Version May 2024
INTRODUCTION — Celiac disease, also known as gluten-sensitive enteropathy, is a common immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals. It differs from food allergies (including wheat allergy), which are mediated by immunoglobulin (Ig) E or IgG. The appropriate treatment is a lifelong gluten-free diet to mitigate the associated mucosal inflammation and prevent future adverse complications, which may include intestinal lymphoma.
The epidemiology, pathogenesis, and clinical manifestations of celiac disease are reviewed here. Other aspects of celiac disease in children are discussed in the following topic reviews:
●(See "Diagnosis of celiac disease in children".)
●(See "Management of celiac disease in children".)
EPIDEMIOLOGY
General population — Celiac disease is a common chronic condition, with a pooled global prevalence of 1.4 percent [1] but can be much higher in certain regions. In a prospective birth cohort study of infants at risk for celiac disease in Europe and the United States, the estimated incidence was as high as 3 percent in Sweden and 2.4 percent in Colorado [1,2]. Besides region of birth, a family history of celiac disease, female sex, and amount of gluten consumed in early life are important factors in disease risk. Females are affected approximately twice as often as males, although the ratio varies depending on the strategy used to find cases [3-5].
Celiac disease is also common in some non-European populations, including northern Africa, the Middle East, and South Asia [1,4]. The prevalence in South America varies considerably by country [6-10]. Celiac disease was previously thought to be uncommon in Asia, but a meta-analysis found pooled seroprevalence of 1.2 in the general population in the Asia-Pacific region [11], and a report based on serologic testing among adolescents and young adults in China specifically suggests that the prevalence may be as high as 0.76 percent in regions where wheat is a prominent part of the diet [12]. The prevalence in some resource-limited countries is probably underestimated due to limited access to diagnostic testing and confounding by other diarrheal diseases that cause small intestinal injury. Overall, the global distribution of the disease seems to parallel the distribution of human leukocyte antigen (HLA) genotypes that predispose to celiac disease, provided that the population is also exposed to gluten [2,13].
Access to medical care and case-finding bias likely play a role in some of the observed differences between populations [14]. Decisions about diagnostic testing should be based on symptoms, signs, and risk factors, without regard to the individual's ancestry or race/ethnicity. (See "Diagnosis of celiac disease in children".)
High-risk groups — The prevalence of celiac disease, as detected by screening programs using specific antibodies, is substantially increased in the following groups compared with the general population (table 1). Because of the increased risk, we suggest routine screening for celiac disease in asymptomatic children with these conditions [15], although this approach is somewhat controversial (see "Diagnosis of celiac disease in children", section on 'Members of high-risk groups'):
●First- and second-degree relatives of individuals with celiac disease
●Autoimmune disorders/immunodeficiency:
•Type 1 diabetes
•Autoimmune thyroiditis
•Juvenile idiopathic arthritis
•Autoimmune liver disease
•Selective IgA deficiency
●Genetic syndromes:
•Down syndrome
•Turner syndrome
•Williams syndrome
For these groups, th e risk of celiac disease is approximately 3- to 10-fold higher than in the general population. Evidence for these associations is discussed below.
●Relatives of individuals with celiac disease – The prevalence of celiac disease is approximately 7.5 percent (1:13) for first-degree relatives of people with celiac disease and approximately 2.3 percent (1:43) for second-degree relatives [16]. The risk is higher in female relatives of the proband compared with male relatives.
●Autoimmune disorders/immunodeficiency
•Type 1 diabetes – Celiac disease is associated closely with type 1 diabetes mellitus [17-19]. Publications report a wide range of prevalence depending on the region and method of screening. In one systematic review, up to 16 percent of children with type 1 diabetes had celiac disease diagnosed by intestinal biopsy [20]. Children with type 1 diabetes are commonly asymptomatic at the time of celiac disease diagnosis [21]. Of note, celiac disease and type 1 diabetes share HLA susceptibility alleles [22], but the co-occurrence of the disorders is not fully explained by shared high-risk HLA and non-HLA genetic loci [19]. Interestingly, there is also regional variation in the prevalence of celiac disease in children with type 1 diabetes, suggesting the importance of environmental factors [23]. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus", section on 'Celiac disease'.)
