The Hepatopulmonary Syndrome

  1. Paul A. Lange, MD; and
  2. James K. Stoller, MD
  1. From the Cleveland Clinic Foundation, Cleveland, Ohio. Requests for Reprints: James K. Stoller, MD, Section of Respiratory Therapy, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Desk A90, 9500 Euclid Avenue, Cleveland, OH 44106. Acknowledgments: The authors thank Beth Dobish for her expert assistance in manuscript preparation.
     
    Next Section

    Abstract

    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.

    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].

    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.

    Previous SectionNext Section

    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.

    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.

    Previous SectionNext Section

    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).

    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].

    Previous SectionNext Section

    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].

    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 25µmin 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 500µmin 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].

    Figure 1. Schematic diagram of the pulmonary vascular abnormality suspected in the hepatopulmonary syndrome. Driving pressure of alveolar arterial oxygen is depicted by arrows. Reproduced with permission of the authors .
    View larger version:
    Figure 1. Schematic diagram of the pulmonary vascular abnormality suspected in the hepatopulmonary syndrome. Driving pressure of alveolar arterial oxygen is depicted by arrows. Reproduced with permission of the authors . Diffusion-perfusion impairment.[33]

    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.

    Previous SectionNext Section

    Diagnosis of Intrapulmonary Vascular Dilatations: Imaging Techniques

    The presence of intrapulmonary vascular dilatations can be confirmed using one of three imaging modalities: contrast-enhanced echocardiography, technetium 99m-labeled macroaggregated albumin scanning, and pulmonary arteriography.

    Contrast-Enhanced Echocardiography

    This method uses indocyanine green dye or agitated saline, which provides a stream of microbubbles 60 to 90µmin 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 20µmin 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 50µmin 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.

    Previous SectionNext Section

    Medical Therapy

    In the context of incomplete understanding of the pathophysiology of the hepatopulmonary syndrome, medical therapy has been disappointing. One strategy has been to administer treatments that might interdict a circulating vasodilator substance. To date, small, observational studies have examined several drugs, including garlic (Allium sativum) [98], indomethacin [12, 79], almitrine bismesylate [33], and octreotide [6, 64, 85, 99], and plasma exchange [4] has been attempted to remove a circulating vasodilator. However, all of these treatments have been associated with—at best—minimal improvement in oxygenation and shunt.

    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.

    Previous SectionNext Section

    Liver Transplantation

    Opinions about the reversibility of the hepatopulmonary syndrome have been mixed, but more recent evidence shows that reversal of the intrapulmonary shunt is possible after liver transplantation [21, 103-105]. Early attempts by several investigators were disappointing because hypoxemia persisted after liver transplantation [4, 106-108], and, as recently as 1988, severe hypoxemia was still considered a contraindication to liver transplantation [109]. However, as shown in Table 1, several early reports and more recent experience have documented striking improvements in oxygenation and reversal of shunt both with resolution of liver disease and after liver transplantation in some patients [110-115]. For example, in 1968, Starzl and colleagues [104] reported improvement in hypoxemia after liver transplantation in three children with the hepatopulmonary syndrome. In 1990, Eriksson and colleagues [21] described six patients with hypoxemia and advanced liver disease whose severe ventilation-perfusion mismatch and shunt improved after liver transplantation, as documented by multiple inert gas elimination testing. A recent report by Stoller and colleagues [103] documents the reversibility of intrapulmonary shunting and digital clubbing after liver transplantation in a patient with primary biliary cirrhosis. Later reports have confirmed resolution of the hepatopulmonary syndrome after liver transplantation [35, 62, 105, 116-120].

    View this table:
    Table 1. Review of Available Reports about Reversal or Improvement of Intrapulmonary Shunt in Patients with Liver Disease

    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.

    Previous SectionNext Section

    Future Prospects

    Many basic questions about the diagnosis and treatment of the hepatopulmonary syndrome remain unanswered. Questions about diagnosis include the following:

    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.

