The condition of protein-losing enteropathy refers to an excessive loss of plasma protein into distinct parts of the gastrointestinal tract. It may be provoked by a variety of infectious, immune-related, neoplastic and idiopathic diseases.
Protein loss results in hypoproteinemia, decreased oncotic pressure, fluid transudation into the extravascular space and finally edema development. Such edema are the most common symptoms of PLE. Patients usually present with swollen legs or generalized peripheral edema. Gastrointestinal disorders are furthermore associated with abdominal pain and diarrhea, possibly hemorrhagic diarrhea. Prolonged illness also results in malnutrition and weight loss.
In patients suffering from PLE due to lymphatic obstruction, lymphopenia and reduced levels of immunoglobulins provoke immune deficiency and increase susceptibility to infection. In this line, recurring infections may be reported .
Of note, the underlying disease may not only affect the gastrointestinal tract and may indeed provoke more severe symptoms than PLE. For instance, patients suffering from tuberculosis, amyloidosis or heart failure most likely present with a variety of symptoms that may overlap with those of PLE .
Patients presenting with peripheral edema of unknown origin should be examined for possible PLE. Laboratory analyses of blood samples generally provide valuable information and reveal hypoalbuminemia and hypoglobulinemia. Additionally, lymphopenia may be observed. Fat malabsorption entails reduced levels of liposoluble vitamins, i.e., vitamins A, D, E and K.
Differential diagnoses for low protein levels are reduced intake or malnutrition, decreased protein synthesis due to hepatic dysfunctions, and protein losing nephropathy . Cutaneous lesions, particularly extended burns, may also account for decreased protein levels. These possible causes may be ruled out when anamnesis, hepatic and renal parameters do not point at such pathologies.
Diagnosis of PLE may be verified by intravenous application of labeled human serum albumin and quantification of the respective isotope in stool samples . The presence of α1-antitrypsin in stool samples results from malabsorption and thus further supports the diagnosis of PLE. This test may, however, not be used in patients suffering from hyperacidity because of α1-antitrypsin degradation in acid environments. Occult blood in stool samples points at gastrointestinal lesions, too. Furthermore, stool samples may be examined for intestinal parasites.
Different, more or less specific tests are required to identify the underlying disease. Serologic tests may be helpful to detect infections. Positive hydrogen breath tests indicate intestinal bacterial overgrowth. Radiography and computed tomography may be applied to detect possibly present neoplasms; the latter is also used to visualize lymphatic obstruction. However, lymphangiography is more sensitive in this regard. Cardiac pathologies are often discernible in radiographic images, but echocardiography may reveal even better results.
The gold standard for diagnosis of gastrointestinal disorders is an endoscopic examination with mucosal biopsy sampling and subsequent pathohistological analysis of these tissue samples.
PLE therapy aims at eliminating the underlying disease, compensating for nutrient deficiencies and promoting gastrointestinal recovery.
Certain underlying diseases may be cured with easy and straightforward therapeutic approaches. Antiparasitic agents, for instance, will relieve the intestines from their parasitic burden. Recovery processes are initiated and protein loss will decrease to physiological levels. ACE inhibitors and diuretics are usually administered to those suffering from cardiac insufficiency and heart failure. In most cases, cardiac function will be improved and venous pressure will be reduced. Several autoimmune disorders are treated with immunosuppressive corticosteroids.
On the other hand, surgical interventions may be required to resect neoplasms and to cure associated diseases, e.g. giant hypertrophic gastritis . Of note, patients suffering from giant hypertrophic gastritis may benefit from therapies aimed at elimination of Helicobacter pylori. Not all neoplasms that entail PLE are easily resectable. This may be the case for lymphoma. Chemotherapy and/or irradiation are indicated then. Surgical approaches may be the method of choice to resolve lymphatic obstruction or to bypass impassable lymphatic vessels by means of lymphovenous anastomosis.
