Budd-Chiari Syndrome Secondary to Antiphospholipid Syndrome

Introduction Abbreviations used in this article: aCL, anticardiolipin antibodies, aPL, antiphospholipid antibodies, APS, antiphospholipid syndrome, BCS, Budd-Chiari syndrome, INR, international normalized ratio, LA, lupus anticoagulant, SLE, systemic lupus erythematosus, TIPS, transjugular intrahepatic portosystemic shunt Budd-Chiari syndrome (BCS) is characterized by structural and functional abnormalities of the liver caused by obstruction to the outflow of hepatic venous blood (13). The consequent liver dysfunction depends on the extension and velocity of instauration of the obstruction. BCS is clinically characterized by abdominal pain, hepatomegaly, and ascites, and the clinical presentation may range from nearly asymptomatic to fulminant liver failure (9,21). The etiology is unknown in a limited proportion of patients, and several myeloproliferative disorders and hypercoagulable states have been implicated, including polycythemia vera, essential thrombocythemia, paroxysmal nocturnal hemoglobinuria, antithrombin, protein C and protein S deficiency, resistance to activated protein C, factor V Leiden, G20210A factor II gene mutation, use of oral contraceptives, pregnancy, and postpartum state (11,13,34,58). In some studies (41,53), a relationship between BCS and elevated levels of antiphospholipid antibodies (aPL) has been suggested. The latter are a group of autoantibodies directed to a complex of phospholipids and proteins and include lupus anticoagulant (LA) and anticardiolipin antibodies (aCL). Several studies have shown that patients with aPL are prone to repeated episodes of thrombosis and spontaneous fetal losses. The association of aPL with these clinical events has been termed the antiphospholipid syndrome (APS) (28), and it is considered “primary” if not associated with other underlying disease (4) or “secondary” if it appears in association with other autoimmune disorders, mainly systemic lupus erythematosus (SLE) (17). In this report, we describe 4 new cases of patients with BCS and aPL. In addition, we review the literature supporting the idea that such an association may be a feature of APS, and present the clinical and immunologic characteristics of 43 patients with this association. Methods We performed a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to identify all cases of BCS associated with aPL published in English, French, and Spanish from 1983 (when APS was first defined [3]) through September 2000 (keywords:Budd-Chiari syndrome, hepatic vein thrombosis, phospholipid, antiphospholipid, antiphospholipid antibodies, anticardiolipin, anticardiolipin antibodies, coagulation inhibitor, lupus anticoagulant), and scanned the bibliographies of all articles for references not identified in the initial search. Only cases with well-documented clinical summaries and relevant information were included. Data were summarized using a standardized data form, including sex, age, previous abortions or thrombotic events, immunologic features, treatment, and evolution. For practical purposes, BCS was classified as fulminant BCS, defined as severe hepatic failure developing within 2 weeks of onset of symptoms, and subacute or chronic BCS, defined as rapid (within 3 months) or slow (more than 3 months) development of severe clinical symptoms (for example, variceal bleeding, ascites). Patients from our center were considered to have BCS secondary to APS if they had the following: thrombosis of hepatic veins demonstrated by ultrasonographic Doppler scans or magnetic resonance imaging techniques; presence of LA or positivity for aCL. LA was detected using activated partial thromboplastin time, diluted Russell viper venom time and tissue thromboplastin inhibition test. The tests were also performed in mixtures with control plasmas or phospholipids following the guidelines of the Subcommittee for the Standardization of Lupus Anticoagulants of the International Society of Thrombosis and Hemostasis (10). The aCL were measured using a standardized enzyme-linked immunosorbent assay (Cheshire Diagnostics, Chester, UK). Results were expressed in IgG and IgM units (GPL and MPL) and reported as negative (≤15 units), low positive (16–25 units), moderate positive (26–40 units), and high positive (>40 units); absence of known thrombophilia as defined by absence of deficiencies in protein C, protein S, antithrombin or plasminogen, and absence of protein C resistance, factor V Leiden mutation, or prothrombin gene G20210A mutation; and normal result of the following procedures: blood and leukocyte differential counts, paroxysmal nocturnal hemoglobinuria immunophenotypic study, and