Coeliac Disease in Adults

1. Clinical Overview

Summary

Coeliac disease is a chronic, immune-mediated systemic disorder triggered by dietary gluten in genetically predisposed individuals carrying HLA-DQ2 or HLA-DQ8 haplotypes. [1] Ingestion of gluten (specifically gliadin peptides from wheat, barley, and rye) initiates an adaptive immune response in the small intestinal mucosa, mediated by tissue transglutaminase (tTG)-modified gliadin peptides presented to CD4+ T cells via HLA-DQ2/DQ8 molecules. [2] This results in characteristic histological changes including villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis (Marsh classification), leading to malabsorption and a spectrum of gastrointestinal and extraintestinal manifestations. [3]

The clinical phenotype ranges from classic malabsorptive disease (diarrhoea, steatorrhoea, weight loss) to non-classic presentations (iron deficiency anaemia, osteoporosis, fatigue, infertility) or entirely silent disease detected through screening of at-risk groups. [4] Diagnosis requires a combination of positive serological markers (IgA anti-tissue transglutaminase antibodies) obtained while the patient is consuming gluten, confirmed by duodenal biopsy demonstrating villous atrophy. [5] Total IgA level must be checked concurrently, as 2-3% of coeliac patients have selective IgA deficiency requiring IgG-based testing. [6]

The only established treatment is a strict, lifelong gluten-free diet (GFD), which results in clinical improvement, serological normalisation, and mucosal healing in the majority of patients. [7] Expert dietitian input is essential for successful dietary management. Untreated or poorly controlled coeliac disease carries increased risks of osteoporosis, anaemia, infertility, and malignancy, most notably enteropathy-associated T-cell lymphoma (EATL). [8]

Key Facts

Clinical Pearls

IgA Deficiency Pearl: Selective IgA deficiency occurs in 2-3% of coeliac patients (10-15x higher than general population). ALWAYS check total IgA level with serology. If IgA deficient, use IgG-tTG or IgG-DGP antibodies. [6]

Gluten Challenge Pearl: Serological and histological findings require gluten exposure. Patients must consume gluten-containing diet for at least 6 weeks (ideally 3+ months with 10g gluten/day, equivalent to 4 slices bread) before testing. [5]

Dermatitis Herpetiformis Pearl: This is the pathognomonic cutaneous manifestation of coeliac disease. 100% of DH patients have coeliac enteropathy on biopsy (often subclinical). Skin biopsy shows granular IgA deposits at dermal papillae tips on direct immunofluorescence. [11]

Family Screening Pearl: First-degree relatives have 10% prevalence of coeliac disease; second-degree relatives 5%. HLA-DQ2/DQ8 testing can exclude coeliac in family members (negative predictive value > 99%). [12]

Bone Health Pearl: Osteoporosis/osteopenia affects 30-40% of newly diagnosed adults. All adults should have DEXA scan at diagnosis. Bone density improves with strict GFD and calcium/vitamin D supplementation. [13]

Oats Pearl: Pure, uncontaminated oats (certified less than 20ppm gluten) are tolerated by most (95%) coeliac patients and can be introduced after initial GFD stabilisation. Small minority develop avenin sensitivity. [14]

Why This Matters Clinically

Coeliac disease is one of the most common lifelong conditions, affecting approximately 1% of the global population, yet remains substantially underdiagnosed with an estimated 5:1 ratio of undiagnosed to diagnosed cases. [9] This "coeliac iceberg" phenomenon means that many patients experience years of preventable morbidity before diagnosis. A high index of suspicion and appropriate serological testing in at-risk groups transforms outcomes. Early diagnosis and strict dietary adherence prevent long-term complications including osteoporosis, anaemia, infertility, and the significantly increased risk of enteropathy-associated T-cell lymphoma. [8,15]

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2. Epidemiology

Prevalence and Incidence

The global seroprevalence of coeliac disease is approximately 1.4%, with biopsy-confirmed prevalence of 0.7%. [9] Prevalence varies geographically and has increased over time, attributed to genuine increases in incidence, improved diagnostic awareness, and better serological testing. [16]

