LIVER TRANSPLANTATION 20:130–139, 2014
REVIEW
Transjugular Intrahepatic Portosystemic Shunts in Liver Transplant Recipients Alexander R. Bonnel,1 Chalermrat Bunchorntavakul,2 and K. Rajender Reddy3 Department of Medicine, Baylor College of Medicine, Houston, TX; 2Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Bangkok, Thailand; and 3Division of Gastroenterology/Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
1
The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure used to relieve the signs and symptoms of portal hypertension in patients with liver disease. The most common indications for placement are refractory ascites and variceal hemorrhage. In properly selected candidates, TIPS placement can serve as a bridge to liver transplantation. Expertise in TIPS placement after transplantation has significantly increased, which has allowed the procedure to become a viable option for retransplant candidates suffering the consequences of recurrent portal hypertension due to portal vein thrombosis, recurrent liver disease, or hepatic venous outflow obstruction (HVOO). However, TIPSs in liver transplant recipients are associated with a lower clinical response rate and a higher rate of complications in comparison with patients with native liver disease, and they are, therefore, generally reserved for patients with a Model for End-Stage Liver Disease (MELD) score 15 and 12 in patients with HCV. The role of TIPS placement in nonliver transplant recipients has been well studied in large trials, and it translates well into clinical applicability to candidates for orthotopic liver transplantation (OLT). However, the experience with OLT recipients is heterogeneous and restricted to small series. Thus, we focus here on reviewing the current literature and discussing the proper use of TIPSs in liver transplant recipients. Liver Transpl 20:130C 2013 AASLD. 139, 2014. V Received August 16, 2013; accepted October 12, 2013. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is used in the management of portal hypertension because this nonsurgical procedure significantly reduces pressure in the portal vein by creating a channel between the portal vein and a hepatic vein branch. Decreasing the portal pressure reduces the risk of variceal bleeding and is an acceptable treatment modality for refractory ascites (RA) as well. Additional less frequent indications include portal hypertension events related to portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). TIPS complications that occur to variable degrees include inadvertent puncture of the liver cap-
sule, shunt dysfunction, liver failure, and hepatic encephalopathy (HE). Survival after TIPS placement is known to be related to the severity of liver disease as indicated by the Model for End-Stage Liver Disease (MELD) score at the time of shunt placement, and it is, therefore, used with caution in patients with high MELD scores.1 TIPSs are created in candidates for orthotopic liver transplantation (OLT) to manage complications of portal hypertension and to preserve their candidacy for transplantation. Special considerations for TIPSs in OLT candidates are taken into account in order to minimize technical challenges during OLT. The vast
Abbreviations: CF, cystic fibrosis; CP, Child-Pugh; ESLD, end-stage liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic encephalopathy; HVOO, hepatic venous outflow obstruction; MELD, Model for EndStage Liver Disease; NASH, nonalcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PSG, portosystemic gradient; PVT, portal vein thrombosis; RA, refractory ascites; SBP, spontaneous bacterial peritonitis; SOS, sinusoidal obstruction syndrome; TIPS, transjugular intrahepatic portosystemic shunt; VH, variceal hemorrhage; VOD, veno-occlusive disease. There was no grant support for this project, and the authors have no conflicts of interest to declare. Address reprint requests to K. Rajender Reddy, M.D., Division of Gastroenterology/Hepatology, Department of Medicine, University of Pennsylvania, 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104. Telephone: 215-662-4311; Fax: 215-349-5915; E-mail: rajender.reddy@uphs. upenn.edu. DOI 10.1002/lt.23775 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
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majority of studies of TIPS placement in transplant candidates have found the procedure to have no impact on intraoperative complications, transplant outcomes, or overall patient survival2-5; recent but limited data suggest that it may in fact promote early graft function by increasing portal flow to the graft, possibly through the effect of reducing collateral blood flow.6 After OLT, a TIPS can be placed to treat portal hypertension–related complications of recurrent endstage liver disease (ESLD) and venous obstructions. TIPS placement in OLT recipients was once thought to be more technically challenging because of their altered anatomy; however, recent experience suggests otherwise.7,8 Because a TIPS in the post-OLT state is often required for patients who have significant liver disease and portal hypertension, the clinical response and survival rates after TIPS placement have been noted to be lower than those for pretransplant patients.9,10 Furthermore, immunosuppression increases the risk of infections, renal failure, and HE after TIPS placement in OLT recipients.10,11
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTS IN LIVER TRANSPLANT RECIPIENTS After liver transplantation, portal hypertension and related complications may evolve because of recurrent disease, allograft failure/rejection, and vascular or biliary complications.12 Indications for a TIPS in the transplant recipient mostly match those for a TIPS in pretransplant patients (ie, variceal bleeding and RA13-16; Table 1). However, the hepatic venous pressure gradient is known to be lower after liver transplantation, so variceal bleeding may not be as common as it is in the pretransplant setting.7 The retrospective nature, small sample sizes, lengths of follow-up, and patient selection of available studies are challenges to determining the success of TIPSs in these patients. Several reports suggest that TIPS placement is an effective treatment for addressing early complications of liver transplantation such as PVT, HVOO, and delayed graft function due to ongoing portal hypertension (Fig. 1).6,7,11,16-19,23
Special Technical Considerations When it was first introduced for OLT recipients, TIPS placement was thought to be more challenging because of the altered anatomy of the hepatic vessels after OLT. Unlike the standard OLT approach of endto-end anastomoses at the suprahepatic and infrahepatic vena cava, the piggyback and cavocaval techniques are not uncommon and require a different approach during TIPS placement.8,13 A Cochrane Database review found the piggyback technique, which involves the preservation of the recipient’s retrohepatic vena cava, to be a safe and effective technique for transplantation.24 In this case, the left internal jugular vein, rather than the right, is used for TIPS placement.7 After cavocaval OLT with a side-to-
