Coeliac disease

For health professionals

About 1 in 100 people have it and most don't know. The diet is the only treatment, about 4 in 10 adults still have villous atrophy on it, and the drug pipeline is a graveyard with one or two survivors. The numbers, the trials, and the gaps.

At a glance

Definition

• Oslo 2013: a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals.
• ACG 2023: a permanent immune-mediated response to gluten in wheat, barley and rye; a multisystem disorder, not just a gut disease.
• Dermatitis herpetiformis is its skin form (about 13% of patients).
• Not the same as: wheat allergy (IgE-mediated) or non-coeliac gluten/wheat sensitivity (symptoms without serology or enteropathy).

Pathophysiology

Genetics

• About 90–95% of patients carry HLA-DQ2.5; most of the rest carry DQ8 or DQ2.2. Under 1% carry neither (ESsCD 2025).
• The genes are necessary but not sufficient: 30–40% of Western populations carry DQ2/DQ8, and 40–50% of Australians.
• Risk is up to 30% with homozygous DQ2.5 vs about 3% with other risk genotypes (ESsCD 2025; likely at-risk cohorts).
• HLA explains about 40% of genetic variance; non-HLA loci about 15%.
• Negative HLA typing makes coeliac disease very unlikely (under 1% per AJGP). Positive typing means little.

Immune cascade

• Gliadin peptides resist digestion. The 33-mer (α-gliadin p55–87) is the classic immunodominant fragment.
• Tissue transglutaminase 2 (TG2) deamidates glutamine to glutamate, increasing peptide binding to HLA-DQ2/DQ8.
• Gluten-specific CD4⁺ T cells drive the response, and B cells make anti-TG2 and anti-DGP antibodies (the serology targets).
• IL-15 licenses cytotoxic CD8⁺ intraepithelial lymphocytes (via NKG2D) to kill enterocytes, causing villous atrophy and crypt hyperplasia.
• Histology is graded on the modified Marsh (Marsh–Oberhuber) scale.

Infant feeding: timing doesn't prevent it

• PreventCD (n=944): small gluten doses at 16–24 weeks gave coeliac disease by age 3 in 5.9% vs 4.5% (HR 1.23, 0.79–1.91). No prevention.
• CELIPREV (n=832): introducing gluten at 12 vs 6 months delayed disease (2 years: 5% vs 12%) but didn't prevent it (5 years: 16% vs 16%).
• TEDDY (observational, n=6,605 at-risk children): each extra 1 g/day of gluten in early childhood gave HR 1.50. Amount may matter more than timing.

Epidemiology

Global

• Prevalence (Singh 2018): seroprevalence 1.4%, biopsy-confirmed 0.7%. Europe and Oceania 0.8%, Asia 0.6%, North America and Africa 0.5%, South America 0.4%.
• Females 0.6% vs males 0.4%; children 0.9% vs adults 0.5%. Diagnosed cases run about 1.5–2 female to 1 male, but screening suggests true occurrence is closer to equal.
• Incidence (King 2020): women 17.4 and men 7.8 per 100,000 person-years; children 21.3 vs adults 12.9. Rising about 7.5% a year.
• Hotspots: Saharawi refugee children 5.6%, the highest reported. Northern India 1.23% seropositive vs southern India 0.10%, with similar HLA carriage, so wheat intake explains the gap.
• Lower rates: Japan about 1 in 20,000. No reliable sub-Saharan African data.

Australia

• Serogenetic study (Anderson 2013): about 1.3% of adults, versus 0.5–0.7% biopsy-confirmed.
• Coeliac Australia and newsGP: about 1 in 70, with about 80% undiagnosed.
• No AIHW national prevalence figures found.

