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Celiac Disease in the Pediatric Population

      Abstract

      Celiac disease is an autoimmune disorder in which the lining of the gastrointestinal tract is damaged by an immune-mediated response to gluten proteins (
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ). It is a polygenetic disease that only appears in genetically susceptible individuals (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). It is a worldwide concern, with North America having a high prevalence rate (
      • Liu E.
      • Dong F.
      • Barón A.E.
      • Taki I.
      • Norris J.M.
      • Frohnert B.I.
      • Rewers M.
      High incidence of celiac disease in a long-term study of adolescents with susceptibility genotypes.
      ). Celiac disease can present in a spectrum of manifestations, making it difficult to identify and diagnosis (
      • Reilly N.R.
      • Green P.H.R.
      Epidemiology and clinical presentations of celiac disease.
      ). High-risk populations include those with a positive family history as well as individuals with other autoimmune disorders (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). Screening and diagnosis are completed with a blood test followed by a biopsy of the small intestinal lining (
      • Zevit N.
      • Shamir R.
      Diagnosis of celiac disease: Where are we heading after the ESPGHAN 2012 Guidelines?.
      ). Currently, the only treatment for celiac disease is a strict, gluten-free diet. Further research is warranted in areas of environmental risk factors and treatments (
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ,
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ).

      Key Words

      Objectives

      Based on the content of the article, you will be able to:
      • 1.
        Identify risk factors for developing celiac disease.
      • 2.
        Describe common presenting symptoms of celiac disease.
      • 3.
        Define the diagnostic tests for celiac disease.
      • 4.
        Recommend appropriate treatment for celiac disease.

      Introduction

      Celiac disease (CD) is a multigenetic, immune-mediated disorder that develops when the intestinal mucosa in susceptible individuals is exposed to gluten proteins. An individual must be genetically predisposed to develop this disorder. Approximately 90% of individuals with CD carry the human leukocyte antigen DQ2 haplotype, and the remaining 10% carry the DQ8 haplotype. DQ2 is found in the White population of western Europe, northern and western Africa, the Middle East, and central Asia, whereas DQ8 is common in individuals from Latin America and northern Europe (
      • Tack G.J.
      • Verbeek W.H.
      • Schreurs M.J.
      • Mulder C.J.
      The spectrum of celiac disease: Epidemiology, clinical aspects and treatment.
      ). CD has been identified in nearly all ethnic groups and nationalities (
      • Leonard M.M.
      • Sapone A.
      • Catassi C.
      • Fasano A.
      Celiac disease and nonceliac gluten sensitivity: A review.
      ).
      Seroconversion to CD may occur at any point in life if the individual is a susceptible host (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ). The diagnosis is most often made in early childhood and during the fourth and fifth decades. Females have a greater risk (2:1 to 3:1) than males under the age of 60 years. In 2010, an estimated 2.2 million children worldwide had been diagnosed with CD, although many cases of CD go undiagnosed (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ,
      • Reilly N.R.
      • Green P.H.R.
      Epidemiology and clinical presentations of celiac disease.
      ). Across the globe, it is estimated that 42,000 children per year die from CD complications, and approximately 4% of all diarrheal deaths may be caused by undiagnosed celiac disease (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). The prevalence of CD is currently estimated at 3.1% (
      • Liu E.
      • Dong F.
      • Barón A.E.
      • Taki I.
      • Norris J.M.
      • Frohnert B.I.
      • Rewers M.
      High incidence of celiac disease in a long-term study of adolescents with susceptibility genotypes.
      ,
      • Reilly N.R.
      • Green P.H.R.
      Epidemiology and clinical presentations of celiac disease.
      ).
      Gluten protein is present in wheat, barley, rye, farina, graham flour, malt, bulgur, semolina, gravies, processed lunch meats, soups, and self-basting poultry. Oats may be contaminated with gluten. Envelope and stamp glue, toothpaste and mouthwash, lip balm, Play-Doh (Hasbro, Pawtucket, RI), vitamin and mineral supplements, and herbal and nutritional supplements may also contain gluten protein (
      • Tack G.J.
      • Verbeek W.H.
      • Schreurs M.J.
      • Mulder C.J.
      The spectrum of celiac disease: Epidemiology, clinical aspects and treatment.
      ).

