thyroid hormone in health and disease

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STARLING REVIEW

. .Thyroid hormone in health and disease

K Boelaert and J A Franklyn

Division of Medical Sciences, IBR Building, 2nd floor, The Medical School, University of Birmingham, Birmingham B15 2TT, UK

(Requests for offprints should be addressed to K Boelaert; Email: [email protected])

Abstract

Thyroid disease is common, affecting around 2% ofwomen and 02% of men in the UK. Our understandingof the effects of thyroid hormones under physiologicalcircumstances, as well as in pathological conditions, hasincreased dramatically during the last two centuries and ithas become clear that overt thyroid dysfunction is associ-

ated with significant morbidity and mortality. Both hypo-and hyperthyroidism and their treatments have beenlinked with increased risk from cardiovascular disease andthe adverse effects of thyrotoxicosis in terms of osteo-porosis risk are well established. Although the evidencesuggests that successful treatment of overt thyroid dysfunc-tion significantly improves overall survival, the issue of

treating mild or subclinical hyper- and hypothyroidismremains controversial. Furthermore, the now well-established effects of thyroid hormones on neurodevelop-ment have sparked a whole new debate regarding the needto screen pregnant women for thyroid function abnor-malities. This review describes the current evidence of the

effects of thyroid hormone on the cardiovascular, skeletaland neurological systems, as well as the influence ofthyroid diseases and their treatments on the developmentof malignancy. Furthermore we will describe some recentdevelopments in our understanding of the relationshipbetween thyroid status and health.Journal of Endocrinology(2005) 187, 115

Introduction

Despite the discovery of a gland in the neck during the

Renaissance period, and the knowledge that its enlarge-ment causes neck swelling, it took until 1656 for thisgland to be given its modern name the thyroid glandby Thomas Wharton (Wharton 1664). During the19th century, Coindet, an Edinburgh-trained physicianworking in Geneva, Switzerland, successfully treatedgoitres with iodine and in 1891, sheep thyroid extract wasused to cure myxoedema (Sawin 2000). It took until 1914before Kendall and Osterberg isolated the active substancein this extract and named it thyroxine (Kendall 1915,Sawin 2000). During the 19th century, thyrotoxicosis wasdescribed for the first time by Robert Graves in womenpresenting with goitre, rapid heartbeat and exophthalmos,

although it was thought that the underlying cause wascardiac in nature (Graves 1835, Sawin 2000). Similarlyhypothyroidism as a clinical syndrome was recognised inthe 1870s and considered either a neurological or a skindisorder (Gull 1874, Sawin 2000). The dramatic increasein our understanding of thyroid hormone action as well asof the clinical implications of thyroid dysfunction that hasoccurred during the last two centuries, will be described inthis review.

Thyroid hormones are key regulators of metabolism anddevelopment and are known to have pleiotropic effects inmany different organs. The thyroid gland synthesises and

releases triiodothyronine (T3) and thyroxine (T4), whichrepresent the only iodine-containing hormones in verte-brates. T4 is the main product of thyroid secretion andlocal deiodination in peripheral tissues produces T3, thebiologically active thyroid hormone. T3 and T4 are boundto thyroglobulin, providing a matrix for their synthesis anda vehicle for their subsequent storage in the thyroid. Morethan 99% of the circulating T3 and T4 is protein bound,mainly to T4-binding globulin and to a lesser extent totransthyretin and albumin. Thyroid hormones can rapidlybe released from these proteins, this process facilitatingtheir entry into cells. The production of thyroid hormonesis controlled by serum thyrotrophin (TSH) synthesised by

the anterior pituitary gland in response to TSH-releasinghormone (TRH), which is secreted by the hypothalamus.Unbound or free T3 and T4 (fT3 and fT4 respectively)exert a negative feedback on the synthesis and release ofTSH and TRH in order to maintain circulating thyroidhormone levels within the required range.

The actions of thyroid hormones are initiated by theirinteraction with thyroid hormone receptors (TRs), whichbelong to a large superfamily of steroid hormone receptors

Journal of Endocrinology(2005) 187, 11500220795/05/0187001 2005 Society for Endocrinology Printed in Great Britain

DOI: 10.1677/joe.1.06131Online version via http://www.endocrinology-journals.org
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other members of which include the sex steroid receptors,vitamin D receptors and retinoic acid receptors. Fourimportant TR isoforms (TR1, TR2, TR1 and TR2)

have been well characterised in humans while severalminor TR isoforms have also been identified morerecently (Williams 2000). TRs have a central DNA-binding domain containing two zinc fingers, a carboxy-terminal ligand-binding domain and a transactivation site,as well as an amino-terminal domain with a poorly definedfunction (Yen 2001). The major functional TRs includeTR1, TR1 and TR2. They bind the ligand, T3, withsimilar affinity and binding kinetics, with K

m values of

110 nM (Lazar 1993, Yen 2001). T3TR complexesthen bind to thyroid hormone response elements (TREs),which are specific DNA sequences found in the regulatoryregions of target genes. During this process, nuclear

proteins known as co-repressors and co-activators arerecruited or excluded from T3TRTRE interactions.This causes a direct conformational change of chromatinthrough the acetylation or deacetylation of histones locally,which results in the loosening or compaction respect-ively of the chromatin structure, thus regulating theaccessibility of the gene to the transcriptional machinery.The functional TRs thus serve to promote or inhibit thetranscription of thyroid hormone responsive genes (Munoz& Bernal 1997) (Fig. 1). TR action typically involves

homo- and hetero-dimerisation with other TR isoformsand steroid receptors. Whereas TRs can be homodimeric,heterodimerisation with retinoid X-receptors strongly

enhances their binding to the TRE (Darling et al. 1993).In contrast to the other TRs, the TR2 protein does notbind T3 and has a postulated modulatory role mediated bycompetitive binding of the 2 protein to TREs. Theexpression and regulation of TRs and thyroid responsivegenes is variable in different tissues, which allows amultitude of possible ways in which thyroid hormones canexert their effects.

