CG86 Coeliac disease: full guideline - appendix 6.6

Coeliac disease appendix 6.6 Evidence tables

Reference Study type/Evidence level

Number of patients

Patient characteristics Intervention Comparison Length of follow-up

Outcome measures

Source of funding

Abrams JA, Brar P, Diamond B, Rotterdam H, Green PH. Utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease. Clinical Gastroenterology & Hepatology 2006;4:726-30

Cohort N=122

Adults

USA

Inclusion: consecutive suspected celiac disease, Jan 2000 to December 2003, 32.4% male, 67.6% female, 100% white, 44.5yrs (SD 15.4)

Exclusion: <16years, selective IgA deficiency (total serum IgA level <0.05g/L), on a GFD, taking immunosuppressants, initial serological testing at >1 lab

IgA anti-t TG (human) antibody determination before upper endoscopy for duodenal biopsies1

Serological testing was performed at various commercial labs

Control group, those with a normal biopsy

Duodenal biopsy (further details not given)

Serological testing at commercial labs around the country

Pathologic diagnosis of CD required intrathelial lymphocytosis and either partial villous atrophy (Marsh IIIA) or total villous atrophy (Marsh IIIB and IIIC)

Diagnosis of CD, had to exhibit histologic or serologic improvements after 6mths on GFD

Not stated

1 All duodenal biopsies reviewed blinded by a single pathologist who did not know the antibody status

NICE clinical guideline 86 Coeliac disease: appendix 6.6 of 111

Effect size:

N=6 excluded selective IgA deficiency

N=102 celiac disease diagnosed2

Anti-t TG:CD, 70.6% (N=72/102) +veNon-CD, 65.0% (N=13/20) –ve PPV 91.1%NPV 30.2%

2X2: (a)TP 72

(b)FP 7

(d)FN30

(c)TN13

CD group:Total villous atrophy 90.0% (N=54/60) +ve anti-tTG, sensitivity 90.0 (79.5 to 96.2, 95% CI)Partial villous atrophy 42.3 (N=18/42) +ve anti-t TG, sensitivity 42.9 (27.7 to 59.0, 95% CI)

(p< 0.0001 difference in sensitivity for total and partial villous atrophy)

NS differences in sensitivity when comparing various modes of presentation

(this study considered 2 commercial labs, there were significant differences in sensitivity and specificity values, the labs used different kits and the authors note that they were not aware of how the labs determined their cut-off rates or whether they used the manufacturer’s recommended values) Reference Study

type/Evidence level

Number of patients


Outcome measures

Source of funding

2 Authors note that the high percentage of diagnosis probably due to being a referral centre for coeliac disease and that the patient population may not reflect that seen by community gastroenterologists


Agardh D. Antibodies against synthetic deamidated gliadin peptides and tissue transglutaminase for the identification of childhood celiac disease. Clinical Gastroenterology & Hepatology 2007;5:1276-81

Cohort N=176

Children – age range 0.7 to 19.0 years, median 5.7 in the biopsy abnormal group (75F, 44M), age range 0.9 to 14.6 years, median 3.5 in the biopsy normal group (26F, 31M)

Sweden

Inclusion: children with suspected CD admitted for an intestinal biopsy at a Department of Paediatrics (no further details reported)

Exclusion: none reported

(Other groups included patients with a known diagnosis of celiac disease on a GFD for a median of 4.5 years with serologic analysis and healthy adult blood donors – results not included in this table)

IgAG-DGP/tTG

IgAG-DGP

IgA-DGP

IgG-DGP

IgA-tTG

IgG-tTG

All QUANTA lite tests, used according to manufacturer’s instructions.

Cut-offs defined as –ve if <20AU, weakly +ve if 20-30AU, and +ve if >30

No details of blinding reported.

‘Intestinal biopsy’ – no further details

Diagnostic accuracy of the tests

CD diagnosed with ESPGAN

Faculty of Medicine, Lund University

Skane Council Foundation for Research Development, Malmo University

Kits provided free of charge by manufacturer

Effect size: (CI 95%)

N=119/176 (68%) diagnosed with coeliac disease, using ESPGAN criteria

IgA deficiency 0.04% (N=7/176)

Of the 121 children with a diagnosis other than coeliac disease (ie biopsy results were normal), most frequent diagnoses were cow’s milk protein intolerance, food

allergy, IgA deficiency (5/7 above), lipase deficiency, Helicobacter pylori gastritis, transient EMA (1 with IDDM). Other reasons for investigation were failure to thrive

or short stature, with remaining children having transient GI symptoms.

PPV, NPV and all confidence intervals calculated from the 2x2 data presented in the paper.


IgAG-DGP/tTG >20sensitivity 97.5% (94.7 to 100), specificity 89.5% (81.5 to 97.4), PPV 95.1% (91.2 to 98.9), NPV 94.4% (88.3 to 100)2X2:

(a)TP 116

(b)FP 6

(c)FN3

(d)TN51

IgAG-DGP/tTG >30sensitivity 100% (n/a), specificity 94.7% (88.9 to 100), PPV 97.5% (94.8 to 100), NPV 100% (n/a)2X2:

(a)TP 119

(b)FP 3

(c)FN0

(d)TN54

IgAG-DGP >20sensitivity 92.4% (87.7 to 97.2), specificity 89.5% (81.5 to 97.4), PPV 94.8% (90.8 to 98.9), NPV 85.0% (76.0 to 94.0)2X2:

(a)TP 110

(b)FP 6

(c)FN9

(d)TN51

IgAG-DGP >30sensitivity 97.5% (94.7 to 100), specificity 98.2% (94.8 to 100), PPV 99.1% (97.5 to 100), NPV 94.9% (89.3 to 100)2X2:

(a)TP116

(b)FP 1

(c)FN3

(d)TN56


IgA-DGP >20sensitivity 79.8% (72.6 to 87.0), specificity 91.2% (83.9 to 98.6), PPV 95.0% (90.7 to 99.3), NPV 68.4% (58.0 to 78.9)2X2:

(a)TP95

(b)FP 5

(c)FN24

(d)TN52

IgA-DGP >30sensitivity 90.8% (85.6 to 96.0), specificity 94.7% (88.9 to 100), PPV 97.3% (94.3 to 100), NPV 83.1% (74.0 to 92.2)2X2:

(a)TP 108

(b)FP 3

(c)FN11

(d)TN54

IgG-DGP >20sensitivity 88.2% (82.4 to 94.0), specificity 86.0% (76.9 to 95.0), PPV 92.9% (88.2 to 97.6), NPV 77.8% (67.5 to 88.0)2X2:

(a)TP 105

(b)FP 8

(c)FN14

(d)TN49

IgG-DGP >30sensitivity 95.0% (91.0 to 98.9), specificity 98.2% (94.8 to 100), PPV 99.1% (97.4 to 100), NPV 90.3% (83.0 to 97.7)2X2:

(a)TP 113

(b)FP 1

(c)FN6

(d)TN56


IgA-tTG >20sensitivity 95.0% (91.0 to 98.9), specificity 96.5% (91.7 to 100), PPV 98.3% (95.9 to 100), NPV 90.2% (82.7 to 97.6)2X2:

(a)TP 113

(b)FP 2

(c)FN6

(d)TN55

IgA-tTG >30sensitivity 96.6% (93.4 to 99.9), specificity 100% (n/a), PPV 100% (n/a), NPV 93.4% (87.2 to 99.7)2X2:

(a)TP 115

(b)FP 0

(c)FN4

(d)TN57

IgG-tTG >20sensitivity 4.2% (0.6 to 7.8), specificity 100% (n/a), PPV 100% (n/a), NPV 33.3% (26.3 to 40.4)2X2:

(a)TP 5

(b)FP 0

(c)FN114

(d)TN57

IgG-tTG >30sensitivity 12.6% (6.6 to 18.6), specificity 100% (n/a), PPV 100% (n/a), NPV 35.4% (28.0 to 42.8)2X2:

(a)TP 15

(b)FP 0

(c)FN104

(d)TN57



Number of patients


Outcome measures

Source of funding

Agency for Healthcare Research and Quality (2004) Celiac Disease, Evidence Report/Technology Assessment Number 104

Systematic review

Chapter 2: celiac 2: incidence and prevalence of CD

Included: general populations from North America or Western Europe, first-degree relatives of patients with CD

Excluded: studies of prevalence or incidence that used AGA tests conducted prior to 1990 due to potential problems with the reliability of older AGA assays; reports which were not sufficiently explicit for data extraction

All included studies were conducted between 1992 and 2003

AHRQ

Effect size:

Included studies – prevalence in the general population:

37 studies identified, duplicate publications removed, 30 unique articles – 3 USA, 3 UK, 1 Switzerland, 6 Sweden, 1 Spain, 1 Republic of San Marino, 1 Norway, 2 Netherlands, 6 Italy, 1 Ireland, 1 Germany, 3 Finland, 1 Denmark and Sweden

Screening test: Primary biopsy – adults, N=4,723 (2 studies), prevalence range 0.00515-0.00605 IgA AGA – adults, N=443 (1 study), prevalence range 0.01129; children, N=3,022 (1 study), prevalence range 0.00629IgA/IgG AGA – adults, N=1,537 (1 study), prevalence range 0.01431IgA AGA, IgA EMA – adults, N=6,999 (5 studies), prevalence range 0.00152-0.01884; children, N=1,823 (1 study), prevalence range 0.00823IgA/IgG AGA, IgA EMA – adults, N=11,351 (5 studies), prevalence range 0.00195-0.01917; children, N=19,297 (2 studies), prevalence range 0.00645-0.00859IgA/IgG AGA, IgA tTG – mostly adults, N=150 (1 study), prevalence range 0.02667IgA EMA – adults (7 studies), prevalence range 0.00171-0.01028; children N=6,127 (1 study), prevalence range 0.01224IgA EMA, IgG tTG – adults, N=10,372 (2 studies), prevalence range 0.00949-0.01156; children N=6,385 (3 studies), prevalence range 0.00312-0.01259

Prevalence by country:USA:


0.00949; N=2,845, adults (EMA-ME, all +ve tTG-HU), 0.00312; N=1,281, children (Fasano 2003)0.00515; N=1,749, adults (biopsy)(Green 2000)0.00400; N=2,000, adults (IgG/IgA-AGA, followed by IgA-EMA ME or HU)(Not 1998)

UK: 0.00823; N=1,823, adults (IgA-AGA, IgA-EMA)(Johnston 1998)0.01917 (serology), 0.01000 (biopsy N=22/23); N=1,200, adults (IgG/IgA-EMA ME)(Sanders 2003)0.01156; N=7,527, adults (IgA-EMA ME, IgA tTGA)(West 2003)

Switzerland:0.00759 (serology), 0.00690 (biopsy N=10/11); N=1,450, children (IgA-EMA ME, IgA tTG, IgG/IgA-AGA)(Rutz 2002)

Sweden:0.01452 (serology), 0.01867 (biopsy); N=482, adults, (biopsy, IgA/IgG-AGA, IgA-EMA ME)(Borch 2001)0.00589 (serology), 0.00375 (biopsy); N=1,866, adults (IgA-AGA, (IgA-EMA, prevalence not reported))(Grodzinsky 1996)0.00475 (serology), 0.00475 (biopsy); N=1,894, adults (IgA/IgG-AGA, IgA-EMA ME, serum IgA level)(Ivarsson 1999)0.01431 (serology), 0.00065 (biopsy, N=13/22), N=1,537, adults (IgG/IgA-AGA)(Sjoberg 1994)0.00152 (serology), 0.00152 (biopsy), N=1,970, adults (IgA-AGAIgA confirmed with EMA ME)(Sjoberg 1999)0.01884 (serology), 0.01594 (biopsy), N=690, children (AGA, EMA, biopsy)(Carlsson 2001)

Spain:0.00171 (serology), 0.00256 (biopsy), N=1,170, adults (IgG/IgA-AGA, IgA-EMA)(Riestra 2000)

Republic of San Marino:0.00179 (serology), 0.00179 (biopsy), N=559, adults (IgA-EMA, biopsy)(Corazzo 1997)

Norway: 0.00387 (serology), 0.00388 (biopsy), N=2,069, adults (IgA/IgG-AGA, IgA-EMA)(Hovdenak 1999)

Netherlands:0.00300 (serology), 0.00300 (biopsy), N=1,000, adults (IgA-EMA)(Rostami 1999)0.01224 (serology), 0.00506 (biopsy N=57/75), N=6,127, children (IgA-EMA)(Csizmadia 1999)

Italy:0.00195 (serology), 0.00195 (biopsy N=38/140), N=4,615, adults (IgA/IgG-AGA, IgA-EMA, biopsy)(Pittscieler 1996)0.00250 (serology), 0.00250 (biopsy), N=4,000, adults (IgA-EMA, biopsy)(Trevisiol 1999)0.00574 (serology), 0.00488 (biopsy), N=3,483, adults (mostly)(IgA-EMA HU, biopsy)(Volta 2001)0.00859 (serology), N=2,096, children (IgG/IgA-AGA, IgA-EMA)(Catassi 2000)0.00645 (serology), 0.00477 (biopsy), N=17,201, children (IgA/IgG-AGA, confirmed with EMA and biopsy)(Catassi 1996)0.00629 (serology), 0.00596 (biopsy), N=3,022, children (IgA-AGA, biopsy)(Di Pietralata 1992)


Ireland: 0.01129 (serology), N=443, adults (IgA-AGA)(Dickey 1992)

Germany:0.02667 (serology), N=150, mostly adults (IgA/IgG-AGA, IgA-tTG)(Jager 2001)

Finland:0.01028 (serology), 0.00748 (biopsy), N=1,070 adults (EMA HU)(Kolho 1998)0.01259 (serology), 0.00739 (biopsy), N=3,654 children (IgA/IgG-tTG, IgA/IgG-EMA, if total serum IgA, HLA DR, DQ2, DQ8)(Maki 2004)0.00605 (serology), N=2,974, mostly adults (biopsy)(Collin 2002)

Denmark & Sweden:0.00254 (serology), N=1,573 adults (serum IgA, IgG-AGA, EMA)(Weile 2001)

Prevalence in patients with suspected coeliac disease:

Adults:N=4 studies, N=3 Italy all from referral centres, N=1 USA at-risk and not-at-risk individuals clinical centre not reported(reasons for suspecting coeliac disease; anaemia, persistent iron deficiency, bowel disturbances, chronic intermittent diarrhoea, abdominal pain, constipation, dyspepsia, severe malabsorption, tiredness and weight loss, mineral metabolism deficienceies, osteoporosis, arthralgias, arthritis, dermatitis, hypertransaminasemia, type 1 diabetes mellitus, infertility, and gluten intolerance in childhood not further investigated)Prevalence:43.3%, N=60 (biopsy)(Bardella 1991), Italy50.0%, N=80 (biopsy)(Bardella 2001), Italy11.6%, N=207 (biopsy)(Carrocio 2002), Italy1.5%, N=1,910 (EMA)(Fasano 2003), USA

Children: N=9 studies, N=3 Canada, N=2 USA, N=1 Denmark, England, Italy, New Zealand(reasons for suspecting coeliac disease; abdominal pain, diarrhoea, failure to thrive/short stature, weight loss, vomiting, abdominal distension, chronic GI symptoms, inflammatory bowel disease, family history of coeliac disease, type 1 diabetes, iron deficiency anaemia, thyroid disease, trisomy 21, enamel hypoplasia, recurrent aphtous stomatitis, autoimmune diseases, IgA deficiency, occult hypertransaminasemia)Prevalence: 13.0%, N=77 (biopsy), referral centre (Chan 2001), Canada17.0%, N=176 (biopsy), referral centre (Chartrand 1997), Canada1.1%, N=92 (EMA), community paediatricians (Fitzpatrick 2001), Canada4.0%, N=1,326 (EMA), clinical setting not reported (Fasano 2003), USA2.5%, N=1,008 (EMA), referral centre (Hill 2000), USA


7.3%, N=191 (biopsy), referral centre (Bode 1993), Denmark4.6%, N=153 (biopsy), referral centre (Day 2000), New Zealand7.9%, N=381 (biopsy), referral centre (Thomas 1992), England 7.5%, N=240 (biopsy), case-finding community paediatricians (Ventura 2001), Italy

All ages:N=1 study case-finding primary care clinics(entry criteria; irritable bowel syndrome, anaemia, family history of coeliac disease, malaabsorption syndrome, diarrhoea, fatigue, thyroid disease, diabetes mellitus, weight loss, short stature, failure to thrive, epilepsy, infertility, arthralgia, eczema)N=1,000, mean age 42.8yrs, 5.3% <10yrs, 3.1% 80-90yrsN=30 EMA +ve, all confirmed by biopsy (N=1 child)

Prevalence in first-degree relatives of those with coeliac disease N=17 studies, N=5 directly evaluated with small bowel biopsy, N=12 serological screening of these N=7 had biopsies in >80% of those positive ARHQ included second-degree relatives studies, these have not been included here

First-degree relatives:Prevalence:20%, N=90 tested (biopsy), diagnostic criteria ESPGAN (Polvi 1996)10.7%, N=121 tested (biopsy), diagnostic criteria some VA (Holm 1993) 10.3%, N=29 tested (biopsy), diagnostic criteria some VA (Robinson 1971)5.6%, N=72 tested (biopsy), diagnostic criteria not reported (Rolles 1974)22.5%, N=182 tested (biopsy), diagnostic criteria some VA (Stokes 1976) 44.1%, N=111 tested (biopsy), diagnostic criteria Marsh I-IV (Tursi 2003)4.0%, N=328 tested (AGA), diagnostic criteria some VA (Corazza 1992)12.0%, N=92 tested (EMA, TTG), diagnostic criteria some VA (Pittschieler 2003)10.9%, N=338 tested (AGA, EMA, Hx) diagnostic criteria ESPGAN (Rostami 2000)8.3%, N=120 tested (AGA, EMA, TTG), diagnostic criteria some VA (Hogberg 2003)9.1%, N=943 tested (EMA), diagnostic criteria some VA (Korponay-Szabo 1998)5.6%, N=675 tested (AGA, EMA) diagnostic criteria some VA (Farre 1999)3.5%, N=151 tested (EMA) diagnostic criteria positive serology (Kotze 2001)4.5%, N=4508 tested (EMA) diagnostic criteria positive serology (Fasano 2003)2.8%, N=642 tested (AGA, EMA) diagnostic criteria positive serology (Vitoria 1994)9.4%, N=466 tested (AGA, EMA) diagnostic criteria positive serology (Mustalahti 2002)17.2%, N=163 tested (EMA, TTG) diagnostic criteria positive serology (Book 2003)

Studies that required some degree of villous atrophy for diagnosis, mean prevalence 7.6% (range 4% to 12%), where Marsh I were also considered diagnostic prevalence was 44.1%


Reported prevalence based on serology results, mean prevalence 4.3% (range 2.8% to 17.2%)

Prevalence of coeliac disease in those with iron deficiency anaemia: 8 studies included – all adult studies with biopsy proven coeliac disease, N≥50 participantsN=93, outpatients with IDA, N=13 (14%) biopsy proven coeliac disease (Akerman 1996)N=71, asymptomatic, N=4 (5.6%) biopsy proven coeliac disease (Annibale 2001)N=200, referred to haematology, N=10 (5%) biopsy proven coeliac disease (Corazzo 1995)N=258, IDA identified through the lab, N=12 (4.7%) biopsy proven coeliac disease (Howard 2002)N=50, outpatients with IDA, N=3 (6%) biopsy proven coeliac disease (McIntyre 1993)N=113, undergoing endoscopy for IDA, N=17 (15%) biopsy proven coeliac disease (Oxentenko 2002)N=484, referred to haematology, N=11 (2.3%) biopsy proven coeliac disease (Ransford 2002)N=59, pre-menopausal women with IDA, N=5 (8.5%) biopsy proven coeliac disease (Annibale 2003)

Prevalence of coeliac disease in those with low bone mineral density:4 studies included – all adult studies with biopsy proven coeliac disease, N≥50 participantsN=92, consecutive patients with idiopathic osteoporosis, N=3 (3%) biopsy proven coeliac disease (Lindh 1992)N=127, postmenopausal women with osteoporosis, N=1 (0.9%) biopsy proven coeliac disease (Gonzalez 2002)N=96, idiopathic low BMD, N=0 biopsy proven coeliac disease (Mather 2001)N=255, females with osteoporosis, N=6 (2.4%) biopsy proven coeliac disease (Nuti 2001)

