Budd-Chiari syndrome

I. What every physician needs to know.

Budd-Chiari syndrome (BCS) is an eponym for obstruction of the hepatic venous outflow tract at any level from the hepatic venules to the suprahepatic inferior vena cava (IVC), regardless of mechanism.

BCS may result from primary thrombosis or secondary compression or invasion of the hepatic venous outflow tract, which leads to increased hepatic sinusoidal and portal pressure and liver injury.

There are geographic differences with regard to prevalence, etiology and site of thrombosis. Primary BCS with pure hepatic vein occlusion is more common in Western countries, while in Asian countries (especially patients from lower socioeconomic backgrounds), the disease is more common overall and typically involves the IVC, often due to the presence of membranous webs.

Those with primary BCS usually have hereditary or acquired thrombophilia; half may have a myeloproliferative disorder, most commonly polycythemia vera.

Doppler ultrasonography is the single most useful non-invasive diagnostic imaging test.

Most patients require long-term anticoagulation. Other therapeutic options include improving flow through the affected veins via thrombolysis or angioplasty/stenting, decompressing liver congestion with portosystemic shunting, or liver transplantation.

II. Diagnostic Confirmation: Are you sure your patient has Budd-Chiari syndrome?

A definitive diagnosis of BCS is made on the basis of direct visualization of hepatic vein or IVC obstruction with or without collaterals by non-invasive radiologic imaging or venography. History and physical examination, serum markers of hepatic function and ascitic fluid analysis are useful in narrowing the differential diagnosis, but are non-specific.

A. History Part I: Pattern Recognition:

The clinical presentation of BCS varies depending on the extent of hepatic venous outflow obstruction, how quickly it develops and the presence or absence of venous collateral circulation. There are fulminant, acute, subacute, and chronic forms of the syndrome. In general, those with a greater degree of hepatic obstruction and limited collateral circulation are more symptomatic. As many as 20% of patients may have no symptoms at the time of diagnosis, suggesting the presence of large venous collaterals.

For all forms of the syndrome, the most common presenting symptoms and signs, occurring in more than two thirds of patients, include the following: abdominal pain (particularly originating in the right upper quadrant), abdominal distension with ascites and hepatomegaly. Suspect BCS in any patient with liver disease and one or more components of this triad. Lower extremity swelling is also among the most common presenting clinical findings.

Those presenting with fulminant and acute forms are more likely to be female and one third or more present with jaundice or with altered mental status due to hepatic encephalopathy, which are both uncommon in subacute and chronic BCS. Because they have not yet had time to develop venous collaterals and they often have involvement of all the major hepatic veins, patients with acute BCS tend to be more symptomatic, often with intractable ascites and evidence of hepatic necrosis.

Subacute or chronic BCS, which is more common than the acute forms in most reported series, should be considered in all patients presenting with unexplained liver disease. Such patients tend to have a more insidious onset, owing to a greater degree of venous collateral circulation and perhaps less thombotic burden. Chronic BCS may result in cirrhosis and consequently presents with stigmata of portal hypertension, including splenomegaly, esophageal varices and gastrointestinal (GI) bleeding.

Suspect primary BCS in a patient with underlying thrombophilia presenting with the above findings, and secondary BCS if such a presentation occurs in a patient with a history of blunt abdominal trauma or intra-abdominal malignancy or infection.

B. History Part 2: Prevalence:

The global prevalence of BCS is unknown. One series estimates the prevalence in Sweden to be 1.4 per million and in Japan it may be as high as 2.4 per million. It is a rare disease in Western countries and occurs in all patient populations, with highest incidence in the 3rd and 4th decades. Gender predominance varies among case series, but the acute form of the disease is more common in females. The disease is also more common in Asian countries, where it is an important cause of liver-related hospitalization.

History is critical to elucidating the underlying etiology of the syndrome. More than 80% of patients with BCS have at least one identifiable risk factor, and as many as half have more than one. All patients should be questioned about personal or family history of venous or arterial thromboses and any known predisposing factors, which broadly fall into thrombotic, immunologic and inflammatory categories.

These include current or recent pregnancy and oral contraceptive use, myeloproliferative diseases (particularly polycythemia vera), malignancy, and other thrombophilic states including factor V Leiden and prothrombin G20210A mutation, deficiencies in protein C, S, or antithrombin, paroxysmal nocturnal hemoglobinuria, hyperhomocysteinemia, and the antiphospholipid syndrome.

Other associated systemic diseases include ulcerative colitis, Bechet’s disease, hypereosinophilic syndrome, and granulomatous venulitis. Secondary BCS may occur with intra-abdominal malignancy, infectious cysts and abscesses, the presence of membranous webs in the IVC, and following blunt trauma or liver transplant.

It is worth emphasizing the association with myeloproliferative disorders, which are the most common etiology of BCS, occurring in as many as half of patients. Among these, polycythemia vera underlies 10-40% of cases of primary BCS.

