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A practical approach to small bowel biopsyinterpretation: Celiac disease and its mimics

Rish K. Pai, MD, PhD

Department of Anatomic Pathology, Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic,Cleveland, Ohio 44195

a r t i c l e i n f o

Keywords:

Differential diagnosis

Intraepithelial lymphocytosis

Villous architecture

Sprue

Gluten

1053/j.semdp.2014.02.006sevier Inc. All rights rese

pair@ccf.org

a b s t r a c t

While celiac disease is the most common cause of villous remodeling and intraepithelial

lymphocytosis in the proximal small bowel, there are many entities that can mimic its

histologic appearance. The purpose of this review is to discuss normal small bowel

histology and the differential diagnosis of celiac disease. Approaches to evaluate increased

intraepithelial lymphocytes are presented, followed by a detailed discussion of the

pathology of celiac disease. Particular emphasis is given to those conditions that cause

intraepithelial lymphocytosis in the setting of preserved villous architecture, although

other important entities, such as peptic injury, idiopathic inflammatory bowel disease,

medication injury, eosinophilic (allergic) gastroenteritis, autoimmune enteropathy, com-

mon variable immunodeficiency, and infections are also reviewed.

& 2014 Elsevier Inc. All rights reserved.

Introduction

Celiac disease (i.e., gluten-sensitive enteropathy or celiacsprue) is the most common cause of small intestinal mucosalremodeling. It usually causes variable villous blunting, crypthyperplasia, plasma cell-rich inflammation, and increasedintraepithelial lymphocytes, although some cases show subtleabnormalities, such as increased intraepithelial lymphocytesin the presence of normal villous architecture. Unfortunately,the diagnosis of celiac disease is not straightforward in allcases, as many other conditions can produce similar histo-logic features (Table 1). The purpose of this review is toprovide the reader with a general approach to small bowelbiopsy evaluation and discuss entities that can cause villousblunting and/or increased intraepithelial lymphocytes.

Histology of normal small bowel

The duodenum, jejunum, and ileum show slight histologicdifferences and are prone to artifactual distortion that poses

rved.

diagnostic challenges. Villi at all sites are lined by absorptivecells with admixed goblet cells, although the ratio of goblet cellsto absorptive cells increases in the distal bowel compared to theduodenum. Paneth cells and endocrine cells are confined to thedeeper crypt region where one may also encounter occasionalmitotic figures. The normal villus-to-crypt ratio in the duodenumis approximately 3–4:1 (Fig. 1A), but villi may be broader andshorter, overlying gastric heterotopias and Brunner glands in theduodenal bulb. In addition, duodenal bulb biopsies frequentlyshow changes of peptic injury that simulate celiac disease, asdescribed in subsequent sections, so biopsies to exclude celiacdisease should always include samples distal to the duodenalbulb. Villi of the jejunum and ileum tend to be slightly taller(Fig. 1B) except in areas overlying lymphoid aggregates wherethey are often broad-based or flat. Tangentially sectioned villiand those that have been stripped of surface epithelium can alsoappear blunted and, thus, these areas should be avoided whenassessing villous architecture. An adequate tissue sample con-sists of at least three or four consecutive, intact villi that are well-oriented in the plane of section.

Table 1 – Causes of villous architectural abnormalities in the small bowel.

Severe villous blunting and crypt hyperplasia Variable villous blunting and crypt hyperplasia

Celiac disease Peptic injuryRefractory sprue Celiac diseaseCollagenous sprue Inflammatory bowel diseaseInflammatory bowel disease Autoimmune enteropathyAutoimmune enteropathy Common variable immunodeficiencyCommon variable immunodeficiency Tropical sprueEosinophilic gastroenteritis Bacterial overgrowthMedications InfectionsChemotherapy Medication injuryTropical sprue Non-gluten protein intolerance

Eosinophilic gastroenteritis

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The small bowel lamina propria normally houses abundantgut-associated lymphoid tissue comprising lymphocytes,plasma cells, and macrophages, as well as scattered

Fig. 1 – (A) The villus:crypt ratio is normally 3–4:1 in the duodenuPaneth cells are confined to the deep crypts. The lamina propriaeosinophils. (B) The villus:crypt ratio is slightly higher in the jejslightly broader. (C) Intraepithelial lymphocytes tend to be preseof the villous tips.

