Overview
Chronic intestinal protein loss is a sign of failure of digestive function that may result from severe acute or chronic inflammatory lesions or from a disruption of chyle absorption and intestinal lymph flow. While the exact mechanisms leading to intestinal protein loss have not been elucidated in the dog, the three basic mechanisms defined for humans with protein-losing enteropathy (PLE) likely also apply to canine PLE. It is frequently associated with severe chronic idiopathic inflammatory enteropathies such as inflammatory bowel disease (IBD) or with idiopathic intestinal lymphangiectasia in specific breeds. Protein loss may result from: 1) erosive or ulcerative mucosal lesions causing secondary exudation of proteins; 2) lymphatic dysfunction causing leakage of protein-rich lymph into the intestinal lumen; 3) mucosal changes disturbing the mucosal barrier, causing abnormal permeability and protein leakage into the lumen; or 4) a combination of all three of the previously listed conditions.
This presentation will focus on chronic intestinal disorders associated with intestinal protein loss in dogs and the dietary and medical treatments for this condition.
Diagnostic Approach
Dogs with PLE often present with typical clinical signs of chronic intermittent small intestinal diarrhea with possible vomiting. In severe cases, hyporexia/anorexia and malnutrition with evidence of malabsorption and weight loss may be observed. However, significant intestinal protein loss and hypoalbuminemia may also occur without obvious diarrheic episodes. In the presence of severe hypoalbuminemia (serum albumin <20 g/1, often ≤15 g/1) the main complaint may relate to significantly decreased oncotic pressure (cavitary effusion, subcutaneous edema).
The first diagnostic challenge consists in establishing the origin of the protein loss by ruling out other processes such as protein-losing nephropathy or liver failure. Generally, PLE is associated with panhypoproteinemia due to non-selective intestinal protein loss, but exceptions may occur. Other common abnormalities of dogs with PLE include hypocholesterolemia, hypocalcemia (total and free/ionized), hypomagnesemia, lymphopenia, and hypocobalaminemia.
Once the GI tract has been confirmed as the site of protein loss, further work-up should include abdominal ultrasound, a technique with acceptable sensitivity that often helps assessing severity and anatomic distribution of intestinal lesions. Hyperechogenic mucosal striations are frequently observed in dogs with PLE, and appear to be quite specific.
Diagnosing the cause of PLE requires histopathologic analysis of intestinal biopsies. However, dogs with severe hypoalbuminemia are often poor anesthetic candidates, and it is sometimes preferable to avoid taking excessive risks and postpone endoscopy or surgery. Additionally, many dogs with PLE have bicavitary effusion, and thoracic radiographs are recommended as a screening tool for the presence of thoracic effusion, as it may represent an additional anesthetic risk. Synthetic colloids such as 6% hetastarch solutions are very useful in order to acutely increase oncotic pressure in critical cases (1 ml/kg/h or 25 mg/kg/day). Transfusions with human albumin have been recommended in the recent past for partial restoration of serum albumin concentration and minimizing the risks of general anesthesia, but are unfortunately associated with immune-mediated vasculitis in approximately 10% of recipients (5% human albumin at 2 ml/kg/h during 10 h/day, total daily volume of 20 ml/kg/day).
Causes of PLE
Diseases frequently associated with PLE include intestinal lymphangiectasia, IBD, and chronic enteropathies with significant mucosal architectural lesions. Moreover, alimentary lymphoma and fungal infections (histoplasmosis) may also cause PLE.
Intestinal Lymphangiectasia (IL)
Primary Idiopathic IL: breeds such as Yorkshire Terriers, Chinese Shar-Peis, Maltese Terriers, Norwegian Lundehunds, and Rottweilers are predisposed. The pathogenesis of primary IL is still poorly understood. It results from obstruction to the flow of lymph in the intestinal wall, and has been associated with granulomas obstructing lymph vessels located in in the deep layers of the intestinal wall. Secondary IL is commonly associated with significant intestinal mucosal inflammation (e.g., IBD) and neoplasia (alimentary lymphoma) that increase tissue pressure and prevent lymph flow in the lamina propria.
