Pulmonary Complications of Cirrhosis

Rowen K. Zetterman, MD


January 16, 2013

In This Article

Hepatopulmonary Syndrome

Hypoxemia is common in patients with end-stage liver disease, with a prevalence that has been reported to be as high as 45% of carefully evaluated patients.[14] When patients awaiting liver transplantation are assessed,15%-30% have hepatopulmonary syndrome.[15,16]

The characteristics of hepatopulmonary syndrome include an oxygen saturation < 80%, an increased alveolar-arterial gradient (> 15 mm Hg) while breathing room air, portal hypertension with or without cirrhosis, and dilation of intrapulmonary vessels.

Dilated pulmonary vessels (15-100 µm in diameter) are characteristic and may be diffuse or localized to pulmonary segments. Pleural and pulmonary arteriovenous and portopulmonary shunts have been described, although portopulmonary shunts appear to be of little clinical significance. These changes result in right-to-left shunting and reduced oxygenation of pulmonary venous blood as a result of ventilation-perfusion mismatch. This mismatch is a consequence of persistent ventilation of alveoli that are deprived of blood flow by intrapulmonary shunts or by rapidity of blood flow past alveoli in dilated vascular channels.

The mechanisms for hepatopulmonary syndrome and its anatomic changes are unknown. Considerations include production of vasodilator substances by the diseased liver, failure to remove vasodilator substances from the circulation, and local production within the lung of factors such as nitric oxide. Nitric oxide concentrations are elevated in the expired air of patients with hepatopulmonary syndrome,[17] and the rise in nitric oxide synthetase that occurs in the pulmonary endothelial cells of patients with hepatopulmonary syndrome can increase nitric oxide synthesis.[18] Endothelial-1 and tumor necrosis factor-alpha might also have a role in the production of increased nitric oxide in patients with advanced liver disease.[19]

Pulse oximetry is a useful screening test, although it can underestimate disease in early hypoxemia. Orthodeoxia, an arterial desaturation that occurs upon assuming an upright posture (or from supine to standing) with a fall in PaO2 of ≥ 5%, can be demonstrated in these patients. Arterial blood gases are the test of choice for confirmation of hepatopulmonary syndrome. Hypoxemia occurs in cirrhosis,[16,20] and evidence of an alveolar-arterial oxygen difference of > 15 mm Hg (or > 20 mm Hg in those 65 years of age or older) while breathing room air can establish the diagnosis. Moderate hypoxemia is defined by a PaO2 of 60-80 mm Hg and severe disease by a PaO2 of 50-60 mm Hg. A PaO2 of < 200 mm Hg in 100% oxygen should also raise suspicion for hepatopulmonary syndrome.

Contrast-enhanced echocardiography can provide a qualitative estimate of shunting following injection of microbubbles into the venous system. The appearance of microbubbles in the left heart within 3-6 cardiac cycles after the appearance of microbubbles in the right heart is indicative of right-to-left shunting. Echocardiography can also identify right ventricular diastolic dysfunction.[21]

Ventilation-perfusion lung scanning using macroaggregated albumin can be a quantitative measure of right-to-left shunting because these macroaggregates are typically trapped within the lung vasculature and do not reach the systemic circulation. The appearance of > 6% of the macroaggregate uptake in the brain and kidney indicates that vascular channels are sufficiently large to permit particles to pass through the lungs to reach systemic sites.

When hepatopulmonary syndrome accompanies severe end-stage liver disease, the prognosis is poor, with an average survival of 11 months.[22] A more recent study comparing patients with hepatopulmonary syndrome with patients who had liver disease of similar clinical severity, but who lacked evidence of hypoxemia, suggests that patients with hypoxemia have a median 5-year survival of 25% vs 63% in those lacking hypoxemia.[23]

Hepatopulmonary syndrome should be suspected in patients with exertional dyspnea or platypnea. Clubbing, cyanosis, and multiple spider angiomata may be observed. The presence of multiple spiders is associated with more severe pulmonary vasodilation and hypoxemia.[24] In addition to a reduced PaO2, hypocapnia and respiratory alkalosis are often seen on arterial blood gases.[20]

Chest radiographs can reveal increased parenchymal markings in the lung bases from the dilated pulmonary vasculature, and CT scans can identify dilated subpleural vessels extending to the pleural surface. Pulmonary arteriography is rarely needed to establish a diagnosis of hepatopulmonary syndrome. If performed, it might show subpleural telangiectatic vessels, arteriovenous malformations, or nodular dilation of peripheral pulmonary vessels.[25]Pulmonary function testing often demonstrates impaired diffusing capacity.[26]

The treatment should include administration of oxygen, especially in patients with a PaO2 < 60 mm Hg. Medications such as somatostatin analogues, corticosteroids, cyclophosphamide, cyclooxygenase inhibitors, and nitric oxide antagonists have been tried but none have been found effective. TIPS has been used as therapy but the evidence is insufficient to recommend its routine use.

The presence of hepatopulmonary syndrome is an indication for liver transplantation because it is the only therapy currently available to patients with significant hypoxemia. The pretransplant evaluation should include arterial blood gases, contrast-enhanced transthoracic echocardiography, arterial blood gases after 100% oxygen administration, and estimation of pulmonary shunting using macroaggregated albumin scanning.[23] Patients with preoperative blood gases showing a PaO2 < 50 mm Hg and a shunt fraction of 20% or more will have a posttransplant mortality risk of up to 30% at 1 year.[27,28] Some improvement of postoperative outcomes in patients with severe pretransplant hypoxemia can be achieved with early prophylactic tracheotomy, prolonged ventilator management, good nursing care, and improved oxygenation both pre-and postoperatively.

Currently, patients with a PaO2 < 60 mm Hg are granted higher priority for liver transplantation. Resolution of hepatopulmonary syndrome generally follows liver transplantation, with a 5-year survival of 70% or more,[27] although increase in biliary complications has been reported.[29]