What are the details of the Marsh criteria for diagnosing celiac disease?

The Marsh Criteria for Diagnosing Celiac Disease

The Marsh criteria is the gold standard histological classification system for diagnosing celiac disease, categorizing small intestinal mucosal damage from type 0 (normal) through type 3 (villous atrophy), with type 3 being diagnostic of celiac disease when accompanied by positive serology. 1

Marsh Classification System

The original Marsh classification describes the progressive immunopathological spectrum of gluten-induced mucosal changes:

Marsh Type 0

• Normal mucosa
• No significant histological abnormalities
• <25 intraepithelial lymphocytes (IELs) per 100 enterocytes

Marsh Type 1 (Infiltrative Lesion)

• Normal mucosal architecture
• Increased IELs (≥25 per 100 enterocytes)
• No crypt hyperplasia or villous atrophy
• Represents innate immune response to gluten

Marsh Type 2 (Hyperplastic Lesion)

• Increased IELs (≥25 per 100 enterocytes)
• Crypt hyperplasia
• Normal villous architecture
• Represents progression toward adaptive immune response

Marsh Type 3 (Destructive Lesion)

• Increased IELs (≥25 per 100 enterocytes)
• Crypt hyperplasia
• Villous atrophy

The Marsh-Oberhuber modification further subdivides type 3 lesions:

• Type 3a: Partial villous atrophy
• Type 3b: Subtotal villous atrophy
• Type 3c: Total villous atrophy

Marsh Type 4 (Atrophic-Hypoplastic Lesion)

• Flat mucosa
• Normal IEL count
• Hypoplastic crypts
• Rare, typically seen in refractory celiac disease

Diagnostic Interpretation

The British Society of Gastroenterology guidelines provide clear interpretation criteria 1:

1. Definite Celiac Disease: Positive serology (IgA-TG2 or EMA) with villous atrophy (Marsh 3)
2. Probable Celiac Disease: Positive serology with increased IELs but no villous atrophy (Marsh 1-2)
3. Potential Celiac Disease: Positive serology with normal histology

When interpreting results, consider:

• Serology status (IgA-TG2, EMA, DGP antibodies)
• IgA status (total IgA levels)
• HLA-DQ2/DQ8 status
• Response to gluten-free diet

Clinical Significance of Different Marsh Stages

• Marsh 1-2 (Minor Lesions): While not traditionally diagnostic of celiac disease, research shows patients with positive serology and Marsh 1-2 lesions benefit from gluten-free diet with symptom improvement and histological normalization 2, 3, 4
• Marsh 3 (Villous Atrophy): Diagnostic of celiac disease when accompanied by positive serology
• Seronegative Marsh 3: Consider other causes of villous atrophy (see differential diagnoses)

Important Diagnostic Considerations

1. Biopsy Technique:

   • Obtain multiple biopsies (at least 6) from second part of duodenum or beyond 1
   • Avoid duodenal bulb due to Brunner's glands and peptic changes
   • Ensure patient is on gluten-containing diet during biopsy

2. Patchy Distribution:

   • Celiac lesions can be patchy, requiring multiple biopsies
   • A duodenal biopsy may be negative when the lesion is only present in the jejunum 1

3. Serology Correlation:

   • Positive serology (particularly IgA-TG2 and EMA) with villous atrophy is diagnostic
   • IgA deficiency (2% of celiac patients) requires IgG-based testing (IgG-TG2 or IgG-DGP)

4. HLA Testing:

   • Nearly 100% of celiac patients have HLA-DQ2 (95%) or HLA-DQ8 (5%)
   • Absence of these alleles provides nearly 100% negative predictive value 1

Differential Diagnosis for Villous Atrophy

When villous atrophy is present without positive celiac serology, consider:

• Common variable immunodeficiency
• Autoimmune enteropathy
• Post-infectious diarrhea
• Giardiasis
• H. pylori gastritis
• Medication-induced enteropathy (NSAIDs, olmesartan)
• Tropical sprue
• Small intestinal bacterial overgrowth
• Crohn's disease

Limitations of the Marsh Classification

• Subclassification of Marsh 3 (a, b, c) has not been shown to aid in diagnosis, treatment decisions, or prognosis 5
• Marsh 1-2 lesions with positive serology may represent early celiac disease requiring treatment, though they don't meet traditional diagnostic criteria 3, 4

Diagnostic Algorithm

1. Perform serologic testing (IgA-TG2, total IgA) while patient is on gluten-containing diet
2. If positive serology, proceed to endoscopy with multiple duodenal biopsies
3. If Marsh 3 lesions with positive serology: diagnose celiac disease
4. If Marsh 1-2 lesions with positive serology: consider probable celiac disease and trial of gluten-free diet
5. If negative serology with villous atrophy: consider other causes and HLA testing
6. If IgA deficient: use IgG-based tests (IgG-TG2, IgG-DGP) or proceed directly to biopsy

The Marsh criteria significantly expanded the diagnostic spectrum of celiac disease, allowing for earlier diagnosis and treatment of patients who previously would have been denied such vital intervention 5.