LYMPHANGIECTASIA

Intestinal lymphangiectasia is a chronic protein­losing enteropathy of dogs that results in malab­sorption. It is characterized by obstruction and dysfunction of the intestinal lymphatic network.

At the time of presentation, dogs with lym­phangiectasia frequently have marked hypopro­teinemia. Prominent clinical consequences include body cavity effusions (ascites, hydrothorax) and dependent pitting edema of the subcutis and limbs. In addition to hypoproteinemia, leakage of fat (chylomicrons) from the lacteals may cause inflam­mation and granuloma formation in the intes­tinal wall, which may further exacerbate lymphatic obstruction.

Potential causes of lymphatic obstruction include congenital malformation of the lymphatic system; infiltration or obstruction due to an inflam­matory, fibrosing, or neoplastic process; obstruction of lymph flow through the thoracic duct; and peri­carditis or congestive heart failure. Generalized inflammatory disease of the intestinal lymphatic network is probably the most common factor in pathogenesis of the disease. The cause of this inflammation is undetermined in most cases. Most dogs with lymphangiectasia also have mild to moderate lymphocytic-plasmacytic infiltration in the lamina propria. The fact that patients with lymphangiectasia often respond better when cor­ticosteroids are included in the treatment regimen adds credence to the theory that an inflamma­tory process is involved in the pathogenesis of the disease.

Lymphangiectasia is not commonly encoun­tered in clinical practice. Of the diseases that cause protein-losing enteropathy, IBD (especially severe lymphocytic-plasmacytic enteritis) is by far the most common. Although some dogs with lym­phangiectasia respond well to treatment, this dis­ease is not as consistently responsive to therapy as is IBD. Breed predilections for intestinal lym­phangiectasia are not documented, but there seems to be an increased incidence in Yorkshire terriers, soft-coated wheaten terriers, lundehunds, and rot­tweilers. Lymphangiectasia should be a leading consideration if hypoproteinemia is detected in any of these breeds.

Clinical Signs

The most common clinical manifestations of lym­phangiectasia are diarrhea and weight loss. It is important to note, however, that some dogs do not have diarrhea until the disease process is advanced, or there may be no incidence of diarrhea at all. Initial presentation may be directly related to signs associated with significant hypoalbuminemia and the effects of reduced colloidal osmotic pressure, including peripheral edema, ascites, and increased respiratory rate and/or distress secondary to hydrothorax. The onset of clinical signs may be acute (less than 21 days in 10 of 17 dogs in one reported case series) or chronic (greater than 21 days in 7 of 17 dogs).

When present, diarrhea is usually watery to semisolid in consistency. It may be persistent or intermittent. Vomiting may be observed in dogs with lymphangiectasia (11 of 17 dogs in one case series). Progressive weight loss is common.

Diagnosis

A definitive diagnosis of lymphangiectasia is made only on intestinal biopsy specimen analysis. The index of suspicion is heightened when the follow­ing test results are identified:

^• Panhypoproteinemia (often between 2.5 and 5.0 g/dl total protein at the time of diagno­sis, with albumin frequently in the range of 0.8 to 1.6 g/dl)

^• Absolute lymphopenia (found in approxi­mately 70% of cases and due to loss of lym­phocytes into the gut lumen)

^• Hypocholesterolemia

^• Hypocalcemia

Lymphopenia is also a common hematologic finding in “stressed” patients however, and this fac­tor should not be overlooked when the hemogram is reviewed (a “stress” leukogram also includes neu­trophilia and eosinopenia).

Lymphangiectasia must be differentiated from other protein-losing enteropathies and from non- intestinal causes of hypoproteinemia (primarily liver and kidney disease). If hypoproteinemia occurs in association with kidney and liver disease, it is usually primarily due to a decrease in the albumin fraction (impaired synthesis in liver disease and increased loss through the glomeruli in protein­losing glomerulonephropathy). Liver function test­ing (e.g., serum bile acids assay) and urine protein determinations (e.g., urine protein-creatinine ratio) are very useful in evaluating for presence of liver and kidney disease.

Intestinal biopsy specimens can be obtained at either endoscopy or surgery. Endoscopy offers a safer approach to obtaining small bowel biopsy samples in protein-losing enteropathy cases in which there is concern that full-thickness biopsy sites may heal slowly. This is an especially important consideration in patients with a total protein level less than 3.5 g/dl. Lymphangiectasia has a characteristic histo­logic appearance. The severity of lesions is usually graded as mild, moderate, or severe. Lymphangitis may be present as well. Concurrent inflammatory cell infiltrates are usually found on histologic examination.

In some cases pronounced gross changes can be seen at endoscopy (white “cottony” appearance or multifocal white granular foci of the mucosa, occasional presence of pooled mucoid lymph fluid in the intestinal lumen). Occasionally a diagnosis of lymphangiectasia is missed if only the descend­ing duodenum is examined and sampled during biopsy. In dogs with hypoproteinemia associated with chronic diarrhea, it is best to examine both upper (duodenum, and jejunum if it can be reached) and lower small intestine (the ileum can be entered after traversing the colon) to obtain samples from as many areas as possible. This approach maximizes the likelihood that represen­tative biopsy samples will be obtained.

