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1 April 1995 | Volume 122 Issue 7 | Pages 521-529
Objective: To review current knowledge about the hepatopulmonary syndrome, including definition and clinical features, methods for diagnosing it, pathophysiologic mechanisms of the associated vascular dilatations, and considerations in treatment, with emphasis on potential reversibility of the syndrome after liver transplantation.
Data Sources: The MEDLINE database from January 1986 to December 1993 and bibliographies of selected articles.
Study Selection: Case studies and series reporting results from patients with the hepatopulmonary syndrome were reviewed. Clinical reviews and animal studies relevant to the hepatopulmonary syndrome were examined.
Data Extraction: Outcomes, including survival and the frequency of reversibility of the hepatopulmonary syndrome, were extracted from available clinical reports.
Data Synthesis: Mild hypoxemia is multifactorial and occurs in approximately one third of all patients with chronic liver disease. The hepatopulmonary syndrome is one cause of hypoxemia that may also cause dyspnea, platypnea, and orthopnea. Intrapulmonary vascular dilatations and the resulting right-to-left intrapulmonary shunt are characteristic of the syndrome. Pharmacologic treatment with almitrine bismesylate, somatostatin analog, and indomethacin and treatment with plasmapheresis have been disappointing. The underlying cause and the predictors of reversibility of the hepatopulmonary syndrome remain unknown, but it has recently been shown that such reversibility is possible and that contrast-enhanced echocardiography appears to be the most sensitive diagnostic test for detecting intrapulmonary vascular dilatations.
Conclusions: In the context of persisting uncertainty about the cause and treatment of the hepatopulmonary syndrome, future studies must focus on better understanding the pathophysiology of the hepatopulmonary syndrome, predicting reversibility after liver transplantation, and identifying other treatment options.
We review the clinical features and current pathophysiologic understanding of the hepatopulmonary syndrome. Specifically, we present the definition and clinical manifestations of the hepatopulmonary syndrome; diagnostic methods for detecting intrapulmonary vascular dilatations; the putative mechanisms underlying the vascular changes seen in patients with the hepatopulmonary syndrome; the efficacy of treatments, including liver transplantation, to reverse the hypoxemia associated with the syndrome; and currently unresolved questions needing further investigation.
The studies we cite were identified by a MEDLINE search and from the bibliographies of eligible studies. We reviewed English-language articles found under the keyword hepatopulmonary that were published between January 1986 and December 1993, inclusive. Because only one study addressed an animal model of the hepatopulmonary syndrome, all studies selected examined humans. Case reports, case series, and observational cohort studies were included, but no randomized controlled trials of treatments for the hepatopulmonary syndrome were identified. Bibliographies of articles identified in the MEDLINE search were reviewed for early descriptions (before 1986) of the hepatopulmonary syndrome; discussions of treatment of the hepatopulmonary syndrome, including organ transplantation; or descriptive series not found in the MEDLINE search.
Several clinical signs and symptoms characterize this syndrome; most persons will present with the signs and symptoms of liver disease, including gastrointestinal bleeding, esophageal varices, ascites, palmar erythema, and splenomegaly [6]. Pulmonary features include digital clubbing, cyanosis, dyspnea, platypnea, and orthodeoxia. Dyspnea is a common symptom; it was the presenting symptom in 18% of patients in the series by Krowka and colleagues [6]; the mean duration of respiratory symptoms in these patients was 4.8 years. Platypnea, defined as dyspnea induced by the upright position and relieved by recumbency [7], and orthodeoxia, defined as arterial deoxygenation accentuated in the upright position and relieved by recumbency [8], are seen in as many as 5% of patients with cirrhosis [9, 10]. However, platypnea and orthodeoxia are more prevalent in patients with the severe hypoxemia characteristic of the hepatopulmonary syndrome. Krowka and colleagues [6] observed orthodeoxia in 14 of 16 patients (88%) with the syndrome, and Edell and colleagues [11] found orthodeoxia in all of 6 patients with cirrhosis and severe hypoxemia. Andrivet and colleagues [12] observed orthodeoxia in 9 patients with cirrhosis and hypoxemia [mean PaO].2, <45 mm Hg) while the patients were breathing 100% oxygen. Although orthodeoxia is not pathognomonic of the hepatopulmonary syndrome, it strongly suggests this diagnosis in the setting of liver dysfunction.
