Introduction
Portopulmonary hypertension is a progressive pulmonary vascular disease that occurs in the setting of portal hypertension and is characterized by an elevated mPAP >20 mmHg and a PVR >240 dynes/sec/cm^-5.¹ Portopulmonary hypertension is categorized as Group 1 PAH by the World Health Organization classification and managed with PAH-specific therapy.¹ PAH therapy can improve symptoms, exercise capacity, hemodynamics and perioperative risk stratification, but medications need to be continued lifelong and are not curative.^2-4 Unlike most forms of PAH, portopulmonary hypertension can improve with liver transplantation.⁴ Remarkably, approximately half of patients with portopulmonary hypertension have post-transplant resolution of portopulmonary hypertension and are able to discontinue PAH therapy.⁴

In considering individuals for liver transplantation, portopulmonary hypertension severity plays an important role in perioperative risk assessment.⁵ Severe portopulmonary hypertension is considered a contraindication to liver transplantation given increased perioperative mortality risk. Because portopulmonary hypertension can improve with liver transplantation, and because waitlist mortality risk is not adequately reflected by an individual's Model for End-Stage Liver Disease (MELD) score, selected patients with portopulmonary hypertension can qualify for a MELD exception with a higher priority transplant waitlist. According to the most recent MELD exception criteria published in 2006, mPAP must be <35 mmHg post PAH-specific therapy in order to qualify for a portopulmonary hypertension MELD exception.⁵ Additionally, mPAP >45-50 mmHg is considered an absolute contraindication for liver transplantation.^5,6 However, these cutoffs are based on older studies conducted over 2 decades ago in which those with untreated portopulmonary hypertension and mPAP of 35-50 mmHg at the time of liver transplantation had 50% perioperative mortality and those with mPAP of >50 mmHg had 100% perioperative mortality.⁷ Furthermore, it has become apparent that mPAP taken as an isolated point of evaluation is a suboptimal treatment goal because it can be influenced not only by an elevated PVR but also by an increase in CO and/or PAWP, both of which are common in the setting of advanced liver disease.

As such, the mPAP threshold of 35 mmHg may not be optimal for assessing perioperative risk in patients with portopulmonary hypertension. The clinical outcomes of patients with treated portopulmonary hypertension and mPAP ≥35 mmHg at the time of liver transplantation have not been fully characterized.

Study Design and Results
The authors performed a multicenter case series evaluating the post-transplant outcomes of 16 patients with treated portopulmonary hypertension who underwent liver transplantation with an elevated mPAP ≥35 mmHg, normal PVR (defined as <250 dynes/sec/cm^-5), and preserved right ventricular function on echocardiogram, at or just before liver transplantation.⁸ Of the 16 patients included in this study, most were female (68.8%) with a median age of 50 years (41-57) and a median MELD-Na score of 18 (11-31). Patients were treated with various PAH-specific therapies including phosphodiesterase 5 inhibitors, endothelin receptor antagonists, parenteral prostacyclin therapy, and inhaled nitric oxide. Interestingly, PAH therapy was associated with a decrease in PVR and mPAP, as expected, but also a marked increase in PAWP and CO, which in turn offsets the expected decrease in mPAP (Figure 1).⁸ Post-treatment hemodynamics prior to transplant showed a median mPAP of 38 mmHg (interquartile range [IQR] 35-42 mmHg), PVR of 191 dynes/sec/cm^-5 (IQR 172-216 dynes/sec/cm^-5), CO of 8.5 L/min (IQR 7.3-9.8 L/min), and a PAWP of 20 mmHg (IQR 14-22 mmHg). Post-transplant mortality at 1 year was 69%, which is comparable to the recently reported 1 year 72% post-transplant survival rates in a cohort of other patients with portopulmonary hypertension from the same center.⁹ Of the 5 deaths noted, only 1 death was attributed to portopulmonary hypertension. Additionally, 63% of surviving patients were weaned off PAH therapy after liver transplantation and "cured" of portopulmonary hypertension.

Significance
The study highlights the importance of understanding all the factors that can contribute to an elevated mPAP in liver disease (i.e., PAWP, PVR, and CO) and how these variables can change with PAH therapy. Understanding these variables is critical in assessing perioperative risk and determining the success or failure of PAH therapy. The findings also make us cognizant of important pitfalls that should be avoided, such as treating an elevated mPAP due to increased CO or PAWP with increased vasodilator therapy. The study's demonstration of similar post-transplant survival in a cohort with an elevated mPAP also supports the notion that mPAP considered alone is perhaps an incomplete evaluation of perioperative risk. The study also highlights how the current MELD exception criteria may place patients with well-treated pulmonary vascular disease but an elevated mPAP due to liver disease-related physiology at a disadvantage, precluding the opportunity for potential cure of both portopulmonary hypertension and liver disease with liver transplantation. Based on this study and other recent studies,^10,11 modifications to the MELD exception criteria have recently been proposed to allow ongoing MELD exceptions for patients with portopulmonary hypertension with an elevated mPAP of 35-45 mmHg as long as PVR is normal (<240 dynes/sec/cm^-5) and echocardiographic right ventricular function is preserved.

References

1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913.
2. Krowka M, Cottreel E, Hoeper MM, et al. Macitentan Improves Risk Categorization for Liver Transplant Mortality in Patients With Portopulmonary Hypertension: A PORTICO Study Post Hoc Analysis. Liver Transpl 2020;26:935-40.
3. Deroo R, Trépo E, Holvoet T, et al. Vasomodulators and Liver Transplantation for Portopulmonary Hypertension: Evidence From a Systematic Review and Meta-Analysis. Hepatology 2020;72:1701-16.
4. Savale L, Guimas M, Ebstein N, et al. Portopulmonary hypertension in the current era of pulmonary hypertension management. J Hepatol 2020;73:130-9.
5. Krowka MJ, Fallon MB, Mulligan DC, Gish RG. Model for end-stage liver disease (MELD) exception for portopulmonary hypertension. Liver Transpl 2006;12:S114-S116.
6. 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;100:1440-52.
7. 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;6:443-50.
8. DuBrock HM, Runo JR, Sadd CJ, et al. Outcomes of Liver Transplantation in Treated Portopulmonary Hypertension Patients With a Mean Pulmonary Arterial Pressure ≥35 mm Hg. Transplant Direct 2020;6:e630.
9. Cartin-Ceba R, Burger C, Swanson K, et al. Clinical Outcomes after Liver Transplantation in Patients with Portopulmonary Hypertension. Transplantation 2020;Oct 12:[Epub ahead of print].
10. DeMartino ES, Cartin-Ceba R, Findlay JY, Heimbach JK, Krowka MJ. Frequency and Outcomes of Patients With Increased Mean Pulmonary Artery Pressure at the Time of Liver Transplantation. Transplantation 2017;101:101-6.
11. DuBrock HM, Goldberg DS, Sussman NL, et al. Predictors of Waitlist Mortality in Portopulmonary Hypertension. Transplantation 2017;101:1609-15.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Lipid Metabolism, Pulmonary Hypertension, Echocardiography/Ultrasound, Hypertension

Keywords: Phosphodiesterase 5 Inhibitors, Nitric Oxide, Epoprostenol, Liver Transplantation, Vasodilator Agents, Endothelin Receptor Antagonists, Ventricular Function, Right, Exercise Tolerance, Goals, Survival Rate, Hypertension, Portal, Motivation, Pulmonary Circulation, Hemodynamics, Echocardiography, Risk Assessment, World Health Organization, Severity of Illness Index, Hypertension, Hypertension, Pulmonary

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