Coeliac Disease

Environmental Factors

• Gluten Peptides:
  • The primary environmental trigger is dietary gluten peptides found in wheat, rye, and barley.
  • Gliadin, a component of gluten, plays a pivotal role in disease pathogenesis by binding to tissue transglutaminase (tTG) in the intestinal mucosa, forming immunogenic complexes.
• Gut Microbiome and Infections:
  • Changes in gut microbiota may predispose individuals to coeliac disease. Early-life infections, such as those caused by reovirus, can disrupt oral tolerance to gluten and increase inflammation.
  • Case-control studies link enterovirus and parechovirus infections in childhood to a heightened risk of developing coeliac disease in genetically predisposed individuals.
• Gluten Exposure Timing:
  • Higher gluten intake during early childhood is associated with an increased risk of developing coeliac disease in individuals carrying HLA-DQ2/DQ8 genotypes.
    
    

Genetic Factors

• HLA-DQ2 and HLA-DQ8:
  • Approximately 90-95% of patients with coeliac disease carry the HLA-DQ2 gene, while 5-10% have the HLA-DQ8 gene.
  • These molecules present deamidated gliadin peptides to CD4+ T cells in the lamina propria, initiating an inflammatory cascade.
• Familial Clustering:
  • Coeliac disease prevalence among first-degree relatives of affected individuals is around 10%.
  • Concordance rates for coeliac disease are 75% in monozygotic twins and approximately 30% among other first-degree relatives.

Immune Mechanisms

• Humoral Immunity:
  • IgA antibodies against endomysium and tTG are hallmark markers of coeliac disease, though 3-5% of patients are IgA deficient, necessitating measurement of total IgA prior to antibody testing.
  • Antigliadin antibodies are also commonly observed in untreated patients.
• Cellular Immunity:
  • The presence of intraepithelial CD8+ T cells and their activation by interleukin-15 is critical for the immune response in coeliac disease.
  • NK-G2D marker expression on intraepithelial lymphocytes is stimulated, leading to enterocyte apoptosis and mucosal damage.
• Tissue Transglutaminase (tTG):
  • tTG deamidates gliadin, enhancing its immunogenicity and interaction with HLA molecules on antigen-presenting cells. This process amplifies the inflammatory response and tissue injury.
    
    

Immune Mechanisms

1. Role of Gluten Peptides:
   • Gluten peptides, such as gliadin (33 amino acids long), resist degradation by gastrointestinal enzymes.
   • Gliadin is deamidated by tissue transglutaminase (tTG), increasing its immunogenicity and facilitating binding to HLA-DQ2/DQ8 molecules on antigen-presenting cells in the lamina propria.
2. Innate Immune Response:
   • Gluten peptides stimulate interleukin-15 (IL-15) production by dendritic cells, macrophages, and epithelial cells.
   • IL-15 promotes activation of intraepithelial lymphocytes, which express cytotoxic markers like NK-G2D, leading to enterocyte apoptosis.
3. Adaptive Immune Response:
   • Gliadin-reactive CD4+ T cells are activated by deamidated gliadin peptides presented on HLA-DQ2/DQ8.
   • These T cells produce pro-inflammatory cytokines, such as interferon-gamma, exacerbating inflammation and tissue damage.
   • B cells produce autoantibodies against tTG and gliadin, which serve as diagnostic markers.
     
     

Intestinal Damage

1. Villous Atrophy and Crypt Hyperplasia:
   • Inflammation leads to destruction of the small intestinal villi, causing loss of absorptive surface area.
   • Crypts become elongated as part of the repair mechanism, contributing to malabsorption.
2. Intraepithelial Lymphocytosis:
   • An increased number of intraepithelial lymphocytes, including gamma-delta T cells, is a hallmark of active coeliac disease.
3. Increased Intestinal Permeability:
   • Gluten peptides bind to CXCR3 receptors on enterocytes, inducing permeability changes and facilitating peptide transport to the lamina propria.
     