Causes and risk factors

• Necessary: HLA-DQ2/DQ8 plus gluten.
• Higher-risk groups (who to test):
  • First-degree relatives: 5–10% lifetime risk, up to 20% with several affected relatives.
  • Type 1 diabetes: 6.0% biopsy-confirmed.
  • Down syndrome 5.8%, Turner syndrome 4.8%, Williams syndrome about 9.5% (one small series).
  • Selective IgA deficiency: about 6% have coeliac disease (BSG 2026).
  • Autoimmune thyroid disease: 1.6%.
  • Iron deficiency anaemia: 3.2% (5.5% in high-quality studies).
  • IBS-type symptoms: OR 4.48 for biopsy-proven coeliac disease.
  • Osteoporosis: 1.6%. Whether to screen is contested.
• Hypothesised environmental triggers: early-life gluten amount (TEDDY) and gut infections. None is proven causal.

Preventable factors

• No intervention has prevented coeliac disease in a trial. Infant gluten timing (PreventCD, CELIPREV) failed.
• No population attributable fractions exist.
• What is preventable is the harm of late diagnosis: anaemia, osteoporosis and fracture (OR 1.43), adverse pregnancy outcomes, and years of symptoms.

Diagnosis essentials

• Must be eating gluten. Gluten challenge if already gluten free:
  • Coeliac Australia: about 10 g a day (about 4 slices of bread; 5 g in children) for at least 6 weeks.
  • BSG 2026: 3–6 g a day for at least 6 weeks, or about 10 g a day if only 2 weeks.
  • ESsCD 2025: at least 3 g a day for 6 weeks. Check HLA first: negative typing can avoid the challenge.
• Serology (Sheppard 2022):
  • tTG-IgA: adults sensitivity 90.7%, specificity 87.4%. Children 97.7% and 70.2%.
  • EMA: adults 88.0% and 99.6%.
  • Always check total IgA (2–3% of patients are IgA deficient) or add DGP-IgG.
  • Australia: tTG-IgA plus DGP-IgG or total IgA (MBS 71164). Expect 10–15% false negatives.
  • Isolated positive DGP predicts coeliac disease in only about 15%.
• Biopsy: at least 4 from the distal duodenum plus 1–2 from the bulb. Bulb biopsies add 6.9% yield.
• No-biopsy pathways:
  • Children (ESPGHAN 2020): tTG-IgA at least 10× upper limit of normal plus positive EMA on a second sample.
  • Adults (ESsCD 2025): tTG-IgA at least 10× ULN confirmed on a second sample, age under 45, no red flags.
  • Adults (BSG 2026): symptomatic adults in secondary care with at least 10× ULN, by shared decision; no age limit and no second sample needed.
  • Only 20–30% of adults with a raised tTG reach 10× ULN, so most still need biopsy.
  • Australia: no Australian adult no-biopsy guidance found. Assays vary and EMA is hard to get, so involve a gastroenterologist.
• Point-of-care tests are not a diagnosis and aren't validated for primary care.

Current treatment

Lifelong gluten-free diet

• Threshold (Catassi 2007 RCT, n=39 completers): 50 mg of gluten a day caused mucosal damage (villous height to crypt depth ratio −20%). 10 mg a day did not significantly (−1%) but was a grey area. One slice of bread holds about 2–3 g.
• Labelling:
  • Australia and NZ: "gluten free" means no detectable gluten (ELISA detects about 1–3 ppm), and no oats.
  • USA, UK and EU: up to 20 ppm.
  • "Low gluten" (up to 200 ppm) is not suitable.
• Oats: fewer than 10% of patients react to avenin, unpredictably. Oats can't be labelled gluten free in Australia; a supervised trial with biopsy is an individual decision.
• Adherence: strict adherence 42–91% across 38 studies.
• Hidden exposure: 88.7% of adults on a long-term GFD had at least one positive stool or urine gluten immunogenic peptide test over 4 weeks.
• Burden: treatment burden scored 44.9/100, above diabetes (41.7) and below dialysis (56.4). Gluten-free baskets cost up to 17% more (Australia, 2016 data).

Follow-up

• Coeliac Australia:
  • Dietitian at diagnosis and ongoing.
  • Serology every 3–6 months until normal, then every 1–2 years.
  • Optional repeat biopsy at about 2 years.
  • DXA for all adults at diagnosis, then every 5 years.
  • Pneumococcal vaccination (hyposplenism); consider meningococcal and Hib.
• About 80% are seronegative by 6–12 months (ACG 2023). Normal serology doesn't guarantee mucosal healing.
• ACG 2023 advises against home gluten-detection devices.

