Matt Johnson + David Dewar

Professor Paul Ciclitira

St Thomas’ Hospital, London

MortalityMortality

• Almost all mortality in CD is due to Almost all mortality in CD is due to malignancymalignancy

• >50% due to EATCL >50% due to EATCL

• Other tumours = mouth, oesophagus, sbOther tumours = mouth, oesophagus, sb

• Mortality 1.9-3.4x control populationMortality 1.9-3.4x control population

• Holmes et al : 2x control popHolmes et al : 2x control pop11

• Mortality normal after 5 yrs on GFDMortality normal after 5 yrs on GFD22

1Holmes GK et al (1976) Gut 17(8): 612-92Holmes GK et al (1989) Gut 30(3): 333-8

Prevalence of coeliac Prevalence of coeliac diseasedisease

• SwedenSweden 1:67 antibody positive1:67 antibody positive

• IrelandIreland 1:100 1:100

• England England 1:1501:150

• Europe Europe 1:3001:300

• N America N America 1:3001:300

• AustraliaAustralia1:3001:300

Cereal TaxonomyFamily GRAMINEAE

Subfamily FESUCOIDEAE PANICOIDEAE

Tribe TRITICEAE AVENEAE ORYZEAETRIPSACEAE

Subtribe TRITICINAE

Genus TRITICUM SECALE HORDEUM AVENA ORYZA ZEA

Species WHEAT RYE BARLEY OATS RICE MAIZE

Are oats safe in coeliac Are oats safe in coeliac disease?disease?Pure oat products are probably safe:Pure oat products are probably safe:

– Janatuinen et al 2002 Janatuinen et al 2002 Gut. Gut. (Finland)(Finland)

•5 year follow up of oat and non-oat eating 5 year follow up of oat and non-oat eating coeliacscoeliacs

•No clinical, serological and histological No clinical, serological and histological differences at 5 years.differences at 5 years.

• UK oat products may have contamination UK oat products may have contamination (harvesting, milling, food preparation)(harvesting, milling, food preparation)

• Gluten free = Gluten free = Food industry standardsFood industry standards 200 ppm 200 ppm

Tissue transglutaminaseTissue transglutaminase

• Auto-antigen target of anti-endomyseal Auto-antigen target of anti-endomyseal antibodiesantibodies

• Intracellular, released during Intracellular, released during inflammationinflammation

• Cross links matrix proteins, stabilising Cross links matrix proteins, stabilising connective tissue during inflammation.connective tissue during inflammation.

• Deamidates specific glutamine residues.Deamidates specific glutamine residues.

• Creation of neo-epitopes with glutenCreation of neo-epitopes with gluten

TAKE THAT

VILLUSES

Pathology – the coeliac Pathology – the coeliac lesionlesion

• Villus atrophyVillus atrophy

• Crypt hyperplasiaCrypt hyperplasia

• Loss of enterocyte heightLoss of enterocyte height

• Lamina propria infiltrationLamina propria infiltration

• Increased intra-epithelial lymphocytes Increased intra-epithelial lymphocytes

• Increased mitotic activity Increased mitotic activity

Intra-epithelial lymphocytes

NORMAL SMALL INTESTINE

COELIAC DISEASE

Clinical categories of Clinical categories of coeliacscoeliacs• Coeliac diseaseCoeliac disease

• Undiagnosed coeliac diseaseUndiagnosed coeliac disease

• Silent coeliac diseaseSilent coeliac disease

• Latent coeliac diseaseLatent coeliac disease

Clinical features in adultsClinical features in adults

• Lethargy “Tired all the time”Lethargy “Tired all the time”

• Anaemia (Fe, folate, B12 and mixed) Anaemia (Fe, folate, B12 and mixed)