Gross lesions that may be observed at lapa­rotomy include a prominent weblike network of dilated milky-white lymphatic channels; small yellow-white granulomas (lipogranulomas) adja­cent to lymphatics; patchy, foamy white deposits on the serosa; and diffuse intestinal thickening.

I have found that it is very difficult to diagnose lymphangiectasia in rottweilers endoscopically. This is primarily because lesions in this breed are frequently most prominent in the jejunum, an area of the small intestine that is difficult to reach in large-breed dogs with an endoscope. Typical clinical signs in rottweilers include weight loss, chronic intermittent diarrhea, decreased appetite, and occasionally peripheral edema. There is usu­ally significant hypoproteinemia (often ranging from 2.8 to 4.0 g/dl). The lymphocyte count is frequently but not always low. Biopsy speci­mens from duodenum and ileum often reveal only mild lymphocytic-plasmacytic enteritis in rottweil­ers with lymphangiectasia. This mild degree of inflammatory infiltrate is not enough to explain the degree of hypoproteinemia and clinical signs that are often present, and this finding certainly should raise suspicions that a more significant process is involved.

If a disorder that is consistent with the clinical presentation is diagnosed at endoscopy (e.g., mod­erate to severe IBD), treatment for that disorder should be instituted. If there is suspicion that a dis­ease other than what was diagnosed at endoscopy is present, ideally exploratory surgery should be done next to evaluate the serosa and mesentery for gross evidence of lymphangiectasia and to obtain full-thickness intestinal biopsy samples. If the dog is judged to be a poor surgical candidate, treatment for lymphangiectasia and IBD should be insti­tuted. The prognosis for reasonable control in rottweilers is guarded to fair. The prognosis is bet­ter if the dog eats enough of the prescribed diet to effect weight gain.

Treatment

The cornerstone of treatment for lymphangiecta­sia is dietary management.

The ideal diet for lymphangiectasia should contain minimal fat (long-chain triglycerides) and provide an ample quantity of high-quality protein. Absorption of long-chain triglycerides from the diet stimulates an increase in intestinal lymph flow, thus promoting further engorgement of intestinal lacteals and subsequent loss of more protein. Fat restriction helps decrease lymphatic hypertension by decreasing lymph flow and aids in controlling diarrhea, presumably by reducing steatorrhea.

Initially a home-prepared diet that includes nonfat or low-fat cottage cheese as the primary protein source and carbohydrate sources such as boiled rice, potatoes, and pasta is fed (one part cot­tage cheese and three parts carbohydrate source). White turkey and potatoes is a formulation that also works well for some dogs. Yogurt can also be used as a source of protein. Diets should be supplemented with a fat-soluble vitamin.

One of the greatest difficulties encountered in managing dogs with lymphangiectasia is that some tend to be inappetent, even when corticosteroids are included in the treatment regimen. Owners should be encouraged to try a variety of low-fat foods until they find something that the dog will eat. Sometimes breakfast cereals are readily ingested. Persistent coaxing may be required. Once a dog with lymphangiectasia begins to eat well, there is often noticeable clinical improve­ment and the prognosis gradually begins to improve. For example, removal of ascitic fluid from a significantly distended abdomen may promote a return to a normal appetite.

As improvement in overall condition occurs (increase in weight, resolution of diarrhea if it was present, increase in serum protein levels), commer­cial foods can be added gradually on a trial basis. Some clinicians elect to feed commercial diets at the outset of therapy. Special commercial diets such as Innovative Veterinary Diets (IVD) Select Care Canine Sensitive formula, IVD Vegetarian Diet, Iams Low Residue (Iams Food Co), and Prescription Diet i/d and/or w/d (Hill's Pet Products) can be tried. One significant disadvan­tage of feeding low-fat calorie-restricted diets such as Prescription Diet r/d in dogs with lymphan­giectasia is that when this type of food is used as the primary diet, it is difficult to meet the patient's total energy requirements. Palatability can also be a problem. Some dogs do best when fed a combi­nation of home-prepared and commercial foods. Long-term dietary management is required in most cases.

Most dogs with lymphangiectasia benefit from corticosteroid therapy. Prednisone is administered at 1 to 1.5 mg/lb daily for 2 to 4 weeks and then gradually decreased to a maintenance level of 0.1 to 0.2 mg/lb every other day. If there is an excellent response to dietary management and corticosteroids, the corticosteroids can often be discontinued after 3 to 6 months' total treatment time.

If there is poor weight gain despite adequate food intake, it is sometimes beneficial to supple­ment the diet with medium-chain triglycerides (MCT Oil). Medium-chain triglycerides are hydrolyzed more rapidly and efficiently than long- chain triglycerides and are absorbed directly into the portal system, thus bypassing the diseased lym­phatics. The primary purpose of supplementing the diet with medium-chain triglycerides is to sup­ply extra calories. MCT Oil contains 8 kcal/ml. The recommended dose is 0.5 to 1 ml/lb mixed in food. Because most dogs (and humans!) do not like the taste of MCT Oil, gradual introduction and thorough mixing in the food are recom­mended. I do not routinely recommend using MCT Oil with dogs other than those that I feel will significantly benefit from its use.

