Primary pulmonary hypertension (PPH) is characterized by the proliferation of smooth-muscle cells, fibroblasts, and endothelial cells in the walls of small pulmonary arteries. In order to evaluate a role for proinflammatory cytokines in this process, we studied the concentration of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the serum of 29 patients with severe PPH referred to our center for lung transplantation. Results were compared with those obtained in 15 normal controls and nine patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD-PH). TNF alpha serum levels were within the normal range in each group. This contrasted with increased IL-1 beta serum levels in severe PPH (118 +/- 36 pg/ml, mean +/- SEM) as compared with controls (3 +/- 1 pg/ml, p < 0.001) or COPD-PH patients (3 +/- 1 pg/ml, p < 0.001). IL-6 serum concentrations were also higher in severe PPH (66 +/- 20 pg/ml) than in controls (14 +/- 6 pg/ml, p < 0.01). This study demonstrates increased serum levels of IL-1 beta and IL-6 in severe PPH, and suggests a role for proinflammatory cytokines in PPH.

The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.

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aaThis review focuses on the pulmonary vascular complications of chronic liver failure and portal hypertension. The wide spectrum of pulmonary vascular disorders in liver disease and portal hypertension ranges from the hepatopulmonary syndrome (HPS), which is characterized by intrapulmonary vascular dilatations, to pulmonary hypertension (portopulmonary hypertension), in which pulmonary vascular resistance (PVR) is elevated. The exact pathophysiological mechanisms of these pulmonary vascular disorders are unknown. However, since HPS and portopulmonary hypertension have been reported in patients with nonhepatic portal hypertension, the factor that determines their development must be portal hypertension.A brief review of the haemodynamic changes observed in cirrhosis with portal hypertension is summarized, and the clinical and experimental evidence suggesting that the liver exerts a critical influence on the regulation of pulmonary vascular tone and angiogenesis is described. Portopulmonary hypertension is then discussed, focusing in turn on its clinical presentations, management and potential mechanisms, and referring to our findings in 39 patients with portopulmonary hypertension and 140 patients with primary pulmonary hypertension (PPH) admitted between 1986 and 1996 at Antoine Béclère Hospital. Finally, HPS will be examined, with a discussion of the mechanisms of hypoxaemia and intrapulmonary vascular dilatation, as well as its clinical presentation, diagnosis and treatment, with special attention to liver transplantation. Haemodynamics in cirrhosis with portal hypertensionAn understanding of pulmonary haemodynamics in liver disease with portal hypertension is important to a study of the pulmonary vascular disorders seen in this setting. A hyperdynamic circulatory state with high cardiac output, low systemic vascular resistance and low PVR is present in 30-50% of patients with cirrhosis and also in animal models of portal hypertension [1][2][3][4]. Compared with healthy subjects ( fig. 1) The wide spectrum of pulmonary vascular disorders in liver disease and portal hypertension ranges from the hepatopulmonary syndrome characterized by intrapulmonary vascular dilatations, to pulmonary hypertension (portopulmonary hypertension), in which pulmonary vascular resistance is elevated. Since hepatopulmonary syndrome and portopulmonary hypertension have been reported in patients with nonhepatic portal hypertension, the common factor that determines their development must be portal hypertension. The clinical presentations are very different, with gas exchange impairment in the hepatopulmonary syndrome and haemodynamic failure in portopulmonary hypertension. The severity of hepatopulmonary syndrome seems to parallel the severity of liver failure, whereas no simple relationship has been identified between hepatic impairment and the severity of portopulmonary hypertension. Resolution of hepatopulmonary syndrome is common after liver transplantation, which has an uncertain effect in portopulmonary hypertension. The pathoph...

To investigate the capacity of the pulmonary vascular bed to acutely vasodilate, we examined in 35 consecutive patients with primary pulmonary hypertension (PPH), the hemodynamic effects of incremental inhalation periods of an air-NO mixture at different concentrations (10, 20, and 40 ppm), and compared them with those of an acute infusion of prostacyclin (PGI2). An individual pulmonary vasodilator response was defined by a fall in total pulmonary resistance (TPR) > or = 30% relative to mean TPR baseline value. Thirteen patients were responders and 22 were nonresponders to both drugs, and they did not significantly differ in overall baseline characteristics except for mean right atrial pressure (p < 0.03). In responders, both drugs produced similar individual vasodilator response. Changes in mean pulmonary arterial pressure and TPR observed during NO and PGI2 were closely correlated (r2 = 0.9, p < 0.001, and r2 = 0.7, p < 0.01, respectively). The vasodilator response to NO was not concentration-related with a maximal effect obtained at 10 ppm. Combination of both drugs did not lead to any additive vasodilator response. Unlike PGI2, NO did not induce any systemic effect, no adverse reaction, but a moderate increase in methemoglobin. Inhaled NO at low dose (10 ppm) appears to be an effective, safe, and reliable substitute for PGI2 in screening for acute pulmonary vasodilator responsiveness during therapeutic assessment of patients with PPH.

These results support the view that HIV infection may now be regarded as another common disease state that can be associated with PPH development. The lower initial severity in HIV-infected patients may be due to the close medical attention usually devoted to such patients, who may account for an earlier diagnosis. However, the overall survival rate of HIV-infected patients with PH appeared to be as poor as in non-HIV-infected patients with PPH.

Not all the risk factors for primary pulmonary hypertension (PPH) are known. Appetite suppressants, including fenfluramine derivatives, are strongly suspected aetiological agents.In a 5 year retrospective study fenfluramine use was evaluated among patients referred to a medical centre specialising in the management of PPH. Fifteen (20%) of 73 patients with PPH had used fenfluramine: all of them were women and in 10 (67%) there was a close temporal relation between fenfluramine use and the development of ezertional dyspnoea. Initial right heart catbeterisation in the 15 women showed severe resting pulmonary hypertension (mean (SD)) with pulmonary artery pressure (PAP) 57 (9) mm Hg, cardi index 2*1 (0-5) Iminim', and pulmonary vascular resastance (PVR) 29 (10) Uhm'. Shortterm epoprostenol infusion produced a significant vasodilator response in 10 patients (mean fall in PVR 24 (15%.) compared with control values). Three fenfluramine users with PPH showed spontaneous clinical and haemodynamic improvement 3, 6 and 12 months after drug withdrawal but there was no significant difference in overall survival (transplant recipients excluded) between fenflurmne users and controls. Histological e mnation of lung tissue from five women who had used fenfluramine and 22 controls, with PPH showed features typical of advanced plexogenic pulmonary arteriopathy in all.These results do not accord with earlier reports that PPH associated with fenfluramine is less severe and has a better outcome. Fenfluramine may be one aetiological agent that can precipitate or hasten the development of PPH. The results of a European case-control study should give new insights into risk factors for PPH and the cause and effect relation with fenfluramine.

In this study, patients with PPH exhibiting a decrease in TPRi > 50% during short-term PGI2 challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.