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Portopulmonary hypertension in cirrhosis: the pathogenetic challenge
  1. F Wong
  1. Correspondence to:
    Dr F Wong
    University of Toronto, 9EN/220, Toronto Hospital, 200 Elizabeth St, Toronto, Ontario, Canada; florence.wongutoronto.ca

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We would like to thank Pellicelli (Gut 2004;53:1721) for his interest in our paper on portopulmonary hypertension in cirrhosis with refractory ascites (Gut 2003;52:1355–62).

We acknowledge that our proposal suggesting the role of endothelin 1 (ET-1) in the pathogenesis of portopulmonary hypertension is based on a small number of patients. However, the strong association between the elevated ET-1 levels in the pulmonary artery and the presence of portopulmonary hypertension in these patients would suggest that this is indeed the case. The confirmatory test would be a reduction in pulmonary pressure following blockade of endothelin receptors in the pulmonary circulation. However, this has not been reported to date. We also acknowledge that we did not measure the gradient of ET-1 across the pulmonary vascular bed, which is an important site for both production and clearance of ET-1. The fact that systemic arterial endothelin levels in patients with advanced cirrhosis are similar to those in control subjects1 would suggest that there is no net production of ET-1 in the pulmonary circulation. Rather, the high levels of ET-1 delivered to the pulmonary circulation are being metabolised locally in these patients. Indeed, in experimental cirrhosis, there is evidence of increased expression of endothelin type B receptors in the pulmonary circulation, and these are responsible for clearance of ET-1.2 Therefore, although our single measurement of ET-1 in the pulmonary artery does not reflect the net result of ET-1 metabolism in the pulmonary vascular bed, it does represent the amount of ET-1 that is delivered to the pulmonary artery, potentially causing pulmonary vasoconstriction.

With respect to measurement of ET-1 across the splanchnic circulation, there is already ample evidence in the literature to support increased production of ET-1 in the splanchnic circulation3,4 as well as in the liver.5 Therefore, it is reasonable to postulate that the increased ET-1 levels in the pulmonary artery, which is downstream from the splanchnic circulation, is largely derived from the increased production in that circulation.

Pellicelli’s proposal of interleukin 6 (IL-6) being one of the mediators involved in the pathogenesis of portopulmonary hypertension in cirrhosis is an interesting one. IL-6 can increase platelet production in small muscular arteries and capillaries as well as enhancing platelet activation.6 In addition, IL-6 promotes the coagulation cascade without affecting fibrinolysis, causing fibrin thrombi.6 If this occurs in the pulmonary circulation, then pulmonary hypertension can develop. Similar to what has been reported in the literature,7 Pellicelli and his group have found increased levels of IL-6 in patients with cirrhosis. However, it is not clear whether the increased plasma levels of IL-6 in cirrhosis are a non-specific inflammatory response in patients who are generally ill or part of a pathogenetic mechanism of some complication of cirrhosis. To date, there is no firm evidence that IL-6 is involved in the pathogenesis of either primary or secondary pulmonary hypertension. The challenge remains for us to find increased IL-6 levels in the pulmonary circulation in patients with portopulmonary hypertension before it can be implicated in the pathogenesis of this serious but uncommon complication of cirrhosis.

References

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Footnotes

  • Conflict of interest: None declared.

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