C. History Part 3: Competing diagnoses that can mimic Budd-Chiari syndrome.

The fulminant/acute forms of BCS share clinical features with other causes of acute liver injury including viral, ischemic, toxic, and autoimmune hepatitis, as well as hepatic veno-occlusive disease and malignancy/infiltrative liver diseases. In BCS, the presence of ascites may be relatively more common than with other causes of acute liver injury, and markers of hepatocellular injury may not rise as quickly.

The subacute/chronic forms of BCS share clinical features with any cause of portal hypertension or cirrhosis. Right-sided heart failure of any cause, right atrial myxoma or constrictive pericarditis may present in a similar fashion to BCS.

Cardiac and pericardial causes may be distinguished on physical examination by elevated jugular venous pressure, which is usually normal in BCS. While the serum-ascites albumin gradient is high (> 1.1g/dL) in most patients with portal hypertension, those with BCS or cardiac causes tend to have high ascitic protein levels (> 3.0g/dL) in contrast to those with other causes of portal hypertension.

D. Physical Examination Findings.

No physical exam finding or constellation of findings is pathognomonic for BCS. The large majority of patients have right upper quadrant tenderness, evidence of hepatomegaly and ascites on physical examination. Approximately one third of those that present with fulminant and acute forms of the syndrome have jaundice and scleral icterus, which is uncommon in subacute and chronic presentations. Roughly one third of those with chronic BCS have palpable splenomegaly.

Lower extremity edema was present in 24-50% of individuals in one series. Occasionally, patients may present with marked dilatation of the superficial abdominal veins. Presence of these latter two findings suggests occlusion of the IVC. Some with the chronic form of the syndrome have coexisting cirrhosis and consequently may have other physical stigmata of chronic liver disease such as cutaneous telangiectasias or palmar erythema.

E. What diagnostic tests should be performed?

Though some laboratory studies may be suggestive, only direct visualization of hepatic vein or IVC obstruction and/or collaterals is diagnostic of BCS.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Serum transaminases, alkaline phosphatase, bilirubin, albumin, and prothrombin time may be normal or increased, and in the fulminant form, may be markedly elevated. No pattern of liver function abnormalities is specific for BCS. Even completely normal liver function studies do not preclude the presence of BCS.

If possible, ascitic fluid should be sent for analysis. A serum-ascites albumin gradient greater than or equal to 1.1g/dL is suggestive of underlying portal hypertension, and ascitic protein greater than 3g/dL suggests BCS or cardiac/pericardial disease.

Due to the high frequency of coexisting renal impairment, serum creatinine should be part of the initial assessment, though this does not help to establish the diagnosis of BCS.

As noted, a coexisting myeloproliferative disorder (polycythemia vera, essential thrombocytosis, primary myelofibrosis, chronic myeloid leukaemia (CML), etc.) or hypercoagulable state can be identified in the large majority of patients with BCS.

For patients with confirmed primary BCS, evaluation for myeloproliferative disorders should start with a complete blood count (CBC), looking for evidence of leukocytosis, polycythemia or thrombocytosis. Even in patients with normal peripheral blood counts, hematology consultation should be considered to determine whether further diagnostic evaluation such as testing for the janus kinase 2 (JAK2) mutation or bone marrow biopsy is indicated.

Likewise, many experts recommend routine evaluation for a hypercoagulable state. This diagnostic evaluation is covered elsewhere. Modestly low levels of protein C, protein S or antithrombin may be seen in patients with acute thrombus or liver disease, and should not be assumed to represent inherited deficiency in the absence of additional evidence such as suggestive family history.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

For patients in whom BCS is suspected, initial evaluation should include imaging with Doppler ultrasonography, contrasted computed tomography (CT) scan or contrasted magnetic resonance imaging (MRI). Of these, Doppler ultrasonography in the hands of an experienced ultrasonographer is probably the best test, and can demonstrate absent flow in a hepatic vein, or the presence of intrahepatic or subcapsular hepatic venous collaterals. CT or MRI are reasonable alternatives or confirmatory tests, though these contrasted studies should be performed with caution in patients with coexisting renal insufficiency.

Hepatic venography and inferior venacavography is the gold standard for diagnosis of BCS and should be performed if non-invasive testing is inconclusive or negative in a patient for whom there remains strong clinical suspicion of BCS. The classic finding in BCS is that of a “spider web” network of collaterals in place of a normal hepatic vein. Venography may also help inform therapeutic decisions. The benefit of contrasted studies should be weighed against the potential for nephrotoxicity.

Liver biopsy rarely provides conclusive evidence of venous thrombosis and should not be performed routinely. BCS may be suggested indirectly by the presence of sinusoidal congestion and centrilobular necrosis with or without fibrosis. Liver biopsy is typically reserved for cases in which the diagnosis is strongly suspected but remains uncertain after non-invasive imaging studies and venography.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Routine hypercoagulability testing in patients with BCS, while recommended in guidelines, is expensive and may not alter management in all patients. Most patients with primary BCS warrant long-term anticoagulation regardless of the results of thrombophilia testing. An alternative approach is to reserve testing for those conditions that will impact clinical decision-making.

