tireopatie autoimmuni e diabete di tipo 1: aspetti genetici e ......endocrinologia e metabolismo...
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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.
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