Budd-Chiari Syndrome

• Jeanette G. Smith, M.D.
• Nicolette J. Rodriguez, M.D., M.P.H.

 Basic Information

Definition

Budd-Chiari syndrome (BCS) is a rare disorder defined by the obstruction of hepatic venous outflow anywhere from the small hepatic veins to the junction of the inferior vena cava (IVC) and the right atrium. Primary BCS is defined by endoluminal obstruction as seen in thromboses, phlebitis or webs. Secondary BCS occurs when the obstruction is caused by compression or invasion by a lesion originating outside of the veins (tumor, abscess, cyst, etc.). It can also be a postoperative complication of orthotopic liver transplantation (OLT).

Synonyms

1. BCS

2. Hepatic vein thrombosis

3. Obliterative endophlebitis of the hepatic veins

4. IVC thrombosis

5. Chiari-Budd syndrome

6. Budd’s syndrome

7. Chiari’s disease

8. Rokitansky’s disease

ICD-10CM CODE
I82.0 Budd	Chiari syndrome

Epidemiology & Demographics

Incidence

Males: 2.0/1 million persons per yr

Females: 2.2/1 million persons per yr

Predominant Sex

In Western countries, women are more commonly affected (approximately 2/3 of cases).

In Asia, men are slightly more affected (approximately 1.5/1).

Predominant Age

In Western countries, presentation is usually in the third and fourth decades of life, with the median age being 35-50 yr.

In Asia, presentation is usually at a median age of 36 yr.

Physical Findings & Clinical Presentation

Clinical presentation and characteristics vary with geography. In Africa and South Asia, intravascular webs are more often associated with IVC thrombosis with a stronger association with subsequent liver cirrhosis and hepatocellular carcinoma. In the United States, BCS is more commonly associated with primary myeloproliferative disorders and underlying hypercoagulable states. Underlying factors that contribute to BCS can be identified in more than 80% of cases; multiple causative factors are identified in up to 50% of cases.

1. •

   Clinical manifestations can be caused by complete or partial occlusion of any or all of the three major hepatic veins or the inferior vena cava.

2. •

   Presentation is variable according to the degree, location, acuity of obstruction, and presence of collateral circulation:

   1. 1.

      Fulminant/acute (25%): severe right upper quadrant abdominal pain, fever, nausea, vomiting, mild jaundice, hepatomegaly, transudative and intractable ascites, marked elevation in serum aminotransferases (AST/ALT > 5 times the upper limit of normal), elevation of alkaline phosphatase to 300–400 IU/L, serum-ascites albumin gradient ≥ 1.1 with total protein ≥ 2.5 g/dl, coagulopathy (usually international normalized ratio (INR) > 1.5), variceal bleeding, encephalopathy within 8 wk of onset of jaundice, renal failure. Biopsy, if performed, would reveal hepatic necrosis. Early recognition and treatment are essential for survival; a slow decrease in ALT is associated with poor survival.

   2. 2.

      Subacute/chronic (60%): vague abdominal discomfort, gradual progression to caudate lobe hypertrophy with atrophy of the rest of the liver, portal hypertension with or without cirrhosis and its sequelae, transudative ascites, lower-extremity edema, esophageal varices, splenomegaly, coagulopathy, mild to moderate elevation in aminotransferases, bilirubin and alkaline phosphatase, hepatorenal syndrome, hepatopulmonary syndrome, and rarely, encephalopathy; biopsy, if performed, could reveal minimal hepatic necrosis.

   3. 3.

      Asymptomatic (up to 20%): usually discovered incidentally by abnormal liver function tests or imaging attained for other reasons.

Etiology: Approximately 80-87% of patients have one prothrombotic risk factor, and approximately 50% have multiple

1. •

   Primary myeloproliferative diseases: Up to 53% of BCS patients have a primary myeloproliferative disease and polycythemia vera is responsible for 10% to 40% of these cases.

   1. 1.

      Essential thrombocythemia and idiopathic myelofibrosis are less common causes.

   2. 2.

      JAK2 mutations are implicated in cases of idiopathic BCS (identified in 25%-60% of cases).

