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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 mortality 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?
MF One of the reasons for increased perioperative mortality in HPS patients is that we have not traditionally screened for HPS in the general population of cirrhotics. HPS is often discovered when patients are symptomatic and cyanotic. Therefore, some of the increased mortality may be due a lack of recognition of HPS until it becomes severe. This concept underscores the need for increased screening for HPS in orthotopic liver transplant (OLT) candidates. Currently, HPS patients with moderate to severe hypoxemia (arterial PO2 <60 mm Hg) are eligible to receive increased transplant priority. Perioperative mortality has been found to be highest in HPS patients with severe hypoxemia (arterial PO2 <50 mm Hg) and significant intrapulmonary shunting, as measured by macro-aggregated albumin lung scanning (>20%). In these patients, careful assessment of comorbidities is advisable prior to determining if OLT is a reasonable option.
G&H Could you describe the HPS screening process?
MF Currently, there are no agreed upon guidelines for screening for HPS. What makes sense is to screen for hypoxemia and then look for further evidence of intrapulmonary shunting in those patients found to have low arterial PO2 values. A simple way to screen for hypoxemia is through pulse oximetry which is routinely available in most clinics. If pulse oximetry is low (< 96%), then arterial blood gas testing is appropriate. If hypoxemia is detected, then contrast echocardiogrphy (bubble echo) is performed to detect intrapulmonary vasodilatation. If hypoxemia and intrapulmonary shunting are present and evaluation does not reveal significant intrinsic cardiopulmonary disease, then the diagnosis of HPS is made.
G&H What is the prevalence of HPS uncovered by screening?
MF As we screen for HPS, we realize that it is not a rare complication of liver disease. Some physicians contend that they do not encounter it. I would argue that they may not be looking for it. If strict criteria for HPS are utilized (widened alveolar-arterial oxygen gradient with intrapulmonary shunting), as many as 30% of cirrhotics will have it. If only HPS patients with hypoxemia (arterial PO2 <70 mm Hg) are considered, approximately 12–20% of cirrhotics will be found to meet these criteria.
G&H How have transjugular intrahepatic portosystemic stent shunt procedures been studied in the setting of HPS?
MF The rationale for investigating transjugular intrahepatic portosystemic stent shunts (TIPS) as therapy for HPS stems from the idea that there may be a relationship between portal hypertension and HPS. Both liver transplantation and TIPS procedures will reverse or at least significantly improve portal hypertension and there is a rationale that if portal hypertension is eliminated, some of the factors leading to vasodilatation will be as well. Therefore, if HPS is a consequence of portal hypertension or portal hypertension is one of the key events that is required, relief of portal hypertension should improve HPS. There are some case reports that suggest that HPS is alleviated by TIPS. However, other cases suggest that TIPS is not effective in improving HPS. In any case, it is not uniformly effective and in this light should not currently be recommended as HPS therapy. However, if a patient needs a TIPS placed for another reason, then I would not advise against TIPS simply because HPS is present.
G&H Are any other potential therapies currently under investigation for HPS?
MF Our group is currently conducting a National Institutes of Health-sponsored pilot study using pentoxifylline (Trental, Sanofi-Aventis), which is an agent that inhibits the action of TNF-alfa. This study is based on experimental data suggesting that TNF-alfa overproduction in the lung contributes to vasodilatation and that pentoxifylline can improve experimental (animal model) HPS.