Biopsy Diagnosis of Celiac

Disease
The Pathologist’s Perspective in Light of
Recent Advances

a, b
Stephen M. Lagana, MD *, Govind Bhagat, MD

KEYWORDS
 Pathology  Celiac disease  Histopathology  Enteropathy  Differential diagnosis
 Duodenum

KEY POINTS
 Celiac disease remains a clinicopathologic diagnosis.
 The differential diagnosis for mild duodenal injury and severe duodenal injury is distinct.
 Small intestinal biopsies should be evaluated in a systematic and reproducible manner.
 Small intestinal biopsies for celiac disease should be reported in a systematic, reproduc-
ible way.
 Good communication between gastroenterologists and pathologists is key to establishing
accurate diagnoses.

INTRODUCTION

Celiac disease (CD), also known as gluten-sensitive enteropathy, or celiac sprue is a

common immune-mediated disorder that occurs in genetically predisposed individ-
uals following consumption of certain grains, including wheat, which is characterized
by a protean clinical syndrome and small intestinal mucosal inflammation.1,2 Histo-
pathologic abnormalities of small intestinal mucosa (intraepithelial lymphocytosis,
lymphoplasmacytic inflammation of the lamina propria, villus atrophy, and crypt hy-
perplasia), now considered characteristic for CD, were first described by Paulley in
19543 (Box 1, Fig. 1). Because these alterations vary in severity, semiquantitative
grading schemes have been developed, starting in the 1990s, when Marsh4

Disclosure Statement: No financial conflicts/disclosures for either author.

a
Columbia University, New York Presbyterian Hospital, 622 West 168th Street, VC14-209, New
York, NY 10032, USA; b Columbia University, New York Presbyterian Hospital, 622 West 168th
Street, VC14-228, New York, NY 10032, USA
* Corresponding author.
E-mail address: SML2179@cumc.columbia.edu

Gastroenterol Clin N Am - (2018) -–-

https://doi.org/10.1016/j.gtc.2018.09.003 gastro.theclinics.com
0889-8553/18/ª 2018 Published by Elsevier Inc.
2 Lagana & Bhagat

Box 1
Histologic findings in active celiac disease

Intraepithelial lymphocytosis
Lymphoplasmacytic inflammation of lamina propria
Villus atrophy
Crypt hyperplasia
Granulocytic infiltrates (neutrophils and eosinophils)
Increased crypt apoptotic activity
Reactive epithelial changes

categorized the histologic patterns of small intestinal mucosal injury. This scheme was
subsequently modified by Oberhuber in 1999 and the modified Marsh-Oberhuber
classification is currently used by many pathologists, although newer simplified
schemes have been suggested that are preferred by some (Table 1).5,6 In our experi-
ence, as a referral center for the diagnosis and management of CD, we have noted that
many pathologists do not assign a formal grade to the mucosal abnormalities. The rea-
sons cited for this include interobserver variability in scoring the severity of mucosal
alterations among pathologists and a lack of correlation between the degree of villus
atrophy and clinical symptoms.7,8 We find value in using grading schemes for several
reasons. First, this allows for semiquantitative assessment of healing after initiation of
gluten-free diet (GFD). Second, it allows for a convenient shorthand that describes all
pertinent biopsy histopathologic features, provided all parties know which scheme is
being referenced.
Beyond the aforementioned “classical” histologic features of active CD (ACD), there
are additional findings that are common, although often overlooked. The enterocytes
(absorptive intestinal epithelial cells) commonly have a reactive appearance, with
mucin depletion, intracytoplasmic vacuolization, and a cuboidal rather than the typical
columnar cell shape (Fig. 2).9,10 Neutrophilic inflammation is common in the lamina
propria, occurring in most newly diagnosed cases of ACD. This phenomenon has
been shown to correlate with the degree of villus atrophy.10 Activated eosinophils
are increased in ACD.11 Crypt apoptosis is often a subtle histologic finding. It
is well described in autoimmune enteropathy (AE), mycophenolate toxicity, and

Fig. 1. Medium-power view of duodenal biopsy demonstrates the features of active celiac
disease (A) and mucosal healing following approximately 18 months on a gluten-free diet
(B). Note that in the active disease state the villi are completely atrophic and there is marked
crypt hyperplasia. In the healed state, the architecture is normal and no inflammation is
identified (hematoxylin and eosin, original magnification 10).
 Biopsy Diagnosis of Celiac Disease 3

Table 1
Comparison of the modified Marsh and Corazza-Villanacci grading schemes

Marsh-Oberhuber Corazza-Villanacci
Histology Classification Classification
Normal architecture, IEL Type 1 Grade A
Normal villi, crypt hyperplasia 1 IEL Type 2
Partial VA 1 IEL Type 3A Grade B1
Subtotal VA 1 IEL Type 3B
Total VA Type 3C Grade B2
Hypoplastic lesion Type 4 Deleted

