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
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
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
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
**Care for any individual patient may vary and
should be carefully decided upon by the child's own
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
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
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
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.
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
- Richard M. Donner, M.D.
- Adult Congenital Heart Disease Program
- The Children's Hospital of Philadelphia
- Parent Reviewer:
- Peter Littlefield
Your feedback is very important! Please e-mail
us with any questions or comments about this article.
Return to Resource Room.