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Acknowledgment
The author gratefully acknowledges the important and valuable contributionsof the authors of previous editions, Drs. Ciaran P. Kelly, Jerry S.Trier, and Richard J. Farrell.
Definitions
Celiac disease is a chronic, immune-mediated enteropathy that is precipitated by dietary gluten in genetically predisposed individuals. Gluten is the commonly used term for the complex of water-insoluble proteins from wheat, rye, and barley that is harmful to patients with celiac disease. Celiac disease is characterized by villus atrophy of the small intestinal mucosa associated with malabsorption of nutrients, clinical and subsequent histologic improvement after adoption of a gluten-free diet (GFD), and clinical and histologic relapse when gluten is reintroduced.
Celiac disease exhibits a wide spectrum of clinical presentations. In the past, typical celiac disease (now called classical celiac disease ) denoted a clinical presentation with signs and symptoms of malabsorption, such as diarrhea, steatorrhea, weight loss, and nutritional deficiencies. The term is now questionable, however, because in modern clinical practice, most patients do not present with these so-called typical manifestations. In contrast, presentations previously described as atypical celiac disease and now termed nonclassical celiac disease (e.g., anemia, fatigue, abdominal bloating and discomfort, osteoporosis, infertility) are now more common. Asymptomatic celiac disease (also called silent celiac disease ) is usually identified by screening using celiac disease-specific serology and is characterized by duodenal villus atrophy in individuals who lack symptoms or signs of celiac disease. Potential celiac disease denotes those with normal small intestinal histology who are at increased risk of developing celiac disease (usually identified by positive celiac disease-specific serology). Nonresponsive celiac disease (NRCD) is defined as ongoing or recurrent symptoms or signs that suggest active celiac disease despite a strict GFD for more than 6 to 12 months. Refractory celiac disease (RCD, a subset of NRCD) is defined as symptomatic, severe small intestinal villus atrophy despite a strict GFD for more than 6 to 12 months. RCD is a diagnosis of exclusion that is not explained by inadvertent gluten ingestion, other causes of villus atrophy, or overt intestinal lymphoma. Celiac disease serology denotes serology tests that specifically identify untreated celiac disease and includes immunoglobulin (Ig)A or IgG tissue transglutaminase (tTG), IgA or IgG endomysium antibodies (EMAs), and IgA or IgG deamidated gliadin peptide (DGP) antibodies. (IgA or IgG antigliadin antibodies (AGAs) are generally excluded because they are relatively nonspecific.) Nonceliac gluten sensitivity refers to symptoms or signs that develop upon gluten ingestion in people in whom a diagnosis of celiac disease has been excluded. The Oslo definitions for celiac disease and related terms provide a more comprehensive elucidation of definitions currently used in celiac disease.
History of Celiac Disease
Celiac disease was recognized as a clinical entity by Aretaeus the Cappadocian in the first century ad . The name sprue was coined in the 18th century and is derived from the Dutch word spruw , which means “aphthous disease,” so named because of the high prevalence of aphthous mouth ulcers in these patients. In 1888, Samuel Gee published his paper “On the Coeliac Affection,” which described many of the clinical features of celiac disease in patients of all age groups and concluded, “If the patient can be cured at all it must be by means of the diet.” It was not until the middle of the 20th century, however, that the link between certain cereals and celiac disease was made by Willem Karel Dicke, a Dutch pediatrician. He became convinced that the consumption of wheat flour was directly responsible for the deterioration in patients suffering from this condition. During the Dutch Famine in World War II, cereals used to make bread were severely scarce in the Netherlands and, during this time, children with celiac disease improved, only to relapse after the supply of cereal was reestablished at the end of the war. This observation confirmed Dicke’s previous observations that wheat ingestion exacerbated celiac disease. Subsequent work by Dicke’s group showed that it was the water-insoluble portion, or gluten moiety, of wheat that produced intestinal injury in patients with celiac disease.
In 1954, Paulley provided the first accurate description of the characteristic intestinal lesion in patients with celiac disease. With the development of effective peroral suction biopsy instruments in the late 1950s, Rubin and coworkers demonstrated that celiac disease in children and idiopathic or nontropical sprue in adults were identical diseases with the same clinical and histopathologic features.
Since the 1980s, we have seen substantial advances in our understanding of the genetic, immunologic, and molecular mechanisms fundamental to the pathogenesis of celiac disease. In 1986, Howell and associates observed that celiac disease was associated with specific HLA-DQ2 haplotypes. In 1993, Lundin and colleagues demonstrated that HLA-DQ2 preferentially presents gluten-derived gliadin peptides to activate intestinal mucosal T cells in celiac patients. Subsequently, the enzyme tTG (more specifically tTG type 2 [tTG2]) was identified as a celiac autoantigen, which led to more accurate serologic diagnostic tests. In 1998, Molberg and colleagues reported that modification of gliadin by host tTG2 enhances gliadin-specific celiac disease T-cell responses. The identification of specific tTG-modified DGPs as dominant α-gliadin T-cell epitopes highlighted the pivotal role played by tTG2 in the pathogenesis of celiac disease.
