ENVIRONMENTAL FACTORS

Celiac disease is a model for autoimmune diseases with a defined environmental trigger. Early work involving 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 four general groups based on their solubility characteristics: prolamins (soluble in ethanol), glutenins (partially soluble in dilute acid or alkali solutions), globulins (soluble in 10% NaCl), and minor 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 suggest that glutenins also can damage the celiac intestinal mucosa.³³

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. 104-3).³⁴ 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 oats, barley, wheat, and rye still have immunologic cross-reactivity because of their common ancestry.³⁵ 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.

Figure 104-3. Taxonomic relationships of the major cereal grains.

(From Kasarda DD, Okita TW, Bernardin JE, et al. Nucleic acid [cDNA] and amino acid sequences of α-type gliadin from wheat [Triticum aestivum]. Proc Natl Acad Sci U S A 1984; 81:4712.)

Gliadin can be separated electrophoretically into four 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 four fractions appear to be toxic to patients with celiac disease.³⁶ The complete amino acid sequences of several of the gliadins and related prolamins in grains other than wheat are known.³³ In 2000, Anderson and colleagues¹⁴ 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. The complexity and diversity of the gliadin-specific T-cell response, however, is far greater than was previously appreciated, and persons with celiac disease can respond to a diverse repertoire of gluten peptides.³⁷ Furthermore, the release of intracellular tTG leads to the deamidation of gluten proteins and an enhancement of T-cell responses to the resulting DGPs.¹⁴

In organ cultures, a synthetic peptide corresponding to amino acids 31 to 49 of α-gliadin has been shown to be toxic to intestinal mucosa and to induce epithelial lesions via recruitment of IELs. Peptide 31-49 does not activate intestinal CD4⁺ T cells from patients with celiac disease in vitro, but a related peptide corresponding to amino acids 31 to 43 is capable of activating peripheral CD4⁺ T cells isolated from patients with celiac disease and of inducing epithelial cell apoptosis and activating macrophages, thereby indicating a likely role for innate immune responses in disease pathogenesis.³⁸ Gianfrani and colleagues³⁹ reported that the α-gliadin-derived peptide corresponding to amino acids 123 to 132 is recognized by CD8⁺ T lymphocytes from patients with celiac disease and is associated with cytotoxic activity. By contrast, another peptide corresponding to amino acids 57 to 68 appears to function in adaptive immunity via stimulation of intestinal T cells in vivo but does not appear to be directly toxic to the intestinal mucosa of patients in vitro.³⁷

It also is possible that immunologic similarities between gliadin protein motifs and enteric pathogens may be involved in the pathogenesis of an immunologic response to gluten antigens. This hypothesis was supported by a study in which analysis of α-gliadin demonstrated an amino acid region that was homologous to the 54-kd E1b protein coat of adenovirus 12, suggesting that exposure to the virus in a susceptible person could be involved in pathogenesis of celiac disease.⁴⁰ Although patients with celiac disease have been reported to have a significantly higher prevalence of past adenovirus 12 infection than do control subjects,⁴¹ the role of adenovirus molecular mimicry in the pathogenesis of celiac disease has not been confirmed.

The reason oats are tolerated by almost all 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.⁴² 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.⁴³ 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.⁴⁴ Daily oats consumption of less than 40 to 60 g/day by patients whose celiac disease is in remission appears to be well tolerated.

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 (two 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.²⁵ This finding suggests that early exposure of the immature immune system to significant amounts of gliadin is a prominent cofactor for the development of overt celiac disease, possibly by skewing the intestinal immune response to gliadin toward a T-helper 1 (Th1) T-cell response.

The age at which gluten is first introduced into an infant’s diet might also play a pivotal role in facilitating gluten tolerance or intolerance. In one study, early exposure to dietary gluten (within three months of birth) was associated with a five-fold increased risk for celiac disease compared with later gluten introduction (four to six months).⁴⁵ In the same study, delaying gluten introduction (after 7 months of age) also was associated with a slightly increased risk for subsequent celiac disease (1.9-fold compared with the nadir at introduction at four to six months).

GENETIC FACTORS

Family studies that demonstrate frequent intrafamilial occurrence of celiac disease reflect the importance of genetic factors in its pathogenesis.⁴⁴ Concordance for celiac disease in first-degree relatives ranges between 8% and 18% and reaches 70% in monozygotic twins.⁴⁶ Our understanding of the nature of this genetic predisposition began with the significant observation by Howell and coworkers¹⁰ 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 three 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.^11,47

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 or (less commonly) α1*0201 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, such as α1*0201. 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 immunoglobulins and other T lymphocytes to secrete cytokines, including interferon (IFN)-γ, as well as IL-4, IL-5, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β.⁴⁸ 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 (Fig. 104-4).

Figure 104-4. Proposed pathogenesis of celiac disease. Gluten is absorbed by the small intestinal mucosa into the lamina propria and presented in conjunction with HLA-DQ2 (or DQ8) cell-surface antigens by antigen-presenting cells, probably dendritic cells, to sensitized T lymphocytes that express the α/β T-cell receptor (afferent limb). Tissue transglutaminase deamidates gliadin peptides, generating acidic negatively charged glutamic acid residues from neutral glutamines (insert). Because negatively charged residues are preferred in positions 4, 6, and 7 of the antigen-binding groove of HLA-DQ2, deamidated gliadin elicits stronger T-lymphocyte responses. These lymphocytes then activate other lymphocytes to generate immune products (cytokines) that damage the enterocytes, resulting in villus atrophy (efferent limb). Induction of aberrant HLA class II cell-surface antigens on the enterocytes can permit additional gluten antigen presentation by these cells to the sensitized lymphocytes. AGA, antigliadin antibodies; HLA, human leukocyte antigen; IFN-γ, interferon gamma; IL-4, interleukin-4; NK, natural killer; TNF-α, tumor necrosis factor alpha; tTG, tissue transglutaminase.

