Protein-Losing Enteropathy following the Fontan Operation
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.
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