REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR.

3, AN 2011 233
REFERATE GENERALE
4
Adresa de coresponden:
Conf. Dr. Lenua Popa, Universitatea de Medicin i farmacie Iuliu Haieganu, Str. Pasteur, Nr. 6, Cluj-Napoca
TIROIDITA AUTOIMUN LA COPII I
ADOLESCENI. ASPECTE ETIOPATOGENETICE,
CLINICE I EVOLUTIVE
Conf. Dr. Lenua Popa
Universitatea de Medicin i Farmacie Iuliu Haieganu, Cluj-Napoca
REZUMAT
Tiroidita cronic limfocitar, numit n cele ce urmeaz tiroidit autoimun (TA), este considerat, alturi de
diabetul zaharat tip 1 (DZ1), cea mai frecvent boal autoimun. Din punct de vedere etiopatogenetic, este
o boal complex determinat de efectele combinate ale polimorsmelor genelor HLA clasa II i ale genelor
non-HLA: CTLA-4, PTPN22, AIRE i/sau FoxP3, gene implicate n realizarea sinapselor imunologice,
activarea limfocitului T i imunoreglare. TA poate considerat un model de boala autoimun mediat celular
i umoral. Se descriu astfel cel puin dou forme clinice i patogenetice diferite de boal: tiroidita Hashimoto
(TH) caracterizat prin creterea rapid n volum a glandei tiroide i, la polul opus, tiroidita atroc cu
hipotiroidism spontan primar (aa-numitul mixedem primar), n care volumul glandei tiroide este, de la caz la
caz, doar uor crescut, normal sau redus. Evoluia TA la copii se caracterizeaz prin remisia spontan a
hipotiroidismului atribuit caracterului autolimitat al TH n unele cazuri sau insucien tiroidian ireversibil,
consecin a atroei i brozei glandulare n alte cazuri. TA se poate asocia cu una sau mai multe boli
autoimune endocrine sau neendocrine. nelegerea etiopatogenezei i caracteristicilor clinice ale acestei boli
endocrine este deosebit de important pentru intervenia terapeutic prompt, necesar n scopul prevenirii
efectelor hipotiroidismului autoimun asupra proceselor de cretere i dezvoltare la copii i adolesceni.
Cuvinte cheie: tiroidita autoimun, hipotiroidism, boli asociate, copii i adolesceni
Bolile tiroidiene autoimune (BTA) reprezentate
de boala Graves i tiroidita cronic limfocitar
(TCL) sunt boli determinate de rspunsul imun
anormal orientat mpotriva antigenelor derivate din
structurile glandulare proprii, generat la rndul su
de pierderea toleranei imune fa de aceste structuri.
(1,2,3,4,5,6,7,8) Boala Graves (BG), principala
cauz de tirotoxicoz la copii, caracterizat prin
gu i hipertiroidism, reprezint 10-15% din tota-
litatea bolilor glandei tiroidei sub vrsta de 18 ani.
Tiroidita autoimun (TA), termen care n cele ce urmeaz
va desemna diferitele forme patogenetice de TCL, este
considerat, alturi de diabetul zaharat tip 1 (DZ1),
cea mai frecvent boal endocrin autoimun i
principala cauz de hipotiroidism dobndit i tiro-
megalie la copii i adolesceni. (1, 3, 4, 5, 6, 7, 8, 9)
Dei descrise ca i componente diametral opuse ale
aceluiai spectru, BG i TA au n comun o serie de
elemente patogenetice reprezentate de reactivitatea
sistemului imun la autoantigenele tiroidiene, inl-
traia limfocitar a glandei tiroide i prezena n ser
nc din stadiile timpurii ale procesului patogenetic
autoimun a anticorpilor antitiroidieni de tip anti
tiroglobulin (Tg) i anti tiroperoxidaz (TPO). (2,
4, 5, 7, 8, 10)
TA este o boal multifactorial cu etiopatogenez
complex, n care factorii genetici reprezentai de
genele de susceptibilitate i factorii de mediu de-
clan atori concureaz la iniierea rspunsului auto-
imun, la susinerea proceselor patogenetice ulterioare
i perpetuarea inamaiei imune. (2, 6, 7, 8, 9, 10,
11, 12) n proporie de 70%, predispoziia pentru
BTA este determinat genetic prin contribuia mai
multor gene cu penetran redus i efecte de cele
mai multe ori minore, astfel c nu toi indivizii care
le motenesc vor dezvolta boala. Combinate, efectele
Abrevieri: AIRE: the autoimmune regulatory; CTLA-4: the cytotoxic T-lymphocyte antigen-4; FosP3 - forkhead box P 3;
PTPN22: protein tyrosine phophatase non-receptor 22
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 234
acestor gene cresc ns riscul de boal autoimun.
(11, 12, 13)
Rolul factorilor genetici n determinarea predis-
poziiei pentru TA a fost demonstrat de studiile
experimentale care au utilizat modele animale de
BTA, rata mare de concordan pentru BTA nre-
gistrat la gemenii monozogoi (20%-40%) com-
parativ cu aceea nregistrat la gemenii dizigoi
(2%), dar i de studiile epidemiologice familiale
care au evideniat existena unui risc crescut de
BTA la rudele de gradul nti ale subiecilor cu TA
(1, 2, 6, 7, 10, 14) Analiza genomului uman, studiul
polimorsmelor unui singur nucleotid, studiile de
asociere la nivel populaional i familial, ca i stu-
diile funcionale au adus o contribuie important
dar insucient n precizarea bazelor genetice ale
TA. Au fost nregistrate progrese semnicative n
identicarea genelor de susceptibilitate, dar nu i a
genelor specice pentru BTA. Genele candidat,
termen care, se aplic genelor cu secvene i poziie
cunoscut care, n virtutea rolului lor ziologic, pot
s e implicate n patogeneza unei boli, sunt aso-
ciate cu o frecven variabil i cu alte boli auto-
imune, ind responsabile de predispoziia gene-
ralizat la autoimunitate. (1, 2, 4, 10, 11, 13) Genele
imunoreglatoare importante pentru iniierea rspun-
sului autoimun i etiopatogeneza TA se ncadreaz
n dou categorii, i anume: 1) genele complexului
major de histocompatibilitate numit la om human
leucocyte antigen (HLA), care codic moleculele
de suprafa ale celulelor prezentatoare de antigen
(CPA) cu rol cheie n selecia limfocitelor T n
timus i prezentarea antigenelor n periferie i 2)
genele non-HLA implicate n realizarea sinapselor
imunologice, activarea limfocitului T i imuno-
reglare reprezentate de gena antigenului-4 al limfo-
citului T citotoxic (CTLA4), gena proteinei non-
receptor tirozin -fosfataz-22 (PTPN22), gena
auto reglatorului imun AIRE, gena forkhead box P3
(FoxP3) (Tabelul 1). (1, 2, 4, 5, 10, 14, 15)
BTA a fost asociat cu polimorsme ale lo-
cusurilor genelor care codic n special clasa a
II-a de molecule HLA. Mutaiile genelor HLA mo-
dic anitatea moleculelor exprimate pe su prafaa
CPA i a celulelor foliculare tiroidiene (CFT) pentru
structurile proteice implicate n pro cesele auto-
imune. Astfel, haplotipul HLA-DR3 de ter min
cre terea de 2-6 ori a riscului pentru apariia TA. n
acele cazuri n care TA coexist cu alte boli auto-
imune, genele de susceptibilitate comune au fost
identicate n regiunile HLA-DR i HLA-DQ. (1,
3, 4, 8, 10, 11, 12) Cea mai important grupare de
gene non-HLA pentru predispoziia la boli auto-
imune este alctuit din genele care codic pro-
teine reglatoare ale activitii limfocitului T capabile
s modice rspunsul imun i, implicit, reactivitatea
autoimun. (10, 11, 12, 13, 14, 16) Gena CTLA-4
ex primat pe suprafaa limfocitelelor T(CD8+) i
Th(CD4+) codic o molecul imunoreceptoare cu
efect costimulator n cadrul interaciunii dintre CPA
i limfocit, care, prin intermediul limfociteleor re-
glatoare TCD4+ controleaz i limiteaz activarea
i proliferarea limfocitelor T autoreactive din pe-
riferie, contribuind astfel la realizarea toleranei
imune. Mai multe mutaii ale genei CTLA-4 au fost
asociate cu autoimunitatea tiroidian, termen care
include BTA i starea de purttor de anticorpi anti-
tiroidieni. (4, 7, 16) S-a demonstrat c polimorsmele
genei CTLA-4 determin 25% din susceptibilitatea
pentru BG, TA, DZ1 asociat cu TA, boala Addison
TABELUL 1. Gene implicate n rspunsul imun i efectele mutaiilor genice n patogeneza bolilor tiroidiene autoimune
Gena
Locusul
genei
Proteina codicat Efectele polimorsmului
Boala
autoimun
HLA-DR, DQ
(clasa II)
6p21.3 Molecule prezentatoare de
antigen
Prezentarea antigenului ataat
limfocitului TCD4
TH, BG, DZ1
CTLA-4
(cytotoxic
T-lymphocyte
antigen-4)
2q33 Molecul imunoreceptoare,
costimulator
Pierderea toleranei imune
Proliferare necontrolat a limfocitelor T
Predispoziie la boli autoimune
TH, BG, DZ1
PTPN22
(protein tirozin
fosfataza 22)
1p13 Tirozin-fosfataza limfocitar Transmiterea semnalului intracelular
limfocitar
TH, BG, DZ1
Tiroglobulin 8q24 Proteina constitutiv a
coloidului tiroidian
Autoimunitate tiroidian TH, BG
AIRE 21q22.3 Factor de transcripie exprimat
n timus
Transcripia genelor antigenelor proprii
Deleia limfocitelor T autoreactive
SPA1
FOXP3 Xp11.23 Factor de transcripie
exprimat n limfocitele T
reglatoare CD4+
Decitul limfocitelor reglatoare
Clone limfocitare autoagresive
IPEX
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 235
i artrita reumatoid, independent de apartenena
etnic a purttorilor. (3, 11, 13, 16) Polimorsmul
ge netic al PTNP22 sau tirozin-fosfataza limfo-
citar, un modulator al activitii kinazelor implicate
n evenimentele intracelulare declanate prin acti-
varea receptorului limfocitului T, a fost, de asemeni,
asociat cu DZ1, BG, LES, artrita reumatoid, boala
celiac, vitiligo i alte boli autoimune. (3,7,12)
Polimorsmele genelor care codic structuri
tiroidiene proprii, i anume gena tiroglobulinei (Tg)
i gena receptorului tirotropinic (rTSH), considerate
gene candidat pentru autoimunitatea tiroidian,
con tribuie la iniierea rspunsului autoimun. (1, 2,
4, 5, 6, 11, 15) Specicitatea procesului autoimun
este determinat de efectele combinate ale genelor
protective, genelor specic tisulare i efectele adi-
ionale ale diverilor factori de mediu. Interaciunile
genice, pe de o parte, i interaciunile acestora cu
factorii epigenetici i de mediu, pe de alt parte,
inueneaz fenotipul i severitatea bolii autoimune.
