naTia rurua autoimunuri Tireoiditis (Hashimoto...

ivane javaxiSvilis saxelobis Tbilisis saxelmwifo universiteti

aleqsandre naTiSvilis morfologiis instituti

naTia rurua

autoimunuri Tireoiditis (Hashimoto) histologiuri da

imunohistoqimiuri kvleva

D

disertacia medicinis dargSi doqtoris

akademiuri xarisxis (PhD) mosapoveblad

avtoris stili daculia

Tbilisi - 2015

sarCevi

Sesavali .................................................................................................................................................................................3

sakiTxis aqtualuroba ............................................................................................................................................3

gamokvlevis mizani da amocanebi ..................................................................................................................6

Tavi I literaturis mimoxilva ...................................................................................................................9

Tavi II gamokvlevis dizaini, masala da meTodebi .................................................................23

2.1 klinikuri masalis SemTxvevaTa SerCeva da Sefaseba

(ZiriTadi da sakontrolo jgufebi)................................................................................23

2.2 histologiuri kvlevis meTodebi.........................................................................................25

2.3 imunohistoqimiuri kvlevis meTodebi ............................................................................26

Tavi III sakuTari gamokvlevebis Sedegebi ...................................................................................32

3.1 Hashimoto-s Tireoiditis klinikuri laboratoriuli

monacemebis Sefaseba procesis aqtivobis TvalsazrisiT …………..32

3.2 difuzuri toqsikuri Ciyvis zogadhistologiuri kvlevis

Sedegebi ……………………………………………………………………………40

3.3 farisebri jirkvlis funqciuri erTeulebis parametrebi Hashi-

moto-s Tireoiditisa da difuzuri toqsikuri Ciyvis dros ………..48

3.4 autoimunuri Tireoiditisa da difuzuri toqsikuri Ciyvis

imunohistoqimiuri kvlevis Sedegebi ………………………………………56

Tavi IV. kvlevis Sedegebis ganxilva ......................................................................................................73

daskvnebi ............................................................................................................................................................................87

literaturis saZiebeli ....................................................................................................................................89

2

Sesavali

Temis aqtuალუროba.

farisebri jirkvlis daavadebebis ricxvis zrdis pirobebSi didi

mniSvneloba eniWeba jirkvlovani qsovilis morfologiuri cvlilebebis

identifikacias, radgan Ciyviseburi transformacia, rogorc wesi dakavSi-

rebulia ara marTo Tireonebis sistemis cakleuli elementebis prolife-

raciul cvlilebebTan, aramed organos histo-hematuri barieris normuli

struqturebis dezorganizaciasTan, rasac Tan axlavs trofikuli,

diferenciuli da specializebuli struqturebis funqciis darRveva.

Tanamedrove endokrinologiSi da paTologiaSi farisebri jirkvlis

gaumjobesebulisadiagnostiko kriteriumebis damuSavebas gansakuTrebuli

adgili uWiravs. literaturuli monacemebis (КоганЕ.А. и соавт.,2006;Полоз Т.Л. и

соавт.,2006; Gogiashvili L. et al., 2007; Магеррамова З.З.,2010) mixedviT maRalgaje-

rebis unaris mqone warmonaqmnebis skanirebis dros yovel meore gamokv-

leuls farisebr jikvalSi aRmoaCnda kvanZebi. ase, magaliTad, ultra-

bgeriTi gamokvlevis gamoyenebam azerbaijanis navTobis mompoveblebis

profesiuli gasinjvisas 100 gamokvleulze gamoavlina 6,13±0,6 paTologiis

axali SemTxveva, rac, avtoris azriT, warmoadgens maCvenebels aucilebeli

sadiagnostiko testirebis CatarebisaTvis saxifaTo profesiis pirebis

profgasinjvebisas. janmo-s informaciiT, planetis sxvadasxva regionebSi

gaizarda farisebri jirkvlis kibos SemTxvevaTa ricxvi, romelic

organoSikeTilTvisebiani winamorbedi procesebis fonze aRmocenda(From,

Mallemgaard et al.,2000; Angini-Lombardi, Antonangeli et al.,2007; Zimmerman, Wegmuller et

al.,2010;Василъева О.А., 2011)

farisebri jirkvlis (fj) paTologia mniSvnelovnad aris damokide-

buli garemos mdgomareobaze. farisebri jirkvali natifad reagirebs

bunebriv da teqnologiur faqtorebze, amitom igi xSirad ganixileba,

rogoc regionis ekologiuri arakeTilsaimedoobis maCvenebeli.

bolo wlebSi specialistebis yuradReba fokusirdeba angiogenezis

faqtorebze, radgan angiogenezi iTvleba zrdis xelSemwyob gadamwyvet

faqtorad; aseve simsivnis metastazirebis, de novo sisxlZarRvebis warmo-

qmnis mastimulirebel faqtorad, rogorc normaSi, aseve paTologiis dros.

neoangiogenezi warmoadgens axali warmonaqmnebis potencialis Sefasebis

3

sakvanZo reaqcias. mkvlevarebi afaseben mas, rogorc mravalsafexurian

process, dakavSirebuls ujredSoris matriqsis modelirebasTan (Gerber,

Ferrara, 2003; Solen et al., 2010) msgavsi midgoma aRiniSneba sarZeve jirkvlis

(Anan K., Moriasaki T., Katano M et al., 1996), saSarde buStis, kuWis, sakvercxis,

saSvilosnos yelis adamianis simsivneebSi, sadac gaZlierebuli angiogenezi

asocirdeba metastazebis ganviTarebasTan da xasiaTdeba mZime prognoziT

(Nagura, Katoh et al.,2001; Vicara et al., 2007)

angiogenezis faqtorebidan aRsaniSnavia sisxlZarRvovani panendo-

Teliuri zrdis faqtori(VEGF), romelic Tavis mxriv ori saxiT arsebobs –

VEGF1 da VEGF2. igi aris mikrosisxlZarRvebis gamomfeni endoTelioci-

tebis zrdis stimulatori, SeuZlia gaaZlieros maTi proliferacia

rogorc fiziologiur, ise paTologiur pirobebSi. VEGF-ganpirobebuli

zogadi efeqti vlindeba endoTeliocitebSi VEGF-2 eqspresiiT, amave

dros,VEGF-1 asrulebs angiogenezis regulatoris rols parakrinuli

efeqtis saSualebiT, aseve autokrinuli regulatoruli rgolis inhibi-

rebiT da sxv. (Gerber, Ferrara, 2003; Iton et al., 2010). neovaskularizaciis

mniSvneloba mikrosisxlZarRvebis simWidrovis cvlilebebTan erTad

farisebri jirkvlis hipofunqciis potencialis gamovlinebas Soris

korelaciis Sesafaseblad ar aris damtkicebuli.ufro metic, arsebobs

gamokvlevebi, romlebic Tireomastimulirebeli hormonis (TSH) aqtivobas,

daavadebis klinikuri gamovlinebas, (hipoTireozi) da zrdis biologiuri

potencials Soris disbalansze miuTiTeben.

Cveni kvlevis specialuri interesidan gamomdinare, unda aRiniSnos,

rom Ciyvisebr-transformaciis ganviTarebaSi angiogenezi mniSvnelovan

rols asrulebs. aRwerilia faqti endoTeluri ujredebis proliferaciis,

romelic win uswrebs Tireocitebis hiperplazias folikulebSi, rac iwvevs

VEGF-s koncentraciis momatebas rogorc sisxlis SratSi, aseve

intraTireoiduli sisxlZarRvovani arealis SigniT, rogorc toqsikuri

Ciyvis dros, ise pacientebSi Hashimoto-s TireoiditiT (Yamada et al.,2006).

aqtualuria vaskularizaciis procesebis aqtiuri kvlevafarisebri

jirkvlis im anTebiTi da proliferaciuli procesebis samkurnalo meTo-

debis gafarToebisTvis, romlebic xSirad ar eqvemdebareba radioaqtiuri

iodiT zemoqmedebas. (АдамоваЯ.Е.,ЧумашенкоА.Н.,РайхлинН.Т., БукаеваИ.А., исоавт.,

4

2011)yuradReba unda mieqcesim garemoebas, rom sxvadasxva avtoris

damokidebuleba am daavadebis mimarT atarebs araerTgvarovan xasiaTs

struqturuli elementebis rolis gansazRvris TvalsazrisiT (Мазурик

М.Ф.,Кузнецова А.А., и соавт., 1981; Камардин Л.Н., Зелъцер М.Е., 1988; Чачбая В.А., 1992;

БубновА.Н., 1997, Кожанов Л.Г., 1999; Harley D.L., 1995; Arlen, Livolsi, 2000; Brekken,

Thorpe, 2001); Hilly, Korea et al., 2013; Ward, Steian L., 2014).

aqedan gamomdinare, mniSvnelovnad gaizarda interesi Hashimoto-s tipis

kvanZovani da autoimunuri paTologiis mimarT, miTumetes, rom xSirad

adgili aqvs Tireoiduli parenqimis hipoTireoidul transformacias

(Хмелъницкий О.К.и соавт., 1996; 1998; Хмелъницкий О.К.,1999) araiSviaTad SeiZleba

gamovlindes raodenobrivi cvlilebebis safuZvelze, rodesac daavadebis

axali substrati jer kidev ar aris Camoyalibebuli (McHenry, Phitaykorn,

2012).

amis garda, hiper- da hipoTireoiduli formebis Ciyvis sxvadasxva

variantebis mravalricxvovani gamokvlevis miuxedavad (Лившиц Ф.Х.,Олейник

Е.Л., 1985; Епишин А.В.,1990; Мамаев Н.Н.,и соавт., 1994; Хмелъницкий О.К.и соавт.,1996;

1998; 2000; Хмелъницкий О.К.,1999; Авдеенко Ю.Л.,2001; Yagi et al., 1979; Mornex et

al.,1980; Shey S.Y., Gorges R. et al.,2003; Mazeto G.M. et al.,2004; Olivera M.L. et al.,2004;

Melello et al., 2010), informacia autoimunuri komponentiT mimdinare farisebri

jirkvlis paTologiis imunohistoqimiur TaviseburebaTa Sesaxeb jer kidev

arasrulia.

zemoTTqmulTan dakavSirebiT, mizanSewonilad miviCnieT Tireoidul

parenqimaSi mimdinare struqturuli cvlilebebis ufro detaluri

gamokvleva - histologiuri, morfometriuli da imunohistoqimiuri kvlevis

meTodebis gamoyenebiT organos sxvadasxva hormonaluri da funqciuri

aqtivobis pirobebSi. kompleqsuri midgoma farisebri jirkvlis gamokvle-

vebis mimarT iZleva informacias struqturuli da funqciuri gardaqmnebis

da maTi „biologiuri qcevis“ tendenciebis Sesaxeb.

sadReisod arsebuli monacemebi gvarwmuneben, rom farisebri jirkvlis

arasimsivnuri da anTebiTi daavadebebis paTomorfozis sakiTxebi klinikuri

endokrinologiis da paTologiis aqtualur problemad rCeba. mraval-

ricxvovan mimoxilviT statiebSi sakmarisad dawvrilebiT da sxvadasxva

poziciebidan ganxilulia klinikuri Taviseburebani, diagnostikis

5

sakiTxebi da mkurnaloba (АдамоваЯ.Е.,ЧумаченкоА.Н., 2007;ШадлинскийИ.Б.исоавт.,

2008; АбросимовА.Ю., КожучнаяС.М., 2011;ВасилъеваО.А., Lasithiootakis,Grisbolakis et al.,

2012).

gansakuTrebiT aqtiuria kvlevebi zrdis faqtorebis rolis Sesaxeb

farisebri jirkvlis(growth factors) (Bidey et al., 1999; Eslinger et al., 2001; Zimmerman

et al., 2004; Lared et al., 2010 McHenry C., Phitayako, 2012;Dardano et al., 2012; РуруаН.З.,

ГогиашвилиЛ.Е., ЦагарелиЗ.Г., 2013.)`klasikuri” da autoimunuri kvanZovani

procesebis ganviTarebaSi.

zemoTTqmulis safuZvelze ganisazRvra kvlevis miznebi da amocაnebi:

1.limfoidurujredovani infiltraciiT mimdinare farisebri jirkvlis hipo

da hiperTireoiduli mdgomareobis struqturuli diferenciacia zrdis

faqtorebis eqspresiis da Hurthle-s ujredebis populaciis aqtivobis

mixedviT;

2.Hashimoto-s Tireoiditis da difuzuri toqsikuri Ciyvis histologiuri da

imunohostoqimiuri variantebis gamovlena da Sefaseba antiperoqsidazul

(TPO) antisxeulebTan mimarTebaSi;

3.farisebri jirkvlis qsovilSi sisxlZarRvovani zrdis faqtorebis

receptoruli aqtivobis da sisxlZarRvTa simWidrovis kvleva Hashimoto-s

Tireoiditis sxvadasxva variantebisa da difuzuri toqsikuri Ciyvis dros;

4.Hurthle-s ujredebis histologiuri da imunohistoqimiuri kvleva Hashimoto-s

Tireoiditis da difuzuri toqsikuri Ciyvis dros, maTi paTologiur

cvlilebebSi monawileobis dadgenis mizniT organos sxvadasxva hormonuli

da funqciuri aqtivobis gaTvaliswinebiT;

5.farisebri jirkvlis struqturuli elementebis –(parenqimis da stromis)

morfometriul, statistikur analizze dafuZnebuli Seswavla da

sistematizacia hiper da hipoTireoidizmiT mimdinare paTologiis dros

Ffarisebri jirkvlis ioddeficituri paTologiis SemdegHashimotoH-s

autoimunuri Tireoiditi (HT) miekuTvneba erTerT yvelaze gavrcelebul

Tireoidul paTologiaTa ricxvs. (Amino, 1998). umravlesoba mkvlevarebisa

aRniSnavsHHashimoto-s TireoiditiTavadobis gaxSirebas ukanasknel aTwle-

ulSi (Braverman, 1997; Kandror V.I 1999; Pearce E.N., Farwell A.P, Braverman L.E 2003; Li

Y, Nishihara E., Hirokawa M et al., 2010) rigi mkvlevarebis monacemebiT,

6

mosaxleobis 4-11% Hashimoto-s TireoiditiTaa daavadebuli (ФадеевВ.В., 2000

Двинский Н.Ю 2010). rogorc pirveladi hipoTireozis erT-erTi mTavari

mizezi, swored manifestirebuli pirveladi Tireoiditi warmoadgens

daavadebis wamyvan klinikur niSans(Tsagareli et al., 2011; Konturek et al., 2013).

autoimunuri, maT Soris Hashimoto-s Tireoiditis paTogenezi naklebadaa

Seswavlili, ris gamoc praqtikulad ar aris cnobili paTogenezurad

dasabuTebuli mkurnalobis meTodebi (Chiovato et al., 1993; Bournard, 2003, Flynn et

al., 2004; Zhou, Ozaki et al., 2012).

msoflios jandacvis organizaciis (WHO) rekomendaciebis

Tanaxmad,Hashimoto-s Tireoiditis sadiagnostiko niSnad unda gamoyenebul

iqnas iseTi „didi“ sadiagnostiko niSnebis erToblioba: antisxeulebi

farisebri jirkvlis qsovilis mimarT, autoimunuri dazianebis da

pirveladi hipoTireoidizmis ultrasonografiuli niSnebi. erTerTi

maTganis ararseboba eWvqveS ayenebs da saTuos xdis diagnozs; Tumca

Tireoperoqsidazas mimarT antisxeulebis SeiZleba vnaxoT farisebri

jirkvlis sxva paTologiis drosac, aseve 0-16% janmrTel pirebSi.

(Landenson P.W. et al.,2000;LiY. et al., 2010-2012;) ultrasonografiuli suraTi ki

yovelTvis ar iZleva Hashimoto-s Tireoiditisa da endemuri da kvanZovani

Ciyvis diferencirebis saSualebas. cnobilia, rom hipoTireozi SeiZleba

ganviTardes genetikurad ganpirobebuli defeqtebis Sedegad, aseve

farisebri jirkvlis endemuri dazianebis dros.

problemis kvlevis Tanamedrove etapze eleqtroforezisa(Невинский

Г.A., 2000) da xazovani diqroizmis meTodebis gamoyenebiT (Подшивалина E.Ю.,

2008) naCvenebia, rom dnm mimarT antisxeulebifermentebis hidrolizuri

Tvisebebis gamo monawileoben apoptozis induqciaSi, (Hammand et al., 1997)

romlis siCqare mravaljeradad izrdeba Hashimoto-s Tireoiditis dros

(Patel et al., 2000) dnm -hidrolizuri antisxeulebi amJamad ganixileba rogorc

autoimunizaciis paTogenezis erT-erTi sakvanZo faqtori, ris dadastu-

rebasac maRalteqnologiuri meTodebi sWirdeba. mimdinare etapze auci-

lebelia sxvadasxva biosensoruli kvlevis meTodebis SemuSaveba, romel-

Tac eqnebaT maRali mgrZnobeloba, seleqtiuroba da kvlevis simartivis

7

meTodologiuri maxasiaTeblebi (Suchkov, 2005; Atashbat et al., 2005; Bournard 2003;

Hg HP.Chistiakov D.A 2005)

8

Tavi I

literaturis mimoxilva

sakiTxis kvlevis Tanamedrove etapze farisebri jirkvlis hiperplazia

Tireoiduli paTologiis erT-erTi uxSiresi gamovlinebaa. qsovilis

hiperplazia gvxvdeba, rogorc hormonis gamoyofis gaZlierebis dros

(hiperTireozi), aseve Tireoiduli hormonis naklebobis (hipoTireozi).

endemuri (euTireoiduli) Ciyvis da hipoTireozis SemTxvevaSi Tireoiduli

qsovilis zrda ganixileba rogorc adaptaciuri reaqcia, romelic viTar-

deba rogorc kompensatoruli pasuxi Tireoiduli hormonis naklebobaze

(Прокопчук В.С., 1980; Алешин Б.П., 1981; Талантов В.В., 1983; Зелъцер М.Е., 1988; Назаров

А.Р., и соавт., 1989; Шадлинский В.Б., 1999; Мычка Н.В., и соавт., 2006; Балаболкин Б.И., и

соавт., 2007; Alexander et al., 2003. Ганиева Г. и соавт. 2012, 2014).

arsebobs hiperTireozis sami varianti: greivsis daavadeba (Graves),

toqsikuri multinodularuli Ciyvi da erTeuli toqsikuri kvanZebi (Michael

E, Mc Dermott, 1998; Blum, Hussian, 2003) Tireotoqsikozis 80% modis difuzur

toqsikur Ciyvze (Баранов В.Г., 1977) toqsikur mravalkvanZovan Ciyvs, romel-

sac aseve uwodeben plameris daavadebas (Plummer H.S) da greivsis daavadebas

aqvT identuri klinikuri gamovlineba, magram gansxvavdebian paTogeneziT.

difuzuri-toqsikuri Ciyvis dros jirkvlis TiTqmis yvela wilaki Tanab-

radaa gadidebuli, mravalkvanZovani toqsikuri CiyvisTvis ki damaxasia-

Tebelia parenqimuli nawilis araTanabari gadideba (Zimmerman et al., 2004; De

la Torre et al.,2006; Cannon, 2011).

bolo wlebSi farisebri jirkvlis daavadebis problema sul ufro

aqtualuri xdeba, rac ganpirobebulia, upirveles yovlisa imiT, rom

avadobis maCveneblebi izrdeba. es garemoeba aisxneba bolo aTaswleu-

lisaTvis damaxasiaTebeli ramdenime faqtoriT: biosferos radiaciuli

dabinZurebis gaZlierebiT, sasmel wyalsa da sakvebSi iodis deficitiT,

nervuli sistemis gadaZabviT, teqnologiuri progresiT (farisebr jirk-

valSi Tireoiduli hormonogenezis mudmivi cvladoba, monawileoba

organizmis adaptaciur reaqciebSi), medikamentebis arasafuZvliani farTe

moxmarebiT, maT ricxvSi iodis preparatebisac, da SesaZlebelia,

diagnostikis gaumjobesebiT.

9

meore mxriv, farisebri jirkvlis mTel rig daavadebaTa paTogenezSi

wamyvan rols aniWeben autoimunur meqanizmebs (Быков В.Л., 2004; Nagy E.V. et al.,

1995; Raju R., Navaneetham D.et al., 1997; Zantur B., Messaoud R et al., 2003; Pearce et al., 2003;

Burek, Rose, 2008) jer kidev 1972 wels G. Werner-ma gamoTqva mosazreba,rom

greivsis daavadebas aqvs autoimunuri xasiaTi da misi klinikuri suraTi da

ganviTarebis Tavisebureba damokidebulia mxolod imunuri pasuxis ama Tu

im komponentze, e.i. Tu imunuri pasuxis done maRali ar aris, Warbobs

hormonmastimulirebeli efeqti difuzuri toqsikuri Ciyvis ganviTarebiT.

avtorma farisebri jirkvlis autoimunuri daavadebebisaTvis SemoiRo

specialuri termini „imunoTireoidizmi“

Catarebuli epidemiologiuri gamokvlevebis safuZvelze Toreoiduli

hiperplaziis warmoSobis mTavar risk-faqtorebad miCneulia jirkvlis

radiaciuli dasxiveba bavSvobis asakSi, gadametebuli hormonaluri

stimulacia hipofizis mxridan, gamowveuli iodis arasakmarisi miwodebiT

wyliT da sakvebi produqtebiT, agreTve memkvidreobiTi midrekileba.

gamoyofen egzogenur da endogenur risk-faqtorebs. erT-erTi egzo-

genuri faqtori aris alimenturi. dadgenilia korelaciuri kavSiri

farisebri jirkvlis disfunqciasa da moxmarebul sakveb produqtebSi

cximis, cximovani mJavebis, kalciumis, boris da siliciumis marilebis,

aseve zogierTi samkurnalo nivTierebebis (rezorcini, PASC, Tireosta-

tikebi, fenobarbitali) gadametebul raodenobas Soris.

Tireoiduli ujredebis hiperplazias iwvevs agreTve iodis, AA da C

vitaminebis da cilebis nakleboba.CamoTvlili nivTierebebidan upiratesi

roli eniWeba iods.am elementis nakleboba ueWvelad xels uwyobs

Tireoiduli qsobilis hiperplaziis ganviTarebas, romlis fonze SemdgomSi

SeiZleba toqsikuri zrdis kera [thyromed.com/urjercy.php 24.12.2011] aRmocendes.

iodis normuli miwodeba astimulirebs farisebri jirkvlis kibos

ujredebis apoptozs, xels uSlis farisebri jirkvlis diferenciaciis

procesebis transformacias aradiferencirebulSi. Tumca, iodis

kompleqsuri SenaerTebis da maTi moqmedebi meqanizmebi farisebri

jirkvlis funqciebze bolomde araa gamokvleuli.Aaqve unda aRiniSnos, rom

Tireoiduli kvanZebis gamovlena ufro xSiria im regionebSi, sadac kvebis

produqtebSi adgili aqvs iodis naklebobas, im regionebTan SedarebiT,

10

sadac iodis mowodeba sakvebTan erTad sakmarisia. varaudoben aseve, rom

farisebri jirkvlis disfunqciis sixSire ufro maRalia im regionebSi,

sadac iodis SeRweva organizmSi araa sakmarisi, magram es warmodgena

iTxovs damtkicebas. amis miuxedavad, regionebSi, sadac organizmSi

arasakmarisi iodi Semodis da endemuri Ciyvis SemTxvevaTa maRali donea,

ufro xSirad aRiniSneba histologiurad verificirebuli kibo im

regionebTan SedarebiT, sadac organizmi iodis sakmaris raodenobas iRebs.

meore mxriv, kvlevis Sedegad dadgenilia, rom profilaqtikis mizniT

iodis moxmareba iwvevs papilaruli kibos procentuli Sefardebis zrdas

da folikuluri da aradiferencirebuli kibos sixSiris mniSvnelovnad

Semcirebas, es eTanxmeba im faqts, rom papiluri kibos sixSire

mniSvnelovnad dominirebs im regionebSi, sadac iodis SeRweva organizmSi

momatebulia (Попов, 2011).

zogierTi mkvlevari fiqrobs, rom farisebr jirkvalze iodis an misi

deficitis zemoqmedebis meqanizmi gamowveulia cvlilebebiT hipofizis

Tireotropuli hormonis sekreciaSi, sxvebi Tireoidul homeostazSi

amdagvar gadaxras ar eTanxmebian. gamoiTqmeba azri imis Sesaxeb, rom iodis

qronikuli moxmareba mniSvnelovnad zrdis kvanZovani, hipoTireoziT

mimdinare procesebis ganviTarebis riks qalebSi, romlebsac anamnezSi

gaaCniaT farisebri jirkvlis subklinikuri disfunqcia da problema

reproduqciuli funqciis mxriv (Павлова Т.В., Малютина Е.С. и соавт.,2012;

Hennessey, 2011).

eqsperimentSi naCvenebia hipofizis Tireotropuli hormonis Semcve-

lobis zrda sisxlSi, aris agreTve sxva mniSvnelovani etiologiuri da

paTogenuri faqtori, romelic farisebri jirkvlis disfunqcias iwvevs.

N(Nishihara, Hirokawa et al., 2010; Dahlgren et al., 2010).

miuxedavad imisa, rom Tireotropuli hormonis, rogorc folikulebis

hiperplaziis uSualo stimulatoris roli eWvis qveSaa, mis gadaWarbebas,

sakvebSi iodis arasakmarisi Semcvelobis da strumogenuri moqmedebis

preparatebis xangrZliv moxmarebisas, ukavSireben hipoTireozis

ganviTarebas. zogierTi avtoris TvalsazrisiT, rigi qimiuri kancerogeni,

Tireotropuli hormoniT farisebri jirkvlis stimulaciasTan erTad

11

zrdis kvanZebis ganviTarebis sixSires da amcirebs maTi gamovlenis

latentur periods [thyromed.com/urjercy.php 24.12.2011]

xazi unda gaesvas imas, rom bavSvobaSi kisris areSi garegani dasxiveba

ariserTaderTi dadgenili garegani faqtori, romlis mimarT dadastu-

rebulia farisebri jirkvlis paTologiis ganviTarebasTan kavSiri.

maRalmTiani regionebis mcxovrebni ganicdian kosmosuri sxivebis

gansakuTrebiT intensiur zemoqmedebas. dResdReobiT, am zonis mosaxle-

obaze Catarebulia ori gamokvleva da orives Sedegebi aRmoCnda uaryo-

fiTi. Tumca gamokvleuli pirebis SedarebiT mcire raodenoba, maTi

ukiduresad mcire diapazoni da dasxivebis dabali dozebi arTuleben am

Sedegebis gansjas (Браверманн Л.И., 2000)

iodis deficitis dominanturi mniSvneloba endemuri Ciyvis paTo-

logiaSi sazogadod miRebulia, magram Znelia aisxnas regionebSi mZime

Ciyvis endemiiT ratom ar avaddeba yvela da iodiT profilaqtika ar axdens

daavadebis srul likvidacias. garkveuliTvalsazrisiT es samarTliania

farisebri jirkvlis kibos da Hashimoto-s autoimunuri Tireoiditis mimarT

Cernobilis Semdgom periodSi, rodesac gamovlinda sxvaoba prognozirebad

da realur avadobas Soris. Sesabamisad, arsebobs sxva mizezebi,

ganpirobebuli TviT organizmis individualuri TaviseburebebiT - adaminis

genetikuri midrekilebebiT da gansxvavebuli reaqciiT garesamyaros

faqtorebis zemoqmedebaze (Пушников Е.Ф., 2006)

sadReisod, Tanamedrove koncefcia euTireoiduli Ciyvis paTogenezis

Sesaxeb arasrulyofilia. am daavadebis klasifikaciac arasakmarisad aris

warmodgenili. organos difuzuri gadidebis da koloid-kvanZovani formis

ganviTarebis mizezebi realurad araa cnobili, Tumca, Li Volsi (1994), Colin da

Tanaavt. (1990) gamoTqves mosazreba, rom autoimunuri Ciyvis paTogenezSi

arsebobs genetikuri komponenti.maTi mosazrebiT, sxvadasxva SemTxvevaSi es

komponenti warmodgenilia sxvadasxva moculobiT. Blum M., Kranjac T. (1976);

Chistiakov D. (2006), Werner G.S et al. (1986) aRniSnaven, rom mniSvnelovani roli

eniWeba ara marto iodis deficits da tranzitorul hipoTireozs.

