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 pleural effusion termed 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 vascular dilatations at the capillary and pre-capillary levels, as demonstrated by a positive contrast-enhanced bubble echocardiogram. HPS occurs in 4-47% of patients with liver disease referred to liver transplantation centers and 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 hypoxemia, progressive cyanosis, and orthodeoxia. Platypnea and orthodeoxia refer to dyspnea and arterial oxygen desaturation, respectively, that improve from the sitting to supine position, which is caused by the gravitational increase in blood flow and shunting through dilated vessels in the lung bases while in the seated 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 mainstay treatment for HPS is supplemental oxygen, however, studies have also shown some improvement in oxygenation with supplemental garlic. Previously considered a contraindication to liver transplant, patients with HPS are now given priority in the organ-allocation process because of good clinical outcomes and a high chance of post-transplant improvement in oxygenation. Without liver transplant, patients with HPS do poorly and usually die of progressive hepatic failure and its associated complications.
PPH is defined by the presence of pulmonary hypertension (mean pulmonary artery pressure [MPAP] at rest) > 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 on screening echocardiography during the evaluation for liver transplant. The physical examination may demonstrate a loud pulmonic component of the second heart sound and other signs of pulmonary hypertension in severe cases.
Once diagnosed, patients are managed to improve portal hypertension. Patients who remain in NYHA functional class II, III, or IV are often given vasodilator therapy (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and/or nitric oxide). Pulmonary hypertension may improve or resolve after liver transplant, but some patients still require vasodilator therapy post-transplant. Without liver transplant, 60% of patients achieve five-year survival if they are managed successfully with vasodilator drugs. Without any medical therapy the prognosis is extremely poor.
The severity of HPS is classified by the degree of impairment in arterial oxygenation as measured by the alveolar-to-arterial (A-a) oxygen gradient and arterial oxygen tension.
Mild HPS: A-a oxygen gradient ≥15 mmHg and a room air arterial oxygen tension (PaO2) ≥80 mmHg
Moderate HPS: A-a gradient ≥15 mmHg and a room air PaO2 between 60 mmHg and 79 mmHg
Severe HPS: A-a gradient ≥15 mmHg and a room air PaO2 between 50 mmHg and 59 mmHg
Very severe HPS: A-a gradient ≥15 mmHg and a room air PaO2 < 50 mmHg or a PaO2 < 300 mmHg breathing 100% oxygen.
PPH is classified by the World Health Organization classification system that divides causes of pulmonary hypertension into five groups. It is included as a subtype within group I patients, who have pulmonary arterial hypertension.
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 progressive dyspnea especially with activity, platypnea, cyanosis, digital clubbing 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 are supine compared to the seated position. Although orthodeoxia may occur in other respiratory conditions, it is highly specific for HPS in the context of underlying liver disease. Both platypnea and orthodeoxia result from gravitational effects in the upright position, which preferentially increase perfusion to the lung bases through dilated pulmonary vessels and therefore increase the right-to-left shunt fraction.
Cutaneous spider angiomata are also commonly seen in patients with HPS. Although this is a nonspecific finding, patients with liver disease who do have spider nevi are more likely to have intrapulmonary shunts.
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.
Because portal hypertension often precedes the onset of pulmonary hypertension by 2-15 years, 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 may have signs of right heart failure.
What other diseases can mimic HPS and PPH?
Patients with impaired hepatic function have other potential causes of respiratory symptoms, hypoxia, and reduced exercise capacity.
Anemia commonly occurs in association with liver disease. Anemic patients may present with dyspnea on exertion; however, they should have normal arterial oxygen saturations and normal pulmonary artery pressures.
Ascites associated with liver disease elevates the diaphragm and causes basilar lung atelectasis with resulting dyspnea and hypoxemia. Furthermore, a hepatic hydrothorax may develop from flow of ascites fluid into the pleural space via diaphragmatic defects. However, the hypoxemia in these situations is usually mild, with resting PaO2 higher than 60 mmHg, in contrast to the typically lower values in patients with 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 hypertension.
Respiratory symptoms with liver disease also warrant consideration of systemic disorders than can affect the lungs and liver. For instance, sarcoidosis, alpha-1-antitrypsin deficiency, and cystic fibrosis all may present with liver and pulmonary manifestations. Interstitial lung disease can co-exist with auto-immune hepatitis. Adverse drug reactions can affect the liver and the lungs, such as in amiodarone toxicity. In addition, patients with HPS or PPH may have coexisting chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis unrelated to their liver disease. If the hypoxemia or pulmonary hypertension appears out of proportion to the severity of COPD or pulmonary fibrosis, HPS and PPH should be considered.
The diagnosis of PPH can be made only when other causes of pulmonary hypertension have been excluded by an extensive clinical evaluation. Patients with liver disease are also often volume overloaded with pulmonary venous hypertension and a high pulmonary artery occlusion pressure. This can only be definitively distinguished from true pulmonary arterial hypertension with a right heart catheterization.