    Previous Section
     

    References

    1. 1.↵
      Fluckiger M. Vorkommen von trommelschagel formigen Fingerend-phalangen ohne chronische Veranderungen an der Lungen oder am Herzen. Wien Med Wochenschr. 1884; 34:1457.
    2. 2.↵
      Snell AM. The effects of chronic disease of the liver on the composition and physiochemical properties of blood: changes in the serum proteins; reduction in the oxygen saturation of the arterial blood. Ann Intern Med. 1935; 9:690-711.
    3. 3.↵
      Kennedy TC, Knudson RJ. Exercise-aggravated hypoxemia and orthodeoxia in cirrhosis. Chest. 1977; 72:305-9.
    4. 4.↵
      Krowka MJ, Cortese DA. Pulmonary aspects of liver disease and liver transplantation. Clin Chest Med. 1989; 10:593-616.
    5. 5.↵
      Krowka MJ, Cortese DA. Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation. Hepatology. 1990; 11:138-42.
    6. 6.↵
      Krowka MJ, Dickson ER, Cortese DA. Hepatopulmonary syndrome. Clinical observations and lack of therapeutic response to somatostatin analogue. Chest. 1993; 104:515-21.
    7. 7.↵
      Altman M, Robin ED. Platypnea (diffuse zone I phenomenon?). N Engl J Med. 1969; 281:1347-8.
    8. 8.↵
      Robin ED, Laman D, Horn BR, Theodore J. Platypnea related to orthodeoxia caused by true vascular lung shunts. N Engl J Med. 1976; 294:941-3.
    9. 9.↵
      Robin ED, Horn B, Goris ML, Theodore J, Kessel AV, Mazoub J, et al. Detection, quantitation and pathophysiology of lung spiders. Trans Assoc Am Physicians. 1975; 88:202-16.
    10. 10.↵
      Krowka MJ, Cortese DA. Pulmonary aspects of chronic liver disease and liver transplantation. Mayo Clin Proc. 1985; 60:407-18.
    11. 11.↵
      Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis. 1989; 140:1631-5.
    12. 12.↵
      Andrivet P, Cadranel J, Housset B, Herigault R, Harf A, Adnot S. Mechanisms of impaired arterial oxygenation in patients with liver cirrhosis and severe respiratory insufficiency. Effects of indomethacin. Chest. 1993; 103:500-7.
    13. 13.↵
      Sherlock S. The liver-lung interface. Seminars in Respiratory Medicine. 1988; 9:247-53.
    14. 14.↵
      Rodriguez-Roisin R, Roca J, Agusti AG, Mastai R, Wagner PD, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis. 1987; 135:1085-92.
    15. 15.↵
      Lee SS. Cardiac abnormalities in liver cirrhosis. West J Med. 1989; 151:530-5.
    16. 16.↵
      Braillon A, Cales P, Valla D, Gaudy D, Geoffroy P, Lebrec D. Influence of the degree of liver failure on systemic and splanchnic haemodynamics and on response to propranolol in patient with cirrhosis. Gut. 1986; 27:1204-9.
    17. 17.↵
      Naeije R, Melot C, Hallemans R, Mols P, Lejeune P. Pulmonary hemodynamics in liver cirrhosis. Seminars in Respiratory Medicine. 1985; 7:164-170.
    18. 18.↵
      Glauser FL. Systemic hemodynamic and cardiac function changes in patients undergoing orthotopic liver transplantation. Chest. 1990; 98:1210-5.
    19. 19.↵
      Vera SR, Williams JW, Peters TG, Britt LG. Hemodynamic study following liver transplantation. Transplant Proc. 1989; 21(1 Pt 2):2302-4.
    20. 20.↵
      Castaing Y, Manier G. Hemodynamic disturbances and VA/Q matching in hypoxemic cirrhotic patients. Chest. 1989; 96:1064-9.
