Elsevier

The Lancet

Volume 363, Issue 9419, 1 May 2004, Pages 1461-1468
The Lancet

Review
Portopulmonary hypertension and hepatopulmonary syndrome

https://doi.org/10.1016/S0140-6736(04)16107-2Get rights and content

Summary

The clinically and pathophysiologically distinct entities of portopulmonary hypertension and hepatopulmonary syndrome occur in a substantial proportion of patients who have advanced liver disease of different causes. These disorders are notoriously underdiagnosed, but they have a substantial impact on survival and require focused treatment. Abnormal intrapulmonary vascular dilatation, the hallmark of hepatopulmonary syndrome, can cause profound hypoxaemia that can be very difficult to treat. By contrast, portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure. Insights into the pathogeneses of these syndromes have led to novel therapeutic approaches. However, in severely affected patients, effective treatment remains a difficult task. In selected patients, liver transplantation represents the only treatment option, but the decision to do isolated liver transplantation is particularly challenging in patients who have severe pulmonary disease involvement. Data from several centres have contributed to provide criteria that allow improved prediction of which patients may, or may not, benefit from liver transplantation alone.

Section snippets

Portopulmonary hypertension

Haemodynamically, portopulmonary hypertension is defined by the presence of the following features in patients with portal hypertension: raised pulmonary arterial pressure (mean pressure determined by right-heart catheterisation of >25 mm Hg at rest and >30 mm Hg during exercise);4 raised pulmonary vascular resistance (>240 dyne s−1 cm−5) in the presence of a pulmonary arterial occlusion pressure; or a left-ventricular end-diastolic pressure of less than 15 mm Hg. According to the current WHO

Pathogenesis

The development of portopulmonary hypertension seems to be independent of the cause of portal hypertension. Although most patients with portopulmonary hypertension have cirrhosis as the underlying disease, the syndrome has been described in patients with portal hypertension due to non-hepatic causes, such as portal venous thrombosis in the absence of chronic hepatic disease.13 Thus, portal hypertension seems to be the required driving force of pulmonary hypertension.

The mechanisms by which

Symptoms and diagnosis

The most common presenting symptom in patients with pulmonary hypertension, irrespective of its cause, is progressive dyspnoea on exertion.12 Other symptoms such as fatigue, palpitations, syncope, or chest pain are less frequent. Physical findings indicating pulmonary hypertension are generally subtle and may be completely absent. The most common findings are an accentuated pulmonary component of the second heart sound and a systolic murmur, indicating tricuspid regurgitation. Extended jugular

Management

Patients who have mild portopulmonary hypertension frequently have no symptoms and signs of pulmonary vascular disease. In these patients, specific treatment of pulmonary hypertension is not generally required. However, regular follow-up examinations, including biannual to annual echocardiographic examinations, are advisable to monitor the potential progression of pulmonary disease. Even mild to moderate portopulmonary hypertension can pose a notable threat to patients in special situations,

Anticoagulation

Anticoagulation is recommended in patients who have primary pulmonary hypertension because it can slow disease progression.26, 27 Efficacy and safety of oral anticoagulants in patients with portopulmonary hypertension have not yet been assessed in trials. Many such patients do not receive anticoagulants because of an increased risk of haemorrhagic complications, especially if there is a history of bleeding from oesophageal or gastric varices. In addition, the failure of liver synthesis leads to

Pharmacotherapy

Intravenous epoprostenol is the best-studied drug in patients with portopulmonary hypertension. Although the efficacy and safety of epoprostenol in such patients has never been addressed in randomised controlled trials, strong evidence from several open-label studies shows that this drug given intravenously improves haemodynamics and exercise capacity in patients with portopulmonary hypertension.15, 28, 29 However, preliminary data from the Mayo Clinic suggest that intravenous epoprostenol does

Liver transplantation

Liver transplantation requires special consideration, and is likely to be beneficial only in a selected cohort of patients with portopulmonary hypertension. The presence of pulmonary hypertension of any severity increases the perioperative and long-term risks of liver transplantation.43 Clinical assessment protocols before liver transplantation should, therefore, specifically include a screening algorithm for portopulmonary hypertension in suspected cases, as outlined above. In addition,

Hepatopulmonary syndrome

The reported frequency of hepatopulmonary syndrome in patients with liver disease is between 4% and 29%.14, 54, 55, 56, 57 The differing incidence is primarily due to heterogeneity of the applied diagnostic criteria. This syndrome is a well-defined cause of hypoxaemia in patients who have liver disease due to abnormal intrapulmonary vascular dilatation, which results in an excess perfusion for a given state of ventilation. This complication is characterised by anatomical shunting and a

Pathogenesis

From a pathophysiological point of view, hepatopulmonary syndrome is almost exactly the opposite of portopulmonary hypertension. Evidence is growing rapidly that abnormal intrapulmonary vascular dilatation is linked to portal hypertension, which in itself leads to altered bowel perfusion and an increased rate of enteral translocation of gram-negative bacteria and endotoxin. This process in turn stimulates the release of vasoactive mediators, which include tumour necrosis factor α,

Symptoms and diagnosis

Patients with hepatopulmonary syndrome complain of progressive dyspnoea and can become increasingly cyanotic. Some patients develop clubbing, and cutaneous telangiectasias (spider angiomas) are typically seen in high numbers.60 In some instances, systemic arterioem-bolisation causing severe complications such as stroke, cerebral haemorrhage or brain abscess may occur.54, 86 Physical examination might reveal evidence of liver disease, but findings in the lungs and the heart are generally normal

Management

The treatment of hepatopulmonary syndrome includes the correction of hypoxaemia by administration of oxygen. However, in severe cases and the presence of right-to-left shunting, hypoxaemia might not be fully correctable.

Theoretically, the ideal treatment of hepatopulmonary syndrome would consist of a drug or any other means to reverse of intrapulmonary vascular dilatation. Unfortunately, this therapeutic goal cannot be fully achieved in most patients with the currently available treatments.

Future perspectives

Although portopulmonary hypertension and the hepatopulmonary syndrome are associated with the same underlying diseases, they have distinct pathophysiological backgrounds. The rapidly increasing knowledge of pulmonary vascular tone regulation and vascular remodelling, including the identification of genes that increase the risk of developing pulmonary vascular disease, will eventually lead to a specifically targeted treatment approach. The treatment of portopulmonary hypertension has been

Search strategy

We did an unrestricted MEDLINE search with use of the key words “porto-pulmonary hypertension”, “pulmonary hypertension and liver”, “pulmonary hypertension and cirrhosis”, and “hepatopulmonary syndrome”. For papers we deemed relevant for this review, we did a secondary search with the “related-articles” option in MEDLINE. We selected retrieved reports on the basis of their scientific merit and relevance for this review.

Conflict of interest statement

M M Hoeper has served as consultant for and

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