Pulmonary Complications of Cirrhosis

Rowen K. Zetterman, MD


January 16, 2013

In This Article

Portopulmonary Hypertension

Pulmonary hypertension occurs in patients with portal hypertension, typically owing to cirrhosis. However, pulmonary hypertension does not predict the severity of associated liver disease and can develop in patients with portal hypertension but without cirrhosis. The onset is insidious, and other causes of pulmonary hypertension (such as multiple pulmonary emboli) should be excluded. Approximately 5% of patients with end-stage liver disease will develop pulmonary hypertension.[30] Women and patients with autoimmune hepatitis may be at greater risk, and those with hepatitis C are at lower risk for pulmonary hypertension.[31] Volume overload from sodium retention can contribute to elevation of pulmonary artery pressures. Patients with pulmonary hypertension often lack ascites.[31] Pulmonary hypertension can also develop following liver transplantation.[5]

Portopulmonary hypertension is characterized by a mean pulmonary artery pressure > 25 mm Hg at rest or > 30 mm Hg with exercise, increased pulmonary vascular resistance (> 240 dynes/sec/cm-5), and a pulmonary capillary wedge pressure < 15 mm Hg (normal left atrial pressure) occurring in a patient with portal hypertension. Portopulmonary hypertension is classified as mild (25-34 mm Hg), moderate (35-44 mm Hg), or severe (> 45 mm Hg).

The mechanism of pulmonary hypertension in the presence of portal hypertension with or without cirrhosis is unclear and is independent of the cause of portal hypertension. A hyperdynamic systemic circulation with increased cardiac output and reduced systemic vascular resistance is present in roughly half of patients with end-stage liver disease.[32] High cardiac output can result in pulmonary artery shear forces that cause endothelial cell proliferation and increased smooth muscle cells in the vessel wall. A role has been suggested for vasoconstrictor substances such as endothelin-1.[33] Circulating levels of endothelin are increased in patients with advanced liver disease, and the presence of portosystemic shunts might increase the quantity of endothelin reaching the lung.[34] Other vasoconstrictor substances might also be released to produce increased pulmonary vascular resistance.

Patients with early disease are often asymptomatic or present with dyspnea.[35] Progressive symptoms include dyspnea on exertion, orthopnea, fatigue, and syncope. Syncope is a late sign of pulmonary hypertension and carries a poor prognosis. Patients often complain of chest discomfort or palpitations. Physical findings include tricuspid regurgitation, an increased P2, and evidence of right heart failure including a right-sided S3 gallop, jugular venous distention, and peripheral edema. If the patient has liver disease, clinical signs of portal hypertension, such as ascites, are often present.

Patients with portal hypertension and dyspnea should be screened by echocardiography to estimate pulmonary arterial pressure. Right ventricular systolic pressures > 40-50 mm Hg should prompt evaluation to confirm the diagnosis. If pulmonary artery pressures at echocardiography are uncertain, right heart catheterization should be performed. Pericardial effusions develop in patients with portopulmonary hypertension.[31] Routine chest x-rays can be normal or demonstrate prominent central pulmonary arteries and right atrial and right ventricular enlargement.[36] An ECG might identify right ventricular hypertrophy, right axis deviation, and/or right bundle branch block. Arterial blood gases typically show low pCO2 and bicarbonate levels with alkalosis due to hyperventilation. Elevated levels of atrial natriuretic peptide are reported.[37]

Patients with portopulmonary hypertension develop intrapulmonary arterial changes similar to those of patients with primary pulmonary hypertension including endothelial and smooth muscle cell proliferation, vasoconstriction, and vascular remodeling that results in fibrosis and obliteration of pulmonary arteries.[38]

The prognosis is poor for patients with portopulmonary hypertension. Early studies suggested a median survival of 6 months and a 5-year survival of < 10%,[39] although more recent studies have found a 5-year survival of 50%.[40] The prognosis of portopulmonary hypertension is worse than that for primary pulmonary hypertension because of associated liver disease.

Diuretic therapy to reduce intrapulmonary vascular volume can have a modest effect on pulmonary artery pressure and improvement of right ventricular function. Beta-blockers are generally discouraged because of their potential vasoconstrictor effect on pulmonary vessels, although little evidence indicates that these drugs should be discontinued when they are prescribed to reduce the risk for bleeding from portal hypertension. Intravenous pulmonary vasodilators have been administered to reduce both vascular resistance and pulmonary artery pressure. Prostanoids, such as epoprostenol, can be administered continuously through a dedicated central venous line. Bosentan, an endothelin-receptor antagonist, also has been used, as have phosphodiesterase-5 inhibitors such as sildenafil.[41,42] Oral therapy with sildenafil can be tried in patients with mild disease, although prostanoids should be used for severe pulmonary hypertension.

Pulmonary hypertension is no longer considered an absolute contraindication to liver transplantation, and patients with mild disease can usually proceed directly to transplantation. Pretransplant evaluation should determine whether pulmonary artery pressures require pretransplant therapy.[43] The goal should be to improve right ventricular function and reduce the mean pulmonary artery pressure to < 35 mm Hg before liver transplantation.[44] Posttransplant mortality is approximately 40% in patients with pressures > 35 mm Hg and 70%-100% in those with pulmonary artery pressures > 45 mm Hg.[45,46] Combined liver, lung, and cardiac transplantation might be required in patients with very high pulmonary artery pressures who are unresponsive to intravenous therapy.[47]

All patients considered for liver transplantation should be evaluated for pulmonary hypertension. Patients who have a mean pulmonary artery pressure < 35 mm Hg and pulmonary vascular resistance < 240 dynes/sec/cm5 can proceed to transplantation, whereas those with pulmonary artery pressures > 35 mm Hg and pulmonary vascular resistance > 240 dynes/sec/cm5 should be treated before transplantation to see whether adequate reduction of pulmonary artery pressure can be achieved.[48] Of patients transplanted with pulmonary hypertension, most can stop their intravascular therapy within 6-12 months of transplantation.

Key Points

Pulmonary symptoms are common in patients with liver disease. Dyspnea can be an early sign of pleural effusion, hepatopulmonary syndrome, or portopulmonary hypertension. Other causes of pulmonary disease should also be considered and excluded. Chronic lung diseases from smoking, chronic bronchitis, and asthma can also occur in patients with cirrhosis, and diseases such as alpha-1 antitrypsin deficiency, sarcoidosis, and cystic fibrosis can produce both liver and lung disease. Patients with intractable hepatic hydrothorax (pleural effusion), hepatopulmonary syndrome, and portopulmonary hypertension should be evaluated for liver transplantation.