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 (e.g., in sub-Saharan Africa or 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.^49–52

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 two- to six-fold increase in the numbers of immunoglobulin-producing B cells in the lamina propria of the small intestine in untreated celiac disease patients.²⁸ 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.^14,53–56 Antigliadin antibodies (AGAs), however, do not appear to be essential for the pathogenesis of celiac disease and might simply reflect a nonspecific response to the passage of incompletely digested antigenic gluten proteins across an abnormally permeable intestinal epithelium. Many normal persons have increased IgA or IgG antigliadin.⁵⁷ 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.^14,54–56 Many persons with celiac disease have increased levels of serum antibodies against other food proteins, such as β-lactoglobulin, casein, and ovalbumin.⁵⁸ 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 normal epithelium, but it is unclear if this results in immune tolerance in persons who are not genetically predisposed to develop celiac disease.

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 virtually pathognomonic for celiac disease and are found only rarely in the absence of disease.⁵⁹ It is now known that the target autoantigen contained within the endomysium is the enzyme tTG-2.¹² 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 nonapeptide antigen-binding groove of the HLA-DQ2 heterodimer (see Fig. 104-4),^13,14,60 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-cell clones, or, stated differently, tTG makes gliadin tastier for the 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.⁶¹ 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.¹⁴ It also has been observed that tTG is necessary for the bioactivation of TGF-β that is required for epithelial differentiation. In a T84-crypt epithelial cell culture system, autoantibodies to tTG-blocked TGF-β–mediated enterocyte differentiation,⁶² a finding that suggests that release of tTG from cells during inflammation potentiates gliadin presentation by HLA-DQ2 and HLA-DQ8 and that local production of autoantibodies to tTG might contribute to the lack of epithelial differentiation observed in the active celiac lesion.

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.⁴⁸ Activated T lymphocytes, most of which are CD4⁺ cells, are abundant in the lamina propria of the small intestine.⁶³ In contrast, IELs, which are present in large numbers in untreated celiac disease, are predominantly CD8⁺ T cells.⁶⁴

There is an influx of primed memory T cells, marked by high CD45RO expression, in the mucosa of untreated celiac disease patients.⁶⁵ 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 six-fold (to 35%) and is considered a hallmark of the disease.⁶⁶ 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.⁶⁷ Their continuous presence in patients on a gluten-free diet might indicate inadvertent gluten ingestion. Patients with refractory celiac disease also have aberrant IELs with restricted γ/δ TCR gene rearrangements indicating oligoclonality. The pathogenetic role of these lymphocytes, compared with lamina propria lymphocytes, continues to evolve (see “Refractory Celiac Disease”).⁶⁸

Studies suggest that IL-15 plays a key role in bridging the innate and adaptive immune responses in pathogenesis of celiac disease.^15,16,69 This enterocyte- and macrophage-derived proinflammatory cytokine is increased massively in the mucosa of patients with active celiac disease and refractory celiac disease. Although the 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.⁶⁹ 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.¹⁶

CHILDHOOD PRESENTATION

The classic presentation of celiac disease in infancy is not easily missed. The typical history is of steatorrhea with or without vomiting and occasional cramping abdominal pain that can occur anytime after weaning when cereals are introduced into the diet, but especially in the first and second years of life. 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. Diagnosis is more difficult when gastrointestinal features are less prominent, and the possibility of gluten sensitivity should be considered in all children who present with short stature or failure to thrive, even when there are no other symptoms to suggest an enteropathy. Once a gluten-free diet is commenced, catch-up growth is well documented.⁷⁰ 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, especially among Asian children with untreated celiac disease. Many pediatric patients enjoy a temporary, spontaneous remission of symptoms during adolescence, and it is unusual for celiac disease to manifest during the teens.

Considerable debate continues as to why celiac disease tends to be diagnosed later and with milder signs and symptoms than in the past. A number of studies suggest that breast-feeding can significantly delay the onset of symptoms,^71,72 but not all studies support this conclusion.⁷³ In one study of at-risk children, the introduction of gluten into the diet during the first three months of life or after seven months of age was associated with a significantly increased risk for celiac disease (hazard ratio [HR] 23.0; 95% confidence interval [CI]: 4.6-115.9; P = 0.001) compared with introduction at four to six months (HR 3.98; 95% CI: 1.18-13.46; P = 0.04).⁷⁴

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 overall mean age at presentation is approximately 45 years. Symptoms also have changed during the past 50 years. Diarrhea now is reported less often, and many patients now present with higher body mass indices and even with obesity. 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 some time. A proportion of these adult patients have short stature or give a history consistent with unrecognized celiac disease in childhood. In many, however, there is nothing to suggest previous disease, and it is possible that celiac disease can develop for the first time in adult life. Celiac disease also is being diagnosed increasingly in later life, with approximately 25% of cases diagnosed in patients older than 60 years.⁷⁵

GASTROINTESTINAL 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 gastrointestinal symptoms including diarrhea, steatorrhea, 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 more than 10 stools per day. Because of their high fat content, the stools of patients with celiac disease may be light tan or grayish and greasy in appearance, with a tendency to float and to be difficult to flush from the toilet bowl; this pallor of the stools is reflected in the ancient Latin term diarrhea alba, alba meaning “white.” Steatorrhea often is absent in patients with disease 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 the malabsorption of fat,⁷⁶ carbohydrate, protein, electrolytes, and other nutrients. In addition, the delivery of excessive dietary fat into the large bowel results in the production by bacteria of hydroxy fatty acids, which are potent cathartics. Electrolytes actually 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, diminishing delivery of bile and pancreatic secretions into the gut lumen and possibly compromising intraluminal digestion.⁷⁷ 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.⁷⁶

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. Malaise, lassitude, and fatigue also are 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 irritable bowel syndrome (IBS). Because of the difficulty in distinguishing celiac disease with mild gastrointestinal manifestations from symptomatic IBS, serologic testing of IgA EMAs or IgA tTG should be considered in patients with symptoms suggesting diarrhea-predominant IBS. In a UK study, Sanders and colleagues⁷⁸ evaluated 300 consecutive new patients who fulfilled Rome II criteria for IBS and 300 healthy age- and sex-matched controls for celiac disease using IgA AGA (antigliadin antibody), IgG AGA, and EMA; two controls (0.7%) (both EMA positive) and 14 IBS patients (4.6%) had celiac disease (P = 0.004; odds ratio [OR], 7.0; 95% confidence interval [CI]: 1.7-28.0). Severe abdominal pain can occur but is uncharacteristic in 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 complaint. Conversely, nausea and vomiting are uncommon in uncomplicated celiac disease. Recurrent severe aphthous stomatitis affects many celiac patients and may be their sole presenting complaint. It is important to exclude celiac disease in cases of recurrent aphthous stomatitis because a significant proportion of these patients respond well to dietary treatment.⁷⁹

EXTRAINTESTINAL FEATURES

As patients with celiac disease get older, they tend to present with complaints not directly referable to the gastrointestinal tract. These extraintestinal symptoms and clinical findings often result from nutrient malabsorption and can involve virtually all organ systems (Table 104-1).⁸⁰ Extraintestinal features, including anemia, osteopenia, neurologic symptoms, and menstrual abnormalities, often prove more distressing to the patient than do the gastrointestinal symptoms.

