Definitions and Epidemiology
Celiac disease (CD) is “a permanent sensitivity to gluten in wheat and related proteins found in barley and rye, occurring in genetically susceptible individuals, and manifesting as an immune mediated enteropathy as defined by characteristic changes seen on intestinal histology.”1 A conservative definition requires the following:
- typical signs or symptoms;
- presence of CD-associated antibodies;
- a small intestinal biopsy showing villous atrophy;
- resolution of clinical manifestations with a gluten-free diet (GFD), including complete healing of the intestinal mucosa;
- reduction or disappearance of the CD-associated antibodies on a GFD.
In practice, it is questionable whether it is necessary to meet all aspects of this definition. Controversy continues about whether a small bowel biopsy is required to diagnose CD. Because of numerous reports of CD-associated seropositive individuals with no signs or symptoms of CD, guidelines continue to require a biopsy to confirm the diagnosis and need for treatment.
- Classic CD refers to a presentation with typical clinical features such as diarrhea, abdominal pain, failure to thrive, or abdominal distention.
- Atypical CD describes a non-traditional presentation, primarily with extraintestinal manifestations, such as arthritis or iron deficiency anemia. In older children and adults, the atypical presentation may be more common than the “classic” presentation.
- Silent CD describes the situation of an individual without signs or symptoms of CD, but who has small bowel biopsy evidence of CD; usually these patients have an associated condition or a family history of CD, and are identified on screening as having CD-associated antibodies.
- Latent CD applies to individuals without signs or symptoms of CD, but who have some risk for future development of CD, such as expression of CD-related antibodies or DQ2 or DQ8 permissive genes, family history of CD, or having an associated condition. These individuals do not have small bowel biopsy changes, but may have CD-associated antibodies.
- Refractory CD describes an individual with defined CD who continues to have signs or symptoms of active CD despite pursuing a GFD. In this situation, considerations include considered exposure to gluten, enteropathy-associated T-cell lymphoma (EATL), or possibly another condition such as allergy or inflammatory bowel disease.
The prevalence in the United States and Europe is roughly 3–13 cases per 1000 individuals (1:300 to 1:80).1 There is a female predominance with a ratio of roughly 2:1.2 These estimates indicate that there are approximately 3 million people with CD in the United States alone, and a roughly equal number in Europe, of which 90% are undiagnosed (Table 18–1). Recent screening studies suggest that in developing countries in Africa, parts of Asia, and South America, the frequency is similar to that of the U.S. and European countries.3 To date, there are very little data exploring the rates of CD in China, Japan, and Southeast Asian countries, and these populations are thought to be at lower genetic risk for CD. A number of conditions are associated with an increased risk of CD in children and adults (Table 18–2).
|1:66 to 1:119
|1:99 to 1:67
|1:166 to 1:104
|Prevalence of CD (%)
|Type 1 diabetes
|First-degree relatives with CD
|Short stature/delayed puberty
|Dental enamel defects
|• Irritable bowel syndrome
|• Persistent aphthous stomatitis
|• Peripheral neuropathy
|• Unexplained cerebellar ataxia
|• Elevated transaminases
|• Unexplained iron deficiency anemia
|• Decreased bone mineral density
Specific HLA types are permissive for development of CD. HLA molecules bind peptide antigens and present them to CD4+ helper T cells. An estimated 95% of CD patients express the HLA-DQ2 gene and the remainder express DQ8.5 HLA II molecules are made up of dimers, expressing one alpha and one beta chain. The vast majority of CD patients express the HLA II subtype DQ2 coded by alleles DQA1*0501 and DQB*0201, or DQ8 coded by alleles DRB*04-DQA1*03-DQB1*0302. The DQ2 dimer contains specific pockets that bind deamidated gluten peptides and present them to CD4+ lymphocytes. Expressing two copies of HLA-DQ2 (homozygous state) increases the risk for developing CD, and an estimated 25% of CD patients are DQ2 homozygous. The genes coding for HLA II are located on chromosome 6p21, termed the CELIAC1 locus.
However, other genetic factors are important, and the absolute necessity of DQ2/DQ8 for development of CD has been questioned, as apparent cases of CD occur in individuals who do not express DQ2 or DQ8.2,4 The DQ2 gene is expressed by approximately 30% of Caucasians, but only 3% of these develop CD. Having a first-degree relative with CD increases the risk of CD to between 5% and 18%.4 There is an estimated 70–86% concordance in monozygotic twins with CD, but only 30–40% with HLA-matched twins, and less than 20% concordance in dizygotic twins and first-degree relatives.6 Expression of DQ2 or DQ8 only accounts for approximately 36–53% of the disease risk. Therefore, other genetic and environmental factors are important.7,8 Gene linkage analysis and genetic-associated studies, including genome-wide association studies, have identified a number of other loci of possible importance in CD5,9 (Tables 18–3 and 18–4).
