Skip to main content

Advertisement

SpringerLink
Log in

Thyroid Dysfunction in Patients with Pulmonary Artery Hypertension (PAH): The Effect of Therapies Affecting the Prostanoid Pathway

  • PULMONARY HYPERTENSION
  • Published:
Lung Aims and scope Submit manuscript

Abstract

Introduction

Epoprostenol, a synthetic prostaglandin I2 (PGI2) analog, has been the mainstay of treatment for severe pulmonary arterial hypertension (PAH) for the last two decades. Treprostinil, another synthetic prostaglandin analog, and selexipag, an oral selective Inositol Phosphate (IP) prostacyclin receptor agonist, have also been approved for treatment of PAH. Prostacyclin and its analogs cause a variety of side effects in patients with PAH; however, thyroid dysfunction is rarely reported.

Methods

After treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association.

Results

We identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves’ disease was seen in three patients, Hashimoto’s disease in two patients and thyrotoxicosis in one patient.

Conclusion

Therapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Galiè N, Humbert M, Vachiery JL et al (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119

    PubMed  Google Scholar 

  2. Badesch DB, Raskob GE, Elliott CG et al (2010) Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 137(2):376–387

    PubMed  Google Scholar 

  3. Curnock AL, Dweik RD, Higgins BH, Saadi HF, Arroliga AC (1999) High prevalence of hypothyroidism in patients with primary pulmonary hypertension. Am J Med Sci 318(5):289–292

    CAS  PubMed  Google Scholar 

  4. Arroliga AC, Dweik RA, Rafanan AL (2000) Primary pulmonary hypertension and thyroid disease. Chest 118(4):1224–1225

    CAS  PubMed  Google Scholar 

  5. Kashyap AS, Kashyap S (2001) Thyroid disease and primary pulmonary hypertension. JAMA 285(22):2853–2854

    CAS  PubMed  Google Scholar 

  6. Marvisi M, Brianti M, Marani G, Del Borello P, Bortesi ML, Guariglia A (2002) Hyperthyroidism and pulmonary hypertension. Respir Med 96(4):215–220

    CAS  PubMed  Google Scholar 

  7. Chu JW, Kao PN, Faul JL, Doyle RL (2002) High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension. Chest 122(5):1668–1673

    PubMed  Google Scholar 

  8. Iervasi G, Molinaro S, Landi P et al (2007) Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 167(14):1526–1532

    PubMed  Google Scholar 

  9. Iervasi G, Pingitore A, Landi P et al (2003) Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 107(5):708–713

    PubMed  Google Scholar 

  10. Miura Y, Fukumoto Y, Sugimura K et al (2010) Identification of new prognostic factors of pulmonary hypertension. Circ J 74(9):1965–1971

    PubMed  Google Scholar 

  11. Vallabhajosula S, Radhi S, Alalawi R, Raj R, Nugent K, Cevik C (2011) Hyperthyroidism and pulmonary hypertension: an important association. Am J Med Sci 342(6):507–512

    PubMed  Google Scholar 

  12. Macchia A, Marchioli R, Tognoni G, Scarano M, Marfisi R, Tavazzi L, Rich S (2010) Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am Heart J 159(2):245–257

    CAS  PubMed  Google Scholar 

  13. Humbert M, Ghofrani HA (2016) The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax 71(1):73–83

    PubMed  Google Scholar 

  14. Rubin LJ, Mendoza J, Hood M et al (1990) Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med 112(7):485–491

    CAS  PubMed  Google Scholar 

  15. Coeytaux RR, Schmit KM, Kraft BD et al (2014) Comparative effectiveness and safety of drug therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Chest 145(5):1055–1063

    PubMed  Google Scholar 

  16. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS (1994) Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 121(6):409–415

    CAS  PubMed  Google Scholar 

  17. McLaughlin VV, Shillington A, Rich S (2002) Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 106(12):1477–1482

    CAS  PubMed  Google Scholar 

  18. Barst RJ, Rubin LJ, Long WA et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301

    CAS  PubMed  Google Scholar 

  19. Badesch DB, Tapson VF, McGoon MD et al (2000) Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 132(6):425–434

    CAS  PubMed  Google Scholar 

  20. Kuhn KP, Byrne DW, Arbogast PG, Doyle TP, Loyd JE, Robbins IM (2003) Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med 167(4):580–586

    PubMed  Google Scholar 

  21. Sitbon O, Channick R, Chin KM et al (2015) Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 373(26):2522–2533

    CAS  PubMed  Google Scholar 

  22. Ferris A, Jacobs T, Widlitz AB, Robyn J, Morse JH (2001) Pulmonary arterial hypertension and thyroid disease. Chest 119(6):1980

    CAS  PubMed  Google Scholar 

  23. Davies A, Frost A (1997) Epoprostenol-associated thyropathy in PPH patients [abstract]. Am J Respir Crit Care Med 155(suppl):A630

    Google Scholar 

  24. Gu Y, Schwarcz MD, Weiss IA (2016) Pulmonary hypertension aggravated by hyperthyroidism: a case report [abstract]. Endocr Rev 37(2):Supplement 1

    Google Scholar 

  25. Nakchbandi IA, Wirth JA, Inzucchi SE (1999) Pulmonary hypertension caused by Graves’ thyrotoxicosis: normal pulmonary hemodynamics restored by 131I treatment. Chest 116(5):1483–1485

    CAS  PubMed  Google Scholar 

  26. Marvisi M, Balzarini L, Mancini C, Mouzakiti P (2013) Thyroid gland and pulmonary hypertension. What’s the link? Panminerva Med 55(1):93–97