Overt thyroid dysfunction is common in the generalpopulation. The Whickham survey, conducted in thenorth of England, revealed a prevalence of thyrotoxicosisor hypothyroidism of at least 2% in females and 02% inmales in the UK (Tunbridge et al. 1977). A 20 year

follow-up study of the population of Whickham reporteda mean incidence of 08/1000 per year for hyper-thyroidism and of 41/1000 per year for hypothyroidism inwomen, the incidences in men being negligible and06/1000 per year respectively (Vanderpumpet al. 1995).Additionally, subclinical thyroid dysfunction, defined asserum TSH levels outside the normal reference range withnormal levels of fT4 and fT3, is even more common.Biochemical assessment of thyroid function in a largecohort of 25 863 subjects attending a State-wide health fair

Figure 1 Transactivation of thyroid hormone responsive genes (THRG) through the binding of T3 to thyroidhormone receptors (TR) followed by T3TR binding to the thyroid response element (TRE) located in thepromoter regions of THRG. Transactivation is regulated by co-activators (CA) and co-repressors (CR) whichbring about conformational changes in the DNA structure, altering the thyroid hormone responsive geneaccessibility to RNA polymerase, the enzyme responsible for gene transcription.

K BOELAERTand J A FRANKLYN Thyroid hormone in health and disease2

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in Colorado revealed a prevalence of elevated TSH of95% and of decreased TSH of 22%, with most subjectssuffering from subclinical disease defined biochemically(Canariset al. 2000). In agreement with previous studies,the prevalence of both subclinical hyper- and hypothy-roidism was found to be greater in women and increasedwith age. Indeed, an earlier UK survey of 1210 subjects

aged over 60 years indicated rates of subclinical hypo-thyroidism of 116% in females and 29% in males, withsimilar values for serum TSH concentrations below thenormal range (Parle et al. 1991).

Abnormal serum TSH concentrations, especially lowserum TSH, may reflect a variety of causes, includingtherapy with drugs such as glucocorticoids and dopamine,as well as non-thyroidal illnesses (Spenceret al. 1990), buta major association is with treatment for thyroid diseaseitself (Davies et al. 1992). Treatment of Graves hyper-thyroidism with antithyroid drugs or radioiodine (131I) isfrequently associated with prolonged suppression of serumTSH despite restoration of normal circulating thyroid

hormone concentrations, while amongst the large popu-lation taking thyroid hormone replacement therapy,serum TSH values are abnormal in approximately half(Parle et al. 1993, Canaris et al. 2000). Furthermore,treatment of hyperthyroidism with either 131I or surgery isassociated with an increased risk of development of eithersubclinical or overt hypothyroidism (Franklyn et al. 1991)and the natural history of nodular goitre is often mani-fest as eventual development of subclinical or overthyperthyroidism.

It is well recognised that overt thyroid disease isassociated with significant symptoms and signs, while forsubclinical thyroid dysfunction the evidence of an associ-

ation with such symptoms and signs remains less clear(Surks et al. 2004). However, there is growing evidencethat both mild and overt thyroid dysfunction and theirtreatments cause clinically significant long-term morbidityand mortality. Before the advent of effective treatmentsfor overt thyrotoxicosis and hypothyroidism, death fromcardiovascular disease often resulted. Cardiovascular dis-ease remains the most significant association with thyroiddysfunction and its treatment at this time. The influence ofthyroid hormone excess on bone metabolism has led toextensive investigation of osteoporosis risk in those withovert and subclinical thyrotoxicosis. The effects of thyroidhormone on the central nervous system (CNS) are now

well recognised and have led to the investigation ofthyroid dysfunction in the context of fetal neurodevelop-ment as well as neuropsychiatric morbidity (especiallydementia) in adults. Given the almost ubiquitous influenceof thyroid hormones on physiological systems in thehuman body it is not surprising that thyroid dysfunctionhas also been associated with significant morbidity unre-lated to the heart, skeleton and CNS. Finally, both thyroiddysfunction and its treatment have been implicated in thedevelopment of cancers, most attention focusing upon the

potential carcinogenic effect of radioiodine therapy in thetreatment of hyperthyroidism.

Current concepts

Thyroid hormone and the heart

The effects of thyrotoxicosis on cardiovascular mor-bidity and mortality Despite the availability of effectivetreatments, the major clinically significant effects of thyro-toxicosis remain those on the cardiovascular system,both at presentation and during treatment. Furthermore,there is growing evidence for long-term influences ofthyrotoxicosis and its treatment on later cardiovascularmorbidity and mortality. Typical cardiovascular symptomsfound at presentation of thyrotoxicosis include palpitation,tachycardia, exercise intolerance, exertional dyspnoea andorthopnoea (Klein & Ojamaa 2001). While these arepresent in the majority of subjects with overt thyroid

hormone excess, their clinical importance is overshadowedby the challenges posed by atrial fibrillation (AF), whichoccurs in 515% of patients with thyrotoxicosis and maybe the presenting problem (Sandler & Wilson 1959, Forfaret al.1979, Sawinet al. 1994, Gilliganet al.1996). Higherprevalence rates are found in older patients and in thosewith known or suspected underlying organic heart disease(Forfaret al.1979, Nordykeet al.1988). Despite this clearassociation between thyrotoxicosis and AF, when subjectswith new onset of AF have been investigated, overthyperthyroidism has been reported to be an uncommoncause (