• Abdominal pain Abdominal pain

• Non-specific abdominal symptomsNon-specific abdominal symptoms

• DiarrhoeaDiarrhoea

• Weight lossWeight loss

• OsteoporosisOsteoporosis

• Sub-fertilitySub-fertility

AssociationsAssociations

• Dermatitis herpetiformisDermatitis herpetiformis• IgA deficiencyIgA deficiency• SBBOSBBO• HyposplenismHyposplenism• Autoimmune conditionsAutoimmune conditions

– Thyroid diseaseThyroid disease– Type 1 diabetesType 1 diabetes– Addison’sAddison’s– Sjogrens syndromeSjogrens syndrome

AD and age at diagnosis:AD and age at diagnosis:

GroupGroup Prevalence ADPrevalence AD

A1 – age<2yrsA1 – age<2yrs 5.1%5.1%

A2 – age 2-10yrsA2 – age 2-10yrs 17%17%

A3 – age>10yrsA3 – age>10yrs 23.6%23.6%

• Prevalence of autoimmune disease is Prevalence of autoimmune disease is related to duration of gluten exposurerelated to duration of gluten exposure

Ventura A (1999) Gastroenterology 117:297-303

OsteoporosisOsteoporosis

• 47% women < 50% men on GFD have 47% women < 50% men on GFD have osteopenia / osteoporosisosteopenia / osteoporosisaa

• Improvement 1 year post treatmentImprovement 1 year post treatmentbb

aMcFarlane (1995) Gut 36:710-14bValdimarsson (1996) Gut 38:322-7

DERMATITIS HERPETIFORMIS

Dermatitis HerpetiformisDermatitis Herpetiformis

• 2 -3%2 -3%

• IgA deposition at the basement IgA deposition at the basement membranemembrane

• RxRx

• 1) GFD = 6-12/121) GFD = 6-12/12

• 2) Dapsone2) Dapsone

SBBOSBBO• 8% of non-responsive coeliac patients8% of non-responsive coeliac patients• SymptomsSymptoms

– Diarrhoea > Pain > Weight loss > Bloating > Diarrhoea > Pain > Weight loss > Bloating > Flatulence > Nausea > SteatorrhoeaFlatulence > Nausea > Steatorrhoea

– Nutritional deficienciesNutritional deficiencies• Vit D (tetany) > Vit A (night blindness) > Cobalamin Vit D (tetany) > Vit A (night blindness) > Cobalamin

(neuropathy) > Vit B12 (macrocytosis) (neuropathy) > Vit B12 (macrocytosis)

• Ix = H2 Lactose / Glucose breath testIx = H2 Lactose / Glucose breath test• Rx = 7-10/7 course of Rx = 7-10/7 course of

– Co-amoxiclav + MetronidazoleCo-amoxiclav + Metronidazole– Cephalexin + Co-trimoxazoleCephalexin + Co-trimoxazole– Gentamicin + MetronidazoleGentamicin + Metronidazole

HyposplenismHyposplenism

• ? 80% of coeliac patients have evidence of ? 80% of coeliac patients have evidence of hyposplenism {Vasquez 1991}hyposplenism {Vasquez 1991}

• FeaturesFeatures– Howell Jolly bodies, target cells, thrombocytopeniaHowell Jolly bodies, target cells, thrombocytopenia

• MxMx– Meningococcal, Pneumococcal + HIB vaccinationsMeningococcal, Pneumococcal + HIB vaccinations– Prophylactic antibioticsProphylactic antibiotics

Microscopic colitis (5%)Microscopic colitis (5%)

• The Cochrane database = 5 RCTs

• 3 x Budesonide 9mg od tapering over 8/52– significant symptomatic and histological benefit– anecdotal evidence suggesting long term remission.

