Case 21.3 – Coeliac Disease [SDL]

Definition:

Coeliac disease is a chronic immune-mediated enteropathy triggered by exposure to dietary gluten in genetically predisposed individuals. It affects approximately 1% of the population in Western countries, though many cases remain undiagnosed.

Pathophysiology:

• Trigger: Gluten proteins (gliadin from wheat, hordein from barley, secalin from rye)
  • Gluten peptides are resistant to complete digestion by gastric and pancreatic enzymes
  • Incompletely digested gluten peptides reach the small intestine
• Immune response in genetically susceptible individuals:
  • Innate immune response: Gluten peptides cause direct epithelial damage
  • Adaptive immune response:
    • Tissue transglutaminase (tTG) deamidates gluten peptides, increasing their immunogenicity
    • Modified gluten peptides are presented by antigen-presenting cells to T cells
    • T cell activation leads to inflammatory cascade
    • Production of antibodies against:
      • Tissue transglutaminase (anti-tTG)
      • Endomysium (anti-EMA)
      • Deamidated gliadin peptides (anti-DGP)
• Tissue damage:
  • Chronic inflammation of small intestinal mucosa
  • Villous atrophy (flattening of intestinal villi)
  • Crypt hyperplasia
  • Increased intraepithelial lymphocytes
  • Results in reduced absorptive surface area → malabsorption

Genetic Factors:

• Strong genetic component:
  • 95% of patients are HLA-DQ2 positive
  • Most others are HLA-DQ8 positive
  • However, ~30% of general population carry these genes but only ~1% develop coeliac disease
  • Other genetic and environmental factors contribute
• First-degree relatives have 10% risk (compared to 1% in general population)
• Concordance in identical twins: ~75%

Environmental Factors:

• Timing and amount of gluten introduction in infancy
• Gastrointestinal infections
• Gut microbiome composition

Classical GI Presentation (more common in children):

• Chronic diarrhoea (often steatorrhoea - pale, floating, offensive stools)
• Abdominal pain and bloating
• Excessive flatulence
• Weight loss or failure to thrive (children)
• Nausea and vomiting

Non-Classical Presentations (increasingly recognized, especially in adults):

Nutritional deficiencies due to malabsorption:

• Iron deficiency anaemia: Most common presentation in adults
  • Often refractory to oral iron
  • Due to malabsorption in proximal small bowel
• Folate and B12 deficiency: Macrocytic anaemia
• Vitamin D and calcium deficiency:
  • Osteoporosis or osteomalacia
  • Increased fracture risk
  • Bone pain
• Vitamin K deficiency: Easy bruising, bleeding tendency
• Fat-soluble vitamin deficiencies: Vitamins A, D, E, K
• Protein malnutrition: Hypoalbuminaemia, peripheral oedema

Dermatological:

• Dermatitis herpetiformis:
  • Intensely itchy, blistering rash
  • Typically on extensor surfaces (elbows, knees, buttocks, scalp)
  • Pathognomonic for coeliac disease
  • IgA deposits in dermal papillae on skin biopsy
• Angular stomatitis
• Atrophic glossitis
• Aphthous ulcers

Reproductive:

• Delayed puberty
• Amenorrhoea or irregular periods
• Infertility (both male and female)
• Recurrent miscarriages

Neurological:

• Peripheral neuropathy
• Ataxia (gluten ataxia)
• Epilepsy
• Cognitive impairment, "brain fog"
• Headaches

Hepatic:

• Abnormal liver function tests (often mild transaminitis)
• Usually normalizes with gluten-free diet

Other:

• Dental enamel hypoplasia
• Short stature in children
• Chronic fatigue
• Depression and anxiety

Asymptomatic/Silent Coeliac Disease:

• Positive serology and villous atrophy on biopsy
• No obvious symptoms
• May be detected through screening of at-risk groups

Differences Between Children and Adults:

Children:

• More likely to present with classical GI symptoms
• Failure to thrive, growth retardation
• Irritability and behavioural changes
• Abdominal distension with muscle wasting ("pot belly" appearance)
• Delayed puberty
• Dental enamel defects

Adults:

• More likely to have non-classical presentations
• Iron deficiency anaemia most common presentation
• Osteoporosis
• Subtle or absent GI symptoms in up to 50%
• May present with extraintestinal manifestations only
• Diagnosis often delayed due to varied presentation

