Definition/General
Introduction:
Celiac disease is an immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals
Characterized by small intestinal villous atrophy and crypt hyperplasia
Also known as gluten-sensitive enteropathy or celiac sprue
Lifelong condition requiring strict gluten-free diet.
Origin:
Results from abnormal immune response to gluten proteins (gliadin, glutenin)
T-cell mediated autoimmune reaction
Tissue transglutaminase (tTG) acts as autoantigen
HLA-DQ2/DQ8 genetic predisposition required
Environmental trigger (gluten) in genetically susceptible host.
Classification:
Classic celiac disease (GI symptoms, villous atrophy)
Non-classic celiac disease (extraintestinal symptoms)
Silent celiac disease (asymptomatic, positive serology)
Potential celiac disease (positive serology, normal histology)
Refractory celiac disease (Types I and II).
Epidemiology:
Prevalence approximately 1% of population worldwide
Higher prevalence in Europeans and their descendants
Female predominance (2-3:1)
Bimodal distribution: early childhood (6 months-2 years) and 3rd-4th decades
Increasing recognition due to improved diagnostics.
Clinical Features
Presentation:
Classic: Chronic diarrhea, steatorrhea, abdominal distension, weight loss
Non-classic: Iron deficiency anemia, osteoporosis, dermatitis herpetiformis, neurological symptoms
Pediatric: Failure to thrive, growth retardation, irritability
Adult: Often subtle, non-specific symptoms.
Symptoms:
Gastrointestinal: Chronic diarrhea (85%), abdominal pain (70%), bloating (75%), steatorrhea
Systemic: Weight loss (65%), fatigue (80%), iron deficiency anemia (40%)
Extraintestinal: Bone disease, dental enamel defects, infertility, neurologic symptoms.
Risk Factors:
HLA-DQ2 (90-95% patients) or HLA-DQ8 (5-10%)
Family history (10% first-degree relatives)
Associated conditions: Type 1 diabetes, autoimmune thyroid disease, Down syndrome
Early gluten introduction (<6 months)
Viral infections (rotavirus, adenovirus).
Screening:
Serology: tissue transglutaminase IgA (tTG-IgA), endomysial antibodies (EMA), deamidated gliadin peptides (DGP)
Total IgA levels (rule out IgA deficiency)
HLA typing (DQ2/DQ8)
Small bowel biopsy (gold standard)
High-risk groups screening recommended.
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Gross Description
Appearance:
Duodenal biopsies typically small and fragmented
Loss of normal villous architecture on low power
Flattened mucosa in severe cases
Scalloped or nodular endoscopic appearance
Reduced duodenal folds on endoscopy.
Characteristics:
Mosaic pattern on endoscopy (patchy involvement)
Fissuring of duodenal folds
Loss of villous ridges
Granular mucosa
Increased friability
Pale appearance due to malabsorption.
Size Location:
Duodenum most severely affected (especially distal duodenum)
Proximal jejunum also involved
Patchy involvement possible
Severity gradient: duodenum > jejunum > ileum
Multiple biopsies recommended (≥4 from duodenum).
Multifocality:
Diffuse involvement of small intestine
Proximal predominance (duodenum/jejunum)
Patchy distribution in some cases
Skip areas possible
Severity varies between biopsy sites.
Microscopic Description
Histological Features:
Villous atrophy (partial to total)
Crypt hyperplasia (increased crypt depth)
Increased intraepithelial lymphocytes (>40/100 epithelial cells)
Chronic inflammation in lamina propria
Surface epithelial damage
Loss of brush border.
Cellular Characteristics:
Increased intraepithelial lymphocytes (IELs) predominantly CD8+ T cells
Surface epithelial flattening and loss of polarity
Enlarged crypt nuclei
Increased mitotic activity in crypts
Plasma cell infiltration in lamina propria
Eosinophils may be present.
Architectural Patterns:
Villous shortening/atrophy
Crypt elongation
Increased villous width
Surface epithelial disarray
Lamina propria expansion
Loss of surface-to-crypt ratio
Architectural distortion.