Prevalence of coeliac disease in those with type 1 diabetes:21 studies included – all with biopsy proven coeliac disease, N≥50 participantsN=185, adults, N=4 (2.2%) biopsy proven coeliac disease (Talal 2002)N=211, mostly children, N=3 (1.4%) biopsy proven coeliac disease (Rossi 1993)N=62, adults, N=7 (11.3%) biopsy proven coeliac disease (Kaukinen 1999)N=848, adults, N=7 (0.8%) biopsy proven coeliac disease (Sjoberg 1998)N=383, adults, N=10 (2.6%) biopsy proven coeliac disease (Sategna-Guidetti 1994)N=263, children, N=12 (4.6%) biopsy proven coeliac disease (Frazer-Reynolds 1998)N=104, children, N=9 (8.2%) biopsy proven coeliac disease (Hansen 2001)N=776, children, N=19 (2.5%) biopsy proven coeliac disease (Saukkonen 1996)N=205, children, N=6 (2.9%) biopsy proven coeliac disease (Spiekerkoetter 2002)N=498, children, N=16 (3.2%) biopsy proven coeliac disease (Barera 1991)N=273, children, N=9 (3.3%) biopsy proven coeliac disease (Barera 2002)N=383, children, N=32 (3.4%) biopsy proven coeliac disease (Valerio 2002)N=141, children, N=4 (2.8%) biopsy proven coeliac disease (Carelo 1996)N=177, children, N=7 (4%) biopsy proven coeliac disease (Roldan 1998)N=93, children, N=6 (6.5%) biopsy proven coeliac disease (Juan 1998)N=459, children, N=21 (4.6%) biopsy proven coeliac disease (Sigurs 1993)N=162, children, N=6 (3.7%) biopsy proven coeliac disease (Agardh 2001)N=167, children, N=8 (4.8%) biopsy proven coeliac disease (Acerini 1998)


N=233, children, N=14 (6%) biopsy proven coeliac disease (Gillett 2001)N=1114, mixed, N=63 (5.7%) biopsy proven coeliac disease (De Vitis 1996)N=491, mixed, N=28 (5.7%) biopsy proven coeliac disease (Not 2001)N=520, mixed mostly children, N=9 (1.7%) biopsy proven coeliac disease (Kordonouri 2000)N=218, mixed mostly children, N=10 (4.6%) biopsy proven coeliac disease (Aktay 2001)N=403, mixed mostly children, N=6 (1.5%) biopsy proven coeliac disease (Schober 2000)

Sensitivity/Specificity papers included from AHRQ report for all serological tests: Included studies, biopsy proven, cohort based (sensitivity/specificity data in forest plots or ROC curves in appendices) IgA AGA, IgG AGA, children (Altunas 1998)IgA AGA, IgG AGA, children (Artan 1998)IgA AGA, IgG AGA, IgA EMA, children (Ascher 1996)IgA AGA, IgG AGA, children (Bahia 2001)IgA AGA, IgA EMA, IgA tTGA, adults (Bardela 2001)IgA AGA, IgG AGA, children (Bode 1993)IgA AGA, IgG AGA, IgA EMA, adults/children (Carroccio 2002)IgA EMA, IgA tTGA, adults (Carroccio 2002)IgA EMA, IgA tTGA, children (Chan 2001)IgA AGA, IgG AGA, children (Chartrand 1997)IgA AGA, IgG AGA, children (Chirdo 1999)IgA AGA, IgG AGA, children (Gonczi 1991)IgA EMA, children (Iltanen 1999)IgA AGA, IgG AGA, IgA EMA, IgA tTGA, adults (Kaukinen 2000)IgA EMA, children (Kumar 1989)IgA AGA, IgG AGA, combined IgA/IgG, children (Lindberg 1985)IgA AGA, IgA EMA, children (Lindquist 1994)IgA AGA, IgA EMA, children (Maki 1991)IgA AGA, IgG AGA, IgA EMA, IgG EMA, adults (McMillan 1991)IgA AGA, IgG AGA, children (Meini 1996)IgA AGA, children (Poddar 2002)IgA AGA, IgG AGA, children (Rich 1990)IgA AGA, IgG AGA, IgA EMA, children (Russo 1999)IgA AGA, IgG AGA, IgA EMA, IgA tTGA, adults/children (Tesei 2003)IgA EMA, IgA tTGA, IgG tTGA, adults/children (Troncone 1999)IgA AGA, IgA EMA, adults (Valdimarss 1996)IgA AGA, IgG AGA, IgA EMA, adults (Vogelsang 1995)IgA AGA, IgG AGA, IgA EMA, IgA tTGA, children (Wolters 2002)



Number of patients


Outcome measures

Source of funding

Bdioui F, Sakly N, Hassine M, Saffar H. Prevalence of celiac disease in Tunisian blood donors. Gastroenterologie Clinique et Biologique 2006;30:33-6

Cohort

Tunisia

N=1418 Inclusion: unselected blood donors, N=1090 (77.3%) men, N=328 (22.7%), mean age men 29yrs, mean age women 26yrs

All lab analyses were performed, validated and interpreted by the same investigator

IgA EMA HU, indirect immunofluorescence

Those considered +ve, ATG (anti-tissue transglutaninase) , ELISA

Effect size:

N=3 IgA EMA +ve, N=2 of these ATG +ve these N=2 had vilous atrophy classified Marsh IIIC and IIIA, the N=1 ATG –ve had no histological lesions

Prevalence: 1/709, 1.4/1000 (95% CI, 0.17 to 5.08)


Number of patients


Outcome measures

Source of funding

Ben Hariz M, Kallel-Sellami M, Kallel L, Lahmer A, Halioui S,

Cohort N=6284

Tunisia

Inclusion: screening study based on drawing lots with schoolchildren in a Tunisian (from a population of 22000), N=3175 boys, N=3109 girls, age 9.7±3yrs, registered during the school year of 2003-2004, study conducted Sept-

IgA-tTGs, ELISA and IgA deficienct, immunodiffusion

Antitissue transglutaminase serology was regarded as borderline between 15 and

Not stated


Bouraoui S et al. Prevalence of celiac disease in Tunisia: mass-screening study in schoolchildren. European Journal of Gastroenterology & Hepatology 2007;19:687-94

Dec 2003

Required sample size was 6094, allowing for an expected refusal rate of 30%, the sample size was raised to 9080

N=2 known to have coeliac disease were not included in the serological screening

Those +ve IgA-EMA, indiect immunofluorescence

Those with IgA deficiency the IgG-EMA was determined

Biopsy

(To confirm the quality of the ELISA N=500 sera –ve for IgA-tTG were tested for IgA-EMA)

20 U

Effect size:

IgA-TTG:N=139/6284 (2.2%) of these N=87 (1.4%) had a value above 20 U and N=52 (37.4%) had a borderline value between 15 and 20 U

IgA-EMA, determined for all samples in the +ve and borderline groups:- +ve group: N=36/87 (41.3%) had +ve IgA-EMA and IgA-tTG rates vs. -ve group: N=51, p<0.001- borderline group: N=4 (7.7%) IgA-EMA +ve, significant difference compared with the +ve IgA-tTG group, p<0.001

Total IgA was decreased in N=17 (0.27%, 1/370), of these N=3 had complete IgA deficiency (0.03%). None of the 17 had IgG-EMA

N=107/139 returned, of these N=28 positive for both serological tests (IgA-tTG and IgA-AE) and were biopsiedN=26/28 signs of coeliac disease, N=23 had villous atrophy, N=3 rise in intraepithelial lymphocyte density, N=2 normal mucosa

N=79 IgA-tTG positive, IgA-AE negative, N=26 biopsied, none had histology compatible with coeliac disease

Prevalence:N=26 biopsy proven, N=2 previously diagnosed, N=12 positive to both serological tests but not been biopsied, prevalence 1/157 (1/217 to 1/115, 95% CI)Biopsy proven prevalence 1/224 (1/333 to 1/154, 95% CI)

Those who were biopsy proven, none had other autoimmune conditions, N=3 had an affected relative, N=11 were asymptomatic



Number of patients


Outcome measures

Source of funding

Biagi F, Campanella J, Bianchi PI, Zanellati G, Capriglione I, Klersy C et al. The incidence of coeliac disease in adult first degree relatives.[see comment]. Digestive & Liver Disease 2008;40:97-100

Cohort N=158

Italy

Inclusion: adult first degree of N=73 coeliac patients referred to an out-patient clinic, diagnosed by means of duodenal biopsy and coeliac antibodies, between Jan 1999 – June 2006, mean 46.4yrs±16.9

IgA-EMA, indirect immunofluorescence

Those +ve biopsied

1-year, participants recontacted by phone, mean follow-up 51.5mths

Not stated

Effect size:

N=130/158 initially tested and –ve, 1 year later N=63 retested, none +ve, N=1 had developed coeliac disease

Prevalence, N=28/158 (17.7%, 95% CI 12.1 to 24.6)

Duodenal biopsy confirmed the diagnosis of coeliac disease in all those who were +ve

Follow-up:N=114/130 who had been EMA –ve, N=63 had a second EMA test, all –ve N=1/64 had been diagnosed with coeliac disease prior to follow-up

Reference Study type/

Number of


Outcome measures

Source of


Evidence level

patients funding

Bingley PJ, Williams AJK, Norcross AJ, Unsworth DJ, Lock RJ, Ness AR et al. Undiagnosed coeliac disease at age seven: Population based prospective birth cohort study. British Medical Journal 2004;328:322-3

Cohort N=5470

UK

Inclusion: children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC), population based cohort study established in 1990

Two stage screening: radioimmunoassay for tTG antibodies, positive samples tested for IgA-EMA by indirect immunofluorescence

Details of GI symptoms and special diets were collected by routine questionnaire at 6.75yrs

Those with tTG antibodies below the 97.5th centile were defined as antibody –ve

Coeliac UK, MRC, Wellcome Trust, UK government departments and various charitable organisations and commercial companies, ALSPAC is part of the WHO initiated European Longitudinal Study of Pregnancy and Childhood

Effect size:

N=137 were tTG antibody +ve but IgA-EMA –ve

IgA-EMA:N=54 IgA-EMA +ve; 1.0% (95% CI; 0.8 to 1.4) IgA EMA more common in females, OR 2.12 (1.20 to 3.75)


tTG antibody –ve controls (N=5333) compared with IgA-EMA +ve (N=54): at age 7.5yrs (interquartile range):Height; 126 (122.4 to 129.6) vs. 122.1 (118.25 to 125.33), p<0.0001Weight; 25.2 (22.8 to 28.0) vs. 23.4 (21.35 to 25.4), p<0.0001SD for height; 0.23 (-0.43 to 0.88) vs. -0.53 (-1.01 to -0.00), p<0.0001SD for weight; 0.18 (-0.45 to 0.86) vs. -0.36 (-1.01 to 0.28), p<0.0001Hb conc; 125 (120 to 130) vs. 123 (118 to 127), NS

Symptoms: tTG antibody –ve (N=4285 questionnaires) compared with IgA-EMA +ve (N=42): at age 6.75yrs (95% CI):Any diarrhoea; 1450 (34%) vs. 21 (50%), OR 1.96 (1.06 to 3.59), no overall difference in the number of episodes of diarrhoea Any vomiting; 1933 (45%) vs. 23 (55%), OR 1.47 (0.80 to 2.71)Any stomach pains; 2557 (60%) vs. 28 (66%), OR 1.35 (0.71 to 2.57)Any constipation; 435 (10%) vs. 6 (14%), OR 1.48 (0.62 to 3.52)≥3 GI symptoms; 931 (22%) vs. 17 (40%), OR 2.45 (1.33 to 4.5)

Author comment: those with IgA-EMA shorter by more than 0.76 SD scores and lighter by 0.54 SD scores, this equates to about 9mths growth and weight gain in an average child around this age.


Number of patients


Outcome measures

Source of funding

Bizzaro et al (2006) Low specificity of anti-tissue transglutaminase antibodies in patients with primary biliary cirrhosis

Cohort N=105

Adults

Italy

Inclusion: patients with primary biliary cirrhosis, N=91 female, N=14 male, mean age 63yrs (range 39 to 94yrs), diagnosis based on lab findings, the presence of anti-mitochondrial antibodies and liver histology, none had clear symptoms of CD (control group: N=40 with CD and N=40 healthy subjects were also tested with all the kits)

IgA anti-tTG 3

(ELISA, 6 methods)(2 human recombinant, 1human placenta, 1 human erythrocytes, 2 GP liver)

IgG anti-tTG (ELISA 3 kits)(2 human recombinant, 1 human red blood cells)

+ve for anti-tTG tested for

IgA EMA IgG EMA(ME)

+ve EMA advised biopsy

+ve anti-tTG and –ve EMA, HLA testing

Not stated

3 Tests performed in a single lab according to the manufacturer’s instructions, including indicated cut-off levels



N=28/105 (26.7%) IgA anti-tTG +ve; N=6/105 (5.7%) IgG anti-tTG +ve; in at least one of the 6 ELISA methods Agreement low, N=7/28 showed reactivity with only 1 method, N=12 with 2 methods, N=2 with 3 methodsOnly N=4 were +ve with all methods, N=3 were +ve with 5 methods For IgG the N=6 +ve were each with only 1 method

N=2/28 were IgA EMA +ve, N=2 biopsied both CD N=0/6 were IgG EMA +ve

HLA determined in N=24/26 tTG+ve and EMA –ve, N=5 HLA +ve, N=4 biopsied

IgA tTG, specificity range; 82.5% to 97.1%IgG tTG, specificity range; 95.1% to 100%


Number of patients


Outcome measures

Source of funding

Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clinical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases. American Journal of Gastroenterology 1999;94:691

N=1026

Mixed

Italy

Inclusion: all subclinical/silent patients with celiac disease in 42 centres diagnosed between 1990 and 1994, N=382 adults (mean age 24.4±12.5, N=271 females, 70.9%, N=111 males, 29.1%), N=644 children (mean age 7.7±4.2, N=431 females, 66.9%, N=213 males, 33.1%)

Not stated


-6

Effect size:

N=1026, of these N=798 (77.8%) subclinical CD and N=228 (22.2%) silent CD

N=192 (18.7%), N=101 children, N=91 adults had a first-degree relative

N=365 (35.6%), N=234 children, N=131 adults, had >1 symptom

Frequency of leading symptoms with subclinical:Iron-deficiency anaemia – total (N=314/798, 39.3%); adults (N=145/313, 46.3%); children (N=169/485, 34.8%)Short stature – total (N=153, 19.2%); adults (N=8, 2.5%); children (N=145, 29.9%)Dermatitis herpetiforms – total (N=73, 9.1%); adults (N=61, 19.5%); children (N=12, 2.5%)Anorexia – total (N=62, 7.8%); adults (N=0), children (N=62, 12.8%)Epilepsy/cerebral calcifications – total (N=26, 3.3%); adults (N=13, 4.2%); children (N=13, 2.7%)Neuropsychic complaints – total (N=25, 3.1%); adults (N=7, 2.2%); children (N=18, 3.7%)Constipation – total (N=21, 2.6%); adults (N=4, 1.3%); children (N=17, 3.5%)Recurrent apthous stomatitis – total (N=16, 2.0%); adults (N=9, 2.9%); children (N=7, 1.4%)Dyspepsia – total (N=12, 1.5%); adults (N=8, 2.5%); children (N=4, 0.8%)Thinnes – total (N=12, 1.5%); adults (N=3, 1.0%); children (N=9, 1.8%)Hypertransaminasemia – total (N=11, 1.4%); adults (N=5, 1.6%); children (N=6, 1.2%)Osteoporosis – total (N=11, 1.4%); adults (N=11, 3.5%); children (N=0)

Others ≤N=10 total: arthromyalgia; delayed puberty; dental enamel hypoplasia; atopy; peripheral oedema; amenorrhoea-abortions; recurrent infections; hypoglycaemia; lipothymia; tetania; obersity; polyuria-polydipsy; onychodystrophy; hypothyroidism; hyperparathyroidism

Frequency of celiac-associated disorders:Insulin-dependent diabetes – total (N=76, 7.4%); adults (N=27, 7.1%); children (N=49, 7.6%)Atopy – total (N=32, 3.1%); adults (N=10, 2.6%); children (N=22, 3.4%)Down’s syndrome – total (N=19, 1.9%); adults (N=1, 0.3%); children (N=18, 2.8%)IgA deficiency – total (N=15, 1.5%); adults (N=4, 1.0%); children (N=11, 1.7%)

Others ≤N=10 total: Turner syndrome; thyroiditis; hyperparathyroidism; rheumatoid arthritis; alopecia; Berger’s disease; psoriasis; sarcodosis; livedo reticularis; Basedow’s disease; primary biliary cirrhosis; Plummer’s adenoma; rheumatic fever; medulloblastoma; immunoploferative intestinal disease

Reference Study Number Patient characteristics Intervention Comparison Length of Outcome Source


type/Evidence level

of patients

follow-up measures of funding

Bottaro G, Failla P, Rotolo N, Sanfilippo G, Azzaro F, Spina M et al. Changes in coeliac disease behaviour over the years. Acta Paediatrica 1993;82:566-8

Retrospective

N=325

Children

Italy

Inclusion: data from children from diagnosed at a Paediatric Gastroenterology Service, children grouped according to year of diagnosis, group A 1984 to 1986, group B 1987 to 1989, age range 3mths to 14yrs, N=176 females, N=146 males

Age at onset of symptoms, age at diagnosis, the three major symptoms related to onset of coeliac disease

Not stated

Effect size:

Symptoms:- chronic diarrhoea; 75.2% in group A and 70.2% in group B- weight loss; 43.6% in group A and 59.6% in group B, p=0.0016- abdominal distension; 35.8% in group A and 28.4% in group B- growth failure; 30.8% in group A and 20.2% in group B- vomiting; 32.5% in group A and 26.1% in group B- anorexia; 25.6% in group A and 35.1% in group B- irritability; 10.3% in group A and 13.9% in group B- minor symptoms; 18.8% in group A and 24.5% in group B

Author’s consider that no changes were noted in the trend of symptoms, notably for chronic diarrhoea


Number of patients


Outcome measures

Source of funding

Brandimarte Cohort N=298 Inclusion: N=81 male, N=217 female, IgA4 and IgG Participant None


G, Tursi A, Giorgetti GM. Changing trends in clinical form of celiac disease. Which is now the main form of celiac disease in clinical practice? Minerva Gastroenterologica e Dietologica 2002;48:121-30

(CHECK) mean age 27.9yrs (range 15 to 65yrs), all were >15yrs and considered adults

Exclusion: other causes of villous atrophy, before making the diagnosis of coeliac disease

Criteria were used and based on the characteristic histological finding of subtotal or severe partial villous atrophy and crypt hyperplasia on small bowel, taking from the descending duodenum and heamotoxylin-eosin stained for histological evaluation- classical CD the presence of a gluten-sensitive enteropathy accompanied by GI symptoms (diarrhoea, weight loss, abdominal pain, vomiting)- subclinical CD the presence of a gluten sensitive enteropathy with extraintestinal symptoms- silent CD the presence of a gluten-sensitive enteropathy not accompanied by any symptoms, but identified during the course of screening of high-risk groups (first-degree relatives of coeliac patients, those with insulin dependent diabetes, Down syndrome, IgA deficiency, thyroid disorders)

AGA (measured by enzyme linked innmunosorbent assay)

IgA EMA (screened by indirect immunofluorescent method on monkey oesophagus)

Sorbitol H2-breath test using 5g of sorbitol in 150ml of tap water

s diagnosed between 1988 to 2000

stated


N=167 referred due to GI symptoms (weight loss, diarrhoea, abdominal pain, flatulence, slow gastric emptying)N=131 referred by other specialists due to unexplained diseases, or diseases unresponsive to standard therapy

N=155 (52%) classical presentation, N=115 (38.5%) subclinical presentation, N=28 (9.4%) silent presentation 1988 classical features 100%, 1988 subclinical/silent 0%2000 classical features 26.2%, 2000 subclinical/silent 76.1%

4 Serum levels of IgA were taken to exclude a condition of selective serum immunoglobulin A deficiency


Extraintestinal markers (those in >5%): iron-deficiency anaemia N=29 (25%), alopecia N=11 (10%), dermatitis herpetiformis N=11 (10%), osteoporosis N=7 (6%), recurrent apthous stomatitis N=7 (6%), amenorrhoea/recurrent abortion N=6 (6%), hypertransaminasaemia N=6 (6%) (also dental enamel hypoplasia, short stature, atopy, depression, epilepsy/cerebral calcifications, lupus, Crohn’s disease, erithema nodosus, onycodystrophy, psoriasis, recurrent fractures, ulcerative colitis, addison’s disease, idrarto, long QT interval, mucoviscidosis, myositis)

Silent disease: first-degree relatives N=10 (36%), hyperthyroidism N=6 (21%), insulin-dependent diabetes N=5 (18%) (also hypothyroidism, IgA deficiency, loss of Kerkring folds at endoscopy, Down syndrome)

Classical form:- IgA AGA 83.22% +ve, IgG AGA 88.38% +ve, EMA 94.83% +ve Subclinical form:- IgA AGA 78.26% +ve, IgG AGA 83.47% +ve, EMA 86.08% +ve