Abbreviation: VA, villus atrophy.

graft-versus-host disease, but is also common in CD.12 It is, however, important to

note that these features although common in CD, are neither pathognomonic nor spe-
cific for it. Pathology outside of the small intestine may also be encountered in patients
with CD, including microscopic colitis and lymphocytic or collagenous gastritis.13,14
The ultimate diagnostic responsibility resides with the gastroenterologist who has to
integrate the histopathologic findings with the clinical and endoscopic features, and
laboratory results, including CD serology and potentially genetic testing.
A standardized approach to small intestinal biopsy procurement, interpretation, and
reporting is beneficial to patient care. From the perspective of the gastrointestinal
pathologist, it is our goal and responsibility to produce a report that it is accurate,
clear, and complete while being free of extraneous (and potentially confusing) informa-
tion. In our practice, we attempt to navigate these challenges by reviewing the histo-
pathology and describing it without reviewing the history (to avoid bias). After the
findings have been documented, the clinical notes/records are reviewed and an inter-
pretive statement, including a differential diagnosis specific to the patient, is provided.
When the clinical data are available, we believe these personalized reports provide
more value than canned quick texts, which include every possible cause of the pattern
of injury described.

Fig. 2. (A) High-power view of a duodenal biopsy in the active disease state shows diffuse
intraepithelial lymphocytosis. The IELs are seen above the black arrow (which indicates
the subepithelial basement membrane). Beneath the black arrow, note that the lamina
propria is packed with plasma cells. (B) Similar features with the additional finding of reac-
tive epithelial changes (red arrow). Note the cytoplasmic vacuolization (hematoxylin and
eosin, original magnification 40).
4 Lagana & Bhagat

APPROACH TO THE DUODENAL BIOPSY

There are three main phases in the “lifecycle” of a duodenal biopsy: (1) preanalytic, (2)
analytical, and (3) postanalytic. Processes must be optimized and, ideally, standard-
ized at each stage to ensure optimal results.

Preanalytic Phase
The most important preanalytic variable is biopsy sampling. This is for two reasons.
First, like Crohn disease, mucosal alterations in CD can be patchy.15 Second, small
intestinal biopsies are not oriented before processing at most centers in the United
States. It has been recommended that four to six biopsy pieces be obtained from
both the second portion of the duodenum and duodenal bulb to ensure optimal sam-
pling, especially when a diagnosis of CD is entertained.15 The American College of
Gastroenterology recommends acquiring biopsies from the postbulbar duodenum
(four samples) and duodenal bulb (two samples), although it is well-known that
many endoscopists do not procure the suggested number of biopsies, potentially
leading to false-negative diagnoses.16,17 One caveat to keep in mind is that the patient
must be consuming gluten at the time of biopsy, because the negative predictive value
of a normal-appearing biopsy is greatly reduced in the setting of a GFD.16
Biopsy of the duodenal bulb, previously disfavored because of the risk of artifacts
(mainly from prominent Brunner glands) helps identify a small group of patients with
CD (13%) who would be missed by postbulbar biopsies alone.18 The quality of the bi-
opsies may also be improved by taking one bite at a time to obtain the samples instead
of multiple samples per pass. This strategy was shown to increase the yield of
adequately oriented biopsies (66% vs 42%) in a prospective study.19 Obtaining six
levels from each small intestinal biopsy block (as opposed to the typical three levels
for other types of gastrointestinal biopsies) is preferred for adequate evaluation. He-
matoxylin and eosin staining of biopsies suffices for routine morphologic assessment.
In our experience, immunohistochemistry (IHC) for T-cell antigens, specifically cluster
of designation 3 (CD3), to highlight increased intraepithelial lymphocytes (IELs) is not
useful in day-to-day practice.20 Some investigators have suggested that CD3 IHC is
“mandatory” in cases where IEL is suspected.21 Some laboratories even perform
CD3 IHC on all small intestinal biopsies “up-front,” a practice that is contrary to evi-
dence.22 There are occasional cases, however, where CD3 IHC can accentuate a sub-
tle increase in IEL density and may highlight their distribution mostly within the villus
tips. So, we reserve this testing for the rare case that remains truly borderline even af-
ter careful hematoxylin and eosin assessment. Furthermore, IHC for CD3 and CD8 is
helpful when evaluating for refractory CD. In such a setting, CD8 positivity by most
(>50%) CD31 IELs is evidence against refractory CD type 2, a clonal lymphoprolifer-
ative disorder, or enteropathy-associated T-cell lymphoma, which are rare complica-
tions of CD (an in-depth review of these conditions has recently been published).23

