Protein-losing enteropathies
Shelly E. Vaden
Introduction
Protein-losing enteropathy (PLE) refers to a syndrome characterized by the non-selective and excessive loss of proteins into the intestinal lumen.
This loss may be due to increased mucosal permeability secondary to cell damage or cell loss, mucosal erosion or ulceration, or altered lymphatic drainage. Hypoproteinemia occurs when protein loss exceeds protein synthesis. Panhypoproteinemia in an animal with clinical evidence of intestinal disease typifies this syndrome. However, animals with PLE may have normal stool frequency and consistency. Prompt diagnosis and treatment of PLE is important because affected animals with severe hypoalbuminemia can deteriorate rapidly and develop life-threatening complications, such as thromboembolism, pleural effusion, or both.Causes of protein-losing enteropathy
PLE is more commonly diagnosed in dogs than in cats. Whether this is because of a lower prevalence of PLE in cats than in dogs or because diagnostic modalities for the diagnosis of PLE in cats are insensitive remains to be determined. Currently, PLE in cats is most often associated with gastrointestinal lymphoma. Conversely, in dogs, PLE is associated with a variety of GI diseases and some systemic disorders (Table 5.9). Basenjis, Chinese Shar Peis, German Shepherd dogs, Norwegian Lundehunds, Rottweilers, Soft-coated Wheaten Terriers, andYorkshire Terriers have all been reported to be at increased risk for PLE.1
Intestinal lymphangiectasia (IL) is believed to be one of the most common disorders associated with PLE in dogs.2 Dilated lymphatics, found in the deeper portion of the mucosa or between the mucosa and submucosa, result in ruptured lac- teals, leading to loss of proteins, lymphocytes, and chylomicrons into the intestinal lumen.3 IL can be primary or secondary.
In people, primary or congenital IL, due to lymphatic malformation, may be associated with diffuse lymphatic dis- ease.4 Similarly, in dogs, intestinal lymphangiectasia has been reported in association with chylothorax.4 Inflammatory cell infiltrates can be found in a patchy distribution along the intestines in dogs with primary IL. Lipogranulomatous lymphangitis is associated with dilated lymphatics in the submucosa, serosal surface, and mesentery.5 These inflammatory lesions may develop in dogs with primary IL in response to stagnated chyle and fat leakage into adjacent tissues. Inflammatory bowel disease (IBD) also is considered to be a common cause of PLE in dogs (see 9.2). Secondary IL develops when inflammatory infiltrates or granulomas obstruct lymphatic flow in patients with IBD.Table 5.9: Diseases associated with PLE in dogs
Inflammatory bowel disease
■ Lymphoplasmacytic
■ Eosinophilic
■ Granulomatous
Adverse food reactions
■ Food allergy
■ Food intolerance
■ Gluten enteropathy
Systemic immune-mediated disease
■ Systemic lupus erythematosus
Viral gastroenteritis
■ Parvovirus
Bacterial gastroenteritis
■ Small intestinal bacterial overgrowth
■ Salmonellosis
Intestinal fungal infections
■ Histoplasmosis
■ Pythiosis
Intestinal neoplasia
■ Lymphosarcoma
■ Adenocarcinoma
Mechanical enteropathy
■ Chronic foreign body
■ Chronic intussusception
Gastrointestinal ulceration
■ Non-steroidal anti-inflammatory drugs
Altered Lymphatic Drainage
■ Lymphangiectasia
- Primary or congenital
Venous hypertension
■ Constrictive pericarditis
■ Right-sided heart failure
■ Portal vein thrombosis
■ Budd-Chiari syndrome
Pathophysiology of serum protein abnormalities
All serum proteins are lost at the same rate in patients with PLE, regardless of their molecular size.
