Pulmonary Hypertension after Splenectomy?

The diagnosis of primary (that is, idiopathic) pulmonary hypertension is based on the presence of sustained elevated mean pulmonary arterial pressure (>25 mm Hg at rest or>30 mm Hg during exercise) and the exclusion of secondary causes, such as myocardial disease, congenital heart defects, parenchymal lung disease, or recurrent thromboembolism (1). It has been estimated that the incidence of sporadic idiopathic pulmonary hypertension is 1 to 2 cases per 1 million persons (2). Patients with HIV infection or liver disease have a much higher risk for developing pulmonary hypertension (0.1% to 2%) (3, 4). The use of certain appetite-suppressant drugs has also been linked to an increased incidence of primary pulmonary hypertension (5), and other unidentified risk factors for pulmonary hypertension may also exist. Three patients with idiopathic pulmonary hypertension who had previously undergone splenectomy were referred to our hospital. We reviewed the charts of all 61 patients with unexplained pulmonary hypertension who were seen at our institution between 1993 and 1998 and identified 4 other patients in whom splenectomy was performed before the first clinical manifestation of pulmonary hypertension. We describe the case histories of the patients who developed pulmonary hypertension after splenectomy and investigate the hypothesis that patients who have had splenectomy may have an increased risk for developing pulmonary hypertension. Methods Case Histories We reviewed the charts of all patients with a clinical diagnosis of primary pulmonary hypertension who were referred to Hannover Medical School in Hannover, Germany, between 1993 and 1998 for evaluation for lung transplantation. The medical histories and (if available) the histopathologic findings of the patients who developed pulmonary hypertension after splenectomy were analyzed. Case-Control Study and Statistical Analysis We used a casecontrol design to compare the prevalence of surgical asplenia in patients with idiopathic pulmonary hypertension with that in patients with other pulmonary diseases (emphysema [n=51], cystic fibrosis [n=33], pulmonary fibrosis [n=46], and the Eisenmenger syndrome [n=21]) who received a lung transplant at our institution. The prevalence of surgical asplenia was calculated for both groups, and the 95% CIs were determined by using the exact method for binomial variables (6). The chi-square test was used for statistical comparisons of both groups. Results Case Summaries In this retrospective analysis of 61 patients with clinically diagnosed primary pulmonary hypertension, we identified 7 patients who had previously undergone splenectomy. The Table lists the indications for splenectomy, the patients' ages when splenectomy was performed, the interval between splenectomy and diagnosis of pulmonary hypertension, the hemodynamic variables at the time of diagnosis of primary pulmonary hypertension, and the diagnostic approaches used to rule out recurrent pulmonary embolism. All patients fulfilled the diagnostic criteria for primary pulmonary hypertension as defined by the registry of the National Institutes of Health (1). No patient had a family history of pulmonary hypertension. Patients with other factors associated with pulmonary hypertension, such as collagen vascular disorders, use of appetite-suppressant drugs, liver disease, or HIV infection, were excluded. Recurrent pulmonary embolism was ruled out by pulmonary angiography in all but 1 patient, in whom venography, ventilation-perfusion scanning, and contrast-enhanced helical computed tomography of the thorax yielded normal results. Table. Clinical Characteristics of Patients Who Developed Pulmonary Hypertension after Splenectomy In the three patients with spherocytosis, mild hemolysis was still present when pulmonary hypertension developed, as indicated by increased reticulocyte counts and elevated serum levels of lactate dehydrogenase and unconjugated bilirubin. The platelet counts were normal or slightly elevated in all patients. All patients had clinically severe pulmonary hypertension. Four are stable and receiving medical treatment, and three have undergone lung transplantation. In the latter group of patients, histologic examination of the explanted lungs confirmed the presence of severe pulmonary vascular disease manifested as medial hypertrophy in conjunction with marked intimal thickening, plexiform lesions, and abundant thrombotic lesions (Figure). Figure. Lung specimens from patients with pulmonary hypertension after splenectomy. Top left. Top right. Bottom left. Bottom right. Two patients died early in the postoperative period. One patient (patient 6) underwent pulmonary retransplantation 5 years after the original transplantation because of chronic graft failure. Histologic examination of the explanted grafts showed (in addition to obliterative bronchiolitis) predominantly vascular lesionsthat is, marked intimal fibrosis with disseminated