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REVIEW

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

ABSTRACT

INTRODUCTION

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: m[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

M Porres-Aguilar and D Mukherjee

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

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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

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M Porres-Aguilar and D Mukherjee LT candidacy or clinical suspicion of PoPH (dyspnoea, chest discomfort, increased P2)

No PoPH

30 to 50 NO PoPH

25

PVR 240 and PAOP 240 and PAOP >15

PoPH

TPG >12

TPG 25-35-45

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

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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

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ate diagnostic approach and available PAH-specific therapies are critical in decreasing LT complications and improving survival.

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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.

© 2014 Asian Pacific Society of Respirology

Portopulmonary hypertension: an update.

Portopulmonary hypertension represents a serious lung vascular disorder, defined as the presence of pulmonary arterial hypertension that is associated...
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