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Abstract

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

Portopulmonary hypertension (POPH) is a serious complication of cirrhosis that is associated with mortality beyond that predicted by the Model for End-Stage Liver Disease (MELD) score. Increased pulmonary vascular resistance (PVR) may be initiated by pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can eventually lead to the classic vascular remodeling (plexiform lesion) that characterizes POPH. Portal hypertension is a prerequisite for the diagnosis of POPH, although the severity of pulmonary hypertension is unrelated to the severity of portal hypertension or the nature or severity of liver disease. POPH precludes liver transplantation (LT) unless the mean pulmonary artery pressure (MPAP) can be reduced to a safe level. The concept of an acceptable pressure has changed: we now consider both MPAP and PVR in the diagnosis, and we include the transpulmonary pressure gradient so that we can factor in fluid overload and left ventricular failure. Pulmonary vasodilator therapy includes oral, inhaled, and parenteral agents, and one or more of these agents may significantly lower pulmonary artery pressures to the point that LT becomes possible. The United Network for Organ Sharing recommends MELD exception points for patients with medically controlled POPH, but this varies by region. Patients who undergo LT need specialized intraoperative and postoperative management, which includes the availability of intraoperative transesophageal echocardiography for assessing right ventricular function, and rapidly acting vasodilators (eg, inhaled nitric oxide and/or epoprostenol). Published case series suggest excellent outcomes after LT for patients who respond to medical therapy. Liver Transpl , 2012. © 2012 AASLD.

Pulmonary artery hypertension (PAH) is a serious lung disease that can be idiopathic or can be associated with a number of medical conditions.1 The classification of PAH was updated during the 4th World Symposium on Pulmonary Hypertension, which took place at Dana Point in 20082 (Table 1). PAH is defined hemodynamically as an elevation of the mean pulmonary artery pressure (MPAP) to ≥25 mm Hg (Table 2). Hence, the confirmation of PAH requires right heart catheterization (Table 2). When PAH occurs in the setting of portal hypertension, it is known as portopulmonary hypertension (POPH). POPH is one of several pulmonary diseases that may affect patients with liver disease.3

Table 1. Updated Dana Point Classification of PH
  1. NOTE: This table was adapted from Simonneau et al.2

Group I. PAH
 Idiopathic
 Hereditary: Bone morphogenetic protein receptor 2  mutation, activin receptor-like kinase 1, or unknown
 Associated with
  Collagen vascular disease
  Congenital heart disease
  Human immunodeficiency virus
  Drugs or toxins
  Portal hypertension
  Chronic hemolytic anemia
  Schistosomiasis
 1′ Pulmonary veno-occlusive disease
 1′ Pulmonary capillary hemangiomatosis
Group II. Pulmonary venous hypertension
 Systolic dysfunction
 Diastolic dysfunction
 Valvular disease
Group III. PH associated with hypoxemia
 Chronic obstructive pulmonary disease
 Interstitial lung disease
 Mixed restrictive and obstructive pattern
 Sleep-disordered breathing
 Alveolar hypoventilation disorders
 Chronic exposure to high altitude
Group IV. Chronic thromboembolic PH
Group V. PH with unclear/multifactorial mechanisms
Table 2. Hemodynamic Classification of Pulmonary Hypertension
  1. NOTE: The definitions of the groups are listed in Table 1.

PHMPAP ≥ 25 mm HgGroups I-IV
PrecapillaryMPAP ≥ 25 mm HgGroup I
PCWP ≤ 15 mm HgGroup III (lung disease etiology)
Normal or reduced cardiac outputGroup IV
 Group V (multifactorial etiology)
PostcapillaryMPAP ≥ 25 mm HgGroup II (left heart disease etiology)
PCWP > 15 mm Hg
Normal or reduced/ increased cardiac output

