Portopulmonary hypertension: An update MATEO PORRES-AGUILAR1 AND DEBABRATA MUKHERJEE2 1
Department of Internal Medicine and 2Department of Medicine, Division of Cardiovascular Diseases, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, Texas, USA
Portopulmonary hypertension represents a serious lung vascular disorder, defined as the presence of pulmonary arterial hypertension that is associated with portal hypertension, with or without the presence of significant liver disease. Transthoracic echocardiography represents the single best initial tool for the diagnostic evaluation in portopulmonary hypertension, and right heart catheterization remains the gold standard for definitive diagnosis. Despite the lack of randomized controlled trials in portopulmonary hypertension, some therapies have demonstrated improvements in cardiopulmonary haemodynamics and right ventricular function as described in case reports and case series. Specialists should be able to recognize indications and contraindications for liver transplantation in the setting of portopulmonary hypertension, and this review focuses on the appropriate diagnostic approach and current advances in medical therapies. Recognition of patients eligible for liver transplantation is needed to improve quality of life and survival.
Portopulmonary hypertension (PoPH) is defined by the presence of pulmonary arterial hypertension (PAH) associated with portal hypertension, with or without underlying liver disease.1–4 Since the 2013 Nice World Pulmonary Hypertension symposium, PoPH has been categorized as one of the associated forms of PAH, belonging to the World Health Organization Group 1.5 The current definition criteria for PoPH includes: (i) presence of portal hypertension with or without liver disease (inferred from the presence of splenomegaly, portosystemic shunts, thrombocytopenia or varices); and (ii) haemodynamic measurements obtained by right heart catheterization (RHC) including a mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg at rest, pulmonary artery occlusion pressure (PAOP) ≤ 15 mm Hg and pulmonary vascular resistance (PVR) >240 dynes/s/cm−5 (PVR = mPAP − PAOP/cardiac output (CO) × 80)1,2 or >3 Wood units (Wood units = mPAP − PAOP/CO).
Key words: liver disease, liver transplantation, portal hypertension, portopulmonary hypertension, pulmonary arterial hypertension.
EPIDEMIOLOGY AND RISK FACTORS
Abbreviations: CO, cardiac output’ ERA, endothelin receptor antagonists’ FHPG, free hepatic venous pressure’ HVPG, transhepatic venous pressure gradient’ MELD, model of endstage liver disease’ NPV, negative predictive value’ PAH, pulmonary arterial hypertension’ PoPH, portopulmonary hypertension’ mPAP, mean pulmonary arterial pressure’ PAOP, pulmonary artery occlusion pressure’ PPV, positive predictive value’ PVR, pulmonary vascular resistance’ RAP, right atrial pressure’ RHC, right heart catheterization’ RVSP, right ventricular systolic pressure’ TTE, transthoracic echocardiography’ TR, tricuspid regurgitant’ WHVP, wedged hepatic venous pressure.
Correspondence: Mateo Porres-Aguilar, Department of Internal Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, 4800 Alberta Avenue El Paso, TX 79905, USA. Email: [email protected]
Received 16 June 2014; invited to revise 30 July, 15 September and 21 October 2014; revised 4 August, 15 September and 22 October 2014; accepted 22 October 2014 (Associate Editor: Tamera Corte). © 2014 Asian Pacific Society of Respirology
Mantz and Craig described the first case of PoPH in 1951 by necropsy that showed a significant portocaval shunt originating at the confluence of the portal, mesenteric and splenic veins draining to the innominate vein as an independent vessel lined sporadically with thrombi.6 Retrospective studies from the 1980s involving post mortem exams in >17 000 patients showed pulmonary arteriopathic changes of PAH more frequently in patients with portal hypertension (0.73%) than in those without (0.13%).7 Prospective studies have evaluated patients using the current pulmonary haemodynamic criteria implemented by the European Respiratory Society.1 Castro et al. found that among 362 patients being evaluated for liver transplantation (LT), 4% were categorized as having PoPH while performing pulmonary artery catheterization after induction of general anaesthesia.8 A study involving 1235 patients evaluated for LT showed that 5% met haemodynamic criteria for PoPH.9 The French PAH registry established an estimated prevalence of 9.4%.10 In the recent United States Registry to Evaluate Early and Long-term (REVEAL) pulmonary arterial Respirology (2015) 20, 235–242 doi: 10.1111/resp.12455