Inflammatory Bowel Disease (IBD)
The inflammatory process located in the GI mucosa may lead to protein loss both by preventing the absorption of nutrients and by compromising the integrity of the intestinal mucosal barrier leading to exudation of proteins into the intestinal lumen. PLE of Soft-coated Wheaten Terriers is a specific form of IBD affecting this breed worldwide. In approximately 50% of these dogs, PLE and protein-losing nephropathy (PLN) occur concurrently. The pathogenesis of PLE in these dogs includes a dietary hypersensitivity component.
Crypt Disease
Crypt dilation and necrosis have been frequently associated with PLE. Dogs with small intestinal crypt abscesses have significant hypoalbuminemia and ultrasound changes of their intestinal mucosa, and their clinical presentation is generally severe.
Therapy
Diet
Dogs with PLE are in a catabolic state, and adequate nutrition is essential. Dietary modification centers on feeding a highly digestible diet with low to very low fat content of less than 20% on a metabolizable energy (ME) basis (this is equivalent to less than 10%on a dry matter [OM] basis) to prevent further dilation and rupture of lacteals. Many common intestinal support diets may be too high in fat (have between 20–30% fat ME, which is between 10–15% fat on an OM basis) and may perpetuate the lacteal dilation despite initiation of other medical managements. Feeding higher fat diets should be avoided during the initial course of treatment whenever possible. Additionally, the diet should contain highly bioavailable dietary proteins and be low in crude fiber (less than 2% crude fiber on an OM basis).
The long-term dietary strategy will depend on whether the animal has a primary fat malabsorption (primary idiopathic IL) or fat malabsorption secondary to an intestinal inflammatory condition (PLE associated with underlying IBD). In dogs with primary idiopathic IL, feeding a highly digestible, fat-restricted diet (i.e., less than 20% fat ME) may be required life-long. In dogs with PLE associated with underlying IBD, good success has been reported with exclusive feeding of low- to moderate-fat diets consisting of either hydrolyzed or novel protein diets. Diet selection should be based on a detailed diet history including all treats and supplements that have been fed in the past. Diet history information may not be readily available during the initial course of treatment and starting with a hydrolyzed protein diet would be prudent until a more detailed diet history can be obtained. In dogs with PLE associated with underlying IBD feeding of fat-restricted diets may not be required for long-term management.
Acceptance of the diet is a critical issue in PLE dogs, particularly in the most severely affected animals, which may be anorexic. Initially, it might be more important to feed a less optimal diet that the dog will be interested in eating, and progressively transition to a more desirable diet. Home-prepared diet formulations may be required for animals requiring both fat restriction and a novel ingredient diet for long-term management.
Management of Inflammation
In dogs with primary IL, anti-inflammatory glucocorticoid therapy (e.g., prednisone at 1 mg/kg/day) is useful and often required for proper management of the disease. Its main desired effect is to decrease inflammation associated with lipogranulomas secondary to chyle leakage and therefore help restoring an adequate flow in intestinal lymphatics. In some dogs, anti-inflammatory treatment can be slowly weaned off over 2–3 months or longer.
Immunosuppressive Therapy
Immunosuppression is the basis for treatment of severe IBD with PLE. The first approach consists of administering prednisone or prednisolone initially at 2 mg/kg q 12 h during 3–5 days, then 2 mg/kg once daily until the dog’s condition has significantly improved and appears stable (clinical improvement and serum albumin reliably >20 g/L). Subsequently the dose can be decreased in 2-week steps with 1 mg/kg/day, then 1 mg/kg every other day and so on.
Other corticosteroids: budesonide is known to be locally efficient and undergo high first pass hepatic metabolism in people, making systemic complications of steroid treatment less likely. In dogs, the drug significantly influences the pituitary-adrenal axis. A recent study reported that budesonide was efficacious in the treatment of canine IBD. The recommended doses are 0.5–3 mg/dog daily (depending on the dog’s size).Concurrent use with other glucocorticoids is not recommended.
