Budd-Chiari syndrome and veno-occlusive disease

CHAPTER 88  Budd-Chiari syndrome and veno-occlusive disease C. Kristian Enestvedt and Susan L. Orloff

Among the etiologies of portal hypertension, those caused by postsinusoidal obstruction are seen infrequently by most clinicians. Nonetheless, these disease processes represent complex clinical challenges and require a thorough knowledge of the available diagnostic and treatment modalities. Included in this group are Budd-Chiari syndrome and venoocclusive disease. The latter condition is also referred to as sinusoidal obstruction syndrome and is most often seen after myeloablation with chemotherapy or radiation therapy before hematopoetic stem cell transplant.

BUDD-CHIARI SYNDROME Budd-Chiari syndrome (BCS) is a group of disorders caused by occlusion of the major hepatic veins, the inferior vena cava (IVC), or both at or near the level of the hepatic vein ostia. Although a brief discussion of this clinical phenomenon first appeared in a book by Budd in 1845, Lambron in 1842 is said to have reported the first case. In 1899, Chiari collected 10 cases and reported three personal cases and presented the first thorough clinicopathologic description of the syndrome, including the hypothesis that the underlying mechanism was endophlebitis of the hepatic veins. The weight of evidence, however, favors the current opinion that the primary process is usually thrombotic rather than inflammatory. Since publication of the initial description, more than 8000 cases of BCS have been described in the medical literature. In recent years, the incidence has increased substantially, most likely as a result of increased awareness of BCS, improvements in diagnostic methods, and widespread use of thrombogenic agents, such as oral contraceptives (Maddrey, 1987; Valla et al, 1986). Nevertheless, BCS remains a relatively uncommon condition. Contemporary reports place the incidence of BCS between 0.2 and 2 per 1 million population, but these numbers are not well established and show substantial regional and geographic variation (Valla, 2009). Obstruction of hepatic venous outflow produces intense congestion of the liver and the clinical manifestations of ascites, hepatomegaly, and abdominal pain. Depending on the rapidity and extent of obstruction of hepatic venous outflow, the course of BCS may be rapid or chronic, progressing to death in weeks or leading to death from liver failure or bleeding esophageal varices after an illness of months or occasionally years. In Western countries, a rapid course is common, and the outcome is often fatal in many reported cases. With prompt diagnosis and improved therapeutics, however, this condition can be managed as a chronic condition or cured entirely. Effective surgical therapy developed at highly specialized centers enables durable decompression of the obstructed hepatic vascular bed. As a result, the previously dismal outlook for patients with BCS 1248

has improved considerably. The advent of less invasive measures, notably the introduction and wide adoption of transjugular intrahepatic portosystemic shunt (TIPS), has further reduced the morbidity related to BCS. For patients in whom these measures fail, liver transplantation remains a viable option, with excellent results despite recurrent disease in some reports. Many centers have adopted a stepwise approach to treatment that has converted this once uniformly fatal process to a well-controlled, manageable condition.

Predisposing Conditions Specific conditions are known to predispose to the development of BCS (Box 88.1). During the past 60 years, a marked change has been observed in the frequency with which a known cause or predisposing condition has been identified in patients with BCS. In the classic collective review of 164 cases of BCS reported by Parker in 1959, a predisposing condition or etiology could not be identified in 70% of the patients. In recent years, the incidence of idiopathic cases of BCS has plummeted to less than 30% (Mahmoud et al, 1996; Menon et al, 2004; Mitchell et al, 1982; Murad et al, 2009; Plessier & Valla, 2008; Valla, 2003), an improvement attributed to two factors: (1) a greater awareness of BCS and (2) improved diagnostic tools to identify the anatomic lesions and to diagnose thrombogenic hematologic disorders. In fact, many experts agree that there may be multiple predisposing risk factors for the development of this syndrome. Regional variation in etiology between the East and West in the predisposing conditions and in the anatomic pattern of BCS has been recognized for some time (Table 88.1). The classic description of BCS falls under the primary designation and is directly attributable to thrombosis at the hepatic veins. Membranous obstruction of the vena cava (MOVC) is rare in the West, but it is a frequent cause of BCS in Eastern countries such as Japan, China, and India as well as South Africa. In the West, thrombosis of the major hepatic veins alone is substantially more common than thrombosis or occlusion of the IVC, whereas in India, China, and Japan, IVC occlusion is much more common than hepatic vein occlusion alone. In North America, the acute or subacute forms of BCS predominate, and chronic BCS is observed less frequently, whereas in the East, the reverse is observed. In the West, BCS is seldom found during pregnancy or the postpartum period, whereas in India, pregnancy is a major predisposing condition for BCS. The same difference is seen in the incidence of infections, such as hepatic amebiasis (see Chapter 73), which are rare in the West but are reported frequently in series of BCS from India. The use of oral contraceptives (OCs) has been frequently associated with BCS in the United States, where OC use is widespread. Finally, an important distinction in etiology regarding the prevalence of



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

BOX 88.1  Conditions Predisposing to Budd-Chiari Syndrome (BCS) Primary BCS Hematologic disorders Polycythemia vera Paroxysmal nocturnal hemoglobinuria Essential thrombocythemia Primary erythrocytosis Myelofibrosis Acute leukemias and lymphomas Hemolytic anemias Protein C deficiency Protein S deficiency Antithrombin III deficiency Lupus anticoagulant (antiphospholipid syndrome) Factor V Leiden mutation JAK2 V617F mutation Prothrombin (factor II) mutation Antiphospholipid syndrome Hyperhomocysteinemia Oral contraceptives Pregnancy and postpartum Connective tissue disorders Behçet’s syndrome Sjögren’s syndrome Mixed connective tissue disease Sarcoidosis Rheumatoid arthritis α1-Antitrypsin deficiency Idiopathic hypereosinophilia syndrome Systemic lupus erythematosus Membranous obstruction of inferior vena cava Secondary BCS Malignant neoplasms Hepatocellular carcinoma Renal cell carcinoma Adrenal carcinoma Leiomyosarcoma of inferior vena cava Others (carcinomas of lung, pancreas, and stomach; melanoma; reticulum cell sarcoma; adrenal sarcoma; tumor of right atrium) Infections Amebic liver abscess Aspergillosis Hydatid disease Schistosomiasis Syphilitic gumma Filariasis Trauma Iatrogenic Malposition/occlusion of transjugular intrahepatic portosystemic shunt Caval filter dysfunction

myeloproliferative disorders (MPDs) highlights additional geographic differences. A recent study from China observed that MPDs were uncommon in the BCS cohort examined, whereas this is a frequent finding in Western studies (Qi et al, 2012; Smalberg et al, 2012).

Hematologic Disorders Hematologic diseases that cause vascular thrombosis are the most common conditions that predispose to BCS in North

1249

TABLE 88.1  Differences Between West and East in Predisposing Conditions and Anatomic Patterns of Budd-Chiari Syndrome (BCS) Feature

West

East

Membranous obstruction of the IVC Hepatic vein occlusion predominates IVC occlusion predominates

Rare

Frequent

+

–

–

Acute or subacute BCS predominates Chronic BCS predominates

+

+ –

Pregnancy/postpartum Infection Oral contraceptives Myeloproliferative disease

Uncommon Rare Frequent Common

–

+ Frequent Common Uncommon Rare

IVC, Inferior vena cava.

America and Western Europe. Of disorders with thrombotic tendencies, myeloproliferative diseases (MPDs) are most often associated with BCS. A review of reported cases indicates myelodysplasia as an underlying etiology in approximately half of affected patients (DeLeve et al, 2009). A recent meta-analysis of BCS studies implicates MPD in 40.9% of 1062 reported cases of BCS (Smalberg et al, 2012). Historically, polycythemia vera has been the most frequently occurring of the MPDs in BCS patients, constituting 8.5% of the cases of BCS in the collected series of Parker (1959) and 10.4% of the cases in the collected series of Mitchell and colleagues (1982). However, in contemporary series the prevalence is considerably higher. In the series of 77 cases reported by Orloff and colleagues (2012), 31% had polycythemia vera, and its association with BCS was noted to diverge from the classic description of BCS in several ways. First, it was found more often in young adults, rather than in middle-aged and elderly patients. Second, polycythemia vera has been shown to be responsive to treatment with hydroxyurea, which should be started as soon as the disease is discovered and continued for life. Other treaments for polycythemia vera include serial phlebotomy, anagrelide, interferon alfa-2b, and ruxolitinib, recently approved by the US Food and Drug Administration (FDA). Whatever treatment regimen is used, the disease runs a benign course if treated early. Paroxysmal nocturnal hemoglobinuria (PNH) is another hematologic disorder associated with BCS (Hartmann et al, 1980; Hoekstra et al, 2009; Liebowitz & Hartmann, 1981; Valla et al, 1987). It was responsible for 6.7% of the cases in the collected series of Mitchell and colleagues (1982) and 12% of the cases in the series of Valla and colleagues (1987). In all the hematologic disorders associated with hepatic vein thrombosis, but particularly in PNH, thrombosis of other splanchnic vessels and even extraabdominal vessels has been observed (Peytremann et al, 1972). When diagnosed early, PNH should be treated with eculizumab to prevent long-term sequelae. While hematologic diagnosis has become progressively more sophisticated, many other thrombogenic conditions have been identified in BCS, including other myeloproliferative states (e.g., essential thrombocythemia, primary erythrocytosis, myelofibrosis) and thrombophilic states, such as protein C deficiency, protein S deficiency, antithrombin III deficiency, and

1250

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

antiphospholipid syndrome with lupus anticoagulant or anticardiolipin antibodies or both (Bertina et al, 1994; Boughton, 1991; Dahlback, 1995; Dahlback et al, 1993; Espinosa et al, 2001; Koster et al, 1993; Mahmoud et al, 1995; Menon et al, 2004; Pelletier et al, 1994; Svensson & Dahlback, 1994; Valla, 2003; Vanderbroucke et al, 1994). Patients with the factor V Leiden mutation, which leads to activated protein C resistance, have a fivefold to tenfold increase in the risk of thrombosis if they are heterozygotic and a 50-fold to 100-fold increase if they are homozygotic (Dahlback, 1995; Deltenre et al, 2001; Janssen et al, 2000). More recent evidence indicates that multiple prothrombotic factors acting concurrently are involved in a substantial percentage of patients with BCS (Denninger et al, 2000; Janssen et al, 2000). Rarely, hematologic malignancies, such as acute leukemia and lymphoma, have been associated with BCS. In 2005, identification of the underlying cause of BCS was enhanced by the discovery of a very reliable and noninvasive marker for chronic MPDs. The marker is the gain-of-function mutation V617F of the JAK2 gene (Baxter et al, 2005; James et al, 2005; Jelinek et al, 2005; Jones et al, 2005; Kralovics et al, 2005; Levine et al, 2005; Steensma et al, 2005; Zhao et al, 2005). By combining identification of this marker with results of bone marrow histology and clonality assay, more than 50% of BCS cases have been found to be caused by an underlying chronic MPD (Primignani et al, 2006). It cannot be overemphasized that every patient found to have BCS should undergo a thorough hematologic evaluation. The assessment is an expansion of the workup proposed by Mahmoud and Elias (1996) and others (Hirschberg et al, 2000; Valla, 2009) (Box 88.2). With these studies, it should be possible to diagnose all the known predisposing thrombogenic hematologic disorders associated with BCS. If this evaluation is uniformly performed, the incidence of idiopathic BCS will likely continue to decline.

Oral Contraceptives An increased incidence of thromboembolic phenomena involving various blood vessels and organs in women taking OCs has been well established. The first case of BCS associated with OC

BOX 88.2  Screening for Hematologic Disorders in Budd-Chiari Syndrome Complete blood count, prothrombin time, partial thromboplastin time, fibrinogen Red blood cell mass, plasma volume Bone marrow biopsy, cell culture, karyotype JAK2 gene, V617F mutation in peripheral blood granulocytes Antithrombin III assay Protein C assay Free protein S antigen assay Lupus anticoagulant Anticardiolipin antibodies Ham’s acid hemolysis test Activated protein C resistance or factor V Leiden mutation or both Endogenous erythroid colony assay Flow cytometry for blood cells deficient in CD55 and CD59 (PNH) Molecular test for G20210A prothrombin gene mutation Anti–β2-glycoprotein-1 antibodies Plasma homocysteine level β-Human chorionic gonadotropin pregnancy screen PNH, Paroxysmal nocturnal hemoglobinuria.

use was reported by Ecker and McKittrick (1966), 5 years after these drugs became available commercially. Since then, more than 200 cases of BCS in patients taking OCs have been described (Janssen et al, 2000; Lewis et al, 1983; Maddrey, 1987; Valla et al, 1986; Zafrani et al, 1983), and the increasing overall incidence of BCS in recent years has been attributed partly to the widespread use of these agents. In the collective review reported by Mitchell and colleagues (1982), use of OCs was believed to be responsible for 9.4% of BCS cases from 1960 to 1980. Valla and associates (1986) reported a relative risk of of 2.37 for hepatic vein thrombosis among OC users, similar to that of cerebrovascular accident (stroke), myocardial infarction, and venous thromboembolism. Recent literature, however, has questioned the strength of the association between OCs and venous thrombotic disease. It has been proposed that OCs are not a primary cause of BCS but contribute to thrombosis only if there is an underlying hematologic disorder (Valla et al, 1986). In addition to causing BCS, OCs have been linked to other liver disorders, including venoocclusive disease, portal vein thrombosis, cholestasis, hepatocellular adenoma, and possibly, hepatocellular carcinoma and angiosarcoma (Marrero et al, 2014; Zafrani et al, 1983).

Pregnancy and Postpartum Budd-Chiari syndrome has been observed in women during pregnancy and, more often, during the postpartum period. The first case of BCS reported by Chiari (1899) occurred in a woman who developed the disorder after childbirth. In the collective review by Mitchell and colleagues (1982), 9.9% of BCS cases occurred during pregnancy or postpartum, and in a series of 105 patients with BCS observed from 1963 through 1978, Khuroo and Datta (1980) reported 16 patients (15.2%) with BCS after pregnancy; eight patients died, and seven were lost to follow-up after discharge. The hypercoagulable state that is known to occur during pregnancy is presumed to be responsible for the association with BCS, although only 1 of 77 cases of BCS occurred peripartum in a recently reported large series (Orloff et al, 2012). As with OCs, it is increasingly clear that many patients in whom BCS develops in association with pregnancy may also have an underlying thrombophilia, either inherited or acquired (Walker, 2000).

Malignant Neoplasms Occlusion of the suprahepatic IVC by invasive tumors has been the cause of BCS in numerous case reports. This etiology represents prototypical secondary BCS. The most common cancers associated with BCS are hepatocellular carcinoma (see Chapter 91), renal cell carcinoma, adrenal carcinoma, and leiomyosarcoma of the IVC (Fig. 88.1). Other malignancies that have been infrequently associated with BCS include carcinomas of the lung, pancreas, and stomach; melanoma; reticulum cell sarcoma; adrenal sarcoma; and sarcoma of the right atrium.

Infections Infections involving the liver were believed to be responsible for 3% of BCS cases reviewed by Parker (1959), 9.9% of the cases reported by Mitchell and colleagues (1982), and none of the cases in sizable series reported in more recent years. The most common infections associated with BCS are those caused by parasites, particularly amebic liver abscesses, hydatid disease, and schistosomiasis (see Chapters 73 and 74). Syphilitic gumma of the liver accounted for 1.8% of BCS cases in Parker’s review

D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease



A

1251

B

FIGURE 88.1.  Axial (A) and coronal (B) magnetic resonance images demonstrate leiomyosarcoma (white arrows) of the intrahepatic inferior vena cava (white arrowhead) with nonopacification of the obstructed right hepatic vein.

but has not been reported as a cause of BCS in recent years. Aspergillosis involving the hepatic veins and IVC has been a rare cause of BCS. In India, Victor and colleagues (1994) provided evidence that filariasis can cause BCS. These cases represent rare entities that are infrequently reported in BCS literature, but may be more prevalent than reported in low- and middle-income countries (personal communication).

Trauma Abdominal trauma may in particular circumstances predispose patients to the development of BCS (see Chapters 122 and 123). Trauma was responsible for 1.2% of BCS cases reported by Parker (1959) and 2.4% of the cases reviewed by Mitchell and colleagues (1982). Blunt and penetrating trauma have been implicated occasionally in BCS patients, in whom severe liver injury leads to deep laceration at the level of the hepatic veins. Endothelial injury at this location can lead to thrombosis, scar, and ultimately the development of BCS.

Connective Tissue Disorders Occasional cases of BCS have been reported in association with various connective tissue and autoimmune diseases, most of which are known to have thrombotic tendencies, including Behçet’s disease, Sjögren’s syndrome, mixed connective tissue disease, sarcoidosis, and rheumatoid arthritis. Numerous cases of BCS in patients with Behçet’s disease have been described (Bazraktar et al, 1997; Orloff & Orloff, 1999). A recent large series examining vascular complications in 5970 patients with Behcet’s reported BCS in 2.4% of the 882 affected patients (Tascilar et al, 2014). Median time from diagnosis to development of BCS was 2.3 years.

Membranous Obstruction of the Vena Cava More than 600 cases of BCS resulting from MOVC have been reported from Japan (Hirooka & Kimura, 1970; Kimura et al, 1972; Okuda, 2002; Ono et al, 1983; Taneja et al, 1979; Yamamoto et al, 1968), China (Wang, 1989; Wang et al, 1989; Wu et al, 1990) and other parts of Asia, India (Khuroo & Datta, 1980), and South Africa (Semson, 1982). In the United States

and Europe, MOVC is rare. A congenital cause of this condition has been proposed, but evidence strongly suggests it represents the end result of acquired thrombosis (Kage et al, 1992; Okuda, 2002; Okuda et al, 1995). MOVC usually runs a chronic course during many years, and extensive hepatic fibrosis or cirrhosis and portal hypertension will have developed in most patients by the time they come to medical attention. An increased incidence of hepatocellular carcinoma has been observed in association with MOVC (Okuda, 2002; Semson, 1982). The therapeutic implications of this condition and other forms of IVC occlusion are distinctly different from those of occlusion confined to the major hepatic veins.

Miscellaneous Rare Conditions Other conditions that have been rarely associated with BCS include inflammatory bowel disease, hepatic torsion after partial resection of the liver, live-donor liver transplantation of the left lateral section, lipoid nephrosis, and protein-losing enteropathy. The latter two conditions are associated with a prothrombotic condition that may predispose patients to BCS.