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(Bar-Selaet al. 1981). Twelve of 30 patients in AF had anembolic event (40%) compared with none in sinus rhythm(112 patients); the mean age of the patients in AF wassignificantly higher than those in sinus rhythm (56 vs39 years). A further retrospective study investigating 610patients with thyrotoxicosis, indicated that age ratherthan the presence of AF was the main risk factor forembolisation, a finding which may be explained by the

relatively small number of patients in AF (Petersen &Hansen 1988). Twelve (13%) of those in AF had anembolic event compared with 15 of the 519 patients(29%) in sinus rhythm. During the first year, thecerebrovascular event frequency (in those with AF andsinus rhythm considered together) was nonetheless higherthan that expected in the general population of the sameage. Taken together, the existing data suggest that the rateof embolism in thyrotoxic AF exceeds that for non-thyrotoxic AF not associated with rheumatic heart disease.Furthermore, the majority of clinically evident emboli inthyrotoxic AF involve the CNS and occur most com-monly early in the course of the disease (Presti & Hart

1989). Whether it is appropriate to extrapolate findingshighlighting the clear association of AF and peripheralemboli in large cohorts without thyrotoxicosis (Gilliganet al. 1996) to those with thyrotoxicosis, and thereforeto support the role of anticoagulation, remains to bedetermined.

In addition to overt thyrotoxicosis, AF has been shownto be associated with subclinical hyperthyroidism. Animportant study of 2007 subjects aged over 60 years andcomprising part of the Framingham population, described

a nearly tripling of the likelihood of AF during a 10 yearfollow-up period in patients with a low serum TSH (Sawinet al.1994). These subjects did not have AF at the start ofthe study and were classified according to their serumTSH concentration (Fig. 2). A total of 192 patients (10%)developed AF and the cumulative incidence of AF at 10years was highest among subjects with a low TSH (28%compared with 11% among those with a normal TSH

(P=0005)). The incidences of AF in those with a slightlylow TSH and a high TSH concentration were notsignificantly different from those with a normal TSHconcentration (16 and 15% respectively). After adjustmentfor other known risk factors (smoking, diabetes, hyperten-sion, left ventricular hypertrophy, myocardial infarction,congestive cardiac failure and cardiac murmur) the relativerisk (RR) for developing AF in those with a low TSH was31 (95% confidence interval (CI) 1755) compared withthose with a normal TSH (P50 mU/l(Reproduced from Sawin et al. 1994, with kind permission from the Massachusetts MedicalSociety).




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concomitant disease, in either a hospital in-patient orout-patient setting. AF was found in 2% of those withnormal serum TSH, 138% of those with overt hyper-thyroidism and 78 of 613 (127%) subjects with subclinical

hyperthyroidism (defined as TSH


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In order to define vascular risk in subjects with endog-enous subclinical hyperthyroidism (i.e. those not takingthyroid hormones), we recently investigated vascular mor-tality in a community-based cohort of subjects with lowserum TSH and followed over a 10 year period (Parleet al.1991, 2001). The cohort comprised 1191 subjects aged 60years and over who were not receiving T4 therapy or

antithyroid medication. A serum TSH concentration wasmeasured at baseline in 19881989. Causes of death weredetermined for those who died after the follow-up periodand were compared with age-, sex- and year-specific datafor England and Wales. Mortality from all causes wasfound to be significantly increased at 2, 3, 4 and 5 yearsafter initial measurement in those with a low serum TSHconcentration (05 mU/l, n=71) compared with theexpected mortality for the control population of Englandand Wales. The SMR at year 2 was 21 (95% CI 1045),at year 3 was 22 (95% CI 1240), at year 4 was 19 (95%CI 1034) and at year 5 was 20 (95% CI 1233). Thisincrease in all-cause mortality was almost completely

accounted for by significant increases in mortality due tocirculatory diseases. A comparison of those with low serumTSH and the remainder of the cohort also confirmedsignificant increases in vascular mortality. The underlyingcause of TSH reduction in this UK cohort was notinvestigated but probably reflected true endogenous (mild)hyperthyroidism (rather than other influences such as drugtherapies or non-thyroidal illnesses) because there was aninverse relationship between mean serum concentrationsof free thyroid hormones and serum TSH amongst thecohort, and many had clinical features of thyroid diseasesuch as goitre. Furthermore, common causes of death,other than vascular causes, were not associated with low

serum TSH in this cohort, which would be expected ifserum TSH were a non-specific reflection of other ill-nesses. The size of this cohort was insufficient to allowdefinition of mortality in those with fully suppressed,rather than low but detectable serum TSH, the formerprobably being the most relevant group in terms oflong-term risk. Nonetheless, these data, together with theAF incidence data evident in the elderly Framinghampopulation (Sawin et al. 1994), have lent support to theview that antithyroid treatment should be considered inthose with persistent suppression of TSH and evidence forunderlying thyroid disease (thyroid nodular disease orGraves disease), especially if associated with AF or known

cardiac disease (Fatourechi 2001, Surks et al. 2004).Crucial evidence for a beneficial effect of such treatment,i.e. reduction in AF incidence or vascular mortality inthose with subclinical hyperthyroidism, awaits the resultsof randomised controlled clinical trials.

The effects of hypothyroidism on cardiovascularmorbidity and mortality The haemodynamic changestypical of hypothyroidism are opposite to those of thyro-toxicosis, but they are generally accompanied by fewer

symptoms and signs (Klein & Ojamaa 2001). Overthypothyroidism has been reported to be specificallyassociated with cardiovascular disease, although evidencefor a true association is largely confined to older litera-ture reporting findings from relatively small numbersof patients (Vanhaelst et al. 1967, Steinberg 1968). Giventhe hypercholesterolaemia and diastolic hypertension

found in overt thyroid failure, such an association is,however, plausible.

