The Use of Oral Budesonide in Adolescents and Adults With Protein-Losing Enteropathy After the Fontan Operation

ORIGINAL ARTICLES: SURGERY: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. The Use of Oral Budesonide in Adolescents and Adults With Protein-Losing Enteropathy After the Fontan Operation Anitha S. John, MD, PhD, David J. Driscoll, MD, Carole A. Warnes, MD, FRCP, Sabrina D. Phillips, MD, and Frank Cetta, MD Division of Pediatric Cardiology, Children s National Medical Center, George Washington University, Washington, DC; and Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota Background. Approximately 5% to 15% of patients develop protein-losing enteropathy (PLE) after the Fontan operation. Oral controlled release (CR) budesonide has been used as a treatment strategy, but its use in the older Fontan population has not been described. Methods. Seven patients with refractory PLE after the Fontan operation were started on oral CR-budesonide at 9 mg. After 3 to 9 months, the dose was weaned to 3 mg. Response to treatment was assessed by clinical evaluation, serum albumin levels, and fecal -1 antitrypsin clearance when available. Results. Median age at last evaluation was 20 years (range, 16 to 32 years). Six patients had increases in serum albumin levels but only 4 patients had symptomatic improvement. Systemic side effects included: cushingoid features (5), adrenal insufficiency (4), and new-onset type 2 diabetes mellitus (2). One patient had improvement in cushingoid features after weaning CR-budesonide to 3 mg. Older patients (ages 27 to 32 years) had the worst side effect profiles and were the most refractory to treatment. These patients had sonographic evidence of hepatic cirrhosis but normal serum liver function tests. Two deaths occurred: 1 from sepsis 1 month after CR-budesonide initiation and 1 from respiratory arrest 5 months after CR-budesonide discontinuation. Conclusions. CR-budesonide can be used to treat PLE in certain patients, but careful assessment of hepatic function should be performed before initiation of therapy as systemic side effects can limit treatment. Normal serum liver function tests do not preclude hepatic dysfunction in the Fontan patient, and it is important to perform radiographic assessments as well. (Ann Thorac Surg 2011;92:1451 6) 2011 by The Society of Thoracic Surgeons Protein-losing enteropathy (PLE) is a serious complication of the Fontan operation and has been observed in 5% to 15% of patients after the Fontan procedure [1, 2]. PLE is characterized by the enteric loss of proteins, such as albumin, immunoglobulins, and clotting factors. As a result, patients with PLE can manifest peripheral edema, ascites, immune deficiency, and clotting disorders. Low cardiac output and elevated systemic venous pressures may be two of the mechanisms that contribute to the development of PLE [3 5]. PLE does not develop in most patients who undergo the Fontan procedure; therefore, the exact mechanisms of this complication are poorly understood and the treatment strategies are varied. Oral controlled-released (CR) budesonide, a steroid with low systemic absorption and high enteric activity, has recently been cited as effective treatment for PLE [6]. Accepted for publication March 28, 2011. Address correspondence to Dr John, Division of Pediatric Cardiology, Children s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010; e-mail: anjohn@cnmc.org. The reported advantage of CR-budesonide is that it has low systemic absorption, and theoretically fewer reported systemic side effects, although its use in this patient population is limited and has not been evaluated in the adult population [6]. We review the use of budesonide in the adolescent and adult Fontan population and discuss the side effects, limitations, and usage modification needed in the older Fontan patient. Patients and Methods Data for patients with PLE after the Fontan operation were retrieved from existing clinical databases. We identified 7 patients (4 men) with refractory PLE, treated with CR-budesonide. All patients presented with clinical symptoms of diarrhea, abdominal pain, and fluid retention. The diagnosis of PLE was made through a combination of elevated fecal -1 antitrypsin levels and albumin of less than 3.0 g/dl. The study excluded patients with other primary causes of protein loss, such as nephrotic syndrome or intestinal lymphangiectasia, and 2011 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2011.03.103