Silent form:- IgA AGA 57.14% +ve, IgG AGA 60.17% +ve, EMA 71.42% +ve

Sorbitol H2-breath test, no differences in the overall positivity among the different forms of coeliac disease, positive in 98.37% (classical), 97.39% (subclinical), 92.85% (silent)

Presence of malabsorption (hypoalbuminemia, hypoproteinemia, low iron levels, hypoferritinemia: classical form N=127/155 (82%), subclinical form N=34/115 (34%), silent form N=4/28 (14%)

Effect of GFD – improvements in GI symptoms and extraintestinal symptoms (disappearance of iron-deficiency anaemia, reversal of osteopenia, disappearance of convulsive crisis in epilepsy, regular pregnancy, better response to mesalazine therapy in ulcerative colitis, reduction of insulin units and insulin administration in diabetes)


Number of patients


Outcome measures

Source of funding


Carroccio A, Di Prima L, Pirrone G, Scalici C, Florena AM, Gasparin M et al. Anti-transglutaminase antibody assay of the culture medium of intestinal biopsy specimens can improve the accuracy of celiac disease diagnosis. Clinical Chemistry 2006;52:1175-80

Cohort N=273

Mixed

Italy

Inclusion: consecutive patients undergoing intestinal biopsy for suspected CD (pediatric gastroenterology clinic and an internal medicine clinic), January 2001 to June 2003Adults; N=153, N=54 male, N=99 female, median age 32yrs (range 17 to 80yrs)Children; N=120, N=50 male, N=70 female, median age 14mths (range 7mths to 14yrs)

Exclusion: patients who had undergone previous histologic evaluation for suspected CD

IgA EMA (immunofluorescence method, monkey oesophagus)(Anti-endomysium, Eurospital)

IgA anti-tTG (ELISA)(human Eu-tTG IgA, Eurospital)(reference values <7% representing a value >2SD above the mean of 850 healthy individuals)

Serum IgA by ELISA to exclude IgA deficiency

(also included results from culture medium, not included here)

Biopsy, specimens obtained from the second duodenal portion5

Adult patients followed as outpatients, children were hospitalised

Ministero dell’Istruzione, dell’Universita e della Ricerca and Ministero delle Politiche Agricole e Forestali


None had IgA deficiency

N=166 +ve for serum IgA EMA and/or anti-tTG, of these N=162 confirmed coeliac disease with histologic findings and clinical follow-upN=4 (N=1 EMA +ve and anti-tTG +ve), (N=3 anti-tTG +ve)

Those EMA and anti-tTG –ve and biopsied, CD diagnosed in N=13/83 adults and N=16/24 children

5 Histologic analysis was performed by an examiner unaware of the clinical condition and lab test results


Total N=81 adults and N=110 children CD diagnosis IgA EMA:2x2:

(a)TP 159

(b)FP 1

(c)FN33

(d)TN81

IgA anti-tTG:2x2:

(a)TP 162

(b)FP 4

(c)FN29

(d)TN78

CD patients with +ve EMA and/or anti-tTG showed more severe intestinal mucosal lesions, grade 3b (25%) and grade 3c (35%) vs. seronegative (P<0.001) or vs. non-CD patients (p<0.0001)Intestinal mucosal damage was less severe in the N=29 with CD with –ve EMA and –ve anti-tTG, none had total villous atrophy


Number of patients


Outcome measures

Source of funding

Castano L, Blarduni E, Ortiz L, Nunez J, Bilbao JR, Rica I et al. Prospective population screening for celiac

Cohort N=830 children(N=1100 offered participation)

Spain

Inclusion: all healthy term newborns from normal deliveries occurring during regular working hours (9-5)

None of the children had a family history of coeliac disease among first-degree relatives (N=8 parents had type 1 diabetes, N=35 autoimmune thyroid disease, N=7 chronic inflammatory bowel disease, N=1 lupus, N=1 vitiligo)

Followed up 1-1.5yrs and approx 2.5yrs


disease: high prevalence in the first 3 years of life. Journal of Pediatric Gastroenterology & Nutrition 2004;39:80-4

Effect size:

1-1.5yrs:N=613/830 (74%) returned; N=0 +ve for anti-tTGase antibodies

2.5yrs:N=484/830 (58.3%) returned N=10 contained anti-tTGase autoantibodies, N=9 repeat +ve result referred to the paediatric GI unit, N=2 –ve AGA and EMA N=7 biopsied all had atrophy of intestinal villi with crypt hyperplasia, all carried coeliac disease risk-associated alleles

Prevalence:Prevalence in the cohort 8.4/1000 children or 1:118 healthy newborns (95% CI, 1:55 to 1:270)Prevalence if include only the N=484 who completed the study 1:69 (95% CI, 1:32 to 1:158)


Number of patients


Outcome measures

Source of funding

Collin P, Reunala T, Pukkala E, Laippala P, Keyrilainen O, Pasternack A. Coeliac disease--associated

Case control

N=335(N=335 control group)

Adults

Finland

Inclusion: adults with coeliac disease diagnosed at a department of internal medicine between 1980 to 1990, N=86 male, N=249 female, mean age at diagnosis 41.4yrs (range 16 to 79)

Control patients selected from outpatients who had upper GI endoscopy, age and sex matched with cases

Grants from the Yrjo Jahnsson Foundation, the Emil Aaltonen Foundation, the


disorders and survival.[see comment]. Gut 1994;35:1215-8

Finnish Foundation for Gastroenterological Research

Effect size:

Annual number of new coeliac patients 1980 to 1983, range 18 to 26; from 1983 on, range from 29 to 49 N=274 diagnosed after clinical suspicion of coeliac disease, N=61 from serological screening

Results following 1-year follow-up after commencing gluten-free diet not reported here

Associated disorders taken from past and present conditions diagnosed by GPs or in hospitals (associated disorders diagnosed during prospective follow-up not reported here)

Endocrine disorders: 12% (CD) vs. 4.2% (control), p=0.0003- insulin dependent diabetes mellitus, N=18, 5.4% (CD) vs. N=5, 1.5% (control), p=0.0094- autoimmune thyroid N=18, 5.4% (CD) vs. N=9, 2.7% (control), this included autoimmune hypothyreosis, N=11 (CD) vs. N=8 (control) and Graves’ disease N=7 (CD) vs. N=1 (control)- parathyroid adenoma N=2 (CD) vs. N=0 (control)- Addison’s disease N=2 (CD) vs. N=0 (control)

Connective tissue disorders: 7.2% (CD) vs. 2.7% (control), p=0.011- Sjogren’s syndrome, N=11, 3.3% (CD) vs. N=1, 0.3% (control), p=0.0059- rheumatoid arthritis, N=6, 1.8% (CD) vs. N=7, 2.1% (control)- ankylosing spondylitis, N=1 (CD) vs. N=1 (control)- scleroderma, N=2 (CD) vs. N=0 (control)- vasculitis, N=1 (CD) vs. N=0 (control)- systemic lupus erythromatous, N=1 (CD) vs. N=0 (control)- mixed connective tissue disease, N=1 (CD) vs. N=0 (control)

Pulmonary disorders: - asthma, N=9 (CD) vs. N=12 (control)- sarcoidosis, N=5 (CD) vs. N=0 (control)

Neurological disorders:- epileptic seizures, N=5 (CD) vs. N=3 (control)


- dementia, N=5 (CD) vs. N=1 (control)

Liver diseases, N=4 (CD) vs. N=0 (control)Glomerulonephritis, N=3 (CD) vs. N=1 (control)Inflammatory bowel disease, N=1 (CD) vs. N=7 (control)Psoriasis, N=4 (CD) vs. N=0 (control)

Malignancy found before diagnosis of CD, N=4; N=7 in the control group


Number of patients


Outcome measures

Source of funding

Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease.[see comment]. Gut 1996;39:382-4

Case control

N=150 with infertilityN=50 with spontaneous abortion(N=control group)


Adults

Finland

Inclusion: successive women examined for infertility, women having two or more spontaneous abortions, between February 1993 and December 1994

Control patients women with a normal obstetric history who had undergone laproscopic sterilisation

IgA AGA, ELISA

(also reticulum, not included here)

+ve serology had upper gastrointestinal endoscopy including biopsy

IgA AGA cut off 0.20 EU/ml

Medical Research Fund of Tampere University Hospital

Effect size:

N=4/150 (2.7%) in the infertility group compared with none in the control group had coeliac disease, p=0.06All of those with coeliac disease had unexplained fertility so the prevalence of coeliac disease in this group was 4.1% (N=4/98), compared with control group N=0/150, p=0.02


All N=4 were AGA +ve


Number of patients


Outcome measures

Source of funding

Del Rosario MA, Fitzgerald JF, Chong SK, Croffie JM, Gupta SK. Further studies of anti-endomysium and anti-gliadin antibodies in patients with suspected celiac disease. Journal of Pediatric Gastroenterology & Nutrition 1998;27:191-5

Cohort N=107

Children

USA

Inclusion: untreated patients of the gastroenterology, endocrinology, pulmonary and developmental paediatric services whose symptoms raised suspicion of celiac disease, from one hospital, March 1996 to July 1997, 67 male, mean age 4.8yrs (5 to 16.7yrs)

N=46 persistent GI symptoms, failure to gain weight or both – intestinal biopsy. Those screened by other services did not have a biopsy where serology was negative

IgA EMA (indirect immunoflourescence) using monkey oesophagus

IgA/IgG AGA (enzyme linked immunosorbent assay)

Total serum IgA

Biopsies from the third portion of the duodenum or proximal jejunum, histological exam considered by paediatric pathologists and reviewed by study authors

Not stated

Effect size:

N=107, EMAN=104, AGA

N=46 /107 biopsy (total serum IgA measured in N=19 who had small bowel biopsy)


EMA:Sensitivity, specificity, PPV, NPV all 100%2X2:

(a)TP 5

(b)FP 0

(d)FN0

(c)TN17

IgA AGA:Sensitivity: 100%Specificity: 92%PPV: 57NPV: 1002X2:

(a)TP 4

(b)FP 3

(d)FN0

(c)TN36

IgG AGA:Sensitivity: 100%Specificity: 38%PPV: 14NPV: 1002X2:

(a)TP 4

(b)FP 24

(d)FN0

(c)TN15

Reference Study type/Evidence

Number of patients


Outcome measures

Source of funding


levelDickey W, McMillan SA, McCrum EE, Evans AE. Association between serum levels of total IgA and IgA class endomysial and antigliadin antibodies: implications for coeliac disease screening. European Journal of Gastroenterology & Hepatology 1997;9:559-62

Cohort/case control

N=318

Mixed

N Ireland

Inclusion: patients attending gastroenterology clinics for suspected celiac disease, mean age 42yrs (range 11 to 88yrs), N=192 (60%) female

(N=1959 controls from a previous study – results not reported here)

IgA EMA (indirect immunofluorescence, monkey oesophagus)(Biogiagnostics)(titre of ≥1:5 taken as positive)

IgA AGA (ELISA)(Labmaster)

Total IgA, IgM and IgG

Irrespective of AGA or EMA results patients were biopsied, at least 3 biopsies taken from the distal duodenum, assessed by experienced histiopathologists

IgA less than 0.8g/l considered low, <0.07g/l considered undectable

Not stated


Indicators which prompted investigation for coeliac disease: diarrhoea (N=163, 51%), anaemia (N=51, 16%), abdominal pain (N=39, 12%), chronic fatigue (N=23, 7%), weight loss (N=20, 6%), abnormal liver biochemistry (N=15, 5%), dermatitis herpetiformis (N=4, 1%), family history of coeliac disease (N=3, 1%)

N=31 (10%) had villous atrophy, of these N=27 (87%) had +ve EMAAll of those with +ve EMA had villous atrophy, AGA >100EU in N=20 (74%) and between 11 and 100EU in N=7 (26%)

IgA EMA: sensitivity 87%, specificity 100%, PPV 100%, NPV 99%2x2:

(a) (b)


TP 27

FP 0

(c)FN4

(d)TN287

IgA EMA (IgA <0.07g/l): sensitivity 94%, specificty 99%, PPV 91%, NPV 99%2x2:

(a)TP 29

(b)FP 0

(c)FN2

(d)TN284

(no patient with villous atrophy and –ve EMA had an AGA >100EU addition of AGA to protocols added nothing to sensitivity or PPV)


Number of patients


Outcome measures

Source of funding

Emami MH. Diagnostic accuracy of IgA anti-tissue transglutaminase in patients suspected of having coeliac disease in Iran. Journal of Gastrointestinal and Liver

Cohort N=350

Mixed

Iran

Inclusion: consecutive patients with suspected coeliac disease6, between April 2004 and October 2006, research institute Iran, N=195 (55.7%) female, mean age 31.44yrs (range 2 to 83yrs), N=98 <18yrs

Biopsies were read by 2 expert histolopathologists who were blinded to the serological results of the patients

IgA tTG (ELISA)(ORG540 A, ORGENTEC Diagnostica GmbH)

Serum levels of IgA

Upper GI endoscopy, at least 4 biopsies from the second part of the duodenum in all patients

Biopsies evaluated using Marsh

In a normal range study with serum samples from healthy blood donors the cut-off of 10U/ml have been established with the anti-tTG test

Isfahan University of medical Science, Iran

Pour Sina Hakim Research Institution

6 Group I, classical presentation including diarrhoea, weight loss, iron deficiency anaemiaGroup II, non-specific prolonged GI symptoms like abdominal pain, abdominal bloating, constipation, steatorrhoeaGroup III, atypical presentation determined during screening of high risk groups


Diseases 2008;17:141-6

Effect size:

Marsh I/II classed as lymphocytic enteritisMarsh III classed as CD

71.4% classical presentation, 4.7% atypical presentation, 23.8% non specific prolonged GI symptoms

N=21 coeliac disease (62% female), Marsh IIIa 38%, Marsh IIIb 38%, Marsh IIIc 24%Prevalence 6% (21/350)

N=8 lymphocytic enteritis (Marsh I, N=4, Marsh II, N=4), all tTG –ve

tTGSensitivity 38%, specificity 98%, PPV 57%, NPV 96%

2X2: (a)TP 8

(b)FP 6

(d)FN13

(c)TN323

Anti-tTG antibody +ve 53% (N=8/15) of those with classical presentation, anti-tTG antibody +ve 0% (N=0/1) of those with non specific GI presentation, tTG +ve 0% (N=0/5) of those with atypical presentation (p<0.05):

- classical; sensitivity 47.9%, specificity 96.4%- non-specific GI; sensitivity 0%, specificity 100%- atypical; sensitivity 0%, specificity 98.2%

Those with CD; 80% (N=4/5) with total villous atrophy, 25% (N=4/16) with partial villous atrophy had +ve anti-tTG antibodies (p<0.05)Marsh IIIc; sensitivity 80%, specificity 98%Marsh IIIa and IIIb; sensitivity 36.8%, specificity 98%

(author conclusion: test sensitivity for tTG antibody is significantly lower in those with lesser degrees of histological damage)



Number of patients


Outcome measures

Source of funding

Ertekin V, Selimoglu MA, Kardas F, Aktas E. Prevalence of celiac disease in Turkish children. Journal of Clinical Gastroenterology 2005;39:689-91

Cohort N=1,263 children

Turkey

Inclusion: randomly selected by systematic sampling method, N=687 (54.4%) male, N=5761 (45.6%) female, mean age 11.9±3.4yrs

None had a family history of coeliac disease

A pathologist blinded to the serology results examined all biopsy specimens according to the modified Marsh criteria

IgA-tTG

Biopsy

Not stated

Effect size: None had IgA deficiency

N=11/1,263 +ve tTG (N=6 boys), total seropositivity was 0.87%N=5/11 of these were asymptomatic, N=4 had iron deficiency anaemia, N=5 failure to thrive, N=1 abdominal pain/diarrhoea/iron deficiency anaemia/failure to thrive Seropositive more frequent vs. seronegative for failure thrive (p=0.0001) and iron anaemia (p=0.04)

N=8 biopsied, N=5 Marsh Type IIIc, N=2 Type IIIb, N=1 normal mucosal histology this patient was considered latent coeliac disease (elevated autoantibody titers without histologic abnormality)N=3 refused further investigations

Prevalence of coeliac disease 1:115, prevalence of biopsy proven, 1:158


Number of patients


Outcome measures

Source of funding

Ferre-Lopez Cohort N=335 Inclusion: consecutive (retrospective) sera ELISA tests ‘Intestinal Diagnostic Ministerio


S, Ribes-Koninckx C, Genzor C, Gamen S, Pena L, Ortigosa L et al. Immunochromatographic sticks for tissue transglutaminase and antigliadin antibody screening in celiac disease. Clinical Gastroenterology & Hepatology 2004;2:480-4

(286 children, 49 adults)

Children – age range 0.9 to 13 yearsAdults – age range 16 to 65 years

Spain

from adults and children, intestinal biopsy to be performed within 1 month of serum sampling, no dietary restrictions

Exclusion: none reported

(group 2: patients with a known diagnosis of celiac disease on a GFD for >2yrs with serologic analysis – results not included in this table)

IgA/AGA homemade ELISA, or CAP gliadin IgA fluorometric immunoassy ’taking into account the cut-off levels of each method for accurate evaulation of results’

IgA-tTG Celikey, with cut-off of 6IU/ml

Stick tests

tTG2-line immunochromatographic sticks

tTG-AGA3-line immunochromatographic sticks

Stick results read blindly within 20 minuntes of testing by 2 independent observers

Blood for

biopsy’ – no further details

accuracy of the tests

de Ciencia y Tecnoogia, coordinated by the group of the Unidad de Gluten, Centro Nacional de Biotecnolgia, and the Operon Company (inventors of the test)


serological tests taken within 1 month of the biopsy


N=172/335 (51%, 142 children – 50% - and 30 adults – 61%) diagnosed with coeliac disease, using ESPGAN criteria

IgA deficiency 0.01% in children only (N=3/286), no cases reported in adults

Of the 121 children and 19 adults with a diagnosis other than coeliac disease (ie biopsy results were normal or minor histological changes of the mucosa), most

frequent diagnoses were cow’s milk protein intolerance, giardiasis, postenteritis syndrome.

PPV, NPV and all confidence intervals calculated from the 2x2 data presented in the paper.

