Diagnostic score model for childhood coeliac disease. Submitted

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1 4 Diagnostic score model for childhood coeliac disease Hogen Esch CE Funke genaamd Küpper B Driessen SRC Dbijou N van Huis M Verhage J von Blomberg BME Putter H Mearin ML These authors contributed equally to this work Submitted

2 Chapter 4 Abstract Background: The existence of specific non-invasive diagnostic tools for coeliac disease (CD), such as the highly specific CD-antibodies, has challenged the status of invasive small bowel biopsies as the gold standard for the diagnosis of the disease. Aim: To create a score model that predicts intestinal lesions consistent for the diagnosis of childhood CD. Method: We analysed the clinical and serological data of all consecutive patients 18 years who underwent a first diagnostic upper-tract endoscopy between Children were excluded if they were on a gluten-free diet at the time of the endoscopy. Logistic regression analysis was performed using the data of children in whom the following information was available: symptoms at presentation, CD-associated disorders, family history of CD, results of endomysial antibodies (EMA) and autoantibodies against tissue transglutaminase type-2 (anti-tg2). The results were used to construct a diagnostic score model to predict CD. Results: 263 children (42%; median age 5.9, range , 144 girls) were included of whom 103 (39%; median age 4.1, range , 71 girls) were diagnosed for CD. Nine covariate values were significant relevant for the diagnosis of CD (diagnostic points between parenthesis): failure-to-thrive (1); chronic diarrhoea (2); vomiting (2); lassitude (2); small stature (2); positive anti-tg2 (3); strong positive anti-tg2 (4); positive EMA (3); strong positive EMA (4). Each patient obtained a score by counting the acquired diagnostic points. Subsequently, the cohort was divided in 4 equallysized subpopulations according to the scores, which resulted in 4 different categories (with scores) for having CD: low 1, low intermediate 2-3, high intermediate 4-8 and high 9. All CD children were scored in the low-and high intermediate (42%) and high (58%) groups. Children without CD were scored in the low (68%) and low-and high intermediate group (32%). Children with low and high scores for having CD do not need to undergo small bowel biopsies, since CD can be discarded or diagnosed, respectively. Conclusion: This validated and easy-to-use diagnostic score model may prevent as much as 58% small bowel biopsies in the diagnostic work-up of childhood CD. 50

3 Diagnostic score model for childhood coeliac disease Introduction Coeliac disease (CD) is an autoimmune disorder of the small intestine that occurs in genetically predisposed individuals.(1-3) CD is caused by an inflammatory T-cell response to the storage proteins in wheat (gliadin), rye (secalin) and barley (hordein), which is collectively called gluten. In the general population, the prevalence of CD is % in both adults and children.(4-6) A higher prevalence of CD (5-10%) is present in patients with CD-related autoimmune diseases, such as Diabetes Mellitus type I (DM 1) and autoimmune thyroiditis, and in some syndromes, such as Down and Turner.(7) The prevalence of CD in first- and second degree relatives of CD patients is 5-15 %.(8) The disorder has a variable clinical presentation: from a clear malabsorption syndrome with diarrhoea, vomiting, abdominal distension and failure-to-thrive in children, to less specific symptoms e.g. irritability, constipation and chronic fatigue. (1) The treatment of CD is a gluten-free diet, which is demanding for patients.(9;10) For the diagnosis of CD, the first non-invasive test of choice is the measurement of the specific coeliac antibodies, among others autoantibodies against tissue transglutaminase type-2 (anti-tg2) and endomysial antibodies (EMA). Clinical paediatric studies have shown the specificity of both EMA and anti-tg2 for glutensensitive enteropathy to be nearly 100%, with a sensitivity ranging from 90% to 100%.(11) Selective IgA deficiency occurs more frequently in patients with CD (3%) than in the general population (0.2%).(12) For this reason, it is advisable to measure the total IgA level in serum. Besides specific antibody tests for CD, genotyping for HLA-DQ2/DQ8 is a valuable tool in the diagnosis of the disease. CD has a strong genetic component; 98% of CD patients possess the histocompatibility class II human leukocyte antigen (HLA) molecules DQ2 and/or DQ8, which is only the case in about 40% of the general population. (13) HLA-DQ2 is encoded by HLA-DR3-DQA1*0501-DQB1*0201(cis configuration) and by HLA-DR5-DQA1*0505-DQB1*0301 or DR7- DQA1*0201 DQB1*0202 (trans configuration). HLA-DQ8 is encoded by HLA-DR4-DQA1*0301-DQB1*0302).(14) The 51