It is well recognised that caution must be exercised inintroducing T4 replacement therapy in those withhypothyroidism and ischaemic heart disease because of therisk of worsening angina or induction of myocardialinfarction. However, these complications are rare andstudy of a large series of patients treated for hypothyroidismand evaluated for new or worsening angina, indicated animprovement in the symptoms of ischaemic heart diseasein many subjects (Keating et al. 1961). One study hasdescribed an increased short-term mortality followingcoronary artery bypass grafting in those receiving T4

replacement therapy when compared with those without(59 vs 26%, P=002). In this study T4 dose and serumT4 concentration were inversely related to mortalityamongst those taking T4 therapy (Zindrou et al. 2002),suggesting that insufficient T4 therapy may have played arole in the described adverse outcome.

Given the likely association of untreated overt hypo-thyroidism with cardiovascular disease, much attention hasfocused on the possible link between subclinical hypo-thyroidism and cardiovascular disease. Again, it has beenhypothesised that such a link could be mediated via anadverse effect of mild thyroid deficiency on the lipidprofile, although the nature and degree of this adverse

influence remain controversial and are probably relativelyminor (Caraccioet al.2002). There is also some evidence,from a study comparing 57 women with subclinicalhypothyroidism and 34 euthyroid controls, of an associ-ation between raised TSH and diastolic hypertension(Luboshitzky et al. 2002). Despite these potential mech-anisms for increased cardiovascular risk, cross-sectionaldata from 3678 subjects enrolled in the CardiovascularHealth Study revealed no differences in prevalences ofangina, myocardial infraction, transient ischaemic attack,stroke or peripheral artery disease, when comparing thosewith subclinical hypothyroidism and controls with normalTSH (Cappola & Ladenson 2003). In accord with this, an

important 20 year follow-up study of the population ofWhickham in the UK (Vanderpumpet al.1996) reportednegative outcomes in terms of morbidity and mortalityfrom ischaemic heart disease in 97% of the original cohort(2779 subjects) who were available for follow-up. Analysisof deaths from all causes, and specifically from ischaemicheart disease, revealed no association with autoimmunethyroid disease. No specific associations with hypothy-roidism, presence of antithyroid antibodies or raised serumTSH levels at the time of first survey, were evident in this




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large cohort study. These findings are in agreement withour own 10 year follow-up study of a cohort of 1191 in thecommunity aged over 60 years, which examined all-causeand vascular mortality according to serum TSH at screen-ing (Parle et al. 2001). While an association between lowserum TSH and increased all-cause and vascular mortalitywas evident, as described above, no adverse effect on

mortality 10 years later was seen for those within thecohort with raised serum TSH at screening.

Data from small case-control and cross-sectional studieshave indicated a link between subclinical hypothyroidismand coronary artery disease (Tieche et al. 1981, Dean &Fowler 1985). A large Dutch study has reported theassociation between subclinical hypothyroidism and aorticcalcification as well as myocardial infarction amongst acohort of 1149 women living in Rotterdam (Hak et al.2000). Subclinical hypothyroidism (defined as serumTSH>4 mU/l) was present in 108% of participants andwas associated with a greater age-adjusted prevalence ofaortic atherosclerosis (odds ratio 17, 95% CI 1126) and

myocardial infarction (odds ratio 23, 95% CI 1340).These associations were slightly stronger in women withboth subclinical hypothyroidism and positive thyroid anti-bodies but the presence of antibodies to thyroid peroxidase(TPO) was not itself independently associated with theseend-points. There was no association with incident myo-cardial infarctions. The authors of this study estimated ahigh population attributable risk for subclinical hypothy-roidism and atherosclerosis. That attributable risk must,however, be viewed cautiously since the estimation isderived from one study alone and should not thereforebe considered comparable with risk attributed to otherextensively investigated factors such as smoking and

diabetes mellitus.

The effects of thyroid hormones on the skeleton

Thyroid hormones are known to exert direct effects uponbone formation and resorption, thyroid hormone excessresulting in net loss of bone and hence reduction in bonemineral density (BMD) (Ross 1994). It is well recognisedthat overt hyperthyroidism results in reduction in BMDand that treatment of the disease results in an increase inBMD. However, even with effective antithyroid therapy acomplete restoration of BMD to pre-morbid levels doesnot always occur (Ross 1994). In a cross-sectional study

comparing women treated for hyperthyroidism withradioiodine with age-matched controls, we found thatfemoral neck and lumbar spine BMD was significantlyreduced in the post-menopausal group, although BMDwas similar in patients and controls in the pre-menopausalgroup (Franklyn et al. 1994). These findings suggest thatpost-menopausal oestrogen-deficient women are the onesat particular risk of potential adverse effects of hyper-thyroidism upon bone metabolism. As is the case withmost of these studies, the clinically important question

remains whether the reductions in BMD associated withovert hyperthyroidism translate into increased risk ofosteoporotic fracture.