    21. 21.↵
      Eriksson LS, Soderman C, Ericzon BG, Eleborg L, Wahren J, Hedenstierna G. Normalization of ventilation/perfusion relationships after liver transplantation in patients with decompensated cirrhosis: evidence for a hepatopulmonary syndrome. Hepatology. 1990; 12:1350-7.
    22. 22.↵
      Agusti AG, Roca J, Rodriguez-Roisin R, Mastai R, Wagner PD, Bosch J. Pulmonary hemodynamics and gas exchange during exercise in liver cirrhosis. Am Rev Respir Dis. 1989; 139:485-91.
    23. 23.↵
      Navasa M, Feu F, Garcia-Pagan JC, Jimenez W, Llach J, Rimola A, et al. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. Hepatology. 1993; 17:355-60.
    24. 24.↵
      Henderson JM, Mackay GJ, Hooks M, Chezmar JL, Galloway JR, Dodson TF, et al. High cardiac output of advanced liver disease persists after orthotopic liver transplantation. Hepatology. 1992; 15:258-62.
    25. 25.↵
      Hadengue A, Lebrec D, Moreau R, Sogni P, Durand F, Gaudin C, et al. Persistence of systemic and splanchnic hyperkinetic circulation in liver transplant patients. Hepatology. 1993; 17:175-8.
    26. 26.↵
      Chezmar JL, Redvanly RD, Nelson RC, Henderson JM. Persistence of portal systemic collaterals and splenomegaly on CT after orthotopic liver transplantation. AJR Am J Roentgenol. 1992; 159:317-20.
    27. 27.↵
      Stanley NN, Woodgate DJ. Mottled chest radiograph and gas transfer defect in chronic liver disease. Thorax. 1972; 27:315-23.
    28. 28.↵
      Krowka MJ, Dickson R, Wiesner RH, Krom RA, Atkinson B, Cortese DA. A prospective study of pulmonary function and gas exchange following liver transplantation. Chest. 1992; 102:1161-6.
    29. 29.↵
      Hourani JM, Bellamy PE, Tashkin DP, Batra P, Simmons MS. Pulmonary dysfunction in advanced liver disease: frequent occurrence of an abnormal diffusing capacity. Am J Med. 1991; 90:693-700.
    30. 30.↵
      Yao EH, Kong BC, Hsue GL, Zhou AC, Wang H. Pulmonary function changes in cirrhosis of the liver. Am J Gastroenterol. 1987; 82:352-4.
    31. 31.↵
      Fahy JV, Kerr KM, Lake JR, Gold WM. Pulmonary function before and after liver transplantation (Abstract). Am Rev Respir Dis. 1992; 143:A303.
    32. 32.↵
      Rodriguez-Roisin R, Agusti AG, Roca J. Pulmonary function and liver disease. Current Opinion in Gastroenterology. 1988; 4:609-14.
    33. 33.↵
      Krowka MJ, Cortese DA. Severe hypoxemia associated with liver disease: Mayo Clinic experience and the experimental use of almitrine bismesylate. Mayo Clin Proc. 1987; 62:164-73.
    34. 34.↵
      Rodriguez-Roisin R. The hepatopulmonary syndrome: new name, old complexities (Editorial). Thorax. 1992; 47:897-902.
    35. 35.↵
      Scott V, Miro A, Kang Y, DeWolf A, Bellary S, Martin M, et al. Reversibility of the hepatopulmonary syndrome by orthotopic liver transplantation. Transplant Proc. 1993; 25:1787-8.
    36. 36.↵
      Oh KS, Bender TM, Bowen A, Ledesma-Medina J. Plain radiographic, nuclear medicine and angiographic observations of hepatogenic pulmonary angiodysplasia. Pediatr Radiol. 1983; 13:111-5.
    37. 37.↵
      Furukawa T, Hara N, Yasumoto K, Inokuchi K. Arterial hypoxemia in patients with hepatic cirrhosis. Am J Med Sci. 1984; 287:10-3.
