Secondary Logo

Journal Logo

Celiac Disease

Updates on Pathology and Differential Diagnosis

Dai, Yinghuan MD, PhD*; Zhang, Qin MD; Olofson, Andrea M. MD; Jhala, Nirag MD§; Liu, Xiuli MD, PhD

doi: 10.1097/PAP.0000000000000242
Review Articles
Free

Celiac disease is a gluten-triggered immune-mediated disorder, characterized by inflammation of the enteric mucosa following lymphocytic infiltration and eventually resulting in villous blunting. There have been many developments in refining diagnostic laboratory tests for celiac disease in the last decade. Biopsy-sparing diagnostic guidelines have been proposed and validated in a few recent prospective studies. However, despite these developments, histologic evaluation of duodenal mucosa remains one of the most essential diagnostic tools as it helps in the diagnosis of celiac disease in individuals who do not fulfill the biopsy-sparing diagnostic criteria and in those not responding to a gluten-free diet. Histologic evaluation also allows for the assessment of mucosal recovery after treatment and in the identification of concurrent intestinal diseases. Therefore, pathologists should be familiar with the histologic spectrum of celiac disease and need to be aware of other disorders with similar symptoms and histopathology that may mimic celiac disease. This review aims to provide pathologists with updates on celiac laboratory testing, biopsy-sparing diagnostic criteria, histopathology, complications, and differential diagnoses of celiac disease.

*Department of Pathology, Second Xiangya Hospital of Central South University, Changsha

Department of Pathology, the Third Central Hospital of Tianjin, Tianjin, China

Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL

§Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA

Y.H. and Q.Z. contributed equally.

The authors have no funding or conflicts of interest to disclose.

All figures can be viewed online in color at www.anatomicpathology.com.

Reprints: Xiuli Liu, MD, PhD, Department of Pathology, Laboratory Medicine, and Immunology, University of Florida, P.O. Box 100275, Gainesville, FL (e-mail: xiuliliu@ufl.edu).

Celiac disease is an immune-mediated disorder of the small intestine elicited by the exposure to gluten and gluten-related proteins in genetically susceptible persons carrying the specific class II human leukocyte antigens (HLA) DQ2 and/or DQ8 genotype. The estimated prevalence is about 0.5% to 1% in most Western European and Northern American populations.1,2 Diagnosis of celiac disease involves a synthesis of clinical manifestations, supportive serologic markers, histopathologic examination of the small intestinal mucosa, and response to gluten-free diet. In rare cases, genetic testing for celiac disease susceptible loci such as HLA DQ2 and DQ8 alleles can be useful, as an absence of HLA DQ2/DQ8 essentially excludes celiac disease. The most commonly used serological antibodies of celiac disease are IgA against tissue transglutaminase (IgA-TTG), which is characterized by high specificity (98%),3 IgA against endomysium (IgA-EMA), and IgG against deamidated gliadin (IgG-DGL). In 2012, the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published a set of diagnostic criteria for celiac disease giving the pediatric gastroenterologist an option to diagnose celiac disease without biopsies on the basis of retrospective data or small single-center studies.4 Recently, several prospective studies reported a very favorable performance of IgA-TTG5 and a combined approach using serology tests IgA-TTG and IgG-DGL6 in diagnosing pediatric celiac disease. Biopsy-sparing strategies have also been advocated to diagnose celiac disease in adults. However, due to intrinsic differences among assays, these biopsy-sparing strategies are suboptimal for achieving a uniform prediction of atrophy in a real-life setting.7 Like celiac serology, other blood tests may be helpful in diagnosing celiac disease. Recently, an HLA-DQ-gluten tetramer blood test was reported to be able to identify patients with and without celiac disease with a high level of accuracy regardless of gluten consumption status.8 Despite the excitement associated with these new developments, these approaches need validation in large prospective studies and duodenal biopsy remains an essential diagnostic tool for celiac disease in most cases at the time being.

Mucosal pathology in celiac disease spans a spectrum of abnormalities including intraepithelial lymphocytosis (IELs), atrophy of the intestinal villi, crypt hyperplasia, increased numbers of mononuclear inflammatory cells in the lamina propria, and in occasional severe cases, crypt hypoplasia. None of these abnormalities are specific for celiac disease as they may be caused by a variety of other disorders such as immunodeficiency, infection or infection-related disorders, inflammatory bowel disease, autoimmunity, diet, nutrition, and medications. Enteropathy-associated T-cell lymphoma (EATL) is a complication of celiac disease and may mimic celiac disease. These differential diagnoses pose diagnostic challenges to pathologists, particularly, who practice general pathology. Herein we review the updates of laboratory tests, pathologic features, and differential diagnoses of celiac disease. Early and correct diagnosis of celiac disease helps initiate a gluten-free diet to avoid complications, such as refractory celiac disease, EATL, and small bowel adenocarcinoma.9 In addition, identification of a nonceliac disease condition to account for the observed “celiac disease”-like histology obviates a life-time or long-term unnecessary gluten-free diet. Histologic examination of duodenal mucosa not only helps diagnose celiac disease but also monitors disease course and response to treatment10,11 and it should be an essential outcome measure in any clinical trials of celiac disease treatment.12

Back to Top | Article Outline

NORMAL HISTOLOGY OF DUODENUM AND JEJUNUM

Duodenal and jejunal villous architecture is determined by the depth of biopsy; if there is muscularis mucosae present, the villi are often taller, slender, and lie more closely together than when this tethering layer is absent. When a normal duodenal mucosa biopsy is well-oriented and cut at right angles, it shows well-formed, long, slender villi projecting from a simple gland layer into the lumen (Fig. 1). The glands are orderly arranged, regularly spaced, and rest on the muscularis mucosae. In the duodenum, the length of the villi is ~3 times the length of the crypt in adults and about twice the length in children. In normal adults, finger-like villi predominate at all levels of small bowel, but leaf-like villi, bifid, trifid, fused or tongue-shaped, and short ridges can be seen.13–16

FIGURE 1

FIGURE 1

The villi are covered by a columnar epithelium that has a brush border, which can be appreciated on hematoxylin and eosin (H&E)-stained tissue sections as a faint density (Fig. 1). The villous epithelium is continuous with the crypt epithelium, which represents the regenerative zone. The surface epithelium is mainly composed of absorptive cells intermixed with a variable number of goblet cells. At the base of the crypt epithelium, Paneth’s cells are present. Occasional enterochromaffin cells are also scattered in the crypts. Goblet cells are present within the glands but progressively decrease in number toward the tip of the villi. Mitotic figures are frequently seen in the crypt epithelium but are normally never present in the villous epithelium.

Occasional IELs can be seen in the normal small bowel epithelium, most often seen as a small, dense nucleus within a vacuole (Fig. 1).17 IELs that lie in the spaces between small bowel epithelial cells are an integral part of the gut-associated lymphoid system including the gut-associated lymphoid follicles, Peyer’s patches, and mesenteric lymph nodes. In normal small bowel mucosa, IELs demonstrate a “decrescendo” sign, which simply means that the density of IELs in the tips of the villi is noticeably lower than that in the proximal third of villi (Fig. 1).18 The ratio of IELs to the surface epithelial cells is 1:5 under normal conditions. Immunohistochemistry shows that more than 70% to 95% of IELs are suppressor, or cytotoxic T cells, 15% to 20% are of the helper phenotype,19 and they are mostly T-cell receptor (TCR) αβ positive with only a small portion carrying TCRγδ. The exact functions of IELs are not known, but it has been suggested that they play a significant role in handling antigens and modulating local immune responses by providing immediate, potent, and long-lasting protection.20–22

Depending upon the applied definition of “normal” or “control,” the location of the biopsy and the thickness of the tissue sections examined, the upper limit of what constitutes a normal IEL number may vary. In the jejunum, there are usually 6 to 40 lymphocytes per 100 villous epithelial cells in adults23 and 12 to 35 per 100 in children.24 In the duodenum, the IEL counts are lower than those in the jejunum. More recent studies have shown, that most, if not all, individuals have no more than 20 to 25 lymphocytes per 100 epithelial cells in normal duodenal mucosa.25–28 On the basis of these recent studies, the current upper limit of normal IEL count most commonly used in the interpretation of duodenal biopsy and cited in the literature is 20 to 25 IELs per 100 epithelial cells.25–27

In routine preparations of small bowel biopsies, the lamina propria of the villous core and surrounding mucosa is composed of delicate, loose connective tissue infiltrated by a small number of lymphocytes with occasional plasma cells, eosinophils, mast cells, and histiocytes. A central blind-ending lacteal, often recognizable as a parallel double row of endothelial nuclei is present in the villous core. The smooth muscle cells that extend upward from the muscularis mucosae can be seen as they surround the central lacteal to the very tip of the villous process. In addition, a capillary plexus lies beneath the basement membrane. The subepithelial collagen band is thin and inconspicuous.

In endoscopically obtained small bowel mucosal biopsies, Brunner’s glands can be seen in the duodenum but variably in the jejunum. They occur on both sides and between the elements of muscularis mucosae. Rarely, small groups of Brunner’s glands occur in the superficial portion of the lamina propria. Prominence or hyperplasia of Brunner’s glands is often associated with broad and short villous architecture. As the ileum is approached, the ratio of goblet cells to absorptive cells increases, and the villi tend to become slightly broader and shorter than in the jejunum; the lymphoid aggregates increase in number and the villi overlying lymphoid areas are often stubby or absent.

Back to Top | Article Outline

PATHOLOGY OF CELIAC DISEASE

Endoscopic appearance alone may lead to a suspicion of celiac disease. For example, Brocchi et al29 described markedly decreased or absent duodenal Kerckring’s folds and recommended biopsy when this sign is present, even if the patient has minimally transient or seemingly unrelated symptomatology.29 Other endoscopic abnormalities of celiac disease include a mosaic pattern, scalloped folds (Fig. 2), and visibility of the underlying blood vessels.30 The presence of significant endoscopic abnormalities, including ulceration and stricture, should alert the clinician to other potential diagnoses such as complicated celiac disease, other inflammatory bowel disease, and malignancies including lymphoma. However, normal appearing mucosa under endoscopy does not exclude celiac disease and biopsies should be taken for histologic examination.31

FIGURE 2

FIGURE 2

While the optimal number of biopsies needed for the diagnosis of celiac disease remains unclear, the American Gastroenterology Association has recommended that 6 biopsies from the distal duodenum are necessary for the diagnosis of celiac disease32 or 4 biopsies from the distal duodenum with 2 biopsies from the duodenal bulb as an alternative approach.33 But the adherence to these biopsy guidelines is suboptimal (at a rate of 35%) in clinical practice despite the fact that adherence to these guidelines increases the detection of celiac disease.34,35 For the time being, it might be best to biopsy at least 2 sites; 1 or 2 biopsies of the duodenal bulb (either 9-o’clock or 12-o’clock position), and at least 4 biopsies of the distal portion of the duodenum due to the possibility of subtle changes or patchy distribution in patients with celiac disease. Biopsies of the proximal jejunum can also be collected if possible.36

Celiac disease affects the proximal small bowel in most patients, with the greatest severity usually seen in the duodenum and proximal jejunum.15,37,38 The ileum may be involved in severe cases.13 The length of the small bowel involvement, rather than the severity, more closely correlates with clinical status.39,40 Because of variation in the diagnostic accuracy of clinical findings and serologic testing, small bowel mucosal biopsy has remained the cornerstone test for celiac disease.13,15,31,32,41–44 Accurate diagnosis of celiac disease in suspected cases has 2 important prerequisites; biopsies should be performed when the patient consumes gluten-containing diet and the biopsy tissue fragments are well oriented.

Previously, the small bowel biopsies were taken by suction capsule, positioned at the distal duodenum, duodeno-jejunal junction, or proximal jejunum under fluoroscopic control.13,15,33 While the use of the distal duodenal biopsy in the investigation of malabsorption has been increasingly used over the years and widely accepted31,41,45 as the duodenal distal to the bulb is not affected by peptic ulcer disease, recent studies also showed that biopsy from the duodenal bulb region may enhance the diagnostic yield of celiac disease.46,47 In addition, biopsy of duodenum under endoscopic direct vision has also been wildly used as a screening procedure for the detection of celiac disease in both normal populations and as a follow-up practice for patients with reticulin and gliadin antibodies but a normal small bowel mucosa.

