|Year : 2014 | Volume
| Issue : 5 | Page : 42-46
|Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Portopulmonary hypertension
Sarfraz Saleemi1, Majdy M. Idrees2
1 Department of Pulmonary Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Prince Sultan Medical Military City, Riyadh, Saudi Arabia
|Date of Submission||29-Mar-2014|
|Date of Acceptance||05-Apr-2014|
|Date of Web Publication||7-Jun-2014|
FCCP, Division of Pulmonary Medicine, Department of Medicine, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Portopulmonary hypertension (POPH) is defined as pulmonary arterial hypertension (PAH) complicated by portal hypertension, with or without advanced hepatic disease. Significant percentage of patients with cirrhotic liver disease has high cardiac output and subsequently elevated pulmonary arterial pressures (PAP). However, patients with POPH develop a progressive increase in pulmonary vascular resistance (PVR), which is generally lower than that observed in other forms of PAH.
The prognosis of untreated patients with POPH is very poor and the outcome of liver transplant (LT) in those patients is determined by the degree of severity of the associated pulmonary hemodynamics.
In this narrative review, we describe the clinical presentation of POPH, the pathobiology, and the clinical implication of pulmonary hemodynamics. We also provide evidence-based recommendations for the diagnosic and management approaches of POPH.
Keywords: Liver transplant, portal hypertension, portopulmonary hypertension, pulmonary arterial hypertension, vasodilator therapy, Saudi Association for Pulmonary Hypertension Guidelines
|How to cite this article:|
Saleemi S, Idrees MM. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Portopulmonary hypertension. Ann Thorac Med 2014;9, Suppl S1:42-6
Portopulmonary hypertension (POPH) is defined as pulmonary arterial hypertension (PAH) complicated by portal hypertension, with or without advanced hepatic disease. It is classified as Group 1 in the current classification of pulmonary hypertension (PH). Although, it affects only 2-5% of the population suffering from portal hypertension, its clinical implications are enormous. ,, The prevalence of POPH in patients undergoing liver transplant (LT) is considered to be higher,  with one study showing prevalence of 8.5%.  Recent evidence from France shows that POPH was the third-most common type of PH seen in the consortium of 17 French hospitals. 
The outcome of LT in the presence of POPH is poor, with a 35% reported mortality rate in LT recipients having a mean pulmonary artery pressure (mPAP) >35 mmHg. A patient with high mPAP may be denied the opportunity for transplant unless the mPAP is brought below 35 mmHg with medical treatment. In patients who do undergo successful LT, there can be the resolution of PH with time.
The diagnostic criteria for POPH are shown in [Table 1].
Approximately 30-50% of patients with cirrhotic liver disease have low systemic vascular resistance and high cardiac output (CO). In these patients, pulmonary arterial pressures (PAP) may be elevated due to increased CO. These patients have lower values of pulmonary vascular resistance (PVR). Some investigators propose that a cut-off of PVR >2 Wood unit be used in order to define POPH in the presence of hyperdynamic circulatory state. 
Certain risk fact is found to be associated with the development of POPH. Female sex and autoimmune hepatitis were associated with an increased risk of POPH, while patients with hepatitis C infection had a lower risk.  In addition, genetic variation in estrogen signaling and cell growth regulators have also been associated with the risk of POPH. 
The survival of untreated patients with POPH is very poor. In a recent retrospective study from the Mayo Clinic LT Group, they identified 74 POPH patients from 1994 to 2007, and categorized them in to three groups:
- No therapy for POPH or LT,
- Therapy for POPH alone and
- Therapy for POPH followed by LT.
