Portopulmonary Hypertension Nadine Al-Naamani, MD, Kari E. Roberts, MD* KEYWORDS  Hypertension, portal  Hypertension, pulmonary  Liver transplantation

KEY POINTS  Portopulmonary hypertension (PoPH) describes the presence of group I pulmonary arterial hypertension (PAH) in patients with portal hypertension caused by cirrhotic or noncirrhotic liver disease.  PoPH should be considered in the differential diagnosis of any patient with advanced liver disease and unexplained dyspnea or refractory ascites and edema.  Transthoracic echocardiography is the screening test of choice, although it has a low positive predictive value because of the systemic hemodynamic consequences of portal hypertension.  Right heart catheterization is required for the diagnosis of PoPH.  PAH-specific therapies, including prostacyclins, endothelial receptor antagonists, and phosphodiesterase inhibitors, can be safely and effectively used for patients with PoPH.  Liver transplantation should be considered for patients with mild or moderate PoPH, although the impact of transplantation on the natural history of PAH is uncertain.

Advanced liver disease can be associated with significant pulmonary and pulmonary vascular dysfunction. Portopulmonary hypertension (PoPH) is defined as pulmonary arterial hypertension (PAH) that occurs in the context of portal hypertension. Portal hypertension, with or without cirrhosis, is the third most common clinical entity associated with PAH. Occurring in up to 6% of patients with advanced liver disease, PoPH is a rare, but lifethreatening, complication of portal hypertension. Recognition of PoPH can be delayed because of the common clinical presentations of liver disease and right ventricular (RV) failure, and accurate diagnosis can be challenging because of the complex systemic hemodynamic effects of portal hypertension. PoPH must also be distinguished from hepatopulmonary syndrome (HPS), a more prevalent but less morbid pulmonary vascular complication of liver disease. Prompt recognition is critical because the cosegregation of pulmonary arterial and portal hypertension carries important implications for

prognosis, medical therapy, and liver transplantation (LT). This article reviews the epidemiology, pathogenesis, clinical features, diagnostic evaluation, and management of PoPH.

DEFINITION OF POPH Using the Dana Point classification of pulmonary hypertension, PoPH is group 1.4.3 PAH (Table 1).1 Portal hypertension, caused by hepatic or extrahepatic disease, is sufficient to cause the pulmonary arteriopathy classically associated with PAH. The presence of portal hypertension is typically confirmed by direct measurement of the portal pressure gradient and the presence of esophageal and gastric varices or liver biopsy confirming cirrhosis.2–4 Intrinsic liver disease and portal hypertension are often accompanied by endothelial dysfunction and a hyperdynamic circulatory state. These systemic changes lead to impaired sodium and water handling, which are reflected clinically as volume overload. Approximately 20% of patients with liver

Disclosures: The authors have no disclosures relevant to this article. Tufts Medical Center, 800 Washington Street, #257, Boston, MA 02111, USA * Corresponding author. Tufts Medical Center, 800 Washington Street, #257, Boston, MA 02111. E-mail address: [email protected] Clin Chest Med 34 (2013) 719–737 http://dx.doi.org/10.1016/j.ccm.2013.08.008 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.



Al-Naamani & Roberts


Table 1 Dana Point classification of pulmonary hypertension 1. 1.1. 1.2. 1.2.1. 1.2.2. 1.2.3. 1.3. 1.4. 1.4.1. 1.4.2. 1.4.3. 1.4.4. 1.4.5. 1.4.6. 1.5. 10 . 2. 2.1. 2.2. 2.3. 3. 3.1. 3.2. 3.3. 3.4. 3.5. 3.6. 3.7. 4. 5. 5.1. 5.2. 5.3.

PAH Idiopathic PAH Heritable BMPR2 ALK1, endoglin Unknown Drug-associated and toxin-associated Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart diseases Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of the newborn Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis Pulmonary hypertension caused by left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease Pulmonary hypertension caused by lung diseases or hypoxia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Chronic thromboembolic pulmonary hypertension Pulmonary hypertension with unclear multifactorial mechanisms Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

Abbreviations: ALK1, activin receptorlike kinase 1; BMPR2, bone morphogenetic protein receptor 2; HIV, human immunodeficiency virus.

