Canine protein-losing enteropathies

Introduction

Protein-losing enteropathy (PLE) reflects a collection of gastrointestinal (GI) diseases characterized by enteric loss of proteins, principally albumin, but also globulins in some cases. Enteric protein loss in dogs can occur through any segment of the GI tract, but oral cavity and esophageal diseases are rare causes of PLE. Disease of the stomach and colon can occasionally cause PLE, but chronic diseases of the small intestine are the most common reasons. This article will provide an overview of the clinical features, diagnostic and treatment considerations for the most common etiologies of canine small intestinal PLE (Table 1) but more detailed information for many of the individual causes of PLE can be found elsewhere 1. 

Signalment and clinical features

Any dog can develop a PLE, but several breeds, including yorkshire Terriers, Rottweilers, Wheaten Terriers, Norwegian Lundehunds, and German Shepherds are predisposed. Canine PLE may develop at any age, and the clinical signs can be variable, although weight loss (which may be seen with a normal or decreased appetite), vomiting and/or diarrhea are commonly noted. Some dogs develop hematemesis or melena if proximal GI tract bleeding occurs. In patients exhibiting diarrhea, features usually, but not always, localize diarrhea to the small intestine. However, not all patients with a PLE exhibit vomiting and/or diarrhea, so the absence of these signs should not lessen the suspicion of a PLE if other clinical aspects are consistent. Some owners will report abdominal distension (from ascites) or peripheral edema, or changes in respiratory rate or character (from pleural effusion) as the primary clinical sign. Occasional patients with a PLE are diagnosed after hypoalbuminemia is found incidentally on a serum biochemical profile and other causes of hypoalbuminemia have been excluded. Uncommonly, seizures secondary to hypocalcemia may be seen 2.

Physical examination abnormalities in dogs with PLE are also variable. Poor body condition could be expected in animals that have experienced weight loss. Peripheral edema, abdominal distension, and a palpable fluid wave are possible in patients with severe hypoalbuminemia. In some cases, there may be thickened loops of bowel or intestinal masses, so a careful and thorough abdominal palpation is a critical component of the physical examination, especially when abdominal effusion is absent. A rectal examination may reveal enlarged sublumbar lymph nodes in dogs with GI lymphoma or other infiltrative GI disease. Melena, which can also be detected by a rectal examination, can be a feature of some dogs with bleeding upper GI tract lesions.

Diagnostic considerations

Laboratory tests

A common approach to the patient with clinical signs consistent with a PLE would be to perform a fecal flotation, or empirically deworm with a broad-spectrum anthelmintic, and obtain a complete blood count (CBC), serum biochemical profile, and urinalysis. CBC results will vary depending on the underlying cause of the PLE. Inflammatory leukograms are possible with any of the diseases associated with inflammation (e.g., inflammatory bowel disease [IBD], neoplasia), but will not be present in all patients. Peripheral eosinophilia may be seen; hypereosinophilia, likely a paraneoplastic phenomenon, has been described in association with canine GI lymphoma. Anemia can be a consequence of chronic inflammation, or acute or chronic GI hemorrhage. There may be features of iron deficiency (microcytosis, hypochromasia) if the cause of PLE itself instigates chronic, low-grade GI hemorrhage. Attention should be paid to the leukogram, because absence of a stress leukogram may suggest hypoadrenocorticism, a cause of PLE infrequently considered by many clinicians (see below). Lymphopenia is variably present in dogs with intestinal lymphangiectasia (IL). Platelet counts may be normal or increased (due to chronic inflammation), but thrombocytopenia would be unusual in most causes of PLE.

The hallmark features of a PLE on a serum biochemical profile are hypoalbuminemia with or without hypoglobulinemia; note that hyperglobulinemia can be seen in some cases. Hypocholesterolemia is common in dogs with IL, but can be seen with other causes of PLE; hypoadrenocorticism is also an important differential for hypocholesterolemia. Hypocalcemia may be noted; this can be a consequence of hypoalbuminemia, or a true hypocalcemia secondary to mucosal disease. An ionized calcium (iCa) assay can clarify if a low total serum calcium level reflects hypoalbuminemia (i.e., iCa will be normal), or a true hypocalcemia (low iCa). Increases in liver enzymes may be seen in some dogs.

