ORIGINAL ARTICLE. Received February 8, 2011; accepted May 25, 2011.

Transcription

1 LIVER TRANSPLANTATION 18: , 2012 ORIGINAL ARTICLE Transjugular Intrahepatic Portosystemic Shunt for the Treatment of Sinusoidal Obstruction Syndrome in a Liver Transplant Recipient and Review of the Literature Isabel Campos-Varela, 1,7,8 Lluís Castells, 1,7,8 Cristina Dopazo, 2 Mercedes Pérez-Lafuente, 3 Helena Allende, 4 Oscar Len, 5 Lluís Llopart, 6 Victor Vargas, 1,7,8 and Ramón Charco 2 1 Liver Unit, Department of Internal Medicine; 2 Liver Transplant Unit, Department of HPB-Surgery and Transplant; 3 Radiology Department; 4 Pathology Department; 5 Infectious Diseases Department; 6 Critical Care Department, Hospital Universitari Vall d Hebron, Institut de Recerca (VHIR), Barcelona, Spain; 7 Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); and 8 Universitat Autónoma de Barcelona, Departament de Medicina Sinusoidal obstruction syndrome (SOS) is a rare, life-threatening clinical syndrome resulting from sinusoidal congestion, and it is characterized by hepatomegaly, ascites, weight gain, and jaundice. The frequency of this condition after liver transplantation (LT) is low, but when SOS is severe and refractory to medical therapy, the ultimate solution is retransplantation. We describe a patient with SOS after LT who was successfully treated by the placement of a transjugular intrahepatic portosystemic shunt (TIPS). Although information on this approach is scarce because of the low incidence of SOS in LT patients, we review the available literature on treating this condition with a TIPS. On the basis of the reported information and our patient s outcome, we suggest that prompt TIPS placement can be considered for SOS when medical treatment fails. Nonetheless, a formal assessment and prospective studies are needed to confidently indicate TIPS placement in this situation. Liver Transpl 18: , VC 2011 AASLD. Received February 8, 2011; accepted May 25, In November 2008, a 54-year-old man underwent liver transplantation (LT) for end-stage liver disease due to a chronic hepatitis B virus (HBV) infection and alcohol abuse. The patient concurrently had a human immunodeficiency virus (HIV) infection; he had no history of opportunistic infections and a total CD4 þ cell count of 536 cells/ml. At the time of LT, he had an undetectable viral load and was receiving antiretroviral therapy (245 mg of tenofovir daily, 200 mg of emtricitabine daily, and 400 mg of raltegravir every 12 hours). His postoperative course was uneventful, and there was no evidence of rejection or infectious complications. His immunosuppressive regimen included tacrolimus and prednisone. For the prevention of recurrent HBV infections, he received tenofovir, emtricitabine, and long-term hepatitis B immune globulin following the standard hospital protocol. Two months after transplantation, the patient was admitted to the hospital because of ascites, peripheral edema (weight gain ¼ 16 kg or 21%), hepatomegaly, and impaired renal function. The serum creatinine concentration was 2.7 mg/dl, and the glomerular filtration rate, which was calculated with the Modification of Diet in Renal Disease formula, was 25.6 ml/ minute. He had no evidence of proteinuria or urinary Abbreviations: HBV, hepatitis B virus; HIV, human immunodeficiency virus; HVPG, hepatic venous pressure gradient; LT, liver transplantation; SCT, stem cell transplantation; SOS, sinusoidal obstruction syndrome; TIPS, transjugular intrahepatic portosystemic shunt. Address reprint requests to Isabel Campos-Varela, MD, Department of Internal Medicine (Liver Unit), Vall d Hebron University Hospital, Passeig Vall d Hebron , Barcelona, Spain Telephone: ; FAX: ; icampos@vhebron.net DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2011 American Association for the Study of Liver Diseases.