Bottazzo, Pujot, BornellBda Tanaavt. (1983) Cuturegli Yejaz da Tanaavt. (2000)

wamoayenes autoimunuri Tireoiditis – Hashimoto-s Ciyvis tropogenuri Teo-

ria: mkvlevarebma Tireotropinis da antiTireoiduli antisxeulebis sekre-

12

ciis gaZlierebaSi wamyvani roli mianiWes gen HLA-DR eqspresias, rasac

Sedegad organos atrofia moyveba.

Hashimoto-s Tireoiditi, aseve cnobili, rogorc qronikuli autoimu-

nuri limfocituri Tireoiditi anu limfomatozuri Ciyvi, pirvelad aRwera

hakaru haSimotom (1912w). amJamad igi ganixileba, rogorc autoimunuri

Tireoiduli paTologia, romelsac axasiaTebs mocirkulire antisxeulebis

titri Tireoglobulinisa da Tireoidperoqsidazas mimarT (Costa, Weller,

Galli, 1997).

tipiuri qsovilovani cvlilebebi Hashimoto-s Tireoiditis dros

warmodgenilia limfoplazmocituri infiltraciiT da limfoiduri foli-

kulebis formirebiT, kargad ganviTarebuli germinaciuli centrebiT.

amavdroulad, Hashimoto-s Tireoiditi histologiurad da histopaTolo-

giurad ar warmoadgens erTgvari rigis dazianebebs. ramdenime qvetipi

Hashimoto-s Tireoiditisa, Sesabamisi kliniur-paTologiuri

TaviseburebebiT, sakmarisad gansxvavdeba tipuri Hashimoto-s Tireoiditis

suraTisagan, rac ukanasknel wlebSi iyo aRwerili (Kamisawa, Funata, Haiashi et

al.,2003; Zen, Harada et al., 2004), rogorc jirkvlovani parenqima, Canacvlebuli

mkveTrad gamoxa-tuli fibroziT, SemomsazRvrel qsovilSi tipuri

Hashimoto-s damaxasia-Tebeli suraTiT. Riedel-is Tireoiditisagan

gansxvavebiT (Pearce, Farwell, Braverman, 2003) Hashimoto-s fibrozuli variantis

dros ar aris gamoxatuli eqstraTireoiduli fibrozi.

ukanaskneli wlebis ganmavlobaSi gamoqveynda kvlevebi IgG4 Tan

dakavSirebul daavadebebTan autoimunuri Tireoiditis damokidebulebis da

kavSiris Sesaxeb. 2001 wels dadasturda pirvelad diagnostirebuli

autoimunuri pankreatitis kavSiri Hashimoto-s Tireoiditis cvlilebaTa

jgufTan. am periodidan Seswavlilia ramdenime aTeuli IgG4–Tan asoci-

rebuli paTologia, autoimunuri pankreatitis msgavsi, magaliTad repro-

peritonealuri fibrozi, masklerozebeli qolangiti (Hamano H, Kawa S, Ochi

Y. et al., 2002) sklerozuli sialoadeniti (Kitagawa S et al., 2005) da aortis

anTebiTi anevrizma (Kasashima S et al., 2008). miuxedavad IgG4 maRali titrisa,

yvela dasaxelebuli paTologia emorCileba steroidul Terapias, Tumca

organoTa dazianeba, saxeldobr, paTologiuri procesi moicavs msgavs

13

cvlilebaTa suraTs.limfoproliferaciuli infiltraciis, fibrozis,

maobliteraciebeli flebitis da IgG4 pozitiuri plazmuri ujredebis

dagrovebis saxiT.

Cveni naSromis ZiriTadi amocanidan gamomdinare, gansakuTrebiT

sayuradReboa hipoTireozis sixSire pacientebSi autoimunuri pankreatitiT,

rac adasturebs axlo paTogenezir kavSirs Hashimoto-s Tireoiditsa da IgG4

dakavSirebul daavadebebs Soris.

2009 wels iaponel mecnierTa jgufma (Kakudo K, Ozaki 2009 da sxv.) aRwera

autoimunuri Tireoiditis ramdenime morfologiuri qvetipi parenqimis

plazmuri ujredebiT infiltraciisa da Tireoiduli qsovilis anTebiTi

cvlilebebis saxiT; rac emsgavseboda IgG4 dakavSirebul sxva daavadebaTa

suraTs.amJamad, Cveni interesi imunohistoqimiuri kvlevebis mimarT

safuZvels gvaZlevs vixelmZRvaneloT arsebuli mosazrebiT da SevafasoT

sakuTari morfologiuri dakvirvebis Sedegebi Hashimoto-s Tireoiditis

dros dazianebis heterogenobis da qveklasebis mixedviT, miTumetes, rom

genderuli Tanafardoba am SemTxvevaSi gamoxatulia maRali proporciiT

qali/mamakaci, procesis ufro swrafi progresiiT, subklinikuri

hipoTireoidizmiT da mocirkulire antisxeulebis maRali titriT.

Cveni masalebis Sefasebis procesSi gamovitaneT daskvna, rom tipuri

Hashimoto-s Tireoiditis garda aris histopaTologiuri maxasiaTeblebis

detalebi, romlebic calkeul qvetipebs Soris gansxvavebis safuZvels

gvaZlevs. Hashimoto-s Tireoiditis SemTxvevebis 2-6%-Si gamovlinda

subklinikuri hipoTireozi. antiTireoiduli antisxeulebis done mniSvne-

lovnad Semcirda, korelacia Tireoiduli disfunqciasa da antiTire-

oiduli antisxeulebis dadebiT titrs Soris ar gamovlinda (Ward, 2014).

eqspertebi askvnian, rom iodis doza 190mg avsebs iodis deficits da

amcirebs endemuri Ciyvis risks moswavleebSi. UIE-s gadidebas Tan axlavs

Tireoiduli autoantisxeulebis titris gazrda da hiper da

hipotropinebis mateba, romelic ar iyo ganpirobebuli autoimunuri

meqanizmiT. HHashimoto-s Tireoiditi, piriqiT, aris multifaqtoruli,

genetikurad da ekologiurad ganpirobebuli paTologia, TireocitebSi

IgG2 dominirebiT (Weibolt, Achterberg et al., 2011).

14

miTiTebul kvlevebSi naCvenebia, rom farisebri jirkvlis paTologiis

dros Tireoiduli parenqimis dazianebebi: kvanZovani, difuzuri, autoi-

munuri, agreTve daavadebis prognozi da sicocxlis xangrZlivoba ar aris

damokidebuli procesis hitologiur tipsa da stadiaze.

endokrinologebis evropuli asociaciis da jandacvis msoflio

organizaciis monacemebi (2001, 2003) cxadyofen, rom farisebri jirkvlis

paTologiis dros („human syndrom”), iseve, rogorc sxva endokrinologiuri

daavadebebis dros ZiriTadia disbalansi saregulacio hipoTalamo-

hipofizur-farisebr rgolSi (HPT-axis), aseve Tireomastimulirebeli

hormonis (TSH) sekreciis da gamoyofis mimarT Tiroqsinis β receptorebis

epitopebis dakargva, rac qmnis fundamenturi ujreduli procesebis:

apoptozis, proliferaciis, ujreduli diferencirebis, angiogenezis,

invaziis da agreTve ujredSorisi kontaqtebis darRvevis winapirobas.

farisebri jirkvlis paTologiis Seswavlisadmi Tanamedrove midgoma

unda iTvaliswinebdes Semdeg komponentebs:

1. qsovilovani erTeulis, e.w. „histionis“, kerZod, stromis da paren-

qimis elementebis da maTi aRdgenis SesaZleblobebis Seswavlas.

2. citokinebis, maT Soris panendoTeluri sisxlZarRvovani zrdis faq-

torebis receptorebis Sefasebas, (VEGF), romlebic, Cveni warmodgeniT,

organos sisxlmomaragebis kritikuli mniSvnelobis koncepciidan

gamomdinare, ZiriTadi paTogenuri meqanizmis erT-erT Semadgenels

warmoadgenen.

angiogenezis fundamenturi gamokvlevebi erTeulia (Спринджук М.В. и

соавт., 2010) aSS janmrTelobis erovnuli instituti (NIH) flobs stati-

stikas 50 relevanturi gamokvlevis Sesaxeb, romlebic adastureben, rom:

1) VEGF eqspresia adenomatozur zrdis dros ufro maRalia, vidre

normul farisebr jirkvalSi;

2) karcinomebis dros arsebobs sisxliT momaragebis gansakuTrebuli

saxe _ glomeruluri, romlis wyaro aris organos fibrozuli kaf-

sula;

3) axali kvanZovani warmonaqmnebi ( Ciyvi) xasiaTdeba VEGF–is dabali

eqspresiiT (Vicava, Bocci eg al., 2007; Demellawy et al., 2008)

15

sakuTari kvlevis masalebze dayrdnobiT da maTi SedarebiT pirobiTi

normis monacemebTan mogvyavs zogierTi zogadbiologiuri cnoba farisebri

jirkvlis struqturisa da fiziologiis Sesaxeb. (Алсимова Н.П., Шизиченко

Н.Д., 1994, Шадлинский В.Б., 1999; Current IDD Status Datafe, http:/www.Iccidd.org.,2003;

Rzegzutko et al., 2004).

farisebri jirkvali akontrolebs, Tu rogor iRebs da anawilebs

organizmi energias, asinTezebs proteinebs, aregulirebs sxvadasxva

hormonebis mimarT mgrZnobelobas, romelTa Soris mTavaria T3 da T4

regulacia. rac xorcieldeba Tireotropuli hormoniT. T4-is dones

TrgunavsTSH, xolo TSH, Tavis mxriv, astimulirebs Tireotropin-rilizing

hormoni.TSH produqcia iTrguneba T4 maRali doniT. Tavis mxriv, TSH done

modulirdeba Tireotropin-rilizding hormoniT TRHH, romelic gamoiyofa

siciviT zemoqmedebisas. TSH produqcia blokirdeba somatostatiniT,

xolo es faqti, Tavis mxriv, zrdis iodis koncentracias sisxlSi.

Ca2+ done sisxlSi aseve regulirdeba farisebri jirkvliT,

saxeldobr, parafolikuluri ujredebi gamoimuSaveben kalcitonins,

Zvlovan qsovilSiCa2+ gadasvlis sapasuxod, paraThormonis (PTH)

efeqtisgan gansxvavebiT kalcitoninis saregulacio done ufro dabalia,

vidre paraThormonis, Ca2+ metabolizmi Tiroideqtomiis Semdgom ar

irRveva.

Tireoiduli paTologia moicavs:

_ hiperTireoidizms (aqtivobis gaZliereba normaze maRla)

_ hipoTireoidizms (aqtivobis Semcireba normaze dabla)

yvela aRniSnulma cvlilebam SeiZleba gamoiwvios farisebri jirkvlis

gadideba, anu gamoixatos Ciyvis saxiT (goiter)

hiperTireoidizmi _ farisebri jirkvlis hiperaqtivobaT3 da T4 Warbi

sekreciis Sedegad aris greivsis daavadebis da autoimunuri Tireoiditis

ganviTarebis xSiri mizezi. autoantisxeulebi gamomuSavdebian Tireoiduli

jirkvlis stimulaciis mizniT, rom ganaxorcielon Tireohormonebis

damatebiTi raodenobis sekrecia. Sedegad viTardeba toqsikuri Ciyvi,

rogorc sapasuxo reaqcia negatiuri ukumeqanizmis principiT.hiperTireozis

simptomebis kupirebisTvis gamoiyeneba β-blokatorebi da antiTireoiduli

16

preparatebi hormonis produqciis Sesamcireblad, gansakuTrebiT, greivsis

daavadebis SemTxvevaSi.

hipoTireoidizmi:

mizezi _ T3 da T4 produqciis darRveva, ZiriTadad Semcireba an

disbalansi.

hipoTireoidizmis mizezi SeiZleba iyos Tandayolili anomalia

_ autoimunuri darRvevebi Hashimoto-s Tireoiditi;

_ iodis deficiti, gansakuTrebiT, ganuviTarebel, CamorCenil qveynebSi;

_ farisebr jirkvalze totaluri an nawilobrivi qirurgiuli Careva;

_ mSobiarobis Semdgomi Tireoiditi;

tipiuri simptomebi - daRliloba, oflianoba, bradikardia.

hipoTireozi ikurneba hormonebiT (CanacvlebiTi Terapia)

zogadi Sexeduleba Semdegia - iodis deficitis dros gamomuSavdeba

Warbi raodenobiT T3 daT4, rac iwvevs organos zrdas aratoqsikuri Ciyvis

formirebiT.

jer kidev klasikur gamokvlevebSi naCvenebi iyo Tireoiduli

epiTeliumis heterogenoba (Bader E.C., 1878; Hurtle, Nonidez, 1932) eleqtronul-

mikroskopiuli kvlevebis SedegebiT Heimann-ma aRmoaCina ujredebi,

romlebic Seicaven mitoqondriebis did raodenobas, iTvleba, rom es

ujredebi Seesabameba Hurtle, Askenazy, Lennox-s mier aRweril ujredebs, maT

Sesabamisad ewodaT Hurtle-ujredebi, B-Tireocitebi an aSkenazis ujredebi,

onkocitebi (Hamperl, 1960). am ujredebis Sesaxeb informacia arasakmarisia.

fiqroben, rom BBtipis ujredebi, ganlagebuli inferfolikulur sivrceSi

farisebr jirkvalSi warmoadgenen difuzuri neiroendokrinuli sistemis

nawils, e.w APUD-ujredebs (Stojadinovic A.et al.,2001) am ujredebis roli

ucnobia, Tumca kondalenko i.f da odinokovam v.a euTireoiduli Ciyvis

parenqimaSi aRmoaCinesHurtle ujredebis ori saxe, romelTa ultra-

struqtura, maTi warmodgeniT, Seesabameba ujredebs, romlebic farisebri

jirkvlis avTvisebiani simsivneebis drosaa aRmoCenili.

mravalricxvovani avtorebi Tvlian, rom mitoqondriebis didi

raodenoba Hurtle ujredebSi ganpirobebulia am ujredebis kompensaciur-

regulaciuri roliT (РайхлинН.T., 1970, 1974) amis damadasturebeli gaxda n.a.

kraevskis da Tanaavtorebis gamokvleva sadac naCvenebia, rom Hurtle

17

ujredebi Seicaven sxvadasxva biogenuri aminebis did raodenobas. isini

miekuTvnebian neiroeqtodermuli genezis ujredebs, romlebic axdenen cila

S-100-s da antimitoqondrialuri antisxeulebis eqspresias (Caplan et al.,1994;

Pusztpszeri et al., 2013).

Hurtle ujredebis reaqcia dazianebaze, gansxvavebiTAtipis folikulebis

gamomfeni ujredebisgan, vlindeba kafsuluri da sisxlZarRvovani invaziiT.

uaxlesi gamokvlevebis monacemebidan gamomdimareobs, rom kvanZovani

euTireoiduli Ciyvis parenqimaSi, aseve Hashimoto-s Tireoiditis dros

aRiniSneba Hurtleujredebis populaciis 40%-mde zrda (ГиоргадзеЕ.Р.,

ГогиашвилиЛ.Е. исоавт, 2007; Tsagareli et al., 2011).

n.ruruas, l.gogiaSvilis, z.cagarelis (РуруаН.З.исоавт., 2013; Rurua N, 2014)

mier naCvenebia, rom Hurtle-ujredebis hiperplazia, sisxlsavseobis da

mikrocirkulaciuri kalapotis simWidrovis gadidebis fonze, aris

ujredebis displaziisa da hipoTireozis (Caturego et al., 2000) prognozuli

niSani. sxva avtorebi HHurtle-ujredebiT ganpirobebul hipoTireoidizms

xsnian interferon γ-s eqspresiiT.

farisebri jirkvlis dazianebas Hurtle-ujredebis monawileobiT

axasiaTebs organos normuli arqiteqtonikis darRveva, xangrZlivi

hipoTireoidizmi da Hurtle-ujreduli metaplazia, romelTa asaxsnelad

gansakuTrebiT mniSvnelovania dasaxelebuli tipis populaciis Seswavla.

Bhatacharyga et al., (2003) mier transgenuri xazis Castle Tagvebze, Stami C57/58

Catarebuli eqsperimentis Sedegebma daadgines cvlilebebis maRali

msgavseba adaminis farisebri jirkvlis paTologiasTan. naCvenebia, rom

Hurtle ujredebis dazianeba aris hipoTireoidizmis prediqti, axasiaTebs

ruxi cximovani qsovilis mniSvnelovani akumulacia interfolikulur

sivrceSi, monocituri homopoezuri ujredebis infiltracia da sakuTriv

Hurtle-ujredebis metaplazia. (Canon et al., 2011)

unda aRvniSnoT, rom toqsikuri Ciyvisgan gansxvavebiT, euTireoiduli

Ciyvis dros konstantirebulia Hurtle-ujredebis (onkocitebis) populaciis

zrda 40 %-iT, rac ujreduli displaziis prognozuli maCvenebelia da

vlindeba moleklur-biologiuri da genetikuri markerebis Tavisebure-

bebiT, saxeldobr, bcl-2 mimarT epitopebis arseboba, Ki-67 dabali eqspresia,

18

C-mycgenebis maRali eqspresia, apoptozis SedarebiT dabali indeqsi

(Renshaw, 2002).

araiSviaTad, punqciur-aspiraciuli biofsiis (FNAB) dros wagrZele-

buli formis epiTelioiduri ujredebi aspiratSi SeiZleba miRebul iqnas

Hurtle ujredebad, romlebic FNAB drosrealurad mxolod nimuSebis 5%-Si

gvxvdeba.sadiagnostiko Secdomis mizezia farisebr jirkvalSi

epiTelioiduri cistis arseboba, romelic gamofenilia wagrZelebuli da

poligonaluri Hurtle msgavsi ujredebiT, mkvrivi, eozinofiluri cito-

plazmiT. umravles SemTxvevaSi es Seesabameba farisebri jirkvlis FNAB

maCveneblebs keTilTvisebiani Hurtle-metaplaziis dros. (Faquin et al., 2005).

mxedvelobaSi misaRebia, rom folikuluri ujredebis raodenobis momateba

mitozuri koeficientis cvlilebebis gareSe aRwerilia eqsperimentuli

Ciyvis drosac (РухадзеР.Г.,2004).

normuli farisebri jirkvlis Tireoiduli epiTeliumis mitozuri

aqtivobis monacemebi upiratesad eqsperimentul xasiaTs atarebs. rigi

avtorebis monacemebiT (ТрехверЮ.Т.,1972; Crisatov et al.,1973) cxovelebis

farisebri jirkvali xasiaTdeba Zalian dabali mitozuri aqtivobiT, Tumca

Redmond da Tanaavt. (1978) aRniSnaven, rom virTagvebis farisebri jirkvlis

folikuluri ujredebis mitozuri aqtivoba sakmaod didia.amave dros eWvs

ar iwvevs is faqti, rom farisebri jirkvlis erT-erTi Tavisebureba aris

misi parenqimis maRaliproliferaciuli potenciali. amis damadasturebelia

misi swrafi regeneraciuli Tviseba rogorc travmis, ise nawilobrivi

Tireoideqtomiis Semdeg da aseve Ciyvis formirebis procesSi

(АлешинБ.В.исоавт.,1988) maRali proliferaciuli aqtivobis miuxedavad

folikulur ujredebSi mitozuri figurebis aRmoCena sakmaod rTulia

(ЦагарелиЗ.Г.исоавт.,2011).

farisebri jirkvlis funqciis cvlilebaTa induqciaSi did rols

TamaSobs misi sisxlis mimoqcevis sistemis cvlileba, gaZliereba an

reduqcia, angiogenezis raodenobrivi an Tvisobrivi gadakeTeba.

angiogenezi warmoadgens mravalsafexurovan process, qsovilis

biopotencialis Sefasebis wamyvan faqtors. (Rzeszutko et al., 2004).

am TvalsazrisiT endokrinuli jirkvlebi yvelaze ufro xelsayreli

eqsperimentuli modelia angiogenezis SeswavlisTvis. neovaskularizacia,

19

romelic isazRvreba mikrosisxlZarRvTa simWidroviT (density) imyofeba

pirdapir kavSirSi angiogenezis fenomenTan (КрючковаА.Н.,ФрейндГ.Г.,2008).

sisxlZarRvovani endoTeluri faqtori (VEGF) endoTeluri ujredebis

zrdis stimulatoria da SeuZlia gaaZlieros maTi hiperplazia rogorc

fiziologiur, ise paTologiur procesSi (Rzeszusko eg al., 2004; Gabreel, England

et al., 2007; Viacava, Bocei, Tonachera et al., 2007) VEGF- iT ganpirobebuli efeqti

vlindeba VEGFR-2 meSveobiT endoTeliocitebze, VEGFR-1 asrulebs

angiogenezis receptorebis regulatoris rols parakrinuli efeqtis

saSualebiT, autokrinuli regulatoruli rgolis inhibirebiT (Gabreel,

Ferrara, 2003 Saleh H.A et al., 2010).

neovaskularizaciasa da mikrosisxlZarRvebis simkvrives Soris damtki-

cebuli korelaciis miuxedavad, farisebri jirkvlis struqturuli Zvrebi

am poziciidan arasakmarisad aris Seswavlili. ufro metic, arsebobs

gamokvlevebi, romlebic miuTiTeben daavadebis gamovlinebis da zrdis

biologiur potencials Soris disbalansze (Sanders, Silverman, 1998; Akslen,

LiVolsi, 2000; Cristopher et al., 2011).

angiogenezimniSvnelovan rols TamaSobs transformirebuli fari-sebri

jirkvlis funqciaSi, rodesac endoTeluri ujredebis proliferacia

uswrebs Tireocitebis hiperplazias.

rig naSromebSi naCvenebia, rom angiogenezis daTrgunva

SesaZlebeliazogierTi zrdis faqtoriT, kerZod, endoTeliocitebis

apoptozis stimu-latoriT, magaliTad, endostatiniT. endostatins SeuZlia

gamoiwvios endoTeliocitebisa da maTi winamorbedebis

endostatindamokidebuli apop-tozi (Hoffman, Hofbauer et al., 2004; Klubo-

Gwedzinska et al., 2007; Saleh Y., Jin et al., 2010). avtorebi erTsulovnebi arian imaSi,

rom imunomarkerebi CD34, CD31, p27 Tireoiduli parenqimis zrdis

potencialis adekvaturi indikatorebia. VEGF produqcias Tvlian

Tireotropin (TSH)-inducirebulad (Hoffman, Hofbauer et al., 2004), radgan TSH

zrdis qsovilSiVEGFmRNA cilis Semcve-lobas. angiogenezi xorcieldeba

axali sisxlZarRvebis formirebis stimulaciiT ukve arsebuli

endoTeliocitebidan.

20

VEGF sisxlZarRvovani endoTeluri zrdis faqtori specialuri

mitogenia endoTeluri ujredebisTvis. dadgenilia angiogenezSi misi mTa-

vari mediatoris funqcia farisebr jirkvalSi (Klubo-Gwedzonska et al., 2007),

angiogenezis biopotencialis Sefasebis safuZvlad miRebulia

perivaskuluri zonebis zrdis Sefaseba, romlebic mgrZnobiarea Semdegi

faqtorebis mimarT:

_ insulinis msgavsi zrdis faqtori - IGF-1 moqmedebis faqtori; TGF –

β1 apoptozis induqtiuri da kolagenis produqciis mastimulire-beli, rac

fibrozis gavrcelebas uwyobs xels.

Rogorc Rzeszutko et al.(2004) Sromebidan irkveva, angiogenezi farisebr

jirkvalSi warmoadgens mravalsafexurian process, dakavSirebuls

ujredSoris matriqsTan, proliferaciasTan da endoTeluri ujredebis

migraciasTan.

bevri mkvlevaris daskvniT farisebr jirkvalSi sxvadasxva antisxeu-

lebis gamoyenebam angiogenezis vizualizaciisTvis da misi Sefasebis

mizniT cvladi parametrebis gamoyenebam SeiZleba migviyvanos gansxvavebul

Sedegebamde da daskvnebamde (Saleh et al., 2010; McHenry et al., 2011).

mikrosisxlZarRvebis raodenoba avlens gansxvavebas sxvadasxva

histologiuri tipis cvlilebebSi. keTilTvisebian procesSi sisxlZarR-

vebis raodenobam gadaaWarba maT ricxvs avTvisebian simsivneebSi. ase

magaliTad, avTvisebian simsivneebs Soris mikrosisxlZarRvebis maqsimumi

aRmoCenili iyo papilur karcinomaSi, rac SeiZleba aisxnas swored

dazianebis konkretuli histologiuri tipiT. am monacemebis saSualebiT

SeiZleba gakeTdes daskvna, rom angiogenezi, romelic Tan axlavs

keTilTvisebian hipertroful cvlilebebs, maT Soris, difuzur toqsikur

Ciyvs, realizdeba mcire diametris mravalricxvovani sisxlZarRvebis

formirebiT, maSin, rodesac avTvisebian simsivneebSi warmodgenilia didi

diametris sisxlZarRvebi.

farisebri jirkvlis dazianebis droscalkeul histologiur tipebis

mixedviT erTidaigive parametris (MVA) Sefasebisas mniSvnelovani

gansxvaveba ar iyo naCvenebi (Ling Lan et al.,2007). sisxlZarRebiT dakavebuli

farTobi farisebri jirkvlis calkeul kvanZovan warmonaqmnebSi iyo

analogiuri, miuxedavad sxvaobisa axalwarmoqmnil mikrosisxlZarRvTa

21

raodenobaSi, amitom, Rzeszutko da Tanaavtorebi(2004), Tseleni-Balafuta et al.(2006)

farisebr jirkvalSi angiogenezis Seswavlisas gamoyofen axali

warmonaqmnebis or saxeobas: hipo da hipervaskularuls. farisebri

jirkvlis kvanZebSi gamoxatuli angiogenezi miuTiTebs keTilTvisebian

procesze, n.rurua, l. gogiaSvili, z. cagareli(2013) Tireoidul qsovilSi

angiogenezis aqtivobis Sefasebis dros mividnen daskvnamde, rom VEGF-

reaqciis dabali intensivoba aRniSnuli iyo farisebr jirkvalSi mcire

hiper da hipoaqtiur ubnebSi.gamoxatul angiogenezs adgili hqonda

avTvisebian kvanZebSi, romlebic gansxvavdebodnen sisxlZarRvebis simWid-

roviT, rac Tavis mxriv, damokidebuli iyo procesis histologiur tipze

(raobaze).

22

Tavi II

gamokvlevis dizaini, masala da meTodebi

2.1 klinikuri masalis SemTxvevaTa SerCeva da Sefaseba

(ZiriTadi da sakontrolo jgufebi)

gamokvlevis relaciur monacemTa bazas warmoadgens orive sqesis

pacientebidan miRebuli operaciul-biofsiuri masala totaluri

Tireoideqtomiis, f.j calmxrivi lobeqtomiis da nawilobrivi rezeqciis

Semdeg. naSromSi aseve gamoyenebulia retrospeqtiuli masala.

mTlianad Seswavlilia Hashimoto-s Tireoiditis 59 SemTxveva,

endokrinologiis erovnuli institutis saarqivo masalebis mixedviT (2006-

2010) _ 21 SemTxveva da 38 axali dakvirveba igive samkurnalo dawesebu-

lebidan (2011-2014) pacientebidan – 10 mamakaci da 49 qali. warmodgenil

kvlevaSi pacientebis saSualo asaki 47 weli (23 dan 70 wlamde) pacientebs

CautardaT totaluri Tireoideqtomia sxvadasxva mizeziT. maT Soris,

Zlieri gadideba (n=12) traqeis stenozi sunTqvis gaZnelebiT gadidebuli

farisebri jirkvlis gamo (n=19), tkivili (n=7) kvanZovani dazianeba (n=17),

papilur karcinomasTan Serwyma (n=4).

klinikuri monacemebi, laboratoriuli da ultrasonografiuli

maCveneblebi, mkurnalobisa da operaciuli Carevis meTodebi miRebulia

Sesabamisi referaluri sabuTebidan pacientis werilobiTi informirebuli

Tanxmobis Semdeg.

laboratoriuli monacemebi miuTiTebdnen antiTireoiduli peroqsi-

dazis mimarT antisxeulebis arsebobaze, calkeul SemTxvevaSi (n=6) aRi-

niSneboda antiTireoglobulinuri antisxeulebi. Hashimoto-s Tireoiditis

klinikuri diagnozi efuZneboda endokrinologTa evropis asociaciis, aSS

klinikur endokrinologTa asociaciisa[ACCE–http://www. aace.com] da

msoflio jandacvis organizaciis gaidlainebs. xolo Semdgom dadasturda

operaciuli masalis histopaTologiuri kvlevebis SedegiT.

rogorc wesi, Hashimoto-sTireoiditis tipiur histopaTologiur

suraTSi warmodgenilia limfoplazmocituri infiltracia, folikulebis

23

germinaciuli centrebis formirebiTa da araiSviaTad, maTi destruqciiT,

Hurtle-s ujredebis cvlilebebi, aseve fibrozis sxvadasxva xarisxi.

fokaluri (araspecifikuri) limfocituri Tireoiditi farisebri

jirkvlis simsivnurad transformirebul qsovilSi kvlevaSi ar aris

Setanili.

aseTive wesiT moZiebulia difuzur-toqsikuri Ciyvis operaciuli

masala (n=83).

yvela dakvirvebis da manipulaciis dros gaTvaliswinebul iqna

iv.javaxiSvilis saxelobis Tbilisis saxelmwifo universitetis bioeTikuri

komisiis moTxovnebi.

difuzuri toqsikuri Ciyvis klinikur-laboratoriuli monacemebi

dakvirvebaSi CarTuli iyo 83 pacienti difuzur-toqsikuri Ciyvis

diagnoziT. asaki 19-49 weli, aqedan mamakaci (n=44) qali (n=39). yvela

gamokvleul SemTxvevaSi farisebri jirkvali iyo difuzurad gadidebuli.

