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Portopulmonary hypertension: From diagnosis to treatment
European Journal of Internal Medicine 22 (2011) 441–447
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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Portopulmonary hypertension: From diagnosis to treatment Sorin Giusca a,⁎, Mariana Jinga b, Ciprian Jurcut b, Ruxandra Jurcut a, Marinela Serban a, Carmen Ginghina a a b
Cardiology Department, Institute for Emergencies in Cardiovascular Diseases “Prof Dr C. C. Iliescu”, Bucharest, Romania Internal Medicine Department, “Dr. Carol Davila” Central University Emergency Military Hospital, Bucharest, Romania
a r t i c l e
i n f o
Article history: Received 9 December 2010 Received in revised form 30 January 2011 Accepted 19 February 2011 Available online 22 March 2011 Keywords: Portopulmonary hypertension Echocardiographic screening Vasodilator treatment
a b s t r a c t Portopulmonary hypertension is a form of pulmonary arterial hypertension that has gained interest in recent years with the development of liver transplantation techniques and new pulmonary vasodilator therapies. Portopulmonary hypertension is defined as pulmonary artery hypertension associated with portal hypertension with or without advanced hepatic disease. Echocardiography plays a major role in screening for portopulmonary hypertension but right heart catheterization remains the gold standard for diagnosis. The treatment of patients with portopulmonary hypertension consists of general measures that apply to all patients that carry the diagnosis of pulmonary hypertension and specific vasodilator therapies. These new therapies showed encouraging results in patients who would otherwise have a contraindication for liver transplantation. The review presents a summary of the current knowledge on the epidemiology, diagnosis, treatment and prognosis of patients with portopulmonary hypertension. © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Patients with chronic liver disease are at risk of developing pulmonary complications that range from hepatopulmonary syndrome to portopulmonary hypertension (POPH) [1]. The latter is a condition characterized by increased pulmonary vascular resistance associated with portal hypertension with or without advanced hepatic disease [2,3]. In the recent Dana Point classification of pulmonary hypertension, POPH is classified in group 1 — pulmonary artery hypertension (PAH) [4]. POPH is defined as an increase in mean pulmonary arterial pressure (mPAP) above 25 mmHg associated with normal capillary wedge pressure and a pulmonary vascular resistance (PVR) above 240 dyn/s/cm− 5 in the settings of portal hypertension [5] (Table 1). A mild increase in pulmonary arterial pressure is often seen (20%–50%) in patients with hepatic cirrhosis, but this is usually due to an increased cardiac output with normal or decreased pulmonary vascular resistance [6]. 2. Epidemiology Autopsy studies showed a five-fold higher incidence of the vascular lesions of pulmonary hypertension in patients with portal hypertension as compared to controls (0.73% versus 0.13%, p b 0.001) [8]. Data from epidemiological studies revealed that around 2–6% of patients with portal hypertension develop POPH [9,10]. Around 10% of ⁎ Corresponding author at: Cardiology Department, “C. C. Iliescu” Institute for Emergencies in Cardiovascular Diseases, Sos Fundeni nr 258, 022322 Bucuresti, Romania. Tel.: +40 213180700. E-mail address: [email protected] (S. Giusca).
these patients do not have liver cirrhosis [11]. In the French Registry for pulmonary hypertension, patients with POPH accounted for 10% of the PAH population, establishing POPH as the fourth cause of PAH, just below idiopathic PAH, PAH associated to congenital heart disease and PAH associated to connective tissue disease [12]. Several other national registries do not report the incidence of this subtype of PAH [13,14]. In patients undergoing liver transplantation, the incidence of POPH was found to be between 4% and 6% [15]. 3. Pathogenesis of portopulmonary hypertension POPH shares the common pathological changes described for group 1 of pulmonary hypertension — PAH: alterations at the level of distal pulmonary arteries with intimal proliferation, medial hypertrophy, fibrotic changes, plexiform lesions and in situ thrombosis [16,17]. No clear cause for the development of pulmonary hypertension in patients presenting with portal hypertension was found. It is considered that this condition has a multifactorial origin. One hypothesis postulates that the hyperdynamic status seen in patients with portal hypertension determines an increased shear stress at the level of the pulmonary vasculature. In response, remodeling occurs and characteristic changes of pulmonary arterial hypertension develop [18]. In addition, the presence of portosystemic shunts allows different vascular mediators to bypass liver metabolism creating an imbalance between vasoconstrictor and vasodilator factors at the level of pulmonary vasculature. Mediators such as endothelin-1, thromboxane A2, Vasoactive Intestinal Peptide (VIP), and serotonin can have direct vasoacitve and mitogenic effects and can cause damage to the pulmonary endothelium [6,19]. The imbalance is
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Table 1 Definition of portopulmonary hypertension [6,7]. Diagnostic criteria for portopulmonary hypertension 1
2 3 4
Presence of portal hypertension ➢ suggested by the presence of splenomegaly,thrombocytopenia, esophageal varices, portosystemic shunt ➢ confirmed by hemodynamic measurements Mean pulmonary artery pressure N25 mmHg Pulmonary vascular resistance N240 dyn/s/cm− 5 Pulmonary capillary wedge pressure b 15 mmHg
further augmented by a decrease in synthesis of vasodilators factors such as nitric oxide (NO) and prostacycline [20,21]. Of these mediators, endothelin-1 appears to play an important role in the pathogenesis of portal hypertension, with increased hepatosplenic production of endothelin contributing to intrahepatic stellate cell contraction and increased hepatic sinusoidal tone [22]. Mediators of smooth muscle vascular tone and growth – alfa-1 adrenergic receptors – were also incriminated in the pathological changes associated to arterial pulmonary hypertension [23]. Several studies suggest a possible role of inflammation in the etiology of POPH with macrophage translocation and pro-inflammatory cytokines playing an active role in vascular remodeling [7,24]. A recent analysis revealed increased levels of Interleukin-6 in patients with POPH, emphasizing a possible new therapeutic target for this condition [25]. Clinical predictors of developing POPH in patients with liver diseases appear to be female sex and the etiology of the disease with autoimmune hepatitis associating the highest risk of POPH and liver cirrhosis secondary to virus C infection the lowest [26]. Although mutations at the level of the gene that codes the Bone Morphogentic Protein Receptor Type 2 (BMPR2) were shown to associate an increased risk of developing idiopathic PAH, Roberts et al. found that mutations in genes encoding for proteins involved in estrogen signaling and cell growth are linked to the development of POPH [27,28].