(6, 11, 13)
Factorii de mediu dein un rol important n
apariia TA la un individ predispus ind implicai n
activarea sistemului imun, iniierea rspunsului
autoimun i transformarea n acest fel a riscului n
boal. (11, 12, 13, 18) O parte dintre aceti factori
opereaz ntr-o manier specic tiroidian. n
aceast categorie se includ iodurile alimentare con-
inute n sarea iodat, laptele de vac i derivatele
de lapte, ou, fructe de mare i alge, amelioratorii
iodai utilizai n patiserie, ciocolat i unele multi-
vitamine. (13, 17, 18) Excesul de iod, component
important al hormonogenezei tiroidiene intervine
n patogeneza TA pe mai multe ci: prin agresiunea
tisular mediat de radicalii liberi de O
2
, prin
inducerea autoimunitii tiroidiene i prin stimularea
sintezei moleculelor de adeziune intercelular 1
(ICAM-1). (4,7) n stadiile iniiale ale procesului
patologic, iodul n exces este oxidat rapid de ctre
TPO, enzima implicat direct n iodinarea tirozinei
i cuplarea oxidativ a idotirozinelor n iodotironine.
Procesul genereaz mediatori autoreactivi de tipul
acidului lipoidic i radicalilor liberi de O
2
. Prin
oxidarea lipidelor i proteinelor din membrana
celular a tirocitelor, aceste specii oxidative produc
leziuni care induc necroza CFT. (4, 18) n acelai
timp, iodinarea excesiv a Tg accentueaz imuno-
genitatea acesteia prin generarea unor noi epitopi
sau expunerea celor mascai n condiii de decit de
iod, facilitnd astfel preluarea antigenului i pro-
cesarea lui de ctre CPA. (1, 3, 4, 12, 13, 18) Iodul
accentueaz expresia glicoproteinei ICAM-1 n
tirocite. Aceasta contribuie, alturi de moleculele
HLA, la activarea limfocitului T citotoxic. (7) Prin
mecanismele imunologice i biochimice pe care le
amorseaz, excesul de iod contribuie la exacerbarea
inamaiei imune. Se explic astfel nivelul redus al
autoimunitii tiroidiene n condiiile decitului de
iod, care pare a avea efecte protective ca i preva-
lena mai mare a TA n rile industrializate n care
con sumul de iod este crescut. Majoritatea factorilor
de mediu reprezentai de decitul de vitamina D,
de citul de seleniu, expunerea terapeutic, explo-
ratorie sau accidental la radiaii ionizante, diverse
tipuri de medicamente (beta-blocante, litiu, amio-
darone, fenilbutazon, glucocorticoizi, furosemid
carbamazepin, ageni antiretrovirali, inclusiv anti-
corpii monoclonali i interferonul-INF), infeciile
virale i bacteriene sau conform teoriei igienei,
absena acestora acioneaz mai puin specic, ind
implicai n etiopatogeneza mai multor boli auto-
imune. (13, 14, 17) Decitul de vitamina D, al crui
efecte imunomodulatorii se exercit n prin cipal la
nivelul CPA, a fost asociat cu con centraiile crescute
ale anticorpilor TPO, n timp ce unii factori nutri-
ionali utilizai n perioada de sugar favorizeaz
apa riia BTA. Astfel, durata mare de expunere la
gluten i vrsta mic la debutul bolii celiace cresc
riscul de BTA. (13) Infeciile, prin interaciunile
dintre microorganism i gazd, pot s iniieze, dar
i s suprime n faz incipient un proces autoimun.
Agenii infecioi induc autoimunitatea prin mi-
metism structural, activarea policlonal a limfo-
citului T i/ sau accentuarea expresiei moleculelor
HLA pe suprafaa celulelor epiteliale tiroidiene.
Educarea sistemului imun presupune expunerea
frecvent la factori infecioi diferii care, prin sti-
mularea elementelor reglatoare i instruirea siste-
mului imun, asigur un bun control al rspunsului
autoimun. Conform ipotezei igienei, numrul n
continu cretere al bolilor alergice i autoimune
nregistrat n prezent n rile industrializate se
explic prin mbuntirea standardelor de via,
scderea expunerii la factori infecioi i scderea
incidenei bolilor infecioase n perioada de sugar i
copil mic. Absena acestei experiene determin
acti varea aberant a celulelor autoimune, distor-
sionarea rspunsului imun i predominena n ab-
sena stimulului infecios a limfocitelor Th2 im-
plicate n sinteza de interleukine IL-4 i IL-5,
sti mularea limfocitelor B, producia de anticorpi i
reaciile mediate de acetia. (6, 15, 17)
TA poate considerat un model de boal auto-
imun mediat celular i umoral. (2, 8) Sediul auto-
rectivitii este glanda tiroid. Structura antigenic
primar, inta reaciilor autoimune, ar putea un
virus cu structur parial identic cu a proteinelor
tiroidiene sau o secven polipeptidic proprie
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 236
prezentat ca antigen de nsi CFT. Principalele
antigene int ale anticorpilor antitiroidieni sunt
proteina constitutiv a coloidului, Tg, enzima im-
plicat n biosinteza hormonilor tiroidieni, TPO,
cotransportorul Na+/I- (NIS) i receptorul tiro-
tropinic (rTSH). (4, 10, 14, 19) La persoanele pre-
dispuse, activarea limfocitului T helper (Th) CD4
de ctre antigenul specic tiroidian ataat la mo-
lecula HLA clasa II de pe suprafaa CPA, declanaz
rspunsul autoimun i recrutarea n glanda tiroid a
limfocitelor TCD8+ citotoxice i a limfocitelor B
productoare de anticorpi. (1, 3, 4, 6, 8, 15, 16) Dis-
funcia nnscut sau dobndit a limfocitelor
TCD4+ i dezechilibrul dintre numrul limfocitelor
Th1 i Th2 contribuie la producerea BAT. Aciunile
Th1 i Th2 sunt reciproc supresive. Astfel, citokinele
pro-inamatoare de tipul IL-1 i IFN eliberate de
limfociteleTh1 sunt implicate n reglarea rspun-
sului imun mediat celular, n timp ce citokinele
secretate de limfocitele Th2 controleaz producia
de anti corpi, remisia bolii i supresia rspunsului
imun. (18) Mai multe mecanisme patogentice deter-
min, izolat sau n asociere, distrucia glandular i
apariia hipotiroidismului autoimun. Inltraia lim-
focitar este responsabil de mrirea n volum a
glandei tiroide i hiperplazia compensatorie a CFT,
modi cri prezente i n BG. (1, 3, 7, 8). Evenimentul
iniial obligatoriu pentru apariia anticorpilor spe-
cici antitiroidieni i derularea proceselor patoge-
netice ulterioare este reprezentat de lezarea CFT de
ctre limfocitele TCD8+ inltrate parafolicular prin
intermediul citokinelor proprii. Efectul citotoxic al
limfocitelor i/sau anticorpilor asupra CFT deter-
min distrugerea foliculilor tiroidieni i apariia hi-
potiroidismului. n plus, apoptoza celulelor fo li-
culare indus de citokine, proces caracteristic TA,
care poate precede distrugerea CFT mediat de
limfocitele TCD8+, contribuie la atroa glandei
tiroide i la instalarea hipotiroidismului ireversibil.
