Portal hypertension

Pulmonary involvement is common in patients with portal hypertension and can manifest in diverse manners. Changes in pulmonary arterial resistance, manifesting either as the hepatopulmonary syndrome or portopulmonary hypertension (PPHTN), have been increasingly recognized in these patients in recent years. This review summarizes the clinicopathologic features, diagnostic criteria, as well as the latest concepts in the pathogenesis and management of PPHTN, which is defined as an elevated pulmonary artery pressure in the setting of an increased pulmonary vascular resistance and a normal wedge pressure in a patient with portal hypertension.

Key words: endothelin; liver; nitric oxide; portal hypertension; portopulmonary hypertension; prostacyclin; pulmonary hypertension; serotonin; transplant

Abbreviations. ET = endothelin; HPS = hepatopulmonary syndrome; NO = nitric oxide; OLT = orthotopic liver transplantation; PAP = pulmonary artery pressure; PPHTN = portopulmonary hypertension; PPH primary pulmonary hypertension; PVR = pulmonary vascular resistance; TGF = transforming growth factor

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Pulmonary hypertension is defined as a mean pulmonary artery pressure (PAP) > 25 mm Hg at rest or > 30 mm Hg during exercise. (1) Diverse factors including hyperdynamic circulation, increased intravascular volume, as well as pulmonary emboli may be responsible for elevation of PAP in a patient with portal hypertension. (2) Cirrhotic cardiomyopathy and intrahepatic arteriovenous fistulas are other causes of liver-related pulmonary hypertension. (3) Systemic conditions such as antiphospholipid syndrome/anticardiolipin antibodies, (4-6) mixed connective tissue disease, (7,8) schistosomiasis, (9-11) sarcoidosis, (12,13) systemic lupus erythematosus, (14,15) microangiopathic hemolytic anemia, (16) and HIV may involve both portal and pulmonary vasculature and result in elevated pressures in both circulations. However, portopulmonary hypertension (PPHTN) is a specific condition characterized by an elevated PAP, increased pulmonary vascular resistance (PVR), and a normal wedge pressure in a setting of underlying portal hypertension (portal pressure > 10 mm Hg; Table 1). (17)

Mantz and Craig (18) were the first to describe an association between pulmonary hypertension and portal hypertension. Since then, a number of case reports and case series have validated this observation. (19-41) Prior to 1998, PPHTN was grouped with other etiologies of "secondary" pulmonary hypertension. The new classification proposed at the World Health Organization meeting in Evian, France, now groups the disorders into categories with similar underlying causative mechanism as well as similar therapeutic management. (42) PPHTN is now a subset of pulmonary arterial hypertension, a group that includes primary pulmonary hypertension (PPH) (sporadic as well as familial) and other causative factors of pulmonary artery hypertension (eg, HIV infection, collagen vascular disease, drugs/toxins, etc.).

Although liver disease is by far the most common cause of portal hypertension complicated by pulmonary hypertension, a minority of patients have portal hypertension secondary to nonhepatic causes. (43) This suggests that portal hypertension, and not cirrhosis, is the primary instigator of pulmonary hypertension. The nonhepatic causes of portal hypertension leading to pulmonary hypertension are diverse and include biliary atresia, (30,31,44) extrahepatic portal vein obstruction, (23,25,34,45) noncirrhotic portal fibrosis, (46) noncirrhotic portal hypertension in systemic lupus erythematosus, (35) and idiopathic portal hypertension. (47) Surgical portosystemic shunts can also be complicated by pulmonary hypertension. (32,48-50) There have been rare reports of hepatobiliary disorders being complicated by pulmonary hypertension in the absence of portal hypertension. (36)

PREVALENCE

Pulmonary hypertension is an uncommon complication of portal hypertension. In a large autopsy series, McDonnell et al (51) found changes of pulmonary hypertension in 0.73% patients with cirrhosis, six times the prevalence in all autopsies. Later efforts utilizing hemodynamic studies have estimated the prevalence of this affliction between 2% and 5%. (28,52,53) However, the prevalence in liver transplant patients may be higher and has ranged from 3.5 to 8.5% in different studies. (54-66) One study estimated the prevalence of elevated PAPs, as diagnosed by two-dimensional echocardiography, in patients undergoing evaluation for orthotopic liver transplantation (OLT), at 12%. (57) However, the diagnosis was not confirmed by a right-heart catheterization. Conversely, portal hypertension is present in approximately 9% of the patients with pulmonary hypertension. (1) On average, the diagnosis of pulmonary hypertension is made 4 to 7 years after the diagnosis of portal hypertension. (28) However, in rare instances, the symptoms of pulmonary hypertension may precede those of portal hypertension. (22,38) The risk of acquiring pulmonary hypertension increases with the duration of portal hypertension. (28,58) While some studies suggest a correlation between pulmonary hypertension and the degree of portal hypertension, (27,54,58) others do not. (28,52)

