INTRODUCTION: The etiology of pulmonary arterial hypertension (PAH) is undefined. Serotonin is thought to have a role in the pathogenesis of PAH. We report the development of PAH in a patient with an islet-cell tumor of the pancreas and elevated levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin.
CASE PRESENTATION: The patient is a 39-year-old male, who had presented with palpitations eight years back. An elevated alkaline phosphatase prompted an abdominal ultrasound that demonstrated a 12x20 cm pancreatic mass, encasing the superior mesenteric artery and vein. Biopsies were suggestive of an islet cell tumor. Immunochemical stains were positive for synaptophysin and chromogranin, with focal areas staining for glucagon and insulin. An octreotride scan was intensely positive. Serial CT scans over the next six years showed stable tumor size so no chemotherapy was initiated. His only symptoms consisted of facial flushing after drinking red wine and occasional diarrhea. In early 2004, he noted increasing dyspnea on exertion (WHO functional class 3). During the next three months, he had two episodes of syncope. An echocardiogram showed a normal left ventricle and a pulmonary artery systolic pressure of 81 mmHg. Right heart catheterization confirmed PAH with a pulmonary artery pressure (PAP) of 73/24 mmHg, a mean PAP of 48 mmHg and a wedge pressure of 15 mmHg. Cardiac output was 4.89 L/min and pulmonary vascular resistance was 540 dyne*sec/cm5. He did not have a response to nitric oxide. His six-minute walk time was 354 meters, with desaturation to 76 percent on room air. 5-HIAA level in the urine was elevated at 10.9 mg/24 hours (normal < 6.0). The patient was placed on oxygen and warfarin. Bosentan (125 mg twice daily) was added for treatment of PAH in combination with fluoxetine (20 mg once daily). He reported a significant improvement in his symptoms (WHO class 2) and no longer destaturated with walking.
DISCUSSIONS: Neuroendocrine cells are present throughout the body and secrete serotonin. In the lungs these cells also secrete other vasoactive peptides in response to hypoxia and hypercarbia. These cells have been found to proliferate in patients with PAH. Serotonin plays a role in the pathogenesis of PAH probably via its potent vasoconstrictor properties and induction of smooth muscle hyperplasia. On a molecular level, polymorphisms in serotonin transporter gene (SERT) may effect expression of bone morphogenetic protein receptor-2 (BMPR-2), the gene whose mutation is associated with familial PAH. Patients with PAH have been found to have high serotonin levels due to problems with processing serotonin. Current research has shown that treatment with serotonin-selective reuptake-inhibitors (SSRI) may be associated with improved outcomes in patients with PAH. Our patient had an elevated serotonin level due to a pancreatic neuroendocrine tumor. Chronic stimulation to his pulmonary vasculature probably led to the development of PAH. He showed significant clinical improvement with the combination of an endothelin-receptor blocker (bosentan) and an SSRI.
CONCLUSION: Patients with increased serotonin levels are at risk for the development of PAH. The role for combination therapy with endothelin-receptor blockers and SSRIs in the treatment of PAH should be explored further.
DISCLOSURE: Paul Strachan, None.