Table 104-1 Extraintestinal Manifestations of Celiac Disease

SEROLOGY

In current clinical practice, there are many serologic studies to aid in the diagnosis of celiac disease; however, the most powerful and clinically useful are the IgA EMA and IgA tTG assays. IgA EMA and IgA tTG are based on the target antigen tTG, and IgA and IgG AGAs are based on the target antigen gliadin.⁹⁷ A second-generation AGA test has been developed based on DGPs with improved diagnostic accuracy.^14,54–56

The approximate sensitivity and specificity of commonly used serum antibody tests are outlined in Table 104-2.^98–102 A working group of 13 European laboratories has attempted to improve standardization by establishing standard curves on reference sera and protocols for calibration of quality controls. This collaboration has reported that IgA EMA has a sensitivity of 90%, specificity of 99%, and reproducibility of 93% and currently remains the gold standard. IgA antihuman tTG is slightly less reliable (sensitivity 93%, specificity 95%, reproducibility 83%), and the anti-IgG AGA and IgA AGA are the least reliable.⁹⁸

In addition to laboratory variation, the reported sensitivities and specificities of these tests depend on the prevalence of the disease in the tested population and the severity of the disease. In one study of 101 patients with biopsy-proven celiac disease, the sensitivity of IgA EMA among patients with total villus atrophy was 100% compared with only 31% in those with partial villus atrophy.¹⁰³

Clinical Application of Serologic Tests

Serologic tests are used to evaluate patients with suspected celiac disease, monitor adherence and response to a gluten-free diet, and potentially, screen asymptomatic persons for the disease.

An approach to diagnosing celiac disease is outlined in Figure 104-5.¹⁰⁸ When the index of suspicion is low—the pretest probability is less than 10%—a negative result for IgA EMA or IgA tTG has a high negative predictive value and can obviate the need for small bowel biopsy. Falsely negative IgA EMA and IgA tTG test results are more likely to occur in very young children (<2 years of age), those with mild celiac enteropathy, and, of course, in IgA deficiency. The AGA tests have lower diagnostic accuracy and are no longer recommended for initial diagnosis of celiac disease.¹⁰⁵ Because the specificities of IgA EMA and IgA tTG tests are high, their positive predictive values are high even in low-risk populations.^105,109,110

Figure 104-5. Diagnosis of celiac disease. A false-positive IgA EMA or tTG is rare; a false-negative IgA EMA and tTG can occur in mild enteropathy, in children younger than 2 years, and in patients with IgA deficiency. AGA, antigliadin antibodies; EMA, endomysial antibody; GI, gastrointestinal; Ig, immunoglobulin; tTG, tissue transglutaminase.

(From Farrell RJ, Kelly CP. Diagnosis of celiac sprue. Am J Gastroenterol 2001; 96:3237.)

When the index of suspicion is moderate to high—the pretest probability is greater than 10%—the very high specificity of IgA EMA and IgA tTG has led to debate as to whether a positive result in the appropriate clinical setting can be considered diagnostic and eliminate the need for small bowel biopsy. We recommend that both IgA tTG (or EMA) and a small bowel biopsy be performed before dietary treatment is recommended, because this approach provides the best means of making a definitive diagnosis of celiac disease at the outset. Because AGA tests have a high false-positive rate, there is no role for a trial of a gluten-free diet for presumed celiac disease based on the finding of an elevated IgA or IgG AGA level. The use of anti-DGP testing was discussed earlier.

Similar to IgA AGA levels, IgA tTG levels decrease in the months following a gluten-free diet and are useful in assessing dietary compliance and excluding inadvertent gluten ingestion.^53,54,111 IgA AGA and IgA tTG currently are the most widely used tests for monitoring adherence and response to a gluten-free diet among patients whose antibody levels are elevated before therapy.^54,107,111 Hence, a pretreatment antibody level should be determined at the time of diagnosis. A normal baseline value typically is reached within 3 to 12 months depending on the pretreatment antibody concentration (IgA tTG concentrations fall with a half-life of approximately six to eight weeks) and on the degree of success in avoiding gluten ingestion. If the levels do not fall as anticipated, the patient may be continuing to ingest gluten either intentionally or inadvertently.

The advent of highly sensitive and specific serologic tests has changed the epidemiology of celiac disease radically by revealing the high incidence of silent celiac disease; this awareness in turn has led to debate on the merits of mass screening. To date, the benefit of screening for asymptomatic celiac disease, usually using IgA tTG or EMA, has not been demonstrated.¹¹² The potential advantages of screening for asymptomatic celiac disease are a reduction in risk for malignancy including enteropathy-associated T-cell lymphoma (EATL); a reversal of unrecognized nutritional deficiency states; resolution of mild or ignored intestinal symptoms; possible reduction in T-cell activation and “antigenic drift” to other autoantigens, thereby reducing the onset of other autoimmune disorders; and an improvement in general well-being.^113,113A

All of these hypothetical benefits, however, depend on compliance with a challenging dietary regimen, and asymptomatic patients might not be motivated sufficiently to adhere to a strict gluten-free diet.¹¹⁴ There also may be adverse psychological effects when asymptomatic individuals are given the diagnosis of celiac disease. Furthermore, the natural history of undetected celiac disease and the consequences of screening and treating silent celiac disease are unknown. For these reasons, mass screening of asymptomatic persons generally is not advocated at this time, even in populations in which the prevalence of celiac disease is high.