1452 JOHN ET AL Ann Thorac Surg ORAL BUDESONIDE IN PLE AFTER THE FONTAN OPERATION 2011;92:1451 6 Table 1. Patient Demographics Pt Sex Age (years) Diagnosis Age at Fontan (years) Fontan Type a Age at PLE Diagnosis (years) Age Budesonide Started (years) 1 Female 32 DILV, TGA 12 AP/NF 27 30 2 Male 28 Heterotaxy, unbalanced AVC (RV dominant), 4 AP/NF 25 28 DORV, PA 3 Female 27 DILV, TGA 4 LT/NF 12 25 4 Female 20 Tricuspid atresia 4 LT/F 17 19 5 Male 19 DILV, TGA 1 LT/NF 2 16 6 Male 16 Heterotaxy, dextrocardia, unbalanced AVC (RV 2.5 LT/F 7 13 dominant), DORV, PA 7 Male 17 Unbalanced AVC (RV dominant), aortic coarctation 5 EC/NF 11 16 a Initial Fontan operation. AP atriopulmonary; AVC atrioventricular canal; DILV double-inlet left ventricle; DORV double-outlet right ventricle; EC extra cardiac; F fenestrated; LT lateral tunnel; NF nonfenestrated; PA pulmonary atresia; PLE protein-losing enteropathy; Pt patient; RV right ventricle; TGA transposition of the great arteries. patients with known inflammatory bowel disease such as Crohn disease or ulcerative colitis. The clinical course of patients, including treatment modalities for PLE, and response to treatment as assessed by laboratory assessment and clinical improvement were recorded. Echocardiograms and cardiac catheterization data were reviewed for valvular regurgitation, ventricular function (visual assessment), cardiac output, intracardiac pressures, and ventricular end-diastolic pressure. Treatment with CR-budesonide was started at 9 mg daily for all patients. The dose in 5 patients was weaned within 6 to 9 months to 3 mg daily or 3 mg every other day. Side effects and exacerbations of PLE occurring during budesonide treatment were recorded. Adrenal insufficiency was determined by symptoms (fatigue, generalized malaise, weakness, nausea, and blood pressure instability) or by low morning serum cortisol levels ( 10 g/dl). Albumin and total protein levels during treatment were recorded and fecal -1 antitrypsin clearance levels were recorded, when available. The protocol was reviewed and approved by the Mayo Foundation Institutional Review Board (Protocol No. 10 004994). Results Patient Population Patient demographics are summarized in Table 1. Patients were a median age of 20 years (range, 16 to 32 years) at the time of the study. Four patients had a systemic left ventricle and 3 patients had a systemic right ventricle. PLE was diagnosed at a median age of 12 years (range, 2 to 27 years). In patient 5, the PLE developed 1 year after the Fontan completion, whereas PLE was diagnosed in the remaining patients at 7 to 15 years after the operation. All patients had a follow-up clinic visit and laboratory assessment within the past 12 months. Two patients died: patient 2 died of septic shock that occurred 1 month after CR-budesonide initiation, and patient 3 died of acute respiratory distress syndrome 5 months after CR-budesonide was discontinued. Surgical Details Median age at Fontan operation was 4 years (range, 1 to 12 years). The types of Fontan procedures included atriopulmonary connections in 2, lateral tunnel in 4, and extracardiac conduit in 1. Fenestrations were created in 2 patients at the time of their initial Fontan operation and in 3 patients by cardiac catheterization or operation after the PLE diagnosis. Fontan takedown was required in 2 patients. In patient 6, this occurred immediately after the procedure and was palliated with a cavopulmonary anastomoses and an aortic-to-pulmonary artery shunt. PLE was diagnosed 5 years after this palliative procedure. In an attempt to treat the PLE, this patient had a one-and-a-half ventricle repair at age 8, with bilateral bidirectional cavopulmonary shunts, atrial septal defect (ASD) and ventricular septal defect (VSD) closure, and a right ventricle-topulmonary artery conduit. Patient 5 had an initial takedown at age 5, with a subsequent attempt at reestablishing an extracardiac Fontan at age 13. PLE was diagnosed at age 2 years, and the first Fontan takedown was performed as a treatment strategy. The Fontan was taken down again 8 months after the second attempt, and bidirectional cavopulmonary and central shunts were placed. A right axillary vein fistula was eventually placed to improve cardiac output. An additional 2 patients underwent Fontan revisions. Patient 1 underwent a fenestrated, lateral-tunnel Fontan at age 14 years and subsequently had a revision at age 29 years due to refractory arrhythmias and aortic regurgitation. This included an extracardiac, fenestrated Fontan with oversewing of the native aortic valve. Patient 4 underwent revision of her Fontan at age 6 due to a large leak in the Fontan baffle. A small fenestration was created during the revision to an extracardiac conduit. Cardiac Hemodynamics Hemodynamic data are recorded in Table 2. Data from echocardiograms and cardiac catheterization were obtained before budesonide treatment was initiated. Ejec-

