Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

Reversal of secondary protein-losing enteropathy after surgical revision of a jejunal Roux-en-Y loop in a patient after liver transplantation.

Secondary protein-losing enteropathy (PLE) is a rare complication following pediatric liver transplantation (LT), mostly related to venous outflow obstruction of the liver. Here, we discuss a thus far unknown cause of secondary PLE following pediatric LT. A 7-month-old boy underwent LT with biliary anastomosis using a Roux-en-Y jejunal loop. Eleven months later he developed PLE. Routine diagnostic workup was negative. No hepatic outflow obstruction was detected during catheterization. Although the hepatic venous pressure gradient was slightly increased (10 mm Hg), there were no clinical signs of portal hypertension. Albumin scintigraphy with specific early recordings suggested focal albumin intestinal entry in the jejunal Roux-en-Y loop. Local bacterial overgrowth or local lymphangiectasia, possibly due to (venous) congestion, was considered. Treatment with metronidazole did not improve albumin loss. Next, surgical revision of the jejunal Roux-en-Y loop was performed. The explanted loop contained a small abnormal area with a thin hyperemic mucosa, near the former anastomosis. Histopathological analysis showed changes both in the blood vessels and the lymphatic vessels with focal deeper chronic active inflammation resulting in congestion of vessels, hampering lymphatic outflow leading to lymphangiectasia and patchy distortion of lymphatic vessels. Following surgical revision, secondary PLE disappeared, up to now, 1.5 year post revision.

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy.

BACKGROUND: Protein-losing enteropathy (PLE) is characterised by gastrointestinal protein leakage due to loss of mucosal integrity or lymphatic abnormalities. PLE can manifest as congenital diarrhoea and should be differentiated from other congenital diarrhoeal disorders. Primary PLEs are genetically heterogeneous and the underlying genetic defects are currently emerging. OBJECTIVES: We report an infant with fatal PLE for whom we aimed to uncover the underlying pathogenic mutation. METHODS: We performed whole exome sequencing (WES) for the index patient. Variants were classified based on the American College of Medical Genetics and Genomics guidelines. WES results and our detailed clinical description of the patient were compared with the literature. RESULTS: We discovered a novel homozygous stop mutation (c.988C>T, p.Q330*) in the Plasmalemma Vesicle-Associated Protein (PLVAP) gene in a newborn with fatal PLE, facial dysmorphism, and renal, ocular and cardiac anomalies. The Q330* mutation is predicted to result in complete loss of PLVAP protein expression leading to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE. Recently, another single homozygous stop mutation in PLVAP causing lethal PLE in an infant was reported. CONCLUSIONS: Our findings validate PLVAP mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.

Somatic PTPN11 Mutation in a Child With Neuroblastoma and Protein Losing Enteropathy.

Neuroblastoma and protein losing enteropathy (PLE) are diagnoses commonly seen by oncologists and gastroenterologists, respectively. The concurrence of these 2 entities is rare, and not well explained. We describe the sixth case of PLE in a child with neuroblastoma, and the first for which genetic information is available. Tumor DNA had a mutation in the PTPN11 gene, which has been described in neuroblastoma, and in Noonan syndrome-a diagnosis in which neuroblastoma and PLE independently have been reported. Constitutional DNA was normal. Genetic studies in future patients will be needed to support the link between neuroblastoma and PLE.

Clinicopathologic and prognostic factors in short- and long-term surviving dogs with protein-losing enteropathy.