bone marrow cytogenetic study, bone marrow biopsy, leukocyte alkaline phosphatase score, vitamin B12, erythropoietin serum levels, and peripheral blood erythroid progenitor culture to exclude an underlying chronic myeloproliferative disorder. According to the above criteria, 4 new and previously unpublished cases of BCS secondary to APS are reported as illustrative case studies. In order to identify factors predisposing to BCS in patients with APS, we compared the main clinical and immunologic features of the present series with a series of 100 APS patients previously described by our group (36). Comparisons were performed by chi-square test or analysis of variance (ANOVA). Case Reports Case 1 A 40-year-old previously healthy woman developed right upper abdominal pain and vomiting. She had no history of abortion or oral contraceptive use. On admission, physical examination revealed mild ascites and hepatomegaly 4 cm below the costal margin. Laboratory investigations showed the following values: normal blood and leukocyte differential counts; aspartate transferase, 350 IU/L (normal, 10–40 IU/L); alanine transferase, 572 IU/L (normal, 10–40 IU/L); γ-glutamyltransferase, 199 IU/L (normal, 5–40 IU/L); alkaline phosphatase, 305 IU/L (normal, 90–290 IU/L); and total bilirubin, 4.5 mg/dL (normal, 0.2–1.0 mg/dL). Tests for antibodies to hepatitis A virus, hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus were negative. With the suspicion of BCS, an ultrasonographic Doppler scan of abdominal vessels was performed, which revealed right and middle suprahepatic vein thrombosis, while the flow through the left suprahepatic vein was reduced. The diagnosis of BCS was confirmed by a hemodynamic study, and further investigation for the cause of BCS was negative. Antinuclear antibodies, antibodies against extractable nuclear antigens, and rheumatoid factor were not detected. LA was not present and IgM aCL were negative, but IgG aCL were positive on 2 occasions (27.7 GPL and 28.4 GPL). We concluded that the patient had subacute BCS secondary to primary APS. Oral anticoagulation was started, and, due to the development of progressive liver failure, a transjugular intrahepatic portosystemic shunt (TIPS) was inserted. The patient was in good health until 1 year later, when the ascites recurred. An ultrasonographic Doppler scan showed a TIPS dysfunction that was corrected by insertion of a new coaxial stent and angioplasty. Case 2 A 35-year-old woman had an acute femoral arterial thrombosis in 1995 with no obvious explanation. In 1998, she was admitted to our hospital complaining of abdominal pain and jaundice. She had no history of abortion or oral contraceptive use. Blood and leukocyte differential counts were normal and liver tests were only slightly abnormal. An ultrasonographic Doppler scan revealed right and middle suprahepatic vein thrombosis, which was confirmed by a hemodynamic study. Antibodies to hepatitis A virus, hepatitis B surface antigen, and hepatitis C virus were negative. LA was not present and IgM aCL were negative, but IgG aCL were positive on 3 occasions (34.6 GPL, 39.7 GPL, and 29.5 GPL). Oral anticoagulation with acenocoumarol was started, but 10 months later the patient developed portal hypertension with variceal bleeding, and a TIPS was inserted. The patient was in good health while on anticoagulant treatment but 6 months later she developed ascites. A hemodynamic study showed TIPS dysfunction secondary to intimal hyperplasia, which was corrected by angioplasty (Figure 1).Fig. 1: Angiogram showing transjugular intrahepatic portosystemic shunt (TIPS) dysfunction secondary to intimal hyperplasia (arrows), which was corrected by angioplasty.Case 3 A 39-year-old man was diagnosed as having SLE in February 2000 (photosensitivity; cutaneous biopsy; lymphopenia; antinuclear antibodies, 1:320; anti-Ro, anti-La, anti-Sm, and anti-RNP antibodies positivity; anti-dsDNA antibodies, 4.8 U/mL [normal < 7 U/mL]). LA was present, IgM aCL were positive on 2 occasions (20.5 MPL and 19.8 MPL), and IgG aCL were negative. Three months later, the patient was admitted to our hospital complaining of abdominal pain and ascites. Laboratory investigations revealed the following abnormal values: γ-glutamyltransferase, 188 IU/L; alkaline phosphatase, 1,992 IU/L; and total bilirubin, 3.5 mg/dL. Antibodies to hepatitis A virus, hepatitis B surface antigen, and hepatitis C virus were negative. Ultrasonographic Doppler scan and magnetic resonance imaging studies showed an atrophic right hepatic lobe and an enlarged left lobe with right and left suprahepatic vein thrombosis, which was confirmed by a hemodynamic study. Oral anticoagulation was