Stephen Nanton, MD
SUNY-Downstate Medical Center
Brooklyn, NY
Pretest Questions
Q1. Which of the following statements about celiac disease is most likely to be true?
a. Children who have celiac disease may present with abdominal distension and vomiting but not constipation.
b. Celiac disease is rare in the United States.
c. Untreated celiac disease may cause failure to thrive in children.
d. Children with celiac disease are asymptomatic until three years of age.
Q2. Populations at increased risk for celiac disease include children with:
a. Down syndrome.
b. Type 2 diabetes mellitus.
c. Cushing syndrome.
d. Seafood allergy.
Q3. Which of the following is the best initial screening serologic test in children with suspected celiac disease?
a. Anti-gliadin IgA
b. anti-tissue transglutaminase
c. anti-gliadin IgG
d. total IgA
Q4. The diagnosis of celiac disease is confirmed by which of the following?
a. an intestinal biopsy consistent with celiac disease
b. a serologic test consistent with celiac disease
c. a history of chronic diarrhea and failure to thrive
d. HLA DQ2 or DQ8.
Q5. (True or False) Children confirmed to have celiac disease should immediately be placed on lifelong gluten free diet.
Q6. The major neoplastic consequence of coelic disease is (are):
a. Esophageal cancer
b. Gastric carcinoma
c. Lymphomas
d. All of the above
Learning Objectives
At the conclusion of this section, physicians and residents will be able to:
1. Identify family and nutritional factors that increase the risk of celiac disease in infants, children, and adolescents.
2. Identify the major clinical manifestations and complications of celiac disease.
3. Discuss the serologic tests currently used in screening for celiac disease.
4. Recognize the characteristic histopathology of celiac disease.
5. Develop an appropriate treatment plan for children with confirmed celiac disease.
Facilitator Preparation
For this section the facilitator should review:
1. Celiac Sprue, New England Journal of Medicine, Vol.346, January 17, 2002.
2. Celiac Disease - How to handle a clinical chameleon, New England Journal of Medicine, Vol.348, June 19, 2003.
3. Celiac disease associated with type 1 diabetes mellitus, Endocrinology and Metabolism Clinics, Vol.33, No.1, March 2004.
4. Guideline for the diagnosis and treatment of Celiac disease in children, Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, 2004.
INTRODUCTION
Celiac disease is an immune mediated disease caused by permanent sensitivity to gluten. The ingestion of even small amounts of gluten by children with celiac disease may lead to small intestinal mucosal damage. Children with celiac disease have both gastrointestinal and non-gastrointestinal symptoms. Some children may have no symptoms at all.
Certain syndromes are associated with celiac disease. These include William and Down syndromes and Type 1 diabetes mellitus. Testing for celiac disease is recommended for children who have symptoms of celiac disease and for asymptomatic children who have conditions that are associated with celiac disease. The initial test for celiac disease is measurement of the IgA antibody to human recombinant tissue transglutaminase (TTG).
An intestinal biopsy is required in all cases for confirmation of the diagnosis of celiac disease. A characteristic histological feature of celiac disease is villous atrophy.
The treatment for celiac disease is life long gluten-free diet. This diet is recommended for all confirmed cases of celiac disease.
Case study:
David S is the 4 year old, first born child of Mrs. S. David has Down syndrome. He is referred to you for evaluation of chronic diarrhea, bloating, flatulence, loss of appetite, and poor weight gain during the past 6 months. You perform a careful history and physical exam which reveal the typical features of Down syndrome and growth parameters consistently at the 3rd percentile for both height and weight using a Down syndrome specific growth chart. Of note Mrs. S is very conscious of good nutrition. David has grown well and has an exemplary diet.
A diet history includes 2 servings of low fat milk and yogurt each day. Only ½ cup of fruit juice with 2 or 3 servings each of fruit and fresh vegetables. There is 1 meat meal a day with either fish or poultry and 5 servings of bread and cereal. Mrs. S gives David raisin bran cereal every morning with one or two slices of her home made whole grain bread - whole wheat, corn, oats and soy flour included in the recipe. David began eating his mother's bread when he was 9 months of age.