Epidemiologic studies using EMA and tTG serology have substantially increased estimates of celiac disease prevalence in the USA as well as the breadth of celiac disease prevalence worldwide. This in turn has led to renewed interest in potential nondietary treatments including gluten detoxification, glutenase therapy, modifiers of small intestinal tight junction function, tTG2 inhibitors, and immune-based interventions including attempts to reverse intolerance to gluten.
Epidemiology
Epidemiologic studies using specific celiac serology testing indicate that celiac disease has a wide geographic distribution and affects individuals from multiple and diverse ethnic and racial backgrounds. The overall prevalence of celiac disease in Europe has been estimated at 1%, with the highest reported prevalence of 2.4% in Finland. Factors such as predominant HLA haplotype, timing of introduction of gluten into the diet, differences in the gliadin concentration of infant formulas, and interobserver variation in interpreting small intestinal biopsy findings might explain differences in prevalence. Celiac disease is particularly prevalent in the Punjab region of northwest India, where wheat rather than rice has, for many generations, been a staple of the diet. The condition has been reported in blacks, Arabs, Hispanics, Israeli Jews, Sudanese of mixed Arab-black descent, and Cantonese and is particularly high among the Saharawi population in northwest Africa. Peoples rarely affected include those of purely sub-Saharan African, African-Caribbean, or Southeast Asian (including Chinese or Japanese) descent. Some authors have noted a female-to-male ratio of 2:1, whereas others have reported equal prevalences in men and women. Most studies measuring diagnosed celiac disease, however, have found a female predominance, suggesting that men are more likely to remain undiagnosed.
Studies in the USA indicate that the prevalence of celiac disease is comparable with that in Europe. A large multicenter study by Fasano and coworkers determined the prevalence of EMAs in more than 13,000 at-risk and not-at-risk American subjects to be 1 in 22 and 1 in 39 among first-degree and second-degree relatives of subjects with celiac disease, respectively. Of most significance, these investigators found a prevalence of antiendomysial antibodies of 1:133 among 4126 “not-at-risk” subjects. An analysis of the National Health and Nutrition Examination Survey (NHANES) in 2009-2010 found that the prevalence of celiac disease (diagnosed and undiagnosed) in the USA was 0.7%. Within the USA, prevalence of celiac disease varies by ethnicity, with individuals of Punjab Indian ethnicity having the highest prevalence.
The population prevalence of celiac disease appears to be increasing. In 1 USA study, tTG seropositivity was 0.2% among 9133 subjects whose blood samples were stored circa 1950 compared with 0.9% in comparable, modern-day sera, suggesting a substantial (4-fold) increase in celiac disease prevalence over time. The estimated prevalence of celiac disease has also risen in Finland, from 1% in 1980 to 2% in 2000. The reason in the rise in seroprevalence has not been identified, but environmental triggers of celiac disease have been proposed (see section later, Environmental Factors ) . Diagnosis rates appear to be changing in the USA. Whereas greater than 80% of cases were undiagnosed in the NHANES during 2009-2010, fewer than 50% were undiagnosed in 2013-2014. This may be due to increased awareness of celiac disease and widespread interest in the GFD in the population at large.
Epidemiologic studies using celiac serology indicate that asymptomatic or minimally symptomatic celiac disease is more common than diagnosed or symptomatic disease. A Finnish study of 3654 schoolchildren of ages 7 to 16 years, using 2 serologic screens with EMA and tTG antibodies, demonstrated that 1 in every 99 children had biopsy-proved celiac disease, although only 10 of 56 subjects (18%) with a positive serology had overt symptoms of celiac disease. Two subjects with elevated antibodies and HLA-DQ2 haplotype had normal mucosa consistent with potential celiac disease. Another study demonstrated fluctuations in tTG2 serology positivity over time in children with potential celiac disease. In the latter study, 12 of 39 children (31%) with potential celiac disease developed villus atrophy over 3 years of follow-up. Thus, there appears to be individual variation in the natural history of celiac disease, at least in children, where tTG2 seropositivity and celiac enteropathy may fluctuate over time.
Pathology
Celiac disease affects the mucosa of the small intestine. The mucosal lesion can vary considerably in severity and in extent. Examination under magnification of the small intestinal mucosal surface in severe untreated celiac disease reveals a flat mucosal surface with complete absence of normal intestinal villi. Histologic examination of tissue sections confirms this loss of normal villus structure ( Fig. 107.1 A and B ). The intestinal crypts are markedly elongated and open onto a flat absorptive surface. The total thickness of the mucosa may be reduced only slightly, because crypt hyperplasia compensates for the absence or shortening of the villi. These architectural changes decrease the amount of epithelial surface available for digestion and absorption.