SemTxvevaSi 64.5%-Si aRiniSneboda III xarisxis difuzurad gadidebuli

farisebri jirkvali, 27,9%-Si IV xarisxi, 6,38%-Si V xarisxis Ciyvi.

pacientebs aReniSnebodaT hiperTireozis simptomatika da sindromebi:

arastabiluri hemodinamika, taqikardia, saerTo sisuste, ofTalmopaTia,

oflianoba, Sromisunaris daqveiTeba, uZiloba, tremori, sunTqvisa da

ylapvis gaZneleba, Termoregulaciis moSla. reproduqciuli asakis

qalebSi aRiniSneboda dismenorea, spontanuri aborti. pacientebis 94,6%-s

aReniSneboda saSualo simZimis Tireotoqsikozi. hormonalur fonSi

dafiqsirda Semdegi Zvrebi: sisxlSi T3,T4 da TSH gamokvleuli iyo

standartuli Kit nakrebiT (“Humman”) T3– 0,69-2,02 ng/mlT4 4,4-11.6 mg/dl TSH

0,4-6,4 ml/l. dadginda T3 da T4 zrda sisxlSi, TSH mkveTri Semcireba

SemTxvevaTa 21.5%-Si aRiniSna mZime formis Tireotoqsikozi, rac TSH

nulovani raodenobiT gamoixata TSH=0

msubuqi formis dros 5,3% pacientebSi T3T4 da TSH ar gansxvavdeboda

normisagan, Tumca TSH saSualo done normis yvelaze mcire zRvars

scildeboda.

klinikuri masalis kvleva mimdinareobda Cvens mier SemuSavebuli anke-

tis mixedviT, romelSic gaTvaliswinebuli iyo: 1) sqesi, 2) asaki, 3) sa-

24

cxovrebeli adgili, 4) anamnezis xangrZlivoba, 5) operaciuli mkurnaloba,

6) memkvidreoba (endokrinologiuri daavadebebi mSoblebSi, axlo naTesa-

vebSi) qalebSi fiqsirdeboda ginekologiuri anamnezi 7) sxva qirurgiuli

Carevebi, kohortul jgufs warmonadgenda 59 pacienti Hashimoto-s Tireoi-

ditiT da 83 difuzur-toqsikuri CiyviT. masala miRebulia endokrino-

logiis erovnuli institutidan (bioqimiuri kvleva, ultrasonografia,

operaciul-biofsiuri masalaa).

sakontrolo jgufi 25 SemTxveva (e.w pirobiTi `norma”) warmodgenilia

sasamarTlo kveTis eqspertizis masaliT (anamnezSi endokrinuli paTo-

logiis gareSe). aseve Sedarebis jgufSi CavrTeT kvanZovani euTireoiduli

Ciyvis 20 SemTxveva.

memkvidreobiTi datvirTva gamovlinda kohortuli kvlevis pacientTa

47%-Si. rogorc msoflio statistikis maCveneblebi adastureben, Cvens

masalazec qalebi Seadgendnen pacientTa umravlesobas, Sefardeba 8:1. aqve

unda iTqvas, rom Hashimoto-s Tireoiditis dros Sefardeba Seadgenda 12:1.

calkeul SemTxvevaSi kvanZovani procesis Sefasebisas gamoyenebuli iyo

wvrilnemsiani aspiraciis meTodiT miRebuli (FNA) monacemebi, romelmac

daadastura koloiduri moproliferacie Ciyvis diagnozi. Sesadarebel

jgufSi (kvanZovani euTireoiduli CiyviNn=20), klinikur suraTs gansa-

zRvravda hormonuli foni, farisebri jirkvlis zomebi, forma, dazianebis

simetria. iseve, rogorc Hashimoto-s Tireoiditis dros, farisebri jirkvlis

zomebi meryeobda II-V xarisxamde, didi zomis kvanZis dros viTardeboda

sasunTqi gzebis kompresia, aseve irgvliv myofi qsovilebis zewola, rac

Hashimoto-s Tireoiditis pirobebSi operaciis Cvenebis erT-erT dominants

wamoadgenda.

2.2 histologiuri kvlevis meTodebi

farisebri jirkvlis sxvadasxva ubnebidan aRebuli qsovilovani nimuSebi

fiqsirdeboda 10% formalinis buferul xsnarSi (pH=7.35). dehidrataciis

Semdeb masalis Cayalibeba xdeboda parafinis blokebSi. seriuli anaTlebi

iRebeboda hematoqsiliniTa da eoziniT. (H&E), zogierT SemTxvevaSi

pikrofuqsiniT van gizonis wesiT.

25

morfologiuri kvlevis mizniT Seswavlilia: folikulaTa ganakveTis

farTobi, Tireocitis, misi birTvebisa da citoplazmis farTobi, kapilaris

ganakveTis farTobi. agreTve gansazRvruli iqna folikulebisa da

Tireocitebis saSualo raodenoba erT folikulSi.

am miznebisaTvis gamoyenebuli iqna trinokularuli mikroskopi Daffodil

MCX100, okular-mikrometri MOB-1 15X . yvela metriuli procedura

tardeboda obieqtivi 90X, okulari 7X gadidebis pirobebSi.

folikulebis da Tireocitebis ricxvis dadgenisas mxedvelobis velSi

viTvlidiT im struqturebs, romelTa diametris 2/3 ze meti iyo misawvdomi

gasazomad. aRebuli iyo 50 (mina) nimuSi Seswavlili jgufebidan. TiToeul

jgufSi aiTvleboda 50 mxedvelobis velze ganlagebuli parametrebis

farTobi da raodenoba. viTvlidiT saSualo mniSvnelobebs, roca

calkeuli maCveneblebis ricxvi Nn=50. farTobi gamosaxulia mkm2-Si.

folikulebis, Tireocitebis, kapilarebis, birTvebis farTobi

gamoiTvleboda formuliT: V=a2bπσ

π = 3.14

a da b – didi da mcire diametri

σ – saSualo ariTmetikuli cdoma (±M)

statistikuri kvlevis mizniT gamoyenebulia paketi IBM SPSS versia 22.0.

Man-Whitney-s koeficientis gamoTvla. statistikurad sarwmuno sxvaobad

iTvleboda p≤0,05

yvela gamokvleuli maCvenebeli Sedarebulia rogorc normasTan, iseve

Seswavlil jgufebs Soris.

2.3 imunohistoqimiuri kvlevis meTodebi

kvlevis mizani iyo sisxlZarRvTa endoTeluri zrdis faqtoris (VEGF),

Tireoidmastimulirebeli hormonis (TSH), S-100 cilis da TTF-1 da CD34

eqspresiis aqtivobis kvleva farisebri jirkvlis yvela Seswavlili

dazianebis dros.

sisxlZarRvTa endoTeliumis zrdis faqtori (VEGF) warmoadgens

endoTeliocitebis sasignalo cilas da SeuZlia gaaaqtiuros maTi zrda

26

rogorc fiziologiur, ise paTologiur pirobebSi (Senino, McDonald 2012;

Tohyama, Matsui, Kodama et al, 2014).

angiogenezi asrulebs sakvanZo rols farisebri jirkvlis Ciyvisebri

transformaciis msgavs procesebSi, gansakuTrebiT, rodesac endoTeluri

ujredebis proliferacia win uswrebs folikulebis zrdas, gansazRvravs

VEGF donis matebas sisxlis SratSi da intraTireoidul arealSi

toqsikuri da Hashimoto-s tipis goitrogenezis dros (Tseleni-Balafouta et al,

2006).

cila CD34- warmoadgens endoTeluri ujredebis proliferaciis mTavar

xelSemwyob faqtors ara marto nodularul procesebSi, aramed anTebiT,

maT Soris autoimunuri aqtivobiT mimdinare procesebSi.

dagegmili amocanis farglebSi cila S-100 receptoruli statusis

kvleva Hurthle-s TireocitebSi, romlebic ar eqspresireben TSH-s,

gamoavlens am ujredTa proliferaciiT mimdinare procesebs

(gamoyenebulia poliklonuri antisxeulebi RTU-S100p neiroendo-krinuli

genezis struqturebisTvis,.

adamianis TTF-1 aris 38 Kd birTvuli proteini (NK-2 jgufis

transkripciis faqtori. asrulebs saregulacio cilisa da organogenezis

maregulirebeli faqtoris rols.Mmas axasiaTebs filtvis, tvinis da

farisebri jirkvlis normul da neoplaziur qsovilSi maRali eqspresia,

ris gamoc warmoadgens farisebri jirkvlis avTvisebiani zrdis

mniSvnelovan markers. VEGF da CD34 prognozuli Rirebuleba ukavSirdeba

operaciis Semdgomi recidivebis prognozis SesaZleblobas.

Cveni kvlevis specialuri amocanebidan gamomdinare mizanmimarTulad

Seswavlilia VEGF, CD34 da TSH eqspresiis Taviseburebani aseve S-100 cilisa

da TTF-1-s aqtivoba farisebri jirkvlis qsovilSi difuzuri toqsikuri

Ciyvis da Hashimoto-s Tireoiditis dros. aseTi midgoma mniSvnelovani da

ganmsazRvrelia, radgan ori dasaxelebuli nozologiuri erTeuli

gansxvavdeba funqciuri aqtivobiT, magram paTogeneziT autoimunur

daavadebaTa gamovlenis or saxeobas warmoadgens. amave dros SeiZleba

vupasuxoT kiTxvaze: aris Tu ara Hurthle-s ujredebis proliferacia

asocirebuli A-tipis Tireocitebis apoptozTan, ris Sedegad adgili aqvs

27

farisebri jirkvlis parenqimis Canacvlebas difuzuri limfoiduri

infiltraciiT hipoTireozis gamosavaliT.

crudadebiTi da cruuaryofiTi Sedegebis gamoricxvis mizniT

imunohistoqimiuri reaqciebi Catarda ganmeorebiT reJimSi, aseve sxva

Tireoiduli paTologiis dros.

WHO klasifikaciis Tanaxmad Cvens masalaSi yvela Seswavlili

Tireoiduli paTologia dayofilia 3 jgufad:

1). Hashimoto-s Tireoiditi (n=20),

2), difuzuri toqsikuri Ciyvi (n=20)

3). kvanZovani Ciyvi (n=20)

aseve 10 SemTxveva, “normuli” qsovilis nimuSebi, moZiebuli

sasamarTlo-samedicino eqspertizis biurodan, e.w “sasamarTlo gakveTis”

masalebi.

yvela anaTali aRebulia poli-L-lysine-T dafarul sasagne minaze. reaqciis

msvleloba Semdegia:

1). deparafinizacia, rehidratacia da inkubacia 30 wT 3% H2O2xsnarSi;

2). 20 wT fosfatur buferSi dayovneba (PBS),

3). antigenis demaskireba mikrotalRuri Rumelis reJimSi (600W) 20 wT)

citratul buferSi gacivebis fazebiT (0.01µ;PH 6.0)

anaTlebis inkubacia xdeboda pirvelad antisxeulebTan 1 saaTiT

oTaxis temperaturaze, 3-jeradi garecxviT PBS oTaxis temperaturaze,

meoradi antisxeulebiT zemoqmedeba da imunuri kompleqsebis identifikacia

streptavidinperoqsidazas saSualebiT. inkubacia xdeboda:

1) poliklonuri anti-VEGF -165 antisxeulebiT 1:50 ganzavebiT

2) poliklonuri anti TSH-antisxeulebTan (BioGenex, aSS)

3)Mmonoklonuri anti CD34-clone QBEnd/10 – ganzaveba 1:20 (BioGenex, aSS)

4) cila S-100 – deteqcia RTU-S100p poliklonuri antisxeulebi (BioGenex,

aSS)

5) TTF-1antisxeulebi, ganzaveba 1:25 (clone SPT24, “Novocastra”).

Sedegebis vizualizacia tardeboda 0,05% 3,3 diaminobenzidinisa da

wyalbadis zeJangis garemoSi, birTvebis daRebva xdeboda hematoqsiliniT,

28

gamWvirvalobis uzrunvelyofa – DPX. yvela proceduras vatarebdiT

mwarmoebeli firmis rekomendaciiT (“BioGenex”, “Novocastra”).

mikrosisxlZarRvTa simWidrovesa da raodenobas vafasebdiT Rzeszutko

da Tanaavt (2004) da Yamamoto da Tanaavt.(2004) mier mowodebuli rekomen-

daciebiTa da meTodologiiT. mikrosisxlZarRvTa simWidrove (MVD)

SeswavliliaVEGF eqspresiis mixedviT 50 mxedvelobis velSi, miuxedavad

imisa, aris Tu ara (vizualizdeba Tu ara) sisxlZarRvTa sanaTurebi,

amdenad,VEGF eqspresiis dros SeRebili endoTeluri ujredebi an maTi

klasterebi identificirebuli iyo rogorc calkeuli mikrosisxlZarRvi.

patara gadidebiT (X40) Seswavlis Semdeg SerCeul iqna sami mxedvelobis

veli fibrozisa da limfoiduri infiltraciis gareSe, sisxlZarRvTa

maqsimaluri koncentraciiT (“hot spots”). momdevno etapzeSuqoptikuri

mikroskopis did gadidebaze (200X) ganisazRvra mikrosisxlZarRvTa

raodenoba da simWidrove (AMC/Field)(Rurua N.Z et al. 2013).

imunohistoqimiuri kvlevis Sedegebisa da mikrosisxlZarRvTa

simWidrovis Sefaseba xdeboda Suqoptikur mikroskopze “Daffodil” MCX-100 (

avstria), romelic aRWurvilia “Sony”-s cifruli fotokameriT mikrosko-

puli gamosaxulebis kompiuterul ekranze gardaqmnis SesaZleblobiT.

TSH, CD34, VEGF, cila S-100 da TTF-1 eqspresiis intensivobas viTvlidiT

naxevradraodenobrivi meTodiT (Rydlova et al., 2008) Semdegi sqemiT: uaryofiTi

(0), 1=≤10%; 2=11-50%; 3=51-80%; 4=>80%

statistikuri analizisTvis gamoiyeneboda programa Microsoft Excel 7.0,

aseve SPSS/PS versia 22.0 Windows-Tvis, saWiroebis dros CarTuli iyo X2

kriteriumi, ranguli, man-uitnisa da livinis dispersiuli

parametrebi.Sesadarebel jgufebs Soris zRvari P≤0.05 iTvleboda

statistikurad sarwmunod.

masalis ganawileba gamoyenebuli morfologiuri kvleviT meTodebis

mixedviT naCvenebia cxrilSi 1:

29

cxrili 1

იმუნოჰისტოქიმია ჯგუფები

SemTxvevaTa raodenoba

VEGF TSH CD34 S100 TTF-1 მორფომეტრია

საკონტროლო(ნორმა)

25 10 10 10 10 10 10

დტჩ 83 45 40 40 40 40 50

ჰაშიმოტოსთირეოიდიტი

59 45 40 40 40 40 50

ეუთირეოიდულიჩიყვი

20 10 10 10 10 10 10

angiogenezis Sefaseba

mikrosisxlZarRvTa simWidrovis mixedviT (microvessels density test)

umravlesoba Seswavlili anaTlebisa farisebri jirkvlis qsovilis

nimuSebidan iyo araerTgvarovani mikrosisxlZarRvebis sxvadasxva

raodenobis da ganawilebis mixedviT. mikrosisxlZarRvTa Semcveli

dadebiTi velebi aiTvleboda dadebiTi reaqciiT VEGF da CD34 mimarT,

VEGF pozitiuri ki gamoiyeneboda sisxlZarRvTa simWidrovis dasadgenad

farTobis erTeulze.

kvlevis pirveli etapi:

sinaTlis mikroskopis gadidebiT X40 SerCeul iqna 3 mxedvelobis veli

mikrosisxlZarRvTa yvelaze maRali simWidroviT (density) e.w `cxeli” werti-

lebi (hot spots) sisxlZarRvebi iTvleboda gadidebiT 200X. CD34 da VEGF

dadebiTi sisxlZarRvovani velebi cifrul mikroskopze Daffodil MCX-100

(avstria) Seswavlis Semdeg procesirdeboda kompiuterul versiaSi

programiT MultiScan 5.10

yvela Seswavlil SemTxvevaSi sisxlZarRvebis totaluri raodenoba

gaTvlili iyo gadidebisTvis 200X (velze) - (MVC). xolo are, dakavebuli

VEGF dadebiTi sisxlZarRvebis mier igive velSi izomeboda, rogorc MVA.

viTvlidiT 10 reprezentul vels da TiToeul ares samjeradad.

30

masalis statistikuri analizi CatardaMicrosoft Excel-7.0 da

SPSSProfessional Statistics-20.0 (USA) versiaSi.saWiroebis dros gamoviyeneT arapa-

rametruli kriteriumi Spearman Rank test VEGF aqtivobis da erTi mxriv

sisxlZarRvTa raodenobis (MVC) da meore mxriv MVA SedarebisTvis.

31

Tavi III. sakuTari gamokvlevis Sedegebi

3.1. Hashimoto-s Tireoiditis klinikur-laboratoriuli monacemebis

Sefaseba procesis aqtivobis TvalsazrisiT

qirurgiuli wesiT amokveTili farisebri jirkvlis qsovilovani

fragmentebi fiqsirebul iqna formalinis 10% neitralur buferul xsnarSi

da Cayalibda parafinSi. seriuli anaTlebi (4mkm sisqis) yvela gamokvleuli

blokidan iRebeboda hematoqsiliniT da eoziniT, aseve imunohistoqimiuri

meTodebiT. ori paTologanatomis z.c da l.g mier Seswavlilia TiToeuli

SemTxvevidan xuTze meti hematoqsiliniT da eoziniT SeRebili

anaTali.erTi blokis principiT SerCeuli iyo masala imunohistoqimiuri

markere-bisTvis. yuradRebas vaqcevdiT Semdeg histologiuri

Taviseburebebs: stromis fibrozi, limfoplazmocituri infiltracia,

farisebri jirkvlis folikulebis zoma, folikulur ujredTa

degeneracia, limfoiduri folikulebis warmoqmna, giganturujredovani

da/an histiocituri infilt-racia, aseve solidur ujredTa budobrivi

hiperplazia da brtyelujre-dovani metaplazia. dasaxelebuli

kriteriumebis gamoyeneba xels uwyobs stromis fibrozis xarisxis

Sefasebas: 3+, Tu Tireoiduli parenqimis naxevari Canacvlebulia

fobrozuli qsoviliT, 2+, Tu 1/3 parenqimisa Canacvlebulia fibrozuli

qsoviliT; 1+, Tu 1/3-ze naklebi Tireoiduli parenqima Canacvlebulia

fibrozuli qsoviliT da _, Tu fibrozi ar aris TvalsaCino.

anaTlebi, romelTa Sefaseba Seadgenda 3+ an 2+ gamoyenebuli iqna

Hashimoto-s Tireoiditis fibrozuli variantis sadiagnostiko kriteriume-

bad, amasTan folikulebis zomebi Sefasda Semdegnairad: mikrofoli-

kulebi, zomiT naklebi vidre normaSi, diametri d<100nm)

normofolikulebi (d 200-400 nm) da makrofolikulebi (normaze ganieri,

d> 500 nm). folikuluri ujredTa degeneracias vafasebdiT degeneraciuli

folikuluri ujredebis procentuli raodenobiT did gadidebaze: mZime (3+,

>50%), zomieri (2+, 33-50%) msubuqi (1+, <33%) aseve “_” negatiuri (degene-

raciuli cvlilebebi ar vizualizdeba).

limfoiduri folikulebis formirebis xarisxi Sefasda limfoiduri

folikulebis siWarbiT Tireoidul stromaSi rogorc: 3+ (xSiri); 2+

32

(zomieri); 1+ (iSviaTi formireba); _ (formacia ar aris). histiocitebis

ricxvi infiltratebSi Seadgenda: didi raodenoba 3+; (>10/ did gadidebaze

erT mxedvelobis velSi), 2+ (zomieri, ≥5 ujredi imave farTobze), 1+

(susti, <5) da _(negatiuri Sedegi).

klinikuri da laboratoriuli monacemebis analizi Sejamebulia

cxrilSi 2; mocirkulire antisxeulebis titri (Tireoiduli peroqsidazasa

da Tireoglobulinuri antisxeulebis done Seadgenda saSualod 95% mde:

antiperoqsidazuli antisxeulebi 186 (63-438), antiTireoglobulinuri anti-

sxeulebi 510 (167-1178), antisxeulebis titri gansakuTrebiT ufro maRali

iyo Tireoiditis im SemTxvevaSi, romelic gamoirCeoda intensiuri plazmo-

cituri infiltraciiT vidre fibrozuli formis jgufSi (cxrili 2).

cxrili 2

ZiriTad klinikur simptomebsa da sisxlSi antiTireoiduli antisxeulebis titrs Soris korelacia

maCveneblebi P

pacientis asaki (wlebi) 47 ± 18

sqesi(mamakaci/qali) 16 / 21

Tireoideqtomiis Cveneba: 1/2/3/4/5 15 / 6 / 2 / 3 / 1

daavadebis xangrZlivoba (wlebi) a5 ± 4

farisebri jirkvlis funqciuri mdgomareoba (subklinikuri hipo/eu/hiperTireoidizmi) b

18 / 11 / 3

antiTireoglobulinuri antisxeulebi 510(167-1178)

antiTireoperoqsidazuli antisxeulebi 186(63-438)

Semoklebebi: 1-gadideba; 2-traqeis stenozi; 3-tkivili; 4-kvanZovani dazianeba;

5-Tanmxlebi papilaruli karcinoma

33

a _ ±Sd

b – yvela pacients ar hqonda sruli gamokvleva.

antiTireoiduli peroqsidazas antisxeulebis titri Seadgenda 85 (55-133),

xolo antiTireoglobulinis antisxeulebi Seadgenden 147 (72-303), (p=0.0086;

p=0.0168, Sesabamisad). unda gaviTvaliswinoT, rom Cveni pacientebis umrav-

lesoba operaciamde iRebda hormonoCanacvlebiT mkurnalobas

levoTiroqsiniT Tireomastimulirebeli hormonis supresiuli dozis

saxiT.

aRsaniSnavia, rom limfoplazmocituri infiltraciisa da msxvili

limfoiduri folikulebis warmoqmnis pirobebSi germinaciuli centrebis

formirebiT, rogorc wesi, gamoxatuli iyo subklinikuri hipoTireoidizmi.

amdenad, zemoT dasaxelebuli Sedegebi safuZvels gvaZlevs davaskvnaT,

rom Hashimoto-s Tireoiditi ar aris erTgvarovani dazianeba. is vlindeba

farisebri jirkvlis parenqimis sxvadasxva cvlilebebiT, romelTa xasiaTi

ganisazRvreba parenqimis limfoplazmocituri infiltraciis intensivobiT.

H&E mikroskopia

qirurgiuli wesiT amokveTili farisebri jirkvlis qsovilis

fragmentebi dafaruli iyo SemaerTebelqsovilovani SemomsazRvreli

kafsuliT, romelic ar iyo mWidrod mixorcebuli qveSmdebare

struqturebTan, rac, erTmniSvnelovnad gamoricxavda ridelis

Tireoiditis diagnozs. nekrozi an kalcifikacia ar aRiniSneboda.

34

b

sur. 1. Hashimoto-s Tireoiditi

a _ kerovani limfoplazmuri infiltracia, Warbujredovani stroma;

b _ difuzuri limfoplazmocituri infiltracia, H&E 100X

zogadmorfologiuri kvleviT dadginda, rom plazmuri ujredebi,

eqstensiuri limfoiduri infiltracia, stromis fibrozi warmoadgenen

mniSvnelovan ganmasxvavebel niSnebs fibrozul formasa da limfoidur

formas Soris. es monacemebi warmodgenilia cxrilSi 3, saidanac Cans, rom

mkveTri difuzuri an kerovani infiltracia fiqsirdeboda didi

raodenobiT plazmuri ujredebis mozidvis dros. (sur 1 a, b)

cxrili 3

zogadhistologiuri cvlilebebi Hashimoto-s Tireoiditis limfoiduri fibrozuli formebis dros

histologiuri varianti

Hashimoto-s Tireoiditis fibrozuli forman=30

Hashimoto-s Tireoiditis limfoiduri forman=29

P

fibrozuli varianti -interfolikuluri/interlobuluri

21 / 9 7 / 22 <0.001

stromis fibrozis xarisxi (3+, 2+, 1+, _)

15 / 11 / 4 / 0 12 /7 /10 / 0 <0.001

limfoplazmocituri infiltracia 3+, 2+, 1+, _

20 / 8 /2 / 0 7 / 10 / 12 / 0 <0.001

plazmuri ujredebis ricxvi mikroskopiT didi gadidebis dros

91 ± 31 57 ± 7 <0.001

35

sawinaaRmdego suraTs vxedavT limfoiduri formis dros. am SemTx-vevaSi

adgili hqonda plazmurujredovan infiltracias stromaSi, magram naklebi

intensivobiT,gansxvavebiT ganxiluli SemTxvevebisgan. mxolod 4

SemTxvevaSi warmodgenili iyo zomieri fibrozi.

sur. 2. Hashimoto-s Tireoiditi, limfoplazmuri ujredebis didi raodenoba, aqve interfolikuluri fibrozis fokusebi H&E, 100X

Hashimoto-s Tireoiditis fibrozuli formis dros SemaerTebel-

qsovilovani struqturebis gavrceleba, masalis mixedviT, SeiZleba daiyos

sam variantad:

1) interlobuluri (wilakTaSorisi) fibrozi;

2) interfolikuluri fibrozi;

3) nawiburovani fibrozi.

aqedan, interlobuluri fibrozi warmoadgens yvelaze xSir variants

Hashimoto-s Tireoiditis aRweril sklerozul cvlilebebSi.

ganmarteba _ interlobuluri fibrozi Seesabameba iseT mdgomareobas,

rodesac fibrozuli qsovili Semoexveva da gascdeba calkeuli wilebis

sazRvrebs (folikulTa mcire jgufebSi).

36

interfolikuluri fibrozi warmoadgens iseT cvlilebas, rodesac

izrdeba fibrozuli qsovilis Semcveloba folikulebs Soris sivrceSi da

hyofs cakleul Tireoidul folikuls (sur. 3 a,b).

calkeul SemTxvevaSi, mkvrivi, keloidis msgavsi fibrozi

gamoixateboda fibrozuli qsovilis CazrdiT calkeul folikuls Soris

sivrceSi. unda aRiniSnos, rom Hashimoto-s Tireoiditis fibrozuli formis

samive varianti SeiZleba arsebobdes sxvadasxva kombinaciaSi, magram

dominanturi iyos erT-erTi, romelic ikavebs organos qsovilis naxevars

mainc.

a

b

sur. 3. Hashimoto-s Tireoiditi: a _ interfolikuluri fibrozis histopaTologiuri suraTi, b _ calkeul folikulebs Soris

faSari Warbujredovani stromaH&E100X

37

Hashimoto-s Tireoiditis is variantebi, romelTac ar axasiaTebdaT

gamoxatuli sklero-fibrozuli kerebi, warmodgenili iyo vrceli limfo-

plazmocituri infiltraciis ubnebiT, didi zomis germinaciuli centriT

da araproporciulad msxvili folikulebis SerwymiT. Tumca am variantSic

adgili hqonda interfolikulur fibrozs parenqimuli elementebis Semci-

rebiT, mkvrivi fibrozuli konebis mier mosazRvreTireoiduli foliku-

lebis Canacvlebas (sur. 4). aqve warmodgenili iyo limfoepiTeluri dazia-

nebis sazRvari (sur. 5).

sur. 4. Hashimoto-s Tireoiditi: interfolikuluri fibrozi:

Tireoiduli folikulebi mcire zomis, kompresiuli gancalkevebuli

fibrozuli SemaerTebeli qsoviliT, foni – vrceli limfoidurujredovani infiltracia. H&E 100X.

