Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 18
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    António, Marta Gordo, Andreia Pereira, Conceição Pinto, Fátima Fragata, Isabel and Fragata, José 2016. Thoracic Duct Decompression for Protein-Losing Enteropathy in Failing Fontan Circulation. The Annals of Thoracic Surgery, Vol. 101, Issue. 6, p. 2370.

    Morsheimer, Megan M. Rychik, Jack Forbes, Lisa Dodds, Kathryn Goldberg, David J. Sullivan, Kathleen and Heimall, Jennifer R. 2016. Risk Factors and Clinical Significance of Lymphopenia in Survivors of the Fontan Procedure for Single-Ventricle Congenital Cardiac Disease. The Journal of Allergy and Clinical Immunology: In Practice, Vol. 4, Issue. 3, p. 491.

    Salgado, F. Rodríguez, A. Ortega, M.V. and Valdivielso, P. 2016. Mujer de 51 años con astenia, pérdida de peso y anasarca. Revista Clínica Española, Vol. 216, Issue. 6, p. 331.

    Tashiro, Katsuya Iida, Chiaki and Ushinohama, Hiroya 2016. Effectiveness of the Additional Administration of Spironolactone on Hypoproteinemia after the Fontan Procedure. Pediatric Cardiology and Cardiac Surgery, Vol. 32, Issue. 1, p. 43.

    Magdo, H. Sonali Stillwell, Terri L. Greenhawt, Matthew J. Stringer, Kathleen A. Yu, Sunkyung Fifer, Carlen G. Russell, Mark W. and Schumacher, Kurt R. 2015. Immune Abnormalities in Fontan Protein-Losing Enteropathy: A Case-Control Study. The Journal of Pediatrics, Vol. 167, Issue. 2, p. 331.

    Schumacher, Kurt R. Stringer, Kathleen A. Donohue, Janet E. Yu, Sunkyung Shaver, Ashley Caruthers, Regine L. Zikmund-Fisher, Brian J. Fifer, Carlen Goldberg, Caren and Russell, Mark W. 2015. Fontan-Associated Protein-Losing Enteropathy and Plastic Bronchitis. The Journal of Pediatrics, Vol. 166, Issue. 4, p. 970.

    Schumacher, Kurt R. Gossett, Jeffrey Guleserian, Kristine Naftel, David C. Pruitt, Elizabeth Dodd, Debra Carboni, Michael Lamour, Jacqueline Pophal, Stephen Zamberlan, Mary and Gajarski, Robert J. 2015. Fontan-associated protein-losing enteropathy and heart transplant: A Pediatric Heart Transplant Study analysis. The Journal of Heart and Lung Transplantation, Vol. 34, Issue. 9, p. 1169.

    Cotts, Timothy Khairy, Paul Opotowsky, Alexander R. John, Anitha S. Valente, Anne Marie Zaidi, Ali N. Cook, Stephen C. Aboulhosn, Jamil Ting, Jennifer Grando Gurvitz, Michelle Landzberg, Michael J. Verstappen, Amy Kay, Joseph Earing, Michael Franklin, Wayne Kogon, Brian and Broberg, Craig S. 2014. Clinical research priorities in adult congenital heart disease. International Journal of Cardiology, Vol. 171, Issue. 3, p. 351.

    Dori, Yoav Keller, Marc S. Fogel, Mark A. Rome, Jonathan J. Whitehead, Kevin K. Harris, Matthew A. and Itkin, Maxim 2014. MRI of Lymphatic Abnormalities After Functional Single-Ventricle Palliation Surgery. American Journal of Roentgenology, Vol. 203, Issue. 2, p. 426.

    John, Anitha S. Johnson, Jennifer A. Khan, Munziba Driscoll, David J. Warnes, Carole A. and Cetta, Frank 2014. Clinical Outcomes and Improved Survival in Patients With Protein-Losing Enteropathy After the Fontan Operation. Journal of the American College of Cardiology, Vol. 64, Issue. 1, p. 54.

    Veldtman, Gruschen R. and Webb, Gary D. 2014. Improved Survival in Fontan-Associated Protein-Losing Enteropathy∗. Journal of the American College of Cardiology, Vol. 64, Issue. 1, p. 63.

    Yoo, Shi-Joon Prsa, Milan Schantz, Daryl Grosse-Wortmann, Lars Seed, Mike Kim, Tae Kyoung Wald, Rachel and Chaturvedi, Rajiv 2014. MR assessment of abdominal circulation in Fontan physiology. The International Journal of Cardiovascular Imaging, Vol. 30, Issue. 6, p. 1065.

