New ESPGHAN guidelines for the diagnosis of Coeliac Disease in Children and Adolescents Steffen Husby Hans Christian Andersen Children’s Hospital Odense University Hospital, Denmark Agenda • • • • Change in clinical paradigm Definitions of coeliac disease New diagnostic guidelines Algorithms Interlaken ESPGHAN criteria (1979) Small intestinal biopsy: villous atrophy Gluten free diet for 1-2 years Biopsy: normal Re-introduction of gluten Biopsy: villous atrophy McNeish et al Arch Dis Childh 1979;54:783 Revised ESPGHAN criteria 1990 Small intestinal biopsy: villous atrophy Clinical and serological improvement after 2-3 months • • No further biopsy Provided age > years Walker‐Smith et al. Arch Dis Child 1990;65:99  Celiac disease as a multiorgan autoimmune disease General: Puberty & growth delay Malignancies Anemia CNS: Ataxia, seizures Depression Heart: Carditis GI system: Diarrhea, vomiting Distension, pain Malnutrition, weight loss Hepatitis, cholangitis Bone: Osteoporosis, fractures Arthritis Dental anomalies Skin & mucosa: Dermatitis herpetiformis Aphtous stomatitis Hair loss Reproductive system: Miscarriage Infertility Modified from Rewers, Gastroenterology 2005 Patient Adrenal antibodies Type Diabetes Coeliac disease Dermatitis herpetiformis Autoimmune hypothyroidism Hansen et al unpublished Towards a new definition of coeliac disease  Chronic  Multi-organ  Small intestinal inflammation  Transglutaminase-related ESPGHAN working group, 2011 Suggestion: New definition  an immune-mediated systemic disorder  elicited by gluten and related prolamines  in genetically (mainly HLA) susceptible individuals  characterized by a combination of: • gluten dependent clinical manifestations • anti-tissue transglutaminase (TG2) antibodies • enteropathy Husby et al JPGN 2012 ESPGHAN classification  Silent CD: positive CD antibodies and biopsy findings, not sufficient symptoms to warrant clinical suspicion of CD  Latent CD: positive CD antibodies, no villous atrophy The patient has had a glutendependent enteropathy Patient may/may not have symptoms  Potential CD: positive antibodies, but no villous atrophy Patient may/may not have symptoms CD may or may not develop The Oslo Definitions  Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals  Discourage the use of classical vs non-classical, typical vs atypical  Discourage the use of the term latent CD Ludvigsson et al Gut 2012 Coeliac Antibodies • IgA Anti-TG2 antibody • IgA Endomysial antibody (EMA) • IgA and IgG Deamidated Gliadin Peptide (DPG) antibody • NOT: IgA and IgG anti-gliadin antibodies DISEASE PREDICTION BY ANTIBODIES (pooled estimates with 95% confidence values; § indicates high hetereog neity) Positive likelihood ratio AGA /IgA 553 (0.038-0.118) (218-1402) 21.8§ 0.060§ 469§ (0.040-0.090) (250-880) 13.6 0.061§ 234 (0.017-0.221) (100-546) 9.4 0.121§ 86.1 (6.8-13.1) Anti-DGP /IgA 0.067§ (8.1-22.8) Anti-DGP /IgG 31.8 (12.9-36.8) Anti-TG2 /IgA Odd’s ratio (18.6-54.3) EMA /IgA Negative likelihood ratio (0.072-0.203) (56-132) 7.3§ 0.186§ 40.6§ (4.5-11.8) (0.095-0.362) (14-117) Giersiepen, Evidence report, JPGN 2012 Development of symptomatic coeliac disease in EMA positive subjects 3654 3617 3644 2001 1994 Diagnosed celiac: 56 1.5% 10 27 1:99 Mäki, N Engl J Med 2003 Predictive values for TG2 antibody Positive predict value Toftedal et al JCLM 2010 Median ELISA values in 14 commercial anti-TG2 assays (data kindly provided by UK NEQAS) 1000 ‘High’ sample xULN Aesku 10.0 95 13.6 89 4.5 Genesis 69 9.9 Immco 48.3 2.4 Inova* 95.5 4.8 Orgentec 65.5 9.9 Phadia ELIA 69.0 9.9 Phadia ImmunoCAP 73.9 10.6 Phadia Varelisa 30 200 Generic Assays 20 57 Eurospital* 10 43 Euroimmun AU in Varelisa [Celikey] 8.3 DiaSorin 10 33.3 BMD Luminex 100 9.0 Binding Site AU 135 30.1 10.0 40 *logarithmic assays Child / Adolescent with Symptoms suggestive of CD Anti-TG2 IgA & total IgA* Anti-TG2 positive Transfer to Paediatric GI Anti-TG2 < 10 x normal EMA & HLA DQ8/DQ2 EMA pos HLA pos CD+ EMA pos HLA neg Consider false neg HLA test Consider biopsies Not CD Consider further diagnostic testing if: IgA deficiency Age: < years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases Paed GI discusses with family the diagnostic pathways and consequences considering patient’s history & anti-TG2 titers Anti-TG2 > 10 x normal Anti-TG2 negative EMA neg HLA neg Consider false pos anti-TG2 Not available EMA neg HLA pos OEGD & biopsies Marsh 0-1 Unclear case Consider: false pos serology false neg biopsy or potential CD Marsh or CD+ Child / Adolescent with Symptoms suggestive of CD Anti-TG2 IgA & total IgA* Anti-TG2 positive Transfer to Paediatric GI Anti-TG2 < 10 x normal EMA & HLA DQ8/DQ2 EMA pos HLA pos CD+ GFD & F/u EMA pos HLA neg Consider false neg HLA test Consider biopsies Not CD Consider further diagnostic testing if: IgA deficiency Age: < years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases Paed GI discusses with family the diagnostic pathways and consequences considering patient’s history & anti-TG2 titers Anti-TG2 > 10 x normal Anti-TG2 negative EMA neg HLA neg Consider false pos anti-TG2 Not available EMA neg HLA pos OEGD & biopsies Marsh 0-1 Unclear case Consider: false pos serology false neg biopsy or potential CD Extended evaluation of HLA/serology/biopsies Marsh or CD+ GFD & F/u Child / Adolescent with Symptoms Suggestive of CD Anti‐TG2 & total IgA*  Anti‐TG2 positive Anti‐TG2 negative Transfer to Paediatric Gastroenterologist Paed. GI discusses with family the 2 diagnostic pathways and  consequences considering patient’s history & anti‐TG2 titers Positive Anti‐TG2 > 10 x normal  Positive Anti‐TG2 < 10 x normal  EMA & HLA testing for DQ2/DQ8 EMA pos HLA pos CD+ EMA pos HLA neg EMA neg HLA neg Consider false neg. HLA test Consider biopsies  Consider false pos. Anti‐TG2  GFD & F/u *or specific IgG based tests Not  available EMA neg HLA pos Not CD Consider further diagnostic testing if: IgA deficient Age:  x normal OEGD & biopsies From bulbus & pars descendens, proper histological work up Marsh or CD+ GFD & F/u No CD, no risk for CD HLA negative DQ2 and/or DQ8 Titer < x normal TG2 negative Not CD EMA EMA positive EMA negative Consider: False neg Results, exclude IgA deficiency and history of low gluten intake or drugs Marsh 0-1 Unclear case F/u on normal diet Consider: False pos serology, false neg biopsy or potential CD Consider: Transient/false pos antiTG2 F/u on normal diet with further serological testing *Or specific IgG based tests Asymptomatic person at genetic risk for CD Explain implication of positive test result(s) and get consent for testning HLA DQ2 / DQ8 (+/- TG2) HLA positive DQ2 and/or DQ8 Consider retesting in intervals or if symptomatic TG2 & total IgA* Titer > x normal OEGD & biopsies From bulbus & pars descendens, proper histological work up Marsh or CD+ GFD & F/u Titer < x normal Not CD, no risk for CD HLA negative DQ2 and/or DQ8 TG2 negative Not CD EMA EMA positive EMA negative Consider: False neg Results, exclude IgA deficiency and history of low gluten intake or drugs Marsh 0-1 Unclear case F/u on normal diet Consider: False pos serology, false neg biopsy or potential CD Consider: Transient/false pos anti-TG2 F/u on normal diet with further serological testing *Or specific IgG based tests Asymptomatic Person at Genetic Risk for CD Explain implication of positive test result(s) and get consent for testing HLA DQ testing (+/‐Anti‐TG2) HLA positive for DQ2 and/or DQ8 Positive Anti‐TG2  3x normal Not CD, HLA negative for DQ2 and/or DQ8 Not CD Anti‐TG2 negative EMA OEGD & biopsies:               1 x bulbus & 4 x pars  descendens, proper   EMA positive histological work up   Marsh 2 or 3 CD+ GFD & F/u EMA negative Consider: age, false neg. results,  exclude IgA deficiency and history  of low gluten intake or drugs  Marsh 0‐1 - Unclear case F/u on normal diet  Consider: false pos.  serology, false neg.  biopsy or potential CD Consider:  Transient / false pos.  anti‐TG2 F/u on normal diet with  further serological testing  *or specific IgG based tests * Why different algorithms for symptomatic and asymptomatic (at risk) patients? False positive or transient TG2 antibody levels more frequent in genetically at risk persons than symptomatic cases TG2 titres with normal histology (Marsh 0) are often of low titre (