Ask the Expert: What are the recommendations for management of protein-losing enteropathy in dogs, including patients that are not corticosteroid responsive?
Canine protein-losing enteropathy (PLE) is a life-threatening clinical condition characterized by excessive protein loss across the intestinal mucosa.1 PLE in dogs can be caused by several conditions, including hypoadrenocorticism, neoplastic disorders, infectious disease, and mechanical and miscellaneous processes; however, the most common causes are chronic inflammatory enteropathy and intestinal lymphangiectasia, which can occur together. In one study, 76% of dogs with PLE and chronic inflammatory enteropathy also had histopathologic evidence of intestinal lymphangiectasia.1,2 Protein loss secondary to these disorders most likely occurs as a result of increased intestinal permeability; direct loss of protein can also occur due to mucosal injury or intestinal lymphatic dilation and dysfunction.
Dogs with PLE typically have a history of chronic relapse or progressive GI signs (eg, diarrhea, weight loss, decreased appetite, vomiting) and may have clinical signs associated with hypoalbuminemia (eg, ascites, pleural effusion, peripheral edema). The most commonly reported GI signs associated with PLE are diarrhea, weight loss, and decreased appetite. Vomiting is less common, and signs of GI bleeding (eg, hematochezia, melena) are rare. Additional uncommon signs may be related to systemic complications of PLE. Dogs with significant ionized hypocalcemia secondary to malabsorption of calcium and vitamin D may exhibit tremors or facial rubbing or develop focal or generalized seizures. Respiratory, neurologic, or musculoskeletal signs may occur as a result of thromboembolic disease. The cause of thromboembolic disease in dogs with PLE is poorly understood but likely related to loss of antithrombotic proteins and an inflammatory state.
Diagnosis
In cases of suspected PLE, other causes of hypoalbuminemia should be definitively excluded, the specific cause of PLE should be identified, and complications (eg, hypocobalaminemia, ionized hypocalcemia) and comorbidities should be screened for.
Urinalysis should be performed to screen for protein-losing nephropathy and exclude other causes of hypoalbuminemia. If proteinuria is identified, a urine protein:creatinine ratio should be performed to determine whether proteinuria is clinically significant. Bile acid testing should also be considered to exclude hepatic dysfunction as the cause of hypoalbuminemia but might be unnecessary in patients with panhypoproteinemia. Diagnostic tests aimed at identifying the cause of PLE include fecal testing (eg, fecal flotation), screening for hypoadrenocorticism (ie, basal cortisol ± adrenocorticotropic hormone stimulation test), diagnostic imaging (ie, abdominal ultrasonography ± thoracic and abdominal radiography), systemic infectious disease testing (depending on clinical suspicion and exposure), and intestinal biopsy and histopathology. Screening for exocrine pancreatic insufficiency with canine trypsin-like immunoreactivity, as well as for hypocobalaminemia and hypofolatemia, is also recommended. Ionized calcium should be evaluated in dogs with severely decreased total serum calcium or clinical signs of ionized hypocalcemia (eg, tremors, focal or generalized seizures, facial rubbing).
A complete diagnostic evaluation is critical because PLE often develops as a result of one or more specific disorders, and treatment should focus on the underlying disease process.
Treatment
In patients with chronic inflammatory enteropathy, treatment should aim to lessen the suspected immune reaction to endogenous or exogenous antigens in the GI tract. In patients with intestinal lymphangiectasia, the goal of treatment is to decrease the workload on the intestinal lymphatic system and reduce inflammation that may have been caused by lymphatic obstruction and leakage. There is no evidence for an autoimmune or immune-mediated pathogenesis in dogs with intestinal lymphangiectasia.
Dietary Management
Dietary management is the cornerstone of therapy for all dogs with PLE. Dietary modification has been successful as both a monotherapy and rescue therapy in patients that do not respond to glucocorticoid and immunosuppressive therapies.3-7 Even in cases of glucocorticoid-responsive PLE, appropriate dietary management is crucial for short- and long-term success.
In general, the ideal diet for dogs with PLE is highly digestible with an adequate amount of protein. For dogs with intestinal lymphangiectasia, the diet should also be low fat (ie, 16-25 g of fat/1,000 kcal) or ultra-low fat (≤15 g of fat/1,000 kcal); however, a thorough dietary history is crucial to determine the best approach in dogs with newly diagnosed or refractory PLE. Dogs with PLE caused by chronic inflammatory enteropathy may benefit from a hydrolyzed diet or a diet with novel protein and carbohydrate sources. Because intestinal lymphangiectasia can be challenging to diagnose, prioritization of a hydrolyzed diet comparatively lower in fat is recommended. A therapeutic, multifunctional, combination hydrolyzed/low-fat diet may also be the best option for dogs with histopathologic evidence of both chronic inflammatory enteropathy and intestinal lymphangiectasia, as well as in patients in which intestinal biopsy has not been performed and underlying disease is thus unknown. Some dogs with PLE seem to respond better to home-cooked or commercially available fresh food diets.