Grading Criteria:
Marsh-Oberhuber classification: Marsh 0: Normal
Marsh 1: >40 IELs/100 epithelial cells
Marsh 2: Crypt hyperplasia + increased IELs
Marsh 3a: Mild villous atrophy
Marsh 3b: Marked villous atrophy
Marsh 3c: Total villous atrophy.
Immunohistochemistry
Positive Markers:
CD3 (highlights intraepithelial lymphocytes)
CD8 (majority of IELs)
Ki-67 (increased proliferation in crypts)
CD117 (mast cells increased)
Chromogranin (enteroendocrine cells).
Negative Markers:
Not routinely required
CD20 (few B cells normally)
CD4 (minority of IELs).
Diagnostic Utility:
CD3 facilitates counting of intraepithelial lymphocytes
CD8 staining confirms T-cell nature of IELs
Ki-67 demonstrates increased crypt proliferation
IEL count >40/100 epithelial cells supports diagnosis.
Molecular Subtypes:
No molecular subtypes
HLA-DQ2.5 (90% patients)
HLA-DQ8 (5-10% patients)
TCR gamma/delta T cells in refractory disease
Cytokine profile changes with treatment.
Molecular/Genetic
Genetic Mutations:
HLA-DQ2 (DQA1*05:01, DQB1*02:01) in 90-95%
HLA-DQ8 (DQA1*03:01, DQB1*03:02) in 5-10%
Non-HLA genes: IL15RA, RGS1, LPP, SH2B3, TAGAP
Over 40 susceptibility loci identified
CTLA4 and PTPN22 variants.
Molecular Markers:
Tissue transglutaminase upregulation
IL-15 overexpression
Interferon-γ production
Matrix metalloproteinases activation
Tight junction proteins disruption
Zonulin elevation.
Prognostic Significance:
Excellent prognosis with gluten-free diet
Histological improvement within 6-24 months
Persistent symptoms suggest non-adherence or refractory disease
Increased lymphoma risk (enteropathy-associated T-cell lymphoma)
Early diagnosis improves outcomes.
Therapeutic Targets:
Strict gluten-free diet (lifelong)
Dietary counseling and monitoring
Nutritional supplementation (iron, B vitamins, calcium, vitamin D)
Corticosteroids for refractory disease
Immunosuppression (refractory celiac disease type II).
Differential Diagnosis
Similar Entities:
Tropical sprue
Common variable immunodeficiency
Crohn disease
Giardiasis
Small bowel bacterial overgrowth
NSAIDs enteropathy
Autoimmune enteropathy.
Distinguishing Features:
Celiac disease: HLA-DQ2/8+, tTG antibodies+
Tropical sprue: Endemic areas, responds to antibiotics
CVID: Hypogammaglobulinemia, recurrent infections
Crohn: Transmural, skip lesions, granulomas
Giardiasis: Parasites identifiable, acute onset.
Diagnostic Challenges:
Distinguishing Marsh 1-2 lesions from other causes of increased IELs
Patchy involvement requiring adequate sampling
Seronegative celiac disease (rare)
Potential celiac disease management
Refractory disease vs non-adherence.
Rare Variants:
Refractory celiac disease type I (polyclonal IELs)
Refractory celiac disease type II (clonal IELs)
Collagenous sprue
Ulcerative jejunitis
Enteropathy-associated T-cell lymphoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen
Duodenal biopsies, [number] pieces
Villous Architecture
Villous architecture: [normal/mild/moderate/severe atrophy]
Intraepithelial Lymphocytes
Intraepithelial lymphocytes: [count]/100 epithelial cells (normal <40)
Marsh Grade
Marsh Grade: [0/1/2/3a/3b/3c]
Inflammation
Chronic inflammation: [mild/moderate/marked] in lamina propria
Diagnosis
Features consistent with celiac disease, Marsh Grade [X]. Recommend gluten-free diet and follow-up.