Protein Losing Enteropathy

Introduction

Protein-losing enteropathy (PLE) refers to the loss of plasma proteins into the gastro-intestinal (GI) tract, exceeding the absorptive capacity of the intestines. PLE can be caused by:

• Disruption to the intestinal wall due to inflammation or infiltrative disease
• Venous congestion of the GI tract
• GI haemorrhage

Hence, there are numerous causes of PLE in cats and dogs, including:

Inflammation

• Inflammatory Bowel Disease (including lymphocytic-plasmacytic enteritis, eosinophilic enteritis, granulomatous enteritis and histiocytic-ulcerative colitis)
• Infectious disease
  • Giardia duodenalis
  • Hookworm
  • Histoplasmosis
• Chronic intussusception in juvenile animals

Lymphangiectasia

Infiltrative disease

• Alimentary lymphoma

Venous congestion

• Portal hypertension
• Posterior caval syndrome
  • Right-sided congestive heart failure

GI haemorrhage

• This may occur with hypoadrenocorticism or with other causes of GI ulceration

Rare causes of PLE include:

• Small intestinal bacterial overgrowth (SIBO)
• Hypoalbuminaemia causing intestinal mural oedema
• Increased activation of tissue plasminogen activator
• Systemic lupus erythematosis (SLE)
• Chemotherapy or radiotherapy

Signalment

Inflammatory bowel disease and lymphoma are the most common causes of PLE in both cats and dogs but lymphangiectasia occurs much more commonly in dogs than in cats. Chronic intussuscepta (usually occurring secondary to acute enteritis) and endoparasite infection are the most common causes of PLE in juvenile cats and dogs.

Basenjis, Norwegian Lundehunds, Soft-coated Wheaten terriers (SCWT), Yorkshire terriers and Shar peis all show breed predispositions for PLE. related to secretory enteropathy Basenjis develop PLE as a result of secretory enteropathy, a type of inflammatory bowel disease. Soft-coated Wheaten Terriers often suffer from concurrent protein-losing nephropathy and most affected animals of this breed have a common ancestor who is thought to have lived in the USA. Females of this breed are more commonly affected than males

Diagnosis

Clinical Signs

• Weight loss is the most evident sign.
• Diarrhoea occurs due to the loss of protein into the GI tract and subsequent osmotic movement of fluid. Melaena may occur with GI haemorrhage.
• Oedema, ascites and pleural effusion due to reduced plasma oncotic pressure.
• Thickened intestines may be detectable on abdominal palpation and this finding may be related to the primary pathological process.
• Thromboembolic disease due to the loss of plasma anticoagulants such as antithrombin III.
• Hypocalcaemic tetany due to a reduced ability to absorb calcium and the fat soluble vitamin D. Apparent hypocalcaemia may also develop as the protein-bound portion of the blood total calcium concentration is reduced.

Laboratory Tests

Changes consistent with possible differential diagnoses, such as hepatic and renal disease, should also be ruled out.

Haematology

Lymphopaenia occurs with lymphangiectasia due to the loss of lymph.

Biochemistry

• Panhypoproteinaemia is a pattern more suggestive of PLE since albumin is usually lost in excess of globulin in protein losing nephropathy. Hypoproteinaemia may also develop with haemorrhage, dermal protein loss (after severe burns of degloving injury) or if the rate of synthesis of albumin is reduced by a severe hepatic insult. Oedema and ascites typically develop when serum albumin concentration drops below 15 g/l.
• Hypocholesterolaemia, especially in lymphangiectasia.
• Hypocalcaemia but ionised calcium concentration should be measured to determine the significance of this finding as serum calcium concentration is closely related to total protein level.

Other Tests

Measurement of faecal alpha1-protease inhibitor - This marker has a similar molecular weight to albumin and it is lost into the GI tract in PLE. Its concentration can therefore be measured in faeces as it is not degraded by GI enzymes. (Faecal samples must be frozen on collection before submission to a laboratory in the USA.)

Administration of 51-Chromium labelled albumin - A radioactive marker (51-Chromium) is attached to recombinant albumin molecules before injection into animal. Faecal samples are collected to determine whether the labelled albumin is being lost into the GI tract. Although this test represents the 'gold standard' test, it is available only at a limited number of referral institutes.

Diagnostic Imaging

Radiography

The results of abdominal radiographs are usually unremarkable but discrete mass lesions or ascites may be evident. Thoracic radiographs may show the presence of pleural effusion, metastatic neoplasia or evidence of histoplasmosis).

Ultrasonography

This may reveal:

1. Changes to intestinal wall structure, including:

• • Thickening without loss of normal layers (as with inflammatory bowel disease)
  • Thickening with loss of layers (as with infiltrative intestinal neoplasia)
  • 'Tiger stripes', an unreliable indicator of lymphangiectasia

1. Ascites or pleural effusion

• Mesenteric lymphadenopathy

Histopathology

Endoscopy can be used to visualise the proximal intestinal luminal surface and to obtain grab biopsies. Surgical biopsies may be obtained for definitive diagnosis of lymphoma and secondary lymphangiectasia. A small fatty meal could be given the night before biopsy to increase the chance of diagnosing lymphangiectasia. Care should be taken with this procedure as animals with PLE have a greater risk of surgical wound dehiscence with the subsequent development of peritonitis.

