Budd-Chiari Syndrome

Budd-Chiari syndrome is an uncommon condition induced by thrombotic or nonthrombotic obstruction of the hepatic venous outflow and is characterized by hepatomegaly, ascites, and abdominal pain.[49] It most often occurs in patients with an underlying thrombotic diathesis, including in those who are pregnant or who have a tumor, a chronic inflammatory disease, a clotting disorder, an infection, or a myeloproliferative disorder, such as polycythemia vera or paroxysmal nocturnal hemoglobinuria. (See Etiology and Presentation.)

Obstruction of large- or small-caliber veins leads to hepatic congestion as blood flows into, but not out of, the liver. Microvascular ischemia due to congestion causes hepatocellular injury. Portal hypertension and liver insufficiency result.[5, 6, 49] (See Pathophysiology.)

Budd-Chiari syndrome should be considered separate from veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, which is characterized by toxin-induced, nonthrombotic obstruction of prehepatic veins (see the images below). (See Presentation and Workup.)

Occlusion of a single hepatic vein is usually silent. Overt Budd-Chiari syndrome generally requires the occlusion of at least 2 hepatic veins.[8] Venous congestion of the liver causes hepatomegaly, which can stretch the liver capsule and be very painful. Enlargement of the caudate lobe is common because blood is shunted through it directly into the inferior vena cava (IVC).

Hepatic function can be affected to a degree, depending on the amount of stasis and the resultant hypoxia. Increased sinusoidal pressure can itself cause hepatocellular necrosis.[49] The literature also suggests that upregulation of specific genes in chronic Budd-Chiari syndrome contributes to liver destruction through the stimulation of extracellular matrix proliferation, which contributes to liver fibrosis.

The most prominent genes involved include matrix metalloproteinase 7 and superior cervical ganglion 10 (SCG10), which are increased in expression, and thrombospondin-1, which is decreased.[9] Overexpression of the proliferating cell nuclear antigen gene, the c -MYC oncogene, and the tumor protein p53 gene may also be etiologic factors for Budd-Chiari syndrome.[10]

Most patients with Budd-Chiari syndrome have an underlying thrombotic diathesis, although in approximately one third of patients, the condition is idiopathic. Thus, it may be a primary venous problem or an intra-/extrahepatic space-occupying lesion compressing/invading the venous outflow.[49] Causes of Budd-Chiari syndrome include the following:

• Hematologic disorders

• Inherited or acquired thrombotic diathesis[49]

• Pregnancy and postpartum[11]

• Oral contraceptives[49]

• Chronic infections

• Chronic inflammatory diseases

• Tumors

• Congenital membranous obstruction

• Hepatic venous stenosis

• Hypoplasia of the suprahepatic veins

• Postsurgical obstruction

• Posttraumatic obstruction

• Malnutrition[49]

• Total parenteral nutrition (TPN): Budd-Chiari syndrome has been reported as a complication of TPN via an IVC catheter in a neonate

Hematologic disorders

These include the following:

• Polycythemia rubra vera

• Paroxysmal nocturnal hemoglobinuria

• Unspecified myeloproliferative disorder

• Antiphospholipid antibody syndrome

• Essential thrombocytosis

Inherited thrombotic diathesis

Coagulopathies include the following:

• Protein C deficiency

• Protein S deficiency

• Antithrombin III deficiency

• Factor V Leiden deficiency

Chronic infections

These include the following:

• Hydatid cysts

• Aspergillosis

• Amebic abscess

• Syphilis

• Tuberculosis

Chronic inflammatory diseases

These include the following:

• Behçet disease

• Inflammatory bowel disease

• Sarcoidosis

• Systemic lupus erythematosus

• Sjögren syndrome

• Mixed connective-tissue disease

Tumors

These include the following:

• Hepatocellular carcinoma (HCC)[12]

• Renal cell carcinoma

• Leiomyosarcoma

• Adrenal carcinoma

• Wilms tumor

• Right atrial myxoma

Congenital membranous obstructions

These include the following:

• Type I: Thin membrane is present in the vena cava or the atrium

• Type II: A segment of the vena cava is absent

• Type III: The inferior vena cava (IVC) cannot be filled, and collaterals have developed

