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Hashimotos Thyroiditis

Last Updated: January 1, 2012


Authors
Takashi Akamizu, M.D., Ph.D.
Professor and Chairman, The First Department of Medicine, a!ayama Medica" Uni#ersity,
$11%1 &imi%idera, a!ayama '(1%$)0*, Japan, a!ami+u,-a!ayama%med.ac./p
Nobuyuki Amino, M.D.
&uma 0ospita", Center for 12ce""ence in Thyroid Care, $%2%3) 4himoyamate%dori, Chuo%!u,
&o5e ')0%0011, Japan, namino,!uma%h.or./p
Leslie J. DeGroot, M.D.
6esearch Professor, Uni#. of 6hode 7s"and8Pro#idence, $0 ashin9ton 4t :room 302;,
Pro#idence, 67 02*03
Historial !e"ie#
7n 1*12 :Fi9. $%1; 0ashimoto descri5ed four patients -ith a chronic disorder of the thyroid, -hich he
termed struma "ymphomatosa. The thyroid 9"ands of these patients -ere characteri+ed 5y diffuse
"ymphocytic infi"tration, fi5rosis, parenchyma" atrophy, and an eosinophi"ic chan9e in some of the
acinar ce""s.:1; C"inica" and patho"o9ic studies of this disease ha#e appeared fre<uent"y since
0ashimoto=s ori9ina" description. The disease has 5een ca""ed 0ashimoto=s thyroiditis, chronic
thyroiditis, "ymphocytic thyroiditis, "ymphadenoid 9oiter, and recent"y autoimmune thyroiditis.
C"assica""y, the disease occurs as a pain"ess, diffuse en"ar9ement of the thyroid 9"and in a youn9 or
midd"e%a9ed -oman. 7t is often associated -ith hypothyroidism. The disease -as thou9ht to 5e
uncommon for many years, and the dia9nosis -as usua""y made 5y the sur9eon at the time of operation
or 5y the patho"o9ist after thyroidectomy. The increasin9 use of the need"e 5iopsy and sero"o9ic tests
for anti5odies ha#e "ed to much more fre<uent reco9nition, and there is reason to 5e"ie#e that it may 5e
increasin9 in fre<uency.:2; 7t is no- one of the most common thyroid disorders.
Fi9ure 1. Dr. 0a!aru 0ashimoto
The first indication of an immuno"o9ic a5norma"ity in this disease -as an e"e#ation of the p"asma
9amma 9"o5u"in fraction detected 5y Fromm et a".:3; This findin9, to9ether -ith a5norma"ities in
serum f"occu"ation test resu"ts:(; indicated that the disease mi9ht 5e re"ated to a "on9%continued
autoimmune reaction. 6ose and ite5s!y:); sho-ed that immuni+ation of ra55its -ith e2tracts of
ra55it thyroids produced histo"o9ic chan9es in the thyroid 9"ands resem5"in9 those seen in 0ashimoto=s
thyroiditis. They a"so found antithyro9"o5u"in anti5odies in the 5"ood of the anima"s. 4u5se<uent"y,
6oitt et a".:'; o5ser#ed that a precipitate formed -hen an e2tract of human thyroid 9"and -as added to
serum from a patient -ith 0ashimoto=s thyroiditis. Thus, it appeared that the serum contained
anti5odies to a constituent of the human thyroid and that these anti5odies mi9ht 5e responsi5"e for the
disease process. These ori9ina" o5ser#ations "ed direct"y to entire"y ne- concepts of the causation of
disease 5y autoimmuni+ation.
Patholo$y
The 9oiter is 9enera""y symmetrica", often -ith a conspicuous pyramida" "o5e. >ross"y, the tissue
in#o"#ed 5y 0ashimoto=s thyroiditis is pin!ish%tan to fran!"y ye""o-ish and tends to ha#e a ru55ery
firmness. The capsu"ar surface is 9ent"y "o5u"ated and non%adherent to peri%thyroid structures.
Microscopica""y, there is a diffuse process consistin9 of a com5ination of epithe"ia" ce"" destruction,
"ymphoid ce""u"ar infi"tration, and fi5rosis. The thyroid ce""s tend to 5e s"i9ht"y "ar9er and assume an
acidophi"ic stainin9 character? they are then ca""ed 0urth"e or @s!ana+y ce""s and are pac!ed -ith
mitochondria. The fo""icu"ar spaces shrin!, and co""oid is a5sent or sparse. Fi5rosis may 5e comp"ete"y
a5sent or present in de9rees ran9in9 from s"i9ht to moderate? it may 5e se#ere, as o5ser#ed in su5acute
or 6iede"=s thyroiditis. Forei9n 5ody 9iant ce""s and 9ranu"omas are not features of 0ashimoto=s
thyroiditis, in contrast to su5acute thyroiditis. 7n chi"dren, o2yphi"ia and fi5rosis are "ess prominent, and
hyperp"asia of epithe"ia" ce""s may 5e mar!ed. Deposits of dense materia" representin9 79> are found
a"on9 the 5asement mem5rane on e"ectron microscopy :Fi9. $%2;.
Fi9ure 2. 1"ectron microscopy ima9e of thyroid tissue from a patient -ith 0ashimotoAs thyroiditis,
sho-in9 e"ectron dense deposits of 79> and T> a"on9 the 5asement mem5rane of fo""icu"ar ce""s.
ithin the fo""ic"es may 5e seen c"usters of macropha9e%"i!e ce""s. The "ymphoid infi"tration in the
interstitia" tissue is accompanied 5y actua" fo""ic"es and 9ermina" centers :Fi9. $%3, 5e"o-;. P"asma ce""s
are prominent. Totterman has studied the characteristics of the "ymphocytes in the thyroid and reports
that they are made up of e<ua" proportions of T and B ce""s.:C; Most infi"tratin9 T ce""s ha#e a"pha85eta
T ce"" receptors. >amma8de"ta T ce""s are rare:$;, a"thou9h their proportion in intrathyroida"
"ymphocytes is hi9her than that in periphera" "ymphocytes:*;. CD(DCD$D ce""s and CD3"o%
TC6a"pha85eta%"o8CD(%CD$% ce""s a"so are present in the infi"trate in the thyroid:*;. 7nfi"tratin9 T ce""s
are considered to 5e a hi9h"y restricted popu"ation, 5ased on the study of T ce"" receptor E a"pha:10;
and 5eta:11; 9ene e2pression. 0euer et a". studied cyto!ine m6F@ e2pression in intrathyroida" T ce""s
and found increased e2pression of 7FF%9amma, 7L%2 and CD2), -hich are Th1%re"ated cyto!ines:12; in
0ashimoto=s thyroiditis. Thyro9"o5u"in%5indin9 "ymphocytes -ere increased in percenta9e re"ati#e to
their occurrence in 5"ood.
Fi9ure 3. Patho"o9y of 0ashimotoAs thyroiditis. 7n this typica" #ie- of se#ere 0ashimotoAs thyroiditis,
the norma" thyroid fo""ic"es are sma"" and 9reat"y reduced in num5er, and -ith the hemato2y"in and
eosin stain are seen to 5e eosinophi"ic. There is mar!ed fi5rosis. The dominant feature is a profuse
mononuc"ear "ymphocytic infi"trate and "ymphoid 9ermina" center formation.
The <uantity of parenchyma" tissue "eft in the thyroid is #aria5"e. 7n some instances it is actua""y
increased, perhaps as a compensatory hyperp"astic response to inefficient iodide meta5o"ism. Typica""y,
the patho"o9ic process in#o"#es the entire "o5e or 9"and. Foca" thyroiditis, -hich is microscopica""y
simi"ar, may 5e found in thyroid 9"ands -ith diffuse hyperp"asia of >ra#es= disease, in association -ith
thyroid tumors, or in mu"tinodu"ar thyroid 9"ands. The thymus, -hich is fre<uent"y en"ar9ed in
thyroiditis as it is in >ra#es= disease, does not present the picture of enhanced immuno"o9ic
acti#ity:13;,:1(;. 0isto"o9ic feature in pain"ess :or si"ent; thyroiditis is a"most simi"ar to that of
0ashimoto=s thyroiditis. @"" specimens sho- chronic thyroiditis, foca" or diffuse type: and "ymphoid
fo""ic"es -ere present in a5out ha"f of the specimen:1);. The fo""icu"ar distruptions are characteristic
and common histo"o9ic feature at the time of destructi#e thyroto2icois 5ut disappear durin9 the "ate
reco#ery phase of disease. Thus pain"ess thyroiditis may 5e induced 5y the acti#ation of autoimmune
reaction -ithin the thyroid 9"and in patients -ith 0ashimoto=s thyroiditis.
Patho$enesis
The putati#e causes of autoimmune thyroid disease :@7TD; are re#ie-ed in Chapter C, and the 5asic
concepts re#ie-ed there app"y of course to 0ashimoto=s thyroiditis. 7n 0ashimoto=s thyroiditis, the
immuno"o9ic attac! appears to 5e typica""y a99ressi#e and destructi#e, rather than stimu"atory, as in
>ra#es= disease, and the difference is most "i!e"y due to the characteristics of the immune response.
0ashimoto=s thyroiditis is reported to occur in t-o #arieties, an atrophic #ariety, perhaps associated
-ith 0L@%D63 9ene inheritance, and a 9oitrous form associated -ith 0L@%D6). The "ar9e U&
Caucasian 0T case contro" cohort study demonstrated c"ear differences in association -ithin the 0L@
c"ass 77 re9ion 5et-een 0ashimoto=s thyroiditis and >ra#es= disease, differences in 0L@ c"ass 77
9enotype may, in part, contri5ute to the different immunopatho"o9ica" processes and c"inica"
presentation of these re"ated diseases :1)a;. 7n studies of autoimmune hypothyroidism in mono+y9otic
t-ins, the concordance rate is 5e"o- 1 and thus en#ironmenta" factors are a"so etio"o9ica""y important.
:1'; Concernin9 suscepti5i"ity 9enes for 0ashimoto=s thyroiditis, non%M0C c"ass 77 9enes ha#e 5een
recent"y in#esti9ated. @ num5er of data accumu"ated, demonstratin9 an association 5et-een cytoto2ic T
ce"" anti9en%( :CTL@%(;, -hich is a ma/or ne9ati#e re9u"ator of T%ce"" mediated immune functions, and
autoimmune diseases inc"udin9 0ashimoto=s thyroiditis. Fe- studies ha#e appeared on the +inc%fin9er
9ene in @7TD suscepti5i"ity re9ion 9ene :GF@T;, the thyro9"o5u"in 9ene, and the protein tyrosine
phosphatase%22 :PTPF22; 9ene.
