Protein Losing Enteropathy in Dogs & Cats
Excessive loss of plasma and other protein-containing tissues into the gastrointestinal tract is referred to as protein losing enteropathy. Protein-losing enteropathy occurs in association with numerous gastrointestinal and systemic disorders including idiopathic inflammatory enteropathies such as lymphocytic-plasmacytic, eosinophilic or granulomatous gastroenteritis, gastrointestinal cancer, foreign bodies, intussuceptions, SIBO (see above), parasitic and fungal enteropathies, acute infectious (viral or bacterial) enteritis, non- specific enteritis,immune-mediated and allergic diseases.
Plasma proteins (there are two types albumen and globulin) normally turn over with half-lives that vary from 8 to 10 days. Albumin is synthesized by the liver, and this function accounts for about 25% of all protein the liver produces. The liver is able to increase the rate of synthesis slightly (no more than two fold) in the face of increased loss of albumin, provided that the required nutrients are provided. The most important site of albumin degradation is unknown. Degradation by the liver and intestine are each believed to accounts for about 10% of the total turnover.
The mechanism for protein loss in protein-losing enteropathy may be related to inflammation or erosion affecting the normal barrier function of the gut, or to acquired or congenital abnormalities in intestinal lymphatic or vascular drainage. Protein-losing enteropathy often arises as a consequence of disruption of absorptive mechanisms of the small intestine . The mucosa of the small and large intestines forms a semipermeable barrier that controls the movement of fluid and electrolytes and restricts that of larger molecules, including proteins, whether they are in the intestinal lumen or on the capillary side of the cell. However, the intestinal lining provides only a minor barrier to the loss of plasma proteins from the body.
The source of the enteric protein loss in protein- losing enteropathy is either the lining blood supply or the area between the cells. Normally, one-third to one-half of plasma proteins are found inside the vascular system , with the remainder outside the blood stream . Cells lining the blood supply in intestinal mucosa have large openings that readily permit molecules to move into the space between cells. In addition, this space is accommodates large amounts of plasma protein. Alteration of the of the intestinal lining by disease results in loss of these plasma proteins into the intestinal lumen. Thus when plasma proteins are lost into the intestinal tract, both albumin and globulins are lost at an equal rate. The resultant hypoalbuminemia and hypoglobulinemia (low protein) is characteristic of protein-losing enteropathies and helps differentiate them from the low of kidneys and liver disease which is usually characterized by hypoalbuminemia (one type of protein) alone.
Protein can be lost into the stomach and intestine without evidence of any damage to the mucosa. Additional factors of potential importance in intestinal protein loss include inflammatory cells in the intestinal lining, as well as frank hemorrhage or oozing of tissue fluids across ulcerated surfaces. cells.
The most important protein-losing gastroenteropathies are associated with chronic inflammatory diseases and circulatory diseases such as impaired drainage of lymph glands of the digestive tract. When loss of plasma proteins is by protein-losing enteropathy due to inflammation, there are often associated clinical signs of gastrointestinal disease such as vomiting, loss of appetite or diarrhea that suggest an underlying problem in the gastrointestinal tract
Protein-losing enteropathy is one mechanism contributing to weight loss in gastrointestinal disease. In some cases there is severe loss of proteins such that the body can not maintain proper plasma protein concentrations. This may be so sever that fluid will accumulate in the abdominal cavity or chest.
Primary Intestinal Lymphangiectasia (improper lymph gland drainage)
This congenital intestinal disorder is arises as a consequence of an unknown abnormality of' lymphatic drainage. It is characterized histologically by a ballooning dilation of the the lymphatic vessels. The disorder is a prominent feature of the associated with protein losing enteropathy in the Lundehund, but the disease is not confined to this breed. Total lymph flow is reduced because the numbers of lymphatic vessels are insufficient to remove fluid between the cells fluid. In some canine patients the lymphatic abnormalities are not confined to the gastrointestinal tract, probably indicating diffuse developmental defects in the lymphatic system.