The pathophysiology of POPH remains unclear: it is a rare complication of cirrhotic or noncirrhotic portal hypertension, and it is related to neither the etiology of liver disease nor the severity of portal hypertension. In the United States, most cases of POPH are associated with cirrhosis. Mild POPH (MPAP < 35 mm Hg) is common in cirrhosis and is usually inconsequential.4, 5 Moderate POPH (MPAP ≥ 35 mm Hg) and severe POPH (MPAP ≥45 mm Hg) are associated with mortality beyond that predicted by the Model for End-Stage Liver Disease (MELD) score.6 This level of POPH, if it is not improved with medical therapy, is generally considered a contraindication to liver transplantation (LT) because of high perioperative and postoperative mortality rates. In one study,7 42% of the patients died within 9 months of transplantation, and an analysis of the literature as well as patients at the Mayo Clinic reported a 50% mortality rate for patients with MPAP levels of 35 to 49 mm Hg and a 100% mortality rate for patients with MPAP levels ≥ 50 mm Hg.4 Our review describes the important features of POPH and emphasizes recent findings.

DEFINITION AND DIAGNOSIS

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

POPH is a condition characterized by an increase in the resistance to pulmonary arterial blood flow in the setting of portal hypertension3 (Fig. 1). POPH is defined as an MPAP ≥ 25 mm Hg at the time of right heart catheterization that is associated with a pulmonary vascular resistance (PVR) ≥ 240 dyn·s·cm−5 and a pulmonary occlusion (wedge) pressure ≤15 mm Hg (see a recent update8 and Table 3). Because patients may present with both fluid overload and POPH, the addition of the transpulmonary gradient (TPG; ie, MPAP − wedge pressure) has also been suggested.6 Moderate POPH (MPAP = 35 to <45 mm Hg) and severe POPH (MPAP ≥ 45 mm Hg) are less common and are associated with a higher mortality rate. Historical data show that the mortality rate after orthotopic liver transplantation (OLT) is 50% if MPAP is >35 mm Hg and 100% if MPAP is >50 mm Hg4, 6 (see Table 4 for definitions of the severity of POPH). The full diagnostic criteria are discussed later.

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Figure 1. Potential causes of MPAP elevations in patients with POPH.

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Table 3. Definition of POPH
  • NOTE: These diagnostic criteria were proposed by the European Respiratory Society/European Society for the Study of the Liver Task Force on Hepatic and Pulmonary Vascular Disorders of POPH.82

  • *

    1 mm Hg min/l (Wood Unit) = 80 dyn·s·cm−5.

Liver disease (clinical portal hypertension)
MPAP ≥ 25 mm Hg
PVR > 240 dyn·sec·cm−5*
PCWP < 15 mm Hg
Table 4. Severity of POPH
SeverityMPAP (mm Hg)
Mild≥25 to <35
Moderate35 to <45
Severe≥45

A number of factors, including an elevated PVR, a high cardiac output, and an elevated pulmonary venous pressure, contribute to the increased pulmonary artery pressure. The relationship between these factors is elucidated by the formula used to calculate PVR:

  • equation image

The 4th World Symposium on Pulmonary Hypertension placed portal hypertension in the diagnostic group I category (Table 1); this means that PAH-specific therapy is available to treat this serious disease.10

The presentation of POPH is variable and depends on the portal of entry into the health care system. Patients referred to a liver service are frequently asymptomatic, whereas those referred to a pulmonary service usually present with dyspnea. For example, a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension (1984-2004) identified 154 patients with POPH; 60% of these patients belonged to New York Heart Association (NYHA) functional class III or IV.11

For patients referred for LT, POPH may be asymptomatic and may be suspected first because of a screening echocardiogram showing an elevated right ventricular systolic pressure (RVSP). Routine screening for POPH during the evaluation for LT is included in the practice guidelines from the American Association for the Study of Liver Diseases.12 LT centers typically screen transplant candidates for both POPH and hepatopulmonary syndrome (HPS) with contrast-enhanced echocardiography. RVSP is estimated on the basis of the tricuspid regurgitant velocity with echocardiography using the modified Bernoulli equation:

  • equation image

where RAP is the right atrial pressure and TR is the right tricuspid regurgitant peak velocity. Right heart catheterization must be performed to confirm POPH if an RVSP elevation is found on the echocardiogram.5 In a study by Krowka et al.,13 the inadequacy of echocardiography was addressed in patients undergoing LT (liver transplant) evaluation. One hundred four of 1235 patients had an RVSP > 50 mm Hg, and 101 of the 104 patients underwent right heart catheterization. Thirty-five percent of the patients in this group had a PVR < 240 dyn·s·cm−5, and 43% of these patients had an elevated pulmonary capillary wedge pressure (PCWP) > 15 mm Hg (ie, volume overload). Only 41 of the remaining 66 patients with a PVR > 240 dyn·s·cm−5 had significant POPH (PVR > 400 dyn·s·cm−5). A TPG > 12 mm Hg was present in all 66 patients with an elevated PVR; however, 24% of these patients had a concomitant PCWP elevation. Hence, right heart catheterization is required to confirm the diagnosis because high flow and fluid overload can be important contributors to an elevated pulmonary artery pressure, whereas the MELD score correlates poorly with hemodynamic measurements.

A number of articles describe coexistent or sequential POPH and HPS (ie, PAH associated with detectable synchronous or metachronous intrapulmonary arteriovenous shunts).14-19 These are rare events that remain unexplained, but they suggest the need for careful evaluations of patients whose symptoms change or return after OLT.

PATHOGENESIS

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

The pathology and physiological consequences of POPH are well described, but no one has been able to explain why this condition develops in only 6% to 8% of patients with cirrhosis. Kawut et al.20 conducted a multicenter case-control study and identified 34 patients with POPH; they determined that female sex and autoimmune disease were important risk factors. The utility of these findings is difficult to assess because most centers have seen patients of both sexes with a variety of etiologies. In 2 molecular articles, researchers have tried to find a genetic basis for POPH.21, 22 A single-nucleotide polymorphism analysis of the serotonin transporter showed no association with POPH.21 A case-control study of 1079 common single-nucleotide polymorphisms showed associations with estrogen receptor 1, aromatase, phosphodiesterase 5 (PDE5), angiopoietin 1, and calcium binding protein A4.22 Although the significance is low for this type of analysis, the biological relevance of the aromatase single-nucleotide polymorphisms is supported by an association with plasma estradiol levels.

A recent article23 compared a number of cytokines in patients with POPH, hyperdynamic circulation, or uncomplicated cirrhosis. The studied cytokines included endothelin 1, interleukin-6, interleukin-1β, and tumor necrosis factor α. Patients with POPH had significantly higher levels of endothelin 1 and interleukin-6, and this suggests that the targeting of these mediators may have a role in the treatment of POPH. Thus, despite sophisticated testing, the pathogenesis of POPH remains elusive.

CLINICAL FEATURES

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

Physical findings in patients with POPH may be absent or subtle and nonspecific. Exertional dyspnea may be a presenting feature, but the absence of symptoms should not prevent screening in appropriate populations. An early study reported a loud pulmonic component to the second heart sound in 82% of patients and a systolic murmur in 61% of patients.24 A later, smaller study reported a loud pulmonic sound in only 38% of patients, although this finding remained much more common in patients with pulmonary hypertension (PH) versus control patients.25 Routine echocardiography remains the mainstay of screening for patients undergoing LT evaluations. Right heart catheterization is required to confirm this diagnosis before any PH-specific therapy is initiated.

NATURAL HISTORY

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

The natural history of POPH has been difficult to characterize. In an early study,26 patients with POPH were found to have a mean survival of 15 months. A retrospective analysis by Kawut et al.27 compared 13 patients with POPH to 34 patients with idiopathic PAH. Patients with POPH had a higher cardiac index and a lower PVR, but the RAP and pulmonary artery pressure values were similar. Despite these favorable hemodynamics, patients with POPH were almost 3 times more likely to die than patients with other types of PAH. This finding is common in other series and undoubtedly reflects the combination of 2 serious diseases, as discussed in the editorial accompanying Kawut et al.'s article.28

A retrospective analysis of patients admitted to the French Referral Center for Pulmonary Hypertension identified 154 patients with POPH from 1984 to 2004.11 Their population was quite ill: 60% belonged to NYHA class III or IV, and this was associated with a low cardiac index (liters/min/m2) (2.7 ± 0.7 in class III and 2.1 ± 0.7 in class IV). The survival rates at 1, 3, and 5 years were 88%, 75%, and 68%, respectively, and they were significantly better than the rates reported for other series. Mortality was related to the severity of cirrhosis (it was higher for Child-Pugh B/C patients) and to the cardiac index (it was worse for patients with a low cardiac index). Surprisingly, the NYHA functional class at enrollment did not correlate with the risk of death during follow-up. The relationship between PoPH in the presence or absence of cirrhosis and mortality is shown in Fig. 2.