The enterocytes, which appear columnar in normal biopsy specimens, are cuboidal or, at times, squamoid in celiac disease. Their cytoplasm is more basophilic (i.e., RNA rich), the basal polarity of the nuclei is disrupted, and the brush border is markedly attenuated. When viewed by electron microscopy, the microvilli of the absorptive cells appear shortened and often fused. The number of free ribosomes is increased, reflecting impaired differentiation and resulting in the increased cytoplasmic basophilia evident on histologic examination. Degenerative changes, including cytoplasmic and mitochondrial vacuolization and the presence of many large lysosomes, are also obvious.
Structural abnormalities of tight junctions between damaged absorptive cells provide a morphologic explanation for the increased permeability of the mucosal barrier in celiac disease. The endoplasmic reticulum is sparse, explaining the low level of synthesis of digestive enzymes, including disaccharidases and peptidases. Thus, mature absorptive cells are reduced in number and functionally compromised.
Unlike the absorptive cells, undifferentiated crypt cells are markedly increased in number in patients with severe untreated celiac disease, and the crypts are therefore lengthened. Moreover, the number of mitoses in crypts is strikingly increased. Cytologic features and histochemistry of the crypt cells are normal by both light and electron microscopy. Studies of epithelial cell kinetics in untreated celiac disease suggest that “villus atrophy” is a misnomer because there is evidence for an actual increase in enteropoiesis in the crypts. Wright and colleagues estimated that intestinal mucosa from patients with celiac disease produces 6 times as many cells per hour per crypt as does normal small intestine, and that the cell cycle time is halved, reflecting premature cell shedding. The experimental evidence suggests, therefore, that the central mechanism of villus shortening in celiac disease is a toxic effect on maturing enterocytes that results in their premature loss into the intestinal lumen and a compensatory increase in cryptal enterocyte replication. Such a mechanism would explain many of the histologic abnormalities described previously.
The cellularity of the lamina propria is increased in the involved small intestine. The cellular infiltrate consists largely of plasma cells and lymphocytes. The number of IgA-, IgM-, and IgG-producing cells is increased 2-fold to 6-fold, but, as in normal mucosa, IgA-producing cells predominate. Polymorphonuclear leukocytes, eosinophils, and mast cells also can contribute substantially to this increased cellularity. The number of intraepithelial lymphocytes (IELs), often reported per 100 enterocytes, is increased in untreated celiac disease. In normal small intestinal mucosa, lamina propria T cells are predominantly CD4 + (helper/inducer) cells, whereas the IELs are mainly CD8 + (cytotoxic/suppressor) cells. In untreated celiac disease, this distribution of lamina propria T cells is maintained, but the density of cells in both compartments is increased.
Marsh pioneered the theory of sequential progression of the celiac lesion in the small intestinal mucosa. Starting with a normal, pre-infiltrative (stage 0) mucosa, the initial observed event is an increase in IELs, followed by infiltration of the lamina propria with lymphocytes (stage 1). Crypt hyperplasia (stage 2) precedes villus atrophy (stage 3) and is observed only in the presence of lamina propria lymphocytosis, suggesting that IELs are not sufficient to induce intestinal architectural changes in celiac disease. Finally, total mucosal atrophy (stage 4) develops and is characterized by complete loss of villi, enhanced apoptosis, and crypt hyperplasia. Marsh classification stages had previously been subdivided according to the degree of villus atrophy, with scores of 3a, 3b, and 3c corresponding with partial, subtotal, and total villus atrophy, respectively. However, because of low interobserver reproducibility for these substages, a quantitative approach to reporting the villus height:crypt depth ratio has been proposed. This classification, termed Quantitative-Mucosal Algorithmic Rules for Scoring Histology (Q-MARSH) , has the potential to be used as an outcome when assessing interventions in the treatment of celiac disease.
The length of small intestinal involvement by the celiac disease lesion varies among untreated individuals. When the intestinal lesion does not involve the entire length of small bowel, the proximal intestine is usually the most severely involved; sparing of proximal intestine with involvement of the distal small intestine can occur, but is uncommon. An increase in IEL count alone is not sufficient for a histologic diagnosis of celiac disease. This finding is nonspecific and is seen in many other conditions including SIBO, peptic duodenitis, Hp infection, NSAID use, and in autoimmune disorders. Thus, some shortening of the villi, crypt hyperplasia, cytologically abnormal surface cells, and increased lamina propria cellularity must be present to establish the diagnosis firmly. When the duodenal bulb is the only involved portion of the small intestine, the term “ultra-short celiac disease” has been used.
