Tireopatie autoimmuni e diabete di tipo 1: aspetti genetici e clinici Marco Giorgio Baroni

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1 Tireopatie autoimmuni e diabete di tipo 1: aspetti genetici e clinici Marco Giorgio Baroni Endocrinologia e Metabolismo Dipartimento di Medicina Sperimentale Sapienza Università di Roma

2 Outline Epidemiology Genetic risk factors Clinical features

3 Historical perspective 1931, Rowntree and Snell reported the first case with Addison s disease, hyperthyroidism and diabetes mellitus 1932 Gowen described a patient affected by Addison s disease, hypothyroidism and diabetes mellitus In 1964 Carpenter reviewed 142 cases with Schmidt s syndrome, and the link with diabetes mellitus was confirmed in this review, where 28 patients (20%) were found to suffer also from diabetes mellitus

4 Classification of autoimmune polyglandular syndromes (APS) Neufeld M. and Blizzard R. M., 1980 Betterle et al. Clin Exp Immunol 2004;137:

5 Features of the Autoimmune Polyendocrine Syndromes Eisenbarth et al NEJM 2004

6 Features of the Autoimmune Polyendocrine Syndromes Nat Rev Endocr 2010

7 Frequenza di autoanticorpi anti-tiroide in popolazioni a diverso rischio % Familiari di soggetti con tiroiditi autoimmuni Pz. con malattie autoimmuni organo-specifiche Addison T1DM LADA Pz. con malattie autoimmuni non-organo specif Anomalie cromosomiche (Turner, Down etc..) Orticaria cronica Depressione endogena Abortività singola o multipla Soggetti sani Tutti 7 Femmine 12 Maschi 2

8 Epidemiology Anti-thyroid peroxidase and/or antithyroglobulin autoantibodies are present in 19%-35% of T1D patients Hypothyroidism (subclinical) is observed in 10%-20% of patients. Subclinical and overt hyperthyroidism occur less frequently (2% and 4%, respectively)

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10 Prevalence of Coexisting Autoimmune Diseases in Index Cases with Graves Disease and Hashimoto s Thyroiditis The American Journal of Medicine, Vol 123, No 2, February 2010

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12 Distribution of thyroid autoantibodies in the 2,670 patients newly diagnosed with type 1 DM 12.3% of the children had thyroid autoantibodies Jonsdottir et al. Diabetologia (2013) 56:

13 Prevalenza di AITD in pazienti T1D: 19.5% stratificata per età e sesso: (5-21 aa) % AITD 35 tutti 30 maschi femmine (Holl et al, Horm Res 52:113, 1999) p< >20 età p< p<0.0001

14 Prevalenza di AITD in pazienti T1D: 21.6% stratificata per età (0-20 aa) N = 7,097 * P < ** P < (Kordonouri et al., Diabetes Care 25, 2002)

15 Prevalenza di AITD in pazienti T1D (the T1D Exchange Clinic Registry) Hughes JW et al., December JCEM 2016

16 Cumulative incidence of autoimmune thyroiditis (AIT) in 341 children with type 1 diabetes according to GADA status at diabetes onset Kordonouri et al., Ped Diabetes 2011

17 Association between islet autoantibodies and autoantibodies against either TPO or TG Jonsdottir et al. Diabetologia (2013) 56:

18 Latent Autoimmune Diabetes in Adults Fourlanos S et al, Diabetologia, 2005; Rolandson O et al, Diabetologia,2010 ü Diabete diagnosticato in età adulta (>30 anni) ü Presenza di almeno un autoanticorpo circolante (GADA, ICA, IA-2). 2-12% dei soggetti diabetici classificati come diabete tipo 2 presentano anticorpi anti-gad ü Non richiede trattamento insulinico nei primi sei mesi dalla diagnosi, (mostra un elevata progressione verso l insulino-dipendenza nei successivi 6 anni). ü Presenza di altre m. autoimmuni (tiroidite)?

19 Prevalenza di AbTPO in pazienti con T2D GADA+ *** Prevalenza TPOAb (%) *** (Gambelunghe et al., Clin. Endocrinol. 52: 565, 2000)

20 Anti-TPO distribution in autoimmune diabetes patients with low (<32U) and high (>32U) GADA titre p=0.002 Patients (%) low GADA titer (n=97) high GADA titer (n=94) Buzzetti R et al Diabetes Care 2007

21 Schloot NC et al Diabetes Care 2016 Anti-TPO distribution in autoimmune diabetes patients 13.5% 36.6% 30% 32.5%

22 TPO antibody titers in patients with autoimmune diabetes with high and low GADA titer and T2DM p< p for trend< units/ml ± ± ± high GADA titer (n=94) low GADA titer (n=97) T2DM (n=382) Buzzetti R et al Diabetes Care 2007

23 SOMMARIO EPIDEMIOLOGIA AITD e T1DM Adulti con AITD: prevalenza autoimmunità T1D: 1% con LADA: prevalenza autoimmunità tiroidea: % Bambini con AITD: prevalenza autoimmunità T1D: 4-8% (vs 0.5% pop. generale) con DMT1: prevalenza autoimmunità tiroidea: 20-35% Presenza di GAD-A e ZnT8-A = OR 2.5 di rischio di Ab anti-tiroide

24 Outline Epidemiology Genetic risk factors Clinical features

25 Selected genes associated with T1D and related autoimmune diseases

26 Gene High risk T1DM High risk Thyroid diseases DRB1 *03, *04 *03, *04, *05 DQA1 *0501, *0301 *0501, *0301 DQB1 *0201, *0302 *0201, *0302 MICA Exon 5 5GCT rep. (children and adolescents) 5.1 (adults and LADA) 5GCT rep. (children) 5.1 (adults) CTLA-4 G position 49 G position 49 PTPN22 T position 1858 T position 1858 Insulin Class I VNTR - Thyreoglobulin - Exon 33 T/T TSH receptor - rs SNP (Graves )

