Hepatopulmonary syndrome: More than just a matter of tone?
Authors: Michael B. Fallon
Journal: Hepatology (2006)

The hepatopulmonary syndrome (HPS) results when intrapulmonary vascular dilatation triggers abnormal gas exchange in the setting of liver disease and/or portal hypertension.1 Over the last 15 years, this syndrome has emerged as an important clinical complication of cirrhosis and portal hypertension that is found in 10% to 20% of patients being evaluated for orthotopic liver transplantation.2, 3 Recent studies support that the presence of HPS significantly increases mortality in cirrhosis, particularly in those with decompensated liver disease.4, 5 A significant component of the increased mortality in these studies was due to well recognized complications of portal hypertension and hepatic failure suggesting that hypoxemia may worsen liver disease. Currently, liver transplantation is the only successful treatment for HPS, although postoperative mortality is increased in the setting of HPS, especially when hypoxemia is severe.6 Based on this data, patients in the United States with HPS who have an arterial PaO2 less than 60 mm Hg are eligible for increased priority for liver transplantation. HPS, hepatopulmonary syndrome; NO, nitric oxide. The pathogenesis and the precise nature of pulmonary vascular abnormalities in HPS are areas of active investigation. To date, the major focus of studies has been on characterizing increased pulmonary production of vasodilator substances, most notably nitric oxide (NO). In the rodent chronic common bile duct ligation model, both increased endothelial nitric oxide synthase derived NO production in the pulmonary microvascular endothelium as well as enhanced inducible nitric oxide synthase production in intravascular macrophages appear to contribute to changes in the microvasculature.7, 8 During the onset of HPS after biliary obstruction, increased biliary production and release of endothelin-1 and enhanced pulmonary microvascular endothelin B receptor expression lead to ET-1 mediated eNOS-derived NO overproduction.9 During the progression of HPS, increased tumor necrosis factor alpha production associated with bacterial translocation contributes to intravascular macrophage accumulation and inducible nitric oxide synthase expression.10 Recently, increased intravascular macrophage heme oxygenase-1 expression and carbon monoxide overproduction have been identified after common bile duct ligation and also appear to contribute to changes in the microvasculature.11 In human HPS, pulmonary NO overproduction, as assessed by exhaled NO levels has also been found.12 In addition, indirect evidence suggests that carbon monoxide overproduction may also be present.13 A case report using inhaled L-NAME, a specific nitric oxide synthase inhibitor, and a small case series using methylene blue, an inhibitor of cyclic guanosine monophosphate generation by guanylate cyclase showed short term improvement in oxygenation in HPS after acute administration.14, 15 These human studies support that pulmonary NO and cyclic guanosine monophosphate production contribute to changes in pulmonary vascular tone that influence oxygenation. The relative importance of changes in pulmonary vascular tone and changes in microvascular architecture, including vascular remodeling, angiogenesis and vasculogenesis, in the gas exchange abnormalities in experimental and human HPS are undefined. In experimental HPS, increased numbers of pulmonary vascular capillaries have been observed by electron microscopy16 but no detailed analysis has been undertaken and the acute effects of inhibition of nitric oxide production on pulmonary vascular tone and gas exchange have not been reported. In human cirrhosis, pulmonary vascular dilatation and "spider nevi" have been observed but are not confined to patients with established HPS.17 The observation that the resolution of HPS after liver transplantation may require prolonged periods of time also indirectly suggests that architectural alterations that take time to resolve are present.18 Understanding the precise nature of the changes in the pulmonary microvasculature is of significant potential importance for understanding the pathogenesis of and defining effective medical therapies for HPS. Although NO may be a key mediator in both alterations in tone and architecture in the pulmonary vasculature, the specific signaling pathways and contributing mediators are likely to be distinct. These pathways may provide novel targets with more precise and localized effects within the pulmonary vasculature. The study by Gómez et al. assesses the effects of a single dose of inhaled L-NAME in 10 patients with evidence of intrapulmonary vascular dilatation and varying degrees of gas exchange abnormalities.19 The design includes a comprehensive and well performed analysis of systemic and pulmonary hemodynamics, ventilation-perfusion distributions using the multiple inert gas elimination technique, arterial blood gases and measurement of exhaled NO and serum nitrite/nitrate levels. The authors find that despite inducing a significant decline in exhaled NO levels and a modest amelioration of hyperdynamic circulatory changes, L-NAME does not improve gas exchange abnormalities or improve ventilation-perfusion alterations. They conclude that vascular remodeling rather than NO dependent vasodilatation may be a more important cause of gas exchange abnormalities in HPS. Several important questions are raised by the findings in the current study. First, why are the results found here different from those found in the two prior reports? Second, do the current results clearly define vascular remodeling as a major factor in human HPS? It is important to recognize that the numbers of patients in each of the studies is small. In the current report the group is quite heterogeneous. Specifically, 4 of the patients have minimal gas exchange abnormalities and have alveolar arterial oxygen gradients within age-corrected normal values. It is difficult to be certain that these patients have significant gas exchange abnormalities due to intrapulmonary vascular dilatation. In addition, 5 of the patients were actively smoking, a factor which is recognized to influence endothelial function and NO signaling and which may influence HPS.20 Finally, despite the overall lack of effect on gas exchange, 2 patients had some improvement in oxygenation over the time period studied. These results suggest that patient and possibly disease heterogeneity may influence experimental findings. When compared to the study using methylene blue, the patients in the current report had less severe baseline hyperdynamic circulatory changes, less amelioration in these changes and less improvement in gas exchange after treatment. Of particular note, the maximum increase in pulmonary vascular resistance after methylene blue administration was markedly greater than that seen after L-NAME inhalation. As the authors note, this difference could reflect that mediators distinct from NO, such as CO, might be involved in modulating vascular tone or could reflect incomplete inhibition of pulmonary NO production by the dose of L-NAME used. Regardless, the findings support that at least in some patients with HPS, modulating pulmonary vascular tone can acutely improve gas exchange. Although the current work does not clearly establish a role for vascular remodeling, angiogenesis or vasculogenesis in HPS, Gómez and colleagues have provided new and important insights that serve to broaden our thinking about what happens in the pulmonary microvasculature of patients with HPS. It is attractive to speculate that chronic pulmonary overproduction of a number of vasoactive mediators, including NO, coupled with systemic inflammation and potential genetic susceptibility may result in variable combinations of alterations in pulmonary microvascular architecture and tone that lead to gas exchange abnormalities. In this regard, insights from studies of the mechanisms of portosystemic collateral formation21 may provide important areas for study and therapeutic targeting. In addition, one might wonder whether more chronic administration of inhaled L-NAME would be of benefit in the pulmonary microvasculature in such a situation. However, the safety and efficacy of widespread NO inhibition resulting from systemic absorption of inhaled L-NAME is unknown. Nonetheless, as our understanding of the nature of vascular alterations in liver disease grows, so do the potential mechanisms. It is now time for us to consider and define whether HPS is more than just a matter of tone.