38

sur. 5. Hashimoto-s Tireoiditi: mkveTri limfoplazmocituri infiltracia folikulur epiTelur ujredebs Soris, Tireoiduli folikulebis

atrofia limfoepiTeluri kontaqtis keraSi, koloidi mkvrivi, mcire raodenobiT. H&E, 200X

Hashimoto-s Tireoiditis ori aRwerili histologiuri variantisa da

difuzur-toqsikuri Ciyvis histopaTologiuri suraTis SedarebiT miRebu-

lia Semdegi Sedegebi: (cxr. 4).

cxrili 4 ujreduli cvlilebebi Hashimoto-s Tireoiditisa (HT)

da difuzur-toqsikuri Ciyvis (DG) dros

HT n=59

DG n=83 PP

Tireodiuli folikulebis zomebi micro / normo / macro 35 / 19 / 5 12 / 23 / 48 0.001

folikuluri ujredebis degeneracia 3+ / 2+ / 1+ / _

22 / 29 / 8 / 0 3 / 17 / 7 / 56 0.001

limfoiduri folikulebis forma 3+ / 2+ / 1+ / _

50 / 9 / 0 / 0 20 / 19 / 30 / 4 0.001

histiocituri infiltracia 3+ / 2+ / 1+ / _

2 / 2 / 5 / 50 0 / 0 / 4 / 79 0.001

brtyelujredovani metaplazia + / _

______ ______

39

Ffibrozuli variantis dros adgili aqvs didi raodenobiT

limfocitebisa da plazmuri ujredebis penetracias folikulur epiTelur

ujredebs Soris sivrceSi, rac iwvevs folikulebis bazaluri membranis

dazianebas da folikuluri ujredebis degeneracias (sur. 5). yovelive

zemoTTqmuli samarTliania antiTireoi-duli antixseulebis maRali

titris dros.

aRniSnuli cvlilebebi iwveven Tireoiduli arqiteqtonikis rRvevas,

fibrozuli qsoviliT parenqimis Canacvlebas, romelic ukavSirdeba

eqstensiur limfoplazmocitur infiltracias. reducirebuli folikulebi

warmodgenilia mcire zomis mikrofolikuluri kunZulebiT, mcire raode-

nobiT mkvrivi koloidiT an mis gareSe (sur. 5).

antiTireoiduli antisxeulebis dabali titris dros folikulur

ujredTa degeneracia ufro msubuq xasiaTs atarebs gavrcelebis mixedviT.

limfoidurifolikulebis arseboba kargad ganviTarebuli germinaciuli

centrebiT warmoadgens erT-erT sadiagnostiko kriteriums Hashimoto-s

Tireoiditis dasaxasiaTeblad.

giganturujredovani infiltracia qvemwvave Tireoiditis citologiur

Taviseburebas warmoadgens, magram calkeul SemTxvevaSi SeiZleba vnaxoT

masalaSi Hashimoto-s Tireoiditis drosac. Cvens masalaze naCvenebia, rom

antiTireoiduli antisxeulebis maRali titris paralelurad aRiniSneba

giganturi ujredebis maRali sixSire (p=0,0002) iseT SemTxvevebSi, sadac

aRniSnuli titri ar iyo mkveTrad momatebuli, giganturi ujredebis

akumulacia warmodgenilia fibrozul stromaSi. aq isini lagdebian

daSlili Tireoiduli folikulebis, limfocitebisa da plazmuri ujrede-

bisgan Semdgar ujredul detritul masaSi an folikulebis sanaTurSi

ganicdian penetracias.

3.2. difuzur-toqsikuri Ciyvis zogadhistologiuri kvlevis Sedegebi

H&E mikroskopia

toqsikuri Ciyvis dros folikulebis zomebis mkveTrad gamoxatul

heterogenobasTan erTad aRsaniSnavia folikulebis gamomfeni A tipis

Tireocitebis hiperplazia, msxvili birTviT, birTvakebiT. damaxasiaTebel

40

niSans warmoadgens bazaluri membranis gasqeleba, ujredis plazmuri

membranis modifikacia. am ukanasknelSi igulisxmeba zedapiruli mikro-

xaoebis, wanazardebis, papilebis da datotvili struqturebis formireba

(sur. 6).

sur. 6. difuzur-toqsikuri Ciyvis hitopaTologiuri suraTi folikulebis gamoxatuli heterogenobiT, H&E, 100X

toqsikuri Ciyvis erT-erTi mniSvnelovani niSani, Cvens masalebze, iyo

Tireocitebis nekrozi, birTvTa jgufis piknozi. parenqimaSi, aseT

pirobebSi gamoxatulia fibroplastikuri xasiaTis cvlilebaTa tendencia

kapilarebis bazaluri membranebis gasqelebiT da eqstrafolikuluri

fibroziT.

hiperTireozis dros araiSviaTad vnaxulobT mravalSrian bazalur

membranas, mis nakecebs, naoWebs, rac kapilarTan misi sakontaqto zedapiris

zrdas emsaxureba. kvlevis ZiriTadi amocanidan gamomdinare, Cveni

yuradReba fokusirdeboda stromisa da eqstrafolikuluri domenis

struqturaze, sadac SedarebiTi morfologiuri kvleviT vafasebdiT

limfoplazmocituri infiltraciis xarisxs, ujredTa Semadgenlobas,

fibrozuli qsovilis gavrcelebis xarisxs da mis struqturas.

41

toqsikuri formis dros Ciyvis qsovilSi mniSvnelovnad iyo

transformirebuli folikulebs Soris stromis elementebi.

difuzuri toqsikuri Ciyvis damaxasiaTebeli iyo fibrozuli qsovilis

grovebi Warbujredovani randomizebuli konebis saxiT. (sur. 7, 8).

sur. 7. difuzur-toqsikuri Ciyvi _ interfolikuluri limfoiduri infiltracia,H&E, 100X

kolagenis boWkoebis Sesivebis, defibrilizaciis da fragmentaciis

paralelurad adgili qhonda maT destruqcias, mTeli konebis homoge-

nizacias da liziss; araiSviaTad, aseTi suraTi morigeobda siderofagebisa

da giganturi ujredebis grovebTan, mudmivad gvxvdeboda fibrozi da

hialinozi stromisa da msxvili sisxlZarRvebis kedelSiD(sur. 8, 9).

SemaerTebelqsovilovani stromis cvlilebebs Tan sdevs mikrocirku-

laciuri kalapotis gardaqmnac. Aase, mag. toqsikuri Ciyvis damaxasiaTe-

belia kapilarizaciis maRali xarisxi, rac gamoixateba ara marto sanaTu-

rebis gaganierebiT, hiperemiiT, aramed kapilarebis Warbi klaknilobiT,

folikulebis kedelTan misi zedmiwevniT axlo dispoziciiT, araiSviaTad

Cans kapilarebis transgresia da zogjer penetraciac ki.

42

sur. 8. difuzuri toqsikuri Ciyvi: limfoidurujredovani infiltracia,

limfoiduri folikulebis warmoqmnis tendenciiT da eqstrafolikuluri fibroziT. H&E, 100X

sur.9. difuzuri toqsikuri Ciyvi, warmodgenilia inkafsulirebuli folikulebi, difuzuri sklerofibrozida hialinozi, H&E, 100X

hiperTireoidizmis mdgomareobisTvis damaxasiaTebelia folikulebis

gamomfeni A-tipis epiTeluri ujredebis hiperplaziis sami varianti:

43

1) nakecebisa da naoWebis warmoqmna folikulis kedelSi (sur. 9);

2) dvrilisebri gamonazardebi – e.w papiluri hiperplazia da hiper-

trofia (sur. 10);

3) mravalSriani, “baliSisebri” struqturebis formireba _ Tireocitebis

stratifikaciis fenomeni (sur. 11).

dakvirvebaTa 42% SemTxvevaSi nanaxia limfoplazmocituri

infiltracia, romelsac aqvs fokaluri xasiaTi da xSir SemTxvevaSi ar

iwvevs limfoiduri folikulebis formirebas stromaSi.

SemTxvevaTa 30%-Si adgili aqvs interfolikuluri stromis gasqelebas,

desmoplaziur reaqciebs, masiur limfoplazmocitur infiltracias

(sur.12), rac Cveni naSromis kvlevis interess warmoadgens, difuzuri

toqsikuri Ciyvis Hashimoto-s TiroiditTan Sedarebisa da diagnostikuri

kriteriumebis SemuSavebis TvalsazrisiT. es ki, stromis yvela elementis,

maT Soris, sisxlZarRvovani komponentis detalur aRweras da Sefasebas

moiTxovs.

sur.10. difuzuri toqsikuri Ciyvi, folikuluri epiTeliumis proliferacia folikulis kedelSi naoWebis da dvrilisebri gamonazardebis warmoqmniT,

stromis desmoplazia, H&E 100

44

sur. 11. difuzuri toqsikuri Ciyvi –Tiroiduli folikulis

sanTurSi asimetriuli, „baliSisebri“ struqturebi, Tireocitebis stratifikacia. H&E, 100X

Seswavlil masalaSi, rogorc wesi, vafiqsirebdiT sisxlSi antiTireo-

iduli antisxeulebis titris dones da calkeul SemTxvevaSi mis zrdas.

aseTi pacientebis rezecirebuli farisebri jirkvlis nimuSebSi vxedavdiT

limfoiduri infiltraciis araerTgvarovan kerebs. infiltraciis inten-

sivoba meryeobda interlobulur qsovilSi erTeuli limfocitis

arsebobidan soliduri mravlobiTi limfoiduri folikulebis formi-

rebamde. araiSviaTad warmodgenili iyo germinaciuli centrebis nekrozi.

araproporciulad didi, Serwymuli folikulebis warmoqmna(sur.12).

45

sur.12. difuzuri toqsikuri Ciyvi.

limfoplazmocituri infiltracia interfolikulur sivrceSi,H&E 100X

warmodgenilia inkafsulirebuli folikulebis jgufi, hemoragiuli ubnebi

da siderofagebi (sur.13).

sur.13. difuzuri toqsikuri Ciyvi stromaSi limfoiduri infiltraciis mcire fokusebi, inkafsulirebuli

folikulebis jgufi, siderofagebi. H&E, 200X

46

unda aRiniSnos ZiriTadi ganmasxvavebeli tendencia limfoplazmo-

cituri infiltratis formebs Soris Hashimoto-s Tireoiditisa da

difuzuri toqsikuri Ciyvis masalaSi.Aautoimunuri Tiroiditi, rogorc

wesi, mimdinareobs farisebri jirkvlis parenqimis kompresiiT, reduqciiT,

masSi cisturi transformaciis kerebis gaCeniT (sur. 14), aseve hormon-

maproducirebeli (TSH) Tireocitebis CanacvlebiT limfoplazmocituri

infiltraciiT, romelic xSirad gamoxatul limfo-epiTeluri dazianebis

niSnebs atarebs. vfiqrobT, rom nekrozi Hashimoto-s Tireoiditis dros T-

limfocitebis citotoqsiuri efeqtiT unda iyos inducirebuli, rasac sxva

mkvlevarebic iziareben (Burek, Rose, 2008).

sur. 14. difuzuri toqsikuri Ciyvi:

farisebrijirkvlis folikulebis Serwyma cisturi transformaciis tendenciiT. parenqimis reduqcia, koloidis gaTxeleba da ganleva. H&E,

200X

T-limfocitebiT inducirebuli nekrozi da difuzuri fibrozi aseve am

ori autoimunuri paTologiis ganmasxvavebel niSans warmoadgens.

47

3.3. farisebri jirkvlis funqciuri erTeulebis parametrebi

Hashimoto-s Tireoiditisa da difuzuri toqsikuri Ciyvis dros

cxrili 5

farisebri jirkvlis struqturuli elementebis raodenobrivi maCveneblebis cvlilebebi

Hashimoto-s Tireoiditis, difuzuri toqsikuri Ciyvis da kvanZovani euTireoiduli Ciyvis

dros “normasTan” SedarebiT

gamokvleuli jgufebi p (Asymp. Sig.)

Seswavlili parametrebi “norma”

difuzuri toqsikuri Ciyvi

Independent Samples T-

Test

Mann-Whitney U-Test

folikulebis farTobi

81.38 ± 0.08 86.40 ± 1.87 0.000000 0.000156

Tireocitebis farTobi

3.17 ± 0.14 8.65 ± 0.20 0.000000 0.000153

citoplazmis farTobi

2.11 ± 0.10 4.40 ± 0.30 0.000000 0.000156

birTvis farTobi 2.02 ± 0.04 4.25 ± 0.28 0.000000 0.000153 kapilaris kveTis farTobi

45.53 ± 1.25 91.20 ± 2.49 0.000000 0.000155

folikulebis raodenoba

42.20 ± 2.44 78.30 ± 4.47 0.000000 0.000153

Tireocitebis raodenoba

26.00 ± 4.97 43.00 ± 2.75 0.000000 0.000154

“norma” Hashimoto-s Tireoiditi folikulebis farTobi

81.38 ± 0.08 80.90 ± 3.84 0.000000 0.000154


3.17 ± 0.14 3.03 ± 0.12 0.031930 0.033889

citoplazmis farTobi

2.11 ± 0.10 1.83 ± 0.09 0.000004 0.000279


45.53 ± 1.25 47.30 ± 0.55 0.000685 0.001917


42.20 ± 2.44 37.50 ± 2.27 0.000308 0.001414


26.00 ± 4.97 22.30 ± 1.57 0.037445 0.066813

“norma” kvanZovani

euTireoiduli Ciyvi folikulebis farTobi

81.38 ± 0.08 101.30 ± 1.57 0.000000 0.000147


3.17 ± 0.14 5.40 ± 1.87 0.001431 0.002807

citoplazmis farTobi

2.11 ± 0.10 2.50 ± 0.10 0.000000 0.000154


45.53 ± 1.25 55.90 ± 1.25 0.000000 0.000157


42.20 ± 2.44 36.10 ± 2.23 0.000016 0.000318


26.00 ± 4.97 30.70 ± 2.06 0.012765 0.020796

48

statistikuri kvlevis Sedegebis analizma gviCvena, rom farisebri

jirkvlis struqturuli parametrebi araerTgvarovnad reagirebs

paTologiuri procesis mimdinareobaze. struqtura aris heterogenuli,

xolo kapilarizaciis xarisxi warmoadgens funqciuri aqtivobis

integralur maCvenebels.

amavdroulad dinamikaSi aRiniSneboda farisebri jirkvlis sxvadasxva

paTologiis dros ganviTarebuli cvlilebebis mkveTri sxvaoba “normis”

maCveneblebTan. unda aRiniSnos, rom normasTan SedarebiT (cxrili 5)

parametrebis zomebis erTmniSvnelovani xazovani mateba aRiniSna

difuzuri toqsikuri Ciyvis dros. gansakuTrebiT aRsaniSnavia kapilarebis

ganivkveTis zrda (maqsimaluri Cvens dakvirvebaSi 91.20±2.49), aseve

Tireocitebis da folikulebis raodenoba, rac hiperfunqciis

struqturul safuZvels iZleva. Mann-Whitney-s testis da P maCveneblis

xarisxi cvlaTa maRal sarwmunoobaze miuTiTebs normasTan SedarebiT.

haSimotos Tireoiditis dros, rogorc histologiuri kvlevis Sedegebidan

irkveva, cvlilebaTa dinamika ZiriTadad jirkvlovani elementebis

struqturis fibrozuli qsoviliT da limfodestruqciuli infiltraciiT

Canacvlebis tendencias adasturebs, rac me-5 cxrilSi asaxuli

morfometriuli monacemebidanac Cans. saxeldobr, kapilarebis ganivkveTis

umniSvnelo zrdis fonze iklebs “normasTan” SedarebiT folikulebis

raodenoba, folikulebSi Tireocitebis saSualo raodenoba, birTvisa da

citoplazmis farTobi, amavdroulad araparametruli koeficientis

mniSvneloba miuTiTebs Tireocitebis saerTo raodenobisa da maTi

farTobis cvlilebaTa dabali xarisxis sarwmunoobaze (U-test=0.66813 da

0.33889, Sesabamisad.) SegviZlia vivaraudoT, rom parenqimis calkeuli

elementebis araerTgvarovani cvlilebebi, siaxlove limfoidur

folikulebTan da limfoepiTeluri dazianebis sazRvarTan qmnis amgvarad

transformirebuli maCveneblebis mniSvnelobebs. aseTive tendenciiT

xasiaTdeba kvanZovani euTireoiduli Ciyvi. aRiniSna Tireocitebis

farTobis cvlilebis naklebi xarisxiT sarwmunooba. (U-test – 0.020796)

normasTan SedarebiT.

Seswavlili parametrebis Sedarebam Tireoiduli paTologiis calkeul

formebs Soris mogvca Semdegi suraTi (cxrili 6)

49

cxrili 6

farisebri jirkvlis struqturuli elementebis raodenobrivi maCveneblebis

cvlilebebi Tireoiduli paTologiis dros

gamokvleuli jgufebi p (Asymp. Sig.)

Seswavlili parametrebi

difuzuri toqsikuri Ciyvi

Hashimoto-s Tireoiditi

Independent Samples T-

Test

Mann-Whitney U-Test

folikulebis farTobi

86.40 ± 1.87 80.90 ± 3.84 0.001320 0.000657


8.65 ± 0.20 3.03 ± 0.12 0.000000 0.000153

citoplazmis farTobi

4.40 ± 0.30 1.83 ± 0.09 0.000000 0.000154


91.20 ± 2.49 47.30 ± 0.55 0.000000 0.000154


78.30 ± 4.47 37.50 ± 2.27 0.000000 0.000153


43.00 ± 2.75 22.30 ± 1.57 0.000000 0.000144

difuzuri

toqsikuri Ciyvi kvanZovani

euTireoiduli Ciyvi folikulebis farTobi

86.40 ± 1.87 101.30 ± 1.57 0.000000 0.000146


8.65 ± 0.20 5.40 ± 1.87 0.000372 0.000153

citoplazmis farTobi

4.40 ± 0.30 2.50 ± 0.10 0.000000 0.000153


91.20 ± 2.49 55.90 ± 1.25 0.000000 0.000155


78.30 ± 4.47 36.10 ± 2.23 0.000000 0.000152


43.00 ± 2.75 30.70 ± 2.06 0.000000 0.000152

Hashimoto-s Tireoiditi

kvanZovani euTireoiduli Ciyvi

folikulebis farTobi

80.90 ± 3.84 101.30 ± 1.57 0.000000 0.000144


3.03 ± 0.12 5.40 ± 1.87 0.000845 0.002478

citoplazmis farTobi

1.83 ± 0.09 2.50 ± 0.10 0.000000 0.000153


47.30 ± 0.55 55.90 ± 1.25 0.000000 0.000156


37.50 ± 2.27 36.10 ± 2.23 0.181714 0.195030


22.30 ± 1.57 30.70 ± 2.06 0.000000 0.000144

gamoirkva, rom haSimotos Tireoiditis dros Semcirda sarwmunoobis

maRali xarisxiT:

50

1. folikulebis farTobi;

2. Tireocitebis raodenoba;

3. Tireocitebis, maTi birTvebisa da citoplazmis farTobi;

4. kapilaris ganakveTis farTobi.

rogorc cxrilis monacemebidan Cans, parenqimis reduqcias, misi

histologiuri elementebis zomebis da raodenobis TiTqmis orjer

Semcirebas mivyavarT klinikuri hipoTireoidizmis ganviTarebamde.

Cveni kvlevis ZiriTadi amocanidan gamomdinare, yuradRebas vaqcevdiT

struqturaTa, maT Soris, folikuluri erTeulebis zomebs da raodenobas

Hashimoto-s Tireoiditis dros, romelsac vadarebdiT difuzuri toqsikuri

Ciyvis monacemebTan, rac am ukanasknelis qsovilSi, aseve

limfoplazmocituri infiltraciis da qronikuli limfocituri

Tireoiditis suraTis arsebobiT aris ganpirobebuli.

histopaTologiuri,morfometriuli da klinikur-laboratoriuli kvlevis

Sedegebis mixedviT gamoirkva, rom Hashimoto-s Tireoiditis upiratesad

fibrozuli variantis dros – antiTireoiduli antisxeulebis SedarebiT

maRali titris pirobebSi – kapilarebis ganikveTis saSuali farTobi

naklebia difuzuri toqsikuri Ciyvis monacemebTan SedarebiT da udris

47,3±0,39mkm2 (P≤0,001), rac aseve naklebia “euTireozis “ saSualo

maCvenebelze.

Hashimoto-s Tireoiditis upiratesad limfoiduri variantis dros –

antiTireoiduli antisxeulebis dabali-zomieri titris pirobebSi

kapilarebis ganikveTis saSualo farTobi calkeul SemTxvevebSi ar

gansxvavdeba difuzuri toqsikuri Ciyvis monacemebisgan da Seadgens

89,3±2,07mkm2.

kapilarTa kveTis farTobis monacemebis analizidan irkveva, (cxrili 6)

rom sanaTuris saSualo maqsimumi aRiniSneba difuzuri toqsikuri Ciyvis

dros, rac, savaraudod, TSH mastimulaciebeli efeqtis Sedegs warmoadgens,

romelic aZlierebs ara marto neoangiogenezs, ris Sedegad izrdeba

kapilarebis raodenoba, aramed moqmedebs maTi sanaTuris ganakveTzec. am

mosazrebas adasturebs is garemoeba, rom kapilarebis sanaTuris kveTis

farTobis saSualo sidide kvanZovani euTireoiduli Ciyvis dros naklebia

difuzur toqsikur CiyvTan SedarebiT rac cvlilebaTa ufro

51

hipertrofiul monomorfuli tipis tendenciaze miuTiTebs. miuxedavad

imisa, rom folikulebis farTobi, ujredis parametrebi da Tireocitebis

raodenoba Hashimoto-s TireoiditTan SedarebiT metia.

amrigad, 1).difuzuri toqsikuri Ciyvis dros, farisebri jirkvlis

funqciuri erTeulebis raodenobrivma kvlevam daafiqsira misi yvela

parametris erTdrouli xazovani gadideba, rac gamovlinda cvlilebaTa

ori tipiT: Tireocitebis hipertrofiiTa da hiperplaziiT. am dros

neoangiogenezic intensiur xasiaTs atarebs.

2)Hashimoto-s Tireoiditis dros Seswavlil qsovilovan nimuSebSi

aRmoCnda parenqimis elementebis Canacvleba: a) aramofunqcie fibrozuli –

sklerozuli qsoviliT an b)parenqimaSi penetrirebuli limfo-

plazmocituri infiltraciis ubnebiT, rac limfoepiTeluri dazianebisa da

folikulebis reduqciis suraTs iZleva da eTanxmeba raodenobrivi

analizis Sedegebs .

euTireoiduli Ciyvi xasiaTdeba mofunqcie kapilarebis SemcirebiT, magram,

imavdroulad, maTi sanaTurebis gafarToebiT.Aamave dros kapilarebis

kalapotis sigrZis Semcireba, erTis mxriv, da sisxlZarRvebis gafarToeba

– meores mxriv, ueWvelad atarebs kompensaciur xasiaTs, SedarebisaTvis

SeiZleba vivaraudoT, rom dasaSvebia parenqimis funqciuri aqtivobis

daqveiTeba miuxedavad klinikurad euTireoiduli mdgomareobisa.

amrigad, Tireoiduli parenqimis mdgomareobis raodenobrivma analizma

aCvena, rom hipoTireozis dros adgili aqvs am ukanasknelis moculobis

gadidebas, folikuluri ujredebis funqciuri aqtivobis struqturuli

uzrunvelyofis xarjze. mofunqcie kapilarebis kalapotis sigrZis

momateba, folikulebis ganakveTis farTobisa da maTi raodenobis zrda

aRiniSneba difuzur-toqsikuri Ciyvis dros.

“normuli” farisebri jirkvlis parenqima umeteswilad warmodgenilia

mcire da saSualo zomis jgufebis folikulebiT. folikulebis sanaTurSi

aris homogenuri eozinofiluri koloidi.

Hashimoto-s Tireoiditis SemTxvevaSi `normasTan” SedarebiT

folikulebis raodenoba Semcirebulia.

Sesadareblad warmodgenili kvanZovani euTireoiduli Ciyvis

SemTxvevaSi aseve vlindeba giganturi folikulebi. amitom kvanZovani

52

euTireoiduli Ciyvis dros folikulebis kveTis saSualo farTobi

sWarbobs sakontrolo jgufis imave maCvenebels (U-test=0.000147). unda

aRiniSnos, rom folikulebis farTobis gadideba Cveni SefasebiT,

upiratesad mimdinareobs sanaTuris da koloidis raodenobis gadidebis

xarjze.

Hashimoto-s Tireoiditi, amrigad, TvalsaCinoa imiTac, rom raodenobrivi

analizi cxadyofs parenqimis kompresiis da reduqciis Sedegad

ganviTarebul cvlilebebs.

amrigad, sxvadasxva funqciuri aqtivobis farisebri jirkvlebis

Sedarebisas vlindeba, rom folikulebis farTobis saSualo maCvenebeli

maqsimalur mniSvnelobas aRwevs euTireozis (101.30 ± 1.57) minimalurs

_autoimunuri Tireoiditis dros (80.90± 3.84) (cxrili 5, cxrili 6)

mxedvelobis velSi folikulebis saSualo raodenobis Sefasebam

aCvena, rom difuzuri toqsikuri Ciyvis dros adgili aqvs aRniSnuli

maCveneblis maqsimalurzrdas. euTireozis pirobebSi Seswavlili

maCveneblis Semcireba normasTan SedarebiT minimaluria (U-test=0.000318)

erT folikulSi Tireocitebis raodenobis Seswavlam mogvca Semdegi

Sedegebi: Hashimoto-sTireoiditis dros folikuluri ujredebis saSualo

raodenoba orjer naklebia SesaZloa folikuluri ujredebis degeneraciis

gamo, gansakuTrebiT limfoiduri variantis dros.

asakis da sqesis mixedviT calkeuli parametrebis analizma Semdegi

procesebi gamoavlina: asakobrivi jgufebis mixedviT aRmoCnda, rom

struqturuli komponentebis Semcvelobas farisebri jirkvlis sxvadasxva

ubnebSi aqvT mkveTri asakobrivi mimarTuleba. ase, magaliTad, 15-19 wlis

asakis mamakacebis farisebr jirkvalSi aRiniSneba koloidis maqsimaluri

Semcveloba, stromisa – 30-39 wlis jgufSi, epiTeluri ujredebis – 60-50

asakSi.

15-19 wlis asakis qalebis farisebr jirkvalSi aseve aRiniSneba

koloidis maqsimaluri Semcveloba, xolo epiTeluri ujredebisa ki – 30-39

wlis asakobriv jgufSi, stromisa – 60 wlis zeviT. unda iTqvas, rom

Hashimoto-s Tireoiditis histologiuri suraTi paTo- da morfogenezis

specifikuri meqanizmebis gamo, ar eqvemdebareba aRniSnul kanonzomierebebs

53

da calkeul SemTxvevaSi parenqimis, stromisa da limfoplazmocituri

qsovilis TanafarToba procesis aqtivobis integraluri maCvenebeli xdeba.

farisebri jirkvlis folikulebis diametri da maTi ganivkveTis

farTobi ar aris damokidebuli sqesze. igi metia farisebri jirkvlis

marcxena wilSi. mamakacebSi folikuluri epiTeliumis simaRlis cvlileba

aRiniSneba 40 wlis Semdeg, aRwevs maqsimums 50 wlamde; xolo qalebSi

epiTeliumis simaRlis da folikulebis diametris cvalebadoba asakTan

mimarTebaSi ar avlens TvalsaCino paralelizms.

orive sqesis pacientebSi koloidis dagrovebis indeqsi erTnairia,

magram asakobrivad dinamika mamakacebSi da qalebSi gansxvavdeba

daaxloebiT 2,74 jer da 20 wlidan iZens asiqronul dinamikas. difuzuri

toqsikuri Ciyvis dros mamakacebSi da qalebSi farisebri jirkvlis yvela

nawilSi sWarboben folikulebi ganivkveTis momrgvalo formebiT.

rogorc vTqviT, farisebri jirkvlis evolucia ontogenezSi

mamakacebsa da qalebSi asinqronulad mimdinareobs.farisebri jirkvlis

struqturuli gardaqmnis Tanxvedra aRiniSneba 30-39 wlis, 50-59 wlis da 60-

70 wlebis asakobriv diapazonSi. farisebri jirkvlis mikrostruqturebis

mniSvnelovani cvalebadoba mamakacebSi xdeba 40-49 wlis asakSi, rac

gansazRvravs avadobaSi erT-erT ZiriTad _ genderul sxvaobas da

mniSvnelobas.