eosinophils and neutrophils. Granulocytes are considerednormal components of the lamina propria, provided theyare not present in crypt or surface epithelium, whereas

m. Goblet cells are interspersed among enterocytes, whereascontains mononuclear cell-rich infiltrates and occasional

unum compared to the duodenum and the villous tips arent predominantly at the bases and sides of villi with sparing

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scattered intraepithelial lymphocytes can be normallypresent in villous epithelium (Fig. 1C). Although the accept-able number of “normal” intraepithelial lymphocytes hasbeen reported to be as high as 40/100 enterocytes, morerecent analyses have defined the upper limit of normal tobe 20–25/100 enterocytes in hematoxylin and eosin (H&E)-stained sections and slightly more (25–35/100 enterocytes)when using an anti-CD3 immunohistochemical stain.1–3 Useof immunohistochemistry to detect intraepithelial lympho-cytes is not recommended, as these stains are not superior toevaluation of H&E-stained sections for diagnosing celiacdisease and may, in fact, lead to overdiagnosis of glutensensitivity.4 Intraepithelial lymphocytes are more numerouson the lateral aspects of villi and diminish in number towardthe villous tips. However, diseases characterized by increasedintraepithelial lymphocytes, particularly celiac disease, showmore intraepithelial lymphocytes in the villous tips.5,6 Thus,analyzing villous tips for intraepithelial lymphocytes is aconvenient way to determine whether or not they areincreased. A count of 6 or more intraepithelial lymphocytesper 20 enterocytes at the villous tip is considered abnormal.6–8 Formal counting of intraepithelial lymphocytes is notnecessary in most cases, as any increase is usually readilyapparent upon careful observation. Of note, increased num-bers of intraepithelial lymphocytes are normally present inepithelium overlying and adjacent to lymphoid aggregates, socare must be taken to avoid over-interpreting this finding.

Celiac disease

Celiac disease is a systemic disease with primarily gastro-intestinal manifestations, particularly in the small intestinewhere it causes malabsorption owing to an abnormalimmune response to dietary gluten. Gluten activates boththe adaptive and the innate immune systems in susceptiblepatients.9 Gliadin, a degradation product of gluten, directlyinteracts with intestinal epithelium, resulting in upregulationof heat shock proteins and secretion of several cytokines,including interleukin-15, which promote recruitment of intra-epithelial lymphocytes. Gliadin also enters the lamina prop-ria where it is modified by tissue transglutaminase (tTG) andpresented to CD4þ T-cells via human leukocyte antigen (HLA)complexes. This action results in T-cell activation and secre-tion of various cytokines that stimulate CD8þ intraepitheliallymphocytes to injure enterocytes. These T-cells also stim-ulate B-cells to produce autoantibodies to tissue transgluta-minase, gliadin, and other proteins.9

Celiac disease is very common in Western populations and isnow diagnosed four times more frequently than it was 60 yearsago. It affects approximately 1% of individuals in North Americaand Europe, although recent estimates suggest that only 20% ofpatients with celiac disease are actually diagnosed with thedisorder.10,11 The disease usually presents in the third andfourth decades, but is increasingly detected in pediatric andolder patients. The disorder is more common among womenthan among men and is heavily influenced by genetic factors.Patients with specific HLA complexes, namely HLA-DQ2 andHLA-DQ8 alleles, are highly susceptible to celiac disease.10

Celiac disease may cause diverse clinical symptoms andlaboratory abnormalities. Adults typically present with

steatorrhea, abdominal cramps, distension, diarrhea, and vom-iting. Non-gastrointestinal symptoms such as iron deficiencyanemia, osteoporosis, neurologic symptoms, infertility, andincreased liver function tests are increasingly recognized aspresenting manifestations of disease.10,12,13 Infants may sufferfrom failure to thrive, vomiting, anorexia, and diarrhea;whereas older children may have short stature, neurologicsymptoms, and anemia.14 Dermatitis herpetiformis, autoim-mune hepatitis, cystic fibrosis, type 1 diabetes mellitus, Sjögrensyndrome, primary biliary cirrhosis, and many other immune-mediated disorders show associations with celiac disease and,thus, diagnosis of these entities should prompt exclusion ofgluten sensitivity.10 Patients with Down syndrome are alsoparticularly at risk for celiac disease.15