Spider nevi are another common clinical feature of patients with the hepatopulmonary syndrome [13]. Rodriguez-Roisin and colleagues [9, 14] noted that patients with cutaneous spider nevi had more systemic and pulmonary vasodilatation, more profound gas exchange abnormalities, and less hypoxic pulmonary vasoconstriction, suggesting that spider nevi might be a cutaneous marker of intrapulmonary vascular dilatations. Similarly, Andrivet and colleagues [12] observed spider nevi in 7 of 9 patients with cirrhosis and hypoxemia (mean Pao2, 64 mm Hg).
Other than orthodeoxia, common cardiopulmonary features of chronic liver disease manifested by patients with the hepatopulmonary syndrome include alveolar hyperventilation with hypocapnia and a hyperdynamic circulation characterized by systemic vasodilatation and elevated cardiac output. The magnitude of the systemic hemodynamic changes is related to both the development of portal hypertension and the degree of impairment of liver function [15, 16]. Although patients with the hepatopulmonary syndrome show pulmonary vasodilatation accompanying intrapulmonary shunt, their systemic hemodynamics resemble those of patients who have cirrhosis without the hepatopulmonary syndrome. Specifically, cardiac output often exceeds 7 L/min, systemic and pulmonary vascular resistances decrease, and the difference between the arterial and the mixed-venous oxygen content narrows [12, 17-21]. Low pulmonary vascular resistance and low pulmonary artery pressures are characteristic of the hepatopulmonary syndrome because the intrapulmonary vascular dilatations further decompress the vascular bed [11, 18, 22]. Restoration of this hyperdynamic cardiovascular state to normal after liver transplantation has been documented in some patients with cirrhosis, some of whom have and some of whom do not have the hepatopulmonary syndrome [18, 19, 21, 23]. Other reports have refuted this observation, showing persistently increased cardiac output and increased splanchnic blood flow after transplantation, presumably because of a persistently elevated, undefined mediator [24-26].
End-stage liver disease may be characterized by various other derangements of pulmonary function, including a restrictive pattern of lung function characterized by decreased total lung capacity, air flow obstruction, impairment of diffusing capacity, and a widened alveolar-arterial oxygen gradient [27-32]. In describing pulmonary function abnormalities in 116 candidates for liver transplantation, Hourani and colleagues [29] reported that the most common abnormality was a reduction in diffusing capacity for carbon monoxide, seen in 52% of patients. Diffusion impairment was accompanied by a restrictive defect in only 35% of persons with impaired diffusing capacity. A restrictive pattern was noted in 25% of patients and airflow obstruction in 3% of patients. Krowka and colleagues [28] studied 159 consecutive patients before liver transplantation and found diffusing capacity values of less than 80% predicted in 55% of patients. Although patients with the hepatopulmonary syndrome also often have low values for diffusing capacity, their lung volumes and expiratory flow rates may remain normal [33-35].
Patients with the hepatopulmonary syndrome may manifest on a chest radiograph the abnormalities that generally occur in patients with cirrhosis, including decreased lung volumes (57%), pleural effusions (19.3%), increased interstitial markings (13.8%), and increased pulmonary vascular markings (3.7%) [29]. More specifically, however, the hepatopulmonary syndrome may be accompanied by characteristically increased basilar interstitial and pulmonary vascular markings. For example, Stanley and Woodgate [27] were the first to describe a "mottled" shadowing on chest radiographs associated with finger clubbing, hypoxemia, and cyanosis in 6% of 170 patients with chronic liver disease. Krowka and colleagues [33] observed bilateral interstitial markings in 8 of 11 patients with severe hypoxemia; these markings are thought to be due to intrapulmonary vascular dilatations [36]. Although these markings may be caused by intrapulmonary vascular dilatations, the possibility of other causes precludes diagnosis of the hepatopulmonary syndrome by chest radiograph alone.