2. •

   Hypercoagulable states (inherited and acquired) often coexist with other causes.

   1. 1.

      Anticardiolipin antibodies (up to 25%)

   2. 2.

      Hyperhomocysteinemia (22%)

   3. 3.

      Paroxysmal nocturnal hemoglobinuria (5%-19%)

   4. 4.

      Factor V Leiden (25%)

   5. 5.

      Factor II gene mutation (5%)

3. •

   Protein C, protein S, and antithrombin III deficiency are difficult to interpret because the presence of liver disease may confound results. However, they account for 4.0%, 3.0%, and 3.0% of BCS, respectively.

4. •

   Heterozygosity for G20210A prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) mutation, Tet methylcytosine dioxygenase 2 mutation, and calreticulin mutation may be seen in BCS.

5. •

   Pregnancy and oral contraceptive pills are also predisposing factors to develop BCS.

6. •

   Malignancy causing external compression or invasion of vascular structures (up to 10% of cases).

   1. 1.

      Most commonly due to hepatocellular carcinoma but also can be due to neoplasms of the kidney, adrenal gland, pancreas, stomach, lung and sarcomas of the right atrium, inferior vena cava, and hepatic veins.

7. •

   Rare but reported: sickle cell anemia, infections with liver abscess, hydatid cyst (echinococcosis), schistosomiasis, sarcoidosis, Behçet’s disease, membranous webs of IVC or hepatic veins (more common in Africa and South Asia, can be congenital or acquired secondary to underlying myeloproliferative disorder), abdominal trauma, liver torsion, granulomatous venulitis, ulcerative colitis, celiac disease, systemic lupus erythematous, minimal change nephrotic syndrome, neurofibromatosis, α-1 antitrypsin deficiency, hypereosinophilic syndrome, idiopathic (10%-25%).

Diagnosis

Differential Diagnosis

1. •

   Hepatitis from ischemia, viral infection, toxin, alcohol

2. •

   Cholecystitis

3. •

   Hepatic veno-occlusive disease (sinusoidal obstruction syndrome)

4. •

   Congestive hepatopathy, also known as cardiac cirrhosis, from tricuspid regurgitation, right atrial myxoma, constrictive pericarditis

5. •

   Cirrhosis from any etiology

Laboratory Tests

1. •

   Assessment of liver injury and function: serum aminotransferases, alkaline phosphatase, prothrombin time (PT), albumin, bilirubin.

2. •

   Exclusion of another form of liver disease: viral hepatitis panel, autoantibodies (antinuclear antibody, anti–smooth muscle antibody, anti-mitochondrial antibody), iron studies, ceruloplasmin, and α-1 antitrypsin.

3. •

   Ascites protein content ≥ 2.5 g/dL and serum ascites albumin gradient ≥ 1.1 g/dL are suggestive of transudative ascites from BCS or cardiac ascites.

4. •

   Evaluation for underlying myeloproliferative disorder and hypercoagulable state: CBC, bone marrow biopsy, tests for hypercoagulable states (Factor V Leiden, prothrombin gene G20210A mutation, protein C, protein S, antithrombin deficiencies, antiphospholipid syndrome, and paroxysmal nocturnal hemoglobinuria). Protein C, protein S, and antithrombin deficiencies may be difficult to interpret in the setting of liver dysfunction, but levels < 20% of normal are suggestive of a true deficiency; thrombophilia screening for the JAK2 V617F mutation, hyperhomocysteinemia, and MTHFR C677T mutation may be useful if no other cause for myeloproliferative disorders or hypercoagulable states are identified.

Imaging Studies

1. •

   Diagnosis of BCS is made by radiographic imaging.

2. •

   Doppler ultrasonography is the first-line test. Diagnostic sensitivity and specificity are 85% to 90%. Findings include large hepatic vein with an absent flow signal, or with reversed or turbulent flow; large intrahepatic or subcapsular collateral vessels; enlarged, stenotic, thickened, or tortuous hepatic veins; spiderweb pattern near hepatic vein ostia and associated absent flow in that region; caudate lobe hypertrophy (as the caudate lobe has an alternate blood supply through anastomoses); flattened or absent hepatic venous waveform without fluttering; hyperechoic cord replacing a normal vein.