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side anastomosis of the donor’s retrohepatic vena cava, a gun-sight approach is used to create a direct cava-to-portal vein TIPS.7,25 Past studies reported multiple attempts at creating a TIPS in these patients because of technical inability or failed cannulation of the portal or hepatic veins.11,12,19 However, the most recent data from interventional radiologists indicate that transplanted livers do not pose any additional technical difficulty in comparison with native livers.8 Although these data remain limited to whole graft recipients, they suggest that technical expertise has significantly improved for TIPS placement in OLT recipients. This supports previous data showing that the reported technical complication rate for this procedure has dropped below the accepted 5% threshold, which is a quality measure determined by the Society of Interventional Radiology.17,26 Successful TIPS placement in increasingly challenging cases, such as patients with small-for-size syndrome after living donor transplantation, has also been described and indicates continued progress in the field of TIPS creation in transplant recipients.12,27
Complications Following Transjugular Intrahepatic Portosystemic Shunt Placement A lower rate of shunt stenosis has been reported after posttransplant TIPS placement versus pretransplant TIPS placement. Approximately 10% to 20% of the stents in OLT recipients require revisions because of the development of strictures or occlusions,9,10,12-14,22,28 whereas up to 70% do in nontransplant patients.1 However, the largest case-control study thus far reported no such complications in its posttransplant group.19 It must be noted that most of the data come from the era of uncoveredstent use and may not be applicable to the current days of polytetrafluoroethylene-covered stents. Immunosuppressive therapies may play a role in reducing rates of shunt stenosis. Experimental studies suggest that tacrolimus and mammalian target of rapamycin inhibitors (everolimus and sirolimus) have inhibitory effects on both smooth muscle cell proliferation and endothelial progenitor cells.29-31 Furthermore, this is supported by the experience with drug-eluting stents in vascular interventions, for which immunosuppressive therapies have been known to significantly reduce stenosis.32,33 Although there are reasons to believe that there are factors in liver transplant recipients that are favorable for shunt patency, it needs to be recognized that sirolimus use has been associated with hepatic artery thrombosis, which potentially presents a risk for precipitating liver failure after TIPS placement.34 Thus, research is needed on shunt patency, specifically after TIPS in the posttransplant setting, and particularly on the mechanistic role of various immunosuppressants. Transplant recipients face a high risk of infection, renal failure, and neurological complications after TIPS placement. Sepsis is the most common complication and cause of death and occurs in approximately 20% to 50% of reported cases.10,11,13,19 The risk of infection in OLT recipients is attributable to their immunosuppressive
7: RA (7)
4: RA (4)
Stewart et al.15 (2004)
Patel et al.7 (2005) Vasta et al.16 (2005)
11: VH (4) and RA (7)
2: SOS (2)
Senzolo et al.18 (2006)
Kim et al.11 (2008)
6: RA (5) and VH (1)*
Van Ha et al.17 (2006)
5: RA (5)
8: VH 1 RA (2) and RA (6)
8: RA (5), VH (1), hydrothorax 1 RA (1), and redo biliary surgery (1) 12: RA (6) and VH (6)
Patients (n): Indications (n)
Abouljoud et al. (1999)
Amesur et al. (1999)
Lerut et al.14 (1999)
Study
Recurrent HCV (7), HVOO (2), PVT (2), chronic rejection (1), recurrent PSC (1), and unknown (1)
Chronic rejection (1), biliary cirrhosis (1), acute rejection (1), HVOO (1), and chronic hepatitis of unknown cause (2) SOS (2)
HCV (2), HVOO (1), and rejection (1) Delayed graft function (5)
HCV (7)
Not reported
Recurrent HCV (5), recurrent HBV (1), lymphoproliferative disease (1), and VOD (1) Recurrent HCV (10), recurrent PBC (1), and unknown (1)
Etiology of Recurrent Portal Hypertension (n)
MELD score 5 16.4 6 6.2
—
—
—
CP class B (4)
—
—
CP class A (1), CP class B (3), and CP class C (2)
CP class B (5) and CP class C (2)
CP Class (n) or MELD Score
Portal hypertension was resolved for 2/2 (100%). 1/2 (50%) had a histological resolution of SOS. 4/7 (57%) with RA responded (nonresponders had chronic renal insufficiency). For VH, 2/4 (50%) had a response.
5/5 (100%) responded. 1/5 (20%) had complete resolution. RA was resolved for 4/5 (80%).† For VH, 1/1 (100%) had a response.
Not reported
4/6 (67%) with RA recovered. For 4/6 (66%), VH was controlled. For 7/8 (88%), RA and portal hypertension were resolved. Not reported
8/8 (100%) responded to TIPS.
Clinical Response
TABLE 1. Summary of Studies of TIPS Placement in OLT Recipients
Complications/Survival
4/11 (36%) developed infections. 9/11 (81%) had new or worse HE. 4/8 (50%) had acute renal failure. N514 of the study and not the N511 relevant to our review.
None
2/6 (33%) died.
For 1/8 (12.5%), TIPS was occluded within 3 months. 3/8 (37.5%) died. 4/7 (57%) died. TIPS placement was associated with a high risk of death (relative risk 5 2.86). There was no difference in the MELD score between patients with a TIPS who died and patients with a TIPS who survived. Not reported 1/4 (25%) died. 0 had HE. 0 had stenosis.
6/8 (75%) had new or worse HE. The 1-year survival rate was 50%. 3 died from liver failure. 2/6 (33%) RA patients died of liver failure within 1 week.
132 BONNEL, BUNCHORNTAVAKUL, AND REDDY LIVER TRANSPLANTATION, February 2014
12
19: RA (19)
26: RA (26)
22: RA (14) and VH (8)
Feyssa et al.10 (2011)
King et al.19 (2011)
10: RA (7), VH (1), and hydrothorax (2)
18: VH (2) and RA (16)
Patients (n): Indications (n)
Saad et al.9 (2010)
Finkenstedt et al.13 (2009)
Choi et al. (2009)
Study
Vascular abnormalities (7), HVOO (4), recurrent HCV (3), recurrent PBC (2), recurrent PSC (2), chronic rejection (1), VOD (1), unknown (1), and cholangiopathy (1)
—
Recurrent HCV or HBV (15)
Recurrent HCV (11), de novo HCV (1), HBV (1), small-for-size syndrome (1), recurrent sarcoidosis (1), and unknown (3) Ductopenic rejection (5), recurrent HCV (4), and PVT (1)
Etiology of Recurrent Portal Hypertension (n)
MELD score 5 13.4 6 5.1
MELD score 5 15
MELD score 5 16 6 4.8
MELD score 5 20
MELD score 5 16
CP Class (n) or MELD Score
TABLE 1. Continued
15/22 (68%) had a reduction in PSG to 15 was significantly associated with decreased survival.
7/10 (70%) had HE. 1 had TIPS dysfunction. 9/10 (90%) died. 5/9 (56%) died of sepsis. The median survival time was 3.3 months.
3/18 (17%) had to undergo a second attempt. 9/12 (75%) died after 3 months.
Complications/Survival
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Patients (n):
Etiology of Recurrent
HCV (21), alcohol (6), HCV/alcohol (1), HBV (3), cryptogenic (3), NASH (1), CF (1), PSC (1), and sarcoidosis (1)
*Two pediatric patients [RA (1) and VH (1)] were included. † For 3 of the 4 adults (75%), RA was resolved.
Saad et al.8 (2013) 38: RA (34) and VH (4)
HCV (9), HCC (3), alcohol (2), and PBC (1)
15: RA (12), hydrothorax (2), and VH (1)
El Atrache et al.22 (2012)
HCV (19)
19: RA (11), hydrothorax (6), and RA 1 hydrothorax (2)
Ghinolfi et al.21 (2012)
HBV/alcohol (1)
Portal Hypertension (n)
1: SOS (1)
Indications (n)
Campos-Varela et al.20 (2012)
Study
MELD score 5 17 6 5
MELD score 5 15.8 6 5.8
MELD score 5 12.4 6 3.2
—
or MELD Score
CP Class (n)
TABLE 1. Continued
Whole graft OLT recipients did not pose additional technical difficulties. For 11/34 (32%), RA was resolved.
7/12 (58%) had a complete resolution of RA.
RA was resolved completely, and the patient remained asymptomatic at 20 months. For 7/19 (37%), RA was resolved. For 4/6 (67%), hydrothorax was resolved.