Analytical Phase
The biopsy examination should begin with a careful and systematic low-power magni-
fication (4 objective) review of the slide evaluating all mucosal compartments. This
allows for evaluation of the architecture and overt inflammatory changes. For
adequate assessment, at least one biopsy piece should be “well-oriented,” that is,
four consecutive parallel crypt-villus units are visualized.24 The interpreting pathologist
must also know the range of normal morphologic variations of small intestinal mucosal
architecture. In the duodenum, the villi should be three to five times taller than
the crypts are deep.25,26 If this ratio is not maintained, then there is villus atrophy
 Biopsy Diagnosis of Celiac Disease 5

and/or crypt hyperplasia. There are no guidelines to define an abnormal density of

lamina propria lymphocytes and plasma cells. These are normal constituents of the in-
testinal lamina propria and their numbers increase in ACD and other inflammatory con-
ditions. An experienced pathologist has a sense for what is normal and what is
excessive. However, neutrophilic granulocytes are not considered a normal compo-
nent of the small intestinal lamina propria.27 The low-power evaluation should be
completed by reviewing the space between the villi (if present) for parasites. Giardia
organisms are often readily appreciated on low-magnification, but can be missed if
the biopsy is not reviewed in a systematic manner.
After the completion of the low-power review, all biopsies should be subjected to
high magnification evaluation. The purpose of this is to examine features that may
not be readily appreciated at low power including IEL density, presence of goblet
and Paneth cells, presence of gastric metaplasia and heterotopia, presence of sube-
pithelial fibrosis, presence and qualitative assessment of granulocytes, presence and
qualitative assessment of plasma cells, and presence of pathogens. Although there is
some disagreement in the literature about the normal number of IELs in the duo-
denum, most experts accept up to 25 per 100 enterocytes.28 An increase greater
than this level constitutes IEL. The distribution of the IELs is also relevant. Normal
duodenal mucosa has a “decrescendo” pattern of IELs, with a greater density present
at the basal portion of the of villi.29 Because of this, it has been shown that increased
IELs at the tips of villi (defined as a mean of 12 IELs per 20 enterocytes in five villus tips)
correlate with CD, whereas IEL increases along the lateral edges of villi are less spe-
cific.29 This altered pattern may also be useful in identifying patients with potential CD
(seropositivity without symptoms or villus atrophy).30 The normal and pathologic IEL
distribution patterns and an increase in IELs cannot be adequately assessed in unor-
iented biopsies or when the villi are detached or completely atrophic.
Once the low- and high-power examination is complete, the observations should be
organized in a consistent fashion. Definitive statements should be made whenever
possible (eg, “Duodenal mucosa, within normal limits,” or “Duodenal mucosa with
giardiasis”). It is not uncommon to identify inflammatory changes, which suggest a
disease, but are not independently diagnostic. In such settings, a differential diagnosis
should be included in the report. If the pathologist has access to the medical records,
and/or to the gastroenterologist, the differential should be tailored to the patient’s
circumstances.

DIFFERENTIAL DIAGNOSIS

It is helpful to think of the differential diagnosis of CD in relation to the Marsh-

Oberhuber pattern. Put another way, when a pathologist is considering a Marsh-
Oberhuber type 1 pattern (normal architecture and increased IELs), the differential is
different from when a Marsh-Oberhuber type 3C pattern (flat mucosa) is encountered.
The common differential diagnoses are summarized in Table 2.

Preserved Architecture with Intraepithelial Lymphocytosis

The differential diagnosis of Marsh-Oberhuber type 1 (or Corazza A) pattern is
broad. This pattern has been detected with increasing frequency in recent years. As
the rate of detection of increased IELs, the positive predictive value of this pattern
with respect to CD has decreased.31 Many cases are idiopathic; however, other etiol-
ogies include partially treated CD, tropical sprue, Helicobacter pylori infection (of the
stomach), medication/drug effect (proton pump inhibitors, selective serotonin reup-
take inhibitors, nonsteroidal anti-inflammatory drugs, and others), small intestinal
6 Lagana & Bhagat

Table 2
Histologic differential diagnosis based on pattern

Villus Atrophy With/Without Increased

Normal Villus Architecture and Increased IELs IELs
Celiac disease Celiac disease, and complicated celiac
Helicobacter pylori–associated disease (eg, refractory sprue,
gastroduodenitis collagenous sprue)
Drugs: NSAIDs, selective serotonin reuptake Angiotensin receptor blocker–associated
inhibitors, proton pump inhibitor enteropathy
Tropical sprue Drugs: mycophenolate mofetil, colchicine
Infections, such as viral enteritis, Giardia, Immune dysregulation: autoimmune
Cryptosporidium enteropathy
Immune conditions: rheumatoid arthritis, Immunodeficiency: common variable
Hashimoto thyroiditis, SLE, autoimmune immune deficiency
enteropathy Graft-versus-host disease
Immunodeficiency: common variable immune Inflammatory bowel disease
deficiency Chemoradiation therapy
Graft-versus-host disease Nutritional deficiency
Inflammatory bowel disease Eosinophilic enteritis
Small intestinal bacterial overgrowth Lymphoma
Irritable bowel syndrome

