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extraintestinal symptoms (iron deficiency ane- mia, neurological problems, alterations in liver function tests, enamel defects and osteoporosis) to asymptomatic cases [3] . Also, the small intes- tinal lesions may range from epithelial lympho- cyte infiltration with preserved villous archi- tecture to severe villous atrophy [4] . The nutri- tion status at diagnosis depends mostly on the extent of the intestinal damage. The classic pre- sentation is accompanied by steatorrhea and fat- soluble vitamin deficiency. Malabsorption of iron, calcium and folic acid is also frequent, as these are absorbed in the proximal small intes- tine [5] .
The diagnostic approach has recently been re- vised [1] . Children found positive for CD-spe- cific antibodies (anti-TG2, EMA and anti-DGP) should undergo duodenal biopsies unless certain conditions are fulfilled which allow the option to omit the confirmatory biopsies. In children and adolescents with signs or symptoms suggestive of CD and very high anti-TG2 (or anti-DGP) titers with levels exceeding 10 times the upper limit of normal, the likelihood for villous atrophy (Marsh score 3) is high. In this situation, the pediatric gastroenterologist may discuss with the parents and patient (as appropriate for the patient’s age) the option of performing further laboratory test- ing (EMA, HLA) in order to make the diagnosis of CD without biopsies. In the case of an asymp-
tomatic child or adolescent with CD-associated conditions, duodenal biopsies are still advocated in all cases.
Gluten-Free Diet
The only treatment for CD is lifelong strict adher- ence to a gluten-free diet (GFD; table 1 ). GFD consist of the dietary exclusion of grains contain- ing gluten (wheat, rye, barley, triticale, couscous, spelt and Kamut). Rice, corn and buckwheat do not contain gluten and can be eaten. Potato, chestnut, tapioca, sorghum, quinoa and ama- ranth are also tolerated. Although there is now a large body of clinical evidence suggesting oats lacking toxicity for CD patients, there are still some important aspects to consider [6] . There are documented cases of oat-dependent villous atro- phy in patients with oat-specific mucosal T cell reactivity. Furthermore, there is also the possibil- ity that symptoms are related to wheat proteins contaminating oats during the harvesting and milling process. Another issue that warrants fur- ther investigation is related to the great heteroge- neity of oat cultivars. On the other hand, the in- corporation of oats into a GFD provides high fi- ber and vitamin B content, increased palatability and beneficial effects on cardiovascular health.
However, it seems wise to add oats only when the
Table 1. Fundamentals of the GFD Grains that should be
avoided
Wheat (including spelt, Kamut, semolina and triticale), rye and barley (including malt)
Safe grains (gluten free) Rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain) and oats (?)
Sources of gluten-free starches that can be used as flour alternatives
Cereal grains: rice, amaranth, buckwheat, corn, millet, quinoa, sorghum and teff Tubers: potato, arrowroot, jicama, taro and tapioca
Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts and soybeans
Nuts: almonds, walnuts, chestnuts, hazelnuts and cashews Seeds: sunflower, flax and pumpkin
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GFD is well established, so that possible adverse reactions can be readily identified by a strict clin- ical follow-up.
There is a general consensus that all CD pa- tients should be treated with a GFD irrespective of the presence of symptoms. However, while it is relatively easy to assess the health improvement after treatment of CD in patients with clinical symptoms of the disease, it proves difficult in persons with asymptomatic CD. A high rate of osteoporosis/osteopenia (60%) was observed in asymptomatic patients with villous atrophy; this finding suggests that, in CD, clinical tolerance does not reflect tolerance to gluten and that, in silent cases, the increased risk of osteoporosis substantiates the need for a GFD. There are no guidelines concerning the need for a GFD in sub- jects with ‘potential’ CD (patients with positive CD-associated serology but without enteropa- thy). Most of the ‘potential’ cases are left on glu- ten-containing diet and strictly monitored for the appearance of complications. While a risk of os- teoporosis also for this group of patients has been reported in the past [7] , no significant differences have recently been found between CD patients on a long-term GFD and ‘latent’ patients (patients with a clear previous diagnosis of CD and no clinical/histological relapse after a long period of GFD) as far as biological tests of malabsorption and the overall nutritional status, including bone mass density, are concerned. Similarly, we did not observe any major nutritional problem in our co- hort of potential CD subjects [8] .
Compliance with GFD
It is important that an experienced dietician with specific expertise in CD counseling educates the family and the child about dietary restrictions. An expert dietician should be consulted in order to evaluate the patient’s current nutritional status, to assess macronutrient and/or micronutrient in- take, to detect deficiencies, to educate the patient to the GFD and to monitor dietary compliance.
Compliance with a GFD can be difficult, especial-
ly in adolescents [9] . It is recommended that chil- dren with CD be monitored with periodic visits for assessment of symptoms, growth, physical status and adherence to GFD. Periodic measure- ments of tissue TG antibody levels to document reductions in antibody titers can be helpful as in- direct evidence of adherence to a GFD, although they are inaccurate in detecting slight dietary transgressions. Recently, methods based on the detection of a 33-mer gliadin peptide in feces have been proposed to assess compliance with the GFD [10] .