    38. 38.↵
      Eriksson LS. Hypoxemia in patients with liver cirrhosis. Acta Gastroenterol Belg. 1990; 53:209-15.
    39. 39.↵
      Rodman T, Sobel M, Close HP. Arterial oxygen unsaturation and the ventilation-perfusion defect of Laennec's cirrhosis. N Engl J Med. 1960; 263:73-7.
    40. 40.↵
      Heinemann HO, Emirgil C, Mijnssen JP. Hyperventilation and arterial hypoxemia in cirrhosis of the liver. Am J Med. 1960; 28:239-46.
    41. 41.↵
      Bashour FA, Cochran P. Alveolar-arterial oxygen tension gradients in cirrhosis of the liver. Further evidence of existing pulmonary arteriovenous shunting. Am Heart J. 1966; 71:734-40.
    42. 42.↵
      Caruso G, Catalano D. Esophageal varices and hepato-pulmonary syndrome in liver cirrhosis. J Hepatol. 1991; 12:262-3.
    43. 43.↵
      Bank ER, Thrall JH, Dantzker DR. Radionuclide demonstration of intrapulmonary shunting in cirrhosis. AJR Am J Roentgenol. 1983; 140:967-9.
    44. 44.↵
      Keys A, Snell AM. Respiratory properties of the arterial blood in normal man and in patients with disease of the liver: Position of the oxygen dissociation curve. J Clin Invest. 1938; 17:59-67.
    45. 45.↵
      Caldwell PR, Fritts HW, Cournard A. Oxyhemoglobin dissociation curve in liver disease. J Appl Physiol. 1965; 20:316-20.
    46. 46.↵
      Astrup J, Rorth M. Oxygen affinity of hemoglobin and red cell 2,3-diphosphoglycerate in hepatic cirrhosis. Scand J Clin Lab Invest. 1973; 31:311-7.
    47. 47.↵
      Krowka MJ, Tajik AJ, Dickson ER, Wiesner RH, Cortese DA. Intrapulmonary vascular dilatations (IPVD) in liver transplant candidates. Screening by two-dimensional contrast-enhanced echocardiography. Chest. 1990; 97:1165-70.
    48. 48.↵
      Krowka MJ, Cortese DA. Hepatopulmonary syndrome (Editorial). Chest. 1990; 98:1053-4.
    49. 49.↵
      Hedenstierna G, Soderman C, Eriksson LS, Wahren J. Ventilation-perfusion inequality in patients with non-alcoholic liver cirrhosis. Eur Respir J. 1991; 4:711-7.
    50. 50.↵
      Davis HH 2d, Schwartz DJ, Lefrak SS, Susman N, Schainker BA. Alveolar-capillary oxygen disequilibrium in hepatic cirrhosis. Chest. 1978; 73:507-11.
    51. 51.↵
      Calabresi P, Abelmann WH. Portocaval and porto-pulmonary anastomoses in Laennec's cirrhosis and in heart failure. J Clin Invest. 1957; 36:1257-65.
    52. 52.↵
      Ruff F, Hughes JM, Stanley N, McCarthy D, Greene R, Aronoff A, et al. Regional lung function in patients with hepatic cirrhosis. J Clin Invest. 1971; 50:2403-13.
    53. 53.↵
      Daoud FS, Reeves JT, Schaefer JW. Failure of hypoxic pulmonary vasoconstriction in patients in patients with liver cirrhosis. J Clin Invest. 1972; 51:1076-80.
    54. 54.↵
      Naeije R, Hallemans R, Mols P, Melot C. Hypoxic pulmonary vasoconstriction in liver cirrhosis. Chest. 1981; 80:570-4.
    55. 55.↵
      Kobayashi S, Aida A, Aio K, Nishimura M, Kawakami Y. Liver cirrhosis with severe hypoxemia and paradoxic pulmonary vascular response to graded inspiratory oxygen tension. Chest. 1993; 103:958-60.
    56. 56.↵
      Melot C, Naeije R, Dechamps P, Hallemans R, Lejeune P. Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis. Am Rev Respir Dis. 1989; 139:632-40.