INTRODUCTION: The aim of the present study was to investigate the differences in the characteristics of short- and long-term surviving dogs with protein-losing enteropathy (PLE) and to identify factors that predict its outcome. We retrospectively reviewed the medical records of 59 client- owned dogs with PLE diagnosed at three different hospitals between January 2009 and November 2013. The dogs were classified as either short-term (= 6 months; STs) or long-term (> 6 months; LTs) survivors. Clinical and clinicopathological variables were investigated between the groups and receiver operating characteristic (ROC) curve analysis was performed. Nineteen dogs were classified as STs and 40 as LTs. Body weight and blood urea nitrogen concentrations were significantly higher in the STs at diagnosis (P < 0.05). At 1 month after initiation of immunosuppressive therapy (data- driven cut-off, T1), chronic canine enteropathy clinical activity index (CCECAI) scores were higher (P < 0.01) and albumin, serum total protein and total cholesterol concentrations were lower (P < 0.01) in the STs. ROC curve analysis showed that CCECAI > 5 evaluated at T1 was the best predictor of poor outcome. Although the severity of clinical signs and the majority of clinicopathological findings at diagnosis did not influence the outcome, survival time was shorter in the dogs with high CCECAI scores at T1 and which did not respond to therapy.

INTRODUCTION: Le présent travail avait pour buts d'étudier quels sont les différences de symptômes chez les chiens survivant à court et à long terme à une d'entéropathie exsudative (PLE) et d'identifier les facteurs ayant une valeur pronostique. On a étudié pour cela les dossiers médicaux de 59 chiens sur lesquels une entéropathie exsudative avait été diagnostiquée dans trois cliniques différentes entre janvier 2009 et novembre 2013. Les chiens ont été classés comme survivants à court terme (= 6 mois; STs) respectivement à long terme (= 6 mois; LTs). Les variations cliniques et clinico-pathologiques entre les groupes ont été relevées et une courbe ROC a été établie. Dixneuf chiens ont été classés comme STs et 40 comme LTs. Le poids corporel et la concentration sanguine d'urée était significativement plus élevée (P < 0.05) chez les STs que chez les LTs. Un mois après le début d'une immunosuppression (cut-off établi sur la base des données disponibles, T1), le score clinique d'activité pour une entéropathie chronique chez le chien (CCEAI) était plus élevé chez les STs que chez les LTs(P < 0.01), les valeur sanguines d'albumine, de protéines totales et de cholestérine totale par contre plus basses (P < 0.01). Dans l'analyse par la courbe ROC, un CCEAI > 5 à T1 s'est avéré être un indice fiable quant à une évolution de courte ou de longue durée. Bien que l'étendue des symptômes cliniques et la quantité des découvertes clinico-pathologiques n'aient pas influencé le pronostic, le taux de survie des chiens avec un CCEAI élevé à T1 et de ceux qui n'avaient pas répondu au traitement a été plus faible.

Sjögren's syndrome associated with protein losing gastroenteropathy manifested by intestinal lymphangiectasia successfully treated with prednisolone and hydroxychloroquine.

Protein-losing gastroenteropathy (PLGE), a rare manifestation of primary Sjögren's syndrome (SS), is characterized by profound edema and severe hypoalbuminemia secondary to excessive serum protein loss from the gastrointestinal tract and is clinically indistinguishable from nephrotic syndrome. We report a case of a 30-year-old Taiwanese woman with PLGE-associated SS. In addition to a positive Schirmer's test, she had eye-dryness, thirst, and high levels of anti-SSA antibodies, fulfilling SS criteria. PLGE diagnosis was highly appropriate given the clinical profile of hypoalbuminemia, hypercholesterolemia, pleural effusion, and ascites, with absent cardiac, hepatic, or renal disease. We were unable to perform technetium-99 m-labeled human serum albumin scintigraphy ((99m)Tc-HAS). However, the patient's edema and albumin level improved dramatically in response to a 3-month regime of oral prednisolone followed by oral hydroxychloroquine.

A rare cause of protein losing enteropathy: collagenous sprue.

Collagenous sprue is a clinicopathological entity with an unknown etiology. Its clinical features include progressive malabsorption, diarrhea, weight loss, unresponsiveness to treatment, and high mortality rates. The age interval of collagenous sprue is quite broad and ranges between 2 and 85 years. As far as to our knowledge, the presented case is the first reported case in infancy.

Classification of intestinal lymphangiectasia with protein-losing enteropathy: white villi type and non-white villi type.

