’
Celiac Disease: An Immune Dysregulation Syndrome Joseph Levy, MD, Leora Bernstein, CPNP, and Nicole Silber, RD
Celiac disease is a chronic immune-mediated condition that develops in genetically predisposed individuals. It is characterized by the presence of circulating auto-antibodies in addition to an enteropathy and at times, other extra-intestinal manifestations triggered by exposure to the gliadin fraction of gluten, a family of proteins found in wheat, barley, and rye. There seems to be a rise in reported adverse reactions to gluten, an entity currently termed non-celiac gluten (or perhaps more accurately, wheat) sensitivity, where neither the enteropathy nor the auto-antibodies are present. Celiac disease has protean extra-intestinal manifestations, and an accurate diagnosis should be sought in people suffering from seemingly unrelated complaints, such as fatigue, anorexia, delayed puberty, short stature, decreased bone density, unusual skin rashes, unexplained iron deficiency, and infertility. The presence of an enteropathy, in conjunction with the positive serology, is considered the diagnostic gold standard for making the diagnosis of celiac disease. It is important to stress that the elimination of gluten, even in asymptomatic
patients, brings about health benefits, particularly in relation to bone health, as well as a decrease in the incidence of small bowel malignancy, especially lymphoma. Better understanding of the pathophysiology of celiac disease and the molecular mechanisms involved in antigen recognition and processing has provided the impetus for the development of pharmacologic agents that might block the recognition of gluten and its conversion to a toxic antigenic target. Inhibition of tight junction dysregulation could also prevent or minimize the damage triggered by gluten. Work on genetically modified wheat cultivars has progressed, and the possibility of a vaccine to block the immune mediated trigger is being actively investigated. Education and guidance by a knowledgeable nutritionist or registered dietitian can go a long way in minimizing the stress and facilitating the acceptance of the diet and the life-style changes that it represents. Curr Probl Pediatr Adolesc Health Care 2014;44:324-327
an entity currently termed non-celiac gluten (or pereliac disease is a chronic immune-mediated haps more accurately, wheat) sensitivity, where neither condition that develops in genetically predisthe enteropathy nor the auto-antibodies are present.2 posed individuals. It is characterized by the presence of circulating auto-antibodies in addition to an enteropathy and at Clinical Wheat-related disorders times, other extra-intestinal manifestaManifestations span a spectrum that tions triggered by exposure to the gliadin fraction of gluten, a family of proteins includes celiac disease, Clinically, the classic prefound in wheat, barley, and rye.1 classic allergic manifesta- sentation of celiac disease As recent surveys have indicated, the was of an irritable child who tions triggered by conprevalence of celiac disease has failed to thrive, developed sumption of wheat and increased to approximately 1% of the abdominal distention, and population over the past two decades. It other cereals, and the still foul-smelling diarrhea (steais not entirely clear why the incidence poorly understood entity of torrhea) after cereals were continues to grow even in populations non-celiac gluten sensitivity introduced into the diet. Typthat until now were thought to be ically, all of the symptoms (NCGS) protected. cleared once a strict glutenAdditionally, there seems to be a rise free diet was instituted. We in reported adverse reactions to gluten, now recognize that in addition to the gastrointestinal signs and symptoms, some From the Department of Pediatrics, New York University School of Medicine, New York, NY. patients might actually present with constipation, or Curr Probl Pediatr Adolesc Health Care 2014;44:324-327 have vague GI complaints reminiscent of functional 1538-5442/$ - see front matter disorders, such as abdominal distention and bloating, & 2014 Mosby, Inc. All rights reserved. crampy abdominal pain, and excessive flatulence. http://dx.doi.org/10.1016/j.cppeds.2014.10.002
C
324
Curr Probl Pediatr Adolesc Health Care, December 2014
TABLE. Recommendations for initial screening
Initially obtain: Tissue transglutaminase (IgA tTg) and total IgA (while on gluten-containing diet). In the setting of IgA deficiency, IgG-based antibody tests should be performed: Tissue transglutaminase (IgG tTg) Endomysial antibodies (IgG EMA) Deaminated gliadin peptide antibodies (IgG DGP) Children o2 years of age should be tested with a combination of tissue transglutaminase and deaminated gliadin peptide antibodies (IgG and IgA). Anti-gliadin antibodies (IgG AGA and IgA AGA) should not to be used for routine screening due to their highly variable sensitivity and specificity. If there is a strong clinical suspicion for CD, despite negative serological tests an intestinal biopsy should be considered.