236 hypertension registry investigating more than 3500 patients, 5% were reported to have PoPH.11 A casecontrol study of 34 patients with confirmed PoPH matched with 134 controls found that the median diagnosis of PoPH was during the fifth decade of life, and the diagnosis of POPH was made an average of 4 to 7 years after the diagnosis of portal hypertension. Female gender and autoimmune liver disease were recognized as independent risk factors for the development of PoPH, whereas chronic hepatitis C appeared to be protective for PoPH.12 Another casecontrol study detected that large spontaneous portosystemic shunts are directly related to the development of moderate to severe PoPH, as compared to milder forms of patients with PoPH without large portosystemic shunts.13 The severity of liver disease measured by the model of end-stage liver disease (MELD) score has not been associated with the presence of PoPH.12 Also, the severity of PoPH measured by RHC has not been found to correlate with the severity of portal hypertension.8,9,14,15
PATHOBIOLOGY AND PATHOPHYSIOLOGY PoPH is pathologically indistinguishable from other phenotypes of PAH.16 Pathologic changes initially include medial hypertrophy with smooth muscle proliferation. As the proliferative process advances, platelet aggregates and in-situ thrombus forms, intimal fibrosis develops, and finally, web-like lesions develop involving the pulmonary arterioles with recanalization (plexiform lesions).16,17 The mechanisms involved in the development of POPH are not entirely known. Endothelial cell prostacyclin synthase deficiency, proliferation and vasoconstriction of periarteriolar smooth muscle, increased circulating endothelin-1 (ET-1) levels and platelet aggregation within small pulmonary arterioles have been documented in POPH.18–21 The deficiency of prostacyclin (a potent vasodilator and anti-proliferative agent) and relative excess of ET-1 (a potent vasoconstrictor) are the two major processes associated with POPH and are currently therapeutic targets. Early studies suggest a causal role of serotonin as a promoter of pulmonary vasoconstriction and vascular smooth muscle mitogenesis,22 although genetic polymorphisms in the serotonin transporter are not predictive for the development of PoPH.23–25 Upregulation of other neurohumoral molecules like thromboxane B-1, proinflammatory cytokines and vascular endothelial growth factor have also been implicated in the pathogenesis of PoPH.26,27 A case-control study involving 1079 single-nucleotide polymorphisms showed associations with estrogen receptor-1, aromatase and angiopoietin-1. The biological significance of the aromatase polymorphisms is supported by an association with plasma estradiol levels.24 The mechanistic link between estrogen signalling, serum estradiol levels, circulating endothelial progenitor cells and PoPH is a current research hypothesis of interest.28–31 Respirology (2015) 20, 235–242