Miscellaneous

Miscellaneous causes of Budd-Chiari syndrome include the following:

• Alpha1-antitrypsin deficiency

• Dacarbazine

• Urethane

Budd-Chiari syndrome is extremely rare, and the incidence is not well reported in the literature, although a study by Rajani et al found an incidence of about 1 case per million population per year in Sweden. Congenital membranous forms of Budd-Chiari syndrome are the most common cause of the disease worldwide, particularly in Asia.[13]

A retrospective (2009-2013) nation-wide, population-based study in South Korea found a total of 424 patients with Budd-Chiari syndrome, with an average age- and sex-adjusted prevalence of 5.29 per million population.[14] The female-to-male ratio was 1.8, the median age was 51 years, and the annual case-fatality rate was 2.8%.[14]

The prevalence of Budd-Chiari syndrome in France appears to 4.04 per million inhabitants, with myeloproliferative neoplasms (48%), use of oral contraceptives (35%), and factor V Leiden (16%) the highest risk factors.[52]

No data suggest that sex affects predisposition to Budd-Chiari syndrome. Nonetheless, in the United States the condition is predominantly seen in women and is associated with hematologic disorders.

Age at presentation is usually in the third or fourth decade of life, although the condition may also occur in children or elderly persons.

The natural history of Budd-Chiari syndrome is not well known. The following factors, however, have been associated with a good prognosis:

• Younger age at diagnosis

• Low Child-Pugh score

• Absence of ascites or easily controlled ascites

• Low serum creatinine level

In a systematic review of 79 studies, investigators found that although univariate analysis indicated bilirubin and creatinine levels as well as ascites might be significant prognostic factors, multivariate analyses did not always reveal achievement of statistical significance.[15]

The following formula has been proposed to calculate the prognostic index for Budd-Chiari syndrome; a score of less than 5.4 is associated with a good prognosis:

• Prognostic index = (ascites score x 0.75) + (Pugh score x 0.28) + (age x 0.037) + (creatinine level x 0.0036)

The 5-year survival rate for patients with the syndrome is 38-87% following portosystemic shunting. The actuarial 5-year survival rate following liver transplantation is 70%.[2, 3, 4] Long-term follow-up in adults has demonstrated 10-year survival rates as high as 55%.

The prognosis is poor, however, in patients with Budd-Chiari syndrome who remain untreated, with death resulting from progressive liver failure in 3 months to 3 years from the time of diagnosis.[1]

In a University of Pennsylvania retrospective study (2008-2013) comprising 47 patients with Budd-Chiari syndrome, there were no significant differences in the treatment outcomes among those receiving anticoagulation therapy alone, transjugular intrahepatic portosystemic shunt (TIPS) placement alone, and TIPS in conjunction with anticoagulation.[16] The investigators noted that the significant prognostic predictors for liver transplantation were age, presence of cirrhosis, and presence of chronic kidney disease.

Morbidity and mortality

Morbidity and mortality in Budd-Chiari syndrome are generally related to complications of liver failure and ascites but can also be impacted by the type of concomitant underlying disease, if any. Complications associated with Budd-Chiari syndrome include the following:

• Hepatic encephalopathy

• Variceal hemorrhage

• Hepatorenal syndrome

• Portal hypertension

• Complications secondary to hypercoagulable state

• Complications secondary to hepatic decompensation

Bacterial peritonitis is always of concern in the patient with ascites, especially if paracentesis is undertaken. Complications must also be considered in relation to therapies used (eg, thrombolytics). The mortality rate can be high in patients who develop fulminant hepatic failure.

Budd-Chiari syndrome can also lead to HCC (or oppositely, in some cases, develop secondary to it). In a retrospective study, Liu et al found evidence that HCC in primary Budd-Chiari syndrome is associated with blockage of the inferior vena cava and stricture of the hepatic venous outflow tract. The investigators’ results also indicated that transcatheter arterial chemoembolization (TACE) is an effective treatment for HCC in these patients, with a significant drop in alpha-fetoprotein levels after TACE treatment. The study included 246 patients with Budd-Chiari syndrome, including 14 with HCC. Ultrasonography, computed tomography (CT) scanning, magnetic resonance imaging (MRI), and angiography were used to determine the imaging characteristics in patients with HCC.[17]

The classic triad of abdominal pain, ascites, and hepatomegaly is observed in the vast majority of patients with Budd-Chiari syndrome,[18] but it is nonspecific. A high index of suspicion is needed to make the diagnosis.