IgA tTG ELISA childrensensitivity 96.4% (93.3 to 99.5), specificity 98.3% (96.1 to 100), PPV 98.5% (96.5 to 100), NPV 96.0% (92.5 to 99.4)2X2:

(a)TP 134

(b)FP 2

(c)FN5

(d)TN119

IgA tTG ELISA adultssensitivity 83.3% (70.0 to 96.7), specificity 94.7% (84.7 to 100), PPV 96.2% (88.8 to 100), NPV 78.3% (61.4 to 95.1)2X2:

(a)TP 25

(b)FP 1

(c)FN5

(d)TN18

IgA/G tTG stick childrensensitivity 97.1% (94.3 to 99.9), specificity 98.3% (96.1 to 100), PPV 98.5% (96.5 to 100), NPV 96.7% (93.6 to 99.9)2X2:

(a) (b)


TP 135

FP 2

(c)FN4

(d)TN119

IgA/G tTG stick adultssensitivity 83.3% (70.0 to 96.7), specificity 100% (n/a), PPV 100% (n/a), NPV 79.2% (62.9 to 95.4)2X2:

(a)TP 25

(b)FP 0

(c)FN5

(d)TN19

IgA tTG tTG-AGA stick childrensensitivity 95.7% (92.3 to 99.1), specificity 98.3% (96.1 to 100), PPV 98.5% (96.5 to 100), NPV 95.2% (91.5 to 98.9)2X2:

(a)TP 133

(b)FP 2

(c)FN6

(d)TN119

IgA tTG tTG-AGA stick adultssensitivity 80.0% (65.7 to 94.3), specificity 100% (n/a), PPV 100% (n/a), NPV 76.0% (59.3 to 92.7)2X2:

(a)TP 24

(b)FP 0

(c)FN6

(d)TN19

IgA AGA ELISA childrensensitivity 86.3% (80.6 to 92.0), specificity 89.3% (83.7 to 94.8), PPV 90.2% (85.2 to 95.3), NPV 85.0% (78.8 to 91.2)2X2:

(a) (b)


TP 120

FP 13

(c)FN19

(d)TN108

IgA AGA ELISA adultssensitivity 90.0% (79.3 to 100), specificity 89.5% (75.7 to 100), PPV 93.1% (83.9 to 100), NPV 85.0% (69.4 to 100)2X2:

(a)TP 27

(b)FP 2

(c)FN3

(d)TN17

IgA AGA tTG-AGA stick childrensensitivity 89.2% (84.1 to 94.4), specificity 95.9% (92.3 to 99.4), PPV 96.1% (92.8 to 99.5), NPV 88.5% (83.1 to 94.0)2X2:

(a)TP 124

(b)FP 5

(c)FN15

(d)TN116

IgA AGA tTG-AGA stick adultssensitivity 83.3% (70.0 to 96.7), specificity 100% (n/a), PPV 100% (n/a), NPV 79.2% (62.9 to 95.4)2X2:

(a)TP 25

(b)FP 0

(c)FN5

(d)TN19

IgA tTG+AGA ELISA children (two tests)sensitivity 98.6% (96.6 to 100), specificity 87.6% (81.7 to 93.5), PPV 90.1% (85.4 to 94.9), NPV 98.1% (95.6 to 100)2X2:

(a) (b)


TP 137

FP 15

(c)FN2

(d)TN106

IgA tTG+AGA ELISA adults (two tests)sensitivity 90.0% (79.3 to 100), specificity 84.2% (67.8 to 100), PPV 90.0% (79.3 to 100), NPV 84.2% (67.8 to 100)2X2:

(a)TP 27

(b)FP 3

(c)FN3

(d)TN16

IgA tTG+AGA stick children (one test)sensitivity 99.3% (97.9 to 100), specificity 95.0% (91.2 to 98.9), PPV 95.8% (92.60 to 99.1), NPV 99.1% (97.5 to 100)2X2:

(a)TP 138

(b)FP 6

(c)FN1

(d)TN115

IgA tTG+AGA stick adults (one test)sensitivity 86.7% (74.5 to 98.8), specificity 100% (n/a), PPV 100% (n/a), NPV 82.6% (67.1 to 98.1)2X2:

(a)TP 26

(b)FP 0

(c)FN4

(d)TN19


Number of


Outcome measures

Source of


Evidence level

patients funding

Fraser JS, King AL, Ellis HJ, Moodie SJ, Bjarnason I, Swift J et al. An algorithm for family screening for coeliac disease. World Journal of Gastroenterology 2006;12:7805-9

Cohort N=914

UK

Inclusion: families identified in the GI outpatients, from consultant colleagues, recruitment drive in magazine published by Coeliac UK, total N=151 families, N=73 single affected family, N=78 multiply affected families (range 2-7)

Control; normal control used to set up the parameters for serological testing, healthy and symptom-free lab staff and relatives, age range 24-60yrs; those with any family history of GI problems, diabetes, and auto-immune thyroid disease were excluded

IgA-tTG

Those above the cut off IgA-EMA

IgA-tTG –ve and IgG-tTG +ve had total IgA and IgG1-EMA

Biopsy, those with +ve serological screening

HLA-DQ typing

Coeliac UK, Action Research, German Federal Ministry of Education and Research, European Union

Effect size (all CI 95%):

IgA-tTG antibodies N=60 +ve, of these N=36 IgA-EMA +ve

IgG-tTG antibodies in the absence of IgA-tTG antibodies in N=194, of these N=3 were IgG1-EMA +ve, N=2of these IgA deficient

Singly affected family:- N=73 with coeliac disease, N=223 relatives, N=11 +ve screening, N=11 1st degree relatives

Multiply affected family:- N=232 with coeliac disease, N=691 relatives, N=28 +ve screening, N=22 1st degree relatives, N=2 2nd degree relatives, N=4 not related

Single-affected family relationships:- mother, N=73 tested, N=5 (6.85%) affected- father, N=73 tested, N=4 (5.58%) affected- sibling, N=37 tested, N=2 (5.41%) affected- child, N=18 tested, N=0 affected- uncle/aunt, N=5 tested, N=0 affected- grandparent, N=6 tested, N=0 affected- grandchild, N=2 tested, N=0 affected- nephew/niece, N=3 tested, N=0 affected


- husband/wife, N=6 tested, N=0 affectedTotal – 5.47% of 1st degree relatives +ve EMA, 0% of 2nd degree relatives (majority of those with coeliac disease in this group were children so not many children of individuals with coeliac disease in this group)

Multiply-affected family relationships:- mother, N=51 tested, N=3 (5.88%) affected- father, N=31 tested, N=3 (9.68%) affected- sibling, N=165 tested, N=9 (5.4%) affected- child, N=137 tested, N=7 (5.11%) affected- uncle/aunt, N=6 tested, N=1 (16.67%) affected- grandparent, N=11 tested, N=0 affected- grandchild, N=39 tested, N=0 affected- nephew/niece, N=67 tested, N=1 (1.49%) affected- 3rd degree or more, N=24 tested, N=0 affected - husband/wife, N=159 tested, N=4 (2.52%) affectedTotal – 5.41% of 1st degree relatives +ve EMA, 1.62% of 2nd degree relatives, N=5 (2.52%) of those related only by marriage to the person with coeliac disease had +ve coeliac antibodies

HLA-typing:N=39 individuals of +ve EMA antibodies had HLA-typing- HLA-type DR3/DRx, N=25 (86.2%)- HLA-type DR3/DR7, N=4 (13.8%)- HLA-type DR5/DR7, DR4, DR3/DR4, DR4/DR7, all N=0

N=35 biopsied, N=32 +ve with partial or sub-total villous atrophy, N=3 normal


Number of patients


Outcome measures

Source of funding

Garampazzi A, Rapa A, Mura S, Capelli A, Valori A, Boldorini R et al. Clinical pattern of celiac disease is still

N=307

Children

Italy

Inclusion: children undergoing oesophagogastroduodenoscopy from 1987 to 2006 were entered on a database from paediatric endoscopy units

Not stated


changing. Journal of Pediatric Gastroenterology & Nutrition 2007;45:611-4

Effect size:

N=307/2422 undergoing oesophagogastroduodenoscopy had coeliac disease

Numbers diagnosed:1987-1991: N=66/778 (8.5%) with coeliac disease, M/F 25/41, age at diagnosis, median range 6.3 (0.8 to 18)1992-1995: N=113/701 (16.1%) with coeliac disease, M/F 32/81, age at diagnosis 3.1 (0.8 to 16)1996-2000: N=43/386 (11.1%) with coeliac disease, M/F 15/28, age at diagnosis 3.3 (0.9 to 14.7)2001-2006: N=85/557 (15.2%) with coeliac disease, M/F 28/57, age at diagnosis 5.9 (1.1 to 17.4)

Significant difference between the % diagnosed from 1987 to 1995 and 2001 to 2006

Symptoms (typical):1987-1991: failure to thrive N=58 (87%), diarrhoea N=36 (60%), abdominal distension N=16 (24%)1992-1995: failure to thrive N=101 (89%), diarrhoea N=59 (52%), abdominal distension N=44 (39%)1996-2000: failure to thrive N=34 (79%), diarrhoea N=14 (32%), abdominal distension N=9 (21%)2001-2006: failure to thrive N=41 (48%), diarrhoea N=11 (12%), abdominal distension N=17 (20%)

Prevalence of typical symptoms at presentation was significantly higher in 1987-1995 than in 1996-2006, p<0.0001 for failure to thrive, p=0.02 for abdominal distension

Symptoms (atypical):1987-1991: isolated anaemia N=2 (3%), recurrent abdo pain N=7 (11%), constipation N=4 (6%), irregular bowel habits N=3 (4%), family history of CD without symptoms N=3 (5%) 1992-1995: isolated anaemia N=21 (19%), recurrent abdo pain N=12 (11%), constipation N=5 (4%), irregular bowel habits N=5 (4%), family history of CD without symptoms N=01996-2000: isolated anaemia N=2 (5%), recurrent abdo pain N=5 (12%), constipation N=5 (12%), irregular bowel habits N=5 (12%), family history of CD without symptoms N=0 2001-2006: isolated anaemia N=7 (8%), recurrent abdo pain N=18 (21%), constipation N=9 (11%), irregular bowel habits N=4 (5%), family history of CD without symptoms N=9 (10%)

Prevalence of recurrent abdominal pain (p=0.02) was significantly higher in 2001-2006 than in 1987-1995


Prevalence of children with typical at least 2 or more typical symptoms decreased every 5yrs from 76% in 1987-1990, 63% in 1991-1995, 62% in 1996-2000, 44% in 2001-2006


Number of patients


Outcome measures

Source of funding

Gomez JC, Selvaggio GS, Viola M, Pizarro B, La Motta G, de Barrio S et al. Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area. American Journal of Gastroenterology 2001;96:2700-4

Cohort N=2000 (offered to N=2011)

Argentina

Inclusion: all couples attending the centralized laboratory for an obligatory prenuptial examination between January 1998-May 2000, were offered participation, mean age 29yr, range 16-79yr, N=996 female

(size of sample was estimated considering a possible prevalence of 0.25%, population of LaPlata area of 643,000; it was calculated that searching 1,280 would be adequate)

IgA/IgG-AGA, those –ve excl

Those +ve for either or both for IgA exclusively tested for IgA EMA

Those +ve for IgG AGA were tested for serum levels of IgA, those with normal total IgA (>200mg/ml) excl, those with low IgA were tested for IgG EMA

Those whose serum samples were +ve for EMA were eligible for small bowel biopsy

The Comision de Investigaciones Cientificas of Buenos Aires Province, Argentina

Effect size:


N=24; IgA/IgG AGA both +ve- IgA EMA; N=9+ve, N=15-ve

N=190; IgA AGA –ve, IgG AGA +ve- IgA deficit, IgG EMA +ve, N=2- Normal total IgA, N=188

N=23; IgA AGA +ve, IgG AGA –ve - IgA EMA –ve, N=22- IgA EMA +ve, N=1

N=12 who were eligible for an intestinal biopsy, overall prevalence 1:167 (6.0/1000, 95% CI, 3.1 to 10.5)N=8 women, prevalence 1:124, 8.0/1000, 95% CI 3.5 to 15.8N=4 men, prevalence 1:251, 4.0/1000, 95% CI 1.1 to 10.2

N=11/12 had small intestinal biopsy, all were biopsy-proven cases presenting with a flat intestinal mucosa - Median age 26yrs, median body weight 57kgs, median height 165cm, median BMI 21.2 - N=1 chronic diarrhoea, N=3 chronic hypochromatic anaemia, N=8 asymptomatic - N=3 reduced BMI, N=1 +ve family history for coeliac disease


Number of patients


Outcome measures

Source of funding

Greco L, Veneziano A, Di Donato L, Zampella C, Pecoraro M, Paladini D et al. Undiagnosed coeliac disease does not appear to be associated with unfavourable outcome

N=5055

Adults

Italy

Inclusion: pregnant women admitted to one of 14 obstetric and gynaecology wards, from November 2001 to January 2002

Exclusion: non-pregnant women, admission lasting less than 24hrs

Participation rate, 94.64%, sample represented approx 30% of the total 16 500 births expected in the region over this period

IgA anti tissue transglutaminase (TGASE) and endomysial antibodies

Duodenal biopsy not considered feasible by the ethics committee for pregnant women near delivery

Not stated


of pregnancy. Gut 2004;53:149-51

Effect size:

N=48 TGASE >9 IU, all had +ve EMA and DQ2 or DQ8N=3 with 7-9 IU TGASE had +ve EMA also considered to have CD

N=51 cases considered +ve, N=12 coeliac cases known before screening

Severe anaemia which was x3 more frequent in those with coeliac disease (N=18/51 and N=4/12 vs. N=564/4997, p=0.0045)

No other events significantly different in those with coeliac disease vs. those without coeliac disease


Number of patients


Outcome measures

Source of funding

Green PHR, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in patients with celiac disease. American Journal of Medicine 2003;115:19

Cohort N=381

Adults

USA

Inclusion: patients older than 18yrs, at a hospital which has a referral centre for coeliac disease, N=245, 64% female, age at diagnosis 44±18yrs (SD), duration of symptoms 5±8yrs

Malignancy Not stated


1-5


N=43 diagnosed with malignancy, N=34 diagnosed before or simultaneously (during the same month or admission) with coeliac disease

Cancers diagnosed before or simultaneously with coeliac disease:- non-Hodgkin’s lymphoma; N=4 observed, N=0.7 expected, SMR7: 5.3 (2.3 to 13), p<0.001- small bowel; N=3 observed, N=0.1 expected, SMR: 45 (34 to 61), p<0.001- colon; N=3 observed, N=2.6 expected, SMR: 1.2 (0.2 to 7.2), NS (0.80)- oesophageal; N=3 observed, N=0.2 expected, SMR: 16 (9.7 to 26), p<0.001- melanoma; N=4 observed, N=0.8 expected, SMR: 5.0 (2.1 to 12), p<0.001- breast; N=5 observed, N=4.0 expected, SMR: 1.3 (0.2 to 7.2), NS (0.61)- lung; N=2 observed, N=2.8 expected, SMR: 0.7 (0.1 to 7.2), NS (0.64)- total8; N=34 observed, N=14 expected, SMR: 2.4 (0.7 to 8.5), NS (0.16)


Number of patients


Outcome measures

Source of funding

Hopper AD, Hadjivassiliou M, Hurlstone DP, Lobo AJ, McAlindon ME, Egner W et al. What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed

Cohort/case control

N=2000

Adults (≥16yrs)

UK

Inclusion: consecutive adults referred for gastroscopy without a previous diagnosis of celiac disease at a single endoscopist department from January 2004 to April 2006, N=1167 (58.3%) female, mean age 55.8yrs (range 16 to 94yrs)

Exclusion: known diagnosis of coeliac disease, a coagulopathy (international normalised ratio > 1.3 or platelet count of < 80), active GI bleed or a suspected carcinoma observed during the examination

(group 2: patients with a known diagnosis of celiac disease on a GFD for >1yr undergoing repeat duodenal biopsies and serologic analysis – results not included in

IgA/IgG AGA (ELISA, AESKU Diagnostics)(cut-off > 15 U/mL)

IgA tTG (ELISA, AESKU Diagnostics)(cut-off > 15 U/mL)

IgA EMA (immunofluorescence, primate oesophagus)

Policy of 4 duodenal biopsy specimens from the second part of the duodenum

Marsh criteriaThose with villous atrophy with supporting signs and symptoms were considered to have coeliac disease

Those with villous atrophy (confirmed on a second review of the sample to ensure a well-oriented sample) and a antibody –ve profile were

Not stated

7(? Standardised Morbidity Ratio, ratio of observed to expected)8 Total includes chronic lymphatic leukaemia, ovarian, cervical, liver, prostate, bladder, endometrial, thyroid cancer, Hodgkin’s disease


study with economic analysis. Clinical Gastroenterology & Hepatology 2008;6:314-20

this table)Total IgA (Behring BN2 nephelometer, Siemens)

Blood for serological tests taken at the same time as the biopsy

classed as seronegative coeliac disease, to confirm this they were required to have DQ2 or DQ* pattern consistent with CD and a clinical and histological response to a GFD


N=77/1000 diagnosed with coeliac disease (prevalence, all patients attending for gastroscopy of 3.9%); N=29 Marsh 3a, N=30 Marsh 3b, 18 Marsh 3c lesions

IgA deficiency 0.7% (N=14/2000)

Symptoms (coeliac disease vs. non coeliac disease):Weight loss (15.6% vs. 5.3%), p<0.05

Diarrhoea (42.9% vs. 5.2%), p<0.05

Dyspepsia (17.3% vs. 1%), p<0.05

Reflux (13.8% vs 1%), p<0.05

Dysphagia (7.2% vs. 0%), p<0.05

Those with coeliac disease were significantly younger (mean age 48.0 vs. 56.1 yrs), p<0.05, there were significantly more females (70.1% vs. 57.9%), p<0.05, than

those without coeliac disease

IgA tTG sensitivity 90.9% (82.4 to 94.5), specificity 90.9% (89.5 to 92.1), PPV 28.6% (23.3 to 34.5), NPV 99.6% (99.2 to 99.8)2X2:

(a)TP 70

(b)FP 175

(c)FN

(d)TN


7 1748

IgA EMA sensitivity 87.0% (77.7 to 92.8), specificity 98.0% (97.4 to 98.6), PPV 64.4% (54.9 to 73.0), NPV 99.4% (99.0 to 99.7)2X2:

(a)TP 67

(b)FP 37

(c)FN10

(d)TN1886

If tTG +ve and then EMA +ve (2-step) sensitivity 85.7% (76.2 to 91.8), specificity 98.6% (98.0 to 99.0), PPV 71.7% (61.8 to 79.9), NPV 99.4% (99.4 to 99.0)2X2:

(a)TP 66

(b)FP 26

(c)FN11

(d)TN1897

Both tTG +ve and EMA +ve sensitivity 85.7% (76.2 to 91.8), specificity 98.6% (98.0 to 99.0), PPV 71.7% (61.8 to 79.9), NPV 99.4% (99.4 to 99.0)2X2:

(a)TP 66

(b)FP 26

(c)FN11

(d)TN1897

Either tTG +ve or EMA +ve sensitivity 92.2% (84.0 to 96.4), specificity 90.3% (88.9 to 91.6), PPV 27.6% (22.5 to 33.4), NPV 99.7% (99.3 to 99.8)2X2:

(a)TP 71

(b)FP 186

(c)FN

(d)TN


6 1737

IgG AGA sensitivity 48.1% (37.3 to 59.0), specificity 95.8% (94.9 to 99.6), PPV 31.6% (23.9 to 40.5), NPV 97.9% (97.1 to 98.4)2X2:

(a)TP 37

(b)FP 77

(c)FN40

(d)TN1849

IgA AGA sensitivity 49.4% (38.5 to 60.2), specificity 89.6% (88.2 to 90.1), PPV 16.0% (11.9 to 21.2), NPV 97.8% (97.0 to 98.4)2X2:

(a)TP 38

(b)FP 200

(c)FN39

(d)TN1723

Both IgA and IgG AGA sensitivity 36.4% (26.5 to 47.5), specificity 98.8% (98.2 to 99.2), PPV 54.9% (41.4 to 67.7), NPV 97.4% (96.7 to 98.1)2X2:

(a)TP 28

(b)FP 23

(c)FN49

(d)TN1900

Using only IgA tTG +ve 245 would have undergone biopsy and 1 in 11 cases of coeliac disease would have been missedUsing only IgA EMA +ve 104 would have undergone biopsy and 1 in 8 cases of coeliac disease would have been missedUsing IgA tTG +ve and then IgA EMA +ve 92 would have undergone biopsy and 1 in 7 cases of coeliac disease would have been missedUsing either IgA tTG +ve or IgA EMA +ve 257 would have undergone biopsy and 1 in 13 cases of coeliac disease would have been missed

Those with partial villous atrophy (Marsh 3a or 3b) had significantly lower mean tTG titre (168.1 U/mL and 165.0 U/mL) than those with total villous atrophy (255 U/mL), p<0.05Those with Marsh 1 or 2 had significantly lower mean tTG titre (27.7 U/mL and 23.0 U/mL) than those with villous atrophy, p<0.05


EMA sensitivity 79% in partial atrophy, 100% in total atrophy, p<0.01tTG sensitivity 86.0% (Marsh 3a), 100% (Marsh 3c), p<0.05


Number of patients


Outcome measures

Source of funding

Johnston SD, McMillan SA, Collins JS, Tham TC, McDougall NI, Murphy P. A comparison of antibodies to tissue transglutaminase with conventional serological tests in the diagnosis of coeliac disease.[see comment]. European Journal of Gastroenterology & Hepatology 2003;15:1001-4

Cohort N=586

Adults

NI

Inclusion: consecutive adult patients who had undergone serological testing for coeliac disease during the first 18mths of the use of tissue transglutaminase antibody assay (retrospectively analysed), recruited from 5 hospitals in NI, N=220 male, average age 46.6yrs

IgA AGA (ELISA)

EMA (indirect immunoflourescence using monkey oesophagus as the antigen)

tTG (ELISA)

Coeliac disease defined as severe partial villous atrophy, sub-total or total villous atrophy

Not stated


Effect size:

N=92 (N=33 male, mean age 51.7yrs) had been followed-up with biopsy, identified as the study group

N=29/92 coeliac disease (N=14, 31% male, mean age 52.5yrs), the remaining N=63 acting as controls had normal histology

For N=92 biopsied:Antitransglutaminase antibodies; sensitivity 86%, specificity 84%, PPV 93%, NPV 71%2X2:

(a)TP 25

(b)FP 10

(c)FN4

(d)TN53

Antiendomysial antibodies; sensitivity 90%, specificity 98%, PPV 95%, NPV 96%2X2:

(a)TP 26

(b)FP 1

(c)FN3

(d)TN62

Antigliadin antibodies; sensitivity 76%, specificity 79%, PPV 88%, NPV 63%2X2:

(a)TP 22

(b)FP 13

(c)FN7

(d)TN50

For N=55 in whom there was clinical grounds for biopsy (eg diarrhoea, weight loss, anaemia, family history):Antitransglutaminase antibodies; sensitivity 86%, specificity 76%Antiendomysial antibodies; sensitivity 95%, specificity 100%Antigliadin antibodies; sensitivity 76%, specificity 76%


