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

Published online by Cambridge University Press:  25 February 2011

Jeffery Meadows*
Affiliation:
Division of Pediatric Cardiology, University of California, San Francisco, California, United States of America
Kathy Jenkins
Affiliation:
Department of Cardiology, Children's Hospital, Boston, Massachusetts, United States of America Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
*
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: jeffery.meadows@ucsf.edu

Abstract

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.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011

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References

1.Feldt, R, Driscoll, D, Offord, K, et al. Protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 1996; 3: 672680.CrossRefGoogle Scholar
2.Mertens, L, Hagler, D, Sauer, U, Somerville, J, Gewillig, M. Protein-losing enteropathy after the Fontan operation: an international multicenter study. J Thorac Cardiovasc Surg 1998; 115: 10631073.CrossRefGoogle Scholar
3.Powell, A, Gauvreau, K, Jenkins, K, Blume, E, Mayer, J, Lock, J. Perioperative risk factors for development of protein-losing enteropathy following Fontan procedure. Am J Cardiol 2001; 88: 12061209.CrossRefGoogle ScholarPubMed
4.Meadows, J, Gauvreau, K, Jenkins, K. Lymphatic obstruction and protein-losing enteropathy in patients with congenital heart disease. Congenit Heart Dis 2008; 3: 269276.CrossRefGoogle ScholarPubMed
5.Davidson, JD, Waldmann, TA, Goodman, DS, JrGordon, RS. Protein-losing gastroenteropathy in congestive heart-failure. Lancet 1961; 1: 899902.CrossRefGoogle ScholarPubMed
6.Wilkinson, P, Pinto, B, Senior, JR. Reversible protein-losing enteropathy with intestinal lymphangiectasia secondary to chronic constrictive pericarditis. N Engl J Med 1965; 273: 11781181.CrossRefGoogle ScholarPubMed
7.Crupi, G, Locatelli, G, Tiraboschi, R, Villani, M, De Tommasi, M, Parenzan, L. Protein-losing enteropathy after Fontan operation for tricuspid atresia (imperforate tricuspid valve). Thorac Cardiovasc Surg 1980; 28: 359363.CrossRefGoogle Scholar
8.Hess, J, Kruizinga, K, Bijleveld, CM, Hardjowijono, R, Eygelaar, A. Protein-losing enteropathy after Fontan operation. J Thorac Cardiovasc Surg 1984; 88: 606609.Google ScholarPubMed
9.Wochner, R, Weissman, S, Waldmann, T. 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.CrossRefGoogle ScholarPubMed
10.Davis, C, Driscoll, D, Perrault, J, et al. Enteric protein loss after the Fontan operation. Mayo Clin Proc 1994; 69: 112114.CrossRefGoogle ScholarPubMed
11.Fujii, T, Shimizu, T, Takahashi, K, et al. Fecal alfa-1 antitrypsin concentrations as a measure of enteric protein loss after modified Fontan operations. J Pediatr Gastroenterol Nutr 2003; 37: 577580.CrossRefGoogle Scholar
12.Thorne, S, Hooper, J, Kemp, M, Somerville, J. Gastro-intestinal protein loss in late survivors of Fontan surgery and other congenital heart disease. Eur Heart J 1998; 19: 514520.CrossRefGoogle ScholarPubMed
13.Kaulitz, R, Luhmer, I, Bergmann, F, Rodeck, B, Hausdorf, G. Sequelae after modified Fontan operation: postoperative haemodynamic data and organ function. Heart 1997; 78: 154159.CrossRefGoogle ScholarPubMed
14.Chakrabarti, S, Keeton, B, Salmon, A, Vettukattil, J. Acquired combined immunodeficiency associated with protein losing enteropathy complicing Fontan operation. Heart 2003; 89: 11301131.CrossRefGoogle ScholarPubMed
