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Fast Facts: Celiac Disease
By Geoffrey Holmes, Carlo Catassi, Alessio Fasano
Health Press LimitedCopyright © 2009 Health Press Ltd.
All rights reserved.
Celiac disease, or gluten-sensitive enteropathy, is characterized by immune-mediated damage to the jejunal mucosa that is triggered in genetically susceptible individuals by gluten, a protein complex in wheat, rye and barley cereals. Definitions of celiac disease have revolved around abnormalities found in the jejunal mucosa as well as responses to gluten withdrawal and challenge and the associated clinical reactions. The finding that certain antibodies are markedly associated with celiac disease has added an important dimension to the definition of the disease. In practice, the diagnosis is usually straightforward and is based on:
typical serology of positive anti-endomysial (AEA) and anti-tissue transglutaminase antibodies (anti-tTG)
characteristic appearance of a small-bowel biopsy
satisfactory response to a gluten-free diet (GFD).
Furthermore, celiac disease develops in the context of a positive HLA-DQ2 and/or -DQ8 haplotype.
For many years, the mucosal changes in celiac disease have been described as total, subtotal or partial villous atrophy; more recently, in an effort to standardize reporting, the modified Marsh classification has been widely adopted for clinical use (Table 1.1). In this classification, types 3a, 3b and 3c equate to partial, subtotal and total villous atrophy, respectively, and are characteristic of untreated celiac disease. It is clear, however, that the range of gluten sensitivity is wider than previously realized; several forms of celiac disease are now identified, and the modified Marsh classification recognizes a spectrum of mucosal change from a mild to a severe abnormality (Figure 1.1). Factors such as the amount of ingested gluten, gastrointestinal infection or the stress of a pregnancy or operation may influence the gradual shift from a minimal-change enteropathy to the typical flat lesion characteristic of celiac disease.
Typical celiac disease
Typical celiac disease is characterized by the classic features of malabsorption, such as weight loss, chronic diarrhea, steatorrhea and, in infants, failure to thrive. Biopsies from the small intestine usually show types 3a to 3c mucosal lesions but occasionally damage can be less severe.
Atypical celiac disease
Atypical celiac disease is characterized by often isolated, usually extraintestinal, manifestations. These include chronic fatigue, anemia, short stature, pubertal delay, arthralgia and infertility. The degree of small-intestinal damage varies from a type 1 lesion to a fully expressed gluten-sensitive enteropathy (type 3c). Atypical forms are encountered more commonly than typical forms in clinical practice.
Silent celiac disease
Silent celiac disease is occasionally found following serological screening in patients who are asymptomatic. Not uncommonly, some report an improvement in psychophysical wellbeing with a GFD. The degree of small-intestinal damage can vary from a type 1 lesion to a fully expressed gluten-sensitive enteropathy (type 3c).
Potential celiac disease
Potential celiac disease is characterized by a type 1 lesion. Patients are positive for anti-tTG and/or AEA and/or subepithelial deposits of tTG-specific immunoglobulin A in the biopsy (Figure 1.2). They can be well or have intestinal symptoms that may respond to a GFD. In time, they may develop a flat mucosa.
Latent celiac disease
Patients with latent celiac disease have a normal biopsy while on a normal diet, but evidence of a flat or severely damaged mucosa at some other time while on a normal diet that recovers on a GFD.CHAPTER 2
Thirty years ago, celiac disease was considered to be a rare disorder affecting individuals of European origin, with onset of symptoms during the first few years of life. Diagnosis was based on the recognition of typical gastrointestinal symptoms and confirmed by small-intestinal biopsy. The introduction of highly sensitive and specific serological tests to detect, first, anti-gliadin (AGA) and, later, anti-endomysial (AEA) and anti-tissue transglutaminase antibodies (anti-tTG) showed an unsuspected high frequency of clinically atypical or even silent forms of celiac disease. Using these simple tests as a first-level screening procedure, a large number of studies have shown that celiac disease is one of the commonest lifelong disorders found worldwide (Figure 2.1).
In Europe, where many studies have been carried out, the prevalence of celiac disease mostly ranges between 0.5 and 1% of the general population, with a trend toward higher values (up to 2%) among genetically isolated groups (e.g. in Finland). This prevalence is far higher than for other permanent conditions, such as familial hypercholesterolemia, selective immunoglobulin A deficiency, type 1 diabetes mellitus and congenital hypothyroidism. Until recently, celiac disease was perceived to be rare in North America. This misconception has been corrected by a large screening study that has shown the prevalence in the US population to be about 1%, the same as in Europe. Similar disease frequencies have been reported from countries mostly populated by individuals of European origin (e.g. Canada, Brazil, Argentina, Australia and New Zealand).