Clinical Response
1/19 (5%) died because of sepsis after 35 days. 6/19 (32%) had HE within 1 month. Survival for patients with a pre-TIPS MELD score 12 did not differ from survival for a control group. There was 1/15 (7%) post-TIPS graft failure. 2 /15 (13%) had HE. 3 /15 (20%) had a shunt occlusion requiring revision. 1 /15 (7%) died from sepsis, 1 died from lung cancer, and 1 /15 (7%) died from congestive heart failure. Earlier allograft dysfunction was more likely with partial or no resolution of RA, but there was no significant difference in survival between complete and partial responders to TIPS. 7/38 (18%) had HE. The mortality rate at 30 days was 7/38 (18%). The mortality rate at 90 days was 10/38 (26%).
None
Complications/Survival
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Figure 1. Summary of the considerations for and outcomes of TIPS placement in the early and late posttransplant periods.
therapies. However, recent data did not show the rate of infectious complications among OLT recipients to be significantly higher than the rate among pretransplant patients,19 in contrast to the findings of a previous casecontrol study.11 Patients with ESLD are often in a state of cirrhosis-associated immune dysfunction.35 Therefore, the conflicting results of recent studies may be explained by differences in the extent of cirrhosis-associated immune dysfunction within each group of TIPS patients. Before periprocedural prophylaxis is routinely recommended, as some authors have suggested,11,13 a further evaluation of the risk of infection after TIPS placement among OLT recipients is needed. Acute renal failure directly following TIPS placement has been encountered in approximately 20% of OLT recipients.10,11 Renal dysfunction in OLT recipients is attributable to a number of factors such as long-term calcineurin inhibitor use, and pretransplant renal dysfunction is due to 1 or more factors, including hepatorenal syndrome, diabetes, and hypertension.36 As a result, radiographic contrast during TIPS placement may precipitate the development of renal failure after the procedure. Calcineurin inhibitors are known to cause neurological complications such as encephalopathy, seizures, psychological disorders, stroke, tremor, and posterior reversible encephalopathy syndrome.37 In OLT recipients, new or worsening HE after TIPS has been documented in 25% to 80% of cases.9-11,13,14,19 Previous findings suggest that OLT recipients may be prone to encephalopathy because of the added neurotoxicity of immunosuppressive drugs.11,14 However, recent data did not show a higher rate of HE after TIPS placement in OLT recipients versus pre-OLT TIPS patients.19 Therefore, the association between immunosuppression and the extent of HE in OLT recipients after TIPS placement remains controversial.
Clinical Response to a Transjugular Intrahepatic Portosystemic Shunt The therapeutic response to TIPSs in OLT recipients is highly variable and is influenced by various factors,
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such as pretransplant conditions, posttransplant complications, and the severity of the recurrent liver disease.35-37 Despite some conflicting data, the overall clinical response rate to TIPSs in liver transplant recipients appears to be lower than that in pretransplant patients.9,15,17,21,38 This difference appears to be more significant for the control of ascites versus the prevention of portal hypertension–related bleeding. Larger studies of liver transplant recipients have reported RA remission rates in the range of 15% to 79%,8-10,19,22 whereas a success rate > 90% has been reported for pretransplant patients.39 Although data on the prevention of portal hypertension–related bleeding in liver transplant recipients are very limited ( 15 in comparison with pretransplant patients with such a MELD score.17,21 In OLT recipients with RA, a 6-month transplant-free survival rate of only 12.5% has been reported.9,10 A significant reason for such poor outcomes is likely related to HCV recur-
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rence. It has recently been suggested that TIPS placement in HCV patients with RA should be reserved for those with a MELD score 12.21 This cutoff likely reflects the extent of HCV disease because the most common cause of death in the study group was progression of HCV. A previous study found TIPS placement in HCV patients to be associated with a high risk of death but did not note a difference in the MELD scores of those who died and those who survived with a TIPS in place.15 Understanding the various mechanisms behind portal hypertension in the setting of recurrent HCV remains a barrier to more refined TIPS candidate selection and warrants caution in these patients. In all OLT recipients with a MELD score > 15 and specifically in OLT recipients with HCV and a MELD score > 12, TIPS placement has been associated with greater failure rates and is, therefore, unlikely to benefit the patient.
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTS FOR VENOUS COMPLICATIONS AFTER LIVER TRANSPLANTATION Portal Vein Thrombosis PVT is a rare but severe complication that typically occurs early after OLT and is often related to abnormal venous reconstruction during surgery in patients with preexisting PVT.23 Interventions for PVT after OLT include surgical thrombectomy, percutaneous thrombolysis, angioplasty, and stent placement, and they are associated with good long-term outcomes.4952 Several case reports have shown a combination of a TIPS and local thrombolysis with or without thrombectomy to be an effective method of transhepatic recanalization of the portal vein.14,53,54 The use of a TIPS in PVT is associated with a reduced risk of bleeding and technical complications in comparison with transhepatic puncture for portal vein interventional procedures.53
Hepatic Venous Outflow Obstruction HVOO after OLT is uncommon and occurs in less than 2% of cases, but it is life-threatening if it is left untreated.55,56 The most common causes of hepatic vein thrombosis are anastomotic complications following transplantation (30%) and disease recurrence (25%).55 TIPS is an effective treatment for hepatic vein thrombosis refractory to medical therapy in the pretransplant setting; however, data on its use in transplant recipients remain limited.7,11 HVOO has been noted to be an independent predictor of mortality after TIPS placement in transplant recipients, and it has been suggested that the pathophysiology of portal hypertension in patients with HVOO is different from the pathophysiology of ESLD-related portal hypertension.19 Yet, a TIPS appears to reduce the complications of portal hypertension and may serve as a bridge to retransplantation in OLT recipients with
LIVER TRANSPLANTATION, Vol. 20, No. 2, 2014
HVOO.57 Because of the small sample size behind the current data on TIPSs in patients with HVOO, concrete recommendations cannot be made. Sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease, includes both central vein and sinusoidal occlusion and has been attributed to acute allograft dysfunction.58,59 Current guidelines do not recommend TIPS placement for SOS1; however, some have suggested that TIPS placement be tried in carefully selected patients with SOS after OLT, particularly if retransplantation is not an option.57,60 A recent case report20 presents TIPS placement as a potentially useful treatment for severe SOS refractory to medical treatment.
CONCLUSIONS TIPS placement is used in the management of portal hypertension–related complications and decreases the risks associated with variceal bleeding, RA, PVT, and HVOO. However, this procedure is not without complications such as transcapsular puncture, shunt thrombosis or stenosis, liver failure, and HE. After OLT, recurrent liver disease and conditions such as venous obstruction may lead to portal hypertension– related complications. Because of the post-OLT altered anatomy, TIPS placement may be challenging and can result in inadvertent puncture of the liver capsule and bleeding complications. However, advances in interventional radiology expertise have made the procedure safe and effective. Immunosuppression may increase the risk of infection, renal failure, and HE after the procedure, although further data in this area are needed. TIPS placement in OLT recipients, in contrast to pretransplant patients, has a lower rate of clinical response, especially in those who undergo the procedure for RA. This finding may be attributable to the increased prevalence of comorbidities among OLT recipients but is likely related to the differences in the pathophysiology underlying RA in this patient population. Recent case-control data suggest that a TIPS may accelerate the progression of advanced liver disease in OLT recipients versus pretransplant patients. Therefore, TIPS placement in general is not recommended for patients with a MELD score > 15 and specifically for HCV patients with a MELD score > 12. In patients with PVT after transplantation, TIPS placement is an important nonsurgical intervention that is associated with good outcomes. TIPS placement in OLT recipients with HVOO should be reserved as a bridge to retransplantation.