Pathology The liver receives approximately one-fourth of the cardiac output through its dual afferent blood supply: the portal vein and hepatic artery. After perfusing the sinusoids, the blood is returned to the heart through the hepatic veins and IVC. Obstruction to the egress of blood from the liver at any point along the outflow route results in numerous serious hemodynamic and morphologic alterations. There is a marked increase in intrahepatic pressure, which is reflected by a similar increase in portal pressure (see Chapter 76). The increased intrahepatic pressure causes extravasation of plasma from the liver sinusoids and lymphatics with formation of ascites (see Chapter 81). Obstruction to the egress of blood from the liver also results in dilation of the sinusoids and intense centrilobular congestion of the hepatic parenchyma, which is greatest around the terminal hepatic venules (central veins) (Fig. 88.2). Ischemia, pressure necrosis, and atrophy of the parenchymal cells in the

1252

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

A

B

FIGURE 88.2.  Liver biopsy demonstrating typical characteristics of venous outflow obstruction under low (A) and high (B) power. Note the marked sinusoidal congestion (black arrowhead) and hepatocyte atrophy (black arrow).

center of the liver lobule are apparent. With persistence of the obstruction, the necrotic parenchyma is replaced by fibrous tissue and regenerating nodules of liver tissue. The end result is cirrhosis of the type associated with chronic congestive heart failure, often referred to as congestive hepatopathy. The rapidity with which cirrhosis develops is related to the severity of outflow obstruction, but it is not unusual for cirrhosis to occur within months (Parker, 1959). This pathophysiology is similar to that seen after liver transplantation in the patient with anastomotic venous outflow obstruction, with similar clinical manifestations. The reversibility of liver damage in BCS is a direct function of the extent and duration of hepatic venous outflow obstruction. Early in the course of the disease, relief of the obstruction can be expected to result in reversal of the parenchymal and hemodynamic abnormalities. Late in the course, the damage to the hepatic parenchyma becomes irreversible; thus the timing of therapy has profound implications for the prognosis. Three major hepatic veins—the right, left, and middle— conduct blood into the IVC from the bulk of the hepatic parenchyma. The left and middle hepatic veins usually form a common trunk just before joining the IVC, and several small hepatic veins, often termed short hepatic veins, enter directly into the retrohepatic IVC and drain the caudate lobe and small central regions of the right and left lobes of the liver (see Chapter 2). Initially, occlusion is limited to one or two of the major veins. During variable intervals, all three of the major hepatic veins become occluded. The small hepatic veins that join the retrohepatic IVC, particularly the veins draining the caudate lobe, often are spared. These veins ultimately form the basis for intrahepatic shunts because they are the only site for adequate parenchymal drainage. In most patients with BCS, occlusion of the hepatic veins is caused by thrombosis (Parker, 1959). The thrombus undergoes organization and ultimately is converted to fibrous tissue that permanently occludes the veins. Although recanalization of the occluded veins sometimes occurs, it rarely results in effective new outflow channels. Indeed, chronic congestion of the liver leads to some degree of irreversible parenchymal injury. Retrograde propagation of the thrombus into smaller hepatic veins is typically found. Prograde propagation of the thrombus from

the hepatic veins into the IVC, with partial or complete occlusion of the IVC, sometimes occurs and greatly changes the therapeutic approach and prognosis. With the use of imaging studies (e.g., angiography) and pressure measurements, it is important to determine whether the IVC has become involved in the occlusive process. In membranous obstruction of the IVC, the “membrane” varies from very thin to several centimeters thick and usually contains fibrous tissue, smooth muscle, and elastic tissue. The location and extent of the membrane vary considerably, and in some cases a long segment of IVC has been replaced by fibrous tissue. Occlusion of one or more of the major hepatic veins often has been associated with membranous obstruction of the IVC. MOVC has been reported to be the most common cause of BCS in Japan (Hirooka & Kimura, 1970; Kimura et al, 1972; Okuda et al, 1995; Ono et al, 1983; Taneja et al, 1979; Yamamoto et al, 1968), India (Khuroo & Datta, 1980), China (Wang, 1989; Wang et al, 1989, 2005; Wu et al, 1990), and in the Bantu population of South Africa (Semson, 1982). Although some experienced authors have proposed a congenital cause (Hirooka & Kimura, 1970; Kimura et al, 1972; Ono et al, 1983; Semson, 1982; Taneja et al, 1979), a strong argument has been made that suggests MOVC is the end result of thrombosis of the IVC, often occurring early in life (Okuda, 2002). Most of the cases have run a chronic course before discovery, and when first seen by a physician, patients have extensive hepatic fibrosis or cirrhosis with portal hypertension and all its manifestations. The therapeutic considerations in patients with MOVC differ from those in patients with BCS caused by obstruction of the hepatic veins.

Clinical Manifestations The clinical manifestations and course of BCS are determined by the extent of occlusion of the hepatic venous outflow system and the rapidity with which the venous occlusion becomes complete. Patients can have an acute or subacute course (typical for patients in Western countries), with rapid progression of liver disease and its consequences during a few weeks to a few months. In some patients, however, BCS develops insidiously, with clinical manifestations appearing gradually during months or years. Patients with MOVC observed in Japan, China, India,

D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease



A

1253

B

FIGURE 88.3.  B-mode (A) and color Doppler (B) ultrasound images showing patent transjugular intrahepatic portosystemic shunt (arrows) with appropriate flow direction and velocity.

and South Africa often come to the physician for the first time with manifestations of well-established cirrhosis after tolerating symptoms for many years. The chronic form of BCS, regardless of etiology, is characterized by portal hypertension and its clinical sequelae. In 77 patients reported by Orloff and colleagues (2012), 12 were referred with advanced cirrhosis, and the remaining 65 patients were referred at a mean 14 weeks after onset of BCS (range, 4-78 weeks). Of the 65 patients, 59 (91%) were referred at less than 18 weeks after onset of symptoms, relatively early in the course of BCS. However, in another contemporary single-center experience, most patients presented with advanced disease at diagnosis, with 92% exhibiting ascites and 55% with cirrhosis (Pavri et al, 2014). In the collected series of Mitchell and colleagues (1982), which excluded patients with MOVC, two-thirds had symptoms for less than 3 months and 83% had symptoms for 6 months or less at diagnosis. In his collected series of 133 patients, Parker (1959) observed that 57% had symptoms for 3 months or less, and 71% had been symptomatic for 6 months or less.

Symptoms Patients with BCS can present with most of the myriad symptoms associated with acute or chronic liver failure (see Chapter 79). The initial symptom in the majority of patients is abdominal distension secondary to ascites, which increases progressively over a few weeks. Abdominal distension caused by ascites occurs at some time in almost every patient with BCS. Most patients report abdominal pain that is dull, nagging, and chronic. The spectrum of pain is localized to the right hypochondrium, diffuse in the upper abdomen, or diffuse throughout the abdomen. The underlying pathophysiology is likey distension of the liver capsule from intense hepatic congestion or rapid accumulation of ascites. Many patients with acute BCS report striking and progressive weakness as a manifestation of their severe illness, with abrupt onset. Additionally, these patients are often malnourished, may exhibit severe anorexia, and can exhibit mild jaundice. CHRONIC LIVER DISEASE.  Patients with the chronic forms of BCS, such as MOVC, often have the usual symptoms of cirrhosis and portal hypertension, including upper gastrointestinal bleeding secondary to ruptured esophagogastric varices (see Chapter 82 and 83), hepatic encephalopathy, hepatorenal syndrome (see Chapter 79), and edema of the lower extremities (see Chapters

81 and 82). Peripheral edema is particularly prominent in patients with MOVC, and some experience varicose veins of the legs (Parker, 1959; Semson, 1982).

Physical Examination Findings Massive ascites on physical examination is one of the most common presenting signs at the time of BCS diagnosis. The reported incidence of ascites ranges from 83% to 100% in the larger reported series (Mitchell et al, 1982; Orloff et al, 2012; Parker, 1959; Pavri et al, 2014). Hepatomegaly resulting from severe congestion of the liver occurs in most patients. During time, this may dissipate to a degree, and in the chronic forms of BCS, hepatomegaly may not be as striking because the liver becomes cirrhotic and contracts. Substantial wasting as a result of loss of lean body mass during a relatively short time is observed in many patients. Signs of portal hypertension are often exhibited, including distension of abdominal veins and palpable splenomegaly. Edema of the lower extremities or lower trunk may indicate involvement of the IVC in the occlusive process, although it is a common finding in patients with liver failure of various etiologies, including BCS. Also, patients with chronic BCS may have the usual manifestations of chronic liver disease: spider angiomata, palmar erythema, asterixis, breast hypertrophy, testicular atrophy, fetor hepaticus, and jaundice.

Diagnostic Studies Ultrasonography Real-time and Doppler duplex ultrasonography (US) of the liver has been shown to be of diagnostic value in BCS (Baert et al, 1983; Becker et al, 1986; Bolondi et al, 1991; Brancatelli et al, 2007; Chaubal et al, 2006; Grant et al, 1989; Gupta et al, 1987; Hosoki et al, 1989; Millener et al, 1993; Powell-Jackson et al, 1986; Rossi et al, 1981) (see Chapter 15). Findings include (1) absence of normal hepatic veins draining into the IVC with flat or reversed flow, (2) an abnormal intrahepatic network of comma-shaped venous structures, (3) thrombus in the IVC and flat or reversed flow in patients with IVC thrombosis, and (4) enlargement of the caudate lobe. Ascites has been shown regularly. US with Doppler may be used as an initial screening tool, with confirmation by CT, MRI, or venography for a definitive diagnosis. Furthermore, US can be used as an appropriate guide to treatment and for surveillance after TIPS placement. Appropriate direction and flow velocity are key requirements for verification of TIPS patency (Fig. 88.3A and B).

1254

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

A

B

D

C

E

FIGURE 88.4.  Early in the acute setting, Budd-Chiari syndrome is demonstrated on sagittal (A) and coronal (B) computed tomographic images, with subtle thrombosis in the hepatic veins with nonopacification (black arrow) and a smooth liver contour. With time, prominent intrahepatic vessels can be seen (C), ascites develops, significant caudate hypertrophy occurs (D, white arrow), and heterogeneous enhancement is seen with central hyper- and peripheral hypo-enhancement (E).

Computed Tomography

Magnetic Resonance Imaging

Contrast-enhanced computed tomography (CT; see Chapter 18) of the liver has considerable diagnostic value in BCS (Baert et al, 1983; Erdon, 2007; Ferral et al, 2012; Kamath, 2006; Lupescu et al, 2008; Mathieu et al, 1987; Vogelzang et al, 1987). CT findings can be quite specific depending on the time course of BCS. In the early, acute period, CT demonstrates a liver with smooth contour (absent cirrhosis), lack of contrast enhancement in hepatic veins at both venous and delayed phases, compression of the intrahepatic IVC, and frequent ascites (Fig. 88.4A and B). In the subacute period, patchy enhancement is a harbinger of deranged blood flow through the liver (Fig. 88.4C). Often, hepatomegaly is observed, with caudate hypertrophy and central enhancement (Fig. 88.4D and E). Collateral vessel development is frequently seen with intrahepatic shunting. In the chronic phase, the liver can appear nodular and cirrhotic. Regenerative nodules often form, with arterial enhancement persisting through the venous phases, in contrast to hepatocellular carcinoma, which typically demonstrates washout in the venous phase. In the chronic stages, IVC occlusion may be observed.

Magnetic resonance imaging (MRI; see Chapter 19) is capable of showing patency or obstruction of the hepatic veins and is particularly effective in visualizing the entire length of the IVC. Imaging features are similar to those seen with CT scan. MRI has been useful in differentiating the acute form of BCS from the subacute and chronic forms (Erdon, 2007; Kamath, 2006; Lupescu et al, 2008; Noone et al, 2000). MRI is an especially effective modality for patients with renal dysfunction, provided there is a relatively preserved glomerular filtration rate (>40). Furthermore, MRI is useful in differentiating regenerative nodules from hepatocellular carcinoma based on T2-weighted signal characteristics (Fig. 88.5A) (Brancatelli et al, 2007). Similar to CT, MRI is efficacious at demonstrating intrahepatic collaterals and shunting (Fig. 88-5B and C).

Hepatic Venography and Pressure Measurements Angiographic examination of the IVC and hepatic veins with pressure measurements is the diagnostic study of greatest value in BCS, particularly if interventional radiology or surgical therapy is contemplated. Venography remains the

D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease



1255

A

B

C

FIGURE 88.5.  Further sequelae seen on axial magnetic resonance images include development of diffuse nodular disease (A); growth of large intrahepatic, often comma-shaped collaterals (B, white arrow); and intrahepatic shunts (C, black arrow) between the portal system and the caudate lobe.

A

B

C

FIGURE 88.6.  Venogram of the inferior vena cava demonstrates compression of the intrahepatic portion of the cava (A, black arrows) during placement of a transjugular intrahepatic portosystemic shunt (single black arrow). Most often, one of the occluded veins can be cannulated, often showing thrombus (B, black arrow). Further injection after accessing the hepatic vein may demonstrate the classic “spiderweb” pattern of small, intrahepatic venous collaterals (C).

gold standard for diagnosis of BCCS. This study may occasionally be combined with hepatic and superior mesenteric arteriography and indirect portography. In BCS confined to the hepatic veins, the IVC is patent, and IVC pressure is relatively normal for patients with ascites. A patent IVC is a prerequisite for portacaval shunt (PCS) and is a crucial finding (see

Chapters 85 and 86). In some patients, the IVC is moderately compressed in its retrohepatic course by the enlarged liver and, in particular, by a hypertrophied caudate lobe (Fig. 88.6A). This finding usually is not clinically significant unless severe compression precludes surgical shunting. In some cases, an IVC stent can be placed percutaneously to expand the

1256

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

pericarditis and congestive heart failure, produce a histologic picture similar to that seen in the acute stage of BCS. Both these cardiac disorders can be eliminated easily from consideration by appropriate cardiac functional studies.

Abnormal Liver Function Tests Results of liver function tests are usually abnormal in BCS, although the type of abnormality varies and is nondiagnostic. Many patients have transaminase elevations 3 to 10 times normal limits, indicating varying degrees of ongoing liver injury. Synthetic and excretory liver dysfunction may be seen with abnormal international normalized ratio (INR) and bilirubin levels. These biochemical abnormalities are not specific to BCS but indicate significant hepatic dysfunction and are an important part of the diagnostic workup.

Nonsurgical Therapy

FIGURE 88.7.  Venogram showing stent placement (black arrows) in a recanalized right hepatic vein.

compressed IVC and allow appropriate portal decompression by the surgical shunt (Clain et al, 1967; Kreel et al, 1967; Redman, 1975; Tavill et al, 1975). The most important angiographic finding is the demonstration by hepatic venography of occlusion or marked narrowing of the major hepatic veins. In some cases, patent hepatic vein orifices cannot be identified, which is indirect evidence that all the major hepatic veins are occluded. Usually, however, it is possible to enter at least one major hepatic vein and show the presence of a thrombus or narrowing and distortion of the vein (Fig. 88.6B). Injection of dye in the wedged position often shows a characteristic spiderweb pattern of small hepatic venous collaterals connecting to portal or systemic veins (Fig. 88.6C). Wedged hepatic vein pressure (WHVP) usually is greatly elevated, which reflects the obstruction to hepatic venous outflow. In patients with hepatic vein occlusion alone, IVC pressure is substantially lower than WHVP. Most often in contemporary management, venography is a platform for interventional radiology procedures. These include TIPS placement, catheter-directed thrombolysis, mechanical thrombectomy and balloon angioplasty, and recanalization of an occluded hepatic vein or vena cava with stent placement (Fig. 88.7). An additional advantage of hepatic venography is facilitating transjugular liver biopsy. Use of hepatic venography may be an essential guide and road map for surgical therapy in BCS (Erdon, 2007; Kamath, 2006).

