Management of Patients with Intact Villi on Biopsy
In patients with intact villi on duodenal biopsy, the clinical management should focus on evaluating for seronegative enteropathies and other conditions that may present with increased intraepithelial lymphocytes (IELs) without villous atrophy. 1
Diagnostic Considerations
Initial Evaluation
- Confirm proper orientation and quality of biopsy specimens with an experienced gastrointestinal pathologist to ensure accurate assessment of villous architecture 1
- Quantify intraepithelial lymphocytes (IELs) - increased IELs (≥25/100 enterocytes) with normal villous architecture may represent early celiac disease or other conditions 2
- Review all available serologic testing for celiac disease, including:
- IgA tissue transglutaminase (tTG) antibodies
- Total IgA levels (to rule out IgA deficiency)
- IgA endomysial antibodies (EMA)
- IgA/IgG deamidated gliadin peptide (DGP) antibodies 1
HLA Testing
- Perform HLA-DQ2/DQ8 typing if not previously done - a negative result effectively rules out celiac disease (<1% of celiac patients are negative for both) 1
- HLA typing is particularly useful in patients who are self-treated on a gluten-free diet without prior proper testing 1
Differential Diagnosis for Intact Villi with Increased IELs
Celiac Disease-Related
- Early or developing celiac disease (may have positive serology but intact villi) 3
- Seronegative celiac disease (negative serology but responds to gluten-free diet) 1
Non-Celiac Causes
- Autoimmune disorders (Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis, etc.) 1, 4
- Inflammatory bowel disease, particularly Crohn's disease 5
- Medication-related (NSAIDs, olmesartan, mycophenolate mofetil) 1, 4
- Infections (H. pylori gastritis, giardiasis, viral infections) 1, 2
- Post-infectious diarrhea 1
- Food protein intolerances (non-celiac gluten sensitivity, cow's milk, soy) 1, 2
- Small intestinal bacterial overgrowth 1, 4
Management Algorithm
For Suspected Celiac Disease
If celiac serology is positive with intact villi:
If celiac serology is negative with intact villi but increased IELs:
- Check HLA-DQ2/DQ8 status
- If HLA-positive: Consider trial of GFD for 6 months
- If HLA-negative: Celiac disease is effectively ruled out 1
For patients already on a self-imposed GFD:
- Perform HLA typing
- If HLA-positive: Consider gluten challenge followed by repeat biopsy
- If HLA-negative: Discontinue GFD and investigate other causes 1
For Non-Celiac Etiologies
- Screen for autoimmune disorders (thyroid function tests, autoantibodies) 4
- Review medication history, particularly NSAIDs and olmesartan 1
- Test for H. pylori infection 1, 2
- Consider stool studies for parasites and bacterial overgrowth 1
- Evaluate for inflammatory bowel disease, especially if focal gastritis is present on gastric biopsies 5
Follow-up Recommendations
For patients with suspected early celiac disease or seronegative celiac disease on GFD:
For patients with persistent symptoms despite negative workup:
Important Caveats
- Intact villi with increased IELs is a nonspecific finding but should not be ignored, as it may represent early celiac disease in approximately 10% of cases 4
- The absence of villous atrophy does not exclude celiac disease, especially in early stages 1, 2
- Patchy distribution of intestinal lesions may lead to sampling errors; multiple biopsies are essential 1
- Histological features alone cannot reliably distinguish between celiac and non-celiac causes of increased IELs 4
- Patients with normal villi but increased IELs may still benefit from a gluten-free diet if they have positive celiac serology 1, 3