Endocrinologia e Metabolismo Dipartimento di Medicina

Sperimentale Sapienza Università di Roma

Tireopatie autoimmuni e diabete di tipo 1: aspetti

genetici e clinici Marco Giorgio Baroni

Outline

•  Epidemiology •  Genetic risk factors •  Clinical features

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

Classification of autoimmune polyglandular syndromes (APS)

Neufeld M. and Blizzard R. M., 1980 Betterle et al. Clin Exp Immunol 2004;137:225–233

Features of the Autoimmune Polyendocrine Syndromes

Eisenbarth et al NEJM 2004

Features of the Autoimmune Polyendocrine Syndromes

Nat Rev Endocr 2010

Frequenza di autoanticorpi anti-tiroide in popolazioni a diverso rischio

% Familiari di soggetti con tiroiditi autoimmuni 40-60 Pz. con malattie autoimmuni organo-specifiche 20-40

Addison 50-60 T1DM 20-35 LADA 25-40

Pz. con malattie autoimmuni non-organo specif. 0-20 Anomalie cromosomiche (Turner, Down etc..) 16-50 Orticaria cronica 10-15 Depressione endogena 20-30 Abortività singola o multipla 25-36 Soggetti sani Tutti 7

Femmine 12 Maschi 2

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)

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

Distribution of thyroid autoantibodies in the 2,670 patients newly diagnosed with type 1 DM

Jonsdottir et al. Diabetologia (2013) 56:1735–1742

12.3% of the children had thyroid autoantibodies

Prevalenza di AITD in pazienti T1D: 19.5% stratificata per età e sesso: (5-21 aa)

0

5

10

15

20

25

30

35 tuttimaschifemmine

0-5 5-10 10-15 15-20 >20

% AITD

età (Holl et al, Horm Res 52:113, 1999)

p<0.02

p<0.0001

p<0.0001

Prevalenza di AITD in pazienti T1D: 21.6% stratificata per età (0-20 aa)

(Kordonouri et al., Diabetes Care 25, 2002)

* P < 0.0001

** P < 0.001

N = 7,097

Prevalenza di AITD in pazienti T1D (the T1D Exchange Clinic Registry)

Hughes JW et al., December JCEM 2016

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

Association between islet autoantibodies and autoantibodies against either TPO or TG

Jonsdottir et al. Diabetologia (2013) 56:1735–1742

Latent Autoimmune Diabetes in Adults

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 dal la diagnosi , (mostra un’elevata progressione verso l’insulino-dipendenza nei successivi 6 anni).

ü Presenza di altre m. autoimmuni (tiroidite)?

Fourlanos S et al, Diabetologia, 2005; Rolandson O et al, Diabetologia,2010

Prevalenza di AbTPO in pazienti con T2D GADA+

Prevalenza TPOAb

(%)

(Gambelunghe et al., Clin. Endocrinol. 52: 565, 2000)

***

***

low GADA titer (n=97)

high GADA titer (n=94)

p=0.002

Patie

nts (%

) Anti-TPO distribution in autoimmune diabetes

patients with low (<32U) and high (>32U) GADA titre

0 5

10

15 20 25 30

35 40 45

Buzzetti R et al Diabetes Care 2007

Anti-TPO distribution in autoimmune diabetes patients

Schloot NC et al Diabetes Care 2016

32.5% 30% 36.6% 13.5%

TPO antibody titers in patients with autoimmune diabetes with high and low GADA titer and T2DM

T2DM (n=382)

low GADA titer (n=97)

high GADA titer (n=94)

Buzzetti R et al Diabetes Care 2007

units

/ml

0

200

400

600

800

1000 p for trend<0.001

p<0.001

836 ± 1521

653 ± 1388

213 ± 1018

SOMMARIO EPIDEMIOLOGIA AITD e T1DM

•  Adulti

•  con AITD: prevalenza autoimmunità T1D: ≤1%

•  con LADA: prevalenza autoimmunità tiroidea: 20-40 %

•  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

Outline

•  Epidemiology •  Genetic risk factors •  Clinical features

Selected genes associated with T1D and related autoimmune diseases

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 - rs2268458 SNP (Graves’)

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)

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

Pathogenic model for the autoimmune polyglandular syndrome

Pathogenic model for the autoimmune polyglandular syndrome

Outline

•  Epidemiology •  Genetic risk factors •  Clinical features

DEVELOPMENT OF THYROID DISEASE IN PATIENTS POSITIVE AND NEGATIVE FOR TPOA AT

DIAGNOSIS OF DIABETES

Glastras SJ et al. Diabetes Care 28, 2005

n = 173

Cox proportional analysis for predicting development of hypothyroidism from age at onset, sex, and TPO status

at diagnosis of diabetes

n. = 173

Umpierrez, GE et al. Diabetes Care 26, 2003

n = 58

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

Prevalenza di disfunzioni tiroidee in 1310 pazienti diabetici

Ipo Iper Ipo sub. Iper sub. % totale

Tutti i casi (n) 75 26 68 7 Prevalenza (%) 5.7 2.0 5.2 0.5 13.4 T1D Maschi (n=186) 5.9 1.1 5.4 0 13.4 Femmine (n=220) 14.5 6.4 9.5 0.9 31.4 T2D Maschi (n=362) 2.5 0.8 3.3 0.3 6.9 Femmine (n=542) 4.2 1.3 4.6 0.7 10.8

Perros et al, Diab Med 12: 622, 1995)

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) 56:1735–1742

Risk ratios for thyroid dysfunction in people with Type 1 diabetes and thyroid autoimmunity

Shun CB et al. Diab. Med 2013

Combined predictive analyses of islet and thyroid autoantibodies for later thyroxine prescription

Jonsdottir B et al. JCEM 2016

Effetti degli ormoni tiroidei sul metabolismo insulinico

Ipertiroidismo: Ipotiroidismo

insulinemia

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

+

Ipoglicemia Iperglicemia

HbA1c levels, insulin requirement and hypoglycaemic episodes in DMT1 cases with subclinical hypothyroidism vs.

controls HbA1C Insulin requirement

Hypoglycaemia

Mohn A, Diab Med 2002

T1D e ipotiroidismo

  Interferenza con il controllo metabolico

  Alterato (ridotto) fabbisogno insulinico

  Peggioramento dislipidemia

  Ritardo di crescita

  Rischio aborto

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 pre-gravidanza e 3 mesi dopo il parto

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%

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.

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

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.