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Hepatopulmonary syndrome: role of nitric oxide and clinical aspects
Digestive and Liver Disease 36 (2004) 303–308
Clinical Review
Hepatopulmonary syndrome: role of nitric oxide and clinical aspects G. Rolla∗ Allergology and Clinical Immunology, Department of Human Oncology, University of Torino, Mauriziano Umberto I Hospital, Largo Turati 62, Turin 10128, Italy Received 22 October 2003; accepted 11 December 2003
Abstract Hepatopulmonary syndrome is defined by oxygenation impairment due to abnormal intra pulmonary vascular dilatations in patients with liver disease. The implication of enhanced pulmonary production of nitric oxide in the pathogenesis of intrapulmonary vascular dilatations has been demonstrated both in murine models and in human hepatopulmonary syndrome. The diagnosis of hepatopulmonary syndrome in chronic liver disease is of paramount importance, considering the fact that severe hypoxemia related to hepatopulmonary syndrome may occur in patients with well compensated liver disease and that survival is reduced in patients with hepatopulmonary syndrome relative to non hepatopulmonary syndrome patients. Priority for liver transplantation, which is presently the only cure, has been recently increased in patients with advanced hepatopulmonary syndrome. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Hepatopulmonary syndrome; Nitric oxide
1. Introduction The term hepatopulmonary syndrome (HPS) was first proposed by Kennedy and Knudson [1] to describe cyanosis which developed 4 years after surgical porto-caval shunt in a patient with liver cirrhosis. The term is now used to indicate abnormal oxygenation (at least alveolar-arterial oxygen gradient, AaDO2 higher than 20 mmHg) due to intrapulmonary vascular dilatations (IPVD) in a patient with hepatic disease, most commonly liver cirrhosis. It is well known that hypoxemia may be associated with liver disease in the absence of cardiac or pulmonary disease. Right-to-left intrapulmonary shunting [2], alveolar capillary diffusion limitation [3], or alveolar ventilation-perfusion (VA/Q) mismatch [4,5] have been the physiopathologic mechanisms to which hypoxemia of liver cirrhosis has been variously attributed. The frequency of oxygenation abnormalities has not been established in the cirrhotic population as a whole, while severe hypoxemia (PaO2 < 60 mmHg) is found in 5–7% of the patients who are referred for liver transplantation [6]. Moreover, mild abnormalities of pulmonary gas exchange are quite common in patients with severe liver disease. A widened alveolar-arterial oxygen ∗
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gradient has been reported in up to 70% of the patients undergoing pre-transplant assessment of pulmonary function [7,8]. There is an increasing evidence that the abnormal gas exchange in cirrhotic patients is due to IPVD [9]. Marked pre-capillary pulmonary vasodilation with pleural spider nevi has been the most prominent post-mortem finding [10,11], while true anatomic shunts have been observed only in few cases [12]. IPVD may lead to impaired oxygen exchange as a result of an increase in O2 diffusion distance across the dilated pulmonary capillaries (diameter ranging from 15 to 500 m, compared to the diameter ranging from 8 to 15 m of normal capillaries) and a decreased transit time of blood through the pulmonary circulation due to hyperdynamic circulation (the so-called diffusion–perfusion defect) [9]. Moreover, as a result of vasodilation, there is excess perfusion (Q) in relation to ventilation (V) that is most marked in the low V/Q units of the basal regions of the lung [13]. 2. Nitric oxide (NO) theory Vallance and Moncada [14] postulated that an increased production of NO may account for the hyperdynamic circulation of liver cirrhosis. Actually serum levels of stable NO metabolites (NO2 − /NO3 − ) have been found to be elevated in cirrhosis [15], particularly in biliary cirrhosis [16]. The