The 5-year survival in patients who received no therapy for POPH and no LT represents the natural history of POPH and was 14%, with 54% dying within 1 year of diagnosis. The median survival in patients who received medical therapy for POPH, but did not undergo LT was 46 months, and 5-year survival was 45%, being significantly better than the former group (P = 0.03). Twelve patients underwent LT, and 5-year survival for the 9 patients receiving therapy for POPH was 67% as compared to 25% in 3 patients who were not pretreated with prostacyclin therapy. 
| Pathogenesis|| |
It has been found that the development of POPH is independent of the cause of the portal hypertension. ,, The severity of the underlying liver disease does not appear to correlate with the severity of POPH.  Hyperdynamic circulatory state and high CO are the hallmarks in most patients with POPH leading to increased shear stress on the pulmonary circulation. The PVR then rises owing to vasoconstriction, progressive pulmonary vascular remodeling, and in situ thrombosis.  The histological abnormalities in POPH are identical to those found in idiopathic pulmonary arterial hypertension (IPAH). The main pathological abnormalities include proliferate arteriopathy, obliteration of the vascular lumen by endothelial and smooth-muscle cells, formation of plexiform lesions, necrotizing arteritis, fibrinoid necrosis and in situ thrombi. ,,
The presence of portosystemic shunts may allow the shunting of the vasoactive substances from the splanchnic circulation to the pulmonary circulation, allowing these vasoactive mediators to bypass the liver metabolism and causing substantial effects on the pulmonary vasculature. ,
| Clinical Features|| |
Dyspnea on exertion is the most common symptom. Other symptoms include fatigue, generalized weakness, light-headedness, and orthopnea. Physical examination may show abnormalities include accentuated and split second heart sound, systolic murmur, right ventricular (RV) heave, right sided S3 gallop, jugular vein extension, edema and the signs of either decompensated cirrhosis or overt right-heart failure, such as ascites and lower leg edema. Lower leg edema out of proportion to ascites due to portal hypertension may suggest associated POPH. , Arterial blood gases may show hypoxemia and increased alveolar-arterial oxygen gradient. The decrease in arterial oxygenation was found to be significantly worse in patients with POPH when compared with a cohort of patients that underwent screening for LT and normal RV systolic pressures (RVSP).  Hypoxemia may worsen POPH through pulmonary vasoconstriction, and therefore supplemental oxygen should be considered for all patients with hypoxemia to maintain oxygen saturation higher than 90% at all times. Electrocardiogram may show evidence of RV hypertrophy, right atrial enlargement, and right axis deviation. Chest X-ray is usually normal, but may show enlarged pulmonary arteries. Pulmonary function tests may be normal or may show mild restrictive defect and decreased diffusion capacity.
| Diagnosis|| |
According to the guidelines by American Association for the Study of Liver Disease, all patients being screened for LT should be evaluated for POPH by transthoracic echocardiography (TTE).  In a large prospective POPH screening study (N = 1235), RVSP of >50 mmHg was noted in 10.9% of patients. Right-heart catheterization (RHC) was conducted in this group of patients. The diagnosis of POPH based upon the current diagnostic criteria was made in 65% of patients having RVSP >50 mm on TTE. Therefore, 35% of these had "false positives" based solely upon Doppler echocardiography results. 
After initial screening with TTE, definitive diagnosis should be made by RHC that includes measurements of mPAP, pulmonary artery wedge pressure, CO, and calculated PVR.  Acute vasoreactivity test with either nitric oxide or prostacyclin may be done for prognostic significance and not to determine patient selection for calcium channel blocker therapy.
The diagnosis of POPH by RHC before LT is crucial as mentioned above because of the increased risk of death following LT in patients with mPAP >35 mmHg. [Figure 1] illustrate the recommended for POPH if pre-LT mPAP is >35 mmHg. Patients with mPAP of <35 mmHg can be transplanted without undergoing specific PAH therapy for POPH. ,,,
|Figure 1: Screening for portopulmonary hypertension. RVSP = Right ventricular systolic pressure, mPAP = Mean pulmonary arterial pressure, PVR = Pulmonary vascular resistance, PAH = Pulmonary arterial hypertension, LT = Liver transplant|
Click here to view
Right-heart catheterization is also important to help classify the severity of POPH  and therapeutic options based on the severity of disease [Table 2].
| Management of Portopulmonary Hypertension|| |
In addition to the general psychosocial factors, vaccination, and rehabilitation, keeping optimum oxygen saturation is crucial, as ongoing or episodic hypoxemia can make POPH worse.