A large prospective study followed 9516 white womenaged over 65 for an average of 41 years for incidentfractures of the femur and revealed a 18-fold increasedRR amongst those with previous hyperthyroidism (95%

CI 1226) (Cummings et al. 1995). In accord with thesefindings, data from our own mortality study describedabove (Franklyn et al. 1998) provided evidence for anincrease in mortality from fracture of the femur in subjectswith hyperthyroidism treated with radioiodine (SMR 29,CI 2039), in accord with the specific incidence datareported for fracture of the femur. A further case-controlstudy, reported an increased fracture incidence rate ratio(126229) around the time of diagnosis amongst 11 776subjects with hyperthyroidism, with return to controlincidence after diagnosis (Vestergaard & Mosekilde 2002).These findings are in contrast to another large prospectivestudy of over 9000 post-menopausal women, which failed

to show an association of thyrotoxicosis with fractures ofthe ankle and foot (Seeley et al. 1996). The effect ofthyroid hormone excess may thus be different dependingon the type of fracture investigated.

Like overt hyperthyroidism, subclinical hyperthy-roidism (especially that associated with T4 therapy) hasbeen implicated in the development of osteoporosis. Earlystudies reported significantly reduced bone mass inpatients on prolonged T4 treatment (Rosset al.1987, Paulet al.1988), resulting in concern about the potential risk ofpremature development of osteoporosis in patients receiv-ing T4 therapy (Franklyn & Sheppard 1990). However,several well-conducted studies subsequently failed to dem-

onstrate any detrimental effect on bone mass in T4-treatedpatients, even in those taking T4 in doses sufficient tosuppress serum TSH (Franklyn et al. 1992, Hanna et al.1998). Two meta-analyses of published literature haveaddressed this controversy and have suggested that thyroidhormone treatment, both in specific groups with sup-pressed serum TSH and in those with normal serum TSH,is associated with a minor but statistically significantreduction in BMD (Faber & Galloe 1994, Uzzan et al.1996), although analysis of the findings is complicated byheterogeneity of patient groups investigated, particularlyin terms of past history of hyperthyroidism. It shouldbe noted that such studies of BMD have not addressed

the question of whether T4 therapy is a risk factor forclinically relevant end-points such as fracture incidenceand mortality.

A study of 1100 patients on T4 replacement in Scotlandfound no significant differences in fracture rates in patientson T4 when compared with the general population (Leeseet al. 1992). The prospective study of over 9516 post-menopausal women described above (Cummings et al.1995) reported an increased RR for incident fracture ofthe femur in those taking thyroid hormone (RR 16, 95%

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CI 1123), but this was no longer significant whenadjusted for a previous history of hyperthyroidism (whichwas present in 36% of those prescribed T4). A prospectivecohort study of 686 women older than 65 years followedfor a mean of 37 years, revealed that hyperthyroidismconferred a 2-fold increase in risk of hip fracture, but theuse of thyroid hormone itself was not associated with

increased risk of hip fracture (Bauer et al. 2001). Onefurther population study of 4473 subjects with auto-immune hypothyroidism has suggested an increasedincidence of fracture both before and after diagnosis(Vestergaard & Mosekilde 2002), although the finding ofan apparent association before diagnosis (i.e. before com-mencement of T4 therapy) argues against an influence ofthyroid hormone excess in producing these findings.

To specifically address the effect of T4 therapy onoccurrence of fracture of the femur we have used the UKGeneral Practice Research database (which records drugprescribing information) in a population-based case-control study of those prescribed T4 (Sheppard et al.

2002). Amongst a cohort of 23 183 subjects prescribedthyroid hormones, the occurrence of fracture of the femurwas not significantly higher compared with a group of92 732 matched controls. Compared with controls, T4takers had higher reported rates of medical diagnoses anddrug therapies, potentially confounding fracture risk. Pre-scription of T4 was not an independent predictor of femurfracture amongst females (adjusted odds ratio (AOR) 103,95% CI 092116), but interestingly it was an indepen-dent predictor amongst males (AOR 169, 95% CI 112256). The prevalence of T4 prescription is much lower inmales than females (reflecting the prevalence of autoim-mune thyroid disease); however, this gender group has

been poorly investigated in terms of effect of thyroid statuson bone, and may be at particular risk.

Overall, the data regarding clinically apparent osteo-porosis and thyroid status support an adverse effect of overthyperthyroidism upon fracture risk, an effect that maybe sustained despite successful antithyroid therapy. Theimportance of subclinical hyperthyroidism in terms ofosteoporosis risk requires further investigation, especiallyrisk related to endogenous subclinical hyperthyroidismsuch as that found in patients with nodular goitre. As yet,there is little evidence that T4 therapy alone, even in dosessufficient to suppress serum TSH, is associated withincreased risk of fracture, although caution must be

exercised in high risk groups, especially postmenopausalwomen (and possibly men).

Thyroid hormones and the neurological system

Effects of thyroid hormones on the developing fetalbrain Classically, maternal thyroid hormones have notbeen thought to play a major role in development of thefetal CNS. However, over the past decade epidemiologicalevidence (Haddow et al. 1999, Pop et al. 1999, 2003)

suggests that even relatively mild maternal hypothyroxi-naemia, particularly in early pregnancy, may adverselyaffect the long-term neurodevelopment of the offspring.These findings have sparked an international debate aboutthe need to screen women prenatally for subclinicalhypothyroidism. The leading cause of maternal hypothy-roidism worldwide remains iodine deficiency and the

prevalence in endemic areas varies widely. In iodine-replete areas, subclinical hypothyroidism is largely ofautoimmune aetiology and prevalence rates in early preg-nancy have been reported to be in the region of 25% inthe US (Kleinet al.1991). However, a study performed inthe north-east of England, which is considered a non-iodine-deficient area, has estimated using urinary iodideexcretion rate measurements that 35% of pregnantwomen are iodine-deficient and a further 40% borderlinedeficient (Kibirige et al. 2004).