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increased levels of circulating NO metabolites have been related to the elevated concentration of endotoxin [17]. The potential causes for systemic endotoxemia in cirrhosis are many, including decreased clearance function of the liver, increased gut permeability and small intestinal bacterial overgrowth, which is associated with bacterial translocation [18]. Exposure to bacteria and their endotoxins, directly or involving cytokines, such as TNF␣, has been associated with increased synthesis of NO [17,19]. NO is synthesised by different isoforms of NO synthase (NOS). Two such isoforms have been investigated extensively in the vasculature [20]. NOS2 or inducible NO synthase (iNOS) is induced by LPS, endotoxins and inflammatory cytokines, and produces large amounts of NO for extended periods of time and NOS3, or endothelial NO synthase (eNOS), which releases NO for short periods, in response to physical stimuli such as flow or pressure induced shear stress. Recent investigations have shown that eNOS is the major enzymatic source for NO overproduction in splanchnic circulation of portal hypertensive rats [21,22]. It is interesting to note that endotoxin and TNF␣, which are well known stimulators of iNOS, can directly increase the activity of eNOS [23]. Supporting the important role of endotoxin and bacteria in promoting vasodilation through NO overproduction is the anedoctical report of improved oxygenation in HPS following antibiotic
treatment [24]. In a recent double-blind placebo controlled study, selective intestinal decontamination with norfloxacin partially reverses the hyperdynamic circulatory state in 14 patients with alcohol-related cirrhosis [25]. Moreover, in a rat model of HPS, Rabiller et al. [26] reported that prophylactic treatment with norfloxacin decreased the incidence of Gram-negative bacterial translocation, the number of macrophages sequestered in pulmonary microvessels, the expression and activity of lung iNOS, and the severity of HPS. In a similar rat model of liver cirrhosis, obtained by ligation of common bile duct, Fallon et al. [27] found overactivity of eNOS in endothelial cells of lung vasculature, possibly due to stimulation of endothelin-1 (ET-1) B type receptors by increased circulating levels of ET-1 [28]. The model implies that HPS develops when both portal hypertension and liver damage coexist, the first by promoting overexpression of ET-B receptors in the lung vaculature, the second by increasing liver and circulating ET-1 levels [29]. While ET-A receptors, which are present in vascular smooth muscle cells, mediate vascoconstriction and proliferation, the ET-B receptor, which is found in endothelium and smooth muscle cells, mediates endothelium dependent vasodilation through the release of NO. Actually, increased plasma ET-1 levels have been reported in patients with liver cirrhosis, both with and without HPS [30,31] (Fig. 1).
Fig. 1. Increased production of NO in the alveolar region in hepatopulmonary syndrome. iNOS of alveolar macrophages is upregulated by LPS of bacteria translocated from the intestine. Constitutive form of eNOS is continuously activated through type B receptor of ET-1, overexpressed on pulmonary capillaries, and stimulated by increased levels of circulating ET-1 (see text for explanation).
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3. Exhaled NO An increased NO output in exhaled air has been reported in patients with advanced cirrhosis, in whom exhaled NO was positively correlated to cardiac index [32]. Exhaled NO was reported to be raised almost threefold in three patients with HPS, compared with normal volunteers and with normoxemic cirrhotic patients [33]. In a study of 45 cirrhotic patients, exhaled NO output and serum NO2 − /NO3 − have been shown to be significantly higher than in normal controls and in all the patients a significant correlation between exhaled NO and alveolar-arterial oxygen gradient was found [34]. In the same study, the nine patients who met the criteria for the diagnosis of HPS also had the highest values of exhaled NO. By using the technique of multiple flow analysis of NO output, Delclaux et al. [35] have recently demonstrated that the increased levels of exhaled NO reported in cirrhosis is of alveolar origin and it was correlated with AaDO2. These observations reinforce the hypothesis that NO locally produced in the lung may play an important role in determining oxygenation abnormalities in patients with cirrhosis. A few clinical studies have investigated the relationship between changes in NO produced in the lung and changes in oxygenation abnormalities in liver cirrhosis. In one case of severe HPS, Rolla et al. [36] reported that i.v. methylene blue (a dye that inhibits the effect of NO on soluble guanylate cyclase thereby preventing the cascade of events leading to vasodilation) acutely improved oxygenation, through a marked decrease in pulmonary shunting. The observation was confirmed by Schenk et al. [37], who showed that i.v. methylene blue improved hypoxemia and hyperdynamic circulation in seven patients