2 202 CAMPOS-VARELA ET AL. LIVER TRANSPLANTATION, February 2012 Figure 2. A liver biopsy specimen showed centrilobular liver cell loss with fibrosis, sinusoidal ectasia, hemorrhaging, and a stenotic hepatic outflow venule: (A) Masson s trichrome staining and (B) reticulin staining (400). Figure 1. Under fluoroscopic guidance, a 7-Fr balloon-tipped catheter (Boston Scientific Medi-Tech, Natick, MA) was guided into the main right hepatic vein for wedged and free hepatic venous pressure measurements. Venography demonstrated suprahepatic vein patency, and there was no evidence of stenosis: (A) an anteroposterior view, (B) an oblique view, and (C) with the occlusion balloon. sediment abnormalities, and his laboratory values were as follows: aspartate aminotransferase level, 62 IU/L; alanine aminotransferase level, 70 IU/L; bilirubin level, 0.9 mg/dl; international normalized ratio, 1.9; and albumin level, 2.8 g/dl. His test results were negative for hepatitis B surface antigen and hepatitis C virus antibodies. The ascitic fluid was found to be a transudate with a protein level of 2 g/dl, a normal cell count, and a negative culture. The patient required repeated large-volume paracenteses, volume expansion with intravenous albumin, and diuretic treatments. An ultrasound study showed massive ascites and no obstruction of the portal vein or suprahepatic veins. The echocardiography findings were normal. Paracentesis with 5 L of fluid was performed, and the hepatic venous pressure gradient (HVPG) was determined. No vascular stenoses were observed (Fig. 1). The HVPG was 22 mm Hg, the inferior vena cava pressure was 10 mm Hg, the free hepatic venous pressure was 10 mm Hg, and the wedge hepatic venous pressure was 32 mm Hg. Transjugular liver biopsy showed no signs of rejection or hepatitis, but congestion and perivenular hepatocyte necrosis were detected; fibrous material occluded some of the central veins and interfered with venous drainage. These features are consistent with sinusoidal obstruction syndrome (SOS; Fig. 2). Twenty days after the patient s hospitalization, a transjugular intrahepatic portosystemic shunt (TIPS) stent (10 mm 10 cm 8 cm Viatorr stent graft, W. L. Gore & Associates, Inc., Flagstaff, AZ) was inserted (Fig. 3), and the patient s HVPG fell to 8 mm Hg. After the TIPS placement, his renal function returned to normal (creatinine level ¼ 1.1 mg/dl), his diuretic requirements progressively decreased, and his ascites was resolved completely with no changes in the immunosuppressive treatment. At the 20-month follow-up visit, the patient was asymptomatic, and his laboratory values were as follows: bilirubin level, 0.9 mg/dl; aspartate

3 LIVER TRANSPLANTATION, Vol. 18, No. 2, 2012 CAMPOS-VARELA ET AL. 203 Figure 3. The TIPS was created with a Viatorr stent graft (10 mm 10 cm 8 cm). The patient s HVPG dropped to 8 mm Hg. aminotransferase level, 29 IU/L; alanine aminotransferase level, 33 IU/L; and creatinine level, 1.2 mg/dl. The HIV viral load was undetectable. The TIPS remained patent, and an ultrasound study found no signs of ascites. DISCUSSION SOS, which was formerly known as veno-occlusive disease, was reported first in South Africa in 1920 and later in Jamaica in This clinical syndrome is characterized by hepatomegaly, ascites, weight gain, and jaundice 1-3 and is caused by sinusoidal congestion, which can result from radiation injuries or the ingestion of alkaloids 4,5 or other toxins (eg, alcohol, oral contraceptives, toxic oil, and terbinafine). The most common cause, however, is hematopoietic stem cell transplantation (SCT). 6,7 SOS has also been described after solid organ transplantation, mainly in the context of azathioprine toxicity The easily recognizable central vein occlusion occurring in patients with this condition inspired the name hepatic veno-occlusive disease. Nonetheless, central vein involvement is not an essential feature because the disease process originates in the sinusoids. 11 Thus, SOS has been proposed as a more appropriate term for the full spectrum of the disease (ie, with or without the involvement of veins). 12 SOS after SCT is a well-recognized condition in the literature, but there are fewer reports of SOS after solid organ transplantation. 13 In the largest series of kidney transplant recipients, the reported incidence ranged from 2% to 5%. 10 The incidence of clinical SOS in the largest series of LT recipients was 1.9%; this value contrasts with the 43% rate of silent reversible hepatic venular stenosis reported in another study. 