Combination of either antiendomysial antibody or tissue transglutaminase antibody positivity gave sensitivity 93%, specificity 83%, PPV 71%, NPV 96%2X2:

(a)TP 27

(b)FP 11

(c)FN2

(d)TN52


Number of patients


Outcome measures

Source of funding

Kocna P, Vanickova Z, Perusicova J, Dvorak M. Tissue transglutaminase-serology markers for coeliac disease. Clinical Chemistry & Laboratory Medicine 2002;40:485-92

Cohort N=1451(a subset from N=2971)

Czech Republic

Inclusion: consecutive samples on which coeliac disease markers had been requested since May 1992, mean age 40.2yrs, N=982 (66%) female, N=510 (34%) male,

IgA/IgG AGA (ELISA, using α-gliadin as antigen)

IgA EMA (indirect immunofluorescence on primate smooth muscle sections)

IgA tTG (ELISA, guinea pig antigen)

Small intestinal biopsy

Ministry of Health and Grant Agency of Charles University, Czech Republic

Effect size:

N=274 biopsied, all coeliac disease markers determined in N=119 cases who were all biopsied, from these sensitivity/specificity markers


N=50 coeliac disease, N=69 non-coeliac disease (N=7 coeliac disease in remission, N=24 isolated lactase deficiency, N=38 normal small bowel mucosa)

IgA AGA:Sensitivity 84.0%, specificity 71.0%

2X2: (a)TP 42

(b)FP 20

(d)FN8

(c)TN49

IgG AGA:Sensitivity 94.0%, specificity 40.3%

2X2: (a)TP 47

(b)FP 41

(d)FN3

(c)TN28

IgA EMA:Sensitivity 68.0%, specificity 93.5%

2X2: (a)TP 34

(b)FP 4

(d)FN16

(c)TN65

IgA tTG:Sensitivity 88.0%, specificity 64.6%

2X2:


(a)TP 44

(b)FP 24

(d)FN6

(c)TN45

Two-step screening algorithms based on N=1451 (effectivity % of CD from 50 biopsy-proven caught by the first marker; accuracy I correctly +ve/-ve from all biopsy-proven ranked by first marker; accuracy II calculated for 2-step process using any of two remaining markers)

First step marker Effectivity Accuracy I Number entering second step

Accuracy II

IgA/IgG AGA 96% 0.598 839 0.821 (EMA)0.750 (atTG)

EMA 68% 0.821 115 0.821 (IgA/IgG AGA)0.804 (atTG)

atTG 88% 0.750 323 0.750 (IgA/IgG AGA)0.804 (EMA)

ELISA producer Antigen

sourceCorrelation coefficient (r)

Concordance (%) Cohen’s Number of samples

DPC Human recombinant

0.781 85.0% 0.61 153

Routine method (Genesis)

Guinea pig n/d 84.1% 0.40 1451

Immco Guinea pig 0.509 90.7% 0.45 161Medipan Guinea pig 0.306 57.5% 0.26 40Orgentec Human cells 0.343 80.7% 0.31 119


Number of patients


Outcome measures

Source of funding


Korponay-Szabo IR, Kovacs JB, Czinner A, Goracz G, Vamos A, Szabo T. High prevalence of silent celiac disease in preschool children screened with IgA/IgG antiendomysium antibodies. Journal of Pediatric Gastroenterology & Nutrition 1999;28:26-30

Cohort N=427

Hungary

Inclusion: apparently healthy, 3-6yr, N=201 female, N=226 male, samples originally obtained for the Hungarian State Institute of Public Health and Health Officer Service of Budapest, children live in the central district of the capital

No known cases of coeliac disease

Collected sera represented 61% of the eligible population

IgA/IgG EMA, indirect immunofluorescence

Those positive IgA/IgG AGA and biopsy

National health Insurance und Administration, the National Institute if Public Health, local authorities of district 5 Budapest

Effect size:

N=6/427 (1.4%) EMA +ve; N=5 strongly +ve, N=1 weakly +ve, N=4 IgA EMA +ve (the 2 –ve cases had IgA deficient sera), N=4 IgG EMA +ve

N=5 (1.17%) severe villous atrophy consistent with coeliac disease

Prevalence of coeliac disease (based only on cases with proven enteropathy) was 1:85 in the study population, 11.6/1000

All celiac cases were IgA-AGA –ve, N=2 with coeliac disease –ve for IgA-AGA and IgG-AGA

None of those with coeliac disease had chronic enteral symptoms or growth retardation, N=2 iron deficiency

(Author note: the sensitivity of AGA tests decreases with age)



Number of patients


Outcome measures

Source of funding

Leeds JS, Horoldt BS, Sidhu R, Hopper AD, Robinson K, Toulson B, Dixon L, Lobo AJ, McAlindon ME, Hurlstone DP, Sanders DS. Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls. Scandinavian Journal of Gastroenterology 2007;42:1214-1220

Case control

N=354 with IBD, N=173 Crohn’s diseaseN=154 ulcerative colitis

N=305 with coeliac disease

(N=601 control)

Adults

UK

Inclusion: patients registered as having irritable bowel disease in one hospital recruited during attendance at out-patient clinics, N=209 female, median age 45yrs; patients with coeliac disease recruited from the specialist clinic during the annual review, N=222 female, median age 52yrs

Control: recruited from 5 general practices in one region

Those in the coeliac disease group were significantly older than those in the IBD group (p<0.0001) and the control group (p=0.002)

Those with IBD who have coeliac diseaseThose with coeliac disease who have IBD

Unfunded study


Effect size: Results of those with coeliac disease who had irritable bowel disease – the prevalence of IBD in coeliac disease 3.3% vs. control 0.33%, OR 9.98 (95%CI, 2.8 to 45.9), p=0.0006

Coeliac disease in those with irritable bowel disease, N=3/354 (0.85%) vs. N=5/601 with control, OR 1.02 (95% CI, 0.24 to 4.29), p=1.0 NS

Stepwise logistical regression was performed to identify factors likely to predict the development of coeliac disease in those with IBD, age, gender, disease type (Crohn’s disease or ulcerative colitis) and extent of disease were NS.


Number of patients


Outcome measures

Source of funding

Lenhardt et al (2004) Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A deficiency

Cohort N=126

Children

Italy

Inclusion: total IgA deficiency, referred to paediatric units, N=60 male, N=66 female, median age 10.8yrs (range 2 to 20yrs), from June 1999 to January 2002, all had recurrent respiratory, none were diagnosed with coeliac disease, all were on a normal diet, levels of other immunoglobulin were normal

IgG AGA (immunoenzyme assay)(Eurospital)(manufacturer cut-off <4U/mL)

IgA/IgG htTG (ELISA)(normal values <16% for IgA and <42% for IgG)

HLA typing

Those +ve for either IgG AGA or IgG htTG had intestinal biopsy following the ESPGHAN criteria

Grants from IRCCS ‘Burlo Garofolo’ and MUIR



N=27/126 (21%) IgG AGA +veN=18/126 (14%) IgG htTG +ve N=5/27 IgG AGA and IgG htTG +ve , all N=5 CD on biopsy, N=22 normal biopsy

N=10/13 IgG htTG +ve alone biopsied, N=5 CD lesions

N=11 total CD diagnosis, 8.7% of those with IgA deficiency, all N=11 were IgG htTG +ve, N=5 were also IgG AGA +ve


Number of patients


Outcome measures

Source of funding

Liu E, Bao F, Barriga K, Miao D, Yu L, Erlich HA et al. Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease. Clinical Gastroenterology & Hepatology 2003;1:356-62

Cohort

Children

N=1803 newborns (from N=25000)

First-degree relatives N=773

Type 1 diabetes N=86

USA

Inclusion: children with 2 types of gentic risk for CD: - newborns with HLA-DR3 subgroup selected for prospective monitoring for the development of transglutaminase autoantibodies

- type 1 diabetes

- first-degree relatives of patients with T1D

Exclusion: biopsy specimens inadequate for proper interpretation

A single pathologist who was unaware of the clinical and lab findings interpreted the sample according to Marsh

Transglutaminase autoantibodies (radiobinding assay developed in vitro, +ve and –ve controls were included in every assay, the upper limit of normal was established, all +ve results and a subset of –ve results were retested, if results were discordant a 3rd

aliquot was evaluated and the status determine by 2 of the 3 samples)

Small intestinal biopsy (2 to 4 samples from the distal duodenum)

Serological screening for CD obtained at blood draws at 9, 15, and 24mths and yearly after

Mean follow-up 1.8yrs

Not stated


Total IgA (nephelometric method)

Effect size:

Any positive test (TGAA index >0.05) was repeated in 3-6months. Where 2 blood samples drawn on separate visits showed a +ve TGAA result the family was referred to a pediatric gastroenterologist, tTGA was repeated at the time of intestinal biopsy.

Persistent TGAASeropositivity in N=52 (N=25/1083 (2.3%) newborns, N=5/86 (5.8%) with T1D, N=22/773 (2.8%) 1st degree relatives of those with T1D

N=42 biopsied, N=28/42 (67%) CD (Marsh 2 or 3), N=12/42 (29%) normal biopsy, N=2 indeterminate biopsy (Marsh 1)

TGAA remained consistently +ve in N=39/42(93%) Mean age at 1st +ve TGAA (±SD) 4.5 (±1.6) for all:- 4.4±1.4 (N=8) for those with a normal biopsy (N=12); 4.6±1.7 (N=14) for those with a positive biopsy (N=28); NS difference

Correlation between TGAA index at the point of biopsy and the degree of intestinal pathology (Marsh score) - +ve biopsy N=22/28 TGAA titer >0.5, adjusting the TGAA level (index) threshold from 0.05 to 0.5 as a cut off improves PPV from 76% to 96% and decrease NPV from 100% to 65%- N=6/28 TGAA titer below 0.5 (p<0.0001)

TG index (cut off) 0.05 0.1 0.25 0.5 0.75PPV 0.76 0.80 0.89 0.96 1NPV 1 1 0.75 0.65 0.39

2X2 cut off 0.05: (a)TP 28

(b)FP 9

(c)FN0

(d)TN3

2X2 cut off >0.5: (a)TP

(b)FP


22 1(c)FN6

(d)TN11


Number of patients


Outcome measures

Source of funding

Liu E, Li M, Bao F, Miao D, Rewers MJ, Eisenbarth GS et al. Need for quantitative assessment of transglutaminase autoantibodies for celiac disease in screening-identified children. Journal of Pediatrics 2005;146:494-9

Cohort

Children

N=54 (N=27 T1D

N=14 1st degree relative of T1D N=13 HLA-DQ2

USA

Inclusion: children under 18yrs identified to be at risk for CD based on; T1D; first-degree relative of T1D; at birth expressing HLA-DQ2

Sera from N=10 healthy donors used as –ve control subjects

Exclusion: prior diagnosis of CD and gluten-free diet

TGAA assay (cut off):- RIA (0.05 index)- Inova Quanta Lite (20U)- Eurospital Eu-tTG (7AU/mL- IMMCO (20 EU/mL)- Biofans (15 AU)- Binding site (4U/mL)

Biopsy (2 samples from the proximal and 2 samples from the distal duodenum, in a few cases only one biopsy was obtained from each site

Selected for biopsy on +ve RIA (confirmed by repeat measures)

Serological screening for CD obtained at blood draws at 9, 15, and 24mths and yearly after

Marsh criteria 9

Marsh 1 was considered indeterminate for CD, Marsh 2 and 3 were considered consistent with CD

Conducted without support from any company manufacturing the assays used

Effect size:

Any positive test (TGAA index >0.05) was repeated in 3-6months, referred for evaluation and biopsy when 2 samples drawn on separate visits were TGAA +ve or

9 A single pathologist who was unaware of clinical and lab findings interpreted the sample according to the system described by Marsh


sooner if requested, TGAA measured at the time of biopsy

N=34 biopsy confirmation of CD, N=20 biopsies without evidence of villous atrophy

Each TGAA assay: (those in bold normal cut-off)- Radioimmunoassay (AUC = 0.8765)

Cut-off 0.05 0.5 0.75 1Sensitivity 100 82 68 38Specificity - 65 95 100

PPV 63 80 95 100NPV - 68 44 49LR - 2.35 12.35 -

2X2 cut off 0.05: (a)TP 34

(b)FP 20

(c)FN0

(d)TN0

- Inova (AUC = 0.8529)Cut-off 20 60 124 140

Sensitivity 97 82 65 56Specificity 20 70 95 100

PPV 67 70 95 100NPV 80 82 61 57LR 1.21 70 12.94 -

2X2 cut off 20: (a)TP 33

(b)FP 16

(c)FN1

(d)TN4

- IMMCO (AUC = 0.8838)Cut-off 20 40 90 121



PPV 84 87 95 100NPV 82 70 59 59LR 3.04 3.97 12.35 -


(b)FP 6

(c)FN3

(d)TN14

- Biofons (AUC = 0.8676)Cut-off 15 35 70 100


PPV 82 83 56 100NPV 81 63 61 59LR 2.61 2.94 12.94 -


(b)FP 7

(c)FN3

(d)TN13

- Binding site (AUC = 0.8644)Cut-off 4 15 26 30


PPV 75 83 96 100NPV 75 61 62 62LR 1.73 2.76 12.67 -


(b)FP 11

(c)FN

(d)TN


3 9

All samples had high concordance on duplicates for all assays (one exception considered to be human error)In all assays normal control sera were –ve.

N=54 +ve RIA, N=5/54 –ve Inova assay, N=17/54 –ve Euorspital, N=17/54 –ve IMMCO, N=16/54 –ve Biofans, N=12/54 –ve Binding site

Sensitivity when compared with intestinal histology ranged from 91% to 97% for all ELISA assays, specificity ranged from 20% to 70%

Inova and Eurospital more sensitive than IMMCO, Biofans, or Binding site, though Inova was less specific at the normal cut-off values.


Number of patients


Outcome measures

Source of funding

Ludvigsson JF, Montgomery SM, Ekbom A. Celiac disease and risk of adverse fetal outcome: a population-based cohort study. Gastroenterology 2005;129:454-63

Cohort N=2078 with coeliac disease

N=2,822,805 without coeliac disease

Inclusion: women identified with a hospital-based discharge diagnosis of CD from 1964 to 2001, through the Swedish national register10, women and children participants were al-live born single infants from 1973 to 2001 to mothers with coeliac disease aged between 15 to 44yrs

Mothers without a diagnosis of coeliac disease

Women diagnosed prior to infant birth and presumably treated at the time of birth

Women with undiagnosed coeliac disease, diagnosed after infant birth

Low birth weight (<2500g), very low birth weight (<1500g), preterm birth (<37 wks), very preterm birth (<30 wks). Low Apgar score at 5mins (<7), caesarean section, IUGR (weight for age below 2 SD), birth weight, pregnancy duration

Grants from the Orebro Society of Medicine, the Sven Jerring Foundation, Karolinska Institute funds, the Swedish Society of Medicine, the

10 To exclude the possibility that the findings were due to the presence of diabetes mellitus, adjustment was made for the presence of diabetes mellitus in a separate analysis


Swedish Research Council, the Majblomman Foundation, Orebro University Hospital


N=2078 with coeliac disease; N=1149 diagnosed before birth, N=929 undiagnosed (N=255 hospital discharge diagnosis of coeliac disease <5yrs after birth, N=674 diagnosis ≥5yrs after birth)

IUGR; no CD N=88073/2806297 (3.1%) vs. undiagnosed CD N=51/923 (5.5%) (adjusted11 OR 1.62, CI 1.22 to 2.15, p=0.001), CD vs. diagnosed CD (N=39/1141, 3.4%) NS difference

Low birth weight; no CD N=95531/2814664 (3.4%) vs. undiagnosed CD N=65/926 (7.0%) (adjusted OR 2.13, CI 1.66 to 2.75, p<0.001), CD vs. diagnosed CD (N=47/1147, 4.1%) NS difference

Very low birth weight; no CD N=14567/2814664 (0.5%) vs. undiagnosed CD N=11/926 (1.2%) (adjusted OR 2.45, CI 1.35 to 4.43, p=0.003), CD vs. diagnosed CD (N=6/1147, 0.5%) NS difference

Preterm birth; no CD N=139921/2815329 (5.0%) vs. undiagnosed CD N=74/925 (8.0%) (adjusted OR 1.71, CI 1.35 to 2.17, p<0.001), CD vs. diagnosed CD (N=72/1146, 6.3%) NS difference

Very preterm birth; no CD 0.3%, undiagnosed CD 0.6%, diagnosed CD 0.3%, NS difference

Low Apgar score; no CD 1.2%, undiagnosed CD 1.6%, diagnosed CD 1.0%, NS difference

Caesarean section; no CD N=65510/2822693 (2.3%) vs. undiagnosed CD N=32/928 (3.4%) (adjusted OR 1.82, CI 1.27 to 2.60, p=0.001), CD vs. diagnosed CD (N=17/1149, 1.5%) NS difference

Placental weight was significantly lower in women with undiagnosed coeliac disease vs. those without coeliac disease (crude difference -28g (CI, -45 to -10g), p=0.001

(Stratifying by non-smoking and smoking in those with undiagnosed coeliac disease showed some apparent differences, this was further investigated and authors

11 Adjusted for maternal age, parity, nationality, calendar period and infant sex


concluded that the interaction of smoking with undiagnosed coeliac disease was not evident and did not produce any statistically significant results for any outcomes)


Number of patients


Outcome measures

Source of funding

Ludvigsson JF, Michaelsson K, Ekbom A, Montgomery SM. Coeliac disease and the risk of fractures - a general population-based cohort study. Alimentary Pharmacology & Therapeutics 2007;25:273-85

Hip fractures:N=14187 with coeliac disease

N=68952 without coeliac disease

Any fractures:N=13724 with coeliac disease


Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=8311, 58.6% female, 66.0% diagnosed between 0 to 15yrs, 34.0% diagnosed ≥16yrs, 3.5% (1964 to 1973), 27.6% (1974 to 1983), 43.8% (1984 to 1993), 25.1% (1994 to 2003) 12

Reference individuals were matched for age, sex, calendar year and area of residence

Exclusion: those with data irregularities

IPR used to define 2 outcome measures; first hip fracture and first fracture of any type

IPR also used to define diabetes (T1D and T2D), thyroid disease and depression

Grant from the Swedish Society of Medicine, the Juhlin Foundation, the Clas Groschinsky Foundation, the Sven Jerring Foundation, the Orebro Society of Medicine, the Majblomman Foundation, the Karolinska Institutet funds, the

12 80% power to detect increased risk of subsequent hip fracture at 5% significance level in those with CD if more than 190/14187 had a subsequent hip fracture, corresponding to a HR of 1.2


Swedish Coeliac Society


Conditional logistic regression estimated the association of coeliac disease and prior hip fracture or prior fractures of any type - increased risk of coeliac disease after hip fracture OR 2.0 (CI: 1.6 to 2.5), p<0.001- increased risk of coeliac disease after any type of fracture OR 1.6 (CI: 1.5 to 1.8), p<0.001

Incidence for hip fractures per 100 000 person-years before and after diagnosis (IR, incidence ratio):- ≥10yrs before diagnosis, no CD 19/100000, CD 37/100000, IR 1.9 (CI: 1.3 to 2.9), p=0.001- 5 to 9.99 yrs before diagnosis, no CD 93/100000, CD 166/100000, IR 1.8 (CI: 1.3 to 2.5), p<0.001- 2 to 4.99 yrs before diagnosis, no CD 181/100000, CD 352/100000, IR 1.9 (CI: 1.4 to 2.6), p<0.001- 0.01 to 1.99 yrs before diagnosis, no CD 310/100000, CD 581/100000, IR 1.9 (CI: 1.4 to 2.5), p<0.001 - 0 to 1.99 yrs after diagnosis, no CD 446/100000, CD 1339/100000, IR 3.0 (CI: 2.4 to 3.7), p<0.001- 2 to 4.99 yrs after diagnosis, no CD 383/100000, CD 871/100000, IR 2.3 (CI: 1.8 to 2.9), p<0.001- 5 to 9.99 yrs after diagnosis, no CD 325/100000, CD 719/100000, IR 2.2 (CI: 1.8 to 2.8), p<0.001- ≥10yrs after diagnosis, no CD 331/100000, CD 565/100000, IR 1.7 (CI: 1.4 to 2.1), p<0.001


Number of patients


Outcome measures

Source of funding

Ludvigsson JF, Elfstrom P, BroomE U, Ekbom A, Montgomery SM. Celiac Disease and Risk of Liver Disease: A General Population-Based Study. Clinical Gastroenterology and