•Autoimmune thyroiditis – Approximately 2 to 7 percent of individuals with autoimmune thyroiditis develop celiac disease [24-26]. The association is weak during childhood and appears to increase with age [27]. Conversely, individuals with celiac disease have up to a fourfold risk of autoimmune thyroiditis. The clinical course of the thyroiditis does not appear to be affected by a gluten-free diet, although data are mixed [28-33]. Antithyroid antibodies at diagnosis have a low predictive value for the development of thyroid hypofunction [31]. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Autoimmune thyroiditis'.)
•Rheumatic diseases – Celiac disease is reported in 2 to 3 percent of children presenting with juvenile idiopathic arthritis, many of whom have no gastrointestinal symptoms [34,35]. Conversely, a Swedish population-based study of children with known celiac disease found a nearly threefold increased risk of developing juvenile idiopathic arthritis [36].
The association between celiac disease and other pediatric rheumatic diseases such as systemic lupus erythematosus is less clear [35].
•Autoimmune liver disease – Children with autoimmune hepatitis also have a higher risk of celiac disease, with a systematic review and meta-analysis finding a pooled prevalence for celiac disease of 3.6 percent [37]. Weaker associations with primary biliary cirrhosis and primary sclerosing cholangitis have also been described [38]. Evidence for these associations is described separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Associated conditions'.)
More commonly, a cryptogenic hypertransaminasemia (also referred to as a celiac hepatitis) is seen in children with untreated celiac disease (pooled proportion 36 percent) [37]. This condition typically resolves during treatment with a gluten-free diet.
•Selective IgA deficiency – Approximately 0.63 to 9.9 percent of individuals with selective IgA deficiency have celiac disease. Conversely, 0.5 to 16.7 percent of individuals with celiac disease may have IgA deficiency [39].
Patients with known IgA deficiency require special strategies when screening for celiac disease because most serologic tests for celiac disease are IgA antibodies. In addition, the possibility of undiagnosed IgA deficiency should be explored when performing serologic screens by measuring a total IgA level, if not already done. (See "Diagnosis of celiac disease in children", section on 'Special populations'.)
●Genetic syndromes – Other disorders possibly associated with celiac disease include:
•Down syndrome – Celiac disease develops in 5 to 12 percent of individuals with Down syndrome [40-43]. Pooled prevalence estimates for celiac disease are 1:13 (7.6 percent), approximately a sixfold increase in risk over the general population, and some studies even point to an 18-fold higher incidence [40,44]. The mechanism for this association is unclear, although it is consistent with the propensity for other autoimmune diseases among individuals with Down syndrome. One theory is that trisomy 21 leads to an activated interferon response, resulting in an increased risk of autoimmunity [45]. (See "Down syndrome: Clinical features and diagnosis", section on 'Immunodeficiency' and "Down syndrome: Clinical features and diagnosis", section on 'Gastrointestinal abnormalities'.)
•Turner syndrome – In a systematic review, the pooled prevalence estimate for celiac disease in Turner syndrome was 4.5 percent [46]. As in Down syndrome, the mechanism of this increased risk is unknown [47].
•Williams syndrome – Up to 10.8 percent of individuals with Williams syndrome have celiac disease, based on limited data [48,49]. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Autoimmune disorders' and "Williams syndrome".)
PATHOGENESIS AND RISK FACTORS — Celiac disease is caused by an inappropriate immune reaction to dietary gluten and related proteins in genetically predisposed individuals. The common grains that contain the triggering proteins are wheat, barley, and rye. Ingestion of these proteins by a susceptible individual causes immune-mediated mucosal inflammation of the proximal small intestine, with villous atrophy and crypt hyperplasia (figure 1), which often leads to malabsorption and gastrointestinal symptoms. The immune response is mediated by gliadin-reactive T cells, in contrast with wheat allergy, which is mediated by IgE or IgG. The intestinal lesions and symptoms resolve when gluten is eliminated from the diet. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Pathogenesis' and "Management of celiac disease in children", section on 'Principles of a gluten-free diet'.)