cirrhosis have a moderate increase in pulmonary pressures that is evident at the time of echocardiography5; however, a few of these are diagnosed with PoPH. The 2 most common causes for pulmonary hypertension are increased cardiac output (CO)5–7 and increased left-sided filling pressures. In both of these circumstances, the transpulmonary gradient (mean pulmonary artery pressure [mPAP]–pulmonary capillary wedge pressure [PCWP]) and pulmonary vascular resistance (PVR) are normal or even low.8 PVR 5 [(mPAP  PCWP)/CO]  80

It is critical to distinguish these patients from true PoPH because they not only enjoy a significantly better prognosis, but in addition, they require a different therapeutic approach. The standard hemodynamic definition for PAH is applied for PoPH9,10: 1. mPAP of 25 mm Hg or greater (at rest), and 2. PCWP of 15 mm Hg or less The spectrum of systemic and pulmonary hemodynamic changes documented in patients with portal hypertension has created some

Portopulmonary Hypertension ambiguity in defining the pulmonary vascular phenotype in this population using conventional PAH hemodynamic criteria. Clinical syndromes consistent with PAH are recognized in patients with portal hypertension and PCWP >15 mm Hg or PVR 120 to 240 dyn s/cm5 (1.5–3 Wood units).11 Previous definitions for PAH have included a PVR greater than 240 dyn s/cm5 (>3 Wood units) as part of the hemodynamic definition of PAH. The usefulness of a PVR threshold to patients with portal hypertension may help to distinguish between increased pulmonary artery pressure in the setting of a hyperdynamic circulation as a result of liver disease from the presence of pulmonary arteriopathy consistent with PAH or PoPH. An increased transpulmonary gradient (>12 mm Hg) may also be helpful in making the distinction between the different forms of pulmonary vascular disease associated with liver disease. Although some experts advocate for flexibility in the hemodynamic definition for patients with portal hypertension, there are insufficient data to validate alternative diagnostic criteria. PoPH is classified as mild, moderate, or severe, as outlined in Table 2.6,12 Right heart catheterization (RHC), with direct measurement of mPAP, PCWP, and CO is required in order to distinguish PoPH from these other forms of pulmonary hypertension. Table 3 shows the 3 common pulmonary hemodynamic patterns seen in portal hypertension.13

EPIDEMIOLOGY AND OUTCOMES The association between portal hypertension and PAH was first described by Mantz and Craige in 1951,14 who presented the case of a 53-year-old woman with portal vein stenosis and cor pulmonale. At autopsy the patient’s pulmonary microcirculation showed endothelial proliferation, intimal thickening, and thrombosis. This initial observation

Table 2 Staging of severity of PoPH

NYHA FC mPAP (mm Hg) CI (L/min/m2) PVR (dyn s/cm5) RAP (mm Hg)




I, II 25–34 >2.5 240–500 0–5

II, III 35–44 >2.5 500–800 5–8

III, IV >45 800 >8

Abbreviations: CI, cardiac index; NYHA FC, New York Heart Association functional class; RAP, right atrial pressure. From Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004;363(9419):1463; with permission.

was later confirmed in a study of more than 17,000 autopsies,15 which reported a higher prevalence of PAH among patients with portal hypertension or cirrhosis than in unselected patients (0.73% vs 0.13%, respectively). Among patients with chronic liver disease, the prevalence of PoPH is estimated to be 2%,16 increasing to 4% to 6% among individuals undergoing LT evaluation.5,11,17 PoPH may be more prevalent (5%–10%) among individuals with extrahepatic portal hypertension such as that associated with extrahepatic obstruction of the portal vein, biliary atresia, or idiopathic portal hypertension.18,19 PoPH accounts for 7% to 10% of all group 1 PAH, and it is the third most common clinical subtype after idiopathic PAH and PAH associated with connective tissue diseases.20,21 Pediatric PoPH has been less well defined, although a recent review19 reported a prevalence of 5.2% among children with portal hypertension. Adults with PoPH typically present in the fifth decade of life, likely a reflection of the demographics of liver disease,5,22 with the diagnosis of portal hypertension preceding PAH by 4 to 7 years.16,23–25 Defining the at-risk minority amongst those with portal hypertension has led to several observations. First, similar to PAH associated with idiopathic and connective tissue disease, female sex is now an accepted risk factor for PoPH. Women with portal hypertension have nearly 3 times the risk of men; this skewed sex ratio is apparent despite the male predominance of portal hypertension.26–28 Second, individuals with autoimmune liver disease have a 4-fold increased risk for PoPH compared with other causes of liver disease. This finding also mirrors the pattern in other types of PAH, in which autoimmunity represents a risk factor for PAH (ie, scleroderma) or manifests itself in other organ systems (autoimmune thyroid disease in PAH). Third, among those with advanced liver disease, hepatitis C infection is associated with a lower risk for PoPH (odds ratio 0.24, 95% confidence interval [CI] 0.09-0.56, P 5 .005).29 Last, there is no demonstrable correlation between risk of PoPH and portal hemodynamics.16,29 PoPH is a morbid and mortal disease. Historically, mean and median survivals of patients with PoPH were 15 and 6 months, respectively, with a 5-year survival less than 10%.30 More contemporary data from the United States show improved outcomes, yet there remains a nearly 4-fold increased risk of death in PoPH relative to idiopathic PAH (hazard ratio 3.6, 95% CI 2.4–5.4).31 Of all subtypes of group I PAH, patients with PoPH have the worst outcomes, with 2-year and 5-year survivals of 67% and 40% (Fig. 1). This finding is despite the fact that patients with



