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(Chest. 2002;121:1869-1875.)
© 2002 American College of Chest Physicians

Arterial Oxygenation Associated With Portopulmonary Hypertension*

Karen L. Swanson, DO and Michael J. Krowka, MD, FCCP

* From the Divisions of Pulmonary and Critical Care (Dr. Swanson), and Gastroenterology and Hepatology (Dr. Krowka), Mayo Clinic and Mayo Graduate School of Medicine, Rochester, MN.

Correspondence to: Michael J. Krowka, MD, FCCP, Mayo Clinic E18, 200 First St SW, Rochester, MN 55905; e-mail: krowka{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: To characterize arterial oxygenation in patients referred to Mayo Clinic for liver transplantation with a diagnosis of portopulmonary hypertension (portoPH).

Design: Prospective study.

Setting: Liver transplantation program and pulmonary hypertension clinic in a tertiary referral center.

Participants: Twenty consecutive patients with abnormal pulmonary hemodynamics documented by right-heart catheterization (mean pulmonary artery pressure [MPAP] >= 25 mm Hg, pulmonary vascular resistance [PVR] >= 120 dyne·s·cm-5, and pulmonary capillary wedge pressure [PCWP] <= 15 mm Hg). Liver transplant candidates with normal pulmonary hemodynamics via screening Doppler echocardiography (n = 40) served as control subjects. A subgroup of patients underwent postural and inspired 100% oxygen blood gas analysis, contrast echocardiography, and technetium-labeled macroaggregated albumin (99mTcMAA) lung/brain scanning to identify and quantitate the degree of intracardiac or intrapulmonary shunting.

Measurements and results: portoPH was moderate to severe (MPAP > 35 mm Hg) in 18 of 20 patients (90%). Arterial-alveolar oxygen pressure gradient (P[A-a]O2) was abnormal (>= 20 mm Hg) in 16 of 20 patients (80%). PaO2 was abnormal (<= 70 mm Hg) in 3 of 20 patients (15%). Pa02 was significantly less and P(A-a)O2 was significantly greater compared to control subjects (p < 0.001). All patients had normal 99mTcMAA brain uptake (< 6%) and negative transthoracic contrast echocardiographic findings. No significant correlations were found between oxygenation and hemodynamic variables (MPAP, PVR, PVR index, and transpulmonary gradient).

Conclusions: Arterial oxygenation associated with portoPH was frequently abnormal and significantly worse when compared to patients with normal pulmonary hemodynamics by Doppler echocardiography. Hypoxemia, as measured by PaO2 and P(A-a)O2, was usually mild even in the setting of moderate-to-severe portoPH.

Key Words: liver cirrhosis • lung scanning • portal hypertension • pulmonary hemodynamics • pulmonary hypertension • shunt


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Portopulmonary hypertension (portoPH) is a pulmonary vascular constrictive/obliterative process believed to develop as a consequence of liver disease complicated by portal hypertension.1 The 1998 World Health Organization Consensus Conference on primary pulmonary hypertension recognized portoPH as a cause of pulmonary artery hypertension.2 The diagnosis of portoPH rests on pulmonary hemodynamic criteria obtained via right-heart catheterization, and include the following: (1) increased mean pulmonary artery pressure (MPAP) at rest (>= 25 mm Hg); (2) increased pulmonary vascular resistance (PVR) [>= 120 dyne·s·cm-5]; and (3) normal pulmonary capillary wedge pressure (PCWP) [<= 15 mm Hg].3 4 The increases in pulmonary artery pressure and vascular resistance are thought to develop from endothelial proliferation, vasoconstriction, and vascular occlusion.5 Pathologic findings are indistinguishable from those seen in primary pulmonary hypertension.6 7 Screening for portoPH has been espoused due to the significant cardiopulmonary mortality reported in patients with portoPH following attempted orthotopic liver transplantation (OLT).8 9 10

Arterial hypoxemia is not uncommon in patients with advanced liver disease.11 12 The most dramatic presentation of hypoxemia is due to hepatopulmonary syndrome (HPS), hypoxemia due to diffuse or discrete pulmonary vascular dilatations.11 Remarkably, the pathophysiology that characterizes HPS can resolve following OLT. However, severe hypoxemia (PaO2 < 50 mm Hg) due to HPS has been associated with a 30% mortality within 90 days of OLT.1 The potential relationship between arterial hypoxemia and portoPH has received little attention since portoPH is primarily a clinical problem involving hemodynamics.