    Hraška, Viktor 2013. Decompression of Thoracic Duct: New Approach for the Treatment of Failing Fontan. The Annals of Thoracic Surgery, Vol. 96, Issue. 2, p. 709.

    Mehra, Mandeep R. 2013. Fat, Cachexia, and the Right Ventricle in Heart Failure. Journal of the American College of Cardiology, Vol. 62, Issue. 18, p. 1671.

    Ohuchi, H. Yasuda, K. Miyazaki, A. Kitano, M. Sakaguchi, H. Yazaki, S. Tsuda, E. and Yamada, O. 2013. Haemodynamic characteristics before and after the onset of protein losing enteropathy in patients after the Fontan operation. European Journal of Cardio-Thoracic Surgery, Vol. 43, Issue. 3, p. e49.

    Rychik, Jack Goldberg, David Rand, Elizabeth Semeao, Edisio Russo, Pierre Dori, Yoav and Dodds, Kathryn 2013. End-organ consequences of the Fontan operation: liver fibrosis, protein-losing enteropathy and plastic bronchitis. Cardiology in the Young, Vol. 23, Issue. 06, p. 831.

    Sreeram, Narayanswami Emmel, Mathias and Bennink, Gerardus 2013. Stent therapy for acute and chronic obstructions in extracardiac Fontan conduits. Cardiology in the Young, Vol. 23, Issue. 05, p. 766.

    Law, Siu-Tong Ma, Kwok Man and Li, Kin Kong 2012. Protein-losing enteropathy associated with or without systemic autoimmune disease. European Journal of Gastroenterology & Hepatology, Vol. 24, Issue. 3, p. 294.


Protein-losing enteropathy: integrating a new disease paradigm into recommendations for prevention and treatment

  • Jeffery Meadows (a1) and Kathy Jenkins (a2) (a3)
  • DOI:
  • Published online: 25 February 2011

Protein-losing enteropathy is a relatively uncommon complication of Fontan procedures for palliation of complex congenital cardiac disease. However, the relative infrequency of protein-losing enteropathy belies the tremendous medical, psychosocial and financial burdens it places upon afflicted patients, their families and the healthcare system that supports them. Unfortunately, because of the complexity and rarity of this disease process, the pathogenesis and pathophysiology of protein-losing enteropathy remain poorly understood, and attempts at treatment seldom yield long-term success. The most comprehensive analyses of protein-losing enteropathy in this patient population are now over a decade old, and re-evaluation of the prevalence and progress in treatment of this disease is needed. This report describes a single institution experience with the evaluation, management, and treatment of protein-losing enteropathy in patients with congenital cardiac disease in the current era, follows with a comprehensive review of protein-losing enteropathy, focused upon what is known and not known about the pathophysiology of protein-losing enteropathy in this patient population, and concludes with suggestions for prevention and treatment.

Corresponding author
Correspondence to: J. Meadows, MD, Division of Pediatric Cardiology, 505 Parnassus Avenue, Box 0632, San Francisco, California 94143-4144, United States of America. Tel: 415 476 4904; Fax: 415 476 3112; E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2.L Mertens , D Hagler , U Sauer , J Somerville , M Gewillig . Protein-losing enteropathy after the Fontan operation: an international multicenter study. J Thorac Cardiovasc Surg 1998; 115: 10631073.

3.A Powell , K Gauvreau , K Jenkins , E Blume , J Mayer , J Lock . Perioperative risk factors for development of protein-losing enteropathy following Fontan procedure. Am J Cardiol 2001; 88: 12061209.

4.J Meadows , K Gauvreau , K Jenkins . Lymphatic obstruction and protein-losing enteropathy in patients with congenital heart disease. Congenit Heart Dis 2008; 3: 269276.

6.P Wilkinson , B Pinto , JR Senior . Reversible protein-losing enteropathy with intestinal lymphangiectasia secondary to chronic constrictive pericarditis. N Engl J Med 1965; 273: 11781181.

7.G Crupi , G Locatelli , R Tiraboschi , M Villani , M De Tommasi , L Parenzan . Protein-losing enteropathy after Fontan operation for tricuspid atresia (imperforate tricuspid valve). Thorac Cardiovasc Surg 1980; 28: 359363.

9.R Wochner , S Weissman , T Waldmann . Direct measurement of the rates of synthesis of plasma proteins in control subjects and in patients with gastrointestinal protein loss. J Clin Invest 1968; 47: 971982.

10.C Davis , D Driscoll , J Perrault , Enteric protein loss after the Fontan operation. Mayo Clin Proc 1994; 69: 112114.

11.T Fujii , T Shimizu , K Takahashi , Fecal alfa-1 antitrypsin concentrations as a measure of enteric protein loss after modified Fontan operations. J Pediatr Gastroenterol Nutr 2003; 37: 577580.

