COELIAC DISEASE

COELIAC DISEASE

AT A GLANCE

Domain	Key point
Definition	Immune-mediated systemic disorder triggered by gluten in genetically susceptible individuals.
Trigger	Wheat, barley, and rye; gluten exposure is required for accurate diagnostic testing unless a validated alternative pathway is being used
First-line test	tTG-IgA plus total serum IgA plus total serum IgA while the patient is eating gluten.
Confirmation	Usually serology plus duodenal histology; a conditional no-biopsy pathway now exists for selected adults <45 years with IgA anti-TG2 ≥10× ULN, confirmed on a second sample, in secondary care.
Core treatment	Lifelong strict gluten-free diet, dietitian counselling, and correction of deficiencies.

WHAT HAS CHANGED? — 2025–2026 • 2025 ESsCD adult diagnostic guidance conditionally permits a no-biopsy diagnosis in selected adults younger than 45 years with IgA anti-TG2 ≥10× ULN, confirmed in a second blood sample, in secondary-care practice. • Routine EMA-IgA is no longer required as a confirmatory test in the adult no-biopsy pathway; validated high-performance IgA anti-TG2 assays are central to diagnosis. • The adult biopsy protocol is more explicit: at least four biopsies from the second part of the duodenum; bulb biopsies are also incorporated in the updated pathway. • 2025/2026 ESsCD management guidance expands structured follow-up, certified gluten-free oats, bone-health stratification, functional asplenia/vaccination considerations, exocrine pancreatic insufficiency, psychosocial care and selected low-FODMAP therapy after histological remission. • The 2026 BSG adult guideline provides another contemporary evidence-based framework for diagnosis and management.

Guideline	Adult no-biopsy pathway
ESsCD 2025	Selected adults <45 yr, IgA anti-TG2 ≥10× ULN, second-sample confirmation
BSG 2026	Symptomatic adults in secondary care with IgA-tTG ≥10× ULN; optional with shared decision-making

Persistent symptoms are not synonymous with refractory coeliac disease: reconfirm the diagnosis, assess gluten exposure and investigate alternative causes first

1. DEFINITION

Coeliac disease (CD) is a chronic, immune-mediated systemic disorder triggered by dietary gluten in genetically susceptible individuals. It produces small-intestinal inflammation with variable villous atrophy, crypt hyperplasia, and coeliac-specific autoantibodies.

The clinical spectrum ranges from classical malabsorption to isolated extraintestinal manifestations or minimal symptoms. It is not simply gluten intolerance.

2. PATHOGENESIS

• Gluten-derived gliadin peptides resist complete digestion.

• Tissue transglutaminase 2 (TG2) deamidates gliadin peptides, increasing their affinity for HLA-DQ2 or HLA-DQ8.

• Gluten-specific CD4-positive T cells initiate the adaptive immune response.

• Intraepithelial lymphocytes and inflammatory mediators contribute to enterocyte injury, crypt hyperplasia, and villous atrophy.

• Autoantibodies may develop against TG2, endomysium, and deamidated gliadin peptides.

Genetics: HLA-DQ2 is present in the great majority of affected individuals; most of the remainder carry HLA-DQ8. Absence of both makes CD very unlikely, whereas their presence alone does not establish the diagnosis.

3. CLINICAL MANIFESTATIONS

3.1 Gastrointestinal

• Chronic or recurrent diarrhoea; steatorrhoea or bulky stools.

• Abdominal distension, bloating, flatulence, or discomfort.

• Weight loss, reduced appetite, or failure to thrive.

• Constipation, nausea, dyspepsia, or other nonspecific symptoms.

3.2 Extraintestinal

System	Manifestations
Haematological	Iron-deficiency anaemia; folate deficiency; occasionally vitamin B12 deficiency
Skeletal	Osteopenia, osteoporosis, osteomalacia, fractures
Dermatological	Dermatitis herpetiformis
Neurological	Peripheral neuropathy, ataxia, headache
Reproductive	Infertility, recurrent pregnancy loss, menstrual disturbance
Hepatic	Unexplained aminotransferase elevation
Oral	Recurrent aphthous ulcers, enamel defects
General	Fatigue, weight loss, failure to thrive

3.3 Clinical phenotypes

Phenotype	Description
Classical	Malabsorption, often with diarrhoea, weight loss, or nutritional deficiencies
Non-classical	Predominantly extraintestinal or nonspecific symptoms
Subclinical	Few or no symptoms, but objective evidence of disease
Potential	Positive coeliac serology with preserved villous architecture
Seronegative	Compatible enteropathy despite negative conventional serology, after excluding alternatives

4. WHO SHOULD BE TESTED?

• Chronic diarrhoea, steatorrhoea, or unexplained weight loss.