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Figure 2. Kaplan-Meier survival estimates for patients with POPH according to the presence or absence of cirrhosis. The survival rates were 85%, 73%, and 68% at 1, 3, and 5 years, respectively, for patients with cirrhosis and 94% at 1, 3, and 5 years for patients without cirrhosis (log-rank P = 0.003). Adapted with permission from American Journal of Respiratory and Critical Care Medicine.11 Copyright 2008, American Thoracic Society.

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A contemporaneous study of survival came from a retrospective analysis of 74 patients seen at the Mayo Clinic between 1994 and 20076 (see Table 5). The survival rate at 5 years was 14% for untreated patients, 45% for patients who were treated with vasodilators but did not undergo transplantation, and 67% for patients who underwent transplantation (see Fig. 3). The authors concluded that any therapy was better than no therapy, and the severity of POPH was unrelated to the severity or etiology of liver disease. A recent report from the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) registry8 describes an observational study in which 174 patients with POPH were compared to 1392 patients with idiopathic PAH and 85 patients with familial PAH. Despite better hemodynamics, the 2- and 5-year survival rates were (again) lower for the patients with POPH (67% versus 85% at 2 years and 40% versus 64% at 5 years).

Table 5. Natural History of POPH
 No Therapy (n = 19)Vasodilators Without Subsequent OLT (n = 43)Vasodilators Followed by OLT (n = 12)
  • NOTE: The data for this table were taken from Swanson et al.6

  • *

    The survival rate was 25% (1/4) for patients who underwent transplantation without previous vasodilator therapy.

5-year survival rate (%)144567*
Mortality rate one year after diagnosis (%)5412Not available
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Figure 3. Survival curves for 74 patients divided by the type of treatment for PH with or without LT. Adapted with permission from American Journal of Transplantation.6 Copyright 2008, John Wiley & Sons, Inc.

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These multiple studies suggest that vasodilator therapy not only is helpful but also might make OLT possible if PH is controlled. According to this logic, patients have been treated with vasodilators to bring their MPAP levels below 35 mm Hg, and this has been followed by OLT (see the later section on LT).

MANAGEMENT

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

The management of POPH includes a growing number of therapeutic agents (which are discussed in detail later). The role of LT is still evolving. OLT in the setting of uncontrolled POPH has an unacceptably high mortality rate,29 and most transplant centers consider severe POPH an absolute contraindication to transplantation.5 On the other hand, a number of reports have confirmed that LT can be performed safely if the hemodynamics are suitably controlled.5, 30-33 OLT for patients with POPH is discussed in detail later.

An unexplained issue is the patient who develops PH after OLT, sometimes in the absence of pretransplant lung disease or in the presence of antecedent HPS. This type of patient requires ongoing pulmonary vasodilator therapy after LT, and the mortality rate is high.15, 34-36 Residual POPH can be explained by irreversible pulmonary vascular remodeling, but de novo PH after LT is unexplained.

SPECIFIC THERAPIES TO TREAT POPH

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

Different classes of drugs, including prostanoid analogues, endothelin receptor antagonists, and PDE5 inhibitors, have been used to treat POPH37-39 (Table 6). Pulmonary vasodilators are generally effective in the treatment of PH, but they should be used only after the diagnosis has been hemodynamically confirmed by right heart catheterization and ensuring that the patient meets the definition of POPH proposed by the European Respiratory Society/European Society for the Study of the Liver Task Force (Table 3).82

Table 6. Agents Used to Treat PH
 Class
PDE5 Inhibitors*Endothelin Receptor AntagonistsProstacyclins
  • *

    Blockers of cyclic guanosine monophosphate degradation.

  • Competitive antagonists of endothelin receptors.

  • Exogenous prostacyclin.

