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Hepatopulmonary Syndrome
Clin Liver Dis 9 (2005) 733 – 746
Hepatopulmonary Syndrome Miguel R. Arguedas, MD, MPH, Michael B. Fallon, MDT Department of Medicine, Division of Gastroenterology/Hepatology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
Respiratory symptoms are common in patients who have chronic liver disease, with estimates ranging as high as 50% to 70% of patients complaining of shortness of breath [1]. The differential diagnosis of dyspnea is broad in these patients, and there are numerous causes to consider. Over the last 15 years, two distinct pulmonary vascular disorders have emerged as important etiologies of pulmonary dysfunction in patients with liver disease or portal hypertension. The hepatopulmonary syndrome (HPS) occurs when intrapulmonary vasodilatation impairs arterial gas exchange [2]. Portopulmonary hypertension (POPH) results when pulmonary arterial constriction and remodeling lead to increased pulmonary arterial pressure [3]. HPS appears to be more common than POPH, and the presence of either entity increases morbidity and mortality in patients who have liver disease. Currently, liver transplantation is the only established treatment for HPS. This article focuses on the clinical features, pathophysiology, and management of HPS.
Definition and differential diagnosis HPS is defined by a widened age-corrected alveolar–arterial oxygen gradient on room air with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension [4–6]. Early studies emphasized that the exclusion of all other causes of cardiopulmonary dysfunction were required to make the diagnosis of HPS [4]. It is now clear, however, that HPS may coexist with other cardiopulmonary abnormalities [7,8] and contribute significantly to gas exchange abnormalities in this setting.
T Corresponding author. E-mail address: [email protected] (M.B. Fallon). 1089-3261/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2005.07.006
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The differential diagnosis of dyspnea and hypoxemia in patients who have chronic liver disease and portal hypertension includes numerous disorders (Box 1). Causes may be classified as primary cardiopulmonary disorders or as cardiopulmonary disorders associated with liver disease. The most common primary cardiopulmonary disorders include chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF). Cardiopulmonary disorders associated with liver disease include complications of cirrhosis and portal hypertension such as fluid retention and muscular wasting, cardiopulmonary disorders associated with specific liver diseases, and pulmonary vascular disorders including HPS and POPH.
Epidemiology, occurrence, and disease associations Intrapulmonary vasodilatation is common in chronic liver disease and may be detected in over 40% of patients being evaluated for liver transplantation [9–11].
Box 1. Differential diagnosis of cardiopulmonary dysfunction in chronic liver disease and portal hypertension Primary cardiopulmonary disorders
COPD CHF Other: asthma, pneumonia, restrictive lung disease
Disorders associated with liver disease and portal hypertension Complications of cirrhosis Ascites Hepatic hydrothorax Muscular wasting and deconditioning Cardiopulmonary-liver disease associations Primary biliary cirrhosis: pulmonary granulomas, fibrosing alveolitis Alpha-1 antitrypsin deficiency: panacinar emphysema Sarcoidosis: restrictive lung disease, cardiomyopathy Hemochromatosis: cardiomyopathy Ethanol: cardiomyopathy Pulmonary vascular disorders Hepatopulmonary syndrome Portopulmonary hypertension
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As many as 8% to 20% of those with intrapulmonary vasodilatation have impaired oxygenation resulting in the diagnosis of HPS. HPS most commonly is recognized in the setting of cirrhosis and appears to occur across the spectrum of etiologies of liver disease [9–11]. Whether the presence or severity of intrapulmonary vasodilatation and HPS correlates with the severity of underlying liver disease is controversial, and studies have found HPS more commonly in both less and more advanced cirrhosis [8–13]. Recently, HPS also has been recognized in patients with portal hypertension in the absence of cirrhosis (portal vein thrombosis, nodular regenerative hyperplasia, congenital hepatic fibrosis, and Budd-Chiari syndrome) [14–17] and has been reported in the setting of acute and chronic hepatitis in the absence of portal hypertension [18,19]. These findings support that advanced liver disease is not required for HPS to develop. Finally, a syndrome similar to HPS has been found in children with congenital cardiovascular abnormalities that result in altered hepatic venous drainage to the lungs [20,21]. This observation supports that factors normally produced or metabolized in the liver modulate the pulmonary vasculature.
Pathophysiology The hallmark of HPS is microvascular dilatation occurring within the pulmonary arterial circulation that appears to result from decreased tone in precapillary arterioles. Whether angiogenesis occurs and contributes to microvascular abnormalities is not defined. In human HPS, enhanced pulmonary production of nitric oxide (NO) has been implicated in the development of intrapulmonary vasodilatation. Exhaled NO levels, a measure of pulmonary production, are increased in cirrhotic patients who have HPS and normalize after OLT [22–24], as HPS resolves. In addition, acute inhibition of NO production or action with NG-nitro-L-arginine methyl ester (L-NAME) or methylene blue, respectively, transiently improves HPS [25–27]. The mechanisms of increased endogenous NO production and its relationship to the presence of portal hypertension, the hyperdynamic circulation and the degree of liver injury, however, remain uncertain. In addition, whether other mediators such as heme oxygenasederived carbon monoxide [28] might contribute to intrapulmonary vasodilatation is not established. Chronic common bile duct ligation (CBDL) in the rat is the only established model that recapitulates the physiologic features of human HPS [29,30] (Fig. 1). It is unique among rodent models of cirrhosis or portal hypertension in that other commonly used models such as thioacetamide-induced cirrhosis and partial portal vein ligation do not result in the development of HPS [31]. Early studies in CBDL animals focused on the vasoconstrictor role of eicosanoids and on an increase in intravascular macrophage-like cells [32,33]. Subsequent work identified increased pulmonary vascular endothelial NO synthase (eNOS) as a major source of pulmonary NO production [34–36] and demonstrated that administering
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Fig. 1. Mechanisms in experimental hepatopulmonary syndrome. Liver injury or portal hypertension triggers alterations that influence the production and release of vasoactive mediators and cytokines and modulate vascular shear stress. In experimental HPS induced by common bile duct ligation, hepatic endothelin-1 release stimulates pulmonary vascular endothelial nitric oxide synthase-derived nitric oxide (NO) production through an increased number of endothelin B receptors (ETB R) leading to vasodilatation. ETB R overexpression is associated with increased vascular shear stress related to the onset of a hyperdynamic circulatory state triggered in part by tumor necrosis factor-alpha (TNF-a) derived from bacterial translocation across the gut. TNF-a overproduction also contributes to macrophage accumulation in the pulmonary vascular lumen, and these cells produce NO from inducible nitric oxide synthase (iNOS) and carbon monoxide (CO) from heme oxygenase-1 (HO-1) contributing to vasodilatation.
