Intestinal Protein Loss Research Articles

A clinical case of edematous syndrome: diagnostic search and treatment tactics of a complex patient in compliance with the internarial and domestic recommendations

Edematous syndrome is quite common in modern clinical practice. Swelling is one of the most common complaints that cause the patient to consult a doctor and often become the first clinical manifestation of many diseases. Fluid makes up approximately 3/5 of the human body weight, 70% of which is located in cells, and about 30% is extracellular. There is a constant exchange of electrolytes and other substances involved in metabolism between the cell and the extracellular fluid. Subcutaneous connective tissue under normal conditions contains a minimal amount of fluid. Edema fluid formed from blood plasma, which in pathological conditions under the influence of various factors is unable to retain water in the vascular bed, and water accumulates in excessive amounts in the tissues. Often, a patient refers to a doctor with the main complaint — the appearance of edema, and the correct interpretation of the origin of edema is important at this stage, because they are often a marker that reflects the severity and/or decompensation of the disease. Therefore, a detailed and comprehensive differential diagnosis of the edematous syndrome allows choosing the optimal tactics of the patient’s treatment.
 The authors present a clinical case of diagnostic search and treatment tactics for edematous syndrome based on global and national recommendations. Patient V., 1983 year of birth, on May 8th, 2023, visited a nephrologist at the L. T. Mala National Therapy Institute. She believed that kidney disease caused swelling of her face and lower limbs. However, considering the long history of intestinal dysfunction, protein loss and edema, the case was revised as a manifestation of gastroenterological pathology. The patient was referred to a gastroenterologist. An extensive diagnostic search was conducted, which allowed not only to establish the correct diagnosis, but also to administer an effective therapy.

S2782 Successful Medical Management of a Patient With Severe Hypoalbuminemia due to Ulcerative Colitis

Introduction: Severe hypoalbuminemia (< 1gm/dL) is a rare complication of ulcerative colitis and may be both debilitating and refractory to therapy. Literature reports indicate that colectomy is curative and imply that it is the treatment of choice. We successfully treated such a patient medically. Case Description/Methods: This 40-year-old female was diagnosed with proctosigmoiditis in 2017, initially treated with oral mesalamine, then lost to care from 2018 through 2021. She presented in November 2021 with a disease flare and was shown to have pan-colitis. She was started on corticosteroids and began therapy with infliximab with initial symptomatic improvement. However, diarrhea continued, she developed increased symptoms plus anasarca during the steroid taper and was admitted. Serum albumin was 0.5 mg/dL. Inflammatory markers were elevated: C-reactive protein 103.8 mg/L and fecal calprotectin 1,126 ug/g. After infection was ruled out, colonoscopy was performed and showed extensive pseudopolyposis. Non-intestinal causes of protein loss were ruled out. Fecal alpha-1 antitrypsin levels were elevated before but not after an infliximab infusion (0.850 vs 0.110 mg/g, respectively). Despite receiving 10 mg/kg of infliximab every 6 weeks, her trough levels were undetectable and low levels of antibodies were detected. Intravenous albumin and diuretics provided some relief, but serum albumin concentration plateaued around 2.5 gm/dL. Mesalamine then was added to the regimen and the patient improved rapidly, with complete cessation of diarrhea, a rise in serum albumin concentration to 3.5 g/dL over 4 weeks, and clearance of the patient’s edema. Discussion: Severe hypoalbuminemia as a result of ulcerative colitis has previously been described and may lead to treatment failure and colectomy, even during treatment with biologic agents. Some cases are not due to intestinal protein losses such as in co-existing Menetriere’s disease or nephrotic syndrome. Elevated clearance rates of the biologic agents lead to subtherapeutic serum levels and antibody formation, promoting treatment failure. This case suggests that there may a role for adjunctive 5-ASA therapy. As part of the medications’ anti-inflammatory effects, they decrease enteric loss of infliximab and elevate its serum levels.