• Unexplained iron-deficiency anaemia or other nutritional deficiency.

• Persistent gastrointestinal symptoms compatible with CD.

• Unexplained elevation of liver aminotransferases.

• Premature osteoporosis, unexplained metabolic bone disease, or fractures.

• Dermatitis herpetiformis.

• Type 1 diabetes or selected associated autoimmune disorders.

• First-degree relative with CD; selected genetic syndromes including Down or Turner syndrome.

Testing is most informative when clinical features, nutritional abnormalities, autoimmune disease, or family history raise pre-test probability.

5. DIAGNOSTIC APPROACH

5.1 Initial serology

Test while the patient is consuming a gluten-containing diet. The preferred initial combination is serum tTG-IgA and total serum IgA.

Test	Role / interpretation
tTG-IgA	Preferred initial test when total IgA is normal
Total serum IgA	Identifies IgA deficiency that can cause false-negative IgA-based tests
EMA-IgA	Highly specific; used in selected confirmatory pathways
DGP-IgG or tTG-IgG	IgG-based testing when total IgA is low/undetectable

Avoid starting a gluten-free diet before completing diagnostic evaluation: serology and mucosal abnormalities may improve, compromising diagnostic accuracy.

5.2 If IgA is deficient

Use an IgG-based assay (for example, DGP-IgG or tTG-IgG). In a patient with high clinical suspicion, proceed to specialist evaluation; negative serology does not always exclude CD.

5.3 Upper GI endoscopy and duodenal biopsy

In adults, biopsy confirmation is generally recommended. Obtain multiple samples because lesions may be patchy:

• At least four biopsies from the distal duodenum.

• One to two biopsies from the duodenal bulb, according to local protocol.

• Ensure correct orientation and histopathological assessment.

5.4 Histopathology

• Increased intraepithelial lymphocytes.

• Crypt hyperplasia.

• Partial or total villous atrophy.

• Variable inflammatory infiltrate in the lamina propria.

Modified Marsh type	Finding
0	Normal mucosa
1	Increased intraepithelial lymphocytes
2	Increased intraepithelial lymphocytes with crypt hyperplasia
3a	Partial villous atrophy
3b	Subtotal villous atrophy
3c	Total villous atrophy

Isolated intraepithelial lymphocytosis is not specific for CD; interpret histology alongside serology, gluten exposure, and clinical context.

5.5 When can biopsy be omitted?

Children/adolescents: ESPGHAN 2020 permits a specialist-led no-biopsy pathway when tTG-IgA is ≥10× the assay-specific upper limit of normal and EMA-IgA is positive in a second blood sample, using appropriate validated assays. HLA-DQ2/DQ8 and symptoms are not obligatory criteria.

Adults: ACG 2023 recommends upper endoscopy with multiple duodenal biopsies for confirmation in most patients. A no-biopsy approach should not be generalized from the paediatric pathway.

5.6 Role of HLA typing

HLA-DQ2/DQ8 is not a routine first-line test.

• Consider it when serology and histology are discordant, the patient has already restricted gluten, the original diagnosis is uncertain, or selected potential/seronegative cases require diagnostic clarification.

• A negative result is useful for exclusion; a positive result is common and does not confirm CeD.

5.7 Adult diagnostic pathway — 2025 ESsCD update

Step	Action
1	Keep the patient on a gluten-containing diet during diagnostic testing whenever possible.
2	Measure IgA anti-TG2/tTG-IgA and total IgA using a validated assay.
3	If IgA anti-TG2 is positive but <10× ULN, duodenal histology remains required for adult confirmation.
4	If IgA anti-TG2 is ≥10× ULN, a no-biopsy pathway may be considered in selected adults <45 years in secondary care, with confirmation in a second blood sample and shared decision-making.
5	If biopsy is performed, obtain at least four biopsies from the second part of the duodenum; include bulb biopsies according to the updated ESsCD protocol.
6	Interpret serology, histology, clinical context and gluten exposure together; do not diagnose from HLA positivity alone.
PRACTICAL ADULT NO-BIOPSY PATHWAY • Age <45 years + compatible clinical context. • IgA anti-TG2 ≥10× ULN using a validated assay. • Repeat/confirm positive serology on a second blood sample while still consuming gluten. • Decision made in secondary care with shared decision-making. • Endoscopy remains appropriate when red flags, diagnostic uncertainty, low-titre serology, discordant findings or other indications are present.