Limits
More information is needed on the daily gluten amount that may be tolerated by CD patients. The data available so far seem to suggest that, although individual variability makes it difficult to set a universal threshold, this should be set below 50 mg/day, a level unlikely to cause significant histo- logical abnormalities. The regulations on the composition and labeling of food suitable for CD patients have recently changed. In 2008, the Co- dex Alimentarius revised the previous standard indicating 2 thresholds: 20 ppm for products to be labeled gluten free and 100 ppm for products with very low gluten content. The 20-ppm threshold is considered a safe option for CD patients, consid- ering the overall consumption of gluten-free products [11] .
Alternative Therapies
Breeding programs and transgenic technology may lead to the production of wheat that is devoid of biologically active peptide sequences. Recently, new, alternative approaches to GFD have been in- vestigated ( table 2 ) [12] . As gliadin peptides are highly resistant to digestive processing, prolyl en- dopeptidase produced by probiotic microorgan- isms has been shown to promote digestion of gli- adin. Clinical trials have already started. Other approaches include restoring intestinal permea-
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 190–194 DOI: 10.1159/000367874
3
bility with anti-zonulin antibodies, preventing gliadin presentation to T cells by blocking HLA binding sites and the use of tissue TG inhibitors.
The efficacy of these approaches needs to be as- sessed in more in vivo studies.
Prevention
Evidence suggests that the first months of life are crucial for CD development; breastfeeding has a protective role, and indeed there is a negative cor- relation between its duration and the develop- ment of CD. Moreover, the age at introduction of gluten to the diet is important: exposure to gluten in the first 3 months significantly increases the risk of CD in genetically susceptible individuals.
One study has suggested the existence of a win- dow of opportunity as the late introduction of gluten to the diet (after the 7th month of life) has been found to be associated with a higher risk. On the basis of the present evidence, breastfeeding should be strongly encouraged and gluten should not be introduced before the 4th month of life, preferably while the baby is still breastfed [13] . Finally, increasing attention is being devoted to the possible role of viruses, which could trigger CD autoimmunity in genetically susceptible chil- dren by increasing intestinal permeability and ac- tivating innate immune pathways linked to CD pathophysiology.
Other Conditions Requiring GFD
The spectrum of gluten-related disorders also in- cludes wheat allergy (WA) and nonceliac gluten sensitivity (NCGS). WA is defined as an adverse immunologic reaction to wheat proteins. De- pending on the allergen exposure and the immu- nologic mechanisms, WA is classified into (1) classic food allergy affecting the skin, gastrointes- tinal tract or respiratory tract, (2) wheat-depen- dent, exercise-induced anaphylaxis, (3) occupa- tional asthma (baker’s asthma) and rhinitis as well as (4) contact urticaria. IgE antibodies play a central role in the pathogenesis of these diseases.
WA is treated by GFD, and the same limits as dis- cussed for CD seem to apply to WA [14] .
NCGS refers to individuals who show distress when eating gluten and improvement when fol- lowing a GFD. CD autoantibodies are absent, the small intestine is usually normal, and allergy tests are negative. Thus, NCGS is a diagnosis by exclu- sion criteria. However, many suggest caution, as there is a noticeable lack of controlled studies un- equivocally demonstrating the role of gluten. Oth- er food components (fermentable oligo-, di- and monosaccharides and polyols or FODMAPs) have been suspected to be responsible for symptoms at- tributed to NCGS. Further caution is required due
Table 2. Alternative therapies for CD 1. Intraluminal therapies
Wheat varieties
(Ancient) wheat variants with low immunogenicity
Genetically modified wheat variants or deletion lines of common wheat with lower
immunogenicity Flour/dough treatment Pretreatment with lactobacilli Transamidation of gliadin
Ingested gliadin peptide modifications Prolyl endopeptidases from Aspergillus niger or
Sphingomonas capsulata
Intraluminal gliadin binding by polymers 2. Transepitelial uptake
Epithelial tight junctions ZOT receptor antagonist AT1001 3. Adaptive immune response
TG2 TG inhibitors HLA-DQ2
Blocking DQ2 analogs 4. Immune modulators
Gluten vaccination
5. Biologicals (T cell or cytokine blockers)
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to the fact that unmotivated GFD is dangerous not only because of the costs imposed upon the com- munity but also because it may affect the health of incorrectly classified patients [15] .
Conclusions
• CD patients should be treated with GFD irre- spective of the presence of symptoms. There is still uncertainty as to whether to treat ‘poten- tial’ CD or not
• It is important that an experienced dietician with specific expertise educates the family and the child about dietary restrictions
• It seems wise to add oats only when the GFD is well established, so that possible adverse re- actions can be readily identified
• The 20-ppm threshold is considered a safe op- tion for CD patients
• To prevent CD, breastfeeding should be strongly encouraged; gluten should not be introduced before the 4th month of life, pref- erably while the baby is still breastfed
11 Gilbert A, Kruizinga AG, Neuhold S, Haoben GF, Canela MA, Fasano A, Ca- tassi C: Might gluten traces in wheat substitutes pose a risk in patients with celiac disease? A population-based prob- abilistic approach to risk estimation.
