Non-Classic Manifestations of Celiac Disease
From The Child's Doctor, Fall 2010
- Maria T. Greene, MD
- Attending physician, Gastroenterology, Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Greene has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
Other Disclosure Information
Identify non-classic symptoms that may prompt screening a child for celiac disease
Order and interpret appropriate screening tests in patients with suspected celiac disease
Distinguish latent from silent celiac disease
Celiac disease is a chronic enteropathy caused by intolerance to gluten. Its clinical spectrum is broad. Presentation of celiac disease varies from absence of symptoms to gastrointestinal (classic) and/or extraintestinal (non-classic) symptoms. Patients without symptoms may havelatent or silent celiac disease. The most common non-classic manifestations of celiac disease in children include iron deficiency anemia, short stature, and delayed onset of puberty. The most characteristic for celiac disease extraintestinal manifestations in children are dermatitis herpetiformis, dental enamel defects, and epilepsy with occipital calcifications. Because celiac disease can be atypical or even clinically silent, many patients remain undiagnosed and at risk for the long-term, sometimes serious complications of untreated celiac disease.
Celiac disease is a chronic, immune-mediated enteropathy triggered by gluten proteins found in wheat, barley and rye. More than 95% of patients with celiac disease have the typical HLA-predisposing genotype (DQ2 or DQ8). The diagnosis of celiac disease is confirmed by intestinal biopsy. Patients with confirmed celiac disease should be on a gluten-free diet for life to avoid the risks of untreated celiac disease. These risks mainly include the development of other autoimmune conditions such as type 1 diabetes, psoriasis, thyroid disease, neurologic problems, autoimmune liver disease and autoimmune cardiomyopathy, as well as the development of malignancies such as intestinal lymphoma, adenocarcinoma of the small intestine, esophageal carcinoma and melanoma.
In North America, the prevalence of celiac disease was thought to be 1:3000 until 2003 when a large multicenter national study found it to be 1:320 among the general not-at-risk pediatric population. About 13,000 high-risk and not-at-risk adults and children were screened. Screening was performed with serology testing; the antibodies measured were endomysial antibodies (EMA) or antigliadin IgG in IgA deficient people. Intestinal biopsy was recommended and performed whenever possible in all EMA-positive subjects. All the EMA-positive subjects who underwent intestinal biopsy had histological changes consistent with celiac disease. The 10-fold increase in prevalence of celiac disease was attributed to the detection of the non-classic and silent forms of the disease.
This article focuses on the atypical presentation of celiac disease seen in about half of celiac disease patients. It is important for primary care physicians to have a high degree of awareness of the different forms of this disease to identify patients with celiac disease early and protect them from the serious complications of untreated disease.
Varied clinical presentations
Clinical manifestations of celiac disease are extremely varied. The classic presentation of the disease occurs between 6 and 24 months of age with diarrhea associated with anorexia, vomiting, poor weight gain or weight loss, irritability, abdominal distention and proximal limb wasting. Gastrointestinal symptoms in older children include diarrhea, nausea and vomiting, abdominal pain, bloating, flatulence, weight loss and constipation.
The non-classic symptoms of celiac disease can be due to malabsorption or associated autoimmune diseases. Some of the most common and characteristic manifestations in each category are discussed below. Table 1 also shows a comprehensive list of non-classic symptoms of celiac disease divided into gastrointestinal and non-gastrointestinal symptoms.[4,5]
Non-classic manifestations due to malabsorption
Anemia: Iron deficiency anemia can be the only abnormality in patients with celiac disease. Based on a study by Bottaro et al, iron deficiency anemia was the most frequent extraintestinal marker of celiac disease; it was the leading symptom in 35% of the 485 children examined. In celiac disease patients, iron deficiency anemia is caused by decreased iron absorption due to chronic intestinal inflammation.
Short stature: The frequency of celiac disease in children with short stature ranges from 2% to 8%. Short stature was found to be the leading extraintestinal symptom of celiac disease in 30% of 485 children in the study by Bottaro et al. Patients showed improved height velocity within 6 to 9 months of starting a gluten-free diet.
Delayed onset of puberty: Untreated celiac disease can lead to delayed onset of puberty in boys and delayed menarche and menstrual abnormalities in girls. Progression in sexual development ensues with the introduction of a gluten-free diet. In adults with celiac disease, sexual dysfunction, infertility and obstetric problems have been described.
Osteopenia: Low vitamin D levels and hypocalcemia are frequently seen in patients with untreated celiac disease. There is strong evidence that patients with untreated disease are at risk for developing low bone mineral density and osteoporosis. Studies in children with celiac disease have shown complete reversal of low bone mineral density after introduction of a gluten-free diet. Screening children with celiac disease for osteopenia with laboratory tests and bone density measurements is not cost-effective.
Transaminitis: Elevation of alanine aminotransferase levels has been reported in about 20% of patients with celiac disease. The mechanisms underlying liver injury in this disease are poorly understood. Two main forms of liver damage have been suggested: “celiac hepatitis” and autoimmune hepatitis. Celiac hepatitis is thought to derive from increased intestinal permeability to different substances that can have a direct toxic effect on the liver or initiate an immunologic reaction toward liver antigens. Transaminase activity due to celiac disease usually normalizes on a gluten-free diet. In cases of autoimmune hepatitis and celiac disease, reintroduction of gluten into the diet may be associated with a relapse in patients not on immunosuppressive therapy.[10,11]
Recurrent abdominal pain: Although the presentation of celiac disease frequently involves abdominal pain or discomfort, a study by Fitzpatrick et al. showed that celiac disease is a rare cause of recurrent abdominal pain in children. Only 1% of children with recurrent abdominal pain had positive celiac serology (1 out of 92 children), the same frequency as the control group.
