Autoimmune thyroid disease: old and new players

12 Pages·2014·0.29 MB·English

GEffraimidisand Autoimmunethyroiddisease: 170:6 R241–R252
Review
WMWiersinga oldandnewplayers
MECHANISMS IN ENDOCRINOLOGY
Autoimmune thyroid disease:
old and new players
Correspondence
GrigorisEffraimidisandWilmarMWiersinga
shouldbeaddressed
toWMWiersinga
DepartmentofEndocrinologyandMetabolism,AcademicMedicalCenter,RoomF5-169,UniversityofAmsterdam,
Email
Meibergdreef9,Amsterdam1105AZ,TheNetherlands
[email protected]
Abstract
Thelast10yearshaveseensomeprogressinunderstandingtheetiologyofautoimmunethyroiddisease(AITD).Thefemale
preponderancecannowbeexplained–atleastinpart–byfetalmicrochimerismandX-chromosomeinactivation.The
numberofidentifiedsusceptibilitygenesforAITDisincreasing(amongothersnowincludingTSHR,TG,HLA,CTLA4,PTPN22,
CD40,FCRL3,IL2RA,andFOXP3),butthesegenestogetherprobablydonotexplainmorethanabout10%oftheheritability
y
og ofAITD.Astwinstudiesindicatethatgenescontributefor70%ofAITD,itfollowsthattheremustbemanymoreloci,eachof
ol
n themcontributingalittle.Whilethegeneticstudieshaveclarifiedwhyvariousautoimmunediseasessooftenclusterinthe
ri
oc samepatient,themolecularmechanismofactionofthesegeneticpolymorphisms(frequentlylocatedinintrons)hashardly
d
n beenexplained.PolymorphismsinAITDsusceptibilitygenesmaybecomehelpfulinclinicalpractice,e.g.inassessingriskof
E
of recurrentGraves’hyperthyroidism(GH)afteracourseofantithyroiddrugs.Moderatealcoholintakedecreasestheriskon
nal overtGHandovertHashimoto’shypothyroidism.Currentsmokers–aswellknown–areatincreasedriskforGraves’disease,
r
ou but–surprisingly–atdiminishedriskforHashimoto’sthyroiditis.LowseleniumandlowvitaminDlevelsmightincreasethe
J
n riskofdevelopingAITD,butdataarestillinconclusive.Currentoptionsforpreventiveinterventionsinsubjectsatriskto
a
e
p developAITDareverylimited.
o
r
u
E
EuropeanJournalof
Endocrinology
(2014)170,R241–R252
Introduction
Autoimmunethyroiddisease(AITD)isamultifactorialor other end. Thyroid peroxidase (TPO) and thyroglobulin
so-called ‘complex’ disease in which autoimmunity (Tg) are the major autoantigens in Hashimoto’s disease,
against thyroid antigens develops against a particular but TPO-Ab and Tg-Ab occur also in w70% of patients
genetic background facilitated by exposure to environ- with Graves’ disease. The thyroid-stimulating hormone
mental factors (Fig. 1). AITD encompasses a spectrum of receptor (TSHR) is the major autoantigen in Graves’
conditions ranging from Hashimoto’s hypothyroidism disease, but TSHR antibodies occur also in some patients
(HH) at one end to Graves’ hyperthyroidism (GH) at the with Hashimoto’s disease. Graves’ and Hashimoto’s
InvitedAuthor’sprofile
W M Wiersinga MD, PhD is Professor Emeritus of Endocrinology at the University of Amsterdam in The
Netherlands. He was Chair of the Division of Endocrinology and Metabolism in the Academic Medical Center,
Amsterdamfrom1995to2008.HeispastpresidentoftheEuropeanThyroidAssociationandservedontheExecutive
Committee of the European Society of Endocrinology. His research interests are autoimmune thyroid diseases in
particularGraves’ophthalmopathy(hewasoneofthefoundersofEUGOGO),nonthyroidalillnesssyndrome,and
amiodarone.
www.eje-online.org (cid:1)2014EuropeanSocietyofEndocrinology PublishedbyBioscientificaLtd.
DOI:10.1530/EJE-14-0047 PrintedinGreatBritain
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WMWiersinga oldandnewplayers
withatransientriseinthyroidantibodies.Thepostpartum
Autoimmune thyroid disease
period carries a risk for the onset of Graves’ disease
although the risk might have been overestimated (2),
Environment Genes
and post partum thyroiditis is often the forerunner of
Smoking TSHR
Alcohol TG permanent autoimmune hypothyroidism (3). In the
Selenium HLA
prospectiveAmsterdamAITDcohortstudy,theprevalence
Vitamin D CTLA4
Iodine PTPN22 of pregnancy and post partum was higher in those
Stress CD40
Infections FCRL3 developing overt hyper-/hypothyroidism than in those
Drugs IL2RA remaining euthyroid (4). Parity as a risk factor for AITD
FOXP3
hasreceivedmuchattentioninrelationtofetalmicrochi-
Existential factors merism. There is transfer of fetal cells into the maternal
Female sex circulation, already in the first trimester. Fetal micro-
Parity
XCI chimerism results when fetal cells persist in maternal
tissues, and it is hypothesized that maternal immune
responses against foreign fetal antigens might trigger
Figure1 autoimmune diseases. Fetal microchimerism has indeed
Venndiagramillustratingthemultifactorialetiologyof beenfoundinbloodandthyroidtissuefromwomenwith
autoimmunethyroiddisease. Hashimoto’s or Graves’ disease (5). Using parity as a
surrogate for increasing fetal cell exposure, one would
y diseasessharesomebutnotallknownAITDsusceptibility
g expectthehigherthenumberofpregnanciesis,thehigher
o
ol genes. Similarly, for environmental exposures: one thefrequencyand/orconcentrationofthyroidantibodies
n
cri environmental factor may constitute a risk for both willbe.However,theresultshavebeenconflicting.Several
o
d Graves’ and Hashimoto’s diseases or for just one of
n population-basedstudieshaveobservedthattherewasno
E them, but another factor can be risky for Graves’ disease
of association between parity and TPO-Ab any longer after
nal butprotectiveforHashimoto’sdisease.Inthisreview,we adjustment for maternal age and other important con-
r focusonwhathasbeenlearntinthelast10yearsonthe
ou founders (6, 7, 8). Other equally large studies do report
J etiology of AITD: Is the predilection for female gender
n associations that remain significant after adjustments,
ea better understood? Have new susceptibility genes been
p using higher cutoff values for TPO-Ab positivity. Odds
o detected? And has progress been made with respect to
ur ratio (OR) for AITD (defined as TPO-Ab O200kU/l) was
E environmental insults? Have there been new players in
increased in women with R1 pregnancy compared with
thisfield,orhaveremainingissueswitholdplayers been
nulliparous women (OR, 1.8; 95% CI, 1.0–3.3) (9).
clarified?Finally,ifindividualsareatrisktodevelopAITD
In another study, the trend analysis for risk of TPO-Ab
inviewoftheirfamilyhistoryofAITD,isthereanything
with increasing parity was significant only at TPO-Ab
theycandointermsofAITDprevention?