Treatment with a GFD results in significant improvement in intestinal structure (see Fig. 107.1 C ). The cytologic appearance of the surface absorptive cells improves first, often within a few days. Tall, columnar absorptive cells with basal nuclei and well-developed brush borders replace the abnormal, immature cuboidal surface cells; the ratio of IELs to absorptive cells decreases. Subsequently, villus architecture reverts toward normal, with lengthening of the villi and shortening of the crypts; the lamina propria decreases in cellularity. The mucosa of the distal small intestine improves more rapidly than that of the more severely involved proximal bowel. In some patients, months to years of gluten withdrawal may be required before the mucosa reverts to normal; indeed, some residual abnormality, which may range from subtle to striking, often persists, possibly because of inadvertent gluten ingestion. Finally, the mucosal lesion of celiac disease can be histologically identical to the mucosal response to injury typical of a wide range of other enteropathies (see “Differential Diagnosis”).
Pathogenesis
The interaction of the water-insoluble protein moiety (gluten) of certain cereal grains with the mucosa of the small intestine in susceptible persons is central to the pathogenesis of celiac disease. Celiac disease is considered an immune disorder that is triggered by an environmental agent (gliadin) in genetically predisposed persons. The wide spectrum of clinical manifestations is the result of a complex interplay of varying environmental, genetic, and immune factors. How these factors control the varied expression of celiac disease and passage from latent to overt disease remains unknown.
Gluten as Antigen
Celiac disease is a model for autoimmune diseases with a defined environmental trigger ( Fig. 107.2 ). Early work that involved physiologic digestion with pepsin and trypsin, followed by separation according to solubility properties, identified several wheat proteins as being responsible for the grain’s toxicity in celiac disease. Wheat protein exists in a number of storage forms that can be categorized into 4 general groups based on solubility characteristics: prolamins (soluble in ethanol), glutenins (partially soluble in dilute acid or alkali solutions), globulins (soluble in 10% NaCl), and albumins (soluble in water). The term gluten encompasses both the prolamins and the glutenins. Although most toxicity studies have been performed with prolamins, there are data to indicate that glutenins also may damage the celiac intestinal mucosa.
The prolamins of wheat are referred to as gliadins . Prolamins from other cereals also are considered to be gluten and are named according to their source ( secalins from rye, hordeins from barley, avenins from oats, and zeins from corn). The taxonomic relationships of the major cereal grain families provide a framework on which their toxicities in celiac disease can be predicted ( Fig. 107.3 ). Wheat, rye, and barley belong to the tribe known as Triticeae, and oats belong to a neighboring tribe known as Aveneae. Avenin is genetically less similar to gliadin than gliadin is to secalin and hordein. Despite their genetic differences, however, prolamins from barley, wheat, and rye still have immunologic cross-reactivity because of their common ancestry. Grains that do not activate disease (rice, corn, sorghum, and millet) are separated still further from wheat, rye, and barley in terms of their derivation from the primitive grasses.
Gliadin can be separated electrophoretically into 4 major fractions that range in molecular weight from 20 to 75 kd and exist as single polypeptide chains. These have been designated α-, β-, γ-, and ω-gliadins, and all 4 fractions appear to be toxic to patients with celiac disease. The complete amino acid sequences of several of the gliadins and related prolamins in grains other than wheat are known. Anderson and colleagues identified a partially deamidated peptide, consisting of amino acids 56 to 75 of α-gliadin as a dominant epitope, responsible for activation of T cells in celiac disease. However, patients with celiac disease can respond to a diverse repertoire of gluten peptides. Furthermore, nongluten proteins in wheat appear to contribute to immune activation in patients with celiac disease. The release of intracellular tTG leads to the deamidation of gluten proteins and an enhancement of T-cell responses to the resulting DGPs.
The reason oats are tolerated by the majority of patients with celiac disease is not obvious, because the prolamin fraction of oats contains the same amino acid sequences (QQQPF, where Q = glutamine, P = proline, and F = phenylalanine) that in wheat gliadin have been shown to be toxic. A possible explanation for this paradox is that oats contain a relatively smaller proportion of this toxic prolamin moiety than do toxic gluten-containing cereals. Although a feature common to prolamins of wheat, rye, and barley is a high content of glutamine (≈30%) and proline (≈15%), the prolamins of oats have an intermediate content of these amino acids, and the nontoxic prolamins of rice, corn, and millet have an even lower content of them. This hypothesis is supported by collectively considering the studies on oat challenge in patients with celiac disease; these studies suggest that tolerance to oats might depend at least in part on the total amount consumed. A systematic review and meta-analysis found that adding oats to a GFD did not adversely affect symptoms, histology, or serologic abnormalities in patients with celiac disease. Because most commercially-produced oats are harvested in a way that is conducive to contamination by gluten-containing grains, patients with celiac disease should be advised to restrict their oat consumption to uncontaminated oats that are labeled gluten-free.