Uujreduli procesebis detaluri Sefaseba gviCvenebs, rom difuzuri

toqsikuri Ciyvis SemTxvevaSi upiratesad warmodgenilia msxvili birTvebi,

romlebic aRemateba Tavisi farTobiT euTireoiduli Ciyvis Sesabamis

monacemebs, Mmiuxedavad imisa, rom Tireocitebis farTobi am ukanasknelSi

momatebulia, rasac Cven hipertrofiis procesebis gaZlierebas mivawerT.

Hashimoto-s Tireoiditis SemTxvevaSi Tireocitebis birTvebis farTobi

mkveTrad mcirdeba, ujredisa da citoplazmis zomis proporciulad.

birTvTa farTobebis Semcireba - SeWmuxvna warmodgenilia limfoepiTeluri

dazianebis ubnebSi, sadac aseve aRiniSneboda nekrozuli birTvebis puli.

miRebuli Sedegebi mowmoben, rom hiperTireoidizmis funqciis

realizacia xdeba Tireocitebis mniSvnelovani hipertrofiis xarjze, xolo

Hashimoto-s Tireoiditis dros ki adgili aqvs yvela Seswavlili parametris

zomebis sxvadasxva intensivobiT Semcirebas. Tireocitebis farTobis

54

maqsimaluri mniSvneloba aRiniSna swored hiperTireozis dros, xolo

minimaluri ki - Hashimoto-s Tireoiditis dros, rac, savaraudod,

ganpirobebulia am ukanasknelSi parenqimis CanacvlebiT

limfoplazmocituri infiltratebiT an fibrozuli qsoviliT. es ki

funqciaSi monawile aqtiuri jirkvlovani qsovilis moculobis Semcirebas

ganapirobebs. Hashimoto-s Tireoiditis dros parenqimaSi vlindeba mofunqcie

ujredebis Camofcqvna, kariopiknozi, koloidis gamkvriveba, an piriqiT

vakuolizacia, rac regresiuli cvlilebebis speqtrs axasiaTebs.

Mmikrocirkulaciuri kalapotis, saxeldobr, kapilarebis ganivkveTisa

da kapilarizaciis intensivobis, aseve neoangiogenezis TvalsazrisiT, Cvens

masalaSi savaraudod, adgili aqvs Semdeg procesebs: Hashimoto-s

Tireoiditi gamoirCeva kapilarebis ganivkveTis SemcirebiT,

vaskularizaciis siRaribiT fibrozuli qsovilis sasargeblod,

neoangiogenezis araerTgvarovani stimuliT.

literaturaSi es sakiTxi aqtualur msjelobis sagans warmoadgens.

gansakuTrebiT, pirveladi hipoTireoidizmi, romlis yvelaze gavrcelebul

formas swored autoimunuri Tireoiditi warmoadgens. (Syreniez A., Syreniez

M.,et al., 2005; Scardina et al., 2007, Amani H.K., 2011) Hashimoto-sTireoiditi

ganixileba, rogorc kaapilaruli qselis sistemuri dazianebis erTerTi

varianti, dinamikaSi, mkvrivi Ciyvidan fibrozul Ciyvamde, minimaluri

funqciiT (Okamoto., 2006) msgavsi Sefaseba gamomdinareobs ara marto TviT

farisebri jirkvlis kapilarebis kvlevis masalebidan, aramed sxva

organoebis, saxeldobr, piris Rrus, enis da tuCebis kapilaruli qselis

anomaliebis gamovlenis safuZvelze Hashimoto-sTireoiditis dros. Cvens

monacemebs exmaureba aseTi cvlilebebis suraTi, rogoricaa sisxlZarRvTa

arqiteqtonikis dezorganizacia, U formis maryuJebisa da badeebis

formireba. tuCebisa da enis lorwovan garsSi aRiniSneboda kapilarebis

ricxvisa da maTi simWidrovis daqveiTeba, rac korelaciaSi imyofeboda

ZiriTad nivTierebaSi proteinuli depozitebis warmoqmnasTan. Pacientebs

Hashimoto-s TireoiditiT aReniSnebodaT makroglosia (Scardina, Messina ). Iseve,

rogorc Cvens masalaze, distanciurad lorwovan garsebSi gamovlinda

kapolaruli qselis reduqcia, cilovan-mucinozuri depozitebi, raac

55

periferiuli mikrocirkulaciis dazianeba da organos e.w “civi stresi”

mohyveba.

vTvliT, rom kapolarebis raodenobrivi da Tvisobrivi maxasiaTeblebis

msgavsi cvlilebebis mimarTeba: yalibis Semcireba, heterogenuli

arqiteqtonika, dezorganizaciis maRali xarisxi aris Hashimoto-s

Tireoiditis erTerTi mniSvnelovani maxasiaTebeli, ganpirobebuli

hipoTireoidizmis sistemuri efeqtebiT.

imavdroulad, ar SeiZleba im faqtis uaryofa, rom Hashimoto-s

Tireoidits axasiaTebs difuzuri, zogjer agresiulad mimdinare

limfoiduri infiltracia, mantiur zonaSi da interfolikulur qsovilSi

plazmuri da limfoiduri mkvrivi xasiaTis infiltratebi, rasac Tan sdevs

Tireoiduli folikulebis atrofia da Hurthle-s ujredovani metaplazia.

Cvens masalaze, Sefasebuli rogorc limfoepiTeluri dazianebis fokusebi,

asruleben Tireoiduli parenqimis dezorganizaciis da SesaZlo limfomis

ganviTarebis adreul stadiebs (Amani KH., 2011). Tireoiduli epiTeliumis

rezidualuri cvlilebebis dinamika, dafiqsirebuli Cvens masalaze sworad

asaxavs folikuluri elementebis atrofiul-involuciur cvlilebebs,

Seesabameba da asabuTebs klinikurad manifestirebuli hipoTireoidizmis

suraTs. Tumca unda aRiniSnos isic, rom destruqciuli xasiaTis

limfoepiTeluri dazianebani Tireoiditis SemTxvevaSi naklebi sixSiriT

gvxvdeba, iseve, rogorc eqstraTireoiduli qsovilis dazianebis suraTi.

Amrigad, farisebri jirkvlis parenqimisa da stromis sxvadasxva

struqturuli elementis raodenoba da zoma adekvaturad asaxavs funqciur

mdgomareobas, xolo aqtivobis donis Sefasebis kriteriumad SeiZleba

CaiTvalos mikrocirkulaciuri kalapotis sisxlZarRvTa struqturuli

parametrebi.

3.4. farisebri jirkvlis imunohistoqimiuri kvlevis Sedegebi

autoimunuri Tireoiditisa da difuzuri toqsikuri Ciyvis dros

informaciuli morfologiuri monacemebis dadgena farisebri

jirkvlis normuli da paTologiuri mdgomareobebis Sefasebis mizniT

adasturebs debulebas, rom Tireoiduli hormonebis disbalansi ara marto

56

aZlierebs organoSi arsebul paTologiur cvlilebebs, aramed SeiZleba

gamoiwvios receptoruli statusis gardaqmna rogorc parenqimul, ise

stromul elementebSi. bolomde ar aris gamorkveuli procesebi, romlebic

akontroleben zrdisa da diferenciaciis regulacias TireocitebSi,

endoTeliocitebsa da stromis ujredebSi.

amJamad aqtualuria sakiTxi farisebri jirkvlis disfunqciis adreuli

gamovlena ujredebis mofologiuri da molekulur-biologiuri Tavise-

burebebis erTiani monacemebis safuZvelze.

farisebri jirkvlis disfunqcia hipo- da hiperTireozis saxiT

SeiZleba gamovlindes latenturi formiT, aseve agresiuli klinikuri

mimdinareobis saxiT. dasaxelebuli procesebis erTerT mizezad SeiZleba

warmodgenil iqnas farisebri jirkvlis paTomorfozis aqtualuri tenden-

cia msoflios bevr qveyanaSi, aseve saqarTveloSi; saxeldobr: 1. kvanZovani

(mravalkvanZovani) formis Ciyvis hiperplaziuri variantebis gaxSireba (Li

Zhou et al., 2012).

2. difuzuri toqsikuri Ciyvis da Hashimoto-s Tireoiditis gardamavali

variantebis simravle subklinikuri hipoTireozis gamosavliT. (Ohye,

Fukata,Kubote et al., 2005; Tohyama, Matsai et al; 2014)

klinikur-morfologiuri kvlevebi gviCveneben, rom Hashimoto-s Tireoi-

ditis qvetipebi gansxvevdebian da xSirad qronikuli limfocituri Tireoi-

ditis msgavsi mimdinareoba axasiaTebT, aseve monacvleoben difuzuri

toqsikuri Ciyvis suraTTan. ufro metic, VEGF done, literaturis

mixedviT, orive aRweril nozologiaSi matulobs Tireoiduli parenqimis

difuzuri limfoidurujredovani infiltraciis dros, qmnis ra tranzi-

toruli hipo- da hiperTireoidizmis mdgomareobebs (Chen, Akpolat, Mody et al,

2006, Smedby, Backlund, Askling, 2006; Spencer et al., 2007; Krohn, Pashke, 2009; Amani H.K.,

2011; Latina A. et al., 2013).

am TvalsazrisiT, autoimunuri Tireoiditis paTo-da morfogenezis

procesSi mkvlevarebi ganixilaven Hurthle-s ujredebis monawileobas,

epiTeluri ujredebisa, romlebic gamoyofen Tireoglobulins da mona-

wileoben farisebri jirkvlis mraval keTilTvisebian gardaqmnaSi, maT

Soris, Hashimoto-s Tireoiditis eTiopaTogenezisa da paTologiuri cvlile-

57

bebis SenarCunebaSi (Pearce, Farewell et al 2003; Sidhu, 2008, Maizlin et al., 2008; Ward

Sterian L., 2014).

Cvens masalaze imunohistoqimiuri kvlevebi Catarebulia Semdegi

faqtorebis mimarT:

1) Tireoidmastimulirebeli hormoni (TSH),

2) sisxl-ZarRvTa panendoTeluri zrdis faqtori (VEGF),

3). endoTeluri zrdis faqtori CD34,

4). specifikuri cila S-100.

5). transkripciuli faqtoris TTF-1 eqspresiis kvleva

TSH eqspresia

Hashimoto-s Tireoiditis receptoruli statusi TSH–is mimarT aris

araerTgvarovani.

sur. 15. Hashimoto-s Tireoiditi. TSH+struqturebis dabali aqtivoba. limfoidurujredovani infiltraciis fokusebSi reaqcia uaryofiTia.

imunoperoqsidazuli reaqcia, 160X

TSH pozitiuri Tireocitebis raodenoba ufro meti iyo nodularul

aratoqsikur CiyvSi – 30-50%. Hurthle-s ujredebis Semcveloba 40%-mde

aRwevda es ki hipoTireoidizmis prediqts warmoadgens. Hashimoto-s

Tireoiditis dros TSH aqtivoba imyofeba kvanZovani Ciyvis aqtivobaze

58

dabali mniSvnelobebi, difuzuri limfoiduri infiltrarebi mravlobiTi

limfoiduri folikuliT, reducirebuli atrofiuli folikuluri

struqturebiT da TireocitebiT, erTmniSvnelovnad uaryofiT an sust

eqspresias avlenen TSH-s mimarT 75%-ze met TireocitebSi (sur 15, 16).

dakvirvebis yvela SemTxvevaSi aRiniSneboda kavSiri rogorc

goitrogenezis procesSi, aseve neoplaziasa da anTebiTi procesis dros

folikulebis arqiteqtonikis dezorganizaciasa da Tireoiduli parenqimis

mononukleuri hemopoezuri ujredebiT infiltracias Soris, aseve Hurthle-

ujredovani metaplaziis dros (Rurua N. et al, 2013) romelic iwvevs farisebri

jikvlis parenqimis transformacias da iTvleba limfoepiTeluri

dazianebis erTerT paTognomur movlenad (Cannon Y., 2011, Montone et al., 2008;

Cibas, Ali, 2009).

ufro metic, Cven aRvniSneT pirdapiri uaryofiTi kavSiris arseboba

Hurthle-ujredul metaplaziasa (sur. 17) da sisxlis SratSi T4 hormonis

dones Soris, romelic ufro dabali iyo dasaxelebuli metaplaziis

Tanaarsebobisas (Rurua NZ. et al, 2013).

sur. 16. Hashimoto Tireoiditi. TSH pozitiuri erTeuli kerebi fonuri

SeRebvis saxiT. imunoperoqsidazuli reaqcia, 160X

59

sur. 17. Hurthle ujredovani hiperplaziis kera parafolikulur domenSi jirkvlovani qsovilis dezorganizaciiT. Hashimoto-s Tireoiditi

H&E, 200X

rogorc aRvniSneT histologiuri cvlilebebis aRwerisas, farisebri

jirkvlis morfofunqciuri mdgomareobis swori identifikaciis mizniT

Hashimoto-s Tireoiditisa da qronikuli limfocituri Tireoiditis dros,

romelic parenqimaSi keTilTvisebiani procesis ganviTarebasTan asocir-

deba, aucilebelia imis gageba, Tu ramdenad xSirad gulisxmobs limfo-

cituri Tireoiditi Hurthle-is ujredebis Tanamonawileobas da maT

hiperplazias. paradoqsulad pozitiuri iyo TSH-ze reaqcia endoTelur

ujredebsa da calkeul hemopoezuri rigis ujredebSi. (sur. 18).

am SemTxvevaSiTSH-is eqspresiis monacemebis mixedviT Cven SeiZleba

vimsjeloT hipoTireoidizmis arsebobaze. TSH-is eqspresiis monacemebis

Sedareba difuzuri toqsikuri Ciyvis dros miRebul suraTTan gviCvenebs

statistikurad sarwmuno sxvaobas (P=0.001) Seswavlil jgufebs Soris.

adgili aqvs TSH-is difuzur CarTvas Tireocitebis birTvebSi da

endoTelur ujredebSi (sur.19).

60

sur. 18. HT. Hurthle – ujredebis hiperplazia, TSH pozitiuri

endoTeliocitebi da hemopoezuri rigis ujredebi. imunoperoqsidazuli reaqcia, 160X

difuzuri toqsikuri Ciyvis dros TSH eqspresirdeboda rogorc

Tireocitebis birTvebSi, ise folikulebis bazalur membranebsa da

endoTeliocitebze zomieridan maRali aqtivobis mniSvnelobebiT (60-75%-

mde).

sur 19. difuzuri toqsikuri Ciyvi. TSH pozitiuri Tireocitebi

61

da endoTeliocitebi. reaqcia intensiuria ujredTa birTvebze. imunoperoqsidazuli reaqcia, 160X

VEGF eqspresia

difuzur toqsikuri Ciyvis dros VEGF aqtivoba (%) endoTeliocitebSi

iyo dadebiTi 18 SemTxvevaSi 20-dan da Seesabameboda fonur citoplazmurs

da ara difuzur an membranul tips (sur. 20).

sur. 20. difuzuri toqsikuri Ciyvi. VEGF pozitiuria endoTeliocitebis citoplazma da Tireoiditi folikulebis

bazaluri membranebi. imunoperoqsidazuli reaqcia, 160X

VEGF aqtivoba dadebiTia 10 SemTxvevaSi 20 dan Hashimoto-s Tireoiditis

dros da 7-Si 20-dan kvanZovani Ciyvis dros (sur. 21). Seswavlil anaTlebSi

iyo fokaluri pozitiuri eqspresia orive ujredul saxeobaSi –

endoTelur da hemopoezur ujredebSi, gansakuTrebiT, Hashimoto-s

Tireoiditis dros. (sur.22)

VEGF imunohistoqimiuri reaqciebi gamoirCeoda maRali receptoruli

aqtivobiT (>80% ujredi) difuzuri toqsikuri Ciyvis yvela SemTxvevaSi.

statistikuri sxvaoba ar gamovlinda sakontrolo masalasa (norma) da

kvanZovani Ciyvis nimuSTa aqtivobas Soris.

62

sur. 21. VEGF eqspresia kvanZovan euTireoiduli Ciyvis qsovilSi reaqcia koloidSi da wvrili sisxlZarRvebis kedlebSi; 160X

sur. 22. Hashimoto-s Tireoiditi. dadebiTi VEGF reaqcia

limfoplazmocituri infiltraciis kerebSi. imunoperoqsidazuli reaqcia, 160X

naxevradraodenobrivma Seswavlam gvaCvena, rom Hashimoto-s Tireoiditis

dros TireocitebSi VEGF eqspresia iyo 2 quliT naklebi 20-dan 5

SemTxvevaSi, iseve, rogorc kvanZovani Ciyvis masalis kvlevisas

63

Hashimoto-s Tireoiditis gamokvleul SemTxvevebSi Tireoiduli

folikulebis irgvliv, mikrosisxlZarRvTa bazalur membranebze VEGF

eqspresia iyo sustad dadebiTi, angiogenuri faqtoris mimarT maRali

mgrZnobeloba dafiqsirda difuzuri toqsikuri Ciyvis dros

amdenad, VEGF imunoeqspresia difuzur toqsikuri Ciyvis dros imave

struqturebSi, sapirispirod, iyo gacilebiT maRali, vidre normul

Tireoidul qsovilSi. SeiZleba vimsjeloT farisebri jirkvlis qsovilis

gansxvavebul “biologiur qcevaze” difuzuri toqsikuri Ciyvis dros. VEGF

aqtivoba iyo maRali aseve Hashimoto-s Tireoiditis dros, Tumca am

ukanasknel SemTxvevaSi xazi unda gaesvas, rom VEGF receptorebis mimarT

aRiniSna ufro dabali eqspresia, vidre sxva nimuSebSi.

endoTelur ujredTa markeris, CD34-s imunohistoqimiuri kvleva

difuzur toqsikuri Ciyvis 16 SemTxvevaSi CD34-seqspresia iyo maRali,

difuzurad, endoTeliocitebsa da TireocitebSi. kvanZovani Ciyvis 20

SemTxvevidan ki mxolod 3-Si da Hashimoto-s Tireoiditis 20 SemTxvevidan 5-

Si, endoTeliocitebis citoplazmaSi. sisxlZarRvTa umravlesoba da

sisxl-ZarRvTa mikroareali aseve CD34 pozitiuri aRmoCnda rogorc

autoimunuri Tireoiditis, aseve difuzur toqsikuri Ciyvis dros. CD34-

sdabali aqtivobiT gamoirCeoda euTireoiduli kvanZovani Ciyvis qsovili.

(sur 23, 24).

cila S-100 (RTU-S100p poliklonuri antisxeulebi) warmodgenili iyo

sxvadasxva intensivobis dadebiTi eqspresiiT rogorc Hashimoto-s

Tireoiditis da DTG qsovilovan nimuSebSi, aseve sxva, Sesadarebeli

jgufis masalaSi (Hurthle ujredovani adenoma, “norma”, kvanZovani euTireo-

iduli Ciyvi).

64

sur.23 Hashimoto-s Tireoiditi. CD34 + sisxlZarRvTa areali da

wvrili sisxlZarRvebis kedlebi. imunoperoqsidazuli reaqcia, 160X

sur. 24. difuzuri toqsikuri Ciyvi. CD34 dadebiTi reaqciis produqti folikulebis bazaluri membranebis sisqeSi.


aRsaniSnavia, rom Hurthle-s ujredebis gansakuTrebuli simWidroviT da

adenomatozuri zrdiT gamoirCeoda Hashimoto-s Tireoiditis limfoiduri

varianti, xolo Hurthle-ujredovan adenomasTan asociaciis dros S100 cilis

65

specifikuri SeRebva gamovlinda dazianebis keris periferiaze da adenomis

kafsulaSi (sur. 25, 26),rac am tipis reaqciisTvis damaxasiaTeblad iTvleba.

sur. 25. Hashimoto-s Tireoiditis limfoiduri varianti. S-100cilis eqspresia vlindeba paraTireoidul domenSi.


aqve aRsaniSnavia, rom S-100 proteinis maRali intensivobiT eqspresia

aRiniSneboda swored im qsovilovan nimuSebSi, sadac Hashimoto-s Tireoi-

ditTan asocirebuli iyo Hurthle-ujredovani adenoma da antiperoqsidazuli

antisxeulebis (anti TPO) maRali titri ≈124IU/ml,xolo TSH meryeobda 8.54 dan

22.56 Uiu/ml.D

difuzuri Ciyvis qsovilovan nimuSebSi S-100cilis eqspresia

fiqsirdeboda, rogorc susti zomieramde reaqcia (±17.8) parafolikulur

domenSi Hurthle-s ujredebis savaraudo lokalizaciis kerebSi (sur. 27).

66

sur.26.Hashimoto-s Tireoiditis limfoiduri varianti.

Hurthle-s ujredebisS-100receptoruli aqtivoba. imunoperoqsidazuli reaqcia, 160X

sur. 27. Hurthle-s ujredovani adenomisa da Hashimoto-s Tireoiditis asociacia. S-100cilis intensiuri eqspresia adenomis periferiaze

da adenomis kafsulaSi. imunoperoqsidazuli reaqcia, 160X

normul qsovilSi Tireoiduli transkripciis faqtori TTF-1 cnobilia

rogorc specifikuri SemakavSirebeli cila, (T/EBP), romlis funqcias

warmoadgens farisebri jirkvlis embrionuli ganviTarebisa da funqciis

67

kontroli (Felton CL., Patel A., Burch H.,et al, 2001). nayofis organizmSi TTF-1

eqspresia vlindeba adreuli organogenezis dros da pasuxismgebelia

Tireoiduli fenotipis diferenciaciaze TTF-1. vlindeba aseve mozrdilis

folikuluri ujredebis birTvebSi, aregulirebs, Sesabamisad, Tireoglo-

bulinis (TG), Tireoperoqsidazis (TPO), Tireotropinis receptoris (TSH-R)

genis eqspresias (Goretzki, Simon et al; 2000). dadgenilia procentuli urTi-

erTqmedeba TSH-s da TTF-1 Soris. TTF-1 ukavSirdeba oqsidaciis Semcirebas,

xolo Tireoiduli qsovilisstatusi pirdapir kontroldeba TSH-s

moqmedebiT.

sur. 28.TTF-1 maRali birTvuli eqspresia Hurthle-s ujredebis birTvebSi Hurthle-s ujredovani adenomisa da Hashimoto-s

Tireoiditis asociaciis dros, 160X

TTF-1 SeRebvis intensivoba HT dros Sefasda, rogorc Tireocitebis

birTvuli eqspresia (sur 28, sur 29) gansakuTrebiT maRali iyo reaqcia

difuzuri toqsikuri Ciyvis dros da Seesabameboda Tireotropuli

hormonis daqveiTebul raodenobas igive pacientebis sisxlis SratSi.

TvalsaCinoa, rom Hurthle-is ujredovani adenoma, asocirebuli Hashimoto-s

TireoiditTan (sur.30) gviCvenebs TTF-1-s maRal eqspresias, romelic

paraleluria TSH-s donis matebisa.

68

sur. 29 Hurthle- ujredovani infiltraciis keraSi birTvuli

TTF1-s eqspresia. imunoperoqsidazuli reaqcia, 160X

sur.30.Hurthle-ujredovani adenomatozuri hiperplazia Hashimoto- s Tireoiditis fonze. TTF1-s eqspresia.


mikrosisxlZarRvTa simWidrovis kvleva

VEGF mimarT mgrZnobiare mikrosisxlZarRvTa ricxvis kvlevam sam

“cxel wertilSi” gviCvena faqtoris dadebiTi eqspresia interfolikulur

69

sivrceSi Tireoiduli qsovilis yvela nimuSSi, rac miuTiTebs angiogenezis

regulaciis auto- an parakrinuli sasignalo meqanizmis arsebobaze.

kvlevis Sedegebma (cxrilebi 7-8) aseve gviCvena, rom VEGF eqspresiis

mixedviT perivaskuluri zonebis Sefaseba iZleva ori tipis cvlilebaTa

gamokveTis SesaZlebobas:

1. VEGF SedarebiT maRali aqtivoba eqstracelulur matriqsSi (2-3

qula ≈ 50-75%);

2. susti moproliferacie da zrdis mastimulirebeli aqtivoba

neoangiogenezis calkeuli kerebiT (fokaluri aqtivoba)

cxrili 7

VEGF-is imunoeqspresia sxvadasxva Tireoiduli paTologiis dros

VEGF Hashimoto

Tireoiditi n=20

dtC

n=20

norma

n=10

kvanZovani Ciyvi n=20

Tireocitebi (%)

10 (50%) 19 (95%) 10 (100%) 12 (60%)

endoTeliocitebi(%)

7 (36,5%) 19 (95%) 3 (33%) 2 (10%)

cxrili 8

mikrosisxlZarRvTa simWidrove (MVD)

sisxlZarRvTa raodenoba (MVC)

sisxlZarRvTa areali(mm2)

Tireoiduli paTologia

MM± SD M± SD

kvanZovani Ciyvi 30,3 12,5 0,278 0,149

dtC

39,2 12,3 0,393 0,105

Hashimoto Tireoiditi

32 13,4 0,331 0,109

Nnorma

35,0 12,5 0,280 0,144

70

I jgufSi gamovlinda VEGF maqsimaluri eqspresiis done,

SenarCunebuli perivaskuluri zrdis zonebSi. gansakuTrebiT aRsaniSnavia

difuzuri toqsikuri Ciyvis dros msxvili folikulebis jgufis mier

sisxlZarRvTa kompresia, ris gamoc zrdis zonebis periferiul velebSi

sanaTurebs hqon-daT viwro napralebis Sesaxedaoba.

II jgufs miekuTvneba Hashimoto-s Tireoiditi: Sualeduri aqtivobis da

MVD maCveneblis mixedviT. statistikurma analizma am SemTxvevaSi

gamoavlina, rom nozologiur tipebs Soris gansxvaveba sarwmunoa. magram

sisxlZarRvTa arealis farTobis mixedviT sxvaoba arcTu ise demonstra-

ciulia, gansakuTrebiT,Tu SevadarebT kvanZovan euTireoidul warmona-

qmnebs.

yvela Catarebuli imnohistoqimiuri reaqciis Sedegebis mixedviT

SeiZleba davaskvnaT Semdegi:

Hashimoto-s Tireoiditi xasiaTdeba msxvili limfoiduri folikulebiT,

difuzuri plazmocituri infiltraciiT, araproporciulad didi reaq-

ciuli germinaciuli centrebiT mantiis zonaSi. farisebri jirkvlis inter

da intrafolikulur qsovilSi aRiniSneba mkvrivi limfur da plazmur-

ujreduli kerebi. limfoepiTeluri daizianebis sazRvarze Tireoiduli

folikulebi gamoiyureba atrofiuli, regresiuli saxiT. aqve adgili aqvs

Hurthle ujredebis metaplazias, maTSi S100 cilis eqspresias eqstensiuri

infiltraciis saxiT, TTF1 vlindeba birTvuli mkafio SeRebviT, zomier

adenomatozur struqturebSi, araiSviaTad, adenomis formirebis

tendenciiT.

amdenad, Hashimoto-s Tireoiditis dros, difuzur toqsikuri Ciyvisagan

gansxvavebiT, aRiniSneba normuli Tireoiduli folikulebis arqiteqto-

nikis rRveva , rac SeiZleba Sefasdes rogorc limfoepiTeluri dazianeba.

literaturis monacemebiT (Soma, Bobzin, Guerlin, Livolsi, 2003, Ohye, Kukata et al,

2005, Sanyal, 2014; Chang-Mo, Oh et al, 2014), limfoiduri folikulebis

germinaciuli centrebi, rogorc Tireoiditis mudmivi komponenti, mZime

formis dros SeiZleba iyos araproporciulad didi zomisac. vfiqrobT,

rom Hashimoto-s Tireoiditis yvela Seswavlil SemTxvevaSi limfoepiTe-

luri dazianebis fenomenis Camoyalibeba aris T-limfocitebis aqtivobis

Sedegi. imavdroulad, Hashimoto-s Tireoiditis limfoplazmocituri

71

variantis dros sklerozuli cvlilebebis fonze izrdeba plazmuri

ujredebis raodenoba.

Hurthle-s ujredebis matebis paralelurad imave SemTxvevebSi sisxlis

SratSi TSH negatiuri populaciis zrda da FT4-s daqveiTeba miuTiTebs

oqsifiluri ujredebis proporciis siWarbeze, rac klinikur

hipoTireoidizms axasiaTebs.