Back to Top | Article Outline

HISTOLOGY OF UNTREATED CELIAC DISEASE

In histologic sections, the cardinal features of celiac disease are crypt hyperplasia, loss of villous height, chronic inflammatory cell infiltration, and surface IEL (Fig. 3). In biopsies from the duodenum in patients with untreated, classic celiac disease, the overall thickness of the mucosa is normal or only slightly decreased, and the crypts are clearly hyperplastic and elongated. The villous blunting can be variable and ranges from completely flat, partial villous blunting, to minimal blunting.13,15 Accompanying the villous blunting, the absorptive epithelium shows a variable amount of damage and an apparent increase in IELs. The surface epithelial cells may show hyperchromasia, a reduction in cell height, and palisading of nuclei that often appear pyknotic with blurring of cytoplasmic boundaries. Accurate assessment of villous blunting requires proper orientation of biopsies. However, biopsies are rarely perfectly oriented and in such cases, an attempt should be made to find 3 to 4 well-oriented villi in a row to assess the architecture. The lamina propria contains an increased number of lymphocytes, plasma cells, some eosinophils, histiocytes, and mast cells. There should not be obvious collagen deposition underneath the surface epithelium.

FIGURE 3

FIGURE 3

On the basis of a substantial amount of clinical research, including a series of dynamic studies, Marsh48 first introduced a scheme to categorize small bowel mucosa lesions seen in celiac disease, which is now well known as the Marsh classification. This Marsh classification scheme recognizes an infiltrative lesion (Marsh type 1), hyperplastic lesion (Marsh type 2), destructive lesion (Marsh type 3), and atrophic lesion (Marsh type 4). Marsh type 3 lesion is the most common pattern for symptomatic celiac disease patients. Of note, there is no cutoff value for the number of IELs stated in the original Marsh classification scheme. Four years later, an updated classification proposed the use of 40 IELs/100 enterocytes as the upper cutoff point for normal and further subdivided group 3 into type 3a, 3b, and 3c on the basis of the severity of villous shortening or blunting.49 This updated classification scheme is now known as the Marsh-Oberhuber classification system and describes 5 histologic lesions associated with celiac disease, termed preinfiltrative (type 0), infiltrative (type 1), infiltrative-hypertrophic (type 2), flat-destructive (type 3), and atrophic-hypoplastic (type 4) (Table 1).

TABLE 1

TABLE 1

Preinfiltrative lesions (type 0) refer to normal mucosa seen predominantly in patients with dermatitis herpetiformis, but without evidence of malabsorption. Infiltrative lesions (type 1) consist of an increase in IELs (IEL) with preserved villous architecture (by definition, villus height, and the villus to crypt ratio is normal or near normal), whereas infiltrative-hyperplastic lesions (type 2) show the additional feature of elongated crypts. Both of these patterns of injury are subtle and can be seen in patients with celiac disease with or without symptoms, patients with dermatitis herpetiformis, and in first-degree relatives of patients with celiac disease. Phenotypic analyses by immunohistochemistry have shown that the increase in IELs is the result of increased number of Tγδ and Tαβ cells.50 The number of TCR αβ but not of TCR γδ IELs correlates with the grade of villous atrophy in celiac patients on a long-term non–gluten-free diet.50 Destructive lesions (type 3) refer to the presence of villous blunting accompanied by crypt hyperplasia and IEL with a variable degree of increased chronic inflammation in the lamina propria. The thickness of the mucosa should be normal or near normal. This is the most common pattern of untreated celiac disease in symptomatic patients.40 The destructive lesion has been further divided into types 3a, 3b, and 3c in the Marsh-Oberhuber classification by the degree of villous blunting. Hypoplastic lesions (type 4) refer to an atrophic small bowel mucosa with complete villous blunting and crypt atrophy. Type 4 is rare and can be seen in patients with refractory sprue.

A different scoring system, the Corazza-Villanacci score, was developed years later and divided the spectrum of celiac disease into 3 grades, grade A, grade B1, and grade B2 (Table 2). This scoring system has less variability and greater agreement between pathologists.51 This system approximates what is often used in clinical practice and demonstrates a fair agreement among pathologists in regard to the severity of villus atrophy with a κ value of 0.39.52 Grade A shows normal crypts and villous architecture but increased IELs (>25 IELs/100 enterocytes), grade B shows atrophic but detectable villi and increased IELs, and grade B2 means flat/undetectable villi and increased IELs. Ensari proposed a 3-type diagnostic scheme for diagnosing celiac disease.33 While the pathologist should use the simplest reliable scheme for initial diagnosis of celiac disease,53 a quantitative histologic evaluation of duodenal mucosa may be more helpful in assessing treatment effect as it includes measurements of villous height, crypt depth, and IEL. Diagnostic specimens should include 5 to 12 villous-crypt units from at least 4 biopsies taken from the distal portion of the second or third part of the duodenum.10 However, this quantitative approach has not gained universal acceptance in the pathology community.

TABLE 2

TABLE 2

Back to Top | Article Outline

METHODS OF ENUMERATING INTRAEPITHELIAL LYMPHOCYTES

As increased IELs is an early and subtle change in the evolution of celiac disease and an integral histologic component of classic untreated celiac disease, accurate evaluation of this feature is critical in pathology practice. In the past several decades, many studies have shed light on appropriate methods to enumerate IELs, stains to use, and methods in which to interpret results (Table 3).

TABLE 3

TABLE 3

Continuous IEL counting: as a rule of thumb, IEL counts should be performed on well-oriented villi in sections cut at 3 to 4 μm in thickness, and only the lymphocytes sitting above the basement membrane are considered as IELs. Choice of reference area is important, and the epithelium of the whole villus should be quantified continuously as the IEL count normally declines toward the tips of villi. At least 300 (or up to 500) enterocytes should be counted in a continuous length along the epithelium in well-oriented villi. The final number of IELs should be given as the mean of the lymphocytes /100 enterocytes.23,25–27 By using this method, several studies established an upper limit of 20 to 25 lymphocytes per 100 epithelial cells in the second portion of the normal duodenal mucosa on H&E-stained sections and/or sections stained for CD3 (Fig. 1).25,26 Further, careful analysis using CD3, γ, or δ T-cell stains has shown that IEL counts of >25 per 100 epithelial cells (or a ratio of >1:4) merit suspicion for potential celiac disease, whereas counts >29 per 100 epithelial cells are found almost exclusively in patients with celiac disease. However, this type of analysis is expensive and time consuming and is therefore deemed impractical in daily practice.

Villus tip IEL counting: A more practical approach has been validated in several studies.54–56 H&E or CD3-stained sections (5 randomly chosen villous tips with 20 epithelial cells in each) were used to obtain a rapid and comparable assessment of IEL counts in the villus tip.54 With this approach, lymphocytes counts of 6 to 12 IELs per 20 epithelial cells in the tips of villi in architecturally normal mucosa are found in patients with serological or other evidence of celiac disease.54 The counts obtained using the villus tip method correlate well with previously cited studies that found that >29 IELs per 100 epithelial cells is abnormal.27 In addition, a higher mean villous tip IEL score was noted in celiac disease patients (11.6 vs. 4.3) in 1 study using this method,55 although overlapping is present.

Back to Top | Article Outline

PATHOLOGY OF LATENT OR POTENTIAL CELIAC DISEASE

As serological testing becomes more commonly used in clinical practice, more cases of celiac disease are caught at an early phase of the disease. When these patients undergo endoscopic evaluation, the small bowel mucosal biopsy often shows only mild IEL in the presence of normal villous architecture (type 0 or 1 mucosal lesion in Marsh-Oberhuber classification scheme) (Fig. 4). This form is named latent or potential celiac disease. In addition, in 10% to 38% of first-degree relatives of patients with celiac disease, IEL can be seen in an otherwise normal duodenal or upper jejunal biopsy (so called “Marsh type 1 lesion”).48,57 Similar histology can be seen in up to 40% to 50% of patients with dermatitis herpetiformis.48,58 In pathologic practice, interpretation of type 0 and 1 lesions is challenging as the assessment of subtle IEL is subjective and may be fraught with interobserver variability. In addition, the histologic pattern of IEL is not specific for celiac disease and may be seen in patients with other diseases. Thus, the interpretation of this pattern requires clinical correlation including serology test results. The difficulty in the interpretation of this pattern is also due to the relative lack of follow-up data on its clinical significance. For example, the proportion of patients with such minimal histologic changes that later develop more severe histologic lesions and symptoms is unknown as the numbers vary greatly among studies. While several studies have attempted to address the clinical significance of this pattern with inconsistent results, 1 small study suggested that 4 of 12 people (33%) with mild changes on duodenal biopsies may progress to celiac disease with flat duodenal mucosa on follow-up biopsy.55 However, in a larger study with 8 to 25 years of follow-up, only 5 of 236 patients (2.1%) with biopsies showing increased IELs or a slight reduction in villus-to-crypt ratio, eventually developed celiac disease.59 Recently, the term “lymphocytic duodenosis” has been used for the Marsh-Oberhuber type 1 lesion60 encountered in pathology practice. Follow-up class 2 HLA typing and serological testing for celiac disease seem to support that one third of these patients may have celiac disease.60

FIGURE 4

FIGURE 4

Back to Top | Article Outline

HISTOLOGIC FOLLOW-UP OF PATIENTS WITH CELIAC DISEASE

While the treatment of celiac disease is standardized by placing patients on a gluten-free diet, follow-up biopsies to confirm histologic recovery are controversial and a considerable variation in practice is observed. Celiac serological testing has a low sensitivity (below 70%) in the detection of persistent villous atrophy,61,62 yet there are no consensus criteria addressing the need and timing of repeat follow-up biopsies in patients following a gluten-free diet. Obviously, in most cases, when patients report symptomatic improvement and exhibit a fall in celiac antibody titers while on gluten-free diet, there is no need for a repeat biopsy.63 However, repeat biopsy may be necessary in patients whose antibodies do not fall within 12 months after confirmation of dietary adherence, in patients with initial negative serology, in patients with continued symptoms, and in those with minimal or ambiguous histologic changes.63 In 2 previous studies that included 284 and 114 adult celiac patients with at least 1 subsequent biopsy, 80% to 100% showed histologic improvement but only 17.5% to 35% of patients returned to normal.64,65 The reported median recovery time is 1.9 years, and patients with less severe disease at diagnosis are more likely to have a better response.64 Furthermore, compliance with a gluten-free diet is associated with the best biopsy score and degree of histologic recovery on follow-up biopsies.64 In pediatric celiac disease cases (diagnosed before 14 y of age), complete histologic normalization is reported to be 74.1%.65

Healing of the small bowel mucosa takes place in a distal to proximal direction,66 in contrast to the progression of the disease with more involvement of the proximal small intestine including the duodenum and upper jejunum with variable extension into the ileum.48,67 Because of the slow rate of IELs (γδsubtype in particular) loss, IEL may be the last feature to return to normal after a gluten-free diet.50,67 Follow-up biopsy in celiac disease patients may demonstrate persistent IEL despite strict adherence to gluten-free diet.68 Therefore, comparison of repeat follow-up biopsies to those collected before initiation of a gluten-free diet may provide the most accurate assessment of histologic improvement in relationship to villous height to crypt depth and IEL.10

The histology of small bowel mucosa may improve but not fully return to normal in a proportion of celiac disease patients who are on gluten-free diet (Fig. 5). The resolution rate of histology becomes higher with longer follow-up. For example, although half of the patients had persistent villous atrophy at the time of routine follow-up (1 y), both long-term mucosal recovery and healing is possible for the vast majority of adult patients with celiac disease.69 The ease of mucosal recovery is generally related to the degree of disease at presentation. The milder the disease is at diagnosis, the easier the mucosal recovery is after the gluten-free diet.

FIGURE 5

FIGURE 5

Back to Top | Article Outline

GLUTEN CHALLENGE WITH DUODENAL BIOPSY

Gluten challenge is now only rarely performed unless there is diagnostic difficulty. The most likely scenario for needing such a test is in a patient who is already on a gluten-free diet despite not having been diagnosed with celiac disease. If such a test is needed, a 4-week challenge with sufficient gluten to reproduce the symptoms before biopsy specimens are taken is adequate in most cases.32 It is important to keep in mind that symptoms triggered by gluten challenge may be due to conditions other than celiac disease. In a recent study, Uhde et al70 found a subset of individuals who experience sensitivity to wheat without celiac disease, a condition called nonceliac gluten or wheat sensitivity (NCGWS). NCGWS is associated with inflammation of the entire intestinal tract with different histologic features such as prominent eosinophilic infiltration.71 Histologic examination of small bowel biopsy is essential to distinguish celiac disease and NCGWS after gluten challenge.