6e9ardin9 en#ironmenta" factors, hi9h iodine inta!e, se"enium deficiency, po""utants such as to5acco
smo!e, infectious diseases such as chronic hepatitis C, and certain dru9s are imp"icated in the
de#e"opment of autoimmune thyroiditis :1'.1: Duntas L0.1n#ironmenta" factors and autoimmune
thyroiditis.Fat C"in Pract 1ndocrino" Meta5. 200$ Ju" $. H1pu5 ahead of printI;. Lon9%term iodine
e2posure "eads to increased iodination of thyro9"o5u"in, -hich increases its anti9enicity and initiates
the autoimmune process in 9enetica""y suscepti5"e indi#idua"s. 4e"enium deficiency decreases the
acti#ity of se"enoproteins, inc"udin9 9"utathione pero2idases, -hich can "ead to raised concentrations of
hydro9en pero2ide and thus promote inf"ammation and disease. 4uch en#ironmenta" po""utants as
smo!e, po"ych"orinated 5ipheny"s, so"#ents and meta"s ha#e 5een imp"icated in the autoimmune
process and inf"ammation. 1n#ironmenta" factors ha#e not yet, ho-e#er, 5een sufficient"y in#esti9ated
to c"arify their ro"es in patho9enesis, and there is a need to assess their effects on de#e"opment of the
autoimmune process and the mechanisms of their interactions -ith suscepti5i"ity 9enes.
0i9h titers of anti5ody a9ainst thyro9"o5u"in :T>; and thyroid pero2idase :TPJ; are present in most
patients -ith 0ashimoto=s thyroiditis:1C;, and TPJ anti5odies are comp"ement fi2in9 and may 5e
cytoto2ic. 0o-e#er, the e#idence for cytoto2icity is scant, especia""y since norma" transp"acenta"
anti5ody passa9e of anti%TPJ @5 to the human fetus does not usua""y induce thyroid dama9e.
Thus it is specu"ated that cytoto2ic T ce""s, or !i""er :&; or natura" !i""er :F&; ce""s, or re9u"atory T
:Tre9; or suppressor T ce""s, may p"ay an important ro"e. @ fe- reports do sho- T ce"" "ine or c"one
cytoto2icity to-ard iso"o9ous thyroid epithe"ia" ce""s, and e2perimenta" thyroiditis can 5e transferred 5y
"ymphocytes. T ce""s from patients -ith 0ashimoto=s disease pro"iferate -hen e2posed to T> and TPJ.
These responses are !no-n to 5e directed to specific se<uences in the TPJ mo"ecu"e, inc"udin9
epitopes at aa 110%12*, 210%230, (20%(3*, and $(2%$'1:1$;. T ce""s from mice immuni+ed to TPJ react
stron9"y to TPJ se<uence )(0%))*, and -hen immuni+ed -ith this peptide, de#e"op hypothyroidism
and thyroiditis. This peptide may 5e a centra" factor in immunity to TPJ:1$.1;. Mui2K et a". identified
natura" 0L@%D6%associated peptides in autoimmune or9ans that -i"" a""o- findin9 peptide%specific T
ce""s in situ :1$.2;. This study reports a first ana"ysis of 0L@%D6 natura" "i9ands from e2 #i#o >ra#es=
disease%affected thyroid tissue. Usin9 mass spectrometry, they identified 1'2 auto"o9ous peptides from
0L@%D6%e2pressin9 ce""s, inc"udin9 thyroid fo""icu"ar ce""s, -ith some correspondin9 to predominant
mo"ecu"es of the thyroid co""oid. Most interestin9"y, ei9ht of the peptides -ere deri#ed from a ma/or
autoanti9en, thyro9"o5u"in. 7n #itro 5indin9 identified 0L@%D63 as the a""e"e to -hich one of these
peptides "i!e"y associates in #i#o. Computer mode"in9 and 5ioinformatics ana"ysis su99ested other
0L@%D6 a""e"es for 5indin9 of other thyro9"o5u"in peptides. 7ncreased & and F& ce"" function has
5een reported in 0ashimoto=s thyroiditis:1*;. Dysfunction of re9u"atory :or suppressor; CD(D T ce""
popu"ations may "ead to the de#e"opment of #arious or9an%specific autoimmune diseases inc"udin9
0ashimoto=s thyroiditis :1*.1;. Despite the "ac! of understandin9 of the primary cause:s;, it is certain
that thyroid autoimmunity dri#es the "ymphocyte co""ection in the thyroid and is responsi5"e for thyroid
epithe"ia" ce"" dama9e. Pro9ressi#e thyroid ce"" dama9e can chan9e the apparent c"inica" picture from
9oitrous hypothyroidism to that of primary hypothyroidism, or LatrophicM thyroiditis. Primary
hypothyroidism is considered to 5e the end sta9e of 0ashimoto=s thyroiditis. 7n the T406%immuni+ed
murine mode" of >ra#es= disease, Tre9 dep"etion :particu"ar"y CD2); induced thyroid "ymphocytic
infi"trates -ith transient or permanent hypothyroidism :1*.2;. Lymphocytic infi"tration -as associated
-ith intermo"ecu"ar spreadin9 of the T406 anti5ody response to other se"f thyroid anti9ens, murine
thyroid pero2idase and thyro9"o5u"in. These data su99est a ro"e for Tre9 in the natura" pro9ression of
hyperthyroid >ra#es= disease to 0ashimoto=s thyroiditis and hypothyroidism in humans.
@n a"ternati#e cause of LatrophicM hypothyroidism is the de#e"opment of thyroid stimu"ation 5"oc!in9
anti5odies :T4B@5;, -hich, as the name imp"ies, pre#ent T40 5indin9 to T40%6, 5ut do not stimu"ate
thyroid ce""s and produce hypothyroidism. 7t has 5een proposed that T4B@5 5ind to epitopes near the
car5o2y" end of the T40%6 e2trace""u"ar domain, in contrast to thyroid stimu"atin9 anti5odies :T4@5;,
-hich 5ind to epitopes near aa (0 at the amino terminus:20;. This syndrome occurs in neonates,
chi"dren and adu"ts. The pre#a"ence of T4B@5 in adu"t hypothyroid patients has 5een reported to 5e
10N:21;. 0o-e#er, in contrast to the usua" pro9ressi#e and irre#ersi5"e thyroid dama9e occurrin9 in
the usua" settin9, these 5"oc!in9 anti5odies tend to fo""o- the course of T4@5Othat is, they decrease or
disappear o#er time, and the patient may 5ecome euthyroid a9ain:22;. @ chan9e from a predominant
T4@5 response to a predominant T4B@5 response can cause patients to ha#e se<uentia" episodes of
hyper% and hypothyroid function:23;. 0L@ anti9ens of hypothyroid patients -ith T4B@5 -ere found to
5e different from patients -ith idiopathic my2edema or 0ashimoto=s thyroiditis, and rather simi"ar to
patients -ith >ra#es= disease:2(;.
7n patients -ith autoimmune hypothyroidism, thyroid dysfunction mi9ht 5e induced 5y cyto!ine%
mediated apoptosis of thyroid epithe"ia" ce""s and infi"tratin9 T "ymphocytes may not direct"y 5e
in#o"#ed in thyrocyte ce"" death durin9 0ashimoto= s thyroiditis. Fra9mented DF@, a characteristic
feature of apoptosis, -as fre<uent"y found in the thyroid fo""icu"ar ce""s in 0ashimoto=s thyroiditis:2);.
The "i9and for Fas:Fas L;-as sho-n to 5e constituti#e"y e2pressed on thyrocytes and "L%1a"pha,
a5undant"y produced in the thyroid 9"and of 0ashimoto=s thyroiditis, induced Fas e2pression on
thyrocytes. Thus Fas%FasL interaction on thyrocytes may induce apoptosis and thyroid ce""
destruction:2';. 7n the thyroid fo""ic"e ce""s of 0ashimoto=s thyroiditis, Fas and FasL are stron9"y
stained and immunostainin9 of Bc"%2 is -ea!, su99estin9 that cyto!ines cause up%re9u"ation of
apoptosis:2C;. 7ncreased serum T40 may inhi5it Fas%mediated apoptosis of thyrocytes:2$;. 7n contrast
T4B@5 5"oc! the inhi5itory action of T40 to-ard Fas%mediated apoptosis and thus induce thyroid
atrophy. Jn the other hand, trans9enic e2pression of Fas L on thyroid fo""icu"ar ce""s actua""y pre#ents
autoimmune thyroiditis, possi5"y throu9h inhi5ition of "ymphocyte infi"tation:2*;. Jther death%receptor
"i9ands mi9ht participate in and TFF%re"ated apoptosis%inc"udin9 thyrocyte !i""in9, inc"udin9 TFF%
"i9and:T6@7L;:30; . 7n re"ation to the Fas%Fas L system, Don9 et a". reported that mutations of Fas,
-hich induce "oss of function, -ere found in thyroid "ymphocytes in 3$.1N of patients -ith
0ashimoto=s thyroiditis:31;. These mutations are found in ').(N of patients -ith ma"i9nant
"ymphoma:32;, -hich usua""y de#e"ops from 0ashimoto=s thyroiditis. These chan9es are possi5"y
important for pro9ression of 0ashimoto=s thyroiditis.
@pparent de%no#o de#e"opment of anti5odies, au9mentation of pre%e2istin9 thyroid autoimmunity,
9oiter, and hypothyroidism, are induced in some cancer patients, -hen 9i#en courses of 7L2, 7L2a p"us
"ympho!ine acti#ated & ce""s and8or 7FF%9amma. 7t is thou9ht that the phenomenon may ref"ect
acti#ation of "ymphocytes 5y the "ympho!ine and "ympho!ine and ce""%mediated attac! on thyroid
tissue:33;. @cti#ated "ymphocytes re"ease TFFa"pha and 7FF9amma, -hich can in/ure or suppress T1C
function. 7FF9amma may a"so au9ment thyrocyte 0L@%D6 e2pression, -hich cou"d ma!e the
thyrocyte a5"e to present se"f%anti9ens. 7nterferon a"pha therapy for chronic acti#e type C hepatitis a"so
au9ments pre%e2istin9 thyroid autoimmunity and can induce autoimmune hypothyroidism. @
humanised anti%CD)2 monoc"ona" anti5ody, Campath%10 may permit the 9eneration of anti5ody%
mediated thyroid autoimmunity :33a,5;. Campath%10 dep"etes "ymphocytes and monocytes, and may
cause the immune response to chan9e from the Th1 phenotype.