4. Clinical presentation Patients with POPH present with similar symptoms as those with other forms of PAH [29]. In the early stages of disease, patients may be asymptomatic or oligosymptomatic. The clinical symptoms of the underlying liver disease or portal hypertension may be present. The first clinical symptom experienced by patients with POPH is usually dyspnea on exertion. The clinical picture is completed by fatigue, weakness, orthopnea, and thoracic pain. In the advanced stages of the disease, patients present with dyspnea at rest with a severe impairment of exercise capacity. The clinical exam may reveal the signs of right heart failure as well as those of the underlying disease. An elevated jugular pressure, a tricuspid systolic murmur secondary to tricuspid regurgitation and a pulmonary diastolic murmur secondary to pulmonary insufficiency can all be signs suggestive for right heart failure [30,31]. In addition, patients may present with ascitis and lower limbs edema.
X-ray an enlargement of the right cardiac chambers can be found as well as dilation of the pulmonary arteries [32,33]. The most important screening and diagnostic test for POPH is transthoracic echocardiography (TTE). The ESC guidelines recommend TTE screening in all symptomatic patients with liver disease and/or patients undergoing liver transplantation due to the high mortality risk associated to performing liver transplantation in a patient with POPH [29]. Using the modified Bernoulli equation, the right ventricular systolic pressure (RVSP) can be estimated from the peak tricuspid regurgitant jet velocity [34] (Fig. 1). A RVSP value above 50 mmHg is considered highly suggestive for the diagnosis of POPH [35], although in other studies a lower cutoff value of 40 mmHg was used [36]. In addition, the effects of RV chronic exposure to pressure overload can be quantified. Several morphological and functional RV parameters can be measured using echocardiography and cutoff values for prediction of RV failure and adverse prognosis have been described [37,38](Fig. 2). Screening for pulmonary hypertension in patients with portal hypertension using TTE poses a challenge, as in this population group the increased pressure can be secondary to either an increased pulmonary vascular resistance or can be the result of an increased flow through the pulmonary circulation (Fig. 3). Therefore, the estimation of pulmonary vascular resistance (PVR) is important for completing the diagnosis. Several formulas have been described for non-invasively estimating PVR using echocardiography [39–41]. They showed good correlation with catheterization derived data. In addition cutoff values have been derived that presented good sensitivity and specificity in differentiating between increased vascular resistance and hyperdynamic states. However, not many studies have tested these formulas in the portal hypertension population. Based on the available data, transthoracic echocardiography is not able to differentiate between hyperdynamic states and increased pulmonary vascular resistance, showing a low positive predictive value for diagnosing POPH. Therefore, at this moment, the gold standard for establishing a definite diagnosis of POPH is right heart catheterization. Using this technique, pressures and cardiac output can be measured and vascular resistances can be derived. It is considered that all patients with a RVSP estimated by echo N50 mmHg should undergo right heart catheterization [6]. Krowka et al. have shown that only 66% of patients presenting with an estimated RVSP N50 mmHg on echocardiography had also an increased pulmonary vascular resistance, stressing the importance of performing heart catheterization for clarifying the diagnosis [42]. In addition to hemodynamic measurements, a vasodilator test using NO or prostacycline may be performed although the recommendations for performing such a test are controversial as calcium channel blockers are not indicated in patients with POPH [43,44]. Even so, a study by Ricci et al. has shown that acute vasodilator testing could help in selecting POPH patients that would respond specific vasodilator therapy prior to liver transplantation [45].
6. Therapy 6.1. Non pharmacological therapy
5. Screening and diagnosis General cardiology screening tests – electrocardiography and chest X-ray – may reveal alterations concordant with right heart enlargement and failure. Their sensitivity is however low and therefore they are not suited for screening purposes. Right ventricular hypertrophy, right atrial hypertrophy, right axis deviation and right bundle branch block can be seen on electrocardiography. On chest
General measures regarding lifestyle and psychosocial support are common for all patients with pulmonary hypertension. Patients should be encouraged to be active within symptom limits. Although no clear studies exist, it is considered that patients with PAH clinically in NYHA class III or IV have a contraindication to air travel as hypoxic conditions can further aggravate their hemodynamic status [46]. Furthermore, although no data from controlled trials exist, anti influenza and anti Pneumococcus vaccination is recommended for these patients [29].
