Pediatric Celiac Disease

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Background
Celiac disease (CD) is the most common genetically related food intolerance, worldwide. Celiac disease 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 present in wheat, rye, and barley), 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.
Within this definition, patients can further be defined as having silent, potential, or latent celiac disease. [2] The term silent celiac disease refers to patients fulfilling the definition above, but presenting no symptoms. Typically, such diagnoses are made by screening asymptomatic individuals who are at increased risk for celiac disease. The term potential celiac disease describes patients who have specific serum autoantibodies and may or may not have symptoms consistent with celiac disease, but lack evidence of the autoimmune insult to the intestinal mucosa. A final category of celiac patients is represented by the so-called latent celiac disease: individuals with normal mucosal morphology (like the potential) but known to have had a gluten-dependent enteropathy at some point in their life.
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.
Data from Rubio-Tapia et al [3] showed that undiagnosed celiac disease in the United States has dramatically increased in the past half century, going from 0.2% in the late 1940s to 0.9% 50 years later.

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. [4]
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. [5]
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. [6] 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])

Epidemiology
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. [7] Screening studies have shown that celiac disease has a very high prevalence, occurring in almost 1% of the general population throughout North America. [8, 9]
International
Celiac disease is as common in Europe as it is in North America, but it has now been detected in populations from many other parts of the world, including African and Middle Eastern countries, and in Asia, with the highest prevalence worldwide in Saharawi children. [10]
Furthermore, the prevalence of celiac disease appears to be increasing quite dramatically during the past few decades. [8, 11, 12, 9] In Northern Sweden, an epidemiological investigation using a combined serological/endoscopic approach in an unselected population of 1000 adults found a prevalence of almost 2%. [13]
Epidemiological data do document worldwide a true increase in prevalence, with rates doubling approximately every 20 years. A concomitance of environmental factors are likely responsible for this, but most of them are still unclear. Among the hypotheses to explain such increase are: the hygiene hypothesis, [14] increased rates of births through elective cesarean delivery, [15] changes in infant feeding practices as dramatically documented by the so-called Swedish epidemic, [16] and repeated infections—by rotavirus but also generic, nongastrointestinal infections in early infancy. [17]
A recent investigation in Sweden proved that early vaccinations are not risk factors for the development of celiac disease. [18]
A study reported that children living in socioeconomically deprived areas in the UK are less likely to be diagnosed with CD. The study added that increased implementation of diagnostic guidelines could result in better case identification in more-deprived areas. [19, 20]

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. [21, 22] Some indirect epidemiological evidence suggests that intestinal malignancies can be a cause of death in patients with undiagnosed celiac disease. [23]
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.

Patient Education
A consensus report by Ludvigsson et al stated that in adolescence, patients with CD should gradually assume exclusive responsibility for their own care, learning how to follow a gluten-free diet and the consequences of not following it. [24]

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. See the figures below.

The celiac iceberg.
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Presentations of celiac disease.
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Currently, [2] 5 possible presentations of celiac disease are recognized, as follows:
Typical: This presentation is primarily characterized by GI signs and symptoms.
Atypical: GI signs and symptoms are minimal or absent, and various extraintestinal manifestations are present.
Silent: The small intestinal mucosa is damaged, and celiac disease autoimmunity can be detected with serology; however, no symptoms are present.
Potential: Patients have a positive specific autoimmune serology and may or may not be symptomatic, but the mucosa morphology is normal. These individuals have genetic compatibility with celiac disease and full-blown celiac disease may develop at a later stage in some or all of these individuals.
Latent: Individuals with normal mucosal morphology who “have had a gluten-dependent enteropathy at some point in their life.” This subset of patients is the rarest of the group.
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. [25] GI symptoms in older children are typically less evident and include nausea, recurrent abdominal pain, bloating, constipation, and intermittent diarrhea.
A study by Mårild et al reported a two-way association between anorexia nervosa and celiac disease. The hazard ratio for future anorexia nervosa after celiac disease diagnosis was 1.46 and 1.31 beyond the first year. The odds ratio for a previous anorexia nervosa diagnosis associated with celiac disease was 2.18. [26, 27]
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. See the images below.

GI signs and symptoms of celiac disease.
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Extraintestinal manifestations of celiac disease.
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The main extraintestinal manifestations of celiac disease are as follows:
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 mostly the permanent dentition, although they have been described also in deciduous teeth. These changes may be the only presenting manifestation of celiac disease.
Aphthous ulcers: These can be present in children and in adults with celiac disease. At this time, it is unclear if these are associated with enamel defects, and their prevalence in celiac disease patients is variable. [28] Oral ulcers are neither characteristic nor specific for celiac disease since aphthous ulcers can also be associated with other medical conditions such as inflammatory bowel disease and Behçet disease. However, it should be noted that these ulcers often regress once the patients are on a gluten-free diet. [28]
Delayed tooth eruption: This has been reported in up to 27% of patients with celiac disease. [28] This is a nonspecific sign, possibly related to malnutrition, and in conjunction with the rest of the oral examination could raise the suspicion of the dental clinician about the possibility of celiac disease.
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. In children, iron deficiency with or without anemia is very common too, but seldom it is seen as the only presenting sign. Anemia can only be the result of folate, vitamin B-12 deficiency, and it may also coexist with anemia of chronic disease as a result of the chronic intestinal inflammation. In addition to anemia, a number of less common hematologic manifestations can be seen, including hyposplenism, thrombocytosis, and selective IgA deficiency. [29]
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]). [30] 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. [31] 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. [#fertilityandceliacdisease]
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. [32] 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.
Of interest, while the increased prevalence of celiac disease in patients with type 1 diabetes is well recognized, the reverse is not true: there seems to be no increased prevalence of type 1 diabetes in patients who had been diagnosed with celiac disease.
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.
A study by Mårild et al found that in a review of pathology records of 7548 females with CD in Sweden, that 20 of the patients (0.26%) also had a diagnosis of Turner syndrome. In contrast, among 34,492 age- and sex-matched controls in the general Swedish population, only 21 (0.06%) had a Turner syndrome diagnosis which corresponded to an odds ratio for celiac disease of 3.29 (95% confidence interval [CI], 1.94 – 5.56). [33, 34]

 

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