      Risk Factors

      CD targets genetically susceptible individuals. The disorder is a highly complex autoimmune disease (
      • Ludvigsson J.F.
      • Green P.H.R.
      The missing environmental factor in celiac disease.
      ) and may be associated with other autoimmune diseases (e.g., Type 1 diabetes, autoimmune thyroiditis, Addison disease, systemic lupus erythematous, rheumatoid arthritis, Sjögren syndrome, and selective IgA deficiency). Individuals with Down syndrome, Turner syndrome, and Williams syndrome appear to have increased risk for CD (
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ,
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). A positive family history of autoimmune disorders places an individual at increased risk for developing CD.
      Not all individuals with DQ2 or DQ8 heterodimers develop CD. Environmental risk factors (e.g., gastrointestinal infections, lack of breastfeeding, the amount and timing of gluten introduction) have been suspected as being triggers in genetically susceptible individuals. Infectious exposure in the pediatric population may change the intestinal mucosa, predisposing children to developing CD (
      • Liu E.
      • Dong F.
      • Barón A.E.
      • Taki I.
      • Norris J.M.
      • Frohnert B.I.
      • Rewers M.
      High incidence of celiac disease in a long-term study of adolescents with susceptibility genotypes.
      ,
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ).

      Presentation

      The classic presentation of CD includes diarrhea, vomiting, abdominal pain and distention, and malabsorption (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ,
      • Reilly N.R.
      • Green P.H.R.
      Epidemiology and clinical presentations of celiac disease.
      ). These symptoms usually appear between 6 and 24 months of age after gluten-containing foods are added to the diet. Young children may present with irritability, suboptimal growth, and failure to thrive (
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ,
      • Reilly N.R.
      • Green P.H.R.
      Epidemiology and clinical presentations of celiac disease.
      ).
      Symptoms usually appear between 6 and 24 months of age after gluten-containing foods are added to the diet.
      Older children may report fatigue, joint pain, weight loss or weight gain, or dermatitis herpetiformis skin lesions, short stature, delayed puberty, decreased bone density, dental enamel defects, iron deficiency anemia unresponsive to iron therapy, low serum albumin levels, recurrent infections, easy bruising, depression and anxiety, hair loss, irregular menses, mouth ulcers, and tingling and numbness in the hands or feet. They may also report foul-smelling stools that are oily and stick to the toilet when flushed (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). The Table provides a summary of the symptoms associated with celiac disease.
      TABLEPresentation of celiac disease
      Classic PresentationYounger ChildrenOlder ChildrenOther
      Abdominal distensionIrritabilityFatigueShort stature
      Abdominal painSuboptimal growthJoint painDelayed puberty
      DiarrheaFailure to thriveWeight loss or gainDecreased bone density
      MalabsorptionSkin lesionsDental enamel defects
      VomitingDermatitis herpetiformis
      Iron deficiency anemia
      Hepatitis
      Note. Some patients may be completely asymptomatic. Source: Adapted from
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ,
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ,
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      , and
      • Reilly N.R.
      • Green P.H.R.
      Epidemiology and clinical presentations of celiac disease.
      .
      Some children will be completely asymptomatic, and CD will be diagnosed only when they are screened because of family history (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ). Current guidelines recommend screening at-risk children beginning at age 3 years (
      • North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
      Diagnosis and treatment of celiac disease in children: Clinical practice guideline summary.
      ). Screening tests include those listed in Box 1. It is essential that patients be consuming gluten-containing food when tested to prevent false-negative results. It is also important to remember that a child must have a competent immune system (i.e., no immunoglobulin A deficiency) for tissue transglutaminase (TTG) levels to be elevated. Stool and saliva antibody measurements are of no value. Figure 1 provides an illustration of the diagnosis process.
      Screening tests for celiac disease
      Tabled 1
      Complete blood count (to check for anemia)
      Complete metabolic profile (to detect low serum albumin level)
      Serum folate and iron levels
      Prothrombin time and serum vitamin B12 and vitamin D levels
      Tissue transglutaminase (TTG) level
      Adapted from
      • North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
      Diagnosis and treatment of celiac disease in children: Clinical practice guideline summary.
      .
      FIGURE 1
      FIGURE 1Celiac disease diagnosis algorithm. CD, celiac disease; EMA, anti-endomysium immunoglobulin A; GI, gastrointestinal; HLA, human leukocyte antigen; IgA, immunoglobulin A; Ped, pediatric; TTG, tissue transglutaminase.
      Source:
      • North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
      Diagnosis and treatment of celiac disease in children: Clinical practice guideline summary.
      .
      Patients with equivocal TTG levels may have anti-endomysium immunoglobulin A (EMA) antibody measurements, because circulating IgA endomysial antibodies are present in 75% to 90% of patients with dermatitis herpetiformis or celiac disease (
      • Owen D.R.
      • Owen D.A.
      Celiac disease and other causes of duodenitis.
      ). Elevated EMA results may negate the need for upper endoscopy with duodenal biopsy to establish the diagnosis. Some clinicians believe a biopsy may not be needed in symptomatic patients with TTG levels at or greater than 10 times the upper limit of normal (
      • Zevit N.
      • Shamir R.
      Diagnosis of celiac disease: Where are we heading after the ESPGHAN 2012 Guidelines?.
      ). These recommendations place heavy emphasis on the high predictability of accurate serology testing and recognize the limitations of biopsy results related to the patchy nature of CD (
      • Zevit N.
      • Shamir R.
      Diagnosis of celiac disease: Where are we heading after the ESPGHAN 2012 Guidelines?.
      ). Despite this research, tissue biopsy is still currently the criterion standard for definitive diagnosis of CD (
      • Cash J.C.
      • Glass C.A.
      Family practice guidelines.
      ,
      • Domagalski J.E.
      • Short M.W.
      Celiac disease.
      ).

