# Celiac Disease and Small Bowel Pathology

## Overview

Celiac disease is an immune-mediated enteropathy triggered by gluten ingestion in genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8. The pathologist plays a central role in confirming the diagnosis through duodenal biopsy interpretation. Small bowel biopsies also reveal a spectrum of other conditions that require systematic morphologic evaluation.

## Celiac Disease

### Pathogenesis

Gluten peptides (specifically gliadin) cross the intestinal epithelium and are deamidated by tissue transglutaminase (tTG). These deamidated gliadin peptides then bind HLA-DQ2 (present in over 90 percent of celiac patients) or HLA-DQ8 and activate CD4-positive T-cells in the lamina propria. Simultaneously, intraepithelial lymphocytes (IELs), which are predominantly CD8-positive T-cells, become activated and cause direct epithelial damage. The resulting cytokine cascade drives crypt hyperplasia and villous destruction. The genetic requirement of HLA-DQ2 or DQ8 is nearly universal in celiac patients (over 99 percent), but these alleles are also present in 30 to 40 percent of the general population, meaning their presence is necessary but not sufficient for disease.

### Serologic Testing

Anti-tissue transglutaminase IgA (tTG-IgA) is the first-line screening test, with sensitivity and specificity exceeding 95 percent. Anti-endomysial antibodies (EMA-IgA) provide approximately 99 percent specificity and serve as a confirmatory test. Deamidated gliadin peptide IgG (DGP-IgG) is useful in IgA-deficient patients, who represent 2 to 3 percent of the celiac population. Total serum IgA must always be checked to exclude IgA deficiency causing false-negative tTG-IgA results. Serology may be negative in patients already following a gluten-free diet (seronegative celiac disease).

### Biopsy Protocol

A minimum of 4 biopsies from the second and third portions of the duodenum (D2/D3) plus 1 to 2 biopsies from the duodenal bulb (D1) should be obtained. Bulb biopsies are important because celiac disease may be patchy and bulb-limited in some cases. Proper orientation is critical, as tangentially cut biopsies artificially shorten villi and can lead to misdiagnosis. The patient must be consuming a gluten-containing diet at the time of biopsy for reliable interpretation.

### Marsh-Oberhuber Classification

| Stage | Name | Villi | IELs | Crypt Hyperplasia |
|---|---|---|---|---|
| 0 | Pre-infiltrative | Normal | Normal | No |
| 1 | Infiltrative | Normal | ≥25/100 enterocytes | No |
| 2 | Hyperplastic | Normal | Increased | Yes |
| 3a | Partial villous atrophy | Mild-moderate blunting | Increased | Yes |
| 3b | Subtotal villous atrophy | Marked blunting | Increased | Yes |
| 3c | Total villous atrophy | Flat mucosa | Increased | Marked |

#### Type 0 (Pre-infiltrative)

This stage shows normal villous architecture and normal IEL counts. It may be seen in latent celiac disease with positive serology.

#### Type 1 (Infiltrative)

Villous architecture remains normal, but IELs are increased to 25 or more per 100 enterocytes (some authors use a threshold of 40 per 100). The IELs are CD3-positive, predominantly CD8-positive T-cells. The differential diagnosis of isolated IEL increase is broad.

#### Type 2 (Hyperplastic)

This stage adds crypt hyperplasia (elongated, hyperplastic crypts) to the increased IELs. Villi are still present but the villous-to-crypt ratio is reduced. It is uncommon to see this stage in isolation without some degree of villous blunting.

#### Type 3a (Partial Villous Atrophy)

Increased IELs and crypt hyperplasia are accompanied by mild to moderate villous blunting. The villous-to-crypt ratio is reduced but villi remain discernible.

#### Type 3b (Subtotal Villous Atrophy)

Marked villous blunting leaves only rudimentary villi. Crypt hyperplasia and increased IELs are prominent.

#### Type 3c (Total Villous Atrophy)

Complete loss of villi produces a flat mucosal surface. Marked crypt hyperplasia is present along with surface enterocyte damage (cuboidal change) and a dense IEL infiltrate.

### Histologic Features Beyond Marsh Classification

Additional findings that support celiac disease include surface enterocyte damage (loss of columnar shape with cuboidal or flattened cells), loss of brush border (diminished glycocalyx on PAS stain), increased lamina propria plasma cells and lymphocytes, intraepithelial lymphocytosis with a tip-heavy distribution (most prominent at villous tips), and increased crypt mitotic activity.

### Differential Diagnosis of Villous Blunting

Beyond celiac disease, villous atrophy can result from tropical sprue (involving the entire small bowel, with a relevant travel history), autoimmune enteropathy (anti-enterocyte antibodies, severe villous atrophy, often pediatric), common variable immunodeficiency (CVID, characterized by absent plasma cells in the lamina propria), giardiasis and other infections, drug-induced enteropathy (olmesartan, mycophenolate, checkpoint inhibitors), small bowel bacterial overgrowth, eosinophilic gastroenteritis, and Whipple disease.

### Differential Diagnosis of Isolated Intraepithelial Lymphocytosis (Marsh 1)

Isolated intraepithelial lymphocytosis (without villous atrophy) has a broad differential that includes early or latent celiac disease, H. pylori gastritis with duodenal involvement, NSAID use, various infections (H. pylori, Giardia, viral), Crohn disease, immune dysregulation, nonspecific lymphocytic duodenosis, and autoimmune conditions (thyroiditis, type 1 diabetes).

### Refractory Celiac Disease

Type I refractory celiac disease has a normal IEL phenotype (polyclonal CD3-positive/CD8-positive T-cells) and responds to immunosuppression. Type II has an aberrant IEL phenotype (CD3-positive but CD8-negative, with monoclonal T-cell receptor rearrangement) and represents a pre-lymphomatous condition. Type II carries a 50 to 60 percent risk of progression to enteropathy-associated T-cell lymphoma (EATL).