     

Systemic Effects

• Malabsorption from intestinal damage leads to nutrient deficiencies, including iron, calcium, and vitamins (e.g., B12, D).
• Systemic inflammation can cause extraintestinal manifestations, such as dermatitis herpetiformis, osteoporosis, fatigue, and neurological symptoms.
  
  

Key Molecular Mechanisms

1. Tissue Transglutaminase (tTG):
   • Acts on gluten peptides, deamidating glutamine residues into glutamic acid, enhancing peptide immunogenicity.
   • tTG autoantibodies can inhibit epithelial differentiation and exacerbate intestinal damage.
2. CD71 Receptors:
   • Overexpression of CD71 (transferrin receptor) on enterocytes facilitates retro-transport of secretory IgA-gluten complexes, which can trigger immune responses in the lamina propria.
3. Non-Gluten Components:
   • Wheat amylase-trypsin inhibitors (ATIs) activate toll-like receptor 4 on macrophages and monocytes, contributing to low-level intestinal inflammation and possibly explaining non-coeliac wheat sensitivity.
     
     

Global Prevalence

• The overall prevalence of coeliac disease is approximately 1.4% based on serologic tests and 0.7% based on biopsy findings.
• Regions with the highest prevalence include Western Europe, North America, and Australia, where approximately 1 in 100 individuals is affected.
• Increasing prevalence is reported in populations from Africa (e.g., Saharawi people), Asia (notably India), and the Middle East.
  
  

Prevalence in the United States

• Coeliac disease affects an estimated 1% of the population, with underdiagnosis being a notable issue.
• Historical cohort studies demonstrated a rise in undiagnosed cases over time. In the 1948-1954 cohort, the prevalence was 0.2%, compared to 0.8-0.9% in more recent cohorts.
• Undiagnosed coeliac disease significantly increases all-cause mortality, with a hazard ratio of 3.9 over 45 years of follow-up.
  
  

Prevalence in Europe

• Approximately 3 million people in Europe are estimated to have coeliac disease, with higher rates in Ireland and Finland.
• Screening programs in countries like Italy reveal that asymptomatic cases outnumber symptomatic ones by a ratio of 7:1.
  
  

Demographics

• Sex: Females are affected slightly more often than males.
• Age: Coeliac disease shows a bimodal distribution:
  • The first peak occurs at 8-12 months when gluten is introduced into the diet.
  • The second peak occurs in early adulthood (3rd to 4th decade).
  • Approximately 20% of diagnoses are made in individuals over the age of 60 years.
• Race: While initially thought to primarily affect populations of European descent, coeliac disease is increasingly recognised in Northern Africa, India, China, and the Middle East.
  
  

High-Risk Populations

• First-degree relatives of patients with coeliac disease have a 10% risk of developing the condition.
• Meta-analysis data indicate:
  • Prevalence of 8.9% (1:11) among siblings.
  • Prevalence of 7.9% (1:13) among offspring.
  • Prevalence of 3% (1:33) among parents.
• Individuals with autoimmune conditions like type 1 diabetes are at significantly higher risk.
  
  

Trends in Diagnosis

• In the United States, serologic screening studies estimate a prevalence of 1:133 in individuals without symptoms or risk factors.
• Despite widespread availability of serologic tests, many cases remain undiagnosed, representing the "tip of the iceberg."
  
  

Gastrointestinal Symptoms

1. Diarrhoea:
   • Most common symptom, present in 45-85% of untreated patients.
   • Features watery, greasy, or frothy stools with a foul odor.
   • In children, extensive diarrhoea can result in dehydration, electrolyte imbalance, and metabolic acidosis.
2. Steatorrhea:
   • Caused by fat malabsorption.
   • Leads to excessive dietary fat in the colon, resulting in bacterial production of hydroxy fatty acids and intestinal fluid secretion.
3. Flatulence and Borborygmus:
   • Prevalent in 28% and 35-72% of patients, respectively.
   • Caused by gas released from bacterial fermentation of undigested nutrients.
4. Weight Loss:
   • Observed in 45% of patients; some compensate through increased caloric intake.
   • In children, failure to thrive and growth retardation are key indicators.
5. Abdominal Pain and Bloating:
   • Commonly presents with cramps and excessive malodorous flatus.
6. Weakness and Fatigue:
   • Affects 78-80% of patients, largely due to malnutrition or anaemia.
     