A urinalysis, while not often giving specific information regarding the nature of the PLE, helps exclude urinary albumin loss as a cause of, or contributor to, hypoalbuminemia. Proteinuria can be seen in certain breeds (such as Wheaten Terriers) known to develop concurrent PLE and protein-losing nephropathy. A urinalysis is important when investigating hypoalbuminemic patients that have no signs of GI tract disease and those that do not have hypoglobulinemia; globulins are not typically lost in the urine as they are generally too large to pass through the glomerulus. In the absence of proteinuria, evidence of abnormal liver function (elevated bile acids, blood ammonia concentrations) or third-space losses (exudative effusions, edema from vasculitis) as a cause of hypoalbuminemia, the default explanation becomes enteric loss, and a PLE should be suspected even if signs of GI disease are absent.

When dogs develop body cavity effusions secondary to PLE, the fluid type is expected to be a pure transudate, a consequence of hypoalbuminemia and low oncotic pressure. Pure transudates in such cases are very low in protein, often < 1.0 g/dL (10 g/L), have low nucleated cell counts, and can look like water. Dogs with a pure transudate and serum albumin concentrations greater than 1.5 g/ dL (15 g/L) should arouse suspicion of a sinusoidal or presinusoidal portal vein abnormality, such as a portal vein thrombus, as pure transudates are not expected when serum albumin concentrations are above this level. Portal vein thrombi have been described in dogs with PLE 3.

Measurement of cobalamin is encouraged in animals suspected of having a PLE, as serum cobalamin concentrations can be low secondary to malabsorption. Measurement of canine pancreatic lipase (cPLI) should be performed if pancreatitis is a consideration; a negative result makes pancreatitis less likely.

The possibility that hypoadrenocorticism can resemble PLE has already been noted, and should be considered as a possible cause for PLE 4. Common findings in such cases include weight loss, poor body condition, a history of intermittent, often chronic, vomiting and/or diarrhea, hypoalbuminemia and hypocholesterolemia. The absence of a stress leukogram, notably an absence of lymphopenia, is a significant finding in affected dogs. Note that there may not be the classic electrolyte abnormalities of hyponatremia and hyperkalemia, which can make suspicion of hypoadrenocorticism difficult. Because of the potential for unnecessary diagnostic intervention for a dog with hypoadrenocorticism, or the administration of excessive doses of glucocorticoids if empirically treating for IBD, the author proposes that a basal cortisol be done in a PLE candidate if there is no evidence of a stress leukogram; if the basal cortisol is < 2 μg/dL (< 55 nmol/L), an ACTH stimulation test should be performed before pursuing other diagnostic options.

Diagnostic imaging

Abdominal imaging can be useful in the approach to a patient with a PLE. Plain abdominal radiography is often not as helpful as ultrasonography, but can help rule out some GI foreign bodies that occasionally cause PLE-like presentations as a result of chronic obstruction. In some patients, an intestinal mass, or evidence of small intestinal dilation suggestive of obstruction, may be appreciated on plain radiography if there is sufficient serosal detail. However, such detail is often poor in PLE patients because of loss of intra-abdominal fat or abdominal effusion. Contrast radiography may exclude or suggest obstructive disease, ulcerative lesions, or masses with more confidence than plain radiographs.

Abdominal ultrasonography is the author’s preferred imaging modality for dogs with features of PLE 5 and the results can help decide if GI biopsy is appropriate and what method (endoscopic vs. surgical) is preferred; evidence for a jejunal lesion, or a disease that appears focal and potentially amenable to surgical resection, would suggest surgery rather than endoscopic evaluation and biopsy. Ultrasonographic abnormalities consistent with PLE can include bright mucosal striations perpendicular to the long axis of the intestine; these may be dilated villus lacteals which can be typical of, but not specific for, IL (Figure 1). Thickening of the intestinal wall, thickened muscularis (more common with lymphoma than other causes), loss of normal wall layering, dilation of bowel segments (obstructive disease), or masses (tumors, foreign bodies) are also possible findings. While not pathognomic, loss of wall layering is highly correlated with neoplastic GI disease. Enlarged mesenteric lymph nodes may be seen, and ultrasoundguided aspirates may allow diagnosis of large-cell/highgrade GI lymphoma or histoplasmosis. Abnormally small adrenal glands are suggestive of hypoadrenocorticism if other features of the disease are present. 

Some limits of abdominal ultrasonography are worth pointing out. Firstly, lesions may not be seen, or can be misinterpreted by the ultrasonographer. The author has seen patients with intestinal obstructions (foreign bodies, focal tumors) that were not noted, or were interpreted as reflecting an abnormality in a different organ/tissue, by board-certified radiologists. Secondly, ultrasonographic images do not provide a cytological or histological diagnosis, so the nature of any ultrasonographic lesion must be confirmed by sampling for cytology or histopathology.

