Analysis of diabetes-associated autoantibodies in children and adolescents with autoimmune thyroid diseases

Marta Rydzewska; Justyna Michalak; Anna Bossowska; Shu Chen; Sarah Black; Michael Powell; Jadwiga Furmaniak; Bernard Rees Smith; Artur Bossowski

doi:10.1515/jpem-2018-0367

Artikel

Analysis of diabetes-associated autoantibodies in children and adolescents with autoimmune thyroid diseases

Marta Rydzewska , Justyna Michalak , Anna Bossowska , Shu Chen , Sarah Black , Michael Powell , Jadwiga Furmaniak , Bernard Rees Smith und Artur Bossowski

Veröffentlicht/Copyright: 23. März 2019

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Aus der Zeitschrift Journal of Pediatric Endocrinology and Metabolism Band 32 Heft 4

Abstract

Background

Zinc transporter 8 autoantibodies (ZnT8Abs) together with glutamic acid decarboxylase autoantibodies (GADAbs), insulinoma antigen 2 autoantibodies (IA-2Abs) and insulin autoantibodies (IAbs) are markers of type 1 diabetes mellitus (T1DM). We studied the prevalence of ZnT8Ab in children with autoimmune thyroid diseases (AITDs) to assess the association of AITDs and T1DM at the serological level.

Methods

The study groups consisted of 44 children with Graves’ disease (GD), 65 children with Hashimoto’s thyroiditis (HT), 199 children with T1DM with or without AITDs and 58 control children. ZnT8Ab, GADAb, IA-2Ab, IAb, 21-hydroxylase autoantibodies (21-OHAbs) and acetylcholine receptor autoantibodies (AChRAbs) were measured.

Results

ZnT8Abs were found in 4/44 (9.1%) patients with GD, and 4/44 (9.1%) patients with GD were positive for GADAb. Of the 65 HT patients, six (9.2%) were positive for ZnT8Ab, while four (6.2%) were positive for GADAb. In the T1DM group, 128/199 (64%) of the patients were positive for ZnT8Ab, 133/199 (67%) for GADAb and 109/199 (55%) for IA-2Ab. One GD patient and one HT patient were positive for all the four diabetes-associated autoantibodies. Two HT patients were positive for three diabetes autoantibodies. Two GD (4.5%) and five HT (7.7%) patients were positive for 21-OHAb only. None of the patients had AChRAb. In the control group, 2/58 (3.4%) were positive for GADAb and 2/58 (3.4%) were positive for ZnT8Ab.

Conclusions

Diabetes-associated autoantibodies including ZnT8Ab were found in children and adolescents with GD and HT.

Keywords: autoantibodies; autoimmune thyroid disease (AITD); Graves’ disease; Hashimoto’s thyroiditis; type 1 diabetes mellitus; zinc transporter 8 autoantibodies (ZnT8Ab)

Corresponding author: Prof. Artur Bossowski, MD, PhD – ETA, ESE, ESC, ESPE member, Department of Pediatrics, Endocrinology and Diabetes with a Cardiology Unit, Medical University of Białystok, ul. Waszyngtona 17, Białystok 15-274, Poland, Phone: +857450-735, Fax: +(085)7450730

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: Shu Chen, Sarah Black, Michael Powell, Jadwiga Furmaniak and Bernard Rees Smith are employees of RSR Ltd. RSR Ltd. is a developer of medical diagnostics including kits for measuring autoantibodies.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for human health: an integrative review. J Res Med Sci 2013;18:144–57.Suche in Google Scholar

2. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993;73:79–118.10.1152/physrev.1993.73.1.79Suche in Google Scholar PubMed

3. Maret W. Zinc biochemistry: from a single zinc enzyme to a key element of life. Adv Nutr 2013;4:82–91.10.3945/an.112.003038Suche in Google Scholar PubMed PubMed Central

4. Dawidson WH, Wenzlau MJ, O’Brien MR. Zinc transporter 8 (ZnT8) and beta cell function. Trends Endocrinol Metab 2014;25:415–24.10.1016/j.tem.2014.03.008Suche in Google Scholar PubMed PubMed Central