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; SLE, systemic lupus erythematosus.

bacterial overgrowth, infections (viral gastroenteritis), morbid obesity, autoimmune

disorders, inflammatory bowel disease, and others.31–38 Because some of the etio-
logic factors are common (eg, medication use) and the patient might have more
than one pathologic condition, it is challenging to determine the instigating/causative
agents. Detailed clinical information and laboratory studies (including genetic testing)
may be needed to exclude CD in such instances. In a patient with known history of CD,
it is reasonable to attribute this finding to minimal gluten exposure. In the setting of
newly diagnosed CD, this pattern is uncommon.10 Studies suggest that 5% to 10%
of patients without a known history of CD whose biopsies exhibit the Marsh-
Oberhuber type 1 pattern will ultimately be determined to have CD.10,39 However, in
one study, approximately 16% of children with abdominal pain, but without CD, H py-
lori gastritis, or other identifiable gastrointestinal disease, had more than 25 IELs per
100 enterocytes.40 Thus, when a clinician receives a pathology report describing a
Marsh-Oberhuber type 1 pattern, it is prudent to perform further studies to exclude
CD, but one should recognize that this finding is common, nonspecific, and often
idiopathic.

Villus Atrophy
The presence of villus atrophy is a more concerning finding, which should not be
accepted as “idiopathic” without significant consideration and potentially referral
to a specialized center. The differential of villus atrophy and increased IELs includes
CD; medication-related enteropathy, particularly the recently described olmesartan-
associated enteropathy (OAE) (occasionally also associated with other angiotensin re-
ceptor blockers [ARBs]), mycophenolate-containing compounds, and colchicine
among others; collagenous sprue; common variable immunodeficiency; AE; lym-
phoma, inflammatory bowel disease; and certain infections.41
Of these entities, the one that has garnered the most attention recently is OAE.
Rubio-Tapia and colleagues42 reported a series of 22 patients who presented with
 Biopsy Diagnosis of Celiac Disease 7

severe diarrhea and profound weight loss following exposure to olmesartan. Biopsies
of the small intestine showed severe villus atrophy and inflammation. Fifteen had total
villus atrophy and 14 had increased IELs. Serologic testing for CD was universally
negative and GFD did not resolve symptoms or mucosal abnormalities. Seven patients
had collagenous sprue. Of 14 patients who also had gastric biopsies, five (36%)
exhibited lymphocytic gastritis and two (14%) displayed features of collagenous
gastritis. Colon biopsies of 5 of the 13 patients (38%) showed microscopic colitis (two
lymphocytic, three collagenous). Clinical symptoms resolved quickly following cessation
of the medications in all cases, and the histologic changes disappeared in most.42
Several additional case reports, series, and reviews have confirmed these findings
and implicated other ARBs.41,43–59 The US Food and Drug Administration approved a
label change for olmesartan in 2013 to acknowledge the risk of enteropathy.60
As is deduced from the preceding description of the histopathology of OAE, it is diffi-
cult (sometimes impossible) to distinguish OAE from ACD based on morphologic fea-
tures alone. In a subset of OAE cases, there are histologic clues that should allow the
attentive pathologist to suggest the diagnosis. The first is the density of IELs. Studies
have shown that some ARB-enteropathy cases do not display significant increased
IELs, a feature that is essentially universal in ACD.42,59 Second, OAE cases commonly
demonstrate increased subepithelial collagen (collagenous sprue-like features), which
is a rare finding in CD (Fig. 3).41,42,61 Ultimately, seronegativity and medication expo-
sure are the most meaningful data points in distinguishing between CD and ARB-
enteropathy and clinical and histopathologic response to a change of medication class
supports medication exposure as the inciting insult. As such, OAE is a good example of
a situation in which knowing the clinical history allows the pathologist to make a more
meaningful statement regarding the cause and the appropriate diagnosis.
Common variable immunodeficiency is an immunodeficiency disorder character-
ized by the failure of B cell maturation into plasma cells, causing decreased serum
immunoglobulin levels. Patients may present with diarrhea and malabsorption and
are prone to infections (giardiasis and bacterial overgrowth).62,63 Duodenal biopsies
can demonstrate a variety of changes, including increased IELs and variable degrees
of villus atrophy.64 Common variable immunodeficiency typically displays an absence
or severe decrease in the number of lamina propria plasma cells. This is in contrast to