Extracellular histones cause intestinal epithelium injury and disrupt its barrier function in vitro and in vivo

Extracellular histones are cytotoxic to various cells and have been extensively proven a vital mediator of multiple organ injuries. However, the effect of extracellular histones on the intestine remains largely unknown. This study aimed to clarify the effect of extracellular histones on the intestine. IEC-6, a cell line of rat small intestinal epithelial crypt, and C57BL/6 or ICR mice were treated with histones. The IEC-6 cells treated with histones from 20 μg/mL to 200 μg/mL for 0−24 h displayed a decline of cell viability and an increase of cell death in a concentration- and time-dependent manner. Moreover, histones (100 μg/mL) induced IEC-6 apoptosis through activating caspase 3 and necroptosis through up-regulation of receptor-interacting serine/threonine protein kinase 1 and 3 (RIPK1 and RIPK3), phosphorylated mixed-lineage kinase domain-like protein (p-MLKL) along with the decrease of caspase-8. Histones treatment disturbed zonular occludens 1 (ZO-1) expression and increased permeability of IEC-6 cell monolayer. In vivo, histones 50 mg/kg injection caused mice intestinal edema, loss apex of villus, epithelial lifting down the sides of the villi, and increased neutrophil infiltration. Elevation of serum intestinal fatty acid binding protein (I-FABP), d-lactate, or Diamine oxidase (DAO) and loss of tight junction protein, ZO-1, at 3 h and 6 h after histones injection strongly indicated severe intestinal epithelium injury, which led to increased permeability of the intestine. In conclusion, extracellular histones cause intestinal epithelial damage via direct cytotoxicity. Consequently, intestinal epithelial tight junction and barrier integrity are disrupted, which may play pivotal roles in diverse diseases.

Clostridium Difficile Infection and Biliary Obstruction

We present a case of a 38-year -old man was admitted to the hospital with biliary obstruction and Clostridium Difficile infection. He presented with moderate increases in the aminotransferase and bilirubin levels suggesting the diagnosis of an autoimmune hepatobiliary disease; intestinal protein loss needs to evaluate an associated inflammatory bowel disease. The clinical diagnosis of autoimmune hepatobiliary disease associated with inflammatory bowel disease is based on the patients symptoms and the presence of a protein-losing enteropathy which are more suggestive of Crohn disease, while moderate increases in the aminotransferase levels in proportion to the increase in the bilirubin level suggesting the diagnosis of primary sclerosing cholangitis. The pathological and positive diagnosis needs an endoscopic retrograde cholangiopancreatography and a biopsy of gastric and duodenum mucosae who showed severe inflammation findings that are diagnostic of Crohn disease.

Measurement of the α1-proteinase inhibitor (α1-antitrypsin) of common marmoset and intestinal protein loss in wasting syndrome.

Although wasting marmoset syndrome (WMS) is one of the biggest problems facing captive marmoset colonies, the mechanisms underlying its pathogenesis remain unclear. In our clinical experience, it is difficult to cure WMS-affected marmosets with severe hypoalbuminemia. Thus, the mechanisms underlying hypoalbuminemia in WMS must be understood. In the present study, we investigated whether intestinal protein loss, a known reason for hypoalbuminemia, occurs in this disease. Fecal α1-proteinase inhibitor (α1-PI, also known as α1-antitrypsin) has been used to diagnose intestinal protein loss in other species. To develop an assay system for this protein, marmoset α1-PI was purified from plasma and antibodies against it were developed using the purified protein. Using the antibodies, a sandwich enzyme-linked immunosorbent assay (ELISA) to measure marmoset α1-PI was developed, and its detection sensitivity for fecal samples was ∼20-fold higher than that of a commercial kit for human α1-PI. From this ELISA, the reference intervals for serum and feces of healthy marmosets were 0.87–1.85 mg/ml and 0.53–395.58 μg/g, respectively. The average concentrations of α1-PI in serum and feces of seven WMS-affected marmosets were 1.17 mg/ml and 1357.58 μg/g, respectively. Although there were no significant differences in the serum concentrations between healthy and WMS-affected marmosets, the fecal concentrations were significantly higher in WMS-affected marmosets than in healthy individuals, suggesting that intestinal protein loss occurs in WMS. Intestinal protein loss of WMS-affected marmosets was significantly attenuated with treatment, suggesting that it is one of the mechanisms involved in the hypoalbuminemia observed in WMS.