     

Extraintestinal Symptoms

1. Hematological Manifestations:
   • Anaemia (10-15%) caused by impaired absorption of iron, folate, or vitamin B12.
   • Bleeding Diathesis from prothrombin deficiency linked to vitamin K malabsorption.
2. Bone Health:
   • Osteopenia/Osteoporosis (1-34%) due to calcium and vitamin D deficiency.
   • Fracture risk is increased; secondary hyperparathyroidism may contribute.
3. Neurological Manifestations:
   • Peripheral Neuropathy, paresthesias, motor weakness, and ataxia due to hypocalcemia or vitamin deficiencies.
   • Seizures associated with cerebral calcifications.
4. Dermatological Manifestations:
   • Dermatitis Herpetiformis (10-20%): Intensely pruritic, vesicular skin lesions on extensor surfaces.
5. Reproductive Health:
   • Amenorrhea, delayed menarche, and infertility in women.
   • Impotence and infertility in men.
6. Hepatic and Renal Manifestations:
   • Elevated liver enzymes that normalise with a gluten-free diet.
   • Co-occurrence with autoimmune liver diseases and IgA nephropathy.
7. Psychiatric Conditions:
   • Increased risk of depression, anxiety, and eating disorders.
   • Psychiatric symptoms improve in 55% of patients after starting a gluten-free diet.
     
     

Risk Factors

1. Family History:
   • First-degree relatives have a 10% risk of developing the disease.
   • Concordance rates in monozygotic twins range from 49-86%.
2. Comorbid Autoimmune Diseases:
   • Type 1 diabetes: Co-occurs in 4-7% of patients.
   • Autoimmune thyroid disease: Strong association, often requiring screening.
3. Genetic Syndromes:
   • Higher prevalence in Down’s syndrome and Turner syndrome.
     
     

Abdominal Examination

• Protuberant and Tympanic Abdomen:
  • Suggests distention due to fluid and gas accumulation in intestinal loops.
• Ascites:
  • Rare; seen in cases of severe hypoproteinemia.
    
    

General Findings

• Evidence of Weight Loss:
  • Includes muscle wasting and loose skin folds.
• Orthostatic Hypotension:
  • Due to volume depletion or electrolyte imbalances.
• Peripheral Edema:
  • Suggests hypoalbuminemia from protein malabsorption.
    
    

Dermatological Findings

• Hyperkeratosis:
  • Caused by fat-soluble vitamin deficiencies.
• Dermatitis Herpetiformis:
  • A hallmark extraintestinal manifestation; pruritic, vesicular lesions commonly found on extensor surfaces, buttocks, scalp, and trunk.
• Cheilosis and Glossitis:
  • Indicate deficiencies in B vitamins or iron.
    
    

Neurological Findings

• Peripheral Neuropathy:
  • May present as burning, tingling, or numbness due to deficiencies of vitamins B12, E, or D.
• Chvostek and Trousseau Signs:
  • Reflect hypocalcemia from vitamin D deficiency.
• Ataxia and Seizures:
  • Result from hypocalcemia or cerebral calcifications.
    
    

Extraintestinal Symptoms

1. Hematologic:
   • Anaemia: From impaired absorption of iron, folate, or vitamin B12.
   • Coagulopathy: Due to vitamin K malabsorption, leading to easy bruising.
2. Skeletal:
   • Osteoporosis and Osteopenia: From calcium and vitamin D deficiencies.
3. Neurological:
   • Muscle weakness, paresthesias, and other neurological deficits.
4. Endocrine/Reproductive:
   • Infertility, delayed menarche, and secondary amenorrhea.
     
