LIVER TRANSPLANTATION 20:635–636, 2014

EDITORIAL

Portopulmonary Hypertension: Formidable Dual Threat Versus Hopeful Dual Therapy Michael J. Krowka and Rodrigo Cartin-Ceba William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN Received March 31, 2014; accepted March 31, 2014.

See Article on Page 724 Portopulmonary hypertension (POPH) poses a clinically important dual threat. It is defined as pulmonary arterial hypertension (PAH) in association with portal hypertension. Pretransplant mortality in POPH patients has been equally distributed between complications of liver disease (gastrointestinal bleeding, infections, and multiorgan failure) and cardiac issues (right heart failure). In studies involving more than 400 POPH patients, the 5-year POPH survival rate ranged from 40% to 68% for those treated with PAHspecific therapy and from only 2% to 14% for those not treated at all.1-4 For those POPH patients being considered for liver transplantation (LT) and treated with PAH-specific drugs, 3 pertinent questions arise: Is there an optimal pre-LT medical therapy for POPH? What is the risk for LT in the presence of treated POPH? Will POPH be resolved if LT is performed? Although a small series, this contribution by Khaderi et al.5 provides a single-institution, long-term experience for addressing these questions.

400 dynescm25. Certainly other PAH-specific agents can attain similar results, but the intravenous prostacyclin approach was the first very successful “kid on the block” to demonstrate significant improvements in pulmonary hemodynamics and survival in the PAH world. Early in the Mayo Clinic experience with transplantation for POPH patients, intravenous epoprostenol was an attractive option because of its success (improved hemodynamics and survival) with other forms of PAH.7 Subsequently, several investigators have reported the effectiveness of intravenous prostacyclin (epoprostenol or treprostinil) before LT.6 In addition to the current oral phosphodiesterase type 5 inhibitors (sildenafil and tadalafil) and endothelin receptor antagonists (bosentan and ambrisentan) used for POPH,6 we will likely see 3 recently Food and Drug Administration–approved agents tried in POPH patients: macitentan (an oral dual endothelin receptor antagonist),8 riociguat (an oral guanylate cyclase stimulator),9 and extended-release treprostinil (an oral form of prostacyclin).10 Reports of the effects of these newer medications (as well as others) on portal hypertension per se and the outcomes of POPH from controlled, multicenter studies will be welcomed by those managing POPH.

OPTIMAL POPH THERAPY? Despite the current availability of 12 Food and Drug Administration–approved PAH medications for the treatment of PAH, there are no controlled studies to guide POPH treatment selection. POPH treatment is, therefore, based on case reports and small case series.6 In 6 of 7 POPH patients, Khaderi et al.5 successfully used 24/7 intravenous epoprostenol as their pre-LT agent to reduce the mean pulmonary artery pressure to less than 35 mm Hg and the pulmonary vascular resistance to less than

RISK FOR LT? Moderate-to-severe POPH (mean pulmonary artery pressure > 35 mm Hg) has been associated with intraoperative mortality and death due to right heart failure during transplant hospitalization.11 However, those experiences were reported in an era of very limited PAHspecific medication use/availability and before Model for End-Stage Liver Disease (MELD) exceptions (initiated in 2002). Each of the patients described by Khaderi

Abbreviations: LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PAH, pulmonary arterial hypertension; POPH, portopulmonary hypertension; RV, right ventricle. Address reprint requests to Michael J. Krowka, M.D., William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, 200 First Street Southwest, Rochester MN 55905. Telephone: 507-284-5398; FAX: 507-266-4372; E-mail: [email protected] DOI 10.1002/lt.23885 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 2014 American Association for the Study of Liver Diseases. V

636 EDITORIAL

et al.5 received a MELD exception, which facilitated transplantation earlier than possible with the calculated MELD scores (range 5 6-12). Did the MELD exceptions reduce the risk? Very limited data suggest a POPH waitlist mortality rate of 7.8% since 2002, with 1- and 3year survival rates of 83% and 76%, respectively.12 However, those data were complicated by regional review board variations in granting exceptions and by the evolution of guidelines in 2006, and only since 2012 have standardized criteria for MELD exceptions for POPH been recognized by the United Network for Organ Sharing. The impact of MELD exceptions granted for POPH requires further analysis, especially with specific hemodynamic data available since 2012.13 Pre-LT risk assessment in the setting of POPH is a continual process. The role of pre-incision and intraoperative hemodynamic measurements via pulmonary artery catheter monitoring and the use of transesophageal echocardiographic monitoring of the right ventricle (RV) are important. The addition of inhaled nitric oxide to enhance pulmonary artery vasodilation is reported by Khaderi et al.,5 although we are not given the particular circumstances for this. Indeed, hemodynamics can change quickly, even with PAH-specific medications on board, especially with reperfusion of the allograft. Hence, POPH patients remain at higher risk for LT complications despite therapeutic advances. Patients and their families should be so informed.

