The hepatopulmonary syndrome

Definition

The diagnostic features of HPS include presence of liver disease or portal hypertension, an elevated age-adjusted alveolar-arterial oxygen gradient (AaPO2), and evidence of intrapulmonary vasodilatation^{1 , 2 , 3 , 14 , 17 , 19}. It is classically defined by a widened alveolar-arterial oxygen gradient (AaPO2) on room air (>15 mmHg, or >20 mmHg in patients >64 years of age) with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension ^{4 , 17 , 18}. In the presence of coexisting cardiac or pulmonary disease, establishing a diagnosis of HPS can be difficult ¹⁹.

Clinical manifestations

Involve respiratory findings associated with chronic liver disease. The insidious onset of dyspnea, particularly on exertion, is the most common complaint, but is not specific. Others symptoms may be present as platypnea and orthodeoxia^{5 , 6}. Spider angiomata are commonly reported but are frequently seen in cirrhotic patients without HPS. Finally, clubbing and distal cyanosis, when present in the setting of liver disease or portal hypertension, should raise suspicion². The majority of patients with HPS are either asymptomatic, particularly if diagnosed during evaluation for liver transplantation. Some cases develop the insidious onset of dyspnea^{4 , 8}.

Diagnosis

HPS diagnosis depends initially on the presence of liver disease or portal hypertension, an elevated age-adjusted alveolar-arterial oxygen gradient (AaPO₂), and evidence of intrapulmonary vasodilatation⁷. It can normally be diagnosed with non-invasive tests. Its diagnosis is suspected based on history and physical exam; arterial blood gas analysis should be performed while breathing room air on pulse oximetry^{2 , 4}. An elevated alveolar-arterial gradient and decrease in arterial blood gas occurs due to the dilatation of pulmonary vasculature leading to shunt with ventilation-perfusion mismatch ¹⁷.

The arterial blood gas reveals an elevated age-adjusted AaPO₂ with or without hypoxemia. In detecting gas exchanges abnormalities, chest radiography and pulmonary function tests for evaluation the presence of other pulmonary abnormalities should be performed. The transthoracic microbubble contrast echocardiography is the preferred screening test for intrapulmonary vasodilatation. Pulmonary angiography, technetium-labeled macroaggregated albumin scan and chest computerized tomography could be useful in some specific situations^{9 , 11 , 14 , 16 , 19} _.

Classification

The ERS Task Force has proposed a classification using arterial oxygen tension (PaO₂) to stage the severity of HPS: PaO₂<50 mmHg indicates very severe; PaO₂50 <60 mmHg suggests severe; and a PaO₂ 60 and <80 mmHg corresponds with moderate stages¹⁷.

Krowka et al.⁷ demonstrated two angiographic patters: type I, or diffuse, normal vessels or fine diffuse spidery arterial vascular abnormalities and type II, or focal, more infrequent, consisted of similar focal arteriovenous communications (Figure 1). Patients with advanced type I or type II, may exhibit a poor response to oxygen breathing⁷.

Figure 1 Hepatopulmonary syndrome classifications 

Treatment

The oxygen supplementation keeps a mainstay of therapy with a PaO₂<60 mmHg or with oxigen desaturation exercise-induced^{8 , 16}. The transjugular intrahepatic portosystemic shunt (TIPS) had limit utility in HPS and need more clinical trials to define the efficacy¹⁵. There are currently no effective medical therapies for HPS.

Hepatopulmonary syndrome algorithm therapeutic proposed by ERS Task Force is detailed in Figure 2.

Figure 2 Hepatopulmonary syndrome therapeutic algorithm 

Liver transplantation is the only effective established therapy for HPS ^{4 , 8}. The total resolution or significant improvement in gas exchange post-liver transplant is observed in more than 85% of reported patients and arterial hypoxemia normalization after transplantation is variable and may be superior to one year ^{4 , 19}.

Outcomes

The causes of death in patients with HPS were mainly due to complications of hepatocellular dysfunction and portal hypertension, and correlated with the severity of hypoxemia. It has been reported that HPS can increase the mortality of patients with liver cirrhosis, especially in those with severe hypoxemia^{6 , 11 , 14 , 19}.

Mortality after liver transplantation also appears to be higher in patients with HPS compared to those without. The strongest predictors of post-liver transplantation mortality were the preoperative PaO₂<50 mmHg alone or in combination with a macroaggregated albumin shunt fraction of 20%^{3 , 8}. A prospective study found that those with severe HPS (PaO₂<50 mmHg) had an important increase in post-liver transplantation mortality³.

HPS increases mortality and liver transplant outcomes and may worsen in cases of advanced stages. Therefore, the worldwide centers may improve the increase priority for liver transplantation in patients with HPS and significant hypoxemia. The MELD score does not apply and reduce the survival in waiting liver transplant list patients in those patients that HPS affect decreasing quality of life^{3 , 4 , 6 , 8}. Liver transplantation has been considered as the only therapy established to reverse intrapulmonary vasodilation, but the postoperative mortality is still high in patients with a partial pressure of oxygen lower than 50 mmHg. A better understanding of the pathophysiological mechanism underlying HPS will help to better guide its treatment^{1 , 2 , 17 , 18}.