If the liver has had time to develop collaterals and decompress, patients can be asymptomatic (≤20%[18] ) or present with few symptoms. As the syndrome progresses, however, it can lead to liver failure and portal hypertension with corresponding symptoms (eg, encephalopathy, hematemesis). The American Association for the Study of Liver Diseases has released guidelines for the management of acute liver failure.[19]

The clinical variants of Budd-Chiari syndrome have been described as follows[5, 6, 7] :

• Acute and subacute forms: Characterized by rapid development of abdominal pain, ascites, hepatomegaly, jaundice, and renal failure.

• Chronic form: Most common presentation; patients present with progressive ascites; jaundice is absent; approximately 50% of patients also have renal impairment

• Fulminant form: Uncommon presentation; fulminant or subfulminant hepatic failure is present, along with ascites, tender hepatomegaly, jaundice, and renal failure.

Patients with acute onset of obstruction typically present with acute right upper quadrant pain. Abdominal distention can also be a significant symptom, because of ascites. Jaundice is rarely observed.

Physical examination may reveal the following findings:

• Jaundice

• Ascites

• Hepatomegaly

• Splenomegaly

• Ankle edema

• Stasis ulcerations

• Prominence of collateral veins

Evaluate patients with Budd-Chiari syndrome for underlying predisposing conditions, such as malignancy or hypercoagulable states, and institute appropriate therapy.

Examination of the ascitic fluid provides useful clues to the diagnosis, including the following:

• Patients usually have high protein concentrations (>2 g/dL); this may not be present in persons with the acute form of Budd-Chiari syndrome

• The white blood cell (WBC) count is usually less than 500/µL

• The serum ascites–albumin gradient is usually less than 1.1 (except in the acute forms of the disease)

Routine biochemical test results are usually nonspecific in Budd-Chiari syndrome, although mild elevations in serum aminotransferase and alkaline phosphatase levels are present in 25-50% of patients.

Imaging is essential for the early identification and evaluation of the disease extent in Budd-Chiari syndrome, which aids in mitigating hepatic congestion and, thereby, restoration of the hepatic function and alleviation of portal hypertension.[20]

2016 European Association for the Study of the Liver (EASL) recommendations on Budd-Chiari syndrome

The EASL clinical practice guidelines on vascular diseases of the liver includes the following recommendations[48] :

• The diagnosis of Budd-Chiari syndrome should be considered in all patients with symptomatic or asyptomatic acute or chronic liver disease.

• The first-line diagnostic study is Doppler ultrasonography; magnetic resonance imaging (MRI) and computed tomography (CT) scanning are for diagnostic confirmation. In the setting of negative imaging studies but high clinical suspicion of Budd-Chiari syndrome, reevaluate the patient with the help of an expert radiologist.

• Refer all patients with Budd-Chiari syndrome to institutions with expertise in this condition.

• Patients with Budd-Chiari syndrome should be screened for hepatocellular carcinoma. Referral to expert centers may be necessary to determine whether liver nodules are benign or malignant.

Ultrasonography

Thrombi can be visualized; color-flow Doppler ultrasonography, the preferred mode, has a sensitivity and specificity of 85-90%.[21, 22] (See the images below.)

Computed tomography (CT) scanning

Detailed imaging studies are required to determine the precise level and degree of obstruction. CT scanning can rarely provide such detail, unless a mechanical obstruction, such as a locally invading tumor, is suspected.[23]

Use of spectral CT scanning to determine normalized iodine concentration appears to be effective in assessing liver function in patients with Budd-Chiari syndrome, as well as in providing posttreatment imaging results for reevaluation, prognosis, and follow-up.[53]

Magnetic resonance imaging (MRI)

MRI, which has a sensitivity and specificity of 90% or higher, is becoming increasingly useful in providing less-invasive venography, angiography, and cholangiography findings.[24] MRI may assist in differentiating acute from chronic Budd-Chiari syndrome, because it is able to provide a larger image of the vasculature, as well as determine if edema of the parenchyma is present (acute form).

