RG Volume 33 Number 5 Kirby et al 1497

Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights. RG Volume 33 Number 5 Kirby et al 1497 Invited Commentary From: Ziv J Haskal, MD Division of Vascular and Interventional Radiology, University of Maryland School of Medicine Baltimore, Maryland Treating complications of portal hypertension has long resided in the innovative hands and minds of interventional radiologists. In 1969, Rösch et al (1) reported the concept of a transjugular intrahepatic portosystemic shunt (ie, TIPS), having created the connection in dog. In 1974, Lunderquist and Vang (2) described transhepatic embolization of bleeding varices, potentially heralding a new treatment option for a typically fatal condition. In 1989, a study of a series of 400 cirrhotic patients treated with transhepatic embolization finally resulted in the discontinuation of that procedure, since 55% of patients experienced repeat bleeding within 6 months (3), and the first human TIPS procedure was reported (4). BRTO was first described in 1984 (5) and further elaborated upon in 1996 (6). A new era in managing otherwise desperate or untreated patients then began. Decades of vigorous efforts in animal and human studies and technologic development ensued, leading to a mature TIPS literature that stands as one of the best evidence-based areas in interventional radiology: More than 30 prospective controlled outcome trials have been reported, multiple meta-analyses conducted, and many documented guidelines developed (7 11). Still, the procedure discomfits many referring physicians because of their unfamiliarity with proved results in well-chosen patients. Referrers may still view TIPS placement as inevitably leading to transplantation, although most TIPS patients will never receive a transplant or may never need one, given control of variceal bleeding or ascites and the improved nutritional status that can occur after TIPS placement (12). The debut of the expanded polytetrafluoroethylene TIPS stent-graft resolved most of the early patency questions by providing a 10-fold advantage over bare stents, making TIPS placement a long-term option. I continue to follow up some patients in whom I created a TIPS nearly 20 years ago. Interventional radiologists may be equally uncomfortable with suggesting TIPS creation because they lack consistent experience in treating portal hypertension, creating shunts, and addressing procedural challenges. Indeed, having performed well over 1000 TIPS and related procedures, I am still struck by its novelty and the continuing need for apprenticeship as the best, albeit the least efficient, way of teaching others. It remains a three-dimensional procedure performed with two-dimensional tools. Better imaging guidance would make it easier and would allow many more patients to be treated. BRTO has taken a different path. Unlike trans hepatic embolization, BRTO provides durable control of gastric varices with relatively little exacerbation of esophageal variceal bleeding. Why does it fare better? In part, because it aims for complete destructive sclerosis of the entire varix, rather than the proximal coil embolizations that accompany most TIPS or transhepatic approaches. The BRTO varix is obliterated, whereas TIPS embolization often only blocks its front door. BRTO is widely practiced in Asia, and uncontrolled trials have been reported; however, its literature is far from being as mature as the TIPS literature. Its increasing use in the United States does not represent the discovery of a new procedure, but deferred Western awareness of the other hemisphere. BRTO is now being westernized with technique modifications and tailoring to U.S. sclerosants such as sodium tetradecyl sulfate; ethanolamine (still the primary agent in Asia), which requires haptoglobin transfusion, will likely never take hold in the United States. One cautionary point is that the majority of BRTO practice and literature describes primary prophylactic treatment of gastric varices (ie, before index bleeding). There is no indication for prophylactic TIPS creation. Patients who have never bled fare better than those who have, regardless of the invasive therapies that are chosen.