Back to Top | Article Outline

FLOW CYTOMETRY OF DUODENAL BIOPSY

Flow cytometry of duodenal biopsies from patients with celiac disease demonstrate an increased number of γδIELs and a decreased number of natural killer–like IELs.72,73 However, flow cytometry is not routinely used to diagnose celiac disease, but it may be helpful in cases where serology, histology, and HLA typing are inconclusive as reported in 1 study that demonstrated a diagnostic sensitivity of 91.7% and a specificity of 93.3%.72

Back to Top | Article Outline

PITFALLS IN DIAGNOSING CELIAC DISEASE

Because the diagnosis requires an accurate assessment of villous atrophy, the duodenal biopsies should be well-oriented and high-quality slides obtained. Very often, the duodenal biopsy is tangentially sectioned and interpretation can be compromised. Tangentially cut sections may lead to a false-positive diagnosis (IEL over interpreted because cross-sections of the base of villi are evaluated or tangentially cut villi are misinterpreted as blunted villi) or false-negative diagnosis (when the villous atrophy is missed). Reprocessing the biopsy may be needed in some cases. The reported unacceptable rate for the biopsy specimen quality is ~8%.74 Sometimes, overstaining with hematoxylin may cause difficulty in the assessment of IELs, particularly when there is epithelial regenerative change. In such cases, restaining the biopsy may be helpful and in truly difficult cases, immunohistochemical stain for CD3 may be useful. Thick sections may also exaggerate IEL leading to false-positive diagnosis. In cases with overlapping nuclei of enterocytes and a seemingly “increased” IEL, a thinner section of the biopsy may help clarify the scenario. Further, interpretation of IEL should not be performed in areas overlying lymphoid aggregates or in cross-sections of the base of villi. And likewise, the interpretation of villous atrophy should not be performed in regions with prominent Brunner’s glands or regions with peptic injury. Also, attention should be paid to the thickness of the subepithelial collagen band so that cases of collagenous sprue are not misdiagnosed as celiac disease.

Previous studies show that there is a progression of mucosal lesions from completely normal mucosa (defined as Marsh 0 lesion) to mucosal inflammation (Marsh I), followed by crypt hyperplasia (Marsh II), and eventually villous atrophy (Marsh III) in the course of celiac disease. This mucosal lesion progression may take years or even decades to develop despite continuous gluten consumption.75,76 An increasing body of evidence demonstrates that in some cases of celiac disease, villous atrophy can be patchy (Fig. 6), being evident only in restricted areas of the small bowel mucosa. In some cases,38,77,78 the duodenal bulb may be the only location with villous atrophy.47,79 Because of the patchy distribution of the disease, several (4 to 6) biopsies from the second part of the duodenum and beyond are necessary for a reliable diagnosis.80 Biopsies from the duodenal bulb may also be helpful,47,79 but the interpretation of these biopsies may be confounded by peptic injury or Brunner’s gland–associated distortion, that is, broader and shorter villi.

FIGURE 6

FIGURE 6

Back to Top | Article Outline

COMPLICATED FORMS OF CELIAC DISEASE

Refractory Sprue

Refractory sprue is defined as persistent villous atrophy and increased IELs in the small bowel despite a strict gluten-free diet over the course of an arbitrary period of 6 months to 1 year that cannot be explained by other causes of villous atrophy or by overt intestinal lymphoma.81–83 In a cohort of 1138 patients with celiac disease who were followed for 25 years, 29 (2.6%) developed refractory celiac disease.9 Clinically defined refractory sprue comprises a heterogenous group of diseases and is a diagnosis of exclusion.84 Endoscopic abnormalities including villous atrophy, erosion, ulcerations, and stricture are noted in >50% of cases. Duodenal biopsies from these cases typically show villous atrophy.85,86 In addition, some cases may show subcryptal chronic inflammation, marked mucosal thinning, acute inflammation, or gastric metaplasia.87 Some cases may evolve from celiac disease and the cytologically normal, noninvasive intraepithelial T lymphocytes may show a clonal rearrangement of the TCRγ gene and/or loss of T-cell antigens such as CD8 and the TCRβ.83,85,86,88,89 These abnormalities can also be seen in their corresponding EATL and therefore, these cases may represent a neoplastic T-cell disorder,86 an intraepithelial T-cell lymphoma, or alternatively, EATL in situ.90

On the basis of the IEL immunophenotype, refractory sprue is divided into 2 types; type 1 refractory sprue has a normal IEL immunophenotype and type 2 an aberrant IEL immunophenotype with clonal intestinal TCRγ gene rearrangement and/or clonal dissemination into the blood. More specifically, in type 1 refractory sprue, the IEL immunophenotype is normal with expression of surface CD3 associated with surface CD8, and TCRβ. In type 2 refractory sprue, the IELs show the expression of intracytoplasmic CD3ε, surface CD103, and lack classic surface T-cell markers such as CD8 and TCRαβ and/or clonal TCR gene rearrangement.85 Some studies suggest that type 2 refractory sprue should be considered as a cryptic T-cell lymphoma as a significant portion of patients with type 2 refractory sprue developed overt T-cell lymphoma.83,88,89 A recent study has shown the clinical use of this classification by demonstrating a much more severe presentation and prognosis of type II refractory sprue.86 In this report, type 1 refractory sprue is defined as normal IEL phenotype (<25% CD103+ or CD45+ IELs lacking surface CD3 on flow cytometry or <50% CD3+CD8 IELs in formalin-fixed sections) and the absence of detectable clonality in duodenal biopsy specimens. Type 2 refractory sprue is defined by the following abnormalities: >25% CD103+ or CD45+ IELs lacking surface CD3/TCR complexes on flow cytometry or >50% IELs expressing intracellular CD3ε but not CD8 in formalin-fixed sections and/or the presence of detectable clonality in duodenal biopsy specimens.86 Using this set of criteria, the study showed that <44% of patients with type 2 refractory sprue survived 5 years after diagnosis in contrast to a 5-year survival rate of 93% in patients with type 1 refractory sprue.86 The presence of detectable clonality in TCRβ and TCTγ in refractory sprue has been confirmed in a recent study.91,92 However, clonality in TCRβ and TCTγ is also noted in healthy normal duodenal mucosa, in patients with active celiac disease or on a gluten-free diet, and patients with type 1 refractory sprue, but at a lower frequency.91,92 Thus, the diagnosis of type 2 refractory sprue should be a synthesis of clinical information, histology, immunophenotyping of IELs, and TCR clonality analysis of duodenal biopsy.92 Malamut and colleagues demonstrated that treatment of type 1 refractory sprue with corticosteroids resulted in a clinical response rate of 90%. However, in type 2 refractory sprue, the response rate of corticosteroids was only 74.2%.86 Several immunomodulators and/or immunosuppressors have been used for the treatment of type 2 refractory sprue with some but limited success.86

While high clinical suspicion for refractory sprue remains critical in cases when alarming symptoms such as abdominal pain, diarrhea, and weight loss develop despite a strict gluten-free diet,93 additional tests on fixed tissue may be helpful in distinguishing it from celiac disease.83,94,95 For example, in 1 small study, a simple immunohistochemical protocol using 2 T-cell markers, CD3 and CD8, on fixed tissue identified 4 of 6 suspected refractory sprue cases which had abnormal expression of CD3c+CD8 IEL and TCRγ gene rearrangements. Of the 2 remaining cases which had normal IEL phenotype and no TCRγ gene rearrangements, 1 patient failed to comply with a gluten-free diet and 1 was a slow responder.95 However, a few recent studies suggest that the utilization of aberrant phenotype IEL (CD3+CD8) may not be sensitive enough for diagnosing refractory celiac disease. This is due to the fact that 100% of refractory celiac disease cases with CD3+CD8+ IEL phenotype were also found to harbor monoclonal T-cell population, and 2 cases were associated with T-cell lymphoma at the time of diagnosis.96 In cases of refractory sprue, molecular analysis of the TCRγ gene may be a useful method for identifying cases with poor prognosis. However, large and prospective studies are needed to further illustrate the prognostic role of this combined approach using immunophenotyping and molecular testing for TCR gene rearrangement in refractory sprue.

Back to Top | Article Outline

Collagenous Sprue

The first case of collagenous sprue was described in 1947 as a syndrome of nontropical sprue with subepithelial deposits of eosinophilic hyaline materials.97 The term collagenous sprue was formally introduced by Weinstein et al98 in a patient with typical celiac disease initially responded to dietary gluten exclusion but subsequently relapsed, followed by a steady deterioration despite a rigid gluten-free diet. Endoscopic abnormalities such as nodular mucosa, scalloping, reduced or absent folds, and/or mosaic pattern are evident in all patients before treatment.99 Severe mucosal atrophy and significant deposition of collagen in the subepithelial zone of the lamina propria can be seen in the jejunal mucosa.98 Collagenous sprue appears to affect females more frequently with a female-to-male ratio of 2.4.99–101 Collagenous sprue also demonstrates a predilection for the elderly (median age at diagnosis: 69 y; range: 33 to 84 y) in contrast to celiac disease.102 Although collagenous sprue shares similar HLA genotypes with celiac disease, many patients with collagenous sprue do not have celiac autoantibodies and often have potential links to medications including olmesartan, nonsteroidal anti-inflammatory drugs (NSAIDs), proton-pump inhibitors, and statins. This would indicate that collagenous sprue is not a form of aggressive celiac disease in some cases.102 Additional case reports and small series have clearly shown that some collagenous sprue cases have a clear history of gluten-sensitive disease which becomes refractory (refractory sprue), but others are unresponsive to gluten-exclusion diets at the time of diagnosis (de novo collagenous sprue).99,101 In some reports, an association between collagenous colitis and gastritis, as well as lymphocytic colitis has been identified.99,101 Autoimmune diseases (other than celiac disease) are reported in up to 63% patients with collagenous sprue.99 The existence of non–celiac disease–associated collagenous sprue has also been substantiated by 1 recent study showing a subset of collagenous sprue patients responded well to corticosteroid treatment only.103

Typical histologic features of collagenous sprue include; partial, subtotal, or total villous blunting, subepithelial collagen band (>12 μm in thickness) with entrapped inflammatory cells and capillaries, variable counts of IELs (7 to 92 IELs/100 epithelial cells), and variable degree (mild to marked) of chronic inflammation in the lamina propria (Fig. 7). Lack of IEL (defined as <25 IELs/100 epithelial cells) is noted in 42% of biopsies before treatment.99,101 Detachment of surface epithelium is a common finding (Fig. 7).101 Neutrophils either in the lamina propria, the surface epithelium, and/or crypt epithelium are noted in 68% of biopsies before treatment (Fig. 7).99 Eosinophilic infiltrate of variable degree may be seen (Fig. 7).99,101 Rarely, pericryptal granulomas can be seen.99

FIGURE 7

FIGURE 7

While some studies reported rare cases with no phenotypically aberrant IELs and a dominant T-cell clone,99 other studies clearly showed 83% (5 of 6) of collagenous sprue cases had a clonal T-cell population identified by polymerase chain reaction (PCR) analysis for TCR gene rearrangement either in small bowel biopsy or peripheral blood.101

One recent case series suggests that collagenous sprue patients have a relative good clinical outcomes and a subset will respond to gluten-free diet alone, although many patients require immunomodulatory therapy for symptom control. Improvement in villous atrophy was noted in 9 (of 11, 81.8%) cases with follow-up small bowel biopsy post diagnosis in patients who were either on gluten-free diet or treated with immunomodulatory,99 and In 7 (of 11, 64%) cases, this is accompanied by a reduction in subepithelial collagen.99 Overall, the clinical improvement is mainly associated with improvement of villous atrophy, and to a lesser degree, with the reduction in subepithelial collagen, but is independent of IEL counts. Among the collagenous sprue patients with a clonal T-cell population either in the bowel biopsy or peripheral blood, 2 patients died from complications of malnutrition, but 4 improved clinically after treatment with steroid (1), steroid and azathioprine (1), steroid and gluten-free diet (1), and surgical resection of small bowel and gluten-free diet (1).99,101 None of the patients received chemotherapy or developed lymphoma.