5.8 Diagnostic pitfalls

• Do not diagnose CeD from a positive HLA-DQ2/DQ8 result alone.

• Do not interpret isolated Marsh-I/IEL increase as diagnostic.

• Do not assume negative serology excludes CeD in IgA deficiency or selected seronegative enteropathy.

• Do not begin a gluten-free diet before diagnostic testing if it can reasonably be avoided.

• Do not generalise the paediatric no-biopsy pathway to every adult.

6. BASELINE ASSESSMENT

Assessment	Purpose
CBC, ferritin, iron profile	Anaemia and iron deficiency
Folate, vitamin B12	Haematinic deficiencies
Calcium, phosphate, ALP, 25-OH vitamin D	Bone/mineral abnormalities
Liver function tests	Associated aminotransferase abnormalities
Albumin, electrolytes	Severe malabsorption/nutritional status
Weight, BMI; growth/puberty in children	Nutritional and developmental baseline
Bone mineral density	Selected patients with fracture risk, severe malabsorption, or osteoporosis concern
Thyroid testing	When clinically indicated or autoimmune thyroid disease is suspected

Individualize additional investigations according to age, symptoms, severity, and comorbidity.

7. MANAGEMENT

7.1 Lifelong strict gluten-free diet

Dietary exclusion of wheat, barley, and rye is the cornerstone of treatment. Prevent cross-contamination during storage, preparation, and food service.

• Naturally gluten-free options include rice, maize, potatoes, pulses, fruits, vegetables, milk, eggs, meat, and fish, provided they are not contaminated.

• In Indian diets, rice, jowar, and bajra can be useful alternatives.

• Wheat atta, maida, suji, and conventional daliya are not suitable for a strict gluten-free diet.

• Only certified gluten-free oats should be recommended. The 2025 ESsCD guideline considers certified gluten-free oats safe for most adults and allows inclusion from diagnosis; a small minority may have avenin-related symptoms.

7.2 Dietitian and nutritional care

• Correct documented deficiencies: iron, folate, vitamin B12, vitamin D, calcium, and others as indicated.

• Severe malnutrition requires individualized nutritional rehabilitation.

Routine corticosteroids or immunosuppressants are not indicated for uncomplicated newly diagnosed CD.

7.3 Functional asplenia and vaccination

Consider functional asplenia in appropriate patients, particularly those with complicated disease. Updated ESsCD guidance recommends pneumococcal vaccination for adults with evidence of functional asplenia, concurrent autoimmune disorders or refractory CeD type II, and for adults older than 65 years, according to the applicable national immunisation schedule.

8. RESPONSE AND FOLLOW-UP

Parameter	Expected course / action
Symptoms	Often improve over weeks; persistent symptoms require review
tTG-IgA	Usually declines over months; interpret trend in context
Nutritional deficiencies	Correct with treatment and mucosal recovery
Mucosal healing	May take months to years, particularly in adults

Timing	Review
At diagnosis	Symptoms, weight, dietary baseline, serology, deficiencies
3–6 months	Symptoms, adherence, weight, relevant laboratory abnormalities
6–12 months	Clinical response, serology trend, correction of deficiencies
Annually	Symptoms, weight, dietary review, relevant labs and associated conditions

Individualize follow-up for children, severe malabsorption, pregnancy, persistent deficiencies, or poor response. Clinical improvement alone does not prove mucosal healing.

Repeat biopsy is not required routinely in every asymptomatic patient. Consider it for persistent symptoms, persistent serological abnormalities despite verified adherence, unexplained deficiencies, or suspected ongoing enteropathy; selected adults may undergo biopsy to document healing.

9. NON-RESPONSIVE COELIAC DISEASE

Persistent or recurrent symptoms despite a gluten-free diet should trigger a structured reassessment. Severe or progressive symptoms warrant earlier investigation rather than waiting for a fixed interval.