Chlorambucil has recently been shown to be more effective when used with prednisolone than a combination of azathioprine and prednisolone in dogs with chronic enteropathies and severe PLE. The survival was greatly improved in dogs receiving the chlorambucil combination. The recommended initial canine dose of chlorambucil is approximately 4 mg/m2 q 24–48 h, and it comes in 2 mg tablets (the drug will need to be appropriately reformulated or compounded for small dogs). Side effects of chlorambucil are rare and include bone marrow suppression. A CBC should be performed after 1 and 3 weeks of treatment and repeated every 2–3 months or if the dog’s condition deteriorates to look for neutropenia.
Cyclosporine has been shown to be successful in a proportion of dogs with steroid-refractory IBD (5 mg/kg PO once daily). Transient adverse effects including include vomiting and loss of appetite, hair coat changes, and gingival hyperplasia may be seen during the first 2 weeks of treatment in approximately ¼ of the dogs and. Most side effects respond to temporary discontinuation followed by dose-reduction.
Complications
Hypocobalaminemia
Low serum cobalamin concentrations are commonly found in dogs with PLE, especially in the presence of underlying IBD, and may delay proper healing of intestinal inflammation. Treatment consists of weekly SC injections of vitamin B12 (from 250 to 1500 µg/dog based on body weight) for 6 weeks. If the treatment is successful, the interval between injections may be increased to 2 weeks for another 6 weeks. The full dosing schedule can be viewed on the site of the Texas A&M University GI Laboratory website (http://vetmed.tamu.edu/gilab). Interestingly, a study published in early 2016 reported that oral administration of vitamin B12 is likely to be effective in dogs with chronic intestinal diseases (0.25 mg q 24 h in dogs weighing 1–10 kg , 0.5 mg q 24 h in 10–20 kg dogs , and 1 mg q 24 h for dogs >20 kg).
Hypercoagulability
Studies have revealed a high prevalence of hypercoagulability in dogs with PLE, which increases the risk of potentially fatal thromboembolic events. However, hypercoagulability does not appear to resolve after successful treatment of PLE. Although there is no scientific evidence to support this, administration of clopidogrel (1–5 mg/kg/day) may be considered in order to prevent thrombosis.
Hypocalcemia
Because 50% of serum calcium is bound to albumin a decrease in serum total calcium is expected with severe hypoalbuminemia. Additionally, malabsorption of fat-soluble vitamins occurs along with the dietary fat malabsorption associated with PLE and low serum ionized calcium concentration, low 25–hydroxyvitamin D, and increased levels of parathyroid hormone are found in dogs with PLE. In dogs with a moderate to severe decrease in ionized calcium, treatment with calcium (e.g., calcium carbonate between 1 g [toy breeds] and 10 g [giant breeds] PO per dog q 24 h ) is recommended, possibly with addition of calcitriol (0.03–0.06 micrograms PO q 24 h) if calcium alone is not successful. Regular rechecks of serum ionized calcium are required for adequate monitoring, particularly to prevent hypercalcemia. Hypovitaminosis D was associated with a negative outcome in a recent retrospective study. Concurrent hypomagnesemia may compromise the success of treatment and should be corrected if present.
Prognosis
In two studies encompassing a total of 150 dogs with chronic enteropathies, hypoalbuminemia (serum albumin <20 g/l) was associated with a less favorable outcome.
Idiopathic Intestinal Lymphangiectasia
Preliminary reports from a few studies show a high mortality among Yorkshire Terriers with IL (50–60%). In one of the author’s practice (FG), some Yorkshire Terriers with IL respond well to a strict diet alone or with anti-inflammatory doses of glucocorticoids. The proportion of refractory cases seems to vary according to geographical location. There are no known parameters that allow early segregation of dogs likely to be refractory to dietary and steroid treatment. In the other author’s practice (LW), feeding of fat-restricted and novel protein (both plant and animal derived) home-prepared diets leads to improved outcomes for dogs with PLE.
Crypt Disease
The presence of crypt abscesses in the small intestine was associated with significantly shorter survival in a study from one of the author’s (FG) group.
References
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