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tion for orthotopic liver transplant outcomes. Exp Clin Transplant 2013;11:426-428. 3. Tripathi D, Therapondos G, Redhead DN, Madhavan KK, Hayes PC. Transjugular intrahepatic portosystemic stentshunt and its effects on orthotopic liver transplantation. Eur J Gastroenterol Hepatol 2002;14:827-832. 4. Garcia-Pag an JC, Heydtmann M, Raffa S, Plessier A, Murad S, Fabris F, et al.; for Budd-Chiari SyndromeTransjugular Intrahepatic Portosystemic Shunt Group. TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients. Gastroenterology 2008;135:808-815. 5. Somberg KA, Lombardero MS, Lawlor SM, Ascher NL, Lake JR. Impact of transjugular intrahepatic portosystemic shunts on liver transplantation: a controlled analysis. NIDDK Liver Transplantation Database. Transplant Proc 1995;27:1248-1249. 6. Guerrini GP, Pleguezuelo M, Maimone S, Calvaruso V, Xirouchakis E, Patch D, et al. Impact of TIPS preliver transplantation for the outcome posttransplantation. Am J Transplant 2009;9:192-200. 7. Patel NH, Patel J, Behrens G, Savo A. Transjugular intrahepatic portosystemic shunts in liver transplant recipients: technical considerations and review of the literature. Semin Intervent Radiol 2005;22:329-333. 8. Saad WE, Darwish WM, Davies MG, Kumer S, Anderson C, Waldman DL, et al. Transjugular intrahepatic portosystemic shunts in liver transplant recipients: technical analysis and clinical outcome. AJR Am J Roentgenol 2013;200:210-218. 9. Saad WE, Darwish WM, Davies MG, Waldman DL. Transjugular intrahepatic portosystemic shunts in liver transplant recipients for management of refractory ascites: clinical outcome. J Vasc Interv Radiol 2010;21:218-223. 10. Feyssa E, Ortiz J, Grewal K, Azhar A, Parsikia A, Tufail K, et al. MELD score less than 15 predicts prolonged survival after transjugular intrahepatic portosystemic shunt for refractory ascites after liver transplantation. Transplantation 2011;91:786-792. 11. Kim JJ, Dasika NL, Yu E, Fontana RJ. Transjugular intrahepatic portosystemic shunts in liver transplant recipients. Liver Int 2008;28:240-248. 12. Choi DX, Jain AB, Orloff MS. Utility of transjugular intrahepatic portosystemic shunts in liver-transplant recipients. J Am Coll Surg 2009;208:539-546. 13. Finkenstedt A, Graziadei IW, Nachbaur K, Jaschke W, Mark W, Margreiter R, Vogel W. Transjugular intrahepatic portosystemic shunt in liver transplant recipients. World J Gastroenterol 2009;15:1999-2004. 14. Lerut JP, Goffette P, Molle G, Roggen FM, Puttemans T, Brenard R, et al. Transjugular intrahepatic portosystemic shunt after adult liver transplantation: experience in eight patients. Transplantation 1999;68:379-384. 15. Abouljoud M, et al. Transjugular intrahepatic portosystemic shunts for refractory ascites after liver transplantation. Transplant Proc 2005;37(2):1248-1250. 16. Amesur NB, et al. Transjugular intrahepatic portosystemic shunt in patients who have undergone liver transplantation. J Vasc Interv Radiol 1999;10(5):569-573. 17. Van Ha TG, Hodge J, Funaki B, Lorenz J, Rosenblum J, Straus C, Leef J. Transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis and concomitant portal vein thrombosis. Cardiovasc Intervent Radiol 2006;29:785-790. 18. Senzolo M, Tibbals J, Cholongitas E, Triantos CK, Burroughs AK, Patch D. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation. Aliment Pharmacol Ther 2006;23:767-775.
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19. King A, Masterton G, Gunson B, Olliff S, Redhead D, Mangat K, et al. A case-controlled study of the safety and efficacy of transjugular intrahepatic portosystemic shunts after liver transplantation. Liver Transpl 2011;17:771-778. 20. Campos-Varela I, Castells L, Dopazo C, P erez-Lafuente M, Allende H, Len O, et al. Transjugular intrahepatic portosystemic shunt for the treatment of sinusoidal obstruction syndrome in a liver transplant recipient and review of the literature. Liver Transpl 2012;18:201-205. 21. Ghinolfi D, De Simone P, Catalano G, Petruccelli S, Coletti L, Carrai P, et al. Transjugular intrahepatic portosystemic shunt for hepatitis C virus-related portal hypertension after liver transplantation. Clin Transplant 2012; 26:699-705. 22. El Atrache M, Abouljoud M, Sharma S, Abbass AA, Yoshida A, Kim D, et al. Transjugular intrahepatic portosystemic shunt following liver transplantation: can outcomes be predicted? Clin Transplant 2012;26:657-661. 23. Lodhia N, Salem R, Levitsky J. Transjugular intrahepatic portosystemic shunt with thrombectomy for the treatment of portal vein thrombosis after liver transplantation. Dig Dis Sci 2010;55:529-534. 24. Gurusamy KS, Pamecha V, Davidson BR. Piggy-back graft for liver transplantation. Cochrane Database Syst Rev 2011:CD008258. 25. Haskal ZJ, Duszak R Jr, Furth EE. Transjugular intrahepatic transcaval portosystemic shunt: the gun-sight approach. J Vasc Interv Radiol 1996;7:139-142. 26. Haskal ZJ, Martin L, Cardella JF, Cole PE, Drooz A, Grassi CJ, et al.; for Society of Interventional Radiology Standards of Practice Committee. Quality improvement guidelines for transjugular intrahepatic portosystemic shunts. J Vasc Interv Radiol 2003;14(pt 2):S265-S270. 27. Xiao L, Li F, Wei B, Li B, Tang CW. Small-for-size syndrome after living donor liver transplantation: successful treatment with a transjugular intrahepatic portosystemic shunt. Liver Transpl 2012;18:1118-1120. 28. Abouljoud M, Yoshida A, Kim D, Jerius J, Arenas J, Raoufi M, et al. Transjugular intrahepatic portosystemic shunts for refractory ascites after liver transplantation. Transplant Proc 2005;37:1248-1250. 29. Hamada N, Miyata M, Eto H, Shirasawa T, Akasaki Y, Nagaki A, Tei C. Tacrolimus-eluting stent inhibits neointimal hyperplasia via calcineurin/NFAT signaling in porcine coronary artery model. Atherosclerosis 2010;208:97-103. 30. Matter CM, Rozenberg I, Jaschko A, Greutert H, Kurz DJ, Wnendt S, et al. Effects of tacrolimus or sirolimus on proliferation of vascular smooth muscle and endothelial cells. J Cardiovasc Pharmacol 2006;48:286-292. 31. Miriuka SG, Rao V, Peterson M, Tumiati L, Delgado DH, Mohan R, et al. mTOR inhibition induces endothelial progenitor cell death. Am J Transplant 2006;6:2069-2079. 32. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, et al.; for RAVEL Study Group (Randomized Study With the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions). A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-1780. 33. Daemen J, Serruys PW. Drug-eluting stent update 2007: part I. A survey of current and future generation drugeluting stents: meaningful advances or more of the same? Circulation 2007;116:316-328. 34. Massoud O, Wiesner RH. The use of sirolimus should be restricted in liver transplantation. J Hepatol 2012;56: 288-290. 35. Bonnel AR, Bunchorntavakul C, Reddy KR. Immune dysfunction and infections in patients with cirrhosis. Clin Gastroenterol Hepatol 2011;9:727-738.
