Diagnostic usefulness of Anti-Tissue Transglutaminase in Celiac Disease: Correlation with Intestinal Mucosal Biopsy.
Objective: To describe the clinical value of Anti-tTG (IgA, IgG) in the diagnostic work-up of celiac disease patients.
Methodology: Children with clinical suspicion of celiac disease, presenting in Gastroenterology and Hepatology out patient department, Children's Hospital and The Institute of Child Health, Multan were recruited. It was a descriptive case series, study was conducted from Jan 2007 to Jan 2009, blood samples for Anti-tTGs (IgG, IgA) and duodenal biopsies for histological analysis were taken. Data was analyzed for descriptive analysis.
Results: Sixty patients with symptoms suggestive of celiac disease were submitted for Anti-tTGs (IgG, IgA) and duodenal biopsy, 46 patients had histological changes according to the Marsh criteria and 49 had raised Anti-tTGs. A total of 54 patients who had one or both the tests positive, were considered for final analysis. 41 patients showed histological changes of celiac disease on duodenal biopsy and raised Anti-tTGs, 5 patients with histological changes of celiac disease had Anti-tTGs levels within normal limits. Five patients with raised Anti-tTGs levels had nonspecific inflammatory changes (not consistent with celiac disease) and 3 patients with raised Anti-tTGs levels had normal histology of intestinal mucosa.
Conclusion: Anti-tTGs (IgA, IgG) is very valuable screening marker in the diagnostic work-up of celiac disease, specially in selecting the patients for duodenal biopsies.
KEY WORDS: Celiac disease, Anti-tTG, Duodenal biopsy.
How to cite this article:
Rabbani MW, Aziz MT, Ali I, Khan WI, Ali Z, Aslam M. Diagnostic usefulness of Anti-Tissue Transglutaminase in Celiac Disease: Correlation with Intestinal Mucosal Biopsy. Pak J Med Sci 2011;27(3):599-602
Celiac Disease, is a common cause of chronic malabsorption in children.1 It is characterized by mucosal damage of the small intestine induced by gluten containing foods, may present with wide spectrum, ranging from silent asymptomatic form to chronic diarrhea, abdominal pain, failure to thrive, dermatitis herpetiformis, dental enemal defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia.2 It is more prevalent among individuals with type-1 diabetes, Down syndrome, Turner syndrome, and first degree relatives of the individuals with celiac disease.3
The diagnosis of celiac disease is based on the presence of symptoms, demonstration of abnormal small bowel histology and clinical response to gluten-free diet.4 Positive serology, according to the European Society for Pediatric Gastroenterology and Nutrition criteria, makes the diagnosis more certain.5-6 Tissue transglutaminase (tTG) has been claimed to play a fundamental role in the pathogenesis of celiac disease, when gluten derived peptides are subjected to tTG action, their complexes originate. These complexes are thought to behave as autoantigens determining the formation of antibodies elicited against gliadin peptides and tTG.7 Several studies suggest that tTG auto-antibodies themselves are pathogenic, they induce epithelial cell proliferation8, increase epithelial permeability and activate monocytes9 and disturb angiogenesis.10 Screening tests (Anti-tTGs) can be utilized to identify individuals at risk for celiac disease, but the small bowel biopsy remains the gold standard.11
In this case series we have tried to see the usefulness of (AntitTGs) in the diagnostic work-up of celiac disease and its relationship with small intestinal biopsy findings.
The study was performed in Pediatric Gastroenterology Department Children Hospital, Multan from January 2007 to January 2009. A detailed history and physical examination, including anthropometric measurement (height, weight) were taken for all the children.
The subjects (2-14 years of age) with strong suspicion of celiac disease during the out patient evaluation were recruited. The presence of one or more of the following clinical findings were used to identify suspected cases for further evaluation: (i) chronic or recurrent diarrhea. (ii) short stature (i.e. linear height below 5th percentile for the age in the absence of any other specific identifiable cause); (iii) failure to thrive / gain weight (i.e. a weight for age below the 5th percentile or a weight for height ratio below the 10th percentile); (iv) unexplained pallor (v) abdominal symptoms (vomiting, abdominal bloating / discomfort),(vi) autoimmune disease such as (type I diabetes mellitus) autoimmune thyroiditis and (vii) being a sibling or descendent of celiac patients.
Table-I: Results of Anti-tTGs of 54 patients.
Patients positive for Anti tTGs 49 (90.74%)
Patients negative for Anti tTGs 5 (9.25%)
Total 60 cases suspected of celiac disease according to the above mentioned criteria, agreed for admission and evaluation. Parents / guardians were explained about risks / benefits of the study and informed consent was taken. They were also explained about duodenal biopsy for the final diagnosis and blood test for (AntitTGs IgA, IgG). The study protocol was approved by the Institutional Ethical Committee.