instituted, but, due to the persistence of marked ascites despite diuretic treatment and a low-sodium diet, a TIPS had to be inserted 4 months later. Case 4 A 31-year-old man presented in 1998 with abdominal pain and jaundice. Physical examination revealed mild ascites and hepatomegaly. Laboratory investigations showed abnormal values as follows: alanine transferase, 68 IU/L; aspartate transferase, 69 IU/L; γ-glutamyltransferase, 452 IU/L; alkaline phosphatase, 524 IU/L; and total bilirubin, 2.9 mg/dL. Antibodies to hepatitis B surface antigen and hepatitis C virus were negative. An ultrasonographic Doppler scan revealed right and middle suprahepatic vein thrombosis whereas the left suprahepatic vein was patent. Further investigation of the cause of BCS was negative. Antinuclear antibodies, antibodies against extractable nuclear antigens, and rheumatoid factor were negative. LA was present and IgG aCL were positive on 2 occasions (22.5 GPL and 23.4 GPL), while IgM aCL were negative. Oral anticoagulant was started, but due to progressive impairment of liver function, with persistence of ascites, a side-to-side portocaval shunt was constructed in March 1999. Four months later, the ascites persisted due to inferior vena cava compression secondary to hypertrophy of the caudate lobe, and a TIPS was inserted. The patient remained in good health until 1 year later when, despite oral anticoagulation, he developed ascites and abdominal pain. A hemodynamic study revealed intimal hyperplasia causing TIPS dysfunction, and a new coaxial stent was therefore inserted. Results A total of 72 patients with BCS associated with aPL were found in the literature search, but 33 of them corresponding to 9 articles were not included because their clinical and immunologic characteristics were not described (1,4,8,11,21,22,25,46,62). Because of this, 43 patients—39 from the literature (2,5–7,14,15,20,23,30,33,37,40–44,47,48,51,53–57,59–61) plus 4 from our hospital—with BCS secondary to APS were finally reviewed. Our 4 cases belonged to a series from our hospital of 22 patients with BCS treated with TIPS partially described earlier (19). In these 4 cases (18% of the series), APS represented the sole etiologic factor for BCS. General characteristics General clinical features of these patients are shown in Table 1. There were 29 (67%) females and 14 (33%) males. Mean age of patients was 30.8 ± 12.3 years (range, 2–64 yr). Thirty-two (74%) patients had primary APS and 8 (19%) were categorized as having APS associated with SLE. The other 3 patients had APS associated with rheumatoid arthritis, lupus-like disease, and ulcerative colitis, respectively.TABLE 1: Clinical characteristics of patients with Budd-Chiari syndrome and antiphospholipid antibodiesClinical presentation and precipitating factors In 28 (65%) patients, BCS was the first clinical manifestation of APS, whereas 9 (21%) patients had a previous history of major venous occlusion. Deep venous thrombosis was reported in 8 (19%) patients, and in 2 was accompanied by pulmonary embolism. One patient had axillary and subclavian vein thrombosis and another had splenic vein thrombosis. Arterial occlusion occurred in 1 patient in the form of thrombosis of the femoral artery. Spontaneous fetal losses had occurred in 10 (35%) of the 29 female patients. Cutaneous nodules were attributed to APS in 2 (5%) patients. One patient (Patient 25) was fortuitously found to have LA without any clinical symptom of APS and developed BCS 3 years later. In Patient 33, aPL were negative during the height of her BCS, but positive 6 years later. In 30 (70%) patients, the clinical presentation of BCS was subacute; in 10 (23%), chronic; and in the remaining 3 (7%) (Patients 16, 30, and 33), fulminant. In 2 patients (Patients 30 and 33), fulminant BCS occurred postpartum (specifically, in Patient 30, BCS developed 6 hours after delivery, and in Patient 33, 2 days following cesarean section). The presenting manifestations of BCS were abdominal pain in 24 (56%) patients, abdominal distention in 9 (21%), fever in 8 (19%), vomiting in 3 (7%), and dyspnea in 2 (5%) patients. Physical examination revealed hepatomegaly in 25 (58%) patients, marked ascites in 23 (53%), jaundice in 11 (26%), and splenomegaly in 4 (9%) patients. In 9 of 38 (24%) patients, precipitating factors contributed to the development of BCS (in 5 patients these data were not mentioned). They included ingestion of oral contraceptives in 6 patients, postpartum period in 2 (with post-fetal loss in 1), and major surgical procedure (cesarean section) in 1. Vascular findings and liver of hepatic veins was found in 33 patients, whereas in patients the hepatic of the inferior