Genetic factors — The genetic basis of the disease is shown by the frequent intrafamilial occurrence and the remarkably close association with the human leukocyte antigen (HLA) DR3-DQ2 and/or DR4-DQ8 gene locus. More than 99 percent of individuals with celiac disease have HLA DR3-DQ2 and/or DR4-DQ8, compared with approximately 40 percent of the general population [50]. Among individuals with celiac disease, approximately 90 percent will have DQ2 and the remainder will have DQ8. Homozygotes for DR3-DQ2 are at the highest risk for celiac disease, which develops in approximately 11 percent of individuals with this genotype by five years of age [51]. While the presence of either the HLA-DQ2 or DQ8 genotype is essential to confer disease, it is not alone sufficient and other genetic, epigenetic, and environmental factors have also been implicated [6]. In rare instances, individuals without these genotypes develop celiac disease [52].
Because of common genetic contributors, several groups are at increased risk for celiac disease (see 'High-risk groups' above). The genetic contributors to celiac disease are discussed in detail separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Genetic factors'.)
Feeding practices in infancy and early childhood — The pathogenesis of celiac disease at any age requires exposure to gluten. Efforts to reduce the risk of celiac disease have focused on the initial timing and amount of gluten exposure and whether breastfeeding or the use of hydrolyzed formula (avoidance of cow's milk protein) reduce the risk of developing celiac disease.
●Breastfeeding and gluten exposure – A preponderance of evidence suggests that the timing of initial gluten introduction during infancy and breastfeeding does not appear to affect celiac disease risk [53]. However, studies indicate that the quantity of gluten in the infant's diet plays a role, such that greater amounts of gluten consumption are associated with higher disease risk in genetically predisposed children. Overall, these studies cannot be translated into clinical practice yet and further research is needed to understand how the amount of gluten may interact with other environmental triggers such as upper respiratory or gastrointestinal infections. Therefore, feeding recommendations should continue to follow standard pediatric guidelines set by each governing body.
Evidence supporting this guidance includes:
•Timing of gluten introduction – Observational studies initially suggested that the timing of gluten introduction (particularly either early introduction before four months of age or late introduction after seven months of age) increased the risk of celiac disease in genetically predisposed individuals [54-59]. However, a subsequent multicenter prospective observational study and two randomized trials failed to confirm this hypothesis and reported no association between the timing of gluten introduction or breastfeeding and celiac disease risk [60]. The role of gluten introduction in celiac disease prevention remains controversial, with another open-label randomized clinical trial finding decreased celiac disease risk in infants who were introduced to gluten (in fairly high quantities) between four to six months of age [61]. Celiac disease was not a primary endpoint of this study, and the results were limited by a small sample size and available parameters for the definition of celiac disease cases. Overall, timing of gluten introduction may play a role in disease risk, but study results are conflicting.
•Quantity of gluten exposure – The quantity of gluten in the infant's diet may affect celiac disease risk or the age of presentation. In a prospective observational multinational study of 6605 children with genetic predisposition for celiac disease due to their HLA antigen genotype, the quantity of gluten exposure during the first five years of life was associated with development of celiac autoimmunity and confirmed celiac disease [62]. A Norwegian prospective cohort study similarly found that higher gluten intake at 18 months of age increased the risk of later development of celiac disease [63].
A separate study found that the amount of gluten consumed between 11 and 36 months of age did not influence the risk of developing celiac disease [64]. Long-term follow-up of these children is needed to determine whether the amount of gluten consumed at an early age ultimately has any effect on the subsequent development of celiac disease.
●Cow's milk protein – Avoidance of cow's milk protein during the weaning period does not appear to reduce the risk for celiac disease autoimmunity or celiac disease. This was shown in a randomized trial of 230 infants who were considered at risk for celiac disease because of their HLA type and at least one family member having type 1 diabetes [65]. Infants weaned to an extensively hydrolyzed formula did not have decreased risk for tissue transglutaminase (tTG) positivity or celiac disease compared with those weaned to a cow's milk-based formula, with up to 10 years follow-up. Observational data from the TEDDY study parallel this finding of no association between milk powder in early childhood and celiac disease risk [66].
