Protein-Losing Enteropathy


Protein-losing enteropathy (PLE) is an uncommon syndrome characterized by excessive gastrointestinal protein loss and results from a wide variety of abnormalities ( Box 33-1 ). It leads mainly to hypoproteinemia and edema, whereas other salient features are diarrhea, ascites, pleural and pericardial effusions, and malnutrition. Depending on the underlying cause, abdominal distension, steatorrhea, lymphopenia, and hypogammaglobulinemia can also be present.

Box 33-1

Diseases Associated With PLE

Increased Interstitial Pressure, Lymphatic Obstruction, or Lymphatic Malformations

  • Primary intestinal lymphangiectasia

  • Cardiac disease (constrictive pericarditis or congestive heart failure)

  • Following Fontan surgical procedure

  • Intestinal malrotation and chronic midgut volvulus

  • Retroperitoneal fibrosis

  • Lymphoenteric fistula

  • Noonan’s syndrome ( OMIM 163950 )

  • Hennekam lymphangiectasia-lymphedema syndrome ( OMIM 235510 )

  • Klippel-Trenaunay-Weber syndrome ( OMIM 149000 )

  • von Recklinghausen syndrome ( OMIM 162200 )

  • Turner syndrome

  • Urioste syndrome

  • Recurrent hemolytic uremic syndrome with hypocomplementemia

Ulcerative/Erosive Gastrointestinal Mucosal Diseases

  • Large erosions or ulcerations of the esophagus, stomach, or intestine

  • Crohn’s disease

  • Ulcerative colitis

  • Idiopathic ulcerative jejunoileitis


  • Kaposi sarcoma

  • Lymphoma

  • Neuroblastoma

  • Neoplasms localized in the superficial mucosa or submucosa

Infectious or Postinfectious Causes

  • Pseudomembranous colitis ( Clostridium difficile )

  • Cytomegalovirus infection

  • Giant hypertrophic gastritis (Ménétrier’s disease) ( OMIM 137280 )

  • Whipple disease

  • Acquired immunodeficiency syndrome (AIDS)

  • Tuberculosis

  • Tropical sprue

  • Some intestinal parasitosis

  • Paracoccidioidomycosis

  • Other enteropathogenic agents

Autoimmune and Allergic

  • Graft-versus-host disease

  • Eosinophilic gastroenteritis.

  • Allergic gastroenteropathy

  • Angioedema

Hematologic and Connective Tissue Disorders

  • Henoch-Schönlein purpura

  • Waldenstrom macroglobulinemia

  • Amyloidosis

  • Sarcoidosis

  • Systemic erythematous lupus

  • Other connective tissue disorders


  • Congenital disorders of glycosylation (CDG)

  • Reduced production of sulfated glycosaminoglycans (e.g., Kwashiorkor)


In general, excessive protein loss across the gut epithelium occurs secondary to mucosal injury, increased permeability, or to lymphatic obstruction leading to an outflow of protein-rich lymph. Therefore, PLE is not a single entity but a complication of a myriad of disorders. On the other hand, protein malabsorption due to loss of normal small-intestinal mucosal surface and/or function, or to diminished exocrine pancreatic secretion of proteases, such as celiac disease, short bowel syndromes, and cystic fibrosis, is not customarily included in the PLE etiology spectrum. In addition to leading to a generalized nutrient malabsorption rather than a primarily protein-losing waste, these conditions do not act through an actual exudative process.

Most clinical manifestations of PLE become evident when enteric protein loss exceeds hepatic protein synthesis. In contrast to normal protein losses into the gastrointestinal tract (e.g., through secretions and sloughed enterocytes), which account for less than 10% of the total body degradation of albumin, those seen in PLE can involve up to 60% of the total albumin pool. Intestinal protein loss can be permanent in certain cases or may go into remission in others.

In the normal homeostatic state, serum protein levels are representative of a balance between protein synthesis and metabolism, since gastrointestinal losses are in general negligible with respect to total protein metabolism. However, in patients with PLE, this equilibrium is altered. Those serum proteins with longer half-lives and incomplete capacity to react quickly to augmented losses are the ones most affected by this abnormal process and are found in significantly decreased concentrations in the bloodstream. This group includes albumin, the protease inhibitor α1-antitrypsin (A1AT), ceruloplasmin, fibrinogen, transferrin, hormone-binding proteins, and most immunoglobulins. Because hepatic protein synthesis is maintained or modestly increased, levels of the rapid-turnover group of proteins, such as prealbumin, insulin, and immunoglobulin E (IgE), are kept within a normal (or slightly) increased range.