(1, 3, 4, 5, 8, 15) Efectorii celulari nali al rspunsu-
lui imun sunt celulele natural killer (NK)CD56+
care interacioneaz cu interleukinele IL-2 sau IL-
12 i determin astfel sinteza i eliberarea de in-
terferon (IFN-). (1) Sinteza intratiroidian de
anticorpi, citokine i chemokine creeaz un mediu
proinamator care favorizeaz exapansiunea depo-
zi tului intra tiro idian de limfocite, exacerbeaz in-
amaia imun, stimuleaz apoptoza CFT i de-
termin dis tru gerea progresiv a foliculilor
ti ro i dieni, dis tor sionarea arhitecturii glandulare i
incapacitatea tem porar sau denitiv de sintez a
hormonilor tiroidieni. (2, 3, 5, 8, 10, 18) Citokinele
proinamatorii de tipul IFN- i TNF- produse de
Th1 acioneaz asupra tirocitelor prin intermediul
receptorilor citokinici de pe suprafaa acestora i
afecteaz ne gativ expresia proteinelor specic
tirocitare: Tg, TPO, NIS i a enzimelor DUOX
generatoare de H
2
O
2
. Reducerea n aceste condiii a
sintezei hor monilor tiroidieni contribuie la apariia
hipotiro i dismului autoimun n absena distruciei
foliculilor tiroidieni i explic astfel variabilitatea
evolutiv a TA observat n practica clinic. (18)
Procesele imunopatogenetice mediate de anticorpii
antitiro idieni antiTPO, antiTg i anti-rTSH produi
n principal de limfocitele inltrate n glanda tiroid
contribuie la variabilitatea fenotipic a BTA i la
existena diferitelor forme clinice i patogenetice
de TA. (5, 14, 19) Anticorpii antiTPO inhib activi-
tatea enzimei, xeaz complementul i stimuleaz
activitatea celulelor NK proces prin care induc cito-
toxicitatea la nivelul CFT. (2, 7, 14, 15, 19)
Concentraiile serice crescute ale acestor anti-
corpi se coreleaz cu producia crescut de citokine
proinamatorii IFN- i TNF- i cu severitatea
leziunilor tiroidiene. Reprezint primul semn detec-
tabil al strii de autoimunitate tiroidian i sunt
nregistrate la >90% dintre copiii i adolescenii cu
TH i la ~75% dintre cei cu BG, la valori mai mici
comparativ cu adulii. (4, 7) Anticorpii antiTg pre-
zeni la ~60% dintre cazurile cu TA au un rol mai
puin bine precizat i semnicaie funcional mo-
dest. (3, 8, 14, 19) Datorit anitii pentru sub-
unitatea intracelular, anticorpii anti rTSH acio-
neaz ca blocani ai glicoproteinei receptor. (5, 14)
Au fost identicai la 10-20% dintre copiii i ado-
lescenii cu TA i forme severe de hipotiroidism, n
unele cazuri sub vrsta de 4 ani, cu prevalen mai
mare la cei cu sindrom Down. (2, 3, 19) Auto anti-
corpii orientai mpotriva altor produi tiroidieni ca
T4 i T3 au fost identicai la 15-35% dintre pa-
cienii cu TA. (2, 14) Denirea exact a bolii i di-
ferenierea de starea de purttor de autoanticorpi
este important n diagnosticul bolii autoimune.
Anticorpii antitiroidieni reprezint elemente esen-
iale de diagnostic pentru TA, dar i pentru starea
de autoimunitate tiroidian asociat cu riscul cres-
cut de boal autoimun. Creterea concentraiei lor
serice precede adesea manifestrile clinice ale bolii
i se regsete la rudele neafectate ale pacienilor
cu BTA i cu frecven difert la subiecii cu gu
simpl (20%), boli tiroidiene nonautoimune sau
carcinom folicular papilar (75%). (6, 15, 19) Con-
cen traiile serice normale ale autoanticorpilor tiroi-
dieni exclud BTA.
Variabilitatea fenotipic a TA determin existena
mai multor formele clinice de TA. n funcie de
volumul glandei tiroide, se difereniaz dou forme
de tiroidit, i anume tiroidita Hashimoto (TH)
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 237
caracterizat prin creterea rapid, difuz n volum
a glandei tiroide, i tiroidita atroc, asociat cu
hipotiroidism spontan primar, aa-numitul mixedem
primar sau boala lui Ord, n care volumul glandei
tiroide este, de la caz la caz, uor crescut, normal
sau redus. (Tabelul 2) Concentraiile serice ale ant-
i corpilor antitiroidieni sunt crescute n ambele
tipuri de TA, mai exprimat n formele atroce.
Tiroidita Hashimoto reprezint cea mai frecvent
boal inamatorie autoimun la copii i cea mai
frecvent form de TA juvenil. Este foarte rar n
primii 3 ani de via, obinuit dup vrsta de 6 ani,
cu un vrf de inciden la adolescen, prevalen
estimat de 1,3%-9,6% la vrsta de colar i pre-
ponderen feminin cu raport F/B de ~4,2. (4,7, 9,
15, 23) La caucazieni este asociat cu genotipul
HLA-DR4 i HLA-DR5. (4, 7, 12) Metaplazia oxi-
lic a CFT i transformarea acestora n celule cu
citoplasm granular eozinilic numite celule
Hrthle sau Askanazy, reprezint trstura histo-
logic a TH. (6, 7) n formele severe exist o pre-
dominan a Th1 i raport Th1/Th2 crescut. Cei mai
muli copii sunt eutiroidieni i asimptomatici. Sen-
zaia de presiune precervical este perceput in-
constant n unele cazuri. Mrirea n volum a glandei
tiroide (tiromegalia sau gua) este cel mai evident
semn clinic a acestei forme de tiroidit. (23)
Disfuncia tiroidian este foarte variabil repre-
zentat. Hipotiroidismul, relevant pentru TH, este
prezent ca manifestare de debut n ~20% dintre
cazuri. (7, 9) Hashitoxicoza, termen care denete
starea de hipertiroidism din stadiile timpurii ale
bolii, poate afecta, pe durat variabil de 1-6 luni,
10% dintre copiii i adolescenii cu TH. (7) Dife-
renierea pe criterii clinice, ultrasonograce i imu-
nologice a TH de BG n aceste cazuri este iniial
dicil. n hashitoxicoz, supresia TSH este mai
puin sever i concentraiile T4 mai puin accentuate
comparativ cu cele din BG. Diagnosticul diferenial
cu dishormonogeneza tiroidian, chistele de canal
tireoglos sau alte tipuri etiologice de tiroidit da-
torate inamaiei acute (supurative) sau subacute
(granulomatoase) este necesar n unele cazuri. O
serie de alte forme intermediare de tiroidit mai
puin bine denite, n care unica manifestare evi-
dent este consistena uor crescut a glandei tiroide,
se interpun ntre TH i mixedemul primar sau boala
lui Ord. Diferenierea este posibil pe baza exa-
menului cito-histologic al aspiratului glandular,
obinut prin puncie biopsie tiroidian ghidat eco-
grac, care permite stabilirea formei de TA i,
totodat, diferenirea de gua simpl, coloidal,
prin caren de iod. Tiroidita IgG4+ reprezint o
form particular de TA, caracterizat prin afectarea
pre pon derent a sexului masculin, concentraii
serice mari ale anticorpilor antiTPO i antiTg, inl-
traii intratiroidiene dense, focale sau difuze, de
IgG4+ derivai din plasm, raport IgG4+/ IgG totale
>30%, broz i degenerare folicular sever i
evoluie rapid progresiv a disfunciei tiroidiene
spre hipotiroidism ireversibil. (7)
Evoluia clinic a TA este foarte variabil, auto-
limitat n unele cazuri sau progresiv spre insu-
cien tiroidian ireversibil, ca urmare a atroei
i brozei glandulare n alte cazuri. Disfuncia tiro-
idian din formele severe de tiroidit poate interfera
procesul normal de cretere i dezvoltare al copilului
i adolescentului i favorizeaz adiio narea unor
factori de risc cardiovascular ca disli pidemia se-
cundar. La copiii eutiroidieni cu con centraii mari
ale anticorpilor antiTPO i antiTg, rata anual de
instalare a hipotiroidismului este de 2-3%. (9, 23,
TABELUL 2. Caracteristicile principalelor forme clinice de tiroidit autoimun
Forma clinic
Caracteristici
Tiroidita Hashimoto Tiroidita atroc
(boala Ord)
Prevalena 90% 10%
Haplotip HLA-DR3, HLA-DR4, HLADR5 HLA-DR3/B8
Caracteristici histologice Inltraie limfocitar difuz
Hiperplazia CFT*
Metaplazie oxilic a CFT (celule Hrthle)
Initraie limfocitar focal
Fibroz
Atroe glandular
Glanda tiroid
Volum Tiromegalie difuz (gu) normal
Consisten
Aspect ecograc Hipoecogenitate difuz Inomogen, trabecular
Autoanticorpi antitiroidieni TPO i/sau Tg rTSH-B, TPO/Tg, IG4 +
Statusul funcional tiroidian Hipotiroidism/hashitoxicoz/eutiroidism Hipotiroidism
Evoluie Variabil Cronic
*CFT celule foliculare tiroidiene; crescut (); redus ()
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 238
24) Remisia bolii, ca i regresia sau dispariia
tiromegaliei, se pot produce spontan n adolescen
sau n aproximativ 25% dintre cazuri, dup mai
muli ani de tratament cu levo-thyroxin. (6, 9, 15,
23, 24) Concentraiile serice anormale ale auto-
anticorpilor oscilez i persist n timp la toi pa-
cienii.
