What is the likely cause of villous atrophy, intraepithelial lymphocytes, and mild acute inflammation of the small bowel mucosa?

Differential Diagnosis of Villous Atrophy with Intraepithelial Lymphocytosis and Mild Acute Inflammation

Celiac disease is the most common cause of this histologic triad, but a systematic evaluation must exclude medication-induced enteropathy, infections (particularly giardiasis), autoimmune enteropathy, common variable immunodeficiency, and tropical sprue before confirming the diagnosis. 1

Primary Diagnostic Consideration: Celiac Disease

Celiac disease characteristically presents with villous atrophy, increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes), and crypt hyperplasia. 1 The pathophysiology involves gluten peptides triggering an autoimmune reaction with T-cell activation, leading to pro-inflammatory cytokines, lymphocyte infiltration, and subsequent tissue injury. 1, 2

Diagnostic Confirmation Required:

• Measure IgA tissue transglutaminase antibodies (tTG-IgA) with total IgA level to rule out IgA deficiency, which occurs in 1-3% of celiac patients. 3
• If IgA deficient, obtain IgG-based tests (IgG-DGP or IgG-tTG), which maintain excellent sensitivity and specificity. 3
• Consider IgA endomysial antibody (EMA) testing for additional specificity if diagnosis remains uncertain. 3
• HLA-DQ2/DQ8 typing has >99% negative predictive value—absence of both alleles virtually excludes celiac disease. 3

Critical Differential Diagnoses to Exclude

Medication-Induced Enteropathy (Must Exclude First)

Olmesartan enteropathy causes severe villous atrophy that mimics celiac disease but responds rapidly to drug cessation. 1 Other medications causing similar enteropathy include:

• Other angiotensin receptor blockers (may aggravate celiac symptoms or slow mucosal healing) 1
• Mycophenolate, methotrexate, and azathioprine 1
• NSAIDs and proton pump inhibitors 3

Infectious Causes

Giardiasis is a critical infectious mimic that produces villous atrophy with increased IELs and must be excluded in seronegative patients. 1, 3

Additional infectious etiologies include:

• Cryptosporidium (especially in AIDS patients) 3
• Whipple's disease (Tropheryma whipplei) 1
• Mycobacterium avium complex 1
• Tuberculosis 1
• HIV enteropathy 1

Autoimmune and Immunodeficiency Disorders

Common variable immunodeficiency disease produces similar symptoms and pathology to celiac disease. 1

Autoimmune enteropathy is diagnosed by:

• Sprue-like biopsy appearance with other autoimmune diseases 1
• Anti-enterocyte and/or anti-goblet cell antibodies 1
• Pathologic features: absence of Paneth or goblet cells and increased crypt apoptotic bodies 1
• May coexist with celiac disease 1

Geographic and Nutritional Causes

Tropical sprue requires travel or residence in tropical countries and is characterized by:

• Folate and/or vitamin B12 deficiency 1
• Partial villous atrophy (often patchy) with less intraepithelial lymphocytosis than celiac disease 1
• Responds rapidly to folic acid and tetracycline treatment 1

Diagnostic Algorithm

Step 1: Confirm Adequate Biopsy Sampling

Obtain multiple biopsies (ideally 6 specimens) from the second part of the duodenum or beyond, as mucosal changes can be patchy. 3 Do not rely on duodenal bulb biopsies alone, as they may be compromised by Brunner's glands or peptic changes. 3

Step 2: Serologic Testing

• Perform celiac serology BEFORE initiating gluten-free diet (tTG-IgA, total IgA, consider EMA) 3
• Patient must consume ≥10g gluten daily for 6-8 weeks before testing to avoid false negatives 3

Step 3: Medication Review

Review all current medications for enteropathy-inducing agents, particularly olmesartan and other ARBs, immunosuppressants, and NSAIDs. 1, 3

Step 4: Infectious Workup

• Stool examination for Giardia, Cryptosporidium 3
• Consider HIV testing 1
• Re-examination by experienced GI pathologist to identify Whipple's disease, tuberculosis, or MAI 1

Step 5: Immunologic Assessment

• Measure immunoglobulin levels to screen for common variable immunodeficiency 1
• Consider autoimmune enteropathy antibodies (anti-enterocyte, anti-goblet cell) if other autoimmune diseases present 1

Step 6: Travel and Nutritional History

• Document travel to tropical regions 1
• Measure folate and vitamin B12 levels if tropical sprue suspected 1

Management Based on Diagnosis

If Celiac Disease Confirmed:

Initiate strict lifelong gluten-free diet immediately after biopsy confirmation with referral to registered dietitian. 3 Clinical and histologic response to gluten-free diet confirms diagnosis in equivocal cases. 3

If Seronegative with Persistent Atrophy:

Consider trial of gluten-free diet for 6 months in patients with compatible histology and HLA-DQ2/DQ8 positivity, as seronegative celiac disease exists. 3, 4

Unclassified Cases:

Patients lacking evidence of specific etiologies may be labeled as "unclassified sprue" or idiopathic villous atrophy, which may represent a form of autoimmune enteropathy. 1

Common Pitfalls to Avoid

Never diagnose celiac disease and commence gluten-free diet without performing celiac serologic testing first—patients with villous atrophy from other causes will not respond to gluten-free diet. 1

Do not overlook medication history, as olmesartan enteropathy can cause severe illness but responds rapidly to drug cessation. 1

Ensure proper biopsy orientation and adequate sampling—poorly oriented specimens may miss villous atrophy, and single biopsies may miss patchy disease. 3