CLINICAL FEATURES

The mean age at presentation for PPHTN is in the fifth decade, (17,29,59,60) compared to the fourth decade for PPH. (61) The female predilection seen in PPH is not seen in PPHTN, where the distribution is even between the two sexes. (28,29,60) Dyspnea on exertion is the most common presenting symptom and is seen in most patients with this disorder. Other symptoms include syncope, chest pain, fatigue, hemoptysis, and orthopnea. (60) However, some patients may not have any symptoms suggestive of pulmonary hypertension, and the discovery of this affliction may be serendipitous. (41) As in patients with PPH, autoimmune antibodies may be present in some patients with PPHTN. (60) This may suggest a role of autoimmunity in the pathogenesis of the disease in a subset of patients with this syndrome.

In the absence of an intervention, the prognosis in these patients is dismal, with a mean survival period after diagnosis of 15 months and a median survival of 6 months. (29) This is in contrast to a mean survival of 2 to 3 years after diagnosis in PPH patients. (61)

DIAGNOSIS

Dyspnea in a patient afflicted with liver disease can stem from diverse etiologies (Table 2). (62-72) Pulmonary hypertension is suspected in a patient with a known liver disease presenting with worsening shortness of breath or dyspnea on exertion without any obvious cause. Dizziness or lightheadedness may occur in the later stages of the disease. Patients with severe pulmonary hypertension have signs of volume overload, including jugular venous distension, ascites, lower limb edema and, occasionally, anasarca. However, the presence of underlying portal vascular pathology makes the interpretation of these signs difficult. The pulmonic component of the second heart sound ([P.sub.2]) is often increased in patients with pulmonary hypertension and may point toward this diagnosis. (29) Murmurs of tricuspid and pulmonic regurgitation may result from increased resistance to right ventricular outflow, or in later stages, from the annular dilatation of the right heart from increased afterload. A flow murmur may be present. (29) Unlike PPH, where the presence of ascites and peripheral edema denote the severity of pulmonary vascular pathology and cor pulmonale, these findings in the context of portal hypertension are less predictive of the severity of pulmonary hypertension.

Arterial blood gases may reveal hypoxemia and hypocapnia. Several mechanisms may contribute to the development of hypoxemia in a patient with liver disease (Table 3). (73-80) The degree of hypoxemia seen in PPHTN is significantly less than that seen with hepatopulmonary syndrome (HPS). (81) A PC[O.sub.2] value < 30 mm Hg has been suggested as a fairly sensitive and specific indicator of pulmonary hypertension in patients with portal hypertension. (59) Chest radiograph findings may be normal or may reveal a prominent pulmonary artery and dilated right ventricle and atrium. Increased vascularity is frequently seen in the upper lobes. (26) ECG findings are frequently abnormal and may reveal right ventricular hypertrophy, right atrial abnormality, right-axis deviation, right bundle-branch block, and sinus tachycardia. (29) Pulmonary function test results late in this disease may reveal mild restrictive pattern as well as reduction in the diffusion capacity of the lung for carbon monoxide. (55)

Two-dimensional transthoracic echocardiography is used for preliminary diagnosis of pulmonary hypertension in suspected patients. It may demonstrate right-heart-chamber enlargement and tricuspid regurgitation. (59) Increasing right ventricular afterload can lead to significant right ventricular dilatation with consequent leftward displacement of the interventricular septum. Use of Doppler echocardiography can provide evidence of pulmonary hypertension by measuring the velocity of the tricuspid regurgitant jet. A systolic PAP > 40 mm Hg indicates pulmonary hypertension.