Fig. 1. Echocardiographic images from a patient with portopulmonary hypertension. Severe tricuspid regurgitation (A), with a right ventricle–right atrial pressure gradient of 70 mmHg (B) which added to the right atrial estimated pressure of 15–20 mmHg (C) allows for an estimation of the systolic pulmonary arterial pressure of 85–90 mmHg.
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Fig. 2. Echocardiographic images from a patient with portopulmonary hypertension. Note the D-shaped left ventricle in a parasternal short-axis view (A) and a severely dilated and apex-forming right ventricle in an apical 4-chamber view (B).
Patients with POPH benefit from oxygen supplementation with a target oxygen arterial blood saturation above 90%. A severe hypoxemia that is not corrected by the administration of oxygen must raise suspicion on the presence of a shunt [7]. 6.2. Pharmacological therapy 6.2.1. Conventional therapy Although recommended for patients with PAH who responded at vasodilator testing, calcium channel blockers are contraindicated in patients with POPH. It was shown that they produce mesenteric dilatation that in turn worsens portal hypertension [43,44]. Betablocking agents are commonly used to prevent first variceal bleeding and rebleeding in patients with portal hypertension, whatever the cause. However, they can reduce patients' exercise capacity and can have a deleterious effect on right heart hemodynamics [47]. The use of anticoagulation therapy in this population group is controversial, as no specific studies exist. In patients with a high risk of bleeding, anticoagulation therapy is not commonly recommended by the
current ESC guidelines for diagnosis and treatment of pulmonary hypertension [29]. Diuretic agents have a clear symptomatic benefit in both patients with right heart failure and liver cirrhosis; therefore, they have an important role in the therapeutic management of patients with POPH that show excess fluid retention. Still, therapy should be closely monitored as their administration can result in decreased cardiac output and prerenal failure. 6.2.2. Specific vasodilator therapy The recent decade has seen the development of novel therapeutic agents for patients with pulmonary arterial hypertension. Prostanoids, endothelin receptor blocking agents and phosphodiesterase type-5 inhibitors have changed the clinical course of patients with PAH. Most of these drugs have been, however, only tested in patients with idiopathic PAH and PAH associated with connective tissue diseases, as patients with POPH were excluded from most of the randomized clinical trials. Therefore, the experience with new therapies in POPH is mostly drawn from observational studies and case series.
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Patients with portal hypertension Symptoms of POPH (i.e.dyspnea) Chest X-Ray Standard ECG Exclusion of alternative diagnostic (pulmonary or cardiac diseases)
Presence of signs suggestive for POPH (i.e. right atrial and ventricular hypertrophy)
Standard TTE Exclusion of alternative diagnostic (structural cardiac diseases) RVSP >50 mmHg Exclusion of other causes of PAH (i.e. connective tissue disease, drugs) Estimation of PVR by echocardiography Right heart catheterization Fig. 3. Proposed algorithm for the diagnosis of POPH.
6.3. Prostanoids agents Epoprostenol is an intravenous analog of prostaglandin. It was shown to be effective in idiopathic PAH and is the only drug that has a proven survival benefit in patients with PAH [48]. In patients with POPH, intravenous administration of epoprostenol was associated with improved symptoms and a decrease in pulmonary pressure and PVR [49,50]. However, the administration of this drug poses some challenges related to the need of continuous intravenous administration. Furthermore, studies have reported an increased incidence of splenomegaly in patients with POPH that received epoprostenol [51]. Inhaled and subcutaneous administrations of other prostanoids were proven clinically beneficial as shown by several case series [6,52–54]. A recent report by Melgosa et al. showed both acute hemodynamic improvement and sustained clinical improvement over a period of 12 months in patients with POPH receiving inhaled iloprost [55]. 6.4. Endothelin receptor antagonists (ERA) These agents act by blocking the receptors for endothelin-1, a potent vasoconstrictor molecule. They are especially attractive in POPH as increased levels of endothelin-1 have been reported in these patients. The drawback is related to the increased transaminase levels that were reported in 10% of patients with PAH that received ERA [56]. Therefore, studies involving ERA excluded patients with liver disease. Several observational studies were published involving the ERA bosentan in patients with POPH. They showed positive results with improved symptoms and increased exercise capacity with a statistical significant drop in PVR [57,58]. Furthermore, no drug related liver injury, expressed by an elevation in transaminase levels, was noted. Even so, a close monitoring of therapy is mandatory in patients with POPH receiving bosentan therapy. Another ERA, ambrisentan was shown in a recent study on 13 patients with POPH to be effective in reducing mPAP and PVR without modifying the levels of liver enzymes [59]. 6.5. Phosphodiesterase 5 inhibitors (PD5I) Sildenafil was the only agent in this class studied in POPH. When administrated alone or in combination with a prostanoid, sildenafil
