Protein-Losing Enteropathy following the Fontan Operation


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P. Syamasundar Rao, MD

Protein-losing enteropathy (PLE) may be defined as excessive loss of proteins across the intestinal mucosa and is due to either a primary gastrointestinal abnormality or secondary to cardiac disease. Initial reports of PLE secondary to cardiac disease, namely, congestive heart failure,1 constrictive pericarditis2,3 and myocarditis4 were published in the early 1960s. The association of PLE with high superior vena caval pressure secondary to an obstructed Mustard baffle5 and superior vena cava-toright pulmonary artery anastamosis (Classical Glenn Operation)6 was subsequently documented. The occurrence of PLE in Fontan patients was first reported in 1980.7 Subsequently, a number of other authors reported PLE following the Fontan procedure. The reported prevalence of PLE varied from 3.7%8 to 24%.9 In one large, carefully-conducted study, the prevalence was 11.1%, with a cumulative risk at 10 years of 13.4%.10

Loss of protein in the bowel appears to be secondary to lymphatic distension and/or rupture of lacteals, which may be due to elevated systemic venous pressure. However, PLE has also been observed in patients with normal pressures for the Fontan circuit. The etiology of PLE is unknown. Multivariate analysis10 of pre- and postoperative risk factors revealed that PLE is associated with non-left ventricular anatomy, long hospital stay at the time of Fontan surgery and renal failure in the immediate postoperative period. The majority of reported PLE patients are from among the patients who underwent an atrio-pulmonary connection-type of Fontan procedure. While PLE has been reported in a total cavo-pulmonary connection-type of Fontan, prevalence in the total cavo-pulmonary group may be lower; a 1.2% prevalence was reported in one recent study.11 PLE patients have been shown to have a high systemic venous pressure, low cardiac index, high pulmonary vascular resistance, decreased left ventricular systolic function and elevated systemic ventricular end-diastolic pressure.8,10 In an earlier study, increased right atrial diastolic pressure is shown to be associated with PLE.12 Superior mesenteric Doppler flow velocity studies13,14 demonstrated a higher mesenteric vascular resistance index in post-Fontan PLE patients compared to those without PLE, which in turn is higher than that in normal subjects. This may be related to increased circulating angiotensin II, which in turn may be secondary to low cardiac output.

Symptoms manifest a few months to 16 years following the Fontan procedure.8,10 PLE has been noted to develop 5 years after the Fontan in nearly 30% of patients.10 Peripheral edema, ascites and/or pleural/pericardial effusions are the usual findings at presentation. Diarrhea, abdominal pain and other gastrointestinal symptoms commonly seen in PLE patients associated with primary gastrointestinal pathology are not common in PLE of Fontan.10 Hypoalbuminemia, hypoproteinemia, low serum calcium, lymphocytopenia, elevated alpha-1 antitrypsin in the stool and increased alpha-1 antitrypsin clearance are present. Confirmation of the syndrome by technetium 99m-labeled human serum albumin scintigraphy may be useful.15 PLE is associated with a high mortality rate,8,10 with a 5-year actuarial survival rate of 46%.10 Because the etiology is largely unknown, the methods of management are arbitrary.

In this issue of the Journal, Shahda et al16 describe a 5-year-old child with hypoplastic left heart syndrome who developed PLE following a Fontan operation. Relief of left pulmonary artery obstruction and aortic recoarctation with stent implantation improved the symptoms associated with PLE. The authors recommend transcatheter intervention to relieve obstructions in the Fontan circuit to prevent or treat PLE. This is a well-written paper reporting good results following stent implantation for treatment of PLE. Although the textbook recommendation for PLE treatment is to evaluate for and relieve17,18 any obstructive lesions in the Fontan circuit, it is not clear if actual documentation of such results exists. This paper reinforces the clinical dictum that obstructions should be searched for thoroughly in PLE patients and treated appropriately.