The diagnosis of celiac disease can be problematic becauseno single test shows 100% sensitivity and specificity in everypatient.13 A presumptive diagnosis of celiac disease is usuallymade in the context of positive serologic studies and character-istic histologic changes present in duodenal biopsies, althoughone may argue that suggestive symptoms and markedlyelevated celiac antibody serologies alone may be adequate toestablish a diagnosis.14 Importantly, a patient must be on agluten-containing diet for serologic and histologic test resultsto be meaningful. The two best serologic studies measure IgAanti-tissue transglutaminase (tTG) antibodies and IgA anti-endomysial antibodies. Of these, anti-tTG is the preferredscreening test. It is easy to perform and shows both highsensitivity (94%) and specificity (97%) for celiac disease.16

However, this marker has several limitations. False-negativeresults may be encountered among patients with IgA defi-ciency, which is seen in approximately 10% of patients withceliac disease. These individuals require testing for the IgGisotype of anti-tTG. False-positive results may be encounteredin patients with inflammatory bowel disease, primary biliarycirrhosis, heart disease, autoimmune enteropathy, and otherimmune-mediated disorders. In addition, serum anti-tTG anti-body titers correlate with severity of histologic damage andtheir positive predictive value can be quite low in patients withminimal histologic abnormalities.17,18 Newer tests that meas-ure antibodies against deamidated gliadin peptidesmay also behelpful in some settings.19

Patients with a positive serologic test should undergoendoscopic examination with biopsies of the duodenum.13

The endoscopic findings are neither sensitive nor specific.The duodenum may appear entirely normal or display innu-merable indentations on mucosal folds, which have beendescribed as showing a scalloped appearance. While evaluat-ing villous architecture in the duodenal bulb can be challeng-ing, recent studies have shown that biopsies from theduodenal bulb improve diagnostic yield in both pediatricand adult patients with celiac disease due to the patchynature of small bowel involvement.20,21 For this reason, mostauthorities suggest obtaining biopsies from multiple siteswithin the duodenum including the duodenal bulb, proximalduodenum, and distal duodenum.22

Classic features of celiac disease include total villous blunting,hyperplastic crypts, expansion of the lamina propria by plasmacell-rich inflammatory infiltrates, and increased intraepitheliallymphocytes (Fig. 2A and B). Indeed, biopsies with severe villousabnormalities bear a close resemblance to colonic mucosa.

Fig. 2 – (A) Most small bowel biopsies from patients with celiac disease show some degree of villous blunting. Although thesection is slightly tangential, crypt hyperplasia is evident and increased intraepithelial lymphocytes are present. (B) Thisbiopsy was taken from a patient with markedly elevated anti-tTG serum antibodies. There is complete villous blunting withmarked crypt hyperplasia. Intraepithelial lymphocytes are present in crypts and surface epithelium. Numerous mitoticfigures are evident (arrows).

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Notably, the absence of villi is accompanied by regeneration andhyperplasia of crypts and, thus, the findings are more appro-priate classified as “villous remodeling” than “villous atrophy.”Surface enterocytes are damaged and may display loss ofpolarity with an attenuated brush border. Mucosal erosionsand ulcerations are quite rare and, if present, may herald theonset of refractory sprue or lymphoma. Scattered neutrophilsare occasionally encountered in crypts and some patients evenhave crypt or surface microabscesses. However, these findingsare generally mild and focal in nature; more substantial neu-trophilic infiltrates should raise the possibility of an alternativediagnosis.23 The severity of histologic damage can be quantifiedusing the Marsh classification scheme. This grading system,which was later modified by Oberhuber et al.,25 assesses thedegree of villous blunting, intraepithelial lymphocytes, and crypthyperplasia (Table 2).24 While the Marsh classification is animportant research tool that can be used to determineresponses to treatment, it is not routinely used in daily practice.The diagnosis of celiac disease is straightforward when the

clinical findings, serologic studies, and biopsy results are allin agreement. However, there are many instances in whichone or more of these tests are negative. Some patients mayhave normal duodenal biopsies in the presence of positive

Table 2 – Modified Marsh–Oberhuber classification ofceliac disease.

Type Intraepitheliallymphocytes

Crypts Villousblunting

0 Normal Normal None1 Increased Normal None2 Increased Hyperplastic None3a Increased Hyperplastic Mild3b Increased Hyperplastic Moderate3c Increased Hyperplastic Severe (flat)4 Increased Atrophic Severe (flat)

serologies. These patients may be provisionally labeled withlatent celiac disease, which may be managed with a combi-nation of repeat biopsies, a trial of gluten withdrawal, or,more commonly, watchful waiting.10,13 If, however, intra-epithelial lymphocytes are encountered in the absence ofother supportive evidence of celiac disease, one shouldconsider alternative explanations for the histologic findings.A strong clinical suspicion in the absence of supportivehistologic or laboratory findings may prompt evaluation forhigh-susceptibility alleles HLA-DQ2 or DQ8 or repeat testingprior to initiation of gluten withdrawal.10

