eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Celiac Disease

Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Phyllis A Vallee, MD, Associate Program Director, Department of Emergency Medicine, Henry Ford Hospital

Updated: Sep 2, 2009

Introduction

Background

Celiac disease (CD) is a multifactorial, autoimmune disorder that occurs in genetically susceptible individuals.¹ It is triggered by a well-identified environmental factor (gluten and related prolamins), and the autoantigen is also well known (ie, the ubiquitous enzyme tissue transglutaminase). The disease primarily affects the small intestine, where it progressively leads to flattening of the small intestinal mucosa. Three cereals contain gluten and are toxic for patients with celiac disease: wheat, rye, and barley.

The genetic susceptibility to celiac disease is conferred by well-identified haplotypes in the human leukocyte antigen (HLA) class II region (ie, DR3 or DR5/DR7 or HLA DR4). Such haplotypes are expressed on the antigen-presenting cells of the mucosa (mostly dendritic cells); approximately 90% of patients express the DQ2 heterodimer, and approximately 7% of patients express the DQ8 heterodimer. The remaining 3% of patients possess only half of the DQ2 heterodimer.

Celiac disease can occur at any stage in life; a diagnosis is not unusual in people older than 60 years.

Because the historical prevalence and long-term outcome of undiagnosed celiac disease were unknown, Rubio-Tapia et al collected serological information on 3 cohorts.² These included 9,133 healthy young adults from whom sera were collected between 1948-1954 and 12,768 gender-matched subjects from 2 recent cohorts, one whose years of birth were similar to those of members of the first cohort, and one in which age at sampling was similar. Sera was tested for tissue transglutaminase and, if abnormal, for endomysial antibodies.

In the older cohort, during 45 years of follow-up, all-cause mortality was nearly 4-fold greater in persons with undiagnosed celiac disease than among those who were seronegative (hazard ratio = 3.9; 95% confidence interval, 2-7.5; P < 0.001). Comparison of the older and newer cohorts suggested that undiagnosed celiac disease in the United States has dramatically increased in the past half century; 0.2% of the older cohort had undiagnosed celiac disease compared with 0.8% ofthe cohort with similar years of birth and 0.9% of those with similar age at sampling (P ≤ .0001).

Pathophysiology

Pathogenesis

Celiac disease is an autoimmune disease, and the enzyme tissue transglutaminase (tTG) has been discovered to be the autoantigen against which the abnormal immune response is directed. Gluten is the single major environmental factor that triggers celiac disease, which has a narrow and highly specific association with class II haplotypes of HLA DQ2 (haplotypes DR-17 or DR5/7) and, to a lesser extent, DQ8 (haplotype DR-4). 

Scientific knowledge on the pathogenesis of celiac disease has markedly increased in the past few years; the combined roles of innate and adaptive immunity are now better understood.
   
Innate immunity

Intraepithelial lymphocytes (IELs) play an important role in the destruction of epithelial cells. Through specific natural killer receptors (NKR) expressed on their surface, IELs recognize nonclassical major histocompatibility complex (MHC)-I molecules induced on the surface of enterocytes by stress and inflammation. This interaction leads to activation of these armed effector IELs to become lymphokine-activated killing cells; they cause epithelial cell death in a T-cell receptor (TCR)–independent manner. This killing is particularly enhanced through the cytokine interleukin (IL)-15, which is highly expressed in celiac mucosa. NKG2D has been found to play a crucial role in intestinal inflammation in celiac disease.³

Adaptive immunity

The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrated in specific binding to HLA-DQ2 or DQ8 molecules and in stimulating gluten-specific CD4 T cells. These T cells express α/β TCR, and can be isolated from the lamina propria and cultivated. In vitro, they have been shown to recognize specific gluten peptides presented through interaction with DQ2 or DQ8 molecules.
 
Gluten is a complex macromolecule that contains abundant proline and glutamine residues, rendering it largely indigestible. Under usual circumstances, gluten is left (in part) unabsorbed by the GI tract. Gluten is composed of glutenins and gliadins, the alcohol-water soluble fraction.  These gliadins are further divided into alpha, gamma, and omega fractions based on electrodensity.
  
