EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Recipients of liver transplant are surviving longer as both the surgical procedure and postsurgical care have improved. Despite improve-ments, serious complications from the procedure remain that significantly affect patient outcome and may result in retransplant. Refractory ascites is one complication, occurring in about 5.6% of transplant recipients. Management of refractory ascites after liver transplant presents a challenge to the multidisciplinary team caring for these patients.

Materials and Methods: We discuss approaches to the diagnosis and treatment of refractory ascites after liver transplant, based on a literature review, with a primary focus on vascular causes. These approaches are illustrated by case examples highlighting our experiences at an academic tertiary medical center. We propose a clinical practice algorithm for optimal endovascular treatment of refractory ascites after liver transplant.

Results: The cornerstone of refractory ascites care is diagnosis and treatment of the cause. Vascular causes are not infrequently encountered and, if not treated early, are associated with graft loss and high morbidity and mortality and are major indications for retransplant. For patients with recurrent disease or graft rejection needing large volume paracentesis, the use of a transjugular intrahepatic portosystemic shunt may serve as a bridge to more definitive treatment (retransplant), although it may not be as effective for managing ascites as splenic artery embolization, arguably underused, which is emerging as a potential alternative treatment option.

Conclusions: A multidisciplinary strategy for the diagnosis and care of patients with refractory ascites after liver transplant is crucial, with endovascular treatment playing an important role. The aim is for this document to serve as a concise and informative reference to be used by those who may care for patients with this rare yet serious diagnosis.

Key words : Refractory ascites, Liver transplant, Transjugular intrahepatic portosystemic shunt (TIPS), Large volume paracentesis, Splenic artery embolization

Refractory ascites (RA) is an infrequent, yet serious, complication after liver transplant with an incidence of about 5.9%.¹ In addition to a poor prognosis, with 1-year transplant-free survival in patients with advanced-stage cirrhosis of 20% to 50%,² patients with RA usually have additional complications such as spontaneous bacterial peritonitis, hepatorenal syndrome, and pleural effusion.³ However, this condition has received little attention in the transplant literature.

Factors that cause RA include allograft failure, rejection, recurrent viral disease, and vascular and bacterial peritonitis. Vascular causes include hepatic vein, inferior vena cava, and portal vein stenosis, splenic arterial steal syndrome, and left-sided portal hypertension. Recurrence of hepatitis C virus is directly associated with increased risk of RA after liver transplant and is also associated with a poor prognosis.¹

Diagnosis and Treatment of Refractory Ascites

To effectively treat RA, it is important to establish its cause. The first diagnostic test is an ascitic fluid analysis, which can help differentiate transudate from exudate. This is to rule out a treatable condition such as bacterial peritonitis. Doppler ultraso-nography is highly sensitive in evaluating the patency of hepatic vein outflow. Angiography with hemodynamic studies should be performed to confirm mechanical stenosis suspected by Doppler imaging. If the cause cannot be diagnosed, recurrent disease or rejection should be suspected, in which case a diagnostic liver biopsy is required. Either a percutaneous ultrasonography-guided biopsy or a transjugular liver biopsy should be used, with the latter reserved for patients with severe coagulopathy, large amount of ascitic fluid, or if pressures in the hepatic vein need to be measured.^1,4 Figure 1 shows a diagnostic algorithm for evaluation of RA after liver transplant.

The successful treatment of RA depends, in part, on its cause. For the purpose of this review, we have divided treatment of RA after liver transplant into 2 categories: treatment for vascular causes and treatment for nonvascular causes. If treated early with an endovascular approach, vascular causes, which include hepatic vein stenosis, inferior vena cava stenosis, portal vein stenosis, and rare hepatic artery to portal vein fistulas, are associated with a good prognosis. Endovascular treatment options also play a limited role in nonvascular causes, such as recurrent infection or rejection needing medical treatment or liver transplant.^1,4,5

Treatment of Vascular Causes of Refractory Ascites

Hepatic vein stenosis
Hepatic vein stenosis is a major and the most common complication after liver transplant, with a reported incidence of 1% to 4%.^6,7 A smaller recipient-to-donor body weight ratio and the use of a reduced graft size are risk factors in pediatric patients and manifest acutely with liver failure. Delayed presentation is due to intimal hyperplasia or perianastomotic fibrosis, with patients then presenting with RA, pleural effusion, and alteration of liver function tests. After diagnosis, usually by Doppler imaging, selective catheterization of the hepatic vein is performed to confirm the stenosis and pressure gradient greater than 3 mm Hg.^6,8 A transjugular transfemoral approach with balloon dilation is the preferred treatment. A transhepatic approach and the use of a metallic stent are reserved for unresponsive patients.^6,9-11 Figure 2 shows a 2-year-old female patient who presented with ascites due to hepatic outflow stenosis after liver transplant. The patient received angioplasty, with successful reduction of pressure gradient from 15 mm Hg to 4 mm Hg and clinical improvement.

