May 30, 2015
A multidisciplinary team of Mayo Clinic specialists cares for patients with chronic liver disease, which occurs most commonly secondary to cirrhosis, including pulmonologists with expertise in the management of lung conditions commonly encountered in this population.
Lung explant from a 37-year-old woman with end-stage primary biliary cirrhosis who underwent combined heart-lung-liver transplantation. Pulmonary artery (left) shows medial hypertrophy, as well as intimal fibroelastosis at the origin of the arterial branch. The branch (right) is involved by two microaneurysms that contain plexiform lesions.
Portopulmonary hypertension (POPH) refers to the presence of pulmonary arterial hypertension (PAH) in patients with portal hypertension with or without cirrhosis. Pulmonary hypertension in patients with liver disease or portal hypertension can be due to multiple mechanisms, including hyperdynamic (high-flow) state, increased pulmonary venous congestion (pulmonary venous hypertension), and vascular constriction or obstruction of the pulmonary arterial bed.
Vascular obstruction to pulmonary arterial flow, reflected by increased pulmonary vascular resistance, is an important parameter that defines POPH. Among patients with portal hypertension, reported incidence rates of POPH range from 2 to 9 percent. The predominant presenting symptom of POPH is dyspnea on exertion or at rest.
Transthoracic echocardiography has been the most practical screening method to detect POPH by estimating right ventricular systolic pressure (RSVP). This screening method has been found to have 97 percent sensitivity and 77 percent specificity to detect moderate to severe PAH.
Patients with right ventricular systolic pressure > 50 mm Hg or right ventricular dysfunction or both should undergo right heart catheterization in order to obtain a definitive diagnosis. In the presence of portal hypertension, POPH is defined as a mean pulmonary artery pressure ≥ 25 mm Hg associated with pulmonary vascular resistance (PVR) ≥ 240 dynes/sec/cm-5 and pulmonary capillary wedge pressure < 15 mm Hg based upon right heart catheterization.
Long-term survival in POPH is poor. The management of POPH includes an emerging number of different therapeutic agents. The immediate goal of PAH-specific treatment for POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow. This can be accomplished by medications that selectively or in combination result in vasodilation, anti-platelet aggregation and anti-proliferation. These goals may be attained by:
- Targeting pulmonary endothelial prostacyclin synthase deficiency (prostacyclin infusion)
- Blocking circulating endothelin-1 effects (endothelin receptor antagonists)
- Enhancing local nitric oxide vasodilatation effects (phosphodiesterase inhibitors)
Favorable responses to PAH-specific therapy have been observed, but prospective, randomized trials are lacking. Severe POPH with right ventricular failure despite PAH-specific therapy is associated with adverse outcomes in the setting of liver transplantation (LT) and is therefore considered a contraindication to LT unless PAH-specific therapy is able to lower the pulmonary vascular resistance to safe levels.
Currently, the United Network for Organ Sharing (UNOS) has approved automatic higher priority for LT (exception points via the Model for End Stage Liver Disease, or MELD) if treatment can improve pulmonary hemodynamics (reduce mean pulmonary artery pressure to less than 35 mm Hg). The post-LT course of patients with treated moderate to severe POPH is unpredictable, but selected patients can be weaned from PAH-specific therapy over time, especially when right ventricular size and function can be normalized prior to transplant.
Hepatopulmonary syndrome (HPS) is a distinct pulmonary complication of end-stage liver disease (ESLD), occurring in between 5 to 32 percent of patients with cirrhosis or portal hypertension or both. HPS is independently associated with worsened survival in patients with ESLD, and this forms the basis for granting MELD exception points in these patients (discussed later).
The pathophysiology of HPS is related to the development of intrapulmonary vascular dilatations (IPVDs), which are abnormally dilated precapillary and capillary vessels between 15 to 100 μm in diameter. These abnormal vascular channels are often present diffusely through the lung and result in intrapulmonary shunting and consequent hypoxemia.