When proteins are lost into the GI tract, they are digested into their constituent amino acids, reabsorbed, and reused for protein synthesis. When losses exceed the intestinal reabsorptive capacity as well as the body’s synthetic capacity, hypoproteinemia occurs. However, the reduction in serum concentrations of the various proteins may differ markedly. Proteins that normally have a long half-life (e.g., IgG, IgM, and IgA) are more substantially impacted than those with shorter half-lives (e.g., insulin and IgE).6 Other factors that may impact plasma protein concentrations include the ability of the liver to produce proteins, the rate of endogenous protein degradation, and the degree of stimulation of globulin production.Because the liver is only able to increase albumin synthesis to about twice the normal production, hypoalbuminemia is common in patients with PLE. Decreased plasma colloidal osmotic pressure becomes clinically relevant when serum albumin concentration decreases to between 1-2 g/dl; with peripheral edema, ascites, or pleural effusion often developing once serum albumin concentrations are below 1.5 g/dL. While hypoglobulinemia is most often found in patients with PLE, serum globulin concentrations are more variable than are serum albumin concentrations. Hypoglobulinemia can sometimes be evident before hypoalbuminemia, as has been seen in Soft-coated Wheaten Terriers (Vaden, unpublished data), because globulin regeneration occurs more slowly than the hepatic synthesis of albumin. Alternatively, normal serum globulin concentrations or hyperglobulinemia may be present in patients with PLE that have an increased globulin production as a result of their primary disease process (i.e., histoplasmosis or immunoproliferative disease in the Basenji).
Diagnosis
PLE should be suspected in dogs and cats that have hypoproteinemia and clinical signs of GI disease (Table 5.10). Chronic, intermittent, small bowel diarrhea is common in animals with PLE.
Most affected animals also have a reduced appetite, weight loss, and vomiting. However, it should be noted that some affected patients do not have these clinical signs.1 Animals with PLE may present for evaluation of dyspnea, which can be due to thromboembolism or pleural effusion. Other animals will have ascites or peripheral edema. Signs of neuromuscular disease may occur secondary to thromboembolic disease or hypocalcemia. Neurological signs secondary to vitamin E deficiency also have been reported in humans with intestinal lymphangiectasia, but have not yet been described in animals.2 Abdominal palpation may reveal thickened loops of bowel, lymphadenopathy, or findings compatible with a chronic foreign body or an intussusception. Animals with PLE resulting from venous hypertension due to cardiac disease may have distended jugular veins and an abnormal thoracic auscultation.In addition to the serum protein abnormalities described above, animals with PLE may have lymphopenia and hypo- cholesterolemia due to excessive intestinal loss of lymphocytes and chylomicrons, respectively. Hypomagnesemia and decreased ionized serum calcium concentrations may also be present, particularly in Yorkshire Terriers.7 Intestinal loss and malabsorption of these minerals and/or abnormalities of vitamin D and parathyroid hormone metabolism are speculative causes.
The diagnostic evaluation of animals with PLE must be designed to allow for the exclusion of other causes of hypoalbu- minemia. These include decreased synthesis (hepatic failure), increased loss (i.e., glomerular disease, blood loss, and severe exudative skin disease), and rarely inadequate intake (i.e., starvation). Therefore, fasting and post-prandial serum bile acid concentrations, a complete urinalysis, a urine protein/creati- nine ratio, and a CBC should be performed. Combined PLE and protein-losing nephropathy has been reported in Soft- coated Wheaten Terriers and also may occur in Yorkshire Terriers at a higher frequency than expected in the general canine population (Vaden, unpublished data).8
51Cr-albumin clearance, determined by intravenous administration of 51Cr, can be used to document excessive GI protein loss.
However, the use of a radionuclide and the need to collect the animal’s feces for 3-5 days makes this test impractical for confirming canine PLE.Alpha1-proteinase inhibitor (α1-PI) is a serum proteinase inhibitor that is of approximately the same size as albumin and is, therefore, lost at about the same rate as is albumin in patients with PLE. As a proteinase inhibitor, α1-PI is not digested or degraded by digestive or bacterial proteases and is therefore excreted intact.9 Fecal α1-PI concentrations have been used as a marker for PLE in humans and dogs, and may prove to be of most value in the early detection of this syndrome. There is a
Table 5.10: Clinical abnormalities associated with protein-losing enteropathy in dogs and cats
Historical Findings
■ Diarrhea (96%[*])
■ Vomiting (56%*)
■ Weight loss (>52%*)
■ Anorexia
■ Polyuria/polydipsia (5%*)
Physical Examination Findings
■ Ascites (41 %*)
■ Pleural effusion (5%*)
■ Peripheral edema (7%*)
■ Signs of thromboembolism (10%*)
■ Neuromuscular signs (4%*)
■ Thickened bowel loops
■ Distended jugular veins[†]
Clinicopathological Findings
■ Hypoalbuminemia
■ Hypoglobulinemia
■ Hypocalcemia
■ Hypomagnesemia
■ Hypocholesterolemia
■ Lymphopenia
■ Increased fecal alpha1-proteinase inhibitor concentration high degree of intra-individual variability in fecal α1-PI concentrations.10 Therefore, three separate naturally voided fecal specimens should be collected into specific specimen tubes provided by the laboratory (Gastrointestinal Laboratory, Texas A&M University, College Station, TX). Samples should be immediately frozen after collection and shipped overnight on ice because substantial degradation occurs within 72 hours at room temperature.