## Small Bowel Neoplasms

### Adenocarcinoma

Small bowel adenocarcinoma is rare, with the duodenum being the most common site. Risk factors include celiac disease, Crohn disease, familial adenomatous polyposis, Lynch syndrome, and Peutz-Jeghers syndrome. Morphologically it resembles colorectal adenocarcinoma and may arise from adenomas.

### Small Bowel Neuroendocrine Tumors (Carcinoid)

Neuroendocrine tumors are the most common small bowel tumor overall, with the ileum as the most frequent site. They are well-differentiated, growing in nests, trabeculae, or glandular patterns composed of uniform cells with salt-and-pepper chromatin. They express synaptophysin and chromogranin. Ki-67 grading classifies them as G1 (less than 3 percent), G2 (3 to 20 percent), or G3 (greater than 20 percent). Serotonin production may cause carcinoid syndrome when hepatic metastases are present.

### Gastrointestinal Stromal Tumor (GIST)

The small bowel is the second most common location for GIST after the stomach. These tumors harbor KIT (CD117) or PDGFRA mutations and show spindle cell or epithelioid morphology. They are positive for DOG1 and CD117, with risk stratification based on size, mitotic rate, and anatomic site.

### Lymphoma

EATL is associated with celiac disease and consists of large pleomorphic T-cells with a poor prognosis. MALT lymphoma is a B-cell neoplasm that includes immunoproliferative small intestinal disease (IPSID/alpha heavy chain disease). Duodenal-type follicular lymphoma is a localized, indolent entity with excellent prognosis. Mantle cell lymphoma may present with a lymphomatous polyposis pattern.

<image>A medical illustration of the Marsh-Oberhuber classification of celiac disease. Five panels showing progressive histologic changes: Marsh 0 (normal villi, normal IEL count), Marsh 1 (normal villi with increased intraepithelial lymphocytes highlighted by CD3 immunostain showing >25 IELs per 100 enterocytes), Marsh 2 (increased IELs with crypt hyperplasia but preserved villi), Marsh 3a (partial villous atrophy with reduced villous:crypt ratio, crypt hyperplasia, and increased IELs), Marsh 3b (subtotal villous atrophy with rudimentary villi), and Marsh 3c (total villous atrophy with flat mucosa, marked crypt hyperplasia, and cuboidal surface enterocytes). Each panel labeled with classification and key diagnostic features.</image>

<image>A medical illustration comparing celiac disease with its histologic mimickers. Panel A (Celiac disease): Villous atrophy, crypt hyperplasia, tip-heavy intraepithelial lymphocytosis, surface enterocyte damage, and increased lamina propria plasma cells. Panel B (Common variable immunodeficiency): Villous atrophy with notably absent plasma cells in the lamina propria, nodular lymphoid hyperplasia. Panel C (Autoimmune enteropathy): Severe villous atrophy with crypt apoptosis and deep crypt destruction, absent goblet cells. Panel D (Olmesartan-associated enteropathy): Villous atrophy mimicking celiac disease with subepithelial collagen deposition and mixed inflammation.</image>

<image>A medical illustration of small bowel neoplasms. Panel A (Small bowel neuroendocrine tumor): Well-circumscribed submucosal tumor composed of uniform cells in nests and trabeculae with salt-and-pepper chromatin, with synaptophysin IHC inset showing diffuse positivity. Panel B (GIST): Spindle cell proliferation in muscularis propria with low mitotic activity, CD117 IHC inset showing strong diffuse membranous and cytoplasmic staining. Panel C (Enteropathy-associated T-cell lymphoma): Destructive infiltrate of large pleomorphic lymphoid cells effacing villous architecture, arising in a background of villous atrophy, with CD3 IHC inset. Panel D (Duodenal-type follicular lymphoma): Nodular lymphoid infiltrate confined to the mucosa and submucosa with well-formed germinal centers, CD10 and BCL2 co-expression.</image>

## Clinical Pearls

Total serum IgA should always be checked when ordering celiac serology because approximately 2 to 3 percent of celiac patients have selective IgA deficiency, causing false-negative tTG-IgA results; DGP-IgG should be used instead in these patients. Tangential sectioning is the most common pitfall in duodenal biopsy interpretation; apparent villous blunting on poorly oriented biopsies should not be diagnosed as celiac disease, and deeper levels or rebiopsy should be requested.

The duodenal bulb should be biopsied routinely because up to 10 percent of celiac disease cases show isolated bulbar involvement with normal D2 biopsies. Absent lamina propria plasma cells in a biopsy showing villous atrophy should raise suspicion for CVID rather than celiac disease. Drug-induced enteropathy (especially olmesartan) can perfectly mimic celiac disease histologically, so the medication list must always be reviewed in seronegative cases with villous atrophy. Refractory celiac disease Type II has aberrant IELs (CD3-positive/CD8-negative) and carries a high risk of EATL transformation; flow cytometry and T-cell receptor clonality studies are essential when refractory disease is suspected.

## References
- Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. *Eur J Gastroenterol Hepatol*. 1999;11(10):1185-1194.
- Rubio-Tapia A, et al. ACG clinical guidelines: Diagnosis and management of celiac disease. *Am J Gastroenterol*. 2013;108(5):656-676.
- Villanacci V, et al. Celiac disease: histology-differential diagnosis-complications. A practical approach. *Pathologica*. 2020;112(3):186-196.
- Brown I, et al. Duodenal intraepithelial lymphocytosis. *J Clin Pathol*. 2006;59(10):1068-1070.
- Odze RD, Goldblum JR. *Odze and Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas*. 4th ed. Elsevier; 2023.