Q1. What is celiac disease?
A1. Celiac disease is an immune mediated disorder caused by sensitivity to gluten. Dietary proteins present in wheat, rye and barley, commonly known as glutens, interact with specific molecules to activate an abnormal immune response and induce tissue damage.
Q2. What factors increase the risk in infants, children, and adolescents?
A2. Some populations have increased risk of celiac disease. These populations include first-degree relatives of persons with celiac disease, children with type 1 diabetes mellitus, William syndrome, Down syndrome, Turner syndrome, autoimmune thyroiditis and selective IgA deficiency.
In the United States, population based studies estimate the prevalence celiac disease to be about 1 %. The frequency of selective IgA deficiency in celiac disease ranges from 2 % to 7 %. Individuals with type 1 diabetes mellitus have a prevalence of celiac disease ranging from 3% to 8%. The prevalence of celiac disease in persons with Down syndrome is between 5 % and 12 percent. In one study, the prevalence of celiac disease in William syndrome was 8%. Children with Turner syndrome have a prevalence of celiac disease ranging from 4% to 8%.
These syndromes and prevalence percentages are shown in Table 1.
TEACHING EXCERCISE:
Ask, "what risk factor did you find in David's history?" Let one resident play the role of physician and others play that of the mother and father
Having Down Syndrome significantly increases David's risk. He also had an early introduction to gluten containing grain. As with all the syndromes and conditions listed above, the presence of chronic diarrhea should bring celiac disease rapidly to mind.
Make sure the attendees ask the right questions
Q3. What are the clinical manifestations of celiac disease?
A3 The clinical manifestations of celiac disease are variable and may present at any age. Celiac disease is a multi-system disorder; symptoms are not limited to the gastrointestinal system.
The classic form of celiac disease in children presents with gastrointestinal symptoms beginning between 4 and 24 months of age. This occurs after the introduction of gluten in the diet. Infants and young children present with abdominal pain, abdominal distention, anorexia, vomiting, chronic diarrhea, weight loss, and failure to thrive. Some children with the condition are constipated. Irritability and other behavioral changes may be present.
Children may present with celiac disease at any age. The gastrointestinal symptoms in older children and adolescents include nausea, vomiting, abdominal pain, bloating, constipation and weight loss.
TEACHING CAPTION: The GI effects of celiac syndrome do not simply reflect malabsorption. Often, there are secondary consequences of celiac disease resulting in Failure to Thrive.
The most significant early GI effect is the celiac crisis. This is characterized by lethargy, marked abdominal distension, explosive diarrhea, dehydration, hypotension and hypokalemia may the presentation in severely affected infants.
Celiac disease may present with extraintestinal manifestations including dermatitis herpetiformis, delayed puberty, vitamin deficiencies, iron deficiency anemia, osteoporosis and fatigue. Dermatitis herpetiformis is an intensely pruritic rash on the extensor surfaces of the extremities. Most children with dermatitis herpetiformis have mucosal changes on mucosal biopsy of the intestinal mucosa. A gluten free diet causes improvement in both the rash and mucosal changes. Other presentations of celiac disease include recurrent apthous stomatitis, dental enamel hypoplasia and elevated transaminases.
TEACHING CAPTION: While the GI presentation is most common, it is necessary to evaluate patients presenting with these conditions for any of the malabsorption syndromes including celiac disease.
Q4. TEACHING EXERCISE
Ask the audience "what clinical signs did you find in David's evaluation?" Attendees can switch roles.
Spend 5 minutes discussion signs in case. Reinforce the associations among early gluten consumption, hereditary or disease associated risk, and the constellation of signs and symptoms of typical patients - diarrhea, bloating, loss of appetite, and at-times, failure to thrive.
Q5. What are the complications of celiac disease?
