Protein-Losing Enteropathies - Low Albumin Is Not Always a Bad Prognosis
World Small Animal Veterinary Association World Congress Proceedings, 2015
Michael Willard1, DVM, MS, DACVIM
1Texas A&M University, College Station, TX, USA

If the patient has substantial hypoalbuminemia, the first step is to examine the skin for obvious lesions which can cause protein loss. Cutaneous lesions sufficient cause such hypoalbuminemia are obvious; you should be able to just look at the patient and know if this is the problem or not. Next, hepatic function testing (e.g., resting and postprandial serum bile acid concentrations) and a urinalysis are requested. If there is any doubt on the urinalysis, then a urine protein:creatinine ratio will quantify the magnitude of urinary protein loss. Severe hypoalbuminemia (i.e., < 2 g/dl) in an animal with diarrhea suggests a protein-losing enteropathy (PLE); however, diarrhea (even when severe) in no way is sufficient to eliminate hepatic disease as the cause of the hypoalbuminemia. Furthermore, a very substantial number of dogs and cats with PLE do not have vomiting or diarrhea. Some only have ascites, and some are found fortuitously on routine blood work. This may be especially true of dogs with primary intestinal lymphangiectasia. In general, once severe, exudative cutaneous disease, protein-losing nephropathy, and hepatic insufficiency are eliminated, then PLE is a reasonable tentative diagnosis of exclusion in patients with a serum albumin < 2.0 g/dl. Finally, contrary to what the textbooks say, PLE may be associated with a low, normal or increased serum globulin concentration.

Perhaps the most important point of this discussion is that while hypoalbuminemia has repeatedly been reported to be a poor prognostic sign in patients with chronic GI disease, there may be one or more subset(s) of patients that respond well to appropriate therapy. Although therapeutic trials can be chosen in place of classic diagnostic tests in many of the more 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 2.0 g/dl. This is true because it may be necessary to perform an antibiotic and/or 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, especially if the serum albumin concentration is falling rapidly.

Any GI disease can cause PLE if it is severe enough. Many acute GI disease cause PLE (e.g., parvoviral enteritis); however, these diseases typically are comparatively easier to treat than the chronic GI disease causing PLE. Therefore, the focus in this lecture is PLE in animals with chronic GI disease. The major causes of PLE in adult dogs tend to be intestinal lymphangiectasia, inflammatory bowel disease (IBD), alimentary tract lymphoma (LSA), and fungal infections (i.e., histoplasmosis and pythiosis). Other causes include alimentary tract ulceration/erosion, severe disease of intestinal crypts, antibiotic-responsive enteropathy, and parasites. The major causes of PLE in juvenile dogs tend to be parasites and chronic intussusception. Cats with PLE usually have IBD or alimentary tract lymphoma. 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 an uncommon cause of PLE in adult animals, pets in select environments (e.g., confined areas where patients can reinfect themselves) may incur substantial parasitic loads.

Diagnostic Approach to PLE Patient

Once PLE has been diagnosed, intestinal biopsy is usually the ultimate means of establishing a diagnosis. Biopsy can be done via laparotomy, laparoscopy, or endoscopy. Feeding a small, fatty meal (use canned food, not dry, and add in cream or corn oil) the night before the procedure might (?) make it easier to diagnose lymphangiectasia. Flexible endoscopy, when done by someone who is trained 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, 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. Furthermore, there are ultrasonographic changes (streaks in the submucosa) that can be diagnostic. If flexible endoscopy will be done, one should biopsy both the duodenum and ileum.

Laparotomy and laparoscopy are good means of obtaining diagnostic samples, but 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. If full-thickness biopsies are obtained in severely hypoalbuminemic 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

Intestinal lymphangiectasia seems particularly common in Yorkshire Terriers and Soft-Coated Wheaten Terriers, but may occur in any breed. Sometimes these dogs have distinct ultrasonographic findings: "steaks" in the mucosa that represent dilated lymphatics. While histopathology is obviously the desired means of diagnosis, one can sometimes make a definitive diagnosis based upon grossly visible endoscopic findings (i.e., numerous, erratic, grossly engorged lacteals seen as large white blebs on the mucosa). These lesions are "fragile" and apparently may be destroyed by biopsying them (both endoscopically and surgically) if the endoscopist or surgeon is not careful. It is important to note that lymphangiectasia can be a relatively localized disease in the intestines, being present in only the ileum or only the jejunum or only the duodenum; therefore, it is important to biopsy as much of the intestinal tract as possible. Furthermore, if one biopsies the intestines and cannot find a cause of PLE, sometimes lymphangiectasia can be tentatively diagnosed by elimination (i.e., by eliminating IBD, lymphoma, parasites, intussusception, fungal infections, etc.).