Diuretics are useful in reducing the increased intrapulmonary vascular volume commonly present in chronic liver disease and thus having modest effect on PAP and improvement of RV function. Diuretics have to be used with caution in patients with POPH as they can reduce the CO by decreasing the RV preload. 
Although digoxin has been shown to improve CO acutely in IPAH, its efficacy is unknown when administered chronically in patients with POPH. 
There is a favorable response with anticoagulation in other forms of PAH, especially in IPAH and chronic thromboembolic pulmonary hypertension (CTEPH) for its ability to slow disease progression. Anticoagulation is traditionally not recommended in patients with POPH because of the inherent risk of hemorrhagic complications in patients with underlying liver disease and portal hypertension, especially in patients with a prior history of gastrointestinal bleeding. 
Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt may worsen POPH because of acute hemodynamic change causing RV strain and dysfunction. It is not recommended in patients with POPH.
Very limited data exist in term of specific medical therapy in POPH. Most of the studies are case series or case reports.
Calcium channel blockers
Calcium channel blockers, which are often considered the first-line treatment in patients who have a positive response to the acute vasodilator challenging test during RHC, are not recommend in POPH, as they could potentially increase the hepatic venous pressure gradient. ,
Prostanoids have been shown to be effective in the treatment of POPH. Epoprostenol is the best-studied prostanoid in POPH. In moderate to severe POPH, intravenous epoprostenol results in significant improvement (both acute and long-term) in PVR, mPAP, and CO. Pulmonary hemodynamics may be improved and brain natriuretic peptide and human atrial natriuretic peptide decrease to normal levels during epoprostenol therapy. Epoprostenol has been shown to significantly improve pulmonary hemodynamics, and so facilitate acceptance of patients who may otherwise be denied LT as a result of POPH. , As use of epoprostenol may potentially worsen hepatic function and cause clinical deterioration of liver disease, careful clinical follow-up is advisable. Another important reported concern with epoprostenol is the development of progressive splenomegaly with worsening thrombocytopenia.  However, recent data from Mayo Clinic does not demonstrate a statistically significant decrease in platelet count in a large cohort of patients with POPH treated with epoprostenol.  Iloprost, a stable prostacyclin analogue, is a valuable alternative to epoprostenol. 
Endothelin receptor antagonists
Combination therapy with intravenous Iloprost and oral bosentan, a dual endothelin-1 receptor antagonist, might extend the survival of selected patients suffering from POPH and recurrent right-heart failure.  Bosentan has been shown to be effective in the treatment of POPH, showing clinical, functional, and hemodynamic benefits without significant elevation of hepatic aminotransferases. ,,,,, Bosentan is an attractive therapy in POPH as it may improve both pulmonary and portal hypertension. Macitentan, a new dual endothelin-receptor antagonist may show a useful addition in the management of POPH in future studies.
Sildenafil has been reported to be effective in decreasing PVR. , Sildenafil was used in 14 patients with moderate to severe POPH from diverse etiologies. Eight patients were newly started on sildenafil, while 6 patients were already on therapy with inhaled prostanoids (iloprost in five and treprostinil in one). Sildenafil appeared to provide therapeutic benefit in term of decreasing the mPAP and PVR when evaluated at 3 months, but the hemodynamic benefit was not sustained after 12 months in 7 patients. The 6-min walk test continued to improve at 3 and 12 months. 
Soluble guanylate cyclase stimulator
Riociguat, a soluble guanylate cyclase stimulator, has been approved for treatment PAH and CTEPH after showing positive results in a double blind randomized controlled trial.  Riociguat has a potential role for future research in POPH.
Combination therapy has been shown to be effective in patients with IPAH,  but its role in POPH has not been established.