O500kU/l and not at lower levels (10). In a population-
based Danish cohort, women with children, compared
with childless women, were at a relative risk of 1.11
Existential factors
(1.08–1.14) for autoimmune diseases with female pre-
There is a strong female preponderance among AITD dominance; associations with parity were found for
patients, with a female:male ratio ranging from 5:1 to Hashimoto’s thyroiditis (1.11; 1.00–1.24) and Graves’
10:1.Thebiologicexplanationofthegenderdifferencehas disease (1.19; 1.14–1.24) (11). Taken together, the data
puzzledphysiciansforalongtime,andonlyrecentlythere suggest that parity is somehow involved in the deve-
havebeensomeclues. lopment of AITD but only to a modest extent, and
parity explains only partially the female preponderance
Parity
of AITD. Fetal microchimerism might contribute, but its
During pregnancy the serum concentrations of thyroid effectisratherlimited.Thepotentialroleofmicrochimer-
antibodies decrease, related to generation of maternal ism in developing thyroid autoimmunity is further
regulatoryT-cells(T )earlyinpregnancythatmaintaina supported by twin studies: both female and male twins
reg
stateoftolerancetofetalalloantigensinordertoprevent of opposite-sex pairs, as opposed to monozygotic pairs,
rejectionofthefetus(1).Afterdelivery,thereisarebound haveanincreasedfrequencyofthyroidantibodies(12).
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WMWiersinga oldandnewplayers
X-chromosomeinactivation cells, but also B-cells) to T-cell receptors on T-cells.
Polymorphisms in these genes are not specific for AITD,
In female mammalian cells, one of the two X chromo-
as they also confer susceptibility for other autoimmune
somesisinactivatedinearlyembryoniclife.Femaletissues
diseases. A single amino acid variation in the peptide-
are thus mosaics of two cell lines, one with the paternal
binding cleft of HLA-DR, resulting in an arginine residue
and the other with the maternal X chromosome as the
at position 74 of the b-chain, is strongly associated with
active X. Usually, there is a random 50:50 ratio of the
Graves’disease.AninteractionwiththeSNPinexon33of
two cell lines. A skewed X-chromosome inactivation
TG has been described, suggesting that HLA-DRb-Arg74
(XCI)isdefined–arbitrarily–asinactivationofthesame
presents the disease-associated TG SNP alleles more
X chromosome in R80% of cells (13). The consequence
efficientlytoT-cells:anexampleofgene–geneinteraction
could be that self-antigens on one X chromosome are
resultinginsynergism(19,21).Manymoresusceptibility
notexpressed atsufficientlyhighlevelsinthethymusor
loci have been detected since 2005 by genome-wide
at peripheral sites involved in tolerance induction. Loss
association studies (22). Among these are HLA class I
of immunological tolerance to X-linked antigens might
molecules, which present endogenous antigens to the
induce autoimmunity. Several studies have shown that
immune system (including those derived from viruses
skewed XCI is associated with an increased risk of
which are possible environmental triggers for AITD).
developing AITD. A meta-analysis confirmed significant
HLA-C demonstrated a much stronger association with
skewingofXCIinwomenwithGraves’disease(OR,2.54;
Graves’diseaseinCaucasiansthanHLA-DRB1,DQA1,and
95% CI, 1.58–4.10) and Hashimoto’s disease (OR, 2.40;
DQB1, with HLA-C*07 predisposing and HLA-C*03 and
95% CI, 1.10–5.26) (14). The epigenetic phenomenon of
y HLA-C*16 being protective; HLA-B was found to be
g skewed XCI may, in part, explain the strong female
o
nol preponderanceinAITD. associated independent of HLA-C (23). In Han Chinese,
ri HLA-B was a risk factor for Hashimoto’s disease (24).
c
o
d CD40, a co-stimulator of antigen-presenting cells, is also
n
E expressedonnonimmunecellssuchasthyrocytes.AnSNP
f Genetic factors
o
al intheKozaksequenceofCD40isassociatedwithGraves’
n
r SusceptibilitygenesforAITDcanbedividedintothyroid- disease in Caucasians and Koreans, but not in Taiwanese
u
o
J specific genes and immunoregulatory genes. Identified (19, 25). It increases the expression of CD40 mRNA and
n
ea thyroid-specificgenesareTSHRandTG,butnotTPO.One proteininthethyroid.ApolymorphismintheFcreceptor-
p
o explanation for this discrepancy could be that TSHR and like 3 gene (FCRL3) is predisposing for several auto-
r
u
E TG (but not TPO) are polymorphic. Single-nucleotide immune diseases including Graves’ disease, in both
polymorphisms (SNPs) in TSHR have been specifically Caucasians and Chinese Han population (26, 27). The
associatedwithGraves’diseaseandnotwithautoimmune associationwithFCRL5issecondarytotheeffectofFCRL3
hypothyroidism in a Caucasian population (15, 16), (26). The gene encodes for a member of the immuno-
although more recently associations with Hashimoto’s globulinreceptorsuperfamily,expressedonB-cells.FCRL3
thyroiditis as well are described in a Chinese Han polymorphisms may be involved in the pathogenesis of
population (17). The functional consequences of these Graves’ disease by excessive inhibition of B-cell receptor
intronicSNPsarenotentirelyclear.Theycouldgiveriseto signaling and the impairment of suppressing function of
RNA splice variants, increasing the level of potential T (27). Two other genes, IL2RA and FOXP3, encode
reg
autoantigenic TSHR-A subunits (16). Alternatively, SNP markers for T -cells and are involved in immunological
reg
carriers may have fewer thymic TSHR mRNA transcripts, tolerance. CD25 is a marker for the interleukin 2 (IL2)
which may decrease central tolerance to TSHR (18). receptorachainpresentpredominantlyonCD25CT-cells,
Multiple SNPs in TG have been associated with both and it is a susceptibility locus for Graves’ disease (28).