Additional trigger factors — In some cases, celiac disease in genetically predisposed individuals may be precipitated by a separate risk or trigger factor in addition to gluten exposure. Prior intestinal infections, and, in particular, infection with rotavirus or enterovirus, are more common in children with celiac disease than in those without [67-69]. If true, the precise mechanisms by which these events affect the onset of disease remain unclear. Exposure to antibiotics is probably not a risk factor, although more research is needed on the effect of the microbiome in disease pathogenesis [70,71].
CLINICAL MANIFESTATIONS — In the past, celiac disease classically presented in infants and young children with malabsorption and failure to thrive. Now, with the increasing recognition of subclinical and nonclassical presentations and widely available serologic testing, celiac disease is often diagnosed in older children with milder gastrointestinal or non-gastrointestinal manifestations [72]. Despite the advancing age at diagnosis and fewer classical presentations, data indicate that celiac disease develops early in childhood (before 10 years) [73], even among those who are not diagnosed until later in life.
"Classical" gastrointestinal symptoms — Classically, celiac disease presented between 6 and 24 months of age, after the introduction of gluten into the diet [27]. 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. Although rare, a few severely affected infants may present with the hemodynamic and metabolic consequences of dehydration, known as a celiac crisis.
Gastrointestinal symptoms in older children and adults are similar but usually less pronounced. In a European collaborative study, symptoms of malabsorption were the most common gastrointestinal manifestation in children under age three, while abdominal pain was the most common gastrointestinal symptom in older children [74].
Paradoxically, the disease may cause either diarrhea (64 percent) or constipation (8 percent) [75]. When diarrhea is present, the stools are often bulky and foul-smelling and may float.
Non-gastrointestinal manifestations — Numerous non-gastrointestinal manifestations of celiac disease have been described (table 2). In some patients, non-gastrointestinal symptoms are the primary presenting complaint and should prompt the consideration of serologic testing. Conditions associated with celiac disease in adults are described in detail separately [76]. (See 'Phenotypes' below and "Diagnosis of celiac disease in children" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)
●Growth and development – Children who develop symptomatic celiac disease often have delayed linear growth. Indeed, between 8 and 10 percent of children with apparent "idiopathic" short stature have serologic evidence of celiac disease [27]. The growth delay may occur even when weight-for-height is relatively normal and in the absence of significant gastrointestinal symptoms [77-79]. Thus, the growth attenuation is probably not entirely attributable to undernutrition. On the other hand, young children with persistently positive celiac-specific antibodies but without symptoms generally have normal growth, suggesting that the effects of celiac disease on growth probably depend on disease severity and/or duration [80]. In children with growth delay, catch-up growth is typically rapid during the first year after starting a gluten-free diet and continues for up to three years, although, in some children, catch-up growth may be incomplete [81].
Studies from the United States, Europe, and Australia report that a substantial number of children (up to 12 percent) have overweight or obesity at the time that celiac disease is diagnosed, although the prevalence of obesity tends to be somewhat lower than in the local population [82-85].
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 [86-90]. Boys with untreated celiac disease have reduced levels of serum dihydrotestosterone in a pattern suggesting androgen resistance [27,86]. Treatment with a gluten-free diet appears to prevent these problems. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Menstrual and reproductive issues'.)
●Behavioral and neurologic symptoms
•Short-term – Subclinical or subtle behavioral or neurologic abnormalities appear to be common and tend to resolve on a gluten-free diet, as shown in these studies:
-Subtle behavioral abnormalities were demonstrated in a study of 3.5-year-old children, in which those with persistently positive tissue transglutaminase (tTG) antibodies on a gluten-containing diet were more likely to manifest behavioral symptoms (anxiety, depression, aggressive behavior, or sleep problems) compared with those with negative antibody tests [91]. Unlike previous studies, the parents were unaware of the child's elevated tTG at the time that they reported the symptoms, avoiding that potential bias. This finding was no longer observed at 4.5 years of age. A similar screening study in school-aged children also reported a modest association between tTG antibody positivity and anxiety symptoms [92]. Finally, in a cross-sectional study of children with celiac disease (from the pre-coronavirus disease 2019 [COVID-19] era), clinically significant concerns for anxiety and depression were present in over one-third of patients, with the majority unrecognized by parents and caregivers [93].