High-Risk Groups Warranting Screening:

Strong indications for testing:

• First-degree relatives of coeliac patients: 10% risk
• Autoimmune conditions:
  • Type 1 diabetes mellitus (5-10% prevalence)
  • Autoimmune thyroid disease
  • Autoimmune hepatitis
  • Primary biliary cholangitis
  • Addison's disease
  • Sjögren's syndrome
• Genetic syndromes:
  • Down syndrome (5-12% prevalence)
  • Turner syndrome
  • Williams syndrome
• IgA deficiency: 10-fold increased risk
  • Important as standard serological tests (IgA-based) will be falsely negative

Clinical presentations requiring testing:

• Chronic or intermittent diarrhoea
• Unexplained iron deficiency anaemia
• Unexplained weight loss
• Persistent or unexplained GI symptoms
• Dermatitis herpetiformis
• Unexplained abnormal liver function tests
• Metabolic bone disease (osteoporosis in young patients)
• Unexplained neurological symptoms (ataxia, peripheral neuropathy)
• Infertility or recurrent miscarriage
• Dental enamel defects
• Chronic fatigue

Investigations:

IMPORTANT: Patients must be on a gluten-containing diet for accurate testing

• Should consume gluten in at least one meal daily for minimum 6 weeks before testing
• Starting gluten-free diet before testing can lead to false negative results

First-line Serological Tests:

• Tissue transglutaminase IgA (tTG-IgA):
  • Test of choice, highest sensitivity and specificity (~95%)
  • Most cost-effective
• Total IgA level:
  • Must be checked simultaneously with tTG-IgA
  • To detect IgA deficiency (which would make tTG-IgA falsely negative)
  • If IgA deficient: use IgG-based tests instead

Additional/Alternative Serological Tests:

• Endomysial antibody IgA (EMA-IgA):
  • Very high specificity (~100%)
  • Used as confirmatory test
  • More expensive and operator-dependent
• Deamidated gliadin peptide (DGP) antibodies (IgA and IgG):
  • Less sensitive than tTG
  • May be useful in children <2 years
  • IgG-DGP used in IgA-deficient patients
• tTG-IgG: For IgA-deficient patients

Definitive Diagnosis - Small Bowel Biopsy:

• Upper GI endoscopy (OGD) with duodenal biopsies:
  • Gold standard for diagnosis in adults
  • Multiple biopsies required (≥4-6 from second part of duodenum)
  • Patchy disease → need multiple samples
• Histological features (Marsh classification):
  • Increased intraepithelial lymphocytes (Marsh 1)
  • Crypt hyperplasia (Marsh 2)
  • Villous atrophy:
    • Partial (Marsh 3a)
    • Subtotal (Marsh 3b)
    • Total (Marsh 3c)
• Biopsy essential because:
  • Confirms diagnosis before committing to lifelong gluten-free diet
  • Other conditions can cause positive serology
  • Establishes baseline for monitoring

Exception in Children:

• ESPGHAN criteria allow diagnosis without biopsy in selected cases:
  • Symptomatic children
  • tTG-IgA >10x upper limit of normal
  • Positive EMA in separate blood sample
  • HLA-DQ2 or DQ8 positive

Genetic Testing (HLA-DQ2/DQ8):

• NOT used for diagnosis (too many false positives in general population)
• Useful for:
  • Ruling out coeliac disease (negative predictive value >99%)
  • Patients already on gluten-free diet who can't/won't do gluten challenge
  • Uncertain cases
  • Screening high-risk individuals

Other Investigations to Assess Complications:

• Full blood count (anaemia)
• Iron studies, B12, folate
• Liver function tests
• Calcium, vitamin D, PTH
• Bone density scan (DEXA) if risk factors for osteoporosis
• Thyroid function (associated autoimmune thyroid disease)

Diagnostic Algorithm:

1. Ensure patient is on gluten-containing diet
2. Check tTG-IgA + total IgA
3. If tTG-IgA positive: refer for endoscopy with duodenal biopsies
4. If total IgA low: use IgG-based tests
5. Diagnosis requires positive serology + characteristic histology (except selected paediatric cases)

Management of Coeliac Disease:

1. Lifelong Strict Gluten-Free Diet (GFD):

• Cornerstone of treatment - only effective therapy
• Complete avoidance of:
  • Wheat, barley, rye, and their derivatives
  • Oats are controversial:
    • Pure, uncontaminated oats may be tolerated by most
    • Some patients react to avenin (oat protein)
    • Introduce cautiously under supervision
• Hidden sources of gluten:
  • Processed foods, sauces, medications, supplements
  • Cross-contamination during food preparation
  • Need careful label reading
• Safe alternatives:
  • Rice, corn, quinoa, buckwheat, millet, sorghum
  • Potatoes, legumes
  • Naturally gluten-free foods (meat, fish, eggs, dairy, fruits, vegetables)
• Expected response to GFD:
  • Symptom improvement within weeks
  • Antibody levels normalize within 6-12 months
  • Histological recovery may take 2 years or longer
  • Some patients (particularly adults) may have incomplete villous recovery

2. Dietitian Support:

• Specialist coeliac dietitian essential
• Education about gluten-free diet
• Nutritional assessment and advice
• Ensure adequate intake of fibre, vitamins, minerals
• Help with meal planning and food label reading
• Ongoing support and monitoring

3. Nutritional Supplementation (Initially):

• Correct deficiencies identified:
  • Iron (often IV if severe malabsorption)
  • Folate and B12
  • Calcium and vitamin D
  • Other vitamins/minerals as needed
• Most can discontinue supplements once mucosa heals

4. Monitoring and Follow-up:

• Regular follow-up essential:
  • Initially 3-6 monthly, then annually
  • Dietitian review
  • Symptom assessment
  • Dietary adherence assessment
  • Screen for complications
• Serological monitoring:
  • Repeat tTG-IgA at 6 months, then annually
  • Should normalize on strict GFD
  • Persistent elevation suggests ongoing gluten exposure or non-adherence
• Repeat biopsy:
  • Not routinely required if clinical and serological response adequate
  • Consider if:
    • Persistent symptoms despite GFD
    • Antibodies remain elevated
    • Concern for complications (e.g., refractory coeliac disease)
• Nutritional monitoring:
  • Annual FBC, iron studies, B12, folate
  • Calcium, vitamin D
  • Liver function tests
  • Thyroid function (increased risk of thyroid disease)
• Bone health:
  • DEXA scan at diagnosis if risk factors
  • Repeat based on initial results and risk factors
  • Ensure adequate calcium and vitamin D

5. Vaccination:

• Pneumococcal vaccination recommended (functional hyposplenism possible)

6. Patient Education and Support:

• Join coeliac support groups
• Education about:
  • Lifelong nature of condition
  • Importance of strict adherence
  • Complications of non-adherence
  • Practical aspects of maintaining GFD
  • Dining out, travel considerations
• Psychological support if needed (adjustment to diagnosis, dietary restrictions)

7. Family Screening:

• Offer screening to first-degree relatives (10% risk)

Refractory Coeliac Disease:

• Persistent symptoms and villous atrophy despite strict GFD for >12 months
• Rare (~1-2% of coeliac patients)
• Type 1: Normal intraepithelial lymphocytes
• Type 2: Abnormal (clonal) intraepithelial lymphocytes - higher risk of lymphoma
• Requires specialist management, may need immunosuppression

Complications of Untreated Coeliac Disease:

Nutritional and Metabolic:

• Anaemia: Iron, folate, B12 deficiency
• Osteoporosis/osteomalacia:
  • Calcium and vitamin D malabsorption
  • Increased fracture risk
  • May be irreversible if diagnosis delayed
• Vitamin and mineral deficiencies
• Malnutrition and weight loss

Reproductive:

• Infertility (male and female)
• Recurrent miscarriage
• Intrauterine growth restriction
• Preterm birth
• Low birth weight

Malignancy:

• Enteropathy-associated T-cell lymphoma (EATL):
  • Rare but serious complication
  • Risk reduced by adherence to GFD
  • Present with refractory symptoms, weight loss, abdominal pain
  • Poor prognosis
• Small bowel adenocarcinoma: Slightly increased risk
• Other malignancies: Small increased risk of oesophageal, oropharyngeal cancers
• Non-Hodgkin lymphoma: Slightly increased risk
• Adherence to strict GFD reduces malignancy risk towards that of general population

Neurological:

• Peripheral neuropathy
• Ataxia
• Epilepsy
• Cognitive impairment

Other Autoimmune Conditions:

• Increased risk of other autoimmune diseases:
  • Type 1 diabetes
  • Autoimmune thyroid disease
  • Autoimmune hepatitis
  • Primary biliary cholangitis
  • Addison's disease

Hyposplenism:

• Functional hyposplenism can occur
• Increased risk of overwhelming bacterial infections
• Pneumococcal vaccination recommended

Quality of Life:

• Chronic symptoms affecting daily functioning
• Fatigue
• Depression and anxiety
• Reduced quality of life

Prognosis:

• Excellent prognosis with strict adherence to GFD
• Most symptoms resolve
• Nutritional status normalizes
• Risk of complications dramatically reduced
• Life expectancy normal with treatment
• Small percentage develop refractory disease despite GFD

This question explores the differential diagnosis of gluten-related disorders.

Non-Coeliac Gluten Sensitivity (NCGS):

• Definition:
  • Symptomatic condition triggered by gluten ingestion
  • Occurs in individuals without coeliac disease or wheat allergy
  • No specific biomarker - diagnosis of exclusion
  • Prevalence uncertain, possibly 0.5-13% of population
• Pathophysiology:
  • Not fully understood
  • May involve innate immune activation
  • No autoimmune component
  • No villous atrophy
  • Debate whether gluten or other wheat components (FODMAPs, ATIs) responsible
• Clinical features:
  • GI symptoms: bloating, abdominal pain, diarrhoea/constipation
  • Extra-intestinal: fatigue, headache, "brain fog", joint/muscle pain
  • Symptoms develop hours to days after gluten ingestion
  • Improve with gluten withdrawal
• Diagnosis:
  • Exclusion of coeliac disease (negative serology and/or biopsy)
  • Exclusion of wheat allergy (negative IgE testing)
  • Symptomatic response to gluten-free diet
  • Symptom recurrence with gluten challenge
  • Ideally confirmed with blinded placebo-controlled challenge

Comparison of Gluten-Related Disorders:

Feature	Coeliac Disease	Wheat Allergy	NCGS
Mechanism	Autoimmune (adaptive immunity)	IgE-mediated allergic reaction	Unclear, possibly innate immunity
Genetics	HLA-DQ2/DQ8 required	No specific association	No HLA-DQ2/DQ8 association
Antibodies	Anti-tTG, anti-EMA, anti-DGP	IgE to wheat proteins	May have AGA (non-specific)
Intestinal damage	Villous atrophy	Normal or mild inflammation	Normal or minimal changes
Onset of symptoms	Hours to days	Minutes to hours	Hours to days
Symptoms	GI + systemic	GI, respiratory, skin, anaphylaxis	GI + systemic (no anaphylaxis)
Complications	Malabsorption, osteoporosis, lymphoma	Anaphylaxis (potentially fatal)	No known long-term complications
Treatment	Strict lifelong GFD essential	Strict wheat avoidance, may carry EpiPen	Gluten reduction/elimination (strict avoidance may not be necessary)
Prognosis	Lifelong condition	May outgrow (especially children)	Variable, may improve over time
Small amounts tolerated?	No (even trace amounts harmful)	No (risk of anaphylaxis)	Possibly (threshold varies)

Clinical Significance:

• Coeliac disease must be excluded before diagnosing NCGS:
  • Serious long-term complications if coeliac disease missed
  • Once on GFD, coeliac disease harder to diagnose (serology becomes negative)
  • Would require prolonged gluten challenge to re-test
• Different management implications:
  • Coeliac: strict lifelong GFD mandatory, regular monitoring needed
  • NCGS: symptom-guided, less strict, no monitoring required
  • Wheat allergy: complete wheat avoidance, allergy management
• No need for family screening in NCGS (unlike coeliac disease)

Diagnostic Approach to Patient with Suspected Gluten-Related Disorder:

1. Patient presents with symptoms possibly related to gluten
2. While still on gluten-containing diet:
   • Test for coeliac disease: tTG-IgA + total IgA
   • Consider wheat allergy testing (IgE) if rapid-onset symptoms
3. If coeliac serology positive → endoscopy + biopsy
4. If coeliac disease confirmed → lifelong strict GFD, specialist follow-up
5. If coeliac disease and wheat allergy excluded but symptoms persist:
   • Trial of gluten-free diet
   • If symptoms improve → consider NCGS
   • Ideally confirm with blinded gluten challenge
6. Consider other causes: IBS, FODMAP sensitivity, other food intolerances