The histologic abnormalities and clinical symptoms ofceliac disease usually regress rapidly upon adherence to agluten-free diet. Incomplete resolution, or recurrence, ofsymptoms despite at least one year of adherence to agluten-free diet is classified as refractory celiac disease.Possible etiologies include non-compliance to gluten with-drawal, collagenous sprue, or concomitant lymphocytosiselsewhere in the gastrointestinal tract. Once these possibil-ities are excluded, refractory celiac disease is classified basedupon the predominant phenotype of intraepithelial T-cells.26,27 Type I refractory celiac disease is characterized bya normal T-cell phenotype (CD3þ/CD8þ), whereas type IIrefractory celiac disease displays loss of CD8 expression andclonality by molecular studies. Type II disease may progressto overt enteropathy-associated T-cell lymphoma. This lethalcomplication of celiac disease consists of an infiltrate ofmedium-to-large cells with round nuclei, prominent nucleoli,and moderate amounts of pale cytoplasm, which is accom-panied by a reactive inflammatory cell infiltrate rich inmacrophages and eosinophils.28

Collagenous sprue

Collagenous sprue was originally described by Weinsteinet al.29 in 1970. It shares many features with celiac disease,

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including severe villous architectural abnormalities, crypthyperplasia, and intraepithelial lymphocytosis, but alsoshows an irregularly thickened layer of type 1 collagensubjacent to the surface epithelium (Fig. 3). Collagenoussprue shares many features with collagenous colitis. Thelamina propria is expanded by a mixed inflammatory cellinfiltrate and increased eosinophils and the subepithelialcollagen layer contains entrapped capillaries and inflamma-tory cells. Most cases show some degree of surface epithelialcell damage, including cytoplasmic vacuolization, loss ofcolumnar shape, and detachment from the basement mem-brane. Occasional neutrophils may be present, but are not aprominent feature.The etiology of collagenous sprue is often unknown,

although some cases are probably related to gluten sensitiv-ity. Several reports describe a well-documented progressionof celiac disease to collagenous sprue, whereas other de novocases of collagenous sprue respond to a gluten-free diet.30–32

Some cases of collagenous sprue have been attributed tomedication injury or immunodeficiency. The disorder iscommonly associated with other immune-mediated diseasesand may be seen in combination with collagenous gastritisand collagenous colitis, raising the possibility that it repre-sents an abnormal immune response to dietary antigensincluding, but not limited to, gluten. First-line treatmentconsists of adherence to a gluten-free diet as well as initiationof immunomodulatory medications if symptoms do notimprove. Unfortunately, histologic features of collagenoussprue often persist despite therapy and some patientsdevelop serious complications, including severe malnutritionand T-cell lymphoma.32

Increased IELs with preserved villous architecture

Increased intraepithelial lymphocytosis may be seen innearly 3% of duodenal biopsies that show normal villous

Fig. 3 – Biopsies of collagenous sprue reveal complete villousshortening with crypt hyperplasia and increasedintraepithelial lymphocytes, reminiscent of celiac disease.However, the subepithelial collagen layer is thickened andcontains entrapped blood vessels and inflammatory cells.The surface epithelium is injured and partially detached.(Photo courtesy of Dr. Rhonda K. Yantiss.)

architecture. Although early reports indicated that biopsiesdisplaying increased intraepithelial lymphocytes in the set-ting of preserved villous architecture may reflect celiacdisease, more recent data suggest that this finding is fairlynon-specific.6,33,34 Kakar et al.35 assessed the clinical featuresof 43 patients with increased intraepithelial lymphocytes andnormal duodenal villous architecture and found that only 9%proved to have celiac disease. Results of larger studies alsoconfirm that only 20% of biopsies with increased intraepithe-lial lymphocytes and normal villous architecture reflect celiacdisease, although it is possible that some patients willdevelop more characteristic clinical and histologic featuresof celiac disease following a gluten challenge.33,36

The differential diagnosis of increased intraepithelial lym-phocytes in the duodenum is broad. There is a strongassociation between Helicobacter pylori gastritis and increasedduodenal intraepithelial lymphocytes, the latter of whichresolves upon successful H. pylori eradication (Fig. 4).37,38