Among these fractions, one particular peptide fragment is the alpha gliadin 33-mer, which contains an immunodominant peptide fragment. This fragment is deamidated by tTG. tTG is a ubiquitous enzyme and is known to deamidate glutamine to glutamic acid, creating a strong negative charge within the peptide. This modification is crucial in increasing selection to the positive charges within the binding pocket of HLA-DQ2 or DQ8 molecules on antigen-presenting cells in the lamina propria. When conveyed to gluten specific CD4+ T cell, it induces proliferation and induction of a Th1 cytokine response, primarily with the release of interferon-γ.
 
B cells receive signals through this HLA interaction, leading to tTG autoantibody production. The role of these autoantibodies is still unclear; they have been shown to be deposited along the subepithelial region even in normal-appearing intestinal biopsy findings prior to positive serology and without the onset of overt epithelial cell damage.

Relevant anatomy

Celiac disease primarily affects the small intestine. This organ is schematically divided into 3 areas: the duodenum (which begins beyond the pylorus, located at the end of the stomach), the jejunum, and the ileum (ending at the ileocecal junction, the beginning of the large intestine). These 3 parts share similar tissue architecture and are responsible for most of the body's nutrient absorption. The intestinal wall has 4 layers, which (from the lumen inward) are termed the mucosa, submucosa, muscularis, and serosa. The 2 main functions of the mucosa are to accomplish all digestive-absorptive processes for nutrients and electrolytes and to provide a barrier function by excluding foreign antigens and toxins.

Celiac disease affects the mucosal layer: here, a cascade of immune events leads to the changes that can be documented by histology.

Pathology

The classic celiac lesion occurs in the proximal small intestine with typical histological changes of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytosis. Three distinctive and progressive histological stages have been described and are termed the Marsh classification.⁴ The histological changes of celiac disease are classified as follows: 

• Type 0 or preinfiltrative stage (normal)
• Type 1 or infiltrative lesion (increased intraepithelial lymphocytes)
• Type 2 or hyperplastic lesion (type 1 plus hyperplastic crypts)
• Type 3 or destructive lesion (type 2 plus villous atrophy of progressively more severe degrees [termed 3a, 3b, and 3c])

Frequency

United States

The availability of sensitive and specific serological tests has made it possible to assess the true prevalence of celiac disease by detecting minimally symptomatic or even asymptomatic cases with typical mucosal changes.⁵ Screening studies have shown that celiac disease has a very high prevalence, occurring in almost 1% of the general population throughout North America.

International

Celiac disease is as common in Europe as it is in North America; recent estimates suggest the prevalence in Europe is actually increasing,⁶  as is the prevalence of other autoimmune conditions, possibly as a result of the reduced exposure in early life to environmental bacterial stimuli (the "hygiene hypothesis").⁷

The prevalence of celiac disease in other areas of the world has been less studied. However, data are available from Latin America, North Africa, the Near East and Middle East, and northwest India; celiac disease has been reported in these areas, and prevalence data did not significantly differ from that seen in Europe and North America. A notable exception is represented by the Sub-Saharan African population, where an astounding prevalence of 5% has been reported.⁸ Thus, celiac disease constitutes one of the most common genetically induced chronic diseases worldwide.

However, celiac disease is considered extremely rare in people of African, Chinese, or Japanese descent, in whom the prevalence of the HLA haplotypes DQ2 and DQ8 is negligible.

Mortality/Morbidity

The morbidity rate of celiac disease can be high. Its complications range from osteopenia, osteoporosis, or both to infertility in women, short stature, delayed puberty, anemia, and even malignancies (mostly related to the GI tract [eg, intestinal T-cell lymphoma]). As a result, the overall mortality in patients with untreated celiac disease is increased.

Evidence also suggests that the risk of mortality is increased in proportion to the diagnostic delay and clearly depends on the diet; subjects who do not follow a gluten-free diet have an increased risk of mortality, as high as 6 times that of the general population. The increased death rates are most commonly due to intestinal malignancies that occur within 3 years of diagnosis.⁹ Some indirect epidemiological evidence suggests that intestinal malignancies can be a cause of death in patients with undiagnosed celiac disease.¹⁰

Race

In some ethnicities, such as in the Saharawi population, celiac disease has been found in as many as 5% of the population. As mentioned, celiac disease is considered extremely rare or nonexistent in people of African, Chinese, or Japanese descent.