72

Tavi IV. gamokvlevis Sedegebis ganxilva

gamokvlevis Sedegebi naTlad metyveleben, rom endokrinul

paTologiebs Soris farisebri jirkvali lideris pozicias inarCunebs

autoimunur da neoplaziur procesSi. am ori dazianebas urTierT-

zemoqmedebis da urTierTSeqcevadobis kavSirebi aqvT (ganwyoba=predispo-

zicias) (L.S. Ward, 2014) miRebulia daskvnad, rom papiluri karcinomis

prognozi gacilebiT keTilsaimedoa, rodesac is asocirebulia Hashimoto-s

TireoiditTan (Konturek et al., 2013). aris Tu ara aq garemo faqtorebis

zemoqmedebis, atmosferuli da samrewvelo, teqnogenuri faqtorebis

sixSire, geografiuli gavrceleba epidemiologiuri TvalsazrisiT Tu sxva

mosazrebebi, mkvlevarTa Sefaseba araerTgvarovania. cnobilia, rom

Hashimoto-s Tireoiditi da masTan dakavSirebuli sawyisi Tireoiduli

disfunqcia pasuxismgebelia rogorc SeZenili hipoTireoidizmis ZiriTadi

mizezi bavSvTa asakis CaTvliT (Latina, Gullo et al, 2013) SratSi antiTireoi-

duli antisxeulebis TPO Ab da TG Ab erTdrouli dakvirvebiT SeiZleba

subklinikuri hiperTireoidizmis xarisxi Sefasdes ±11.7, (Revenga S, Trimarehi

F. (2008), Cho, Choi, Perk et al. (2013) Chang Votoh, Park et al. (2014) masalebiT

autoimunuri HT sixSirem mkveTrad moimata 1975-2005 da gansakuTrebiT, 1988-

2007 wlebis periodSi. mniSvnelovania, rom ar Secvlila araautoimunuri

anTebiTi procesebis sixSire. mag: de Quervain-is da Riedel-is Tireoiditebisa

(Ferlay, Soerjomataram, Ervik, 2013),rac aZlevs mkvlevarebs uflebas daaskvnan,

rom garemo faqtorebis zemoqmedeba mniSvnelovnad cvlis swored Hashimoto-

s Tireoiditis sixSires. (Erdogan, Erdem et al., 2009).

Hashimoto-s Tireoiditi, amJamad cnobili, rogorc autoimunuri paTo-

logia, gamoirCeva mocirkulire antisxeulebis maRali titriT Tiroiduli

peroqsidazisa da Tireoglobulinis mimarT. ukanaskneli wlebis manZilze

bevrad win waiwia codnam Hashimoto-s Tireoiditis Sesaxeb. daixvewa kvlevis

meTodebi, romlebic saSualebas iZlevian HT qvetipebi Sefasdes, rogorc

morfologiuri, aseve imunohistoqimiuri da imunogenetikuri poziciebidan

(Li, Zhou, Ozaki et al., 2012; Dardano et al., 2012),Tumca yvelaze xSiri varianti aris

fibrozuli qvetipi, romelic xasiaTdeba Tireoiduli parenqimis mkveTri

fibrozulqsovilovani CanacvlebiT, gansxvavebiT Riedeli-sTireoiditisagan.

73

Aam variantis dros ar aris gamoxatuli eqstraTireoiduli fibrozi. mag:

siloadeniti, tubulointersticiuli nefriti, retroperitonealuri

fibrozi da anTebiTi genezis aortis anevrizma. Tumca imunuri sistemis

dazianebiT mimdinare procesebs aqvT saerTo Taviseburebani:

limfoplazmocituri infiltracia, fibrozi, obliteraciuli flebitebi

da plazmuri ujredebis mniSvnelovani rekrutizacia. (Kamisawa, Hamano, Ochi

et al, 2008).

amJamad, Hashimoto-s Tireoiditis Sesaxeb codnis Tanamedrove done,

saqarTvelos sxvadasxva regionebidan moZiebuli postoperaciuli masalis

Sedareba saSualebas gvaZlevs vimsjeloT hipoTireoidizmis maRal

sixSireze pacientebSi autoimunuri Tireoiditis dros da mis damamZimebel

tendenciebze.

Cveni masalis histologiuri kvlevis Sedegebi, difuzuri toqsikuri

Ciyvisa da Hashimoto-s Tireoiditis dros gamoxatuli limfoplazmocituri

infiltratebis SedarebiTi Sefaseba gvafiqrebinebs, rom difuzuri

toqsikuri Ciyvi da HT erTi paTologiis or mxares warmoadens. arsebobs

autoimunuri Tireoiditis TireotoqsikozSi transformaciis SesaZlebloba

(Wiebelt et al; 2011) es mosazreba eyrdnoba interleikin-1 asocirebuli

receptoris antagonisti genis defeqtis arsebobas Greaves-is daavadebis

SemTxvevaSi (Pusztaszeri et al., 2013).

Hashimoto-s Tireoiditis diagnostika eyrdnoba kombinirebulad ramde-

nime meTodis gamoyenebis Sedegebs, rogoricaa klinikuri da ultrasono-

grafiuli kvlevebi. bioqimiuri monacemebi zogjer gamoavlens euTire-

oidizms, xSirad subklinikur hipoTireozs, es ukanaskneli ganisazRvreba

FT4-s momatebuli doniT; manifestirebuli hipoTireozi vlindeba TSH

matebiT da normaze dabali T3 erTdrouli arsebobiT, anda Tg Ab/TPO Ab

pozitiuri SedegebiT.

klasikuri rutinuli kvlevebi gviCveneben, rom ZiriTadi zogadmorfo-

logiuri niSnebi warmoadgenen ramdenime procesis gamoxatulebas. aseTebia

plazmuri ujredebis didi raodenobiT mozidva, eqstensiuri limfo-

plazmocituri infiltracia, stromis fibrozi. es cvlilebebi, rogorc

Cveni dakvirveba gviCvenebs, ukavSirdeba TPO antisxeulebis dones. limfoi-

duri formis dros aRiniSneboda mravlobiTi folikuli germinaciuli

74

centrebis SerwymiT da gamoxatuli limfoepiTeluri dazianebis suraTiT,

Warbujredovan stromaSi aseve vxvdebodiT plazmurujredovan infilt-

racias (cxrili 3). gansxvavebiT, fibrozuli variantis dros sWarbobda

SemaerTebelqsovilovani struqturebis sxvadasxva intensivobiT

gavrceleba: wilakTaSorisi, wilakTaSida da nawiburovani fibrozi.

araiSviaTad warmodgenili iyo samive varianti sxvadasxva moculobiT,

magram erTerTi dasaxelebuli sWarbobda da ikavebda parenqimis naxevars

mainc, rac ganapirobebda ufro Rrma, ujeduli cvlilebebis

suraTs(cxrili 4). folikulaTa bazaluri membranebis dazianeba,

Tireocitebis degeneracia, gamowveuli limfoplazmuri infiltraciis Rrma

penetraciiT intrafolikulur arealSi.

dasaxelebuli Sedegebis gaTvaliswinebiT, SeiZleba iTqvas, rom

hipoTireozis morfologiur substrats warmoadgens Tireoiditi

interfolikuluri fibrozis dominirebiT, degeneraciuli Tireoiduli

epiTeliumi susti vardisferi koloidiT da zomieri birTvuli atipiiT.

gamokvlevis Sedegebis klinikuri aspeqtebi migvaniSnebs Semdeg

mniSvnelovan Taviseburebebze. saxeldobr, maRali anti TPO done da swrafi

progresi, subklinikuri hipoTireozi, aseve dabali eqogenoba, axalgazrda

mamakacebis prevalensi axasiaTebs Hashimoto-s Tireoiditis im jgufs,

romelTac operaciamdeli periodi hqondaT ufro xanmokle, vidre pa-

cientTa jgufs, sadac Warbobdnen qalebi. xangrZlivi anamneziT (≈10 weli);

anti-TPO done naklebad iyo momatebuli.

Lloyd, Douglas (2002), Li, Nishihara, Hirokawa (2009) da sxva avtorebi ganmartaven

Hashimoto-s Tireoiditis fibrozul variants, rogorc damoukidebel

nozologiur erTeuls, romelsac axasiaTebs gansakuTrebuli intensivobiT

folikulebis degeneracia, histiocitebiT giganturi ujredebiT infilt-

racia, rac ultrasonografiulad dasturdeba mkveTri hipoeqogenobiT.

uaxlesi wlebis kvlevebi ukavSireben erTmaneTs TPO antisxeulebis

maRal dones plazmaSi Riedel-is Tireoiditis calkeul variantebs da Tvli-

an, rom es ori anTebiTi procesi paTofiziologiurad IgG4-asocirebul

daavadebas warmoadgens. es debulebebi Semdgom kvlevas da dazustebas

moiTxovs (Dahlgren, Khosroshahi et al., 2010).

75

Cvens monacemebze dayrdnobiT da literaturaSi arsebul gamokvlevaTa

Sedegebis gaTvaliswinebiT farisebr jirkvalSi mimdinare procesebi

Hashimoto-s Tireoiditis dros SevafaseT Semdegi saxiT: Hashimoto-s

Tireoiditis diagnozis umTavresi sakvanZo niSania anti TPO antisxeulebi,

magram aqac vxedavT maCvenebelTa Soris did sxvaobas. maT Soris normis

mdgomareobasac, rac gvafiqrebinebs, rom autoimunuri dazianebis adreuli

procesi SesaZlebelia latenturad mimdinareobdes. ufro metic,

saubklinikuri da klinikuri hipoTireozi asocirebuli iyo am dros gul-

sisxlZarRvTa da neirofsiqiatriul simptomatikasa da CivilTan, rac

zrdis citologiuri/biofsiuri sadiagnostiko kvlevebis Rirebulebas

(Zhen, Nakanura, 2010). umetesoba Cveni pacientebis umetesoba iyo pre-

menopauzuri qalebis jgufidan, gamoxatuli Tiroqsinis deficitiT.

difuzuri toqsikuri Ciyvisagan gansxvavebiT, miuxedavad Ciyvis

arsebobisa, aRiniSneba misi dabali eqogenoba, heterogenoba, hipervasku-

larizacia, rac Cvenma kvlevebma antigenuri faqtorebis CarTviTa da

mikrosisxlZarRvTa simWidrovis gaangariSebiTac daadastura. Tumca, aris

kvlevebi (Donkol et al, 2013, Anderson et al, 2010, Sangal D., 2014), romelSic

dopleriT dadgeniliqna sisxlis nakadis Semcireba Hashimoto-s Tireoiditis

dros, greivsis daavadebisagan gansxvavebiT. am ukanasknelTan

imunohistoqimiuri da morfometriuli maCveneblebis diferencirebis mizniT

Cvens mier Seswavlilia folikulebis raodenoba, birTvebisa da citoplaz-

mis farTobi, sxvadasxva hiperplaziuri fenomenebi, rogoricaa foliku-

laTa kedlis naoWianoba, stratifikacia, gamonazardebi, dvrilisebri

struqturebi, rac dtC-s dros damaxasiaTebel mravalSrianobas iZleva. am

monacemebis Tanaxmad, Tireocitebis morfometriuli parametrebi Cven

Sesadarebel masalaze maqsimalur mniSvnelobebs aRweven swored dtC-s

dros, xolo minimalurs - Hashimoto-s Tireoiditis dros.

folikulur-koloiduri indeqsis maCvenebeli, vizualurad sakmaod

gazrdilia, xolo am fonze, HT-s dros TviT Tireocitebis farTobi

Semcirebuli. euTireoiduli kvanZovani Ciyvis da “normis” maCveneblebi

ikaveben Sualedur pozicias.

Tireotoqsikozis dros naklebad gamoxatulia Hurthle-s ujredebis

aqtivoba. HT dros ki cila S -100 eqspresia vlindeba vrcel infiltratebSi

76

da adenomatozur struqturebSireaqciiT, rac folikuluri epiTelis

Canacvlebis fonze difuzuri limfoplazmocituri infiltraciiT,

hipoTireoidizmis struqturul-morfologiur baziss qmnis. aseTive

daskvnebs akeTeben sxva mkvlevarebic (Amani K, 2011, Hsi et al, 1998), rac

transkripciul-polimerazuli reaqciiTa da citofotometriis monacemebiT

dadasturda. gamovlinda, agreTve,Ig kappa da lambda jaWvebis dadebiTi

homogenoba kappa da uaryofiTi lambda imunoeqspresiis mimarT.

Cvens SemTxvevaSi, arqiteqtonikis dezorganizacia asocirdeboda ara

marto Hurthle-hiperplaziur reaqciebTan (adenomatozi, adenoma), aramed

limfoepiTelur dazianebasTan, rac T-limfocitebis citotoqsikuri

reaqciebiT aixsneba. (CD3+ CD4+)(Amani, 2011), Cvens mxriv, am mosazrebas

adasturebs mkveTrad intensiuri TTF-1 imunoeqspresia Hurthle-s ujredebis

proliferaciis zonebSi da domenSi. aseT SemTxvevaSi Cydney L., Felton, Anneta,

Patel, et al, (2011) aRniSnaven Tireoiditis agresiul klinikur dinamikas.

Cveni Sromis ZiriTadi amocanebidan gamomdinare histologiuri kvlevi-

sas yuradRebas vamaxvilebdiT autoimunuri komponentis gamoxatulebis

intensivobaze, radgan difuzuri toqsikuri Ciyvi aseve warmoadgens

autoimunur daavadebaTa kategorias (Zantour et al, 2003; Mazeto et al, 2004; Latrofa,

Fiore et al, 2013).

Ddifuzuri toqsikuri Ciyvis dros mudmivad gvxvdeboda limfoiduri

infiltraciis ubnebi. savaraudoa, romT-limfocitebis efeqtoruli

cilebis zemoqmedebiT fibrilogenezis stimulaciis xarjze

sinTezirdeboda didi raodenobiT kolageni, Tumca erTdroulad

aRiniSneboda misi lizisic. aseTi boWkoebi ganicdidnen homogenizacias da

destruqcias, rasac aRniSnaven specializirebul kvlevebSi Vivier, Raulet,

Moretta da sxv (2011).

Hashimoto-s Tireoiditis fibrozuli variantis aRiareba, rogorc

damoukidebeli nozologiuri erTeulis, swored stromis hiperplaziis

TaviseburebebiT da sklerofobrozis imunoglobulindamokidebuli, anti

TPO antisxeulebis zemoqmedebiT aixsneba (Anderson et al, 2010; Sangal,2014).

mniSvnelovani informacia Hashimoto-s Tireoiditis dros parenqimuli

struqturebis dazianebis Sesaxeb mogvca morfometriulma kvlevam. am

monacemebis Tanaxmad Tireocitebis birTvisa da citoplazmis farTobi

77

iklebs sakontrolo jgufebTan SedarebiT, aseve difuzuri toqsikuri

Ciyvis monacemebTan SedarebiT. am ukanasknelSi dafiqsirda maqsimalurad

didi zomis Tireocitebi, maTi hiperplaziis faqtebi dadasturebuli

vizualurad mravlobiTi naoWis, stratifikaciis kerebis, adenomatozuri

zrdis saxiT, da aseve, morfometriuladac. calkeul SemTxvevaSi

morfometriulma analizma gamoavlina mikrofolikuluri struqturebi,

rac zogadad, plazmuri membranebis da Semxebi zedapirebis zrdis

maCvenebelia da jirkvlis funqciis gaZlierebaze miuTiTebs.

Hashimoto-s Tireoiditis dros cvlilebebi Rebulobs hipoTireoiduli

transformaciis saxes. romelsac aZlierebs parenqimuli struqturebis

Canacvleba limfoidurujredovani infiltraciiT. es ukanaskneli cvlis

Tireocitebis receptorebis statuss. aZlierebs antiTireoiduli

antisxeulebis, Cvens SemTxvevaSi, anti TPO antisxeulebis citotoqsiur

efeqts. unda aRiniSnos, arom swored aseTi membranozuli Zvrebis

safuZvelze Hashimoto-s Tireoiditis dros minimaluria folikulebis

raodenoba, maTi ganakveTis farTobi, Tireocitebis ricxvi da farTobi erT

folikulSi, rac fibrozuli qsovilis agresiuli zrdiT aixsneba. didi

raodenobiT aqtiuri germinaciuli centrebis Serwyma, maTSi plazmuri

ujredebis hiperplazia da limfoepiTeluri dazianebis sazRvari,

limfoplazmuri penetracia intra da interfolikulur domenSi qmnian

Hashimoto-s Tireoiditis paTologiur suraTs. HT dros Cven masalaze vnaxeT

Hurthle-s ujredebis receptorTa qsovilovani aqtivoba. parafolikulur

domenSi aRiniSneboda rogorc difuzuri-fokaluri hiperplazia, aseve

adenomatozuri zrdis tendencia da Hurthle-ujredovani adenomebi. am

procesebs axasiaTebdaT specifikuri S-100 cilis eqspresiis zrda

infiltraciis kerebSi birTvebis intensiuri SeRebviT,

Tireotransformaciis faqtoris TTF-1 CarTva birTvebSi da difuzuri fonis

gaZlierebis saxiT, gansakuTrebiT, adenomisa da adenomatozis keraSi.

difuzur toqsikur CiyvSi TTF-1 CarTva iyo ufro masiuri da intensiuri,

vodre Hashimoto-s Tireoiditis dros. Hurthle-s ujredebis proporciis

raodenobrivi da Tvisobrivi zrda, SesaZlebelia am ujredebis

metaplaziuri cvlilebebis gamosaxvad CaiTvalos. rac, sakuTriv

jirkvlovani parenqimis arqiteqtonikis cvlilebas iwvevs: wvrili

78

folikulebi daSorebuli fibrozuli qsovilis depozitebiT da

interfolikulur domenSi limfoplazmocituri infiltratebi. gamomfeni

Tireocitebis oqsifiluri transformacia erT SemTxvevaSi, roca anti TPO

done ar iyo maRali da meore mxriv, mkveTri limfoplazmocituri

infiltratebi, romlebic limfocitebis da plazmuri ujredebis didi

raodenobiT gamoirCevian stromasa da irgvliv Tireoidul folikulebSi

epiTeliumis gaswvriv. da calkeul SemTxvevaSi TviT folikulebis

sanaTurSi. aseTi suraTis Tanmxlebi cvlilebebia Tireoiduli

folikulebis atrofia Ria vardisfrad SeRebili birTvebis atipiiT, mcire

raodenobiT mkvrivi koloidiT maRali anti-TPO antisxeulebis fonze

sisxlis SratSi. literaturis monacemebi (Li, Nishihara et al., 2009, Khosroshahi,

Stone, 2011) miuTiTebs, rom aseTi cvlilebebi mkafiod gamoxatuli

fibrozuli variantis saxiT, klinikurad tipuri Hashimoto-s

Tireoiditisagan gansxvavdebian, iZlevian didi zomis mkvriv Ciyvisebr

zrdas, araiSviaTad malignizaciis cru diagnoziT, Tireoglobulinis

titris matebis da mkveTri hipoTireoidizmiT. igive Sedegebs iziarebs

avtorTa jgufi (Li, Zhou, Ozaki, Nishihara et al., 2012) romelTa dakvirvebiTac

imunoglobulin IgG4 asocirebuli Tireoiditi (da swored aseTi

histologiuri struqturiT) warmoadgens interfolikuluri fibroziT

mimdinare qronikul process.

Hurthle-s ujredovan metaplazias xsnian xangrZlivad mimdinare

hipoTireoidizmiT, SesaZloa, gama-interferonis eqspresiiT, apoptozis

dabali indeqsiT, C-myc genebis maRali eqspresiiT (Amani K., 2009, Sangal, 2014)

Hashimoto-s Tireoiditisa da difuzuri toqsikuri Ciyvis dros

farisebri jirkvlis disfunqciis ganviTarebaSi mniSvnelovania

sisxlZarRvovan-stromul urTierTobaTa cvlilebebis da zrdis faqtorTa

molekuluri eqspresiis dinamika. CvenTvis am kvlevis procesSi gamoikveTa

rigi Teoriuli debuleba, romelic hiperTireoidizms axasiaTebs.

saxeldobr, Tiroqsinisa da triiodTironinis Warbi gamomuSavebis dros

aRiniSneba kolagenis daSla, rac T4 da T3 SemaerTebel qsovilze

zemoqmedebiT ukavSirdeba glikozaminoglikanebis sulfatirebis gziT

(Ramsden, 2000, Spencer, Hollowell et al, 2007). swored bazaluri membranis gasqeleba

da eqstraceluluri matriqsis Sesiveba warmoadgens Tireotoqsikozis erT-

79

erT wamyvan niSans, xolo araproporciulad didi folikulebi, (LiVolsi,

2003, Demellawy et al, 2008; Latina et al, 2013,) mosazrebiT, datvirTuli

sensibilizebuli T limfocitebiT zemoqmedeben makrofagebze stromis sxva

citokinmaproducirebel ujredebze efeqtoruli kileruli ujredebis

gamomuSavebiT.

interleikinebi -1,2 amcireben ra limfocitebis proliferaciul

aqtivobas (Bossowski et al, 2008) sabolood ayalibeben e,w “mankier wres”,

romelSic interleikin – 1 iwvevs Tireocitebis mier interleikin-6

produqcias, rac aZlierebs limfocitebis priduqcias. am kaskadSi

CarTulia fobroblastebi kolagenmasinTezebeli funqciis gaaqtivebiT

(Lebrero et al;2000, Kamisawa, Okamato, 2008). msgavs meqanizmebs aqvT sistemuri

xasiaTi da universaluria sxva autoimunuri daavadebisTvisac

eqstraTireoiduli fibroziT – ridelis Ciyvi, anTebiTi genezis aortis

anevrizma, retroperitoneuli fibrozi (Komatsu et al.,2005, Hennessey., 2011)

aRniSnaven, rom hipoTireozi aris Hashimoto-s Tireoiditis da ridelis

Ciyvis Tvisobrioba, aramed didi sixSiriT vlindeba pacientebSi

autoimunuri pankreatitiT. SeiZleba vifiqroT, rom sensibilizebuli

limfocitebi (Amani.,2011; Salim, 2014) pirdapiri citotoqsikuri efeqtis

realizaciis procesSi iwveven aseve Tiroqsinmaproducirebeli ujredebis

Semcirebas, rac Cvens masalaSi vlindeba TSH eqspresiis mkveTri

SemcirebiT. Hashimotos-s Tireoiditis dros,TTF-1 intensiuri reaqciiT

difuzuri toqsikuri Ciyvis dros da aseve papiluri karcinomis qsovilSi

(Rurua, Gogiashvili et al; 2013, 2015). imunohistoqimiuri reaqciis Sedegebi,

saxeldobr, sisxlZarRvTa simWidrovis maCvenebeli VEGF eqspresiis

suraTiT miuTiTeben, rom difuzuri toqsikuri Ciyvis dros (hiperTireozi)

es parametri gaZlierebulia. aseve, Cvens mier adre arsebul kvlevebSi

papilaruli karcinomis qsovilSi (crudadebiTi reaqcia)( Rurua N., et al., 2013).

am cvlilebebs savsebiT eTanxmeba difuzuri toqsikuri Ciyvis dros

miRebuli faqtebi kapilaruli qselis funqciis gaZlierebis, qselis

suraTis, calkeul sisxlZarRvTa sanaTuris zrdis Sesaxeb, xolo Hashimoto-

s Tireoiditis dros Tireoiduli parenqima hipovaskularizacias ganicdis.

xdeba aqtiur cirkulaciaSi monawile kapilaruli qselis reduqcia

fibrozuli qsovilis CanacvlebiT, neoangiogenezis stabilurad dabali

80

xarisxiT. amdenad, realurad gamoxatulia da subklinikuri hipoTireozi

sinqronizebulia Tireocitebis hormonmasinTezebeli funqciis

daTrgunvasTan. Tireocitebis TSH –receptoruli aqtivoba ramdenjerme

mcirdeba dtC da euTireoidul CiyvTan SedarebiT (cxrilebi), rasac aseve

xels uwyobs limfoiduri qsovilis hiperplazia. limfoplazmocituri

infiltraciis intensivoba stromasa da parenqimaSi gvafiqrebinebs, rom T

limfocitebis pirdapiri Tu gaSualebuli citotoqsiuri efeqti

Tireocitebis birTvis cilebze gamowveuli unda iyos birTvakis

organizatoris transkripciuli aqtivobis SemcirebiT, razec n. raixlinis

Sromebi miuTiTeben. (РаихлинН.Т.,исоавт2010). dadgenilia argirofilur

cilaTa eqspresiis Semcireba, swored Ag-NOP-maRali eqspresia maCvenebelia

imisa, rom ujredTa umravlesoba aris S da G2 fazaSi. am cilebis

inhibicia mitogenuri stimulis ararsebobis pirobebSi amcirebs G1 fazaSi

Semavali ujredebis ricxvs, rasac hipoTireozis dros aqvs adgili.

amdenad, hipoTireozi Hashimoto-s Tireoiditis dros SeiZleba iyos rogorc

Tiroqsinmaproducirebeli ujredebis Semcirebis, aseve TSH-s mimarT

mgrZnobelobis daqveiTebis Sedegi. igive masalaze Seswavlilia TSH- s

angiogenezis mastimulirebeli efeqti (Tsagareli Z., Gogiashvili L., Nikobadze E., et

al, 2011) ramac aCvena Tireocitebis VEGF-is aqtivobis daTrgunva

hipoTireozis dros. amdenad, mikrocirkulaciuri kalapotis saerTo

sigrZis da simWidrovis Semcireba ganisazRvreba, rogorc am or sasignalo

faqtorze mgrZnobelobis daqveiTebis Sedegi. cnobilia, rom angiogenezis

endogenur stimulatorebs Soris VEGF aris ukve arsebuli kapilarebidan

Zlieri signali kapilaris avtonomiuri ganviTarebisaTvis neoangiogenezis

stimulatori. Cvens masalaze naCvenebia, rom VEGF-is produqciis ZiriTad

wyaros warmoadgenen swored A tipis Tireocitebi.

fiziologiur pirobebSi da euTireoiduli Ciyvis dros angiogenezs

axasiaTebs stabiluri done, damaxasiaTebli mocemuli tipis qsovilisTvis.

sisxlZarRvTa simWidrovis Sefaseba paTologiis dros xdeba angiogenezis

aqtivobis imunohistoqimiuri gamovleniT: VEGF, CD34, CD31 da VIII

faqtorebis mimarT. aRniSbuli markerebis eqspresia saSualebas iZleva

ganarCioT fsevdoneoplaziuri hipertrofia da neoplazia. (Offersen et al., 2003,

Batista A., et al,Nakamura et al.,2006) VEGF-s gamoyenebiT SeiZleba ganisazRvros

81

swored is, neovaskularizaciasTan asocirebuli mikrosisxlZarRvebis

simWidrove, romelsac aRweren, rogorc “angiogenezuri mimikria” (Rydlova et

al.,2008). keTilTvisebiani hiperplazia papiluri struqturis Zlieri

vaskularizaciiT xasiaTdeba sisxlZarRvTa raodenobis matebiT (dtC,

folikuluri adenoma). sisxlZarRvebis mier dakavebuli farTobis

Seswavlis procesSi gamovlinda Semdegi suraTi: angiogenezi difuzuri

toqsikuri Ciyvis dros (hipertrofia+hiperplazia) xasiaTdeba mcire

diametris axali sisxlZarRvebis formirebiT. avTvisebiani zrdis dros

qsovilSi aRiniSneba didi yalibis sisxlZarRvebis de novo warmoqmna.

rogorc cxrilebidan Cans, sisxlZarRvTa mier dakavebuli farTobi VEGF-

aqtivobis mixedviT mxolod dtC-s qsovilSi aris momatebuli. Hashimoto-s

TireoiditSi es maCvenebeli qveiTdeba, rac SeiZleba aixsnas Semdegi

Teoriuli mosazrebiT: amJamad, angiogenezis regulaciis kvlevaSi

aRiniSneba mniSvnelovani progresi: Willerbrand faqtors (VIII), CD34, CD31,

aseve VEGF –rogorc panendoTeluri zrdis faqtorebi gamoiyeneba

sisxlZarRvTa simWidrovis kvlevis mizniT. maT Soris, Cvens mier

Seswavlilia CD34 da VEGF romlebic neovaskularizaciis deteqcias

axdenen. CD34, romlis winamorbeds homopoezuri Rerovani ujredis markeri

CD133 cila warmoadgens, asrulebs angiogenuri signalis rols Semdegi

sqemiT: endoTeluri ujredi → ujredi da ujredi → matriqsis urTierT-

qmedeba da signalis transduqcia → (Kendo, Schuf et al., 2007) CarTulia stromis

angiogenezis procesSi da misi eqspresia korelaciaSia parenqimis biolo-

giur `qcevasTan”; VEGF da CD34 deteqciis miRebuli kompleqsuri suraTi

gviCvenebs adamianis mikrosisxlZarRvTa endoTeliocitebis intensiur

angiogenezSi CarTuli ujredebis aqtivobas regeneraciul da anTebiT

procesSi. Eendokrinul organoTa angiogenezi naklebad Seswavlilia.

paTologiuri procesis ganviTarebaSi CarTulobis TvalsazrisiT aris

mcire raodenoba Sromebisa jarisebri jirkvlis papiluri da meduluri

karcinomis angiogenezis Sesaxeb. (Jebriel, Alaeddin et al., 2007; Rydlova et al., 2008;

Ludvikova et al., 2005) literaturis monacemebi da Cveni sakuTari kvlevis

masalebi gviCveneben, rom ar aris TvalsaCino sxvaoba Tireoiduli

paTologiis iseT saxeebSi, rogoricaa folikuluri adenoma da karcinoma

(РуруаН.З. исоавт, 2013) magram faqtebi miuTiTeben, rom keTilTvisebian

82

procesebs Soris, mag: Hashimoto-s Tireoiditsa da difuzur toqsikur Ciyvs

Soris aris variabeloba endoTeluri antigenis specifikurobasa da

mgrZnobelobas Soris sxvaoba. CD34+ aRniSnavs maRali mgrZnobeloba

sisxlZarRvTa kerovan grovebSi da naklebad fokusirdeba winamorbedi

kapilaruli qselidan axalwarmoqmnili sisxlZarRvebis endoTeliumSi.

mikrosisxlZarRvTa simWidrovis daTvlis meTodis gamoyenebiT (Ranefall,

Wester etal., 1998; Erdem O., Erdem M., Erdem A. et al., 2007) naCvenebi gvaqvs vrceli

cvalebadoba Ciyvis sxvadasxva variantebs Soris. maT Soris, adenomatozuri

jgufis Ciyvis qsovilSi (Rurua N., Gogiashvili L., Tsagareli Z., 2014, 2015), rasac

vxsniT folikuluri komponentisTvis damaxasiaTebeli degeneraciuli

cvlilebebis farTe speqtriT. (makro-mikrofolikuluri kvanZebi) da

stromasa da folikulur komponents Soris Tanafardobis cvladi

proporciebiT. rogorc naSromis literaturuli mimoxilvis dros

aRvniSneT, SeiZleba gakeTdes daskvna, rom angiogenezi, romelic Tan

axlavs keTilTvisebian hipertrofiul cvlilebebs, maT Soris, difuzur

toqsikur Ciyvs, realizdeba mcire diametris mravlricxvovani

sisxlZarRvebis formirebiT, maSin, rodesac avTvisebian simsivneebSi gvaqv

naklebi raodenobis da didi diametris sisxlZarRvebi. Ffarisebri

jirkvlis dazianebis dros calkeuli histologiuri tipebis mixedviT

erTidaigive parametris (MVA) Sefasebisas mniSvnelovani gansxvaveba ar iyo

naCvenebi. sisxlZarRvebiT dakavebuli farTobi farisebri jirkvlis

cakleul kvanZovan warmonaqmnebSi iyo analogiuri, miuxedavad sxvaobisa

axalwarmoqmnil mikrosisxlZarRvTa raodenobaSi. Aamitom, gamovyofT

farisebr jirkvalSi angiogenezis Sefasebisas ori saxeobas: hipo da

hipervaskularuls.