studies suggest that under these circumstances the Celiac disease has protean extra-intestinal manifesbiopsy could be omitted.6 tations and an accurate diagnosis should be sought in people suffering from seemingly unrelated complaints, Given the varied spectrum of clinical manifestations, such as fatigue, anorexia, delayed proactive screening should be purpuberty, short stature, decreased sued. Through this proactive bone density, unusual skin rashes, screening, it has become clear that unexplained iron deficiency, and The gold standard for diag- the “classical” or “typical” celiac infertility.3 Recently, various neu- nosing celiac disease is the disease is but the tip of the iceberg, rological manifestations have been histologic demonstration of and that there are many who are affected yet remain asymptomatic associated with celiac disease, the enteritis present in with what is referred to as “silent” including cerebellar ataxia, numbendoscopically obtained celiac disease. In silent celiac disness, seizures, brain calcifications, and psychiatric disorders.4 biopsies. The availability of ease, the enteropathy is present and In patients in whom there is a sensitive and specific sero- the subject has mounted the response, but the patient suspicion of celiac disease, serologic markers helps screen immune is clinically asymptomatic. A third logic screening should be obtained (Table). In the setting of abnormal candidates for the definitive category, latent celiac disease, is diagnosis. reserved for those who have had screening or other clinical indicadocumented villus blunting and in tors that raise the concern for whom the mucosa heals after celiac disease, an upper intestinal adherence to a gluten-free diet endoscopy with biopsies of the and remains normal even after the reintroduction of distal and proximal duodenum should be obtained. gluten. A second variant of latent celiac disease applies to those who initially had a normal biopsy Histopathology while on gluten and later develop the enteropathy of The enteropathy of celiac disease is characterized by celiac disease. Patients with other autoimmune conthe presence of increased intra-epithelial lymphocytes ditions, such as thyroiditis or type I diabetes, might fall (IELs), as well as by crypt hyperplasia and various into this category.7 degrees of villus blunting progressing to total villus atrophy.5 Until now, it is the presence of this enteropathy, in conjunction with the positive serology, Pathophysiology which is considered the diagnostic gold standard for making the diagnosis of celiac disease. Histological Exposure to gliadin, a protein rich in proline and confirmation has been recommended to justify lifelong glutamine, causes recognition by specific T cells in the elimination of gluten. Lately, some flexibility in the setting of specific HLA allelles, DQ2, and DQ8. Once diagnostic algorithm has begun to be discussed for the enzyme tissue transglutaminase tTG2 modifies the subjects where the clinical manifestations, HLA pheglutamine into glutamic acid, the gliadin molecule can notype and markedly elevated titer of auto-antibodies tightly adhere with the HLA lymphocytes. It is unclear (IgA tissue transglutaminase 4100) are present. Some how the auto-antibodies against tTG2 are actually Curr Probl PediatrAdolesc Health Care, December 2014
325
dramatically once gluten is removed from the diet formed. The gluten peptides activate both the innate and recur upon re-challenge.11 Some postulate that it is and the adaptive branches of the immune system, þ þ including CD4 and CD8 T-cell responses. IL-15 the carbohydrate components of wheat, specifically the induction is a key step in the pathogenesis, as this fructans that trigger the GI symptoms. These fructans, cytokine is involved in expressing natural killer (NK)so-called fermentable, oligo-, di-, mono-saccharides, like receptors on the IEL's. This, in turn, increases the and polyols (FODMAPs) are fermentable carbohydrate damaging effects of the IELs. Interestingly, environpolymers and may be the culprit rather than gluten. mental triggers, such as bacteria or viral infections can Many subjects with NCGS have been managed for play a role in setting the stage for a high proinflammayears for presumed irritable bowel syndrome or other tory profile, initially in the epithelium and subsefunctional or psychiatric disorders, and in many quently in the lamina propria. The gliadin peptides, instances, the association with gluten exposure is made bound to dentritic cells, activate a proinflammatory empirically or serendipitously. There are no bioresponse in which CD4þ cells participate in upregulamarkers to make this diagnosis with certainty at this time, but celiac disease should be ruled out with the tion of IFN-gamma, TNF-alpha, and IL-21. The