• 1 x Bismuth subsalicylate (n=12), three chewable 262mg tablets tds for 8/52– symptomatic and histological improvement– with resolution of the collagenous band– Pepto-Bismol has three different potential modes of action as an antibacterial, anti-

inflammatory and anti-diarrhoeal – Denol does not have the subsalicylate component

• 1 x High dose Prednisolone (50mg) – can provide symptom relief, but often without histological improvement– relapses are common

• Given the evidence, we advocate using • 1st and 2nd line therapy = Budesonide and bismuth subsalicylate (Pept-Bismol) • 3rd line = consider trying mesalazine in LC and cholestyramine in CC

Ulcerative jejunitisUlcerative jejunitis

• Rare (6Rare (6thth decade) decade)• Related to Enteropathy-associated T cell Related to Enteropathy-associated T cell

lymphoma (EATL)lymphoma (EATL)• Gastroscopy / Enteroscopy - May be segmentalGastroscopy / Enteroscopy - May be segmental• Laparoscopy and full thickness biopsyLaparoscopy and full thickness biopsy• CT / repeat barium studiesCT / repeat barium studies• T Cell receptor PCR T Cell receptor PCR monomonoclonalityclonality

– UCL – Prof. IsaacsonUCL – Prof. Isaacson– Atypical gTcell receptor abnormalitiesAtypical gTcell receptor abnormalities

• Steroids, nutritional support, close observationSteroids, nutritional support, close observation

CT

MRI

DiagnosisDiagnosis

• SerologySerology

• D2 Bx (D2 Bx (≥≥3 biopsies with jumbo 3 biopsies with jumbo forceps)forceps)

• Repeat biopsy on gluten-free dietRepeat biopsy on gluten-free diet

• Repeat challenge (>10g per day, 2/52)Repeat challenge (>10g per day, 2/52)

• ESPGAN guidelinesESPGAN guidelines

Coeliac antibodiesCoeliac antibodies

• Anti-reticulin, anti-gliadin, anti-jejunalAnti-reticulin, anti-gliadin, anti-jejunal

• Anti-endomysialAnti-endomysial

• Anti-tissue transglutaminaseAnti-tissue transglutaminase

Serological screening testsSerological screening tests

SensitivitySensitivity SpecificitySpecificity

IgA Anti-GliadinIgA Anti-Gliadin 83%83% 82%82%

IgA Anti EndomysiumIgA Anti Endomysium 90%90% 99%99%

IgA Anti tissue IgA Anti tissue transglutaminase (Human transglutaminase (Human Umbilical cord)Umbilical cord)

93%93% 95%95%

Developments in serological Developments in serological teststests

• IgA deficiency occurs in 2-3% of coeliacsIgA deficiency occurs in 2-3% of coeliacs– Coeliacs disease occurs in 8% of IgA deficientsCoeliacs disease occurs in 8% of IgA deficients

• Serology Ix Serology Ix – IgG1 subgroup testing more specific than IgGIgG1 subgroup testing more specific than IgG– Combine both IgA and IgG1 EMA/tTG testingCombine both IgA and IgG1 EMA/tTG testing

• 10-15% are symptomatic10-15% are symptomatic– Recurrent sinopulmonary infectionsRecurrent sinopulmonary infections– AI associationsAI associations– Anaphylactic Transfusion ReactionsAnaphylactic Transfusion Reactions– GI Disorders (failure to clear large proteins from GI mucosal barrierGI Disorders (failure to clear large proteins from GI mucosal barrier

Using Serology to Monitor Using Serology to Monitor PatientsPatients

• IgA gliadin and TTG normalise on a IgA gliadin and TTG normalise on a strict GFD after 3-6/12strict GFD after 3-6/12

• Must have pre-treatment levelsMust have pre-treatment levels

• IgG gliadin can be used but takes IgG gliadin can be used but takes longer to normaliselonger to normalise

• IgA endomyseal is costly and more IgA endomyseal is costly and more difficult to quantifydifficult to quantify

Screening Relatives Screening Relatives Fraser J: GUT; Fraser J: GUT; 20042004

• 11stst Degree relatives = 5%-15% Degree relatives = 5%-15%• 2nd Degree relatives no increased prevalence

• 11.4% of these would be missed using IgA EMA in isolation and so an algorithm has been devised

• Coeliac disease can occur in antibody negative individuals and that biopsy is recommended if there is a high index of suspicion.

