Protein-Losing Enteropathy In Dogs And Cats
World Small Animal Veterinary Association World Congress Proceedings, 2005
Michael Willard
Texas A&M University
College Station, TX, USA

Severe hypoalbuminemia (i.e., < 2 gm/dl) in an animal with diarrhea suggests a protein-losing enteropathy (PLE). If severe, exudative cutaneous disease, protein-losing nephropathy, and hepatic insufficiency are eliminated, then PLE is a reasonable tentative diagnosis. Contrary to what the textbooks say, PLE may be associated with a low, normal or increased serum globulin concentration. In general, animals with PLE tend to have severe alimentary tract disease that needs to be diagnosed promptly to maximize the chance for successful therapy. Although therapeutic trials can appropriately be chosen in place of classic diagnostic tests in many common alimentary tract diseases (e.g., dietary allergy, dietary intolerance, antibiotic-responsive enteropathy, parasites), such an approach is generally ill-advised if the serum albumin concentration is less than or equal to 2.0 g/dl. This is true because it may be necessary to perform a dietary therapeutic trial for 3-6 weeks in order to ascertain if it is being effective, and a patient with severe PLE can become markedly worse in that time period.

The major causes of PLE in adult dogs in our practice are intestinal lymphangiectasia, inflammatory bowel disease (IBD), alimentary tract lymphosarcoma, and fungal infections (i.e., histoplasmosis and pythiosis). Other causes include alimentary tract ulceration/erosion, severe disease of intestinal crypts, and parasites. The major causes of PLE in juvenile dogs in our area are parasites and chronic intussusception. Inflammatory bowel disease is a very rare cause of PLE in juvenile dogs (or for any disease in juvenile dogs, for that matter). Cats with PLE usually have IBD or alimentary tract lymphosarcoma. Cats almost never develop intestinal lymphangiectasia, and seldom have parasite infestations severe enough to cause problems.

The general diagnostic approach is to measure serum albumin concentrations and find out if it is decreased. Do not use human clinical pathology laboratories as they often use a technology that does not detect canine albumin (meaning that they routinely report serum albumin concentrations of < 1.5 gm/dl in clinically normal dogs). If the patient has substantial hypoalbuminemia, then examining the skin for obvious lesions which can be responsible for protein loss is the next step. Then, hepatic function testing (e.g., resting and post-prandial serum bile acid concentrations are typical) and a urinalysis are generally the next steps. If there is any doubt on the urinalysis, then a urine protein: creatinine ratio may be requested to quantify the magnitude of urinary protein loss. Many dogs with PLE have hypocholesterolemia. Pets with protein-losing nephropathies usually have hypercholesterolemia, while those with hepatic insufficiency often have hypocholesterolemia. Fecal examinations for parasites are appropriate. Although parasites are a very uncommon cause of PLE in adult animals, pets which are kept in confined areas can reinfect themselves and thereby incur substantial parasitic loads.

Once PLE has been diagnosed, then intestinal biopsy is usually the ultimate means of establishing a diagnosis. Biopsy can be done via laparotomy, laparoscopy, or endoscopy. Regardless of which technique will be employed, I recommend feeding a small, fatty meal the night before the procedure in hopes of making it easier to diagnose lymphangiectasia. Flexible endoscopy, when done by someone who is trained not only in manipulating the endoscope but also in how to take diagnostic tissue samples and submit them, is usually more than adequate to obtain diagnostic samples. However, if endoscopy will be used to biopsy the small intestines, then it is preferable to first ultrasound the abdomen to make sure that there are no focal infiltrates that are out of reach of the endoscope, or which might be more easily diagnosed by ultrasound-guided fine needle aspiration. Radiographs and barium series are seldom as sensitive as ultrasound, and certainly require as much or more work than ultrasound. If flexible endoscopy will be done, I recommend biopsying both the duodenum and the ileum. We have had cases in which lymphangiectasia was obvious in the ileum but not in the duodenum. It is generally not necessary to enter the ileum in order to obtain a good tissue sample of the ileal mucosa.

Laparotomy and laparoscopy are good means of obtaining diagnostic samples, but one must realize that it is surprisingly easy to procure non-diagnostic samples with these techniques (i.e., "full-thickness sample" is not synonymous with "diagnostic sample"). Endoscopy does have the advantage of allowing one to visualize mucosal lesions that are "invisible" when looking at the serosa. In some cases, the diagnosis can only be obtained by biopsying these focal lesions. Full-thickness intestinal biopsy performed on a patient with a serum albumin concentration less than 1.5 gm/dl seems to carry with it some increased risk of dehiscence of the intestinal incisions. If such full thickness biopsies are obtained in severely hypoalbuminemia animals, then serosal patch grafting will minimize the risk of suture line leakage. A nonabsorbable or a poorly absorbable suture (PDS) should also be used.