Patients with end-stage liver disease and severe PH may be considered for combined liver - lung, which is offered in a few highly specialized centers in the world. The largest series of combined liver - lung transplantation so far has reported a 3-year survival of 62%.  However, patients with mild to moderate POPH do not routinely require lung transplantation, as the disease might stabilize, or even improve, after LT.
| Conclusion|| |
Portopulmonary hypertension is a type of PAH associated with portal hypertension. The proposed pathophysiology includes hyperdynamic pulmonary circulation leading to shear stress of pulmonary vasculature causing obstructive vasculopathy and increased pulmonary resistance. The diagnosis of POPH is suggested by TTE and is confirmed by RHC. Mortality in advance liver disease in the presence of PH is high. Every effort should be made to treat these patients with specific vasodilator therapy to reduce mPAP and PVR, and ultimately improve RV function. Treatment with a combined approach of specific PAH therapy and LT may improve long-term survival in patients with POPH. Randomized controlled trials are needed to determine the future direction in the management of POPH. [Table 3] shows the class of recommendation and the level of evidence for POPH management.
| References|| |
|1.||Mandell MS, Groves BM. Pulmonary hypertension in chronic liver disease. Clin Chest Med 1996;17:17-33. |
|2.||Budhiraja R, Hassoun PM. Portopulmonary hypertension: A tale of two circulations. Chest 2003;123:562-76. |
|3.||Castro M, Krowka MJ, Schroeder DR, Beck KC, Plevak DJ, Rettke SR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients. Mayo Clin Proc 1996;71:543-51. |
|4.||Bozbas SS, Eyuboglu F. Evaluation of liver transplant candidates: A pulmonary perspective. Ann Thorac Med 2011;6:109-14. |
|5.||Hadengue A, Benhayoun MK, Lebrec D, Benhamou JP. Pulmonary hypertension complicating portal hypertension: Prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-8. |
|6.||Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: Results from a national registry. Am J Respir Crit Care Med 2006;173:1023-30. |
|7.||Passarella M, Fallon MB, Kawut SM. Portopulmonary hypertension. Clin Liver Dis 2006;10:653-63, x. |
|8.||Kawut SM, Krowka MJ, Trotter JF, Roberts KE, Benza RL, Badesch DB, et al. Clinical risk factors for portopulmonary hypertension. Hepatology 2008;48:196-203. |
|9.||Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med 2009;179:835-42. |
|10.||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. |
|11.||Idrees MM, Al-Hajjaj M, Khan J, Al-Hazmi M, Alanezi M, Saleemi S, et al. Saudi guidelines on diagnosis and treatment of pulmonary arterial hypertension. Ann Thorac Med 2008;3:1-57. |
|12.||Saleemi S. Portopulmonary hypertension. Ann Thorac Med 2010;7:5-9. |
|13.||Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352:719-25. |
|14.||Pellicelli AM. Cytokines in portopulmonary hypertension. Gut 2004;53:1721. |
|15.||Edwards BS, Weir EK, Edwards WD, Ludwig J, Dykoski RK, Edwards JE. Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Coll Cardiol 1987;10:1233-8. |
|16.||Jamison BM, Michel RP. Different distribution of plexiform lesions in primary and secondary pulmonary hypertension. Hum Pathol 1995;26:987-93. |
|17.||Rodríguez-Roisin R, Krowka MJ, Hervé P, Fallon MB, ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004;24:861-80. |
|18.||Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004;363:1461-8. |
|19.||Porres-Aguilar M, Anaya-Ayala JE, Porres-Muñoz M, Bracamontes F. Pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Cir Cir 2007;75:131-8. |
|20.||Krowka MJ. Pulmonary hypertension: Diagnostics and therapeutics. Mayo Clin Proc 2000;75:625-30. |
|21.||Swanson KL, Krowka MJ. Arterial oxygenation associated with portopulmonary hypertension. Chest 2002;121:1869-75. |
|22.||Murray KF, Carithers RL Jr, AASLD. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology 2005;41:1407-32. |
