Budd-Chiari syndrome (BCS) is a severe liver disorder characterized by hepatic venous outflow obstruction, mainly resulting from thrombosis of the terminal part of the hepatic veins or the inferior vena cava (1). It causes hepatic congestion, ascites, portal hypertension, and collateral circulation between the obstructed and contiguous patent venous territories. During evolution, acute ischemia episodes may lead to liver failure. The main criteria on which a prognosis can be based are the presence of portal thrombosis, the degree of liver failure, age, and difficulty in treating ascites (2). In BCS, thrombosis may be due to myeloproliferative disorders, antiphospholipid syndrome, factor II or factor V Leiden mutation, Behçet disease, paroxysmal nocturnal hemoglobinuria, or coagulation inhibitor deficiency (1,3,4). Essential thrombocythemia (ET) is one of the most frequent myeloproliferative disorders that cause BCS, and in some cases ET is revealed by BCS (3,5–11). Many treatments have been proposed for BCS, routine anticoagulation therapy being recommended as the first therapeutic approach (1). Some short-length stenosis of hepatic veins can be corrected by percutaneous recanalization (3,12). Mesocaval or mesoatrial shunting was until recently the only possible therapeutic option, if liver transplantation was not required (1–3,9,13,14). Transjugular intrahepatic portosystemic shunt (TIPS) was first used as rescue therapy for complete BCS in an adult patient (15). More recently, TIPS has been proposed as an alternative to surgical shunt, aiming at minimal invasiveness (2,3,5,12,16,17). To date, few cases of BCS due to myeloproliferative disorders have been reported in children, with ages ranging between 11 and 16 years (9,10,11,13,16,18), and only a few TIPS procedures have been carried out in adolescents with BCS (2,11,16). We report the case of a 7-year-old girl with BCS and ET in whom the TIPS procedure led to a favorable outcome.
A 7-year-old girl (weight 25 kg, height 127 cm) was seen at the emergency department for abdominal pain, dizziness, and increasing abdominal girth for the previous 2 weeks. The family medical history was remarkable for polycythemia vera in 2 aunts on her mother's side. Clinical examination revealed massive ascites, hepatomegaly, and splenomegaly. The hematological and biochemical data are summarized in Table 1. Blood count revealed thrombocytosis, leukocytosis (segmented granulocytes 84%), and normal erythrocyte count.
Liver tests showed mild cytolysis, cholestasis, and decreased prothrombin time. Abdominal Doppler ultrasonography confirmed the presence of hepatosplenomegaly and suggested BCS because of widening of the right hepatic vein with visible intraluminal thrombus and irregular aspect of the left suprahepatic vein. The middle hepatic vein flow was not detected. Portal hypertension was characterized by an inversion of flow in the portal vein trunk and in the right portal branch and by the presence of portosystemic derivations. Computed tomography confirmed the ultrasonography findings and the diagnosis of BCS. Upper digestive endoscopy showed first-degree esophageal varices. The hematopoietic marrow was hypercellular, with increased megakaryocytic precursor cells. Cytogenetic analysis showed a normal 46XX karyotype excluding BCR-ABL mutation involved in most cases of chronic myelogenous leukemia (19). Culture of the bone marrow progenitor cells revealed spontaneous and selective formation of megakaryocytic colony units (20). A heterozygous Val617Phe JAK2 mutation was present in the bone marrow cells (21–24). This mutation was also found to be heterozygous in genomic DNA extracted from peripheral lymphocytes. These hematological findings fulfilled the criteria for ET. A search for additional prothrombotic risk factors revealed low protein C and S activity values. These changes are thought to reflect a secondary liver cell disorder rather than primary inborn errors associated with an increased risk of thrombosis (25). Both parents exhibited normal protein C and S activity values. Hydroxyurea (20 mg · kg−1 · day−1) treatment was initiated. Thrombocytes decreased to 205 × 109/L. Ascites was refractory to diuretic therapy. Because of an acute increase in serum transaminases (10 times normal), extensive thrombosis was suspected. As a first-step therapy, hypocoagulation with intravenous heparin was initiated, and systemic intravenous thrombolysis was performed (Alteplase, Boehringer Ingelheim, France). Alteplase therapy was adapted from an adult liver unit protocol (A. Plessier, personal communication). An intravenous bolus (10 mg × body surface/1.73) was administered over 2 minutes followed by an intravenous injection of 1 to 1.5 mg · kg−1 · hour−1 over 2 hours with a maximal dose of 180 mg. Thereafter, abdominal Doppler did not show any modification of the thrombus or vascular flows in the suprahepatic veins. Therefore, an attempt to recanalize the right hepatic vein by transjugular catheter angioplasty was performed, but also failed (Fig. 1A). Inferior vena cava venography showed an extrinsic stenosis caused by retrohepatic compression of the vena cava by a hypertrophic Spiegel lobe. Venous pressure in the subhepatic vena cava was 24 mmHg against a 12-mmHg pressure in the right auricle. This pressure gradient did not allow mesocaval shunt surgery. The TIPS procedure was considered and preferred to a mesoatrial shunt, which requires a complex surgical procedure. Two polytetrafluoroethylene-covered stents (Viator, W.L. Gore, Flagstaff, AZ) were placed between the inferior vena cava and the right portal vein (Fig. 1B). Hypocoagulant heparin therapy was continued by use of subcutaneous injections of low molecular weight heparin. After the TIPS procedure, the child's clinical status improved dramatically. The ascites disappeared and did not recur after the discontinuation of diuretics. The liver test results remained stable, with subnormal transaminase values, and prothrombin time value improved (61%). Abdominal Doppler ultrasonography confirmed permeability of the stents with progressive disappearance of portal hypertension signs (Fig. 1C). Six months after the TIPS procedure, the child was in good clinical condition with stable biochemical and hematological parameters under anticoagulation and hydroxyurea therapies.