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showed a sustained improvement in the 6 min walking distance and a decrease in BNP levels. However, the hemodynamic benefit seen at 3 months (improvement in mPAP and PVR) was not sustained at 12 months [60]. Furthermore it was shown to be efficient in reducing pulmonary vascular resistance in patients prior to liver transplantation [61]. 6.6. Combination therapy The simultaneous administration of more than one specific drug for PAH has been shown to be beneficial in patients with PAH. Data are derived mostly from case series, as long term randomized control trials are lacking. Scarce information exists in the literature regarding combination therapy in POPH. Case reports document a clear hemodynamic improvement in patients who received a PD5I and/or an ERA on top of prostanoid therapy [62]. 7. Liver transplantation In general, liver transplantation is contraindicated in patients presenting with POPH due to an increased postoperative mortality [63]. Potential candidates should be evaluated in experienced centers and the surgical risk should always be thoroughly assessed. A mPAP N35 mmHg and a PVR N250 dyn/s/cm− 5 are considered contraindications for this surgical procedure [64], although new therapeutic strategies based on modern PAH vasodilator therapy can improve the hemodynamic status of patients, making them suitable for the surgical procedure [61,65]. The target for vasodilator therapy would be an mPAP b35 mmHg and a PVR b400 dyn/s/cm− 5 as these values do not associate additional operative risk [9]. Even so, case series showed successful liver transplantation in patients with a mPAP N35 mmHg [63]. 8. Prognosis When compared to patients with idiopathic PAH, patients with POPH have a worst survival profile, with a 3 year survival of only 38% versus 78% for idiopathic PAH [66]. Data published from the Mayo Clinic showed a 5-year survival of 45% in patients with POPH receiving vasodilator therapy, significantly higher compared to only 14% on a similar period of time in patients with POPH who were not on vasodilator medication [67]. In patients undergoing liver transplantation, the level of mPAP is a strong predictor of survival, a value above 35 mmHg being associated to a mortality rate of around 60% postoperatively [63]. 9. Conclusions Portopulmonary hypertension is becoming a well recognized subtype of pulmonary arterial hypertension. It represents a complication of liver disease although it can develop in patients who only present portal hypertension and no structural liver alterations. The pathological changes seen in the pulmonary vascular tree are similar to those seen in other types of pulmonary arterial hypertension. The main hypothesis for these changes is related to the increased shear stress present at the level of pulmonary vasculature secondary to an increased cardiac output. Transthoracic echocardiography plays a major role in screening for this entity but right heart catheterization remains the gold standard for establishing a definite diagnosis. Although most of the randomized controlled studies did not include patients with portopulmonary hypertension, observational studies have shown a clear hemodynamic and symptomatic benefit in patients with this condition that received any of the new vasodilator specific therapy: prostanoids, endothelin receptor antagonist and phosphodiesterase 5-inhibitor. Still, more studies are needed to establish the therapeutic role of each of this drug and also to draw
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indications for combination therapy. The presence of portopulmonary hypertension is usually a contraindication for liver transplantation. Even so, in patients with portopulmonary hypertension that would otherwise benefit from liver transplantation, new vasodilator therapies can be tried as they were shown to be effective in reducing preoperative pulmonary vascular resistance, thus making the surgical procedure possible. Learning points • Portopulmonary hypertension is a subtype of pulmonary arterial hypertension defined hemodynamically as an increase in mean pulmonary arterial pressure (mPAP) above 25 mmHg associated with normal capillary wedge pressure and a pulmonary vascular resistance (PVR) above 240 dyn/s/cm− 5. • It is ranked 4th in the group of pulmonary arterial hypertension based on prevalence. • It can develop in patients who present with portal hypertension but do not have liver cirrhosis. • Echocardiography is the main clinical tool for screening for portopulmonary hypertension. • Right heart catheterization is the gold standard for diagnosis and should be performed in all patients who are scheduled for liver transplantation and are suspected of having portopulmonary hypertension. • New vasodilator therapies such as prostanoids, endothelin receptor antagonists and phosphodiesterase 5 inhibitors have shown promising results both in clinical and hemodynamic improvements in this patients' population. • Liver transplantation is contraindicated in patients with portopulmonary hypertension, but data from literature have shown hemodynamic improvement in patients with portopulmonary hypertension receiving vasodilator therapy, making them suitable for the surgical procedure. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgment This work was supported by CNCSIS-UEFISCSU project number PNII-IDEI 246/2008. References [1] Pham DM, Subramanian R, Parekh S. Coexisting hepatopulmonary syndrome and portopulmonary hypertension: implications for liver transplantation. J Clin Gastroenterol 2010;44:e136–40. [2] Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004;363:1461–8. [3] Golbin JM, Krowka MJ. Portopulmonary hypertension. Clin Chest Med 2007;28: 203–18 ix. [4] Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43–54 (1 Suppl.). [5] Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004;24:861–80. [6] Porres-Aguilar M, Zuckerman MJ, Figueroa-Casas JB, Krowka MJ. Portopulmonary hypertension: state of the art. Ann Hepatol 2008;7:321–30. [7] Chabot F, Gomez E, Boyer L, Kheir A, Le Pavec J, Stitbon O, et al. Porto-pulmonary hypertension. Rev Mal Respir 2006;6:629–41. [8] McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983;127:437–41. [9] 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. [10] Budhiraja R, Hassoun PM. Portopulmonary hypertension: a tale of two circulations. Chest 2003;123:562–76. [11] Lebrec D, Capron JP, Dhumeaux D, Benhamou JP. Pulmonary hypertension complicating portal hypertension. Am Rev Respir Dis 1979;120:849–56.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Portopulmonary hypertension: From diagnosis to treatment Sorin Giusca a,⁎, Mariana Jinga b, Ciprian Jurcut b, Ruxandra Jurcut a, Marinela Serban a, Carmen Ginghina a a b
Cardiology Department, Institute for Emergencies in Cardiovascular Diseases “Prof Dr C. C. Iliescu”, Bucharest, Romania Internal Medicine Department, “Dr. Carol Davila” Central University Emergency Military Hospital, Bucharest, Romania
a r t i c l e
i n f o
Article history: Received 9 December 2010 Received in revised form 30 January 2011 Accepted 19 February 2011 Available online 22 March 2011 Keywords: Portopulmonary hypertension Echocardiographic screening Vasodilator treatment
