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Clinical manifestations and diagnosis of celiac disease in children

Last literature review version 17.3: September 2009  |  This topic last updated: September 2, 2009   (More)

INTRODUCTION — Celiac disease (also known as gluten-sensitive enteropathy or nontropical sprue) is an immune-mediated inflammation of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically sensitive individuals. The disorder is common, occurring in 0.5 to 1 percent of the general population in most countries [1].

The grains that contain the triggering proteins are wheat, barley, and rye; there is some controversy as to whether oats also can cause the disease. The small intestinal mucosa improves morphologically when treated with a gluten-free diet and relapses when gluten is reintroduced. In a study from an era in which celiac disease was not treated, mortality was 12 percent [2]. The appropriate treatment is a gluten-free diet for life, and this results in complete resolution of symptoms for most individuals.

The diagnosis and clinical manifestations of celiac disease are reviewed here. Its management and the use of antibodies for diagnosis are presented separately. (See "Management of celiac disease in children" and "Diagnosis of celiac disease".)

This topic also is discussed in an official position statement issued by the American Gastroenterological Association [3] and a consensus statement from the National Institutes of Health [4]. The discussion below also reflects guidelines developed by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) [1]. The pediatric guidelines are available on the NASPGHAN Web site (www.naspghan.org).

PATHOGENESIS — The cause of celiac disease was unexplained until the Dutch pediatrician Willem K Dicke recognized an association between the consumption of bread and cereals and relapsing diarrhea. This observation was corroborated when, during periods of food shortage in the Second World War, the symptoms of his patients improved once bread was replaced by non-cereal-containing foods; this finding confirmed the benefit of earlier, empirical diets that used pure fruit, potatoes, banana, milk, or meat [5-7].

Because symptoms reoccurred when bread was reintroduced after the war, Dicke and van de Kamer initiated controlled experiments exposing children with celiac disease to defined diets and then determined fecal weight and fecal fat as a measure of malabsorption. Wheat, barley, rye, and (to a minor degree) oats triggered malabsorption, which could be reversed after exclusion of these "toxic" cereals from the diet [8]. Shortly thereafter, the toxic agents were found to be present in gluten, the primary protein found in wheat [9].

The celiac lesion in the proximal small intestine was first described in 1954. The primary findings were mucosal inflammation, crypt hyperplasia, and villous atrophy (picture 1) [10]. With the development of peroral biopsy, it became apparent that celiac disease and adult nontropical sprue shared the same features and pathogenesis [11].

Genetic factors — Celiac disease is an immune disorder that is triggered by an environmental agent (gluten) in genetically predisposed individuals [12,13]. The genetic basis of the disease is shown by the frequent intrafamilial occurrence and the remarkably close association with the HLA-DQ2 and/or DQ8 gene locus. While the presence of either the HLA DQ2 or DQ8 genotype is essential to confer disease, it is not sufficient, and another gene or genes at a non-HLA locus must also participate. Non-HLA genes are likely to be a stronger determinant of disease susceptibility than the HLA locus.

Because of common genetic contributors, several groups are at increased risk for celiac disease. The genetic contributors to celiac disease are discussed in detail separately. (See 'High-risk groups' below and "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Genetic factors'.)

Autoimmunity — Celiac disease is associated with a number of autoimmune disorders including type 1 diabetes mellitus and autoimmune thyroid disease. In addition, the intestinal lesion of celiac disease is associated with several different autoantibodies that are useful for diagnostic purposes. IgA-antibodies against endomysium and the endomysial autoantigen tissue transglutaminase are highly sensitive and specific. (See 'Associated conditions' below and 'Diagnostic approach' below.)

It is possible that immunologic similarities between gliadin protein motifs and enteral pathogens may be involved in pathogenesis of an immunologic response to antigens in gluten. This hypothesis was supported in one study, in which analysis of alpha gliadin demonstrated an amino acid region that was homologous to the 54KDa E1b protein coat of adenovirus 12, suggesting that exposure to the virus in a susceptible person could be involved in the pathogenesis of celiac disease [14]. (See "Epidemiology and clinical manifestations of adenovirus infection".)