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36. Burra P, Senzolo M, Masier A, Prestele H, Jones R, Samuel D, Villamil F. Factors influencing renal function after liver transplantation. Results from the MOST, an international observational study. Dig Liver Dis 2009;41: 350-356. 37. Saner FH, Nadalin S, Radtke A, Sotiropoulos GC, Kaiser GM, Paul A. Liver transplantation and neurological side effects. Metab Brain Dis 2009;24:183-187. 38. Nishida S, Gaynor JJ, Nakamura N, Butt F, Illanes HG, Kadono J, et al. Refractory ascites after liver transplantation: an analysis of 1058 liver transplant patients at a single center. Am J Transplant 2006;6:140-149. 39. Membreno F, Baez AL, Pandula R, Walser E, Lau DT. Differences in long-term survival after transjugular intrahepatic portosystemic shunt for refractory ascites and variceal bleed. J Gastroenterol Hepatol 2005;20:474-481. 40. Cirera I, Navasa M, Rimola A, Garcıa-Pag an JC, Grande L, Garcia-Valdecasas JC, et al. Ascites after liver transplantation. Liver Transpl 2000;6:157-162. 41. Ohkohchi N. Mechanisms of preservation and ischemic/ reperfusion injury in liver transplantation. Transplant Proc 2002;34:2670-2673. 42. Bahirwani R, Reddy KR. Outcomes after liver transplantation: chronic kidney disease. Liver Transpl 2009; 15(suppl 2):S70-S74. 43. Campbell MS, Kotlyar DS, Brensinger CM, Lewis JD, Shetty K, Bloom RD, et al. Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation. Liver Transpl 2005;11:1048-1055. 44. Weber ML, Ibrahim HN, Lake JR. Renal dysfunction in liver transplant recipients: evaluation of the critical issues. Liver Transpl 2012;18:1290-1301. 45. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931940. 46. Lan BY, Landry GM, Tan VO, Bostrom A, Feng S. Ascites in hepatitis C liver transplant recipients frequently occurs in the absence of advanced fibrosis. Am J Transplant 2008;8:366-376. 47. Blasco A, Forns X, Carri on JA, Garcıa-Pag an JC, Gilabert R, Rimola A, et al. Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 2006; 43:492-499. a C, Enea M, R€ ossle M, Wong F. Trans48. Salerno F, Camm jugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133:825-834. 49. Olcott EW, Ring EJ, Roberts JP, Ascher NL, Lake JR, Gordon RL. Percutaneous transhepatic portal vein angioplasty and stent placement after liver transplantation: early experience. J Vasc Interv Radiol 1990;1:17-22. 50. Haskal ZJ, Naji A. Treatment of portal vein thrombosis after liver transplantation with percutaneous thrombolysis and stent placement. J Vasc Interv Radiol 1993;4: 789-792. 51. Cherukuri R, Haskal ZJ, Naji A, Shaked A. Percutaneous thrombolysis and stent placement for the treatment of portal vein thrombosis after liver transplantation: longterm follow-up. Transplantation 1998;65:1124-1126. 52. Woo DH, Laberge JM, Gordon RL, Wilson MW, Kerlan RK Jr. Management of portal venous complications after liver transplantation. Tech Vasc Interv Radiol 2007;10:233-239. 53. Ciccarelli O, Goffette P, Laterre PF, Danse E, Wittebolle X, Lerut J. Transjugular intrahepatic portosystemic shunt approach and local thrombolysis for treatment of early posttransplant portal vein thrombosis. Transplantation 2001;72:159-161.
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54. L opez-Benıtez R, Barrag an-Campos HM, Richter GM, Sauer P, Mehrabi A, Fonouni H, et al. Interventional radiologic procedures in the treatment of complications after liver transplantation. Clin Transplant 2009; 23(suppl 21):92-101. 55. Settmacher U, N€ ussler NC, Glanemann M, Haase R, Heise M, Bechstein WO, Neuhaus P. Venous complications after orthotopic liver transplantation. Clin Transplant 2000;14:235-241. 56. Senzolo M, Patch D, Cholongitas E, Triantos C, Marelli L, Stigliano R, et al. Severe venoocclusive disease after liver transplantation treated with transjugular intrahepatic portosystemic shunt. Transplantation 2006;82: 132-135.
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57. Senzolo M, Germani G, Cholongitas E, Burra P, Burroughs AK. Veno occlusive disease: update on clinical management. World J Gastroenterol 2007;13:3918-3924. 58. Kitajima K, Vaillant JC, Charlotte F, Eyraud D, Hannoun L. Intractable ascites without mechanical vascular obstruction after orthotopic liver transplantation: etiology and clinical outcome of sinusoidal obstruction syndrome. Clin Transplant 2010;24:139-148. 59. Sterneck M, Wiesner R, Ascher N, Roberts J, Ferrell L, Ludwig J, Lake J. Azathioprine hepatotoxicity after liver transplantation. Hepatology 1991;14:806-810. 60. Senzolo M, Burra P, Patch D, Burroughs AK. TIPS for portal vein thrombosis (PVT) in cirrhosis: not only unblocking a pipe. J Hepatol 2011;55:945-946.
