Experience With LT in POPH
Seventy-two percent of respondents described their experience with LT in patients with POPH as overall favorable, and all responded that they had prior experience with LT in patients with POPH. Opinions regarding the safety of LT were significantly impacted by prior experience. Respondents with a favorable experience were more likely to answer that LT was nearly always or often safe (35/49, 71.4%) as compared to respondents with either neutral (8/14, 57.1%) or unfavorable experiences (0/4, 0%) (P = 0.01). The majority of respondents (76.8%) reported prior experience with LT being canceled at the time of surgery due to the presence of PH with a range of 1–10 canceled liver transplants per respondent (average 3.3). In most cases, PH was newly detected at the time of planned transplant.
Attitudes Regarding the Current MELD Exception for POPH
Almost half of respondents (49.3%) agreed that the current MELD exception criteria for POPH should be modified while 32.8% were neutral and 17.9% disagreed (Figure 3). Specific aspects of the POPH MELD exception criteria that respondents thought should be modified are detailed in Table 2. Providers from smaller LT centers were more likely than providers from larger LT centers to agree that there should be specific criteria regarding liver disease severity (45.7% versus 17.9%, P = 0.01). Other responses regarding the POPH MELD exception did not differ by center size (P > 0.05). More PH providers than hepatologists (P = 0.001) thought that the hemodynamic criteria for response to PAH therapy should be modified (Table 2). Other suggested modifications included implementation of specific regional criteria to facilitate timely transplant, a need for improved phenotyping of patients with POPH, higher prioritization for patients with POPH on PAH therapy for a longer period of time and modification of the criteria, so mPAP was not the primary determinant of eligibility with the need to properly define an elevated mPAP due to a high flow state.
The approach to a patient with treated POPH and an elevated mPAP >35 mm Hg due to a high cardiac output with a normal PVR varied by specialty (P = 0.02) (Table 2). Individualized approaches to this scenario included aggressive diuresis or ultrafiltration, repeat right heart catheterization, lowering the dose of PAH therapy, and trying to reduce the cardiac output with midodrine. Only 5.4% of respondents thought that an mPAP >35 mm Hg regardless of PVR should be an absolute contraindication to LT (Table 2) and more PH providers than hepatologists thought that an mPAP >35 mm Hg with an elevated PVR >400 dynes was a contraindication to LT (P = 0.047) (Table 2).
Management of POPH
Most respondents agreed that liver transplant candidates with moderate-to-severe POPH should be managed in centers with expertise in POPH (Table 2). Most responses regarding beta-blocker use and transjugular intrahepatic portosystemic shunt in POPH were concordant with current guidelines (Table 2). PH providers were asked additional questions regarding PAH therapy. Treatment with PAH therapy was diverse, spanning the spectrum from oral to inhaled to parenteral therapy. No particular therapeutic class emerged as a favored approach to treatment (Table 2). One respondent reported using calcium channel blockers for treatment of POPH despite current guidelines that recommend avoiding their use in POPH. Providers had varied experience with weaning and discontinuing PAH therapy posttransplant, with some reporting that they nearly always weaned or discontinued PAH therapy and others reporting that they rarely or never weaned or discontinued PAH therapy (Figure 4). The approach to weaning therapy also varied among PH providers (Table 2).
We performed the first multidisciplinary survey of transplant hepatologists and PH providers to better understand their attitudes and practice patterns regarding the management of POPH and to compare current practice to clinical guidelines. We found that there was marked variability in management, and nearly half thought that the current POPH MELD exception criteria should be modified. Additionally, in contrast to current guidelines, many agreed that POPH should be an indication for LT, even in the setting of compensated cirrhosis. This study highlights the need for prospective studies to address evidence gaps and inform clinical practice and for improved understanding of barriers to adoption of guidelines in order to standardize care for patients with POPH.
We chose to study hepatologists and PH providers, as these physicians are involved in the management of POPH regardless of whether they are LT candidates. Other specialists, such as transplant anesthesiologists, play a critical role in the perioperative management of LT candidates with POPH but are not typically involved in the long-term management of POPH, so they were not included. We also surveyed transplant surgeons but did not include their responses in the article due to the low response rate. All of the respondents reported prior experience with LT in POPH. Although this may be due to response bias, this suggests that most providers at large LT centers manage patients with POPH and that the respondents in our survey were equipped to answer questions regarding POPH management.
