Coeliac Disease (Adult)

1. Topic Overview

Summary

Coeliac disease is a chronic, immune-mediated enteropathy triggered by the ingestion of dietary gluten in genetically susceptible individuals who carry the HLA-DQ2 or HLA-DQ8 haplotype. [1,2] The disease is characterised by a T-cell mediated inflammatory response to gluten-derived peptides, particularly gliadin, leading to small intestinal mucosal damage with villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. [3] This results in malabsorption of macro- and micronutrients with consequent nutritional deficiencies.

The global prevalence is approximately 1% of the population, though the majority of cases remain undiagnosed due to the heterogeneous clinical presentation. [4] While classical coeliac disease presents with gastrointestinal symptoms including chronic diarrhoea, steatorrhoea, and weight loss, the majority of adult patients now present with non-classical or "silent" disease manifesting as iron deficiency anaemia, osteoporosis, elevated transaminases, or neurological symptoms. [5]

Diagnosis requires serological testing with tissue transglutaminase IgA antibodies (tTG-IgA) as the first-line investigation, followed by confirmatory duodenal biopsy demonstrating villous atrophy while the patient is consuming a gluten-containing diet. [6] Treatment is a strict, lifelong gluten-free diet (GFD) which leads to clinical, serological, and histological remission in the majority of patients. [7] Untreated coeliac disease is associated with significant morbidity including osteoporotic fractures, infertility, and a two- to four-fold increased risk of malignancy, particularly enteropathy-associated T-cell lymphoma (EATL). [8]

Key Facts

Clinical Pearls

"Must Be Eating Gluten" Rule: Both serology AND biopsy are only valid if the patient is currently consuming a gluten-containing diet (minimum 6 weeks, ideally 6-8 weeks of ≥10g gluten/day). Recommending a GFD before investigations are complete causes false negatives and diagnostic difficulty. [6]

IgA Deficiency Trap: Selective IgA deficiency occurs in 2-3% of coeliac patients (10-15 times more common than in the general population). If total IgA is low (less than 0.07 g/L), tTG-IgA will be falsely negative. Request IgG-based tests: tTG-IgG or deamidated gliadin peptide IgG (DGP-IgG). [9]

Think Beyond the Gut: The majority of adult patients present with extraintestinal manifestations rather than classical GI symptoms. Screen for coeliac in unexplained iron deficiency anaemia, osteoporosis/osteomalacia, persistently elevated transaminases, recurrent miscarriage, or neurological symptoms including peripheral neuropathy and ataxia. [5]

Biopsy Orientation Matters: At least four duodenal biopsies (two from D1 and two from D2) are required, as villous atrophy can be patchy. Proper orientation of biopsies is essential for accurate histological assessment. [10]

Why This Matters Clinically

Coeliac disease represents one of the most common autoimmune conditions globally, yet remains significantly underdiagnosed due to its protean manifestations. [4] Early diagnosis and treatment with a gluten-free diet prevents serious long-term complications including osteoporotic fractures, infertility, and malignancy. [8] The disease has significant implications for quality of life, requiring lifelong dietary modification and ongoing monitoring. Understanding the pathophysiology, diagnostic approach, and management of coeliac disease is essential for all clinicians, particularly those in gastroenterology, primary care, and internal medicine.

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2. Epidemiology

Incidence & Prevalence

The epidemiology of coeliac disease has been transformed by serological screening, revealing a much higher prevalence than historically appreciated. [4]

Regional Variation:

• Highest prevalence in Europe, North America, Middle East, and North Africa
• Lower prevalence in East Asia (related to lower wheat consumption and HLA-DQ2/DQ8 frequency)
• Saharawi population (Western Sahara) has the highest reported prevalence globally (5.6%)
• Prevalence increasing in developing countries with "westernisation" of diet [4]

Demographics

Risk Factors

Genetic Factors (Essential but Not Sufficient):

Family History:

Associated Conditions (Screen for Coeliac Disease):

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3. Pathophysiology

Overview of Disease Mechanism

Coeliac disease results from a complex interplay between genetic susceptibility (HLA-DQ2/DQ8), environmental trigger (dietary gluten), and an aberrant immune response leading to intestinal damage. [2,3] The pathophysiology involves both adaptive immunity (CD4+ T-cell mediated) and innate immunity (intraepithelial lymphocyte activation).

