Intravenous route for folate supplementation in a patient with celiac disease treated by pemetrexed-based chemotherapy for non-small-cell lung cancer.

INTRODUCTION: Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation. CASE REPORT: We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy. MANAGEMENT AND OUTCOMES: Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia. DISCUSSION/CONCLUSION: This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed-antifolate-based chemotherapy.

Nutri-epigenetics: the effect of maternal diet and early nutrition on the pathogenesis of autoimmune diseases.

Autoimmune diseases comprise a wide group of diseases involving a self-response of the immune system against the host. The etiopathogenesis is very complex involving disease-specific factors but also environmental factors, among which the diet. Maternal diet during pregnancy as well as early nutrition recently attracted the interest of the scientists as contributing to the immune programming. In this paper, we reviewed the most recent literature on the effect of maternal diet and early nutrition in modulating the immune system in a selected subset of autoimmune diseases: type 1 diabetes, celiac disease, inflammatory bowel disease, juvenile idiopathic arthritis and rheumatoid arthritis. Particularly, we focused our narrative on the role of maternal and perinatal nutrition in the epigenetic mechanisms underlying the auto-immune response. Maternal diet during pregnancy as well as breastfeeding and early nutrition play a big role in many epigenetic mechanisms. Most of the nutrients consumed by the mother and the infant are known exerting epigenetic functions, such as folate, methionine, zinc, vitamins B12 and D, fibers, casein and gliadin, and they were linked to gene expression changes in the immune pathways. Despite the common role of maternal diet, breastfeeding and early nutrition in almost all the autoimmune diseases, each disease seems to have specific diet-driver epigenetic mechanisms that require further investigations. The research in this field is opening new routes to establishing a precision nutrition approach to the auto-immune diseases.

Exposure to the Danish Mandatory Vitamin D Fortification Policy in Prenatal Life and the Risk of Developing Coeliac Disease-The Importance of Season: A Semi Ecological Study.

Few studies have examined the role of maternal diet in relation to development of coeliac disease (CD). In Denmark, cancellation of mandatory vitamin D fortification of margarine in June 1985 provided this opportunity. This study examined if season of birth or prenatal exposure to extra vitamin D from food fortification were associated with developing CD later in life. A strength of this study is the distinctly longer follow-up of patients (30 years). This register-based study has a semi-ecological design. Logistic regression analysis was used to estimate odds ratios and to calculate 95% confidence intervals. The odds ratio for developing CD was 0.81 (95% CI 0.66; 1.00 p = 0.054), comparing those with fetal exposure to mandatory vitamin D fortification policy of margarine to those without after adjusting for gender and season of birth. There was a statistically significant season effect particularly for children born in autumn (OR 1.6 95% CI 1.16; 2.21) and born in summer (OR 1.5 95% CI 1.1; 2.1) when compared to children born in winter. Although this study did not find evidence to support the premise that prenatal exposure to small extra amounts of vitamin D from a mandatory food fortification policy lowered risk of developing CD, the small number of CD cases and observed association between season of birth and CD suggest that environmental exposure ought to be further explored.

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease.

In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLA-DQ2/DQ8-restricted adaptive Th1 immune response. Epithelial stress, induced by other non-antigenic gliadin peptides, is required for gliadin to become fully immunogenic. We found that cystic-fibrosis-transmembrane-conductance-regulator (CFTR) acts as membrane receptor for gliadin-derived peptide P31-43, as it binds to CFTR and impairs its channel function. P31-43-induced CFTR malfunction generates epithelial stress and intestinal inflammation. Maintaining CFTR in an active open conformation by the CFTR potentiators VX-770 (Ivacaftor) or Vrx-532, prevents P31-43 binding to CFTR and controls gliadin-induced manifestations. Here, we evaluated the possibility that the over-the-counter nutraceutical genistein, known to potentiate CFTR function, would allow to control gliadin-induced alterations. We demonstrated that pre-treatment with genistein prevented P31-43-induced CFTR malfunction and an epithelial stress response in Caco-2 cells. These effects were abrogated when the CFTR gene was knocked out by CRISP/Cas9 technology, indicating that genistein protects intestinal epithelial cells by potentiating CFTR function. Notably, genistein protected gliadin-sensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadin-induced IFN-γ production by celiac peripheral-blood-mononuclear-cells (PBMC) cultured ex-vivo in the presence of P31-43-challenged Caco-2 cells. Our results indicate that natural compounds capable to increase CFTR channel gating might be used for the treatment of CD.

Q-X1-P-X2 motif search for potential celiac disease risk has poor selectivity.