Al-Naamani & Roberts

Table 3 Patterns of hemodynamics in portal hypertension

Normal values Hyperdynamic Volume overload PoPH





92%), but variable sensitivity (54.5%–100%) and a low positive predictive value (18%–60%).17,85,86 Compared with the standard cutoff of 40 mm Hg, using a threshold of sPAP 50 mm Hg or greater is associated with a higher sensitivity; however, even at this threshold, one-third of patients have a normal PVR at time of RHC.87 A recent study of TTE in patients with portal hypertension attempted to refine TTE criteria for PoPH. The presence of RV dilatation (defined as RV end diastolic diameter >3.3 cm) raises suspicion for PoPH and should lead to RHC. It has been recently proposed that individuals with sPAP 38 mm Hg or greater should undergo RHC for definitive diagnosis.88 This cutoff is 100% sensitive and 82% specific. When combined with the presence of RV dysfunction, the specificity is



Al-Naamani & Roberts increased to 93%. Alternative echocardiographic indices of RV function such as the tricuspid annular plane systolic excursion, Tei index, or longitudinal shortening have not been studied in the portal hypertension population.89–91 TTE should be performed in all patients with suspected PoPH as well as anyone undergoing LT evaluation.2,23,92–95 In addition to assessment of the right ventricle and pulmonary pressures, it allows visualization of the left-sided valves, atrium, and ventricle. The presence of left-sided heart disease makes PoPH unlikely. Contrast TTE should be strongly considered in this population, because it facilitates the identification of HPS, which is 3 times more prevalent than PoPH.4,13,96 The clinical and diagnostic distinctions between PoPH and HPS are outlined in Table 4. Current guidelines recommend that finding of any of the following in a patient with portal hypertension should prompt RHC: RVSP 50 mm Hg or higher or the presence of: right atrial enlargement, RV enlargement, or reduced RV systolic function.11,22 Emerging data suggest that a more aggressive approach may be indicated in order to start treatment with PAH-specific therapy earlier as well as to improve pretransplant risk-benefit assessment. As a result, some transplant centers consider RHC in patients with RVSP greater than 40 mm Hg or RV dilatation. Once a diagnosis of pulmonary hypertension is contemplated, a ventilation-perfusion scan should be performed to rule out the presence of chronic thromboembolic disease, because the treatment of this condition is different from that of PoPH. RHC remains the gold standard for the diagnosis of PoPH. Careful measurement of right atrial

pressure, PAP, PCWP, and CO is critical for a thoughtful appraisal of the hemodynamics seen in advanced liver disease and portal hypertension (see Table 3). Acute vasodilator challenge with inhaled nitric oxide or intravenous epoprostenol is also recommended at the time of diagnostic catheterization, even though fewer than 2% of patients with PoPH have an acute vasodilator response.97,98 The presence of an acute vasodilator response is helpful in staging severity and therapeutic expectations of the disease, and may indicate a better hemodynamic tolerance at the time of LT. Unlike idiopathic PAH, vasodilator response in PoPH should not be used to assess for the ability to respond to calcium channel blockers, because their use is contraindicated in portal hypertension.22,74,99 Dyspnea as well as refractory ascites or lower extremity edema should prompt an assessment for the presence of PoPH. History and physical findings can be nonspecific, and therefore accurate diagnosis requires a high clinical suspicion and careful interpretation of diagnostic testing. TTE is the screening test of choice. Because of the inability of TTE to distinguish between alternative causes of pulmonary hypertension in patients with portal hypertension (specifically volume overload or hyperdynamic circulation), RHC is recommended for patients with sPAP greater than 50 mm Hg or evidence of RV/atrial volume or pressure overload. Other causes of pulmonary hypertension should be excluded using history, laboratory, and imaging data as per consensus guidelines. Fig. 4 outlines the diagnostic approach to patients with suspected PoPH.