    57. 57.↵
      Rydell R, Hoffbauer FW. Multiple pulmonary arteriovenous fistulas in juvenile cirrhosis. Am J Med. 1956; 21:450-60.
    58. 58.↵
      Berthelot P, Walker JG, Sherlock S, Reid L. Arterial changes in the lungs in cirrhosis of the liver—lung spider nevi. N Engl J Med. 1966; 274:291-8.
    59. 59.↵
      Genovesi MG, Tierney DF, Taplin GV, Eisenberg H. An intravenous radionuclide method to evaluate hypoxemia caused by abnormal alveolar vessels. Limitation of conventional techniques. Am Rev Respir Dis. 1976; 114:59-65.
    60. 60.↵
      Wolfe JD, Tashkin DP, Holly FE, Brachman MB, Genovesi MG. Hypoxemia of cirrhosis: detection of abnormal small pulmonary vascular channels by a quantitative radionuclide method. Am J Med. 1977; 63:746-54.
    61. 61.↵
      Williams A, Trewby P, Williams R, Reid L. Structural alterations to the pulmonary circulation in fulminant hepatic failure. Thorax. 1979; 34:447-53.
    62. 62.↵
      Thorens JB, Junod AF. Hypoxaemia and liver cirrhosis: a new argument in favour of a diffusion-perfusion defect. Eur Respir J. 1992; 5:754-6.
    63. 63.↵
      Hopkins WE, Waggoner AD, Barzilai B. Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease. Am J Cardiol. 1992; 70:516-9.
    64. 64.↵
      Hobeika J, Houssin D, Bernard O, Devictor D, Grimon G, Chapuis Y. Orthotopic liver transplantation in children with chronic liver disease and severe hypoxemia. Transplantation. 1994; 57:224-8.
    65. 65.
      Agusti AG, Roca J, Bosch J, Rodriguez-Roisin R. The lung in patients with cirrhosis. J Hepatol. 1990; 10:251-7.
    66. 66.↵
      Hind CR, Wong CM. Detection of pulmonary arteriovenous fistulae in patients with cirrhosis by contrast 2D echocardiography. Gut. 1981; 22:1042-5.
    67. 67.↵
      Shub C, Tajik AJ, Seward JB, Dines DE. Detecting intrapulmonary right-to-left shunt with contrast echocardiography. Observations in a patient with diffuse pulmonary arteriovenous fistulas. Mayo Clin Proc. 1976; 51:81-4.
    68. 68.↵
      Meltzer RS, Tickner EG, Popp RL. Why do the lungs clear ultrasonic contrast? Ultrasound Med Biol. 1980; 6:263-9.
    69. 69.↵
      Nemec JJ, Davison MB, Marwick TH, Chimowitz MI, Stoller JK, Klein AL, et al. Detection and evaluation of intrapulmonary vascular shunt with contrast Doppler transesophageal echocardiography. J Am Soc Echocardiogr. 1991; 4:79-83.
    70. 70.↵
      Gates GF, Orme HW, Dore EK. Cardiac shunt assessment in children with macroaggregated albumin technetium-99m. Radiology. 1974; 112:649-53.
    71. 71.↵
      Lebrec D, Capron JP, Dheumeaux D, Benhamou JP. Pulmonary hypertension complicating portal hypertension. Am Rev Respir Dis. 1979; 120:849-56.
    72. 72.↵
      McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis. 1983; 127:437-41.
    73. 73.↵
      Lockhart A. Pulmonary arterial hypertension in portal hypertension. Clin Gastroenterol. 1985; 14:123-38.
    74. 74.↵
      Hamdani R, Chelluri L, Selby R, Kramer D, Kang Y, Wood S, et al. Sudden death in patients with pulmonary hypertension undergoing orthotopic liver transplantation (Abstract). Hepatology. 1991; 14:282A.
    75. 75.↵
      Robin ED. Some basic and clinical challenges in the pulmonary circulation. Chest. 1982; 81:357-63.