The European Food Safety Authority (EFSA) recently published guidelines for assessment of potential celiac disease risk for newly expressed proteins in genetically modified (GM) crops. This novel step-wise approach prescribes, in part, how to conduct sequence identity searches between a newly expressed protein and known celiac disease peptides including a Q/E-X1-P-X2 amino acid motif. To evaluate the specificity of the recommended sequence identity searches in the context of risk assessment, protein sequences from celiac disease causing crops, as well as from crops not associated with celiac disease, were compared with known HLA-DQ restricted epitopes and searched for the presence of motifs followed by peptide analysis. Searches for the presence of the Q/E-X1-P-X2-motif were found to generate a high proportion of false-positive hits irrelevant to celiac disease risk. Identification of a 9mer exact match between a newly expressed protein and the known celiac disease peptides (recommended by the guideline) along with a supplementary sequence comparisons (suggested by FARRP/AllergenOnline) is considered better suited to more specifically capture the potential risk of a newly expressed protein for celiac disease.

Green Tea Polyphenols Mitigate Gliadin-Mediated Inflammation and Permeability in Vitro.

SCOPE: Green tea, a polyphenol-rich beverage, has been reported to mitigate a number of inflammatory and hypersensitivity disorders in laboratory models, and has been shown to moderate pathways related to food allergies in vitro. The present study investigates the impact of decaffeinated green tea extract (GTE) on the digestion of gliadin protein in vitro and the effect of physical interactions with GTE on the ability of gliadin to stimulate celiac disease-related symptoms in vitro. METHODS AND RESULTS: Complexation of GTE and gliadin in vitro is confirmed by monitoring increases in turbidity upon titration of GTE into a gliadin solution. This phenomenon is also observed during in vitro digestion when gliadin is exposed to the digestive proteases pepsin and trypsin. SDS-PAGE and enzymatic assays reveal that GTE inhibits digestive protease activity and gliadin digestion. In differentiated Caco-2 cell monolayers as a model of the small intestinal epithelium, complexation of gliadin with GTE reduces gliadin-stimulated monolayer permeability and the release of interleukin (IL)-6 and IL-8. CONCLUSION: There are potential beneficial effects of GTE as an adjuvant therapy for celiac disease through direct interaction between gliadin proteins and green tea polyphenols.

Maternal use of dietary supplements during pregnancy is not associated with coeliac disease in the offspring: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Perinatal exposure to nutrients and dietary components may affect the risk for coeliac disease (CD). We investigated the association between maternal use of vitamin D, n-3 fatty acids (FA) and Fe supplements during pregnancy and risk for CD autoimmunity (CDA) and CD in the offspring. Children at increased genetic risk were prospectively followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. CDA was defined as having persistently positive tissue transglutaminase autoantibodies (tTGA). Diagnosis of CD was either biopsy-confirmed or considered likely if having persistently elevated levels of tTGA>100 AU. Of 6627 enrolled children, 1136 developed CDA at a median 3·1 years of age (range 0·9-10) and 409 developed CD at a median 3·9 years of age (range 1·2-11). Use of supplements containing vitamin D, n-3 FA and Fe was recalled by 66, 17 and 94 % of mothers, respectively, at 3-4 months postpartum. The mean cumulative intake over the entire pregnancy was 2014 µg vitamin D (sd 2045 µg), 111 g n-3 FA (sd 303 g) and 8806 mg Fe (sd 7017 mg). After adjusting for country, child's human leucocyte antigen genotype, sex, family history of CD, any breast-feeding duration and household crowding, Cox's proportional hazard ratios did not suggest a statistically significant association between the intake of vitamin D, n-3 FA or Fe, and risk for CDA or CD. Dietary supplementation during pregnancy may help boost nutrient intake, but it is not likely to modify the risk for the disease in the offspring.

Minimally symptomatic hypocalcaemia unmasking celiac disease.

INTRODUCTION: Celiac disease is an autoimmune disease of the small intestine which occurs in genetically predisposed people of all ages. A large clinical spectrum of manifestations accompanies the onset of the disease with diarrhoea, flatulence and weight loss being the most common. However, findings like osteoporosis, iron deficiency, anaemia and hypocalcaemia could also insinuate the existence of the disease. CASE PRESENTATION: We report the case of a 55-year-old man with numbness and tingling of the upper extremities due to hypocalcaemia that proved to be an uncommon case of celiac disease. CONCLUSION: A non-negligible number of adult patients with celiac disease can present with only minor and subclinical manifestations of the disease. As such, hypocalcaemia may be the sole manifestation of celiac disease. A high index of suspicion is needed for prompt diagnosis.