Fig. 3. This patient presented with intractable diarrhea and profound weight loss. Duodenal
biopsy showed total villus atrophy, as is seen in celiac disease. Notably, the subepithelial
collagen layer was thickened (arrow), and the epithelium seemed to slough off. This diag-
nostic clue coupled with the lack of intraepithelial lymphocytosis suggested a diagnosis of
olmesartan-associated enteropathy. Discussion at an interdisciplinary conference confirmed
medication exposure with negative celiac serology, and the patient responded dramatically
to a medication change (hematoxylin and eosin, original magnification 40).
8 Lagana & Bhagat

Box 2
Template used to describe findings in small intestinal biopsies performed for evaluation of
celiac disease

I. Clinical Information
None provided
Rule out celiac disease
Previous diagnosis of celiac disease
Refractory celiac disease
Other (specify): _____________
II. Type of Mucosa
Duodenal
Jejunal
III. Number of Biopsy Pieces
__________
IV. Adequacy of Specimen Orientation (at least four consecutive well-oriented crypt-villus
units)
Yes
No
V. Villus Length
Normal
Abnormal
Cannot be determined
VI. Crypt Length
Normal
Elongated
Shortened
VII. Crypt-to-Villus Ratio
Normal (1:3–1:5)
Abnormal (specify):__________
VIII. Villus Atrophy
None
Total
Subtotal
Partial
Diffuse
Patchy
IX. Intraepithelial Lymphocytes
Normal (up to 30 per 100 epithelial nuclei)
Increased, specify: mild, moderate, severe, focal, diffuse
X. Lamina Propria Inflammatory Cells
Normal
Increased, specify: plasma cells, eosinophils, lymphocytes, neutrophils
XI. Gastric Metaplasia
Present
Absent
XII. Subepithelial Collagen
Normal
Increased
XIII. Diagnosis
Small intestinal mucosa, histologically unremarkable
Focal chronic inflammation with or without focal intraepithelial lymphocytes,
nonspecific
Diffuse intraepithelial lymphocytosis, normal villi, consistent with celiac disease (Marsh
type 1)
 Biopsy Diagnosis of Celiac Disease 9

Diffuse intraepithelial lymphocytosis and crypt hyperplasia, consistent with celiac

disease (Marsh type 2)
Partial villus atrophy, crypt hyperplasia and intraepithelial lymphocytosis, consistent
with celiac disease (Marsh type 3a)
Subtotal villous atrophy, crypt hyperplasia and intraepithelial lymphocytosis, consistent
with celiac disease (Marsh type 3b)
Total villous atrophy, crypt hyperplasia and intraepithelial lymphocytosis, consistent
with celiac disease (Marsh type 3c)
Villous atrophy, crypt hypoplasia and intraepithelial lymphocytosis, consistent with
celiac disease (Marsh type 4)

CD, where the plasma cells are increased. At times, the increase of lamina propria lym-
phocytes may be significant, making it difficult to discern the lack of plasma cells.
The term “autoimmune enteropathy” refers to a group of rare autoimmune condi-
tions which primarily afflict infants, but can also rarely present in adults. In young
males, an X-linked severe form of the disorder is associated with immune dysregula-
tion and polyendocrinopathy caused by a germline mutation in the FOXP3 gene
located on the X chromosome.65 Patients with this disease may present with failure
to thrive, secretory diarrhea, weight loss, and malabsorption, requiring total parental
nutrition. AE commonly affects the proximal small bowel, with involvement of the
stomach, distal small bowel, and colon described in some cases. Duodenal biopsies
show variable villus atrophy and crypt hyperplasia, often with a diminished number of
Paneth and goblet cells. A dense lymphoplasmacytic infiltrate in the lamina propria is
common and neutrophils with crypt abscesses are seen in severe cases.66–68
Although an increase in IELs may be seen, this is more prominent in the crypts. This
feature may help distinguish AE from CD, which usually demonstrates marked in-
crease in surface IELs.67 Crypt apoptosis is often prominent in AE, although again,
this finding is not specific because it is identified in other disorders and CD.12 Labora-
tory tests may demonstrate the presence of antienterocyte antibodies and some pa-
tients may also have anti–goblet cell, anti–parietal cell, and anti–smooth muscle
antibodies. Antigliadin and antireticulin antibodies have also been described in
AE.68 We have encountered a case of OAE where the ileal biopsy showed near total
loss of goblet and Paneth cells, raising suspicion for AE. However, these cells were
readily identified on a subsequent biopsy after olmesartan was discontinued.45 There
is considerable morphologic overlap in these entities, highlighting the importance of
attention to detail and clinical correlation.