Demographics

Risk Factors for Coeliac Disease

Environmental Factors

While HLA-DQ2/DQ8 is necessary for coeliac disease development, only 2-3% of HLA-DQ2/DQ8-positive individuals develop disease, indicating that environmental and non-HLA genetic factors are important. [10]

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3. Pathophysiology

Molecular Pathogenesis

The pathogenesis of coeliac disease involves a complex interplay between environmental triggers (gluten), genetic susceptibility (HLA-DQ2/DQ8), and immune dysregulation. [2,20]

Exam Detail: #### Step 1: Genetic Susceptibility (HLA-DQ2/DQ8)

The HLA class II molecules DQ2 and DQ8 are the strongest genetic risk factors for coeliac disease:

Key concept: DQ2.5 homozygotes have 5x higher risk than heterozygotes due to enhanced gluten peptide presentation. [10]

The HLA-DQ2/DQ8 molecules have peptide-binding grooves with preference for negatively charged amino acids at specific anchor positions, explaining their affinity for deamidated gliadin peptides. [20]

Step 2: Gluten Structure and Digestion

Gluten composition:

• Gliadin (monomeric, soluble) - primary immunogenic component
• Glutenin (polymeric, insoluble)

Gluten proteins are uniquely rich in proline and glutamine residues, making them resistant to complete proteolytic digestion by gastric, pancreatic, and brush border enzymes. [2] The resulting peptides (particularly the immunodominant 33-mer from alpha-gliadin) reach the lamina propria intact and are highly immunogenic.

Immunodominant peptides:

• α-gliadin 33-mer (residues 56-88): Contains multiple overlapping T-cell epitopes
• α-gliadin p31-43: Innate immune activator
• γ-gliadin and ω-gliadin peptides: Additional T-cell epitopes

Step 3: Intestinal Permeability and Peptide Entry

Gliadin peptides cross the intestinal epithelium via:

1. Transcellular transport: Via CD71 (transferrin receptor)-mediated transcytosis of IgA-gliadin complexes [20]
2. Paracellular transport: Via zonulin-mediated tight junction opening
3. Epithelial damage: During active inflammation

Zonulin pathway: Gliadin peptides bind to CXCR3 on enterocytes, triggering zonulin release and tight junction disassembly, increasing intestinal permeability. [2]

Step 4: Tissue Transglutaminase Modification

Tissue transglutaminase (tTG/TG2) is the key enzyme in coeliac pathogenesis:

The deamidation reaction converts neutral glutamine (Q) residues to negatively charged glutamic acid (E) residues at specific positions, creating peptides that bind with high affinity to the positively charged pockets of HLA-DQ2/DQ8. [2,20]

Key deamidation sites on α-gliadin 33-mer:

• Q65→E65
• Q72→E72
• Q80→E80

Step 5: Adaptive Immune Response

Antigen Presentation:

1. Dendritic cells in lamina propria capture deamidated gliadin peptides
2. Peptides loaded onto HLA-DQ2/DQ8 molecules
3. Presented to gliadin-specific CD4+ T cells

CD4+ T-Cell Response (Th1 dominant):

• Secretion of IFN-γ (primary effector cytokine)
• IL-21, IL-17 production
• Activation of cytotoxic pathways
• Help for B cells → antibody production

B-Cell Response:

• Production of anti-gliadin antibodies (AGA)
• Production of anti-tTG antibodies (tTG-IgA, tTG-IgG)
• Production of anti-endomysial antibodies (EMA)
• Anti-deamidated gliadin peptide antibodies (DGP)

Autoantibody generation: Anti-tTG antibodies arise because tTG becomes covalently linked to gliadin during deamidation, and B cells recognising gliadin-tTG complexes receive T-cell help from gliadin-specific T cells (hapten-carrier mechanism). [2]

Step 6: Innate Immune Response

In parallel with adaptive immunity, gliadin peptides (particularly p31-43) trigger innate immune responses:

IL-15 is the key innate cytokine, driving:

• Intraepithelial lymphocyte (IEL) expansion
• Upregulation of NKG2D on CD8+ IELs
• MICA/MICB stress molecule expression on enterocytes
• NK-like cytotoxicity independent of TCR recognition