Venography

Catheterization and venography can clearly delineate the nature and severity of an obstruction. Occasionally, therapeutic interventions can be undertaken at the same time, including balloon angioplasty, localized thrombolysis, and the placement of a stent or transjugular intrahepatic portacaval shunt (TIPS).[23, 25, 26, 27]

Percutaneous liver biopsy can be of prognostic assistance, particularly if liver transplantation is being considered, to establish the degree of hepatocellular damage and the presence and degree of fibrosis.[28]

Pathologic findings in liver biopsy are (1) high-grade venous congestion and centrilobular liver cell atrophy, and, possibly, (2) thrombi within the terminal hepatic venules. The extent of fibrosis can be determined based on biopsy findings. The most severe findings can include fulminant hepatic failure with massive centrilobular necrosis.

Studies have indicated, however, that early pathology related to Budd-Chiari syndrome does not have a significant impact on survival.[29]

In patients with Budd-Chiari syndrome, aggressively seek specific therapy aimed at correcting or alleviating the obstruction. Also treat the underlying conditions aggressively.[30]  For example, patients with complications of portal hypertension should begin treatment on the basis of therapeutic recommendations for individuals with cirrhosis.[48]

Although medical therapy can be instituted for short-term, symptomatic benefit,[31]  the use of such treatment alone is associated with a high 2-year mortality rate (80-85%). All individuals with Budd-Chiari syndrome should have close monitoring for early identification of liver deterioration.[48]

Anticoagulant therapy

Anticoagulation is needed in some patients, especially those with underlying hematologic disorders as the cause of Budd-Chiari syndrome.

Prothrombin time and activated partial thromboplastin time should be monitored once anticoagulation is started and should be maintained within the therapeutic range.

The European Association for the Study of the Liver (EASL) indicates that in the setting of adequately treated complications of portal hypertension, anticoagulant therapy is not contraindicated.[48]  A brief interruption in anticoagulation therapy may be considered in patients undergoing an invasive procedure, including paracentesis.

Thrombolytic therapy

This therapy has been used in a few cases. Agents include streptokinase, urokinase, recombinant tissue-type plasminogen activator (rt-PA), and other modalities.

Radiologic intervention

Systemic thrombolysis can be a high-risk endeavor; local thrombolysis performed by an interventional radiologist is preferable.

Other available radiologic interventions include balloon angioplasty, as well as placement of a stent or a transjugular intrahepatic portacaval shunt (TIPS).[18, 32, 33]

In a single-center retrospective study (1996-2012), Tripathi et al reported good long-term outcomes in 67 patients with Budd-Chiari syndrome following successful transjugular intrahepatic portosystemic stent-shunt (TIPSS) using either polytertrafluoroethane (PTFE)-covered (n=40) or bare (n=27) stents.[34]  At a mean follow-up of 82 months, 15% of patients experienced post-TIPSS encephalopathy; 2 patients underwent transplantation, 2 patients developed hepatocellular cancer, and 6 patients had liver-related deaths. The PTFE-covered stents had significantly better primary patency (76%) and shunt reinterventions (22%) compared to the bare stents (27% and 100%, respectively). Survival at 6 and 12 months was at 92% or above; that at 24 and 60 months was 80% or above; and 120-month survival was 72%. The investigators indicated that in symptomatic patients in whom hepatic vein patency cannot be restored, TIPSS should be considered as the first-line therapy.[34]

In another single center retrospective study (2008-2014) of 190 patients with Budd-Chiari syndrome who underwent endovascular procedures (hepatic vein, collateral vein or IVC plasty with or without stenting, or TIPSS), venous recanalization and TIPPS were safe and effective: 153 patients (80.5%) experienced treatment response, with 19 patients (10.0%) requiring repeat interventions and 9 patients (4.7%) with complications.[35]  Of the 190 patients, 147 had hepatic vein obstruction, 40 had IVC obstruction, and 3 had both. Thirty-eight patients underwent hepatic vein/stenting; 3, collateral vein stenting; 40, IVC plasty/stenting; 3, hepatic vein and IVC stenting; and 106, TIPSS.[35]