a b s t r a c t Portopulmonary hypertension is a form of pulmonary arterial hypertension that has gained interest in recent years with the development of liver transplantation techniques and new pulmonary vasodilator therapies. Portopulmonary hypertension is defined as pulmonary artery hypertension associated with portal hypertension with or without advanced hepatic disease. Echocardiography plays a major role in screening for portopulmonary hypertension but right heart catheterization remains the gold standard for diagnosis. The treatment of patients with portopulmonary hypertension consists of general measures that apply to all patients that carry the diagnosis of pulmonary hypertension and specific vasodilator therapies. These new therapies showed encouraging results in patients who would otherwise have a contraindication for liver transplantation. The review presents a summary of the current knowledge on the epidemiology, diagnosis, treatment and prognosis of patients with portopulmonary hypertension. © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Patients with chronic liver disease are at risk of developing pulmonary complications that range from hepatopulmonary syndrome to portopulmonary hypertension (POPH) [1]. The latter is a condition characterized by increased pulmonary vascular resistance associated with portal hypertension with or without advanced hepatic disease [2,3]. In the recent Dana Point classification of pulmonary hypertension, POPH is classified in group 1 — pulmonary artery hypertension (PAH) [4]. POPH is defined as an increase in mean pulmonary arterial pressure (mPAP) above 25 mmHg associated with normal capillary wedge pressure and a pulmonary vascular resistance (PVR) above 240 dyn/s/cm− 5 in the settings of portal hypertension [5] (Table 1). A mild increase in pulmonary arterial pressure is often seen (20%–50%) in patients with hepatic cirrhosis, but this is usually due to an increased cardiac output with normal or decreased pulmonary vascular resistance [6]. 2. Epidemiology Autopsy studies showed a five-fold higher incidence of the vascular lesions of pulmonary hypertension in patients with portal hypertension as compared to controls (0.73% versus 0.13%, p b 0.001) [8]. Data from epidemiological studies revealed that around 2–6% of patients with portal hypertension develop POPH [9,10]. Around 10% of ⁎ Corresponding author at: Cardiology Department, “C. C. Iliescu” Institute for Emergencies in Cardiovascular Diseases, Sos Fundeni nr 258, 022322 Bucuresti, Romania. Tel.: +40 213180700. E-mail address: [email protected] (S. Giusca).
these patients do not have liver cirrhosis [11]. In the French Registry for pulmonary hypertension, patients with POPH accounted for 10% of the PAH population, establishing POPH as the fourth cause of PAH, just below idiopathic PAH, PAH associated to congenital heart disease and PAH associated to connective tissue disease [12]. Several other national registries do not report the incidence of this subtype of PAH [13,14]. In patients undergoing liver transplantation, the incidence of POPH was found to be between 4% and 6% [15]. 3. Pathogenesis of portopulmonary hypertension POPH shares the common pathological changes described for group 1 of pulmonary hypertension — PAH: alterations at the level of distal pulmonary arteries with intimal proliferation, medial hypertrophy, fibrotic changes, plexiform lesions and in situ thrombosis [16,17]. No clear cause for the development of pulmonary hypertension in patients presenting with portal hypertension was found. It is considered that this condition has a multifactorial origin. One hypothesis postulates that the hyperdynamic status seen in patients with portal hypertension determines an increased shear stress at the level of the pulmonary vasculature. In response, remodeling occurs and characteristic changes of pulmonary arterial hypertension develop [18]. In addition, the presence of portosystemic shunts allows different vascular mediators to bypass liver metabolism creating an imbalance between vasoconstrictor and vasodilator factors at the level of pulmonary vasculature. Mediators such as endothelin-1, thromboxane A2, Vasoactive Intestinal Peptide (VIP), and serotonin can have direct vasoacitve and mitogenic effects and can cause damage to the pulmonary endothelium [6,19]. The imbalance is
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.02.018
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Table 1 Definition of portopulmonary hypertension [6,7]. Diagnostic criteria for portopulmonary hypertension 1
2 3 4
Presence of portal hypertension ➢ suggested by the presence of splenomegaly,thrombocytopenia, esophageal varices, portosystemic shunt ➢ confirmed by hemodynamic measurements Mean pulmonary artery pressure N25 mmHg Pulmonary vascular resistance N240 dyn/s/cm− 5 Pulmonary capillary wedge pressure b 15 mmHg
further augmented by a decrease in synthesis of vasodilators factors such as nitric oxide (NO) and prostacycline [20,21]. Of these mediators, endothelin-1 appears to play an important role in the pathogenesis of portal hypertension, with increased hepatosplenic production of endothelin contributing to intrahepatic stellate cell contraction and increased hepatic sinusoidal tone [22]. Mediators of smooth muscle vascular tone and growth – alfa-1 adrenergic receptors – were also incriminated in the pathological changes associated to arterial pulmonary hypertension [23]. Several studies suggest a possible role of inflammation in the etiology of POPH with macrophage translocation and pro-inflammatory cytokines playing an active role in vascular remodeling [7,24]. A recent analysis revealed increased levels of Interleukin-6 in patients with POPH, emphasizing a possible new therapeutic target for this condition [25]. Clinical predictors of developing POPH in patients with liver diseases appear to be female sex and the etiology of the disease with autoimmune hepatitis associating the highest risk of POPH and liver cirrhosis secondary to virus C infection the lowest [26]. Although mutations at the level of the gene that codes the Bone Morphogentic Protein Receptor Type 2 (BMPR2) were shown to associate an increased risk of developing idiopathic PAH, Roberts et al. found that mutations in genes encoding for proteins involved in estrogen signaling and cell growth are linked to the development of POPH [27,28].