BACKGROUND/AIMS: We classified intestinal lymphangiectasia (IL) into two categories, the white and non-white villi types, and evaluated their clinical characteristics and therapeutic responses. METHODS: Of the 988 patients who underwent double-balloon enteroscopy, 14 consecutive patients (7 men and 7 women, median age at onset 34 years) were enrolled with immunohistochemically confirmed IL with protein-losing enteropathy. RESULTS: Enteroscopically the white villi type (n = 8) showed white plaques and white-tipped villi were scattered in the small bowel, while non-white villi type (n = 6) showed that apparently normal but under more detailed observation, low and round villi with a normal color were diffused. The serum albumin levels and fecal α1-antitrypsin clearance before treatment were significantly worse in the non-white villi type (p = 0.017 and 0.039, respectively), whereas the serum immunoglobulin A and M levels were significantly lower in the white villi type (p = 0.010 and 0.046, respectively). At gastroscopy, a non-cirrhotic snakeskin appearance was significantly observed in the non-white villi type (p = 0.015). The corticosteroid response was better in the non-white villi type (p = 0.015). CONCLUSION: Two distinct subgroups were found in IL. This classification was useful in pathophysiological clustering and in predicting the therapeutic response.

Use of octreotide for the treatment of protein-losing enteropathy in dogs: Retrospective study of 18 cases.

BACKGROUND: More than 50% of dogs with protein-losing enteropathy (PLE) fail to respond to standard therapies. Octreotide, a somatostatin analogue, is used in cases of intestinal lymphangiectasia (IL) in humans with some success. OBJECTIVES: Describe the use of octreotide in dogs with PLE including reason for and details of prescription, adverse effects, and apparent response. ANIMALS: Eighteen dogs with PLE, 13 with histopathology available. Ninety-two percent (12/13) had IL diagnosed on biopsy. All 13 dogs had intestinal inflammatory infiltrates noted. METHODS: Multicenter, retrospective, descriptive study. Cases were volunteered for inclusion by individual attending veterinarians who reported the use of octreotide in cases of PLE. RESULTS: In 16/18 (89%) cases octreotide was prescribed to PLE dogs with a clinical suspicion or confirmed diagnosis of IL that were refractory to standard therapies. Median serum albumin at the time of octreotide prescription was 1.7 g/dL (range, 1.0-3.1 g/dL). The median dose of octreotide prescribed was 20 µg/kg, SQ, daily with a range of 4-39 µg/kg, SQ, daily. Adverse effects were noted in 3/18 (17%, 95% CI [4%, 41%]) of dogs; discontinuation of the drug was necessary in 1 dog. Improvement in clinical signs was noted in 6/12 (50%, 95% CI [21%, 79%]). CONCLUSIONS AND CLINICAL IMPORTANCE: Octreotide was most commonly prescribed to dogs with PLE and suspected or confirmed IL that had failed to respond to standard therapies. Though a benefit to PLE dogs cannot be confirmed, octreotide was well tolerated by the majority of dogs at the doses prescribed in this study.

Randomized controlled trial of hydrolyzed fish diets in dogs with chronic enteropathy.

