Glycomacropeptide Ameliorates Indomethacin-Induced Enteropathy in Rats by Modifying Intestinal Inflammation and Oxidative Stress.

Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is considered a serious and increasing clinical problem without available treatment. Glycomacropeptide (GMP) is a 64-amino acid peptide derived from milk κ-casein with numerous biological activities. The aim of this study was to investigate the protective effect of GMP on NSAID enteropathy in rats. Enteropathy was induced by seven days oral indomethacin administration. Rats were orally GMP treated from seven days previous and during the establishment of the enteropathy model. Changes in metabolism, hematological and biochemical blood alterations, intestinal inflammation and oxidative damage were analyzed. Integrity barrier markers, macroscopic intestinal damage and survival rate were also evaluated. GMP treatment prevented anorexia and weight loss in animals. Furthermore, prophylaxis with GMP ameliorated the decline in hemoglobin, hematocrit, albumin and total protein levels. The treatment had no therapeutic efficacy on the decrease of occludin and mucin (MUC)-2 expression in intestinal tissue. However, GMP markedly decreased neutrophil infiltration, and CXCL1, interleukin-1ß and inducible nitric oxide synthase expression. Nitric oxide production and lipid hydroperoxide level in the small intestine were also diminished. These beneficial effects were mirrored by preventing ulcer development and increasing animal survival. These results suggest that GMP may protect against NSAID enteropathy through anti-inflammatory and antioxidant properties.

The Consequence of Excessive Consumption of Cow's Milk: Protein-Losing Enteropathy with Anasarca in the Course of Iron Deficiency Anemia-Case Reports and a Literature Review.

Cow's milk is a key component of a child's diet. While the consumption of even trace amounts can result in allergy to its proteins and/or hypolactasia, excessive cow's milk consumption can result in numerous health complications, including iron deficiency, due to the diet being improperly balanced. Although the incidence of iron deficiency has declined, it remains the most widespread nutritional deficiency globally and the most common cause of anemia. One rare consequence of anemia caused by iron deficiency is protein-losing enteropathy; however, the mechanisms of its development are unclear. The following manuscript, based on a literature review, presents two rare cases of children, a 16-month-old boy and a 2.5-year-old girl, who developed severe microcytic anemia, enteropathy with hypoalbuminemia, and anasarca as a result of excessive cow's milk consumption. It highlights the possible relationship between excessive consumption of cow's milk in children and severe iron deficiency anemia with accompanying hypoalbuminemia; it may also result in serious clinical conditions, even in children that do not demonstrate food hypersensitivity.

Cyclophosphamide-associated enteritis presenting with severe protein-losing enteropathy in granulomatosis with polyangiitis: A case report.

BACKGROUND: Although cyclophosphamide (CPA) is the key drug for the treatment of autoimmune diseases including vasculitides, it has some well-known adverse effects, such as myelosuppression, hemorrhagic cystitis, infertility, and infection. However, CPA-associated severe enteritis is a rare adverse effect, and only one case with a lethal clinical course has been reported. Therefore, the appropriate management of patients with CPA-associated severe enteritis is unclear. CASE SUMMARY: We present the case of a 61-year-old woman diagnosed with granulomatosis with polyangiitis based on the presence of symptoms in ear, lung, and, kidney with positive myeloperoxidase-antineutrophil cytoplasmic antibody. She received pulsed methylprednisolone followed by prednisolone 55 mg/d and intravenous CPA at a dose of 500 mg/mo. Ten days after the second course of intravenous CPA, she developed nausea, vomiting, and diarrhea, and was admitted to the hospital. Laboratory testing revealed hypoalbuminemia, suggesting protein-losing enteropathy. Computed tomography revealed wall thickening of the stomach, small intestine, and colon with contrast enhancement on the lumen side. Antibiotics and immunosuppressive therapy were not effective, and the patient's enteritis did not improve for > 4 mo. Because her condition became seriously exhausted, corticosteroids were tapered and supportive therapies including intravenous hyperalimentation, replenishment of albumin and gamma globulin, plasma exchange, and infection control were continued. These supportive therapies improved her condition, and her enteritis gradually regressed. She was finally discharged 7 mo later. CONCLUSION: Immediate discontinuation of CPA and intensive supportive therapy are crucial for the survival of patients with CPA-associated severe enteritis.