The diagnosis can be confirmed by directly measuring the right ventricular and mean PAPs via right-heart catheterization. At the time of initial right-heart catheterization, all patients should undergo acute testing with a short-acting vasodilator to determine vasodilator responsiveness. (42) IV adenosine, IV epoprostenol sodium, or inhaled nitric oxide (NO) may be used for the testing. A reduction in the mean PAP of > 20%, associated with either no change or an increase in cardiac output, can be considered a positive response. A positive response to acute vasodilator testing may predict a favorable response to treatment with long-term oral vasodilators. (42)

SCREENING

In view of the uncommon incidence of PPHTN, routine screening for pulmonary hypertension is not recommended in patients with portal hypertension. Screening should be performed only in patients with signs or symptoms suggestive of pulmonary hypertension. (42) A Doppler echocardiogram is a highly sensitive, noninvasive diagnostic modality; therefore, it should be considered the screening method of choice. (82) However, positive predictive value of this test in some studies has been as low as 30%. (83) This, as well as the fact that 30 mm Hg rather than 40 mm Hg was considered as a cutoff for systolic PAP for the diagnosis of pulmonary hypertension, may explain the high incidence of the disease (20% of cirrhotics) suggested by Auletta and colleagues (58) in a study based on echocardiographic findings. A study by Kim et al (82) revealed lower specificity of this technique with PAP > 50 mm Hg. Therefore, if echocardiographic screening is suggestive of pulmonary hypertension, a right-heart catheterization should always be performed to confirm the diagnosis. Torregrosa et al (83) found pulmonary acceleration time, ie, the time from the onset of ejection to the time of peak flow velocity as seen on echocardiography, to be a better predictor of pulmonary hypertension than systolic PAP measurement. Since pulmonary hypertension can have a significant bearing on the outcomes of liver transplantation, (84) all such patients should undergo Doppler echocardiography to assess pulmonary hemodynamics.

HISTOLOGY

The histopathologic changes seen in PPHTN are similar to the changes of primary pulmonary arteriopathy. Plexiform arteriopathy, medial hypertrophy, intimal fibrosis, adventitial proliferation, and fibrinoid necrosis of small arteries may be seen. (17,25,51) Obstructive intimal thickening and formation of plexiform lesions are prominently seen in blood vessels, especially at the level of small arteries and arterioles. (25,85) Plexiform lesions are the characteristic glomeruloid structures seen in pulmonary hypertension and result from proliferation of phenotypically distinct endothelial cells. (86) These lesions are located in the small distal branches of the pulmonary artery, usually at more proximal sites than the occlusive lesions, (86-88) Neoangiogenesis may be present. (89) Endothelium of these lesions may strongly express endothelial NO synthase. (90) Thromboembolic lesions may be present. (25) In essence, there are no characteristic histologic distinguishing features between PPHTN and other causes of pulmonary arterial hypertension.

PATHOGENESIS

The pathogenesis of the structural changes seen in pulmonary hypertension is poorly understood. In 1980, Kibria and colleagues (91) attempted to reproduce PPHTN in rats by partially ligating or totally occluding the portal vein. However, despite evidence of sustained portal hypertension, none of these animals showed structural changes of portal hypertension. This led the authors to hypothesize that it was some humoral factor rather than a simple mechanical obstruction of portal vein that led to pulmonary hypertension. (91) In 1989, Hiyama (92) studied the hemodynamic changes and pathologic findings in the lungs of 97 rats killed between 1 month and 24 months after portosystemic shunt operations. This author found evidence of increased right ventricular systolic pressure, right ventricular changes, as well as plexiform lesions, concentric intimal proliferation, and medial hypertrophy of the pulmonary vasculature in 87 of these animals. Pulmonary venous levels of thromboxane [B.sub.2] were increased, while the levels of prostaglandin [F.sub.1] were decreased. However, later attempts at producing such a model have not been successful.

In the case of PPHTN, the shear stress from increased pulmonary blood flow may result in endothelial injury, which may set off a cascade of events that finally produces the characteristic vascular pathologic changes (Fig 1). However, Hadengue et al (28) did not find the amount of blood shunted from portal circulation to be an independent risk factor for development of pulmonary hypertension. This, as well as the fact that only a small minority of patients with hyperdynamic circulation acquires pulmonary hypertension, suggests that additional factors may be involved. Whether these factors include an increased genetic susceptibility, a humoral mediator, or an environmental insult remains a mystery. Possible determinants of a hypertensive pulmonary vascular outcome in a patient with portal hypertension are discussed in detail later.