Back to Top | Article Outline

NEOPLASTIC COMPLICATIONS OF CELIAC DISEASE

Long-term celiac disease has 2 known neoplastic complications; EATL and small bowel adenocarcinoma.9 EATL will be discussed in the differential diagnosis section in detail. Patients with celiac disease–associated small bowel adenocarcinoma have a median age of 53 years (28 to 72) with a duration of intestinal disorder (celiac disease) of 17 months at the time of cancer diagnosis.104 Celiac disease–associated small bowel adenocarcinoma harbors microsatellite instability (about 65%), high tumor-infiltrating lymphocytes more frequently (about 61%) and shows better outcome than non–celiac disease–associated small bowel adenocarcinoma.104 Information regarding celiac disease–associated small bowel adenocarcinoma precursor lesions is scarce. In 1 study, evidence of residual adenomatous polypoid growth was only noted in 1 of 26 cases, but focal flat dysplasia was observed adjacent to the invasive cancer in 4 cases.105 The current evidence suggests SOX-9-positive immature hyperplastic crypts or flat β-catenin-positive dysplasia are potential precursors to invasive disease in celiac disease–associated small bowel tumorigenesis.105

Back to Top | Article Outline

OTHER RARE COMPLICATIONS IN CELIAC DISEASE

Celiac crisis: celiac crisis is a rarely documented life-threatening presentation of the disease. Patients mainly present with profound intractable diarrhea with severe metabolic disturbance (such as acidosis and hypokalemia), hypotension, neuromuscular weakness, cardiac arrhythmias, and respiratory failure.106

Liver abnormalities in celiac disease (so called “celiac hepatitis”): this is a heterogenous condition. It refers to celiac patients who subsequently develop abnormal liver function tests and/or patients presenting with liver disease who are found to have TTG.107 Some cases of celiac hepatitis may also have serological markers for autoimmune liver disease.107 In the literature, celiac disease has also been reported to be associated with cryptogenic hepatitis/cirrhosis and autoimmune liver disease such as autoimmune hepatitis, primary biliary cirrhosis/cholangitis, and primary sclerosing cholangitis.107–109 A subset of celiac hepatitis may have unique etiopathogenesis and may respond well to gluten-free diet treatment.108 Liver histology in celiac hepatitis includes mild reactive hepatitis, chronic hepatitis, steatosis, steatohepatitis, and cirrhosis.107,110 Trial of a gluten-free diet may result in clinicopathologic improvement of celiac hepatitis and there have been 3 reported cases which had a remarkable clinical improvement69,107,110 with near-total regression of marked liver steatohepatitis and fibrosis after a gluten-free diet.107,110 In 1 report, gluten-free diet also led to a marked reduction in CD8+ lymphocytic infiltration in liver biopsy.107

Chronic ulcerative jejunitis: This is an ill-defined entity. The disease is characterized by multiple chronic benign ulcers of the small bowel, most frequently the jejunum, with later progression to intestinal stricture.111 Patients usually present with severe diarrhea, abdominal pain, fever, steatorrhea, and hypoproteinemia due to enteric loss of plasma protein.111,112 It may include a spectrum of disorders such as; a clinical presentation of occult gluten-sensitive enteropathy due to ulceration at a time when the disease is no longer responsive to gluten exclusion,113 a progression from celiac disease to EATL85 or a manifestation of EATL.114 Biopsies from the jejunum shows villous atrophy but the surgical specimen and/or the postmortem small bowel reveals multiple mucosal ulcers with adjacent areas of both atrophic and normal mucosa.111,112 Immunohistochemistry and PCR analysis of clonality of the TCRγ gene using duodenal and jejunal mucosal tissue reveal a loss of CD8 and TCRβ expression as well as clonal TCRγ gene rearrangement,85,89 strongly suggesting that some cases of chronic ulcerative jejunitis are indeed cryptic EATLs. Patients usually do not respond to gluten-free diet but may variably benefit from corticosteroid treatment or other immunomodulators/immunosuppressors.112

Back to Top | Article Outline

DIFFERENTIAL DIAGNOSES OF CELIAC DISEASE

Depending upon the histologic pattern seen in celiac disease, that is, IEL or villous blunting, the differential diagnoses may vary. Regardless, there is a long list of differential diagnoses for each histologic pattern (Table 4).

TABLE 4

TABLE 4

Back to Top | Article Outline

DIFFERENTIAL DIAGNOSIS OF CELIAC DISEASE WITH VILLOUS BLUNTING AND/OR INTRAEPITHELIAL LYMPHOCYTOSIS

The pattern of villous atrophy seen for celiac disease is not etiologically specific. The diagnosis of celiac disease requires clinicopathologic correlation. There is a long list of differential diagnoses. Poor histologic technique, inexperienced interpretation, and lack of proper controls account for many of the reports that have led to conflicting results and much controversy.74

Back to Top | Article Outline

IMMUNODEFICIENCY

Diarrhea and a malabsorption syndrome can complicate primary hypogammaglobulinemia of the congenital and acquired types128 and varies in severity from case to case.

Infantile X-linked immunodeficiency: small bowel biopsy usually shows only sparsity or absence of lamina propria plasma cells, and the mucosa-associated lymphoid tissue lacks germinal centers.115,116 Villi are usually normal. But the case reported by Rhee et al116 had crypt hyperplastic villous atrophy and intramucosal bacteria, in addition to an absence of plasma cells. In this case, neutrophilic infiltration of the surface epithelium and lamina propria was noted.

Common variable immunodeficiency (CVID): a recent large cohort study reported chronic diarrhea as the most common gastrointestinal symptom (92%), and biological evidence of malabsorption was observed in 54% of patients with CVID.117 Endoscopic abnormalities such as disappearance of folds and mosaic pattern were seen in 22% of cases in this series. Small biopsies available from 41 patients in this series showed moderate increase in intestinal IELs in 31 patients (75.6%) and villous atrophy in 21 patients (51%) (Fig. 8). However, these cases show a profound depletion in plasma cells and follicular lymphoid hyperplasia, 2 distinctive features.117 In 22.6% cases, there may be a coexisting Giardia infestation.117 Features that may help distinguish enteropathy-associated with CVID from celiac disease are a profound depletion of plasma cells and follicular lymphoid hyperplasia as these 2 features are present in 96.3% and 55% enteropathy-associated CVID, respectively. In addition, serology testing for celiac disease may also be helpful as only 3 (of 26, 11.5%) had celiac antibodies.117 Gluten-free diet improved only 2 (of 12) patients with villous atrophy and intravenous immunoglobulin therapy had no effect on enteropathy-related symptoms. However, all patients (7/7) responded to steroid therapy with reduction in inflammation and restoration of mucosal architecture.117

FIGURE 8

FIGURE 8

Selective IgA deficiency: selective IgA deficiency is the most common primary immunodeficiency in humans. Diarrhea and steatorrhea are the most common intestinal manifestation which may be due to giardiasis, celiac disease, or cow’s milk intolerance. In some cases with selective IgA deficiency, a celiac disease-like mucosal lesion (including villous blunting and IEL) can be seen in small bowel biopsy.118

IgG deficiency: In a study by Perlmutter et al,119 50% of 55 infants with low IgG levels and chronic diarrhea showed crypt hyperplasic villous atrophy varying from mild to severe.

Small bowel disease in T-cell deficiency or severe combined immunodeficiency: In patients with T-cell deficiency or combined T and B severe combined immunodeficiency, T lymphocyte and/or B lymphocyte functions are compromised. The jejunal mucosa from these patients may show villous blunting, crypt hyperplasia, IEL, and edema of the lamina propria (Fig. 9). In this disease, however, the presence of many foamy macrophages containing material stainable by PAS, toluidine blue, and Giemsa in the lamina propria may be a striking feature.120 In some cases, viral infection may also contribute to small bowel disease and protracted diarrhea in patients with combined severe immunodeficiency.121

FIGURE 9

FIGURE 9

Back to Top | Article Outline

INFECTION OR INFECTION-RELATED DISORDERS

Helicobacter pylori gastritis: recently, Helicobacter pylori gastritis has been well documented as a major etiology for observed cases with IEL but no or only minimal villous changes in the duodenal mucosa. Features useful in distinguishing this condition from celiac disease are the heavy neutrophilic infiltration (of the lamina propria and/or the surface epithelium), relatively mild villous blunting, and the presence of foveolar metaplasia.33 The ultimate differentiation of this disease from celiac disease, of course, requires biopsy of the stomach, particularly the antrum, or documentation of Helicobacter pylori infection by other methods. In a recently reported study, the duodenal IEL count is significantly lower 2 months after Helicobacter pylori eradication.122 However, cases of coexisting celiac disease and Helicobacter pylori gastritis have been reported.

Tropical sprue: The clinical presentation and endoscopic characteristics of tropical sprue and celiac disease overlap considerably.123 The morphologic abnormality in tropical sprue varies greatly from “normal” to “very abnormal.”124 Compared with celiac disease, patients with tropic sprue are found to have milder villous abnormalities, and the IELs are more often seen to infiltrate the basal one third of villi or the mucosal crypts.123 Tropic sprue is more likely to be patchy and to have higher density of eosinophils than celiac disease.123 Other information, such as the history of travel to endemic area immediately before the onset diarrhea, negative celiac serology test results, and the dramatic response to antibiotic and folic acid treatment, helps diagnose tropical sprue.

Stasis or blind loop syndrome: In stasis or blind loop syndrome, bacterial colonization occurs in parts of the small bowel where normally there is only a transient population. Sometimes the mucosa associated with this abnormal bacterial colonization may show morphologic changes similar to, or overlapping with, celiac disease. However, the morphology in this scenario is often patchy in distribution and of only moderate severity (ie, a crypt hyperplasia with slight to moderate villous atrophy). Clinically, the patient may have a history of intra-abdominal surgery or evidence of bowel obstruction on imaging studies.

Viral gastroenteritis and/or postinfective malabsorption syndrome: Bacterial and viral gastroenteritis are known to cause mucosal damage.125,126 The mucosal abnormality in this scenario is only mild or moderately severe. However, in some cases, severe mucosal lesions (including loss of villi, crypt hyperplasia, and marked increase in inflammatory cells in the lamina propria) that are comparable to those seen in celiac disease have been described.125,127 One of the characteristics suggestive of an infective lesion is its more obviously acute inflammatory nature such as hyperemia, edema, margination of neutrophils of the capillaries, and crypt abscesses. In addition, patients with postinfective malabsorption syndrome give a clear history of gastroenteritis of acute onset and typical symptomatology. In addition, clinical improvement and mucosa histology recovery are seen shortly after the resolution of infection.125,127

Back to Top | Article Outline

PARASITIC DISEASES

Parasitic diseases can cause malabsorption and mild mucosal abnormality including slight villous atrophy with crypt hyperplasia and a slight but definite increase in the number of inflammatory cells within the lamina propria. The rate of mucosal abnormality can be variable. For example, villous atrophy, IEL and/or crypt hyperplasia have been reported in children with giardiasis but at a very low rate.129 Therefore, if parasitic organisms are seen in association with villous atrophy comparable to that in untreated celiac disease, a coexisting celiac disease and giardia infection should be suspected. A celiac serology may not be helpful in such cases as a recent study reported a transient elevation of IgA-TTG and IgA-EMA levels in Giardia infection.130 In such cases, repeating celiac serology after successful Giardia eradication may help clarify the scenario to avoid over diagnosis of celiac disease in those cases with only transient elevation and to diagnose a coexisting celiac disease in those with persistent elevation.130 Conversely, in all small bowel biopsy specimens with mucosal abnormalities, searching for parasitic organisms is warranted; and a high proportion of eosinophils should prompt a diligent search for parasites. A case of giardiasis with mild villous blunting and mild IEL is illustrated in Figure 10.