Clinical utility of currently available biomarkers in inflammatory enteropathies of dogs.

Chronic inflammatory enteropathies (CIE) in dogs are a group of disorders that are characterized by chronic persistent or recurrent signs of gastrointestinal disease and histologic evidence of mucosal inflammation. These CIEs are classified as either food‐responsive, antibiotic‐responsive, or immunosuppressant‐responsive enteropathy. Patients not clinically responding to immunomodulatory treatment are grouped as nonresponsive enteropathy and dogs with intestinal protein loss as protein‐losing enteropathy. Disease‐independent clinical scoring systems were established in dogs for assessment of clinical disease severity and patient monitoring during treatment. Histopathologic and routine clinicopathologic findings are usually not able to distinguish the subgroups of CIE. Treatment trials are often lengthy and further diagnostic tests are usually at least minimally invasive. Biomarkers that can aid in defining the presence of disease, site of origin, severity of the disease process, response to treatment, or a combination of these would be clinically useful in dogs with CIE. This article summarizes the following biomarkers that have been evaluated in dogs with CIE during the last decade, and critically evaluates their potential clinical utility in dogs with CIE: functional biomarkers (cobalamin, methylmalonic acid, folate, α1‐proteinase inhibitor, immunoglobulin A), biochemical biomarkers (C‐reactive protein, perinuclear anti‐neutrophilic cytoplasmic antibodies, 3‐bromotyrosine, N‐methylhistamine, calprotectin, S100A12, soluble receptor of advanced glycation end products, cytokines and chemokines, alkaline phosphatase), microbiomic biomarkers (microbiome changes, dysbiosis index), metabolomic biomarkers (serum metabolome), genetic biomarkers (genomic markers, gene expression changes), and cellular biomarkers (regulatory T cells). In addition, important performance criteria of diagnostic tests are briefly reviewed.

Combination Antibiotics Improves Disease Activity and Alters Microbial Communities in Children With Ulcerative Colitis.

Combinations of antibiotics have shown promise in off-label treatment of Inflammatory Bowel Disease (IBD) flares in adult and pediatric patients1–6. In a small pediatric cohort of moderate-severe medically refractory Ulcerative Colitis (UC), half achieved remission with a regimen of 3–4 antibiotics6. The rationale is to decrease mucosal inflammation by altering intestinal microbiota, however, to date no study has documented these changes. We report our experience with combination oral antibiotics in symptomatic pediatric patients with steroid-dependent or -resistant UC, and demonstrate significant alterations in gut microbiota during and after antibiotic therapy with reductions in inflammatory markers.

Marginal Zone Lymphoma Complicated by Protein Losing Enteropathy.

Protein losing enteropathy (PLE) refers to excessive intestinal protein loss, resulting in hypoalbuminemia. Underlying pathologies include conditions leading to either reduced intestinal barrier or lymphatic congestion. We describe the case of a patient with long-lasting diffuse abdominal problems and PLE. Repetitive endoscopies were normal with only minimal lymphangiectasia in biopsies. Further evaluations revealed an indolent marginal zone lymphoma with minor bone marrow infiltration. Monotherapy with rituximab decreased bone marrow infiltration of the lymphoma but did not relieve PLE. Additional treatments with steroids, octreotide, a diet devoid of long-chain fatty-acids, and parenteral nutrition did not prevent further clinical deterioration with marked weight loss (23 kg), further reduction in albumin concentrations (nadir 8 g/L), and a pronounced drop in performance status. Finally, immunochemotherapy with rituximab and bendamustine resulted in hematological remission and remarkable clinical improvement. 18 months after therapy the patient remains free of gastrointestinal complaints and has regained his body weight with normal albumin levels. We demonstrate a case of PLE secondary to indolent marginal zone lymphoma. No intestinal pathologies were detected, contrasting a severe and almost lethal clinical course. Immunochemotherapy relieved lymphoma and PLE, suggesting that a high suspicion of lymphoma is warranted in otherwise unexplained cases of PLE.