Step-by-Step Pathogenic Mechanism

Exam Detail: Step 1: Gluten Ingestion and Partial Digestion

Gluten is a storage protein found in wheat, barley, and rye. It comprises two main fractions:

• Gliadin (alcohol-soluble; prolamins) — immunogenic fraction
• Glutenin (alcohol-insoluble)

Gliadin is rich in proline and glutamine residues, making it resistant to complete digestion by gastric, pancreatic, and brush border enzymes. Partially digested gliadin peptides, particularly the 33-mer peptide from α-gliadin, remain intact in the intestinal lumen and are highly immunogenic. [3]

Key immunogenic peptides:

• α-gliadin 57-73: Primary T-cell epitope
• α-gliadin 33-mer (p56-88): Contains multiple overlapping epitopes
• γ-gliadin and ω-gliadin peptides: Additional epitopes

Step 2: Epithelial Permeability and Peptide Translocation

Gliadin peptides cross the intestinal epithelium via:

1. Paracellular transport: Gliadin triggers zonulin release from enterocytes, increasing tight junction permeability [11]
2. Transcellular transport: Retro-transcytosis via secretory IgA-CD71 (transferrin receptor) pathway
3. Direct epithelial damage: Gliadin peptides (particularly p31-43) directly activate innate immune responses in enterocytes, inducing IL-15 production

Zonulin Pathway:

• Gliadin binds to CXCR3 on enterocytes
• Triggers MyD88-dependent zonulin release
• Zonulin disrupts tight junction proteins (ZO-1, occludin)
• Increases paracellular permeability
• Allows larger gliadin peptides to access lamina propria [11]

Step 3: Deamidation by Tissue Transglutaminase (tTG)

Tissue transglutaminase (tTG2), a ubiquitous enzyme in the lamina propria, plays a central role:

1. Deamidation: tTG converts glutamine residues in gliadin peptides to negatively charged glutamic acid
2. Enhanced HLA binding: Deamidated gliadin peptides have dramatically increased affinity for HLA-DQ2/DQ8 molecules (10-fold increase)
3. Crosslinking: tTG can crosslink gliadin to itself, creating tTG-gliadin complexes

This deamidation step explains why antibodies to tTG (anti-tTG) are generated and serve as the primary diagnostic marker. [3]

Step 4: Antigen Presentation and Adaptive Immune Response

Deamidated gliadin peptides are presented by antigen-presenting cells (dendritic cells, macrophages, B-cells) via HLA-DQ2 or HLA-DQ8 molecules to CD4+ T-helper cells in the lamina propria.

HLA-DQ2 Molecule:

• Preferentially binds negatively charged peptides at positions P4, P6, P7
• Deamidation creates optimal binding motif
• Present in 90-95% of coeliac patients
• DQ2.5 (cis or trans) confers highest risk

HLA-DQ8 Molecule:

• Alternative presenter in DQ2-negative patients
• Binds deamidated gliadin with different position preferences
• Present in 5-10% of patients

Step 5: T-Cell Activation and Inflammatory Cascade

Activated gluten-specific CD4+ T-cells drive the pathological response:

Cytokine Production:

• IFN-γ: Principal pro-inflammatory cytokine; activates macrophages, induces epithelial damage
• IL-21: Amplifies Th1 response; enhances IFN-γ production; activates NK and cytotoxic cells
• IL-17: Contributes to inflammatory milieu
• TNF-α: Pro-inflammatory; epithelial damage

B-Cell Activation: B-cells recognise tTG-gliadin complexes through their B-cell receptor, receive T-cell help, and differentiate into plasma cells producing:

• Anti-tTG antibodies (diagnostic)
• Anti-endomysial antibodies (EMA) — recognise tTG in smooth muscle
• Anti-deamidated gliadin peptide (DGP) antibodies

Step 6: Innate Immune Activation and Intraepithelial Lymphocytosis

Parallel to the adaptive response, innate immunity contributes to epithelial damage:

IL-15 Axis:

• Gliadin peptide p31-43 directly activates enterocytes to produce IL-15
• IL-15 acts on intraepithelial lymphocytes (IELs) expressing NKG2D receptor
• Stressed enterocytes upregulate MICA/MICB (NKG2D ligands)
• NKG2D-MICA interaction triggers cytotoxic killing of enterocytes by IELs