Graves’andHashimoto’sdiseases,butSNPsarelocatedin FOXP3 encodes a forkhead/winged helix transcription
exons in Caucasians and in introns in Japanese (19, 20). factor expressed in naturally arising T , committing
reg
The immunoregulatory genes HLA class II, CTLA4, and na¨ıve T-cells to become T . Mutations in FOXP3 result
reg
PTPN22werealreadyrecognizedasriskfactorsinthe20th in the fatal immunodysregulation, polyendocrinopathy,
century by case–control studies. They are all involved in enteropathy, X-linked (IPEX) syndrome. Polymorphisms
the immunological synapse, in which antigenic peptides in FOXP3 have been associated with AITD in Caucasians
complexed in HLA molecules are presented by antigen- (especiallywithGraves’diseasedevelopingbelowtheage
presenting cells (not only macrophages and dendritic of 30 years) but not in Japanese (29, 30). The location of
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WMWiersinga oldandnewplayers
FOXP3 on the X chromosome might contribute to the The OR for Graves’ ophthalmopathy is even higher: OR
femalepreponderanceofAITD.Mutationsinautoimmune 4.40(95%CI,2.88–6.73)ineversmokersvsneversmokers.
regulator (AIRE) gene, expressed in thymic medullary Theriskdisappearsafewyearsaftercessationofsmoking:
epithelial cells, result in failure to present self-antigens theORforGraves’diseaseinex-smokersvsneversmokers
correctlyinthethymusleadingtoalossofself-tolerance is 1.41 (95% CI, 0.77–2.58), not significant any longer.
and thereby to autoimmune polyglandular syndrome These figures were already published in a 2002 meta-
type 1. However, AIRE mutations are rarely present in analysis,whichatthattimealsoconcludedthatsmoking
adult AITD patients (in about 0.3–0.6% of patients with was not associated with hypothyroidism (37). In the last
Graves’ disease and autoimmune hypothyroidism); thus few years, however, convincing evidence has been
AIRE is not considered as a susceptibility gene contribu- obtained that current smoking protects against (auto-
ting to the more common autoimmune endocrinopathies immune) hypothyroidism. Although smoking is an old
(31,32).Genome-wideassociationstudiescontinuetodetect player in the relation between environmental exposures
additionalgenesandlociconferringriskforAITD(21). and autoimmunity, the discovery of its protective effect
What can be learnt from this multitude of genetic allows the label ‘new player’ (Fig. 2). The evidence is
studies? First, it has provided a deeper insight into the derived from large cross-sectional population-based sur-
molecular mechanisms involved in the immunopatho- veys and from prospective observational studies. In
genesis of AITD. But at the same time it must be NHANES III, the prevalence of TSH O4.5mU/l is lower
acknowledged that the mechanism of action of many in smokers than in nonsmokers (2.6 vs 5.5%, relative
susceptibilitylociisincompletelyunderstood(whyareso risk (RR) 0.5 with 95% CI, 0.4–0.6), in a dose-dependent
y manySNPslocatedinnoncodingpartsofthegene?),that manner (38). In the Norwegian HUNT study, the ORs
g
o
ol themechanismsaremuchmorecomplexthanpreviously (current smokers vs never smokers) for subclinical and
n
ri thought,andthatwehavehardlystartedstudyinggene– overt hypothyroidism are 0.54 (95% CI, 0.45–0.66) and
c
o
d gene and gene–environment interactions. Secondly, we 0.60 (95% CI, 0.38–0.95) respectively in women; the
n
E have a better understanding as to why autoimmune correspondingfiguresinmenare0.37(95%CI,0.26–0.52)
f
o
al diseases are associated with each other, and so often and0.51(95%CI,0.15–1.73).ORsforformersmokerswere
n
r clusterinthesamepatient.Thirdly,theORofeachlocus not significant (39). Inthisstudy,thecauseofhypothyr-
u
o
J forAITDisratherlowintheorderof1.5–2.0,withslightly oidism was not specified but most probably it was
n
ea higher OR of 2.0–4.0 for HLA. Combining the effects of Hashimoto’s thyroiditis because subjects with previously
p
o four HLA loci and five non-HLA loci, they accounted for known and treated thyroid disease had been excluded.
r
u
E only 9.3% of heritability of Graves’ disease in a Chinese Subsequentstudiesindeeddemonstrateaprotectiveeffect
study(33).Twinstudieshaveconvincinglydemonstrated
thatgeneticfactorscontributeabout70%tothedevelop-
Increased risk
mentofAITD,leavingonly30%forenvironmentalfactors
of Graves’ disease
(34). The data strongly suggest that there must be many
more still undetected susceptibility genes, each variant
contributing just a little to the development of AITD.
Fourthly, application of knowledge about susceptibility
genes is slowly entering clinical practice. Some poly-
morphisms have predictive value for whether or not
GHwillrecurafteracourseofantithyroiddrugs(35,36).
Onemayexpectthatsusceptibilitygenesaregoingtoplay
asubstantialroleinpersonalizedmedicine.
Decreased risk
Environmental factors: new players
of Hashimoto’s disease
Smoking
Smoking is a well-established risk factor for Graves’ Figure2
disease. The OR for GH is 3.30 (95% CI, 2.09–5.22) in CurrentsmokingisariskfactorforGraves’diseasebut
current smokers when compared with never smokers. protectiveforHashimoto’sdisease.
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againstHashimoto’sdisease.InNHANESIII,TPO-Abswere consumption for the development of autoimmune
presentin11%ofsmokersvs18%innonsmokers(OR0.57; hypothyroidism. ORs were as follows: 1.98 (95% CI,
95%CI,0.48–0.67),withadose–responserelationship(38). 1.21–3.33) for 0 alcoholic units/week, 1.00 for 1–10
IntheAmsterdamAITDcohortstudyatbaseline,25%of units/week (reference), 0.41 (95% CI, 0.20–0.83) for
subjects, with TPO-Ab at baseline, smoked vs 38% of 11–20 units/week, and 0.90 (95% CI, 0.41–2.00) for R21
subjectswithoutTPO-Ab(OR0.69;95%CI,0.48–0.99)(40). units/week (47). Abstainers are 2.17 times more likely to
InDenmark,smokingwasalsonegativelyassociatedwith developautoimmunehypothyroidismthannonabstainers
Tg-AbandtoalesserdegreewithTPO-Ab(41).Follow-upof (R1unit/week).Remarkably,moderatealcoholconsump-
subjects in the Amsterdam AITD cohort, who had no tionislikewiseassociatedwithaconsiderablereductionin
thyroid antibodies at baseline, revealed that cessation of the risk of GH. ORs were 1.73 (95% CI, 1.17–2.56) for
smokingincreasedtheriskofdenovodevelopmentofTPO- 0 units/week, 1.00 for 1–2 units/week (reference), 0.56
Ab and Tg-Ab (42); there was a significant trend toward (95% CI, 0.39–0.79) for 3–10 units/week, 0.37 (95% CI,
morequittersinsubjectswhoprogressedtoautoimmune 0.21–0.65) for 11–20 units/week, and 0.22 (95% CI,
hypothyroidismthaninsubjectswhoremainedeuthyroid 0.08–0.60) for R21 units/week (48). No interaction was
(4).IntheprospectiveDanThyrstudy,patientswithnewly found with the type of alcohol (wine vs beer), smoking
diagnosed autoimmune hypothyroidism had more often habits, gender, or iodine intake. Two previous case–
quittedsmokinginthelast2yearsthancontrols(16.4vs control studies reported similar protective effects of
3.4%) (43). The increased risk after smoking cessation, alcoholforGHwithORsof0.3(95%CI,0.2–0.7)and0.4
however,wastransient:ORs!1,1–2,and3–10yearsafter (95% CI, 0.2–0.8) (49, 50), although not confirmed in
y quittingare7.36(95%CI,2.27–23.90),6.34(95%CI,2.59– another study (51). The observed associations likely
g
o
ol 15.3), and 0.75 (95% CI, 0.30–1.87) respectively. Finally, indicate a cause-and-effect relationship in view of the
n
ri using Danish nationwide registers, mothers who smoke strength and the consistency of the associations and the
c
o
d during pregnancy have a subsequent decreased risk of presence of a dose–response effect. Moreover, alcohol is
n
E developinghypothyroidism(hazardratio(HR),0.75;95% knowntoprotectagainstotherautoimmunediseasessuch
f
o
al CI, 0.70–0.81) and an increased risk of hyperthyroidism as rheumatoid arthritis and type 1 diabetes. The most
n
r (HR,1.38;95%CI,1.27–1.49)(44).Thus,currentsmoking likely explanation for the protective effect of alcohol on
u
o
J diminishes the risk of developing TPO-Ab/Tg-Ab and AITD is that moderate alcohol consumption has a
n
ea autoimmune hypothyroidism in a dose-dependent man- beneficial impact on the immune system compared with
p
o ner, but the protective effect disappears a few years after alcohol abuse or abstinence (52). However, the effect of
r
u
E quitting smoking. The contrast with the increased risk alcohol on the immune system is complex, and how
ofsmokingforGHisstriking,butpoorlyunderstood.One alcohol suppresses autoimmunity remains incompletely
mayhypothesizeinvolvementofnicotine,whichreduces understood. Alcohol has also a direct toxic effect on the
theseverityofexperimentalautoimmuneencephalomye- thyroid gland, which, however, is difficult to reconcile
litis by a shift from pathogenic Th1 and Th17 responses withitsprotectiveeffectagainsthypothyroidism.