4 Chapter 4 main role of HLA-DQ genotyping in the diagnosis of CD is to exclude the disease or to make it very unlikely.(15;16) CD is characterised by histological alterations in small bowel biopsy specimens, revealing alterations of gluten-sensitive enteropathy.(17) The small bowel specimens can be obtained by upper gastro-intestinal endoscopy or by suction capsule, which are invasive procedures. In children, endoscopy is frequently performed under general anaesthesia or deep sedation. The histological features of the small bowel in CD are classified according to Marsh-Oberhuber.(18;19) For a long time, the histological results of small bowel biopsies have been the gold standard for the diagnosis of CD.(17) However, the last years this diagnostic method has been subject of criticism due to its invasive character as well as for several pitfalls for the diagnosis of CD (20), such as the difficult interpretation in cases of patchy patterns of villous atrophy (21) and the interobserver variation of the histological results.(22) In addition, the existence of specific non-invasive diagnostic tools, such as the determination of specific CD antibodies, has challenged the status of the small bowel biopsies as the gold standard for the diagnosis of CD.(16) Furthermore, recent studies suggests that combinations of non-invasive parameters, such as high anti-tg2 levels and HLA-DQgenotyping, are predictive for intestinal alterations in CD.(15;16;23-26) The aim of our study was to create a score model that predicts intestinal lesions consistent for the diagnosis of childhood CD. Methods Patients In this retrospective cohort study we analysed the data of all consecutive patients 18 years who underwent a first diagnostic upper-tract endoscopy between at the Leiden University Medical Center (LUMC) and at the Rijnstate Hospital Alysis Zorggroep, Arnhem, the Netherlands. In all patients at least four small bowel biopsies were taken from duodenum and, in the LUMC since 2005, also two from the bulb. All data, including the final diagnosis, were collected from the medical patient files. The age at diagnosis of CD was defined as the age at the moment of the small bowel biopsies. 52

5 Diagnostic score model for childhood coeliac disease Children were excluded if they were on a gluten-free diet at the time of the endoscopy. We inventarised clinical symptoms at presentation characteristics for CD; e.g. abdominal distension, anorexia, chronic abdominal pain, chronic diarrhoea, constipation, nausea, vomiting, weight loss, lassitude, failure-to-thrive (Decrease of 2 standard deviations (SD) for length and at least 1 SD for weight), small stature (<-2SD), irritability. We also assessed CD-associated disorders, family history for CD, serology results of EMA and anti-tg2 and histology results of small bowel biopsies. The children were analysed according to their final diagnosis: CD or non-cd. The diagnosis of CD was established according to the ESPGHAN criteria from 1990, including histological results of multiple small bowel biopsies showing alterations characteristics for CD.(17) The histological abnormalities were classified according to Marsh-Oberhuber.(18;19) CD specific antibodies For anti-tg2 determinations in serum, 8 different kits were used with the following substrates (between parenthesis the cut off values for positivity of the kit as recommended by the manufacturer): a.) Guinea pig TG2: Sigma, in house assay ( 7 U/ml for IgA; 46 U/mL for IgG), b.) Human recombinant TG2: Varelisa Celikey ( 8 U/ml) and EliA Celikey ( 10 U/ml) both from Phadia GmbH; Orgentec Diagnostica ( 10 U/ml for both IgA and IgG) GmbH; Diarect AG ( 6 U/ml); Roboscreen ( 6 U/ ml) GmbH; Aeskulisa Diagnostics ( 15 U/ml); Binding Site Group Ltd ( 10 U/ml). To compare the quantitative values of the different anti-tg2 tests, we calculated the ratio of each anti-tg2 measurement by dividing each anti-tg2 result (U/ml) by the cut off value (U/ml) for positivity as recommended by the manufacturers. The ratio of 1 is the cut off point for positivity. IgA and IgG EMA determinations in serum were performed by standard indirect immune fluorescence tests with monkey oesophagus as a substrate and using a serum dilution of 1:2.(27) Immunofluorescence tests were scored independently by two observers as negative (-), borderline (+/-), weakly positive (+), positive (++) or strongly positive (+++). Test quality was checked in each test run with a negative control sample, as well as a weakly positive and strongly positive control sample. Total serum IgA was measured in all children, using the local standard cut-off point. 53