Intraepithelial Lymphocyte (IEL) Changes:

• Normal: less than 25 IELs per 100 enterocytes
• Coeliac: > 25 IELs per 100 enterocytes (Marsh 1+)
• IELs are predominantly CD3+ CD8+ γδ T-cells and cytotoxic αβ T-cells
• In refractory coeliac disease type 2: aberrant IEL clone (CD3+ CD8- with clonal TCR rearrangement)

Step 7: Mucosal Damage — Villous Atrophy

The combined effects of adaptive and innate immune activation result in:

1. Crypt hyperplasia: Increased epithelial proliferation in crypts (compensatory)
2. Villous atrophy: Loss of villous height from apoptosis of mature enterocytes
3. Reduced absorptive surface: Results in malabsorption
4. Inflammatory infiltrate: Lymphocytes, plasma cells in lamina propria

Marsh Classification of Histological Changes

The Marsh classification (modified Marsh-Oberhuber) grades the severity of mucosal damage: [10]

Important Notes:

• Marsh 3 is required for definitive diagnosis in adults
• Marsh 1-2 requires positive serology + clinical correlation for diagnosis
• Patchy distribution: at least 4 biopsies required (2 from D1, 2 from D2)
• Proper orientation essential; tangential cuts mimic villous atrophy

Consequences of Villous Atrophy

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4. Clinical Presentation

Clinical Phenotypes

Coeliac disease presentation has evolved, with non-classical presentations now predominating in adults: [5]

Gastrointestinal Symptoms (Classical Presentation)

Extraintestinal Manifestations (Non-Classical Presentation)

Exam Detail: Haematological:

Metabolic Bone Disease:

Hepatic:

Dermatological:

Neurological:

Reproductive:

Other:

Signs on Examination

General Inspection:

• May appear entirely normal
• Pallor (anaemia)
• Low body mass index or weight loss (severe cases)
• Short stature (undiagnosed childhood coeliac)
• Muscle wasting (severe malabsorption)

Specific Signs:

Red Flags

[!CAUTION] Red Flags Requiring Urgent Attention:

• Refractory coeliac disease: Persistent symptoms and villous atrophy despite strict GFD for > 12 months
• Unexplained weight loss with documented dietary compliance
• New abdominal mass or palpable lymphadenopathy (lymphoma risk)
• Gastrointestinal bleeding: Haematemesis, melaena, overt rectal bleeding
• Bowel perforation or obstruction symptoms
• Rapid clinical deterioration after initial improvement on GFD
• Progressive neurological symptoms despite treatment
• Severe malnutrition or hypoalbuminaemia

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5. Differential Diagnosis

Primary Differential Diagnoses

Causes of Villous Atrophy Other Than Coeliac Disease

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6. Investigations

Diagnostic Algorithm

SUSPECTED COELIAC DISEASE
          ↓
┌─────────────────────────────────────────────────────────┐
│ STEP 1: CONFIRM PATIENT IS EATING GLUTEN               │
│                                                         │
│ • Minimum 6 weeks of gluten-containing diet             │
│ • ≥10g gluten/day (equivalent to 4 slices bread)        │
│ • If already on GFD: gluten challenge required          │
└─────────────────────────────────────────────────────────┘
          ↓
┌─────────────────────────────────────────────────────────┐
│ STEP 2: SEROLOGICAL TESTING                             │
│                                                         │
│ • tTG-IgA (first-line) + Total IgA                      │
│ • If IgA deficient: tTG-IgG or DGP-IgG                  │
└─────────────────────────────────────────────────────────┘
          ↓
    ┌─────────┴─────────┐
    ↓                   ↓
NEGATIVE            POSITIVE
    ↓                   ↓
Coeliac          ┌──────────────────────────────────────┐
unlikely*        │ STEP 3: DUODENAL BIOPSY               │
                 │                                        │
                 │ • OGD with ≥4 biopsies                 │
                 │ • 2 from D1, 2 from D2                 │
                 │ • Proper orientation for histology     │
                 └──────────────────────────────────────┘
                              ↓
                   ┌──────────┴──────────┐
                   ↓                      ↓
           MARSH 3 (VA+)           MARSH 0-2 (No VA)
                   ↓                      ↓
        ┌──────────────────┐    ┌──────────────────────┐
        │ COELIAC DISEASE   │    │ Consider:             │
        │ CONFIRMED         │    │ • Potential coeliac   │
        │                   │    │ • HLA-DQ2/DQ8 testing │
        │ Start GFD         │    │ • Repeat biopsy later │
        │ Dietitian referral│    │ • Alternative diagnoses│
        └──────────────────┘    └──────────────────────┘

