Pediatric Protein-Losing Enteropathy 

Updated: Jul 25, 2017
Author: Simon S Rabinowitz, MD, PhD, FAAP; Chief Editor: Carmen Cuffari, MD 

Overview

Practice Essentials

Protein-losing enteropathy (PLE) is not a single disease but a symptom. Although it occurs in multiple conditions through various pathophysiologic processes, the end result is the loss of serum proteins into the GI tract. Protein losses from other regions of the GI tract are also considered PLE.

Hypoalbuminemia can result from protein loses through the skin, the kidneys, or the respiratory tract as well as decreased synthesis in the face of normal turnover. 

PLE is generally secondary to 1 of 3 mechanisms: 

  • Lymphatic obstruction
  • Inflamed mucosa
  • Molecular changes in the epithelial barrier in the absence of other signs of pathology 

 

Background

Although PLE implies an intestinal disease associated with the small bowel, the term "protein-losing enteropathy" is commonly used to also include loss of protein from the colon, stomach, and, rarely, the esophagus. Some authors have used the term protein-losing gastroenteropathy. While there is nothing unique about PLE in children, the relative prevalence of various etiologies is different in children from that described in adults.

PLE can be either a primary manifestation or a subclinical component of various diseases. Historically, patients with hypoalbuminemia of unknown cause were referred to as having idiopathic hypoproteinemia, edema disease, or nephrosis. These patients had neither a decrease in the production of albumin (ie, no signs of malnutrition or hepatic disease) nor an increase in albumin losses from the respiratory tract, kidneys, or skin.

In 1949, Albright et al demonstrated an increase in protein turnover in patients with PLE. In 1958, Citrin et al were the first to use radiolabeled tracers to demonstrate the actual loss of a protein-containing fluid into the GI tract. However, a major advance was made when Crossley and Elliot demonstrated that measurement of alpha1-antitrypsin (A1-AT) levels in the stool was a practical, reproducible, and inexpensive investigation to diagnose PLE. This approach has identified various conditions that have subclinical PLE as a component of the disease process. With the application of newer genetic screening techniques, the number of distinct entities that can lead to PLE continues to grow.

Pathophysiology

No single mechanism can account for the loss of protein into the GI tract seen in a wide range of underlying clinical conditions. Several molecular changes in epithelial cells have been shown to yield PLE by increasing the permeability to serum proteins.[1, 2, 3, 4]  Modification of the epithelial matrix component, by congenital molecular abnormalities, by dysfunctional lymphatic drainage or by inflammation, offers an intriguing and unifying hypothesis for the many causes of PLE that merits further investigation.

In vitro analyses have demonstrated that loss of these proteoglycans not only directly causes PLE but also potentiates the effects of other reputed factors such as inflammatory cytokines and increased lymphatic pressure.[5]  In addition, infants and children with various forms of congenital glycosylation defects, another potential mechanism for loss of heparin sulfate proteoglycans, also have PLE secondary to increased intestinal permeability.[6]

PLE must always be distinguished from the loss of protein through other organs, most commonly the kidney and skin. One potential clue is that renal losses of protein are usually limited to smaller proteins such as albumin, whereas the GI tract and skin losses are less discriminating. In addition, hypoalbuminemia may be secondary to synthetic dysfunction or excessive catabolism rather than the result of increased losses. Synthetic dysfunction itself can be seen in liver disease or as a result of inadequate precursors (ie, malnutrition or malabsorption).

For practical purposes, the disease processes that cause PLE can be grouped into the following 3 major categories: (1) lymphatic obstruction or defects in structural integrity; (2) mucosal erosion or ulceration; and (3) epithelial cell dysfunction in the absence of macroscopic compromise.

Obstruction of lymphatics from any cause can produce increased pressure throughout the lymphatic system of the GI tract. This results in the stasis of lymph and, if the pressure is high enough, the loss of lymphatic fluid rich in albumin and other proteins from the lacteals in intestinal microvilli into the lumen of the GI tract. Alternatively, compromise of the lymphatic channels themselves can also result in leakage. If the loss of albumin exceeds the rate of synthesis, hypoalbuminemia and, eventually, edema develop. In addition to the loss of albumin, other important components of lymph are also lost into the bowel, including lymphocytes, immunoglobulins, and hydrophobic molecules such as cholesterol, lipids, and fat-soluble vitamins that yield other complications.