We hypothesized that portoPH would be associated with abnormal arterial oxygenation. Thus, the purpose of this study was to determine the frequency and severity of arterial oxygenation abnormalities (as measured by PaO2 and the alveolar-arterial oxygen pressure gradient [P(A-a)O2]), in consecutive patients referred to the Mayo Clinic Liver Transplantation program who satisfied diagnostic criteria for portoPH. Oxygenation correlates with pulmonary hemodynamic variables were studied. A subgroup of portoPH patients underwent additional, specialized assessments that measured PaO2 breathing room air and 100% oxygen in the supine and standing positions and sought to quantify shunting (intracardiac or intrapulmonary) via extrapulmonary (brain) uptake following technetium-labeled macroaggregated albumin (99mTcMAA) lung perfusion scanning.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient Selection and Measurement of Pulmonary Hemodynamics
Since 1996, patients with advanced liver disease meeting minimal listing criteria for liver transplantation at Mayo Clinic have undergone transthoracic, color-flow Doppler screening echocardiography for the purpose of detecting possible pulmonary hypertension and arterial blood gas assessment breathing room air in the sitting position. Patients with right ventricular systolic pressure (RVsys) estimates > 50 mm Hg (determined by measuring tricuspid systolic peak regurgitant flow and applying the modified Bernoulli equation to determine the right atrial-right ventricular pressure gradient) have undergone right-heart catheterization to further characterize the pulmonary hemodynamic profiles if OLT was to be accomplished. Previous data from our institution have shown that patients with screening RVsys < 50 mm Hg by echocardiography rarely have significant pulmonary hemodynamic abnormalities.8 Right-heart catheterization was performed via the femoral or internal jugular vein using the Seldinger technique. Cardiac output was measured in triplicate using the thermodilution technique. Cardiac index was calculated from the cardiac output and body surface area (cardiac output/body surface area). Pulmonary vascular index was calculated from the MPAP, PCWP, and cardiac index by the following equation: ([MPAP - PCWP]/cardiac index) x 80. Mixed venous hemoglobin saturations from the mid-right atrium were documented.

Control data characterizing pulmonary hemodynamics at the time of liver transplantation was obtained via pulmonary artery catheter measurement after the induction of anesthesia from eight patients with hepatopulmonary syndrome (HPS). HPS was defined as: (1) the presence of chronic liver disease, (2) PaO2 < 70 mm Hg or P(A-a)O2 > 20 mm Hg, and (3) intrapulmonary vascular dilatation by contrast echocardiography.1 portoPH was defined by the following criteria1 7 : (1) MPAP >= 25 mm Hg, (2) PVR >= 120 dyne·s·cm-5, and (3) PCWP <= 15 mm Hg.

Arterial Blood Gases
Arterial blood gases were obtained with the patient breathing room air in the sitting position at rest. Patients were in clinically stable condition, and assessments were accomplished as outpatients. As an arterial oxygenation control group, arterial blood gases were analyzed from 40 consecutive liver transplant candidates with normal screening Doppler echocardiographic findings (RVsys < 35 mm Hg). The P(A-a)O2 was calculated from the standard formula using daily barometric pressure measurements and assuming a respiratory quotient of 0.8:

where PAO2 is alveolar oxygen pressure.

Special Studies
Postural Room Air and Inspired 100% Oxygen Arterial Blood Gases:
Ten consecutive portoPH patients underwent an institutional review board-approved protocol to assess postural PaO2 breathing room air, to evaluate PaO2 response to 100% inspired oxygen, and to determine the presence of shunt by measuring brain uptake following lung perfusion scanning. PaO2 measurements were obtained in the following sequence after assuming each position for a minimum of 10 min and maximum of 20 min: supine, breathing room air; standing, breathing room air; supine, breathing 100% oxygen; and standing, breathing 100% oxygen. All patients inspired 100% oxygen for 20 min supine. As a control group with advanced liver disease, but with pulmonary hemodynamics distinct from that seen in patients with portoPH, 10 patients with HPS underwent the same protocol.