Case control



Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=5710, 41.3% female, 67.4% diagnosed between 0 to 15yrs, 32.6% diagnosed ≥16yrs, 3.5% (1964 to 1973), 27.6% (1974 to 1983), 44.2% (1984 to 1993), 24.8% (1994 to 2003)



Association of coeliac disease with various liver diseases and 2 common symptoms of liver disease (ascites and hepatomegaly)

Grants from the Swedish Research Council, Orebro University Hospital, the Swedish Society of Medicine, the Majblom


Hepatology 2007;5:63-9

man Foundation, the Juhlin Foundation, the Clas Groschinsky Foundation, the Karolinska Institute funds, the Swedish Coeliac Society


Coeliac disease and later liver disease – results not reported here

Prior liver disease and coeliac disease13:- acute hepatitis; OR 4.38 (CI: 1.59 to 12.06), p=0.004- chronic hepatitis; OR 5.79 (CI: 3.13 to 10.70), p<0.001- primary sclerosing cholangitis; OR 4.42 (CI: 2.38 to 8.24), p<0.001- fatty liver; OR 5.83 (CI: 1.96 to 17.36), p<0.002- ascites; OR 5.00 (CI: 2.08 to 12.01), p<0.001- liver failure, extended; OR 5.88 (CI: 4.05 to 8.54), p<0.001- liver failure, restricted; OR 8.33 (CI: 1.99 to 34.87), p<0.004- liver cirrhosis/fibrosis; OR 5.83 (CI: 3.86 to 8.81), p<0.001- primary biliary cirrhosis; OR 15.00 (CI: 4.84 to 46.51), p<0.001- hepatomegaly; OR 2.00 (CI: 0.39 to 10.31), NS


Number of


Outcome measures

Source of

13 Conditional logistic regression estimated the risk of CD with prior liver disease


Evidence level

patients funding

Ludvigsson JF, Reutfors J, Osby U, Ekbom A, Montgomery SM. Coeliac disease and risk of mood disorders--a general population-based cohort study. Journal of Affective Disorders 2007; 99:117-26

Case control

N=13776with coeliac disease


Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1973 to 2003, through the Swedish national inpatient register, N=8074, 58.6% female, 67.0% diagnosed between 0 to 15yrs, 33.0% diagnosed ≥16yrs, 29.5% (1973 to 1983), 45.0% (1984 to 1993), 25.4% (1994 to 2003)14



Coeliac disease and mood disorders; depression and bipolar disorder

Grants from the Swedish Research Council, Orebro University Hospital, the Swedish Society of Medicine, the Majblomman Foundation, the Juhlin Foundation, the Clas Groschinsky Foundation, the Karolinska Institute funds, the Swedish Coeliac Society

14 At significance level of 5%, 80% power to detect an increased risk of subsequent depression in those with CD with HR of 1.3 or above, for subsequent bipolar disorder the power to detect an increased HR of 1.5 or above



Coeliac disease and subsequent depression, and subsequent bipolar disorder – results not reported here

Conditional logistic regression estimated the association of coeliac disease and prior history of mood disorder- prior depression; OR 2.3 (CI: 2.0 to 2.8), p<0.001- prior bipolar disorder; OR 1.7 (CI: 1.2 to 2.3), p=0.001


Number of patients


Outcome measures

Source of funding

Ludvigsson JF, Olsson T, Ekbom A, Montgomery SM. A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases. Alimentary Pharmacology & Therapeutics 2007;25:1317-27

Case control



Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=8442 (58.7%) female, 65.2% diagnosed between 0 to 15yrs old, 34.8% diagnosed ≥16yrs, 3.5% (1964 to 1973), 27.4% (1974 to 1983), 43.8% (1984 to 1993), 25.4% (1994 to 2003)15



Follow-up ended on the date of the first discharge diagnosis of neurological disease, emigration, death or end of the study period (31st

Dec 2003)

Coeliac disease and later neurological disease

Prior neurological disease and coeliac disease

Grants from the Swedish Research Council, Orebro University Hospital, the Swedish Society of Medicine, the Majblomman Foundation, the Juhlin Foundation, the Clas Groschinsky

15 At significance level of 5%, had 80% power to detect increased risk of MS if the HR was ≥2.0, 1.7 for Alzheimer’s disease, 1.5 for Parkinson’s disease, 1.7 for polyneuropathy


Foundation, the Karolinska Institute funds, the Swedish Coeliac Society


Those with CD at an increased risk of later polyneuropathy; HR 3.4 (CI, 2.3 to 5.1), p<0.00116, risk estimates NS lower for those diagnosed with CD in childhood (HR 1.4) and those diagnosed in adulthood (HR 3.9)

CD not significantly associated with any other neurological disease; MS (HR: 0.9, CI: 0.3 to 2.3), Parkinson’s disease (HR: 1.2, CI: 0.8 to 1.9), Alzheimer’s disease (HR: 1.5, CI: 0.9 to 2.6), hereditary ataxia (HR: 1.3, CI: 0.5 to 3.6), the symptom ataxia (HR: 1.9, CI: 0.6 to 6.2), Huntington’s disease (HR: 1.7, CI: 0.3 to 8.6), myasthenia gravis (HR: 0.8, CI: 0.2 to 3.8), spinal muscular atrophy (HR: 0.5, CI: 0.1 to 3.8)

Prior polyneuropathy before study entry had increased risk of subsequent CD, OR: 5.4 (CI: 3.6 to 8.2), p<0.001

Other neuro diseases not associated with subsequent CD

NS association between the symptom ataxia and later CD, OR: 2.8 (CI: 0.9 to 8.3)


Number of patients


Outcome measures

Source of funding

Ludvigsson JF, Wahlstrom J, Grunewald J, Ekbom A, Montgomery

Case control


N=69998 without

Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=5917, 41.2% female, 65.3% diagnosed between 0 to 15yrs, 34.7% diagnosed ≥16yrs, 3.5% (1964 to 1973), 27.4% (1974 to 1983),

Link between coeliac disease and sarcoidosis

Grants from the Swedish Research Council, Orebro Universit

16 Adjustment for those with diabetes mellitus did not affect risk estimate, exclusion of those with a diagnosis of lymphoma did not affect risk estimates


SM. Coeliac disease and risk of sarcoidosis. Sarcoidosis Vasculitis & Diffuse Lung Diseases 2007;24:121-6

coeliac disease

43.8% (1984 to 1993), 25.3% (1994 to 2003)



y Hospital, the Swedish Society of Medicine, the Majblomman Foundation, the Juhlin Foundation, the Clas Groschinsky Foundation, the Karolinska Institute funds, the Swedish Coeliac Society


Coeliac disease and subsequent sarcoidosis – results not reported here

Coeliac disease and prior history of sarcoidosis:Conditional logistic regression showed an increased risk in those with prior sarcoidosis; OR 3.58 (CI; 1.98 to 6.45), p<0.001


Number of patients


Outcome measures

Source of funding


Ludvigsson JF, Olen O, Bell M, Montgomery SM. Coeliac disease and risk of sepsis. Gut 2008;57:1074-1080.

Cohort N=15,533 with coeliac disease

N=14,494 inpatient reference individuals

Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=8956, 58.4% female, 25.1% diagnosed between 0 to 15yrs, 74.9% diagnosed ≥16yrs, 3.5% (1964 to 1973), 26.4% (1974 to 1983), 42.3% (1984 to 1993), 27.8% (1994 to 2003)

Reference individuals were matched for age, sex, calendar year and country


Sepsis Grant from the Swedish Society of Medicine, the Swedish research Council, the Sven Jerring Foundation, the Obrebro Society of Medicine, the Karolinska Institute, the Clas Groschinsly Foundation, the Juhlin Foundationm the Majblomman Foundation, Obrebro University Hospital, the Swedish Coeliac


Society, the Mjolkdroppen Fund


Coeliac disease and subsequent sepsis – results not reported here

Conditional logistic regression found an increased risk of subsequent coeliac disease in individuals with prior sepsis; OR 2.2 (1.7 to 3.0), p<0.001


Number of patients


Outcome measures

Source of funding

Ludvigsson JF, Wahlstrom J, Grunewald J, Ekbom A, Montgomery SM. Coeliac disease and risk of tuberculosis: A population based cohort study. Thorax 2007;62:23-8.

Cohort N=14,335 with coeliac disease

N=69,888 without coeliac disease

Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=8426, 58.8% female, N=9368 diagnosed between 0 to 15yrs, N=4967 diagnosed ≥16yrs, 3.5% (1964 to 1973), 27.3% (1974 to 1983), 43.8% (1984 to 1993), 25.3% (1994 to 2003)

Reference individuals were matched for age, sex, calendar year and country


TB Grant from the Swedish Society of Medicine, the Swedish Research Council, the Sven Jerring Foundation, the Orebro Society of Medicine, the Majblomman Foundation, the Swedish


Coeliac Society


Coeliac disease and subsequent tuberculosis – results not reported here

Conditional logistic regression found an increased risk of subsequent coeliac disease in individuals with prior tuberculosis; OR 2.5 (1.75 to 3.55), p<0.001


Number of patients


Outcome measures

Source of funding

Melo SB, Fernandes MI, Peres LC, Troncon LE, Galvao LC. Prevalence and demographic characteristics of celiac disease among blood donors in Ribeirao Preto, State of Sao Paulo, Brazil. Digestive Diseases & Sciences 2006;51:1020-5

Cohort N=3000

Brazil

Inclusion: apparently healthy Brazilian blood donors, from Ribeirao Peto, from Sept 2001-Oct 2002, N=15000 male, N=1500 female, aged 18-45yrs (mean 27.9yrs), female 18-24yrs (42.4%), 25-34yrs (32.8%), 35-45yrs (24.8%), male 18-24yrs (32.7%), 25-34yrs (35.4%), 35-45yrs (0.9%)

Significant difference in age between the sexes, women being younger

IgA anti-hTG, ELISA

Those positive had IgA EMA, indirect immunofluorescence

Positive to both, biopsy

Not stated



N=13; weakly +ve anti-hTG antibodies (20-30 IU), -ve EMA N=24; moderate/strongly +ve anti-htTG (=30 IU), N=15 of these +ve EMA, N=9 were –ve EMA

N=13/15 biopsied, of these N=2 Marsh 0, N=2 Marsh II, N=4 Marsh III, N=1 Marsh IV

Prevalence of coeliac disease 1:273 (0.36%, 95% CI, 0.15 to 0.58), N=1 male, N=10 female (81.8%)N=9 (77%) GI symptoms; constipation, abdominal pain, feeling of fullness, more than 3 evacuations/day, N=1 had raised transaminanse levelsN=0 extraintestinal disease

Those with coeliac disease vs. those without had significantly higher family history of GI cancer, p<0.05


Number of patients


Outcome measures

Source of funding

Meloni GF, Dessole S, Vargiu N, Tomasi PA, Musumeci S. The prevalence of coeliac disease in infertility. Human Reproduction 1999;14:2759-61

Case control

N=99

Adults

Italy

Inclusion: successive women examined for infertility in a university department of obstetrics and gynaecology, mean age 33.38±4.17yrs, range 26 to 45yrs), between August 1997 to October 1998

Control group used the data from a previous screening study for coeliac disease carried out on a sample of 1607 apparently healthy schoolchildren from the same geographical area, that showed a 1.06% (17/1607) prevalence of histologically proven coeliac disease

IgA/G AGA, ELISA

IgA AEA, indirect immunofluorescence using HU

Total serum IgA measured in those who were IgG AGA +ve and EMA –ve All who tested +ve for at least 2/3 underwent jejunal biopsy, samples taken from the descending part of the

Infertility classed according to a specified protocol

Cut off 7 IU for IgA AGA Cut off 15 IU for IgG AGA

All biopsy samples examined by the same pathologist and classified according to Marsh criteria

Not stated


duodenum Effect size (all CI 95%):

N=0/99 IgA AGA +veN=4 (4.04%) IgG AGA +ve and IgA AEA +ve, N=3 (3.03%) had histological features of coeliac disease on jejunal biopsy

N=2 with coeliac disease had unexplained infertility

The frequency of coeliac disease was about x3 that in the population as a whole (N=3/99 vs. N=17/1607, NS) With unexplained fertility this was N=2/25 vs. N=17/1607, p=0.037


Number of patients


Outcome measures

Source of funding

Niveloni S, Sugai E, Cabanne A, Vazquez H, Argonz J, Smecuol E et al. Antibodies against synthetic deamidated gliadin peptides as predictors of celiac disease: prospective assessment in an adult population with a high pretest probability of disease. Clinical

Cohort N=141

Adults

Argentina

Inclusion: unselected consecutive adult patients at first attendance at a small bowel disease clinic from December 2004 to December 2005, median age 38yrs (range 16 to 80yrs), N=114 female, N=27 male

Exclusion: previous diagnosis of CD, prior treatment with a GFD, CD-related serology tests performed before enrolment, diagnosis of dermatitis herpetiforms

IgA anti-tissue trasnglutaminase (a-tTG) (Quanta Lite h-tTG IgA, Inova Diagnostic, manufacturer cut-off 20kU/L)

IgG/IgA anti-deamidated gliadin-related peptide (a-DGP)ELISA(Diagnostic cut-off determined in a former study, 20 kU/L)

IgA antiactin antibodies (AAAs)ELISA(according to previous study cut-off was 25

Intestinal biopsy, samples obtained from the distal duodenum following a standard protocol, at least 3 samples were obtained using conventional endoscopic forceps

Categorised on histological criteria (Marsh II lesion or greater)

Consejo de Investigacion en Salud del Ministerio de Salud del Gobierno Autonomo de la Ciudad de Buenos Aires, Argentina


Chemistry 2007;53:2186-92

kU/L)


All study participants underwent intestinal biopsy irrespective of the clinical and/or endoscopic findings; serum samples were obtained from all study patients at the time of the endoscopic procedure

Symptoms inducing consultation: chronic diarrhoea (N=114), weight loss (N=115), chronic anaemia (N=95), distension (N=11)

Histology criteria used as gold standard, N=60/141 CD

Mean BMI with CD 19.3 (3.2) kg/cm2, mean without CD 21.5 (4.2) kg/cm2 (p<0.002)

N=3 of those with CD had –ve a-tTG and EmA results, diagnosis supported by improvement of the intestinal mucosa at rebiopsy

IgA a-DGP sensitivity 98.3% (91.0 to 99.7), specificity 93.8% (86.2 to 97.9), PPV 92.2%, NPV 98.7%, PLR 15.9, NLR 0,02 AUC/ROC 0.9952X2 for20kU/L cut-off:

(a)TP 59

(b)FP 5

(c)FN1

(d)TN76

IgG a-DGP sensitivity 96.7% (88.4 to 99.5), specificity 100% (95.5 to 100), PPV 100%, NPV 97.6%, PLR N/R, NLR 0.03 AUC/ROC 0.9892X2 for20kU/L cut-off:

(a)TP 58

(b)FP 0

(c)FN2

(d)TN81

IgA+IgG a-DGP sensitivity 98.3% (91.0 to 99.7), specificity 98.8% (93.3 to 99.8), PPV 98.3%, NPV 98.8%, PLR 79.6, NLR 0.02 AUC/ROC 0.996


2X2 for20kU/L cut-off: (a)TP 59

(b)FP 1

(c)FN1

(d)TN80

IgA a-tTG sensitivity 95.0% (86.1 to 98.9), specificity 97.5% (91.3 to 99.6), PPV 96.6%, NPV 96.3%, PLR 38.5, NLR 0.05 AUC/ROC 0.9962X2 for20kU/L cut-off:

(a)TP 57

(b)FP 2

(c)FN3

(d)TN79

IgA AAA – results not included in this ET

IgA a-DGP and IgA a-t TGSensitivity 100% (94.0 to 100), specificity 92.6% (84.6 to 97.2), PPV 96.7, NPV 100, PLR 40, NLR 0

IgG a-DPG and IgA a-tTGSensitivity 100% (94.0 to 100), specificity 97.5% (91.3 to 99.6), PPV 96.7, NPV 100, PLR 40, NLR 0

IgA and IgG a-DGP and a-tTG Sensitivity 100% (94.0 to 100), specificity 96.3% (89.5 to 99.2), PPV 95.2, NPV 100, PLR 27.0, NLR 0


Number of patients


Outcome measures

Source of funding

Olen O, Montgomery SM, Elinder G, Ekbom A, Ludvigsson JF.

Case control


N=69967

Inclusion: all individuals identified with a hospital-based discharge diagnosis of CD from 1964 to 2003, through the Swedish national inpatient register, N=8430, 58.8% female, N=9353 diagnosed between 0 to 15yrs, N=4994 diagnosed ≥16yrs, 3.5%

Coeliac disease and immune thrombocytopenic purpura (ITP)

Grants from the Sachs’ Children’s Hospital,


Increased risk of immune thrombocytopenic purpura among inpatients with coeliac disease. Scandinavian Journal of Gastroenterology 2008;43:416-22

without coeliac disease

(diagnosed 1964 to 1973) 27.4% (1974 to 1983), 43.8% (1984 to 1993), 25.3% (1994 to 2003) 17



Subject information anonymised prior to analysis

Swedish Research Council, Orebro University Hospital, the Swedish Society of Medicine, the Majblomman Foundation, the Juhlin Foundation, the Clas Groschinsky Foundation, the Karolinska Institute funds, the Swedish Coeliac Society


Coeliac disease and later ITP of any kind or later chronic ITP – results not reported here

Prior immune thrombocytopenic purpura and coeliac disease- prior ITP was a +ve risk factor for subsequent coeliac disease; OR 2.96 (CI; 1.60 to 5.50), p=0.001

17 At a significance level of 5% had a power of 80% to detect a 1.7 fold increased risk of later ITP in those with CD and a 2.7 fold increased risk of later chronic ITP


- those with prior chronic ITP had a 6-fold increased risk for later CD; OR 6.00 (CI; 1.83 to 19.66), p=0.003- with unspecified thrombocytopenia excluded, ITP of any kind, OR for coeliac disease 1.88 (CI: 0.50 to 7.07), NS; chronic ITP, OR for coeliac disease 15.00

(CI: 1.56 to 144.20), p=0.019


Number of patients


Outcome measures

Source of funding

Oliveira RP, Sdepanian VL, Barreto JA, Cortez AJ, Carvalho FO, Bordin JO et al. High prevalence of celiac disease in Brazilian blood donor volunteers based on screening by IgA antitissue transglutaminase antibody. European Journal of Gastroenterology & Hepatology 2007;19:43-9

Cohort N=3000

Brazil

Inclusion: blood donor volunteers, Sept 2003-July 2004, Sao Paulo, consecutive blood donors, good health, aged 18-65yrs, >50kg, average age 34.4yrs, age range 18-65yrs, N=1500 male

N=9 had anaemia, N=8 male

Exclusion: those who presented the criteria for exclusion established by the blood donation sites

Power calculated on an estimated prevalence of coeliac disease of 0.16%, power at 80%, significance level 5%

Antitissue transglutaminase antibody, ELISA

>10 IU biopsy

Not stated



N=45/3000 (1.5%) +ve, >10 IU/ml; weakly +ve N=94/3000 (3.1%), 4-10 IU/ml

N=21/45 (46.7%) biopsied; N=14/21 (66.7%) Marsh III, N=3/21 (14.3%) Marsh I, N=4/21 (19.0%) normal biopsy

Coeliac disease diagnosis probable N=14/3000, 1 out of every 214 blood donor volunteers

NS difference in the proportion of coeliac disease between female (N=8/1484, 0.54%) and male (N=6/1492, 0.40%) NS difference between those who were white and nonwhite


Number of patients


Outcome measures

Source of funding

Pereira MA, Ortiz-Agostinho CL, Nishitokukado I, Sato MN, Damiao AO, Alencar ML et al. Prevalence of celiac disease in an urban area of Brazil with predominantly European ancestry. World Journal of Gastroenterology 2006;12:6546-50

Cohort N=2086

Brazil

Inclusion: healthy blood donors, Curitiba, from January to December 2001, aged 20-62yrs, mean 33yrs

All serological tests for HIV, hepatitis B, hepatitis C and alanine transaminase were normal

N=1437 (68.88%) male, N=649 (31.12%), mean age 33yrsN=1179 claimed European ancestry

Samples +ve for IgA anti-tTG by ELISA had an immunofluorescence test for IgA EMA using HU Those +ve for both IgA anti-tTG and IgA EMA underwent small bowel endoscopic biopsy in which 4 samples were collected (this is the procedure accepted by ESPGAN for confirmation of a diagnosis of coeliac disease)


Effect size:

N=6 (N=4 male, N=2 female) +ve for both anti-tTG and EMA N=5 biopsy (N=1 refused)N=3 Marsh IIIb lesions, N=2 Marsh II

Prevalence: Biopsy confirmed coeliac disease: 1:417 among healthy blood donorsConfirmed through EMA prevalence 1:347 among healthy blood donors

(sensitivity anti-tTG 100%, specificity 96%)