end recommended serologic screening. results are the observed villus Other diagnoses, including blunting and atrophy.8 inflammatory bowel disease, food An important element in the pathophysiology of celiac disease The challenge of adhering to intolerance and food allergy, and is a change in gut permeability a strict gluten-free diet for irritable bowel syndrome should be and confirmed or ruled caused by a loss of integrity of the life is a challenging propo- investigated out. Awareness of NCGS has paracellular tight junctions. A key participant in this phenomenon is sition that requires on-going increased given the widespread education, guidance, and promotion and popularity of the zonulin, an intestinal peptide that gluten-free diet, leading many to regulates the tight junctions. It is support to minimize the speculated that once the integrity psychosocial impact of this try elimination diets and fostering an interesting mystique around the is breached and permeability diagnosis. nefarious effects of this food comincreases (“leaky gut”), transit of ponent. A particularly targeted the toxic gliadin peptides towards population has been the vulnerable the lamina propria could be facilichildren with autism and other developmental tated, thus amplifying the immunological chain reacdisabilities.12 tion.9 Not surprisingly, research efforts have focused on blocking zonulin upregulation.10 Agents are in the pipeline and in clinical trials with the hope that by preventing the increased permeability, access to the Management and Future Directions deeper epithelium and lamina propria will be curtailed, slowing the damage caused by the activated Th-1 The treatment of celiac disease is a lifelong complete response described above. avoidance of barley, rye, and wheat-containing foodstuff to promote villous healing. It remains controversial whether even uncontaminated oats can be safely consumed.13 Monitoring for disappearance of the tTG Non-Celiac Gluten Sensitivity (NCGS) auto-antibodies and normalization of nutritional indices (particularly vitamin D and iron) is important, as is NCGS is probably more prevalent than celiac dismonitoring regularly for the presence of other autoease, but its diagnosis remains elusive. Only recently immune co-morbidities, such as Hashimoto's thyroihas a more concerted effort been made to properly ditis and type 1 diabetes. It is important to stress to define this obscure clinical entity. Patients with NCGS asymptomatic patients that the elimination of gluten often complain of vague abdominal pain, bloatedness, brings about health benefits that might not be immeweight loss, and diarrhea. Other manifestations include diately experienced, but are nonetheless important and tiredness, a “foggy brain,” depression and other worth the sacrifices that a gluten-free diet imposes. behavioral changes, as well as dermatitis, and anemia, This is particularly relevant insofar as bone health is among others. Patient's symptoms improve
326
Curr Probl Pediatr Adolesc Health Care, December 2014
concerned, as well as a decrease in the incidence of small bowel malignancy, especially lymphoma.14 Instituting a strict gluten-free diet can be very challenging and can take a psychological and financial toll on patients and families. The fear of crosscontamination can become an obsession, significantly impacting on quality of life. Initially, reduced levels of lactase and sucrase activities might necessitate further dietary restrictions until the villi have healed and those sugars are better tolerated. Education and guidance by a knowledgeable nutritionist or registered dietitian familiar with the subtleties of food labeling and food planning can go a long way in minimizing the stress and facilitating the acceptance of the diet and the lifestyle changes that it represents. Processed gluten-free foods are often nutritionally inferior and studies have suggested that a gluten-free diet can be inadequate in fiber and vitamins and have a higher caloric content. Preventing nutritional deficiencies and fostering normal growth and weight gain are often best accomplished with the help of a professional nutritionist or registered dietitian. Pharmacological agents addressing antigen recognition, processing, and transport through the permeable tight junctions are in various stages of development, as is work on genetically modified wheat cultivars. The possibility of a vaccine to block the immune-mediated trigger leading to celiac disease is also being investigated.15 However, until novel approaches prove to be safe alternatives, the gluten-free diet remains the linchpin of celiac disease management.
References 1. Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut 2013;62:43–52. 2. Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 2013; 5(10):3839–53.