-Subclinical neurologic abnormalities were suggested by a study of children with newly diagnosed celiac disease, in which almost 20 percent had subclinical neurologic abnormalities [94]. Among 27 children, two had peripheral polyneuropathy documented with electromyography, one had prolonged latencies in somatosensory evoked potential, and two had central magnetic resonance imaging abnormalities consisting of pontine demyelination or cortical atrophy. Similarly, there is some evidence of regional brain hypoperfusion in adults with untreated celiac disease [95]. In most, but not all, such conditions, improvement was observed after treatment with a gluten-free diet [96-99].
•Long-term – Celiac disease may be associated with a modestly increased risk of neurobehavioral disorders in long-term follow-up. The best evidence comes from a large case-control study in Sweden, which found that individuals with childhood-onset celiac disease had a 1.4-fold increased risk of developing a neurobehavioral or psychiatric disorder in long-term follow-up (median follow-up 9.6 years), including mood, anxiety, eating, and behavioral disorders; attention deficit hyperactivity disorder (ADHD); autism spectrum disorder; and intellectual disability [100]. This higher risk was not observed in siblings of the patients with celiac disease, arguing against a genetic component. Other less robust studies also suggest an association between celiac disease and mood disorders, behavioral disorders, developmental delay, ADHD, headache, and cerebellar ataxia [97,101-103].
Epileptic disorders are only slightly more common among children with celiac disease, and there is no increase in frequency of tic disorders. Conversely, celiac disease does not appear to be overrepresented in groups of children with neurologic or psychiatric disorders [102,104].
Reports of neurologic and neuropsychiatric symptoms in adults with celiac disease are discussed separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Neuropsychiatric'.)
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 tTG-IgA deposition around blood vessels in the cerebellum has been described [105]. In particular, antiganglioside antibodies may be involved in the pathogenesis of neurologic symptoms [106], although relevant studies have yielded somewhat conflicting results. These findings suggest that an immune-mediated process may lead to gluten ataxia and/or peripheral neuropathy [105,107].
●Liver disease – Studies of children with celiac disease suggest that aminotransferase elevations are also common at diagnosis (15 to 35 percent), particularly in patients presenting with the classical symptoms of the disease [37,108,109]. In most patients, the aminotransferases normalize with a gluten-free diet. In adults, similar mild elevations in serum alanine aminotransferase or aspartate aminotransferase were seen in 42 percent of adult patients with celiac disease [110]. Conversely, celiac disease is found in 5 to 10 percent of adults with chronic elevations of aminotransferases [111].
Patients with celiac disease also appear to have increased risks for a broad spectrum of liver diseases, including acute hepatitis, primary biliary cholangitis (previously known as primary biliary cirrhosis), and chronic hepatitis including autoimmune hepatitis [112-115]. Several cases of severe liver disease with cirrhosis in children with celiac disease have been reported [116], but celiac disease was not established as a causative factor. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Liver disease'.)
●Iron deficiency – The prevalence of iron deficiency is increased among children with celiac disease and appears to be correlated with severity of mucosal injury. In one prospective study, the prevalence of low ferritin (defined in this case as <10 micrograms/mL) was 21 percent in patients with "potential" celiac disease, 35 percent in those with partial villous atrophy, and 87 percent among those with total villous atrophy, compared with 0 percent in healthy controls [117]. Conversely, a systematic review and meta-analysis found that celiac disease was found in approximately 3 percent of individuals with iron deficiency anemia [118]. For this reason, testing for celiac disease is indicated in children with iron deficiency anemia who have no other clear reason for the deficiency.