4. Clinical presentation Patients with POPH present with similar symptoms as those with other forms of PAH [29]. In the early stages of disease, patients may be asymptomatic or oligosymptomatic. The clinical symptoms of the underlying liver disease or portal hypertension may be present. The first clinical symptom experienced by patients with POPH is usually dyspnea on exertion. The clinical picture is completed by fatigue, weakness, orthopnea, and thoracic pain. In the advanced stages of the disease, patients present with dyspnea at rest with a severe impairment of exercise capacity. The clinical exam may reveal the signs of right heart failure as well as those of the underlying disease. An elevated jugular pressure, a tricuspid systolic murmur secondary to tricuspid regurgitation and a pulmonary diastolic murmur secondary to pulmonary insufficiency can all be signs suggestive for right heart failure [30,31]. In addition, patients may present with ascitis and lower limbs edema.
X-ray an enlargement of the right cardiac chambers can be found as well as dilation of the pulmonary arteries [32,33]. The most important screening and diagnostic test for POPH is transthoracic echocardiography (TTE). The ESC guidelines recommend TTE screening in all symptomatic patients with liver disease and/or patients undergoing liver transplantation due to the high mortality risk associated to performing liver transplantation in a patient with POPH [29]. Using the modified Bernoulli equation, the right ventricular systolic pressure (RVSP) can be estimated from the peak tricuspid regurgitant jet velocity [34] (Fig. 1). A RVSP value above 50 mmHg is considered highly suggestive for the diagnosis of POPH [35], although in other studies a lower cutoff value of 40 mmHg was used [36]. In addition, the effects of RV chronic exposure to pressure overload can be quantified. Several morphological and functional RV parameters can be measured using echocardiography and cutoff values for prediction of RV failure and adverse prognosis have been described [37,38](Fig. 2). Screening for pulmonary hypertension in patients with portal hypertension using TTE poses a challenge, as in this population group the increased pressure can be secondary to either an increased pulmonary vascular resistance or can be the result of an increased flow through the pulmonary circulation (Fig. 3). Therefore, the estimation of pulmonary vascular resistance (PVR) is important for completing the diagnosis. Several formulas have been described for non-invasively estimating PVR using echocardiography [39–41]. They showed good correlation with catheterization derived data. In addition cutoff values have been derived that presented good sensitivity and specificity in differentiating between increased vascular resistance and hyperdynamic states. However, not many studies have tested these formulas in the portal hypertension population. Based on the available data, transthoracic echocardiography is not able to differentiate between hyperdynamic states and increased pulmonary vascular resistance, showing a low positive predictive value for diagnosing POPH. Therefore, at this moment, the gold standard for establishing a definite diagnosis of POPH is right heart catheterization. Using this technique, pressures and cardiac output can be measured and vascular resistances can be derived. It is considered that all patients with a RVSP estimated by echo N50 mmHg should undergo right heart catheterization [6]. Krowka et al. have shown that only 66% of patients presenting with an estimated RVSP N50 mmHg on echocardiography had also an increased pulmonary vascular resistance, stressing the importance of performing heart catheterization for clarifying the diagnosis [42]. In addition to hemodynamic measurements, a vasodilator test using NO or prostacycline may be performed although the recommendations for performing such a test are controversial as calcium channel blockers are not indicated in patients with POPH [43,44]. Even so, a study by Ricci et al. has shown that acute vasodilator testing could help in selecting POPH patients that would respond specific vasodilator therapy prior to liver transplantation [45].
6. Therapy 6.1. Non pharmacological therapy
5. Screening and diagnosis General cardiology screening tests – electrocardiography and chest X-ray – may reveal alterations concordant with right heart enlargement and failure. Their sensitivity is however low and therefore they are not suited for screening purposes. Right ventricular hypertrophy, right atrial hypertrophy, right axis deviation and right bundle branch block can be seen on electrocardiography. On chest
General measures regarding lifestyle and psychosocial support are common for all patients with pulmonary hypertension. Patients should be encouraged to be active within symptom limits. Although no clear studies exist, it is considered that patients with PAH clinically in NYHA class III or IV have a contraindication to air travel as hypoxic conditions can further aggravate their hemodynamic status [46]. Furthermore, although no data from controlled trials exist, anti influenza and anti Pneumococcus vaccination is recommended for these patients [29].