Liver Biopsy Percutaneous or transjugular needle liver biopsy yields histologic findings characteristic of BCS early in the disease course; along with hepatic angiography, it provides conclusive diagnostic information (Tang et al, 2001). The diagnostic features are quite spectacular and include intense centrilobular congestion combined with centrilobular loss of parenchyma and necrosis (see Fig 88.2). Mild to moderate fibrosis of the liver parenchyma is found in early and subacute disease, but in chronic or rapidly progressive disease, cirrhosis of the cardiac type develops. In fact, cirrhosis has been observed within months of the onset of symptoms. Only two other conditions, constrictive

The objectives of nonoperative therapy of BCS are to (1) remove the cause of the venous thrombosis, (2) relieve the high pressure and congestion within the liver, (3) prevent extension of the venous thrombosis, and (4) reverse the massive ascites. These objectives are quite challenging to accomplish. Medical therapy alone to treat BCS has seen limited success. Most reports indicate failure of medical therapy and the need for additional intervetions. However, systemic anticoagulation is a mainstay of therapy for patients with a history of BCS, whether they were treated with interventional radiologic measures, surgical shunting, or transplantation. Contemporary management prescribes heparin for treatment of the acuteonset BCS while definitive management planning is underway. Long-term therapy with anticoagulation is essential to prevent recurrence. Most often, this is accomplished with warfarin, for a goal of INR in the 2 to 3 range. However, newer anticoagulation medications are gaining favor that do not require laboratory monitoring; although not yet used widely for BCS, these will be included in the therapeutic options while indications for their use expand. In BCS caused by hematologic disorders, such as polycythemia vera and PNH, some dramatic responses to intravenous (IV) heparin therapy have been reported, although relapses have been common (Hartmann et al, 1980; Liebowitz & Hartmann, 1981; Peytremann et al, 1972). Long-term anticoagulation with oral warfarin has been recommended to follow the initial IV use of heparin during the acute phase of BCS, although initiation or enhancement of bleeding is a potential complication of anticoagulant therapy, particularly in patients in whom cirrhosis and esophageal varices deveop. Thrombolytic therapy with urokinase or streptokinase has been used in many patients in an attempt to dissolve the thrombi and restore hepatic venous outflow (Barrault et al, 2004; Cassel & Morely, 1974; DeLeve et al, 2009; Gooneratne et al, 1979; Greenwood et al, 1983; Hodkinson et al, 1978; Hoekstra et al, 2008; Malt et al, 1978; Menon et al, 2004; Mitchell et al, 1982; Murad et al, 2009; Plessier & Valla, 2008; Powell-Jackson et al, 1982; Sharma et al, 2004; Thijs et al, 1978; Warren et al, 1972; Zimmerman et al, 2006). The experience with thrombolytic therapy has been recorded in anecdotal reports with relatively short follow-up. Approximately one-third of patients were believed to have had a clinical response to treatment for periods of 2 months to 1 year. Half of the patients died as a result of BCS during the brief periods of observation. In the small-number experience of



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

Powell-Jackson and colleagues (1982), all four patients who received thrombolytic treatment in the acute phase of BCS died without evidence of a response. However, thrombolytic therapy combined with angioplasty has produced more durable results in select contemporary reports. In a recent series from China, 12 or 13 patients had patent hepatic veins without recurrent thrombosis after a mean follow-up of 24 months. The one initial treatment failure was salvaged by repeat angioplasty (Zhang et al, 2013). In current Western practice, tissue plasminogen activator (tPA) is the direct thrombolytic of choice. Administration is best accomplished with catheter-directed methods, although systemic delivery has been described for other indications. Careful monitoring is required for systemic delivery in particular because of a high risk of bleeding. Single case reports have described successful thrombus resolution with systemic thrombolysis alone (Clark et al, 2012). In addition to tPA administration, percutaneous mechanical thrombectomy has been reported as a successful method of clot extraction in BCS (Ding et al, 2010; Doyle et al, 2013). Anticoagulant therapy has been used widely in BCS to prevent propagation of the thrombi (DeLeve et al, 2009; Ecker & McKittrick, 1966; Hartmann et al, 1980; Khuroo & Datta, 1980; Langer et al, 1975; Lewis et al, 1983; Liebowitz & Hartmann, 1981; Mitchell et al, 1982; Peytremann et al, 1972; Plessier et al, 2008; Powell-Jackson et al, 1982; Thijs et al, 1978; Valla, 2009; Zimmerman et al, 2006). Most reports of the effectiveness of this form of treatment have been anecdotal and lack long-term follow-up. There is no evidence that the use of either heparin or warfarin (Coumadin) brings about dissolution of established thrombosis. As previously mentioned, many of the patients who are seen with BCS have a concomintant prothrombotic state, and most need to be placed indefinitely on anticoagulant therapy after intervention to prevent recurrent thrombosis. This is true for patients irrespective of therapeutic intervention. Newer oral anticoagulants, such as the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and the direct thrombin inhibitors (e.g., dabigatran), although not initially approved for BCS, will likely see application in the BCS population in the near future. Control of ascites is feasible in some patients with BCS by use of the usual diuretic regimens, although ascites is resistant to therapy in many patients (see Chapter 81). Therapeutic measures include stringent sodium restriction, administration of diuretic drugs, and repeated IV infusion of albumin, particularly as a replacement of ascitic fluid after paracentesis if required for symptom control. Renal function should be monitored closely during diuretic therapy to avoid precipitating the hepatorenal syndrome, which may complicate cases of chronic BCS. There is no evidence that control of ascites alone influences long-term outcome.

Interventional Radiologic Therapy Percutaneous Transluminal Angioplasty Use of percutaneous transluminal angioplasty has been reported in more than 300 patients with BCS (Anonymous, 1982; Baijal et al, 1996; Furui et al, 1990; Griffith et al, 1996; Jeans et al, 1983; Li et al, 2009; Martin et al, 1990; Sato et al, 1990; Tyagi et al, 1996; Wu et al, 2002; Xu et al, 1996; Yamada et al, 1983, 1991; Yang et al, 1996) (see Chapter 30). Most of the patients had chronic liver disease of long duration, and many had obstruction of the IVC of the membranous or segmental type.

1257

The obstructed vein was dilated with one or more balloon catheters. In all cases, the pressure gradient that existed before balloon dilation was substantially reduced or eliminated at the time of dilation. Stenosis often recurred, however, and required repeated balloon dilation. Most of the patients have not had long-term follow-up, so it is difficult to evaluate the ultimate effectiveness of percutaneous transluminal angioplasty. Of the few patients who have been observed for several years, the longterm success rate is less than 50% (Griffith et al, 1996; Martin et al, 1990; Sato et al, 1990; Yamada et al, 1991), although Wu and associates (2002) reported restenosis in only 1 of 41 patients during follow-up of 32 (±12) months. The use of expandable metallic stents has been added to the interventional radiologic armementarium in an attempt to maintain prolonged patency of the IVC (Baijal et al, 1996; Furui et al, 1990; Li et al, 2009; Sawada et al, 1991; Xu et al, 1996). The follow-up period of the patients who have IVC stents is too short to evaluate the efficacy of this procedure. In our opinion, based on the available evidence, percutaneous transluminal angioplasty and placement of expandable metallic stents warrant consideration only in patients with chronic BCS resulting from stenosis of the IVC. Patients treated by transluminal angioplasty should have careful follow-up that includes venography and pressure measurements every 3 to 6 months to detect recurrent stenosis of the IVC in the initial postsurgical period. Follow-up with Doppler US thereafter is recommended at a minimum.

Transjugular Intrahepatic Portosystemic Shunt Transjugular intrahepatic portosystemic shunt (TIPS; see Chapter 87) is a side-to-side portacaval shunt (SSPCS) inserted percutaneously under radiographic visualization and control. As such, TIPS is based on the same rationale for relieving hepatic venous outflow obstruction and intrahepatic portal hypertension as the surgical SSPCS. The attractiveness of TIPS is that it can be done without a major surgical abdominal operation in patients who have liver disease and thus are often quite ill. Its major disadvantage is a substantial incidence of occlusion of the TIPS that may require repeated revision and hospitalization and often involves recurrence of symptoms. In some patients who have complete occlusion of the hepatic veins or complete occlusion of the IVC, an additional disadvantage is technical inability to insert the TIPS. Insertion of the TIPS by direct puncture of the retrohepatic IVC, which sometimes is the only way that the shunt can be created, may be associated with a substantial incidence of complications (Rössle et al, 2004). Between 1995 and 2004, there were many reports of TIPS treatment of BCS, each involving a few patients (Blum et al, 1995; Cejna et al, 2002; Ganger et al, 1999; Huber et al, 1997; Mancuso et al, 2003; Michl et al, 1999; Perello et al, 2002; Rogopoulos et al, 1995; Rössle et al, 1998; Uhl et al, 1996). The largest and longest reported experience with TIPS in BCS during that period was that of Rössle and colleagues (2004) at the University Hospital of Freiburg, Germany, who described their experience with 35 patients—11 acute, 13 subacute, and 11 chronic—who were followed for a mean of 37 (±29) months. Shunt failure occurred in seven patients (20%): two were technical failures, two required liver transplantation (LT) (one died), and three died after TIPS. Excluding the two patients who required LT but including the two who could not have TIPS for technical reasons, the 5 year survival rate was 74%. TIPS occlusion requiring revision occurred in 19 (58%) of 33

1258

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

patients. One patient required 10 revisions during a follow-up period of 53 months. Results reported by others were not as good as those of the Freiburg group. Mancuso and associates (2003) described a series of 15 patients, with five deaths and one technical failure, a 40% negative outcome. Cejna and colleagues (2002) reported a series of eight patients; two (25%) died 2 weeks after TIPS, one developed TIPS occlusion requiring LT, and three others required two to seven revisions for TIPS stenosis. Only two (25%) of eight of the initial series of patients had revision-free TIPS patency. Perello and colleagues (2002) reported a series of 13 patients with three shunt failures (23%). The failures included one death, one TIPS thrombosis that necessitated a surgical shunt, and one patient who required LT. Of the remaining 10 patients, seven (70%) experienced TIPS occlusion. In five of these, TIPS dysfunction had not been corrected. These initial, underpowered series describing the early experience for TIPS in BCS were not encouraging. Since 2004, use of TIPS in BCS has increased substantially, mainly in Europe, in part as a result of the availability of polytetrafluoroethylene (PTFE)–covered stents. Most of the reports have involved retrospective reviews of small numbers of cases followed for short periods. In 2006, Rössle and colleagues reported results of TIPS with PTFE-covered stents in 112 patients, 17 of whom had BCS. Of these, 12 patients were lost to follow-up, and 16 experienced TIPS failure. The 1 year TIPS failure rate was 10%, 22 patients died, and three underwent LT. The mortality rate without and with the patients lost to follow-up was 20% and 30%, respectively. The authors concluded that the TIPS procedure was improved by the PTFEcovered stent. More recent reports of TIPS treatment for BCS include an experience totaling more than 120 patients, most with similar results (Attwell et al, 2004 [17 patients]; Eapen et al, 2006 [30 patients]; Gandini et al, 2006 [13 patients]; Hernandez-Guerra et al, 2004 [25 patients]; Murad et al, 2008 [16 patients]; Plessier et al, 2006 [20 patients]). In a multicenter review conducted by Garcia-Pagán and colleagues (2008), 124 BCS patients treated with TIPS in six European centers were analyzed retrospectively for 1993 to 2006. It is noteworthy that 147 of 221 patients with BCS were

eligible for TIPS, but 14 were excluded for technical contraindications, and attempts at TIPS failed in an additional nine patients. Thus, in a population of patients with BCS, only 60% actually underwent TIPS. Twenty-two patients had complications associated with the TIPS procedure, and two died as a result. Sixty-one (41%) of the 124 patients had TIPS dysfunction during follow-up that required restenting in 35, angioplasty in 20, and thrombolysis in six patients. Portosystemic encephalopathy developed in 21% of patients within 1 year. During follow-up, 16 patients died (13%), and eight required LT (6.5%). Actuarial LT-free survival at 1, 5, and 10 years was 88%, 78%, and 69%, respectively. During the past 2 decades, however, results for interventional treatment alone in BCS have improved steadily. Primary patency has dramatically improved with the advent of covered stents and is better than 75% in larger series, with secondary patency of 99% at a mean follow-up of 82 months (Tripathi et al, 2014). In this single-center experience, long-term follow-up included 72% survival at 10 years. The largest reported systematic review looked at 2255 patients treated with percutaneous techniques (Zhang et al, 2015). This metaanalysis included 29 studies in patients who underwent recanalization or TIPS. The restenosis rate at 1 year in the TIPS group was 12% (95% confidence interval [CI], 8%-16%). Survival at 1 and 5 years in the TIPS group was 87.3% and 72.1%, respectively. Overall survival for any interventional strategy was 92% at 1 year and 76% at 5 years.

Surgical Therapy Findings at Operation The operative experience reported by Orloff and colleagues (2012) provides a valuable picture of the intraoperative findings in 65 patients who underwent surgical portal decompression and typifies what can be expected in patients with BCS (Table 88.2). All patients had marked ascites ranging in volume from 2.6 to 15.9 L, congestive hepatomegaly, splenomegaly, and extensive portosystemic collateral veins. In the group of 39 patients with thrombosis confined to the hepatic veins, the mean portal vein (PV)–IVC pressure gradient was 244 mm saline. In all 39 of these patients, portal pressure was

TABLE 88.2  Intraoperative Pressure Measurements* in 65 Patients With Budd-Chiari Syndrome Who Underwent Surgical Portal Decompression PRESHUNT PRESSURES

POSTSHUNT PRESSURES PV-RA Gradient

PV

IVC

PV-IVC Gradient

RA

PV-RA Gradient

Hepatic Vein Occlusion Alone SSPCS (n = 39) Mean 376 132 244 — Range 265 to 438 74 to 250 134 to 338 —

— —

166 116 to 292

161 118 to 284

5 –12 to 40

— —

— —

IVC and Hepatic Vein Occlusion Mesoatrial Shunt (n = 8) Mean 320 305 9 101 Range 274 to 368 256 to 348 –8 to 46 90 to 112

211 162 to 256

244 196 to 248

— —

— —

147 124 to 162

78 52 to 94

IVC and Hepatic Occlusion Combined PCS and CAS (n = 18) Mean 308 296 12 112 196 Range 266 to 348 264 to 320 –8 to 34 95 to 125 140 to 240

170 158 to 184

164 160 to 178

6 –6 to 10

148 136 to 162

22 8 to 42

Group

PV

IVC

PV-IVC Gradient

RA

*In millimeters (mm) of saline.

CAS, Cavoatrial shunt; IVC, inferior vena cava; PCS, portacaval shunt; PV, portal vein; RA, right atrium; SSPCS, side-to-side portacaval shunt. From Orloff MJ, et al: Budd-Chiari syndrome revisited: 38 years’ experience with surgical portal decompression. J Gastrointest Surg 16:286-300, 2012.



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

substantially higher than IVC pressure, so a direct side-to-side portacaval shunt (SSPCS) was feasible. In contrast, in the group of 26 patients with IVC occlusion and hepatic vein occlusion, the mean PV-IVC pressure gradient was only 11 mm saline, because the high pressure in the obstructed IVC was similar to the high portal pressure. All 26 patients had a large pressure gradient between the PV and right atrium that averaged 202 mm saline. A wedge liver biopsy specimen obtained at operation showed intense centrilobular congestion and marked centrilobular cell loss and necrosis in all but one patient, and 35 (54%) of the 65 patients had hepatic fibrosis; this was mild or moderate in 30 patients and severe in five patients, four of whom had cirrhosis. In patients with the chronic forms of BCS, and in most patients with venoocclusive disease, the surgical findings are typical of cirrhosis of the liver by the time the patient receives treatment.

A

1259

30°

B FIGURE 88.8.  Position of patient for side-to-side portacaval shunt.

Side-to-Side Portacaval Shunt With the advent and increasing adoption of interventional radiologic techniques for treatment of BCS, surgical techniques are becoming something of a lost art. These procedures are crucial options for some patients, however, and require the skill and experience typically seen only in specialized centers. Historically, definitive management of BCS centered ultimately on the use of various surgical shunt procedures (see Chapters 85 and 86). Treatment by direct SSPCS or its hemodynamic equivalents—the portacaval interposition graft, mesocaval interposition graft, or splenorenal shunt—of BCS caused by occlusion of the hepatic veins has been reported in almost 400 patients (Ahn et al, 1987; Auvert & Farge, 1963; Bachet et al, 2007; Bismuth & Sherlock, 1991; Cameron et al, 1983; Dong et al, 2005; Eisenmenger & Nickel, 1960; Erlik et al, 1962; Fisher et al, 1999; Gentil-Kocher et al, 1988; Gibson, 1960; Hemming et al, 1996; Henderson et al, 1990; Hoyumpa et al, 1971; Huguet et al, 1979; Klein et al, 1990; Langer et al, 1975; Ludwick et al, 1967; Malt et al, 1978; McCarthy et al, 1985; Millikan et al, 1985; Montano-Loza et al, 2009; Murad et al, 2004; Noble, 1976; Panis et al, 1994; Pezzuoli et al, 1985; Powell-Jackson et al, 1982; Prandi et al, 1975; Schramek et al, 1974; Singhal et al, 2006; Slakey et al, 2001; Vons et al, 1986; Wang, 1989; Wu et al, 1990; Zeitoun et al, 1999). Of these, SSPCS proved to be the most widely applied and durable. This technique is indicated only in patients with BCS who have a patent IVC and an IVC pressure that is substantially lower than WHVP or portal pressure. Obstruction or occlusion of the IVC is a contraindication to PCS. It is not unusual for patients with BCS caused by hepatic vein occlusion to have an elevated pressure in the IVC as a result of caval compression by an enlarged, congested liver, massive ascites, or both. The absolute level of IVC pressure is not crucial to the effectiveness of SSPCS, as long as the portal pressure is substantially higher than caval pressure, and the IVC is shown to be patent. In the event that caval compression persists after SSPCS, an IR-placed caval stent can be used to expand the retrohepatic caval compression, and this approach will afford complete resolution of ascites and peripheral edema. Fig. 88.8 to 88.17 describe the technique for SSPCS.

Mesoatrial Shunt When BCS is caused by thrombosis of the IVC and the hepatic veins, SSPCS and equivalent decompressive procedures are ineffective, because the high pressure in the infrahepatic IVC

FIGURE 88.9.  Long, right subcostal incision used for side-to-side portacaval shunt.

FIGURE 88.10.  Exposure of the operative field for side-to-side portacaval shunt.

does not permit adequate decompression of the portal system and liver. Under such circumstances, a mesoatrial shunt has been advocated. Synthetic Dacron or Gore-Tex grafts ranging from 14 to 20 mm in diameter have been used in most cases and have been connected end-to-side to the superior mesenteric vein (SMV) in the abdomen and the right atrium (RA) in the thorax. In the mesoatrial shunt, a midline laparotomy combined with a median sternotomy is the standard approach. The SMV is isolated circumferentially for a distance of approximately 3 cm in the root of the small bowel mesentery, and the pericardium is opened to expose the lateral wall of the RA. The graft is anastomosed to the side of the SMV with continuous 5-0 vascular suture, tunneled through the root of the transverse

1260

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

A

FIGURE 88.11.  Circumferential isolation of the inferior vena cava between renal veins and liver in preparation for side-to-side portacaval anastomosis.

C

B

E

D

FIGURE 88.12.  Exposure of portal vein in preparation for side-to-side portacaval anastomosis.

FIGURE 88.14.  Measurement of pressures in the inferior vena cava (IVC) and portal vein (PV) with a saline (spinal) manometer by direct needle puncture before performance of portacaval anastomosis. All portal pressures are corrected by subtracting the IVC pressure from the portal pressure. Pressures in the IVC and PV are measured again after completion of the shunt. A, For all pressure measurements, the bottom of the manometer is positioned at the level of the IVC, which is marked on the skin surface of the body with a towel clip. B, IVC pressure. C, Free portal pressure. D, Hepatic occluded portal pressure, obtained on the hepatic side of a clamp occluding the portal vein. E, Splanchnic occluded portal pressure, obtained on the intestinal side of a clamp occluding the portal vein.

mesocolon and greater omentum, then passed anterior to the stomach and left lobe of the liver into the mediastinum through an opening made in the anterior diaphragm. Alternatively, the graft can be tunneled behind the right lobe and through a fenestration in the diaphragm. The prosthesis is anastomosed to the side of the RA with a continuous 5-0 vascular suture.

Combined SSPCS and Cavoatrial Shunt

FIGURE 88.13.  Mobilization of a long length of portal vein, including the segment behind the pancreas, in preparation for side-to-side portacaval anastomosis.