The current standard of care is a case-finding approach, which targets at-risk subjects such as patients with mild gastrointestinal symptoms, iron deficiency anemia, or IBS-like symptoms, all instances in which the value of serologic testing for celiac disease is accepted widely. Simply by case finding among at-risk subjects in a primary care setting, Hin and colleagues¹¹⁵ observed a four-fold increase in the number of celiac disease diagnoses during a one-year period. Thus, for now, increased awareness of the typical and atypical presentations of celiac disease, coupled with a low threshold for serologic testing in at-risk subjects, can uncover a substantial portion of the submerged iceberg.

GENETIC TESTING

As discussed earlier, almost all patients with celiac disease are positive for HLA DQ2 or DQ8. As a result, HLA testing may be helpful in excluding celiac disease in specific clinical situations, mainly before embarking on a gluten challenge (see later) or evaluating a patient who has a celiac-like enteropathy but negative IgA tTG, EMA, and DGP serologies, in which case a negative result indicates the need to investigate for an alternative diagnosis. Approximately 40% of persons of European ancestry are DQ2 or DQ8 positive, however, so a positive result is of little diagnostic value.^97,116–118

SMALL INTESTINE BIOPSY

Although the diagnosis of celiac disease may be suspected on clinical grounds or as a result of abnormal serologic tests, biopsy of the small intestine has remained the standard test to establish the diagnosis. Biopsies usually are performed during endoscopic examination of the upper gastrointestinal tract, an examination that may be indicated for reasons related or unrelated to celiac disease, such as investigation of iron deficiency anemia or upper abdominal discomfort.¹¹⁹ Multiple biopsies should be obtained (e.g., a total of six to eight biopsies from the second and third parts of the duodenum). Biopsies taken from the duodenal bulb also may be diagnostic, but might show mucosal architectural distortion produced by Brunner’s glands and changes caused by peptic duodenitis, both of which can cause difficulty in histopathologic diagnosis.⁹

Scalloping or absence of duodenal folds has been noted in some patients with celiac disease (Fig. 104-6).¹²⁰ Scalloping is not specific for celiac disease, however, and may be seen in eosinophilic enteritis, giardiasis, amyloidosis, tropical disease, and human immunodeficiency virus enteropathy.¹²¹ Other endoscopic features include multiple fissures or a mosaic-like appearance where the fissures circumscribe areas of mucosal nodularity in a manner similar to the grouting around a mosaic tile. The mucosa of celiac disease, however, often appears normal at endoscopy, and absence of the previously described macroscopic features does not obviate the need for biopsy and histologic examination if celiac disease is suspected, based on clinical grounds or serologic testing.

Figure 104-6. Endoscopic view of the duodenum showing scalloping of the folds in a patient with celiac disease; if present, this finding should alert the endoscopist to the possibility of this diagnosis. Scalloping, however, is not specific for celiac disease and has been seen in other conditions, including eosinophilic gastroenteritis, giardiasis, amyloidosis, tropical sprue, and human immunodeficiency virus enteropathy.

Once the biopsy tissue has been obtained, handling should be minimized to avoid artifactual damage. By gently floating the tissue on a small amount of saline, an experienced observer can examine even small endoscopic biopsy specimens using a dissecting microscope or a magnifying lens. The villus structure of normal small intestinal mucosa is readily apparent. In severe untreated celiac disease, a flat, featureless mucosa is recognized easily. The mosaic pattern of less complete forms of villus atrophy also may be recognized, although differentiation from the normal is more difficult and requires some experience.

Capsule endoscopy and enteroscopy provide opportunities to examine the more distal small intestine, where the macroscopic features just described might also be evident. Because these features are not specific, however, capsule endoscopy cannot replace biopsy and histopathologic examination, and it is not necessary for routine diagnosis and management. Capsule endoscopy may be valuable in patients with complicated or refractory celiac disease in whom ulcerative jejunitis or intestinal lymphoma may be seen.

GLUTEN CHALLENGE

In the past, gluten challenge—discontinuation of the gluten-free diet, followed by repeat biopsy of the small intestine—was considered an important confirmatory step in the diagnosis of celiac disease. In current practice, however, gluten challenge is reserved for the few patients in whom the diagnosis remains in doubt after a period of treatment with a gluten-free diet. Gluten challenge is seldom necessary for patients who present with typical signs or symptoms of celiac disease and have documented abnormalities consistent with a celiac lesion on small bowel biopsy. A positive IgA EMA or IgA tTG test before treatment lends further support to the diagnosis of celiac disease and makes a later gluten challenge superfluous.

A gluten challenge should be considered in patients who began a gluten-free diet empirically without documentation of a characteristic intestinal lesion or the presence of IgA EMA antibody. In such patients, symptomatic response to a gluten-free diet might indicate the presence of gluten-sensitive enteropathy or simply reflect a change in gastrointestinal function in response to a major dietary change. Mild and nonspecific gastrointestinal symptoms after ingesting gluten are not a reliable way to diagnose celiac disease. For example, patients with IBS might experience improvement in symptoms, including abdominal bloating, cramping, or diarrhea, after beginning a gluten-free diet.¹²² Gluten challenge also should be considered if a diagnosis of celiac disease was made during childhood based on small intestinal biopsy abnormalities in the absence of a positive IgA EMA or IgA tTG, because a number of transient childhood enteropathies can mimic the celiac lesion (see later).

Before embarking on a gluten challenge, patients should be evaluated to determine their current response to treatment with a gluten-free diet. This should include a careful nutritional history noting their symptomatic responses to previous episodes of inadvertent or purposeful ingestion of gluten-containing foods. Patients who experience substantial symptoms following gluten ingestion are unlikely to tolerate formal gluten challenge and might prefer to remain on a gluten-free diet despite diagnostic uncertainty. Serologic studies, such as IgA tTG, should be performed, and HLA typing for DQ2 and DQ8 may be helpful because a negative result virtually excludes celiac disease. A small bowel biopsy should be obtained as a baseline because an abnormal biopsy likely obviates the need for challenge.

Gluten challenge must be initiated with caution because occasionally patients are exquisitely sensitive to small amounts of gluten¹²³; other patients might require prolonged challenge before symptoms or significant histologic abnormalities recur. If a small amount of gluten, such as a cracker or one quarter of a slice of bread, is tolerated, the amount can be doubled every three days until the patient is ingesting the equivalent of at least four slices of bread daily. The challenge should be continued for at least six weeks or until more severe symptoms redevelop, at which time both serum IgA EMA or IgA tTG and small bowel biopsy should be performed. A total of 10 g of gluten daily for a period of six to eight weeks is usually sufficient to result in definite histologic deterioration.