Lupus-associated protein losing enteropathy (LUPLE) complicated by a hypercoagulable state and successfully treated with belimumab.

Protein-losing enteropathy (PLE) is a condition characterized by gut mucosal injury that typically manifests with edema and hypoalbuminemia due to protein loss in the GI tract. We present a rare case of lupus-associated PLE (LUPLE) manifested by profound edema, diarrhea, and thrombotic complications. Through our case report, we discuss the typical clinical presentation, diagnostic studies available, and treatment options for these patients. Our patient's clinical picture and laboratory markers improved with the initiation of corticosteroids and belimumab, which is a novel treatment regimen for LUPLE. Moreover, our patient was found to have a clinically significant hypercoagulable state that was ultimately attributed to PLE in the setting of systemic lupus erythematosus (SLE). We highlight the increased thrombotic risk in these patients and the subsequent management implications with regard to anticoagulation. Gastroenterologists are likely to be involved in the care of these patients, and may be the first to recognize the constellation of findings in PLE, leading to potentially very effective treatment.

Intestinal toxicity of non-steroidal anti-inflammatory drugs.

We review the adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the small and large intestine. NSAIDs cause small intestinal inflammation in 65% of patients receiving the drugs long-term. The clinical implications of NSAID-induced enteropathy are that patients bleed and lose protein from the inflammatory site, contributing to iron deficiency and hypoalbuminemia, respectively. Some patients develop intestinal strictures, which may require surgery, and the occasional one may develop discrete ulcers with perforations. There are a number of therapeutic options available to treat the enteropathy and the attendant complications, including antibiotics, sulphasalazine and misoprostol. The colon, by comparison, is only rarely affected by NSAIDs, but colitis is well recognized and NSAIDs may be an important factor in diverticular complications and the relapse of inflammatory bowel disease. There is an association between NSAID intake and appendicitis in the elderly.

Pharmacological protection of NSAID-induced intestinal permeability in the rat: effect of tempo and metronidazole as potential free radical scavengers.

Recently, NSAID-induced changes in both the structure and function of the distal intestine have been found to occur more frequently and with greater toxicological significance than previously thought. We have previously validated a suitable animal model to evaluate intestinal permeability changes using orally administered 51Cr-EDTA that correlates with intestinal ulceration. In this study we investigated the suitability of metronidazole and the nitroxide stable free radical scavenger (tempo) as protective agents against NSAID-induced intestinal permeability. Male Sprague-Dawley rats were dosed with two doses of metronidazole (50 mg/kg, 12 and 1 h pre-NSAID) or a single 100 mg/kg dose of tempo 1 h prior to NSAIDs. The urinary excretion of the orally administered marker 51Cr-EDTA was measured. Both tempo and metronidazole dramatically reduced indomethacin (20 mg/kg) and flurbiprofen (10 mg/kg)-induced intestinal permeability. All the animals exposed to indomethacin alone died within 48-96 h and presented with histological evidence of drug-induced enteropathy, ulceration and frank peritonitis. Protection by tempo and metronidazole suggests that free radicals and/or bacteria may be important mediators in the pathogenesis of intestinal mucosal damage induced by NSAIDs. Nitric oxide donor compounds used concomitantly with NSAIDs may protect gastrointestinal tract.

Fecal alpha1-proteinase inhibitor concentration in dogs receiving long-term nonsteroidal anti-inflammatory drug therapy.