Although the response rate for the survey was low, there was a wide spectrum of responses, reflecting a diverse range of attitudes and practice of both hepatologists and PH providers from 35 LT centers across the country with representation from 10/11 UNOS regions. Although our results may not be representative of all hepatologists and PH providers, this study is the first to provide insight into the diverse attitudes and practice of providers from across the country.
Screening for POPH
In concordance with current guidelines,12 most transplant hepatologists perform screening echocardiograms at the time of LT evaluation. In the setting of insufficient data to guide the need for invasive testing, however, there was marked variability among hepatologists in the estimated RVSP that would prompt further workup of POPH, ranging from >30 to >50 mm Hg. This variability in practice may lead to overutilization of invasive testing at some institutions and inadequate recognition or delayed diagnosis of POPH at other centers.
A high percentage of respondents reported prior experience with canceled liver transplants, predominantly due to the presence of newly detected PH. This suggests that improved screening practices are needed in order to identify and treat these patients prior to LT. Due to inadequate evidence, current guidelines are vague regarding optimal time intervals and indications for subsequent echocardiograms in waitlisted LT candidates.3,12 Multicenter prospective studies to better understand clinical risk factors for POPH and its rate of development and progression could help inform evidence-based screening practice and guidelines.
Attitudes and Experience Regarding LT and POPH
There was variability in attitudes regarding the safety of LT in patients with POPH and the expected posttransplant outcomes. In an effort to better understand reasons for this variability, we found that attitudes regarding safety were impacted by a provider’s prior experience with LT in POPH (favorable versus unfavorable). We also observed that respondents from regions with a higher median MELD at transplant were less likely to respond that POPH improves with LT. One possible explanation for this finding is that patients with POPH MELD exceptions have longer waitlist times in regions with a higher median MELD at LT and may have less reversible disease at the time of LT.
The most recent guidelines state that the unpredictability of post-LT outcomes precludes POPH from being considered an indication for LT,3 but half of respondents thought that POPH should be an indication for LT in patients with compensated cirrhosis, and the majority thought that POPH should be an indication for LT in decompensated cirrhosis. This disparity between current guidelines and provider attitudes highlight the need for better understanding of long-term outcomes in patients with POPH as well as factors that influence provider attitudes. This is especially important given the scarcity of organs and the unknown long-term survival benefit of LT in patients with POPH. Although several recent studies have been published regarding long-term outcomes of POPH with LT, findings and conclusions from these studies are conflicting.13-16 Savale et al13 reported 77% survival 3 years post-LT and concluded that stabilization or improvement of POPH was possible with the combination of PAH therapy and LT, while Verma et al reported 53.8% 5-year post-LT survival with the majority of deaths occurring within the first 6 months and concluded that POPH in isolation should no longer be a valid consideration to LT.16
We identified several significant differences between hepatologists and PH providers regarding attitudes and management which highlight the need for improved communication and integration of care among specialists. For example, hepatologists were more likely than PH providers to agree that POPH should be an indication for LT in compensated cirrhosis. The reasons for this are not known but could be due to differences in opinion regarding the reversibility of POPH with LT or differences in awareness of the efficacy of current PAH therapy.
Attitudes Regarding the Current MELD Exception for POPH
Responses regarding the POPH MELD exception policy were insightful, and we hope that this study can provide groundwork for future efforts to examine and revise the current POPH MELD exception policy. Respondents highlighted several key issues with the current MELD exception policy for POPH. (1) More respondents agreed that POPH should be an indication for LT in decompensated cirrhosis rather than compensated cirrhosis. Prior studies have also found that MELD score significantly impacts waitlist mortality risk.9 Despite this, there is no liver disease severity requirement as part of the current MELD exception criteria. (2) Half of respondents thought there should be specific criteria regarding RV function as part of the MELD exception criteria. Although preserved RV function is essential to the safety of LT, it has not been well studied in POPH, and it is not clear how RV function should be defined or what thresholds should preclude LT. (3) A third and major issue concerned successful response to PAH therapy. It is clear from responses that the clinical scenario of high-flow–mediated elevations in mPAP should be addressed as provider attitudes and practice differed markedly from current policies. Although a posttreatment mPAP <35 mm Hg is required for MELD exception eligibility, only 5.4% of respondents thought that an mPAP >35 mm Hg regardless of PVR should be an absolute contraindication to LT. The approach to a patient with treated POPH and an elevated mPAP due to a high cardiac output also varied with some providers stating they would perform interventions, such as initiation of diuretics, ultrafiltration, or medications, such as midodrine, with no evidence that these interventions reduce perioperative risk.