The data on oats also highlight the important relationship between the amount of gluten consumed and the severity of disease manifestation. A 5- to 10-fold higher incidence of overt celiac disease in children from Sweden compared with Denmark (2 populations with similar genetic backgrounds) has long been cited as evidence of the importance of environmental over genetic factors in pathogenesis of celiac disease. Subsequent studies found as much as a 40-fold difference in the gliadin concentration of Swedish compared with Danish infant formula. This finding suggests that early exposure of the immature immune system to significant amounts of gliadin may be a relevant cofactor for the development of overt celiac disease.
The timing and/or quantity of gluten introduction in infancy may play an important role in facilitating gluten tolerance or intolerance. A cohort study found that introduction of gluten during the fourth through sixth month was associated with a decreased risk of celiac disease. This, in addition to the concerns that high quantity of gluten at first exposure may play a role in the Swedish epidemic, formed the rationale for 2 randomized trials of infant feeding strategies. One trial evaluated the intervention of gluten introduction at 4 months and the other evaluated gluten introduction at 12 months; both trials used gluten introduction at 6 months as the comparator. Neither the early nor delayed strategy yielded a decreased risk of celiac disease compared with introduction at 6 months. Thus, the optimal timing of gluten introduction is yet to be established.
Other Environmental Factors
The rise in celiac disease prevalence in recent decades has led to efforts to identify environmental cofactors for triggering its development. Recurrent rotavirus infection was found to be associated with an increased risk of subsequent celiac disease in a cohort study and receipt of the rotavirus vaccine may be protective against celiac disease. Reovirus infection, when introduced simultaneously with gluten, was shown to induce a pro-inflammatory milieu and AGAs in a mouse model, and patients with celiac disease do have higher titers of antibodies to reovirus compared with healthy controls. Gastric colonization with Hp is inversely associated with celiac disease, raising the possibility that the ongoing decline in Hp prevalence is contributing to the rise in celiac disease. Other proposed environmental risk factors include northern latitude (in the USA), elective Caesarian section, and antibiotic use.
Genetic Factors
Family studies that demonstrate frequent intrafamilial occurrence of celiac disease reflect the importance of genetic factors in its pathogenesis. Concordance for celiac disease in first-degree relatives ranges between 8% and 18% and estimates for concordance in monozygotic twins range from 49% to 83%. Our understanding of the nature of this genetic predisposition began with the observation that celiac disease was associated with specific HLA-DQ2 haplotypes. HLA class II molecules are glycosylated transmembrane heterodimers (α and β chains) that are organized into 3 related subregions—DQ, DR, and DP—and encoded within the HLA class II region of the major histocompatibility complex on chromosome 6p. An important link to a genetic predisposition was provided by the isolation of gliadin-specific HLA-DQ2-restricted T-cell clones from celiac disease mucosa.
The HLA class II molecule DQ2 is present in more than 90% of persons with celiac disease compared with approximately 35% of the general white population. DQ2 is a heterodimer composed of either α1∗0501 (DQ2.5) or, less commonly, α1∗0201 (DQ2.2) together with β1∗02. The DQ α1∗0301, β1∗0302 heterodimer, known as HLA-DQ8, is found in almost all of the remaining patients with celiac disease. Occasional cases of celiac disease have been reported in patients who are DQ2 and DQ8 negative but nonetheless carry a single DQ2 allele. Thus, in some cases, typing of individual celiac-associated alleles may be helpful in addition to determining DQ2 and DQ8 status. A gene dose-effect also has been identified, whereby persons who are homozygous for DQ2 are at greater risk than heterozygotes for developing celiac disease.
It is now known that after gluten is absorbed, lamina propria antigen-presenting cells (probably dendritic cells) that express HLA-DQ2 or HLA-DQ8, present gliadin peptides on their α/β heterodimer antigen-presenting grooves to sensitized T lymphocytes expressing the α/β T-cell receptor (TCR). These lymphocytes then activate B lymphocytes to generate Igs and other T lymphocytes to secrete cytokines, including interferon (IFN)-γ, as well as interleukin (IL)-4, IL-5, IL-6, IL-10, TNF-α, and transforming growth factor (TGF)-β. These cytokines induce not only enterocyte injury but also expression of aberrant HLA class II cell-surface antigens on the luminal surface of enterocytes, possibly facilitating additional direct antigen presentation by these cells to the sensitized lymphocytes (see Fig. 107.2 ).
Only a minority of persons who express DQ2 actually develop celiac disease. HLA-DQ2 is expressed by approximately 35% of Europeans and their descendants, but it is rare in other populations (in sub-Saharan Africa, far eastern Asia). Thus, much of the genetic predisposition to celiac disease is conferred by genes other than those encoding HLA-DQ molecules. The search for other genes that confer susceptibility to celiac disease has revealed numerous loci of interest on several different chromosomes, some of which also are associated with susceptibility to type 1 diabetes.