If serologic tests and small bowel biopsy both are negative, the patient should be monitored for signs and symptoms of celiac disease on a normal diet for at least six months, after which serologic testing should be repeated.

STOOL EXAMINATION

If malabsorption is sufficient to produce significant steatorrhea, a watery or bulky, semi-formed, light tan or grayish, malodorous, greasy-appearing stool results. Microscopic evaluation of the fat content of a stool suspension stained with Sudan III or IV after hydrolysis with glacial acetic acid and heat is a helpful test. To document steatorrhea unequivocally, the amount of fat in a three-day collection of stool may be determined quantitatively, using the reliable van de Kamer chemical method.

HEMATOLOGY AND BIOCHEMISTRY TESTS

A variety of hematologic and biochemical abnormalities may be found in persons with untreated celiac disease, including deficiencies of iron, folic acid, and vitamin D. These abnormalities reflect nutritional deficiency states secondary to enteropathy-induced malabsorption. Iron deficiency anemia is common in both children and adults with celiac disease, and combined iron and folate deficiency is characteristic, especially in children. With the exception of pregnancy, severe anemia is uncommon, usually develops with extensive disease, and should raise the suspicion of a complication, such as lymphoma. The peripheral blood film might reveal target cells, siderocytes, Heinz bodies, crenated red blood cells, and Howell-Jolly bodies, which suggest splenic atrophy.⁸¹

Although they are relevant to patient evaluation and management, none of these hematologic or biochemical tests is sufficiently sensitive or specific to serve as useful screening or diagnostic tools. Similarly, although an oral d-xylose test, lactulose-mannitol test, or fecal fat evaluation may be abnormal in untreated celiac disease, they, too, lack sensitivity and specificity and so are not useful as routine investigations in suspected celiac disease. Chronically elevated serum aminotransferase levels in the range of 1.5 to 2 times normal values have been reported in 9% to 40% of patients with untreated celiac disease, and in most patients, the elevated levels resolve on a gluten-free diet.

RADIOLOGY

Barium studies of the small intestine seldom are required in evaluating patients with suspected celiac disease. Abnormal roentgen findings include dilatation of the small intestine and replacement of the normal delicate feathery mucosal pattern with either marked thickening or complete obliteration of the mucosal folds and straightening of the valvulae conniventes. Even with modern, less viscous barium preparations, flocculation, segmentation, and clumping of contrast is occasionally seen in severe cases. In patients with mild or moderate disease, the distorted mucosal pattern usually is confined to the proximal small intestine, whereas patients with severe disease may have an abnormal mucosal pattern through the entire small intestine. Excessive secretion of fluid into the proximal small intestine, coupled with defective absorption of intraluminal contents, causes dilution of the barium, resulting in decreased contrast in the distal small intestine.

Small bowel studies are most useful in suggesting diagnoses other than celiac disease, including Crohn’s disease (terminal ileitis), scleroderma (hypotonicity), bacterial overgrowth (small bowel diverticulosis), or collagenous disease (bowel wall rigidity). Patients with mild celiac disease might have a normal small bowel barium study, and these studies are not as sensitive as small intestinal biopsy or serology in providing diagnostic information. Routine small bowel barium studies are unnecessary in most patients with celiac disease and are considered mainly to exclude complications, such as lymphoma, carcinoma, ulcerative jejunoileitis, or stricture. Abdominal computed tomography (CT) or magnetic resonance imaging (MRI) might provide a diagnostic clue to the presence of celiac disease or refractory celiac disease by revealing splenic atrophy, ascites, mesenteric lymphadenopathy, and the presence of cavitating mesenteric lymph nodes. A bone survey might reveal diffuse demineralization with a generalized decrease in bone density. Occasionally, the secondary effects of osteopenic bone disease are seen, including vertebral body compression fractures and pseudofractures (Milkman’s lines).

DISEASES ASSOCIATED WITH CELIAC DISEASE

A large number of diseases occur more commonly among patients with celiac disease and are delineated in Table 104-3.¹²⁸ In addition to an association with autoimmune disorders, some of the associated diseases also have similar HLA haplotype associations.

Table 104-3 Disorders Associated with Celiac Disease

Definite Association

Possible Association

Modified from Mulder CJ, Tytgat GN. Coeliac disease and related disorders. Neth J Med 1987;31:286.

GLUTEN-FREE DIET

Removal of gluten from the diet is essential for treating patients with celiac disease (Table 104-4).⁸⁰ The importance of gluten withdrawal was established by Dicke’s, van de Kamer’s, and Weijers’ astute studies in the early 1950s when the toxicity of wheat protein in children with celiac disease was demonstrated.^6,7 In 1962, Rubin and colleagues³¹ showed that instillation of wheat, barley, and rye flour into the histologically normal small intestine of persons with treated celiac disease rapidly induced celiac-like symptoms and that these symptoms were accompanied by the development of the typical celiac lesions in the exposed mucosa.

Table 104-4 Principles of Initial Dietary Therapy for Patients with Celiac Disease

ppm, parts per million.

Modified from Trier JS. Celiac sprue and refractory sprue. In: Feldman M, Scharschmidt BF, Sleisenger MH, editors. Gastrointestinal and Liver Disease. 6th ed. Philadelphia: WB Saunders; 1997. p 1557.

Because a gluten-free diet represents a lifetime commitment for patients with celiac disease, is more expensive than a normal diet, and carries a social liability, it should not be undertaken casually or as a therapeutic trial. In reality, complete dietary elimination of all gluten-containing cereal grains is a challenge for most patients to achieve and maintain. Hidden gluten is present in a wide variety of processed foods, because wheat flour is used widely in the food industry as a thickener and inexpensive filler for many commercial products, precooked meals, and convenience foods, including ice cream, pasta, sausages, fish sticks, cheese spreads, salad dressings, soups, sauces, mixed seasonings, mincemeat for mince pies, and even some medications¹⁵⁶ and vitamin preparations (Table 104-5). Furthermore, grains that are naturally gluten-free can become contaminated with wheat, particularly when mills use the same production lines and equipment to process both gluten-containing and gluten-free products. Beers, lagers, ales, and stout should be avoided (apart from the few available specifically gluten-free products), but wines, many liqueurs, and ciders as well as spirits, including brandy, malt, and scotch whiskey, can be consumed (unless gluten-containing flavorings have been added after distillation).