This creates a "perfect storm" where adaptive immune recognition of gliadin combines with innate immune-mediated epithelial destruction. [20]

Step 7: Epithelial Damage and Villous Atrophy

The final common pathway involves:

1. Cytotoxic IELs: CD8+ αβ and γδ T cells kill enterocytes via perforin/granzyme
2. Apoptosis induction: Fas/FasL and MICA/NKG2D pathways
3. Matrix remodelling: MMPs degrade basement membrane
4. Crypt hyperplasia: Compensatory proliferation (increased crypt mitotic index)
5. Villous atrophy: Net loss of absorptive surface area

Histological Changes: Marsh-Oberhuber Classification

The Marsh classification, modified by Oberhuber, grades the severity of small intestinal damage: [3]

Marsh 3 (any subtype) = diagnostic of coeliac disease when combined with positive serology and clinical context.

Exam Detail: Histological features to identify:

• Intraepithelial lymphocytes (IELs): > 25 per 100 enterocytes; predominantly CD3+CD8+ T cells; also γδ T cells
• Crypt hyperplasia: Increased crypt depth, increased mitotic figures, crypt branching
• Villous atrophy: Reduced villous height:crypt depth ratio (normal > 3:1)
• Surface enterocyte changes: Loss of brush border, cuboidal rather than columnar cells
• Lamina propria inflammation: Increased plasma cells, lymphocytes

Villous height:crypt depth ratio:

• Normal: 3-5:1
• Partial villous atrophy (3a): 2-3:1
• Subtotal villous atrophy (3b): 1-2:1
• Total villous atrophy (3c): less than 1:1 or flat mucosa

Consequences of Villous Atrophy

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4. Clinical Presentation

Coeliac disease has a highly variable clinical phenotype. The Oslo definitions classify presentations into distinct categories: [1]

Classification of Clinical Presentations

Gastrointestinal Symptoms

Extraintestinal Manifestations

Exam Detail: #### Haematological | Manifestation | Frequency | Mechanism | |---------------|-----------|-----------| | Iron deficiency anaemia | 30-50% (most common adult presentation) | Duodenal iron malabsorption | | Folate deficiency | 20-40% | Jejunal folate malabsorption | | Vitamin B12 deficiency | 5-20% | Less common; terminal ileum usually spared | | Thrombocytosis | Variable | Reactive; iron deficiency | | Hyposplenism | 30-50% | Functional hyposplenism; mechanism unclear |

Bone and Metabolic

Neurological

Reproductive

Dermatological

Hepatic

Dental

Associated Autoimmune Conditions

Coeliac disease associates with numerous autoimmune conditions, sharing HLA and non-HLA genetic risk loci: [18]

Red Flags Requiring Urgent Assessment

[!CAUTION] Urgent referral and investigation required for:

• Severe, unexplained weight loss or malnutrition
• Failure to respond to strict gluten-free diet after 6-12 months (refractory coeliac disease)
• New abdominal pain, mass, or lymphadenopathy (concern for EATL)
• Severe or widespread dermatitis herpetiformis
• Progressive neurological symptoms (ataxia, neuropathy)
• Recurrent small bowel obstruction
• GI bleeding without obvious cause

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5. Clinical Examination

General Inspection

Skin Examination

Abdominal Examination

Other Systems

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6. Investigations

Diagnostic Algorithm

The diagnosis of coeliac disease requires serological testing followed by duodenal biopsy, both performed while the patient is consuming a gluten-containing diet. [5]