The spontaneous mortality of BCS in adults approaches 70% at 1 year and 90% at 3 years (1,2). In children, mortality that is either spontaneous or caused by liver failure after shunt surgery may involve 25% of cases (9). In adults, BCS is often associated with an activation of the hemostatic system due to thrombophilic anomalies or clonal disorders of hematopoiesis as myeloproliferative disorders (1,3–8,11). In children, myeloproliferative disorders associated with BCS are rare, but in some cases elevated red blood cell or thrombocyte counts have been noted, arousing suspicion of a myeloproliferative disorder (9,10,11,13,16,18,26). This case report shows that BCS can develop in children with ET and that TIPS can be an effective procedure in this severe situation.
In this case, ET diagnosis was confirmed by the typical aspect of the bone marrow, the culture of bone marrow progenitor cells, and the presence of the Val617Phe JAK2 mutation in bone marrow cells (20–24). In patients with BCS, hemodilution, occult bleeding, and hypersplenism due to portal hypertension may mask the changes in blood cell count. Also, myeloproliferative disorders associated with BCS can present with an atypical phenotype, making the conventional diagnostic criteria elusive (19,20,26). Some molecular aberration of the JAK2 gene has been proposed as a noninvasive marker for myeloproliferative disorders (21–24). The Val617Phe JAK2 mutation is a somatic and heterozygous mutation that has been recently reported to occur in some patients with myeloproliferative disorders. Several reports suggest that these patients have an increased rate of thrombosis and often need cytoreductive therapy. In our case, JAK2 mutation was heterozygous but was present both in tumor cells and peripheral lymphocytes, likely representing a germline mutation. This fact, along with the presence of other cases of myeloproliferative syndrome in the family, suggests a familial genetic predisposition to thrombosis. In cases of BCS and myeloproliferative syndrome, cytoreductive therapy is often necessary in addition to anticoagulant therapy. In our case, hydroxyurea treatment was adapted to ensure a normal platelet count.
Many treatments have been proposed for BCS. The rarity of BCS in childhood has precluded important therapeutic trials. In adults, therapeutic strategies have changed during recent years, aiming at minimal invasiveness (3). Plessier et al (3) have reported excellent results in a strategy of 4 successive steps for acute BCS: anticoagulation therapy, and cytoreductive drug in case of associated myeloproliferative disorder; percutaneous recanalization; TIPS; and liver transplantation as a final option. This rational strategy has been reported to be effective in several patients (2,3,5,11,12,16,17). According to the symptoms, we consider that the BCS case reported here was acute. We first started intravenous anticoagulation and thrombolysis, which unfortunately failed, as did the attempt at percutaneous recanalization of the right suprahepatic vein. Until recently, the gold standard of therapy for BCS treatment in children was considered to be portosystemic surgical shunt, a procedure that may be uncertain in a case of advanced BCS with massive ascites (2). Sometimes, as was seen in our patient, hypertrophy of the Spiegel lobe leads to increased pressure in the inferior vena cava, which makes a mesocaval shunt impossible. In this situation, a mesoatrial shunt may be considered, but it represents a difficult surgical procedure. For this reason, the TIPS procedure was considered the most appropriate approach to this severe BCS (15). Owing to the length between the inferior vena cava and the right portal vein branch, 2 covered TIPS were placed. Hypocoagulant heparin therapy was maintained to prevent TIPS obstruction. After this successful TIPS procedure, disappearance of Spiegel lobe hypertrophy and expansion of lower vena cava are expected in the long term, making mesocaval shunt an alternative therapeutic option in case of TIPS dysfunction. It is proposed that in case of failure of steps 1 and 2 of the above-mentioned strategy, TIPS should be considered for children with severe BCS before shunt surgery or liver transplantation is considered. In a recent report of a child with polycythemia vera and BCS, liver transplantation was performed immediately after failure of percutaneous recanalization (10). According to the data presented here, we hypothesize that this child may have benefited from the TIPS procedure after the failure of suprahepatic vein recanalization.