In a series of three follow-up studies on the offspring ofpregnant women in The Netherlands, Pop and colleaguesexamined the effects of low thyroid hormone levels in

pregnancy on child neurodevelopment. In the first study(Pop et al. 1995), aimed at investigating the relationshipbetween maternal depression and thyroid disease, bloodsamples were obtained at 32 weeks of gestation and fT4 aswell as TPO antibodies were determined. Not only didthe children of depressed women attain significantly lowerGeneral Cognitive Index (a correlate of IQ) scores on theMcCarthy test at aged 5, logistic regression analysis alsorevealed that the strongest predictor of IQ was maternalTPO antibody level, not maternal depression. Pop specu-lated that this correlation reflected an epiphenomenon,which may be due to thyroid insufficiency earlier ingestation rather than the direct effect of the antibodies on

the fetal brain (Pop et al. 1995).In a second study, this group measured fT4 and TPO

antibody levels in another cohort of pregnant women atboth 12 and 32 weeks of gestation and found that maternalfT4 concentrations at 12 weeks of gestation was indeed thestrongest predictor of infant mental development (Popet al. 1999). The third study compared women with lowfT4 levels (at or below the 10th centile) at 12 weeks ofgestation with women who had normal fT4 levels at thisstage of pregnancy. Women who were not diagnosed withhypothyroxinaemia, and were therefore not treated duringpregnancy, were further subdivided according to their fT4levels at two subsequent time-points in pregnancy. They

found that infants of women with initially low fT4 levelsthat were sustained throughout pregnancy were mostlikely to show delayed development. In contrast, womenwith initially low levels who recovered through the courseof pregnancy had children at less risk of later impairment.The offspring of women with marginally normal fT4 levelsinitially that declined later in pregnancy were moderatelyat risk of impairment (Pop et al. 1999, 2003).

Further evidence of the effects of maternal hypo-thyroidism on fetal development comes from a




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well-publicised 1999 study from the US, by Haddow et al.(1999). It describes the neurodevelopmental status of thechildren of 62 women with serum TSH concentrationsabove the 98th percentile at 16 weeks of gestation com-pared with 124 matched controls. None of the childrenscreened positive for neonatal hypothyroidism. In mostcases, the maternal hypothyroidism was unknown during

pregnancy because the women were asymptomatic andhypothyroidism was only recognised after tests were con-ducted on stored serum samples many years later. Com-pared with controls, the children of hypothyroid mothershad significantly reduced intelligence levels (on average 4points lower on the Wechsler Intelligence Scale forChildren) and performed less well on all 15 of theneuropsychological tests performed at assessment betweenthe ages of 7 and 9 years.

The children of a subgroup of 14 women who receivedT4 treatment during pregnancy (albeit inadequate dosessince their TSH levels were elevated at 16 weeks), hadmore normal IQ scores but several specific deficits such as

poor attention were more marked than in the untreatedgroup. The children of the remaining 48 biochemicallyhypothyroid women who were not treated during thepregnancy performed worse, with an average 7 pointlower IQ score compared with controls; 19% of thesescored 85 or less, which is clinically significant in terms ofspecial educational and social needs. Interestingly, theserum total T4 and fT4 concentrations in the treated andthe non-treated hypothyroid women were similar duringpregnancy. This study has been considered pivotal since itsuggests that subclinical hypothyroidism in women canhave long-term consequences upon the neuropsycho-logical development in their offspring, and that T4 sup-

plementation can improve the outcome, even whensupplementation is inadequate.

All of these studies demonstrate the sensitivity of thefetal CNS to changes in thyroid status. They also demon-strate that not only the severity of maternal hypo-thyroidism, but also the timing of it are important. Normalmaternal thyroid hormone concentrations thus appearcritical, particularly in the first trimester, to attain normalneurodevelopment. Appreciable amounts of thyroid hor-mones are only detectable in the human fetal circulationfrom 1416 weeks of gestation, which is believed torepresent the time of onset of endogenous thyroid hor-mone release (Thorpe-Beeston et al. 1991, Fisher 1997)

even though the fetal thyroid gland begins accumulatingiodide from 1012 weeks of gestation (Shepard 1967,Fisheret al. 1976). The fetus is, therefore, entirely relianton the maternal supply of thyroid hormones fornormal development in the first and early part of thesecond trimester. Hence, a rise in iodine intake or T4supplementation from the first trimester is necessary inpregnant women with potential iodine deficiency and/orpre-existing hypothyroidism. A recent prospective studyof hypothyroid women who were planning pregnancy

indicated a mean 47% increase in T4 requirements duringthe first half of pregnancy. The need for an increaseoccurred from as early as 5 weeks of gestation and contin-ued until delivery (Alexanderet al. 2004). The authors ofthat study proposed that all women with hypothyroidismshould receive a 30% increase in T4 treatment as soon aspregnancy is confirmed, with a subsequent adjustment

of T4 replacement dosage depending on the serumTSH levels.

We do, however, need to exercise caution as the humanfetal brain may be intolerant of maternal hyperthyroxinae-mia, as well as hypothyroxinaemia. A recent study onuncontrolled maternal Graves disease during pregnancyhas found an adverse impact on the development fetalpituitary function resulting in central congenital hypo-thyroidism (Kempers et al. 2003), although this scenariomay be less common than mild neurodevelopmental delaycaused by maternal hypothyroidism.

Despite what appears to be a sizeable proportion ofthe pregnant population being affected by subclinical

hypothyroidism, the issue of screening remains contro-versial. A Symposium on Thyroid Health in PregnantWomen held in April 2004 brought together leadingphysicians and scientists in this field; the consensus opinionreached was that there is currently insufficient scientificevidence to recommend universal thyroid function screen-ing of all women before or during pregnancy; however,there should be a low threshold for screening those at risk,for example those with a personal or family history ofthyroid dysfunction, a personal history of other autoim-mune conditions such as diabetes mellitus, or obstetriccomplications known to be associated with hypothy-roidism (i.e. recurrent miscarriage and preterm labour)

(Sullivan 2004). A similar consensus view was reached bythe expert panel which carried out the systematic reviewof studies on subclinical thyroid dysfunction and providedguidelines for its management (Surks et al. 2004).