Curr Probl PediatrAdolesc Health Care, December 2014
3. Lasa JS, Zubiaurre I, Soifer LO. Risk of intertility in patients with celiac disease: a meta-analysis of observational studies. Arq Gastroenterol 2014;51(2):144–50. 4. Johnson AM, Dale RC, Wienholt L, Hadjivassiliou M, Aeschlimann D, Lawson JA. Coeliac disease, epilepsy, and cerebral calcifications: association with TG6 autoantibodies. Dev Med Child Neurol 2013;55:90–3. 5. Levinson-Castiel R, Hartman C, Morgenstern S, et al. The role of duodenal bulb biopsy in the diagnosis of celiac disease in children. J Clin Gastroenterol 2011;45(1):26–9. 6. Klapp G, Masip E, Bolonio M, et al. Celiac disease: the new proposed ESPGHAN diagnostic criteria do work well in a selected population. J Pediatr Gastroenterol Nutr 2013;56: 251–6. 7. Maki M. Coeliac disease: lack of consensus regarding definitions of coeliac disease. Nat Rev Gastroenterol Hepatol 2012;9:305–6. 8. Meresse B, Malamut G, Cerf-Bensussan N. Celiac disease: an immunological jigsaw. Immunity 2012;36(6):907–19. 9. Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to chemo receptor—CXCR3. Gastroenterology 2008;135:194–204. 10. Fassano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol 2012;10(10):1096–100. 11. Carroccio A, Mansueto P, D’Alcamo A, Iacono G. Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. Am J Gastroenterol 2013;108(12): 1845–52. 12. Van De Sande MM, van Buul VJ, Brouns FG. Autism and nutrition: the role of the gut-brain axis. Nutr Res Rev 2014;8: 1–16. http://dx.doi.org/10.1017/S0954422414000110. 13. Haboubi NY, Taylor S, Jones S. Coeliac disease and oats: a systematic review. Postgrad Med J 2006;82:672–8. 14. Lebwhol B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoprolipherative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013;159(3): 169–75. 15. Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol 2013; 25(3):410–7.
327
Celiac Disease: An Immune Dysregulation Syndrome Joseph Levy, MD, Leora Bernstein, CPNP, and Nicole Silber, RD
Celiac disease is a chronic immune-mediated condition that develops in genetically predisposed individuals. It is characterized by the presence of circulating auto-antibodies in addition to an enteropathy and at times, other extra-intestinal manifestations triggered by exposure to the gliadin fraction of gluten, a family of proteins found in wheat, barley, and rye. There seems to be a rise in reported adverse reactions to gluten, an entity currently termed non-celiac gluten (or perhaps more accurately, wheat) sensitivity, where neither the enteropathy nor the auto-antibodies are present. Celiac disease has protean extra-intestinal manifestations, and an accurate diagnosis should be sought in people suffering from seemingly unrelated complaints, such as fatigue, anorexia, delayed puberty, short stature, decreased bone density, unusual skin rashes, unexplained iron deficiency, and infertility. The presence of an enteropathy, in conjunction with the positive serology, is considered the diagnostic gold standard for making the diagnosis of celiac disease. It is important to stress that the elimination of gluten, even in asymptomatic
patients, brings about health benefits, particularly in relation to bone health, as well as a decrease in the incidence of small bowel malignancy, especially lymphoma. Better understanding of the pathophysiology of celiac disease and the molecular mechanisms involved in antigen recognition and processing has provided the impetus for the development of pharmacologic agents that might block the recognition of gluten and its conversion to a toxic antigenic target. Inhibition of tight junction dysregulation could also prevent or minimize the damage triggered by gluten. Work on genetically modified wheat cultivars has progressed, and the possibility of a vaccine to block the immune mediated trigger is being actively investigated. Education and guidance by a knowledgeable nutritionist or registered dietitian can go a long way in minimizing the stress and facilitating the acceptance of the diet and the life-style changes that it represents. Curr Probl Pediatr Adolesc Health Care 2014;44:324-327