FIGURE 10

FIGURE 10

Back to Top | Article Outline

DIET, NUTRITION, AND MEDICATIONS

Food allergy: Dietary proteins other than gluten can also cause malabsorption, producing histology in the small bowel similar to that of celiac disease, and can therefore pose a diagnostic challenge.131–133 However, these food protein-sensitive enteropathies are usually transient and clinical correlation with diet history and withdrawal is essential. In addition, an increased eosinophil count is often seen in these conditions.133

Malnutrition: Patients with severe protein-energy malnutrition can present with diarrhea and malabsorption. Jejunal biopsies from children with malnutrition demonstrate mucosal lesions similar to those in celiac disease including; partial villous blunting,134 variable degree of chronic inflammatory infiltration in the lamina propria, and in some cases, epithelial lymphocytosis. However, these changes respond to oral/and intravenous therapy.134 In patients with pernicious anemia either due to vitamin B12 or folic acid deficiency, small bowel biopsy shows mild villous blunting with moderate to heavy infiltration of mononuclear cells in the lamina propria.135,136 These changes are accompanied by megaloblastic changes in the epithelial cells and can be reversed with vitamin B12 and folic acid replacement.135,136

Medications: It has been shown that many types of NSAIDs are associated with duodenal mucosal lesions including IEL with normal mucosal architecture.137 Olmesartan is an angiotensin II receptor blocker used for the treatment of hypertension. The use of olmesartan can cause severe diarrhea and weight loss. Duodenal biopsy may reveal partial or complete villous atrophy and increased IELs mimicking celiac disease.138 In some cases, neutrophilic inflammation, deposition of subepithelial collagen, and foci of crypt cell apoptosis may be present.138–141 Recently, additional cases of medication-associated sprue-like enteropathy have been reported and the causative medications include oxcarbazepine,142 mycophenolate mofeti,143 and azathioprine.144 Antitumoral immunotherapy can also potentially cause celiac disease-like enteropathy. A temporal relationship between the medication and diarrhea, negative celiac serology, and an improvement or resolution of symptoms and histopathology upon medication cessation aids in the diagnosis.

Back to Top | Article Outline

PEPTIC ACID INJURY

Patchy jejunal atrophy and microulceration are described in patients with Zollinger-Ellison syndrome with hyperchlorhydria.145 In this situation, the mucosa, however, shows a much more robust neutrophilic infiltrate than is seen in celiac disease (Fig. 11). In addition, there are also severe degenerative changes (ie, erosion and superficial gastric epithelial metaplasia) in the surface epithelium.

FIGURE 11

FIGURE 11

Back to Top | Article Outline

AUTOIMMUNITY

Intractable diarrhea of early infancy: Intractable (protracted) diarrhea of early infancy146 characterizes a subgroup of patients younger than 3 months of age with diarrhea of no apparent cause that is intractable to treatment. This condition is frequently fatal. In 1 study, Rossi et al147 showed that the condition was usually associated with mucosal abnormalities including total villous atrophy with crypt hyperplasia148 and in some cases, villous atrophy with crypt hypoplasia.149–151 Some of the cases show a tendency to occur on a familial basis149,152 and in association with severe combined immunodeficiency (Fig. 12).121 In some patients, the enteropathy may have an autoimmune basis, and circulating antibodies to both intestinal goblet cells and enterocytes have been demonstrated.150–153 Occasionally, biopsies from these patients may show a reduced number, or a complete loss, of intestinal goblet cells.154 A positive test for enterocyte antibody is diagnostic of this condition, and a persistent high titer indicates a poor prognosis.151,155

FIGURE 12

FIGURE 12

Adult autoimmune enteropathy: An adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies84,153 may rarely present as refractory sprue. In 1 study, jejunal biopsies from 4 cases with adult autoimmune enteropathy had subtotal villous atrophy and increased IEL counts (42 to 51 IELs/100 epithelial cells) before steroid treatment.153 Some of these patients had antienterocyte antibodies and appeared to respond to steroid treatment.153 Therefore, in patients with malabsorption in a setting of villous atrophy and IEL, serology testing for antienterocyte autoantibody may assist in the diagnosis of autoimmune enteropathy.

Crohn disease: Crohn disease can manifest as duodenitis with villous atrophy resulting in malabsorption and intestinal failure requiring parenteral nutrition.156 A diagnosis of Crohn disease in a case with villous atrophy is a diagnosis of exclusion after effectively ruling out celiac disease via a combination of negative serology, absence of the HLA DQ2/DQ8, and lack of response to gluten-free diet. Other potential diagnoses that must be excluded include: immunodeficiency, autoimmune enteropathy, medication-associated enteropathy, and infections.

Back to Top | Article Outline

DIFFERENTIAL DIAGNOSIS FOR LATENT CELIAC DISEASE

IEL in an otherwise normal duodenal or upper jejunal biopsy, designated by the term IEL with normal villous architecture (IELNVA), has been increasingly identified in many patients with celiac disease due to an increase in the utilization of diagnostic serology testing and endoscopic examination of first-degree relative of patients with celiac disease. While this finding is sensitive for potential celiac disease, it is not specific, and overlaps in IEL counts can occur in patients with celiac disease and those without. It has become increasingly recognized that high numbers of IELs with normal architecture is associated with a variety of conditions other than celiac disease (Table 5). Several large studies have examined the prevalence and clinical significance of IELNVA.26,137 The prevalence of IELNVA varies from 1.3% to 2.2% when different cutoff values are used.26,137 In 1 study using 40 IELs/100 epithelial cells as cutoff criteria for IEL, the histologic pattern of IELNVA occurs at a rate of 1.3% (43 of 3190 patients undergoing upper GI endoscopy) and is associated with CD (9.3%), immunologic diseases (14.3%), NSAIDs use (14%), inflammatory bowel disease (11.6%), bacterial overgrowth (4.4%), tropical sprue (2.3%), microscopic colitis (6.9%), and other, nonspecified diagnoses (37.2%).137 In addition, morbid obesity,157Helicobacter pylori gastritis,18,122,158 partially treated tropical sprue,137 and cow’s milk protein intolerance24 are also reported to cause IELNVA. Immune regulation disorders that have been associated with IELNVA include; Hashimoto thyroiditis, Graves disease, rheumatoid arthritis, psoriasis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, progressive systemic sclerosis, and glomerulonephritis.137,159–162

TABLE 5

TABLE 5

As IELNVA is not an uncommon histologic finding in duodenal biopsies, several studies have attempted to examine whether additional features (the count and/or distribution of IEL) would allow the differentiation of celiac disease from other etiologies. One study has suggested that loss of the IEL ‘decrescendo pattern’ due to an increased density of IELs at the distal sides and tips of villi is a relatively specific and reproducible feature of latent or potential celiac disease.55 The modest sensitivity (75%) noted for this feature, in conjunction with other studies that report no particular pattern of IEL distribution (villous base>tip, villous tip>base, or uniform) to be associated with latent celiac disease,137 indicates this feature’s limited clinical use. A mean of 12 or more IELs per 20 enterocytes in the tips of several villi are suggestive of celiac disease in 1 study but again, with a sensitivity of only 50%.55 Two studies have suggested the use of a tip-to-base ratio of CD3+ IELs plus the percentage of β-F1 positive IELs to distinguish latent celiac disease from other causes of IELNVA.137,163 However, these approaches add extra expense and are time consuming, therefore, have not been widely accepted in clinical practice.

It has also been increasingly recognized that idiopathic inflammatory diseases of the bowel such as ulcerative colitis, Crohn disease, as well as lymphocytic and collagenous colitis may also be associated with IELNVA in the proximal small bowel.137,164 The association of lymphocytic and collagenous colitis with IELNVA in the proximal small bowel may be independent of celiac disease despite the recognized association of both conditions with celiac disease.39,165,166

While previous small studies with short-term follow-up have shown gradual development of villous atrophy in celiac disease,55,164,167,168 recent studies have shown that IEL with or without a slight decrease in villous height/crypt depth ratio is a common finding and follow-up screening in this patient group does not, yield significantly more positive cases of celiac disease than screening in the general population.59 In cases with lymphocytic duodenosis without clinical and serological evidence of celiac disease, HLA testing for the relevant DQ alleles can be a useful adjunct in an exclusionary sense when the diagnosis based on other tests is not clear.32,42

Back to Top | Article Outline

ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA

Longstanding celiac disease may be complicated by bowel or abdominal lymph node lymphoma.39,169,170 Age-related immune senescence may contribute to uncontrolled gastrointestinal inflammation and subsequent transformation to T-cell lymphoma.171 A significant increase in the incidence of EATL in the United State may reflect the increasing seroprevalence of celiac disease and better recognition of rare types of T-cell lymphomas.172 EATL also arises in the setting of autoimmune enteropathy, thus representing a heterogenous entity.173 EATL has a dismal prognosis; the median overall survival and the median failure-free survival are reported to be 10 and 6 months, respectively.174 A large tumor size (>5 cm), nonambulatory performance status, and elevated lactate dehydrogenase and C-reactive protein levels are risk factors significantly associated with a worse survival.174

EATL is seemingly characterized by clinical deterioration including; recurrence of diarrhea, a reversal of the response to gluten withdrawal, fever, weight loss, abdominal pain, and finger clubbing. EATL occurs most commonly in the jejunum and ileum, but it may also involve other areas of the gastrointestinal tract as well as nongastrointestinal sites. The tumor usually presents as multiple ulcerating raised mucosal masses, a large exophytic mass, or ≥1 ulcerations. In cases involving the jejunum, the jejunal biopsy may show features that, together with the clinical and biochemical abnormalities, allow a diagnosis to be strongly suspected. The typical histologic finding consists of a flat mucosa with total villous atrophy and crypt hyperplasia that exhibits an obviously dense cellular infiltrate of the lamina propria. The mucosa may be slightly thicker than normal, but it is the infiltrate that may be of diagnostic importance. There is a plasma cell component in obvious excess of that seen in an ordinary celiac mucosa. There will be a variable number of abnormal cells of a wide range of cytomorphologic appearances suggesting they are malignant.175 These cells form collections that show a range of abnormalities from enlarged normal-appearing cells to frankly atypical and malignant cells. A characteristic feature is the tendency for these cells to invade the epithelium of glands in small groups. These cellular infiltrates often extend below the muscularis mucosae.

The 2008 WHO classification recognizes 2 subtypes of EATL, namely EATL type 1 and EATL type 2, on the basis of histology.90 EATL type 1 shows a variable histologic pattern consisting of either a monomorphic infiltrate of medium-sized to large-sized lymphoma cells that contain nuclei with irregular contours and a variable amount of cytoplasm or large anaplastic lymphoma cells. EATL type 1 may also show marked polymorphism with variable numbers of eosinophils, histiocytes, small lymphocytes, and plasma cells. In contrast, EATL type 2 is composed of a monomorphic small to medium-sized lymphoid cells with round, hyperchromatic nuclei that have a stippled chromatin pattern.

Back to Top | Article Outline

Enteropathy-associated T-Cell Lymphoma Type 1

EATL type 1 usually develops in the background of celiac disease and has a high frequency in Europe.174 In 1 series of 47 EATL type 1 cases, clinical history or histologic features of celiac disease were noted in 60% of patients.174 Histologic features of celiac disease were reported in the mucosa adjacent to the tumor in 39.3% cases.174 The tumor cells are usually CD3+, CD5, CD8/+, CD4, CD103+, and contain cytotoxic granule-associated proteins.174 In many cases, a varying proportion of tumor cells express CD30.174,176,177 The IELs in the adjacent enteropathic mucosa may show clonal T-cell receptor gene rearrangement176 and/or an abnormal immunophenotype, usually CD3+, CD5, CD8, and CD4, identical to that of the lymphoma. This finding supports the idea that EATL occurs in a background of celiac disease as demonstrated by the evolution of neoplastic T-cell clones from the reactive T-cell population present in the enteropathic bowel.176 Clonal T-cell receptor gene rearrangement alone should not lead to a diagnosis of EATL type 1. Hussein et al92 identified clonal T-cell receptor gene rearrangements (TCR-GRs) present in duodenal biopsies from patients with celiac disease who were refractory to gluten-free diet and in celiac disease patients who were responsive to a gluten-free diet. The final diagnosis of EATL requires a synthesis of histomorphology, immunophenotype, and demonstration of clonal rearrangement of TCRβ and/or γ genes.