5. Murgia C, Devirgiliis C, Mancini E, Donadel G, Zalewski P, et al. Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands. Nutr Metab Cardiovasc Dis 2009;19:431–9.10.1016/j.numecd.2008.09.004Suche in Google Scholar PubMed

6. Huang L, Tepaamorndech S. The SLC30 family of zinc transporters – a review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 2013;34:548–60.10.1016/j.mam.2012.05.008Suche in Google Scholar PubMed

7. Pound LD, Sarkar SA, Benninger RK, Wang Y, Suwanichkul A, et al. Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J 2009;421:371–6.10.1042/BJ20090530Suche in Google Scholar PubMed PubMed Central

8. Kawasaki E. Type 1 diabetes and autoimmunity. Clin Pediatr Endocrinol 2014;23:99–105.10.1297/cpe.23.99Suche in Google Scholar PubMed PubMed Central

9. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA 2007;104:17040–5.10.1073/pnas.0705894104Suche in Google Scholar PubMed PubMed Central

10. Wenzlau JM, Frisch LM, Gardner TJ, Sarkar S, Hutton JC, et al. Novel antigens in type 1 diabetes: the importance of ZnT8. Curr Diab Rep 2009;9:105–12.10.1007/s11892-009-0019-4Suche in Google Scholar PubMed

11. Han S, Donelan W, Wang H, Reeves W, Yang LJ. Novel autoantigens in type 1 diabetes. Am J Transl Res 2013;5:379–92.Suche in Google Scholar

12. Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983;222:1337–9.10.1126/science.6362005Suche in Google Scholar PubMed

13. Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990;347:151–6.10.1038/347151a0Suche in Google Scholar

14. Bonifacio E, Lampasona V, Bingley PJ. IA-2 (islet cell antigen 512) is the primary target of humoral autoimmunity against type 1 diabetes-associated tyrosine phosphatase autoantigens. J Immunol 1998;161:2648–54.10.4049/jimmunol.161.5.2648Suche in Google Scholar

15. Cappa M, Bizzarri C, Crea F. Autoimmune thyroid diseases in children. J Thyroid Res 2011;2011:675703.10.4061/2011/675703Suche in Google Scholar

16. Bossowski AT, Reddy V, Perry LA, Johnston LB, Banerjee K, et al. Clinical and endocrine features and long-term outcome of Graves’ disease in early childhood. J Endocrinol Invest 2007;30:388–92.10.1007/BF03346315Suche in Google Scholar

17. Bossowski A, Harasymczuk J, Moniuszko A, Bossowska A, Hilczer M, et al. Cytometric evaluation of intracellular INF-y and IL-4 levels in thyroid follicular cells from patients with autoimmune thyroid diseases. Thyroid Res 2011;4:13.10.1186/1756-6614-4-13Suche in Google Scholar

18. Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab 2006;91:1210–7.10.1210/jc.2005-1679Suche in Google Scholar

19. Laberge G, Mailloux CM, Gowan K, Holland P, Bennett DC, et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res 2005;18:300–5.10.1111/j.1600-0749.2005.00242.xSuche in Google Scholar

20. Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015;14:174–80.10.1016/j.autrev.2014.10.016Suche in Google Scholar

21. Jenkins RC, Weetman AP. Disease associations with autoimmune thyroid disease. Thyroid 2002;12:977–88.10.1089/105072502320908312Suche in Google Scholar

22. Betterle C, Presotto F. Autoimmune polyendocrine syndromes (APS) or multiple autoimmune syndromes (MAS). In: Walker S, Jara LJ, editors. Handbook of systemic autoimmune diseases, endocrine manifestations of systemic autoimmune diseases. Amsterdam: Elsevier, 2008:135–48.10.1016/S1571-5078(07)00212-7Suche in Google Scholar

23. Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol 2009;169:749–55.10.1093/aje/kwn408Suche in Google Scholar PubMed

24. Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, et al. The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and report of a large series of patients. Autoimmun Rev 2016;15:1125–8.10.1016/j.autrev.2016.09.009Suche in Google Scholar