Several immune-mediated diseases, including Hashimotothyroiditis, Grave disease, rheumatoid arthritis, psoriasis,multiple sclerosis, systemic lupus erythematosis, Crohn dis-ease, and ulcerative colitis may also cause intraepitheliallymphocytosis, although care must be taken to exclude celiacdisease in these patients since they all may have concom-itant gluten sensitivity.5,33,35,39 Other etiologies includeautism, lactose intolerance, peptic injury, medications, infec-tion, obesity, and non-gluten food allergies.40,41 Medicationsare increasingly recognized for their effects on small bowelinflammation. Kakar et al.35 found that 14% of patients withincreased intraepithelial lymphocytes and normal villousarchitecture were taking non-steroidal anti-inflammatorydrugs (NSAIDs) compared to only 2.2% of those without thishistologic finding. Some infections such as those by Giardialamblia, Cryptosporidium, and Cystoisospora belli may also elicitintraepithelial lymphocytes as described in the manuscriptby Lai et al. in this issue.

Peptic duodenitis

The duodenal bulb is susceptible to symptomatic or subclin-ical acid-induced injury due to exposure to acidic gastriccontents. Peptic injury is characterized by variable villousblunting and intraepithelial lymphocytosis that mimic fea-tures of celiac disease. However, the lamina propria usuallycontains increased neutrophils and the surface epitheliumdisplays gastric mucous cell (foveolar) metaplasia with, orwithout, associated neutrophils (Fig. 5). Brunner gland hyper-plasia has been described as a feature of peptic duodenitis,although it may be seen in the normal duodenum as well.The features of peptic injury are quite non-specific and can beseen in the setting of medication injury, particularly NSAIDs,Crohn disease, and some infections.

Idiopathic inflammatory bowel disease

Patients with established ulcerative colitis or Crohn diseasemay have duodenal biopsies that demonstrate increasedintraepithelial lymphocytes. While there are conflictingreports regarding the association between idiopathic inflam-matory disease and celiac disease, one may consider the

Fig. 4 – (A) Increased intraepithelial lymphocytes are present in this biopsy that shows normal villous architecture withoutvillous blunting or crypt hyperplasia. (B) Close examination reveals an increase in intraepithelial lymphocytes, especially atthe tips of the villi. (C) While some patients with this pattern of increased intraepithelial lymphocytes may have celiacdisease, the antral biopsy in this patient showed chronic active gastritis with intestinal metaplasia. Numerous bacteriaconsistent with H. pylori were also identified.

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possibility of coexistent gluten sensitivity in these individu-als.42,43 However, both ulcerative colitis and Crohn diseasemay have manifestations in the duodenum. Indeed, 10–22%of ulcerative colitis patients have features of duodenitis uponendoscopic examination and biopsy, including variable vil-lous blunting, expansion of the lamina propria by plasmacell-rich inflammation, and active inflammation.39,44,45 Sev-eral recent reports also describe patients with well-documented ulcerative colitis who developed severe, diffuseinflammatory changes in the upper gastrointestinal tractcharacterized by shallow ulcers, marked villous shortening,and basal lymphoplasmacytosis.46,47

Crohn disease is a well-known cause of small intestinalinflammation and villous distortion. Endoscopically apparentstrictures, aphthous erosions, and linear ulcerations arecommonly present in the ileum, biopsies of which show

active inflammation, villous architectural distortion, basallymphoplasmacytosis, and pseudopyloric gland metaplasia.Granulomata are helpful in confirming the diagnosis, butthey are present in less than half of cases. Clinically apparentduodenal Crohn disease is less frequent, but a substantialnumber of patients without upper gastrointestinal tractsymptoms have microscopic disease.48 Biopsies show varia-ble active inflammation, villous architectural distortion, basallymphoplasmacytosis, foveolar metaplasia, and occasionalgranulomata (Fig. 6). In contrast to celiac disease, most casesof Crohn disease that elicit villous shortening are accompa-nied by neutrophil-rich inflammation, crypt abscesses, andedema. The primary differential diagnosis includes peptic ormedication-related injury. Correlation with biopsy findingsfrom other sites is also helpful, as isolated duodenal Crohndisease is extremely rare.49

Fig. 5 – Exposure of duodenal mucosa to acidic gastriccontents results in Brunner gland hyperplasia and foveolarmetaplasia (arrow). Note the villi are somewhat distortedover Brunner glands. This finding should not be interpretedto represent villous blunting.