Lesions that may be observed on histopathological analysis of biopsy samples include: signs of inflammatory bowel disease, dilated lymphatics and lipogranulomatous lymphangitis (especially in Soft-coated Wheaten terriers).

PLE may also be associated with protein losing nephropathy (PLN). PLN may be a chronic sequelae to the PLE. It follows immune complex deposition in the glomerulus, causing glomerulonephritis or glomerulosclerosis. PLN causes hypoalbuminaemia and hypercholesterolaemia. Similar PLN and PLE lesions are seen in young Besenjis with immunoproliferative enteropathy and glomerulosclerosis.

Treatment

Treatment of the underlying cause of disease should be initiated, if possible. In the case of severe respiratory embarrassment, treatment should be directed at draining any pleural effusion and providing support in case of a pulmonary thromboembolus.

Plasma transfusion

This may be used to increase plasma volume but, as much of the albumin is lost into the gut, there may be a disappointing increase in serum albumin concentration after transfusion. Large colloids (such as hetastarch) may also be administered to try to maintain plasma oncotic pressure.

Diuretics

These may be used to reduce any ascites or pleural effusion and it has been suggested that spironolactone may be more effective than frusemide for this purpose.

Antithrombotic therapy

Treatment may be initiated with low dose aspirin to prevent the development of thrombo-embolism.

Dietary Supplementation with Calcium

Calcium carbonate may be added to the diet if a low serum concentration of ionised calcium is documented.

Prognosis

This depends on the underlying cause but Soft-coated Wheaten terriers are known to have a median survival time of five months after diagnosis of PLE and of two months if they suffer from concurrent protein-losing nephropathy.

Protein-Losing Enteropathy (PLE)

• Affects soft coated wheaten terriers.
  • Common male ancestor for most of the dogs.
  • Bitches are affected more often than dogs.
  • Also affects Besenji, Lundehund.
• Normally, dietary protein and protein from shed enterocytes is almost completely absorbed.
  • In PLE there is excess loss of protein into the gut lumen.
    • The loss is non-selective i.e. albumin and globulin.
  • Causes panhypoproteinaemia and hypocholesterolaemia.
• If this is severe, oedema and weight loss may result.
• Enteropathy not due to gluten sensitivity.
• Can diagnose PLE on basis of finding α1-protease inhibitor in the faeces in dogs.

Causes of PLE

• Severe inflammatory disease.
  • Protein is lost in exudate.
• Lymphangiectasia.
  • Loss of protein-rich lymph due to obstruction of gut lymphatics.
• Increased mucosal permeability.
  • E.g. erosions, loss of tight junctions, lymphosarcoma.
• Increased loss of enterocytes (less important).
• Also:
  • Immunoproliferative enteropathy
  • Lymphocytic plasmacytic enteritis
  • Eosinophilic enteritis
  • GI ulceration/erosion
  • Giardiasis
  • Chronic intussusception
  • Small intestinal bacterial overgrowth
  • Neoplasia
  • Hypoalbunimaemia causing mural oedema
  • Increased activation of tissue plasminogen activator
  • Systemic lupus erythematosis (SLE)
  • Vascular lesion in the GI mucosa
  • Chemotherapy/radiotherapy.

Pathology

• Lesions include:
  • Inflammatory bowel disease
  • Dilated lymphatics
  • Lipogranulomatous lymphangitis.
• Intestinal crypts become dilated with mucus, sloughed epithelial cells with or without inflammatory cells.
• PLE is also associated with protein losing nephropathy (PLN).
  • PLN may be a chronic sequelae to the PLE.
  • Follows immune complex deposition in the glomerulus, causing glomerulonephritis or glomerulosclerosis.
  • PLN causes hypoalbunaemian and hypercholesterolaemia.
  • Similar PLN and PLE lesions seen in young Besenjis with immunoproliferative enteropathy and glomerulosclerosis.

Literature Search

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Protein Losing Enteropathy publications

References

• Littman MP, Dambach DM, Vaden SL, Giger U (2000) Familial protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (1983-1997) J Vet Intern Med. 2000 Jan-Feb;14(1):68-80.
• Ettinger, S.J. and Feldman, E. C. (2000) Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat Volume 2 (Fifth Edition) W.B. Saunders Company.
• Hall, E.J, Simpson, J.W. and Williams, D.A. (2005) BSAVA Manual of Canine and Feline Gastroenterology (2nd Edition) BSAVA.
• Nelson, R.W. and Couto, C.G. (2009) Small Animal Internal Medicine (Fourth Edition) Mosby Elsevier.
• Willard, M. (2005) Protein-Losing Enteropathy in Dogs and Cats 30th World Congress of the WSAVA.