Portopulmonary hypertension is a state of high pulmonary vascular resistance (PVR) in the background of portal hypertension that ultimately leads to right heart failure. The diagnosis of portopulmonary hypertension is confirmed during right heart catheterization demonstrating a mean pulmonary artery pressure (mPAP) ≥25 mmHg, pulmonary capillary wedge pressure <15 mmHg, and PVR ≥3 Wood units.¹

The presence of portopulmonary hypertension portends a poorer prognosis in patients with liver disease and is an increased risk of mortality for those considered for liver transplantation.^2,3 Histologically, the remodeling of the pulmonary arterial vasculature is similar to pulmonary arterial hypertension (PAH), placing this disease within the World Health Organization group 1 PAH classification.⁴ The PAH group of disorders have been extensively studied and incredible growth in knowledge both in basic science and clinical aspects occurred in the past decades, treatment choices have expanded to 12 different medications that have changed the once obscure previously known outcomes.⁵

The majority of the prospective, randomized, controlled trials on treatment options for PAH has systematically excluded patients with portopulmonary hypertension. In the most extensive study of prevalent and incident cases of PAH in the United States, the REVEAL registry (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management), the presence of portopulmonary hypertension as a diagnosis had a strong signal of worse outcome and all-cause hospitalization rates; when survival scores are elaborated, the diagnosis of portopulmonary hypertension confers negative points, leading to increased mortality at 1 year.⁶ In a separate analysis of the REVEAL registry, patients with portopulmonary hypertension were less likely to be on PAH-specific therapies compared with the rest of the PAH diagnosis despite better hemodynamic profile.³ It has been advocated that in part, this could explain why by itself portopulmonary hypertension provides a worse prognosis and may not be related to the process itself but rather the unclear obstacles for less-than-ideal care.

Patients with portal hypertension often develop a hyperdynamic state, which imposes an increased load to the pulmonary circulation. The diagnosis of portopulmonary hypertension is challenging because elevation of pulmonary pressures measured routinely by echocardiography is commonly related to the presence of high output state, leading frequently to disease misclassification. Right heart catheterization is an essential step in diagnosis and requires a high degree of accuracy and expertise; furthermore, therapies are not prohibited or delayed.

Patients with portopulmonary hypertension benefit from PAH-specific therapies.^7,8 In a small retrospective trial, bosentan, a dual endothelin-receptor antagonist, demonstrated hemodynamic and functional improvement in up to 1 year of follow up.⁹ In an observational study of 13 patients with moderately severe portopulmonary hypertension receiving monotherapy with ambrisentan from 2007 to 2009, there was significant improvement in both mPAP and PVR without adverse effects in liver function.¹⁰ Most recently in the only prospective, randomized, double-blind, placebo-controlled trial in patients with portopulmonary hypertension, macitentan demonstrated at week 12 a 35% reduction in PVR compared with those on placebo without effect in systolic blood pressure or hepatic venous pressure gradients.¹¹ Fluid retention was noted to be significant with the use of these medications; rapid attention to diuresis must be established.

In retrospective studies, prostacyclins delivered intravenously have provided a signal of benefit in patients with portopulmonary hypertension.^12,13 Inhaled prostacyclins have been used without major complications but have an unclear effect on disease progression.^14,15 Concerns of the antiaggregant properties of prostacyclins arise in patients with thrombocytopenia, development of splenomegaly, and enhanced risk of bleeding.¹⁶ In a small study of 10 patients treated with sildenafil, patients enjoyed improved hemodynamics and functional class and exercise tolerance.¹⁷ PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1) randomized 13 patients with portopulmonary hypertension to riociguat, a stimulator of soluble guanylate cyclase, and 3 patients with portopulmonary hypertension to placebo. The study demonstrated good tolerance to the medication and sustained improvement in 6-minute walk distance and World Health Organization functional class. In the open-label portion of the study, benefits were sustained for 2 years.¹⁸

Many of the patients with liver disease also suffer from comorbid encephalopathy and hospitalizations that often pose challenges for appropriate follow-up and adherence to appropriate treatments. Of no less importance, the metabolism of PAH-specific medications is affected by abnormal liver function, as it was described with bosentan, demonstrating that levels of the medication were higher for patients with more advanced liver cirrhosis compared with idiopathic PAH.¹⁹

Not uncommonly, patients with portopulmonary hypertension are diagnosed while they are in the process of evaluation for liver transplantation. The presence of portopulmonary hypertension with mPAP above 50 mmHg is associated with 100% cardiopulmonary mortality in the perioperative period.²⁰ The presence of portopulmonary hypertension in a candidate provides a MELD (model for end-stage liver disease) score exception advantage only if, after appropriate supervised PAH-targeted therapies, a safe hemodynamic profile is present by right heart catheterization.²¹ Currently, it is accepted that improvement in mPAP ≤35 mmHg and PVR ≤5 Wood units or PVR ≤3 Wood units, irrespective of mPAP with satisfactory right ventricular function by echocardiogram, are prerequisites to receive MELD-exception status and possibly be listed safely for this surgery.¹ It is yet unclear what percentage of patients who undergo liver transplantation have their portopulmonary hypertension disease improved, stabilized, or worsened after stabilization from the surgical event. Moreover, the appropriate monitoring or length of therapy that is adequate for the treatment of portopulmonary hypertension after transplantation is unknown.