Non-classic manifestations due to associated autoimmune diseases
Dermatitis herpetiformis: Dermatitis herpetiformis, a rare disease in children, is an extremely itchy, bullous skin rash that affects the extensor surfaces of the limbs, trunk and scalp (Figure 1). Most patients with dermatitis herpetiformis have concomitant intestinal mucosal changes of celiac disease on biopsy even in the absence of gastrointestinal symptoms. Other patients with dermatitis herpetiformis have latent celiac disease (for definition of latent disease see next page). Pediatric patients with dermatitis herpetiformis should be referred to a pediatric gastroenterologist for endoscopic evaluation. Both the rash and intestinal changes improve on a gluten-free diet. Treatment with dapsone suppresses the skin rash, but has no effect on the intestinal damage.
Enamel permanent tooth defects:
These are imperfections in the permanent tooth enamel that develop during the first 7 years of life. They are primarily thought to be the result of gluten-induced immunologic disturbances during this time. Dental enamel defects include discoloration (white, yellow, or brown spots on the teeth) and structural changes of teeth (poor enamel formation, pitting or banding of teeth, and mottled or translucent-looking teeth). Enamel permanent tooth defects are not specific for celiac disease. Other explanations include excess fluoride intake, use of tetracycline and less frequently, bulimia.
Aphthous ulcers: A significant increase in the rate of aphthous ulcers and a significant association between enamel defects and aphthous ulcers has been reported in children with celiac disease. Aphthae usually improve on the gluten-free diet.
Neurological manifestations: Neurological complaints were the leading extra-intestinal symptom of celiac disease in only 4% of the 485 children examined in the study by Bottaro et al.7 However, about half of patients with celiac disease had neurological disorders or findings in a study by Zelnik et al. Current evidence suggests that neurological manifestations are immune mediated. The most commonly found neurological disorder is headache. Headaches seen in celiac disease are migraines, tension or nonspecific headaches. They improve with the introduction of a gluten-free diet. Other neurological manifestations include hypotonia, attention deficit hyperactivity disorder, learning disabilities and cerebellar ataxia. Epilepsy with occipital calcifications is a characteristic neurological manifestation of celiac disease.
Arthritis: This is fairly common in adults with celiac disease, including patients on a gluten-free diet. Up to 3% of children with juvenile chronic arthritis have been reported to have celiac disease.
Evaluation and management
Evaluation for celiac disease includes IgA tissue transglutaminase (tTG) and/or IgA endomysial (EMA) titers in combination with quantitative IgA testing. If total levels of IgA are not measured and the patient has selective IgA deficiency, this can result in false-negative IgA tTG or EMA testing and thus, false-negative screening for celiac disease. In the event of low or deficient IgA levels and negative serology testing, screening should be continued with IgG tTG and/or IgG EMA testing. The value of antigliadin and deamidated gliadin peptide antibody testing is limited in screening due to their lower sensitivity and specificity compared to tTG and EMA (Table 2).[3,19,20]
Patients who have positive screening should be referred to a pediatric gastroenterologist for endoscopic evaluation. Patients who have histological identification of intestinal mucosal features compatible with celiac disease are placed on the only treatment available for celiac disease: gluten-free (<20 ppm or <20mg/kg) diet for life.
Silent and latent celiac disease
In the majority of cases, celiac disease is asymptomatic. There are 2 forms of asymptomatic celiac disease: silent and latent. In both forms the serology is abnormal. The 2 forms differ in the intestinal biopsy findings; silent celiac disease has mucosal architecture at the intestinal biopsy examination consistent with celiac disease, whereas latent celiac disease has normal or minimally abnormal intestinal mucosal architecture.
A gluten-free diet is indicated in silent but not in latent celiac disease. Patients with latent disease should have testing for the celiac disease predisposing genotypes HLA DQ2 and HLA DQ8. If those are present, repeated intestinal biopsy may be needed every few years (more specific guidelines are not currently available). This is important to avoid complications from untreated celiac disease, such as development of other autoimmune conditions and intestinal lymphoma.
High-risk groups for celiac disease
Screening for celiac disease should be performed every 3 years in high-risk group asymptomatic individuals, because they may have silent disease. If they develop symptoms, testing should be done earlier. Alternatively, such individuals may be tested for the celiac disease predisposing genotypes: HLA DQ2 and DQ8. If they have neither genotype, the chance of them having celiac disease is as low as 0.5% and no further testing is needed. On the other hand, a positive genetic testing is not as helpful because these genotypes are frequently encountered in the general population.
High-risk groups for celiac disease are listed below:
• First degree relatives of patients with celiac disease
• Turner syndrome
• Williams syndrome
• Down syndrome
• Diabetes mellitus type 1
• IgA deficiency
• Autoimmune thyroiditis
Symptoms of celiac disease are diverse and patients can frequently be asymptomatic. The leading extraintestinal symptoms of celiac disease in children are iron deficiency anemia, short stature and delayed onset of puberty. In evaluating patients who present with non-classic symptoms of celiac disease and patients at high-risk for the disease, pediatricians should include screening for celiac disease with IgA tissue transglutaminase or endomysial antibody titers with quantitative IgA testing. Referral to a pediatric gastroenterologist is recommended for patients who have positive serology screening in order to confirm the diagnosis of celiac disease.
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