Meta-analysis of effect of a mono-component xylanase on the nutritional value of wheat supplemented with exogenous phytase for broiler chickens

A total of 1600 Ross broiler chicks were used in six separate balance studies (with equivalent protocols) to investigate the effect of an exogenous xylanase on the nutritional value of wheat (supplemented with a background of exogenous phytase) sourced from Asia, North America and Europe. The mean apparent metabolisable energy of the 10 batches of wheat per se was 13.4 MJ/kg DM and the addition of xylanase increased (P &lt; 0.001) this by an average of 0.43 MJ/kg DM (~3.2%). Apparent ileal digestibility of nitrogen in the 10 batches of wheat per se was 69.8% and xylanase addition increased (P &lt; 0.001) this by 2%. The apparent ileal disappearance of soluble and insoluble non-starch polysaccharides (NSP) was –53% and +5%, respectively and xylanase addition increased these by 28% and 15%, respectively. The apparent ileal disappearance of total arabinose + xylose was –10% and xylanase increased this by 21%. The apparent ileal flow of fucose was 0.38 g/kg DM intake and xylanase addition reduced (P &lt; 0.05) this by 0.03 g/kg DM intake. There was a significant negative correlation between the apparent ileal flow of fucose and the digestibility of nitrogen and energy in the wheat and the wheat plus xylanase. These results demonstrate the continued effectiveness of exogenous xylanase to enhance the nutritional value of wheat for broiler chickens. Furthermore, the degradation of NSP fractions is confirmatory of both soluble and insoluble fibre hydrolysis in the intestine of the birds. Finally, although de-caging, viscosity amelioration and microbial changes are likely to be involved, the reduced flow of fucose in the intestine of birds fed wheat with supplemental xylanase is indicative of reduced endogenous (mucin) loss with net energy and enteric health implications. The effect of wheat pentosans and xylanase on intestinal secretion and endogenous protein and energy loss is an area for future study. Finally, the results presented herein suggest a reduction in soluble NSP concentrations in wheat over the past 2–3 decades, which is a trend that may explain anecdotal observations that the incidence of so-called sticky wheats is in decline. Systematic assessment of the implications of changing substrate concentrations and characteristics for new xylanase development is warranted.

Impact of fenestration creation on managing patients with protein loosing enteropathy complicating Fontan procedure

Protein loosing enteropathy (PLE) is well known complication following Fontan procedure and one way of managing such complication is to create fenestration if it is not present or enlarging it if it is small to reduce the Fontan pressure and reduce venous congestion which end up by intestinal protein loss. To evaluate the effect of such procedure in our population. From February 2006 through October 2011 9 patients who underwent fenestration creation due to development of PLE was assessed in regard to clinical, laboratory result and hemodynamic effect prior and post procedure. Median age is 7 years(4–21) , median weight is 23 kg (15–52) , male: female ratio is 3.5:1 ( male & 2 female), median saturation pre and post procedure was 93% and 82% respectively, median albumin pre and post procedure was 18 gm/dl and 31 gm/dl during the first 2 wks and 36 gm/dl thereafter, median pulmonary artery pressure before and after was 25 mmhg ( 17–32 mmhg) and 16 mmhg (14–19 mmhg), transpulmonary pressure gradient reduced from a median of 11 mmhg to 5 mmhg, No immediate deaths , 2 patients need re-dilatation, there was 2 (22%) late deaths (one t has stent thrombosis one month after followed by fulminant pulmonary embolism, though all patients were on anticoagulant other one with sudden arrest came to the emergency could not be resuscitated ) 3 (33%) patients have persistent low albumin though the fenestration is patent. Transcatheter fenestration creation as a management of PLE following Fontan procedure is feasible procedure, can be done in the cath. lab with little morbidity and mortality and with beneficial effect, however late complication and complete resolving of PLE is of concern especially if done late.