●Dermatitis herpetiformis – Dermatitis herpetiformis is a common skin manifestation of celiac disease, occurring in up to 24 percent of adult patients with celiac disease [119,120]. It is rare in children, but cases have been reported [121,122]. Similar to celiac disease, antibodies to tTG are elevated in patients with dermatitis herpetiformis, confirming the pathogenic similarities between these diseases [123].
Approximately 85 percent of adult patients with dermatitis herpetiformis have the characteristic changes of celiac disease on intestinal biopsy, although most have no gastrointestinal symptoms. Dermatitis herpetiformis is less common prior to puberty but has been reported in patients as young as eight months old [124,125].
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 1A-B). It is commonly misdiagnosed as atopic dermatitis, scabies, or linear IgA dermatosis [126]. The clinical manifestations and diagnosis of dermatitis herpetiformis are discussed separately. (See "Dermatitis herpetiformis", section on 'Clinical findings'.)
Many experts recommend a lifelong gluten-free diet based on the results of the skin biopsy alone, and an intestinal biopsy is not required. Although patients with dermatitis herpetiformis may have a symptomatic response to medications such as dapsone, the skin lesions usually will not resolve without gluten withdrawal [127]. (See "Dermatitis herpetiformis", section on 'Treatment'.)
●Dental enamel defects – Dental enamel defects involving the secondary dentition are more common among children and adults with celiac disease compared with the general population and may occur in the absence of gastrointestinal symptoms [128-130]. The enamel defects considered to be specific to celiac disease are symmetrically distributed and detectable in all four quadrants of the dentition [129]. Defects may consist of cream, yellow, or brown opacities; loss of enamel glaze; horizontal grooves; or shallow pits (picture 2). The incisors are most commonly affected. There is some evidence that these defects are mediated by immunologic mechanisms (associated with the human leukocyte antigen [HLA] allele DR3) and not by malabsorption of nutrients such as calcium [131]. Early identification and treatment of celiac disease may prevent the development of the enamel defects [132].
●Metabolic bone disease – Bone loss (usually osteomalacia) occurs commonly in untreated celiac disease and can occur in patients without gastrointestinal symptoms [78,133-137]. These patients have secondary hyperparathyroidism that is probably caused by vitamin D deficiency [138,139]. Children with a lower body mass index at diagnosis may be at higher risk of metabolic bone disease [140].
In children, metabolic bone disease generally resolves with a gluten-free diet [137,139,141,142]. 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 [142].
●Arthritis – Arthralgias or arthritis are reported by approximately 10 percent of children at diagnosis of celiac disease [143], sometimes with few or no gastrointestinal symptoms [34]. In some cases, the symptoms are attributable to co-occurring juvenile idiopathic arthritis, which is associated with celiac disease. (See 'High-risk groups' above.)
It is uncertain whether treatment with a gluten-free diet improves arthritic symptoms. Most reports of children with celiac disease and arthritis experience improvement in joint effusions and arthritic symptoms after initiating a gluten-free diet [34,144,145], but one study of children with confirmed juvenile idiopathic arthritis reported a more severe disease course among those with celiac disease [146].
Subclinical disease — Many individuals with celiac disease have mild and nonspecific symptoms, such as fatigue, anemia (usually due to iron deficiency), attenuated growth, or otherwise unexplained elevations in serum aminotransferases [78,147,148], or no symptoms at all [136].
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 [149]. Most of these children had minimal gastrointestinal symptoms. However, there were numerous important clinical and laboratory findings, such as recurrent abdominal pain, mood changes, and iron deficiency. In another study, 31 percent of patients with subclinical disease (versus 67 percent with classic symptoms) were malnourished (defined as body weight less than 90 percent of ideal) [150]. 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, especially fatigue and abdominal pain.
Even in individuals with minimal symptoms, establishing and treating subclinical celiac disease may help to identify and treat unsuspected nutritional deficiencies and to reduce adverse birth and pregnancy outcomes. It is less clear whether these individuals have increased risk for autoimmune diseases or malignancies 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 with the general population. The incidence of cancer does not appear to be increased during childhood or adolescence.