Caracteristicile BTA n ansamblu sunt repre-
zentate de: 1) agregarea familial; 2) variabilitatea
fenotipic intrafamilial; 3) prezena anticorpilor
antitiroidieni la rudele asimptomatice ale persoa-
nelor afectate ntr-o proporie mai mare dect n
rndul populaiei generale i 4) asocierea frecvent
cu cu alte boli autoimune.
Agregarea familial este obinuit, explicabil
prin fondul genetic comun i/sau expunerea la fac-
tori de mediu comuni. Prevalena TA la rudele de
gradul nti ale persoanelor afectate este de peste
25%. Bolile autoimune prezint tendina de agluti-
nare la acelai individ i n cadrul aceleai familii.
(8, 11, 12, 13, 15) Mecanismul patogenetic al acestor
interconexiuni este nc neprecizat. (13)
Asocierea TA cu una sau mai multe boli auto-
imune endocrine sau sistemice caracterizeaz aa-
numitele sindroame poliendocrine autoimune
(SPA). Termenul poliendocrin nu este n esen
foarte potrivit, ntruct nu toi subiecii prezint
afeciuni endocrine multiple i, n multe cazuri,
asocierea TA se face cu boli autoimune neendo-
crine.
Se descriu mai multe tipuri de SPA, care difer
sub raportul etiopatogenezei, prevalenei, momentul
debutului, modului de transmitere, natura i com-
binaia dintre bolile asociate (Tabelul 3). Prevalena
TA n componena acestor sindroame este diferit,
mai mare (75%) n SPA tip 2 (SPA2), n care este
componenta major, denitorie pentru existena
sindromului i semnicativ mai redus n SPA tip 1
(SPA1) n care apare cu frecven de doar 10%, ca
una dintre componentele minore. (15) TA apare ca
i component n dou tipuri de SPA cu determinism
monogenic i debut n copilrie, i anume SPA1 i
sindromul X-lincat al disfunciei imune severe,
asociat cu poliendocrinopatie i enteropatie (IPEX).
SPA1 este consecina mutaiilor genei auto-
reglatorului imun (AIRE), factor de transcripie nu-
clear care controleaz n cursul ontogenezei trans-
cripia autoantigenelor specice de organ la nivelul
timusului. Se transmite autozomal recesiv. Mutaiile
genei AIRE determin selecia defectuoas a timo-
citelor autoreactive, persistena limfocitelor T auto-
reactive, pierderea toleranei imune centrale i
pre dispoziia la autoimunitate multiorganic. Tr -
s turile fenotipice majore ale SPA 1 sunt candidoza
cronic cutaneo-mucoas (prima mani festare a sin-
dromului prezent n 60% dintre cazuri n primii 2
ani de via), hipoparatiroidismul auto imun i in-
suciena adrenal prezent la vrsta de 15 ani la
aproape toi copiii afectai. Pentru denirea SPA1
sunt necesare dou dintre componentele triadei cla-
sice menionate, care debuteaz de cele mai multe
ori la vrsta de sugar. Asocierea com ponentelor
minore este variabil i se produce pe parcursul ur-
mtoarelor decenii de via. Identicarea recent a
autoantigenului paratiroidian NACHT leucine-rich-
repeat protein 5 (NALP5) explic att hipo para-
tiroidismul autoimun, ct i ooforita responsabil
TABELUL 3. Caracteristicile sindroamelor poliglandulare autoimune
Tipul SPA SPA tip 1 SPA tip 2 IPEX
Prevalen redus 1/29.000 Foarte redus
Etiologie monogenic multifactorial Monogenic
Mod de transmitere AR AD X-lincat
Raportul sexelor 1:1 3:1 0:1
Vrsta la debut Sugar/copil mic Copilrie/adult tnr Nou-nscut
Componente majore Candidoza cutaneomucoas
Hipoparatiroidism
Boala Addison
DZ tip 1/Boala Addison DZ tip 1 neonatal
TA
Enteropatie sever
Decit imun
Componente minore Distroe ectodermal
DZ tip 1
Insucien ovarian (60%)
Vitiligo
Alopecie areata
BTA (10%)
Hepatit autoimun
Asplenie
Vitiligo
Alopecie areata
Anemie pernicioas
* > in Finlanda, Iran, Sardinia; AR autozomal recesiv; AD autozomal dominant
DZ1 - Diabet zaharat tip 1.
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 239
de insuciena ovarian pre zent la 60% dintre
fetie dup vrsta de 12 ani. (10, 15, 19, 20, 21)
Sindromul X-lincat al disfunciei imune severe
asociat cu poliendocrinopatie autoimun i entero-
patie (IPEX) se manifest precoce postnatal la
bieii purttori ai mutaiilor genei FOXP3. Gena
FOX3 codic un factor de transcripie de tip
forkhead-winged-helix numit Scurn, reglator al
diferenierii limfocitelor T. Decitul FOXP3 are ca
i consecin activarea improprie i proliferarea
clonelor limfocitare autoagresive i autoimunitatea
multiorganic. Enteropatia autoimun este res-
ponsabil de falimentul creterii la sugarii afectai.
Hipotiroidismul autoimun i DZ1 cu debut neonatal
sunt prezente la 50% i, respectiv, 90% dintre su-
gari. n formele severe, evoluia este letal i de-
cesul survine, n absena transplantului medular,
anterior vrstei de doi ani. (10, 15, 21, 22) SPA2
este deter minat poligenic i se caracterizeaz prin
varia bi litatea i diversitatea componenetelor care l
alc tuiesc. (15, 22) Asocierea cea mai frecvent
ntre bolile endocrine autoimune, considerat de-
ni torie pentru existena SPA2 este de departe
aceea dintre DZ1 i BTA (Tabelul 3). DZ1 care, cu
mici excepii, este determinat de distrucia mediat
imun a ce lulelor pancreatice insulare, este asociat
n pro porii egale cu TH i BG, spre deosebire de
boala Addison, o alt component major a SPA 2,
care, n mod particular i, de asemeni, denitoriu,
se asociaz exclusiv cu TH. (21) Studii transversale
reprezenta tive au identicat prezena anticorpilor
anti TPO la 10%-20% dintre copiii i adolescenii
cu DZ1, ju mtate dintre acetia ntrunind criteriile
pentru coexistena BTA. Autoimunitatea reciproc
a fost demonstrat prin identicarea anticorpilor
anti celule insulare la 2,3% dintre copiii cu BTA.