15.Cheung, Y, Tsang, H, Kwok, J. Immunologic profile of patients with protein-losing enteropathy complicating congenital heart disease. Pediatr Cardiol 2002; 23: 587593.CrossRefGoogle ScholarPubMed
16.Koch, A, Hofbeck, M, Feistel, H, Buheitel, G, Singer, H. Circumscribed intestinal protein loss with deficiency in CD4+ lymphocytes after Fontan procedure. Eur J Pediatr 1999; 10: 847850.CrossRefGoogle Scholar
17.Muller, C, Wolf, H, Gottlicher, J, Zielinski, C, Eidl, M. Cellular immunodeficiency in protein-losing enteropathy. Predominant Reduction of CD3+ and CD4+ Lymphocytes Dig Dis Sci 1991; 36: 116122.Google ScholarPubMed
18.Thomas, D, Sinatra, F, Merritt, R. Random fecal alpha-1-antitrypsin concentration in children with gastrointestinal disease. Gastroenterology 1981; 4: 776782.Google Scholar
19.Mbonda, E, Forget, P, Saye, Z, Leclercq-Foucart, J. Usefulness of random fecal alpha 1-antitrypsin and chymotrypsin determinations in children. J Pediatr Gastroenterol Nutr 1989: 8588.CrossRefGoogle ScholarPubMed
20.Florent, C, L'Hirondel, C, Desmazures, C, Aymes, C, Bernier, J. Intestinal clearance of alpha 1-antitrypsin. A sensitive method for the detection of protein-losing enteropathy. Gastroenterology 1981; 4: 777780.Google Scholar
21.Bernier, JJ, Florent, C, Desmazures, C, Aymes, C, L'Hirondel, C. Diagnosis of protein-losing enteropathy by gastrointestinal clearance of alpha1-antitrypsin. Lancet 1978; 2: 763764.CrossRefGoogle ScholarPubMed
22.Quigley, EM, Ross, IN, Haeney, MR, Holbrook, IB, Marsh, MN. Reassessment of faecal alpha-1-antitrypsin excretion for use as screening test for intestinal protein loss. J Clin Pathol 1987; 40: 6166.CrossRefGoogle ScholarPubMed
23.Choudhary, S, Gibson, PR, Deacon, MC, Young, GP. Measurement of faecal alpha 1-antitrypsin: methodologies and clinical application. J Gastroenterol Hepatol 1996; 11: 311318.CrossRefGoogle ScholarPubMed
24.Puri, A, Aggarwal, R, Gupta, R, et al. Intestinal lymphangiectasia: evaluation by CT and scintigraphy. Gastrointest Radiol 1992; 17: 119121.CrossRefGoogle ScholarPubMed
25.Werbeloff, L, Bank, S, Marks, I. Radiological findings in protein-losing gastroenteropathy. Br J Radiol 1969; 42: 605612.CrossRefGoogle Scholar
26.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: e242e247.CrossRefGoogle ScholarPubMed
27.Asakura, H, Miura, S, Morishita, T, et al. Endoscopic and histopathologic study on primary and secondary lymphangiectasia. Dig Dis Sci 1981; 4: 312320.CrossRefGoogle Scholar
28.Gleason, W, Roodman, S, Laks, H. Protein-losing enteropathy and intestinal lymphangiectasia after superior vena cava-right pulmonary artery (Glenn) shunt. J Thorac Cardiovasc Surg 1979; 6: 843846.Google Scholar
29.Zellers, T, Brown, K. Protein-losing enteropathy after the modified Fontan operation: oral prednisone treatment with biopsy and laboratory proved improvement. Pediatr Cardiol 1996; 17: 115117.CrossRefGoogle ScholarPubMed
30.Blalock, A, Robsinson, C, Cunningham, R, Gray, M. Experimental studies on lymphatic blockage. Arch Surg 1937: 10491071.CrossRefGoogle Scholar
31.Ji, R, Kato, S. Histochemical analysis of lymphatic endothelial cells in lymphostasis. Microsc Res Tech 2001; 55: 7080.CrossRefGoogle ScholarPubMed
32.Casley-Smith, JR, Clodius, L, Piller, NB. Tissue changes in chronic experimental lymphoedema in dogs. Lymphology 1980; 13: 130141.Google ScholarPubMed