Dietary adjustments are recommended for certain PLE cases. In this context, low-fat diets supplemented with medium-chain triglycerides are suggested to improve the condition of patients with lymphangiectasias. Its effect is, however, controversially discussed . Celiac disease requires a gluten-free diet.
Prognosis largely depends on the underlying disease. If it is potentially curable, prognosis improves considerably. Due to the availability of better therapeutics, morbidity and mortality of PLE are decreasing .
PLE may result from excessive protein loss into the stomach, the small intestine or the large intestine. PLE may result from local or systemic pathologies and may effect one or more of the aforementioned parts of the gastrointestinal tract. As has been mentioned before, erosive and non-erosive gastrointestinal disorders may account for protein loss as well as those diseases associated with increased lymphatic or central venous pressure. This classification is based on the pathogenesis of PLE but does not reflect its actual triggers. Here, infectious, immune-related, neoplastic and idiopathic causes may be distinguished. Of note, some triggers may belong to more than one category.
Neoplasms affecting the gastrointestinal tract
Due to the large variety of underlying diseases, no reliable data regarding incidence and prevalence of PLE can be provided. Despite the long list of possible triggers, it is considered to be a rare disease.
There is no unique pathogenesis to PLE, but the above mentioned underlying diseases result in either intestinal mucosal erosion or ulceration, epithelial cell dysfunction without macroscopic evidence for mucosal damage, or increased lymphatic or central venous pressure. The precise link between the underlying disease and intestinal damage could not be identified for each cause of PLE. Such is the case with Fontan heart surgery. To date, there is no conclusive evidence regarding the pathophysiological events leading to PLE after realizing the Fontan procedure . Postoperative increases of venous pressure, reduced pulmonary vascular compliance and augmented levels of serum hepatocyte growth factor have been proposed as potential triggers of PLE .
Gastrointestinal disorders with or without macroscopic evidence for mucosal lesions may contribute to protein loss in the form of detached enterocytes or infiltrating inflammatory cells, as well as blood and lymph that may pour out of lesioned vessels. With regards to increased lymphatic or central venous pressure, these conditions most commonly result from cardiac insufficiency. In patients suffering from cardiac insufficiency, a reduced stroke volume entails increased end-diastolic ventricular pressure, preload and venous pressure. The hydrostatic pressure in intestinal veins increases significantly, may even damage blood vessels and provoke remodelling processes, and protein-rich exudate is pressed into the intestine. Similarly, PLE triggered by increased lymphatic pressure results in lymph stasis, augmented hydrostatic pressure and protein-rich exudates. Mesenterial lymphatic obstruction may evoke these pathophysiological events. Contrary to blood, lymph also contains high concentrations of liposoluble molecules such as lipids, cholesterol and liposoluble vitamins. Thus, not only are nutrients poorly absorbed by the damaged intestine, but proteins as well as lipids are lost into the intestinal lumen. These conditions lead to nutrient deficiencies and malnutrition.
Recently published studies have proposed heparan sulfate proteoglycans, which can be found on the basolateral surface of intestinal epithelial cells and in the extracelluar matrix, as key factors in PLE. Presumably, inflammatory processes as well as increased pressure impair proteoglycan function, thus evoking an increased epithelial permeability and protein loss. Furthermore, loss of proteoglycans seems to potentiate the detrimental effects of pro-inflammatory cytokines and elevated lymphatic pressure. The hypothesis of heparan sulfate proteoglycans as mediators of epithelial protein permeability is further supported by the fact that patients suffering from genetic disorders that cause loss of proteoglycans also present with increased intestinal permeability and secondary PLE.
Preventive measures can be recommended to avoid certain diseases associated with PLE, e.g., infectious diseases and cardiac insufficiency. However, this is not the case for PLE itself.