Portal vein stenosis
Portal vein stenosis is a rare cause (1%-2%)⁷ of RA and usually presents with symptoms of portal hyper-tension, such as ascites or hemorrhage. Confirmation of stenosis and pressure gradient is usually via transhepatic portography. The treatment option for the stenosis is balloon angioplasty. Use of stents, especially in pediatric patients, is reserved for recurrent or residual stenosis. The procedure is associated with a good success rate, with complications, if any, due to the transhepatic approach, for which embolization can be performed with agents such as coils or Gelfoam.^7,12,13

Inferior vena cava stenosis
Inferior vena cava stenosis is rare (1%)¹² and usually caused by stenosis at the site of anastomosis or just superior to it and can be iatrogenic or related to the scar. Clinical manifestations are ascites, renal failure, lower limb swelling, or altered liver function tests. The initial approach is usually via a transfemoral route, using interior vena cava venography, identifying the stenosis, and then verifying its significance with pressure measurements. Balloon angioplasty is the first treatment choice; however, larger balloons or simultaneous inflation of multiple balloons may be needed, due to the large size of the inferior vena cava.¹⁴ Angioplasty may not be effective due to elastic recoil.¹⁵ Multiple dilations may be needed to ensure long-term patency. Stent placement is indicated for residual or recurrent stenosis but sometimes as primary treatment.^15,16 Figure 3 shows a 56-year-old liver transplant recipient who presented with recurrent ascites due to high-grade stricture at the level of the proximal inferior vena cava accompanied by anastomosis, exending to the hepatic veins. The patient received a venous angioplasty, resulting in significant angiographic and clinical improvement, although her pressure gradient was not significantly changed.

Hepatic artery to portal vein fistulas
Hepatic artery to portal vein fistulas are very rare, with about 15 published case reports, most of which were associated with hepatic trauma or needle intervention and 1 rare case report due to surgery. Clinical presentation varies from asymptomatic to mild abnormalities of liver function, which can progress to hepatic fibrosis and failure. With regard to treatment, there is significant overlap between hemodynamically significant and clinically significant fistulas. Although treatment is only warranted when the patient is symptomatic, the advent of safe, effective, and minimally invasive endovascular techniques has allowed the approach to be more aggressive. Doppler ultrasonography is particularly useful because it has high sensitivity and specificity for hemodynamically significant hepatic artery to portal vein fistulas.^17-19 Treatment of this rare condition is mainly endovascular, with surgery reserved for complex cases.^17,20,21 Embolization is also challenging as the actual fistulous com-munication is very short and liver allografts are relatively hypoperfused and hence susceptible to ischemia. Attention to proper technique and the proper embolic agent is important.^17,19 For hepatic artery to portal vein fistulas, the embolic agent should be selected according to the size of the vascular communication and flow. In larger fistulas with high flow, there is risk of distal migration and portal vein thrombosis. Embolization can be achieved with use of detachable coils, fibered coils, and glue, used separately or in combination.^22,23 Figure 4 and Figure 5 show a 5-year-old male patient with a large liver from a second transplant. Because of size discrepancy, back-table preparation of liver graft was performed with left-side lobe reduction. He presented with recurrent ascites and a large pleural effusion on his right side and an intrahepatic artery to portal vein fistula. Using an endovascular approach, our group placed Ruby microcoils (Peumbra Inc.) with satisfactory angiography results and no complications.There was complete resolution of the ascites.

Treatment of Nonvascular Causes of Refractory Ascites

When the etiology is unknown, for example, with allograft rejection or recurrent infection, there are just a few therapeutic options. Liver transplant is a definitive treatment, but the risks of a second liver transplant are significantly higher than those of a first transplant, and some patients may not be good candidates (eg, those with recurrent hepatitis C virus infection). The therapeutic options for these patients with nonvascular causes of RA are essentially the same as those for the nontransplant population and include large volume paracentesis, peritoneovenous shunt, and transjugular intrahepatic portosystemic shunt (TIPS). A few differences however are noted.^1,4 There is also the evolving role of splenic artery embolization.⁵

Paracentesis
The standard therapy for patients with RA after liver transplant is large volume paracentesis. Large volume paracentesis palliates the patient's symptoms; however, it does not treat the cause and in fact may contribute to renal dysfunction.²⁴ The LeVeen shunt, a peritoneovenous shunt, may be another option in treating RA. However, it is associated with complications, including infection and thrombosis. Heart function should be monitored carefully after the placement of a LeVeen shunt due to risk of heart failure.²⁵