POSTANALYTIC PHASE

Postanalytic variables in the context of duodenal biopsies mainly concern reporting

terminology. Many centers use “quick texts” to describe gastrointestinal biopsy find-
ings; however, important information is often missed as a consequence.7 To ensure
that all relevant data are conveyed in pathology reports, we use a worksheet for bi-
opsies, which come with a request to assess for CD or to evaluate the cause of persis-
tent symptoms or response to therapy (Box 2). The idea is to use a scheme similar to
tumor staging checklists, and analogous to the staging forms. Our worksheet was
developed as a collaboration between clinicians and pathologists.

SUMMARY

We have described an approach to the duodenal biopsy and discussed consider-

ations related to the differential diagnosis and optimal reporting of CD. Although a
10 Lagana & Bhagat

clinicopathologic diagnosis of CD may be straightforward in many instances, there are

also many opportunities for confusion and error. Good communication between
gastroenterologist and pathologist is vital for accurate diagnosis. This is achieved
via access to comprehensive notes or reports in the electronic medical record,
communication by e-mails or telephone calls, and ideally, by participating in interdis-
ciplinary conferences.

REFERENCES

1. Dicke WK, Weijers HA, Van De Kamer JH. Coeliac disease. II. The presence in
wheat of a factor having a deleterious effect in cases of coeliac disease. Acta
Paediatr 1953;42(1):34–42.
2. Abadie V, Sollid LM, Barreiro LB, et al. Integration of genetic and immunological
insights into a model of celiac disease pathogenesis. Annu Rev Immunol 2011;
29:493–525.
3. Paulley JW. Observation on the aetiology of idiopathic steatorrhoea; jejunal and
lymph-node biopsies. Br Med J 1954;2(4900):1318–21.
4. 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(1):330–54.
5. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac dis-
ease: time for a standardized report scheme for pathologists. Eur J Gastroenterol
Hepatol 1999;11(10):1185–94.
6. Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver
reproducibility with different histologic criteria used in celiac disease. Clin Gastro-
enterol Hepatol 2007;5(7):838–43.
7. Arguelles-Grande C, Tennyson CA, Lewis SK, et al. Variability in small bowel his-
topathology reporting between different pathology practice settings: impact on
the diagnosis of coeliac disease. J Clin Pathol 2012;65(3):242–7.
8. Brar P, Kwon GY, Egbuna II, et al. Lack of correlation of degree of villous atrophy
with severity of clinical presentation of coeliac disease. Dig Liver Dis 2007;39(1):
26–9 [discussion: 30–2].
9. Bao F, Green PH, Bhagat G. An update on celiac disease histopathology and the
road ahead. Arch Pathol Lab Med 2012;136(7):735–45.
10. Brown IS, Smith J, Rosty C. Gastrointestinal pathology in celiac disease: a case
series of 150 consecutive newly diagnosed patients. Am J Clin Pathol 2012;
138(1):42–9.
11. Colombel JF, Torpier G, Janin A, et al. Activated eosinophils in adult coeliac dis-
ease: evidence for a local release of major basic protein. Gut 1992;33(9):1190–4.
12. Shalimar DM, Das P, Sreenivas V, et al. Mechanism of villous atrophy in celiac dis-
ease: role of apoptosis and epithelial regeneration. Arch Pathol Lab Med 2013;
137(9):1262–9.
13. Green PH, Yang J, Cheng J, et al. An association between microscopic colitis and
celiac disease. Clin Gastroenterol Hepatol 2009;7(11):1210–6.
14. Carmack SW, Lash RH, Gulizia JM, et al. Lymphocytic disorders of the gastroin-
testinal tract: a review for the practicing pathologist. Adv Anat Pathol 2009;16(5):
290–306.
15. Hopper AD, Cross SS, Sanders DS. Patchy villous atrophy in adult patients with
suspected gluten-sensitive enteropathy: is a multiple duodenal biopsy strategy
appropriate? Endoscopy 2008;40(3):219–24.
 Biopsy Diagnosis of Celiac Disease 11

16. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis
and management of celiac disease. Am J Gastroenterol 2013;108(5):656–76
[quiz: 677].
17. Lebwohl B, Kapel RC, Neugut AI, et al. Adherence to biopsy guidelines increases
celiac disease diagnosis. Gastrointest Endosc 2011;74(1):103–9.
18. Gonzalez S, Gupta A, Cheng J, et al. Prospective study of the role of duodenal
bulb biopsies in the diagnosis of celiac disease. Gastrointest Endosc 2010;
72(4):758–65.
19. Latorre M, Lagana SM, Freedberg DE, et al. Endoscopic biopsy technique in the
diagnosis of celiac disease: one bite or two? Gastrointest Endosc 2015;81(5):
1228–33.
20. Mino M, Lauwers GY. Role of lymphocytic immunophenotyping in the diagnosis of
gluten-sensitive enteropathy with preserved villous architecture. Am J Surg
Pathol 2003;27(9):1237–42.
21. Volta U, Villanacci V. Celiac disease: diagnostic criteria in progress. Cell Mol Im-
munol 2011;8(2):96–102.
22. Hudacko R, Kathy Zhou X, Yantiss RK. Immunohistochemical stains for CD3 and
CD8 do not improve detection of gluten-sensitive enteropathy in duodenal bi-
opsies. Mod Pathol 2013;26(9):1241–5.
23. Chander U, Leeman-Neill RJ, Bhagat G. Pathogenesis of enteropathy-associated
T cell lymphoma. Curr Hematol Malig Rep 2018;13(4):308–17.
24. Perera DR, Weinstein WM, Rubin CE. Symposium on pathology of the gastroin-
testinal tract-part II. Small intestinal biopsy. Hum Pathol 1975;6(2):157–217.
25. Serra S, Jani PA. An approach to duodenal biopsies. J Clin Pathol 2006;59:
1133–50.
26. Dickson BC, Streutker CJ, Chetty R. Coeliac disease: an update for pathologists.
J Clin Pathol 2006;59(10):1008–16.
27. Villanacci V, Ceppa P, Tavani E, et al. Coeliac disease: the histology report. Dig
Liver Dis 2011;43(Suppl 4):S385–95.
28. Hayat M, Cairns A, Dixon MF, et al. Quantitation of intraepithelial lymphocytes in
human duodenum: what is normal? J Clin Pathol 2002;55(5):393–4.
29. Goldstein NS, Underhill J. Morphologic features suggestive of gluten sensitivity in
architecturally normal duodenal biopsy specimens. Am J Clin Pathol 2001;116(1):
63–71.
30. 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(8):835–9.
31. Shmidt E, Smyrk TC, Boswell CL, et al. Increasing duodenal intraepithelial
lymphocytosis found at upper endoscopy: time trends and associations. Gastro-
intest Endosc 2014;80(1):105–11.
32. 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(8):1134–44.
33. Harpaz N, Levi GS, Yurovitsky A, et al. Intraepithelial lymphocytosis in architec-
turally normal small intestinal mucosa: association with morbid obesity. Arch
Pathol Lab Med 2007;131(3):344 [author reply: 344].
34. Brown IS, Bettington A, Bettington M, et al. Tropical sprue: revisiting an underre-
cognized disease. Am J Surg Pathol 2014;38(5):666–72.
35. Masia R, Peyton S, Lauwers GY, et al. Gastrointestinal biopsy findings of auto-
immune enteropathy: a review of 25 cases. Am J Surg Pathol 2014;38(10):
1319–29.
12 Lagana & Bhagat

