The Lungs in Liver Disease
What every physician needs to know:
- Are you sure your patient has HPS or PPH? What should you expect to find?
Beware: there are other diseases that can mimic HPS and PPH:
- How and/or why did the patient develop HPS or PPH?
- Which individuals are at greatest risk of developing HPS and PPH?
- What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of HPS and PPH?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of HPS and PPH?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of HPS and PPH?
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of HPS and PPH?
- If you decide the patient has HPS or PPH, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
What other considerations exist for patients with HPS or PPH?
What’s the evidence?
What every physician needs to know:
Several pulmonary conditions occur in association with underlying liver disease. Ascites elevates the diaphragms and causes basilar atelectasis, which contributes to dyspnea and mild hypoxia. Some patients with ascites have diaphragmatic defects that allow ascites fluid to flow into the chest, causing a hydrothorax. (These topics are discussed in the chapters on liver disease and pleural disease.) However, the more serious pulmonary complications of liver disease, hepatopulmonary syndrome (HPS) and portopulmonary syndrome (PPH), affect the pulmonary vasculature.
HPS is characterized by impaired oxygenation in the setting of chronic and (rarely) acute liver disease. It is defined by the combination of liver disease, an increased alveolar-arterial gradient with impaired arterial oxygenation, and evidence of intrapulmonary vasodilatation (termed intrapulmonary vascular dilatations) at the capillary and pre-capillary levels, as demonstrated by contrast-enhanced bubble echocardiography. HPS occurs in 4-47 percent of patients with liver disease referred to liver transplantation centers, but it also occurs across the full range of etiologies of liver disease, regardless of the presence or absence of portal hypertension. The severity of underlying liver disease does not predict the presence of HPS or the degree of associated hypoxemia.
Patients with HPS present with dyspnea, platypnea, resting arterial oxygen desaturation, progressive cyanosis, and orthodeoxia. Platypnea and orthodeoxia, which refer to dyspnea and arterial oxygen desaturation, respectively, improve from the sitting to recumbent position because of the gravitational increase in blood flow through dilated vessels in the lung bases in the sitting position.
HPS should be considered in any patient who has liver disease and hypoxemia. The diagnosis is confirmed by the demonstration of pulmonary vascular dilatation with contrast-enhanced echocardiography. The only treatment for HPS is supplemental oxygen. Previously considered a contraindication to liver transplantation, patients with HPS are now given priority in the organ-allocation process because of good clinical outcomes compared to those of non-HPS patients and post-transplantation improvement in oxygenation. Without liver transplantation, patients with HPS do poorly and usually die of progressive hepatic failure and variceal hemorrhage.
PPH is defined by the presence of pulmonary hypertension (mean pulmonary artery pressure [MPAP] at rest) higher than 25 mmHg and increased pulmonary vascular resistance (>240 dynes.s.cm-5) in patients who have liver disease and portal hypertension but no elevation in pulmonary artery occlusion pressures (PAOP <15 mmHg). Its underlying pathophysiologic mechanisms are unknown, and most patients are diagnosed with PPH when they undergo evaluation for liver transplantation with screening echocardiography. The physical examination may demonstrate a loud pulmonic component of the second heart sound and other signs of pulmonary hypertension.
Once diagnosed, patients are managed to improve portal hypertension. Patients who remain in NYHA functional class II, III, or IV undergo vasodilator and vasomodulator therapy (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and/or nitric oxide). Pulmonary hypertension may improve or resolve after liver transplantation, but many patients still require vasodilator therapy. Without liver transplantation, 65 percent of patients survive five years if they are managed successfully with vasodilator drugs.
No classification system exists for subtypes of HPS because it occurs in all forms of liver disease, and its clinical course and prognosis do not differ based on clinical context. Some investigators have classified the severity of HPS by the degree of impairment in arterial oxygenation, as measured by the alveolar-to-arterial (A-a) oxygen gradient and arterial oxygen tension.