Lymphopenia is a common finding associated with PLE due to primary intestinal lymphangiectasia, Whipple disease, or constrictive pericarditis. In cases of PLE associated with lymphatic obstruction, alleviating the obstruction corrects the lymphopenia. A decrease in the circulating levels of immunoglobulins is also a feature of lymphatic obstruction, but because the synthetic machinery remains intact, response to antigenic challenge is usually adequate. In patients with lymphatic obstruction, fat malabsorption may develop secondary to losses from the lymphatics. In these patients, failure to thrive, poor weight gain, and deficiencies in the fat-soluble vitamins (ie, A, D, E, K) can also occur.

A wide variety of infectious diseases and noninfectious diseases can produce inflammation and ulceration of the GI mucosa resulting in PLE. Each of these processes has a unique pathophysiology. Similar to lymphatic obstruction, these inflammatory pathologies may also be associated with hypogammaglobulinemia.[1]

The Fontan procedure is a palliative surgical procedure performed in patients with a functional or anatomic single ventricle. It creates a venous pathway that directs the inferior vena caval flow into the pulmonary arteries, resulting in the entire systemic venous flow returning passively into the pulmonary arteries.[7] This creates a system where a single ventricle pumps blood into separate, in-series systemic and pulmonary circulations, thereby relieving cyanosis. PLE has long been recognized as a complication after cardiac surgery, especially in patients who have had the Fontan procedure. This complication is known to carry a high mortality rate. Research in this area remains active; however, the exact pathophysiology of the protein loss in this setting has still not been elucidated.[8]  Numerous publications have provided data to support various hypotheses including early elevations of postoperative central venous pressure,[9]  low pulmonary vascular compliance,[10]  and elevated serum hepatocyte growth factor.[11]  Retrospective series have defined the additional risks seen in patients with PLE after Fontan procedure (see Prognosis section below).

A case-control study compared 8 patients who underwent the Fontan procedure with PLE to 8 patients who underwent the Fontan procedure without PLE. The patients with PLE had immunologic abnormalities similar to patients with PLE and intestinal lymphangiectasia who had not had a Fontan procedure (eg, severely low CD4 counts with mildly decreased CD8 counts, hypogammaglobulinemia, depressed cell mediated immunity). These authors postulated that dysfunctional lymphatic drainage was a key contributor to Fontan-related PLE.[2]

A survey-based study also identified clinical features that suggest inadequate lymphatic drainage may play a role in post-Fontan PLE. Several patient specific factors associated with the diagnosis were noted, including the following:

  • Abdominal swelling may be the best symptom to use in screening for early signs of PLE 
  • Patients with PLE were more likely to have had prolonged chylous chest tube drainage.

This study also found that most patients with PLE had been treated with only one specific therapy. Multiple therapies are often needed for treatment. These authors recommended that “best practice” guidelines should be developed to assure successful management.[3]

One case report surprisingly suggests that post-Fontan PLE may be a consequence of lactase deficiency. In this report, a 12-year old girl with PLE shortly after undergoing the Fontan procedure was found to have an intestinal lactase deficiency based on her history. Although the patient failed a therapeutic trial of cortisone and heparin as well as other cardiac interventions, her symptoms improved after beginning a lactose-free diet. Importantly, her serum protein values and electrolytes normalized. The authors suggest that dietary treatment of lactose intolerance, a common condition whose incidence increases with age, may improve the outcomes in selected patients. Not mentioned by the authors is the fact that Lactaid milk often has lower fat than regular milk, which may have played a role in their outcome.