Intestinal lymphangiectasia is most common in Yorkshire terriers and Soft-Coated Wheaten terriers, but may occur in any breed. Therapy for intestinal lymphangiectasia revolves around an ultra-low fat diet. We used to recommend supplementation with medium chain triglyceride oil (MCT). MCT oil supposedly bypasses intestinal lymphatics thus preventing further rupturing of the lacteals. Pancreatic enzymes was often added to the diet to ensure digestion of the medium chain triglyceride oil. In fact, we seldom use MCT oil anymore, probably because appropriate dietary therapy without supplements is usually more than sufficient. Feeding homemade diets that are highly digestible and ultra low in fat (e.g., white turkey meat plus potato or rice) is often very helpful in these patients. Sometimes corticosteroids and other drugs such as cyclosporin are also useful. We think they are useful because they can inhibit lipogranulomas that may form around the lymphatics in the intestines, further impeding lymphatic flow. However, be aware that some of the causes of PLE are made much worse by corticosteroids (e.g., histoplasmosis). Furthermore, you need to monitor cyclosporin blood levels because it is impossible to predict the blood levels that a specific dog will achieve when receiving this drug.

If the serum albumin is very low (e.g., < 1.3 gm/dl), a plasma transfusion may be needed while waiting to see what effect the diet will have. However, it is difficult to increase serum albumin concentrations by transfusing PLE patients. This is because so much of the albumin is quickly lost into the gut, plus the fact that a substantial amount of albumin that is transfused into a patient does not remain in the intravascular compartment. You would probably have to give at least two units of plasma to a 15 lb dog in order to raise the serum albumin from 1.0 gm/dl to 1.8 gm/dl, and sometimes you would have to give 3 or 4 units. If it is critical to raise the plasma oncotic pressure, then administering hetastarch may be preferred due to the facts that it costs less than plasma, and it stays in the intravascular compartment longer than albumin.

Lesions of the intestinal crypts have been recognized as being associated with PLE in dogs. We have identified two different lesions of the small intestinal crypts that can cause PLE. One type is characterized by crypts (usually duodenal) that are filled and somewhat distended with proteinaceous fluid and necrotic inflammatory cells. While such dilated crypts can be found in many animals, including clinically normal dogs, finding large numbers of them in multiple tissue samples seems to be consistently associated with PLE. We do not know if this is a cause-and-effect relationship, or if the dilated crypts are simply a marker for some other process but are not causing the protein loss themselves. Several of these patients have responded to therapy with elemental diets, total parenteral nutrition, prednisolone, azathioprine, and/or metronidazole. We have seen this lesion unassociated with IBD as well as being associated with lymphangiectasia.

For animals with IBD or crypt lesions, feeding elemental diets (e.g., Vivonex HN) can be very beneficial. These diets are ultra easy to digest and absorb, plus they do not cause intestinal irritation in patients with increased intestinal permeability. However, we routinely add crystalline amino acids (i.e., the intravenous preparation) to the Vivonex, because dogs and cats (and especially hypoalbuminemic dogs and cats) have higher protein requirements than are supplied by Vivonex.

Chronic intussusception is a relatively important, and often missed, cause of PLE in juvenile animals. The classic history is one of acute enteritis (e.g., parvoviral enteritis) which does not resolve as expected. The patient feels somewhat better, but continues to have diarrhea, and the serum albumin concentration gradually diminishes. It can be very hard to palpate an ileo-colic intussusception; abdominal ultrasound is clearly the preferred way to diagnose intussusception. Therapy is surgical.

Although uncommon, nematodes may cause PLE in adult animals if there are large numbers of them. Whipworms and hookworms in particular may occasionally be responsible for PLE in older dogs.

References

1.  Peterson PB, Willard MD: Protein-losing Enteropathies. Vet Clin N Am 33: 1061-1082, 2003.

2.  Willard MD, Zenger E, Mansell JL: Protein-losing enteropathy associated with cystic mucoid changes in the intestinal crypts of two dogs. J Am Anim Hosp Assoc 39: 187-191, 2003.

3.  Bush WW, Kimmel SE, Wosar MA, Jackson MW: Secondary hypoparathyroidism attributed to hypomagnesemia in a dog with protein-losing enteropathy. J Am Vet Med Assoc 219: 1732-1734, 2001.

4.  Kull PA, Hess RS, Craig LE, Saunders HM, et al: Clinical, clinicopathologic, radiographic, and ultrasonographic characteristics of intestinal lymphangiectasia in dogs: 17 cases (1996-1998). J Am Vet Med Assoc 219: 197-202, 2001.

5.  Littman MP, Dambach DM, Vaden SL, Giger U: Familial protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (1983-1997). J Vet Int Med 14: 68-80, 2000.

6.  Willard MD, Helman G, Fradkin JM, Becker T, et al: Intestinal crypt lesions associated with protein-losing enteropathy in the dog. J Vet Int Med 14: 298-307, 2000.

Speaker Information
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Michael Willard, DVM
USA


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