              SUSPECTED COELIAC DISEASE
                        │
                        ▼
┌───────────────────────────────────────────────────────────┐
│  STEP 1: SEROLOGICAL TESTING (while on gluten)           │
│  • IgA-tTG (first-line)                                  │
│  • Total IgA level (to exclude IgA deficiency)           │
└───────────────────────────────────────────────────────────┘
                        │
         ┌──────────────┼──────────────┐
         ▼              ▼              ▼
   IgA-tTG         IgA-tTG        IgA deficient
   POSITIVE        NEGATIVE       (less than 0.07 g/L)
         │              │              │
         ▼              │              ▼
┌─────────────────┐     │    ┌─────────────────────┐
│ Refer for       │     │    │ Request IgG-tTG     │
│ duodenal biopsy │     │    │ and/or IgG-DGP      │
└─────────────────┘     │    └─────────────────────┘
         │              │              │
         ▼              ▼              ▼
┌───────────────────────────────────────────────────────────┐
│  STEP 2: DUODENAL BIOPSY (≥4 D2 + 1-2 bulb biopsies)     │
│  • Villous atrophy (Marsh 3a-3c) = DIAGNOSTIC            │
│  • Marsh 1-2 alone: consider other causes                │
└───────────────────────────────────────────────────────────┘
         │
         ▼
   ┌─────────────────────────────────────────────────────┐
   │  BIOPSY SHOWS MARSH 3 + POSITIVE SEROLOGY           │
   │                    │                                │
   │                    ▼                                │
   │        COELIAC DISEASE CONFIRMED                    │
   │  • Initiate strict gluten-free diet                 │
   │  • Essential: expert dietitian referral             │
   │  • Baseline nutritional assessment                  │
   │  • DEXA scan                                        │
   │  • Discuss family screening                         │
   │  • Pneumococcal vaccination                         │
   │  • Follow-up serology at 6-12 months                │
   └─────────────────────────────────────────────────────┘

Serological Testing

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

Critical requirements:

• Patient must be consuming gluten (≥3g/day for ≥6 weeks, ideally 10g/day for 3+ months)
• Always check total IgA level concurrently (2-3% of coeliacs are IgA deficient)
• High titres (> 10x ULN) strongly predictive of coeliac disease

In IgA Deficiency (Total IgA less than 0.07 g/L)

Use IgG-based testing:

• IgG-tTG: Sensitivity 90-95%, specificity 95%
• IgG-DGP (deamidated gliadin peptide): Sensitivity 90-95%, specificity 95%

Other Serological Tests

Exam Detail: False positives for tTG:

• Autoimmune diseases (SLE, RA)
• Chronic liver disease
• Heart failure
• Infections (rarely)
• Inflammatory bowel disease

False negatives for tTG:

• IgA deficiency (check total IgA!)
• Gluten-free diet prior to testing
• Immunosuppression
• Age less than 2 years (use DGP)
• Very early disease

HLA Typing (DQ2/DQ8)

Important: Positive HLA-DQ2/DQ8 does NOT confirm coeliac disease (30-40% of population positive).

Duodenal Biopsy

Gold standard for diagnosis. [5]

Exam Detail: Biopsy technique:

1. Oesophagogastroduodenoscopy (OGD)
2. Multiple biopsies using standard forceps
3. Orient biopsies correctly (villous surface up)
4. Biopsies from D2 (4+) and duodenal bulb (1-2)
5. Submit in formalin; specify "query coeliac disease"

Histopathological assessment:

• IEL count (CD3 immunostaining if needed)
• Villous:crypt ratio
• Crypt hyperplasia
• Surface enterocyte morphology
• Lamina propria inflammation
• Marsh-Oberhuber classification

Pitfalls in biopsy interpretation:

• Poor orientation
• Tangential sectioning
• Peptic duodenitis mimicking changes
• Inadequate number of biopsies
• Patient already on GFD

Other causes of villous atrophy (differential):

• Tropical sprue
• Giardiasis
• Common variable immunodeficiency
• Autoimmune enteropathy
• Drugs (olmesartan, mycophenolate)
• Crohn's disease
• Small bowel bacterial overgrowth
• HIV enteropathy
• Whipple's disease
• Eosinophilic enteritis

No-Biopsy Diagnosis (Selected Cases)

ESPGHAN 2020 guidelines (primarily paediatric, increasingly applied to adults): [5]

Biopsy may be omitted if ALL of the following criteria met:

1. IgA-tTG > 10x upper limit of normal
2. Positive EMA-IgA (on separate sample)
3. Positive HLA-DQ2 or DQ8
4. Symptomatic (classical or non-classical symptoms)
5. Full understanding and acceptance by patient/family

BSG guidelines recommend confirmatory biopsy remains standard of care in adults.