Number of patients


Outcome measures

Source of funding

Rampertab SD, Pooran N, Brar P, Singh P, Green PH. Trends in the presentation of celiac disease.[see comment]. American Journal of Medicine 2006;119:355-14

N=590

Adults

USA

Inclusion: all patients presenting to a single medical centre between 1981 and 2004, adults (>16yrs), biopsy-proven coeliac disease, N=401 female, N=189 male, mean age at diagnosis 44.9±18.7yrs (men), 42.7±16.8yrs (women), 25.1% known family history of coeliac disease, 9% initially diagnosed in childhood and subsequently rediagnosed in adults

6 groups based on year of diagnosis:Group 1, before 1981Group 2, between 1981 and 1985Group 3, between 1986 and 1990Group 4, between 1991 and 1995Group 5, between 1996 and 2000Group 6, after 2000

Not stated

Effect size:

Mean duration of symptoms before diagnosis was 4.6±7.5yrs (range 0 to 60yrs)

Diarrhoea presenting manifestation in 46.7%


There was a significant negative linear trend in the proportion presenting with diarrhoea, from 91.3% before 1981 and 37.2% after 2000 (p<0.001)

There was a significant positive linear trend in the proportion detected by screening 0% groups 1-4 to a mean of 15.2% for the groups 5-6 (p<0.001)

NS difference in time of those presenting with bone disease, anaemia or incidentally at biopsy


Number of patients


Outcome measures

Source of funding

Reeves GE, Squance ML, Duggan AE, Murugasu RR, Wilson RJ, Wong RC et al. Diagnostic accuracy of coeliac serological tests: a prospective study.[see comment]. European Journal of Gastroenterology & Hepatology 2006;18:493-501

Cohort N=254

Mixed (mostly adult, 3.5% children)

Australia

Inclusion: those referred for endoscopic biopsy with symptoms consistent with CD, mean age 47.8 (age range 6 to 82yrs), N=177 female, N=77 male

Exclusion: <4yrs, receiving anticoagulant treatment

IgA TTG

IgG TTG

IgA AGA

IgG AGA

(number of kits used, all test performed according to kit recommendations)

IgA EMA (indirect immunofluroscence)( primate substrate)(Immco)(1:10 considered +ve)

All had endoscopic biopsy

Not stated (kits provided free by several manufacturers)

Effect size:

N=26 biopsy-confirmed coeliac disease, N=228 no biopsy evidence of coeliac disease


IgA deficiency, those with coeliac disease (N=3, 11.5%), those without coeliac disease (N=24, 10.6%)

IgA EMA:Dual (IgA and IgG????) EMA, monkey bladder; sensitivity (68.4%), specificity (98.6%), AUROC (0.83; 0.73 to 0.94), +ve LR (47.8), -ve LR (0.32) IgA EMA, monkey oesophagus; sensitivity (61.9%), specificity (92.1%), AUROC (0.77; 0.66 to 0.88), +ve LR (7.88), -ve LR (0.48)IgA EMA, monkey bladder; sensitivity (61.9%), specificity (80.0%), AUROC (0.71; 0.60 to 0.82), +ve LR (3.10), -ve LR (0.67)

Results from best performing kits:Dual (IgA and IgG????) EMA; sensitivity (68.4%), specificity (98.6%), AUROC (0.83; 0.73 to 0.94), +ve LR (47.8), -ve LR (0.32) 2X2:

(a)TP 18

(b)FP 3

(c)FN8

(d)TN225

IgA TTG; sensitivity (88.5%), specificity (83.8%), AUROC (0.91; 0.82 to 1.00), +ve LR (5.45), -ve LR (0.14) 2X2:

(a)TP 23

(b)FP 37

(c)FN3

(d)TN191

IgG TTG; sensitivity (84.6%), specificity (89.0%), AUROC (0.88; 0.78 to 0.97), +ve LR (7.72), -ve LR (0.17)2X2:

(a)TP 22

(b)FP 25

(c)FN4

(d)TN203

Dual TTG; sensitivity (92.3%), specificity (%), AUROC (0.92; 0.86 to 0.99), +ve LR (5.40), -ve LR (0.09)2X2:

(a)TP 24

(b)FP 39


(c)FN2

(d)TN189

IgA AGA; sensitivity (46.2%), specificity (85.1%), AUROC (0.75; 0.65 to 0.86), +ve LR (3.10), -ve LR (0.63)2X2:

(a)TP 12

(b)FP 34

(c)FN14

(d)TN194

IgG AGA; sensitivity (61.5%), specificity (84.1%), AUROC (0.82; 0.74 to 0.89), +ve LR (3.87), -ve LR (0.46)2X2:

(a)TP 16

(b)FP 36

(c)FN10

(d)TN192

IgA def; sensitivity (15.7%), specificity (89.5%), AUROC (0.53), +ve LR (1.50), -ve LR (0.94)2X2:

(a)TP 4

(b)FP 24

(c)FN22

(d)TN204


Number of patients


Outcome measures

Source of funding

Roka V, Potamianos SP,

Cohort N=2230

Greece

Inclusion: apparently healthy individuals recruited after random sampling from the Registry of the Prefecture, data collected

Not stated


Kapsoritakis AN, Yiannaki EE, Koukoulis GN, Stefanidis I et al. Prevalence of coeliac disease in the adult population of central Greece. European Journal of Gastroenterology & Hepatology 2007;19:982-7

between Oct 2002-Feb 2006, N=1004 male, N=1226 female, mean age 46yrs, range 18-80yrs, 18-25yrs (308, 14%), 26-35yrs (387, 17%), 36-45yrs (400, 18%), 46-55yrs (422, 19%), 56-65yrs (385, 17%), >66yrs (328, 15%)

NS difference were found in age and sex distribution between the participants of the study NS difference between those who consented to participate and those who did not

Exclusion: migrants or minorities to ensure a homogenous population

Sample size considered to be adequate after a power analysis that considered 1% as a possible prevalence rate


N=2230 (74%) acceptance rate Total IgA normal for all N=2230

N=12; IgA-tTG +ve and IgG-tTG –veN=2210; IgA-tTG -ve and IgG-tTG –veN=0; IgA-tTG +ve and IgG-tTG +veN=8; IgA-tTG -ve and IgG-tTG +ve

Of the N=12 IgA-tTG +ve and IgG-tTG –ve; N=4 EMA +ve, N=8 EMA –ve Of the N=8 IgA-tTG – ve and IgG-tTG +ve; N=0 EMA +ve, N=8 EMA –ve

The N=4 EMA +ve biopsied and HLA typed, all coeliac disease

Prevalence of coeliac disease, 1:558 (0.18%, 1.8/1000, SE 0.13)


Number of


Outcome measures

Source of


Evidence level

patients funding

Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice.[see comment]. American Journal of Gastroenterology 1999;94:888-94

Case control (CHECK)

N=69 untreated coeliac disease

N=16 controls

Inclusion: untreated coeliac disease, median age 41yrs (range 2 to 76yrs), N=25 male, N=44 female

Controls: first-degree relatives with minor histological abnormalities (Marsh I, II)

Diagnosis of coeliac disease was based on small intestinal biopsy specimens showing the appropriate histopathological features and clinical improvement of GFD, according to diagnostic criteria

18

IgA EMA (verified in 2 labs using monkey oesophagus as substrate in the immunoflurorescence assay)

IgA AGA (enzyme linked immunosorbent assay, ELISA)

Serum IgA levels (levels >25AU/ml was considered elevated)

Small intestinal biopsy sampling was done, minimal requirements were 4 distal duodenal or jejunal biopsies19

Princess Irene Children’s Hospital Foundation


Histological evaluation:Partial villous atrophy (Marsh IIIa) N=29/69, subtotal villous atrophy (Marsh IIIb) N=23/69, total villous atrophy (Marsh IIIc) N=17/69

Sensitivity:EMA; overall 60% (N=42/69); subgroups with Marsh IIIc 100%; Marsh IIIa N=9/29 (31%), Marsh IIIb N=16/23 (70%) were EMA positive

18 Serum samples and intestinal biopsies were analysed in a blinded fashion 19 Biopsy specimens were evaluated according to Marsh


The difference between EMA positive results was significant between Marsh IIIa and Marsh IIIc (p=0.013)

Total IgA, (N=3 had IgA deficiency):AGA positive N=9/29 (31%) with Marsh IIIa, N=16/23 (70%) with Marsh IIIb, N=14/17 (82%) with Marsh IIIc AGA detected in N=39/69 (56%)The difference between Marsh IIIa and Marsh IIIb compared with Marsh IIIc was significant (p<0.01)

IgA EMA 2X2:

(a)TP 42

(b)FP 0

(c)FN27

(d)TN16

IgA AGA 2X2:

(a)TP 39

(b)FP 3

(c)FN30

(d)TN13

Combination of EMA and AGA showed sensitivity of 76% (N=53/69) for all histopathological subgroupsIgA EMA/AGA 2X2:

(a)TP 53

(b)FP 3

(c)FN16

(d)TN13


Number of


Outcome measures

Source of


Evidence level

patients funding

Salardi S, Volta U, Zucchini S, Fiorini E, Maltoni G, Vaira B et al. Prevalence of celiac disease in children with type 1 diabetes mellitus increased in the mid-1990 s: an 18-year longitudinal study based on anti-endomysial antibodies. Journal of Pediatric Gastroenterology & Nutrition 2008;46:612-4

Cohort N=331

Children

Italy

Inclusion: consecutive unselected with type 1 diabetes at a paediatric clinic, mean age at diagnosis 8.1±4.3yrs (range 0.08 to 14.9yrs)

Immunological evaluation at diagnosis of diabetes, every 6 to 12mths after (duration 1 to 18yrs, mean 9yrs

EMA (same immunology lab, prospectively 1994 to 2004, retrospectively 1987 to 1993), sensitivity and specificity of test remained constant throughout the study

Coeliac disease Not stated


N=2/331 previously diagnosed CD

N=29 EMA +ve, N=23 biopsied, N=18 CD (of the N=5 with normal mucose N=2 had subsequent biopsies (N=1 at 1yr, N=1 at 4.5yrs) +ve for CD, the remaining N=3 were –ve at subsequent biopsies (2 to 8yrs))

Overall N=22/331 (6.6%) coeliac disease in those with type 1 diabetes


1987 to 1994; N=6/180 (3.3%) with coeliac disease1995 to 2004; N=16/151 (10.6%) with coeliac disease

(author’s comment: same screening methods (EMA), all tests carried out in the same reference lab, consistent assay performance, population referring to the clinic did not change over time, suggest that the risk of CD increased in diabetic children after 1994)


Number of patients


Outcome measures

Source of funding

Sanders DS, Hopper AD, Azmy IA, Rahman N, Hurlstone DP, Leeds JS et al. Association of adult celiac disease with surgical abdominal pain: a case-control study in patients referred to secondary care. Annals of Surgery 2005;242 :201-7

Case control

N=300(N=591 control)

Inclusion: consecutive, unselected patients presenting with acute abdominal pain in a university hospital, from November 2002 to November 2003, median age 57yrs (range 16 to 95yrs), N=150 female

Control: recruited from local GR surgeries from those accompanying patients, age and sex matched

Coeliac disease Not stated


Effect size:

Diagnosis of those with abdo pain: nonspecific abdominal pain N=86 (28.7%), urologic obstruction N=40 (13.3%), medical cause N=29 (9.7%), urologic infection N=27 (9%), abdominal malignancy N=17 (5.7%), miscellaneous urologic cause N=15 (5%), inflammatory bowel disease N=16 (5.3%), diverticular disease N=14 (4.7%), gall stone disease N=13 (4.3%), other >N=10

N=9 (3%) of 300 with acute abdo pain, all had nonspecific abdominal pain so prevalence of CD in those with nonspecific abdo pain 10.5% (N=9/86)OR of having CD whe presenting with acute abdo pain 4.6 (CI: 1.11 to 19.05), NS

Prevalence of coealic disease with nonspecific abdominal pain, p=0.006


Number of patients


Outcome measures

Source of funding

Shahbazkhani B, Malekzadeh R, Sotoudeh M, Moghadam KF, Farhadi M, Ansari R et al. High prevalence of coeliac disease in apparently healthy Iranian blood donors. European Journal of Gastroenterology & Hepatology

Cohort N=2000

Iran

Inclusion: apparently healthy blood donors, Nov 1998-Feb 1999, N=1580 male, N=420 female, mean age 35.5yrs, range 18-65yrs, all Caucasion

Exclusion: IgA deficient cases

All biopsy specimens reviewed by two investigators

Total serum IgA

IgA AGA, ELISA

Those +ve had IgA EMA, immunofluorescence

Both +ve, biopsy

Digestive Disease Research Centre


2003;15:475-8


N=49; +ve IgA AGA (N=38 male, N=11 female, mean age 38.6yrs), >20 IU considered +ve Of the N=49, N=12 +ve EMA (N=10 male, N=2 female), of these N=12, N=5 flatulence, N=2 of these occasional dyspepsia, no other major abdominal or extra-abdominal symptoms, N=2 mild anaemia

N=12 biopsies compatible with gluten sensitive enteropathy, N=3 Marsh I, N=4 Marsh II, N=5 Marsh IIIa

Prevalence calculated as 1/116 in asymptomatic blood donors, if only Marsh III (N=5) as the prerequisite then the minimum prevalence is 1/400


Number of patients


Outcome measures

Source of funding

Silano M, Volta U, Mecchia AM, Dessi M, Di Benedetto R, De Vincenzi M et al. Delayed diagnosis of coeliac disease increases cancer risk. BMC Gastroenterology 2007;7:8

Cohort N=1968 Inclusion: those diagnosed with coeliac disease at collaborating centres between 1st January 1982 and 31st March 2005 , N=1485 female, female: male ratio 2.6, mean age at diagnosis 36.2±13.8yrs

Coeliac disease and cancer risk

Not stated



Mean duration of symptoms before diagnosis of coeliac disease 6±2.2yrs

N=55/1968 (2.09%) diagnosed with cancer before or simultaneously with the diagnosis of coeliac disease compared with 42.1 expected20 (SIR21=1.3, 95% CI: 1.0 to 1.7), p=0.001

Cancer where those with coeliac disease showed a higher risk;- Non-Hodgkin’s lymphoma, observed N=20, expected 4.2, SIR 4.7 (CI: 2.9 to 7.3), p<0.001- colon, observed N=7, expected 6.2, SIR 1.1 (CI: 0.68 to 1.56), p<0.001 - small bowel, observed N=5, expected 0.19, SIR 25 (CI: 8.5 to 51.4), p<0.001- Hodgkin’s lymphoma, observed N=4, expected 0.4, SIR 10 (CI: 2.7 to 25), p=0.01- stomach, observed N=3, expected N=1, SIR 3 (CI: 1.3 to 4.9), p=0.08

Cancer where those with coeliac disease showed a lower risk;- breast, observed N=3, expected N=14, SIR 0.2 (CI: 0.04 to 0.62), p<0.001- others, observed N=13, expected N=12, SIR 1 (CI: 0.9 to 8.5), p=0.06

The mean age at diagnosis of coeliac disease for those diagnosed with cancer before or simultaneously 47.6±10.2yrs which was significantly higher than the age at diagnosis of those who did not develop a malignancy 28.6±18.2yrs


Number of patients


Outcome measures

Source of funding

Szaflarska-Szczepanik A,.Czerwionka-Szaflarska M. The frequency of occurrence and clinical picture of celiac disease in

Cohort N=254

Poland

Inclusion: pairs of parents randomly selected children with celiac disease diagnosed in accordance with the ESPGHAN criteria, 25-58yrs (mean 38.8yrs), 96.1% one child with coeliac disease, N=5 (3.9%) two siblings with coeliac disease

Total IgA

IgA/IgG EMA, indirect immunofluorescence

Those +ve biopsied

Not stated

20 Expected number of malignancies calculated in eah sex and 5-yr stratum of the population by multiplying the number of patients in each stratum by the site specific incidence rate from WHO Globoscan 200221 Standardised Incidence Ratio, ratio of the observed to the expected cases


the parents of children with the disease. Medical Science Monitor 2001;7:971-6


IgA normal in all

N=5 (2%) IgA EMA +ve, N=3 male

IgA EMA varied within the limits of +20 IF to +640 IF

N=4/5 biopsied, all had atrophy of the villi of the mucous membrane in the small intestine, class IV (N=3) or class III/IV

N=3 abdominal pains, N=3 short stature, N=1 no symptoms


Number of patients


Outcome measures

Source of funding

Vestergaard P,.Mosekilde L. Fracture risk in patients with celiac Disease, Crohn's disease, and ulcerative colitis: a nationwide follow-up study of 16,416

Case control


Adults

Denmark

Inclusion: all patients diagnosed with new cases of coeliac disease between 1st January 1983 and 31st December 1996, fracture occurrence assessed between 1980 and 1996, identified through the National Patient Discharge Register, N=588, 58% males, N=433, 42% females, mean age at diagnosis 31.5yrs (SD 24.7),

Exclusion: those not residing in Denmark

Controls: drawn randomly from the background population, 3 age and gender matched controls for each patient

Fracture risk Aarhus University Research Foundation


patients in Denmark. American Journal of Epidemiology 2002;156:1-10


Results for Crohn’s disease and ulcerative colitis not reported here

Fracture risks before diagnosis: - all fractures, N=24 cases, N=103 controls, IRR 0.70 (0.45 to 1.09)- skull and jaws, N=0 cases, N=5 controls, IRR 0- spine, rib and pelvis, N=5 cases, N=7 controls, IRR 2.14 (0.70 to 6.57)- upper arm, N=24 cases, N=103 controls, IRR 0.70 (0.45 to 1.09)- forearm, N=7 cases, N=17 controls, IRR 1.23 (0.51 to 2.97)- Colles’ fracture, N=4 cases, N=6 controls, IRR 2.00 (0.58 to 6.91)- hand and finger, N=2 cases, N=4 controls, IRR 1.50 (0.28 to 8.09)- hip and femur, N=7 cases, N=29 controls, IRR 0.72 (0.32 to 1.65)- femoral neck, N=5 cases, N=21 controls, IRR 0.71 (0.27 to 1.89)- lower leg, N=4 cases, N=32 controls, IRR 0.37 (0.14 to 1.02)- foot, N=0 cases, N=2 controls, IRR 0 - osteoporosis, N=1 cases, N=1 controls, IRR 3.00 (0.21 to 41.91)

Patients with coeliac disease had no increase in fracture risk before or after diagnosis, age was the only significant risk factor (risk estimate 1.02, CI: 1.01 to 1.03)


Number of patients


Outcome measures

Source of funding

Vilppula A, Collin P, Maki M, Valve R, Luostarinen M, Krekela I et al.

N=2815

Adults

Inclusion: 66% of the N=4242 from the original GOAL study (Good Ageing in the Lahti region) which included randomly selected individuals in the years 1946-1950, 1936-1940 and 1926-1930 living in a hospital district, study sample was representative of the general population in

Competitive Research Funding of the Pirkanmaa


Undetected coeliac disease in the elderly: a biopsy-proven population-based study. Digestive & Liver Disease 2008;40:809-13

Finland the respective age groups, age 52 to 74yrs

Hospital District and Paijat-Hame Central Hospital and the Academy of Finland


N=25 (0.89%)/2815 had previously established coeliac disease

N=44 tTG and EMA +ve, N=39 biopsied, N=35 coeliac disease, total frequency of coeliac disease in the elderly population was N=60/2815, 2.13% (CI: 1.60 to 2.67)

Symptoms:- diarrhoea N=15 (N=14 clinically detected, N=1 screen detected)- weight loss N=10 (N=9 clinically detected, N=1 screen detected)- anaemia or malabsorption N=14 (N=10 clinically detected, N=4 screen detected)- dermatitis herpetiformis (N=6 clinically detected)- abdominal pain, distension, flatulence N=19 (N=5 clinically detected, N=14 screen detected)- occasional diarrhoea or loose stools N=13 (N=4 clinically detected, N=9 screen detected)- fatigue N=5 (N=2 clinically detected, N=3 screen detected)- blisters in mouth N=2 (N=2 screen detected)- no symptoms N=20 (N=20 screen detected)

Associated conditions:- lymphoma N=2 (N=2 clinically detected)- carcinoma of stomach N=2 (N=1 clinically detected, N=1 screen detected)- ovarian cancer N=1 (N=1 screen detected)- autoimmune thyroid disease N=8 (N=1 clinically detected, N=7 screen detected)- Sjogren’s syndrome N=1 (N=1 clinically detected)- pernicious anaemia N=2 (N=1 clinically detected, N=1 screen detected)- Type 1 diabetes N=1 (N=1 screen detected)- psoriasis N=3 (N=3 screen detected)



Number of patients


Outcome measures

Source of funding

Viola L, Lugli L, Melegari A, Marotti E, Amarri S, Balli F. Antitransglutaminase enzyme-linked immune-adsorbed assay in coeliac disease diagnosis: evaluation of a diagnostic algorithm. Pediatria Medica e Chirurgica 2004;26:126-31

Cohort/case control??