(13, 25, 26) Prevalena autoimunitii tiroidiene la
ca zurile cu DZ1 crete odat cu vrsta, n principal
la sexul feminin. Ali factori precum pubertatea,
vrsta la debutul pubertii sau apartenena etnic,
inu eneaz asocierea DZ1 cu BTA. Comparativ cu
populaia general, subiecii cu DZ1 prezint un risc
de 5 ori mai mare pentru a dezvolta BTA. Substratul
asocierii nu este bine precizat. Ambele sunt boli
autoimune mediate de limfocitul T. Genele de sus-
ceptibilitate comune sunt gene imunoreglatoare.
Rolul major l dein genele HLA clasa II. Haplotipul
HLA-DR3 confer susceptibilitate la DZ1 i la
coexistena la nivel individual i intrafamilial a
DZ1 cu BTA. Haplotipul DR3-DQ2 i DR4-DQ8
predispune la coexistena DZ1 i BTA i se asociaz
cu cel mai mare nivel de risc pentru DZ1 n perioada
adolescenei (5% la vrsta de 15 ani). (25, 26) Poli-
morsmul genelor CTLA-4 i PTPN22 contribuie
la realizarea predispoziiei pentru ambele boli auto-
imune. (10, 13, 25, 26) Asocierile TA cu bolile cro-
mozomiale numerice (sindromul Down, Turner,
Klinefelter) sau structurale (sindroame de deleie),
rubeola congenital sau procesele proliferative in-
tra tiroidiene sunt bine cunoscute.
Sindromul Down, determinat de trisomia 21, se
caracterizeaz prin prevalena crescut a bolilor en-
docrine i neendocrine autoimune ca BTA, DZ1,
hi poparatiroidism, boala celiac, hepatita cronic
autoimun, vitiligo i alopecia. Numrul redus de
limfocite T, limfopenia B i dezechilibrul ntre sub-
populaiile de limfocite T responsabile de frecvena
crescut a infeciilor respiratorii i a bolilor auto-
imune la copiii cu sindrom Down se explic prin
tul burrile de dezvoltare a timusului. Suprapunerea
semnelor de hipotiroidism prezent la ~15% dintre
cazuri peste trsturile fenotipice caracteristice sin-
dromului face dicil diagnosticul clinic i motiveaz
screeningul anual pentru hipotiroidism ncepnd cu
al doilea an de via la aceast categorie de copii.
(27, 28) TA, n general asimptomatic, este prezent
la 24% dintre cazurile cu sindrom Turner, uneori
anterior vrstei de 4 ani. Prevalena TA este par-
ticular de mare (~40%) la fetiele cu izocromozom
X i cariotip 46,Xi(Xq) realizat prin deleia braului
scurt i duplicaia braului lung al cromozomului X,
aspect care sugereaz importana genelor de pe
braul lung q al cromozomului X pentru patogeneza
TA. Ca i n cazul altor asocieri, frecvena TA i a
autoimunitii tiroidiene la pacientele cu sindrom
Turner crete cu vrsta, se dubleaz n a doua de-
cad de via i realizeaz un vrf de inciden la
vrsta de 15 ani. (23, 29) Bieii cu sindrom
Klinefelter prezint, de asemeni, un risc crescut
pentru boal tiroidian autoimun.
Asocierile menionate argumenteaz pentru
exis tena unui fond genetic i a unor mecanisme
patogenetice comune i motiveaz screeningul TA
la categoriile cu risc crescut. Cunoaterea mecanis-
melor etiopatogenetice i a particularitilor clinice
i evolutive ale acestui tip de boal endocrin pre-
zint importan pentru elaborarea i aplicarea
corect a programelor de screening i a strategiilor
terapeutice. Identicarea hipotiroidismului auto-
imun i combaterea efectelor deletorii pe care acesta
le are asupra proceselor de cretere i dezvoltare la
vrsta copilriei i adolescenei constituie una
dintre preocuparile curente ale endocrinologiei pe-
diatrice.
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 240
The autoimmune thyroid diseases (AITD), re-
pre sented by Graves disease (GD) and chronic
lymphocytic thyroiditis (CLT), are disorders caused
by the abnormal immune response directed against
self-glandular antigens that is linked to the break-
down of immune tolerance. (1,2,3,4,5, 6,7,8)
Graves disease (GD) is the main cause of thyro-
toxicosis in children. It is characterized by goiter
and hyperthyroidism and represents 10-15% of all
thyroid diseases under 18 years of age. Autoimmune
thyroiditis (AIT) term used to describe different
pathogenetic forms of CLT in this paper is recog-
nized besides type 1 diabetes mellitus (DM1) as the
most frequent autoimmune inammatory disease
and the main cause of the acquired hypthyroidism
and thyromegaly in childhood and adolescence.
(1,3,4,5,6,7,8,9)
Although described as opposite components of
the same spectrum, GD and AIT share some
commune ethiopathogenetic characteristics as reac-
tivity of immune system to thyroid antigens,
lymphocytic inltration of thyroid gland, and the
presence in the early stage of the pathogenetic
processes of circulating antibodies of thyroglobulin
(Tg) and thyroid peroxidase (TPO). (2,4,5,7,8,10)
As other autoimmune diseases as well, AIT is a
complex, multifactorial disease which is caused by
an interaction between susceptibility genes and
environmental triggers that act in concert to initiate
the immune respons to thyroid antigens and to
support pathogenetic processes and further immune
inammatory state. (2,6,7,8,9,10,11,12) About 70%
of AITD susceptibility has a genetic determination
by contribution of a number of genes characterized
by low penetrance and minor effects so that not all
carriers will develop the disease. Combined effects
of these genes will increase the risk for autoimmune
disease. (11,12,13)
The paradigm of genetic susceptibility playing a
central role in the development of autoimmune
thyroiditis is supported by animal models of AITD
in experimental studies, the higher concordance
rate in monozygotic twins (20%-40%) compared
with dizygotic twins (2%), and increased risk of
AITD in rst-degree relatives of of affected indi-
viduals revealed by epidemiological family studies.
(2,6,7,10,14) Further evidence supporting the the
role of genetic factors in autoimmune disease me-
cha nisms have been provided by genetic linkage
techniques, population-based association studies or
family-based association analyses, candidate genes
analysis, whole genome screening and whole ge-
nome linkage analysis, studies on single-nucleotide
polymorphisms. (13,15) Signicant progress has
The autoimmune thyroiditis in children and adolescents.
Ethiopathogenetic aspects and clinical outcomes
Lenua Popa, MD, PhD, Asst. Prof.
University of Medicine and Pharmacy Iuliu Haieganu, Cluj-Napoca, Romania
ABSTRACT
The autoimmune thyroiditis (AT) and type 1 diabetes are the most frequent autoimmune inammatory
diseases in children and adolescents. AT is a genetically complex disease, the result of the combined effects
of polymorsms of HLA class II genes and polymorphisms of non-HLA genes: CTLA-4, PTPN22, AIRE and /
or FoxP3 that are altogether involved in immunological synapses, T-cell activation and immune response
regulation. AT may be considered as a model of an autoimmune disease mediated by both humoral and
cellular mechanisms. At least two main forms of AT have been described: Hashimotos thyroiditis (HT)
characterized by rapid increase in thyroid volume and atrophic thyroiditis or spontaneous primary
hypothyroidism (idiopathic myxedema) without goiter but with a slight increased, normal or small thyroid
gland. The clinical course of AT is variable and may be characterized by spontaneous remission in some
adolescents with a self-limited form of HT and by irreversible thyroid insufciency as the consequence of
atrophic and brouse transformation of the thyroid gland in other cases. AT may be associated with many
other autoimmune endocrine and nonendocrine disorders. The understanding of ethiopathogenetic
mechanisms and clinical characteristics of this endocrine desease is particulary important for prompt
therapeutical intervention necessary to prevent the effects of autoimmune hypothyroidism on growth and
development in children and adolescents.
Key words: autoimmune thyroiditis, hypothyroidism, associated diseases, children and
adolescents
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 241
been made in identifying susceptibility genes to
AITD but no specic genes for ATD were identied
until now. The candidate genes, that are genes of
known sequence and location, which due to their
physiological functions may be involved in
pathogenesis of a multifactorial disease, are asso-
ciated with variable frequency with other auto-
immune diseases. (1,2,4,10,11,13)
Associations with AITD have been rmly
established for two categories of immun regulatory
genes involved because of their polimorsms in
autoimmune response to thyroid antigens and AIT
ethiopathogenesis: 1) the major histocompatiblity
complex genes named in human human leucocyte
antigen (HLA), a number of genes that encode
spe cic molecules expressed on the surface of
antigen presentig cells (APC) and play a pivotal
role in T-cell repertoire selection in the thymus and
in antigen presentation in the periphery and 2) non-
HLA genes involed in immunologic synapses,
T-lymphocyte activation and control of immune
processes represented by cytotoxic T-lymphocyte-
associated (CTLA-4) gene, non-receptor tyrosine
phosphatase-22 protein (PTPN22) gene, auto-
immune regulator (AIRE) gene and the forkhead
box P3 (FOXP3) gene. (Table 1) (1,2,4,5,10,14,15)
The AITD was associated with polymorphisms
of loci of the genes that encode especially HLA
molecules class II. Mutations of HLA genes modify
the afnity of the HLA glycoproteins from APC
and thyroid follicular cells (TFC) surface for
various proteins involved in autoimmune processes.