27 Suscettibilità HLA per T1D con/senza AITD Suscettibilità T1D + AITD (DR3) DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) Suscettibilità per solo T1D (DR4) DRB1*0401-DQA1*0301-DQB1*0302 (DR4-DQ8) (Huang et al, J Clin Endocrinol Met, 1996)

28 Odds ratios for selected genes associated with T1D and related autoimmune diseases

29 Pathogenic model for the autoimmune polyglandular syndrome

30 Pathogenic model for the autoimmune polyglandular syndrome

31 Outline Epidemiology Genetic risk factors Clinical features

32 DEVELOPMENT OF THYROID DISEASE IN PATIENTS POSITIVE AND NEGATIVE FOR TPOA AT DIAGNOSIS OF DIABETES n = 173 Glastras SJ et al. Diabetes Care 28, 2005

33 Cox proportional analysis for predicting development of hypothyroidism from age at onset, sex, and TPO status at diagnosis of diabetes n. = 173 n = 58 Umpierrez, GE et al. Diabetes Care 26, 2003

34 TSH values according to the numbers of elevated thyroid antibody titers (100 IU/ml or 1:100) in 7,097 children and adolescents with type 1 diabetes Kordonouri, O et al. Diabetes Care 25, 2002

35 Prevalenza di disfunzioni tiroidee in 1310 pazienti diabetici Ipo Iper Ipo sub. Iper sub. % totale Tutti i casi (n) Prevalenza (%) T1D Maschi (n=186) Femmine (n=220) T2D Maschi (n=362) Femmine (n=542) Perros et al, Diab Med 12: 622, 1995)

36 Association between thyroid autoantibodies and possible clinical thyroid disease based on analyses of TSH and free T4 at onset of type 1 diabetes Jonsdottir et al. Diabetologia (2013) 56:

37 Risk ratios for thyroid dysfunction in people with Type 1 diabetes and thyroid autoimmunity Shun CB et al. Diab. Med 2013

38 Combined predictive analyses of islet and thyroid autoantibodies for later thyroxine prescription Jonsdottir B et al. JCEM 2016

39 Effetti degli ormoni tiroidei sul metabolismo insulinico Ipertiroidismo: Ipotiroidismo Aumentato assorbimento intest. glucosio Ipersecrezione glucagone Aumento gluconeogenesi e glicogenolisi Insulino-resistenza Alterata secrezione insulinica Ridotto assorbimento intest. glucosio Ridotto rilascio epatico di glucosio Ridotta controregolazione Alterata clereance insulinica + insulinemia Iperglicemia Ipoglicemia

40 HbA1c levels, insulin requirement and hypoglycaemic episodes in DMT1 cases with subclinical hypothyroidism vs. controls HbA1C Insulin requirement Hypoglycaemia Mohn A, Diab Med 2002

41 T1D e ipotiroidismo Interferenza con il controllo metabolico Alterato (ridotto) fabbisogno insulinico Peggioramento dislipidemia Ritardo di crescita Rischio aborto

42 Post-Partum Thyroiditis e DMT1 In donne con DMT1 il rischio di sviluppare PPT è > 3 volte rispetto a donne non diabetiche 25% di donne con DMT1 (Alvarez-Martinez et al, JCEM 1994) soprattutto nel primo trimestre e fino al primo anno dopo il parto Si raccomanda in donne con DMT1 il dosaggio del TSH e degli anticorpi tiroidei alla visita pregravidanza e 3 mesi dopo il parto

43 SOMMARIO Aspetti clinici AITD e T1DM l Prevalenza delle tireopatie nel diabete: ipotiroidismo 5-10% ipotiroidismo sub-clinico 9-13% ipertiroidismo 2% tiroidite post-partum 10-25%

44 ADA 2016 GUIDELINES FOR TYPE 1 DIABETES ASSOCIATED AUTOIMMUNE CONDITIONS Consider testing children with type 1 diabetes for ab-tpo e ab-tg soon after the diagnosis. Measure TSH concentrations soon after the diagnosis of type 1 diabetes and after glucose control has been established Thyroid function tests may be misleading (euthyroid sick syndrome) if performed at time of diagnosis owing to the effect of previous hyperglycemia, ketosis or ketoacidosis, weight loss,etc If normal, consider rechecking every 1 2 years or sooner if the patient develops symptoms suggestive of thyroid dysfunction, thyromegaly, an abnormal growth rate, or an unexplained glycemic variation.

45 LINEE GUIDA SID/AMD 2016 PER PATOLOGIE AUTOIMMUNI ASSOCIATE AL DIABETE DI TIPO 1 Lo screening della patologia tiroidea (e della malattia celiaca) sono indicati alla diagnosi e nel corso del follow-up in considerazione della loro elevata frequenza e del possibile effetto sullo sviluppo psicofisico. Nei diabetici tipo 1 alla diagnosi screening di tiroidite autoimmune: TSH, FT4, anticorpi antitiroide. Se Ab-positivi: controllo TSH e Abs annuale Se TSH normale e Ab-neg.: controllare ogni 2 anni TSH e anticorpi antitiroide. Livello della prova VI, Forza della raccomandazione B

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47 Screening suggestions for autoimmune thyroid disease in children and adolescents with type 1 diabetes 2017 Screening for autoimmune thyroid disease should be done at diabetes diagnosis with TPOAb and TSH TPOAb negative at type 1 diabetes diagnosis with normal TSH: TSH measurement every other year. TPOAb positive with normal TSH and/or GADA positive individuals under 5 years: TSH measurements every year.