1、March 2017|Volume 8|Article 50 1Mini Reviewpublished:20 March 2017doi:10.3389/fendo.2017.00050Frontiers in Endocrinology|www.frontiersin.orgEdited by:Antonino Belfiore,Magna Grcia University,ItalyReviewed by:Pasqualino Malandrino,University of Catania,Italy Daniela Pasquali,Universit degli Studi del
2、la Campania“Luigi Vanvitelli”C,Italy Marialuisa Appetecchia,Istituti Fisioterapici Ospitalieri(IRCCS),Italy*Correspondence:Alessandro Antonelli alessandro.antonellimed.unipi.itSpecialty section:This article was submitted to Cancer Endocrinology,a section of the journal Frontiers in EndocrinologyRece
3、ived:20January2017Accepted:03March2017Published:20March2017Citation:FerrariSM,FallahiP,AntonelliA and BenvengaS(2017)Environmental Issues in Thyroid Diseases.Front.Endocrinol.8:50.doi:10.3389/fendo.2017.00050environmental issues in Thyroid DiseasesSilvia Martina Ferrari1,Poupak Fallahi1,Alessandro A
4、ntonelli1*and Salvatore Benvenga2,3,41 Department of Clinical and Experimental Medicine,University of Pisa,Pisa,Italy,2 Department of Clinical and Experimental Medicine,University of Messina School of Medicine,Messina,Italy,3 Master Program of Childhood,Adolescence and Womens Endocrine Health,Univer
5、sity of Messina School of Medicine,Messina,Italy,4 Interdepartmental Program of Molecular&Clinical Endocrinology,and Womens Endocrine Health,University Hospital,Policlinico G.Martino,Messina,ItalyEnvironmental factors are determinant for the appearance of autoimmune thyroid dis-eases(AITD)in suscept
6、ible subjects.Increased iodine intake,selenium,and vitamin D deficiency,exposure to radiation,from nuclear fallout or due to medical radiation,are environmental factors increasing AITD.Cigarette smoking is associated with Graves disease and Graves ophthalmopathy,while it decreases the risk of hypoth
7、yroidism and thyroid autoimmunity.Viral infections are important environmental factors in the patho-genesis of AITD,too,particularly human parvovirus B19(EVB19)and hepatitis C virus.Among the many chemical contaminants,halogenated organochlorines and pesticides variably disrupt thyroid function.Poly
8、chlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins,such as transthyre-tin,displace thyroxine,and disrupt thyroid function.Among drugs,interferon-and iodine-containing drugs have been associated with AITD.Moreover intestinal dysbiosis caus
9、es autoimmune thyroiditis.To reduce the risk to populations and also in each patient,it is necessary to comprehend the association between environmental agents and thyroid dysfunction.Keywords:autoimmune thyroid diseases,genetic influences,environmental influences,thyroid cancer,antithyroid antibodi
10、esin TRODUCTiOnGraves disease(GD)and Hashimotos thyroiditis(HT)are the principal clinical presentations of autoimmune thyroid diseases(AITD),characterized by lymphocytic infiltration of the thyroid parenchyma,and clinically by thyrotoxicosis and hypothyroidism,respectively.AITD lead to an immune att
11、ack on the thyroid,whose mechanisms are still unclear.Genetic susceptibility and environmental triggers interact as the principal active part toward the development of the disease.Autoimmune thyroid diseases prevalence is about 5%(1,2)while that of antithyroid antibodies(ATAs)without clinical diseas
12、e could be higher(3).Abbreviations:AITD,autoimmune thyroid diseases;GD,Graves disease;HT,Hashimotos thyroiditis;ATA,antithyroid antibodies;TPOAb,thyroid peroxidase antibodies;GO,Graves ophthalmopathy;TgAb,thyroglobulin antibodies;AT,autoim-mune thyroiditis;TSH,thyroid-stimulating hormone;HIV,human i
13、mmunodeficiency virus;HCV,hepatitis C virus;EVB19,erythrovirus B19;TC,thyroid cancer;PTC,papillary thyroid cancer;CHC,chronic hepatitis C;MC,mixed cryoglobulinemia;IFN,interferon;AIH,amiodarone-induced hypothyroidism;AIT,amiodarone-induced thyrotoxicosis;PCB,polychlorinated biphenyl;T3,triiodothyron
14、ine;T4,thyroxine;Cd,cadmium;Mn,manganese.2Ferrari et al.Environmental Influences on Thyroid DiseasesFrontiers in Endocrinology|www.frontiersin.org March 2017|Volume 8|Article 50enDOGenOUS FACTORS ASSOCiATeD wiTH AiTDAutoimmune thyroid diseases commonly affect more fre-quently females than males,such
15、 as in many other autoimmune diseases(4).This is probably due to differences between male and female immune systems(5),which are present in many animal species;in fact,males have immune suppression versus females,which is linked to male sexual activity(6).Females show greater immune reactivity(7),an
16、d this increased immunocompetence might translate to greater resilience to infectious and non-infectious disorders.In females,the immunological changes during pregnancy and their regression in the postpartum period are determinant,even if the predisposition of females to AITD is observed in nullipar
17、ous women,too.Microchimerism(i.e.,the presence of small popula-tions of cells from one subject in another genetically distinct one)is an endogenous factor associated with AITD(8).Antithyroid antibodies frequency has a peak around 4555years,and hypothyroidism due to HT is more frequent in advanced ag
