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 Protein-Losing Enteropathy After the Fontan Operation






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Protein-Losing Enteropathy After the Fontan Operation

Written by:
Jack Rychik, M.D.
Director of Echocardiography,
The Children's Hospital of Philadelphia
Assistant Professor of Pediatrics,
University of Pennsylvania School of Medicine
Philadelphia, PA

Posted: May 9, 1997
Updated: May 2, 2001
Edited by: Mona Barmash

Our understanding of congenital heart disease of the functional single ventricle type has improved considerably over the past two decades. The use of a staged surgical approach resulting in the Fontan operation has allowed for the survival of many children with a variety of complex defects, including Tricuspid Atresia, single left ventricle, and Hypoplastic Left Heart Syndrome. Common to these defects is the lack of a functioning pumping chamber (ventricle) capable of delivering blood to the lungs (separate from the pumping chamber delivering blood to the body).

In the early 1970's, Dr. Francois Fontan developed and formalized an intriguing concept. He felt that if conditions were appropriate, venous blood returning from the body could be channeled to the lungs in a passive fashion without the use of a ventricular pumping chamber. By effectively connecting the veins carrying blood returning from the body (vena cavae) directly to the vessels carrying blood to the lungs (pulmonary arteries), blood circulatory patterns similar to that found in the normal heart could be achieved.

Success with this surgery has heralded an era of aggressive treatment for children with single ventricle type of congenital heart disease.

What is Protein-Losing Enteropathy?

As the number of survivors after the Fontan operation have increased, an unusual and inexplicable ailment called "protein-losing enteropathy" or PLE, has been noted to occur in some children within a few weeks after the Fontan operation, or years later, in children who are otherwise doing well from a cardiovascular standpoint.

Symptoms of this ailment may include swelling of the abdomen, shin and ankle area, and a change in bowel habits with the development of diarrhea and abdominal discomfort.

Children with PLE lose protein molecules from the blood serum into the intestinal tract. Over time, the concentration of serum protein in the blood stream can be significantly depleted. One consequence of a low concentration of serum protein is the inability to maintain fluid within the vascular space.

Low serum protein levels can result in the accumulation of fluid outside of the normal vascular spaces and in the abdomen, ankles and shins. An abdominal fluid collection is called "ascites", and fluid in other tissues is generally referred to as "edema."

The loss of protein into the stool results in a change in bowel habits with the development of diarrhea and abdominal discomfort. Edema of the intestinal walls may result in poor absorption of food which promotes further worsening of the diarrhea. Another consequence of intestinal protein loss is the depletion of serum immunoglobulins which fight off infection. Patients with severe PLE are therefore at risk for serious infections at a time when the body is already weakened by other symptoms related to edema and ascites.

What is the cause of this disease and why does it afflict children after the Fontan operation?

Unfortunately we do not yet know the precise answer to this question. A number of primary gastrointestinal disorders as well as infections may cause protein-losing enteropathy, however children after Fontan operation do not have these. Is there a direct link or association between congenital heart disease and PLE? This is unlikely since PLE is not seen in patients with congenital heart disease who have not yet had the Fontan operation. In fact it is not seen after a hemi-Fontan or bi-directional Glenn operation either, both intermediate steps to the Fontan operation.

It is possible to assume that there must be a physiologic change that occurs only after the Fontan operation, which predisposes some patients to the development of PLE. Venous pressures are always higher after Fontan operation relative to the normal, or to the pre-operative, state. Yet interestingly, elevated venous pressure is not the only factor involved in predisposing to PLE. Although PLE has been diagnosed in some patients with high venous pressures (15-20 mm Hg), it is quite commmon to notice the development of PLE in children considered to have completely satisfactory, low, normal pressures, typical for after Fontan surgery (in the range of 10-15 mm Hg).

Sometimes evidence of ventricular dysfunction or a narrowing of branch pulmonary arteries is found in children with PLE, however proving cause and effect between these abnormalities and PLE is difficult, since not all patients with these findings necessarily develop the disease.

What all this means is that PLE is likely related to the presence of a hemodynamic abnormality that is fostered by the Fontan physiology in a select group of patients. This hemodynamic abnormality is not always detectable by our present standard means of cardiac evaluation. In addition, this abnormality, in some unknown fashion, results in a change of the intestinal cells at a molecular level, leading to a leak of proteins into the intestinal lumen.

Diagnosis and Treatment

The diagnosis of PLE is made on the basis of clinical symptoms and laboratory confirmation.

If edema and diarrhea develop after Fontan operation, blood serum proteins should be obtained. Normal values vary from laboratory to laboratory, however a normal serum albumin (an important component of protein), should generally be above 3.5 grams/deciliter and a normal total protein level should be above 5.5 grams/deciliter.

In order to confirm the site of protein loss as originating from the intestinal tract, a test called "alpha-1-antitrypsin stool clearance" should be performed. This involves the collection of stool over a 24 hour period of time and the drawing of a single blood specimen.

Alpha-1-antitrypsin is a protein normally found in the blood and in the stool. If PLE is present, the quantity in the stool increases in relation to the blood sample, indicating that protein loss is originating from the gut.

Endoscopy has been performed in some children with PLE. Most of the time, there are no gross or microscopic abnormalities noted. Sometimes a swollen intestinal lining may be seen. Vessels (lymphatics) may be dilated or enlarged, however this is not uniformly seen.

There is no standard or universally accepted approach to the treatment of PLE and many correct and rational strategies exist. What follows in general is the approach I have used at The Children's Hospital of Philadelphia. These thoughts are my own, and should not be construed as universally accepted by the field of pediatric cardiology at large.