REVIEW
Transjugular Intrahepatic Portosystemic Shunts in Liver Transplant Recipients Alexander R. Bonnel,1 Chalermrat Bunchorntavakul,2 and K. Rajender Reddy3 Department of Medicine, Baylor College of Medicine, Houston, TX; 2Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Bangkok, Thailand; and 3Division of Gastroenterology/Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
1
The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure used to relieve the signs and symptoms of portal hypertension in patients with liver disease. The most common indications for placement are refractory ascites and variceal hemorrhage. In properly selected candidates, TIPS placement can serve as a bridge to liver transplantation. Expertise in TIPS placement after transplantation has significantly increased, which has allowed the procedure to become a viable option for retransplant candidates suffering the consequences of recurrent portal hypertension due to portal vein thrombosis, recurrent liver disease, or hepatic venous outflow obstruction (HVOO). However, TIPSs in liver transplant recipients are associated with a lower clinical response rate and a higher rate of complications in comparison with patients with native liver disease, and they are, therefore, generally reserved for patients with a Model for End-Stage Liver Disease (MELD) score 15 and 12 in patients with HCV. The role of TIPS placement in nonliver transplant recipients has been well studied in large trials, and it translates well into clinical applicability to candidates for orthotopic liver transplantation (OLT). However, the experience with OLT recipients is heterogeneous and restricted to small series. Thus, we focus here on reviewing the current literature and discussing the proper use of TIPSs in liver transplant recipients. Liver Transpl 20:130C 2013 AASLD. 139, 2014. V Received August 16, 2013; accepted October 12, 2013. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is used in the management of portal hypertension because this nonsurgical procedure significantly reduces pressure in the portal vein by creating a channel between the portal vein and a hepatic vein branch. Decreasing the portal pressure reduces the risk of variceal bleeding and is an acceptable treatment modality for refractory ascites (RA) as well. Additional less frequent indications include portal hypertension events related to portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). TIPS complications that occur to variable degrees include inadvertent puncture of the liver cap-
sule, shunt dysfunction, liver failure, and hepatic encephalopathy (HE). Survival after TIPS placement is known to be related to the severity of liver disease as indicated by the Model for End-Stage Liver Disease (MELD) score at the time of shunt placement, and it is, therefore, used with caution in patients with high MELD scores.1 TIPSs are created in candidates for orthotopic liver transplantation (OLT) to manage complications of portal hypertension and to preserve their candidacy for transplantation. Special considerations for TIPSs in OLT candidates are taken into account in order to minimize technical challenges during OLT. The vast
Abbreviations: CF, cystic fibrosis; CP, Child-Pugh; ESLD, end-stage liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic encephalopathy; HVOO, hepatic venous outflow obstruction; MELD, Model for EndStage Liver Disease; NASH, nonalcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PSG, portosystemic gradient; PVT, portal vein thrombosis; RA, refractory ascites; SBP, spontaneous bacterial peritonitis; SOS, sinusoidal obstruction syndrome; TIPS, transjugular intrahepatic portosystemic shunt; VH, variceal hemorrhage; VOD, veno-occlusive disease. There was no grant support for this project, and the authors have no conflicts of interest to declare. Address reprint requests to K. Rajender Reddy, M.D., Division of Gastroenterology/Hepatology, Department of Medicine, University of Pennsylvania, 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104. Telephone: 215-662-4311; Fax: 215-349-5915; E-mail: rajender.reddy@uphs. upenn.edu. DOI 10.1002/lt.23775 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
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majority of studies of TIPS placement in transplant candidates have found the procedure to have no impact on intraoperative complications, transplant outcomes, or overall patient survival2-5; recent but limited data suggest that it may in fact promote early graft function by increasing portal flow to the graft, possibly through the effect of reducing collateral blood flow.6 After OLT, a TIPS can be placed to treat portal hypertension–related complications of recurrent endstage liver disease (ESLD) and venous obstructions. TIPS placement in OLT recipients was once thought to be more technically challenging because of their altered anatomy; however, recent experience suggests otherwise.7,8 Because a TIPS in the post-OLT state is often required for patients who have significant liver disease and portal hypertension, the clinical response and survival rates after TIPS placement have been noted to be lower than those for pretransplant patients.9,10 Furthermore, immunosuppression increases the risk of infections, renal failure, and HE after TIPS placement in OLT recipients.10,11
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTS IN LIVER TRANSPLANT RECIPIENTS After liver transplantation, portal hypertension and related complications may evolve because of recurrent disease, allograft failure/rejection, and vascular or biliary complications.12 Indications for a TIPS in the transplant recipient mostly match those for a TIPS in pretransplant patients (ie, variceal bleeding and RA13-16; Table 1). However, the hepatic venous pressure gradient is known to be lower after liver transplantation, so variceal bleeding may not be as common as it is in the pretransplant setting.7 The retrospective nature, small sample sizes, lengths of follow-up, and patient selection of available studies are challenges to determining the success of TIPSs in these patients. Several reports suggest that TIPS placement is an effective treatment for addressing early complications of liver transplantation such as PVT, HVOO, and delayed graft function due to ongoing portal hypertension (Fig. 1).6,7,11,16-19,23
Special Technical Considerations When it was first introduced for OLT recipients, TIPS placement was thought to be more challenging because of the altered anatomy of the hepatic vessels after OLT. Unlike the standard OLT approach of endto-end anastomoses at the suprahepatic and infrahepatic vena cava, the piggyback and cavocaval techniques are not uncommon and require a different approach during TIPS placement.8,13 A Cochrane Database review found the piggyback technique, which involves the preservation of the recipient’s retrohepatic vena cava, to be a safe and effective technique for transplantation.24 In this case, the left internal jugular vein, rather than the right, is used for TIPS placement.7 After cavocaval OLT with a side-to-
BONNEL, BUNCHORNTAVAKUL, AND REDDY 131
side anastomosis of the donor’s retrohepatic vena cava, a gun-sight approach is used to create a direct cava-to-portal vein TIPS.7,25 Past studies reported multiple attempts at creating a TIPS in these patients because of technical inability or failed cannulation of the portal or hepatic veins.11,12,19 However, the most recent data from interventional radiologists indicate that transplanted livers do not pose any additional technical difficulty in comparison with native livers.8 Although these data remain limited to whole graft recipients, they suggest that technical expertise has significantly improved for TIPS placement in OLT recipients. This supports previous data showing that the reported technical complication rate for this procedure has dropped below the accepted 5% threshold, which is a quality measure determined by the Society of Interventional Radiology.17,26 Successful TIPS placement in increasingly challenging cases, such as patients with small-for-size syndrome after living donor transplantation, has also been described and indicates continued progress in the field of TIPS creation in transplant recipients.12,27