6 Chapter 4 HLA-typing HLA-genotyping was performed using the line probe method for HLA class II low resolution typing. Diagnostic score model To create a diagnostic score model for CD we first categorised symptoms, anti-tg2, EMA, CD-associated diseases and family history for CD as negative and positive, and for anti-ttg2 and EMA also as strong positive. Anti-TG2 was defined as negative if ratio <1; positive if ratio 1-10 and strong positive if ratio >10. EMA was defined as negative if immunofluorescence tests were scored as negative (-) and borderline (+/-) ; positive if weakly positive (+) and positive (++) ; and strong positive if strong positive (+++). Positive family history for CD was considered if a child had at least a first and/or a second degree relative with CD. Statistical analysis Continuous data are expressed as mean ± standard deviation or as median and ranges; dichotomous data are presented as numbers and percentages. Comparison of continuous or dichotomous data was performed with the 2-sides t-test for paired and unpaired data and Chi-square test was used corrected with the Fisher s exact test for small sizes of groups. We used the information from the children in whom all the data was known to construct a usable diagnostic score model. Logistic regression analysis was used to determine significant relevant parameters for the diagnosis of CD. Diagnostic points were obtained by dividing the Beta regression coefficients of the logistic regression analysis by 1.5 and rounding. For each patient a diagnostic score was obtained by adding the diagnostic points according to his/her covariate values. For all tests, a p-value <0.05 was considered significant. All statistical analyses were performed by using SPSS version Ethics This study was approved by the Medical Ethical Committee of the LUMC and the Rijnstate Hospital Alysis Zorggroep, Arnhem, The Netherlands. 54

7 Diagnostic score model for childhood coeliac disease Results We analysed the data of 622 children: median age at endoscopy 8.1 years (range years), 331 girls. Thirteen children (median age 1.5 years; range years) were excluded because they had no gluten in their diet: 6 of them already followed a GFD as treatment of CD and in 7 children gluten was not introduced yet into the diet. The diagnostic score model was created by using the data of the 263 children with complete information, to be called Group 1 (42%; median age 5.9, range ; 144 girls). Group 2 was formed by the rest, 359 children, whose data were not used to construct the diagnostic score model. No differences were seen between the baseline characteristics of children with CD in Group 1 or 2 (Table 1). The children without CD in both groups were significant different with respect to age (younger in Group 1), frequency of failure-to-thrive (more in Group 1) and vomiting (less in Group 1) and the distribution of the Marsh classification (less Marsh 0 and more Marsh 1 in Group 1) (Table 1). Table 2 shows the distribution of diagnoses of the children. The diagnoses of CD, potential CD and gluten hypersensitivity were significantly more frequent in Group 1. Gastroesophageal reflux, oesophagitis, gastritis and inflammatory bowel diseases were significantly more frequent in the children of Group 2. Construction of the diagnostic score model (by using data of Group 1) The sensitivity and specificity for CD of anti-tg2 and EMA, were in the 263 children (Group 1) 0.92 (95% CI ) and 0.91 (95% CI ), and 0.95 (95% CI ) and 0.92 (95% CI ) respectively. No children were IgA deficient. Three (2%) of the children with CD, all of them younger than 2 years of age, were negative for both anti-tg2 and EMA. In 2 of them IgA and IgG Gliadin antibodies were measured and were found to be elevated. In addition, 5 CD children were negative for anti-tg2 but positive for EMA, and another 2 were positive for EMA but negative for anti-tg2. These 10 children with CD had small bowel histological alternations classified as Marsh 3. One child was diagnosed for CD with Marsh 1 small bowel alternations. This child presented with vomiting, had a positive family history for CD, and was positive for HLA-DQ2/DQ8, EMA and anti-tg2. 55