33.Casley-Smith, J, Clodius, L, Piller, N. Tissue changes in chronic experimental lymphoedema in dogs. Lymphology 1980: 130141.Google ScholarPubMed
34.Driscoll, D, Offord, K, Feldt, R, Schaff, H, Puga, F. Danielson G. 5–15 yr follow-up after the Fontan operation. Circulation 1992; 85: 469496.CrossRefGoogle Scholar
35.McCaffrey, C, Levy, M. Effect of furosemide on thoracic duct lymph flow in the dog. Am J Physiol 1980; 238: F363F371.Google ScholarPubMed
36.Ringel, R, Peddy, S. Effect of high-dose spironolactone on protein-losing enteropathy in patients with Fontan palliation of complex congenital heart disease. Am J Cardiol 2003; 8: 10311032.CrossRefGoogle Scholar
37.Grattan, MJ, McCrindle, BW. 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.CrossRefGoogle Scholar
38.Donelly, J, Rosenthal, A, Castle, V, Holmes, R. Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation. J Pediatr 1997; 130: 474478.CrossRefGoogle Scholar
39.Bendayan, I, Casaldaliga, J, Castello, F, Miro, L. Heparin therapy and reversal of protein-losing enteropathy in a case with congenital heart disease. Pediatr Cardiol 2000; 21: 267268.CrossRefGoogle Scholar
40.Kelly, A, Feldt, R, Driscoll, D, Danielson, G. Use of heparin in the treatment of protein-losing enteropathy after Fontan operation for complex congenital heart disease. Mayo Clin Proc 1998; 73: 777779.CrossRefGoogle ScholarPubMed
41.Ryerson, L, Goldberg, C, Rosenthal, A, Armstrong, A. Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle palliation. Am J Cardiol 2008; 101: 248251.CrossRefGoogle ScholarPubMed
42.Vlodavsky, I, Abboud-Jarrous, G, Elkin, M, et al. The impact of heparanese and heparin on cancer metastasis and angiogenesis. Pathophysiol Haemost Thromb 2006; 35: 116127.CrossRefGoogle ScholarPubMed
43.Tan, Y. Basic fibroblast growth factor-mediated lymphangiogenesis of lymphatic endothelial cells isolated from dog thoracic ducts: effects of heparin. Jpn J Physiol 1998; 48: 133141.CrossRefGoogle ScholarPubMed
44.Tyrrell, DJ, Horne, AP, Holme, KR, Preuss, JM, Page, CP. Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv Pharmacol 1999; 46: 151208.CrossRefGoogle ScholarPubMed
45.Oster, JR, Singer, I, Fishman, LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: 575586.CrossRefGoogle ScholarPubMed
46.Muir, JM, Andrew, M, Hirsh, J, et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood 1996; 88: 13141320.Google ScholarPubMed
47.Murch, S, Winyard, P, Koletzko, S, et al. Congenital enterocyte heparin sulphate deficiency with massive albumin loss; secretory diarroea; and malnutrition. Lancet 1996; 347: 13011303.CrossRefGoogle Scholar
48.Westphal, V, Murch, S, Kim, S, et al. Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation. Am J Pathol 2000; 157: 19171925.CrossRefGoogle Scholar
49.Bode, L, Freeze, HH. Applied glycoproteomics--approaches to study genetic-environmental collisions causing protein-losing enteropathy. Biochim Biophys Acta 2006; 1760: 547559.CrossRefGoogle ScholarPubMed
50.Bode, L, Salvestrini, C, Park, PW, et al. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J Clin Invest 2008; 118: 229238.CrossRefGoogle ScholarPubMed
51.Rothman, A, Snyder, J. Protein-losing enteropathy following the Fontan operation: resolution with prednisone therapy. Am Heart J 1991; 121: 618619.CrossRefGoogle ScholarPubMed