However, the pathogenetic role of these antibodies remains to be clarified. Both humoral and cell-mediated immune mechanisms are involved, and the range of gluten peptides triggering the reaction may vary with the age of the patient. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Autoantibodies and intraepithelial lymphocytes'.)

Infant feeding practices — The pathogenesis of celiac disease at any age requires exposure to gluten. However, there is emerging evidence that the timing and manner of gluten exposure may affect the risk for or clinical expression of celiac disease. Observational studies suggest that the risk for celiac disease might be reduced by continuing breast feeding while introducing gluten into an infant's diet, and by introducing gluten gradually [15,16].

These factors are thought to be implicated in an epidemic of celiac disease that occurred in Sweden between 1984 and 1996, in which the frequency of symptomatic celiac disease in children younger than two years increased four-fold [17]. The onset and end of this epidemic were abrupt, and coincided with specific changes in infant feeding practices. Rates of celiac disease among children born during this epidemic are as high as 3 percent by age 12 [18]. One third of these cases came to attention because of symptoms, and the remaining cases were diagnosed by population screening. Currently, infant feeding practices in Sweden emphasize gradual introduction of gluten while breast-feeding is ongoing, and the prevalence of celiac disease in young children has returned to pre-epidemic levels. Future studies are needed to determine whether these measures decrease the lifetime risk for celiac disease, or merely delay onset of disease.

CLASSIFICATION — For many years, celiac disease was defined by a set of classic clinical manifestations. However, the combination of serologic, genetic, and histologic data has led to an appreciation of the highly variable clinical manifestations of the condition and the description of other categories of celiac disease.

Classic disease — The classic description of celiac disease, or gluten-sensitive enteropathy, includes the following three features:

  • Symptoms of malabsorption such as steatorrhea, weight loss, or other signs of nutrient or vitamin deficiency [11].
  • The presence of characteristic histologic changes (including villous atrophy) on small intestinal biopsy.
  • Resolution of the mucosal lesions and symptoms upon withdrawal of gluten-containing foods, usually within a few weeks to months.

The degree of the villous atrophy does not necessarily correlate with the severity of clinical symptoms. Although there is a gradient of decreasing severity from the proximal to the distal small intestine, correlating with the higher proximal concentration of dietary gluten, sampling error can occur due to some inhomogeneity of mucosal inflammation.

The histologic features range from a mild alteration characterized only by increased intraepithelial lymphocytes (Marsh type 1 lesion) to a flat mucosa with total mucosal atrophy, complete loss of villi, enhanced epithelial apoptosis, and crypt hyperplasia (Marsh type 3 lesion) (figure 1 and picture 1) [11,19-23]. The Marsh type 4 lesion has the same histologic features seen in the type 3 lesion except that the crypts are hypoplastic.

Failure to improve on a gluten-free diet is usually due to poor dietary compliance or other underlying malabsorptive disorders. However, in rare cases, diet-refractory celiac disease may be related to sprue-associated lymphoma or to collagenous sprue, a related but little-understood disorder. (See "Management of celiac disease in adults", section on 'Refractory sprue'.)

Atypical disease — In some patients, the extraintestinal manifestations are predominant, and there are few or no gastrointestinal symptoms. As for patients with classical disease, the diagnosis requires serologic testing, biopsy evidence of villous atrophy, and improvement of symptoms on a gluten-free diet.

Silent/subclinical celiac disease — These patients have no discernable symptoms of celiac disease, but have a positive specific serologic test for celiac disease and biopsy evidence of villous atrophy. These cases are usually detected by screening of high-risk groups. The term "silent" may be a misnomer; after treatment with a gluten-free diet, many of these patients retrospectively recognize symptoms that they had not previously considered to be abnormal. (See 'Subclinical disease' below.)

Latent/potential disease — Individuals with celiac disease, but who have normal jejunal mucosa and no or minor symptoms at least at one time point while on a normal, gluten-containing diet, are said to have "latent" celiac disease [23]. Two variants of latent celiac disease have been identified:

  • Celiac disease was present before, usually in childhood; the patient recovered completely with a gluten-free diet, remaining "silent" even when a normal diet is adopted.
  • A normal mucosa was diagnosed at an earlier occasion while ingesting a normal diet, but celiac disease developed later.

