ADVANCES IN HEPATOLOGY C u r r e n t D e v e l o p m e n t s i n t h e Tr e a t m e n t o f H e p a t i t i s a n d H e p a t o b i l i a r y D i s e a s e

Section Editor: Eugene R. Schiff, MD

Current Research and Management of Hepatopulmonary Syndrome Michael B. Fallon, MD

Professor of Medicine University of Alabama, Birmingham

G&H Could you describe the pathogenesis of the hepatopulmonary syndrome and the ways that liver disease affects the pulmonary system? MF The pathogenesis of the hepatopulmonary syndrome (HPS) involves pulmonary microvascular dilatation. It may also involve remodeling or angiogenesis. These changes impair the ability of oxygen to diffuse from the alveoli to the vasculature and result in impaired oxygenation, a primary clinical feature of HPS. The specific mechanisms through which liver disease causes pulmonary vascular abnormalities are not fully understood. We do know that HPS most commonly develops in the setting of cirrhosis and portal hypertension although it can also develop in patients with portal hypertension from other causes, including portal vein thrombosis and Budd-Chiari syndrome. Therefore, in most cases, HPS occurs in the setting of portal hypertension and a hyperdynamic circulatory state. However, there are also cases reported in acute viral and ischemic hepatitis and in chronic hepatitis, supporting the idea that significant portal hypertension is not an absolute requirement. Beyond this understanding, the precise events that result in vasodilatation in humans are not clear. One factor appears to be overexpression of endothelial nitric oxide synthase (eNOS) in the endothelium of the microvasculature of the lung. This generates excess nitric oxide, which is a vasodilator, and may also trigger or at least contribute to angiogenesis. In animal models, changes in endothelin signaling and receptors in the microvasculature of the lung contribute to eNOS overexpression. In addition,

these models support the idea that bacterial translocation and increased levels of tumor necrosis factor (TNF)-alfa occurring in cirrhosis/portal hypertension also contribute to alteration in lung vasculature. However, how these changes contribute in humans is still in question. G&H Do these endothelial changes take place specifically in the pulmonary vasculature or are they systemic? MF There are systemic changes in the endothelium that occur in the setting of cirrhosis. However, in patients who develop HPS, additional unique changes occur in the lungs. In the cirrhotic liver, the endothelium is dysfunctional and there is impairment of nitric oxide release, which contributes to portal hypertension. In the lung of patients with HPS, there appears to be too much nitric oxide synthase and too much nitric oxide is generated. This excess is also seen in the splanchnic and peripheral vessels as well and is one manifestation of the hyperdynamic state associated with cirrhosis. Because not every cirrhotic patient with a hyperdynamic circulation develops HPS, those who do develop HPS most likely have an additional unique susceptibility. The nature of this susceptibility is currently under study. G&H What therapeutic options are currently available to patients with HPS? MF There are no established effective medical therapies for HPS. There are case studies to suggest that some medical therapies might work but the only known modality to cure HPS is liver transplantation. In patients with HPS who undergo transplantation, perioperative mortal-

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ity appears to be greater than that in non-HPS patients. Generally, the more severe the HPS, the higher the risk of the operation. G&H Given the curative effect and increased mortality that are both associated with liver transplantation in HPS patients, how does the presence of the syndrome affect the decision to operate?

monary shunting), as many as 30% of cirrhotics will have it. If only HPS patients with hypoxemia (arterial PO2