The HLA-DR-3 haplotype carriers have a two- to
six-fold increased risk for the occurrence of AIT.
When AT coexisted with other autoimmune
diseases, the commune susceptibility genes were
localized in HLA-DR and HLA-DQ regions.
(1,3,4,8,10,11,12)
Regulatory genes of lymphocyte-T activity can,
by their product, modify the immune response and
autoimmune reactivity and are the most important
non-HLA genes known to be related to autoimmune
diseases susceptibility. (10,11,12,13,14,16) The
CTLA-4 gene, expressed on T(CD8+) and
Th(CD4+) lymphocytes encodes an immunorecep-
tor molecule with costimulatory activity in in te-
raction between T cells and APC that downregulates
T-cell activation, limits T-lymphocyte proliferation.
CD4+ regulatory T cells, whose action is mediated
by the co-stimulatory molecules CD28 and CTLA-4,
suppress the activation and function of self-reactive
T cells in the periphery, and induce the immune
tolerance. (4,7,16) A number of mutations of
CTLA-4 gene are associated with thyroid auto-
immunity term that denes both AITD and carrier
status of serum thyroid antibodies. The CTLA-4
gene polymorphisms determine 25% of suscep-
tibility to GD, AT, DM1 associated with AIT,
Addison disease and rheumatic arthritis without
ethnic specicity. (3,11,13,16) Genetic polymor-
phism of PTNP22 gene, encoding lymphoid
tyrosine phosphatase, a modulator of kinase acti-
vation involved in intracellular processes related to
lymphocyte-T receptor activity, have been asso-
ciated with DM1, GD, LES, rheumatic arthritis,
celiac disease, vitiligo and other autoimmune
diseases. (3,7,12)
A variety of studies have also reported asso-
ciations between polymorphisms of genes encoding
the specic structures of the thyroid gland as Tg,
TPO thyrotropinic receptor (TSHr) and risk of
AITD. They are candidate genes for thyroid auto-
immunity and contribute to the initiation of auto-
immune response. (1,2,4,5,6,11,15) The next step
in understanding the role of genetic factors in AITD
development is to investigate the functional
TABLE 1. Susceptibility genes to AIT
Gene Chromosom
locus
Encoded Protein Effects of
polymorphismes
Autoimmune
disease
HLA-DR, DQ
(class II)
6p21.3 Antigen
Presenting molecule
TCD4-Antigen presentation HT, GD, T1D
CTLA-4 2q33 Immunoreceptor molecule
Costimulatory molecule
Uncontrolled T-cell proliferation
Loss of immune tolerance
Predisposition to autoimmunity
HT, GD, T1D
PTPN22 1p13 Protein tyrosine phosphatase
22 non-receptor
Early signalling events following
T-cell receptor (TCR) engagement
HT, GD, T1D
Thyroglobulin 8q24 Constitutive protein of the
thyroidal coloid
Thyroid autoimmunity HT, GD,
FOXP3 Xp11 Forkhead-wingedhelix
Transcription factor
Inability to generate regulatory T
cells
IPEX syndrome
AIRE 21q22.3 Transcription factor Decreased activation of genes
transcription
APS 1
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 242
consequences of the genes polymorphism and to
search for genotype-phenotype correlations. (13,
15) The specicity of autoimmune process is the
result to combined effects of protective genes,
tissue specic genes and environmental factors.
Genes interactions, on the one hand, and interactions
of genes with epigenetic and environmental factors,
on the other hand, modify the autoimmune disease
phenotype and severity. (6,11,13)
Environmental factors play an important role in
occurance of AIT in a predisposed individuals due
to activation of the immune system, initiation of
autoimmune response and convertion on this way
of the risk in the disease. Some of these factors as
dietary iodine from iodized salt, milk and dairy
produce, eggs, iodized alimentary additives, cho-
colate, and some multivitamins act in a specic
manner. (13,17,18) Iodine, a necessary component
of normal thyroid hormonogenesis can promote
antithyroid immunity in a number of ways. First, in
the early stages of autoimmune processes, high
amounts of iodine are rapidly oxidized by TPO, the
enzyme directly involved in iodination process and
oxidation of iodothyrosine to iodothyronine. This
process generates autoreactive mediators such as
lipoic acid and oxygen reactive metabolites. By
oxidation of the the lipid and protein components
of the cellular membrane this oxidative species
damage and induce necrosis of TFC. (4,18) Second,
the excessive iodination of thyroglobulin amplies
its immunogenicity by creating new epitops or
exposing cryptic epitopes hidden in iodine de-
ciency conditions. These may explain protective
role of iodine deciency contributing to reduced
thyroid autoimmunity as well as increased AIT
prevalence in population with excessive iodine
con suming. Highly iodinated Tg may facilitate
antigen uptake and processing by APC. Third,
iodine itself could increase expression of inter-
cellular adhesion molecule (ICAM)-1 in the thyro-
cytes. (4,7) It is a single-chain cell surface glyco-
protein that plays a role in inammatory processes
and functions as a costimulatory molecule on APC
to activate HLA class II restricted T-cells, and on
other cell types in association with HLA class I to
activate cytotoxic T-cells. (7) Thus, iodine excess
exacerbates local immune inamation by immunolo-
gically and biochemically mechanisms. The ma-
jority of environmental factors represented by
vitamin D deciency, selenium deciency, ionized
radiations by therapeutically, exploratory or acci-
dental exposure, medicines (beta-blockers, lithium,
amiodarone, phenilbutasone, glucocorticoids, furo-
semide, carbamazepinum, antiretroviral agents,
monoclonal-antibodies and interferon INF), viral
and bacterial infections, or according with hygiene
hypothesis, lack of the infections, are less specic
and are involved in the ethiopathogenesis of the
other autoimmune diseases as well. (13,14,17)
Vitamin D plays an immunemodulating role mainly
on CPA. Vitamin D deciency was associated with
increased levels of TPO antibodies. Some early
nutritional factors, used during the rst year of life,
appear to be associated with an increased prevalence
of thyroid autoimmunity. Thus, long exposure to
gluten and the young age at the onset of celiac
disease increase the risk of AITD. (13) Infections,
by interactions among microorganisms and host,
may initiate or suppress in the early stage an
autoimmune process. Infectious agents may induce
autoimmunity by different mechanisms, such as
molecular mimicry, polyclonal T-cell activation,
and enhanced expression of HLA molecules on the
thyroid epithelial cells.
The hygiene hypothesis implies that the
immune system is educated by multiple exposures
to different infections allowing it to better control
autoimmune responses. (17) Frequent microbial
exposure during rst years of life has an important
role in immune system instruction by stimulating
the regulatory elements of the immune system. (6)
Consistent with this hypothesis, the increased level
of allergic and autoimmune disease in industrialized
countries is the result of improved living standards
associated with decreased exposure to infections
and decreased infections number during the rst
years of life. Lack of this experience may lead to
aberrant activation of autoimmune cells, modied
immune response and Th2-lymphocytes predomi-
nance that are involved in syntesis of interleukine
IL-4 and IL-5, activation of B-lymphocytes, syntesis
of specic antibodies, and antibodies mediated
reactions. (6,15,17)
AIT is a model of both cellular and humoral
mediated autoimmune diseases. (2,8) A major site
of autoreactivity is within the thyroid gland itself.
The primary antigenic structure as the target of
autoimmune reactivity, could be a virus that has
identical sequence to the proteins of the thyroid
gland itself, or a self protein that is presented by the
TFC as an antigen. The main target antigens of the
thyroid antibodies are colloid constitutive protein
Tg, the enzyme involved in thyroid hormone
synthesis TPO, Na/I-symporter (NIS) and thyrotro-
pinic receptor (rTSH). (4,10,14,19) The activation
of T-helper lymphocyte (Th) CD4 by a specic
thyroid antigen presented by an APC, in predisposed
individuals, triggers the antithyroid immune
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 243
response and the recruitment, in the thyroid gland,
of the cytotoxic lymphocytes TCD8+, as well as of
the B lymphocytes. (1,3,4,6,8,15,16)
Inherited or acquired dysfunctions of TCD4+
lymphocytes and unbalanced Th1/Th2 ratio, con-
tribute to AITD occurence. The Th1 and Th2
activities are mutually suppressive. Pro-inam-
matory cytokines, like IL-1 and INF released by
Th1 lymphocytes, are involved in cellular mediated
immune response, while Th2 lymphocytes cyto-
kines are related to antibodies synthesis, the re-
mission of disease, and immune system suppression.