Patients who have never had a biopsy consistent with celiac disease but show immunologic abnormalities characteristic for the disorder (eg, positive IgA to endomysium, a "celiac intestinal antibody pattern," and increased intraepithelial lymphocytes) are said to have "potential" celiac disease [24]. These patients often have a genetic predisposition, especially HLA-DQ2, and a first-degree relative with celiac disease [21]. (See 'High-risk groups' below.)

EPIDEMIOLOGY

General population — Celiac disease occurs primarily in Caucasians. In Europe and the United States, prevalence estimates range from 1:80 to 1:300 children (3 to 13 per 1000 children) [1].

Prevalence estimates have increased with the advent of highly sensitive and specific screening tests, which identified many patients with minimal or no symptoms. Epidemiological studies using these tests with biopsy verification established prevalences of 1:300 to 1:500 in most countries [25]. A large screening study in the United States suggested a prevalence of 1:133 among patients with no risk factors or symptoms [26]. These estimates are similar to those found in European studies [27-30].

Even those not ethnically derived from European populations can develop celiac disease if they have an appropriate genetic background. Punjabis from India living in England and eating a gluten-rich diet developed this disorder 2.9 times more often than Europeans [31]. A disorder named "summer diarrhea" had long been known in their indigenous country, when wheat replaced maize during the summer season. Furthermore, a very high prevalence rate of 5 percent was documented for the Saharawi population of Northern Africa [32]. It is also common in Egypt [33], Tunisia [34], and other populations in North Africa, the Middle East, and Southern Asia [35]. The prevalence in some developing countries is probably underestimated due to limited access to diagnostic facilities and confounding of the disease with other causes of small intestinal damage. Overall, the global distribution of the disease seems to parallel the distribution of HLA genotypes that predispose to celiac disease, provided that the population is also exposed to gluten [36].

One of the largest screening investigations of celiac disease was performed in 17,201 school children, aged 6 to 15 years, who were recruited from several regions of Italy and represented 69 percent of the eligible population [37]. The prevalence was 1:184 and the ratio of asymptomatic to symptomatic cases was a remarkable 7:1 (table 1). Based upon these data, it was estimated that the number of affected persons in Italy alone was 220,000, three-quarters of whom were unidentified [38].

These findings indicate that the number of so-called silent celiacs (a misnomer because most of these patients suffer from nonspecific symptoms) is much higher than the number of patients with classic celiac disease.

High-risk groups — The prevalence of celiac disease as detected by screening programs using specific antibodies is substantially increased in the following groups as compared to the general population (table 2):

  • First- and second-degree relatives of patients with celiac disease [1,26]
  • Down syndrome [1,39]
  • Type 1 diabetes [40-42]
  • IgA deficiency [1,43]
  • Turner syndrome [44]
  • Williams syndrome [45]
  • Autoimmune thyroiditis [1,46,47]

Individuals with Down syndrome appear to have the highest risk, as up to 16 percent are affected (a 20-fold increase in risk over the general population). For the other groups, between 2 and 7 percent are affected, representing a 3- to 10-fold increase in risk as compared to the general population [1,26,40-42,44,45]. For autoimmune thyroiditis, the association is weak during childhood and appears to increase with age [1].

Evidence for these associations is discussed in detail separately. (See 'Diabetes mellitus' below and "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Associated conditions'.)

SYMPTOMS — Although originally recognized largely as a disease of infants, celiac disease most often presents later, between the ages of 10 and 40. Thus, the classical description of a child with life-threatening malabsorption often is replaced by the mostly atypical presentation of adult celiac disease. This changing presentation of the disease may be due to longer periods of breast-feeding and the later introduction of gluten into the infant diet, and increasing recognition of subclinical disease due to advances in serological screening.

Gastrointestinal symptoms — Classically, celiac disease presented between 6 and 24 months of age, after the introduction of gluten into the diet [1]. The children have chronic diarrhea, anorexia, abdominal distension and pain, and failure to thrive or weight loss; some may also have vomiting. If the diagnosis is delayed, children may present with signs of severe malnutrition. Severely affected infants may present with a celiac crisis and the hemodynamic and metabolic consequences of dehydration.