* Consider IgA deficiency, seronegative coeliac (rare), or 
  gluten exclusion at time of testing

Serological Testing

Exam Detail: First-Line: tTG-IgA (Tissue Transglutaminase IgA)

Mechanism: Antibodies to tissue transglutaminase enzyme generated as part of the immune response to tTG-gliadin complexes.

False Positives:

• Autoimmune liver disease
• Inflammatory bowel disease
• Heart failure
• Other autoimmune conditions
• Transient in children with viral infections

False Negatives:

• IgA deficiency (2-3% of coeliac patients)
• Gluten-free diet at time of testing
• Young children (less than 2 years) — may not yet mount antibody response
• Immunosuppressive therapy
• Early/mild coeliac disease

Total IgA Level:

• MUST be checked with tTG-IgA
• Selective IgA deficiency (less than 0.07 g/L) occurs in 2-3% of coeliac patients
• If IgA deficient: use IgG-based serology

Second-Line Tests:

HLA-DQ2/DQ8 Testing:

Serology in IgA Deficiency:

1. Check total IgA with tTG-IgA
2. If IgA less than 0.07 g/L: Request tTG-IgG and/or DGP-IgG
3. Both IgG-based tests recommended for optimal sensitivity

Histological Confirmation (Duodenal Biopsy)

Procedure Requirements:

• Upper GI endoscopy (OGD)
• Minimum 4 biopsies: 2 from duodenal bulb (D1), 2 from second part of duodenum (D2)
• Additional biopsies recommended (up to 6) as lesions can be patchy
• Proper orientation by histopathologist essential [10]

Histological Features of Coeliac Disease:

Immunohistochemistry (if needed):

• CD3 staining: Highlights IELs; count > 25/100 enterocytes
• γδ T-cell receptor staining: Increased in coeliac
• tTG deposits: Subepithelial deposits in early disease

Additional Investigations

Baseline Investigations at Diagnosis:

Bone Mineral Density (DEXA Scan):

• Recommended for all adults at diagnosis
• T-score ≤-1.0: Osteopenia; ≤-2.5: Osteoporosis
• Repeat in 1-2 years if abnormal; assess response to GFD and supplementation [12]

Imaging:

• Not routinely required
• Small bowel MRI/CT enterography: If complications suspected (lymphoma, strictures, ulcerative jejunitis)
• Findings in coeliac: Jejunisation of ileum, ilealisation of jejunum, mesenteric lymphadenopathy

Diagnostic Criteria

NICE NG20 (2015) — Adult Diagnosis: [6]

Diagnosis of coeliac disease requires:

1. Positive serology (tTG-IgA ± EMA) while on gluten-containing diet
2. Duodenal biopsy demonstrating villous atrophy (Marsh 3)

ESPGHAN Criteria (Children — Not Adults):

• In children with tTG-IgA > 10× upper limit of normal, positive EMA, positive HLA-DQ2/DQ8, and symptoms: biopsy may be omitted
• This "no-biopsy" pathway is NOT recommended for adults

Seronegative Coeliac Disease:

• Rare (less than 5% of cases)
• Villous atrophy on biopsy with negative serology
• Exclude other causes of villous atrophy
• HLA-DQ2/DQ8 positive
• Response to GFD supports diagnosis

