International Liver Transplantation Society practice guideline update on portopulmonary hypertension

Portopulmonary Hypertension: The Next Step

Portopulmonary hypertension (PPHTN) has the distinction of being an orphan disease under the umbrella of another orphan disease. PPHTN is sub-classified under WHO Group I pulmonary arterial hypertension (PAH) because the limited data available indicate that patients with PPHTN appear to share the pathology, clinical course and response to treatment seen in other forms of PAH. PPHTN is a rare disease and little progress has been made into the delineation of its pathologic mechanisms and treatment since its initial description in 1951. Because the paucity of large cohorts, evolving clinical experience has been the principal driver of change in the management of these patients. PPHTN is defined as pulmonary hypertension with coexisting portal hypertension. It is defined haemodynamically as an elevated mean pulmonary artery pressure (mPAP > 25 mmHg), an increased pulmonary vascular resistance (PVR) (> 3 wood units) and a normal pulmonary artery occluding pressure (PAOP) <15 mm Hg or elevated transpulmonary gradient (TPG-mPAP-PAOP, normal 12). This lengthy definition is particularly important in PPHTN because of the variety of haemodynamic derangements identified in patients with liver disease. Many patients with liver disease and portal hypertension will exhibit a high cardiac output state and a low systemic vascular resistance, which are thought to be caused by overproduction of nitric oxide. These patients may exhibit a high mean pulmonary artery pressure (mPAP) on right heart catheterisation, but they will have a normal PVR. In addition, patients with liver disease are often volume overloaded and exhibit elevated mean PA pressures and PAOPs, but normal transpulmonary gradients and PVRs. True PPHTN is characterised by both an elevated mPAP and PVR, but because this disease may coexist with volume overload in liver disease, an elevated transpulmonary gradient may be used rather than the PAOP for diagnosis (1). Nearly all of the descriptive data about PPHTN arises from liver transplant. Within the liver transplant population, prevalence ranges from 2 to 20% (2). The severity of the PPHTN does not correlate with the severity of the liver disease or the portal hypertension. Yet, the presence of PPHTN in the patient with liver disease markedly affects prognosis. A retrospective analysis published in 1991 revealed that patients with PPHTN who are neither treated nor transplanted have a mean survival of 15 months (median 6 months) from the time of diagnosis with half of the deaths attributed to PPHTN (3). Because of these sobering survival statistics, liver transplantation as an option for treatment was pursued. Despite reported cures of PPHTN after liver transplantation, early mortality data were disappointing. In 1997, Ramsay et al., demonstrated that PPHTN patients had a 3-year postliver transplant survival of only 21% (4). In addition, a more recent multi-centre database analysis indicated that perioperative mortality was 36% in those with a mPAP > 35 mmHg. Interestingly, this database revealed that the majority of the diagnoses of PPHTN were made in the operating room and thus patients were not treated for their PPHTN prior to transplantation (5). In response to these statistics, for a few years many liver transplantation centres avoided liver transplantation in PPHTN patients. Subsequently, few centres began to report case series of successful liver transplantation in PPHTN patients, and reinforced that the PPHTN is often cured in the weeks to months after liver transplant. It was in this climate that, the European Respiratory Society's Task force on Pulmonary-Hepatic Vascular Disorders met and created diagnostic treatment recommendations for PPHTN. These included liver transplantation for those with mild (< 35 mmHg mPAP) PPHTN and consideration for treatment with pulmonary vasodilators for those with moderate (mPAP 35–45 mmHg) PPHTN prior to transplantation (1). As experience mounted with liver transplantation, a disparity between the poor survival of these patients without liver transplant and their low model for end-stage liver disease (MELD) score was noted. The severity of the PPHTN appears to be unrelated to the severity of liver disease in these patients, and thus the MELD underestimates their risk of mortality on the wait-list. The MELD Exception Points Study Group and Conference attempted to account for this disparity with exception recommendations published in 2006 (6). MELD exception is a process by which additional MELD points may be granted through the regional review board, thereby increasing the patient's chances for liver transplantation regardless of their baseline synthetic liver function. The committee's recommendations suggest that MELD exception should be based on standardised data, which can then be collected