Mimics in Gastrointestinal Pathology
Case 2 -
Celiac Disease Versus Peptic Duodenitis
Alyssa Krasinskas, Jeffrey Goldsmith and Susan Abraham
The attached photomicrographs were taken from the duodenal biopsies obtained from a 53 year-old male
who presented with bloating, gas, and constipation. Subsequent laboratory findings revealed iron
deficiency anemia. Endoscopy showed diffuse granularity and contact bleeding present in the proximal
duodenum; the endoscopic appearances of the stomach, esophagus, terminal ileum, and colon were normal.
The endoscopic findings were consistent with a clinical diagnosis of peptic duodenitis. Biopsies of the
duodenal bulb (illustrated case) and second portion of the duodenum show subtotal villous blunting with
crypt hyperplasia. The surface epithelium shows marked foveolar-type metaplasia with some acute
inflammation. In areas, there is marked intraepithelial lymphocytosis with up to 60 intraepithelial
lymphocytes (IELs) per 100 enterocytes. The presence of significant intraepithelial lymphocytosis and
villous architectural changes prompted the following diagnosis:
Note: The presence of intraepithelial lymphocytes raises the possibility of celiac disease.
- Duodenal bulb, biopsy:
- Chronic active duodenitis with:
- Brunner gland hyperplasia and focal gastric mucous cell metaplasia
- Villous shortening and increased intraepithelial lymphocytes; see note.
- Second portion of duodenum, biopsy:
- Duodenal mucosa with marked villous shortening and increased intraepithelial lymphocytes; see note.
Subsequent clinical laboratory testing showed a markedly positive IgA anti-tissue transglutaminase.
After 2 months of adherence to a strict gluten-free diet, the patient had complete resolution of his
Background & Pathogenesis:
Celiac disease (CD) is an enteropathy where, in certain predisposed individuals, there is an
inappropriate, destructive inflammatory reaction to various proline-rich proteins in certain grains,
including gliadin in wheat, secalin in rye, and hordein in barley. This reaction results in destructive
inflammation in which begins in the proximal duodenum and proceeds distally to involve the entire small
intestine; severe cases may show additional involvement of the stomach and large intestine .
CD is a disease that was previously thought to be uncommon in western populations. However, recent
recognition of the extreme variability in both age of onset and symptomatology at presentation has
resulted in the observation that CD occurs in approximately 1:100 – 1:300 people in the western
The clinical impact of CD is profound. Many adult patients with celiac suffer from signs and symptoms
including diarrhea, fatigue, abdominal pain, neurologic symptoms, iron-deficiency anemia, and vitamin
deficiency. Pediatric patients typically present with diarrhea and growth retardation .
Patients with celiac disease also are at risk for various malignancies including esophageal squamous cell
carcinoma, small intestinal adenocarcinoma, and enteropathy-associated T-cell lymphoma .
Adherence to a strict gluten free diet often relieves the symptoms associated with celiac disease within
months; a histologic response to a gluten-free diet may take years . There is also evidence
that a gluten-free diet decreases, if not eliminates, the risk of neoplastic
The pathogenesis of celiac disease is still the subject of intense research; however, many aspects of
the mechanism of disease have been elucidated in recent years. Celiac disease nearly always occurs in
persons who have inherited HLA DQ2 or DQ8. In these predisposed individuals, relatively indigestible
glutens, which include gliadin, secalin, hordein, and other, less common disease causing proteins,
traverse the enterocyte and enter the lamina propria, by an unknown mechanism. In the lamina propria,
the partially digested gluten peptides are deamidated by tissue transglutaminase. These deamidated
gluten peptides become bound to HLA DQ2 or DQ8 which are expressed on antigen presenting cells. These
antigen presenting cells then activate CD4 positive T-cells which then secrete various cytokines,
including interferon-gamma and matrix metaloproteinases that subsequently recruit CD8 positive T-cells.
The mechanism and significance of the CD8 positive intraepithelial lymphocytosis characteristic of celiac
disease remains unknown
Diagnosis of Celiac Disease
Clinical Findings & Laboratory Studies:
As noted above, the age at presentation and the clinical symptoms of CD vary widely. However, the
classic symptoms of CD in adults are steatorrhea, abdominal distention, edema and lethargy .