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7. Management

Management Overview

CONFIRMED COELIAC DISEASE
          ↓
┌─────────────────────────────────────────────────────────┐
│ IMMEDIATE MANAGEMENT                                    │
├─────────────────────────────────────────────────────────┤
│ 1. Dietitian Referral (Essential)                       │
│ 2. Start Gluten-Free Diet (GFD)                         │
│ 3. Correct Nutritional Deficiencies                     │
│ 4. DEXA Scan (Bone Mineral Density)                     │
│ 5. Vaccinations (Pneumococcal for hyposplenism)         │
│ 6. Patient Education and Support                        │
└─────────────────────────────────────────────────────────┘
          ↓
┌─────────────────────────────────────────────────────────┐
│ ONGOING MONITORING                                      │
├─────────────────────────────────────────────────────────┤
│ • Annual clinical review                                │
│ • Serology: tTG-IgA (should normalise 6-12 months)      │
│ • FBC, ferritin, folate, B12, calcium, vitamin D, LFTs  │
│ • Dietitian review as needed                            │
│ • DEXA repeat if osteopenia/osteoporosis detected       │
└─────────────────────────────────────────────────────────┘
          ↓
┌─────────────────────────────────────────────────────────┐
│ IF NOT RESPONDING TO GFD (After 6-12 months)            │
├─────────────────────────────────────────────────────────┤
│ 1. Assess dietary compliance (dietitian review)         │
│ 2. Consider inadvertent gluten exposure                 │
│ 3. Repeat biopsy to assess histological response        │
│ 4. Exclude alternative diagnoses                        │
│ 5. If truly refractory: Specialist referral             │
└─────────────────────────────────────────────────────────┘

Gluten-Free Diet (GFD)

Principle: Complete, lifelong avoidance of gluten is the only effective treatment. [7]

Exam Detail: Gluten-Containing Cereals (MUST AVOID):

Controversial: Oats

• Pure, uncontaminated oats tolerated by most coeliac patients (> 95%)
• Avenin (oat prolamin) is immunogenic in a minority
• Cross-contamination with wheat is common in commercial oats
• Recommendation: Avoid initially; reintroduce pure oats after symptoms settle (if tolerated)
• Maximum 50-70g/day of pure, uncontaminated oats [13]

Naturally Gluten-Free Foods:

Gluten-Free Threshold:

• Codex Alimentarius standard: less than 20 ppm gluten to be labelled "gluten-free"
• This level is safe for the vast majority of coeliac patients
• Cross-contamination: Major concern; separate preparation surfaces, utensils [14]

Practical Challenges:

• Hidden gluten: Sauces, gravies, soups, processed foods, medications
• Eating out: Risk of cross-contamination
• Social situations: Difficult to maintain strict adherence
• Cost: Gluten-free products often more expensive
• Nutritional adequacy: Risk of low fibre, high fat if relying on processed GF foods

Prescribable Gluten-Free Foods (UK NHS):

• Gluten-free bread, flour, pasta
• Availability varies by region
• Prescription options being reduced in some areas

Dietitian Referral

Essential for all newly diagnosed patients. [7]

Dietitian Role:

1. Education on gluten-free diet
2. Label reading skills
3. Avoiding cross-contamination
4. Nutritional adequacy assessment
5. Identifying hidden sources of gluten
6. Practical meal planning
7. Assessing compliance
8. Addressing psychosocial impact

Follow-up:

• Initial intensive support (multiple sessions)
• Ongoing access as needed
• Particularly important if non-responsive or struggling with adherence

Nutritional Supplementation

Iron:

• If iron deficiency: Oral iron (ferrous sulphate 200mg TDS or equivalent)
• Check ferritin at 3-4 months
• If not responding: Consider IV iron, reassess compliance
• Usually corrects with GFD alone in mild deficiency

Calcium and Vitamin D:

• If deficient or osteopenia/osteoporosis:
  • Calcium 1000-1200mg/day (diet + supplements)
  • Vitamin D 800-2000 IU/day (colecalciferol)
• Correct severe deficiency with loading dose
• Bone-specific treatment (bisphosphonates) if osteoporosis and fracture risk

Folate and B12:

• Correct deficiency with supplementation
• Folate 5mg daily until corrected
• B12: Oral if dietary deficiency; IM if malabsorption/severe

Zinc and Copper:

• Replace if symptomatic deficiency
• Zinc supplementation if deficient (consider acrodermatitis enteropathica-like picture)

Vaccination

Pneumococcal Vaccination (Essential): [15]

• Functional hyposplenism in 30-50% of coeliac patients
• Increased risk of encapsulated organism infection (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis)
• Recommendation:
  • "Pneumococcal polysaccharide vaccine (PPV23): All adults at diagnosis"
  • "Pneumococcal conjugate vaccine (PCV13): Consider in high-risk"
  • Booster every 5 years

Other Vaccinations:

