Budd-Chiari Syndrome

Etiology

In 80% of the cases, some underlying prothrombotic cause leads to the development of Budd-Chiari syndrome, and the majority are related to a hypercoagulable state. This aspect of Budd-Chiari syndrome must be considered for diagnosis and treatment.[1]

Myeloproliferative Disorders

Almost half of the cases of Budd-Chiari syndrome are associated with a myeloproliferative disorder, eg, polycythemia vera and essential thrombocythemia, because some hypercoagulability almost always accompanies these myeloproliferative disorders.

Malignancy

Approximately 10% of Budd-Chiari syndrome cases are related to malignancy, which causes either direct compression or invasion of vessels. These, along with hypercoagulability, lead to venous thrombosis and obstruction. The most common cancer related to the Budd-Chiari syndrome is hepatocellular carcinoma, followed by cancers of the adrenal gland, renal cell carcinoma, leiomyosarcoma, right atrial myxoma, and Wilms tumor.

Benign Lesions of the Liver

An infection or a space-occupying lesion of the liver may compress the vasculature. Hepatic cysts, adenomas, cystadenomas, invasive aspergillosis, and aortic aneurysms are lesions that may lead to Budd-Chiari syndrome.

Pregnancy and Oral Contraceptives

Oral contraceptives and pregnancy lead to a hypercoagulable state and are responsible for about 20% of cases of Budd-Chiari syndrome.

Idiopathic

An estimated 20% of Budd-Chiari syndrome cases are idiopathic. 

Additional Etiologies

Other hypercoagulable states responsible for Budd-Chiari syndrome include:

• Factor V (Leiden) mutation that leads to protein C resistance
• Antiphospholipid antibody syndrome
• Antithrombin deficiency
• Protein C deficiency
• Paroxysmal nocturnal hemoglobinuria

Epidemiology

Other than in Asia, Budd-Chiari syndrome is usually diagnosed in the third or fourth decade of life, is predominantly seen in females, and is most commonly caused by hepatic vein blockage. In Asian countries, however, this syndrome is more common in males and is most commonly due to inferior vena cava (IVC) blockage or a combination of IVC and hepatic vein blockage.[2]

Pathophysiology

The occlusion of a single hepatic vein usually remains silent, but when 2 hepatic veins get occluded, it causes venous congestion that stretches the liver capsule. This can cause significant abdominal pain. The sinusoids begin to dilate, and interstitial fluid infiltrates, leading to hepatic congestion. When the filtrated fluid exceeds the capacity of the lymphatic system to drain it, it starts passing through the liver capsule, leading to ascites.[3][4] Following the thrombosis and obstruction to hepatic venous flow, fibrosis occurs due to ischemia and necrosis, eventually resulting in portal hypertension and ascites.

As a result, hypoxic injury to the centrilobular hepatocytes occurs. With sudden vascular occlusion, severe liver dysfunction occurs [5], while in chronic cases, vascular occlusion can lead to ascites and hepatomegaly with preserved liver function. Over time, fibrosis develops, leading to cirrhosis.[6] As a compensatory mechanism, intrahepatic collaterals are developed, and arterial blood flow is increased to limit ischemia. These collateral vessels lead to an imbalance between portal and arterial perfusion, promoting the development of regenerative or neoplastic hepatocyte nodules, which can lead to the development of hepatocellular carcinoma.[5]

The caudate lobe is most commonly affected in Budd-Chiari syndrome because its blood is directly shunted into the IVC. Hence, when the hepatic veins are occluded, the caudate lobe undergoes hypertrophy.[7]

Histopathology

Biopsy of the liver in patients with Budd-Chiari syndrome can show the following findings:

• Necrosis of hepatic cells in the centrilobular area
• Sinusoidal dilation due to stasis of blood flow
• Sometimes, macro nodules can also be seen in this syndrome [8]
• Perisinusoidal fibrosis, mostly in centrilobular regions, which may evolve into cirrhosis [5]

History and Physical

Budd-Chiari Syndrome Classification

Budd-Chiari syndrome presentations are often divided into the following categories by disease duration and severity:

• Acute: Clinical manifestations develop rapidly over a few weeks, with intractable ascites and hepatic necrosis. Venous collaterals are not seen. Fulminant liver failure can occur and is characterized by acute liver injury along with elevated transaminases, jaundice, prolonged prothrombin time/international normalized ratio (PT/INR), and hepatic encephalopathy. The latter usually develops within 8 weeks of the development of jaundice.
• Subacute: Subacute manifestations of Budd-Chiari syndrome have an insidious onset, with patients taking up to 3 months to develop symptoms. Venous collaterals develop, leading to minimal ascites and hepatic necrosis.
• Chronic: Patients with chronic Budd-Chiari syndrome present with complications of cirrhosis. Venous collaterals are also present.[9][10]

The majority of patients with Budd-Chiari syndrome present with the classic triad of abdominal pain, ascites, and hepatomegaly. Due to the nonspecific nature of findings and a wide range of presentations, a high degree of suspicion is needed to diagnose this condition.

Clinical features

Acute and subacute presentations of Budd-Chiari syndrome include symptoms such as sudden onset of ascites, abdominal pain, jaundice, hepatomegaly, hepatic encephalopathy, and renal failure. Chronic presentations, which are the most common, include progressive ascites and absence of jaundice; half of Budd-Chiari syndrome cases can present with renal impairment.

 On physical examination, the following findings can be seen in patients with Budd-Chiari syndrome:

• Jaundice
• Ascites
• Hepatomegaly
• Splenomegaly
• Pedal edema
• Stasis ulcerations

Additionally, Budd-Chiari syndrome should be suspected when the following findings are noted:

• Sudden onset of ascites and painful hepatomegaly
• Massive ascites with relatively normal liver function studies
• Sinusoidal dilation in liver biopsy without heart disease
• Fulminant hepatic failure, along with hepatomegaly and ascites
• Unexplained chronic liver disease
• Liver disease with an underlying thrombogenic disorder [7]

Evaluation

No individual test establishes the diagnosis of Budd-Chiari syndrome, which is based on classic clinical manifestations and conditions predisposed to thrombosis.

Radiological Evaluation

Doppler ultrasonography is the initial test of choice and usually helps confirm the diagnosis. Computed tomography (CT) or magnetic resonance imaging (MRI) may be helpful if a Doppler study is unavailable, has equivocal results, or cannot be performed. Venography may be beneficial if these tests fail to establish a diagnosis, but suspicion is still high.

Ultrasonography, preferably with color flow Doppler, can visualize the thrombi with a sensitivity and specificity of 85% to 90%. Typical findings in the sonographic evaluation of Budd Chiari syndrome include:

• Presence of hepatic venous thrombosis
• IVC webs and thrombi
• Decreased IVC diameter
• Increased caudate lobe size
• Ascites
• Presence of intrahepatic or extrahepatic collaterals
• Monophasic flow in the hepatic veins
• Remarkably high flow velocity in areas of stenosis can be detected in the IVC or hepatic veins.[11][12]

CT scanning is helpful if a mechanical obstruction is suspected as an underlying cause. However, MRI is becoming the noninvasive modality of choice with a sensitivity and specificity of >90%.[13] Additionally, venography can accurately show the site and severity of obstruction, but its invasive nature limits its usefulness. Liver elastography may show increased liver stiffness due to congestion.[14]

Diagnostic Paracentesis and Laboratory Studies

Examination of ascitic fluid provides invaluable clues to Budd-Chiari syndrome diagnosis and form of presentation. Elevated protein levels >2 g/dL and white blood cells <500/µL are usually present in patients with chronic Budd-Chiari syndrome. The serum ascites-albumin gradient is generally high (>1.1 g/dL), consistent with portal hypertension.[11]

Laboratory evaluation is typically indicated to assess liver function. Mild elevation in serum aminotransferases (ALT/AST) and alkaline phosphatase levels are found in 25% to 50% of patients with Budd-Chiari syndrome.

Liver Biopsy

Liver biopsy may be diagnostic, often showing necrosis, hemorrhage, and congestion in the central zone.