T he"per type 1C :Th1C; "ymphocytes, -hich producea proinf"ammatory cyto!ine 7L%1C, ha#e recent"y
5een sho-n to p"ay a ma/or ro"e in numerous autoimmune diseases that had pre#ious"y 5een thou9ht to
5e Th1%dominant diseases, such as 0ashimoto = s thyroiditis.7t is reported that there is an increased
differentiation of Th1C "ymphocytes and an enhanced synthesis of Th1C cyto!ines in 0ashimoto=s
disease :33c;.7n a mouse mode" of 0ashimoto=s thyroiditis, iodine%induced autoimmune thyroiditis in
nono5ese dia5etic%02:h(; mice, 5oth Th1 and Th1C ce""s are found to 5e critica" T:eff; su5sets for the
patho9enesis of spontaneous autoimmune thyroiditis :33d;.
The 79>(%re"ated disease :79>(%6D; is a ne- diseaseentity first proposed in re"ation to autoimmune
pancreatitis :@7P; 5y 0amano et a". in 2001 :33e;. @ hi9h pre#a"ence of hypothyroidism has 5een
reported in patients -ith @7P :33f;. 7n 200*, it -as reported that on the 5asis of the
immunohistochemistry of 79>(, 0T can 5e di#ided into t-o 9roups, -hich -ere proposed as 79>(
thyroiditis :79>(%positi#e p"asma ce""%rich 9roup; and non%79>( thyroiditis :79>(%positi#e p"asma
ce""poor 9roup; :339;. The 79>( thyroiditis 9roup sho-s indistin9uisha5"e histo"o9ica" features and
may ha#e a c"ose re"ationship -ith 79>(%6D in other or9ans. 7n 2010, it -as demonstrated that 79>(
thyroiditis is c"inica""y associated -ith a "o-er fema"e%to%ma"e ratio, more rapid pro9ress, su5c"inica"
hypothyroidism, diffuse "o- echo9enicity, and a hi9her "e#e" of circu"atin9 thyroid autoanti5odies than
non%79>( thyroiditis :33h;.6iede" thyroiditis :6T; is another candidate for 79>(%6D. 7t is a rare form of
chronic thyroiditis, characteri+ed 5y inf"ammatory pro"iferati#e fi5rosis -hich in#o"#es the thyroid
parenchyma and surroundin9 tissue structures. 7n 2010, Dah"9ren et a". reported that 79>(%6D -as the
under"yin9 condition in a part of the cases of 6T :33i;. hen 79>(%6D occurs in a systemic pattern, the
thyroid in#o"#ement may present as 6T rather than 0T :33/;.
7odine consumption inf"uences the incidence of 0ashimoto=s thyroiditis and hypothyroidism :see
5e"o-: L7odide Meta5o"ism and 1ffectsM in this chapter;. 4mo!in9 has a"so 5een identified as a ris!
factor for hypothyroidism, 5ut the reason for the association is un!no-n:3(;.
@n increase in the pre#a"ence of thyroid autoanti5odies :@T@s; -as reported '%$ yr after the Cherno5y"
accident in radiation%e2posed chi"dren and ado"escents :3(a;.TPJ@5 pre#a"ence in ado"escents
e2posed to radioacti#e fa""out -as sti"" increased in Be"arus 13%1) yr after the Cherno5y" accident
:3(5;. This increase -as "ess e#ident than pre#ious"y reported and -as not accompanied 5y thyroid
dysfunction. These data su99est that radioacti#e fa""out e"icited a transient autoimmune reaction,
-ithout tri99erin9 fu""%5"o-n thyroid autoimmune disease. Lon9er o5ser#ation periods are needed to
e2c"ude "ater effects.
Ce"iac disease -as positi#e"y associated -ith hypothyroidism :0a+ard 6atio P (.(? *)N Confidence
7nter#a" P 3.(%).'? p Q 0.001;, thyroiditis :3.'? 1.*%'.C? p Q 0.001; and hyperthyroidism :2.*? 2.0%(.2? p
Q 0.001; :3(c;. The hi9hest ris! estimates -ere found in chi"dren :hypothyroidism '.0? 3.(%10.',
thyroiditis (.C? 2.1%10.) and hyperthyroidism (.$? 2.)%*.(;. 7n post%hoc ana"yses, -here the reference
popu"ation -as restricted to inpatients, the ad/usted 06 for hypothyroidism -as 3.( :2.C%(.(? p Q
0.001;, thyroiditis 3.3 :1.)%C.C? p Q 0.001; and hyperthyroidism 3.1 :2.0%(.$? p Q 0.001;.This indicates
shared etio"o9y and that these indi#idua"s are more suscepti5"e to autoimmune disease.
0ashimoto thyroiditis is often associated -ith type 1 dia5etes and other autoimmune disorders such as
coe"iac disease, type 2 and type 3 po"y9"andu"ar autoimmune disorders :@P4;. Type 2 @P4 is defined
5y the occurrence of @ddison=s disease -ith thyroid autoimmune disease and8or Type 1 dia5etes
me""itus.Type 3 @P4 is thyroid autoimmune diseases associated -ith other autoimmune diseases
:e2c"udin9 @ddison=s disease and8or hypoparathyroidism;. C"inica""y o#ert disorders are considered
on"y the tip of the autoimmune ice5er9, since "atent forms are much more fre<uent :3(d;. 0ashimoto
thyroiditis is a"so often associated in "ymphocytic hypophysitis :3(e;.
%nidene and Distribution
The incidence of 0ashimoto=s thyroiditis seen in practice is un!no-n 5ut is rou9h"y e<ua" to that of
>ra#es= disease :on the order of 0.3 O 1.) cases per 1,000 popu"ation per year.;:3)%3C; The disease is 1)
O 20 times as fre<uent in -omen as in men. 7t occurs especia""y durin9 the decades from 30 to )0, 5ut
may 5e seen in any a9e 9roup, inc"udin9 chi"dren. 7t is certain that it e2ists -ith a much hi9her
fre<uency than is dia9nosed c"inica""y, and its fre<uency seems to 5e increasin9. Fami"y studies a"-ays
5rin9 to "i9ht a num5er of re"ati#es -ith moderate en"ar9ement of the thyroid 9"and su99esti#e of
0ashimoto=s thyroiditis. Many of these persons ha#e T> and TPJ anti5odies, and most are entire"y
asymptomatic. 7noue et a". found 3N of Japanese chi"dren a9ed ' O 1$ to ha#e thyroiditis:3$;. 7n most
instances, 5iopsy re#ea"ed foca" rather than diffuse thyroiditis.
7n addition to o#ert thyroiditis, rou9h"y 10N of most popu"ations ha#e positi#e T> and TPJ anti5ody
test resu"ts:3)%3C; in the apparent a5sence of thyroid disease 5y physica" e2amination. 7n a c"assic
study of an entire community, Tun5rid9e et a".:3C; found that 1.* O 2.CN of -omen had present or past
thyroto2icosis, 1.*N had o#ert hypothyroidism, C.)N had e"e#ated T40 "e#e"s, 10.3N had test resu"ts
positi#e for TPJ :microsoma" anti9en; @5 measured 5y hema99"utination assay :MC0@;, and a5out
1).0N had 9oiter. Men had 10 to (%fo"d "o-er incidence of thyroid a5norma"ities. 7n a study of chi"dren
-hose parents had history of thyroid disease, Carey et a".:3*; found a 2(N pre#a"ence of thyroid
La5norma"itiesM, inc"udin9 a pre#a"ence of '.*N a5norma" thyroids, and *.3N -ith positi#e T> @5
measured 5y hema99"utination assay :T>0@; and C.$N positi#e MC0@ assays. >ordin et a".:3);
found that $N of adu"t Finns had positi#e T>0@ resu"ts, and 2'N had positi#e MC0@ resu"ts. T40
"e#e"s -ere e"e#ated in 30N of these persons. Jn the 5asis of positi#e anti5ody titers and e"e#ated T40
"e#e"s, 2 O )N -ere 5e"ie#ed to ha#e asymptomatic thyroiditis. These test resu"ts corre"ate -ith foca"
co""ection of "ymphocytes on histo"o9ic e2amination of the thyroid 9"ands:(0;, are fre<uent"y
associated -ith e"e#ated "e#e"s of T40:(1;, and pro5a5"y represent one end of a spectrum of thyroid
dama9e. omen -ith 5oth positi#e anti5ody test resu"ts and raised T40 "e#e"s 5ecome hypothyroid at
the rate of )N8year:(2;. @ reasona5"e appro2imation of the pre#a"ence of positi#e anti5ody tests in
-omen is 9reater than 10N, and of c"inica" disease is at "east 2N. Men ha#e one%tenth this pre#a"ence.
&ourse o' the Disease (Table )*+,
0ashimoto=s thyroiditis 5e9ins as a 9radua" en"ar9ement of the thyroid 9"and and 9radua" de#e"opment
of hypothyroidism. 7t is often disco#ered 5y the patient, -ho finds a fu""ness of the nec! or a ne- "ump
-hi"e se"f%e2aminin9 5ecause of a #a9ue discomfort in the nec!. Perhaps most often, it is found 5y the
physician durin9 the course of an e2amination for some other comp"aint.
Table +. Presentations o' Hashimotos Thyroiditis
1. 1uthyroidism and 9oiter
2. 4u5c"inica" hypothyroidism and 9oiter
3. Primary thyroid fai"ure
(. 0ypothyroidism
). @do"escent 9oiter
'. Pain"ess thyroiditis or si"ent thyroiditis
C. Postpartum pain"ess thyroto2icosis
$. @"ternatin9 hypo% and hyperthyroidism
7n some instances the thyroid 9"and may en"ar9e rapid"y? rare"y, it is associated -ith dyspnea or
dyspha9ia from pressure on structures in the nec!, or -ith mi"d pain and tenderness. 6are"y, pain is
persistent and unresponsi#e to medica" treatment and re<uires medica" therapy or sur9ery. The 9oiter of
0ashimoto=s thyroiditis may remain unchan9ed for decades:3C;, 5ut usua""y it 9radua""y increases in
si+e. Jccasiona""y the course is mar!ed 5y symptoms of mi"d thyroto2icosis, especia""y durin9 the ear"y
phase of the disease. 4ymptoms and si9ns of mi"d hypothyroidism may 5e present in 20N of patients
-hen first seen:(1;, or common"y de#e"op o#er a period of se#era" years. Pro9ression from su5c"inica"
hypothyroidism :norma" FT
(
5ut e"e#ated T40; to o#ert hypo%thyroidism occurs in a certain fraction
:perhaps 3%)N; each year. 1#entua""y thyroid atrophy and my2edema may occur:(3;. This assertion is
5ased on the c"inica" o5ser#ation that patients -ith 0ashimoto=s thyroiditis often de#e"op my2edema,
and the !no-"ed9e that patients -ith my2edema due to atrophy of the thyroid ha#e a hi9h incidence of
T> @5 in their serum. The disease fre<uent"y produces 9oitrous my2edema in youn9 -omen, and -e
ha#e occasiona""y o5ser#ed a 9oitrous and hypothyroid patient -ho -ent on to de#e"op thyroid
atrophy.Jccasiona""y, patients -ith 0ashimoto thyroiditis ha#e persistent pain -hich is unresponsi#e
to nonsteroida" anti%inf"ammatory dru9s, rep"acement -ith thyroid hormone, and recurs after therapy
-ith steroids. &on and De>root recent"y reported se#en patients -ho fina""y came to su5tota" or near%
tota" thyroidectomy, some of -hom recei#ed su5se<uent radioacti#e iodide thyroid a5"ation, -ith fina"
re"ief of symptoms :&on, RC? De>root, LJ. Painfu" 0ashimoto thyroiditis as an indication for
thyroidectomy: c"inica" characteristics and outcome in se#en patients. J C"in 1ndocrino" Meta5 $$
2''C%2'C2 2003;.
