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False-negative IgA Anti-tissue Transglutaminase

Nada Boutrid*, Hakim Rahmoune, Mounira Amrane

Department of Pediatrics, University Hospital of Setif; Setif 1 University, Algeria

Abstract: The expanding knowledge about gluten-related autoimmunity led to a serology-based step-wised approach to diagnose celiac disease that might be misleading due to laboratory techniques. We present a rare case associating initial false-negative anti-transglutaminase IgA antibodies while CD was confirmed by IgG anti-transglutaminase and subsequent duodenal biopsy.

Keywords: celiac disease, autoimmunity, immunoglobulin A, tissue transglutaminase

Received September 11, 2018; Revised October 15, 2018; Accepted January 04, 2019

Citation: Nada Boutrid, Hakim Rahmoune, Mounira Amrane, False-negative IgA Anti-tissue Transglutaminase. International Journal of Celiac Disease, 6 (3). 87-88. January 2018. doi:10.12691/ijcd-6-3-2

1. Introduction

Celiac disease (CD) is an autoimmune disease occurring on specific genetic (i.e. Human Leukocytes Antigens HLA DQ2/DQ8) backgrounds [1,2]; its prevalence is increasing over the last decades and recent estimates in Europe and the United States range from 1:80 to 1: 300 children to 13 per 1000 children) [1] and CD is reported at a very high frequency in North Africa: a prevalence as high as 5.6% was found in the Sahrawi population [3,4], and the world’s highest frequency ( = 16%) of CD in diabetic children was retrieved in Algeria [5].

In addition, the diagnosis of this clinical chameleon is made at any age and st short stature may be associated or even indicative of celiac disease, specially in such high-frequency areas.

Through a retrospective study of short stature screening in algerian primary schools, we depict a peculiar case of a child diagnosed as CD: initial negative IgA anti-transglutaminase antibodies were confusing until CD was confirmed by IgG anti-transglutaminase and subsequent duodenal biopsy.

2. Case Presentation

A cross-sectional descriptive anthropometric study was conducted in a sample of preschool and primary school pupils in the town of Setif (Algeria) from october to december 2014.

Out of 2493 pupils, 47 short children < - 2 standard deviation (SD) in height were detected.

Short stature pupils benefited of a celiac serological screen with IgA and IgG anti-tissue transglutaminase II, along with total serum IgA.

Five children of this investigated group had a positive celiac serology.

This panel of celiac patients encompassed:

- 04 children already diagnosed as celiac patients

- an asymptomatic boy, newly detected by this screening.

The last patient, aged 9 years and 9 months without any personal nor familial history, had a statural deficiency at (- 2.04) SD.

His celiac serology was confusing as he had an initial negative IgA anti-transglutaminase < 5 IU / ml. He did not exhibit any total Ig A deficiency; while IgG anti-transglutaminase levels were as high as 90.73 IU / ml.

Subsequent duodenal-jejunal biopsy confirmed the diagnosis of celiac disease (Marsh type 3, according to the Marsh Classification of Histologic Findings in CD).

When checking the laboratory work-up of celiac serology (Samples were centrifuged at 4000 rpm for 10 min), we deduced that long-lasting blood samples and consequent hemolysis are the most probable source of this diverting result.

3. Discussion

Only one, non-symptomatic, boy was detected de novo in this screening: such silent forms are more reported in boys; while girls carry more frequently the HLA DQ2 genes haplotype which is associated with early digestive complaints [6].

Similar cases with IgA negative /IgG positive anti-transglutaminase (with normal total IgA and 9 fold upper-limit IgG anti-transglutaminase) are sparse but were diversely reported worldwide. [7,8].

Even if IgA anti-tissue transglutaminase represent a cheap, reliable biomarker of celiac disease, hemolysis may be a crucial pre-analytical factor [9].

In fact, tissue transglutaminase is an ubiquitous enzyme and is particularly plentiful in erythrocytes.

Thus, hemolysis during immunoassay release the enzyme that may bind IgA anti-tissue transglutaminase to the coated enzyme and induce a false negative test. [10].

An interesting study recently conducted in Denmark clearly showed how hemolysis may affect IgA anti-transglutaminase detection, and authord suggested to enhance test reliability with other tests such as deamidated gliadin peptide-antibodies and anti-endomysial antibodies. [11].

4. Conclusion

The modern, serology-based screening and diagnosis of celiac disease should be warranted through a robust laboratory management (i.e. without hemolysis )

False-negative results in such cases, specially in asymptomatic patients, may drive a long odyssey before a correct diagnosis can be definitely assessed.

Check twice before saying tests are nice!

Acknowledgements

The authors would thank the biochemistry laboratory at University Hospital of Setif for kind collaboration.

References

[1]   | Hill ID, Dirks MH, Liptak GS, 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.
[2]   | Rahmoune H,Boutrid N,Bioud B. HLA & Celiac Disease. Moroccan Health Journal, 2017; 18 :14-15.
[3]   | Catassi C, Ratsch IM, Gandolfi L, Pratesi R, Fabiani E, El Asmar R, Frijia M, Bearzi I, Vizzoni L. Why is coeliac disease endemic in the people of the Sahara?.The Lancet. 1999; 354: 647-8.
[4]   | Barada K, Bitar A, Mokadem MA, Hashish JG, Green P. Celiac disease in Middle Eastern and North African countries: a new burden? World J Gastroenterol 2010; 16:1449-1457.
[5]   | Boudraa G, Hachelaf W, Benbouabdellah M, Belkadi M, Benmansour FZ, Touhami M. Prevalence of coeliac disease in diabetic children and their first‐degree relatives in West Algeria: screening with serological markers. Acta paediatrica. 1996; 85: 58-60.
[6]   | Megiorni F, Mora B, Bonamico M, Barbato M, Montuori M, Viola F, Trabace S, Mazzilli MC. HLA-DQ and susceptibility to celiac disease: evidence for gender differences and parent-of-origin effects. The American journal of gastroenterology. 2008; 103: 997-1003.
[7]   | Ivanovski P, Nikolić D, Dimitrijević N, Ivanovski I, Perišić V. Erythrocytic transglutaminase inhibition hemolysis at presentation of celiac disease. World Journal of Gastroenterology: WJG. 2010 Nov 28; 16(44): 5647.
[8]   | Arguelles-Grande C, Norman GL, Bhagat G, Green PH. S2054 Hemolysis Induces Tissue Transglutaminase, but Not Deamidated Gliadin Peptide, False Negative Results in Celiac Disease Patients With Low Antibody Levels. Gastroenterology. 2010 May 1; 138(5): S-310.
[9]   | Arguelles-Grande C, Norman GL, Bhagat G, Green PH. Hemolysis Interferes with the Detection of Anti–Tissue Transglutaminase Antibodies in Celiac Disease. Clinical chemistry. 2010 Jun 1;56(6): 1034-6.
[10]   | Wolf J, Haendel N, Remmler J, Kutzner CE, Kaiser T, Mothes T. Hemolysis and IgA‐antibodies against tissue transglutaminase: When are antibody test results no longer reliable?. Journal of clinical laboratory analysis. 2018 May 1:e22360.

[11]  
Eriksen F, Charoenpatrawut J, Zaman S, Thomasen IN, Bathum L. Hemolysis may cause false negative results and underdiagnosis of celiac disease when measuring anti-tissue transglutaminase antibodies in serum by immunoassays. Scandinavian journal of clinical and laboratory investigation. 2018 May 14: 1-2.