Transjugular intrahepatic portosystemic shunt
Although a TIPS relieves portal hypertension in native livers,^1,4,5 its role in treatment of ascites after orthotopic liver transplant is reported to have variable success (16%-57%).²⁶ Transjugular intra-hepatic portosystemic shunt is highly effective for treatment of portal hypertension related to sinusoids or Chiari-Budd syndrome. Because the cause of ascites after orthotopic liver transplant is a multivariate combination of liver dysfunction (rejection, recurrent viral infection), left-sided portal hyperension, and splenic arterial steal syndrome, the efficacy of a treatment such as a TIPS that solely targets the portal hypertension secondary to sinusoidal or venous obstruction is likely to have mixed results. The hypothesis is that the intact reciprocal relation that exists in native livers, potentially allowing the arterial circulation to increase flow to compensate for the diversion of the portal flow away from the liver, is lost in orthotopic liver transplant grafts. This may result in even greater liver dysfunction, perhaps reducing ascites formation but leading to global hepatic failure requiring repeat transplant.²⁷ Transjugular intra-hepatic portosystemic shunt can also lead to portal-systemic encephalopathy, which is of great significance after orthotopic liver transplant.^1,28

Splenic artery embolization
A lesser known yet minimally invasive treatment option is proximal splenic nerve embolization.⁸ Splenic nerve embolization has been effective as a minimally invasive therapeutic option in a variety of conditions, including hematologic disorders and splenic trauma, replacing surgery that has been associated with morbidity and mortality.²⁹ Recently, the role of splenic nerve embolization in hyper-splenism associated with portal hypertension has increased.

Splenic nerve embolization decreases splenic blood flow, thereby decreasing splenic and portal venous pressures. In addition to this primary effect, splenic nerve embolization has been shown to effectively increase hematologic indexes and improve liver function tests. Specifically in the transplant setting, splenic nerve embolization has been effective in the treatment of splenic artery steal syndrome, a condition in which increased splenic blood flow due to low splenic arterial resistance, secondary to splenohepatomegaly, siphons blood from the already decreased blood flow due to increased hepatic arterial resistance in the transplant liver, thereby causing liver dysfunction.^29-32 There is also limited evidence that splenic artery embolization may help reduce the incidence of portal-systemic encephalopathy.^33,31

Published reports on the use of splenic artery embolization in the treatment of RA after liver transplant are scarce. In the setting of liver transplant, Chang and associates,³⁴ Quintini and associates,⁵ and Kim and associates³⁵ showed that splenic artery embolization was safe and effective in reducing the portal vein velocity immediately, translating into resolution of ascites in most of the patients. In contrast to distal embolization, a proximal embolization technique allows decreased splenic flow to produce the desired amount of ischemia while allowing distal revascularization, thereby preventing significant splenic infarct and complications.^30,36,37 Although coils have been described for proximal splenic artery embolization,^5,38 some disadvantages of coil migration have been shown, with a need for multiple coils before complete occlusion is achieved.

An AMPLATZER type II vascular plug (St. Jude Medical, Inc., St. Paul, MN) has the potential advantage of precise deployment, resistance to migration when appropriately sized, and possible reduction in fluoroscopic time necessary for embolization. The occlusion and procedure times are arguably lower than with coil embolization, although no study in the literature to our knowledge has specifically addressed this. However, a major limitation for embolization with this plug device is the need for a sheath delivery system to be advanced to the embolization site, which can be circumvented with the use of a coaxial guiding catheter.³⁸ Figure 6 shows a 53-year-old male patient with massive ascites and right pleural effusion after liver transplant, refractory to TIPS and other treatment. Because of recurrent ascites, portal-systemic encephalopathy, and not being a transplant candidate, we decided to perform a splenic artery embolization. Proximal splenic artery embolization was performed with 8-mm AMPLATZER type II vascular plug, which resulted in both technical and clinical success with resolution of portal-systemic encephalopathy, ascites, and pleural effusion.

Refractory ascites is an infrequent yet serious complication occurring in 5.6% of liver transplant recipients. The cornerstone of treatment is correct diagnosis and treatment of the cause. Endovascular interventions must be considered and offered to patients with a vascular cause early in the course to prevent graft loss. For patients with recurrent disease or graft rejection, treatment of the cause and/or supportive care with paracentesis and TIPIS may improve survival or serve as a bridge to more definitive treatment (retransplant). In the posttransplant setting, TIPS may not be as effective for treatment of ascites. Splenic artery embolization, arguably underused, is emerging as a potential alternative treatment option. A multidisciplinary strategy for the diagnosis and care of patients with RA after liver transplant is crucial. We propose a clinical practice algorithm for optimal endovascular care of these patients (Figure 7).

Volume: 13 Issue: 5 October 2015

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