Gastrointestinal symptoms in older children and adults are similar, but usually less dramatic. Paradoxically, the disease may cause either constipation or diarrhea. When diarrhea is present, the stools are often bulky and foul-smelling, and may float because of steatorrhea. Flatulence and abdominal distension (caused by colonic bacterial digestion of malabsorbed nutrients) are common. These symptoms may be accompanied by the consequences of malabsorption, such as growth failure, weight loss, severe anemia, neurologic disorders from deficiencies of B vitamins, and osteopenia from deficiency of vitamin D and calcium.

Nongastrointestinal manifestations — Numerous nongastrointestinal manifestations of celiac disease have been described (table 3). Conditions associated with celiac disease in adults are described in detail separately [48]. In many patients, nongastrointestinal symptoms are the presenting complaint and should prompt the consideration of serologic testing. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults" and "Diagnosis of celiac disease".)

Growth and development — Between 8 and 10 percent of children with apparent "idiopathic" short stature have serologic evidence of celiac disease [1]. Patients with gastrointestinal symptoms have slightly attenuated adult height unless treated prior to puberty [49]. Delay in linear growth may occur even when weight for height is relatively normal, and in the absence of significant gastrointestinal symptoms. Thus, the process is probably not entirely attributable to undernutrition.

Boys with untreated celiac disease have reduced levels of serum dihydrotestosterone in a pattern suggesting androgen resistance [1,50]. Adolescent girls may have an increased frequency of menstrual abnormalities such as delayed menarche, and later may have problems with infertility and experience an early menopause [50-54]. Treatment with a gluten-free diet appears to prevent these problems. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Infertility'.)

Neurologic disease and behavioral symptoms — Celiac disease may have as its primary manifestation neurologic or behavioral symptoms. Several reports in adults have described an association between celiac disease and neuropsychiatric symptoms such as ataxia, peripheral neuropathy, depression, anxiety, or epilepsy [55-61]. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Neuropsychiatric disease'.)

In children with celiac disease, clinically apparent neurologic disorders are uncommon, and the evidence supporting the association with celiac disease is weak. Disorders that may be associated with celiac disease include hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia [62,63]. Epileptic disorders are only slightly more common among children with celiac disease, and there is no increase in the frequency of tic disorders. A population-based study in Italy found that clinically diagnosed neurologic or psychiatric disorders among children with celiac disease was only slightly increased as compared to healthy controls [64]. In the same report, children with known or cryptogenic neurologic disorders did not have a higher prevelance of celiac disease as compared to the general population. Similarly, celiac disease was not overrepresented in a population of adolescent psychiatric outpatients in Finland [65], but depression and disruptive behavioral disorders were nonetheless more common among children with celiac disease than in matched controls [66].

Although clinically apparent neurologic disorders are unusual in children with celiac disease, subclinical neurologic abnormalities are common, and may affect the central and peripheral nervous systems. In a study of children with newly diagnosed celiac disease, almost 20 percent had subclinical neurologic abnormalities [67]. Among 27 children, two had peripheral polyneuropathy documented with electromyography, one had prolonged latencies in somatosensory evoked potential, and two had MRI abnormalities consisting of pontine demyelinization or cortical atrophy. Similarly, there is some evidence of regional hypoperfusion of the cerebrum in adult patients with untreated celiac disease [65]. In most, but not all such conditions, improvement is observed after treatment with a gluten-free diet [60,62,68,69].

The pathogenesis of the neurologic symptoms is unclear. Some of the disorders, such as infantile hypotonia and developmental delay, may be caused by malnutrition, including specific micronutrient deficiencies; these problems tend to resolve on a gluten-free diet. However, there is increasing evidence that some or all of these neurologic abnormalities are caused by autoimmune mechanisms. As an example, widespread IgA tissue transglutaminase deposition around vessels in the cerebellum has been described [70]. In particular, anti-ganglioside antibodies may be involved in the pathogenesis of neurologic symptoms [71], although studies examining this possibility have had somewhat conflicting results. These findings suggest that an immune-mediated process may lead to gluten ataxia and/or peripheral neuropathy [70].

Dermatitis herpetiformis — There are a number of skin manifestations of celiac disease. Dermatitis herpetiformis is the most common (table 4), occurring in up to 24 percent of adult patients with celiac disease [72,73]. A few reports have suggested an association between psoriasis and elevated levels of antibodies to gliadin, reticulin, or tissue transglutaminase, but a strong association between psoriasis and celiac disease has not been documented [74,75].