vena cava was In addition, 3 (7%) patients also presented with portal vein thrombosis, and 1 with and thrombosis. was performed in patients. findings were marked in in in and hyperplasia in was found in only 1 patient with previously diagnosed chronic BCS. Laboratory findings The of the patients in this series is shown in Table 10 9 was reported in patients (in 3 was not reported and in the remaining 6 it was reported only as of in (65%) patients, and Laboratory test was positive in patients. LA was detected in patients and the aCL was positive in patients in which this test was patients were positive for the IgG of aCL, whereas of patients were positive for the IgM LA and aCL positivity were detected in patients. Antinuclear antibodies were positive in (35%) patients, in low 3 patients had or antibodies were found in patients with defined Laboratory findings in patients with Budd-Chiari syndrome and antiphospholipid oral was the treatment, used in patients (in 5 patients treatment was not mentioned). was the only treatment used in patients. In 4 anticoagulation was by treatment or in high were used in 14 patients, for was used in only 3 in 2 for which not to treatment with and in 1 for was used in 4 patients by anticoagulation in 1), and was used in only 1 of surgical such as side-to-side or were performed in 11 patients. angioplasty was performed in 4 patients by oral anticoagulation in Our 4 patients were treated with a TIPS shunt performed by due to the presence of portal hypertension in 3 and progressive liver failure in the secondary to intimal hyperplasia after the of the stent was in 3 patients and was corrected with the insertion of a new coaxial stent and angioplasty. of the 3 patients (Patients and developed dysfunction of the TIPS with an international normalized of and whereas the remaining patient had an of 9 patients presented with development of BCS, only 1 was on anticoagulant The clinical after hepatic vein thrombosis be from the data (in patients the was not but 2 of the 7 patients (Patients 2 and not anticoagulant after diagnosed with BCS had new thrombotic events, 1 of them 6 years after the diagnosis of BCS. 1 patient (Patient presented with obstruction of the inferior vena cava and 14 months after anticoagulation was and another patient (Patient presented with ascites 1 after she to oral One patient (Patient in the of APS, and the remaining 2 (Patients and were treated with With a of 24 months (range, of 25 patients with anticoagulant were in good whereas 6 of the (19%) patients with reported had occurred in 3 patients with primary APS, in 2 patients with defined SLE, and in 1 with lupus-like The of were hepatic failure and due to in a patient with and and APS case of the BCS series with a series of 100 APS patients The of the of the 2 of patients are shown in Table The of clinical and immunologic characteristics was were found only in with a of in patients with BCS in BCS compared with in APS and in which was in the BCS group in BCS in APS latter be by the of portal hypertension in patients with liver impairment secondary to BCS. in 6 cases the of was not of present series of 43 patients with BCS and previous series of 100 patients with BCS has been to several hypercoagulable mainly the chronic myeloproliferative disorders of the association between aPL and BCS, an search for the of hepatic vein thrombosis is of published studies on the of BCS are by the of for levels of antithrombin have been reported in only of 43 (35%) cases levels of protein C in levels of protein S in 11 (26%), and culture of erythroid in 9 cases V Leiden and G20210A factor II gene were only reported in our 4 On the other test blood in was performed in only 14 (33%) and bone marrow cytogenetic and studies in oral was reported in 6 of whereas these data were not in case The presence of aPL has been as the cause of BCS to other the of these antibodies is In our 4 case aPL were the only identified etiologic for BCS, corresponding to of the 22 patients in our patients had a chronic myeloproliferative with a factor V 4 had paroxysmal nocturnal hemoglobinuria, and 1 was for and the etiologic study not In a study, the etiology of hepatic vein thrombosis in a series of patients. In order of 1 or coagulation disorders were present in of these patients, by chronic myeloproliferative in and the of the 2 in With to coagulation disorders, factor V Leiden was found in 7 patients, by aPL in 6 In 2 patients, aPL were associated with chronic myeloproliferative and factor V Leiden, whereas in the aPL were the factor detected. in a series of patients with BCS, the cause of venous obstruction was identified in of the chronic myeloproliferative in