Tripathi et al reported similar findings for venous recanalization and TIPPS in 122 patients.[36]

More recently, retrospective data (2011-2016) from another study with 68 patients revealed excellent efficacy and long-term outcomes of endovascular therapy (hepatic vein recanalization and accessory hepatic vein recanalization) for hepatic vein-type Budd-Chiari syndrome.[50] Investigators found a 100% technical success rate, with a 95.6% clinical success rate. The mean follow-up period was 39.4 ± 13.6 months. At 1 year, the primary and secondary patency rates were 80.0% and 93.8%; at 2 years, 72.8% and 90.3%; and at 5 years, 67.9% and 91.2%, respectively. Survival was 96.9% at 1 year, 93.4% at 2 years, and 91.2% at 5 years.[50]

Variceal treatment

Gastroscopy should be performed to help rule out the presence of esophageal and gastric varices. If present, they may be obliterated with banding or sclerotherapy. Nonselective beta blockers (eg, propranolol, nadolol) can be administered for primary prophylaxis against variceal bleeding.

Diet

A low-sodium diet is recommended for the control of ascites.

Paracentesis

Symptomatic treatment for Budd-Chiari syndrome includes diuretics and therapeutic paracentesis, when necessary, although paracentesis can be associated with catastrophic complications, such as bacterial peritonitis. Consequently, the benefits of therapeutic paracentesis must be carefully weighed against its risks.

Portal decompression

Decompression of the hepatic vasculature should be offered if portal hypertension is the cause of the symptoms. Either surgery or a transjugular intrahepatic portosystemic shunt (TIPS) procedure can be performed.[2, 6, 27, 37, 38, 39, 40]  

Liver transplantation

Liver transplantation should be offered if decompensated liver cirrhosis is present [4, 41]  or as salvage treatment in the setting of failed portal derivative techniques.[48]  Posttransplantation anticoagulation is required in most patients with Budd-Chiari syndrome.[48]

In a Polish retrospective study (2000-2009), the long-term clinical outcomes (eg, patient and graft survival) following liver transplantation and anticoagulation maintenance for Budd-Chiari syndrome were good in 25 patients with myeloproliferative disease and recurrent thrombosis.[42]

Similar findings were reported in an Indian retrospective study (2011-2015) of 9 patients with Budd-Chiari syndrome and chronic liver disease who underwent living donor liver transplantation.[43]  The investigators noted that prevention of recurrent thrombosis was dependent on "meticulous surgical technique, perfect and wide outflow anastomoses, and a strict anticoagulation protocol. Moreover, the use of synthetic (PTFE) graft for inferior vena cava interposition was safe, feasible, and provided good reconstruction results.[43]

Consultations

Early involvement of a hepatologist can help to establish the direction of workup and therapy. Consultation with interventional radiologists, hematologists, oncologists, gastroenterologists, and general surgeons may be required, depending on the situation.[44]

Follow-up and monitoring

Patients with lesions that are amenable to balloon dilatation or stents require follow-up catheterizations and, frequently, repeat dilatations or stent replacement. In addition, patients should have routine surveillance for hepatocellular carcinoma (HCC).[18, 45]

 

The European Association for the Study of the Liver (EASL) indicates angioplasty/stenting should be considered the first-line decompressive procedure in patients with short hepatic vein or inferior vena cava stenosis.[48]  For those in whom initial therapy or angioplasty/stenting is ineffective, treat with portal derivative techniques, of which transjugular intrahepatic portosystemic shunt (TIPS) using polytertrafluoroethane (PTFE)-covered stents is deemed the derivative therapy of choice by the EASL. Consider surgical shunting in the setting of TIPS unfeasibility or failure.[48]

Angioplasty procedure can help relieve obstruction caused by membranous webs. In a study of 101 patients with Budd-Chiari syndrome, Li et al concluded that the condition can be safely and effectively treated with percutaneous transhepatic balloon angioplasty (PTBA).[46]  The authors reported successful PTBA (performed after hepatovenography, with or without stenting) in 92 of the study’s patients, with all of the successful procedures resulting in significant symptom improvement.