intravenous L-NAME improved hypoxemia after CBDL [37]. Further studies have revealed that increased hepatic production of endothelin-1 (ET-1) with release into the circulation is an important mechanism for triggering the increase in pulmonary eNOS and the onset of vasodilatation after CBDL [35,38]. This effect appears to be driven by a shear stress-mediated increase in pulmonary vascular endothelial endothelin B (ETB) receptor expression that enhances endothelial NO production by ET-1 [39]. Accordingly, administration of a selective ETB receptor antagonist to CBDL animals decreases pulmonary endothelial eNOS and ETB receptor levels and significantly improves HPS [40]. Recent preliminary data support that biliary epithelium is an important source of hepatic ET-1 production after CBDL and may explain the unique susceptibility of CBDL animals to HPS [41]. As experimental HPS progresses, there is a steady accumulation of intravascular macrophages. These cells transiently produce inducible NO synthase
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(iNOS) [36,37] and progressively produce heme oxygenase 1 (HO-1) [36,42]. These events contribute to further vasodilatation through production of iNOSderived NO and HO-1-derived carbon monoxide (CO). Accordingly, HO inhibition improves experimental HPS. In addition, prolonged treatment of CBDL animals beginning at the time of ligation with norfloxacin to inhibit bacterial translocation and tumor necrosis factor-a (TNF-a) production decreases macrophage accumulation and prevents the transient increase in iNOS [43], supporting that TNF-a contributes to macrophage accumulation. Further, pentoxifylline, a nonspecific phosphodiesterase inhibitor that increases intracellular cAMP levels and also inhibits TNF-a production in macrophages [44], given over a similar time frame, can prevent the onset or decrease the severity of HPS [45]. Both of these agents initiated at the onset of liver injury influence the development of the hyperdynamic state and may modify ETB receptor expression and endothelinrelated signaling events in the pulmonary microvasculature. Fig. 1 summarizes the current understanding of mechanisms of experimental HPS.
Clinical features The clinical features of HPS typically involve respiratory complaints and findings associated with chronic liver disease. The insidious onset of dyspnea, particularly on exertion, is the most common complaint, but it is nonspecific. Platypnea (shortness of breath exacerbated by sitting up and improved by lying supine) and orthodeoxia (hypoxemia exacerbated in the upright position) are described classically and result from a gravitational increase in blood flow through dilated vessels in the lung bases [46]. These findings appear to be relatively specific but are of low sensitivity [47]. Cough is not a common finding in HPS. Spider angiomas also are reported commonly in HPS but are seen frequently in cirrhotic patients without HPS. Finally, clubbing and distal cyanosis, when present in the setting of liver disease or portal hypertension, should increase suspicion for HPS [2].
Natural history and prognosis The natural history of hepatopulmonary syndrome is characterized incompletely. Most patients appear to develop progressive intrapulmonary vasodilatation and worsening gas exchange [48] over time, and spontaneous improvement is rare [49]. A recent prospective study has evaluated the natural history of HPS in a cohort of 111 patients with cirrhosis of whom 27 (24%) had HPS [50]. The median survival among patients who had HPS was significantly shorter (10.6 months) compared with patients who did not have HPS (40.8 months). Mortality remained higher in those who had HPS after adjusting for severity of
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Liver Disease Portal Hypertension Risk Factors for Chronic Liver Disease Dyspnea Clubbing Low Pulse Oximetry / Hypoxemia OLT Evaluation
CXR, ABG, PFTs, Chest CT
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Treat as appropriate Contrast Echocardiogram Symptoms persist
Normal
No HPS
Delayed Shunting (>3 heart beats)
HPS
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Instrinsic cardiopulmonary disease
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Elevated A-a gradient (age adjusted) Hypoxemia Low DLco No intrinsic cardiopulmonary disease
Contrast Echocardiogram
MAA if hypoxia and delayed shunting
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underlying liver disease and after excluding patients who underwent liver transplantation during follow-up. The causes of death in patients with HPS were mainly caused by complications of hepatocellular dysfunction and portal hypertension and correlated with the severity of hypoxemia in HPS. Mortality after liver transplantation also appears to be higher in patients who have HPS compared with those who do not have HPS. The utility of the severity of HPS as a predictor of outcome after liver transplantation has been evaluated prospectively in a cohort of 24 patients who had cirrhosis and HPS [51]. The authors found that mortality after liver transplantation was increased markedly in severe HPS, in part because of the development of unique postoperative complications recognized in patients who had HPS [52,53]. A preoperative PaO2 of at least 50 mm Hg alone or in combination with a macroaggregated albumin shunt fraction of at least 20% were the strongest predictors of postoperative mortality. These results support that the presence of HPS may affect survival in patients with cirrhosis adversely and that the outcome of transplantation for HPS worsens as HPS progresses.
