Gluten-related disorders include celiac disease (CD), wheat allergy, and nonceliac gluten sensitivity. CD is an autoimmune enteropathy caused by damage to small intestinal mucosa when gluten is ingested in genetically susceptible individuals. Currently, the only available treatment of CD is gluten-free diet. Several potential treatments are being researched. Wheat allergy is a hypersensitivity reaction caused by IgE-mediated and/or non-IgE-mediated immune response, and can involve the gastrointestinal tract, skin, or respiratory tract. Nonceliac gluten sensitivity is one of a variety of immunologic, morphologic, or symptomatic manifestations precipitated by ingestion of gluten in individuals in whom CD and wheat allergy are excluded.
Key points
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Celiac disease is found in genetically susceptible individuals who carry the HLA DQ2 or DQ8 gene.
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Celiac serology testing is a good screening tool.
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The gold standard for diagnosis is still an upper endoscopy to acquire small bowel biopsies.
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Currently the only available treatment is gluten-free diet.
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NCGS can be considered in those without evidence of celiac disease and wheat allergy who have clinical improvement on a gluten-free diet.
Introduction
Celiac disease (CD) is an autoimmune enteropathy that causes damage to the small intestinal mucosa when gluten, found in wheat, barley, and rye, is ingested, which only occurs in genetically susceptible individuals. Innate gluten sensitivity, adaptive gluten sensitivity, and autoimmunity are essential in the development of CD.
The prevalence of CD has been increasing worldwide, most likely because of greater awareness and better testing. Gluten has a high concentration of glutamine and proline residues referred to as prolamines, which are specifically found in wheat, barley, and rye. It is thought that under stressful situations, such as infection or surgery, the gliadin protein enters the lamina propria where it is deaminated by the enzyme tissue transglutaminase (tTG) and then it becomes attached to it to form a complex. This specific complex is then presented to the antigen-presenting cell resulting in secretion of proinflammatory mediators. This process ultimately produces intestinal inflammation resulting in crypt hyperplasia and villous atrophy. CD should also be considered in certain populations with an increased prevalence of CD, such as those with selective IgA deficiency, first-degree relatives of patients with CD, autoimmune thyroiditis, type I diabetes, Down syndrome, Turner syndrome, and Williams syndrome.
Introduction
Celiac disease (CD) is an autoimmune enteropathy that causes damage to the small intestinal mucosa when gluten, found in wheat, barley, and rye, is ingested, which only occurs in genetically susceptible individuals. Innate gluten sensitivity, adaptive gluten sensitivity, and autoimmunity are essential in the development of CD.
The prevalence of CD has been increasing worldwide, most likely because of greater awareness and better testing. Gluten has a high concentration of glutamine and proline residues referred to as prolamines, which are specifically found in wheat, barley, and rye. It is thought that under stressful situations, such as infection or surgery, the gliadin protein enters the lamina propria where it is deaminated by the enzyme tissue transglutaminase (tTG) and then it becomes attached to it to form a complex. This specific complex is then presented to the antigen-presenting cell resulting in secretion of proinflammatory mediators. This process ultimately produces intestinal inflammation resulting in crypt hyperplasia and villous atrophy. CD should also be considered in certain populations with an increased prevalence of CD, such as those with selective IgA deficiency, first-degree relatives of patients with CD, autoimmune thyroiditis, type I diabetes, Down syndrome, Turner syndrome, and Williams syndrome.
Epidemiology
CD occurs in genetically susceptible individuals, but the pattern of genetic inheritance is still somewhat obscure. The prevalence of CD is about 1% within the United States and Europe, and this may be even higher in certain Northern European countries. It is now becoming a common disorder in North Africa, the Middle East, and India. However, the diagnostic rates are low in these regions because of low availability of diagnostic facilities and poor disease awareness. It is thought that the increase in prevalence is also attributed to the adaptation of Western gluten-rich dietary patterns. Many new diagnoses are also being made through screening individuals who are at risk because of family history of CD.
Symptoms
The range of symptoms present in CD is a wide spectrum. Individuals may have the classic symptoms of abdominal pain with diarrhea or constipation, neurologic manifestations, or be completely asymptomatic. Symptoms are described as typical, atypical, and latent. Table 1 lists the specific symptoms according to their categories. The classic, or typical symptoms, usually emerge in the pediatric age and consist of diarrhea, abdominal pain, and weight loss, and poor growth. The atypical presentations include osteoporosis, dermatitis herpetiformis, peripheral neuropathy, short stature, delayed puberty, dental enamel hypoplasia, and anemia. A mild elevation of serum liver enzymes is well described as an initial presentation of CD in pediatric patients. Headaches, seizures, and psychiatric symptoms are also associated with CD.
| Typical | Atypical | Latent |
|---|---|---|
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The latent form of CD is defined as having a predisposing gene, normal biopsy findings, and weakly positive serologies. It is thought that environmental factors affect the disease’s clinical presentation, the time at presentation, and the characteristics of the disease. Theories are now emerging in regards to infectious agents playing a role, at least on the timing of the presentation.
