Definition

• Any disease process that is characterized by excessive loss of protein into the gastrointestinal lumen.
• Diseases associated with PLE include primary gastrointestinal diseases such as inflammatory bowel disease, intestinal lymphoma, or intestinal lymphangiectasia and systemic disorders such as congestive heart failure.

Pathophysiology

• Under physiologic conditions, two-thirds of normal protein loss in dogs occurs through the small intestine.
• Plasma proteins that leak into the gastrointestinal lumen are rapidly digested into constituent amino acids that can then be reabsorbed and used for the synthesis of new proteins.
• This normal loss of plasma proteins can be accelerated by gastrointestinal mucosal disease or by increased leakage of lymph into the gastrointestinal lumen.
• Gastrointestinal protein loss is associated with loss of both albumin and globulin.
• In response to increased gastrointestinal protein loss, the liver increases albumin synthesis. However, the liver cannot increase albumin synthesis to more than twice the normal output.
• When protein loss exceeds protein synthesis, hypoproteinemia results.
• Severe hypoproteinemia causes decreased plasma oncotic pressure, which may be associated with hemodynamic changes and may lead to effusion into body cavities or, less commonly, peripheral edema.
• Dogs and cats with PLE are not always panhypoproteinemic, and can have low-normal serum globulin concentrations with hypoalbuminemia.

Systems Affected

• Coagulation-patients with PLE also lose antithrombin and may be hypercoagulable.
• Gastrointestinal-primary gastrointestinal disease that may be associated with diarrhea, vomiting, or other clinical signs of GI disease.
• Hemodynamic-ascites or pleural effusion due to decreased oncotic pressure leading to abdominal discomfort or even dyspnea.
• Lymphatic-lymphangiectasia.
• Respiratory-dyspnea due to pleural effusion.
• Skin-subcutaneous edema.

Genetics

A hereditary nature of PLE due to specific underlying causes is suspected, based on an increased prevalence of such conditions in specific dog breeds.

Incidence/Prevalence

• The true incidence and prevalence are unknown.
• Many dogs with subacute or acute gastroenteritis have transient PLE.

Signalment

Signs

Causes

Risk Factors

• Gastrointestinal disease
• Lymphatic disease
• Heart disease

Differential Diagnosis

• Hypoalbuminemia due to PLE must be differentiated from other causes of hypoalbuminemia.
• Hypoalbuminemia due to hepatic failure is most often associated with a normal or even increased serum globulin concentration. Hepatic enzyme activities may be increased, serum BUN, cholesterol, and even glucose may be decreased, and serum pre- and postprandial bile acids concentrations may also be increased.
• Hypoalbuminemia due to PLN: mild in patients with fever or hyperadrenocorticism, moderate to severe in patients with glomerulonephritis or amyloidosis; is commonly associated with a normal or even increased serum globulin concentration-ruled out by a normal urine protein:creatinine ratio.
• Hypoalbuminemia due to severe blood loss is associated with hypoglobulinemia-blood loss can be excluded by assessment of erythrogram on CBC and a thorough physical examination; in some cases a test for fecal occult blood may be necessary.
• Inadequate protein intake (i.e., starvation) is a rare cause of hypoalbuminemia.
• Hypoalbuminemia due to PLE is often associated with hypoglobulinemia-confirmed by an increased fecal ₁-protease inhibitor concentration (must be assessed in naturally passed and freshly frozen fecal samples from 3 consecutive days).

CBC/Biochemistry/Urinalysis

• Hypoalbuminemia and frequently hypoglobulinemia (panhypoproteinemia).
• A normal or increased serum globulin concentration in some cases, when the underlying disease is associated with chronic antigenic stimulation (e.g., immunoproliferative enteropathy of the Basenji).
• Hypocalcemia-secondary to hypoalbuminemia.
• Hypocholesterolemia can be seen.
• Lymphopenia may be seen with lymphangiectasia.

Other Laboratory Tests

• Increased fecal ₁-protease inhibitor concentration.
• Once PLE has been identified as the cause of the hypoalbuminemia, specific tests may be useful to determine the specific cause of PLE-multiple fecal examinations (smears and centrifugation flotations) to rule-out intestinal parasitism as a cause of PLE; serum cobalamin and folate concentrations to diagnose small intestinal dysbiosis or cobalamin deficiency.

Imaging

• Thoracic radiographs may show evidence for cardiac or fungal disease.
• Abdominal radiographs may show evidence for a mechanical enteropathy or other causes of PLE.
• Abdominal ultrasound also may show evidence for a mechanical enteropathy or other causes of PLE.
• Abdominal ultrasound is helpful for evaluating the intestinal wall layering pattern associated with a variety of enteropathies. A hyperechoic linear or “tiger stripe” effect associated with distension of intestinal lacteals with lymph fluid can be seen in many dogs with lymphangiectasia and is characterized by hyperechoic lacteals extending from the lumen of the bowel to the submucosal layer.
• Cardiac ultrasound may show evidence for cardiac disease.