[FIGURE 1 OMITTED]

Regardless of what initiates it, the endothelial injury may lead to proliferation of these cells. Overexpression of proliferative and angiogenetic mediators such as vascular e[alpha] endothelial growth factor, hypoxia-inducible factor-1[alpha], and hypoxia-inducible factor-[beta] may sustain this endothelial cell proliferation, ultimately resulting in plexiform lesions. (93) Mutations in transforming growth factor (TGF)-[beta] receptor 2, an important growth regulatory gene, have been described in endothelial cells in PPH. (94) Such mutations have been proposed to impair the TGF-[beta] signaling system, an important growth suppressor, thus assisting in cell proliferation. The possibility of similar mutations in PPHTN is yet to be explored. An imbalance between the vasodilator/antiproliferative mediators (eg, prostacyclin, NO) and vasoconstrictor/growth mediators (eg, endothelin [ET]-1, thromboxane) [vide infra] normally secreted by endothelial cells has also been invoked. (95,96) This may result in smooth-muscle hypertrophy as well as vascular luminal narrowing. A resulting increase in intravascular pressure may elicit an adaptive structural response characterized by further smooth-muscle hypertrophy and adventitial collagen deposition in the strained vessels. A concomitant increase in procoagulants as well as a decrease in fibrinolytics may mediate in situ thrombosis and cause further narrowing of the vessel lumen. (97)

Imbalance in Endothelium-Derived Vasoactive Mediators

Prostacyclin/Thromboxane Imbalance: Prostacyclin is a principal arachidonic acid metabolite of vascular endothelial and smooth-muscle cells. It is a potent vasodilator and opposes hypoxia-mediated vasoconstriction. (98,99) It also has antiproliferative properties. (100) An imbalance between prostacyclin and thromboxane was first suggested by Christman et al, (101) who found decreased urinary levels of 2,3-dinor-6-keto-prostaglandin F1[alpha], a metabolite of prostacyclin, as well as increased level of 11-dehydro-thromboxane [B.sub.2], a thromboxane [A.sub.2] metabolite, in patients with PPH as well as secondary pulmonary hypertension. Endothelial cells are the primary sites of prostacyclin synthase protein expression in the pulmonary circulation. Tuder and colleagues (102) reported decreased expression of prostacyclin synthase in small and medium-sized pulmonary arteries of patients with severe pulmonary hypertension, four of whom had cirrhosis-related pulmonary hypertension.

NO/ET Imbalance: Increased levels of ET-1, a potent vasoconstrictor with mitogenic activity on pulmonary arterial smooth-muscle cells, (103) are found in rat models of pulmonary hypertension. (104) ET-1 levels are also increased in patients with pulmonary hypertension secondary to congenital heart disease (105,106) and other causes. (107,108) Increase in ET levels is proportionate to the pulmonary blood flow (109) and cardiac output. (110) ET-1 has also been implicated as a mediator of the increased intrahepatic resistance in an animal model of noncirrhotic portal hypertension. (111) Increased ET-1 levels have been reported in patients with liver disease. (112,113) This raises the possibility of involvement of ET-1 as a modulator of pulmonary vascular pressure in patients with liver disease.

Reduced NO synthase has been reported in liver tissue from cirrhotic animals. (114) Cella et al (115) reported significantly lower NO levels in patients with PPH and secondary pulmonary hypertension compared with the control subjects. Hence, this mediator may be involved in the pulmonary vascular alterations seen in PPHTN.

Genetic Derangements

Gene mutation in bone morphogenetic protein receptor-2 has been described in PPH. (116,117) How the mutation translates into clinical disease is still unknown. Alteration of TGF-[beta]-mediated regulation of cells has been proposed. (118) A subset of the patients with PPH has a familial variant that involves more than one family member. (61) It would be interesting to see whether a portal hypertensive family member of a patient with PPH, unusual as the combination might be, is more prone for acquiring PPHTN. Conversely, if a thorough history and physical examination of family members of patients with PPHTN suggests pulmonary hypertension, relevant investigations may expose an interesting familial undercurrent to this disease. Alternatively, microarray technology, a technique that allows comparative analysis of genes expressed by two different cohorts, can be used to detect any genetic alterations vis-a-vis PPH patients or normal control subjects. (119)

A high percentage of patients with PPH have an L-allelic variant of serotonin gene promoter, which confers increased susceptibility of the pulmonary artery smooth-muscle cells of these patients to the growth promoting effects of serum and serotonin. (120) The possibility of existence of a similar variant in patients with portal hypertension who eventually acquire pulmonary hypertension is yet to be explored.