Ann Thorac Surg JOHN ET AL 2011;92:1451 6 ORAL BUDESONIDE IN PLE AFTER THE FONTAN OPERATION 1453 Table 2. Hemodynamics Before Budesonide Pt Ventricular EF Ventricular EDP (mm Hg) Cardiac Index (L/min/m 2 ) PA Pressure a (mm Hg) AVVR Aortic or Neoaortic Regurgitation 1 0.45 8 2.3 12 Mild None 2 0.25 7 1.6 22 Trivial None 3 0.60 8 2.5 13 Trivial None 4 0.60 11 2.1 13 None None 5 0.60 7 2.7 17 Mild Mild 6 b 0.55 9 2.6 13 Moderate Mild 7 0.26 12 2.3 14 None Moderate a Equivalent to pressures in Fontan pathway. tion fraction was reduced in 3 patients, and the remaining patients had normal ventricular function, with ejection fractions of 0.55 to 0.60 (55% to 60%) by visual estimate. In general, ventricular end-diastolic pressures were within normal range, with a median of 8 mm Hg (range, 7 to 12 mm Hg), and cardiac outputs were in the lower range, with a median of 2.4 L/min/m 2 (range, 1.6 to 2.7 L/min/m 2 ). Efficacy of Budesonide Use Laboratory responses to treatment are summarized in Table 3 and Figure 1. Mean albumin values after 6 months of CR-budesonide therapy were 3.3 g/dl (range 1.7 to 4.1 g/dl), whereas the mean albumin value pretreatment was 2.1 g/dl (range, 1.7 to 2.3 g/dl). Four of the 7 patients reported some symptomatic relief, with less abdominal pain and diarrhea. One patient had relief of pulmonary artery stenosis by stent placement at the same time CR-budesonide treatment was initiated. Dosages were weaned in 6 patients due to medication side effects. Patient 2 died 1 month after budesonide initiation, so weaning did not occur. Controlled-release budesonide was discontinued in 3 patients. Budesonide was weaned and discontinued in 1 patient and then restarted after a PLE exacerbation. PLE b Severe right ventricular-to-pulmonary artery conduit regurgitation. AVVR atrioventricular valve regurgitation; EDP end-diastolic pressure; EF ejection fraction; PA pulmonary artery; Pt patient. exacerbations occurred in 5 patients while they were receiving budesonide treatment, with a subsequent fall in albumin levels despite continuing low-dose budesonide therapy (patient 1) or maintaining a 9-mg dose (Patients 2, 3, 5, 6). Additional Treatment Methods A variety of treatments were used for the patients before budesonide therapy was initiated (Table 4). All patients received heparin, except patient 7 due to a history of heparin-induced thrombocytopenia. At the onset of PLE, 4 patients were diagnosed with hemodynamic Fontan or pulmonary artery obstruction and underwent cardiac catheterization with stent placement in the pulmonary arteries (n 2), in the inferior vena cava (n 1), or by surgical relief of baffle obstruction (n 1). PLE symptoms recurred in 3 patients with Fontan obstruction after relief of the obstruction, and 1 patient underwent stenting of the pulmonary artery at the time of CR-budesonide administration. A total of 5 patients had patent fenestrations, from the initial Fontan procedure in 1 or created subsequent to the diagnosis of PLE in 4. One patient had Fontan takedown and eventual one-and-a-half ventricle repair and did not have a fenestration. Cardiac catheterization interventions Table 3. Patient Response to Budesonide Treatment Prebudesonide Budesonide Therapy a After Exacerbation b Pt Albumin A1AT Albumin A1AT Exacerbations Albumin Current Dose g/dl mg/g g/dl mg/g on Budesonide g/dl (mg/d) 1 2.3 1156 3.0 760 Yes 1.9 None 2 1.9 267 2.4 NA Yes 1.7 n/a 3 1.7 415 1.8 NA Yes 1.3 None 4 2.1 NA 4.2 71 No c n/a 9 5 d 2.2 204 4.1 NA Yes 2.2 None 6 1.8 184 4.1 NA Yes 2.6 3 7 3.2 457 3.6 NA No N/a 3 Mean 2.1 447 3.3 n/a n/a 1.9 n/a a 6 to 9 months of therapy. b On budesonide therapy. c Total duration of therapy was 6 months. d Weaned off dosage, but restarted due to adrenal insufficiency. A1AT -1 antitrypsin; NA values not available; n/a not applicable; Pt patient.