Sex

Most studies indicate a prevalence for the female sex, ranging from 1.5:1 to 3:1.

Age

Celiac disease can occur at any stage in life; a diagnosis is not unusual in people older than 60 years.

• Classic GI pediatric cases usually appear in children aged 9-18 months.
• Celiac disease may also occur in adults and is usually precipitated by an infectious diarrheal episode or other intestinal disease.

Clinical

History

Clinical presentation

Celiac disease (CD) may occur without any symptoms; asymptomatic or minimally symptomatic celiac disease is probably the most common form of the disease, especially in older children and adults.

The different presentations of celiac disease.

The celiac iceberg.

• Typical presentation: This presentation is primarily characterized by GI signs and symptoms.
• Atypical presentation: GI signs and symptoms are minimal or absent, and various extraintestinal manifestations are present.
• Silent presentation: The small intestinal mucosa is damaged, and celiac disease autoimmunity can be detected with serology; however, no symptoms are present.
• Potential presentation: Patients are symptomatic, and the mucosa morphology is normal. These individuals have genetic compatibility with celiac disease and may also show positive autoimmune serology. Full-blown celiac disease may develop at a later stage in some of these individuals.

Typical presentation

The so-called typical form of celiac disease presents with GI symptoms that characteristically appear at age 9-24 months. Symptoms begin at various times after the introduction of foods that contain gluten. Infants and young children typically present with chronic diarrhea, anorexia, abdominal distension, abdominal pain, poor weight gain or weight loss, and vomiting. Severe malnutrition can occur if the diagnosis is delayed. Behavioral changes are common and include irritability and an introverted attitude. Rarely, severely affected infants present with a celiac crisis, which is characterized by explosive watery diarrhea, marked abdominal distension, dehydration, hypotension, and lethargy, often with profound electrolyte abnormalities, including severe hypokalemia.

Older children with celiac disease who present with GI manifestations may have onset of symptoms at any age. The variability in the age of symptom onset possibly depends on the amount of gluten in the diet and other environmental factors, such as duration of breast feeding. In fact, in the author's experience, if gluten is introduced during breast feeding, the symptoms tend to be less often GI related and tend to appear later in life.¹¹ GI symptoms in older children are typically less evident and include nausea, recurrent abdominal pain, bloating, constipation, and intermittent diarrhea. 
 
Atypical presentation

An increasing number of patients are being diagnosed without typical GI manifestations at older ages. A reasonable assumption is that approximately 70% of patients with newly diagnosed celiac disease do not present with the typical major GI symptoms. Once again, a relationship between the age of onset and the type of presentation is noted; in infants and toddlers, GI symptoms and failure to thrive predominate, whereas, during childhood, minor GI symptoms, inadequate rate of weight and height gain, and delayed puberty tend to be more common. In teenagers and young adults, anemia is the most common form of presentation. In adults and in the elderly, GI symptoms are more prevalent, although they are often minor.

GI signs and symptoms of celiac disease.

Extraintestinal manifestations of celiac disease.

