Enteropathy Caused by Food Hypersensitivity

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Celiac Disease

The incidence of celiac disease (CD) is increasing worldwide, with a prevalence as high as 1:300 and even 1:80 children [9]. One of the major reasons for the increase in prevalence is improved serological screening in subjects without overt gastrointestinal complaints. However, regional differences are emerging. The incidence of histological abnormalities suggestive of CD is lower than 1/250 children undergoing upper endoscopy for various indications (pers. data). Wheat, rye and barley are the predominant grains containing gluten peptides, very rich in proline and glutamine and resistant to digestive enzymes, known to cause CD. Variability exists in the age of onset of symptoms, in extraintestinal and autoimmune manifestations, in serological positivity, and in severity of histological involvement and no clear explanation has emerged despite major advances in the identification of toxic peptides, immune cascade and genetic susceptibility. The incidence of CD in mothers giving birth to preterm or immature babies is higher than in a control population (pers. data); in other words, undiagnosed CD in pregnant women challenges the outcome of pregnancy, and subsequently the nutritional status of the newborn. The variable histological findings of CD include increased intraepithelial lymphocytes (>30 lymphocytes per 100 enterocytes, with a mitotic index >0.2%), inflammatory infiltration into the lamina propria and crypt hyperplasia, decreased height of the epithelial cells (changes from columnar to cuboid to flat epithelium) and decreased villous/crypt ratio, and partial to total villous atrophy. Modern histological (Marsh) classification consists of 4 CD types ranging from a normal preinfiltrative stage (type 0), to infiltrative lesions with increased intraepithelial lymphocytes (type 1), hyperplastic lesions (type 2: type 1 + hyperplastic crypts), destructive lesions (type 3: type 2 + variable degree of villous atrophy), and hypoplastic lesions with total villous atrophy and crypt hypoplasia (type 4). Marsh type 3 was subsequently modified into type 3a (partial villous atrophy), type 3b (subtotal villous atrophy) and type 3c (total villous atrophy). In Marsh type 1 and type 2 lesions, positive celiac antibodies and clinical and serological response to a gluten-free diet support the diagnosis of CD [9]. After diagnosis of CD, a life-long gluten-free diet results in the disappearance of clinical manifestations, mucosal healing and reduction of CD-related complications. However the importance of dietetic compliance in asymptomatic patients, the real risk of complications in patients with only subtle mucosal involvement (Marsh type 1), the individual threshold of gluten sensitivity and the clinical significance of seropositivity in the absence of enteropathy require further clarification [10]. The role of prolonged breastfeeding, timing of introduction and dosing of gluten-containing food especially in subjects with a high genetic risk is under evaluation.

Future therapeutic strategies include peptidase supplementation (from experimental bacterial sources) which cleaves residues next to proline to facilitate proteolysis of immunogenic peptides, transgenic wheat without antigenic peptides, modulation of permeability (by control of the immune cascade and zonulin release) and block of innate and acquired immunity triggered by gluten in celiac patients [10]. Further efforts are needed to clarify and standardize the definition of a gluten-free diet, to simplify the labeling of ingredients in food products, to improve and support the social life of celiac patients and to increase early identification of celiac patients [10].

Food Allergy

Cow's milk protein (CMP), soy, wheat, oats, rice, eggs and fish have all been reported to cause enteropathy in selected children [11, 12]. A 30-kD protein in soy cross-reacts with casein [13] and may favor a concomitant soy and cow's milk hypersensitivity especially in infants with (IgE-negative) CMP enteropathy or enterocolitis. In the last decades an increased number of children has been reported to be sensitized to multiple food antigens, especially (or even) during exclusive breastfeeding, with allergic manifestations early in life due to an impaired development of oral tolerance. In selected infants, acute gastroenteritis increasing permeability and contact of antigens in the lamina propria may provoke sensitization to dietary antigens.

Chronic diarrhea, malabsorption, edema and failure to thrive are the most common clinical manifestations of food-related enteropathy. Other gastrointestinal (abdominal pain, frequent regurgitation or vomiting, constipation, refusal to feed, protein-losing enteropathy), dermatological (atopic dermatitis, napkin rash, swelling of the lips or eye lids), respiratory (runny nose, chronic cough or wheezing, laryngeal edema), and general (persistent distress, colic) manifestations may be additional features. In many patients, the nongastrointesinal manifestations are predominant. Especially regarding CMP, most children will tolerate the offending allergen after the age of 1 year although food enteropathy may persist longer in a minority of them [14].