1454 JOHN ET AL Ann Thorac Surg ORAL BUDESONIDE IN PLE AFTER THE FONTAN OPERATION 2011;92:1451 6 Table 5. Complications During Budesonide Use Patient Complications 1 2 3 4 5 6 7 Infection No Yes No No No No No Cushingoid features Yes No Yes No Yes Yes Yes Osteoporosis/growth Yes No Unk Unk Yes Yes Yes delay Hyperglycemia Yes No Yes No No No No Adrenal insufficiency Yes No Yes Unk Yes Yes No Fig 1. Serum albumin responses to treatment with oral controlledrelease budesonide. included fenestration creation in 3 patients with either a fenestrated ASD device (n 1) or a stent (n 2) to maintain patency. Patient 1 underwent catheterization to reopen a closed fenestration. Sildenafil (10 to 20 mg, three times daily) was used in 5 patients. It was not used in 2 patients due to concerns of hypotension. Usage of the higher 20-mg dose was limited by hypotension in 3 patients. In 1 patient, sildenafil was discontinued at the time of a gastrointestinal hemorrhage. Five patients had dual-chamber pacemakers because of complete heart block (n 3) or bradyarrhythmias/sinus node dysfunction (n 2). In addition, prednisone was used in Patients 5 and 6, overlapping with initial budesonide use. Table 4. Prior Treatment Strategies for Protein-Losing Enteropathy Patient Treatment Strategy 1 2 3 4 5 6 7 Relief of Fontan obstruction No Yes No Yes Yes a No Yes Heparin Yes Yes Yes Yes Yes Yes No Low-fat high-protein diet Yes Yes Yes Yes Yes Yes Yes Anemia therapy Yes Yes Yes Yes Yes Yes No Medications Diuretics Yes Yes Yes Yes Yes Yes Yes ACE inhibitor/arb Yes Yes Yes Yes Yes Yes Yes Aldactone/eplerenone Yes Yes Yes No Yes Yes Yes Antiarrhythmogenics Yes Yes No Sildenafil Yes No Yes b No Yes Yes Yes Pacemaker therapy Yes Yes Yes Yes No No Yes Fontan conversion Yes No No Yes No No No Fenestration No c No Catheter based Yes Yes Yes Yes Surgically created Yes Yes a Pulmonary artery stent. b Sildenafil was stopped at the time of gastrointestinal hemorrhage. c Original fenestrated Fontan taken down. ACE angiotensin-converting enzyme; ARB angiotensin receptor blocker. Unk unknown. Complications All patients had evidence of side effects (Table 5), including cushingoid features in 5, adrenal insufficiency in 4, and infection in 1. These occurred within 3 to 6 months of starting CR-budesonide. Budesonide was weaned because of these side effects, and to date, patients 1 and 3 have been weaned from the medication. CR-budesonide was restarted in patient 5 because of adrenal insufficiency. New-onset diabetes mellitus developed in 2 patients. Growth delay in 2 patients and osteoporosis in 1 were reported, but 2 patients also had a history of prednisone usage overlapping with CR-budesonide initiation. In addition, because no formal testing of bone growth was done before steroids were initiated, the osteoporosis and growth delay could also have been a result of the PLE. Patient 2 died of sepsis that occurred 1 month after budesonide administration. In addition to cushingoid features, myalgias and nonspecific muscular symptoms also developed in patient 7; both side effects improved after budesonide was weaned. Comment Protein-losing enteropathy occurs in 5% to 15% of patients after the modified Fontan operation and is an extremely difficult complication to treat successfully [2, 7]. Numerous theories exist to explain the exact mechanism. Decreased mesenteric blood flow and elevated mesenteric venous pressures may promote systemic inflammation, leading to elevation of inflammatory markers, such as tumor necrosis factor-, and gaps in the intestinal mucosa [8, 9]. The protein loss that occurs leads to the clinical findings of peripheral edema, ascites, diarrhea, weight loss, and malabsorption. Use of oral corticosteroids to target intestinal inflammation has been attempted, but the efficacy was limited due to the significant side effects [10]. Oral CRbudesonide, a steroid that is reported to have 90% first-pass metabolism through the liver, has been used to successfully treat inflammatory bowel disease with relatively low systemic side effects. Thacker and colleagues [6] were the first to report the successful use of CRbudesonide for the treatment of PLE in 9 patients after the Fontan operation. Consistent with the study by Thacker and colleagues, 6 patients in our cohort did have an increase in serum