Immune Factors
There is substantial evidence implicating both humoral- and cell-mediated immune responses to gliadin and related prolamins in the pathogenesis of celiac disease. There is a 2- to 6-fold increase in the numbers of Ig-producing B cells in the lamina propria of the small intestine in untreated celiac disease patients. In addition, IgA and IgG serum antibodies to purified gliadin, all major fractions of gliadin, and DGPs can be detected in the sera of most patients with untreated celiac disease. Many healthy persons without celiac disease have increased levels of IgA or IgG antigliadin. The frequency of elevated IgA or IgG DGP antibodies in healthy controls, however, is very low, possibly reflecting the antigenic potency of DGPs and their more central role in disease pathogenesis. Many persons with celiac disease have increased levels of serum antibodies against other food proteins, such as β-lactoglobulin, casein, and ovalbumin. It is unclear whether this reflects a general aberrant immune responsiveness to food antigens in patients with celiac disease or enhanced systemic exposure to these proteins because of increased small intestinal permeability. Gluten can be absorbed across the normal intestinal epithelium, but it is unclear if this results in immune tolerance in persons who are not genetically predisposed to develop celiac disease. Patients with celiac disease develop antibodies to some, but not all, nongluten wheat proteins.
The identification of more specific autoantibody responses has altered our understanding of the pathogenesis of celiac disease. IgA antibodies to endomysium, a connective tissue structure surrounding smooth muscle, are highly specific for celiac disease. It is now known that the target autoantigen contained within the endomysium is the enzyme tTG-2. Gliadin is a preferred substrate for this ubiquitous calcium-dependent intracellular enzyme, and it has been shown that tTG deamidates key neutral glutamine residues in gliadin and converts them into negatively charged glutamic acid residues, which are preferred in positions 4, 6, and 7 of the nonpeptide antigen-binding groove of the HLA-DQ2 heterodimer, thereby facilitating antigen presentation. Thus, tTG-mediated modification of gliadin to generate DGPs plays a pivotal role in eliciting a stronger proliferative response by gliadin-specific T cells.
With gliadin serving as the glutamine donor, tTG also can generate additional novel antigenic epitopes by cross-linking molecules of the extracellular matrix with gliadin or with tTG-gliadin complexes. As evidence of the fundamental role of tTG in celiac disease pathogenesis, one of the dominant epitopes responsible for the T-cell response contains a deamidated glutamine residue (Q65E) of α-gliadin.
Given the marked infiltration of lymphocytes into the small intestinal mucosal epithelium and lamina propria in active disease, it is not surprising that cell-mediated immune responses also are important in the pathogenesis of celiac disease. Many findings support interplay between adaptive immunity, characterized by a specific and memory T-cell response to gluten peptides, and innate immunity, involving less specific mechanisms. Many of the T cells in the small intestinal mucosa are activated in untreated celiac disease and release potent proinflammatory mediators such as IFN-γ, TNF-α, IL-2, IL-6, and TGF-β. Activated T lymphocytes, most of which are CD4+ cells, are abundant in the lamina propria of the small intestine. In contrast, IELs, which are present in large numbers in untreated celiac disease, are predominantly CD8+ T cells. There is an influx of primed memory T cells, marked by high CD45RO expression, in the mucosa of untreated celiac disease patients. In healthy persons, more than 90% of IELs express the α/β TCR, whereas expression of the γ/δ TCR by IELs in patients with untreated celiac disease is increased as much as 6-fold (to 35%) and is considered a hallmark of the disease. These primitive lymphocytes recognize bacterial nonpeptide antigens and unprocessed stress-related proteins. They appear to act as mucosal guardians and might protect the intestinal mucosa from chronic exposure to dietary gluten in gluten-tolerant persons by secreting IL-4, which dampens Th1 in favor of Th2 reactivity. Their continuous presence in patients on a GFD might indicate inadvertent gluten ingestion. Patients with RCD type 2 also have aberrant IELs with restricted γ/δ TCR gene rearrangements indicating oligoclonality (see “Refractory Celiac Disease”).
Studies suggest that IL-15 may play a key role in bridging the innate and adaptive immune responses in the pathogenesis of celiac disease. This enterocyte- and macrophage-derived proinflammatory cytokine is increased greatly in the mucosa of patients with active celiac disease and RCD. Although mechanisms that lead to its overproduction remain unknown, IL-15 regulates IEL homeostasis by promoting migration, preventing apoptosis, and enhancing the capacity of dendritic cells to function as antigen-presenting cells. In response to gliadin peptides, IL-15 triggers an adaptive CD4 + T-cell response in the lamina propria and also is capable of inducing direct epithelial cell injury by inducing IEL secretion of IFN-γ.