Diagnosis of celiac disease
Until the 1950s, CD was a clinical diagnosis based on observations focused on malabsorptive features. Now, the first step in determining if a patient has CD is to obtain serologies. The sensitivity and specificity of detecting CD is now close to 95% or greater, despite its checkered past. The antigliadin antibodies were first developed in the 1980s, but showed a sensitivity and specificity between 80% and 90%. The endomysial antibody (EMA) was developed next in the mid-1980s, which was found to be highly accurate, but difficult to standardize. This assay requires monkey esophagus or human tissue as a substrate, and an individual reading the sample, adding to interobserver variability. Despite the disadvantages, the sensitivity and specificity of EMA is found to be greater than 90%. In the late 1990s, tTG was identified as a CD autoantigen and it has now become the test of choice not only for diagnosis, but also for monitoring CD, given its sensitivity of 99%. The accuracy of deaminated gliadins is controversial. It seems to be the most sensitive and specific in those younger than 3 year old. It is important to remember that a total IgA level should always be ordered to assess for selective IgA deficiency, because it is the most common immune deficiency in children If this is truly present, it will lead to false-negative results. Of note, low levels of IgA that are not deficient will not affect the test specificity. However, if an individual truly has selective IgA deficiency, serologic testing offers little advantage over directly proceeding to intestinal biopsy to establish the diagnosis. Table 2 lists the antibody tests available and their associated sensitivities and specificities.
| Sensitivity % | Specificity % | |
|---|---|---|
| AGA IgA | 69–85 | 73–90 |
| AGA IgG | 75–90 | 82–95 |
| DGP IgA | 74–99 | 90–99 |
| DGP IgG | 63–95 | 90–99 |
| EMA (IgA) | 85–98 | 97–100 |
| tTG IgA | 90–99 | 94–99 |
| tTG IgG | 45–95 | 94–97 |
HLA testing should also be considered during a work-up for CD. It is known that 95% of those with CD are HLA DQ2 positive and the rest are HLA DQ8 positive. However, about 40% of the general population also carries one of these genes, making genetic testing poorly specific. This test may be of benefit in those who are asymptomatic with negative serologies, but belong to an at-risk group. The high negative predictive value of genetic testing allows one to eliminate the possibility of ever developing the disease.
The gold standard for diagnosis is still with a small intestinal biopsy when an individual is consuming gluten, to document duodenal damage, mainly villous atrophy. Gross findings during an upper endoscopy include scalloping of the duodenal mucosa ( Fig. 1 ). However, if this is not present, it does not exclude a diagnosis, because the microscopic changes are mainly consistent with a diagnosis. The characteristic histologic features include infiltration of lymphocytes in the epithelium (>25 lymphocytes per 100 epithelial cells), increased density and depth of crypts, and varying degrees of villous atrophy. This progression was first described by Marsh in 1992, and his scoring system, from stage 0 (normal) to stage 3 (villous blunting) subsequently modified by Oberhuber and colleagues, is now widely used by pathologists ( Table 3 for Marsh classification). Biopsy findings are not necessarily pathognomonic and are seen in other conditions. Box 1 provides a list of other causes of villous atrophy occurring in the duodenum. It is the constellation of clinical, histologic, and serologic findings, and response to therapy, that ultimately provide a confirmation of a CD diagnosis ( Figs. 2–4 ).
| Marsh 0 | Marsh 1 | Marsh 2 | Marsh 3A | Marsh 3B | Marsh 3C |
|---|---|---|---|---|---|
| No histologic changes | Increased IEL | Increased IEL with crypt hyperplasia | Increased IEL, crypt hyperplasia, partial villous atrophy | Increased IEL, crypt hyperplasia, subtotal villous atrophy | Increased IEL, crypt hyperplasia, total villous atrophy |
Marasmus
Crohn disease
Giardiasis
Autoimmune enteropathy
Drug induced (ie, olmesartan)
Graft-versus-host disease
AIDS-associated enteropathy
Intestinal lymphoma
Tropical sprue