The combined procedure is performed through a long, right subcostal incision for the PCS and a median sternotomy for the cavoatrial shunt (CAS) (Figs. 88.18 and 88.19). After completion of the SSPCS, a 20-mm-diameter, ring-reinforced GoreTex graft is anastomosed to the side of the IVC at the level of the PCS. The graft is channeled anterior to the liver through an opening made in the right leaf of the diaphragm and is anastomosed to the side of the RA.



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

A

B

1261

C

FIGURE 88.15.  Side-to-side portacaval anastomosis. A, Placement of clamps on the inferior vena cava (IVC) and portal vein (PV). B, Strips of IVC and PV 2.5 cm in length have been excised. C, Placement of a posterior row of continuous 5-0 vascular suture from inside the lumina of IVC and PV.

Combined PC shunt and CA shunt FIGURE 88.16.  Side-to-side portacaval anastomosis. Placement of anterior row of two continuous everting sutures of 5-0 vascular material.

FIGURE 88.18.  Combined side-to-side portacaval (PC) shunt and cavoatrial (CA) shunt using a 20-mm ring-reinforced Gore-Tex graft. The operation was done in 18 patients with Budd-Chiari syndrome secondary to inferior vena cava occlusion. (From Orloff MJ, et al: Treatment of Budd-Chiari syndrome due to inferior vena cava occlusion by combined portal and vena caval decompression. Am J Surg 163:137-143, 1992.)

Surgical Outcomes

FIGURE 88.17.  Completed side-to-side portacaval anastomosis.

Success rates of portal decompression in BCS have ranged from 85% to 97% after direct SSPCS (Ahn et al, 1987; Bismuth & Sherlock, 1991; Hemming et al, 1996; McCarthy et al, 1985; Orloff et al, 1992; Panis et al, 1994; Pezzuoli et al, 1985) and 67% after splenorenal shunt (Ahn et al, 1987; McCarthy et al, 1985; Millikan et al, 1985; Wang, 1989). Mesocaval or portacaval interposition grafts with autologous internal jugular vein have been reported in approximately 50 patients with BCS, most of them in France, with a success rate of 89% (Bismuth & Sherlock, 1991; Gentil-Kocher et al, 1988; McCarthy et al, 1985; Panis et al, 1994; Pezzuoli et al, 1985; Vons et al, 1986). Mesocaval or portacaval interposition grafts using synthetic materials, such as Dacron or PTFE (Gore-Tex), have been successful in approximately 52% of 39 patients with BCS, which is the lowest success rate of the various in-continuity portal decompressive procedures (Ahn et al, 1987; Hemming et al, 1996; Henderson et al, 1990; Klein et al, 1990; McCarthy et al, 1985; Millikan et al, 1985; Pezzuoli et al, 1985; Wang, 1989). Although all three shunts are hemodynamically similar,

1262

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

FIGURE 88.19.  Shunt catheterization and venogram showing patency of the portacaval shunt (PCS) and cavoatrial shunt (CAS) 1 year after performance of combined PCS and CAS in a patient with Budd-Chiari syndrome secondary to inferior vena cava occlusion. Serial angiographic studies showed patency and excellent function of the PCS and CAS in all patients. (From Orloff MJ, et al: Treatment of Budd-Chiari syndrome due to inferior vena cava occlusion by combined portal and vena caval decompression. Am J Surg 163:137-143, 1992.)

use of synthetic interposition portacaval or mesocaval grafts and the splenorenal shunt are probably inferior to direct SSPCS in the treatment of BCS. Occlusion of the shunt is a serious complication that may result in death; the splenorenal shunt and the synthetic interposition grafts have a substantial incidence of thrombosis, not only in BCS, but also in other diseases that cause portal hypertension (Dowling, 1979; Hemming et al, 1996; Orloff, 1977, 1998; Orloff & Orloff, 1992). The largest single-center experience of surgical treatment for BCS, which included SSPCS, mesoatrial shunt, and combined SSPCS with CAS, in the West was reported by Orloff and colleagues in 2012. Table 88.3 summarizes long-term results, with follow-up of 5 to 38 (mean, 15) years. In total, 38 patients (97%) recovered from the SSPCS procedure and were longterm survivors, with an overall survival rate of 95%. All the survivors have remained free of ascites without requiring diuretic therapy. Results of periodic liver function tests were consistently normal except in the three patients who had established cirrhosis at referral. None of the patients had encephalopathy. Of the 37 current survivors, 36 (97%) are leading productive lives of good quality. Liver biopsies and angiographic or US studies were performed periodically for 37 years after surgical shunt therapy in the 38 survivors (see Table 88.3). Cirrhosis persisted in three patients who had established cirrhosis at the shunt operation, including one patient with Behçet’s disease. In 97% of the survivors, no evidence of hepatic congestion or necrosis was found in the follow-up biopsy specimens (Orloff et al, 2012). Mild to moderate fibrosis was found in 42% of the patients; 50% had normal liver biopsy specimens (Fig. 88.20). Angiography or US showed patency of the PCS and IVC, and pressure measurements showed a widely patent anastomosis with a gradient that ranged from 0 to 44 mm saline and averaged 4 mm across the shunt. Two patients with polycythemia vera

TABLE 88.3  Long-Term Results of Portal Decompression Operations in 65 Patients With Budd-Chiari Syndrome HEPATIC VEIN OCCLUSION ALONE

IVC AND HEPATIC VEIN OCCLUSION

SSPCS

Mesoatrial Shunt

Combined SSPCS and CAS

No. patients Onset to Operation (Weeks)

39

8

18

≤17 (%) Mean Range Follow-up (Years) Mean Range Ascites (%) Need for diuretics (%) Abnormal liver function tests (%) Portosystemic encephalopathy (%) Employed or housekeeping (%) Survival (%) 30-day Current

92

88

100

16 4 to 78

12 7 to 19

15 10 to 18

15 5 to 38 0 0 8 0 95

17 20 to 24 63 63 63 38 25

14 5 to 25 0 0 0 0 94

97 95

100 38

CAS, Cavoatrial shunt; IVC, inferior vena cava; SSPCS, side-to-side portacaval shunt. From Orloff MJ, et al: Budd-Chiari syndrome revisited: 38 years’ experience with surgical portal decompression. J Gastrointest Surg 16:286-300, 2012.)

100 100

D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease



A

1263

B

C FIGURE 88.20.  Photomicrographs of liver biopsy specimens obtained just before and 2 years after side-to-side portacaval shunt from Budd-Chiari syndrome patient. A, Before portacaval shunt (PCS), intense centrilobular congestion and necrosis with substantial fibrosis can be seen (×50). B and C, Two years after PCS, a normal liver architecture, a striking reversal of the pathologic process of Budd-Chiari syndrome, can be seen (B, ×80; C, ×160.)

developed thrombosis of the PCS 1 week and 3 months postoperatively. Both patients underwent reoperation with thrombectomy and reconstructed portacaval anastomosis with an H-graft of autologous internal jugular vein and required lifelong anticoagulation with warfarin. One patient has remained well for 28 years since revision of the shunt. Unfortunately, the other patient developed recurrent shunt thrombosis and required LT. Accordingly, mesoatrial shunt suffers from a fairly high thrombosis rate, and future therapy in these patients may likely require a combination of interventional, medical, and surgical techniques. For mesoatrial shunt recipients, five (63%) of the eight patients subsequently developed thrombosis of the graft and died of liver failure. Three of the deaths occurred during the first postoperative year, one occurred in the second year, and one occurred in the fifth year. All five patients developed recurrence of ascites, and three developed portosystemic encephalopathy while their hepatic function deteriorated. The three long-term survivors of the mesoatrial shunt (38%) have been followed up for 23 years, 21 years, and 21 years, respectively. Angiography and US have shown patency of their grafts. They are free of ascites, have normal liver function, and do not require diuretics; two of the three are gainfully employed. Serial liver biopsy specimens show residual congestion in one patient and moderate fibrosis in two. In one patient, the liver appears

normal. In the results for the combined shunt, all 18 patients survived the operation and are alive 5 to 25 years postoperatively (see Table 88.3). Mean follow-up is 12 years. All patients are free of ascites, and none requires diuretics; hepatomegaly and splenomegaly are gone; and liver function tests results are normal in all survivors, with no instance of portosystemic encephalopathy. Other series of mesoatrial shunting that involve five or more patients have been reported, although follow-up generally has been relatively short. Stringer and colleagues (1989) of London reported excellent results in five patients, but follow-up of 9 to 16 months was too short to warrant conclusions. Wang and colleagues (1989, 2005) of Beijing reported survival of 61% and 50% at 5 and 10 years, respectively, in 70 patients, but their reports contain insufficient details to determine how many of these patients had patent and functioning grafts, how well the patients were followed, or the exact nature of the BCS being treated. Emre and colleagues (2000) of Istanbul reported 85% survival in 13 patients during follow-up of 1 to 76 months, with one known thrombosed shunt. Behera and associates (2002) of Chandigarh, India, described 100% graft patency during 6 to 71 months of follow-up of 10 patients, with survival of 90%. Khanna and colleagues (1991) of Chandigarh, India, reported a 62% survival rate in 13 patients during follow-up of 2 months to 7.5 years.

1264

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

Study results of nine patients (Henderson et al, 1990), 15 patients (Klein et al, 1990; Slakey et al, 2001), and eight patients in our own investigations are representative of the experience with mesoatrial shunting in the United States. Survival rates ranged from 38% to 67%, and the percentage of patients with grafts that were patent and decompressing was only 33% to 60% during relatively short follow-up periods. Cameron and colleagues (1984; Klein et al, 1990) reported improved results with the use of an 8 cm external silicone rubber sleeve around a 16 mm ring-reinforced Gore-Tex prosthesis to prevent compression of the graft by the sternum. This innovation may reduce the frequency of graft thrombosis, but the results of mesoatrial shunting generally have been disappointing. The combined surgical experience for BCS emphasizes the importance of performing SSPCS, mesoatrial shunt, or combined SSPCS and CAS early in the disease course. Hepatic venous outflow obstruction produces widespread destruction of the hepatic parenchyma by pressure necrosis and ischemia, and the liver damage becomes irreversible in a surprisingly short time; some patients developed cirrhosis within 3 or 4 months of the onset of symptoms. Thus, the authors admonish that relieving ascites is much less important than decompressing the liver, and referral for surgical intervention should be made early in the course of BCS to salvage the liver and avoid LT.

Membranous Obstruction of Vena Cava: Surgical Options Patients with MOVC described in the literature largely have had a chronic disorder that has progressed to cirrhosis and portal hypertension by the time they came to medical attention. The lesion causing IVC obstruction has varied from a thin membrane located in the suprahepatic IVC to an extensive area of stenosis involving the retrohepatic IVC. Japanese surgeons have reported the largest experience with the treatment of MOVC. When the area of IVC obstruction is short and is located at or above the level of the hepatic vein orifices, two treatment options are available: percutaneous transluminal angioplasty and transcardiac membranotomy. Early reported experience with percutaneous transluminal angioplasty in MOVC was limited to short follow-up with high rates of recurrent IVC thrombosis or stenosis (Eguchi, 1974; Griffith et al, 1996; Hirooka & Kimura, 1970; Iwahashi, 1981; Sato et al, 1990; Sharma et al, 1992; Tyagi et al, 1996; Yamada et al, 1991; Yang et al, 1996). Long-term IVC patency has been achieved in more recent reports, however, indicating that many of these patients can be treated with interventional techniques particularly when stenting is used (Srinivas et al, 2012). For circumstances in which percutaneous approaches are unavailable or inappropriate, transcardiac membranotomy has been the most frequently used treatment of MOVC when the membrane is thin. The technique involves fracture of the membrane by the finger or a dilator inserted through the right atrial appendage (Fig. 88.21). More than 125 cases have been described, with a successful outcome in 70% to 90% during follow-up that ranged from 2 months to 7 years but generally was brief (Espana et al, 1980; Hirooka & Kimura, 1970; Iwahashi, 1981; Kimura et al, 1972; Okamoto et al, 1983; Semson, 1982; Suchato et al, 1976; Takeuchi et al, 1971; Taneja et al, 1979; Wang, 1989; Wu et al, 1990; Yamamoto et al, 1968). When more than a thin membrane causes obstruction of the IVC, and particularly when a long area of stenosis involves the retrohepatic IVC, the treatment options are different and

FIGURE 88.21.  Technique of transcardiac membranotomy. (From Iwahashi K: Surgical correction of the inferior vena cava obstruction with Budd-Chiari syndrome. Arch Jpn Chir 50:559-570, 1981.)

consist mainly of direct excision and repair of the involved area of IVC (endovenotomy) or a cavoatrial bypass graft. A direct attack on the lesion generally has involved excising the obstructing tissue in the lumen of the IVC and repairing the vein with a synthetic or pericardial patch graft. Twelve such attempts have been described in the literature, with success in five patients and failure in seven, four of whom died (Hirooka & Kimura, 1970; Iwahashi, 1981; Kimura et al, 1972). Koja and colleagues (1996; Kuniyoshi et al, 1998) reported direct removal of the IVC obstruction under partial cardiopulmonary bypass in 32 patients with impressive results, although the reported follow-up was short. Use of a cavoatrial bypass graft has been reported in 11 patients who had a long segment of IVC stenosis. The procedure succeeded during short periods of follow-up in three patients and failed in eight, four of whom died (Eguchi et al, 1974; Hirooka & Kimura, 1970; Ohara et al, 1963; Reichart et al, 1981; Yamamoto et al, 1968). When the IVC obstruction involves or extends below the orifices of the hepatic veins, cavoatrial bypass does not decompress the liver. Under such circumstances, consideration should be given to adding SSPCS to the cavoatrial bypass. The combined procedure of IVC and portal decompression has not been reported in MOVC.

Surgical Removal of Venous Obstruction Senning (1981, 1983) reported a direct method of removing obstruction of the IVC and hepatic veins in patients with chronic BCS. The operation is performed with cardiopulmonary bypass and involves opening the suprahepatic IVC and RA, removing any vena caval thrombus, resecting the dorsocranial part of the liver containing the confluence of the occluded major hepatic veins, and reconstructing the hepatic outflow tract by suturing the RA to the liver capsule. Since his initial description, Senning (1987) and others (Pasic et al, 1993) have reported the results of the operation in 17 patients, two of whom (12%) died within 2 weeks of operation and four who died later. Actuarial 1 year and 3 year survival rates were 76% and 57%, respectively; LT was required for two patients,



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

and three developed recurrent thrombosis. During follow-up of 7 months to 11 years, 10 (67%) of the 15 early survivors had prolonged relief of BCS. Kawashima and colleagues (1991) reported success of the Senning operation in five of seven patients during follow-up of 2 months to 5 years, and Nakao and colleagues (1988) described success in two patients followed for 1 to 2 months. In a modification of the operation, Koja and associates (1996; Kuniyoshi et al, 1998) described direct removal of the IVC obstruction under partial cardiopulmonary bypass in 32 patients with chronic BCS resulting from IVC obstruction of 1 to 42 years’ duration. Koja and associates (1996; Kuniyoshi et al, 1998) reopened the IVC and occluded hepatic veins under direct vision without resecting the liver and reconstructed the hepatic outflow tract with a patch graft of autologous pericardium. Many of the patients had cirrhosis or severe fibrosis of the liver, and 29 of the 32 had esophageal varices. No operative deaths were reported. During 1.5 to 17 years of follow-up, there were four late deaths, and hepatocellular carcinoma developed in seven patients. Survival rates at 5 and 10 years were 93.6% and 81%, respectively. In a follow-up to their 1998 report, in 2009 Kuniyoshi and colleagues reported their results from 1979 to 2008 in 53 patients (Inafuku et al, 2009). Overall mortality was 32%, and total obstruction or severe stenosis of the reconstructed IVC developed in 14% of survivors; therefore it does not appear that radical open-end venectomy is the firstchoice procedure for IVC occlusion.

Liver Transplantation Indications Liver transplantation is a radical, drastic treatment for BCS, but it is effective when a patient’s life is at stake and other therapeutic options have been exhausted or are not technically feasible (see Chapter 112). LT is not in competition with SSPCS or any other type of treatment. It is useful in far advanced, decompensated liver disease, when liver dysfunction has progressed beyond a salvageable state by other portal decompression procedures. It is imperative that the indications for the use of LT in BCS be established and clearly understood. Indications include the following: 1. Cirrhosis with progressive liver failure that has reached the point of permitting a reasonable prediction that the patient will die within 1 year—the most common indication for LT and the same used widely in other liver diseases (Scharschmidt, 1984; Schenker, 1984). 2. Failure of a portosystemic shunt or TIPS, usually because of thrombosis, with persistence or recurrence of symptoms and signs of BCS. 3. BCS with unshuntable portal hypertension secondary to thrombosis of the PV, splenic vein, and much of the SMV—a rare indication that applies only if patent blood vessels are available to vascularize the liver allograft. 4. Acute fulminant hepatic failure—a rare indication that we have encountered only once in the past 20 years.