Celiac disease is increasingly reported from areas of the developing world, particularly North Africa, the Middle East and India, where it contributes substantially to childhood morbidity and mortality. In the Saharawis, an Arab population living in Western Sahara, the prevalence is 5.6%. The reasons for this high figure are unclear, but could primarily relate to genetic factors and to the high level of consanguinity in this population. In North India, celiac disease is particularly common in the so-called 'celiac belt', a part of the country where wheat is a staple food. Clinical series from India usually describe typical cases, with chronic diarrhea, anemia and stunting being the commonest symptoms in children (Figure 2.2). However, atypical cases present with short stature, anemia, abdominal distension, rickets, constipation, type 1 diabetes and delayed puberty.
There are only anecdotal reports of celiac disease in other parts of the world (e.g. Sub-Saharan African countries, China, Japan and Central America). The genes predisposing to celiac disease are common throughout the world, however, with few exceptions (e.g. native Highlanders from Papua New Guinea) (Table 2.1). Furthermore, wheat is increasingly being consumed by populations that previously ate other staple cereals such as rice or millet (Figure 2.3). These factors suggest that celiac disease will be reported increasingly from countries that so far have been almost free from the disease. Celiac disease has been reported only rarely in African Americans, but it may be underdiagnosed.
The celiac iceberg
Remarkably, only a small proportion of celiac patients are diagnosed on clinical grounds. Most escape diagnosis unless identified by screening with serological markers, such as serum anti-tTG. In developed countries, 5–7 cases remain undiagnosed for each diagnosed case of celiac disease, even though the detection rate is rapidly increasing. These observations have led to the concept of the celiac iceberg, which is made up of:
a visible part, representing patients who are clinically diagnosed, usually because they are sick
a far bigger submerged portion that includes all individuals with gluten-sensitive enteropathy who remain undiagnosed, mostly because of atypical complaints or lack of symptoms (Figure 2.4).
The level of the water line, indicative of the ratio of diagnosed to undiagnosed cases, is primarily influenced by the physician's awareness of the protean manifestations of celiac disease and the threshold for requesting serological tests. Current evidence suggests that all celiac patients, regardless of the intensity of their symptoms, are exposed to the long-term complications of this condition, such as anemia, infertility, osteoporosis and lymphoma.
Genetic. Celiac disease tends to cluster in families (Figure 2.5). In identical twins, the concordance for celiac disease is about 70%, while 5–15% of first-degree relatives are affected. The disease risk for a sibling of an affected individual is about 20-fold higher than for the general population. The familial predisposition depends on human leukocyte antigen (HLA)-related and unrelated genes (see Chapter 3). HLA-DQ2 or HLA-DQ8 genes are necessary for disease development, but are not sufficient in isolation to cause disease. Many other genes involved in adaptive and innate immune responses, intestinal permeability and susceptibility to autoimmune diseases may also influence the risk.
Sex. The prevalence of celiac disease is 1.5–2-fold higher in women, similar to ratios noted for some other autoimmune conditions. It should be noted, however, that these figures are derived from diagnoses made in clinics after biopsy. In general, women are more likely than men to visit their doctor and therefore are likely to have more tests that bring celiac disease to light. When the seroprevalence of celiac disease in the population is considered, this difference between the sexes narrows considerably or disappears.
Diet. The amount and the quality of gluten in the diet may play a role, as well as other dietary components. A protective peptide has been found in durum wheat and beans. Current research is focused on the possible role of early nutritional factors in the later development of celiac disease. The risk of celiac disease seems to be reduced in infants who receive prolonged breastfeeding.
Infections. Intestinal infections can facilitate the immune responses leading to celiac disease. Antibodies directed against the VP7 capsid component of rotaviruses, a common cause of diarrhea worldwide, appear to cross-react with tTG, the major autoantigen in celiac disease.
Other diseases. The prevalence of celiac disease is increased in some patients with other autoimmune disorders, perhaps because of disturbed immunity and shared HLA genotypes (Table 2.2).
Celiac disease did not exist in the Paleolithic time when hunter–gatherers ate meat, fish, vegetables, pulses and fruit. Cultivation of wheat and barley was first exploited some 10 000 years ago in the so-called 'Fertile Crescent', an area that extends from the Mediterranean Coast on its Western extreme to the great Tigris–Euphrates plain eastward. Farming spread from here and reached the Western edge of Europe some 6000 years ago. According to an old theory, the spread of wheat consumption exerted a negative selective pressure on genes predisposing to celiac disease. This could explain the higher frequency of the disease in Northern Europe, which until relatively recently had a low exposure to cereals. This theory did not survive recent epidemiological developments, as the HLA-related haplotypes predisposing to celiac disease do not show a clear-cut East–West gradient of prevalence. Furthermore, the overall prevalence of celiac disease is not lower in Middle Eastern countries than in Europe, as should be the case if the longer history of agriculture tended to eliminate the genetic predisposing backbone.
Is the incidence of celiac disease changing?
