A 49-year-old woman with known alcohol related liver disease (Model for End-Stage Liver Disease score of 6) was referred to our center for consideration for liver transplantation (LT). She had successfully undergone variceal band ligation 5 years previously following her index bleed. Past medical history was unremarkable but she was smoking two cigarettes per day with a past history of 30 pack-years. On examination, she was noted to have digital clubbing (Fig. 1), peripheral cyanosis, and spider nevi. Clinical examination was unremarkable.
Arterial blood gas analysis on room air demonstrated type 1 respiratory failure (partial pressure of oxygen in arterial blood [PaO2] = 7.44 kPa, PaCO2 = 4.34 kPa) with an increased alveolar-arterial gradient (P[A-a]O2) of 7.1 kPa (normal range = 2-3 kPa). Orthodeoxia was also evident (supine PaO2 = 7.44 kPa; standing PaO2 = 6.18 kPa). A chest radiograph was normal. Pulmonary function tests (PFTs) demonstrated a mild obstructive pattern (1-second forced expiratory volume [FEV1]/forced vital capacity [FVC] 68% and a FEV1 75% of predicted value) and computed tomography (CT) of the chest demonstrated mild emphysematous changes only with no evidence of lung malignancy. The patient underwent a two-dimensional transthoracic contrast echocardiogram with agitated saline, which demonstrated echogenic microbubbles appearing first in the right cardiac chambers followed by appearance within the left chambers after three cardiac cycles (Fig. 2A-C). A diagnosis of moderate hepatopulmonary syndrome (HPS) was made.
Respiratory symptoms are common in patients with chronic liver disease, dyspnea being reported in 70% of patients being assessed for LT.1 Our patient had a positive smoking history and mild emphysematous changes on chest CT, but only a mild obstructive pattern on PFTs. HPS is characterized by a triad of hepatic dysfunction, an arterial oxygenation defect (with or without hypoxemia), and evidence of intrapulmonary vascular dilatations.2 HPS most commonly occurs in patients with cirrhosis, affecting 4%-29% of these patients,3, 4 although this is thought to be an underestimate due to the nonspecific symptoms, i.e., fatigue and dyspnea. Nitric oxide–mediated pulmonary vasodilatation, probably secondary to increased intestinal bacterial translocation, and increased pulmonary angiogenesis both contribute to the pathogenesis of HPS.5
Clinical signs include spider nevi, cyanosis, clubbing, and telangiectasia. Although digital clubbing is not a specific sign for HPS, its occurrence with hypoxia in a patient with liver disease is suggestive of HPS. Platypnea (dyspnea exacerbated when sitting up and improved when lying down) and orthodeoxia are both described and occur because of worsening ventilation-perfusion matching and an increase in shunt fraction in the upright position secondary to increased perfusion of lower lobes. The diagnosis of HPS is made by demonstrating hypoxemia and evidence of pulmonary shunting. Chest CT findings include distal vascular dilatation associated with an abnormally large number of visible terminal vessel branches concentrated in the lower zones.6 An increased ratio of the segmental arterial diameter to the adjacent bronchial diameter has also been described in patients with HPS when compared to patients with normoxemic cirrhosis.6 The appearance of microbubbles in the left heart three-six cardiac cycles after contrast enters the right heart is diagnostic of pulmonary shunting. Technetium-99–labeled macroaggregated albumin can also be used, and is diagnostic of HPS with appearance of technetium in the brain or spleen.
Treatments for HPS remain limited. Patients usually require long-term home oxygen therapy. The benefit of coil embolization of pulmonary shunts remains unproven. The mainstay of treatment has been LT with reported 5-year survival rates of 76% versus 23% for those who did not undergo LT,7 but it may take months for an improvement in hypoxemia and shunt fraction.
HPS is an underdiagnosed but important complication of chronic liver disease. Clinical clues, such as hypoxemia and clubbing, should prompt a diagnostic assessment for HPS, and when diagnosed, the patient should be considered for potential LT.