Classification of hepatopulmonary syndrome based on severity of oxygenation abnormalities:
Mild HPS – A-a oxygen gradient greater than or equal to 15 mmHg and a room air arterial oxygen tension (PaO2) greater than or equal to 80 mmHg
Moderate HPS – A-a gradient greater than or equal to15 mmHg and a room air PaO2 between 60 mmHg and 79 mmHg
Severe HPS – A-a gradient greater than15 mmHg and a room air PaO2 between 50 mmHg and 59 mmHg
Very severe HPS – A-a gradient greater than or equal to 15 mmHg and a room air PaO2 less than 50 mmHg or a PaO2 less than 300 mmHg breathing 100 percent oxygen.
PPH is classified by the World Health Organization classification system that groups causes of pulmonary hypertension into five groups. Group 1 patients have pulmonary arterial hypertension, and PPH is included as a subtype within this group.
World Health Organization classification of pulmonary hypertension
Group 1. Pulmonary arterial hypertension
Group 2. Pulmonary hypertension from left heart disease
Group 3. Pulmonary hypertension from lung diseases without or without hypoxia
Group 4. Chronic thromboembolic pulmonary hypertension
Group 5. Pulmonary hypertension with unclear multifactorial mechanisms
Are you sure your patient has HPS or PPH? What should you expect to find?
Characteristic features of HPS include dyspnea, platypnea, resting arterial oxygen desaturation, progressive cyanosis, and orthodeoxia. Platypnea describes improvement in dyspnea when patients move from the sitting position to the supine position, which is a classic but nonspecific symptom of HPS. Similarly, orthodeoxia describes the improvement in arterial blood oxygen tension or oxygen saturation when patients lie supine from the sitting position. Although orthodeoxia may occur in other respiratory conditions, it is a highly specific finding in the context of underlying liver disease. Both platypnea and orthodeoxia result from the gravitational effects of sitting up, which preferentially increase perfusion of the lung bases through dilated pulmonary vessels and increase the right-to-left shunt fraction.
Patients with HPS almost always have cutaneous spider nevi, although this is a nonspecific finding, but patients with liver disease who do have spider nevi are more likely to have intrapulmonary shunts. However, the sine qua non of HPS is the presence of intrapulmonary vascular dilatations with resulting intrapulmonary shunt. Any patient with liver disease, dyspnea, and hypoxemia should undergo testing for a shunt, which defines HPS in combination with hypoxia. Even so, detection of an intrapulmonary shunt in the absence of hypoxemia does not establish a diagnosis of HPS.
Because portal hypertension precedes the onset of pulmonary hypertension by 2-15 years in most patients, the initial clinical manifestations usually relate to liver disease and portal hypertension, rather than to respiratory complaints. Rarely, patients present with respiratory symptoms alone, which requires an evaluation to identify occult liver disease. Patients with mild PPH have subtle or no respiratory symptoms.
Manifestations of PPH, which are similar to those of other causes of pulmonary hypertension, include dyspnea on exertion, fatigue, chest pain, syncope, and hemoptysis. In contrast to those with HPS, patients with PPH experience orthopnea, rather than platypnea. In addition to signs of portal hypertension, patients have an accentuated pulmonary component of the second heart sound, increased S2 split, jugular venous distension, right ventricular lift, a systolic murmur from tricuspid insufficiency, pulsatile liver, and peripheral edema. With severe PPH, patients have general signs of right ventricular failure.
Beware: there are other diseases that can mimic HPS and PPH:
Patients with impaired hepatic function have other potential causes of respiratory symptoms, hypoxia, and poor exercise capacity. Anemia commonly occurs in association with liver disease. Although patients with anemia uncomplicated by cardiopulmonary disease have normal arterial oxygen saturations and normal pulmonary artery pressures, they may present with dyspnea. The presence of hypoxia in a patient with anemia and liver disease warrants evaluation for a shunt.
Ascites associated with liver disease elevates the diaphragm and causes basilar lung atelectasis with resulting dyspnea and hypoxemia. However, the hypoxemia from ascites is usually mild, with resting PaO2 higher than 60 mmHg, in contrast to the typically lower values in patients with HPS. A hydrothorax may develop from flow of ascites fluid into the pleural space, which is an additional mimic of HPS.
Nonspecific features of liver disease, such as muscle wasting and deconditioning, are additional causes of dyspnea but are not associated with hypoxia or pulmonary arterial hypertension.