Secondary Intestinal Lymphangiectasia
The lymphatic stasis that apparently develops in adult animals is usually associated with obstructive lesions developing throughout the lymphatics.
Lymphatic stasis in congestive heart failure
Animals with protein-losing enteropathies usually exhibit signs of weight loss (muscle wasting and decreased body fat). There may be vomiting and diarrhea but these signs are by no means always seen, and it should be emphasized that failure to exhibit diarrhea or other characteristic signs of gastrointestinal disease does not eliminate the possibility of protein-losing enteropathy.
Signs related to the underlying disease responsible for protein-losing enteropathy may be present, and physical examination may reveal evidence of thickened bowel loops, an abdominal mass, or cardiac abnormalities. If hypoalbuminemia is severe then this may be responsible for the sole presenting signs (swelling of the limbs,fluid accumulation in the abdominal cavity, or difficult breathing due to fluid accumulation in the chest cavity). Limb swelling and fluid accumulation in the abdomen are generally present when the serum albumin concentration decreases to 1.0 g/dl.
Unless a specific diagnosis is made based upon history, physical examination, or results of a complete blood count, serum biochemical profile, urinalysis, or fecal examination for parasites etc., diagnosis is at present most commonly made by elimination of liver disease (serum bile acids) and protein losing nephropathy (urinalysis and if necessary urine protein to creatinine ratio) as causes of low albumin. If low globulin accompanies low albumin then protein- losing enteropathy is nearly always the cause of low albumin, since low globulin is very rarely seen with protein loosing nephropathy. However, not all patients with protein-losing enteropathy will have low globulin, since for example in histoplasmosis the systemic infection may lead to a significant. increase in globulin production as part of the inflammatory response. Serum cobalamine and Iblate concentrations, or results of breath hydrogen testing or testing of intestinal permeability may provide additional evidence for gastrointestinal disease.
The protein-losing enteropathy reported in Basenji dogs is unusual in that it is characterized by high globulin and low albumin. A recently reported protein-losing enteropathy in Soft-coated Wheaten Terriers that it appears to be accompanied by coexistent protein-losing nephropathy. In many cases there is protein loss from the stomach, as well as from the intestine , and so the term protein-losing gastroenteropathies may be a more accurate one.
Low calcium is sometimes present. This finding is primarily a reflection of decreased serum albumin Vitamin D malabsorption may also play a role in the hypocalcemia, but the intestinal absorption of calcium has been reported to be normal in humans with lymphangiectasia. Low cholesterolemia is common in dogs with lymphangiectasia, and presumably results from the fat mal absorption The classical gold standard for diagnosis of protein-losing enteropathy is to quantitative loss of radioactive (51Cr-labeled) albumin into the gastrointestinal tract. Obvious technical constraints (separating urine from feces, prolonged hospitalization in a metabolism cage in a facility approved for radioisotope use), safety concerns related to exposure to radioisotope, aesthetic considerations related to handling large volumes of feces, and expense have all limited the application of this approach.
Assay of a1-protcasc inhibitor (a1-PI) in a single sample of feces has been shown to be a reliable method to detect protein-losing enteropathy in human patients.
There are substantial species differences in the antigenic determinants of a1-PI, and specific immunologic methods usually need to be developed for each species. A commercially available kit for human a1-PI unfortunately does not detect canine a1-Pl. Preliminary investigation of a radial immunodiffusion assay for canine al-PI showed concentrations in feces to be increased in dogs with protein-losing enteropathy and prompted development of a more sensitive and accurate immunoassay. Assay of canine a1-PI is currently being used in the author's laboratory to study the fate of a1-PI lost into the lumen of the canine gastrointestinal tract. The method shows promise as a new test for the diagnosis of protein-losing enteropathy in dogs and for indirect quantitation of enteric protein loss.