Fig. 1. Echocardiographic images from a patient with portopulmonary hypertension. Severe tricuspid regurgitation (A), with a right ventricle–right atrial pressure gradient of 70 mmHg (B) which added to the right atrial estimated pressure of 15–20 mmHg (C) allows for an estimation of the systolic pulmonary arterial pressure of 85–90 mmHg.
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Fig. 2. Echocardiographic images from a patient with portopulmonary hypertension. Note the D-shaped left ventricle in a parasternal short-axis view (A) and a severely dilated and apex-forming right ventricle in an apical 4-chamber view (B).
Patients with POPH benefit from oxygen supplementation with a target oxygen arterial blood saturation above 90%. A severe hypoxemia that is not corrected by the administration of oxygen must raise suspicion on the presence of a shunt [7]. 6.2. Pharmacological therapy 6.2.1. Conventional therapy Although recommended for patients with PAH who responded at vasodilator testing, calcium channel blockers are contraindicated in patients with POPH. It was shown that they produce mesenteric dilatation that in turn worsens portal hypertension [43,44]. Betablocking agents are commonly used to prevent first variceal bleeding and rebleeding in patients with portal hypertension, whatever the cause. However, they can reduce patients' exercise capacity and can have a deleterious effect on right heart hemodynamics [47]. The use of anticoagulation therapy in this population group is controversial, as no specific studies exist. In patients with a high risk of bleeding, anticoagulation therapy is not commonly recommended by the
current ESC guidelines for diagnosis and treatment of pulmonary hypertension [29]. Diuretic agents have a clear symptomatic benefit in both patients with right heart failure and liver cirrhosis; therefore, they have an important role in the therapeutic management of patients with POPH that show excess fluid retention. Still, therapy should be closely monitored as their administration can result in decreased cardiac output and prerenal failure. 6.2.2. Specific vasodilator therapy The recent decade has seen the development of novel therapeutic agents for patients with pulmonary arterial hypertension. Prostanoids, endothelin receptor blocking agents and phosphodiesterase type-5 inhibitors have changed the clinical course of patients with PAH. Most of these drugs have been, however, only tested in patients with idiopathic PAH and PAH associated with connective tissue diseases, as patients with POPH were excluded from most of the randomized clinical trials. Therefore, the experience with new therapies in POPH is mostly drawn from observational studies and case series.
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Patients with portal hypertension Symptoms of POPH (i.e.dyspnea) Chest X-Ray Standard ECG Exclusion of alternative diagnostic (pulmonary or cardiac diseases)
Presence of signs suggestive for POPH (i.e. right atrial and ventricular hypertrophy)
Standard TTE Exclusion of alternative diagnostic (structural cardiac diseases) RVSP >50 mmHg Exclusion of other causes of PAH (i.e. connective tissue disease, drugs) Estimation of PVR by echocardiography Right heart catheterization Fig. 3. Proposed algorithm for the diagnosis of POPH.
6.3. Prostanoids agents Epoprostenol is an intravenous analog of prostaglandin. It was shown to be effective in idiopathic PAH and is the only drug that has a proven survival benefit in patients with PAH [48]. In patients with POPH, intravenous administration of epoprostenol was associated with improved symptoms and a decrease in pulmonary pressure and PVR [49,50]. However, the administration of this drug poses some challenges related to the need of continuous intravenous administration. Furthermore, studies have reported an increased incidence of splenomegaly in patients with POPH that received epoprostenol [51]. Inhaled and subcutaneous administrations of other prostanoids were proven clinically beneficial as shown by several case series [6,52–54]. A recent report by Melgosa et al. showed both acute hemodynamic improvement and sustained clinical improvement over a period of 12 months in patients with POPH receiving inhaled iloprost [55]. 6.4. Endothelin receptor antagonists (ERA) These agents act by blocking the receptors for endothelin-1, a potent vasoconstrictor molecule. They are especially attractive in POPH as increased levels of endothelin-1 have been reported in these patients. The drawback is related to the increased transaminase levels that were reported in 10% of patients with PAH that received ERA [56]. Therefore, studies involving ERA excluded patients with liver disease. Several observational studies were published involving the ERA bosentan in patients with POPH. They showed positive results with improved symptoms and increased exercise capacity with a statistical significant drop in PVR [57,58]. Furthermore, no drug related liver injury, expressed by an elevation in transaminase levels, was noted. Even so, a close monitoring of therapy is mandatory in patients with POPH receiving bosentan therapy. Another ERA, ambrisentan was shown in a recent study on 13 patients with POPH to be effective in reducing mPAP and PVR without modifying the levels of liver enzymes [59]. 6.5. Phosphodiesterase 5 inhibitors (PD5I) Sildenafil was the only agent in this class studied in POPH. When administrated alone or in combination with a prostanoid, sildenafil