to protective Th2 responses. Anatabine – a tobacco
alkaloidwithastructuresimilartonicotine–reducesthe
Selenium
incidence and severity of experimental autoimmune
thyroiditis(45). Glutathione peroxidases and thioredoxin reductases are
selenoproteins involved in regulation of the redox state
andprotectionfromoxidativedamage.Thethyroidgland
Alcohol
containsmoreseleniumpergramoftissuethananyother
Case–control studies nested in the Amsterdam AITD organ. The enzyme GPx3 protects thyrocytes from
cohort did not observe an association between alcohol oxidative stress generated by the action of H O . Low
2 2
consumption (defined as O10 units/week) and de novo selenium levels have been associated with poor immune
occurrence of TPO-Ab, but the prevalence of alcohol function(53,54).Ithasthusbeenhypothesizedthateven
consumption was lower in subjects developing auto- mild nutritional selenium deficiency may promote the
immune hypothyroidism during the 5-year follow-up initiationorprogressionofthyroidautoimmunity.Totest
than in those remaining euthyroid (6.7 vs 23.7%) (46). the hypothesis that selenium supplementation decreases
A population-based case–control study in Denmark also the serum concentration of TPO-Ab, six randomized
provided evidence for a protective role of alcohol clinicaltrialshavebeenperformed(55,56,57,58,59,60).
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The results are equivocal: selenium compared with Crohn’s disease. The situation with respect to AITD is
placebodecreasedTPO-Abinthreestudiesbutnotinthe less clear. The prospective Amsterdam AITD cohort was
other three studies. The discrepant results could not be used for a nested case–control study: cases and controls
explained from the use of sodium selenite or seleno- had baseline normal TSH and no thyroid antibodies, but
methionine,samplesize,baselineserumconcentrationsof during the 5-year follow-up, cases did develop de novo
Se(rangingfrom69to75mg/l),andTPO-Ab(rangingfrom TPO-Ab whereas controls remained without antibodies.
172to1875kU/l),norbeexplainedfromtheconcomitant Controlswerecarefullymatchedtocasesnotonlyforthe
use of levothyroxine (L-T4) (60). At present, it cannot be duration of follow-up, but also for conditions known to
excluded that selenium supplementation will decrease affect vitamin D levels such as age, BMI, smoking status,
TPO-Ab specifically in regions with iodine deficiency estrogen use, and month of blood sampling (not for sex
(which increases the amount of oxidative stress to the because the Amsterdam AITD cohort consists of women
thyroid gland), or when given for a period longer than only). Serum 25(OH)D and 1,25(OH) D concentrations
2
6 months. Selenium supplementation has proven to were not different between cases and controls, neither
prevent deterioration of mild Graves’ ophthalmopathy at baseline nor at the time of seroconversion (67). The
(61) and the post partum surge of TPO-Ab and thyroid remaining studies are all cross-sectional in nature. Some
dysfunction (62). These randomized clinical trials were of them do find lower vitamin D levels in subjects with
performed in countries with marginally low selenium TPO-Ab (68, 69, 70), while others do not (71, 72).
bloodlevels,anditisnotknownifequallyfavorableresults Interpretation of their study results is difficult because
areseeninselenium-repleteareas.Theseleniumdoseused controls were not always matched to cases for the many
y sofaris200mgdaily.IntheDutchtrial,itincreasedplasma otherconditionsaffectingvitaminDlevels.Forexample,
g
olo Se concentrations from 73mg/l at baseline to 96mg/l at inonestudy,theinverserelationshipbetweenvitaminD
n
ri 3 months and 95mg/l at 6 months; obviously, a plateau statusandthyroidantibodieswaslostaftercorrectingfor
c
o
d had been reached within 3 months, which was also true sex and age (72). However, a recent study from Korea in
n
E forSelenoproteinP(60).Supplementationofseleniumto 6685subjectsundergoingroutinehealthcheckupstriedto
f
o
al peoplewhoalreadyhaveadequateSeintakewiththeirfood avoid confounding factors and observed lower 25(OH)D
n
r might increase their risk of developing type 2 diabetes, levels in women with TPO-Ab than in control women
u
Jo particularly when baseline plasma Se concentrations are without TPO-Ab (22.0 vs 23.5ng/ml; PZ0.03); there was
n
ea R122mg/l(63).Theremaybehealthbenefitsandnoextra no difference in men (73). The prevalence of TPO-Ab in
p
o risk for people with baseline (Se) !122mg/l by raising women with vitamin D deficiency, insufficiency, and
r
u
E their selenium status, perhaps to 130–150mg/l, which is sufficiency was 21.2, 15.5, and 12.6% respectively
associated with minimal mortality (63). Finally, it might (PZ0.027). ORs adjusted for age, BMI, serum calcium,
be possible that individual requirements for selenium smoking,menopause,andseasonwere(relativetoanOR
differ because of polymorphisms in selenoprotein genes. of 1.00 for vitamin D sufficiency) 1.95 for vitamin D
A Cochrane systematic review concludes that data at deficiencyand1.31forvitaminDinsufficiency.Whether
present do not allow confident decision making about vitamin D supplementation will prevent AITD has not
the use of selenium supplementation for Hashimoto’s beenstudied.Finally,polymorphismsintheVDRgeneare
thyroiditis(64). associatedwithAITD:whereasApaIorFokIcarrynorisk,
the BsmI and TaqI polymorphisms decrease the risk for
AITD(OR,0.80;95%CI,0.71–0.91andOR,0.85;95%CI,
VitaminD
0.76–0.96respectively)(74).