Baseline Investigations at Diagnosis

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7. Classification and Staging

Oslo Definitions (2012) [1]

Marsh-Oberhuber Classification

See Section 3 (Pathophysiology) for detailed classification.

Refractory Coeliac Disease Classification [21]

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8. Management

Management Overview

              CONFIRMED COELIAC DISEASE
                        │
    ┌───────────────────┼───────────────────┐
    │                   │                   │
    ▼                   ▼                   ▼
DIETARY             NUTRITIONAL        MONITORING
TREATMENT           SUPPORT            & SCREENING
    │                   │                   │
    ▼                   ▼                   ▼
┌──────────────┐ ┌─────────────────┐ ┌─────────────────┐
│ Strict       │ │ Dietitian       │ │ Serology        │
│ gluten-free  │ │ referral        │ │ at 6-12 months  │
│ diet         │ │ (ESSENTIAL)     │ │                 │
│              │ │                 │ │ Annual clinical │
│ Lifelong     │ │ Nutritional     │ │ review          │
│              │ │ supplementation │ │                 │
│ Education    │ │ (iron, Ca, D)   │ │ DEXA scan       │
│              │ │                 │ │                 │
│ Support      │ │ Bone health     │ │ Family screening│
│ groups       │ │                 │ │                 │
│              │ │ Vaccinations    │ │ Consider repeat │
│ Coeliac UK   │ │                 │ │ biopsy if non-  │
│              │ │                 │ │ responsive      │
└──────────────┘ └─────────────────┘ └─────────────────┘

Gluten-Free Diet (GFD)

The cornerstone of treatment is a strict, lifelong gluten-free diet. [7]

Foods to AVOID (Contain Gluten)

Safe Foods (Gluten-Free)

Exam Detail: #### Gluten Thresholds

Oats in Coeliac Disease [14]

• Pure, uncontaminated oats (certified less than 20ppm) are safe for 95% of coeliacs
• Introduce after initial GFD stabilisation (6-12 months)
• Limit to 50g dry oats/day
• 5% of patients develop avenin sensitivity (oat storage protein)
• Monitor clinically and serologically after introduction

Dietitian Referral (ESSENTIAL)

Expert dietitian input is MANDATORY for successful management. [7]

Nutritional Supplementation

Bone Health Management [13]

Vaccinations [7]

Follow-Up and Monitoring

Exam Detail: #### Monitoring Response to GFD

Symptomatic response:

• GI symptoms typically improve within 2-4 weeks
• Fatigue, other symptoms over weeks to months

Serological response:

• tTG-IgA should decrease by ≥50% at 6-12 months
• May normalise by 12-24 months
• Persistent elevation suggests ongoing gluten exposure

Histological response:

• Mucosal healing occurs over 6-24 months
• May take longer in adults (1-2 years)
• Repeat biopsy not routinely required unless non-responsive

Definition of non-responsive coeliac disease (NRCD):

• Persistent symptoms and/or
• Persistently elevated serology and/or
• Persistent villous atrophy despite ostensibly strict GFD for ≥12 months

Causes of NRCD (in order of frequency):

1. Ongoing gluten exposure (most common: 50-70%)
2. Incorrect initial diagnosis (7-10%)
3. Concomitant conditions (IBS, lactose intolerance, SIBO, microscopic colitis) (10-30%)
4. Refractory coeliac disease Type I (less than 10%)
5. Refractory coeliac disease Type II (less than 2%)

Special Populations

Pregnancy [22]

Elderly

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9. Complications

Malignancy [8,15]

Exam Detail: #### Enteropathy-Associated T-Cell Lymphoma (EATL) [15]

Warning signs:

• Unexplained weight loss
• New or worsening abdominal pain
• GI bleeding or obstruction
• B symptoms (fever, night sweats)
• Failure to respond to GFD (RCD-II)

Refractory Coeliac Disease (RCD) [21]

Investigation of suspected RCD:

1. Confirm strict GFD adherence (dietitian assessment)
2. Repeat duodenal biopsy (persistent villous atrophy)
3. IEL immunophenotyping (flow cytometry)
4. T-cell receptor gene rearrangement (clonality)
5. Small bowel imaging (CT/MRI, capsule endoscopy)
6. PET-CT if lymphoma suspected

Other Complications

Dermatitis Herpetiformis [11]

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10. Prognosis and Outcomes

Response to Gluten-Free Diet [7]

Long-Term Outcomes [8]

Prognostic Factors

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11. Prevention and Screening

Primary Prevention

Currently, no proven strategies to prevent coeliac disease development. [19]

Screening Recommendations

Who to screen:

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12. Key Guidelines

BSG Guidelines (2021) [7]

Key recommendations:

1. First-line test: IgA-tTG with total IgA
2. Duodenal biopsy remains standard for adult diagnosis
3. Minimum 4 biopsies from D2 + 1-2 from duodenal bulb
4. Lifelong strict GFD as sole treatment
5. Expert dietitian referral essential
6. DEXA scan for all adults at diagnosis
7. Annual follow-up recommended
8. Pneumococcal vaccination for hyposplenism

NICE NG20 (2015, updated 2022) [23]

Key recommendations:

1. Screen high-risk groups (IBS, Type 1 diabetes, autoimmune thyroid, first-degree relatives)
2. Test IgA-tTG with total IgA
3. Refer for biopsy if positive serology
4. Do not start GFD before diagnosis confirmed
5. Offer DEXA to adults at diagnosis
6. Consider repeat biopsy if non-responsive

ACG Guidelines (2023) [17]

Key recommendations:

1. IgA-tTG as first-line test
2. Confirm diagnosis with duodenal biopsy (≥4 biopsies)
3. Gluten-free diet is currently the only effective treatment
4. Screen first-degree relatives, T1DM, autoimmune thyroid
5. Monitor adherence with dietitian support
6. Assess for refractory disease if non-responsive

ESPGHAN Guidelines (2020) [5]

Key recommendations:

1. No-biopsy diagnosis acceptable in children with IgA-tTG > 10x ULN + positive EMA + HLA-DQ2/DQ8 + symptoms
2. Adults: biopsy still recommended for diagnosis
3. Total IgA essential to exclude deficiency
4. HLA typing useful for exclusion

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13. Exam-Focused Content

Common MRCP/FRACP Questions

1. "What is the pathophysiology of coeliac disease?"
2. "How would you investigate suspected coeliac disease?"
3. "A patient with known coeliac disease is not responding to GFD. What are the causes and your approach?"
4. "What complications are associated with coeliac disease?"
5. "Who should be screened for coeliac disease?"
6. "Describe the Marsh classification."
7. "What is the significance of HLA-DQ2/DQ8 testing?"
8. "How would you manage a patient with refractory coeliac disease?"

Viva Points

Viva Point: Opening statement: "Coeliac disease is a chronic immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8 haplotypes. It has a prevalence of approximately 1% worldwide and is characterised by villous atrophy on duodenal biopsy, positive anti-tissue transglutaminase antibodies, and clinical response to a strict gluten-free diet."

Key facts to articulate:

• Prevalence 1%; 5 undiagnosed for every diagnosed case
• HLA-DQ2 (90-95%) or HLA-DQ8 (5-10%) necessary but not sufficient
• Tissue transglutaminase deamidates gliadin → enhanced HLA-DQ2/DQ8 binding → CD4+ T-cell activation
• Diagnosis: IgA-tTG (sensitivity/specificity 95-98%) + duodenal biopsy (Marsh 3)
• Always check total IgA (2-3% IgA deficient)
• Treatment: strict lifelong GFD + expert dietitian
• Complications: osteoporosis, anaemia, EATL, refractory coeliac disease
• Strict GFD normalises mortality after 3-5 years

Model Answers

Q: A 35-year-old woman presents with fatigue and is found to have iron deficiency anaemia. How would you approach suspected coeliac disease?

A: "I would approach this systematically. Iron deficiency anaemia is the most common presentation of coeliac disease in adults, affecting 30-50% at diagnosis.