DrugTadalafilSildenafilAmbrisentanBosentanEPOTreprostinilIloprostTyvaso
Individual dose40 mg20 mg5-10 mg62.5-125 mg0.5 to >100 mg/kg/minute0.5 to >100 mg/ kg/minute2.5 or 5 μg9-12 breaths
Frequency of administrationDaily3 times per dayDailyTwice dailyContinuous infusionContinuous infusionEvery 2 hours4 times per day
Elimination half-life17.5 hours3-5 hours15 hours5.4 hours3-5 minutes3-4 hours20-30 minutes3-4 hours
Route of administrationOralOralOralOralIntravenous infusionIntravenous or subcutaneous infusionInhalation treatmentInhalation treatment
Side effectsHeadache, myalgia, back pain, flushing, dyspepsia, diarrhea, nausea, and pain in extremitiesHeadache, myalgia, back pain, flushing, dyspepsia, and diarrheaPeripheral edema, headaches, dizziness, and nasal congestionPeripheral edema, headaches, dizziness, coughing, syncope, and abnormal hepatic functionHeadache, flushing, jaw pain, anxiety/ nervousness, diarrhea, flu-like symptoms, nausea, and vomitingHeadache, diarrhea, nausea, jaw pain, flu-like symptoms, and, with subcutaneous infusion, site pain, reactions, and bleedingHeadache, flushing, flu-like symptoms, nausea, vomiting, jaw muscle spasms, coughing, tongue pain, and syncopeCoughing, headache, pharyngolaryngeal pain, throat irritation, nausea, flushing, and syncope

Prostanoids

Although reports of the investigational use of prostacyclin in patients with PAH date back to the 1980s, prostacyclin and prostaglandin analogues entered routine clinical practice in the 1990s.40 Evidence suggests that endogenous prostacyclin levels are decreased in patients with PAH.41 Prostanoid receptors in the lungs are thought to be involved in regulating vascular tone, platelet activation, and immunological cell responses. Prostaglandin analogues may be administered intravenously, subcutaneously, or by inhalation.9, 38, 40, 42

Epoprostenol (EPO), also known as synthetic prostaglandin I2 (PGI2) or prostacyclin, was the first therapy approved by the US Food and Drug Administration as a continuous intravenous infusion for the treatment of PAH in 1995.43-45 Derived from the metabolism of arachidonic acid, it is a potent pulmonary and systemic vasodilator and an inhibitor of platelet aggregation, and it may modulate pulmonary vascular remodeling.46, 47 EPO is an extremely potent vasodilator; one study reported an immediate 11.8% decline in MPAP, a 24% decline in PVR, and a 28% drop in systemic vascular resistance during an EPO infusion.48 The authors showed that EPO was more potent than nitric oxide in acutely lowering PVR, and they suggested that EPO might be used to predict the ultimate reversibility of POPH.

EPO is administered as a continuous infusion and requires a dedicated central line. The systemic half-life is short (3-5 minutes), so EPO must be delivered continuously by a specialized pump. Complications attributable to EPO infusions include jaw pain, flushing, nausea, vomiting, diarrhea, flu-like symptoms, and line sepsis. Patients on EPO for POPH must be monitored closely for a prostanoid overdose: when EPO enters the systemic circulation, it increases systemic vasodilatation in patients with already low systemic vascular tone. In this situation, cardiac output may increase to the point of high cardiac output failure, and MPAP, driven by a high cardiac output rather than a high PVR, may remain elevated (Fig. 1C). At this point, right heart catheterization is required to determine PVR and/or TPG. Although MPAP has been the historical focus of POPH, the most important factor that allows safe OLT is adequate right ventricular function in the perioperative period. If MPAP is high in the setting of normal to low PVR/TPG values, a vasodilator-induced high cardiac output state is likely (Fig. 1C). In this situation, we have successfully lowered the EPO dose with a resulting decrease in both the associated cardiac output and MPAP.