Ann Thorac Surg JOHN ET AL 2011;92:1451 6 ORAL BUDESONIDE IN PLE AFTER THE FONTAN OPERATION 1455 albumin within 6 months after beginning treatment, but only the 4 youngest patients (aged 16 to 20 years) had symptomatic improvement after starting therapy. Of these 4 patients, 1 had continued improvement in symptoms and side effects with weaning of CR-budesonide. The response to CR-budesonide in the other 3 patients is difficult to assess. One patient had relief of pulmonary artery obstruction simultaneously with CR-budesonide initiation, and the remaining 2 patients were treated with prednisone in addition to the CR-budesonide. Therefore, it is difficult to know whether the improvement in symptoms was due to the CR-budesonide or to the other interventions. Notably, the adult patients (patients 1, 2 and 3) were the most refractory to treatment and none of these patients experienced any improvement in symptoms despite high-dose budesonide therapy. In contrast to the study by Thacker and colleagues, 5 patients in our study had PLE relapses or worsening of PLE while receiving CR-budesonide therapy, despite initially increasing albumin levels. Relapses were defined as worsening edema, ascites, and malaise, with a decrease in serum albumin levels. After relapses, albumin levels were refractory to retreatment with higher-dose CR-budesonide or were much slower to respond than noted during the initial treatment period. The patients who had PLE exacerbations while taking CR-budesonide were also the patients with the worst side effect profile. Certainly, the fluid retention and immune compromises that can result from systemic steroids can worsen the clinical course of a patient with PLE. The use of oral CR-budesonide in our population was limited by the occurrence of systemic side effects. Cushingoid features, adrenal insufficiency, or marked fluid retention developed in all but 2 patients. Although weaning the CR-budesonide dose helped reduce the side effects in the younger patients, profound systemic side effects persisted in the older patients, those aged 27 to 32 years. This was likely due to impaired hepatic clearance of CR-budesonide. In fact, hepatic ultrasound imaging showed the 3 older patients had course echotexture and nodularity consistent with sonographic cirrhosis, but the 3 youngest patients had normal or nonspecific changes. An interesting finding was that liver function test results were normal in our cohort, suggesting that the laboratory assessment of liver function may not be an accurate indictor of hepatic dysfunction in this population. Hepatic dysfunction and progressive fibrosis has been noted after the Fontan operation, and several investigators have reported that cirrhosis and even hepatocellular carcinoma can result [11, 12]. Additional studies have suggested a significant correlation exists between the degree of fibrosis and the duration of time since the Fontan operation. Those with cirrhosis had significantly higher mean hepatic vein pressures [13]. As with PLE, the mechanism is poorly understood, because cirrhosis does not develop in all patients after the Fontan operation. Several other side effects occurred in patients while taking budesonide. Infection occurred in patient 2, and sepsis resulted in death 1 month after budesonide treatment was initiated. This patient had multiple comorbidities, including dialysis-dependent renal failure, a history of sepsis, and refractory arrhythmias; therefore, the relation to budesonide is unknown. PLE might place patients at an increased risk of infection given potential loss of immunoglobulins and an impaired enteric immune system [14, 15]. The addition of CR-budesonide may exacerbate this risk. Other important side effects included hyperglycemia