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DIAGNOSTIC APPROACHES Dyspnoea on exertion is a common symptom, however, is often related to other conditions directly associated with liver disease (e.g. refractory ascites with extrathoracic restriction, hepatic hydrothorax, anaemia, cirrhotic cardiomyopathy or sarcopenia and deconditioning). Other common symptoms include generalized weakness, lightheadedness and orthopnea. In advanced stages of PoPH, syncope, chest pain, dyspnoea at rest can occur.32,33 Important findings in the physical examination include elevated jugular venous distention, an accentuated second heart sound and a systolic murmur during right ventricular (RV) systole due to tricuspid regurgitation. In severe PoPH, there may be peripheral oedema, mild to moderate ascites and a gallop presumably due to significant RV wall stiffness.2,4,32,33 Chest radiography can demonstrate cardiomegaly with enlargement of the central pulmonary arteries. Electrocardiogram may reveal right axis deviation, right bundle branch block and inverted T waves in precordial leads V1 to V4, suggesting RV diastolic overload. Arterial blood gases may show mild to moderate hypoxemia with decreased carbon dioxide tension;34 however, hypocapnia is well documented in liver disease and is not a unique finding in PoPH. A comprehensive diagnostic evaluation is warranted in order to exclude other forms of pulmonary hypertension (PH). The differential diagnosis include idiopathic PAH, PH associated with collagen vascular diseases, HIV infection and PH associated with left heart disease or chronic lung disease. Complete pulmonary function testing may identify decreased carbon monoxide diffusing capacity. Ventilation/ perfusion lung scan is usually normal. This, however, is very useful in excluding chronic thromboembolic PH.35,36
Specific screening for PoPH Transthoracic echocardiography (TTE) is pivotal for all symptomatic patients with portal hypertension with high clinical suspicion of PoPH, as endorsed by the European Society of Cardiology and the American Association for the Study of Liver Diseases. It is also a fundamental part of the evaluation for LT,37,38 given the high morbidity and mortality of PoPH in the perioperative LT setting. TTE allows the estimation of the right ventricular systolic pressure (RVSP) using the peak tricuspid regurgitant (TR) jet velocity and applying the modified Bernoulli’s equation (RVSP = 4 × [TR2] + RAP), where the estimated right atrial pressure (RAP) is incorporated in to the equation.1–4 Colle et al.15 aimed to determine a cut-off value that could identify PoPH of any severity in 165 patients with portal hypertension. Seventeen met the echocardiographic criteria for undergoing RHC based on a RVSP cut-off >30 mm Hg, finding a positive predictive value (PPV) of 59%, a negative predictive value (NPV) of 100% and a very poor specificity. However, different RVSP cut-off values have been used by many tertiary LT referral institutions according to their clinical needs. We suggest that patients with RVSP © 2014 Asian Pacific Society of Respirology
between 30 to 50 mm Hg but with evidence of RV dysfunction by TTE should undergo RHC. TTE in fact provides other parameters that could be of great value while screening for PoPH including signs of RV dilatation, hypertrophy, dysfunction and paradoxical interventricular septal motion. All can be indirect signs of PAH.39,40 Recently, Raevens et al.41,42 evaluated different RVSP cut-off values (30 mm Hg to 50 mm Hg) aiming to determine the most accurate cut-off value for defining the need of RHC to detect PoPH. A cut-off value of 38 mm Hg improved the specificity to 82% without changes in the sensitivity, although the PPV still remained low at 22%. They were able to improve the accuracy of this RVSP cut-off value by adding the presence of RV dilatation (defined as right ventricular end-diastolic diameter > 3.3 cm), improving the specificity to 92% and PPV to 41% without any changes in the sensitivity. The main goal of screening for PoPH in patients with portal hypertension is to identify and treat those who are at highest risk of experiencing adverse perioperative cardiovascular events during LT. Pulmonary haemodynamics in LT candidates may change over time, highlighting the need for updating haemodynamic studies every 6–12 months.15,37,38 Recently, Kia et al. studied 216 patients retrospectively and found that pre-LT echocardiographic findings, such as the severity of tricuspid regurgitation were associated with worsening morbidity and mortality in the post-LT period.43 Further information on the fundamental concept about LT eligibility is provided later on in this review.