A few studies suggest that the risk for malignancy is reduced by long-term treatment with a gluten-free diet. 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 "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Prognosis'.)
PHENOTYPES — Historically, celiac disease was defined by its 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 subcategories of celiac disease. According to the Oslo criteria, celiac disease can be categorized as classic, nonclassic, subclinical, symptomatic, asymptomatic, or potential, depending on the clinical phenotype (table 3) [151]. This classification scheme helps to identify patients who present with different clinical features and to monitor those who do not meet full diagnostic criteria for celiac disease.
NONCELIAC GLUTEN SENSITIVITY — Nonceliac gluten sensitivity (NCGS) describes a syndrome of symptomatic response to gluten ingestion in patients with no serologic or histologic evidence of celiac disease. The most common complaints are abdominal pain, bloating, and/or change in bowel patterns, but some patients complain of extraintestinal symptoms. The onset is typically within hours or a few days of ingesting gluten. This time course distinguishes NCGS from the rapid onset of symptoms in wheat allergy (minutes to hours) but can overlap with the delayed onset of symptoms in celiac disease (days to weeks) (table 4) [15].
●Pathophysiology – In many patients with symptoms that they attribute to gluten, gluten is probably not the specific trigger. The symptoms are not replicated on double-blind gluten challenge, suggesting a placebo or non-gluten-related physiologic effect. An example of the latter are adults whose gastrointestinal symptoms appear to be induced by the fermentable, poorly absorbed short-chain carbohydrates (fermentable oligo-, di-, and monosaccharides and polyols [FODMAP]). Since these sugars are also reduced in a gluten-free diet, the clinical response may result from reduction in the oligosaccharides rather than from elimination of the gluten itself [152]. These patients are probably more accurately categorized as having irritable bowel syndrome triggered by oligosaccharides rather than NCGS. (See "Treatment of irritable bowel syndrome in adults", section on 'Gluten avoidance'.)
In a smaller number of patients with these symptoms, it appears that gluten itself is the specific trigger for symptoms, in which case, they are appropriately categorized as NCGS. The most compelling evidence comes from a double-blind, placebo-controlled crossover food challenge in Italian children with suspected NCGS, based on reported symptomatic response to dietary gluten and lack of serologic evidence of celiac disease or IgE-mediated allergy to wheat or gluten. NCGS was confirmed in 39 percent of subjects, based on the development of symptoms in response to the gluten challenge (with no change in FODMAP content) [153]. NCGS was disproven in the remaining 61 percent. The estimated prevalence of NCGS in children with functional gastrointestinal symptoms was between 0.3 and 1 percent.
For a subset of individuals who appear to react to gluten-containing grains, another possible trigger of symptoms is the presence of amylase trypsin inhibitors (ATIs), which are found in grains including wheat, rye, and barley. ATIs are a group of proteins that contribute to the natural defense against pests and pathogens and have been proposed to activate the innate immune system [154]. (See "Grain allergy: Allergens and grain classification".)
Together, these studies suggest that a clinical response to a gluten-free diet may be caused by a variety of mechanisms, including placebo effect and FODMAP reduction, as well as by true NCGS in fewer than one-half of patients.
●Diagnosis – For children with symptoms that they attribute to gluten, it is important to rule out both celiac disease and IgE-mediated wheat allergy. Serologic testing (and further evaluation for celiac disease, if indicated) should be performed before eliminating gluten from the diet because these tests may be falsely negative if performed while on a gluten-free diet. Individuals with positive testing should be referred to a pediatric gastroenterologist for further workup because positive serology alone does not confirm the diagnosis. The diagnostic evaluation for celiac disease is discussed separately (see "Diagnosis of celiac disease in children", section on 'Initial serologic testing'), including strategies for evaluating patients who are already on a gluten-free diet. (See "Diagnosis of celiac disease in children", section on 'Special populations'.)