      Treatment

      The only current treatment for CD is a strict, lifelong gluten-free diet (
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ). A sample gluten-free diet appears in Figure 2. Adherence to this diet reverses malabsorption, nutritional deficiencies, and symptoms and decreases comorbidities. Intestinal mucosa healing begins, and serum antibody levels normalize within a few months of beginning the diet (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ,
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). Research is being performed on potential medications (e.g., gluten neutralizers or binding agents, medications to block intestinal leaking, and agents to target the immune system;
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ). Efforts are also underway to genetically modify wheat to eliminate or inactivate gluten proteins. Adherence to the diet is difficult and expensive. Barriers to diet adherence are insurmountable for some individuals. Patients with CD may tolerate 10 to 50 mg of gluten per day. One slice of regular bread contains approximately 1.6 g (1,600 mg) of gluten (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ). Buckwheat, corn, cornmeal, rice, soy, quinoa, tapioca, and potato flours can be substituted for gluten-containing grains. Gluten-free packaged foods frequently contain greater densities of fats and sugars than their gluten-containing counterparts (
      • Sue A.
      • Dehlsen K.
      • Ooi C.Y.
      Paediatric patients with coeliac disease on a gluten-free diet: Nutritional adequacy and macro- and micronutrient imbalances.
      ). Patients often experience weight gain and constipation when following the gluten-free diet.
      FIGURE 2
      FIGURE 2Gluten-free meal plan. Adapted from
      • The Celiac Disease Foundation
      7-day pediatric gluten-free meal plan.
      .
      Source: Adapted from
      • The Celiac Disease Foundation
      7-day pediatric gluten-free meal plan.
      . This figure appears in color online at www.jpedhc.org.
      Cross-contamination in processed foods is a concern. A group of researchers at Columbia University (New York, NY) is currently testing a phone application gluten-sensor device that can detect gluten in liquid and solid foods in 3 minutes (
      • Lebwohl B.
      Gluten sensor device to promote gluten free diet adherence and quality of life in patients with celiac disease.
      ). This tool would appeal to adolescents' interest in technology and enable individuals with CD to select food more easily.
      There is also a risk for toxicity, because excessive intake of some grains (e.g., rice) may expose the individual to high levels of arsenic. Not all gluten-free products are fortified, which increases the risk for deficiencies in B vitamins, folate, and iron (
      • Reilly N.R.
      The gluten-free diet: Recognizing fact, fiction, and fad.
      ).
      Children and adolescents may not be developmentally ready to process the necessity of adhering to this strict diet (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ). Adolescents report social challenges related to diet adherence (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ). Diet recalls and symptom diaries can be used to monitor symptom exacerbation or regression (
      • Allen P.J.
      Gluten-related disorders: Celiac disease, gluten allergy, non-celiac gluten sensitivity.
      ). Some clinicians use the EMA test to monitor dietary compliance.
      Food is not the only source of gluten protein. Some commonly prescribed medications (e.g., amoxicillin, azithromycin, cephalexin, levothyroxine, metformin, prednisone, albuterol, and extended-release methylphenidate) also contain gluten within their inactive ingredients such as starches (
      • King A.R.
      University of Kansas Drug Information Center Experiential Rotation Students
      Gluten content of the top 200 medications: Follow-up to the influence of gluten on a patient's medication choices.
      ).

