Protein losing enteropathy (PLE) is defined as an excessive loss of serum proteins into the gastrointestinal (GI) tract, resulting in hypoproteinemia. Protein loss into the GI tract reflects always a significant damage, destruction, or structural change of the gastrointestinal wall and can be caused by any GI disease if it is severe enough. PLE is suspected in any patient with clinical signs related to GI tract and with hypoalbuminemia. It is important to keep in mind that PLE is not always associated with obvious GI signs (e.g., dogs with PLE can be presented because of abdominal effusion due to hypoalbuminemia), and that hypoalbuminemia in a dog with GI signs is not always due to GI loss. Therefore, in any patient with significant hypalbuminemia (<2 gm/dl; reference range 2.5–4.4 gm/dl), following tests should be performed: a urinary dipstick test in order to rule out protein loss in the urinary tract, serum bile acids to rule out liver dysfunction, and diagnostic imaging.

In case fluid is present in body cavities, it is necessary to determine protein concentration in order to rule out albumin loss. Rarely, albumin concentration can be low due to exudative skin disease or as a compensation due to extensive hyperglobulinemia. GI protein loss can be documented directly by measuring α₁-proteinase inhibitor concentration in dog fecal samples, however, this test is currently available only in the USA.

Once albumin loss is localized to the GI tract, sensitive tests to detect intestinal parasites (e.g., roundworms, especially hookworms and acute Giardia sp. infection in young dogs) should be performed. Additionally, basal cortisol levels should be determined, since hypoadrenocorticism can mimic primary intestinal disease causing PLE. After intestinal parasitism and Addison’s disease have been ruled out, intestinal biopsy should be performed as the ultimate means for diagnosing inflammatory bowel disease, intestinal lymphangiectasia, intestinal lymphoma, crypt lesions, and fungal granuloma.

Abdominal imaging is an important tool for making a decision on how to biopsy the GI tract (via laparotomy or via endoscopy). After ruling out metastatic or multifocal lesions, surgical removal is indicated in focal GI disorders (such as localised neoplastic infiltration, intussusception, fungal granuloma, and foreign body). If enlarged lymph nodes are detected, they should be aspirated. Additionally, abdominal ultrasonographic examination is useful for detecting hyperechoic mucosal striations, which are suggestive of PLE, and for guiding the biopsies. Administration of medium chain triglyceride oil, cream or corn oil orally 2 to 4 hours before ultrasound or endoscopy can improve the detection of enlarged lymph vessels in the intestinal mucosa. If a diffuse infiltrative intestinal disease is suspected, endoscopic biopsies should be performed. Endoscopy allows visualizing mucosal lesions and minimizes the risk of bacterial infections compared to possible suture line leakage in surgical biopsy cases.

Before performing an expensive diagnostic work up, the owners should be informed about the risks and prognosis. PLE carries a guarded prognosis, due to complications during and after invasive procedures. Vitamin D (cholecalciferol) can be used as a prognostic marker, since hypovitaminosis D in PLE dogs has been associated with poor outcome.

In patients with low albumin levels (<1.5 gm/dl), low oncotic pressure in the blood vessels can lead to effusions in body cavities, edema, and low blood pressure. Synthetic colloid support, amino acid solutions, and plasma (primarily in small dogs) should be given before anaesthesia to minimize the risks of anaesthetic complications. The effect of osmotic fluids is of a short duration and can cause side effects (e.g., thrombocytopathia). Human albumin should be restricted only to critical cases, since severe and sometimes fatal adverse reactions were observed in dogs with PLE. In some patients, hypocalcemia due to PLE can cause clinical signs (e.g., weakness, increased muscle activity) and has to be addressed by supplementation of calcium and possibly vitamin D.

Treatment of patients with PLE is focused on the primary disease causing the protein loss. Non-specific treatment in all cases includes nutritional support, prevention of thromboembolism, and supplementation of deficient vitamins. The goal of nutritional support is to provide high-energy support by restricting the fat content to 10% of fat in dogs with lymphangiectasia. In severely affected cases, total parenteral nutrition can be beneficial at least initially. In cases of intestinal inflammation suggestive of food allergy, a low fat hypoallergenic diet should be introduced and clinical improvement assessed after several weeks.

Clopidogrel is a platelet aggregation inhibitor and should be routinely administered in dogs with significant hypoalbuminemia or low antithrombin activity to prevent serious life-threatening thromboembolic events. Cobalamin concentration should be determined in any dog with intestinal disorders, and supplemented in case of hypocobalaminemia. Since low cobalamin serum concentration is frequently associated with GI albumin loss, supplementation should be started while the test result for serum cobalamin concentration is pending.

Immunosuppressive therapy is also indicated, except in dogs with infectious diseases. In order to prevent the formation of lipogranulomas due to leakage of lymphatic fluid, anti-inflammatory treatment should be administered even to dogs with primary lymphangiectasia without signs of significant inflammation. In most dogs with PLE due to IBD, a combination of immunosuppressive drugs is necessary for effective treatment. Steroids (e.g., short acting prednisolone 2 mg/kg once daily) can be combined with cyclosporine A (e.g., 5 mg/kg once daily), and should be tapered down depending on clinical response, serum albumin concentration, and side effects. Frequently, a parenteral administration of medication (as well as nutrition) is useful as long as the absorption through the diseased, edematous intestinal wall is poor. Results of a study performed in dogs with PLE suggest that a chlorambucil- prednisolone protocol can be used and is more efficacious compared with an azathioprine­ prednisolone combination.

In summary, PLE describes a diverse group of severe intestinal disorders with excessive loss of serum proteins into the GI tract. Since PLE is most frequently associated with inflammatory or neoplastic infiltration of the intestinal wall or with lymphangiectasia, intestinal biopsy is recommended as a definitive diagnostic tool. Specific diets in combination with immunosuppressive treatment are indicated in the most cases.