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 nitric oxide (NO) mediated pulmonary vasodilation. A combination of factors increase NO levels including impaired hepatic clearance, increased hepatic production of circulating mediators such as cytokines and growth factors, and overproduction of NO by the lung via increased levels of endothelin-1.
These factors also induce pulmonary angiogenesis with vascular remodelling via vascular endothelial growth factor A, which results in an increased absolute number of vessels in the lung, most of which are dilated. Recent genetic studies have also identified single nucleotide polymorphisms in genes related to angiogenesis in patients with HPS. 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 due to decreased intrapulmonary blood transit time in the setting of an often hyperdynamic circulation, which all leads to 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 imbalance of 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, and decreased synthesis of prostaglandin and NO. 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 been shown to represent risk factors for HPS. In one study, clubbing had the highest positive predictive value for HPS and the absence of dyspnea had 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. Risk factors for PPH include being female and autoimmune hepatitis, whereas hepatitis C appears to be associated with a decreased risk in patients with advanced liver disease. Certain genetic factors also seem to play a role, such as the presence of single nucleotide polymorphisms in genes involved in estrogen signaling and cell growth regulation. The prevalence of PPH in cirrhosis is less than 1%, increasing to 4-10% in patients with advanced liver disease who are undergoing evaluation for liver transplantation. However, the severity of liver disease or the degree of portal hypertension does not predict the severity of PPH.
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 an arterial blood gas while in the seated position. Detection of an arterial oxygen < 80 mmHg measured at sea level demonstrates hypoxemia. Calculation of the A-a gradient using the alveolar gas equation is a more sensitive indicator of impaired oxygenation, with values ≥ 15 mmHg representing an elevated A-a gradient. The equation for calculating the A-a gradient is shown here:
A-a gradient = [FIO2 * (Patm–PH2O) – PaCO2/0.8)] – PaO2
FIO2 = fraction of inhaled oxygen
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, a characteristic feature of HPS, is present in 90% of patients. Although not routinely done, arterial blood gas analysis can be performed with the patient in the seated and supine positions, and then the PaO2 values are compared. A decrease in arterial oxygen tension of > 4 mmHg after sitting upright defines orthodeoxia.
Patients with suspected PPH should undergo extensive diagnostic 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).
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. In normal individuals, intravenous injection of agitated normal saline should result in opacification of only the right cardiac chambers because of the pulmonary capillaries’ ability to filter microbubbles and prevent 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; delayed appearance of microbubbles in more than three heartbeats is consistent with an intrapulmonary shunt.
Transesophageal contrast-echocardiography and intracardiac echocardiography can detect microbubbles as they enter the pulmonary veins, establishing the presence of an intrapulmonary shunt and excluding an intracardiac shunt. Despite their higher specificity, these procedures are more invasive than transthoracic echocardiography and are often avoided in this patient population.
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.
CT of the chest can exclude other causes of hypoxemia and can rarely show arteriovenous malformations though they are typically too small to be visualized on imaging.
CXR may demonstrate enlarged pulmonary arteries and pulmonary artery outflow track, with evidence of right ventricular enlargement. Transthoracic doppler echocardiography has a 97% sensitivity for demonstrating moderate to severe pulmonary hypertension, right ventricular strain, and tricuspid valve regurgitation with an elevated right ventricular systolic pressure. It can also exclude causes of pulmonary hypertension from left-sided cardiac abnormalities. CT of the chest 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 disease 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 airflow.
What diagnostic procedures will be helpful in making or excluding the diagnosis of HPS and PPH?
Pulmonary angiography is rarely performed to diagnose HPS because of the procedure’s invasiveness and risk. It is reserved for complex patients to look for large arteriovenous malformations, which may be amenable to coiling/embolization.
Detection of pulmonary hypertension by echocardiography needs to be followed by right heart catheterization to confirm PPH because many patients with liver disease have elevated pulmonary artery pressures that are due to the increased cardiac output and blood volume, a hyperdynamic circulatory state that is commonly associated with liver disease. In such patients, pulmonary vascular resistance may be low or normal despite elevated pulmonary pressures because of an elevated cardiac output and pulmonary capillary wedge pressure. True PPH is associated with an abnormally high pulmonary vascular resistance and represents true pulmonary arterial hypertension.
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 medical management for HPS remains limited. Long-term supplemental oxygen is the mainstay for hypoxemia and dyspnea. Oral garlic supplementation has been shown to significantly improve oxygenation in a pilot study and subsequent small randomized controlled trial. It is speculated that garlic increases the rate of NO synthesis, thus resulting in more uniform vasodilation throughout the lung and improving ventilation-perfusion mismatch. Pentoxifylline, a TNF-alpha inhibitor that decreases angiogenesis, has also been shown to be effective in improving PaO2 in animal studies and two pilot human studies. Among other medical interventions that have been studied, treatment with beta blockade, cyclo-oxygenase inhibitors, corticosteroids, cyclophosphamide, NO inhibitors (i.e. methylene blue), and somatostatin analogues have not demonstrated benefit.