8 Chapter 4 Table 1. Comparison of the baseline characteristics of the children whose data were used (Group 1) or not (Group 2) to construct the diagnostic score model Characteristics CD (n= 103) n (%) Group 1 (n=263) Group 2 (n=359) Total (n=622) Non-CD (n=160) n (%) CD (n= 61) n (%) Non-CD (n=298) n (%) n (%) p-value Median age Yrs (range) 4.1 (0.9-18) 8.1 (0.9-18) 5 (1.1-17) 10.5 (0.6-18)* 8.1 (0.6-18) Girls (53) ns Symptoms (n =55) (n=288) (n= 606) Abdominal distension 35 (34) 16 (10) 20 (36) 16 (6) 87 (14) ns Anorexia 20 (19) 27 (17) 11 (20) 48 (17) 106 (18) ns Chronic abdominal pain 38 (37) 77 (48) 25 (45) 153 (53) 293 (48) ns Chronic diarrhoea 37 (36) 48 (30) 24 (44) 80 (28) 189 (31) ns Constipation 16 (16) 26 (16) 9 (16) 43 (15) 94 (16) ns Nausea 3 (3) 16 (10) 2 (4) 46 (16) 67 (11) ns Vomiting 22 (21) 25 (16) 11 (20) 77 (27)* 15 (22) Weight loss 16 (16) 20 (13) 10 (18) 45 (16) 91 (15) ns Lassitude 23 (22) 29 (18) 10 (18) 41 (14) 103 (17) ns Failure-to-thrive 24 (33) 38 (24)* 19 (35) 39 (14) 130 (21) Small stature 17 (17) 6 (4) 5 (9) 6 (2) 34 (6) ns Irritability 17 (17) 13 (8) 7 (13) 20 (7) 57 (9) ns Marsh classification small bowel biopsies * (0) 144 (90) 0 (0) 287 (96) 431 (69) 1 1 (1) 16 (10) 1 (2) 10 (3) 28 (5) 2 0 (0) 0 (0) 1 (2) 1 (0.3) 2 (0.3) 3A 28 (27) 0 (0) 20 (33) 0 (0) 48 (8) 3B 47 (46) 0 (0) 24 (39) 0 (0) 71 (11) 3C 27 (26) 0 (0) 15 (25) 0 (0) 42 (7) *p<0.05; ns= not significant; p-value is based on the comparison of CD versus CD and Non-CD versus Non-CD between Group 1 and Group 2 56

9 Diagnostic score model for childhood coeliac disease Table 2. Distribution of diagnoses in children whose data were used (Group 1) or not (Group 2) to construct a diagnostic score model for coeliac disease Diagnoses Group 1 (n=263) n (%) Group 2 (n=359) n (%) Coeliac disease 103 (40)* 61 (17) Functional gastrointestinal disorders 48 (18) 86 (24) Gastroesophageal reflux/ oesophagitis/gastritis 33 (13) 116 (32)* Inflammatory bowel disease 16 (6) 41 (11) * Screening for CD 19 (7) 14 (4) Gastro-intestinal infection 10 (4) 10 (3) Growth disorders e.c.i. 7 (3) 5 (1) Cow s milks allergy 3 (1) 5 (1) Potential coeliac disease 15 (6)* 5 (1) Gluten hypersensitivity 5 (2)* 0 (0) Lactose intolerance 4 (2) 1 (0.3) Other 0 (0) 15 (4) * *p<0.05; Irritable bowel syndrome, functional abdominal pain, non-ulcus dyspepsia and functional constipation; Family member with CD (n=22), Down syndrome (n=8), autoimmune disorder (n=3); Giardia Lamblia (n=9), Dientamoebe fragilis (n=1), (post) viral gastroenteritis (n= 10); genetically predisposed for CD and seropositive but with normal small bowel biopsies; Gastrointestinal symptoms that responds to gluten exclusion but without specific CD antibodies and histological abnormalities consistent for CD. Surveillance familial adenomatous polyposis (n=7), Percutaneous endoscopic gastrostomy (n=3), Graft versus Host Disease (n=4), and Beçhet s disease (n=1) Nineteen (12%) of the 160 children without CD had elevated specific CD-antibodies and no small bowel histological abnormalities (Marsh 0-1). Fifteen of them could be considered as cases of potential CD because they were HLA-DQ2 and/or DQ8 positive. The remaining 4 were HLA-DQ2 and-dq8 negative and they underwent small bowel biopsies because of chronic abdominal pain, failure-to-thrive, screening for CD in DM1, and chronic vomiting. HLA-genotyping was performed in 143 (54%) of the 263 children, including 66 children with CD. All children with CD carried HLA-DQ2 and/or DQ8 except for 1 who carried DR5-DQ7/DR1-DQ5. This child had strong positive anti-tg2 and EMA and had small bowel histological alternations Marsh 3C. HLA-DQ2 and/or DQ8 positivity was found in 81% of the children without CD. The sensitivity and specificity of HLA- DQ2/DQ8-genotyping for CD was 0.98 (95% CI ) and 0.19 (95% CI ) respectively. 57