Diagnosis The diagnostic features of HPS include evidence of liver disease or portal hypertension, an elevated age-adjusted alveolar–arterial oxygen gradient (AaPO2), and evidence of intrapulmonary shunting. In the presence of coexisting cardiac or pulmonary disease, establishing a diagnosis of HPS can be difficult. Fig. 2 presents an algorithm for the diagnosis of HPS. A logical evaluation of dyspnea in the patient with liver disease or portal hypertension begins with a careful history and physical examination. Such an evaluation may lead the clinician to consider alternate, more common diagnoses such as COPD, CHF, or myocardial ischemia. If the common causes of dyspnea can be excluded, and particularly if platypnea or digital clubbing is present, however, further evaluation for HPS is warranted. In patients with liver disease found to have dyspnea or clubbing, or in those undergoing transplant evaluation, pulse oximetry is a simple noninvasive screening test for hypoxemia, and a decreased SpO2 should lead to arterial blood gas (ABG) analysis. Caution must be exercised, however, in interpreting a normal SpO2, as pulse oximetry may overestimate SaO2 in nearly 50% of patients with cirrhosis [54]. Therefore, to reliably detect hypoxemia, ABG analysis should be considered when the SpO2 values are 97% or less. In addition, if hypoxemia or HPS is suspected strongly based on history and physical exam, ABG analysis
Fig. 2. Diagnostic algorithm for hepatopulmonary syndrome. Abbreviations: ABG, arterial blood gas; OLT, orthotopic liver transplantation; CXR, chest radiography; Dlco, diffusing capacity for carbon monoxide; PFTs, pulmonary function tests; MAA, macroaggregated albumin scan.
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should be performed while breathing room air regardless of pulse oximetry. In HPS, ABG reveals an elevated age-adjusted AaPO2 with or without hypoxemia. The expected room air AaPO2 at a given age can be calculated from the following equation: AaPO2 = 0.26 age – 0.43 [55]. If gas exchange abnormalities are detected, chest radiography and pulmonary function tests are performed to evaluate for the presence of other pulmonary abnormalities. Because cardiopulmonary disorders unrelated to liver disease or those related to ascites are more common than HPS, treating these abnormalities before further evaluation for HPS is reasonable in the absence of significant hypoxemia (PaO2 less than 70 mm Hg). If HPS is suspected, contrast echocardiography is the preferred screening test for intrapulmonary vasodilatation [9]. Contrast echocardiography is performed by injecting agitated saline intravenously during normal transthoracic echocardiography, producing microbubbles that are visible on sonography. This bolus opacifies the right ventricle within seconds, and in the absence of rightto-left shunting, bubbles are absorbed in the lungs. If an intracardiac shunt is present, contrast agent enters the left ventricle within three heartbeats (early shunting). If intrapulmonary shunting, characteristic of hepatopulmonary syndrome, is present, the left ventricle opacifies at least three heartbeats after the right (delayed shunting). Up to 40% of patients with cirrhosis have a positive contrast echocardiogram [9], although only a subset of these patients have sufficient vasodilatation to cause abnormal gas exchange and fulfill criteria for HPS. If a patient who has liver disease or portal hypertension and hypoxemia has a positive contrast echocardiogram in the absence of significant cardiopulmonary disease, a diagnosis of HPS has been made. A semiquantitative scoring system for assessing intrapulmonary shunting during contrast echocardiography has been developed, although whether the degree of shunting predicts the degree of gas exchange abnormalities has not been established [56]. In hypoxemic patients with both intrapulmonary vasodilatation and intrinsic cardiopulmonary disease, the technetium-labeled macroaggregated albumin scan (MAA scan) may be useful in defining the contribution of HPS to gas exchange abnormalities. In this test, radiolabeled aggregates of albumin measuring approximately 20 mm in diameter are infused into the venous system. Ordinarily, particles of this size become trapped in the pulmonary microvasculature, and scintigraphy reveals nearly complete uptake in the lungs. In the presence of significant intrapulmonary shunting, a fraction of the macroaggregated albumin passes through the lungs and into the systemic circulation. Scintigraphy then also reveals uptake in other organs in addition to the lung, allowing the calculation of the shunt fraction. In one study, the MAA scan was positive only in patients who had HPS and a PaO2 less than 60 mm Hg and not in patients who had COPD with a similar degree of hypoxemia [8]. The MAA scan, however, is less sensitive than contrast echocardiogram and may be most useful in defining if HPS contributes to hypoxemia in patients with concomitant obstructive pulmonary disease.
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Pulmonary angiography is expensive and invasive and has a low sensitivity for detecting intrapulmonary vasodilatation. Therefore, it is not used routinely to diagnose HPS. High-resolution chest CT and evaluation of pulmonary blood transit time are newer diagnostic modalities for assessing HPS [57,58]. In one study, the degree of pulmonary microvascular dilatation observed on chest CT correlated with the severity of gas exchange abnormalities in a small cohort of patients with HPS, suggesting that quantitation of intrapulmonary vasodilatation was possible. In another study, pulmonary transit time of erythrocytes, measured by echocardiographic analysis of human serum albumin-air microbubble complexes through the heart, also correlated with gas exchange abnormalities in a small group of patients with HPS. The utility of these techniques in evaluating HPS remains to be defined.