    76. 76.↵
      Hall GH, Sackner MA. Inactivation of endogenous vasodilator material: a detoxification process of the lung. J Appl Physiol. 1966; 21:23-30.
    77. 77.↵
      Zipser RD, Hoefs FS, Speckart PF, Zia PK, Horton R. Prostaglandins: modulator of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab. 1979; 48:895-900.
    78. 78.↵
      Hamilton G, Phing RC, Hutton RA, Dandona P, Hobbs KE. The relationship between prostacyclin activity and pressure in the portal vein. Hepatology. 1982; 2:236-42.
    79. 79.↵
      Shijo H, Sasaki H, Yuh K, Sakaguchi S, Okumura M. Effects of indomethacin on hepatogenic pulmonary angiodysplasia. Chest. 1991; 99:1027-9.
    80. 80.↵
      Bruix J, Bosch J, Kravetz D, Mastai R, Rodes J. Effects of prostaglandin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver. Gastroenterology. 1985; 88:430-5.
    81. 81.↵
      Ebeid AM, Escourrou J, Soeters PB, Murray P, Fischer JE. Hepatic inactivation of vasoactive intestinal peptide in man and dog. Ann Surg. 1978; 188:28-33.
    82. 82.↵
      Henriksen JH, Staun-Olsen P, Fahrenkrug P, Ring-Larsen H. Vasoactive intestinal polypeptide (VIP) in cirrhosis: arteriovenous extraction in different vascular beds. Scand J Gastroenterol. 1980; 15:787-92.
    83. 83.↵
      Eriksson LS, Hagenfeldt L, Mutt V, Wahren J. Influence of vasoactive intestinal polypeptide (VIP) on splanchnic and central hemodynamics in healthy subjects. Peptides. 1989; 10:481-4.
    84. 84.↵
      Marco J, Diego J, Villanueva ML, Diaz-Fierros M, Valverde I, Segovia JM. Elevated plasma glucagon levels in cirrhosis of the liver. N Engl J Med. 1973; 289:1107-11.
    85. 85.↵
      Salem O, Dindzans V, Freeman J, O'Dorisio T, Ruthardt F, Van Thiel D, et al. Liver transplantation following preoperative closure of intrapulmonary shunt (Abstract). Hepatology. 1989; 10:569.
    86. 86.↵
      Hortnagl H, Singer EA, Lenz K, Kleinberger G, Lochs H. Substance P is markedly increased in plasma of patients with hepatic coma. Lancet. 1984; 1:480-3.
    87. 87.↵
      Claria J, Jimenez W, Ros J, Asbert M, Castro A, Arroyo V, et al. Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide. Hepatology. 1992; 15:343-9.
    88. 88.↵
      Pizcueta P, Pique JM, Fernandez M, Bosch J, Rodes J, Whittle BJ, et al. Modulation of the hyperdyamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology. 1992; 103:1909-15.
    89. 89.↵
      Sieber CC, Groszmann RJ. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in cirrhotic rats. Gastroenterology. 1993; 104:1750-4.
    90. 90.↵
      Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet. 1991; 337:776-8.
    91. 91.↵
      Perrella MA, Edell ES, Krowka MJ, Cortese DA, Burnett JC Jr. Endothelium-derived relaxing factor in pulmonary and renal circulations during hypoxia. Am J Physiol. 1992; 263(1 Pt 2):R45-50.
    92. 92.↵
      Gines P, Jimenez W, Arroyo V, Navasa M, Lopez C, Tito L, et al. Atrial natriuretic factor in cirrhosis with ascites: plasma levels, cardiac release and splanchnic extraction. Hepatology. 1988; 8:636-42.
    93. 93.↵