Another unique barrier dysfunction also is reported to yield PLE. An infant with PLE was found to have a mutation in PLVAP, which is a cationic, integral membrane protein expressed in endothelial cells. The same phenotype had been previously described in a PLVAP knock-out mice. The child presented with intractable secretory diarrhea that was felt to be secondary to the absence of PLAVP, which is responsible for organizing the diaphragms in endothelial cells.[4]

In addition to dysfunctional glycosylation of membrane proteins, this becomes the second ultrastructural defect that can account for PLE. Whether these are examples of a more generalized phenomenon that could account for an appreciable proportion of the PLE which is noted in the absence of both mucosal erosions and lymphatic leakage, remains to be determined.[4]

Epidemiology

Frequency

United States

No published data have reported an accurate incidence or prevalence of PLE in any parts of the United States.

International

No published have reported an accurate incidence or prevalence. The incidence is highest in areas with significant infectious enterocolitis. A recent multicenter European review of over 3000 patients with Fontan procedure describes a prevalence of 3.9%.[12] These authors used stringent criteria; three fourths of the patients had effusions and edema. Other studies have reported an even higher prevalence after this surgery.

Mortality/Morbidity

Morbidity and mortality is dependent on the diseases that are the cause of the PLE and the availability of prompt recognition and treatment. In the European cohort of Fontan patients described above, medical treatment was ineffective in 75%, with a mortality of 46%, and surgical treatment was ineffective in 81%, with a mortality of 62%.

Race

No racial predilection is noted. For some entities, especially infections of the GI tract, the prevalence is higher in the developing world and in those races more commonly found there.

Prognosis

Most cases of PLE secondary to mucosal inflammation are able to be resolved with effective therapy for the underlying enteropathy. Conversely, most of the inheritable forms of PLE are part of a larger constellation of deficits related to a genetic mutation. Therefore, the most common setting for PLE investigations is among patients who have had the Fontan procedure with several centers publishing retrospective series. A 20-year study from Germany followed 434 patients who had total cavopulmonary connection between May 1994 and March 2015. Although these patients had less problems than patients who underwent the Fontan procedure (eg, tachyarrhythmia, need for revisions, thromboembolism), PLE, liver dysfunction, and exercise limitations remained problematic.[13] ​ A prospective series from Children's Hospital of Philadelphia examined 33 patients undergoing the Fontan procedure, preoperatively, early postoperatively, and intermediately postoperatively (3-9 mo).[14] Although none of these patients showed consistent PLE in the time frames reported, 6 episodes of elevated stool A1-AT were identified, and 5 of those 6 episodes were associated with significant hemodynamic disturbances that required intervention.

A study from Michigan examining immune abnormalities prospectively in 16 patients after the Fontan procedure compared 8 patients with PLE to 8 without PLE.[15] Patients who underwent the Fontan procedure who had PLE had extensive quantitate immune abnormalities, including CD4 deficiency. These were similar to patients who did not undergo the Fontan procedure who had PLE secondary to lymphatic abnormalities. Of note, most of the 8 children who had PLE after Fontan procedure had negative titers for measles, mumps, and rubella vaccinations.

A retrospective study compared 96 patients with PLE waiting for a heart transplant who underwent the Fontan procedure and to 260 patients with PLE without the Fontan procedure also waiting for a heart transplant.[16] In this large multicenter cohort, the diagnosis of PLE was not associated with increasing waiting list mortality or posttransplant morbidity or mortality.

Another series consisting of 42 patients with protein-losing enteropathy followed at the Mayo Clinic noted decreased survival among patients with Fontan pressure, decreased ventricular function, higher pulmonary vascular resistance, lower cardiac index, and lower mixed venous saturation compared with survivors.[17] However, the authors concluded that although protein-losing enteropathy remains difficult to effectively treat in this population, survival has improved with advances in treatment.

 

Presentation

History

Most commonly, protein-losing enteropathy (PLE) presents with edema. When analyzing the cause of edema, certain aspects of the history and physical examination should be emphasized.

A complete dietary history should be obtained to evaluate for possible protein malnutrition, which results in diminished albumin synthesis (kwashiorkor).

Query about possible renal diseases (increased protein loss) or hepatic diseases (decreased protein synthesis) that could also result in hypoalbuminemia. Nephrotic syndrome or liver disease are often the primary cause of hypoalbuminemia. However, either can also increase the pressure in the intra-abdominal lymphatic system and thus also yield PLE.