12.S Thorne , J Hooper , M Kemp , J Somerville . Gastro-intestinal protein loss in late survivors of Fontan surgery and other congenital heart disease. Eur Heart J 1998; 19: 514520.

13.R Kaulitz , I Luhmer , F Bergmann , B Rodeck , G Hausdorf . Sequelae after modified Fontan operation: postoperative haemodynamic data and organ function. Heart 1997; 78: 154159.

14.S Chakrabarti , B Keeton , A Salmon , J Vettukattil . Acquired combined immunodeficiency associated with protein losing enteropathy complicing Fontan operation. Heart 2003; 89: 11301131.

15.Y Cheung , H Tsang , J Kwok . Immunologic profile of patients with protein-losing enteropathy complicating congenital heart disease. Pediatr Cardiol 2002; 23: 587593.

19.E Mbonda , P Forget , Z Saye , J Leclercq-Foucart . Usefulness of random fecal alpha 1-antitrypsin and chymotrypsin determinations in children. J Pediatr Gastroenterol Nutr 1989: 8588.

22.EM Quigley , IN Ross , MR Haeney , IB Holbrook , MN Marsh . Reassessment of faecal alpha-1-antitrypsin excretion for use as screening test for intestinal protein loss. J Clin Pathol 1987; 40: 6166.

23.S Choudhary , PR Gibson , MC Deacon , GP Young . Measurement of faecal alpha 1-antitrypsin: methodologies and clinical application. J Gastroenterol Hepatol 1996; 11: 311318.

24.A Puri , R Aggarwal , R Gupta , Intestinal lymphangiectasia: evaluation by CT and scintigraphy. Gastrointest Radiol 1992; 17: 119121.

25.L Werbeloff , S Bank , I Marks . Radiological findings in protein-losing gastroenteropathy. Br J Radiol 1969; 42: 605612.

26.FL Connor , S Angelides , M Gibson , Successful resection of localized intestinal lymphangiectasia post-Fontan: role of (99m)technetium-dextran scintigraphy. Pediatrics 2003; 112: e242e247.

29.T Zellers , K Brown . Protein-losing enteropathy after the modified Fontan operation: oral prednisone treatment with biopsy and laboratory proved improvement. Pediatr Cardiol 1996; 17: 115117.

30.A Blalock , C Robsinson , R Cunningham , M Gray . Experimental studies on lymphatic blockage. Arch Surg 1937: 10491071.

31.R Ji , S Kato . Histochemical analysis of lymphatic endothelial cells in lymphostasis. Microsc Res Tech 2001; 55: 7080.

34.D Driscoll , K Offord , R Feldt , H Schaff , F Puga . Danielson G. 5–15 yr follow-up after the Fontan operation. Circulation 1992; 85: 469496.

37.MJ Grattan , BW McCrindle . Recurrent exacerbations of protein-losing enteropathy after initiation of growth hormone therapy in a Fontan patient controlled with spironolactone. Congenit Heart Dis 2010; 5: 165167.

38.J Donelly , A Rosenthal , V Castle , R Holmes . Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation. J Pediatr 1997; 130: 474478.

39.I Bendayan , J Casaldaliga , F Castello , L Miro . Heparin therapy and reversal of protein-losing enteropathy in a case with congenital heart disease. Pediatr Cardiol 2000; 21: 267268.

40.A Kelly , R Feldt , D Driscoll , G Danielson . Use of heparin in the treatment of protein-losing enteropathy after Fontan operation for complex congenital heart disease. Mayo Clin Proc 1998; 73: 777779.

41.L Ryerson , C Goldberg , A Rosenthal , A Armstrong . Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle palliation. Am J Cardiol 2008; 101: 248251.

42.I Vlodavsky , G Abboud-Jarrous , M Elkin , The impact of heparanese and heparin on cancer metastasis and angiogenesis. Pathophysiol Haemost Thromb 2006; 35: 116127.

43.Y Tan . Basic fibroblast growth factor-mediated lymphangiogenesis of lymphatic endothelial cells isolated from dog thoracic ducts: effects of heparin. Jpn J Physiol 1998; 48: 133141.

44.DJ Tyrrell , AP Horne , KR Holme , JM Preuss , CP Page . Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv Pharmacol 1999; 46: 151208.

45.JR Oster , I Singer , LM Fishman . Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: 575586.

47.S Murch , P Winyard , S Koletzko , Congenital enterocyte heparin sulphate deficiency with massive albumin loss; secretory diarroea; and malnutrition. Lancet 1996; 347: 13011303.

48.V Westphal , S Murch , S Kim , Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation. Am J Pathol 2000; 157: 19171925.