an entity currently termed non-celiac gluten (or pereliac disease is a chronic immune-mediated haps more accurately, wheat) sensitivity, where neither condition that develops in genetically predisthe enteropathy nor the auto-antibodies are present.2 posed individuals. It is characterized by the presence of circulating auto-antibodies in addition to an enteropathy and at Clinical Wheat-related disorders times, other extra-intestinal manifestaManifestations span a spectrum that tions triggered by exposure to the gliadin fraction of gluten, a family of proteins includes celiac disease, Clinically, the classic prefound in wheat, barley, and rye.1 classic allergic manifesta- sentation of celiac disease As recent surveys have indicated, the was of an irritable child who tions triggered by conprevalence of celiac disease has failed to thrive, developed sumption of wheat and increased to approximately 1% of the abdominal distention, and population over the past two decades. It other cereals, and the still foul-smelling diarrhea (steais not entirely clear why the incidence poorly understood entity of torrhea) after cereals were continues to grow even in populations non-celiac gluten sensitivity introduced into the diet. Typthat until now were thought to be ically, all of the symptoms (NCGS) protected. cleared once a strict glutenAdditionally, there seems to be a rise free diet was instituted. We in reported adverse reactions to gluten, now recognize that in addition to the gastrointestinal signs and symptoms, some From the Department of Pediatrics, New York University School of Medicine, New York, NY. patients might actually present with constipation, or Curr Probl Pediatr Adolesc Health Care 2014;44:324-327 have vague GI complaints reminiscent of functional 1538-5442/$ - see front matter disorders, such as abdominal distention and bloating, & 2014 Mosby, Inc. All rights reserved. crampy abdominal pain, and excessive flatulence. http://dx.doi.org/10.1016/j.cppeds.2014.10.002
C
324
Curr Probl Pediatr Adolesc Health Care, December 2014
TABLE. Recommendations for initial screening
Initially obtain: Tissue transglutaminase (IgA tTg) and total IgA (while on gluten-containing diet). In the setting of IgA deficiency, IgG-based antibody tests should be performed: Tissue transglutaminase (IgG tTg) Endomysial antibodies (IgG EMA) Deaminated gliadin peptide antibodies (IgG DGP) Children o2 years of age should be tested with a combination of tissue transglutaminase and deaminated gliadin peptide antibodies (IgG and IgA). Anti-gliadin antibodies (IgG AGA and IgA AGA) should not to be used for routine screening due to their highly variable sensitivity and specificity. If there is a strong clinical suspicion for CD, despite negative serological tests an intestinal biopsy should be considered.
studies suggest that under these circumstances the Celiac disease has protean extra-intestinal manifesbiopsy could be omitted.6 tations and an accurate diagnosis should be sought in people suffering from seemingly unrelated complaints, Given the varied spectrum of clinical manifestations, such as fatigue, anorexia, delayed proactive screening should be purpuberty, short stature, decreased sued. Through this proactive bone density, unusual skin rashes, screening, it has become clear that unexplained iron deficiency, and The gold standard for diag- the “classical” or “typical” celiac infertility.3 Recently, various neu- nosing celiac disease is the disease is but the tip of the iceberg, rological manifestations have been histologic demonstration of and that there are many who are affected yet remain asymptomatic associated with celiac disease, the enteritis present in with what is referred to as “silent” including cerebellar ataxia, numbendoscopically obtained celiac disease. In silent celiac disness, seizures, brain calcifications, and psychiatric disorders.4 biopsies. The availability of ease, the enteropathy is present and In patients in whom there is a sensitive and specific sero- the subject has mounted the response, but the patient suspicion of celiac disease, serologic markers helps screen immune is clinically asymptomatic. A third logic screening should be obtained (Table). In the setting of abnormal candidates for the definitive category, latent celiac disease, is diagnosis. reserved for those who have had screening or other clinical indicadocumented villus blunting and in tors that raise the concern for whom the mucosa heals after celiac disease, an upper intestinal adherence to a gluten-free diet endoscopy with biopsies of the and remains normal even after the reintroduction of distal and proximal duodenum should be obtained. gluten. A second variant of latent celiac disease applies to those who initially had a normal biopsy Histopathology while on gluten and later develop the enteropathy of The enteropathy of celiac disease is characterized by celiac disease. Patients with other autoimmune conthe presence of increased intra-epithelial lymphocytes ditions, such as thyroiditis or type I diabetes, might fall (IELs), as well as by crypt