Abnormal urinary tract symptoms (urinary frequency, urine color, pain with urination) or a history of high blood pressure should lead to an evaluation for renal disease.

Alcohol consumption or a previous history of hepatitis, fatigue, or jaundice should lead to an evaluation for liver disease.

Dermatologic conditions, including significant burns, can also account for albumin losses that can yield edema.

Obtain a complete GI history, looking for any suggestions of diarrhea, hematochezia, and abdominal issues (ie, gut sources of excessive protein loss).

Primary lymphangiectasia may be long-standing; therefore, questions about symptoms may date back to the neonatal period. Query the patient or parents about other lymphatic abnormalities, especially asymmetric edema that might have been present in infancy.

Obtain a cardiac history, including congenital heart disease, prior episodes of pericarditis, serious streptococcal infection, prior heart surgery and the presence of either chylothorax or chest tubes.

Physical

Begin the physical examination by taking appropriate anthropometric measurements, including the following:

  • Head circumference
  • Height
  • Weight
  • Triceps skinfold thickness as an assessment of the nutritional status (if available)

Emphasize that weight alone may be misleading because fluid retention can occur in the setting of hypoalbuminemia.

Examine the patient for evidence of the following:

  • Acute liver disease (eg, enlarged, firm, nodular liver, and/or tenderness in the right upper quadrant)
  • Chronic liver disease (eg, liver findings mentioned above along with jaundice, splenomegaly, abdominal wall venous prominence due to collateral circulation)

Include in the assessment of cardiac function evaluation for the following, which suggest increased right-sided pressures in the heart as the cause for PLE:

  • Hepatosplenomegaly
  • Lower lobe rales (bilateral)
  • Jugular vein distention 

The finding of elevated blood pressure may suggest renal or cardiac disease.

GI findings compatible with PLE include the following:

  • Abdominal tenderness or distension, including dilated, tender loops of bowel
  • Macroscopic or microscopic blood and mucus determined on rectal examination

Localized edema is suggestive of primary intestinal lymphangiectasia

Causes

As indicated above, many disease processes can lead to PLE. The following is an approach to categorizing the underlying etiology.

Lymphatic losses are as follows:

  • Enteric lymphatic obstruction
    • Primary enteric lymphatic obstruction
      • Primary intestinal lymphangiectasia
      • Secondary intestinal lymphangiectasia (eg, mesointestinal fibrosis) [18]  
      • Whipple disease
      • Malrotation/volvulus                                 
      • Tuberculosis                                       
      • Sarcoidosis                                       
      • Amyloidosis [19]  
      • Radiation enteritis
      • Retroperitoneal fibrosis or tumor
      • Arsenic poisoning
      • Secondary to unusual causes of bowel infiltration - Leukemia, [20]  Gaucher disease, [21]  Langerhans cell histiocytosis, [22]  and infantile systemic hyalinosis syndrome [23]  
    • Cardiac causes of increased systemic venous pressure

Genetic causes include the following:

  • Congenital disorders of glycosylation (may involve enterocyte disruption without any ulceration)
  • Juvenile polyposis  [26]
  • Mutations in plasmalemma vesicle associated protein (PLVAP) may lead to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE [4]

Inflammation of the GI tract includes the following:

  • Infectious causes involving enterocyte disruption without ulceration                
  • Infectious causes with mucosal ulceration
    • Bacterial enterocolitis - Salmonellae, Shigella, Yersinia, Campylobacter, some forms of Escherichia coli
    • Toxin mediated enterocolitis - Clostridia difficile toxin, some forms of E coli and Shigella
    • Viral mediated enterocolitis - Cytomegalovirus (most commonly), herpes
    • Tuberculosis
  • Noninfectious causes with mucosal ulceration
  • Noninfectious causes with breakdown of enterocyte barrier
    • Celiac disease (Gluten sensitive enteropathy)
    • Hypertrophic gastropathy (Menetrier disease)
    • Juvenile rheumatoid arthritis
    • Malnutrition
    • Systemic lupus erythematosus (SLE): Protein-losing gastroenteropathy may be the first manifestation of SLE in children. This is associated with hypocomplementemia.  [31]
    • Systemic phenobarbital hypersensitivity
    • Tropical sprue
    • Severe iron deficiency [32]
    • Budd Chiari syndrome/hepatic venous outlet obstruction/post-liver transplant [33]
    • Collagenous colitis/gastritis [34]

Physical Examination

Edema is often noted, especially when the albumin becomes quite low.