The authors thank Dr F. Gauthier, Pediatric Surgery Unit; Dr P. Durand, Pediatric Intensive Care Unit; and Dr C. Baujard, Anesthesiology Unit, Bicêtre Hospital; Dr J. Landmann-Parker, Pediatric Hematology Unit, Trousseau Hospital; Dr N. Casadevall, Biology Unit, Hotel Dieu Hospital; and Dr A. Bennaceur Griscelli, Biology Unit, Paul Brousse Hospital, Paris, France, for their helpful participation, and Dr P. Lykavieris for careful reading of the manuscript.
1. Zimmerman MA, Cameron AM, Ghobrial RM. Budd-Chiari syndrome. Clin Liver Dis 2006; 10:259–273.
2. Murad SD, Valla DC, de Groen PC, et al
. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004; 39:500–508.
3. Plessier A, Sibert A, Consigny Y, et al
. Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome. Hepatology 2006; 44:1308–1316.
4. Brancaccio V, Iannaccone L, Margaglione M, et al
. Multiple thrombophilic factors in a patient with Budd-Chiari syndrome. Clin Lab Haematol 2002; 24:61–63.
5. Brunerova L, Bartakova H, Jankovska M, et al
. The Budd-Chiari syndrome in a patient with primary thrombocythemia treated with interferon alfa and transjugular portosystemic shunt. Cas Lek Cesk 2004; 143:198–201.
6. Corredoira JC, Gonzalez M, Casariego E, et al
. Budd-Chiari syndrome as a preceding phase of essential thrombocythemia. Sangre (Barc) 1989; 34:381.
7. Anger BR, Seifried E, Scheppach J, et al
. Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases. Klin Wochenschr 1989; 67:818–825.
8. Garza Trasobares E, Gonzalez Sanz-Agero P, et al
. Budd-Chiari syndrome in a case of essential thrombocythemia. Rev Esp Enferm Apar Dig 1988; 73:64–66.
9. Gentil-Kocher S, Bernard O, Brunelle F, et al
. Budd-Chiari syndrome in children: report of 22 cases. J Pediatr 1988; 113:30–38.
10. Cario H, Pahl HL, Schwarz K, et al
. Familial polycythemia vera with Budd-Chiari syndrome in childhood. Br J Haematol 2003; 123:346–352.
11. Cobo F, Cervantes F, Garcia-Pagan JC, et al
. Budd-Chiari syndrome associated with chronic myeloproliferative syndromes: analysis of 6 cases. Med Clin (Barc) 1996; 107:660–663.
12. Eapen CE, Velissaris D, Heydtmann M, et al
. Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome. Gut 2006; 55:878–884.
13. Melear JM, Goldstein RM, Levy MF, et al
. Hematologic aspects of liver transplantation for Budd-Chiari syndrome with special reference to myeloproliferative disorders. Transplantation 2002; 74:1090–1095.
14. Lang H, Oldhafer KJ, Kupsch E, et al
. Liver transplantation for Budd-Chiari syndrome: palliation or cure? Transpl Int 1994; 7:115–119.
15. Opitz T, Buchwald AB, Lorf T, et al
. The transjugular intrahepatic portosystemic stent-shunt (TIPS) as rescue therapy for complete Budd-Chiari syndrome and portal vein thrombosis. Z Gastroenterol 2003; 41:413–418.
16. Safka V, Hulek P, Krajina A, et al
. Budd-Chiari syndrome and TIPS: twelve years' experience. Cas Lek Cesk 2005; 144(Suppl 3):38–42.
17. Khuroo MS, Al-Suhabani H, Al-Sebayel M, et al
. Budd-Chiari syndrome: long-term effect on outcome with transjugular intrahepatic portosystemic shunt. J Gastroenterol Hepatol 2005; 20:1494–1502.
18. Min AD, Atillasoy EO, Schwartz ME, et al
. Reassessing the role of medical therapy in the management of hepatic vein thrombosis. Liver Transpl Surg 1997; 3:423–429.
19. Pagliuca A, Mufti GJ, Janossa-Tahernia M, et al
. In vitro colony culture and chromosomal studies in hepatic and portal vein thrombosis: possible evidence of an occult myeloproliferative state. Q J Med 1990; 76:981–989.
20. Valla D, Casadevall N, Lacombe C, et al
. Primary myeloproliferative disorder and hepatic vein thrombosis: a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med 1985; 103:329–334.
21. Primignani M, Barosi G, Bergamaschi G, et al
. Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis. Hepatology 2006; 44:1528–1534.
22. Cheung B, Radia D, Pantelidis P, et al
. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol 2006; 132:244–245.
23. Patel RK, Lea NC, Heneghan MA, et al
. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology 2006; 130:2031–2038.
24. Bellanne-Chantelot C, Chaumarel I, Labopin M, et al
. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 2006; 108:346–352.
25. Dubuisson C, Boyer-Neumann C, Wolf M, et al
. Protein C, protein S and antithrombin III in children with portal vein obstruction. J Hepatol 1997; 27:132–135.
26. Lazareth I, Delarue R, Priollet P. When should a myeloproliferative syndrome be suggested in vascular medicine? J Mal Vasc 2005; 30:46–52.