Diagnostic Procedures

• Broad-spectrum anthelminthic agent-to treat for potential parasitism with a variety of gastrointestinal endoparasites.
• Feeding trial of an elimination diet containing an intact protein source or hydrolyzed protein source-to rule out adverse reactions to food.
• Rectal mucosal scraping-to help rule out histoplasmosis in geographic regions where histoplasmosis is endemic.
• Gastroduodenoscopy and colonoscopy-to visualize the gastrointestinal mucosa and to collect endoscopic biopsies for histopathologic evaluation. Visualizing white “plaques” (e.g., chylomicron distended lacteals) along the mucosa suggests lymphangiectasia. Endoscopic biopsies should contain full-thickness mucosa to maximize the diagnostic yield of tissue specimens.
• Abdominal exploratory laparotomy may show dilated intestinal lymphatics and allows for full-thickness biopsies of intestines and lymph nodes.
• Fecal ₁-protease inhibitor concentration to document excessive gastrointestinal protein loss. ₁-protease inhibitor is a plasma protein with a similar molecular weight to albumin and is thus lost at a similar rate to albumin. Assays for the measurement of ₁-protease inhibitor are species-specific for dogs and cats and are only available through the Gastrointestinal Laboratory at Texas A&M University. Samples from 3 consecutive defecations need to be collected in special pre-weighed fecal tubes that can be sourced from the GI Lab.

Pathologic Findings

PLE is not associated with any specific gross or histopathologic lesions. Lesions identified are those of the specific cause of PLE.

Nursing Care

• In cases of severe hypoalbuminemia that are associated with clinical signs due to edema or effusion plasma transfusions or colloids (such as hetastarch or dextran) should be considered to increase plasma oncotic pressure.
• Abdominocentesis to remove ascites or pleurocentesis to remove pleural effusion in cases with compromise from severe effusion.

Activity

Normal

Diet

• May need to be modified depending on the underlying cause of PLE.
• If lymphangiectasia is diagnosed or highly suspected, a low-fat diet that contains <25% fat in a ME basis should be used. An elemental diet can also be used in patients with severe disease.

Client Education

Prepare clients for long-term therapy; spontaneous cures are rare.

Surgical Considerations

• Hypoalbuminemia increases postoperative morbidity because of slow wound healing.
• Some causes of PLE (e.g., intussusception, chronic foreign body, and some intestinal neoplasias), however, require surgical intervention.

Drug(s) Of Choice

• There is no pharmacologic therapy for PLE itself. Instead, the underlying cause of PLE must be addressed. See “Treatment” for these conditions.
• However, patients with PLE also lose antithrombin and can be hypercoagulable. Thus, patients should be treated with a platelet aggregation inhibitor:
  • In dogs or cats: clopidogrel bisulfate (3–5 mg/kg PO q24h in dogs; 18.75 mg/cat PO q24h, which equals one-fourth of a 75-mg tablet).
  • In dogs: low-dose aspirin (0.5 mg/kg q12h PO; use an 81-mg tablet of aspirin and put into the barrel of a 10-mL syringe, add 8.1 mL of water and shake until completely dissolved to make a 10-mg/mL solution; discard unused portion immediately).

Contraindications

• Aspirin and clopidogrel should not be used concurrently.
• Clopidogrel should not be used with other NSAIDs, phenytoin, torsemide, or warfarin.

Precautions

Bleeding may be enhanced in patients treated with platelet aggregation inhibitors that have to undergo surgery.

Alternative Drug(s)

• Diuretics such as furosemide (1 mg/kg PO q12h) in combination with spironolactone (1 mg/kg PO q12h) have been used by some clinicians to control edema, pleural effusion, and ascites. However, they do not work consistently in patients with PLE because of decreased plasma oncotic pressure and may be associated with side effects.
• There are anecdotal reports about the use of the long-acting somatostatin analogue octreotide in dogs with PLE, but no clinical trials have been completed to date.

Patient Monitoring

Check body weight, serum albumin concentration, and evidence of recurrent clinical signs (i.e., pleural effusion, ascites, and/or edema). Frequency depends on the severity of the condition. Monitor serum cobalamin concentrations after initial 6-week induction phase of weekly administrations.

Possible Complications

• Respiratory difficulty from pleural effusion
• Severe protein-calorie malnutrition
• Intractable diarrhea

Expected Course and Prognosis

• Prognosis is guarded and depends on the underlying cause. Smaller breed dogs carry a more favorable prognosis because nutritional support is easier to perform.
• The primary disease cannot be treated in many cases.

Associated Conditions

Soft-coated Wheaten terriers may have PLN in conjunction with PLE and should be evaluated accordingly.

Zoonotic Potential

Histoplasmosis, hookworms, and coccidia have zoonotic potential to humans.

Abbreviations

• GI = gastrointestinal
• NSAID = nonsteroidal anti-inflammatory drug
• PCV = packed cell volume
• PLE = protein-losing enteropathy
• PLN = protein-losing nephropathy

Internet Resources

http://vetmed.tamu.edu/gilab/

Author Jörg M. Steiner

Consulting Editor Stanley L. Marks

Client Education Handout Available Online