Approximately 85 percent of adult patients with dermatitis herpetiformis have the characteristic changes of celiac disease on intestinal biopsy, although the majority have no gastrointestinal symptoms. Dermatitis herpetiformis is less common prior to puberty, but has been reported in patients as young as 8 months old [76,77]. It is commonly misdiagnosed as atopic dermatitis, scabies, or linear IgA dermatosis [78].

Dermatitis herpetiformis is characterized by an itchy papular vesicular eruption usually located symmetrically on the extensor surfaces of the elbows, knees, buttocks, sacrum, face, neck, trunk, and occasionally within the mouth (picture 2A-B). The predominant symptoms are itching and burning that are rapidly relieved with rupture of the blisters.

The earliest abnormality comprises a small erythematous macule 2 to 3 mm in diameter that quickly develops into a papule. Small vesicles then appear to coalesce. Scratching causes them to rupture, dry up, and leave an area of pigmentation and scarring. The diagnosis can be confirmed by the demonstration of granular IgA deposition in an area of the skin not affected by blistering, along the subepidermal membrane. The results of the skin biopsy are sufficient to make the diagnosis of dermatitis herpetiformis. Many experts recommend a lifelong gluten-free diet based on the results of the skin biopsy alone, and an intestinal biopsy is not required.

Similar to celiac disease, anti-tTG antibodies are elevated in patients with dermatitis herpetiformis, confirming the pathogenetic relation of the diseases [79]. Although patients with dermatitis herpetiformis may have a symptomatic response to medications such as dapsone, complete resolution of the skin lesions in most patients will not occur without gluten withdrawal [80]. (See "Management of celiac disease in children", section on 'Dermatitis herpetiformis'.)

Dental enamel defects — Dental enamel defects involving the secondary dentition are more common among children and adults with celiac disease, and may occur in the absence of gastrointestinal symptoms [81]. The enamel defects considered to be specific to celiac disease are symmetrically distributed and detectable in all four quadrants of the dentition [82]. Defects may consist of cream, yellow, or brown opacities, loss of enamel glaze, horizontal grooves, or shallow pits (picture 3). The incisors are most commonly affected. The prevalence of enamel defects in children with celiac disease varies from 38 to 96 percent, as compared to 0.6 to 17 percent in control subjects [82,83]. There is some evidence that these defects are mediated by immunologic mechanisms (associated with the HLA allele DR3), and not by malabsorption of nutrients such as calcium [84]. Early identification and treatment of celiac disease may prevent the development of the enamel defects [85].

Metabolic bone disease — Bone loss (usually osteomalacia) occurs commonly in celiac disease and can occur in patients without gastrointestinal symptoms [86-89]. These patients have secondary hyperparathyroidism that probably is caused by vitamin D deficiency [90,91].

In children, metabolic bone disease generally resolves with a gluten-free diet [91-93]. In a study of 30 children and adolescents maintained on a long-term gluten-free diet (average 10.7 years), bone mineral density and serum markers of bone metabolism completely normalized [93].

In adults, metabolic bone disease generally improves on a gluten-free diet, including in those with clinically silent celiac disease. However, the abnormalities may not resolve entirely [88,90]. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disease'.) The American Gastroenterological Association (AGA) guideline for osteoporosis in gastrointestinal diseases [94], as well as other AGA guidelines, can be accessed through the AGA Web site at www.gastro.org/wmspage.cfm?parm1=4453.

Arthritis — About 25 percent of adults with celiac disease have arthritis [95]. In children, celiac disease is reported in 2 to 3 percent of those presenting with juvenile idiopathic arthritis or juvenile chronic arthritis [96,97].

Liver disease — Mild elevations in serum aminotransferases (AST and ALT) were seen in 42 percent of adult patients with celiac disease [98]. Conversely, celiac disease is found in 5 to 10 percent of adults with chronic elevations of aminotransferases [99]. Studies of children with celiac disease suggest that aminotransferase elevations are also common at diagnosis (32 to 54 percent), particularly in patients presenting with the classical symptoms of the disease [100,101]. In most patients the aminotransferases normalize with a gluten-free diet.