     

Primary Investigations

1. Serological Testing:
   • IgA-tissue Transglutaminase (IgA-tTG):
     • First-line test for suspected coeliac disease.
     • Higher titres correlate with increased diagnostic specificity and sensitivity.
     • Requires a gluten-containing diet for accurate results.
   • Quantitative IgA:
     • Assesses for IgA deficiency, which can render IgA-tTG insensitive.
     • Low IgA levels necessitate alternative testing.
   • IgG-Deamidated Gliadin Peptide (IgG-DGP):
     • Preferred in patients with IgA deficiency.
     • Elevated titres suggest coeliac disease, though normal results do not exclude it.
   • Endomysial Antibody (EMA):
     • High specificity but lower sensitivity compared to IgA-tTG.
     • Used as an alternative when IgA-tTG is unavailable.
2. Small Bowel Endoscopy and Biopsy:
   • Gold-standard diagnostic test.
   • Biopsies should include two samples from the duodenal bulb and four from the distal duodenum.
   • Findings include villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis, graded using the Marsh criteria:
     • Stage 0: Normal.
     • Stage 1: Increased intraepithelial lymphocytes.
     • Stage 2: Crypt hyperplasia without villous atrophy.
     • Stage 3: Villous atrophy (mild, moderate, or severe).
     • Stage 4: Mucosal hypoplasia.
3. Skin Biopsy:
   • Performed in patients with dermatitis herpetiformis.
   • Direct immunofluorescence shows granular IgA deposits in dermal papillae.
     
     

Secondary Investigations

1. Genetic Testing (HLA Typing):
   • Detects HLA-DQ2 or HLA-DQ8, which are present in over 95% of patients with coeliac disease.
   • Useful for ruling out the disease in patients already on a gluten-free diet or with equivocal findings.
2. Gluten Challenge:
   • Required for patients already adhering to a gluten-free diet.
   • Patients consume gluten (e.g., two slices of bread daily) for 2–8 weeks, followed by repeat serological and histological testing.
3. Video Capsule Endoscopy:
   • Enables imaging of the entire small intestine.
   • Useful for detecting complications like ulcerative jejunitis or lymphoma.
     
     

Supporting Laboratory Tests

1. Hematologic Tests:
   • Complete Blood Count (CBC):
     • Identifies anaemia (microcytic or macrocytic) due to iron, folate, or B12 deficiency.
   • Prothrombin Time (PT)/International Normalized Ratio (INR):
     • Prolonged PT or elevated INR due to vitamin K deficiency.
2. Nutritional Studies:
   • Assess deficiencies in calcium, phosphate, vitamin D, and serum carotene.
   • Electrolytes like potassium and magnesium may be depleted in severe malabsorption.
3. Stool Examination:
   • Fat malabsorption can be quantified with a 72-hour fecal fat collection.
4. Oral Tolerance Tests:
   • D-xylose Test: Identifies proximal small intestinal malabsorption.
   • Lactose Tolerance Test: Elevated hydrogen in breath suggests malabsorption.
     
     

Imaging Studies

1. Small Bowel Radiography:
   • Barium studies may show intestinal dilation, coarse mucosal patterns, or flocculation of barium.
2. Bone Mineral Density (BMD) Testing:
   • Recommended for adults with malabsorption or osteopenia/osteoporosis.
     
     

Recommendations for Special Populations

• Children:
  • Routine BMD testing is unnecessary unless clinical evidence of bone disease exists.
  • Growth monitoring and vitamin D assessments are prioritized.
• Adults:
  • BMD testing and nutritional assessments are performed at diagnosis and during follow-up.
    