9 In this setting, SOS is considered a part of the cellular rejection process with an endothelial predilection and is mainly related to azathioprine. There are no reports of a relationship between SOS and tacrolimus or any of the antiviral drugs used in our patient. In 1995, Buckley et al. 14 described an association between SOS and HIV/acquired immune deficiency syndrome; they found a frequency of 7.3% in HIVinfected patients (mainly intravenous drug abusers). However, their study was performed in the era before highly active antiretroviral therapy, and similar findings have not been reported by other researchers. 15 In the case reported here, an examination of the explanted liver showed no signs of SOS. Therefore, a role of HIV in our patient s condition seems unlikely. The classic presentation of SOS is a triad of weight gain caused by fluid retention, tender hepatomegaly, and hyperbilirubinemia with no apparent cause. In patients who have undergone SCT and are receiving cyclophosphamide, SOS occurs within 10 to 20 days, whereas with other regimens, SOS appears later. 16 In LT recipients, the interval before SOS is longer (a mean of 9 weeks after the procedure). 17 Posttransplant ascites is a serious clinical dilemma, and persistent ascites can be indicative of venous outflow obstruction syndrome; therefore, SOS should be excluded. 18 The diagnosis of SOS is based on clinical criteria, and other entities, such as fibrosing cholestatic hepatitis due to HBV or hepatitis C virus reinfection, must be ruled out. The currently accepted clinical diagnostic criteria for SOS 19 have been described and validated in SCT recipients. In LT patients, to confirm the diagnosis of SOS and exclude other causes of ascites, the HVPG should be determined, and liver biopsy should be performed. HVPG has both diagnostic and prognostic value for these patients because values greater than 20 mm Hg correlate with a poor prognosis. On the basis of a large cohort of SCT recipients, Bearman et al. 20 developed a model for estimating the survival of SOS patients; this model includes the serum bilirubin level, the percentage of body weight gained, ascites, and peripheral edema. Severe SOS was associated with a 98% mortality rate 100 days after SCT. Similarly, a body weight increase greater than 20% was associated with a dismal prognosis. 16 Prognostic models for LT patients with SOS have not been validated, and additional studies are needed. Treatment for SOS is controversial, although there is more experience with SCT patients. In mild cases, supportive measures lead to spontaneous recovery in approximately 70% to 85% of patients, but severe cases require specific treatments. 17 Because of microthrombosis and fibrin deposition in the hepatic venules, the objective of any treatment is the promotion of fibrinolysis with or without anticoagulation. 21 Treatment with recombinant human tissue plasminogen activator (with or without heparin) has been described, but patients should be treated early in the course of SOS. In patients with multiorgan failure, the risk of severe bleeding is increased, and recombinant

4 204 CAMPOS-VARELA ET AL. LIVER TRANSPLANTATION, February 2012 TABLE 1. Summary of LT Recipients With TIPS-Treated SOS in the Literature Study Patients (n) Age (Years) Sex Immunosuppression Time to Diagnosis After LT (Weeks) Severity Follow-Up (Months) Lerut et al Cyclosporine 8 Severe Died (1999) Sebagh et al Male Cyclosporine, azathioprine, 567 Severe Re-LT (1999) and steroids Senzolo et al Male Tacrolimus 11 Severe Alive (10) (2006) 57 Female Sirolimus and 3 Severe Alive (13) mycophenolate mofetil Kitajima et al Male Tacrolimus, mycophenolate 26 Severe Alive (21) (2010) mofetil, and steroids 58 Female Tacrolimus, mycophenolate 9 Severe Re-LT mofetil, and steroids Present Case 1 54 Male Tacrolimus and steroids 8 Severe Alive (20) tissue plasminogen activator should be avoided. Another treatment option is defibrotide, which is a polydeoxyribonucleic acid derived from porcine and bovine mucosa that has profibrinolytic and antithrombotic properties but no significant systemic anticoagulant effects. The response rate has been approximately 41%, and there have been no severe adverse events. 22 To the best of our knowledge, there is only 1 published report on SOS after LT; 2 patients were given defibrotide, and only 1 survived. 