Treatment No clearly effective medical therapy for HPS is available. Somatostatin, almitrine, indomethacin, and plasma exchange have been tried without success in small uncontrolled reports [15]. Aspirin increased arterial oxygenation in two children who had HPS [59], and a case report [60] and subsequent open label trial [61] using garlic also suggested a beneficial effect. In the latter trial, garlic powder was administered for a minimum of 6 months. Six of 15 (40%) patients who had HPS had improvements greater than 10 mm Hg in the PaO2, and one subject had resolution of hypoxemia (PaO2: 46 mm Hg to 80 mm Hg) over a 1.5-year period. Acute infusion of methylene blue, a dye that inhibits the effect of NO on soluble guanylate cyclase, also transiently improved oxygenation in two reports comprising a total of eight patients [25,27]. In addition, acute administration of inhaled L-NAME, to inhibit nitric oxide production, also transiently improved oxygenation in one patient [26]. Finally, a single case report suggests that norfloxacin also may have contributed to improvement in oxygen saturation in HPS [62]. These reports underscore the need to evaluate agents targeted at likely pathogenetic mechanisms in randomized multi-center trials to determine efficacy. Seven case reports have evaluated the effects of transjugular intrahepatic portosystemic shunt (TIPS) on HPS in cirrhosis. Six have found a degree of improvement in oxygenation. Short duration of follow-up in two [63] and the presence of coexistent hepatic hydrothorax in another [64], however, limit evaluation of the utility of TIPS in these cases. In a fourth report, arterial oxygenation clearly improved by 20 mm Hg 6 months after TIPS placement [65]. Significant intrapulmonary shunting, however, persisted based on radionuclide lung perfusion scanning, and the cardiac output increased after TIPS. These findings suggest that improved oxygenation may not have been caused by reversal of intrapulmonary vasodilatation. Two other reports have been reported. One was in an 11-year-old girl who had biliary atresia where oxygenation and intrapulmonary shunting were improved and sustained over 8 months [66]. The
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other was in a 46-year-old woman with presumed alcohol-related cirrhosis where oxygenation and shunting improved and were sustained over 3 years [67] after TIPS placement. There is a seventh report of failure of TIPS to improve oxygenation in one patient and identification of two patients where HPS developed in the setting of a functioning TIPS [68]. Together, these findings document the considerable uncertainty regarding the utility of TIPS for HPS. TIPS should be considered an experimental treatment, and its use should be confined to the setting of clinical trials so that efficacy may be judged. Liver transplantation is the only established effective therapy for HPS based upon the total resolution or significant improvement in gas exchange postoperatively in more than 85% of reported patients [69]. The length of time for arterial hypoxemia to normalize after transplantation, however, varies and may be more than 1 year [70]. In addition, mortality is increased after transplantation in patients who have HPS compared with subjects who do not have HPS [51,69], and unique postoperative complications, including pulmonary hypertension [71], cerebral embolic hemorrhages [72], and immediate postoperative deoxygenation requiring prolonged mechanical ventilation [73] have been reported. Innovative approaches such as frequent body positioning [74] or inhaled NO [75,76] have been used to improve postoperative gas exchange. Further investigation focused on the peri-operative medical management of HPS patients is needed to optimize survival.
Summary HPS occurs when pulmonary microvascular dilatation impairs arterial oxygenation in the setting of liver disease or portal hypertension. The syndrome is found in as many as 20% of cirrhotics and should be considered in any patient with chronic liver disease who develops dyspnea or hypoxemia. Recognition is important, because the presence of HPS increases mortality in the setting of cirrhosis. Contrast echocardiography and standard cardiopulmonary testing are generally sufficient to make the diagnosis of HPS, but further testing may be needed in patients who have both intrinsic cardiopulmonary disease and intrapulmonary vasodilatation. Treatment consists of supplemental oxygen and consideration of orthotopic liver transplantation if significant hypoxemia is present. The recognition in experimental models that a sequence of molecular alterations leads to endothelin-1 and TNF-a modulation of pulmonary microvascular tone may lead to the development of novel and effective medical therapies.
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[51] Arguedas M, Abrams GA, Krowka MJ, et al. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 2003;37:192 – 7. [52] Kaspar MD, Ramsay MA, Shuey Jr CB, et al. Severe pulmonary hypertension and amelioration of hepatopulmonary syndrome after liver transplantation. Liver Transpl Surg 1998;4:177 – 9. [53] Martinez-Palli G, Barbera JA, Taura P, et al. Severe portopulmonary hypertension after liver transplantation in a patient with preexisting hepatopulmonary syndrome. J Hepatol 1999; 31:1075 – 9. [54] Abrams GA, Sanders MK, Fallon MB. Utility of pulse oximetry in the detection of arterial hypoxemia in liver transplant candidates. Liver Transpl 2002;8:391 – 6. [55] Harris E, Kenyon A, Nisbet H, et al. The normal alveolar-arterial oxygen-tension gradient in man. Clin Sci Mol Med 1974;46:89 – 104. [56] Vedrinne JM, Duperret S, Bizollon T, et al. Comparison of transesophageal and transthoracic contrast echocardiography for detection of an intrapulmonary shunt in liver disease. Chest 1997; 111:1236 – 40. [57] Katsuta Y, Honma H, Zhang X, et al. Pulmonary blood transit time and impaired arterial oxygenation in patients with chronic liver disease. J Gastroenterol 2005;40:57 – 63. [58] Lee KN, Lee HJ, Shin WW, et al. Hypoxemia and liver cirrhosis (hepatopulmonary syndrome) in eight patients: comparison of the central and peripheral pulmonary vasculature. Radiology 1999;211:549 – 53. [59] Song JY, Choi JY, Ko JT, et al. Long-term aspirin therapy for hepatopulmonary syndrome. Pediatrics 1996;97:917 – 20. [60] Caldwell SH, Jeffers LJ, Narula OS, et al. Ancient remedies revisited: does Allium sativum (garlic) palliate the hepatopulmonary syndrome? J Clin Gastroenterol 1992;15:248 – 50. [61] Abrams GA, Fallon MB. Treatment of hepatopulmonary syndrome with Allium sativum (garlic): a pilot trial. J Clin Gastroenterol 1998;27:232 – 5. [62] Anel RM, Sheagren JN. Novel presentation and approach to management of hepatopulmonary syndrome with use of antimicrobial agents. Clin Infect Dis 2001;32:E131 – 6. [63] Reigler JL, Lang KA, Johnson SP, et al. Transjugular intrahepatic portosystemic shunt improves oxygenation in hepatopulmonary syndrome. Gastroenterol 1995;109:978 – 83. [64] Selim KM, Akriviadis EA, Zuckerman E, et al. Transjugular intrahepatic portosystemic shunt: a successful treatment for hepatopulmonary syndrome. Am J Gastroenterol 1998;93:455 – 8. [65] Allgaier HP, Haag K, Ochs A, et al. Hepatopulmonary syndrome: Successful treatment by transjugular intrahepatic portosystemic stent-shunt (TIPS). J Hepatol 1995;23:102 – 5. [66] Paramesh A, Hussain S, Shneider B, et al. Improvement of hepatopulmonary syndrome after transjugular intrahepatic portasystemic shunting: case report and review of literature. Pediatr Transplant 2003;7:157 – 62. [67] Chevallier P, Novelli L, Motamedi JP, et al. Hepatopulmonary syndrome successfully treated with transjugular intrahepatic portosystemic shunt: a three-year follow-up. J Vasc Interv Radiol 2004;15:647 – 8. [68] Corley DA, Scharschmidt B, Bass N, et al. Lack of efficacy of TIPS for hepatopulmonary syndrome. Gastroenterol 1997;113:728 – 31. [69] Lange PA, Stoller JK. The Hepatopulmonary Syndrome: effect of liver transplantation. Clin Chest Med 1996;17(1):115 – 23. [70] Philit F, Wiesendanger T, Gille D, et al. Late resolution of hepatopulmonary syndrome after liver transplantation. Respiration (Herrlisheim) 1997;64:173 – 5. [71] Mandell MS, Groves BM, Duke J. Progressive plexogenic pulmonary hypertension following liver transplantation. Transplantation 1995;59:1488 – 90. [72] Abrams GA, Rose K, Fallon MB, et al. Hepatopulmonary syndrome and venous emboli causing intracerebral hemorrhages after liver transplantation: a case report. Transplantation 1999;68:1 – 3. [73] Scott V, Mira A, Kang Y, et al. Reversibility of the hepatopulmonary syndrome by orthotopic liver transplantation. Transplant Proc 1993;25:1787 – 8. [74] Meyers C, Low L, Kaufman L, et al. Trendelenburg positioning and continuous lateral rotation
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improve oxygenation in hepatopulmonary syndrome after liver transplantation. Liver Transpl Surg 1998;6:510 – 2. [75] Alexander J, Greenough A, Rela M, et al. Nitric oxide treatment of severe hypoxemia after liver transplantation in hepatopulmonary syndrome. Liver Transpl Surg 1997;1:54 – 5. [76] Durand P, Baujard C, Grosse AL. Reversal of hypoxemia by inhaled nitric oxide in children with severe hepatopulmonary syndrome, type 1, during and after liver transplantation. Transplantation 1998;65:437 – 9.
Hepatopulmonary Syndrome Miguel R. Arguedas, MD, MPH, Michael B. Fallon, MDT Department of Medicine, Division of Gastroenterology/Hepatology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
Respiratory symptoms are common in patients who have chronic liver disease, with estimates ranging as high as 50% to 70% of patients complaining of shortness of breath [1]. The differential diagnosis of dyspnea is broad in these patients, and there are numerous causes to consider. Over the last 15 years, two distinct pulmonary vascular disorders have emerged as important etiologies of pulmonary dysfunction in patients with liver disease or portal hypertension. The hepatopulmonary syndrome (HPS) occurs when intrapulmonary vasodilatation impairs arterial gas exchange [2]. Portopulmonary hypertension (POPH) results when pulmonary arterial constriction and remodeling lead to increased pulmonary arterial pressure [3]. HPS appears to be more common than POPH, and the presence of either entity increases morbidity and mortality in patients who have liver disease. Currently, liver transplantation is the only established treatment for HPS. This article focuses on the clinical features, pathophysiology, and management of HPS.
Definition and differential diagnosis HPS is defined by a widened age-corrected alveolar–arterial oxygen gradient on room air with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension [4–6]. Early studies emphasized that the exclusion of all other causes of cardiopulmonary dysfunction were required to make the diagnosis of HPS [4]. It is now clear, however, that HPS may coexist with other cardiopulmonary abnormalities [7,8] and contribute significantly to gas exchange abnormalities in this setting.
T Corresponding author. E-mail address: [email protected] (M.B. Fallon). 1089-3261/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2005.07.006
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The differential diagnosis of dyspnea and hypoxemia in patients who have chronic liver disease and portal hypertension includes numerous disorders (Box 1). Causes may be classified as primary cardiopulmonary disorders or as cardiopulmonary disorders associated with liver disease. The most common primary cardiopulmonary disorders include chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF). Cardiopulmonary disorders associated with liver disease include complications of cirrhosis and portal hypertension such as fluid retention and muscular wasting, cardiopulmonary disorders associated with specific liver diseases, and pulmonary vascular disorders including HPS and POPH.
Epidemiology, occurrence, and disease associations Intrapulmonary vasodilatation is common in chronic liver disease and may be detected in over 40% of patients being evaluated for liver transplantation [9–11].