The possibility of NCGS may be entertained if celiac disease and wheat allergy have been excluded. However, no tests can reliably distinguish those with true NCGS from those with irritable bowel syndrome or other symptoms that are not specifically related to gluten. Therefore, the diagnosis of NCGS should be approached with caution and should not be based solely on a short-term improvement in symptoms on a gluten-free diet. Neither antigliadin antibodies nor other serologic biomarkers can reliably identify patients with NCGS [155], nor is there a genetic test for this condition. The diagnosis of NCGS relies on patient-reported symptoms but can be made more objectively by use of a standardized questionnaire before and six weeks after instituting a gluten-free diet, or by use of a double-blind gluten challenge and crossover in patients already on a gluten-free diet [156]. However, a rigorous double-blind gluten challenge is difficult to implement in a clinical setting and is rarely performed except in research studies.
Before a patient with suspected NCGS embarks on a gluten elimination diet, the patient and family should be educated on the possible reasons for a clinical response to this diet and counseled on the potential nutritional deficiencies associated with a gluten-free diet. Involving a knowledgeable dietitian in the care of children who are beginning a gluten-free diet is highly recommended. There are no known long-term complications of NCGS. Therefore, the gluten-free diet may not need be as strict as that for celiac disease and treatment may be based solely on symptom control.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Celiac disease" and "Society guideline links: Dermatitis herpetiformis".)
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●Basics topic (see "Patient education: Celiac disease (The Basics)")
●Beyond the Basics topic (see "Patient education: Celiac disease in children (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Celiac disease is an immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically sensitive individuals. The grains that contain the triggering proteins are wheat, barley, and rye. The small intestinal mucosa improves morphologically when treated with a gluten-free diet and relapses when gluten is reintroduced. (See 'Pathogenesis and risk factors' above.)
●Epidemiology and risk factors – Celiac disease is common, occurring in 0.5 to 1 percent of the general population in most countries, but is as high as 2 to 3 percent of the population in certain regions. The prevalence of celiac disease is substantially increased in first- and second-degree relatives of patients with celiac disease and in individuals with certain genetic syndromes, type 1 diabetes mellitus, selective IgA deficiency, and several autoimmune conditions (table 1).
We suggest routine surveillance for celiac disease in pediatric patients in high-risk groups, although this approach is somewhat controversial. This is discussed separately. (See 'High-risk groups' above and "Diagnosis of celiac disease in children", section on 'Indications for testing'.)
●Clinical manifestations
•Gastrointestinal – Classic gastrointestinal symptoms of patients with celiac disease include symptoms of malabsorption such as diarrhea, steatorrhea, weight loss, or other signs of nutrient or vitamin deficiency. (See '"Classical" gastrointestinal symptoms' above.)
•Extraintestinal – Some patients with celiac disease have non-gastrointestinal manifestations, in addition to or instead of gastrointestinal symptoms. The most specific extraintestinal manifestation is dermatitis herpetiformis, which is uncommon prior to puberty (picture 1A-B). Other extraintestinal manifestations include delayed growth and pubertal development, neurologic disease and behavioral symptoms, arthritis, dental enamel defects, liver disease, and iron deficiency (table 2). (See 'Non-gastrointestinal manifestations' above.)
●Phenotypes of celiac disease
•Classic celiac disease is characterized by gastrointestinal and/or other symptoms outlined above, with associated villous atrophy on small intestinal biopsy (picture 3A-B), and resolution of the clinical symptoms and mucosal lesions upon withdrawal of gluten-containing foods. (See 'Phenotypes' above.)
•Other phenotypes of celiac disease including nonclassic, subclinical, asymptomatic, and potential are summarized in the table (table 3). (See 'Phenotypes' above.)
●Nonceliac gluten sensitivity (NCGS) – This describes a syndrome of symptomatic response to gluten ingestion in patients with no serologic or histologic evidence of celiac disease or wheat allergy. In many patients with symptoms that they attribute to gluten, gluten is probably not a specific trigger. In a smaller number of patients with these symptoms, it appears that gluten itself is the specific trigger for symptoms, in which case, they are appropriately categorized as NCGS. (See 'Nonceliac gluten sensitivity' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ivor D Hill, MD, who contributed to earlier versions of this topic review.
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