N=91

(N=23 coeliac disease controls, results not reported here)

Children

Italy

Inclusion: symptoms suggestive of coeliac disease referred to a paediatric clinic, N=51 male, N=40 female, median age 6.1yrs (range 1 to 18yrs)

IgA values were normal for all participants

IgA/IgG AGA (ELISA, Eurospital)(cut-off, ≥15 index were considered positive)

IgA EMA (indirect immunoflourescence, monkey oesophagus, Eurospital)(tests considered +ve where there was fluorescence observed)

IgA tTG (ELISA, Eurospital, guinea pig)(cut off, ≥ 7 AU were considered +ve)

Duodenojejunal biopsy in those with +ve AGA and/or EMA

Not stated


All participants had EMA and IgA tTG, those under 4yrs also had IgA/IgG AGA

N=31/91 (34.1%) IgA tTG +ve, N=29/92 (31.9%) EMA +ve, N=27 biopsy confirmed CD

N=4 +ve IgA tTG and –ve EMA, none had biopsy confirmed coeliac disease


IgA AGA; those without CD 2.74 (2.00 to 3.75), those with CD 5.73 (3.19 to 10.28), p=0.015IgG AGA; those without CD 12.09 (8.73 to 16.76), those with CD 23.51 (14.26 to 38.76), p=0.022IgA tTG; those without CD 1.24 (0.92 to 1.67), those with CD 11.10 (2.51 to 7.81), p<0.001

IgA tTGsensitivity 93.1%, specificity 93.6%, PPV 87.1%, NPV 96.7% 2X2 for ≥ 7 AU cut-off:

(a)TP 27

(b)FP 4

(c)FN2

(d)TN58

EMAsensitivity 93.1%, specificity 96.7%, PPV 93.1%, NPV 96.7% 2X2 for EMA +ve:

(a)TP 27

(b)FP 2

(c)FN2

(d)TN60

IgA AGAsensitivity 31.8%, specificity 81.0%, PPV 46.7%, NPV 69.4% 2X2 for index ≥ 7cut-off:

(a)TP 7

(b)FP 8

(c)FN15

(d)TN34

IgG AGAsensitivity 68.2%, specificity 59.5%, PPV 46.9%, NPV 78.1% 2X2 for index ≥ 15 cut-off:


(a)TP 15

(b)FP 17

(c)FN7

(d)TN25

Age ≤ 2yrs:IgA tTG; sensitivity 90.9%, specificity 93.8%, PPV 90.9%, NPV 93.8% IgA EMA; sensitivity 90.9%, specificity 93.8%, PPV 90.9%, NPV 93.8% IgA AGA; sensitivity 37.5%, specificity 72.7%, PPV 50.0%, NPV 61.5% IgG AGA; sensitivity 75.0%, specificity 45.5%, PPV 50.0%, NPV 71.4%

Age > 2yrs:IgA tTG; sensitivity 94.4%, specificity 93.5%, PPV 85.0%, NPV 97.7% IgA EMA; sensitivity 94.4%, specificity 97.8%, PPV 94.4%, NPV 97.8% IgA AGA; sensitivity 28.6%, specificity 83.9%, PPV 44.4%, NPV 72.2% IgG AGA; sensitivity 64.3%, specificity 64.5%, PPV 45.0%, NPV 80.0%

Evidence tables below are for those with specified conditions who were tested for the presence of coeliac disease. Note; assumption that all studies have CD confirmed by ESPGAN or biopsy and having used AGA, EMA or tTG tests – otherwise studies were excluded; all CI 95%


Number of patients

Patient characteristics Intervention Comparison Outcome measures

Effect size Source of funding

Bonamico M, Mariani P, Danesi HM, Crisogianni M, Failla P, Gemme G et al. Prevalence and clinical

Cohort N=1202(N=1110 children, N=92 adults)

Mixed

Inclusion: consecutively enrolled patients with Down Syndrome enrolled by the Italian Society of Paediatric Gastroenterology and Hepatology and the Clinical Genetics Group of the Italian Society of Paediatrics, N=1110 children; aged 15mths to 18yrs, N=92 adults; 18 to 46yrs, N=609 males, N=593 females

Coeliac disease

N=55 (N=48 children, N=7 adults)(4.6%) with CD

N=55 with CD had higher

Not stated


picture of celiac disease in italian down syndrome patients: a multicenter study. Journal of Pediatric Gastroenterology & Nutrition 2001;33:139-43

Italy

percentages of those with growth failure (p<0.001), anorexia (p<0.01), constipation (p<0.05), and higher frequency of cases of low haemoglobin, low serum iron and low calcium (p<0.01) than in N=55 who were IgA AGA +ve and IgA EMA –ve, and than N=57 IgA AGA –ve and IgA EMA –ve

N=38 (69%) classic CD, N=6 (11%) atypical symptoms, N=11 (20%) silent CD

Bonamico Cohort N=389 Inclusion: patients with Turner syndrome Coeliac IgA AGA Consiglio


M, Pasquino AM, Mariani P, Danesi HM, Culasso F, Mazzanti L et al. Prevalence and clinical picture of celiac disease in Turner syndrome. Journal of Clinical Endocrinology & Metabolism 2002;87:5495-8

Mixed

Italy

enrolled by the Italian Society of Pediatric Gastroenterology and Hepatology and the TS Italian Study Group from various centres of the northern, central, southern, and insular regions, making the sample fairly representative of the whole population, age range 7 to 38yrs

disease and/or EMA and biopsies, N=25 (6.4%) diagnosed with coeliac disease

N=10 (40%) classic form of coeliac disease, N=8 (32%) atypical, N=7 (28%) silent

Nazionale delle Ricerche Grant

Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease Gut 1996;39:382-384

Cohort N=150 women with infertilityN=50 women with spontaneous abortions(N=150 control)

Adults

Finland

Inclusion: successive women examined for infertility and women having 2 or more spontaneous abortions, treated at a department of obstetrics and gynaecology in a university hospital, between February 1993 and December 1994

Control: women with normal obstetric history who had undergone laproscopic sterilisation

Coeliac disease

N=4/150 (2.7%) in the infertility group and N=0 in the control group had coeliac disease, p=0.06

All of the N=4/98 (4.1%) had unexplained infertility vs. N=0/150 with

Grant from the Medical Research Fund of Tampere University Hospital


control, p=0.02

Cronin CC, Jackson LM, Feighery C, Shanahan F, Abuzakouk M, Ryder DQ et al. Coeliac disease and epilepsy. Qjm 1998;91:303-8

Case control


Adults

Ireland

Inclusion: patients attending a seizure clinic of a university hospital, N=80 male, N=97 female, N=80 male, mean age 36yrs (range 14 to 80yrs), median age at onset of epilepsy was 14yrs (range 1 to 63yrs)

Control group from patients attending an ante natal clinic

Coeliac disease

N=4 EMA +ve, +ve for coeliac disease on biopsy, frequency of CD 1:44

(control N=2 EMA +ve, frequency of CD 1:244)

Not stated

Dickey W, McMillan SA, Callender ME. High prevalence of celiac sprue among patients with primary biliary cirrhosis. Journal of Clinical Gastroenterology 1997;25:328-9

Cohort N=57

Adults

N Ireland

Inclusion: those attending clinics with primary biliary cirrhosis, N=52 female, mean age 57yrs (30 to 79yrs), none had low total serum IgA

Coeliac disease

N=6 (11%) EMA +ve, N=4 biopsied all had results consistent with coeliac disease

Prevalence of coeliac disease; 1:14 (7%)

Not stated

Farre C, Domingo-Domenech E, Font R, Marques T,

Case control

N=298 (N=251 controls)

Adults

Inclusion: consecutive patients with lymphoid malignancy at 4 centres in Spain, May 1998 to January 2000, mean 58yrs, N=173 male, B-cell lymphoma (79.83%), T-cell lymphoma (8.72%),

Coeliac disease

Coeliac disease in N=2/298 (0.67%) vs. N=3/251

Spanish Ministry of Health


Fernandez dS, Alvaro T et al. Celiac disease and lymphoma risk: a multicentric case--control study in Spain. Digestive Diseases & Sciences 2004;49:408-12

Spain

Hodgkin’s lymphoma (11.74%) (1.2%) controls

Francis J, Carty JE, Scott BB. The prevalence of coeliac disease in rheumatoid arthritis. European Journal of Gastroenterology & Hepatology 2002;14:1355-6

Cohort N=160

Adults

UK

Inclusion: consecutive patients with rheumatoid arthritis attending the rheumatology outpatients, mean age 61yrs (range 20 to 84yrs), N=107 (67%) female, mean disease duration 12yrs

Coeliac disease

N=1 with CD, which had been previously diagnosed, prevalence of CD in RA 0 (95% CI; 0 to 24%)

Rheumatology Fund, Lincoln County Hospital, Postgraduate Medical federation, Lincoln

Frustaci A, Cuoco L, Chimenti C, Pieroni M, Fioravanti G, Gentiloni N et al. Celiac disease

Case control

N=187

Adults

Italy

Inclusion: consecutive patients with myocarditis admitted with either heart failure (N=110), with cardiac arrhythmias (N=77), N=118 male, mean age 41.7±14.3yrs, none had IgA deficiency

Coeliac disease

N=13 +ve IgA-tTGN=9 +ve for AEA and had iron-deficiency anaemia

MURST project


associated with autoimmune myocarditis. Circulation 2002;105:2611-8

and had histologic evidence of coeliac disease

Prevalence of coeliac disease 4.4% with myocarditis vs. N=1 (0.3%), p<0.003

George EK, Hertzberger-ten Cate R, Suijlekom-Smit LW, von Blomberg BM, Stapel SO, van Elburg RM et al. Juvenile chronic arthritis and coeliac disease in The Netherlands. Clinical & Experimental Rheumatology 1996;14:571-5

Cohort N=62

Children

Netherlands

Inclusion: children with juvenile chronic arthritis (JCA) being followed at 3 departments of paediatric rheumatology during 1993 and 1994, N=36 female, mean age 9.9±3.5SD (range 3.3 to 16.8yrs), IgG AGA used in one case of IgA deficiency

Coeliac disease

N=8 with at least 1 +ve screening test, N=5 biopsed, N=4 normal biopsy

Frequency of coeliac disease 1.5%

Not stated

Germenis Case N=738 Inclusion: consecutive patients with Coeliac N=4/738 Not


AE, Yiannaki EE, Zachou K, Roka V, Barbanis S, Liaskos C et al. Prevalence and clinical significance of immunoglobulin A antibodies against tissue transglutaminase in patients with diverse chronic liver diseases. Clinical & Diagnostic Laboratory Immunology 2005;12:941-8

controls (N=1350 controls)

Mixed

Greece

chronic liver disease at an academic liver unit, over the last 5yrs, N=406 males, median age 53yrs (range 6 to 85yrs)(N=462 with viral hepatitis; N=117 with autoimmune hepatitis; N=113 with alcoholic liver disease/non-alcoholic fatty liver diseaseTotal IgA levels in all subjects were within normal limits

disease with diverse chronic liver disease IgA EMA +ve; prevalence 1:185 (0.54%)

N=3/4 biopsied, N=2 coeliac disease

N=4/1350 controls IgA EMA +ve, all biopsied and had histologic changes compatible with coeliac disease; prevalence 1:338 (0.3%)

stated

Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D. Cancers and immune related

Case control

N=1453(N=460000 control)

Mixed

Inclusion: data from the Oxford Record Linkage Study, this includes brief statistical abstracts of records of all hospital admissions, including day cases in the NHS and all deaths wherever they occurred, in defined populations within the former Oxford NHS region from January 1963 to March 1999, the Down’s

Coeliac disease (rates of each cancer or immune related disease based on person-years at risk

Results for cancers and other immune conditions not reported here

Oxford Health Authority, Research and Development Directora


diseases associated with Down's syndrome: a record linkage study. Archives of Disease in Childhood 2004;89:1014-8

UKsyndrome cohort obtained from statistical records, the reference cohort from records of admission for other medical and surgical conditions, N=937 0 to 14yrs, N=516 15 to 59yrs

N=4 with coeliac disease observed in the Down’s cohort, expected number N=0.9, Adjusted risk ratio 4.7 (CI: 1.3 to 12.2)

te at the Department of Health

Guliter S, Yakaryilmaz F, Ozkurt Z, Ersoy R, Ucardag D, Caglayan O et al. Prevalence of coeliac disease in patients with autoimmune thyroiditis in a Turkish population. World Journal of Gastroenterology 2007;13:1599-601

Case control

N=136

Adults

Turkey

Inclusion: consecutive patients with newly diagnosed autoimmune thyroiditis between January and September 2006, mean age 43.1±10.5 (range 17 to 65yrs), none had other autoimmune diseases

Control, healthy blood donors

Age and gender were similar in both groups

Coeliac disease

IgA tTG +ve in N=8(5.9%), N=1 control, OR7.38 (CI: 0.91 to 59.85), p=0.04

N=6 biopsied, N=4 had CD

N=1 control biopsied, had CD

Not stated

Imanzadeh F, Sayyari AA, Yaghoobi M,

Case control


Inclusion: consecutive patients with small bowel type chronic diarrhoea (voluminous watery diarrhoea lasting 6wks or more) attending a department of

Coeliac disease

N=57 (6.9%) IgA EMA +ve vs. N=7

Not stated


Akbari MR, Shafagh H, Farsar AR. Celiac disease in children with diarrhea is more frequent than previously suspected.[comment]. Journal of Pediatric Gastroenterology & Nutrition 2005;40:309-11

Children

Iran

gastroenterology, June 1997 to March 2003, N=389 female, N=436 male, mean age 8.5yrs (range 3mths to 14yrs), total serum IgA within normal limits in all

Exclusion: those with bloody diarrhoea, renal failure, previous CD

Control group, those attending paediatric clinics with non-GI symptoms

(0.8%) with the control groupN=57 biopsied, N=54 (8.96%) diagnosis coeliac disease vs. N=5/825 (0.61%) control group, p<0.001

(some data on other symptoms, not reported here)

Karnam US, Felder LR, Raskin JB. Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study. Southern Medical Journal 2004;97:30-4

Cohort N=105

Adults

USA

Inclusion: all patients presenting to an endoscopy unit for evaluation of iron-deficiency anaemia (<12g/dl in women and <14 g/dl in men) between March 1998 and June 2000, were candidates for study entry, all participants had colonscopy and gastroduodenoscopy Average Hb 8.9g/dl and average haematocrit 27.4% (for men 9.0g/dl and 27.8%; for women 8.9g/dl and 26.8%)

Coeliac disease

N=3 had coeliac disease (N=2 haemoccult +ve), none had diarrhoea, skin rash or other evidence of CD

Not stated


Lepore L, Martelossi S, Pennesi M, Falcini F, Ermini ML, Ferrari R et al. Prevalence of celiac disease in patients with juvenile chronic arthritis. Journal of Pediatrics 1996;129:311-3

Cohort N=119

Children

Italy

Inclusion: children with juvenile chronic arthritis being treated at two centres for paediatric rheumatology, mean age 11.5yrs (range 2 to 16yrs), N=87 female

Coeliac disease

N=4 (3.3%) AEA +ve, N=3 biopsy +ve for CD

Not stated

Meloni GF, Dessole S, Vargiu N, Tomasi PA, Musumeci S. The prevalence of coeliac disease in infertility. Human Reproduction 1999; 14:2759-1999

Case control


Adults

Italy

Inclusion: successive women (and their partners) examined for infertility at a department of obstetrics and gynaecology of a university, mean age 33.38yrs (range 26 to 45yrs), between August 1997 and October 1998

Control: from a previous screening study for coeliac disease carried out on healthy school children from the same geographical area

Coeliac disease

N=4 (4.04%) IgG AGA and EMA +ve, N=3 +ve for coeliac disease on jejunal biopsy (3.03%)

Frequency of coeliac disease: N=3/99 vs. population as a whole N=17/1607, NS difference

Not stated


Subgroup with unexplained infertility: N=2/25 vs. population as a whole N=17/1607, p=0.037

Picarelli et al (2005) Anti-endomysial antibody of IgG1 isotype strongly increases the prevalence of coeliac disease in patients affected with type 1 diabetes mellitus

Case control

N=94 (N=83 control)

Adults

Italy

Inclusion: consecutive adult patients with IDDM1 regularly attending a centre for the study of diabetes, N=43 male, N=51 female, mean age 46.9yrs (range 18 to 70yrs), none had any symptoms attributable to enteropathy, any evidence of malabsorbtion or been previously diagnosed with coeliac disease, all on gluten containing diet

Controls: blood donors without IDDM1, CD, other auto-immune conditions, or first-degree relative with any autoimmune condition

Coeliac disease

All had IDDM1 for >15yrs and satisfactory metabolic control

N=13 (6.4%) with coeliac disease

EMA =ve vs. EMA –ve

Ministry of University and Research (MIUR), the non-governmental association for research on coeliac disease and diabetes mellitus

Pratesi R, Gandolfi L, Martins RC, Tauil PL, Nobrega YK, Teixeira WA. Is the prevalence of celiac disease increased among epileptic patients?

Case control


Mixed

Brazil

Inclusion: adults and children attending 2 clinics, N=119 children; N=49 female, mean age 7.97yrs, median age 8yrs (range 1 to 14yrs), N=136 adults; N=64 female, mean age 30.27yrs, median age 29yrs (range 15 to 65yrs)

Control, N=2034 children, N=2371 adults

Coeliac disease

N=2/255 (N=1 adult, N=1 child)with coeliac disease; 1:127

Control N=15/4405 with coeliac disease; 1:293

Not stated


Arquivos de Neuro-Psiquiatria 2003;61:330-4

Sategna-Guidetti C, Bruno M, Mazza E, Carlino A, Predebon S, Tagliabue M et al. Autoimmune thyroid diseases and coeliac disease.[see comment]. European Journal of Gastroenterology & Hepatology 1998;10:927-31

Case control

N=152 autoimmune thyroid diseases


(N=170 control)

Adults

Italy

Inclusion: consecutive patients at a thyroid outpatients clinic none of who were taking medications that could interfere with the immunological response, N=100 with Graves’ disease, N=52 autoimmune throiditis/ subclinical hypothyroidism/euthyroidism, N=128 female, ages 15 to 80yrs Consecutive patients attending a coeliac disease outpatients, N=53 (N=41 female, median age 36yrs, range 19 to 67yrs) newly diagnosed therefore untreated, N=132 (N=89 female, median age 37yrs, range 16 to 81yrs)on GFD

Controls, healthy volunteers

Coeliac disease in those with autoimmune thyroid disease

Autoimmune thyroid disease in those with coeliac disease

EMA and biopsy +ve N=5/152 (3.29%) of those with autoimmune thyroid diseases

Autoimmune thyroid disease identified in N=38/185 (20.54%) of those with coeliac disease vs. N=19/170 control group (11.17%), X2 =5.09, p=0.02, the prevalence of autoimmune thyroid diseases among patients and controls did not differ among age

Not stated


groups Szodoray P, Barta Z, Lakos G, Szakall S, Zeher M. Coeliac disease in Sjogren's syndrome--a study of 111 Hungarian patients. Rheumatology International 2004;24:278-82

Cohort N=111

Adults

Hungary

Inclusion: consecutive patients with Sjogren Syndrome attending an outpatient clinic

Coeliac disease

N=5/111 (4.54%) diagnosed with CD

The age of those with CD 39.8 (28 to 53) vs. those without CD 57 (38 to 77), p<0.001

Duration of Sjogren syndrome at the time of the study similar in both groups

GI symptoms, N=41/111 (36.93%) abdo discomfort, N=11 (7.2%) lack of appetite, N=6 (5.4%) nausea, N=10 (9%) diarrhoea, N=6(5.4%) iron

Grants from the National Research Fund and the Ministry of Welfare


deficiency anaemia due to malabsorbtion

Thevenot T, Denis J, Jouannaud V, Monnet E, Renou C, Labadie H et al. Coeliac disease in chronic hepatitis C: A French multicentre prospective study. Alimentary Pharmacology and Therapeutics 2007;26:1209-16

Cohort N=624

Adults

France

Inclusion: consecutive patients with hepatitis C virus attending 8 outpatients departments between June 2003 and November 2005, N=373 male, mean age 52±14yrs

Exclusion: <18yrs, viral hepatitis B infection, +ve HCV antibodies with –ve HCV-RNA

Coeliac disease

N=1 AEA +ve, biopsy did not show CD, N=34 biopsied in total, none showed CD, prevalence 0%

None


CG86 Coeliac disease: full guideline - appendix 6.6

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