Outcomes To date, the English literature contains reports of more than 1000 patients with BCS who have undergone LT; Table 88.4 summarizes these reports. The largest number of case reports have come from reviews of 248 patients registered in the European Liver Transplantation Registry and 510 patients

1265

registered in the United Network for Organ Sharing (UNOS) Liver Standard Transplant Analysis and Research files. All the reports were based on retrospective reviews of medical records. No prospective studies of LT in BCS patients have been done. As shown in Table 88.4, the indications for LT varied greatly, and it cannot be said that LT was done in patients who had 1 year or less to live because of cirrhosis with progressive liver failure. In several series the indications were not clearly stated (Jamieson et al, 1991; Melear et al, 2002; Ringe et al, 1995; Segev et al, 2007). Ulrich and colleagues (2008) reported 12% of the 39 patients were Child-Turcotte-Pugh (CTP) class A, and 57% were class B, obviously not in liver failure. The report of Halff and colleagues (1990) stated, “The decrease in synthetic function was not as severe as in many other causes of end-stage liver disease.” Every series had some patients who underwent LT because of a failed portosystemic shunt. In the registry review of Mentha and associates (2006), 49 of the 248 patients had failure of a portosystemic shunt (Campbell et al, 1988; Krom et al, 1984). Table 88.5 shows the survival statistics in the reported series. All the studies suffer from the short follow-up of many patients, sometimes less than 1 year. A substantial variation in patient selection was apparent from one series to the next, particularly with regard to severity of liver disease, so comparisons cannot be made. The early mortality in series that had 10 or more patients ranged from 5% to 36% and averaged 15%. The 5 year survival rate, when reported, ranged from 45% to 95% and averaged 71%. Segev and colleagues (2007), in their UNOS registry review, reported that since introduction in 2002 of the Model for End-Stage Liver Disease (MELD) scoring system for organ allocation by disease severity, 3 year patient survival has increased from 72.6% to 84.9%, and 3 year graft survival has increased from 64.5% to 80.6%. Most of the series did not report the results of pathologic examination of the explanted liver in the patient with BCS. The reports of Ringe and colleagues (1995) on 43 patients, Halff and colleagues (1990) on 32 patients, Sakai and Wall (1991, 1994) on 11 patients, and Srinivasan and associates (2002) on 19 patients described the findings in the host liver, however, and confirmed the clinical impression that many patients underwent LT without having decompensated liver disease. Only 17 of the 43 patients of Ringe and colleagues (1995) had cirrhosis; the others had congestion alone (14 patients) and fibrosis alone, lesions that are found in the early stages of BCS. Similarly, in the report of Halff and colleagues (1990), none of the 32 patients had cirrhosis, and Sakai and Wall (1994) reported that 3 of 11 of their patients had central congestion and necrosis but no fibrosis or cirrhosis. An important concern about LT in BCS is recurrence of BCS in the transplanted liver (Bahr et al, 2003; Cruz et al, 2005; Goldstein et al, 1991). Table 88.6 shows the incidence of recurrent BCS in the liver allograft. Some investigators reported no recurrence of BCS, whereas others (Cruz et al, 2005; Halff et al, 1990; Knoop et al, 1994a, 1994b) reported substantial recurrence rates of 13% to 27% despite treatment with anticoagulants. Most series have shown a substantial incidence of posttransplant thrombosis in other splanchnic blood vessels, particularly in the PV (range, 9%-40%), often with disastrous consequences. The frequent development of thrombosis makes it mandatory that patients receive early and lifelong anticoagulation therapy after LT. At the same time, it should be recognized that one of the potential benefits of LT in certain

1266

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

TABLE 88.4  Indications for Liver Transplantation in 15 Retrospective Series of Budd-Chiari Syndrome (BCS) Reported in the Literature Reference

No. Patients

Srinivasan et al, 2002

19

Melear et al, 2002 Hemming et al, 1996

17 10

Ringe et al, 1995

43

Knoop et al, 1994a, 1994b

8

Galati et al, 1993

32

Shaked et al, 1992

14

Halff et al, 1990; Iwatsuki et al, 1991

32

Sakai & Wall, 1994

11

Jamieson et al, 1991

26

Ulrich et al, 2008

42

Cruz et al, 2005

11

Plessier et al, 2006 Mentha et al, 2006 European Liver Transplantation Registry, 1988-1999

11 248

Segev et al, 2007 (UNOS Registry, 1987-2006)

510

Indications for OLT Failed shunt, 5 Acute liver failure, 6 Chronic liver failure, 8 Not stated Failed shunt, 3 Advanced cirrhosis, 4 IVC obstruction, 2 Unclear, 39 Failed shunt, 4 Child class C, 5 Child class B, 3 Failed shunt, 2 Cirrhosis—? Hepatic necrosis—? Failed shunt, 2 Advanced cirrhosis, 4 Poor synthetic function, 8 Failed shunt, 5 Intractable ascites, 17 Recurrent variceal bleeding, 14 Encephalopathy, 15 Chronic BCS, 5 Acute fulminant BCS, 3 Failed shunt, 3 Failed shunt, 2 Unclear, 24 Cirrhosis, 11 Portal vein occlusion, 10 Hepatic necrosis, 12 Severe acute liver failure, 8 Hepatocellular carcinoma, 3 Hepatic artery occlusion, 2 Failed TIPS, 5 Failed PSS, 1 Intractable ascites, 1 Portal-systemic encephalopathy, 3 Failed therapy with anticoagulation and TIPS, 11 Fulminant hepatic failure, 47 Renal failure, 40 Portal vein thrombosis, 47 Failed PSS, 49 Failed TIPS, 11 Failed percutaneous angioplasty, 18 Not reported

IVC, Inferior vena cava; OLT, orthotopic liver transplantation; PSS, portosystemic shunt; TIPS, transjugular intrahepatic portosystemic shunting; UNOS, United Network for Organ Sharing.

thrombogenic disorders, such as antithrombin III deficiency and protein C deficiency, is correction of the underlying defect by transplantation of a liver from a normal donor. It has been suggested that LT is preferable to SSPCS in the treatment of BCS because if SSPCS fails, the risk of performing subsequent LT is increased. It has been proposed that mesocaval shunt is preferable to SSPCS because it is advantageous to

avoid dissection of the hepatic hilum should subsequent LT be required (Bismuth & Sherlock, 1991; McMaster, 1994; Slakey et al, 2001). In 11 more recent studies, previous portosystemic shunt, regardless of type, had no influence on the outcome of LT (Aboujaoude et al, 1991; Bismuth et al, 1990; Boillot et al, 1991; Iwatsuki et al, 1988; Langnas et al, 1992; Mazzaferro et al, 1990; Minegaux et al, 1994; Turrion et al, 1991).

D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease



1267

TABLE 88.5  Survival After Liver Transplantation for Budd-Chiari Syndrome Reported in the Literature Reference

No. Patients

Follow-up (mo)

Early Mortality (%)

Srinivasan et al, 2002

19

1 to 119

5

Melear et al, 2002

17

1 to 158

6

Hemming et al, 1996

10

?

10

Ringe et al, 1995

43

2 to 137

30

8

4 to 59

13

Galati et al, 1993 Shaked et al, 1992

9 14

2 to 60 2 to 60

0 14

Halff et al, 1990 Iwatsuki et al, 1991 Sakai & Wall, 1994 Jamieson et al, 1991

32

12 to 132

25

11 26

12 to 72 12 to 60

36 31

Ulrich et al, 2008

42

1 to 203 (median 96)

Cruz et al, 2005

11

1 to 132

18

Plessier et al, 2006

11

17 to 56

9

Mentha et al, 2006

248

Knoop et al, 1994a, 1994b

Segev et al, 2007

510

Long-term via registry (mean, 48)

Long-term via registry

7

13

15

Survival ≥1 Year (%) 1 to 119 mo (84) 1 yr (95) 5 yr (95) 10 yr (78) 1 to 158 mo (88) 1, 5, and 10 yr: NR 1 yr (82) 5 yr (67) 1 yr (69) 5 yr (69) 1 yr (88), > 1 yr: NR 2 to 60 mo (100) 1 yr (86) 3 yr (76) 1 yr (69) 5 yr (45) 1 to 6 yr (64) 1 yr (69) 5 yr (50) 1 yr (92) 5 yr (89) 10 yr (83.5) 1 yr (81) 5 yr (65) 10 yr (65) 1 yr (91) 3 yr (91) 1 yr (76) 5 yr (71) 10 yr (68) 1 yr (82) 3 yr (76)

NR, Not reported.

Aboujaoude and colleagues (1991) emphasized that thrombosis of a portosystemic shunt may seriously compromise performance of LT. Long-term shunt patency should therefore be the main factor that determines the type of shunt selected for the potential LT candidate, which applies even more to patients with BCS. Direct PCS has had a thrombosis rate of 0.5% or less compared with occlusion rates of 24% to 53% reported for mesocaval interposition shunts using synthetic grafts (Fletcher et al, 1981; Hemming et al, 1996; Orloff et al, 2000, 2012; Smith et al, 1980; Terpstra et al, 1987). Mesocaval interposition shunts using autologous internal jugular vein grafts, which have been used widely in France, have shown patency rates comparable to direct SSPCS (Bismuth & Sherlock, 1991; Gentil-Kocher et al, 1988; Vons et al, 1986). The third and fourth indications previously listed for orthotopic liver transplantation (OLT) in BCS are rare, and there are only scant reports, without many details, in the literature. These are unshuntable patients with portal hypertension resulting from thrombosis of the portal venous system, provided

patent blood vessels are available to vascularize the liver allograft, and acute fulminant hepatic failure (Sakai & Wall, 1994). We have had one patient with fulminant hepatic failure caused by BCS who was listed for LT, but the patient experienced brain herniation before a liver allograft became available. It is important to emphasize that SSPCS and LT are not competing forms of treatment. SSPCS is the appropriate treatment in the early and middle stages of BCS, when portal decompression would sustain life by reversing or stabilizing the liver disease. OLT is the appropriate treatment in the late stages of BCS, when the liver disease is no longer reversible, and when stabilization of progressive hepatic decompensation is impossible. Most patients who are candidates for LT should be in CTP class C. In considering treatment of BCS by LT, it is important to take into account the downside of such therapy: (1) the vast shortage of donor livers to treat the many patients who need LT; (2) long wait times where disease progression can lead to

1268

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

TABLE 88.6  Reported Rates of Recurrence of Budd-Chiari Syndrome and Other Thrombosis After Liver Transplantation for Budd-Chiari Syndrome RECURRENCE Reference Srinivasan et al, 2002 Melear et al, 2002 Ringe et al, 1995 Hemming et al, 1996 Knoop et al, 1994a, 1994b Shaked et al, 1992 Halff et al, 1990 Sakai & Wall, 1994 Jamieson et al, 1991 Ulrich et al, 2008 Cruz et al, 2005 Plessier et al, 2006 Mentha et al, 2006 Segev et al, 2007

No. Patients 19 17 43 10 8 14 23 11 26 42 11 11 248 510

OTHER THROMBOSIS

No.

%

No.

%

2 0 0 0 1 0 3/18 0 2 3 3 1 5 7

11 0 0 0 13 0 17 0 8 7 27 9 2 8

2 3 10 1 1 NR 4 1 5 5 3 4 35 36

11 18 23 14 13 NR 22 9 19 12 27 36 14 40

NR, Not reported.

drop-off; (3) the unpredictabile availability of donor organs; (4) the need for and consequences of lifelong immunosuppression; and (5) the high cost of LT, which may or may not be costeffective depending on the alternative therapies pursued and the potential repeat interventions required.

VENOOCCLUSIVE DISEASE In 1954, Bras and colleagues coined the term venoocclusive disease (VOD) to describe a common liver disease in Jamaican children caused by the ingestion of “bush teas” made from plants of the Crotolaria and Senecio genera, which contain the well-known hepatotoxic pyrrolizidine alkaloids. VOD of the liver, more recently called sinusoidal obstruction syndrome, may mimic BCS clinically, because both conditions involve hepatic venous outflow obstruction. However, VOD involves the sinusoids and the central and sublobular hepatic veins within the liver rather than the hepatic veins (Kumar et al, 2003; Shulman et al, 1987, 1994). The underlying process in VOD is subendothelial sclerosis of the hepatic veins and sinusoids secondary to endothelial injury caused by toxic agents, such as pyrrolizidine alkaloids, antineoplastic drugs, radiation, or stem cell transplant. More than 20 drugs have been implicated, most notably busulfan, 6-mercaptopurine, azathioprine, and cyclophosphamide. Thrombosis of the small hepatic veins may occur after damage to the venous intima. Electron microscopic studies of liver biopsy specimens obtained from children with VOD caused by pyrrolizidine poisoning showed marked endothelial damage in the sinusoids and subterminal and terminal hepatic veins in all zones of the liver, with extravasation of erythrocytes into the space of Disse and narrowing of the lumen where the sinusoid entered the central vein (Brooks et al, 1970). Similar to BCS, hemorrhagic necrosis of the liver parenchyma around the centrilobular veins occurs early in the course of VOD. Extensive occlusion of the small hepatic veins ultimately leads to diffuse fibrosis and cirrhosis. Patients with VOD caused by chronic pyrrolizidine poisoning often have

well-established cirrhosis when first seen by a physician. VOD that develops as a complication of therapy for another condition—such as occurs during cancer chemotherapy, radiation therapy, or bone marrow transplantation (BMT)—usually is detected early in the course of disease.

Symptoms and Signs Venoocclusive disease has been observed in individuals of all ages, including infants and adults in their sixth decade; however, VOD caused by pyrrolizidine alkaloids has been seen most frequently in infants and children. The clinical manifestations depend on the disease stage at which the patient seeks medical treatment (Brooks et al, 1970; Ghanem & Hershko, 1981; Gore et al, 1961; Safouh & Shehata, 1965; Stuart & Bras, 1957). The acute stage is often preceded for 1 or 2 weeks by a febrile illness with upper respiratory symptoms, vomiting and diarrhea, or both. The patient then experiences abrupt onset of abdominal pain, weakness, anorexia, fever, and abdominal distension secondary to ascites (Kumar et al, 2003; Senzolo et al, 2007; Wadleigh et al, 2003). Jaundice is the rule, and splenomegaly with thrombocytopenia is common. Some patients experience edema of the feet and occasionally of the hands and face, and physical examination in the acute phase invariably shows hepatomegaly and ascites. Many patients have splenomegaly; some have distension of the superficial veins of the abdominal wall, and some have peripheral edema and a pleural effusion. Bone marrow transplant recipients usually experience the clinical features of VOD within 3 weeks after transplantation. Many patients have died during the acute stage from liver failure, bleeding esophageal varices, or intercurrent infection. Patients other than BMT recipients may be initially seen in the chronic stage of VOD with the usual clinical manifestations of cirrhosis of the liver: ascites, hepatomegaly, splenomegaly, wasting, abdominal venous distension, spider angiomata, palmar erythema, asterixis, and peripheral edema. Bleeding from esophageal varices is a major cause of death in the chronic stage, and cirrhosis of the liver has been observed 3 months after acute onset of VOD (Gore et al, 1961).



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

Diagnostic Studies The diagnosis of VOD is strongly suspected when, in the proper setting, such as following BMT, ascites, jaundice, hepatomegaly, and right upper quadrant abdominal pain develop in patients (Senzolo et al, 2007). The most important diagnostic study in VOD is needle liver biopsy, which shows the specific abnormality of extensive occlusion of the small hepatic veins within the liver (Brooks et al, 1970; Gore et al, 1961; Shulman et al, 1995; Stuart & Bras, 1957). In the acute stage of VOD, an additional biopsy finding is centrilobular hemorrhagic necrosis of the hepatic parenchyma. In the chronic stage of VOD, the biopsy specimen shows diffuse fibrosis or cirrhosis of the liver. Angiographic studies are not as helpful in VOD as they are in BCS (see Chapter 21). The major hepatic veins and IVC are normal on venography, but WHVP is invariably elevated, a finding that supports the diagnosis of VOD. Findings on hepatic arteriography and indirect portography are similar to the findings in BCS. Because of the significant risk of bleeding after BMT, it is safest in such patients to perform liver biopsy by the percutaneous transjugular route. WHVP can be measured at the same time. Imaging studies, including Doppler US, CT, and MRI, are important adjuncts to exclude BCS. Liver function test results are invariably abnormal in VOD and do not differ from the results seen in BCS; these abnormalities reflect serious hepatic dysfunction but are not specific for VOD. After BMT, elevated plasma levels of plasminogen activator inhibitor (PAI)-1 have been reported to be a useful marker in distinguishing VOD from several other causes of posttransplant hepatic dysfunction, such as graft-versus-host disease, drug-induced hepatotoxicity, sepsis, and viral hepatitis (Salat et al, 1997a). PAI-1 has been implicated in the pathology of VOD.

Treatment Substantial experience has been reported with treatment of patients with VOD caused by pyrrolizidine alkaloids (Bras & McLean, 1963; Ghanem & Hershko, 1981; Gore et al, 1961; Stuart & Bras, 1957). If such patients are seen during the acute stage of VOD, the initial treatment consists of withdrawal of the causative agent and measures to support the damaged liver. Approximately one-fourth of patients recover from the acute phase with supportive medical therapy, approximately one-fifth die of liver failure or bleeding esophageal varices, and the remainder experience a chronic condition that waxes and wanes while cirrhosis of the liver evolves. SSPCS is indicated during the acute phase in patients who bleed from esophageal varices and in patients who, within 4 to 8 weeks of onset, show no signs of recovery, such as disappearance of ascites, improvement in liver function, and improvement in the lesions seen on percutaneous needle biopsy of the liver. Serial liver biopsy specimens are helpful in assessing the course of the disease. During the past decade there has been a marked increase in the use of BMT and a corresponding increase in the frequency of VOD. This increase has given rise to numerous trials of various interventions aimed at preventing and treating VOD. In mild forms of VOD, spontaneous recovery is reported in 70% to 85% of patients (Senzolo et al, 2007). However, severe forms do not resolve without treatment (Schlegel et al, 1998). Agents studied in prophylaxis of VOD include defibrotide, ursodeoxycholic acid (UDCA), tPA, antithrombin III (ATIII), prostaglandin E1 (PGE1), and anticoagulation with low-dose

1269

heparin (Ho et al, 2008; Senzolo et al, 2007). Of these, the most promising is defibrotide. In five retrospectively controlled studies of VOD prophylaxis, the incidence and severity of VOD were reduced by defibrotide (Chalandon et al, 2004; Corbacioglu et al, 2006; Dignan et al, 2007; Qureshi et al, 2008; Versluys et al, 2004). In five of the trials, UDCA showed a significant benefit, with reductions in both incidence of VOD and mortality (Essell et al, 1998; Giles et al, 2002; Ohashi et al, 2000; Park et al, 2002; Ruutu et al, 2002; Tay et al, 2007). Pharmacologic options for the treatment of established VOD include defibrotide, tPA, ATIII, and methylprednisolone. Of these, defibrotide has been subject to the most extensive investigation. In six studies of defibrotide treatment of patients with established VOD, all or most at high risk with multiorgan failure, 36% to 76% had complete remission of VOD (Bulley et al, 2007; Chopra et al, 2000; Corbacioglu et al, 2004; Richardson et al, 1998, 2002, 2006). Encouraging responses to defibrotide have been found in children as well as following liver transplantation (Corbacioglu et al, 2004, Mor et al, 2001). Use of tPA in treatment of VOD has been evaluated in several series totaling 130 patients (Senzolo et al, 2007; Vaughan et al, 1989). The response rate has approached 30% in the largest series (Bearman et al, 1997); however, no response was seen in patients with renal, respiratory, or multiorgan failure. Moreover, 24% severe bleeding developed in 24%. Thus, administration of profibrinolytics and anticoagulants should be avoided in these patients, but conversely, these agents have benefit early in the course of VOD. Several studies of ATIII in treatment of VOD have been reported. In a retrospective review of the largest series (48 patients), Peres and colleagues (2008) observed that ATIII failed to reduce the incidence of VOD but seemed to be beneficial in mild to moderate VOD and especially in severe VOD. These results were similar to those of Haussmann and colleagues (2006) in pediatric patients. A single study investigated methylprednisolone treatment of VOD, with results suggesting a therapeutic benefit (Al Beihany et al, 2008). However, prospective comparative studies are needed to warrant use of this agent. Transjugular intrahepatic portosystemic shunting has been used in a small number of patients with VOD. Senzolo and colleagues (2007) summarized the results of TIPS in 27 patients with generally severe VOD, 24 of them following BMT. All but three of the BMT patients died. Available data suggest that although portal hypertension and ascites improve after TIPS, long-term efficacy and overall survival remain poor (Alvarez et al, 2000; Azoulay et al, 2000; de la Rubia et al, 1996; Fried et al, 1996; Senzolo et al, 2005, 2006; Smith et al, 1996). Because of the high mortality rate of severe VOD after BMT, LT warrants consideration. Experience with LT in severe VOD is limited, with case reports in the literature on 12 patients (Bunin et al, 1996; Hagglund et al, 1996; Membreno et al, 2008; Nimer et al, 1990; Rapoport et al, 1991; Salat et al, 1997b; Schlitt et al, 1995), with 5 of the 12 long-term survivors. The problems associated with use of LT, not unique to VOD, include predicting which patients will not survive despite other forms of treatment; the timing of the LT operation, before multiorgan failure is so severe that survival is not possible; and obtaining a suitable liver graft. One-fourth of patients with VOD experience the severe form of the disease. The causes of death in severe VOD are hepatic failure, renal failure secondary to hepatorenal syndrome, respiratory failure from pulmonary

1270

PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital

VOD or infection, gastrointestinal bleeding, sepsis, and congestive heart failure. In the Seattle study of a cohort of 355 patients, the mortality rate of severe VOD was 98% (McDonald et al, 1993). Side-to-side portacaval shunt has been used effectively in severe VOD after BMT, but the experience has been limited because of a general reluctance to subject these very ill patients to a major operation despite their almost certain death without effective nonsurgical treatment (Murray et al, 1987). Experience is similarly small with the use of TIPS in severe VOD secondary to BMT, and its role remains to be defined.