>enera""y the pro9ression from euthyroidism to hypothyroidism has 5een considered an irre#ersi5"e
process due to thyroid ce"" dama9e and "oss of thyroida" iodine stores :Fi9. $%(;. 0o-e#er, it is no-
c"ear that up to one%fourth of patients -ho are hypothyroid may spontaneous"y return to norma"
function o#er the course of se#era" years. This se<uence may ref"ect the initia" effect of hi9h titers of
thyroid stimu"ation 5"oc!in9 anti5odies -hich fa"" -ith time and a""o- thyroid function to return:23;.
Fi9ure (. F"uorescent thyroid scan in thyroiditis. The norma" thyroid scan :"eft; a""o-s identification of
a thyroid -ith norma" sta5"e :12C7; stores throu9hout 5oth "o5es. @ mar!ed reduction in 12C7 content is
apparent throu9hout the entire 9"and in#o"#ed -ith 0ashimotoAs thyroiditis :ri9ht;.
ithin the past fe- years, se#era" unusua" syndromes 5e"ie#ed to 5e associated -ith or part of the
c"inica" spectrum of 0ashimoto=s thyroiditis ha#e 5een descri5ed. Jccasiona" patients de#e"op amy"oid
deposits in the thyroid:((;. 4ha- et a".:(); descri5ed fi#e patients -ith a re"apsin9 steroid%responsi#e
encepha"opathy inc"udin9 episodes "i!e stro!e and sei+ures, hi9h C4F protein, a5norma" 11>, and
norma" C@T scans:see 0ashimoto=s encepha"opathy 5e"o-;. &hardon et a".:('; descri5ed a steroid
responsi#e "ymphocytic interstitia" pneumonitis in four patients. 7t remains uncertain ho- these
i""nesses re"ate to "ymphocytic thyroiditis, -hich has unti" no- 5een "ar9e"y identified as an or9an
specific disease.
@t ) years of fo""o-%up of the natura" course of euthyroid 0ashimoto=s thyroiditis in 7ta"ian chi"dren,
more than )0N of the patients remained or 5ecame euthyroid :('%1;. The presence of 9oiter and
e"e#ated T>a5 at presentation, to9ether -ith pro9ressi#e increase in 5oth TPJa5 and T40, may 5e
predicti#e factors for the future de#e"opment of hypothyroidism.
0ashimoto=s thyroiditis and hypothyroidism are associated -ith @ddison=s disease, dia5etes me""itus,
hypo9onadism, hypopara%thyroidism, and pernicious anemia. 4uch com5inations are descri5ed as the
po"y9"andu"ar fai"ure syndrome. T-o forms of po"y9"andu"ar autoimmunity ha#e 5een reco9ni+ed:(C;.
7n the Type 7 syndrome patients ha#e hypoparathyroidism, muco%cutaneous candidiasis, @ddison=s
disease, and occasiona""y hypothyroidism. Type 77, more fre<uent, often inc"udes fami"ia" associations
of dia5etes me""itus, hypothyroidism, hypoadrena"ism, and occasiona""y 9onada" or pituitary fai"ure. 7n
these syndromes, anti5odies reactin9 -ith the affected end or9ans are characteristica""y present.
Eiti"i9o, hi#es, and a"opecia are associated -ith thyroiditis. There is a"so a c"ear association -ith
primary and secondary 4/o9ren=s syndrome:($;. 4ome patients appear to start -ith 0ashimoto=s
thyroiditis, and pro9ress -ith time to the picture of 6iede"=s thyroiditis inc"udin9 the fre<uent"y%
associated retroperitonea" fi5rosis:(*;.
Muscu"os!e"eta" symptoms, inc"udin9 chest pain, fi5rositis, and rheumatoid arthritis, occur in one%
<uarter of patients:)0;, and of course, any of the muscu"os!e"eta" symptoms of hypothyroidism may
"i!e-ise occur.
7t has 5een su99ested that thyroiditis predisposes to #ascu"ar disease and coronary occ"usion.
@5norma""y e"e#ated titers of thyroid autoanti5odies and the morpho"o9ic chan9es of thyroiditis are
said to occur -ith an increased fre<uency amon9 patients -ith coronary artery disease. Mi"d
hypothyroidism:)1; associated -ith asymptomatic atrophic thyroiditis cou"d predispose patients to
heart disease. Jthers ha#e fai"ed to find increased T> @5 in%patients -ith coronary artery disease:)2;
or increased coronary disease in association -ith thyroiditis.
@"thou9h chronic inf"ammation, "eadin9 to neop"astic transformation, is a -e""%esta5"ished c"inica"
phenomenon, the "in! 5et-een 0ashimoto=s thyroiditis and thyroid cancer remains contro#ersia".
Larson et a". reported that patients -ith 0ashimoto=s thyroiditis -ere three times more "i!e"y to ha#e
thyroid cancer, su99estin9 a stron9 "in! 5et-een chronic inf"ammation and cancer de#e"opment :)2%1;.
P73&8@!t e2pression -as increased in 5oth 0ashimoto=s thyroiditis and -e""%differentiated thyroid
cancer, su99estin9 a possi5"e mo"ecu"ar mechanism for thyroid carcino9enesis.
7n chi"dren, retarded 9ro-th, retarded 5one a9e, decreased hydro2ypro"ine e2cretion, and e"e#ated
cho"estero" "e#e"s may 5e seen :Fi9. $%);.
Fi9ure ). 7dentica" ma"e t-ins -ith 0ashimotoAs thyroiditis -ere photo9raphed at a9e 12. @t a9e $, they
had the same hei9ht and appearance. Durin9 the inter#enin9 ( years, sma"" 9oiters de#e"oped and the
9ro-th of the t-in on the ri9ht a"most stopped. Biopsy indicated 0ashimotoAs thyroiditis in each t-inAs
thyroid.
0ashimoto=s Thyroiditis in 7dentica" T-in BoysS
D.L. -as seen at a9e 12 for fai"ure to 9ro- o#er the past ( years. The patient had an identica" t-in,
-hose de#e"opment up to a9e $ had 5een entire"y norma". Pu5erta" chan9es had de#e"oped at a9e 11.
Fo 9oiter had 5een noted.
Jn physica" e2amination, he -as a short, cooperati#e, pu5erta" 5oy of norma" inte""i9ence, 12* cm in
hei9ht and 3) !9 in -ei9ht. The thyroid 9"and -as smooth and firm, and of norma" si+e. The s!in -as
dry, coo", and mott"ed. 6ef"e2 re"a2ation -as de"ayed. 1stimated T
(
"e#e"s -ere Q ( u98d", and the 2(%
hour 6@7U -as (N. Thyroid scan sho-ed a norma" thyroid 9"and. Bone a9e -as $ years. The
potassium thiocyanate dischar9e test resu"t -as ne9ati#e. Thyroid 5iopsy sho-ed a moderate"y diffuse
"ymphocytic infi"trate -ith "ymphoid 9ermina" centers and a diffuse, dense fi5rous reaction.
6.L. -as seen simu"taneous"y -ith D.L. and -as an acti#e, hea"thy%appearin9 5oy -ith ear"y pu5erta"
chan9es. 0is hei9ht -as 1(* cm, and his -ei9ht -as 3*.C !9. The pu"se -as 10(. The s!in -as norma".
The thyroid 9"and -as en"ar9ed to a5out three times the norma" si+e and -as not nodu"ar. PB7 "e#e"s
-ere '.( and C.2 u98d", and the 2(% hour 6@7U -as 21N. Bone a9e -as 11 years. @ potassium
thiocyanate dischar9e test caused no decrease in nec! radioacti#ity. Biopsy sho-ed diffuse "ymphocytic
infi"tration, "ymphoid fo""ic"es and 9ermina" centers, atrophy of thyroid fo""ic"es, o2yphi"ic cytop"asm,
and dense fi5rosis.
4imi"ar fin9erprints, simi"ar "ip and ear shapes, and identity of 1) 5"ood factors indicated that they -ere
identica" t-ins. There -as no fami"y history of thyroid disease.
7odide !inetic studies sho-ed rapid turno#er of thyroid iodide and production of e2cess <uantities of
p"asma 5utano"%inso"u5"e iodine. 0ema99"utination test resu"ts for T> @5 -ere ne9ati#e, 5ut an
immunof"uorescence assay sho-ed a stron9"y positi#e reaction a9ainst a cytop"asmic anti9en. Bioassay
of the serum for thyroid%stimu"atin9 acti#ity 9a#e a T40%type response.S These patients -ere studied in
cooperation -ith Dr. i""iam 0. Mi"5urn, to -hom -e are 9reat"y inde5ted.
hen 9oiter is induced 5y iodine administration, "ymphocytic thyroiditis is fre<uent"y found and
thyroid autoanti5odies are often present:)3;.
6emission of 0ashimoto=s thyroiditis, -ith "oss of 9oiter, hypothyroidism, and serum thyroid
autoanti5odies, has 5een reported durin9 pre9nancy, -ith re"apse after de"i#ery:)(;. @nti5ody "e#e"s
usua""y fa"" durin9 pre9nancy:));. These phenomena may ref"ect the immunosuppressi#e effects of
pre9nancy. @fter de"i#ery thyroid autoanti5ody "e#e"s rise, and after 2%' months there may 5e sudden
de#e"opment :T return; of 9oiter and hypothyroidism:)';. Concernin9 mana9ement of thyroid
dysfunction durin9 pre9nancy and postpartum, an 1ndocrine 4ociety C"inica" Practice >uide"ine -as
de#e"oped :)'a, Chapter 1(;. Mana9ement of thyroid diseases durin9 pre9nancy re<uires specia"
considerations 5ecause pre9nancy induces ma/or chan9es in thyroid function, and materna" thyroid
disease can ha#e ad#erse effects on the pre9nancy and the fetus. Care re<uires coordination amon9
se#era" hea"thcare professiona"s. @#oidin9 materna" :and feta"; hypothyroidism is of ma/or importance
5ecause of potentia" dama9e to feta" neura" de#e"opment, an increased incidence of miscarria9e, and
preterm de"i#ery. Materna" hyperthyroidism and its treatment may 5e accompanied 5y coincident
pro5"ems in feta" thyroid function. @utoimmune thyroid disease is associated -ith 5oth increased rates
of miscarria9e, for -hich the appropriate medica" response is uncertain at this time, and postpartum
thyroiditis. Fine%need"e aspiration cyto"o9y shou"d 5e performed for dominant thyroid nodu"es
disco#ered in pre9nancy. 6adioacti#e isotopes must 5e a#oided durin9 pre9nancy and "actation.