Respiratory symptoms with liver disease also warrant consideration of systemic disorders than can affect the lungs and liver. Sarcoidosis, alpha-1-antitrypsin deficiency, and cystic fibrosis may present with liver and pulmonary manifestations. Interstitial lung disease can occur in patients with liver disease because of auto-immune hepatitis and adverse drug reactions that damage the liver and the lungs, as can occur with amiodarone. In addition, patients with HPS or PPH may have coexisting chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis unrelated to their liver disease. When hypoxia or pulmonary hypertension appears out of proportion to the severity of COPD or pulmonary fibrosis, assessment for HPS or PPH should be performed.
The diagnosis of PPH can be made only when other causes of pulmonary hypertension have been excluded by an extensive clinical evaluation.
How and/or why did the patient develop HPS or PPH?
The etiology of HPS is unknown, but the hallmark of the condition is microvascular dilatation of the pulmonary arterial circulation with a ten-fold increase in capillary diameter. It has been proposed that this dilatation results from a combination of factors that include impaired hepatic clearance or increased hepatic production of circulating mediators, like cytokines and growth factors, and overproduction of the vasodilator nitric oxide (NO) by the lung.
These factors also induce pulmonary angiogenesis with vascular remodeling that results in an increased absolute number of vessels in the lung, most of which are dilated. Patients with HPS also have increased amounts of NO in exhaled breaths. Impaired hepatic clearance of intestinal endotoxins in the portal circulation with induction of tumor necrosis factor may also play a role. The vasodilatation of pulmonary vessels causes ventilation-perfusion mismatching, anatomical and functional right-to-left shunt physiology, and impaired lung diffusion, which combine to cause hypoxemia.
Any form of chronic liver disease, with or without portal hypertension, has been associated with HPS, with rare reports of HPS occurring in patients with acute liver disease. The severity of the underlying liver disease does not predict the presence or severity of HPS.
The cause of PPH is unknown, but theories suggest the likelihood of roles for circulating vascular mediators like cytokines, serotonin, angiotensin II, and endothelin-1 that enter the pulmonary circulation through portosystemic collaterals, bypassing the liver, where they would normally be metabolized. Additional theories propose a role for microvascular thrombosis, pulmonary vascular endothelial injury from sheer stress initiated by the hyperdynamic circulatory state associated with liver disease, depressed synthesis of prostaglandin and NO, and genetic predispositions. The resulting changes in small pulmonary arteries include medial hypertrophy, endothelial and smooth muscle cell proliferation, fibrosis, and thrombosis, which are identical to those observed in patients with idiopathic pulmonary arterial hypertension.
Which individuals are at greatest risk of developing HPS and PPH?
Patients with chronic liver disease have a greater risk of developing HPS than do patients with acute liver disease. The underlying cause of liver disease does not determine an individual’s risk. The presence of portal hypertension or other clinical features of the liver disease have not clearly been shown to represent risk factors for HPS. In one study, clubbing had the highest positive predictive value (75%) for HPS, and absence of dyspnea the highest negative predictive value.
Portal hypertension must be present for PPH to develop. Patients usually have chronic liver disease, usually because of cirrhosis, but other causes of portal hypertension in the absence of liver disease, such as hepatic vein sclerosis and portal vein thrombosis, can also cause PPH. The prevalence of PPH in cirrhosis is less than 1 percent, increasing to 4-16 percent in patients with advanced liver disease who are undergoing evaluation for liver transplantation. However, it does not appear that the severity of liver disease or the degree of portal hypertension predicts the severity of PPH. Because not all patients with portal hypertension develop PPH, a genetic predisposition is supposed but has not been proven.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
Patients suspected of having HPS should undergo measurement of blood oxygenation by an arterial blood gas while they are in the sitting position. Detection of an arterial oxygen less than 80 mmHg measured at sea level demonstrates hypoxemia. However, calculation of the A-a gradient using the alveolar gas equation is a more sensitive indicator of impaired oxygenation than is arterial oxygen measure, with values greater than or equal to 15 mmHg representing an abnormally increased A-a gradient. The equation for calculating the A-a gradient is shown here:
A-a gradient = [FIO2 * (Patm–PH2O) – PaCO2/0.8)] – PaO2FIO2 = fraction of inhaled oxygen, where
Patm = atmospheric barometric pressure
PH2O = partial pressure of water
PaCO2 = arterial carbon dioxide tension
PaO2 = arterial oxygen tension
If an increased A-a gradient is confirmed, the patient should undergo imaging assessment to detect intrapulmonary vascular dilatations and the presence of an intrapulmonary shunt.
