Download Pulmonary Arterial Hypertension Associated with

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
Cellular processes implicated in the
pathogenesis of PAH
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 !