Protein Calorie Malnutrition in Liver Cirrhosis

Malnutrition is prevalent in all forms of liver diseases. Protein calorie malnutrition (PCM) is associated with an increased risk of morbidity and mortality in patients with cirrhosis and occurs in 50% 90% of these patients. Although the pathogenesis of PCM is multifactorial, alterations in protein metabolism plays an important role. This article is based on a selective literature review of protein calorie malnutrition in liver cirrhosis. Malnutrition is prevalent in liver cirrhosis due to the presence of ascites, nausea, vomiting, insufficient food intake, malabsorption and metabolic disorders, poor dietary intake, malabsorption, increased intestinal protein losses, low protein synthesis, and hyper metabolism.

Gastrointestinal safety of NSAIDs and over-the-counter analgesics

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used. It is well recognised that they may adversely cause damage throughout the gastrointestinal tract and aggravate pre-existing disease. Their side effects on the upper gastrointestinal tract can be assessed by various means; each study type has different clinical connotations. Short-term use (less than 14 days) demonstrates dose-dependent damage of prescribed NSAIDs; the damage is proportional to the acidity of the drugs and not seen with Cyclooxygenase-2 (COX-2) selective inhibitors that have a pKa over 7.0. There have not been any serious outcomes, such as bleeding or perforation in these studies, and Helicobacter pylori (HP) plays no role in this damage. Long-term (3 months or more) endoscopy studies in patients show ulcer rates from 15%-35% with the various NSAIDs, but serious outcomes are exceedingly rare. Epidemiological studies show an association between NSAID intake and serious events. Ibuprofen is consistently at the lower end of toxicity rankings, whereas ketorolac and azapropazone are the worst. The risk of bleeding is increased with advancing age, presence of HP, previous history of bleeding, anticoagulant use, etc. The mega-trials show that COX-2 selective agents halve the bleeding episodes, but NSAID-induced gastric bleeding is very rare usually, less than 1 in 200 subjects taking them for a year. Seventy percent of patients develop NSAID-enteropathy, which is associated with intestinal blood and protein loss and rarely strictures. Over-the-counter (OTC) use of ibuprofen and diclofenac is associated with symptomatic gastrointestinal side effects comparable with placebo. Ibuprofen is shown to be remarkably well tolerated at OTC doses in a number of studies. There are recent studies to suggest that OTC NSAIDs should be taken on a fasting stomach, not with food as commonly advocated.

Impact of fenestration creation on managing patients with protein losing enteropathy complicating Fontan procedure

Protein losing enteropathy (PLE) is a well known complication following Fontan procedure and one way of managing such complication is to create fenestration if it is not present or enlarging it if it is small to reduce the Fontan pressure and reduce venous congestion which end up by intestinal protein loss. To evaluate the effect of such procedure in our population. From February 2006 through October 2011, 9 patients who underwent fenestration creation due to development of PLE were assessed in regard to clinical, laboratory results and hemodynamic effect prior and post-procedure. Median age is 7 years (4–21), median weight is 23 kg (15–52), male:female ratio is 3.5:1 (male and 2 female), median saturation pre- and post-procedure was 93% and 82%, respectively, median albumin pre- and post-procedure was 18 g/dl and 31 g/dl during the first 2 weeks and 36 g/dl thereafter, median pulmonary artery pressure before and after was 25 mmHg (17–32 mmHg) and 16 mmHg (14–19 mmHg), transpulmonary pressure gradient reduced from a median of 11 mmHg to 5 mmHg, no immediate deaths, 2 patients need re-dilatation, there was 2 (22%) late deaths (one has stent thrombosis 1 month after followed up by fulminant pulmonary embolism, though all patients were on anticoagulant, other one with sudden arrest came to the emergency could not be resuscitated) 3 (33%) patients have persistent low albumin though the fenestration is present in patient. Transcatheter fenestration creation as a management of PLE following Fontan procedure is a feasible procedure, can be done in the cath. lab with little morbidity and mortality and with beneficial effect, however late complication and complete resolving of PLE is of concern especially if done late.

