Hypercoagulability in dogs with protein-losing enteropathy

Background: Dogs with protein‐losing enteropathy (PLE) have previously been reported to present with thromboembolism; however, the prevalence and pathogenesis of hypercoagulability in dogs with PLE have not been investigated so far. Hypothesis: Dogs with PLE are hypercoagulable compared with healthy control dogs. Animals: Fifteen dogs with PLE. Thirty healthy dogs served as controls (HC). Methods: A prospective study was performed including 15 dogs with PLE. All dogs were scored using the canine chronic enteropathy activity index (CCECAI). Thromboelastography (TEG) and other measures of coagulation were evaluated. Recalcified, unactivated TEG was performed and reaction time (R), kinetic time (K), alpha angle (α), and maximum amplitude (M_A) values were recorded. Nine dogs were reassessed after initiation of immunosuppressive treatment. Results: All dogs with PLE in the study were hypercoagulable with decreased R (PLE: median 7.8, range [2.4–11.2]; HC: 14.1 [9.1–20.3]), decreased K (PLE: 2.5 [0.8–5.2]; HC: 8.25 [4.3–13.1]), increased α (PLE: 56.7 [38.5–78.3]; HC: 25.6 [17–42.4]), and increased M_A (PLE: 68.2 [54.1–76.7]; HC: 44.1, [33.5–49]) (all P < .001). Median antithrombin (AT) concentration was borderline low in PLE dogs; however, mean serum albumin concentration was severely decreased (mean 1.67 g/dL ± 5.1, reference range 2.8–3.5 g/dL). Despite a significant improvement in serum albumin and CCECAI, all 9 dogs with PLE were hypercoagulable at re‐examination. Conclusions and Clinical Importance: The hypercoagulable state in dogs with PLE cannot be solely attributed to loss of AT. Despite good clinical response to treatment, dogs remained hypercoagulable and could therefore be predisposed to thromboembolic complications.     

Familial protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (1983-1997)

Records and pedigrees of Soft Coated Wheaten Terriers (SCWT) with protein-losing enteropathy (PLE) or protein-losing nephropathy (PLN) were studied retrospectively. Criteria for inclusion were defined based on analysis of blood (panhypoproteinemia for PLE, hypoalbuminemia for PLN) and urine (proteinuria for PLN) and histopathologic examination of tissue. Two hundred twenty-two affected dogs (female:male ratio = 1.6, P < .001) were clinically identified. Dogs were diagnosed with PLE earlier (P < .005; mean +/- SD age: 4.7+/-2.6 years, n = 76) than with PLN (6.3+/-2.0 years, n = 84) or with both diseases (5.9+/-2.2 years, n = 62). Clinical signs included vomiting, diarrhea, weight loss, pleural and peritoneal effusions, and less commonly thromboembolic disease. Dogs with PLE generally had panhypoproteinemia and hypocholesterolemia; intestinal lesions included inflammatory bowel disease, dilated lymphatics, and lipogranulomatous lymphangitis. Dogs with PLN generally had hypoalbuminemia, proteinuria, hypercholesterolemia, and azotemia; renal lesions typically showed chronic glomerulonephritis/glomerulosclerosis, and less commonly endstage renal disease. Dogs with combined PLE/PLN had intermediate mean values (P < .001) for serum total protein, albumin, globulin, and cholesterol but had a higher mean urine protein:creatinine ratio than did PLN dogs (P < .05); intestinal and renal lesions in these dogs were similar to those in the other groups. Two dogs had incidental mild renal dysplasia. Pedigree analysis from 188 dogs demonstrated a common male ancestor, although the mode of inheritance is unknown. Both PLE and PLN are common diseases in this small breed population. The prognosis is poor. Compared with previously reported intestinal and renal diseases in dogs, a new, distinctive familial predisposition for both PLE and PLN has been recognized in the SCWT breed.     