A5 The major complications are neoplastic. Non-Hodgkin lymphoma including enteropathy associated T-cell lymphoma (EATL) is a rare long-term complication of celiac disease. Gluten- free diet may reduce the risk of lymphoma .The risk of adenocarcinoma of the small intestine is increased and there may be increased risk of other carcinoma elsewhere in the gastrointestinal tract.
Q6. Which children should be tested for celiac disease?
A6 There are three categories for testing. "Recommended immediately," "Recommended delayed," and "to be considered"
The clinical features of celiac disease are often related to the gastrointestinal tract but many patients have atypical presentations .The clinician must be aware of the varied and sometimes subtle presentations of celiac disease.
Immediate serologic testing for celiac disease is recommended in children presenting with persistent diarrhea and poor weight gain or failure to thrive. Celiac disease must also be considered in children presenting with persistent abdominal pain, anorexia, vomiting and constipation.
Classical celiac disease has a predominance of gastrointestinal symptomatology including diarrhea, abdominal pain, abdominal distension, vomiting and evidence of intestinal malabsorption. The diagnosis of classical celiac disease is confirmed by positive serology, intestinal biopsy evidence of villous atrophy and improvement on a gluten free diet.
Delayed serologic testing is recommended for asymptomatic children belonging to specific groups at risk for celiac disease. These groups include children with selective IgA deficiency, Turner syndrome, Down syndrome, William syndrome, type 1 diabetes, autoimmune thyroiditis and first-degree relatives of established cases of celiac disease. Routine serologic testing in these high-risk groups of children should begin after the child has received a sufficient gluten containing diet for at least 1 year. Therefore testing should begin after 3 years of age.
Testing for celiac disease should be considered in children with extraintestinal symptoms associated with celiac disease including, dermatitis herpetiformis, dental enamel hypoplasia, iron deficient anemia, delayed puberty and osteopenia.
David's celiac disease might have been picked up a year earlier if he had been screened at 3 years of age. Currently available data, however, does not support the screening of the general population for celiac disease.
Q7. How is celiac disease classified?
A7 One classification of the sub-types of celiac disease includes: classical celiac disease, celiac disease with atypical symptoms, silent celiac disease and latent celiac disease.
Classic celiac disease occurs after the introduction of gluten in the diet. Infants and young children present with abdominal pain, abdominal distention, anorexia, vomiting, chronic diarrhea, weight loss, constipation and failure to thrive. Irritability and other behavioral changes may be present.
Atypical celiac disease has a predominance of extraintestinal symptoms including dermatitis herpetiformis, dental enamel hypoplasia, iron deficient anemia, short stature, failure to thrive, delayed puberty, osteopenia, hepatitis and arthritis. The increasing recognition of the atypical manifestations of celiac disease is attributed to the increasing prevalence of celiac disease. The diagnosis of atypical celiac disease is established by positive serology, intestinal biopsy evidence of villous atrophy and improvement on a gluten free diet.
Silent celiac disease describes persons who are clinically asymptomatic but have positive celiac serology and villous atrophy on small intestinal biopsy. Silent celiac disease is usually detected by screening of high-risk individuals.
Latent celiac disease is characterized by positive serology but no villous atrophy on small intestinal biopsy .As with silent celiac disease these children are asymptomatic and are usually detected by screening high-risk individuals. Persons with latent celiac disease may develop symptoms had histological changes later in life.
David's case represents classic celiac disease in a high risk population.
Q8. What is the best first serologic test for screening David for celiac disease?
A8 Serologic test should be performed while the individual is on a gluten containing diet. There are a number of serologic test used for screening individuals for celiac disease.
The commercially available tests include anti-gliadin IgA, anti-gliadin IgG (AGA IgA and AGA IgG), anti-reticulin (ARA-IgA), anti-tissue transglutaminase (TTG IgA) and anti-endomysium antibodies. Based on currently available evidence, the anti-endomysium and anti-tissue transglutaminase antibodies are the most highly sensitive and specific test for celiac disease.
