Introduction¹

An excessive loss of plasma proteins into the gastrointestinal tract is referred to as protein-losing enteropathy (PLE). In many cases there is protein loss from both the gastric and the intestinal mucosa and the term protein-losing gastroenteropathy may be a more appropriate. Protein-losing enteropathy occurs in association with a number of gastrointestinal as well as systemic disorders including idiopathic inflammatory bowel disease, gastrointestinal neoplasia, foreign bodies, intussusceptions, small intestinal bacterial overgrowth (SIBO), infectious gastroenteritis (viral, bacterial, fungal, and parasitic), adverse reactions to food, sepsis, hypoadrenocorticism, lymphangiectasia, and others. Plasma proteins usually have serum half-lives from 8 to 10 days. Albumin is synthesized by the liver and the liver is able to increase the rate of synthesis by up to two-fold in the face of increased albumin loss if the required nutrients are available.

The mechanism for protein loss during PLE may be due to inflammation or erosion altering the normal barrier function of the gut, or may be due to congenital or acquired abnormalities of the intestinal lymphatic or vascular drainage. The source of the enteric protein loss in PLE is either the mucosal vasculature or the mucosal interstitial space. Usually, both albumin and globulins are lost during PLE at an equal rate, resulting in panhypoproteinemia that is characteristic of PLE and helps to differentiate PLE from other causes of increased protein loss. However, especially in inflammatory conditions serum globulin concentration may be normal or even elevated due to increased globulin synthesis in the face of increased loss.

Primary intestinal lymphangiectasia is a congenital disorder that is due to an idiopathic abnormality of lymphatic drainage.² Histologically lymphangiectasia is characterized by a ballooning dilation of the lacteals in the villi and distension of the submucosal lymphatic vessels. Lymphangiectasia is a prominent feature of PLE in the Norwegian Lundehund, but lymphangiectasia also occurs in other breeds. Total lymph flow is reduced because the number of lymphatic vessels is insufficient to remove interstitial fluid. In some canine patients the lymphatic abnormalities are not confined to the gastrointestinal tract.

Secondary lymphangiectasia is usually associated with obstructive lesions of the lymphatic system. Lipogranulomatous lesions within and around the lymphatics are commonly observed, and may even be present in other organs. It is possible that secondary lymphangiectasia develops in dogs with a congenitally compromised lymphatic system that leads to leakage of lymph. Lymphatic leakage then leads to a granulomatous response, leading to lymphatic obstruction and lymphangiectasia. Lymphatic stasis can also arise due to venous hypertension, as is the case in right-sided heart failure. Lymphatic stasis results in lymphatic hypertension, which causes interstitial fluid to leak out into the abdominal cavity and into the lumen of the intestine. Lymphatic obstruction also causes a loss of lymphocytes into the intestinal lumen. Lymphangiectasia is therefore characterized by hypoproteinemia as well as lymphopenia. However, lymphopenia is not specific for lymphangiectasia, especially since lymphopenia is common in animals with a stress response during disease states.

Clinical signs

Animals with PLE usually exhibit signs of weight loss. There may be vomiting and diarrhea but failure to exhibit diarrhea or other characteristic signs of gastrointestinal disease does not eliminate the possibility of protein-losing enteropathy. Signs that are related to the underlying disease process may also be present. If hypoalbuminemia is severe clinical signs due to a subnormal oncotic pressure, such as edema, ascites, or dyspnea due to pleural effusion may be seen and maybe the only clinical signs the patient is presented for. Edema and ascites generally develop when serum albumin concentration falls below 1.0 g/dl, but may occur at higher albumin concentrations if there is concomitant capillary hypertension or vasculitis.

Diagnosis

Protein-losing enteropathy is diagnosed by way of exclusion of other causes of hypoalbuminemia. During physical examination the patient is carefully evaluated for signs of heart failure and/or blood loss. A CBC, serum chemistry profile, and serum pre- and postprandial bile acid concentrations are useful to evaluate the patient for possible hepatic failure. A urine protein-creatinine ratio is used to exclude protein-losing nephropathy (PLN). However, the diagnosis of PLN does not preclude a concurrent diagnosis of PLE. In fact 1/3 of all soft-coated Wheaton Terriers have both PLE and PLN.³ Finally, a fecal occult blood test helps to exclude subclinical blood loss into the GI tract. Serum cobalamin and folate concentrations provide additional evidence for gastrointestinal disease. Hypocalcemia may be present in dogs with PLE, but is primarily a reflection of the decreased serum albumin and thus maybe seen in other diseases that are associated with hypoalbuminemia.