36. Patterson ER, Shmidt E, Oxentenko AS, et al. Normal villous architecture with
increased intraepithelial lymphocytes: a duodenal manifestation of Crohn dis-
ease. Am J Clin Pathol 2015;143(3):445–50.
37. Lauwers GY, Fasano A, Brown IS. Duodenal lymphocytosis with no or minimal en-
teropathy: much ado about nothing? Mod Pathol 2015;28(Suppl 1):S22–9.
38. Aziz I, Evans KE, Hopper AD, et al. A prospective study into the aetiology of lym-
phocytic duodenosis. Aliment Pharmacol Ther 2010;32(11–12):1392–7.
39. Kakar S, Nehra V, Murray JA, et al. Significance of intraepithelial lymphocytosis in
small bowel biopsy samples with normal mucosal architecture. Am J Gastroen-
terol 2003;98(9):2027–33.
40. Guz-Mark A, Zevit N, Morgenstern S, et al. Duodenal intraepithelial lymphocytosis
is common in children without coeliac disease, and is not meaningfully influenced
by Helicobacter pylori infection. Aliment Pharmacol Ther 2014;39(11):1314–20.
41. DeGaetani M, Tennyson CA, Lebwohl B, et al. Villous atrophy and negative celiac
serology: a diagnostic and therapeutic dilemma. Am J Gastroenterol 2013;
108(5):647–53.
42. Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy
associated with olmesartan. Mayo Clin Proc 2012;87(8):732–8.
43. Malfertheiner P, Ripellino C, Cataldo N. Severe intestinal malabsorption associ-
ated with ACE inhibitor or angiotensin receptor blocker treatment. An observa-
tional cohort study in Germany and Italy. Pharmacoepidemiol Drug Saf 2018;
27(6):581–6.
44. Abdelghany M, Gonzalez L 3rd, Slater J, et al. Olmesartan associated sprue-like
enteropathy and colon perforation. Case Rep Gastrointest Med 2014;2014:
494098.
45. Burbure N, Lebwohl B, Arguelles-Grande C, et al. Olmesartan-associated sprue-
like enteropathy: a systematic review with emphasis on histopathology. Hum
Pathol 2016;50:127–34.
46. de Fonseka A, Tuskey A, Moskaluk C. A case of olmesartan induced enteropathy.
Inflamm Bowel Dis 2012;18(S17).
47. Dreifuss SE, Tomizawa Y, Farber NJ, et al. Spruelike enteropathy associated with
olmesartan: an unusual case of severe diarrhea. Case Rep Gastrointest Med
2013;2013:618071.
48. Fiorucci G, Puxeddu E, Colella R, et al. Severe spruelike enteropathy due to ol-
mesartan. Rev Esp Enferm Dig 2014;106(2):142–4.
49. Freeman HJ. Olmesartan enteropathy. IJCD 2016;4(1):24–6.
50. Herman M, Rubio-Tapia A, Wu TT, et al. ACG Case Rep J 2015;2(2):92–4.
51. Khan AS, Peter S, Wilcox CM. Olmesartan-induced enteropathy resembling ce-
liac disease. Endoscopy 2014;46(Suppl 1 UCTN):E97–8.
52. Marthey L, Cadiot G, Seksik P, et al. Olmesartan-associated enteropathy: results
of a national survey. Aliment Pharmacol Ther 2014;40(9):1103–9.
53. Nielsen JA, Steephen A, Lewin M. Angiotensin-II inhibitor (olmesartan)-induced
collagenous sprue with resolution following discontinuation of drug. World J Gas-
troenterol 2013;19(40):6928–30.
54. Scialom S, Malamut G, Meresse B, et al. Gastrointestinal disorder associated with
olmesartan mimics autoimmune enteropathy. PLoS One 2015;10(6):e0125024.
55. Stanich PP, Yearsley M, Meyer MM. Olmesartan-associated sprue-like enteropa-
thy. J Clin Gastroenterol 2013;47(10):894–5.
56. Talbot GH. Small bowel histopathologic findings suggestive of celiac disease in
an asymptomatic patient receiving olmesartan. Mayo Clin Proc 2012;87(12):
1231–2 [author reply: 1232].
 Biopsy Diagnosis of Celiac Disease 13

57. Theophile H, David XR, Miremont-Salame G, et al. Five cases of sprue-like enter-
opathy in patients treated by olmesartan. Dig Liver Dis 2014;46(5):465–9.
58. Tran TH, Li H. Olmesartan and drug-induced enteropathy. P T 2014;39(1):47–50.
59. Ianiro G, Bibbo S, Montalto M, et al. Systematic review: sprue-like enteropathy
associated with olmesartan. Aliment Pharmacol Ther 2014;40(1):16–23.
60. FDA. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA
approves label changes to include intestinal problems (sprue-like enteropathy)
linked to blood pressure medicine olmesartan medoxomil. 2013. Available at:
http://www.fda.gov/drugs/drugsafety/ucm359477.htm. Accessed June 19, 2014.
61. Vakiani E, Arguelles-Grande C, Mansukhani MM, et al. Collagenous sprue is not
always associated with dismal outcomes: a clinicopathological study of 19 pa-
tients. Mod Pathol 2010;23(1):12–26.
62. Ament ME, Ochs HD, Davis SD. Structure and function of the gastrointestinal tract
in primary immunodeficiency syndromes. A study of 39 patients. Medicine 1973;
52(3):227–48.
63. Washington K, Stenzel TT, Buckley RH, et al. Gastrointestinal pathology in pa-
tients with common variable immunodeficiency and X-linked agammaglobulin-
emia. Am J Surg Pathol 1996;20(10):1240–52.
64. Malamut G, Verkarre V, Suarez F, et al. The enteropathy associated with common
variable immunodeficiency: the delineated frontiers with celiac disease. Am J
Gastroenterol 2010;105(10):2262–75.
65. Le Bras S, Geha RS. IPEX and the role of Foxp3 in the development and function
of human Tregs. J Clin Invest 2006;116(6):1473–5.
66. Montalto M, D’Onofrio F, Santoro L, et al. Autoimmune enteropathy in children and
adults. Scand J Gastroenterol 2009;44(9):1029–36.
67. Russo PA, Brochu P, Seidman EG, et al. Autoimmune enteropathy. Pediatr Dev
Pathol 1999;2(1):65–71.
68. Corazza GR, Biagi F, Volta U, et al. Autoimmune enteropathy and villous atrophy
in adults. Lancet 1997;350(9071):106–9.