Complications included acute hepatic vein thrombosis, occurring during or after the operation (n=3); sustained intraperitoneal bleeding from the transhepatic puncture track (n=2); pulmonary embolism, which occurred during the procedure (n=1); and intrahepatic hematoma (n=1).[46]  All were managed nonsurgically. Primary patency rates at 6-, 12-, and 24-month follow-up were 84%, 78%, and 76%, respectively (with several patients lost to follow-up); secondary patency rates were 95%, 92%, and 84%, respectively. Despite these satisfactory midterm patient outcomes, the authors cautioned that long-term outcomes in patients treated with PTBA for Budd-Chiari syndrome require investigation.[46]

 

Patients with liver failure and ascites have total body sodium overload, despite typically low serum sodium concentrations. Inducing negative sodium balance can reduce the amount of ascites. Take special care when using diuretics, to avoid inducing hepatorenal syndrome or creating electrolyte and fluid disturbances through overly aggressive diuresis. Electrolyte levels should be monitored closely.

Secondary hyperaldosteronism is part of this clinical picture, making spironolactone typically the first-line diuretic. Chlorothiazide or furosemide is often added, which can provide synergy and avoid hyperkalemia.

Medications commonly used in patients with Budd-Chiari syndrome include diuretics, anticoagulants, and thrombolytics. The therapeutic interventions used (medical or otherwise) must be tailored to each patient's condition. The use of thrombolytics should be reserved for experts familiar with the special circumstances in which they may be appropriate. The use of anticoagulants should be directed towards therapy of an underlying coagulopathy.

Class Summary

These agents prevent recurrent or ongoing thromboembolic occlusion.

Warfarin (Coumadin, Jantoven)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor the dose to maintain an international normalized ratio (INR) in the range of 2-3.

Class Summary

Fibrinolytic drugs are used to dissolve a pathologic intraluminal thrombus or embolus that has not been dissolved by the endogenous fibrinolytic system. They are also used for the prevention of recurrent thrombus formation and for the rapid restoration of hemodynamic disturbances.

Urokinase

Urokinase is a direct plasminogen activator that acts on the endogenous fibrinolytic system and converts plasminogen to the enzyme plasmin, which, in turn, degrades fibrin clots, fibrinogen, and other plasma proteins. It is most often used for local fibrinolysis of thrombosed catheters and superficial vessels. An advantage to this agent is that it is nonantigenic. However, urokinase is more expensive than streptokinase, limiting its use. When it is used for local fibrinolysis, urokinase is administered as a local infusion directly into the area of the thrombus, with no bolus given. The dose should be adjusted to achieve clot lysis or patency of the affected vessel.

Alteplase (Activase)

Alteplase is a tissue plasminogen activator used in the management of acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. Its safety and efficacy with concomitant administration of heparin or aspirin during the first 24 hours after symptom onset have not been investigated.

Class Summary

Diuretics can be useful to reduce the amount of ascites, providing symptomatic relief and reducing the need for paracentesis.

Spironolactone (Aldactone)

Spironolactone is a potassium-sparing diuretic. It competes with aldosterone for receptor sites in the distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

This agent is often preferred because of its potassium-sparing effects, particularly in a clinical setting that includes secondary hyperaldosteronism.

Furosemide (Lasix)

Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Torsemide (Demadex)

Torsemide increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. It increases the excretion of water, sodium, chloride, magnesium, and calcium. If a switch is made from intravenous to oral administration, an equivalent oral dose should be used. Doses vary depending on the patient's clinical condition.

Chlorothiazide (Diuril)

A thiazide diuretic, chlorothiazide inhibits sodium-chloride symport, blocking sodium reabsorption in the distal convoluted tubule.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide acts on the distal nephron to impair sodium reabsorption, enhancing sodium excretion. It has been in use for more than 40 years and is generally an important agent for the treatment of essential hypertension.