diagnosis
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Diagnosis is based on symptoms + blood tests + intestinal biopsy. A key challenge: gluten must be actively consumed at the time of testing — antibodies and biopsy findings normalise on a GFD.
Diagnosis often takes over a decade after symptom onset due to diverse presentations and low clinical awareness.
Pre-Test Requirements
- Patient must be eating gluten (at least several weeks prior)
- Those already on GFD must undergo a gluten challenge (>10g/day for 3 months, or until TG2 IgA becomes positive) before testing is reliable
Step 1: Blood Tests (Serology)
First-Line: TTG IgA
Tissue transglutaminase IgA (TTG IgA / TG2 IgA)
- Sensitivity: 92.8% | Specificity: 97.9%
- Cost-efficient, widely available
- Severity of intestinal damage correlates with TTG IgA levels
- Test simultaneously for IgA deficiency — more common in celiac (~1 in 40 patients vs ~1 in 500 general pop)
If IgA Deficient: IgG-Based Tests
- DGP IgG (deamidated gliadin peptide)
- EMA IgG (endomysial antibody)
- TTG IgG — less accurate than IgA testing
- IgA-based tests are unreliable in IgA deficiency
EMA (Endomysial Antibody)
- Near 100% specificity; lower sensitivity
- Costly, hard to interpret, observer-dependent
- Useful to confirm borderline TTG IgA levels
Deprecated Tests (No Longer Recommended)
- Antigliadin antibodies (AGA)
- Antireticulin antibodies (ARA) — superseded by more accurate tests
Paediatric Shortcut (ESPGHAN 2020)
Biopsy can be avoided in children if all three are present:
- Symptoms of celiac disease
- TTG IgA ≥10× upper normal limit
- Positive EMA antibody
Step 2: Endoscopy + Biopsy
Upper endoscopy with duodenal biopsy — beyond the duodenal bulb or from jejunum.
- Multiple biopsies taken (patchy involvement → single biopsy may miss disease)
- Endoscopic features: scalloping of folds, fissures, mosaic mucosa pattern, prominence of submucosal blood vessels, nodular mucosa
- Capsule endoscopy — alternative for those unable/unwilling to undergo standard endoscopy
Marsh-Oberhuber Classification (Histology)
| Type | Increased IELs (>40/100 enterocytes) | Crypt Hyperplasia | Villous Atrophy |
|---|---|---|---|
| 0 (normal) | No | No | No |
| 1 (infiltrative) | Yes | No | No |
| 2 (hyperplastic) | Yes | Yes | No |
| 3a (destructive) | Yes | Yes | Mild |
| 3b (destructive) | Yes | Yes | Moderate |
| 3c (destructive) | Yes | Yes | Complete |
Note: These histological features are not exclusive to celiac — context (serology, clinical) is required.
Step 3: Genetic Testing (Optional)
- Not needed for routine diagnosis
- Useful to rule out celiac when borderline results (high negative predictive value — if neither DQ2 nor DQ8, celiac is very unlikely)
- Helps decide whether to perform gluten challenge in those already on GFD
Differential Diagnosis
Conditions that can mimic celiac disease histologically or serologically:
| Mimics with villous atrophy / elevated IELs | Positive blood tests without villous atrophy |
|---|---|
| Tropical sprue | Errors in blood collection |
| Eosinophilic gastroenteritis | Recent infections |
| Lactose intolerance | Congestive heart failure |
| Lymphoma | Chronic liver disease |
| Crohn's disease | Hypergammaglobulinaemia |
| H. pylori infection | |
| Drug-induced (azathioprine, methotrexate, olmesartan, NSAIDs, PPIs) | |
| Whipple disease, Giardiasis, tuberculosis | |
| Zollinger–Ellison syndrome, HIV enteropathy | |
| SIBO, collagenous sprue | |
| CVID, autoimmune enteropathy |
Non-Celiac Gluten Sensitivity (NCGS)
- Intestinal + extraintestinal symptoms triggered by gluten
- Faster onset and offset than celiac
- Diagnosed by exclusion: rule out celiac and wheat allergy, then confirm resolution on GFD
- No autoimmune markers; no villous atrophy
NICE Testing Indications
Recommended:
- Persistent unexplained GI symptoms
- Faltering growth
- Chronic fatigue
- Severe/persistent mouth ulcers
- Unexplained iron, B12, or folate deficiency
- Type 1 diabetes (at diagnosis)
- Autoimmune thyroid disease (at diagnosis)
- IBS in adults
- First-degree relatives of celiac patients
Considered:
- Metabolic bone disease
- Unexplained neurological symptoms (neuropathy, ataxia)
- Fertility problems / recurrent miscarriage
- Persistently raised liver enzymes
- Dental enamel defects
- Down syndrome, Turner syndrome
Source Basis
Current synthesis incorporates guideline and guideline-summary sources including:
raw/american_college_of_gastroenterology_guidelines.17.pdf(American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease, 2023)raw/practice-guidelines-celiac-disease.pdf(Diagnosis and Management of Celiac Disease: Guidelines From the American College of Gastroenterology, 2024)raw/WJG-28-154.pdf(Current guidelines for the management of celiac disease, 2022)
These sources support the diagnostic sequence of serology while eating gluten, total IgA assessment, biopsy confirmation in most cases, selective pediatric non-biopsy pathways, and HLA testing mainly as an exclusion tool when results conflict or gluten has already been removed.
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