—  SHORT COURSE #08  —

Mimics in Gastrointestinal Pathology

Case 2 - Celiac Disease Versus Peptic Duodenitis

Alyssa Krasinskas, Jeffrey Goldsmith and Susan Abraham


Case Description:
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:
  1. Duodenal bulb, biopsy:
    • Chronic active duodenitis with:
      • Brunner gland hyperplasia and focal gastric mucous cell metaplasia

      • Villous shortening and increased intraepithelial lymphocytes; see note.

  2. Second portion of duodenum, biopsy:
    • Duodenal mucosa with marked villous shortening and increased intraepithelial lymphocytes; see note.
Note: The presence of intraepithelial lymphocytes raises the possibility of celiac disease.

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 symptoms.

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 [1]. 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 world [19].

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 [7]. 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 [4]. 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 [31]. There is also evidence that a gluten-free diet decreases, if not eliminates, the risk of neoplastic complications [18].

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 [14, 20].

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 [7]. Symptoms in children include abdominal distention, anorexia, diarrhea, weight loss, and irritability [8]. 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 [32].

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) [17]. Titers of TTG decline with institution of a gluten-free diet.

Endoscopic findings:
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 [27]. It is important to note that the endoscopic appearances are quite insensitive. The gold standard for the diagnosis of celiac remains the endoscopic biopsy.

Histologic findings:
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) [22, 26] It is 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 [26].

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 [9, 10]. However, recent studies have suggested that the normal number of intraepithelial lymphocytes in the duodenum may be approximately 25-30 IELs / 100 enterocytes [16, 30]. 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 [12, 13]. 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 [28].

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 [3, 5, 15, 24] . 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 [6, 21]. 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 villous atrophy [11, 23, 29] 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 [25].

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 [2].

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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