Box 1. Differential diagnosis of cardiopulmonary dysfunction in chronic liver disease and portal hypertension Primary cardiopulmonary disorders
COPD CHF Other: asthma, pneumonia, restrictive lung disease
Disorders associated with liver disease and portal hypertension Complications of cirrhosis Ascites Hepatic hydrothorax Muscular wasting and deconditioning Cardiopulmonary-liver disease associations Primary biliary cirrhosis: pulmonary granulomas, fibrosing alveolitis Alpha-1 antitrypsin deficiency: panacinar emphysema Sarcoidosis: restrictive lung disease, cardiomyopathy Hemochromatosis: cardiomyopathy Ethanol: cardiomyopathy Pulmonary vascular disorders Hepatopulmonary syndrome Portopulmonary hypertension
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As many as 8% to 20% of those with intrapulmonary vasodilatation have impaired oxygenation resulting in the diagnosis of HPS. HPS most commonly is recognized in the setting of cirrhosis and appears to occur across the spectrum of etiologies of liver disease [9–11]. Whether the presence or severity of intrapulmonary vasodilatation and HPS correlates with the severity of underlying liver disease is controversial, and studies have found HPS more commonly in both less and more advanced cirrhosis [8–13]. Recently, HPS also has been recognized in patients with portal hypertension in the absence of cirrhosis (portal vein thrombosis, nodular regenerative hyperplasia, congenital hepatic fibrosis, and Budd-Chiari syndrome) [14–17] and has been reported in the setting of acute and chronic hepatitis in the absence of portal hypertension [18,19]. These findings support that advanced liver disease is not required for HPS to develop. Finally, a syndrome similar to HPS has been found in children with congenital cardiovascular abnormalities that result in altered hepatic venous drainage to the lungs [20,21]. This observation supports that factors normally produced or metabolized in the liver modulate the pulmonary vasculature.
Pathophysiology The hallmark of HPS is microvascular dilatation occurring within the pulmonary arterial circulation that appears to result from decreased tone in precapillary arterioles. Whether angiogenesis occurs and contributes to microvascular abnormalities is not defined. In human HPS, enhanced pulmonary production of nitric oxide (NO) has been implicated in the development of intrapulmonary vasodilatation. Exhaled NO levels, a measure of pulmonary production, are increased in cirrhotic patients who have HPS and normalize after OLT [22–24], as HPS resolves. In addition, acute inhibition of NO production or action with NG-nitro-L-arginine methyl ester (L-NAME) or methylene blue, respectively, transiently improves HPS [25–27]. The mechanisms of increased endogenous NO production and its relationship to the presence of portal hypertension, the hyperdynamic circulation and the degree of liver injury, however, remain uncertain. In addition, whether other mediators such as heme oxygenasederived carbon monoxide [28] might contribute to intrapulmonary vasodilatation is not established. Chronic common bile duct ligation (CBDL) in the rat is the only established model that recapitulates the physiologic features of human HPS [29,30] (Fig. 1). It is unique among rodent models of cirrhosis or portal hypertension in that other commonly used models such as thioacetamide-induced cirrhosis and partial portal vein ligation do not result in the development of HPS [31]. Early studies in CBDL animals focused on the vasoconstrictor role of eicosanoids and on an increase in intravascular macrophage-like cells [32,33]. Subsequent work identified increased pulmonary vascular endothelial NO synthase (eNOS) as a major source of pulmonary NO production [34–36] and demonstrated that administering
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Fig. 1. Mechanisms in experimental hepatopulmonary syndrome. Liver injury or portal hypertension triggers alterations that influence the production and release of vasoactive mediators and cytokines and modulate vascular shear stress. In experimental HPS induced by common bile duct ligation, hepatic endothelin-1 release stimulates pulmonary vascular endothelial nitric oxide synthase-derived nitric oxide (NO) production through an increased number of endothelin B receptors (ETB R) leading to vasodilatation. ETB R overexpression is associated with increased vascular shear stress related to the onset of a hyperdynamic circulatory state triggered in part by tumor necrosis factor-alpha (TNF-a) derived from bacterial translocation across the gut. TNF-a overproduction also contributes to macrophage accumulation in the pulmonary vascular lumen, and these cells produce NO from inducible nitric oxide synthase (iNOS) and carbon monoxide (CO) from heme oxygenase-1 (HO-1) contributing to vasodilatation.
intravenous L-NAME improved hypoxemia after CBDL [37]. Further studies have revealed that increased hepatic production of endothelin-1 (ET-1) with release into the circulation is an important mechanism for triggering the increase in pulmonary eNOS and the onset of vasodilatation after CBDL [35,38]. This effect appears to be driven by a shear stress-mediated increase in pulmonary vascular endothelial endothelin B (ETB) receptor expression that enhances endothelial NO production by ET-1 [39]. Accordingly, administration of a selective ETB receptor antagonist to CBDL animals decreases pulmonary endothelial eNOS and ETB receptor levels and significantly improves HPS [40]. Recent preliminary data support that biliary epithelium is an important source of hepatic ET-1 production after CBDL and may explain the unique susceptibility of CBDL animals to HPS [41]. As experimental HPS progresses, there is a steady accumulation of intravascular macrophages. These cells transiently produce inducible NO synthase
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(iNOS) [36,37] and progressively produce heme oxygenase 1 (HO-1) [36,42]. These events contribute to further vasodilatation through production of iNOSderived NO and HO-1-derived carbon monoxide (CO). Accordingly, HO inhibition improves experimental HPS. In addition, prolonged treatment of CBDL animals beginning at the time of ligation with norfloxacin to inhibit bacterial translocation and tumor necrosis factor-a (TNF-a) production decreases macrophage accumulation and prevents the transient increase in iNOS [43], supporting that TNF-a contributes to macrophage accumulation. Further, pentoxifylline, a nonspecific phosphodiesterase inhibitor that increases intracellular cAMP levels and also inhibits TNF-a production in macrophages [44], given over a similar time frame, can prevent the onset or decrease the severity of HPS [45]. Both of these agents initiated at the onset of liver injury influence the development of the hyperdynamic state and may modify ETB receptor expression and endothelinrelated signaling events in the pulmonary microvasculature. Fig. 1 summarizes the current understanding of mechanisms of experimental HPS.
Clinical features The clinical features of HPS typically involve respiratory complaints and findings associated with chronic liver disease. The insidious onset of dyspnea, particularly on exertion, is the most common complaint, but it is nonspecific. Platypnea (shortness of breath exacerbated by sitting up and improved by lying supine) and orthodeoxia (hypoxemia exacerbated in the upright position) are described classically and result from a gravitational increase in blood flow through dilated vessels in the lung bases [46]. These findings appear to be relatively specific but are of low sensitivity [47]. Cough is not a common finding in HPS. Spider angiomas also are reported commonly in HPS but are seen frequently in cirrhotic patients without HPS. Finally, clubbing and distal cyanosis, when present in the setting of liver disease or portal hypertension, should increase suspicion for HPS [2].