with liver cirrhosis and severe HPS. A significant correlation between the decrease in exhaled NO after liver transplantation and the improvement in oxygenation has been reported in 18 patients with cirrhosis who did not have obvious cardio-respiratory diseases [38]. Five of these patients met the criteria for the diagnosis of HPS before transplantation and the syndrome was cured by transplantation. The correlation between the decrease in exhaled NO after liver transplantation and the improvement in oxygenation reinforces the hypothesis that NO is an important mediator of impaired oxygenation in patients with cirrhosis. Very recently, in a case of HPS associated with HCV related cirrhosis, nebulised NG -nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthesis, acutely improved oxygenation, because of a decrease of IPVD, as evaluated by contrast-enhanced echocardiogram [39]. In conclusion, many clinical observations support the theory that NO plays a major role in oxygenation abnormalities of patients with liver cirrhosis, complicated by HPS. Alveolar NO concentration might be used to assess the development and the severity of HPS. However, the enthusiasm for inhibiting NO as therapeutical strategy in HPS has been mitigated by the observation of Carter et al. [40], who showed that the vasodilatory action of NO alone did not completely account for the abnormal vasoreactivity of cir-
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rhotic rat lungs. There is evidence that NO can induce heme oxygenase-1 (HO-1) expression [41] and HO-1 derived CO may contribute significantly to pulmonary vasodilation [42]. A partial reversal of HPS was obtained by inhibiting HO-1 in rats with HPS induced by common bile duct ligation [43]. These observations suggest that the development of HPS is a multifactorial process, involving not only NO, but, at least, also HO-1 and carbon monoxide [44].
4. Clinical findings HPS has been reported with many hepatic diseases and even in patients with pre-hepatic portal hypertension [45]. There is no clear relationship between the severity of liver disease and the severity of hypoxia [46]. Dyspnoea, particularly on exertion, is the most prevalent symptom in patients with HPS. Obviously, it is not a specific symptom, since anaemia, ascites, right pleural effusion are the most common clinical explanations for dyspnoea in cirrhotic patients. Sometimes patients with HPS report that dyspnoea is worse when they assume the erect position and it is alleviated by the supine position (platypnoea). Cyanosis and clubbing of the fingers may be present in the most severe cases. Spider nevi are commonly reported in high number. In some patients cyanosis appears only in upright position (orthodeoxia). Occasionally stroke or brain abscess complication may be the complaint of patients with HPS [24,47]. These lesions are thought to be directly due to the pulmonary vascular dilatations that allow for the unopposed passage of emboli or microorganisms to the systemic circulation.
5. Diagnosis Arterial blood gas analysis, obtained in seated upright position, should be the starting test when HPS is suspected. A PaO2 value ≤65 mmHg may be considered a good cut-off value for evaluating the presence of IPVD in patients with hepatic disease [48]. In these patients arterial PaO2 should also be measured during 100% oxygen breathing to assess the amount of right-to-left shunt. A normal response to 100% O2 breathing is defined by a value of PaO2 > 500 mmHg. IPVD may be easily identified by contrast enhanced echocardiography [6]. Microbubbles (mean diameter 35 m), which are simply obtained by shaking normal saline, are the mostly used contrast. When injected in a peripheral vein, microbubbles appear normally in the right heart chambers and after 4–6 beats, they appear also in the left heart chambers if there are IPVD or anatomical shunts (Fig. 2). An earlier appearance of contrast in the left heart chambers is indicative of intracardiac right-to-left shunt. IPVDs may also be identified by lung scintigraphic perfusion scanning with 99m Tc albumin macroaggregates (diameter 20–80 m), which normally are trapped in the pulmonary circulation but, in the case of right-to-left shunt or IPVD, abnormal uptake of 99m Tc can
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Fig. 2. Contrast-enhanced echocardiography in HPS. (A) Microbubble opacification of right heart chamber after i.v. injection of agitated saline. (B) Delayed (4–6 beats) microbubble opacification of left heart cavities in the same patient.