Octreotide in Hennekam syndrome-associated intestinal lymphangiectasia

A number of disorders have been described to cause protein losing enteropathy (PLE) in children. Primary intestinal lymphangiectasia (PIL) is one mechanism leading to PLE. Few syndromes are associated with PIL; Hennekam syndrome (HS) is one of them. The principal treatment for PIL is a high protein, low fat diet with medium chain triglycerides supplementation. Supportive therapy includes albumin infusion. Few publications have supported the use of octreotide to diminish protein loss and minimize hypoalbuminemia seen in PIL. There are no publications on the treatment of PIL with octreotide in patients with HS. We report two children with HS and PLE in which we used octreotide to decrease intestinal protein loss. In one patient, octreotide increased serum albumin to an acceptable level without further need for albumin infusions. The other patient responded more dramatically with near normal serum albumin levels and cessation of albumin infusions. In achieving a good response to octreotide in both patients, we add to the publications supporting the use of octreotide in PIL and suggest that octreotide should be tried in patients with PIL secondary to HS. To the best of our knowledge, this is the first case report on the use of octreotide in HS-associated PIL.

Protein-losing enteropathy in paracoccidioidomycosis identified by scintigraphy: report of three cases

Paracoccidioidomycosis (PCM) or South American Blastomycosis is a systemic fungal infection caused by a dimorphic fungus, Paracoccidioides brasiliensis. It represents the most important systemic mycosis in South America and with higher prevalence among male inhabitants of the rural area. PCM usually affects the lungs, and rarely the intestines. The authors report three cases of PCM, treated at the University Hospital of Universidade Federal de Mato Grosso do Sul whose scintigraphy with technetium-99 labeled human albumin revead intestinal protein loss

Epithelial Myosin Light Chain Kinase Activation Induces Mucosal Interleukin-13 Expression to Alter Tight Junction Ion Selectivity

Intestinal barrier function is reduced in inflammatory bowel disease (IBD). Tumor necrosis factor (TNF) and interleukin (IL)-13, which are up-regulated in IBD, induce barrier defects that are associated with myosin light chain kinase (MLCK) activation and increased claudin-2 expression, respectively, in cultured intestinal epithelial monolayers. Here we report that these independent signaling pathways have distinct effects on tight junction barrier properties and interact in vivo. MLCK activation alters size selectivity to enhance paracellular flux of uncharged macromolecules without affecting charge selectivity and can be rapidly reversed by MLCK inhibition. In contrast, IL-13-dependent claudin-2 expression increases paracellular cation flux in vitro and in vivo without altering tight junction size selectivity but is unaffected by MLCK inhibition in vitro. In vivo, MLCK activation increases paracellular flux of uncharged macromolecules and also triggers IL-13 expression, claudin-2 synthesis, and increased paracellular cation flux. We conclude that reversible, MLCK-dependent permeability increases cause mucosal immune activation that, in turn, feeds back on the tight junction to establish long-lasting barrier defects. Interactions between these otherwise distinct tight junction regulatory pathways may contribute to IBD pathogenesis.

Les entéropathies exsudatives d'origine non néoplastique du chien: étude rétrospective de 34 cas

This study reports the results in 34 dogs with protein-losing enteropathy (PLE). Rottweilers and Yorkshire Terriers were overrepresented. Most obvious clinical signs and laboratory findings were diarrhea (91 %), weight loss (74 %), anorexia (56 %), lethargy (51 %), ascites (18 %), ascites without gastrointestinal signs (9 %), hypoalbuminemia (<12 g/l, 65 %) and hypocholesterolemia (51 %). Ultrasonographic findings included intestinal wall thickening in 71 %, abnormal echogenicity in 68 %, and no abnormalities in 29 %. The most important endoscopic findings were diffuse and profound dilation of villi in 35 %, a more granular appearing mucous membrane in 32 % and a "rice-grain" appearing villus dilation in 12 %. In 21 % of the dogs the mucous membrane was considered unremarkable. Histologically, 62 % had lymphangiectasia, in 86 % of these associated with moderate to severe inflammatory infiltrates, and in 71 % associated with dilatation of intestinal crypts. In 68 % of the dogs lesions in intestinal crypts were found, 35 % of these without lymphangiectasia. In 12 % of the dogs the histological findings failed to explain intestinal protein loss. This study shows the important prevalence of crypts' lesions in protein-losing enteropathy.