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showed a sustained improvement in the 6 min walking distance and a decrease in BNP levels. However, the hemodynamic benefit seen at 3 months (improvement in mPAP and PVR) was not sustained at 12 months [60]. Furthermore it was shown to be efficient in reducing pulmonary vascular resistance in patients prior to liver transplantation [61]. 6.6. Combination therapy The simultaneous administration of more than one specific drug for PAH has been shown to be beneficial in patients with PAH. Data are derived mostly from case series, as long term randomized control trials are lacking. Scarce information exists in the literature regarding combination therapy in POPH. Case reports document a clear hemodynamic improvement in patients who received a PD5I and/or an ERA on top of prostanoid therapy [62]. 7. Liver transplantation In general, liver transplantation is contraindicated in patients presenting with POPH due to an increased postoperative mortality [63]. Potential candidates should be evaluated in experienced centers and the surgical risk should always be thoroughly assessed. A mPAP N35 mmHg and a PVR N250 dyn/s/cm− 5 are considered contraindications for this surgical procedure [64], although new therapeutic strategies based on modern PAH vasodilator therapy can improve the hemodynamic status of patients, making them suitable for the surgical procedure [61,65]. The target for vasodilator therapy would be an mPAP b35 mmHg and a PVR b400 dyn/s/cm− 5 as these values do not associate additional operative risk [9]. Even so, case series showed successful liver transplantation in patients with a mPAP N35 mmHg [63]. 8. Prognosis When compared to patients with idiopathic PAH, patients with POPH have a worst survival profile, with a 3 year survival of only 38% versus 78% for idiopathic PAH [66]. Data published from the Mayo Clinic showed a 5-year survival of 45% in patients with POPH receiving vasodilator therapy, significantly higher compared to only 14% on a similar period of time in patients with POPH who were not on vasodilator medication [67]. In patients undergoing liver transplantation, the level of mPAP is a strong predictor of survival, a value above 35 mmHg being associated to a mortality rate of around 60% postoperatively [63]. 9. Conclusions Portopulmonary hypertension is becoming a well recognized subtype of pulmonary arterial hypertension. It represents a complication of liver disease although it can develop in patients who only present portal hypertension and no structural liver alterations. The pathological changes seen in the pulmonary vascular tree are similar to those seen in other types of pulmonary arterial hypertension. The main hypothesis for these changes is related to the increased shear stress present at the level of pulmonary vasculature secondary to an increased cardiac output. Transthoracic echocardiography plays a major role in screening for this entity but right heart catheterization remains the gold standard for establishing a definite diagnosis. Although most of the randomized controlled studies did not include patients with portopulmonary hypertension, observational studies have shown a clear hemodynamic and symptomatic benefit in patients with this condition that received any of the new vasodilator specific therapy: prostanoids, endothelin receptor antagonist and phosphodiesterase 5-inhibitor. Still, more studies are needed to establish the therapeutic role of each of this drug and also to draw
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indications for combination therapy. The presence of portopulmonary hypertension is usually a contraindication for liver transplantation. Even so, in patients with portopulmonary hypertension that would otherwise benefit from liver transplantation, new vasodilator therapies can be tried as they were shown to be effective in reducing preoperative pulmonary vascular resistance, thus making the surgical procedure possible. Learning points • Portopulmonary hypertension is a subtype of pulmonary arterial hypertension defined hemodynamically as an increase in mean pulmonary arterial pressure (mPAP) above 25 mmHg associated with normal capillary wedge pressure and a pulmonary vascular resistance (PVR) above 240 dyn/s/cm− 5. • It is ranked 4th in the group of pulmonary arterial hypertension based on prevalence. • It can develop in patients who present with portal hypertension but do not have liver cirrhosis. • Echocardiography is the main clinical tool for screening for portopulmonary hypertension. • Right heart catheterization is the gold standard for diagnosis and should be performed in all patients who are scheduled for liver transplantation and are suspected of having portopulmonary hypertension. • New vasodilator therapies such as prostanoids, endothelin receptor antagonists and phosphodiesterase 5 inhibitors have shown promising results both in clinical and hemodynamic improvements in this patients' population. • Liver transplantation is contraindicated in patients with portopulmonary hypertension, but data from literature have shown hemodynamic improvement in patients with portopulmonary hypertension receiving vasodilator therapy, making them suitable for the surgical procedure. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgment This work was supported by CNCSIS-UEFISCSU project number PNII-IDEI 246/2008. References [1] Pham DM, Subramanian R, Parekh S. Coexisting hepatopulmonary syndrome and portopulmonary hypertension: implications for liver transplantation. J Clin Gastroenterol 2010;44:e136–40. [2] Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004;363:1461–8. [3] Golbin JM, Krowka MJ. Portopulmonary hypertension. Clin Chest Med 2007;28: 203–18 ix. [4] Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43–54 (1 Suppl.). [5] Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004;24:861–80. [6] Porres-Aguilar M, Zuckerman MJ, Figueroa-Casas JB, Krowka MJ. Portopulmonary hypertension: state of the art. Ann Hepatol 2008;7:321–30. [7] Chabot F, Gomez E, Boyer L, Kheir A, Le Pavec J, Stitbon O, et al. Porto-pulmonary hypertension. Rev Mal Respir 2006;6:629–41. [8] McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983;127:437–41. [9] 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. [10] Budhiraja R, Hassoun PM. Portopulmonary hypertension: a tale of two circulations. Chest 2003;123:562–76. [11] Lebrec D, Capron JP, Dhumeaux D, Benhamou JP. Pulmonary hypertension complicating portal hypertension. Am Rev Respir Dis 1979;120:849–56.
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