Back to Top | Article Outline

Enteropathy-associated T-Cell Lymphoma Type 2

EATL type 2 represents a distinct aggressive lymphoma with frequent γδ T-cell receptor expression. EATL type 2 has been reported to be the predominant subtype in Asian populations and may or may not be associated with celiac disease.174 EATL type 2 is characterized by monotonous small to medium-sized cells with round nuclei having a stippled chromatin pattern. It has a tendency to involve adjacent mucosa with or without atrophy.174,178 The most common immunophenotype of EATL type 2 lymphoma cells is CD3+, CD5, CD4, CD8+, CD56+, TIA1+, CD30, and Epstein-Barr virus negative.174,178 The lesion is often composed of a central zone, a peripheral zone, and a zone of IEL.178 In 1 report, foci of IEL (defined as >30IELs per 100 epithelial cells) were identified in the surrounding bowel mucosa of all 18 EATL type 2 cases evaluated.178 The IEL zone is in continuity with the peripheral zone of the tumor, but in rare cases, it may occur at a considerable distance from the tumor edge. Mild villous atrophy was only noted in 2 (of 18) cases and no crypt hyperplasia was identified.178 While morphologically, the IELs do not show significant atypia, in most cases they show an aberrant immunohistochemical phenotype (such as CD5 loss and CD56 expression).174,178 The IELs express γδ T-cell receptor in 65% of cases.178 Therefore, in small bowel biopsy specimens from patients with high clinical suspicion for small intestinal lymphoma, a careful search for IEL and further work up of IELs by immunohistochemical studies and/or PCR analysis for clonal TCRγ gene rearrangement may be indicated.

Back to Top | Article Outline

OTHER LYMPHOMAS ASSOCIATED WITH A MALABSORPTION SYNDROME

Mediterranean lymphoma, also known as immunoproliferative small intestinal disease (IPSID) is a primary small intestine and regional node lymphoma associated with a malabsorption syndrome.179 It occurs mainly in the Middle East, North Africa, and other underdeveloping countries. This condition does not seem to be related to celiac disease. Jejunal biopsy plays a significant role in the diagnosis of this disorder.180 Areas involved by this disease show a dense lamina propria cellular infiltrate of plasmacytoid cells or, less characteristically, large undifferentiated cells. The cellular infiltrate is so dense that it also alters the crypt pattern, tending to push the crypts apart. The villous pattern is also abnormal likely secondary to the dense cellular infiltration.180 The villi are often shortened and appear bloated and deformed, but the epithelial abnormalities seen in celiac disease are usually absent. In later stages, the villous pattern is more or less completely lost as the lamina propria becomes packed with cellular elements. Distinguishing celiac disease from IPSID can be carried out on the basis of epidemiological and clinical grounds. The histomorphologic features [ie, the presence of total villous atrophy (rather than the villous broadening or effacement seen in IPSID), hyperplastic, elongated crypts (rather than shortened, sparse crypts), IEL, and surface epithelial flattening] may also help distinguish these 2 entities.179 Searching for features of a B-cell MALToma including lymphoplasmacytic proliferation of the lamina propria extending to the submucosa, malignant centrocyte-like cells deep in the mucosa and submucosa, and adjacent reactive follicle are also helpful as they are seen in IPSID.179

Back to Top | Article Outline

OTHER LYMPHOMAS

Other lymphomas characterized by a proliferation of small to medium-sized lymphocytes that may involve the duodenum and jejunum are follicular lymphoma, MALT lymphoma, and mantle cell lymphoma.181–184 However, most cases demonstrate abnormal mucosal findings such as ulceration, a mass/protrusion, or polyposis.181–184 Histologically, they are characterized by small nodules of lymphoid infiltrates within the lamina propria without obvious IEL.181,184 In cases where such differential diagnoses arise, immunohistochemistry studies using a panel of T and B lymphocyte markers and/ or a flow cytometric analysis of fresh tissue will easily solve the issue.

Back to Top | Article Outline

SUMMARY

There have been several significant improvements and new developments in the diagnosis of celiac disease in the last decade including; refinement of celiac serology, biopsy-sparing diagnostic criteria/guidelines in pediatric and adult populations, and HLA-DQ-gluten tetramer blood test. While these approaches help diagnose celiac disease in a subset of patients with malabsorption, histologic evaluation of small bowel biopsies remains an essential modality for diagnosing celiac disease, particularly in patients who do not fulfill the biopsy-sparing celiac disease diagnostic criteria, patients who are not responding to gluten-free diet, and in clinical trials. Histologic examination of duodenal mucosa not only helps diagnose celiac disease in many cases but also helps monitor disease course and response to treatment as well detect other potential complications such as EATL, adenocarcinoma, and concurrent intestinal diseases.