Fig. 6 – This duodenal biopsy from a patient with Crohndisease displays patchy villous shortening with active(neutrophilic) inflammation and edema in the laminapropria. A single epithelioid granuloma is also present(arrow).

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Medication injury

Medication-related gastrointestinal injury is increasingly com-mon. Perhaps the most common is injury by NSAIDs, many ofwhich are available without a prescription and cause a widevariety of colonic and small intestinal injuries. Mucosal injurymay not elicit symptoms and manifest only as occult bleedingand/or anemia. The stomach and duodenum are most com-monly affected, but distal small bowel and colonic injury areincreasingly recognized. Endoscopic findings include diffuseerythema and well demarcated, punched out ulcers anderosions. Jejunal and ileal changes are similar to those of theduodenum, although diaphragm disease shows a predilectionfor the distal small bowel.50 Diaphragm disease is caused byprolonged use of non-steroidal anti-inflammatory drugs and ischaracterized by numerous thin, web-like mucosal septa thatcause luminal narrowing and obstruction. The villi in theseareas are often blunted and pseudopyloric gland metaplasia iscommon. These agents can also be responsible for increasedintraepithelial lymphocytes in small bowel biopsies eitherwith, or without, villous architectural abnormalities.Recent reports describe severe gastrointestinal injury

related to the use of the angiotensin-II receptor antagonistolmesartan.51,52 Rubio-Tapia et al.52 evaluated the findings in22 patients with olmesartan-induced enteropathy and foundthat all had at least partial villous blunting and 15 showedcomplete villous shortening in duodenal biopsies (Fig. 7).Most (68%) cases showed some degree of neutrophilic inflam-mation, 64% displayed increased intraepithelial lymphocytesin the duodenum, and 32% had thickened subepithelialcollagen that raised the possibility of collagenous sprue.Indeed, the clinical diagnosis for many of these patientswas non-responsive celiac disease or unclassified sprue.Importantly, none of the patients had positive celiac serolo-gies or responded to a gluten-free diet. Abnormal histologicfindings were also seen in the stomach and colon. Discontin-uation of olmesartan resulted in reversion of duodenalhistology to normal in most cases.

Other medications that can cause villous abnormalitiesinclude colchicine, mycophenolate mofetil, ipilimumab (anti-CTLA4), and various chemotherapy agents. Colchicine causesmitotic arrest, producing an abundance of mitotic figures,including ring mitoses.53 Mycophenolate mofetil, a medicationcommonly used in solid organ transplantation, induces villousabnormalities, inflammation, and increased epithelial cellapoptosis.54–58 Ipilimumab is a monoclonal antibody that isincreasingly being used to treat advancedmelanoma, renal cell,ovarian, and prostate cancer. It causes increased crypt epithe-lial cell apoptosis, active inflammation, and villous bluntingresembling autoimmune enteropathy.59 Celiac disease mayrarely develop in patients receiving ipilimumab, raising thepossibility that this medication can unmask latent celiacsprue.60 Numerous chemotherapy medications and radioactivematerials can also injure the small bowel. A complete discus-sion of medication-related gastrointestinal tract injury is pro-vided in the article by Panarelli, which is included in this issue.

Eosinophilic (allergic) gastroenteritis

Eosinophil-rich inflammatory infiltratesmay be encountered insmall bowel biopsies obtained in a diverse range of settings,including medication injury, parasitic infection, Crohn disease,collagen vascular disease, hematologic malignancies, and idi-opathic eosinophilic (allergic) gastroenteritis.61 Idiopathic eosi-nophilic gastroenteritis is a diagnosis of exclusion and, thus,should only be entertained after other potential causes ofincreased eosinophils are excluded. Mucosal involvement byidiopathic eosinophilic gastroenteritis may result in variablevillous shortening with crypt hyperplasia and intraepitheliallymphocytosis that simulates celiac disease, although it is alsocharacterized by a prominent eosinophil-rich inflammatoryinfiltrate, often in combination with other abnormalities,including degranulated eosinophils, intraepithelial eosinophils,eosinophilic crypt abscesses, epithelial degenerative changes,villous blunting, and deep eosinophils in the muscularismucosa and submucosa.

Fig. 7 – (A) Olmesartan, an angiotensin-II receptor antagonist, caused marked duodenitis and villous blunting in this patient.Biopsies revealed expansion of the lamina propria by a mixed inflammatory infiltrate with numerous eosinophils.Neutrophilic cryptitis is readily apparent. (B) Increased intraepithelial lymphocytes were present in other areas.