Patients with celiac disease also appear to have increased risks for a broad spectrum of liver diseases, including acute hepatitis, primary biliary cirrhosis, and chronic hepatitis including autoimmune hepatitis [102-104]. Several cases of severe liver disease with cirrhosis in children with celiac disease have been reported [105], but celiac disease is not established as a causative factor.

Iron deficiency — Celiac disease is a frequent cause of iron deficiency anemia in adults [106,107]. Consequently, iron deficiency anemia is an indication for celiac screening in adults. Although anemia is common among children with celiac disease, there is not good evidence that the prevalence of celiac disease is significantly increased among children with iron deficiency anemia [1].

Subclinical disease — The development and widespread availability of serologic screening has led to the understanding that celiac disease can exist in a very mild form and may go largely undetected because most patients have mild and nonspecific symptoms, such as fatigue, borderline iron deficiency, or otherwise unexplained elevations in serum aminotransferases [108,109], or no symptoms at all [89]. Sometimes the child's only overt problem may be short stature. Monosymptomatic forms of celiac disease have been reported such as severe constipation, anemia, dental enamel hypoplasia [110], delayed puberty, and sterility in women [111]. The most common type of anemia in celiac disease is caused by iron deficiency; megaloblastic anemia is rare. Serum iron, serum folate, and red cell folate are usually all reduced in patients older than 1 year. (See 'Iron deficiency' above.)

The range of symptoms in children with subclinical disease is illustrated by a study of children whose celiac disease was diagnosed through a screening program [37]. Most of these children had minimal gastrointestinal symptoms. However, there were numerous important clinical and laboratory findings, such as iron deficiency, recurrent abdominal pain, and mood changes (table 5). In another study, 31 percent of patients with subclinical disease (versus 67 percent with classic symptoms) were malnourished [112]. Once on a gluten-free diet, all reported objective and subjective improvement of well-being, as they recognized symptoms they had not previously considered to be abnormal.

Even in individuals with minimal symptoms, establishing and treating subclinical celiac disease may help to identify and treat unsuspected nutritional deficiencies, and to reduce the risk of low-birth-weight infants born to affected mothers. It is less clear whether these individuals have increased risk for malignancies or autoimmune diseases that might be reduced by treatment with a gluten-free diet.

Risk of malignancy — Several reports have suggested increased risk for some malignancies, particularly non-Hodgkin lymphoma and gastrointestinal cancers, in adults with celiac disease compared to the general population. The incidence of cancers does not appear to be increased during childhood or adolescence.

At least one study suggests that the risk for malignancy is reduced by long-term treatment with a gluten-free diet [113]. Although this has not been fully established, it is one of the rationales for recommending lifelong treatment for all patients with celiac disease, even for those with minimal gastrointestinal symptoms. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on Risk of malignancy.)

ASSOCIATED CONDITIONS — Celiac disease frequently is associated with Down syndrome, Williams syndrome, Turner syndrome, selective IgA deficiency, and several autoimmune conditions such as type 1 diabetes mellitus, and thyroid disease (table 2).

Diabetes mellitus — Celiac disease is associated closely with type 1 diabetes mellitus [114-117]. In several reports, between 2.6 and 7.8 percent of adults with type 1 diabetes had IgA autoantibodies to endomysium or to tissue transglutaminase; most such patients were proven to have celiac disease with small bowel biopsy [73,118]. Many such patients had no overt clinical manifestations of celiac disease [73]. Other reports have demonstrated that as many as 3.5 percent of children of parents with type 1 diabetes have celiac disease, the prevalence of which increases with age [41].

A causal relationship between celiac disease and diabetes mellitus has been suggested, but not established. A few studies in humans [119] and animals [120,121] suggest that celiac disease may trigger autoimmune processes leading to diabetes. One study noted that the prevalence of autoimmune diseases, including Type 1 diabetes mellitus, may be related to the duration of exposure to gluten, and may reach more than 30 percent in patients diagnosed with celiac disease after age 20 [122]. However, other observations suggest that celiac disease does not trigger diabetes: the age of onset and the severity of diabetes do not appear to be influenced by the presence of celiac disease [73] and celiac autoantibodies usually develop after the onset of diabetes [123]. Thus, larger and prospective clinical studies are required to clarify the relationship between celiac disease, type 1 diabetes, and other autoimmune disorders.