Role of Mediators Escaping Hepatic Metabolism

Shunting of vasoactive compounds from the splanchnic circulation to the pulmonary circulation, thus escaping liver metabolism, has been postulated to play a role in increasing the impedance in the pulmonary vessels in patients with preexisting portal hypertension and/or liver disease. (17,121) Tokiwa and colleagues (34) found elevated serum concentrations of prostaglandin [F.sub.2][alpha] and thromboxane [B.sub.2] in the inferior vena cava, and angiotensin 1 in the inferior vena cava and right ventricle in a patient with PPHTN. All three of these compounds are vasoconstrictors and may be involved in the pathogenesis of PPHTN. However, the coexistence of HPS and PPHTN in some patients (38,122-125) suggests that the pathogenesis may be more complex than a simple imbalance between vasoconstrictors and vasodilators. Gosney and Resl (126) studied the pulmonary endocrine system of the autopsy lungs of a woman with PPHTN. They measured "protein gene product," a marker for gastrin-releasing peptide, calcitonin, calcitonin gene-related peptide, and serotonin. The levels of this marker were normal, leading them to postulate that the pulmonary endocrine system was normal in PPHTN, and some other humoral mediator might play a pathogenetic role. However, the absence of any similar data prevents basing any conclusion on this report.

Serotonin has been hypothesized to play a role in the genesis of PPH. (127) It mediates smooth-muscle hypertrophy and hyperplasia in vivo. (128) Normally, liver metabolizes serotonin before it reaches the lungs. However, with hepatic dysfunction, or in the presence of portosystemic shunts, lungs may be exposed to higher levels of serotonin. Eddahibi et al (129) showed an increased expression and activity of serotonin transporter (5 HTT) in platelets and lungs from patients with primary and secondary forms of pulmonary hypertension. Abnormal handling of serotonin by platelets, as suggested by low platelet serotonin concentration, has been postulated to contribute to the genesis of PPH. (130) Similar changes in platelet serotonin concentrations have been described in cirrhotics. (131)

Role of Thromboembolism

In the past, pulmonary embolism from distant sites has been postulated to be the cause of PPHTN. (132-134) However, later studies showed presence of PPHTN without the presence of emboli, disproving embolism as a major etiologic factor in this disease. In situ thrombosis, however, is seen in the hypertensive pulmonary vessels in these patients, (25) and seems to emanate from an alteration in the physiologic antithrombotic properties of the pulmonary endothelium resulting from the disease.

Autoimmunity

The increased prevalence of autoimmune antibodies in patients with PPHTN points toward a possible immune origin of PPHTN, at least in a subset of cases. (60) A number of reports suggesting an association between primary biliary cirrhosis, an autoimmune liver disease, and pulmonary hypertension, make it tempting to propose an autoimmune origin for both these disorders. (36,135-139) This may also explain the development of pulmonary hypertension in a patient with primary biliary cirrhosis in absence of portal hypertension. (36)

Dysfunctional Potassium Channels

Down-regulation of the voltage-gated potassium channels in the pulmonary vascular smooth muscle has been hypothesized to play a role in PPH. (140) Such down-regulation or abnormal closure of these channels impedes the outflow of the potassium ions across their gradient, resulting in a net positive charge inside the cell membrane and, hence, depolarization. Calcium channels open in response to depolarization, resulting in entry of calcium, which acts on actin-myosin complex to cause contraction. Although not yet described, a similar defect might exist in PPHTN. Of interest is the fact that the blunted hypoxic pressor response seen in an animal model of HPS, a liver-lung disease characterized by low PVR, can be restored by blocking calcium-activated potassium channels. (141)

Alteration in Vascular Compliance

Whether an abnormal pulmonary circulatory response to volume overload may be more generalized in patients with liver disease, thus contributing to the development of pulmonary artery hypertension, is suggested by a study by Kuo et al. (40) These authors found a significant increase in the PAPs in response to volume infusion in 41% of the patients without preexisting pulmonary hypertension awaiting OLT. (40)

TREATMENT

There are no long-term studies or guidelines on the use of pharmacotherapy in PPHTN. In view of the rarity of this disease, much of the traditional treatment of this disease has been empirical. Table 4 summarizes the medical and surgical therapeutic options for this disease. (54,56,142-154)

Calcium-channel blockers have been shown to improve survival in patients with PPH. (155) However, in absence of similar studies in PPHTN, their role in this disease is not clear. If tried, they should be used only in patients with positive response to acute vasodilator testing (vide supra).

Inhaled NO decreases the PAPs in some patients with PPHTN and may hold promise for long-term treatment of this disease. (148) Other medications reported to cause amelioration of pulmonary hypertension in patients with portal hypertension include [beta]-blockers (24,149,156) and nitrates. (150) In view of the decreased incidence of variceal bleeding in patients on [beta]-blockers and nitrates, we encourage the use of these medications in patients with PPHTN.

Owing to an increased risk of variceal bleeding, use of anticoagulation in this group of patients is debated. If used, we feel that the dose of warfarin should be titrated to keep the international normalized ratio at the lower end of the therapeutic range. We strongly recommend individualizing this therapy. For instance, a history of recent GI bleeding would be a contraindication to this therapy.