Symptoms in children include abdominal distention, anorexia, diarrhea, weight loss, and irritability
. Dermatitis herpetiformis (DH), a dermatologic condition strongly associated with CD, is an
intensely puritic papulovesciular rash that typically presents on the elbows, knees, buttocks and scalp.
Approximately 80% of patients with DH either have or will develop CD. DH typically resolves after
institution of a gluten-free diet .
In patients whom the diagnosis of CD is suspect, the patients are first screened using serologic
studies for autoantibodies including IgA anti-endomysial antibodies and IgA anti-tissue transglutaminase
(TTG). It is important to note that these studies are only useful in IgA competent patients. Thus,
screening for IgA deficiency is also performed at presentation. Both IgA anti-endomysial and TTG tests
are highly sensitive and specific for celiac disease (approximately 95% sensitive and specific)
. Titers of TTG decline with institution of a gluten-free diet.
The endoscopic appearances of the duodenal mucosa in patients with celiac disease are relatively
non-specific. However, the presence of 'scalloped folds' (which correspond to a notched appearance of
the plica circulares) is suggestive of celiac disease. In patients with severe disease, the small
intestinal mucosa may appear atrophic with loss of the typical mucosal fold pattern; increased
vascularity has also been noted . It is important to note that the endoscopic appearances
are quite insensitive. The gold standard for the diagnosis of celiac remains the endoscopic biopsy.
The classic histologic findings in celiac disease are complete villous atrophy, crypt hyperplasia,
intraepithelial lymphocytosis, increased lamina propria inflammation, and enterocyte damage. When all of
these features are present, the diagnosis of celiac disease is relatively straightforward. However, in
recent years, it has become evident that biopsies with more subtle histologic findings are also
associated with celiac disease. The histologic spectrum of findings in CD were best classified by
Oberhuber et al as a modification of the original Marsh classification (Table 1)
also important to note that the histologic changes of CD may be focal. As such, up to four duodenal
biopsies may be required to establish a diagnosis .
Intraepithelial lymphocytosis, predominantly composed of CD8 positive T- lymphocytes, is the single
most sensitive histologic feature of celiac disease. Increased intraepithelial lymphocytes have
classically been defined as greater than 40 intraepithelial lymphocytes per 100 enterocytes which is
derived from early studies of normal jejunum
However, recent studies have suggested
that the normal number of intraepithelial lymphocytes in the duodenum may be approximately 25-30 IELs /
It is important to note that the presence of increased IELs over
mucosal lymphoid aggregates is a normal physiologic finding, and is not indicative of disease. In
addition to the absolute number of IELs, the distribution of these cells along the villous has been noted
to vary in persons with CD. In normal villi, IELs are more numerous towards the base of the villi with
the number of IELs decreasing towards the villous tips. However, in patients with CD, the density of
intraepithelial lymphocytes may be uniform along the entire villous height or may actually increase
towards the villous tip
Anecdotally, the presence of vertical arrays of IELs, as
opposed to their more normal basal intraepithelial location, has been associated with CD.
The other classic histologic finding in patients with CD are villous architecture changes, which may
range from normal villous height with crypt hyperplasia to complete villous loss with marked crypt
hyperplasia. The sensitivity of these histologic findings is lower than increased IELs for two reasons:
Firstly, the villous architecture can only be evaluated in well-oriented biopsies. One must see at least
2-3 well-oriented villi to consider the biopsy adequate for evaluation of villous architecture.
Secondly, changes in the villous architecture (Marsh types 2 and above) are thought to be preceded by an
increase in the IELs without altered mucosal architecture (Marsh type 1; see above). Indeed, some
studies have suggested that a up to 60% of patients with Marsh 1 lesions revert to normal histology after
following a gluten-free diet .
The presence of enterocyte damage, as manifest by decreased cytoplasmic volume and increased nuclear
size, and increased lamina propria inflammation, including increased numbers of lymphocytes and plasma
cells with fill and sometimes expand the lamina propria, are neither sensitive nor specific for celiac
disease. These features are only present in cases with marked mucosal architectural abnormalities and
increased intraepithelial lymphocytosis.