Krowka and colleagues [6] have proposed two radiographic patterns for the hepatopulmonary syndrome on the basis of pulmonary angiographic features in seven patients with this syndrome. Type 1, or minimal pattern, is characterized by a pattern of finely diffuse, spidery infiltrates, and type 2 is characterized by discrete, localized arteriovenous communications. As Krowka and colleagues have speculated, the type 1 pattern may be associated with severe hypoxemia, orthodeoxia, and a good oxygenation response to 100% inspired oxygen, and the type 2 pattern may respond poorly to supplemental oxygen. Additionally, the type 1 "minimal" pattern may evolve into a type 1 "advanced" pattern, which Krowka and colleagues [6] describe as having a diffuse spongy or blotchy angiographic appearance and which may be less responsive to 100% oxygen. Although these patterns are appealing, their description is based on only a few patients with the hepatopulmonary syndrome, and further study is needed before their significance in terms of severity, prognosis, or the prospect of reversibility can be confirmed.
Because patients with advanced liver disease typically have a rapid respiratory rate that results in hypocapnia, the alveolar-arterial oxygen gradient (which incorporates the partial pressure of carbon dioxide and the inspired oxygen concentration) is a more accurate clinical measure of impaired gas transfer [39, 40]. Naeije and colleagues [17] found a mean alveolar-arterial oxygen gradient of 34.4 mm Hg in a group of candidates for portocaval shunt. Bashour and colleagues [41] found a mean alveolar-arterial oxygen gradient of 44.8 mm Hg in 26 patients with cirrhosis. Hourani and colleagues [29] reported a widened alveolar-arterial oxygen gradient in 45% of candidates for liver transplantation (mean alveolar-arterial oxygen gradient, 36.7 mm Hg). Fahy and colleagues [31] found that 69% of candidates for liver transplantation (n = 207) had an elevated alveolar-arterial oxygen gradient. Although Caruso and colleagues [42] have suggested a correlation between the severity of esophageal varices and the hepatopulmonary syndrome, no consistent relation among the severity of liver disease, the Child classification, or clinical features and hypoxemia has been clearly established in patients with the hepatopulmonary syndrome [6, 34]. In fact, gas exchange abnormalities may occasionally predate hepatic disease [43].
Vascular abnormalities referred to as intrapulmonary vascular dilatations are thought to be the major cause of severe hypoxemia and are the defining feature of the hepatopulmonary syndrome [4, 11, 47, 48, 50]. The anatomical derangement of the pulmonary microvasculature in patients with cirrhosis and the hepatopulmonary syndrome was first documented in 1956 by Rydell and Hoffbauer [57], who identified numerous postmortem intrapulmonary arteriovenous anastomoses in a patient with juvenile cirrhosis and cyanosis. Several years later, Berthelot and colleagues [58] used injections of micro-opaque gelatin to show dilatation of the fine peripheral branches of the pulmonary artery at both the precapillary and capillary levels of the lung and to show spider nevi on the pleura. In addition to this anatomical evidence, physiologic support for a dilated pulmonary microvasculature (such as intrapulmonary vascular dilatations) comes from studies showing that intravenous radiolabeled macroaggregated albumin particles exceeding 25 microns in diameter traverse the pulmonary circulation and enter the systemic circulation [9, 29, 48, 59, 60]. Intrapulmonary capillary and precapillary vascular dilatations [4, 5, 47-49] ranging from 15 to 500 microns in diameter [58, 61] allow the macroaggregated albumin particles to traverse the lung and are the likely source of observed shunt. It has been hypothesized that orthodeoxia is caused by preferential perfusion of intrapulmonary vascular dilatations in the lung bases so that shunt is increased when the patient is upright [8, 9, 47].