52.Rychik, J, Piccoli, D, Barber, G. Usefulness of corticosteroid therapy for protein-losing enteropathy after the Fontan procedure. Am J Cardiol 1991; 68: 819821.CrossRefGoogle ScholarPubMed
53.Therrien, J, Webb, G, Gatzoulis, M. 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.CrossRefGoogle ScholarPubMed
54.Schuyler, M, Gerblich, A, Urda, G. Prednisone and T-cell subpopulations. Arch Intern Med 1984; 5: 973975.CrossRefGoogle Scholar
55.Hedman, L, Lundin, P. The effect of steroids on the circulating lymphocyte population. I. Changes in the thoracic duct lymphocyte population of the rat after neonatal thymectomy and prednisolone treatment. Lymphology 1977; 4: 185191.Google Scholar
56.Fraisse, A, Bonnet, J. Protein-losing enteropathy: radiofrequency fenestration of the atrial septum after failure of transseptal needle puncture. Pediatr Cardiol 1998; 4: 355357.Google Scholar
57.Jacobs, M, Rychik, J, Byrum, C, Norwood, WJ. Protein-losing enteropathy after Fontan operation: resolution after baffle fenestration. Ann Thorac Surg 1996; 1: 206208.CrossRefGoogle Scholar
58.Lemes, V, Murphy, A, Osterman, F, Laschinger, J, Kan, J. Fenestration of extracardiac fontan and reversal of protein-losing enteropathy: case report pediatric cardiology. Pediatr Cardiol 1998; 19: 355357.CrossRefGoogle Scholar
59.Vyas, H, Driscoll, DJ, Cabalka, AK, Cetta, F, Hagler, DJ. Results of transcatheter Fontan fenestration to treat protein losing enteropathy. Catheter Cardiovasc Interv 2007; 69: 584589.CrossRefGoogle ScholarPubMed
60.Cohen, M, Rhodes, L, Wernovsky, G, Gaynor, J, Spray, T, Rychik, J. Atrial pacing: an alternative treatment for protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 2001; 3: 582583.CrossRefGoogle Scholar
61.Heinemann, MK, Gass, M, Breuer, J, Ziemer, G. DDD pacemaker implantation after Fontan-type operations. Pacing Clin Electrophysiol 2003; 26: 492495.CrossRefGoogle ScholarPubMed
62.Dodge-Khatami, A, Rahn, M, Pretre, R, Bauersfeld, U. Dual chamber epicardial pacing for the failing atriopulmonary Fontan patient. Ann Thorac Surg 2005; 80: 14401444.CrossRefGoogle ScholarPubMed
63.Sheikh, AM, Tang, AT, Roman, K, et al. The failing Fontan circulation: successful conversion of atriopulmonary connections. J Thorac Cardiovasc Surg 2004; 128: 6066.CrossRefGoogle ScholarPubMed
64.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: 340346.CrossRefGoogle ScholarPubMed
65.Weinstein, S, Chan, D. Extracardiac Fontan conversion, cryoablation, and pacemaker placement for patients with a failed Fontan. Semin Thorac Cardiovasc Surg 2005; 17: 170178.CrossRefGoogle ScholarPubMed
66.van Son, JA, Mohr, FW, Hambsch, J, Schneider, P, Hess, H, Haas, GS. Conversion of atriopulmonary or lateral atrial tunnel cavopulmonary anastomosis to extracardiac conduit Fontan modification. Eur J Cardiothorac Surg 1999; 15: 150157; discussion 7–8.CrossRefGoogle ScholarPubMed
67.Kreutzer, J, Keane, JF, Lock, JE, et al. Conversion of modified Fontan procedure to lateral atrial tunnel cavopulmonary anastomosis. J Thorac Cardiovasc Surg 1996; 111: 11691176.CrossRefGoogle ScholarPubMed
68.Brancaccio, G, Carotti, A, D'Argenio, P, Michielon, G, Parisi, F. Protein-losing enteropathy after Fontan surgery: resolution after cardiac transplantation. J Heart Lung Transplant 2003; 4: 484486.CrossRefGoogle Scholar