(18) Many of pathogenetic mechanisms isolated or
in association lead to glandular destruction and
subsequent autoimmune hypothyroidism. Lympho-
cytic inltration of thyroid gland results in increased
thyroid volume and compensatory TFC hyperplasia.
(1,3,7,8) Parafollicular inltrated TCD8+ lympho-
cytes mediates, via cytokines, the damage of TFC
an essential step required for the initiation of
specic antibodies synthesis and to trigger sub-
sequent pathogenic mechanisms. The cytotoxicity
mediated by lymphocytes and/or antibodies cause
TFC distruction and autoimmune hypothyroidism.
Follicular cells apoptosis induced by cytokines, a
characteristic process to AIT, may lead to disap-
pearance of TFC before of TCD8+ lymphocytes
cytotoxic effect on thyrocytes and contributes to
thyroid atrophy and irreversible hypothyroidism.
(1,3,4,5,8,15) Final effectors of immune response
are natural killer cells (NK)CD56+ that interact
with IL-2 and IL-12 and leads to synthesis and
release of INF (1,3,19). Increased intraglandular
syntesis of antithyroid antibodies, cytokines and
chemokines, creates a pro-inammatory environ-
ment, favors expending of intra-thyroidal lympho-
cytic deposit and emphasizes the immune inam-
mation, stimulates apoptosis of thyrocytes and lead
to progressive thyroid follicles destruction, glan-
dular architecture disorganization and temporary or
denitive loss of thyroid hormones synthesis capa-
city. (2,3,5,8,10,18) Cytokines are crucial in the
regulation of immune and inammatory responses.
(4) Th1 cytokines act directly on thyrocytes through
cytokinic receptors on their surface and negatively
affects the expression of tyrocytic-specic proteins:
Tg, TPO, NIS and DUOX enzymes that generate
H2O2. In these conditions, diminishing the hor-
monal synthesis is contributing to the occurrence of
AIT, even in the absence of TFC destruction and
also explains the variability of clinical evolution
previously observed in clinical practice. (18)
The immune-pathogenic processes, mediated by
anti-thyroid antibodies, contribute also to the
phenotypic variation of AITD, and to the clinical
and pathogenetic variability of the different forms
of AIT. (5,14,19) The antithyroid antibodies are
produced by inltrated lymphocytes in the thyroid
gland. (14) TPO antibodies, inhibit the activation
of the enzyme, are the major mediators of com-
plement xation and activation within the thyroid
gland and stimulate the NK cells activity, a process
that induces the cytotoxicity at the TFC level.
(2,7,14,15,19)
Increased serum antithyroid antibodies concen-
trations is the rst detectable sign of AIT and were
found in more than 90% of children and adolescents
with TH, and in more than 75% of those with GD,
at the smaller lavel as compared to adults. The
serum concentration of TPO antibodies is generally
correlated with increased production of pro-
inammatory cytokines (IFN- and TNF-), and
with severity of thyroid lesions. Tg antibodies,
found in about 60% of TA patients, have a less
precise pathogenetic role and a modest functional
signicance. Due to their afnity to intracellular
subunit, the anti-rTSH antibodies can alter the
target cells function and act as blockers of the
glycoprotein receptor. They were found in 10-20%
of children with AT and severe hypothyroidism,
sometimes in younger than 4 years old children,
with higher prevalence in subjects with Down
syndrome. (2,3,19) The exact denition of the
disease and the differentiation from the auto anti-
bodies carrier status are important tools in diag-
nosing the autoimmune disease. Antityroid anti-
bodies represent the essential diagnostic elements
for AIT, but also for the thyroid autoimmunity
which is associated with increased risk of auto-
immune disease. The increased concentration of
antityroid antibodies often precedes the clinical
manifestation of the AITD and can also be found at
one of unaffected relatives of AITD patients, and
less frequently at subjects with common goiter
(20%), non-immune thyroid diseases, or papillar-
folicullar carcinoma (75%). Normal serum concen-
tration of antithyroid antibodies rules-out the AITD.
(6,15,19) AIT is a heterogenous condition with
different clinical and pathogenetic subtypes. Two
main forms differentiated by the tyroid volume, are
described: Hashimoto thyroiditis (TH) charac-
terized by rapid and diffuse growing of the thyroid
gland volume and, at the opposite side, atrophic
thyroiditis associated with primary spontaneously
hypothyroidism, so called primar mixedem, without
goiter but with a slightly increasing of the thyroid
gland or with normal or reduced volum of the
thyroid. Serum concentrations of antityriodian
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 244
antibodies increase in both diseases, and may be
slightly greater in atrophic forms (Table 2).
HT is the most frequent autoimmune in-
ammatory disease in children and the most
frequent form of juvenile thyroiditis. It is very rare
during the rst 3 years of life, quite common after
the age of 6, with a peak of incidence at adolescence
and estimated prevalence at the school age of 1.3%-
9.6%, with a female preponderence and with a FM
ratio of 4.2. (4,7,9,15,23) HLA-DR4 and HLA-
DR5 haplotypes are associated with increased risk
for HT in Caucasians, while HLA-DR3 haplotype
is associated with atrophic form of chronic
thyroiditis (4,7,12). There is a predominance of
Th1 and an increased Th1/Th2 ratio associated with
severe forms of HT. The oxyiphilic metaplazia of
TFC and the occurance of the Hrthle or Askanazy
cells with granular eosinophilic cytoplasm
represents the histological feature of HT.
Most of children are euthyroid and asymtomatic.
A precervical tenderness is non-consistently
perceived. The thyromegaly (goiter) is the most
obvious clinical sign of TH. (23) There is a high
variability of thyroid disfunction. (7, 9) Hashito-
xicosis, the name of hypertyroidal state belonging
to the early stages of TH, can affect, on a variable
duration of 1-6 moths, up to 10% of cases. As one
of the hallmarks of HT, symptoms and signs of
hypothyroidism occur as initial manifestation in
approximately 20% of patients. (7) Differential
diagnosis between TH and GD on clinical, ultra-
sonographic, and immunologic criteria, is initially
difcult. There is a lower suppression of TSH and
in the same time a slightly elevated concentrations
of T4 in hashitaxicoza compared to GD. Differential
diagnosis with thyroid dyshor mogenesis, thyreo-
glossal duct cysts or other ethyologial types of
thyroiditis produced by acute (supurative) or
subacute (granulomatoase) inammation may be
necessary in some cases.
A series of intermediate, less dened, forms of
thyroiditis, in which the only obvious manifestation is
a slightly increased of thyroid gland consistency, can
be interposed between the two opposite forms
represented by TH and primary mixedema or Ords
disease. Differentiation may be made by histopa-
thologic examination of the thyroid ultrasound-guided
biopsy pieces that is conramatory of diag nosis and
allows differential diagnosis with endemic goiter.
IgG4+ thyroiditis is characterized by pre-
dominance at male gender, high level of TPO and
Tg autoantibodies, diffuse or nodular dense inl-
tration of IgG4+ plasma cells, with IgG4+/IgG total
ratio >30%, brosis and sever follicular dege-
neration, and rapid cours to irreversible hypo-
thyroidism. Clinical evolution in AIT is variable,
self-limited or progressive due to glandular brosis
and atrophy. In severe forms the thyroid dysfunction
interfere the growing process in children and
adolescents and increase the cardiovascular risk by
secondary dyslipidemia. Spontaneous remission of
AIT is possible at adolescence or after a variable
period of treatment with L-thyroxine in 25% of
cases. In euthyroid children with high TPO and Tg
antibodies levels, the incidence of hypothyroidism
is 2-3% per year. Goiter may reduce or cure
spontaneously by hormonal treatment. High serum
concentration of thyroid antibodies can vary and
often persist over time. The general characteristics
of AITD are: 1) intrafamilial aggregation; 2)
intrafamilial phenotypic variability; 3) the presence
of thyroid antibodies in asymptomatic relatives of
an affected person at higher levels comparative to
general population; 4) the association with other
autoimmune diseases.