**Care for any individual patient may vary and should be carefully decided upon by the child's own pediatric cardiologist.

I believe that treatment of PLE should be instituted in a step-wise fashion, and in response to the severity of the disease. First, I would recommend hemodynamic assessment via cardiac catheterization. Although no abnormalities may be discovered, treatment of ventricular dysfunction and relief of structural abnormalities should be vigorously pursued.

The use of medication such as captopril or enalapril may aid in improving the flow of blood through the heart, and increase cardiac output which should generally result in improved hemodynamics. Branch pulmonary artery stenosis should be treated via balloon angioplasty, or via stenting if necessary.

Second, management should focus on reduction of symptoms. Diuretics such as lasix and aldactone, or at times a drug called "zaroxylin," may be used to reduce swelling. Diet should change with a focus on increasing protein content and, more importantly, on limiting fat intake to foods high in "medium chain triglycerides" (MCT). Foods high in MCT type fats are rapidly absorbed and reduce the amount of high protein lymph fluid moving through the vessels within the intestines, thereby reducing the quantity of protein loss.

Patients with less severe forms of PLE will sometimes respond by increasing their serum protein values and have less swelling (edema), yet normal protein levels may still not be achieved.

When children have severe forms of PLE and very low protein levels, fluid may collect around the lungs (pleural effusion) or the heart (pericardial effusion). If this occurs, supplemental albumin in the form of 25% albumin solution through an IV may be tried to quickly raise the serum protein levels. This is only a temporary measure, since if the PLE is still active, losses in the stool will continue and the administered albumin will be lost. Nevertheless, increasing the protein level along with the use of diuretics may result in significant relief of symptoms, and allow time for other treatments to take effect.

There have been a number of reports in the literature of patients with PLE responding to the administration of steroids. We in fact reported our early experience with steroid use for PLE in 1991.

Steroids were administered to patients intravenously at high doses for approximately 1-2 weeks. Oral prednisone at 1-2 mg/kg day was then given. Initially, good responses were observed with complete resolution of PLE . In our experience, however, serious side effects were exhibited and no child was succesfully permanently weaned from steroid treatment.

In essence, steroid therapy for PLE seems to be effective when used at high doses and for long periods of time. It likely works in halting protein leakage via stabilization of the intestinal cell membrane at the molecular level, however the primary cause (which we believe is probably a hemodynamic abnormality) remains unaffected. Hence steroids should only be considered as symptomatic treatment for PLE, however it creates new and often troublesome symptoms on it's own. Although potentially effective, a careful risk - benefit analysis must be made for each individual patient prior to this treatment pathway for PLE.

An innovative and quite surprising new treatment has been recently reported for PLE. Patients given continuous intravenous heparin (a drug that inhibits clotting) have been noted to have improved serum protein values and relief of symptoms. Why it works is unknown, yet just like steroid therapy, it is likely to effect the intestinal cells by halting the protein leakage. The primary hemodynamic abnormality, however, is most likely still unchanged. Heparin treatment is quite new and deserving of further attention, with much greater investigation of this therapy forthcoming.

Recently, we have taken a more aggressive approach to patients with severe PLE who have not done been helped by the above therapies, in particular in children unable to be weaned from chronic steroids. We have been successful in treating PLE by creating a "fenestration" or hole/defect in the "Fontan channel." This allows for shunting across from the right to the left side of the heart with subsequent blueness (cyanosis).

The fenestration is performed at the start in all patients at the time of Fontan operation in a number of centers, including our own. Patients who have had a fenestrated Fontan operation seem to have less trouble immediately after surgery and do extremely well, although there will be some degree of blueness (cyanosis) present. The degree of cyanosis does not appear to influence heart function or affect the child in any negative way. Interestingly, hemodynamics, and in particular cardiac output, after fenestrated Fontan have been shown to be far better than that after a non-fenestrated Fontan.

By taking patients with diagnosed PLE and a non-fenestrated Fontan and creating a fenestration, we have successfully been able to eliminate PLE. We believe that the fenestration likely improves the hemodynamic abnormality that is present, resulting in a lessening of symptoms.

We have created fenestrations reliably via surgery. Catheter techniques for creating a reliable fenestration, in particular in patients in which the "Fontan channel" is composed of artificial material such as Gore-tex, has not been reliable in the past. Nevertheless, it is certainly possible, and may be achieved using novel catheter techniques presently being developed at our institution and others.

Another option for treatment is one reserved only for children who have not responded to any of the above measures and continue to have significant symptoms. Abandoning the "Fontan physiology" and replacing the heart via heart transplant has been effective in eliminating PLE. Once again, this form of therapy alters the primary hemodynamic abnormality, which results in improvement in the intestinal tract.


PLE after Fontan operation is a puzzling disease. At the moment, treatment options are limited, but include:

1) general symptomatic relief by using diuretics and changes in diet

2) treatment at the intestinal level with steroids or heparin infusion

3) treatment at the cardiac level by mproving hemodynamics either with medicine (captopril, enalapril), or with a fenestration or a heart transplant.

Still unknown is the precise mechanism of this disease and why it afflicts some children and not others. Further research into the cause of PLE is needed. Once the cause is better understood, more effective treatment options may then be used for this troublesome illness.

Additional Resources:

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 Apr;5(2):135-7

Landzberg BR, Pochapin MB. Protein-Losing Enteropathy and Gastropathy Current treatment options in gastroenterology. 2001 Feb;4(1):39-49

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 Aug;82(2):241-3

This article was reviewed prior to publication by:

Richard M. Donner, M.D.
Adult Congenital Heart Disease Program
The Children's Hospital of Philadelphia
Parent Reviewer:
Peter Littlefield

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