Evaluation of intestinal permeability and gluten sensitivity in Soft-Coated Wheaten Terriers with familial protein-losing enteropathy, protein-losing nephropathy, or both

OBJECTIVE: To evaluate intestinal permeability and gluten sensitivity in a family of Soft-Coated Wheaten Terriers (SCWT) affected with protein-losing enteropathy (PLE), protein-losing nephropathy (PLN), or both. ANIMALS: 6 affected adult dogs. PROCEDURE: Intestinal biopsy specimens, urine protein-to-creatinine ratio, serum concentrations of albumin and globulin, and concentration of alpha1-protease inhibitor in feces were evaluated before, during, and 13 weeks after daily administration of 10 g of gluten for 7 weeks. Eosinophils and lymphocytes-plasmacytes were enumerated in intestinal biopsy specimens. Intestinal permeability was evaluated before and during the sixth week of gluten administration via cellobiose-mannitol and chromium-EDTA absorption tests. RESULTS: Serum globulin concentration decreased significantly after prolonged administration of gluten. Although not significant, there was an increase in lymphocytes-plasmacytes and a decrease in eosinophils in intestinal biopsy specimens. Furthermore, these counts were greater than those reported for clinically normal dogs. Gluten administration did not increase intestinal permeability. CONCLUSIONS AND CLINICAL RELEVANCE: Daily administration of gluten was associated with a significant decrease in serum globulin concentration in SCWT affected with PLE or PLN, but other variables remained unchanged. Although enhanced wheat-gluten sensitivity may be one factor involved in the pathogenesis of PLE or PLN in SCWT, this syndrome does not appear to be the result of a specific sensitivity to gluten.     

A case of protein-losing enteropathy treated with methotrexate in a dog

A 9-year-old female Pug was presented to us with chronic diarrhea. Hematologic findings indicated severe hypoproteinemia and hypoalbuminemia, and endoscopy revealed severe edema of the duodenal mucosa. Based on these results and on additional histopathological findings, we made a diagnosis of protein-losing enteropathy caused by lymphocytic-plasmacytic enteritis with lymphangiectasia. The dog was initially treated with prednisolone and cyclosporine. This treatment regimen was not effective. However, when methotrexate was substituted for cyclosporine, progress was obtained and the diagnosis was confirmed.     

Protothecal enteritis as a cause of protein-losing enteropathy in a bull

Prototheca spp are achlorophyllic saprophytic algae found in wastewater, sewage, agricultural waste, and possibly elsewhere in the environment. Infections with these organisms have been reported in cattle, humans, and dogs; affected cattle commonly develop mastitis. A 5-year-old Brahman-cross bull was evaluated because of a history of diarrhea and weight loss. The history and physical examination and clinicopathologic findings were similar to those associated with granulomatous enteritis caused by Mycobacterium avium subsp paratuberculosis (Johne's disease), which is the most common protein-losing enteropathy of cattle. However, diagnostic tests for paratuberculosis yielded negative results. Biopsy specimens from the ileum, jejunum, and ileocecal lymph node were collected for histologic examination and preparation of tissue impression smears; Prototheca-like organisms were identified. Because of the poor prognosis associated with this infection and the lack of safe and economical therapeutic agents for cattle, the owner decided to euthanatize the bull. Infection with Prototheca organisms was confirmed postmortem. As this case illustrates, protothecosis may be a cause of granulomatous enteritis in cattle.     

Prognostic value of small intestinal dilatation in dogs with protein-losing enteropathy

To date, little is known about the prognostic significance of ultrasonographic findings in dogs with protein-losing enteropathy (PLE). The aim of this retrospective study was to examine the prognostic value of ultrasonographic findings in dogs with PLE. A total of 26 dogs with PLE were included: 20 dogs with chronic enteropathy and 6 dogs with gastrointestinal lymphoma. The presence of small intestinal dilatation was associated with shorter survival time in dogs with PLE (P=0.003). The presence of hyperechoic intestinal mucosal striations was associated with longer survival time in dogs with PLE (P=0.0085). The results of the current study indicate that the presence of small intestinal dilatation might be associated with poor prognosis in dogs with PLE.     