In contrast to the typically selective protein loss of the nephrotic syndrome, where those proteins with a low molecular weight (albumin) are leaked in the highest proportion, in PLE, owing to the more macroscopic scale of the underlying damage, protein depletion occurs independently of molecular weights. As a result, the daily rate of degradation is comparable among various serum proteins, including albumin, ceruloplasmin, and immunoglobulins.

For the reasons stated earlier, in normal intake conditions, the final systemic profile of the various plasma proteins in PLE will represent the algebraic sum of their compound loss rate (endogenous degradation, gut losses, other losses) and their hepatic synthesis. Commonly, this profile is characterized by hypoalbuminemia coexisting with hypoglobulinemia. Because albumin is instrumental in maintaining plasma oncotic pressure and transporting a variety of other serum molecules (hormones, bilirubin, and fatty acids), its deficiency generates a variety of homeostatic and nutritional complications, which can become quite severe.

Some Causes of PLE

Intestinal lymphangiectasia (OMIM 152800)

Intestinal lymphangiectasia, a rather uncommon condition characterized by diffuse or local dilation of the enteric lymphatics, is the best-known abnormality of the lymphatic system leading to PLE. It can exist as a congenital defect (primary intestinal lymphangiectasia, or PIL) or secondary to other diseases.

Primary lymphangiectasia : The prevalence of clinically overt PIL is unknown but is believed to affect less than 200,000 of the population of the United States. PIL can cause severe, even life-threatening, complications and adopt a chronic or recurrent course in some patients, or present as a mild, transient, or even asymptomatic condition in others.

In some patients, PIL can be associated with different congenital abnormalities of the lymphatic system of variable severity and extent, including peripheral lymphedema and various types of effusions. Five genetic syndromes, including von Recklinghausen, Turner, Noonan, Klippel-Trenaunay, and Hennekam are classically known to be associated with intestinal lymphangiectasia. More recently, it has been shown that CCBE1 mutations over­all can cause a mild form of generalized lymphatic dysplasia, including lymphangiectasia. A mild form of lymphangiectasia is also a salient feature of the group of disorders known as congenital disorders of glycosylation (CDG). These entities are caused by defects in the synthesis of glycans and in the attachment of glycans to other molecules and, in addition to involving the gut, they can determine liver, cardiac, and neurologic developmental involvement. One form of CDG, the CDGIb ( OMIM 602579 ), is dominated by gastrointestinal and liver manifestations, including PLE.

Intestinal lymphangiectasia was first reported by Waldmann et al. in their seminal 1961 paper, as “idiopathic hypoproteinemia.” The structurally abnormal lym­phatics can be located in the mucosa, submucosa, or subserosa, and because of lymph stasis and vessel engorgement, they are constantly prone to rupture, which causes leakage into the gut lumen. Because lymphatic fluid is rich in albumin, globulins, and other proteins as well as chylomicrons, fat-soluble vitamins, long-chain dietary fats, and lymphocytes, its bulk loss leads to a progressive depletion of these elements from the systemic pool and to serious nutritional consequences. Medium- and short-chain fatty acids, on the other hand, are more dependent on the mesenteric venous blood, which transports them to the liver, than on the integrity of the lymphatic flow.

Hypoalbuminemic edema (which is often asymmet­rical) is a hallmark of PIL, other major manifestations or sequelae being, diarrhea, steatorrhea, abdominal pain, nausea/vomiting, chylous effusions, and growth retardation. The core laboratory features of intestinal lymphangiectasia are hypoalbuminemia, hypogammaglobulinemia, and peripheral lymphopenia. These two latter conditions may lead to the development of an immune deficiency state with abnormalities of both the humoral and cellular immune systems. Although this imbalance would theoretically predispose these patients to infections, in practice these are rather unusual.

Diagnosis of PIL is often made before 3 years of age and can usually be documented by the characteristic finding of variable degrees of dilation of the lymph vessels in the mucosa, on endoscopy, and in the submucosa, on small intestinal biopsies ( Figures 33-1 through 33-3 ). Whereas the finding of diffuse lymphangiectasia supports the diagnosis of the congenital PIL, the presence of the focal form would suggest the secondary type of lymphangiectasia. If the endoscopic procedure is carried out after a high-fat meal, typical scattered white spots on the mucosa of the duodenum are visible to the examiner. The use of capsule endoscopy and double balloon endoscopy may be considered in selected patients, when endoscopic findings are not contributory.