• Dermatitis herpetiformis: A blistering skin rash that involves the elbows, knees, and buttocks are associated with dermal granular immunoglobulin (Ig) A deposits. The rash and mucosal morphology improve on a gluten-free diet. Dermatitis herpetiformis is a rare occurrence in childhood and is described almost exclusively in teenagers and adults.
• Dental enamel hypoplasia: These enamel defects involve only the permanent dentition and may be the only presenting manifestation of celiac disease. Often, GI symptoms are minimal or absent.
• Iron-deficiency anemia: In several studies, iron-deficiency anemia that is resistant to oral iron supplementation is reportedly the most common extraintestinal manifestation of celiac disease in adults. However, in children, iron deficiency is seldom seen as the only presenting sign, although the finding of anemia is common.
• Short stature and delayed puberty: Short stature may be the only manifestation of celiac disease. As many as 10% of children with idiopathic short stature may have celiac disease that can be detected on serologic testing. Some patients with short stature also have impaired growth hormone production following provocative stimulation testing; this production returns to normal when the patient is put on a gluten-free diet. Adolescent girls with untreated celiac disease may have delayed onset of menarche.
• Chronic hepatitis and hypertransaminasemia : Patients with untreated celiac disease commonly have elevated transaminase levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). As many as 9% of patients with elevated transaminase levels of unclear etiology may have silent celiac disease. Liver biopsy findings in these patients reveal nonspecific reactive hepatitis. In most cases, liver enzymes normalize on a gluten-free diet.
• Arthritis and arthralgia: Arthritis can be a common extraintestinal manifestation of adults with celiac disease, including those on a gluten-free diet. As many as 3% of children with juvenile chronic arthritis may have celiac disease.
• Osteopenia and osteoporosis: Approximately 50% of children and 75% of adults have a low bone mineral density at the time of diagnosis; this low density reaches severe degrees, including osteoporosis. Bone mineral density improves in most patients on gluten-free diet and returns to normal as soon as 1 year after starting the diet in children. However, the response to the diet can be much less marked in adults.
• Neurological problems: Numerous neurological conditions have been attributed to celiac disease in adults and, to a lesser extent, in children. Celiac disease may cause occipital calcifications and intractable epilepsy; these patients can be resistant to antiseizure medicines but can benefit from a gluten-free diet if it is started soon after onset of seizures. The association with cerebellar ataxia is well described in adults; the term gluten-induced ataxia has been proposed.
• Psychiatric disorders: Although a large number of behavioral problems and disorders (eg, autism, attention deficit hyperactivity disorder) have been thought to be caused by celiac disease, no evidence has been conclusive. However, celiac disease can be associated with some psychiatric disorders, such as depression and anxiety. These conditions can be severe and usually respond to a gluten-free diet. 
• Subfertility or infertility: Although somewhat controversial, reports have indicated that as many as 6% of women who experience infertility or repeated miscarriages have celiac disease.¹² Some studies recommend increased screening for celiac disease in pregnant women; however, screening is associated with its own risks and expense. Because of the potential serious effects of undiagnosed celiac disease on the outcome of pregnancy, the need for screening pregnant women for celiac disease is currently under investigation.

Associated diseases

Celiac disease is also known to be strongly associated with numerous disorders, specifically with autoimmune conditions and genetic syndromes (eg, Down syndrome, Williams syndrome, Turner syndrome).

The association of celiac disease with autoimmune conditions is well known. A strong positive correlation between the age at diagnosis and the prevalence of autoimmune disorders (eg, type 1 diabetes mellitus, thyroiditis, alopecia) is recognized; this suggests that the continuous ingestion of gluten before diagnosis may induce the development of other autoimmune conditions.

• Type 1 diabetes mellitus
  • Approximately 10% of patients with type 1 diabetes mellitus have typical findings of celiac disease on duodenal biopsy samples.
  • Many individuals with type 1 diabetes mellitus who initially had negative serological test results for celiac disease eventually had positive findings; this highlights the need for repeated testing.
  • Because celiac disease only occurs with specific human leukocyte antigen (HLA) haplotypes, an algorithm based on the determination of these HLA haplotypes has been proposed to avoid repeat testing in all patients with diabetes; this allows patients with diabetes in whom the HLA haplotypes are inconsistent with celiac disease to avoid repeat testing.
  • Typically, diagnosis of diabetes precedes diagnosis celiac disease by years; celiac disease in these patients most commonly presents with mild GI symptoms or absent symptoms. Because some of these symptoms are also seen in patients with diabetes (eg, bloating, diarrhea), diagnosis of celiac disease may be missed unless a screening is performed.
  • Although no convincing evidence has suggested that a gluten-free diet has any obvious effect on diabetes, these patients must follow the diet to prevent all long-term complications of celiac disease. Thus, screening patients with type 1 diabetes mellitus for celiac disease seems well founded.
• Down syndrome
  • The best documented and most well-known nonautoimmune disorder associated with celiac disease is Down syndrome.
  • As assessed by screening methods, the prevalence of Down syndrome in celiac disease is 8-12%.
  • Most patients with Down syndrome who have celiac disease have some GI symptoms, such as abdominal bloating, intermittent diarrhea, anorexia, or failure to thrive; however, about one third of these patients do not have GI symptoms.
  • As with patients who have type 1 diabetes mellitus, periodic serologic testing is indicated only in patients with Down syndrome who are genetically compatible with celiac disease (ie, those who have either HLA DQ2 or DQ8).
  • A similar strategy should be applied for patients with Turner syndrome or Williams syndrome, in whom an increased incidence of celiac disease has also been reported.