Pythiosis

Pythiosis is a severe and often fatal cause of chronic GI or cutaneous disease in dogs living mostly in tropical or subtropical climates. In the United States most cases are seen in the Gulf Coast region, but it has been seen as far north as southern Indiana, Missouri, Kentucky, and North Carolina. There are also rare cases in cats that involve mostly invasive subcutaneous lesions. Pythiosis is caused by the aquatic oomycete Pythium insidio­sum. The infective stage of P. insidiosum is thought to be the zoospore, which is released into warm water environments. Infection is caused either through encystment in the skin or through ingestion. GI pythiosis causes severe segmental transmural thickening of the GI tract with variable mucosal ulceration and mesenteric lymphadenopathy.

There are other fungal agents of the class Zygomycetes that can cause severe intestinal and skin disease. It is difficult to differentiate some of the agents, however, and so the general term zygomycosis is often used. Dogs with zygomycosis oftentimes are undifferentiated from those cases with pythiosis. These infections were formerly misnamed phycomycosis (outdated name that should no longer be used).

Historically, definitive diagnosis of pythiosis and zygomycosis has been difficult because of the challenges inherent in obtaining a culture-based confirmation of these organisms. Therefore a pre­sumptive diagnosis has often been made (i.e., “sus­pected pythiosis”) based on histopathologic findings. Newer tests are now available that are making specific diagnosis somewhat easier.

Clinical signs include chronic intractable diar­rhea and vomiting, loss of appetite, depression, and chronic weight loss. The diarrhea may become bloody due to intestinal necrosis and ulceration. Extensive granulomatous reaction may cause pal­pable enteromesenteric masses to develop. There may eventually be spread to other abdominal viscera.

Baseline laboratory tests may reveal mild to mod­erate nonregenerative anemia, neutrophilic leukocy­tosis, and panhypoproteinemia. Survey abdominal radiography may reveal a mass effect, and barium contrast radiography may identify an area of obstruction. Abdominal ultrasonography can iden­tify intestinal thickening and lymphadenopathy. Rectal scraping cytologic analysis may reveal organ­isms as may a fecal culture. Historically diagnosis has been dependent on histologic identification of characteristic hyphae in biopsy samples of stomach, intestine, or abdominal lymph nodes. Diagnostic tissue samples are best obtained surgically, because endoscopic biopsy techniques do not reliably har­vest adequate tissue in all cases for diagnosis of pythiosis. Extensive tissue reaction may be evident at laparotomy, and this should not be mistaken for neoplasia. It is best to obtain tissues and await a his­tologic diagnosis rather than making assumptions based on visual inspection alone.

The clinical faculty at Louisiana State University has extensive experience in diagnosis and manage­ment of pythiosis and zygomycosis, and some prom­ising new tests have recently been developed in their laboratory. These include polymerase chain reaction (PCR)-based assays and serologic analysis. There is now a PCR test available for identification of P. insidiosum. This assay can be applied to DNA extracted either from cultured isolates or from appropriately preserved infected tissue samples. The test will reliably differentiate P. insidiosum from other Pythium species. A new highly specific and sensitive mycelial antigen-based ELISA assay for the detec­tion of anti—P. insidiosum antibodies is also now available for use on samples from both dogs and cats. This test provides an excellent means for mak­ing an early, noninvasive diagnosis and also provides an excellent means for monitoring response to therapy. This is especially important with regard to the GI form of the disease because, unlike skin lesions, the lesions cannot be visually monitored by the owner.

Treatment

The treatment of choice for pythiosis is aggressive surgical removal of lesions. Complete resection provides the best chance for long-term cure. For intestinal lesions the goal is to resect infected tis­sues with 4- to 6-cm margins. Postoperative med­ical management is also necessary, because there is always a chance for local recurrence. Medical management using itraconazole either with or without terbinafine is recommended for a period of 2 to 4 months after surgery. Drug cost is a sig­nificant concern for some owners. If medical man­agement cannot be afforded, then ELISA serologic analysis is recommended at several-month inter­vals for up to a year after surgery to monitor for evidence of recurrence.

Medical management alone is often unreward­ing, but this is the only choice in patients that have diffuse nonresectable disease. The internal medicine service at Louisiana State University has reported that in recent years about 15% of their cases of pythiosis in dogs have responded to either itraconazole at 5 mg/lb every 24 hours for 3 to 6 months or amphotericin B lipid com­plex (Abelcet) 1 to 1.5 mg/lb administered intra­venously over several hours every other day to a cumulative dose of 11 to 12.5 mg/lb. The drugs can also be used in combination, or, alternatively, itraconazole and terbinafine (2.5 to 5 mg/lb per 24 hours) can be used in combination. Com­bination has been shown to achieve a better response overall, although the prognosis still remains very guarded.