Am J Clin Nutr 2013; 97: 109–116.
12 Gianfrani C, Auricchio S, Troncone R:
Possible drug targets for celiac disease.
Expert Opin Ther Targets 2006; 10: 601–
611.
13 Szajewska H, Chmielewska A, Pieścik- Lech M, Ivarsson A, Kolacek S, Koletzko S, Mearin ML, Shamir R, Auricchio R, Troncone R; PREVENTCD Study Group:
Systematic review: early infant feeding and the prevention of coeliac disease.
Aliment Pharmacol Ther 2012; 36: 607–
618.
14 Hischenhuber C, Crevel R, Jarry B, Mọki M, Moneret-Vautrin DA, Romano A, Troncone R, Ward R: Review article:
safe amounts of gluten for patients with wheat allergy or coeliac disease. Aliment Pharmacol Ther 2006; 23: 559–575.
15 Di Sabatino A, Giuffrida P, Corazza GR:
Still waiting for a definition of nonceliac gluten sensitivity. J Clin Gastroenterol 2013; 47: 567–569.
References
1 Husby S, Koletzko S, Korponay-Szabó IR, et al; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition: European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.
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2 Mustalahti K, Catassi C, Reunanen A, Fabiani E, Heier M, McMillan S, Murray L, Metzger MH, Gasparin M, Bravi E, Mọki M; Coeliac EU Cluster, Project Epidemiology: The prevalence of celiac disease in Europe: results of a central- ized, international mass screening proj- ect. Ann Med 2010; 42: 587–595.
3 Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C: The Oslo definitions for coeliac disease and related terms. Gut 2013; 62: 43–52.
4 Oberhuber G, Granditsch G, Vogelsang H: The histopathology of coeliac disease:
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5 Garcia-Manzanares A, Lucendo JA: Nu- tritional and dietary aspects of celiac disease. Nutr Clin Pract 2011; 26: 163–
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8 Tosco A, Salvati VM, Auricchio R, Mag- lio M, Borrelli M, Coruzzo A, Paparo F, Boffardi M, Esposito A, D’Adamo G, Malamisura B, Greco L, Troncone R:
Natural history of potential celiac dis- ease in children. Clin Gastroenterol Hepatol 2011; 9: 320–325.
9 Errichiello S, Esposito O, Di Mase R, Camarca ME, Natale C, Limongelli MG, Marano C, Coruzzo A, Lombardo M, Strisciuglio P, Greco L: Celiac disease:
predictors of compliance with a gluten- free diet in adolescents and young adults. J Pediatr Gastroenterol Nutr 2010; 50: 54–60.
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Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 190–194 DOI: 10.1159/000367874
3 Nutritional Challenges in Special Conditions and Diseases
Key Words
Food allergy ã Lactose intolerance ã Enteropathy, food protein-induced ã Enterocolitis syndrome, food protein-induced ã Proctocolitis, food
protein-induced ã Elimination diet ã Hypoallergenic formula ã Amino acid-based formula ã Hydrolyzed formula ã Soy formula
Key Messages
• Food allergy is an immune-mediated reaction against food proteins, whereas food intolerances can be caused by any food constituent and do not involve immunological mechanisms
• Treatment of food allergies involves strict avoid- ance of the offending food allergen, either by use of a hypoallergenic infant formula or a specific elimi- nation diet. By contrast, patients with food intoler- ances generally tolerate small quantities of the of- fending food ingredient (dose-response relation- ship)
• Infants and young children with gastrointestinal food allergies and persistent vomiting or diarrhea are at high risk of failure to thrive, particularly if there are associated feeding difficulties
• Correct identification of food allergies and intoler- ances in infancy and childhood is important in or- der to prevent growth impairment and nutritional deficiency states
• Close monitoring of dietary intake and growth pa- rameters, regular reassessment of persistent aller- gies and dietary introduction of tolerated food pro- teins are essential steps in the nutritional manage- ment of children with food allergies
© 2015 S. Karger AG, Basel
Introduction
Food allergy is defined as a reproducible, T helper lymphocyte type 2-mediated reaction to food proteins. Over the past decades, the prevalence of food allergy has increased dramatically in many developed countries. Cow’s milk, egg, soy, wheat, peanuts, tree nuts, fish and shellfish cause more than 90% of food allergies [1] . A recent popula- tion-based study in Australia demonstrated chal- lenge-proven, immunoglobulin E (IgE)-mediat- ed food allergy in more than 10% of 12-month- old infants [2] . Possible reasons for the increased prevalence of food allergy in children include ge- netic factors, epigenetic dysregulation of gene ex- pression, exposure to toxins and pollutants (e.g.
tobacco smoke), dietary factors, reduced environ- mental microbial exposure and reduced fecal mi- crobial diversity [3, 4] .
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 195–202 DOI: 10.1159/000360340