Hematologic Disorders

Hematologic diseases that cause vascular thrombosis are the most common conditions that predispose to BCS in North America and Western Europe. Of disorders with thrombotic tendencies, polycythemia rubra vera is the most frequent, 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). In our series of 77 cases of BCS, 31% had polycythemia rubra vera, which is associated with BCS in some distinctly different ways compared with the classic disease. For one thing, it is found in young adults, rather than in middle-aged and elderly patients, and it is responsive to treatment with hydroxyurea or anagrelide, which should be started as soon as the disease is discovered and should be continued for life. In our experience, the disease runs a benign course if treated. Finally, polycythemia rubra vera associated with BCS is compatible with a long life, if it is treated with hydroxyurea.

Paroxysmal nocturnal hemoglobinuria 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 of the hematologic disorders associated with hepatic vein thrombosis, but particularly in paroxysmal nocturnal hemoglobinuria, thrombosis of other blood vessels outside of the liver has sometimes been observed. These cases of multiple sites of thrombosis have involved the portal, splenic, and superior mesenteric veins; pelvic veins; deep calf veins; splanchnic arteries; pulmonary artery; coronary arteries; and cerebral arteries (Peytremann et al, 1972).

As hematologic diagnosis has become progressively more sophisticated, many other thrombogenic conditions have been identified in BCS, including other myeloproliferative states—such as essential thrombocythemia, primary erythrocytosis, and myelofibrosis—and thrombophilic states, such as protein C deficiency, protein S deficiency, antithrombin III deficiency, and 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; Vandenbroucke et al, 1994). Subjects with the factor V Leiden mutation, which leads to activated protein C resistance, have a 5-fold to 10-fold 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 myeloproliferative disorders. 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, over 50% of the cases of BCS have been found to be due to an underlying chronic myeloproliferative disorder (Primignani et al, 2006).

It cannot be overemphasized that every patient found to have BCS should undergo a thorough hematologic evaluation. The workup that we perform is an expansion of the workup proposed by Mahmoud and Elias (1996) and others (Hirschberg et al, 2000; Valla, 2009) and is shown in Box 77.2. With these studies, it should be possible to diagnose all of the predisposing thrombogenic hematologic disorders known to be associated with BCS. If an evaluation such as this is done uniformly, it is highly likely that the incidence of idiopathic BCS will continue to decline.

Oral Contraceptives

An increased incidence of thromboembolic phenomena involving various blood vessels and organs in women taking oral contraceptives has been well established. The first case of BCS associated with use of oral contraceptives 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 oral contraceptive 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 oral contraceptives was believed to be responsible for 9.4% of the cases of BCS during the period 1960 to 1980. Valla and associates (1986) reported that the relative risk of hepatic vein thrombosis among oral contraceptive users was close to that of stroke, myocardial infarction, and venous thromboembolism. In our series of 77 cases of BCS, 23% of patients gave a history of oral contraceptive use. The incidence is even higher if the denominator consists only of the number of women in each series. In our series, 49% of the 37 women with BCS used oral contraceptives.

Some authors have proposed that oral contraceptives are not a primary cause of BCS but contribute to thrombosis only if there is an underlying hematologic disorder (Valla et al, 1986). In our series, no hematologic disease was identified in users of oral contraceptives, but until relatively recently, our patients did not undergo the extensive hematologic workup shown in Box 77.2. The duration of usage of oral contraceptives before the diagnosis of BCS has ranged from 2 weeks to 10 years. In addition to causing BCS, oral contraceptives have been linked to other liver disorders, including VOD, portal vein thrombosis, cholestasis, hepatocellular adenoma, focal nodular hyperplasia, and possibly hepatocellular carcinoma and angiosarcoma (Zafrani et al, 1983).

Pregnancy and Postpartum

BCS has been observed in women during pregnancy and, more commonly, 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 the cases of BCS 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 cases (15.2%) of BCS after pregnancy; 8 of the patients died, and 7 were lost to follow-up after discharge from the hospital. The hypercoagulable state that is known to occur during pregnancy is presumed to be responsible for the association of BCS with this condition, although only 1 of our 77 cases of BCS occurred during pregnancy or postpartum.