3. •

   MRI with gadolinium contrast is the second-line test. It is superior to contrast-enhanced CT (Fig. E1) with a sensitivity and specificity of approximately 90% and it is preferred in younger patients due to the lack of radiation. Findings include obstructed hepatic veins or IVC, large intrahepatic or subcapsular collaterals, and caudate lobe hypertrophy. MRI is beneficial to visualize the entire length of the IVC and distinguish between acute, subacute, and chronic BCS. Three-dimensional contrast-enhanced magnetic resonance angiography (MRA, see Fig. 2) rivals hepatic venography in sensitivity.

   

   

4. •

   Contrast-enhanced CT may reveal similar findings as Doppler ultrasound as well as delayed or absent filling of the hepatic veins, parenchymal opacification of the liver, narrowing and/or compression of the inferior vena cava, and caudate lobe hypertrophy. Contrast enhancement localizes more centrally than peripherally and has a patchy and flea-bitten appearance. The use of CT is limited given that in almost 50% of patients, the test is indeterminate or a false-positive. Ultrasonography is more accurate than CT for detecting lesions in the hepatic veins and IVC.

5. •

   CT image reconstruction of vasculature is becoming more available.

6. •

   Venography: not essential for diagnosis; it should be performed when other noninvasive imaging tests are nondiagnostic in the setting of strong clinical suspicion for BCS. Measurement of pressure gradients can help predict success of percutaneous or surgical shunt intervention. Confirms the pathognomonic web pattern caused by collateral venous flow.

7. •

   Liver biopsy: not necessary to diagnose BCS but may be helpful in patients with cirrhosis in whom the diagnosis remains uncertain and is critical for differentiating from hepatic venoocclusive disease or congestive hepatopathy. Findings include hepatic congestion, hepatocyte necrosis and fibrosis in centrilobular areas, and compensatory nodular regenerative hyperplasia with progression to fibrosis and cirrhosis. In advanced BCS, infarction caused by concomitant thrombosis of the intrahepatic, extrahepatic, and portal veins may be seen. There are conflicting studies regarding the association of histologic findings and prognosis.

Treatment

Nonpharmacologic Therapy

1. •

   Goal of therapy is decompression of hepatic congestion.

2. •

   In general, therapeutic procedures should be introduced by order of increasing invasiveness based on response/failure to therapy rather than disease severity. Fig. 3 illustrates a treatment algorithm for patients with Budd-Chiari syndrome.

   

3. •

   Hypercoagulable states should be investigated in all patients.

Acute General Rx

1. •

   Anticoagulation, first with low-molecular-weight heparin (LMWH), followed by warfarin, even in the absence of an underlying hypercoagulable disorder. Recent research also suggests that using direct-acting oral anticoagulants in BCS is safe and effective.

2. •

   In situ thrombolysis: can be successful when performed in patients with recently thrombosed veins (within 2-3 weeks after symptom onset) that are well defined on venography. Mature clots are nonresponsive to thrombolysis, and bleeding risk is high if portal hypertension has developed.

3. •

   Balloon angioplasty: complicated by 50% restenosis rate within two years; effective when membranous webs or short segment hepatic vein stenosis are the etiology.

4. •

   Stenting: may improve long-term patency rates to 90%, but if placed above the intrahepatic IVC, may complicate future liver transplantation.

5. •

   Transjugular intrahepatic portosystemic shunt (TIPS) (Fig. 4): Indicated with diffuse hepatic vein thrombosis, refractory ascites, recurrent variceal bleeding and progressive liver failure. Polytetrafluoroethylene (ePTFE)-coated stents have improved TIPS-patency rates, especially in patients with underlying hypercoagulable defects with a 76% 10-year survival rate.

   

6. •

   Surgical portal systemic shunts: Indicated when angioplasty and stenting have failed and when complications from portal hypertension are also present. This option is no longer common practice and provides no survival benefit.