and the development in 2 adult patients of new-onset type 2 diabetes. The decreased hepatic clearance of CR-budesonide in these patients likely contributed to the development of these side effects. Blood glucose levels should be closely monitored during therapy with CR-budesonide. Although CR-budesonide must be used with caution in patients with hepatic dysfunction, there may still be a role for its use in PLE. A recent case report cited intermittent bolus dosing of intravenous and oral steroids as an effective method for PLE treatment in 1 patient [16]. For patients with hepatic dysfunction, this method of treatment might be a potential alternative to avoid long-term systemic side effects. Certainly, additional long-term treatment strategies need to be explored. One patient in our cohort had relief of symptoms with monthly octreotide administration and correction of anemia, and treatment for any sources of gastrointestinal blood loss has also helped stabilize some of our patients [17]. Mortality rates for PLE have been reported to be as high as 50% within 5 years of diagnosis. Of interest in our series, only 2 patients died and 4 patients survived 6 to 17 years after diagnosis. Improvements in medical therapy and continued understanding of the mechanisms of PLE may have resulted in this increased survival. This study has some limitations. This small cohort of 7 patients makes definitive statements difficult. All patients in our series had refractory PLE, and multiple therapies were used before oral CR-budesonide was initiated. The efficacy of budesonide, if begun earlier in the course of PLE, is unknown. In addition, 2 of our younger patients also were receiving systemic steroids intermittently, and 1 patient underwent simultaneous stenting of a pulmonary artery stenosis while taking CR-budesonide. In conclusion, PLE in the cardiac patient remains a difficult complication to treat. Medical management should be aimed at optimizing Fontan hemodynamics, including arrhythmia control, relieving Fontan obstruction, and maximizing cardiac function. CR-budesonide can be an effective treatment for some patients, but use in our older patients with ultrasound evidence of cirrhosis was severely limited due to the systemic absorption and side effect profile. Patients should undergo careful assessment of hepatic function, including laboratory and radiologic testing, before treatment with CR-budesonide is initiated. Budesonide may still have a role in the treatment of PLE in adult patients with hepatic dysfunction, but further study is needed to determine the best strategy of treatment. References 1. Crupi G, Locatelli G, Tiraboschi R, et al. Protein-losing enteropathy after Fontan operation for tricuspid atresia

1456 JOHN ET AL Ann Thorac Surg ORAL BUDESONIDE IN PLE AFTER THE FONTAN OPERATION 2011;92:1451 6 (imperforate tricuspid valve). Thorac Cardiovasc Surg 1980;28:359 63. 2. Feldt RH, Driscoll DJ, Offord KP, et al. Protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 1996;112:672 80. 3. Vyas H, Driscoll DJ, Cabalka AK, Cetta F, Hagler DJ. Results of transcatheter Fontan fenestration to treat protein losing enteropathy. Catheter Cardiovasc Interv 2007;69:584 9. 4. 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:e39 40. 5. Rychik J, Spray TL. Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg 2002;5:3 11. 6. Thacker D, Patel A, Dodds K, et al. Use of oral budesonide in the management of protein-losing enteropathy after the Fontan operation. Ann Thorac Surg 2010;89:837 42. 7. Driscoll DJ, Offord KP, Feldt RH, et al. Five- to fifteen-year follow-up after Fontan operation. Circulation 1992;85:469 96. 8. Rychik J, Gui-Yang S. Relation of mesenteric vascular resistance after Fontan operation and protein-losing enteropathy. Am J Cardiol 2002;90:672 4. 9. 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;101:248 51. 10. Rychik J, Piccoli DA, Barber G. Usefulness of corticosteroid therapy for protein-losing enteropathy after the Fontan procedure. Am J Cardiol 1991;68:819 21. 