BACKGROUND: The role of diet in the pathogenesis and treatment of chronic enteropathies (CE) in dogs is unresolved. OBJECTIVES: To compare the ability of diets composed of hydrolyzed fish, rice starch, and fish oil without (HF) or with prebiotics, turmeric, and high cobalamin (HF+) against a limited ingredient diet containing mixed nonhydrolyzed antigens and oils (control) to resolve clinical signs and maintain serum cobalamin and folate concentrations in dogs with nonprotein losing CE (non-PLE). To determine the ability of hydrolyzed fish diets to support recovery and remission in dogs with PLE. ANIMALS: Thirty-one client-owned dogs with CE: 23 non-PLE, 8 PLE. METHODS: Randomized, blinded, controlled trial. Diets were fed for 2 weeks; responders continued for 12 weeks. Nonresponders were crossed over to another diet for 12 weeks. Response was determined by standardized clinical evaluation with long-term follow-up at 26 weeks. Concurrent medications were allowed in PLE. RESULTS: Nineteen of 23 (83%; 95% confidence interval [CI], 60%-94%) non-PLE CE responded clinically to their initial diet, with no difference between diets (P > .05). Four nonresponders responded to another diet, with sustained remission of 18/18 (100%; 95%CI, 78%-100%) at 26 weeks. Serum cobalamin concentration was increased (P < .05) and maintained by diet. Serum folate concentration decreased posttreatment (P < .05) but was restored by dietary supplementation. Hydrolyzed fish diets supported weight gain, serum albumin concentration, and recovery (P < .05) in dogs with PLE. CONCLUSIONS AND CLINICAL IMPORTANCE: Changing diet, independent of antigen restriction or supplemental ingredients, induced long-term remission in dogs with non-PLE CE. Serum cobalamin and folate concentrations were maintained by diet. Hydrolyzed fish diets supported clinical recovery and remission in PLE.

Intestinal helminths-an outlander in a case of protein losing enteropathy.

Malabsorption is the major disease burden in tropical countries. Both primary and secondary forms exist and a secondary form overshadows the primary category. Intestinal parasitic infections lead to secondary form of tropical malabsorption in both native and travelers and presentation varies from mild glossitis to severe protein losing enteropathy. The underlying condition is often masked unless an endoscopic biopsy is performed. This is followed by a histopathological examination which unravels the etiology.

Computed tomographic features of focal lipogranulomatous lymphangitis for differentiating from malignant intestinal lesions in a dog.

An eight-year-old Maltese dog presented with diarrhea and anorexia. Ultrasonography revealed marked focal wall thickening with loss of layering in the distal ileum. Contrast-enhanced computed tomography (CT) revealed a preserved wall layer with hypoattenuating middle wall thickening. In some segments of the lesion, small nodules protruding toward the mesentery from the outer layer were observed. Histopathology revealed focal lipogranulomatous lymphangitis (FLL) with lymphangiectasia. This is the first report to describe the CT features of FLL in a dog. CT features of preserved wall layers with hypoattenuating middle wall thickening and small nodules can assist in diagnosing FLL in dogs.

Progressive mesenteric lymphadenopathy with protein-losing enteropathy; a devastating complication in Gaucher disease.

Mesenteric lymphadenopathy has been rarely reported in pediatric patients with Gaucher disease, developing despite the enzyme replacement therapy. The clinical implication of this condition is undetermined, with no consensus on treatment strategies. However, this condition can reflect the progression of Gaucher disease. Moreover, it can be accompanied by the serious complication, protein-losing enteropathy. Our experience underlines the importance of careful monitoring and early intervention for mesenteric lymphadenopathy, especially in pediatric patients with neuronopathic Gaucher disease.

Endoscopic and imaging findings in protein-losing enteropathy.