Prostacyclin

Prostacyclin (epoprostenol) is a potent pulmonary vasodilator. It has significant antiproliferative and antiplatelet aggregating effects. It also appears to be able to reverse the remodeling of pulmonary vasculature that may be responsible for "fixed" pulmonary hypertension not responsive to vasodilators. (157) By virtue of this fact, prostacyclin is beneficial even in patients without response to acute vasodilator challenge. Due to its short half-life in the pulmonary circulation (3 to 5 min), it needs to be administered continually through an indwelling IV catheter.

Kuo and others (142) showed a decrease in mean PAP, PVR, as well as a 25 to 75% increase in cardiac output in a cohort of four patients with PPHTN after 6 to 14 months of epoprostenol therapy. McLaughlin et al (158) studied patients with secondary pulmonary hypertension, including seven patients with PPHTN, on an average of 12.7 [+ or -] 5.6 months after initiation of continuous epoprostenol infusion. This treatment resulted in a 33% decrease in the mean PAP and a 68% decrease in PVR, as established by. right-heart catheterization. Another study by Krowka et al, (159) in 15 consecutive patients with PPHTN, confirmed the short-term as well as long-term benefits of prostacyclin therapy in this population. The role of this drug in preoperative, and perioperative management of PPHTN is discussed later.

The need for continuous IV infusion of prostacyclin is a major drawback in the administration of this medication. Apart from the inconvenience of use, this route of delivery exposes the patient to catheter-related complications such as sepsis and venous thromboembolism. Malfunction of the pump can lead to abrupt cessation in the delivery of medication, with deleterious and potentially lethal consequences such as a rebound in pulmonary hypertension and acute cor pulmonale. This has led to a search for alternate routes for administration of this beneficial drug. These include oral, inhalation, as well as subcutaneous routes.

Schroeder and colleagues (160) demonstrated an acute decline in the PAPs with aerosolized inhaled epoprostenol in patients with PPHTN. Another study of patients with PPH and pulmonary hypertension related to connective tissue diseases or liver cirrhosis revealed significant improvement in hemodynamic parameters in response to long-term inhalation of iloprost, a chemically stable prostacyclin analog. (161) In addition to alleviating increased PAPs, iloprost and other prostacyclin analogs may have cytoprotective action on liver cells, (162-164) making them compelling agents for treating PPHTN.

On a pessimistic note, there have been reports of splenomegaly with attendant thrombocytopenia and leukopenia after use of prostacyclin for PPHTN. (165) Notable is the fact that all four patients described in this series had either autoimmune hepatitis or cryptogenic cirrhosis as their primary diagnosis, suggesting a possible link between the etiology of liver disease and the occurrence of epoprostenol-related splenomegaly. The drop in counts varied from moderate to severe, the WBC count decreasing in the most severe ease from 5.6 x [10.sup.9] to < 1.0 x [10.sup.9]/L, and platelet count falling from 152 x [10.sup.9] to 47 x [10.sup.9]/L over a 9- to 18-month duration of epoprostenol infusion. This report is concerning and may limit the usefulness of epoprostenol in this group. For the time being, we recommend closely monitoring these parameters, as well as the spleen size, in patients receiving long-term prostacyclin therapy.

Future Pharmacotherapeutic Options for PPHTN

Prostacyclin Analogs: The "clinicopathologic" classification of pulmonary hypertensive disorders has allowed the evolution of new therapeutic strategies. Prostacyclin, initially used for PPH, has now been embraced as a stellar therapy for other "category companions" such as pulmonary hypertension secondary to HIV and connective tissue disease. The advent of this drug seems to have expanded the limited options hitherto available for management of PPHTN. Availability of prostacyclin analogs that can be delivered through less cumbersome routes will further facilitate the treatment. The subcutaneous analog treprostinil (143) has recently been approved by the US Food and Drug Administration for use in pulmonary arterial hypertension, and oral beraprost (144) and inhaled iloprost (145) are currently being evaluated for pulmonary hypertension, and should be available for clinical use in the near future.

ET-1 Antagonists: The remarkable clinical improvement seen with prostacyclin has spurred enthusiasm for exploring novel vasodilators that are similar in effectiveness, but less demanding from a technical and financial perspective. The orally active selective ET-A receptor antagonist sitaxsentan (166) and nonselective endothelial receptor blocker bosentan (151,167) are being evaluated for their role in management of PPH. However, the potential of liver toxicity associated with these drugs may substantially limit their role in PPHTN. In a recent trial in patients with pulmonary arterial hypertension (primary or associated with connective tissue disease), 9% of patients receiving bosentan therapy acquired abnormal hepatic function in a dose-dependent manner. (151) Such abnormalities were also reported in another study with sitaxsentan. (152) These drugs are presently not recommended in patients with liver disease.