Whether a gluten-free diet improves diabetes in diabetic patients with celiac disease is unclear. Only two small studies, one retrospective [124] and one short-term [115], investigated the effect of a strict gluten-free diet on type 1 diabetics with silent celiac disease. Patients showed at best a trend toward an increased body mass index, but no change in folate or hemoglobin levels or insulin requirements. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Diabetes mellitus'.)

Other — Celiac disease occurs in up to 16 percent of individuals with Down syndrome [39] and up to 10 percent of individuals with selective IgA deficiency [43] or autoimmune thyroiditis [47]; the prevalence of celiac disease is also increased in Williams and Turner syndromes [1].

Weaker associations with primary biliary cirrhosis, as well as a variety of other liver diseases, have been described in adults. Evidence for these associations is described separately. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Associated conditions'.)

DIAGNOSIS — The steps to establishing a diagnosis of celiac disease are summarized here, and discussed in detail separately. The following guidelines are recommended by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition [1]. (See "Diagnosis of celiac disease".)

Diagnostic approach — The diagnosis of celiac disease typically requires both of the following:

  • The presence of characteristic histologic changes on small intestinal biopsy in a symptomatic individual.
  • Complete symptom resolution on a gluten free diet.

Serological tests that revert from positive to negative on a gluten-free diet may be used as supportive evidence of the diagnosis, and are particularly valuable in individuals with minimal symptoms.

The diagnosis is presumptively established when there is concordance between the serologic results and the biopsy findings. It is confirmed when symptoms resolve subsequently on a gluten-free diet. Demonstration of histologic normalization is no longer required.

Who to test — The benefit of screening for asymptomatic celiac disease has not yet been established by evidence-based criteria. Such a strategy could possibly result in recognition and correction of subclinical nutritional deficiency states, resolution of mild symptoms, and potentially decrease the risk for malignancy. However, there are few data to support these beneficial effects and the strategy would require many asymptomatic individuals to adhere to a difficult dietary regimen.

We agree with the NASPGHAN and international recommendations that serologic screening for celiac disease be performed in the following groups of children, provided they are on a gluten-containing diet [1,35].

Patients with the following clinical signs and symptoms, if not otherwise explained:

  • Failure to thrive
  • Persistent diarrhea
  • Chronic constipation, recurrent abdominal pain, or vomiting
  • Dental enamel hypoplasia of permanent teeth (symmetric distribution)
  • Idiopathic short stature
  • Significant pubertal delay
  • Iron deficiency anemia not responsive to supplementation

All members of the following high-risk groups:

  • First-degree relatives of patients with celiac disease
  • Autoimmune thyroiditis
  • Type 1 diabetes
  • Down syndrome
  • Turner syndrome
  • Williams syndrome
  • Selective IgA deficiency

In suggesting screening for asymptomatic individuals in these high-risk groups, these guidelines differ from those used for adults in the United States [4]. This difference in recommendations reflects a debate about the utility of screening for celiac disease among truly asymptomatic individuals belonging to a high-risk group, because the benefit of treating such individuals has not been proven. Guidelines from the United Kingdom encourage testing for the first three of these high-risk groups, and suggest consideration of testing for the other groups on this list, as well as for individuals with a variety of nonspecific symptoms [125]. (See "Diagnosis of celiac disease", section on 'Who should be tested'.)

The debate continues about whether asymptomatic individuals in these high-risk groups should be screened, and recommendations may change as new information arises about the potential risks and benefits of screening. As an example, a study of a celiac screening program for children with type 1 diabetes mellitus compared clinical characteristics of 71 children with asymptomatic celiac disease with matched controls [126]. The children with celiac disease were slightly thinner (as indicated by a lower body mass index z-score), but height, bone mineral density and diabetes control were similar. Thus, it is reasonable to question the need for celiac screening and the added burden of a gluten-free diet for patients with type 1 diabetes and no symptoms of celiac disease, and to make treatment decisions on a case-by-case basis, based on a discussion of estimated risks, symptoms, and treatment burden. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus".)