Lack of response to one dietary approach does not mean the patient will not respond positively to a different approach or that the condition will not improve with optimized dietary therapy. Dietary trials should be strictly performed; treats or palatability enhancers should only be added once the response to the specific dietary intervention has been determined. Dogs with GI disease often respond to a dietary therapy within 1 week; if no improvement is seen by then, another diet should be considered.
Pharmacologic Management & Other Treatment Strategies
Glucocorticoids are also indicated in many cases of PLE because of their anti-inflammatory and immunosuppressive effects. Prednisone/prednisolone (1-2 mg/kg PO every 24 hours) are commonly used and have been recommended for dogs with chronic inflammatory enteropathy2; however, literature-based and anecdotal evidence suggest higher doses of corticosteroids do not necessarily produce better outcomes.8 The author thus recommends not exceeding 1 mg/kg PO every 24 hours in any dog with PLE and considering a more conservative initial dose (0.5-0.75 mg/kg PO every 24 hours) if intestinal lymphangiectasia appears to be the primary cause of protein loss. In corticosteroid-responsive patients, the author tapers the drug by ≈25% after 3 to 4 weeks and again by 25% every ≈4 weeks until physiologic doses are reached (ie, a dose in the physiologic dose range that does not cause adverse effects). Once reached, the physiologic dose is continued for 3 to 4 months before being discontinued, and the condition is then controlled with diet alone. If clinical signs recur or albumin drops during tapering, prednisone/prednisolone can be temporarily increased to the previous effective dose as needed. If well tolerated, the increased dose can be continued long term. If the corticosteroid is not well tolerated at an effective dose, the patient can be transitioned to once-daily oral budesonide (based on body weight; 6.6-15.4 lb [3-7 kg]: 0.5-1 mg; 15.5-33 lb [7.1-15 kg]: 2 mg; 33.1-66 lb [15.1-30 kg]: 2-3 mg; ≥66.1 lb [≥30 kg]: 3-4 mg) for long-term management. Cyclosporine could also be considered for steroid-responsive cases in which the corticosteroid dose necessary to achieve remission is not tolerated, although the author prefers budesonide when tolerated and effective.
Additional management strategies include preventing complications (thromboprophylaxis should be considered; the author usually uses clopidogrel [2-3 mg/kg PO every 24 hours]), treating deficiencies (eg, hypocobalaminemia, hypovitaminosis D), and providing supportive care.9
Managing Patients Unresponsive to Corticosteroids
Some dogs with PLE have limited to no clinical or clinicopathologic response to anti-inflammatory or immunosuppressive doses of corticosteroids and second-line immunosuppressive agents. The author has not found considerable success with secondary immunosuppressive agents in dogs not responsive to corticosteroids, so typically does not use these medications for treatment of corticosteroid-refractory PLE. Many corticosteroid-refractory dogs with PLE improve clinically and clinicopathologically in response to specifically formulated home-cooked (or commercially available fresh food) diets.5,6 Such diets should be implemented in corticosteroid-refractory cases prior to secondary agent immunosuppressive therapies (if not already added). These diets are generally formulated to be both novel protein and lower in fat than commercially available kibble or canned diets. A dietary trial to assess clinical response can include equal parts of a lean novel protein (eg, cod, tilapia), white rice or pasta, and sweet potato—calculated based on body weight.10 If response is positive, follow-up with a board-certified veterinary nutritionist to ensure important nutrient requirements are met is critical for long-term management with home-cooked diets.
In the author’s experience, reducing the corticosteroid dose to ≤1 mg/kg PO every 24 hours and discontinuing any secondary immunosuppressive agents is also important in corticosteroid-refractory dogs with PLE. In the author’s clinical opinion, immunosuppressive therapies may prove detrimental in a subset of dogs with PLE because of possible clinical and clinicopathologic improvement after discontinuation of secondary immunosuppressive medications. The reason for this is unclear, but potential explanations include adverse effects of immunosuppression on lymphatic function or tight junctions, or increased susceptibility to bacterial translocation, which can lead to life-threatening secondary infections in immunocompromised patients.
Outcome
Traditional management strategies focused on immunosuppression have resulted in positive outcomes in ≈50% of dogs with PLE.1 Placing less emphasis on immunosuppression and more emphasis on dietary management can be key to success, particularly in dogs not considered corticosteroid responsive.