      Caramelo C, Fernandez-Gallardo S, Santos JC, Inarrea P, Sanchez-Crespo M, Lopez-Novoa JM, et al. Increased levels of platelet-activating factor in blood from patients with cirrhosis of the liver. Eur J Clin Invest. 1987; 17:7-11.
    94. 94.↵
      Henriksen H, Ring-Larsen H, Christensen NJ. Circulating noradrenaline and central haemodynamics in patients with cirrhosis. Scand J Gastroenterol. 1985; 20:1185-90.
    95. 95.↵
      Pizcueta MP, Pique JM, Bosch J, Whittle BJ, Moncada S. Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension. Br J Pharmacol. 1992; 105:184-90.
    96. 96.↵
      Castro A, Jimenez W, Claria J, Ros J, Martinez JM. Impaired responsiveness to angiotensin II in experimental cirrhosis: role of nitric oxide. Hepatology. 1993; 18:367-72.
    97. 97.↵
      Chang SW, Ohara N. Pulmonary circulatory dysfunction in rats with biliary cirrhosis. An animal model of the hepatopulmonary syndrome. Am Rev Respir Dis. 1992; 145(4 Pt 1):798-805.
    98. 98.↵
      Caldwell SH, Jeffers LJ, Narula OS, Lang EA, Reddy KR, Schiff ER. Ancient remedies revisited: does Allium sativum (garlic) palliate the hepatopulmonary syndrome? J Clin Gastroenterol. 1992; 15:248-50.
    99. 99.↵
      Schwartz SM, Pound DC. Hepatopulmonary syndrome: failure of response to somatostatin analogue (Abstract). Gastroenterology. 1992; 102(Pt 2):A882.
    100. 100.↵
      Nakos G, Evrenoglou D, Vassilakis N, Lampropoulos S. Haemodynamics and gas exchange in liver cirrhosis: the effect of orally administered almitrine bismesylate. Respir Med. 1993; 87:93-8.
    101. 101.↵
      Cadranel JL, Milleron BJ, Cadranel JF, Fermand JP, Andrivet P, Brouet JC. Severe hypoxemia-associated intrapulmonary shunt in a patient with chronic liver disease: improvement after medical treatment. Am Rev Respir Dis. 1992; 146:526-7.
    102. 102.↵
      Felt RW, Kozak BE, Rosch J, Duell BP, Barker AF. Hepatogenic pulmonary angiodysplasia treated with coil-spring embolization. Chest. 1987; 91:920-2.
    103. 103.↵
      Stoller JK, Moodie D, Schiavone WA, Vogt D, Broughan T, Winkelman E, et al. Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation. Hepatology. 1990; 11:54-8.
    104. 104.↵
      Starzl TE, Groth CG, Brettschneider L, Moon JB, Fulginiti VA, Cotton EK, et al. Extended survival in 3 cases of orthotopic homotransplantation of human liver. Surgery. 1968; 63:549-63.
    105. 105.↵
      Dimand RJ, Heyman MB, Bass NM, Lake JR, Roberts JP, Ascher NL. Hepatopulmonary syndrome: response to hepatic transplantation (Abstract). Hepatology. 1991; 14(Pt 2):55A.
    106. 106.↵
      Van Thiel DH, Schade RR, Gavaler JS, Shaw BW Jr, Iwatsuki S, Starzl TE. Medical aspects of liver transplantation. Hepatology. 1984; 4(1 Suppl):79S-83S.
    107. 107.↵
      Iwatsuki S, Shaw BW Jr, Starzl TE. Current status of hepatic transplantation. Semin Liver Dis. 1983; 3:173-80.
    108. 108.↵
      Mews CF, Dorney SF, Sheil AG, Forbes DA, Hill RE. Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting. J Pediatr Gastroenterol Nutr. 1990; 10:230-3.
    109. 109.↵
      Maddrey WC, Van Thiel DH. Liver transplantation: an overview. Hepatology. 1988; 8:948-59.
    110. 110.↵
      Silverman A, Cooper MD, Moller JH, Good RA. Syndrome of cyanosis, digital clubbing, and hepatic disease in siblings. J Pediatr. 1968; 72:70-8.
