BIOPSY AVOIDANCE IN CHILDREN: THE EVIDENCE Steffen Husby Hans Christian Andersen Children s Hospital Odense University Hospital DK-5000 Odense C, Denmark
Agenda Background Algorithm Symptoms HLA Antibodies Biopsy Conclusions
High serum anti-tg2 antibodies predict coeliac disease with Marsh II-III lesions Hill & Holmes, Aliment Pharm Ther 2008
High anti-tg2 antibodies correlate with higher grade histology lesions Dahlbom et al. JPGN, 2009
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: < 2 years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases OEGD & biopsies Marsh 0-1 Unclear case Consider: false pos. serology false neg. biopsy or potential CD Extended evaluation of HLA/serology/biopsies Marsh 2 or 3 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: < 2 years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases OEGD & biopsies Marsh 0-1 Unclear case Consider: false pos. serology false neg. biopsy or potential CD Extended evaluation of HLA/serology/biopsies Marsh 2 or 3 CD+ GFD & F/u *
Child / Adolescent with Symptoms Suggestive of CD Anti-TG2 & total IgA* Anti-TG2 positive Anti-TG2 negative Consider further diagnostic testing if: IgA deficient Age: < 2 years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases 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 DQ2 (DQA1*0501; *0505), DQ8 (DQB1*0201,*0202) EMA pos. HLA pos. CD+ GFD & F/u EMA pos. HLA neg. EMA neg. HLA neg. Not available Not CD OEGD & biopsies (1 x bulp & 4 x pars descendens, proper histological work-up) EMA neg. HLA pos. Marsh 0-1 Unclear case Consider false neg. HLA test Consider biopsies Consider false pos. Anti-TG2 *or specific IgG based tests Consider: false pos. serology false neg. biopsy or potential CD Extended evaluation of HLA/serology/biopsies Marsh 2 or 3 CD+ GFD & F/u *
Parameters for diagnosis Clinical presentation HLA-DQ2 (DQA1*0501, DQA1*0505), DQ8 (DQB1*0201, *0202) Celiac antibodies Intestinal biopsy (histology)
Symptoms Gastrointestinal/malabsorption symptoms* Chronic diarrhoea Chronic constipation Abdominal pain Nausea Flatulence Vomiting Distended abdomen Irregular bowel habits *Modified after NICE Clinical Guidelines no. 86 (Recognition and assesment of coeliac disease), UK 2009.
Symptoms: pre-test probability Isolated failure-to-thrive Anemia Chronic diarrhea Malabsorption in general Chronic constipation Recurrent abdominal pain Dermatitis herpetiformis 10-40 % 15 % 15 % 20 % 9% Carampazzi 2007 Rashid 2005 van Rijn 2005 Ferrara 2005
Parameters for diagnosis Clinical presentation HLA-DQ2 (DQA1*0501, DQA1*0505), DQ8 (DQB1*0201, *0202) Celiac antibodies Intestinal biopsy (histology)
HLA-DQ2/DQ8 Population 1% CD 40% DQ2 DQ8 Sensitivity 96% (84-100) Specificity 54% (12-68) High Negative Predictive Value
HLA-DQ2 and DQ8 Genotype Phenotype General population Freq. in CD Relative Risk Level DQA1*05xx/B1*02xx, DQA1*05xx/B1*05xx or DQA1*05xx/B1*02xx, A1*0201/B1*02xx DQ2.5/DQ2.5 2% 25 % 10-13 % (very high) DQA1*05xx/B1*02xx /DQA1*03xx/B1*030 2 DQ2.5/DQ8 1% 10 % high DQA1*05xx/DQB1*0 2xx DQA1* /DQB1*$ DQ2.5/DQx 20 % 60 % increased DQA1*0301/B1*030 2, DQA1* /DQB1*$ DQ8/DQx 20 % 3-5 % CD possible DQA1*0201/B1*020 2, DQA1* /DQB1*$ DQ2.2 10 % 1% CD unlikely DQ2.5/DQ2.2 Husby & Murray, 2014 ( Mayo Clinic)
Parameters for diagnosis Clinical presentation HLA-DQ2 (DQA1*0501, DQA1*0505), DQ8 (DQB1*0201, *0202) Celiac antibodies Intestinal biopsy (histology)
Antibodies IgA Endomysial antibody (EMA) IgA Transglutaminase 2 antibody (TG2-IgA) IgG Deamidated gliadin antibody (DGP-IgG)
Disease prediction by antibodies (pooled estimates with 95% confidence values; indicates high heterogeneity) EMA /IgA Anti-TG2 /IgA Anti-DGP /IgG Anti-DGP /IgA AGA /IgA Positive likelihood ratio Negative likelihood ratio Odd s ratio 31.8 0.067 553 (18.6-54.3) (0.038-0.118) (218-1402) 21.8 0.060 469 (12.9-36.8) (0.040-0.090) (250-880) 13.6 0.061 234 (8.1-22.8) (0.017-0.221) (100-546) 9.4 0.121 86.1 (6.8-13.1) (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
Pre- and post-test probabilities Vermeersch et al. 2013
Sequential antibody testing? Wolf et al. Plos One 2014
Parameters for diagnosis Clinical presentation HLA-DQ2 (DQA1*0501, DQA1*0505), DQ8 (DQB1*0201, *0202) Celiac antibodies Intestinal biopsy (histology)
Marsh Classification
Importance of orientation Marsh, Johnson & Rostami, Gastro. Hepatol. From Bed to Bench2015
Other causes of villous atrophy Cow s milk protein enteropathy (infants) Giardia lamblia infestation Rotavirus infection Postinfectious damage Primary immunodeficiencies HIV-infection Tropical sprue
Possible avoidance of biopsy Reference Avoidance Percent avoidance Population Geography Klapp, JPGN 2013 116/160 77% children Spain Mubarak WJG 2012 83/183 45% children Netherlands Oyaert, Clin Chem Lab Med. 2015 47/156 32% children and adults Belgium Panetta Acta Paed 2011 102/169 60% children < 2y Italy Anderson BMC Medicine 2013 116/356 33% adults Australia Singh J Clin Gastro 2015 89/366 24% adults India
Conclusions Celiac antibodies are reliable, depending on pre-test probability Biopsy does not per se qualify for reference standard, but so far is the best available All diagnostic parameters should be considered and the biopsy may be omitted in carefully selected patients Follow-up is an important diagnostic tool
th 6 WCPGHAN rd 53 ESPGHAN COPENHAGEN 3-6 JUNE, 2020