occlusion of small pulmonary arteries and extensive thrombotic lesions. These findings were similar to those in grafts explanted from the patient's native lungs before the original transplantation (Figure). Case-Control Studies A casecontrol study was performed to determine the odds of developing unexplained pulmonary hypertension in a patient who previously had splenectomy. We compared the patients in the pulmonary hypertension group with 151 patients who received a lung transplant at our institution for reasons other than idiopathic pulmonary hypertension. None of these 151 patients had undergone splenectomy before transplantation. The two groups did not differ significantly for age or sex (mean age, 41 14 years in the pulmonary hypertension group compared with 43 13 years in the control group; female-male ratio, 1.2:1 in the pulmonary hypertension group compared with 0.9:1 in the control group). The prevalence of asplenia was 11.5% (95% CI, 4.7% to 22.2%) in the pulmonary hypertension group and 0% (CI, 0% to 3.2%) in the control group. This difference was statistically significant (P<0.001). Discussion We report on seven patients in whom severe pulmonary hypertension developed 4 to 34 years after splenectomy. In all cases, the clinical diagnosis was primary pulmonary hypertension in accordance with established criteria (1). However, the histopathologic findings suggest that the pathogenetic mechanisms involved in postsplenectomy pulmonary hypertension may differ from common primary pulmonary hypertension, even though both entities may be clinically indistinguishable. Lung tissue for histologic examination was available from three of our patients and revealed pulmonary vascular changes consistent with the diagnosis of primary pulmonary hypertension (medial thickening, intimal fibrosis, and plexiform lesions). However, all of these patients had many thrombotic lesions. In one patient who underwent pulmonary retransplantation 5 years after receiving the first lung transplant, histologic examination of the explanted grafts showed signs of chronic rejection and pulmonary vasculopathy consisting of extensive intimal fibrosis and widespread thrombotic occlusion of small pulmonary arteriesfindings similar to those in the patient's native lungs. Primary pulmonary hypertension has not yet been reported to recur after lung transplantation. These findings suggest that the pathogenetic process that caused pulmonary hypertension in this patient was still active after lung transplantation. The prevalence of asplenia in this study was significantly higher in patients with unexplained pulmonary hypertension than in the control group of patients with unrelated pulmonary diseases. Unfortunately, no valid information is available about the number of splenectomies performed each year in Germany. In the United States, about 35 000 splenectomies are performed annually (7). On the basis of these data, the number of splenectomies in Germany could be estimated as approximately 15 000 per year, or 0.02% of the general population. Thus, the expected prevalence of asplenia would be roughly 1% in a mixed population of persons with a mean age of 50 years. In contrast, patients who previously had splenectomies represented 11.5% (CI, 4.7% to 22.2%) of the patients with unexplained pulmonary hypertension who were referred to our center during the past 5 years. In these patients, asplenia may have been a causative factor for the development of pulmonary hypertension. An increased risk for pulmonary hypertension after splenectomy has previously been suggested in patients with certain hemolytic disorders, such as thalassemia or hereditary stomatocytosis (8-11). Aessopos and colleagues (8) reported on pulmonary hypertension in seven patients with thalassemia, six of whom were asplenic. Sonakul and Fucharoen (9) and Sumiyoshi and coworkers (10) described autopsy findings from 58 patients with thalassemia. In this group, pulmonary vascular changes indicative of microthromboembolism were found in 54% of patients who had had splenectomy but in only 16% of patients who had not had splenectomy. In addition, Steward and coworkers (11) have shown that in patients with hereditary stomatocytosis, splenectomy may also be a risk factor for thromboembolic complications and pulmonary hypertension. As in our patients, the interval between splenectomy and manifestation of pulmonary hypertension for patients in two of these studies was usually longer than 10 years (8, 10). The underlying pathogenetic mechanisms are unclear, but it has been hypothesized that because of loss of the filter function of the spleen, abnormal erythrocytes remain in the circulatory system longer and may trigger platelet activation; these activated platelets could then become trapped in the pulmonary vascular bed (7-10). Such mechanisms could be active in any patient who has had splenectomy but would be aggravated in the presence of hemolytic disorders. Further evidence for a relation between splenectomy and