and analysed through the NIH-supported study group for pulmonary vascular complications of liver disease. Many, but not all, regional review boards have adopted these recommendations. The study group suggested that exception points be given to patients who meet the haemodynamic definition of PPHTN and who are acceptable liver transplant candidates. To achieve extra points, PPHTN patients must initially have moderate to severe PPHTN (mPAP> 35 mmHg) and have been treated with an FDA-approved pulmonary hypertension therapy with a good response. That response is defined as an improvement in mPAP (< 35), PVR (< 5 wood units), and satisfactory right ventricular function. If patients demonstrate this haemodynamic response to treatment, their MELD score for transplantation would automatically be increased to 26. They also recommended consideration for an additional MELD upgrade after 6 months on the wait-list. These criteria aim to reserve liver transplantation for those who would benefit from and are more likely to survive the transplant process according to available data. This standardisation not only makes liver transplantation more accessible to PPHTN patients but also allows more reliable collection and analysis of data across various centres. In addition, it will provide a framework for a description of the appropriate in PPHTN patients. As more PPHTN patients undergo liver transplantation, the data will continue to evolve and will likely provoke further change in clinical practice. Subsequent to the MELD exception points study group findings, the Mayo group published a retrospective screening-RHC analysis of its PPHTN database and analysed their survival according to treatment for PPHTN and transplant status (7). Although the database spanned a 14-year time period, during which the treatments and clinical practice varied, they noted a marked change in survival between different treatment approaches. Patients who received neither a liver transplant nor PH therapy did worst, with a 14% 5-year survival. The patients who were transplanted without PH therapy also did rather poorly with a 25% 5-year survival. The patients who were treated for PH but not transplanted had a 45% 5-year survival. The group with the best outcome were those who were treated for PH before liver transplantation, who exhibited a 67% 5-year survival. Mortality did not correlate with initial haemodynamics, type of liver disease, or the severity of their liver disease. This study underscored the importance of screening for PPHTN in the liver transplant population and prioritising PH therapy. Meticulous, collaborative collection of outcome data for PPHTN patients is essential to evolve our clinical pratice and ensure appropriate organ allocation. Yet, as screening for PPHTN becomes more aggressive, it is possible that the one-size-fits-all approach to transplant evaluation is doing a disservice to some. PH specialists are sometimes faced with patients who have both minimal liver dysfunction and PPHTN that was initially severe, but responded dramatically to medication. In this case, under the current MELD exception guidelines one could list this very functional patient for liver transplantation and have an organ match within months. The long term-prognosis of some of these 'responders' to PPHTN may be quite good, and the perioperative risks of transplant may be unacceptable. On the other hand, if we wait, do we risk the development of 'fixed' pulmonary arteriopathy and decrease the chance that it will 'regress' after liver transplantation? It is very likely that there are disparate practices with regards to these patients between transplant centres with some favouring an aggressive early transplant approach and others favouring a more conservative approach. This nuance is unlikely to be detectable in the current data collection. PPHTN is a rare disease which affects not only each patient's individual survival but also the availability and allocation of donor organs. Continued description of the characteristics, pathology and prognosis of PPHTN will require cooperation between multiple centres, strict adherence to guidelines for the standardisation of data, and diligent documentation and sharing of information. The study of PPHTN may also have broader implications for PAH in general. PPHTN has the unique position of being pathologically identical to PAH, yet curable with liver transplantation while leaving the heart and lungs intact. This is an unmatched opportunity for studying the development and resolution of pulmonary arteriopathy in vivo. As data emerges from the study group for pulmonary vascular complications of liver disease, we will need to continually alter our collection of information to target emerging clinical questions. As no single centre will be able to harness enough timely data for analysis in this rare condition, we must work together to maximise treatment and outcomes for our patients.