APS in paroxysmal nocturnal hemoglobinuria in and in 8 patients the of APS and the clinical and immunologic characteristics of these patients were not In only 2 patients in a series of 43 patients with BCS had LA whereas in another series including BCS patients, APS were not reported in any case (13). The of aPL in BCS is that the liver abnormalities caused by the venous outflow obstruction be in the of these antibodies, which be an secondary to the liver in some cases aPL were detected the onset of BCS, and only 1 patient described in the literature presented hepatic in the that the of aPL was not a of the liver no in clinical and immunologic features were found between patients with BCS secondary to APS in this series and the group of 100 APS patients with other thrombotic events are the clinical of APS, in the venous and arterial with a high from to of patients to series oral anticoagulation was identified as the treatment for of thrombosis In the present only 1 patient presented with the development of BCS was on anticoagulant treatment, and of 25 patients with anticoagulant after BCS diagnosis were in good health with a of 24 of the 7 patients not anticoagulant after BCS was 4 had new thrombotic events, 1 in the of APS, and the remaining 2 were treated with some have reported that anticoagulation was than anticoagulation in the was the range because aPL, LA, may with the prothrombin time the for some patients with APS is in the BCS patients with liver failure, as this also of the partial thromboplastin The shunt dysfunction or reported in the literature from within 6 months to within the first year during a TIPS occurred in of and dysfunction occurred in 3 of 4 patients were treated with TIPS and in the anticoagulation was In this TIPS dysfunction due to or occlusion was a major in a series of patients with BCS, in 5 of 10 patients with ascites, despite anticoagulation Four of these 5 patients had a hypercoagulable such as polycythemia or protein C The above data have been confirmed by a anticoagulation with an than in patients with BCS hyperplasia causing or of the of the shunt is the cause of shunt dysfunction The of this intimal hyperplasia is not but it has been shown that may cause and intimal hyperplasia In this patients with APS and thrombotic events have levels of prothrombin an In BCS, is not a in patients with APS and may be the first clinical manifestation of this no predisposing factor to BCS has been identified in patients with APS. the for for LA and aCL in all cases of hepatic vein thrombosis. In these patients, TIPS may be an treatment for portal but in any case anticoagulation treatment is essential in order to thrombosis. The clinical and immunologic characteristics of 43 patients with Budd-Chiari syndrome (BCS) and antiphospholipid syndrome (APS) from our hospital and from a computer-assisted review of the literature from 1983 through September are (67%) patients were female and 14 (33%) Mean age presentation of BCS was 30.8 ± 12.3 Thirty-two (74%) patients had primary APS, 8 (19%) had defined systemic lupus erythematosus, and the other 3 had APS associated with rheumatoid arthritis, lupus-like syndrome, and ulcerative colitis, In 28 (65%) patients, BCS was the first clinical manifestation of APS, whereas 9 (21%) patients had a previous history of major venous arterial occlusion occurred in 1 and spontaneous fetal losses had occurred in 10 (35%) of the 29 female patients. was reported in of patients, and was detected in LA was demonstrated in of patients and the aCL was positive in of patients. patients were positive for IgG of aCL, whereas were positive for the IgM LA and aCL positivity was detected in of patients. Antinuclear antibodies were positive in of patients, in low was the treatment of the by and of surgical were performed in of patients, and angioplasty in Our 4 patients were treated with a transjugular intrahepatic portosystemic shunt due to the presence of portal hypertension and progressive liver dysfunction after the of the stent was in 3 patients and was corrected with the insertion of a new coaxial stent and angioplasty. 9 patients presented with the development of BCS, only 1 was on anticoagulant 7 patients not anticoagulant after diagnosed with BCS, 4 had new thrombotic of 25 patients with anticoagulant were in good health a of 24 months (range, of the (19%) patients with reported the of hepatic failure and due to and APS case The of the present review the clinical of for the presence of LA and aCL in all patients with hepatic vein thrombosis. In these patients, a transjugular intrahepatic portosystemic shunt may be an treatment for portal but in any anticoagulation is to thrombosis.