Table 2. Clinical Characteristics of AIT
Characteristics Hashimotos Thyroiditis
Atrophic Thyroiditis
(Ords disease )
Prevalence 90% 10%
Haplotip HLA DR3, HLA DR4, HLA DR5 HLA-DR3/B8
Pathological ndings Diffuse lymphocytic inltration
TFC* hyperplasia
Oxyphilic metaplasia (Hrthle cells)
Focal lymphocytic inltration
Fibrosis
Atrophy
Thyroid volume Difuse thyromegaly (Goiter) N ormal
Thyroid consistency (tender)
Ultrasonographic ndings Diffuse thyroid hypoechogenity nomogen, trabecular appearance
Thyroid-specic autoantibodies TPO and / or Tg rTSH-B, TPO / Tg, IG4+
Thyroid functional status Hypothyroidism Hashitoxicosis
Eutyroidism
Hypothyroidism
Cours Variable Chronic
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 245
Intrafamilial aggregation can be explained by
the shared genetic and/ or environmental common
factors. The prevalence of AIT in rst-degree re la-
tives of an affected person is more than 25%. Auto-
immune diseases clusters in the same individual
and in the same family by an unknown pathogenetic
mechanism. (8,11,12,13,15) AIT association with
one or more endocrine or systemic autoimmune
diseases is known as the autoimmune polyendocrine
syndromes (APS). This may be a misnomer because
not all patients have multiple endocrine diseases
and in many cases AIT is associated with non-
endocrine autoimmune diseases. There are many
type of APS that may be differentiated by prevalence,
the moment of the onset, pattern of inheritance and
associated diseases. (Table 3). AT is present in all
APS types, more frequent in the type 2 (75%), in
which it is a major component, comparative with
type 1 (10%), in which is a minor component. (15)
AIT is the component of two monogenic autoimmun
syndromes with the childhood onset: APS type1
(APS1) and severe immune dysregulation, poly-
endo crinopathies and enteropathy X-linked syn-
drome (IPEX).
APS1 is a rare autosomal recesive disorder de-
ned by a characteristic association, a classic triad
of mucocutaneous candidiasis, hypopara thyroidism,
and adrenocortical failure, two of which are required
for the diagnosis. The initial mani festation is muco-
cutaneous candidiasis present in 60% of cases
during rst two years of life. Addison disease is
present in almost all affected children at the age of
15. A dozen autoimmune endocrine and other com-
ponents occurred variably. (table 3) The prevalence
of most components increased with age. (15) APS1
is caused by mutations in the autoimmune regulator
(AIRE) gene that encodes a nuclear trans cription
factor. AIRE control during thymus onto genesis
transcription of organ specic auto anti genes. AIRE
gene mutations lead to defective negative selection
of potentially autoreactive thy mocytes and inef-
fective peripheral antigen presen tation for some
antigens, and to persistence of selfreactive
T-lymphocytes, losing central im muntolerance and
predisposition to multiple sys temic autoimmunity.
Recent studies identied the parathyroid antigen
NACHT leucine-rich-repeat protein 5 (NALP5).
Self-reactivity of the immune system against
NALP5 can explain both hypo thyroidism as well as
oophoritis at a girl with APS1, and consequently
gonadal insufciency present over 12 years of age
at 60% of girls. (10,15,19, 20,21)
The second monogenic syndrome, IPEX, is
caused by mutations in the FOXP3 gene that lead to
inappropriate activation and proliferation of CD4
lymphocytes and self aggressive lymphocytic
clones, to proliferation of self aggressive lympho-
cytic clones and multiple systemic autoimmunity.
FOXP3 gene encodes a forkhead-winged-helix
transcription factor designated Scurn, the master
regulator of regulatory T cell differentiation. IPEX
is typically presents during infancy, in a male infant,
as a severe disorder characterized by failure to
thrive due to autoimmune enteropathy, chronic
TABLE 3. Characteristics of autoimmune polyglandular syndroames
APS type APS 1 APS2 IPEX
Prevalence reduced* 1 /20. 000 very reduced
Ethiology monogenic multifactorial
poligenic
monogenic
Inheritance AR AD X-linked
Sex ratio F/M 1:1 3:1 0:1
Age of the onset infancy / toddler childhood / young adult neo-nate
Major components Cutaneomucous candidiasis
Hypoparathyroidism
Addison disease
T1D or
Addison disease
AITD (75%)
T1D with
neonatal onset
AIT
Secretory enteropathy
Immune disorders
Minor components Ectodermal dystrophy
T1D
Ovarian failure (60%)
Vitiligo
Alopecia areata
AITD (10 %)
Autoimmune hepatitis
Asplenism
Vitiligo
Alopecia areata
Pernicious anemia
IPEX- immune dysregulation, polyendocrinopathies and enteropathy X-linked syndrome
* > in Finlanda, Iran, Sardinia; AR autosomal recesive; AD autosomal dominant
T1D Type 1 diabetes
REVISTA ROMN DE PEDIATRIE VOLUMUL LX, NR. 3, AN 2011 246
eczema, anaemia and thrombocytopenia. Auto-
immune hypothyroidism and T1D with neonatale
onset develop in the rst year of life in about 50%
and 90% of males, respectively. Without bone
marrow transplantation the most affected subjects
usually die before the age of 2 years of age. (10, 15,
21,22)
APS2 includes with a hight variability numerous
multifactorial, plogenic diseases. (15,22) The AITD
and T1D as-sociation, perhaps the strongest as so-
ciation between two autoimmune conditions, is the
most commune endocrine diseases association
characteristic to APS2. (Table 3) T1D resulted from
selective destruction of the pancreatic insulin-
secreting cells due to immune mediated attack is
equally associated with HT and GD unlike the
Addison disease which is associated only with HT.
21 T1D increase the risk to develop AITD about 5
times comparative to general population.Transver-
sal studies have identify the presence of TPO
antibodies at 10-20% in T1D affected children and
adolescents of which 50% comprise the common
criteria that diagnose them with AITD. Antibodies
against pancreatic insular cells were found in 2,3%
cases of AITD in children. (13,25,26) Prevalence of
thyroid autoimmunity is related to age and female
gender. Puberty, age of the onset of puberty, are
also related to T1D and to association between T1D
and AITD. The substrate of this association is not
entirely known. Both diseases are T-lymphocyte
mediated. The same immunoregulatory genes are
associated with AITD and T1D. HLA class II genes
seem to play the major role. HLA-DR3 haplotype
confer the susceptibility to T1D and to association
of T1D and AITD at familial and individual level.
DR3-DQ2 and DR4-DQ8 haplotypes predispose to
association of T1D and AITD and is related to high
frequency of T1D during adolescence (5% at 15
years of age) (25,26).
Polymorphisms of h CTLA-4 and PTPN22
genes are involved in susceptibility to both
autoimmune diseases. (10,13,25,26) AT is associated
with many other diseases like numeric or structural
chromosomal diseases (Down, Turner, Klinefelter
syndrome, deletion syndromes), congenital rubella
or proliferative thyroid processes. Down syndrome
caused by 21 trisomy is characterized by increased
prevalence of autoimmune, endocrine or non en-
docrine diseases such T1D, celiac disease, auto-
immune hepatitis, alopecia, vitiligo, hypo para-
thyroidism as well as congenital and AITD. Reduced
T lymphocytes number, B lymphopenia, T lympho-
cytic subpopulations disproportions that lead to
recurrent infections and autoimmune diseases in
this patients are explained by thymic gland abnormal
development. The coexistence of classic symptoms
of hypothyroidism present in 15% of cases with
specic phenotypic characteristics may delay diag-
nosis of the thyroid disease. Thus, annual screening
for hypothyroidism is recommanded in Down syn-
drome children after 12 months of age. (27,28)
Turner syndrome characterized by total or partial
deletion of an X chromosome and female phenotype
is associated to asymptomatic AIT in 24% of cases,
some time before 4 years of age. Prevalence of AIT
is particularly increased (~40%) in girls with
isochromosome X and 46Xi(Xq) by the deletion of
short arm and duplication of long arm of the X
chromosom. This high prevalence of AT is indicative
of the importance of the genes wich are located on
long arm q of X chromosome for AT pathogenesis.
Like in other cases, incidence of AT and thyroid
autoimmunity increases with age in Turner disease,
double in the second decade of life and peak at 15
years of age. (23,29) An association between
Klinefelter syndrome and autoimmune thyroid
disease has been reported.The discussed associa-
tions argue the commune genetic basis and patho-
genetic mechanisms and motivate the periodic
evaluation of these patients.
The understanding of ethiopathogenetic mecha-
nisms and the clinical and evolutive characteristics
of this endocrine desease is particulary important
for the correct screening of autoimmune thyroid
diseases in order to prevent effects of autoimmune
hypothyroidism on growth and development in
childhood and adolescence.