Loading in 2 Seconds...
Loading in 2 Seconds...
Pulmonary Arterial Hypertension Associated with a Neuroendocrine Pancreatic Tumor Successfully Treated with Bosentan and Fluoxetine. By Paul Strachan MD*, Subani Chandra MD**, Sophy Dedopoulos NP***, Arunabh Talwar MD***
Pulmonary Arterial Hypertension Associated with a Neuroendocrine Pancreatic Tumor Successfully Treated with Bosentan and Fluoxetine By Paul Strachan MD*, Subani Chandra MD**, Sophy Dedopoulos NP***, Arunabh Talwar MD*** *Division of Pulmonary & Critical Care, SUNY Stony Brook Medical Center, Stony Brook, NY ** Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY *** Division of Pulmonary, Critical Care and Sleep Medicine, North Shore-Long Island Jewish Health System, Manhasset, NY
Disclosure • Consulting and speakers fees: Encysive Pharmaceuticals. • Stock holdings: Pfizer Inc.
Introduction • There is current interest in the link between Pulmonary Arterial Hypertension (PAH) and Serotonin. • We present a case of a patient with a serotonin secreting pancreatic islet cell tumor who developed PAH. • His symptoms significantly improved after treatment with bosentan and fluoxetine.
The Case • The patient is a 39 year old male. • He initially presented in 1998, at age 31, with palpitations. • Laboratory evaluation revealed an elevated Alkaline Phosphatase. • Ultrasound of the Abdomen showed a large mass in the pancreas.
The Mass • Patient had an exploratory laparotomy. • The mass was encasing the superior mesenteric artery & vein. • Not resectable • Biopsies were obtained. • Stains were consistent with a Neuroendocrine Tumor (Islet Cell) of the Pancreas.
From Then to Now • He was followed with serial CT scans. • The mass remained stable in size, therefore chemotherapy was never initiated. • Throughout this time period his only symptoms were occasional diarrhea and facial flushing.
The Present Illness • In January 2004, the patient noted increasing dyspnea on exertion. • At his PMD, an echocardiogram was notable for pulmonary hypertension. • Over the next three months, he had two episodes of syncope and worsening dyspnea. • Hospitalized after the second syncope.
Medical History • PMH • PNA 12 years ago • Systemic HTN • Dx 1 year prior to the mass being detected. • PSH • Exp Lap (to biopsy the mass) 1998 • Social History • No Tobacco or Alcohol use • Works in Finance (no occupational exposures) • Family History • No Pulm HTN, No history of NE tumors
On Examination • Vitals • P 84, R 18, BP 120/90, O2 Sat 98% on RA • HEENT • NC/AT, PERRL, EOMI, Membranes: moist • Neck • Supple, No JVD • Lungs • Decreased air entry in right base, otherwise clear. • Heart • Increased S2 • Abdomen • + BS, Soft, NT, ND, healed surgical scar • Extremities • No edema
Testing • Serologies – Negative • Echocardiogram • Normal LV size and function • Moderate RA dilatation • RV enlargement with significant decreased function • Moderate TR, with Pulmonary Artery Systolic Pressure = 81 mmHg • 6MWT • 414 meters • Oxygen desaturation to 88% • Pulmonary Function Tests • Moderate restriction • Mild diffusion abnormality
Further Testing • VQ Scan – No PE • CT Chest - Angio • Enlarged PA • No PE, No fibrosis • Urine 5-HIAA • 10.9 mg/24 hours (nl < 0.6 mg/24 hr). • Octreoscan • Positive in area of abdominal mass. • PSG • No significant sleep disordered breathing (RDI=4). • Low baseline oxygen saturation (86%).
Hemodynamics • Baseline • RAP: 13 mmHg • PA S/D/M: 73/24/40 mmHg • PCW: 15 mmHg • CO: 4.89 l/min (via Fick) • CI: 2.30 l/min/m2 • PVR 540 (dyne*sec)/cm5 • After Nitric Oxide 40 PPM • PA S/D/M: 70/18/35 mmHg • PCW: 12 mmHg
Treatment • He was placed on warfarin, diuretics and oxygen prior to discharge. • The patient declined treatment with intravenous therapy. • During follow-up, he noticed minimal change in symptoms. • 6MWT • 353 meters • Oxygen desaturation to 76% • He was started on Bosentan 62.5mg BID and titrated up to 125mg BID. • Fluoxetine was also started at 20 mg QD.
Clinical Course • From June 2004 – present: • He remains on Bosentan 125 mg BID and Fluoxetine 20 mg qd. • He has not required any escalation in therapy. • Off Warfarin - frequent nosebleeds • He has seen continued improvement in symptoms. • His 6MWT in June 2006 – 545 meters. • Tumor remains stable in size.