Clinical Features
Although some patients still present with severe illness due to significant malabsorption, many have few, subtle, or no symptoms at diagnosis. The latter cases may be identified by screening relatives of patients with celiac disease or from screening patients with associated disorders, such as type 1 diabetes mellitus (T1DM), autoimmune thyroid disease, or Down syndrome. Hematologic (e.g., iron deficiency anemia) or biochemical abnormalities (e.g., elevated serum aminotransferase levels) or neurologic (e.g., peripheral neuropathy) or skeletal (osteoporosis) disorders also can lead to a diagnosis of celiac disease ( Table 107.1 ).
Childhood Presentation
The classic presentation of celiac disease in infancy is with diarrhea, steatorrhea, and occasional cramping abdominal pain that can occur any time after cereals are introduced into the diet, but especially in early childhood. Classically, the child fails to thrive, is apathetic and irritable, and has muscle wasting, hypotonia, and abdominal distention. Watery diarrhea, or occasionally constipation, may be reported. The diagnosis is more difficult when GI features are less prominent, and the possibility of celiac disease should be considered in all children who present with short stature or failure to thrive, even when there are no other symptoms to suggest enteropathy. Once a GFD is commenced, catch-up growth is well documented. Nutritional deficiencies, particularly anemia, are another common mode of presentation, especially in older children. With earlier diagnosis, clinical rickets now is an uncommon complication but is seen occasionally.
Adulthood Presentation
In the past, celiac disease was perceived to be a pediatric disorder, but the diagnosis now is being made increasingly in adults; currently, the 5th decade is the most common age at presentation. Celiac disease also is being diagnosed increasingly in later life, with approximately 25% of cases diagnosed in patients older than 60 years. Symptoms also have changed over time, with the presenting symptom of diarrhea now occurring in less than half of patients with celiac disease. The unmasking of asymptomatic disease by surgery that induces rapid gastric emptying (e.g., gastric resection, pyloroplasty) or the finding of the typical lesion in asymptomatic relatives of celiac disease patients suggests that adults can have silent celiac disease for many years.
GI Features
Clinical manifestations of celiac disease vary tremendously from patient to patient. Because many of the symptoms result from intestinal malabsorption, they are not specific for celiac disease and resemble those seen in other malabsorptive disorders. Many adults present with GI symptoms including diarrhea, steatorrhea, abdominal bloating, flatulence, and weight loss similar to those seen in childhood celiac disease. Diarrhea often is episodic rather than continuous. Nocturnal, early morning, and postprandial diarrhea are common. Patients with extensive intestinal involvement can have greater than 10 stools per day. Steatorrhea often is absent in patients with disease that is limited to the proximal small intestine.
Several factors contribute to the diarrhea associated with celiac disease. The stool volume and osmotic load delivered to the colon are increased by malabsorption. In addition, the delivery of excessive dietary fat into the colon results in bacterial production of hydroxy fatty acids, which are potent cathartics. Electrolytes are secreted into, rather than absorbed from, the lumen of the severely damaged upper small intestine in symptomatic patients. This secretion further increases luminal fluid in an intestine with an already compromised absorptive capacity. There also is evidence that secretin and cholecystokinin release in response to a meal are impaired in celiac disease, thus diminishing delivery of bile and pancreatic secretions into the intestinal lumen and possibly compromising intraluminal digestion. Alterations in the secretion of other intestinal peptides have been noted and can contribute to the observed diarrhea. Finally, if the disease extends to and involves the ileum, patients can experience the direct cathartic action of malabsorbed bile salts on the colon. Pancreatic insufficiency is common in active celiac disease, as is microscopic colitis ; both may contribute to diarrhea. The amount of weight loss in a patient with celiac disease depends on the severity and extent of the intestinal lesion and on the ability of the patient to compensate for the malabsorption by increasing dietary intake. Some celiac disease patients with substantial malabsorption have enormous appetites and lose little or no weight. Rarely, in severe disease, anorexia develops with associated rapid and severe weight loss. In such debilitated patients, some of the weight loss may be masked by fluid retention caused by hypoproteinemia. Fatigue is common even when anemia is absent. Occasionally, severe hypokalemia resulting from fecal loss of potassium causes severe muscle weakness.
Vague abdominal discomfort and especially abdominal bloating are extremely common and can lead to a mistaken diagnosis of IBS. Because of the difficulty in distinguishing celiac disease with mild GI manifestations from symptomatic IBS, serologic testing with IgA tTG should be considered in patients with symptoms that suggest diarrhea-predominant IBS. Severe abdominal pain can occur but is not characteristic of uncomplicated celiac disease; its occurrence can suggest the presence of complications such as intussusception, ulcerative jejunitis, or intestinal lymphoma. Abdominal distention with excessive amounts of malodorous flatus is a common symptom. Conversely, nausea and vomiting are uncommon in uncomplicated celiac disease. Symptoms of GERD may be significantly more common in untreated celiac disease and improve on a GFD. Recurrent, severe, aphthous stomatitis affects many celiac patients, may be their sole presenting symptom, and often resolves on a GFD.