Complications Following Transjugular Intrahepatic Portosystemic Shunt Placement A lower rate of shunt stenosis has been reported after posttransplant TIPS placement versus pretransplant TIPS placement. Approximately 10% to 20% of the stents in OLT recipients require revisions because of the development of strictures or occlusions,9,10,12-14,22,28 whereas up to 70% do in nontransplant patients.1 However, the largest case-control study thus far reported no such complications in its posttransplant group.19 It must be noted that most of the data come from the era of uncoveredstent use and may not be applicable to the current days of polytetrafluoroethylene-covered stents. Immunosuppressive therapies may play a role in reducing rates of shunt stenosis. Experimental studies suggest that tacrolimus and mammalian target of rapamycin inhibitors (everolimus and sirolimus) have inhibitory effects on both smooth muscle cell proliferation and endothelial progenitor cells.29-31 Furthermore, this is supported by the experience with drug-eluting stents in vascular interventions, for which immunosuppressive therapies have been known to significantly reduce stenosis.32,33 Although there are reasons to believe that there are factors in liver transplant recipients that are favorable for shunt patency, it needs to be recognized that sirolimus use has been associated with hepatic artery thrombosis, which potentially presents a risk for precipitating liver failure after TIPS placement.34 Thus, research is needed on shunt patency, specifically after TIPS in the posttransplant setting, and particularly on the mechanistic role of various immunosuppressants. Transplant recipients face a high risk of infection, renal failure, and neurological complications after TIPS placement. Sepsis is the most common complication and cause of death and occurs in approximately 20% to 50% of reported cases.10,11,13,19 The risk of infection in OLT recipients is attributable to their immunosuppressive
7: RA (7)
4: RA (4)
Stewart et al.15 (2004)
Patel et al.7 (2005) Vasta et al.16 (2005)
11: VH (4) and RA (7)
2: SOS (2)
Senzolo et al.18 (2006)
Kim et al.11 (2008)
6: RA (5) and VH (1)*
Van Ha et al.17 (2006)
5: RA (5)
8: VH 1 RA (2) and RA (6)
8: RA (5), VH (1), hydrothorax 1 RA (1), and redo biliary surgery (1) 12: RA (6) and VH (6)
Patients (n): Indications (n)
Abouljoud et al. (1999)
Amesur et al. (1999)
Lerut et al.14 (1999)
Study
Recurrent HCV (7), HVOO (2), PVT (2), chronic rejection (1), recurrent PSC (1), and unknown (1)
Chronic rejection (1), biliary cirrhosis (1), acute rejection (1), HVOO (1), and chronic hepatitis of unknown cause (2) SOS (2)
HCV (2), HVOO (1), and rejection (1) Delayed graft function (5)
HCV (7)
Not reported
Recurrent HCV (5), recurrent HBV (1), lymphoproliferative disease (1), and VOD (1) Recurrent HCV (10), recurrent PBC (1), and unknown (1)
Etiology of Recurrent Portal Hypertension (n)
MELD score 5 16.4 6 6.2
—
—
—
CP class B (4)
—
—
CP class A (1), CP class B (3), and CP class C (2)
CP class B (5) and CP class C (2)
CP Class (n) or MELD Score
Portal hypertension was resolved for 2/2 (100%). 1/2 (50%) had a histological resolution of SOS. 4/7 (57%) with RA responded (nonresponders had chronic renal insufficiency). For VH, 2/4 (50%) had a response.
5/5 (100%) responded. 1/5 (20%) had complete resolution. RA was resolved for 4/5 (80%).† For VH, 1/1 (100%) had a response.
Not reported
4/6 (67%) with RA recovered. For 4/6 (66%), VH was controlled. For 7/8 (88%), RA and portal hypertension were resolved. Not reported
8/8 (100%) responded to TIPS.
Clinical Response
TABLE 1. Summary of Studies of TIPS Placement in OLT Recipients
Complications/Survival
4/11 (36%) developed infections. 9/11 (81%) had new or worse HE. 4/8 (50%) had acute renal failure. N514 of the study and not the N511 relevant to our review.
None
2/6 (33%) died.
For 1/8 (12.5%), TIPS was occluded within 3 months. 3/8 (37.5%) died. 4/7 (57%) died. TIPS placement was associated with a high risk of death (relative risk 5 2.86). There was no difference in the MELD score between patients with a TIPS who died and patients with a TIPS who survived. Not reported 1/4 (25%) died. 0 had HE. 0 had stenosis.
6/8 (75%) had new or worse HE. The 1-year survival rate was 50%. 3 died from liver failure. 2/6 (33%) RA patients died of liver failure within 1 week.
132 BONNEL, BUNCHORNTAVAKUL, AND REDDY LIVER TRANSPLANTATION, February 2014
12
19: RA (19)
26: RA (26)
22: RA (14) and VH (8)
Feyssa et al.10 (2011)
King et al.19 (2011)
10: RA (7), VH (1), and hydrothorax (2)
18: VH (2) and RA (16)
Patients (n): Indications (n)
Saad et al.9 (2010)
Finkenstedt et al.13 (2009)
Choi et al. (2009)
Study
Vascular abnormalities (7), HVOO (4), recurrent HCV (3), recurrent PBC (2), recurrent PSC (2), chronic rejection (1), VOD (1), unknown (1), and cholangiopathy (1)
—
Recurrent HCV or HBV (15)
Recurrent HCV (11), de novo HCV (1), HBV (1), small-for-size syndrome (1), recurrent sarcoidosis (1), and unknown (3) Ductopenic rejection (5), recurrent HCV (4), and PVT (1)
Etiology of Recurrent Portal Hypertension (n)
MELD score 5 13.4 6 5.1
MELD score 5 15
MELD score 5 16 6 4.8
MELD score 5 20
MELD score 5 16
CP Class (n) or MELD Score
TABLE 1. Continued
15/22 (68%) had a reduction in PSG to 15 was significantly associated with decreased survival.
7/10 (70%) had HE. 1 had TIPS dysfunction. 9/10 (90%) died. 5/9 (56%) died of sepsis. The median survival time was 3.3 months.
3/18 (17%) had to undergo a second attempt. 9/12 (75%) died after 3 months.
Complications/Survival
LIVER TRANSPLANTATION, Vol. 20, No. 2, 2014 BONNEL, BUNCHORNTAVAKUL, AND REDDY 133
Patients (n):
Etiology of Recurrent
HCV (21), alcohol (6), HCV/alcohol (1), HBV (3), cryptogenic (3), NASH (1), CF (1), PSC (1), and sarcoidosis (1)
*Two pediatric patients [RA (1) and VH (1)] were included. † For 3 of the 4 adults (75%), RA was resolved.
Saad et al.8 (2013) 38: RA (34) and VH (4)
HCV (9), HCC (3), alcohol (2), and PBC (1)
15: RA (12), hydrothorax (2), and VH (1)
El Atrache et al.22 (2012)
HCV (19)
19: RA (11), hydrothorax (6), and RA 1 hydrothorax (2)
Ghinolfi et al.21 (2012)
HBV/alcohol (1)
Portal Hypertension (n)
1: SOS (1)
Indications (n)
Campos-Varela et al.20 (2012)
Study
MELD score 5 17 6 5
MELD score 5 15.8 6 5.8
MELD score 5 12.4 6 3.2
—
or MELD Score
CP Class (n)
TABLE 1. Continued
Whole graft OLT recipients did not pose additional technical difficulties. For 11/34 (32%), RA was resolved.
7/12 (58%) had a complete resolution of RA.
RA was resolved completely, and the patient remained asymptomatic at 20 months. For 7/19 (37%), RA was resolved. For 4/6 (67%), hydrothorax was resolved.
Clinical Response
1/19 (5%) died because of sepsis after 35 days. 6/19 (32%) had HE within 1 month. Survival for patients with a pre-TIPS MELD score 12 did not differ from survival for a control group. There was 1/15 (7%) post-TIPS graft failure. 2 /15 (13%) had HE. 3 /15 (20%) had a shunt occlusion requiring revision. 1 /15 (7%) died from sepsis, 1 died from lung cancer, and 1 /15 (7%) died from congestive heart failure. Earlier allograft dysfunction was more likely with partial or no resolution of RA, but there was no significant difference in survival between complete and partial responders to TIPS. 7/38 (18%) had HE. The mortality rate at 30 days was 7/38 (18%). The mortality rate at 90 days was 10/38 (26%).