Stigmata of heart disease, enteropathy, and infections, which can be limited to the GI tract or generalized, may also be suggested by physical findings.

 

DDx

Diagnostic Considerations

Protein-losing enteropathy (PLE) is a symptom related to a diverse group of disorders (see Causes). With the increased identification of syndromes in the neonatal period and infancy, numerous discrete entities can now be considered when PLE presents in the first year of life. 

Alpha-1,3-glucosyltransferase has been described in 89 patients making it one of the most common forms of congenital disorders of glycosylation. All patients have developmental delay and hypotonia.[35] Epilepsy, ataxia, proximal muscle weakness, failure to thrive, intractable seizures, coagulation anomalies, and autistic spectrum features are frequently noted. Affected children exhibiting PLE often die in the first decade of life.

A child with severe skeletal dysplasia, thanatophoric dysplasia type I, died due to severe PLE by age 6 months, secondary to lymphangiectasia in the small intestine.[36]

DGAT-1, an inborn error of lipid metabolism that is associated with severe diarrhea and hypoalbuminemia, was found to be the cause of PLE in 3 additional children from 2 families with early onset of symptoms.[37]

A case of neonatal diabetes with pancreatic hypoplasia due to GATA6 mutation complicated by protein losing enteropathy has been reported. GATA6 gene is known to be involved in intestinal development with hepatobiliary malformations and gut abnormalities.[38]

Hennekam syndrome is associated with widespread congenital lymphatic dysplasia that presents with lymphedema, lymphangiectasia, and intellectual disability. One cause of this syndrome is mutation in CCBE1 (collagen and calcium-binding epidermal-growth factor domain containing protein-1). One report describes affected siblings with a marked decrease of this protein in lymphatics but not in mucosal blood vessels or muscularis mucosae.[39] Another report described a 5-week-old Pakistani girl with consanguineous parents who had PLE that resolved; however, lymphedema persisted in her extremities, with normal development.[40]  Another report of Hennekam syndrome resulted in thyroid and intestinal lymphangiectasia, leading to hypothyroidism and PLE. The hypothyroidism in this case required very high levothyroxine dosage due to its malabsorption in the gut.[41]

PLE was documented in a 4-month-old breastfed girl who presented with failure to thrive, erythema, and edema. She was found to have egg allergy; maternal dietary adjustment along with cromolyn and epinastine resolved the symptoms.[42]

Differential Diagnoses

 

Workup

Approach Considerations

Patients with edema and documented hypoalbuminemia but without clinical or biochemical evidence of liver or renal disease should have a thorough evaluation for protein-losing enteropathy (PLE). In the past, PLE was often considered a diagnosis of exclusion; however, several approaches for determining abnormal protein loss in the GI tract are currently noted. The ideal test for PLE would detect a serum protein in the stool that is not secreted, digested, or reabsorbed in the GI tract. However, no ideal test is available.

Laboratory Studies

Three established types of tests have been used to evaluate for PLE. The earliest tests involved the intravenous administration of a radiolabeled substrate followed by the determination of radioactivity in the feces. The second type of test directly measures endogenous proteins in the feces. A third approach is the use of nuclear scintigraphy, not only for diagnosis, but also to identify potential regional or localized areas of protein loss. A recent publication described the use of MRI as an alternative method to diagnose and localize this condition.[43]