be observed in other organs such as the brain or the spleen. Fractional brain uptake of radioisotope has been found to be related to hypoxemia [49]. The method cannot discriminate between intracardiac and intrapulmonary shunting. IPVD are the most common pathological abnormalities which explain oxygenation impairment in HPS. In case of severe hypoxemia, which is not responsive to 100% oxygen breathing, arterio-venous shunts should be considered and spiral CT scan of the chest should be performed [50]. Pulmonary angiography study in patients with HPS [9] may reveal two angiographic patterns, the type I or diffuse pattern and the type II or focal pattern. The “minimal” type I pattern is characterised by normal vessels or finely diffused spidery vascular abnormalities during the arterial phase. The “advanced” type I pattern is seen as a diffused spongy or blotchy appearance. The type II pattern, which is rare, consists of focal arterio-venous malformations similar to those seen in hereditary haemorrhagic telangiectasia. Patients with “advanced” type I and type II pattern should be considered for embolisation.
7. Therapeutic options Several medical treatments have been used in single cases or small series of patients with HPS and with no clear advantage. Theoretically, the most promising treatments should be targeted to decrease NO effect (e.g. methylene blue) or its production. Inhibitors of NO synthesis, ET-B receptors antagonists and antibiotics to decrease bacterial translocation and endotoxemia might be useful in HPS treatment, but this remains to be studied by randomised, placebo-controlled studies. Other therapeutic strategies have been directed to decrease portal hypertension, which is an important pathophysiological component of HPS. While pharmacological treatments such as beta-adrenergic receptor blockers and nitrates have not been shown to be useful, transjugular portosystemic shunting (TIPS) has been reported to improve oxygenation in some patients with HPS [53], but not in all [54].
8. Liver transplantation 6. Natural history and prognosis Current studies demonstrate that as many as 40% of the patients with cirrhosis have echocardiographic evidence of intrapulmonary vasodilatation, which produces oxygenation impairment in 10–15% of them. The natural course of mild oxygenation abnormalities due to IPVD is not presently known. Once PaO2 is lower than 50 mmHg the prognosis is poor, with 1 year survival rates between 16 and 38% [51]. Recently, Schenk et al. [52] have published a prospective study investigating the prognostic significance of HPS in 111 patients with cirrhosis. Twenty seven patients (24%) had HPS and their mortality was significantly higher (median survival, 10.6 months) compared to patients without HPS (40.8 months) even after being adjusted for liver disease severity. The presence of HPS independently worsens prognosis of patients with cirrhosis. This should accelerate the evaluation process for liver transplantation.
In the past, HPS was considered a contraindication for liver transplantation when severe hypoxemia was present, because of an expected high post-operative mortality and because of the lack of information about long-term outcome. Several case reports and case series have subsequently demonstrated that even severe hypoxemia could reverse after LT, although the improvement in oxygenation may take several months or even years. The lower the pre-operative PaO2 , the longer the time to reverse hypoxaemia. HPS is presently considered as an indication for LT per se, whatever the severity of the underlying liver disease [55] may be. LT is the only possible cure for HPS. The perioperative mortality rate ranges from 9 to 16%, with 1 year mortality rate of 26% [56]. Improvement of oxygenation has generally been observed in the majority of patients who survived the perioperative period, even in the most severe cases. Severe hypoxemia, poor 100% oxygen response, high shunt fraction have been reported to be strong risk factors for increased post-liver transplantation mortality [55,57],
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although in a recent case series none of the above factors were associated with a significant excess of mortality [56,58]. This supports the newly implemented United Network for Organ Sharing (UNOS) criteria that LT for HPS may be extended to include patients with PaO2 < 60 mmHg [59]. Conflict of interest statement None declared.
List of abbreviations AaDO2 , alveolar-arterial oxygen gradient; eNOS, endothelial NO synthase; ET-1, endothelin-1; HO-1, heme oxygenase-1; HPS, hepatopulmonary syndrome; iNOS, inducible NO synthase; IPVD, intrapulmonary vascular dilatation; LT, liver transplantation; NO, nitric oxide.