Table 4 A comparison of PoPH and HPS



Arterial blood gas Contrast TTE Hemodynamics Role of LT



Dyspnea Chest pain Syncope Loud P2 RV heave Lower extremity edema Normal to mild hypoxemia

Dyspnea Platypnea

Negative or 1 intracardiac shunt (positive within 240 dyn s/cm5 Relatively contraindicated; consider in selected patients if mPAP 20 Positive for intrapulmonary shunting (3–6 cardiac cycles) Normal or low PVR Indicated; exception points granted if room air PaO2 3  ULN (n 5 1), dose reduced Thrombocytopenia (n 5 2), drug discontinued None

























Bleeding (n 5 1), drug discontinued None

Sildenafil 1 treprostinil Bosentan  sildenafil












LFT >3  ULN (n 5 7), drug discontinued

13 18 19


Child-Pugh B, C NYHA FC 1–3 MELD 14 NYHA FC 3 MELD 15 NYHA FC 2–3 Child-Pugh A (62%) NYHA FC 2–3 NA




Child-Pugh A, B NYHA FC 2–4

10 12 13

Abbreviations: 6MWD, 6-minute walk distance; ERA, endothelin receptor antagonist; inh, inhaled prostacyclin; LFT, liver function test; MELD, Model for End-Stage Liver Disease; NA, data not available; NYHA FC, New York Heart Association Functional Class; ULN, upper limit of normal. a Change from baseline to follow-up was significant.

Portopulmonary Hypertension

Krowka et al,108 1999 Hoeper et al,112 2005



Al-Naamani & Roberts in PoPH. In 2 retrospective studies of patients,119,120 investigators at the University of Rochester and Vanderbilt University successfully used sildenafil as a bridge to LT. There was no increased risk of adverse effects compared with patients with other forms of PAH treated with PDI. The impact of PDI therapy on portal hemodynamics is variable, with both improvement121,122 and worsening123 of portal pressures reported. Overall PDI are a viable therapeutic option for patients with PoPH. Combination therapy The benefit of combination therapy in PAH is unclear, although it is common practice to add additional vasodilator agents when patients are clinically progressing.124–129 Published series in PoPH include all potential combinations of the 3 vasodilator classes, with no evidence that outcomes are different when compared with other clinical subtypes of PAH.130–132 Nevertheless this experience is limited (50 mm Hg).139–141 A period of reflection on the risk/benefit of LT for PoPH followed. Patients with PAH represent one of the highest risk groups for major surgery, general anesthesia, and positive pressure ventilation, because of a limited capacity for the right ventricle in these patients to handle insults to its contractility, or changes in preload or afterload.142 LT creates a challenging hemodynamic environment for any patient. This situation is especially relevant at the time of reperfusion of the new liver, a transition point that is characterized by an abrupt increase in preload and a decrease in systemic vascular resistance accompanied by significant shifts in hydrogen ion and potassium levels (reviewed in Ref.143). In the setting of the fixed pulmonary vascular remodeling and chronic RV dysfunction characteristic of PoPH, LT can prove fatal, because of dramatic swings in preload and CO as well as marked increases in pulmonary arterial pressures. The resultant RV failure, which can develop at the time of reperfusion or up to a week after transplant, is a well-described phenomenon in patients with PoPH and it is often refractory to intervention.144–147 Contemporary liver transplant outcomes in PoPH (with the advent of earlier diagnosis, better risk assessment and the use of PAH-specific therapies) are more encouraging. Carefully selected patients with mild PoPH (mPAP

Portopulmonary hypertension.

Diagnosis of portopulmonary hypertension (PoPH), is challenging because of the multitude of cardiac and pulmonary diseases that cosegregate with advan...
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