Evidence of Systemic Absorption of Enteral Budesonide in Patients with Fontan-Associated Protein-Losing Enteropathy

  • Richard Ogden RobertsIIIEmail author
  • Michael V. Di Maria
  • Dania Brigham
  • Stephanie Hsu
Original Article


To evaluate for evidence of systemic glucocorticoid absorption in cases of Fontan-associated protein-losing enteropathy (PLE) treated with enteral budesonide, we reviewed the charts of 27 patients with Fontan-associated PLE followed at Children’s Hospital Colorado from 2005 to 2018. Cases were excluded for lack of budesonide thserapy or a treatment duration of less than 6 months. Charts were examined by two endocrinologists for review of prior biochemical endocrine evaluations, alterations in linear growth, and physical exam findings consistent with steroid excess. Twelve patients met inclusion criteria. Eight had prior documented cortisol screening. Three patients were tested while on treatment with a median fasting AM cortisol of 0.9 mcg/dL; two of these had a concomitantly measured ACTH, both below the detectable limit. Five patients were tested while weaning or having discontinued budesonide, with a median fasting AM cortisol of 9.1 mcg/dL. Eleven patients had decreases in height velocity associated with starting budesonide. Six patients had documentation of cushingoid features by an endocrinologist. In this cohort of children treated with budesonide for PLE following Fontan, clinical signs of systemic glucocorticoid absorption were frequent. Cortisol secretion was suppressed while on therapy, with adrenal recovery noted once budesonide was discontinued. Growth failure and cushingoid features were common findings. While these findings should be confirmed in larger cohorts, we recommend that the evaluation for systemic absorption of exogenous steroids be considered in patients treated with long-term enteral budesonide given the potential risk for adrenal crisis in times of physiologic stressors.


Fontan Protein-losing enteropathy Budesonide Adrenal suppression 


Author Contributions

ROR, MVD, and SH developed the concept for the study. MVD supplied the data for analysis. ROR and SH designed the study, completed the data analysis and interpretation, and co-wrote the article. MVD, DB, and SH critically revised the article.

Compliance with Ethical Standards

Conflict of Interest

Richard Ogden Roberts III declares that he has no conflict of interest. Michael V. Di Maria declares that he has no conflict of interest. Dania Brigham declares that she has no conflict of interest. Stephanie Hsu declares that she has no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was conducted under the review of the Colorado Multiple Institutional Review Board (COMIRB #14-1072).