Neuropsychiatric morbidity from thyroid dysfunc-tion and its treatment There is no doubt that overtthyroid dysfunction is associated with significant symptomsand an adverse effect on quality of life. As neuropsycho-logical tools have become more sensitive, it has becomeapparent that even mild TH insufficiency in humans canproduce measurable deficits in very specific neuropsycho-logical functions, and that the specific consequences of TH

deficiency depends on the precise developmental timing ofthe deficiency (Zoeller & Rovet 2004). Few studies have,however, addressed the prevalence of symptoms and othernon-specific markers of morbidity in those with sub-clinical thyroid dysfunction. While some studies havesuggested an association between various symptomsand mild or subclinical thyroid dysfunction, overall theevidence for a link is relatively weak (Surks et al. 2004).

Very few studies have investigated more finite end-points such as the presence of significant psychiatric




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disease. A possible association between dementia andsubclinical hyperthyroidism has been described. A study ofa subgroup of the Rotterdam cohort in whom thyroidfunction had been examined (n=1843) suggested thatreduced serum TSH (


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tumours (Holmet al. 1991). Overall cancer incidence wasincreased (standardised incidence ratio (SIR) 106, 95% CI101111) and analysis of a sub-group of 10 year survivorsrevealed significantly increased risks for cancers of thestomach, kidney and brain. Furthermore, the risk ofstomach cancer has been reported to increase with timeand with increasing dose of radioactivity administered

(Holm et al. 1991, Hall et al. 1992a). Other studies,comparing cancer risk in those treated for hyperthyroidismwith radioiodine and those treated surgically, failed toreveal any difference in cancer incidence or mortality atthese or other specific sites (Hoffman et al. 1982).

Since the thyroid is the major site of radiation exposurefollowing radioiodine treatment, attention has focused onthe risk of malignancy in this organ. The small size of mostpublished studies of those treated for hyperthyroidism andthe relatively low incidence of thyroid cancer mean that anincrease in thyroid cancer incidence after radioiodinetherapy has not been convincingly described. However,analysis of 35 593 patients with hyperthyroidism, 65% of

whom received radioiodine, and seen in 26 centresthroughout the US and UK from 1946 to 1964 did revealan increase in thyroid cancer mortality (Ron et al. 1998).Increased cancer risk was not confined to those treatedwith 131I, being observed in addition in those treatedexclusively with antithyroid drugs.

We also examined both cancer incidence and mortalityin a cohort of 7417 subjects treated with 131I for hyper-thyroidism (Franklyn et al. 1999). During 72 073 person-years of follow-up, 634 cancer diagnoses were madecompared with an expected number of 761 (SIR 083,95% CI 077090). The RR of cancer mortality was alsoreduced in the cohort (observed cancer deaths 448,

expected 499; SMR 090, 95% CI 082098). Thereduction in cancer risk reflected significant decreases inincidence of cancers of the pancreas, bronchus and trachea,bladder and lymphatic and haematopoietic systems. Mor-tality from cancers at each of these sites was also reduced.It is notable, however, that there were significant increasesin incidence and mortality for cancers of the small bowel(SIR 481, 95% CI 2161072; SMR 703, 95% CI3161566) and thyroid (SIR 325, 95% CI 169625;SMR 278, 95% CI 116667), although absolute risk ofdevelopment or death from these cancers was small. Thefindings from this study as well as the large study of Ronet al.(1998) are reassuring in terms of overall safety of 131I

treatment and cancer risk. The evidence does suggestan increased RR of thyroid cancer in hyperthyroidpatients treated with radioiodine, although the absoluterisk remains small, and indeed is likely to reflect, at least inpart, association with underlying thyroid disease ratherthan 131I exposure per se.

While studies have so far examined the risk of cancerfollowing treatment of hyperthyroidism with radioiodine,it should be noted that this therapy is increasingly used inthe treatment of benign goitre (Hegedus et al. 2003).

Extrapolation of data from those with hyperthyroidismto those with goitre may be appropriate; however,further studies of the latter patient group should beundertaken. Radiation treatment is also used in those withthyroid disease in the context of orbital radiotherapy forGraves ophthalmopathy. One study has addressed subse-quent cancer risk in a small cohort of 250 patients and

found no evidence for radiation induced cancers (Schaeferet al. 2002).

Future perspectives

Identification of a new thyroid hormone transporter

Although it was originally believed that thyroid hormonesenter the cells by passive diffusion it is now clear thatcellular uptake is effected by carrier-mediated processes.Several inorganic anion transporters and L-type amino-acid transporters have been shown to facilitate plasmamembrane transport of thyroid hormone (Hennemannet al. 2001).

The recent characterisation of monocarboxylate trans-porter 8 (MCT8), the most specific and powerful T3transporter found to date (Friesema et al. 2003), hasemphasised a significant role for membrane transporters inthe regulation of local T3 action. The MCT8 gene on theX chromosome encodes a 613 amino acid protein with 12predicted transmembrane domains. Different novel muta-tions in the MCT8 gene have been described in associ-ation with a new syndrome of X-linked mental retardationfound so far in male infants from more than six differentfamilies worldwide (Dumitrescuet al.2004, Friesemaet al.