[Lactose intolerance: past and present. Part 1]. / A laktózintoleranciáról: Múlt és jelen - I. rész.

Lactose intolerance is the most prevalent intestinal malabsorption disorder. After presentation of its history, the author describes the emergence of lactose intolerance during the evolution of species, and the biochemistry of lactose as well as features of human and bacterial lactase enzymes are then described. The unequal distribution of lactose intolerance in different continents and population is discussed, followed by presentation of past and present prevalence data in Hungary. Adult-type hypolactasia is caused by a polymorphism of the MCM6 gene located upstream from the lactase gene on the long arm of the chromosome 2. It can be determined with the polymerase chain reaction. The intestinal symptoms of lactose intolerance are well known, but its extra-intestinal manifestations are less recognised. Invasive diagnostic methods (determination of lactase activity from small intestinal biopsies, lactose tolerance test), are accurate, but have been replaced by the non-invasive methods; their gold standard is the H2 breath test. Genetic testing is being used more and more frequently in Hungary too, and, presumably, the methane breath test will be also available in the near future. Lactose intolerance can be accompanied by inflammatory bowel diseases, coeliac disease and irritable bowel syndrome; it could be established whether this association is causal or not in order to start a correct diet and therapy.

Early-life vitamin D deficiency and childhood-onset coeliac disease.

Many studies have investigated the aetiological roles of genetic and environmental factors in coeliac disease (CD) with the long-term goal of developing an effective primary prevention strategy. CD is a condition with dysregulated systemic and intestinal mucosal immune responses to dietary gluten proteins among genetically predisposed individuals. We recently described spring birth as a novel risk factor for CD in children. We believe that the association between season of birth and CD is due to seasonal differences in sunlight exposure and subsequent vitamin D status. Concomitant with global increases in CD prevalence, vitamin D deficiency also is increasingly recognized in children worldwide. Recent studies have shown that vitamin D deficiency can cause improper immune responses, abnormal intestinal mucosal integrity and impaired local defence to pathogenic microbial agents. In conjunction with other potential aetiological factors, we propose a hypothesis model of early-life vitamin D deficiency in the pathogenesis of childhood-onset CD.

Celiac disease: the search for adjunctive or alternative therapies.

Celiac disease is a widespread disorder caused by intolerance to gluten, a common protein in food. Currently, a life-long gluten-free diet is the only available treatment for patients with celiac disease. However, adherence to gluten-free diet is difficult due to the widespread use of wheat-derived gluten in the food industry. Therefore, there is a pressing need for the development of novel non-dietary therapies. In this article, we will review several promising strategies focusing on reducing gluten immunogenicity or sequestering to gluten prevent its uptake by the intestinal epithelium. Other possible treatment strategies that will be reviewed include the suppression of the adaptive immune response, permeability modulation and the use of systemic T-cell or cytokine blockers.

Externalities from grain consumption: a survey.

The US Department of Agriculture (USDA) publishes their MyPyramid plan as a recommended eating model for all Americans. As part of this model, grain consumption is emphasized. This grain consumption has the potential to generate positive externalities, such as reduced rates of obesity, diabetes and other chronic diseases. Such positive externalities can potentially produce tangible economic benefits in terms of public health. In contrast, newer nutritional research shows that grain consumption may have negative effects on health for certain population groups. Celiac disease is four times as common as it was 50 years ago and is often under-diagnosed. Other population groups exhibit gluten sensitivity which can impact the development of asthma, allergies and neurological difficulties. This survey intends to provide a comprehensive description of both the positive and negative externalities associated with grain consumption and the resulting impact on human health.

Immunological evaluation of the alcohol-soluble protein fraction from gluten-free grains in relation to celiac disease.

Celiac disease (CD) is a gluten-sensitive enteropathy with an immune basis. We established the immune reactivity of the alcohol-soluble fraction from two minor cereals (tef and millet) and two pseudocereals (amaranth and quinoa) which are believed to be nontoxic based on taxonomy. Grains were examined in intestinal T-cell lines (iTCLs), cultures of duodenal explants from HLA-DQ2(+) CD patients and HLA-DQ8 transgenic mice for signs of activation. Our data indicated that tef, millet, amaranth, and quinoa did not show any immune cross-reactivity toward wheat gliadin, and therefore confirming their safety in the diet of CD patients.

Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.

Gluten screening of several dietary supplements by immunochromatographic assay.