Table 104-5 Some Potential Sources of Hidden Gluten

Helpful recipes as well as detailed instructions regarding gluten-free diets have been published in excellent, inexpensive books that are of great value to patients with celiac disease.¹⁵⁷ National celiac societies in many countries publish regularly updated handbooks that list the available gluten-free products. Food lists are applicable for use only in the country in which they were compiled. Similar foods with well-known brand names may be made under franchise using slightly different recipes in different countries and may be gluten-free in one country and not in others. Consequently, patient education is crucial, and the institution of an effective gluten-free diet requires extensive and repeated instruction of the patient by the physician and dietitian, as well as a motivated and basically suspicious, label-reading patient. The importance of patient education and support by a multidisciplinary team of health care providers was emphasized in the recently published National Institutes of Health consensus development conference statement (Table 104-6).¹⁵⁸

Table 104-6 Key Elements in the Management of Celiac Disease

From the National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-30, 2004. Gastroenterology 2005;128:S1-S9.

There is considerable variation among patients with celiac disease in their ability to tolerate gluten. Some patients can ingest small amounts of gluten without developing symptoms. Others are exquisitely sensitive to ingestion of even minute amounts of gluten and can develop massive watery diarrhea reminiscent of acute cholera within hours of eating very small amounts of gluten. Occasionally, the diarrhea is so severe that it can induce acute dehydration, termed gliadin shock or celiac crisis.¹²³

Patients with untreated celiac disease might have accompanying brush border lactase deficiency secondary to damage to surface epithelial cells. Therefore, milk and dairy products should be avoided upon initiation of a gluten-free diet. After the disease responds to the diet, however, these products can be reintroduced, if they are tolerated.

It is now clear that moderate amounts of oats are not toxic to the vast majority of patients with celiac disease. In a carefully conducted randomized clinical trial, adults with celiac disease who consumed 50 to 70 g of oats per day for 6 to 12 months did not differ in regard to symptoms, nutritional status, or duodenal mucosal histology compared with patients maintained on an oat-restricted, gluten-free diet¹⁵⁹; in a smaller follow-up study, the same investigators showed no harm in celiac disease patients from five years of oat ingestion.¹⁶⁰ Patients with DH also can include moderate amounts of oats in their gluten-free diet without deleterious effects to the skin or intestine,¹³⁰ and an open-labeled study showed that a six-month trial of commercial oat breakfast cereal also was safe for children with newly diagnosed celiac disease beginning a gluten-free diet.¹⁶¹ It should be stressed, however, that oat products obtained from the grocery store shelf can contain significant amounts of other grains, especially wheat, because of contamination in the field, during harvesting or transport, or at the mill. Consequently, oats often are avoided initially in patients with newly diagnosed celiac disease until remission is achieved on a gluten-free diet. Subsequently, up to 2 ounces of oats per day from a reliable source may be introduced and continued if tolerated.

A gluten-free diet can be rich in nutrition and conducive to excellent general health. Careful attention is needed, however, to avoid certain pitfalls of the gluten-free diet. The gluten-free diet often contains inadequate iron, calcium, vitamin D, and B vitamins.¹⁶² Hence nutritional counseling and monitoring together with a daily gluten-free multivitamin supplement is recommended to avoid deficiency states. Avoiding wheat, barley, and rye often leads to inadequate fiber intake and constipation unless steps are taken to replace these with other sources of dietary fiber. Some weight gain is common after starting a gluten-free diet as malabsorption resolves; however, excess weight gain or obesity can easily ensue, especially if fat- and calorie-rich gluten-free processed foods and snacks are consumed in excess. Preparing meals using fresh ingredients including gluten-free grains and reducing the use of prepared or processed foods are often the keys to a healthy gluten-free diet.

After starting a gluten-free diet, most patients improve within a few weeks. In many, substantial symptomatic improvement is noticed within 48 hours, although it can take weeks or months to achieve full clinical remission. Pink and Creamer¹⁶³ reported that 70% of patients with celiac disease who started a gluten-free diet returned quickly to normal health and reported improvement in their symptoms within two weeks. The speed and eventual degree of histologic improvement are unpredictable, but they invariably lag behind the clinical response.

Although an increase in enterocyte height may be evident within a week of gluten withdrawal, the return of villus architecture toward normal takes considerably longer and might not be evident on rebiopsy for two or three months. In some patients, histologic resolution can take up to two years; the main reason for this slow or partial recovery is inadvertent exposure to gluten.³¹ Although a return to normal is common in children, in approximately 50% of adults on a gluten-free diet, biopsies show only partial improvement; the less severely damaged distal intestine recovers more rapidly than the maximally damaged proximal intestine.¹⁶⁴ The investigation and management of patients who have celiac disease and whose symptoms or signs do not respond to dietary gluten avoidance are discussed later (see the discussions of nonresponsive and refractory celiac disease).

DIETARY SUPPLEMENTS

In addition to the gluten-free diet, patients with newly diagnosed celiac disease should receive appropriate supplemental therapy to help correct nutritional deficiencies caused by malabsorption; iron deficiency is the most common. Deficiencies of vitamin D, vitamin B₁₂, or folic acid are not uncommon. Patients with purpura, bruising, or other evidence of bleeding might have prolongation of their prothrombin time and require supplemental vitamin K. Patients with severe diarrhea and dehydration require vigorous intravenous replacement of fluids and electrolytes. Intravenous calcium gluconate (1 to 2 g) should be administered promptly to a patient who has tetany. If there is no response, the tetany may be caused by hypomagnesemia and require magnesium replacement.