The anti-tissue transglutaminase (TTG IgA) is recommended as the first line of testing for celiac disease in children based on the ease of performance, reliability and relatively low cost of the test. Anti-gliadin antibody (AGA) tests are no longer routinely recommended because of their inferior sensitivity and specificity.
Q9. Ask the audience "what serologic test should be used in this case?" If the test(s) is (are) positive you would order a procedure(s). Which one(s)?
Spend 3 minutes discussion.
The Case discussion continued.
You send the anti-tissue tranglutaminase blood test. This comes back positive, and you refer David to a pediatric gastroenterologist for small intestinal biopsy. The pathologist reports that the histopathologic examination is consistent with celiac disease...
Discussion
Although serologic tests are frequently used to screen children for celiac disease, an intestinal biopsy is recommended for confirmation of the diagnosis of celiac disease in all cases. Diagnosing celiac disease based on clinical symptoms alone is not sufficiently reliable and results in an incorrect diagnosis in more than 50% of cases.
Characteristic histopathologic changes seen with celiac disease include an increase in the number of intraepithelial lymphocytes (> 30 lymphocytes per 100 enterocytes), decrease in the number of goblet cells, Partial to total villous atrophy and a decreased villous: crypt ratio.
Q10. What is the role of genetic markers in the evaluation of children with celiac disease?
A10 In individuals with conflicting serologic and histopathologic results, testing for genetic markers namely, human leukocyte antigen (HLA) DQ2 and DQ8; can help to determine the risk for celiac disease.
More than 97% of individuals with celiac disease have the DQ2 and or the DQ8 HLA haplotypes compared to only 40 % of the general population.
Persons who are negative for DQ2 or DQ8 are highly unlikely to have celiac disease.
Q11. What is the treatment for celiac disease?
A11 The treatment of celiac disease is a lifelong gluten-free diet (GFD). Treatment for celiac disease should begin only after a complete evaluation including serologic testing and intestinal biopsy.
A gluten-free diet is a diet that excludes wheat, barley and rye. These are the predominant grains which contain the peptides or glutens known to cause celiac disease. Farina, couscous, bulgur, einkorn and semolina are other forms of wheat that are harmful to children with celiac disease.
Kamut, spelt and triticale (a combination of wheat and rye) should be avoided.
TEACHING CAPTION:A list is essential in promoting a gluten free diet. Many sources are not recognized. Malt, for example, is made from barley and is harmful to individuals with celiac disease. Beer and many foods contain malt should be avoided.
And celiac disease patients need a list of the foods that they can eat.
TEACHING CAPTION:
Oats appear to be safe for persons with celiac disease. However contamination of oats with gluten during processing is known to occur and the inclusion of oats in a gluten free diet is limited unless the purity of the oats can be guaranteed.
Current evidence show that even small amount of gluten may be harmful and a lifelong gluten free diet is the only scientifically proven effective therapy for children with celiac disease.
The Case continues
David is put on a gluten free diet with remarkable good effect. Signs and symptoms disappear. He begins to grow. He is less irritable. Several months later, however, he returns from a school trip with a full blown attack of abdominal cramping and bloating. His mother finds out that the children shared sandwiches, and David had three hot dogs on regular hot dog buns.
You begin therapy again, and while he improves, he does not do as well as before. David's mother notices that milk causes bloating, too.
Q12. Is there an overlap between celiac syndrome and lactose intolerance?
A12 The brush border of the intestine is denuded in the immediate aftermath of an acute exacerbation of celiac disease. This leads to transient lactose intolerance. Children may benefit from a milk free diet, but only for the time of recovery. A traditional therapy for this period is French fried potatoes. David may enjoy the respite from the nutritionally beneficial foods characteristic of the standard gluten-free diet.
Q13. How does one monitor children with confirmed celiac disease?
A13. A multidisciplinary team based approach (including the physician, dietitian and advocacy groups) is essential in the management of celiac disease. Periodic visits with the dietitian and physician are necessary to assess adherence to gluten free diet and to monitor for symptoms and complications of celiac disease.