• Haemophilus influenzae type b (Hib): If not vaccinated
• Meningococcal vaccine: Consider in high-risk
• Annual influenza vaccine: Recommended
• Ensure up-to-date with routine vaccinations

Follow-Up and Monitoring

Annual Review Components:

Expected Response to GFD:

• Symptomatic improvement: Weeks to months
• Serological normalisation: 6-12 months (tTG-IgA)
• Histological recovery: Variable; may take 2-5 years in adults
• Complete mucosal healing occurs in 60-80% at 2 years

Repeat Biopsy:

• Not routinely required if clinical and serological response
• Consider if: Non-responsive, high-risk complications, unclear initial diagnosis
• Some centres repeat at 1-2 years to confirm healing

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8. Refractory Coeliac Disease

Definition

Refractory coeliac disease (RCD) is defined as persistent or recurrent symptoms and villous atrophy despite strict adherence to a gluten-free diet for at least 12 months, in the absence of other causes. [16]

Prevalence: 1-2% of coeliac patients

Classification

Assessment

Confirm True Refractory Disease:

1. Verify strict dietary compliance (dietitian assessment, GIP testing)
2. Exclude inadvertent gluten exposure
3. Exclude other diagnoses (microscopic colitis, SIBO, lactose intolerance, pancreatic insufficiency)
4. Repeat duodenal biopsy: Confirm persistent villous atrophy
5. Review original diagnosis (was it definitely coeliac?)

Investigations for RCD:

• Small bowel MRI/CT enterography: Exclude lymphoma, strictures
• Capsule endoscopy: Assess small bowel mucosa
• IEL immunophenotyping: Flow cytometry for CD3, CD8, TCR
• TCR gene rearrangement: Clonality assessment (PCR)
• PET-CT: If lymphoma suspected

Management

RCD Type 1:

• Strict GFD reinforcement
• Nutritional support (TPN if severe)
• Immunosuppression:
  • Budesonide (9mg daily; topically acting corticosteroid)
  • Prednisolone (if budesonide insufficient)
  • Azathioprine or 6-mercaptopurine (steroid-sparing)
• Prognosis: Generally good with treatment

RCD Type 2:

• Specialist centre management essential
• High risk of progression to EATL
• Treatment options:
  • Corticosteroids (prednisolone)
  • Azathioprine/6-MP
  • Cladribine (purine analogue)
  • Autologous stem cell transplantation (investigational)
  • Anti-IL-15 antibodies (investigational)
• Close surveillance for lymphoma (regular imaging, PET-CT)

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9. Complications

Nutritional Complications

Malignancy

Enteropathy-Associated T-Cell Lymphoma (EATL): [8,17]

Other Malignancies:

Protective Effect of GFD:

• Strict adherence to GFD reduces malignancy risk toward general population
• Risk reduction takes 3-5 years of strict adherence

Dermatitis Herpetiformis

Definition: Cutaneous manifestation of coeliac disease characterised by intensely pruritic papulovesicular eruption. [18]

Dapsone:

• Rapid symptom relief (24-48 hours)
• Does not treat underlying enteropathy
• Dose: 50-150mg daily
• Side effects: Methaemoglobinaemia, haemolysis (check G6PD), agranulocytosis
• Aim to wean off once GFD controls symptoms (6-24 months)

Hyposplenism

Prevalence: 30-50% of coeliac patients

Mechanism: Lymphoid depletion, altered splenic function

Evidence of Hyposplenism:

• Howell-Jolly bodies on blood film (nuclear remnants in RBCs)
• Acanthocytes
• Target cells
• Reduced splenic size on imaging

Clinical Significance:

• Increased susceptibility to encapsulated organisms
• Risk of overwhelming post-splenectomy-like infection (OPSI)
• Organisms: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis

Management:

• Pneumococcal vaccination (PPV23) essential
• Consider Hib and meningococcal vaccines
• Patient education on infection risk
• Early antibiotic therapy for febrile illness

Neurological Complications

Other Complications

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10. Prognosis & Outcomes

Natural History

Untreated Coeliac Disease:

• Progressive malnutrition and nutritional deficiencies
• Increased morbidity: Osteoporotic fractures, anaemia, subfertility
• Increased mortality: Standardised mortality ratio (SMR) 1.2-1.4 [8]
• Malignancy risk: 2-4 fold increased (particularly EATL)
• Quality of life: Significantly impaired