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Clinical Review
Hepatopulmonary syndrome: role of nitric oxide and clinical aspects G. Rolla∗ Allergology and Clinical Immunology, Department of Human Oncology, University of Torino, Mauriziano Umberto I Hospital, Largo Turati 62, Turin 10128, Italy Received 22 October 2003; accepted 11 December 2003
Abstract Hepatopulmonary syndrome is defined by oxygenation impairment due to abnormal intra pulmonary vascular dilatations in patients with liver disease. The implication of enhanced pulmonary production of nitric oxide in the pathogenesis of intrapulmonary vascular dilatations has been demonstrated both in murine models and in human hepatopulmonary syndrome. The diagnosis of hepatopulmonary syndrome in chronic liver disease is of paramount importance, considering the fact that severe hypoxemia related to hepatopulmonary syndrome may occur in patients with well compensated liver disease and that survival is reduced in patients with hepatopulmonary syndrome relative to non hepatopulmonary syndrome patients. Priority for liver transplantation, which is presently the only cure, has been recently increased in patients with advanced hepatopulmonary syndrome. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Hepatopulmonary syndrome; Nitric oxide
1. Introduction The term hepatopulmonary syndrome (HPS) was first proposed by Kennedy and Knudson [1] to describe cyanosis which developed 4 years after surgical porto-caval shunt in a patient with liver cirrhosis. The term is now used to indicate abnormal oxygenation (at least alveolar-arterial oxygen gradient, AaDO2 higher than 20 mmHg) due to intrapulmonary vascular dilatations (IPVD) in a patient with hepatic disease, most commonly liver cirrhosis. It is well known that hypoxemia may be associated with liver disease in the absence of cardiac or pulmonary disease. Right-to-left intrapulmonary shunting [2], alveolar capillary diffusion limitation [3], or alveolar ventilation-perfusion (VA/Q) mismatch [4,5] have been the physiopathologic mechanisms to which hypoxemia of liver cirrhosis has been variously attributed. The frequency of oxygenation abnormalities has not been established in the cirrhotic population as a whole, while severe hypoxemia (PaO2 < 60 mmHg) is found in 5–7% of the patients who are referred for liver transplantation [6]. Moreover, mild abnormalities of pulmonary gas exchange are quite common in patients with severe liver disease. A widened alveolar-arterial oxygen ∗
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gradient has been reported in up to 70% of the patients undergoing pre-transplant assessment of pulmonary function [7,8]. There is an increasing evidence that the abnormal gas exchange in cirrhotic patients is due to IPVD [9]. Marked pre-capillary pulmonary vasodilation with pleural spider nevi has been the most prominent post-mortem finding [10,11], while true anatomic shunts have been observed only in few cases [12]. IPVD may lead to impaired oxygen exchange as a result of an increase in O2 diffusion distance across the dilated pulmonary capillaries (diameter ranging from 15 to 500 m, compared to the diameter ranging from 8 to 15 m of normal capillaries) and a decreased transit time of blood through the pulmonary circulation due to hyperdynamic circulation (the so-called diffusion–perfusion defect) [9]. Moreover, as a result of vasodilation, there is excess perfusion (Q) in relation to ventilation (V) that is most marked in the low V/Q units of the basal regions of the lung [13]. 2. Nitric oxide (NO) theory Vallance and Moncada [14] postulated that an increased production of NO may account for the hyperdynamic circulation of liver cirrhosis. Actually serum levels of stable NO metabolites (NO2 − /NO3 − ) have been found to be elevated in cirrhosis [15], particularly in biliary cirrhosis [16]. The
