肝肺综合征

Revie on Mi 290 and clinical features, and to provide guidelines for diag- studies emphasized that the exclusion of all other causes A fundamental question regarding pathogenesis in in the lung are similar to those involved in the system- ic and splanchnic alterations in the hyperdynamic cir- HPS has also been recognized in patients with portal hypertension in the absence of cirrhosis (portal vein thrombosis, nodular regenerative hyperplasia, iver. Published by Elsevier B.V. All rights reserved. Available online 25 July 2006 * Corresponding author. Tel.: +1 205 957 9698; fax: +1 205 975 9777. E-mail address: mfallon@uab.edu (M.B. Fallon). Journal of Hepatology 45 ( 0168-8278/$32.00 � 2006 European Association for the Study of the L 2. Definition HPS is classically defined by a widened alveolar-arte- rial oxygen gradient (AaPO2) on room air (>15 mmHg, or >20 mmHg in patients >64 years of age) with or with- out hypoxemia resulting from intrapulmonary vasodila- culatory state of cirrhosis. HPS is found most commonly in the setting of cirrhosis and appears to occur across the spectrum of etiologies of liver disease [5,11,12]. However, whether the presence or severity of intrapulmonary vasodilatation and HPS correlate with the severity of underlying liver disease is controversial and studies have found HPS more commonly in both less and more advanced cirrhosis [5,11–14]. Recently, nosis and treatment. HPS is whether the mechanisms of vascular alterations 1. Background Respiratory symptoms are exceedingly common in patients who have chronic liver disease with estimates ranging as high as 50–70% of patients complaining of shortness of breath [1]. The differential diagnosis of dyspnea is extensive in such patients and numerous causes should be considered. Over the last 15 years, pul- monary vascular abnormalities have been increasingly recognized as important clinical entities that influence survival and liver transplant candidacy in affected patients. The most common such abnormality, the hep- atopulmonary syndrome (HPS), occurs when intrapul- monary vasodilatation impairs arterial oxygenation. This syndrome is now recognized as many as 15–20% of patients undergoing evaluation for orthotopic liver transplantation (OLT) [2]. The presence of HPS increas- es mortality in the setting of cirrhosis and may influence the frequency and severity of complications of portal hypertension [3]. The purpose of this review is to pro- vide an update on HPS, including the pathophysiology The hepatopulm David T. Palma, University of Alabama at Birmingham Liver Center, MCLM doi:10.1016/j.jhep.2006.07.002 of cardiopulmonary dysfunction was required to estab- lish the diagnosis of HPS [7]. However, it is now evident that HPS may coexist with other cardiopulmonary abnormalities [8,9] and contribute significantly to gas exchange abnormalities in this setting. In addition, the AaPO2 normally increases with age and varies signifi- cantly even in healthy adults. Therefore, using values above the 95% confidence interval for the age-corrected AaPO2 is appropriate to avoid over-diagnosis of HPS [10]. 3. Pathophysiology 3.1. Mechanisms in humans w ary syndrome chael B. Fallon* , 1918, University Boulevard, Birmingham, AL 35294, USA tation in the presence of hepatic dysfunction or portal hypertension [4–7]. From a practical vantage point, identifying patients with PaO2 <70 mmHg is useful for recognizing those with clinically significant HPS. Early www.elsevier.com/locate/jhep 2006) 617–625 congenital hepatic fibrosis and Budd–Chiari syn- drome) [15–18] and has been reported in the setting of acute and chronic hepatitis in the absence of portal hypertension [19,20]. These findings support that advanced liver disease is not required for HPS to develop and that the pathophysiologic events occur- ring in the pulmonary microvasculature of patients with HPS are unique relative to the systemic and splanchnic circulations. The pathogenetic hallmark of HPS is microvascular dilatation within the pulmonary arterial circulation. These changes may result from decreased pre-capillary arteriolar tone alone or could involve additional mechanisms such as angiogenesis, remodelling, and vasculogenesis, which have been recently suggested [21]. In human HPS, the vasodilatation is assumed to result from excessive vascular production of vasodi- lators, particularly nitric oxide (NO). This has been based on the observation that exhaled NO levels, a measure of pulmonary production, are increased in cirrhotic patients with HPS and normalize after OLT [22–24], as HPS resolves. In addition, a