Technetium-Labeled Macroaggregated Albumin Lung Perfusion Scans With Brain Uptake:
Technetium-labeled macroaggregated albumin (99mTcMAA) lung and brain scanning was performed to quantitate the degree of intrapulmonary vascular dilatation. Twenty minutes after injection of 2 mCi of 99mTcMAA (Pulmolite; Dupont; Billerica, MA) [90% of the macroaggregated albumin particle size between 10 µm and 90 µm], quantitative brain imaging was performed in the supine position. A brain uptake percentage (assuming a constant 13% blood flow to the brain) was obtained via the following calculation:

where GMT is the geometric mean counts of 99mTcMAA in the brain and lung. Abnormal uptake was defined as >= 6%.

Transthoracic contrast enhanced echocardiography was also performed to detect any component of intracardiac or intrapulmonary shunting. Contrast echocardiograms were considered positive for intrapulmonary vascular dilatations if there was visual evidence of delayed opacification of left-heart chambers (more than three cardiac cycles) after the appearance of microbubbles in the right ventricle with the administration of 10 mL of agitated normal saline solution in the supine position via an upper-extremity peripheral vein. These findings suggested intrapulmonary passage of microbubbles through either dilated precapillary and capillary vessels or direct arteriovenous communications. Immediate opacification within the left atrium (less than three cardiac cycles) suggested an intracardiac shunt.

Statistics
Data were summarized as mean ± 1 SD. Mean comparisons were accomplished by using an unpaired Student t test, with p < 0.05 considered significant. Pearson product linear correlations were used to describe relationships between oxygenation and hemodynamic data.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Arterial Oxygenation
Arterial blood gas and cardiopulmonary hemodynamic data from 20 portoPH patients are shown in Table 1 . A subgroup (n = 7) of patients with increased MPAP, PVR, PVR index [PVRI], and PCWP were also identified, and their data are shown separately. Technically, these patients did not satisfy the specific diagnostic criteria for portoPH (because PCWP was increased), but each had an increased transpulmonary gradient (TPG), strongly suggestive of a pulmonary vascular flow abnormality. The etiology of end-stage liver disease was as follows: autoimmune hepatitis in six patients, hepatitis C virus in six patients, alcoholic cirrhosis in five patients, nonalcoholic steatohepatitis in three patients, cryptogenic cirrhosis in three patients, hepatitis C virus/alcoholic cirrhosis in two patients, Budd-Chiari syndrome in one patient, and granulomatous hepatitis in one patient.


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  		Table 1. Arterial Blood Gas and Pulmonary Hemodynamic Data in Patients With portoPH*

 
Only three of the 20 portoPH patients (15%) had a PaO2 < 70 mm Hg (range 53 to 97 mm Hg), but 16 patients (80%) had P(A-a)O2 > 20 mm Hg. Nine of these patients had never smoked cigarettes (including the three patients with PaO2 values < 70 mm Hg), three patients had quit smoking, and eight patients were current smokers. The PaO2 was not significantly different when never-smokers were compared with current and previous smokers (data not shown). Spirometry was performed in nine patients and showed an FEV (percent predicted) that ranged from 66 to 79% (mean, 72%). None of the patients had large amounts of ascites with hemidiaphragm elevation shown on chest radiography that might have affected gas exchange. Mixed venous hemoglobin saturations obtained at the time of right-heart catheterization (mid-right atrium) ranged from 57 to 82% (mean, 71 ± 6%), and did not correlate with either PaO2 or P(A-a)O2 (r < 0.05). Mixed venous hemoglobin saturations were, however, positively correlated with cardiac index (r = 0.66; Fig 1 ).



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  		Figure 1. Correlation between cardiac index and mixed venous oxygen saturation.

 
Compared to the control group of 40 transplant candidates (Table 2 ), room air PaO2 was significantly worse in the patients with pulmonary hypertension (76 ± 9 mm Hg vs 87 ± 7 mm Hg, p < 0.001). The P(A-a)O2 gradient was significantly greater compared to control subjects (26 ± 11 mm Hg vs 13 ± 8 mm Hg, p < 0.001). PaCO2 was less in patients with portoPH compared to control subjects (33 ± 3 mm Hg vs 36 ± 3 mm Hg, p < 0.01).