|23.||Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary hypertension: Results from a 10-year screening algorithm. Hepatology 2006;44:1502-10. |
|24.||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. |
|25.||Ramsay MA, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg 1997;3:494-500. |
|26.||Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, Manzarbeitia C, et al. Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter liver transplant database. Liver Transpl 2004;10:174-82. |
|27.||Starkel P, Vera A, Gunson B, Mutimer D. Outcome of liver transplantation for patients with pulmonary hypertension. Liver Transpl 2002;8:382-8. |
|28.||Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 1998;114:787-92. |
|29.||Ota K, Shijo H, Kokawa H, Kubara K, Kim T, Akiyoshi N, et al. Effects of nifedipine on hepatic venous pressure gradient and portal vein blood flow in patients with cirrhosis. J Gastroenterol Hepatol 1995;10:198-204. |
|30.||Navasa M, Bosch J, Reichen J, Bru C, Mastai R, Zysset T, et al. Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension. Hepatology 1988;8:850-4. |
|31.||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. |
|32.||Fix OK, Bass NM, De Marco T, Merriman RB. Long-term follow-up of portopulmonary hypertension: Effect of treatment with epoprostenol. Liver Transpl 2007;13:875-85. |
|33.||Tan HP, Markowitz JS, Montgomery RA, Merritt WT, Klein AS, Thuluvath PJ, et al. Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol. Liver Transpl 2001;7:745-9. |
|34.||Kuo PC, Johnson LB, Plotkin JS, Howell CD, Bartlett ST, Rubin LJ. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997;63:604-6. |
|35.||Findlay JY, Plevak DJ, Krowka MJ, Sack EM, Porayko MK. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transpl Surg 1999;5:362-5. |
|36.||Golbin JM, Krowka MJ. Effect of prostacyclins on thrombocytopenia in portopulmonary hypertension. Data Presented at the 2006 Pulmonary Hypertension Association International Conference. Minneapolis, MN: June 23-25, 2006. |
|37.||Minder S, Fischler M, Muellhaupt B, Zalunardo MP, Jenni R, Clavien PA, et al. Intravenous iloprost bridging to orthotopic liver transplantation in portopulmonary hypertension. Eur Respir J 2004;24:703-7. |
|38.||Halank M, Kolditz M, Miehlke S, Schiemanck S, Schmeisser A, Hoeffken G. Combination therapy for portopulmonary hypertension with intravenous iloprost and oral bosentan. Wien Med Wochenschr 2005;155:376-80. |
|39.||Kuntzen C, Gülberg V, Gerbes AL. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: A safe and effective therapy? Gastroenterology 2005;128:164-8. |
|40.||Hinterhuber L, Graziadei IW, Kähler CM, Jaschke W, Vogel W. Endothelin-receptor antagonist treatment of portopulmonary hypertension. Clin Gastroenterol Hepatol 2004;2:1039-42. |
|41.||Hoeper MM, Halank M, Marx C, Hoeffken G, Seyfarth HJ, Schauer J, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J 2005;25:502-8. |
|42.||Halank M, Miehlke S, Hoeffken G, Schmeisser A, Schulze M, Strasser RH. Use of oral endothelin-receptor antagonist bosentan in the treatment of portopulmonary hypertension. Transplantation 2004;77:1775-6. |
|43.||Chua R, Keogh A, Miyashita M. Novel use of sildenafil in the treatment of portopulmonary hypertension. J Heart Lung Transplant 2005;24:498-500. |
|44.||Makisalo H, Koivusalo A, Vakkuri A, Hockerstedt K. Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transpl 2004;10:945-50. |
|45.||Reichenberger F, Voswinckel R, Steveling E, Enke B, Kreckel A, Olschewski H, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J 2006;28:563-7. |
|46.||Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40. |
|47.||Murali S. Combination therapy: The future of medical management for PAH. Medscape Cardiol 2005;9:2. |
|48.||Grannas G, Neipp M, Hoeper MM, Gottlieb J, Lück R, Becker T, et al. Indications for and outcomes after combined lung and liver transplantation: A single-center experience on 13 consecutive cases. Transplantation 2008;85:524-31. |
[Table 1], [Table 2], [Table 3]