Hypocholesterolemia is common in dogs with PLE due to lymphangiectasia, and presumably results from fat malabsorption associated with failure of chylomicron transport. The classical gold standard for diagnosis of PLE is ⁵¹Cr-albumin clearance.⁴ The labeled albumin lost into the GI tract is degraded by digestive enzymes, but the chromium label is not reabsorbed and is excreted in feces. The test can be performed by administration of labeled ⁵¹Cr-albumin or by administration of the ⁵¹Cr label alone, which leads to in vivo labeling of albumin. Quantification of radioactivity in feces collected over several days provides an index of gastrointestinal protein loss. While this test is fairly reliable in diagnosing PLE it is impractical for routine clinical use.

Estimation of fecal α1-proteinase inhibitor clearance has been shown to be a reliable method to diagnose PLE in human patients.⁴ Alpha₁-proteinase inhibitor has a molecular weight similar to that of albumin, and is present in the vascular space, in the intercellular space, and in lymph. Thus, α₁-PI and albumin are lost into the gastrointestinal tract together. Unlike albumin, α₁-PI is not degraded by proteolytic enzymes in the gastrointestinal lumen because of its broad spectrum inhibition of digestive proteases and is passed in feces essentially intact. An ELISA for the quantification of canine α₁-PI in feces has recently been developed and validated. In a recent study dogs with increased fecal ⁵¹Cr excretion also showed increased fecal α₁-PI concentrations.⁵ In human beings serum α₁-PI concentrations vary widely and several α₁-PI deficiency states have been described. Therefore, determination of fecal α₁-PI clearance is important in human patients suspected of gastrointestinal protein loss. This is not the case in dogs and it appears that estimation of fecal α₁-PI excretion measured by fecal α₁-PI concentration is a valuable marker for gastrointestinal protein loss.

After diagnosing of PLE identification of the underlying disease process leading to PLE should be attempted. In many cases this requires further diagnostic testing, including evaluation of gastrointestinal biopsies. With lymphangiectasia, the mucosa may appear more granular on endoscopic examination, and patches of white, lipid-filled dilated villi may be visible. While endoscopic examination and biopsy may provide diagnostic information in some cases, full thickness intestinal biopsy may be required to demonstrate the presence of this disease.

Risk of hypotension and other anesthetic problems may be minimized by plasma transfusion or administration of hetastarch prior to anesthesia. During exploratory laparotomy the major intestinal lymphatics of patients with lymphangiectasia will often be abnormally dilated and prominent. It should be remembered that dilated lacteals are also occasionally seen in association with lymphocytic-plasmacytic enteritis and other enteropathies, and that this acquired change may be restricted to mucosal lymphatic vessels. Thus diagnosis of true lymphangiectasia requires full-thickness biopsies. The risk of dehiscence of full thickness biopsy sites in debilitated hypoalbuminemic patients should be minimized by using nonabsorbable suture material.

Treatment

Recovery of dogs with acute PLE due to infectious or parasitic enteropathies is often rapid. Parasitic enteropathies require treatment with anthelmintic agents. Viral enteropathies maybe self-limiting provided that aggressive supportive care is instituted.

Treatment of chronic protein-losing enteropathies is directed at treatment of the underlying disease process, if identified. Surgical removal of localized gastric or enteric chronic inflammatory, ulcerative, or neoplastic lesions may successfully halt enteric protein loss. In cases that are due to an adverse reaction to food a single source protein and single source carbohydrate diet may be useful. In many instances the underlying abnormality cannot be identified and/or corrected. In these patients feeding a high quality protein, low fat diet to minimize the distension of intestinal lymphatic vessels may be useful if lymphangiectasia is the underlying disease process. Also, in patients with lymphangiectasia dietary triglycerides containing long-chain fatty acids should be limited as absorption of long-chain triglycerides is a major stimulus for intestinal lymph flow. After digestion and absorption, these fatty acids are re-esterified and incorporated into chylomicrons that must be transported by intestinal lymphatics. Restriction of dietary long-chain triglyceride reduces lymphatic distension and thereby reduces gastrointestinal protein loss and lipid exudation into the perilymphatic space.