Uni#ersa" screenin9 of pre9nant -omen for thyroid disease is not yet supported 5y ade<uate studies,
5ut case findin9 tar9eted to specific 9roups of patients -ho are at increased ris! is stron9"y supported.
Jne report recommended screenin9 a"" pre9nant -omen for autoimmune thyroid disease in the first
trimester in terms of cost%effecti#eness :)'5;.
Jf course materna" anti5odies cross the p"acenta, and as in >ra#es= disease, may affect the fetus and
neonate. TPJ and T> @5 typica""y appear to ha#e no ad#erse effect. 4ome e#idence su99ests cytoto2ic
anti5odies, -hich are thou9ht to 5e different from TPJ @5 or T> @5, cou"d cause feta"
hypothyroidism:)C;. 0o-e#er, T4B@5 can rare"y produce neonata" hypothyroidism, -hich is se"f%
"imitin9 o#er (%' -ee!s as the materna" 79> is meta5o"i+ed. omen -ith positi#e TPJ anti5ody 5efore
assisted reproduction ha#e a si9nificant"y increased ris! for miscarria9e, -ith an odds ratio of
3.CC:Poppe, &? >"inoer, D? Tournaye, 0? De#roey, P? #an 4teirte9hem, @? &aufman, L? Ee"!eniers, B.
@ssisted reproduction and thyroid autoimmunity: an unfortunate com5inationT J C"in 1ndocrino"
Meta5 $$ (1(*%(1)2 2003;.
R.L.C., 2(%Rear%J"d oman, Postpartum, Fot%4o%Transient 0ypothyroidism
The patient had menarche at a9e 1' and had re9u"ar periods. 4he married at a9e 2( and -as not a5"e to
concei#e. @fter recei#in9 dana+o" therapy for C months for treatment of e2tensi#e endometriosis, she
5ecame pre9nant and de"i#ered after 3' -ee!s= 9estation. Durin9 the course of this pre9nancy, her
thyroid 9"and -as noted to 5e norma"? no thyroid function tests -ere done. @fter de"i#ery, she nursed
the infant for 1 -ee!. 4he then stopped nursin9, 5ut 9a"actorrhea and amenorrhea continued for the
ne2t ) months. @fter the fourth month, she -as noted to ha#e an en"ar9ed thyroid 9"and? the FT
(
7 -as
found to 5e 3.( :norma", '.0 O 10.); and T40 "e#e" 2C uU8m". There -ere symptoms of mi"d
hypothyroidism, -ith some "o-erin9 of the #oice and increase in fati9ue. @ sister had an o#eracti#e
thyroid and mi"d e2ophtha"mos.
0er thyroid -as estimated to -ei9h a5out (0 9, -ith a smooth surface and an en"ar9ed "o5e. 4!in -as
dry, and there -as some de"ay in the ref"e2 re"a2ation. T>@5 -ere present at a titer of 181'0 and
TPJ@5 at 1820($0. 4erum T
3
"e#e" -as 123 n98d", and the 6@7U -as 1'N at ( hours and 32N at 2(
hours. The thyroid scan -as -ithin norma" "imits. Pro"actin :P6L; "e#e" -as e"e#ated at (3 n98m". 4e""a
turcica U%ray fi"ms and a CT scan of the head -ere norma".
7t -as hypothesi+ed that the patient had postpartum hypothyroidism due to transient e2acer5ation of
thyroiditis and that this condition mi9ht reso"#e spontaneous"y. hether the hyperpro"actinemia,
amenorrhea, and 9a"actorrhea -ere secondary to the hypothyroidism or -ere independent pro5"ems
-as at first unc"ear. The patient -as treated e2pectant"y, since she appeared to 5e in no distress and
there -as no e#idence of pituitary tumor. Jne month after the initia" o5ser#ations, the T40 "e#e" had
fa""en to 13.) uU8m" and the T
3
"e#e" remained at 12' n98d". 1i9ht -ee!s "ater, the FT
(
7 had risen to
).$, the T
3
"e#e" -as 113 n98d", T40 *.1 uU8m", and the P6L remained at '' n98m". Later, a"" test
resu"ts 5ecame norma".
Painless (silent, and Post-artum Thyroiditis
7n the "ast decade se#era" syndromes in#o"#in9 c"inica""y si9nificant, 5ut se"f%"imited, e2acer5ations of
@7TD ha#e 5een de"ineated:)(;%:)*;. 4i"ent :pain"ess; thyroiditis is a syndrome that has a c"inica"
course of thyroid dysfunction simi"ar to su5acute thyroiditis 5ut -ith no anterior nec! pain and no
tenderness of the thyroid. 7nitia""y, patients ha#e a thyroto2ic phase, "ater passin9 throu9h euthyroidism
to hypothyroidism and, fina""y, return to euthyroidism. Postpartum thyroiditis occurs -ithin ' months
after de"i#ery and runs an identica" c"inica" course:)C;. Postpartum thyroiditis is no- considered to 5e
identica" to si"ent thyroiditis, and this term is used for patients -ho de#e"oped si"ent thyroiditis in the
postpartum period:)C;. @fter de"i#ery, other forms of autoimmune thyroid dysfunction a"so occur,
inc"udin9 >ra#es= disease, transient hypothyroidism -ithout precedin9 destructi#e thyroto2icosis, and
persistent hypothyroidism :Fi9. $%';. 7n recent years, the term pain"ess thyroiditis a"so has 5een used
fre<uent"y, and the same disorder has 5een descri5ed usin9 different names, such as thyroto2icosis -ith
pain"ess thyroiditis:'0;, occu"t su5acute thyroiditis:'1;, hyperthyroiditis:'(;, "ymphocytic thyroiditis
-ith spontaneous"y reso"#in9 hyperthyroidism:'2;, pain"ess thyroiditis and transient hyperthyroidism
-ithout 9oiter:'3;, and transient hyperthyroidism -ith "ymphocytic thyroiditis:');. The thyroto2icosis
is induced 5y "ea!a9e of intrathyroida" hormones into the circu"ation caused 5y dama9e to thyroid
epithe"ia" ce""s from inf"ammation. Thus the thyroid radioacti#e iodine upta!e :6@7U; is "o-:)*;.
Therefore, the ear"y phase of thyroto2icosis in si"ent thyroiditis, postpartum thyroiditis, and su5acute
thyroiditis can 5e 9rouped to9ether as destruction%induced thyroto2icosis or simp"y as destructi#e
thyroto2icosis:'';. hen the measurement of radioacti#e iodine upta!e is difficu"t, the measurement of
anti%T40 receptor anti5ody and8or thyroid 5"ood f"o- 5y u"trasono9raphy may 5e usefu" to
differentiate 5et-een destruction%induced thyroto2icosis and >ra#es= thyroto2icosis. The <uantitati#e
measurement 5y po-er Dopp"er u"trasono9raphy -as more effecti#e than that of anti%T40 receptor
anti5ody for differentia" dia9nosis of these t-o types of thyroto2icosis and may omit the radioacti#e
iodine upta!e test :''%1;.
Fi9ure '.
Much e#idence, inc"udin9 histopatho"o9ica" and immuno"o9ica" studies, indicates that this disorder is
an autoimmune thyroid disease:'$;. 7t is 5e"ie#ed to 5e due to autoimmune induced dama9e to the
thyroid causin9 e2cess hormone re"ease, and for this reason is not responsi#e to antithyroid dru9s, &7 or
&CLJ
(
, 5ut does, if treatment is necessary, respond to prednisone:'C;. Durin9 the c"inica" course of
su5c"inica" or #ery mi"d autoimmune thyroiditis, a99ra#atin9 factors cause e2acer5ation of the
destructi#e process. @"" -omen -ith su5c"inica" autoimmune thyroiditis:(0; and antithyroid
microsoma" anti5odies of more than 1:)120 5efore pre9nancy de#e"op postpartum thyroiditis:)C;. @
si9nificant percenta9e of patients -ith si"ent thyroiditis ha#e persona" or fami"y histories of
autoimmune thyroid disease. Most patients ha#e a comp"ete remission, 5ut some de#e"op persistent
hypothyroidism:C0;. 4ome patients ha#e had a"ternatin9 episodes of typica" Lhi9h%upta!eM
thyroto2icosis and episodes of LtransientM "o-%upta!e thyroto2icosis:'*;. 6ecurrence of disease is
common in si"ent thyroiditis 5ut #ery rare in su5acute thyroiditis. Considerin9 a"" these data, it is
assumed that si"ent thyroiditis is caused 5y an e2acer5ation of autoimmune thyroiditis induced 5y
a99ra#atin9 factors. Thyroiditis fre<uent"y recurs, and seasona" a""er9ic rhinitis is reported to 5e an
initiation factor:C1;. Physica""y #i9orous massa9e on the nec! a"so -as reported to 5e a contri5utin9
factor for si"ent thyroiditis:C2;. The pre#a"ence of si"ent thyroiditis, inc"udin9 postpartum disease, is
around ) per cent of a"" types of thyroto2icosis. 4pontaneous si"ent thyroiditis is three times more
fre<uent than postpartum thyroiditis.
@n immune re5ound mechanism has 5een esta5"ished for the induction of postpartum thyroiditis:)C;.
Postpartum thyroid destruction is associated -ith an increase in F& ce"" counts and acti#ity:)C;.