Algorithm for Screening 1Algorithm for Screening 1

RelativesRelatives

Treatment of coeliac Treatment of coeliac diseasedisease

• Gluten-free dietGluten-free diet

• Avoidance of wheat, rye and barleyAvoidance of wheat, rye and barley

• Oats (probably OK)Oats (probably OK)

• DieticianDietician

• Codex Codex AAlimentariuslimentarius

• Coeliac societiesCoeliac societies handbook handbook

Treatment of coeliac Treatment of coeliac diseasedisease• Gluten-free dietGluten-free diet• Avoidance of wheat, rye and barleyAvoidance of wheat, rye and barley• Oats (probably OK)Oats (probably OK)• DieticianDietician• Codex Codex AAlimentariuslimentarius• Coeliac societiesCoeliac societies handbook handbook

• BUT NOT CORNFLAKESBUT NOT CORNFLAKES

Efficacy of Gluten-free dietEfficacy of Gluten-free diet

• 70% 70% respond symptomaticallyrespond symptomatically

• 30%30%refractoryrefractory

non-compliantnon-compliant

inadvertent intakeinadvertent intake

another diagnosisanother diagnosis

Dewar D, Johnson MW, Ciclitira PJ, GUT 2005

Gluten-free diet failureGluten-free diet failure

• Check diagnosis correctCheck diagnosis correct

• Consider second diagnosis Consider second diagnosis – pancreatic insufficiencypancreatic insufficiency

• Check ComplianceCheck Compliance– inadvertent/intentionalinadvertent/intentional

• Refractory sprueRefractory sprue

•REPEAT DUODENAL BIOPSYREPEAT DUODENAL BIOPSY

PitfallsPitfalls

• Insufficient advice (or effort)Insufficient advice (or effort)

• Malted cereals + CornflakesMalted cereals + Cornflakes

• Beer contaminationBeer contamination

• Cooking saucesCooking sauces

• Oat contaminationOat contamination

Refractory coeliac diseaseRefractory coeliac disease

• Continued symptomsContinued symptomsPrednisolone 7.5-20 mgPrednisolone 7.5-20 mg

• Consider an immuno-modulator (AZA) Consider an immuno-modulator (AZA)

• UnwellUnwellWeight lossWeight lossHypoalbuminaemiaHypoalbuminaemiaDehydrationDehydrationSteatorrhoeaSteatorrhoeaPrednisolone 0.5 mg/kgPrednisolone 0.5 mg/kg

CD in the Elderly (5-20%)CD in the Elderly (5-20%) Johnson,MW: Johnson,MW:

GUT; 2003GUT; 2003

>65yrs <65yrs Stata p values

Overall D2 Bx rate 276/628 (43.9%) 222/576 (38.8%) 0.07

Anaemia 223/351 (63.5%) 96/118 (81.4%) 0.0003 Malabsorption 27/30 (90%) 77/79 (97.5%) NS Atypical Dyspepsia 16/113 (14.2%) 38/204 (18.6%) NS Abdominal pain 11/122 (9.8%) 38/204 (38%) 0.03 Altered Bowel habit 10/11 (90.9%) 12/16 (75%) NS Weight loss 18/64 (28.1%) 22/36 (61.1%) 0.0012 Profound Tiredness 1/2 (50%) 0/0 NA

No. with combinations 3/57 (5.3%) 3/71(4.2%) NSNo. diagnosed 4/628 (0.64%) 17/576 (2.95%) 0.0001.

Mortality 1/276 (3.6 per 1000) 0/222 0.0038

Coeliac disease gCoeliac disease guidelinesuidelines

• AGA Technical Review on Celiac SprueAGA Technical Review on Celiac Sprue Gastroenterology 2001; 120:1526-1540Gastroenterology 2001; 120:1526-1540

• British Society of Gastroenterology British Society of Gastroenterology 19961996Guidelines for the Management of Patients Guidelines for the Management of Patients with Coeliac Diseasewith Coeliac Disease(soon to be updated)(soon to be updated)