Pitfalls during RHC for definitive diagnosis of PoPH TTE cannot discriminate between PoPH, hyperdynamic state due to liver disease with normal to low PVR or fluid overload (Supplementary Figure S1). RHC therefore represents the gold standard and remains mandatory for the definitive diagnosis of PoPH.1–4 Approximately 40% to 50% of patients being screened for PoPH have low systemic vascular resistance and high CO while performing RHC. In this particular subgroup of patients, mPAP could be elevated as the consequence of high CO with low PVR ( 35 mm Hg) who attained significant haemodynamic improvement with therapy (mPAP < 35 mm Hg and PVR < 400 dynes/s/cm−5) were granted higher priority for LT,51 highlighting the importance of timely treatment of PoPH. Respirology (2015) 20, 235–242
M Porres-Aguilar and D Mukherjee LT candidacy or clinical suspicion of PoPH (dyspnoea, chest discomfort, increased P2)
30 to 50 NO PoPH
PVR 240 and PAOP 240 and PAOP >15
Figure 1 Proposed algorithm for the diagnostic approach and therapeutic strategies in PoPH. All pressure and vascular resistance determinations are expressed in mm Hg and dynes/s/cm−5. PVR criterion of above or below 250 is used, when to get to this point they had to have a PVR > 240 dynes/s/cm−5 upon initial diagnostic RHC and mPAP > 25 mm Hg. This highlights the point that in order to have an accurate diagnosis of PoPH, patients must have a high PVR, whereas mPAP does not necessarily mean the presence of PoPH, since mPAP could be elevated due to high cardiac output state. Abbreviations: LT, liver transplantation; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PAOP, pulmonary arterial occlusion pressure; PoPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RVSP, right ventricle systolic pressure; TPG, transpulmonary gradient; TTE, transthoracic echocardiogram. †Some centres report the estimated pulmonary arterial systolic pressure, which is equivalent to RVSP in the absence of right ventricular outflow obstruction; ‡The presence of right ventricular dilation or dysfunction by TTE would favor performing RHC; §Alternative causes of pulmonary hypertension (PH) need to be ruled out on a case by case basis. Modified with permission from reference Porres-Aguilar et al.2 (Porres-Aguilar M, Altamirano JT, Torre-Delgadillo A, Charlton MR, Duarte-Rojo A. Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview. Eur. Respir. Rev. 2012; 21: 223–33) by the European Respiratory Society.
MANAGEMENT The general goals of therapy for PoPH are to provide symptomatic relief, improve quality of life, exercise capacity and facilitate LT in a selected group of patients. Important distinctions should be made in regards to calcium channel blockers for PoPH. The Respirology (2015) 20, 235–242
latter are recommended for the minority of patients with IPAH that have shown a sustained acute vasodilator challenge response during RHC.52 Its use in PoPH however is contraindicated as they produce mesenteric vasodilation, worsening portal hypertension.53 Despite the broad use of beta blockers prophylactically for variceal haemorrhage, it has been © 2014 Asian Pacific Society of Respirology
demonstrated that their use in PoPH has been associated with deterioration of exercise capacity and haemodynamics likely due to their negative inotropic and chronotropic effects.54 It is the authors’ opinion that beta blockers are to be avoided or used with caution. Warfarin is generally not recommended due to the increased risk of haemorrhage inherent to severe liver disease. Loop and potassium sparing diuretics may offer symptomatic relief in patients with RV dysfunction, and have an important role in PoPH patients who have significant volume overload and fluid retention. Monitoring is required since they may reduce venous return and CO by reducing the RV preload, thus, facilitating prerenal azotemia and systemic hypoperfusion. Since hypoxaemia in PoPH can promote hypoxic vasoconstriction, supplemental oxygen is recommended, particularly when PaO2 is 35 mm Hg and/or PVR > 400 dynes/s/cm−5 are both associated with peri-LT mortality of 50%.68 mPAP > 45 mm Hg and/or PVR > 400 dynes/s/cm−5 is considered an absolute contraindication for LT.1–4 The impact of PAH-specific therapies in achieving improvement in the post-LT outcomes is still evolving. Importantly, reperfusion during the LT procedure represents a critical time when