    

Common Differential Diagnoses

1. Irritable Bowel Syndrome (IBS):
   • Symptoms: Abdominal pain, bloating, and altered bowel habits.
   • Investigations: Normal serology and small bowel histology; diagnosis based on symptom criteria.
2. Small Intestinal Bacterial Overgrowth (SIBO):
   • Symptoms: Bloating, Diarrhoea, and malabsorption.
   • Investigations: Positive jejunal aspirate culture (>10⁵ bacteria/mL) or abnormal hydrogen breath test.
3. Lactose Intolerance:
   • Symptoms: Diarrhoea, flatulence, and abdominal pain after dairy consumption.
   • Investigations: Positive hydrogen breath test or lactose intolerance test; normal small bowel biopsy.
4. Inflammatory Bowel Disease (IBD):
   • Symptoms: Chronic Diarrhoea, abdominal pain, and weight loss.
   • Investigations: Endoscopy reveals segmental involvement; histology shows transmural inflammation (Crohn’s) or mucosal inflammation (ulcerative colitis); negative coeliac serology.
5. Microscopic Colitis:
   • Symptoms: Chronic watery Diarrhoea, often nocturnal.
   • Investigations: Colonoscopic biopsy shows lymphocytic or collagenous inflammation.
6. Chronic Pancreatitis:
   • Symptoms: Steatorrhea, abdominal pain, and diabetes.
   • Investigations: Pancreatic enzyme levels, imaging (CT or MRI), and fecal elastase test.
7. Non-Coeliac Gluten Sensitivity (NCGS):
   • Symptoms: Similar to coeliac disease but without serological or histological abnormalities.
   • Investigations: Normal IgA-tTG and biopsy; improvement with a gluten-free diet.
     
     

Infectious Causes

1. Giardiasis:
   • Symptoms: Watery Diarrhoea, bloating, and abdominal cramps.
   • Investigations: Stool microscopy or antigen tests for Giardia lamblia.
2. Tropical Sprue:
   • Symptoms: Diarrhoea, weight loss, and nutritional deficiencies.
   • Investigations: Villous atrophy on biopsy; negative coeliac serology.
3. Post-Infectious Gastroenteritis:
   • Symptoms: Persistent Diarrhoea after an episode of acute gastroenteritis.
   • Investigations: Diagnosis of exclusion; may involve stool cultures.
     
     

Immunological and Autoimmune Conditions

1. Common Variable Immune Deficiency (CVID):
   • Symptoms: Recurrent infections, Diarrhoea, and malabsorption.
   • Investigations: Hypogammaglobulinemia and absence of plasma cells on biopsy; negative coeliac serology.
2. Autoimmune Enteropathy:
   • Symptoms: Diarrhoea and villous atrophy unresponsive to dietary gluten restriction.
   • Investigations: Negative IgA-tTG; presence of enterocyte antibodies on immunofluorescence.
3. Graft-Versus-Host Disease (GVHD):
   • Symptoms: Severe Diarrhoea following bone marrow transplantation.
   • Investigations: Biopsy shows crypt apoptosis and lymphocytic infiltration.
     
     

Drug-Induced Enteropathy

1. Olmesartan-Associated Enteropathy:
   • Symptoms: Diarrhoea and villous atrophy resembling coeliac disease.
   • Investigations: Normal IgA-tTG; symptoms resolve after discontinuation of the drug.
2. NSAID-Associated Enteropathy:
   • Symptoms: Non-specific Diarrhoea and mucosal inflammation.
   • Investigations: Normal coeliac serology; endoscopic findings of mucosal inflammation.
     
     

Other Conditions

1. Peptic Duodenitis:
   • Symptoms: Epigastric pain often relieved by antacids.
   • Investigations: Biopsy shows mucosal changes related to acid injury; normal IgA-tTG.
2. Eosinophilic Enteritis:
   • Symptoms: Diarrhoea, weight loss, and Anaemia.
   • Investigations: Biopsy shows eosinophilic infiltrates in the bowel wall.
     
     

Dietary Management

1. Gluten-Free Diet:
   • Essential and lifelong; adherence significantly improves quality of life, though not all patients achieve complete normalization of symptoms.
   • Gluten-free oats can be included unless cross-contamination or sensitivity to avenin is suspected.
   • Education on avoiding cross-contamination and reading food labels is critical.
2. Dietary Counseling:
   • Referral to a dietitian specializing in coeliac disease is recommended.
   • Education extends beyond gluten elimination to ensure balanced nutrition, as the gluten-free diet is often associated with:
     • Lower intake of fiber, vitamins, and minerals.
     • Higher consumption of calories, simple carbohydrates, and saturated fats, increasing the risk of obesity.
3. Social Support:
   • Encourage participation in coeliac advocacy groups to improve adherence and provide emotional support.
     