BACKGROUND: Fecal alpha(1)-proteinase inhibitor (alpha(1)-PI) clearance is a reliable, noninvasive marker for protein-losing enteropathy (PLE) in human beings. An assay for measurement of this protein in the dog has been developed and validated and may be useful for the investigation of gastrointestinal disease in this species. Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently are administered to dogs and may have adverse effects on the gastrointestinal tract, including gastroduodenal ulceration and altered mucosal permeability. The value of fecal alpha(1)-PI measurement in detecting unrelated gastrointestinal disease may be limited in dogs on NSAID therapy, but alpha(1)-PI may be a useful marker for NSAID-induced gastrointestinal damage. OBJECTIVE: The aim of this study was to evaluate the effects of long-term administration of NSAIDs on fecal alpha(1)-PI concentrations in dogs. METHODS: Fecal samples were collected from 2 groups of dogs: 1) 21 clinically-healthy client-owned dogs without signs of gastrointestinal disease and receiving no NSAIDs and 2) 7 dogs referred for investigation and treatment of orthopedic disorders; the dogs had received either meloxicam or carprofen daily for at least 30 days. Fecal alpha(1)-PI concentration was measured by ELISA. RESULTS: Fecal alpha(1)-PI concentrations, expressed as micro g/g of feces, were not significantly different between groups 1 and 2 (median [range], group 1: 9.9 micro g/g [0.0-32.1 micro g/g]; group 2: 5.6 micro g/g [1.1-32.3 micro g/g]; P =.81). CONCLUSIONS: These results suggest that use of cyclooxygenase-2-selective NSAIDs, such as carprofen and meloxicam, does not significantly affect fecal alpha(1)-PI measurements. However, study numbers were small, and larger prospective trials are required to assess more accurately the gastrointestinal effects of NSAIDs in dogs.

Protein-losing enteropathy associated with collagenous colitis cured by withdrawal of a proton pump inhibitor.

A 63-year-old woman was admitted with symptoms of watery diarrhea and generalized edema lasting for five months. She had been administered 15 mg/day of lansoprazole. Laboratory findings revealed severe hypoproteinemia with normal liver, renal, thyroid and adrenal functions and no proteinuria. Colonoscopy revealed edematous mucosa, minor diminished vascular transparency and apparent longitudinal linear lacerations. The histopathological findings were compatible with a diagnosis of collagenous colitis (CC). Protein leakage from the colon was identified on (99m)Tc-human serum albumin scintigraphy. The results indicated CC associated with protein-losing enteropathy. Discontinuing lansoprazole ameliorated the watery diarrhea and generalized edema, increased the serum albumin level and improved the hypoproteinemia.

Gastrointestinal plasma protein loss during ethanol ingestion.

Plasma and "equivalent" albumin loss in the feces were quantitated before and during ingestion of 40% ethanol using 51Cr-labeled albumin. Five subjects were studied in each classification of normal gastric mucosa, superficial gastritis, and chronic atrophic gastritis. During the control period, plasma albumin loss was minimal and similar in all three groups. Exposure to ethanol resulted in a greater output of plasma albumin in the feces of all subjects. This loss was statistically significant in subjects with superficial gastritis (P less that 0.01) and chronic atrophic gastritis (P less than 0.005). Two subjects from each group underwent gastric clearance studies of 51Cr-labeled albumin. Increased gastric clearance of plasma was observed in all 6 subjects during ethanol ingestion; the increase was highly significant in subjects with atrophic gastritis (P less than 0.001). We conclude that ethanol ingestion can cause increased loss of plasma protein in the feces, which may be of clinical significance in subjects with atrophic gastritis.

[Mercuric chloride-induced enteropathy in the rat: a model of gastrointestinal disease with immunologic pathogenesis]. / Quecksilberchlorid-induzierte Enteropathie der Ratte: Modell einer gastrointestinalen Erkrankung mit immunologischer Pathogenese.

Protein-loss into the gastrointestinal tract is a feature of many different diseases, a number of which are immunologically mediated, e.g. systemic lupus erythematosus or Crohn's disease. The pathogenic mechanism of protein-losing enteropathy in diseases without obvious enterocyte injury are unknown. Brown-Norway-rats (BN-rats) were gavaged with low doses of HgCl2 for 39 weeks. Within 2 weeks, the intestines showed strong linear staining for IgG and IgA along vascular and intestinal basement membranes. Granular deposits containing IgG and C3 were present along intestinal basement membrane only in the late stages of the experiment; only in these animals increased intestinal protein loss as measured by fecal Cr-51 excretion was found. These findings suggest that immune complex deposition along the intestinal basement membrane can lead to protein-losing enteropathy. This disease may be used as a model for the study of immunologically mediated intestinal disease.

