What are the histopathological findings and management of celiac disease?

Celiac Disease Histopathology

Classic Histopathological Features

The gold standard histopathological findings of celiac disease include a spectrum from partial to total villous atrophy, crypt hyperplasia with lengthening, increased lamina propria cellularity, and intraepithelial lymphocytosis (≥25 IELs per 100 enterocytes). 1

• Villous atrophy is required for definitive diagnosis of celiac disease in adults, though lesser degrees of damage (≥25 IELs without villous atrophy) may also indicate celiac disease but should not be considered diagnostic on their own 1
• The histological changes exist on a spectrum: isolated intraepithelial lymphocytosis without architectural changes may represent latent celiac disease or gluten-sensitive enteropathy but is not diagnostic of celiac disease 1
• Intraepithelial lymphocytosis alone is a nonspecific finding with low specificity for celiac disease, requiring careful correlation with clinical and serological data 2

Critical Biopsy Technique Requirements

Multiple biopsies (ideally 6 specimens) must be obtained from the second part of the duodenum or beyond, as mucosal changes can be patchy and duodenal bulb biopsies may be compromised by Brunner's glands or peptic changes. 1

• At least 4 biopsies from the second part of duodenum plus 1-2 from the duodenal bulb provide optimal diagnostic yield 3
• Proper orientation of biopsy specimens is crucial for accurate histological assessment 4
• Visual endoscopic examination alone is insufficient to rule out celiac disease, as endoscopic appearance of villous atrophy lacks adequate sensitivity 1

Essential Pre-Biopsy Requirements

Patients must remain on a gluten-containing diet (at least 10g daily for 6-8 weeks) before biopsy, as gluten avoidance reduces lesion severity and causes false-negative results. 5, 3

• Biopsy should be performed promptly after positive serologic testing, with explicit instructions not to avoid gluten until after specimens are obtained 1, 5
• For patients already on a gluten-free diet requiring re-evaluation, a 4-week gluten challenge reproducing symptoms is adequate for most, though some patients may require several months to years for relapse 1, 5

Histological Mimics and Differential Diagnosis

The following conditions can produce villous atrophy with or without increased IELs and must be excluded in seronegative patients:

Common causes: 1, 4

• Medication-induced enteropathy (olmesartan, NSAIDs, mycophenolate mofetil, chemotherapy)
• Helicobacter pylori gastritis
• Small intestinal bacterial overgrowth
• Autoimmune enteropathy

Infectious causes: 1, 4

• Giardiasis
• Post-infectious enteropathy
• Tropical sprue
• Cryptosporidium (especially in AIDS)
• Whipple's disease

Other immune-mediated conditions: 1

• Common variable immunodeficiency
• IgA deficiency
• Collagenous enteritis
• Crohn's disease

Management Approach

Strict lifelong adherence to a gluten-free diet is the only effective treatment, requiring immediate referral to a registered dietitian for comprehensive education after biopsy confirmation. 1, 4

• Clinical and histologic response to gluten-free diet confirms the diagnosis in equivocal cases with compatible pathology and HLA haplotypes 1
• Follow-up includes serologic testing to assess dietary adherence, screening for nutritional deficiencies, and evaluation for associated autoimmune conditions 4
• Gluten challenge with repeat biopsy is no longer required when initial biopsy shows characteristic histology and objective response to gluten-free diet occurs 1

Role of HLA Testing

HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles virtually excludes celiac disease. 1, 5, 3

• Approximately 95% of celiac patients have HLA-DQ2, and 5% have HLA-DQ8 1, 5
• HLA testing is most useful when diagnosis remains uncertain despite negative serology, in patients with equivocal biopsies, or those already on gluten-free diet who were never properly tested 5, 3
• A very small number of patients have only DQA105 or DQB102 (usually with HLA-DR7) 1

Common Diagnostic Pitfalls

• Never initiate gluten-free diet before completing diagnostic workup, as this causes false-negative serology and inconclusive biopsies 4, 3
• Do not diagnose celiac disease based on serology alone without biopsy confirmation in adults (biopsy remains essential except in patients with coagulation disorders or pregnancy) 1
• Do not rely on duodenal bulb biopsies alone, as they may miss patchy disease or be confounded by other pathology 1
• Seronegative celiac disease exists—negative serology does not exclude the diagnosis when histology is suggestive 3, 1
• Communication between pathologists and gastroenterologists is paramount given the nonspecific nature of intraepithelial lymphocytosis 2

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