Natural history and prognosis The natural history of hepatopulmonary syndrome is characterized incompletely. Most patients appear to develop progressive intrapulmonary vasodilatation and worsening gas exchange [48] over time, and spontaneous improvement is rare [49]. A recent prospective study has evaluated the natural history of HPS in a cohort of 111 patients with cirrhosis of whom 27 (24%) had HPS [50]. The median survival among patients who had HPS was significantly shorter (10.6 months) compared with patients who did not have HPS (40.8 months). Mortality remained higher in those who had HPS after adjusting for severity of
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Liver Disease Portal Hypertension Risk Factors for Chronic Liver Disease Dyspnea Clubbing Low Pulse Oximetry / Hypoxemia OLT Evaluation
CXR, ABG, PFTs, Chest CT
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Treat as appropriate Contrast Echocardiogram Symptoms persist
Normal
No HPS
Delayed Shunting (>3 heart beats)
HPS
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Instrinsic cardiopulmonary disease
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Elevated A-a gradient (age adjusted) Hypoxemia Low DLco No intrinsic cardiopulmonary disease
Contrast Echocardiogram
MAA if hypoxia and delayed shunting
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underlying liver disease and after excluding patients who underwent liver transplantation during follow-up. The causes of death in patients with HPS were mainly caused by complications of hepatocellular dysfunction and portal hypertension and correlated with the severity of hypoxemia in HPS. Mortality after liver transplantation also appears to be higher in patients who have HPS compared with those who do not have HPS. The utility of the severity of HPS as a predictor of outcome after liver transplantation has been evaluated prospectively in a cohort of 24 patients who had cirrhosis and HPS [51]. The authors found that mortality after liver transplantation was increased markedly in severe HPS, in part because of the development of unique postoperative complications recognized in patients who had HPS [52,53]. A preoperative PaO2 of at least 50 mm Hg alone or in combination with a macroaggregated albumin shunt fraction of at least 20% were the strongest predictors of postoperative mortality. These results support that the presence of HPS may affect survival in patients with cirrhosis adversely and that the outcome of transplantation for HPS worsens as HPS progresses.
Diagnosis The diagnostic features of HPS include evidence of liver disease or portal hypertension, an elevated age-adjusted alveolar–arterial oxygen gradient (AaPO2), and evidence of intrapulmonary shunting. In the presence of coexisting cardiac or pulmonary disease, establishing a diagnosis of HPS can be difficult. Fig. 2 presents an algorithm for the diagnosis of HPS. A logical evaluation of dyspnea in the patient with liver disease or portal hypertension begins with a careful history and physical examination. Such an evaluation may lead the clinician to consider alternate, more common diagnoses such as COPD, CHF, or myocardial ischemia. If the common causes of dyspnea can be excluded, and particularly if platypnea or digital clubbing is present, however, further evaluation for HPS is warranted. In patients with liver disease found to have dyspnea or clubbing, or in those undergoing transplant evaluation, pulse oximetry is a simple noninvasive screening test for hypoxemia, and a decreased SpO2 should lead to arterial blood gas (ABG) analysis. Caution must be exercised, however, in interpreting a normal SpO2, as pulse oximetry may overestimate SaO2 in nearly 50% of patients with cirrhosis [54]. Therefore, to reliably detect hypoxemia, ABG analysis should be considered when the SpO2 values are 97% or less. In addition, if hypoxemia or HPS is suspected strongly based on history and physical exam, ABG analysis
Fig. 2. Diagnostic algorithm for hepatopulmonary syndrome. Abbreviations: ABG, arterial blood gas; OLT, orthotopic liver transplantation; CXR, chest radiography; Dlco, diffusing capacity for carbon monoxide; PFTs, pulmonary function tests; MAA, macroaggregated albumin scan.
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should be performed while breathing room air regardless of pulse oximetry. In HPS, ABG reveals an elevated age-adjusted AaPO2 with or without hypoxemia. The expected room air AaPO2 at a given age can be calculated from the following equation: AaPO2 = 0.26 age – 0.43 [55]. If gas exchange abnormalities are detected, chest radiography and pulmonary function tests are performed to evaluate for the presence of other pulmonary abnormalities. Because cardiopulmonary disorders unrelated to liver disease or those related to ascites are more common than HPS, treating these abnormalities before further evaluation for HPS is reasonable in the absence of significant hypoxemia (PaO2 less than 70 mm Hg). If HPS is suspected, contrast echocardiography is the preferred screening test for intrapulmonary vasodilatation [9]. Contrast echocardiography is performed by injecting agitated saline intravenously during normal transthoracic echocardiography, producing microbubbles that are visible on sonography. This bolus opacifies the right ventricle within seconds, and in the absence of rightto-left shunting, bubbles are absorbed in the lungs. If an intracardiac shunt is present, contrast agent enters the left ventricle within three heartbeats (early shunting). If intrapulmonary shunting, characteristic of hepatopulmonary syndrome, is present, the left ventricle opacifies at least three heartbeats after the right (delayed shunting). Up to 40% of patients with cirrhosis have a positive contrast echocardiogram [9], although only a subset of these patients have sufficient vasodilatation to cause abnormal gas exchange and fulfill criteria for HPS. If a patient who has liver disease or portal hypertension and hypoxemia has a positive contrast echocardiogram in the absence of significant cardiopulmonary disease, a diagnosis of HPS has been made. A semiquantitative scoring system for assessing intrapulmonary shunting during contrast echocardiography has been developed, although whether the degree of shunting predicts the degree of gas exchange abnormalities has not been established [56]. In hypoxemic patients with both intrapulmonary vasodilatation and intrinsic cardiopulmonary disease, the technetium-labeled macroaggregated albumin scan (MAA scan) may be useful in defining the contribution of HPS to gas exchange abnormalities. In this test, radiolabeled aggregates of albumin measuring approximately 20 mm in diameter are infused into the venous system. Ordinarily, particles of this size become trapped in the pulmonary microvasculature, and scintigraphy reveals nearly complete uptake in the lungs. In the presence of significant intrapulmonary shunting, a fraction of the macroaggregated albumin passes through the lungs and into the systemic circulation. Scintigraphy then also reveals uptake in other organs in addition to the lung, allowing the calculation of the shunt fraction. In one study, the MAA scan was positive only in patients who had HPS and a PaO2 less than 60 mm Hg and not in patients who had COPD with a similar degree of hypoxemia [8]. The MAA scan, however, is less sensitive than contrast echocardiogram and may be most useful in defining if HPS contributes to hypoxemia in patients with concomitant obstructive pulmonary disease.