Celiac disease (CD) is a chronic intestinal disorder of public health concern caused by gluten ingestion in sensitive individuals. Gluten is a protein found not only in gluten-containing food but also as normal component of drugs and dietary supplements. Detection of gluten in dietary supplements is a very important task required for establishing their gluten status, which is highly important for the safety of products consumed by CD and gluten-sensitive patients. In this paper, we investigated the presence of gluten in twenty one common dietary supplements from the national market using the immunochromatographic assay. This visual assay proved to be an efficient rapid tool for gluten screening as an alternative to the ELISA techniques. The results have shown the presence of gluten in 23.8% of the investigated samples (vitamins, minerals, plant extracts, probiotics supplements, lactoferrin, propolis supplements). The results provide information which may contribute to the completion of the existing lists of gluten-free pharmaceuticals. It is known that for CD patients obtaining accurate information about the gluten content of a particular item is a difficult and time-consuming process.

[Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases]. / Carenza di selenio nella malattia celiaca: rischio di tireopatie autoimmuni.

The essential trace mineral selenium is of fundamental importance to human health. It is incorporated in the proteome in the forms of the genetically encoded amino acids selenocysteine and selenomethionine, which are the characteristic components of selenoproteins (SeP) such as glutathione peroxidases (GPx), thioredoxin reductases and iodothyronine deiodinase families. Thyroid is especially sensitive to selenium deficiency, because SeP can modify thyreocytes function by acting as antioxidants and modifying redox status and thyroid hormone metabolism. SeP are also involved in apoptosis, cell growth and modification of the action of cell signalling systems and transcription factors. Some intestinal GPx modulate apoptosis by removing the cells affected by oxidative damage preserving tissue integrity. The malfunctioning of the GPx antioxidant system in intestinal mucosa can trigger a continuous cycle of reactive oxygen species and inflammation. Selenium deficiency is a risk factor, due to the malabsorption, in celiac disease (CD) because the inflammatory damage affects the small intestine; this deficiency can modulate SeP genes expression, with consequent reiteration of inflammation and increase of mucosal damage. In active CD, overexpression of interleukin-15 (IL-15) may increase activation of effector mechanisms of epithelial damage by stimulating T helper 1 cytokine proliferation and production and intraepithelial lymphocytes cytotoxicity by protecting these lymphocytes from apoptosis. Blocking IL-15 has the potential to provide new therapeutic tools to prevent both tissue damage and complication of CD such as autoimmune thyroid diseases (AITD) where IL-15 expression is also increases. In view of the role played by SeP in apoptosis inhibition, the presence of environmental factors such as selenium deficiency can be considered an important direct factor of thyroidal damage in development of AITD.

Can a change in policy of complementary infant feeding reduce the risk for type 1 diabetes and celiac disease?

According to recent epidemiologic evidence, introducing solids while infants are still breastfed, and in any case not before the fourth month of life, could have positive impact on immune-related chronic disorders such as Type 1 Diabetes and coeliac disease.

Complications of collagenous colitis.

Microscopic forms of colitis have been described, including collagenous colitis. This disorder generally has an apparently benign clinical course. However, a number of gastric and intestinal complications, possibly coincidental, may develop with collagenous colitis. Distinctive inflammatory disorders of the gastric mucosa have been described, including lymphocytic gastritis and collagenous gastritis. Celiac disease and collagenous sprue (or collagenous enteritis) may occur. Colonic ulceration has been associated with use of nonsteroidal anti-inflammatory drugs, while other forms of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, may evolve from collagenous colitis. Submucosal "dissection", colonic fractures or mucosal tears and perforation from air insufflation during colonoscopy may occur and has been hypothesized to be due to compromise of the colonic wall from submucosal collagen deposition. Similar changes may result from increased intraluminal pressure during barium enema contrast studies. Finally, malignant disorders have also been reported, including carcinoma and lymphoproliferative disease.

Celiac disease and gluten-associated diseases.

Celiac disease develops from an autoimmune response to specific dietary grains that contain gluten. Diagnosis can be made based on the classical presentation of diarrhea, fatty stools, and abdominal bloating and cramping, as well as the presence of specific serum antibodies. In addition, gluten ingestion has increasingly been found to be associated with other conditions not usually correlated with gluten intolerance. The subsequent diversity of the clinical presentation in these cases can complicate decision-making and delay treatment initiation in conditions such as ataxia, headaches, arthritis, neuropathy, type 1 diabetes mellitus, and others. This review explores the etiology and pathology of celiac disease, presents support for the relationship between gluten and other diseases, and provides effective screening and treatment protocols.