TIPS placement does not consistently demonstrate benefit in HPS and is not recommended. However ,it is safe to perform TIPS in the setting of HPS if necessary for other reasons e.g., variceal bleeding or ascites.
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% of transplanted patients. Improvement in oxygenation may be delayed, with full improvement not occurring for 6-12 months. Inhaled nitric oxide paradoxically can be useful in severe, refractory hypoxemia in the post-operative setting after liver transplant via its preferential dilatation of unaffected vessels contributing to improved ventilation-perfusion matching.
In the most recent literature, even patients with severe hypoxemia (PaO2 < 50 mm Hg) have favorable survival rates with liver transplant that are comparable to survival rates in other conditions warranting liver transplant. However, those with a preoperative PaO2 of < 44 mmHg may have worsened survival. Possible complications post-liver transplant in HPS include prolonged mechanical ventilation requiring tracheostomy, biliary complications and bleeding or vascular complications. Rare cerebral embolic events have also been reported and all patients with HPS should have bubble filters placed on all their intravenous lines to minimize this risk.
Because most patients with mild PPH (MPAP < 35 mmHg) have minimal respiratory symptoms, specific therapy is not required unless it is in the context of an anticipated liver transplant. Patients with moderate to severe PPH may benefit from therapy to improve functional status and decrease pulmonary artery pressures. However, no long-term studies or guidelines exist. Diuretics and supplemental oxygen should be utilized as needed. Anticoagulation can be considered based on improved outcomes in those with idiopathic pulmonary arterial hypertension, but most patients with PPH have contraindications to anticoagulation due to their underlying liver disease. Beta blockers and calcium channel blockers should also be avoided in the setting of PPH because of worsening hemodynamics and portal hypertension respectively.
Vasodilator and vasomodulating drugs are used in patients with PPH if the patients remain in NYHA functional class II, III, or IV after treatment of their portal hypertension, but the drugs’ efficacy is mostly extrapolated from use in patients with idiopathic pulmonary arterial hypertension. These drugs include prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and nitric oxide.
Select patients with mild PPH may benefit from liver transplantation, but mean PAP must be below 35 mmHg to prevent an unacceptably high perioperative mortality rate. Patients with mean PAP from 35-50 mmHg have perioperative mortality rates of 50-70%; thus these patients should be treated with pulmonary vasodilators for varying periods of time to improve their chances of future liver transplant candidacy assuming their PA pressures reach the goal of less than 35 mm Hg. More recently, a MELD exception has been made available for PPH patients meeting certain hemodynamic and treatment criteria and a number of centers have started transplanting select patients with significant PPH with favorable outcomes.
What is the prognosis for patients managed in the recommended ways?
The presence of HPS is an important risk factor for poor outcomes in patients with cirrhosis and possibly other liver diseases. The median survival in patients with cirrhosis and HPS is 10.6 months, compared with 40.8 months in case-matched controls without HPS.
In the post-MELD exception era (since 2002), liver transplantation has significantly improved overall survival as compared to the early transplant experience with HPS. In fact, 5-year survival is around 80%, which is equivalent to that of control patients without HPS undergoing liver transplantation.
The leading cause of death is gastrointestinal bleeding and other complications of liver disease. Patients rarely die of hypoxic respiratory failure, although the hypoxemia in patients with HPS usually progresses. The degree of hypoxemia does seem to influence survival; post liver transplant mortality was highest in patients with pre-transplant PaO2 < 44 mmHg in one recent series.
The advent of vasodilator therapy has improved the clinical course of patients with PPH over that of historical controls. Before vasodilator therapy, 50% of patients with PPH survived six months, while five-year survival with vasodilator therapy now approximates 50%. Five-year survival with vasodilator therapy followed by liver transplantation approaches 70%. There have been reports of improvement and resolution of PPH with liver transplantation; however, predictors of which patients will sustain significant improvement have not been identified. Based on the limited available data, mortality does not appear to correlate with baseline hemodynamics or severity of liver disease.
What other considerations exist for patients with HPS or PPH?
Various case reports studying the role of TIPS in HPS have yielded conflicting results. There is concern that TIPS might worsen oxygenation if it aggravates the hyperkinetic state associated with liver disease, therefore increasing pulmonary vasodilatation and the degree of shunting. Currently there is no sufficient evidence to support its use in HPS.
TIPS may also worsen the clinical course of patients with PPH and should be in general avoided in clinically significant PPH.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- What every physician needs to know:
- Are you sure your patient has HPS or PPH? What should you expect to find?
- What other diseases 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?