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  		Table 2. Mean Arterial Blood Gas Data Between Patients With portoPH and Control Group*

 
Postural Room Air and Inspired 100% Oxygen Arterial Blood Gases
Ten consecutive portoPH patients underwent an institutional review board-approved protocol to assess postural PaO2 (supine vs standing) breathing room air and PaO2 response to 100% inspired oxygen. These patients were compared to a group of patients with HPS (Table 3 ). In the standing position, the portoPH group did not significantly change their PaO2 when compared with their supine position value (p = 0.12). In the standing position breathing 100% oxygen, the PaO2 increased in the portoPH group from 476 to 513 mm Hg (p = 0.05), whereas it decreased significantly in patients with HPS.


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  		Table 3. Mean Postural Room Air and Inspired 100% Oxygen Arterial Blood Gases*

 
99mTcMAA Lung Perfusion Scans With Brain Uptake
Ten patients with portoPH and 9 patients with HPS underwent 99mTcMAA lung and brain scanning to quantitate the degree of intrapulmonary vascular dilatation. Each patient with portoPH had normal brain uptake; each patient with HPS had abnormal brain uptake. Mean brain uptake was significantly less for patients with portoPH compared to the HPS group (2% vs 14%, p < 0.005). All patients with portoPH also had negative contrast echocardiographic findings, while the contrast study finding was positive in each patient with HPS.

Pulmonary Hemodynamics
Table 1 summarizes the pulmonary hemodynamic findings in the study cohort. The range of the PVR was 126 to 818 dyne·s·cm-5; the range of the PVRI was 261 to 1,673 dyne·s·cm-5. The range in MPAP was 25 to 60 mm Hg. Cardiac output ranged from 4.1 to 11.9 L/min; cardiac index varied from 2.6 to 5.4 L/min/m2. There was a positive correlation between cardiac index and mixed venous oxygen saturation (r = 0.66; Fig 1 ). This correlation was similar for cardiac output and mixed venous oxygen saturation (r = 0.62). Poor correlations were found between arterial oxygenation and the severity of pulmonary hypertension as measured by MPAP, PVR, PVRI, and TPG (Fig 2 , 3 ). There was a negative correlation between cardiac output and PVR (r = -0.87) and between cardiac index and PVRI (r = -0.85; Fig 4 ). Subsequently, 9 of 20 patients (45%) began long-term therapy with continuous IV epoprostenol. No patient experienced a decline in PaO2 > 5 mm Hg during long-term epoprostenol administration (range, 3 to 48 months). Seven of the 20 patients died during the follow-up period (Table 1) .



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  		Figure 2. Correlation between PVRI and PO2.

 


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  		Figure 3. Correlation between PVRI and P(A-a)O2 (A-a gradient).

 


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  		Figure 4. Correlation between cardiac index and PVRI.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Pulmonary Hemodynamics
The majority of patients in this prospective study each satisfied the accepted criteria for the diagnosis of portoPH in terms of MPAP, PVR, and PCWP. However, we noted a subgroup of patients (n = 7) with significantly elevated MPAP and PVR (PVRI) associated with a slight-to-moderate increase in the PCWP (range, 16 to 27 mm Hg). Should such a subgroup be classified as portoPH? Indeed each patient had an increased TPG (TPG = MPAP - PCWP), suggesting abnormal pulmonary vascular flow (normal TPG <= 10 mm Hg). Ideally, a repeat right-heart catheterization following diuresis would allow for the most accurate classification of such patients, but that approach was not clinically practical in this study. In view of the marked MPAP and PVR (PVRI) at the time of our study (in the absence of obvious left ventricular dysfunction by clinical or echocardiographic assessment), we presented this as a separate subgroup of patients in our analysis. Quite possibly with diuresis, some of these patients with increased MPAP and PVR (PVRI) would still have satisfied published criteria for portoPH. Further study of this subgroup is warranted, especially if liver transplantation is to be considered.

While PVR (PVRI) is increased in both primary pulmonary hypertension and portoPH, it tends to be somewhat lower in portoPH. This is likely related to the increase in cardiac index seen in portoPH consistent with the hyperdynamic state of liver disease. In contrast, the cardiac index in patients with primary pulmonary hypertension in general is reduced resulting in a further increase in PVR (PVRI).