Figure 33-1

Intestinal lymphangiectasia. Prominent valvulae conniventes are present throughout the small bowel.

Figure 33-2

Endoscopic view of the duodenum showing snowflake-like lesions; histologically these represent dilated lacteals.

Figure 33-3

Lymphangiectasia. (A) Low-power magnification of expanded villi (V) with dilated lymphatic channels (arrow) (hematoxylin and eosin stain, ×50). (B) Higher-power magnification of a villus with dilated lacteal (arrow) (hematoxylin and eosin stain, ×200).

Secondary lymphangiectasia : Disorders leading to secondary lymphangiectasia act by causing obstruction of the lymph vessels or elevation of the lymph pressure due to raised venous pressure. In the first group, some relevant causes are lymphoma, inflammatory bowel disease, and some connective-tissue disorders, such as sarcoidosis, systemic lupus erythematosus, and amyloidosis, whereas the elevated lymph pressure group is composed mainly of patients with congestive heart failure and constrictive pericarditis. Other proposed mechanisms for secondary lymphangiectasia, as exemplified by Waldenström’s macroglobulinemia, are a high viscosity of the interstitial fluid leading to lymphatic dilation and obstruction, and infiltration, and subsequent distortion, of the mesenteric lymph nodes resulting in the same problem; such a mechanism has been described in low-grade lymphoma.

Cardiac disease was first identified as a cause of PLE in adult patients with constrictive pericarditis and severe cardiac failure. Subsequently, several cases of PLE secondary to constrictive pericarditis were reported in pediatric patients. In this condition, the resulting elevation of central venous pressure leads to congestion of lymphatic vessels in the bowel wall, and to rupture of lacteals in the gut or direct lymph leakage through the surface epithelium into the lumen.

In more recent decades, as reconstructive palliative procedures of previously intractable, complex congenital cardiac disease have become more common, PLE has emerged as a significant complication of this far-reaching surgical approach. As a result, it has added a substantial burden on patients and families already struggling with complicated medical and social issues. Over time, patients undergoing the Fontan operation, a surgical procedure used in children born with a single functional ventricle, due in most cases to a hypoplastic left heart or to defective valves (tricuspid atresia or pulmonary atresia), are at risk of developing PLE, even several years after surgery. Although this outcome occurs in a minority, 2% to 13% of the operated children, it is nevertheless associated with a high degree of morbidity and an ominous prognosis, which entails a 5-year survival rate of 46% to 50%, despite vigorous (and usually frustratingly ineffective) treatment. Risk factors for this complication have been discussed recently.

The various potential complications of the Fontan procedure are rooted in what is regarded as the primary inadequacy of its resulting circulatory arrangement, since the procedure never leads to a physiologically normal hemodynamic state. Although still poorly understood, the complex pathophysiology of PLE in patients with Fontan operations is thought to stem from a spiral of increased lymph production, decreased drainage, and increased thoracic duct pressure with lymphatic stasis and engorgement. This, in turn, apparently involves as major causative mechanisms, an abnormal mesenteric vascular resistance, a low cardiac output secondary to a diminished preload, and an elevated central venous pressure, particularly in the perihepatic interstitium, following the Fontan procedure. The ultimate result is insufficiency and failure of a lymphatic system that operates beyond its physiologic limits. However, the ultimate trigger in the development of PLE remains unclear. It has been proposed that the chain of events is precipitated by the ongoing chronic low cardiac output. The latter, by paving the way to the increased release of inflammatory markers, among them tumor necrosis factor α (TNFα) seems to play an added role in the pathophysiology of PLE. By altering the glycosaminoglycan makeup and the anatomic and electrostatic integrity of epithelial mucosal cells (in like manner to the nephrotic syndrome), TNFα would ultimately allow the abnormal diffusion of albumin and other proteins from the bloodstream into the gut lumen. In vitro models of PLE have lent support to this hypothesis.