23 The last treatment option is LT, but underlying malignancies and multiorgan failure contraindicate LT in the setting of SCT. TIPS use has been reported for the treatment of SOS associated with SCT, but there was no improvement in the prognosis of the patients. 17 Because of these poor results, recent clinical practice guidelines do not recommend SOS as an indication for TIPS placement. 24 This recommendation was made in the setting of multiorgan failure, which predicts a poor prognosis regardless of the treatment. When severe SOS that is refractory to medical treatment occurs in an LT recipient, TIPS placement can be considered. 17 Some authors 25 have suggested that for TIPS placement to be effective, it should be performed before the syndrome is far advanced. This case presented several factors that are associated with severe SOS and a poor prognosis: an HVPG greater than 20 mm Hg, peripheral edema, ascites, a body weight increase greater than 20%, and renal failure 20 (although the serum bilirubin level was not increased). This situation prompted us to attempt TIPS placement, which proved to be effective for resolving the patient s condition despite his poor prognosis. We believe that TIPS placement is a potentially useful treatment for severe SOS associated with LT, although there is very little experience with this population; a formal assessment is recommended. We carried out a MEDLINE search with the terms sinusoidal obstruction syndrome after liver transplant, veno-occlusive disease after liver transplant, and transjugular intrahepatic portosystemic shunt, and we found 6 additional cases of TIPS-treated SOS among LT recipients. 8,26,27 The clinical characteristics and outcomes of these patients and our case are listed in Table 1. Only 1 patient received azathioprine, and 3 of the 7 received mycophenolate mofetil. All but 1 of the TIPStreated LT recipients with SOS survived (86%). Two required liver retransplantation (29%), and the other 4 patients progressed favorably with resolution of their ascites and clinical improvement. In 3 of these 4 asymptomatic patients, liver biopsy was performed 5, 7, and 21 months after TIPS; histological resolution was observed in only 1 case. Similarly, histological improvement after TIPS placement was reported in only 1 of 3 patients with SOS after SCT. 25 We could not determine whether the reported failures were due to a misdiagnosis of SOS 17 or to the fact that TIPS placement was performed too late. In most of the related reports of LT patients, the interval between the onset of SOS and TIPS treatment is not mentioned, and this factor may have an influence on the success of TIPS placement. In agreement with other authors, 16,27,28 we believe that when there is no response to medical treatment, prompt TIPS placement should be contemplated. When multiorgan failure ensues, the window of opportunity may close. Nonetheless, the precise benefits of an early intervention require a formal assessment. Because TIPS treatment has provided an acceptable outcome for LT patients with SOS (a complete response for 4 patients, a partial response for 2 patients, and death for 1 patient), this procedure can be considered one of the current management options for these patients. When TIPS placement fails to resolve SOS, liver retransplantation is the last available treatment option. In conclusion, SOS is rare after LT but should be suspected when a liver recipient develops refractory ascites; the prompt diagnosis of this condition is important. In severe SOS cases refractory to medical treatment, early TIPS placement can resolve the condition or mitigate it and allow time for liver retransplantation. Because of the infrequency of SOS in LT

5 LIVER TRANSPLANTATION, Vol. 18, No. 2, 2012 CAMPOS-VARELA ET AL. 205 recipients, it would be worthwhile for future prospective studies to focus on this event in their evaluations. ACKNOWLEDGMENT The authors thank Celine Cavallo for English language edition and Esther Delgado for her secretarial work. REFERENCES 1. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984;4: Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995;85: Richardson P, Guinan E. The pathology, diagnosis, and treatment of hepatic veno-occlusive disease: current status and novel approaches. Br J Haematol 1999;107: Bras G, Jelliffe DB, Stuart KL. Veno-occlusive disease of liver with nonportal type of cirrhosis, occurring in Jamaica. AMA Arch Pathol 1954;57: Zuckerman M, Steenkamp V, Stewart MJ. 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