VEGF eqspresiis Seswavlisas naCvenebia, rom Hurthle adenomatoziT da

adenomis TanxlebiT mimdinare Hashimoto-s Tireoiditis qsovilSi ufro

maRalia, vidre HT klasikur variantSi. Tumca VEGF aqtivoba receptoris

statusis mixedviT autoimunuri dazianebis dros iyo yvelaze naklebi.

Phytaykorn L, Mc Henry CR., (2006) aRniSnaven amasTan dakavSirebiT, rom

arsebobs maRali korelacia VEGF eqspresiasa da Tireoiduli parenqimis

tumorogenul potencials Soris. es gansakuTrebiT aqtualuri mtkicebaa

sadReisod, radgan, mkvlevarTa ramdenime damoukidebeli jgufis mosa-

83

zrebiT Hashimoto-s Tireoiditis papilur variantSi arsebobs genetikuri

winaprebi, rasac klinikuri statistikac adasturebs. (Scarpino et al., 2000,

Palucka, Banchelau, 2012, Yanofsky, Mitsui et al., 2013) amasTan dakavSirebiT, klini-

cistebi akvirdebodnen xangrZlivad gamoxatul adgilobriv imunur reaq-

cias da konkurentul qronikul limfoidur Tireoidits, romelic

keTilsaimedo/arakeTilsaimedo prognozul mniSvnelobas iZenda pacien-

tebSi diferencirebuli Tireoiduli karcinomiT (DTC) (Melillo, Guarino, Avilla

et al., 2010)

cnobilia, rom Hashimoto-s Tireoiditi da difuzuri toqsikuri Ciyvi

(Greaves daavadeba) warmoadgens autoimunuri Tireoiditis yvelaze cnobil

da gavrcelebul formebs, orives axasiaTebs limfoiduri infiltratebi da

autoaqtiuroba Tireoiduli autoantigenebis mimarT. Qqronikuli

limfoiduri Tireoiditi autoimunuri daavadebaa, romelsac axasiaTebs

fibrozi, limfocituri infiltracia da parenqimuli atrofia. Hashimoto-s

Tireoiditi gamoirCeva Tireoiduli parenqimis infiltraciiT imunuri

ujredebiT. rogorc aRvniSneT, Tan sdevs hipoTireoidizmi, gamowveuli

parenqimis destruqciiTa da fibrozuli qsoviliT CanacvlebiT. Hashimoto-s

Tireoiditis dros imunuri sistema warmoqmnis Tireospecifiur

antisxeulebs Tireoidspecifikuri antisxeulebis mimarT. Cvens masalaze

aseTi gamokvleuli antisxeulebi warmodgenili iyo Tireoperoqsidazuli

(TPO), romlebic miekuTvnebian Tireoidul autoimunizaciaSi pirvelad

antigens (Burek, Rose., 2008; Flynn et al., 2004) zustad ar aris cnobili T

helperebTan asocirebuli (CD4+) meore donis leikocitaluri antigenis

(MNC II klasi: HLA-DR3, HLA-DR4 da HLA-DR5) gaaqtiveba ramdenad pirdapir

korelaciaSia dazianebis autoimunur fonTan. aris Sexeduleba, rom

citotoqsikuri limfocitebi (CD8+) axdenen citokinebis gaadvilebul

gamoTavisuflebas, rac azianebs Tireoidul folikulebs da aaqtivebs B-

limfocitebs (Konturek, Barcynski, Wierchowski et al.,2013). sabolood, Hashimoto-s

Tireoiditi xasiaTdeba Tireoiduli funqciis mkveTri daqveiTebiT, CiyviT

da T ujreduli infiltraciiT. Aaavadebs ra upiratesad qalebs, vidre

mamakacebs, 7:1 genderuli doniT, da gamoxatuli genetikuri predispo-

ziciiT. Cvens masalaze gamoikveTa Tireoiduli epiTeliumis progesuli

degeneracia, maTi Canacvleba mononuklearuli ujredebiT da Hurthle-s

84

ujredebiT, romlebic, hiperplaziis intensiurobis mixedviT avlenen S-100

cilisa da TTF-1 faqtoris mimarT zomier-maRal eqspresias adenomur

struqturebSi, gansakuTrebiT, birTvebis reaqcias, romelTa umravlesoba

swored NF-β transkripciuli kontrolis qveS aris, rac Cvens masalaze

imunohistoqimiuri reaqciiT gamovlinda. reducirebuli Tireocitebis mier

mudmivad NF-β produqcia folikulur ujredebSi, ayalibebs gaurkvevel

kavSirs (damakavSirebel qsels Tireoidul epiTeluri ujredebisa, Hurthle-s

ujredebisa da anTebiT ujredebs Soris (PaciOco, Leonardi., 2010, Ward Sterian

L.,2014). Hashimoto-s Tireoidits da difuzur toqsikur Ciyvs Soris ujre-

duli paralelebisa da sxvaobis, aseve maTi imunohistoqimiuri

receptoruli statusis kvlevam Cveni Sromis ZiriTadi amocanebidan

gamomdinare, ganapiroba ujredebis fokusireba makrofagebsa da

histiocitebze da dendritul ujredebze. romelTa raodenobis zrda,

maTive damaxasiaTebel Met protein-is Sesabamisi aqtivobiT aRiniSna Hurthle-s

ujredovan populaciaSi hiperplaziuri klasterebis da adenomis saxiT.

Ddendrituli ujredebi (DCS) rogorc imunuri ujredebis mcirericxvovani

qvetipi, viTardebian Zvlis tvinidan da gvxvdeba adamianis organizmis yvela

qsovilSi. (Steinman, Banchereau, 2007). DCS aris profesiuli antigen-

maprezentaciebeli ujredebi, romelTa aqtivoba eyrdnoba antigenis

prezentacias MHC II klasis receptorebze da iwvevs gansakuTrebulad

feqtur stimulacias imunogenezis sakvanZo ujredebSi. (Yanofsky, Mitsui et al.,

2013). Cveni kvlevis amovanebidan gamomdinare, mniSvnelovania, rom

dendrituli ujredebis gamovlena SevZeliT S-100 cilis eqspresiis

saSualebiT, rac ara marto gamoavlens am ujreduli populaciis

aqtivobas, maTTvis Cveuli CD68+ dadebiT reaqciasTan erTad, aramed

saSualebas gvaZlevs SevafasoT infiltratebSi imunologiuri fenomenis

aqtivobis kompleqsebi, xolo calkeuli mkvlevaris azriT, (Hilly, Koren et al.,

2013), gamovavlinoT korelacia S-100 pozitiur dendritul ujredebsa da

Tireoduli papiluri karcinomis aRmocenebis risks Soris.

gamomdinare am specifiuri interesidan, rasac Hurthle-s ujredebis

kvlevis mimarT viCendiT, autoimunuri da noduluri procesebis aRweris

dros, (Rurua N et al., 2013) aRvniSneT, rom Hashimoto-s Tireoiditis, aseve,

85

hiperfunqciis dros, greivsis daavadebis SemTxvevaSi, adgili aqvs Hurthle-s

ujredebSi S-100 cilis eqspresiis gaZlierebas. rasac specialur kvlevebSi

metproteinisa da urokinazas tipis plazminogenis receptorebis gaaqti-

vebas ukavSireben, xolo es ori faqtori ki Hashimoto-s Tireoiditis dros

warmoadgens Tireoiduli ujredebis alteraciis da DCS ujredebis

infiltraciis adreul markers (Hilly, Koren et al, 2013; Pusztaszeri, Sadow, Faquin,

2013).

amrigad, kompleqsuri kvlevis Sedegebi gviCvenebs, ori morfologiuri

variantis Hashimoto-s Tireoidits: 1. Llimfoplazmocituri 2. Ffibrozuli.

calkeuli varianti Seicavs qvesaxeebs intensivobis da gavrclebis

mixedviT. Ddadgenilia histologiuri variantebis mWidro kavSiri anti-TPO

antisxeulebis titrTan. Dadgenilia Hurthle-s ujredebis stabiluri CarTva

Hashimoto-s Tireoiditis histopaTologiur suraTSi. Adenomatozis da

adenomis asociaciis saxiT, rac hipoTireoidizmis erT-erT struqturul

baziss qmnis.

Hurthle-s ujredebis deteqciis 2 imunohistoqimiuri faqtori – S-100

cila da TTF-1 intensiurad CairTveba dasaxelebuli ujredebis birTvebSi,

infiltrirebul kerebSi da adenomis kafsulur struqturebSi. rac

uflebas gvaZlevs movaxdinoT am cvlilebaTa inkorporacia paTolog-

anatomiur komponentSi, rogorc autoimunuri Tireoiditis erT-erTi

histopaTologiuri fenomeni.

86

daskvnebi:

1. autoimunuri Hashimoto-s Tireoiditis morfologiur suraTi hetero-

genulia, Tireocitebisa da eqstrafolikuluri domenis 2 principulad

gansxvavebuli variantiT aris warmodgenili:

a) Hashimoto-s Tireoiditis limfoiduri varianti _ Tireoiduli foli-

kulebis reduqcia, limfoepiTeluri dazianebis suraTi, limfoiduri

folikulebis germinaciuli centrebis nekrozi, fibrozuli qsovilis

interfolikulur-interlobuluri invazia, maRali TSH da anti-ATPO-

antisxeulebis dabali-zomieri titri, dabali T3 koncentracia - sisxlis

SratSi, xangrZlivi anamnezi diagnostikidan operaciamde.

b) Hashimoto-s Tireoiditis fibrozuli varianti _ interfolikuluri da

nawiburovani tipis fibroplaziuri dazianeba, parenqimis difuzuri

limfoplazmocituri infiltracia, anti-TPO-antisxeulebis maRali titri,

xanmokle anamnezi diagnostikidan operaciamde.

2. difuzuri toqsikuri Ciyvis dros parenqimis hipertrofiul-hiper-

plaziuri transformacia proporciulia sisxlis SratSi TSH, T4 daT3

koncentraciis, gamoirCeva permanentulad gamoxatuli meoradi

cvlilebebis speqtriT da difuzuri limfoidurujredovani infilt-

raciiT. axasiaTebs parenqimis moculobis Semcireba, gardamavali

hipoTireozi, SesaZloa autoimunuri Tireoiditi.

3. Hashimoto-s Tireoiditis dros Tireocitebis receptoruli statusis

Sesusteba aRiniSneba zrdis faqtorebis VEGF da CD34 mimarT, rac

angiogenezisa da parenqimis funqciis daqveiTebasa da hipoTireoidizmis

damaxasiaTebel suraTs qmnis: Tireomastimulaciebeli hormonis (TSH) susti

eqspresia miuTiTebs aramarto hormonmastimulaciebeli funqciis

daTrgunvaze aramed sisxlZarRvTa endoTeluri zrdis faqtoris (VEGF) da

CD34 signalis sinqronulad sinTezisa da aqtivobis daqveiTebaze

mofunqcie parenqimis avaskulur struqturaze.

gamonakliss warmoadgens hemopoezur ujredTa infiltrirebuli kerebi -

CD34 da VEGF ‐ dadebiTi.

4.Hashimoto-s Tireoiditis damaxasiaTebel struqturul da imunohisto-

qimiur niSans warmoadgens Hurthle-is ujredebis populaciis zrda

87

parafolikulur domenSi cila S 100-s da Tireotranskripciuli faqtoris

TTF-1-s maRali birTvuli eqspresiiT, gansakuTrebiT adenomatozur da

infiltraciul kerebSi, gansazRvravs Tireoiduli parenqimis displazias

da arqiteqtonikis dezorganizacias.

S 100 cilisa da TTF-1 CarTvis intensivoba anti-TPO-antisxeulebis titrTan

pirdapir kavSirSia.

5.difuzuri toqsikuri Ciyvis parenqimaSi zrdis faqtorebis, VEGF da CD34

eqspresia maqsimaluria. vlindeba folikuluri ujredebis birTvebSi,

koloidsa da bazalur membranebSi, adgili aqvs neoangiogenezis aqtiur

procesebs de novo mikrosisxlZarRvebis warmoqmnis xarjze.

cila-S 100‐s eqspresiis xasiaTi, ganawileba da intensivoba

hiperTireoidizmis dros fonuria da specifikuri struqturebisa da

samizne ujredebis (Hurthle-is populacia) dabal metabolur aqtivobaze

miuTiTebs.

6. Hashimoto-s Tireoiditis dros farisebri jirkvlis yvela struqturuli

elementis moculoba, farTobi erTmniSvnelovnad icvleba regresis

tendenciiT eqstrafolikuluri domenis struqturaTa moculobisa da

receptoruli aqtivobis zrdis sasargeblod, rac hipoTireozis erT-erT

niSanTvisebad SeiZleba dasaxeldes.

7.sisxlZarRvTa simWidrovis maCveneblis mixedviT SeiZleba gamovyoT

cvlilebaTa 3 kategoria:

1) maRali MVD- difuzuri toqsikuri Ciyvi

2) MVD zogadi dabali done – euTireoidul Ciyvi

3) Sualeduri varianti ‐ Hashimoto-s Tireoiditi.

8.zrdis perivaskuluri zonebis Sefaseba da mikrososxlZarRvTa simWdrove

VEGF imunoeqspresiis mixedviT iZleva 2 autoimunuri paTologiis –

difuzuri toqsikuri Ciyvis da Hashimoto-s Tireoiditis angiogenezis

sadiferenciacio kriteriumebs.

88

literaturis saZiebeli

1. Aghini-Lombardi F, Berti P Antonangeli L.Incidental thyroid carcinoma in a large series of

consecutive patients operated on for benign thyroid disease.ANZ J Surg. 2006 Mar;76(3):123-6.

2. Akslen LA, LiVolsi VA (2000) Increased andiogenezis in papillary thyroid carcinoma but lack of

prognostic importance. Hum Pathol 31:439-42.

3. Akslen LA. LiVolsi VA (2000) Prognostic sighnificance of histologic grading compared with

subclassification of papillary thyroid carcinoma. Cancer 88:1902-1908

4. Alexander E.K., Hurwitz S., Heering J.P. et al. Natural history of benign solid and cystic thyroid

nodules// Ann. Intern. Med., 2003 – 138 №4 – P. 315-318.

5. Allen EM, Appel MC, Braverman LE: The effect of iodide ingestion on the development of

spontaneuslympholytic thyroiditis in the diabetesprone BB/W rat. Endocrinology 1986,118:1977-81

6. Amani H K. Histopathologic and immunohistochemical features of Hashimoto thyroiditis. Indian J

Pathol Microbiol [serial online] 2011

7. Anan K, Moriasaki T, Katano M et al. Vascular endothelial growth factor and platelet derived

growth factor are potential angiogenic metastatic factors in human breast cancer. Surgery, 1996,

119,33-39.

8. Anil C, Goksel S, Gursoy A (2010) Hashimoto thyroiditis is not associated with increased risk of

tumor, single-center prospective study. Thyroid 20:601-606

9. Arscott PL, Baker JR: Apoptosis and Thyroiditis, ClinImmunolImmunopathol 1998, 87:207-217

10. Blakemore AI, Watson PF, Weetman AP, Duff GW: Association of Graves’ disease with an allele

of the interleukin-1 receptor antagonist gene. J ClinEndocrinolMetab 1995, 80:111-115

11. Bossowski A, Czarnocka B, bardadin K, et al., Expression of Bcs-2 family proteins in thyrocytes

from young patients with immune and nonimmune thyroid diseases. Horm Res. 2008;70(3)155-164

12. Bossowski A, Czarnoska B, Stasiak-Barmuta A, BardadinK,et al., Analysis of Fas, FasL and

Caspase-8 in Thyroid gland in young patients with immune and non-immune thyroid diseases.

Endokrynol Pol. 2007 Jul-aug;58(4):303-13

13. Brekken RA, Thorpe PE. Vascular endothelial growth factor and vascular targeting of solid tumors.

Anticancer Res. 2001.21.4221-4229.

14. Burek C.L, and Rose N.R. Autoimmune thyroiditis and ROS, Autoimmunity Reviews, vol 7, no 7

pp530-537

15. Caturegli P. Hejazi M, Suzuki K, Doham O. et al. Hypothyroidism in transgenic mice

espressingIFN-γ in thyroid. Proe. Natl. Acad. USA 2000,97,1719-1724.

89

http://www.ncbi.nlm.nih.gov/pubmed/16626346


16. Chazenbalk G, Bartoletto C, Heneidi S, Jumatobay M et al. Novel pathway of adipogenesis through

cross-talk between adipose tissue macrophages, adipose cells and adipocytes: evidence of cell

plasticity. PLoS.One. 2011 Mar 31;6(3):e17834

17. Chiovato L, Bassi P, Santini F Antibodies producing complement-mediated thyroid cytotoxicity in

patients with atrophic or goitrous autoimmune thyroiditis. J Clin Endocrinol Metab. 1993

Dec;77(6):1700-5.

18. Chistiakov D.A. New advances in the immunogenetics of Hashimoto’s thyroiditis; Scientific

Communications, 2006

19. Chistiakov DA. Immunogenetics of Hashimoto’s Thyroiditis. Journal of Autoimmune Diseases.

2005, 2:1

20. Collini P, Sampietro G, Rosai J, et al. Minimally invasive (encapsulated) follivulat carcinoma of

the thyroid land is the low-risk couterpart of wodely invasive follicular carcinoma but not insular

carcinoma. Virchows Arch. 2003; 442:71-76.

21. DahlgrenM, KhosroshahiA ,Petur Nielsen G et al. Riedel's Thyroiditis and Multifocal Fibrosclerosis

are part of the IgG4-related systemic disease spectrumArthritis Care & Research. Volume 62, Issue

9, pages 1312–1318, September 2010

22. De la Torre NG, Buley I, Wass JA, Turner HE. Angiogenesis and lymphangiogenesis in thyroid

proliferative lesions: relationship to type and tumor behavior. Endoc. Relat. Cancer, 2006,13,931-

944.

23. Demellawy D. El., Nasr A., Alowami S. – Application of CD56, p63 and CK19

immunohistochemistry in the diagnosis of papillary carcinoma of the thyroid – Diagn. Pathol.,

2008, 3, 5-11.

24. Devendra D, Eisenbarth GS:17 Immunological endocrine disorders. J Allergy ClinImmunol 2003,

111: 624-636

25. Donkol RH, Nada M , and Boughattas S. Role of color Doppler in differentiation of Graves'

disease and thyroiditis in thyrotoxicosisWorld J Radiol. 2013 Apr 28; 5(4): 178–183.

26. Eguchi K: Appoptpsis in autoimmune diseases. Intern Med 2001, 40:275-284

27. El Demellawy D, Nasr AL, Babay S, Alowami S, Diagnostic utility of CD56

immunohistochemistry in papillary carcinoma of the thyroid, Pathol Res Pract, 2009, 205(5):303–

309

28. Erdem O., Erdem M., Memis L., Akyol G.,Expression of Vascular Endothelial Growth Factor and

assessment of microvascular density with CD34 and endoglin in proliferative endometrium,

endometrial hyperplasia and endometrial carcinoma, Int.J. Gynecol.Cancer, 2007, 17:1325-32

90


http://www.ncbi.nlm.nih.gov/pubmed/?term=Chiovato%20L%5BAuthor%5D&cauthor=true&cauthor_uid=7903315

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bassi%20P%5BAuthor%5D&cauthor=true&cauthor_uid=7903315

http://www.ncbi.nlm.nih.gov/pubmed/?term=Santini%20F%5BAuthor%5D&cauthor=true&cauthor_uid=7903315


http://onlinelibrary.wiley.com/doi/10.1002/acr.v62:9/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/acr.v62:9/issuetoc

http://www.ncbi.nlm.nih.gov/pubmed/?term=Donkol%20RH%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Nada%20AM%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Boughattas%20S%5Bauth%5D

29. Eslinger M, Krohn K, Kratzsch J, Voigt C, Pashke R. Growth Factor Exspression in Cold and Hot

Thyroid Nodules. Thyroid. February 2001:125-135

30. Eszlinger M., Krohn K., Kratzsch Y., Voigt C., Paschke R. Growth factor expression in cold and

hot thyroid nodules – Thyroid, 2001, 11(2), p. 125-135.

31. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;

9(6):669-76.

32. G.Mehdi, F.A.Siddiqui, H.A. Ansari & S Amjad Ali Rizvi: Hurthle cell adenoma as an incidental

finding in Hashimoto’s thyroiditis – case report and short review of literature. The Internet Journal

of Pathology.2009 Volume 8 Number 1

33. Gilliland FD, Hunt WC, Morris DM, Key CR(1997) Prognostic factors for thyroid carcinoma.

Cancer 79:564-573

34. Gogiashvili L, Giorgadze E, Nikobadze E et al. Spectrum of thyroid gland injury during goiter

(morphofunctional parallels) in various regions of Georgia. GMN.2007.146(5)77-81.

35. Gogiashvili L, Tsagareli Z, Nikobadze E, Kvachadze T, Melikadze E. Macrophages ultrastructure

and function in white adipose tissue and peripheral blood stream in obese humans. Allergology and

Immunology (rus) 2010,11.(2) pp 119-121

36. Goldstein NS, Czako P, Neill JS. Metatsatic minimally invasive (encapsulated) follicular and

Hurthel cell thyroid carcinoma: a stydy of 34 patients. Mod Oathol 2000;13(2):123-130

37. Gora-Tybor J. Blonski JZ &Robak T. Circulatind vascular endothelial growth factor (VEGF) and its

soluble receptors in patients with chronic lymphocystic leukemia. Europian Cytokine Network

2005(16) : 41-46

38. Hamano H, Kawa S, Ochi Y, et. Al. – Hydronephrosis associated with retroperitoneal fibrosis and

sclerosing pancreatitis. Lancet 2002;359:1403-1404. /Article./ /PubMed/ISI/CAS/.

39. Hashimoto H. ZurKenntnis der lymphomatösenVeränderung der Schilddrüse (Struma

lymphomatosa). Arch KlinChir 1912;97:219-248

40. Hennessey JV.Clinical review: Riedel’s thyroiditis: a clinical review. J ClinEndocrinolMetab

2011;96:3031-3041.

41. Hilly O, Koren R, Raz R, et al. The role of S100-positive dendritic cells in prognosis of papillary

thyroid carcinoma. American Journal of Clinical Pathology, vol 139, no.1 pp 87-92. 2013

42. Hoffman S., Hofbaur L.C., Scharrenbach V., Wunderlich A. et al. Thyrotropin (TSH)-induced

production of vascular endothelial growth factor in thyroid cancer cells in vitro: Evaluation of TSH

signal transduction and of angiogenesis – stimulating growth factors. J. Clin. Endocrinol., 2000,

166, p. 475-480.

91

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ferrara%20N%5BAuthor%5D&cauthor=true&cauthor_uid=12778165

http://www.ncbi.nlm.nih.gov/pubmed/?term=Gerber%20HP%5BAuthor%5D&cauthor=true&cauthor_uid=12778165

http://www.ncbi.nlm.nih.gov/pubmed/?term=LeCouter%20J%5BAuthor%5D&cauthor=true&cauthor_uid=12778165


43. Huang SM, Lee JC, Wu TJ, Chow NH(2001) Clinical relevance of vascular endothelial growth

factor for thyroid neoplasms. World J Surg 25:302-306

44. Huber A, Mensoni F, Corathers S et al. Joint genetic suspeptibility to type 1 diabetis and

autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev. Oct 2008;29(6):697-

725.[Medline]

45. I Y. Nishihara E, Hirokawa M, et al. – Distinct clinical, serological, and sonographic characteristics

of Hashimoto’sthyroiditis based with and withoutlgG4-positive plasma cells. J Clin Endocrinil

Metab 2010;95: 1309-1317./Article/PubMed

46. Imaizumi M, Pritsker A, Kita M, Ahmad L, Unger P, Davies T: Pregnancy and murine thyroiditis:

thyrodlobulin immunization leads to fetal loss in specific allogeneic pregnancies. Endocrinology

2001. 142:823-829

47. Ito Y, Yoshida H, Tomoda C., Uruno, A et al, S100 A4 expression is an early event of papillary

carcinoma of the thyroid, Oncology, 67 (2004), p397

48. Itoh A, Iwase K, Jimbo S, Yamamoto H. et al. Expression of vascular endothelial growth factor and

presence of angiovascular cells in tissues from different thyroid disorders.World J.Surg. 2010,

Feb.34(2)242-8.

49. Iwama S, De Remigis A, Bishop J, kimura HJ, Caturegli P. Hürtle cells predict hypothyroidism in

interferon-γ transgenic mice of different genetic background. Endocrinology.2012 Aug.153(8)4058-

4066

50. Jaume JC, Guo J, Wang J, Rapoport B, McLachlan SM: Cellular Thyroid peroxidase (TPO), unlike

purified TPO and adjuvant, induces antibodies in mice that resemble autoantibodies in human

autoimmune thyroid disease. J ClinEndocrinolMetab 1999, 84:1951-1957

51. Jebreel A, England J, Bedford K, Murphy J et al. Vascular endothelial growth factor (VEGF),

VEGF receptors expression and microvascular density in benign and malignant thyroid diseases.