Malignant Neoplasms

Malignant neoplasms were responsible for 13.4% of the collected cases of BCS reported by Parker (1959), 8.8% of the collected cases reported by Mitchell and colleagues (1982), and 12% of the cases reported by Powell-Jackson and colleagues (1982). Because we do not operate on patients with BCS caused by cancer, none of our 77 patients had malignant neoplasms. Occlusion of the suprahepatic IVC by invasive tumors has been the cause of BCS in many cases. The most common cancers associated with BCS are hepatocellular carcinoma, renal cell carcinoma, adrenal carcinoma, and leiomyosarcoma of the IVC. Other malignancies that rarely have caused 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 responsible for 3% of the collected cases of BCS reviewed by Parker (1959), 9.9% of the collected cases reported by Mitchell and colleagues (1982), and none of the cases in sizable series reported in more recent years, including our own series. The most common infections associated with BCS are those caused by parasites, particularly amebic liver abscess, hydatid disease, and schistosomiasis (see Chapters 67 and 68). Syphilitic gumma of the liver accounted for 1.8% of the cases in Parker’s review 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.

Trauma

Abdominal trauma has uncommonly predisposed to the development of BCS. Trauma was responsible for 1.2% of the collected cases of BCS reported by Parker (1959) and 2.4% of the collected cases reviewed by Mitchell and colleagues (1982). Blunt and penetrating trauma have been implicated in occasional cases 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. Included among these are Behçet disease, Sjögren syndrome, mixed connective tissue disease, sarcoidosis, and rheumatoid arthritis. Numerous cases of BCS in patients with Behçet disease, including five of our own, have been described (Bazraktar et al, 1997; Orloff & Orloff, 1999).

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 over many years, and most patients will have developed extensive hepatic fibrosis and cirrhosis and portal hypertension 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, lipoid nephrosis, and protein-losing enteropathy.

Budd-Chiari Syndrome

The liver receives about one fourth of the cardiac output via 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. The increased intrahepatic pressure causes extravasation of plasma from the liver sinusoids and lymphatics with formation of ascites. 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. 77.1). Ischemia, pressure necrosis, and atrophy of the parenchymal cells in the 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. The rapidity with which cirrhosis develops is related to the severity of outflow obstruction, but it is not unusual for cirrhosis to occur within a matter of months (Parker, 1959).

FIGURE 77.1 Photomicrographs of preoperative liver biopsy specimens obtained from Budd-Chiari syndrome (BCS) patients 4 (A) and 5 (B) in our series, showing a typical picture of BCS consisting of intense centrilobular congestion and necrosis with widespread loss of hepatocytes. A thrombosed hepatic vein is seen in the center in A (×50).

(From Orloff MJ, Johansen KH, 1978: Treatment of Budd-Chiari syndrome by side-to-side portacaval shunt: experimental and clinical results. Ann Surg 188:494-512.)

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; hence the timing of therapy has profound implications with regard to 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 enter directly into the retrohepatic IVC and drain the caudate lobe and small central regions of the right and left lobes of the liver. Our BCS experience indicates that all three major hepatic veins usually are occluded, although occasionally the occlusion is limited to one or two of the major veins. The small hepatic veins that join the retrohepatic IVC, particularly the veins draining the caudate lobe, often are spared.

In most cases of 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. Retrograde propagation of the thrombus into smaller hepatic veins is commonly found. Prograde propagation of the thrombus from the hepatic veins into the IVC, with partial or complete occlusion of the IVC, sometimes occurs and markedly changes the therapeutic approach and prognosis. It is important to determine by imaging studies that include angiography and pressure measurements whether the IVC has become involved in the occlusive process.

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). 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. 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 et al, 2002). Most of the cases have run a chronic course before discovery, and when first seen by a physician, patients have had extensive hepatic fibrosis or cirrhosis with portal hypertension and all of its manifestations. The therapeutic considerations in patients with MOVC differ from those in patients with BCS caused by obstruction of the hepatic veins.