Because supplemental oxygen enhances oxygenation more than would be expected with true "anatomic" shunts [4, 33], a new mechanism has been invoked to explain the hypoxemia associated with the hepatopulmonary syndrome. This mechanism has been called diffusion-perfusion impairment [5, 33, 48, 59] or alveolar-capillary oxygen disequilibrium [50] (Figure 1). Diffusion-perfusion impairment relates to the mechanism of hypoxemia associated with intrapulmonary vascular dilatations. Specifically, because the capillary is dilated and has an expanded diameter, oxygen molecules from adjacent alveoli cannot diffuse to the center of the dilated vessel to oxygenate hemoglobin in erythrocytes at the center stream of venous blood [59]. At the same time, supplemental oxygen provides enough driving pressure to partially overcome this relative diffusion defect. According to Krowka and colleagues [5], intrapulmonary vascular dilatations include two discrete types of vascular abnormalities: vascular dilatations at the precapillary level close to the normal gas exchange units of the lung and larger arteriovenous communications that may be distant from gas exchange units. Supplemental oxygen would be expected to improve arterial oxygenation in the former but not in the latter type [5, 9, 33]. The presence of a diffusion impairment in patients with the hepatopulmonary syndrome is supported by some studies in which multiple inert gas elimination techniques were used [11, 20, 49]. REVIEW
The Hepatopulmonary Syndrome
Interactions between the lung and the liver have been studied since 1884, when Fluckiger [1] first saw a woman with cirrhosis, cyanosis, and digital clubbing. This "hypoxemia of cirrhosis" was further clarified in 1935 by Snell [2], who recognized a decreased arterial saturation in three patients with cirrhosis and described what is currently called the "hepatopulmonary syndrome." This term, first suggested in 1977 by Kennedy and Knudson [3], aptly characterizes the association of severe hypoxemia with intrapulmonary vascular dilatations in the setting of hepatic dysfunction. In the current era, successful liver transplantation has renewed interest in the pathophysiology of lung and liver interactions [4].
Definition and Clinical Manifestations of the Hepatopulmonary Syndrome
The hepatopulmonary syndrome is defined as the triad of liver disease, an increased alveolar-arterial gradient while breathing room air, and evidence of intrapulmonary vascular dilatations [5]. Other cardiopulmonary abnormalities (such as pleural effusions or decreased lung volumes) are common and may coexist in patients with the hepatopulmonary syndrome.
Hypoxemia associated with the Hepatopulmonary Syndrome
Impaired arterial oxygenation is a hallmark of the hepatopulmonary syndrome. Mild hypoxemia is a frequent feature of chronic liver disease; it occurs in approximately one third of all patients [13, 17, 37, 38] and is multifactorial. In contrast, severe hypoxemia (Pao2 < 60 mm Hg) is less common with cirrhosis alone and is unusual without associated cardiopulmonary disease. In the absence of independent lung disease (obstructive or restrictive), severe hypoxemia in the setting of liver disease suggests the possibility of the hepatopulmonary syndrome [10, 34]. For example, in a series of 100 patients with cirrhosis, Naeije and colleagues [17] found that 28% of patients had a resting room air Pao2 of less than 70 mm Hg but that only 8% had a resting room air Pao2 of less than 60 mm Hg. In the largest available retrospective study of patients with the hepatopulmonary syndrome (n = 22), Krowka and colleagues [6] found that 59% (n = 13) had a Pao2 less than 60 mm Hg (mean supine Pao2, 62 mm Hg).
Mechanisms of Hypoxemia in the Hepatopulmonary Syndrome
The mechanisms underlying impaired gas exchange in liver cirrhosis and, specifically, in the hepatopulmonary syndrome have been the focus of intense investigation and ongoing debate. Putative mechanisms include changes in the affinity of hemoglobin for oxygen [44-46], intrapulmonary [9, 12, 20, 47-49, 50] and portopulmonary shunt [51], alveolar capillary diffusion limitation [11, 45-47, 49], ventilation-perfusion inequality [14, 20-22, 52-56], and combinations of these factors. Changes in hemoglobin dissociation and portopulmonary shunt have largely been dismissed as causes of the severe hypoxemia characteristic of the hepatopulmonary syndrome [4, 9, 10, 38].
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In the context of a diffusion-like impairment of oxygenation in the hepatopulmonary syndrome, oxygenation is further limited by the increased cardiac output associated with liver disease, which reduces the transit time through the lung vasculature and the amount of time available for oxygen diffusion [5, 50]. Thorens and colleagues [62] demonstrated the effect of this shortened transit time by showing that exercising a patient with cirrhosis who was breathing 100% oxygen caused further impairment of oxygenation and development of a larger shunt fraction.