If screening is undertaken for asymptomatic individuals in these high-risk groups, testing should be performed at three years of age or older and on a gluten-containing diet for at least one year. If initial results are negative, screening tests should be repeated at intervals, or if symptoms develop. The optimal time interval for subsequent screening has not been studied, but in our practice, we screen asymptomatic members of these groups every three to five years during childhood.

Patients with dermatitis herpetiformis established by skin biopsy are presumed to have celiac disease and treated without other diagnostic studies. A baseline measurement of tTG-antibodies is valuable to monitor improvement after institution of a gluten free diet.

How to test — Serologic tests for celiac disease are useful for screening and are an important step in the diagnosis of the disease (table 6). Currently, the most valuable test is for antibodies against tissue transglutaminase (anti-tTG), which is highly sensitive, specific, and more cost-effective than other antibody tests. The diagnostic accuracy of IgA anti-tTG immunoassays has been optimized by the use of human tTG in place of the non-human tTG preparations used in earlier immunoassay kits. Using second-generation ELISA technology, the sensitivity and specificity of anti-tTG antibodies for biopsy-proven celiac disease are generally above 96 percent [1,127,128].

Immunofluorescence test for IgA antibodies to endomysium, a structure of the smooth muscle connective tissue, is also highly sensitive and specific [27]. However, this test is generally more expensive than anti-tTG, and its accuracy is more dependent on interpretation by laboratory personnel. Tests measuring IgG and IgA antibodies to gliadin are considerably less reliable [129], although a second generation anti-gliadin antibody test (Deamidated Gliadin Peptide (DGP)) yields far higher diagnostic accuracy [130]. Tests of antireticulin antibodies have reasonably high specificity, but lower sensitivity, and are no longer commonly used [131]. (See "Diagnosis of celiac disease", section on 'Serologic evaluation'.)

For most patients, we recommend measuring IgA antibodies to human recombinant tissue transglutaminase (tTG). This test is highly specific and sensitive, although false-positive and false-negative results may still occur with some frequency in populations with a low risk for celiac disease. Measurement of IgA antibodies to endomysium are equally accurate, but more expensive and somewhat dependent on interpretation error. (See 'Autoimmunity' above and "Diagnosis of celiac disease".)

For individuals with known selective IgA deficiency, testing should be performed with IgG antibodies to tTG instead of the usual IgA-based antibody test. Approximately 2 percent of children with celiac disease will have previously unrecognized IgA deficiency. Therefore, total IgA should be measured in children with negative results of IgA-tTG but a high clinical suspicion of celiac disease.

All individuals with positive tTG antibodies or antiendomysial antibodies should have an intestinal biopsy to establish the diagnosis of celiac disease. The biopsy should be performed with the patient on a gluten-containing diet. Multiple biopsies should be taken from the distal duodenum and duodenal bulb and interpreted by an expert pathologist; the disease may have a patchy distribution [132-134]. (See "Diagnosis of celiac disease", section on 'Diagnostic approach'.)

Who to treat — Treatment with a gluten-free diet is recommended for both diagnostic and therapeutic purposes for all children in one of the following groups:

  • Children with characteristic findings on intestinal biopsy and symptoms consistent with celiac disease (including nonspecific symptoms such as constipation or abdominal pain).
  • Children with characteristic findings on intestinal biopsy and belonging to one of the above high-risk groups (eg, relatives of patients with established celiac disease, or patients with type 1 diabetes), whether or not there are associated symptoms.
  • Patients with dermatitis herpetiformis confirmed by skin biopsy.

Patients with positive tests for tissue transglutaminase or anti-endomysial antibodies, but normal results of small bowel biopsies, are considered to have latent or potential celiac disease. We suggest NOT treating such patients with a gluten-free diet. However, it is important that the evaluation of such patients include expert review of multiple intestinal biopsies since the histologic abnormalities can be patchy. Furthermore, these patients should be carefully monitored for growth failure and other symptoms that might suggest active celiac disease, and should be rebiopsied if symptoms develop.

Treatment of individuals with confirmed celiac disease consists of a lifelong gluten-free diet. Details of treatment and monitoring are discussed separately. (See "Management of celiac disease in children".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Celiac disease in children".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

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