Treatment / Management

The treatment of Budd-Chiari syndrome is focused on alleviating the obstruction, preventing the progression of the clot, limiting progressive liver injury, and preventing or managing complications. The goals of treatment include:

• Limiting growth or extension of the clot
• Relieving obstruction of occluded vessels
• Correcting underlying conditions 
• Monitoring liver deterioration [15]

Treatment Approaches

Anticoagulation

Anticoagulation is the first intervention in the absence of contraindications. Anticoagulation is initiated with low-molecular-weight heparin and then transitioned to warfarin, which is continued lifelong. The PT/INR should be monitored and should be kept in the therapeutic range for patients on warfarin. While direct oral anticoagulants can be used, data on their efficacy is sparse.[16][5] (B2)

Budd-Chiari syndrome patients with esophageal varices or other bleeding risks must be addressed by treating the risk factors first. Endoscopy and initiation of beta-blockade reduce risk in patients with esophageal varices, with band ligation done if the varices show signs of a high risk of bleeding. Anticoagulation alone, however, is inadequate to facilitate the recanalization of the occluded vessels or to allow the development of collateral vessels.

Angioplasty and stent placement

Angioplasty and stent placement can be done in the acute or subacute setting. The stent serves to maintain vascular patency; however, placement in the IVC above the liver may complicate eventual liver transplantation or may make this impossible to perform.

Thrombolysis

Thrombolysis is an option within 1 month of clot development, and this has a high level of success if the clot includes either the hepatic vein or IVC, but not both.[17] Use in chronic Budd-Chiari syndrome is contraindicated because the risk of bleeding from complications of portal hypertension outweighs the benefit.(B2)

Surgical shunts

A transjugular intrahepatic portosystemic shunt (TIPSS) may be placed in acute or subacute cases of Budd-Chiari syndrome failing to respond to anticoagulation alone. This serves to treat complications of portal hypertension, particularly in the setting of acute liver failure in advance of liver transplantation.[18] Surgical shunt procedures, including mesocaval, splenorenal, and portocaval shunts, have a role in some individuals with a nonthrombosed IVC. However, the TIPSS procedure has supplanted surgery in more recent years.

Liver transplantation

In patients who fail all therapies or who have developed decompensated cirrhosis, liver transplantation is an option. The 1-year, 5-year, and 10-year survival rates were 84%, 77%, and 68%, based on findings of the European Liver Transplant Registry, and all were improved in patients transplanted in or after the year 2000. Hepatic graft survival rates were reported as 79%, 70%, and 62%, respectively, since 2000. The advanced age of the donor or recipient, female transplant recipients, and a higher MELD score portended poorer outcomes, while continuous anticoagulation improved patient and graft survival rates.[19]

Differential Diagnosis

Differential diagnoses of Budd Chiari syndrome include the following:

• Right-sided heart failure
• Metastatic liver disease
• Alcoholic liver disease
• Granulomatous liver disease
• Alpha-1 antitrypsin deficiency
• Infectious hepatitis
• Fitz-Hugh Curtis syndrome
• Congestive heart failure
• Niemann-Pick disease type C
• Infectious hepatitis
• Neonatal hemochromatosis
• Biliary atresia
• Congenital hepatic fibrosis
• Cystic fibrosis
• Inborn errors of metabolism
• Hemochromatosis
• Drug-induced hepatitis[20][21][22][23]

Prognosis

Factors contributing to a good prognosis for Budd-Chiari syndrome include:

• Younger age
• Low Child-Pugh score
• Low serum creatinine level
• Absence of ascites

Factors contributing to a poor prognosis include:

• Involvement of all 3 hepatic veins or the portal vein
• Presence of ascites
• Older age at the time of presentation
• High Child-Pugh score
• Chronic disease at presentation [24][25][26]

 Many prognostic scores have been developed, which aid in classifying its severity.[5]

Complications

Complications of Budd-Chiari syndrome are mostly related to underlying conditions and degree of liver failure. In general, untreated Budd-Chiari syndrome is associated with the following complications:

• Portal hypertension
• Hepatic encephalopathy
• Variceal hemorrhage
• Hepatorenal syndrome
• Bacterial peritonitis in the presence of ascites
• Heptocellular carcinoma