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increased levels of circulating NO metabolites have been related to the elevated concentration of endotoxin [17]. The potential causes for systemic endotoxemia in cirrhosis are many, including decreased clearance function of the liver, increased gut permeability and small intestinal bacterial overgrowth, which is associated with bacterial translocation [18]. Exposure to bacteria and their endotoxins, directly or involving cytokines, such as TNF␣, has been associated with increased synthesis of NO [17,19]. NO is synthesised by different isoforms of NO synthase (NOS). Two such isoforms have been investigated extensively in the vasculature [20]. NOS2 or inducible NO synthase (iNOS) is induced by LPS, endotoxins and inflammatory cytokines, and produces large amounts of NO for extended periods of time and NOS3, or endothelial NO synthase (eNOS), which releases NO for short periods, in response to physical stimuli such as flow or pressure induced shear stress. Recent investigations have shown that eNOS is the major enzymatic source for NO overproduction in splanchnic circulation of portal hypertensive rats [21,22]. It is interesting to note that endotoxin and TNF␣, which are well known stimulators of iNOS, can directly increase the activity of eNOS [23]. Supporting the important role of endotoxin and bacteria in promoting vasodilation through NO overproduction is the anedoctical report of improved oxygenation in HPS following antibiotic
treatment [24]. In a recent double-blind placebo controlled study, selective intestinal decontamination with norfloxacin partially reverses the hyperdynamic circulatory state in 14 patients with alcohol-related cirrhosis [25]. Moreover, in a rat model of HPS, Rabiller et al. [26] reported that prophylactic treatment with norfloxacin decreased the incidence of Gram-negative bacterial translocation, the number of macrophages sequestered in pulmonary microvessels, the expression and activity of lung iNOS, and the severity of HPS. In a similar rat model of liver cirrhosis, obtained by ligation of common bile duct, Fallon et al. [27] found overactivity of eNOS in endothelial cells of lung vasculature, possibly due to stimulation of endothelin-1 (ET-1) B type receptors by increased circulating levels of ET-1 [28]. The model implies that HPS develops when both portal hypertension and liver damage coexist, the first by promoting overexpression of ET-B receptors in the lung vaculature, the second by increasing liver and circulating ET-1 levels [29]. While ET-A receptors, which are present in vascular smooth muscle cells, mediate vascoconstriction and proliferation, the ET-B receptor, which is found in endothelium and smooth muscle cells, mediates endothelium dependent vasodilation through the release of NO. Actually, increased plasma ET-1 levels have been reported in patients with liver cirrhosis, both with and without HPS [30,31] (Fig. 1).
Fig. 1. Increased production of NO in the alveolar region in hepatopulmonary syndrome. iNOS of alveolar macrophages is upregulated by LPS of bacteria translocated from the intestine. Constitutive form of eNOS is continuously activated through type B receptor of ET-1, overexpressed on pulmonary capillaries, and stimulated by increased levels of circulating ET-1 (see text for explanation).
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3. Exhaled NO An increased NO output in exhaled air has been reported in patients with advanced cirrhosis, in whom exhaled NO was positively correlated to cardiac index [32]. Exhaled NO was reported to be raised almost threefold in three patients with HPS, compared with normal volunteers and with normoxemic cirrhotic patients [33]. In a study of 45 cirrhotic patients, exhaled NO output and serum NO2 − /NO3 − have been shown to be significantly higher than in normal controls and in all the patients a significant correlation between exhaled NO and alveolar-arterial oxygen gradient was found [34]. In the same study, the nine patients who met the criteria for the diagnosis of HPS also had the highest values of exhaled NO. By using the technique of multiple flow analysis of NO output, Delclaux et al. [35] have recently demonstrated that the increased levels of exhaled NO reported in cirrhosis is of alveolar origin and it was correlated with AaDO2. These observations reinforce the hypothesis that NO locally produced in the lung may play an important role in determining oxygenation abnormalities in patients with cirrhosis. A few clinical studies have investigated the relationship between changes in NO produced in the lung and changes in oxygenation abnormalities in liver cirrhosis. In one case of severe HPS, Rolla et al. [36] reported that i.v. methylene blue (a dye that inhibits the effect of NO on soluble guanylate cyclase thereby preventing the cascade of events leading to vasodilation) acutely improved oxygenation, through a marked decrease in pulmonary shunting. The observation was confirmed by Schenk et al. [37], who showed that i.v. methylene blue improved hypoxemia and hyperdynamic circulation in seven patients with liver cirrhosis and severe HPS. A