Whether the diagnosis is timely established and therapies are to be prescribed, the cost of PAH-specific therapies is prohibitive for patients to undertake without appropriate insurance coverage. This is not specific to portopulmonary hypertension but is, nevertheless, a very important limitation. If treatments are covered, the choice of therapy and possible combination treatments is a challenge by itself to the practitioner.

In summary, patients with World Health Organization group 1 portopulmonary hypertension face significant barriers for accurate diagnosis and management. Moreover, limited therapy choices have been proven to be effective, and side effects are prevalent. Expertise on the management of these patients should be limited to centers with qualified practitioners who are able to navigate the intricacies inherent to the multiple associated conditions.²² The advancements are many, as are the difficulties; it is our responsibility to find the best pathways to care for these disadvantaged individuals.

References

1. 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.
2. Sithamparanathan S, Nair A, Thirugnanasothy L, et al. Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry. J Heart Lung Transplant 2017;36:770-79.
3. Krowka MJ, Miller DP, Barst RJ, et al. Portopulmonary hypertension: a report from the US-based REVEAL Registry. Chest 2012;141:906-15.
4. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41.
5. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62:D60-72.
6. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164-72.
7. 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;8:2445-53.
8. Faisal M, Siddiqi F, Alkaddour A, Bajwa A, Shujaat A. Effects Of PAH Specific Therapy On Pulmonary Hemodynamics And Six Minute Walk Distance In Porto-Pulmonary Hypertension: A Systematic Review And Meta-Analysis. Am J Respir Crit Care Med 2014;189:A4759.
9. Hoeper MM, Halank M, Marx C, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J 2005;25:502-8.
10. Cartin-Ceba R, Swanson K, Iyer V, Wiesner RH, Krowka MJ. Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. Chest 2011;139:109-14.
11. Sitbon O, Bosch J, Cottreel E, et al. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respir Med 2019;7:594-604.
12. Awdish RL, Cajigas HR. Early initiation of prostacyclin in portopulmonary hypertension: 10 years of a transplant center's experience. Lung 2013;191:593-600.
13. 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;30:641-8.
14. Hoeper MM, Seyfarth HJ, Hoeffken G, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J 2007;30:1096-102.
15. Melgosa MT, Ricci GL, García-Pagan JC, et al. Acute and long-term effects of inhaled iloprost in portopulmonary hypertension. Liver Transpl 2010;16:348-56.
16. Findlay JY, Plevak DJ, Krowka MJ, Sack EM, Porayko MK, et al. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transpl Surg 1999;5:362-5.
17. Hemnes AR, Robbins IM. Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation. Liver Transpl 2009;15:15-9.
18. Cartin-Ceba R, Halank M, Ghofrani HA, et al. Riociguat treatment for portopulmonary hypertension: a subgroup analysis from the PATENT-1/-2 studies. Pulm Circ 2018;8:2045894018769305.
19. Savale L, Magnier R, Le Pavec J, et al. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur Respir J 2013;41:96-103.
20. 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.
21. Freeman RB Jr, Gish RG, Harper A, et al. Model for end-stage liver disease (MELD) exception guidelines: results and recommendations from the MELD Exception Study Group and Conference (MESSAGE) for the approval of patients who need liver transplantation with diseases not considered by the standard MELD formula. Liver Transpl 2006;12:S128-36.
22. AbuHalimeh B, Krowka MJ, Tonelli AR. Treatment Barriers in Portopulmonary Hypertension. Hepatology 2019;69:431-43.

Keywords: Pulmonary Circulation, Pulmonary Artery, Prostaglandins I, Liver Transplantation, Ventricular Function, Right, Blood Pressure, Splenomegaly, Exercise Tolerance, Retrospective Studies, Double-Blind Method, Pulmonary Wedge Pressure, Vulnerable Populations, Follow-Up Studies, Prospective Studies, Sulfonamides, Pyrimidines, Portal Pressure, Pyridazines, Pyrazoles, Phenylpropionates, Phenylpropionates, Hypertension, Pulmonary, Hypertension, Portal, Endothelin Receptor Antagonists, Vascular Resistance, Heart Failure, Liver Cirrhosis, Echocardiography, Hospitalization, Perioperative Period, Registries, Cardiac Catheterization, Thrombocytopenia, Disease Progression, Insurance Coverage, Severity of Illness Index, Hypertension

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