We have described 8 consecutive POPH patients treated with intravenous EPO (2-8 ng/kg/minute dose). MPAP was reduced, and 4 of the patients successfully underwent transplantation with good long-term outcomes.32 Although no large series exist, similarly positive results from 3 other centers have been published.30, 31, 33, 49

EPO may also be delivered by continuous inhalation in hospitalized patients. Although this is not practical for the management of ambulatory patients, inhaled EPO is used commonly by anesthesiologists to treat perioperative PH.50 We have found no published records of inhaled EPO for POPH, but we are aware that several centers have used both EPO and nitric oxide to manage POPH in the perioperative period. We also have found no literature on a tapering protocol for EPO after transplantation. We generally stop EPO within 48 hours of OLT, although some patients may require the reinstitution of EPO with a slower taper over a period of 2 to 3 weeks. As noted previously, some patients require no medication after OLT, but some require an oral agent.

Two additional prostanoids are available: treprostinil and iloprost. Treprostinil can be administered subcutaneously or intravenously or can be nebulized. Subcutaneous dosing may be limited by pain. The inhaled form of treprostinil (Tyvaso) was recently approved by the US Food and Drug Administration9 (Table 6). Iloprost is an inhaled drug with a short half-life and requires dosing 6 to 9 times daily. In a recent study,51 12 POPH patients treated with inhaled iloprost were followed for up to 12 months. The functional class and the 6-minute walk distance improved, but the systolic pulmonary artery pressure (SPAP) by echocardiography did not change. Two patients died, 2 suffered hepatic decompensation, and 2 experienced worsening of PH. The authors concluded that iloprost may provide symptomatic improvements and improve exercise capacity, but they did not discuss the possibility of LT.

An oral synthetic prostacyclin analogue, beraprost, is available in Japan and Europe but not in the United States. A series of 116 patients with PAH showed a short-term benefit, but it was disappointing in the long term.52 Beraprost use in a single patient with POPH was recently reported: the symptoms improved, and the pulmonary artery pressure was controlled for 18 months.53

Endothelin Receptor Antagonists

Endothelin receptors are G protein–coupled receptors; activation leads to elevated intracellular calcium levels. Three receptors have been described: endothelin A, endothelin B1, and endothelin B2. Therapeutic agents include the nonspecific antagonist bosentan and the endothelin A–specific agents ambrisentan and sitaxsentan (which is not US Food and Drug Administration–approved).

Bosentan use in POPH patients has been limited, in part because of fears about its idiosyncratic hepatotoxicity. The use of bosentan as a single agent54 and in combination with other vasodilators55 has been described, but the experience in POPH patients is limited. Ambrisentan monotherapy was nonhepatotoxic in 13 patients with POPH who were treated for a median of 390 days.56 MPAP and PVR improved, 2 patients died, and 1 patient successfully underwent transplantation. Hoeper et al.57 reported a retrospective analysis of 31 POPH patients treated with inhaled iloprost and bosentan. In that study, both survival and event-free survival rates improved in patients treated with bosentan, and there were improvements in the walk distance and hemodynamics. Another prospective study reported 11 POPH patients who were treated with bosentan for more then 1 year.58 Improved symptoms and exercise capacity and reduced PVR were documented. These few studies show the tolerability of bosentan in this population without evidence of liver injury in a small number of POPH patients.

PDE5 Inhibitors

PDE5 inhibitors prevent the breakdown of cyclic guanosine monophosphate, which is the mediator of nitric oxide–induced vasodilation,59 and thus reduce the pulmonary artery pressure.60 The most recognizable agent is sildenafil, which has been proven to be effective and safe in several small POPH series.61-63 Other drugs in this class include vardenafil and tadalafil.39, 64, 65 In one study, Reichenberger et al.66 treated 14 POPH patients with sildenafil for 12 years. Approximately half of these patients were receiving background therapy with inhaled iloprost (n = 5) or inhaled treprostinil (n = 1). The patients showed improved walk distances and reductions in b-type natriuretic peptide (BNP) levels. This study showed that patients could be safely treated with a PDE5 inhibitor and receive functional and clinical benefits. None of these patients underwent LT.

Milrinone

Milrinone is a potentially useful agent because of its combination of inotropic and vasodilator properties.67 It is commonly used for left ventricular failure in patients with adequate systemic blood pressure. Its use has been described for chronic PAH68 and for PH after heart transplantation.69 A case report describes milrinone use in a patient with POPH that was discovered at the time of OLT.70 This case is interesting because POPH was not present during the evaluation but was recognized immediately before OLT. Milrinone was used to prove that the pulmonary vascular bed was responsive and was then used intermittently during the transplant. A similar case at a different center died after OLT,33 and this suggests that the perioperative management of an unstable POPH patient should be undertaken with caution. The authors did not explain why they chose milrinone instead of one of the more commonly used vasodilators.