Manyimmunocompetentcells(monocytes,macrophages,
dendritic cells, T-lymphocytes, and B-lymphocytes)
express the vitamin D-activating enzyme CYP27B1 and Environmental factors: old players
the vitamin D receptor (VDR). The active hormone
Iodine
1,25(OH) D (derived from the systemic circulation or
2
from local conversion of 25(OH)D) binds to VDR and Thyroidantibodiesandautoimmunehypothyroidismare
modulatesboththeinnateandadaptiveimmunesystems more common in iodine-replete areas than in iodine-
(65, 66). Low vitamin D levels have been identified as a deficient areas. Further elegant proof of this has recently
riskfactorforvariousautoimmunediseasessuchastype1 beenobtainedfrompopulation-basedstudiesinDenmark.
diabetes, rheumatoid arthritis, multiple sclerosis, and Prevalence figures before and after mandatory iodization
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Review GEffraimidisand Autoimmunethyroiddisease: 170:6 R247
WMWiersinga oldandnewplayers
of salt were 14.3 and 23.8% for TPO-Ab, and 13.7 and studycontributedtothyroidautoimmunitybyunmasking
19.9%forTg-Abrespectively;ORswere1.80(TPO-Ab)and acrypticepitopeonTg(78).
1.49 (Tg-Ab). The increase in frequency was most
pronounced in young females and at low concentrations
Stress
of antibodies (75). The incidence rate of hypothyroidism
at baseline was 38.3/100000 per year, increasing to It has been known for a long time that stress could be a
47.2/100000 per year 5–7 years after iodine fortification provocative factor for GH, although the evidence is
ofsalt(RR,1.23;95%CI,1.07–1.42)(76).Voluntaryiodine circumstantial (79). Annual assessment of stressful life
prophylaxis in a small rural community in Italy also events and daily hassles in the prospective Amsterdam
resulted in an increased frequency of thyroid antibodies AITD cohort demonstrated no association between
(12.6vs19.5%)andhypothyroidism(2.8vs5.0%)15years stress exposure and de novo occurrence of TPO-Ab or
later (77). Implementation of iodine prophylaxis in this autoimmune hypothyroidism (80). Thus, in contrast to
Stage l Stage ll Stage lll Stage lV
TSH = fT = TSH = fT = TSH fT = TSH fT
4 4 4 4
TPO-Ab = TPO-Ab + TPO-Ab + TPO-Ab +
Strees Post partum
y
g
o
ol TPO-Ab low titer
rin m TPO-Ab high titer
ndoc oidis TBll
nalofE yperthyr Negative Positive
ur H
Jo High Iodine Estrogens Alcohol
ean GH Lroiswk Smoking
p
o
r
u
E m GH-specific genes
s
di Shared susceptibility
oi genes for autoimmunity
yr
h
ut HH-specific genes Post partum
E
High Smoking Alcohol
GH risk
m Iodine
s Low
di
oi
yr
h
ot
p TPO-Ab low titer
y
H TPO-Ab high titer
Stage l Stage ll Stage lll Stage lV
TSH = fT = TSH = fT = TSH fT = TSH fT
4 4 4 4
TPO-Ab = TPO-Ab + TPO-Ab + TPO-Ab +
Figure3
Naturalhistoryofautoimmunethyroiddisease.GH,Graves’hyperthyroidism;HH,Hashimoto’shypothyroidism.
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Review GEffraimidisand Autoimmunethyroiddisease: 170:6 R248
WMWiersinga oldandnewplayers
Graves’ disease, stress is apparently not involved in immune reconstitution syndrome, expressed as GH and
Hashimoto’sthyroiditis. lessfrequentlyashypothyroidism(94).
Infections
Natural history of AITD and prevention
Infection with Yersinia enterocolitica (YE) has long been
implicatedinthepathogenesisofAITD,becauseIgGfrom Figure3schematicallydepictsthenaturalhistoryofAITD.
Graves’ patients inhibit binding of TSH to outer mem- InstageI,allthyroidfunctiontestsarenormalandthyroid
branes of YE, and IgG from patients with YE infection antibodiesareabsentinserum.Butatthisstageinsubjects
inhibit binding of TSH to thyroid membranes. Biological at risk to develop AITD (like those with a family history
plausibilityofanassociationhasrecentlybeenenhanced of AITD), evidence of immune activation can already be
by cross-reactivity between YE outer membrane proteins found from a characteristic pattern of serum proteins
(YOP) and epitopes of TSHR antibodies (81, 82, 83). related to growth/connective tissue abnormalities and
Clinical evidence about the role of YE infection remains migration/accumulation abnormalities of macrophages
controversial.IntwinpairsdiscordantforGraves’disease, and dendritic cells (95). In stage II, thyroid antibodies
subjects with Graves’ disease had an increased OR becomedetectableinserum.Theconcentrationofthyroid
of YE infection (IgA, 1.84; 95% CI, 0.99–3.45 and IgG, antibodies gradually increases, TSH but not FT becomes
4
1.90; 95% CI, 1.02–3.55) (84). The Amsterdam AITD abnormalandweareenteringstageIII:subclinicalthyroid
cohort, the only prospective study in this area, however, dysfunction.Thedurationofsubclinicalhyperthyroidism
gy didnotfindanyevidenceofanassociationbetweenYOP untilovertGHoccurs(stageIV)ismuchshorterthanthe
olo IgA or IgG status and de novo occurrence of thyroid duration of subclinical hypothyroidism until overt HH
n
cri antibodies or development of overt autoimmune hyper/ develops (stage IV) (4, 96). A number of prospective
o
nd hypothyroidism (85). Hepatitis C virus (HCV) might be population-based studies have identified serum TSH and
E ‘the only infectious agent that is clearly associated with
f thyroidantibodiesaspredictorsoffuturehypothyroidism
o
al an increased risk for autoimmune thyroiditis’ (86). HCV and hyperthyroidism (97, 98, 99, 100). The quantitative
n
r can infect human thyrocytes resulting in production of
u risk of developing overt AITD can be estimated by the
o
J proinflammatory cytokines, which may enhance the
n Thyroid Events Amsterdam (THEA) score based on TSH,
pea autoimmune response (87). Indeed, thyroid antibodies TPO-Ab, and family history of AITD (97). The question
o are more frequent in children with untreated HCV
ur ariseswhetherapersonatriskcantakepreventiveaction
E infection than in controls (88). Enteroviruses have been
in order to diminish the risk. As shown in Table 1, the
detected in thyroid tissue of subjects with Hashimoto’s
options are very limited. To stop smoking will steer
thyroiditis(89).Itishypothesizedthatgutmicrobiotamay
the natural history away from Graves’ disease toward
trigger Hashimoto’s thyroiditis (90). One can even
Hashimoto’s disease. Moderate alcohol intake would
speculate that the profound changes in gut microbiota
make sense, but there is insufficient evidence to justify
induced by smoking cessation (91) are related to the
preventive medication with selenium or vitamin D.
loss of the protective effect of current smoking for
Moreover, to refrain from pregnancy and to avoid stress
Hashimoto’sdisease.
arenotveryhelpfulrecommendationseither.