Serotonin • Serotonin is 5-hydroxytryptamine. • It is secreted by neuroendocrine (NE) cells throughout the body as well as platelets. • It has potent vasoconstrictor properties and induces smooth muscle hyperplasia. • Experimental treatment with serotonin induced pulmonary hypertension (PH) in chronically hypoxic rats. Eddahibi S, Raffestin B, Pham I, et al. Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol 1997;272:H1173-H1181
From Gut to Lungs • Serotonin is produced throughout the GI tract, but is usually metabolized in the liver. • This prevents it from reaching the lungs. • Serotonin from GI origin could reach the lungs if the capacity for liver metabolism is overwhelmed or changes in blood flow exist (i.e. abnormal channels). • This may also explain the association between pulmonary and portal hypertension.
Serotonin in the Lungs • Pulmonary NE cells secrete vasoactive substances in response to hypercapnia and hypoxia. • These cells increase in patients with pulmonary hypertension. • This leads to increases in many substances, including serotonin.
Serotonin from Platelets • Circulating serotonin is taken up by endothelial cells and platelets. • Dense Granules – take up serotonin • If this system does not function or is overwhelmed, PH develops. • Various thoughts of how platelets are involved in PAH including: • Destruction • Aggregation • Thrombosis • Hypothesized to have a role in CTEPH and IPAH. Herve P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995;99:249-254
Carcinoid and PAH • Carcinoid Heart Disease • Initially described as left heart disease • Serotonin is thought to cause morphological changes in the right heart. • One study showed Tricuspid Regurgitation is the most common valvular disease in patients with carcinoid • 22/37 patients had TR (Mild to moderate in 8/22) • Another study showed four of 16 patients with metastatic GI carcinoid had slight pulmonary hypertension. Jacobsen MB, Nitter-Hauge S, Bryde PE, et al. Cardiac manifestations of mid-gut carcinoid disease. Eur Heart J 1995;16:263-268 Tornebrandt K, Eskilsson J, Nobin A. Heart involvement in metastatic carcinoid disease. Clin Cardiol 1986;9:13-19
Genetics in PH • Mutations in the Bone Morphogenetic Protein Receptor 2 (BMPR2) have been identified in IPAH and familial PAH. • Only 20% of family members with BMPR2 mutations develop PAH. • This suggests other factors are involved • A chronic infusion of serotonin caused increased PASP, RVH, and pulmonary artery remodeling in BMPR2+/- mice compared with wild-type. • There was a greater effect under hypoxic conditions. • Long L, MacLean MR, Jeffery TK, et al. Serotonin Increases Susceptibility to Pulmonary Hypertension in BMPR2-Deficient Mice Circ Res 2006 98: 818 - 827
Serotonin Receptors in PH • Serotonin Receptors • 5-HT1B/1D - thought to mediate vasoconstriction. • Serotonin Transporter (SERT) • Located on chromosome 17q11.1-q12 • Over expressed in the lung tissues of pts with PAH. • Long (L)/Short (S) functional polymorphisms in the promotor region • Evidence suggests a correlation of the SERT L/S polymorphism and the development of PAH. • Recent study examined this in IPAH and FPAH. • No correlation in IPAH • In FPAH, LL polymorphism correlated with an earlier age of diagnosis, although similar survival to the SL or SS polymorphisms. Willers ED, Newman JH, Loyd JE, et al. Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 173: 798-802.
Serotonin Blockade Treating PH • Serotonin Selective Reuptake Inhibitors (SSRI) are a commonly used medication in the treatment of depression. • Recent study retrospectively evaluated SSRI use and clinical course of PAH. • Found a 50% reduction in risk of death (not statistically significant) in patients on SSRIs. Kawut SM, Horn EM, Berekashvili KK, et al. Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulm Pharmacol Ther. 2006;19(5):370-4.
Endothelin and Serotonin • Recent study showed Bosentan partially reversed upregulation of the serotonin 1b receptor in an experimental model of PH. Rondelet B, Van Beneden R, Kerbaul F, et al. Expression of the serotonin 1b receptor in experimental pulmonary hypertension Eur Respir J 2003; 22: 408–412
Conclusions • The exact role of serotonin in PAH has not yet been elucidated. • Patients with elevated 5-HIAA levels are at increased risk for PH. • These patients should be screened for PH. • Treatment with a medications specific for PH in combination with an SSRI may be beneficial for PAH patients, but larger studies are needed.
Thank You !