What is the diagnosis and treatment for a patient with increased intraepithelial lymphocytes and villous blunting in the duodenal mucosa, without evidence of dysplasia or malignancy?

Diagnosis and Management of Duodenal Villous Blunting with Increased Intraepithelial Lymphocytes

Primary Diagnosis

The histologic findings of increased intraepithelial lymphocytes and villous blunting are highly suggestive of celiac disease, and the next critical step is to obtain celiac serologic testing (IgA tissue transglutaminase antibody with total IgA level) while the patient remains on a gluten-containing diet. 1

Diagnostic Algorithm

Immediate Serologic Workup Required

• Obtain IgA tissue transglutaminase (IgA-TG2) antibody testing as the most efficient single serologic test for celiac disease 1
• Measure total IgA level to rule out IgA deficiency, which occurs in 1-3% of celiac patients and would cause falsely negative IgA-based tests 2
• If IgA deficient, obtain IgG-based tests (IgG tissue transglutaminase and/or IgG deamidated gliadin peptide) which have excellent sensitivity and specificity in this setting 1
• Consider IgA endomysial antibody (EMA) testing for additional specificity (99.6%) if diagnosis remains uncertain 1

Interpretation Based on Serology Results

If serology is positive:

• The combination of positive celiac serology with villous blunting and increased intraepithelial lymphocytes confirms the diagnosis of celiac disease 1
• Definitive diagnosis of celiac disease requires villous atrophy, but lesser degrees of damage (≥25 intraepithelial lymphocytes per 100 enterocytes with villous blunting) may also indicate celiac disease 1

If serology is negative:

• Consider HLA-DQ2/DQ8 testing, as the absence of these alleles strongly argues against celiac disease 1, 3
• If HLA-DQ2/DQ8 positive, this represents possible seronegative celiac disease and warrants a trial of gluten-free diet with clinical and histologic monitoring 2, 3
• Evaluate the extensive differential diagnosis of villous atrophy with negative celiac serology 1

Critical Differential Diagnosis to Exclude

Common Causes (Must Evaluate)

• Medication-induced enteropathy: Specifically olmesartan, NSAIDs, mycophenolate mofetil, and chemotherapy agents 1
• Helicobacter pylori gastritis: Common cause of increased intraepithelial lymphocytes 1
• Small intestinal bacterial overgrowth: Particularly in elderly patients 1
• Autoimmune enteropathy: Consider in patients with other autoimmune conditions 1

Infectious Causes

• Giardiasis: Must be excluded with stool testing 1
• Post-infectious enteropathy: Recent history of acute gastroenteritis 1
• Tropical sprue: Relevant travel history 1

Other Important Considerations

• Common variable immunodeficiency: Check immunoglobulin levels 1
• Microscopic colitis/collagenous duodenitis: May coexist with celiac disease 1
• Non-celiac gluten sensitivity: Diagnosis of exclusion 1

Management Strategy

If Celiac Disease Confirmed

Initiate strict gluten-free diet immediately after biopsy confirmation as the only effective treatment 2

• Refer to registered dietitian experienced in celiac disease for comprehensive dietary education 2
• Screen for nutritional deficiencies: CBC, iron studies, vitamin D, vitamin B12, folate, calcium 2
• Evaluate for associated autoimmune conditions: Thyroid function tests (autoimmune thyroid disease occurs in 10-30% of celiac patients), fasting glucose or HbA1c (type 1 diabetes) 2
• Follow-up serologic testing schedule: At 6 months after starting gluten-free diet, at 12 months, then annually 2

If Diagnosis Uncertain (Negative Serology)

• Trial of gluten-free diet for 6 months with monitoring of clinical response and repeat serology 3
• Consider repeat biopsy in 12-24 months to assess for histological changes if clinical response to gluten-free diet 3
• If symptoms persist despite negative workup, consider repeat biopsy with samples from jejunum or video capsule endoscopy 3

Critical Pitfalls to Avoid

• Never initiate gluten-free diet before completing diagnostic workup, as this leads to false negative serology and inconclusive biopsies 2
• Ensure adequate biopsy sampling: At least 6 specimens from the second part of duodenum or beyond, as mucosal changes can be patchy 1
• Confirm proper orientation of biopsy specimens with experienced gastrointestinal pathologist to ensure accurate assessment of villous architecture 3
• Do not rely solely on serology without biopsy confirmation, especially with discordant results 2

Prognosis and Long-term Monitoring

• Persistent intraepithelial lymphocytosis may occur in 56% of patients despite strict gluten-free diet and normal villous architecture, but this has good prognosis without signs of malabsorption or increased malignancy risk 4
• If symptoms persist despite gluten-free diet and negative serology, consider complications such as refractory celiac disease or enteropathy-associated T-cell lymphoma 2
• Refractory celiac disease occurs in approximately 1% of celiac patients and requires specialized evaluation including flow cytometry of intraepithelial lymphocytes 1