Outcomes with Treatment (Gluten-Free Diet)

Prognostic Factors

Good Prognosis:

• Early diagnosis (younger age at diagnosis in adults)
• Strict dietary compliance
• Classical presentation (often responds well)
• Serological and histological normalisation
• Absence of complications at diagnosis
• Good nutritional status

Poor Prognosis:

• Delayed diagnosis (older age, long duration of untreated disease)
• Refractory coeliac disease (particularly Type 2)
• Non-adherence to GFD
• Severe malnutrition at presentation
• Development of EATL or other malignancy
• Neurological complications (may be irreversible)

Adherence Rates

Adherence Monitoring:

• Clinical assessment: Symptom recurrence
• Serological: Rising tTG-IgA suggests gluten exposure
• Dietitian interview: Detailed dietary history
• Gluten immunogenic peptides (GIP): Urine/stool testing detects recent gluten ingestion (research/emerging tool)

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11. Prevention & Screening

Primary Prevention

No proven strategies to prevent coeliac disease development. Previous theories about timing of gluten introduction have not been supported by evidence. [20]

Factors NOT Shown to Prevent Coeliac Disease:

• Delayed introduction of gluten beyond 6 months
• Early introduction of gluten at 4 months
• Breastfeeding (may delay onset but does not prevent)
• Probiotics during infancy

Screening Recommendations

Who to Screen: [6]

Population Screening:

• Not currently recommended
• Rationale: Majority of screen-detected cases are asymptomatic; benefit of GFD in silent disease uncertain; dietary burden
• May change as evidence evolves

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12. Emerging Therapies & Research

Investigational Therapies

Exam Detail: | Therapy | Mechanism | Development Stage | |---------|-----------|-------------------| | Latiglutenase | Glutenase enzyme; digests gluten in stomach | Phase 2b; adjunct to GFD | | Larazotide acetate | Tight junction regulator; prevents zonulin-mediated permeability | Phase 3; reduces symptoms | | Nexvax2 | Peptide vaccine; induces tolerance to gluten | Discontinued 2019 (failed Phase 2) | | Anti-IL-15 antibodies | Blocks IL-15 axis; reduces IEL activation | Early phase for RCD | | Transglutaminase inhibitors | Prevents deamidation of gliadin | Preclinical | | Gluten sequestrants | Polymer binds gluten in gut; prevents absorption | Early phase | | CAR-T cells | Targeting aberrant IELs in RCD Type 2 | Investigational |

Key Points:

• No approved pharmacological alternatives to GFD
• Investigational therapies likely to be adjuncts, not replacements
• GFD will remain mainstay for foreseeable future
• RCD Type 2 has most urgent need for novel therapies

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13. Key Guidelines

Major Guidelines

Summary of Key Recommendations

1. Diagnosis: tTG-IgA + total IgA; confirm with duodenal biopsy while on gluten
2. Treatment: Strict lifelong GFD; dietitian essential
3. Monitoring: Annual review with serology and bloods
4. Bone health: DEXA at diagnosis for adults
5. Vaccination: Pneumococcal (hyposplenism)
6. Screening: Target high-risk groups
7. Refractory disease: Specialist referral; exclude RCD Type 2

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14. Viva Preparation

Opening Statement

Viva Point: "Coeliac disease is a chronic, immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals carrying HLA-DQ2 or DQ8. It affects approximately 1% of the population and causes small intestinal villous atrophy leading to malabsorption. Diagnosis requires positive serology with tTG-IgA and confirmatory duodenal biopsy while on a gluten-containing diet. Treatment is a strict lifelong gluten-free diet."

Common Viva Questions and Model Answers

Q: What is the pathophysiology of coeliac disease?

A: "Coeliac disease results from an immune response to gluten-derived peptides in genetically susceptible individuals. Gliadin peptides cross the intestinal epithelium and are deamidated by tissue transglutaminase, creating negatively charged peptides that bind strongly to HLA-DQ2 or DQ8 molecules. These are presented to CD4+ T-cells, triggering a Th1 response with IFN-gamma and IL-21 production. This leads to villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. B-cells produce anti-tTG and anti-endomysial antibodies. The innate immune response via IL-15 further amplifies epithelial damage."

Q: How would you diagnose coeliac disease?