OBJECTIVES: Protein-losing enteropathy (PLE) is often difficult to diagnose. We evaluated the diagnostic yields of underlying diseases of PLE among esophagogastroduodenoscopy, colonoscopy, fluoroscopic conventional enteroclysis (FCE), videocapsule endoscopy (VCE), and double-balloon enteroscopy (DBE) and prognosis after treatment. METHODS: Between June 2003 and August 2010, 25 consecutive patients with PLE confirmed by fecal α1-antitrypsin clearance (n=18) and technetium 99m human serum albumin scintigraphy (n=19) were enrolled, investigated, and treated. RESULTS: Of 25 patients, 4 (16%) with intestinal lymphangiectasia secondary to macroglobulinemia (n=1), amyloidosis (n=2), and strongyloidiasis (n=1) were diagnosed at preceding esophagogastroduodenoscopy or colonoscopy, and 7 (32%) with primary intestinal lymphangiectasia and chronic nonspecific multiple ulcers unrelated to nonsteroidal anti-inflammatory drugs of the small intestine were newly diagnosed at FCE or VCE. Other 11 (44%) patients with primary intestinal lymphangiectasia, small-bowel tumors, amyloidosis, chronic nonspecific multiple ulcers unrelated to nonsteroidal anti-inflammatory drugs of the small intestine, Crohn's disease, and small-bowel ulcers due to polyarteritis nodosa were diagnosed only at DBE with biopsy. Three patients with primary intestinal lymphangiectasia, cirrhosis after living donor liver transplantation, and congestive heart failure were not diagnosed at any small-bowel examination. The overall diagnostic yield of FCE, VCE, and DBE was 62% (8/13), 83% (14/17), and 88% (22/25), respectively. Eight patients (32%) died of underlying disorders regardless of medical treatment over the follow-up period. CONCLUSIONS: DBE with pathologic findings of biopsy specimens was useful for the differential diagnosis of PLE. Noninvasive VCE might be preferable and useful for screening and follow up of PLE without stricture. Prognosis of a subgroup of PLE was poor regardless of treatment.

An indigenous case of intestinal capillariasis with protein-losing enteropathy in Korea.

We encountered an indigenous case of intestinal capillariasis with protein-losing enteropathy in the Republic of Korea. A 37-year-old man, residing in Sacheon-si, Gyeongsangnam-do, admitted to the Gyeongsang National University Hospital (GNUH) due to long-lasting diarrhea, abdominal pain, anasarca, and weight loss. He recalled that he frequently ate raw fish, especially the common blackish goby (Acanthogobius flavimanus) and has never been abroad. Under the suspicion of protein-losing enteropathy, he received various kinds of medical examinations, and was diagnosed as intestinal capillariasis based on characteristic sectional findings of nematode worms in the biopsied small intestine. Adults, juvenile worms, and eggs were also detected in the diarrheic stools collected before and after medication. The clinical symptoms became much better after treatment with albendazole 400 mg daily for 3 days, and all findings were in normal range in laboratory examinations performed after 1 month. The present study is the 6th Korean case of intestinal capillariasis and the 3rd indigenous one in the Republic of Korea.

Alterations of selected serum biochemical and urinary parameters in dogs with chronic enteropathy.

Background: No specific study on concurrent nephropathy has been conducted in dogs with chronic enteropathy (CE), except for soft-coated Wheaten Terriers. Moreover, limited information exists regarding the urinary profile in dogs with CE. Aim: To describe, compare, and discuss the alterations in selected serum biochemical and urinary parameters in dogs with CE. Methods: Multicentric retrospective study on dogs with CE diagnosed after exclusion of extra-gastrointestinal diseases. In addition, dogs with azotemia and lower urinary tract diseases were excluded. Information on canine chronic enteropathy clinical activity index (CCECAI) score, muscular condition score (MCS), presence of glycosuria, proteinuria [urine protein-to-creatinine (UPC) ratio > 0.5], and/or cylindruria (>1-2 casts/hpf) at diagnosis were gleaned from the medical records. Dogs were retrospectively classified as food-responsive enteropathy, immunosuppressant-responsive enteropathy, or nonresponsive enteropathy based on the presence of gastrointestinal histological inflammation and the treatment response. In addition, based on the serum albumin concentration (ALB), dogs were classified as having protein-losing enteropathy (PLE). Results: Ninety CE dogs were included. Fifty-two dogs had mild-to-severely decreased MCS and 38 dogs showed altered urinary parameters. No significant associations were found between CCECAI and altered urinary parameters. No significant association was found between PLE dogs and altered urinary parameters. PLE dogs showed higher prevalence of proteinuria than non-PLE dogs (p = 0.03; OR = 2.8; 95% CI = 1-6.8). Conclusion: Despite the presence of altered urinary profile in dogs with CE, further studies are needed to explore a possible link between gastrointestinal and renal inflammation.

Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function.

Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.