Orthodeoxia, which is a characteristic feature of HPS, is present in 90 percent of patients. Arterial blood gas analysis is performed with the patient in the sitting position and the recumbent positions, and the PaO2 values are compared. A decrease in PaO2 of more than or equal to 5 percent or a drop of 4 mmHg in oxygen saturation after sitting upright defines the presence of orthodeoxia.
Patients with signs and symptoms compatible with PPH should undergo extensive clinical evaluation with an algorithmic approach, as is proposed for any patient with suspected pulmonary arterial hypertension. Blood tests include HIV testing, collagen vascular disease panels, and B-type natriuretic peptide (BNP). BNP may be of value in following patients to assess the effects of vasodilator therapy on ventricular overload.
What imaging studies will be helpful in making or excluding the diagnosis of HPS and PPH?
Transthoracic contrast-enhanced echocardiography performed when the patient is in the upright position is a sensitive imaging tool for detecting an intrapulmonary right-to-left shunt associated with HPS. Intravenous injection of hand-agitated normal saline usually causes only the right cardiac chambers to appear opacified on echocardiographic images because the pulmonary capillaries filter microbubbles, preventing their entry into the left atrium and ventricle. Opacification of the left cardiac chambers indicates that either an intracardiac or an intrapulmonary right-to-left shunt exists. Early appearance of microbubbles into the left side of the heart within three heartbeats identifies an intracardiac shunt, and later appearance in more than three heartbeats establishes the presence of an intrapulmonary shunt.
Transesophageal contrast-echocardiography can detect microbubbles as they enter the pulmonary veins, establishing the presence of an intrapulmonary shunt and excluding an intracardiac shunt. This procedure is reserved for instances in which transthoracic echocardiography is not indicated because of the discomfort of intubating the esophagus with the transesophageal ultrasound probe.
Technetium-labeled macroaggregated albumin scanning
Nuclear scanning with technetium-labeled macroaggregated albumin is an alternative imaging study that can demonstrate right-to-left shunts. Injection of macroaggregates into the venous circulation usually results in filtering of the macroaggregates in the pulmonary capillaries. Demonstration of uptake of the radionuclide by the brain, spleen, or kidney indicates the presence of a shunt. Although nuclear scanning, cannot differentiate between intracardiac and intrapulmonary shunts, it can quantify shunt fraction by calculating the proportion of radionuclide uptake by the kidneys and the brain.
The chest radiograph may demonstrate enlarged pulmonary arteries and pulmonary artery outflow track, with evidence of right ventricular enlargement. Transthoracic Doppler echocardiography has a 97 percent sensitivity for demonstrating moderate to severe pulmonary hypertension, right ventricular strain, and tricuspid valve regurgitation. It can also exclude causes of pulmonary hypertension from left-sided cardiac abnormalities. Computerized tomography can identify enlarged pulmonary arteries and evaluate patients for other causes of pulmonary hypertension, such as thromboembolic disease.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of HPS and PPH?
Echocardiography is the preferred study for determining the presence of intrapulmonary venous dilatations.
Pulmonary function testing typically demonstrates a reduced diffusing capacity for carbon monoxide (DLCO) because of the longer distances needed for gas exchange and hemoglobin binding between alveoli and dilated pulmonary capillaries. However, this finding is nonspecific. In the absence of other lung diseases or diaphragmatic elevation from ascites, patients with HPS have normal measured airflow and normal lung volumes.
The EKG is usually abnormal, with evidence of right ventricular and right atrial enlargement, right axis deviation, and right bundle branch block. Polysomnography can exclude obstructive sleep apnea as a cause of pulmonary hypertension. Pulmonary function testing typically demonstrates a reduced DLCO, with normal lung volumes and air flow.
What diagnostic procedures will be helpful in making or excluding the diagnosis of HPS and PPH?
Arterial blood gas analysis performed with the patient in the sitting position establishes the presence of hypoxemia. It can also define orthodeoxia when results obtained with the patient in the sitting and recumbent positions are compared.