Beta-Blockers

Because beta-blockers are commonly recommended for patients with portal hypertension, the report by Provencher et al.71 deserves mention. In that study, 10 patients with moderate to severe POPH (MPAP = 52 mm Hg) were examined with a 6-minute walk test and right heart catheterization at the baseline and 2 months after beta-blocker withdrawal. After beta-blocker withdrawal, 9 of the 10 patients increased their 6-minute walk distance. More importantly, their cardiac output increased by 28% with no change in MPAP, and this resulted in a 19% decrease in PVR. The increases in cardiac output were related to a 25% increase in the heart rate with a stable stroke volume. They concluded that patients with moderate to severe POPH should not use beta-blockers.

Therapeutic Options

Because of the relative paucity of data specific to the POPH population, most PH centers use a treatment strategy comparable to that used for other types of PAH. Specifically, a risk assessment is performed to account for the patient's functional capacity, hemodynamics, right ventricular function, and liver status (the MELD score). Sicker patients (ie, those with a higher risk of decline over the next year) are often considered for more aggressive therapy with a prostaglandin infusion. Patients with more favorable hemodynamics and a more favorable functional status may first try an oral medication regimen, with more aggressive medications added if they have a suboptimal response to therapy.72

LT

Although POPH may occur in the setting of noncirrhotic portal hypertension, the majority of patients with POPH in Western countries have cirrhosis. The mortality rate is high, so LT is an attractive therapy because it is potentially curative. The role of LT in the management of POPH has evolved over the past 15 years. When the danger of uncontrolled PH was recognized, many centers refused to perform transplantation for patients with POPH.30, 32, 73 With the availability of potent vasodilators and their use in patients with idiopathic PH, several centers reported successful OLT after medical control of POPH was achieved.30-33, 49 An early study of 6 patients with POPH (MPAP = 38-52 mm Hg) and modestly elevated PVR (301-404 dyn·s·cm−5) reported survival for 5 of the 6 patients after LT. We subsequently reported 8 consecutive patients with severe POPH who were treated with sequential EPO infusions.32 In that prospective study, 7 of the 8 patients experienced a significant reduction in MPAP and PVR with an associated increase in cardiac output. Four of the 6 patients who were listed for LT successfully underwent transplantation and were alive 9 to 18 months after OLT. All 4 survived another 5 years after OLT (Safdar, Sussman, unpublished data, 2012). Sequential vasodilator therapy and OLT have been extended to living related donors.74

The success of empirical treatments for POPH has been followed by a better understanding of the hemodynamic changes that take place during the course of POPH and LT. Under normal circumstances, the right ventricle is able to manage the same volume as the left ventricle, but it is less muscular and is much less able to pump against a significant pressure gradient. In the presence of PH, right ventricular hypertrophy occurs, and the right ventricular output may remain stable for some time. Right ventricular failure may eventually occur if the pulmonary artery pressure continues to increase because pulmonary arteriolar vasoconstriction progresses to intimal thickening and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may also occur as a result of depressed myocardial function (as seen in patients with cirrhotic cardiomyopathy).5

LT represents a special case of acute right ventricular stress. Cardiac output increases acutely at the time of reperfusion (up to 3-fold in 15 minutes), as shown in Fig. 4.5 In the setting of a noncompliant vascular bed, acute right heart failure may ensue, and this is the probable explanation for the historically high mortality rate after LT. Many transplant centers now believe that patients can undergo LT safely if MPAP is reduced to approximately 35 mm Hg in the setting of a PVR < 400 dyn·s·cm−5. This corresponds to an adequate right ventricular reserve and sufficient compliance in the pulmonary vascular bed. Even with good pressure control, the anesthesiology and posttransplant management teams must be prepared to deal with acute PH and acute right heart failure during or after OLT. Continuous intraoperative transesophageal echocardiography has been recommended for following right heart function.5 In the event of a pulmonary hypertensive crisis, the most effective agents are inhaled or intravenous vasodilators, as described previously. In our experience, patients can be weaned from EPO 1 to 2 days after OLT, and EPO can be replaced by an oral agent. Half of our patients have required long-term therapy with an oral agent (Safdar, Sussman, unpublished data, 2012).