The caloric content of the diet may be increased by supplementation with medium chain triglyceride oil at a dose of 1-2 mL/kg per day. Medium-chain triglycerides (MCTs) are readily hydrolyzed by pancreatic lipase, but a considerable proportion of MCTs is absorbed without prior lipolysis. Absorption of medium-chain triglycerides is not dependent on micelle formation, and once absorbed MCTs do not need to be re-esterified, but instead rapidly enter the portal circulation, thus bypassing the lymphatic system and minimizing lymphatic distension. Medium chain triglyceride oil does not provide essential fatty acids. However, these can be provided by adding a small amount of vegetable oil to the diet. Furthermore medium chain triglyceride oil is expensive and not particularly palatable for some animals. Alternatives to adding MCT oil to the diet are the use of a diet containing a significant portion of the fat as MCT or by use of a powdered elemental diet mix that contains MCTs.⁶

Glucocorticoid therapy, to inhibit inflammation, exert an immunosuppressive effect, and to promote enterocyte function, is also often administered and appears effective provided that specific infectious or obstructive enteropathies are carefully ruled out. In patients that respond poorly to glucocorticoids or that develop unacceptable side effects due to corticosteroid therapy, other immunosuppressive agents such as azathioprine, cyclosporine, or cyclophosphamide may be effective. Administration of plasma usually has no long-term benefit since alleviation of hypoproteinemia is only transient. However, plasma transfusion is of value immediately prior to general anesthesia, in order to minimize the risk of hypotension. Plasma transfusion may also be crucial to support oncotic pressure until more specific therapeutic strategies lead to a decreased loss of plasma proteins.

As with protein losing nephropathy, there may be significant loss of antithrombin III, which has a similar molecular weight to albumin and α1-PI. Excessive loss of antithrombin III may predispose patients with PLE to thromboembolic disease. Thus, serum antithrombin III concentrations should be measured in dogs with PLE and plasma transfusion should be considered if serum antithrombin III concentrations fall below 50% of control values. Unfortunately, there are few reports of long-term follow up of dogs with PLE. The effectiveness of the above-mentioned therapeutic measures has not been documented, and is largely anecdotal.

In general the prognosis for canine patients with PLE of inflammatory origin is guarded. Many patients with severe inflammatory bowel disease will eventually respond, but the therapy is often protracted and may need to be life long. Lymphangiectasia also carries a guarded prognosis. Response to therapy is unpredictable and is affected by the severity of the disease process at presentation. Patients that are anorectic and severely malnourished at presentation have a poor prognosis.

References

1.  Williams DA. Malabsorption, Small Intestinal Bacterial Overgrowth, and Protein-Losing Enteropathy. In: Strombeck DR, Guilford WG, Center SA, Meyer DJ. eds. Small Animal Gastroenterology. Philadelphia: W.B. Saunders, 1996;367-380.

2.  Kull PA, Hess RS, Craig LE, et al. Clinical, clinicopathologic, radiographic, and ultrasonographic characteristics of intestinal lymphangiectasia in dogs: 17 cases (1996-1998). J Am Vet Med Assoc 2001; 219:197-202.

3.  Littman MP, Dambach DM, Vaden SL, et al. Familial protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (1983-1997). J Vet Int Med 2000; 14:68-80.

4.  Karbach U, Ewe K, Bodenstein H. Alpha1-antitrypsin, a reliable endogenous marker for intestinal protein loss and its application in patients with Crohn's disease. Gut 1983; 24:718-723.

5.  Melgarejo T, Tamayo A, Williams DA. Fecal alpha1-protease inhibitor (α1-PI) for the diagnosis of canine protein-losing enteropathy. J Vet Int Med 1997; 11:115

6.  Fossum TW. Protein-losing enteropathy. Semin Vet Med Surg 1989; 4:219-225.