     

Nutritional Supplementation

1. Vitamin and Mineral Deficiencies:
   • Common deficiencies include:
     • Iron, vitamin D, vitamin B12, and folate.
   • Recommendations:
     • Routine calcium and vitamin D supplementation for all.
     • Iron supplementation only in documented deficiency.
     • Correct vitamin B12 and folate deficiencies.
2. Bone Health:
   • Assessment of bone mineral density (BMD) for osteopenia or osteoporosis:
     • Recommended at diagnosis in high-risk patients (age >50, severe villous atrophy, or additional risk factors for osteoporosis).
     • Repeat testing after 1–2 years on a gluten-free diet if abnormalities persist.

Monitoring and Follow-Up

1. Annual Review:
   • Assess weight, height, symptoms, and adherence to the gluten-free diet.
   • Consider repeat serological testing and nutritional evaluations.
   • Refer for additional specialist advice if concerns arise.
2. Serological Monitoring:
   • IgA-tTG levels are used to monitor gluten exposure and intestinal injury.
   • Persistently high or normalising titres guide further investigation and dietary review.
     
     

Non-Responsive Coeliac Disease

1. Definition:
   • Persistence of symptoms despite 12 months of a strict gluten-free diet.
2. Evaluation:
   • Assess for ongoing gluten exposure with a repeat dietary review.
   • Exclude alternative diagnoses such as:
     • Irritable bowel syndrome.
     • Small intestinal bacterial overgrowth (SIBO).
     • Microscopic colitis.
     • Other food intolerances.
3. Diagnostic Steps:
   • Repeat IgA-tTG testing and small bowel biopsy if symptoms persist.
     
     

Refractory Coeliac Disease

1. Definition:
   • Villous atrophy and malabsorption persist despite a gluten-free diet and exclusion of other conditions.
2. Subtypes:
   • Type 1: Responsive to immunosuppressive therapies.
   • Type 2: Associated with complications like ulcerative jejunitis or enteropathy-associated T-cell lymphoma.
3. Management:
   • Managed in specialized centers with experience in refractory coeliac disease.
   • Consider corticosteroids or other immunosuppressive treatments.
     
     

Coeliac Crisis

1. Presentation:
   • Rare and severe manifestation with hypovolemia, electrolyte imbalances, and severe diarrhoea.
2. Management:
   • Parenteral fluid replacement, nutritional support, and electrolyte correction.
   • Short-term glucocorticoids (e.g., budesonide or prednisolone) are often required until gluten-free diet benefits take effect.
     
     

General Prognosis

• Excellent for Treated Patients:
  • Up to 90% of patients achieve complete symptom resolution with a strict gluten-free diet.
  • Persistent symptoms in the remaining 10% are often due to ongoing gluten exposure, concurrent conditions like irritable bowel syndrome or lactose intolerance, or refractory coeliac disease.
• Poor for Refractory Cases:
  • Approximately 1% of patients develop refractory coeliac disease, which is associated with a higher risk of complications, including lymphomas and malabsorption.
    
    

Morbidity and Mortality

1. Morbidity:
   • Coeliac disease is rarely fatal but can cause debilitating symptoms and systemic effects, including:
     • Chronic Diarrhoea, steatorrhea, abdominal bloating, weight loss, and fatigue.
     • Malabsorption syndromes leading to Anaemia, osteopenia, and vitamin deficiencies.
     • Increased risks of malignancies, particularly gastrointestinal and lymphoproliferative cancers.
2. Mortality:
   • Untreated or refractory coeliac disease carries a modest increase in overall mortality risk, primarily due to cardiovascular diseases and malignancies.
   • Absolute mortality risk is higher in patients with persistent villous atrophy compared to those with mucosal healing.
     