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Autoimmune enteropathy

Autoimmune enteropathy was first described by McCarthyet al.62 who reported a patient with severe enteropathyassociated with total villous blunting and gut autoantibodies.A few years later, Walker-Smith et al.63 coined the term“autoimmune enteropathy” to describe findings in a 15-month-old child with severe enteropathy and antibodiesdirected against gut epithelium. Powell et al.64 later identifieda genetic basis for the disease when they studied a familywith eight boys afflicted with severe diarrhea, insulin-dependent diabetes, and other endocrinopathies. This pedia-tric X-linked syndrome of immune dysregulation polyendoc-rinopathy autoimmune enteropathy (IPEX) proved to resultfrom mutations in FOXP3, a gene that controls regulatory T-cells.65 Recent data suggest that autoimmune enteropathy

Fig. 8 – (A) Autoimmune enteropathy produced subtotal villoussimulating the appearance of celiac disease. However, goblet ceapoptosis is also identified and can be a helpful clue.

can also occur in young girls without features of IPEXsyndrome, as well as adults.65–67

Autoimmune enteropathy shows a predilection to affectthe small bowel and colon. It induces variable, but oftensevere, villous shortening and crypt hyperplasia, which isaccompanied by dense mononuclear cell rich inflammationof the lamina propria, similar to celiac disease (Fig. 8). Theseentities can usually be distinguished owing to the presence ofneutrophilic inflammation and prominent crypt epithelialcell apoptosis typically present in cases of autoimmuneenteropathy. Autoimmune enteropathy also showsdecreased, or absent, specialized intestinal cells such asgoblet, Paneth, and endocrine cells. It tends to display moresevere intraepithelial lymphocytosis affecting crypts com-pared to the surface epithelium, whereas celiac diseaseshows similar degrees of lymphocytosis in crypt and surface

blunting and mildly increased intraepithelial lymphocytes,lls and Paneth cells are not present. (B) Prominent crypt

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epithelium. Importantly, some patients with autoimmuneenteropathy have small bowel biopsies that show histologicfeatures indistinguishable from those of celiac disease andthese patients may even have anti-tTG antibodies in additionto anti-enterocyte antibodies.67 However, patients with auto-immune enteropathy do not respond to a gluten-free diet.68

Common variable immunodeficiency

Common variable immunodeficiency (CVID) is the second mostcommon primary immunodeficiency with an estimated preva-lence between 1:10,000 and 1:50,000.69,70 The diagnostic criteriainclude exclusion of other causes of immunodeficiency, recur-rent infections, decreased serum IgG levels at least two stand-ard deviations below normal accompanied by decreased levelsof least one other immunoglobulin subclass, and a failure tomount a response to vaccination.69,70 The disease is equallyprevalent among males and females and can occur at any age,although patients most commonly present between the firstand third decades of life. Common variable immunodeficiencylikely represents a heterogeneous group of disorders, thegenetic basis of which is unknown in the majority of cases.Most patients with common variable immunodeficiency

suffer from recurrent respiratory tract infections as well assymptoms related to the gastrointestinal tract. The two sitesmost commonly affected are the small bowel and colon,followed in frequency by changes in the stomach andesophagus.71–74 Nearly two-thirds of small bowel biopsiesfrom patients with common variable immunodeficiencyshow intraepithelial lymphocytosis, which is often accom-panied by villous architectural abnormalities that simulatethe features of celiac disease.74 Findings that help distinguishthese two entities include prominent crypt apoptosis and apaucity, or absence, of plasma cells in the former (Fig. 9),whereas plasma cells are quite prominent in the latter.However, data from a recent study suggest that up to 30%

Fig. 9 – (A) Subtotal villous blunting is seen in this example of craises the possibility of celiac disease, the lamina propria is “emScattered intraepithelial lymphocytes are present. Close examin

of common variable immunodeficiency cases contain normalnumbers of plasma cells, so this feature may prove to be oflimited diagnostic utility.74 Other findings typically present inbiopsies from patients with common variable immunodefi-ciency include intraepithelial neutrophils, granulomata, andlymphoid aggregates that may raise concern for Crohn dis-ease or autoimmune enteropathy. Patients with commonvariable immunodeficiency are prone to gastrointestinalinfections, particularly giardiasis and cytomegalovirus.72,74

Thus detection of either of these diseases should promptthe pathologist to exclude the possibility of common variableimmunodeficiency.