Intestinal crypt lesions associated with protein-losing enteropathy in the dog

Six dogs were diagnosed with protein losing enteropathy (PLE). There was no evidence of inappropriate inflammatory infiltrates or lymphangiectasia in multiple mucosal biopsies of the small intestine of 4 of the dogs. The 5th and 6th dogs had obvious lymphangiectasia and a moderate infiltrate of inflammatory cells in the intestinal mucosa. All 6 dogs had a large number of dilated intestinal crypts that were filled with mucus, sloughed epithelial cells, and/or inflammatory cells. Whether PLE occurs in these dogs because of protein lost from the dilated crypts into the intestinal lumen or whether the dilated crypts are a mucosal reaction due to another undetermined lesion that is responsible for alimentary tract protein loss is unknown. However, when large numbers of dilated intestinal crypts are present, they appear to be associated with PLE even if there are no other remarkable lesions in the intestinal mucosa.     

Small intestinal adenomatous polyposis resulting in protein-losing enteropathy in a horse

A 4-year-old Quarter Horse gelding was presented with a history of weight loss of 6 months duration, along with extensive ventral subcutaneous edema. Clinicopathologic findings included a markedly low serum total protein (2.9 g/dl) and a low packed cell volume (24%). The mucosal surface of the distal jejunum and entire ileum were carpeted with numerous polypoid, papillary, and glandular masses comprised of pseudostratified tall columnar cells and large numbers of interspersed goblet cells. Neoplastic change was diffuse throughout the mucosa of each mass, but abrupt demarcation occurred between neoplastic masses and adjacent mucosa. Immunohistochemical staining for protein of the p53 tumor suppressor gene revealed only occasional cytoplasmic reactivity within polyps and normal mucosa. Nuclear staining for papillomavirus antigens was not observed. Electron microscopic examination revealed features of well-differentiated intestinal epithelial cells, including apical tight junctions and microvilli, desmosomes, and the presence of numerous goblet cells. Microorganisms were not detected. Small intestinal polyposis should be considered as a rare differential diagnosis for protein-losing enteropathy in the horse.     

Secondary hypoparathyroidism attributed to hypomagnesemia in a dog with protein-losing enteropathy.

Severe hypomagnesemia (0.8 mg/dl; reference range, 1.6 to 2.3 mg/dl), hypocalcemia, and protein-losing enteropathy were identified in a 5-year-old castrated male 3-kg (6.6 lb) Shih Tzu examined because of anorexia, lethargy, paresis, and abdominal distention. Histologic examination of intestinal biopsy specimens revealed lymphangiectasia and lymphocytic, plasmacytic, neutrophilic infiltrates. Initial treatment included administration of magnesium (0.80 mEq/kg [0.36 mEq/lb]) of body weight in a balanced electrolyte solution. This treatment resulted in normalization of the serum magnesium concentration (1.7 mg/dl); resolution of the lethargy, paresis, and tachycardia; and an increase in the serum parathyroid hormone and ionized calcium concentrations. Findings were consistent with secondary hypoparathyroidism attributable to hypomagnesemia. Magnesium concentration should be monitored in all dogs with gastrointestinal tract disease, especially those with protein-losing enteropathy, anorexia, and weakness.     

Chronic enteritis associated with the malabsorption and protein-losing enteropathy in the horse

Chronic granulomatous enteritis associated with weight loss and hypoproteinemia was identified in 2 horses. Both horses continued to have normally formed feces. Malabsorption of carbohydrate and lipid, with concomitant gastrointestinal protein loss was demonstrated in 1 case. One horse was treated symptomatically and gained 108 kg. In both cases, principal gastrointestinal lesions were partial to total villus atrophy and transmural mononuclear leukocytosis, with lymphocytes and histiocytes predominating. The cause of the condition was not identified in either case.     

Food hypersensitivity reactions in Soft Coated Wheaten Terriers with protein-losing enteropathy or protein-losing nephropathy or both: gastroscopic food sensitivity testing, dietary provocation, and fecal immunoglobulin E