Non-responsive and refractory disease

• Ongoing gluten exposure causes over a third of non-response. True refractory disease (RCD) is about 10% of non-responders. Exclude microscopic colitis, SIBO, pancreatic insufficiency and IBS first.
• RCD I (normal intraepithelial lymphocytes): open-capsule budesonide gave clinical response in 92% and histological response in 89% (Mukewar 2017, n=57).
• RCD II (aberrant clonal lymphocytes): 5-year survival 58% vs 96% in RCD I. 52% progressed to enteropathy-associated T-cell lymphoma (EATL), with 2-year survival of 15–20% (Amsterdam series).

Dermatitis herpetiformis

• Dapsone 25–50 mg a day (up to 100 mg) controls the itch within days. It doesn't treat the gut; the GFD does.

Emerging treatments and trials

No drug is approved anywhere. FDA guidance on drugs as an add-on to the GFD is still a draft (2022).

Still standing

• TAK-227 / ZED1227 (oral TG2 inhibitor):
  • Phase 2a (NEJM 2021, n=159, 3 g gluten a day for 6 weeks): protected the mucosa at all doses.
  • Phase 2b CEC-004 (n=397, villous atrophy despite GFD): missed the primary endpoint (27.1/16.9/25.3% vs 19.3% on placebo). 50 mg once daily improved histology. ICDS abstract, November 2026; not yet peer reviewed.
  • A phase 2 in non-responsive disease is recruiting.
• DONQ52 (antibody against the HLA-DQ2.5–gluten complex): phase 1 (n=63) suppressed gluten-induced T-cell and IL-2 responses. ICDS abstract, 2026.
• KAN-101 (tolerogenic, liver-targeted): phase 2 reported symptom benefit without numbers (2025). FDA Fast Track.
• TPM502 (tolerising nanoparticle): phase 2a "positive" tolerance markers (2024); data not released.
• IMU-856 (barrier regeneration): phase 1b (n=43) showed less villous height loss after gluten challenge (21–23 µm vs 60 µm). Post hoc and exploratory.
• Ordesekimab (anti-IL-15): phase 2 in non-responsive disease (n=388) completed in 2024. No public results.

Fallen

• Larazotide (tight-junction regulator): phase 3 CeDLara stopped in 2022; the sample size needed was too large.
• Nexvax2 (peptide vaccine): stopped in 2019, no benefit over placebo.
• Latiglutenase (CeliAction, n=494): missed its histology endpoint. Post hoc symptom signals in seropositive patients.
• AMG 714 (anti-IL-15, n=64): primary endpoint negative.
• TAK-062 (zamaglutenase) and TAK-101 (nanoparticle): discontinued by Takeda. TAK-101 cut interferon-γ responses by 88% but histology wasn't significant.

Gaps and open questions

Labelled hypotheses, not recommendations.

• Screening: USPSTF (2017) found insufficient evidence for screening asymptomatic people.
  • Screening finds 1.5–2.9% positive in children (Colorado ASK 1.5%, Italian pilot 2.8–2.9%) and 2.6% in Danish adolescents.
  • Italy now screens children aged 2–10 by law.
  • Whether screen-detected, asymptomatic patients benefit from a lifelong diet is untested.
• Hypothesis: the gluten threshold is individual. One small 90-day RCT underpins the 10–50 mg a day range. Some patients react at 10 mg.
• Hypothesis: the end point is wrong. Persistent villous atrophy (43% in a Swedish cohort) carried higher lymphoma risk (102.4 vs 31.5 per 100,000 a year) but no excess mortality (HR 0.99). We don't know whether chasing mucosal healing improves hard outcomes.
• Hypothesis: amount of early gluten matters, not timing. TEDDY's dose signal is observational. A dose-limiting infant trial in high-risk HLA children is the logical test.
• Australian gaps: no adult no-biopsy consensus, no national prevalence data, and no EMA access in many labs.
• Excluded populations: Asia, Africa and the Middle East are under-studied despite rising wheat intake; most trials enrol white Europeans and North Americans.
• Hypothesis: drugs will be adjuncts, not cures. Every drug so far is aimed at reducing harm from accidental exposure on top of a GFD, not replacing it.