None
Complications/Survival
134 BONNEL, BUNCHORNTAVAKUL, AND REDDY LIVER TRANSPLANTATION, February 2014
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Figure 1. Summary of the considerations for and outcomes of TIPS placement in the early and late posttransplant periods.
therapies. However, recent data did not show the rate of infectious complications among OLT recipients to be significantly higher than the rate among pretransplant patients,19 in contrast to the findings of a previous casecontrol study.11 Patients with ESLD are often in a state of cirrhosis-associated immune dysfunction.35 Therefore, the conflicting results of recent studies may be explained by differences in the extent of cirrhosis-associated immune dysfunction within each group of TIPS patients. Before periprocedural prophylaxis is routinely recommended, as some authors have suggested,11,13 a further evaluation of the risk of infection after TIPS placement among OLT recipients is needed. Acute renal failure directly following TIPS placement has been encountered in approximately 20% of OLT recipients.10,11 Renal dysfunction in OLT recipients is attributable to a number of factors such as long-term calcineurin inhibitor use, and pretransplant renal dysfunction is due to 1 or more factors, including hepatorenal syndrome, diabetes, and hypertension.36 As a result, radiographic contrast during TIPS placement may precipitate the development of renal failure after the procedure. Calcineurin inhibitors are known to cause neurological complications such as encephalopathy, seizures, psychological disorders, stroke, tremor, and posterior reversible encephalopathy syndrome.37 In OLT recipients, new or worsening HE after TIPS has been documented in 25% to 80% of cases.9-11,13,14,19 Previous findings suggest that OLT recipients may be prone to encephalopathy because of the added neurotoxicity of immunosuppressive drugs.11,14 However, recent data did not show a higher rate of HE after TIPS placement in OLT recipients versus pre-OLT TIPS patients.19 Therefore, the association between immunosuppression and the extent of HE in OLT recipients after TIPS placement remains controversial.
Clinical Response to a Transjugular Intrahepatic Portosystemic Shunt The therapeutic response to TIPSs in OLT recipients is highly variable and is influenced by various factors,
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such as pretransplant conditions, posttransplant complications, and the severity of the recurrent liver disease.35-37 Despite some conflicting data, the overall clinical response rate to TIPSs in liver transplant recipients appears to be lower than that in pretransplant patients.9,15,17,21,38 This difference appears to be more significant for the control of ascites versus the prevention of portal hypertension–related bleeding. Larger studies of liver transplant recipients have reported RA remission rates in the range of 15% to 79%,8-10,19,22 whereas a success rate > 90% has been reported for pretransplant patients.39 Although data on the prevention of portal hypertension–related bleeding in liver transplant recipients are very limited ( 15 in comparison with pretransplant patients with such a MELD score.17,21 In OLT recipients with RA, a 6-month transplant-free survival rate of only 12.5% has been reported.9,10 A significant reason for such poor outcomes is likely related to HCV recur-
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rence. It has recently been suggested that TIPS placement in HCV patients with RA should be reserved for those with a MELD score 12.21 This cutoff likely reflects the extent of HCV disease because the most common cause of death in the study group was progression of HCV. A previous study found TIPS placement in HCV patients to be associated with a high risk of death but did not note a difference in the MELD scores of those who died and those who survived with a TIPS in place.15 Understanding the various mechanisms behind portal hypertension in the setting of recurrent HCV remains a barrier to more refined TIPS candidate selection and warrants caution in these patients. In all OLT recipients with a MELD score > 15 and specifically in OLT recipients with HCV and a MELD score > 12, TIPS placement has been associated with greater failure rates and is, therefore, unlikely to benefit the patient.
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTS FOR VENOUS COMPLICATIONS AFTER LIVER TRANSPLANTATION Portal Vein Thrombosis PVT is a rare but severe complication that typically occurs early after OLT and is often related to abnormal venous reconstruction during surgery in patients with preexisting PVT.23 Interventions for PVT after OLT include surgical thrombectomy, percutaneous thrombolysis, angioplasty, and stent placement, and they are associated with good long-term outcomes.4952 Several case reports have shown a combination of a TIPS and local thrombolysis with or without thrombectomy to be an effective method of transhepatic recanalization of the portal vein.14,53,54 The use of a TIPS in PVT is associated with a reduced risk of bleeding and technical complications in comparison with transhepatic puncture for portal vein interventional procedures.53
Hepatic Venous Outflow Obstruction HVOO after OLT is uncommon and occurs in less than 2% of cases, but it is life-threatening if it is left untreated.55,56 The most common causes of hepatic vein thrombosis are anastomotic complications following transplantation (30%) and disease recurrence (25%).55 TIPS is an effective treatment for hepatic vein thrombosis refractory to medical therapy in the pretransplant setting; however, data on its use in transplant recipients remain limited.7,11 HVOO has been noted to be an independent predictor of mortality after TIPS placement in transplant recipients, and it has been suggested that the pathophysiology of portal hypertension in patients with HVOO is different from the pathophysiology of ESLD-related portal hypertension.19 Yet, a TIPS appears to reduce the complications of portal hypertension and may serve as a bridge to retransplantation in OLT recipients with
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HVOO.57 Because of the small sample size behind the current data on TIPSs in patients with HVOO, concrete recommendations cannot be made. Sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease, includes both central vein and sinusoidal occlusion and has been attributed to acute allograft dysfunction.58,59 Current guidelines do not recommend TIPS placement for SOS1; however, some have suggested that TIPS placement be tried in carefully selected patients with SOS after OLT, particularly if retransplantation is not an option.57,60 A recent case report20 presents TIPS placement as a potentially useful treatment for severe SOS refractory to medical treatment.
CONCLUSIONS TIPS placement is used in the management of portal hypertension–related complications and decreases the risks associated with variceal bleeding, RA, PVT, and HVOO. However, this procedure is not without complications such as transcapsular puncture, shunt thrombosis or stenosis, liver failure, and HE. After OLT, recurrent liver disease and conditions such as venous obstruction may lead to portal hypertension– related complications. Because of the post-OLT altered anatomy, TIPS placement may be challenging and can result in inadvertent puncture of the liver capsule and bleeding complications. However, advances in interventional radiology expertise have made the procedure safe and effective. Immunosuppression may increase the risk of infection, renal failure, and HE after the procedure, although further data in this area are needed. TIPS placement in OLT recipients, in contrast to pretransplant patients, has a lower rate of clinical response, especially in those who undergo the procedure for RA. This finding may be attributable to the increased prevalence of comorbidities among OLT recipients but is likely related to the differences in the pathophysiology underlying RA in this patient population. Recent case-control data suggest that a TIPS may accelerate the progression of advanced liver disease in OLT recipients versus pretransplant patients. Therefore, TIPS placement in general is not recommended for patients with a MELD score > 15 and specifically for HCV patients with a MELD score > 12. In patients with PVT after transplantation, TIPS placement is an important nonsurgical intervention that is associated with good outcomes. TIPS placement in OLT recipients with HVOO should be reserved as a bridge to retransplantation.
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