Inhaled NO: The role of inhaled NO in the management of this disease is still not clear. Although Findlay et al (148) demonstrated an acute drop in PAP and PVR in five of the six patients with PPHTN they studied, others have reported no change in PAP with use of inhaled NO at similar and even higher doses in these patients. (168,169) An effort to find out what separates the "NO responders" from "`non-NO responders" could further assist in elucidating the pathogenic mechanisms of this disease.

Phosphodiesterase Inhibitors: Phosphodiesterase inhibitors like dipyridamole and, more recently, sildenafil have been used in different forms of pulmonary hypertension. (146,170-172) NO causes vasodilatation by increasing cyclic guanosine monophosphate in the vascular smooth muscle. (173) Phosphodiesterase inhibitors presumably exert their effect by inhibiting the degradation of cyclic guanosine monophosphate by phosphodiesterase enzymes. They may also play a role in stabilizing cyclic adenosine monophosphate, the second messenger of prostacyclin, and hence may potentiate the action of prostacyclin and its analogs. These drugs have not been studied for PPHTN but may be potentially beneficial.

L-Arginine: L-Arginine is a substrate for production of NO by the enzyme NO synthase via conversion to citrulline. Supplementation with L-arginine can plausibly augment endogenous NO production. A short-term study in patients with PPH revealed decreased PAPs after i week of oral supplementation of L-arginine. (147) The implanted graft in liver transplantation is known to release excessive amounts of arginase. (174) This may result in depletion of arginine-derived NO and worsen any preexisting pulmonary hypertension. Animal studies reveal the role of NO as a protective mediator in hepatic ischemia-reperfusion injury, (175,176) and that of exogenous L-arginine in prevention of such injury. (177,178) This further increases the attraction of this drug, at least in the perioperative phase, in a patient with PPHTN undergoing liver transplantation. However, the clinical utility of this approach might be limited by the fact that the increase in NO after L-arginine administration is modest at best. (177,179)

Liver Transplantation

Pulmonary hypertension complicating portal hypertension is associated with a significant intraoperative and postoperative morbidity and mortality, and has traditionally been considered a contraindication to liver transplant. However, reports suggest a significant decrease in PAP of patients with PPHTN after OLT. (33,37,39,161,180-182) The mortality risk is minimal with mean PAPs < 35 mm Hg but may rise significantly as the pressures increase > 35 mm Hg. (84) Plevak et al (183) and Taura et al (54) did not find any relation between mild-to-moderate pulmonary hypertension and adverse events associated with OLT. A retrospective study of 1,205 patients who underwent OLT revealed no added mortality if the systolic PAP was < 60 mm Hg. (56) A higher value resulted in a mortality of 42% 9 months after the procedure and an overall poor quality of life. The 3-year survival after liver transplantation is reduced in patients with moderate-to-severe pulmonary hypertension (21%) compared to those with mild or no pulmonary hypertension. (56) Taken together, these studies suggest a low risk for patients with mean PAP < 40 mm Hg. (54-56) In view of the altered pulmonary vascular response to volume overload in patients with end-stage liver disease, (40) Kuo et al (3) recommend performing a dobutamine stress echocardiography with volume challenge in OLT candidates. This involves 1-L saline solution infusion > 10 min after a maximum dose of dobutamine infusion has been achieved. If the mean PAP increases > 40 mm Hg after this maneuver, authors recommend postponing surgery and starting chronic epoprostenol infusion. (3)

The resolution of symptoms after liver transplantation may be slow and may take months or even years for complete resolution. (39,181) There have been reports of persistence or progression of pulmonary hypertension after liver transplantation. (184-186) Persistence of pulmonary hypertension may result from remodeling of the pulmonary vasculature. Continued presence of portopulmonary shunts may allow shunting of some unfiltered mediators to pulmonary circulation that may aid the persistence or worsening of elevated PAP after OLT. Recurrence of pulmonary hypertension resulting from failure of the transplanted liver after an OLT has also been reported. (187) In this particular case, a second liver transplant resulted in the regression of pulmonary hypertension.