Prognosis and quality of life

• Mortality (Lebwohl, JAMA 2020; 49,829 Swedish cases): 9.7 vs 8.6 deaths per 1,000 person-years, HR 1.21. HR 1.69 at age 18–39 and 2.34 in the first year after diagnosis.
• Small bowel adenocarcinoma: about 3-fold risk but rare: 0.06% vs 0.02%, 1 extra case per 2,944 patients over 10 years.
• Lymphoma: higher with persistent villous atrophy (102.4 vs 31.5 per 100,000 a year; general population 24.2).
• Fracture: OR 1.43 (meta-analysis, 20,955 patients).
• Pregnancy (untreated disease): low birthweight RR 1.75, fetal growth restriction 1.54, preterm birth 1.37, miscarriage 1.39. The excess risk isn't significant on a GFD. Coeliac disease is commoner in unexplained infertility (OR 5.06).
• Mucosa: recovery in 34% at 2 years and 66% at 5 years in adults.
• Gluten ataxia remains a contested entity: antigliadin antibodies in about 41% of sporadic idiopathic ataxia in one series.

Guidelines

• Coeliac Australia: testing for coeliac disease (health professionals)
• Coeliac Australia: monitoring and follow-up (PDF)
• Coeliac Australia: gluten challenge (PDF)
• AJGP 2018: interpreting tests for coeliac disease (Tye-Din)
• BSG 2026: diagnosis and management of adult coeliac disease (PDF)
• ESsCD 2025 guideline, part 1
• ACG 2023 clinical guideline: diagnosis and management of celiac disease
• ESPGHAN 2020: diagnosis of coeliac disease in children
• NICE NG20: coeliac disease, recognition, assessment and management
• World Gastroenterology Organisation 2016 global guideline

Key trials

• Catassi (2007): 50 mg gluten a day damages the mucosa; 10 mg is a grey area.
• PreventCD (2014): early small-dose gluten doesn't prevent coeliac disease.
• CELIPREV (2014): later gluten delays but doesn't prevent it.
• CeliAction (latiglutenase, 2017): histology endpoint missed.
• Nexvax2 (2019): stopped for futility.
• AMG 714 (2019): primary endpoint missed.
• TEDDY (2019): more early gluten, more coeliac disease (HR 1.50 per g/day; observational).
• Lebwohl mortality cohort (2020): HR 1.21.
• ZED1227 phase 2a (2021): TG2 inhibition protected the mucosa.
• TAK-101 (2021): immune tolerance signal; histology not significant.
• CeDLara (larazotide, 2022): stopped.
• IMU-856 phase 1b (2023): exploratory villous protection.
• TAK-227 phase 2b (2026): primary endpoint missed; histology signal at 50 mg.