After admission in the ward, their hemoglobin, platelets, prothrombin time (PT), activated partial thromboplastin time (APTT), hepatitis B surface antigen and anti HCV were sent to the Children Hospital laboratory. If any derangement was found in these tests, it was corrected by packed cells, platelets, fresh frozen plasma (FFP) transfusions, which ever was needed. Blood samples of the patients were sent to the Aga Khan Laboratory, Karachi for antitTGs (IgA and IgG) to be measured by the ELISA procedure, (Normal cut off value for IgA is 0-7U/ml and of IgG is 0-17U/ml). At the same time these prepared patients underwent upper gastrointestinal endoscopy under local / general anesthesia (Olympus GIF 160 end-viewing gastroscope, Tokyo, Japan) for small bowel biopsy taken from the second part of the duodenum (Biopsy forceps, Olympus FB25K, Tokyo). At least two biopsy samples were obtained for each subject.
The biopsies were preserved in formalin and sent for histopathological examination to Shaukat Khanam Hospital, laboratory Lahore. Histopathology was expressed according to the Marsh Criteria. The final analysis was done on fifty four (54) patients, who had one or both the tests positive.
Fifty four patients (2 to 14 years of age), who had one or both the tests (Anti-tTG, duodenal biopsy) positive, were included for final analysis. There were 28 (52%) males and 26 (48%) females. In small bowel biopsy, 46 patients had histological changes of celiac
Table-II: Histological changes of duodenal mucosal biopsy of 54 patients.
Patients having histological changes consistent with celiac disease###46(85.2%)
Patients having non-specific histological changes (not consistent with celiac disease)###5(9.59%)
Patients having normal duodenal mucosa###3(5.5%)
Table-III: Co-relation of anti-tTGs with duodenal mucosal damage. Total patients having histological changes Positive anti-tTGs = 41 (89.13%) of celiac disease = 46 Negative anti-tTGs =05 (10.86%)
Total patients having histological changes###Positive anti-tTGs =###41(89.13%)
of celiac disease = 46###Negative anti-tTGs =###05(10.86%)
Total patients having positive anti-tTGs = 49###Histological changes of celiac
###Non-specific chronic inflammation but
###not consistent with celiac disease = 05(10.20%)
###Normal histology =###03(6.12%)
disease according to the marsh criteria, five had nonspecific chronic inflammatory changes (not consistent with celiac disease) and three with normal histology were noted. Anti tTGs were found raised in 49(90.74%) patients and within normal range in 5(9.25%). The correlation of anti tTGs with duodenal mucosal damage is given in Table-III. It was seen that among 46 biopsy proven cases, 41 (89.13%) were having raised anti-tTGs, 5 with raised Anti-tTGs had nonspecific inflammatory changes and three with raised Anti-tTGs had normal histology of intestinal mucosa. It was also noted that five patients who had high levels of anti-tTGs (IgG and/or IgA greater than 100 units/ ml) were also having severe mucosal damage according to the Marsh criteria.
Small intestinal biopsy is the gold standard for the diagnosis of celiac disease but anti-tTGs(IgG, IgA) is a valuable screening test with high sensitivity and specificity, moreover, it may be used in monitoring the success of therapy with gluten free diet.12 . In our study a total of 54 patients who had one or both the tests positive, were considered for the final analysis, 46 patients had histological changes according to the Marsh criteria and 49 had raised Anti-tTGs , raised antibodies assay have been observed in about 90% of the cases where histological evidence of celiac disease is present, which is comparable with the study done by Biagi F and colleagues.13
There is a strong correlation between disease specific autoantibodies (Anti tTG's) level and severity of duodenal mucosal lesions in celiac disease, this correlation demonstrated in this study, suggests that antibodies may have a role in immunologic injury which has also been observed in another international study done by Pena AS, et al.14
In present study we noted 5 biopsy proven celiac disease cases, who were negative for anti tTG's, it is important to remember that a child in high risk group, whose serology is negative at initial screening may develop a positive serology subsequently if not treated . Similarly 03 of our patients with normal histology and 05 with non specific inflammatory changes (not consistent with celiac disease) were positive for anti tTG's (IgA, IgG). This finding may be explained on the basis of false positive results of anti-tTG's, insufficient biopsy bites / inappropriate site or latent / potential forms of celiac disease.15,16
In the clinical setting of celiac disease, presence of these antibodies (Anti tTG's, IgA, IgG) along with typical intestinal mucosal changes almost confirms the diagnosis of celiac disease, even before response to gluten free diet is available.17 It is crucial that the diagnosis is made correctly, and a trial of gluten exclusion in suspected celiac disease patients, is not recommended without confirmation. We believe that Anti tTG's,(IgG and IgA) is a useful screening test in the diagnostic work-up of celiac disease and may be used in selecting the patients for duodenal biopsies.
We are thankful to our team in Gastroenterology department including Medical Officers, Staff Nurses and Endoscopy Technician for their support in this survey.
1. Sood MR. Disorders of malabsorbtion. In: Behrman RE, Kleigman RM, Jenson HB, editors. Nelson's textbook of pediatrics Philadelphia: WB Saunders; 2007: 1587-602.
2. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40:1-19.
3. Gautam A, Jain BK, Midha V, Sood A, Sood N. Prevalence of celiac disease among siblings of celiac disease patients. Indian J Gastroenterol 2006;25(5):233-5.