A: "I would first ensure the patient is consuming a gluten-containing diet. I would request tTG-IgA as the first-line serological test along with total IgA level, as 2-3% of coeliac patients have IgA deficiency. If IgA deficient, I would use tTG-IgG or DGP-IgG. If serology is positive, I would arrange OGD with at least four duodenal biopsies, two from D1 and two from D2. Histology showing villous atrophy with increased intraepithelial lymphocytes, Marsh 3, confirms the diagnosis."

Q: A patient with coeliac disease is not responding to a gluten-free diet. How would you approach this?

A: "I would take a systematic approach. First, I would assess dietary compliance with detailed dietitian review, as inadvertent gluten exposure is the most common cause. If adherent, I would exclude other conditions such as lactose intolerance, microscopic colitis, small intestinal bacterial overgrowth, and pancreatic insufficiency. I would repeat serology; persistently elevated tTG suggests ongoing gluten exposure. I would repeat duodenal biopsy to confirm persistent villous atrophy. If truly refractory after 12 months of strict GFD, I would consider refractory coeliac disease and refer to a specialist centre for IEL phenotyping to distinguish Type 1 from Type 2, given the malignancy risk with Type 2."

Q: What are the complications of coeliac disease?

A: "Complications include nutritional deficiencies, particularly iron, folate, B12, calcium, and vitamin D, leading to anaemia and metabolic bone disease. Osteoporosis affects 20-30% and increases fracture risk. There is a 6-10 fold increased risk of enteropathy-associated T-cell lymphoma, particularly in untreated or refractory disease. Dermatitis herpetiformis is the skin manifestation. Hyposplenism occurs in 30-50%, increasing infection risk with encapsulated organisms. Neurological complications include gluten ataxia and peripheral neuropathy. There is increased risk of subfertility and adverse pregnancy outcomes. Strict GFD reduces most of these risks."

Common Mistakes to Avoid

❌ Mistakes That Fail Candidates:

• Testing serology or taking biopsy when patient already on gluten-free diet
• Forgetting to check total IgA level with tTG-IgA
• Not taking sufficient biopsies (minimum 4, from D1 and D2)
• Missing the diagnosis in patients with extraintestinal manifestations
• Forgetting pneumococcal vaccination for hyposplenism
• Not referring to dietitian at diagnosis
• Failing to consider refractory coeliac disease in non-responders
• Not screening for associated conditions (thyroid, diabetes)
• Missing red flags suggesting malignancy

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15. Patient Information

What is Coeliac Disease?

Coeliac disease is a condition where your immune system reacts abnormally to gluten, a protein found in wheat, barley, and rye. When you eat gluten, your immune system attacks the lining of your small intestine, damaging it and making it difficult to absorb nutrients from food.

Why Does it Matter?

Without treatment, coeliac disease can cause:

• Anaemia (low iron levels) making you tired
• Weak bones (osteoporosis) increasing fracture risk
• Difficulty becoming pregnant
• Long-term, a slightly increased risk of some bowel cancers

The good news is that treatment is very effective. With a gluten-free diet, the gut heals and most people feel completely better.

How is it Treated?

Gluten-free diet for life:

• You need to completely avoid wheat, barley, and rye
• This means avoiding most breads, pasta, cereals, cakes, and biscuits unless specifically gluten-free
• Even small amounts of gluten can cause damage, even if you don't have symptoms

Safe foods include:

• Rice, potatoes, corn, quinoa
• Meat, fish, eggs
• Fruits and vegetables
• Milk, cheese, butter

You will receive:

• Referral to a dietitian who will teach you how to read food labels and avoid hidden gluten
• Blood tests to check for vitamin and mineral deficiencies
• A bone density scan to check bone health
• Vaccinations to protect against certain infections

What to Expect

• Symptoms often improve within weeks of starting a gluten-free diet
• Complete gut healing can take 1-2 years
• Annual blood tests and check-ups are important
• You will need to follow the diet for life

When to Seek Help

See your doctor if:

• Symptoms don't improve on the gluten-free diet
• You are losing weight unexpectedly
• You have new or worsening symptoms
• You are struggling to follow the diet

Support

• Coeliac UK (www.coeliac.org.uk) provides excellent resources and support
• Ask your GP about gluten-free foods available on prescription

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate guidelines and specialists for patient care.