Cessation of steroid therapy has initiated si"ent thyroiditis in a patient -ith autoimmune thyroiditis and
rheumatoid arthritis:C3;, presuma5"y 5ecause this a"so a""o-s immune re5ound. 7n patients -ith
Cushin9=s syndrome -ho ha#e associated su5c"inica" autoimmune thyroiditis, si"ent thyroiditis has
occurred after uni"atera" adrena"ectomy:C(;. Typica""y, pain"ess thyroiditis or destructi#e thyroto2icosis
occurs at 2 to ( months postpartum. The pre#a"ence of postpartum thyroiditis ran9es from 3 to $ per
cent of a"" pre9nancies:)C;.PJ447BL1 P61E1FT7JF JF PPT%7n a randomi+ed prospecti#e contro""ed
study, CC TPJD pre9nant -omen recei#ed 200 u9 se"enomethionine dai"y startin9 at the 12th -ee! of
pre9nancy, and C( TPJD -omen recei#ed a p"ace5o. The treated 9roup had si9nificant"y "o-er TPJ
anti5ody "e#e"s at the end of pre9nancy and durin9 the post%partum -hi"e on treatment. The incidence
of PPT -as reduced from ($.' to 2$.'N in the treated 9roup, and the incidence of permanent
hypothyroidism -as e<ui#a"ent"y reduced. Thyroid hormone "e#e"s did not differ.: Fe9ro 6, >reco >,
Man9ieri T, Pe++arossa @, Da++i D, 0assan 0. The inf"uence of se"enium supp"ementation on
postpartum thyroid status in pre9nant -omen -ith thyroid pero2idase autoanti5odies.J C"in 1ndocrino"
Meta5. 200C @pr?*2:(;:12'3%$;
Hashimotos ene-halo-athy
0ashimoto=s encepha"opathy or encepha"itis is a #ery rare comp"ication of 0ashimoto=s thyroiditis.
Feuro"o9ica" comp"ications are sometimes associated -ith thyroid dysfunction 5ut patients -ith this
encepha"opathy are usua""y euthyroid. 7t is treata5"e, steroid%responsi#e, pro9ressi#e or re"apsin9
encepha"opathy associated -ith e"e#ation of thyroid specific autoanti5odies:C);. This condition -as
first descri5ed in 1*'':C'; and may present as a su5acute or acute encepha"opathy -ith sei+ures and
stro!e%"i!e episodes, often in association -ith myoc"onus and tremor:CC;. 7t is associated -ith
a5norma" 11> and hi9h C4F proteins -ithout p"eocytosis. 4ome patients suffer from a si9nificant
residua" disa5i"ity:C$;. @nti5ody to V%eno"ase has 5een identified in some patients:C*; 5ut this anti5ody
is a"so fre<uent"y found in other autoimmune diseases. 4a-!a et a". reported that this condition is not
caused 5y thyroid dysfunction or antithyroid anti5odies 5ut represents an association of an uncommon
autoimmune encepha"opathy -ith a common autoimmune thyroid disease:$0;. 7dentification of
anti5odies to 5rain specific anti9ens may disc"ose the rea" patho9enesis of this condition. 6ecent"y,
autoanti5odies a9ainst the amino :F0
2
;%termina" of V%eno"ase :referred to as F@1; -ere reported to
5e hi9h"y specific in sera from a "imited num5er of 01 patients :'$%$3N -ith 01? 11N, 2 of 1C -ith
0T -ithout any neuropsychiatric features? none of contro"s H)0 indi#idua"sI inc"udin9 those -ith other
neuro"o9ica" or immuno"o9ica" conditions in#o"#in9 encepha"opathy H2) indi#idua"sI; :$0.1, $0.2;.
4teroid re#ersi5"e cere5ra" hypometa5o"ism -as recent"y documented 5y P1T scannin9 in this
condition. :$0.3;
Hashimotos o-hthalo-athy
Thyroid%associated or5itopathy :T@J; usua""y occurs in >ra#es = s disease -ith hyperthyroidism, and
sometimes in euthyroid and hypothyroid patients. 4ince most euthyroid and hypothyroid patients -ith
or5itopathy are thyrotropin receptor anti5ody :T6@5;%positi#e, they are dia9nosed as ha#in9 euthyroid
>ra#es = disease or hypothyroid >ra#es = disease. hen euthyroid and hypothyroid patients -ith
or5itopathy are T6@5%ne9ati#e 5ut associated -ith 0ashimoto = s thyroiditis, L 0ashimoto=s
ophtha"opathy M may 5e considered :$0.(, $0.);.Because patients -ith 0ashimoto = s thyroiditis test
ne9ati#e for T6@5, other autoanti5odies a9ainst an eye musc"e anti9en, such as ca"se<uestrin,
f"a#oprotein, or >2s are postu"ated :$0.';.
%odide Metabolism and .''ets
Many patients -ith 0ashimoto=s thyroiditis do not respond to in/ected T40 -ith the e2pected increase
in 6@7U or re"ease of hormone from the 9"and:$1;. These findin9s pro5a5"y mean that the 9"and is
partia""y destroyed 5y the autoimmune attac! and is una5"e to au9ment iodine meta5o"ism further.
Further, the thyroid 9"and of the patient -ith 0ashimoto=s disease does not or9anify norma""y:$2; :Fi9.
$%(;. @dministration of (00 m9 potassium perch"orate 1 hour after 9i#in9 a tracer iodide re"eases 20 O
'0N of the 9"andu"ar radioacti#ity. @"so, a fraction of the iodinated compounds in the serum of patients
-ith 0ashimoto=s thyroiditis is not so"u5"e in 5utano", as are the thyroid hormones, 5ut is an a5norma"
peptide%"in!ed iodinated component. This "o-%-ei9ht iodoprotein is pro5a5"y serum a"5umin that has
5een iodinated in the thyroid 9"and. @ simi"ar iodoprotein is a"so found in se#era" other !inds of thyroid
disease, inc"udin9 carcinoma, >ra#es= disease, and one form of 9oitrous cretinism. 7t may 5e formed as
part of the hyperp"astic response. T> is a"so detecta5"e in their serum.
7odide is acti#e"y transported from 5"ood to thyrocytes and recent"y the sodium 8 iodide symporter
:F74; has 5een c"oned. @nti5odies a9ainst F74 -ere found in autoimmune thyroid disease:$3;. This
anti5ody has an inhi5itory acti#ity on iodide transport and may modu"ate the thyroid function in
0ashimoto=s thyroiditis. More recent studies reported rather "o- pre#a"ence :"ess than 10N; of anti%F74
anti5odies in 0ashimoto=s disease and c"inica" re"e#ance is sti"" un!no-n:$(;,:$);.
7n anima" e2periment iodine dep"etion pre#ents the de#e"opment of autoimmune thyroiditis:$';. 7t is
su99ested that mi"d iodine deficiency part"y protect a9ainst autoimmune thyroid disease:$C;, a"thou9h
it is contro#ersia":$$;. 7n a re9ion -here iodine%containin9 food :such as sea-eed; is common, as in
Japan, e2cessi#e dietary iodine inta!e :1000 micro 98day or more; may cause transient hypothyoidism
in patients -ith su5c"inica" autoimmune thyroiditis. This condition is easi"y re#ersi5"e -ith a reduction
in iodine inta!e:$*;. 7odine is important not on"y for thyroid hormone synthesis 5ut a"so for induction
and modu"ation of thyroid autoimmunity. 7n 9enera", iodine deficiency attenuates, -hich iodine e2cess
acce"erates autoimmune thyroiditis in autoimmune prone indi#idua"s:*0;. 7n anima" e2periment, it is
re#ea"ed that enhanced iodination of thyro9"o5u"in faci"itates the se"ecti#e processin9 and presentation
of a cryptic phato9enic peptide in #i#o or in #itro. Moreo#er, it is su99ested that iodine e2cess
stimu"ates thymus de#e"opment and effects function of #arious immune ce""s:*1;.
Dia$nosis
Dia9nosis in#o"#es t-o considerations W the differentia" dia9nosis of the thyroid "esion and the
assessment determination of the meta5o"ic status of the patient.
@ diffuse, firm 9oiter -ith pyramida" "o5e en"ar9ement, and -ithout si9ns of thyroto2icosis, shou"d
su99est the dia9nosis of 0ashimoto=s thyroiditis. Most often the 9"and is 5osse"ated or Lnu55ey.M 7t is
usua""y symmetrica", a"thou9h much #ariation in symmetry :as -e"" as consistency; can occur. The
trachea is rare"y de#iated or compressed. The association of 9oiter -ith hypothyroidism is a"most
dia9nostic of this condition, 5ut is a"so seen in certain syndromes due to defecti#e hormone synthesis or
hormone response, as descri5ed in Chapter *. Pain and tenderness are unusua" 5ut may 5e present. @
rapid onset is a"so unusua", 5ut the 9oiter may rare"y 9ro- from norma" to se#era" times the norma" si+e
in a fe- -ee!s. Most common"y the 9"and is t-o to four times the norma" si+e. 4ate""ite "ymph nodes
may 5e present, especia""y the De"phian node a5o#e the isthmus. Mu"tinodu"ar 9oiter occurs in
si9nificant incidence in adu"t -omen? thus the co%occurrence of mu"tinodu"ar 9oiter and 0ashimoto=s
thyroiditis is not rare, and may pro#ide the findin9 of a 9ross"y nodu"ar 9"and in a patient -ho is mi"d"y
hypothyroid and has positi#e anti5ody tests.
The T
(
concentration and the FT
(
ran9e from "o- to hi9h 5ut are most typica""y in the norma" or "o-
ran9e:*2;. The 6@7U :rare"y re<uired; is #aria5"e and ran9es from 5e"o- norma" to e"e#ated #a"ues,
dependin9 on such factors as T40 "e#e"s, the efficiency of use of iodide 5y the thyroid, and the nature
of the components 5ein9 re"eased into the circu"ation. >amma9"o5u"in "e#e"s may 5e e"e#ated, a"thou9h
usua""y they are norma":*3;. This a"teration e#ident"y ref"ects the presence of hi9h concentrations of
circu"atin9 anti5odies to T>, for an anti5ody concentration as hi9h as ).2 m98m" has 5een reported.
T
(
and FT7 are norma" or "o-:*2;. 4erum T40 ref"ects the patient=s meta5o"ic status. 0o-e#er, some
patients are c"inica""y euthyroid, -ith norma" FT7 and T
3
"e#e"s, 5ut ha#e mi"d"y e"e#ated T40.
hether this Lsu5c"inica" hypothyroidismM represents partia" or comp"ete compensation is a matter of
de5ate. TPJ@5, and "ess fre<uent"y T>@5 are present in serum. 0i9h "e#e"s are dia9nostic of
autoimmune thyroid disease. T>@5 are positi#e in a5out $0N of patients, and if 5oth T>@5 and
TPJ@5 are measured, *CN are positi#e. Roun9 patients tend to ha#e "o-er and occasiona""y ne9ati#e
"e#e"s. 7n this a9e 9roup, e#en "o- titers si9nify the presence of thyroid autoimmunity.