preload increases, cytokines are released and/or thrombi migrate into the pulmonary vasculature. Intraoperative death from acute RV failure can occur.69 The effect of LT on PoPH is unpredictable, even within the current MELD exception criteria, since PoPH itself is not an indication for LT, as it is certainly in the clinical setting of hepatopulmonary syndrome. LT programmes in the United States allow higher priority to perform LT if haemodynamics can be significantly improved and meet standardized MELD exception guidelines.50 Since 2006, LT waitlist candidates with PoPH have been eligible to receive waitlist priority upgrades (MELD exception points) based on formalized criteria set forth by the Organ Procurement and Transplantation Network (OPTN).50 The rationale for such approach is to prevent progression of PoPH and subsequent irreversible PAH, leading to progressive RV failure and death. Patients who do not undergo LT within 6 months may be granted additional MELD exception points after a careful analysis by the regional review boards. Respirology (2015) 20, 235–242
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Treatment goals for MELD exception in the United States are detailed below: 1 Moderate to severe PoPH diagnosis by RHC: a mPAP ≥ 35 mm Hg b PVR > 400 dynes/s/cm−5 c PAOP ≤ 15 mm Hg 2 Improvement with PAH-specific therapies by: a mPAP < 35 mm Hg or, b PVR < 400 dynes/s/cm−5 regardless of mPAP and, c Satisfactory RV function by TTE (e.g. improvement in RV dilation and function). 3 MELD exception updated (additional 10% MELD points) every 3months: a Give additional MELD exception if RHC data satisfies criteria # 2. This policy has the intention to expedite LT before definitive contraindications occur, given that survival has not been shown to be inferior when compared to all LT patients.50,70 If the decision is made to proceed with LT in a patient with significant PoPH and haemodynamic improvement with PAH-specific therapies, transesophageal echocardiography to monitor for RV failure, veno-venous bypass to prevent RV afterload after reperfusion, as well as the use of inhaled nitric oxide and IV epoprostenol may be considered as intraoperative strategies to minimize the risk of abrupt RV failure.70 Patients with PoPH should be ideally treated in referral LT centres involving a multidisciplinary team experienced in the perioperative management of PoPH.71 MELD exception is generally not granted under current US policy if the mPAP remains >35 mm Hg despite normalization of PVR and RV function with pre-LT therapies. In such patients, the elevation in mPAP reflects a change in physiology and is the result of vasoactive therapies increasing the existing high flow state, and decreasing the PVR. We suggest that in those patients where there is normalization of RV function documented by TTE, MELD exception could be considered despite ‘abnormal mPAP’. It is hypothesized that for those individuals, reversal of PoPH after LT can be obtained, presumably due to a significant reduction in PVR and objective evidence of improvement of RV function demonstrated by TTE.72 In most post-LT patients that have clinical improvement and echocardiographic normalization of RV function, RHC is not routinely performed. Periodic RHC should be considered to allow adjustment of PAH-specific therapies and identify patients who may be weaned off these medications, however, given the lack of evidence it should not be mandatory.
CONCLUSIONS PoPH represents a serious lung vascular complication of portal hypertension. PoPH is relatively common, particularly in a screening population. PAH-specific therapies in PoPH can significantly improve pulmonary haemodynamics and RV function. The potential to ‘reverse’ PoPH with a combination of PAH-specific therapies and LT appears to be an attainable goal in a cohort of patients yet to be characterized. Appropri© 2014 Asian Pacific Society of Respirology
ate diagnostic approach and available PAH-specific therapies are critical in decreasing LT complications and improving survival.