Patients suffering from protein-losing enteropathy (PLE) lose increased amounts of plasma protein into different parts of the intestine. Physiologically, intestinal loss of plasma protein is very limited. It mainly results from enterocyte detachment due to mucosal regeneration and distinct secretions. Less than 2% of the entire amount of plasma protein and less than 10% of the entire amount of albumin are lost daily in healthy individuals . These values are by far exceeded in PLE patients and here, up to 60% of the overall amount of albumin may be lost enterically in a single day. Moreover, lymphocytes, lipids, dietary minerals and trace elements may be lost. There are several diseases that may evoke PLE, especially gastrointestinal disorders that may or may not involve mucosal erosion and those diseases that cause increased lymphatic or central venous pressure . Because lymph has a particularly high protein content, obstruction of mesenterial lymphatic vessels and subsequent leakage of lymph may result in protein loss as severe as that observed due to intestinal erosions and ulcers.
PLE results in hypoproteinemia and thus entails pleural effusion and ascites, pericardial effusion and peripheral edema development. Although protein anabolism will be stimulated in order to restore physiological protein levels, concentrations of those proteins with longer half-lives will be decreased for longer periods of time. This applies to albumin, the majority of immunoglobulins and ceruloplasmin. In contrast, levels of proteins with shorter half-lives, e.g., prealbumin, immunoglobulin E and insulin, may be elevated . Additionally, lost protein is no longer available for nutrition and chronic PLE is therefore associated with malnutrition.
The condition of protein-losing enteropathy (PLE) describes excessive loss of plasma protein into the intestinal tract. Thus, it is a symptom rather than its own pathologic entity.
There are many diseases that may cause PLE. In general, such diseases may either directly lead to intestinal lesions, mucosal erosion and ulceration, or impair enterocyte functionality without provoking visible mucosal damage, or increase lymphatic or venous pressure. Infectious agents, autoimmune disorders, tumors as well as cardiovascular diseases are worth considering.
Common pathological conditions associated with PLE are bacterial or parasitic infections of the gastrointestinal tract, AIDS, celiac disease, Crohn disease, ulcerative colitis, lymphoma, cardiac insufficiency and intestinal lymphangiectasia.
Excessive loss of plasma protein mainly affects albumin and immunoglobulin pools. Albumin fulfills a myriad of functions, one of them being the maintenance of intravascular oncotic pressure. If there is less protein inside the vessel than outside this also means there is more water inside than outside. To compensate for this apparent imbalance, water diffuses into the surrounding tissues. Edema develops. Indeed, swollen legs are the most common symptom of PLE. On the other hand, immunoglobulins are key factors of the immune system. Low immunoglobulin levels weaken the immune system and leave the patient more susceptible to infections.
In the long term, PLE patients will probably suffer weight loss. Not only does the body lose essential proteins and even fat into the intestinal lumen, the lesioned intestinal mucosa is also unable to absorb nutrients. Subsequent malnutrition leads to weight loss.
If patients present with the above described symptoms, the physician will obtain blood samples and verify albumin and immunoglobulin levels. Because hepatic and renal pathologies may trigger symptoms similar to those of PLE, additional parameters will be measured to assess the functionality of these organs.
There are specific tests that may prove intestinal protein loss. For instance, a patient may be intravenously administered labeled albumin. If this labeled albumin is lost into the intestinal lumen, it will appear in stool samples that are subsequently obtained. Also, certain substances should never be secreted into the intestine or readily be absorbed after oral intake. If their concentration in stool samples exceeds reference values, this finding points at limited absorption of nutrients.
In order to evaluate the actual condition of the intestine, endoscopic examination, biopsy sampling and histopathological evaluation may be required.
Additional diagnostic measures may be taken to identify the underlying disease.
If at all possible, treatment aims at eliminating the source of PLE. If the underlying disease can be cured, protein levels and nutrient absorption usually normalize. Any therapy has to be adjusted to the underlying disease and therapeutic options range from antibiotics, antiparasitic drugs, immunosuppressive medication and ACE inhibitors to chemotherapy, irradiation and surgical intervention.