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Figure 4. Acute elevations in cardiac output and pulmonary artery pressure at the time of liver reperfusion. Adapted with permission from Current Opinions in Anaesthesiology.5 Copyright 2010, Lippincott Williams & Wilkins.

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MELD upgrade points for POPH have been suggested to account for the increased mortality of these patients versus patients with similar MELD scores on the LT wait list.75 However, the utilization of MELD upgrades and the particulars of the upgrade process have been under the purview of individual regional review boards. United Network for Organ Sharing policy 3.6.4.5.6 suggests an upgrade to a MELD score of 22 with an increase every 3 months as long as MPAP remains <35 mm Hg and PVR remains <400 dyn·s·cm−5.76 As shown in Table 7, the performance of LT with exception points granted for POPH varies widely by region, and only 79 patients have undergone transplantation for this exception since 2007.

Table 7. LT for POPH by Region: 2007-2011
RegionYearTotal
20072008200920102011
  1. NOTE: The data were obtained from the Organ Procurement and Transplantation Network (11/15/2011). This work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

1210104
2100001
3101204
49332118
53421515
6000000
72323212
82244012
9000000
10111025
11112228
Total221515151279

A question embedded in the MELD upgrade discussion is whether the prognosis of the patient is related to the severity of POPH. As discussed in the previous section on treatment, patients with severe right ventricular failure often need intravenous prostaglandins to control their disease, but the disease of other patients may be controlled by a single oral agent. Better epidemiological data are needed to determine whether all patients with POPH have similar prognoses or some may do well with long-term medical therapy. We may find that patients whose POPH is well controlled with an oral agent are not disadvantaged by the MELD system and may be safely managed solely on the basis of the severity of their liver disease (ie, their MELD scores). The rarity of POPH, the scarcity of donor organs, and ethical considerations make it unlikely that we will ever see a randomized trial comparing OLT to no OLT in patients on oral vasodilators.

Noncirrhotic POPH

Infection with Schistosoma mansoni may be the most common form of POPH in the world. Two hundred million people are estimated to be infected, and up to 10% may develop severe disease.77 The parasite enters through the skin and produces an immune complex–mediated hypersensitivity reaction in the lungs. Schistosoma mansoni is also associated with presinusoidal portal hypertension. When this occurs, ova bypass the liver and re-enter the lungs, in which they set up a granulomatous inflammatory response. Pulmonary vascular remodeling may, therefore, occur for 2 reasons: the direct effect of the parasite and POPH related to portal hypertension.78-80 Mild HPS has also been described.81

CONCLUSION

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES

POPH is a rare complication of cirrhosis that is caused by a combination of pulmonary arteriolar vasoconstriction and intimal and smooth muscle thickening. POPH is becoming easier to treat with the availability of multiple vasodilators. Available evidence suggests that patients treated with vasodilator therapy alone do not fare as well as patients who undergo transplantation after POPH is controlled medically. MPAP must be controlled before LT, but the decision to perform transplantation must include the entire hemodynamic profile and not focus on MPAP alone. Beta-blockers may have an adverse effect and should be avoided. Pulmonary pressure must be carefully managed during the perioperative period: rapidly acting agents such as intravenous EPO, inhaled EPO, and nitric oxide are now routinely available. A patient is at greatest risk for a pulmonary hypertensive crisis at the time of reperfusion. Intraoperative monitoring of right ventricular function with transesophageal echocardiography may be helpful. POPH usually improves after LT, although ongoing oral medication may be required.

REFERENCES

  1. Top of page
  2. Abstract
  3. DEFINITION AND DIAGNOSIS
  4. PATHOGENESIS
  5. CLINICAL FEATURES
  6. NATURAL HISTORY
  7. MANAGEMENT
  8. SPECIFIC THERAPIES TO TREAT POPH
  9. CONCLUSION
  10. REFERENCES