  1. 1.
    Levitt DG, Levitt MD (2017) Protein losing enteropathy: comprehensive review of the mechanistic association with clinical and subclinical disease states. Clin Exp Gastroenterol 10:147–168. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rychik J (2007) Protein-losing enteropathy after Fontan operation. Congenit Heart Dis 2(5):288–300. CrossRefPubMedGoogle Scholar
  3. 3.
    Mertens L, Hagler DJ, Sauer U, Somerville J, Gewillig M (1998) Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg 115 (5):1063–1073CrossRefGoogle Scholar
  4. 4.
    Feldt RH, Driscoll DJ, Offord KP, Cha RH, Perrault J, Schaff HV, Puga FJ, Danielson GK (1996) Protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 112(3):672–680. CrossRefPubMedGoogle Scholar
  5. 5.
    Rychik J, Spray TL (2002) Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 5:3–11. CrossRefPubMedGoogle Scholar
  6. 6.
    Ringel RE, Peddy SB (2003) Effect of high-dose spironolactone on protein-losing enteropathy in patients with Fontan palliation of complex congenital heart disease. Am J Cardiol 91 (8):1031–1032, A1039CrossRefGoogle Scholar
  7. 7.
    Bhagirath KM, Tam JW (2007) Resolution of protein-losing enteropathy with low-molecular weight heparin in an adult patient with Fontan palliation. Ann Thorac Surg 84(6):2110–2112. CrossRefPubMedGoogle Scholar
  8. 8.
    Ryerson L, Goldberg C, Rosenthal A, Armstrong A (2008) Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle palliation. Am J Cardiol 101(2):248–251. CrossRefPubMedGoogle Scholar
  9. 9.
    Thacker D, Patel A, Dodds K, Goldberg DJ, Semeao E, Rychik J (2010) Use of oral budesonide in the management of protein-losing enteropathy after the Fontan operation. Ann Thorac Surg 89(3):837–842. CrossRefPubMedGoogle Scholar
  10. 10.
    John AS, Driscoll DJ, Warnes CA, Phillips SD, Cetta F (2011) The use of oral budesonide in adolescents and adults with protein-losing enteropathy after the Fontan operation. Ann Thorac Surg 92(4):1451–1456. CrossRefPubMedGoogle Scholar
  11. 11.
    Rychik J, Piccoli DA, Barber G (1991) Usefulness of corticosteroid therapy for protein-losing enteropathy after the Fontan procedure. Am J Cardiol 68(8):819–821CrossRefGoogle Scholar
  12. 12.
    Gursu HA, Erdogan I, Varan B, Oktay A, Ozcay F, Ozkan M, Aslamaci S (2014) Oral budesonide as a therapy for protein-losing enteropathy in children after the Fontan operation. J Card Surg 29(5):712–716. CrossRefPubMedGoogle Scholar
  13. 13.
    Schumacher KR, Cools M, Goldstein BH, Ioffe-Dahan V, King K, Gaffney D, Russell MW (2011) Oral budesonide treatment for protein-losing enteropathy in Fontan-palliated patients. Pediatr Cardiol 32(7):966–971. CrossRefPubMedGoogle Scholar
  14. 14.
    Bowden SA, Henry R (2018) Pediatric adrenal insufficiency: diagnosis, management, and new therapies. Int J Pediatr 2018:1739831. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM (2008) The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93(5):1526–1540. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Younes AK, Younes NK (2017) Recovery of steroid induced adrenal insufficiency. Transl Pediatr 6(4):269–273. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hamedani R, Feldman RD, Feagan BG (1997) Review article: drug development in inflammatory bowel disease: budesonide—a model of targeted therapy. Aliment Pharmacol Ther 11(Suppl 3):98–107; discussion 107–108CrossRefGoogle Scholar
  18. 18.
    Abdalla MI, Herfarth H (2016) Budesonide for the treatment of ulcerative colitis. Expert Opin Pharmacother 17(11):1549–1559. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    O'Donnell S, O'Morain CA (2010) Therapeutic benefits of budesonide in gastroenterology. Ther Adv Chronic Dis 1(4):177–186. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cheifetz AS (2013) Management of active Crohn disease. JAMA 309(20):2150–2158. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kuenzig ME, Rezaie A, Kaplan GG, Otley AR, Steinhart AH, Griffiths AM, Benchimol EI, Seow CH (2018) Budesonide for the induction and maintenance of remission in Crohn's disease: systematic review and meta-analysis for the Cochrane Collaboration. J Can Assoc Gastroenterol 1(4):159–173. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Arntzenius A, van Galen L (2015) Budesonide-related adrenal insufficiency. BMJ Case Rep CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    De Maeyer F, Lapauw B, Hoorens A, Geerts A, Van Vlierberghe H, Verhelst X (2018) Secondary adrenal insufficiency after treatment with budesonide for autoimmune hepatitis. Case Rep Gastroenterol 12(3):597–601. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Iborra M, Alvarez-Sotomayor D, Nos P (2014) Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis. Clin Exp Gastroenterol 7:39–46. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lopez-Sanroman A, Clofent J, Garcia-Planella E, Menchen L, Nos P, Rodriguez-Lago I, Domenech E (2018) Reviewing the therapeutic role of budesonide in Crohn's disease. Gastroenterol Hepatol 41(7):458–471. CrossRefPubMedGoogle Scholar
  26. 26.
    Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A, Endocrine S (2015) Treatment of Cushing's syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100(8):2807–2831. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shulman DI, Palmert MR, Kemp SF, Lawson Wilkins D, Therapeutics C (2007) Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics 119(2):e484–494. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Section of Endocrinology, Department of PediatricsChildren’s Hospital Colorado, University of Colorado Anschutz Medical CampusAuroraUSA
  2. 2.Section of Cardiology, Department of PediatricsChildren’s Hospital Colorado, The Heart Institute, University of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.Section of Gastroenterology, Hepatology and Nutrition, Department of PediatricsChildren’s Hospital Colorado, The Digestive Health Institute, University of Colorado Anschutz Medical CampusAuroraUSA

Personalised recommendations