Back to Top | Article Outline

REFERENCES

1. Green PH, Krishnareddy S, Lebwohl B. Clinical manifestations of celiac disease. Dig Dis. 2015;33:137–140.
2. Tonutti E, Bizzaro N. Diagnosis and classification of celiac disease and gluten sensitivity. Autoimmun Rev. 2014;13:472–476.
3. Leffler DA, Schuppan D. Update on serologic testing in celiac disease. Am J Gastroenterol. 2010;105:2520–2524.
4. Husby S, Koletzko S, Korponay-Szabó IR, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54:136–160.
5. Werkstetter KJ, Korponay-Szabó IR, Popp A, et al. Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice. Gastroenterology. 2017;153:924–935.
6. Wolf J, Petroff D, Richter T, et al. Validation of antibody-based strategies for diagnosis of pediatric celiac disease without biopsy. Gastroenterology. 2017;153:410–419.
7. Efthymakis K, Serio M, Milano A, et al. Application of the biopsy-sparing ESPGHAN guidelines for celiac disease diagnosis in adults: a real-life study. Dig Dis Sci. 2017;62:2433–2439.
8. Sarna VK, Lundin KEA, Morkrid L, et al. HLA-DQ-gluten tetramer blood test accurately identified patients with and without celiac disease in absence of gluten consumption. Gastroenterology. 2018;154:886–896.
9. Eigner W, Bashir K, Primas C, et al. Dynamics of occurrence of refractory coeliac disease and associated complication over 25 years. Aliment Pharmacol Ther. 2017;45:364–372.
10. Adelman DC, Murray J, Wu TT, et al. Measuring change in small intestinal histology in patients with celiac disease. Am J Gastroenterol. 2018;113:339–347.
11. Hindryckx P, Levesque BG, Holvoet T, et al. Disease activity indices in coeliac disease: systemic review and recommendations for clinical trials. Gut. 2018;67:61–69.
12. Ludvigsson JF, Giacci C, Green PH, et al. Outcome measures in coeliac disease trials: the Tampere recommendations. Gut. 2018;67:1410–1424.
13. Holmes R, Hourihane DO, Booth CC. Dissecting microscope appearance of jejunal biopsy specimen from patients with “idiopathic steatorrhea”. Lancet. 1961;277:81–83.
14. Cocco AE, Dohrmann MJ, Hendrix TR. Reconstruction of human jejunal biopies: three dimensional histology. Gastroenterology. 1966;51:24–31.
15. Stewart JS, Pollock DJ, Hoffbrand AV, et al. A study of proximal and distal intestinal structure and absorptive function in idiopathic steatorrhea. Q J Med. 1967;36:425–444.
16. Pena AS, Truelove SC, Whitehead R. Morphology and disaccharidase levels of jejunal biopsy specimens from healthy British subjects. Digestion. 1973;8:317–323.
17. Fichtelius KE, Yunis JE, Good RA. Occurrence of lymphocytes within the gut epithelium of normal and neonatally thymectomised mice. Proc Soc Exp Biol. 1968;128:185–188.
18. Goldstein NS. Proximal small-bowel mucosal villous intraepithelial lymphocytes. Histopathology. 2004;44:199–205.
19. Selby WS, Janossy G, Bofill M, et al. Lymphocyte subpopulations in the human small intestine: the findings in normal small mucosal in the mucosa of patients with celiac disease. Clin Exp Immunol. 1983;52:219–228.
20. Cerf-Bensussan N, Quaroni A, Kurnick JT, et al. Intraepithelial lymphocytes modulate Ia expression by intestinal epithelial cells. J Immunol. 1984;132:2244–2252.
21. Cheroutre H, Madakamutile L. Acquired and natural memory T cells join forces at the mucosal front line. Nat Rev Immunol. 2004;4:290–300.
22. Hayday A, Theodoridis E, Ramsburg E, et al. Intraepithelial lymphocytes: exploring the third way in immunology. Nat Immunol. 2001;2:997–1003.
23. Ferguson A, Murray D. Quantitation of intraepithelial lymphocytes in human jejunum. Gut. 1971;12:988–994.
24. Phillips AD, Rice SJ, France NE, et al. Small intestinal intraepithelial lymphocyte levels in cow’s milk protein intolerance. Gut. 1979;20:509–512.
25. Hayat M, Cairns A, Dixon MF, et al. Quantitation of intraepithelial lymphocytes in human duodenum: What is normal? J Clin Pathol. 2002;55:393–394.
26. Mahadeva S, Wyatt JI, Howdle PD. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinical relevant? J Clin Pathol. 2002;55:424–428.
27. Veress B, Franzen L, Bodin L, et al. Duodenal intraepithelial lymphocyte-count revisited. Scand J Gastroenterol. 2004;39:138–144.
28. Pellegrino S, Villanacci V, Sansotta N, et al. Redefining the intraepithelial lymphocytes thresholdl to diagnose gluten sensitivity in patients with architecturally normal duodenal histology. Aliment Pharmacol Ther. 2011;33:697–706.
29. Brocchi E, Corazza G, Galetti G, et al. Endoscopic demonstration of loss of duodenal folds in the diagnosis of celiac disease. N Engl J Med. 1988;319:741–744.
30. Maurino E, Capizzano H, Niveloni S, et al. Value of endoscopic markers in celiac disease. Dig Dis Sci. 1993;38:2028–2033.
31. Sanfilippo G, Pantane R, Fusto A, et al. Endoscopic approach to childhood celiac disease. Acta Gastroenterologica. 1986;49:401–408.
32. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) institute technical review on the diagnosis and management of coeliac disease. Gastroenterology. 2006;131:1981–2002.
33. Ensari A. Gluten-sensitive enteropathy (celiac disease): controversies in diagnosis and classification. Arch Pathol Lab Med. 2010;134:826–836.
34. Lebwohl B, Kapel RC, Neugut AI, et al. Adherence to biopsy guidelines increases celiac disease diagnosis. Gastrointest Endosc. 2011;74:103–109.
35. Wallach T, Genta RM, Lebwohl B, et al. Adherence to celiac disease and eosinophilic esophagitis biopsy guidelines is poor in children. J Pediatr Gastroenterol Nutr. 2017;65:64–68.
36. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656–676.
37. Dickey W, Hughes DF. Histology of the terminal ileum in celiac disease. Scand J Gastroenterol. 2004;39:665–667.
38. Ravelli A, Villanacci V, Monfredini C, et al. How patchy is patchy villous atrophy? Distribution pattern of histological lesions in the duodenum of children with celiac disease. Am J Gastroenterol. 2010;105:2103–2110.
39. Freeman HJ. Collagenous colitis as the presenting feature of biopsy: defined coeliac disease. J Clin Gastroenterol. 2004;38:664–668.
40. Ravelli A, Bolognini S, Gambarotti M, et al. Variability of histologic lesions in relation to biopsy site in gluten-sensitive enteropathy. Am J Gastroenterol. 2005;100:177–185.
41. Mee AS, Burke M, Vallon AG, et al. Small bowel biopsy for malabsorption: comparison of the diagnosis adequacy of endoscopic forceps and capsule biopsy specimens. Br Med J. 1985;291:769–772.
42. Lindfors K, Koshinen O, Kaukinen K. An update on the diagnostics of celiac disease. Int Rev Immunol. 2011;30:185–196.
43. Pelkowski TD, Viera AJ. Celiac disease: diagnosis and management. Am Fam Physician. 2014;89:99–105.
44. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63:1210–1228.
45. Achkar E, Carey WD, Petras R, et al. Comparison of suction capsule and endoscopic biopsy of small bowel mucosa. Gastrointest Endosc. 1986;32:278–281.
46. Evans KE, Aziz I, Cross SS, et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroenterol. 2011;106:1837–1842.
47. Vogelsang H, Hanel S, Steiner B, et al. Diagnostic duodenal bulb biopsy in celiac disease. Endoscopy. 2001;33:336–340.
48. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992;102:330–354.
49. Oberhuber G, Granditsch G, Volgelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11:1185–1194.
50. Kultu T, Brousse N, Rambaud C, et al. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut. 1993;34:208–214.
51. Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin Gastronterol Hepatol. 2007;5:838–843.
52. Villanacci V, Lorenzi L, Donato F, et al. Histopathological evaluation of duodenal biopsy in the Prevent CD project. An observational interobserver agreement study. APMIS. 2018;126:208–214.
53. Ozakinici H, Kirmizi A, Savas B, et al. Classification chaos in coeliac disease: does it really matter? Pathol Res Pract. 2016;212:1174–1178.
54. Biagi F, Luinetti O, Campanella J, et al. Intraepithelial lymphocytes in the villous tip: Do they indicate potential coeliac disease? J Clin Pathol. 2004;57:835–839.
55. Goldstein NS, Underhill J. Morphologic features suggestive of gluten sensitivity in architecturally normal duodenal biopsy specimens. Am J Clin Pathol. 2001;116:63–71.
56. Jarvinen TT, Collin P, Rasmussen M, et al. Villous tip intraepithelial lymphocytes as markers of early-stage coeliac disease. Scan J Gastroenterol. 2004;39:428–433.
57. Marsh MN, Bjarnason I, Shaw J, et al. Studies of intestinal lymphoid tissue. XIV-HLA status, mucosal morphology, permeability and epithelial lymphocyte population in first degree relatives of patients with coeliac disease. Gut. 1990;31:32–36.
58. Fry L, Seah PP, Harper PG, et al. The small intestine in dermatitis herpetiformis. J Clin Pathol. 1974;27:817–824.
59. Lahdeaho ML, Kaukinen K, Collin P, et al. Celiac disease: from inflammation to atrophy: a long-term follow-up study. J Pediatr Gastroenterol Nutr. 2005;41:44–48.
60. Vande Voort JL, Murray JA, Lahr BD, et al. Lymphocytic duodenosis and the spectrum of celiac disease. Am J Gastroenterol. 2009;104:142–148.
61. Silvester JA, Kurada S, Szwajcer A, et al. Tests for serum transglutaminase and endomysial antibodies do not detect most patients with celiac disease and persistent villous atrophy on gluten-free diets: a meta-analysis. Gastroenterology. 2017;153:689–701.
62. Lau MS, Mooney PD, White WL, et al. The role of an IgA/IgG-deamidated gliadin peptide point-of-care test in predicting persistent villous atrophy in patients with celiac disease on a gluten-free diet. Am J Gastroenterol. 2017;112:1859–1867.
63. Ciclitira PJ, Dewar DH, McLaughlin SD, et al. British Society of Gastroenterology. The management of adults with coeliac disease. 2010. Available at: www.bsg.org.uk. Accessed March 15, 2012.
64. Hutchinson JM, West NP, Robins GG, et al. Long-term histological follow-up of people with coeliac disease in a UK teaching hospital. Q J Med. 2010;103:511–517.
65. Bardella MT, Velio P, Cesana BM, et al. Coeliac disease: a histological follow-up study. Histopathology. 2007;50:465–471.
66. Freeman HJ. Lymphoproliferative and intestinal malignancies in 214 patients with biopsy-defined celiac disease. J Clin Gastroenterol. 2004;38:429–434.
67. Marsh MN, Ensari A, Morgan SR. Evidence that gluten sensitivity is an immunologic disease. Curr Opin Gastroenterol. 1993;9:994–1000.
68. Zanini B, Marullo M, Villanacci V, et al. Persistent intraepithelial lymphocytosis in celiac disease patients adhering to gluten-free diet is not abolished despite a gluten contamination elimination diet. Nutrients. 2016;8:525–537.
69. Kaukinen K, Halme L, Collin P, et al. Celiac disease in patients with severe liver disease: Gluten-free diet may reverse hepatic failure. Gastroenterology. 2002;122:881–888.
70. Uhde M, Ajamian M, Caio G, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65:1930–1937.
71. Carroccio A, Giannone G, Mansueto P, et al. Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity. Clin Gastroenterol Hepatol. 2019;17:682–690.
72. Valle J, Morgado JMT, Ruiz-Martin J, et al. Flow cytometry of duodenal intraepithelial lymphocytes improves diagnosis of celiac disease in difficult cases. United European Gastroenterol J. 2017;5:819–826.
73. Saborido R, Martinon N, Regueiro A, et al. Intraepithelial lymphocyte immunophenotype: a useful tool in the diagnosis of celiac disease. J Physiol Biochem. 2018;74:153–158.
74. Pinto Sanchez MI, Smecuol E, Vasquez H, et al. Very high rate of misdiagnosis of celiac disease in clinical practice. Acta Gastroenterol Latinoam. 2009;39:250–253.
75. Kurppa K, Koskinen O, Collin P, et al. Changing phenotype of celiac disease after long-term gluten exposure. J Pedistr Gastroenterol Nutr. 2008;47:618–622.
76. Matysiak-Budnik T, Malamut G, de Serre NP, et al. Long-term follow-up of 61 coeliac patients diagnosed in childhood: evolution toward latency is possible on a normal diet. Gut. 2007;56:1379–1386.
77. Murray JA, Rubio-Tapia A, Van Dyke CT, et al. Mucosal atrophy in celiac disease: extent of involvement, correlation with clinical presentation, and response to treatment. Clin Gastroenterol Hepatol. 2008;6:186–193.
78. Weir DC, Glickman JN, Roiff T, et al. Variability of histopathological changes in childhood celiac disease. Am J Gastroenterol. 2010;105:207–212.
79. Bonamico M, Thanasi E, Mariani P, et al. Duodenal bulb biopsies in celiac disease: a multicenter study. J Pediatr Gastroenterol Nutr. 2008;47:618–622.
80. Pais WP, Duerksen DR, Pettigrew NM, et al. How many duodenal biopsy specimens are required to make a diagnosis of celiac disease? Gastrointest Endosc. 2008;67:1082–1087.
81. Trier JS. Celiac sprue. N Engl J Med. 1991;325:1709–1719.
82. Trier JS. Diagnosis of celiac disease. Gastroenterology. 1998;115:211–216.
83. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet. 2000;356:203–208.
84. Ryan BM, Kelleher D. Refractory celiac disease. Gastroenterology. 2000;119:243–251.
85. Daum S, Weiss D, Hummel M, et al. Frequency of clonal intraepithelial T lymphocyte proliferation in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut. 2001;49:804–812.
86. Malamut G, Afchain P, Verkarre V, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136:81–90.
87. Robert ME, Ament ME, Weinstein WM. The histologic spectrum and clinical outcome of refractory and unclassified sprue. Am J Surg Pathol. 2000;24:676–687.
88. Carbonnel F, Grollet-Bioul L, Brouet JC, et al. Are complicated forms of celiac disease cryptic T-cell lymphoma? Blood. 1998;92:3879–3886.
89. Bagdi E, Diss TC, Munson P, et al. Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population. Blood. 1999;94:260–264.
90. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematolopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.
91. Ritter J, Zimmermann K, Johrens K, et al. T-cell repertoires in refractory coelic disease. Gut. 2018;67:644–653.
92. Hussein S, Gindin T, Lagana SM, et al. Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease. J Clin Pathol. 2018;71:825–831.
93. Green PHR, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–1743.
94. Cellier C, Patey N, Mauvieux L, et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology. 1998;114:471–481.
95. Patey-Mariaud DSN, Cellier C, Jabri B, et al. Distinction between coeliac disease and refractory sprue: a simple immunohistochemical method. Histopathology. 2000;37:70–77.
96. De Mascarel A, Belleannee G, Stanislas S, et al. Mucosal intraepithelial T-lymphocytes in refractory celiac disease: a neoplastic population with a variable CD8 phenotype. Am J Surg Pathol. 2008;32:744–751.
97. Schein J. Syndrome of nontropical sprue with hitherto undescribed lesions of the intestine. Gastroenterology. 1947;8:438–460.