case report revealed that acute inhibition of NO production or action with NG-nitro-L-arginine methyl ester (L- NAME) or cyclic GMP inhibitor methylene blue, respectively, transiently improves HPS [25–27]. However, a recent study found that administration of inhaled L-NAME did not acutely improve intrapul- monary vasodilatation [21], raising the possibility that factors other than NOS-derived NO effects on vascu- lar tone contribute to HPS. The exact mechanisms of increased endogenous NO production and its relationship to the presence of portal hypertension, the hyperdynamic circulation and the degree of liver injury remain uncertain. In addition, whether other mediators such as heme oxygenase- derived carbon monoxide [28] might contribute to intrapulmonary vasodilatation and explain the lack of improvement of HPS with NO inhibition in some patients has not yet been established. 3.2. Mechanisms in experimental HPS Chronic common bile duct ligation (CBDL) in the rat is the only established model that reproduces the physiologic features of human HPS [29,30] (Fig. 1). It is unique among rodent models of cirrhosis and/or portal hypertension in that other commonly used mod- els 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 618 D.T. Palma, M.B. Fallon / Journal of Hepatology 45 (2006) 617–625 Fig. 1. Potential mechanisms and treatments in experimental HPS (see text for details). and result from a gravitational increase in blood flow through dilated vessels in the lung bases [47]. While history and physical examination. Such an evaluation may lead the clinician to consider alternate, more com- al of increase in intravascular macrophage-like cells [32,33]. Subsequent work identified increased pulmonary vascu- lar endothelial nitric oxide synthase (eNOS) as a major source of pulmonary NO production [34–36] and dem- onstrated that the administration of 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 trigger- ing the increase in pulmonary eNOS and the onset of vasodilatation after CBDL [35,38]. This effect may be driven by a shear stress mediated increase in pulmon- ary vascular endothelial endothelin B (ETB) receptor expression which 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 data sup- port 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 [41,42]. As experimental HPS progresses, there is a steady accumulation of intravascular macrophages. These cells transiently produce inducible nitric oxide synthase (iNOS) [36,37] and progressively produce heme oxygen- ase 1 (HO-1) [36,43]. These events contribute to further vasodilatation through production of iNOS-derived NO and HO-1-derived carbon monoxide (CO). Accordingly, HO inhibition improves experimental HPS. In addition, prolonged treatment of CBDL ani- mals beginning at the time of ligation with norfloxacin to inhibit bacterial translocation and tumor necrosis factor-alpha (TNF-a) production decreases macro- phage accumulation and prevents the transient increase in iNOS [44], supporting that TNF-a contributes to macrophage accumulation. Further, pentoxifylline, a non-specific phosphodiesterase inhibitor that increases intracellular cAMP levels and also inhibits TNF-a pro- duction in macrophages [45], given over a similar time frame can prevent the onset or decrease the severity of HPS [46]. Both of these agents initiated at the onset of liver injury influence the development of the hyperdy- namic state and may modify ETB receptor expression and endothelin related signalling events in the pulmon- ary microvasculature. Findings to date in the CBDL model suggest that a sequence of events related in part to increased vascu- lar shear stress and to hepatic ET-1 production may trigger the onset of experimental HPS. The observa- tion that hepatic and plasma ET-1 levels increase within 1 week after CBDL [42] suggests that hepatic ET-1 production and release may occur with relatively modest degrees of bile duct proliferation. The finding that macrophages accumulate in the pulmonary micro- D.T. Palma, M.B. Fallon / Journ vasculature and may be influenced by TNF-a inhibi- mon diagnoses such as COPD, CHF or myocardial ischemia. However, if the common causes of dyspnea can be excluded, and particularly if platypnea or digital clubbing is present, further evaluation for HPS is orthodeoxia has been observed in a variety of condi- tions, including post-pneumonectomy, recurrent pul- monary thromboemboli, and atrial septal defects (such as patent foramen ovale), it is highly specific for HPS in the setting of liver disease [48]. The sen- sitivity of orthodeoxia for HPS is relatively low, but increases in cases of severe HPS [49,50]. Cough is not a common finding in HPS. Spider angiomata are commonly reported in HPS but are frequently seen in cirrhotic patients without HPS. One study observed that patients with these cutaneous lesions had more pulmonary vasodilatation and higher alve- olar-arterial oxygen gradients than those without vas- cular spiders (AaPO2: 20 mmHg versus 8 mmHg) [51]. Finally, clubbing and distal cyanosis, when present in the setting of liver disease or portal hypertension, should raise suspicion for HPS [2]. 