Radiolabeled proteins

  • Use of radiolabeled proteins to measure albumin turnover dates back to 1950 with Kinsell. [44]  
  • In the late 1950s, Swartz, and later Citrin, administered iodine 131–albumin to patients in an attempt to measure albumin turnover. In a patient with hypertrophic gastritis and PLE, Citrin reported that the 131 I-albumin lost in the stomach was degraded and the free 131 I was then absorbed and excreted in the urine, making the measurement of 131 I in the stools unreliable.
  • In 1957, Gordon reported the use of polyvinylpyrrolidone iodine I 125 ( 131 I-PVP) as a marker for protein metabolism. [45]  PVP is a macromolecule that is not digested by intestinal enzymes and is poorly absorbed when taken by mouth. In patients with PLE, intravenously administered 131 I-PVP results in detectable levels of radioactivity in the stool. The problem with this substance is that it is not a normal metabolite, has a wide range of molecular weights, and can be partially absorbed and secreted. More importantly, the 131 I is easily released from the carrier, which then can be absorbed and excreted in the urine. This is problematic if urine contamination of the stool occurs as in pediatric patients.
  • In 1961, the next radioactive substrate used was chromium 51–albumin. This method had several advantages. The 51 Cr bound tightly to albumin and was poorly absorbed from the GI tract. Thus, little or no radioactivity was detectable in the urine.
  • In practice, approaches using radiolabeled compounds are now rarely used because 48-72 hours of stool collection is required in the hospital, care must be taken to avoid contamination of stool collection with urine, and the tests involve radiation exposure.
  • Endogenous Proteins
    • In 1977, Crossley and Elliot demonstrated that the stools of patients with PLE as determined by51 Cr-albumin excretion also had high levels of alpha-1-antitrypsin, (A1-AT).
    • A1-AT is an endogenous protein not present in the diet; the molecular weight is similar to albumin. It is normally not actively secreted, absorbed, or digested.
    • A1-AT is stable in feces at 37°C, allowing collection over several days.
    • Because A1-AT is not excreted in urine, urine contamination of the stool sample does not alter the spot determination of fecal A1-AT.
    • Stool samples are simply lyophilized, and A1-AT is extracted by solubilization.
    • Fecal A1-AT can then be detected by immunoassay. Measurement of fecal A1-AT can be used as a spot determination or the clearance of A1-AT can be more formally calculated using the following formula:A1-AT clearance = [(fecal A1-AT concentration) (stool volume/24 h]/(A1-AT serum concentration).
    • Many studies have demonstrated the efficacy of using fecal A1-AT levels and A1-AT clearance for diagnosis and follow-up care in patients with PLE.

Imaging Studies

Several radiopharmaceuticals tagged to proteins have been used to examine protein-losing enteropathy, including indium-111 (In-111)–transferrin, technetium-99m (Tc-99m)–human serum albumin, and 99mTc-dextran. The latter compound is reported to be superior for numerous technical reasons. Technetium Tc-99m MDP scintigraphy, an initial method of choice to detect skeletal metastases in cancer patients, was also reported to detect protein-losing enteropathy incidentally in a patient suspected of having bone metastases.[46]  Both Tc-99m and In-111 have been shown to have a high sensitivity for diagnosis and localization of protein-losing enteropathy; however, current evidence shows that low specificity may limit the usefulness of this imaging modality. Though this technique has been reported to be useful in the diagnosis of protein-losing enteropathy, no studies have compared the sensitivity of scintigraphy with fecal A1-AT determination. However, it may be extremely useful in identifying sites of involvement in protein-losing enteropathy (ie, stomach vs small intestine or even regional differences in the small bowel).

MRI has been used to identify lymphatic abnormalities yielding protein-losing enteropathy in both the intestine and mesentery, including dilated thoracic duct and mesenteric lymphatic as well as prominent subcutaneous lymphatics in the extremity.[43]  Specialized MRI lymphatic imaging, including dynamic contrast-enhanced magnetic resonance lymphangiography, intranodal lymphangiography, and liver lymphangiography, have been used to localize abnormal lymphatic leakage from the liver and duodenum.[47]

Procedures

In addition to the investigations listed above to document and localize the PLE, a thorough orderly evaluation is required in the patient with PLE to determine the underlying etiology of the protein loss. This usually begins with cultures and other tests for the infectious causes listed above, serologic evaluation for the immune conditions listed above, and radiographic studies (nuclear medicine, contrast studies, CT scans, MRI) to localize the area of involvement and identify characteristic patterns.