Physical

Examination findings depend on extent of celiac disease.

• Dry mucosal membranes with vomiting or diarrhea indicate the degree of dehydration.
• Oral aphthae are more frequent than in normal population.
• Dental enamel hypoplasia is a highly specific but relatively uncommon finding.
• Bloating of the abdomen is a relatively common finding.
  
  

  

  Potbelly and muscle wasting in a child with celiac disease.

  
  
• Muscle wasting is an obvious but uncommon finding and is part of the malnutrition that ensues because of the malabsorptive condition.
• Celiac disease may occur in asymptomatic individuals without any positive clinical findings, as noted above.

Causes

• Celiac disease is caused by an abnormal immune reaction to the ingestion of gluten in genetically predisposed individuals. However, other environmental factors are necessary to trigger this multifactorial condition and are related to infant feeding practices and early intestinal infections.
• Breast feeding has a protective role.¹³ Having gluten introduced while breast feeding is continued has a strong protective effect.
• Additionally, evidence now strongly suggests that early (age ≤3 mo) first exposure to gluten may favor the onset of celiac disease in predisposed individuals.
• Large amounts of gluten at weaning are associated with an increased risk for developing celiac disease, as is documented in studies from Scandinavian countries.¹⁴
• Finally, repeated rotavirus infections in infancy appear to be associated with a higher risk of developing celiac disease autoimmunity in genetically predisposed individuals.¹⁵

Differential Diagnoses

Protein Intolerance

Workup

Laboratory Studies

• Celiac disease (CD) is diagnosed as follows:
  • Duodenal mucosa histology changes are documented while on a gluten-containing diet and are characterized by a progressive deterioration of the villous architecture associated with a progressive increase in crypt length and density. Biopsy samples are now almost universally obtained by endoscopy. Multiple biopsy samples (at least 4) are recommended because celiac disease may be patchy and areas of villous atrophy may be adjacent to normal areas.¹⁶ Although endoscopically visible changes have been described (eg, scalloping or nodularity of the mucosa, sparse duodenal folds), such changes are neither constant nor specific, and a diagnosis of celiac disease should never be based on their presence or absence.
  • The clinical and laboratory response to a gluten-free diet is documented. In particular, the positive autoantibodies (anti-tTG or antiendomysium antibodies) must progressively normalize.
• Substantial agreement is observed between the evidence-based guidelines introduced in 2005 by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and those published by the American Gastroenterological Association (AGA) in 2006.^17,18  Both describe the diagnostic approach in great detail. In part, these guidelines follow previous, only partially evidence-based guidelines proposed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) in 1990.¹⁹
• The role of serology in the diagnosis of celiac disease is as follows:
  • In clinical practice, serologic tests for celiac disease are useful in identifying children who require intestinal biopsy findings to diagnose the condition. In addition, these serologic test findings are supportive of the diagnosis in those with characteristic histopathologic features of celiac disease on small intestinal biopsy findings and may have a role in monitoring response to treatment.
  • Numerous serologic tests are now commercially available.
  • Sensitivities and specificities for the antigliadin tests widely vary. Immunoglobulin (Ig)G-based antigliadin (AGA) tests are generally poor in both parameters, whereas the IgA-based test was poorly sensitive but more specific. Using AGA testing to screening for celiac disease is not currently recommended. The variability and generally lower accuracy associated with the AGA tests make them unsuitable for screening purposes; however, they can be used to monitor dietetic compliance because they are known to react more promptly to dietary transgression.
  • The IgA endomysium (EMA-IgA) and tissue transglutaminase (TTG-IgA) tests are both highly sensitive and highly specific, with values for both parameters exceeding 96% in most studies. No identifiable differences between adults and children are noted with respect to these tests.