The risks of osteopenia and osteoporosis should be explained to all patients with celiac disease and general advice should be given about weight-bearing exercises, dietary calcium and vitamin D intake, and the adverse effects of smoking and excessive alcohol consumption. There is compelling evidence that strict adherence to a gluten-free diet protects against further bone loss and initially is associated with an increase in bone mineral density (BMD).¹⁶⁵ A total daily calcium intake of 1500 mg should be ensured—a cup of skim milk provides 300 mg. If dietary calcium is inadequate, 500 to 1500 mg of supplemental calcium should be given. Vitamin D deficiency should be sought and treated (particularly in patients with significant steatorrhea), until the malabsorption has responded to gluten withdrawal, to prevent mobilization of skeletal calcium.

One year of gluten withdrawal has been shown to reverse osteopenia in most patients, including postmenopausal women and patients with incomplete mucosal recovery,¹⁶⁶ but patients who have secondary hyperparathyroidism at the time celiac disease is diagnosed tend to have more refractory osteopenia, and their BMD might not normalize even after several years of gluten withdrawal.¹⁶⁷

Clinicians often rely on serum calcium, phosphate, and alkaline phosphatase measurements, but osteomalacia still can exist even if these tests are normal. If these tests are normal and osteomalacia still is suspected, a serum 25-hydroxy vitamin D level can be determined; this test is expensive, however, and the less expensive parathormone assay may be considered. A low-normal calcium and an elevated parathormone level indicates secondary hyperparathyroidism, and calcium (500 to 1000 mg daily) together with vitamin D (400 to 800 units daily) should be given.¹⁶⁸ The serum calcium level must be monitored and supplementation promptly discontinued if hypercalcemia develops.

All patients should have their BMD measured one year after diagnosis. Recent guidelines suggest that patients with treated celiac disease who have progressive osteoporosis despite correction of calcium and vitamin D deficiency should be offered oral biphosphonate therapy and have their BMD checked every one to two years.¹⁶⁸

Vitamin A, thiamine, riboflavin, niacin, pyridoxine, vitamin C, and vitamin E, all in the form of a multivitamin preparation, probably should be taken daily by all patients with celiac disease in light of their predisposition to malabsorption and the risks for nutritional deficiencies associated with a gluten-free diet.¹⁶² Some patients have reported symptomatic improvement with correction of magnesium, copper, and zinc deficiencies.¹⁶⁹

Drugs, like nutrients, may be absorbed capriciously by patients with severe celiac disease. Medications considered essential for the patient’s well-being might need to be administered parenterally or monitored closely until absorption improves in response to treatment with a gluten-free diet.

GLUCOCORTICOIDS

In vitro studies have shown that the addition of glucocorticoids prevented the harmful effects of gluten on biopsy specimens from patients with celiac disease.¹⁷⁰ Although celiac disease can be treated with glucocorticoids, with rapid improvement in symptoms, the effect rarely persists once treatment is stopped, and significant side effects are common.¹⁷¹ Therefore, glucocorticoids are not indicated in the routine management of celiac disease but are reserved for severely ill patients who present with acute celiac crisis manifested by severe diarrhea, dehydration, weight loss, acidosis, hypocalcemia, and hypoproteinemia.¹⁷² These few patients might benefit from a short course of glucocorticoids until the gluten-free diet takes effect. A brief course of glucocorticoids also may be used in the rare instances of gliadin shock that occurs occasionally in treated patients who are subject to gluten challenge.¹²³

ULCERATIVE JEJUNOILEITIS

Ulcerative jejunoileitis, also known as chronic, nongranulomatous ulcerative enterocolitis or nongranulomatous jejunitis, is a rare but serious complication of celiac disease characterized by ulceration and strictures of the small intestine (see Chapter 115). Whether ulcerative jejunoileitis truly is a discrete entity has been questioned, because lymphoma ultimately is diagnosed in many of these patients.¹⁷⁶ Indeed, ulcerative jejunoileitis in association with EATL previously was designated malignant histiocytosis.

Ulcerative jejunoileitis should be suspected in patients with celiac disease who present with weight loss, abdominal pain, and diarrhea that do not respond to a gluten-free diet. Typically, patients also experience recurrent episodes of intestinal ulceration and obstruction with gradual weight loss despite surgery and strict adherence to a gluten-free diet. Areas of intestinal ulceration and stricture formation typically cause hemorrhage and obstruction (Fig. 104-9); perforation with peritonitis also can occur. Diagnosis is made by enteroscopy, contrast studies of the small intestine, abdominal CT, capsule endoscopy, or laparotomy.

Figure 104-9. A small bowel barium contrast study and corresponding histopathology from a patient with ulcerative jejunoileitis complicating celiac disease. A, A segmental area of fixed narrowing with associated mucosal distortion and ulceration in the distal jejunum and proximal ileum is seen. B, Histology of a segment of resected small intestine showing ulcerated mucosa with adjacent diffuse villus atrophy and lymphocytic infiltrate consistent with celiac disease. Lymphocytes within the epithelium and lamina propria were positive for T-cell antigen (CD3); no overt lymphoma was evident, but Southern blot analysis revealed clonal T-cell receptor gene rearrangements in both the involved and uninvolved small intestine and an adjacent mesenteric lymph node consistent with cryptic enteropathy-associated T-cell lymphoma.

Some patients respond to a gluten-free diet, but surgical excision of the worst affected segments of small intestine so far has proved to be the most effective treatment. There is a high risk for transition to diffuse or multifocal EATL, but in a few patients with well-documented celiac disease and localized jejunoileitis, no evidence of malignant disease develops and there is a response to either surgical resection or therapy with glucocorticoids and azathioprine.¹⁷⁷ Even in the absence of overt malignant transformation, however, the five-year survival rate for patients with ulcerative jejunoileitis is less than 50%.

COLLAGENOUS SPRUE

Collagenous disease is characterized by the development of a subepithelial collagen band thicker than 10 mm in the small intestine. Although collagenous disease has been regarded as an entity distinct from celiac disease,¹²⁷ deposition of collagen under the intestinal epithelial cells has been noted in up to 36% of patients with classic celiac disease.¹⁷⁸ Furthermore, there are several reports of patients with collagenous disease who have EMA¹⁷⁹ and complications of refractory celiac disease, specifically ulcerative jejunoileitis¹⁸⁰ and lymphoma.¹⁵

Although collagenous disease often is refractory to therapy, the presence of subepithelial collagen does not, a priori, preclude a successful response to gluten withdrawal.^178,181 Collagenous disease should be distinguished from collagenous colitis, which rarely accompanies celiac disease and should be considered in the differential diagnosis of nonresponsive celiac disease.¹⁵⁴ Compared with both celiac disease and collagenous colitis, the prognosis in collagenous disease is grim, with most reported patients dying from the disease.