     

Cancer Risks

1. Lymphomas:
   • Enteropathy-Associated T-Cell Lymphoma (EATL):
     • Poor prognosis and increased incidence in refractory coeliac disease.
   • Non-Hodgkin Lymphoma:
     • Increased risk compared to the general population.
2. Gastrointestinal Malignancies:
   • Adenocarcinomas of the small intestine, esophagus, colon, and hepatobiliary tract are more common.
   • The absolute risk remains low but is higher in patients with villous atrophy or poor adherence to a gluten-free diet.
     
     

Impact of a Gluten-Free Diet

1. Symptom Improvement:
   • Most patients experience significant symptom resolution and improved quality of life.
   • The diet reduces risks of complications, including fractures, infertility, and malignancies.
2. Mucosal Healing:
   • Mucosal healing is associated with lower cancer risks and reduced mortality.
   • Persistent villous atrophy despite adherence to the diet warrants further investigation for refractory coeliac disease.
     
     

Bone Health

1. Osteoporosis and Osteopenia:
   • Pathogenesis: Malabsorption of calcium and vitamin D impairs bone mineralisation.
   • Timeframe: Improvements typically occur within 1 year of strict gluten withdrawal.
   • Management:
     • Bone mineral density evaluation.
     • Calcium and vitamin D supplementation.
     • Weight-bearing exercise.

Dermatological Complications

1. Dermatitis Herpetiformis:
   • Manifestation: Intensely pruritic vesicular rash, commonly found on extensor surfaces.
   • Management:
     • Gluten-free diet.
     • Dapsone for symptomatic relief, although episodes may recur even with dietary compliance.

Malignancies

1. Increased Cancer Risk:
   • Types:
     • Enteropathy-Associated T-Cell Lymphoma (EATL): A rare but aggressive complication with a poor prognosis.
     • Non-Hodgkin Lymphoma: Includes T-cell and B-cell types.
     • Adenocarcinomas: Primarily of the small intestine, esophagus, colon, and hepatobiliary tract.
   • Epidemiology:
     • Cancer risk peaks within the first year after diagnosis (HR 2.47) due to ascertainment bias.
     • Long-term risk is modest (HR 1.11) and primarily affects individuals diagnosed after 60 years of age.
   • Monitoring: Persistent symptoms or Anaemia despite a gluten-free diet should prompt re-evaluation, though routine cancer screening is not currently recommended.

Neurological and Psychological Complications

1. Seizures and Ataxia:
   • Result from vitamin deficiencies (B12, D) or autoimmune activity against neural antigens.
2. Peripheral Neuropathy:
   • Characterised by burning, tingling, or numbness in extremities.
3. Psychiatric Disorders:
   • Increased prevalence of anxiety, depression, and other mood disorders.
     
     

Reproductive and Developmental Issues

1. Pregnancy Complications:
   • Risks: Miscarriage, low birth weight, and congenital malformations.
   • Mitigation: Early diagnosis and adherence to a gluten-free diet improve outcomes.
2. Growth Impairments:
   • Children with untreated coeliac disease may develop stunted growth and delayed puberty due to malnutrition.
     
     

Infectious Risks

1. Pneumococcal Infections:
   • Pathogenesis: Hyposplenism increases susceptibility to encapsulated bacteria (e.g., pneumococcus).
   • Prevention: Vaccination against pneumococcus, Haemophilus influenzae, and meningococcus is recommended.
2. Hepatitis B Vaccine Non-Response:
   • Observation: Poor immune response to the vaccine is noted in untreated patients.
   • Management: Re-vaccination following gluten-free diet adherence.
     
     

Gastrointestinal Complications

1. Pancreatitis:
   • Includes recurrent acute or chronic pancreatitis in rare cases.
   • Pancreatic exocrine insufficiency should be considered in patients with persistent Diarrhoea despite treatment.
2. Small Intestinal Bacterial Overgrowth (SIBO):
   • Can mimic coeliac symptoms and requires targeted treatment.
     