    CAS  PubMed  Google Scholar 

  27. Castillo MP, García FH, Montero PB, González RL, Ocaña CM, Sánchez JR (2009) Thyroid dysfunction in patients with pulmonary arterial hypertension. A cohort study of 58 patients. Med Clin (Barc) 132(18):695–700

    Google Scholar 

  28. Srimatkandada P, Farber HW, Coviello AD (2014) Rapid development of compressive goiter and severe hyperthyroidism in a patient with pulmonary arterial hypertension after treatment with epoprostenol [abstract]. Endocr Rev 35(3)

  29. Srimatkandada P, Coviello AD (2015) Severe autoimmune hyperthyroidism in two patients with pulmonary arterial hypertension after treatment with epoprostenol. J Thyroid Disord Ther. 4(176):2

    Google Scholar 

  30. Funasako M, Miyaji K, Sakuma M, Takagi Y, Kyotani S, Nakanishi N (2010) Long-term epoprostenol infusion therapy could induce hyperthyroidism in patients with idiopathic and hereditary pulmonary arterial hypertension [abstract]. Circulation 122(21_MeetingAbstracts):Supplement 1

    Google Scholar 

  31. Galie N, Rubin LJ, Hoeper MM et al (2008) Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371(9630):2093–2100

    CAS  PubMed  Google Scholar 

  32. Galiè N, Olschewski H, Oudiz RJ et al (2008) Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117(23):3010–3019

    PubMed  Google Scholar 

  33. Rubin LJ, Badesch DB, Fleming TR et al (2011) Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 140(5):1274–1283

    CAS  PubMed  Google Scholar 

  34. Zor U, Kaneko T, Lowe IP, Bloom G, Field JB (1969) Effect of thyroid-stimulating hormone and prostaglandins on thyroid adenyl cyclase activation and cyclic adenosine 3′, 5′-monophosphate. J Biol Chem 244(19):5189–5195

    CAS  PubMed  Google Scholar 

  35. Virgolini I, Steurer G, Keminger K, Sinzinger H, Kraupp O (1987) Evaluation of prostaglandin receptors in the human thyroid gland. Prog Clin Biol Res 242:35–42

    CAS  PubMed  Google Scholar 

  36. Kasai K, Hiraiwa M, Suzuki Y et al (1986) Prostacyclin stimulation of adenylate cyclase activity in human thyroid membranes. Horm Metab Res 18(09):625–629

    CAS  PubMed  Google Scholar 

  37. Chadha C, Pritzker M, Mariash C (2009) Effect of epoprostenol on the thyroid gland: enlargement and secretion of thyroid hormone. Endocr Pract 15(2):116–121

    PubMed  Google Scholar 

  38. Satoh M, Aso K, Nakayama T, Saji T (2017) Effect of treatment with epoprostenol and endothelin receptor antagonists on the development of thyrotoxicosis in patients with pulmonary arterial hypertension. Endocr J 64(12):1173–1180

    CAS  PubMed  Google Scholar 

  39. Virgolini I, Hermann M, Sinzinger H (1989) Decrease of the prostaglandin I2 binding capacity in thyroids from patients with Graves’ disease. Prostaglandins Leukot Essent Fatty Acids 37(2):121–128

    CAS  PubMed  Google Scholar 

  40. Yoh-ichiro K, Kanemaru Y, Noguchi T, Onaya T (1987) Circulating prostacyclin and thromboxane in patients with Graves’ disease. Prostaglandins Leukot Essent Fatty Acids 26(1):75–84

    Google Scholar 

  41. Brix TH, Hegedüs L (2011) The complexity of the etiology of autoimmune thyroid disease is gravely underestimated. Thyroid 21(12):1289–1292

    PubMed  Google Scholar 

  42. Frey A, Kroiss M, Berliner D et al (2013) Prognostic impact of subclinical thyroid dysfunction in heart failure. Int J Cardiol 168:300–305

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Aravind A. Menon

  2. Houston Methodist Hospital Lung Center, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA

    Sandeep Sahay

  3. Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA, USA

    Lewis E. Braverman

  4. Pulmonary, Critical Care and Sleep Medicine, Tufts University Medical Center, Boston, MA, USA

    Harrison W. Farber

Authors
  1. Aravind A. Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandeep Sahay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lewis E. Braverman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harrison W. Farber
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AAM, SS, and HWF were involved in the study design, data collection (including figures), data interpretation, and literature review; all authors contributed to the writing and revision of the manuscript. AAM, SS, and HWF are the guarantors of and take responsibility for the content of the manuscript.

Corresponding author

Correspondence to Aravind A. Menon.

Ethics declarations

Conflict of interest

AA.M and L.E.B have no conflicts of interest to disclose. S.S has received consultant fees from Actelion Pharmaceuticals and speaker fees from Actelion Pharmaceuticals, Bayer AG and United Therapeutics Corporation. H.W.F. has received research grants from Gilead; Actelion Pharmaceuticals US Inc; and United Therapeutics Corporation and consulting fees from Gilead; Actelion Pharmaceuticals US, Inc; United Therapeutics Corporation; Bayer AG; Arena, Boehringer-Ingelheim; and Bellerophon. He also has served on a speaker’s bureau or given presentations on behalf of Actelion Pharmaceuticals US, Inc; Gilead; and Bayer AG.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Menon, A.A., Sahay, S., Braverman, L.E. et al. Thyroid Dysfunction in Patients with Pulmonary Artery Hypertension (PAH): The Effect of Therapies Affecting the Prostanoid Pathway. Lung 197, 761–768 (2019). https://doi.org/10.1007/s00408-019-00283-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-019-00283-8

Keywords

Search

Navigation