1498 September-October 2013 radiographics.rsna.org Thus, comparing the published results of TIPS and BRTO series requires comparing apples to apples; secondary treatment is not the same as primary prophylaxis. Whether BRTO should play a primary prophylactic role in the West is still an open question, notwithstanding the advent of endoscopic glue injection for gastric varices (13). In addition to these two cornerstone therapies, Kirby et al (14) note the myriad of other interventions for portal hypertension, from closing and reopening veins and shunts to reducing load through organ embolization. Although these procedures account for only a tiny fraction of all interventions, a proper interventional toolkit must include them as well. For instance, the fact that ectopic varices can be causes of occult intraperitoneal or gastrointestinal hemorrhage may be overlooked (15). The degree of suspicion must be high in patients with imaging signs of cirrhosis and low thresholds for interventional diagnosis and therapy, since the negative predictive value of endoscopy is too low to depend upon in such cases. Kirby et al describe techniques that highlight the merging of BRTO-type techniques with TIPS-type approaches to both reach varices and locally destroy them (with or without concomitant TIPS formation); even direct US-guided percutaneous variceal access can be used. I had several specific comments regarding the article by Kirby et al (14). First, the authors mention the oft-quoted TIPS gradient endpoint of 12 mm Hg. This threshold emerged from early reports of free versus wedged hepatic venous pressures, in which patients with nonbleeding esophageal varices tended to have gradients less than 12 mm Hg. Used alone, this number is misleading because the endpoint gradients reported in virtually all TIPS series are measured between the right atrium and the portal vein. The free hepatic vein pressure is always offset by 3 5 mm Hg from the right atrial pressure, rendering the original 12-mm-gradient literature out of step with all published TIPS literature. In addition, there is no evidence that a gradient of 12 mm Hg applies to patients with ascites or hydrothorax, gastric or ectopic varices, or Budd-Chiari syndrome. In point of fact, it does not apply. Some investigators suggest that the degree of reduction is what matters most (16). In patients with Budd-Chiari syndrome, a condition in which the highest opening portal pressures are seen (often 40 50 mm Hg), a gradient of 18 mm Hg may remain after 10-mm-diameter TIPS creation. Within a week of spontaneous diuresis, the gradient can drop to 8 mm Hg. Furthermore, every interventionalist is aware of the many cases in which real-time pressures in both the atrium and portal vein fluctuate by 3 5 mm Hg in either direction from second to second, raising practical questions about the accuracy and precision of gradients. The goal is to create the smallest possible shunt in each patient, thereby minimizing the side effects of encephalopathy or worsened hepatic function. One should leave the smallest TIPS possible. There are even patients in whom shunt obsolescence is desired, such as (a) those treated for acute portomesenteric thrombosis (17), (b) those treated for postoperative ascites with small-for-size transplants, or (c) those whose liver function has improved with abstinence from alcohol. Second, the authors overstate the evidence for survival advantages in patients with refractory ascites who undergo TIPS placement as opposed to large-volume paracentesis. Individual studies have not convincingly shown this effect. The report by Salerno et al (10) is a unique reanalysis of individual patient data from several completed prospective trials. Although it did show a collective benefit, the combined cohorts were heterogeneous, the entry criteria different, and so on. Although I firmly believe that TIPS creation does indeed improve survival in selected patients, additional prospective studies will be needed to address the question. Indeed, such studies are already under way. On the other hand, a 2010 controlled trial reported by García-Pagán et al (11) showed a clear survival benefit, less recurrent bleeding, and less time in the intensive care unit for patients with acute esophageal variceal hemorrhage who underwent TIPS creation with an expanded polytetrafluoroethylene stent-graft within 72 hours rather than medical and endoscopic therapies. This evidence argues strongly for rapid access to TIPS creation.

RG Volume 33 Number 5 Kirby et al 1499 Third, Budd-Chiari syndrome requires further investigation, since it represents one of the few conditions in which portosystemic diversion will halt and prevent cirrhosis (18,19). A 5-year mortality rate of 31% has been reported in patients with Budd-Chiari syndrome who have been treated medically (20). This is underappreciated by clinicians who may prescribe years of diuretic and anticoagulant therapy, allowing unabated hepatocyte necrosis and fibrosis. A portosystemic shunt and, today, a TIPS, can offer decades of biopsy-proved cirrhosis prophylaxis in these patients (19), many of whom are quite young. Finally, acute portosplenomesenteric thrombosis is another area that is worth noting. Affected patients are hypercoagulable and present with mesenteric ischemia due to extensive venous outflow obstruction. In the absence of necrotic bowel warranting resection, patients have few options. TIPS approaches have allowed rapid pharmacomechanical thrombolysis and the benefit of an artificial outflow for endogenous lysis. Indeed, the shunt has even been used to prevent total PVT or create conduits for transplantation in patients with occlusion (17,21). In summary, responsibility for the management of most aspects of portal hypertension rests with the interventional radiologist, and committed physicians should be capable of using (or at least aware of) all the approaches that Kirby et al (14) have described. This capability requires a detailed reading of and familiarity with the primary source literature. Furthermore, we should provide the same long-term continuing care that we offer our patients with cancer, peripheral arterial disease, and so on. I congratulate Kirby et al for making all of us aware of how varied and rewarding this field is. References 1. Rösch J, Hanafee WN, Snow H. Transjugular portal venography and radiologic portacaval shunt: an experimental study. Radiology 1969;92(5): 1112 1114. 