69.Holmgren, D, Berggren, H, Wahlander, H, Hallberg, M, Myrdal, U. Reversal of protein-losing enteropathy in a child with Fontan circulation is correlated with central venous pressure after heart transplantation. Pediatr Transplant 2001; 2: 135137.CrossRefGoogle Scholar
70.Sierra, C, Calleja, F, Picazo, B, Martinez-Valverde, A. Protein-losing enteropathy secondary to Fontan procedure resolved after cardiac transplantation. J Pediatr Gastroenterol Nutr 1997; 2: 229230.CrossRefGoogle Scholar
71.Gamba, A, Merlo, M, Fiocchi, R, et al. Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg 2004; 127: 555562.CrossRefGoogle ScholarPubMed
72.Jayakumar, KA, Addonizio, LJ, Kichuk-Chrisant, MR, et al. Cardiac transplantation after the Fontan or Glenn procedure. J Am Coll Cardiol 2004; 44: 20652072.CrossRefGoogle ScholarPubMed
73.Lamour, JM, Addonizio, LJ, Galantowicz, ME, et al. Outcome after orthotopic cardiac transplantation in adults with congenital heart disease. Circulation 1999; 100: II200II205.CrossRefGoogle ScholarPubMed
74.Witte, MH, Dumont, AE, Clauss, RH, Rader, B, Levine, N, Breed, ES. Lymph circulation in congestive heart failure: effect of external thoracic duct drainage. Circulation 1969; 39: 723733.CrossRefGoogle ScholarPubMed
75.Cole, WR, Witte, MH, Kash, SL, Rodger, M, Bleisch, WR, Muelheims, GH. Thoracic duct-to-pulmonary vein shunt in the treatment of experimental right heart failure. Circulation 1967; 36: 539543.CrossRefGoogle ScholarPubMed
76.Rychik, J, Spray, TL. Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002; 5: 311.CrossRefGoogle ScholarPubMed
77.Ostrow, AM, Freeze, H, Rychik, J. Protein-losing enteropathy after fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg 2006; 82: 695700.CrossRefGoogle ScholarPubMed
78.Bode, L, Murch, S, Freeze, HH. Heparan sulfate plays a central role in a dynamic in vitro model of protein-losing enteropathy. J Biol Chem 2006; 281: 78097815.CrossRefGoogle Scholar
79.Glockler, M, Severin, T, Arnold, R, et al. 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.CrossRefGoogle ScholarPubMed
80.Drake, RE, Gabel, JC, Laine, GA, et al. Effect of outflow pressure on liver lymph flow in unanesthetized sheep. Outflow pressure reduces lymph flow rate from various tissues. Am J Physiol 1990; 259: R780R785.Google Scholar
81.Wegria, R, Zekert, H, Walter, K, et al. Effect of systemic venous pressure on drainage of lymph from the thoracic duct. Am J Physiol 1963; 204: 284288.Google ScholarPubMed
82.Brace, R, Valenzuela, G. Effects of outflow pressure and vascular volume loading on thoracic duct lymph flow in adult sheep. Am J Physiol 1990; 258 (1 Pt 2): R240R244.Google ScholarPubMed
83.Szabo, G, Magyar, Z. Effect of increased systemic venous pressure on lymph pressure and flow. Am J Physiol 1967; 6: 14691474.Google Scholar
84.Drake, R, Abbott, R. Effect of increased neck vein pressure on intestinal lymphatic pressure in awake sheep. Am J Physiol 1992; 262 (5 Pt 2): R892R894.Google ScholarPubMed
85.Menon, S, Hagler, D, Cetta, F, Gloviczki, P, Driscoll, D. Role of caval venous manipulation in treatment of protein-losing enteropathy. Cardiol Young 2008; 18: 275281.CrossRefGoogle ScholarPubMed
86.Andrew, M, David, M, Adams, M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian registry of VTE. Blood 1994; 83: 12511257.Google ScholarPubMed
87.Schmidt, B, Andrew, M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 5: 939943.Google Scholar
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