Ideally the presence of suspected gastroenteropathy is confirmed by identification of the underlying cause and/or by gastrointestinal biopsy. 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 disease. Certainly, full- thickness biopsy is required to document sub- mucosal lymphatic obstruction in patients with primary or secondary intestinal lymphangiectasia. The risk of surgical break down of full thickness biopsies in debilitated low albumin animals is minimized if' nonabsorbable suture material is used, and this complication is rare.
In many cases the diagnosis is presumptive, since either patients are poor candidates for anesthesia and intestinal biopsy because of malnutrition and hypoproteinemia, or the expense of plasma transfusion and exploratory surgery or endoscopy is prohibitive.
Recovery from acute protein-losing enteropathies associated with infectious arid parasitic enteropathies is rapid following specific treatment (parasitic enteropathies) and often self limiting (viral enteritis) providing supportive care is provided.
Treatment of chronic protein-losing enteropathies is directed at the underlying disease, if identified. Surgical removal of localized gastric or enteric chronic inflammatory, ulcerative, or neoplastic lesions can successfully halt enteric protein loss. In many instances the underlying abnormality cannot be corrected, however in such patients non-specific treatment, including feeding a high quality protein, low fat content diet (to minimize distension of intestinal lymphatic vessels) is helpful. In some instances feeding a single source of carbohydrate and a single source of protein (such as a rice arid low fat cottage cheese based diet) is beneficial. Dietary triglycerides containing long-chain fatty acids must be minimized because absorption of long-chain triglyceride is a major stimulus for intestinal lymph flow. Restriction of dietary long-chain triglyceride reduces lymphatic distension and thereby reduces gastrointestinal protein loss.
The caloric content of the diet may be increased by supplementation with medium chain triglyceride oil (Mead Johnson, Evansville, IN) at a dose of 1- 2 mL/kg per day. Medium-chain triglycerides are readily hydrolyzed by pancreatic lipase, but a considerable proportion of medium-chain triglyceride is absorbed intact without prior lipolysis. Medium chain fatty acid are an alternative-but very expensive and not palatable. An alternative to medium chain triglyceride oil is a powdered elemental diet mix (Portagen, Mead Johnson, Evansville, IN) (1 Y cups added to water to make a 1 quart mixture that contains 1 calorie/mL).
Steroid therapy (to inhibit inflammation, exert an immunosuppressive effect, and to promote enterocyte function) is also often given and appears effective provided that specific infectious or obstructive enteropathies are not present. In patients that respond poorly to steroids or in which adverse side effects of therapy are unacceptable, immunosuppressive agents such as azathioprine or chlorambucil may be effective.
Plasma administration is usually of no long-term value since alleviation of hypoproteinemia is only transient. Plasma transfusion is of value immediately prior to general anesthesia however, in order to minimize risk of hypotension when vascular compensatory mechanisms are inhibited. Enhanced intestinal fibrinolytic activity has been reported in mucosal biopsies from some human patients with refractory protein losing enteropathy. Some human patients reportedly respond to antifibrinolytic therapy with agents such as mans-4-arninomethyl cyclohexane carboxylic acid. There are no reports of this approach to therapy in canine or feline patients with protein-losing enteropathy.
Unfortunately there are few reports of long-term follow up of dogs or cats with protein-losing enteropathy. The effectiveness of the above- mentioned therapeutic measures has not been documented, and is largely anecdotal. It is hoped that availability of an assay for canine a1-PI will facilitate objective evaluation of different therapeutic options. In general however, the prognosis for protein-losing enteropathies of inflammatory origin is guarded. Lifelong management will probably be required. Many patients with severe inflammatory bowel disease will eventually respond. but the therapy is often protracted and may need to be life long. Lymphangiectasia (lymph flow abnormalities) also carries a guarded prognosis. Response to therapy is unpredictable, and is dependent to a large extent on the severity of the disease process at presentation. Patients that are inappetant and severely malnourished at presentation should receive a poor prognosis.
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