Imaging Studies

• Radiography of the GI tract with a barium swallow study and a small intestinal follow-through may show nonspecific changes because of the mucosal inflammation and possible concomitant protein-losing enteropathy (edema of the bowel walls, dispersion of the barium column).
• The findings are clearly nonspecific, and radiographic investigation is not indicated.

Procedures

• Most centers today include diagnostic duodenal biopsy during esophagogastroduodenoscopy (EGD). Obtaining at least 4 biopsy samples from the bulb and from the distal duodenum is highly recommended because mucosal changes in celiac disease may be patchy.
• Colonoscopy may be indicated if bloody stools are reported or if symptoms of colitis are also present.

Histologic Findings

Mucosal biopsy of the duodenum shows the changes described above.

• However, changes referred to as Marsh 1 or even Marsh 2 are nonspecific because they can also be found in food-allergic enteropathies, such as cow's milk allergy or soy allergy (especially in infancy). 
• These changes are also observed in giardiasis and in autoimmune enteropathy.
• Although also not pathognomonic for celiac disease, changes referred to as Marsh 3 are usually much more specific, especially if they are associated with supportive serology findings.
• Evidence suggests that patients with Marsh type 1 changes who have a positive serology findings may develop more severe changes if they continue a gluten-containing diet; this challenges the idea that celiac disease is only observed in those who have more advanced findings.²⁰

Treatment

Medical Care

Total lifelong avoidance of gluten ingestion is the cornerstone treatment for patients with celiac disease (CD). Wheat, rye, and barley are the grains that contain toxic peptides. They should be eliminated as completely as possible, although daily intake doses larger than 10 mg are likely needed to cause mucosal reaction.²¹ GI symptoms in patients with symptomatic celiac disease who adhere to a gluten-free diet typically resolve within a few weeks; these patients experience the normalization of nutritional measures, improved growth in height and weight (with resultant normal stature), and normalization of hematological and biochemical parameters.

Furthermore, treatment with a gluten-free diet reverses the decrease in bone mineralization and the risk for fractures . Symptomatic children treated with a gluten-free also improve their sense of physical and psychological well being.

For a long time, oats were considered toxic as well, and their elimination from the diet had been recommended. However, over the past decade, a growing body of scientific evidence obtained from in vitro studies as well as from clinical investigations (particularly in adults but also, more recently, in children) suggests that oats are totally safe. Because of uncontrolled harvesting and milling procedures, as well as the possibility that lines of manufacturing used for wheat-based flours are also used in the preparation of oat-based foods, cross-contamination of oats with gluten is still a concern.

Lactose is often eliminated in the initial phases of dietary treatment as well. This is because lactase deficiency is thought to accompany the flat mucosa. However, most newly diagnosed patients with celiac disease are diagnosed in the absence of overt malabsorptive symptoms; in these circumstances, clinically significant lactose malabsorption or intolerance is rarely seen. Furthermore, even in cases with obvious malabsorption, the recovery of lactase activity is typically fast; thus, a lactose-free diet must be used on a short-term basis only, even in these individuals.

The American Dietetic Association (ADA) publishes guidelines for the dietary treatment of celiac disease. They are a reliable source of information for a gluten-free. However, because of the dynamics of this field, the diet requires ongoing collaboration between patients, health care providers, and dietitians.

Consultations

Diet

See Medical Care.

Activity

No additional restriction is necessary beyond that imposed by the patient's fatigue. However, if a completely gluten-free diet is followed, celiac disease completely regresses, and individuals have a completely normal quality of life.

Medication

Glucocorticoids

Corticosteroids can rapidly control severe symptoms of celiac disease (CD). They may also have a role in rare cases in which the patient has no response to diet; this condition is known as refractory celiac disease and occurs exclusively in adults (1-3% of total).

For celiac disease in children, steroids are almost never needed.