25. Warncke K, Frohlich-Reiterer EE, Thon A, Hofer SE, Wiemann D, et al. Polyendocrinopathy in children, adolescents, and young adults with type 1 diabetes: a multicenter analysis of 28,671 patients from the German/Austrian DPV-Wiss database. Diabetes Care 2010;33:2010–2.10.2337/dc10-0404Suche in Google Scholar

26. American Diabetes Association. Standards of medical care in diabetes – 2014. Diabetes Care 2014;37:14–80.10.2337/dc14-S014Suche in Google Scholar

27. Petruzelkova L, Ananieva-Jordanova R, Vcelakova J, Vesely Z, Stechova K, et al. The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of type 1 diabetes mellitus. Diabet Med 2014;31:165–71.10.1111/dme.12308Suche in Google Scholar

28. Brooking H, Ananieva-Jordanova R, Arnold C, Amoroso M, Powell M, et al. A sensitive non-isotopic assay for GAD65 autoantibodies. Clin Chim Acta 2003;331:55–9.10.1016/S0009-8981(03)00088-3Suche in Google Scholar

29. Masuda M, Powell M, Chen S, Beer C, Fichna P, et al. Autoantibodies to IA-2 in insulin-dependent diabetes mellitus. Measurements with a new immunoprecipitation assay. Clin Chim Acta 2000;291:53–66.10.1016/S0009-8981(99)00199-0Suche in Google Scholar

30. Tanaka H, Perez MS, Powell M, Sanders JF, Sawicka J, et al. Steroid 21-hydroxylase autoantibodies: measurements with a new immunoprecipitation assay. J Clin Endocrinol Metab 1997;82:1440–6.10.1210/jc.82.5.1440Suche in Google Scholar

31. Levin L, Tomer Y. The etiology of autoimmune diabetes and thyroiditis: evidence for common genetic susceptibility. Autoimmun Rev 2003;2:377–86.10.1016/S1568-9972(03)00080-6Suche in Google Scholar

32. Kontiainen S, Schlenzka A, Koskimies S, Rilva A, Maenpaa J. Autoantibodies and autoimmune diseases in young diabetics. Diabetes Res 1990;13:151–6.Suche in Google Scholar

33. Kawasaki E, Abiru N, Yano M, Uotani S, Matsumoto K, et al. Autoantibodies to glutamic acid decarboxylase in patients with autoimmune thyroid disease: relation to competitive insulin autoantibodies. J Autoimmun 1995;8:633–43.10.1006/jaut.1995.0047Suche in Google Scholar PubMed

34. Moriguchi M, Noso S, Kawabata Y, Yamauchi T, Harada T, et al. Clinical and genetic characteristics of patients with autoimmune thyroid disease with antiislet autoimmunity. Metabolism 2011;60:761–6.10.1016/j.metabol.2010.07.025Suche in Google Scholar PubMed

35. Marwaha RK, Garg MK, Tandon N, Kanwar R, Narang A, et al. Glutamic acid decarboxylase (anti-GAD) and tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity. Indian J Med Res 2013;137:82–6.Suche in Google Scholar

36. Larizza D, De Amici M, Klersy C, Albanesi M, Albertini R, et al. Anti-zinc transporter protein 8 antibody testing is not informative in routine prediabetes screening in young patients with autoimmune thyroiditis and celiac disease. Horm Res Paediatr 2016;86:100–5.10.1159/000448003Suche in Google Scholar PubMed

37. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013;309:2473–9.10.1001/jama.2013.6285Suche in Google Scholar PubMed PubMed Central

38. Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015;38:1964–74.10.2337/dc15-1419Suche in Google Scholar PubMed PubMed Central

39. Chimienti F, Devergnas S, Favier A, Seve M. Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 2004;53:2330–7.10.2337/diabetes.53.9.2330Suche in Google Scholar PubMed

40. Gyulkhandanyan AV, Lu H, Lee SC, Bhattacharjee A, Wijesekara N, et al. Investigation of transport mechanisms and regulation of intracellular Zn2ţ in pancreatic alphacells. J Biol Chem 2008;283:10184–97.10.1074/jbc.M707005200Suche in Google Scholar PubMed