INT.J. Exp.Path., 2007.Aug.88(4)271-77

52. Kahaly GJ. Cardiovascular and atherogenic Aspects of Subclinical Hypothyroidism. Thyroid.

August 2000:665-679

53. Kajdaniuk D, Marek B, Foltin W, Kos-KudlaB.Vascular endothelial growth factor (VEGF) –part 2 :

in endocrinology and oncology. Polish Journal of Endocrinology, Vol62 N5/2011

54. Kamisawa T, Funata N, Hayashi Y, et.al. – A nev clinicopathological entity oflgG4-related

autoimmune disease. J Gastroenterok.2003; 38:982-984. /Article./ /PubMed/ISI/CAS/

55. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4 related

autoimmune disease. J Gastroenterol 2003;38:982-984

92

56. Kamisawa T, Okamoto A. IgG4-related sclerosing disease. World J Gastroenterol 2008;14:3948-

3955.

57. Karaca Z, Tanriverdi F, Unluhizarci K, Gokalmetoglu S et al. VEGFR1 espression is related to

lymph node metastasis and setum VEGF may be a marker of progression in the follow-up of

patients with differentiated thyroid carcinoma. Eur J Endocrinol February1, 2011,164,277-284

58. Kasashima S, Zen Y, Kawashima A, et al. Inflamatory abdominal aortic aneurysm: close

relationship to IgG4-related periaortitis. Am J SurgPathol 2008;32:197-204.

59. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin

Rheumatol. 2011 Jan;23(1):67-71.

60. Kitagava S,Zen Y, Harad,a K. et al. – Abundant lgG4-positive plasma cell infiltration characterizes

chronic sclerosing sialadenitis (Kuttner’s tumor). Am JSurg Pathol 2005;29:783-791./Article./

/PubMed/ISI/

61. Klein M, Vignaual JM, Hennequin V et al. Increased expression of the vascular endothelial growth

factor is a pejorative prognosis marker in papillary thyroid carcinoma. J.Clin.Endocrinol.Metab.,

2001.86.656-658

62. Klubo-Gwiedzinska J., R. Junik, E. Kopczynska, O. Juraniec and H. Kardymovich. The comparison

of serum vascular endothelial growth factor levels between patients with metastatic and non-

metastatic thyroid cancer, and patients with nontoxic multinodular goiter. Eur. J. Endocrinol,

October 1, 2007, 157(4). p. 521-527.

63. 1 Komatsu K, Hamano H, Ochi Y, Takayama M, Muraki T, Yoshizawa

K, Sakurai A, Ota M, Kawa S.High prevalence of hypothyroidism in patients with autoimmune

pancreatitis.Dig Dis Sci. 2005 Jun;50(6):1052-7.

64. Konturek A, Barczynski M, Wierzchowski W, Stopa M, Nowak W. Coexistance of papillary

thyroid cancer with Hashimoto thyroiditis “Langenbeck Archives of Surgery”, vol 398,no3, pp.389-

94.3013

65. Konturek A., Barczynski M et al Coexistnce of papillary thyroid cancer with Hashimoto thyroiditis

“Langenbeck’s Archives of Surgery, vol.398,no 3, pp.389-394, 2013

66. Krohn K, Pashke R; Causes of hot thyroid nodules. Hot Thyroidology-Journal owned by the

European Thyroid Association. 2009

67. Kumar Dhar D, Kubota H, Kotoh R, Tabara H, Watanabe R et al (1998) Tumor vascularity predicts

recurrence in differentiated thyroid carcinoma. Am J Surg 176:442-447

68. Ladenson PW, Singer PA American Thyroid Association guidelines for detection of thyroid

dysfunction. Arch Intern Med. 2000 Jun 12;160(11):1573-5.

93

http://www.ncbi.nlm.nih.gov/pubmed/?term=Khosroshahi%20A%5BAuthor%5D&cauthor=true&cauthor_uid=21124087

http://www.ncbi.nlm.nih.gov/pubmed/?term=Stone%20JH%5BAuthor%5D&cauthor=true&cauthor_uid=21124087



http://www.ncbi.nlm.nih.gov/pubmed/?term=Komatsu%20K%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Hamano%20H%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ochi%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Takayama%20M%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Muraki%20T%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Yoshizawa%20K%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Yoshizawa%20K%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sakurai%20A%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ota%20M%5BAuthor%5D&cauthor=true&cauthor_uid=15986853

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kawa%20S%5BAuthor%5D&cauthor=true&cauthor_uid=15986853


http://www.ncbi.nlm.nih.gov/pubmed/?term=Ladenson%20PW%5BAuthor%5D&cauthor=true&cauthor_uid=10847249

http://www.ncbi.nlm.nih.gov/pubmed/?term=Singer%20PA%5BAuthor%5D&cauthor=true&cauthor_uid=10847249


69. Lam-Tse WK, Lernmark A, Drexhage HA: Animal models of endocrine/organ-specific

autoimmune diseases: do they really help us to understand human autoimmunity? Springer

SeminImmunopathol 2002,24:297-321

70. Latina A, Gullo D, Trimarchi F., Benvenga S. Hashimoto’s Thyroiditis: Similar and dissimilar

characteristics neighboring areas. Possible implications for the epidemioloty thyroid cancer. PLOS

Doi: 10.1371

71. 1 Latrofa F, Fiore E, Rago T, Antonangeli L, Montanelli L et al. Iodine

contributes to thyroid autoimmunity in humans by unmasking a cryptic epitope on thyroglobulin.J

Clin Endocrinol Metab. 2013 Nov;98(11):E1768-74.

72. Lazaris AC, Tseleni-Balafouta S, Papathomas T, Brousalis T et al., Immunohistochemical

investigation of angiogenic factors in patathyroid proliferative lesions. Europian Journal of

Endocrinology (2006) 154, 827-833

73. Lewy-Trenda I, Wierzchniewska-Lawska A (2002) Expression of vascular endothelial growth

factor (VEGF) in human thyroid tumors. Pol J Pathol 53:129-132

74. Li Y, Nishihara E, Hirikawa M, et al. Distinct clinical, serological, and sonographic characteristics

of Hashimoto’s thyroiditis based with and without IgG4-positive plasma cells. J

ClinEndocrinolMetab 2010;95:1309-1317.

75. Li Y, Zhou G, Ozaki T, Nishihara E, Matsuzuka F, et al. Distinct histopathological features of

Hashimoto’s thyroiditis with respect to IgG4-related disease. Modern Pathology (2012), 25 1086-

1097.

76. Limachi F, Basso S: Apoptosis: life through planned cellular death ragulating mechanisms, control

systems, and relations with thyroid disease. Thyroid 2002, 12:27-34

77. LiVolsi VA. Surgical Pathology of the thyroid .In:Benington JL. Editor Major problems in

Pathology. Vol.22 Philadelphia: W.B. Saunders; 1990:pp0357-363

78. Lloyd RV, Douglas BR. King DW(ed) Atlas of nontumor pathology. Endocrine diseases, Tumor-

like conditions of the thyroid gland. Amer. Reg. of Pathology and Armed forces Inst of Pathology,

2002

79. Lowin B, Hahne M, Mattmann C, Tschopp J: Cytolytic T-cell cytotoxity is mediated through

perfotin and Fas lytic pathways. Nature 1994, 370:650-652

80. Maitra A, Abbas AK. The endocrine system. In: Kumar V, Abbas AK, Fausto N, Editors. Robbins

and Cotran-Pathologic Basis of Disease. 7th Edition. New Delhi: 2004: pp 1169-1170

81. Malkomes P, Oppermann E, Bechstein WO, Holzer K. Vascular endothelial frowth factor-marker

for proliferation in thyroid diseases? ExpClinEndocrinolDiabetis. 2013 Jan;121(1):6-13

94

http://www.ncbi.nlm.nih.gov/pubmed/?term=Latrofa%20F%5BAuthor%5D&cauthor=true&cauthor_uid=24064687

http://www.ncbi.nlm.nih.gov/pubmed/?term=Fiore%20E%5BAuthor%5D&cauthor=true&cauthor_uid=24064687

http://www.ncbi.nlm.nih.gov/pubmed/?term=Rago%20T%5BAuthor%5D&cauthor=true&cauthor_uid=24064687

http://www.ncbi.nlm.nih.gov/pubmed/?term=Antonangeli%20L%5BAuthor%5D&cauthor=true&cauthor_uid=24064687

http://www.ncbi.nlm.nih.gov/pubmed/?term=Montanelli%20L%5BAuthor%5D&cauthor=true&cauthor_uid=24064687



82. Marenholz, C.W. Heizmann, G et al. S100 proteins in mouse and man: from ecolution to function

and pathology (including an update of the nomenclature) Biochem. Biophys, Res. Commun,m 322

(2004) p.1111

83. Maximo V, Botelho T, Capela J, Soares P et al. Somatic and germline mutations in GRIM-19, a

dual function gene involved in mitochondrial metabolism and cell death in linked to mitochondrion

rich (Hurthle cell) tumour of the thyroid. Br J Cancer 2005; 92: 1892-1898.

84. Mazeto G.M., Padovani C.R., Montenegro M.R., Aragon F.F., Schmitt F.C. – Thyroid cell

proliferation in Grave’s disease. Use of MIB-1 monoclonal antibody. // Act. Cytol., 2004, 48, p.57-

63

85. Mc Henry CR, Phitiakorn R. Follicular and Hürtle cell carcinoma: predicting outcome and directing

therapy surgery. 1998.124

86. McHenry CR, Phitaiakorn R, Follicular adenoma and carcinoma of the thyroid gland. Oncologist

2011 16(5):585-593

87. Melillo R M, Guarino V, Avilla E, Galdiero M R, Liotti F, et al. 2010. "Mast cells have

aprotumorigenic role in human thyroid cancer." Oncogene 29 (47)

88. Mete O, Asa SL. Oncocytes, oxyphils, Hürtle and Askanazy cells: morphological and molecular

factors of oncocystic thyroid nodules. Endocr.Pathol.2010,21,16-24.

89. Miyagi E, Katoh R, Li X, Lu S et al. Thyroid stimulating hormone downregulates vascular

endothelial growth factor expression in FRTL-5 cells. Thyroid, Volume 11 Issue 6:p539.

July9,2004

90. Mornex R., Orgiazzi J.J. – Hyoerthyroidism // In: The Thyroid Gland (ed. By M. De Visscher),

Raven Press, New York, 1980, p.279-362

91. Nagura S, Katoh R, Miyagi E, Shibuyam M, Kawaoi A. Expression of vascular endothelial growth

factor(VEGF) and VGEF receptor-1(fit-1) in Graves disease possibly correlated with increased

vascular density. Hum.Pathol.2001,32,10-17

92. Nakamura K, Taguchi E, Miura T, Yamamoto A et al. KRN951, a highly potent inhibitor of

vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects

functional vascular properties.Cancer Res. 2006 Sep 15;66(18):9134-42.

93. Offersen BV, Borre M, Overgaard J. Quantification of angiogenesis as a prognostic marker in

human carcinomas: a critical evaluation of histopathological methods for estimation of vascular

densityEuropean Journal of Cancer 06/2003; 39(7):881-90.

94. PaciOco E, Leonardi A. Role of NF-kB in thyroid cancer “Molecular and cellular Endocrinology,

col 321, no, 1, pp 29-35, 2010

95

http://scicurve.com/paper/20729915

http://scicurve.com/paper/20729915

http://www.ncbi.nlm.nih.gov/pubmed/?term=Nakamura%20K%5BAuthor%5D&cauthor=true&cauthor_uid=16982756

http://www.ncbi.nlm.nih.gov/pubmed/?term=Taguchi%20E%5BAuthor%5D&cauthor=true&cauthor_uid=16982756

http://www.ncbi.nlm.nih.gov/pubmed/?term=Miura%20T%5BAuthor%5D&cauthor=true&cauthor_uid=16982756

http://www.ncbi.nlm.nih.gov/pubmed/?term=Yamamoto%20A%5BAuthor%5D&cauthor=true&cauthor_uid=16982756


https://www.researchgate.net/journal/0959-8049_European_Journal_of_Cancer

95. Paknys G, Kondrotas AJ, Kevelaitis E. Risk factors and pathogenesis of Hashimoto thyroiditis.

Medicina (Kaunas) 2009; 45(7):574-83

96. Palucka K, Banchereau J Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012

Mar 22;12(4):265-77.

97. Papi G, LiVolsi VA. Current concepts on Riedel thyroiditis. Am J ClinPathol 2004;121(Suppl):S50-

S63.

98. Pearce EN, Farewell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-2655

99. Phitaiakorn R, McHenry CR. Follicular and Hurthle cell carcinoma of the thyroid gland,

SurgOncolClin N Am.2006;15:603-623.ix-x.

100. Pisarev MA, DeGroot LJ and Wilber JF . Cyclic-AMP production of goiter. Endocrinology 87:339-

342,1970

101. Pusztaszeri MP, Sadow PM, Faquin WC. CD117: a novel ancillary marker for papillary thyroid

carcinoma in fine-needle aspiration biopsies. Cancer Cytopathol. 2014 Aug;122(8):596-603

102. Ramsden JD. Angiogenesis in the thyroid gland. J. Endocrinol., 2000, 166, p. 475-480.

103. Ranefall, P. Towards Automatic Quantification of Immunohistochemistry Using Colour Image

AnalysisUppsala University, Disciplinary Domain of Science and Technology, Mathematics and

Computer Science, Centre for Image Analysis.1998

104. Rapoport B, McLachlan SM: Thyroid autoimmunity. J Clin Invest 2001, 108:1253-1259

105. Roberts CG, Ladenson PW. Hypothyroidism. Lancet. 2004 Mar 6;363(9411):793-803.

106. Rurua N, Gogiashvili L, Tsagareli Z Immunohistochemical Investigation of Angiogenesis Activity

in Thyroid Gland under Hashimoto’s Thyroiditis versusDiffuse Toxic Goiter . Journal of Basic &

Clinical Medicine 2015, 4(1):32-36

107. Rurua N.Z et al. Structural and immunohistochemical profile of angiogenesis in the thyroid gland

at different thyroid diseases. GEORGIAN MEDICAL NEWS, 2013, 12. pp 97-104

108. Ruwhof C, Draxhage HA: Iodine and thyroid autoimmune disease in animal models. Thyroid 2001,

11:427-436

109. Rydlova M, Ludvikova M., Stankova I. Potential diagnostic markers in nodular lesions of the

thyroid gland: An immunohistochemical study. Biomed Pap. MEd fac Univ. Palacky Olom. Czech

Resp., 2008, 152(1) 53-60

110. Rzeszutko M, Rzeszutko W, Dziegiel P. The morphological analysis of vasculature in thyroid

tumours: immunoexpression of CD34 antigen. FOLIA HISTOCHEMICA ET CYTOBIOLOGICA.

Vol. 42, No.4, 2004 pp.235-240

111. Saleh HA, Jin B, Barnwell J, Alzohaili O. Utility of immunohistochemical markers in

differentiating benigh from malignant folliculat-derived thyroid nodules. DiagnPathol 2010;5:9

96

http://www.ncbi.nlm.nih.gov/pubmed/?term=Palucka%20K%5BAuthor%5D&cauthor=true&cauthor_uid=22437871

http://www.ncbi.nlm.nih.gov/pubmed/?term=Banchereau%20J%5BAuthor%5D&cauthor=true&cauthor_uid=22437871


http://www.ncbi.nlm.nih.gov/pubmed/?term=Pusztaszeri%20MP%5BAuthor%5D&cauthor=true&cauthor_uid=24920192

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sadow%20PM%5BAuthor%5D&cauthor=true&cauthor_uid=24920192

http://www.ncbi.nlm.nih.gov/pubmed/?term=Faquin%20WC%5BAuthor%5D&cauthor=true&cauthor_uid=24920192


http://www.ncbi.nlm.nih.gov/pubmed/?term=Roberts%20CG%5BAuthor%5D&cauthor=true&cauthor_uid=15016491

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ladenson%20PW%5BAuthor%5D&cauthor=true&cauthor_uid=15016491


112. Sanders LE, Silverman M. Follicular and hurthle cell carcinoma: predicting outcome and directing

therapy. Surgery. 1998;124:967-974.

113. Scarpino S, Stoppacciaro A et al. Papillary carcinoma of the thyroid: hepatocyte growth factor

(HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells, e American

Journal of Pathology, vol 156, no 3 pp 831-837 2000

114. Senino B, McDonald DM. – Controlling escape from angiogenesis inhibitors. Nature, 2012

115. Shimojo N, Arima T, Yamaguchi K, Kikuoka S, et al. A novel mouse model of Grave’s disease:

implications for a role of abberant MHC class II expression in it’s pathogenesis. Int Rev.

Immunol.2000 19:619-631

116. Shimojo N, Arima T, Yamaguchi K, Kikuoka S, Kohn LD, Kohno Y: A novel mouse model of

Graves’ disease: implications for a role of abberabt MHC class II espression in its pathogenesis. Int

Rev Immunol 2000, 19:619-631

117. Shimojo N, Kohno Y, Yamaguchi K, Kikuoka S, Hoshioka A, Niimi H et al., Induction of Graves-

like deisease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and

a class II molecule. ProcNatlAcadSci USA 1996, 93:11074-11079

118. Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE2007 National Health and Nutrition

Examination Survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships

demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin

Endocrinol Metab 92:4236–4240

119. Stafford EA, Rose NR, Newer insights into the pathogenesis of experimental autoimmune

thyroiditis. Int Rev Immunol 2000, 19:501-533

120. Steinman, R.M. and Banchereau, J. Taking Dendritic Cells into Medicine. Nature, 449:419-426,

2007

121. Stuart A. The changing scene in Hashimoto’s disease: a review. Med Hypotheses, 2011,77,424-426.

122. Tohyama O., Matsui J.,Kodama K.,Hafa-Susi N et al, Antitumor Activity of Lenvantini b(E7080)

Angiogenesis inhibitor multiple receptor Tyrosine kinases in preclinical human thyroid cancer. J

of Thyroid Research. 2014, Art. ID 638747, 13p

123. Tomer Y, Davies TF: Infection, Thyroid disease and autoimmunity. Endocrine Rev 1993, 14:107-

120

124. Tseleni-Balafouta S, Kaventzas N, Balafoutas D, Patsouris E; Applied immunohistochemistry &

molecular morphology: June 2006-Volume 14 Issue 2 –pp 203-207

125. Turner HE, Harris AL, Melmed S et al. Angiogenesis in endocrine tumors. Endocr Rev

2003;24:600-632

97

http://lab.rockefeller.edu/steinman/pdf/banchereau_nature_07.pdf

126. Udelsman R, Westra WH, Donovan PI, et al. Randomized prospective evaluation of frozen-section

analysis for folliculat neoplasms of the thyroid. Ann Surg.2001;233:716-722

127. Umehara H, Okazaki K, Miyasaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD):

general concept and details. Mod Rheumatol 2012;22:1-14.

128. Vanderpump MP, Tunbridge WM: Epidemiology and prevention of clinical and subclinical

hypothyroidism. Thyroid 2002, 12:839-847

129. Vanderpump MPJ, Tunbridge WMG. The epidemiology of thyroid diseases. In: The Thyroid.

Breverman LE, UtigerR(eds). Lippincott: Philadelphia, 474-482,1996

130. Visava P, Bocci G, Tonacchera M, Finelli F, De Servi M, et al. Markers of cell proliferation,

apoptosis and angiogenesis in thyroid adenomas: a comparative immunohistochemical and genetic

investigation of functioning and nonfunctioning nodules. Thyroid. 2007, Mar.17(3)191-7.

131. Vivier E, RauletDH, Moretta A,Caligiuri MA,et al. Innate or adaptive immunity? The example of

natural killer cellsScience 331 (6013), 44-49

132. Ward Laura Sterian "Immune response in thyroid cancer: widening the boundaries." Scientifica

2014

133. Weisberg SP, McCann D, Desao M., Rosenbaum M et al. Obesity in associated with microphage

accumulation in adipose tissue. J Clin Invest 2003.112.1796-1808.

134. Yamada E, Yamazaki K, Takano K, Obara R, Sato K. Iodide inhibits vascular endothelial growth

factor-A expression in cultured human thyroid follicles: a microarray search for effects of

thyrotropin and iodide on angiogenesis factors. Thyroid. 2006,16,545-554

135. Yamamato S, Konishi I, Mandai M, et al. Expression of vascular endothelial growth factor(VEGF)

in epithelial ovarian neoplasms correlation with clinicopathology and patiens survival and analysis

of serum VEGF levels. BR. J Cancer. 1997,76.0221-

136. Yanofsky V, Mitsui H, et al. Understanding Dendritic Cells and Their Role in Cutaneous

Carcinoma and Cancer Immunotherapy Clinical and Developmental Immunology

Volume 2013 (2013), Article ID 624123, 14 pages

137. Yaqiong Li, Gengyin Zhou, Takashi Ozaki, Eijun Nashihara, Fumio Matsuzuka, Yanhua Bai,

Zhiyan liu, Emiko Taniguchi, Akira Miyauchi and Kennichi Kakudo - Distinct histopathological

features of Hashimoto’s thyroiditis with respect to lgG4- related disease.

138. Yunus M, Ahmed Z.Significance of ultrasound features in predicting malignant solid thyroid

noedules: Need for fine-needle aspiration. Journal of Pakistan Medical Association, 2010;10

139. Zen Y, Harad,a K Sasaki M, et al. - lgG4related sclerosing cholangitis with and without hepatic

inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they

98

http://scholar.google.com/citations?view_op=view_citation&hl=ru&user=NlmFOgMAAAAJ&citation_for_view=NlmFOgMAAAAJ:YsMSGLbcyi4C

http://scholar.google.com/citations?view_op=view_citation&hl=ru&user=NlmFOgMAAAAJ&citation_for_view=NlmFOgMAAAAJ:YsMSGLbcyi4C

http://www.hindawi.com/41586295/

http://www.hindawi.com/70432183/

belong to a spectrum of sclerosing pancreatitis? Am J Surg Palhol 2004;28:1193-

1203./Article/PubMed/ISI/.

140. Zimmermann MB, Wegmüller R, Zeder C, Torresani T, Chaouki N. Rapid relapse of thyroid

dysfunction and goiter in school-age children after discontinuation of salt iodization. Am J Clin

Nutr. 2004 Apr;79(4):642-5.

141. Алешин Б.В., Бриндак О.М., Машина В.В., Кривобок Ю.В. Особенности размножения

тиреоцитов в пролиферирующем тиреоидном эпителии. Проблемы эндокринологии, 1988,

т.34, №4, стр.60-64

142. Балаболкин М.Н. Патогенез аутоиммунных заболеваний щитовидной железы. Пробл.

эндокринол., 1986, №6, с.35-40

143. Бубнов А.Н., Кузмичев А.С., Гринева Е.Н., Трунин Е.М. Узловой зоб. Санкт-Петербург, 1997

144. Ганиева Г.М., Шадлинский Б.В., Гогиашвили Л.Е., Цагарели З.Г. – Параметры

функциональных единиц щитовидной железы при диффузно-токсическом и узловом

эутиреоидном зобе у населения приграничных районов Азербайджана и Грузии –

GeorgianMedicalNews, 2013, 5, p. 67-72.

145. Зельцер М.Е. Эутиреоидная гиперплазия щитовидной железы. Актуальные проблемы

современной эндокринологии. Пробл. эндокринологии, 1988, т.34, с.43-45

146. Зельцер М.Е. Эутиреоидная гиперплазия щитовидной железы. Актуальные проблемы

современной эндокринологии. Пробл. эндокринологии, 1988, т.34, с.43-45

147. Камардин Л.Н. Тактика хирургического лечения узлового эутиреоидного зоба. Вест. хир.,

1985, 5., с.127-131

148. Кожанов Л.Г., Трошина Е.А. Узловой эутиреоидный зоб с позиций онкологии. Мат. москов.

город. конф. эндокр., 1999

149. Лившиц А.Х., Олейник Е.К. Изменение показателей иммунного статуса больных диффузным

токсическим зобом на разных стадиях заболевания. Пробл. эндокринологии, 1985, №6, с.6-

10

150. Магеррамова З.З. Частота выявления патологии щитовидной железы у нефтяников методом

ультразвукового исследования при профилактических осмотрах – Междун. Медицинский

журнал, 2010, 1, 25-28.

151. Мазурик М.Ф., Кузнецов А.А., Сидора В.Д. и др. Исход оперативного лечения больных

уэловым эутиреоидным зобом. Клиническая хирургия, 1981, 12., с.4-6

152. Мычка Н.В., Скударнова И.М., Соболева Н.В. Гормоны щитовидной железы: пособие для

врачей. ЗАО «Вектор-Бест» - Кольцово: ЗАО «Вектор-Бест», 2006. 32с.

99

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zimmermann%20MB%5BAuthor%5D&cauthor=true&cauthor_uid=15051609

http://www.ncbi.nlm.nih.gov/pubmed/?term=Wegm%C3%BCller%20R%5BAuthor%5D&cauthor=true&cauthor_uid=15051609

http://www.ncbi.nlm.nih.gov/pubmed/?term=Zeder%20C%5BAuthor%5D&cauthor=true&cauthor_uid=15051609

http://www.ncbi.nlm.nih.gov/pubmed/?term=Torresani%20T%5BAuthor%5D&cauthor=true&cauthor_uid=15051609

http://www.ncbi.nlm.nih.gov/pubmed/?term=Chaouki%20N%5BAuthor%5D&cauthor=true&cauthor_uid=15051609



153. Назаров А.Н., Суриков С.И. К патогенезу эутиреоидного зоба. Пробл. эндокринологии, 1989,

т.35, №1 с.35-39

154. Назаров А.Н., Суриков С.И. К патогенезу эутиреоидного зоба. Пробл. эндокринологии, 1989,

т.35, №1 с.35-39

155. Петрова Н.И. Эпителиально-стромальные отношения в щитовидной железе у собак в норме и

при различных режимах двигательной активности// Н.И. Петрова, О.В. Бирюкова//

Морфология, 2002, №2-3, с. 123.

156. Прокопчук В.С. Морфогенез эндемического зоба. Авт. дисс.

157. Райхлин Н.Т., Букаева И.А., Смирнова Е.А, ПРОГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ

ИССЛЕДОВАНИЯ СТЕПЕНИ ЭКСПРЕССИИ АРГИРОФИЛЬНЫХ БЕЛКОВ ОБЛАСТЕЙ

ЯДРЫШКОВЫХ ОРГАНИЗАТОРОВ НА ПРИМЕРЕ ПАПИЛЛЯРНОГО РАКА

ЩИТОВИДНОЙ ЖЕЛЕЗЫАрхив патологии, 2010.-N 4.-С.49-52. Библ. 19 назв

158. Рухадзе Р.Г. – Структурно-функциональные особенности щитовидной железы и некоторых

органов при гипер-, эу- и гипотиреозе. Автореф. дис. докт. мед. наук, 1994, Тбилиси, 52 стр.

159. Рухадзе Р.Г., Гачечиладзе Ц.В. Количественный анализ параметров нормальной щитовидной

железы в возрастном аспекте. Georgian Medical News, 1999, №2, с.6-7

160. Спринджук М.В., Демидчик Ю.Е., Ковалев В.А., Дмитрук А.А., Богуш А.Л. и др. Анализ

злокачественных опухолей щитовидной железы и яичников. Возможность цифровой

обработки микроскопических исследований. Ars. Medica, 2010, №1 (21), p. 9-24.

161. Талантов В.В., Зельцер М.Е., Ионисянц В.П., Левит И.Д. Актуальные проблемы

эндемического зоба. Пробл. эндокринологии, 1983, т.29, №3, с.82-86

162. Фадеев В.В. Узловые образования щитовидной железы: международные алгоритмы и

отечественная клиническая практика// Врач, 2002, №7, с. 12-16.

163. Хмельницкий О.К., Котович В.М. Дифференциальная диагностика заболеваний щитовидной

железы при морфологичес4ом исследовании СПБ, 1997

164. Хмельницкий О.К., Третьякова М.С. Морфометрическое исследованиеп щитовидной железы

(учебно-методическое исследование). СПБ, 1997

165. Хмельницкий О.К., Третьякова М.С. Щитовидная железа как объект морфометрического

исследования. Архив патол. 1998, вып.4, с.47-49

166. Цагарели ЗГ, Гогиашвили ЛЕ, Никобадзе ЕГ, Дгебуадзе МА Экспрессия факторов роста в

ткани зобноизмененной щитовидной желези. Корелляция с клинико-морфологическими и

электрономикроскопически михарактеристиками. (GMN)2007(5)77-81

167. Шадлинский В.Б. Морфофункциональные особенности структурной организации

щитовидной железы. Ж. «Морфология», М., 1998, №3, с.130 (соавт. Рустамова С.М.)

100

naTia rurua autoimunuri Tireoiditis (Hashimoto...

Documents

Transcript of naTia rurua autoimunuri Tireoiditis (Hashimoto...