significant correlation between the decrease in exhaled NO after liver transplantation and the improvement in oxygenation has been reported in 18 patients with cirrhosis who did not have obvious cardio-respiratory diseases [38]. Five of these patients met the criteria for the diagnosis of HPS before transplantation and the syndrome was cured by transplantation. The correlation between the decrease in exhaled NO after liver transplantation and the improvement in oxygenation reinforces the hypothesis that NO is an important mediator of impaired oxygenation in patients with cirrhosis. Very recently, in a case of HPS associated with HCV related cirrhosis, nebulised NG -nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthesis, acutely improved oxygenation, because of a decrease of IPVD, as evaluated by contrast-enhanced echocardiogram [39]. In conclusion, many clinical observations support the theory that NO plays a major role in oxygenation abnormalities of patients with liver cirrhosis, complicated by HPS. Alveolar NO concentration might be used to assess the development and the severity of HPS. However, the enthusiasm for inhibiting NO as therapeutical strategy in HPS has been mitigated by the observation of Carter et al. [40], who showed that the vasodilatory action of NO alone did not completely account for the abnormal vasoreactivity of cir-
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rhotic rat lungs. There is evidence that NO can induce heme oxygenase-1 (HO-1) expression [41] and HO-1 derived CO may contribute significantly to pulmonary vasodilation [42]. A partial reversal of HPS was obtained by inhibiting HO-1 in rats with HPS induced by common bile duct ligation [43]. These observations suggest that the development of HPS is a multifactorial process, involving not only NO, but, at least, also HO-1 and carbon monoxide [44].
4. Clinical findings HPS has been reported with many hepatic diseases and even in patients with pre-hepatic portal hypertension [45]. There is no clear relationship between the severity of liver disease and the severity of hypoxia [46]. Dyspnoea, particularly on exertion, is the most prevalent symptom in patients with HPS. Obviously, it is not a specific symptom, since anaemia, ascites, right pleural effusion are the most common clinical explanations for dyspnoea in cirrhotic patients. Sometimes patients with HPS report that dyspnoea is worse when they assume the erect position and it is alleviated by the supine position (platypnoea). Cyanosis and clubbing of the fingers may be present in the most severe cases. Spider nevi are commonly reported in high number. In some patients cyanosis appears only in upright position (orthodeoxia). Occasionally stroke or brain abscess complication may be the complaint of patients with HPS [24,47]. These lesions are thought to be directly due to the pulmonary vascular dilatations that allow for the unopposed passage of emboli or microorganisms to the systemic circulation.
5. Diagnosis Arterial blood gas analysis, obtained in seated upright position, should be the starting test when HPS is suspected. A PaO2 value ≤65 mmHg may be considered a good cut-off value for evaluating the presence of IPVD in patients with hepatic disease [48]. In these patients arterial PaO2 should also be measured during 100% oxygen breathing to assess the amount of right-to-left shunt. A normal response to 100% O2 breathing is defined by a value of PaO2 > 500 mmHg. IPVD may be easily identified by contrast enhanced echocardiography [6]. Microbubbles (mean diameter 35 m), which are simply obtained by shaking normal saline, are the mostly used contrast. When injected in a peripheral vein, microbubbles appear normally in the right heart chambers and after 4–6 beats, they appear also in the left heart chambers if there are IPVD or anatomical shunts (Fig. 2). An earlier appearance of contrast in the left heart chambers is indicative of intracardiac right-to-left shunt. IPVDs may also be identified by lung scintigraphic perfusion scanning with 99m Tc albumin macroaggregates (diameter 20–80 m), which normally are trapped in the pulmonary circulation but, in the case of right-to-left shunt or IPVD, abnormal uptake of 99m Tc can
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Fig. 2. Contrast-enhanced echocardiography in HPS. (A) Microbubble opacification of right heart chamber after i.v. injection of agitated saline. (B) Delayed (4–6 beats) microbubble opacification of left heart cavities in the same patient.