Histologic Mimics of Celiac Disease
Major mimic: Peptic Duodenitis
In the group of patients with the appropriate clinical history and positive laboratory tests, the
presence of the characteristic histologic findings is diagnostic of celiac disease. However, in patients
with atypical clinical presentations and/or equivocal laboratory findings, the presence of duodenal
mucosal architectural abnormalities and increased IELs are not necessarily diagnostic of celiac disease.
As illustrated in the current case, peptic duodenitis (PD) is one of the major mimics of celiac
disease. Patients with peptic duodenitis, which is usually secondary to either the ingestion of
non-steroidal anti-inflammatory medications or gastric Helicobacter pylori
infection, may show partial villous blunting and/or crypt hyperplasia along with foveolar
metaplasia and increased numbers of mucosally-located Brunner's glands. Increased IELs are not typically
in the histologic spectrum of peptic duodenitis; however, increased duodenal IELs have been reported in
cases of gastric H. pylori-induced peptic duodentitis
Thus, in duodenal biopsies with intact villous architecture and increased IELs (modified Marsh type 1
lesions), distinguishing PD from celiac disease using histologic criteria can be difficult; however, it
is incumbent on the pathologist to raise the possibility of celiac disease when increased numbers of
intraepithelial lymphocytes are present. In this situation, knowledge of the patient's celiac
disease-related serologies and H. pylori status would help in this
distinction. Additionally, since gastric foveolar metaplasia and mild villous blunting can be present in
the duodenal bulb of asymptomatic patients, and since the proximal duodenum is most affected in patients
with PD, biopsies of the duodenal bulb should be interpreted with caution.
Other Mimics of Celiac Disease
1. Infections: Certain infections
including giardiasis may show mucosal changes that mimic celiac disease including increased IELs and
villous architecture changes. Of course, the discovery of these microorganisms in the biopsy material
would resolve this difficulty.
2. Viral gastroenteritis:
Pediatric patients with prolonged diarrhea, which is presumably due to an antecedent viral
gastroenteritis may result in histologic changes that is indistinguishable from CD
Patients with this clinical scenario will have slow resolution of their symptoms without intervention.
Laboratory testing for CD associated autoantibodies in these patients are negative.
3. Food allergies: Allergies to
various foods, including cow's milk and eggs, may result in biopsy findings that simulate celiac
disease. Biopsy findings may range from increased IELs with intact mucosal architecture to complete
Patients with this disease may show increased lamina propria
eosinophils and will respond to a diet devoid of the disease-causing allergen.
4. Crohn disease: It is thought,
though not well documented, that some morphologic features of CD, including intraepithelial
lymphocytosis, may be an early histologic clue of either undiagnosed Crohn disease or the development of
upper tract Crohn disease. The classic findings of either a localized destructive duodenitis, including
acute inflammation and crypt destruction with non-caseating granulomas helps separate these two entities.
5. Tropical sprue: Patients with
this disease can show morphologic findings that are histologically identical to CD. The absence of
celiac disease-associated laboratory findings and a clinical response to antibiotic and folate therapies
will resolve this differential diagnosis .
6. Autoimmune enteropathy: This
disease is a rare, destructive autoimmune phenomenon that classically arises in infants. The classic
histologic findings of autoimmune enteropathy include destructive acute enteritis with complete villous
atrophy and a loss of goblet cells and/or Paneth cells. However, in less developed cases, the histology
may simulate CD. Clinical laboratory tests and/or trial of a gluten-free diet would resolve this
differential diagnosis. Autoimmune enteropathy is a disease mainly confined to children; however, rare
cases of adult onset have been documented.
7. Immunodeficiency states:
Various congenital immunodeficiency states, most commonly common variable immunodeficiency (CVID) can
show features reminiscent of CD. However, patients with CVID show a complete or near-complete absence of
plasma cells with marked lymphoid hyperplasia .
Table 1: Modified Marsh Classification of Celiac Disease
|Marsh Type ||IELs per 100 enterocytes ||Crypt Hyperplasia ||Villous Architecture|
|0 ||<40 ||Absent ||Normal|
|1 ||>40 ||Absent ||Normal|
|2 ||>40 ||Present ||Normal|
|3a ||>40 ||Present ||Mild Atrophy|
|3b ||>40 ||Present ||Marked Atrophy|
|3c ||>40 ||Present ||Complete Atrophy|
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