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Standards of Care November 2002 (Vol 4, No 10)

Protein-Losing Enteropathy

by Adam Gonzales, DVM, Mary Anna Labato, DVM, DACVIM (Small Animal)

    Introduction

    Protein-losing enteropathy (PLE) is a nonselective loss of proteins via the gastrointestinal (GI) tract. It is important to recognize that a multitude of diseases can result in a loss of proteins from the GI tract. Diseases that commonly cause GI ulceration, GI inflammation, or disorders in the intestinal hemolymphatic system (Table 1) may result in PLE. The clinical signs seen with PLE are related to the inciting cause and decreased protein (primarily albumin). The majority of PLE cases typically present as chronic disorders. Acute cases of PLE are usually related to an acute insult to the intestinal tract resulting in a severe enteritis or ulceration (e.g., parvoviral enteritis or hemorrhagic gastroenteritis).

    
PLE may be categorized into one of two broad categories: mucosal abnormalities (increased mucosal permeability or erosion/ulceration) or intestinal lymphangiectasia. A compromised intestinal mucosa results in the loss of serum and its proteins from the mucosal vasculature and/or mucosal interstitial space. On the other hand, intestinal lymphangiectasia results in the loss of chyle and its components from dilated or rupturing lacteals. In either case, significant amounts of protein loss can exceed the liver’s ability to compensate, resulting in hypoproteinemia.

    Lymphangiectasia and lymphocytic-plasmacytic enteritis are two of the most common causes of PLE. Lymphangiectasia is classified into primary lymphangiectasia (congenital abnormality) or secondary lymphangiectasia (Table 2). Primary lymphangiectasia results from an idiopathic abnormality of lymphatic drainage. Secondary lymphangiectasia is related to flow stasis and hypertension in the lymphatics resulting from venous hypertension or obstruction of the lymphatics. Many of the current management and diagnostic strategies focus on these two diseases because they are associated frequently with PLE.

    Cases of PLE typically vary in disease severity but are generally managed medically on an outpatient basis. However, disease complications can arise and lead to life-threatening or emergency situations. The complications encountered with PLE are usually related to the systemic effects of hypoalbuminemia, loss of other vital proteins such as antithrombin, and loss of or decreased absorption of electrolytes, minerals, or nutrients due to intestinal disease and malabsorption (Table 3).

    Table 1: Protein-Losing Enteropathy
    Table 2: Protein-Losing Enteropathy
    Table 3: Protein-Losing Enteropathy

    Diagnostic Criteria

    Historical Information

    
Gender and Age Predisposition: None

    Breed Predisposition:

    • Cats: None
    • Dogs: Yorkshire terriers, soft-coated wheaten terriers, Lundehunds, basenjis

    Owner Observations:

    • Weight loss
    • Anorexia
    • GI signs (vomiting/diarrhea)
    • Signs related to hypoalbuminemia (abdominal distention, peripheral edema, dyspnea due to pleural effusion)

    
Other Historical Considerations/Predispositions: GI signs may be absent.

    Physical Examination Findings

    
General

    Vary with the underlying cause(s) of PLE but can include:

    • Poor body condition
    • Muscle wasting/decreased body fat
    • Abdominal fluid wave
    • Peripheral edema
    • Thickened bowel loops
    • Lymphadenopathy
    • Dyspnea or increased respiratory effort secondary to pleural effusion or severe abdominal ascites
    • Seizure-like episodes or tetany resulting from a hypocalcemic state
    • Evidence of cardiac disease (heart murmur, jugular venous distention, abnormal lung sounds, arrhythmia)
    • Evidence of septic shock (febrile, weak pulses, tachycardia) or hypovolemic shock (tachycardia, weak pulses) secondary to complications such as septic peritonitis or hypovolemia from fluid loss in the GI tract or third spacing of fluids due to decreased oncotic pressure

    Laboratory Findings

    
Initial diagnostics should include a minimum database (complete blood count [CBC]/serum chemistry profile), urinalysis, fecal flotation, and cytology examination.
    CBC
    Occasionally lymphopenia due to the loss of lymphocytes in the chyle

    Serum Chemistry

    • Hypoalbuminemia
    • Hypoglobulinemia in most cases
    • Hypocholesterolemia (due to its loss in the chyle)
    • Hypocalcemia can be seen but usually corrects when a calcium correction is performed to account for low albumin. However, true cases of hypocalcemia can be seen and may require therapy if clinical signs are present.
    • Decreased serum magnesium levels

    
Urinalysis
    No significant proteinuria

    
Fecal Examination

    • GI parasite ova (hookworms, roundworms, whipworms)
    • Cytological evaluation for fungal or protozoal organisms

    
Coagulation Screening
    Antithrombin levels can be assessed to evaluate for decreased serum levels, which may predispose the patient to a hypercoagulable state. This is well documented in protein-losing nephropathy (PLN) but can also occur in PLE.