be observed in other organs such as the brain or the spleen. Fractional brain uptake of radioisotope has been found to be related to hypoxemia [49]. The method cannot discriminate between intracardiac and intrapulmonary shunting. IPVD are the most common pathological abnormalities which explain oxygenation impairment in HPS. In case of severe hypoxemia, which is not responsive to 100% oxygen breathing, arterio-venous shunts should be considered and spiral CT scan of the chest should be performed [50]. Pulmonary angiography study in patients with HPS [9] may reveal two angiographic patterns, the type I or diffuse pattern and the type II or focal pattern. The “minimal” type I pattern is characterised by normal vessels or finely diffused spidery vascular abnormalities during the arterial phase. The “advanced” type I pattern is seen as a diffused spongy or blotchy appearance. The type II pattern, which is rare, consists of focal arterio-venous malformations similar to those seen in hereditary haemorrhagic telangiectasia. Patients with “advanced” type I and type II pattern should be considered for embolisation.
7. Therapeutic options Several medical treatments have been used in single cases or small series of patients with HPS and with no clear advantage. Theoretically, the most promising treatments should be targeted to decrease NO effect (e.g. methylene blue) or its production. Inhibitors of NO synthesis, ET-B receptors antagonists and antibiotics to decrease bacterial translocation and endotoxemia might be useful in HPS treatment, but this remains to be studied by randomised, placebo-controlled studies. Other therapeutic strategies have been directed to decrease portal hypertension, which is an important pathophysiological component of HPS. While pharmacological treatments such as beta-adrenergic receptor blockers and nitrates have not been shown to be useful, transjugular portosystemic shunting (TIPS) has been reported to improve oxygenation in some patients with HPS [53], but not in all [54].
8. Liver transplantation 6. Natural history and prognosis Current studies demonstrate that as many as 40% of the patients with cirrhosis have echocardiographic evidence of intrapulmonary vasodilatation, which produces oxygenation impairment in 10–15% of them. The natural course of mild oxygenation abnormalities due to IPVD is not presently known. Once PaO2 is lower than 50 mmHg the prognosis is poor, with 1 year survival rates between 16 and 38% [51]. Recently, Schenk et al. [52] have published a prospective study investigating the prognostic significance of HPS in 111 patients with cirrhosis. Twenty seven patients (24%) had HPS and their mortality was significantly higher (median survival, 10.6 months) compared to patients without HPS (40.8 months) even after being adjusted for liver disease severity. The presence of HPS independently worsens prognosis of patients with cirrhosis. This should accelerate the evaluation process for liver transplantation.
In the past, HPS was considered a contraindication for liver transplantation when severe hypoxemia was present, because of an expected high post-operative mortality and because of the lack of information about long-term outcome. Several case reports and case series have subsequently demonstrated that even severe hypoxemia could reverse after LT, although the improvement in oxygenation may take several months or even years. The lower the pre-operative PaO2 , the longer the time to reverse hypoxaemia. HPS is presently considered as an indication for LT per se, whatever the severity of the underlying liver disease [55] may be. LT is the only possible cure for HPS. The perioperative mortality rate ranges from 9 to 16%, with 1 year mortality rate of 26% [56]. Improvement of oxygenation has generally been observed in the majority of patients who survived the perioperative period, even in the most severe cases. Severe hypoxemia, poor 100% oxygen response, high shunt fraction have been reported to be strong risk factors for increased post-liver transplantation mortality [55,57],
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although in a recent case series none of the above factors were associated with a significant excess of mortality [56,58]. This supports the newly implemented United Network for Organ Sharing (UNOS) criteria that LT for HPS may be extended to include patients with PaO2 < 60 mmHg [59]. Conflict of interest statement None declared.
List of abbreviations AaDO2 , alveolar-arterial oxygen gradient; eNOS, endothelial NO synthase; ET-1, endothelin-1; HO-1, heme oxygenase-1; HPS, hepatopulmonary syndrome; iNOS, inducible NO synthase; IPVD, intrapulmonary vascular dilatation; LT, liver transplantation; NO, nitric oxide.
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