41. Smidt K, Pedersen SB, Brock B, Schmitz O, Fisker S, et al. Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese. Mol Cell Endocriol 2007;264:68–73.10.1016/j.mce.2006.10.010Suche in Google Scholar PubMed

42. Overbeck S, Uciechowski P, Ackland ML, Ford D, Rink L. Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9. J Leukoc Biol 2008;83:368–80.10.1189/jlb.0307148Suche in Google Scholar PubMed

43. Jonsdottir B, Andersson C, Carlsson A, Delli A, Forsander G, et al. Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents. Diabetologia 2013;56:1735–42.10.1007/s00125-013-2934-9Suche in Google Scholar PubMed

44. Bossowski A, Niklinska W, Gasowska M, Goralczyk A, Polnik D, et al. Identification of zinc transporter ZnT8 in thyroid tissues from children and adolescents with thyroid nodular hyperplasia. ESPE Abstracts 2016:86:P-P1-902.Suche in Google Scholar

45. Betterle C, Volpato M, Rees Smith B, Furmaniak J, Chen S, et al. II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison’s disease. J Clin Endocrinol Metab 1997:82:939–42.10.1210/jcem.82.3.3849Suche in Google Scholar PubMed

46. Małunowicz EM, Romer TE, Urban M, Bossowski A. 11Betahydroxysteroid dehydrogenase type 1 deficiency (‘apparent cortisone reductase deficiency’) in a 6-year-old boy. Horm Res 2003;59:205–10.Suche in Google Scholar

47. Glowinska-Olszewska B, Michalak J, Luczynski W, Del Pilar Larosa M, Chen S, et al. Organ-specific autoimmunity in relation to clinical characteristics in children with long-lasting type 1 diabetes. J Pediatr Endocrinol Metab 2016;29:647–56.10.1515/jpem-2015-0190Suche in Google Scholar PubMed

48. Andersson C, Larsson K, Vaziri-Sani F, Lynch K, Carlsson A, et al. The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes. Autoimmunity 2011;44:394–405.10.3109/08916934.2010.540604Suche in Google Scholar PubMed

49. Glastras SJ, Craig ME, Verge CF, Chan AK, Cusumano JM, et al. The role of autoimmunity at diagnosis of type 1 diabetes in the development of thyroid and celiac disease and microvascular complications. Diabetes Care 2005;28:2170–5.10.2337/diacare.28.9.2170Suche in Google Scholar PubMed

50. Reghina AD, Albu A, Petre N, Mihu M, Florea S, et al. Thyroid autoimmunity in 72 children with type 1 diabetes mellitus: relationship with pancreatic autoimmunity and child growth. J Pediatr Endocrinol Metab 2012;25:723–6.10.1515/jpem-2012-0090Suche in Google Scholar PubMed

51. Kabelitz M, Liesenkotter KP, Stach B, Willgerodt H, Stablein W, et al. The prevalence of anti-thyroid peroxidase antibodies and autoimmune thyroiditis in children and adolescents in an iodine replete area. Eur J Endocrinol 2003;148:301–7.10.1530/eje.0.1480301Suche in Google Scholar PubMed

52. Milakovic M, Berg G, Eggertsen R, Lindstedt G, Nystrom E. Screening for thyroid disease of 15–17-year-old schoolchildren in an area with normal iodine intake. J Intern Med 2001;250: 208–12.10.1046/j.1365-2796.2001.00878.xSuche in Google Scholar PubMed

53. Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995;12:622–7.10.1111/j.1464-5491.1995.tb00553.xSuche in Google Scholar PubMed

54. Kordonouri O, Klinghammer A, Lang EB, Gruters-Kieslich A, Grabert M, et al. Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey. Diabetes Care 2002;25:1346–50.10.2337/diacare.25.8.1346Suche in Google Scholar PubMed

Received: 2018-08-19

Accepted: 2019-02-08

Published Online: 2019-03-23

Published in Print: 2019-04-24

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https://doi.org/10.1515/jpem-2018-0367

Schlagwörter für diesen Artikel

autoantibodies; autoimmune thyroid disease (AITD); Graves’ disease; Hashimoto’s thyroiditis; type 1 diabetes mellitus; zinc transporter 8 autoantibodies (ZnT8Ab)