SUMMARY Budd-Chiari Syndrome Although no etiologic or predisposing condition can be identified in some cases of BCS, in recent years an underlying disorder has been found in more than 70% of patients. The most common conditions that predispose to BCS are hematologic disorders with thrombotic tendencies, such as polycythemia vera and paroxysmal nocturnal hemoglobinuria. Evidence indicates that multiple prothrombotic hematologic factors acting concurrently are involved in many patients with BCS. In the Western experience, hematologic factors play a primary role, whereas in the East, membranous obstruction of the vena cava is common. The pathologic lesion of BCS is thrombosis of the major hepatic veins or the inferior vena cava (IVC) or both, which results in hepatic venous outflow obstruction; intrahepatic and portal hypertension; dilation of the liver sinusoids; intense centrilobular congestion of the hepatic parenchyma; and ischemia, pressure necrosis, and atrophy of the parenchymal cells in the center of the liver lobule. Early in the course of BCS, these lesions are reversible, if the obstruction is relieved. Persistence of the high pressure and congestion within the liver results in irreversible damage, hepatic fibrosis, and progression to cirrhosis, often within months. The two paramount dangers in BCS are development of irreversible liver damage and extension of thrombosis from the hepatic veins into the IVC. The most striking difference between the East and West in the pathology of BCS is the site of the venous occlusion causing hepatic outflow obstruction: in the East, it is usually in the IVC; in the West, it is most often in the major hepatic veins. The diagnosis of BCS in the initial weeks and months is based on finding the typical symptoms and signs combined with abnormal results of several diagnostic studies (US, CT, MRI, or angiographic examination of IVC and hepatic veins). Liver biopsy reveals the typical lesions of obstruction to hepatic venous outflow: intense centrilobular congestion and centrilobular loss of parenchyma and necrosis. Liver function tests invariably show significant hepatic dysfunction. In surgical patients with BCS confined to the hepatic veins, the clinical manifestations and results of diagnostic studies are confirmed by the findings of marked ascites; an enlarged, congested liver; splenomegaly; extensive portosystemic collateral veins; IVC pressure that is substantially lower than portal vein (PV) pressure; portal hypertension; and a markedly elevated hepatic occluded portal pressure, which sometimes is higher than the free portal pressure. Treatment of BCS has evolved; initial experience predominantly led to surgical intervention, but percutaneous techniqueshave supplanted surgical shunt procedures as a more popular

treatment strategy. Nonsurgical therapy of BCS includes medical treatment with thrombolytic agents, anticoagulants, and diuretics and radiologic therapy consisting of transluminal angioplasty, venous stenting, and TIPS. Additional techniques include infusion of thrombolytic agents, such as streptokinase, urokinase, or tPA, or recanalization with mechanical thrombectomy. Anticoagulant therapy to prevent propagation of the thrombi has produced a limited, short-term response when used alone but is an essential component of long-term management in any patient with an underlying prothrombotic state. Radiologic therapy consisting of percutaneous transluminal angioplasty with and without the use of metallic stents has had some short-term success in patients with chronic BCS resulting from stenosis of the IVC. The TIPS procedure is used with increasing frequency for all forms of BCS. The advantage of TIPS is that it does not require a major operation; disadvantages are a high rate of TIPS stenosis and occlusion requiring repeated revision, frequent recurrence of symptoms, and numerous radiologic procedures and hospitalizations. The incidence of TIPS occlusion has decreased greatly with the introduction of PTFE-covered stents but is still significant. In the most experienced hands, 5 year survival after TIPS has been inferior to the largest single-center experience with surgical shunting (Orloff, 2010). Side-to-side portacaval shunt has proved to be the most effective therapy of BCS caused by thrombosis of the hepatic veins; it converts the valveless PV into an outflow tract, decompressing the obstructed hepatic vascular bed. Splenorenal shunt, interposition mesocaval shunt, and portacaval shunt using synthetic grafts are hemodynamically similar to SSPCS but are inferior operations in BCS because of a high incidence of thrombosis and occlusion. Interposition shunt using an autogenous internal jugular vein H-graft has produced results similar to those of direct SSPCS. Important technical features of SSPCS are proper positioning of the patient; use of a long, right subcostal incision; and extensive mobilization of the IVC and PV so that the two vessels can be brought together. SSPCS is contraindicated when BCS is caused by thrombosis or occlusion of the IVC. In these patients, a mesoatrial shunt has been used with some short-term success, although incidence of thrombosis of the bypass graft is high.The combined cavoatrial shunt/SSPCS has replaced the mesoatrial shunt as the preferred treatment for BCS caused by IVC occlusion. Liver transplantation is indicated in patients with chronic BCS who have cirrhosis with progressive hepatic failure and in patients who have had an unsuccessful portosystemic shunt. In approximately 1043 patients with advanced liver disease secondary to BCS, LT has resulted in a mean actuarial 5 year survival rate of 71%. BCS recurred in 13% to 27% of the liver grafts, and thrombosis of other blood vessels, particularly the PV, occurred in 9% to 40% of patients. LT and SSPCS are not competing forms of treatment; LT is appropriate therapy in late stages of BCS, when the liver disease no longer can be reversed by SSPCS. The most effective treatment strategy for BCS involves a multidisciplinary approach to include hepatologists, hematologists, interventional and diagnostic radiologists, and transplant surgeons. Initial measures most frequently use the less invasive percutaneous approaches. Although surgical therapy with portacaval shunt is losing popularity globally, it should remain a crucial tool in the management of BCS patients. Careful integration of all treatment options in a stepwise method, with



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease

inclusion of the patient in the clinical decision making, will produce successful and durable outcomes.

Venoocclusive Disease Also called sinusoidal obstruction syndrome, VOD is a group of disorders in which hepatic venous outflow obstruction is caused by subendothelial sclerosis of the sublobular hepatic veins, terminal hepatic venules, and sinusoids within the liver. VOD is caused by antineoplastic drugs, ingestion of plants containing pyrrolizidine alkaloids, and irradiation of the liver. In the Western Hemisphere the most frequent cause is bone marrow transplantation (BMT). Extensive occlusion of the small hepatic veins results in centrilobular hemorrhagic necrosis of the liver parenchyma, which progresses to diffuse fibrosis and cirrhosis. Although it can occur at any age, VOD caused by pyrrolizidine alkaloids has been observed most often in children; after a prodromal febrile illness, acute-onset abdominal distension from ascites ensues, along with abdominal pain, hepatosplenomegaly, weakness, and sometimes jaundice and peripheral edema. The most important symptoms and signs of VOD after BMT are ascites, jaundice, and abdominal pain. Some patients recover from the acute stage of VOD, but approximately one-fifth of patients with pyrrolizidine poisoning die; cirrhosis develops rapidly in the remainder, with all its clinical manifestations. Mortality from severe VOD after BMT has been reported at 98%. The most important diagnostic study in VOD is percutaneous needle liver biopsy, which shows the specific

1271

abnormality of extensive occlusion of the small hepatic veins within the liver and centrilobular hemorrhagic necrosis. Substantial experience with treatment of VOD involves patients who ingested pyrrolizidine alkaloids. In the acute stage, supportive medical therapy is used. SSPCS is indicated during the acute stage if bleeding esophageal varices develop, or if the clinical and liver biopsy signs of hepatic venous outflow obstruction do not subside after 4 to 8 weeks. In the chronic phase of VOD, with the usual manifestations of cirrhosis, SSPCS is recommended even before variceal hemorrhage has occurred. Mortality in patients with chronic VOD is high, and the major cause of death is bleeding esophageal varices. Medical therapy of the many patients who have developed VOD after BMT has included defibrotide, tPA, ursodeoxycholic acid, antithrombin III, prostaglandin E1, anticoagulation with low-dose heparin, and high-dose corticosteroids. None of these agents has been uniformly effective, but the most promising agent in prophylaxis and treatment of VOD is defibrotide, reported to produce a complete response rate of 36% and a 100-day survival rate of 35% in severe VOD. In addition, SSPCS, TIPS, and LT have been used in a few patients with severe VOD. These procedures have had some success and deserve further evaluation, particularly because one-fourth of patients with VOD experience the severe form, and again, BMT-associated mortality in severe VOD is reportedly 98%. References are available at expertconsult.com.



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease 1271.e1

REFERENCES Aboujaoude MM, et al: Effect of portosystemic shunts on subsequent transplantation of the liver, Surg Gynecol Obstet 172:215–219, 1991. Ahn SS, et al: Selective surgical therapy of the Budd-Chiari syndrome provides superior survivor rates than conservative medical management, J Vasc Surg 5:28–37, 1987. Al Beihany A, et al: Successful treatment of hepatic veno-occlusive disease after myeloablative allogenic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone, Bone Marrow Transplant 41:287–291, 2008. Alvarez R, et al: Percutaneous intrahepatic portosystemic shunting in the treatment of veno-occlusive disease of the liver after bone marrow transplantation, Gastroenterol Hepatol 23:177–180, 2000. Anonymous: Case records of the Massachusetts General Hospital, N Engl J Med 307:236–242, 1982. Attwell A, et al: Treatment of Budd-Chiari syndrome in a liver transplant unit: the role of transjugular intrahepatic porto-systemic shunt and liver transplantation, Aliment Pharmacol Ther 20:867–873, 2004. Auvert J, Farge C: Hypertension portale de l’enfant: dans une série de 123 cas, étude des cas difficiles nécessitant plusieurs interventions: intérêt de l’anastomose cavomésentérique, Ann Chir 17:281, 1963. Azoulay D, et al: Transjugular intrahepatic portosystemic shunt (TIPS) for severe veno-occlusive disease of the liver following bone marrow transplantation, Bone Marrow Transplant 25:987–992, 2000. Bachet JB, et al: Long-term portosystemic shunt patency as a determinant of outcome in Budd-Chiari syndrome, J Hepatol 46:60–68, 2007. Baert AL, et al: Early diagnosis of Budd-Chiari syndrome by computed tomography and ultrasonography: report of five cases, Gastroenterology 894:587–595, 1983. Bahr MJ, et al: Recurrence of Budd-Chiari syndrome after liver transplantation in paroxysmal nocturnal hemoglobinuria, Transpl Int 16:890–894, 2003. Baijal SS, et al: Management of idiopathic Budd-Chiari syndrome with primary stent placement: early results, J Vasc Interv Radiol 7:545– 553, 1996. Barrault C, et al: Non-surgical treatment of Budd-Chiari syndrome: a review, Gastroenterol Clin Biol 28:40–49, 2004. Baxter EJ, et al: Cancer Genome Project: acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders, Lancet 365:1054–1061, 2005. Bazraktar Y, et al: Budd-Chiari syndrome: a common complication of Behcet’s disease, Am J Gastroenterol 92:858–862, 1997. Bearman SI, et al: Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients, Blood 89:1501–1506, 1997. Becker C, et al: Hepatic vein occlusion: morphologic features on computed tomography and ultrasonography, Gastrointest Radiol 11:305– 311, 1986. Behera A, et al: Treatment of Budd-Chiari syndrome with inferior vena caval occlusion by mesoatrial shunt, Eur J Surg 168:355–359, 2002. Bertina RM, et al: Mutation in blood coagulation factor V associated with resistance to activated protein C, Nature 369:64–67, 1994. Bismuth H, Sherlock DJ: Portasystemic shunting versus liver transplantation for the Budd-Chiari syndrome, Ann Surg 214:581–589, 1991. Bismuth H, et al: Options for elective treatment of portal hypertension in cirrhotic patients in the transplantation era, Am J Surg 160:105– 110, 1990. Blum U, et al: Budd-Chiari syndrome: technical, hemodynamic, and clinical results of treatment with transjugular intrahepatic portosystemic shunt, Radiology 197:805–811, 1995. Boillot O, et al: Liver transplantation in patients with a surgical portasystemic shunt, Gastroenterol Clin Biol 15:876–880, 1991. Bolondi L, et al: Diagnosis of Budd-Chiari syndrome by pulsed Doppler ultrasound, Gastroenterology 100(5 Pt 1):1324–1331, 1991. Boughton BJ: Hepatic and portal vein thrombosis closely associated with chronic myeloproliferative disorders [editorial], Br Med J 302: 192–193, 1991. Brancatelli G, et al: Budd-Chiari syndrome: spectrum of imaging findings, AJR Am J Roentgenol 188:168–176, 2007. Bras G, McLean E: Toxic factors in veno-occlusive disease, Ann N Y Acad Sci 3:392–396, 1963.

Bras G, et al: Veno-occlusive disease of the liver with non-portal type of cirrhosis occurring in Jamaica, Arch Pathol 57:285–300, 1954. Brooks SHE, et al: Acute veno-occlusive disease of the liver: fine structure in Jamaican children, Arch Pathol 89:507–520, 1970. Budd G: On diseases of the liver, London, 1845, John Churchill, p 146. Bulley SR, et al: Defibrotide for the treatment of hepatic veno-occlusive disease in children, Pediatr Blood Cancer 48:700–704, 2007. Bunin N, et al: Related donor liver transplant for veno-occlusive disease following T-depleted unrelated donor bone marrow transplantation, Transplantation 61:664–666, 1996. Cameron JL, et al: The Budd-Chiari syndrome: treatment by mesenteric-systemic venous shunts, Ann Surg 198:335–346, 1983. Cameron JL, et al: Mesoatrial shunt: a prosthesis modification, Surgery 96:114–116, 1984. Campbell DA Jr, et al: Hepatic transplantation with perioperative and long-term anticoagulation as treatment for Budd-Chiari syndrome, Surg Gynecol Obstet 166:511–518, 1988. Cassel GA, Morely JE: Hepatic vein thrombosis treated with streptokinase, S Afr Med J 48:2319–2320, 1974. Cejna M, et al: Repeat interventions for maintenance of transjugular intra-hepatic portosystemic shunt function in patients with BuddChiari syndrome, J Vasc Interv Radiol 13:193–199, 2002. Chalandon Y, et al: Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation, Biol Blood Marrow Transplant 10:347–354, 2004. Chaubal N, et al: Sonography in Budd-Chiari syndrome, J Ultrasound Med 25:373–379, 2006. Chiari H: Über der selbständige Phlebitis obliterans der Hauptstämme der Venae hepaticae als Todesursache, Beitr z path Anat u z allg Path 26:1–18, 1899. Chopra R, et al: Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study, Br J Haematol 111:1122–1129, 2000. Clain D, et al: Clinical diagnosis of the Budd-Chiari syndrome: a report of six cases, Am J Med 43:544–554, 1967. Clark PJ, et al: Systemic thrombolysis for acute, severe Budd-Chiari syndrome, J Thromb Thrombolysis 34:410–415, 2012. Corbacioglu S, et al: Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention, Bone Marrow Transplant 33:189–195, 2004. Corbacioglu S, et al: Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide, Bone Marrow Transplant 38:547–553, 2006. Cruz E, et al: High incidence of recurrence and hematologic events following liver transplantation for Budd-Chiari syndrome, Clin Transplant 19:501–506, 2005. Dahlback B: Resistance to activated protein C, the Arg506 to Gln mutation in the factor V gene and venous thrombosis, Thromb Haemost 73:739–742, 1995. Dahlback B, et al: Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C, Proc Natl Acad Sci USA 90:1004–1008, 1993. De la Rubia J, et al: Successful treatment of hepatic veno-occlusive disease in a peripheral blood progenitor cell transplant patient with a transjugular intrahepatic portosystemic stent-shunt (TIPS), Haematologica 81:536–539, 1996. DeLeve LD, et al: Vascular disorders of the liver, Hepatology 49:1729– 1764, 2009. Deltenre P, et al: Factor V Leiden–related Budd-Chiari syndrome, Gut 48:264–268, 2001. Denninger MH, et al: Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors, Hepatology 31:587– 591, 2000. Dignan F, et al: Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from venoocclusive disease, Bone Marrow Transplant 40:79–82, 2007. Ding PX, et al: Agitation thrombolysis for fresh iatrogenic IVC thrombosis in patients with Budd-Chiari syndrome, J Vasc Surg 52:782– 784, 2010. Dong X-W, et al: Splenocaval versus mesocaval shunt with artificial vascular graft for the treatment of Budd-Chiari syndrome, Hepatobiliary Pancreat Dis Int 4:68–70, 2005.