49.L Bode , HH Freeze . Applied glycoproteomics--approaches to study genetic-environmental collisions causing protein-losing enteropathy. Biochim Biophys Acta 2006; 1760: 547559.

50.L Bode , C Salvestrini , PW Park , Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J Clin Invest 2008; 118: 229238.

51.A Rothman , J Snyder . Protein-losing enteropathy following the Fontan operation: resolution with prednisone therapy. Am Heart J 1991; 121: 618619.

52.J Rychik , D Piccoli , G Barber . Usefulness of corticosteroid therapy for protein-losing enteropathy after the Fontan procedure. Am J Cardiol 1991; 68: 819821.

53.J Therrien , G Webb , M Gatzoulis . Reversal of protein losing enteropathy with prednisone in adults with modified Fontan operations: long term palliation or bridge to cardiac transplantation? Heart 1999; 82: 241243.

58.V Lemes , A Murphy , F Osterman , J Laschinger , J Kan . Fenestration of extracardiac fontan and reversal of protein-losing enteropathy: case report pediatric cardiology. Pediatr Cardiol 1998; 19: 355357.

59.H Vyas , DJ Driscoll , AK Cabalka , F Cetta , DJ Hagler . Results of transcatheter Fontan fenestration to treat protein losing enteropathy. Catheter Cardiovasc Interv 2007; 69: 584589.

61.MK Heinemann , M Gass , J Breuer , G Ziemer . DDD pacemaker implantation after Fontan-type operations. Pacing Clin Electrophysiol 2003; 26: 492495.

62.A Dodge-Khatami , M Rahn , R Pretre , U Bauersfeld . Dual chamber epicardial pacing for the failing atriopulmonary Fontan patient. Ann Thorac Surg 2005; 80: 14401444.

63.AM Sheikh , AT Tang , K Roman , The failing Fontan circulation: successful conversion of atriopulmonary connections. J Thorac Cardiovasc Surg 2004; 128: 6066.

64.CF Marcelletti , FL Hanley , C Mavroudis , Revision of previous Fontan connections to total extracardiac cavopulmonary anastomosis: a multicenter experience. J Thorac Cardiovasc Surg 2000; 119: 340346.

65.S Weinstein , D Chan . Extracardiac Fontan conversion, cryoablation, and pacemaker placement for patients with a failed Fontan. Semin Thorac Cardiovasc Surg 2005; 17: 170178.

66.JA van Son , FW Mohr , J Hambsch , P Schneider , H Hess , GS Haas . Conversion of atriopulmonary or lateral atrial tunnel cavopulmonary anastomosis to extracardiac conduit Fontan modification. Eur J Cardiothorac Surg 1999; 15: 150157; discussion 7–8.

67.J Kreutzer , JF Keane , JE Lock , Conversion of modified Fontan procedure to lateral atrial tunnel cavopulmonary anastomosis. J Thorac Cardiovasc Surg 1996; 111: 11691176.

71.A Gamba , M Merlo , R Fiocchi , Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg 2004; 127: 555562.

72.KA Jayakumar , LJ Addonizio , MR Kichuk-Chrisant , Cardiac transplantation after the Fontan or Glenn procedure. J Am Coll Cardiol 2004; 44: 20652072.

73.JM Lamour , LJ Addonizio , ME Galantowicz , Outcome after orthotopic cardiac transplantation in adults with congenital heart disease. Circulation 1999; 100: II200II205.

74.MH Witte , AE Dumont , RH Clauss , B Rader , N Levine , ES Breed . Lymph circulation in congestive heart failure: effect of external thoracic duct drainage. Circulation 1969; 39: 723733.

75.WR Cole , MH Witte , SL Kash , M Rodger , WR Bleisch , GH Muelheims . Thoracic duct-to-pulmonary vein shunt in the treatment of experimental right heart failure. Circulation 1967; 36: 539543.

76.J Rychik , TL Spray . Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002; 5: 311.

77.AM Ostrow , H Freeze , J Rychik . Protein-losing enteropathy after fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg 2006; 82: 695700.

78.L Bode , S Murch , HH Freeze . Heparan sulfate plays a central role in a dynamic in vitro model of protein-losing enteropathy. J Biol Chem 2006; 281: 78097815.

79.M Glockler , T Severin , R Arnold , First description of three patients with multifocal lymphangiomatosis and protein-losing enteropathy following palliation of complex congenital heart disease with total cavo-pulmonary connection. Pediatr Cardiol 2008; 29: 771774.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Cardiology in the Young
  • ISSN: 1047-9511
  • EISSN: 1467-1107
  • URL: /core/journals/cardiology-in-the-young
Please enter your name
Please enter a valid email address
Who would you like to send this to? *