Since the etiology of PLE is principally unknown, a number of arbitrary treatment modalities have been used by clinicians with varying degrees of success, and these include elemental diet,19 calcium replacement,20 regular high-molecular and low-molecular weight heparin,21–23 high-dose spironolacone,24 prednisone,25–28 sildenafil,29 resection of localized intestinal lymphangiectasia,30 relief of obstructive lesions,16 occlusion of aorto-pulmonary connections,18,31,32 reduction of right atrial pressure by creating an atrial fenestration,33–38 pacing,10,39,40 conversion to total cavopulmonary connection41,42 and heart transplantation.43–46

Once diagnosed with PLE, the initial management includes appropriate adjustment of anticongestive therapy (digoxin, diuretics and afterload-reducing agents), administration of parenteral albumin, sodium restriction and a lowfat, high-protein, medium-chain triglyceride diet. Replacement of immunoglobulin and calcium may also be considered. Obstructive lesions, if any, in the Fontan circuit must be evaluated for and, if present, relieved by means of transcatheter or surgical therapy. Similarly, aorto-pulmonary connections, naturally-occurring or prior surgical shunts, should be sought out and closed by either transcatheter methodology (coils, devices, etc.) or surgery. Resection of localized intestinal lymphangiectasia, if demonstrated, has beenused with success.30 Reduction of right atrial pressure by creating an atrial septal defect has been helpful in some patients; a number of reports show success with this method.33–38 Surgical or transcatheter methods may be used depending upon the postsurgical anatomy. Alternative approaches include systemic steroids25–28 to modulate the intestinal mucosa, or heparin therapy21–23 to stabilize cell membranes of the capillary endothelium of the intestinal mucosa. In patients with rhythm abnormality, atrial or dual-chamber pacing10,39,40 may be used to increase cardiac output which in turn may reverse the PLE. In patients with an atrio-pulmonary-type of Fontan, conversion to total cavo-pulmonary connection may be helpful,41,42 although such converting operations are likely to have high mortality rates.

In conclusion, a comprehensive treatment plan should be developed in the management of PLE and should encompass: (1) symptomatic treatment to relieve edema, correct hypoalbuminemia and replace lost immunoglobulin and calcium; (2) treatment of congestive heart failure and low cardiac output should be instituted with particular attention to angiotensin-converting enzyme inhibitors, especially in view of recent findings of high mesenteric vascular resistance; (3) correct anatomic abnormalities such as obstructive lesions in and outside the Fontan circuit and aorto-pulmonary connections; (4) address intestinal mucosal abnormality with prednisone and/or heparin if the other methods do not result in resolution of PLE; and (5) PLE is a potentially fatal disease and should be promptly treated. Conversion to total cavopulmonary connection and cardiac transplantation are options that should also be considered if other methods fail.



1. Davidson JD, Waldmann TA, Goodman DS, Gordon RS Jr. Protein-losing gastroenteropathy in congestive heart failure. Lancet 1961;1:899–902.

2. Petersen VP, Mastrup J. Protein-losing gastro-enteropathy in constrictive pericarditis. Acta Medica Scand 1963:173:401–403.

3. Wilkinson P, Pinto B, Senior JR. Reversible protein losing enteropathy with intestinal lymphangiectasia secondary to chronic constrictive pericarditis. N Engl J Med 1965;273:1178–1181.

4. Valberg LS, Cohen WEN, McCorriston JR. Excessive loss of plasma protein into the gastrointestinal tract associated with primary myocardial disease. Am J Med 1965;39:668–673.

5. Moodie DS, Feldt RH, Wallace RB. Transient protein-losing enteropathy secondary to elevated caval pressures and caval obstruction after Mustard procedure. J Thorac Cardiovasc Surg 1976;72:379–382.

6. Gleason WA, Jr, Roodman ST, Laks H. Protein-losing enteropathy and intestinal lymphangiectasia after superior vena cava-right pulmonary artery (Glenn) shunt. J Thorac Cardiovasc Surg 1979;77:843–846.

