence of post-procedure TIPS obstruction or dysfunction [[53], [67]]. TIPS placement in patients with BCS requires special training. Indeed, in more than 45% of cases, a transcaval approach (direct puncture from the intrahepatic IVC) may be required due to complete thrombosis of the hepatic veins [67].

OLT in patients with BCS is associated with a survival [68] similar to that obtained in patients initially treated with TIPS [67]. It has been suggested that the placement of previous TIPS can make a posterior OLT more difficult if it is needed. However, this has not been confirmed in more recent studies [[67], [69]]. BCS recurrence may occur after OLT. The incidence of this complication has markedly dropped since the initiation of early anticoagulation treatment after OLT and its lifelong maintenance. An exception for the need for anticoagulation could be in those patients whom the prothrombotic disorder is corrected by OLT (e.g. most inherited thrombophilia). The natural history of MPN must also be considered in the post-transplant course.

There are patients with severe BCS who may benefit from being treated directly with OLT, without previous use of TIPS. However, up until now there is no reliable method to identify such patients [[53], [67]].

Budd-Chiari and pregnancy

Pregnancy in patients with BCS has an excellent maternal outcome provided patients have a well controlled disease. Fetal outcome is less favourable but it has been reported that pregnancies reaching week 20 of gestation are associated with an acceptable fetal prognosis even when 76% had preterm delivery [70]. VKA are associated with a high risk of miscarriage and congenital malformations [71]. Therefore, a pregnancy test must be done as early as possible, if positive mothers should switch to LMWH [72] with periodic monitoring of anti-Xa activity.

Prognosis

There have been various attempts to determine parameters or combinations of parameters that may predict prognosis in BCS patients [[53], [62], [67], [73]]. Although all of these prognostic indices are valid for the assessment of transplant-free survival and invasive therapy-free survival, their predictive accuracy is suboptimal for use in individual patients in day to day clinical practice [74]. Development of HCC or progression of the haematological disease may modify prognosis of BCS.