1271.e2 PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital Dowling JB: Ten years’ experience with mesocaval grafts, Surg Gynecol Obstet 149:518–522, 1979. Doyle A, et al: Use of the AngioJet percutaneous thrombectomy system for the treatment of acute Budd-Chiari syndrome, BMJ Case Rep 2013. doi: 10.1136/bcr-2013-008632. Eapen CE, et al: Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome, Gut 55:878–884, 2006. Ecker JE, McKittrick JE: Thrombosis of the hepatic veins: the “BuddChiari syndrome”—a possible link between oral contraceptives and thrombosis formation, Am J Gastroenterol 45:429–443, 1966. Eguchi S, et al: Successful balloon membranotomy for obstruction of the hepatic portion of the inferior vena cava, Surgery 76:837–840, 1974. Eisenmenger WJ, Nickel WF: Indications for portacaval anastomosis, Med Clin North Am 44:779–787, 1960. Emre A, et al: Mesoatrial shunt in Budd-Chiari syndrome, Am J Surg 179:304–308, 2000. Erdon A: Budd-Chiari syndrome: a review of imaging findings, Eur J Radiol 61:44–56, 2007. Erlik D, et al: Surgical cure of primary hepatic vein occlusion syndrome by side-to-side portacaval shunt, Surg Gynecol Obstet 114:368–374, 1962. Espana P, et al: Membranous obstruction of the inferior vena cava and hepatic veins, Am J Gastroenterol 73:28–32, 1980. Espinosa G, et al: Budd-Chiari syndrome secondary to antiphospholipid syndrome: clinical and immunologic characteristics of 43 patients, Medicine (Baltimore) 80:345–354, 2001. Essell JH, et al: Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation: a randomized, doubleblind, placebo-controlled trial, Ann Intern Med 128(12 Pt 1):975– 981, 1998. Ferral H, et al: Budd-Chiari syndrome, AJR Am J Roentgenol 199:737– 745, 2012. Fisher NC, et al: Managing Budd-Chiari syndrome: a retrospective review of percutaneous hepatic vein angioplasty and surgical shunting, Gut 44:568–574, 1999. Fletcher MS, et al: Long-term follow-up of interposition mesocaval shunting in portal hypertension, Br J Surg 68:485–487, 1981. Fried MW, et al: Transjugular intrahepatic portosystemic shunt for the management of severe veno-occlusive disease following bone marrow transplantation, Hepatology 24:588–591, 1996. Furui S, et al: Hepatic inferior vena cava obstruction: treatment of two types with Gianturco expandable metallic stents, Radiology 176:665– 670, 1990. Galati JS, et al: The Budd-Chiari syndrome: a therapeutic quandary, Gastroenterology 104:A904, 1993. Gandini R, et al: Transjugular intrahepatic portosystemic shunt patency and clinical outcome in patients with Budd-Chiari syndrome: covered versus uncovered stents, Radiology 241:298–305, 2006. Ganger DR, et al: Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome or portal vein thrombosis: review of indications and problems, Am J Gastroenterol 94:603–608, 1999. Garcia-Pagán JC, et al: TIPS for Budd-Chiari syndrome: long-term results and prognostic factors in 24 patients, Gastroenterology 135:808–815, 2008. Gentil-Kocher S, et al: Budd-Chiari syndrome in children: report of 22 cases, J Pediatr 113:30–38, 1988. Ghanem J, Hershko C: Veno-occlusive disease and primary hepatic vein thrombosis in Israeli Arabs, Isr J Med Sci 17:339–347, 1981. Gibson JB: Chiari’s disease and the Budd-Chiari syndrome, J Pathol 79:381–401, 1960. Giles F, et al: Ursodiol does not prevent hepatic venoocclusive disease associated with Mylotag therapy, Haematologica 87:114–116, 2002. Goldstein R, et al: Prevention of recurrent thrombosis following liver transplantation for Budd-Chiari syndrome associated with myeloproliferative disorders: treatment with hydroxyurea and aspirin, Transplant Proc 23:1559–1560, 1991. Gooneratne NS, et al: Dimple sign” in hepatic vein thrombosis, Br J Radiol 52:584–586, 1979. Gore DO, et al: Veno-occlusive disease of the liver: surgical aspects, Surgery 49:334–346, 1961. Grant E, et al: Budd-Chiari syndrome: the results of duplex and color Doppler imaging, AJR Am J Roentgenol 152:377–381, 1989.

Greenwood LH, et al: Urokinase treatment of Budd-Chiari syndrome, AJR Am J Roentgenol 141:1057–1059, 1983. Griffith JF, et al: Radiological intervention in Budd-Chiari syndrome: techniques and outcome in 18 patients, Clin Radiol 51:775–784, 1996. Gupta S, et al: Comparison of ultrasonography, computed tomography and 99mTc liver scan in diagnosis of Budd-Chiari syndrome, Gut 28:242–247, 1987. Hagglund H, et al: Treatment of hepatic venoocclusive disease with recombinant human tissue plasminogen activator or orthotopic liver transplantation after allogeneic bone marrow transplantation, Transplantation 62:1076–1080, 1996. Halff G, et al: Liver transplantation for the Budd-Chiari syndrome, Ann Surg 211:43–49, 1990. Hartmann RC, et al: Fulminant hepatic venous thrombosis (BuddChiari syndrome) in paroxysmal nocturnal hemoglobinuria: definition of a medical emergency, Johns Hopkins Med J 146:247–254, 1980. Haussmann U, et al: Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy, Haematologica 91:795–800, 2006. Hemming AW, et al: Treatment of Budd-Chiari syndrome with portosystemic shunt or liver transplantation, Am J Surg 171:176–181, 1996. Henderson MJ, et al: Surgical options, hematologic evaluation, and pathologic changes in Budd-Chiari syndrome, Am J Surg 159:41–50, 1990. Hernandez-Guerra M, et al: PTFE-covered stents improve TIPS patency in Budd-Chiari syndrome, Hepatology 40:1197–1202, 2004. Hirooka M, Kimura C: Membranous obstruction of the hepatic portion of the inferior vena cava, Arch Surg 100:656–663, 1970. Hirschberg B, et al: Flow cytometric analysis of autonomous growth of erythroid precursors in liquid culture detects occult polycythemia vera in the Budd-Chiari syndrome, J Hepatol 32:574–578, 2000. Ho VT, et al: Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies, Bone Marrow Transplant 41:229–237, 2008. Hodkinson HJ, et al: Postpartum veno-occlusive disease treated with ascitic fluid reinfusion, S Afr Med J 54:366–368, 1978. Hoekstra J, et al: Vascular liver disease: diagnosis, treatment and prognosis of Budd-Chiari syndrome, Neth J Med 66:334–339, 2008. Hoekstra J, et al: Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study, J Hepatol 51:696–706, 2009. Hosoki T, et al: Hepatic venous outflow obstruction: evaluation with pulsed Doppler sonography, Radiology 170:733–737, 1989. Hoyumpa AM Jr, et al: Budd-Chiari syndrome in women taking oral contraceptives, Am J Med 50:137–140, 1971. Huber M, et al: Budd-Chiari syndrome: long-term results after treatment with transjugular intrahepatic portosystemic shunt (TIPS), Hepatology 26:204A, 1997. Huguet C, et al: Interposition mesocaval shunt for chronic primary occlusion of the hepatic veins, Surg Gynecol Obstet 148:691–698, 1979. Inafuku H, et al: A three-decade experience of radical endvenectomy with pericardial patch graft for correction of Budd-Chiari syndrome, J Vasc Surg 50:590–593, 2009. Iwahashi K: Surgical correction of the inferior vena cava obstruction with Budd-Chiari syndrome, Arch Jpn Chir 50:559–570, 1981. Iwatsuki S, et al: Liver transplantation in the treatment of bleeding esophageal varices, Surgery 104:697–705, 1988. Iwatsuki S, et al: Liver transplantation for Budd-Chiari syndrome. In Proceedings of the second international symposium on Budd-Chiari syndrome, Kyoto, Japan, VIPL-2, 1991. James C, et al: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera, Nature 434:1144–1148, 2005. Jamieson NV, et al: Liver transplantation for Budd-Chiari syndrome, 1976–1990, Ann Chir 45:362–365, 1991. Janssen HI, et al: Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with BuddChiari syndrome and portal vein thrombosis: results of a case-control study, Blood 96:2364–2368, 2000. Jeans WD, et al: Treatment of hepatic vein and inferior vena caval obstruction by balloon dilatation, Br J Radiol 56:687–689, 1983.



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease 1271.e3

Jelinek J, et al: JAK2 mutation 1849G>T is rare in acute leukemia but can be found in CMML, Philadelphia chromosome-negative CML, and mega-karyocytic leukemia, Blood 106:3370–3373, 2005. Jones AV, et al: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders, Blood 106:2162–2168, 2005. Kage M, et al: Histopathology of membranous obstruction of the inferior vena cava in the Budd-Chiari syndrome, Gastroenterology 102:2081–2090, 1992. Kamath PS: Budd-Chiari syndrome: radiologic findings, Liver Transpl 12:S21–S22, 2006. Kawashima Y, et al: Senning’s operation for the treatment of BuddChiari syndrome. In Proceedings of the second international symposium on Budd-Chiari syndrome, Kyoto, Japan, II01-6, 1991. Khanna SK, et al: Shunt surgery in Budd-Chiari syndrome: our experience. In Proceedings of the second international symposium on BuddChiari syndrome, Kyoto, Japan, IL02-5, 1991. Khuroo MS, Datta DV: Budd-Chiari syndrome following pregnancy: report of 16 cases with roentgenologic, hemodynamic and histologic studies of the hepatic outflow tract, Am J Med 68:113–121, 1980. Kimura C, et al: Membranous obstruction of the hepatic portion of the inferior vena cava: clinical study of nine cases, Surgery 72:551–559, 1972. Klein AS, et al: Current management of the Budd-Chiari syndrome, Ann Surg 212:144–149, 1990. Knoop M, et al: Liver transplantation for Budd-Chiara syndrome, Transplant Proc 26:3577–3578, 1994a. Knoop M, et al: Treatment of the Budd-Chiari syndrome with orthotopic liver transplantation and long-term anticoagulation, Clin Transplant 8:67–72, 1994b. Koja K, et al: Radical open end venectomy with autologous pericardial patch graft for correction of Budd-Chiari syndrome, Cardiovasc Surg 4:500–504, 1996. Koster T, et al: Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study, Lancet 342:1503–1506, 1993. Kralovics R, et al: A gain-of-function mutation of JAK2 in myeloproliferative disorders, N Engl J Med 352:1779–1790, 2005. Kreel L, et al: Vascular radiology in the Budd-Chiari syndrome, Br J Radiol 40:755–759, 1967. Krom RAF, et al: Orthotopic liver transplantation in Groningen, The Netherlands (1979-1983), Hepatology 4:61S–65S, 1984. Kumar S, et al: Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation, Mayo Clin Proc 78:589–598, 2003. Kuniyoshi Y, et al: Improvement in esophageal varices and liver histology postoperatively in Budd-Chiari syndrome, Ann Thorac Surg 65:1711–1714, 1998. Langer B, et al: Clinical spectrum of the Budd-Chiari syndrome and its surgical management, Am J Surg 129:137–145, 1975. Langnas AN, et al: Influence of a prior porta-systemic shunt on outcome after liver transplantation, Am J Gastroenterol 87:714–718, 1992. Levine RL, et al: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelo-fibrosis, Cancer Cell 7:387–397, 2005. Lewis JH, et al: Budd-Chiari syndrome associated with oral contraceptive steroids: review of treatment of 47 cases, Dig Dis Sci 28:673–683, 1983. Li T, et al: Feasibility and midterm outcomes of percutaneous transhepatic balloon angioplasty for symptomatic Budd-Chiari syndrome secondary to hepatic venous obstruction, J Vasc Surg 50:1079–1084, 2009. Liebowitz AI, Hartmann RC: The Budd-Chiari syndrome and paroxysmal nocturnal haemoglobinuria, Br J Haematol 48:1–6, 1981. Ludwick JR, et al: Chiari’s disease: a clinicopathological study, Arch Surg 91:697–704, 1967. Lupescu IG, et al: Spiral computed tomography and magnetic resonance angiography evolution in Budd-Chiari syndrome, J Gastrointestin Liver Dis 17:223–226, 2008. Maddrey WC: Hepatic vein thrombosis (Budd-Chiari syndrome): possible association with the use of oral contraceptives, Semin Liver Dis 7:32–39, 1987. Mahmoud AEA, Elias E: New approaches to the Budd-Chiari syndrome, J Gastroenterol Hepatol 11:1121–1123, 1996. Mahmoud AEA, et al: Budd-Chiari syndrome and factor V Leiden mutation, Lancet 345:526, 1995.

Mahmoud AEA, et al: Clinical spectrum, investigations and treatment of Budd-Chiari syndrome, Q J Med 89:37–43, 1996. Malt RA, et al: Side-to-side portacaval shunt versus nonsurgical treatment of Budd-Chiari syndrome, Am J Surg 136:387–389, 1978. Mancuso A, et al: TIPS for acute and chronic Budd-Chiari syndrome: a single-centre experience, J Hepatol 38:751–754, 2003. Marrero JA, et al: ACG clinical guideline: the diagnosis and management of focal liver lesions, Am J Gastroenterol 109:1328–1347, 2014. Martin LG, et al: Angioplasty for long-term treatment of patients with Budd-Chiari syndrome, AJR Am J Roentgenol 154:1007–1010, 1990. Mathieu D, et al: Budd-Chiari syndrome: dynamic CT, Radiology 165:409–413, 1987. Mazzaferro V, et al: Liver transplantation in patients with previous portasystemic shunt, Am J Surg 160:111–115, 1990. McCarthy P, et al: The Budd-Chiari syndrome: medical and surgical management of 30 patients, Arch Surg 120:657–662, 1985. McDonald GB, et al: Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients, Ann Intern Med 118:255–267, 1993. McMaster P: Budd-Chiari syndrome: shunt or transplant? HPB Surg 7:257–259, 1994. Melear JM, et al: Hematologic aspects of liver transplantation for Budd-Chiari syndrome with special reference to myeloproliferative disorders, Transplantation 7:1090–1095, 2002. Membreno FE, et al: Liver transplantation for sinusoidal obstructive syndrome (veno-occlusive disease): case report with review of the literature and the UNOS database, Clin Transplant 22:397–404, 2008. Menon KVN, et al: The Budd-Chiari syndrome, N Engl J Med 350:578–585, 2004. Mentha G, et al: Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 centers, J Hepatol 44:520– 528, 2006. Michl P, et al: Successful treatment of chronic Budd-Chiari syndrome with transjugular intrahepatic portosystemic shunt, J Hepatol 32: 516–520, 1999. Millener P, et al: Color Doppler imaging findings in patients with Budd-Chiari syndrome: correlation with venographic findings, Am J Roentgenol 161(2):307–312, 1993. Millikan WJ Jr, et al: Approach to the spectrum of Budd-Chiari syndrome: which patients require portal decompression? Am J Surg 149:167–176, 1985. Minegaux F, et al: Comparison of transjugular and surgical portosystemic shunts on the outcome of liver transplantation, Arch Surg 129:1018–1024, 1994. Mitchell MC, et al: Budd-Chiari syndrome: etiology, diagnosis and management, Medicine (Baltimore) 61:199–218, 1982. Montano-Loza AJ, et al: Rotterdam score predicts early mortality in Budd-Chiari syndrome and surgical shunting prolongs transplantfree survival, Aliment Pharmacol Ther 30:1060–1069, 2009. Mor E, et al: Defibrotide for the treatment of veno-occlusive disease after liver transplantation, Transplantation 72:1237–1240, 2001. Murad SD, et al: Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome, Hepatology 39:500–508, 2004. Murad SW, et al: Long-term outcome of a covered vs. uncovered transjugular intrahepatic portosystemic shunt in Budd-Chiari syndrome, Liver Int 15:249–256, 2008. Murad SW, et al: Etiology, management, and outcome of the BuddChiari syndrome, Ann Intern Med 151:167–175, 2009. Murray JA, et al: Successful treatment of hepatic veno-occlusive disease in a bone marrow transplant patient with side-to-side portocaval shunt, Gastroenterology 92:1073–1077, 1987. Nakao K, et al: Budd-Chiari syndrome treated by Senning’s procedure, J Cardiovasc Surg (Torino) 29:746–750, 1988. Nimer SD, et al: Successful treatment of hepatic veno-occlusive disease in a bone marrow transplant patient with orthotopic liver transplantation, Transplantation 49:819–821, 1990. Noble JA: Hepatic vein thrombosis complicating polycythemia vera: successful treatment with a portacaval shunt, Arch Intern Med 120:105–108, 1976. Noone TC, et al: Budd-Chiari syndrome: spectrum of appearances of acute, subacute, and chronic disease with magnetic resonance imaging, J Magn Reson Imaging 11:44–50, 2000.