4. Aziz S, Muzaffar R, Zafar MN, Mehnza A, Mubarak M, Abbas Z, et al. Celiac disease in children with persistent diarrhea and failure to thrive. J Coll Physicians Surg Pak 2007;17(9):554-7.
5. Walker-Smith JA, for Working Group of European Society of Paediatric Gatroenterology and Nutrition. Revised criteria for diagnosis of celiac disease. Report of Working Group of European Society of Paedriatric Gastroenterology and Nutrition. Arch Dis Child 1990;65:909-11.
6. Garcia-Carega M, Kerner JA. Malabsorptive disorders. In: Behrman RE, Kleigman RM, Jenson HB, editors. Nelson's textbook of pediatrics. Philadelphia: WB Saunders; 2004: 1257-71.
7. Schuppan D Dieterich W, Riecken EO. Exposing gliadin as a tasty food for lymphocytes. Deamidation of wheat gliadin by tissue transglutaminase promotes its binding to HLA-DQ2 and its recognition by gut T cells, suggesting a novel mechanism in celiac disease. Nat Med 1998;4:666-667.
8. Barone MV, Caputo I, Ribecco MT, Maqlio M, Marzari R, Sblattero D, et al. Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease. Gastroenterolgy 2007;132:1245-1253.
9. Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Beri R, et al. In celiac disease, a subset of autoantibiodies against transglutaminase binds toll-like receptor 4 and induces activation monocytes. PLoS Med 2006;3(9):e358.
10. Myrsky E, Kaukinen K, Syrjanen M, Korponay-Szabo IR, Maki M, and Lindfors K. Coeliac disease-specific autoantibodies targeted against transglutaminase 2 disturb angio1genesis. Clin Exp Immunol 2008;152(1):111-119.
11. Dutta AK, Chacko A, Avinash B. Suboptimal performance of IgG anti tissue transglutaminase in the diagnosis of celiac disease in tropical country. Dig Dis Sci 2010;55:698-702.
12. Yachha SK, Aggarwal R, Srinivas S, Srivastava A, Somani SK, Itha S. Antibody testing in Indian children with celiac disease. Indian J Gastroentology 2006;25(3):132-35.
13. Biagi F, Ellis HJ, Yiannakou JY, Brusco G, Swift GL, Smith PM, et al. Tissue transglutaminase antibodies in celiac disease. Am J Gastroenterol 1999;94(8):2187-2192.
14. Pena AS, Garrote JA and Crusius JB. Advances in the immunogenetics of celiac disease. Clues for understanding the pathogenesis and disease heterogeneity. Scand J Gastroenterol 2002;38:56.
15. Jarvinen TT, Kaukinen K, Laurila K, Kyronpalo S, Rasmussen M, Maki M, et al. Intraepithelial lymphocytes in celiac disease. Am J Gastroenterol 2003;98(6):1332-1337.
16. Westerholm-Ormio M, Garioch J, Ketola I, Saxilahti E. Inflammatory cytokines in small intestinal mucosa of patients with potential coeliac disease. Clin Exp Immunol 2002;128(1):94-101.
17. Yachha Sk, Poddat U. Celiac disease in Asia In: Catassi C, Fasano A, Corazza GR, Eds. The Global Village of coeliac disease. Italy: Italian Coeliac Society. 2005: 101-8.
Rabbani MW: Conceived, designed, did statistical analysis and editing of manuscript. Aziz MT, Ali I, Khan WI: Did data collection, manuscript writing. Ali Z, Aslam M: Review of manuscript.
Muhammad Waqar Rabbani, Muhammad Tariq Aziz, Ibad Ali, Waqas Imran Khan, Zulfqar Ali, Muhammad Aslam ,Dr. Muhammad Waqar Rabbani, DCH, FCPS, Dr. Muhammad Tariq Aziz, FCPS, Dr. Ibad Ali, DCH FCPS, Dr. Waqas Imran Khan, DCH, FCPS, Dr. Zulfqar Ali, DCH, FCPS, Dr. Muhammad Aslam, DCH, FCPS, 1-6: The Children Hospital and The institute of Child Health, Multan, Pakistan. Correspondence: Dr. Muhammad Waqar Rabbani, DCH, FCPS, Associate Professor Paediatrics, Department of Paediatric Medicine, The Children Hospital and The institute of Child Health, Multan, Pakistan. E-mail: firstname.lastname@example.org Received for Publication: February 11, 2011 Revision Received: February 28, 2011 Second Revision: May 17, 2011 Final Revision Accepted: May 18, 2011
|Printer friendly Cite/link Email Feedback|
|Author:||Rabbani, Muhammad Waqar; Ali, Ibad; Khan, Waqas Imran; Ali, Zulfqar; Aslam, Muhammad; Aziz, Muhammad|
|Publication:||Pakistan Journal of Medical Sciences|
|Date:||Sep 30, 2011|
|Previous Article:||Thyroid disorders in rheumatoid arthritis and osteoarthritis.|
|Next Article:||Nutritional Rickets: Correlation between clinical, biochemical and radiological profile.|