FF@ can 5e a usefu" dia9nostic procedure 5ut is infre<uent"y re<uired, e2cept in patients that seem to
ha#e% or ha#e% a discreet nodu"e in the 9"and. FF@ typica""y re#ea"s "ymphocytes, macropha9es, scant
co""oid, and a fe- epithe"ia" ce""s -hich may sho- 0urth"e ce"" chan9e. 7n this conte2t 0urth"e ce""s do
not represent a discrete adenoma. 0o-e#er if on"y a5undant 0urth"e ce""s dominate the specimen, and
there are fe- or no "ymphocytes or macropha9es, the 5iopsy must 5e interpreted as a possi5"e 0urth"e
ce"" tumor. Biopsy resu"ts are "ess fre<uent"y dia9nostic in chi"dren:*);.
Thyroid isotope scan is not usua""y necessary, 5ut can 5e he"pfu". The ima9e is characteristica""y that of
a diffuse or mott"ed upta!e in an en"ar9ed 9"and, in stri!in9 contrast to the foca" Lco"dM and LhotM areas
of mu"tinodu"ar 9oiter. Foca" "oss of isotope accumu"ation may occur in se#ere"y diseased portions of
the thyroid.
Table /. Guideline 'or the dia$nosis o' Hashimotos thyroiditis (&hroni thyroiditis,
0 1ome liniians dont use the term Hashimotos thyroiditis i' -atients ha"e no $oiter, althou$h
assoiation o' -ositi"e antibodies and lym-hoyti in'iltration in the thyroid $land #as -ro"ed by
histolo$ial e2amination.
1. C"inica" findin9s Diffuse s-e""in9 of the thyroid 9"and -ithout any other cause :such as
>ra#es= disease;
2. La5oratory findin9s
1. Positi#e for anti%thyroid microsoma" anti5ody or anti%thyroid pero2idase:TPJ; anti5ody
2. Positi#e for anti%thyro9"o5u"in anti5ody
3. Lymphocytic infi"tration in the thyroid 9"and confirmed -ith cyto"o9ica" e2amination
1. @ patient sha"" 5e said to ha#e 0ashimoto=s thyroiditis if he8she has satisfied c"inica" criterion
and any one "a5oratory criterion.Fotes
1. @ patients sha"" 5e suspected to ha#e 0ashimoto=s thyroiditis, if he8she has primary
hypothyroidism -ithout any other cause to induce hypothyroidism.
2. @ patient sha"" 5e suspected to ha#e 0ashimoto=s thyroiditis, if he8she has anti%thyroid
microsoma" anti5ody and8or anti%thyro9"o5u"in anti5ody -ithout thyroid dysfunction
nor 9oiter formation.S
3. 7f a patient -ith thyroid neop"asm has anti%thyroid anti5ody 5y chance, he or she shou"d
5e considered to ha#e 0ashimoto=s thyroiditis.
(. @ patient is possi5"e to ha#e 0ashimoto=s thyroiditis if hypoechroic and8or
inhomo9eneous pattern is o5ser#ed in thyroid u"trasono9raphy.
U"trasound may disp"ay an en"ar9ed 9"and -ith norma" te2ture, a characteristic picture -ith #ery "o-
echo9enicity, or a su99estion of mu"tip"e i""%defined nodu"es. Dia9nostic 9uide"ines made 5y The Japan
Thyroid @ssociation are sho-n in Ta5"e $%2. The f"o- chart of dia9nosis is sho-n in Fi9ure $%C.The
incidenta" findin9 of diffuse"y increased :1$;F%FD> upta!e in the thyroid 9"and is most"y associated
-ith chronic "ymphocytic :0ashimoto=s; thyroiditis and does not seem to 5e affected 5y thyroid
hormone therapy :*).1;.
Di''erential Dia$nosis
0ashimoto=s thyroiditis is to 5e distin9uished from nonto2ic nodu"ar 9oiter or >ra#es= disease. The
presence of 9ross nodu"arity is stron9 e#idence a9ainst 0ashimoto=s thyroiditis, 5ut differentiation on
this 5asis is not infa""i5"e. 7n mu"tinodu"ar 9oiter, thyroid function test resu"ts are usua""y norma", and
the patient is on"y rare"y c"inica""y hypothyroid. Thyroid autoanti5odies tend to 5e a5sent or titers are
"o-, and the scan resu"t is typica". FF@ can reso"#e the <uestion 5ut is usua""y unnecessary. 7n fact, the
t-o conditions <uite common"y occur to9ether in adu"t -omen. hether this is 5y chance, or due to the
effect of thyroid 9ro-th stimu"atin9 anti5odies :or other causes; is un!no-n.
Moderate"y and diffuse"y en"ar9ed thyroid 9"ands in teena9ers are usua""y the resu"t of thyroiditis, 5ut
some may 5e true ado"escent 9oiters? that is, the en"ar9ement may resu"t from moderate hyperp"asia of
the thyroid 9"and in response to a temporari"y increased demand for hormone. This condition is more
often dia9nosed than pro#ed. Thyroid function test resu"ts shou"d 5e norma". @nti5ody assays may
reso"#e the issue. The dia9nosis can 5e sett"ed -ith certainty on"y 5y a 5iopsy disc"osin9 norma" or
hyperp"astic thyroid tissue and a5sence of findin9s of thyroiditis. The possi5i"ity of co""oid 9oiter may
5e entertained in the differentia" dia9nosis. Co""oid 9oiter is a definite patho"o9ic entity, as descri5ed in
Chapter 1C. Presuma5"y it is the restin9 phase after a period of thyroid hyperp"asia.
Tumor must a"so 5e considered in the differentia" dia9nosis, especia""y if there is rapid 9ro-th of the
9"and or persistent pain. The diffuse nature of autoimmune thyroiditis, the characteristic
hypothyroidism and in#o"#ement of the pyramida" "o5e are usua""y sufficient for differentiation. FF@ is
indicated if there is uncertainty. 0o-e#er, it must 5e remem5ered that "ymphoma or a sma""%ce""
carcinoma of the thyroid can 5e and has 5een mista!en for 0ashimoto=s thyroiditis. C"usters of nodes at
the upper po"es stron9"y su99estin9 papi""ary cancer may disappear -hen thyroid hormone rep"acement
therapy is 9i#en. 0o-e#er, -e ha#e seen a sufficient num5er of patients -ith 5oth thyroiditis and tumor
to !no- that one dia9nosis in no -ay e2c"udes the other. Thyroid "ymphoma must a"-ays 5e
considered if there is continued :especia""y asymmetric; en"ar9ement of a 0ashimoto=s 9"and, or if pain,
tenderness, hoarseness, or nodes de#e"op. Thyroiditis is a ris! factor for thyroid "ymphoma, a"thou9h
the incidence is #ery "o-. Thyroid "ymphoma de#e"ops in most cases in 9"ands -hich har5or
thyroiditis. Distin9uishin9 thyroid "ymphoma from 0ashimoto=s thyroiditis is sometimes <uite difficu"t
6e#erse transcription%po"ymerase chain reaction :6T%PC6; detectin9 the monoc"ona"ity of
immuno9"o5u"in hea#y chain m6F@ is usefu" for differentiation 5et-een the t-o:**;. This condition
and its mana9ement are discussed in Chapter 1$.
Jccasiona""y the picture of 0ashimoto=s thyroiditis 5"ends rather impercepti5"y into that of
thyroto2icosis, and some patients ha#e symptoms of mi"d thyroto2icosis, 5ut then de#e"op typica"
0ashimoto=s thyroiditis. 7n fact, it is 5est to thin! of >ra#es= disease and 0ashimoto=s thyroiditis as t-o
#ery c"ose"y re"ated syndromes produced 5y thyroid autoimmunity. Cate9ori+ation depends on
associated eye findin9s and the meta5o"ic "e#e", 5ut the patho9enesis, histo"o9ic picture, and function
may o#er"ap.
Li!e-ise, -e ha#e seen patients -ho appear to ha#e a mi2ture of 0ashimoto=s thyroiditis and su5acute
thyroiditis, -ith 9oiter, positi#e thyroid autoanti5odies, norma" or "o- FT
(
, and 5iopsies -hich ha#e
su99ested 0ashimoto=s on one occasion and inc"uded 9iant ce""s on another. @ form of painfu" chronic
thyroiditis -ith amy"oid infi"tration has a"so 5een descri5ed, and is pro5a5"y etio"o9ica""y distinct from
0ashimoto=s thyroiditis:100;.
Thera-y
Many patients need no treatment, for fre<uent"y the disease is asymptomatic and the 9oiter is sma"".
This approach is /ustified 5y the study of Eic!ery and 0am"in:101;, -ho found, on 5oth c"inica" and
patho"o9ic 9rounds, that the disease may remain static and the c"inica" condition unchan9ed o#er many
years.
7f the 9oiter is a pro5"em 5ecause of "oca" pressure symptoms, or is unsi9ht"y, thyroid hormone therapy
is indicated. Thyroid hormone often causes a 9ratifyin9 reduction in the si+e of the 9oiter after se#era"
months of treatment:100;. e ha#e 5een especia""y impressed -ith this resu"t in youn9 peop"e. 7t seems
"i!e"y that in o"der patients there may 5e more fi5rosis and therefore "ess tendency for the thyroid to
shrin!. 7n youn9 patients the response often occurs -ithin 2 O ( -ee!s, 5ut in o"der ones the thyroid
decreases in si+e more 9radua""y. @!soy et a" :100a; report that Lprophy"acticM thyroid hormone
treatment is associated after 1) months -ith a decrease in thyroid si+e and in thyroid anti5ody "e#e"s.
Thyroid hormone in a fu"" rep"acement dose is, of course, indicated if hypothyroidism is present.
Therapy is pro5a5"y indicated if the T40 "e#e" is e"e#ated and the FT
(
is "o- norma", since the onset of
hypothyroidism is predicta5"e in such patients. There is no e#idence that thyroid rep"acement actua""y
ha"ts the on9oin9 process of thyroiditis, 5ut in some patients recei#in9 treatment, anti5ody "e#e"s
9radua""y fa"" o#er many years:102;.
Fi9ure C. Dia9nosis of 0ashimoto=s thyroiditis :chronic thyroiditis;
The dosa9e of thyro2ine shou"d norma""y 5e that re<uired to 5rin9 the serum T40 "e#e" to the "o-
norma" ran9e, such as .3 O 1 uU8m". This is typica""y achie#ed -ith 1 u9 L%T
(
8"5 5ody -ei9ht8day,
ran9es from C) O 12) u98day in -omen, and 12) O 200 u98day in men. 7t is sensi5"e to initiate therapy
-ith a partia" dose, since in some instances the thyroid 9"and may 5e nonsuppressi5"e e#en thou9h
functionin9 at a "e#e" 5e"o- norma". Jnce thyro2ine treatment is initiated, it is re<uired indefinite"y in
most patients. 0o-e#er, it has 5een found that up to 20N of initia""y hypothyroid indi#idua"s -i"" "ater
reco#er and ha#e norma" thyroid function if cha""en9ed 5y rep"acement hormone -ithdra-a". This may
represent su5sidence of cytoto2ic anti5odies, modu"ation of T4B@5, or some other mechanism:22;.