    Key To Costs

    Other Diagnostic Findings

    Radiography $

    • Abdominal radiographs may document obstruction or organomegaly. However, the presence of abdominal fluid may cause a loss of abdominal detail and limit the evaluation of the abdominal viscera.
    • Thoracic radiographs may show evidence of pleural effusion or changes in the cardiac silhouette or pulmonary vasculature suggestive of heart disease.

    
Ultrasonography $

    • Abdominal ultrasound is a useful modality in evaluating for abnormalities in the GI tract. Findings may reveal intestinal wall thickening and a hyperechoic mucosa layer, which is suggestive of an inflammatory condition or inflammatory bowel disease (IBD). Loss of layering in the intestines may also be found in infiltrative diseases such as neoplasia. Other findings can include mesenteric lymphadenopathy, hepatic or splenic changes, or evidence of thromboembolism in the vasculature.
    • In cases where GI obstruction is present, the etiology of the obstructive lesion (foreign body, intestinal mass, or intussusception) may be identified.

    
Thoracocentesis/Abdominocentesis $
    If fluid accumulation is found in the thoracic or abdominal cavity, a diagnostic centesis should be performed to obtain a fluid sample for analysis and cytology. Fluid analysis results are typically described as low-protein, pure transudate in cases of PLE.

    Fecal Alpha1-Proteinase Inhibitor Assay
    $
    Fecal alpha1-proteinase inhibitor assay is a protease inhibitor with a molecular weight similar to albumin. Alpha1-proteinase inhibitor is lost in the GI tract with other proteins in PLE and is excreted intact in the feces. It can be detected and quantified in the feces with a species-specific immunoassay. Increased quantities are detected in the feces in PLE cases.

    Endoscopy $$
    Endoscopy is the least invasive modality, which allows visual examination of the intestinal mucosa and facilitates acquisition of mucosal biopsies. Mucosal cytology and rectal scrapings can also be performed to evaluate for diseases such as histoplasmosis. Endoscopic examination reveals various gross findings from normal mucosa to irregular mucosa with a cobblestone-surface appearance or dilated mucosal lacteals in cases of lymphangiectasia. Mucosal biopsies are helpful in determining a cause such as lymphangiectasia or lymphocytic-plasmacytic enteritis.

    
Laparotomy or Laparoscopy $$$
    Abdominal exploratory surgery makes it possible to examine the entire intestinal tract and perform full thickness biopsies. The advantage of a laparotomy is that it provides an opportunity to thoroughly visualize and palpate the entire intestinal tract and surrounding organs. The disadvantage of a laparotomy is that a significant amount of protein loss can occur if a large amount of abdominal fluid is removed during the surgery. Laparoscopy has the advantage of being a less invasive method to obtain full thickness biopsies. The disadvantage to laparoscopy is that it only provides a limited visual evaluation of the intestinal tract and surrounding organs. With both procedures, poor tissue/incision healing can be an issue or lead to complications in a severely hypoproteinemic patient undergoing surgery and full thickness biopsies.

    Summary of Diagnostic Criteria

    • Panhypoproteinemia is the most consistent finding of PLE. However, in cases of basenji enteropathy, histoplasmosis, or hyperglobulinemia prior to protein loss, the globulin levels may be elevated or normal with a decreased albumin.
    • Intestinal biopsy is very informative and may be helpful in identifying the underlying cause. Biopsy results can document lymphocytic-plasmacytic enteritis, lymphangiectasia, neoplasia, or other inciting causes.
    • Elevated alpha1-antitrypsin excretion can confirm PLE and provide an objective measurement of protein loss.

    
Differential Diagnoses

    
In the presence of hypoalbuminemia, PLN, liver disease, and blood loss should be considered and excluded. Evaluating the minimum database, globulin values, and other diagnostic tests aids in establishing the diagnosis.

    • PLN should be ruled out by evaluating for proteinuria and performing a urine:protein creatinine ratio. Serum globulin values are typically normal. It is important to note that in some cases a concurrent PLN can be seen with PLE, similar to that described in soft-coated wheaten terriers.
    • Severe hepatic disease should be ruled out by determining bile acid levels to assess liver function. Serum globulin values can vary from normal to elevated.
    • Historical or physical exam evidence of bleeding or anemia is usually present in cases of blood loss.

    Treatment Recommendations

    Appropriate treatment and supportive care should be implemented for any identified cause that is found. In cases where an identified cause is not found, treatment should consist of nutritional management and antiinflammatory medical management. The two most common causes of PLE are IBD and lymphangiectasia. Treatment of the two diseases should include dietary management with glucocorticoid therapy or other immunosuppressive agents. In cases of histoplasmosis, antifungal therapy will be necessary.

    Diet $

    • Nutritional management typically involves the introduction of diets with a high-quality protein (high bioavailability) and a low fat content. Several prescription diets that can be used for the treatment of PLE are available.
    • Long-chain fatty acids should be minimized because they are absorbed by the lymphatics and can contribute to chyle production and lymphatic hypertension.
    • A homemade diet with a protein source (low-fat cottage cheese, boiled chicken breast) and carbohydrate source (boiled rice, baked potato, pasta) can also be used but should be evaluated for appropriate nutrient balance.
    • Parenteral nutrition should be considered in the initial management of cases where severe vomiting or diarrhea is present. Reports have shown increased serum protein levels, weight gain, and relief of symptoms while receiving parenteral nutrition support.