Step	Action
1. Reconfirm	Review original serology, histology, clinical phenotype and whether the patient was consuming gluten at diagnosis.
2. Verify GFD	Experienced dietitian review for hidden gluten, cross-contamination, food labelling and dietary adequacy; use serology and, where available/appropriate, gluten immunogenic peptide testing as supportive evidence.
3. Check consequences	Assess weight, CBC, ferritin/iron, folate, B12, vitamin D, calcium and other deficiencies as indicated.
4. Search for alternatives	IBS/functional dyspepsia, lactose/fructose intolerance, microscopic colitis, IBD, infection, SIBO, pancreatic exocrine insufficiency and drug-induced enteropathy.
5. Assess mucosa	Upper GI endoscopy with duodenal biopsies when persistent enteropathy or another indication is suspected.
6. Escalate	If villous atrophy persists despite verified adherence, refer to an expert centre and evaluate for refractory CeD and other enteropathies.

 Differential diagnosis of persistent symptoms

Cause	Examples / evaluation
Ongoing gluten exposure	Hidden gluten, cross-contamination; expert dietitian assessment
Functional disorders	IBS, functional dyspepsia
Intestinal disorders	Microscopic colitis, inflammatory bowel disease
Malabsorption	Exocrine pancreatic insufficiency; consider PERT if confirmed
Infection / dysbiosis	SIBO; selected infections
Carbohydrate intolerance	Lactose or fructose intolerance
Alternative enteropathy	Drug-induced enteropathy including olmesartan, CVID, autoimmune enteropathy, tropical sprue
Other	Consider malignancy/complication when clinically indicated

10. REFRACTORY COELIAC DISEASE

Refractory CD (RCD) is rare. Consider it only after confirming the original diagnosis and excluding ongoing gluten exposure and other causes of persistent enteropathy. It is characterized by persistent/recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, generally for ≥12 months.

Subtype	Defining feature
RCD type I	No aberrant clonal intraepithelial lymphocyte population
RCD type II	Aberrant clonal intraepithelial lymphocyte population; higher risk of enteropathy-associated T-cell lymphoma

• Refer to a specialist centre; obtain expert histopathology review.

• Use immunophenotyping, flow cytometry, and T-cell receptor clonality studies when indicated.

• Assess for ulcerative jejunoileitis and enteropathy-associated T-cell lymphoma.

• Provide nutritional support; treatment (including corticosteroids or other agents) should be specialist-directed.

11. COMPLICATIONS

• Iron-deficiency anaemia and other nutritional deficiencies.

• Osteopenia, osteoporosis, and fractures.

• Growth failure and delayed puberty in children.

• Reproductive complications and associated autoimmune disorders.

• Persistent enteropathy and, rarely, refractory disease.

• Enteropathy-associated T-cell lymphoma, particularly in RCD; small-bowel adenocarcinoma is uncommon.

The absolute malignancy risk is low. CD alone does not justify cancer screening beyond established age- and risk-appropriate recommendations.

12. IMPORTANT DIFFERENTIALS

Condition	Clues / evaluation
Tropical sprue	Epidemiological context, nutritional deficiencies, response to appropriate treatment
Giardiasis	Stool antigen/PCR or other appropriate testing
Common variable immunodeficiency	Immunoglobulin abnormalities, recurrent infections
Autoimmune enteropathy	Clinical context and specialized histology
Drug-induced enteropathy	Medication history, particularly olmesartan and other implicated drugs
Crohn disease	Clinical, endoscopic, histological, and imaging findings
Non-coeliac gluten sensitivity	No coeliac autoimmunity or characteristic enteropathy; diagnosis of exclusion

13. REFERENCES

1. Al-Toma A, Zingone F, Branchi F, et al. European Society for the Study of Coeliac Disease 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 1: Diagnostic Approach. United European Gastroenterology Journal. 2025;13(10):1–32. doi:10.1002/ueg2.70119.
2. Al-Toma A, Branchi F, Zingone F, et al. European Society for the Study of Coeliac Disease 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 2: Management, Follow-Up, and Complex Disease Courses. United European Gastroenterology Journal. 2026;14(2):e70195. doi:10.1002/ueg2.70195.
3. Penny HAShiha MG, Raju SA, et al. The 2026 British Society of Gastroenterology guidelines on the diagnosis and management of adult coeliac disease. Gut. 2026. doi:10.1136/gutjnl-2025-337747.
4. Rubio-Tapia A, Hill ID, Semrad C, et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2023;118(1):59–76. doi:10.14309/ajg.0000000000002075.
5. Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 22nd ed. McGraw Hill; 2025. Chapter 336: Disorders of Absorption
6. Chung RT, Rubin DT, Wilcox CM, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 12th ed. Elsevier; 2026. Chapter 109: Celiac Disease.