18、e.The HT prevalence and that of AT As differ among races(810).Incidence of HT shows an elevated geographic variability.However,worldwide,the current incidence rates of hypothyroid-ism and HT are higher than previously in similar regions(11);it is unclear whether this depends on the use of more accur
19、ate diagnostic procedures or actual increased incidence perse(12).GeneTiC SUSCePTiBiLiTYThe importance of genetic susceptibility has been suggested by the familial clustering of AITD(2030%in siblings of affected subjects,with a sibling risk ratio of approximately 17;high preva-lence of ATA(about 50%
20、)in siblings of AITD patients)(13).The concordance rate of monozygotic twin studies is ranging from 0.3 to 0.6 versus 0.000.1 for dizygotic twins(8,14);heritability of ATA is 70%,of GD 79%(8).Among genes linked to AITD and/or the presence of ATA(15,16),whose function is known,7 out of 11 take part i
21、n Tcells function,leading to hypothesize that Tlymphocytes are impor-tant in the pathogenesis of AITD.enviROnMenTAL FACTORSEnvironmental factors influence the occurrence of AITD of approximately 20%,as they are associated with the activation of innate immune response and AITD development in suscepti
22、ble individuals(17,18).external RadiationThe prevalence of ATA increased in children and adolescents exposed to radiations about 68years after the Chernobyl acci-dent.Thyroid peroxidase antibodies(TPOAb)prevalence was higher in radiation-exposed Belarusian children(6.4 versus 2.4%in not exposed)and
23、in adolescents exposed to radioactive fallout 1315years after the Chernobyl accident(19).The radiation dose was related to increased TPOAb prevalence,thereby suggesting that important clinical changes could appear gradually(20).The onset of GD,and even of Graves ophthalmopathy(GO),may occur after ra
24、dioiodine treatment of toxic goiter(21).Thyroid ionizing radiation exposure was related with the occurrence of tardive hypothyroidism,thyroid nodules,or cancer,and even acute thyroiditis(22,23).iodineIodine is essential for thyroid function.Constant iodine prophylaxis and increased iodine intake gra
25、dually reduce iodine deficiency-related thyroid disorders(24).In the Danish population,a 53%higher incidence of spontaneous overt hypo-thyroidism(probably autoimmune)was observed in mild,than in moderate,iodine deficiency(25).Iodine excess,owing to a great environmental iodine exposure besides poor
26、monitoring,is a precipitating environmental factor in the development of AITD.Excessive amounts of iodide have been associated with the onset of autoimmune thyroiditis(AT)(26).SeleniumSelenium,whose necessary intake ranges from 60 to 75g/day,exerts an influence on immunological responses,cell growth
27、,and viral defense and is necessary for normal thyroid function and homeostasis in humans.Selenium is essential for the activity of enzymes,such as glutathione peroxidases,deiodinases,and thioredoxin reductases,and for the synthesis and function of thyroid hormones and protects cells against free ra
28、dicals and oxidative damage.A low selenium concentration is associated with the appearance of AT or GD(27).As selenium is involved in regulation of cell cycle,a decreased concentration is also important in the development of thyroid cancer(TC)(28,29).In a cross-sectional observational study in Shaan
29、xi Province(China),the relationship between selenium status,dietary fac-tors,and pathological thyroid conditions was investigated.In the adequate-selenium county,the prevalence of pathological thyroid disorders(subclinical hypothyroidism,hypothyroidism,AT,and enlarged thyroid)was significantly lower
30、 than in the low-selenium county(18.0 versus 30.5%;P 0.001).Elevated circulating selenium level was associated with reduced odds ratio(95%confidence interval)of subclinical hypothyroidism(0.68;0.58,0.93),hypothyroidism(0.75;0.63,0.90),AT(0.47;0.35,0.65),and enlarged thyroid(0.75;0.59,0.97)(30).A pap
31、er(31)evaluated the real efficacy of selenium sup-plementation in HT,measuring thyroid-stimulating hormone(TSH),thyroid hormones,TPOAb and thyroglobulin antibod-ies(TgAb)levels,and thyroid echogenicity after 6months of l-selenomethionine treatment.The authors concluded that the short-term l-selenome
32、thionine supplementation has a restricted impact on the natural course in euthyroid HT.SmokingThe data about the effect of smoking on ATA(TgAb and TPOAb)and chronic AT(32,33)are conflicting.A meta-analysis reported the association of smoking with HT and postpartum thyroid dysfunction(34).By contrast
33、,a 3Ferrari et al.Environmental Influences on Thyroid DiseasesFrontiers in Endocrinology|www.frontiersin.org March 2017|Volume 8|Article 50prospective cohort study demonstrated,in subjects at risk of developing AITD,that smoking was negatively associated with the presence of TPOAb(35,36),which was c