During the last 2 or 3 decades, the incidence of celiac disease has risen in many countries, generally in association with an increase in the age at diagnosis. This is readily explained by a greater awareness of the many clinical presentations of celiac disease and the availability of accurate screening tests that allow the recognition of atypical or even silent forms of the disease that previously would have been overlooked.
However, it appears that the overall prevalence of celiac disease is also increasing. The prevalence doubled in Finland over 20 years, from 1% in 1978–80 to 2% in 2000–01 (Figure 2.6). According to the hygiene hypothesis, the main factor underlying the increased prevalence of celiac disease and other autoimmune diseases in developed countries is the reduction in the incidence of infectious diseases. An early childhood infection could down-regulate immunity and suppress autoimmune disorders. Alternatively, the increased prevalence of celiac disease could reflect changes in environmental factors that influence the risk of developing celiac disease, such as the duration of breastfeeding and the amount of gluten ingested.
Is mass screening for celiac disease worthwhile?
Celiac disease would appear to fulfill the criteria for mass screening.
It is a potentially serious condition that produces significant morbidity.
Early clinical detection is often difficult.
If not recognized early, it can present with severe complications, such as malignancy, osteoporosis and neurological problems, which are difficult to manage.
A gluten-free diet is an effective therapy.
Sensitive, simple and cheap screening tests are available.
However, the time for mass celiac disease screening has not yet come, as important pieces of information are still lacking. A deeper understanding of the natural history of the condition is needed to ascertain the outcome in the many affected individuals who escape a clinical diagnosis and to determine whether they are susceptible to the complications affecting those patients diagnosed clinically. Given the variable timing of gluten sensitization, the age at which screening should be performed has not been clarified. Furthermore, the negative impact of the gluten-free diet on the long-term psychosocial quality of life should be considered when measuring the cost/benefit of mass screening.
Currently, the best approach to the iceberg of undiagnosed celiac disease is a systematic process of case-finding focused on at-risk groups, such as relatives of patients or those with type 1 diabetes, a procedure that minimizes costs and is ethically appropriate. Increased awareness of the clinical polymorphism of celiac disease, coupled with a low threshold for serological testing, can efficiently uncover a large portion of the submerged part of the iceberg. Primary care is the natural setting for selective screening programs.CHAPTER 3
Celiac disease is a multifactorial disorder that depends on both genetic and environmental factors for expression. The disease appears to be specific to humans, and the lack of an animal model has hampered research. Although the pathogenesis of celiac disease is not yet completely understood, there is evidence to indicate that it is an autoimmune disorder triggered and maintained by an external antigen, namely gluten, in the diet.
The term gluten is generically applied to a family of storage proteins found in wheat, rye and barley (8–14% by weight) (Figure 3.1). All the proteins that are harmful to patients with celiac disease are rich in proline and glutamine, and are collectively called prolamins. The prolamin fractions of the various cereals carry different names: gliadin (wheat), secalin (rye) and hordein (barley). The prolamins of oats (avenin) account for only 5–15% of the total seed protein, which could partly explain why celiac patients may tolerate oats in the diet.
The toxic protein fractions of gluten are not only gliadins (alcohol soluble) but also glutenins (alcohol insoluble), with gliadins containing monomeric proteins and glutenins containing aggregated proteins. The protein components and amino acid sequences of gliadins and glutenins are similar and repetitive. In a single wheat variety, there are approximately 45 different gliadins, which can be subdivided into α, γ, and ω subfractions according to their electrophoretic mobility. This complexity has made gluten a difficult substance to investigate within the context of celiac disease.
The sequence of A-gliadin, a protein made up of 266 amino acids, has been determined. The amino acid sequence(s) responsible for celiac disease have not been fully elucidated. Different parts of the gliadin molecules show different biological properties, all potentially involved in the pathogenesis of the disease (Figure 3.2). Several human leukocyte antigen (HLA)-DQ2-restricted T-cell epitopes have been found clustering in proline-rich regions of gliadin. A gliadin peptide of 33 residues, α2-gliadin 57–89, has been identified. It is produced by normal gastrointestinal proteolysis and contains six partly overlapping copies of three T-cell epitopes. This 33-mer is an immunodominant peptide that is a remarkably potent T-cell stimulator after deamidation by intestinal tissue transglutaminase (tTG). Other sequences of Agliadin (e.g. amino acids 31–43) have been shown to activate innate immunity mechanisms or interact with CD8+ cytotoxic T cells.
Excerpted from Fast Facts: Celiac Disease by Geoffrey Holmes, Carlo Catassi, Alessio Fasano. Copyright © 2009 Health Press Ltd.. Excerpted by permission of Health Press Limited.
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Table of Contents
ContentsGlossary of abbreviations, 4,
Clinical manifestations, 39,
Non-malignant complications, 72,
Dermatitis herpetiformis, 83,
Malignant complications, 91,
Future trends, 116,
Useful resources, 124,