Does the hyperdynamic circulatory state of advanced liver disease predispose to pulmonary endothelial damage and subsequent portoPH? Our study was not designed to answer that question. However, we speculate that a combination of genetic predisposition and specific circulating vascular mediators related to the hepatic pathophysiology in the setting of high cardiac output (shear stress) create an appropriate environment for pulmonary endothelial damage, proliferation, and in situ thrombosis.

Arterial Blood Gases
Patients who satisfied criteria for portoPH had frequent arterial hypoxemia as measured by the P(A-a)O2 (80%), albeit the severity of hypoxemia was severe in only one patient. Significantly worse arterial oxygenation occurred in the portoPH patients when compared to the control group of liver transplant candidates with normal RVsys determined by Doppler echocardiography. Hypoxemia associated with portoPH was not due to clinically significant intracardiac or intrapulmonary shunting as demonstrated by the contrast echocardiograms, normal lung perfusion shunt studies, and the PaO2 response to 100% oxygen. Hypoxemia was also not related to smoking history or spirometric abnormalities. Ventilation-perfusion mismatch and diffusion limitation were the most likely reasons for the hypoxemia, although small effects of shunting could not be excluded. Prior studies13 14 have indicated that the increase in the P(A-a)O2 seen in patients with chronic obliterative pulmonary vascular disease as measured by the multiple inert gas elimination technique (MIGET), is explained by ventilation/perfusion abnormalities. These mild ventilation/perfusion abnormalities did not however explain the degree of hypoxemia in these patients. A subsequent study showed that the hypoxemia was related to a decrease in the mixed venous PO2 in addition to the mild impairment in ventilation/perfusion abnormality (measured by the MIGET).14 Marked mixed venous oxygen saturation abnormalities did not appear to exist in our cohort, and may relate to the fact that patients with portoPH in our study had no limitation in cardiac index.

Although severe hypoxemia was distinctly uncommon in our patients, it can occur in the setting of portoPH as a direct consequence of intracardiac right-to-left shunting. Such shunts result, in part, from high resistance to pulmonary arterial flow, tricuspid regurgitant flow, and right-to-left shunting through a patent foramen ovale or atrial septal defect. Raffy et al15 described two such patients whose hemodynamic and hypoxemic abnormalities improved when ß-blockade was discontinued.

The only positive correlation between oxygenation and hemodynamic variables was between mixed venous oxygen saturation and cardiac index (Fig 1) . We found no other clinically important correlations between measurements of oxygenation and selected pulmonary hemodynamic parameters (MPAP, PVR, PVRI, TPG, cardiac output, and cardiac index). As a corollary, the more severe cases of portoPH were not accompanied by proportionate abnormalities in arterial oxygenation. The subsequent use of continuous IV epoprostenol in our patients was not associated with worsening hypoxemia (change in PaO2 > 5 mm Hg from baseline) in any case. Poor correlation between oxygenation (as measured by PaO2) and pulmonary hemodynamics was reported by Naeije et al16 in their study of 100 patients who underwent pulmonary hemodynamic measurements during inpatient evaluation for GI bleeding.

With the exception of the series by Kuo et al,4 we were unable to find a systematic study of arterial oxygenation in portoPH patients, especially those considered for OLT. Those investigators evaluated 30 patients with portoPH and compared gas exchange with patients undergoing evaluation for liver transplantation and with patients having primary pulmonary hypertension.4 Unlike our results, they did not find any significant difference in PaO2 when comparing patients with portoPH with the other two groups. The patients with portoPH in their study did have lower PaO2 values than the liver transplantation control candidates (84.7 mm Hg vs 92.5 mm Hg); however, this did not reach significance. As in our study, however, P(A-a)O2 was significantly increased in their patients with portoPH compared with the control subjects (27 mm Hg vs 12 mm Hg, p < 0.05), implying a gas exchange abnormality.4 Studies17 18 have suggested that nitric oxide may play a role in the abnormal oxygenation seen in patients with cirrhosis, and correlates with the abnormalities in P(A-a)O2. Nitric oxide can increase the ventilation/perfusion mismatching by eliminating hypoxic vasoconstriction.