Often, endoscopy is also performed to assess for specific mucosal features such as the hypertrophic gastric folds of Menetrier disease, the pseudomembranes of C difficile colitis, the scalloping of the duodenum in sprue, and the stigmata of inflammatory bowel disease. Nonerosive erythematous gastric mucosa is the most frequent endoscopic finding in PLE associated with SLE.[31]  At the time of endoscopy, biopsies are obtained to confirm the histological findings listed below.

Histologic Findings

Intestinal and more rarely gastric, colonic, and esophageal biopsies are at times required to definitively diagnose the underlying diseases that are the cause of the protein-losing enteropathy. Examples include Crohn disease, ulcerative colitis, celiac disease, graft versus host disease, Whipple disease, lymphoma, Hirschsprung disease, pseudomembranous colitis, eosinophilic gastroenteritis, allergic enteropathy, and some infectious diseases.

Lymphangiectasia, dilated lacteals in the mucosa, is also a histologic diagnosis.

 

Treatment

Medical Care

Therapeutic approaches for protein-losing enteropathy (PLE) depend on the underlying etiology. In PLE associated with primary intestinal lymphangiectasia or lymphatic obstruction, relieving the pressure in the lymphatic system decreases lymphatic flow and intestinal protein loss. Obstruction of lymphatics has been reported with structural heart disease, constrictive pericarditis, cardiomyopathy, and surgical repair of congenital heart disease. When losses from the intra-abdominal lymphatic system are the cause of PLE, removal of long-chain triglycerides from the diet decreases the pressure in the lacteals and the lymphatic circulation. Replacing fat in the diet with medium-chain triglycerides (MCTs) increases net fat absorption and the nutritional status of the patient. The use of MCT oil in these cases does not relieve any inflammation, but because MCT oil is not absorbed via the lymphatic system, it reduces the pressure of the lacteals. Fat soluble (ADEK) vitamin supplementation is required as their absorption is attenuated by the compromise in the lymphatic flow. 

PLE that results after heart surgery (with increased pressure in the right side) is a known postoperative complication of the Fontan procedure that has been a challenge to the surgical procedure's long-term success. Multiple treatments have been used, including corticosteroids, heparin, and additional surgical intervention (baffle fenestration or heart transplantation).[48]  

As many as 13.4% of patients undergoing a Fontan procedure develop PLE within 10 years of surgery, and the mortality rate associated with this complication has been reported to be as high as 56% in 5 years.

The use of steroids has produced temporary clinical and pathological resolution of PLE.

A single-center retrospective review examined the use of budesonide, an oral steroid with extensive first pass metabolism, for 6 months or longer in Fontan-related PLE patients. This treatment was associated with significant symptomatic improvement and sustained increases in serum albumin but did not markedly change the ultimate outcome and was associated with significant side effects.[49]

Heparin has also been reported to improve PLE in children after the Fontan procedure. Heparin is thought to possibly have a stabilizing effect on the capillary endothelium, reducing protein leakage into the extravascular space and gut lumen, although the precise mechanism of action is unknown. Although heparin has been successfully used to treat some patients with PLE that develops after the Fontan procedure, it is by no means the treatment of choice for all the etiologies of PLE.

A retrospective review of 42 patients with PLE following the Fontan procedure found that treatments used more frequently in survivors included spironolactone (68%), octreotide (21%), sildenafil (19%), and surgical intervention (71%).[17]

Corticosteroids, including budesonide, have been used in patients with PLE associated with collagen vascular diseases, inflammatory bowel disease, heart surgery, and others. Sporadic case reports have documented the successful use of other agents such as cyclosporine for PLE. Immunosuppressive drugs should never be used in cases of PLE secondary to infections.