    Antiinflammatory Medication $

    • Metronidazole (10 to 15 mg/kg PO bid) can be used for its immunomodulating properties or to treat IBD or small intestinal bacterial overgrowth.
    • Glucocorticoid therapy can help inhibit inflammation and exert an immunosuppressive effect. Prednisone (2 to 3 mg/kg PO q24h) can be used. A slow tapering schedule should be used once a response to therapy is noted. Long-term maintenance is usually required.

    Stabilization or Emergency Procedures

    • 
Thoracocentesis may be indicated and oxygen therapy provided in dyspneic animals with compromising pleural effusion.
    • Dyspnea secondary to pulmonary thromboembolism requires oxygen therapy; aggressive management with heparin should be considered.
    • Hypocalcemia resulting in neuromuscular or cardiovascular abnormalities should be treated with calcium supplementation (calcium gluconate 10 mg/kg/h IV followed with oral supplementation).
    • Hypomagnesemia has also been reported to cause neuromuscular, cardiovascular, and metabolic abnormalities, and supplementation may be required. Recommended dose for magnesium sulfate is 1.0 mEq/kg/day IV.
    • Synthetic colloids may be necessary in animals with severe hypovolemia and hypotension to help improve oncotic pressure. Pretreating animals prior to anesthesia is also recommended in an attempt to minimize hypotension during anesthesia.

    Alternative/Optional Treatments/Therapy

    • In cases of IBD, if the patient is not responding to corticosteroids or is experiencing side effects to the medication, other immunosuppressive agents can be initiated. Azathioprine (2 mg/kg PO daily) can be used. After a response to therapy is seen, a tapering schedule should be started.
    • MCT oil can be supplemented to increase the calorie content in the diet if the patient continues to lose weight and be malnourished. A dose of 1 to 2 ml/kg/day PO can be used. However, because of palatability issues and possible occurrence of diarrhea, the use of MCT oil may be of limited use. 

    Supportive Treatment

    • 
Gastroprotectants (H2-receptor antagonists) can be used if gastric ulceration is a concern.
    • A broad-spectrum dewormer (fenbendazole 50 mg/kg PO once daily for 3 days) should be given as a prophylactic treatment in all cases.
    • If small intestinal bacterial overgrowth is present, vitamin B12 supplementation is recommended (300 to 400 µg SC once a week for 4 to 6 weeks, then once every 6 to 12 months).

    On The News Front: Protein-Losing Enteropathy

    Patient Monitoring

    • The body weight and caloric intake of the animal should be closely monitored with weekly body weight checks and reevaluation of the nutritional plan.
    • Serum albumin concentrations should be evaluated every 7 to 14 days.
    • Recheck examinations should be performed every 7 to 14 days to monitor for resolving or returning clinical signs (ascites, peripheral edema, pleural effusion).

    Home Management

    • Owners should keep a log recording the pet’s nutritional intake and appetite.
    • Owners should monitor for vomiting or diarrhea or record any improvement or deterioration in ongoing vomiting or diarrhea.
    • Respiratory rate and effort should be monitored for an increase in rate or effort.

    
Milestones/Recovery Timeframes

    • 
Serum protein levels should slowly start to increase and normalize with a response to therapy.
    • Body condition should improve and a documented weight gain should be seen.
    • Clinical signs such as ascites, peripheral edema, and diarrhea should begin to improve and/or resolve.

    Resource List: Protein-Losing Enteropathy

    
Treatment Contraindications

    
The risks and benefits of glucocorticoid therapy must be considered in cases of severe protein loss and antithrombin loss. Severe antithrombin loss may result in a hypercoagulable state, which may be compounded with the use of steroids because steroids can also predispose animals to a hypercoagulable state. Glucocorticoids can also have a catabolic effect on metabolism, which is a major concern in animals that are already malnourished and in a catabolic state.

    Prognosis

    • Depends on the underlying disease and its severity
    • Fair to guarded prognosis for inflammatory causes

    Favorable Criteria

    • Treatable underlying cause
    • Responds well to initial therapy

    
Unfavorable Criteria

    • Patient continues to have GI signs
    • Patient continues to lose weight or is malnourished
    • Relapse of the disease
    • Thromboembolism

    Bonagura JD: Kirk’s Current Veterinary Therapy XIII: Small Animal Practice. Philadelphia, WB Saunders, 2000, pp 641–643.

    Ettinger SJ, Feldman EC: Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders, 2000, pp 1201–1202.

    Fossum TW: Protein-losing enteropathy. Semin Vet Med Surg (Small Anim) 4(3):219–225, 1989.

    Strombeck DR: Strombeck’s Small Animal Gastroenterology. Philadelphia, WB Saunders, 1996, pp 375–378.

    Tams TR, Twedt DC: Canine protein-losing gastroenteropathy syndrome. Compend Contin Educ Pract Vet 3:105–114, 1981.

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