Sources

• Ludvigsson JF et al. Oslo definitions for coeliac disease. Gut 2013
• Singh P et al. Global prevalence of celiac disease. Clin Gastroenterol Hepatol 2018
• King JA et al. Incidence of celiac disease is increasing over time. Am J Gastroenterol 2020
• Anderson RP et al. Australian serogenetic study. BMC Med 2013
• newsGP: detecting coeliac disease in general practice
• Ramakrishna BS et al. Prevalence of coeliac disease in India. Am J Gastroenterol 2016
• Catassi C et al. Coeliac disease in Saharawi children. Bull WHO 2001
• Review: genetics and immunopathogenesis of coeliac disease. Front Immunol 2021
• Vriezinga SL et al. PreventCD. NEJM 2014
• Lionetti E et al. CELIPREV. NEJM 2014
• Andrén Aronsson C et al. TEDDY gluten intake. JAMA 2019
• Elfström P et al. Coeliac disease in type 1 diabetes. Aliment Pharmacol Ther 2014
• Coeliac disease in Down syndrome: meta-analysis. Oncotarget 2018
• Coeliac disease in Turner syndrome: meta-analysis. Front Med 2021
• Giannotti A et al. Coeliac disease in Williams syndrome. J Med Genet 2001
• Roy A et al. Coeliac disease in autoimmune thyroid disease. Thyroid 2016
• Mahadev S et al. Coeliac disease in iron deficiency anaemia. Gastroenterology 2018
• Coeliac disease in osteoporosis: meta-analysis
• Irvine AJ et al. Coeliac disease in IBS-type symptoms. Am J Gastroenterol 2017
• Sheppard AL et al. Diagnostic accuracy of serology. Aliment Pharmacol Ther 2022
• Catassi C et al. Safe gluten threshold RCT. Am J Clin Nutr 2007 (PDF)
• Coeliac Australia: making a gluten-free claim (FSANZ)
• Coeliac Australia: oats and the gluten-free diet
• Hall NJ et al. Adherence to a gluten-free diet: systematic review. Aliment Pharmacol Ther 2009
• Stefanolo JP et al. Gluten exposure on a gluten-free diet (GIP). Clin Gastroenterol Hepatol 2021
• Rubio-Tapia A et al. Mucosal recovery and mortality. Am J Gastroenterol 2010
• Lebwohl B et al. Persistent villous atrophy and lymphoma. Ann Intern Med 2013 (release)
• HCPLive: ACG 2023 guideline summary
• MDedge: causes of non-responsive coeliac disease (Leffler 2007)
• Al-toma A et al. Survival in refractory coeliac disease and EATL. Gut 2007 (PDF)
• Mukewar SS et al. Open-capsule budesonide for refractory coeliac disease. Am J Gastroenterol 2017
• Lebwohl B et al. Mortality in coeliac disease. JAMA 2020 (PDF)
• Karolinska: small bowel cancer risk (Emilsson, Gastroenterology 2020)
• Olmos M et al. Fracture risk in coeliac disease: meta-analysis. Dig Liver Dis 2008
• Tersigni C et al. Coeliac disease and reproduction. Hum Reprod Update 2014 (PDF)
• Shah S et al. Treatment burden in coeliac disease. Am J Gastroenterol 2014
• University of Wollongong: cost of gluten-free food (2016)
• Salmi TT. Dermatitis herpetiformis review. 2019 (PDF)
• Gluten ataxia: fact or fiction (Hadjivassiliou, Brain 2003)
• FDA draft guidance: developing drugs for adjunctive treatment to a GFD (2022)
• Healio: ZED1227 phase 2a (Schuppan, NEJM 2021)
• ICDS 2026 abstract: TAK-227 phase 2b CEC-004
• Trial listing: ZED1227 in non-responsive coeliac disease
• ICDS 2026 abstract: DONQ52 phase 1
• Fierce Biotech: Takeda discontinues TAK-062 and TAK-101
• Kelly CP et al. TAK-101 phase 2a. Gastroenterology 2021 (PDF)
• 9 Meters: CeDLara (larazotide) phase 3 stopped (2022)
• Coeliac UK: Nexvax2 trials discontinued (2019)
• Healio: latiglutenase CeliAction (Dig Dis Sci 2017)
• Lähdeaho ML et al. AMG 714 phase 2a. Lancet Gastroenterol Hepatol 2019 (PDF)
• Anokion: KAN-101 phase 2 (2025)
• Topas: TPM502 phase 2a (2024)
• Immunic: IMU-856 phase 1b (2023)
• USPSTF 2017: screening for celiac disease (AFP)
• Healio: ASK Colorado screening (Am J Gastroenterol 2021)
• AOECS: Italy's paediatric screening law
• Danish adolescent screening study. JPGN 2022

Information only. Test choice, gluten challenge amounts and biopsy rules differ between guidelines and labs. Check local pathways and current guidance before acting.

Reviewed 31 October 2026. General education for health professionals; not a substitute for local protocols.

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