Management of POPH
The heterogeneity in terms of clinical practice and medications used to treat POPH reflects how little is known about optimal management of this disease. Patients with POPH have been excluded from almost all clinical trials of PAH therapy and providers are left to guess based on their prior experience how to approach treatment of POPH. For uncommon disease such as POPH, more published data are needed from both clinical trials as well as real-world experience in order to improve and standardize care.
There are several important limitations to our study. First, our results may not be generalizable to smaller transplant centers that perform <50 LTs per year or centers in countries outside the United States, as they were not included in the survey. Similarly, our results may not reflect the attitudes and practice of other providers involved in the management of patients with POPH, such as transplant surgeons and anesthesiologists. We intended to include transplant surgeons but did not due to the low response rate and likelihood of bias. These specialists likely have a unique perspective, particularly regarding perioperative and intraoperative management. We also did not have data from nonresponders to further explore factors that may have impacted response rates and results. Last, our sample size was small and may not accurately reflect national practice due to the low response rate and limitations that apply to the nature of the study, such as recall bias, response bias, and sampling error.
In summary, the results of this multidisciplinary survey suggest that there is significant variability in provider attitudes and practice patterns across the country regarding the management of POPH and the role of LT. We also found marked discordance between published guidelines and provider attitudes and clinical practice. This study highlights the need for multicenter prospective studies to address current evidence gaps in POPH and for improved implementation of practice guidelines in order to standardize care for these complex patients.
1. Krowka MJ, Swanson KL, Frantz RP, et al. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology. 2006;44:1502–1510.
2. Colle IO, Moreau R, Godinho E, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology. 2003;37:401–409.
3. Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society practice guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation. 2016;100:1440–1452.
4. Krowka MJ, Miller DP, Barst RJ, et al. Portopulmonary hypertension: a report from the US-based REVEAL registry. Chest. 2012;141:906–915.
5. Swanson KL, Wiesner RH, Nyberg SL, et al. Survival in portopulmonary hypertension: Mayo clinic experience categorized by treatment subgroups. Am J Transplant. 2008;8:2445–2453.
6. DuBrock HM, Channick RN, Krowka MJ. What’s new in the treatment of portopulmonary hypertension? Expert Rev Gastroenterol Hepatol. 2015;9:983–992.
7. 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.
8. Goldberg DS, Batra S, Sahay S, et al. MELD exceptions for portopulmonary hypertension: current policy and future implementation. Am J Transplant. 2014;14:2081–2087.
9. DuBrock HM, Goldberg DS, Sussman NL, et al. Predictors of waitlist mortality in portopulmonary hypertension. Transplantation. 2017;101:1609–1615.
10. Le Pavec J, Souza R, Herve P, et al. Portopulmonary hypertension: survival and prognostic factors. Am J Respir Crit Care Med. 2008;178:637–643.
11. Lai JC, Roberts JP, Vittinghoff E, et al. Patient, center and geographic characteristics of nationally placed livers. Am J Transplant. 2012;12:947–953.
12. Murray KF, Carithers RL Jr; AASLD. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology. 2005;41:1407–1432.
13. Savale L, Sattler C, Coilly A, et al. Long-term outcome in liver transplantation candidates with portopulmonary hypertension. Hepatology. 2017;65:1683–1692.
14. Sithamparanathan S, Nair A, Thirugnanasothy L, et al; National Pulmonary Hypertension Service Research Collaboration of the United Kingdom and Ireland. Survival in portopulmonary hypertension: outcomes of the United Kingdom national pulmonary arterial hypertension registry. J Heart Lung Transplant. 2017;36:770–779.
15. Reymond M, Barbier L, Salame E, et al. Does portopulmonary hypertension impede liver transplantation in cirrhotic patients? A French multicentric retrospective study. Transplantation. 2018;102:616–622.
16. Verma S, Hand F, Armstrong MJ, et al. Portopulmonary hypertension: still an appropriate consideration for liver transplantation? Liver Transpl. 2016;22:1637–1642.
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