Background.Portopulmonary hypertension (POPH), pulmonary arterial hypertension (PAH) that develops in the setting of portal hypertension, affects 5%–6% of patients with liver disease and is associated with significant morbidity and mortality. A mean pulmonary arterial pressure (mPAP) threshold of 35 mm Hg is used to stratify perioperative risk and liver transplant eligibility in treated POPH patients but does not take into account the specific factors that contribute to the pressure elevation.Methods.In this case series, we describe the characteristics and posttransplant outcomes of patients with treated POPH and an mPAP ≥35 mm Hg and pulmonary vascular resistance (PVR) <250 dynes-s-cm−5 at or just before liver transplantation (LT). We also describe the effect of PAH therapy on pulmonary hemodynamics in patients with POPH.Results.Sixteen patients were included. All patients were on PAH therapy at the time of LT. PAH therapy resulted in a decrease of mPAP (median 18.4%; interquartile range [IQR] 8.9%–27.0%) with a reduction in PVR (median 50.5%; IQR, 45.4%–70.7%), and an increase in both cardiac output (CO) (median 28.1%; IQR 5.7%–63.8%) and PAWP (median 50.0%; IQR 16.7%–108.3%) before LT. One year posttransplant survival was 69% (11/16); however, only 1 death was attributed to POPH. At 1-year posttransplant, 63.6% (7/11) of patients were weaned off all PAH therapy with clinical and echocardiographic resolution of POPH.Conclusions.In treated POPH patients with an mPAP ≥35 mm Hg and PVR < 250 dynes-s-cm−5 before LT, 1-year posttransplant survival was 69% and the majority of patients were able to discontinue PAH therapy.

Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: A safe and effective therapy?

Portopulmonary Hypertension: Management and Liver Transplantation Evaluation

PORTOPULMONARY HYPERTENSION PRACTICE PATTERNS AFTER LIVER TRANSPLANTATION

Worsening Dyspnea in Patients With Idiopathic Portal Hypertension

Transthoracic echocardiography screening for the detection of portopulmonary hypertension: A work in progress

Pulmonary artery hypertension (PAH) in the setting of liver disease (portopulmonary hypertension [POPH]) remains a challenge. This diagnosis has significant implications for liver transplant candidates. It is a "deal breaker" if pulmonary hemodynamics and right ventricular function cannot be" improved" or normalized with the medical therapy options. POPH is equally challenging for those not deemed appropriate for transplant; despite medical treatments, survival at 5 years in this group is only 40%.1 The paper by Jose et al2 is timely in describing the spectrum of treatment and management options reported by the pulmonologists and cardiologists who manage specific POPH therapies. The authors highlight the slight variations in managing POPH, given the paucity of randomized prospective drug studies to guide management. The PORTICO studies provided the only large-scale prospective, randomized trial of medication (macitentan) to improve the pulmonary hemodynamics in POPH and change the potential transplant risk.3,4 Other nonmedication management issues have been addressed by the 2016 International Liver Transplantation Society practice guidelines.5 These guidelines were a consensus based on experience and several retrospective analyses of data. They were the best available resource at the time to provide guidance for a disorder that was causing intraoperative death when not diagnosed and treated aggressively. For example, screening echocardiogram recommendations to detect pulmonary hypertension were brought forth in the guidelines, based on large center studies, and subsequently evolved into national policies—a major contribution. Treatment options could only be suggested because of limited experiences treating PAH in patients with liver disease. Interestingly, based upon the survey results in the Jose et al paper, endothelin receptor antagonists (such as macitentan that was studied in PORTOCO) were favored by the cardiologists, more so, than pulmonologists in treating POPH. Note there are now 14 FDA-approved drugs available to treat POPH, but no published POPH studies support the use of 1 oral therapy over the others. In addition, the drug-ordering patterns are often governed by who staffs PAH clinics (pulmonologists, cardiologists, or a combination of both) at various transplant institutions and their personal preference for therapies, often based upon experiences in treating idiopathic pulmonary hypertension. In addition, as reported in the Jose et al paper, management posttransplant remains variable, with no "best weaning approaches" identified. The use of 6-minute walks and monitoring circulating BNP levels to guide treatment was different among physician groups but not supported by any published literature. Discontinuation of iv prostacyclin was done more aggressively by the cardiologists, in conjunction with repeat right heart catheterizations, not unexpectedly. However, outcomes of that approach were not reported, nor within the scope of the study. The hope has always been that the hepatic graft removes any offending vasoactive factors, resolves the hyperdynamic circulation of liver disease, and replaces any deficient entities needed to normalize the pulmonary arterial bed. The expectation has been tempered by the experiences of a successful transplant, yet the persistence of POPH and right ventricular dysfunction still occurs in about 50% of those transplanted. Identifying which factors or drug patterns predict such continuation of therapies has been elusive to date. Aside from the buffet of treatment options, diagnostic criteria for POPH have changed (2018 WHO and 2022 ERS), and UNOS/OPTN POPH MELD exception criteria have been modified.6,7 Specifically, the diagnosis of PAH (and by default POPH) has changed with mean pulmonary artery pressure (mPAP) >20 mm Hg now the cutoff criteria rather than >25 mm Hg. Normal pulmonary vascular resistance is now thought to be <2 Wood units rather than 3 Wood units (especially in POPH due to the inherent higher cardiac outputs associated with portal hypertension). MELD exception criteria for POPH have also been appended recently by including those patients who attain with treatment mPAP <35 mm Hg or mPAP 35 to 45 mm Hg with normal PVR.8 Previously, only mPAP <35 mm Hg was acceptable for transplant listing. Thus, many evolving issues impact our management of POPH patients and the trend to use a combination and even triple PAH therapies to treat POPH. For hepatologists, transplant surgeons, and anesthesiologists, it is obviously important to know what pulmonologists and cardiologists suggest and can demonstrate as the optimal strategies and medical therapies for POPH. Over the last 2 years of publications, large single-center data results, United network for Organ Sharing/Organ Procurement and Transplantation Network data summaries, and literature reviews remain the best guidance to date.9–13 Can a large multicenter registry for POPH be accomplished? Perhaps. The disease is uncommon (less than 5% of all liver transplant candidates), so large prospective studies are problematic but doable, as shown by PORTICO. An update for the 2016 International Liver Transplantation Society guidelines would be prudent and is under consideration. Despite our best intentions, we will continue to "disagree" on the best management approaches and optimal drug approaches. Overall, the differences in drug treatments and management issues in this study are probably minimal from a practical perspective. The real question is whether they relate to different outcomes—an issue not addressed in this study. Short of prospective studies, outcomes studies through large center studies, registries, and shared "real world" data analyses can hopefully identify the "best" approaches for our patients.

This paper provides a critical exploration of the ‘journey metaphor’ promoted in much business discourse on sustainability - in corporate reports and advertisements, and in commentators’ reports in the political and professional business literature. The portrayal of sustainability as a journey evokes images of corporate adaptation, learning, and a movement away from business-as-usual practices. The journey metaphor, however, masks the issue of towards what it is that businesses are actually, or even supposedly, moving. It is argued that business is constructing ‘sustainability’ as a journey to avoid specifying some future desirable state of affairs. We suggest that by portraying ‘sustainability’ in this way, businesses, and the related political and professional literature, have invoked a subtle and powerful, use of language that appears to seriously engage with elements of the discourse around sustainable development and sustainability. Yet at the same time, by constructing and promoting its own version of the discourse, it de-emphasises discussion of desirable future states of living, and neatly sidesteps any debate about, or need to radically change course. The paper illustrates how journeying is invoked throughout corporate reports and other forms of business communication in a process of corporate myth-making. Businesses are shown to be constructing a ‘wonderland’ discourse.