In food allergy, duodenal, ileal and colonic lymphonodular hyperplasia may be detected [15] as a consequence of immune activation. Histological abnormalities are variable: from total to patchy or even absent villous atrophy, mild to moderately increased intraepithelial CD8 cells, lymphoid follicles, activated lamina propria CD4 cells (with increased IFN-7 with or without IL-4 or TNF-a) and decreased regulatory cytokines (especially TGF-p) [16].

Different from CD, enteropathy caused by food allergy presents a thin mucosa, a prominent patchy distribution, only moderate crypt hyperplasia and less intraepithelial lymphocyte infiltration. The infiltration of eosinophils and mast cells is frequent and related to antigen-induced dysmotility and enteric neural dysfunction. The mucosal lesions may cause reduction in brush border disaccharidase expression and secondary exocrine pancreatic impairment, caused by decreased duodenal CCK production, with mild-to-moderate steat-orrhea and reduced fecal elastase [17].

As food-related enteropathy is mostly cellular mediated, total and specific serum IgE and skin prick tests are often negative. PATCH tests seem a promising diagnostic tool for T cell (late) response to dietary antigen. Fecal cal-protectin has recently been proposed as an (unspecific) noninvasive marker of enteropathy.

Mechanisms inducing oral tolerance are in general not complete at birth but develop postnatally, mainly in response or intimate relation to the gut flora and to activation of specific Toll-like receptors on regulatory T cells [1, 18]. The key role of the luminal bacteria is highlighted by the impaired tolerance in germfree mice [1], by the different intestinal flora in populations that will develop atopy, by the immune-modulatory properties of specific probiotics and by the promising results of interventional studies. Allergic infants showed, even before the appearance of symptoms, a significantly higher prevalence of clostridia, coliforms and Stapkylococcus aureus versus lactobacilli and Bifidobacterium (bifidum). Manipulation of the gut flora as early as in the first days or months of life may influence through microenvironment modification and competition subsequent colonization and expression of regulatory cytokines. Specific probiotics including LGG may induce anti-inflammatory IL-10 and TGF-p [19] and possibly exert a tolerogenic effect before sensitization occurs. According to 2 trials using supplementation of LGG and E. coli in the perinatal period, in particular non-IgE-mediated allergies are reduced [19, 20]. Maternal supplementation with LGG during pregnancy and 6 months after delivery increases the concentration of TGF-p in the breast milk of at-risk mothers and confers protection against atopy.

Supplementation of a cow's milk-based formula with prebiotics has the ability to manipulate the intestinal flora with a bifidogenic effect, but a beneficial prospective effect on food allergy has not been demonstrated so far with prebiotic supplementation. Comparing symptoms suggesting atopic sensitiza-tion at the age of 3-4 years in 27 exclusively breastfed babies during 6 months, in 16 infants on oligosaccharide-supplemented formula and in 17 infants on standard infant formula, the incidence was similar in breastfed and standard formula-fed infants (59 vs. 58%) and decreased by 50% in the supplemented formula group (31%) (pers. data).

Prenatal prevention is complex and multifactorial and dietetic intervention during pregnancy is not currently substantiated by scientific evidence [21]. Postnatally, dietetic prevention is actually recommended in high-risk infants only and is based on the promotion of breastfeeding (with no conclusive evidence of inconsistently proposed exclusion of peanuts and nuts), hypoallergenic formulas for bottle-fed infants and late introduction of solid foods. Compared to extensive hydrolysate formulas (eHFs), partial hydrolyzed formulas offer economical and taste advantages and a theoretical benefit in inducing oral tolerance to CMP as they still have enough residual allergenicity to induce tolerance but too low allergenicity to induce allergic reactions.

Up to now, for the treatment of food allergies, guidelines worldwide recommend exclusion of the causative antigen. For the infant who is sensitized while being breastfed, maternal exclusion of the more relevant antigens (CMP, egg white, (pea)nut) is advised. In cow's milk-sensitive enteropathy, eHF or, in those refusing to drink eHF or those not responding to the elimination diet, amino acid formulas are recommended. Infants and children with multiple food allergy have often more severe symptoms with possible reactions even to a small quantity of antigens (like those present in breast milk), are unresponsive to eHFs, and have late acquisition of tolerance. The maintenance of a nutritionally adequate diet is not easy especially in the case of compromised absorption or multiple allergies but is mandatory for each child. It is fortunate that manufacturers continue to make efforts to be able to offer new formulas with improved hydrolyzation, amino acid profile, additional beneficial components such as prebiotics, probiotics, nucleotides, medium-chain triglycerides (MCT) and long-chain polyunsaturated fatty acids, and last but not least cost and taste.

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