10 Chapter 4 In the children with and without CD there was a similar distribution (17% vs. 9%) of CD-associated disorders, i.e. DM 1, autoimmune thyroiditis, autoimmune hepatitis, rheumatoid arthritis, alopecia/ vitiligo/ psoriasis/ oral aphthous ulcers and Down and -Turner syndrome. The same was the case for positive family history for CD: 24% in CD and 29% in non-cd. One child without CD had Down syndrome and also autoimmune thyroiditis. By logistic regression analysis 9 covariate values were found to be significant relevant for the diagnosis of CD (Table 3). Each patient obtained a score by counting the diagnostic points of his/her covariate values (Table 3). Subsequently we divided the cohort into 4 equally-sized subpopulations according to the acquired diagnostic points, which resulted in 4 different categories (with scores) for having CD: low 1, low intermediate 2-3, high intermediate 4-8 and high 9. No children with CD were classified in the low score group and only children with CD were classified in the high one. Forty-three (42%) of the children with CD were scored in the low intermediate and high intermediate groups because of negative CD serology (3 children younger than 2 years), discrepant serology results between EMA and anti- TG2 (n=7), positive specific CD antibodies without symptoms characteristic for CD (n=22), or positive CD antibodies and symptom(s) characteristic for CD (n=11). The CD child in the low intermediate group was one of the 3 children younger than 2 years who had negative EMA and anti-tg2 results, but positive IgA and IgG Gliadin antibodies. Hundred-two (64%) children without CD were categorised in the low intermediate and high intermediate score groups because of negative CD serology (n=83), discrepant serology results for EMA and anti-tg2 (n=11), positive specific CD antibodies without symptoms characteristic for CD (n=5) or positive CD antibodies and symptom(s) characteristic for CD (n=3). The cases of potential CD were scored in the high intermediate group (n=12) and in the low intermediate group (n=3) (Table 4). 58

11 Diagnostic score model for childhood coeliac disease Table 3. Logistic regression analysis for the diagnosis of coeliac disease in 263 children who underwent first diagnostic small bowel biopsies between Beta regression Diagnostic points Variables coefficient Standard error p-value Failure-to-thrive Chronic diarrhoea Vomiting Lassitude Small stature Anti-TG2 3 Positive Strong positive < EMA 3 Positive <0.001 Strong positive < Obtained by dividing the Beta regression coefficients by 1.5 and rounding Table 4. Easy-to-use score model for the diagnosis of coeliac disease (CD) constructed with the data of 263 children who underwent small bowel biopsies Coeliac disease diagnostic score 263 Children Category Scores Small bowel biopsies needed for diagnosis CD (n= 103) n (%) Non-CD (n= 160) n (%) Low 1 No 0 (0) 58 (100) Low intermediate 2-3? 1 (1) 66 (99) High intermediate 4-8 Yes 42 (54) 36 (46) High 9 No 60 (100) 0 (0) Obtained by counting the diagnostic points (between parenthesis) of the child: failure-tothrive (1); chronic diarrhoea (2); vomiting (2); lassitude (2); small stature (2); positive anti-tg2 (3); strong positive anti-tg2 (4); positive EMA (3); strong positive EMA (4) Discussion We here present a validated diagnostic score model to diagnose childhood CD. We constructed the model by analysing clinical and serological data of a large cohort of consecutive children who underwent first diagnostic upper intestinal endoscopy during irrespectively if they had clinical manifestations of CD and/or elevated specific coeliac antibodies. Our diagnostic score model can be useful in 59

12 Chapter 4 clinical practice because it is an easy-to-use tool that distinguishes between risks for having CD. In addition, the score distinguishes between these children who should undergo small bowel biopsies during the diagnostic work-up for CD. Children with low and high scores for CD do not need undergo small bowel biopsies, since in them CD can be discarded or diagnosed, respectively (Table 4). By using the diagnostic score, we could have avoided invasive small bowel biopsies in 60 (58%) of the 103 CD children in our cohort (Table 4), resulting in a considerable reduction of stress in these patients and their parents. In addition, the minimal total costs for performing an upper gastroduodenoscopy in the Netherlands is 1230,- (including costs for anaesthesia, endoscopist, and hospitalization of the child), representing a minimal saving of health-care costs of The risk for developing CD when being scored in the low intermediate group around 1% and in the high intermediate group is 54%. The question is whether small bowel biopsies should be preformed in children in the low intermediate group since the chance of CD is so low. In our cohort the only child with CD in this group was younger than 2 years of age. In this age category (<2 years) it may be advisable to perform antibody testing for IgA and IgG Gliadin and/or deamidated Gliadin peptides and when positive to perform an uppertract endoscopy. The retrospective design of our study brings some limitations, since the clinical and serological data needed for the construction of the diagnostic score model were only complete in 42% of the children (Group 1). This was mostly due to lack of CD specific antibodies determinations in children who were not clinical suspected of CD. However, the sensitivity and specificity for EMA and anti-tg2 in this selected group of children were comparable with the ones generally reported in CD.(11;15) However, the few significant differences in the baseline characteristics of the children without CD in Group 1 and 2 may have resulted in a suboptimal diagnostic model. For this reason it is important to test the diagnostic score model prospectively as our group is doing at the moment. The status of small bowel biopsies as gold standard in the diagnosis of CD is being challenged and several diagnostic score models or algorithms have been proposed. (16;28-30) A mayor characteristic of our score is that it has been developed and 60

