Background
Protein-losing enteropathy (PLE) is not a single disease but a symptom. While it occurs in multiple conditions through various pathophysiologic processes, the end result is the loss of serum proteins into the GI tract. Although enteropathy 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 protein-losing enteropathy in children, the relative prevalence of various etiologies is different in children from that described in adults.
Protein-losing enteropathy 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 protein-losing enteropathy. 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. Several additional diagnostic techniques using radiolabeled substrates were developed, but a major advance was made when Crossley and Elliot demonstrated that measurement of alpha1-antitrypsin (A1-AT) levels in the stool was a reliable and simple test for protein-losing enteropathy. This approach has identified various conditions that have subclinical protein-losing enteropathy as a component of the disease process. With the recognition of newer genetic mutations that can be screened through this technique, the number of distinct entities that can lead to protein-losing enteropathy 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 protein-losing enteropathy 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 protein-losing enteropathy that merits further investigation.
In vitro analyses have demonstrated that loss of these proteoglycans not only directly causes protein-losing enteropathy 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 protein-losing enteropathy secondary to increased intestinal permeability. [6]
Protein-losing enteropathy 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 protein-losing enteropathy 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 protein-losing enteropathy due to primary intestinal lymphangiectasia, Whipple disease, or constrictive pericarditis. In cases of protein-losing enteropathy 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 protein-losing enteropathy. Each of these processes has a unique pathophysiology. Similar to lymphatic obstruction, these inflammatory pathologies may also be associated with hypogammaglobulinemia. [1]
Protein-losing enteropathy 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. [7] Numerous publications have provided data to support various hypotheses including early elevations of postoperative central venous pressure, [8] low pulmonary vascular compliance, [9] and elevated serum hepatocyte growth factor. [10] Retrospective series have defined the additional risks seen in patients with protein-losing enteropathy after Fontan procedure (see Prognosis section below).
A case-control study comparing 8 patients who underwent the Fontan procedure with protein-losing enteropathy to 8 patients who underwent the Fontan procedure without protein-losing enteropathy found that the patients with protein-losing enteropathy had immune abnormalities similar to patients who did not undergo the Fontan procedure and who have intestinal lymphangiectasia (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 protein-losing enteropathy. [2]
A survey-based study also identified clinical features that suggest inadequate lymphatic drainage may play a role in post-Fontan protein-losing enteropathy. Several patient specific factors associated with the diagnosis were noted, including the following:
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Abdominal swelling may be the best symptom to use in screening for early signs of protein-losing enteropathy
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Patients with protein-losing enteropathy were more likely to have had prolonged chylous chest tube drainage.
This study also found that most patients with protein-losing enteropathy 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 protein-losing enteropathy may be a consequence of lactase deficiency. In this report, a 12-year old girl with protein-losing enteropathy 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.
Another report describes another unique barrier dysfunction that results in protein-losing enteropathy. An infant 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 protein-losing enteropathy. Whether these are examples of a more generalized phenomenon that could account for an appreciable proportion of the protein-losing enteropathy, 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 protein-losing enteropathy 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%. [11] 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 protein-losing enteropathy 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
There is no known racial predilection. 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
Several cardiothoracic centers have published retrospective series describing the outcomes of patients who have had the Fontan procedure. A 20-year study from Germany followed 434 patients who had total cavopulmonary connection between May 1994 and March 2015. While these patients had less problems than patients who underwent the Fontan procedure (eg, tachyarrhythmia, need for revisions, thromboembolism), protein-losing enteropathy, liver dysfunction, and exercise limitations remain problems. [12] 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). [13] Although none of these patients showed consistent protein-losing enteropathy in the time frames reported, 6 episodes of elevated stool alpha-1-antitrypsin 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 with protein-losing enteropathy and 8 without protein-losing enteropathy. [14] Patients who underwent the Fontan procedure who had protein-losing enteropathy had extensive quantitate immune abnormalities, including CD4 deficiency. These were similar to patients who did not undergo the Fontan procedure who had protein-losing enteropathy secondary to lymphatic abnormalities. Of note, most of the 8 children who had protein-losing enteropathy after Fontan procedure had negative titers for measles, mumps, and rubella vaccinations.
A retrospective study compared 96 patients who underwent the Fontan procedure and had protein-losing enteropathy with 260 patients who did not undergo the Fontan procedure and had protein-losing enteropathy who were waiting for a heart transplant. [15] In this large multicenter cohort, the diagnosis of protein-losing enteropathy 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. [16] However, the authors concluded that although protein-losing enteropathy remains difficult to effectively treat in this population, survival has improved with advances in treatment.