34、onfirmed in popula-tion studies(3740).Smoking during pregnancy was inversely correlated with the risk of thyroiditis,while it raised the preva-lence of postpartum thyroiditis(41).On the whole,smoking decreases the risk of appearance of TPOAb and TgAb and autoimmune hypothyroidism of approxi-mately 4
35、0%;this protective effect disappears few years after cessa-tion.It has been suggested that while activating nicotine receptors on immune cells,the autoimmune profile moves away from Th1 and Th17 responses(42,43).The proportion of smoking people was more elevated in patients with severe ophthalmopath
36、y(64.2%in GO and 47.9%in GD versus 30%in control subjects)(32,4447).Smoking is related to an increased risk of Graves hyperthyroidism(twofold),GO(three to four times),or relapse of GD or GO(48,49),and it is linked to a more severe GO.Many different hypotheses about how smoking may enhance the risk o
37、f GD or GO have been reported(5058).virusesViruses activate the adaptive and innate immunity and might cause HT.Human T-cell lymphotropic virus-1,herpes simplex virus,rubella,mumps virus,EpsteinBarr virus,enterovirus in HT,retroviruses human T-cell lymphotropic virus-1,human foamy virus or human imm
38、unodeficiency virus(HIV),and Simian virus 40 in GD have been shown(59).Acquired immunodeficiency syndrome and HIV have been associated with various thyroid diseases(60).Hepatitis C virus(HCV)and human parvovirus B19(EVB19)are candidate viruses for AITD(59,61).Parvovirus B19EVB19 DNA was detected in
39、about 12%of HT cases versus 3%controls(P0.03),suggesting that acute EVB19 infection could be associated with the appearance of AT(62,63).In slides of paraffin-embedded thyroid tissues from 112 patients undergoing thyroidectomy,EVB19 DNA was revealed in thyrocytes(or in lymphocytes),particularly in p
40、apillary TC(PTC),leading to hypothesize that EVB19 is implicated in thyroid carcinogenesis(64).In another study,EVB19 was present in 88%PTC tumors(65).EVB19 was present in thyrocytes in patients with multinodu-lar goiters,thyroiditis,or GD,by immunohistochemistry,PCR or insitu hybridization(66,67).I
41、n addition,in primary thyrocytes,after EVB19 NS1 transfection,positive regulatory domain zinc finger protein 1 upregulation was observed(68).The relationship between EVB19 and different thyroid disor-ders needs to be investigated(69).Chronic HCv infection and ThyroidViral replication occurs in hepat
42、ocytes and also in extrahe-patic tissues and peripheral blood mononuclear cells(70,71).Extrahepatic manifestations(72,73)mixed cryoglobulinemia(MC),endocrinological diseases(AITD and type 2 diabetes),Sjogrens syndrome are present in about 3876%patients with chronic hepatitis C(CHC).HCV interferes wi
43、th functions and self-recognition mechanisms(in immune system or in thyrocytes)leading to destruction of thyroid and beginning the autoimmune disease(74).The association between HCV infection and thyroid autoim-munity has been shown(7582).Thyroid disorders frequency in interferon(IFN)-free HCV subje
44、cts is approximately 1015%(8389).Thyroid autoimmune abnormalities frequency was also significantly increased in MC+HCV patients versus controls(AT 35 versus 16%;subclinical hypothyroidism,11 versus 2%).In female patients with MC+HCV,or CHC,thyroid disorders were represented by higher risk for AT and
45、 hypothyroidism and elevated circulating TPOAb(88,90).An increased prevalence of PTC has been shown in CHC,with or without MC,overall when AT was present(9197),suggesting that AT might be a predisposing condition for TC(9597).An elevated mortality for TC in HCV patients(98)has been shown,suggesting
46、that it impacts survival of these patients,and giving the advice of a careful thyroid monitoring in HCV patients in presence of thyroid nodules.HCV thyroid infection upregulates CXCL10 expression and secretion of thyroid cells,recruiting other Th1 lymphocytes into the gland,leading to the appearance
47、 of AITD in predisposed individuals(99,100).A careful thyroid function and nodules follow-up in subjects showing risk factors(female gender,a border line high initial TSH,TPOAb+,a small and hypoechoic thyroid)for the appearance of AITD in HCV and MC+HCV should be performed.DrugsAmong drugs,IFN-and i
48、odine-containing drugs have been associated with AITD.The“de novo”presence of ATA and overt dysfunctions in euthyroidism have been reported upon IFN-therapy,suggesting that it can exacerbate or induce latent thyroid disorders,inducing AITD(74).The standard dual therapy with pegylated IFN-/ribavirin
49、has been substituted by a triple therapy with new direct-acting antiviral drugs(NS3/4A serine protease inhibitor)(74)(with/without ribavirin),thereby ameliorating the patient compliance and decreasing the risk for thyroid autoim-munity(74).Drugs containing iodide may induce hypothyroidism in euthyro
50、id HT patients,131-I or surgically treated GD,or follow-ing hemithyroidectomy for nodules.Medications can also induce hyperthyroidism in patients with endemic iodine-deficient goiter,autonomous nodules,or non-toxic nodular goiter,or in patients recently treated with antithyroid drugs for GD.Rarely,h