First, I would take a detailed history focusing on GI symptoms (diarrhoea, bloating, abdominal pain), extraintestinal features (fatigue, bone pain, skin rash), and family history of coeliac disease or autoimmunity.

For investigation, I would request IgA tissue transglutaminase (IgA-tTG) as the first-line serological test, along with total IgA level to exclude IgA deficiency. The patient must be consuming a gluten-containing diet for accurate results.

If IgA-tTG is positive, I would refer for upper GI endoscopy with duodenal biopsies – at least 4 from D2 and 1-2 from the duodenal bulb – looking for villous atrophy (Marsh 3 classification).

If confirmed, I would initiate a strict gluten-free diet with essential dietitian referral, arrange baseline nutritional investigations (ferritin, B12, folate, calcium, vitamin D, LFTs, TFTs), perform a DEXA scan for osteoporosis screening, ensure pneumococcal vaccination for hyposplenism, and discuss family screening.

Follow-up would include repeat serology at 6-12 months, which should show falling antibody titres, and annual review thereafter."

Q: What are the causes of non-responsive coeliac disease?

A: "Non-responsive coeliac disease is defined as persistent symptoms, elevated serology, or villous atrophy despite an ostensibly strict gluten-free diet for 12 months or more.

The causes, in order of frequency, are:

1. Ongoing gluten exposure – the most common cause (50-70%), often inadvertent from hidden sources
2. Incorrect initial diagnosis – other causes of villous atrophy such as tropical sprue, giardiasis, CVID
3. Concomitant conditions – lactose intolerance, IBS, small intestinal bacterial overgrowth, microscopic colitis, exocrine pancreatic insufficiency
4. Refractory coeliac disease Type I – persistent villous atrophy with polyclonal IELs despite strict GFD
5. Refractory coeliac disease Type II – aberrant clonal IEL expansion; pre-lymphomatous condition with poor prognosis

My approach would be: confirm dietary adherence with expert dietitian assessment, repeat duodenal biopsy, test for other causes, and if RCD suspected, perform IEL immunophenotyping and TCR gene rearrangement studies."

Common Mistakes

❌ Mistakes that fail candidates:

• Testing serology when patient already on GFD (false negative)
• Not checking total IgA level (miss IgA-deficient patients)
• Taking insufficient biopsies (miss patchy disease)
• Not biopsying the duodenal bulb (bulb-only disease in 9-13%)
• Diagnosing coeliac without villous atrophy (Marsh 1-2 alone is insufficient)
• Not referring to expert dietitian
• Forgetting to screen for osteoporosis (DEXA)
• Forgetting pneumococcal vaccination (hyposplenism)
• Missing hidden gluten sources as cause of non-response

Differential Diagnosis

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14. References

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2. Sollid LM, Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol. 2013;13(4):294-302. doi:10.1038/nri3407

3. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology. 1992;102(1):330-354. doi:10.1016/0016-5085(92)91819-P

4. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70-81. doi:10.1016/S0140-6736(17)31796-8

5. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70(1):141-156. doi:10.1097/MPG.0000000000002497

6. Chow MA, Lebwohl B, Reilly NR, et al. Immunoglobulin A deficiency in celiac disease. J Clin Gastroenterol. 2012;46(10):850-854. doi:10.1097/MCG.0b013e31824b2277

7. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63(8):1210-1228. doi:10.1136/gutjnl-2013-306578

8. Lebwohl B, Green PHR, Söderling J, et al. Association between celiac disease and mortality risk in a Swedish population. JAMA. 2020;323(13):1277-1285. doi:10.1001/jama.2020.1943

9. Singh P, Arora A, Strand TA, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2. doi:10.1016/j.cgh.2017.06.037

10. Sollid LM, Markussen G, Ek J, et al. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med. 1989;169(1):345-350. doi:10.1084/jem.169.1.345

11. Salmi TT, Hervonen K, Kautiainen H, et al. Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from Finland. Br J Dermatol. 2011;165(2):354-359. doi:10.1111/j.1365-2133.2011.10385.x

12. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163(3):286-292. doi:10.1001/archinte.163.3.286

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Last Reviewed: 2026-01-09 | MedVellum Editorial Team | Topic 853/1071