Drugs Table1 Possiblepreventiveinterventionstodecreasetherisk
ofdevelopingautoimmunethyroiddisease.
Treatment with interferon a frequently results in Hashi-
moto’sthyroiditis(lessofteninGraves’disease),especially
Riskof Riskof
in women with pre-existent TPO-Ab (92). It may induce Hashimoto’s Graves’
autoimmune hypothyroidism by direct toxic effects on Preventive Riskof hypo- hyper-
intervention TPO-Ab thyroidism thyroidism
thyrocytesaswellasprovocationofdestructivebystander
Stopsmoking Increase Increase Decrease
immune responses (93). Treatment with alemtuzumab
Usealcohol Nochange Decrease Decrease
(anti-CD52 MAB) or highly active anti-retroviral therapy Useselenium ? ? ?
causes depletion of lymphocytes; in the recovery phase, UsevitaminD ? ? ?
when CD4CT-cells rise, there is a risk of the emergence Avoidpregnancy Decrease Decrease Decrease
Avoidstress Nochange Nochange Decrease
ofautoreactiveclones.Thus,bothdrugscouldinducethe
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Review GEffraimidisand Autoimmunethyroiddisease: 170:6 R249
WMWiersinga oldandnewplayers
13 BrixTH,KnudsenGPS,KristiansenM,KyvikKO,OrstavikKH&
Declarationofinterest HegedusL.HighfrequencyofskewedX-chromosomeinactivationin
The authors declare that there is no conflict of interest that could be femaleswithautoimmunethyroiddisease:apossibleexplanationfor
perceivedasprejudicingtheimpartialityofthereview. thefemalepredispositiontothyroidautoimmunity.JournalofClinical
EndocrinologyandMetabolism2005905949–5953.(doi:10.1210/jc.
2005-1366)
14 SimmondsMJ,KavvouraFK,BrandOJ,NewbyPR,JacksonLE,
Funding HargreavesCE,FranklynJA&GoughSC.SkewedXchromosome
Thisreviewdidnotreceiveanyspecificgrantfromanyfundingagencyin inactivationandfemalepreponderanceinautoimmunethyroid
thepublic,commercialornot-for-profitsector. disease:anassociationstudyandmeta-analysis.JournalofClinical
EndocrinologyandMetabolism201499E127–E131.(doi:10.1210/jc.
2013-2667)
15 DechairoBM,ZabanehD,CollinsJ,BrandO,DawsonGJ,GreenAP,
References MackayI,FranklynJA,ConnellJM,WassJAetal.Associationofthe
1 WeetmanAP.Immunity,thyroidfunctionandpregnancy: TSHRgenewithGraves’disease:thefirstdiseasespecificlocus.
molecularmechanisms.NatureReviews.Endocrinology20106311–318. EuropeanJournalofHumanGenetics2005131223–1230.(doi:10.1038/
(doi:10.1038/nrendo.2010.46) sj.ejhg.5201485)
2 RodondiM,PiraliB,LodigianiS,BrayS,ChytirisS,BalzanoS,MagriF 16 BrandOJ,BarrettJC,SimmondsMJ,NewbyPR,McCabeCJ,BruceCK,
&ChiovatoL.ThepostpartumperiodandtheonsetofGraves’disease: KyselaB,Carr-SmithJD,BrixT,HuntPJetal.Associationofthe
anoverestimatedriskfactor.EuropeanJournalofEndocrinology2008 thyroidstimulatinghormonereceptorgene(TSHR)withGraves’
159161–165.(doi:10.1530/EJE-08-0236) disease.HumanMolecularGenetics2009181704–1713.(doi:10.1093/
3 Stagnaro-GreenA,SchwartzA,GismondiR,TinelliA,MangieriT& hmg/ddp087)
NegroR.Highrateofpersistenthypothyroidisminalarge-scale 17 LiuL,WuHQ,WangQ,ZhuYF,ZhangW,GuanLJ&ZhangJA.
prospectivestudyofpostpartumthyroiditisinsouthernItaly.Journalof Associationbetweenthyroidstimulatinghormonereceptorintron
ClinicalEndocrinologyandMetabolism201196652–657.(doi:10.1210/ polymorphismsandautoimmunethyroiddiseaseinaChineseHan
y jc.2010-1980) population.EndocrineJournal201259717–723.(doi:10.1507/endocrj.
g
o 4 EffraimidisG,StriederTG,TijssenJG&WiersingaWM.Naturalhistory EJ12-0024)
ol 18 ColobranR,ArmengolMP,FauerR,GartnerM,TykocinskiLO,
n ofthetransitionfromeuthyroidismtoovertautoimmunehypo-or
cri hyperthyroidism:aprospectivestudy.EuropeanJournalofEndocrinology LucasA,RuizM,JuanM,KyewskiB&Pujol-BorrellR.Associationofan
do 2011164107–113.(doi:10.1530/EJE-10-0785) SNPwithintrathymictranscriptionofTSHRandGraves’disease:arole
En 5 LepezT,VandewoestyneM,HussainS,vanNieuwerburghF,PoppeK, fordefectivethymictolerance.HumanMolecularGenetics201120
of VelkeniersB,KaufmanJ-M&DeforceD.Fetalmicrochimericcellsin 3415–3423.(doi:10.1093/hmg/ddr247)
urnal 6bloe2o9d6o4f6w.(odmoei:n10w.1it3h71an/joauurtnoiaml.pmounnee.0t0h2y9r6o4id6)disease.PLoSONE2011 19 Jreacceopbtosor,nanEMdP&TPTNo2m2egreYn.eTqhueinCtDet40a,nCdTitLsAc-o4n,tthriybruogtiloobnutlion,thTySrHoid
o autoimmunity:backtothefuture.JournalofAutoimmunity200728
J 6 WalshJP,BremnerAP,BulsaraMK,O’LearyP,LeedmanPJ,FeddemaP
n 85–98.(doi:10.1016/j.jaut.2007.02.006)
a &MichelangeliV.Parityandtheriskofautoimmunethyroiddisease:
e 20 BanY,TozakiT,TaniyamaM,SkrabanekL,NakanoY,BanY&
p acommunity-basedstudy.JournalofClinicalEndocrinologyand
o HiranoT.MultipleSNPsinintron41ofthyroglobulingeneare
Eur 7 MBueltoawbolPiesmde2rs0e0n5I9,0La5u3r0b9er–g53P1,2K.n(uddosi:e1n0.N1,21Jo0r/gjce.n2s0e0n5-T0,7P7e1r)rildH, associatedwithautoimmunethyroiddiseaseintheJapanese
population.PLoSONE20127e37501.(doi:10.1371/journal.pone.