7. Crupi G, Locatelli G, Villani M, et al. Protein-losing enteropathy after Fontan operation for tricuspid atresia (imperforate tricuspid valve). J Thorac Cardiovasc Surg 1980;28:359–263.

8. Mertens L, Hagler DJ, Sauer U, et al. Protein-losing enteropathy after the Fontan operation: An international multicenter study. PLE study group. J Thorac Cardiovasc Surg 1998;115:1063–1073.

9. Malcic I, Sauer U, Stern H, et al. The influence of pulmonary artery banding on outcome after the Fontan operation. J Thorac Cardiovasc Surg 1992;104:743–747.

10. Feldt RH, Driscoll DJ, Offord KP, et al. Protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 1996;112:672–680.

11. Giannico S, Hammad F, Amodeo A, et al. Clinical outcome of 193 extracardiac Fontan patients: the first 15 years. J Am Coll Cardiol 2006;47:2065–2073.

12. Hess J, Kruizinga K, Bijleveld CMA, et al. Protein-losing enteropathy after Fontan operation. J Thorac Cardiovasc Surg 1984;88:606–809.

13. Rychik J, Gui-Yang S. Relation of mesenteric vascular resistance after Fontan operation and protein-losing enteropathy. Am J Cardiol 2002;90:672–674.

14. Ostrow AM, Freeze H, Rychik J. Protein-losing enteropathy after Fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg 2006;82:695–700.

15. Chiu NT, Lee BF, Hwang SJ, et al. Protein-losing enteropathy: Diagnosis with (99m)Tc-labeled human serum albumin scintigraphy. Radiology 2001;219:86–90.

16. Shahda S, Zahra M, Fiore A, Jureidini S. Stents in the successful management of proteinlosing enteropathy after Fontan. J Invasive Cardiol 2007;19:444–446.

17. Rao PS. Tricuspid atresia. In: Pediatric Cardiovascular Medicine.Moller JH, Hoffman JIE (eds). Churchill Livingstone: New York. 2000, pp. 421–441.

18. Rao PS. Tricuspid atresia. In: e-medicine Pediatrics

19. Guariso G, Cerutti A, Moreolo GS, Milanesi O. Protein-losing enteropathy after Fontan operation: Treatment with elementary diet in one case. Pediat Cardiol 2000;21:292.

20. Kim SJ, Park IS, Song JY, et al. Reversal of protein-losing enteropathy with calcium replacement in a patient after Fontan operation. Ann Thorac Surg 2004;77:1456–1457.

21. Donnelly JP, Rosenthal A, Castle VP, Holmes RD. Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation. J Pediatr 1997;130:474–478.

22. Kelly AM, Feldt RH, Driscoll DJ, Danielson GK. Use of heparin in the treatment of protein-losing enteropathy after Fontan operation for complex congenital heart disease. Mayo Clin Proc 1998;73:777–779.

23. Facchini M, Guldenschuh I, Turina J, et al. Resolution of protein-losing enteropathy with standard high molecular heparin and urokinase after Fontan repair in a patient with tricuspid atresia. J Cardiovasc Surg (Torino) 2000;41:567– 570.

24. Ringel RE, Peddy SB. Effect of high-dose spironolactone on protein-losing enteropathy in patients with Fontan palliation of complex congenital heart disease. Am J Cardiol 2003;91:1031–1032.

25. Rothman A, Snyder J. Protein-losing enteropathy following the Fontan operation: Resolution with prednisone therapy. Am Heart J 1991;121:618–619.

26. Rychik J, Piccoli D, Barber G. Usefulness of corticosteroid therapy for protein-losing enteropathy after Fontan procedure. Am J Cardiol 1991;68:819–821.

27. Zellers TM, Brown K. Protein-losing enteropathy after the modified Fontan operation: Oral prednisone treatment with biopsy and laboratory proved improvement. Pediatr Cardiol 1996;17:115–117.