13 Diagnostic score model for childhood coeliac disease validated using the data from a large group of children with and without CD, meanwhile other scores have been constructed on empirical/pragmatic basis. (28;30) Another diagnostic score, called SAGE (29), has recently been created and is based on symptoms, antibody results, HLA genotype and endoscopic histology. However this score, based on hospital populations, has included children who were EMA and/or anti-tg2 positive, resulting in selection-bias, moreover the SAGE score does not distinguish between the different specific symptoms characteristic for CD. To construct our score we identified 5 symptoms that are characteristic for CD and therefore useful to distinguish clinically between the children in whom CD may or may not be present: failure-to-thrive, chronic diarrhoea, vomiting, lassitude, and small stature. Recently, ESPGHAN has proposed new evidence-based diagnostic guidelines for childhood CD that do not make histology of small bowel biopsies compulsory in a group of well-defined children, with among others, typical symptoms of CD and positive CD-specific antibodies. However, also the new guidelines do not specify the symptoms and our score may help to identify the symptoms that should be taken into account during the diagnosis of childhood CD. Previous studies have suggested that small bowel biopsies are not necessary to diagnose CD in patients who have high titres of anti-tg2 and/or EMA, due to their high sensitivity and specificity.(15;23-25) In our diagnostic score, the results of specific CD antibodies also play an important role, however symptoms are also taken into account. In our cohort, not every CD child who was categorised in the high risk group had strong high titres of CD-specific antibodies, but some of them had positive antibodies combined with symptoms characteristic for CD. In our study we have used different anti-tg2 tests, which is common in clinical practice. For this reason, the new ESPGHAN guidelines for the diagnosis of CD (16) advise to use the upper limit of normal (ULN) for the different anti-tg2 tests as defined by UKNEQAS.(16) However, UKNEQAS does not define ULN s for every anti- TG2 assay. To solve this issue we calculated the ratio for anti-tg2 measurements by dividing each anti-tg2 result (U/ml) by the cut off value (U/ml) for positivity as recommended by the manufacturers. In this way the different anti-tg2 results can be easily compared to each other and be classified in low (<1), positive (1-10) and strong positive (>10). 61

14 Chapter 4 Our score does not take HLA-DQ2/DQ8-genotypes into account. One of the reasons is that being positive for HLA-DQ2 and/or DQ8 is not specific for CD since about 40% of the general population carries HLA-DQ2 and/or DQ8, and only 1% develops CD.(31) In our cohort, we even found 81% of the children without CD who carried HLA-DQ2 and/or DQ8. This overrepresentation is possibly due to the large number of patients who visit our departments because of having CD-related diseases or familiar CD. The diagnostic value of HLA-genotyping in CD is its negative predictive value as high as 98%, which makes the genotyping of importance to exclude the disease (15) and it is also taken into account in the new ESPGHAN guidelines for the diagnosis of CD.(16) However, HLA-genotyping is relatively expensive and not wide available. For these reasons, we suggest, when using our score model, to limit HLA-genotyping to these children in the low intermediate and high intermediate group. When a child is negative for HLA-DQ2/DQ8, it is very unlikely that he/she has CD and further diagnostic investigations should not generally be performed. By HLA-typing we could have ruled out CD in at least 7 (13%) of the 36 children without CD who were categorised in the high intermediate group. In conclusion, we present a score model that may prevent as much as 58% small bowel biopsies in the diagnostic work-up of childhood CD. Our score model based on symptoms and antibodies, has parallels to the new guidelines of ESPGHAN (16) and it represents an instrument which is easy-to-use in daily clinical practice. Further prospective investigations should be performed to improve and establish the added value of our score model in a large cohort of patients. 62

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