Both the mean and the maximum concentrations should be considered, with a mean above 8-9 μg∕g feces or a maximum above 15μg∕g feces being considered abnormal. Care should be taken not to digitally remove the feces from the rectum as this may falsely increase fecal α1-PI concentrations. An assay for the measurement of feline α1-PI in cat feces has recently been developed and validated, but the clinical usefulness of this test for the diagnosis of feline PLE has not yet been determined.Gastrointestinal biopsies can be collected via endoscopy, laparoscopy, or laparotomy. Laparotomy allows for full-thickness biopsies to be obtained from sites that may not be reached via endoscopy. Biopsy specimens of other organs (e.g., liver, kidney) can be obtained if needed by either laparotomy or laparoscopy. However, animals with PLE may be at greater risk for developing complications post-operatively, including dehiscence, delayed wound healing, and thromboembolism. Serosal patch grafting of the biopsy site may reduce the likelihood of dehiscence or peritonitis. Care should be taken to minimize the loss of abdominal fluid during laparotomy or laparoscopy. Rapid fluid shifts that can occur post-operatively when ascites rapidly reforms can lead to central volume depletion, further complicating patient recovery. Endoscopy is associated with fewer complications than is laparotomy or laparoscopy, making it a good first choice in most patients. However, endoscopy may not be indicated if abdominal ultrasound leads to the identification of lesions that are believed to be beyond the reach of the endoscope (e.g., jejunum). At least eight quality biopsy samples should be obtained from each accessible site: stomach, duodenum, ileum, and colon.11 Endoscopically- obtained biopsies may not be diagnostic if the mucosal pathology is not reflective of the deeper intestinal layers. Although finding expanded white villi via endoscopy is suggestive of lymphangiectasia, endoscopically obtained biopsies may not be diagnostic in some animals with lymphangiectasia. Feeding a high fat meal (e.g., corn oil or cream) the night before endoscopy can make lymphangiectasia more evident during endoscopy and also during histopathologic evaluation of the biopsy specimens.
Treatment
The first step in the management of PLE is the implementation of appropriate treatment for the primary disease process. Dietary management is a cornerstone to the management of both IL and IBD.12 Diets should be highly digestible and low in fat. When serum albumin is with PLE that had failed traditional management following sodium cromoglycate administration (100 mg, administered PO 3-4 times daily; Vaden, unpublished data). The drug is believed to be minimally absorbed from the normal GI tract and has a low incidence of toxicity but more studies are needed to validate the efficacy and safety of this drug in dogs with PLE.
Plasma transfusions or the administration of hetastarch or dextran may be needed in order to increase plasma oncotic pressure prior to anesthesia, but will not provide long-term benefits. Spironolactone may be more effective and safer than furosemide in the long-term management of edema or effusions.
Key Facts
■ PLE can result from any disease that causes increased mucosal permeability, mucosal ulceration, or altered lymphatic drainage.
■ Most dogs and cats with PLE have diarrhea, anorexia, and weight loss, although some dogs with PLE do not exhibit these clinical signs.
■ Most affected animals have panhypoproteinemia, but some patients may only have hypoalbuminemia.
■ Care should be taken to exclude other causes of hypoalbuminemia: hepatic failure, glomerular disease, blood loss, and severe exudative skin disease.
■ Prompt diagnosis and treatment of PLE is important because affected animals with severe hypoalbuminemia can deteriorate rapidly and develop life-threatening complications.