The hemodynamic and gas exchange manifestations of intrapulmonary vascular dilatations vary greatly among patients with the hepatopulmonary syndrome. For example, the fraction of cardiac output conducted by intrapulmonary vascular dilatations may vary between 20% and 70% of the cardiac output [10, 41, 50, 60]. Furthermore, although they can be shown by contrast-enhanced echocardiography in as many as 47% of patients with cirrhosis [63], intrapulmonary vascular dilatations are not associated with hypoxemia in some patients and cause profound hypoxemia in others [47]. Specifically, in a prospective study of candidates for liver transplantation, Krowka and colleagues [47] showed intrapulmonary vascular dilatations in 5 patients (13.2%) by contrast-enhanced echocardiography, but only 2 of 7 patients (28.6%) with hypoxemia (Pao2 < 70 mm Hg) had intrapulmonary vascular dilatations. Three of 31 patients (9.7%) with preserved oxygenation (for example, Pao2 > 70 mm Hg while breathing room air) had intrapulmonary vascular dilatations. Although the occurrence of intrapulmonary vascular dilatations without hypoxemia may appear to challenge the definition of the hepatopulmonary syndrome (see above), this diagnosis should be considered when hypoxemia and attendant symptoms (such as dyspnea and platypnea) occur. Also, many studies suggest that the degree of intrapulmonary shunting is not associated with the degree of liver disease, ascites, splenomegaly, portal hypertension, or any specific cause of liver disease [4, 10, 33, 34]. Furthermore, oxygenation can worsen over time without any accompanying decline in liver function [6, 33, 64].
The hepatopulmonary syndrome encompasses a spectrum of gas exchange abnormalities partitioned into components of ventilation-perfusion mismatch, intrapulmonary shunt, and limitation of oxygen diffusion *RF 34,36,65 *. Generally, patients with the most severe hypoxemia have diffuse pulmonary vascular dilatation that causes increased shunt, orthodeoxia, loss of hypoxic pulmonary vasoconstriction, and perfusion of low ventilation units [63]. Other patients manifest less severe hypoxemia induced primarily by ventilation-perfusion imbalance and more modest degrees of shunt. Nonvascular factors, such as cardiac output and minute ventilation, modulate the degree of arterial hypoxemia.
Diagnosis of Intrapulmonary Vascular Dilatations: Imaging Techniques
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Contrast-Enhanced Echocardiography
This method uses indocyanine green dye or agitated saline, which provides a stream of microbubbles 60 to 90 microns in diameter that usually opacify only the right heart chambers [66, 67]. Under normal circumstances, these microbubbles are filtered by the pulmonary capillary bed and do not appear in the left side of the heart [68]. However, in the presence of an intrapulmonary or intracardiac right-to-left shunt, indocyanine dye or microbubbles will opacify the left heart chambers [5, 47, 67]. The distinction between intracardiac and intrapulmonary shunt depends on the timing of the appearance of the left-sided bubbles after contrast injection. In intracardiac right-to-left shunt, dye or microbubbles generally appear within three heartbeats after the appearance of bubbles in the right heart chambers. In intrapulmonary shunt, the appearance of contrast in the left heart chambers is delayed, occurring only four to six heartbeats after the initial appearance of contrast in the right side of the heart [63]. However, contrast-enhanced echocardiography cannot differentiate among precapillary, capillary, or pleural dilatations and direct arteriovenous anastomoses. By detecting contrast in specific pulmonary veins, transesophageal echocardiography offers the possible advantage of being able to localize the major site of intrapulmonary vascular dilatations. Alternatively, visualizing symmetric and bilateral bubbles indicates diffuse, bilateral arteriovenous communications [69].