The role of liver transplantation (LT) in the management of portopulmonary hypertension (POPH) is poorly understood. The aim of this study was to better understand provider attitudes and practice patterns regarding the management of patients with POPH and to assess the concordance between clinical practice and current guidelines. We performed a multicenter survey study of hepatologists and pulmonary hypertension (PH) physicians at US LT centers that performed >50 transplants per year. Survey responses are summarized as number (%). Associations were assessed using a Wilcoxon-rank sum, chi-square, or Fisher exact test, as appropriate. Seventy-four providers from 35 centers were included. There was marked variability regarding screening practices, management, and attitudes. Forty-two percent responded that POPH nearly always or often improves with LT, and 15.5% reported that POPH rarely or never improves. In contrast to current guidelines, 50.7% agreed that treated POPH should be an indication for LT in patients with compensated cirrhosis. Hepatologists were more likely than PH physicians to agree that POPH should be an indication for LT (P = 0.02). Forty-nine percent of respondents thought that the current POPH Model for End-stage Liver Disease exception criteria should be modified, and management of patients with an elevated mean pulmonary arterial pressure and normal pulmonary vascular resistance differed from current policies. There is marked variability in provider attitudes and practice patterns regarding the management of POPH. This study highlights the need for prospective studies to inform practice and for improved implementation of practice guidelines in order to standardize care.

Portopulmonary hypertension (PoPH) is a rare subtype of Group 1 pulmonary arterial hypertension (PAH) with a poor prognosis. According to the most up-to-date definition, PoPH is characterized by a mean pulmonary arterial pressure (PAP) of >20 mmHg at rest, a pulmonary artery wedge pressure of ≤15 mmHg, and a pulmonary vascular resistance (PVR) of >2 Wood units with portal hypertension. Like PAH, PoPH is underpinned by an imbalance in vasoactive substances. Therefore, current guidelines recommend PAH-specific therapies for PoPH treatment; however, descriptions of the actual treatment approaches are inconsistent. Given the small patient population, PoPH is often studied in combination with idiopathic PAH; however, recent evidence suggests important differences between PoPH and idiopathic PAH in terms of hemodynamic parameters, treatment approaches, survival, socioeconomic status, and healthcare utilization. Therefore, large, multi-center registry studies are needed to examine PoPH in isolation while obtaining statistically meaningful results. PoPH has conventionally been excluded from clinical drug trials because of concerns over hepatotoxicity. Nevertheless, newer-generation endothelin receptor antagonists have shown great promise in the treatment of PoPH, reducing PVR, PAP, and World Health Organization functional class without causing hepatotoxicity. The role of liver transplantation as a treatment option for PoPH has also been controversial; however, recent evidence shows that this procedure may be beneficial in this patient population. In the future, given the shortage of liver donors, predictors of a favorable response to liver transplantation should be determined to select the most eligible patients. Collectively, advances in these three areas could help to standardize PoPH treatment in the clinic.

Background.Model for end-stage liver disease (MELD) exception criteria for portopulmonary hypertension (POPH) were created to prioritize patients for liver transplant before POPH progression. Little is known about trends in POPH exception frequency, disease severity, pulmonary hypertension treatment patterns, or outcomes since the POPH MELD exception began.Methods.Using data from the Organ Procurement and Transplantation Network database, we describe the frequency of POPH MELD exceptions between 2006 and 2019, compare baseline patient characteristics, and characterize trends in liver disease and POPH severity‚ as well as POPH treatment and outcomes‚ over time. To facilitate comparison, we divided this 14-y period into 3 “eras” (2006–2010, 2011–2015, and 2016–2019).Results.Between 2006 and 2019, 504 unique POPH MELD exceptions were granted. Both liver disease severity and patient age have increased over time (P = 0.04 and P = 0.006, respectively). Posttreatment hemodynamic values (mean pulmonary arterial pressure and pulmonary vascular resistance) have significantly improved (P < 0.001 and P = 0.008, respectively). Treatment with endothelin receptor antagonists has become more prevalent, whereas use of parenteral therapy and monotherapy regimens has decreased (P < 0.001). Neither waitlist nor liver transplant mortality outcomes have significantly changed over the eras analyzed.Conclusions.In conclusion, 504 patients have received POPH MELD exceptions between 2006 and 2019. Since 2010, nearly all patients granted POPH MELD exceptions have met hemodynamic criteria for POPH. Over time, there has been a trend toward older age and higher MELD scores with significant changes in pulmonary arterial hypertension treatment patterns and an improvement in posttreatment hemodynamics without major change in outcomes.

“Porto-pulmonary hypertension: A comprehensive review”

The coexistence of portopulmonary hypertension and hepatopulmonary syndrome.