|Contains RGS1, regulator of G protein signaling molecule. Involved in B-cell activation/proliferation; found in intestinal intraepithelial lymphocytes
|2 genes coding for receptor for IL-18 that stimulates T-cell synthesis of IFN-gamma
|Large cluster of chemokine receptor genes CCR1, CCR2, CCR3, CCR5, CCRL2, and XCR1
|Immediately 5′ of IL-12 gene. IL-12 induces Th1 IFN-gamma secretion
|Associated with LPP gene of unclear significance
|Strongest current association with CD outside HLA locus. Cluster of 8 associated single nucleotide polymorphisms; 2 contain genes for IL2 and IL21, involved in T-cell activation. Associated with type 1 diabetes and rheumatoid arthritis
|Contains TAGAP gene (T-cell activation GTPase-activating protein) expressed in activated T cells
|Contains LNK and ATXN2—strongly expressed in monocytes, dendritic cells, and small intestine
The exact mechanism by which ingestion of gluten proteins by genetically susceptible individuals leads to immune-mediated intestinal injury remains unclear (Figure 18–1). An inciting event such as a viral infection, plus additional genetic factors, may be important to development of CD. Both innate and adaptive immunity are thought to be involved.
Cartoon highlighting steps involved in pathogenesis of CD.41 Gluten peptides survive digestion and cross the mucosal epithelium, where deamidation by tissue transglutaminase (TG2) occurs. HLA-DQ2 or -DQ8 molecules on antigen-presenting cells present these peptides in the intestinal lamina propria where they are recognized by specific CD4+ T cells Adapted by permission from Ref.41 (Macmillan Publishers Ltd).
Gluten proteins are found in wheat and related grains, and can be divided into gliadin and glutenin components. Hordeins in barley and secalins in rye are equivalent proteins that promote the CD process. The oat avedin protein is more distantly related to Triticeae glutens, and seems to be non-immunogenic for most CD patients.10
Several properties of gluten may be important in stimulating the immune response of CD:
- Gliadin stimulation of IL-15 secretion through a non-HLA-binding mechanism.
- Gliadin induction of zonulin expression in small intestinal epithelium, with subsequent increase in intestinal permeability, CD4+T-cell antigen exposure, and alteration in cell morphology.
- The high proline (15%) and glutamine (35%) content confers important chemical properties to gluten. First, gluten peptides resist human acid and peptic digestion, and reach the intestinal mucosa in antigenic segments. Second, constitutively expressed tissue transglutaminase (TTG) in the small intestine alters gliadin peptides by deamidating specific glutamine residues to the negatively charged glutamate. Individuals with CD express antibodies to both TTG and deamidated gliadin peptides; these antibodies are specific serologic markers for CD. Deamidated gliadin peptides show enhanced binding to specific pockets in the DQ2 molecule, resulting in enhanced presentation to CD4+T cells by local antigen-presenting cells (APCs).
Both activated APCs and CD4+ T cells secrete increased amounts of inflammatory cytokines such as IFN-gamma and IL-15, causing local recruitment of fibroblasts and clonal expansion of cytotoxic intraepithelial lymphocytes (IELs). The increased numbers of IELs and the subsequent mucosal damage are the classic changes seen on intestinal biopsy of CD patients.
Well-recognized clinical presentations of pediatric CD include: failure to thrive, chronic diarrhea, distended abdomen, irritability, constipation, and growth or pubertal delay (Table 18–5).1,11 Extraintestinal manifestations such as arthritis, iron deficiency anemia, dental enamel defects, and dermatitis herpetiformis (DH) are also common. Asymptomatic children may be identified on screening because of increased risk due to having an associated condition or a family history of CD or diabetes (Table 18–2). Recently, a variety of presentations have been imputed to be related to undiagnosed CD in adults (Table 18–2). These include neuropsychiatric presentations such as ataxia and epilepsy, as well as infertility. Because the signs and symptoms may be mild, vague, and non-specific, delays in diagnosis are common.11–13
|Failure to thrive*
|Dental enamel defects*
|Epilepsy +/– cerebral calcifications†
|Abnormal liver function tests*
|Pubertal delay/short stature*
|Recurrent fetal loss†
“Celiac crisis” is a rare medical emergency characterized by explosive, watery diarrhea and dehydration/electrolyte imbalances, marked abdominal distension, hypotension, and lethargy. It is typically seen in toddlers and responds to corticosteroids within a few days.
With institution of a GFD, symptoms often improve by the second week, but may take months to completely resolve. Normalization of the intestinal histology may take 6–12 months. Lactose intolerance tends to resolve within a few weeks. Treatment of nutritional deficiencies, such as iron deficiency, is generally not needed over long term. Adults tend to improve more slowly.
For those with silent or latent CD, continued exposure to gluten leads to eventual clinical manifestations in at least some individuals.14 Data from the adult literature also show a mortality risk significantly above the standard mortality rate (SMR) by a factor of two- to three-fold for patients not adhering to a GFD, not responding to the GFD, or with lengthy delay in diagnosis.15 There is reasonable evidence that early compliance with a GFD reduces the risk of mortality to close to baseline.16