Celiac crisis is a rare, life-threatening syndrome in which children or adults with untreated celiac disease present with profuse diarrhea that leads to severe dehydration, metabolic disturbances, renal dysfunction and, in some instances, hemodynamic instability. Early diagnosis is important, and management includes IV fluids as well as glucocorticoids and/or parenteral nutrition where indicated. Patients eventually respond well to a GFD.
Extraintestinal Features
As patients with celiac disease get older, they tend to present with symptoms not directly referable to the GI tract. These extraintestinal symptoms and clinical findings often result from nutrient malabsorption and can involve virtually all organ systems ( Table 107.1 ).
TABLE 107.1
Extraintestinal Manifestations of Celiac Disease
| Manifestation | Probable Cause(s) |
|---|---|
| C UTANEOUS | |
| Ecchymoses and petechiae | Vitamin K deficiency; rarely, thrombocytopenia |
| Edema | Hypoproteinemia |
| Dermatitis herpetiformis | Epidermal (type 3) tTG autoimmunity |
| Follicular hyperkeratosis and dermatitis | Vitamin A malabsorption, vitamin B complex malabsorption |
| E NDOCRINOLOGIC | |
| Short stature, delayed puberty | Malnutrition, hypothalamic-pituitary dysfunction |
| Amenorrhea, infertility, impotence | Malnutrition, hypothalamic-pituitary dysfunction, immune dysfunction |
| Secondary hyperparathyroidism | Calcium and/or vitamin D malabsorption with hypocalcemia |
| H EMATOLOGIC | |
| Anemia | Iron, folate, or vitamin B 12 , deficiency |
| Hemorrhage | Vitamin K deficiency; rarely, thrombocytopenia due to folate deficiency |
| Thrombocytosis, Howell-Jolly bodies | Hyposplenism |
| H EPATIC | |
| Elevated liver biochemical test levels Autoimmune hepatitis |
Lymphocytic hepatitis Autoimmunity |
| M USCULAR | |
| Atrophy | Malnutrition due to malabsorption |
| Weakness | Generalized muscle atrophy, hypokalemia |
| N EUROLOGIC | |
| Peripheral neuropathy | Deficiencies of vitamin B 12 and thiamine; immune-based neurologic dysfunction |
| Ataxia | Cerebellar and posterior column damage |
| Demyelinating CNS lesions | Immune-based neurologic dysfunction |
| Seizures | Unknown |
| S KELETAL | |
| Osteopenia, osteomalacia, and osteoporosis | Malabsorption of calcium and vitamin D, secondary hyperparathyroidism, chronic inflammation |
| Osteoarthropathy | Unknown |
| Pathologic fractures | Osteopenia and osteoporosis |
tTG, tissue transglutaminase.
Anemia
Anemia is a common manifestation of celiac disease in children and adults and usually is caused by impaired iron or folate absorption from the proximal intestine; in severe disease with ileal involvement, vitamin B 12 absorption also is impaired, though this also may be due to gastric achlorhydria, pancreatic insufficiency, or inadequate dietary intake. Coagulopathy resulting from impaired intestinal absorption of fat-soluble vitamin K occurs rarely, and in such cases bleeding can aggravate preexisting anemia. Hyposplenism of unknown cause, with thrombocytosis, deformed erythrocytes, and splenic atrophy, occurs in up to 50% of adults with celiac disease but is only rarely seen in children and may account for the increased risk of pneumococcal infection. Evidence of hyposplenism may disappear with elimination of gluten from the diet.
Low Bone Density
Osteopenia is a common complication of celiac disease. More than 70% of patients with untreated celiac disease have osteopenia, and osteoporosis occurs in more than one quarter of all celiac disease patients. Osteopenia develops as a result of impaired calcium absorption (secondary to defective calcium transport by the diseased small intestine), vitamin D deficiency (caused by impaired absorption of this fat-soluble vitamin), and binding of intraluminal calcium and magnesium to unabsorbed dietary fatty acids (forming insoluble soaps, which are then excreted in the feces). Chronic intestinal inflammation also contributes to bone loss through release of inflammatory mediators.
Patients can present with bone pain, especially of the lower back, rib cage, and pelvis. Calcium and magnesium depletion can cause paresthesias, muscle cramps, and rarely tetany. With prolonged calcium malabsorption, patients may develop secondary hyperparathyroidism, resulting in mobilization of calcium from the bones, further exacerbating the osteopenia.
Osteopenia is less common in patients with silent celiac disease, in whom prevalence rates between 30% and 40% have been reported. Whereas bone disease generally is more severe among patients with symptomatic disease, osteopenia has been reported in up to one third of symptom-free adults whose celiac disease was diagnosed during childhood and who resumed a normal diet during adolescence.
Compared to the general population, patients with celiac disease have an increased risk of fracture both before and after their celiac disease diagnosis.
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