2. Lunderquist A, Vang J. Transhepatic catheterization and obliteration of the coronary vein in patients with portal hypertension and esophageal varices. N Engl J Med 1974;291(13):646 649. 3. L Herminé C, Chastanet P, Delemazure O, Bonnière PL, Durieu JP, Paris JC. Percutaneous transhepatic embolization of gastroesophageal varices: results in 400 patients. AJR Am J Roentgenol 1989; 152(4):755 760. 4. Richter GM, Palmaz JC, Nöldge G, et al. The trans jugular intrahepatic portosystemic stentshunt: a new nonsurgical percutaneous method [in German]. Radiologe 1989;29(8):406 411. 5. Olson E, Yune HY, Klatte EC. Transrenal-vein reflux ethanol sclerosis of gastroesophageal varices. AJR Am J Roentgenol 1984;143(3):627 628. 6. Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. J Gastroenterol Hepatol 1996;11(1): 51 58. 7. Boyer TD, Haskal ZJ; American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 2005;41(2): 386 400. 8. Khan S, Tudur Smith C, Williamson P, Sutton R. Portosystemic shunts versus endoscopic therapy for variceal rebleeding in patients with cirrhosis. Cochrane Database Syst Rev 2006 (4):CD000553. 9. Saab S, Nieto JM, Lewis SK, Runyon BA. TIPS versus paracentesis for cirrhotic patients with refractory ascites. Cochrane Database Syst Rev 2006 (4):CD004889. 10. Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133(3):825 834. 11. García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med 2010;362(25):2370 2379. 12. Plauth M, Schütz T, Buckendahl DP, et al. Weight gain after transjugular intrahepatic portosystemic shunt is associated with improvement in body composition in malnourished patients with cirrhosis and hypermetabolism. J Hepatol 2004;40(2):228 233. 13. Lo GH, Liang HL, Chen WC, et al. A prospective, randomized controlled trial of transjugular intrahepatic portosystemic shunt versus cyanoacrylate injection in the prevention of gastric variceal rebleeding. Endoscopy 2007;39(8):679 685. 14. Kirby JM, Cho KJ, Midia M. Image-guided intervention in the management of complications of portal hypertension: more than TIPS for success. RadioGraphics 2013;33(5):1473 1496. 15. Akhter NM, Haskal ZJ. Diagnosis and management of ectopic varices. Gastrointest Interv 2012;1(1): 3 10. 16. Rössle M, Siegerstetter V, Olschewski M, Ochs A, Berger E, Haag K. How much reduction in portal pressure is necessary to prevent variceal rebleeding? a longitudinal study in 225 patients with transjugular intrahepatic portosystemic shunts. Am J Gastroenterol 2001;96(12):3379 3383.

1500 September-October 2013 radiographics.rsna.org 17. Haskal ZJ, Edmond J, Brown R. Mesenteric venous thrombosis. N Engl J Med 2002;346(16):1252 1253. 18. Cura M, Haskal Z, Lopera J. Diagnostic and interventional radiology for Budd-Chiari syndrome. RadioGraphics 2009;29(3):669 681. 19. García-Pagán JC, Heydtmann M, Raffa S, et al. TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients. Gastroenterology 2008;135(3):808 815. 20. Darwish Murad S, Valla DC, de Groen PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004;39(2):500 508. 21. D Avola D, Bilbao JI, Zozaya G, et al. Efficacy of transjugular intrahepatic portosystemic shunt to prevent total portal vein thrombosis in cirrhotic patients awaiting for liver transplantation. Transplant Proc 2012;44(9):2603 2605. Authors Response From: John Martin Kirby, MB, BCh, BAO, MRCP, FRCR Mehran Midia, MD, FRCPC Department of Radiology, McMaster University Medical Center, Hamilton Health Sciences Hamilton, Ontario, Canada Kyung J. Cho, MD Department of Radiology, University of Michigan Ann Arbor, Michigan We thank Dr Haskal for his insightful and informative comments. The central role of the interventional radiologist in managing complicated portal hypertension in the unwell cirrhotic patient is indeed a major responsibility. Although several clinical trials attest to the safety and efficacy of TIPS placement for secondary prevention of variceal bleeding and in the treatment of refractory ascites, a decision not to offer a TIPS procedure may be particularly challenging, since other therapeutic options may be limited or exhausted and the prognosis often poor. Offering a modified or alternate interventional procedure requires careful consideration. Clinical and biochemical assessment, along with a thorough understanding of imaging modalities and angiographic methods for evaluation of hepatic blood flow, are important for diagnosis and developing treatment strategies. Referral to, or consultation with, a large-volume center may be appropriate. Dr Haskal highlights several important issues regarding the measurement and value of gradient endpoints. Pressure measurements from the right atrium, IVC, free hepatic vein, and portal vein, in addition to corrected sinusoidal pressure (wedged hepatic or portal pressure minus IVC pressure), may improve the accuracy and precision of portosystemic gradient endpoint measurement after TIPS placement. The commonly used abbreviation, HVPG, can be misleading because it stands for hepatic venous pressure gradient, suggesting a pressure gradient between the free hepatic vein and the right atrium. A more accurate term is portosystemic pressure gradient, which indicates a pressure gradient between the portal vein and right atrium. Guidelines from the Society of Interventional Radiology and the American Association for the Study of Liver Disease (1) suggest a reduction in HVPG to less than 12 mm Hg when the indication is bleeding esophageal varices. Although the guidelines acknowledge that the degree of reduction in HVPG needed to control ascites is unclear, a gradient of 12 mm Hg or less is nevertheless suggested as a reasonable goal. Dr Haskal s comments regarding patients with higher pressures are reassuring, particularly when the angiographic findings are satisfactory. Gradients below 5 mm Hg have been reported as an indicator of poor outcome and have been associated with an increase in the risk of liver failure and hepatic encephalopathy requiring intervention such as TIPS reduction (2). Clinical examination and US may noninvasively infer a satisfactory TIPS outcome in patients with ascites. Many physicians follow up varices with routine endoscopy; however, the use of routine venography and manometry for TIPS placement in patients with varices has decreased significantly since the advent of covered stents. Nonetheless, angiography and manometry remain of value in the evaluation of patients with recurrent or persistent ascites or recurrent bleeding.