Falling Serum Albumin Predicts Severity of Acute Graft-Vs.-Host Disease and Non-Relapse Mortality After Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Abstract 1146Poster Board I-168 BACKGROUNDAcute graft-vs.-host disease (aGVHD) varies in its intensity and response to therapy. Biomarkers capable of differentiating treatment-responsive from severe aGVHD at symptom onset may enable risk-stratified therapy. With the advent of prophylactic ursodiol, liver aGVHD has become rare, and gut involvement is responsible for much of the morbidity and mortality associated with severe aGVHD. Protein loss through altered epithelial tight junctions, and ultimately through mucosal necrosis, results in hypoalbuminemia in severe aGVHD (Weisdorf et al., Gastroenterology 1983 85:1076-81). We hypothesized that intestinal protein loss correlated with severity of aGVHD and thus predicted outcome. To test this hypothesis, we retrospectively evaluated changes in serum albumin as a marker of protein loss at the onset of aGVHD symptoms. To reduce the confounding effect of regimen-related gut toxicity, we restricted our analysis to patients who received non-myeloablative conditioning. PATIENTS AND METHODSAmong 708 recipients of a first non-myeloablative allogeneic HCT at our Center, 412 (58%) developed aGVHD grade II–IV. We retrospectively evaluated these 412 patients (336 grade II; 76 grade III/IV). Patients were conditioned with 2 Gy total body irradiation, with or without fludarabine 90 mg/m2. Post-grafting immunosuppression consisted of cyclosporine and mycophenolate mofetil, and corticosteroids were used as first-line treatment of aGVHD. Median patient age was 55 (range, 1–75) years. 170 patients (41%) had related donors. Among the 242 patients (59%) with unrelated donors, there were 31 HLA-allele-mismatched donors, 28 HLA-antigen-mismatched donors, and 6 allele and antigen mismatched donors. We reviewed all serum albumin values from 30 days before to 45 days after clinical onset of aGVHD. The lowest albumin value in the 30 days before HCT was considered a patient's baseline value. Trends in serum albumin before and after aGVHD onset were compared among patients with peak grade II vs. peak grade III/IV aGVHD. We also compared 6-month estimates of non-relapse mortality (NRM) associated with changes in serum albumin and the performance of falling serum albumin as a predictor of grade III/IV aGVHD. RESULTSClinical onset of aGVHD in the study cohort occurred at a median of 35 days after HCT. Patients who went on to develop severe (grade III/IV) aGVHD showed sharp decreases from baseline serum albumin levels; these decreases were already apparent at the onset of clinical aGVHD (Fig. 1). In contrast, patients whose aGVHD never exceeded grade II showed no changes on average from baseline serum albumins at aGVHD onset. Receiver-operator characteristic (ROC) curves demonstrated that among patients with new-onset symptoms of aGVHD requiring treatment, a drop from baseline in serum albumin of 0.5 g/dL optimally discriminated between those who went on to develop severe aGVHD versus those whose aGVHD peaked at grade II (ROC area under curve, 0.75). A drop from baseline albumin of 0.5 g/dL at onset of aGVHD symptoms was also associated with an increased risk of NRM at 6 months after aGVHD onset (28% vs. 8%, HR 2.13 [1.3–3.4], p=0.002; Fig. 2). CONCLUSIONA sharp decrease in serum albumin may precede and predict severe aGVHD as well as NRM. Serial measurement of serum albumin is an inexpensive and readily available potential prognostic biomarker in patients with new-onset symptoms of aGVHD after non-myeloablative allogeneic HCT. In combination with other biomarkers or clinical predictors of aGVHD severity, the kinetics of serum albumin may enable specific and risk-stratified targeting of therapies for aGVHD, reserving intensive and protracted immunosuppression for the small percentage of patients at highest risk of severe aGVHD.FIGURES: [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Neonatal hyperbilirubinemia increases intestinal protein permeability and the prevalence of cow's milk protein intolerance