Pulmonary angiography is rarely performed to diagnose HPS because of the procedure's invasiveness and risk. It is reserved for complex patients who require evaluation to exclude other causes of hypoxia, such as pulmonary hypertension and arteriovenous malformations.
Detection of pulmonary hypertension by echocardiography necessitates right heart catetherization to confirm PPH because some patients with liver disease have elevated pulmonary artery pressures that are due to the increased cardiac output and blood volume (high flow state) that are commonly associated with liver disease. In such patients, pulmonary vascular resistance may be low or normal despite pulmonary hypertension because of an elevated cardiac output and pulmonary artery occlusion pressure. True PPH is associated with an abnormally high pulmonary vascular resistance.
Right heart catheterization also allows measurement of the hepatic venous wedge pressure to determine the severity of portal hypertension. Vasodilator studies during catheterization to determine the role of calcium channel blocker drugs are not performed because patients with PPH do not tolerate these agents.
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of HPS and PPH?
If you decide the patient has HPS or PPH, how should the patient be managed?
Current management for HPS is limited to long-term supplemental oxygen to treat hypoxemia and dyspnea, as no other medical therapies have been found to improve hypoxemia or clinical outcomes. Among the medical interventions that have been studied, treatment with beta-blocking agents, cyclo-oxygenase inhibitors, corticosteroids, cyclophosphamide, NO inhibitors, methylene blue, and somatostatin analogues have no demonstrated benefit.
TIPS placement has anecdotal evidence for improving hypoxemia but is not recommended because of the absence of consistently demonstrated benefit.
Initially considered a contraindication to liver transplantation, HPS with severe and refractory hypoxemia is now an indication for high-priority listing in the organ-allocation waiting list. Liver transplantation has demonstrated consistent benefit in improving oxygenation and pulmonary vascular dilatation, with complete resolution of signs and symptoms of HPS observed in more than 80 percent of transplanted patients. Improvement in oxygenation may be delayed, with full improvement not occurring for 6-12 months. The presence of HPS does not affect long-term survival after liver transplantation unless patients have a preoperative PaO2 less than 50 mm Hg and shunt fraction of more than 20 percent. However, immediate post-operative survival is lower in patients who have HPS than in those who do not.
Because most patients with mild PPH (MPAP < 35 mmHg) have little or no respiratory symptoms, specific therapy is not required, but patients with moderate to severe PPH may benefit from therapy to improve functional status and decrease pulmonary artery pressures. Anticoagulation is recommended for these patients because of improved outcomes in those with idiopathic pulmonary arterial hypertension, but most patients with PPH have contraindications to anticoagulant therapy. Diuretics and oxygen are prescribed as indicated. Many patients with liver disease who are at risk for variceal hemorrhage receive beta-blocker drugs, although their use in PPH is problematic because these drugs may worsen exercise capacity and pulmonary hemodynamic measures.
Vasodilator and vasomodulating drugs are used in patients with PPH if the patients remain in NYA function class II, III, IV after treatment of their portal hypertension, but the drugs' efficacy is extrapolated from use in patients with idiopathic pulmonary arterial hypertension. These drugs include prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and nitric oxide.
A few selected patients with PPH may benefit from liver transplantation, but MPAP must be below 50-60 mmHg to prevent an unacceptably high postoperative mortality rate. Patients with MPAP between 35 to 50 mmHg, who are at increased risk for postoperative complications, should be treated with vasodilators for varying periods to improve their operability. Specific hemodynamic criteria for selecting or excluding patients for liver transplantation have not been established. Unlike HPS, PPH is not an indication for liver transplantation, but if they are managed correctly, some patients may do well with transplantation despite the presence of PPH. Vasodilator and vasomodulator therapy may help bridge patients to transplantation if they are not initially operable candidates because of the severity of their pulmonary hypertension.
What is the prognosis for patients managed in the recommended ways?
The presence of HPS is an important risk factor for a poor outcome in patients with cirrhosis and (possibly) other liver diseases. The median survival time in patients who have cirrhosis with HPS is 10.6 months, compared with 40.8 months in similar patients without HPS. The leading cause of death is gastrointestinal bleeding and other complications of the liver disease. Patients rarely die of hypoxic respiratory failure, although the severity of hypoxemia in patients with HPS usually progresses. The degree of hypoxemia influences survival; mortality is highest in patients with baseline PaO2 less than or equal to 50 mmHg.