TREATMENT

In patients with celiac disease and no demonstrable cause for lack of response to a gluten-free diet, a variety of treatments (based mostly on small, uncontrolled studies) have been described; these include glucocorticoids, immunosuppressive drugs, elimination diets, and dietary supplementation with zinc and copper.^182–186

Evidence supporting the use of immunosuppressive therapy in the treatment of refractory celiac disease is based mainly on anecdotal reports; to date, no controlled trials have been performed.¹⁸⁵ Glucocorticoid treatment also may be necessary in patients with refractory celiac disease (see later). Azathioprine or 6-mercaptopurine may be used as a glucocorticoid-sparing agent if a dose of 10 mg of prednisolone or more per day is required to keep the condition under control.¹⁸² In one open pilot study, 13 adult patients with refractory celiac disease were treated for two months with oral cyclosporine, in doses titrated to achieve serum levels of 100 to 200 ng/mL; small intestinal histology improved in eight patients (61%), and villi normalized in five (38%).¹⁸⁶ Cyclosporine therapy has been reported to be lifesaving in occasional patients with refractory celiac disease–like disease, and it can result in reversal of glucocorticoid resistance, but its efficacy remains unproved.¹⁸³ There also has been a report on the efficacy of infliximab, a chimeric antibody to TNF-α, in refractory celiac disease.¹⁸⁴

In a study of patients with refractory celiac disease, 16 of 29 (55%) responded fully to treatment with oral enteric-release budesonide (Entocort, 9 mg daily), and an additional six (21%) showed a partial response.¹⁸⁷ Improvements were evident in patients with coexisting microscopic colitis and in those without. Oral budesonide was well tolerated, and no serious side effects were reported. Because of its good side-effect profile, oral budesonide is fast becoming a drug of first choice for treatment of refractory celiac disease.

Although a trial of immunosuppressive therapy is worth considering in all patients with refractory celiac disease, caution must be used, because these patients often are malnourished and hyposplenic; hence they may be prone to opportunistic infections. Unfortunately, some patients have only partial or no response to immunosuppressive therapy, and the clinical course is characterized by progressive malabsorption necessitating total parenteral nutrition.

COMPLICATIONS

It has long been appreciated that patients with refractory celiac disease are at high risk for developing fatal complications such as ulcerative jejunoileitis and lymphoma. Until recently, the precise link between refractory celiac disease and these complications as well as between refractory celiac disease and celiac disease remained controversial. The spectrum of autoimmune enteropathy was implicated in a handful of adult refractory celiac disease patients by the presence of antienterocyte antibodies.^188,189 It is now becoming clear, however, that refractory celiac disease, EATL, and ulcerative jejunoileitis represent a heterogeneous, but related, group of clinical conditions at the extreme end of the celiac disease spectrum. Moreover, there is now a growing realization that many of these patients have a cryptic intestinal T-cell lymphoma, characterized by phenotypically abnormal IELs that have monoclonal rearrangements of the TCR γ gene.¹⁵

Early immunophenotypical studies demonstrated that the normal cell counterpart of EATL was the IEL.¹⁹⁰ It was not until 1995, however, that Murray and colleagues¹⁹¹ made the remarkable observation that in patients with overt EATL, lymphocytes from adjacent nonlymphomatous mucosa contained the identical monoclonal TCR gene rearrangement as the overt lymphoma and coined the term cryptic intestinal T-cell lymphoma. Ashton-Key and colleagues¹⁹² later confirmed this finding and showed that both the inflammatory ulcers and the intact (nonlymphomatous) mucosa in cases of ulcerative jejunoileitis harbored a monoclonal T-cell population and that the lymphomas that developed in these patients consisted of the identical T-cell clone.

Cellier and colleagues⁶⁸ showed that the IELs in refractory celiac disease patients are abnormal in that they lack expression of CD8, which is consistently found on most normal or celiac disease IELs. Subsequent work confirmed this finding and showed that the abnormal IELs in ulcerative jejunoileitis and nonlymphomatous mucosa in EATL shared not only the genotype but also the immunophenotype of the lymphoma.¹⁹³ Cellier and colleagues¹⁵ detected aberrant clonal IELs (similar to those in most cases of EATL) in 16 (84%) of 19 patients with refractory celiac disease (type II refractory celiac disease). Of these 19, 7 (37%) had collagenous disease, 6 (32%) had ulcerative jejunoileitis, 6 (32%) had mesenteric lymph node cavitation, and 3 (16%) developed overt EATL that was clonally identical to the IELs of the preexisting refractory celiac disease. The three patients (16%) without aberrant clonal IELs (type I refractory celiac disease) all made a complete clinical and histologic recovery with glucocorticoid therapy plus a gluten-free diet.

Thus, the cumulative evidence now points to type II refractory celiac disease being a manifestation of an aberrant clonal IEL-mediated neoplastic process. These cells have destructive properties, possible related to their cytotoxic phenotype,¹⁹⁴ which leads to mucosal ulceration and lymph node cavitation, and they sometimes, but not always, undergo further molecular and clinical progression to lymphoma. As noted earlier, the proinflammatory cytokine IL-15 is massively increased in the intestine of patients with refractory celiac disease. IL-15 induces IEL secretion of IFN-γ and increases IEL cytotoxicity against epithelial cells, thereby favoring the severe enteropathy characteristic of type II refractory celiac disease.¹⁶ Increasing evidence suggests that IL-15, through its key role in modulating IEL homeostasis, ultimately might lead to lymphomatous transformation because IL-15 provides signals mandatory for the survival or expansion of the abnormal clonal IELs.

Based on this evidence, patients with suspected refractory celiac disease should have TCR and monoclonal antibody studies performed on their small intestinal biopsy samples. In the future, early recognition of the malignant potential of the intestinal infiltrate in type II refractory celiac disease might permit curative surgery or chemotherapy. Alternatively, novel anti–IL-15 biological agents might prevent the progression of refractory celiac disease and the development of lymphoma.