7. •

   Liver transplant may be indicated in patients with cirrhosis or fulminant hepatic failure and in patients who fail to respond to TIPS; 10-year survival is reported to range between 69% and 84%.

8. •

   Supportive measures.

Chronic Rx

1. •

   Lifelong anticoagulation: Warfarin therapy, with a target INR of 2 to 3 or low-molecular-weight heparin, lessens, but does not completely prevent, recurrence. Anticoagulation should be continued permanently unless the patient has an adverse event to anticoagulation, the obstruction is because of an anatomic cause that has been corrected, or anticoagulation is contraindicated.

2. •

   In patients with an underlying myeloproliferative disorder first-line treatment is with hydroxyurea and aspirin.

3. •

   Treat liver dysfunction and complications related to portal hypertension such as ascites and variceal bleeding.

4. •

   Invasive interventions should be reserved for symptomatic patients who do not improve with medical therapy.

5. •

   Manage shunt thrombosis; which is a common complication.

6. •

   Liver transplantation is another treatment option with a 71-89% survival rate at five years; up to 27% recurrence of BCS after transplant has been recognized.

7. •

   Monitor for development of hepatocellular carcinoma and transformation of myeloproliferative disease in patients with longstanding, well-controlled BCS and post-transplant lymphoma in orthotopic liver transplantation (OLT) recipients.

Disposition

Prognosis is variable and depends on multiple factors, including time to recognition and treatment, etiology, acuity, the type of intervention, and the condition of the patient at the time of treatment. Overall mortality rates are decreasing with the use of anticoagulation and early diagnosis of asymptomatic cases. Given numerous therapeutic options, the survival rate is 90%, 83%, and 72% at 1, 5, and 10 yr from diagnosis. A prognostic index called the Rotterdam BCS Index has been described: 1.27 × Encephalopathy + 1.04 × Ascites + 0.72 × PT + 0.004 × Bilirubin. Encephalopathy and ascites are scored as 1 for present or 0 as absent, and PT is scored as greater (1) or less than (0) an INR of 2.3. An index of <1.1 correlates to low risk (5-yr survival rate, 89%), 1.1 to 1.5 with intermediate risk (5-yr survival rate, 74%), and > 1.5 with high risk (5-yr survival rate, 42%). There is also the BCS-TIPS PI score, which is a prognostic index for survival one year after TIPS: age (years) × 0.08 + bilirubin × 0.16 + INR × 0.63. Seven is the most specific discriminative factor with those scoring above 7 necessitating emergent OLT as the first line treatment.

Referral

Fulminant presentations should immediately be referred to a center capable of liver transplantation. All cases benefit from referral to a hepatologist, a hematologist, an interventional radiologist, and a surgeon specializing in hepatobiliary disease.

Pearls & Considerations

Comments

1. •

   Look for one or more underlying causes, especially hypercoagulable or hematologic disorders, and malignancies or space-occupying lesions that may compress or invade the hepatic outflow tract.

2. •

   Myeloproliferative disorders are most common.

3. •

   Diagnosis relies on imaging; beginning with Doppler ultrasound.

4. •

   Treatment with anticoagulation comes first; followed by invasive interventions as needed. Prophylaxis of portal hypertension can reduce the risk of major bleeding associated with anticoagulation therapy.

5. •

   Referral for liver transplantation may be necessary.

6. •

   Prognostic indices can assist in management and estimate survival rates.

Prevention

In the setting of known risk factors, such as a hypercoagulable state or myeloproliferative disorder, any additional risks, such as smoking or oral contraceptive therapy, should be avoided.

Suggested Readings

• A. Copelan, et al.: Diagnosis and management of Budd Chiari Syndrome: an update. Cardiovasc Intervent Radiol. 38 (1):1–12 2015

• M.A. Fox, et al.: Budd-Chiari syndrome—a review of the diagnosis and management. Acute Medicine. 10 (1):5–9 2011 21573256

Related Content

1. Budd-Chiari Syndrome (Patient Information)

2. Hypercoagulable States (Related Key Topic)