Case reports have described success in patients with PLE secondary to primary intestinal lymphangiectasia (Waldmann disease) using everolimus[50]  and rapamycin in a child with tuberous sclerosis complex.[51]

Surgical Care

Conner et al reported a case in which localized resection of the involved bowel successfully treated the condition.[52]

In patients who have undergone a Fontan procedure, fenestration of the baffle that separates the systemic venous pathway from the pulmonary venous atrium has been performed to treat PLE, and in some cases the symptoms have resolved, presumably because of the decrease in systemic venous pressure.

Cardiac transplantation has also been performed for the management of intractable PLE related to previous Fontan surgery, with complete resolution of symptoms in most cases and with survival comparable to patients with other indications for undergoing transplantation.[53]

In another case series of 3 patients who presented with PLE after undergoing the Fontan procedure and 2 patients after undergoing thoracic duct ligation, abnormal lymphatics visualized on lymphatic imaging were percutaneously accessed and embolized with lipiodol or n-BCA glue. This resulted in improvement in albumin level and symptoms.[47]

Pericardiectomy resulted in significant improvement of severe hypoalbuminemia in patients with constrictive pericarditis-associated PLE.[54]

Diet

In patients whose PLE is related to lymphatic pathology, decreasing the lymphatic circulation provides some benefit. This requires dietary limitation of long-chain triglycerides because their absorption from the gut stimulates lymphatic flow. In order to provide adequate energy, medium-chain triglycerides must be added as an alternative source of lipid calories.

As described below, fat soluble vitamins must also be supplemented because their absorption is compromised in these patients.

Long-Term Monitoring

Serial measurements of albumin, immunogloblins, lymphocytes, cholesterol, and fat soluble vitamins should be incorporated into the management of any patients with previous history or risk factors for PLE. 

 

 

Medication

Vitamins

Class Summary

In protein-losing enteropathy (PLE) related to lymphatic pathology, providing supplementation with fat-soluble vitamins (eg, A, D, E, K) is important. These agents are necessary for growth and health. For healthy individuals, they are needed in small amounts only and are available in the foods of a daily diet. However, soluble vitamin supplementation is essential in patients with protein-losing enteropathy because the small amounts available in a regular diet are insufficient in the face of the malabsorption that occurs.

ADEK vitamins (AquADEKs Pediatric Liquid, ADEKs Chewable)

PO multinutrient specially formulated for use under medical supervision to provide nutritional supplementation in individuals with malabsorptive conditions. Each 1 mL dose contains water-miscible forms of fat-soluble vitamins A (5,751 U), D (400 U), E (65 U), and K (400 mcg) plus other nutrients, including vitamin C (15 mcg), B-complex vitamins, biotin, selenium (10 mcg), and zinc gluconate (5 mg). Available as chewable tab or pediatric drops.

Vitamin A (Aquasol A)

Needed for night vision and growth of skin, bones, male reproductive organs, and female reproductive organs.

Ergocalciferol (Calciferol, Drisdol)

Form of vitamin D used in vitamin supplements, necessary for strong bones and teeth.

Vitamin E (Vita-Plus E Softgels, Vitec)

Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects red blood cells against hemolysis.

Vitamin K (AquaMEPHYTON)

Fat-soluble vitamin absorbed by the gut and stored in the liver; necessary for the function of clotting factors in the coagulation cascade; used to replace essential vitamins not obtained in sufficient quantities in the diet or to further supplement levels.

 

Follow-up

Further Outpatient Care

All patients diagnosed with or at risk for protein-losing enteropathy (PLE) require regular evaluation for adequate growth and evidence of fat-soluble vitamin (ADEK) deficiencies.

Patients who develop PLE after Fontan procedures represent a particularly vulnerable cohort with a high rate of significant morbidity and mortality.

Close follow-up coupled with an aggressive approach to reverse this problem is warranted.

Complications

Complications may include debilitating edema, failure to thrive, fat-soluble vitamin deficiencies.

Prognosis

The most important variable is the underlying cause of the protein-losing enteropathy.

Patient Education

Familiarize the patient and his or parents with the signs of edema and the earliest signs and symptoms of fat-soluble vitamin deficiency, and inform them that increased infections could be secondary to loss of immunoglobulins and/or lymphocytes. An ongoing relationship with the physician and frequent monitoring is essential to minimize morbidity.