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Pulmonary angiography is expensive and invasive and has a low sensitivity for detecting intrapulmonary vasodilatation. Therefore, it is not used routinely to diagnose HPS. High-resolution chest CT and evaluation of pulmonary blood transit time are newer diagnostic modalities for assessing HPS [57,58]. In one study, the degree of pulmonary microvascular dilatation observed on chest CT correlated with the severity of gas exchange abnormalities in a small cohort of patients with HPS, suggesting that quantitation of intrapulmonary vasodilatation was possible. In another study, pulmonary transit time of erythrocytes, measured by echocardiographic analysis of human serum albumin-air microbubble complexes through the heart, also correlated with gas exchange abnormalities in a small group of patients with HPS. The utility of these techniques in evaluating HPS remains to be defined.
Treatment No clearly effective medical therapy for HPS is available. Somatostatin, almitrine, indomethacin, and plasma exchange have been tried without success in small uncontrolled reports [15]. Aspirin increased arterial oxygenation in two children who had HPS [59], and a case report [60] and subsequent open label trial [61] using garlic also suggested a beneficial effect. In the latter trial, garlic powder was administered for a minimum of 6 months. Six of 15 (40%) patients who had HPS had improvements greater than 10 mm Hg in the PaO2, and one subject had resolution of hypoxemia (PaO2: 46 mm Hg to 80 mm Hg) over a 1.5-year period. Acute infusion of methylene blue, a dye that inhibits the effect of NO on soluble guanylate cyclase, also transiently improved oxygenation in two reports comprising a total of eight patients [25,27]. In addition, acute administration of inhaled L-NAME, to inhibit nitric oxide production, also transiently improved oxygenation in one patient [26]. Finally, a single case report suggests that norfloxacin also may have contributed to improvement in oxygen saturation in HPS [62]. These reports underscore the need to evaluate agents targeted at likely pathogenetic mechanisms in randomized multi-center trials to determine efficacy. Seven case reports have evaluated the effects of transjugular intrahepatic portosystemic shunt (TIPS) on HPS in cirrhosis. Six have found a degree of improvement in oxygenation. Short duration of follow-up in two [63] and the presence of coexistent hepatic hydrothorax in another [64], however, limit evaluation of the utility of TIPS in these cases. In a fourth report, arterial oxygenation clearly improved by 20 mm Hg 6 months after TIPS placement [65]. Significant intrapulmonary shunting, however, persisted based on radionuclide lung perfusion scanning, and the cardiac output increased after TIPS. These findings suggest that improved oxygenation may not have been caused by reversal of intrapulmonary vasodilatation. Two other reports have been reported. One was in an 11-year-old girl who had biliary atresia where oxygenation and intrapulmonary shunting were improved and sustained over 8 months [66]. The
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other was in a 46-year-old woman with presumed alcohol-related cirrhosis where oxygenation and shunting improved and were sustained over 3 years [67] after TIPS placement. There is a seventh report of failure of TIPS to improve oxygenation in one patient and identification of two patients where HPS developed in the setting of a functioning TIPS [68]. Together, these findings document the considerable uncertainty regarding the utility of TIPS for HPS. TIPS should be considered an experimental treatment, and its use should be confined to the setting of clinical trials so that efficacy may be judged. Liver transplantation is the only established effective therapy for HPS based upon the total resolution or significant improvement in gas exchange postoperatively in more than 85% of reported patients [69]. The length of time for arterial hypoxemia to normalize after transplantation, however, varies and may be more than 1 year [70]. In addition, mortality is increased after transplantation in patients who have HPS compared with subjects who do not have HPS [51,69], and unique postoperative complications, including pulmonary hypertension [71], cerebral embolic hemorrhages [72], and immediate postoperative deoxygenation requiring prolonged mechanical ventilation [73] have been reported. Innovative approaches such as frequent body positioning [74] or inhaled NO [75,76] have been used to improve postoperative gas exchange. Further investigation focused on the peri-operative medical management of HPS patients is needed to optimize survival.
Summary HPS occurs when pulmonary microvascular dilatation impairs arterial oxygenation in the setting of liver disease or portal hypertension. The syndrome is found in as many as 20% of cirrhotics and should be considered in any patient with chronic liver disease who develops dyspnea or hypoxemia. Recognition is important, because the presence of HPS increases mortality in the setting of cirrhosis. Contrast echocardiography and standard cardiopulmonary testing are generally sufficient to make the diagnosis of HPS, but further testing may be needed in patients who have both intrinsic cardiopulmonary disease and intrapulmonary vasodilatation. Treatment consists of supplemental oxygen and consideration of orthotopic liver transplantation if significant hypoxemia is present. The recognition in experimental models that a sequence of molecular alterations leads to endothelin-1 and TNF-a modulation of pulmonary microvascular tone may lead to the development of novel and effective medical therapies.
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