Contrast-enhanced echocardiography has been a valuable tool for showing the presence and prevalence of intrapulmonary vascular dilatations in patients with hypoxemia and liver disease [5, 34, 47, 66]. In a prospective evaluation of 38 candidates for liver transplantation in which contrast-enhanced echocardiography was used, Krowka and colleagues [47] found that 13.2% of all patients had intrapulmonary vascular dilatations. Among the 7 patients with hypoxemia (who accounted for 18.4% of the candidates for liver transplantation), 2 (28.6%) had positive results on a contrast-enhanced echocardiogram for intrapulmonary vascular dilatations. Only 9.7% of the 31 normoxemic patients had positive results; this surprising finding suggests that subclinical pulmonary vasodilatation can occur without overt hypoxemia [48]. Alternatively, a positive result may reflect vasodilatation of pleural vessels, which conduct a smaller amount of the total cardiac output.
In contrast to Krowka and colleagues, Hopkins and colleagues [63], who studied 53 patients with severe liver disease before liver transplantation, suggested a higher prevalence of intrapulmonary vascular dilatations in patients with cirrhosis. Overall, 47% had positive results on a contrast-enhanced echocardiogram, although no patient had hypoxemia (room air Pao2 < 60 mm Hg). The mean Pao2 did not differ between groups with positive and negative echocardiographic results. However, when the extent of shunting was qualitatively assessed on a scale of 1+ to 4+, patients with opacification of 2+ had significantly lower Pao2 than patients without evidence of shunt (66 ±3 mm Hg compared with 82 ±11 mm Hg) [63].
Perfusion Lung Scanning
Technetium 99m-labeled macroaggregated albumin scanning is a second method of detecting intrapulmonary vascular dilatations [59, 60, 70]. Because albumin macroaggregates exceed 20 microns in diameter and should be trapped in the normal pulmonary capillary bed (diameter, 8 to 15 microns), a scan showing uptake of radionuclide over the kidneys, the brain, or both suggests transit through the lung caused by either an intrapulmonary or an intracardiac shunt. The magnitude of shunt is estimated by calculating the ratio of systemic to total body activity of the radionuclide [60]. In normal patients, 3% to 6% of albumin macroaggregates pass through the pulmonary vasculature [9, 60]. In contrast, investigators have used this technique to document large degrees of shunt in patients with hypoxemia and cirrhosis [29, 60]. Wolfe and colleagues [60] documented shunts ranging from 10% to 71% in three patients with moderate to severe hypoxemia. Discrepancies between the percentage of shunt calculated by breathing 100% oxygen and by radionuclide scanning may occur because dilated pulmonary vessels large enough to allow passage of particles 20 to 50 microns in diameter can still participate in gas exchange, especially when the driving pressure is increased by administering 100% oxygen [59].
Pulmonary Arteriography
Because pulmonary arteriography is the most invasive method used to evaluate intrapulmonary vascular dilatations, it has been less widely used than other methods. As noted earlier, pulmonary arteriography in seven patients with the hepatopulmonary syndrome has suggested two angiographic patterns [6], but further study of the importance of these patterns is warranted. In addition to visualizing intrapulmonary vascular dilatations in patients suspected of having the hepatopulmonary syndrome, pulmonary artery catheterization with hemodynamic measurements may help exclude the possibility of cirrhosis-associated pulmonary hypertension, which is a rare (<1%) [71-73] complication of liver disease that is distinct from the hepatopulmonary syndrome and less amenable to reversal after liver transplantation [74]. In contrast to those in patients with pulmonary hypertension, hemodynamic measurements in patients with the hepatopulmonary syndrome usually show normal or low pulmonary artery pressures and pulmonary vascular resistance because of the lowered resistance offered by profuse, intrapulmonary vascular dilatations [11, 18, 22].
Postulated Mechanisms for Intrapulmonary Vascular Dilatations in the Hepatopulmonary Syndrome
Although the cause of the hepatopulmonary syndrome remains unknown, several mechanisms have been postulated as causes for intrapulmonary vascular dilatations, including failure of the damaged liver to clear circulating pulmonary vasodilators, production by the damaged liver of a circulating vasodilator, and inhibition by the damaged liver of a circulating vasoconstrictive substance [4, 5, 38, 63, 75, 76].
