Coeliac Disease

Alternate Names

• The disease is also referred to as gluten-sensitive enteropathy or coeliac sprue.

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

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.

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.

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

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.

Intraepithelial Lymphocytosis

• An increased number of intraepithelial lymphocytes, including gamma-delta T cells, is a hallmark of active coeliac disease.

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

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.

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.

Non-Gluten Components

• Wheat amylase-trypsin inhibitors (ATIs) activate toll-like receptor 4 on macrophages and monocytes.
• This contributes to low-level intestinal inflammation and may explain 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:
  • 0.2% prevalence in the 1948–1954 cohort
  • 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.
• Higher rates are observed in Ireland and Finland.
• Screening programs in countries like Italy show 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 has a bimodal distribution:
  • First peak: 8–12 months, coinciding with gluten introduction.
  • Second peak: Early adulthood (3rd to 4th decade).
  • Around 20% of diagnoses occur in individuals over the age of 60.
• Race: Once thought to affect mostly those 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% lifetime risk.
• Meta-analysis data indicate:
  • 8.9% (1:11) prevalence among siblings
  • 7.9% (1:13) among offspring
  • 3% (1:33) among parents
• Individuals with autoimmune diseases (e.g., type 1 diabetes) are at significantly higher risk.

Trends in Diagnosis

• In the United States, serologic screening studies show a prevalence of 1:133 in asymptomatic individuals.
• Despite the availability of reliable serologic tests, many cases remain undiagnosed—representing the "tip of the iceberg."

Gastrointestinal Symptoms

 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.

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.

Flatulence and Borborygmus

• Prevalent in 28% and 35–72% of patients, respectively.
• Caused by gas released from bacterial fermentation of undigested nutrients.

Weight Loss

• Observed in 45% of patients; some compensate through increased caloric intake.
• In children, failure to thrive and growth retardation are key indicators.

Abdominal Pain and Bloating

• Commonly presents with cramps and excessive malodorous flatus.

Weakness and Fatigue

• Affects 78–80% of patients, largely due to malnutrition or anaemia.

Extraintestinal Symptoms

 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.

Bone Health

• Osteopenia/osteoporosis (1–34%) due to calcium and vitamin D deficiency.
• Fracture risk is increased; secondary hyperparathyroidism may contribute.

Neurological Manifestations

• Peripheral neuropathy, paresthesias, motor weakness, and ataxia due to hypocalcemia or vitamin deficiencies.
• Seizures associated with cerebral calcifications.

Dermatological Manifestations

• Dermatitis herpetiformis (10–20%): Intensely pruritic, vesicular skin lesions on extensor surfaces.

Reproductive Health

• Amenorrhea, delayed menarche, and infertility in women.
• Impotence and infertility in men.

Hepatic and Renal Manifestations

• Elevated liver enzymes that normalise with a gluten-free diet.
• Co-occurrence with autoimmune liver diseases and IgA nephropathy.

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

 Family History

• First-degree relatives have a 10% risk of developing the disease.
• Concordance rates in monozygotic twins range from 49–86%.

Comorbid Autoimmune Diseases

• Type 1 diabetes: Co-occurs in 4–7% of patients.
• Autoimmune thyroid disease: Strong association, often requiring screening.

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 Oedema

• 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

 Hematologic

• Anaemia: From impaired absorption of iron, folate, or vitamin B12.
• Coagulopathy: Due to vitamin K malabsorption, leading to easy bruising.

Skeletal

• Osteoporosis and Osteopenia: From calcium and vitamin D deficiencies.

Neurological

• Muscle weakness, paresthesias, and other neurological deficits.

Endocrine/Reproductive

• Infertility, delayed menarche, and secondary amenorrhea.

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.

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

Skin Biopsy

• Performed in patients with dermatitis herpetiformis.
• Direct immunofluorescence shows granular IgA deposits in dermal papillae.

Secondary Investigations

 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.

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.

Video Capsule Endoscopy

• Enables imaging of the entire small intestine.
• Useful for detecting complications like ulcerative jejunitis or lymphoma.

Supporting Laboratory 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.

Nutritional Studies

• Assess deficiencies in calcium, phosphate, vitamin D, and serum carotene.
• Electrolytes like potassium and magnesium may be depleted in severe malabsorption.

Stool Examination

• Fat malabsorption can be quantified with a 72-hour faecal fat collection.

Oral Tolerance Tests

D-xylose Test

• Identifies proximal small intestinal malabsorption.

Lactose Tolerance Test

• Elevated hydrogen in breath suggests malabsorption.

Imaging Studies

 Small Bowel Radiography

• Barium studies may show intestinal dilation, coarse mucosal patterns, or flocculation of barium.

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 prioritised.

Adults

• BMD testing and nutritional assessments are performed at diagnosis and during follow-up.

Common Differential Diagnoses

Irritable Bowel Syndrome (IBS)

• Symptoms: Abdominal pain, bloating, and altered bowel habits.
• Investigations: Normal serology and small bowel histology; diagnosis based on symptom criteria.

Small Intestinal Bacterial Overgrowth (SIBO)

• Symptoms: Bloating, diarrhoea, and malabsorption.
• Investigations: Positive jejunal aspirate culture (>10⁵ bacteria/mL) or abnormal hydrogen breath test.