     

Other Rare Complications

1. Hyposplenism:
   • Associated with an increased risk of encapsulated bacterial infections.
   • Regular monitoring and preventive measures are advised.
2. Coeliac Crisis:
   • A rare but severe manifestation with hypovolemia, electrolyte imbalances, and severe malnutrition.
   • Requires urgent medical intervention, including corticosteroids and nutritional support.
     
     

1. Al-Toma A, Volta U, Auricchio R, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterology Journal. 2019;7(5):583-613.
2. Andrén Aronsson C, Lee HS, Hård Af Segerstad EM, et al. Association of gluten intake during the first 5 years of life with incidence of coeliac disease autoimmunity and coeliac disease among children at increased risk. JAMA. 2019;322(6):514-523.
3. Bouziat R, Hinterleitner R, Brown JJ, et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of coeliac disease. Science. 2017;356(6333):44-50.
4. Catassi C, Gatti S, Fasano A. The new epidemiology of celiac disease. Journal of Pediatric Gastroenterology and Nutrition. 2014;59 Suppl 1:S7-S9.
5. Dieterich W, Esslinger B, Schuppan D. Pathomechanisms in coeliac disease. International Archives of Allergy and Immunology. 2003;132(2):98-108.
6. Fasano A, Catassi C. Celiac disease. New England Journal of Medicine. 2012;367(25):2419-2426.
7. Green PHR, Cellier C. Celiac disease. New England Journal of Medicine. 2007;357(17):1731-1743.
8. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. 2005;40(1):1-19.
9. Husby S, Koletzko S, Korponay-Szabó IR, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for diagnosing coeliac disease. Journal of Pediatric Gastroenterology and Nutrition. 2020;70(1):141-156.
10. Ilus T, Kaukinen K, Virta LJ, et al. Incidence of malignancies in diagnosed celiac patients: A population-based estimate. American Journal of Gastroenterology. 2014;109(9):1471-1477.
11. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70-81.
12. Leffler DA, Green PHR, Fasano A. Extraintestinal manifestations of coeliac disease. Nature Reviews Gastroenterology & Hepatology. 2015;12(10):561-571.
13. Lionetti E, Gatti S, Pulvirenti A, Catassi C. Celiac disease from a global perspective. Best Practice & Research Clinical Gastroenterology. 2015;29(3):365-379.
14. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in coeliac disease. Journal of the American Medical Association (JAMA). 2009;302(11):1171-1178.
15. Mårild K, Dong F, Lund-Blix NA, et al. Gluten intake and risk of coeliac disease: Long-term follow-up of an at-risk birth cohort. American Journal of Gastroenterology. 2019;114(8):1307-1314.
16. Mårild K, Ludvigsson JF. Celiac disease in Africa: A new problem for an old continent? Clinical Gastroenterology and Hepatology. 2015;13(5):842-843.
17. National Institute for Health and Care Excellence (NICE). Coeliac disease: Recognition, assessment, and management (NG20). National Institute for Health and Care Excellence. 2015. Available at: www.nice.org.uk.
18. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131(6):1981-2002.
19. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. American Journal of Gastroenterology. 2013;108(5):656-676.
20. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. American Journal of Gastroenterology. 2012;107(10):1538-1544.
21. Shan L, Molberg Ø, Parrot I, et al. Structural basis for gluten intolerance in coeliac sprue. Science. 2002;297(5590):2275-2279.
22. Singh P, Arora A, Strand TA, et al. Global prevalence of celiac disease: Systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2018;16(6):823-836.
23. Sollid LM, Jabri B. Is celiac disease an autoimmune disorder? Current Opinion in Immunology. 2005;17(6):595-600.
24. Sollid LM, Markussen G, Ek J, et al. Evidence for a primary association of coeliac disease to a particular HLA-DQ alpha/beta heterodimer. Journal of Experimental Medicine. 1989;169(1):345-350.