To the extent that increased circulation of a pulmonary vasodilator is the favored mechanism, much attention has been given to possible humoral mediators of pulmonary vasodilation. Possible substances include vasodilator prostaglandins (such as prostacyclin, prostaglandin E1, and prostaglandin I2) [77-80], vasoactive intestinal peptide [81-83], calcitonin [5], glucagon [84, 85], substance P [86], nitric oxide [87-91], atrial natriuretic factor [92], and platelet-activating factor [93].
Those proposing that circulating vasoconstrictors are inhibited or metabolized in the hepatopulmonary syndrome have implicated several vasoconstrictors, including tyrosine, serotonin, and endothelin, but little proof of their role in the hepatopulmonary syndrome is available [5, 94].
Finally, increased attention has been given to blunted hypoxic pulmonary vasoconstriction as an important cause of hypoxemia in patients with the hepatopulmonary syndrome [14, 17, 53, 54, 56]. Impaired vascular responsiveness to angiotensin II is also a common feature of cirrhosis, and recent studies have shown that nitric oxide, a powerful local vasodilator of endothelial origin, is increased in animal models of cirrhosis [87, 89, 91, 95, 96]. In a rat model of cirrhosis, Castro and colleagues [96] showed that the attenuated vasoconstrictor effect of angiotensin II was reversed by inhibiting nitric oxide synthesis, suggesting that reduced vascular reactivity to angiotensin II in cirrhosis is mediated by nitric oxide. Also, in a rat model of biliary cirrhosis, Chang and colleagues [97] showed partial reversal of attenuated hypoxic pulmonary vasoconstriction by infusing angiotensin II. These results suggest that the liver plays an important role in regulating pulmonary vascular tone. To the extent that reversal of hypoxemia in the animal model resembles clinical reversal of hypoxemia in the hepatopulmonary syndrome after liver transplantation, the roles of angiotensin II and nitric oxide warrant further investigation.
Medical Therapy
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The most recent pharmacologic studies have focused on a somatostatin analog called octreotide, a potent inhibitor of vasodilating neuropeptides. Despite an earlier report by Salem and colleagues [85] suggesting that subcutaneous somatostatin caused a decrease in intrapulmonary shunt in one patient, thereby allowing subsequent liver transplantation, subsequent studies with more patients have not suggested efficacy for this somatostatin analog. Schwartz and Pound [99] reported a lack of response to somatostatin analog injection in three patients. Krowka and colleagues [6] reported that somatostatin analog (150 µg every 8 hours for 4 days) failed to improve oxygenation in seven recipients, and Hobeika and colleagues [64] found no improvement in two recipients of somatostatin analog.
Almitrine bismesylate, which improves ventilation-perfusion matching in patients with chronic obstructive pulmonary disease, has been administered to a few patients with the hepatopulmonary syndrome in an attempt to im-prove ventilation-perfusion matching. However, Krowka and colleagues [33] found that only one of five patients receiving almitrine bismesylate had any improvement in oxygenation and that the magnitude of the response was small (<10 mm Hg increase in oxygen tension while breathing room air) in the one patient who did respond. In a more recent study by Nakos and colleagues [100], almitrine bismesylate failed to produce a significant increase in Pao2 in six recipients with the hepatopulmonary syndrome.
Against the background of disappointing attempts to interdict or remove a vasodilator, Cadranal and colleagues [101] recently reported that in a single patient with transient noncirrhotic hepatocellular failure from angioimmunoblastic lymphadenopathy, the shunt dramatically improved after antineoplastic treatment with cyclophosphamide and corticosteroids. This report emphasizes that the hepatopulmonary syndrome may be reversible if the underlying liver disease can be corrected, an observation that has emerged with the advent of liver transplantation.
Finally, in addition to pharmacologic therapy for the hepatopulmonary syndrome, Felt and colleagues [102] have reported treatment of intrapulmonary vascular dilatations by spring-coil embolization. The response was disappointing, with an improvement in room air Pao2 ranging from 38 to 53 mm Hg after 22 coil-spring devices were deployed during three separate angiographic sessions.