Diagnosis by means of endoscopic biopsy is certainly possible if the endoscopist is trained in taking high quality tissue samples. However, recent work has demonstrated that poor quality mucosal biopsies (e.g., primarily villus tips or substantial "squash" artifact) makes is much more difficult or even impossible to find the lesions. If one is taking high quality tissue samples (i.e., total length of the villi plus subvillus mucosa down to the border of the mucosa and muscularis mucosa), it typically takes about 6–7 tissue samples to have 90–99% confidence in finding lymphangiectasia. However, it can take 5–7 times as many tissue samples to have the same assurance if you are obtaining poor quality tissue samples that primarily consist of villus tips.

When doing endoscopy, it is important that ileal biopsies be taken in addition to the typical duodenal biopsies. We are finding that ileal biopsies often reveal lesions not found on duodenal biopsies. This is true for lymphangiectasia as well as lymphoma and other lesions. With basic training, an endoscopist should be able to obtain ileal biopsies endoscopically at least 85% + of the time. Typically, ileal biopsies are often of higher quality than duodenal biopsies.

Therapy for intestinal lymphangiectasia revolves around an ultra-low fat diet, preferably with antiinflammatory therapy designed to alleviate the lipogranuloma formation that commonly occurs within the intestinal wall and/or mesentery. Supplementation with medium chain triglyceride oil (MCT) used to be recommended because MCT oil supposedly bypasses intestinal lymphatics thus preventing further rupturing of the lacteals. Pancreatic enzymes were often added to the diet to ensure digestion of the medium chain triglyceride oil. MCT oil is seldom used anymore, probably because appropriate dietary therapy 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) or feeding commercial diets is often very helpful in these patients. Commercial low fat diets can be used very successfully, but they need to have the lowest possible fat content. Such a diet can be so successful that it might occasionally be appropriate to use it as a therapeutic trial. Dogs with lymphangiectasia often show a marked increase in serum albumin concentration within 7–14 days of starting such a diet. The important of lipogranulomas in the intestinal wall and mesentery is uncertain. However, it is hypothesized that some patients fail to respond to appropriate dietary therapy because of formation of very large or excessive numbers of lipogranulomas that so completely obstruct the intestinal lymphatics that even an ultra-low fat diet cannot prevent lacteal rupture. Therefore, once a diagnosis of lymphangiectasia is made (either by histology, grossly at endoscopy, or tentatively by response to an ultra-low fat diet), it seems to be appropriate to use antiinflammatory therapy designed to prevent granuloma formation/enlargement. Prednisolone, azathioprine, and/or cyclosporin are commonly used for this purpose. I do not like prednisolone, simply because of all the side effects it has in these patients. Be aware that if you use cyclosporine, it is critical that you measure blood levels of the drug. Not only is there a major difference between patients in how much they absorb, but the bioavailability of the same product may change as the intestine heals.

References

1.  Dossin O, Lovoue R. Protein-losing enteropathies in dogs. Vet Clin North Am Small Anim Pract. 2011;41:399–421.

2.  Okanishi H, Yoshioka R, Kagawa Y, et al. The clinical efficacy of dietary fat restriction in treatment of dogs with intestinal lymphangiectasia. J Vet Intern Med. 2014;28(3):809–817.

3.  Pollard RE, Johnson EG, Pesavento PA, et al. Effects of corn oil administered orally on conspicuity of ultrasonographic small intestinal lesions in dogs with lymphangiectasia. Vet Radiol Ultrasound. 2013;54:390–397.

4.  Simmerson SM, Armstrong PJ, Wuenschmjann A, et al. Clinical features, intestinal histopathology, and outcome in protein-losing enteropathy in Yorkshire Terrier dogs. J Vet Intern Med. 2014;28:331–337.

  

Speaker Information
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Michael Willard, DVM, MS, DACVIM
Texas A&M University
College Station, TX, USA


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