Growth and development must also be monitored. These periodic visits also provide the opportunity for health care providers to reinforce the benefits of strict lifelong adherence to gluten free diet.
The North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), recommends measurement of tissue transglutaminase (TTG) in children after 6 months of treatment with a gluten free diet. A decrease in antibody titer is an indirect indicator of adherence to gluten free diet. A rise in antibody levels suggests lack of adherence to a gluten-free diet or unintended gluten ingestion.
Children who do not respond to gluten-free diet require reevaluation.
TEACHING CAPTION: As with all other chronic illnesses, care is not simply laying out the facts and assuming the best. A multi-system approach to therapy is essential.
Post-test
Q1. The risk of celiac disease is increased in all the following conditions except
(a) Turner Syndrome
(b) Williams Syndrome
(c) Fanconi Syndrome
(d) Down Syndrome
Q2. Celiac disease may present with which of the following
(a) chronic diarrhea
(b) failure to thrive
(c) abdominal distension
(d) all of the above
Q3. True or False. Celiac disease has no long-term complications.
Q4. Which of the following is the best initial serologic test in children with suspected celiac disease?
(a) Anti-gliadin IgA
(b) anti-tissue transglutaminase
(c) anti-gliadin IgG
(d) total IgA
Q5. The diagnosis of celiac disease is confirmed by which of the following?
(a) an intestinal biopsy consistent with celiac disease
(b) a serologic test consistent with celiac disease
(c) a history of chronic diarrhea and failure to thrive
(d) HLA DQ2 or DQ8.
Q6. Which of the following is the best initial treatment for children with confirmed celiac disease?
(a) Prednisone
(b) a gluten free diet
(c) dapsone
(d) a lactose free diet
Q7. The major genetic predisposition to celiac disease is attributed to which of the following genetic markers?
(a) HLA-DQ4 and HLA- DQ6
(b) HLA-DQ2 and HLA-DQ8
(c) HLA-DQ4 and HLA-DQ7
(d) HLA-DQ1 and HLA-DQ5
Q8. True or False. A team-based approach (including the physician, dietitian and advocacy groups) is important in the management of celiac disease.
Answers
1 = c; 2 = d; 3= False; 4 = b; 5 = a; 6 = b; 7 = b; 8 = True
Annotated Pre-test answers:
A1. The answer is c. While it may seem odd that a child with a malabsorption might be constipated, this is a fairly common experience. The disorder can occur at all ages and is reasonably common in the United States with an incidence of XX/1,000 persons.
A2. The answer is a. Children with Down syndrome have an increase in gluten sensitivity as do persons with William syndrome and Type 1 DM, not Type 2. Cushing syndrome is unrelated.
A3. The answer is b. The anti-tissue transglutaminase (TTG IgA) is recommended as the first line of testing for celiac disease in children based on the ease of performance, reliability and relatively low cost of the test. A s fore the other tests, the others: antigliadin antibody has poor sensitivity and specificity. Tissue transglutaminase levels should be unaffected, and Total IgA can be low or high.
A4. The answer is a. Various tests suggestive of coelic disease indicate a high risk and a need for a biopsy. The biopsy result is the gold standard
A5. The answer is True. Early treatment includes elimination of gluten. Occasional patients tolerate some gluten later in life, but this is unusual
A6. The answer is d. Non-Hodgkin lymphoma including enteropathy associated T-cell lymphoma (EATL) is a rare long-term complication of celiac disease. Gluten- free diet may reduce the risk of lymphoma .The risk of adenocarcinoma of the small intestine is increased and there may be increased risk of other carcinoma elsewhere in the gastrointestinal tract.
A7. An unresolved question. It is commonly taught that wheat products should not be given to infants before 8 months of age - some would say one year. This will make wheat allergy less likely because the endothelial lining is not tightly linked at an early age, and foreign antigens enter the system stimulating T-, then B- cell function. While no direct connection to celiac disease has been made, it is a logical assumption, (the classic Genetics X environment scenario) that early wheat ingestion by a genetically susceptible person increases the likelihood of celiac disease occurring.