Multiorgan Transplantation

Dennis et al (153) performed a heart-lung-liver transplantation in a patient with biliary atresia and pulmonary hypertension with good long-term results. Recently, Pirenne et al (154) performed a lung-liver transplant in a 52-year-old woman with chronic hepatitis C infection and severe pulmonary hypertension (systolic PAP > 90 mm Hg) and a heart-liver-lung transplant in a 42-year-old man with congenital liver fibrosis, hepatitis C, and severe pulmonary hypertension (mean PAP of 50 mm Hg). Although the former died of cardiogenic shock 24 h after the procedure, the latter patient did well and was reported as symptom free 13 months after transplant. Such multiorgan transplantation may be needed in patients with severe pulmonary hypertension not responding to optimal medical management. However, any recommendation regarding this procedure is premature considering the current lack of experience and paucity of supporting data.

Perioperative Management

Use of prostacyclin as a bridging therapy before transplantation has generated significant optimism in patients with advanced PPHTN, allowing some of them to be eventually considered as candidates for transplant. (188) Use of preoperative and intraoperative epoprostenol may render a patient with moderate pulmonary hypertension amenable to OLT. (189,190) Epoprostenol may also be beneficial in progressive pulmonary hypertension after OLT. (184) Apart from ameliorating pulmonary hypertension, prostacyclin may improve hepatic-splanchnic oxygenation and thereby reduce reperfusion injury after OLT. (191) Special operative techniques may be helpful in minimizing the complications in patients undergoing such surgery. (54,192) Case reports suggest beneficial effects of perioperative use of NO. (193,194)

Prevention of hypothermia and hypoxia during surgery helps limit the adverse consequences such as acute exacerbation of pulmonary hypertension. Other measures include prompt recognition and treatment of acidosis, hypercarbia, and electrolyte derangements. (3) Both hypervolemia and hypovolemia are undesirable and should be avoided. A transesophageal echocardiogram can be used to assist in the evaluation of intravascular volume status. (3,54) Use of a venovenous bypass from the inferior vena cava and portal vein to the axillary vein may prevent sudden increase in right ventricular preload and a consequent increase in PAP that often results from reperfusion of the grafted liver. (54) Multiple factors involved in such a surgery make the anesthetic consideration complex. Isoflurane therapy has the ability to decrease mean PAP by as much as 25% without causing systemic hypotension. (195) It is also considered safe for liver transplantation (196) and may be used in patients with PPHTN undergoing OLT. (197)

FOLLOW-UP

A 6-min walk test is a noninvasive test that provides important prognostic information in patients with PPH. (197) It is a strong predictor of mortality in these patients. (198) The usefulness of this test in patients with PPHTN, however, may be limited secondary to decreased mobility related to ascites or lower limb edema, which are common consequences of increased portal pressure. Cardiopulmonary exercise testing has also been used to provide similar information in patients with PPH. (199) A decreased exercise capacity correlates with decreased survival. (200) Determination of maximum oxygen uptake during the exercise study has been shown to be helpful in assessing response to the vasodilator therapy. (201) However, many factors such as cirrhotic myopathy and chronotropic dysfunction (blunting of heart rate response to effort) may result in exercise limitation in patients with cirrhosis, (68) diminishing the predictive value of mentioned parameters. We utilize clinical assessment as well as echocardiography to follow up patients with mild PPHTN. However, serial right-heart catheterizations may be required to assess the disease progression and the effect of therapy in patients with severe PPHTN.

FUTURE DIRECTIONS

The absence of an animal model coupled with the rarity of the disease has prevented a better understanding of the pathogenetic mechanisms as well as improved management of PPHTN. However, the extensive amount of research underway in the field of pulmonary hypertension should shed light on the pathobiology of this disease, which hopefully will translate into novel therapeutic modalities.

Genomic research represents a new era in understanding and management of pulmonary hypertension. (202) Gene transfer therapy involving endothelial NO synthase, (203) prostacyclin synthase, (204) calcitonin gene-related peptide, (205) atrial natriuretic peptide, (206) and vascular endothelial growth factor (207) genes have already shown promising results in animal models of pulmonary hypertension and could prove to be a promising therapeutic modality for this disease.

A national database of pulmonary hypertension in chronic liver disease was instituted in 1997 with the aim of defining the natural history of these patients, conducting multicenter therapeutic trials, and understanding the factors that predict the survival of these patients during and after liver transplantation surgery. (208) The results from this registry should further improve our understanding of the natural history, pathogenetic mechanisms, and treatment of PPHTN.

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* From the Pulmonary and Critical Care Division, Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA.

Manuscript received March 26, 2002; revision accepted July 16, 2002.

Correspondence to: Paul M. Hassoun, MD, Associate Professor of Medicine, Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care, 5501 Hopkins Bayview Circle, Baltimore, MD 21224

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