98. Weinstein WM, Saunders DR, Tytgat GN, et al. Collagenous sprue-an unrecognized type of malabsorption. N Engl J Med. 1970;283:1297–1301.
99. Vakiani E, Arguelles-Grande C, Mansukhani MM, et al. Collagenous sprue is not always associated with dismal outcomes: a clinicopathological study of 19 patients. Mod Pathol. 2010;23:12–26.
100. Zhao X, Johnson RL. Collagenous sprue: a rare, severe small-bowel malabsorption disorder. Arch Pathol Lab Med. 2011;135:803–809.
101. Maguire AA, Greenson JK, Lauwers GY, et al. Collagenous sprue: A clinicopathology study of 12 cases. Am J Surg Pathol. 2009;33:1440–1449.
102. Kung VL, Liu TC, Ma C. Collagenous enteritis is unlikely a form of aggressive celiac disease despite sharing HLA-DQ2/DQ8 genotypes. Am J Surg Pathol. 2018;42:545–552.
103. Lan N, Shen B, Yuan L, et al. Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis. J Gastroenterol Hepatol. 2017;32:120–127.
104. Vanoli A, Di Sabatino A, Furlan D, et al. Small bowel carcinomas in coeliac or Crohn’s disease: Clinico-pathological, molecular, and prognostic features. A study form the small bowel cancer Italian consortium. J Crohn Colitis. 2017;11:942–953.
105. Vanoli A, Di Sabatino A, Martino M, et al. Small bowel carcinomas in celiac or Crohn’s disease: distinctive histophenotypic, molecular and histogenetic patterns. Mod Pathol. 2017;30:1453–1466.
106. Forrest EA, Wong M, Nama S, et al. Celiac crisis, a rare and profound presentation of celiac disease: a case report. BMC Gastroenterol. 2018;18:59.
107. Majumdar K, Sakhuja P, Puri AS, et al. Coeliac disease and the liver: spectrum of liver histology, serology and treatment response at a tertiary referral centre. J Clin Pathol. 2018;71:412–419.
108. Mounajjed T, Oxentenko A, Shmidt E, et al. The liver in celiac disease: clinical manifestations, histologic features, and response to gluten-free diet in 30 patients. Am J Clin Pathol. 2011;136:128–137.
109. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology. 2001;120:636–651.
110. Gaur K, Sakhuja P, Puri AS, et al. Gluten-free hepatomiracle in “Celiac Hepatitis”: a case highlighting the rare occurrence of nutrition-induced near total reversal of advanced steatohepatitis and cirrhosis. Saudi J Gastroenterol. 2016;22:461–464.
111. Armstrong BK, Ammon RK, Finlay-Jones LR, et al. A further case of chronic ulcerative enteritis. Gut. 1973;14:649–652.
112. Jeffries GH, Steinberg H, Sleisenger MH. Chronic ulcerative (nongranulomatous) jejunitis. Am J Med. 1968;44:47–59.
113. Robertson DAF, Dixon MF, Scott BB, et al. Small intestinal ulceration: diagnostic difficulties in relation to celiac disease. Gut. 1983;24:565–574.
114. Isaacson PG, Wright DHWhitehead R. Gut-associated lymphoid tumors. Gastrointestinal and Esophageal Pathology. Edinburgh: Churchill Livingstone; 1995:755–775.
115. Ochs HD, Ament ME, Davis SD. Giardiasis with malabsorption in X-linked agammaglobulinemia. N Engl J Med. 1972;287:341–342.
116. Rhee JW, Gryboski JD, Sheahan DG, et al. Reversible enteritis and lymphopenia in infantile x-linked agammaglobulinemia. Am J Dig Dis. 1975;20:1071–1075.
117. Malamut G, Verkarre V, Suarez F, et al. The enteropathy associated with common variable immunodeficiency: the delineated frontier with celiac disease. Am J Gastroenterol. 2010;105:2262–2275.
118. Joo M, Sang HS, Sun HC, et al. Nodular lymphoid hyperplasia and histologic changes mimicking celiac disease, collagenous sprue, and lymphocytic colitis in a patient with selective IgA deficiency. Pathol Res Pract. 2009;205:876–880.
119. Perlmutter DH, Leichtner AM, Goldman H, et al. Chronic diarrhea associated with hypogammaglobulinemia and enteropathy in infants and children. Dig Dis Sci. 1985;30:1149–1155.
120. Horowitz A, Lorenzsonn VW, Olsen WA, et al. Small intestinal disease in T cell deficiency. J Pediatr. 1974;85:457–462.
121. Booth IW, Chrystie IL, Levinsky RJ, et al. Protracted diarrhea, immunodeficiency and viruses. Eur J Pediatr. 1982;138:271–272.
122. Nahon S, Patey-Mariaud De Serre N, Lejeune O, et al. Duodenal intraepithelial lymphocytosis during Helicobacter pylori infection is reduced by antibiotic treatment. Histopathology. 2006;48:417–423.
123. Sharma P, Baloda V, Gahlot GP, et al. Clinical, endoscopic, and histological differentiation between celiac disease and tropical sprue: A systematic review. J Gastroenterol Hepatol. 2019;34:74–83.
124. Baker SJ, Mathan VJCard WI, Creamer B. In: Card WI, Creamer B, eds. Modern Trends in Gastro-enterology, Vol 4. London: Butterworth; 1970:198.
125. Davidson GP, Barnes GL. Structural and functional abnormalities of the small intestine in infants and young children with rotavirus enteritis. Acta Pediatric Scandinavica. 1979;68:181–186.
126. Ulshen MH, Rollo JL. Pathogenesis of Escherichia coli gastroenteritis in man– Another mechanism. N Engl J Med. 1980;302:99–101.
127. Barnes GL, Townley RRW. Duodenal mucosal damage in 31 infants with gastroenteritis. Arch Dis Child. 1973;48:343–349.
128. Barandun D, Riva G, Spengler GABergsma D, Good RA. Immunological deficiency diseases in man. Birth Defects Original article series IV, 1. New York: The National Foundation – March of Dimes; 1968:40.
129. Koot BG, ten Kate FJ, Juffrie M, et al. Does Giardia lamblia cause villous atrophy in children?: A retrospective cohort study of the histological abnormalities in giardiasis. J Pediatr Gastroenterol Nutr. 2009;49:304–308.
130. Hanevik K, Wik E, Langeland N, et al. Transient elevation of anti-transglutaminase and anti-endomysium antibodies in Giardia infection. Scand J Gastroenterol. 2018;53:809–812.
131. Rosekrans PC, Meijer CJ, Cornelisse CJ, et al. Use of morphometry and immunohistochemistry of small intestinal biopsy specimens in the diagnosis of food allergy. J Clin Pathol. 1980;33:125–130.
132. Vitoria JC, Camarero C, Sojo A, et al. Enteropathy related to fish, rice, and chicken. Arch Dis Child. 1982;57:44–48.
133. Challacombe DN, Wheeler EE, Campbell PE. Morphometric studies and eosinophil cell counts in the duodenal mucosa of children with chronic nonspecific diarrhoea and cow’s mild allergy. J Pediatr Gastroenterol Nutr. 1986;5:887–891.
134. Shiner M, Redmond AO, Hansen JD. The jejunal mucosa in protein-energy malnutrition. A clinical, histological, and ultrastructural study. Exp Mol Pathol. 1973;19:61–78.
135. Foroozan P, Trier JS. Mucosa of the small intestine in pernicious anemia. N Engl J Med. 1967;277:553–558.
136. Bianchi A, Chipman DW, Dreskin A, et al. Nutritional folic acid deficiency with megaloblastic changes in the small-bowel epithelium. N Engl J Med. 1970;282:859–861.
137. Kakar S, Nehra V, Murray JA, et al. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol. 2003;98:2027–2033.
138. Sáez González E, Díaz Jaime FC, Del Val Antoñana A. Clinical, laboratory, serological, and histological profile of sprue-like enteropathy associated with olmesartan use. Rev Esp Enferm Dig. 2016;108:685–686.
139. Marthey L, Cadiot G, Seksik P, et al. Olmesartan-associated enteropathy: results of a national survey. Aliment Pharmacol Ther. 2014;40:1103–1109.
140. Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012;87:732–738.
141. Choi EY, McKenna BJ. Olmesartan-associated enteropathy: a review of clinical and histologic findings. Arch Pathol Lab Med. 2015;139:1242–1247.
142. Gonzálezcordero PL, Fernandezgonzalez N, Molinainfante J. Sprue-Like Enteropathy Associated With Oxcarbazepine. Am J Gastroenterol. 2016;111:1662–1663.
143. Parfitt JR, Jayakumar S, Driman DK. Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes. Am J Surg Pathol. 2008;32:1367–1372.
144. Ziegler TR, Fernández-Estívariz C, Gu LH, et al. Severe villus atrophy and chronic malabsorption induced by azathioprine. Gastroenterology. 2003;124:1950–1957.
145. Singleton J, Kkern F, Waddell W. Diarrhea and pancreatic islet cell tumor: report of a case with a severe jejunal mucosal lesion. Gastroenterology. 1965;49:197–208.
146. Avery GB, Villavicencio O, Lilly JR, et al. Intractable diarrhea in early infancy. Pediatrics. 1968;41:712–722.
147. Rossi TM, Lebenthal E, Nord KS, et al. Extent and duration of small intestinal mucosal injury in intractable diarrhea of infancy. Pediatrics. 1980;66:730–735.
148. Stern M, Gruttner R, Krumbach J. Protracted diarrhea: secondary monosaccharide malabsorption and zinc deficieny with cutaneous manifestation during total parenteral nutrition. Eur J Pediatr. 1980;135:175–180.
149. Davidson GP, Cutz E, Hamilton JR, et al. Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villous atrophy. Gastroenterology. 1978;75:783–790.
150. Fisher SE, Boyle JT, Holtzapple P. Chronic protracted diarrhea and jejunal atrophy in infant: cimetidine-associated stimulation of jejunal mucosal growth. Dig Dis Sci. 1981;26:181–186.
151. Savage MO, Mirakian R, Wozniak ER, et al. Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhea. J Pediatr Gastroenterol Nutr. 1985;4:187–195.
152. Walker-Smith JA, Unsworth DJ, Hutchins P, et al. Autoantibodies against gut epithelium in child with small intestinal enteropathy. Lancet. 1982;319:566–567.
153. Corazza GR, Biagi F, Volta U, et al. Autoimmune enteropathy and villous atrophy in adults. Lancet. 1997;350:106–109.
154. Patey-Mariaud de Serre N, Canioni D, Ganousse S, et al. Digestive histopathologic presentation of IPEX syndrome. Mod Pathol. 2009;22:95–102.
155. Mirakian R, Richardson A, Milla PJ, et al. Protracted diarrhea of infancy: evidence in support of an autoimmune variant. Br Med J. 1986;293:1132–1136.
156. McCulloch J, Barclay M, Levene A, et al. Seronegative enteropathy and malnutrition: a diagnostic challenge. BMJ Case Rep. 2018;2018:bcr-2018-224397.
157. Harpaz N, Levi GS, Yurovitsky A, et al. Intraepithelial lymphocytosis in architecturally normal small intestinal mucosa: association with morbid obesity. Arch Pathol Lab Med. 2007;131:344.
158. Memeo L, Jhang J, Hibshoosh H, et al. Duodenal intraepithelial lymphocytosis with normal villous architecture: Common occurrence in H. pylori gastritis. Mod Pathol. 2005;18:1134–1144.
159. Ferguson A. Intraepithelial lymphocytes of the small bowel. Gut. 1977;18:921–937.
160. Michaelsson G, Kraaz W, Gerden B, et al. Increased lymphocytic infiltration in duodenal mucosa from patients with psoriasis and serum IgA antibodies in gliadin. Br J Dermatol. 1995;133:896–904.
161. Rostoker G, Delchier JC, Chaumette MJ. Increased intraepithelial T lymphocytes in primary glomerulonephritis: a role of oral tolerance breakdown in the pathophysiology of human primary glomerulonephritis. Nephrol Dial Transpant. 2001;16:513–517.
162. Brown I, Mino-Kenudson M, Deshpande V, et al. Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa. Arch Pathol Lab Med. 2006;130:1020–1025.
163. Mino M, Lauwers G. Role of lymphocytic immunophenotyping in the diagnosis of gluten-sensitive enteropathy with preserved villous architecture. Am J Surg Pathol. 2003;27:1237–1242.
164. Tobin JM, Sinha B, Ramani P, et al. Upper gastrointestinal mucosal disease in pediatric Crohn disease and ulcerative colitis: a blinded, controlled study. J Pedistr Gastroenterol Nutr. 2001;32:443–448.
165. Wang N, Dumot JA, Achkar E, et al. Colonic epithelial lymphocytosis without a thickened subepithelial collagen table: a clinicopathological study of 40 cases supporting a heterogeneous entity. Am J Surg Pathol. 1999;23:1068–1074.
166. Koskela RM, Niemela SE, Karttunen TJ, et al. Clinical characteristics of collagenous and lymphocytic colitis. Scand J Gastroenterol. 2004;39:837–845.
167. Niveloni S, Pedreira S, Sugai E, et al. The natural history of gluten sensitivity: report of two new celiac disease patients resulting from long-term follow-up of nonatrophic, first-degree relatives. Am J Gastroenterol. 2000;95:463–468.
168. Collin P, Helin H, Maki M, et al. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small bowel biopsy findings. Scand J Gastroenterol. 1993;28:595–598.
169. Austad WI, Cornes JS, Gough KR, et al. Steatorrhea and malignant lymphoma. Am J Dig Dis. 1967;12:475–490.
170. Harris OD, Cooke WT, Thompson M, et al. Malignancy in adult celiac disease and idiopathic steatorrhea. Am J Med. 1967;42:899–912.
171. Uppal G, Chodoff A, Wang ZX, et al. EBV-associated Peripheral T-Cell Lymphoma of Gastrointestinal Tract Presented With Widespread Chronic Inflammation: A Case Report. Appl Immunohistochem Mol Morphol. 2017;25:e1–e8.
172. Sharaiha RZ, Lebwohl B, Reimers L, et al. Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973-2008. Cancer. 2012;118:3786–3792.
173. Ciccocioppo R, Croci GA, Biagi F, et al. Intestinal T-cell lymphoma with enteropathy-associated T-cell lymphoma-like features arising in the setting of adult autoimmune enteropathy. Hematol Oncol. 2018;36:481–488.
174. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project. Blood. 2011;118:148–155.
175. Isaacson P, Norton AJ. Extranodal Lymphomas. Edinburgh: Churchill Livingstone; 1994.
176. Murray A, Cuevas EC, Jones DB, et al. Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. Am J Pathol. 1995;146:509–519.
177. Wright DH. Enteropathy associated T cell lymphoma. Cancer Surv. 1997;30:249–261.
178. Chan JK, Chan AC, Cheuk W, et al. Type II enteropathy-associated T-cell lymphoma: a distinct aggressive lymphoma with frequent γδ T-cell receptor expression. Am J Surg Pathol. 2011;35:1557–1569.
179. Fine KD, Stone MJ. Alpha-heavy chain disease, mediterranean lymphoma, and immunoproliferative small intestinal disease: a review of clinicopathological features, pathogenesis, and differential diagnosis. Am J Gastroenterol. 1999;94:1139–1152.
180. Nasr K, Haghighi P, Bakhshandeh K, et al. Primary upper small intestinal lymphoma: a report of 40 cases from Iran. Am J Dig Dis. 1976;21:313–323.
181. Yanai S, Nakamura S, Takeshita M, et al. Translocation t(14;18)/IGH-BCL2 in gastrointestinal follicular lymphoma: correlation with clinicopathologic features in 48 patients. Cancer. 2011;117:2467–2477.
182. Yoshida N, Nomura K, Wakabayashi N, et al. Cytogenetic and clinicopathological characterization by fluorescence in situ hybridization on paraffin-embedded tissue sections of twenty-six cases with malignant lymphoma of small intestine. Scand J Gastroneterol. 2006;41:212–222.
183. Iwamuro M, Okada H, Kawahara Y, et al. Endoscopic features and prognoses of mantle cell lymphoma with gastrointestinal involvement. World J Gastroenterol. 2010;16:4661–4669.
184. Salar A, Juanpere N, Bellosillo B, et al. Gastrointestinal involvement in mantle cell lymphoma: a prospective clinic, endoscopic, and pathology study. Am J Surg Pathol. 2006;30:1274–1280.
Keywords:

celiac disease; duodenum; intraepithelial lymphocytosis; villous atrophy; anti tissue transglutaminase antibodies; refractory celiac disease

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.