There was a significant difference in PaCO2 in our study between the portoPH and the control groups. Compared with the study by Kuo et al,4 which found that patients with portoPH frequently had PaCO2 values < 30 mm Hg, our patients did not exhibit this severity of respiratory alkalosis. They suggest that PaCO2 values < 30 mm Hg are essentially equivalent to that of ECG and/or echocardiographic data with a high sensitivity, specificity, positive, and negative predictive value. Our data do not support this contention. Only 2 of our 20 patients with portoPH (10%) had a PaCO2 value < 30 mm Hg. Our patients with portoPH did, however, have a significantly higher pH than the liver transplant control candidates (7.45 vs 7.43, p < 0.001), but was not on the basis of the PaCO2 or the bicarbonate.

Postural Room Air and Inspired 100% Oxygen Arterial Blood Gases
In both the supine position as well as standing position breathing 100% oxygen, there was a significant increase in PaO2 in portoPH patients. Such a response to 100% inspired oxygen essentially precluded clinically significant intracardiac or intrapulmonary shunting. In the standing position, the PaO2 did not decrease (as frequently documented in HPS), thus excluding orthodeoxia in this type of pulmonary vascular abnormality. There was a significant increase in PaO2 breathing 100% oxygen in the upright position that may be related to an improved ventilation/perfusion mismatch in these patients.

99mTcMAA Lung Perfusion Scans
All patients with portoPH had normal shunt fractions by the 99mTcMAA perfusion scan methodology and negative contrast echocardiographic findings. In our opinion, these findings essentially excluded the existence of clinically significant anatomic shunts or intrapulmonary vascular dilatation that has been described in patients with liver disease.19 In this study, we could only surmise that arterial hypoxemia could be attributed to a combination of ventilation-perfusion mismatch and/or diffusion limitation. Alveolar hypoventilation was excluded by the finding of respiratory alkalosis, which was almost universal in our patients.

Limitations
More focused reasons for arterial oxygenation in patients with portoPH documented at rest could be determined using the MIGET. Such an investigation has not been described in portoPH patients to date, but would be instructive. The determination of arterial oxygenation during sleep and exercise was not part of our analysis. In view of the potential for worsening pulmonary hemodynamics with exercise, such additional investigations would be of practical, clinical interest. The timing of arterial blood gas measurements and right-heart catheterization measurements could have been more uniform, but such testing was primarily dictated by clinical schedules. In all instances, the measurements of arterial oxygenation and right-heart catheterization were accomplished within 10 days of each other and reflected usual clinical practice. Our data, although prospective, are based on a relatively small number of patients with portoPH and should be interpreted in this context. Finally, selection bias cannot be excluded with reference to the degrees of pulmonary hypertension measured in patients referred to our institution.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Arterial oxygenation, as measured by PaO2 and P(A-a)O2, is commonly abnormal in patients with clinically significant portoPH complicating their advanced liver disease. The degree of arterial hypoxemia was mild in this study cohort. We could not demonstrate evidence for significant intracardiac or intrapulmonary shunting in such patients. At rest, PaO2 and P(A-a)O2 correlated poorly with measures of portoPH severity.


   Footnotes
 
Abbreviations: HPS = hepatopulmonary syndrome; MIGET = multiple inert gas elimination technique; MPAP = mean pulmonary artery pressure; OLT = orthotopic liver transplantation; P(A-a)O2 = alveolar-arterial oxygen pressure gradient; PCWP = pulmonary capillary wedge pressure; portoPH = portopulmonary hypertension; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; RVsys = right ventricular systolic pressure; 99mTcMAA =technetium-labeled macroaggregated albumin; TPG = transpulmonary gradient

Received for publication September 6, 2001. Accepted for publication December 5, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Krowka, MJ (2000) Hepatopulmonary syndromes. Gut 46,1-4[Free Full Text]
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R. Rodriguez-Roisin, M.J. Krowka, Ph. Herve, M.B. Fallon, and on behalf of the ERS Task Force Pulmonary-Hepatic
Pulmonary-Hepatic vascular Disorders (PHD)
Eur. Respir. J., November 1, 2004; 24(5): 861 - 880.
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