POPH and HPS characteristics
Differentiating characteristics of portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are identified.
In contrast to POPH, intrapulmonary vasoconstriction, in situ thrombosis and plexiform lesions are not part of the pathophysiology of HPS. Patients with HPS typically present with dyspnea and hypoxemia that is often worse in the upright position (platypnea and orthodeoxia, respectively). Clubbing may be seen. The degree of hypoxemia can range from mild to very severe, and patients may present with resting cyanosis. Pulmonary function tests typically show a low diffusing capacity.
The room air resting PaO2 is used to grade severity of HPS:
- Mild: ≥ 80 mm Hg
- Moderate: ≥ 60 to < 80 mm Hg
- Severe: ≥ 50 to < 60 mm Hg
- Very severe: < 50 mm Hg
Diagnosis of HPS requires the demonstration of intrapulmonary shunting in the setting of hypoxemia. Contrast transthoracic echocardiography (bubble study) is a simple, sensitive and noninvasive test for the diagnosis of HPS and is recommended for both diagnosis and screening. The test involves the injection of agitated saline (microbubble diameter approximately 8 to 15 μm) via a peripheral vein.
Transthoracic echocardiography bubble study
Microbubbles from agitated saline are injected into a peripheral vein and appear in the right atrium and ventricle (bottom left). Their appearance in the left heart three to six cardiac cycles later (bottom right) indicates intrapulmonary shunting.
The appearance of bubbles in the left atrium three to six cardiac cycles after their initial appearance in the right atrium indicates intrapulmonary shunting. A quantitative measure of shunting can also be obtained by the brain shunt index using 99m-labeled macroaggregated albumin. Neither test distinguishes IPVDs from discrete pleural or pulmonary arteriovenous malformations, which can occasionally be seen in HPS and may be amenable to percutaneous embolization, coiling or both. Other causes of hypoxemia such as POPH, COPD, ascites, pulmonary embolism, interstitial lung disease and hepatic hydrothorax need to be excluded during the evaluation process.
Liver transplantation is currently the only proven treatment for HPS and results in resolution of hypoxemia and shunting in almost all patients within the first year of transplant. Overall, post liver transplant survival in patients with HPS is similar to outcomes in ESLD patients without HPS. Even patients with severe hypoxemia have excellent survival and outcomes post-transplant.
Therefore, the severity of hypoxemia alone should not be a barrier to liver transplantation in otherwise suitable candidates, according to an article by Vivek N. Iyer, M.D., at Mayo Clinic's campus in Rochester, Minnesota, and others in the June 2013 issue of Hepatology.
Given the significant adverse impact of HPS on survival, patients with a resting room air PaO2 < 60 mm Hg receive additional MELD points to facilitate early transplantation. Thus HPS should be a diagnostic consideration in all ESLD patients with dyspnea or hypoxemia or both.
Mayo Clinic has developed an organization-wide diagnosis and treatment algorithm for POPH and HPS. Mayo Clinic Pulmonary and Critical Care Medicine participates in interventional trials, including Sorafenib for Hepatopulmonary Syndrome (SHPS) and Ambrisentan in Patients With Porto-pulmonary Hypertension: A Multicenter Open Label Trial (Portopulm), as well as prospective cohort studies.
An ongoing Mayo Clinic prospective cohort study of POPH patients (over 250 patients enrolled to date) provides a foundation to facilitate further clinical research in these disorders.
For more information
Iyer VN, et al. Hepatopulmonary syndrome: Favorable outcomes in the MELD exception era. Hepatology. 2013;57:2427.
University of Pennsylvania. Sorafenib for Hepatopulmonary Syndrome (SHPS). ClinicalTrials.gov.
Tufts Medical Center. Ambrisentan in Patients With Porto-pulmonary Hypertension: A Multicenter Open Label Trial (Portopulm). ClinicalTrials.gov.