5. Diagnosis The diagnostic features of HPS include evidence of liver disease or portal hypertension, an elevated age-ad- justed alveolar-arterial oxygen gradient (AaPO2), and evidence of intrapulmonary vasodilatation. In the pres- ence of coexisting cardiac or pulmonary disease, estab- lishing a diagnosis of HPS can be difficult. Fig. 2 presents an algorithm for the diagnosis of HPS. A logi- cal evaluation of dyspnea in the patient with liver dis- ease or portal hypertension begins with a careful tion supports that these cells may also contribute to vasodilatation. Fig. 1 includes potential therapeutic targets for treatment in HPS based on experimental data. 4. Clinical manifestations 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 com- plaint but is non-specific. Platypnea (shortness of breath exacerbated by sitting up and improved by lying supine) and orthodeoxia (hypoxemia exacerbat- ed in the upright position) are classically described Hepatology 45 (2006) 617–625 619 warranted. iver al Hy Dy w pul y, Exa tests FT's, shun art b rdiac ails). 620 D.T. Palma, M.B. Fallon / Journal of Hepatology 45 (2006) 617–625 5.1. Assessment of arterial oxygenation In patients with liver disease found to have dyspnea L Port Lo Histor Other (P Elevated A-a gradient Hypoxemia Low suspicion of intrinsic cardiopulmonary disease Contrast echocardiogram Normal Early (< 3 he Delayed shunting (>3 heart beats) No HPS HPS Intraca Fig. 2. Diagnosis of HPS (see text for det or clubbing, or in those undergoing transplant evalua- tion, pulse oximetry is a simple, non-invasive screening test for hypoxemia and a decreased SpO2 should lead to arterial blood gas (ABG) analysis. However, caution must be exercised in interpreting a ‘‘normal’’ SpO2 as pulse oximetry may overestimate SaO2 in nearly one- half of patients with cirrhosis [52]. 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 strongly suspected based on histo- ry and physical exam, arterial blood gas analysis should be performed while breathing room air regardless of pulse oximetry. In HPS, ABGs reveal an elevated age-adjusted AaPO2 with or without hypoxemia. The expected upper limit of normal for room-air AaPO2 at a given age (>95% confidence interval) can be calculated using the following equation: AaPO2 = [0.26 age � 0.43] + 10 [10]. If gas exchange abnormalities are detected, chest radiography and pulmonary function tests are per- formed to evaluate for the presence of other pulmonary abnormalities. Since cardiopulmonary disorders unrelated to liver disease or those related to ascites are more common than HPS, treating these abnormal- ities prior to further evaluation for HPS is reasonable in the absence of significant hypoxemia (PaO2 <70 mmHg). The ERS Task Force has proposed a classification system that uses arterial oxygen tension (PaO2) to stage the severity of HPS. According to this system, a Disease pertension spnea se oximetry m, CXR, ABG, as appropriate Chest CT) Suspect intrinsic cardiopulmonary disease Treat as appropriate Symptoms persist Contrast echocardiogramting eats) MAA if delayed shunting shunt [This figure appears in colour on the web.] PaO2 <50 mmHg indicates very severe HPS, a PaO2P50 and <60 mmHg suggests severe HPS, and a PaO2P60 and <80 mmHg corresponds with moderate HPS [4]. Staging the severity of HPS is important as a means of predicting survival [13,53], and determining the timing and risks of orthotopic liver transplantation [3,6,53]. 