1271.e4 PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital Ohara I, et al: A bypass operation for occlusion of the hepatic inferior vena cava, Surg Gynecol Obstet 117:151–155, 1963. Ohashi K, et al: The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation, Am J Hematol 64:32–38, 2000. Okamoto E, et al: Simultaneous radical surgical treatment for membranous obstruction of the inferior vena cava and the coincident hepatocellular carcinoma: the first successful case, Jpn J Surg 13: 135–140, 1983. Okuda H, et al: Epidemiological and clinical features of Budd-Chiari syndrome in Japan, J Hepatol 22:1–9, 1995. Okuda K: Inferior vena cava thrombosis at its hepatic portion (obliterative hepatocavopathy), Semin Liver Dis 22:15–26, 2002. Ono J, et al: Membranous obstruction of the inferior vena cava, Ann Surg 197:454–458, 1983. Orloff MJ: The liver. In Sabiston DE Jr, editor: Davis-Christopher textbook of surgery, ed 11, Philadelphia, 1977, Saunders, pp 1185– 1187. Orloff MJ: Invited discussion of Hemming et al: treatment of BuddChiari syndrome with portosystemic shunt or liver transplantation, HPB Surg 11:136–139, 1998. Orloff MJ: Anatomy of the portal system and experience with portacaval shunt. In Fischer J, Bland K, editors: Mastery of surgery, ed 6, Philadelphia, 2010, Lippincott Williams & Wilkins. Orloff MJ, Orloff MS: Bleeding oesophageal and gastric varices: shunts. In Dudley H, et al, editors: Rob and Smith’s operative surgery: alimentary tract and abdominal wall, ed 4, Oxford, 1992, Butterworth, pp 478–500. Orloff MJ, Orloff MS: Bleeding oesophageal and gastric varices: shunts. In Jamieson CG, Denas HT, editors: Rob and Smith’s operative surgery: surgery of the upper gastrointestinal tract, London, 1994, Chapman & Hall, pp 493–515. Orloff LA, Orloff MJ: Budd-Chiari syndrome caused by Behcet disease: treatment by side-to-side portacaval shunt, J Am Coll Surg 188:396– 407, 1999. Orloff MJ, et al: Portacaval shunts: side-to-side and end-to-side. In Clavien P-A, et al, editors: Atlas of upper gastrointestinal and HepatoPancreatico-Biliary surgery, Berlin-Heidelberg, 2007, Springer-Verlag, pp 687–702. Orloff MJ, et al: Treatment of Budd-Chiari syndrome due to inferior vena cava occlusion by combined portal and vena caval decompression, Am J Surg 163:137–143, 1992. Orloff MJ, et al: A 27-year experience with surgical treatment of BuddChiari syndrome, Ann Surg 232:340–352, 2000. Orloff MJ, et al: Budd-Chiari syndrome revisited: 38 years’ experience with surgical portal decompression, J Gastrointest Surg 16:286–300, 2012. Panis Y, et al: Portosystemic shunt in Budd-Chiari syndrome: longterm survival and factors affecting shunt patency in 25 patients in Western countries, Surgery 115:276–281, 1994. Park SH, et al: A randomized trial of heparin plus ursodiol vs. heparin alone to prevent hepatic veno-occlusive disease after hematopoietic stem cell transplantation, Bone Marrow Transplant 29:87–143, 2002. Parker RGF: Occlusion of the hepatic veins in man, Medicine (Baltimore) 38:369–402, 1959. Pasic M, et al: Transcaval liver resection with hepatoatrial anastomosis for treatment of patients with the Budd-Chiari syndrome: late results, J Thorac Cardiovasc Surg 106:275–282, 1993. Pavri TM, et al: Budd-Chiari syndrome: a single-center experience, World J Gastroenterol 20(43):16236–16244, 2014. Pelletier S, et al: Antiphospholipid syndrome as the second cause of non-tumorous Budd-Chiari syndrome, J Hepatol 21:76–80, 1994. Perello A, et al: TIPS is a useful long-term derivative therapy for patients with Budd-Chiari syndrome uncontrolled by medical therapy, Hepatology 35:132–139, 2002. Peres E, et al: Early intervention with antithrombin III therapy to prevent progression of hepatic venoocclusive disease, Blood Coagul Fibrinolysis 19:203–207, 2008. Peytremann R, et al: Thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) with particular reference to progressive, diffuse hepatic venous thrombosis, Ser Haematol 5:115–136, 1972. Pezzuoli G, et al: Portacaval shunt in the treatment of primary BuddChiari syndrome, Surgery 98:319–323, 1985. Plessier A, Valla DC: Budd-Chiari syndrome, Semin Liver Dis 28:259– 269, 2008.

Plessier A, et al: Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome, Hepatology 44:1308–1316, 2006. Powell-Jackson PR, et al: Budd-Chiari syndrome: clinical patterns and therapy, Q J Med 201:79–88, 1982. Powell-Jackson PR, et al: Ultrasound scanning and 99mTc sulphur colloid scintigraphy in diagnosis of Budd-Chiari syndrome, Gut 27: 1502–1506, 1986. Prandi D, et al: Side-to-side portacaval shunt in the treatment of BuddChiari syndrome, Gastroenterology 68:137–141, 1975. Primignani M, et al: Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis, Hepatology 44:1528–1534, 2006. Qi X, et al: Prevalence of the JAK2 V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis: a prospective study, J Gastroenterol Hepatol 27:1036–1043, 2012. Qureshi A, et al: Defibrotide in the prevention and treatment of venoocclusive disease in autologous and allogeneic stem cell transplantation in children, Pediatr Blood Cancer 50:831–832, 2008. Rapoport AP, et al: Orthotopic liver transplantation for life-threatening veno-occlusive disease of the liver after allogeneic bone marrow transplant, Bone Marrow Transplant 8:421–424, 1991. Redman HC: The Budd-Chiari syndrome: angiography and its complications, Can Assoc Radiol J 26:271–278, 1975. Reichart B, et al: Surgical treatment for congenital occlusion of the inferior vena cava in its diaphragmatic portion, Thorac Cardiovasc Surg 29:180–182, 1981. Richardson P, et al: Defibrotide (DF) for the treatment of severe venoocclusive disease (sVOD) and multi-organ failure (MOF) post SCT: final results of a multi-center, randomized, dose-finding trial, Blood 108:178, 2006. Richardson PG, et al: Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population, Blood 92:737–744, 1998. Richardson PG, et al: Multiinstitutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multi-systemic organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome, Blood 100:4337–4343, 2002. Ringe B, et al: Which is the best surgery for Budd-Chiari syndrome: venous decompression of liver transplantation? A single-center experience with 50 patients, Hepatology 21:1337–1344, 1995. Rogopoulos G, et al: Transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome after failure of surgical shunting, Arch Surg 130:227–228, 1995. Rossi P, et al: CT diagnosis of Budd-Chiari syndrome, J Comput Assist Tomogr 5:366–369, 1981. Rössle M, et al: The first decade of the transjugular intrahepatic portosystemic shunt (TIPS): state of the art, Liver 18:73–89, 1998. Rössle M, et al: The Budd-Chiari syndrome: outcome after treatment with the transjugular intrahepatic portosystemic shunt, Surgery 135:394–403, 2004. Rössle M, et al: The use of polytetrafluorethylene-covered stent graft for transjugular intrahepatic portosystemic shunt (TIPS): long-term follow-up of 100 patients, Acta Radiol 47:660–666, 2006. Ruutu T, et al: Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation, Blood 100: 1977–1983, 2002. Safouh M, Shehata AH: Hepatic vein occlusion disease of Egyptian children, J Pediatr 67:415–422, 1965. Sakai Y, Wall WJ: Liver transplantation for Budd-Chiari syndrome. In Proceedings of the second international symposium on Budd-Chiari syndrome, Kyoto, Japan, VIPa-4, 1991. Sakai Y, Wall WJ: Liver transplantation for Budd-Chiari syndrome: a retrospective study, Jpn J Surg 24:49–53, 1994. Salat C, et al: Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplantation, Blood 89:2184–2188, 1997a. Salat C, et al: Laboratory markers of veno-occlusive disease in the course of bone marrow and subsequent liver transplantation, Bone Marrow Transplant 19:487–490, 1997b. Sato M, et al: Percutaneous transluminal angioplasty in segmental obstruction of the hepatic inferior vena cava: long-term results, Cardiovasc Intervent Radiol 13:189–192, 1990. Sawada S, et al: Budd-Chiari syndrome treated by interventional radiology including percutaneous transluminal angioplasty and selfexpandable metallic stent placement. In Proceedings of the second



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 88  Budd-Chiari syndrome and veno-occlusive disease 1271.e5

international symposium on Budd-Chiari syndrome, Kyoto, Japan, IPA3, 1991. Scharschmidt BF: Human liver transplantation: analysis of data of 540 patients from four centers, Hepatology 4(Suppl):95–101, 1984. Schenker S: Medical treatment vs. transplantation in liver disorders, Hepatology 4:102S–106S, 1984. Schlegel PG, et al: Hepatic veno-occlusive disease in pediatric stem cell recipients: successful treatment with continuous infusion of prostaglandin E1 and low-dose heparin, Ann Hematol 76:37–41, 1998. Schlitt HJ, et al: Allogeneic liver transplantation for hepatic venoocclusive disease after bone marrow transplantation: clinical and immunologic considerations, Bone Marrow Transplant 16:473–478, 1995. Schramek A, et al: New observations in the clinical spectrum of the Budd-Chiari syndrome, Ann Surg 180:368–372, 1974. Segev DL, et al: Twenty years of liver transplantation for Budd-Chiari syndrome: a national registry analysis, Liver Transpl 13:1285–1294, 2007. Semson IW: Membranous obstruction of the inferior vena cava and hepato-cellular carcinoma in South Africa, Gastroenterology 82:171– 178, 1982. Senning A: Budd-Chiari syndrome: a contribution to surgical therapy, Schweiz Med Wochenschr 111:2036–2039, 1981. Senning A: Transcaval posterocranial resection of the liver as treatment of the Budd-Chiari syndrome, World J Surg 7:632–640, 1983. Senning A: The cardiovascular surgeon and the liver, J Thorac Cardiovasc Surg 93:1–10, 1987. Senzolo M, et al: TIPS for veno-occlusive disease: is the contraindication real? Hepatology 42:240–241, author reply 241, 2005. Senzolo M, et al: Severe venoocclulsive disease after liver transplantation treated with transjugular intrahepatic portosystemic shunt, Transplantation 82:132–135, 2006. Senzolo M, et al: Veno-occlusive disease: update on clinical management, World J Gastroenterol 13:3918–3924, 2007. Shaked A, et al: Portosystemic shunt versus orthotopic liver transplantation for the Budd-Chiari syndrome, Surg Gynecol Obstet 174:453– 459, 1992. Sharma S, et al: Percutaneous balloon membranotomy combined with prolonged streptokinase infusion for management of inferior vena cava obstruction, Am Heart J 123:515–518, 1992. Sharma S, et al: Pharmacological thrombolysis in Budd-Chiari syndrome: a single-centre experience and review of the literature, J Hepatol 40:172–180, 2004. Shulman HM, et al: Hepatic veno-occlusive disease after bone marrow transplantation: immunohistochemical identification of the material within occluded central venules, Am J Pathol 127:549–558, 1987. Shulman HM, et al: Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms, Hepatology 19:1171–1181, 1994. Shulman HM, et al: Utility of transvenous liver biopsies and wedged hepatic venous pressure measurements in sixty marrow transplant recipients, Transplantation 59:1015–1022, 1995. Singhal D, et al: Current role of portosystemic shunt surgery in the management of hepatic venous outflow obstruction, Dig Surg 23:358–369, 2006. Slakey DP, et al: Budd-Chiari syndrome: current management options, Ann Surg 233:522–527, 2001. Smalberg JH, et al: Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis, Blood 120:4921– 4928, 2012. Smith FO, et al: Transjugular intrahepatic portosystemic shunting (TIPS) for treatment of severe hepatic veno-occlusive disease, Bone Marrow Transplant 18:643–646, 1996. Smith RB, et al: Dacron interposition shunts for portal hypertension: an analysis of morbidity correlates, Ann Surg 192:9–17, 1980. Srinivas BC, et al: Inferior vena cava obstruction: long-term results of endovascular management, Indian Heart J 64(2):162–169, 2012. Srinivasan P, et al: Liver transplantation for Budd-Chiari syndrome, Transplantation 73:973–977, 2002. Steensma DP, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelo-dysplastic syndromes, Blood 106:1207–1209, 2005. Stringer MD, et al: Mesoatrial shunt: a surgical option in the management of the Budd-Chiari syndrome, Br J Surg 76:474–478, 1989.

Stuart KL, Bras G: Veno-occlusive disease of the liver, Q J Med 26:291– 315, 1957. Suchato C, et al: Suprahepatic membranous obstruction of vena cava, Can Assoc Radiol J 26:148–149, 1976. Svensson PJ, Dahlback B: Resistance to activated protein C as a basis for venous thrombosis, N Engl J Med 330:517–522, 1994. Takeuchi J, et al: Budd-Chiari syndrome associated with obstruction of the inferior vena cava, Am J Med 5:11–20, 1971. Taneja A, et al: Budd-Chiari syndrome in childhood secondary to inferior vena caval obstruction, Pediatrics 63:808–812, 1979. Tang TJ, et al: The prognostic value of histology in the assessment of patients with Budd-Chiari syndrome, J Hepatol 35:338–343, 2001. Tascilar K, et al: Vascular involvement in Behçet’s syndrome: a retrospective analysis of associations and the time course, Rheumatology 53:2018–2022, 2014. Tavill AS, et al: The Budd-Chiari syndrome: correlation between hepatic scintigraphy and the clinical, radiological and pathological findings in nineteen cases of hepatic venous outflow obstruction, Gastroenterology 63:509–518, 1975. Tay J, et al: Systematic review of controlled clinical trials on the use of ursodeoxycholic acid for the prevention of hepatic veno-occlusive disease in hematopoietic stem cell transplantation, Biol Blood Marrow Transplant 13:206–217, 2007. Terpstra OT, et al: Late results of mesocaval interposition shunting for bleeding oesophageal varices, Br J Surg 74:787–790, 1987. Thijs LG, et al: The use of nuclear medicine procedures in the diagnosis of Budd-Chiari syndrome, Clin Nucl Med 3:389–392, 1978. Tripathi D, et al: Good clinical outcomes following transjugular intrahepatic portosystemic stent-shunts in Budd-Chiari syndrome, Aliment Pharmacol Ther 39:864–872, 2014. Turrion VS, et al: Retrospective evaluation of liver transplantation for cirrhosis: a comparative study of 100 patients with or without previous portosystemic shunt, Transplant Proc 23:1570–1571, 1991. Tyagi S, et al: Balloon dilatation of inferior vena cava stenosis in BuddChiari syndrome, J Assoc Physicians India 4:378–380, 1996. Uhl MD, et al: Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome, Dig Dis Sci 41:1494–1499, 1996. Ulrich F, et al: Eighteen years of liver transplantation experience in patients with advanced Budd-Chiari syndrome, Liver Transpl 14:144–150, 2008. Valla D-C: The diagnosis and management of the Budd-Chiari syndrome: consensus and controversies, Hepatology 38:793–803, 2003. Valla D-C: Primary Budd-Chiari syndrome, J Hepatol 50:195–203, 2009. Valla D, et al: Risk of hepatic vein thrombosis in relation to recent use of oral contraceptives, Gastroenterology 90:807–811, 1986. Valla D, et al: Hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria: a spectrum from asymptomatic occlusion of hepatic venules to fatal Budd-Chiari syndrome, Gastroenterology 93:569–575, 1987. Vanderbroucke JP, et al: Increased incidence of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation, Lancet 344:1453–1457, 1994. Vaughan DE, et al: PGE1 accelerates thrombolysis by tissue plasminogen activator, Blood 73:1213–1217, 1989. Versluys B, et al: Prophylaxis with defibrotide prevents veno-occlusive disease in stem cell transplantation after gemtuzumab ozogamicin exposure [letter], Blood 103:1968, 2004. Victor S, et al: Budd-Chiari syndrome and pericaval filariasis, Trop Gastroenterol 15:161–168, 1994. Vogelzang R, et al: Budd-Chiari syndrome CT observations, Radiology 163:329–333, 1987. Vons C, et al: Results of portal systemic shunts in Budd-Chiari syndrome, Ann Surg 203:366–370, 1986. Wadleigh M, et al: Hepatic veno-occlusive disease: pathogenesis, diagnosis and treatment, Curr Opin Hematol 10:451–462, 2003. Walker ID: Thrombophilia in pregnancy, J Clin Pathol 53:573–580, 2000. Wang Z: Recognition and management of Budd-Chiari syndrome: experience with 143 patients, Chin Med J 102:338–346, 1989. Wang Z, et al: Recognition and management of Budd-Chiari syndrome: report of one hundred cases, J Vasc Surg 10:149–156, 1989. Wang ZG, et al: Evolution of management for Budd-Chiari syndrome: a team’s view from 2564 patients, ANZ J Surg 75:55–63, 2005. Warren RL, et al: Treatment of Budd-Chiari syndrome with streptokinase [abstract], Gastroenterology 62:200, 1972.

1271.e6 PART 7  HEPATIC DISEASE  Section I  Infective, Inflammatory, and Congenital Wu T, et al: Budd-Chiari syndrome: surgical treatment of 45 cases, Chin Med J 103:400–405, 1990. Wu T, et al: Percutaneous balloon angioplasty of inferior vena cava in Budd-Chiari syndrome, Int J Cardiol 83:175–178, 2002. Xu K, et al: Budd-Chiari syndrome caused by obstruction of the hepatic inferior vena cava: immediate and 2-year treatment results of transluminal angioplasty and metallic stent placement, Cardiovasc Intervent Radiol 19:32–36, 1996. Yamada R, et al: Segmental obstruction of the hepatic inferior vena cava treated by transluminal angioplasty, Radiology 149:91–96, 1983. Yamada R, et al: Percutaneous transluminal angioplasty in the treatment of Budd-Chiari syndrome: twelve years’ results and new devices. In Proceedings of the second international symposium on BuddChiari syndrome, Kyoto, Japan, IPL-2, 1991. Yamamoto S, et al: Budd-Chiari syndrome with obstruction of the inferior vena cava, Gastroenterology 54:1070–1084, 1968. Yang X-L, et al: Successful treatment by percutaneous balloon angioplasty of Budd-Chiari syndrome caused by membranous obstruction

of inferior vena cava: 8-year follow-up study, J Am Coll Cardiol 28:1720–1724, 1996. Zafrani ES, et al: Drug-induced vascular lesions of the liver, Arch Intern Med 143:495–502, 1983. Zeitoun G, et al: Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting, Hepatology 30:84–89, 1999. Zhang F, et al: The outcomes of interventional treatment for BuddChiari syndrome: systematic review and meta-analysis, Abdom Imaging 40:601–608, 2015. Zhang Q, et al: Catheter-directed thrombolytic therapy combined with angioplasty for hepatic vein obstruction in Budd-Chiari syndrome complicated by thrombosis, Exp Ther Med 6:1015–1021, 2013. Zhao R, et al: Identification of an acquired JAK2 mutation in polycythemia vera, J Biol Chem 280:22788–22792, 2005. Zimmerman MA, et al: Budd-Chiari syndrome, Clin Liver Dis 10:259– 273, 2006.