OvesenL&RasmussenLB.Lackofassociationbetweenthyroid
0037501)
antibodiesandparityinapopulationstudyarguesagainst
21 HodgeSE,BanY,StrugLJ,GreenbergDA,DaviesTF,ConcepcionES,
microchimerismasatriggerofthyroidautoimmunity.European
VillanuevaR&TomerY.PossibleinteractionbetweenHLA-DRb1and
JournalofEndocrinology200615439–45.(doi:10.1530/eje.1.02070)
thyroglobulinvariantsinGraves’disease.Thyroid200614351–356.
8 SgarbiJA,KasamatsuTS,MatsumuraLK&MacielRM.Parityisnot
(doi:10.1089/thy.2006.16.351)
relatedtoautoimmunethyroiddiseaseinapopulation-basedstudy
22 SimmondsMJ.GWASinautoimmunethyroiddisease:redefiningour
ofJapaneseBrazilians.Thyroid2010201151–1156.(doi:10.1089/
understandingofpathogenesis.NatureReviews.Endocrinology20139
thy.2009.0424)
277–287.(doi:10.1038/nrendo.2013.56)
9 FriedrichN,SchwarzS,ThonackJ,JohnU,WallaschofskiH&
23 SimmondsMJ,HowsonJM,HewardJM,Carr-SmithJ,FranklynJA,
VolzkeH.Associationbetweenparityandautoimmunethyroiditis ToddJA&GoughSC.AnovelandmajorassociationofHLA-Cin
inageneralfemalepopulation.Autoimmunity200841174–180. Graves’diseasethateclipsestheclassicalHLA-DRB1effect.Human
(doi:10.1080/08916930701777629) MolecularGenetics2007162149–2153.(doi:10.1093/hmg/ddm165)
10 GreerLG,CaseyBM,HalvorsonLM,SpongCY,McIntireDD& 24 HuangCY,ChangTY,ChuCC,LoFS,TingWH,LinCH,WuYL,
CunninghamG.Antithyroidantibodiesandparity:furtherevidence ChuSY,ChangSC,ChenWFetal.TheHLA-BgeneandHashimoto
formicrochimerisminautoimmunethyroiddisease.American diseaseinHanchildren:acase–controlandfamily-basedstudy.
JournalofObstetricsandGynecology2011205471.e1–471.e4. TissueAntigens201280431–436.(doi:10.1111/tan.12003)
(doi:10.1016/j.ajog.2011.06.060) 25 HsiaoJY,TienKJ,HsiaoCT&HsiehMC.AC/Tpolymorphismin
11 JorgensenKT,PedersenBV,NielsenNM,JacobsenS&FrischM. CD40geneisnotassociatedwithsusceptibilityandphenotypeof
Childbirthsandriskoffemalepredominantandotherautoimmmune Graves’diseaseinTaiwanese.EndocrineJournal200855477–484.
diseasesinapopulation-basedDanishcohort.JournalofAutoimmunity (doi:10.1507/endocrj.K07E-071)
201238J81–J87.(doi:10.1016/j.jaut.2011.06.004) 26 SimmondsMJ,BrandOJ,BarrettJC,NewbyPR,FranklynJA&
12 BrixTH,HansenPS,KyvikKO&HegedusL.Aggregationofthyroid GoughSC.AssociationofFcreceptor-like5(FCRL5)withGraves’
antibodiesintwinsfromopposite-sexpairssuggestthatmicrochi- diseaseissecondarytotheeffectofFRCL3.ClinicalEndocrinology2010
merismmayplayaroleintheearlystagesofthyroidautoimmunity. 73654–660.(doi:10.1111/j.1365-2265.2010.03843.x)
JournalofClinicalEndocrinologyandMetabolism2009944439–4443. 27 ZhaoS-X,LiuW,ZhanM,SongZ-Y,YangS-Y,XueL-Q,PanC-M,
(doi:10.1210/jc.2009-0813) GuZ-H,LiuB-L,WangH-Netal.ArefinedstudyofFRCLgenesfroma
www.eje-online.org
Downloaded from Bioscientifica.com at 12/31/2022 01:21:15AM
via free access
Review GEffraimidisand Autoimmunethyroiddisease: 170:6 R250
WMWiersinga oldandnewplayers
genome-wideassociationstudyforGraves’disease.PLoSONE20138 EuropeanJournalofEndocrinology2008158367–373.(doi:10.1530/
e57758.(doi:10.1371/journal.pone.0057758) EJE-07-0595)
28 BrandOJ,LoweCE,HewardJM,FranklynJA,CooperJD,ToddJA& 42 EffraimidisG,TijssenJG&WiersingaWM.Discontinuationof
GoughSC.Associationoftheinterleukin-2receptora(IL-2Ra)/CD25gene smokingincreasestheriskfordevelopingthyroidperoxidase
regionwithGraves’diseaseusingamultilocustestandtagSNPs.Clinical antibodiesand/orthyroglobulinantibodies:aprospectivestudy.
Endocrinology200766508–512.(doi:10.1111/j.1365-2665.2007.02762.x) JournalofClinicalEndocrinologyandMetabolism2009941324–1328.
29 OwenCJ,EdenJA,JenningsCE,WilsonV,CheethamTD&PearceSH. (doi:10.1210/jc.2008-1548)
GeneticassociationstudiesoftheFOXP3geneinGraves’diseaseand 43 CarleA,BulowPedersenI,KnudsenN,PerrildH,OvesenL,
autoimmuneAddison’sdiseaseintheUnitedKingdompopulation. RasmussenLB,JorgensenT&LaurbergP.Smokingcessationis
JournalofMolecularEndocrinology20063797–104.(doi:10.1677/jme.1. followedbyasharpbuttransientriseintheincidenceofovert
02072) autoimmunehypothyroidism–apopulation-based,case–control
30 BanY,TozakiT,TobeT,BanY,JacobsonEM,ConcepcionES& study.ClinicalEndocrinology201277764–772.(doi:10.1111/
TomerY.TheregulatoryTcellgeneFOXP3andgeneticsusceptibility j.1365-2265.2012.04455.x)
tothyroidautoimmunity:anassociationanalysisinCaucasianand 44 AndersenSL,OlsenJ,WuCS&LaurbergP.Smokingreducestheriskof
Japanesecohorts.JournalofAutoimmunity200728201–207. hypothyroidismandincreasestheriskofhyperthyroidism:evidence
(doi:10.1016/j.jaut.2007.02.016) from450842mothersgivingbirthinDenmark.ClinicalEndocrinology
31 NithiyananthanR,HewardJM,AllahabadiaA,BarnettAH, 201480307–314.(doi:10.1111/cen.12279)
FranklynJA&GoughSC.Aheterozygousdeletionoftheautoimmune 45 CaturegliP,DeRemigisA,FerlitoM,Landek-Salgado,IwamaS,
regulator(AIRE1)gene,autoimmunethyroiddisease,andtype1 TzouS-C&LadensonPW.Anatabineamelioratesexperimental
diabetes:noevidenceforassociation.JournalofClinicalEndocrinology autoimmunethyroiditis.Endocrinology20121534580–4587.