Hydrocortisone (A-Hydrocort, Solu-Cortef)

Some cases of refractory celiac disease (with all other forms of colitis and enteritis excluded) respond to parenteral corticosteroids, for reasons unknown. Exclude other etiologies of failure to thrive, especially in children, because systemic steroids can pose risk to growth. Sodium succinate salt formulation may be administered IV or IM.

Dosing

Adult

100-500 mg IV q12h

Pediatric

20-120 mg/m² IV/IM q12h or 0.67-4 mg/kg IV/IM q12h

Interactions

CYP450 2D6 and 3A3/4 substrate; corticosteroid clearance may increase with phenytoin, barbiturates, or rifampin treatment or decrease with estrogens; cholestyramine may decrease AUC; corticosteroids may increase digitalis toxicity secondary to hypokalemia; coadministration with potassium depleting agents (eg, diuretics) may increase risk of hypokalemia; corticosteroids may decrease growth-promoting effect of GH; decreases effects of salicylates and vaccines used for immunization; monitor for hypokalemia with coadministration of diuretics or amphotericin B; antagonizes effects of anticholinergics; may increase anticoagulant effects of warfarin; decreases hypoglycemic effects of sulfonylureas and insulin; increases toxicity of cyclosporine

Contraindications

Active bacterial infection, chickenpox, measles or concurrent immunosuppressant therapy; avoid in patients with HIV, tubercular infection, congestive heart failure, renal disease, diabetes, or myasthenia gravis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Compare dose for surface area to dose for weight to avoid overdose in overweight child (good rule is use former if weight dose higher); typical child with sprue is severely malnourished and underweight, so mg/kg should present no problem; avoid prolonged use (ie, >1 wk) in children without checking growth parameters and adrenal function; caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

Follow-up

Further Outpatient Care

• After the diagnosis of celiac disease (CD) has been established and a strict diet has been initiated, the first follow-up requirement is to monitor the patient's response to the diet. Depending on the severity of the clinical situation and the type of symptoms, the first outpatient appointment is typically scheduled for 4-8 weeks after the diagnosis. At this time, serologic tests for celiac disease are not needed because antibody levels still have not declined.
• Further follow-up appointments are dedicated to assessing the patient's dietetic compliance and the adequacy of growth and well-being. Anti-tTG and the newer deamidated antigliadin antibodies should be periodically monitored for regression; their levels usually return to normal within 4-6 months after the beginning of a rigorous diet. However, the best indicator of dietary compliance is attainable by a careful review of the diet, and simple survey questionnaires have been developed for use in adults.²²  For patients whose initial levels of anti-tTG were particularly elevated, normalization can take up to 12-18 months. For asymptomatic patients and for those who are clinically responding well to diet, follow-up appointments are usually scheduled annually.
• Celiac disease can be associated with numerous autoimmune disorders. If any are present (eg, type I diabetes mellitus, thyroiditis), follow-up care must include an adequate assessment of these conditions, which most often do not respond to the diet, and referral to other specialists is required (see Consultations).
• A dietitian must be present at each of the follow-up appointments because the questions that most interest the patient's family are, by far, those concerning the diet.
• In patients who had obvious malabsorption at diagnosis, assessment of the status of specific nutritional deficiencies (eg, iron deficiency, folate deficiency, zinc deficiency) is appropriate.

Deterrence/Prevention

• The only way to prevent recurrences is to closely monitor the patient's diet.
• Because celiac disease is more common in relatives of patients, first-degree relatives should at least be serologically screened (see Causes). Concerned parents usually accept this simple procedure, which often reveals previously undetected celiac disease, even in asymptomatic individuals. This effective preventive strategy must be encouraged.
• Also, prevention of complications by early diagnosis (secondary prevention) may be achieved by applying a protocol of blood screening to all patients who belong to other at-risk categories (eg, type 1 diabetes mellitus, Down syndrome).
• With elucidation of the role that infant feeding practices and rotavirus infections play, primary prevention of celiac disease no longer seems impossible. Primary prevention (at least in some cases) may be achieved through the expected reduction of rotavirus infections after the introduction of the vaccine and through proper breast feeding and gluten introduction in infants born to at-risk families.