      Complications

      Untreated or partially treated CD can lead to osteoporosis, kyphoscoliosis, fractures, splenic malfunction, infertility, repeated pregnancy loss, low-birth-weight offspring, ulcerative colitis, neurologic impairment (e.g., cerebellar ataxia, peripheral neuropathy), and intestinal lymphoma (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ). Celiac crisis, a life-threatening syndrome of severe diarrhea and metabolic and electrolyte impairments leading to hypoproteinemia can develop in small children (
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ).
      Some individuals with CD report diminished quality of life (QOL). One group of researchers found that age at diagnosis affected perceived QOL, with those diagnosed at a younger age reporting higher QOL scores (
      • Byström I.M.
      • Hollen E.
      • Falth-Magnusson K.
      • Johansson A.K.
      Health-related quality of life in children and adolescents with celiac disease: From the perspectives of children and parents.
      ).
      Some individuals with CD report diminished quality of life.

      Practice Implications

      Provider responsibilities for patients with CD begin with developing an index of suspicion for this disorder in the presence of a wide range of symptoms and risk factors. After individuals receive the diagnosis of CD, they need ongoing education to facilitate adherence to the diet. Providers who are aware of the psychosocial and financial barriers to adherence can initiate conversations with patients and families. Box 2 lists common barriers to adherence to a gluten-free diet.
      Barriers to compliance
      Tabled 1
      Expense/lack of resources
      Food preferences
      Lack of education
      Preparation
      Need for alternatives to dining out and special events
      Source: Adapted from
      • Fasano A.
      • Catassi C.
      Celiac disease.
      ,
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      , and
      • Porto A.
      Celiac disease in children & teens.
      .
      Families may be unaware that public schools with free or reduced meals are required to provide gluten-free alternatives (
      • Porto A.
      Celiac disease in children & teens.
      ). They may also need referrals to support groups such as the Celiac Disease Foundation, ROCK (Raising Our Celiac Kids), National Foundation for Celiac Awareness, and the Celiac Support Association.
      Providers also need to be aware of the limitations in screening for and diagnosing CD. False-negative results and mismatches between serology and intestinal biopsy results can confuse patients (
      • Newton K.P.
      • Singer S.A.
      Celiac disease in children and adolescents: Special considerations.
      ,
      • Zevit N.
      • Shamir R.
      Diagnosis of celiac disease: Where are we heading after the ESPGHAN 2012 Guidelines?.
      ). In these situations, providers may need to intervene and consult with specialists on behalf of patients.
      Providers also need to be aware of the limitations in screening for and diagnosing CD.

      Conclusion

      CD is a serious multigenetic autoimmune disorder that is being diagnosed with increasing frequency. This chronic disorder creates unique concerns and opportunities for patients, their families, and health care providers. The only treatment at this time is a strict gluten-free diet. Providers must stay abreast of new developments in prevention, diagnosis, and management of CD.

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        Celiac disease in children and adolescents: Special considerations.
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      Biography

      Jessica Durham, Graduate Student, Nursing Department, Clemson University, Clemson, SC.
      Heide S. Temples, Pediatric Primary Care Nurse Practitioner and Assistant Professor, Clemson University, Clemson, SC.