Venoocclusive Disease

VOD of the liver, more recently called sinusoidal obstruction syndrome, may mimic BCS clinically, because both conditions involve hepatic venous outflow obstruction. VOD involves the sinusoids and the central and sublobular hepatic veins within the liver, however, 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 a toxic agent, such as a pyrrolizidine alkaloid, antineoplastic drug, radiation, or a stem cell transplant. 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—usually is detected early in the course of the disease.

Symptoms

Findings on Physical Examination (Signs)

Hepatic Angiography and Pressures

The diagnostic study of greatest value in BCS, particularly if surgical therapy is contemplated and venous pressure measurements are required, is angiographic examination of the IVC and hepatic veins with pressure measurements (Clain et al, 1967; Kreel et al, 1967; Redman, 1975; Tavill et al, 1975). This study usually is 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 subjects with ascites (Fig. 77.2). Patency of the IVC is a prerequisite for portacaval shunt (PCS) and is a crucial finding (see Chapter 76A, Chapter 76B, Chapter 76C, Chapter 76D, Chapter 76E ). 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. 77.3). This finding usually is not clinically significant (Clain et al, 1967; Kreel et al, 1967; Redman, 1975; Tavill et al, 1975).

FIGURE 77.2 Inferior venacavogram in Budd-Chiari syndrome patient 3 in our series, showing a widely patent inferior vena cava; pressure was 62 mm saline.

(From Orloff MJ, Johansen KH, 1978: Treatment of Budd-Chiari syndrome by side-to-side portacaval shunt: experimental and clinical results. Ann Surg 188:494-512.)

FIGURE 77.3 Inferior venacavogram in Budd-Chiari syndrome patient 6 in our series, showing a patent inferior vena cava with side-to-side compression in its retrohepatic course by the enlarged liver. IVC pressure at this time was 102 mm saline.

(From Orloff MJ, Johansen KH, 1978: Treatment of Budd-Chiari syndrome by side-to-side portacaval shunt: experimental and clinical results. Ann Surg 188:494-512.)

The most important angiographic finding is the demonstration by hepatic venography of occlusion or marked narrowing of the major hepatic veins. Sometimes it is not possible to find patent orifices of any of the hepatic veins, which is indirect evidence that all of the major hepatic veins are occluded. Usually it is possible, however, to enter at least one major hepatic vein and to show the presence of a thrombus or of narrowing and distortion of the vein (Fig. 77.4A). Injection of dye in the wedged position often shows a characteristic spiderweb pattern of small hepatic venous collaterals connecting to portal or systemic veins (see Fig. 77.4B). Wedged hepatic vein pressure (WHVP) usually is markedly elevated, which reflects the obstruction to hepatic venous outflow. In patients with hepatic vein occlusion alone, IVC pressure is substantially lower than WHVP.

FIGURE 77.4 Hepatic venogram in Budd-Chiari syndrome patient 2 in our series. A, Filling defects (thrombi) in the right hepatic vein occupy much of the lumen. B, Typical spiderweb pattern of small venous collaterals shown by injection of dye with the catheter in the wedged position.

(From Orloff MJ, Johansen KH, 1978: Treatment of Budd-Chiari syndrome by side-to-side portacaval shunt: experimental and clinical results. Ann Surg 188:494-512.)

In our series of 77 patients, angiographic studies showed occlusion of the hepatic veins alone in 51 patients and occlusion of both the hepatic veins and IVC in 26 patients. In all of our patients with hepatic vein occlusion alone, all three major hepatic veins were occluded.

A spiderweb pattern was observed in 48 patients (62%). WHVP was markedly elevated in all patients in whom it was measured. In the 51 patients with thrombosis confined to the hepatic veins, the IVC was patent, with relatively normal pressures for patients with ascites, ranging from 62 to 160 mm saline (Table 77.3). Many patients had moderate compression of the retrohepatic IVC by the enlarged liver, but invariably WHVP was substantially higher than IVC pressure—a crucial finding. In contrast, in the 26 patients with IVC occlusion, IVC pressure and WHVP were similar. All patients had stretched and attenuated hepatic artery branches within the liver and a patent portal vein (PV).

Table 77.3 Results of Diagnostic Studies in 77 Patients with Budd-Chiari Syndrome Treated by the Authors