Medical management for these cases has included the use of diuretics, periodic albumin infusions, subcutaneous unfractionated heparin, and high-dose corticosteroids, as well as other therapeutic approaches, either alone or in various combinations. These schemes have frequently followed a course where the initial enthusiasm has been tempered by the subsequent recognition of their often-significant side effects and short-lived beneficial impact. Baffle fenestration is another approach that has brought about a temporary improvement in some patients, whereas others have received no benefit. Increased hypoxemia and a greater risk of stroke are known risks of this procedure. Parenteral nutrition support, customarily employed in concert with supplementation with medium-chain triglycerides (MCTs) and other nutrients, is an intuitively rational treatment but it is often as ineffective in the long term as the other approaches already described. Bearing in mind this dismal scenario, an early detection of this complication of the Fontan operation could plausibly help to plan a comprehensive therapeutic strategy. This one, focused on certain crucial interventions, should be applied before irreversible changes in the enteric lymphatic system develop. One early parameter that helps to detect increased gastrointestinal protein loss seems to be A1AT concentration; therefore, it has been proposed that serial measurement of this marker could constitute an early predictor of PLE in patients who have undergone a Fontan procedure.

Ménétrier’s Disease

Ménétrier’s disease, also known as giant hypertrophic gastropathy, is a rare disorder characterized macroscopically by giant rugal folds in the stomach, and histologically, by foveolar hyperplasia, cystic dilation of pits, and a reduced population of parietal and chief cells. Although the fundus and body of the stomach are involved, the antrum is typically spared. An increase in intracellular permeability and wider tight junctions between cells is the cause of the protein loss that often accompanies this disorder. This condition is now believed to result from enhanced EGFR (epidermal growth factor receptor) signaling in the gastric mucosa due to local upregulation of transforming growth factor α (TGFα) signaling through the receptor tyrosine kinase (RTK). However, the basic defect that causes overproduction of TGFα in Ménétrier’s disease is not known.

The main clinical manifestations of this disorder, besides the expected consequences of a PLE state, are vomiting, nausea, anorexia, and weight loss. Anemia, due to gastric blood loss and hypochlorhydria, secondary to significantly reduced population of parietal cells, can also be found.

In children, a major etiology of Ménétrier’s disease is cytomegalovirus infection, although is some cases Helicobacter pylori has also been implicated. Unlike adults, where Ménétrier’s disease often follows a chronic course, in children, the condition is mostly self-limited and neither recurs nor causes sequelae.

Ulcerative Lesions of the Gastrointestinal Tract

It is intuitively logical to expect that in conditions characterized by extensive mucosal injury or ulcerative lesions of the gastrointestinal tract there should be enhanced leakage of protein-rich fluids across the diseased mucosa. This complication has indeed been reported in some patients with Crohn’s disease, ulcerative colitis, and other inflammatory disorders of the gut. Normally these conditions do not give rise to hypoproteinemia unless this protein loss is massive.

Active inflammatory states can elicit local hyperemia, increased epithelial permeability, and breakup of the integrity of the epithelial cell barrier. To these well-established mechanisms, other elements may contribute to the excessive protein loss. An important factor is increased local production of proinflammatory cytokines such as interferon (IFN)γ and TNFα. These cytokines can further impair the structural and physiologic properties of the epithelial cell barrier by virtue of their ability to induce the release of mediators, such as the proteolytic enzymes, matrix metalloproteinases. The latter are capable of altering and remodeling bowel wall structure with consequent increase in its permeability to proteins, among other effects. In addition, secondary lacteal dilation may occur in inflammatory bowel disease (IBD), with subsequent leakage of protein-rich lymph to the lumen of the gut.

Certain enteric infections leading to extensive mucosal damage, mainly of the large intestine, can also cause a clinically evident PLE state, although in the general context of infectious diarrhea in children, this occurrence is rare. Aggressive enteroinvasive pathogens such as Shigella , acting through the secretion of Shiga toxin, can induce extensive colonic vascular damage, intestinal ischemia, and destruction of colonic epithelial cells of variable extent and severity, all of which represent potential mechanisms of excessive protein loss. These losses can also occur during pseudomembranous enterocolitis due to Clostridium difficile as well as strains of E. coli that can disrupt macroscopically the intestinal mucosa and hence, its barrier attributes. In addition, PLE has been described in acute (and post-) measles enteritis, and in concomitance with giardiasis.

PLE has also been reported in patients using nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanism of damage in this case seems to result from a multistage process. This is initiated by the NSAID triggering biochemical damage to the enterocytes and followed by increased permeability of the affected tissue, which allows mucosal access of a variety of luminal substances thereby leading to subsequent inflammation. This progression may even favor the development of strictures or even perforation in some individuals. NSAIDs can act by direct exposure after oral administration and by systemic effects after absorption (which can be augmented following enterohepatic recirculation of the drug). Different potential preventive strategies have been suggested, but to date there is no effective way to prevent this damage. Approaches aimed at reducing intestinal permeability look particularly promising.