Non-parasitic infections

Numerous infections, including tropical sprue, viral enteritis,bacterial overgrowth, Whipple disease, and Mycobacteriumavium complex (MAC), can produce villous abnormalitieseither with or without increased intraepithelial lymphocytes.Tropical sprue affects residents of tropical areas, such asIndia, Southeast Asia, and the Caribbean. It likely results froman infectious agent, as epidemics and seasonal variations arewell described. Small bowel aspirates from affected patientsgrow a variety of bacteria, although no one species isimplicated in the pathogenesis of this disorder.75 Symptomsand histologic features are indistinguishable from those ofceliac disease, but treatment consists of antibiotic adminis-tration as well as supplementation with folate and vitaminB12. Of note, the ileum tends to be affected to the samedegree as the duodenum in patients with tropical sprue.Viral enteritis also elicits intraepithelial lymphocytosis

with variable villous blunting, although infected patientsare rarely biopsied because their symptoms spontaneouslyresolve. Detection of adenovirus is facilitated by recognitionof smudgy intranuclear viral inclusions in epithelial cells thatcan be enhanced using immunohistochemistry. Patients

ommon variable immunodeficiency. Although this findingpty” and lacks substantial plasma cell-rich inflammation. (B)ation of the lamina propria reveals a paucity of plasma cells.

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infected with the human immunodeficiency virus (HIV) maydevelop chronic diarrhea (41 month), malabsorption, andweight loss, yet they lack other detectable pathogens. Thesepatients are presumed to have HIV enteropathy.76–78 Featuresof this disorder are diverse and include focal active inflam-mation, erosions, villous blunting, crypt epithelial cell apop-tosis, and intraepithelial lymphocytosis.Bacterial infections, such as Whipple disease and infection

by Mycobacterium avium complex, expand the lamina propriawith numerous foamy macrophages. Whipple disease iscaused by failed phagocytosis of Tropheryma whipplei, whichcan be detected in lysosomes ultrastructurally and appears aschunky PAS-D-positive material in macrophages. Whippledisease is often accompanied by dilated lacteals and extrac-ellular lipid deposits that can be a helpful diagnostic feature(Fig. 10).79 Polymerase chain reaction for T. whipplei can be

Fig. 10 – (A) Whipple disease elicits variable villous architecturamacrophage-rich infiltrate in the lamina propria. Dilated lactealsPAS-D stain highlights chunky, PAS-positive material within mcharacterized by a macrophage-rich infiltrate as well, but dilateintralysozomal material seen in Whipple disease, the organismsfast stains.

used to confirm the infection.80 In contrast, Mycobacteriumavium complex appears as long, thin cytoplasmic rods rem-iniscent of sheaves of wheat. These organisms show acid-fastand PAS-D positivity (Fig. 10C and D). Small bowel bacterialovergrowth is another potential cause of villous blunting.81

Overgrowth with anaerobic bacteria occurs in patients withdecreased motility resulting from neural disorders, amyloi-dosis, or diabetes mellitus; structural defects due to stricturesor surgical manipulation; and immune deficiency states.Patients with bacterial overgrowth present with diarrheaand malabsorptive symptoms. Histologic features are varia-ble. Some symptomatic patients have entirely normal smallbowel biopsies, whereas approximately 25% show somedegree of villous blunting. Intraepithelial lymphocytosis hasbeen reported in some studies, whereas others have failed toidentify this as a consistent finding.81,82

l distortion. In this case, the villi are expanded by aare also present and represent a helpful diagnostic clue. (B) Aacrophages. (C) Mycobacterium avium complex infection isd lacteals are lacking. (D) In contrast to the coarseare long and delicate. They stain with both PAS-D and acid-

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Conclusions

Small bowel biopsy interpretation may be hampered by avariety of influences, including inadequate knowledge of theclinical situation, artifacts related to poor tissue processing andorientation, sample size, and a failure to recognize the spec-trum of normal findings. One frustrating issue pathologists faceis the lack of specificity of histologic findings for variousdiseases that may have small intestinal manifestations. Anincreasing number of immune-mediated, infectious, and sys-temic diseases are now recognized to have similar manifes-tations in the small bowel and the list of medications that cancause injury to the gastrointestinal tract continues to grow.Many of these processes cause variably severe villous architec-tural abnormalities with, or without, intraepithelial lymphocy-tosis. Pathologists should be careful to exclude thesepossibilities prior to rendering a diagnosis of celiac disease,especially in the absence of characteristic serologic and clinicalfindings. Communication with the treating gastroenterologistmay be necessary to arrive at the correct diagnosis.

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