POPH RESOLUTION AFTER LT? Khaderi et al.5 describe only 2 POPH patients who were off all PAH-specific medications after LT (4.4 and 8.5 years). Other patients, followed by serial transthoracic echocardiography, continued on various combinations of sildenafil, ambrisentan, and digoxin. We are not informed about the hemodynamic or echocardiographic criteria followed when the oral medications were initiated after LT. POPH resolution after LT has been reported by other authors.6 In most cases, resolution has been defined in a practical, hemodynamic manner via transthoracic echocardiography: normalization of systolic RV pressure estimates and, in some cases, RV size and function. Understandably, a demonstration of the pathological resolution of POPH after LT has not been reported; repeat right heart catheterization in the setting of a normal echocardiogram (with the patient on or off PAH-specific medications) is arguable from a cost perspective unless it is part of a research study. Who is most likely to experience a post-LT hemodynamic resolution of POPH and favorable long-term survival? Certainly, function of the hepatic allograft is paramount. We take issue with Khaderi et al.’s perspective that we cannot predict POPH resolution,5 and we put forth the following hypothesis. If the RV size and function can be normalized with PAH-specific medications before LT, this is the best predictor of freedom from all PAH-specific medications and for a hemodynamic cure of POPH with LT. Such an improvement in pulmonary artery/RV hemodynamics may be a

LIVER TRANSPLANTATION, June 2014

result of relieving vasoconstriction and/or reversing the abnormal vascular remodeling over time. As first noted by Yoshida et al.14 many years ago, eliminating the causes and consequences of portal hypertension with LT is a key component in resolving POPH. As shown by the long-term outcomes in this study by Khaderi et al.,5 PAH-specific medications and LT, possibly facilitated by MELD exceptions, offer a hopeful dual therapy against a formidable dual threat.

REFERENCES 1. Krowka MJ, Miller DP, Barst RJ, Taichman D, Dweik RA, Badesch DB, McGoon MD. Portopulmonary hypertension: a report from the US-based REVEAL registry. Chest 2012;141:906-915. 2. Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, et al. Portopulmonary hypertension: survival and prognostic factors. Am J Respir Crit Care Med 2008;178:637-643. 3. Swanson KL, Wiesner RH, Nyberg SL, Rosen CB, Krowka MJ. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant 2008;8:2445-2453. 4. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coll Cardiol 1991; 17:492-498. 5. Khaderi S, Khan R, Safdar Z, Stribling R, Vierling JM, Goss JA, Sussman NL. Long-term follow-up of portopulmonary hypertension patients after liver transplantation. Liver Transpl 2014;20:724-727. 6. Cartin-Ceba R, Krowka MJ. Portopulmonary hypertension. Clin Liver Dis 2014;18:421-438. 7. Krowka MJ, Frantz RP, McGoon MD, Severson C, Plevak DJ, Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999;30:641-648. 8. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie` N, Ghofrani HA, et al.; for SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-818. 9. Ghofrani HA, Galie` N, Grimminger F, Gr€ unig E, Humbert M, Jing ZC, et al.; for PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-340. 10. Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013;127:624-633. 11. Krowka MJ, Plevak DJ, Findlay JY, Rosen CB, Wiesner RH, Krom RA. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6:443-450. 12. Krowka MJ, Wiesner RH, Heimbach JK. Pulmonary contraindications, indications and MELD exceptions for liver transplantation: a contemporary view and look forward. J Hepatol 2013;59:367-374. 13. Krowka MJ, Fallon MB, Mulligan DC, Gish RG. Model for EndStage Liver Disease (MELD) exception for portopulmonary hypertension. Liver Transpl 2006:12(suppl 3):S114-S116. 14. Yoshida EM, Erb SR, Pflugfelder PW, Ostrow DN, Ricci DR, Ghent CN, et al. Single-lung versus liver transplantation for the treatment of portopulmonary hypertension—a comparison of two patients. Transplantation 1993;55:688-690.

Portopulmonary hypertension: formidable dual threat versus hopeful dual therapy.

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