2004). Interestingly, these boys demonstrate global neuro-logical defects and elevated circulating T3 levels withoutany of the skeletal and bowel manifestations associatedwith hypothyroidism, which suggests a specific role forMCT8 in CNS development. MCT8 protein has beendetected in adult rat brain and a neuronal localisation indeveloping rat CNS has been postulated (Friesema et al.2004). However, the precise anatomical and temporalexpression of MCT8 during brain development has yet tobe described in rodents or humans.

Tests of thyroid dysfunction and non-thyroidal illness

There is considerable evidence that abnormalities ofcirculating thyroid hormones and TSH characteristic ofthe euthyroid sick syndrome are associated with adverseoutcome in terms of morbidity and mortality related toother illnesses. This association undoubtedly reflects theinfluence of non-thyroidal illnesses of increasing severityon thyroid hormone metabolism and TSH secretion. Forexample, low serum T3 has been reported to be anindependent predictor of poor survival among critically illpatients (Maldonadoet al.1992) and low serum T4 and T3




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are associated with poor outcome in subjects undergoingbone marrow transplantation (Vexiau et al. 1993, Schulteet al. 1998). Furthermore, in elderly subjects, reducedcirculating thyroid hormones are associated with worsenutritional state and worse post-operative outcome inthose undergoing emergency surgery (Girventet al.1998).In a retrospective case note review of nursing home

residents, low serum TSH (found in 40 subjects andtypically associated with normal T4 and low serum T3)was associated with increased mortality during a shortperiod of follow-up (Drinkaet al. 1996). Since the findingof a low serum TSH was shown to be transient inapproximately half, it was likely that in many subjects inthis study this reflected the influence of an illness staterather than thyroid hormone excess.

These associations between the changes in thyroidfunction tests associated with non-thyroidal illness andmorbidity and mortality have led to speculation thatcorrection of these biochemical abnormalities may im-prove prognosis. Several studies have now addressed this

possibility. Two such studies have examined the role ofthyroid hormone supplementation in children undergoingcardiac surgery. One study randomised 14 infants aged lessthan 1 year and undergoing surgery for ventricular septaldefect or tetralogy of Fallot to receive placebo or T3infusion (04 g/kg) immediately before cardiopulmonarybypass and again with myocardial reperfusion. As ex-pected, the control group demonstrated a prompt reduc-tion in circulating T3 at the time of surgery and this waseffectively reversed in the T3-treated group. T3 treatmentwas associated with an increase in heart rate and product ofpeak systolic pressure and rate, suggesting enhancement ofcardiac reserve (Portman et al. 2000). A larger trial

involving 40 children again undergoing surgery for con-genital heart disease randomised subjects to T3 infusion(2 g/kg on day 1 after surgery, then 1 g/kg up to 12days post-operatively). In the placebo group, concen-trations of TSH, T4, fT4 and T3 fell after surgery andreverse T3 rose. Serum T3 was significantly higher in theT3-treated group while other measurements were unaf-fected. In addition, the mean change in cardiac index washigher in the T3-treated subjects (204 vs 100%) andsystolic cardiac function improved most in those withlonger cardiopulmonary bypass operations. Adverse eventswere not observed and T3 treatment was associated withreduction in the need for post-operative intensive care

(Bettendorf et al. 2000).One study of adults has provided some evidence for a

beneficial effect of thyroid hormone supplementation inadults (Klempereret al. 1995). This study of 142 subjectsundergoing coronary artery bypass surgery and randomisedto receive T3 (08 g/kg bolus at time of aortic cross-clamp removal and then as an infusion (0113 g/kg per hfor 6 h)). The mean post-operative cardiac index washigher, and the systemic vascular resistance lower, in theT3 group compared with the placebo group, although

there was no difference in the incidence of arrhythmias, inthe need for vasodilator or inotropic drugs, or in peri-operative morbidity or mortality. Thus, unlike in children,the infusion of T3 in adults undergoing cardiac surgery,while resulting in a change in haemodynamic parameters,did not affect clinically significant end-points. A routinerole for T3 supplementation in subjects undergoing cardio-

pulmonary bypass, as well as those in other situations (e.g.emergency surgery, critically ill subjects) associated withreduction in circulating T3, remains to be established infurther randomised controlled trials.

The use of tissue-selective thyroid hormone analogues

Many of the actions of thyroid hormones are tissue-specificand are primarily mediated by a panel of TR isoforms thatare expressed in different ratios in different tissues. Be-cause of these tissue-specific hormone signalling pathways,the development of synthetic thyroid hormone analogueswith tissue-selective hormone actions appears highly de-

sirable (Scanlan et al. 2001). In 1963, the first of thesethyroid hormone analogues was described (Blank et al.1963) and medicinal chemistry efforts since have demon-strated that selective thyromimetics can be producedthrough a variety of approaches. Specifically, liver-selective, cardiac-sparing thyromimetics have been inves-tigated as potential cholesterol-lowering drugs and theiruse for the prevention and reversal of atherosclerosis hasbeen advocated (Tayloret al. 1997, Chiellini et al. 1998).Animal studies have shown promising results (Tayloret al.1997) and selective TR activation in rats and monkeyshas been shown to provide a potentially useful treatmentfor obesity and cholesterol reduction (Groveret al. 2004).

However, the widespread use of these compounds for thetreatment of metabolic disorders appears a long way off.

Acknowledgements

This work was supported by the Wellcome Trust, theR&D Directorate of the former WMRHA and the UHBcharities. The authors declare that there is no conflict ofinterest that would prejudice the impartiality of thisscientific work.

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Received in final form 26 April 2005Accepted 17 May 2005

Made available online as an Accepted Preprint23 May 2005



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