1 Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonaryhepatic vascular disorders (PHD). Eur. Respir. J. 2004; 24: 860–80. 2 Porres-Aguilar M, Altamirano JT, Torre-Delgadillo A, Charlton MR, Duarte-Rojo A. Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview. Eur. Respir. Rev. 2012; 21: 223–33. 3 Cartin-Ceba R, Krowka MJ. Portopulmonary hypertension. Clin. Liver Dis. 2014; 18: 421–38. 4 Porres-Aguilar M, Zuckerman MJ, Figueroa-Casas JB, Krowka MJ. Portopulmonary hypertension: state of the art. Ann. Hepatol. 2008; 7: 321–30. 5 Simonneau G, Gatzoulis MA, Adatia A, Celermajer D, Denton C, Ghofrani A, Gomez-Sanchez MA, Krishna-Kumar R, Landzberg M, Machado RF et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 2013; 62(25 Suppl.): D34– 41. 6 Mantz FA Jr, Craig E. Portal axis thrombosis with spontaneous portocaval shunt and persistent cor pulmonale. AMA Arch. Pathol. 1951; 52: 401–9. 7 McDonnell JP, Toye PA, Hutchins PM. Primary pulmonary hypertension and liver cirrhosis: are they related? Am. Rev. Respir. Dis. 1983; 127: 437–41. 8 Castro M, Krowka MJ, Schroeder DR, Beck KC, Plevak DJ, Rettke SR, Cortese DA, Wiesner RH. Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients. Mayo Clin. Proc. 1996; 71: 543–51. 9 Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 2006; 44: 1502–10. 10 Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzemblum E, Cordier JF, Chabot F et al. Pulmonary arterial hypertension in France: results from a National registry. Am. J. Respir. Crit. Care Med. 2006; 173: 1023–30. 11 Krowka MJ, Miller DP, Barst RJ, Taichman D, Dweik RA, Badesch DB, McGoon MD. Portopulmonary hypertension: a report from the US-based REVEAL registry. Chest 2012; 141: 906–15. 12 Kawut SM, Krowka MJ, Trotter JF, Roberts KE, Benza RL, Badesch DB, Taichman DB, Horn EM, Zacks S, Kaplowitz N et al. Clinical risk factors for portopulmonary hypertension. Hepatology 2008; 48: 196–203. 13 Talwalker JA, Swanson KL, Krowka MJ, Andrews JC, Kamath PS. Prevalence of spontaneous portosystemic shunts in patients with portopulmonary hypertension and effect on treatment. Gastroenterology 2011; 141: 1673–9. 14 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. 15 Colle IO, Moreau R, Godinho E, Belghiti J, Ettori F, Cohen-Solal A, Mal H, Bemuau J, Marty J, Lebrec D et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology 2003; 37: 401–9. 16 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. 17 Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transpl. 2000; 6: 241–2. 18 Benjaminov FS, Prentice M, Sniderman KW, Siu S, Liu P, Wong F. Portopulmonary hypertension in decompensated liver cirrhosis and refractory ascites. Gut 2003; 52: 1355–62. 19 Kamath PS, Carpenter HA, Lloyd RV, McKusick MA, Steers JL, Nagorney DM, Miller VM. Hepatic localization of endothelin-1 in © 2014 Asian Pacific Society of Respirology
33 34 35
patients with idiopathic portal hypertension and cirrhosis of the liver. Liver Transpl. 2000; 6: 596–602. Neuhofer W, Gulberg V, Gerbes AL. Endothelin and endothelin receptor antagonism in portopulmonary hypertension. Eur. J. Clin. Invest. 2006; 36(Suppl. 3): 54–61. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am. J. Respir. Crit. Care Med. 1999; 159: 1925–32. Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, Poubeau P, Cerrina J, Duroux P, Drouet L. Increased plasma serotonin levels in primary pulmonary hypertension. Am. J. Med. 1995; 99: 249–54. Roberts KE, Fallon MB, Krowka MJ, Benza RL, Knowles JA, Badesch DB, Brown RS Jr, Taichman DB, Trotter J, Zacks S et al. Serotonin transporter polymorphisms in patients with portopulmonary hypertension. Chest 2009; 135: 1470–5. Roberts KE, Fallon MB, Krowka MJ, Brown RS Jr, Trotter JF, Peter I, Knowles JA, Rabinowitz D, Benza RL, Badesch DB et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am. J. Respir. Crit. Care Med. 2009; 179: 835–42. Peng M, Zamanian RT, Krowka MJ, Benza RL, Roberts KE, Taichman DB, Rybak D, Trotter JF, Brown RS Jr, Fallon MB et al. Plasma levels of S100A4 in portopulmonary hypertension. Biomarkers 2009; 14: 156–60. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N. Engl. J. Med. 2004; 351: 1655–65. Pellicelli AM, Barbaro G, Puoti C, Guarascio P, Lusi EA, Bellis L, D’Ambrossio C, Villani R, Vennarecci G, Liotta G et al. Plasma cytokines and portopulmonary hypertension in patients with cirrhosis awaiting orthotopic liver transplantation. Angiology 2010; 61: 802–6. Yeager ME, Frid MG, Stenmark KR. Progenitor cells in pulmonary vascular remodeling. Pulm. Circ. 2011; 1: 3–16. Arnal JF, Fontaine C, Billon-Gales A, Favre J, Laurell H, Lenfant F, Gourdy P. Estrogen receptors and endothelium. Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1506–12. Krowka MJ. Portopulmonary hypertension. Semin. Respir. Crit. Care Med. 2012; 33: 17–25. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 2009; 135: 794–804. Elliot CG, Barst RJ, Porres-Aguilar M, Seeger W, Brown LM, Zamanian RT, Rubin LJ. Worldwide physician education and training in pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 2010; 137(Suppl. 6): 85S– 94S. Mandel JS, Poch D. In the clinic. Pulmonary hypertension. Ann. Intern. Med. 2013; 158: ITC5-1–16. Swanson KL, Krowka MJ. Arterial oxygenation associated with portopulmonary hypertension. Chest 2002; 121: 1869–75. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2011; 183: 1605–13. Hoeper MM, Barbera JA, Channick RN, Hassoun PM, Lang IM, Manes A, Martinez JF, Naeije R, Olschewski H, Pepke-Zaba J et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J. Am. Coll. Cardiol. 2009; 54(Suppl. 1): S85–96. Murray KF, Carithers RL. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 2005; 41: 1407–32. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the diagnosis and treatment of pulmonary hypertension European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the Respirology (2015) 20, 235–242
International Society of Heart and Lung Transplantation (ISHLT). Eur. Heart J. 2009; 30: 2493–537. Bossone E, D’Andrea AE, D’Alto M, Citro R, Argiento P, Ferrara F, Cittadini A, Rubenfire M, Naeije R. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J. Am. Soc. Echocardiogr. 2013; 26: 1–14. Bossone E, Citro R, Blasi F, Allegra L. Echocardiography in pulmonary arterial hypertension: an essential tool. Chest 2007; 131: 339–41. Raevens S, Colle IO, Reyntjens K, Geerts A, Berrevoet F, Rogiers X, Troisi RI, Van Vlierbherghe H, De Pauw M. Echocardiography for the detection of portopulmonary hypertension in liver transplantation candidates: analysis of different cut-off values. Liver Transpl. 2013; 19: 602–10. Porres-Aguilar M, Duarte-Rojo A, Krowka MJ. Transthoracic echocardiography screening for the detection of portopulmonary hypertension: work in progress. Liver Transpl. 2013; 19: 573–4. Kia L, Shah SJ, Wang E, Sharma D, Selvaraj S, Medina C, Cahan J, Mahon H, Levitsky J. Role of pretransplant echocardiographic evaluation in predicting outcomes following liver transplantation. Am. J. Transplant. 2013; 13: 2395–401. Moller S, Bernardi M. Interactions of the heart and the liver. Eur. Heart J. 2013; 34: 2804–11. Bosch J, Abraldes JG, Berzigotti A, García-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nat. Rev. Gastroenterol. Hepatol. 2009; 6: 573–82. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J. Am. Coll. Cardiol. 1991; 17: 492–8. 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. Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian D, Jais X, Yaici A, Humbert M, Simonneau G et al. Portopulmonary hypertension: survival and prognostic factors. Am. J. Respir. Crit. Care Med. 2008; 178: 637–43. Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A et al. Riociguat for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 2013; 369: 330–40. Krowka MJ, Fallon MB, Mulligan DC, Gish RG. Model for endstage liver disease (MELD) exception for portopulmonary hypertension. Liver Transpl. 2006; 12(Suppl. 3): S114–16. Krowka MJWR, Rosen CB, Nyberg SL, Heimbach JK. Portopulmonary hypertension outcomes in the era of MELD exception [Abstract]. Liver Transpl. 2012; 18(Suppl. 1): S259. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Herve P, Simonneau G. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105–11. Ota K, Shijo H, Kokawa H, Kubara K, Kim T, Akiyoshi N, Yokoyama M, Okumura M. Effects of nifedipine on hepatic venous pressure gradient and portal vein flow in patient with cirrhosis. J. Gastroenterol. Hepatol. 1995; 10: 198–204. Provencher S, Herve P, Jais X, Lebrec D, Humbert M, Simonneau G, Sitbon O. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 2006; 130: 120–6. Hoeper MM, Halank M, Marx C, Hoefken G, Seyfarth HJ, Schauer J, Niedermeyer J, Winkler J. Bosentan therapy for portopulmonary hypertension. Eur. Respir. J. 2005; 25: 502–8. Savale L, Magnier R, LePavec J, Jais X, Montani D, O’Callaghan DS, Humbert M, Dingemanse J, Simonneau G, Sitbon O. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur. Respir. J. 2013; 41: 96–103. Cartin-Ceba R, Swanson KL, Iyer V, Wiesner RH, Krowka MJ. Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. Chest 2011; 139: 109–14.