Overall, despite a wide range of treatment approaches, including pharmacologic strategies, plasma exchange, and attempted mechanical occlusion of intrapulmonary vascular dilatations, therapy for the hepatopulmonary syndrome has been ineffective and invites consideration of new approaches.
Liver Transplantation
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These recent reports of reversing hypoxemia after liver transplantation have challenged the older view that hypoxemia is a contraindication to liver transplantation. Although the reversibility of the hepatopulmonary syndrome after transplantation or improvement in the underlying liver condition has now been established, the effect of the severity of pretransplantation hypoxemia on response to transplantation remains controversial. Hobeika and colleagues [64] reported that a preoperative PaO2 of less than 60 mm Hg on room air predicts high surgery-related mortality. Specifically, of nine patients with the hepatopulmonary syndrome having liver transplantation, four of the five with severe hypoxemia (PaO2 < 60 mm Hg; range, 45 to 58 mm Hg) died, whereas only one of the four whose PaO2 exceeded 60 mm Hg died. In contrast, Gunnarson and colleagues [121] studied 17 patients with chronic liver disease, of whom 6 had hypoxemia (mean PaO2 ±SD, 64 ±3 mm Hg). Although postoperative time on the ventilator was three times longer in the group with hypoxemia (56 hours compared with 18 hours), the number or severity of postoperative complications and outcome did not differ between the two groups.
Also, although the reversibility of the hepatopulmonary syndrome is now clear, estimates of the frequency of reversal vary among series because available studies have not systematically screened candidates for liver transplantation. For example, in 22 patients with the hepatopulmonary syndrome, Krowka and colleagues [6] found that 1 of the 2 patients who had had liver transplantation died of respiratory failure, and the other failed to show resolution of the discrete vascular abnormalities. In a preliminary report, Barry and colleagues [119] retrospectively reviewed the shunt fractions of 30 patients who had liver transplantation. Thirteen of these patients (43%) had shunt fractions exceeding 15%, and of the 7 patients with elevated shunt fractions who were studied again after liver transplantation, all had a mild to moderate reduction in shunt fraction. Finally, we have recently reviewed our experience with 98 liver transplant recipients at the Cleveland Clinic Foundation, 4 (4%) of whom were clinically suspected of having the hepatopulmonary syndrome. All showed marked improvement in post-transplant intrapulmonary shunt (reduced from a mean fraction of 18.7% to 4.5%) and improved oxygenation (mean alveolar-arterial oxygen gradient decreased from 58.1 mm Hg to 33.4 mm Hg) after liver transplantation [122].
Recent demonstrations that the hepatopulmonary syndrome can reverse after liver transplantation and that hypoxemia can worsen despite clinically stable liver disease [6, 64] challenge older views that hypoxemia is a contraindication to liver transplantation. Rather, these newer observations suggest that liver transplantation may actually be indicated in this setting [5, 6, 48]. Unfortunately, a clear understanding of the cause of reversal and predictors of improvement after liver transplantation remains elusive and currently awaits further study.
Future Prospects
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1. What is the precise role of contrast-enhanced echocardiography compared with other tests in screening patients for the hepatopulmonary syndrome?
2. Is there a role for transesophageal echocardiography [5, 69] or transcranial doppler studies [123]?
3. What is the significance of anatomical evidence of intrapulmonary shunt without associated hypoxemia? Do patients with this condition progress to develop hypoxemia, and are there identifiable clinical correlates that can help clinicians identify such patients?
Remaining basic questions about pathophysiology include the following:
1. What is the mechanism of pulmonary vasodilation? More specifically, what are the specific humoral mediators of the hepatopulmonary syndrome, and what is their precise mechanism?
2. What is the mechanism of blunted hypoxic vasoconstriction?
Finally, further therapeutic advances are needed. To the extent that currently available pharmacologic and nonsurgical treatments have been disappointing, further investigation is required to provide other options. Although reports of reversal of the hepatopulmonary syndrome after liver transplantation are encouraging, the mechanism of reversal, time to resolution, and predictors of reversal remain unclear. It is hoped that the availability of an animal model of the hepatopulmonary syndrome and further clinical investigation will help elucidate the answers to some of these pressing questions.
Author and Article Information
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References
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