andMetabolism2000851320–1322. (doi:10.1210/en.2012-1452)
32 MeyerG,DonnerH,HerwigJ,BohlesH,UsadelKH&BadenhoopK. 46 EffraimidisG,TijssenJG&WiersingaWM.Alcoholconsumptionasa
ScreeningforanAIRE-1mutationinpatientswithAddison’sdisease, riskfactorforautoimmunethyroiddisease:aprospectivestudy.
type1diabetes,Graves’diseaseandHashimoto’sthyroiditisaswellas EuropeanThyroidJournal2012199–104.(doi:10.1159/000338920)
APECEDsyndrome.ClinicalEndocrinology200154335–338. 47 CarleA,BulowPedersenI,KnudsenN,PerrildH,OvesenL,
y (doi:10.1046/j.1365-2265.2001.01230.x) RasmussenLB,JorgensenT&LaurbergP.Moderatealcohol
g
o 33 ChuX,PanCM,ZhaoSX,LiangJ,GaoGQ,ZhangXM,YuanGY, consumptionmayprotectagainstovertautoimmunehypothyroid-
ol LiCG,XueLQ,ShenMetal.Agenome-wideassociationstudy ism:apopulation-basedcase–controlstudy.EuropeanJournalof
n
ri identifiestwonewrisklociforGraves’disease.NatureGenetics201143 Endocrinology2012167483–490.(doi:10.1530/EJE-12-0356)
c
do 897–901.(doi:10.1038/ng.898) 48 CarleA,BulowPedersenI,KnudsenN,PerrildH,OvesenL,
En 34 BrixTH&HegedusL.Twinstudiesasamodelforexploringthe RasmussenLB,JorgensenT&LaurbergP.Graves’hyperthyroidism
of aetiologyofautoimmunethyroiddisease.ClinicalEndocrinology2012 andmoderatealcoholconsumption:evidencefordiseaseprevention.
al 76457–464.(doi:10.1111/j.1365-2265.2011.04318.x) ClinicalEndocrinology201379111–119.(doi:10.1111/cen.12106)
rn 35 InoueN,WatanabeM,YamadaH,TakemuraK,HayashiF, 49 YoshiuchiK,KumanoH,NomuraS,YoshimuraH,ItoK,KanajiY,
u
o YamakawaN,AkahaneM,ShimizuishiY,HidakaY&IwataniY. OhashiY,KubokiT&SuematsuH.Stressfullifeeventsandsmoking
J
n Associationsbetweenautoimmunethyroiddiseaseprognosisand wereassociatedwithGraves’disease,butnotinmen.Psychosomatic
a
e functionalpolymorphismsofsusceptibilitygenes,CTLA4,PTPN22, Medicine199860182–185.
p
o CD40,FCRL3,andZFAT,previouslyrevealedingenome-wide 50 WinsaB,AdamiHO,BergstromR,GamstedtA,DahlbergPA,
r
Eu associationstudies.JournalofClinicalImmunology2012321243–1252. AdamsonU,JanssonR&KarlssonA.StressfullifeeventsandGraves’
(doi:10.1007/s10875-012-9721-0) disease.Lancet19913381475–1479.(doi:10.1016/0140-
36 WangPW,ChenIY,JuoSHH,HisE,LiuRT&HsiehCJ.Genotypeand 6736(91)92298-G)
phenotypepredictorsofrelapseofGraves’diseaseafterantithyroid 51 HolmIA,MansonJE,MichelsKB,AlexanderEK,WillettWC&
drugwithdrawal.EuropeanThyroidJournal20121251–258. UtigerRD.SmokingandotherlifestylefactorsandtheriskofGraves’
(doi:10.1159/000342021) hyperthyroidism.ArchivesofInternalMedicine20051651606–1611.
37 VestergaardP.Smokingandthyroiddisorders–ameta-analysis. (doi:10.1001/archinte.165.14.1606)
EuropeanJournalofEndocrinology2002146153–161.(doi:10.1530/ 52 RomeoJ,WarnbergJ,NovaE,DiazLE,Gomez-MartinezS&MarcosA.
eje.0.1460153) Moderatealcoholconsumptionandtheimmunesystem:areview.
38 BelinRM,AstorBC,PoweNR&LadensonPW.Smokeexposureis BritishJournalofNutrition200798(Suppl1)S111–S115.
associatedwithalowerprevalenceofserumthyroidautoantibodies 53 DuntasLH.Seleniumandthethyroid:aclose–knitassociation.
andthyrotropinconcentrationelevationandahigherprevalenceof JournalofClinicalEndocrinologyandMetabolism2010955180–5188.
mildthyrotropinconcentrationsuppressioninthethirdNational (doi:10.1210/jc.2010-0191)
HealthandNutritionExaminationSurvey(NHANESIII).Journalof 54 SchomburgL.Selenium,selenoproteinsandthethyroidgland.
ClinicalEndocrinologyandMetabolism2004896077–6086. NatureReviews.Endocrinology20118160–171.(doi:10.1038/nrendo.
(doi:10.1210/jc.2004-0431) 2011.174)
39 AsvoldBO,BjoroT,NilsenTI&VattenLJ.Tobaccosmokingand 55 GartnerR,GasnierBC,DietrichJW,KrebsB&AngstwurmMW.
thyroidfunction:apopulation-basedstudy.ArchivesofInternal Seleniumsupplementationinpatientswithautoimmunethyroiditis
Medicine20071671428–1432.(doi:10.1001/archinte.167.13.1428) decreasesthyroidperoxidaseantibodiesconcentrations.Journalof
40 StriederTG,PrummelMF,TijssenJG,EndertE&WiersingaWM.Risk ClinicalEndocrinologyandMetabolism2002871687–1691.
factorsforandprevalenceofthyroiddisordersinacross-sectional (doi:10.1210/jcem.87.4.8421)
studyamonghealthyfemalerelativesofpatientswithautoimmune 56 DuntasLH,MantzouE&KoutrasDA.Effectofasix-monthtreatment
thyroiddisease.ClinicalEndocrinology200359396–401.(doi:10.1046/ withselenomethionineinpatientswithautoimmunethyroiditis.
j.1365-2265.2003.01862.x) EuropeanJournalofEndocrinology2003148389–393.(doi:10.1530/eje.
41 BulowPedersenI,LaurbergP,KnudsenN,JorgensenT,PerrildH, 0.1480389)
OvesenL&RasmussenLB.Smokingisnegativelyassociatedwiththe 57 TurkerO,KumanliogluK,KarapolatI&DoganI.Seleniumtreatment
presenceofthyroglobulinautoantibodyandtoalesserdegreewith inautoimmunethyroiditis:9-monthfollow-upwithvariabledoses.
thyroidperoxidaseautoantibodyinserum:apopulationstudy. JournalofEndocrinology2006190151–156.(doi:10.1677/joe.1.06661)
www.eje-online.org
Downloaded from Bioscientifica.com at 12/31/2022 01:21:15AM
via free access