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M Porres-Aguilar and D Mukherjee 58 Reichenberger F, Voswinckel R, Steveling E, Enke B, Kreckel A, Olschewski H, Grimmenger F, Seeger W, Ghofrani HA. Sildenafil treatment for portopulmonary hypertension. Eur. Respir. J. 2006; 28: 563–7. 59 Krowka MJ, Frantz RP, McGoon MD, Severson C, Plevak DJ, Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol: a study of 15 patients with moderate and severe portopulmonary hypertension. Hepatology 1999; 30: 641–8. 60 Fix OK, Bass NM, De Marco T, Merriman RB. Long-term follow up in portopulmonary hypertension: effect of treatment with epoprostenol. Liver Transpl. 2007; 13: 875–85. 61 Sussman N, Kaza V, Barshes N, Stribling R, Goss J, O’Mahony C, Zhang E, Vierling J, Frost A. Successful liver transplantation following medical management of portopulmonary hypertension: a single center series. Am. J. Transplant. 2006; 6: 2177–82. 62 Melgosa MT, Ricci GL, Garcia Pagan JC, Blanco I, Escribano P, Abraldes JG, Roca J, Bosch J. Acute and long-term effects of iloprost in portopulmonary hypertension. Liver Transpl. 2010; 16: 348–56. 63 Hollatz TJ, Musat A, Whestphal S, Decker C, D’Alessandro AM, Keevil J, Zhanhai L, Runo JR. Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension. Liver Transpl. 2012; 18: 886–95. 64 Halank M, Marx C. Usicenko S. Inhaled iloprost in patients with portopulmonary hypertension. Am. J. Respir. Crit. Care Med. 2003; 168: A277. 65 Eriksson C, Gustavsson A, Kronvall T, Tysk C. Hepatotoxicity by bosentan in a patient with portopulmonary hypertension: case report and review of the literature. J. Gastrointestin. Liver Dis. 2011; 20: 77–80. 66 Halank M, Knudsen L, Seyfarth HJ, Ewert R, Weidemann B, Kolditz M, Hoffken G, Hoeper MM. Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension. Z. Gastroenterol. 2011; 49: 1258–62. 67 Krowka MJ, Swanson KL. How should we treat portopulmonary hypertension? Eur. Respir. J. 2006; 28: 466–7. 68 Krowka MJ, Mandell SM, Ramsay MA, Kawut SM, Fallon MB, Manzarbeitia E, Pardo M Jr, Marotta P, Uemoto S, Stoffel MP et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report from the multicenter liver transplant database. Liver Transpl. 2004; 10: 174–82. 69 Ramsay M. Portopulmonary hypertension and right heart failure in patients with cirrhosis. Curr. Opin. Anaesthesiol. 2010; 23: 145– 50. 70 Ashfaq M, Chinnakotla S, Rogers L, Ausloos K, Saadeh S, Klintmalm GB, Ramsay M, Davis GL. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am. J. Transplant. 2007; 7: 1258–64. 71 Raval Z, Harenstein ME, Skaro AI, Erdogan A, DeWolf AM, Shah SJ, Fix OK, Kay N, Abecassis MI, Flaherty JD. Cardiovascular risk assessment for the liver transplant candidate. J. Am. Coll. Cardiol. 2011; 58: 223–31. 72 Bandara M, Gordon FD, Sarwar A, Knauft ME, Pomfret EA, Freeman RB, Wirth JA. Successful outcomes following living donor liver transplantation for portopulmonary hypertension. Liver Transpl. 2010; 16: 983–9.
Supplementary Information Additional Supplementary Information can be accessed via the html version of this article at the publisher’s web-site. Supplementary Figure S1 Pulmonary haemodynamic patterns documented by right heart catheterization in portal hypertension. Modified with permission from Cartin-Ceba and Krowka3 (CartinCeba R, Krowka MJ. Portopulmonary hypertension. Clin. Liver Dis. 2014; 18: 421–38) by ELSEVIER, the publisher.
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