RG Volume 33 Number 5 Kirby et al 1501 Dr Haskal draws attention to the lack of evidence for adhering to a threshold of 12 mm Hg for gastric or ectopic varices. Most isolated fundal or fundal-cardiac varices drain through a developed gastrorenal shunt, such that the portal pressure in these patients is quite low. Patients with massive upper gastrointestinal bleeding and a portosystemic gradient of less than 12 mm Hg have either gastric or ectopic varices or are bleeding from a source other than esophageal varices. Such observations support the rationale for BRTO in these patients. Hepatic vein occlusion, the Budd-Chiari syndrome, is an uncommon cause of portal hypertension and has many etiologies. These include hypercoagulation states such as polycythemia vera, sickle cell anemia, paroxysmal nocturnal hemoglobinuria, use of oral contraceptives, and occlusion of the hepatic segment of the IVC by a web or thrombosis. Hepatoma and renal cell carcinoma are rare causes. Treatment depends on the underlying cause and the anatomic lesions that are present. TIPS placement may be appropriate and may prevent later development of cirrhosis; however, hepatic vein recanalization with stent placement avoids potential encephalopathy following TIPS placement and, if feasible, should be considered as the initial treatment option. Portal hypertension due to presinusoidal block (extrahepatic portal vein stenosis or occlusion) is generally treated with portal vein recanalization, angioplasty, and stent placement, regardless of the underlying cause. Acute portomesenteric thrombosis causing mesenteric venous hypertension and mesenteric ischemia may be treated with removal of the thrombus using catheter-directed thrombolysis and thromboaspiration carried out with various currently available thrombectomy devices. If portal vein flow remains sluggish after thrombectomy or portal pressure remains high, a TIPS can be placed to decrease portal pressure and prevent portal vein rethrombosis, as noted by Dr Haskal. We accept Dr Haskal s comments regarding the survival benefit of TIPS placement (versus largevolume paracentesis) for patients with refractory ascites. The 2007 meta-analysis by Salerno et al (3) differed from three previous meta-analyses of essentially the same studies that did not identify a survival benefit, by using individual-level (rather than aggregate) data, allowing an analysis of survival as a time-dependent variable. Although a survival was reported, the applicability of the findings is unclear. The authors themselves caution that selection criteria in the individual randomized controlled trials limited inclusion to between 21% and 53% of the general population of cirrhotic patients with refractory ascites (3). In addition, apart from allocation to TIPS, age, serum bilirubin levels, and serum sodium levels were identified as independent predictors of better survival at multivariate analysis, suggesting that there is probably a subgroup of patients in whom TIPS is likely to be particularly beneficial. More recently, Narahara et al (4) demonstrated improved survival in a TIPS group compared with a paracentesis group; however, all patients had good liver and renal function. On a historical footnote, we feel it right to acknowledge the pioneering work of Colapinto et al (5) in 1983, who created portosystemic shunts by inflating the balloon of a Grüntzig dilation catheter in the needle track between the portal and hepatic veins in six patients with portal hypertension and life-threatening upper gastrointestinal hemorrhage from esophageal varices (5). All six patients died within 6 months, but in three of the four postmortem examinations, the shunts were easily identified and shown to be patent, the last of these 6 weeks after the procedure. The technique became reproducibly successful with the development of endovascular stents in the mid-1980s. References 1. Boyer TD, Haskal ZJ; American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology 2010;51(1):306. 2. Chung HH, Razavi MK, Sze DY, et al. Portosystemic pressure gradient during transjugular intrahepatic portosystemic shunt with Viatorr stent graft: what is the critical low threshold to avoid medically uncontrolled low pressure gradient related complications? J Gastroenterol Hepatol 2008;23(1):95 101. 3. Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133(3):825 834. 4. Narahara Y, Kanazawa H, Fukuda T, et al. Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial. J Gastroenterol 2011; 46(1):78 85. 5. Colapinto RF, Stronell RD, Gildiner M, et al. Formation of intrahepatic portosystemic shunts using a balloon dilatation catheter: preliminary clinical experience. AJR Am J Roentgenol 1983;140(4): 709 714.