The effect of cyclophosphamide and vincristine on intestinal protein loss in rats.

24 and 48 hours after a single intraperitoneal dose of 80 mg/kg cyclophosphamide (I. group) and 0.20 mg/kg vincristine (II. group) the intestinal protein loss has been studied using the 51CrCl3 isotope method. 16 animals were used as control (III. group). In case of both cytostatics, the intestinal protein loss was significantly higher. Histologically the small bowel mucosa, on the first day after injection, showed, in the crypts, necrotic cells and mitoses arrested in metaphase. By the second day, after injection, severe villous atrophy and occasional mucosal erosions were seen. The causes of these changes are discussed together with the question of the disrupted barrier function of the small bowel.

[Tetracyclin intoxication versus idiopathic pancreatitis: report of a case with multiple organ involvement (author's transl)]. / Tetracyklinintoxikation oder idiophatische Pankreatitis: Bericht einer Erkrankung mit komplexer Beteiligung innerer Organe.

The tetracycline class of antibiotics is infrequently used in clinical pediatrics due to its side effects: they include anorexia, nausea, vomiting and diarrhea. Hypersensitivity, a photosensibility reaction and a brownish discoloration of teeth is less frequently, a pseudotumor cerebri is rarely seen. Once therapeutic plasma levels are exceeded however, either by overdosage or decreased renal or hepatic clearance of the drug, serious complications like a secondary Fanconi-Syndrom or a nephrogenic diabetes insipidus can occur. The increased toxicity of tetracyclines in pregnant women is well known. We would like to report a fatal case, where serious complications like a secondary Fanconi-Syndrom, toxic degeneration of the liver, a clinically undected pancreatitis and a protein loosing enteropathy are though to be either direct consequences of tetracycline overdosage or the indirect effect of a shocklike syndrom by means of a nonoliguric renal failure induced by tetracycline.

Measurement of canine gastric vascular permeability to plasma proteins in the normal and protein-losing states.

An isolated segment of the greater curvature of a dog's stomach was perfused at constant flow through a single cannulated artery with donor blood containing 131I-albumin, 125I-fibrinogen, and papaverine. Perfusion pressure was 30-50 mmHg, and venous pressure was set at 15 mmHg. Venous blood was collected in 1-min samples for 60 min. Filtration of fluid and loss of labeled proteins were calculated as the difference between measured arterial inflow and venous outflow. Permeability-surface area products (PS) were calculated for the proteins, and reflection coefficients (sigma) were calculated from solute flux and filtration. Intraarterial infusion of histamine (1.6-1.9 microgram . ml-1) increased filtration and PS and decreased sigma for albumin but not fibrinogen. When protein-losing was established by topical irrigation with 10 mM dithiothreitol in neutral solution, filtration and PS increased, and sigma for albumin but not fibrinogen decreased. Irrigation of the mucosa with 10 mM salicylic acid in 100 mN HCl caused bleeding that was quantitated by addition of 51Cr-erythrocytes to perfusing blood. Filtration and PS increased, and sigma for albumin but not fibrinogen decreased. Hematocrit of blood lost remained low during extensive mucosal damage. Effects of histamine infusion were attenuated or abolished by cimetidine (4 mg . kg-1 loading, 1.4 mg . kg-1 . h-1 continuous infusion) or by pyrilamine maleate (5 mg . kg-1 bolus injection at beginning of irrigation, repeated at 40-50 min). Pyrilamine attenuated or abolished effects of topical dithiothreitol or salicylic acid. We conclude that during protein loss caused by dithiothreitol or salicylic acid, histamine released within the mucosa causes increased vascular permeability for plasma proteins.