11. Ghaferi AA, Hutchins GM. Progression of liver pathology in patients undergoing the Fontan procedure: Chronic passive congestion, cardiac cirrhosis, hepatic adenoma, and hepatocellular carcinoma. J Thorac Cardiovasc Surg 2005;129:1348 52. 12. Kendall TJ, Stedman B, Hacking N, et al. Hepatic fibrosis and cirrhosis in the Fontan circulation: a detailed morphological study. J Clin Pathol 2008;61:504 8. 13. Kiesewetter CH, Sheron N, Vettukattill JJ, et al. Hepatic changes in the failing Fontan circulation. Heart 2007;93:579 84. 14. Lenz D, Hambsch J, Schneider P, et al. Protein-losing enteropathy in patients with Fontan circulation: is it triggered by infection? Crit Care 2003;7:185 90. 15. Garty BZ. Deficiency of CD4 lymphocytes due to intestinal loss after Fontan procedure. Eur J Pediatr 2001;160:58 9. 16. Hoashi T, Ichikawa H, Ueno T, Kogaki S, Sawa Y. Steroid pulse therapy for protein-losing enteropathy after the Fontan operation. Congenit Heart Dis 2009;4:284 7. 17. Vyas H, Driscoll DJ, Cetta F, Loftus CG, Connolly HM. Gastrointestinal bleeding and protein-losing enteropathy after the Fontan operation. Am J Cardiol 2006;98:666 7. INVITED COMMENTARY Protein-losing enteropathy (PLE) is an enigmatic ailment that strikes children and young adults after a Fontan operation. Over the past 20 years myriad treatments have been proposed ranging from ameliorating the circulatory failure of the Fontan circuit through fenestration creation to the use of medications such as steroidal agents, unfractionated heparin, and high-dose spironolactone. For each of these strategies, great initial enthusiasm has ultimately been tempered by the finding of only modest utility with limited long-term efficacy. Data suggest that inflammation may play an important role in PLE after a Fontan operation. On theoretical grounds, oral controlled-release budesonide is an ideal intestinal antiinflammatory agent. Unlike prednisone, it has high enteric affinity and is 90% metabolized at first pass through the liver, theoretically reducing the risk of steroid-related systemic side effects. Borrowing from a broad experience in children with inflammatory bowel disease, we reported in The Annals of Thoracic Surgery in 2010 on the successful use of budesonide in raising serum protein levels in patients treated at a median age of 15 years (range, 4 to 29 years). John and colleagues [1] from the Mayo Clinic now report their experience with budesonide in a group of patients treated at a median age of 20 years (range, 16 to 32 years) They found a high rate of steroid-related side effects as well as a high rate of treatment failure. The high rate of side effects likely reflects indolent progressive hepatic dysfunction related to time after Fontan operation. The high failure rate suggests a resistance to disease treatment in those with long-standing illness, perhaps related to chronic changes in the gut lumen over time. The growing experience with oral budesonide as treatment for PLE provides a number of lessons. There is clearly a subgroup of patients who respond well, with the ability to wean to low doses with improvement in symptoms and quality of life, and a subgroup that does not respond. Budesonide is a potentially useful agent but should be tried with caution. If serious side effects are noted, or no response is seen within a limited time (3 to 6 months), weaning and discontinuation is indicated. More effective strategies for this debilitating disease await a clearer fundamental understanding of the mechanism of the disorder, which to date continues to elude us. Jack Rychik, MD Division of Cardiology The Cardiac Center at The Children s Hospital of Philadelphia 34th and Civic Center Blvd Philadelphia, PA 19104 e-mail: rychik@email.chop.edu Reference 1. John AS, Driscoll DJ, Warnes CA, Phillips SD, Cetta F. The use of oral budesonide in adolescents and adults with protein-losing enteropathy after the Fontan operation. Ann Thorac Surg 2011;92:1451 6. 2011 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2011.04.077