The advent of vasodilator therapy has improved the clinical course of patients with PAH over that of historical controls. The prognosis depends on the severity of the liver disease and the degree of pulmonary hypertension. Before vasodilator therapy, 50 percent of patients with PAH survived six months, while five-year survival with vasodilator therapy approximates 65 percent. Mortality after liver transplantation increases for patients as pulmonary hypertension increases. Three-year mortality with mild pulmonary hypertension (systolic PAP 30-44 mmHg) is less than 30 percent, but it but increases to 70 percent with systolic PAP values higher than 60 mmHg.
What other considerations exist for patients with HPS or PPH?
Although TIPS has had inconsistent results in treating HPS, there is concern that it might worsen oxygenation if it aggravates the hyperkinetic state associated with liver disease and, consequently, aggravate pulmonary vasodilatation and the degree of shunting. TIPS may also worsen the clinical course of patients with PPH; its application as a measure of portal hypertension should be carefully considered in patients with PPH.
What’s the evidence?
Ho, V. "Current concepts in the management of hepatopulmonary syndrome". Vasc Health Risk Manag. vol. 4. 2008. pp. 1035-1041.An excellent update on the spectrum of management issues related to hepatopulmonary syndrome.
Khan, AN, Al-Jahdali, H, Abdullah, K, Irion, KL, Sabih, Q, Gouda, A. "Pulmonary vascular complications of chronic liver disease: pathophysiology, imaging, and treatment". Ann Thorac Med. vol. 6. 2011. pp. 57-65.This review presents the major clinical features of and pathophysiologic mechanisms for all of the vascular complications related to chronic liver disease.
Kim, YK, Kim, Y, Shim, SS. "Thoracic complications of liver cirrhosis: radiologic findings". Radiographics. vol. 29. 2009. pp. 825-837.The authors present the classic thoracic radiologic findings in patients with pulmonary complications of liver cirrhosis.
Kochar, R, Nevah Rubin, MI, Fallon, MB. "Pulmonary complications of cirrhosis". Curr Gastroenterol Rep. vol. 13. 2011. pp. 34-39.Another recent update of all of the major pulmonary complications of cirrhosis.
Kochar, R, Fallon, MB. "Pulmonary diseases and the liver". Clin Liver Dis. vol. 15. 2011. pp. 21-37.
Rodriguez-Roisin, R, Krowka, MJ. "Hepatopulmonary syndrome--a liver-induced lung vascular disorder". N Engl J Med. vol. 358. 2008. pp. 2378-2387.
Spagnolo, P, Zeuzem, S, Richeldi, L, du Bois, RM. "The complex interrelationships between chronic lung and liver disease: a review". J Viral Hepat. vol. 17. 2010. pp. 381-390.
Sussman, NL, Kochar, R, Fallon, MB. "Pulmonary complications in cirrhosis". Curr Opin Organ Transplant. vol. 16. 2011. pp. 281-288.
Swanson, KL, Krowka, MJ. "Screen for portopulmonary hypertension especially in liver transplant candidates". Cleve Clin J Med. vol. 75. 2008. pp. 121-2, 125-30, 133 passim.
Swanson, KL, Wiesner, RH, Nyberg, SL, Rosen, CB, Krowka, MJ. "Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups". Am J Transplant. vol. 8. 2008. pp. 2445-2453.
Talwalkar, JA, Swanson, KL, Krowka, MJ, Andrews, JC, Kamath, PS. "Prevalence of spontaneous portosystemic shunts in patients with portopulmonary hypertension and effect on treatment". Gastroenterology. vol. 141. 2011. pp. 1673-9.
Yeshua, H, Blendis, LM, Oren, R. "Pulmonary manifestations of liver diseases". Semin Cardiothorac Vasc Anesth. vol. 13. 2009. pp. 60-69.
Zhang, ZJ, Yang, CQ. "Progress in investigating the pathogenesis of hepatopulmonary syndrome". Hepatobiliary Pancreat Dis Int. vol. 9. 2010. pp. 355-360.
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