Complications

• Celiac disease is fully reversible if trigger foods are avoided. However, when compliance is suboptimal, complications may occur. The level of gluten that is safe to consume widely varies among people with celiac disease; hence, a zero-tolerance policy must be enforced. Available evidence suggests that although almost no individuals with celiac disease show signs or symptoms of relapse while ingesting as much as 10-20 mg of gliadin per day, most react to ingestion of more than 100 mg/d.²¹
• Complications in noncompliant patients include the following:
  • Osteopenia/osteoporosis
  • Adverse effects during pregnancy, including miscarriages
  • Anemia
  • Ulcerative jejunitis, colitis, refractory celiac disease (thought to be a low-grade intestinal lymphoma)
  • GI malignancies, most commonly an enteropathy-associated T-cell lymphoma (EATL)

Prognosis

• The prognosis is excellent; the disorder is fully reversible if trigger foods are avoided.

Patient Education

• In modern society, living a life without gluten is not easy. Educating patients and their families about how to select and properly maintain such a diet is a major, ongoing task.
• The role of support groups can never be overestimated. The physician has a duty to care for patients with celiac disease and to adequately inform the family about how to connect with such groups.
• Several university-associated centers that provide excellent materials for patient education are now available in the United States (eg, the University of Chicago Celiac Disease Center²³ ) and in Europe. In the United States, the American Celiac Disease Alliance (ACDA) offers patient education as well as links to other centers.
• For excellent patient education resources, visit also eMedicine's Esophagus, Stomach, and Intestine Center and Teeth and Mouth Center. Also, see eMedicine's patient education articles Celiac Sprue, Anatomy of the Digestive System, and Canker Sores.

Miscellaneous

Medicolegal Pitfalls

• Failure to perform a sweat test on children with any type of malabsorption syndrome to exclude cystic fibrosis (CF), a more serious condition that may present similarly at onset, is a pitfall.
• If the patient's condition fails to respond to dietary changes after the initial diagnosis (remember that the diagnosis depends not only on biopsy results but also a clear response to diet), failure to consider alternative diagnoses is a pitfall. Such diagnoses include food allergies; other GI diseases; immunodeficiency disorders; and viral, bacterial, parasitic, and fungal infections.

Multimedia

Media file 1: Potbelly and muscle wasting in a child with celiac disease.

Media file 2: The celiac iceberg.

Media file 3: The different presentations of celiac disease.

Media file 4: Extraintestinal manifestations of celiac disease.

Media file 5: GI signs and symptoms of celiac disease.

Media file 6: Approximate prevalence of celiac disease in other autoimmune disorders.

References

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Keywords

celiac sprue, celiac disease, gluten-sensitive enteropathy, nontropical sprue, wheat, potbelly, rye, barley, osteopenia, osteoporosis, short stature, delayed puberty, anemia, intestinal T-cell lymphoma, diarrhea, abdominal distension, malnutrition, celiac crisis, explosive watery diarrhea, dehydration, hypotension, hypokalemia, constipation, failure to thrive, dermatitis herpetiformis, dental enamel hypoplasia, iron-deficiency anemia, chronic hepatitis, hypertransaminasemia, arthritis, arthralgia, Down syndrome, Williams syndrome, Turner syndrome, diabetes mellitus type 1, alopecia, thyroiditis, rotavirus

Contributor Information and Disclosures

Author

Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Stefano Guandalini, MD is a member of the following medical societies: American Gastroenterological Association, European Society for Paediatric Gastroenterology, Hepatology & Nutrition, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Coauthor(s)

Phyllis A Vallee, MD, Associate Program Director, Department of Emergency Medicine, Henry Ford Hospital
Phyllis A Vallee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Medical Association, and Michigan State Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Jorge H Vargas, MD, Professor of Pediatrics and Clinical Professor of Pediatric Gastroenterology, David Geffen School of Medicine, University of California at Los Angeles; Consulting Physician, Department of Pediatrics, University of California at Los Angeles Health System
Jorge H Vargas, MD is a member of the following medical societies: American Liver Foundation, American Society for Gastrointestinal Endoscopy, American Society for Parenteral and Enteral Nutrition, Latin American Society of Pediatric Gastroenterology, Hepatology & Nutrition, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ginette V Busschots, MD, to the writing and development of this article.

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