Bilirubin is a newly discovered modulator of the gut barrier in vitro and in vivo. We studied the effect of bilirubin on the serosal to mucosal intestinal permeability in vivo. We also investigated the prevalence of cow's milk protein intolerance (CMPI) in infants with moderate hyperbilirubinemia versus matched controls. Faecal alpha 1 antitrypsin (a1AT) was used to monitor intestinal protein loss; a large cohort was prospectively followed for 12 months for sign and symptoms of CMPI. Neonates with hyperbilirubinemia had higher stool excretion of a1AT than controls (0.68 +/- 0.28 mg/g vs. 0.25 +/- 0.11 mg/g; p < 0.01). Faecal a1AT correlates with total serum bilirubin (TSB) (r = 0.85; p < 0.01). Also, in the first 12 months of life, formerly hyperbilirubinemic infants had an higher prevalence of CMPI (14/353 vs. 4/339; chi2= 4.018, p = 0.045). Neonatal hyperbilirubinemia increases stool protein loss and is also a mild risk factor for CMPI.

Allergic Eosinophilic Gastroenteritis With Protein-Losing Enteropathy: Intestinal Pathology, Clinical Course, and Long-term Follow-up

Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH. J Pediatr Gastroenterol Nutr. 2006;42:516–521 PURPOSE OF THE STUDY. To identify gross and/or histologic distinguishing features of antral and duodenal biopsy specimens as well as clinical response to various treatment regimens in the subset of patients with eosinophilic gastroenteritis (AEG) with protein-losing enteropathy (PLE). STUDY POPULATION. The experimental group consisted of 6 children with anemia and hypoalbuminemia and biopsy-proven AEG identified retrospectively from a series of 93 patients with AEG who were evaluated at Mount Sinai Medical Center (New York, NY) over a 7.5-year period. METHODS. Two comparison groups were used in addition to the experimental group. The first included 6 randomly selected patients from the series of 93 patients with AEG without anemia and/or hypoalbuminemia. The second comparison group included 5 patients who presented with symptoms consistent with possible AEG yet normal gross findings and histology after endoscopy. Causes of eosinophilia other than AEG were ruled out. The diagnoses of AEG required the presence of &amp;gt;20 eosinophils per high-power field in antral biopsy specimens and &amp;gt;50 in the duodenum. Hematoxylin/eosin staining and immunohistochemical staining of tryptase were used for identification of eosinophils and mast cells, respectively. The cell count was taken from the high-power field with maximum infiltration. RESULTS. Various therapies were attempted in the experimental group including oral corticosteroids, cromolyn sodium, 6-mercaptopurine, food-elimination diets, and montelukast. They were, at best, partially or temporarily beneficial. All experimental patients received an exclusive amino acid–based formula diet at some point in their care; this formula was associated with rapid improvement of anemia and hypoalbuminemia as well as clinical symptoms. These patients eventually tolerated the addition of various foods to their diet. In duodenal biopsy specimens, mast cells were significantly increased in patients with AEG and PLE compared with those with AEG only, whereas eosinophil numbers were comparable. This was not seen in the antral samples. Eosinophilia was more prominent in the antrum of patients with AEG and PLE compared with those with AEG only. Patchy duodenal villous blunting was seen in 1 patient with AEG and PLE and 1 with AEG. CONCLUSIONS. As in the treatment of eosinophilic esophagitis, amino acid–based formulas seem to be the most effective form of therapy. After improvement on an amino acid–based formula diet, many patients eventually tolerate expanded diets. Malabsorption and villous blunting do not seem to be the cause of hypoalbuminemia and anemia in those patients with AEG and PLE. Increased intestinal mast cells seen in the patients with AEG with PLE may be the source of the intestinal protein loss. REVIEWER COMMENTS. Although the sample size in this study was small, these data provide additional insight into the specific role of mast cells in patients with AEG and PLE.