Miscellaneous Conditions

The hypoalbuminemia seen at times in children with food (milk, soy) sensitivity or allergic eosinophilic gastroenteritis has been attributed to mast cell infiltration, which may ultimately produce increased intestinal permeability and protein loss. On the other hand, in Henoch-Schönlein purpura, as well as other vascular diseases, hypoalbuminemia is secondary to increased capillary permeability.


The characteristic clinical manifestations of PLE, added to the history and physical examination, should constitute in many cases a solid base for a provisional diagnosis of PLE. In a patient with edema, hypoalbuminemia, and lymphopenia, the diagnosis of intestinal lymphangiectasia can be anticipated with confidence.

Hypoalbuminemia can be originated from a variety of clinical disorders, of which overt edema is an extreme manifestation. Although discussion of differential diagnosis of an edematous child is beyond the scope of this chapter, PLE should stand among the various etiologies considered in this case, when the patient does not obviously have nephrotic syndrome or severe dietary deprivation-induced protein-energy malnutrition. An edematous child constitutes a medical emergency. Celiac disease and cystic fibrosis are other key etiologies of hypoalbuminemic edema stemming from the alimentary tract.

The detection of A1AT in stools has been widely used as a tool in the diagnosis of PLE. This test can be performed in a random stool sample and its rationale derives from the fact that this protease inhibitor has similar molecular weight to that of albumin and is not actively secreted or absorbed and, in addition, does not undergo degradation beyond the stomach. Thus, stool A1AT can be used as a confirmatory test of intestinal protein loss, provided the leakage is not gastric in origin. The measurement of A1AT clearance is preferred over that taken from a random stool sample and requires on one hand, the determination of A1AT plasma levels and, on the other, a 24-hour stool collection to assess stool volume and stool A1AT level. An A1AT clearance is normal when its value is ≤ 24 mL per 24 hours in patients without diarrhea, and ≤ 56 mL in patients with diarrhea. Values above these limits render a PLE diagnosis very likely, although the site of protein loss cannot be ascertained with this method. If a gastropathy is suspected, the prior use of a proton pump inhibitor can inhibit degradation of A1AT by gastric acid and thus make determination of abnormal protein loss due to that cause much more reliable.

Caution should be exerted when studying neonates, since the meconium content of A1AT could be a source of false-positive results. In addition, in intestinal bleeding, interpretation of A1AT clearance is an unreliable analysis, since clearance rates are increased.

The measurement of fecal calprotectin has recently been advocated as another marker of gut inflammation and protein loss.

Pinpointing the actual site of the protein loss can be a difficult task in some cases. Tc-99m human serum albumin (Tc-99m HSA) is one of various radiopharmaceuticals used as tracers for this purpose. Functional imaging with this tracer has been described as having good sensitivity and specificity to identify the area of protein leakage.

After confirming the abnormal protein loss, it is necessary to document the underlying disease if at this stage it has not already become evident. Careful consideration of possible differential diagnoses should prompt clinicians to rule these out with the appropriate battery of tests. Protein electrophoresis, hematologic work-up, (mal)absorption tests and nutritional indices (serum carotene, serum calcium, and phosphate, and so on), acute phase proteins, viral serologic studies, stool studies, radiographic imaging, and cardiac work-up are among the suggested investigations, depending on the particular clinical manifestations present in each case.

It must be kept in mind that, theoretically, an abnormally increased clearance of A1AT can occur in any circumstance that causes disruption of the gut epithelial barrier. Indeed this phenomenon has been reported in many instances—mostly in infectious and inflammatory disorders (as discussed earlier). However, a clinically evident PLE state requires more than a transient or self-limited leaky gut. To become manifestly edematous, a patient should arguably undergo a severe protein loss, a combination of predisposing factors, or have a sig­nificant underlying condition that makes him/her prone to develop a failure of his/her protein and fluid homeostasis.

Some of the procedures employed to document PIL have already been described in the respective section. Endoscopy is also particularly useful to investigate other putative causes of PLE, as for instance when inflammatory processes of the upper gastrointestinal tract are suspected. The presence of mucosal inflammation or polyps that may involve the small bowel or colon can be confirmed by colonoscopy. Wireless capsule endoscopy or double balloon enteroscopy may help identify small bowel lesions not reachable by conventional endoscopes. Investigation of some obstructive conditions leading to PLE may require the use of magnetic resonance enterography and computed tomography enhanced by contrast.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Jul 24, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on Protein-Losing Enteropathy

Full access? Get Clinical Tree

Get Clinical Tree app for offline access