hyperplasia and various into this category.7 degrees of villus blunting progressing to total villus atrophy.5 Until now, it is the presence of this enteropathy, in conjunction with the positive serology, Pathophysiology which is considered the diagnostic gold standard for making the diagnosis of celiac disease. Histological Exposure to gliadin, a protein rich in proline and confirmation has been recommended to justify lifelong glutamine, causes recognition by specific T cells in the elimination of gluten. Lately, some flexibility in the setting of specific HLA allelles, DQ2, and DQ8. Once diagnostic algorithm has begun to be discussed for the enzyme tissue transglutaminase tTG2 modifies the subjects where the clinical manifestations, HLA pheglutamine into glutamic acid, the gliadin molecule can notype and markedly elevated titer of auto-antibodies tightly adhere with the HLA lymphocytes. It is unclear (IgA tissue transglutaminase 4100) are present. Some how the auto-antibodies against tTG2 are actually Curr Probl PediatrAdolesc Health Care, December 2014
325
dramatically once gluten is removed from the diet formed. The gluten peptides activate both the innate and recur upon re-challenge.11 Some postulate that it is and the adaptive branches of the immune system, þ þ including CD4 and CD8 T-cell responses. IL-15 the carbohydrate components of wheat, specifically the induction is a key step in the pathogenesis, as this fructans that trigger the GI symptoms. These fructans, cytokine is involved in expressing natural killer (NK)so-called fermentable, oligo-, di-, mono-saccharides, like receptors on the IEL's. This, in turn, increases the and polyols (FODMAPs) are fermentable carbohydrate damaging effects of the IELs. Interestingly, environpolymers and may be the culprit rather than gluten. mental triggers, such as bacteria or viral infections can Many subjects with NCGS have been managed for play a role in setting the stage for a high proinflammayears for presumed irritable bowel syndrome or other tory profile, initially in the epithelium and subsefunctional or psychiatric disorders, and in many quently in the lamina propria. The gliadin peptides, instances, the association with gluten exposure is made bound to dentritic cells, activate a proinflammatory empirically or serendipitously. There are no bioresponse in which CD4þ cells participate in upregulamarkers to make this diagnosis with certainty at this time, but celiac disease should be ruled out with the tion of IFN-gamma, TNF-alpha, and IL-21. The end recommended serologic screening. results are the observed villus Other diagnoses, including blunting and atrophy.8 inflammatory bowel disease, food An important element in the pathophysiology of celiac disease The challenge of adhering to intolerance and food allergy, and is a change in gut permeability a strict gluten-free diet for irritable bowel syndrome should be and confirmed or ruled caused by a loss of integrity of the life is a challenging propo- investigated out. Awareness of NCGS has paracellular tight junctions. A key participant in this phenomenon is sition that requires on-going increased given the widespread education, guidance, and promotion and popularity of the zonulin, an intestinal peptide that gluten-free diet, leading many to regulates the tight junctions. It is support to minimize the speculated that once the integrity psychosocial impact of this try elimination diets and fostering an interesting mystique around the is breached and permeability diagnosis. nefarious effects of this food comincreases (“leaky gut”), transit of ponent. A particularly targeted the toxic gliadin peptides towards population has been the vulnerable the lamina propria could be facilichildren with autism and other developmental tated, thus amplifying the immunological chain reacdisabilities.12 tion.9 Not surprisingly, research efforts have focused on blocking zonulin upregulation.10 Agents are in the pipeline and in clinical trials with the hope that by preventing the increased permeability, access to the Management and Future Directions deeper epithelium and lamina propria will be curtailed, slowing the damage caused by the activated Th-1 The treatment of celiac disease is a lifelong complete response described above. avoidance of barley, rye, and wheat-containing foodstuff to promote villous healing. It remains controversial whether even uncontaminated oats can be safely consumed.13 Monitoring for disappearance of the tTG Non-Celiac Gluten Sensitivity (NCGS) auto-antibodies and normalization of nutritional indices (particularly vitamin D and iron) is important, as