III. Default Management.

BCS is a rare disease and there are few randomized controlled trials to guide management. Treatment should be individualized based on the patient’s clinical features and causal factors and informed by institutional expertise with the following goals in mind:

Symptomatic treatment of the complications of portal hypertension
Reduction in hepatic outflow obstruction
Decompression of the liver to avoid hepatic necrosis

In the case of secondary BCS, treatment should be directed at the underlying infection, malignancy, etc. Treatment of primary BCS should proceed as follows:

Manage underlying risk factors: Where possible, correct any underlying risk factors. For instance, oral contraceptive medications are contraindicated in BCS and should be discontinued. Any underlying myeloproliferative disorder should be treated.
Treat complications of portal hypertension: Many patients require diuretic therapy with spironolactone and a loop diuretic in addition to dietary sodium restriction to achieve negative sodium balance. In refractory patients, large-volume paracentesis with intravenous albumin infusion may be necessary.
Anticoagulation: Immediately begin anticoagulation with low molecular weight heparin (LMWH), targeting anti-Xa activity to 0.5-0.8IU/mL, and with a vitamin K antagonist (e.g. warfarin) titrated to a goal international normalized ratio (INR) of 2-3. Assuming adequate anticoagulant monitoring is achievable, bleeding risk factors are absent, and the underlying causal factors have not been resolved, anticoagulation should be continued indefinitely. Anticoagulation alone may be adequate for patients with subacute or chronic forms of BCS with well-compensated liver disease.
Restore patency of hepatic outflow: Patients that remain symptomatic on anticoagulation should be assessed for short segments of venous obstruction that may be amenable to thrombolysis or percutaneous angioplasty/stenting.
Liver decompression: Patients that remain symptomatic on anticoagulation should also be considered for transjugular intrahepatic portosystemic shunt (TIPS) with a polytetrafluoroethylene (PTFE) covered stent. If TIPS placement is unsuccessful or not technically possible, consideration should be given to surgical shunting.
Liver transplant: Liver transplant should be considered in patients whose symptoms remain refractory to anticoagulation and shunting, or those with fulminant hepatic failure.
Monitoring: Patients with long-standing BCS should be monitored for development of hepatocellular carcinoma or transformation of underlying myeloproliferative disease.

A. Immediate management.

The rare patient with fulminant hepatic failure may require prompt transfer to a facility where urgent evaluation for liver transplant may be undertaken. The large majority of patients with BCS do not require emergent management, but care and clinical decision making is complex, and input is often needed from numerous specialists including hepatology, hematology, radiology, interventional radiology, and hepatobiliary surgery.

Hospitalists may play an essential role in coordinating care of the various specialists. Even in patients with subacute and chronic forms of BCS, taking stock of local resources is appropriate so a decision can be made as to whether transfer is appropriate.

B. Physical Examination Tips to Guide Management.

Daily monitoring of ascites and abdominal tenderness aids diuretic and pain management.

Patients on anticoagulation with a drop in hemoglobin may require stool hemocult testing.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Current guidelines recommend routine laboratory monitoring in all patients requiring anticoagulation. For those on unfractionated or LMWH, periodic assessment of hemoglobin and platelets is recommended as follows: obtain a CBC at the start of therapy, 24 hours after starting therapy, then every 2-3 days through 14 days of therapy or until heparin is discontinued, whichever occurs first.

For patients started on warfarin therapy, INR should be obtained at baseline, repeated 2 or 3 days after starting therapy, then daily thereafter until INR stabilizes in the therapeutic range.

D. Long-term management.

There are no standardized recommendations regarding long-term management. Most patients require long-term anticoagulation. Patients with identified risk factors, e.g. myeloproliferative disorders, may require additional ongoing monitoring, therapy and specialist follow-up. Patients with BCS may be at increased risk for development of hepatocellular carcinoma and follow-up with appropriate specialists is recommended.

E. Common Pitfalls and Side-Effects of Management

Management of patients with BCS is complex and requires diligent coordination of care and communication among specialists and with the patient and family. This coordination of care is the most important role of the hospitalist and can significantly improve patients’ satisfaction with, and understanding of, the care they receive.

Imaging studies utilizing iodinated contrast place patients at risk for contrast-induced nephropathy. When possible, appropriate preventive measures should be employed for patients at high risk (see “Radiocontrast dye-induced kidney failure”).

Anticipated side effects vary with treatment modality. Most patients receive anticoagulation, and many will require invasive procedures, placing patients at risk for bleeding complications and infection.

It is important to remember that guidelines recommend bridging with LMWH for at least 5 daysand until the INR is more than 2 in patients treated with vitamin K antagonists.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

LMWH requires dose adjustment in patients with severe renal impairment (creatinine clearance less than 30ml/minute/1.73m²). In such patients, some prefer to avoid LMWH altogether, instead using unfractionated heparin as a bridge to warfarin therapy.

Patients with serum creatinine of more than or equal to 1.5mg/dl or estimated glomerular filtration rate (GFR) less than 60ml/minute/1.73m² are at higher risk of contrast-induced nephropathy, and caution should be exercised in the use of contrasted CT studies in the diagnostic evaluation of patients with BCS and coexisting renal insufficiency (see the chapter “Radiocontrast dye-induced kidney failure”).