The purpose of this study was to evaluate Soft Coated Wheaten Terriers (SCWTs) affected with protein-losing enteropathy (PLE) or protein-losing nephropathy (PLN) or both for allergy to food. We performed gastroscopic food-sensitivity testing, a provocative dietary trial, and measurement of fecal immunoglobulin E (IgE) in 6 SCWTs affected with PLE or PLN or both. Positive gastroscopic food-sensitivity test reactions were noted in 5 of 6 dogs. Positive reactions were found to milk in 4 dogs, to lamb in 2 dogs, and to wheat and chicken each in 1 dog. Adverse reactions to food (diarrhea, vomiting, or pruritus) were detected in all 6 dogs during the provocative dietary trial. Adverse reactions were found to corn in 5 dogs, to tofu in 3 dogs, to cottage cheese in 2 dogs, to milk in 2 dogs, to farina cream of wheat in 2 dogs, and to lamb in 2 dogs. Serum albumin concentrations significantly decreased and fecal alpha1-protease inhibitor concentration significantly increased 4 days after the provocative trial when compared with baseline values. Antigen-specific fecal IgE varied throughout the provocative trial, with peak levels following ingestion of test meals. We conclude that food hypersensitivities are present in SCWTs affected with the syndrome of PLE/PLN. Mild inflammatory bowel disease was already established in the 6 SCWTs of this report at the time of study, making it impossible to determine if food allergies were the cause or result of the enteric disease.     

Serum concentrations of the third component of complement in healthy dogs and dogs with protein-losing nephropathy

OBJECTIVE: To develop a method for determining the concentration of the third component of complement (C3) in canine serum, to establish a reference range for C3 in healthy dogs, and to evaluate dogs with protein-losing nephropathy (PLN) to determine whether PLN is associated with decreased serum C3 concentrations. ANIMALS: 30 healthy dogs and 49 dogs with PLN. PROCEDURES: Serum samples were obtained from healthy dogs at the time of examination, whereas serum samples were obtained from dogs with PLN at the time of diagnosis. All samples were frozen at -70 degrees C until analyzed. Serum C3 concentrations were determined by use of a sandwich ELISA. Concentrations were expressed as the number of dilutions in which C3 could be detected. RESULTS: C3 was detectable in healthy control dogs (range, 1,920,000 to 15,400,000 dilutions; median, 9,600,000 dilutions). This represented a range of four 2-fold serum dilutions. In addition, C3 was detectable in dogs with PLN (range, 1,460,000 to 30,070,000 dilutions; median, 7,680,000 dilutions), which represented a range of six 2-fold serum dilutions. There was no significant difference in C3 concentrations between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: C3 is a critical part of the immune defense system that has not been extensively examined in veterinary medicine. An ELISA was developed for measuring C3 concentrations, and a reference range for healthy dogs was established. Significant decreases in C3 concentrations were not detected in any dog with PLN. Additional studies will be required to definitively determine the importance of serum C3 concentrations in PLN.     

Hypocalcaemia associated with low serum vitamin D metabolite concentrations in two dogs with protein-losing enteropathies

Protein-losing enteropathies were diagnosed in two dogs that were initially presented with diarrhoea and weight loss. Plasma biochemistry in both cases revealed low concentrations of albumin, calcium and ionised calcium. Both dogs had an elevated plasma parathyroid hormone concentration and low serum 25-hydroxyvitamin D (25[OH]D) concentration. The first dog was diagnosed with lymphangiectasia on postmortem examination, and the second dog was diagnosed with chronic lymphocytic/ plasmacytic enteritis and severe cystic mucoid changes based on endoscopic duodenal biopsies. While a causal effect was not demonstrated, the protein-losing enteropathies may have caused reduced intestinal absorption of vitamin D leading to low plasma concentrations of ionised calcium and secondary hyperparathyroidism. To the authors' knowledge, this is the first report of low ionised calcium concentrations, low 25(OH)D and 1,25-dihydroxyvitamin D concentrations, and high parathyroid hormone concentrations in dogs with protein-losing enteropathies.     

Cranial edema associated with a protein-losing nephropathy in a golden-mantled flying fox (Pteropus pumilus).

An adult golden-mantled flying fox (Pteropus pumilus) was diagnosed with nephrotic syndrome on the basis of the findings of proteinuria, hypoalbuminemia, hypercholesterolemia, and cranial edema. Membranoproliferative glomerulitis and interstitial nephritis were confirmed antemortem by renal biopsy. The bat had received seven injections of oxytocin in the period immediately prior to presentation. The possible role of oxytocin in the development of the nephropathy is discussed. Supportive care and treatment with a single plasma transfusion, furosemide, and prednisone led to a gradual but complete resolution of the nephrotic syndrome in this animal.