Biopsy findings

Definitive diagnosis of the common causes of PLE requires an intestinal biopsy of adequate quality. Intestinal biopsies can be obtained via endoscopy, or acquired surgically via laparotomy or with laparoscopic assistance. Note hypoalbuminemia is not an absolute contraindication to surgical biopsies – studies have not demonstrated an increased likelihood of intestinal dehiscence in such patients – but the low oncotic pressure can make anesthetic and perioperative management more challenging than with endoscopy.

Gross endoscopic findings in the duodenum can be suggestive of IL if dilated lacteals, which often appear as white dots/villus tips in the duodenal mucosa, are observed (Figure 2). Prominent villus tips can be seen with lymphocytic/plasmacytic enteritis or GI lymphoma. Ulcerative lesions of the stomach and duodenum can also be appreciated during endoscopic examination. If an exploratory laparotomy is performed, IL may be suggested if lymphatic vessels are visualized on the serosal surface of the GI tract or within the mesentery. Small nodules, often characterized histologically as lipogranulomas, may be seen on the serosal surface of the intestine or interspersed along the mesenteric lymphatic vessels. Some dogs will have accumulations of gritty material in the intestinal serosa (Figure 3). Biopsies of duodenum, jejunum and ileum, and enlarged lymph nodes (if found) should be obtained during surgery. 

To be of adequate quality, endoscopic biopsies should span villus tip to submucosa and contain several villi. Including crypt epithelium in the sample is important, as some lesions of PLE are more prominent in the crypts than in the villi. If adequate quality biopsies of representative lesions are submitted for microscopic examination, a histologic diagnosis that fits the clinical picture is expected for most patients. The most common histologic diagnoses for dogs with PLE are IBD, IL and GI lymphoma, but other causes are possible (Table 1)

Treatment

Treatment will be dictated by the underlying cause. For dogs with focal lesions (e.g., foreign bodies, tumors), the treatment will be surgical intervention, possibly followed by chemotherapy if appropriate (e.g., intestinal lymphoma). Treatment of IBD and IL typically involves diet changes and administration of immunomodulatory drugs. Currently, there is no consensus as to the “best” drug therapy for these diseases, although prednisone is widely accepted as a reasonable starting point for most. Table 2 details drugs and dosages that have been reported as beneficial in dogs with IBD or IL 1 6 7; prednisone can be combined with other drugs if a patient does not respond to a single agent. 

Alterations in diet (such as novel proteins and hydrolyzed protein diets) are an important factor when treating both IBD and IL. Foods restricted in fats can be helpful, as patients with PLE often have a degree of fat malassimilation; this seems especially true of patients with IL 8. Some patients with PLE will do well without drugs if fed an appropriate diet, although this can take some trial and error. A strategy that the author has used with some success in patients that have not responded to other treatment approaches (other diets, drugs) is to feed a two-ingredient diet using a novel protein and novel carbohydrate. Owners boil, bake, or braise the two ingredients without any other additive (e.g., spices, oils); if a clinical response is appreciated (often within 10-14 days in the author’s experience), then consultation with a nutrition service is recommended to ensure a balanced diet for long-term feeding.

For patients with cobalamin deficiencies, supplementation is indicated. A recent paper 9 demonstrated that oral cobalamin supplementation in dogs with chronic enteropathy is effective in normalizing serum cobalamin concentrations; subcutaneous administration of cobalamin is still an acceptable route of administration. Because cobalamin is extremely safe – the author is not aware of toxicity associated with cobalamin administration – empirically treating a PLE patient with cobalamin is, in the author’s opinion, a reasonable consideration that will lessen the expense associated with monitoring responses to cobalamin supplementation.

Treatment of GI lymphoma is typically based on administration of chemotherapeutic drugs. Consultation with a veterinary oncologist is recommended to choose a protocol that best suits the needs of both patient and client. At a minimum, administration of prednisone alone can be considered and may improve clinical signs for a time in some dogs.

Summary

In summary, PLE should be suspected in any dog with hypoalbuminemia, with or without vomiting or diarrhea, if other causes of hypoalbuminemia have been excluded. Remember that hypoadrenocorticism can look like PLE, so obtain a basal cortisol in PLE-like dogs that have no stress leukogram. Abdominal imaging and intestinal biopsy play important roles in the diagnostic approach to PLE candidates, and diet and immunosuppressive drugs are cornerstones of treatment for IBD and IL. Ultimately, it is essential to emphasize that the prognosis for a dog with PLE is variable and reflects the underlying disease.