    111. 111.↵
      Chen NS, Barnett CA, Farrer PA. Reversibility of intrapulmonary arteriovenous shunts in liver cirrhosis documented by serial radionuclide perfusion lung scans. Clin Nucl Med. 1984; 9:270-82.
    112. 112.↵
      Shijo H, Nakayama K, Sasaki H, Ueki T, Sakaguchi S, Sakata H, et al. Reversibility of pulmonary telangiectasia in liver cirrhosis evidenced by serial dynamic pulmonary perfusion imaging. Clin Nucl Med. 1989; 14:909-11.
    113. 113.↵
      Levin DP, Pison CF, Brandt M, Weber A, Paradis K, Laberge JM, et al. Reversal of intrapulmonary shunting in cirrhosis after liver transplantation demonstrated by perfusion lung scan. J Nucl Med. 1991; 32:862-4.
    114. 114.↵
      Shijo H, Sasaki H, Sakata H, Kusuhara H, Ueki T, Okumura M. Reversibility of hepatopulmonary syndrome evidenced by serial pulmonary perfusion scan. Gastroenterol Jpn. 1993; 28:126-31.
    115. 115.↵
      McCloskey JJ, Schleien C, Schwarz K, Klein A, Colombani P. Severe hypoxemia and intrapulmonary shunting resulting from cirrhosis reversed by liver transplantation in a pediatric patient. J Pediatr. 1991; 118:902-4.
    116. 116.↵
      Laberge JM, Brandt ML, Lebecque P, Moulin D, Veykemans F, Paradis K, et al. Reversal of cirrhosis-related pulmonary shunting two children by orthotopic liver transplantation. Transplantation. 1992; 53:1135-8.
    117. 117.↵
      Itasaka H, Hershon JJ, Cox KL, Tokunaga Y, Concepcion W, Nakazoto P, et al. Transient deterioration of intrapulmonary shunting after pediatric liver transplantation. Transplantation. 1993; 55:212-4.
    118. 118.↵
      Schwarzenberg SJ, Freese DK, Regelmann WE, Gores PF, Boudreau RJ, Payne WD. Resolution of severe intrapulmonary shunting after liver transplantation. Chest. 1993; 103:1271-3.
    119. 119.↵
      Barry S, Pingleton S, Kindscher J, Eisenach J, Forster J. Comparison of shunt fractions pre- and post-liver transplantation. Transplant Proc. 1993; 25:1801.
    120. 120.↵
      Van Obbergh L, Carlier M, de Clety SC, Sokal E, Rennotte MT, Veyckemans F, et al. Liver transplantation and pulmonary gas exchanges in hypoxemic children. Am Rev Respir Dis. 1993; 148:1408-10.
    121. 121.↵
      Gunnarsson L, Eleborg L, Eriksson LS. Anesthesia for liver transplantation in patients with arterial hypoxemia. Transpl Int. 1990; 3:103-7.
    122. 122.↵
      Lange PA, Vogt DA, Carey WB, Stoller JK. Prevalence and reversibility of hepatopulmonary syndrome following liver transplantation: The Cleveland Clinic Experience (Abstract). Am Rev Respir Dis. 1993; 147(Pt 2):A540.
    123. 123.↵
      Chimowitz MI, Nemec JJ, Marwick TH, Lorig RJ, Furlan AJ, Salcedo EE. Transcranial Doppler ultrasound identifies patients with right-to-left cardiac or pulmonary shunts. Neurology. 1991; 41:1902-4.
    « Previous | Next Article »Table of Contents

    This Article

    1. Ann Intern Med April 1, 1995 vol. 122 no. 7 521-529
    1. AbstractFREE
    2. Figures
    3. » Full Text
    4. Full Text (PDF)

    Rapid Responses

    1. Submit a response
    2. No responses published

    Navigate This Article

    Current Issue

    1. February 2, 2010, 152 (3)
    1. Alert me to current issues