5.2. Contrast echocardiography If hepatopulmonary syndrome is suspected, trans- thoracic microbubble contrast echocardiography is the preferred screening test for intrapulmonary vasodi- latation [12]. Contrast echocardiography is performed by injecting agitated saline intravenously during nor- mal transthoracic echocardiography, producing micro- bubbles that are visualized by sonography. This bolus opacifies the right ventricle within seconds and in the absence of right-to-left shunting, bubbles are absorbed in the lungs. If an intra-cardiac shunt is present, con- trast agent enters the left ventricle within three heart beats (early shunting). If intrapulmonary shunting characteristic of hepatopulmonary syndrome is pres- ent, the left ventricle opacifies at least three heart beats after the right (delayed shunting). While up to 40% of patients with cirrhosis have a positive contrast echocardiogram [12], only a subset of these patients whom 27 (24%) had HPS [3]. The median survival among patients with HPS was significantly shorter al of have sufficient vasodilatation to cause abnormal gas exchange and fulfill criteria for hepatopulmonary syn- drome. If a patient with liver disease or portal hyper- tension and hypoxemia has a positive contrast echocardiogram in the absence of significant cardio- pulmonary disease, the diagnosis of hepatopulmonary syndrome has been established. A semi-quantitative scoring system for assessing intrapulmonary shunting during contrast echocardiography has been developed, though it remains unclear whether the degree of shunting correlates with the degree of gas exchange abnormalities [54]. 5.3. Macroaggregated albumin scan 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 contribu- tion of HPS to gas exchange abnormalities. In this test, radiolabeled aggregates of albumin measuring approximately 20 lm 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 intrapulmo- nary shunting, a fraction of the macroaggregated albumin passes through the lungs and into the sys- temic circulation. Scintigraphy then also reveals uptake in other organs in addition to the lung, allow- ing the calculation of the shunt fraction. In one study, the MAA scan was positive only in patients with HPS and a PaO2 <60 mmHg and not in COPD patients with a similar degree of hypoxemia [8]. How- ever, the MAA scan is less sensitive than contrast echocardiogram and may be most useful in determin- ing whether HPS contributes to hypoxemia in patients with concomitant obstructive pulmonary disease. 5.4. Pulmonary function studies While abnormal pulmonary function studies are fre- quently observed in HPS, these findings are of low specificity [55]. In the absence of concomitant obstruc- tive or restrictive lung disease, measurements of total lung capacity and expiratory flow rates in HPS patients are generally normal. Diffusion impairment is commonly seen in HPS [55]. In one study, the dif- fusing capacity for carbon monoxide (DLCO) was less than 80% of the predicted value in 15 of 18 patients with HPS [49]. However, the presence of decreased DLCO with normal spirometry is not specific for HPS, and is routinely observed in patients with early interstitial lung disease, vasooclusive disease, and pro- D.T. Palma, M.B. Fallon / Journ found anemia [56]. (10.6 months) compared to patients without HPS (40.8 months). Mortality remained higher in those with HPS after adjusting for severity of underlying liv- er disease and after excluding patients who underwent liver transplantation during follow-up. The causes of death in patients with HPS were mainly due to com- plications of hepatocellular dysfunction and portal hypertension and correlated with the severity of hyp- oxemia in HPS. These data raises the possibility that the presence of HPS may be an important factor that influences the progression of liver disease and the risk of complications related to portal hypertension. Final- ly, even modest hypoxemia related to HPS may wors- en during sleep based on the observation that nocturnal oxygen saturation decreased in a small cohort of non-HPS cirrhotic patients [61]. Mortality after liver transplantation also appears to be higher in patients with HPS compared to those without HPS. The utility of the severity of HPS as a predictor of outcome after liver transplantation has been prospectively evaluated in a cohort of 24 patients 5.5. Other diagnostic techniques Pulmonary angiography is expensive and invasive and has a low sensitivity for detecting intrapulmonary vasodilatation. Therefore, it is not routinely utilized in the diagnosis of HPS. High-resolution chest computer- ized tomography (CT) and evaluation of pulmonary blood transit time are newer diagnostic modalities for assessing HPS. In one study, the degree of pul- monary 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 [57]. In another study, pul- monary 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 [58]. Whether these tech- niques have diagnostic utility for HPS remains to be determined. 6. Natural history and prognosis The natural history of hepatopulmonary syndrome is incompletely characterized. Most patients appear to develop progressive intrapulmonary va