These indi#idua"s can 5e identified 5y administration of T60, -hich -i"" induce an increase in serum T
(
and T
3
if the thyroid has reco#ered:103;. 6ep"acement T
(
therapy shou"d 5e ta!en se#era" hours
5efore or after medications such as cho"estero" 5indin9 resins, carafate, and F4J(, -hich can reduce
a5sorption:10(;. :4ee Chapter *; @utoimmune disease is usua""y ta!es an on9oin9 process and
0ashimoto=s thyroiditis de#e"ops into hypothyroidism. 6ecent tria" of prop"y"actic treatment -ith T
(

:1.0 X 2.0Y98&98day; for one year in euthyroid patients -ith 0ashimoto=s thyroiditis sho-ed decrease
of anti%TPJ anti5odies and thyroid B%"ymphocytes:10);, su99estin9 prophy"actic T
(
therapy mi9ht 5e
usefu" to stop pro9ression of disease. The "on9%term c"inica" 5enefit shou"d 5e esta5"ished in the
future.hether or not su5c"inica" hypothyroidism shou"d 5e treated is sti"" under de5ate :see Chapter
*.10 4UBCL7F7C@L 0RPJT0R6J7D74M;. Cardiac dysfunction may 5e associated -ith su5c"inica"
hypothyroidism, e#en -hen serum T40 is sti"" in the norma" ran9e. These a5norma"ities are re#ersi5"e
-ith "%T
(
rep"acement therapy :22%1;.
7n some instances the acute onset of the disease, in association -ith pain, has prompted therapy -ith
9"ucocorticoids. This treatment a""e#iates the symptoms and impro#es the associated 5iochemica"
a5norma"ities, and in some studies has 5een sho-n to increase p"asma T
3
and T
(
"e#e"s 5y suppression
of the autoimmune process:10';. B"i++ard and co%-or!ers:10C; ha#e 9i#en steroids o#er se#era"
months to chi"dren in an attempt to suppress anti5ody production and possi5"y to achie#e a permanent
remission. The adrenocortica" hormones dramatica""y depress c"inica" acti#ity of the disease and
anti5ody titers, 5ut a"" return to pre%therapy "e#e"s -hen treatment is -ithdra-n. e cannot recommend
steroid therapy for this condition 5ecause of the undesira5"e side effects of the dru9. Ch"oro<uine has
5een reported in one study to reduce anti5ody titers:10$;. Because of to2icity, its use is not ad#ised. U%
ray therapy a"so resu"ts in a decrease in 9oiter si+e, and fre<uent"y in my2edema, 5ut shou"d not 5e used
5ecause of the possi5"e induction of thyroid carcinoma.
41L1F7UM% 7n a randomi+ed prospecti#e contro""ed study, CC TPJD pre9nant -omen recei#ed 200 u9
se"enomethionine dai"y startin9 at the 12th -ee! of pre9nancy, and C( TPJD -omen recei#ed a
p"ace5o. The treated 9roup had si9nificant"y "o-er TPJ anti5ody "e#e"s at the end of pre9nancy and
durin9 the post%partum -hi"e on treatment. The incidence of PPT -as reduced from ($.' to 2$.'N in
the treated 9roup, and the incidence of permanent hypothyroidism -as e<ui#a"ent"y reduced. Thyroid
hormone "e#e"s did not differ. This one report is certain"y most interestin9, 5ut needs confirmation
5efore this treatment can 5e su99ested for 9enera" app"ication :10$.1;. Confirmin9 ear"ier studies, in
0ashimoto = s patients, 200 mu9 4e in the form of "%se"enomethionine ora""y for ' months caused a
si9nificant decrease of 21N in serum anti%TPJ "e#e"s. Cessation caused an increase in the anti%TPJ
concentrations.:10$.2;. @ s"i9ht"y opposin9 study, ho-e#er, has reported no immuno"o9ica" 5enefit of
se"enium in patients -ith moderate disease acti#ity :in terms of TPJ@5 and cyto!ine production
patterns; may not :e<ua""y; 5enefit as patients -ith hi9h disease acti#ity :10$.3;. 4e"enium
responsi#eness may 5e different amon9 patients -ith 0ashimoto = s thyroiditis.
1ur$ery has 5een used as a method of therapy. This treatment, of course, remo#es the 9oiter 5ut
usua""y resu"ts in hypothyroidism. e 5e"ie#e that it is not indicated un"ess si9nificant pain, cosmetic,
or pressure symptoms remain after a fair tria" of thyroid therapy, and pro5a5"y steroid therapy, 5ut is
appropriate in some cases. @mon9 patients -ith postpartum thyroid dysfunction, the most common
type is destructi#e thyroto2icosis and simp"e symptomatic treatment, usin9 5eta%adrener9icO
anta9onists, is usua""y sufficient:10*;. 7n the case of postpartum hypothyroidism, rep"acement -ith a
su5ma2ima" dose of T
3
is usefu" to re"ie#e symptoms more <uic!"y and to predict spontaneous
reco#ery -hich is detected 5y an increase of T
(
.
4ome patients do not fit easi"y into the usua" dia9nostic cate9ories? accordin9"y, choosin9 an
appropriate course of therapy is more difficu"t. Fre<uent"y, it is impossi5"e to differentiate 0ashimoto=s
thyroiditis from mu"tinodu"ar 9oiter short of performin9 an open 5iopsy. 7n these cases, if there is no
su99estion of carcinoma, it is "o9ica" to treat the patient -ith hormone rep"acement and to o5ser#e
c"ose"y. @ reduction in the 9oiter /ustifies continuation of the therapy, e#en in the a5sence of a
dia9nosis.
7n some patients, especia""y teena9ers, the e2amination disc"oses peri%thyroida" "ymph nodes or an
apparent discrete nodu"e, in addition to the diffuse"y en"ar9ed thyroid of 0ashimoto=s thyroiditis. 4uch
nodu"es shou"d 5e e#a"uated 5y FF@, u"trasound and possi5"y scintiscan. Thyroid hormone treatment
may cause re9ression of the nodes or nodu"e. 7f after fu"" e#a"uation uncertainty persists, if nodes
remain present, or if a nodu"e 9ro-s, sur9ica" e2p"oration is indicated.
Treatment of chi"dren and ado"escents -ith 1.3u98!98day thyro2ine for 2( months -as sho-n in a
recent study to cause si9nificant reduction in thyroid si+e in patients -ith @utoimmune thyroiditis, 5ut
not affect anti5ody "e#e"s, or si9nificant"y a"ter T40 or freeT
(
. :110;
Jccasiona""y, symptoms of serositis or arthritis su99est the coincident occurrence of another
autoimmune disorder. e ha#e 9i#en thyroid hormone to decrease thyroid acti#ity and possi5"y reduce
a tendency to anti5ody formation, and ha#e treated the 9enera"i+ed disorder independent"y as indicated.
1ummary
0ashimoto=s thyroiditis is characteri+ed c"inica""y as a common"y occurrin9, pain"ess, diffuse
en"ar9ement of the thyroid 9"and occurrin9 predominant"y in midd"e%a9ed -omen. The patients are
often euthyroid, 5ut hypothyroidism may de#e"op. The thyroid parenchyma is diffuse"y rep"aced 5y a
"ymphocytic infi"trate and fi5rotic reaction? fre<uent"y, "ymphoid 9ermina" fo""ic"es are #isi5"e.
@ttention has 5een focused on this process 5ecause of the demonstration of autoimmune phenomena in
most patients. Persons -ith 0ashimoto=s thyroiditis ha#e serum anti5odies reactin9 -ith T>, TPJ, and
a9ainst an unidentified protein present in co""oid. 7n addition, many patients ha#e ce"" mediated
immunity directed a9ainst thyroid anti9ens, demonstra5"e 5y se#era" techni<ues. Ce"" mediated
immunity is a"so a feature of e2perimenta" thyroiditis induced in anima"s 5y in/ection of thyroid anti9en
-ith ad/u#ants.
@"" theories a"so emphasi+e a 5asic a5norma"ity in the immune sur#ei""ance system, -hich in some -ay
a""o-s autoimmunity to de#e"op a9ainst thyroid anti9ens, and as -e"" a9ainst other tissues, inc"udin9
stomach, adrena", and o#aries, in many patients -ith thyroiditis.
e su99est that 0ashimoto=s thyroiditis, primary my2edema, and >ra#es= disease are different
e2pressions of a 5asica""y simi"ar autoimmune process, and that the c"inica" appearance ref"ects the
spectrum of the immune response in the particu"ar patient. This response may inc"ude cytoto2ic
anti5odies, stimu"atory anti5odies, 5"oc!in9 anti5odies, or ce"" mediated immunity. Thyroto2icosis is
#ie-ed as an e2pression of the effect of circu"atin9 thyroid stimu"atory anti5odies. 0ashimoto=s
thyroiditis is predominant"y the c"inica" e2pression of ce"" mediated immunity "eadin9 to destruction of
thyroid ce""s, -hich in its se#erest form produces thyroid fai"ure and idiopathic my2edema.
The c"inica" disease is more fre<uent than >ra#es= Disease -hen mi"d cases are inc"uded. The incidence
is on the order of three to si2 cases per 10,000 popu"ation per year, and pre#a"ence amon9 -omen is at
"east 2N.
The 9"and in#o"#ed 5y thyroiditis tends to "ose its a5i"ity to store iodine, produces and secretes
iodoproteins that circu"ate in p"asma, and is inefficient in ma!in9 hormone. Thus, the thyroid 9"and is
under increased T40 stimu"ation, fai"s to respond to e2o9enous T40, and has a rapid turno#er of
thyroida" iodine.
Dia9nosis is made 5y the findin9 of a diffuse, smooth, firm 9oiter in a youn9 -oman, -ith stron9"y
positi#e titers of T> @5 and8or TPJ @5 and a euthyroid or hypothyroid meta5o"ic status.
@ patient -ith a sma"" 9oiter and euthyroidism does not re<uire therapy un"ess the T40 "e#e" is
e"e#ated. The presence of a "ar9e 9"and, pro9ressi#e 9ro-th of the 9oiter, or hypothyroidism indicates
the need for rep"acement thyroid hormone. 4ur9ery is rare"y indicated. De#e"opment of "ymphoma,
thou9h #ery unusua", must 5e considered if there is 9ro-th or pain in the in#o"#ed 9"and.
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