Lactose Intolerance

• Symptoms: Diarrhoea, flatulence, and abdominal pain after dairy consumption.
• Investigations: Positive hydrogen breath test or lactose intolerance test; normal small bowel biopsy.

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.

Microscopic Colitis

• Symptoms: Chronic watery diarrhoea, often nocturnal.
• Investigations: Colonoscopic biopsy shows lymphocytic or collagenous inflammation.

Chronic Pancreatitis

• Symptoms: Steatorrhoea, abdominal pain, and diabetes.
• Investigations: Pancreatic enzyme levels, imaging (CT or MRI), and faecal elastase test.

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

Giardiasis

• Symptoms: Watery diarrhoea, bloating, and abdominal cramps.
• Investigations: Stool microscopy or antigen tests for Giardia lamblia.

Tropical Sprue

• Symptoms: Diarrhoea, weight loss, and nutritional deficiencies.
• Investigations: Villous atrophy on biopsy; negative coeliac serology.

Post-Infectious Gastroenteritis

• Symptoms: Persistent diarrhoea after an episode of acute gastroenteritis.
• Investigations: Diagnosis of exclusion; may involve stool cultures.

Immunological and Autoimmune Conditions

Common Variable Immune Deficiency (CVID)

• Symptoms: Recurrent infections, diarrhoea, and malabsorption.
• Investigations: Hypogammaglobulinaemia and absence of plasma cells on biopsy; negative coeliac serology.

Autoimmune Enteropathy

• Symptoms: Diarrhoea and villous atrophy unresponsive to dietary gluten restriction.
• Investigations: Negative IgA-tTG; presence of enterocyte antibodies on immunofluorescence.

Graft-Versus-Host Disease (GVHD)

• Symptoms: Severe diarrhoea following bone marrow transplantation.
• Investigations: Biopsy shows crypt apoptosis and lymphocytic infiltration.

Drug-Induced Enteropathy

Olmesartan-Associated Enteropathy

• Symptoms: Diarrhoea and villous atrophy resembling coeliac disease.
• Investigations: Normal IgA-tTG; symptoms resolve after discontinuation of the drug.

NSAID-Associated Enteropathy

• Symptoms: Non-specific diarrhoea and mucosal inflammation.
• Investigations: Normal coeliac serology; endoscopic findings of mucosal inflammation.

Other Conditions

Peptic Duodenitis

• Symptoms: Epigastric pain often relieved by antacids.
• Investigations: Biopsy shows mucosal changes related to acid injury; normal IgA-tTG.

Eosinophilic Enteritis

• Symptoms: Diarrhoea, weight loss, and anaemia.
• Investigations: Biopsy shows eosinophilic infiltrates in the bowel wall.

Dietary Management

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.

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.

Social Support

• Encourage participation in coeliac advocacy groups to improve adherence and provide emotional support.

Nutritional Supplementation

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.

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

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.

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

Definition

• Persistence of symptoms despite 12 months of a strict gluten-free diet.

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

Diagnostic Steps

• Repeat IgA-tTG testing and small bowel biopsy if symptoms persist.

Refractory Coeliac Disease

Definition

• Villous atrophy and malabsorption persist despite a gluten-free diet and exclusion of other conditions.

Subtypes

• Type 1: Responsive to immunosuppressive therapies.
• Type 2: Associated with complications like ulcerative jejunitis or enteropathy-associated T-cell lymphoma.

Management

• Managed in specialized centers with experience in refractory coeliac disease.
• Consider corticosteroids or other immunosuppressive treatments.

Coeliac Crisis

Presentation

• Rare and severe manifestation with hypovolemia, electrolyte imbalances, and severe diarrhoea.

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

• 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.
• Approximately 1% of patients develop refractory coeliac disease, which is associated with a higher risk of complications, including lymphomas and malabsorption.

Morbidity and Mortality

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

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

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.

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

Symptom Improvement

• Most patients experience significant symptom resolution and improved quality of life.
• The diet reduces risks of complications, including fractures, infertility, and malignancies.

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

 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

 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

 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

 Seizures and Ataxia

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

Reproductive and Developmental Issues

 Pregnancy Complications

• Risks: Miscarriage, low birth weight, and congenital malformations.
• Mitigation: Early diagnosis and adherence to a gluten-free diet improve outcomes.

Growth Impairments

• Children with untreated coeliac disease may develop stunted growth and delayed puberty due to malnutrition.

Infectious Risks

 Pneumococcal Infections

• Pathogenesis: Hyposplenism increases susceptibility to encapsulated bacteria (e.g., pneumococcus).
• Prevention: Vaccination against pneumococcus, Haemophilus influenzae, and meningococcus is recommended.

 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

 Pancreatitis

• Includes recurrent acute or chronic pancreatitis in rare cases.
• Pancreatic exocrine insufficiency should be considered in patients with persistent Diarrhoea despite treatment.

Small Intestinal Bacterial Overgrowth (SIBO):

• Can mimic coeliac symptoms and requires targeted treatment.

Other Rare Complications

 Hyposplenism

• Associated with an increased risk of encapsulated bacterial infections.
• Regular monitoring and preventive measures are advised.

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.