The exact mechanism of serum protein exudation is not known in all instances of PLE. Three basic causes have been proposed: mucosal ulceration, epithelial alteration, and impaired lymphatic flow. A combination of these mechanisms often is responsible for the PLE that occurs in many disorders.
Examples include Crohn disease, posttransplant lymphoproliferative disease, and messenteric venous thrombosis or ischemia. Impaired lymphatic flow probably is the most frequent cause of protracted PLE. Reduced systemic venous return, such as that found in cardiac failure or constrictive pericarditis, can lead indirectly to PLE by compromising lymph flow through the thoracic duct into the systemic circulation. In addition to compromised mesenteric lymphatic flow, bowel wall edema and damage also are likely contributing factors when hepatic or splanchnic venous blood flow or both are hindered (e.g., hepatic, portal, and mesenteric venous thrombosis; intermittment, segmental intestinal volvulus). These factors are thought to be responsible for the devastating PLE that occurs in children who have undergone Fontan operations for congenital heart disease.

In affected children, Ménétrier disease, also termed hypertrophic gastritis, appears to follow a self-limited clinical course, as opposed to the progressive form of this disorder that afflicts adults, probably because childhood Ménétrier disease often is caused by viral gastritis. Similarly, other GI infections are transient causes of PLE; intestinal bacterial overgrowth syndrome also is a cause. Pneumonia or systemic infections can result in PLE. The mechanism is unknown at present but could involve alteration of gut permeability secondary to systemic cytokine release.

A growing group of recognized inherited diseases that result in defective glycosylation of serum proteins, termed the carbohydrate-deficient glycoprotein syndromes, also now is a recognized cause of PLE. These disorders are thought to result in a defective epithelial basement membrane barrier or extracellular mucosal matrix in the gut that are the putative mechanisms for PLE.

PLE appears to be a nonselective process. Cellular elements, usually lymphocytes, also may be lost from the bowel, especially in patients with impaired intestinal lymphatic drainage. Levels of serum proteins with short half-lives, such as fibrinogen, are less affected than are those with long turnover times, such as albumin. Hypoproteinemia does not occur in every case of PLE because increased hepatic synthesis of serum proteins can compensate for ongoing losses. This synthesis is possible both because of the efficiency of intraluminal digestion and reabsorption of protein exuded from the bowel and because of the capacity of the liver to increase its rate of protein synthesis if nutritional intake is adequate. Disproportionate protein loss occurs in patients with GI bleeding from generalized intestinal mucosal diseases, such as chronic inflammatory bowel disease or posttransplant lymphoproliferative disease.

Many other primary GI disturbances can be associated with PLE. Frequently, generalized malabsorption occurs with PLE if the bowel wall lymphatics or mucosal surfaces are severely involved (e.g., lymphangiectasia, celiac disease). Children with severe fat malabsorption, as manifested by steatorrhea or low serum levels of fat-soluble vitamins but without concomitant PLE, are likely to have a primary disorder of intraluminal digestion (e.g., pancreatic insufficiency resulting from cystic fibrosis). The finding of gross or occult blood in the stool also may help to localize the site of dysfunction or damage to the intestinal mucosal surface.

In most cases of PLE, the clinical findings of the primary underlying disorder dominate the picture. The associated PLE is suggested by edema or hypoproteinemia. Occasionally, these findings are the presenting manifestations of the underlying disease. PLE should be considered in all cases of unexplained edema or hypoproteinemia. Anemia and lymphocytopenia can occur concomitantly with PLE.