is NCGS is probably more prevalent than celiac dismonitoring regularly for the presence of other autoease, but its diagnosis remains elusive. Only recently immune co-morbidities, such as Hashimoto's thyroihas a more concerted effort been made to properly ditis and type 1 diabetes. It is important to stress to define this obscure clinical entity. Patients with NCGS asymptomatic patients that the elimination of gluten often complain of vague abdominal pain, bloatedness, brings about health benefits that might not be immeweight loss, and diarrhea. Other manifestations include diately experienced, but are nonetheless important and tiredness, a “foggy brain,” depression and other worth the sacrifices that a gluten-free diet imposes. behavioral changes, as well as dermatitis, and anemia, This is particularly relevant insofar as bone health is among others. Patient's symptoms improve
326
Curr Probl Pediatr Adolesc Health Care, December 2014
concerned, as well as a decrease in the incidence of small bowel malignancy, especially lymphoma.14 Instituting a strict gluten-free diet can be very challenging and can take a psychological and financial toll on patients and families. The fear of crosscontamination can become an obsession, significantly impacting on quality of life. Initially, reduced levels of lactase and sucrase activities might necessitate further dietary restrictions until the villi have healed and those sugars are better tolerated. Education and guidance by a knowledgeable nutritionist or registered dietitian familiar with the subtleties of food labeling and food planning can go a long way in minimizing the stress and facilitating the acceptance of the diet and the lifestyle changes that it represents. Processed gluten-free foods are often nutritionally inferior and studies have suggested that a gluten-free diet can be inadequate in fiber and vitamins and have a higher caloric content. Preventing nutritional deficiencies and fostering normal growth and weight gain are often best accomplished with the help of a professional nutritionist or registered dietitian. Pharmacological agents addressing antigen recognition, processing, and transport through the permeable tight junctions are in various stages of development, as is work on genetically modified wheat cultivars. The possibility of a vaccine to block the immune-mediated trigger leading to celiac disease is also being investigated.15 However, until novel approaches prove to be safe alternatives, the gluten-free diet remains the linchpin of celiac disease management.
References 1. Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut 2013;62:43–52. 2. Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 2013; 5(10):3839–53.
Curr Probl PediatrAdolesc Health Care, December 2014
3. Lasa JS, Zubiaurre I, Soifer LO. Risk of intertility in patients with celiac disease: a meta-analysis of observational studies. Arq Gastroenterol 2014;51(2):144–50. 4. Johnson AM, Dale RC, Wienholt L, Hadjivassiliou M, Aeschlimann D, Lawson JA. Coeliac disease, epilepsy, and cerebral calcifications: association with TG6 autoantibodies. Dev Med Child Neurol 2013;55:90–3. 5. Levinson-Castiel R, Hartman C, Morgenstern S, et al. The role of duodenal bulb biopsy in the diagnosis of celiac disease in children. J Clin Gastroenterol 2011;45(1):26–9. 6. Klapp G, Masip E, Bolonio M, et al. Celiac disease: the new proposed ESPGHAN diagnostic criteria do work well in a selected population. J Pediatr Gastroenterol Nutr 2013;56: 251–6. 7. Maki M. Coeliac disease: lack of consensus regarding definitions of coeliac disease. Nat Rev Gastroenterol Hepatol 2012;9:305–6. 8. Meresse B, Malamut G, Cerf-Bensussan N. Celiac disease: an immunological jigsaw. Immunity 2012;36(6):907–19. 9. Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to chemo receptor—CXCR3. Gastroenterology 2008;135:194–204. 10. Fassano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol 2012;10(10):1096–100. 11. Carroccio A, Mansueto P, D’Alcamo A, Iacono G. Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. Am J Gastroenterol 2013;108(12): 1845–52. 12. Van De Sande MM, van Buul VJ, Brouns FG. Autism and nutrition: the role of the gut-brain axis. Nutr Res Rev 2014;8: 1–16. http://dx.doi.org/10.1017/S0954422414000110. 13. Haboubi NY, Taylor S, Jones S. Coeliac disease and oats: a systematic review. Postgrad Med J 2006;82:672–8. 14. Lebwhol B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoprolipherative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013;159(3): 169–75. 15. Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol 2013; 25(3):410–7.
327