28. Therrien J, Webb GD, Gatzoulis MA. Reversal of protein losing enteropathy with prednisone in adults with modified Fontan operations: long term palliation or bridge to cardiac transplantation? Heart 1999;82:241–243.

29. Uzun O, Wong JK, Bhole V, Stumper O. Resolution of protein-losing enteropathy and normalization of mesenteric Doppler flow with sildenafil after Fontan. Ann Thorac Surg 2006;82:39–40.

30. Connor FL, Angelides S, Gibson M, et al. Successful resection of localized intestinal lymphangiectasia post-Fontan: Role of (99m) technetium-dextran scintigraphy. Pediatrics 2003;112:242–247.

31. Ventriglia F, Mundo L, Bosco G, Colloridi V. Regression of post-Fontan protein-losing enteropathy after surgical correction of hemodynamic faults other than high right atrial pressure. Texas Heart Inst J 1996;23:233–235.

32. Masetti P, Marianeschi SM, Cipriani A, et al. Reversal of protein-losing enteropathy after ligation of systemic-pulmonary shunt. Ann Thorac Surg 1999;67:235–236.

33. Mertens L, Doumoulin M, Gewilling M. Effect of percutaneous fenestration of the atrial septum on protein-losing enteropathy after Fontan operation. Brit Heart J 1994;72:591–592.

34. Jacobs ML, Rychik J, Byrum CJ, Norwood WI Jr. Protein losing enteropathy after Fontan operation: Resolution after baffle fenestration. Ann Thor Surg 1996;61:206–208.

35. Warnes CA, Feldt RH, Hagler DJ. Protein losing enteropathy after the Fontan operation: Successful treatment by percutaneous fenestration of the atrial septum. Mayo Clin Proc 1996;71:378–379.

36. Rychik J, Rome JJ, Jacobs ML. Late surgical fenestration for complications after Fontan operation. Circulation 1997;96:33–36.

37. Lemes V, Murphy AM, Osterman FA, et al. Fenestration of extracardiac Fontan and reversal of protein-losing enteropathy: Case report. Pediatr Cardiol 1998;19:355–357.

38. Fraisse A, Bonnet JL. Protein-losing enteropathy: Radiofrequency fenestration of the atrial septum after failure of transseptal needle puncture. Pediatr Cardiol 2004;25:84–86.

39. Cohen MI, Rhodes LA, Wernovsky G, et al. Atrial pacing: An alternative treatment for protein- losing enteropathy following Fontan operation. J Thorac Cardiovasc Surg 2001;121:582–583

40. Dodge-Khatami A, Rahn M, Prêtre R, Bauersfeld U. Dual chamber epicardial pacing for the failing atriopulmonary Fontan patient. Ann Thorac Surg 2005;80:1440–1444.

41. Kreutzer J, Keane JF, Lock JE, et al. Conversion of modified Fontan procedure to lateral tunnel cavopulmonary anastomosis. J Thorac Cardiovasc Surg 2997;111:1169–1176.

42. Marcelletti CF, Hanley FL, Mavroudis C, et al. Revision of previous Fontan connections to total extracardiac cavopulmonary anastomosis: A multicenter experience. J Thorac Cardiovasc Surg 2000;119:340–346.

43. Sierra C, Calleja F, Picazo B, Martinez-Valverde A. Protein-losing enteropathy secondary to Fontan procedure resolved after cardiac transplantation. J Pediat Gastroenterol Nutrition 1997;24:229–230.

44. Brancaccio G, Carotti A, D'Argenio P, et al. Protein-losing enteropathy after Fontan surgery: Resolution after cardiac transplantation. J Heart Lung Transplant 2003;22:484–486.

45. Gamba A, Merlo M, Fiocchi R, et al. Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg 2004;127:555–562.

46. Bernstein D, Naftel D, Chin C, et al. Pediatric heart transplant study. Outcome of listing for cardiac transplantation for failed Fontan: A multi-institutional study. Circulation 2006;114:273–280.

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